WO2004089470A2 - New amide derivatives and pharmaceutical use thereof - Google Patents

New amide derivatives and pharmaceutical use thereof Download PDF

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Publication number
WO2004089470A2
WO2004089470A2 PCT/DK2004/000250 DK2004000250W WO2004089470A2 WO 2004089470 A2 WO2004089470 A2 WO 2004089470A2 DK 2004000250 W DK2004000250 W DK 2004000250W WO 2004089470 A2 WO2004089470 A2 WO 2004089470A2
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WO
WIPO (PCT)
Prior art keywords
alkyl
phenyl
methyl
methanone
bicyclo
Prior art date
Application number
PCT/DK2004/000250
Other languages
French (fr)
Other versions
WO2004089470A3 (en
Inventor
Henrik Sune Andersen
Gita Camilla Tejlgaard Kampen
Inge Thøger Christensen
John Patrick Mogensen
Annette Rosendal Larsen
John Paul Kilburn
Original Assignee
Novo Nordisk A/S
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to EP04725891A priority Critical patent/EP1615698B1/en
Priority to AT04725891T priority patent/ATE482747T1/en
Priority to JP2006504353A priority patent/JP2006522746A/en
Priority to DE602004029346T priority patent/DE602004029346D1/en
Publication of WO2004089470A2 publication Critical patent/WO2004089470A2/en
Publication of WO2004089470A3 publication Critical patent/WO2004089470A3/en
Priority to US11/265,794 priority patent/US20060111366A1/en
Priority to US12/006,765 priority patent/US20080108598A1/en
Priority to US12/493,698 priority patent/US20090264414A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
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    • A61K31/16—Amides, e.g. hydroxamic acids
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
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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
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to use of substituted amides and pharmaceutical compositions comprising the compounds for treating disorders where it is desirable to modulate the activity of 11 ⁇ -hydroxysteroid dehydrogenase type 1 (11 ⁇ HSDl ).
  • the present invention also relates to novel substituted amides, to their use in therapy, to pharmaceutical compositions comprising the compounds, to the use of said compounds in the manufacture of medicaments, and to therapeutic methods comprising the administration of said compounds.
  • the present compounds modulate the activity of 11 ⁇ - hydroxysteroid dehydrogenase type 1 (11 ⁇ HSDl) and are accordingly useful in the treatment of diseases in which such a modulation is beneficial, such as the metabolic syndrome.
  • the metabolic syndrome is a major global health problem. In the US, the prevalence in the adult population is currently estimated to be approximately 25%, and it continues to increase both in the US and worldwide.
  • the metabolic syndrome is characterised by a combination of insulin resistance, dyslipidemia, obesity and hypertension leading to increased morbidity and mortality of cardiovascular diseases. People with the metabolic syndrome are at increased risk of developing frank type 2 diabetes, the prevalence of which is equally escalating. In type 2 diabetes, obesity and dyslipidemia are also highly prevalent and around
  • 11 ⁇ -hydroxysteroid dehydrogenase type 1 (11 ⁇ HSDl) catalyses the local generation of active glucocorticoid in several tissues and organs including predominantly the liver and adipose tissue, but also e.g. skeletal muscle, bone, pancreas, endothelium, ocular tissue and certain parts of the central nervous system.
  • 11 ⁇ HSDl serves as a local regulator of glucocorticoid actions in the tissues and organs where it is expressed (Tannin et al., J. Biol.
  • 11 ⁇ HSDl in the metabolic syndrome and type 2 diabetes is supported by several lines of evidence.
  • treatment with the non-specific 11 ⁇ HSDl inhibitor carbenoxolone improves insulin sensitivity in lean healthy volunteers and people with type 2 diabetes.
  • 11 ⁇ HSDl knock-out mice are resistant to insulin resistance induced by obesity and stress. Additionally, the knock-out mice present with an anti-atherogenic lipid profile of decreased VLDL triglycerides and increased HDL-cholesterol.
  • mice that overexpress 11 ⁇ HSDl in adipocytes develop insulin resistance, hyperlipidemia and vis- ceral obesity, a phenotype that resembles the human metabolic syndrome (Andrews et al., J. Clin.
  • 11 ⁇ HSDl modulation and thereby modulation of intracellular levels of active glucocorticoid have been investigated in several rodent models and different cellular systems.
  • 11 ⁇ HSDl promotes the features ofthe metabolic syndrome by increasing hepatic expression of the rate-limiting enzymes in gluconeogenesis, namely phosphoenolpyuvate carboxykinase and glucose-6-phosphatase, promoting the differentiation of preadipocytes into adipocytes thus facilitating obesity, directly and indirectly stimulat- ing hepatic VLDL secretion, decreasing hepatic LDL uptake and increasing vessel contractility (Kotelevtsev et al., Proc. Natl. Acad. Sci.
  • WO 01/90090, WO 01/90091, WO 01/90092, WO 01/90093 and WO 01/90094 dis- closes various thiazol-sulfonamides as inhibitors of the human 11 ⁇ -hydroxysteroid dehydrogenase type 1 enzyme, and further states that said compounds may be useful in treating diabetes, obesity, glaucoma, osteoporosis, cognitive disorders, immune disorders and depression.
  • the present compounds can be used to treat disorders where a decreased level of active intracellular glucocorticoid is desirable, such as e.g.
  • One object of the present invention is to provide compounds, pharmaceutical compositions and use of compounds that modulate the activity of 11 ⁇ HSDl .
  • halo includes fluorine, chlorine, bromine, and iodine.
  • trihalomethyl includes trifluoromethyl, trichloromethyl, tribromomethyl, and triiodomethyl.
  • trihalomethoxy includes trifluorometoxy, trichlorometoxy, tribromometoxy, and triiodometoxy.
  • alkyl includes C ⁇ Cs straight chain saturated and methylene aliphatic hydrocarbon groups, C 3 -C 8 branched saturated hydrocarbon groups having the specified number of carbon atoms.
  • this definition shall include but is not limited to methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu), pentyl, hexyl, isopropyl (i-Pr), isobutyl (i-Bu), terf-butyl (--Bu), sec-butyl (s-Bu), isopentyl, neopentyl, and the like.
  • alkenyl includes C 2 -C 6 straight chain unsaturated aliphatic hydrocarbon groups and branched C 3 -C 6 unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • this definition shall include but is not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl, methylpropenyl, methylbutenyl and the like.
  • alkynyl includes C 2 -C 6 straight chain unsaturated aliphatic hydrocarbon groups and C -C 6 branched unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • this definition shall include but is not limited to ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylbutynyl, and the like.
  • saturated or partially saturated cyclic, bicyclic or tricyclic ring system represents but are not limit to aziridinyl, azepanyl, azocanyl, pyrrolinyl, pyrrolidinyl, 2- imidazolinyl, imidazolidinyl, 2-pyrazoIinyl, morpholinyl, piperidinyl, thiomorpholinyl, piperaz- inyl, phthalimide, 1,2,3,4-tetrahydro-quinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, 1,2,3,4- tetrahydro-quinoxalinyl, indolinyl, 1, 6-aza-bicyclo[3.2.1]octane, 2-aza-bicyclo[4.1.1]octane, 2-aza-bicyclo[3.2.1]octanyl, 7-aza-bicyclo[4.1.1]octanyl, 9-aza-bicyclo
  • saturated or partially saturated cyclic ring system represents but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclo- hexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, tetrahydrofuranyl ortetra- hydropyranyl.
  • saturated or partially saturated aromatic ring system represents but are not limited to cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridyl or pyrimidinyl.
  • cycloalkyl e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohep- tyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo[3.2.1]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl and the like
  • cycloalkylalkyl (e.g. cyclopropylmethyl, cyclobutylethyl, adamantylmethyl and the like) represents a cycloalkyl group as defined above attached through an alkyl group having the indicated number of carbon atoms or substituted alkyl group as defined above.
  • cycloalkenyl (e.g. cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl and the like) represents a partially saturated, mono-, bi-, tri- or spirocarbocyclic group having the specified number of carbon atoms.
  • cycloalkylcarbonyl e.g. cyclopropylcarbonyl, cyclohexylcarbonyl repre- sents an cycloalkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group.
  • hetcycloalkylcarbonyl (e.g. 1-piperidin-4-yl-carbonyl, 1 -(1,2,3,4- tetrahydro-isoquinolin-6-yl)carbonyl) represents an hetcycloalkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group.
  • cycloalkylalkylcarbonyl (e.g. cyclohexylmethylcarbonyl, cycloheptylethyl- carbonyl and the like) represents a cycloalkyl group as defined above attached through an alkyl group having the indicated number of carbon atoms or substituted alkyl group as defined above.
  • heteroalkyl tetrahydrofuranyl, tetrahydropyranyl, tertahydrothiopyranyl, piperidine, pyridzine and the like
  • hetcycloalkyl represents a saturated mono-, bi-, tri- or spirocarbocyclic group having the specified number of carbon atoms and one or two additional heteroatoms or groups selected from nitrogen, oxygen, sulphur, SO or S0 2 .
  • hetcycloalkylalkyl (e.g. tetrahydrofuranylmethyl, tetrahydropyranylethyl, tertahydrothiopyranylmethyl, and the like) represents a hetcycloalkyl group as defined above attached through an alkyl group having the indicated number of carbon atoms or substituted alkyl group as defined above.
  • alkyloxy (e.g. methoxy, ethoxy, propyloxy, allyloxy, cyclohexyloxy) represents an alkyl group as defined above having the indicated number of carbon atoms attached through an oxygen bridge.
  • alkyloxyalkyl (e.g. methyloxymethyl and the like) represents an alkyloxy group as defined above attached through an “alkyl” group.
  • aryloxyhetaryl e.g. 2-phenoxy-pyridyl and the like
  • aryloxy e.g. phenoxy, naphthyloxy and the like
  • hetaryloxy e.g. 2-pyridyloxy and the like
  • hetaryloxy represents a hetaryl group as defined below attached through an oxygen bridge.
  • arylalkyloxy e.g. phenethyloxy, naphthylmethyloxy and the like repre- sents an arylalkyl group as defined below attached through an oxygen bridge.
  • hetarylalkyloxy (e.g. 2-pyridylmethyloxy and the like) represents a hetary- lalkyl group as defined below attached through an oxygen bridge.
  • alkyloxycarbonyl e.g. methylformiat, ethylformiat and the like
  • aryloxycarbonyl e.g. phenylformiat, 2-thiazolylformiat and the like
  • arylalkyloxycarbonyl e.g. benzylformiat, phenyletylformiat and the like
  • arylalkyloxycarbonyl represents an “arylalkyloxy” group as defined above attached through a carbonyl group.
  • alkylthio (e.g. methylthio, ethylthio and the like) represents an alkyl group as defined above attached through a sulphur bridge.
  • arylthio (e.g. benzenthiol, naphthylthiol and the like) represents an aryl group as defined below attached through a sulphur bridge.
  • hetarylthio e.g. pyridine-2-thiol, thiazole-2-thiol and the like
  • arylthioalkyl e.g. methylsulfanyl benzene, ethylsulfanyl naphthalene and the like
  • alkyl group having the indicated number of carbon atoms.
  • hetarylthioalkyl e.g. 2-methylsulfanyl-pyridine, 1-ethylsulfanyl-isoquino- line and the like
  • hetarylthioalkyl represents a hetarylthio group as defined below attached through an alkyl group having the indicated number of carbon atoms.
  • hetaryloxyaryl e.g. 1-phenoxy-isoquinolyl, 2-phenoxypyridyl and the like
  • hetaryloxyhetaryl e.g. 1-(2-pyridyloxy-isoquinoline), 2-(imidazol-2-yloxy- pyridine) and the like
  • hetaryloxyhetaryl represents a hetaryloxy group as defined above attached through a "hetaryl” group as defined below.
  • aryloxyalkyl e.g. phenoxymethyl, naphthyloxyethyl and the like
  • aryloxyaryl e.g. 1-phenoxy-naphthalene, phenyloxyphenyl and the like
  • aryloxy group as defined above attached through an "aryl” group as defined below.
  • arylalkyloxyalkyl (e.g. ethoxymethyl-benzene, 2-methoxymethyl- naphthalene and the like) represents an arylalkyloxy group as defined above attached through an “alkyl” group having the indicated number of carbon atoms.
  • hetaryloxyalkyl e.g. 2-pyridyloxymethyl, 2-quinolyloxyethyl and the like
  • hetaryloxyalkyl represents a hetaryloxy group as defined above attached through an “alkyl” group having the indicated number of carbon atoms.
  • hetarylalkyloxyalkyl (e.g. 4-methoxymethyl-pyrimidine, 2-methoxymethyl- quinoline and the like) represents a hetarylalkyloxy group as defined above attached through an "alkyl” group having the indicated number of carbon atoms.
  • arylalkyl e.g. benzyl, phenylethyl, 3-phenylpropyl, 1-naphtylmethyl, 2-(1- naphtyl)ethyl and the like
  • arylalkyl represents an aryl group as defined below attached through an alkyl having the indicated number of carbon atoms or substituted alkyl group as defined above.
  • hetarylalkyl or “hetaralkyl” (e.g. (2-furyl)methyl, (3-furyl)methyl, (2- thienyl)methyl, (3-thienyl)methyl, (2-pyridyl)methyl, 1-methyl-1-(2-pyrimidyl)ethyl and the like) represents a hetaryl group as defined below attached through an alkyl having the indicated number of carbon atoms or substituted alkyl group as defined above.
  • alkylcarbonyl e.g. octylcarbonyl, pentylcarbonyl, 3-hexenylcarbonyl
  • alkylcarbonyl represents an alkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group.
  • arylcarbonyl e.g. benzoyl
  • hetarylcarbonyl e.g. 2-thiophenylcarbonyl, 3-methoxy-anthrylcarbonyl, oxazolylcarbonyl and the like
  • carbonylalkyl (e.g. acetyl and the like) represents a carbonyl group at- tached through alkyl group as defined above having the indicated number of carbon atoms.
  • alkylcarbonylalkyl e.g. propan-2-one, 4,4-dimethyl-pentan-2-one and the like
  • alkylcarbonylalkyl represents an alkylcarbonyl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • arylcarbonylalkyl e.g. 1-phenyl-propan-1-one, 1-(3-chloro-phenyl)-2- methyl-butan-1-one and the like
  • arylcarbonylalkyl represents a arylcarbonyl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • hetarylcarbonylalkyl e.g. 1-pyridin-2-yl-propan-1-one, 1-(1-H-imidazol-2- yl)-propan-1-one and the like
  • arylalkylcarbonyl e.g. phenylpropylcarbonyl, phenylethylcarbonyl and the like
  • hetarylalkylcarbonyl (e.g. imidazolylpentylcarbonyl and the like) represents a hetarylalkyl group as defined above wherein the alkyl group is in turn attached through a carbonyl.
  • alkylcarbonylamino (e.g. methylcarbonylamino, cyclopentylcarbonyl- aminomethyl, methylcarbonylaminophenyl) represents an "alkylcarbonyl” group as defined above wherein the carbonyl is in turn attached through the nitrogen atom of an amino group. The nitrogen atom may itself be substituted with an alkyl or aryl group.
  • alkylcarbonylaminoalkyl e.g.N-propyl-acetamide, N-butyl-propionamide and the like
  • alkylcarbonylamino represents an "alkylcarbonylamino" group attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • arylalkylcarbonylamino e.g. phenylacetamide, 3phenyl-propionamide and the like
  • arylalkylcarbonylamino represents an “arylalkylcarbonyl” group as defined above attached through an amino group.
  • arylalkylcarbonylaminoalkyl e.g. N-ethyl-phenylacetamide, N-butyl-3- phenyl-propionamide and the like
  • arylcarbonylamino represents an "arylcarbonylamino” group attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • arylcarbonylamino e.g. benzamide, naphthalene-1 -carboxylic acid amide and the like
  • arylcarbonylaminoalkyl e.g. N-propyl-benzamide, N-Butyl-naphthalene- 1 -carboxylic acid amide and the like
  • arylcarbonylaminoalkyl represents an "arylcarbonylamino" group attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • alkylcarboxy e.g. heptylcarboxy, cyclopropylcarboxy, 3-pentenylcarboxy
  • alkylcarboxy represents an alkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
  • arylcarboxy e.g. benzoic acid and the like
  • alkylcarboxyalkyl e.g. heptylcarboxymethyl, propylcarboxy tert-butyl, 3- pentylcarboxyethyl
  • arylalkylcarboxy e.g. benzylcarboxy, phenylpropylcarboxy and the like
  • arylalkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
  • arylalkylcarboxyalkyl e.g. benzylcarboxymethyl, phenylpropylcar- boxypropyl and the like
  • arylalkylcarboxyalkyl represents an arylalkylcarboxy group as defined above wherein the carboxy group is in turn attached through an alkyl group as defined above having the indi- cated number of carbon atoms.
  • hetarylcarboxy e.g. pyridine-2-carboxylic acid and the like
  • hetarylcarboxy represents a hetarylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
  • hetarylalkylcarboxy e.g. (1-H-imidazol-2-yl)-acetic acid, 3-pyrimidin-2-yl- propionic acid and the like
  • hetarylalkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
  • aryl includes but is not limited to a carbocyclic aromatic ring system being either monocyclic, bicyclic, or polycyclic, such as phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl and the like.
  • Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic aromatic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1 ,2,3,4-tetrahydronaphthyl, ,4-dihydronaphthyl and the like.
  • aryll includes phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, and fluorenyl.
  • aryl2 includes phenyl, biphenyl, and naphthyl.
  • heteroaryl includes but is not limited to pyrrolyl (2-pyrrolyl), pyrazolyl (3- pyrazolyl), imidazolyl (1 -imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3- triazol-1-yl, 1 ,2,3-triazol-2-yl 1 ,2,3-triazol-4-yl, 1 ,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4- oxazolyl, 5-oxazolyl), isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiophenyl (2-thiophenyl, 3-thiophenyl, 4-thiophenyl, 5-thiophenyl), furanyl (2-pyrroly
  • alkylSO m (e.g. ethylsulfonyl, ethylsulfinyl and the like) represents an alkyl group as defined above, wherein the alkyl group is in turn attached through a sulphur bridge wherein the sulphur is substituted with m oxygen atoms.
  • arylSO m (e.g. phenylsulfinyl, naphthyl-2-sulfonyl and the like) represents an aryl group as defined above, wherein the aryl group is in turn attached through a sulphur bridge wherein the sulphur is substituted with m oxygen atoms.
  • hetarylSO m e.g. thiazol-2-sulfinyl, pyridine-2-sulfonyl and the like repre- sents a hetaryl group as defined above, wherein the hetaryl group is in turn attached through a sulphur bridge wherein the sulphur is substituted with m oxygen atoms.
  • NR 4 R 5 carbonylalkyl e.g. /V./V-dimethyl- propionamide, ⁇ /-isopropyl-W-methyl-propionamide and the like
  • alkylR 6 alkyl e.g. 2-ethoxymethyl, N-ethyl-
  • N-methy amine, methyl-propyl-amide, ethanesulfonic acid methylamide and the like represents an alkyl group as defined above, substituted by R 6 , which is substituted by an alkyl group as defined above.
  • arylR 6 alkyl e.g. ethoxy-benzene, N-ethyl- N-methyl-phenyl-amine, ⁇ /-ethyl-benzamide, ⁇ /-isobutyl-benzenesulfonamide and the like
  • R 6 represents an aryl group as defined above, substituted by R 6 , which is substituted by an alkyl group as defined above.
  • arylalkylR 6 alkyl e.g. benzyloxymethyl, N- ethyl-N-methyl-benzyl-amine, /V-ethyl-benzylamide and the like
  • R 6 represents an arylalkyl group as defined above, substituted by R 6 , which is substituted by an alkyl group as defined above.
  • hetarylR 6 alkyl e.g. 2-ethoxy-1r7-imidazol, ethyl-quinolin-2-yl-amine, thiazole-2-carboxylic acid, methyl-propyl-amide, pyridine-3-sulfonic acid isobutyl-amide and the like
  • R 6 represents a hetaryl group as defined above, substituted by R 6 , which is substituted by an alkyl group as defined above.
  • arylcarbonylNR 15 (e.g. /V-benzyl- ⁇ /- methyl-benzamide and the like) represents an arylcarbonyl group as defined above, substituted by NR 15 .
  • arylSO m NR 8 (e.g. ⁇ /-methyl-benzene- sulfonamide and the like) represents an aryl group as defined above, wherein the aryl group is in turn attached through a SO m NR 8 group wherein the sulphur is substituted with m oxygen atoms and the nitrogen atom substituted by R 8 .
  • alkylNR 5 alkyl e.g. N-ethyl-N-isobutyl-amine, N,N-dimethylamine and the like wherein the amino group (N) is substituted with R 5 as de- fined below
  • alkylNR 5 group as defined above attached through an "alkyl” group.
  • arylalkylNR 5 alkyl e.g. N-benzyl-N-methyl- amine, N-phenethyl-N-ethyl-amine and the like wherein the amino group (N) is substituted • with R 5 as defined below
  • arylalkylNR 5 group as defined above attached through an "alkyl” group.
  • treatment is defined as the management and care of a patient for the purpose of combating or alleviating the disease, condition or disorder, and the term includes the administration of the active compound to prevent the onset of the symptoms or complica- tions, or alleviating the symptoms or complications, or eliminating the disease, condition, or disorder.
  • pharmaceutically acceptable is defined as being suitable for administration to humans without adverse events.
  • prodrug is defined as a chemically modified form of the active drug, said prodrug being administered to the patient and subsequently being converted to the active drug. Techniques for development of prodrugs are well known in the art.
  • the present invention provides the use of a substituted amide, a pro- drug thereof, or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms for a) modulation of the activity of 11 ⁇ HSDl ;or b) inhibition of 11 ⁇ HSDl, in a patient in need thereof.
  • the present invention provides the use of a substituted amide, a prodrug thereof, or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of any disorder and disease where it is desirable to a) modulate the activity of 11 ⁇ HSDl ; or b) inhibit 11 ⁇ HSD1, in a patient in need thereof.
  • the invention provides the present use of substituted am- ides, or a prodrug thereof of the general formula (I)
  • R 1 is C 3 -C 10 cycloalkyl, C 3 -C ⁇ 0 hetcycloalkyl, d-C 8 alkyl, aryl, hetaryl, arylCrC 6 alkyl or hetarylC ⁇ -C 6 alkyl, wherein the cycloalkyl, hetcycloalkyl, alkyl, arylalkyl and hetarylalkyl groups independently are optionally substituted with one or more of R 4 .
  • R 2 is hydrogen, C r C 8 alkyl, aryl, hetaryl, arylCrCealkyl, Cs-docycloalkyld-Cealkyl, C C 6 alkyl-carboxyCrC 6 alkyl wherein the alkyl, aryl and cycloalkyl groups independently are optionally substituted with one or more of R 5 ; or
  • R 1 and R 2 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrCealkyl, aryl, hetaryl, arylC C 6 alkyl, hetarylC ⁇ -C 6 alkyl, hydroxy, oxo, cyano, d-C 6 alkyloxy, aryld-Cealkyloxy, hetaryld- C 6 alkyloxy, d-Cealkyloxyd-Cealkyl, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylC r C 6 alkylcarbonyl, hetarylC r C 6 alkylcarbonyl, d-C 6 alky
  • R 3 is CrC 8 alkyl, C C 6 alkenyl, d-C 6 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, aryl, hetaryl, arylCrCealkyl, d-CealkyloxyCi-Cealkyl, hetarylCrC 6 alkyl, aryl-R 6 -CrC 6 alkyl, hetaryl- R 6 -d-C 6 alkyl or arylC ⁇ -C 6 alkyl-R 6 -C.-C 6 alkyl wherein the alkyl, cycloalkyl, hetcycloalkyl, al- kenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 7 ;
  • R 4 and R 5 independently are hydrogen, hydroxy, oxo, cyano, halo, methylendioxo, NR 8 R 9 , d-C 8 alkyl, C C 6 alkyloxy, trihalomethyl, trihalomethyloxy, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcyclo- alkyl, C 3 -C ⁇ 0 cycloalkenyl, aryl, hetaryl, hetarylSO n , arylCrC 6 alkyloxy, hetaryld-C 6 alkyloxy, C.-C 6 alkyl-R 6 -d-C 6 alkyl, aryld-C-ealkyl-R ⁇ d-Cealkyl, C C 6 alkylcarbonyl, arylcarbonyl, aryld-C 6 alkylcarbonyl, hetarylcarbonyl, hetarylC.-C 6 alky
  • R 6 is oxygen, sulphur, SO n or NR 16.
  • R 7 is hydrogen, halo, hydroxy, cyano, nitro, COOR 17 , CrC 8 alkyl, C 3 -C ⁇ ocycloalkyl, C 3 -C 10 het- cycloalkyl, methylendioxo, trihalomethyl, trihalomethyloxy, aryl, arylC C 6 alkyl, CrC 6 alkyloxy, CrC ⁇ alkyloxyCrCealkyl, aryloxy, arylC C 6 alkyloxy, aryloxyC C 6 alkyl, arylCrC 6 alkyloxyd- C 6 alkyl, hetaryl, hetarylCrC 6 alkyl, hetaryloxy, hetarylC ⁇ -C 6 alkyloxy, hetaryloxyd-Cealkyl, hetaryld-Cealkyl-oxyd-Cealkyl, NR 8 R 9 , S0 2 NR 8 R
  • R 8 and R 9 independently are hydrogen, C C 8 alkyl, aryl, hetaryl, aryld-C 6 alkyl or hetaryld- C 6 alkyl wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 11 ; or
  • R 8 and R 9 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system optionally being substituted with at least one halo, cyano, d-C ⁇ alkyl, aryl, hetaryl, arylCrCealkyl, hetarylCrC 6 alkyl, hydroxy, oxo, d-C 6 alkyloxy, arylCrC 6 alkyloxy, hetaryld- C 6 alkyloxy, CrC 6 alkyloxyCrC 6 alkyl, CrC 6 alkyl-carbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC 6 alkylcarbonyl, hetarylCrC 6 alkylcarbonyl, d-C 6 alkyl
  • R 10 and R 11 independently are hydrogen, hydroxy, oxo, halo, cyano, nitro, d-C 8 alkyl, d- C 6 alkyloxy, NR 12 R 13 , methylendioxo, trihalomethyl or trihalomethyloxy;
  • R 12 and R 13 independently are hydrogen, d-C 8 alkyl or arylCrC 6 alkyl
  • R 14 is hydrogen, halo, hydroxy, oxo, nitro, cyano, C C 8 alkyl, d-C 6 alkyloxy or aryloxy;
  • R 15 is hydrogen, halo, hydroxy, oxo, nitro, cyano, CONR 8 R 9 or COOR 17 ;
  • R 16 is hydrogen, C r C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, aryl, arylCrC 6 alkyl, hetaryl, hetarylC ⁇ -C 6 alkyl, alkylcarbonyl, arylcarbonyl, arylCrC 6 alkylcarbonyl, aryloxyd- C 6 alkyl, hetaryloxyCr Cealkyl, arylthioC C 6 alkyl or hetarylthioCrC 6 alkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 10 ;
  • R is hydrogen, CrC 8 alkyl, aryl or arylCrCealkyl
  • R 8 is C C 6 alkyl, C 2 -C 6 alkenyl, aryl, arylCrC 6 alkyl, hetaryl, hetarylCrC 6 alkyl, C 3 - C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, CrC 6 alkyloxy, aryloxy, arylC C 6 alkyloxy, aryld- C 6 alkyloxyCrC 6 alkyl, hetaryloxy, hetarylCrC 6 alkyloxy, hetarylCrCealkyloxyCrCealkyl or R 8 R 9 NCrC 6 alkyl wherein the alkyl, alkenyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups are optionally substituted with R 15 ;
  • R 19 is d-Cealkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, aryl, arylCrC 6 alkyl, hetaryl, hetaryl- CrC 6 alkyl;
  • n 1 or 2;
  • n 0, 1 or 2;
  • the invention provides the present use of a substituted amide, or a prodrug thereof of the above general formula (I) wherein
  • R 1 is C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, CrCealkyl, aryl, hetaryl, arylCrCealkyl or hetaryl- CrCealkyl, wherein the cycloalkyl, hetcycloalkyl, alkyl, arylalkyl and hetarylalkyl groups independently are optionally substituted with one or more of R 4 ;
  • R 2 is hydrogen, CrC 8 alkyl, aryl, hetaryl, arylCrC 6 alkyl, d-docycloalkyld-Cealkyl, d-Ce- alkylcarboxyCrC 6 alkyl wherein the alkyl, aryl and cycloalkyl groups independently are op- tionally substituted with one or more of R 5 ; or
  • R 1 and R 2 are together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC 8 alkyl, aryl, hetaryl, arylC C 6 alkyl, hetarylCrC 6 alkyl, hydroxy, oxo, cyano, CrC 6 alkyloxy, arylCrC 6 alkyloxy, hetarylC C 6 alkyloxy, d-Cealkyloxyd-Cealkyl, d-C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, aryld-C 6 alkylcarbonyl, hetarylCrC 6 alkylcarbonyl, CrC 6 alkylcarboxy,
  • R 3 is CrC 8 alkyl, CrC 6 alkenyl, CrC 6 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, aryl, hetaryl, arylCrC 6 alkyl, CrCealkyloxyCrCealkyl, hetarylCrC 6 alkyl, aryl-R 6 -CrC 6 alkyl, hetaryl- R 6 -d-C 6 alkyl or arylCrC 6 alkyl-R 6 -CrC 6 alkyl wherein the alkyl, cycloalkyl, hetcycloalkyl, al- kenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 7 ;
  • R 4 and R 5 independently are hydrogen, hydroxy, oxo, cyano, halo, methylendioxo, NR 8 R 9 , C r C 8 alkyl, d-Cealkyloxy, trihalomethyl, trihalomethyloxy, C 3 -C 10 cycloalkyl, C 3 - dohetcycloalkyl, C 3 -C 10 cycloalkenyl, aryl, hetaryl, hetarylSO n , arylCrC 6 alkyloxy, hetaryld- C 6 alkyloxy, d-Cealkyl-R ⁇ d-Cealkyl, arylCrC 6 alkyl-R 6 -CrC 6 alkyl, CrC 6 alkylcarbonyl, arylcarbonyl, arylCrC 6 alkylcarbonyl, hetarylcarbonyl, hetaryld-C 6 alkyl-carbonyl
  • R 7 is hydrogen, halo, hydroxyl, cyano, nitro, COOR 17 , C C 8 alkyl, C 3 -C ⁇ 0 cycloalkyl, C 3 -C 10 het- cycloalkyl, methylendioxo, trihalomethyl, trihalomethyloxy, aryl, arylCrC 6 alkyl, CrC 6 alkyloxy, CrC 6 alkyloxyCrC 6 alkyl, aryloxy, aryloxyd-Cealkyl, arylCrC 6 alkyloxyCrC 6 alkyl, hetaryl, hetarylCrC 6 alkyl, hetaryloxy, hetarylCrC 6 alkyloxy, hetaryloxyCrC 6 alkyl, hetaryld-C 6 alkyl- oxyd-C 6 alkyl, NR 8 R 9 , S0 2 NR 8 R 9 , NR 4
  • R 8 and R 9 independently are hydrogen, C r C 8 alky1, aryl, hetaryl, arylCrC 6 alkyl or hetaryld- C 6 alkyl wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 11 ; or
  • R 8 and R 9 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system optionally being substituted with at least one d-C 8 alkyl, aryl, hetaryl, arylCrC 6 alkyl, hetarylCrC 6 alkyl, hydroxy, oxo, CrC 6 alkyloxy, arylCrC 6 alkyloxy, hetarylCrC 6 alkyloxy, d- C 6 alkyloxyd-C 6 alkyl, d-C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, aryld-Ci-alkyl- carbonyl, hetarylCrC 6 alkylcarbonyl, d-C 6 alkylcarboxy,
  • R 10 and R 11 independently are hydrogen, hydroxy, oxo, halo, cyano, nitro, CrC ⁇ alkyl, CrCealkyloxy, NR 12 R 13 , methylendioxo, trihalomethyl or trihalomethyloxy;
  • R 12 and R 13 independently are hydrogen, C r C 8 alkyl or arylCrC 6 alkyl;
  • R 14 is hydrogen, halo, hydroxy, oxo, nitro, cyano, d-C 8 alkyl, d-Cealkyloxy or aryloxy;
  • R 15 is hydrogen, halo, hydroxy, oxo, nitro, cyano or COOR 17 ;
  • R 16 is hydrogen, C C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, aryl, arylCrC 6 alkyl, hetaryl, hetarylCrC 6 alkyl, alkylcarbonyl, arylcarbonyl, arylCrC 6 alkylcarbonyl, aryloxyd- C 6 alkyl, hetaryloxyd-C-ealkyl, arylthioCrC 6 alkyl or hetarylthioCrC 6 alkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 10 ;
  • R 17 is hydrogen, C C 8 alkyl, aryl or arylCrCealkyl
  • n 1 or 2;
  • n 0, 1 or 2;
  • the invention provides the present use of a substituted amide, or a prodrug thereof of the general formula (I) wherein R 1 is C 3 -C 10 cycioalkyl or C 3 - dohetcycloalkyl wherein the cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 4 as defined above.
  • the invention provides the present use of a substituted amide, or a prodrug thereof of the general formula (I) wherein R 1 is C 3 -C 10 cycloalkyl optionally substituted with one or more of R 4 as defined above.
  • the invention provides the present use of a substituted amide, or a prodrug thereof of the general formula (I) wherein R 2 is hydrogen or C C 8 alkyl, wherein the the alkyl group is optionally substituted with one or more of R 5 as defined above.
  • the invention provides the present use of a substituted amide, or a prodrug thereof of the general formula (I) wherein R 2 is C r C 8 alkyl optionally substituted with one or more of R 5 as defined above.
  • the invention provides the present use of a substituted am- ide, or a prodrug thereof of the general formula (I) wherein R 3 is C 3 -C 10 cycloalkyl, C 3 -
  • the invention provides the present use of a substituted amide, or a prodrug thereof of the general formula (I) wherein R 3 is aryl or hetaryl, wherein the aryl and hetaryl groups are optionally substituted with one or more of R 7 as defined above.
  • the invention provides the present use of a substituted am- ide, or a prodrug thereof of the general formula (I) wherein R 3 is is phenyl optionally substituted with one or more of R 7 as defined above.
  • the invention provides the present use of a substituted amide, or a prodrug thereof of the general formula (I) wherein R 3 is phenyl optionally substituted independently in position 2(ortho) or 4(para) with one or more of R 7 as defined above.
  • the invention provides the present use of a substituted amide, or a prodrug thereof of the general formula (I) wherein R 4 and R 5 independently are hydrogen, hydroxy, oxo, halo, d-C 8 alkyl, wherein the alkyl group is optionally substituted with one ore more of R 15 .
  • the invention provides the present use of a substituted am- ide, or a prodrug thereof of the general formula (I) wherein R 6 is oxygen.
  • the invention provides the present use of a substituted amide, or a prodrug thereof of the general formula (I) wherein R 7 is hydrogen, halo, hydroxy, cyano, d-C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 het-cycloalkyl, trihalomethyl, aryl, arylCrC 6 alkyl, CrC 6 alkyloxy, d-C-ealkyloxyd-Cealkyl, aryloxy, arylCrC 6 alkyloxy, aryloxyd-Cealkyl, aryld- CealkyloxyCrCealkyl, hetaryl, hetarylCrC 6 alkyl, hetaryloxy, hetarylCrC 6 alkyloxy, hetary- loxyd-C 6 alkyl, hetary- loxyCrCeCe
  • the invention provides the present use of a substituted am- ide, or a prodrug thereof of the general formula (I) wherein R 8 and R 9 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system optionally being substituted with at least one halo, cyano, d-C 8 alkyl, aryl, hetaryl, arylCrCealkyl, hetarylCrC 6 alkyl, hydroxy, oxo, d-C 6 alkyloxy, arylCrC 6 alkyloxy, hetarylCrC 6 alkyloxy, d-Cealkyloxyd-
  • the invention provides the present use of a substituted am- ide, or a prodrug thereof of the general formula (I) wherein R 15 is CONR 8 R 9 .
  • the invention provides the present use of a substituted amide, or a prodrug thereof of the general formula (I) wherein R 18 is d-Cealkyl optionally substi- tuted with R 15 ;
  • the invention provides the present use of a substituted am- ide, or a prodrug thereof of general formula (I), selected from the group consisting of:
  • Adamantane-1 -carboxylic acid (3-benzyloxy-2-ethyl-6-methyl-pyridin-4-yl)-amide; (6-Fluoro-2-methyl-3,4-dihydro-2H-quinolin-1 -yl)-(3,4,5-trimethoxy-phenyl)-methanone;
  • Biphenyl-4-yl-piperidin-1 -yl-methanone Azepan-1 -yl-(3,5-dichloro-phenyl)-methanone;
  • N,N-Dibenzyl-4-methyl-benzamide (2-Chloro-phenyl)-(2-methyl-piperidin-1 -yl)-methanone;
  • Cyclohexanecarboxylic acid [2-methyl-1-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6- carbonyl)-butyl]-amide; 3-Cyclopentyl-N-[2-methyl-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-bu-yl]- propionamide;
  • Furan-2-carboxylic acid [4-(4-methyl-piperidine-1 -sulfonyl)-phenyl]-amide; N-(2-Cyclohex-1 -enyl-ethyl)-2-o-tolyloxy-acetamide;
  • N-Cyclooctyl-2-p-tolyloxy-acetamide (3,5-Dimethyl-piperidin-1-yl)-(4-methyl-3-nitro-phenyl)-methanone;
  • N-Benzyl-N-cyclohex-1-enyl-isonicotinamide 1 -[4-(4-Fluoro-phenyl)-piperazin-1 -yl]-2-(2-methyl-benzylsulfanyl)-ethanone;
  • Benzo[b]thiophene-3-carboxylic acid (3,3,5-trimethyl-cyclohexyl)-amide; 2-(2,6-Dimethyl-phenoxy)-N-(2-isopropyl-phenyl)-acetamide;
  • Acetic acid 4-(4-methyl-piperidine-1-carbonyl)-phenyl ester; Acetic acid 4-(4-benzyl-piperidine-1 -carbonyl)-phenyl ester;
  • N-(4-tert-Butyl-3-nitro-phenyl)-acetamide (2,6-Dimethyl-piperidin-1-yl)-[5-(2,3,5,6-tetrafluoro-phenoxymethyl)-furan-2-yl]-methanone; N-Cyclohexyl-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-N-methyl-propionamide;
  • Adamantane-1 -carboxylic acid (naphthalen-1 -ylmethyl)-amide; Adamantane-1 -carboxylic acid (benzo[1 ,3]dioxol-5-ylmethyl)-amide;
  • Dec-3-enoic acid (4-hydroxy-benzyl)-(4-trifluoromethyl-benzyl)-amide; 6-Oxo-6-phenyl-hexanoic acid (4-hydroxy-benzyl)-(4-trifluoromethyl-benzyl)-amide; 2-(3,4-Difluoro-phenyl)-N-(4-hydroxy-benzyl)-N-thiophen-2-ylmethyl-acetamide;
  • the present invention is concerned the substituted amides or prodrugs thereof of the general formula (II)
  • R 1 is C 3 -C 10 cycloalkyl or C 3 -C 10 hetcycloalkyl, wherein the cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 4 ;
  • R 2 is hydrogen, C C 8 alkyl, arylCi -C h alky!, wherein the alkyl and aryl groups independently are optionally substituted with one or more of R 5 ; or
  • R 1 and R 2 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-C 8 alkyl, aryl, hetaryl, aryld- C 6 alkyl, hetarylCrC 6 alkyl, hydroxy, oxo, cyano, CrC 6 alkyloxy, arylCrC 6 alkyloxy, hetaryld- C 6 alkyloxy, d-Cealkyloxyd-Cealkyl, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetaryld-Cealkylcarbonyl, C C 6 alkylcarboxy
  • R 3 is C 3 -C ⁇ 0 cycloalkyl, C 3 -C 10 hetcycloalkyl, aryl or hetaryl, wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 7 ;
  • R 4 and R 5 independently are hydrogen, hydroxy, oxo, cyano, halo, methylendioxo, NR 8 R 9 , d-C 8 alkyl, CrC 6 alkyloxy, trihalomethyl, trihalomethyloxy, C 3 -C 10 cycloalkyl, C 3 -C.
  • R 6 is oxygen, sulphur, SO n or NR 16 ;
  • R 7 is hydrogen, halo, hydroxy, cyano, nitro, COOR 17 , d-C 8 alkyl, C 3 -d 0 cycloalkyl, C 3 -C 10 het- cycloalkyl, methylendioxo, trihalomethyl, trihalomethyl, trihalomethyloxy, aryl, arylCrCealkyl, CrC 6 alkyloxy, CrCealkyloxyCrC 6 alkyl, aryloxy, arylC 1 -C 6 alkyloxy, aryloxyCrC 6 alkyl, arylCrC 6 alkyloxyCr C 6 alkyl, hetaryl, hetarylC C 6 alkyl, hetaryloxy, hetarylCrCealkyloxy, hetaryloxyd-Cealkyl, hetaryld-Cealkyl-oxyd-Cealkyl, NR 8
  • R 8 and R 9 independently are hydrogen, d-C 8 alkyl, aryl, hetaryl, CrC 6 alkylSO m , arylSO m , arylCrC 6 alkylSO m , arylCrC 6 alkyl or hetaryld-Cealkyl wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 11 ; or
  • R 8 and R 9 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system optionally being substituted with at least one halo, cyano, d-C 8 alkyl, aryl, hetaryl, arylCrC 6 alkyl, hetarylCrC 6 alkyl, hydroxy, oxo, d-C 6 alkyloxy, arylCrC 6 alkyloxy, hetaryld- C 6 alkyloxy, CrC 6 alkyloxyCrC 6 alkyl, CrC 6 aIkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC 6 alkylcarbonyl, hetarylCrC 6 alkylcarbonyl, CrC 6 alkylcar
  • R 10 and R 11 independently are hydrogen, hydroxy, oxo, halo, cyano, nitro, d-C 8 alkyl, d- C 6 alkyl-oxy, NR 12 R 13 , methylendioxo, trihalomethyl or trihalomethyloxy;
  • R 12 and R 13 independently are hydrogen, d-C 8 alkyl or arylCrC 6 alkyl
  • R 14 is hydrogen, halo, hydroxy, oxo, nitro, cyano, d-C 8 alkyl, d-C 6 alkyloxy or aryloxy;
  • R 15 is hydrogen, halo, hydroxy, oxo, nitro, cyano, CONR 8 R 9 or COOR 17 ;
  • R 16 is hydrogen, C r C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, aryl, arylCrC 6 alkyl, hetaryl, hetarylCrC 6 alkyl, alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, aryloxyd- Cealkyl, hetaryloxyCrC 6 alkyl, arylthioCrC 6 alkyl or hetarylthioCrC 6 alkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 10 ;
  • R 17 is hydrogen, d-C 8 alkyl, aryl or arylCrCealkyl;
  • R 18 is CrCealkyl, C 2 -C 6 alkenyl, aryl, aryld-Cealkyl, hetaryl, hetarylCrC 6 alkyl, C 3 - C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, CrC 6 alkyloxy, aryloxy, arylCrC 6 alkyloxy, aryld- C 6 alkyloxyCrCealkyl, hetarylCrC 6 alkyloxyCrC 6 alkyl, hetaryloxy, hetarylCrCealkyloxy or R 8 R 9 NCrC 6 alkyl wherein the alkyl, alkenyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups are optionally substituted
  • R 19 is CrCealkyl, C 3 -C 10 cycloalkyl, C 3 -C ⁇ 0 hetcycloalkyl, aryl, arylCrC 6 alkyl, hetaryl, hetarylCrC 6 alkyl;
  • n 1 or 2;
  • n 0, 1 or 2;
  • R 1 is C 3 -C 10 cycloalkyl or C 3 -C 10 hetcycloalkyl, wherein the cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 4 as defined above.
  • R 2 is hydrogen or d-
  • R 1 and R 2 together with the nitrogen to which they are attached are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of C C 8 alkyl, aryl, hetaryl, aryld-Cealkyl, hetarylC ⁇ -C 6 - alkyl, hydroxy, oxo, cyano, d-C-ealkyloxy, aryld-C 6 alkyloxy, hetarylCrCealkyloxy, d-C 6 alkyl- oxyd-Cealkyl, d-C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylcarbonyl, hetarylcarbonyl,
  • R 1 and R 2 together with the nitrogen to which they are attached are 6-aza-bicyclo[3.2.1]octane.
  • R 3 is aryl or hetaryl, wherein the aryl and hetaryl groups independently are optionally substituted with one or more of R 7 as defined above.
  • R 3 is C 3 -C 10 cycloalkyl or C 3 - dohetcycloalkyl, optionally substituted with one or more of R 7 as defined above.
  • R 4 and R 5 independently are hydrogen, hydroxy, oxo, halo, d-C 8 alkyl, wherein the alkyl group is optionally substituted with one ore more of R 15 as defined above.
  • R 7 is hydrogen, halo, hydroxy, cyano, CrCealkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 het-cycloalkyl, trihalomethyl, aryl, aryld- Cealkyl, CrC 6 alkyloxy, d-Cealkyloxyd-Cealkyl, aryloxy, arylCrC 6 alkyloxy, aryloxyCrC 6 alkyl, arylCrCealkyloxyd-Cealkyl, hetaryl, hetarylCrC 6 alkyl, hetaryloxy, hetarylCrCealkyloxy, hetaryloxyd-C 6 alkyl, hetarylCrC 6 alkyl-oxyCrC 6 alkyl, NR 8 R 9 , R 18 carbonylNR 8 , or R 19 SO
  • R 7 is halo, cyano, d- C 8 alkyl, C 3 -C 10 hetcycloalkyl, trihalomethyl, aryl, d-C 6 alkyloxy, aryloxy, arylCrC 6 alkyloxy, aryloxyd-Cealkyl, arylCrCealkyloxyCrC 6 alkyl, hetaryl, hetaryloxy, hetarylCrCealkyloxy, hetaryloxyd-Cealkyl, hetaryld-Cealkyloxyd-Cealkyl, NR 8 R 9 , R 18 carbonylNR 8 , or R 19 SO m NR 8 , wherein the aryl and hetaryl groups are independently optionally substituted with one or more R 10 as defined above.
  • R 7 is R 18 carbonylNR 8 or R 19 SO m NR 8 ; wherein m, R 8 , R 18 and R 19 are defined as above.
  • R 8 is CrCealkyl.
  • R 8 and R 9 together with the nitrogen to which they are attached are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system optionally being substituted with at least one halo, cyano, C C 8 alkyl, aryl, hetaryl, arylCrCealkyl, hetarylCrCealkyl, hydroxy, oxo, CrC 6 alkyIoxy, arylCrC 6 alkyloxy, hetarylCrCealkyloxy, C Cealkyloxyd-Cealkyl, d-C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCr
  • R 15 is CONR 8 R 9 .
  • R 18 is CrC 6 alkyl, optionally substituted with R 15 as defined above.
  • R 18 is aryl or hetaryl.
  • R 18 is arylCrC 6 alkyl- oxyd-C 6 alkyl or hetaryld-Cealkyloxyd-Cealkyl.
  • R 18 is R 8 R 9 Nd-C 6 - alkyl; wherein R 8 and R 9 are defined as above.
  • R 19 is aryl or hetaryl
  • the aryl group is phenyl or pyridyl.
  • the hetaryl group is thienyl, imidazolyl, oxazolyl, thiazolyl, or indolyl.
  • the compounds or prodrugs thereof of the general formula (II) are selected from the group consisting of the compounds of exam- pies 4 through 8 as described under EXAMPLES, COMPOUNDS OF GENERAL FORMULAS (I) AND (II).
  • the present invention is concerned the substituted amides or prodrugs thereof of the general formula (III)
  • R 1 is aryl, arylCrC 6 alkyl, hetaryl or hetarylCr -C 6 alkyl optionally substituted with one or more of R 6 independently;
  • R 2 is halo, d-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylCrC- 6 - alkyl, trihalomethyl, aryl, aryld-Cealkyl, d-C-ealkyloxyd-Cealkyl, aryld-Cealkyloxyd-Cealkyl, CrC 6 alkylNR 5 CrC 6 alkyl, arylCrC 6 alkylNR 5 CrC 6 alkyl, hetaryl or hetarylC C 6 alkyl wherein the alkyl, alkenyl, alkynyl, cycloalkyl and aryl groups independently are optionally substituted with one or more R 7 ;
  • R 3 is CrC 6 alkyl optionally substituted with one or more of R 8 ;
  • R 4 is Ce-docycloalkyl, C 6 -C ⁇ ohetcycloalkyl, Ce-CiocycloalkylCrC ⁇ alkyl or C 6 -C 1Q hetcyclo- alkylCrC 6 alkyl wherein the alkyl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 8 ; or
  • R 3 and R 4 together with the nitrogen to which they are attached, are forming a saturated or partially saturated bicyclic/bridge ring system containing from 7 to 12 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-Cealkyl, aryl, hetaryl, arylCrC 6 alkyl, hetaryl- CrC ⁇ alkyl, hydroxy, oxo, CrC 6 alkyloxy, arylCrC 6 alkyloxy or hetarylCrCealkyloxy, wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R 9 ;
  • R 5 is CrC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, C 3 -C 10 - cycloalkylCrC 6 alkyl, C3-C 10 hetcycloalkylCrC 6 alkyl, aryl, hetaryl, arylC ⁇ -C 6 alkyl or hetaryld- C 6 alkyl wherein the alkyl, alkenyl, alkynyl, aryl, hetaryl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 9 ;
  • R 6 and R 7 independently are hydrogen, hydroxy, oxo, halo, nitro, cyano, CrC 6 alkyl, CrCealkyloxy, trihalomethyl, trihalomethoxy, NR 10 R 11 , arylCrC 6 alkyloxy, hetarylCrCealkyloxy, C C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, CrC 6 alkyloxycarbonyl, aryloxycarbonyl, aryld-C 6 alkyloxycarbonyl, CrC 6 alkylcarboxy, arylcarboxy or arylCrC 6 alkyI- carboxy;
  • R 8 and R 9 independently are hydrogen, d-C 6 alkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrC 6 - alkyl, hydroxy, oxo, cyano, NR 10 R 11 , CrC 6 alkyloxy, aryloxy, arylCrC 6 alkyloxy, hetaryloxy, hetarylCrCealkyloxy, CrCealkyloxyCrCealkyl, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrC 6 alkylcarbonyl, C ⁇ -C 6 alkylcarboxy, arylcarboxy or aryld-C 6 alkylcarboxy;
  • R 10 and R 11 independently are hydrogen, d-C 8 alkyl, aryl, hetaryl, arylCrC 6 alkyl, C 3 -C ⁇ o- cycloalkyl, C 3 -C 0 hetcycloalkyl, C 3 -C 10 cycloalkylCrC 6 alkyl, CrC 6 alkylcarbonyl, d- C 6 alkylcarboxyCrC 6 alkyl; or
  • R 10 and R 11 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon at- oms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-Cealkyl, aryl, hetaryl, aryld- Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, C C 6 alkyloxy, arylCrC 6 alkyloxy, hetaryld- C 6 alkyloxy, d-Cealkyloxyd-Cealkyl, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcar
  • the present invention is concerned with compounds or pro- drugs thereof of the general formula (III) wherein: R 1 is aryl or hetaryl optionally substituted with one or more R 6 independently;
  • R 2 is halo, d-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C ⁇ ocycloalkylCrC 6 - alkyl, aryl, arylCrCealkyl, CrC-ealkyloxyd-Cealkyl, aryld-Cealkyloxyd-Cealkyl, d-C 6 - alkylNR 5 CrC 6 alkyl, arylCrC- 6 alkylNR 5 CrC 6 alkyl, hetaryl or hetarylC C 6 alkyI wherein the alkyl, alkenyl, alkynyl, cycloalkyl and aryl groups independently are optionally substituted with one or more R 7 ;
  • R 3 is CrC 6 alkyl optionally substituted with one or more of R 8 ;
  • R 4 is C 6 -docycloalkyl, C 6 -C 10 hetcycloalkyl, C 6 -C ⁇ ocycloalkylCrC 6 alkyl or C 6 -C ⁇ 0 hetcyclo- alkylC r C 6 alkyl wherein the alkyl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 8 ;
  • R 5 is CrC 6 alkyl, C 2 -Cealkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, C 3 -C 10 - cycloalkyICrC 6 alkyl, C3-C 10 hetcycloalkylC ⁇ -C 6 alkyl, aryl, hetaryl, aryld-Cealkyl or hetaryld- C 6 alkyl wherein the alkyl, alkenyl, alkynyl, aryl, hetaryl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 9 ;
  • R 6 and R 7 independently are hydrogen, hydroxy, oxo, halo, nitro, cyano, C ⁇ -C 6 alkyl, d-C 6 - alkyloxy, trihalomethyl, trihalomethoxy, NR 10 R 11 , arylCrC 6 alkyloxy, hetarylCrCealkyloxy, d- C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, CrCealkyloxycarbonyl, aryloxycarbonyl, aryICrC 6 alkyloxycarbonyl, CrC 6 alkylcarboxy, arylcarboxy or arylCrC 6 aIkyl- carboxy; R 8 and R 9 independently are hydrogen, C C 6 alkyl, aryl, hetaryl, aryld-C 6 alkyl, hetarylCrCealkyl, hydroxy,
  • R 10 and R 11 independently are hydrogen, d-C 8 alkyl, aryl, hetaryl, arylCrC 6 alkyl, C 3 -C 10 - cycloalkyl, C 3 -C 10 hetcycloalkyl, C 3 -C 10 cycloalkylCrC 6 alkyl, CrCealkylcarboxyCrC 6 alkyl; or
  • R 10 and R 11 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-C 8 alkyl, aryl, hetaryl, aryld- C 6 alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC 6 alkyloxy, aryld-C 6 alkyloxy, hetaryl d-C 6 alkyloxy, CrC 6 alkyloxyCrC 6 alkyl, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC 6 alkylcarbonyl, hetarylCrC 6 alkylcarbonyl, C C 6 alkylcarboxy,
  • R 1 is aryl, aryld- Cealkyl or hetaryl optionally substituted with one or more of R 6 .
  • R 1 is aryl optionally substituted with one or more of R 6 .
  • R 1 is aryld-Cealkyl optionally substituted with one or more of R 6 .
  • R 1 is hetaryl optionally substituted with one or more of R 6 .
  • R 2 is CrC 6 alkyl, C 3 - docycloalkyl, C 3 -C 10 cycloalkylCrC 6 alkyl, trihalomethyl, arylCrCealkyl, or hetarylC C 6 alkyl wherein the alkyl, cycloalkyl and aryl groups independently are optionally substituted with one or more R 7 .
  • R 2 is CrC 6 alkyl op- tionally substituted with one or more R 7 .
  • R 2 is trihalomethyl.
  • R 3 is C C 6 alkyl optionally substituted with one or more of R 8 .
  • R 4 is C 6 -C 10 cyclo- alkyl, or C 6 -C 10 hetcycloalkyl, wherein the cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 8 .
  • R 4 is C 6 -C 10 cyclo- alkyl optionally substituted with one or more of R 8 .
  • R 4 is C 6 C 6 -C 10 het- cycloalkyl optionally substituted with one or more of R 8 .
  • R 3 and R 4 together with the nitrogen to which they are attached are forming a saturated or partially saturated bi- cyclic/bridge ring system containing from 7 to 12 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being sub- stituted with at least one of CrC 6 alkyl, aryl, hetaryl, arylCrC 6 alkyl, hetarylCrCealkyl, hydroxy, oxo, CrC 6 alkyloxy, arylCrC 6 alkyloxy or hetaryld-C 6 alkyloxy, wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R 9 .
  • the saturated or partially saturated bicyclic/bridge ring system is 6-aza-bicyclo[3.2.1]octane.
  • R 6 and R 7 independently are hydrogen, hydroxy, oxo, halo, cyano, CrC ⁇ alkyl, d-C 6 alkyloxy, trihalomethyl, NR 10 R 11 , arylCrC 6 alkyloxy, hetarylCrCealkyloxy, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC 6 alkylcarbonyl, CrCealkyloxycarbonyl, aryloxycarbonyl or aryld- C 6 alkyloxycarbonyl.
  • R 8 and R 9 independently are hydrogen, CrC 6 alkyl, hydroxy, oxo, d-dalkyl
  • R 10 and R 11 independently are hydrogen or d-C 8 alkyl.
  • the compound of the general for- mula (III) or a prodrug thereof is 1 -(4-Chloro-phenyl)-5-propyl-1 /-/-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
  • the compounds of the general for- mula (III) or a prodrug thereof is selected from the group consisting of: 1 -(4-Chloro-phenyl)-5-trifluoromethyl-1 H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; [1-(4-Methoxy-phenyl)-5-methyl- -H-pyrazol-4-yl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6- yl)-methanone; 1 [1-(4-Chloro-phenyl)-5-propyl-1r7-pyrazol-4-yl]-(1 ,3,3-trimethyl-6-aza- bicyclo[3.2.1]oct-6-yl)-methanone; [1 -(3,5-Dichloro-phenyl)-5-propyl-1 H-pyrazol-4-yl]-(1 ,3,3-trimethyl-6
  • the compounds of the general formula (III) or a prodrug thereof is selected from the group consisting of: 1 -(Phenyl)-5-methyl-1 r/-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; 1 -(4-Fluoro-phenyl)-5-methyl-1 H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; 1 -(4-Methoxy-phenyl)-5-methyl-1 H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; 1 -(4-Chloro-phenyl)-5-methyl-1 H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; 1 -(2-Methyl-phenyl)-5-methyl-1 H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; 1 -(4-Amino-phenyl
  • the present invention is concerned with compounds or prodrugs thereof of the general formula (IV)
  • R 1 is hydrogen, trihalomethyl, CrC 6 alkyl, d-C 6 alkyloxy, CrC 6 alkylthio, aryl, arylCrC 6 alkyl, hetaryl or hetaralkyl, wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 8 ;
  • R 2 , R 3 , R 4 and R 5 independently are hydrogen, halo, nitro, cyano, hydroxy, NR 9 R 10 , trihalomethyl, CrC 6 alkyl, CrC 6 alkyloxy, CrC 6 alkylthio, aryl, arylCrC 6 alkyl, hetaryl or hetaralkyl, wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 8 ; or
  • R 2 together with R 3 are forming a saturated or partially saturated cyclic ring system containing from 3 to 6 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrCealkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrCealkyl, hydroxy, oxo, CrC 6 alkyloxy, aryloxy, arylCrC 6 alkyloxy or hetarylCrCealkyloxy; or
  • R 3 together with R 4 are forming a saturated or partially saturated cyclic ring system containing from 3 to 6 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-C 6 - alkyl, aryl, hetaryl, aryld-C 6 alkyl, hetarylCrCealkyl, hydroxy, oxo, CrCealkyloxy, aryloxy, arylCrC 6 alkyloxy or hetarylCrC 6 alkyloxy; or
  • R 4 together with R 5 are forming a saturated or partially saturated cyclic ring system containing from 3 to 6 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrCealkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrCealkyl, hydroxy, oxo, d-Cealkyloxy, aryloxy, aryld-C 6 alkyloxy or hetarylCrC 6 alkyloxy;
  • R 6 is aryl, hetaryl, aryld-C 6 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, C 3 -C 10 cycloalkylCr C 6 alkyl, d-Cealkylcarboxyd-Cealkyl, wherein the alkyl, aryl and cycloalkyl groups independently are optionally substituted with one or more of R 11 ;
  • R 7 is C r C 8 alkyl, aryl, hetaryl, aryld-Cealkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, C 3 - C ⁇ ocycloalkylCrC 6 alkyl, CrC 6 alkylcarboxyCrC 6 alkyl, wherein the alkyl, aryl and cycloalkyl groups independently are optionally substituted with one or more of R 11 ; or
  • R 6 and R 7 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-C 8 alkyl, aryl, hetaryl, arylC C 6 alkyl, hetaryl -Cealkyl, hydroxy, oxo, cyano, CrC 6 alkyloxy, arylCrC 6 alkyloxy, hetaryld- C 6 alkyloxy, d-Cealkyloxyd-Cealkyl, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-C 6 alkylcar
  • R 9 and R 10 independently are hydrogen, C C 8 alkyl, aryl, hetaryl, aryld-Cealkyl, C 3 -C 10 - cycloalkyl, C 3 -C ⁇ ohetcycloalkyl, C 3 -C ⁇ ocycloalkylCrC 6 alkyl, CrCealkylcarboxyCrCealkyl, wherein the alkyl, aryl and cycloalkyl groups independently are optionally substituted with one or more of R 11 ; or
  • R 9 and R 10 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-C 8 alkyl, aryl, hetaryl, aryld- Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C 6 alkyloxy, arylCrC 6 alkyloxy, hetaryld- C 6 alkyloxy, d-Cealkyloxyd-Cealkyl, d-C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-C 6 al
  • R 8 and R 11 independently are hydrogen, halo, hydroxy, oxo, nitro, cyano, d-C 8 alkyl, d-C 6 - alkyloxy or aryloxy; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mix- ture of optical isomers, including a racemic mixture, or any tautomeric forms.
  • R 1 is hydrogen or C C 6 alkyl, wherein the alkyl group is optionally substituted with one or more of R 8 .
  • R 1 is hydrogen.
  • R 2 , R 3 , R 4 and R 5 are hydrogen.
  • R 3 together with R 4 are forming a saturated or partially saturated cyclic ring system containing from 3 to 6 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring sys- tem optionally being substituted with at least one of d-C 6 alkyl, aryl, hetaryl, arylCrC 6 alkyl, hetarylCrCealkyl, hydroxy, oxo, CrC 6 alkyloxy, aryloxy, aryld-C 6 alkyloxy or hetarylCrCealkyloxy.
  • R 4 together with R 5 are forming a saturated or partially saturated cyclic ring system containing from 3 to 6 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of d-C ⁇ alkyl, aryl, hetaryl, arylCrC 6 alkyl, hetarylCrCealkyl, hydroxy, oxo, CrC 6 alkyloxy, aryloxy, arylCrC 6 aIkyloxy or hetarylCrCealkyloxy.
  • R 6 and R 7 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of C C 8 alkyl, aryl, hetaryl, arylCrCealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C 6 alkyloxy, arylCrC 6 alkyloxy, hetarylCrCealkyloxy, d-C 6 alkyloxyCr C 6 alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC 6 alkylcarbonyl, hetaryld- C 6 alkylcarbonyl,
  • R 6 and R 7 together with the nitrogen to which they are attached, are forming a saturated or partially saturated bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of C C 8 alkyl, aryl, hetaryl, arylCrC 6 alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, C C 6 alkyloxy, arylCrC 6 alkyloxy, hetarylCrCealkyloxy, CrC 6 alkyloxyCrC 6 alkyl, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrC 6 alkyI- carbonyl, CrCealkylcar
  • R 9 and R 10 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of C C 8 alkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-Cealkyloxy, aryld-Cealkyloxy, hetarylCrCealkyloxy, d-C-ealkyloxyd- C 6 alkyl, d-Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetaryld- C 6 alkylcarbon
  • a compound of the general formula (IV) or a prodrug thereof is pyrazolo[1,5-a]pyridin-3-yl-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct- 6-yl)-methanone; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
  • the compounds of the general formula (IV) or a prodrug thereof are:
  • the present invention is concerned with compounds or prod- rugs thereof of the general formula (V)
  • the present invention is concerned with compounds or prodrugs thereof of the general formula (V) :
  • R 1 is hydrogen, d-C 8 alkyl, CrC 6 alkyloxyd-C 6 alkyl, aryl, hetaryl, arylCrCealkyl, hetarylC r C 6 alkyl, CrC 6 S0 2 , arylS0 2 , hetarylS0 2 , arylC C 6 alkylS0 2 or hetaryld-C 6 alkylS0 2 all of which is optionally substituted with one or more R 8 ;
  • R 2 and R 5 independently are hydrogen, halo, nitro, cyano, trihalomethyl, CrC 6 alkyl, aryl, arylCrC 6 alkyl, hetaryl or hetarylCrCealkyl wherein the alkyl, aryl, arylalkyl, hetaryl and hetarylalkyl groups independently are substituted with one or more R 9 ; and
  • R 3 is hydrogen; and R 4 is C(0)NR 7 R 8 ; or R 3 is C(0)NR 7 R 8 ; and R 4 is hydrogen; and R 6 is hydrogen, halo, cyano, trihalomethyl, NR 12 R 13 , CrC 6 alkyl, aryl, arylCrCealkyl, hetaryl or hetarylCrCealkyl wherein the alkyl, aryl, arylalkyl, hetaryl and hetarylalkyl groups independently are substituted with one or more R 9 ; and
  • R 7 and R 8 independently are d-C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, C 3 -C 10 cyclo- alkyld-C 6 alkyl, wherein the alkyl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 10 ; or
  • R 7 and R 8 together with the nitrogen to which they are attached, are forming a saturated or partially saturated bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of d-C 8 alkyl, arylCrC 6 alkyl, hetarylCrCealkyl, hydroxy, cyano, CrC 6 alkyloxy, arylCrC 6 alkyloxy, hetarylCrCealkyloxy, d-Cealkyloxyd- C 6 alkyl, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetaryld- C 6 alkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy wherein the
  • R 9 is hydrogen, hydroxy, oxo, halo, nitro, cyano, CrC 6 alkyl, d-Cealkyloxy, trihalomethyl, trihalomethoxy, NR 12 R 13 , C(0)NR 12 R 13 , aryld-C 6 alkyloxy, d-C 6 alkylcarbonyl, arylcarbonyl, aryld-C 6 alkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
  • R 10 and R 1 independently are hydrogen, halo, oxo, hydroxy, CrC 6 alkyl, aryl, arylCrC 6 alkyl, hetaryl or hetarylalkyl;
  • R 12 and R 13 independently are hydrogen, d-C 8 alkyl, aryl, hetaryl, aryld-C 6 alkyl, C 3 -C 10 - cycloalkyl, C 3 -C 10 hetcycloalkyl, Cs-docycloalkyld-C-ealkyl, d-C 6 alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, hetarylcarbonyl, hetarylCrCealkylcarbonyl, d-C 6 alkylcarboxyCr C 6 alkyl; or
  • R 12 and R 13 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-C 8 alkyl, aryl, hetaryl, aryld- Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C 6 alkyloxy, arylCrC 6 alkyloxy, hetaryld- C 6 alkyloxy, CrC 6 alkyl-oxyCrC 6 alkyl, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC 6 alkyl-carbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarbox
  • the present invention is concerned with compounds or pro- drugs thereof of the general formula (Va)
  • R 1 is hydrogen, d-C 8 alkyl, aryl, hetaryl, aryld-Cealkyl or hetarylCrCealkyl optionally substituted with one or more R 8 ;
  • R 2 and R 5 independently are hydrogen, halo, nitro, cyano, trihalomethyl, CrC 6 alkyl, aryl, arylCrC 6 alkyl, hetaryl or hetarylCrCealkyl wherein the alkyl, aryl, arylalkyl, hetaryl and hetarylalkyl groups independently are substituted with one or more R 8 ; and
  • R 3 is hydrogen; and R 4 is C(0)NR 6 R 7 ; or R 3 is C(0)NR 6 R 7 ; and R 4 is hydrogen;
  • R 6 and R 7 independently are C C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, C 3 -C 10 cyclo- alkyld-C 6 alkyl, wherein the alkyl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 9 ; or
  • R 6 and R 7 together with the nitrogen to which they are attached, are forming a saturated or partially saturated bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of d-C 8 alkyl, aryld-Cealkyl, hetarylCrCealkyl, hydroxy, cyano, d-C 6 alkyloxy, arylCrC 6 alkyloxy, hetarylCrCealkyloxy, CrC 6 alkyloxyCr C 6 alkyl, C C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetaryld- C 6 alkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy wherein the
  • R 8 is hydrogen, hydroxy, oxo, halo, nitro, cyano, d-C 6 alkyl, CrC 6 alkyloxy, trihalomethyl, trihalomethoxy, NR 11 R 12 , arylCrC 6 alkyloxy, CrC 6 alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, d-C 6 alkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
  • R 9 and R 10 independently are hydrogen, halo, oxo, hydroxy, CrC 6 alkyl, aryl, arylCrC 6 alkyl, hetaryl or hetarylalkyl;
  • R 11 and R 2 independently are hydrogen, d-C 8 alkyl, aryl, hetaryl, aryld-Cealkyl, C 3 -C 10 - cycloalkyl, C 3 -C 10 hetcycloalkyl, C 3 -C 10 cycloalkylCrC 6 alkyl, CrCealkyl-carboxyCrCealkyl; or
  • R 11 and R 12 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-C 8 alkyl, aryl, hetaryl, aryld- Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC 6 alkyloxy, arylCrQ-alkyloxy, hetaryld- C 6 alkyloxy, CrC 6 alkyl-oxyCrC 6 alkyl, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, aryld-C 6 alkyl-carbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy,
  • R 1 is hydrogen, d-C 8 alkyl, arylCrC 6 alkyl, hetarylCrCealkyl, arylS0 2 , hetarylS0 2 , arylCrC 6 alkylSO 2 or hetarylCrCealkylS0 2 all of which is optionally substituted with one or more R 8 .
  • R 1 is hydrogen, C C 8 alkyl, aryld-Cealkyl, hetarylCrCealkyl all of which is optionally substituted with one or more R 8 .
  • R 1 is arylS0 2 , hetarylS0 2 , arylCrC 6 alkylS0 2 or hetarylCrC 6 alkylS0 2 all of which is optionally substituted with one or more R 8 .
  • R 2 is hydro- gen.
  • R 3 is hydrogen and R 4 is C(0)NR 7 R 8 .
  • R 3 is C(0)NR 7 R 8 and R 4 is hydrogen.
  • R 5 is hydrogen.
  • R 6 is hydrogen, NR 12 R 13 , CrC 6 alkyl, aryl or hetaryl wherein the alkyl, aryl and hetaryl independently are substituted with one or more R 9 .
  • R 7 and R 8 independently are C C 8 alkyl or C 3 -C 10 cycloalkyl, wherein the alkyl and cycloalkyl groups independently are optionally substituted with one or more of R 10 .
  • R 7 and R 8 together with the nitrogen to which they are attached are forming a saturated or partially saturated bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of d-C 8 alkyl, arylCrC 6 alkyl, hetarylCrCealkyl, hydroxy, cyano, CrC 6 alkyloxy, arylCrC 6 alkyloxy, hetarylCrCealkyloxy, d-Cealkyloxyd-Cealkyl, CrC 6 alkyl- carbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC 6 alkylcarbonyl, hetarylCrC 6 alkylcarbonyl, CrCealkylcarboxy, arylcarboxy, arylcarboxy, arylcarboxy, ary
  • R 9 is hydrogen, hydroxy, oxo, halo, nitro, cyano, d-C 6 alkyl, d-C 6 alkyloxy, trihalomethyl, trihalomethoxy, NR 12 R 13 , C(0)NR 12 R 13 , arylC C 6 alkyloxy, d-C 6 alkylcarbonyl, arylcarbonyl, aryld- C 6 alkylcarbonyl.
  • R 10 and R 11 independently are hydrogen, halo, oxo, hydroxy, CrCealkyl, aryl, aryld-Cealkyl, hetaryl or hetarylalkyl.
  • R 11 and R 12 together with the nitrogen to which they are attached are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of d-C 8 alkyl, aryl, hetaryl, aryld-Cealkyl, hetaryld- C 6 alkyl, hydroxy, oxo, cyano, d-C 6 alkyloxy, arylCrC 6 alkyloxy, hetarylCrC 6 alkyloxy, d- C 6 alkyl-oxyC C 6 alkyl, d-C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC 6 alkyl-car- bonyl, hetarylC
  • the compound of the general formulas (V) and (Va), or a prodrug thereof is 1H-Benzoimidazole-5-carboxylic acid cyclohexyl- methyl-amide; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
  • the compounds of the general formulas (V) and (Va), or a prodrug thereof is selected from the group consisting of: 1 -Benzyl-1 rV-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide;
  • the compounds of general formulas (V) and (Va), or a prodrug thereof is sleceted from the group consisting of: lsopropyl-2-trifluoromethyl-1 H-benzoimidazole- ⁇ -carboxylic acid cyclohexyl-methyl-amide; 1 -Benzyl-1 H-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide; 2-Methyj-l V-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide; 2-Hydroxymethyl-1H-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide; 2-(4-Amino-phenyl)-1H-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide; (1H-Benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bic
  • X is oxygen or (CR 1 R 2 ) n ;
  • R 1 , R 2 , R 3 , and R 4 independently are hydrogen, C C 6 alkyl, aryl, arylCrCealkyl, hetaryl or hetarylCrCealkyl optionally substituted with one or more R 8 independently; or
  • R 1 and either R 3 or R 4 together are forming a saturated or partially saturated ring system containing from 4 to 8 carbon atoms, the ring system optionally being substituted with at least one of CrC 6 alkyl, hydroxy, oxo, aryl, hetaryl, arylCrCealkyl or hetarylCrC 6 alkyl; or
  • R 1 and either R 3 or R 4 together with the single bond are forming a carbon-carbon double bond
  • R 5 is d-C 8 alkyl optionally substituted with one or more of R 9 ;
  • R 6 is Qrdocycloalkyl, C 3 -C 10 hetcycloalkyl, C 3 -C 10 cycloalkylCr Cealkyl, wherein the alkyl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 9 ; or
  • R 5 and R 6 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC 6 alkyl, aryl, hetaryl, aryld- Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC 6 alkyIoxy, arylCrC 6 alkyloxy, hetaryld- C 6 alkyloxy, CrC 6 alkyloxyCrC 6 alkyl, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcar
  • R 7 is hydrogen, halo, nitro, NR 12 R 13 , cyano, trihalomethyl, CrC 6 alkyl, aryl, aryld-Cealkyl, d- C 6 alkyloxy, aryloxy, arylCrC 6 alkyloxy, hetaryl, hetarylCrCealkyl, hetaryloxy or hetarylCrCealkyloxy optionally substituted with one or more R 11 independently;
  • R 8 and R 9 independently are hydrogen, hydroxy, oxo, halo, nitro, cyano, d-C 6 alkyl, CrCealkyloxy, trihalomethyl, trihalomethoxy, NR 2 R 13 , arylCrC 6 alkyloxy, CrC 6 alkylcarbonyl, aryl- carbonyl, arylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
  • R 10 is hydrogen, d-C 8 alkyl, arylCrC 6 alkyl, hetarylCrCealkyl, CrC 6 alkyloxy, arylCrC 6 alkyl- oxy, hetarylCrCealkyloxy;
  • R 11 is hydrogen, halo, hydroxy, oxo, nitro, cyano, d-C 8 alkyl, CrC 6 alkyloxy, aryloxy or hetaryloxy;
  • R 12 and R 13 independently are hydrogen, d-C 8 alkyl, aryl, hetaryl, arylCrC 6 alkyl, C 3 -C 10 cyclo- alkyl, C 3 -C 10 hetcycloalkyl, CrC 6 alkylcarbonyl, arylCrCealkylcarbonyl, C 3 -C 10 cycloalkylCrC 6 - alkyl, CrCealkyloxycarbonyl; or
  • R 12 and R 13 are together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrCealkyl, aryl, hetaryl, aryld- Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C 6 alkyloxy, arylCrC 6 alkyloxy, hetaryld- C 6 alkyloxy, d-C-ealkyloxyd-Cealkyl, C C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarbox
  • n 1 or 2;
  • X is (CR 1 R 2 ) n , wherein R 1 , R 2 and n are as defined above.
  • n 1
  • X is oxygen.
  • R 1 , R 2 , R 3 , and R 4 independently are hydrogen, d-C 6 alkyl or aryld-Cealkyl, optionally substituted with one or more R 8 .
  • R 1 and either R 3 or R 4 together with the single bond are forming a carbon-carbon double bond.
  • R 5 is C C 8 alkyl op- tionally substituted with one or more of R 9 .
  • R 6 is C 3 -C 10 cyclo- alkyl or C 3 -C 10 hetcycloalkyl each of which is optionally substituted with one or more of R 9 .
  • R 6 is C 3 -C 10 cyclo- alkyl optionally substituted with one or more of R 9 .
  • R 5 and R 6 together with the nitrogen to which they are attached are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-C 6 alkyl, aryl, hetaryl, aryld-Cealkyl, hetarylC C 6 - alkyl, hydroxy, oxo, cyano, CrC 6 alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, C C 6 alkyl- oxyCrC 6 alkyl, d-C 6 alkylcarbony
  • R 7 is hydrogen, halo, NR 12 R 13 , trihalomethyl, d-C 6 alkyloxy, aryloxy, arylCrCealkyloxy or hetaryloxy optionally substituted with one or more R 11 independently.
  • R 8 and R 9 independently are hydrogen, hydroxy, oxo, halo, nitro, cyano, d-C 6 alkyl, d-C 6 alkyloxy, trihalomethyl, or NR 12 R 13 .
  • R 10 is hydrogen or d-C 8 alkyl.
  • the bicyclic ring system is 6-aza-bicyclo[3.2.1]octane optionally substituted with one or more of CrC 6 alkyl.
  • the bicyclic ring system is 1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane.
  • a compound of the general formula (VI) or a prodrug thereof is 2,3-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
  • the compounds of the general formula (VI) or a prodrug thereof is selected from the group consisting of: 2,5-Dimethyl-3-phenyl-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; 2,2-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; 2-Methyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide;
  • Benzofuran-7-carboxylic acid cyclohexyl-methyl-amide 2,3-Dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; 3,3-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; Chroman-8-carboxylic acid cyclohexyl-methyl-amide; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
  • the compounds ofthe general formula (VI) or a prodrug thereof is selected from the group consisting of: 2,3-Dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; Benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; 2-Methyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; 2-Methyl-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; 3,3-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; (2,3-Dimethyl-2,3-dihydro-benzofuran-7-yl)-(2,4,4-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone;
  • the present invention is concerned with compounds or prodrugs thereof of the general formula (VII)
  • R 1 is hydrogen, d-C 8 alkyl, hetaryl, aryld-Cealkyl or hetarylCrCealkyl optionally substituted with one or more R 9 ;
  • R 2 , R 3 , R 4 , R 5 and R 6 independently are hydrogen, halo, nitro, cyano, trihalomethyl, carboxy, N(R 12 R 13 ), C(0)NR 7 R 8 , C r C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, N(R 12 R 13 )C C 6 alkyl, CrCealkyloxy, CrCealkyloxyCrC 6 alkyl, aryl, arylCrC 6 alkyl, aryloxy, aryloxyd- C 6 alkyl, arylCrCealkyloxy, aryld-Cealkyloxyd-C-ealkyl, CrCealkylcarboxy, arylcarboxy, arylCrCealkylcarboxy, hetaryl, hetarylCrCealkyl, hetarylCrCe
  • R 7 is hydrogen or C C 8 alkyl optionally substituted with one or more of R 10 ;
  • R 8 is C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, C 3 -C 10 cycloalkylCrC 6 alkyl, wherein the cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 10 ; or
  • R 7 and R 8 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon at- oms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of d-C 8 alkyl, aryl, hetaryl, arylC ⁇ -C 6 alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C 6 alkyloxy, aryld-C 6 alkyloxy, hetarylCrCealkyloxy, d-Cealkyloxyd-Cealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-C 6 alkyl
  • R 9 is hydrogen, hydroxy, oxo, halo, nitro, cyano, CrC 6 alkyl, CrCealkyloxy, trihalomethyl, trihalomethoxy, NR 12 R 13 , arylC C 6 alkyloxy, d-C 6 alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, d-C 6 alkylcarboxy, arylcarboxy or aryld-C 6 alkylcarboxy;
  • R 10 and R 11 independently are hydrogen, halo, oxo, hydroxy, CrC 6 alkyl, aryl, aryld-Cealkyl, hetaryl or hetarylalkyl;
  • R 12 and R 13 independently are hydrogen, CrC 8 alkyl, aryl, hetaryl, arylCrC 6 alkyl, C 3 -C 10 - cycloalkyl, C 3 -d 0 hetcycloalkyl, C 3 -C 10 cycloalkylCrCealkyl, CrC 6 alkylcarbonyl, arylcarbonyl, aryld-Cealkylcarbonyl, C 3 -C 10 cycloalkylcarbonyl, C 3 -C 10 hetcycloalkylcarbonyl or C 3 -C 10 cyclo- alkylCrC 6 alkylcarbonyl wherein the alkyl and aryl groups independently are optionally substituted with one or more of R 11 , wherein R 11 is as defined above; or
  • R 12 and R 13 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of C C 8 alkyl, aryl, hetaryl, aryld- C 6 alkyl, hetarylCrC 6 alkyl, hydroxy, oxo, cyano, CrC 6 alkyloxy, arylC C 6 alkyloxy, hetaryld- C 6 alkyloxy, d-Cealkyl-oxyd-Cealkyl, d-C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, aryld-C 6 alkyl-carbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarbox
  • the present invention is concerned with compounds or pro- drugs thereof of the general formula (VII) wherein
  • R 1 is hydrogen, C C 8 aIkyl, hetaryl, arylCrCealkyl or hetarylCrCealkyl optionally substituted with one or more R 9 ;
  • R 2 and R 5 independently are hydrogen, halo, nitro, cyano, trihalomethyl, C r C 6 alkyl, CrCealkyloxy, d-Cealkyloxyd-C-ealkyl, aryl, arylCrC 6 alkyl, aryloxy, aryloxyC C 6 alkyl, arylCrCealkyloxy, arylCrCealkyloxyCrCealkyl, hetaryl or hetarylCrCealkyl wherein the alkyl, aryl, ary- lalkyl, hetaryl and hetarylalkyl groups independently are substituted with one or more R 9 ; and
  • R 3 is C(0)NR 7 R 8 , and R 4 is hydrogen; or R 3 is hydrogen, and R 4 is C(0)NR 7 R 8 ;
  • R 6 is d-C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, N(R 2 R 13 )CrC 6 alkyl, d-C 6 alkyloxyCr C 6 alkyl, aryloxyCrC 6 alkyl, aryld-Cealkyloxy or arylCrCealkyloxyCrCealkyl;
  • R 7 is d-C 8 alkyl optionally substituted with one or more of R 10 ;
  • R 8 is C 3 -C 10 cycloalkyl, C 3 -C ⁇ ohetcycloalkyl, C 3 -C 0 cycloalkylCrC 6 alkyl, wherein the cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 10 ; or
  • R 7 and R 8 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring sys- tem optionally being substituted with at least one of d-C 8 alkyl, aryl, hetaryl, arylCrC 6 alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C 6 alkyloxy, aryld-Cealkyloxy, hetarylCrCealkyloxy, d-Cealkyloxyd-Cealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkyl
  • R 9 is hydrogen, hydroxy, oxo, halo, nitro, cyano, d-C 6 alkyl, CrC 6 alkyloxy, trihalomethyl, trihalomethoxy, NR 12 R 13 , arylCrC 6 alkyloxy, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
  • R 10 and R 11 independently are hydrogen, halo, oxo, hydroxy, CrCealkyl, aryl, arylCrC 6 alkyl, hetaryl or hetarylalkyl;
  • R 12 and R 13 independently are hydrogen, d-C 8 alkyl, aryl, hetaryl, aryld-Cealkyl, C 3 -C ⁇ o- cycloalkyl, C 3 -C 10 hetcycloalkyl, C 3 -C 10 cycloalkylCrC 6 alkyl, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, C 3 -C 10 cycloalkylcarbonyl, C 3 -C ⁇ 0 hetcycloalkylcarbonyl or C 3 -C 10 cyclo- alkylCrC 6 alkylcarbonyl; or
  • R 12 and R 13 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-C 8 alkyl, aryl, hetaryl, aryld- Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C 6 alkyloxy, aryld-C-ealkyloxy, hetaryld- C 6 alkyloxy, d-Cealkyl-oxyd-Cealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, aryld-C-ealkyl-carbonyl, hetarylCrCealkylcarbonyl, CrCeal
  • R 2 is C(0)NR 7 R 8 and R 3 R and R 5 are hydrogen, wherein R 7 and R 8 are as defined above.
  • R 3 is C(0)NR 7 R 8 and R 2 R 4 and R 5 are hydrogen, wherein R 7 and R 8 are as defined above.
  • R 4 is C(0)NR 7 R 8 and R 2 R 3 and R 5 are hydrogen, wherein R 7 and R 8 are as defined above.
  • R 5 is C(0)NR 7 R 8 and
  • R 2 R 3 and R are hydrogen, wherein R 7 and R 8 are as defined above.
  • R 6 is C(0)NR 7 R 8 , wherein R 7 and R 8 are as defined above.
  • R 3 is C(0)NR 7 R 8 and R 4 is hydrogen, wherein R 7 and R 8 are as defined above.
  • R 3 is hydrogen and R 4 is C(0)NR 7 R 8 , wherein R 7 and R 8 are as defined above.
  • R 8 is C 3 -C 10 cycloalkyl or drdohetcycloaikyl, each of which is optionally substituted with one or more of R 10 , wherein R 10 is as defined above.
  • R 7 and R 8 together with the nitrogen to which they are attached are forming a saturated or partially saturated bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of d-C 8 alkyl, aryl, hetaryl, arylCrC 6 alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C 6 alkyloxy, arylCrCealkyloxy, hetarylCrC 6 alkyl-oxy, d-C 6 alkyl- oxyCrC 6 alkyl, d-Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, hetarylCrCealkyl
  • the bicyclic ring system is 6-aza-bicyclo[3.2.1]octane optionally substituted with one or more CrC 6 alkyl.
  • the bicyclic ring system is 1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane.
  • the compounds of the general formula (VII) or a prodrug thereof is selected from the group consisting of: (1H-lndol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; 1H-lndole-6-carboxylic acid cyclohexyl-methyl-amide; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mix- ture of optical isomers, including a racemic mixture, or any tautomeric forms.
  • the compounds or prodrugs thereof of the general formula (VII) are selected from the group consisting of the compounds of examples 3 through 20 as described under EXAMPLES, COMPOUNDS OF GENERAL FORMULA (VII).
  • the present invention is concerned with compounds or prodrugs thereof of the general formula (VIII)
  • X is NR 4 , S or O;
  • R 1 and R 2 independently are hydrogen, halo, cyano, trihalomethyl, d-Cealkyl or CrCealkyloxy, wherein the alkyl groups independently are optionally substituted with one or more of R 7 ;
  • R 3 is hydrogen, CrC 6 alkyl, C 3 -C ⁇ 0 cycloalkyl, CrC 6 alkyloxy, CrC 6 alkylthio, aryl, arylCrCealkyl, hetaryl or hetarylalkyl, wherein the alkyl, cycloalkyl, aryl, hetaryl and hetarylalkyl groups independently are optionally substituted with one or more of R 7 ;
  • R 4 is hydrogen, C C 8 alkyl, CrC 6 alkyloxyCrC 6 alkyl, aryl, hetaryl, hetarylCrCealkyl, aryld- Cealkyl, arylCrC 6 alkyloxyCrC 6 alkyl, C 3 -C 10 cycloalkyl, C 3 -C ⁇ ohetcycloalkyl, C 3 -C 10 cyclo- alkylCrC 6 alkyl, CrCealkylcarboxyCrCealkyl wherein the alkyl, aryl, hetaryl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 7 ;
  • R 5 is hydrogen
  • R 6 is adamantyl optionally substituted with hydroxy, CrC 6 alkyloxy, aryl, arylCrC 6 alkyl, aryloxy, aryld-C 6 alkyloxy, hetaryl, hetaryloxy or hetarylCrCealkyloxy wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 7 ; or
  • R 5 and R 6 are together with the nitrogen to which they are attached, forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC 6 alkyl, aryl, hetaryl, aryld- Cealkyl, hetarylalkyl, hydroxy, oxo, cyano, d-C 6 alkyloxy, arylCrCealkyloxy, hetaryld- C 6 alkyloxy, d-Cealkyloxyd-Cealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcar
  • R 7 are independently hydrogen, halo, hydroxy, oxo, nitro, NR 9 R 10 , cyano, COOR 8 ,
  • R 8 is hydrogen, d-C 6 alkyl, aryl, aryld-Cealkyl, hetarylalkyl, wherein the alkyl, aryl and het- arylalkyl groups independently are optionally substituted with one or more of R 7 ;
  • R 9 and R 10 independently are hydrogen, C C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, C 3 - docycloalkyld-Cealkyl, wherein the alkyl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 7 ; or R 9 and R 10 together with the nitrogen to which they are attached, are forming a saturated or partially saturated bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of C C 8 alkyl, arylCrC 6 alkyl, hetarylCrC 6 alkyl, hy- droxy, cyano, d-C 6 alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy
  • R 11 is hydrogen, halo, oxo, hydroxy, d-C 6 alkyl, aryl, arylCrC 6 alkyl, hetaryl or hetarylalkyl;
  • hetcycloalkyl cannot be 7- aza[2,2, 1 jbicycleheptane.
  • the present invention is concerned with compounds or prodrugs thereof of the above general formula (VIII) wherein
  • X is NR 4 , S or O
  • R 1 and R 2 independently are hydrogen, halo, cyano, trihalomethyl, C C 6 alkyl or CrCealkyloxy, wherein the alkyl groups independently are optionally substituted with one or more of R 7 ;
  • R 3 is hydrogen, d-C 6 alkyl, C 3 -C 10 cycloalkyl, C C 6 alkyloxy, d-Cealkylthio, aryl, arylCrCealkyl, hetaryl or hetarylalkyl, wherein the alkyl, cycloalkyl, aryl, hetaryl and hetarylalkyl groups independently are optionally substituted with one or more of R 7 ;
  • R 4 is hydrogen, CrC 8 alkyl, d-Cealkyloxyd-Cealkyl, aryl, hetaryl, arylCrC 6 alkyl, arylC C 6 alkyloxyCrC 6 alkyl, C 3 -C.
  • R 5 is hydrogen
  • R 6 is adamantyl optionally substituted with hydroxy, d-C 6 alkyloxy, aryl, arylCrCealkyl, aryloxy, arylCrCealkyloxy, hetaryl, hetaryloxy or hetarylCrCealkyloxy wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 7 ; or
  • R 5 and R 6 are together with the nitrogen to which they are attached, forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 5 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-Cealkyl, aryl, hetaryl, aryld- C 6 alkyl, hetarylalkyl, hydroxy, oxo, cyano, CrC 6 alkyloxy, arylCrCealkyloxy, hetaryld- C 6 alkyloxy, d-Cealkyloxyd-Cealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, aryl
  • R 7 are independently hydrogen, halo, hydroxy, oxo, nitro, NR 5 R 6 , cyano, COOR 8 , CONR 5 R 6 , d-C 8 alkyl, d-C 6 alkyloxy, aryloxy or hetaryloxy;
  • R 8 is hydrogen, CrC 6 alkyl, aryl, arylCrC 6 alkyl, hetarylalkyl, wherein the alkyl, aryl and het- arylalkyl groups independently are optionally substituted with one or more of R 7 ; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
  • X is NR 4 or S wherein R 4 is defined as above.
  • X is O. In another embodiment of the present invention, in formula (VIII) X is S. In another embodiment of the present invention, in formula (VIM) is NR 4 wherein R 4 is defined as above. In another embodiment of the present invention, in formula (VIII) R 1 and R 2 independently are hydrogen, halo, trihalomethyl or d-C e alkyl, wherein the alkyl groups independently are optionally substituted with one or more of R 7 .
  • R 3 is hydrogen, d- C 6 alkyl, aryl, aryld-Cealkyl, hetaryl or hetarylalkyl, wherein the alkyl, cycloalkyl, aryl, hetaryl and hetarylalkyl groups independently are optionally substituted with one or more of R 7 .
  • R 4 is hydrogen, d- C 8 alkyl, aryl, hetaryl, hetarylCrCealkyl, arylCrC 6 alkyl, wherein the alkyl, aryl, hetaryl, groups independently are optionally substituted with one or more of R 7 .
  • R 5 and R 6 are to- gether with the nitrogen to which they are attached, forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-Cealkyl, aryl, hetaryl, aryld-Cealkyl, hetarylalkyl, hydroxy, oxo, cyano, d-C 6 alkyloxy, arylCrCealkyloxy, hetarylCrC 6 alkyloxy, d-C 6 alkyloxyCr C 6 alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetaryld- C 6 alkyl,
  • R 5 and R 6 together with the nitrogen to which they are attached, are azepane, azocane, 6-aza- bicyclo[3.2.1]octane, 8-aza-bicyclo[3.2.1]octane, 3-aza-bicyclo[3.2.1]octane, 2-aza- bicyclo[3.2.1]octane, 3-oxa-6-aza-bicyclo[3.2.1]octane, 6-aza-bicyclo[3.2.2]nonane, 3-aza- bicyclo[3.2.2]nonane, 4-aza-tricyclo[4.3.1.1 3,8 ]undecane.
  • the compounds of the general formulas (VIII) or a prodrug thereof is selected from the group consisting of : (4-Methyl-2-phenyl-thiazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone ; (2,4-Dimethyl-thiazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; (4-Methyl-2-pyrazin-2-yl-thiazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone; [4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6- yl)-methanone;
  • the compounds of the general formulas (VIM) or a prodrug thereof is selected from the group consisting of : (1-Methyl-1H-imidazol-4-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; [1-(6-Methyl-pyridin-2-yl)-1H-imidazol-4-yl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone;
  • the compounds of the present invention have asymmetric centers and may occur as racemates, racemic mixtures, and as individual enantiomers or diastereoisomers, with all isomeric forms being included in the present invention as well as mixtures thereof.
  • the present invention also encompasses pharmaceutically acceptable salts of the present compounds.
  • Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, sulphates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hydroxynaph- thoates, glycero
  • compositions include the pharmaceutically acceptable salts listed in J. Pharm. Sci., 66, 2 (1977), which is incorporated herein by reference.
  • metal salts include lithium, sodium, potassium, barium, calcium, magnesium, zinc, calcium salts and the like.
  • amines and organic amines include ammonium, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, propylamine, bu- tylamine, tetramethylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, choline, N,N'-dibenzylethylenediamine, N-benzylphenylethylamine, N- methyl-D-glucamine, guanidine and the like.
  • cationic amino acids include lysine, arginine, histidine and the like.
  • some of the compounds of the present invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of the invention.
  • the pharmaceutically acceptable salts are prepared by reacting a compound of the present invention with 1 to 4 equivalents of a base such as sodium hydroxide, sodium meth- oxide, sodium hydride, potassium fe/f-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, THF, methanol, tet -butanol, dioxane, isopropanol, ethanol etc. Mixtures of solvents may be used. Organic bases like lysine, arginine, diethanolamine, choline, guandine and their derivatives etc. may also be used.
  • acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvents may also be used.
  • acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic
  • stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods.
  • Some of the pre- ferred methods include use of microbial resolution, enzymatic resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or chiral bases such as brucine, ( .)- or (S)-phenylethylamine, cinchona alkaloids and their derivatives and the like.
  • the compound of the present invention may be converted to a 1 :1 mixture of diastereomeric amides by treating with chiral amines, aminoac- ids, aminoalcohols derived from aminoacids; conventional reaction conditions may be employed to convert acid into an amide; the diastereomers may be separated either by fractional crystallization or chromatography and the stereoisomers of compound of formula I may be prepared by hydrolysing the pure diastereomeric amide.
  • polymorphs of the compounds forming part of this invention may be prepared by crystallization of said compounds under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the com- pound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe nmr spectroscopy, ir spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
  • the invention also encompasses prodrugs of the present compounds, which on ad- ministration undergo chemical conversion by metabolic processes before becoming active pharmacological substances.
  • prodrugs will be functional derivatives of the present compounds, which are readily convertible in vivo into the required compound of the present invention.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • esters for instance methyl esters, ethyl esters, tert-butyl, acetoxymethyl, pivaloyloxymethyl esters or other acy- loxymethyl esters.
  • esters for instance methyl esters, ethyl esters, tert-butyl, acetoxymethyl, pivaloyloxymethyl esters or other acy- loxymethyl esters.
  • 'modified compounds' for instance methyl esters, ethyl esters, tert-butyl, acetoxymethyl, pivaloyloxymethyl esters or other acy- loxymethyl esters.
  • the invention also encompasses active metabolites of the present compounds.
  • the compounds according to the invention alter, and more specifically, reduce the level of active intracellular glucocorticoid and are accordingly useful for the treatment, prevention and/or prophylaxis of disorders and diseases in which such a modulation or reduction is beneficial.
  • the present compounds may be applicable for the treatment, prevention and/or prophylaxis of the metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), Latent Autoimmune Diabetes in the Adult (LADA), type 1 diabetes, diabetic late complications including cardiovascular diseases, cardiovascular disorders, disorders of lipid metabolism, neurodegenerative and psychiatric disorders, dysregulation of intraocular pressure including glaucoma, immune disorders, inappropriate immune responses, musculo-skeletal disorders, gastrointestinal disorders, polycystic ovarie syndrome (PCOS), reduced hair growth or other diseases, disorders or conditions that are influenced by intracellular glucocorticoid levels, adverse effects of increased blood levels of active endogenous or exogenous glucocorticoid, and any combination thereof, adverse effects of increased plasma levels of endogenous active glucocorticoid, Cushing's disease, Cushing's syndrome, adverse effects of glucocorticoid receptor agonist treatment of
  • the present compounds may be applicable for the treatment, pre- vention and/or prophylaxis of the metabolic syndrome, type 2 diabetes, diabetes as a consequence of obesity, insulin resistance, hyperglycemia, prandial hyperglycemia, hyperinsuline- mia, inappropriately low insulin secretion, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), increased hepatic glucose production, type 1 diabetes, LADA, pediatric diabetes, dyslipidemia, diabetic dyslipidemia, hyperlipidemia, hypertriglyceridemia, hyperlipopro- teinemia, hypercholesterolemia, decreased HDL cholesterol, impaired LDL/HDL ratio, other disorders of lipid metabolism, obesity, visceral obesity, obesity as a consequence of diabetes, increased food intake, hypertension, diabetic late complications, micro-/macroalbu- minuria, nephropathy, retinopathy, neuropathy, diabetic ulcers, cardiovascular diseases, arteriosclerosis, atherosclerosis, coronary artery disease, cardiac hypertrophy, myocardial ischemia
  • asthma cystic fibrosis, emphysema, bronchitis, hypersensitivity, pneu- monitis, eosinophilic pneumonias, pulmonary fibrosis, adverse effects of glucocorticoid re- ceptor agonist treatment of inflammatory bowel disease such as Crohn's disease and ulcera- tive colitis; adverse effects of glucocorticoid receptor agonist treatment of disorders of the immune system, connective tissue and joints e.g.
  • glucocorticoid receptor agonist treatment of cancer such as spinal cord diseases, neoplastic compression of the spinal cord, brain tumours, acute lym- phoblastic leukemia, Hodgkin's disease, chemotherapy-induced nausea, adverse effects of glucocorticoid receptor agonist treatment of diseases of muscle and at the neuro-muscular joint e.g. myasthenia gravis and heriditary myopathies (e.g. Duchenne muscular dystrophy), adverse effects of glucocorticoid receptor agonist treatment in the context of surgery & trans- plantation e.g.
  • cancer such as spinal cord diseases, neoplastic compression of the spinal cord, brain tumours, acute lym- phoblastic leukemia, Hodgkin's disease, chemotherapy-induced nausea, adverse effects of glucocorticoid receptor agonist treatment of diseases of muscle and at the neuro-muscular joint e.g. myasthenia gravis and heriditary myopathies (e.
  • the invention relates to a compound according to the invention for use as a pharmaceutical composition.
  • the invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound according to the invention together with one or more pharmaceutically acceptable carriers or diluents.
  • the pharmaceutical composition is preferably in unit dosage form, comprising from about 0.05 mg/day to about 2000 mg/day, preferably from about 1 mg/day to about 500 mg/day of a compound according to the invention.
  • the patient is treated with a compound according to the in- vention for at least about 1 week, for at least about 2 weeks, for at least about 4 weeks, for at least about 2 months or for at least about 4 months.
  • the pharmaceutical composition is for oral, nasal, transdermal, pulmonal or parenteral administration.
  • the invention relates to the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of disorders and diseases wherein a modulation or an inhibition of the activity of 11 ⁇ HSDl is beneficial.
  • the invention also relates to a method for the treatment, prevention and/or prophylaxis of disorders and diseases wherein a modulation or an inhibition of the activity of 11 ⁇ HSDl is beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound according to the invention.
  • the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of any diseases and conditions that are influenced by intracellular glucocorticoid levels as mentioned above.
  • the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of conditions and disorders where a decreased level of active intracellular glucocorticoid is desirable, such as the conditions and diseases mentioned above.
  • the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of the metabolic syndrome including insulin resistance, dyslipidemia, hypertension and obesity.
  • the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG).
  • IGT impaired glucose tolerance
  • IGF impaired fasting glucose
  • the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to type 2 diabetes.
  • the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression of the metabolic syndrome into type 2 diabetes.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of diabetic late complications including cardiovascular diseases; arteriosclerosis; atherosclerosis.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of neurodegenerative and psychiatric disorders.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of adverse effects of glucocorticoid receptor agonist treatment or therapy.
  • the route of administration may be any route which effectively transports a compound according to the invention to the appropriate or desired site of action, such as oral, nasal, buccal, transdermal, pulmonai, or parenteral.
  • the present compounds are administered in combination with one or more further active substances in any suitable ratios.
  • Such further active substances may e.g. be selected from antiobesity agents, antidiabetics, agents modifying the lipid metabolism, antihypertensive agents, glucocorticoid receptor agonists, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity.
  • the present compounds may be administered in combination with one or more antiobesity agents or appetite regulating agents.
  • agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotro- pin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, ⁇ 3 agonists, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, se- rotonin re-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors, mixed serotonin and noradrenergic compounds
  • CART cocaine amp
  • the antiobesity agent is leptin; dexamphetamine or amphetamine; fenfluramine or dexfenfluramine; sibutramine; orlistat; mazindol or phen- termine.
  • Suitable antidiabetic agents include insulin, insulin analogues and derivatives such as those disclosed in EP 792290 (Novo Nordisk A/S), e.g. N ⁇ B29 -tetradecanoyl des (B30) human insulin, EP 214 826 and EP 705275 (Novo Nordisk A/S), e.g. Asp B28 human insulin, US 5,504,188 (Eli Lilly), e.g.
  • Lys B28 Pro B29 human insulin EP 368 187 (Aventis), eg Lantus, which are all incorporated herein by reference, GLP-1 (glucagon like peptide-1 ) and GLP-1 derivatives such as those disclosed in WO 98/08871 to Novo Nordisk A/S, which is incorporated herein by reference as well as orally active hypoglycaemic agents.
  • the orally active hypoglycaemic agents preferably comprise sulphonylureas, bigua- nides, meglitinides, glucosidase inhibitors, glucagon antagonists such as those disclosed in WO 99/01423 to Novo Nordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1 agonists, potassium channel openers such as those disclosed in WO 97/26265 and WO 99/03861 to Novo Nordisk A/S which are incorporated herein by reference, DPP-IV (dipeptidyl peptidase- IV) inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, glucose uptake modulators, compounds modifying the lipid metabolism such as antihyperlipidemic agents and antilipidemic agents as PPAR ⁇ modulators, PPAR ⁇ modulators, cholesterol absorption inhibitors, HSL (hormone-sensitive lipase) inhibitors and HMG CoA inhibitors (statins
  • the present compounds are administered in combination with insulin or an insulin analogue or derivative, such as N ⁇ B29 -tetradecanoyl des (B30) human insulin, Asp 628 human insulin, Lys B28 Pro 829 human insulin, Lantus®, or a mix-preparation comprising one or more of these.
  • an insulin analogue or derivative such as N ⁇ B29 -tetradecanoyl des (B30) human insulin, Asp 628 human insulin, Lys B28 Pro 829 human insulin, Lantus®, or a mix-preparation comprising one or more of these.
  • the present compounds are administered in combination with a sulphonylurea e.g. tolbutamide, glibenclamide, glipizide or glicazide.
  • present compounds are administered in combination with a biguanide e.g. metformin.
  • present compounds are administered in combination with a meglitinide e.g. repaglinide or senaglinide.
  • the present compounds are administered in combination with a thiazolidinedione e.g. troglitazone, ciglitazone, pioglitazone, rosiglitazone or compounds disclosed in WO 97/41097 such as 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazo- linyl]methoxy]phenyl-methyl]thiazolidine-2,4-dione or a pharmaceutically acceptable salt thereof, preferably the potassium salt.
  • a thiazolidinedione e.g. troglitazone, ciglitazone, pioglitazone, rosiglitazone or compounds disclosed in WO 97/41097 such as 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazo- linyl]methoxy]phenyl-methyl]thiazolidine-2,4-dione or
  • the present compounds may be administered in combination with the insulin sensitizers disclosed in WO 99/19313 such as (-) 3-[4-[2-Phenoxazin- 10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid or a pharmaceutically acceptable salts thereof, preferably the arginine salt.
  • the insulin sensitizers disclosed in WO 99/19313 such as (-) 3-[4-[2-Phenoxazin- 10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid or a pharmaceutically acceptable salts thereof, preferably the arginine salt.
  • the present compounds are administered in combination with an ⁇ -glucosidase inhibitor e.g. miglitol or acarbose.
  • an ⁇ -glucosidase inhibitor e.g. miglitol or acarbose.
  • the present compounds are administered in combination with an, agent acting on the ATP-dependent potassium channel of the ⁇ -cells e.g. tolbu- tamide, glibenclamide, glipizide, glicazide or repaglinide.
  • an, agent acting on the ATP-dependent potassium channel of the ⁇ -cells e.g. tolbu- tamide, glibenclamide, glipizide, glicazide or repaglinide.
  • the present compounds may be administered in combination with nateglinide.
  • the present compounds are administered in combination with an antihyperlipidemic agent or antilipidemic agent e.g. cholestyramine, colestipol, clofi- brate, gemfibrozil, fenofibrate, bezafibrate, tesaglitazar, EML-4156, LY-818, MK-767, ator- vastatin, fluvastatin, lovastatin, pravastatin, simvastatin, acipimox, probucol, ezetimibe or dextrothyroxine.
  • an antihyperlipidemic agent or antilipidemic agent e.g. cholestyramine, colestipol, clofi- brate, gemfibrozil, fenofibrate, bezafibrate, tesaglitazar, EML-4156, LY-818, MK-767, ator- vastatin, fluvastatin, lovastatin, pravastatin,
  • the present compounds are administered in combination with more than one of the above-mentioned compounds e.g. in combination with a sulphony- lurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin, insulin and lovastatin, etc.
  • the present compounds may be administered in combination with one or more antihypertensive agents.
  • antihypertensive agents are ⁇ -blockers such as alprenolol, atenolol, timolol, pindolol, propranolol, metoprolol, bisoprololfumerate, esmolol, acebutelol, metoprolol, acebutolol, betaxolol, celiprolol, nebivolol, tertatolol, oxprenolol, amusolalul, carvedilol, labetalol, ⁇ 2-receptor blockers e.g.
  • S-atenolol, OPC-1085, ACE (angiotensin converting enzyme) inhibitors such as quinapril, lisinopril, enalapril, captopril, benazepril, perindopril, trandolapril, fosinopril, ramipril, cilazapril, delapril, imidapril, moexipril, spirapril, temocapril, zofenopril, S-5590, fasidotril, Hoechst-Marion Roussel: 100240 (EP 00481522), omapatrilat, gemopatrilat and GW-660511 , calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem, amlodipine, nitrendipine
  • loop-diuretics e.g. bumetanide, furosemide and torasemide
  • potassium sparing diuretics e.g. amiloride, spironolactone
  • endothelin ET-A antagonists such as ABT-546, ambrisetan, atrasentan, SB- 234551, CI-1034, S-0139 and YM-598
  • endothelin antagonists e.g. bosentan and J-104133
  • renin inhibitors such as aliskiren, vasopressin V1 antagonists e.g.
  • vasopressin V2 antagonists such as tolvaptan, SR-121463 and OPC-31260
  • B-type natriuretic peptide agonists e.g. Nesiritide, angiotensin II antagonists such as irbesartan, candesartancilexetil, losartan, valsartan, telmisartan, eprosartan, candesartan, CL-329167, eprosartan, iosartan, olmesartan, pratosartan, TA-606, and YM-358, 5-HT2 agonists e.g.
  • adenosine A1 antagonists such as naftopidil, N-0861 and FK-352
  • thromboxane A2 antagonists such as KT2-962
  • endopeptidase inhibitors e.g. ecadotril
  • nitric oxide agonists such as LP-805
  • dopamine D1 antagonists e.g. MYD-37
  • dopamine D2 agonists such as nolomirole, n-3 fatty acids e.g. omacor
  • prostacyclin agonists such as treprostinil, beraprost
  • PGE1 agonists e.g.
  • ecraprost Na+/K+ ATPase modulators e.g. PST-2238, Potassium channel activators e.g. KR-30450, vaccines such as PMD-3117, Indapamides, CGRP- unigene, guanylate cyclase stimulators, hydralazines, methyldopa, docarpamine, moxo- nidine, CoAprovel, MondoBiotech-811.
  • the present compounds may be administered in combination with one or more glucocorticoid receptor agonists.
  • glucocorticoid receptor agonists examples include betametasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, beclomethasone, butixicort, clobetasol, flunisolide, flucatisone (and analogues), momethasone, triamcinolonacetonide, triamcinolonhexacetonide GW-685698, NXC-1015, NXC-1020, NXC-1021, NS-126, P-4112, P-4114, RU-24858 and T-25 series. It should be understood that any suitable combination of the compounds according to the invention with one or more of the above-mentioned compounds and optionally one or more further pharmacologically active substances are considered to be within the scope of the present invention.
  • the compounds ofthe present invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses.
  • the pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and ex- cipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy,19 th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
  • compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
  • Pharmaceutical compositions for oral administration include solid dosage forms such as hard or soft capsules, tablets, troches, dragees, pills, lozenges, powders and granules.
  • Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
  • compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use.
  • De- pot injectable formulations are also contemplated as being within the scope of the present invention.
  • a typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages.
  • the exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
  • a typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain from 0.05 to about 2000 mg, e.g. from about 0.1 to about 1000 mg, from about 0.5 mg to about 500 mg., from about 1 mg to about 200 mg, e.g. about 100 mg.
  • parenteral routes such as intravenous, intrathecal, intramuscular and similar administration
  • typically doses are in the order of about half the dose employed for oral administra- tion.
  • the compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof.
  • examples are an acid addition salt of a compound having the utility of a free base and a base addition salt of a compound having the utility of a free acid.
  • pharmaceutically acceptable salts refers to non-toxic salts of the com- pounds for use according to the present invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid or by reacting the acid with a suitable organic or inorganic base.
  • a compound for use according to the present invention contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of the compound with a chemical equivalent of a pharmaceutically acceptable acid.
  • salts are prepared in a conventional manner by treating a solution or suspension of the compound with a chemical equivalent of a pharmaceutically acceptable base.
  • Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion.
  • Other salts which are not pharmaceutically acceptable may be useful in the preparation of compounds for use according to the present invention and these form a further aspect of the present invention.
  • solutions of the present compounds in sterile aqueous solution aqueous propylene glycol or sesame or peanut oil may be employed.
  • aqueous solutions should be suitable buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, syrup, phospholipids, gelatine, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaery-hritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
  • compositions formed by combining the compounds of the inven- tion and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
  • the formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.
  • compositions intended for oral use may be prepared according to any known method, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents, and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically-acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulat- ing and disintegrating agents, for example corn starch or alginic acid; binding agents, for example, starch, gelatine or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyc- eryl distearate may be employed. They may also be coated by the techniques described in U.S. Patent Nos. 4,356,108; 4,166,452; and 4,265,874, incorporated herein by reference, to form osmotic therapeutic tablets for controlled release.

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Abstract

The use of substituted amides for modulating the activity of 11 β-hydroxysteroid dehydrogenase type 1 (11 βHSD1) and the use of these compounds as pharmaceutical compositions, are described. Also a novel class of substituted amides, their use in therapy, pharmaceutical compositions comprising the compounds, as well as their use in the manufacture of medicaments are described. The present compounds are modulators and more specifically inhibitors of the activity of 11 βHSD1 and may be useful in the treatment, prevention and/or prophylaxis of a range of medical disorders where a decreased intracellular concentration of active glucocorticoid is desirable.

Description

PHARMACEUTICAL USE OF SUBSTITUTED AMIDES
FIELD OF INVENTION
The present invention relates to use of substituted amides and pharmaceutical compositions comprising the compounds for treating disorders where it is desirable to modulate the activity of 11 β-hydroxysteroid dehydrogenase type 1 (11 βHSDl ).
The present invention also relates to novel substituted amides, to their use in therapy, to pharmaceutical compositions comprising the compounds, to the use of said compounds in the manufacture of medicaments, and to therapeutic methods comprising the administration of said compounds. The present compounds modulate the activity of 11 β- hydroxysteroid dehydrogenase type 1 (11 βHSDl) and are accordingly useful in the treatment of diseases in which such a modulation is beneficial, such as the metabolic syndrome.
BACKGROUND OF THE INVENTION
The metabolic syndrome is a major global health problem. In the US, the prevalence in the adult population is currently estimated to be approximately 25%, and it continues to increase both in the US and worldwide. The metabolic syndrome is characterised by a combination of insulin resistance, dyslipidemia, obesity and hypertension leading to increased morbidity and mortality of cardiovascular diseases. People with the metabolic syndrome are at increased risk of developing frank type 2 diabetes, the prevalence of which is equally escalating. In type 2 diabetes, obesity and dyslipidemia are also highly prevalent and around
70% of people with type 2 diabetes additionally have hypertension once again leading to increased mortality of cardiovascular diseases.
In the clinical setting, it has long been known that glucocorticoids are able to induce all of the cardinal features of the metabolic syndrome and type 2 diabetes. 11 β-hydroxysteroid dehydrogenase type 1 (11 βHSDl) catalyses the local generation of active glucocorticoid in several tissues and organs including predominantly the liver and adipose tissue, but also e.g. skeletal muscle, bone, pancreas, endothelium, ocular tissue and certain parts of the central nervous system. Thus, 11 βHSDl serves as a local regulator of glucocorticoid actions in the tissues and organs where it is expressed (Tannin et al., J. Biol. Chem., 266, 16653 (1991 ); Bujalska et al., Endocrinology, 140, 3188 (1999); Whorwood et al., J Clin Endocrinol Metab., 86, 2296 (2001); Cooper et al., Bone, 27, 375 (2000); Davani et al., J. Biol. Chem., 275, 34841 (2000); Brem et al., Hypertension, 31, 459 (1998); Rauz et al., Invest. Ophthalmol. Vis. Sci., 42, 2037 (2001); Moisan et al., Endocrinology, 127, 1450 (1990)).
The role of 11 βHSDl in the metabolic syndrome and type 2 diabetes is supported by several lines of evidence. In humans, treatment with the non-specific 11 βHSDl inhibitor carbenoxolone improves insulin sensitivity in lean healthy volunteers and people with type 2 diabetes. Likewise, 11 βHSDl knock-out mice are resistant to insulin resistance induced by obesity and stress. Additionally, the knock-out mice present with an anti-atherogenic lipid profile of decreased VLDL triglycerides and increased HDL-cholesterol. Conversely, mice that overexpress 11 βHSDl in adipocytes develop insulin resistance, hyperlipidemia and vis- ceral obesity, a phenotype that resembles the human metabolic syndrome (Andrews et al., J. Clin. Endocrinol. Metab., 88, 285 (2003); Walker et al., J. Clin. Endocrinol. Metab., 80, 3155 (1995); Morton et al., J. Biol. Chem., 276, 41293 (2001); Kotelevtsev et al., Proc. Natl. Acad. Sci. USA, 94, 14924 (1997); Masuzaki et al., Science, 294, 2166 (2001)).
The more mechanistic aspects of 11 βHSDl modulation and thereby modulation of intracellular levels of active glucocorticoid have been investigated in several rodent models and different cellular systems. 11 βHSDl promotes the features ofthe metabolic syndrome by increasing hepatic expression of the rate-limiting enzymes in gluconeogenesis, namely phosphoenolpyuvate carboxykinase and glucose-6-phosphatase, promoting the differentiation of preadipocytes into adipocytes thus facilitating obesity, directly and indirectly stimulat- ing hepatic VLDL secretion, decreasing hepatic LDL uptake and increasing vessel contractility (Kotelevtsev et al., Proc. Natl. Acad. Sci. USA, 94, 14924(1997); Morton et al., J. Biol. Chem. 276, 41293 (2001); Bujalska et al., Endocrinology, 140, 3188 (1999); Souness et al., Steroids, 67, 195 (2002), Brindley & Salter, Prog. Lipid Res., 30, 349 (1991)).
WO 01/90090, WO 01/90091, WO 01/90092, WO 01/90093 and WO 01/90094 dis- closes various thiazol-sulfonamides as inhibitors of the human 11 β-hydroxysteroid dehydrogenase type 1 enzyme, and further states that said compounds may be useful in treating diabetes, obesity, glaucoma, osteoporosis, cognitive disorders, immune disorders and depression.
We have now found substituted amides that modulate the activity of 11 βHSDl lead- ing to altered intracellular concentrations of active glucocorticoid. More specifically, the present compounds inhibit the activity of 11 βHSDl leading to decreased intracellular concentrations of active glucocorticoid. Thus, the present compounds can be used to treat disorders where a decreased level of active intracellular glucocorticoid is desirable, such as e.g. the metabolic syndrome, type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glu- cose (IFG), dyslipidemia, obesity, hypertension, diabetic late complications, cardiovascular diseases, arteriosclerosis, atherosclerosis, myopathy, muscle wasting, osteoporosis, neurodegenerative and psychiatric disorders, and adverse effects of treatment or therapy with glucocorticoid receptor agonists. One object of the present invention is to provide compounds, pharmaceutical compositions and use of compounds that modulate the activity of 11 βHSDl .
DEFINITIONS
In the following structural formulas and throughout the present specification, the following terms have the indicated meaning: The term "halo" includes fluorine, chlorine, bromine, and iodine.
The term "trihalomethyl" includes trifluoromethyl, trichloromethyl, tribromomethyl, and triiodomethyl.
The term "trihalomethoxy" includes trifluorometoxy, trichlorometoxy, tribromometoxy, and triiodometoxy. The term "alkyl" includes C^Cs straight chain saturated and methylene aliphatic hydrocarbon groups, C3-C8 branched saturated hydrocarbon groups having the specified number of carbon atoms. For example, this definition shall include but is not limited to methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu), pentyl, hexyl, isopropyl (i-Pr), isobutyl (i-Bu), terf-butyl (--Bu), sec-butyl (s-Bu), isopentyl, neopentyl, and the like. The term "alkenyl" includes C2-C6 straight chain unsaturated aliphatic hydrocarbon groups and branched C3-C6 unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, this definition shall include but is not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl, methylpropenyl, methylbutenyl and the like. The term "alkynyl" includes C2-C6 straight chain unsaturated aliphatic hydrocarbon groups and C -C6 branched unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, this definition shall include but is not limited to ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylbutynyl, and the like.
The term "saturated or partially saturated cyclic, bicyclic or tricyclic ring system" represents but are not limit to aziridinyl, azepanyl, azocanyl, pyrrolinyl, pyrrolidinyl, 2- imidazolinyl, imidazolidinyl, 2-pyrazoIinyl, morpholinyl, piperidinyl, thiomorpholinyl, piperaz- inyl, phthalimide, 1,2,3,4-tetrahydro-quinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, 1,2,3,4- tetrahydro-quinoxalinyl, indolinyl, 1, 6-aza-bicyclo[3.2.1]octane, 2-aza-bicyclo[4.1.1]octane, 2-aza-bicyclo[3.2.1]octanyl, 7-aza-bicyclo[4.1.1]octanyl, 9-aza-bicyclo[3.3.2]decanyl, 4-aza- tricyclo[4.3.1.13,8]undecanyl, 9-aza-tricyclo[3.3.2.03,7]decanyl. The term "saturated or partially saturated cyclic ring system" represents but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclo- hexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, tetrahydrofuranyl ortetra- hydropyranyl. The term "saturated or partially saturated aromatic ring system" represents but are not limited to cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridyl or pyrimidinyl.
The term "cycloalkyl" (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohep- tyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo[3.2.1]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl and the like) represents a saturated, mono-, bi-, tri- or spirocarbocyclic group having the specified number of carbon atoms.
The term "cycloalkylalkyl" (e.g. cyclopropylmethyl, cyclobutylethyl, adamantylmethyl and the like) represents a cycloalkyl group as defined above attached through an alkyl group having the indicated number of carbon atoms or substituted alkyl group as defined above.
The term "cycloalkenyl" (e.g. cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl and the like) represents a partially saturated, mono-, bi-, tri- or spirocarbocyclic group having the specified number of carbon atoms.
The term "cycloalkylcarbonyl" (e.g. cyclopropylcarbonyl, cyclohexylcarbonyl) repre- sents an cycloalkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group.
The term "hetcycloalkylcarbonyl" (e.g. 1-piperidin-4-yl-carbonyl, 1 -(1,2,3,4- tetrahydro-isoquinolin-6-yl)carbonyl) represents an hetcycloalkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group. The term "cycloalkylalkylcarbonyl" (e.g. cyclohexylmethylcarbonyl, cycloheptylethyl- carbonyl and the like) represents a cycloalkyl group as defined above attached through an alkyl group having the indicated number of carbon atoms or substituted alkyl group as defined above.
The term "hetcycloalkyl" (tetrahydrofuranyl, tetrahydropyranyl, tertahydrothiopyranyl, piperidine, pyridzine and the like) represents a saturated mono-, bi-, tri- or spirocarbocyclic group having the specified number of carbon atoms and one or two additional heteroatoms or groups selected from nitrogen, oxygen, sulphur, SO or S02.
The term "hetcycloalkylalkyl" (e.g. tetrahydrofuranylmethyl, tetrahydropyranylethyl, tertahydrothiopyranylmethyl, and the like) represents a hetcycloalkyl group as defined above attached through an alkyl group having the indicated number of carbon atoms or substituted alkyl group as defined above.
The term "alkyloxy" (e.g. methoxy, ethoxy, propyloxy, allyloxy, cyclohexyloxy) represents an alkyl group as defined above having the indicated number of carbon atoms attached through an oxygen bridge.
The term "alkyloxyalkyl" (e.g. methyloxymethyl and the like) represents an alkyloxy group as defined above attached through an "alkyl" group.
The term "aryloxyhetaryl" (e.g. 2-phenoxy-pyridyl and the like) represents an aryloxy group as defined below attached through a "hetaryl" group. The term "aryloxy" (e.g. phenoxy, naphthyloxy and the like) represents an aryl group as defined below attached through an oxygen bridge.
The term "hetaryloxy" (e.g. 2-pyridyloxy and the like) represents a hetaryl group as defined below attached through an oxygen bridge.
The term "arylalkyloxy" (e.g. phenethyloxy, naphthylmethyloxy and the like) repre- sents an arylalkyl group as defined below attached through an oxygen bridge.
The term "hetarylalkyloxy" (e.g. 2-pyridylmethyloxy and the like) represents a hetary- lalkyl group as defined below attached through an oxygen bridge.
The term "alkyloxycarbonyl" (e.g. methylformiat, ethylformiat and the like) represents an alkyloxy group as defined above attached through a carbonyl group. The term "aryloxycarbonyl" (e.g. phenylformiat, 2-thiazolylformiat and the like) represents an aryloxy group as defined above attached through a carbonyl group.
The term "arylalkyloxycarbonyl" (e.g. benzylformiat, phenyletylformiat and the like) represents an "arylalkyloxy" group as defined above attached through a carbonyl group.
The term "alkylthio" (e.g. methylthio, ethylthio and the like) represents an alkyl group as defined above attached through a sulphur bridge.
The term "arylthio" (e.g. benzenthiol, naphthylthiol and the like) represents an aryl group as defined below attached through a sulphur bridge.
The term "hetarylthio" (e.g. pyridine-2-thiol, thiazole-2-thiol and the like) represents an hetaryl group as defined below attached through a sulphur bridge. The term "arylthioalkyl" (e.g. methylsulfanyl benzene, ethylsulfanyl naphthalene and the like) represents an arylthio group as defined below attached through an alkyl group having the indicated number of carbon atoms.
The term "hetarylthioalkyl" (e.g. 2-methylsulfanyl-pyridine, 1-ethylsulfanyl-isoquino- line and the like) represents a hetarylthio group as defined below attached through an alkyl group having the indicated number of carbon atoms. The term "hetaryloxyaryl" (e.g. 1-phenoxy-isoquinolyl, 2-phenoxypyridyl and the like) represents a hetaryloxy group as defined above attached through an "aryl" group as defined below.
The term "hetaryloxyhetaryl" (e.g. 1-(2-pyridyloxy-isoquinoline), 2-(imidazol-2-yloxy- pyridine) and the like) represents a hetaryloxy group as defined above attached through a "hetaryl" group as defined below.
The term "aryloxyalkyl" (e.g. phenoxymethyl, naphthyloxyethyl and the like) represents an aryloxy group as defined above attached through an "alkyl" group having the indicated number of carbon atoms. The term "aryloxyaryl" (e.g. 1-phenoxy-naphthalene, phenyloxyphenyl and the like) represents an aryloxy group as defined above attached through an "aryl" group as defined below.
The term "arylalkyloxyalkyl" (e.g. ethoxymethyl-benzene, 2-methoxymethyl- naphthalene and the like) represents an arylalkyloxy group as defined above attached through an "alkyl" group having the indicated number of carbon atoms.
The term "hetaryloxyalkyl" (e.g. 2-pyridyloxymethyl, 2-quinolyloxyethyl and the like) represents a hetaryloxy group as defined above attached through an "alkyl" group having the indicated number of carbon atoms.
The term "hetarylalkyloxyalkyl" (e.g. 4-methoxymethyl-pyrimidine, 2-methoxymethyl- quinoline and the like) represents a hetarylalkyloxy group as defined above attached through an "alkyl" group having the indicated number of carbon atoms.
The term "arylalkyl" (e.g. benzyl, phenylethyl, 3-phenylpropyl, 1-naphtylmethyl, 2-(1- naphtyl)ethyl and the like ) represents an aryl group as defined below attached through an alkyl having the indicated number of carbon atoms or substituted alkyl group as defined above.
The term "hetarylalkyl" or "hetaralkyl" (e.g. (2-furyl)methyl, (3-furyl)methyl, (2- thienyl)methyl, (3-thienyl)methyl, (2-pyridyl)methyl, 1-methyl-1-(2-pyrimidyl)ethyl and the like) represents a hetaryl group as defined below attached through an alkyl having the indicated number of carbon atoms or substituted alkyl group as defined above. The term "alkylcarbonyl" (e.g. octylcarbonyl, pentylcarbonyl, 3-hexenylcarbonyl) represents an alkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group.
The term "arylcarbonyl" (e.g. benzoyl) represents an aryl group as defined below attached through a carbonyl group. The term "hetarylcarbonyl" (e.g. 2-thiophenylcarbonyl, 3-methoxy-anthrylcarbonyl, oxazolylcarbonyl and the like) represents a hetaryl group as defined below attached through a carbonyl group.
The term "carbonylalkyl" (e.g. acetyl and the like) represents a carbonyl group at- tached through alkyl group as defined above having the indicated number of carbon atoms.
The term "alkylcarbonylalkyl" (e.g. propan-2-one, 4,4-dimethyl-pentan-2-one and the like) represents an alkylcarbonyl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term "arylcarbonylalkyl" (e.g. 1-phenyl-propan-1-one, 1-(3-chloro-phenyl)-2- methyl-butan-1-one and the like) represents a arylcarbonyl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term "hetarylcarbonylalkyl" (e.g. 1-pyridin-2-yl-propan-1-one, 1-(1-H-imidazol-2- yl)-propan-1-one and the like) represents a hetarylcarbonyl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms. The term "arylalkylcarbonyl" (e.g. phenylpropylcarbonyl, phenylethylcarbonyl and the like) represents an arylalkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group.
The term "hetarylalkylcarbonyl" (e.g. imidazolylpentylcarbonyl and the like) represents a hetarylalkyl group as defined above wherein the alkyl group is in turn attached through a carbonyl.
The term "alkylcarbonylamino" (e.g. methylcarbonylamino, cyclopentylcarbonyl- aminomethyl, methylcarbonylaminophenyl) represents an "alkylcarbonyl" group as defined above wherein the carbonyl is in turn attached through the nitrogen atom of an amino group. The nitrogen atom may itself be substituted with an alkyl or aryl group. The term "alkylcarbonylaminoalkyl" (e.g.N-propyl-acetamide, N-butyl-propionamide and the like) represents an "alkylcarbonylamino" group attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term "arylalkylcarbonylamino" (e.g. phenylacetamide, 3phenyl-propionamide and the like) represents an "arylalkylcarbonyl" group as defined above attached through an amino group.
The term "arylalkylcarbonylaminoalkyl" (e.g. N-ethyl-phenylacetamide, N-butyl-3- phenyl-propionamide and the like) represents an "arylalkylcarbonylamino" group attached through an alkyl group as defined above having the indicated number of carbon atoms. The term "arylcarbonylamino" (e.g. benzamide, naphthalene-1 -carboxylic acid amide and the like) represents an "arylcarbonyl" group as defined above attached through an amino group.
The term "arylcarbonylaminoalkyl" (e.g. N-propyl-benzamide, N-Butyl-naphthalene- 1 -carboxylic acid amide and the like) represents an "arylcarbonylamino" group attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term "alkylcarboxy" (e.g. heptylcarboxy, cyclopropylcarboxy, 3-pentenylcarboxy) represents an alkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge. The term "arylcarboxy" (e.g. benzoic acid and the like) represents an arylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
The term "alkylcarboxyalkyl" (e.g. heptylcarboxymethyl, propylcarboxy tert-butyl, 3- pentylcarboxyethyl) represents an
The term "arylalkylcarboxy" (e.g. benzylcarboxy, phenylpropylcarboxy and the like) represents an arylalkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
The term "arylalkylcarboxyalkyl" (e.g. benzylcarboxymethyl, phenylpropylcar- boxypropyl and the like) represents an arylalkylcarboxy group as defined above wherein the carboxy group is in turn attached through an alkyl group as defined above having the indi- cated number of carbon atoms.
The term "hetarylcarboxy" (e.g. pyridine-2-carboxylic acid and the like) represents a hetarylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
The term "hetarylalkylcarboxy" (e.g. (1-H-imidazol-2-yl)-acetic acid, 3-pyrimidin-2-yl- propionic acid and the like) represents a hetarylalkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
The term "aryl" includes but is not limited to a carbocyclic aromatic ring system being either monocyclic, bicyclic, or polycyclic, such as phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl and the like. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic aromatic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1 ,2,3,4-tetrahydronaphthyl, ,4-dihydronaphthyl and the like.
The term "aryll" includes phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, and fluorenyl. The term "aryl2" includes phenyl, biphenyl, and naphthyl. The term "hetaryl" includes but is not limited to pyrrolyl (2-pyrrolyl), pyrazolyl (3- pyrazolyl), imidazolyl (1 -imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3- triazol-1-yl, 1 ,2,3-triazol-2-yl 1 ,2,3-triazol-4-yl, 1 ,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4- oxazolyl, 5-oxazolyl), isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiophenyl (2-thiophenyl, 3-thiophenyl, 4-thiophenyl, 5-thiophenyl), furanyl (2-furanyl, 3-furanyl, 4-furanyl, 5-furanyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl, 5- pyridyl), 5-tetrazolyl, pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3- quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1 -isoquinolyl, 3- isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), ben- zo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6- benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-ben- zo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro- benzo-[b]furanyl), 6-(2,3-dihydro-benzo-[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl)), benzo[b]thiophenyl (2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5- benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiop- henyl (2-(2,3-dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-di- hydrobenzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thio- phenyl), 7-(2,3-dihydro-benzo[b]thiophenyl)), 4,5,6,7-tetrahydro-benzo[b]thiophenyl (2- (4,5,6,7-tetrahydro-benzo[b]thiophenyl), 3-(4,5,6,7-tetrahydro-benzo[b]thiophenyl), 4-(4,5,6,7- tetrahydro-benzo[b]thiophenyl), 5-(4,5,6,7-tetrahydro-benzo[b]thiophenyl), 6-(4,5,6,7-tetra- hydro-benzo[b]thiophenyl), 7-(4,5,6,7-tetrahydro-benzo[b]thiophenyl)), thieno[2,3-b]thio- phenyl, 4,5,6,7-tetrahydro-thieno[2,3-c]pyridyl (4-(4,5,6,7-tetrahydro-thieno[2,3-c]pyridyl), 5- 4,5,6,7-tetrahydro-thieno[2,3-c]pyridyl), 6-(4,5,6,7-tetrahydro-thieno[2,3-c]pyridyl), 7-(4,5,6,7- tetrahydro-thieno[2,3-c]pyridyl)), indolyl (1 -indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6- indolyl, 7-indolyl), isoindolyl (1-isoindolyl, 2-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl), 1 ,3-dihydro-isoindolyl (1-(1,3-dihydro-isoindolyl), 2-(1 ,3-dihydro- isoindolyl), 3-(1 ,3-dihydro-isoindolyl), 4-(1 ,3-dihydro-isoindolyl), 5-(1 ,3-dihydro-isoindolyl), 6- (1 ,3-dihydro-isoindolyl), 7-(1 ,3-dihydro-isoindolyl)), indazole (1-indazolyl, 3-indazolyl, 4- indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1 -benzimidazolyl, 2-benz- imidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8- benzimidazolyl), benzoxazolyl (1-benz-oxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzo- thiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzo- thiazolyl), benzo-[1 ,2,5]oxadiazolyl, (4-benzo[1 ,2,5]oxadiazole, 5-benzo[1 ,2,5]oxadiazole), carbazolyl (1-carbazolyl, 2-carbazoIyl, 3-carbazolyl, 4-carbazolyl), piperidinyl (2-piperidinyl, 3- piperidinyl, 4-piperidinyl), pyrrolidinyl (1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl).
The term "alkylSOm" (e.g. ethylsulfonyl, ethylsulfinyl and the like) represents an alkyl group as defined above, wherein the alkyl group is in turn attached through a sulphur bridge wherein the sulphur is substituted with m oxygen atoms.
The term "arylSOm" (e.g. phenylsulfinyl, naphthyl-2-sulfonyl and the like) represents an aryl group as defined above, wherein the aryl group is in turn attached through a sulphur bridge wherein the sulphur is substituted with m oxygen atoms.
The term "hetarylSOm" (e.g. thiazol-2-sulfinyl, pyridine-2-sulfonyl and the like) repre- sents a hetaryl group as defined above, wherein the hetaryl group is in turn attached through a sulphur bridge wherein the sulphur is substituted with m oxygen atoms.
With respect to formula I and II, the term "NR4R5carbonylalkyl" (e.g. /V./V-dimethyl- propionamide, Λ/-isopropyl-W-methyl-propionamide and the like) represents NR R5 substituted by a carbonylalkyl group as defined above. With respect to formula I and II, the term "alkylR6alkyl" (e.g. 2-ethoxymethyl, N-ethyl-
N-methy amine, methyl-propyl-amide, ethanesulfonic acid methylamide and the like) represents an alkyl group as defined above, substituted by R6, which is substituted by an alkyl group as defined above.
With respect to formula I and II, the term "arylR6alkyl" (e.g. ethoxy-benzene, N-ethyl- N-methyl-phenyl-amine, Λ/-ethyl-benzamide, Λ/-isobutyl-benzenesulfonamide and the like) represents an aryl group as defined above, substituted by R6, which is substituted by an alkyl group as defined above.
With respect to formula I and II, the term "arylalkylR6alkyl" (e.g. benzyloxymethyl, N- ethyl-N-methyl-benzyl-amine, /V-ethyl-benzylamide and the like) represents an arylalkyl group as defined above, substituted by R6, which is substituted by an alkyl group as defined above.
With respect to formula I and II, the term "hetarylR6alkyl" (e.g. 2-ethoxy-1r7-imidazol, ethyl-quinolin-2-yl-amine, thiazole-2-carboxylic acid, methyl-propyl-amide, pyridine-3-sulfonic acid isobutyl-amide and the like) represents a hetaryl group as defined above, substituted by R6, which is substituted by an alkyl group as defined above.
With respect to formula I and II, the term "arylcarbonylNR15" (e.g. /V-benzyl-Λ/- methyl-benzamide and the like) represents an arylcarbonyl group as defined above, substituted by NR15.
With respect to formula I and II, the term "arylSOmNR8" (e.g. Λ/-methyl-benzene- sulfonamide and the like) represents an aryl group as defined above, wherein the aryl group is in turn attached through a SOmNR8 group wherein the sulphur is substituted with m oxygen atoms and the nitrogen atom substituted by R8.
With respect to formula III, the term "alkylNR5alkyl" (e.g. N-ethyl-N-isobutyl-amine, N,N-dimethylamine and the like wherein the amino group (N) is substituted with R5 as de- fined below) represents an alkylNR5 group as defined above attached through an "alkyl" group.
With respect to formula III, the term "arylalkylNR5alkyl" (e.g. N-benzyl-N-methyl- amine, N-phenethyl-N-ethyl-amine and the like wherein the amino group (N) is substituted • with R5 as defined below) represents an arylalkylNR5 group as defined above attached through an "alkyl" group.
Certain of the above defined terms may occur more than once in the structural formulae, and upon such occurrence each term shall be defined independently of the other.
The term "optionally substituted" as used herein means that the groups in question are either unsubstituted or substituted with one or more of the substituents specified. When the groups in question are substituted with more than one substituent, the substituents may be the same or different.
The term "treatment" is defined as the management and care of a patient for the purpose of combating or alleviating the disease, condition or disorder, and the term includes the administration of the active compound to prevent the onset of the symptoms or complica- tions, or alleviating the symptoms or complications, or eliminating the disease, condition, or disorder.
The term "pharmaceutically acceptable" is defined as being suitable for administration to humans without adverse events.
The term "prodrug" is defined as a chemically modified form of the active drug, said prodrug being administered to the patient and subsequently being converted to the active drug. Techniques for development of prodrugs are well known in the art.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present invention provides the use of a substituted amide, a pro- drug thereof, or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms for a) modulation of the activity of 11 βHSDl ;or b) inhibition of 11 βHSDl, in a patient in need thereof. In another aspect, the present invention provides the use of a substituted amide, a prodrug thereof, or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of any disorder and disease where it is desirable to a) modulate the activity of 11 βHSDl ; or b) inhibit 11βHSD1, in a patient in need thereof.
In another embodiment, the invention provides the present use of substituted am- ides, or a prodrug thereof of the general formula (I)
O
R3/% R1
R2 R (I) wherein
R1 is C3-C10cycloalkyl, C3-Cι0hetcycloalkyl, d-C8alkyl, aryl, hetaryl, arylCrC6alkyl or hetarylCι-C6alkyl, wherein the cycloalkyl, hetcycloalkyl, alkyl, arylalkyl and hetarylalkyl groups independently are optionally substituted with one or more of R4.
R2 is hydrogen, CrC8alkyl, aryl, hetaryl, arylCrCealkyl, Cs-docycloalkyld-Cealkyl, C C6alkyl-carboxyCrC6alkyl wherein the alkyl, aryl and cycloalkyl groups independently are optionally substituted with one or more of R5; or
R1 and R2 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrCealkyl, aryl, hetaryl, arylC C6alkyl, hetarylCι-C6alkyl, hydroxy, oxo, cyano, d-C6alkyloxy, aryld-Cealkyloxy, hetaryld- C6alkyloxy, d-Cealkyloxyd-Cealkyl, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkylcarbonyl, hetarylCrC6alkylcarbonyl, d-C6alkylcarboxy, arylcarboxy or aryld- C6alkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R14;
R3 is CrC8alkyl, C C6alkenyl, d-C6alkynyl, C3-C10cycloalkyl, C3-C10hetcycloalkyl, aryl, hetaryl, arylCrCealkyl, d-CealkyloxyCi-Cealkyl, hetarylCrC6alkyl, aryl-R6-CrC6alkyl, hetaryl- R6-d-C6alkyl or arylCι-C6alkyl-R6-C.-C6alkyl wherein the alkyl, cycloalkyl, hetcycloalkyl, al- kenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R7;
R4 and R5 independently are hydrogen, hydroxy, oxo, cyano, halo, methylendioxo, NR8R9, d-C8alkyl, C C6alkyloxy, trihalomethyl, trihalomethyloxy, C3-C10cycloalkyl, C3-C10hetcyclo- alkyl, C3-Cι0cycloalkenyl, aryl, hetaryl, hetarylSOn, arylCrC6alkyloxy, hetaryld-C6alkyloxy, C.-C6alkyl-R6-d-C6alkyl, aryld-C-ealkyl-R^d-Cealkyl, C C6alkylcarbonyl, arylcarbonyl, aryld-C6alkylcarbonyl, hetarylcarbonyl, hetarylC.-C6alkyl-carbonyl, CrC6alkylSOn, C C6- alkyl-carboxy, arylcarboxy, hetarylcarboxy, aryld-C6alkylcarboxy or hetarylC C6alkylcarboxy wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one ore more of R15;
R6 is oxygen, sulphur, SOn or NR 16.
R7 is hydrogen, halo, hydroxy, cyano, nitro, COOR17, CrC8alkyl, C3-Cιocycloalkyl, C3-C10het- cycloalkyl, methylendioxo, trihalomethyl, trihalomethyloxy, aryl, arylC C6alkyl, CrC6alkyloxy, CrCβalkyloxyCrCealkyl, aryloxy, arylC C6alkyloxy, aryloxyC C6alkyl, arylCrC6alkyloxyd- C6alkyl, hetaryl, hetarylCrC6alkyl, hetaryloxy, hetarylCι-C6alkyloxy, hetaryloxyd-Cealkyl, hetaryld-Cealkyl-oxyd-Cealkyl, NR8R9, S02NR8R9, NR4R5carbonyld-C6alkyl, arylthio, hetarylthio, R18carbonylNR8, arylSOn, hetarylSOn, R19SOmNR8, arylthioC.-C6alkyl, hetaryl- thioCι-C6alkyl or arylCι-C6alkylR6C1-C6alkyl; wherein the aryl and hetaryl groups independently are optionally substituted with one or more R10;
R8 and R9 independently are hydrogen, C C8alkyl, aryl, hetaryl, aryld-C6alkyl or hetaryld- C6alkyl wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R11; or
R8 and R9 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system optionally being substituted with at least one halo, cyano, d-Cβalkyl, aryl, hetaryl, arylCrCealkyl, hetarylCrC6alkyl, hydroxy, oxo, d-C6alkyloxy, arylCrC6alkyloxy, hetaryld- C6alkyloxy, CrC6alkyloxyCrC6alkyl, CrC6alkyl-carbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkylcarbonyl, hetarylCrC6alkylcarbonyl, d-C6alkylcarboxy, arylcarboxy, hetarylcarboxy, aryld-C6alkylcarboxy or hetaryld-C6alkylcarboxy;
R10 and R11 independently are hydrogen, hydroxy, oxo, halo, cyano, nitro, d-C8alkyl, d- C6alkyloxy, NR12R13, methylendioxo, trihalomethyl or trihalomethyloxy;
R12 and R13 independently are hydrogen, d-C8alkyl or arylCrC6alkyl;
R14 is hydrogen, halo, hydroxy, oxo, nitro, cyano, C C8alkyl, d-C6alkyloxy or aryloxy;
R15 is hydrogen, halo, hydroxy, oxo, nitro, cyano, CONR8R9 or COOR17;
R16 is hydrogen, CrC8alkyl, C3-C10cycloalkyl, C3-C10hetcycloalkyl, aryl, arylCrC6alkyl, hetaryl, hetarylCι-C6alkyl, alkylcarbonyl, arylcarbonyl, arylCrC6alkylcarbonyl, aryloxyd- C6alkyl, hetaryloxyCr Cealkyl, arylthioC C6alkyl or hetarylthioCrC6alkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R10;
R is hydrogen, CrC8alkyl, aryl or arylCrCealkyl;
R 8 is C C6alkyl, C2-C6alkenyl, aryl, arylCrC6alkyl, hetaryl, hetarylCrC6alkyl, C3- C10cycloalkyl, C3-C10hetcycloalkyl, CrC6alkyloxy, aryloxy, arylC C6alkyloxy, aryld- C6alkyloxyCrC6alkyl, hetaryloxy, hetarylCrC6alkyloxy, hetarylCrCealkyloxyCrCealkyl or R8R9NCrC6alkyl wherein the alkyl, alkenyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups are optionally substituted with R15;
R19 is d-Cealkyl, C3-C10cycloalkyl, C3-C10hetcycloalkyl, aryl, arylCrC6alkyl, hetaryl, hetaryl- CrC6alkyl;
m is 1 or 2;
n is 0, 1 or 2; or
a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mix- ture of optical isomers, including a racemic mixture, or any tautomeric forms. In another embodiment, the invention provides the present use of a substituted amide, or a prodrug thereof of the above general formula (I) wherein
R1 is C3-C10cycloalkyl, C3-C10hetcycloalkyl, CrCealkyl, aryl, hetaryl, arylCrCealkyl or hetaryl- CrCealkyl, wherein the cycloalkyl, hetcycloalkyl, alkyl, arylalkyl and hetarylalkyl groups independently are optionally substituted with one or more of R4;
R2 is hydrogen, CrC8alkyl, aryl, hetaryl, arylCrC6alkyl, d-docycloalkyld-Cealkyl, d-Ce- alkylcarboxyCrC6alkyl wherein the alkyl, aryl and cycloalkyl groups independently are op- tionally substituted with one or more of R5; or
R1 and R2 are together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC8alkyl, aryl, hetaryl, arylC C6alkyl, hetarylCrC6alkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrC6alkyloxy, hetarylC C6alkyloxy, d-Cealkyloxyd-Cealkyl, d-C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, aryld-C6alkylcarbonyl, hetarylCrC6alkylcarbonyl, CrC6alkylcarboxy, arylcarboxy or aryld- 6alkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R14;
R3 is CrC8alkyl, CrC6alkenyl, CrC6alkynyl, C3-C10cycloalkyl, C3-C10hetcycloalkyl, aryl, hetaryl, arylCrC6alkyl, CrCealkyloxyCrCealkyl, hetarylCrC6alkyl, aryl-R6-CrC6alkyl, hetaryl- R6-d-C6alkyl or arylCrC6alkyl-R6-CrC6alkyl wherein the alkyl, cycloalkyl, hetcycloalkyl, al- kenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R7;
R4 and R5 independently are hydrogen, hydroxy, oxo, cyano, halo, methylendioxo, NR8R9, CrC8alkyl, d-Cealkyloxy, trihalomethyl, trihalomethyloxy, C3-C10cycloalkyl, C3- dohetcycloalkyl, C3-C10cycloalkenyl, aryl, hetaryl, hetarylSOn, arylCrC6alkyloxy, hetaryld- C6alkyloxy, d-Cealkyl-R^d-Cealkyl, arylCrC6alkyl-R6-CrC6alkyl, CrC6alkylcarbonyl, arylcarbonyl, arylCrC6alkylcarbonyl, hetarylcarbonyl, hetaryld-C6alkyl-carbonyl, CrC6alkylSOn, CrC6alkyl-carboxy, arylcarboxy, hetarylcarboxy, aryld-C6alkylcarboxy or hetarylCrC6alkyl- carboxy wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one ore more of R15; R6 is oxygen, sulphur, SOn, NR16;
R7 is hydrogen, halo, hydroxyl, cyano, nitro, COOR17, C C8alkyl, C3-Cι0cycloalkyl, C3-C10het- cycloalkyl, methylendioxo, trihalomethyl, trihalomethyloxy, aryl, arylCrC6alkyl, CrC6alkyloxy, CrC6alkyloxyCrC6alkyl, aryloxy, aryloxyd-Cealkyl, arylCrC6alkyloxyCrC6alkyl, hetaryl, hetarylCrC6alkyl, hetaryloxy, hetarylCrC6alkyloxy, hetaryloxyCrC6alkyl, hetaryld-C6alkyl- oxyd-C6alkyl, NR8R9, S02NR8R9, NR4R5carbonylalkyl, arylcarbonylNR8, arylthio, hetarylthio, arylSOn, hetarylSOn, arylSOmNR8, arylthioCrC6alkyl, hetarylthiod-C6alkyl or arylC C6alkylR6CrC6alkyl; wherein the aryl and hetaryl groups independently are optionally substituted with one or more R10;
R8 and R9 independently are hydrogen, CrC8alky1, aryl, hetaryl, arylCrC6alkyl or hetaryld- C6alkyl wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R11 ; or
R8 and R9 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system optionally being substituted with at least one d-C8alkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrC6alkyl, hydroxy, oxo, CrC6alkyloxy, arylCrC6alkyloxy, hetarylCrC6alkyloxy, d- C6alkyloxyd-C6alkyl, d-C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, aryld-Ci-alkyl- carbonyl, hetarylCrC6alkylcarbonyl, d-C6alkylcarboxy, arylcarboxy, hetarylcarboxy, aryld- C6alkyl-carboxy or hetarylCrC6alkylcarboxy;
R10 and R11 independently are hydrogen, hydroxy, oxo, halo, cyano, nitro, CrCβalkyl, CrCealkyloxy, NR12R13, methylendioxo, trihalomethyl or trihalomethyloxy;
R12 and R13 independently are hydrogen, CrC8alkyl or arylCrC6alkyl;
R14 is hydrogen, halo, hydroxy, oxo, nitro, cyano, d-C8alkyl, d-Cealkyloxy or aryloxy;
R15 is hydrogen, halo, hydroxy, oxo, nitro, cyano or COOR17; R16 is hydrogen, C C8alkyl, C3-C10cycloalkyl, C3-C10hetcycloalkyl, aryl, arylCrC6alkyl, hetaryl, hetarylCrC6alkyl, alkylcarbonyl, arylcarbonyl, arylCrC6alkylcarbonyl, aryloxyd- C6alkyl, hetaryloxyd-C-ealkyl, arylthioCrC6alkyl or hetarylthioCrC6alkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R10;
R17 is hydrogen, C C8alkyl, aryl or arylCrCealkyl;
m is 1 or 2;
n is 0, 1 or 2; or
a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
In another embodiment, the invention provides the present use of a substituted amide, or a prodrug thereof of the general formula (I) wherein R1 is C3-C10cycioalkyl or C3- dohetcycloalkyl wherein the cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R4 as defined above. In another embodiment, the invention provides the present use of a substituted amide, or a prodrug thereof of the general formula (I) wherein R1 is C3-C10cycloalkyl optionally substituted with one or more of R4 as defined above.
In another embodiment, the invention provides the present use of a substituted amide, or a prodrug thereof of the general formula (I) wherein R2 is hydrogen or C C8alkyl, wherein the the alkyl group is optionally substituted with one or more of R5 as defined above. In another embodiment, the invention provides the present use of a substituted amide, or a prodrug thereof of the general formula (I) wherein R2 is CrC8alkyl optionally substituted with one or more of R5 as defined above.
In another embodiment, the invention provides the present use of a substituted am- ide, or a prodrug thereof of the general formula (I) wherein R3 is C3-C10cycloalkyl, C3-
Ciohetcycloalkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrC6alkyl, aryl-R6-CrC6alkyl, hetaryl-R6- d-C6alkyl or aryld-Cealkyl-R^d-Cealkyl wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R7. In another embodiment, the invention provides the present use of a substituted amide, or a prodrug thereof of the general formula (I) wherein R3 is aryl or hetaryl, wherein the aryl and hetaryl groups are optionally substituted with one or more of R7 as defined above.
In another embodiment, the invention provides the present use of a substituted am- ide, or a prodrug thereof of the general formula (I) wherein R3 is is phenyl optionally substituted with one or more of R7 as defined above.
In another embodiment, the invention provides the present use of a substituted amide, or a prodrug thereof of the general formula (I) wherein R3 is phenyl optionally substituted independently in position 2(ortho) or 4(para) with one or more of R7 as defined above. In another embodiment, the invention provides the present use of a substituted amide, or a prodrug thereof of the general formula (I) wherein R4 and R5 independently are hydrogen, hydroxy, oxo, halo, d-C8alkyl, wherein the alkyl group is optionally substituted with one ore more of R15.
In another embodiment, the invention provides the present use of a substituted am- ide, or a prodrug thereof of the general formula (I) wherein R6 is oxygen.
In another embodiment, the invention provides the present use of a substituted amide, or a prodrug thereof of the general formula (I) wherein R7 is hydrogen, halo, hydroxy, cyano, d-C8alkyl, C3-C10cycloalkyl, C3-C10het-cycloalkyl, trihalomethyl, aryl, arylCrC6alkyl, CrC6alkyloxy, d-C-ealkyloxyd-Cealkyl, aryloxy, arylCrC6alkyloxy, aryloxyd-Cealkyl, aryld- CealkyloxyCrCealkyl, hetaryl, hetarylCrC6alkyl, hetaryloxy, hetarylCrC6alkyloxy, hetary- loxyd-C6alkyl, hetarylCrC6alkyl-oxyCrCealkyl, NR8R9, NR4R5carbonylCrC6alkyl, R18car- bonylNR8, R19SOmNR8, wherein the aryl and hetaryl groups independently are optionally substituted with one or more R10.
In another embodiment, the invention provides the present use of a substituted am- ide, or a prodrug thereof of the general formula (I) wherein R8 and R9 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system optionally being substituted with at least one halo, cyano, d-C8alkyl, aryl, hetaryl, arylCrCealkyl, hetarylCrC6alkyl, hydroxy, oxo, d-C6alkyloxy, arylCrC6alkyloxy, hetarylCrC6alkyloxy, d-Cealkyloxyd-
C6alkyl, CrC6alkyl-carbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkylcarbonyl, hetaryld- C6alkylcarbonyl, d-C6alkylcarboxy, arylcarboxy, hetarylcarboxy, arylCrC6alkylcarboxy or hetarylCrC6alkylcarboxy.
In another embodiment, the invention provides the present use of a substituted am- ide, or a prodrug thereof of the general formula (I) wherein R15 is CONR8R9. In another embodiment, the invention provides the present use of a substituted amide, or a prodrug thereof of the general formula (I) wherein R18 is d-Cealkyl optionally substi- tuted with R15;
In another embodiment, the invention provides the present use of a substituted am- ide, or a prodrug thereof of general formula (I), selected from the group consisting of:
3-(10, 11 -Dihydro-dibenzo[b,f]azepin-5-yl)-1 -[4-(1 H-imidazol-4-yl)-piperidin-1 -yl]-propan-1 - one;
4-(10, 11 -Dihydro-dibenzo[b,fjazepin-5-yl)-1 -[4-(3H-imidazol-4-yl)-piperidin-1 -yl]-butan-1 -one;
2,4-Bis-benzyloxy-benzamide; (1 H-lndol-4-yl)-piperidin-1 -yl-methanone;
N-(1 ,4-Dioxo-1 ,4-dihydro-naphthalen-2-yl)-benzamide;
N-(2,3-Dihydroxy-propyl)-2-(2-phenyl-adamantan-2-yl)-acetamide;
(6-Fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-phenyl-methanone;
(2-Chloro-phenyl)-(6-fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-methanone; 3-Cyclopentyl-1-(6-fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-propan-1-one;
(3-Chloro-thieno[2,3-b]thiophen-2-yl)-thiomorpholin-4-yl-methanone;
2-[2-(4-Chloro-phenyl)-adamantan-2-yl]-1-[4-(4-methoxy-phenyl)-piperazin-1-yl]-ethanone;
1-(4-Benzyl-piperazin-1-yl)-2-[2-(4-chloro-phenyl)-adamantan-2-yl]-ethanone;
2-[2-(4-Chloro-phenyl)-adamantan-2-yl]-1-(4-methyl-piperazin-1-yl)-ethanone; 1 -[4-(6-Chloro-pyridin-2-yl)-piperazin-1 -yl]-2-(2-phenyl-adamantan-2-yl)-ethanone;
4-Chloro-N-(1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl)-benzamide;
3-Chloro-benzo[b]thiophene-2-carboxylic acid (2-cyano-ethyl)-cyclohexyl-amide;
2-[2-(Bicyclo[2.2.1]hept-5-en-2-ylamino)-4-oxo-4,5-dihydro-thiazol-5-yl]-N-(2-chloro-phenyl)- acetamide; [3-(4-sec-Butyl-phenoxy)-phenyl]-piperidin-1 -yl-methanone;
3-(6-Chloro-pyridin-2-yloxy)-N-ethyl-benzamide;
N-Benzyl-2,4-dichloro-N-pyridin-2-yl-benzamide;
2-[Benzoyl-(3-chloro-4-fluoro-phenyl)-amino]-propionic acid butyl ester;
2-[Benzoyl-(3-chloro-4-fluoro-phenyl)-amino]-propionic acid pentyl ester; 3-(4-Fluoro-phenyl)-1-(4-phenyl-piperidin-1-yl)-but-2-en-1-one;
N-(1,7,7-Trimethyl-bicyclo[2.2.1]hept-2-yl)-benzamide;
1-(3-Cyclopentyl-propionyl)-piperidine-3-carboxylic acid ethyl ester;
4-Phenyl-1-phenylacetyl-piperidine-4-carbonitrile;
1-Octanoyl-4-phenyl-piperidine-4-carbonitrile; 2,2-Dimethyl-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-propan-1-one; (4-Chloro-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
N-[1-(4-Methanesulfonyl-phenyl)-ethyl]-N-(tetrahydro-furan-2-ylmethyl)-benzamide;
2-(2-Amino-phenylsulfanyl)-1-(5-fluoro-2,3-dihydro-indol-1-yl)-ethanone;
N-(1-Methyl-2,3-dihydro-1H-indol-5-ylmethyl)-N-(tetrahydro-furan-2-ylmethyl)-benzamide; 1-Benzoyl-piperidine-2-carboxylic acid ethyl ester;
N-(2-Chloro-phenyl)-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetamide;
(Decahydro-naphthalen-1-yl)-(4-methyl-piperazin-1-yl)-methanone;
(4-Methyl-piperazin-1-yl)-(2-p-tolylsulfanyl-phenyl)-methanone;
Adamantane-1 -carboxylic acid (3-benzyloxy-2-ethyl-6-methyl-pyridin-4-yl)-amide; (6-Fluoro-2-methyl-3,4-dihydro-2H-quinolin-1 -yl)-(3,4,5-trimethoxy-phenyl)-methanone;
N-Bicyclo[2.2.1]hept-2-yl-3-cyclopentyl-propionamide;
(2-Benzo[1,2,5]oxadiazol-5-yl-thiazol-4-yl)-piperidin-1-yl-methanone;
Thiophene-2-carboxylic acid [4-(4-fluoro-phenyl)-4-hydroxy-butyl]-isopropyl-amide;
N-Cyclohexyl-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionamide; 2-[(Adamantane-1 -carbonyl)-amino]-3-(1 H-indol-3-yl)-propionic acid methyl ester;
Adamantane-1 -carboxylic acid [3-(1 H-benzoimidazol-2-ylsulfanyl)-5-nitro-phenyl]-amide;
N-Benzyl-N-(1-cyclopropyl-ethyl)-4-fluoro-benzamide;
Thiophene-2-carboxylic acid 2-[2-(2-phenyl-adamantan-2-yl)-acetylamino]-ethyl ester;
N-(4-Acetyl-phenyl)-2-(2-phenyl-adamantan-2-yl)-acetamide; 2-[2-(4-Chloro-phenyl)-adamantan-2-yl]-N-(2-hydroxy-ethyl)-acetamide;
(4-Benzoyl-piperidin-1-yl)-thiophen-2-yl-methanone;
N-(2-Benzoyl-4-methyl-phenyl)-3-phenyl-acrylamide;
N-(2-Benzoyl-4-methyl-phenyl)-2-fluoro-benzamide;
Adamantane-1 -carboxylic acid (4-ethoxy-benzothiazol-2-y!)-amide; Adamantane-1 -carboxylic acid (5-benzoyl-4-phenyl-thiazol-2-yl)-amide;
3-(2-Hydroxy-phenyl)-1 ,3-di-piperidin-1 -yl-propan-1 -one;
N-(1-Methyl-2-phenyl-ethyl)-3-phenyl-propionamide;
4-Oxo-4-piperidin-1-yl-butyric acid 4-tert-butyl-cyclohexyl ester;
N-tert-Butyl-N-(4-methoxy-benzyl)-4-nitro-benzamide; {4-[(Adamantane-1-carbonyl)-amino]-phenoxy}-acetic acid;
2-(4-lsobutyl-phenyl)-N-(1-phenyl-ethyl)-propionamide;
Adamantane-1 -carboxylic acid 4-[(adamantane-1-carbonyl)-amino]-2,6-dimethyl-pyridin-3-yl ester;
2-Phenyl-1 -(3-phenyl-pyrrolidin-1 -yl)-ethanone; Adamantane-1 -carboxylic acid 4-[(adamantane-1 -carbonyl)-amino]-2-ethyl-6-methyl-pyridin-
3-yl ester;
N-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-N-(4-hydroxy-phenyl)-benzamide;
Biphenyl-4-yl-piperidin-1 -yl-methanone; Azepan-1 -yl-(3,5-dichloro-phenyl)-methanone;
Azepan-1-yl-biphenyl-4-yl-methanone;
Azepan-1-yl-(4-chloro-phenyl)-methanone;
3-Heptylcarbamoyl-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid;
Adamantan-1 -yl-azepan-1 -yl-methanone; N,N-Dibenzyl-3,4-dimethoxy-benzamide;
N-Benzyl-N-isopropyl-4-nitro-benzamide;
N-[2-(1H-lndol-3-yl)-1-methyl-ethyl]-2-(4-isobutyl-phenyl)-propionamide;
N-tert-Butyl-2-(4-isobutyl-phenyl)-propionamide;
Adamantane-1 -carboxylic acid (2-acetyl-phenyl)-amide; N-(1 ,3-Dioxo-1 ,3-dihydro-isoindol-2-ylmethyl)-N-(4-fluoro-phenyl)-benzamide;
(Octahydro-quinolin-l-yl)-phenyl-methanone;
(7-Hydroxy-octahydro-quinolin-1-yl)-phenyl-methanone;
N-(1 ,3-Dioxo-1 ,3-dihydro-isoindol-2-ylmethyl)-N-p-tolyl-benzamide;
N,N-Dibenzyl-4-methyl-benzamide; (2-Chloro-phenyl)-(2-methyl-piperidin-1 -yl)-methanone;
[4-Bromo-3-(piperidine-1-sulfonyl)-phenyl]-piperidin-1-yl-methanone;
2-Chloro-N-(3,4-dimethyl-phenyl)-benzamide;
1 -Azepan-1 -yl-2-(3,3-dimethyl-3,4-dihydro-2H-isoquinolin-1-ylidene)-ethanone;
N-Cyclohexyl-4-(2,4-dichloro-phenoxy)-butyramide; N-Benzo[1 ,3]dioxol-5-yl-2-chloro-benzamide;
(4-Benzyl-piperidin-1-yl)-(2-chloro-phenyl)-methanone;
2-(Benzothiazol-2-ylsulfanyl)-N-cyclohexyl-acetamide;
Cyclohexanecarboxylic acid (7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-quinazolin-2-yl)-amide;
2,4-Dichloro-N-ethyl-N-o-tolyl-benzamide; (4-Benzyl-piperidin-1 -yl)-(4-fluoro-phenyl)-methanone;
N-Cyclohexyl-4-(2,4-dichloro-phenoxy)-N-methyl-butyramide;
3-[2-(1 ,3-Dioxo-1 ,3-dihydro-isoindol-2-yl)-ethyl]-adamantane-1 -carboxylic acid;
Morpholin-4-yl-(3-p-tolyl-adamantan-1-yl)-methanone;
N-Benzyl-2,4-dichloro-N-methyl-benzamide; Thiophene-2-carboxylic acid dibenzylamide; Azepan-1-yl-(2-bromo-phenyl)-methanone;
(3,4-Dichloro-phenyl)-(4-methyl-piperidin-1-yl)-methanone;
N,N-Dibenzyl-3,4-dichloro-benzamide;
4-(2,4-Dichloro-phenoxy)-1 -piperidin-1 -yl-butan-1 -one; N,N-Dibenzyl-2-fluoro-benzamide;
(2-Chloro-phenyl)-piperidin-1-yl-methanone;
2-Chloro-N-(3-trifluoromethyl-phenyl)-benzamide;
N-Benzyl-N-ethyl-2-phenyl-acetamide;
(3,4-Dihydro-2H-quinolin-1-yl)-p-tolyl-methanone; Thiophene-2-carboxylic acid benzyl-ethyl-amide;
N-Adamantan-1-yl-2-dibenzylamino-acetamide;
N-Cyclohexyl-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-phenyl-propionamide;
Thiophene-2-carboxylic acid cycloheptylamide;
N-Cyclohexyl-3-diethylsulfamoyl-4-methyl-benzamide; 4-Benzoyl-N-methyl-N-phenyl-benzamide;
N-Benzyl-2-bromo-N-methyl-benzamide;
2-Chloro-N-methyl-N-phenyl-benzamide;
4-Chloro-N-ethyl-N-o-tolyl-benzamide;
N-Benzyl-4,N-dimethyl-benzamide; 2-(4-Chloro-3,5-dimethyl-phenoxy)-N-cyclohexyl-N-methyl-acetamide;
N-Benzyl-2-bromo-N-isopropyl-benzamide;
3-(2-Chloro-phenyl)-N-cyclohexyl-N-methyl-acrylamide;
N-Phenyl-N-(2,2,5-trimethyl-hex-4-enyl)-acetamide;
N-m-Tolyl-N-(2,2,5-trimethyl-hex-4-enyl)-acetamide; (3-Chloro-benzo[b]thiophen-2-yl)-(4-methyl-piperazin-1 -yl)-methanone;
Adamantane-1 -carboxylic acid (5-methyl-pyridin-2-yl)-amide;
3-Bromo-N-[2-methyl-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-butyl]- benzamide;
4-Chloro-N-[2-methyl-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-butyl]- benzamide;
4-Methyl-N-[2-methyl-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-butylj- benzamide;
Cyclohexanecarboxylic acid [2-methyl-1-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6- carbonyl)-butyl]-amide; 3-Cyclopentyl-N-[2-methyl-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-bu-yl]- propionamide;
2-Chloro-N-[2-(4-ethyl-benzoylamino)-ethyl]-N-(4-fluoro-phenyl)-benzamide;
N-{1-Benzyl-2-[4-(3-cyclopentyl-propionyl)-piperazin-1-yl]-2-oxo-ethyl}-3-cyclopentyl- propionamide;
N-Bicyclo[2.2.1]hept-5-en-2-ylmethyl-3-cyclopentyl-N-[2-(1H-indol-3-yl)-ethyl]-propionamide;
N-Bicyclo[2.2.1]hept-5-en-2-ylmethyl-2,4-dichloro-N-[2-(1H-indol-3-yl)-ethyl]-benzamide;
Naphthalene-2-carboxylic acid (2-oxo-azepan-3-yl)-thiophen-3-ylmethyl-amide;
3,4,5-Trimethoxy-N-(4-methyl-benzyl)-N-[6-(pyridin-2-ylamino)-hexyl]-benzamide; 3-Cyclopentyl-N-(4-methyl-benzyl)-N-[6-(pyridin-2-ylamino)-hexyl]-propionamide;
N-(3,4-Dimethoxy-benzyl)-3-methoxy-N-[6-(pyridin-2-ylamino)-hexyl]-benzamide;
N,N-Dimethyl-2-[3-(4-nitro-phenyl)-adamantan-1-yl]-acetamide;
Adamantane-1 -carboxylic acid [4-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl)-butyl]-p-tolyl-amide;
2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-3-methyl-N-(2-trifluoromethyl-phenyl)-butyramide; 2-(4-Chloro-2-methyl-phenoxy)-N-(2-trifluoromethyl-phenyl)-propionamide;
4-(2,4-Dichloro-phenoxy)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-butan-1-one;
(3,4-Dihydro-2H-quinolin-1-yl)-[3-(piperidine-1-sulfonyl)-phenyl]-methanone;
Acetic acid 4-(azepane-1-carbonyl)-phenyl ester;
N-Adamantan-1-ylmethyl-benzamide; [3-(4-Nitro-phenyl)-adamantan-1 -yl]-piperidin-1 -yl-methanone;
N-(1 , 1 -Dimethyl-hexyl)-2-morpholin-4-yl-acetamide;
Adamantyl-1 -carboxylic acid (2-methoxy-ethyl)-amide;
N-(4-Adamantan-1-yl-2-methyl-phenyl)-acetamide;
3-p-Tolyl-adamantane-1 -carboxylic acid (2,5-dichloro-phenyl)-amide; (3-Chloro-adamantan-1 -yl)-pyrrolidin-1 -yl-methanone;
2-Amino-5-cyclohexylcarbamoyl-4-methyl-thiophene-3-carboxylic acid ethyl ester;
N-(2-Chloro-phenyl)-2-{3-[(2-chloro-phenylcarbamoyl)-methyl]-adamantan-1-yl}-acetamide;
3-p-Tolyl-adamantane-1 -carboxylic acid (2,4-difluoro-pheny!)-amide;
Adamantyl-1 -carboxylic acid tert-butylamide; 2-Adamantan-1-yl-N-tert-butyl-acetamide;
N-Methyl-N-phenyl-4-(pyrrolidine-1-sulfonyl)-benzamide;
N-(1 -Adamantan-1 -yl-ethyl)-2-fluoro-benzamide;
Adamantane-1 -carboxylic acid [2-(3,4-dimethoxy-phenyl)-ethyl]-amide;
Adamantane-1 -carboxylic acid dimethylamide; N-Benzyl-4-chloro-N-(1-cyclopropyl-vinyl)-benzamide; 3,5-Dimethyl-adamantane-1 -carboxylic acid benzylamide;
2,4-Dichloro-N-cyclohexyl-N-(2-hydroxy-ethyl)-benzamide;
N-Adamantan-1-yl-2,4-dichloro-N-ethyl-benzamide;
2-[(3-p-Tolyl-adamantane-1-carbonyl)-amino]-propionic acid methyl ester; N-Adamantan-1 -yl-3-morpholin-4-yl-propionamide;
3-p-Tolyl-adamantane-1 -carboxylic acid isopropylamide;
N-Adamantan-1-yl-2-benzylamino-acetamide;
N-Benzyl-2,4-dichloro-N-(1-cyclopropyl-ethyl)-5-methyl-benzamide;
2-[(Adamantane-1-carbonyl)-amino]-benzoic acid ethyl ester; N-Benzyl-N-isopropyl-4-methyl-3-nitro-benzamide;
(3,4-Dihydro-2H-quinolin-1-yl)-(2-fluoro-phenyl)-methanone;
N-Ethyl-2-fluoro-N-phenyl-benzamide;
2-Phenethyl-N-(2-trifluoromethyl-phenyl)-benzamide;
1-(3,4-Dihydro-2H-quinolin-1-yl)-2-o-tolyloxy-ethanone; 2-(1 -Benzyl-1 H-imidazol-2-ylsulfanyl)-N-cyclohexyl-acetamide;
Cyclohexanecarboxylic acid (2-propoxy-phenyl)-amide;
2-{3-[4-(2-Chloro-phenyl)-piperazin-1-yl]-3-oxo-propyl}-isoindole-1,3-dione;
N-Cyclopentyl-2-(2,4-dichloro-phenoxy)-propionamide;
Adamantane-1 -carboxylic acid (2-trifluoromethyl-phenyl)-amide; (4-Chloro-3-nitro-phenyl)-(2,6-dimethyl-piperidin-1-yl)-methanone;
4-(2-Ethyl-phenyl)-4-aza-tricyclo[5.2.2.02'6]undec-8-ene-3,5-dione;
2-Phenyl-N-(2-trifluoromethyl-phenyl)-butyramide;
N-Adamantan-1-yl-4-chloro-2-nitro-benzamide;
3-p-Tolyl-adamantane-1 -carboxylic acid (2,3-dimethyl-phenyl)-amide; N-Benzyl-3-methyl-4-p-tolyl-butyramide;
N-(2-Cyclohex-1 -enyl-ethyl)-2-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl)-propionamide;
(4-tert-Butyl-phenyl)-(3,4-dihydro-1H-isoquinolin-2-yl)-methanone;
2-[1-(4-Chloro-benzenesulfonyl)-1H-benzoimidazol-2-ylsulfanyl]-N-thiophen-2-ylmethyl- acetamide; 2-Phenoxy-1 -[4-(2-trifluoromethyl-benzyl)-piperazin-1 -yl]-ethanone;
Cyclohexanecarboxylic acid [5-(2-fluoro-benzylsulfanylmethyl)-[1 ,3,4]thiadiazol-2-yl]-amide;
4-Methyl-2-phenyl-thiazole-5-carboxylic acid naphthalen-1 -ylamide;
4-Fluoro-N-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]- benzenesulfonamide; (3-Methoxy-phenyl)-(4-o-tolyl-piperazin-1 -yl)-methanone; N-Adamantan-1 -yl-3-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl)-propionamide;
N-Cyclooctyl-2-methoxy-3-methyl-benzamide;
2-[4-(2,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-isoindole-1,3-dione;
(2,3-Diphenyl-quinoxalin-6-yl)-(2,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; Adamantan-1 -yl-(1 ,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-methanone;
N-{4-[1-(Naphthalene-2-sulfonyl)-piperidin-3-yl]-butyl}-N'-p-tolyl-oxalamide;
N-Benzyl-N-(2-oxo-2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide;
(4-Amino-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
1-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-(2-isopropyl-5-methyl-phenoxy)-ethanone; Adamantane-1 -carboxylic acid benzyl-pyridin-2-yl-amide;
Adamantan-1 -yl-piperidin-1 -yl-methanone;
Adamantan-1 -yl-pyrrolidin-1 -yl-methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-o-tolyl-methanone;
Adamantyl-1 -carboxylic acid benzylamide; Pyridine-2-carboxylic acid adamantan-2-ylamide;
(3-Chloro-adamantan-1-yl)-piperidin-1 -yl-methanone;
Adamantan-1 -yl-(4-methyl-piperidin-1 -yl)-methanone;
2-[3-(Azepane-1 -carbonyl)-phenyl]-isoindole-1 ,3-dione;
2-[3-(Piperidine-1 -carbonyl)-phenyl]-isoindole-1 ,3-dione; 4-(Benzyl-methanesulfonyl-amino)-N-furan-2-ylmethyl-benzamide;
(4-Nitro-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
1 -Cyclohexyl-5-oxo-pyrrolidine-3-carboxylic acid (4-chloro-3-nitro-phenyl)-amide;
N-(2-Chloro-phenyl)-2-(2-oxo-2-phenyl-ethylsulfanyl)-acetamide;
3-(4-Hydroxy-phenyl)-N-isochroman-1-ylmethyl-3-phenyl-propionamide; (4-Ethoxy-phenyl)-(2-methyl-piperidin-1 -yl)-methanone;
1 -Cyclohexyl-5-oxo-pyrrolidine-3-carboxylic acid (3-chloro-phenyl)-amide;
N-[4-(Benzyl-isopropyl-sulfamoyl)-phenyl]-acetamide;
N-(3,4-Dimethyl-phenyl)-N-[4-(piperidine-1-carbonyl)-benzyl]-methanesulfonamide;
2-(5-Phenyl-1 H-imidazol-2-ylsulfanyl)-N-(1 ,1 ,3,3-tetramethyl-butyl)-acetamide; 2-(Benzothiazol-2-ylsulfanyl)-N-(1 , 1 ,3,3-tetramethyl-butyl)-acetamide;
2-(Benzooxazol-2-ylsulfanyl)-N-(1 , 1 ,3,3-tetramethyl-butyl)-acetamide;
2-(Naphthalen-2-ylcarbamoylmethylsulfanyl)-N-(1,1,3,3-tetramethyl-butyl)-acetamide;
Acetic acid 4-(3,5-dimethyl-piperidine-1-carbonyl)-phenyl ester;
[1-(4-Chloro-benzenesulfonyl)-piperidin-3-yl]-(octahydro-quinolin-1-yl)-methanone; (4-Fluoro-phenyl)-(3,4,4a,8a-tetrahydro-2H-quinolin-1-yl)-methanone; N-Adamantan-1-yl-2-ethoxy-acetamide;
2-(2-Oxo-2-phenothiazin-10-yl-ethyl)-hexahydro-isoindole-1 ,3-dione;
Adamantane-1 -carboxylic acid (tetrahydro-furan-2-ylmethyl)-amide;
2-Bromo-N-cycloheptyl-benzamide; Bicyclo[2.2.1]hept-2-yl-[4-(2-ethoxy-phenyl)-piperazin-1 -yl]-methanone;
N-Furan-2-ylmethyl-2-phenyl-2-phenylsulfanyl-acetamide;
Adamantane-1 -carboxylic acid benzyl-methyl-amide;
1-(3,4-Dihydro-2H-quinolin-1-yl)-3-(4-fluoro-phenyl)-propenone;
Adamantan-1 -yl-(2,6-dimethyl-piperidin-1 -yl)-methanone; 4-Methyl-N-homoadamantyl-3-yl-benzamide;
(3,5-Dimethyl-piperidin-1-yl)-(3-methyl-4-nitro-phenyl)-methanone;
Quinoline-2-carboxylic acid cyclooctylamide;
Adamantane-1 -carboxylic acid [2-(2,4-dimethoxy-phenyl)-ethyl]-amide;
(3,4-Dihydro-1H-isoquinolin-2-yl)-o-tolyl-methanone; (3,6-Dichloro-benzo[b]thiophen-2-yl)-(4-methyl-piperazin-1 -yl)-methanone;
3-(1-Benzyl-1H-imidazol-2-ylsulfanyl)-N-cyclohexyl-propionamide;
Propionic acid 2-amino-4-methyl-5-p-tolylcarbamoyl-thiophen-3-yl ester;
2-Cyclohexyl-N-(2,6-dimethyl-phenyl)-N-furan-2-ylmethyl-acetamide;
(3-Methoxy-phenyl)-(2,2,4-trimethyl-4-phenyl-3,4-dihydro-2H-quinolin-1-yl)-methanone; 1-[4-(2,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-pyrrolidine-2,5-dione;
1 -(3,4-Dihydro-2H-quinolin-1 -yl)-2-(1 -naphthalen-1 -yl-1 H-tetrazol-5-ylsulfanyl)-ethanone;
[4-(2,3-Dimethyl-phenyl)-piperazin-1-yl]-o-tolyl-methanone;
(4-Benzyl-piperidin-1-yl)-(4-methyl-3-nitro-phenyl)-methanone;
N-(2-Cyano-phenyl)-2-(9-ethyl-9H-1,3,4,9-tetraaza-fluoren-2-ylsulfanyl)-acetamide; N-(2-Cyano-phenyl)-2-(9-methyl-9H-1,3,4,9-tetraaza-fluoren-2-ylsulfanyl)-acetamide;
1-(Thiophene-2-carbonyl)-2,3-dihydro-1H-quinolin-4-one;
(3-Chloro-6-nitro-benzo[b]thiophen-2-yl)-piperidin-1-yl-methanone;
(4-Bromo-phenyl)-(3,5-dimethyl-piperidin-1-yl)-methanone;
2-Morpholin-4-yl-N-(1-phenyl-cyclopentylmethyl)-acetamide; 9-Oxo-9H-fluorene-1 -carboxylic acid (3-methyl-butyl)-amide;
[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-(4-methyl-piperidin-1-yl)-methanone;
N-Cycloheptyl-3-diethylsulfamoyl-benzamide;
(4-Methoxy-phenyl)-(3-phenyl-piperidin-1-yl)-methanone;
3-Amino-N-cyclohexyl-N-methyl-benzamide; N-Ethyl-3,4-dimethyl-N-phenyl-benzamide; N-Benzyl-3,4,N-trimethyl-benzamide;
(4-Fluoro-phenyl)-(3-phenyl-piperidin-1-yl)-methanone;
[4-(2,3-Dimethyl-phenyl)-piperazin-1-yl]-(3-methoxy-phenyl)-methanone;
Furan-2-carboxylic acid [4-(4-methyl-piperidine-1 -sulfonyl)-phenyl]-amide; N-(2-Cyclohex-1 -enyl-ethyl)-2-o-tolyloxy-acetamide;
5-(2-Chloro-phenoxymethyl)-furan-2-carboxylic acid (1 -bicyclo[2.2.1 ]hept-2-yl-ethyl)-amide;
3-(2-Chloro-phenyl)-1-[4-(2,3-dimethyl-phenyl)-piperazin-1-yl]-propenone;
N-[3-(Azepane-1-carbonyl)-phenyl]-benzamide;
[3-(Piperidine-1 -carbonyl)-pyrazol-1 -yl]-o-tolyl-methanone; N-(1 -Phenyl-cyclopentylmethyl)-2-piperidin-1 -yl-propionamide;
2-Morpholin-4-yl-N-(1-phenyl-cyclopentylmethyl)-propionamide;
N-[4-(Azepane-1-sulfonyl)-phenyl]-2,2,2-trifluoro-acetamide;
2,3-Dihydro-benzo[1 ,4]dioxine-6-carboxylic acid (1 -adamantan-1 -yl-ethyl)-amide;
N-Adamantan-1-yl-2-(3-methoxy-phenoxy)-acetamide; 3-Chloro-benzo[b]thiophene-2-carboxylic acid (2-cyano-ethyl)-phenyl-amide;
[4-(4-Nitro-benzyl)-piperidin-1-yl]-phenyl-methanone;
[4-(2-Nitro-benzyl)-piperidin-1-yl]-phenyl-methanone;
3-[5-(4-Fluoro-phenyl)-furan-2-yl]-1 -(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1 ]oct-6-yl)-propenone;
2-(3-Fluoro-benzoylamino)-4-methyl-5-(piperidine-1-carbonyl)-thiophene-3-carboxylic acid methyl ester;
N-(2-Ethyl-phenyl)-2-(3-methyl-piperidin-1-yl)-acetamide;
2-(2-Methoxy-benzoylamino)-4-methyl-5-(piperidine-1-carbonyl)-thiophene-3-carboxylic acid methyl ester;
1 -Phenyl-cyclopentanecarboxylic acid (4-phenyl-tetrahydro-pyran-4-ylmethyl)-amide; 4-(2,4-Dichloro-phenoxy)-1 -(4-phenyl-piperazin-1 -yl)-butan-1 -one;
Naphthalene-1 -carboxylic acid cycloheptylamide;
N-lndan-5-yl-2-methyl-3-nitro-benzamide;
N-Cyclohexyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzamide;
2-Methoxy-N-(1-phenyl-cyclopentylmethyl)-benzamide; [5-(2,5-Dichloro-phenoxymethyl)-furan-2-yl]-(2,6-dimethyl-morpholin-4-yl)-methanone;
[5-(2-Bromo-phenoxymethyl)-furan-2-yl]-(2-methyl-piperidin-1-yl)-methanone;
5-(2-Methoxy-phenoxymethyl)-furan-2-carboxylic acid cycloheptylamide;
(3,4-Dihydro-1H-isoquinolin-2-yl)-[1-(2-nitro-benzenesulfonyl)-piperidin-3-yl]-methanone;
N-Cyclooctyl-2-(4-methoxy-phenoxy)-acetamide; N-(2,3-Dimethyl-phenyl)-4-[methyl-(toluene-4-sulfonyl)-amino]-butyramide; N-Phenyl-N-[4-(piperidine-1-carbonyl)-benzyl]-benzenesulfonamide;
N-[4-(3,4-Dihydro-1H-isoquinoline-2-carbonyl)-benzyl]-N-(3,4-dimethyl-phenyl)- methanesulfonamide;
2,3-Dihydro-benzo[1 ,4]dioxine-2-carboxylic acid bicyclo[2.2.1]hept-2-ylamide; 4,5,6,7-Tetrahydro-benzo[b]thiophene-3-carboxylic acid cycloheptylamide;
N-(2-Azepan-1-yl-2-oxo-ethyl)-N-benzyl-4-fluoro-benzenesulfonamide;
1 -(2,6-Dimethyl-morpholin-4-yl)-3,3-diphenyl-propan-1 -one;
N-Bicyclo[2.2.1jhept-2-yl-4-morpholin-4-ylmethyl-benzamide;
[3-(2-Chloro-6-nitro-phenoxy)-phenyl]-piperidin-1-yl-methanone; N-Adamantan-1 -yl-2-(4-methyl-quinolin-2-ylsulfanyl)-acetamide;
Cyclohexanecarboxylic acid (2-phenylsulfanyl-phenyl)-amide;
(4-Hydroxy-4-phenyl-octahydro-quinolin-1-yl)-phenyl-methanone;
3-Cyclohexyl-N-(3-phenyl-propyl)-propionamide;
2-[1-(2,5-Dimethyl-phenyl)-1H-tetrazol-5-ylsulfanyl]-N-isopropyl-N-phenyl-acetamide; N-{2-[4-(3,4-Dihydro-1 H-isoquinoline-2-sulfonyl)-phenyl]-ethyl}-acetamide;
N-Benzyl-N-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethyl]-benzenesulfonamide;
[4-(2-Chloro-6-nitro-phenoxy)-phenyl]-piperidin-1-yl-methanone;
N-Cycloheptyl-3-phenyl-propionamide;
(3-Chloro-6-methyl-benzo[b]thiophen-2-yl)-piperidin-1-yl-methanone; N-Cycloheptyl-2,4-dimethoxy-benzamide;
N-(3-Chloro-phenyl)-2-(8,11,11 -trimethyl-3,4,6-triaza-tricyclo[6.2.1.02'7]undeca-2(7),3,5-trien-
5-ylsulfanyl)-acetamide;
N-(2-Nitro-phenyl)-2-(8,11 ,11-trimethyl-3,4,6-triaza-tricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-5- ylsulfanyl)-acetamide; N-Phenyl-2-(8,11 ,11-trimethyl-3,4,6-triaza-tricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-5- ylsulfanyl)-acetamide;
N-Ethyl-3-methyl-N-o-tolyl-benzamide;
N-[5-(2,4-Dichloro-benzylsulfanyl)-[1,3,4]thiadiazol-2-yl]-2,2-dimethyl-propionamide;
4-Bromo-1 -ethyl-1 H-pyrazole-3-carboxylic acid (2-methylsulfanyl-phenyl)-amide; 5-Benzoyl-furan-2-carboxylic acid diisopropylamide;
N-{2-[2-(4-Bromo-phenyl)-2-oxo-ethylsulfanyl]-benzothiazol-6-yl}-acetamide;
2-(6-Amino-benzothiazol-2-ylsulfanyl)-N-cyclohexyl-acetamide;
N-(2-Cyclohexylcarbamoylmethylsulfanyl-benzothiazol-6-yl)-2-methoxy-benzamide;
Benzofuran-2-yl-(4-phenyl-piperidin-1-yl)-methanone; 1-(2-Nitro-phenyl)-piperidine-3-carboxylic acid diethylamide; 1-(4-Nitro-phenyl)-piperidine-3-carboxylic acid diethylamide;
5-Bromo-furan-2-carboxylic acid adamantan-2-ylamide;
3,3-Dimethyl-pentanedioic acid bis-[(2,4-difluoro-phenyl)-amide];
2-(3-Bromo-benzylsulfanyl)-1-(4-phenyl-piperazin-1-yl)-ethanone; N-(2-Azepan-1-yl-2-oxo-ethyl)-N-benzyl-4-bromo-benzenesulfonamide;
1 -(2,3-Dihydro-indol-1 -yl)-2-p-tolylsulfanyl-ethanone;
[4-(4-Bromo-benzenesulfonyl)-piperazin-1-yl]-furan-2-yl-methanone;
[5-(2-Bromo-phenoxymethyl)-furan-2-yl]-(2,6-dimethyl-morpholin-4-yl)-methanone;
5-(2-Chloro-phenoxymethyl)-furan-2-carboxylic acid diethylamide; 5-(2-Bromo-phenoxymethyl)-furan-2-carboxylic acid diethylamide;
5-(2-Chloro-phenoxymethyl)-furan-2-carboxylic acid methyl-phenyl-amide;
[5-(2-Chloro-phenoxymethyl)-furan-2-yl]-(4-methyl-piperidin-1-yl)-methanone;
[3-(2,5-Dichloro-phenoxymethyl)-phenyl]-pyrrolidin-1 -yl-methanone;
[5-(4-Ethoxy-phenoxymethyl)-furan-2-yl]-(4-methyl-piperidin-1-yl)-methanone; 3-(1 ,3-Dioxo-1 ,3-dihydro-isoindol-2-yl)-N-(2-methyl-cyclohexyl)-propionamide;
3-(3,4-Dihydro-2H-quinoline-1-carbonyl)-N-phenyl-benzenesulfonamide;
[3-(2,3-Dihydro-indole-1-sulfonyl)-phenyl]-(3,4-dihydro-2H-quinolin-1-yl)-methanone;
[3-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-(4-methyl-piperidin-1-yl)-methanone;
N-Cyclohexyl-3-(2-hydroxy-4-methyl-phenyl)-3-phenyl-propionamide; 2-Diethylamino-N-(1 -phenyl-cyclopentylmethyl)-propionamide;
(6-Fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-(3-trifluoromethyl-phenyl)-methanone;
(2,6-Dimethyl-morpholin-4-yl)-[4-(naphthalen-1-yloxymethyl)-phenyl]-methanone;
N-Benzyl-4-bromo-N-ethyl-benzamide;
(3-Methyl-piperidin-1-yl)-[4-(naphthalen-1-yloxymethyl)-phenyl]-methanone; Azepan-1-yl-[5-(2-chloro-phenoxymethyl)-furan-2-yl]-methanone;
(4-Methyl-piperidin-1-yl)-[4-(naphthalen-1-yloxymethyl)-phenyl]-methanone;
Azepan-1-yl-[5-(2,4-dichloro-phenoxymethyl)-furan-2-yl]-methanone;
N-Cycloheptyl-4-(4-methoxy-2-methyl-phenyl)-butyramide;
2-(4-Benzothiazol-2-yl-piperazin-1-yl)-N-cyclohexyl-acetamide; N-Cycloheptyl-2-(2,6-dimethyl-phenoxy)-acetamide;
(3,4-Dihydro-2H-quinolin-1-yl)-(3-iodo-phenyl)-methanone;
N-Cycloheptyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzamide;
Azepan-1 -yl-[4-(2-chloro-phenoxymethyl)-phenyl]-methanone;
(2,6-Dimethyl-morpholin-4-yl)-[4-(naphthalen-2-yloxymethyl)-phenyl]-methanone; Azepan-1 -yl-[3-(4-ethoxy-phenoxymethyl)-phenyl]-methanone; Benzo[b]thiophene-3-carboxylic acid (1 ,2,3,4-tetrahydro-naphthalen-1-yl)-amide;
2-(4-Chloro-2-methyl-phenoxy)-N-cycloheptyl-acetamide;
2,4-Dichloro-N-cyclohexyl-N-methyl-benzamide;
N-Cyclooctyl-2-p-tolyloxy-acetamide; (3,5-Dimethyl-piperidin-1-yl)-(4-methyl-3-nitro-phenyl)-methanone;
Biphenyl-4-yl-(2,6-dimethyl-piperidin-1-yl)-methanone;
N-Cyclohexyl-4-fluoro-N-methyl-benzamide;
N-[4-(Azepane-1-carbonyl)-phenyl]-N-methyl-benzenesulfonamide;
N-Cycloheptyl-2-fluoro-benzamide; N-Cycloheptyl-4-methyl-benzamide;
(3-Methyl-piperidin-1-yl)-p-tolyl-methanone;
[2-(3,4-Dimethoxy-phenylcarbamoyl)-piperidin-1-yl]-acetic acid benzyl ester;
N-[4-(2-Methyl-piperidine-1-sulfonyl)-phenyl]-acetamide;
2-(2,4-Dichloro-phenoxy)-N-(2-methyl-butyl)-propionamide; [4-(2-Chloro-6-nitro-phenyl)-piperazin-1 -yl]-(4-methoxy-phenyl)-methanone;
N-Cyclohexyl-4-(4-methoxy-3-methyl-phenyl)-butyramide;
(3-Chloro-6-methoxy-benzo[b]thiophen-2-yl)-(3,4-dihydro-1H-isoquinolin-2-yl)-methanone;
2-(4-Methyl-benzylsulfanyl)-1 -piperidin-1 -yl-ethanone;
N-Cyclohexyl-N-[(4-phenyl-thiazol-2-ylcarbamoyl)-methyl]-benzamide; N-(2-Azepan-1-yl-2-oxo-ethyl)-N-(4-isopropyl-phenyl)-methanesulfonamide;
N-Adamantan-1-yl-3-p-tolylsulfanyl-propionamide;
6-(2,4-Dichloro-phenylcarbamoyl)-3,4-dimethyl-cyclohex-3-enecarboxylic acid;
(4-Butyl-cyclohexyl)-morpholin-4-yl-methanone;
(3,4-Dichloro-phenyl)-(3,4-dihydro-2H-quinolin-1-yl)-methanone; N-(2-Cyclohex-1 -enyl-ethyl)-3-methoxy-benzamide;
N-Adamantan-2-yl-3-(1 ,5-dimethyl-1 H-pyrazol-4-yl)-acrylamide;
N-Adamantan-1 -yl-N-methyl-4-(4-nitro-pyrazol-1 -ylmethyl)-benzamide;
5-(4-Chloro-3,5-dimethyl-pyrazol-1 -ylmethyl)-furan-2-carboxylic acid adamantan-2-ylamide;
2-(4-Chloro-phenoxy)-N-(2-fluoro-5-methyl-phenyl)-2-methyl-propionamide; N-Adamantan-1-yl-2-(4-chloro-3,5-dimethyl-phenoxy)-acetamide;
2-[(3-Carboxy-bicyclo[2.2.1]heptane-2-carbonyl)-amino]-5,6-dihydro-4H- cyclopenta[b]thiophene-3-carboxylic acid propyl ester;
2-Adamantan-1 -yl-N-[1 -(2,5-dimethyl-phenyl)-ethyl]-acetamide;
3-Methyl-thiophene-2-carboxylic acid cyclooctylamide; N-p-Tolyl-2-(8,11 ,11-trimethyl-3,4,6-triaza-tricyclo[6.2.1.02'7]undeca-2,4,6-trien-5-ylsulfanyl)- propionamide;
Azepan-1-yl-[5-(4-chloro-5-methyl-3-nitro-pyrazol-1-ylmethyl)-furan-2-yl]-methanone;
N-Adamantan-2-yl-3-(4-bromo-3-nitro-pyrazol-1-ylmethyl)-benzamide; N-Bicyclo[2.2.1]hept-2-yl-2-chloro-benzamide;
[5-(3-Chloro-phenoxymethyl)-furan-2-yl]-piperidin-1-yl-methanone;
1-(4-Ethyl-benzoyl)-6-methoxy-2-methyl-2,3-dihydro-1H-quinolin-4-one;
6-Fluoro-2-methyl-1-{3-[4-(propane-1-sulfonyl)-phenoxymethyl]-benzoyl}-2,3-dihydro- r7- quinolin-4-one; N-Cycloheptyl-2-(naphthalen-1 -yloxy)-acetamide;
N-Cyclohexyl-4-o-tolyloxy-butyramide;
(2-Benzylsulfanyl-phenyl)-morpholin-4-yl-methanone;
(2-Chloro-5,6-difluoro-3-methyl-phenyl)-(4-methyl-piperidin-1-yl)-methanone;
(3-Bromo-phenyl)-[4-(4-chloro-2-nitro-phenyl)-piperazin-1-yl]-methanone; 2-Bromo-N-(1 ,1 ,3,3-tetramethyl-butyl)-benzamide;
N-Adamantan-1-yl-2-(2-benzoyl-5-methoxy-phenoxy)-acetamide;
N-Cyclohexyl-3-methyl-4-p-tolyl-butyramide;
[5-(4-Methyl-2-nitro-phenoxymethyl)-furan-2-yl]-thiomorpholin-4-yl-methanone;
[5-(2,5-Dichloro-phenoxymethyl)-furan-2-yl]-thiomorpholin-4-yl-methanone; 5-(4-Chloro-2-nitro-phenoxymethyl)-furan-2-carboxylic acid adamantan-1 -ylamide;
4,5,6,7-Tetrahydro-benzo[b]thiophene-3-carboxylic acid cyclohexylamide;
4-Chloro-1 ,5-dimethyl-1 H-pyrazole-3-carboxylic acid adamantan-1-yl-methyl-amide;
4-(4-Methoxy-3-methyl-phenyl)-N-(2-methyl-cyclohexyl)-butyramide;
3-Benzo[1,3]dioxol-5-yl-1-(3,4-dihydro-1H-isoquinolin-2-yl)-propenone; N-Bicyclo[2.2.1]hept-2-yl-3-phenylsulfanyl-propionamide;
Azepan-1-yl-[5-(2-nitro-phenoxymethyl)-furan-2-yl]-methanone;
N-Benzyl-2-(4-chloro-phenylsulfanyl)-N-methyl-acetamide;
1 -(4-Benzyl-piperidin-1 -yl)-2-benzylsulfanyl-ethanone;
2-(4-tert-Butyl-phenoxy)-1 -(4-ethyl-piperazin-1 -yl)-ethanone; [4-(4-Ethoxy-phenoxymethyl)-phenyl]-(4-methyl-piperidin-1-yl)-methanone;
5-(4-Bromo-3,5-dimethyl-pyrazol-1-ylmethyl)-furan-2-carboxylic acid adamantan-2-ylamide;
1 -Azepan-1 -yl-3-(4-chloro-phenylsulfanyl)-propan-1 -one;
N-Bicyclo[2.2.1]hept-2-yl-2-(2-chloro-benzylsulfanyl)-acetamide;
2-(2-Methyl-benzylsulfanyl)-1-(4-phenyl-piperazin-1-yl)-ethanone; N-[2-(1 -Benzo[1 ,3]dioxol-5-yl-3-furan-2-yl-3-oxo-propylsulfanyl)-phenyl]-acetamide; (3,5-Dimethyl-piperidin-1-yl)-(3-iodo-phenyl)-methanone;
[5-(2-Bromo-phenoxymethyl)-furan-2-yl]-(6-fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)- methanone;
N-Benzyl-N-cyclohex-1-enyl-isonicotinamide; 1 -[4-(4-Fluoro-phenyl)-piperazin-1 -yl]-2-(2-methyl-benzylsulfanyl)-ethanone;
2-(2-Bromo-4-methyl-phenoxy)-N-(2-cyclohex-1-enyl-ethyl)-acetamide;
2-[5-(2-Hydroxy-phenyl)-[1 ,3,4]oxadiazol-2-ylsulfanyl]-1 -piperidin-1 -yl-ethanone;
5-(4-Nitro-pyrazol-1 -ylmethyl)-furan-2-carboxylic acid adamantan-2-ylamide;
3-Benzo[1 ,3]dioxol-5-yl-3-(2-methoxy-phenyl)-1 -pyrrolidin-1 -yl-propan-1 -one; N-Adamantan-2-yl-3,4-dichloro-benzamide;
Benzo[b]thiophen-3-yl-(6-fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-methanone;
2-Adamantan-1-yl-1-(3,4-dihydro-1H-isoquinolin-2-yl)-ethanone;
4,5,6,7-Tetrahydro-benzo[b]thiophene-3-carboxylic acid (2-cyclohex-1 -enyl-ethyl)-amide;
Benzo[b]thiophene-3-carboxylic acid (3,3,5-trimethyl-cyclohexyl)-amide; 2-(2,6-Dimethyl-phenoxy)-N-(2-isopropyl-phenyl)-acetamide;
4-Bromo-N-[3-(piperidine-1-carbonyl)-phenyl]-benzamide;
N-Benzo[1,3]dioxol-5-ylmethyl-2-(2-cyano-phenylsulfanyl)-benzamide;
N-Adamantan-1-yl-2-(naphthalen-2-yloxy)-acetamide;
[4-(4-Chloro-phenylsulfanylmethyl)-phenyl]-morpholin-4-yl-methanone; Thiophene-2-carboxylic acid (3,3,5-trimethyl-cyclohexyl)-amide;
Benzo[1,3]dioxol-5-yl-(3,4-dihydro-2H-quinolin-1-yl)-methanone;
3-Chloro-benzo[b]thiophene-2-carboxylic acid cyclooctylamide;
2-[2-Morpholin-4-yl-1-(4-nitro-benzyl)-2-oxo-ethyl]-isoindole-1 ,3-dione;
2-Hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-enecarboxylic acid phenylamide; (2,4-Dichloro-phenyl)-(2,6-dimethyl-piperidin-1-yl)-methanone;
Adamantane-1 -carboxylic acid furan-2-ylmethyl-p-tolyl-amide;
Azocan-1-yl-(4-tert-butyl-phenyl)-methanone;
3-Chloro-benzo[b]thiophene-2-carboxylic acid benzyl-methyl-amide;
Adamantane-1 -carboxylic acid (2-fluoro-phenyl)-amide; 2-(Piperidine-1 -carbonyl)-5-piperidin-1 -yl-oxazole-4-carbonitrile;
N-(4,6-Dimethyl-5-nitro-pyridin-3-yl)-benzamide;
Adamantan-1-yl-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone;
(2-Methyl-piperidin-1-yl)-o-tolyl-methanone;
N-Benzyl-4-chloro-N-isopropyl-3-nitro-benzamide; N-(3-Hexylsulfanyl-[1,2,4]thiadiazol-5-yl)-3-methyl-butyramide; 4,N-Dimethyl-N-[4-(piperidine-1-carbonyl)-phenyl]-benzenesulfonamide;
Azepan-1-yl-(5-tert-butyl-2H-pyrazol-3-yl)-methanone;
2-Amino-4-methyl-5-(piperidine-1-carbonyl)-thiophene-3-carboxylic acid ethyl ester;
5-Methyl-furan-2-carboxylic acid (1 -adamantan-1 -yl-ethyl)-amide; (3-Chloro-6-methyl-benzo[b]thiophen-2-yl)-(3,4-dihydro-./-/-isoquinolin-2-yl)-methanone;
N-Adamantan-1-yl-2-trifluoromethyl-benzamide;
(3-Bromo-phenyl)-(2,2,4-trimethyl-4-phenyl-3,4-dihydro-2ry-quinolin-1-yl)-methanone;
Benzo[1 ,3]dioxole-5-carboxylic acid dipropylamide;
N-(3,3-Diphenyl-propyl)-4-methoxy-benzamide; [4-(2-Chloro-6-nitro-phenyl)-piperazin-1 -yl]-p-tolyl-methanone;
Furan-2-yl-[4-(toluene-4-sulfonyl)-piperazin-1-yl]-methanone;
3-(2-Chloro-6-fluoro-phenyl)-1 -(3,4-dihydro-2H-quinolin-1 -yl)-propenone;
2-Chloro-N-cycloheptyl-benzamide;
1 -[4-(4-Nitro-phenyl)-piperazin-1 -yl]-3-phenyl-propan-1 -one; (3,4-Dihydro-1 H-isoquinolin-2-yl)-(3,4-dimethyl-phenyl)-methanone;
(1 -Adamantan-1 -yl-4-bromo-1 H-pyrazol-3-yl)-morpholin-4-yl-methanone;
2-Phenyl-cyclopropanecarboxylic acid cyclooctylamide;
3-[4-(2-Ethoxy-phenyl)-piperazine-1-carbonyl]-isochromen-1-one;
[3-(4-Bromo-pyrazol-1-ylmethyl)-phenyl]-(4-methyl-piperidin-1-yl)-methanone; 2-Azepan-1 -yl-N-biphenyl-2-yl-acetamide;
N-[5-(3,4-Dimethoxy-benzyl)-[1 ,3,4]thiadiazol-2-yl]-3-methyl-butyramide;
Adamantan-1 -yl-(4-phenyl-piperidin-1-yl)-methanone;
N-(2-Azepan-1-yl-2-oxo-ethyl)-N-(4-ethoxy-phenyl)-4-methylsulfanyl-benzenesulfonamide;
1 -Adamantan-1 -yl-4-bromo-1 H-pyrazole-3-carboxylic acid diethylamide; (6-Fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-(2-fluoro-phenyl)-methanone;
3-[4-(2,3-Dimethyl-phenyl)-piperazine-1-carbonyl]-isochromen-1-one;
N-Cyclooctyl-2-(2-methoxy-phenoxy)-acetamide;
N-Cyclohexyl-N-methyl-2-nitro-benzamide;
Adamantane-1 -carboxylic acid (1 ,1-dioxo-tetrahydro-thiophen-3-yl)-amide; N-Adamantan-2-yl-2-(4-chloro-phenyl)-acetamide;
(2,4-Dichloro-phenyl)-(3-methyl-piperidin-1-yl)-methanone;
2-(4-tert-Butyl-phenoxy)-N-cyclooctyl-acetamide;
(10,11-Dihydro-dibenzo[b,f]azepin-5-yl)-(2-methoxy-phenyl)-methanone;
(3-Chloro-phenyl)-(2-methyl-piperidin-1-yl)-methanone; (3-Chloro-6-nitro-benzo[b]thiophen-2-yl)-(3-methyl-piperidin-1-yl)-methanone; (2,5-Dichloro-phenyl)-(4-methyl-piperidin-1-yl)-methanone;
N-[5-(3,4-Dichloro-benzyl)-[1,3,4]thiadiazol-2-yl]-2,2-dimethyl-propionamide;
4-(4-Chloro-2-methyl-phenoxy)-1-(3,4-dihydro-2H-quinolin-1-yl)-butan-1-one;
(3,4-Dichloro-phenyl)-[4-(2,3-dimethyl-phenyl)-piperazin-1-yl]-methanone; Cyclooctanecarboxylic acid [1-(naphthalene-2-sulfonyl)-pyrrolidin-2-yl]-amide;
1-Butyl-pyrrolidine-2-carboxylic acid benzo[1 ,3]dioxol-4-ylamide;
5-Methyl-furan-2-carboxylic acid dibenzylamide;
(3,4-Dihydro-2H-quinolin-1-yl)-[3-(4-phenyl-piperazine-1-sulfonyl)-phenyl]-methanone;
Bicyclo[2.2.1]hept-2-yl-[4-(2,3-dimethyl-phenyl)-piperazin-1-yI]-methanone; N-Adamantan-1 -yl-2-benzoyl-benzamide;
[5-(2-Chloro-phenoxymethyl)-furan-2-yl]-(3-methyl-piperidin-1-yl)-methanone;
(3,5-Dimethyl-piperidin-1-yl)-(2-iodo-phenyl)-methanone;
1-Benzenesulfonyl-pyrrolidine-2-carboxylic acid cyclooctylamide;
(3,4-Dimethoxy-phenyl)-(6-fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-methanone; 3-(2,6-Dichloro-phenyl)-1 -(2-ethyl-piperidin-1 -yl)-propenone;
N-(3,4-Difluoro-phenyl)-2,6-difluoro-benzamide;
2,6-Difluoro-N-naphthalen-1-yl-benzamide;
(4-Chloro-phenyl)-(3,5-dimethyl-piperidin-1-yl)-methanone;
N-[4-(2,6-Dimethyl-piperidine-1-carbonyl)-phenyl]-2-(naphthalen-2-yloxy)-acetamide; (2-Chloro-phenyl)-(3-methyl-piperidin-1 -yl)-methanone;
N-{2-[4-(Piperidine-1-sulfonyl)-phenyl]-ethyl}-acetamide;
N-Biphenyl-2-yl-2-(pyridin-2-ylsulfanyl)-acetamide;
Azepan-1-yl-[5-(4-chloro-3,5-dimethyl-pyrazol-1-ylmethyl)-furan-2-yl]-methanone;
Acetic acid 4-(4-methyl-piperidine-1-carbonyl)-phenyl ester; Acetic acid 4-(4-benzyl-piperidine-1 -carbonyl)-phenyl ester;
Benzo[1 ,3]dioxole-5-carboxylic acid cycloheptylamide;
2-(2,4-Dimethyl-phenoxy)-1-(6-fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-ethanone;
Acetic acid 4-(3,4-dihydro-2H-quinoline-1-carbonyl)-phenyl ester;
Azepan-1-yl-(3,5-dibromo-phenyl)-methanone; (3,5-Dibromo-phenyl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone;
N-Cyclooctyl-4-isopropyl-benzamide;
N-Cyclooctyl-2-(4-methoxy-phenyl)-acetamide;
(4-tert-Butyl-piperidin-1-yl)-phenyl-methanone;
N-(4-tert-Butyl-3-nitro-phenyl)-acetamide; (2,6-Dimethyl-piperidin-1-yl)-[5-(2,3,5,6-tetrafluoro-phenoxymethyl)-furan-2-yl]-methanone; N-Cyclohexyl-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-N-methyl-propionamide;
2-(4-Chloro-3-methyl-phenoxy)-N-cyclohexyl-N-methyl-acetamide;
N-Cyclopentyl-3-(3,4-dihydro-2H-quinoline-1-carbonyl)-benzenesulfonamide;
(3,4-Dihydro-1H-isoquinolin-2-yl)-(3-dimethylamino-phenyl)-methanone; 3-Cyclohexylcarbamoyl-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid isopropyl ester;
1-(3,4-Dihydro-1H-isoquinolin-2-yl)-2-(2-methoxy-phenyl)-ethanone;
N-Benzyl-N-cyclohex-1 -enyl-benzamide;
[1 -(Thiophene-2-sulfonyl)-piperidin-4-yl]-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1 ]oct-6-yl)- " methanone; N-Adamantan-1 -yl-2-(1 -phenyl-1 H-tetrazol-5-ylsulfanyl)-acetamide;
(3,4-Dihydro-2H-quinolin-1-yl)-[4-(morpholine-4-sulfonyl)-phenyl]-methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-[4-(pyrrolidine-1-sulfonyl)-phenyl]-methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-[1-(thiophene-2-sulfonyl)-piperidin-4-yl]-methanone;
(1-Benzenesulfonyl-piperidin-3-yl)-(3,4-dihydro-1H-isoquinolin-2-yl)-methanone; 6,7-Dimethyl-4-oxa-tricyclo[4.3.0.03,7]nonane-3-carboxylic acid cyclohexylamide;
6,7-Dimethyl-4-oxa-tricyclo[4.3.0.03,7]nonane-3-carboxylic acid (2-chloro-phenyl)-amide;
(6,7-Dimethyl-4-oxa-tricyclo[4.3.0.03'7]non-3-yl)-piperidin-1-yl-methanone;
2-(5,6-Dimethyl-4-oxo-3,4-dihydro-thieno[2,3-d]pyrimidin-2-ylsulfanyl)-N-furan-2-ylmethyl- acetamide; N-Allyl-2-(5,6-dimethyl-4-oxo-3,4-dihydro-thieno[2,3-d]pyrimidin-2-ylsulfanyl)-acetamide;
N-Adamantan-1-yl-2-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ylsulfanyl)- acetamide;
1 -(3,4-Dihydro-2H-quinoline-1 -carbonyl)-4,7,7-trimethyl-2-oxa-bicyclo[2.2.1 ]heptan-3-one;
1-(3,4-Dihydro-1H-isoquinoline-2-carbonyl)-4,7,7-trimethyl-2-oxa-bicyclo[2.2.1]heptan-3-one; Azepan-1-yl-(6,7-dimethyl-4-oxa-tricyclo[4.3.0.03,7]non-3-yl)-methanone;
2,5-Dimethyl-f uran-3-carboxylic acid (1 -adamantan-1 -yl-ethyl)-amide;
1 -Cyclohexyl-5-oxo-pyrrolidine-3-carboxylic acid (3-cyano-4,5,6,7-tetrahydro- benzo[b]thiophen-2-yl)-amide;
2-(2-Cyano-phenylsulfanyl)-N-cyclopentyl-benzamide; [5-(2-Methoxy-4-propyl-phenoxymethyl)-furan-2-yl]-(3-methyl-piperidin-1-yl)-methanone;
(4-tert-Butyl-phenyl)-(3,5-dimethyl-piperidin-1-yl)-methanone;
[4-(2-Methoxy-naphthalen-1-ylmethyl)-piperazin-1-yl]-(4-methoxy-phenyl)-methanone;
(3,4-Dichloro-phenyl)-(3,5-dimethyl-piperidin-1-yl)-methanone;
(4-Ethoxy-phenyl)-(4-methyl-piperidin-1-yl)-methanone; 2-Phenethyl-N-(tetrahydro-furan-2-ylmethyl)-benzamide; N-Cyclohep-yl-2-phenoxy-benzamide;
Adamantane-1 -carboxylic acid (2-ethoxy-phenyl)-amide;
N-Adamantan-2-yl-2-o-tolyloxy-acetamide;
(2-Chloro-phenyl)-(3,5-dimethyl-piperidin-1-yl)-methanone; 1 -Morpholin-4-yl-2-[3-(4-nitro-phenyl)-adamantan-1 -yl]-ethanone;
2-Dimethylamino-N-(2-nitro-phenyl)-benzamide;
N-Benzyl-2-(4,4,6-trimethyl-1-p-tolyl-1,4-dihydro-pyrimidin-2-ylsulfanyl)-acetamide;
[4-(3,5-Dinitro-phenoxy)-phenyl]-(2-ethyl-piperidin-1-yl)-methanone;
1 -(4-Chloro-benzoyl)-2,3-dihydro-1 H-benzo[g]quinolin-4-one; 2-[(Adamantane-1-carbonyl)-amino]-3-phenyl-propionic acid methyl ester;
[Benzyl-(4-nitro-benzoyl)-amino]-acetic acid ethyl ester;
9-Oxo-9H-fluorene-3-carboxylic acid methyl-(4-nitro-phenyl)-amide;
Adamantane-1 -carboxylic acid [2-(4-methoxy-phenyl)-ethyl]-amide;
(10,11 -Dihydro-dibenzo[b,f]azepin-5-yl)-(4-fluoro-phenyl)-methanone; 2-Benzylsulfanyl-N-[2-(2-methoxy-phenoxy)-ethyl]-acetamide;
N-Adamantan-1-yl-2-(2-oxo-4-phenyl-pyrrolidin-1-yl)-acetamide;
2-Bromo-N-tricyclo[3.2.1.02,4]oct-6-ylmethyl-benzamide;
Adamantane-1 -carboxylic acid (2,6-dimethoxy-pyrimidin-4-yl)-amide;
Hexanedioic acid (2,7,7-trimethyl-bicyclo[2.2.1]hept-1-yl)-amide (1,7,7-trimethyl- bicyclo[2.2.1 ]hept-2-yl)-amide;
2-Chloro-N-(2-cyclohexyl-ethyl)-benzamide;
2-[3-(2-Ethyl-piperidin-1-yl)-3-oxo-propyl]-isoindole-1 ,3-dione;
N-Adamantan-1-yl-2-hydroxy-2,2-diphenyl-acetamide;
Adamantane-1 -carboxylic acid (naphthalen-1 -ylmethyl)-amide; Adamantane-1 -carboxylic acid (benzo[1 ,3]dioxol-5-ylmethyl)-amide;
1 -(Azepane-1 -carbonyl)-fluoren-9-one;
2-(Quinolin-2-ylsulfanyl)-N-p-tolyl-acetamide;
2,4-Dichloro-N-[3-(piperidine-1-carbonyl)-phenyl]-benzamide;
2-Chloro-4,5-difluoro-N-(3,3,5-trimethyl-cyclohexyl)-benzamide; 2-(2-Chloro-benzylsulfanyl)-N-p-tolyl-acetamide;
[4-(4-Chloro-phenylsulfanylmethyl)-phenyl]-pyrrolidin-1-yl-methanone;
N-Adamantan-1-yl-N-methyl-isonicotinamide;
Azepan-1-yl-[4-(4-chloro-phenylsulfanylmethyl)-phenyl]-methanone;
(2-Chloro-phenyl)-(1,5,7-trimethyl-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methanone; (3-Chloro-benzo[b]thiophen-2-yl)-(4-methyl-piperidin-1-yl)-methanone; Benzoic acid 1-benzoyl-decahydro-quinolin-4-yl ester;
2-(3-Bromo-benzylsulfanyl)-1-[4-(2-methoxy-phenyl)-piperazin-1-yl]-ethanone;
4-Methyl-N-[2-(phenoxazine-10-carbonyl)-phenyl]-benzenesulfonamide;
2-[1-(Azepane-1-carbonyl)-2-methyl-propyl]-isoindole-1 ,3-dione; 2-(3-Bromo-benzylsulfanyl)-1 -piperidin-1 -yl-ethanone;
1-[3-(4-Bromo-phenyl)-1-furan-2-yl-3-oxo-propyl]-pyrrolidin-2-one;
2-Chloro-N-cyclooctyl-4,5-difluoro-benzamide;
2,4-Dichloro-N-(2-furan-2-ylmethyl-cyclohexyl)-benzamide;
N-(4-Benzoyl-furazan-3-yl)-2-fluoro-benzamide; N-Adamantan-1 -yl-2-(3-cyano-4-methoxymethyl-6-methyl-pyridin-2-ylsulfanyl)-acetamide;
4-tert-Butyl-N-cyclooctyl-benzamide;
N-Adamantan-1-yl-2-phenyl-butyramide;
(3-Chloro-6-methoxy-benzo[b]thiophen-2-yl)-piperidin-1-yl-methanone;
(3,7-Dichloro-6-methoxy-benzo[b]thiophen-2-yl)-piperidin-1-yl-methanone; Acetic acid 1-benzoyl-decahydro-quinolin-4-yl ester;
2-Bromo-N-methyl-N-phenyl-benzamide;
N-Benzo[1,3]dioxol-5-yl-2,4-dichloro-benzamide;
(3-Chloro-6-fluoro-benzo[b]thiophen-2-yl)-piperidin-1-yl-methanone;
N-(1,2,3,5,6,7-Hexahydro-s-indacen-1-yl)-2-piperidin-1-yl-acetamide; 2-[2-(1 ,3-Dioxo-1 ,3-dihydro-isoindol-2-yl)-3-phenyl-propionylamino]-3-methyl-butyric acid methyl ester;
2-(6-Oxo-6-piperidin-1-yl-hexyl)-isoindole-1 ,3-dione;
2-[2-(1 ,3-Dioxo-1 ,3-dihydro-isoindol-2-yl)-3-phenyl-propionylamino]-3-methyl-butyric acid methyl ester; Adamantane-1 -carboxylic acid (2,6-dihydroxy-pyrimidin-4-yl)-amide;
Adamantane-1 -carboxylic acid methyl-phenyl-amide;
3-Chloro-benzo[b]thiophene-2-carboxylic acid dibenzylamide;
N-Adamantan-1-yl-2-(3-cyano-6-methyl-4-trifluoromethyl-pyridin-2-ylsulfanyl)-acetamide;
2-(3-Oxo-3-phenyl-propenyl)-isoindole-1 ,3-dione; N-[5-(5-Chloro-benzooxazol-2-yl)-2-methyl-phenyl]-2-methoxy-benzamide;
N-[2-(2-Bromo-phenyl)-benzooxazol-5-yl]-2-methoxy-benzamide;
2-(4-Chloro-phenoxy)-N-(4-chloro-3-trifluoromethyl-phenyl)-acetamide;
2,2-Dimethyl-N-(5-propyl-[1,3,4]thiadiazol-2-yl)-propionamide;
2-[2-(2,6-Dimethyl-morpholin-4-yl)-1-methyl-2-oxo-ethyl]-isoindoIe-1 ,3-dione; 2-(2-Cyano-phenylsulfanyl)-N-(2-trifluoromethyl-phenyl)-benzamide; Azepan-1-yl-(3,6-dichloro-benzo[b]thiophen-2-yl)-methanone;
Benzo[1 ,3]dioxol-5-yl-(4-benzyl-piperidin-1 -yl)-methanone;
Azepan-1-yl-(3-chloro-6-methyl-benzo[b]thiophen-2-yl)-methanone;
N-(5-Hexyl-[1,3,4]thiadiazol-2-yl)-isobutyramide; (3-Chloro-phenyl)-(10,11-dihydro-dibenzo[b,fjazepin-5-yl)-methanone;
(2-Chloro-phenyl)-(10,11 -dihydro-dibenzo[b,f]azepin-5-yl)-methanone;
2-Amino-5-(azepane-1-carbonyl)-4-methyl-thiophene-3-carboxylic acid ethyl ester;
Adamantan-1-yl-(4-cyclopropyl-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl)-methanone;
Adamantan-1-yl-(4-trifluoromethyl-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl)-methanone; Adamantan-1 -yl-[4-(1 H-benzoimidazol-2-ylsulfanyl)-piperidin-1 -yl]-methanone;
Adamantan-1-yl-(1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl)-methanone;
[4-(1H-lmidazol-4-yl)-piperidin-1-yl]-(4-pentyl-phenyl)-methanone;
3-Cyclohexyl-1 -[4-(1 H-imidazol-4-yl)-piperidin-1 -yl]-propan-1 -one;
1 -(4-Propyl-piperazin-1 -yl)-3-(4-trifluoromethyl-phenyl)-propan-1 -one; N-(2-Hydroxy-benzyl)-3-thiophen-3-yl-N-(2-thiophen-2-yl-ethyl)-acrylamide;
N-(1,3-Dimethyl-pentyl)-2-(3-fluoro-phenyl)-N-(4-hydroxy-benzyl)-acetamide;
N-Cyclobutyl-2-(3-fluoro-phenyl)-N-(4-hydroxy-benzyl)-acetamide;
N-Cyclobutyl-N-(4-hydroxy-benzyl)-4-trifluoromethyl-benzamide;
N-(3-Hydroxy-benzyl)-2-methyl-3-nitro-N-(4-sulfamoyl-benzyl)-benzamide; N-(4-Bromo-benzyl)-N-(4-hydroxy-benzyl)-2-naphthalen-1-yl-acetamide;
6-(2-Bromo-phenylsulfanyl)-hexanoic acid (3-amino-2,2-dimethyl-propyl)-amide;
N-(3-Amino-2,2-dimethyl-propyl)-4-[2-(2-isopropyl-phenylsulfanyl)-ethyl]-benzamide;
N-(3-Amino-2,2-dimethyl-propyl)-4-[4-(4-chloro-phenyl)-pyrimidin-2-ylsulfanylmethyl]-3-nitro- benzamide; 4-(4-Bromo-phenyl)-N-(2-hydroxy-benzyl)-4-oxo-N-thiophen-2-ylmethyl-butyramide;
N-[2-(2,4-Dichloro-phenyl)-ethyl]-N-(4-hydroxy-benzyl)-2-thiophen-3-yl-acetamide;
N-(2-Chloro-benzyl)-N-(4-hydroxy-benzyl)-2-thiophen-2-yl-acetamide;
Heptanoic acid benzyl-(4-hydroxy-benzyl)-amide;
N-(4-Fluoro-benzyl)-N-(4-hydroxy-benzyl)-2-thiophen-3-yl-acetamide; 4-Methyl-pentanoic acid (4-fluoro-benzyl)-(4-hydroxy-benzyl)-amide;
N-Allyl-2-(4-chloro-phenyl)-N-(4-hydroxy-benzyl)-acetamide;
N-Allyl-2-benzo[b]thiophen-3-yl-N-(4-hydroxy-benzyl)-acetamide;
Heptanoic acid (3-ethoxy-propyl)-(4-hydroxy-benzyl)-amide;
Dec-3-enoic acid (4-hydroxy-benzyl)-(4-trifluoromethyl-benzyl)-amide; 6-Oxo-6-phenyl-hexanoic acid (4-hydroxy-benzyl)-(4-trifluoromethyl-benzyl)-amide; 2-(3,4-Difluoro-phenyl)-N-(4-hydroxy-benzyl)-N-thiophen-2-ylmethyl-acetamide;
2-Methyl-pent-4-enoic acid (3-hydroxy-benzyl)-[2-(2-methoxy-phenyl)-ethyl]-amide;
Heptanoic acid (3-hydroxy-benzyl)-(4-isopropyl-benzyl)-amide;
5-(2,6-Dichloro-phenylsulfanyl)-pentanoic acid (naphthalen-1 -ylmethyl)-amide; N-(6,6-Dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-4-[2-(5-methyl-1H-benzoimidazol-2-ylsulfanyl)- ethylj-benzamide;
N-(6,6-Dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-4-[2-(4-phenoxy-pyrimidin-2-ylsulfanyl)-ethyl]- benzamide;
N-(6,6-Dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-4-[2-(4-fluoro-phenylsulfanyl)-ethyl]- benzamide;
4-(2,6-Dichloro-phenylsulfanyl)-N-(6,6-dimethyl-bicyclo[3.1.1 ]hept-2-ylmethyl)-butyramide;
5-(3-Methylsulfanyl-[1 ,2,4]thiadiazol-5-ylsulfanyl)-pentanoic acid (6,6-dimethyl- bicyclo[3.1.1]hept-2-ylmethyl)-amide;
5-(2,6-Dichloro-phenyIsulfanyl)-pentanoic acid [2-(3-trifluoromethyl-phenyl)-ethyl]-amide; 4-[2-(2,6-Dichloro-phenylsulfanyl)-ethyl]-N-[2-(2-fluoro-phenyl)-ethyl]-benzamide;
2-Cyclohexylamino-thiazole-4-carboxylic acid (1 ,2,3,4-tetrahydro-naphthalen-1-yl)-amide;
2-Cyclohexylamino-thiazole-4-carboxylic acid (3-chloro-4-hydroxy-phenyl)-amide;
2-Cyclohexylamino-thiazole-4-carboxylic acid (1 ,2-dimethyl-propyl)-amide;
2-Cyclohexylamino-thiazole-4-carboxylic acid (1 -ethyl-propyl)-amide; 2-Cyclohexylamino-thiazole-4-carboxylic acid [3-(1-hydroxy-ethyl)-phenyl]-amide;
2-Cyclohexylamino-thiazole-4-carboxylic acid (1 -ethynyl-cyclohexyl)-amide;
2-Cyclohexylamino-thiazole-4-carboxylic acid (2-methoxy-dibenzofuran-3-yl)-amide;
2-Cyclohexylamino-thiazole-4-carboxylic acid [2-(4-hydroxy-phenyl)-ethyl]-amide;
2-Cyclohexylamino-thiazole-4-carboxylic acid (4-hydroxy-cyclohexyl)-amide; 2-(2,6-Difluoro-benzylamino)-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-acetamide;
4-{4-[2-(4-Dimethylamino-phenyl)-acetyl]-piperazin-1-yl}-3-(2-phenyl-propylamino)- benzamide;
2-(2-Ethyl-phenylsulfanyl)-3-[methyl-(2-pyridin-4-yl-ethyl)-amino]-N-prop-2-ynyl- propionamide; 4-Methyl-cyclohexanecarboxylic acid {[2-(2-chloro-6-fluoro-benzylsulfanyl)-ethylcarbamoyl]- methyl}-prop-2-ynyl-amide;
2-Benzylsulfanyl-N-{[2-(2-chloro-6-fluoro-benzylsulfanyl)-ethylcarbamoyl]-methyl}-N-(2- methoxy-ethyl)-acetamide;
4-[2-(5-Cyclopropylmethylsulfanyl-[1,3,4]thiadiazol-2-ylsulfanyl)-ethyl]-N-(6,6-dimethyl- bicyclo[3.1.1 ]hept-2-ylmethyl)-benzamide; N-(6,6-Dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-2-p-tolyloxy-acetamide;
Bicyclo[2.2.1 ]hept-5-ene-2-carboxylic acid [4-(2,5-difluoro-phenoxy)-butyl]-amide;
4-Trifluoromethyl-cyclohexanecarboxylic acid [6-(2,6-difluoro-phenoxy)-hexyl]-amide;
N-Cyclopropyl-3-methoxy-N-(2-piperidin-4-yl-ethyl)-5-(pyridine-2-carbonyl)-benzamide; 3-Methoxy-N-(2-methoxy-ethyl)-N-(2-piperidin-4-yl-ethyl)-5-(pyridine-2-carbonyl)-benzamide;
3-Methoxy-N-(2-piperidin-4-yl-ethyl)-5-(pyridine-2-carbonyl)-N-(tetrahydro-furan-2-ylmethyl)- benzamide;
3-Methoxy-N-(2-oxo-azepan-3-yl)-N-(2-piperidin-4-yl-ethyl)-5-(pyridine-2-carbonyl)- benzamide; 3-Methoxy-N-[3-(2-oxo-pyrrolidin-1 -yl)-propyl]-N-(2-piperidin-4-yl-ethyl)-5-(pyridine-2- carbonyl)-benzamide;
3-Methoxy-N-methyl-N-(2-piperidin-4-yl-ethyl)-5-(pyridine-2-carbonyl)-benzamide;
[2-({Cyclopropyl-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-methyl)-phenoxy]-acetic acid; (2-{[[3-Methoxy-5-(pyridine-2-carbonyl)-benzoyl]-(3-methyl-butyl)-amino]-methyl}-phenoxy)- acetic acid;
[2-({Cyclopentyl-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-methyl)-phenoxy]-acetic acid;
[2-({(2-Methoxy-ethyl)-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-methyl)-phenoxy]- acetic acid;
[2-({Carbamoylmethyl-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-methyl)-phenoxy]- acetic acid;
[2-({[3-Methoxy-5-(pyridine-2-carbonyl)-benzoyl]-pyridin-4-yl-amino}-methyl)-phenoxy]-acetic acid; [2-({Cyclopropylmethyl-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-methyl)- phenoxyj-acetic acid;
[2-({[3-Methoxy-5-(pyridine-2-carbonyl)-benzoyl]-methyl-amino}-methyl)-phenoxy]-acetic acid;
[4-(4-Hydroxy-benzyl)-piperazin-1-yl]-[3-methoxy-5-(pyridine-2-carbonyl)-phenyl]-methanone; {Carbamoylmethyl-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-acetic acid;
{(3-lmidazol-1-yl-propyl)-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-acetic acid;
{[3-Methoxy-5-(pyridine-2-carbonyl)-benzoyl]-pyridin-4-yl-amino}-acetic acid;
[[3-Methoxy-5-(pyridine-2-carbonyl)-benzoyl]-(2-oxo-azepan-3-yl)-amino]-acetic acid;
3-Methoxy-N-(2-methoxy-ethyl)-N-piperidin-3-ylmethyl-5-(pyridine-2-carbonyl)-benzamide; 4-[3-Methoxy-5-(pyridine-2-carbonyl)-benzoylamino]-piperidine-1 -carboxylic acid ethyl ester; 3-Methoxy-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-5-(pyridine-2-carbonyl)-benzamide;
3-({Carbamoylmethyl-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-methyl)-benzoic acid;
3-({(3-lmidazol-1-yl-propyl)-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-methyl)- benzoic acid;
4-Amino-N-(3-hydroxy-benzyl)-N-indan-2-yl-2-propionylamino-butyramide;
5-Amino-2-propionylamino-pentanoic acid (3-hydroxy-benzyl)-indan-2-yl-amide;
N-Ethyl-2-hexylamino-N-(4-hydroxy-benzyl)-acetamide;
2-Hexylamino-N-(4-hydroxy-benzyl)-N-methyl-acetamide; 1 -[1 -(6-Phenyl-hexanoyl)-piperidin-4-yl]-1 ,3-dihydro-benzoimidazol-2-one;
1-[1-(3-Cyclohexyl-propionyl)-piperidin-4-yl]-1 ,3-dihydro-benzoimidazol-2-one;
N-(2-Hydroxy-benzyl)-N-isobutyl-benzamide;
N-(2-Hydroxy-benzyl)-2-(4-hydroxy-phenyl)-N-isobutyl-acetamide;
N-(2-Hydroxy-benzyl)-N-(3-methyl-butyl)-benzamide; N-(4-Hydroxy-benzyl)-N-isobutyl-benzamide;
4-Hydroxy-N-(4-hydroxy-benzyl)-N-isobutyl-benzamide;
N-(4-Hydroxy-benzyl)-2-(4-hydroxy-phenyl)-N-isobutyl-acetamide;
N-(4-Hydroxy-benzyl)-N-(3-methyl-butyl)-benzamide;
N-(2-Ethoxy-ethyl)-4-hydroxy-N-(4-hydroxy-benzyl)-benzamide; N-(4-Hydroxy-benzyl)-N-(3-isopropoxy-propyl)-benzamide;
N-(3-Hydroxy-benzyl)-N-(4-methyl-pentyl)-benzamide;
N-(3-Hydroxy-benzyl)-2-(4-hydroxy-phenyl)-N-(4-methyl-pentyl)-acetamide;
N-(3-Hydroxy-benzyl)-N-(3-isopropoxy-propyl)-benzamide;
N-(2-Hydroxy-benzyl)-N-(3-methyl-butyl)-4-propyl-benzamide; N-(4-Hydroxy-benzyl)-N-(6-hydroxy-hexyl)-4-propyl-benzamide;
N-(4-Hydroxy-benzyl)-N-(3-methyl-butyl)-4-propyl-benzamide;
N-[2-(4-Fluoro-benzylamino)-thiazol-4-ylmethyl]-N-phenethyl-butyramide; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms. In another embodiment, the present invention is concerned the substituted amides or prodrugs thereof of the general formula (II)
Figure imgf000042_0001
wherein R1 is C3-C10cycloalkyl or C3-C10hetcycloalkyl, wherein the cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R4;
R2 is hydrogen, C C8alkyl, arylCi -Chalky!, wherein the alkyl and aryl groups independently are optionally substituted with one or more of R5; or
R1 and R2 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-C8alkyl, aryl, hetaryl, aryld- C6alkyl, hetarylCrC6alkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrC6alkyloxy, hetaryld- C6alkyloxy, d-Cealkyloxyd-Cealkyl, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetaryld-Cealkylcarbonyl, C C6alkylcarboxy, arylcarboxy or aryld- C6alkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R14;
R3 is C3-Cι0cycloalkyl, C3-C10hetcycloalkyl, aryl or hetaryl, wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R7;
R4 and R5 independently are hydrogen, hydroxy, oxo, cyano, halo, methylendioxo, NR8R9, d-C8alkyl, CrC6alkyloxy, trihalomethyl, trihalomethyloxy, C3-C10cycloalkyl, C3-C.0hetcyclo- alkyl, C3-Cιocycloalkenyl, aryl, hetaryl, hetarylSOn, arylCrC6alkyloxy, hetarylCrCealkyloxy, CrC6alkyl-R6-CrC6alkyl, arylCrC6alkyl-R6-CrC6alkyl, CrC6alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, hetarylcarbonyl, hetarylCrC6alkylcarbonyl, CrC6alkylSOn, d-C6- alkylcarboxy, arylcarboxy, hetarylcarboxy, aryld-C6alkylcarboxy or hetarylCrC6alkylcarboxy wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one ore more of R15;
R6 is oxygen, sulphur, SOn or NR16;
R7 is hydrogen, halo, hydroxy, cyano, nitro, COOR17, d-C8alkyl, C3-d0cycloalkyl, C3-C10het- cycloalkyl, methylendioxo, trihalomethyl, trihalomethyloxy, aryl, arylCrCealkyl, CrC6alkyloxy, CrCealkyloxyCrC6alkyl, aryloxy, arylC1-C6alkyloxy, aryloxyCrC6alkyl, arylCrC6alkyloxyCr C6alkyl, hetaryl, hetarylC C6alkyl, hetaryloxy, hetarylCrCealkyloxy, hetaryloxyd-Cealkyl, hetaryld-Cealkyl-oxyd-Cealkyl, NR8R9, SOmNR8R9, NR4R5carbonyld-C6alkyl, arylthio, hetarylthio, R18carbonylNR8, arylSOn, hetarylSOn, R19SOmNR8, arylthioC C6alkyl, hetarylthioCrCealkyl or arylCrC6alkylR6CrC6alkyl; wherein the aryl and hetaryl groups independently are optionally substituted with one or more R10;
R8 and R9 independently are hydrogen, d-C8alkyl, aryl, hetaryl, CrC6alkylSOm, arylSOm, arylCrC6alkylSOm, arylCrC6alkyl or hetaryld-Cealkyl wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R11; or
R8 and R9 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system optionally being substituted with at least one halo, cyano, d-C8alkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrC6alkyl, hydroxy, oxo, d-C6alkyloxy, arylCrC6alkyloxy, hetaryld- C6alkyloxy, CrC6alkyloxyCrC6alkyl, CrC6aIkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkylcarbonyl, hetarylCrC6alkylcarbonyl, CrC6alkylcarboxy, arylcarboxy, hetarylcarboxy, arylCrC6alkylcarboxy or hetarylCrC6alkylcarboxy;
R10 and R11 independently are hydrogen, hydroxy, oxo, halo, cyano, nitro, d-C8alkyl, d- C6alkyl-oxy, NR12R13, methylendioxo, trihalomethyl or trihalomethyloxy;
R12 and R13 independently are hydrogen, d-C8alkyl or arylCrC6alkyl;
R14 is hydrogen, halo, hydroxy, oxo, nitro, cyano, d-C8alkyl, d-C6alkyloxy or aryloxy;
R15 is hydrogen, halo, hydroxy, oxo, nitro, cyano, CONR8R9 or COOR17;
R16 is hydrogen, CrC8alkyl, C3-C10cycloalkyl, C3-C10hetcycloalkyl, aryl, arylCrC6alkyl, hetaryl, hetarylCrC6alkyl, alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, aryloxyd- Cealkyl, hetaryloxyCrC6alkyl, arylthioCrC6alkyl or hetarylthioCrC6alkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R10;
R17 is hydrogen, d-C8alkyl, aryl or arylCrCealkyl; R18 is CrCealkyl, C2-C6alkenyl, aryl, aryld-Cealkyl, hetaryl, hetarylCrC6alkyl, C3- C10cycloalkyl, C3-C10hetcycloalkyl, CrC6alkyloxy, aryloxy, arylCrC6alkyloxy, aryld- C6alkyloxyCrCealkyl, hetarylCrC6alkyloxyCrC6alkyl, hetaryloxy, hetarylCrCealkyloxy or R8R9NCrC6alkyl wherein the alkyl, alkenyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups are optionally substituted with R15;
R19 is CrCealkyl, C3-C10cycloalkyl, C3-Cι0hetcycloalkyl, aryl, arylCrC6alkyl, hetaryl, hetarylCrC6alkyl;
m is 1 or 2;
n is 0, 1 or 2; or
a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mix- ture of optical isomers, including a racemic mixture, or any tautomeric forms.
In another embodiment of the present invention, in formula (II) R1 is C3-C10cycloalkyl or C3-C10hetcycloalkyl, wherein the cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R4 as defined above. In another embodiment of the present invention, in formula (II) R2 is hydrogen or d-
C8alkyl, wherein the alkyl group is optionally substituted with one or more of R5 as defined above.
In another embodiment of the present invention, in formula (II) R1 and R2 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of C C8alkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCι-C6- alkyl, hydroxy, oxo, cyano, d-C-ealkyloxy, aryld-C6alkyloxy, hetarylCrCealkyloxy, d-C6alkyl- oxyd-Cealkyl, d-C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrC6alkylcarbonyl, d-Cealkylcarboxy, arylcarboxy or arylCrC6alkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R14;as defined above.
In another embodiment of the present invention, in formula (II) R1 and R2 together with the nitrogen to which they are attached are 6-aza-bicyclo[3.2.1]octane. In another embodiment of the present invention, in formula (II) R3 is aryl or hetaryl, wherein the aryl and hetaryl groups independently are optionally substituted with one or more of R7 as defined above.
In another embodiment of the present invention, in formula (II) R3 is C3-C10cycloalkyl or C3- dohetcycloalkyl, optionally substituted with one or more of R7 as defined above.
In another embodiment of the present invention, in formula (II) R4 and R5 independently are hydrogen, hydroxy, oxo, halo, d-C8alkyl, wherein the alkyl group is optionally substituted with one ore more of R15 as defined above.
In another embodiment of the present invention, in formula (II) R7 is hydrogen, halo, hydroxy, cyano, CrCealkyl, C3-C10cycloalkyl, C3-C10het-cycloalkyl, trihalomethyl, aryl, aryld- Cealkyl, CrC6alkyloxy, d-Cealkyloxyd-Cealkyl, aryloxy, arylCrC6alkyloxy, aryloxyCrC6alkyl, arylCrCealkyloxyd-Cealkyl, hetaryl, hetarylCrC6alkyl, hetaryloxy, hetarylCrCealkyloxy, hetaryloxyd-C6alkyl, hetarylCrC6alkyl-oxyCrC6alkyl, NR8R9, R18carbonylNR8, or R19SOmNR8, wherein the aryl and hetaryl groups independently are optionally substituted with one or more R10 as defined above.
In another embodiment of the present invention, in formula (II) R7 is halo, cyano, d- C8alkyl, C3-C10hetcycloalkyl, trihalomethyl, aryl, d-C6alkyloxy, aryloxy, arylCrC6alkyloxy, aryloxyd-Cealkyl, arylCrCealkyloxyCrC6alkyl, hetaryl, hetaryloxy, hetarylCrCealkyloxy, hetaryloxyd-Cealkyl, hetaryld-Cealkyloxyd-Cealkyl, NR8R9, R18carbonylNR8, or R19SOmNR8, wherein the aryl and hetaryl groups are independently optionally substituted with one or more R10 as defined above.
In another embodiment of the present invention, in formula (II) R7 is R18carbonylNR8 or R19SOmNR8; wherein m, R8, R18 and R19 are defined as above.
In another embodiment of the present invention, in formula (II) R8 is CrCealkyl. In another embodiment of the present invention, in formula (II) R8 and R9 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system optionally being substituted with at least one halo, cyano, C C8alkyl, aryl, hetaryl, arylCrCealkyl, hetarylCrCealkyl, hydroxy, oxo, CrC6alkyIoxy, arylCrC6alkyloxy, hetarylCrCealkyloxy, C Cealkyloxyd-Cealkyl, d-C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetaryld-C-ealkylcarbonyl, CrC6alkylcarboxy, arylcarboxy, hetarylcarboxy, arylCr C6alkylcarboxy or hetarylC C6alkylcarboxy.
In another embodiment of the present invention, in formula (II) R15 is CONR8R9. In another embodiment of the present invention, in formula (II) R18 is CrC6alkyl, optionally substituted with R15 as defined above.
In another embodiment of the present invention, in formula (II) R18 is aryl or hetaryl.
In another embodiment of the present invention, in formula (II) R18 is arylCrC6alkyl- oxyd-C6alkyl or hetaryld-Cealkyloxyd-Cealkyl.
In another embodiment of the present invention, in formula (II) R18 is R8R9Nd-C6- alkyl; wherein R8 and R9 are defined as above.
In another embodiment of the present invention, in formula (II) R19 is aryl or hetaryl
In another embodiment of the present invention, in formula (II) the aryl group is phenyl or pyridyl.
In another embodiment of the present invention, in formula (II) the hetaryl group is thienyl, imidazolyl, oxazolyl, thiazolyl, or indolyl.
In another embodiment of the present invention, the compounds or prodrugs thereof of the general formula (II) are selected from the group consisting of the compounds of exam- pies 4 through 8 as described under EXAMPLES, COMPOUNDS OF GENERAL FORMULAS (I) AND (II).
In another embodiment, the present invention is concerned the substituted amides or prodrugs thereof of the general formula (III)
Figure imgf000047_0001
(III) wherein
R1 is aryl, arylCrC6alkyl, hetaryl or hetarylCr -C6alkyl optionally substituted with one or more of R6 independently;
R2 is halo, d-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C3-C10cycloalkylCrC-6- alkyl, trihalomethyl, aryl, aryld-Cealkyl, d-C-ealkyloxyd-Cealkyl, aryld-Cealkyloxyd-Cealkyl, CrC6alkylNR5CrC6alkyl, arylCrC6alkylNR5CrC6alkyl, hetaryl or hetarylC C6alkyl wherein the alkyl, alkenyl, alkynyl, cycloalkyl and aryl groups independently are optionally substituted with one or more R7;
R3 is CrC6alkyl optionally substituted with one or more of R8; R4 is Ce-docycloalkyl, C6-Cιohetcycloalkyl, Ce-CiocycloalkylCrCβalkyl or C6-C1Qhetcyclo- alkylCrC6alkyl wherein the alkyl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R8; or
R3 and R4 together with the nitrogen to which they are attached, are forming a saturated or partially saturated bicyclic/bridge ring system containing from 7 to 12 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-Cealkyl, aryl, hetaryl, arylCrC6alkyl, hetaryl- CrCβalkyl, hydroxy, oxo, CrC6alkyloxy, arylCrC6alkyloxy or hetarylCrCealkyloxy, wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R9;
R5 is CrC6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C3-C10hetcycloalkyl, C3-C10- cycloalkylCrC6alkyl, C3-C10hetcycloalkylCrC6alkyl, aryl, hetaryl, arylCι-C6alkyl or hetaryld- C6alkyl wherein the alkyl, alkenyl, alkynyl, aryl, hetaryl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R9;
R6 and R7 independently are hydrogen, hydroxy, oxo, halo, nitro, cyano, CrC6alkyl, CrCealkyloxy, trihalomethyl, trihalomethoxy, NR10R11, arylCrC6alkyloxy, hetarylCrCealkyloxy, C C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, CrC6alkyloxycarbonyl, aryloxycarbonyl, aryld-C6alkyloxycarbonyl, CrC6alkylcarboxy, arylcarboxy or arylCrC6alkyI- carboxy;
R8 and R9 independently are hydrogen, d-C6alkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrC6- alkyl, hydroxy, oxo, cyano, NR10R11, CrC6alkyloxy, aryloxy, arylCrC6alkyloxy, hetaryloxy, hetarylCrCealkyloxy, CrCealkyloxyCrCealkyl, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrC6alkylcarbonyl, Cι-C6alkylcarboxy, arylcarboxy or aryld-C6alkylcarboxy;
R10 and R11 independently are hydrogen, d-C8alkyl, aryl, hetaryl, arylCrC6alkyl, C3-Cιo- cycloalkyl, C3-C 0hetcycloalkyl, C3-C10cycloalkylCrC6alkyl, CrC6alkylcarbonyl, d- C6alkylcarboxyCrC6alkyl; or
R10 and R11 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon at- oms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-Cealkyl, aryl, hetaryl, aryld- Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, C C6alkyloxy, arylCrC6alkyloxy, hetaryld- C6alkyloxy, d-Cealkyloxyd-Cealkyl, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or aryld-6- alkylcarboxy; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
In another embodiment, the present invention is concerned with compounds or pro- drugs thereof of the general formula (III) wherein: R1 is aryl or hetaryl optionally substituted with one or more R6 independently;
R2is halo, d-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C3-CιocycloalkylCrC6- alkyl, aryl, arylCrCealkyl, CrC-ealkyloxyd-Cealkyl, aryld-Cealkyloxyd-Cealkyl, d-C6- alkylNR5CrC6alkyl, arylCrC-6alkylNR5CrC6alkyl, hetaryl or hetarylC C6alkyI wherein the alkyl, alkenyl, alkynyl, cycloalkyl and aryl groups independently are optionally substituted with one or more R7;
R3 is CrC6alkyl optionally substituted with one or more of R8;
R4 is C6-docycloalkyl, C6-C10hetcycloalkyl, C6-CιocycloalkylCrC6alkyl or C6-Cι0hetcyclo- alkylCrC6alkyl wherein the alkyl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R8;
R5 is CrC6alkyl, C2-Cealkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C3-C10hetcycloalkyl, C3-C10- cycloalkyICrC6alkyl, C3-C10hetcycloalkylCι-C6alkyl, aryl, hetaryl, aryld-Cealkyl or hetaryld- C6alkyl wherein the alkyl, alkenyl, alkynyl, aryl, hetaryl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R9;
R6 and R7 independently are hydrogen, hydroxy, oxo, halo, nitro, cyano, Cι-C6alkyl, d-C6- alkyloxy, trihalomethyl, trihalomethoxy, NR10R11, arylCrC6alkyloxy, hetarylCrCealkyloxy, d- C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, CrCealkyloxycarbonyl, aryloxycarbonyl, aryICrC6alkyloxycarbonyl, CrC6alkylcarboxy, arylcarboxy or arylCrC6aIkyl- carboxy; R8 and R9 independently are hydrogen, C C6alkyl, aryl, hetaryl, aryld-C6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, NR10R11, CrC6alkyloxy, aryloxy, arylCrC6alkyloxy, hetaryloxy, hetarylCrCealkyloxy, CrC6alkyloxyCrC6alkyl, CrC6alkyl-carbonyl, arylcarbonyl, hetarylcar- bonyl, arylCrCealkylcarbonyl, hetarylCrC6alkyl-carbonyl, CrCealkylcarboxy, arylcarboxy or arylCrC6alkylcarboxy;
R10 and R11 independently are hydrogen, d-C8alkyl, aryl, hetaryl, arylCrC6alkyl, C3-C10- cycloalkyl, C3-C10hetcycloalkyl, C3-C10cycloalkylCrC6alkyl, CrCealkylcarboxyCrC6alkyl; or
R10 and R11 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-C8alkyl, aryl, hetaryl, aryld- C6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, aryld-C6alkyloxy, hetaryl d-C6alkyloxy, CrC6alkyloxyCrC6alkyl, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkylcarbonyl, hetarylCrC6alkylcarbonyl, C C6alkylcarboxy, arylcarboxy or aryld-6- alkylcarboxy; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mix- ture of optical isomers, including a racemic mixture, a prodrug thereof, or any tautomeric forms.
In another embodiment of the present invention, in formula (III) R1 is aryl, aryld- Cealkyl or hetaryl optionally substituted with one or more of R6.
In another embodiment of the present invention, in formula (III) R1 is aryl optionally substituted with one or more of R6.
In another embodiment of the present invention, in formula (III) R1 is aryld-Cealkyl optionally substituted with one or more of R6.
In another embodiment of the present invention, in formula (III) R1 is hetaryl optionally substituted with one or more of R6. In another embodiment of the present invention, in formula (III) R2 is CrC6alkyl, C3- docycloalkyl, C3-C10cycloalkylCrC6alkyl, trihalomethyl, arylCrCealkyl, or hetarylC C6alkyl wherein the alkyl, cycloalkyl and aryl groups independently are optionally substituted with one or more R7.
In another embodiment of the present invention, in formula (III) R2 is CrC6alkyl op- tionally substituted with one or more R7. In another embodiment of the present invention, in formula (III) R2 is trihalomethyl.
In another embodiment of the present invention, in formula (III) R3 is C C6alkyl optionally substituted with one or more of R8.
In another embodiment of the present invention, in formula (III) R4 is C6-C10cyclo- alkyl, or C6-C10hetcycloalkyl, wherein the cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R8.
In another embodiment of the present invention, in formula (III) R4 is C6-C10cyclo- alkyl optionally substituted with one or more of R8.
In another embodiment of the present invention, in formula (III) R4 is C6 C6-C10het- cycloalkyl optionally substituted with one or more of R8.
In another embodiment of the invention, in formula (III) R3 and R4 together with the nitrogen to which they are attached, are forming a saturated or partially saturated bi- cyclic/bridge ring system containing from 7 to 12 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being sub- stituted with at least one of CrC6alkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrCealkyl, hydroxy, oxo, CrC6alkyloxy, arylCrC6alkyloxy or hetaryld-C6alkyloxy, wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R9.
In another embodiment of the present invention, in formula (III) the saturated or partially saturated bicyclic/bridge ring system is 6-aza-bicyclo[3.2.1]octane. In another embodiment of the present invention, in formula (III) R6 and R7 independently are hydrogen, hydroxy, oxo, halo, cyano, CrCβalkyl, d-C6alkyloxy, trihalomethyl, NR10R11, arylCrC6alkyloxy, hetarylCrCealkyloxy, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkylcarbonyl, CrCealkyloxycarbonyl, aryloxycarbonyl or aryld- C6alkyloxycarbonyl. In another embodiment of the present invention, in formula (III) R8 and R9 independently are hydrogen, CrC6alkyl, hydroxy, oxo, d-dalkyloxy or arylCrC6alkyloxy.
In another embodiment of the present invention, in formula (III) R10 and R11 independently are hydrogen or d-C8alkyl.
In another embodiment of the present invention the compound of the general for- mula (III) or a prodrug thereof is 1 -(4-Chloro-phenyl)-5-propyl-1 /-/-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
In another embodiment of the present invention the compounds of the general for- mula (III) or a prodrug thereof is selected from the group consisting of: 1 -(4-Chloro-phenyl)-5-trifluoromethyl-1 H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; [1-(4-Methoxy-phenyl)-5-methyl- -H-pyrazol-4-yl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6- yl)-methanone; 1 [1-(4-Chloro-phenyl)-5-propyl-1r7-pyrazol-4-yl]-(1 ,3,3-trimethyl-6-aza- bicyclo[3.2.1]oct-6-yl)-methanone; [1 -(3,5-Dichloro-phenyl)-5-propyl-1 H-pyrazol-4-yl]-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6- yl)-methanone; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
In yet another embodiment of the present invention the compounds of the general formula (III) or a prodrug thereof is selected from the group consisting of: 1 -(Phenyl)-5-methyl-1 r/-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; 1 -(4-Fluoro-phenyl)-5-methyl-1 H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; 1 -(4-Methoxy-phenyl)-5-methyl-1 H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; 1 -(4-Chloro-phenyl)-5-methyl-1 H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; 1 -(2-Methyl-phenyl)-5-methyl-1 H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; 1 -(4-Amino-phenyl)-5-methyl-1 /--pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; 1 -(2-Pyridyl)-5-methyl-1 /-/-pyrazoIe-4-carboxylic acid cyclohexyl-methyl-amide; 1-(2-Pyridyl)-5-propyl-1 .-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mix- ture of optical isomers, including a racemic mixture, or any tautomeric forms.
In another embodiment, the present invention is concerned with compounds or prodrugs thereof of the general formula (IV)
Figure imgf000052_0001
(IV) wherein
R1 is hydrogen, trihalomethyl, CrC6alkyl, d-C6alkyloxy, CrC6alkylthio, aryl, arylCrC6alkyl, hetaryl or hetaralkyl, wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R8; R2 , R3, R4 and R5 independently are hydrogen, halo, nitro, cyano, hydroxy, NR9R10, trihalomethyl, CrC6alkyl, CrC6alkyloxy, CrC6alkylthio, aryl, arylCrC6alkyl, hetaryl or hetaralkyl, wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R8; or
R2 together with R3are forming a saturated or partially saturated cyclic ring system containing from 3 to 6 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrCealkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrCealkyl, hydroxy, oxo, CrC6alkyloxy, aryloxy, arylCrC6alkyloxy or hetarylCrCealkyloxy; or
R3 together with R4are forming a saturated or partially saturated cyclic ring system containing from 3 to 6 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-C6- alkyl, aryl, hetaryl, aryld-C6alkyl, hetarylCrCealkyl, hydroxy, oxo, CrCealkyloxy, aryloxy, arylCrC6alkyloxy or hetarylCrC6alkyloxy; or
R4 together with R5are forming a saturated or partially saturated cyclic ring system containing from 3 to 6 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrCealkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrCealkyl, hydroxy, oxo, d-Cealkyloxy, aryloxy, aryld-C6alkyloxy or hetarylCrC6alkyloxy;
R6 is aryl, hetaryl, aryld-C6alkyl, C3-C10cycloalkyl, C3-C10hetcycloalkyl, C3-C10cycloalkylCr C6alkyl, d-Cealkylcarboxyd-Cealkyl, wherein the alkyl, aryl and cycloalkyl groups independently are optionally substituted with one or more of R11;
R7 is CrC8alkyl, aryl, hetaryl, aryld-Cealkyl, C3-C10cycloalkyl, C3-C10hetcycloalkyl, C3- CιocycloalkylCrC6alkyl, CrC6alkylcarboxyCrC6alkyl, wherein the alkyl, aryl and cycloalkyl groups independently are optionally substituted with one or more of R11; or
R6 and R7, together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-C8alkyl, aryl, hetaryl, arylC C6alkyl, hetaryl -Cealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrC6alkyloxy, hetaryld- C6alkyloxy, d-Cealkyloxyd-Cealkyl, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-C6alkylcarboxy, arylcarboxy or aryld-Ce- alkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R8;
R9 and R10 independently are hydrogen, C C8alkyl, aryl, hetaryl, aryld-Cealkyl, C3-C10- cycloalkyl, C3-Cιohetcycloalkyl, C3-CιocycloalkylCrC6alkyl, CrCealkylcarboxyCrCealkyl, wherein the alkyl, aryl and cycloalkyl groups independently are optionally substituted with one or more of R11; or
R9 and R10, together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-C8alkyl, aryl, hetaryl, aryld- Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C6alkyloxy, arylCrC6alkyloxy, hetaryld- C6alkyloxy, d-Cealkyloxyd-Cealkyl, d-C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-Cealkylcarboxy, arylcarboxy or aryld-C6- alkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R8;
R8 and R11 independently are hydrogen, halo, hydroxy, oxo, nitro, cyano, d-C8alkyl, d-C6- alkyloxy or aryloxy; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mix- ture of optical isomers, including a racemic mixture, or any tautomeric forms.
In one embodiment of the present invention, in formula (IV) R1 is hydrogen or C C6alkyl, wherein the alkyl group is optionally substituted with one or more of R8.
In another embodiment of the present invention, in formula (IV) R1 is hydrogen. In another embodiment of the present invention, in formula (IV) R2, R3, R4 and R5 are hydrogen.
In another embodiment of the present invention, in formula (IV) R3 together with R4 are forming a saturated or partially saturated cyclic ring system containing from 3 to 6 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring sys- tem optionally being substituted with at least one of d-C6alkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrCealkyl, hydroxy, oxo, CrC6alkyloxy, aryloxy, aryld-C6alkyloxy or hetarylCrCealkyloxy.
In another embodiment of the present invention, in formula (IV) R4 together with R5 are forming a saturated or partially saturated cyclic ring system containing from 3 to 6 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of d-Cβalkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrCealkyl, hydroxy, oxo, CrC6alkyloxy, aryloxy, arylCrC6aIkyloxy or hetarylCrCealkyloxy.
In another embodiment of the present invention, in formula (IV) R6 and R7, together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of C C8alkyl, aryl, hetaryl, arylCrCealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C6alkyloxy, arylCrC6alkyloxy, hetarylCrCealkyloxy, d-C6alkyloxyCr C6alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkylcarbonyl, hetaryld- C6alkylcarbonyl, C C6alkylcarboxy, arylcarboxy or aryld-C6alkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R8;
In another embodiment of the present invention, in formula (IV) R6 and R7; together with the nitrogen to which they are attached, are forming a saturated or partially saturated bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of C C8alkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, C C6alkyloxy, arylCrC6alkyloxy, hetarylCrCealkyloxy, CrC6alkyloxyCrC6alkyl, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrC6alkyI- carbonyl, CrCealkylcarboxy, arylcarboxy or arylCrC6alkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R8.
In another embodiment of the present invention, in formula (IV) R9 and R10, together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of C C8alkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-Cealkyloxy, aryld-Cealkyloxy, hetarylCrCealkyloxy, d-C-ealkyloxyd- C6alkyl, d-Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetaryld- C6alkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrC6alkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R8. In another embodiment of the present invention a compound of the general formula (IV) or a prodrug thereof is pyrazolo[1,5-a]pyridin-3-yl-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct- 6-yl)-methanone; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
In another embodiment of the present invention the compounds of the general formula (IV) or a prodrug thereof are:
(2-Methyl-pyrazolo[1,5-a]pyridin-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone; Pyrazolo[1 ,5-a]pyridine-3-carboxylic acid cyclohexyl-methyl-amide; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
In another embodiment, the present invention is concerned with compounds or prod- rugs thereof of the general formula (V)
Accordingly, the present invention is concerned with compounds or prodrugs thereof of the general formula (V) :
Figure imgf000056_0001
(V) wherein
R1 is hydrogen, d-C8alkyl, CrC6alkyloxyd-C6alkyl, aryl, hetaryl, arylCrCealkyl, hetarylCr C6alkyl, CrC6S02, arylS02, hetarylS02, arylC C6alkylS02 or hetaryld-C6alkylS02 all of which is optionally substituted with one or more R8;
R2 and R5 independently are hydrogen, halo, nitro, cyano, trihalomethyl, CrC6alkyl, aryl, arylCrC6alkyl, hetaryl or hetarylCrCealkyl wherein the alkyl, aryl, arylalkyl, hetaryl and hetarylalkyl groups independently are substituted with one or more R9; and
either R3 is hydrogen; and R4 is C(0)NR7R8; or R3 is C(0)NR7R8; and R4 is hydrogen; and R6 is hydrogen, halo, cyano, trihalomethyl, NR12R13, CrC6alkyl, aryl, arylCrCealkyl, hetaryl or hetarylCrCealkyl wherein the alkyl, aryl, arylalkyl, hetaryl and hetarylalkyl groups independently are substituted with one or more R9; and
R7 and R8 independently are d-C8alkyl, C3-C10cycloalkyl, C3-C10hetcycloalkyl, C3-C10cyclo- alkyld-C6alkyl, wherein the alkyl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R10; or
R7 and R8 together with the nitrogen to which they are attached, are forming a saturated or partially saturated bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of d-C8alkyl, arylCrC6alkyl, hetarylCrCealkyl, hydroxy, cyano, CrC6alkyloxy, arylCrC6alkyloxy, hetarylCrCealkyloxy, d-Cealkyloxyd- C6alkyl, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetaryld- C6alkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R11;
R9 is hydrogen, hydroxy, oxo, halo, nitro, cyano, CrC6alkyl, d-Cealkyloxy, trihalomethyl, trihalomethoxy, NR12R13, C(0)NR12R13, aryld-C6alkyloxy, d-C6alkylcarbonyl, arylcarbonyl, aryld-C6alkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
R10 and R1 independently are hydrogen, halo, oxo, hydroxy, CrC6alkyl, aryl, arylCrC6alkyl, hetaryl or hetarylalkyl;
R12 and R13 independently are hydrogen, d-C8alkyl, aryl, hetaryl, aryld-C6alkyl, C3-C10- cycloalkyl, C3-C10hetcycloalkyl, Cs-docycloalkyld-C-ealkyl, d-C6alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, hetarylcarbonyl, hetarylCrCealkylcarbonyl, d-C6alkylcarboxyCr C6alkyl; or
R12 and R13 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-C8alkyl, aryl, hetaryl, aryld- Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C6alkyloxy, arylCrC6alkyloxy, hetaryld- C6alkyloxy, CrC6alkyl-oxyCrC6alkyl, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkyl-carbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or aryld- C6alkylcarboxy; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, a prodrug thereof, or any tautomeric forms.
In another embodiment, the present invention is concerned with compounds or pro- drugs thereof of the general formula (Va)
Figure imgf000058_0001
(Va) wherein
R1 is hydrogen, d-C8alkyl, aryl, hetaryl, aryld-Cealkyl or hetarylCrCealkyl optionally substituted with one or more R8;
R2 and R5 independently are hydrogen, halo, nitro, cyano, trihalomethyl, CrC6alkyl, aryl, arylCrC6alkyl, hetaryl or hetarylCrCealkyl wherein the alkyl, aryl, arylalkyl, hetaryl and hetarylalkyl groups independently are substituted with one or more R8; and
either R3 is hydrogen; and R4 is C(0)NR6R7; or R3 is C(0)NR6R7; and R4 is hydrogen;
R6 and R7 independently are C C8alkyl, C3-C10cycloalkyl, C3-C10hetcycloalkyl, C3-C10cyclo- alkyld-C6alkyl, wherein the alkyl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R9; or
R6 and R7 together with the nitrogen to which they are attached, are forming a saturated or partially saturated bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of d-C8alkyl, aryld-Cealkyl, hetarylCrCealkyl, hydroxy, cyano, d-C6alkyloxy, arylCrC6alkyloxy, hetarylCrCealkyloxy, CrC6alkyloxyCr C6alkyl, C C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetaryld- C6alkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R10;
R8 is hydrogen, hydroxy, oxo, halo, nitro, cyano, d-C6alkyl, CrC6alkyloxy, trihalomethyl, trihalomethoxy, NR11R12, arylCrC6alkyloxy, CrC6alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, d-C6alkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
R9 and R10 independently are hydrogen, halo, oxo, hydroxy, CrC6alkyl, aryl, arylCrC6alkyl, hetaryl or hetarylalkyl;
R11 and R 2 independently are hydrogen, d-C8alkyl, aryl, hetaryl, aryld-Cealkyl, C3-C10- cycloalkyl, C3-C10hetcycloalkyl, C3-C10cycloalkylCrC6alkyl, CrCealkyl-carboxyCrCealkyl; or
R11 and R12 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-C8alkyl, aryl, hetaryl, aryld- Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrQ-alkyloxy, hetaryld- C6alkyloxy, CrC6alkyl-oxyCrC6alkyl, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, aryld-C6alkyl-carbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylC C6alkylcarboxy; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
In another embodiment of the present invention, in formula (V) and (Va) R1 is hydrogen, d-C8alkyl, arylCrC6alkyl, hetarylCrCealkyl, arylS02, hetarylS02, arylCrC6alkylSO2 or hetarylCrCealkylS02 all of which is optionally substituted with one or more R8.
In another embodiment of the present invention, in formula (V) and (Va) R1 is hydrogen, C C8alkyl, aryld-Cealkyl, hetarylCrCealkyl all of which is optionally substituted with one or more R8.
In another embodiment of the present invention, in formula (V) and (Va) R1 is arylS02, hetarylS02, arylCrC6alkylS02 or hetarylCrC6alkylS02 all of which is optionally substituted with one or more R8.
In another embodiment of the present invention, in formula (V) and (Va) R2 is hydro- gen. In another embodiment of the present invention, in formula (V) and (Va) R3 is hydrogen and R4 is C(0)NR7R8.
In another embodiment of the present invention, in formula (V) and (Va) R3 is C(0)NR7R8 and R4 is hydrogen. In another embodiment of the present invention, in formula (V) and (Va) R5 is hydrogen.
In another embodiment of the present invention, in formula (V) R6 is hydrogen, NR12R13, CrC6alkyl, aryl or hetaryl wherein the alkyl, aryl and hetaryl independently are substituted with one or more R9. In another embodiment of the present invention, in formula (V) and (Va) R7 and R8 independently are C C8alkyl or C3-C10cycloalkyl, wherein the alkyl and cycloalkyl groups independently are optionally substituted with one or more of R10.
In another embodiment of the present invention, in formula (V) and (Va) R7 and R8 together with the nitrogen to which they are attached, are forming a saturated or partially saturated bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of d-C8alkyl, arylCrC6alkyl, hetarylCrCealkyl, hydroxy, cyano, CrC6alkyloxy, arylCrC6alkyloxy, hetarylCrCealkyloxy, d-Cealkyloxyd-Cealkyl, CrC6alkyl- carbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkylcarbonyl, hetarylCrC6alkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrC6alkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R11.
In another embodiment of the present invention, in formula (V) and (Va) R9 is hydrogen, hydroxy, oxo, halo, nitro, cyano, d-C6alkyl, d-C6alkyloxy, trihalomethyl, trihalomethoxy, NR12R13, C(0)NR12R13, arylC C6alkyloxy, d-C6alkylcarbonyl, arylcarbonyl, aryld- C6alkylcarbonyl.
In another embodiment of the present invention, in formula (V) and (Va) R10 and R11 independently are hydrogen, halo, oxo, hydroxy, CrCealkyl, aryl, aryld-Cealkyl, hetaryl or hetarylalkyl.
In another embodiment of the present invention, in formula (V) and (Va) R11 and R12 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of d-C8alkyl, aryl, hetaryl, aryld-Cealkyl, hetaryld- C6alkyl, hydroxy, oxo, cyano, d-C6alkyloxy, arylCrC6alkyloxy, hetarylCrC6alkyloxy, d- C6alkyl-oxyC C6alkyl, d-C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkyl-car- bonyl, hetarylCrC6alkylarbonyl, d-C6alkylcarboxy, arylcarboxy or arylCrCealkylcarboxy.
In another embodiment of the present invention the compound of the general formulas (V) and (Va), or a prodrug thereof is 1H-Benzoimidazole-5-carboxylic acid cyclohexyl- methyl-amide; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
In yet another embodiment of the present invention the compounds of the general formulas (V) and (Va), or a prodrug thereof is selected from the group consisting of: 1 -Benzyl-1 rV-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide;
(1 --Benzoimidazol-5-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
In another embodiment of the present invention, the compounds of general formulas (V) and (Va), or a prodrug thereof is sleceted from the group consisting of: lsopropyl-2-trifluoromethyl-1 H-benzoimidazole-δ-carboxylic acid cyclohexyl-methyl-amide; 1 -Benzyl-1 H-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide; 2-Methyj-l V-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide; 2-Hydroxymethyl-1H-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide; 2-(4-Amino-phenyl)-1H-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide; (1H-Benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; (2-Methyl-1H-benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; (2-Amino-1 .-benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; (2-Benzo[1 ,3]dioxol-5-yl- . r7-benzoimidazol-5-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1 ]oct-6-yl)- methanone;
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-.H-benzoimidazol-2-yl]-benzoic acid methyl ester;
(2-Thiophen-2-yl-.H-benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone; [2-(2-Nitro-phenyl)-./-/-benzoimidazol-5-yl]-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanon; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, a prodrug thereof, or any tautomeric forms. In another embodiment, the present invention is concerned with compounds or prodrugs thereof of the general formula (VI)
Figure imgf000062_0001
(VI) wherein
X is oxygen or (CR1R2)n;
R1, R2, R3, and R4 independently are hydrogen, C C6alkyl, aryl, arylCrCealkyl, hetaryl or hetarylCrCealkyl optionally substituted with one or more R8 independently; or
R1 and either R3 or R4 together are forming a saturated or partially saturated ring system containing from 4 to 8 carbon atoms, the ring system optionally being substituted with at least one of CrC6alkyl, hydroxy, oxo, aryl, hetaryl, arylCrCealkyl or hetarylCrC6alkyl; or
R1 and either R3 or R4 together with the single bond are forming a carbon-carbon double bond;
R5 is d-C8alkyl optionally substituted with one or more of R9;
R6 is Qrdocycloalkyl, C3-C10hetcycloalkyl, C3-C10cycloalkylCr Cealkyl, wherein the alkyl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R9; or
R5 and R6 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC6alkyl, aryl, hetaryl, aryld- Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC6alkyIoxy, arylCrC6alkyloxy, hetaryld- C6alkyloxy, CrC6alkyloxyCrC6alkyl, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylC C6alkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R10;
R7 is hydrogen, halo, nitro, NR12R13, cyano, trihalomethyl, CrC6alkyl, aryl, aryld-Cealkyl, d- C6alkyloxy, aryloxy, arylCrC6alkyloxy, hetaryl, hetarylCrCealkyl, hetaryloxy or hetarylCrCealkyloxy optionally substituted with one or more R11 independently;
R8 and R9 independently are hydrogen, hydroxy, oxo, halo, nitro, cyano, d-C6alkyl, CrCealkyloxy, trihalomethyl, trihalomethoxy, NR 2R13, arylCrC6alkyloxy, CrC6alkylcarbonyl, aryl- carbonyl, arylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
R10 is hydrogen, d-C8alkyl, arylCrC6alkyl, hetarylCrCealkyl, CrC6alkyloxy, arylCrC6alkyl- oxy, hetarylCrCealkyloxy;
R11 is hydrogen, halo, hydroxy, oxo, nitro, cyano, d-C8alkyl, CrC6alkyloxy, aryloxy or hetaryloxy;
R12 and R13 independently are hydrogen, d-C8alkyl, aryl, hetaryl, arylCrC6alkyl, C3-C10cyclo- alkyl, C3-C10hetcycloalkyl, CrC6alkylcarbonyl, arylCrCealkylcarbonyl, C3-C10cycloalkylCrC6- alkyl, CrCealkyloxycarbonyl; or
R12 and R13 are together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrCealkyl, aryl, hetaryl, aryld- Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C6alkyloxy, arylCrC6alkyloxy, hetaryld- C6alkyloxy, d-C-ealkyloxyd-Cealkyl, C C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or aryld- 6alkylcarboxy;
n is 1 or 2; or
a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, a prodrug thereof, or any tautomeric forms. In one embodiment of the present invention, in formula (VI) X is (CR1R2)n, wherein R1, R2 and n are as defined above.
In another embodiment of the present invention, in formula (VI) n is 1.
In another embodiment of the present invention, in formula (VI) X is oxygen. In another embodiment of the present invention, in formula (VI) R1, R2, R3, and R4 independently are hydrogen, d-C6alkyl or aryld-Cealkyl, optionally substituted with one or more R8.
In another embodiment of the present invention, in formula (VI) R1 and either R3 or R4 together with the single bond are forming a carbon-carbon double bond.
In another embodiment of the present invention, in formula (VI) R5 is C C8alkyl op- tionally substituted with one or more of R9.
In another embodiment of the present invention, in formula (VI) R6 is C3-C10cyclo- alkyl or C3-C10hetcycloalkyl each of which is optionally substituted with one or more of R9.
In another embodiment of the present invention, in formula (VI) R6 is C3-C10cyclo- alkyl optionally substituted with one or more of R9. In another embodiment of the present invention, in formula (VI) R5 and R6 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-C6alkyl, aryl, hetaryl, aryld-Cealkyl, hetarylC C6- alkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, C C6alkyl- oxyCrC6alkyl, d-C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R10.
In another embodiment of the present invention, in formula (VI) R7 is hydrogen, halo, NR12R13, trihalomethyl, d-C6alkyloxy, aryloxy, arylCrCealkyloxy or hetaryloxy optionally substituted with one or more R11 independently.
In another embodiment of the present invention, in formula (VI) R8 and R9 independently are hydrogen, hydroxy, oxo, halo, nitro, cyano, d-C6alkyl, d-C6alkyloxy, trihalomethyl, or NR12R13. In another embodiment of the present invention, in formula (VI) R10 is hydrogen or d-C8alkyl.
In yet another embodiment of the present invention, in formula (VI) the bicyclic ring system is 6-aza-bicyclo[3.2.1]octane optionally substituted with one or more of CrC6alkyl.
In yet another embodiment of the present invention, in formula (VI) the bicyclic ring system is 1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane. In yet another embodiment of the present invention a compound of the general formula (VI) or a prodrug thereof is 2,3-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
In another embodiment of the present invention the compounds of the general formula (VI) or a prodrug thereof is selected from the group consisting of: 2,5-Dimethyl-3-phenyl-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; 2,2-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; 2-Methyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide;
(2,3-Dimethyl-2,3-dihydro-benzofuran-7-yl)-(2,4,4-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone;
4-Methoxy-2-methyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide;
2-Methyl-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; (2-Methyl-2,3-dihydro-benzofuran-7-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone;
Benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; 2,3-Dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; 3,3-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; Chroman-8-carboxylic acid cyclohexyl-methyl-amide; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
In another embodiment ofthe present invention the compounds ofthe general formula (VI) or a prodrug thereof is selected from the group consisting of: 2,3-Dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; Benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; 2-Methyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; 2-Methyl-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; 3,3-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; (2,3-Dimethyl-2,3-dihydro-benzofuran-7-yl)-(2,4,4-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone;
4-Methoxy-2-methyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; 2,2-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; (2-Methyl-2,3-dihydro-benzofuran-7-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1 ]oct-6-yl)- methanone; Chroman-8-carboxylic acid cyclohexyl-methyl-amide; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, a prodrug thereof, or any tautomeric forms.
In another embodiment, the present invention is concerned with compounds or prodrugs thereof of the general formula (VII)
Figure imgf000066_0001
(VII) wherein
R1 is hydrogen, d-C8alkyl, hetaryl, aryld-Cealkyl or hetarylCrCealkyl optionally substituted with one or more R9;
R2, R3, R4, R5 and R6 independently are hydrogen, halo, nitro, cyano, trihalomethyl, carboxy, N(R12R13), C(0)NR7R8, CrC8alkyl, C3-C10cycloalkyl, C3-C10hetcycloalkyl, N(R12R13)C C6alkyl, CrCealkyloxy, CrCealkyloxyCrC6alkyl, aryl, arylCrC6alkyl, aryloxy, aryloxyd- C6alkyl, arylCrCealkyloxy, aryld-Cealkyloxyd-C-ealkyl, CrCealkylcarboxy, arylcarboxy, arylCrCealkylcarboxy, hetaryl, hetarylCrCealkyl, hetarylCrCealkyloxy, hetaryloxyCrC6alkyl or hetarylCrCealkyloxyCrCealkyl wherein wherein the alkyl, aryl, arylalkyl, hetaryl and hetarylalkyl groups independently are substituted with one or more R9;
R7 is hydrogen or C C8alkyl optionally substituted with one or more of R10;
R8 is C3-C10cycloalkyl, C3-C10hetcycloalkyl, C3-C10cycloalkylCrC6alkyl, wherein the cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R10; or
R7 and R8 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon at- oms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of d-C8alkyl, aryl, hetaryl, arylCι-C6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C6alkyloxy, aryld-C6alkyloxy, hetarylCrCealkyloxy, d-Cealkyloxyd-Cealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-C6alkylcarboxy, arylcarboxy or arylCrCealkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R11;
R9 is hydrogen, hydroxy, oxo, halo, nitro, cyano, CrC6alkyl, CrCealkyloxy, trihalomethyl, trihalomethoxy, NR12R13, arylC C6alkyloxy, d-C6alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, d-C6alkylcarboxy, arylcarboxy or aryld-C6alkylcarboxy;
R10 and R11 independently are hydrogen, halo, oxo, hydroxy, CrC6alkyl, aryl, aryld-Cealkyl, hetaryl or hetarylalkyl;
R12 and R13 independently are hydrogen, CrC8alkyl, aryl, hetaryl, arylCrC6alkyl, C3-C10- cycloalkyl, C3-d0hetcycloalkyl, C3-C10cycloalkylCrCealkyl, CrC6alkylcarbonyl, arylcarbonyl, aryld-Cealkylcarbonyl, C3-C10cycloalkylcarbonyl, C3-C10hetcycloalkylcarbonyl or C3-C10cyclo- alkylCrC6alkylcarbonyl wherein the alkyl and aryl groups independently are optionally substituted with one or more of R11, wherein R11 is as defined above; or
R12 and R13 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of C C8alkyl, aryl, hetaryl, aryld- C6alkyl, hetarylCrC6alkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylC C6alkyloxy, hetaryld- C6alkyloxy, d-Cealkyl-oxyd-Cealkyl, d-C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, aryld-C6alkyl-carbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylC C6alkylcarboxy; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
In another embodiment, the present invention is concerned with compounds or pro- drugs thereof of the general formula (VII) wherein
R1 is hydrogen, C C8aIkyl, hetaryl, arylCrCealkyl or hetarylCrCealkyl optionally substituted with one or more R9; R2 and R5 independently are hydrogen, halo, nitro, cyano, trihalomethyl, CrC6alkyl, CrCealkyloxy, d-Cealkyloxyd-C-ealkyl, aryl, arylCrC6alkyl, aryloxy, aryloxyC C6alkyl, arylCrCealkyloxy, arylCrCealkyloxyCrCealkyl, hetaryl or hetarylCrCealkyl wherein the alkyl, aryl, ary- lalkyl, hetaryl and hetarylalkyl groups independently are substituted with one or more R9; and
either R3 is C(0)NR7R8, and R4 is hydrogen; or R3 is hydrogen, and R4 is C(0)NR7R8;
R6 is d-C8alkyl, C3-C10cycloalkyl, C3-C10hetcycloalkyl, N(R 2R13)CrC6alkyl, d-C6alkyloxyCr C6alkyl, aryloxyCrC6alkyl, aryld-Cealkyloxy or arylCrCealkyloxyCrCealkyl;
R7 is d-C8alkyl optionally substituted with one or more of R10;
R8 is C3-C10cycloalkyl, C3-Cιohetcycloalkyl, C3-C 0cycloalkylCrC6alkyl, wherein the cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R10; or
R7 and R8 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring sys- tem optionally being substituted with at least one of d-C8alkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C6alkyloxy, aryld-Cealkyloxy, hetarylCrCealkyloxy, d-Cealkyloxyd-Cealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R11;
R9 is hydrogen, hydroxy, oxo, halo, nitro, cyano, d-C6alkyl, CrC6alkyloxy, trihalomethyl, trihalomethoxy, NR12R13, arylCrC6alkyloxy, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
R10 and R11 independently are hydrogen, halo, oxo, hydroxy, CrCealkyl, aryl, arylCrC6alkyl, hetaryl or hetarylalkyl;
R12 and R13 independently are hydrogen, d-C8alkyl, aryl, hetaryl, aryld-Cealkyl, C3-Cιo- cycloalkyl, C3-C10hetcycloalkyl, C3-C10cycloalkylCrC6alkyl, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, C3-C10cycloalkylcarbonyl, C3-Cι0hetcycloalkylcarbonyl or C3-C10cyclo- alkylCrC6alkylcarbonyl; or
R12 and R13 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-C8alkyl, aryl, hetaryl, aryld- Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C6alkyloxy, aryld-C-ealkyloxy, hetaryld- C6alkyloxy, d-Cealkyl-oxyd-Cealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, aryld-C-ealkyl-carbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or aryld- C6alkylcarboxy; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
In another embodiment, the present invention, in formula (VII) R2 is C(0)NR7R8 and R3 R and R5 are hydrogen, wherein R7 and R8 are as defined above.
In another embodiment, the present invention, in formula (VII) R3 is C(0)NR7R8 and R2 R4 and R5 are hydrogen, wherein R7 and R8 are as defined above.
In another embodiment, the present invention, in formula (VII) R4 is C(0)NR7R8 and R2 R3and R5 are hydrogen, wherein R7 and R8 are as defined above. In another embodiment, the present invention, in formula (VII) R5 is C(0)NR7R8 and
R2 R3and R are hydrogen, wherein R7 and R8 are as defined above.
In another embodiment, the present invention, in formula (VII) R6 is C(0)NR7R8, wherein R7 and R8 are as defined above.
In another embodiment, the present invention, in formula (VII) R3 is C(0)NR7R8 and R4 is hydrogen, wherein R7 and R8 are as defined above.
In another embodiment, the present invention, in formula (VII) R3 is hydrogen and R4 is C(0)NR7R8, wherein R7 and R8 are as defined above.
In another embodiment, the present invention, in formula (VII) R8 is C3-C10cycloalkyl or drdohetcycloaikyl, each of which is optionally substituted with one or more of R10, wherein R10 is as defined above.
In another embodiment, the present invention, in formula (VII) R7 and R8 together with the nitrogen to which they are attached, are forming a saturated or partially saturated bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of d-C8alkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C6alkyloxy, arylCrCealkyloxy, hetarylCrC6alkyl-oxy, d-C6alkyl- oxyCrC6alkyl, d-Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R11, wherein R11 is as defined above.
In a further embodiment of the present invention, in formula (VII) the bicyclic ring system is 6-aza-bicyclo[3.2.1]octane optionally substituted with one or more CrC6alkyl.
In yet a further embodiment of the present invention, in formula (VII) the bicyclic ring system is 1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane. In another embodiment of the present invention the compounds of the general formula (VII) or a prodrug thereof is selected from the group consisting of: (1H-lndol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; 1H-lndole-6-carboxylic acid cyclohexyl-methyl-amide; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mix- ture of optical isomers, including a racemic mixture, or any tautomeric forms.
In another embodiment of the present invention, the compounds or prodrugs thereof of the general formula (VII) are selected from the group consisting of the compounds of examples 3 through 20 as described under EXAMPLES, COMPOUNDS OF GENERAL FORMULA (VII).
In another embodiment, the present invention is concerned with compounds or prodrugs thereof of the general formula (VIII)
Figure imgf000070_0001
wherein X is NR4, S or O;
R1 and R2 independently are hydrogen, halo, cyano, trihalomethyl, d-Cealkyl or CrCealkyloxy, wherein the alkyl groups independently are optionally substituted with one or more of R7; R3 is hydrogen, CrC6alkyl, C3-Cι0cycloalkyl, CrC6alkyloxy, CrC6alkylthio, aryl, arylCrCealkyl, hetaryl or hetarylalkyl, wherein the alkyl, cycloalkyl, aryl, hetaryl and hetarylalkyl groups independently are optionally substituted with one or more of R7;
R4 is hydrogen, C C8alkyl, CrC6alkyloxyCrC6alkyl, aryl, hetaryl, hetarylCrCealkyl, aryld- Cealkyl, arylCrC6alkyloxyCrC6alkyl, C3-C10cycloalkyl, C3-Cιohetcycloalkyl, C3-C10cyclo- alkylCrC6alkyl, CrCealkylcarboxyCrCealkyl wherein the alkyl, aryl, hetaryl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R7;
R5 is hydrogen, and R6 is adamantyl optionally substituted with hydroxy, CrC6alkyloxy, aryl, arylCrC6alkyl, aryloxy, aryld-C6alkyloxy, hetaryl, hetaryloxy or hetarylCrCealkyloxy wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R7; or
R5 and R6 are together with the nitrogen to which they are attached, forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC6alkyl, aryl, hetaryl, aryld- Cealkyl, hetarylalkyl, hydroxy, oxo, cyano, d-C6alkyloxy, arylCrCealkyloxy, hetaryld- C6alkyloxy, d-Cealkyloxyd-Cealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylC C6alkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R7;
R7 are independently hydrogen, halo, hydroxy, oxo, nitro, NR9R10, cyano, COOR8,
CONR9R10, d-C8alkyl, CrC6alkyloxy, aryloxy, arylCrCealkyloxy, hetaryloxy or he-aryld- C6alkyloxy;
R8 is hydrogen, d-C6alkyl, aryl, aryld-Cealkyl, hetarylalkyl, wherein the alkyl, aryl and het- arylalkyl groups independently are optionally substituted with one or more of R7;
R9 and R10 independently are hydrogen, C C8alkyl, C3-C10cycloalkyl, C3-C10hetcycloalkyl, C3- docycloalkyld-Cealkyl, wherein the alkyl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R7; or R9 and R10 together with the nitrogen to which they are attached, are forming a saturated or partially saturated bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of C C8alkyl, arylCrC6alkyl, hetarylCrC6alkyl, hy- droxy, cyano, d-C6alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, d-C6alkyloxyCr
C6alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetaryld- C6alkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R11;
R11 is hydrogen, halo, oxo, hydroxy, d-C6alkyl, aryl, arylCrC6alkyl, hetaryl or hetarylalkyl;
a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
In the definitions of R4, in the above formula (VIII), hetcycloalkyl cannot be 7- aza[2,2, 1 jbicycleheptane.
In another embodiment, the present invention is concerned with compounds or prodrugs thereof of the above general formula (VIII) wherein
X is NR4, S or O;
R1 and R2 independently are hydrogen, halo, cyano, trihalomethyl, C C6alkyl or CrCealkyloxy, wherein the alkyl groups independently are optionally substituted with one or more of R7;
R3 is hydrogen, d-C6alkyl, C3-C10cycloalkyl, C C6alkyloxy, d-Cealkylthio, aryl, arylCrCealkyl, hetaryl or hetarylalkyl, wherein the alkyl, cycloalkyl, aryl, hetaryl and hetarylalkyl groups independently are optionally substituted with one or more of R7;
R4 is hydrogen, CrC8alkyl, d-Cealkyloxyd-Cealkyl, aryl, hetaryl, arylCrC6alkyl, arylC C6alkyloxyCrC6alkyl, C3-C.0cycloalkyl, C3-C10hetcycloalkyl, C3-C10cycloalkylCrCealkyl, C C6alkylcarboxyCrC6alkyl wherein the alkyl, aryl, hetaryl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R7; R5 is hydrogen, and R6 is adamantyl optionally substituted with hydroxy, d-C6alkyloxy, aryl, arylCrCealkyl, aryloxy, arylCrCealkyloxy, hetaryl, hetaryloxy or hetarylCrCealkyloxy wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R7; or
R5 and R6 are together with the nitrogen to which they are attached, forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 5 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-Cealkyl, aryl, hetaryl, aryld- C6alkyl, hetarylalkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrCealkyloxy, hetaryld- C6alkyloxy, d-Cealkyloxyd-Cealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or aryld- C6alkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R7;
R7 are independently hydrogen, halo, hydroxy, oxo, nitro, NR5R6, cyano, COOR8, CONR5R6, d-C8alkyl, d-C6alkyloxy, aryloxy or hetaryloxy;
R8 is hydrogen, CrC6alkyl, aryl, arylCrC6alkyl, hetarylalkyl, wherein the alkyl, aryl and het- arylalkyl groups independently are optionally substituted with one or more of R7; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
In one embodiment of the present invention, in formula (VIII) X is NR4 or S wherein R4 is defined as above.
In another embodiment of the present invention, in formula (VIII) X is O. In another embodiment of the present invention, in formula (VIII) X is S. In another embodiment of the present invention, in formula (VIM) is NR4 wherein R4 is defined as above. In another embodiment of the present invention, in formula (VIII) R1 and R2 independently are hydrogen, halo, trihalomethyl or d-Cealkyl, wherein the alkyl groups independently are optionally substituted with one or more of R7.
In another embodiment of the present invention, in formula (VIII) R3 is hydrogen, d- C6alkyl, aryl, aryld-Cealkyl, hetaryl or hetarylalkyl, wherein the alkyl, cycloalkyl, aryl, hetaryl and hetarylalkyl groups independently are optionally substituted with one or more of R7. In another embodiment of the present invention, in formula (VIII) R4 is hydrogen, d- C8alkyl, aryl, hetaryl, hetarylCrCealkyl, arylCrC6alkyl, wherein the alkyl, aryl, hetaryl, groups independently are optionally substituted with one or more of R7.
In another embodiment of the present invention, in formula (VIII) R5 and R6 are to- gether with the nitrogen to which they are attached, forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-Cealkyl, aryl, hetaryl, aryld-Cealkyl, hetarylalkyl, hydroxy, oxo, cyano, d-C6alkyloxy, arylCrCealkyloxy, hetarylCrC6alkyloxy, d-C6alkyloxyCr C6alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetaryld- C6alkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R7.
In yet another embodiment of the present invention, in formula (VIII) R5 and R6, together with the nitrogen to which they are attached, are azepane, azocane, 6-aza- bicyclo[3.2.1]octane, 8-aza-bicyclo[3.2.1]octane, 3-aza-bicyclo[3.2.1]octane, 2-aza- bicyclo[3.2.1]octane, 3-oxa-6-aza-bicyclo[3.2.1]octane, 6-aza-bicyclo[3.2.2]nonane, 3-aza- bicyclo[3.2.2]nonane, 4-aza-tricyclo[4.3.1.13,8]undecane.
In another embodiment of the present invention the compounds of the general formulas (VIII) or a prodrug thereof is selected from the group consisting of : (4-Methyl-2-phenyl-thiazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone ; (2,4-Dimethyl-thiazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; (4-Methyl-2-pyrazin-2-yl-thiazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone; [4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6- yl)-methanone;
(3-Aza-bicyclo[3.2.2]non-3-yl)-(2,4-dimethyl-thiazol-5-yl)-methanone; (1 H-lmidazol-4-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone ; (3-Aza-bicyclo[3.2.2]non-3-yl)-(4-methyl-2-phenyl-thiazol-5-yl)-methanone ; 2,4-Dimethyl-thiazole-5-carboxylic acid cycloheptylamide; Azepan-1 -yl-(2,4-dimethyl-thiazol-5-yl)-methanone;
2,4-Dimethyl-thiazole-5-carboxylic acid adamantan-1 -ylamide;
(3-Aza-bicyclo[3.2.2]non-3-yl)-(1H-imidazol-4-yl)-methanone;
2,4-Dimethyl-thiazole-5-carboxylic acid (3-hydroxy-adamantan-1-yl)-amide; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mix- ture of optical isomers, including a racemic mixture, or any tautomeric forms. In another embodiment of the present invention the compounds of the general formulas (VIM) or a prodrug thereof is selected from the group consisting of : (1-Methyl-1H-imidazol-4-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; [1-(6-Methyl-pyridin-2-yl)-1H-imidazol-4-yl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone;
[1 -(4-Chloro-benzyl)-5-methyl-1 H-imidazol-4-yl]-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1 ]oct-6-yl)- methanone; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
The compounds of the present invention have asymmetric centers and may occur as racemates, racemic mixtures, and as individual enantiomers or diastereoisomers, with all isomeric forms being included in the present invention as well as mixtures thereof.
The present invention also encompasses pharmaceutically acceptable salts of the present compounds. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, sulphates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hydroxynaph- thoates, glycerophosphates, ketoglutarates and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci., 66, 2 (1977), which is incorporated herein by reference. Examples of metal salts include lithium, sodium, potassium, barium, calcium, magnesium, zinc, calcium salts and the like. Examples of amines and organic amines include ammonium, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, propylamine, bu- tylamine, tetramethylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, choline, N,N'-dibenzylethylenediamine, N-benzylphenylethylamine, N- methyl-D-glucamine, guanidine and the like. Examples of cationic amino acids include lysine, arginine, histidine and the like. Further, some of the compounds of the present invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of the invention.
The pharmaceutically acceptable salts are prepared by reacting a compound of the present invention with 1 to 4 equivalents of a base such as sodium hydroxide, sodium meth- oxide, sodium hydride, potassium fe/f-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, THF, methanol, tet -butanol, dioxane, isopropanol, ethanol etc. Mixtures of solvents may be used. Organic bases like lysine, arginine, diethanolamine, choline, guandine and their derivatives etc. may also be used. Alternatively, acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvents may also be used.
The stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods. Some of the pre- ferred methods include use of microbial resolution, enzymatic resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or chiral bases such as brucine, ( .)- or (S)-phenylethylamine, cinchona alkaloids and their derivatives and the like. Commonly used methods are compiled by Jaques et al. in "Enantiomers, Racemates and Resolution" (Wiley Interscience, 1981 ). More specifically the compound of the present invention may be converted to a 1 :1 mixture of diastereomeric amides by treating with chiral amines, aminoac- ids, aminoalcohols derived from aminoacids; conventional reaction conditions may be employed to convert acid into an amide; the diastereomers may be separated either by fractional crystallization or chromatography and the stereoisomers of compound of formula I may be prepared by hydrolysing the pure diastereomeric amide.
Various polymorphs of the compounds forming part of this invention may be prepared by crystallization of said compounds under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the com- pound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe nmr spectroscopy, ir spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
The invention also encompasses prodrugs of the present compounds, which on ad- ministration undergo chemical conversion by metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of the present compounds, which are readily convertible in vivo into the required compound of the present invention. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
It is a well known problem in drug discovery that compounds, such as enzyme inhibitors, may be very potent and selective in biochemical assays, yet be inactive in vivo. This lack of so-called bioavailability may be ascribed to a number of different factors such as lack of or poor absorption in the gut, first pass metabolism in the liver and/or poor uptake in cells. Although the factors determining bioavailability are not completely understood, there are many examples in the scientific literature - well known to those skilled in the art - of how to modify compounds, which are potent and selective in biochemical assays but show low or no activity in vivo, into drugs that are biologically active.
It is within the scope of the invention to modify the compounds of the present inven- tion, termed the Original compound', by attaching chemical groups that will improve the bioavailability of said compounds in such a way that the uptake in cells or mammals is facilitated.
Examples of said modifications, which are not intended in any way to limit the scope of the invention, include changing of one or more carboxy groups to esters (for instance methyl esters, ethyl esters, tert-butyl, acetoxymethyl, pivaloyloxymethyl esters or other acy- loxymethyl esters). Compounds of the invention, original compounds, such modified by attaching chemical groups are termed 'modified compounds'.
The invention also encompasses active metabolites of the present compounds. The compounds according to the invention alter, and more specifically, reduce the level of active intracellular glucocorticoid and are accordingly useful for the treatment, prevention and/or prophylaxis of disorders and diseases in which such a modulation or reduction is beneficial.
Accordingly, the present compounds may be applicable for the treatment, prevention and/or prophylaxis of the metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), Latent Autoimmune Diabetes in the Adult (LADA), type 1 diabetes, diabetic late complications including cardiovascular diseases, cardiovascular disorders, disorders of lipid metabolism, neurodegenerative and psychiatric disorders, dysregulation of intraocular pressure including glaucoma, immune disorders, inappropriate immune responses, musculo-skeletal disorders, gastrointestinal disorders, polycystic ovarie syndrome (PCOS), reduced hair growth or other diseases, disorders or conditions that are influenced by intracellular glucocorticoid levels, adverse effects of increased blood levels of active endogenous or exogenous glucocorticoid, and any combination thereof, adverse effects of increased plasma levels of endogenous active glucocorticoid, Cushing's disease, Cushing's syndrome, adverse effects of glucocorticoid receptor agonist treatment of autoimmune diseases, adverse effects of glucocorticoid receptor agonist treatment of inflammatory diseases, adverse effects of glucocorticoid receptor agonist treatment of diseases with an inflammatory component, adverse effects of glucocorticoid receptor agonist treatment as a part of cancer chemotherapy, adverse effects of glucocorticoid receptor agonist treatment for surgical/post-surgical or other trauma, adverse effects of glucocorticoid receptor agonist therapy in the context of organ or tissue transplantation or adverse effects of glucocorticoid receptor agonist treatment in other diseases, disorders or conditions where glucocorticoid receptor agonists provide clinically beneficial effects.
More specifically the present compounds may be applicable for the treatment, pre- vention and/or prophylaxis of the metabolic syndrome, type 2 diabetes, diabetes as a consequence of obesity, insulin resistance, hyperglycemia, prandial hyperglycemia, hyperinsuline- mia, inappropriately low insulin secretion, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), increased hepatic glucose production, type 1 diabetes, LADA, pediatric diabetes, dyslipidemia, diabetic dyslipidemia, hyperlipidemia, hypertriglyceridemia, hyperlipopro- teinemia, hypercholesterolemia, decreased HDL cholesterol, impaired LDL/HDL ratio, other disorders of lipid metabolism, obesity, visceral obesity, obesity as a consequence of diabetes, increased food intake, hypertension, diabetic late complications, micro-/macroalbu- minuria, nephropathy, retinopathy, neuropathy, diabetic ulcers, cardiovascular diseases, arteriosclerosis, atherosclerosis, coronary artery disease, cardiac hypertrophy, myocardial ischemia, heart insufficiency, congestional heart failure, stroke, myocardial infarction, arryth- mia, decreased blood flow, erectile dysfunction (male or female), myopathy, loss of muscle tissue, muscle wasting, muscle catabolism, osteoporosis, decreased linear growth, neurodegenerative and psychiatric disorders, Alzheimers disease, neuronal death, impaired cognitive function, depression, anxiety, eating disorders, appetite regulation, migraine, epilepsia, ad- diction to chemical substances, disorders of intraocular pressure, glaucoma, polycystic ovary syndrome (PCOS), inappropriate immune responses, inappropriate T helper-1/T helper-2 polarisation, bacterial infections, mycobacterial infections, fungal infections, viral infections, parasitic infestations, suboptimal responses to immunizations, immune dysfunction, partial or complete baldness, or other diseases, disorders or conditions that are influenced by intracel- lular glucocorticoid levels and any combination thereof, adverse effects of glucocorticoid receptor agonist treatment of allergic-inflammatory diseases such as asthma and atopic dermatitis, adverse effects of glucocorticoid receptor agonist treatment of disorders of the respiratory system e.g. asthma, cystic fibrosis, emphysema, bronchitis, hypersensitivity, pneu- monitis, eosinophilic pneumonias, pulmonary fibrosis, adverse effects of glucocorticoid re- ceptor agonist treatment of inflammatory bowel disease such as Crohn's disease and ulcera- tive colitis; adverse effects of glucocorticoid receptor agonist treatment of disorders of the immune system, connective tissue and joints e.g. reactive arthritis, rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus, lupus nephritis, Henoch-Schόnlein pur- pura, Wegener's granulomatosis, temporal arteritis, systemic sclerosis, vasculitis, sarcoido- sis, dermatomyositis-polymyositis, pemphigus vulgaris; adverse effects of glucocorticoid receptor agonist treatment of endocrinological diseases such as hyperthyroidism, hypoaldos- teronism, hypopituitarism; adverse effects of glucocorticoid receptor agonist treatment of hematological diseases e.g. hemolytic anemia, thrombocytopenia, paroxysmal nocturnal he- moglobinuria; adverse effects of glucocorticoid receptor agonist treatment of cancer such as spinal cord diseases, neoplastic compression of the spinal cord, brain tumours, acute lym- phoblastic leukemia, Hodgkin's disease, chemotherapy-induced nausea, adverse effects of glucocorticoid receptor agonist treatment of diseases of muscle and at the neuro-muscular joint e.g. myasthenia gravis and heriditary myopathies (e.g. Duchenne muscular dystrophy), adverse effects of glucocorticoid receptor agonist treatment in the context of surgery & trans- plantation e.g. trauma, post-surgical stress, surgical stress, renal transplantation, liver transplantation, lung transplantation, pancreatic islet transplantation, blood stem cell transplantation, bone marrow transplantation, heart transplantation, adrenal gland transplantation, tra- cheal transplantation, intestinal transplantation, corneal transplantation, skin grafting, kerato- plasty, lens implantation and other procedures where immunosuppression with glucocorticoid receptor agonists is beneficial; adverse effects of glucocorticoid receptor agonist treatment of brain absess, nausea/vomiting, infections, hypercalcemia, adrenal hyperplasia, autoimmune hepatitis, spinal cord diseases, saccular aneurysms or adverse effects to glucocorticoid receptor agonist treatment in other diseases, disorders and conditions where glucocorticoid receptor agonists provide clinically beneficial effects. Accordingly, in a further aspect the invention relates to a compound according to the invention for use as a pharmaceutical composition.
The invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound according to the invention together with one or more pharmaceutically acceptable carriers or diluents.
The pharmaceutical composition is preferably in unit dosage form, comprising from about 0.05 mg/day to about 2000 mg/day, preferably from about 1 mg/day to about 500 mg/day of a compound according to the invention.
In another embodiment, the patient is treated with a compound according to the in- vention for at least about 1 week, for at least about 2 weeks, for at least about 4 weeks, for at least about 2 months or for at least about 4 months.
In yet another embodiment, the pharmaceutical composition is for oral, nasal, transdermal, pulmonal or parenteral administration.
Furthermore, the invention relates to the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of disorders and diseases wherein a modulation or an inhibition of the activity of 11 βHSDl is beneficial.
The invention also relates to a method for the treatment, prevention and/or prophylaxis of disorders and diseases wherein a modulation or an inhibition of the activity of 11 βHSDl is beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound according to the invention.
In a preferred embodiment of the invention the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of any diseases and conditions that are influenced by intracellular glucocorticoid levels as mentioned above.
Thus, in a preferred embodiment of the invention the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of conditions and disorders where a decreased level of active intracellular glucocorticoid is desirable, such as the conditions and diseases mentioned above. In yet a preferred embodiment of the invention the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of the metabolic syndrome including insulin resistance, dyslipidemia, hypertension and obesity.
In yet another preferred embodiment of the invention the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG). In yet another preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to type 2 diabetes.
In yet another preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression of the metabolic syndrome into type 2 diabetes.
In still another preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of diabetic late complications including cardiovascular diseases; arteriosclerosis; atherosclerosis.
In a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of neurodegenerative and psychiatric disorders.
In yet a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of adverse effects of glucocorticoid receptor agonist treatment or therapy.
In another embodiment of the present invention, the route of administration may be any route which effectively transports a compound according to the invention to the appropriate or desired site of action, such as oral, nasal, buccal, transdermal, pulmonai, or parenteral.
In still a further aspect of the invention the present compounds are administered in combination with one or more further active substances in any suitable ratios. Such further active substances may e.g. be selected from antiobesity agents, antidiabetics, agents modifying the lipid metabolism, antihypertensive agents, glucocorticoid receptor agonists, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity.
Thus, in a further aspect of the invention the present compounds may be administered in combination with one or more antiobesity agents or appetite regulating agents. Such agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotro- pin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, β3 agonists, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, se- rotonin re-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone releasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin ago- nists, DA agonists (bromocriptin, doprexin), lipase/amylase inhibitors, PPAR (peroxisome proliferator-activated receptor) modulators, RXR (retinoid X receptor) modulators, TR β agonists, AGRP (Agouti related protein) inhibitors, H3 histamine antagonists, opioid antagonists (such as naltrexone), exendin-4, GLP-1 and ciliary neurotrophic factor.
In one embodiment of the invention the antiobesity agent is leptin; dexamphetamine or amphetamine; fenfluramine or dexfenfluramine; sibutramine; orlistat; mazindol or phen- termine.
Suitable antidiabetic agents include insulin, insulin analogues and derivatives such as those disclosed in EP 792290 (Novo Nordisk A/S), e.g. NεB29-tetradecanoyl des (B30) human insulin, EP 214 826 and EP 705275 (Novo Nordisk A/S), e.g. AspB28 human insulin, US 5,504,188 (Eli Lilly), e.g. LysB28 ProB29 human insulin, EP 368 187 (Aventis), eg Lantus, which are all incorporated herein by reference, GLP-1 (glucagon like peptide-1 ) and GLP-1 derivatives such as those disclosed in WO 98/08871 to Novo Nordisk A/S, which is incorporated herein by reference as well as orally active hypoglycaemic agents.
The orally active hypoglycaemic agents preferably comprise sulphonylureas, bigua- nides, meglitinides, glucosidase inhibitors, glucagon antagonists such as those disclosed in WO 99/01423 to Novo Nordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1 agonists, potassium channel openers such as those disclosed in WO 97/26265 and WO 99/03861 to Novo Nordisk A/S which are incorporated herein by reference, DPP-IV (dipeptidyl peptidase- IV) inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, glucose uptake modulators, compounds modifying the lipid metabolism such as antihyperlipidemic agents and antilipidemic agents as PPARα modulators, PPARδ modulators, cholesterol absorption inhibitors, HSL (hormone-sensitive lipase) inhibitors and HMG CoA inhibitors (statins), nicotinic acid, fibrates, anion exchangers, compounds lowering food intake, bile acid resins, RXR agonists and agents acting on the ATP-dependent potassium channel of the β-cells.
In one embodiment, the present compounds are administered in combination with insulin or an insulin analogue or derivative, such as NεB29-tetradecanoyl des (B30) human insulin, Asp628 human insulin, LysB28 Pro829 human insulin, Lantus®, or a mix-preparation comprising one or more of these. In a further embodiment the present compounds are administered in combination with a sulphonylurea e.g. tolbutamide, glibenclamide, glipizide or glicazide.
In another embodiment the present compounds are administered in combination with a biguanide e.g. metformin. In yet another embodiment the present compounds are administered in combination with a meglitinide e.g. repaglinide or senaglinide.
In still another embodiment the present compounds are administered in combination with a thiazolidinedione e.g. troglitazone, ciglitazone, pioglitazone, rosiglitazone or compounds disclosed in WO 97/41097 such as 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazo- linyl]methoxy]phenyl-methyl]thiazolidine-2,4-dione or a pharmaceutically acceptable salt thereof, preferably the potassium salt.
In yet another embodiment the present compounds may be administered in combination with the insulin sensitizers disclosed in WO 99/19313 such as (-) 3-[4-[2-Phenoxazin- 10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid or a pharmaceutically acceptable salts thereof, preferably the arginine salt.
In a further embodiment the present compounds are administered in combination with an α-glucosidase inhibitor e.g. miglitol or acarbose.
In another embodiment the present compounds are administered in combination with an, agent acting on the ATP-dependent potassium channel of the β-cells e.g. tolbu- tamide, glibenclamide, glipizide, glicazide or repaglinide.
Furthermore, the present compounds may be administered in combination with nateglinide.
In still another embodiment the present compounds are administered in combination with an antihyperlipidemic agent or antilipidemic agent e.g. cholestyramine, colestipol, clofi- brate, gemfibrozil, fenofibrate, bezafibrate, tesaglitazar, EML-4156, LY-818, MK-767, ator- vastatin, fluvastatin, lovastatin, pravastatin, simvastatin, acipimox, probucol, ezetimibe or dextrothyroxine.
In a further embodiment the present compounds are administered in combination with more than one of the above-mentioned compounds e.g. in combination with a sulphony- lurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin, insulin and lovastatin, etc.
Further, the present compounds may be administered in combination with one or more antihypertensive agents. Examples of antihypertensive agents are β-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol, metoprolol, bisoprololfumerate, esmolol, acebutelol, metoprolol, acebutolol, betaxolol, celiprolol, nebivolol, tertatolol, oxprenolol, amusolalul, carvedilol, labetalol, β2-receptor blockers e.g. S-atenolol, OPC-1085, ACE (angiotensin converting enzyme) inhibitors such as quinapril, lisinopril, enalapril, captopril, benazepril, perindopril, trandolapril, fosinopril, ramipril, cilazapril, delapril, imidapril, moexipril, spirapril, temocapril, zofenopril, S-5590, fasidotril, Hoechst-Marion Roussel: 100240 (EP 00481522), omapatrilat, gemopatrilat and GW-660511 , calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem, amlodipine, nitrendipine, verapamil, lacidipine, lercanidipine, aranidipine, cilnidipine, clevidipine, azelnidipine, bamidipine, efonodipine, iasidipine, iemildipine, iercanidipine, manidipine, nilvadipine, pranidipine, fumidipine, α-blockers such as doxazosin, urapidil, prazosin, terazosin, bunazosin and OPC-28326, diuretics such as thiazides/sulphonamides (e.g. bendro- flumetazide, chlorothalidone, hydrochlorothiazide and clopamide), loop-diuretics (e.g. bumetanide, furosemide and torasemide) and potassium sparing diuretics (e.g. amiloride, spironolactone), endothelin ET-A antagonists such as ABT-546, ambrisetan, atrasentan, SB- 234551, CI-1034, S-0139 and YM-598, endothelin antagonists e.g. bosentan and J-104133, renin inhibitors such as aliskiren, vasopressin V1 antagonists e.g. OPC-21268, vasopressin V2 antagonists such as tolvaptan, SR-121463 and OPC-31260, B-type natriuretic peptide agonists e.g. Nesiritide, angiotensin II antagonists such as irbesartan, candesartancilexetil, losartan, valsartan, telmisartan, eprosartan, candesartan, CL-329167, eprosartan, iosartan, olmesartan, pratosartan, TA-606, and YM-358, 5-HT2 agonists e.g. fenoldopam and ketanserin, adenosine A1 antagonists such as naftopidil, N-0861 and FK-352, thromboxane A2 antagonists such as KT2-962, endopeptidase inhibitors e.g. ecadotril, nitric oxide agonists such as LP-805, dopamine D1 antagonists e.g. MYD-37, dopamine D2 agonists such as nolomirole, n-3 fatty acids e.g. omacor, prostacyclin agonists such as treprostinil, beraprost, PGE1 agonists e.g. ecraprost, Na+/K+ ATPase modulators e.g. PST-2238, Potassium channel activators e.g. KR-30450, vaccines such as PMD-3117, Indapamides, CGRP- unigene, guanylate cyclase stimulators, hydralazines, methyldopa, docarpamine, moxo- nidine, CoAprovel, MondoBiotech-811.
Further reference can be made to Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995. Furthermore, the present compounds may be administered in combination with one or more glucocorticoid receptor agonists. Examples of such glucocorticoid receptor agonists are betametasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, beclomethasone, butixicort, clobetasol, flunisolide, flucatisone (and analogues), momethasone, triamcinolonacetonide, triamcinolonhexacetonide GW-685698, NXC-1015, NXC-1020, NXC-1021, NS-126, P-4112, P-4114, RU-24858 and T-25 series. It should be understood that any suitable combination of the compounds according to the invention with one or more of the above-mentioned compounds and optionally one or more further pharmacologically active substances are considered to be within the scope of the present invention.
PHARMACEUTICAL COMPOSITIONS
The compounds ofthe present invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and ex- cipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy,19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen. Pharmaceutical compositions for oral administration include solid dosage forms such as hard or soft capsules, tablets, troches, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well-known in the art. Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. De- pot injectable formulations are also contemplated as being within the scope of the present invention.
Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc. A typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain from 0.05 to about 2000 mg, e.g. from about 0.1 to about 1000 mg, from about 0.5 mg to about 500 mg., from about 1 mg to about 200 mg, e.g. about 100 mg.
For parenteral routes, such as intravenous, intrathecal, intramuscular and similar administration, typically doses are in the order of about half the dose employed for oral administra- tion.
The compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof. Examples are an acid addition salt of a compound having the utility of a free base and a base addition salt of a compound having the utility of a free acid. The term "pharmaceutically acceptable salts" refers to non-toxic salts of the com- pounds for use according to the present invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid or by reacting the acid with a suitable organic or inorganic base. When a compound for use according to the present invention, contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of the compound with a chemical equivalent of a pharmaceutically acceptable acid. When a com- pounds for use according to the present invention, contains a free acid such salts are prepared in a conventional manner by treating a solution or suspension of the compound with a chemical equivalent of a pharmaceutically acceptable base. Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion. Other salts which are not pharmaceutically acceptable may be useful in the preparation of compounds for use according to the present invention and these form a further aspect of the present invention.
For parenteral administration, solutions of the present compounds in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed. Such aqueous solutions should be suitable buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, syrup, phospholipids, gelatine, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaery-hritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
The pharmaceutical compositions formed by combining the compounds of the inven- tion and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.
Compositions intended for oral use may be prepared according to any known method, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents, and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically-acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulat- ing and disintegrating agents, for example corn starch or alginic acid; binding agents, for example, starch, gelatine or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyc- eryl distearate may be employed. They may also be coated by the techniques described in U.S. Patent Nos. 4,356,108; 4,166,452; and 4,265,874, incorporated herein by reference, to form osmotic therapeutic tablets for controlled release.
Formulations for oral use may also be presented as hard gelatine capsules where the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or a soft gelatine capsule wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions may contain the active compounds in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide such as lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyl- eneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as a liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be pre- served by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active compound in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipi- ents, for example, sweetening, flavouring, and colouring agents may also be present.
The pharmaceutical compositions comprising a compound for use according to the present invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example a liquid paraffin, or a mixture thereof. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, leci- thin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, preservative and flavouring and colouring agent. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known methods using suitable dispersing or wetting agents and suspend- ing agents described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conveniently employed as solvent or suspending medium. For this purpose, any bland fixed oil may be employed using synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compositions may also be in the form of suppositories for rectal administration of the compounds of the present invention. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will thus melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols, for example.
For topical use, creams, ointments, jellies, solutions of suspensions, etc., containing the compounds ofthe present invention are contemplated. For the purpose of this application, topical applications shall include mouth washes and gargles. The compounds for use according to the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes may be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
In addition, some ofthe compounds for use according to the present invention may form solvates with water or common organic solvents. Such solvates are also encompassed within the scope ofthe present invention.
Thus, in a further embodiment, there is provided a pharmaceutical composition comprising a compound for use according to the present invention, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and one or more pharmaceutically acceptable carriers, excipi- ents, or diluents. If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emul- sion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
A typical tablet which may be prepared by conventional tabletting techniques may contain: Core: Active compound (as free compound or salt thereof) 5.0 mg
Lactosum Ph. Eur. 67.8 mg
Cellulose, microcryst. (Avicel) 31.4 mg
AmberliteφIRP88* 1.0 mg
Magnesii stearas Ph. Eur. q.s.
Coating:
Hydroxypropyl methylcellulose approx. 9 mg
Mywacett 9-40 T** approx. 0.9 mg
* Polacrillin potassium NF, tablet disintegrant, Rohm and Haas. ** Acylated monoglyceride used as plasticizer for film coating.
The compounds of the invention may be administered to a patient which is a mammal, especially a human in need thereof. Such mammals include also animals, both domestic animals, e.g. household pets, and non-domestic animals such as wildlife.
Any novel feature or combination of features described herein is considered essential to this invention.
The present invention also relate to the below methods of preparing the compounds of the invention. The present invention is further illustrated in the following representative examples which are, however, not intended to limit the scope of the invention in any way.
EXAMPLES, COMPOUNDS OF GENERAL FORMULAS (I) AND (II)
The following examples and general procedures refer to intermediate compounds and final products for general formula (I) and (II) identified in the specification and in the synthesis schemes. The preparation of the compounds of general formula (I) and (II) of the present invention is described in detail using the following examples. Occasionally, the reaction may not be applicable as described to each compound included within the disclosed scope of the invention. The compounds for which this occurs will be readily recognised by those skilled in the art. In these cases the reactions can be successfully performed by conventional modifications known to those skilled in the art, which is, by appropriate protection of interfering groups, by changing to other conventional reagents, or by routine modification of reaction conditions. Alternatively, other reactions disclosed herein or otherwise conventional will be applicable to the preparation of the corresponding compounds of the invention. In all prepa- rative methods, all starting materials are known or may easily be prepared from known starting materials. The structures of the compounds are confirmed by either elemental analysis or nuclear magnetic resonance (NMR), where peaks assigned to characteristic protons in the title compounds are presented where appropriate. H NMR shifts (δH) are given in parts per million (ppm) down field from tetramethylsilane as internal reference standard. M.p.: is melt- ing point and is given in °C and is not corrected. Column chromatography was carried out using the technique described by W.C. Still et al., J. Org. Chem. 43: 2923 (1978) on Merck silica gel 60 (Art. 9385). HPLC analyses are performed using 5μm C184 x 250 mm column eluted with various mixtures of water and acetonitrile, flow = 1 ml/min, as described in the experimental section.
Microwave oven synthesis: The reaction was heated by microwave irradiation in sealed microwave vessels in a single mode Emrys Optimizer EXP from PersonalChemistry®.
Preparative HPLC: Column: 1.9 x 15 cm Waters XTerra RP-18. Buffer: linear gradient 5 - 95 % in 15 min, MeCN, 0.1 % TFA, flow rate of 15 ml/min. The pooled fractions are either evaporated to dryness in vacuo, or evaporated in vacuo until the MeCN is removed, and then frozen and freeze dried.
The abbreviations as used in the examples have the following meaning:
TLC: Thin layer chromatography
CDCI3: Deuterio chloroform CD3OD: Tetradeuterio methanol
DCM: Dichloromethane
DMF: N,N-dimethylformamide DMSO-d6: Hexadeuterio dimethylsulfoxide y ι
DMSO: Dimethylsulfoxide
DIPEA: Diisopropylethylamine
EDAC: 1 -(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
EtOAc: Ethyl acetate
THF: Tetrahydrofuran
DMF: N,N-dimethylformamide
HOBT: 1 -Hydroxy-benzotriazole
MeCN: Acetonitrile
NMP: N-Methylpyrrolidinone
TFA: Trifluoroacetic acid
EDAC: 1 -(3-Dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride min: minutes hrs: hours
General method A:
Figure imgf000092_0001
III
By allowing an acid (I) wherein R3 is defined as above to be coupled with an amine (II) wherein R1 and R2 are defined as above under standard amide forming conditions using a coupling reagent (III) (e.g. HOBT, EDAC and DIPEA in dry THF) affording amide (IV) wherein R1, R2 and R3 are defined as above.
General method B:
Figure imgf000092_0002
By allowing an acid derivative (I) wherein X is halo, R3(C=0)0-, d-C6alkyloxy or aryld-Cealkyloxy and R3 are defined as above to react with an amine (II) wherein R1 and R2 are defined as above under basic conditions (e.g. triethylamine, K2C03, NaH and the like) in a solvent (e.g. THF, DCM, DMF, NMP and the like) affording amide (III); wherein R1, R2 and R3 are defined as above.
General method C:
Figure imgf000093_0001
or
1 (a) III
By allowing an acid derivative (I) wherein X is halo, R20(C=O)O-, d-C6alkyloxy or arylCrCealkyloxy, R20 is d-C6alkyl or aryld-Cealkyl and R3 and X are defined as above to react with an amine (II) wherein R1 and R2 are defined as above under basic conditions (e.g. triethylamine, K2C03, NaH and the like) in a solvent (e.g. THF, DCM, DMF, NMP and the like) affording amide (III); wherein R1, R2 and R3 are defined as above; or when X is hydroxy the acid derivative (I) wherein R3 is as defined above is coupled with an amine (II) wherein R and R2 are defined as above under standard amide forming conditions using a coupling reagent (a) (e.g. HOBT, EDAC and DIPEA in dry THF) affording amide (III) wherein R1, R2 and R3 are as defined above.
Example 1 (General method (A))
4-(Benzori,31dioxol-5-yloxy)-Λ/-cvclohexyl-Λ/-methyl-butyramide
Figure imgf000093_0002
To a solution of 4-(benzo[1 ,3]dioxol-5-yloxy)-butyric acid (1.0 g, 4.46 mmol), HOBT (0.66 g, 4.91 mmol) in dry THF (75 ml) was added EDAC (0.94 g, 4.91 mmol) and the mix- ture was stirred for 20 minutes. Di-isopropyl ethyl amine (DIPEA) (860 μl, 4.91 mmol) and cyclohexyl-methyl-amine (555 mg, 4.91 mmol) was added and the resulting mixture was stirred for 16 hrs. at room temperature. The volatiles were evaporated in vacuo and the residue was purified by silicagel chromatography using a mixture of ethyl acetate/hexane (1 :4) as eluent. Pure fractions were collected and the solvent evaporated in vacuo to dryness. The oily residue crystallized on standing affording 1.1 g (77%) of the title compounds as a solid. 1H NMR (300 MHz, CDCI3) δ 1.07-1.85 (m, 11H), 2.10 (m, 2H), 2.48 (t, 1H), 2.53 (t, 1H), 2.81 and 2.83 (2x s, 3H, N-Me rotamers), 3.96 (t, 2H), 5.90 (s, 2H), 6.32 (dd, 1H), 6.49 (d, 1H),
6.69 (d, 1H).
Calculated for C18H25N04;
C, 67.69 %; H, 7.89 %; N, 4.39 %. Found:
C, 67.74 %; H, 7.99 %; N, 4.34 %.
Example 2 (General method (A)) Λ/-Methyl-Λ/-(1-methyl-piperidin-4-yl)-4-phenoxy-butyramide
Figure imgf000094_0001
To a solution of 4-phenoxy-butyric acid (1.0 g, 5.55 mmol), HOBT (0.83 g, 6.1 mmol) in dry THF (75 ml) was added EDAC (1.17 g, 6.1 mmol) and the mixture was stirred for 20 minutes. Di-isopropyl ethyl amine (DIPEA) (1.06 ml, 6.1 mmol) and methyl-(1-methyl- piperidin-4-yl)-amine (783 mg, 6.1 mmol) was added and the resulting mixture was stirred for 16 hrs. at room temperature. The volatiles were evaporated in vacuo and the residue was purified by silicagel chromatography using a mixture of ethyl acetate/triethyl amine (1 :25) as eluent. Pure fractions were collected and the solvent evaporated in vacuo to dryness affording 1.1 g (68%) of the title compounds as an oil.
1H NMR (300 MHz, CDCI3) δ 1.57 (m, 2H), 1.74 (dq, 1H), 1.86-2.18 (m, 5H), 2.28 (t, 3H), 2.52 (m, 2H), 2.82 and 2.85 (2x s, 3H, N-Me rotamers), 2.89 (bd, 2H), 3.60 and 4.51 (2x dt, 1 H), 4.04 (t, 2H), 6.91 (m, 3H), 7.28 (m, 2H). Calculated for C. H26N202; C, 70.31 %; H, 9.02 %; N, 9.65 %. Found: C, 69.72 %; H, 9.29 %; N, 10.12 %.
Example 3 (General method (A)) Azepan-1 -yl-.3-chloro-phenyl)-methanone
Figure imgf000094_0002
To a solution of 3-chloro benzoic acid (1.0 g, 6.39 mmol), HOBT (0.95 g, 7.03 mmol) in dry THF (50 ml) was added EDAC (1.35 g, 7.03 mmol) and the mixture was stirred for 20 minutes. Di-isopropyl ethyl amine (DIPEA) (1.22 ml, 7.03 mmol) and azepane (697 mg, 7.03 mmol) was added and the resulting mixture was stirred for 4 hrs. at room temperature. The volatiles were evaporated in vacuo, water (50 ml) was added, the resulting mixture extracted with diethyl ether (2 x 25 ml), dried (Na2S04), filtered and evaporated in vacuo. The residue was purified by silicagel chromatography using a mixture of ethyl acetate/heptane (1 :1) as eluent. Pure fractions were collected and the solvent evaporated in vacuo to dryness affording 0.9 g (59%) of the title compounds as an oil.
1H NMR (300 MHz, CDCI3) δ 1.61 (m, 6H), 1.84 (m, 2H), 3.35 (t, 2H), 3.67 (t, 2H), 7.23-7.39 (m, 4H).
Example 4 (General procedure C)
(4-Tetrazol-1 -yl-phenyl)-(1.3,3-trimethyl-6-aza-bicvclo.3.2.1.oct-6-yl)-methanone
Figure imgf000095_0001
To a mixture of 4-(1/-/-tetrazol-5-yl)-benzoic acid (0.5 g, 2.63 mmol) and HOBT (0.39 g, 2.89 mmol) in dry THF (35 mL) was added EDAC (0.55 g, 2.89 mmol). The resulting mix- ture was stirred for 10 min. followed by addition of a mixture of DIPEA (0.50 ml, 2.89 mmol) and 1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane (0.49 ml, 2.89 mmol). The reaction mixture was stirred for an additional 6 hrs. and evaporated to dryness. To the residue was added water (10 ml) and the resulting mixture was extracted with diethyl ether (2 x 10 ml). The combined organic phases were dried (Na2S04), filtered and evaporated in vacuo. The resulting residue was purified by column chromatography (silica gel) using a mixture of EtOAc- Heptane (1:2) as eluent. Pure fractions were collected and evaporated to dryness. To the residue was added diethyl ether (5 ml) and the precipitate was filtered off, washed with diethyl ether and dried in vacuo at 50 °C affording 220 mg (26 %) of the title compound as a solid. TLC: EtOAc-Heptan (2: 1 ), Rf: 0.18
1H-NMR (300 MHz, CDCI3) δ 0.95 - 1.15 (m, 9H), 1.21 - 1.64 (m, 5.5H), 2.25 (m, 0.5H), 3.17 - 3.32 (m, 1.5H), 3.63 (d, 0.5H), 3.98 and 4.60 (2x1, 1H), 7.68 (t, 2H), 7.78 (m, 2H), 9.06 (s, 1H).
The following compounds were made in a similar way as described in example 4 above:
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000101_0002
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Example 5 (General procedure C) 8-,4-Dimethylamino-benzoyl)-8-aza-bicvclo.3.2.11octan-3-one
Figure imgf000105_0001
To a mixture of 8-aza-bicyclo[3.2.1]octane (1.8 g, 14.38 mmol), dry THF (75 ml) and TEA (4 ml, 28.76 mmol) was added dropwise a solution of 4-dimethylamino-benzoyl chloride (3.17 g, 17.26 mmol) in dry THF (75 ml). The resulting mixture was stirred for 1 hr. at room temperature followed by filtration and evaporation in vacuo. The residue was purified by column chromatography (silica gel) using a mixture of EtOAc-Heptane (1 :2) as eluent. Pure fractions were collected and evaporated to dryness. The residue was crystallized from diethyl ether (25 ml), filtered off and dried in vacuo at 50 °C affording 1.9 g (48 %) of the title compound as a solid. TLC: EtOAc-Heptane (3:1 ), Rf: 0.4
1 H-NMR (300 MHz, CDCI3) δ 1.74 (m, 2H), 2.15 (m, 2H), 2.39 (d, 2H), 2.27 (bs, 2H), 3.02 (s, 6H), 4.80 (bs, 2H), 6.68 (d, 2H), 7.50 (d, 2H).
Example 6 (General procedure C)
(4-Dimethylamino-phenyl)-(3-hvdroxy-8-aza-bicvclor3.2.1loct-8-yl)-methanone
Figure imgf000105_0002
To a solution of 8-(4-dimethylamino-benzoyl)-8-aza-bicyclo[3.2.1]octan-3-one (2.0 g, 7.34 mmol) in MeOH (75 ml) was added NaBH4 (0.45 g, 11.02 mmol, pellets). The resulting mixture was stirred for 18 hrs, evaporated and to the residue was added water (75 ml). The aqueous phase was acidified to pH 1 with cone. HCI and washed with diethyl ether (50 ml). The aqueous phase was neutralized to pH 7 with 1 N NaOH. The precipitate was filtered off and washed with water, diethyl ether and dried in vacuo at 50 °C affording 1.15 g (57 %) of the title compound as a solid.
1H-NMR (400 MHz, CDCI3) δ 1.66 - 1.95 (m, 6H), 2.22 (d, 2H), 2.99 (s, 6H), 4.17 (m, 1H), 4.22 (bs, 1H), 4.74 (bs, 1H), 6.66 (d, 2H), 7.41 (d, 2H).
Example 7 (General procedure C)
(4-Dimethylamino-phenyl)-(3-hvdroxy-3-methyl-8-aza-bicvclor3.2.noct-8-yl)-methanone
Figure imgf000106_0001
To a solution of 8-(4-dimethylamino-benzoyl)-8-aza-bicyclo[3.2.1]octan-3-one (200 mg, 0.734 mmol) in dry THF (40 ml) was added dropwise a solution of methylmagnesium bromide (0.74 ml, 2.20 mmol, 3M in diethyl ether). The resulting mixture was stirred for 36 hrs. at room temperature and quenched by addition of saturated aqueous ammonium chloride (50 ml). The aqueous phase was extracted with EtOAc (2 x 100 ml) and the combined organic phases were dried (Na2S04), filtered and evaporated in vacuo. The residue was purified by column chromatography (silica gel) using a mixture of EtOAc-Heptane (5:1) as eluent. Pure fractions were collected and evaporated to dryness affording 45 mg (21 %) of the title compound as a solid. TLC: EtOAc, Rf: 0.39
1H-NMR (400 MHz, CDCI3) δ 1.21 (s, 3H), 1.75 (d, 2H), 1.92 (m, 2H), 2.15 (bs, 1H), 2.22 (d, 2H), 3.0 (s, 6H), 4.26 (bs, 1 H), 4.77 (bs, 1H), 6.66 (d, 2H), 7.42 (d, 2H).
Example 8 (General procedure C) Trifluoro-acetic acid 8-,4-dimethylamino-benzoyl)-8-aza-bicvclo.3.2.11oct-3-yl ester
Figure imgf000106_0002
NaBH4 (0.3 g, 2 pellets) was added to TFA (20 ml) at 0 °C and stirred for 30 min. To this mixture was added a solution of 8-(4-dimethylamino-benzoyl)-8-aza-bicyclo[3.2.1]octan- 3-one (0.3 g, 1.102 mmol) in DCM (10 ml). The resulting mixture was stirred for 64 hrs. at room temperature, the volatiles evaporated and to the residue was added water (10 ml). The aqueous phase was neutralized to pH 7 with 1 N NaOH and extracted with diethyl ether (2 x 25 ml). The combined organic phases were evaporated in vacuo and the residue purified by column chromatography (silica gel) using a mixture of EtOAc-Heptane (1 :2) as eluent. Pure fractions were collected and evaporated to dryness affording 25 mg (9 %) of the title com- pound as a solid.
TLC: EtOAc-Heptane (2:1), Rf: 0.54
LC/MS: m/z: 371 H+
1H-NMR (400 MHz, CDCI3) δ 1.81 - 1.94 (m, 2H), 2.05 (s, 4H), 2.31 (bs, 2H), 3.01 (s, 6H),
4.59 (bs, 2H), 5.35 (t, 1 H), 6.67 (d, 2H), 7.42 (d, 2H). EXAMPLES, COMPOUNDS OF GENERAL FORMULA (III)
The following examples and general procedures refer to intermediate compounds and final products for general formula (III) identified in the specification and in the synthesis schemes. The preparation of the compounds of general formula (III) of the present invention is described in detail using the following examples. Occasionally, the reaction may not be applicable as described to each compound included within the disclosed scope of the invention. The compounds for which this occurs will be readily recognised by those skilled in the art. In these cases the reactions can be successfully performed by conventional modifications known to those skilled in the art, that is, by appropriate protection of interfering groups, by changing to other conventional reagents, or by routine modification of reaction conditions. Alternatively, other reactions disclosed herein or otherwise conventional will be applicable to the preparation of the corresponding compounds of the invention. In all preparative methods, all starting materials are known or may easily be prepared from known starting materials. The structures of the compounds are confirmed by either elemental analysis or nuclear mag- netic resonance (NMR), where peaks assigned to characteristic protons in the title compounds are presented where appropriate. 1H NMR shifts (δH) are given in parts per million (ppm) down field from tetramethylsilane as internal reference standard. M.p.: is melting point and is given in °C and is not corrected. Column chromatography was carried out using the technique described by W.C. Still et al., J. Org. Chem. 43: 2923 (1978) on Merck silica gel 60 (Art. 9385). HPLC analyses are performed using 5μm C18 4 x 250 mm column eluted with various mixtures of water and acetonitrile, flow = 1 ml/min, as described in the experimental section.
The abbreviations as used in the examples have the following meaning: TLC: thin layer chromatography CDCI : deuterio chloroform
CD3OD: tetradeuterio methanol
DMSO-d6: hexadeuterio dimethylsulfoxide
DMSO: dimethylsulfoxide
THF: tetrahydrofuran DMF: N,N-dimethylformamide
HOBT: 1-hydroxy-benzotriazole
EDAC: 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride min: minutes hrs: hours The compounds of the invention are prepared as illustrated in the following reaction scheme 1 :
Figure imgf000108_0001
III
Figure imgf000108_0002
General method:
By allowing 2,2-dimethyl-1 ,3-dioxane-4,6-dione (Meldrum's acid) (I) to react with an acid chloride (II), wherein R2 is defined above, in a solvent mixture of pyridine and DCM and the like affording an acyl Meldrum's acid (III), wherein R2 is as defined above. The acyl Meldrum's acid (III) is aminolysed with an substituted amine (IV), wherein R3 and R4 are defined above, in a solvent such as benzene, toluene, dioxane, and the like at a temperature interval from 50 °C up to reflux affording a befa-keto amide (V) wherein R2, R3 and R4 are as defined above. The befø-keto amide (V) is treated with otf/70-formiate (VI) in a solvent such as acetic acid anhydride and the like at a temperature interval from 50 °C up to reflux affording enol ether (VII) wherein R2, R3, and R4 are as defined above. Condensation of the enol ether (VII) wherein R2, R3, and R4 are as defined above with hydrazide (VIII) wherein R1 is as defined above yields pyrazole (IX) wherein R1, R2, R3, and R4 are as defined above, in a solvent such as EtOH, /-PrOH, tert-B O and the like.
Example 1 1 -,4-Chloro-phenyl)-5-propyl-1 H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide
Figure imgf000108_0003
To a solution of 1-(4-chloro-phenyl)-5-propyl-1- .-pyrazole-4-carboxylic acid (1.0 g, 3.78 mmol), HOBT (0.56 g, 4.16 mmol) in dry THF (50 ml) was added EDAC (0.8 g, 4.16 mmol) and the mixture was stirred for 10 minutes. Di-isopropyl ethyl amine (DIPEA) (724 μl, 4.16 mmol) and cyclohexyl-methyl-amine (0.54 ml, 4.16 mmol) was added and the resulting mixture was stirred for 16 hrs. at room temperature. The volatiles were evaporated in vacuo and the residue was purified by silicagel chromatography using a mixture of ethyl acetate and heptane (1:4) as eluent. Pure fractions were collected and the solvent evaporated in vacuo affording 1.1 g (81%) of the title compounds as an oil.
1H NMR (300 MHz, CDCI3) δ 0.81 (t, 3H), 1.1 - 1.86 (m, 13H), 2.81 (t, 2H), 2.98 (s, 3H), 3.89 and 4.50 (2 x bs, 1 H), 7.37 (m, 2H), 7.47 (m, 2H), 7.58 (bs, 1H). Calculated for C2oH26CIN30, 0.4 H20; C, 65.44 %; H, 7.36 %; N, 11.45 %. Found: C, 65.47 %; H, 7.89 %; N, 11.56 %.
The following compound was made in a similar way as described in example 1 above
Example 2
1-(4-Chloro-phenyl)-5-trifluoromethyl-1 H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide
Figure imgf000109_0001
Calculated for C18H19CIF3N30; C, 56.04 %; H, 4.96 %; N, 10.89 %. Found: C, 56.02 %; H, 5.16 %; N, 10.76 %.
Example 3 ri-.4-Methoχy-phenyl)-5-methyl- - /--pyrazol-4-vn-(1.3.3-trimethyl-6-aza-bicvclor3.2.noct-6- yl)-methanone
Figure imgf000109_0002
1H NMR (400 MHz, CDCI3) δ 0.97 (t, 5H), 1.11 (t, 4H), 1.25 - 1.61 (m, 4H), 1.79 (m, 2H), 2.20 (d, 0.5H), 2.44 (d, 3H), 3.29 (d, 0.5H), 3.40 (d, 0.5H), 3.59 (m, 0.5H), 3.86 (s, 3H), 4.37 (m, 0.5H), 4.60 (m, 0.5H), 6.99 (d, 2H), 7.33 (d, 2H), 7.74 (s, 1H). EXAMPLES, COMPOUNDS OF GENERAL FORMULA (IV)
The following examples and general procedures refer to intermediate compounds and final products for general formula (IV) identified in the specification and in the synthesis schemes. The preparation of the compounds of general formula (IV) of the present invention is described in detail using the following examples. Occasionally, the reaction may not be applicable as described to each compound included within the disclosed scope of the invention. The compounds for which this occurs will be readily recognised by those skilled in the art. In these cases the reactions can be successfully performed by conventional modifications known to those skilled in the art, that is, by appropriate protection of interfering groups, by changing to other conventional reagents, or by routine modification of reaction conditions. Alternatively, other reactions disclosed herein or otherwise conventional will be applicable to the preparation of the corresponding compounds of the invention. In all preparative methods, all starting materials are known or may easily be prepared from known starting materials. The structures of the compounds are confirmed by either elemental analysis or nuclear mag- netic resonance (NMR), where peaks assigned to characteristic protons in the title compounds are presented where appropriate. 1H NMR shifts (5H) are given in parts per million (ppm) down field from tetramethylsilane as internal reference standard. M.p.: is melting point and is given in °C and is not corrected. Column chromatography was carried out using the technique described by W.C. Still et al., J. Org. Chem. 43: 2923 (1978) on Merck silica gel 60 (Art. 9385). HPLC analyses are performed using 5μm C18 4 x 250 mm column eluted with various mixtures of water and acetonitrile, flow = 1 ml/min, as described in the experimental section.
The abbreviations as used in the examples have the following meaning: TLC: Thin layer chromatography CDCI3: Deuterio chloroform
CD3OD: Tetradeuterio methanol
DMSO-d6: Hexadeuterio dimethylsulfoxide
DMSO: Dimethylsulfoxide
THF: Tetrahydrofuran DMF: N,N-Dimethylformamide
HOBT: 1-Hydroxy-benzotriazole
EDAC: 1 -(3-Dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride min: minutes hrs: hours The compounds of the invention are prepared as illustrated in the following reaction scheme 1 :
Scheme 1
Hydrolysis
Figure imgf000111_0001
Figure imgf000111_0002
Amide formation HN
V
Figure imgf000111_0003
VI
General method:
By allowing a N-aminopyridinium iodide (I), wherein R2, R3, R4and R5are as defined, above to react with a propiolate (II), wherein alkyl and R1 are as defined above, in a solvent such as DMF and the like, with a suitable base, such as potassium carbonate and the like affording a pyrazolo[1 ,5-a]pyridine-3-carboxylic acid ester (III), wherein R , R2, R3, R4, R5and alkyl are as defined above. The pyrazolo[1,5-a]pyridine-3-carboxylic acid ester (III) is hydro- lysed with a base affording a pyrazolo[1,5-a]pyridine-3-carboxylic acid (IV), wherein R1, R2, R3, R4 and R5are as defined above. The pyrazolo[1,5-a]pyridine-3-carboxylic acid (IV) is coupled with an amine (V), wherein R6 and R7 are as defined above, under standard amide forming conditions (e.g. HOBT, EDAC and DIPEA in dry THF) affording pyrazolo[1 ,5- a]pyridine-3-amide (VI), wherein R1, R2, R3, R4, R5, R6 and R7 are as defined above.
Example 1
Pyrazoloπ,5-a1pyridin-3-yl-(1,3.3-trimethyl-6-aza-bicyclor3.2.noct-6-yl)-methanone
Figure imgf000112_0001
A solution of pyrazolo[1 ,5-A]pyridine-3-carboxylic acid (97 mg, 0.6 mmol), HOBT (89 mg, 0.66 mmol), EDAC (126 mg, 0.66 mmol) and di-isopropyl ethyl amine (DIPEA) (115 μl, 0.66 mmol) in dry THF (10 ml) was stirred for 1 hr. and 1,3,3-trimethyl-6-azabicyclo[3.2.1]- octane (101 mg, 0.66 mmol) was added. The mixture was stirred for 16 hrs. at room temperature. The mixture was quenched by addition of water (30 ml), extracted with EtOAc (2 x 50 ml), dried (MgS04), filtered and evaporated in vacuo. The crude product was stirred with water (10 ml) for 30 min., filtered off and dried in vacuo affording 130 mg (73 %) of the title compound as a white solid. 1H NMR (400 MHz, CDCI3) δ 0.95 (s, 3H), 1.05 (d, 3H), 1.15 (d, 3H), 1.36 - 1.88 (m, 5.5H), 2.23 (d, 0.5H), 3.37 (d, 0.5H), 3.51 (d, 0.5H), 3.61 (d, 0.5H), 3.73 (d, 0.5H), 4.56 (m, 0.5H), 4.71 (m, 0.5H), 6.92 (m, 1 H), 7.33 (m, 1 H), 8.19 (s, 1H), 8.47 (m, 2H
The following compounds were made in a similar way was described in example 1 above.
Example 2
(2-Methyl-pyrazolori .5-alpyridin-3-vn-.1.3.3-trimethyl-6-aza-bicvclor3.2.1loct-6-yl)- methanone
Figure imgf000112_0002
1H NMR (400 MHz, CDCI3) δ 0.88 (s, 3H), 1.00 (d, 3H), 1.14 (d, 3H), 1.22 - 1.45 (m, 3.5H), 1.58 (d, 0.5H), 1.80 - 1.90 (m, 1.5H), 2.40 (d, 0.5H), 2.50 (s, 3H), 3.20 (dd, 1.5H), 3.82 (d, 0.5H), 4.02 (m, 0.5H), 4.57 (m, 0.5H), 6.75 (t, 1H), 7.18 (t, 1 H), 7.38 (t, 1H), 8.36 (d, 1H).
Example 3
Pyrazolo.1 ,5-a1pyridine-3-carboxylic acid cyclohexyl-methyl-amide
Figure imgf000113_0001
1H NMR (400 MHz, CDCI3) δ 1.12 (m, 1H), 1.39 (m, 2H), 1.57 - 1.70 (m, 3H), 1.83 (m, 4H), 3.07 (bs, 3H), 4.30 (bs, 1H), 6.89 (t, 1H), 7.30 (d, 1H), 8.08 (m, 2H), 8.48 (d, 1H).
EXAMPLES, COMPOUNDS OF GENERAL FORMULA (V) The following examples and general procedures refer to intermediate compounds and final products for general formulas (V) and (Va) identified in the specification and in the synthesis schemes. The preparation of the compounds of general formulas (V) and (Va) of the present invention is described in detail using the following examples.. Occasionally, the reaction may not be applicable as described to each compound included within the disclosed scope of the invention. The compounds for which this occurs will be readily recognised by those skilled in the art. In these cases the reactions can be successfully performed by conventional modifications known to those skilled in the art, that is, by appropriate protection of interfering groups, by changing to other conventional reagents, or by routine modification of reaction conditions. Alternatively, other reactions disclosed herein or otherwise conventional will be applicable to the preparation of the corresponding compounds of the invention. In all preparative methods, all starting materials are known or may easily be prepared from known starting materials. The structures of the compounds are confirmed by either elemental analysis or nuclear magnetic resonance (NMR), where peaks assigned to characteristic protons in the title compounds are presented where appropriate. 1H NMR shifts δπ) are given in parts per million (ppm) down field from tetramethylsilane as internal reference standard. M.p.: is melting point and is given in °C and is not corrected. Column chromatography was carried out using the technique described by W.C. Still et al., J. Org. Chem. 43: 2923 (1978) on Merck silica gel 60 (Art. 9385). HPLC analyses are performed using 5μm C184 x 250 mm column eluted with various mixtures of water and acetonitrile, flow = 1 ml/min, as described in the experimental section.
The abbreviations as used in the examples have the following meaning: TLC: Thin layer chromatography
CDCI3: Deuterio chloroform
CD3OD: Tetradeuterio methanol DIPEA: Diisopropylethyl amine
DMSO-d6: Hexadeuterio dimethylsulfoxide DMSO: Dimethylsulfoxide
THF: Tetrahydrofuran
DMF: N,N-dimethylformamide
HOBT: 1 -Hydroxy-benzotriazole
EDAC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride min: minutes hrs: hours
The compounds of the invention are prepared as illustrated in the following reaction schemes:
Scheme 1
Figure imgf000114_0001
General method A
Benzimidazol carboxylic acids (I) wherein R1, R2, R3, R5, R6 and R7 are as defined above are generally prepared as described in the following literature references;
Sekikawa; Bull. Chem. Soc. Jpn. 31, (1958), 252. Zehra; Chem. Ber. 23, (1890), 3629. Palmer, B. D. etal.; J. Med. Chem. 41, (1998), 5457 - 5465. Chi, Y.-C. and Sun, C.-M.; Syn. Lett. 5, (2000), 591 - 594. Wu, Z. etal.; Tetrahedron Lett. 41, (2000), 9871 - 9874.
By allowing an acid (I) wherein R1, R2, R3, R5, R6 and R7 are as defined above to be coupled with an amine (II) wherein R1 and R2 are defined as above under standard amide forming conditions using a coupling reagent (a) (e.g. HOBT, EDAC and DIPEA in dry THF) affording amide (III) wherein R1, R2, R3, R4, R5, X, Y and Z are as defined above. General method B
Figure imgf000115_0001
I III
By allowing an acid derivative (I) wherein X is halo, R8(C=0)0-, d-C6alkyloxy or aryld-Cealkyloxy, R8 is C C6alkyl or aryICrC6alkyl and R1, R2, R3, R5, R6 and R7 are defined as above to react with an amine (II) wherein R6 and R7 are defined as above under basic conditions (e.g. triethylamine, K2C03, NaH and the like) in a solvent (e.g. THF, DCM, DMF, NMP and the like) affording amide (III); wherein R1, R2, R3, R4, R5, R6 and R7 are defined as above.
Scheme 2
Figure imgf000115_0002
III
General method A
Benzimidazol carboxylic acids (I) wherein R1, R2, R3, R5, and R6 are as defined above are generally prepared as described in the following literature references;
Sekikawa; Bull. Chem. Soc. Jpn. 31, (1958), 252. Zehra; Chem. Ber. 23, (1890), 3629. Palmer, B. D. etal.; J. Med. Chem. 41, (1998), 5457 - 5465. Chi, Y.-C. and Sun, C.-M.; Syn. Lett. 5, (2000), 591 - 594. Wu, Z. et al.; Tetrahedron Lett. 41, (2000), 9871 - 9874. By allowing an acid (I) wherein R1, R2, R3, R5, and R6 are as defined above to be coupled with an amine (II) wherein R7 and R8 are defined as above under standard amide forming conditions using a coupling reagent (a) (e.g. HOBT, EDAC and DIPEA in dry THF) affording amide (III) wherein R1, R2, R3, R5, R5, R7 and R8 are as defined above.
General method B
Figure imgf000116_0001
I III
By allowing an acid derivative (I) wherein X is halo, R9(C=0)0-, CrC6alkyloxy or arylCrCealkyloxy, R9 is d-C6alkyl or arylCrC6alkyl and R1, R2, R3, R5 and R6 are defined as above to react with an amine (II) wherein R7 and R8 are defined as above under basic conditions (e.g. triethylamine, K2C03, NaH and the like) in a solvent (e.g. THF, DCM, DMF, NMP and the like) affording amide (III); wherein R1, R2, R3, R4, R5, R6, R7 and R8 are defined as above.
Example 1
1r.-Benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide
Figure imgf000116_0002
A solution of 1 .-benzoimidazole-5-carboxylic acid (10 g, 61.67 mmol) and HOBT (9.17 g, 67.84 mmol) in dry THF (250 ml) was stirred for 1 h. EDAC (13 g, 67.84 mmol) was added and the mixture was stirred for another 1 h. Di-isopropyl ethyl amine (DIPEA) (11.8 ml, 67.84 mmol) and cyclohexyl-methyl-amine (8.8 ml, 67.84 mmol) was added and the resulting mixture was stirred for 16 hrs. at room temperature. The precipitate was filtered off and the volatiles were evaporated in vacuo. To the residue was added water (150 ml) and diethyl ether (75 ml) and the resulting mixture was stirred for 15 minutes. The precipitate was filtered off and washed with water followed by diethyl ether and drying in vacuo at 50 °C which afforded 7.7 g (49%) of the title compounds as a solid.
1H NMR (300 MHz, CDCI3) δ 1.03 (bs, 2H), 1.53 - 1.86 (m, 8H), 2.93 (bd, 3H), 3.57 and 4.56 (2 x bs, 1H), 7.19 (d, 1H), 7.44 (bs, 1H), 7.62 (s, 1H), 7.79 (s, 1H), 11.8 (bs, 1H, NH). Calculated for C15H19N30;
C, 70.01 %; H, 7.44 %; N, 16.33 %. Found: C, 69.63 %; H, 7.45 %; N, 16.17 %.
The following compounds were synthesised in a similar way as described in example 1
Example 2 lsopropyl-2-trifluoromethyl-1 r7-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide
Figure imgf000117_0001
Calculated for C.9H24F3N30; C 62.11 %; H 6.58 %; N 11.44 %. Found C 62.10 %; H 6.69 %; N 11.66 %.
Example 3
1 -Benzyl-1 H-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide
Figure imgf000117_0002
Calculated for C22H25N30; C 76.05 %; H 7.25 %; N 12.09 %. Found C 75.89 %; H 7.39 %; N 12.03 %.
Example 4
2-Methyl-1 r.-benzoimidazole-5-carboχylic acid cvclohexyl-methyl-amide
Figure imgf000118_0001
Calculated for Cι6H21N30; 0.1 x H20; C 70.35 %; H 7.82 %; N 15.38 %. Found C 70.09 %; H 7.78 %; N 15.41 %.
Example 5
2-Hvdroxymethyl-1 H-benzoimidazole-5-carboxylic acid cvclohexyl-methyl-amide
Figure imgf000118_0002
Calculated for d6H21N302; C 66.88 %; H 7.37 %; N 14.62 %. Found C 66.62 %; H 7.50 %; N 14.43 %.
Example 6
2-,4-Amino-phenyl)-1 /--benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide
Figure imgf000118_0003
LC/MS m/z: 349 H+ 1 H NMR (300 MHz, CDCI3) δ 1.03 - 1.3 (m, 4H), 1.45 - 1.80 (m, 6H), 2.84 (bd, 3H), 5.65 (bs, 2H), 6.66 (d, 2H), 7.12 (m, 1H), 7.48 (m, 2H), 7.84 (d, 2H), 12.6 (bs, 1H, NH).
Example 7
(1/-.-Benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclof3.2.noct-6-yl)-methanone
Figure imgf000118_0004
LC/MS m/z: 298 H+ 1H NMR (400 MHz, CDCI3) δ 0.95 (d, 3H), 1.04 (d, 3H), 1.15 (d, 3H), 1.19 - 1.87 (m, 5.5H), 2.25 (m, 0.5H), 3.24 - 3.34 (m, 1.5H), 3.69 (d, 0.5H), 3.99 (m, 0.5H), 4.66 (m, 0.5H), 7.60 (t, 1H), 7.84 (t, 1H), 7.94 (d, 1H), 9.08 (s, 1H).
Example 8
(2-Methyl-1H-benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bicvclor3.2.noct-6-vn-methanone
Figure imgf000119_0001
1H NMR (300 MHz, CDCI3) δ 0.93 (d, 3H), 1.02 (d, 3H), 1.15 (m, 3H), 1.19 - 1.85 (m, 5.5H), 2.27 (m, 0.5H), 2.50 (s, 3H), 3.22 - 3.35 (m, 1.5H), 3.64 (d, 0.5H), 4.06 (m, 0.5H), 4.64 (m, 0.5H), 7.22 ( , 2H), 7.58 (m, 1H).
Example 9
(2-Amino-1H-benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclor3.2.noct-6-yl)-methanone
Figure imgf000119_0002
LC/MS m/z: 313 H+
1H NMR (300 MHz, CDCI3) δ 0.91 (d, 3H), 1.04 (d, 3H), 1.13 (s, 3H), 1.2 - 1.82 (m, 5.5H), 2.18 (m, 0.5H), 3.22 - 3.26 (m, 1.5H), 3.62 (d, 0.5H), 4.01 (m, 0.5H), 4.54 (m, 0.5H), 7.21 (m, 3H), 8.14 (m, 2H).
EXAMPLES, COMPOUNDS OF GENERAL FORMULA (VI)
The following examples and general procedures refer to intermediate compounds and final products for general formula (VI) identified in the specification and in the synthesis schemes. The preparation of the compounds of general formula (VI) of the present invention is described in detail using the following examples. Occasionally, the reaction may not be applicable as described to each compound included within the disclosed scope of the invention. The compounds for which this occurs will be readily recognised by those skilled in the art. In these cases the reactions can be successfully performed by conventional modifica- tions known to those skilled in the art, that is, by appropriate protection of interfering groups, by changing to other conventional reagents, or by routine modification of reaction conditions. Alternatively, other reactions disclosed herein or otherwise conventional will be applicable to the preparation of the corresponding compounds of the invention. In all preparative methods, all starting materials are known or may easily be prepared from known starting materials. The structures of the compounds are confirmed by either elemental analysis or nuclear mag- netic resonance (NMR), where peaks assigned to characteristic protons in the title compounds are presented where appropriate. 1H NMR shifts (δH) are given in parts per million (ppm) down field from tetramethylsilane as internal reference standard. M.p.: is melting point and is given in °C and is not corrected. Column chromatography was carried out using the technique described by W.C. Still et al., J. Org. Chem. 43: 2923 (1978) on Merck silica gel 60 (Art. 9385). HPLC analyses are performed using 5μm C184 x 250 mm column eluted with various mixtures of water and acetonitrile, flow = 1 ml/min, as described in the experimental section.
The abbreviations as used in the examples have the following meaning: TLC: thin layer chromatography CDCI3: deuterio chloroform
CD3OD: tetradeuterio methanol
DMSO-d6: hexadeuterio dimethylsulfoxide
DMSO: dimethylsulfoxide
THF: tetrahydrofuran DMF: N,N-dimethylformamide
HOBT: 1-hydroxy-benzotriazole
EDAC: 1-(3-dimethylaminopropyI)-3-ethylcarbodiimide, hydrochloride min: minutes hrs: hours
The compounds of the invention are prepared as illustrated in the following reaction scheme 1 :
Scheme 1
Figure imgf000121_0001
Figure imgf000121_0002
V VII
General method A:
By allowing a carboxylic acid ester (I) wherein R13 is C C6alkyl or aryld-Cealkyl and R7 is as defined above to react with an alkene (II) wherein X is halo and R1, R2, R3, R4, and n are as defined above under basic conditions using a base (K2C03, TEA, DIPEA in dry acetone, MIBK and the like) affording aryl ether (III) wherein R1, R2, R3, R4, R7, R13 and n are as defined above. Aryl ether (III) wherein R1, R2, R3, R4, R7, R13 and n are as defined above is rearranged in e.g. NMP at reflux temperature into phenol (IV) wherein R1, R2, R3, R4, R7, R13 and n are as defined above. Treatment of phenol (IV) wherein R1, R2, R3, R4, R7, R13 and n are as defined above with 90% formic acid followed by basic hydrolysis and acidic work up affords dihydrobenzofurane (V) wherein R1, R2, R3, R4, R7 and n are as defined above. Dihydrobenzofurane (V) wherein R1, R2, R3, R4, R7 and n are as defined above is coupled with an amine (VI) wherein R5 and R6 are defined as above under standard amide forming conditions using a coupling reagent (a) (e.g. HOBT, EDAC and DIPEA in dry THF) affording amide (VII) wherein R1, R2, R3, R4, R5, R6, R7 and n are as defined above. General method B:
Figure imgf000122_0001
By allowing an acid derivative (I) wherein Y is halo, R13(C=0)0-, d-C6alkyloxy or aryld-Cealkyloxy, R13 is d-C6alkyl or arylCrC6alkyl and R3, R4, R7 and X are defined as above to react with an amine (II) wherein R5 and R6 are defined as above under basic conditions (e.g. triethylamine, K2C03, NaH and the like) in a solvent (e.g. THF, DCM, DMF, NMP and the like) affording amide (III); wherein R3, R4, R5, R6, R7 and X are defined as above.
In the following "general methods C to H" is provided guidelines for synthesis of substituted benzofuranes-, 2,3-dihydrobenzofuranes-7-carboxylic acids and croman-8-carboxylic acids (compound V in scheme 1) according to literature references;
General method C:
Reduction
Figure imgf000122_0002
Figure imgf000122_0003
wherein X is halo, R13 and R14 are independently d-C6alkyl or arylCrCealkyl and R1, R3, and
R7 are defined as above.
Cherif, M.; Cotelle, P.; Catteau, J.-P.; Heterocycles (1992), 34, 1749-1758.
Barker, P.; Finke, P.; Thompson, K.; Synth Commun (1989), (19), 257.
General method D:
Figure imgf000123_0001
PPh,
Figure imgf000123_0002
wherein X is OH or halo; R13 is d-C6alkyl or arylCrC6alkyl and R\ R3, and R7 are defined as above.
Catalyst: AIBN: Graham, S. R.; Murphy, J. A.; Coates, D.; Tetrahedron Lett., 40, (1999),
2415 - 2416.
Catalyst: Pd(OAc)2: Larock, R. C; Stinn, D. E.; Tetrahedron Lett.; 29; (1988), 4687 - 4690.
General method E:
Figure imgf000124_0001
Figure imgf000124_0002
wherein R' is CN or COOR"; R1 is hydrogen, CrC6alkyl, aryl, heteroaryl or aryld-Cealkyl; R3 is aryl, heteroaryl, cyano, COR13, nitro or COOR", wherein R" and R13 independently are Cr
C6alkyl, aryl, heteroaryl, or arylCrC6alkyl;
Lau, C. K. etal.; J. Med. Chem. 32, (1989) 1190-1197.
For conversion of R' = CN to COOH see e.g. Cagniant; Bull. Soc. Chim. Fr.; (1957), 827 -
834.
General method F:
Figure imgf000124_0003
or or K2C03 Pd(0), C02
Figure imgf000124_0004
wherein R' is hydrogen or bromo; R1, R3 and R7 are defined as above;
Al-bojuk, N. R.; El-Abadelah, M. M.; Sabri, S. S.; Michel, A.; Voelter, W.; M.-Moessmer, C;
Al-Abed, Y.; Heterocycles; 55, (2001), 1789 - 1804. Stanetty, P.; Koller, H.; Puerstinger, G.; Monatsh.Chem., 121, (1990), 883-891.
General method H:
Figure imgf000125_0001
Figure imgf000125_0002
wherein R13 is CrC6alkyl, aryl, heteroaryl, or aryICrC6alkyl and R1, R2 and R7 are defined as above;
Kakigami, T.; Baba, K.; Usui, T.; Heterocycles; 48, (1998), 2611 - 2620.
Example 1 (General method B) 2,3-Dimethyl-2.3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide
Figure imgf000125_0003
To a solution of 2,3-dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid (0.5 g, 2.60 mmol), HOBT (0.39 g, 2.86 mmol) in dry THF (25 ml) was added EDAC (0.55 g, 2.86 mmol). The mixture was stirred for 10 min. followed by addition of di-isopropyl ethyl amine (DIPEA) (0.5 ml, 2.86 mmol) and cyclohexyl-methyl-amine (0.37 ml, 2.86 mmol). The resulting mixture was stirred for 16 hrs. at room temperature, the volatiles were evaporated in vacuo and to the residue was added water (25 ml) and diethyl ether (75 ml). The organic phase was separated and dried (Na2S04), filtered and the solvent evaporated in vacuo. The residue was dissolved in a mixture of AcOEt/Heptane (1:1) and filtered through a 2.5 cm silicagel plug. The solvent was evaporated in vacuo affording 0.7 g (93%) of the title compounds as an oil. 1H NMR (300 MHz, CDCI3) δ 1.06 (m, 3H), 1.29 (m, 4H), 1.48 (m, 5H), 1.67 - 1.8 (m, 4H), 2.77 and 2.97 (d and s, 3H, rotamer), 3.05 and 4.37 (2 x m, 1H), 3.35 and 4.55 (2 x m, 1H), 3.39 and 4.89 (2 x m, 1 H), 6.86 (t, 1 H), 7.12 (t, 2H). Calculated for C.8H25N02, 0.15 H20 C, 74.52 %; H, 8.79 %; N, 4.83 %. Found: C, 74.54 %; H, 8.98 %; N, 4.98 %.
The following compounds were synthesised in a similar way as described in Example 1 (general method B).
Figure imgf000126_0001
Figure imgf000127_0001
EXAMPLES, COMPOUNDS OF GENERAL FORMULA (VII)
The following examples and general procedures refer to intermediate compounds and final products for general formula (VII) identified in the specification and in the synthesis schemes. The preparation of the compounds of general formula (VII) of the present invention is described in detail using the following examples. Occasionally, the reaction may not be applicable as described to each compound included within the disclosed scope of the invention. The compounds for which this occurs will be readily recognised by those skilled in the art. In these cases the reactions can be successfully performed by conventional modifica- tions known to those skilled in the art, that is, by appropriate protection of interfering groups, by changing to other conventional reagents, or by routine modification of reaction conditions. Alternatively, other reactions disclosed herein or otherwise conventional will be applicable to the preparation of the corresponding compounds of the invention. In all preparative methods, all starting materials are known or may easily be prepared from known starting materials. The structures of the compounds are confirmed by nuclear magnetic resonance (NMR), where peaks assigned to characteristic protons in the title compounds are presented where appropriate. 1H NMR shifts δπ) are given in parts per million (ppm) down field from tetramethylsilane as internal reference standard. M.p.: is melting point and is given in °C and is not corrected. Column chromatography was carried out using the technique described by W.C. Still et al., J. Org. Chem. 43: 2923 (1978) on Merck silica gel 60 (Art. 9385). LC-MS analyses are performed using Waters XTerra MS C-3 x 18 mm RP-C18 column eluted with various mixtures of water and acetonitrile, flow = 1 mlJmin, with UV detection at 210 nm and MS scanning (ES+) from 100-1000 amu. An injection volume of 1 μL was used.
Microwave oven synthesis: The reaction was heated by microwave irradiation in sealed microwave vessels in a single mode Emrys Optimizer EXP from PersonalChemistry®.
Solid-phase synthesis: All reactions were performed in Teflon apparatus suitable for solid- phase synthesis or on an ACT 496 robot employing the standard procedures described.
Preparative HPLC: Column: 1.9 x 15 cm Waters XTerra RP-18. Buffer: linear gradient 5 - 95 % in 15 min, MeCN, 0.1 % TFA, flow rate of 15 mL/min. The pooled fractions are either evaporated to dryness in vacuo, or evaporated in vacuo until the MeCN is removed, and then frozen and freeze dried.
The abbreviations as used in the examples have the following meaning: TLC: Thin layer chromatography
CDCI3: Deuterio chloroform
CD3OD: Tetradeuterio methanol DMSO-d6: Hexadeuterio dimethylsulfoxide DMSO: Dimethylsulfoxide
THF: Tetrahydrofuran
DMF: N,N-dimethylformamide
HOBT: 1 -Hydroxy-benzotriazole
EDAC: 1 -(3-Ddimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride min: minutes hrs: hours
The compounds of the invention are prepared as illustrated in the following reaction schemes:
General method A
Scheme 1
Figure imgf000129_0001
lndole-7-carboxylic acids (I) wherein R1, R3, R4, R5and R6 are as defined above are generally prepared as described in the following literature references;
Clark, R. D. et al.; J. Heterocycl. Chem. 22, (1985), 121-125. Kasahara, A. et al.; J. Heterocycl. Chem. 26, (1989), 1405-1413. Kamiya, S. et al.; Chem. Pharm. Bull. 43, (1995), 1692-1695. Somei, M. etal.; Chem. Pharm. Bull. 34, (1986), 4116-4125. Wiedenau, P. et al.; Synth. Commun. 27, (1997), 2033-2040. Soederberg, B. C. et al.; J. Org. Chem. 62, (1997), 5838-5845.
By allowing an acid (I) wherein R1, R3, R4, R5and R6 are as defined above to be coupled with an amine (II) wherein R7 and R8 are defined as above under standard amide forming conditions using a coupling reagent (a) (e.g. HOBT, EDAC and DIPEA in dry DMF) affording amide (III) wherein R1, R3, R4, R5, R6, R7 and R8 are as defined above. General method B
Scheme 2
II
Figure imgf000130_0001
III
lndole-6-carboxylic acids (I) wherein R1, R2, R4, R5 and R6 are as defined above are generally prepared as described in the following literature references;
Kermack; J. Chem. Soc. 125, (1924), 2288.
Tischler, A. N.; Lanza, T. J.; Tetrahedron Lett. 27, (1986), 1653-1656.
Gharagozloo, P. etal.; Tetrahedron, 52, (1996), 10185-10192.
Zhang, H.-C. etal.; Tetrahedron Lett. 39, (1998), 4449-4452.
Kasahara, A. et al.; J. Heterocycl. Chem. 24, (1987), 1555-1556.
Brown, F. J. etal.; J. Med. Chem. 35, (1992), 2419-2439.
Izumi, T. et al.; J. Heterocycl. Chem. 29, (1992), 1625-1629.
Soederberg, B. C and Shriver, J. A.; J. Org. Chem. 62, (1997), 5838-5845.
Kitano, M. et al.; Chem. Pharm. Bull. 47, (1999), 1538-1548.
Snyder et al.; J. Am. Chem. Soc. 80, (1958), 4622-4624.
By allowing an acid (I) wherein R1, R2, R4, R5 and R6 are as defined above to be coupled with an amine (II) wherein R7 and R8 are defined as above under standard amide forming conditions using a coupling reagent (a) (e.g. HOBT, EDAC and DIPEA in dry DMF) affording amide (III) wherein R1, R2, R4, R5, R6, R7 and R8 are as defined above.
General method C
Scheme 3
Figure imgf000131_0001
I III lndole-5-carboxylic acids (I) wherein R1, R2, R3, R5and R6 are as defined above are generally prepared as described in the following literature references;
Singer, S., J. Org. Chem. 20, (1955), 1458. Noland, W. E. and Reich, C; J. Org. Chem. 32, (1967), 828-832. Street, L. J. et al.; J. Med. Chem. 36, (1993), 1529-1538. Bosch, J. et al.; Tetrahedron, 57, (2001), 1041-1048. Agarwal, A. et al.; J. Med. Chem. 36, (1993), 4006-4014. Kasahara, A. et al.; J. Heterocycl. Chem. 26, (1989); 1405-1413. Boettcher, H. and Gericke, R.; LiebigsAnn. Chem. (1988), 749-752. Somei, M. et al.; Chem. Pharm. Bull. 34, (1986), 4116-4125. Kamiya, S. et al.; Chem. Pharm. Bull. 43, (1995), 1692-1695. Odle, R. et al.; J. Org. Chem. 45, (1980), 2709-2710.
By allowing an acid (I) wherein R1, R2, R3, R5and R6 are as defined above to be coupled with an amine (II) wherein R7 and R8 are defined as above under standard amide forming conditions using a coupling reagent (a) (e.g. HOBT, EDAC and DIPEA in dry DMF) affording amide (III) wherein R1, R2, R3, R5, R6, R7 and R8 are as defined above.
General method D
Scheme 4
Figure imgf000132_0001
I III
lndole-4-carboxylic acids (I) wherein R1, R2, R3, R4 and R6 are as defined above are generally prepared as described in the following literature references;
Beswick, P. J. et al.; Tetrahedron 44, (1988), 7325. Muchowski, J. M. et al.; Tetrahedron Lett. 28, (1987), 3453. Kasahara, A. etal.; J. Heterocycl. Chem. 26, (1989); 1405-1413. Kasahara, A. etal.; J. Heterocycl. Chem. 24, (1987), 1555-1556. Clark, R. D. etal.; J. Heterocycl. Chem. 22, (1985), 121-125. Kruse, L I. Heterocycles, 16, (1981), 1119-1124. Soederberg, B. C. Org. Synth. 80, (2002), 75.
By allowing an acid (I) wherein R1, R2, R3, R4 and R6 are as defined above to be coupled with an amine (II) wherein R7 and R8 are defined as above under standard amide forming conditions using a coupling reagent (a) (e.g. HOBT, EDAC and DIPEA in dry DMF) affording amide (III) wherein R1, R2, R3, R4, R6, R7 and R8 are as defined above.
General method E
Scheme 5
Figure imgf000132_0002
III lndole-3-carboxylic acids (I) wherein R1, R2, R3, R4 and R5 are as defined above are generally prepared as described in the following literature references;
Weissgerber; Chem. Ber. 43, (1910), 3526.
Whalley; J. Chem. Soc. (1954), 1651.
Bravo, P. etal.; Tetrahedron Lett. 10, (1969), 679.
Sus, O. etal.; Justus Liebigs Ann. Chem. (1953), 583, 150.
Melzer, M. S. et al.; J. Org. Chem. 27, (1962), 496.
Amat, M. etal.; J. Org. Chem. 59, (1994), 10-11.
By allowing an acid (I) wherein R1, R2, R3, R4 and R6 are as defined above to be coupled with an amine (II) wherein R7 and R8 are defined as above under standard amide forming conditions using a coupling reagent (a) (e.g. HOBT, EDAC and DIPEA in dry DMF) affording amide (III) wherein R1, R2, R3, R4, R5, R7 and R8 are as defined above.
Example 1
(1H-lndol-5-yl)-(1.3.3-trimethyl-6-aza-bicvclor3.2.noct-6-yl)-methanone
Figure imgf000133_0001
A solution of 1H-indole-5-carboxylic acid (1.0 g, 6.21 mmol), HOBT (0.9 g, 6.83 mmol) in dry THF (50 mL) and EDAC (1.31 g, 6.83 mmol) was stirred for 10 mins. Di- isopropyl ethyl amine (DIPEA) (1.2 mL, 6.83 mmol) and 6-aza-bicyclo[3.2.1]octyl)-amine (1.16 mL, 6.83 mmol) was added and the resulting mixture was stirred for 16 hrs. at room temperature. The volatiles were evaporated in vacuo and to the residue was added water (25 mL) followed by extraction with diethyl ether (2 x 25 mL). The combined organic phases were dried (Na2S0 ), filtered and evaporated in vacuo. The residue was purified by silicagel chro- matography using a mixture of ethyl acetate and heptane (1 :2) as eluent. Pure fractions were collected and the solvent evaporated in vacuo. To the residue was added diethyl ether (10 mL) and the resulting mixture was stirred for 1 h. The precipitate was filtered off and dried in vacuo at 50 °C affording 1.3 g (71 %) of the title compounds as a solid.
MS-ESI m/z 297; 1H NMR (300 MHz, CDCI3) δ 0.93 - 1.44 (m, 13H), 1.62 (m, 1H), 1.76 (m, 1H), 2.29 and 3.28 (2x m, 1H), 3.31 and 3.62 (2x m, 1H), 4.10 and 4.65 (2x m, 1H), 6.59 (s, 1H), 7.22 - 7.35 (m, 3H), 7.74 (d, 1H), 8.69 (bs, 1H, NH). Example 2
1 H-lndole-6-carboxylic acid cvclohexyl-methyl-amide
Figure imgf000134_0001
A solution of 1H-indole-6-carboxylic acid (1.0 g, 6.21 mmol), HOBT (0.92 g, 6.83 mmol) in dry THF (50 mL) and EDAC (1.31 g, 6.83 mmol) was stirred for 20 mins. Di- isopropyl ethyl amine (DIPEA) (1.2 L, 6.83 mmol) and cyclohexyl-methyl-amine (0.9 mL, 6.83 mmol) was added and the resulting mixture was stirred for 16 hrs. at room temperature. To the precipitate was added water (50 mL), the solid filtered off, washed with water followed by diethyl ether and dried in vacuo at 50 °C which afforded 0.6 g (38%) of the title com- pounds as a solid.
1H NMR (300 MHz, CDCI3) δ 1.05 (bm, 2H), 1.15 - 1.85 (m, 8H), 2.96 (bs, 3H), 3.65 and 4.55 (2x m, 1H), 6.54 (s, 1H), 7.09 (d, 1H), 7.24 (m, 1H), 7.50 (s, 1H), 7.60 (d, 1H), 8.89 (bs, 1H, NH). Calculated for C16H2oN20; C, 74.97 %; H, 7.86 %; N, 10.93 %. Found:C, 74.90 %; H, 8.01 %; N, 10.88 %.
Example 3
(1H-lndol-7-vn-(1.3.3-trimethyl-6-aza-bicvclor3.2.noct-6-yl)-methanone
Figure imgf000134_0002
A solution of 1H-indole-7-carboxylic acid (323 mg, 2 mmol), HOAt (300 mg, 2.2 mmol) in dry DMF (10 mL) and EDAC (500 mg, 2.6 mmol) was stirred for 10 mins. Triethylamine (TEA) (0.84 mL, 6 mmol) and 6-aza-bicyclo[3.2.1]octyl)-amine (338 mg, 2.2 mmol) was added and the resulting mixture was stirred for 16 hrs. at room temperature. The volatiles were evaporated in vacuo and to the residue was added water (10 mL) followed by extraction with dichloromethane (DCM, 2 x 25 mL). The combined organic phases were dried (MgS04), filtered and evaporated in vacuo. The residue was purified by preparative HPLC, dried in vacuo at 50 °C affording 283 mg (47%) of the title compound as a solid.
MS-ESI m/z 297; 1H NMR (300 MHz, DMSO) δ 0.85-1.40 (m, 13H), 1.50-1.54 (m, 1H), 1.80-1.86 (m, 1H), 2.19-2.24 and 2.43-2.57 (2x m, 1H), 3.13 and 3.32 (m, 1H), 3.84- 3.87 and 4.47-4.50 (2x m, 1H), 6.46-6.49 (m, 1H), 7.00 - 7.19 (m, 2H), 7.30-7.34 (m, 1H), 7.60-7.63 (m, 1 H), 10.97 (d, 1H, NH).
Example 4
(1H-lndol-6-vn-(1.3.3-trimethyl-6-aza-bicvclof3.2.1loct-6-ylVmethanone
Figure imgf000135_0001
A solution of 1 H-indole-6-carboxylic acid (1 g, 6.2 mmol), HOAt (929 mg, 6.82 mmol) in dry DMF (20 mL) and EDAC (1.54 g, 8.06 mmol) was stirred for 10 mins. TEA (2.59 mL, 18.6 mmol) and 6-aza-bicyclo[3.2.1]octyl)-amine (1.04 g, 6.82 mmol) was added and the resulting mixture was stirred for 5 hrs. at room temperature. The volatiles were evaporated in vacuo and to the residue was added water (10 mL) followed by extraction with dichloromethane (DCM, 2 x 50 mL). The combined organic phases were dried (MgS04), filtered and evaporated in vacuo. The residue was purified by silicagel chromatography using a mixture of ethyl acetate and heptane (3:7) as eluent. Pure fractions were collected, the solvent evaporated in vacuo and dried in vacuo at 50 °C affording 1.6 g (87%) of the title compounds as a solid.
MS-ESI m/z 297; 1H NMR (300 MHz, CDCI3) δ 0.93 (d, 3H), 1.02 (d, 3H), 1.11-1.15 (m, 4H), 1.26-1.39 (m, 2H), 1.56-1.66 (m, 1 H), 1.73-1.79 and 2.27-2.33 (2x m, 2H), 3.22- 3.35 and 3.61-3.65 (m, 2H), 4.07-4.10 and 4.62-4.65 (2x m, 1 H), 6.52-6.54 (m, 1H), 7.17 - 7.25 (m, 2H), 7.53-7.63 (m, 2H), 9.03 (bs, 1H, NH).
The following compounds were synthesised employing a similar method to the ones described in examples 1 , 2, 3 and 4 above:
MS-ESI
No Molecule MW lUPAC Name m/z
Figure imgf000135_0002
Figure imgf000136_0001
1/- -lndole-6-carboxylic acid (8- -3 283,37 methyl-8-aza-bicyclo[3.2.1]oct- 284
Figure imgf000136_0002
3-yl)-amide
Figure imgf000136_0003
(1 H-lndol-4-yl)-(1 ,3,3-trimethyl- -6 296.40 6-aza-bicyclo[3.2.1 ]oct-6-yl)- 297 methanone
(1 H-lndol-3-yl)-(1 ,3,3-trimethyl- -7 296.40 6-aza-bicyclo[3.2.1]oct-6-yl)- 297 methanone
(1 /.-lndol-2-yl)-(1 ,3,3-trimethyl- -8 296.40 6-aza-bicyclo[3.2.1]oct-6-yl)- 297 methanone
Figure imgf000136_0004
Figure imgf000136_0005
H-indole-3- -11 acid cycloheptyla271
Figure imgf000137_0001
1 -Methyl-1 H-indole-3- -12 308.42 carboxylic acid adamantan-1- 309 ylamide
(3-Aza-bicyclo[3.2.2]non-3-yl)- -13 282.39 (1 -methyl-1 /.-indol-3-yl)- 283 methanone
(1 -Methyl-1 W-indol-3-yl)-(4- -14 257.34 methyl-piperazin-1-yl)- 258 rnethanone
1 -Methyl-1 H-indole-3- -15 324.43 carboxylic acid (3-hydroxy- 325 adamantan-1 -yl)-amide
1 -Methyl-1 H-indole-3- -16 324.42 carboxylic acid azepan-1 - 325 ylamide
1 -Methyl-1 H-indole-3- -17 285.35 carboxylic acid (2-oxo-azepan- 286
3-yl)-amide
(4-Benzyl-piperidine-1 -yl)-(1 - -18 332.45 methyl-1 H-indol-3-yl)- 333 methanone
Figure imgf000137_0002
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Example 5
6-(1.3,3-Trimethyl-6-aza-bicvclof3.2.noctane-6-carbonyl)-1H-indole-3-carboxylicacid
Figure imgf000141_0001
To a solution of (1H-lndol-6-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone (1.49 g, 5.02 mmol) in pyridine (0.81 mL, 5.02 mmol) and DCM (25 mL) at 0°C was added trichloroacetyl chloride after which cooling was stopped and the resulting mixture was stirred for 16 hrs. at room temperature. The volatiles were evaporated in vacuo and to the residue was added water (20 mL) followed by extraction with dichloromethane (DCM, 2 x 50 mL). The combined organic phases were dried (MgS0 ), filtered and evaporated in vacuo to afford 2.48 g (100%) of 2,2,2-Trichloro-1-[6-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6- carbonyl)-1H-indol-3-yl]-ethanone . To 2,2,2-Trichloro-1-[6-(1,3,3-trimethyl-6-aza-bicyclo- [3.2.1]octane-6-carbonyl)-1 H-indol-3-yl]-ethanone (100 mg, 0.22 mmol) was added a solution of ethanol:THF:1M NaOH solution (20 mL, 1:2:1, v/v/v) and the mixture was stirred at room temperature for 5 hrs. The organic solvents were evapourated in vacuo and the aqueous collections were acidified to pH 1 with concentrated hydrochloric acid followed by extraction with ethyl acetate (2x 20 mL). The combined organic phases were dried (MgS04), filtered, eva- pourated and the residue after trituration with diethyl ether was filtered and dried in vacuo at 50°C affording 56 mg (72%) of the title compound as a solid.
MS-ESI /77/Z 341; 1H NMR (300 MHz, DMSO) δ 0.91 (d, 3H), 0.97 (d, 3H), 1.09 (s, 3H), 1.13-1.54 (m, 4H), 1.73-1.78 (m, 1H), 3.13-3.18 (m, 1H), 3.30-3.47 (m, 2H), 3.98-4.02 and 4.38-4.42 (2x m, 1H), 7.19 - 7.28 (m, 1H), 7.53 (d, 1H), 7.99-8.04 (m, 1H), 8.09 (d, 1H), 11.92 (bs, 1 H, NH), 12.05 (bs, 1 H, OH).
Example 6
6-(1.3.3-Trimethyl-6-aza-bicyclor3.2.noctane-6-carbonvπ-1H-indole-3-carboxylic acid ethyl ester
Figure imgf000141_0002
To a solution of 2,2,2-Trichloro-1-[6-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6- carbonyl)-1H-indol-3-yl]-ethanone (100 mg, 0.22 mmol) in ethanol (2 mL) was added sodium ethoxide (77 mg, 1.13 mmol) and the resulting mixture was stirred for 16 hrs. at room tempe- rature. The volatiles were evaporated in vacuo and the residue was purified by preparative HPLC, dried in vacuo at 50 °C affording 33 mg (43%) of the title compound as a solid.
MS-ESI m/z 369; 1H NMR (300 MHz, CDCI3) δ 0.91-1.01 (m, 3H), 1.12 (d, 3H), 1.17- 1.36 (m, 1 H), 1.40-1.44 (m, 4H), 1.56-1.61 (m, 1 H), 1.73-1.78 (m, 1 H), 3.20-3.33 and 3.62- 3.66 (m, 2H), 4.05-4.08 and 4.58-4.61 (m, 1H), 4.38 (q, 2H), 7.29 - 7.33 (m, 1 H), 7.55 (d, 1H), 7.97-7.99 (m, 1H), 8.15-8.19 (m, 1H), 10.01 (d, 1H, NH).
The following compounds were synthesised employing a similar method to the ones described in examples 5 and 6.
MS-ESI
No Molecule MW lUPAC Name m/z
5-(1 ,3,3-Trimefhyl-6-aza- bicyclo[3.2.1]octane-6-
6-1 340.42 carbonyl)-1H-indole-3- 341
Figure imgf000142_0001
carboxylic acid
5-(1 ,3,3-Trimethyl-6-aza- bicyclo[3.2.1 ]octane-6-
6-2 368.47 carbonyl)-1 H-indole-3- 369 carboxylic acid ethyl ester
4-(1 ,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6-
6-3 340.42 carbonyl)-1H-indole-3- 341 carboxylic acid
4-(1 ,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6-
6-4 368.47 carbonyl)-1H-indole-3- 369 carboxylic acid ethyl ester
Figure imgf000142_0002
Example 7 r3-.Piperidine-1-carbonvn-1H-indol-5-yll-(1.3.3-trimethyl-6-aza-bicvclor3.2.noct-6-yl)- methanone
Figure imgf000143_0001
To 4-hydroxy-2,3,5,6-tetrafluorobenzamidomethyl polystyrene (PS-TFP resin, 100 mg, 1 mmol/g, 100-200 mesh, polystyrene-divinylbenzene 1%, Argonaut technologies, USA) pre-swollen in DCM was added a solution of 5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6- carbonyl)-1H-indole-3-carboxylic acid (51 mg, 0.15 mmol) in DMF (0.25 mL) followed by a solution of DMAP (7.3 mg, 0.06 mmol) in DCM (0.75 mL). The mixture was shaken for 10 min before a solution of Λ/,Λ/-diisopropylcarbodiimide (DIG, 56 mg, 0.44 mmol) in DCM (0.25 mL) was added and the resulting mixture shaken for 16 hrs. at room temperature. The excess solvents were removed by filtration and the resin was washed with DMF (3 x 1 mL) and DCM (10 x1 mL). To the resin was added a solution of piperidine (7.3 mg, 0.085 mmol) in 1 ,2-dichloroethane (1.2 mL) and DIPEA (0.03 mL, 0.17 mmol). The resulting mixture was shaken for 16 hrs. at room temperature. The product was removed by filtration and the resin washed with DCM:MeOH (1 mL, 3:1, v/v). The volatiles were evaporated in vacuo and the residue was purified by preparative HPLC, dried in vacuo at 50 °C affording 22 mg (54%) of the title compound as a solid.
MS-ESI m/z 408; 1H NMR (300 MHz, CDCI3) δ 0.94 (d, 3H), 1.02 (d, 3H), 1.14 (s, 3H), 1.15-1.19 (m, 1H), 1.34-1.46 (m, 3H), 1.58-1.69 (m, 7H), 1.78-1.83 (m, 1H), 2.25-2.31 and 3.27-3.29 (2 x m, 1H), 3.33-3.34 (m, 1H), 3.64-3.67 (m, 4H), 4.08-4.11 and 4.62-4.64 (2 x m, 1H), 7.25 - 7.28 (m, 1H), 7.32-7.37 (m, 1H), 7.47-7.49 (m, 1H), 7.69-7.71 (m, 1H), 9.65 (bd, 1H, NH).
The following compounds were synthesised employing a similar method to the ones described in example 7.
MS-ESI No Molecule MW IUPAC Name m/z 5-(1 ,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6- -1 378.48 carbonyl)-1H-indole-3- 379 carboxylic acid
Figure imgf000144_0001
cyanomethyl-amide
Figure imgf000144_0002
5-(1 ,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6- -6 397.52 carbonyl)-1H-indole-3- 398 carboxylic acid (2-methoxy-
Figure imgf000144_0003
ethyl)-amide 5-(1 ,3,3-Trimethyi-6-aza- bicyclo[3.2.1 ]octane-6- -7 459.59 carbonyl)-1 H-indole-3- 460 carboxylic acid 4-methoxy- benzylamide
5-(1 ,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6- -8 423.56 carbonyl)-1 H-indole-3- 424 carboxylic acid (tetrahydro- furan-2-ylmethyl)-amide
[3-(2-Methoxymethyl- pyrrolidine-1-carbonyl)-1H- -9 437.59 indoi-5-yl]-(1 ,3,3-trimethyl-6- 438 aza-bicyclo[3.2.1]oct-6-yl)- methanone
[3-(2,6-Dimethyl- morpholine-4-carbonyI)-1 H- -10 437.59 indol-5-yl]-(1 ,3,3-trimethyl-6- 438 aza-bicyclo[3.2.1]oct-6-yl)-
Figure imgf000145_0001
methanone
Figure imgf000145_0002
5-(1 ,3,3-Trimethyl-6-aza-
Figure imgf000145_0003
amide 5-(1 ,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6- -13 497.57 carbonyl)-1H-indole-3- 498 carboxylic acid 4- trifluoromethyl-benzylamide
5-(1 ,3,3-Trimethyl-6-aza- bicyclo[3.2.1 ]octane-6- -14 419.53 carbonyl)-1H-indole-3- 420 carboxylic acid (furan-2-
Figure imgf000146_0001
ylmethyl)-amide
[3-(2,3,5,6-Tetrahydro-
Figure imgf000146_0002
methanone
5-(1 ,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6- -16 carbonyl)-1H-indole-3- 422 carboxylic acid (2H-tetrazol-
Figure imgf000146_0003
5-ylmethyl)-amide
[3-(1 ,3,3-Trimethyl-6-aza-
Figure imgf000146_0004
methanone
3-{[5-(1 ,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6- -18 439.56 carbonyl)-1H-indole-3- 440 carbonyl]-amino}-propionic
Figure imgf000146_0005
acid ethyl ester 5-(1 ,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6- -19 445.57 carbonyl)-1 H-indole-3- 446
Figure imgf000147_0001
carboxylic acid (4-methoxy- phenyl)-amide
Figure imgf000147_0002
[4-(4-Chloro-phenyl)-4- -26 84 hydroxy-piperidin-1 -yl]-(1 H- 356
Figure imgf000148_0001
indol-5-yl)-methanone
Figure imgf000148_0002
Figure imgf000149_0001
Example 8
■3-Methanesulfonylmethyl-1H-indol-5-yl)-(1 ,3,3-trimethyl-6-aza-bicvclor3.2.noct-6-yl)- methanone
Figure imgf000149_0002
A solution of (1H-lndol-5-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone (300 mg, 1.01 mmol), paraformaldehyde (35 mg, 1.16 mmol), sodium methylsulfinate (103 mg, 1.01 mmol) and acetic acid (0.1 mL) in DMF (2 mL) was heated at 90°C for 3 hrs. After cooling, the mixture was poured onto water (100 mL) followed by extraction with DCM (3 x 50 mL). The combined organic phases were dried (MgS04), filtered and evaporated in vacuo. The residue was purified by preparative HPLC, dried in vacuo at 50 °C affording 167 mg (43%) of the title compound as a solid.
MS-ESI m/z 389; 1H NMR (300 MHz, CDCI3) δ 0.94 (d, 3H), 1.03 (d, 3H), 1.14-1.17 (m, 4H), 1.29-1.40 (m, 2H), 1.57-1.62 (m, 1 H), 1.79-1.84 (m, 1H), 2.67 (d, 3H), 3.25-3.34 and 3.64-3.67 (2 x m, 2H), 4.08-4.11 and 4.61-4.64 (2 x m, 1 H), 4.39 (s, 2H), 7.22-7.32 (m, 3H), 7.78 (d, 1 H), 9.42 (s, 1 H, NH).
Example 9
■3-Dimethylaminomethyl-1H-indol-6-yl)-(1.3,3-trimethyl-6-aza-bicvclof3.2.1loct-6-yl)- methanone
Figure imgf000149_0003
To a solution of (1H-lndol-6-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone (200 mg, 0.67 mmol) in DCM (10 mL) was added /V,Λ/-dimethylammonium iodide and the resulting mixture stirred at room temperature for 16 hrs. The volatiles were evaporated in vacuo and the resulting residue was purified by preparative HPLC, dried in vacuo at 50 °C affording 54 mg (23%) of the title compound isolated as the trifluoroacetate salt.
MS-ESI m/z 354; 1H NMR (400 MHz, DMSO) δ 0.90 (d, 3H), 0.97 (d, 3H), 1.08-1.17 (m, 4H), 1.28-1.53 (m, 4H), 1.72-1.79 (m, 1H), 2.76 (s, 6H), 3.14-3.16 (m, 1H), 3.33-3.36 and 3.44-3.47 (2 x m, 1H), 4.08-4.15 and 4.39-4.42 (2 x m, 1H), 4.45 (s, 2H), 7.19 (dd, 1H), 7.54 (d, 1H), 7.69 (s, 1H), 7.81 (t, 1H), 9.90 (s, 1H), 11.74 (s, 1H).
Example 10
1 -(3-Acetyl-2-.5-( 1.3.3-trimethyl-6-aza-bicvclor3.2.1 loctane-6-carbonyl )-1 H-indol-3-vπ-2,3- dihvdro-imidazol-1 -yl)-ethanone
Figure imgf000150_0001
To a solution of imidazole (23 mg, 0.34 mmol) in acetic anhydride at 125°C was added dropwise over 40 min a solution of (1H-lndol-5-yl)-(1 ,3,3-trimethyl-6-aza- bicyclo[3.2.1]oct-6-yl)-methanone (100 mg, 0.34 mmol) in acetic anhydride (13 mL). The re- suiting mixture was heated at 125°C for 30 min then cooled and solvents evaporated in vacuo. The resulting residue was purified by preparative HPLC, dried in vacuo at 50 °C to afford 5.4 mg (4%) of the title compound as a solid.
MS-ESI m/z 449; 1H NMR (400 MHz, DMSO) δ 0.94 (d, 3H), 0.97 (d, 3H), 1.08-1.17 (m, 4H), 1.28-1.62 (m, 4H), 1.72-1.79 (m, 1H), 2.05-2.08 (m, 6H), 3.14-3.16 (m, 1H), 3.26- 3.28 (m, 1H), 3.33-3.36 and 3.63-3.67 (2 x m, 1H), 4.04-4.06 and 4.61-4.63 (2 x m, 1H), 6.33-6.40 (m, 2H), 6.96-7.00 (m, 1H), 7.17-7.49 (m, 2H), 7.67-7.82 (m, 1H), 8.94 (s, 1H).
Example 11
1 -Ethyl-3-.5-(1 ,3,3-trimethyl-6-aza-bicyclo.3.2. noctane-6-carbonyl)-1 H-indol-3-vn-pyrrolidine- 2,5-dione
Figure imgf000150_0002
A solution of (1H-lndol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone (100 mg, 0.34 mmol) and /V-ethylmaleimide (127 mg, 1.01 mmol) in acetic acid (2 mL) was heated at 160°C employing microwave irradiation for 1 hr. The solvents were evaporated in vacuo and the resulting residue purified by preparative HPLC, dried in vacuo at 50 °C to af- ford 25 mg (18%) of the title compound as a solid.
MS-ESI m/z 422; 1H NMR (400 MHz, CDCI3) δ 0.93-0.96 (m, 3H), 1.01-1.06 (m, 3H), 1.13-1.17 (m, 3H), 1.21-1.25 (m, 3H), 1.28-1.44 (m, 3H), 1.55-1.64 (m, 1H), 1.73-1.81 (m, 1H), 2.05-2.28 (m, 1H), 2.78-2.87 (m, 1H), 3.17-3.34 (m, 1H), 3.57-3.68 (m, 3H), 4.01-4.07 and 4.62-4.64 (2 x m, 1H), 4.24-4.28 (m, 1H), 7.11-7.12 (m, 1H), 7.22-7.31 (m, 3H), 7.53- 7.60 (m, 1H), 8.83 (s, 1H).
Example 12
,3-Thiazol-2-yl-1 H-indol-5-yl )-( 1 ,3,3-trimethyl-6-aza-bicvclo.3.2. πoct-6-yl.-methanone
Figure imgf000151_0001
To a slurry of (1H-lndol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone (300 mg, 1.01 mmol) in benzene (8 mL) under an inert atmosphere of nitrogen was added methylmagnesium iodide (0.34 mL, 1.01 mmol), after stirring for 10 mins 2- bromothiazole was added where upon the mixture was heated at 90°C for 16 hrs. Water (20 mL) was added and the organics were extracted with DCM (3 x 20 mL). The combined organic phases were dried (MgS04), filtered and evaporated in vacuo. The residue was purified by preparative HPLC, dried in vacuo at 50 °C affording 48 mg (25%) of the title compound as a solid.
MS-ESI m/z 380; 1H NMR (300 MHz, CDCI3) δ 0.93-1.08 (m, 6H), 1.16-1.20 (m, 5H), 1.39-1.47 (m, 2H), 1.59-1.64 (m, 1H), 1.80-1.85 (m, 1H), 3.21-3.24 (m, 1H), 3.34-3.38 and 3.65-3.69 (2 x m, 1H), 4.01-4.03 and 4.65-4.68 (2 x m, 1H), 7.31-7.35 (m, 2H), 7.48-7.52 (m, 1 H), 7.82 (d, 1 H), 7.91 (d, 1 H), 8.34 (s, 1 H), 9.77 (s, 1 H).
Example 13
■3-lodo-1 H-indol-5-yl V, 1 ,3.3-trimethyl-6-aza-bicvclo.3.2. noct-6-yl)-methanone
Figure imgf000152_0001
To a solution of (1 H-lndol-5-yi)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone (1 g, 3.37 mmol) and potassium hydroxide (364 mg, 6.75 mmol) in DMF (40 mL) was added iodine (0.86 g, 3.41 mmol). The reaction mixture was stirred for 1 hr at room tem- perature then poured onto water (100 mL), extracted with DCM (3 x 20 mL). The combined organic phases were washed with water and brine then dried (MgS04), filtered and evaporated in vacuo. The resulting solid was dried in vacuo at 50 °C affording 1.18 g (83%) of the title compound.
MS-ESI m/z 423; 1H NMR (300 MHz, DMSO) δ 0.90 (d, 3H), 0.98 (d, 3H), 1.10 (d, 3H), 1.15-1.45 (m, 4H), 1.50-1.54 (m, 1H), 1.75-1.78 (m, 1H), 3.15-3.18 (m, 1 H), 3.30-3.33 and 3.41-3.45 (2 x m, 1H), 3.98-4.00 and 4.40-4.42 (2 x m, 1H), 7.22-7.42 (m, 2H), 7.44-7.47 (m, 1 H), 7.64 (s, 1 H), 11.73 (s, 1 H).
Example 14
6-(1,3,3-Trimethyl-6-aza-bicvclor3.2.noctane-6-carbonyl)-1H-indole-3-carbonitrile
Figure imgf000152_0002
To an ice-cooled slurry of (1H-lndol-6-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6- yl)-methanone (1 g, 3.37 mmol) in acetonitrile (25 mL) was added dropwise a solution of chlorosulfunylisocyanate (0.48 g, 3.37 mmol). The reaction mixture was stirred for 1 hr at 0°C then triethylamine (0.33 g, 3.3 mmol) was added dropwise maintaining an internal temperature of 0°C. The reaction mixture was allowed to warm to room temperature over 2 hrs. The solvents were evaporated in vacuo and the residue treated with DCM (10 mL) and an ice cold solution of sodium bicarbonate (5%, 10 mL) and the organics were extracted with DCM (3 x 20 mL). The combined organic phases were dried (MgS04), filtered and evaporated in vacuo. The residue was purified by preparative HPLC, dried in vacuo at 50 °C affording 182 mg (17%) of the title compound as a solid.
MS-ESI m/z 322; 1H NMR (400 MHz, DMSO) δ 0.90 (d, 3H), 0.98 (d, 3H), 1.09 (s, 3H), 1.15-1.54 (m, 5H), 1.74-1.78 (m, 1H), 3.13-3.16 (m, 1H), 3.29-3.32 and 3.44-3.47 (2 x m, 1H), 3.94-3.98 and 4.40-4.42 (2 x m, 1H), 7.27-7.35 (m, 1H), 7.60 (d, 1H), 7.66-7.70 (m, 1H), 8.35-8.37 (m, 1H), 12.32 (s, 1H).
The following compound was synthesised employing a similar method to the one described in example 14.
MS-ESI No Molecule MW lUPAC Name m/z
5-(1 ,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6-
14-1 321.42 carbonyl)-1 H-indole-3- 322 carbonitrile
Figure imgf000153_0001
Example 15
6-(1.3.3-Trimethyl-6-aza-bicvclor3.2.noctane-6-carbonyl)-1H-indole-3-carboxylic acid amide
Figure imgf000153_0002
To a solution of 6-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-in ole- 3-carbonitrile (65 mg, 0.2 mmol) in 1 ,4-dioxane (2 mL) was added sodium hydroxide solution (2 mL, 1 M) and hydrogen peroxide (2 mL) and the resulting solution was heated at 50°C for 16 hrs. The solvents were evaporated in vacuo and the residue was purified by preparative HPLC, dried in vacuo at 50 °C affording 15 mg (21%) of the title compound as a solid.
MS-ESI m/z 340; 1H NMR (400 MHz, CDCI3) δ 0.92 (d, 3H), 0.98 (d, 3H), 1.10 (d, 3H), 1.15-1.54 (m, 5H), 1.74-1.79 (m, 1H), 3.18-3.21 (m, 1H), 3.25-3.28 and 3.61-3.64 (2 x m, 1H), 4.01-4.03 and 4.55-4.58 (2 x m, 1H), 6.11 (bs, 2H), 7.19-7.23 (m, 1 H), 7.34-7.38 (m, 1H), 7.77-7.80 (m, 1H), 7.95-7.99 (m, 1H), 10.80 (s, 1H).
Example 16
.3-.2H-Tetrazol-5-yl)-1 H-indol-6-yll-(1.3,3-trimethyl-6-aza-bicvclo.3.2.1 ,oct-6-yl, -methanone
Figure imgf000154_0001
A slurry of 6-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1 H-indole-3- carbonitrile (100 mg, 0.31 mmol), zinc bromide (70 mg, 0.31 mmol) and sodium azide (22 mg, 0.34 mmol) in water (0.65 mL) was heated at 200°C employing microwave irradiation for 6 min. A solution of sodium hydroxide (3 mL, 0.25 M) was added and the mixture stirred for 45 min. Filtration of the inorganics followed by acidification of the filtrate with concentrated HCI to pH 1 yielded after filtration crude product which was purified by preparative HPLC, dried in vacuo at 50 °C affording 6 mg (5%) of the title compound as a solid.
MS-ESI m/z 365; 1H NMR (400 MHz, DMSO) δ 0.92 (d, 3H), 0.99 (d, 3H), 1.10 (d, 3H), 1.15-1.55 (m, 5H), 1.74-1.79 (m, 1H), 3.15-3.20 (m, 1H), 3.25-3.32 and 3.45-3.48 (2 x m, 1H), 4.01-4.03 and 4.41-4.43 (2 x m, 1H), 7.26-7.35 (m, 1H), 7.61 (d, 1H), 8.15-8.18 (m, 1H), 8.21-8.25 (m, 1H), 11.98 (s, 1H).
Example 17
Λ/-f3-(1,3,3-Trimethyl-6-aza-bicvclor3.2.1loctane-6-carbonyl)-1H-indol-7-vn-acetamide
Figure imgf000154_0002
To a solution of (7-nitro-1H-indol-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone (730 mg, 2.14 mmol) in MeOH (40 mL) was added palladium on activated charcoal (10% Pd, 50% H20, 0.2 g). The reaction mixture was stirred for 16 hrs under an atmosphere of hydrogen. The catalyst was removed by filtration and the solvents were evaporated in vacuo and the solid dried in vacuo at 50 °C affording 481 mg (72%) of (7-amino-1 H-indol- 3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone. To a solution of (7-amino-1H- indol-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone (100 mg, 0.32 mmol) in DCM (1 mL) was added DIPEA (829 mg, 6.4 mmol) and acetic anhydride (327 mg, 3.21 mmol), the solution was stirred at room temperature for 1 hr. Solvents were evaporated in vacuo and the residue was purified by preparative HPLC, dried in vacuo at 50 °C affording 47 mg (42%) of the title compound as a solid. .MS-ESI m/z 354; 1H NMR (300 MHz, CDCI3) δ 0.82-1.13 (m, 10H), 1.22-1.54 (m, 6H), 1.75-1.78 (m, 1H), 3.10-3.25 (m, 1H), 3.27-3.37 and 3.59-3.66 (2 x m, 1H), 4.20-4.22 and 4.49-4.52 (2 x m, 1H), 6.88-7.01 (m, 1H), 7.02-7.08 (m, 1H), 7.40-7.61 (m, 3H), 8.77 (s, 1H), 11.21 (bd, 1H).
Example 18
(1-Benzenesulfonyl-1H-indol-5-yl)-(1.3,3-trimethyl-6-aza-bicvclo[3.2.1loct-6-yl)-methanone
Figure imgf000155_0001
To a solution of (1H-lndol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone (1 g, 3.37 mmol) in dry THF (2 mL) at -78°C under an inert atmosphere of nitro- gen was added a solution of n-butyl lithium (2.14 mL, 1.65 M in hexane). Cooling was removed and the solution was allowed to warm to room temperature with stirring. The solution was cooled to -78°C where upon benzenesulphonyl chloride (655 mg, 3.71 mmol) was added and the reaction mixture was stirred for 16 hrs whilst warming to room temperature. The reaction was quenched by the addition of sodium bicarbonate solution (5%, 200 mL) and ex- tracted with DCM (3 x 50 mL). The combined organic phases were washed with water and brine then dried (MgS04), filtered and evaporated in vacuo. The resulting solid was purified by flash column chromatography (mobile phase ethylacetate: heptane, 1 :2). Product fractions were combined, evaporated in vacuo, dried in vacuo at 50 °C to afford 1.46 g (99%) of the title compound. MS-ESI A77/Z437; 1H NMR (300 MHz, CDCI3) δ 0.94 (d, 3H), 1.02 (d, 3H), 1.12-1.17
(m, 3H), 1.24-1.40 (m, 2H), 1.45 (s, 1H),1.50-1.61 (m, 2H), 1.73-1.78 (m, 1H), 3.15-3.25 (m, 1H), 3.26-3.31 and 3.58-3.63 (2 x m, 1H), 3.96-3.99 and 4.60-4.62 (2 x m, 1H), 6.68-6.70 (m, 1H), 7.37-7.47 (m, 3H), 7.53-7.63 (m, 3H), 7.84-7.87 (m, 2H), 7.99-8.03 (m, 1H).
Example 19 (1 -Benzenesulfonyl-2-methyl-1 H-indol-5-yl)-(1 ,3,3-trimethyl-6-aza-bicvclo.3.2.1.oct-6-yl)- methanone
Figure imgf000156_0001
To a solution of (1-Benzenesulfonyl-1H-indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo- [3.2.1]oct-6-yl)-methanone (100 mg, 0.23 mmol) in dry THF (2 mL) at -78°C under an inert atmosphere of nitrogen was added a solution of lithium Λ/,/V-diisopropylamide (0.165 mL, 1.5 M in cyclohexane). The mixture was stirred for 1 hr at -78°C then cooling was removed and the solution was allowed to warm to room temperature with stirring. The solution was cooled to -78°C where upon methyl iodide (48 mg, 0.343 mmol) was added and the reaction mixture was stirred for 16 hrs whilst warming to room temperature. The reaction was quenched by the addition of saturated ammonium chloride solution (10 mL) and extracted with DCM (3 x 10 mL). The combined organic phases were dried (MgS0 ), filtered and evaporated in vacuo. The residue was purified by preparative HPLC, dried in vacuo at 50 °C affording 12 mg (11 %) of the title compound as a solid.
MS-ESI m/z 451 ; 1H NMR (300 MHz, CDCI3) δ 0.94 (d, 3H), 1.04 (d, 3H), 1.13-1.15 (m, 3H), 1.25-1.40 (m, 2H), 1.45 (s, 1 H), 1.55-1.61 (m, 2H), 1.74-1.80 (m, 1H), 2.60 (s, 3H), 3.17-3.25 (m, 1H), 3.27-3.31 and 3.59-3.64 (2 x m, 1H), 4.00-4.02 and 4.61-4.63 (2 x m, 1H), 6.38 (s, 1H), 7.32-7.58 (m, 5H), 7.74-7.77 (m, 2H), 8.16-8.20 (m, 1H).
Example 20
(1-methyl-1H-indol-5-vn--1.3.3-trimethyl-6-aza-bicvclof3.2.noct-6-yl)-methanone
Figure imgf000156_0002
To a solution of (1 H-lndol-5-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone (500 mg, 1.69 mmol) in dry DMF (10 mL) at room temperature under an inert atmosphere of nitrogen was added sodium hydride (53 mg, 2.19 mmol, 60% dispersion in oil), after stirring for 30 min methyl iodide (263 mg, 1.85 mmol) was added and the reaction mixture was stirred for 16 hrs at 60°C. The reaction was quenched by the addition of water (20 mL) followed by extraction with DCM (3 x 50 mL). The combined organic phases were dried (MgS04), filtered and evaporated in vacuo. The resulting solid was purified by preparative HPLC, dried in vacuo at 50 °C affording 261 mg (50%) of the title compound as a solid. MS-ESI m/z 311; 1H NMR (300 MHz, DMSO) δ 0.89 (d, 3H), 0.96 (d, 3H), 1.07-1.21 (m, 4H), 1.23-1.53 (m, 4H), 1.72-1.78 (m, 1H), 3.10-3.15 (m, 1H), 3.34-3.47 (m, 1H), 3.80 (d, 3H), 4.01-4.04 and 4.38-4.40 (2 x m, 1H), 6.48-6.50 (m, 1H), 7.18-7.28 (m, 1 H), 7.39 (d, 1H), 7.43-7.48 (m, 1 H), 7.64 (d, 1 H).
The following compounds were synthesised employing a similar method to the ones described in example 20.
MS-
No Molecule MW 1UPAC Name ESI /z
Figure imgf000157_0001
{1 -[2-(2-Methoxy-ethoxy)- ethyl]-1H-indol-6-yl}-(1,3,3-
20-4 398.54 trimethyl-6-aza- 399 bicyclo[3.2.1]oct-6-yl)-
Figure imgf000157_0002
methanone
Figure imgf000157_0003
Figure imgf000158_0001
[1 -(Tetrahydro-furan-2- ylmethyl)-1H-indol-5-yl]- 20-7 380-53 (1 ,3,3-trimethyl-6-aza- 381 bicyclo[3.2.1]oct-6-yl)-
Figure imgf000158_0002
methanone
Figure imgf000158_0003
methanone
Figure imgf000158_0004
EXAMPLES, COMPOUNDS OF GENERAL FORMULA (VIII)
The following examples and general procedures refer to intermediate compounds and final products for general formula (VIII) identified in the specification and in the synthesis schemes. The preparation of the compounds of general formula (VIII) of the present inven- tion is described in detail using the following examples. Occasionally, the reaction may not be applicable as described to each compound included within the disclosed scope of the invention. The compounds for which this occurs will be readily recognised by those skilled in the art. In these cases the reactions can be successfully performed by conventional modifica- tions known to those skilled in the art, that is, by appropriate protection of interfering groups, by changing to other conventional reagents, or by routine modification of reaction conditions. Alternatively, other reactions disclosed herein or otherwise conventional will be applicable to the preparation of the corresponding compounds of the invention. In all preparative methods, all starting materials are known or may easily be prepared from known starting materials. The structures of the compounds are confirmed by either elemental analysis or nuclear magnetic resonance (NMR), where peaks assigned to characteristic protons in the title compounds are presented where appropriate. 1H NMR shifts δπ) are given in parts per million (ppm) down field from tetramethylsilane as internal reference standard. M.p.: is melting point and is given in °C and is not corrected. Column chromatography was carried out using the technique described by W.C. Still et al., J. Org. Chem. 43: 2923 (1978) on Merck silica gel 60 (Art. 9385). HPLC analyses are performed using 5μm C184 x 250 mm column eluted with various mixtures of water and acetonitrile, flow = 1 ml/min, as described in the experimental section.
The abbreviations as used in the examples have the following meaning: TLC: thin layer chromatography
CDCI3: deuterio chloroform
CD3OD: tetradeuterio methanol
DMSO-d6: hexadeuterio dimethylsulfoxide
DMSO: dimethylsulfoxide THF: tetrahydrofuran
DMF: N,N-dimethylformamide
HOBT: 1-hydroxy-benzotriazole
EDAC: 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride min: minutes hrs: hours
The compounds of the invention are prepared as illustrated in the following reaction scheme 1 :
Scheme 1
Figure imgf000160_0001
Solvent
Figure imgf000160_0002
Base
nBuLi CO,
Figure imgf000160_0004
Figure imgf000160_0003
IV V VII
General method:
By allowing a 2-halo-3-oxo-propionic acid ester (I) wherein Y is halo, R1 is d- C6alkyl, aryl, arylC Cealkyl and R2 is as defined above to react with an amide (II), wherein R3 is as defined above and X is O or S, in a solvent such as ethanol and the like affording an thiazole, oxazol or imidazol carboxylic acid ester (III), wherein R2 and R3 is as defined above. The thiazole, oxazol or imidazol carboxylic acid ester (III) is hydrolysed with base affording thiazole, oxazol or imidazol carboxylic acid (V), wherein R2 and R3 are as defined above. The thiazole, oxazol or imidazol carboxylic acid (V) can also be obtained from the corresponding bromo or iodo substituted thiazole, oxazol or imidazol (IV) via halogen lithium exchange followed by reaction with carbon dioxide in a solvent such as THF. The thiazole, oxazol or imidazol carboxylic acid (V) is coupled with an amine (VI), wherein R5 and R6 are as defined above, under standard amide forming conditions (e.g. HOBT, EDAC and DIPEA in dry THF) affording thiazole, oxazol or imidazol (VII), wherein R2, R3, R5 and R6 are as defined above. Example 1
4-Methyl-2-phenyl-thiazol-5-yl)-(1.3.3-trimethyl-6-aza-bicvclor3.2.noct-6-yl)-methanone
Figure imgf000161_0001
A solution of 4-methyl-2-phenyl-1 ,3-thiazole-5-carboxylic acid (0.44 g, 2.00 mmol), HOBT (0.297 g, 2.2 mmol), EDAC (0.42 g, 2.2 mmol) and di-isopropyl ethyl amine (DIPEA) (383 μl, 2.2 mmol) in dry THF (30 ml) was stirred for 30 minutes and 1 ,3,3-trimethyl-6- azabicyclo[3.2.1]octane (0.34 g, 2.2 mmol) was added. The mixture was stirred for 16 hrs. at room temperature. The mixture was added water (30 ml) and extracted with ETOAc (2 x 50 ml), dried (MgS0 ), filtered and evaporated in vacuo affording 0.67 g (94%) of the title com- pounds as an oil.
1H-NMR (400 MHz, CDCI3) δ 0.94 - 1.14 (m, 9 H), 1.26 - 1.8 (m, 5 H), 2.25 (m, 1H), 2.55 (d, 3H), 3.26 (m, 1H), 3.44 and 3.66 (2xd, 1H), 4.18 and 4.60 (2xt, 1H), 7.44 (m, 3H), 7.92 (m, 2H).
Example 2 ,2,4-Dimethyl-thiazol-5-yl )-, 1 ■3.3-trimethyl-6-aza-bicvclor3.2.11oct-6-yl .-methanone
Figure imgf000161_0002
A solution of 2,4-dimethyl-1 ,3-thiazole-5-carboxylic acid (0.47 g, 3.00 mmol), HOBT (0.46 g, 3.3 mmol), EDAC (0.63 g, 3.3 mmol) and di-isopropyl ethyl amine (DIPEA) (575 μl, 3.3 mmol) in dry THF (50 ml) was stirred for 40 minutes and 1,3,3-trimethyl-6-azabicyclo- [3.2.1]octane (0.51 g, 3.3 mmol) was added. The mixture was stirred for 16 hrs. at room temperature. The mixture was added water (30 ml) and extracted with ETOAc (2 x 50 ml), dried (MgS04), filtered and evaporated in vacuo affording 0.145 g (17%) of the title compounds as an oil. 1H-NMR (400 MHz, CDCI3) δ 0.97 - 1.15 (m, 9,5 H), 1.35 - 1.63 (m, 4.5 H), 2.17 (dd, 1H), 2.53 (d, 3H), 2.89 (d, 3H), 3.24 (m, 1H), 3.4 and 3.67 (2xd, H), 4.10 and 4.58 (2xt, 1H). Example 3
(4-Methyl-2-pyrazin-2-yl-thiazol-5-yl)-(1.3,3-trimethyl-6-aza-bicvclof3.2.1loct-6-yl)-methanone
Figure imgf000162_0001
A solution of 4-methyl-2-(2-pyrazinyl)-1,3-thiazole-5-5-carboxylic acid (0.22 g, 1.00 mmol), HOBT (0.17 g, 1.1 mmol), EDAC (0.21 g, 1.1 mmol) and di-isopropyl ethyl amine (DIPEA) (192 μl, 1.1 mmol) in dry THF (10 ml) was stirred for 30 minutes and 1 ,3,3-trimethyl- 6-azabicyclo[3.2.1]octane (0.17 g, 1.1 mmol) was added. The mixture was stirred for 16 hrs. at room temperature. The mixture was added water (30 ml) and extracted with ETOAc (2 x 50 ml), dried (MgS04), filtered and evaporated in vacuo. affording 0.345 g (97%) of the title compounds as an oil.
The following compounds were prepared in a similar way as described in Example 3 above.
Example 4 r4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl1-(1.3.3-trimethyl-6-aza-bicvclor3.2.noct-6- vO-methanone
Figure imgf000162_0002
1H-NMR (400 MHz, CDCI3) δ 0.94 (m, 3H), 1.07 (t, 3H), 1.17 (t, 3H), 1.32 - 1.84 (m, 4.5 H), 2.25 (m, 0.5H), 2.58 (d, 3H), 2.86 (d, 0.5H), 3.23 (q, 1H), 3.4 (d, 0.5H), 3.66 (d, 0.5H), 3.80 (m, 0.5H), 4.18 (m, 0.5H), 4.60 (m, 0.5H), 7.68 (t, 2H), 8.04 (d, 2H).
Example 5
( .H-lmidazol-4-vπ-.1.3.3-trimethyl-6-aza-bicvclor3.2.noct-6-yl)-methanone
Figure imgf000162_0003
1H-NMR (400 MHz, CDCI3) δ 0.94 - 0.99 (m, 6H), 1.15 (d, 3H), 1.37 (d, 1H), 1.44 - 1.52 (m, 2H), 1.60 (d, 1H), 1.74 ( , 0.5H), 1.83 (m, 0.5H), 2.09 (t, 1 H), 3.29 (d, 0.5H), 3.45 (d, 0.5H), 3.61 (d, 0.5H), 3.77 (d, 0.5H), 4.68 (m, 0.5H), 4.80 (bs, 0.5H), 7.49 (d, 1H), 7.69 (d, 1H), 11.45 (bs, 1H).
Example 6
(3-Aza-bicvclor3.2.21non-3-yl)-(4-methyl-2-phenyl-thiazol-5-yl)-methanone
Figure imgf000163_0001
1H-NMR (400 MHz, CDCI3) δ 1.70 (bs, 10H), 2.48 (s, 3H), 3.75 (bs, 4H), 7.43 (t, 3H), 7.91 (m, 2H).
Example 7
■ 1-Methyl-1H-imidazol-4-yl)-(1.3.3-trimethyl-6-aza-bicvclor3.2.1loct-6-yl)-methanone
Figure imgf000163_0002
1H-NMR (400 MHz, CDCI3) δ 0.93 (s, 3H), 0.98 (d, 3H), 1.11 (s, 3H), 1.28 - 1.46 (m, 3H), 1.55 (d, 1H), 1.69 (m, 0.5H), 1.80 (m, 0.5H), 2.05 - 2.16 (m, 1 H), 3.22 (dd, 0.5H), 3.62 (dq, 1H), 3.71 (s, 3H), 4.12 (d, 0.5H), 4.64 (m, 0.5H), 5.36 (m, 0.5H), 7.39 (d, 1H), 7.58 (d, 1H).
Example 8 ri--6-Methyl-Pyridin-2-yl)-1 H-imidazol-4-yll-(1.3.3-trimethyl-6-aza-bicvclor3.2.noct-6-yl)- methanone
Figure imgf000163_0003
1H-NMR (400 MHz, CDCl3) δ 0.94 (s, 3H), 1.00 (d, 3H), 1.13 (d, 3H), 1.25 - 1.44 (m, 3H), 1.56 (m, 1H), 1.72 (m, 0.5H), 1.83 (m, 0.5H), 2.08 - 2.18 (m, 1H), 2.57 (s, 3H), 3.26 (d, 0.5H), 3.65 (q, 1 H), 4.16 (d, 0.5H), 4.68 (m, 0.5H), 5.42 (m, 0.5H), 7.12 (d, 1H), 7.18 (d, 1 H), 7.72 (t, 1H), 8.24 (s, 1H), 8.35 (s, 1H). Example 9 r 1 -(4-Chloro-benzvn-5-methyl-1 H-imidazol-4-yll-π .3.3-trimethyl-6-aza-bicvclor3.2.1 loct-6-yl)- methanone
Figure imgf000164_0001
1H-NMR (300 MHz, CDCI3) δ 0.93 (s, 3H), 1.01 (d, 3H), 1.10 (d, 3H), 1.26 - 1.46 (m, 3H), 1.55 (d, 1 H), 1.69 (m, 0.5H), 1.79 (m, 0.5H), 2.04 - 2.18 (m, 1 H), 2.41 (d, 3H), 3.22 (d, 0.5H), 3.59 (d, 1H), 4.06 (d, 0.5H), 4.64 (m, 0.5H), 5.05 (s, 2H), 5.15 (m, 0.5H), 7.00 (d, 2H), 7.32 (d, 2H), 7.43 (d, 1H).
PHARMACOLOGICAL METHODS
11 βHSDl enzyme assay
Materials
3H-cortisone and anti-rabbit Ig coated scintillation proximity assay (SPA) beads were purchased from Amersham Pharmacia Biotech, β-NADPH was from Sigma and rabbit anti- cortisol antibodies were from Fitzgerald. An extract of yeast transformed with h-11 βHSDl (Hult et al., FEBS Lett., 441 , 25 (1998)) was used as the source of enzyme. The test compounds were dissolved in DMSO (10 mM). All dilutions were performed in a buffer containing 50 mM TRIS-HCI (Sigma Chemical Co), 4 mM EDTA (Sigma Chemical Co), 0.1% BSA (Sigma Chemical Co), 0.01% Tween-20 (Sigma Chemical Co) and 0.005% bacitracin (Novo Nordisk A S), pH=7.4. Optiplate 96 wells plates were supplied by Packard. The amount of 3H- cortisol bound to the SPA beads was measured on TopCount NXT, Packard.
Methods h-11βHSD1 , 120 nM 3H-cortisone, 4 mM β-NADPH, antibody (1:200), serial dilutions of test compound and SPA particles (2 mg/well) were added to the wells. The reaction was initiated by mixing the different components and was allowed to proceed under shaking for 60 min at 30°C The reaction was stopped be the addition of 10 fold excess of a stopping buffer containing 500 μM carbenoxolone and 1 μM cortisone. Data was analysed using GraphPad Prism software.
Table 1 Inhibition of 11 βHSDl by compounds of the invention
Figure imgf000165_0001

Claims

1. Use of a substituted amide, a prodrug thereof, or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a ra- cemic mixture or any tautomeric forms, for a) modulation of the activity of 11 βHSDl; or b) inhibition of 11 βHSDl , in a patient in need thereof.
2. Use of a substituted amide, a prodrug thereof, or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture or any tautomeric forms, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of any disorder and disease where it is desirable to a) modulate the activity of 11 βHSDl ; or b) inhibit 11 βHSDl , in a patient in need thereof.
3. The use according to claim 1 or 2 wherein the substituted amide or a prodrug thereof is of the general formula (I)
Figure imgf000166_0001
wherein
R1 is C3-C10cycloalkyl, C3-C10hetcycloalkyl, d-C8alkyl, aryl, hetaryl, aryld-Cealkyl or hetarylCrCealkyl, wherein the cycloalkyl, hetcycloalkyl, alkyl, arylalkyl and hetarylalkyl groups independently are optionally substituted with one or more of R4.
R2 is hydrogen, C C8alkyl, aryl, hetaryl, arylCrCealkyl, C3-C10cycloalkylCrC6alkyl, C Cealkyl-carboxyd-C-ealkyl wherein the alkyl, aryl and cycloalkyl groups independently are optionally substituted with one or more of R5; or R1 and R2 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of C C8alkyl, aryl, hetaryl, aryld- Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrCealkyloxy, hetaryld- C6aIkyloxy, d-Cealkyloxyd-C-ealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or aryld- C6alkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R14;
R3 is CrC8alkyl, d-Cealkenyl, CrC6alkynyl, C3-C.0cycloalkyl, C3-C10hetcycloalkyl, aryl, hetaryl, aryld-C6alkyl, d-Cealkyloxyd-Cealkyl, hetarylCrCealkyl, aryl-R6-CrC6alkyl, hetaryl- R6-d-C6alkyl or
Figure imgf000167_0001
wherein the alkyl, cycloalkyl, hetcycloalkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R7;
R4 and R5 independently are hydrogen, hydroxy, oxo, cyano, halo, methylendioxo, NR8R9, CrCealkyl, d-C6alkyloxy, trihalomethyl, trihalomethyloxy, C3-C10cycloalkyl, C3- dohetcycloalkyl, C3-C10cycloalkenyl, aryl, hetaryl, hetarylSOn, arylCrCealkyloxy, hetaryld- C6alkyloxy, d-Cealkyl-R^d-Cealkyl, aryld-Cealkyl-R^d-Cealkyl, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, hetarylcarbonyl, hetarylCrC6alkyl-carbonyl, CrC6alkylSOn, CrC6alkyl-carboxy, arylcarboxy, hetarylcarboxy, arylCrC6alkyIcarboxy or hetaryld- C6alkylcarboxy wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one ore more of R15;
R6 is oxygen, sulphur, SOn or NR16
R7 is hydrogen, halo, hydroxy, cyano, nitro, COOR17, C C8alkyl, C3-C10cycloalkyl, C3-C10het- cycloalkyl, methylendioxo, trihalomethyl, trihalomethyloxy, aryl, arylCrC6alkyl, CrC6alkyloxy, d-Cealkyloxyd-Cealkyl, aryloxy, arylC C6alkyloxy, aryloxyCrC6alkyl, arylCrC6alkyIoxyCr C6alkyl, hetaryl, hetarylCrCealkyl, hetaryloxy, hetarylCrCealkyloxy, hetaryloxyd-C-ealkyl, hetaryld-Cealkyl-oxyd-Cealkyl, NR8R9, S02NR8R9, NR4R5carbonyld-C6alkyl, arylthio, hetarylthio, R18carbonylNR8, arylSOn, hetarylSOn, R19SOmNR8, arylthioCrC6alkyl, hetaryl- thioCrC6alkyl or arylCrC6alkylR6CrC6alkyl; wherein the aryl and hetaryl groups independ- ently are optionally substituted with one or more R10; R8 and R9 independently are hydrogen, C C8alkyl, aryl, hetaryl, aryld-C6alkyl or hetarylCr C6alkyl wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R11; or
R8 and R9 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system optionally being substituted with at least one halo, cyano, CrC8alkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrCealkyl, hydroxy, oxo, d-C6alkyloxy, arylCrCealkyloxy, hetaryld- C6alkyloxy, d-Cealkyloxyd-Cealkyl, d-C6alkyl-carbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetarylcarboxy, arylCrCealkylcarboxy or hetarylCrC6alkylcarboxy;
R10 and R11 independently are hydrogen, hydroxy, oxo, halo, cyano, nitro, d-C8alkyl, C C6alkyloxy, NR12R13, methylendioxo, trihalomethyl or trihalomethyloxy;
R12 and R13 independently are hydrogen, d-C8alkyl or aryld-C6alkyl;
R14 is hydrogen, halo, hydroxy, oxo, nitro, cyano, d-C-8alkyl, d-C-ealkyloxy or aryloxy;
R15 is hydrogen, halo, hydroxy, oxo, nitro, cyano, CONR8R9 or COOR17;
R16 is hydrogen, d-C8alkyl, C3-C10cycloalkyl, C3-C10hetcycloalkyl, aryl, aryld-Cealkyl, hetaryl, hetarylCrC6alkyl, alkylcarbonyl, arylcarbonyl, arylCrC6alkylcarbonyl, aryloxyd- C6alkyl, hetaryloxyCrC6alkyl, arylthioCrC6aIkyl or hetarylthioCrC6alkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R10;
R17 is hydrogen, d-C8alkyl, aryl or aryld-Cealkyl;
R18 is C C6alkyl, C2-C6alkenyl, aryl, arylCrC6alkyl, hetaryl, hetaryld-C6alkyl, C3- C10cycloalkyl, C3-C10hetcycloalkyl, CrC6alkyloxy, aryloxy, arylCrCealkyloxy, aryld- C-ealkyloxyd-Cealkyl, hetaryloxy, hetarylCrCealkyloxy, hetarylCrCealkyloxyCrCealkyl or R8R9NC C6alkyl wherein the alkyl, alkenyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups are optionally substituted with R15;
R19 is CrC6alkyl, C3-C10cycloalkyl, C3-C10hetcycloalkyl, aryl, aryld-C6alkyl, hetaryl, hetarylCrCealkyl;
m is 1 or 2;
n is 0, 1 or 2; or
a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
4. The use according to any of the claims 1-3, wherein the substituted amide or a prodrug thereof is of the general formula (I)
Figure imgf000169_0001
wherein
R1 is C3-C10cycloalkyl, C3-C10hetcycloalkyl, C C8alkyl, aryl, hetaryl, arylCrCealkyl or hetarylCrCealkyl, wherein the cycloalkyl, hetcycloalkyl, alkyl, arylalkyl and hetarylalkyl groups independently are optionally substituted with one or more of R4;
R2 is hydrogen, d-C8alkyl, aryl, hetaryl, aryld-Cealkyl, C3-C10cycloalkylCrC6alkyl, Cr C6alkylcarboxyCrC6alkyl wherein the alkyl, aryl and cycloalkyl groups independently are op- tionally substituted with one or more of R5; or
R1 and R2 are together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of C C8alkyl, aryl, hetaryl, aryld- Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrCealkyloxy, hetaryld- C6alkyloxy, CrCealkyloxyCrC6alkyl, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, C C6alkylcarboxy, arylcarboxy or arylC 6alkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R14;
R3 is d-C8aIkyl, CrC6alkenyl, CrC6alkynyl, C3-Cιocycloalkyl, C3-C10hetcycloalkyl, aryl, hetaryl, aryld-Cealkyl, d-Cealkyloxyd-Cealkyl, hetarylCrCealkyl, aryl-R6-CrC6a]kyl, hetaryl- R6-CrC6alkyl or arylCrC6alkyl-R6-CrC6alkyl wherein the alkyl, cycloalkyl, hetcycloalkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R7;
R4 and R5 independently are hydrogen, hydroxy, oxo, cyano, halo, methylendioxo, NR8R9, C Cealkyl, CrC6alkyloxy, trihalomethyl, trihalomethyloxy, C3-C10cycloalkyl, C3- dohetcycloalkyl, C3-C10cycloalkenyl, aryl, hetaryl, hetarylSOn, aryld-Cealkyloxy, hetaryld- C6alkyloxy, d-Cealkyl-R^d-C-ealkyi, aryiCrC6alkyl-R6-CrC6alkyl, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, hetarylcarbonyl, hetarylCrC6alkyl-carbonyl, CrC6alkylSOn, CrC6alkyl-carboxy, arylcarboxy, hetarylcarboxy, arylCrCealkylcarboxy or hetaryld-
C6alkylcarboxy wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one ore more of R 5;
R6 is oxygen, sulphur, SOn, NR 16.
R7 is hydrogen, halo, hydroxyl, cyano, nitro, COOR17, d-C8alkyl, C3-Cιocycloalkyl, C3-Cιohet- cycloalkyl, methylendioxo, trihalomethyl, trihalomethyloxy, aryl, arylCrCealkyl, CrC6alkyloxy, CrC6alkyloxyCrCealkyl, aryloxy, aryloxyCrC6alkyl, arylCrC6alkyloxyCrC6alkyI, hetaryl, hetarylCrCealkyl, hetaryloxy, hetarylCrCealkyloxy, hetaryloxyCrC6alkyl, hetarylCrC6alkyl- oxyd-C6alkyl, NR8R9, S02NR8R9, NR4R5carbonylalkyl, arylcarbonylNR8, arylthio, hetarylthio, arylSOn, hetarylSOn, arylSOmNR8, arylthioCrC6alkyl, hetarylthioCrC6alkyl or aryld- C6alkylR6CrCealkyl; wherein the aryl and hetaryl groups independently are optionally substituted with one or more R10;
R8 and R9 independently are hydrogen, CrC8alkyl, aryl, hetaryl, aryld-C6alkyl or hetaryld- C6alkyl wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R11; or
R8 and R9 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon at- oms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system optionally being substituted with at least one d-C8alkyl, aryl, hetaryl, aryld-C6alkyl, hetarylCrCealkyl, hydroxy, oxo, C C6alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, C C6alkyloxyCrC6alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, aryld- C6alkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetarylcarboxy, aryld-C6alkyl-carboxy or hetarylCrC6alkylcarboxy;
R10 and R11 independently are hydrogen, hydroxy, oxo, halo, cyano, nitro, CrC8alkyI, d- C6alkyloxy, NR12R13, methylendioxo, trihalomethyl or trihalomethyloxy;
R12 and R13 independently are hydrogen, d-C8alkyl or arylCrC6alkyl;
R14 is hydrogen, halo, hydroxy, oxo, nitro, cyano, C C8alkyl, CrCealkyloxy or aryloxy;
R15 is hydrogen, halo, hydroxy, oxo, nitro, cyano or COOR17;
R16 is hydrogen, C C8alkyl, C3-C1ocycloalkyl, C3-C10hetcycloalkyl, aryl, arylCrC6alkyl, hetaryl, hetaryld-Cealkyl, alkylcarbonyl, arylcarbonyl, aryld-C6alkylcarbonyl, aryloxyd- C6alkyl, hetaryloxyCrC6alkyl, arylthioCrC6alkyl or hetarylthioCrC6alkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 0;
R17 is hydrogen, d-C8alkyl, aryl or arylC C6alkyl;
m is 1 or 2;
n is 0, 1 or 2; or
a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mix- ture of optical isomers, including a racemic mixture, or any tautomeric forms.
5. The use according to any of the claims 1-4, wherein R1 is is C3-Cιocycloalkyl, C3- dohetcycloalkyl, wherein the cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R4.
6. The use according to any of the claims 1-5, wherein R2 is hydrogen or CrC8alkyl, wherein the alkyl group is optionally substituted with one or more of R5.
7. The use according to any of the claims 1-4, wherein R1 and R2 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC8alkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, C C6alkyloxy, aryld-Cealkyloxy, hetarylCrCealkyloxy, d- CealkyloxyCrCealkyl, d- C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrC6alkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R14.
8. The use according to any of the claims 1-7, wherein R3 is C3-C10cycloalkyl, C3-dohet- cycloalkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrCealkyl, aryl-R6-CrC6alkyl, hetaryl-R6-C
C6alkyl or arylCrC6alkyI-R6-CrC6alkyl wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R7.
9. The use according to any of the claims 1-8, wherein R4 and R5 independently are hydro- gen, hydroxy, oxo, halo, , d-C8alkyl, wherein the alkyl group is optionally substituted with one ore more of R15.
10. The use according to any of the claims 1-9, wherein R6 is oxygen.
11. The use according to any of the claims 1-10, wherein R7 is hydrogen, halo, hydroxy, cyano, C C8alkyl, C3-C10cycloalkyl, C3-C10het-cycloalkyl, trihalomethyl, aryl, arylCrC6alkyl, CrC6alkyloxy, d-Cealkyloxyd-Cealkyl, aryloxy, arylCrCealkyloxy, aryloxyd-C6alkyl, aryld- C6alkyloxyCrC6alkyl, hetaryl, hetarylCrCealkyl, hetaryloxy, hetarylCrCealkyloxy, hetary- loxyd-C6alkyl, hetaryld-Cealkyl-oxyd-Cealkyl, NR8R9, NR4R5carbonylCrC6alkyl, R18carbonylNR8, R19SOmNR8, wherein the aryl and hetaryl groups independently are optionally substituted with one or more R10.
12. The use according to any of the claims 1-11 , wherein R8 and R9 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional het- eroatoms selected from nitrogen, oxygen or sulfur, the ring system optionally being substituted with at least one halo, cyano, d-C8alkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrCealkyl, hydroxy, oxo, d-C6alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, CrC6alkyloxyCr C6alkyl, CrC6alkyl-carbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetaryld- C6alkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetarylcarboxy, arylCrCealkylcarboxy or hetaryld-Cealkylcarboxy.
13. The use according to any of the claims 1-12, wherein R15 is CONR8R9.
14. The use according to any of the claims 1-13, wherein R18 is d-Cealkyl.
15. The use according to any of the claims 1-14, wherein the substituted amide or a prodrug thereof of general formula (I) is selected from the group consisting of:
3-(10, 11 -Dihydro-dibenzo[b,f]azepin-5-yl)-1 -[4-(1 H-imidazol-4-yl)-piperidin-1 -yl]-propan-1 - one;
4-(10, 11 -Dihydro-dibenzo[b,fJazepin-5-yl)-1 -[4-(3H-imidazol-4-yl)-piperidin-1 -yl]-butan-1 -one;
2,4-Bis-benzyloxy-benzamide;
(1 H-lndol-4-yl)-piperidin-1 -yl-methanone;
N-(1 ,4-Dioxo-1 ,4-dihydro-naphthalen-2-yl)-benzamide; N-(2,3-Dihydroxy-propyl)-2-(2-phenyl-adamantan-2-yl)-acetamide;
(6-Fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-phenyl-methanone;
(2-Chloro-phenyl)-(6-fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-methanone;
3-Cyclopentyl-1 -(6-fluoro-2-methyl-3,4-dihydro-2H-quinolin-1 -yl)-propan-1 -one;
(3-Chloro-thieno[2,3-b]thiophen-2-yl)-thiomorpholin-4-yl-methanone; 2-[2-(4-Chloro-phenyl)-adamantan-2-yl]-1 -[4-(4-methoxy-phenyl)-piperazin-1 -yl]-ethanone;
1-(4-Benzyl-piperazin-1-yl)-2-[2-(4-chloro-phenyl)-adamantan-2-yl]-ethanone;
2-[2-(4-Chloro-phenyl)-adamantan-2-yl]-1-(4-methyl-piperazin-1-yl)-ethanone;
1-[4-(6-Chloro-pyridin-2-yl)-piperazin-1-yl]-2-(2-phenyl-adamantan-2-yl)-ethanone;
4-Chloro-N-(1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl)-benzamide; 3-Chloro-benzo[b]thiophene-2-carboxylic acid (2-cyano-ethyl)-cyclohexyl-amide;
2-[2-(Bicyclo[2.2.1]hept-5-en-2-ylamino)-4-oxo-4,5-dihydro-thiazol-5-yl]-N-(2-chloro-phenyl)- acetamide;
[3-(4-sec-Butyl-phenoxy)-phenyl]-piperidin-1-yl-methanone;
3-(6-Chloro-pyridin-2-yloxy)-N-ethyl-benzamide; N-Benzyl-2,4-dichloro-N-pyridin-2-yl-benzamide; 2-[Benzoyl-(3-chloro-4-fluoro-phenyl)-amino]-propionic acid butyl ester;
2-[Benzoyl-(3-chloro-4-fluoro-phenyl)-amino]-propionic acid pentyl ester;
3-(4-Fluoro-phenyl)-1-(4-phenyl-piperidin-1-yl)-but-2-en-1-one;
N-(1 ,7,7-Trimethyl-bicyclo[2.2.1 ]hept-2-yl)-benzamide; 1-(3-Cyclopentyl-propionyl)-piperidine-3-carboxylic acid ethyl ester;
4-Phenyl-1-phenylacetyl-piperidine-4-carbonitrile;
1-Octanoyl-4-phenyl-piperidine-4-carbonitrile;
2,2-Dimethyl-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-propan-1-one;
(4-Chloro-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; N-[1 -(4-Methanesulfonyl-phenyl)-ethyl]-N-(tetrahydro-furan-2-ylmethyl)-benzamide;
2-(2-Amino-phenylsulfanyl)-1-(5-fluoro-2,3-dihydro-indol-1-yl)-ethanone;
N-(1-Methyl-2,3-dihydro-1H-indol-5-ylmethyl)-N-(tetrahydro-furan-2-ylmethyl)-benzamide;
1-Benzoyl-piperidine-2-carboxylic acid ethyl ester;
N-(2-Chloro-phenyl)-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetamide; (Decahydro-naphthalen-1 -yl)-(4-methyl-piperazin-1 -yl)-methanone;
(4-Methyl-piperazin-1-yl)-(2-p-tolylsulfanyl-phenyl)-methanone;
Adamantane-1 -carboxylic acid (3-benzyloxy-2-ethyl-6-methyl-pyridin-4-yl)-amide;
(6-Fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-(3,4,5-trimethoxy-phenyl)-methanone;
N-Bicyclo[2.2.1 ]hept-2-yl-3-cyclopentyl-propionamide; (2-Benzo[1 ,2,5]oxadiazol-5-yl-thiazol-4-yl)-piperidin-1 -yl-methanone;
Thiophene-2-carboxylic acid [4-(4-fluoro-phenyl)-4-hydroxy-butyl]-isopropyl-amide;
N-Cyclohexyl-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionamide;
2-[(Adamantane-1-carbonyl)-amino]-3-(1H-indol-3-yl)-propionic acid methyl ester;
Adamantane-1 -carboxylic acid [3-(1 H-benzoimidazol-2-ylsulfanyl)-5-nitro-phenyl]-amide; N-Benzyl-N-(1-cyclopropyl-ethyl)-4-fluoro-benzamide;
Thiophene-2-carboxylic acid 2-[2-(2-phenyl-adamantan-2-yl)-acetylamino]-ethyl ester;
N-(4-Acetyl-phenyl)-2-(2-phenyl-adamantan-2-yl)-acetamide;
2-[2-(4-Chloro-phenyl)-adamantan-2-yl]-N-(2-hydroxy-ethyl)-acetamide;
(4-Benzoyl-piperidin-1-yl)-thiophen-2-yl-methanone; N-(2-Benzoyl-4-methyl-phenyl)-3-phenyl-acrylamide;
N-(2-Benzoyl-4-methyl-phenyl)-2-fluoro-benzamide;
Adamantane-1 -carboxylic acid (4-ethoxy-benzothiazol-2-yl)-amide;
Adamantane-1 -carboxylic acid (5-benzoyl-4-phenyl-thiazol-2-yl)-amide;
3-(2-Hydroxy-phenyl)-1 ,3-di-piperidin-1 -yl-propan-1 -one; N-(1 -Methyl-2-phenyl-ethyl)-3-phenyl-propionamide; 4-Oxo-4-piperidin-1-yl-butyric acid 4-tert-butyl-cyclohexyl ester;
N-tert-Butyl-N-(4-methoxy-benzyl)-4-nitro-benzamide;
{4-[(Adamantane-1 -carbonyl)-amino]-phenoxy}-acetic acid;
2-(4-lsobutyl-phenyl)-N-(1-phenyl-ethyl)-propionamide; Adamantane-1 -carboxylic acid 4-[(adamantane-1 -carbonyl)-amino]-2,6-dimethyl-pyridin-3-yl ester;
2-Phenyl-1 -(3-phenyl-pyrrolidin-1 -yl)-ethanone;
Adamantane-1 -carboxylic acid 4-[(adamantane-1 -carbonyl)-amino]-2-ethyl-6-methyl-pyridin-
3-yl ester; N-(1 ,3-Dioxo-1 ,3-dihydro-isoindol-2-ylmethyl)-N-(4-hydroxy-phenyl)-benzamide;
Biphenyl-4-yl-piperidin-1-yl-methanone;
Azepan-1-yl-(3,5-dichloro-phenyl)-methanone;
Azepan-1 -yl-biphenyl-4-yl-methanone;
Azepan-1-yl-(4-chloro-phenyl)-methanone; 3-Heptylcarbamoyl-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid;
Adamantan-1 -yl-azepan-1 -yl-methanone;
N,N-Dibenzyl-3,4-dimethoxy-benzamide;
N-Benzyl-N-isopropyl-4-nitro-benzamide;
N-[2-(1H-lndol-3-yl)-1-methyl-ethyl]-2-(4-isobutyl-phenyl)-propionamide; N-tert-Butyl-2-(4-isobutyl-phenyl)-propionamide;
Adamantane-1 -carboxylic acid (2-acetyl-phenyl)-amide;
N-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-N-(4-fluoro-phenyl)-benzamide;
(Octahydro-quinolin-l-yl)-phenyl-methanone;
(7-Hydroxy-octahydro-quinolin-1-yl)-phenyl-methanone; N-(1 ,3-Dioxo-1 ,3-dihydro-isoindol-2-ylmethyl)-N-p-tolyl-benzamide;
N,N-Dibenzyl-4-methyl-benzamide;
(2-Chloro-phenyl)-(2-methyl-piperidin-1-yl)-methanone;
[4-Bromo-3-(piperidine-1-sulfonyl)-phenyl]-piperidin-1 -yl-methanone;
2-Chloro-N-(3,4-dimethyl-phenyl)-benzamide; 1 -Azepan-1 -yl-2-(3,3-dimethyl-3,4-dihydro-2H-isoquinolin-1 -ylidene)-ethanone;
N-Cyclohexyl-4-(2,4-dichloro-phenoxy)-butyramide;
N-Benzo[1,3]dioxol-5-yl-2-chloro-benzamide;
(4-Benzyl-piperidin-1-yl)-(2-chloro-phenyl)-methanone;
2-(Benzothiazol-2-ylsulfanyl)-N-cyclohexyl-acetamide; Cyclohexanecarboxylic acid (7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-quinazolin-2-yl)-amide; 2,4-Dichloro-N-ethyl-N-o-tolyl-benzamide;
(4-BenzyI-piperidin-1-yl)-(4-fluoro-phenyl)-methanone;
N-Cyclohexyl-4-(2,4-dichloro-phenoxy)-N-methyl-butyramide;
3-[2-(1 ,3-Dioxo-1 ,3-dihydro-isoindol-2-yl)-ethyl]-adamantane-1 -carboxylic acid; Morpholin-4-yl-(3-p-tolyl-adamantan-1 -yl)-methanone;
N-Benzyl-2,4-dichloro-N-methyl-benzamide;
Thiophene-2-carboxylic acid dibenzylamide;
Azepan-1-yl-(2-bromo-phenyl)-methanone;
(3,4-Dichloro-phenyl)-(4-methyl-piperidin-1-yl)-methanone; N,N-Dibenzyl-3,4-dichloro-benzamide;
4-(2,4-Dichloro-phenoxy)-1 -piperidin-1 -yl-butan-1 -one;
N,N-Dibenzyl-2-fluoro-benzamide;
(2-Chloro-phenyl)-piperidin-1-yl-methanone;
2-Chloro-N-(3-trifluoromethyl-phenyl)-benzamide; N-Benzyl-N-ethyl-2-phenyl-acetamide;
(3,4-Dihydro-2H-quinolin-1-yl)-p-tolyl-methanone;
Thiophene-2-carboxylic acid benzyl-ethyl-amide;
N-Adamantan-1 -yl-2-dibenzylamino-acetamide;
N-Cyclohexyl-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-phenyl-propionamide; Thiophene-2-carboxylic acid cycloheptylamide;
N-Cyclohexyl-3-diethylsulfamoyl-4-methyl-benzamide;
4-Benzoyl-N-methyl-N-phenyl-benzamide;
N-Benzyl-2-bromo-N-methyl-benzamide;
2-Chloro-N-methyl-N-phenyl-benzamide; 4-Chloro-N-ethyl-N-o-tolyl-benzamide;
N-Benzyl-4,N-dimethyl-benzamide;
2-(4-Chloro-3,5-dimethyl-phenoxy)-N-cyclohexyl-N-methyl-acetamide;
N-Benzyl-2-bromo-N-isopropyl-benzamide;
3-(2-Chloro-phenyl)-N-cyclohexyl-N-methyl-acrylamide; N-Phenyl-N-(2,2,5-trimethyl-hex-4-enyl)-acetamide;
N-m-Tolyl-N-(2,2,5-trimethyl-hex-4-enyl)-acetamide;
(3-Chloro-benzo[b]thiophen-2-yl)-(4-methyl-piperazin-1-yl)-methanone;
Adamantane-1 -carboxylic acid (5-methyl-pyridin-2-yl)-amide;
3-Bromo-N-[2-methyl-1 -(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1 ]octane-6-carbonyl)-butyl]- benzamide; 4-Chloro-N-[2-methyl-1 -(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-butyl]- benzamide;
4-Methyl-N-[2-methyl-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-butyl]- benzamide; Cyclohexanecarboxylic acid [2-methyl-1-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6- carbonyl)-butyl]-amide;
3-Cyclopentyl-N-[2-methyl-1-(1,3,3-trimethyl-6-aza-bicycIo[3.2.1]octane-6-carbonyl)-butyl]- propionamide;
2-Chloro-N-[2-(4-ethyl-benzoylamino)-ethyl]-N-(4-fluoro-phenyl)-benzamide; N-{1-Benzyl-2-[4-(3-cyclopentyl-propionyI)-piperazin-1-yl]-2-oxo-ethyl}-3-cyclopentyl- propionamide;
N-Bicyclo[2.2.1]hept-5-en-2-ylmethyl-3-cyclopentyl-N-[2-(1H-indol-3-yl)-ethyl]-propionamide;
N-Bicyclo[2.2.1]hept-5-en-2-ylmethyl-2,4-dichloro-N-[2-(1H-indol-3-yl)-ethyl]-benzamide;
Naphthalene-2-carboxyIic acid (2-oxo-azepan-3-yl)-thiophen-3-ylmethyl-amide; 3,4,5-Trimethoxy-N-(4-methyl-benzyl)-N-[6-(pyridin-2-ylamino)-hexyl]-benzamide;
3-Cyclopentyl-N-(4-methyl-benzyl)-N-[6-(pyridin-2-ylamino)-hexyl]-propionamide;
N-(3,4-Dimethoxy-benzyl)-3-methoxy-N-[6-(pyridin-2-ylamino)-hexyl]-benzamide;
N,N-Dimethyl-2-[3-(4-nitro-phenyl)-adamantan-1-yl]-acetamide;
Adamantane-1 -carboxylic acid [4-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl)-butyl]-p-tolyl-amide; 2-(1 ,3-Dioxo-1 ,3-dihydro-isoindol-2-yl)-3-methyl-N-(2-trifluoromethyl-phenyl)-butyramide;
2-(4-Chloro-2-methyl-phenoxy)-N-(2-trifluoromethyl-phenyl)-propionamide;
4-(2,4-Dichloro-phenoxy)-1 -[4-(4-fluoro-phenyl)-piperazin-1 -yl]-butan-1 -one;
(3,4-Dihydro-2H-quinolin-1-yl)-[3-(piperidine-1-sulfonyl)-phenyl]-methanone;
Acetic acid 4-(azepane-1-carbonyl)-phenyl ester; N-Adamantan-1 -ylme thyl-benzamide;
[3-(4-Nitro-phenyl)-adamantan-1-yl]-piperidin-1 -yl-methanone;
N-(1 , 1 -Dimethyl-hexyl)-2-morpholin-4-yl-acetamide;
Adamantyl-1 -carboxylic acid (2-methoxy-ethyl)-amide;
N-(4-Adamantan-1-yl-2-methyl-phenyl)-acetamide; 3-p-Tolyl-adamantane-1 -carboxylic acid (2,5-dichloro-phenyl)-amide;
(3-Chloro-adamantan-1 -yl)-pyrrolidin-1 -yl-methanone;
2-Amino-5-cyclohexylcarbamoyl-4-methyl-thiophene-3-carboxylic acid ethyl ester;
N-(2-Chloro-phenyl)-2-{3-[(2-chloro-phenylcarbamoyl)-methyl]-adamantan-1-yl}-acetamide;
3-p-Tolyl-adamantane-1 -carboxylic acid (2,4-difluoro-phenyl)-amide; Adamantyl-1 -carboxylic acid tert-butylamide; 2-Adamantan-1-yl-N-tert-butyl-acetamide;
N-Methyl-N-phenyl-4-(pyrrolidine-1-sulfonyl)-benzamide;
N-(1 -Adamantan-1 -yl-ethyl)-2-fluoro-benzamide;
Adamantane-1 -carboxylic acid [2-(3,4-dimethoxy-phenyl)-ethyl]-amide; Adamantane-1 -carboxylic acid dimethylamide;
N-Benzyl-4-chloro-N-(1-cyclopropyl-vinyl)-benzamide;
3,5-Dimethyl-adamantane-1 -carboxylic acid benzylamide;
2,4-Dichloro-N-cyclohexyl-N-(2-hydroxy-ethyl)-benzamide;
N-Adamantan-1-yl-2,4-dichloro-N-ethyl-benzamide; 2-[(3-p-Tolyl-adamantane-1 -carbonyl)-amino]-propionic acid methyl ester;
N-Adamantan-1-yl-3-morpholin-4-yl-propionamide;
3-p-Tolyl-adamantane-1 -carboxylic acid isopropylamide;
N-Adamantan-1 -yl-2-benzylamino-acetamide;
N-Benzyl-2,4-dichloro-N-(1-cyclopropyl-ethyl)-5-methyl-benzamide; 2-[(Adamantane-1 -carbonyl)-amino]-benzoic acid ethyl ester;
N-Benzyl-N-isopropyl-4-methyl-3-nitro-benzamide;
(3,4-Dihydro-2H-quinolin-1-yl)-(2-fluoro-phenyl)-methanone;
N-Ethyl-2-fluoro-N-phenyl-benzamide;
2-Phenethyl-N-(2-trifluoromethyl-phenyl)-benzamide; 1 -(3,4-Dihydro-2H-quinolin-1 -yl)-2-o-tolyloxy-ethanone;
2-(1 -Benzyl-1 H-imidazol-2-ylsulfanyl)-N-cyclohexyl-acetamide;
Cyclohexanecarboxylic acid (2-propoxy-phenyl)-amide;
2-{3-[4-(2-Chloro-phenyl)-piperazin-1-yl]-3-oxo-propyl}-isoindole-1 ,3-dione;
N-Cyclopentyl-2-(2,4-dichloro-phenoxy)-propionamide; Adamantane-1 -carboxylic acid (2-trifluoromethyl-phenyl)-amide;
(4-Chloro-3-nitro-phenyl)-(2,6-dimethyl-piperidin-1-yl)-methanone;
4-(2-Ethyl-phenyl)-4-aza-tricyclo[5.2.2.02,6]undec-8-ene-3,5-dione;
2-Phenyl-N-(2-trifluoromethyl-phenyl)-butyramide;
N-Adamantan-1-yl-4-chloro-2-nitro-benzamide; 3-p-Tolyl-adamantane-1 -carboxylic acid (2,3-dimethyl-phenyl)-amide;
N-Benzyl-3-methyl-4-p-tolyI-butyramide;
N-(2-Cyclohex-1-enyl-ethyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionamide;
(4-tert-Butyl-phenyl)-(3,4-dihydro-1H-isoquinolin-2-yl)-methanone;
2-[1-(4-Chloro-benzenesulfonyl)-1H-benzoimidazol-2-ylsulfanyl]-N-thiophen-2-ylmethyl- acetamide; 2-Phenoxy-1-[4-(2-trifluoromethyl-benzyl)-piperazin-1-yl]-ethanone;
Cyclohexanecarboxylic acid [5-(2-fluoro-benzylsulfanylmethyl)-[1 ,3,4]thiadiazol-2-yl]-amide;
4-Methyl-2-phenyl-thiazole-5-carboxylic acid naphthalen-1 -ylamide;
4-Fluoro-N-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]- benzenesulfonamide;
(3-Methoxy-phenyl)-(4-o-tolyl-piperazin-1-yl)-methanone;
N-Adamantan-1 -yl-3-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl)-propionamide;
N-Cyclooctyl-2-methoxy-3-methyl-benzamide;
2-[4-(2,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-isoindole-1 ,3-dione; (2,3-Diphenyl-quinoxalin-6-yl)-(2,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
Adamantan-1-yl-(1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-methanone;
N-{4-[1-(Naphthalene-2-sulfonyl)-piperidin-3-yl]-butyl}-N'-p-tolyl-oxalamide;
N-Benzyl-N-(2-oxo-2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide;
(4-Amino-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; 1 -[4-(4-Fluoro-phenyl)-piperazin-1 -yl]-2-(2-isopropyl-5-methyl-phenoxy)-ethanone;
Adamantane-1 -carboxylic acid benzyl-pyridin-2-yl-amide;
Adamantan-1 -yl-piperidin-1 -yl-methanone;
Adamantan-1 -yl-pyrrolidin-1 -yl-methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-o-tolyl-methanone; Adamantyl-1 -carboxylic acid benzylamide;
Pyridine-2-carboxylic acid adamantan-2-ylamide;
(3-Chloro-adamantan-1-yl)-piperidin-1 -yl-methanone;
Adamantan-1 -yl-(4-methyl-piperidin-1 -yl)-methanone;
2-[3-(Azepane-1 -carbonyl)-phenyl]-isoindole-1 ,3-dione; 2-[3-(Piperidine-1 -carbonyl)-phenyl]-isoindole-1 ,3-dione;
4-(Benzyl-methanesulfonyl-amino)-N-furan-2-ylmethyl-benzamide;
(4-Nitro-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
1 -Cyclohexyl-5-oxo-pyrrolidine-3-carboxylic acid (4-chloro-3-nitro-phenyl)-amide;
N-(2-Chloro-phenyl)-2-(2-oxo-2-phenyl-ethylsulfanyl)-acetamide; 3-(4-Hydroxy-phenyl)-N-isochroman-1-ylmethyl-3-phenyl-propionamide;
(4-Ethoxy-phenyl)-(2-methyl-piperidin-1-yl)-methanone;
1 -Cyclohexyl-5-oxo-pyrrolidine-3-carboxylic acid (3-chloro-phenyl)-amide;
N-[4-(Benzyl-isopropyl-sulfamoyl)-phenyl]-acetamide;
N-(3,4-Dimethyl-phenyl)-N-[4-(piperidine-1-carbonyl)-benzyl]-methanesulfonamide; 2-(5-Phenyl-1 H-imidazol-2-ylsulfanyl)-N-(1 , 1 ,3,3-tetramethyl-butyl)-acetamide; 2-(Benzothiazol-2-ylsulfanyl)-N-(1 , 1 ,3,3-tetramethyl-butyl)-acetamide;
2-(Benzooxazol-2-ylsulfanyl)-N-(1,1,3,3-tetramethyl-butyl)-acetamide;
2-(Naphthalen-2-ylcarbamoylmethylsulfanyl)-N-(1 , 1 ,3,3-tetramethyl-butyl)-acetamide;
Acetic acid 4-(3,5-dimethyl-piperidine-1-carbonyl)-phenyl ester; [1-(4-Chloro-benzenesulfonyl)-piperidin-3-yl]-(octahydro-quinolin-1-yl)-methanone;
(4-Fluoro-phenyl)-(3,4,4a,8a-tetrahydro-2H-quinolin-1-yl)-methanone;
N-Adamantan-1-yl-2-ethoxy-acetamide;
2-(2-Oxo-2-phenothiazin-10-yl-ethyl)-hexahydro-isoindole-1 ,3-dione;
Adamantane-1 -carboxylic acid (tetrahydro-furan-2-ylmethyl)-amide; 2-Bromo-N-cycloheptyl-benzamide;
Bicyclo[2.2.1]hept-2-yl-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-methanone;
N-Furan-2-ylmethyl-2-phenyl-2-phenylsulfanyl-acetamide;
Adamantane-1 -carboxylic acid benzyl-methyl-amide;
1-(3,4-Dihydro-2H-quinolin-1-yl)-3-(4-fluoro-phenyl)-propenone; Adamantan-1 -yl-(2,6-dimethyl-piperidin-1 -yl)-methanone;
4-Methyl-N-homoadamantyl-3-yl-benzamide;
(3,5-Dimethyl-piperidin-1-yI)-(3-methyl-4-nitro-phenyl)-methanone;
Quinoline-2-carboxylic acid cyclooctylamide;
Adamantane-1 -carboxylic acid [2-(2,4-dimethoxy-phenyl)-ethyl]-amide; (3,4-Dihydro-1 H-isoquinolin-2-yl)-o-tolyl-methanone;
(3,6-Dichloro-benzo[b]thiophen-2-yl)-(4-methyl-piperazin-1-yl)-methanone;
3-(1-Benzyl-1H-imidazol-2-ylsulfanyl)-N-cyclohexyI-propionamide;
Propionic acid 2-amino-4-methyl-5-p-tolylcarbamoyl-thiophen-3-yl ester;
2-Cyclohexyl-N-(2,6-dimethyl-phenyl)-N-furan-2-ylmethyl-acetamide; (3-Methoxy-phenyl)-(2,2,4-trimethyl-4-phenyl-3,4-dihydro-2H-quinolin-1-yl)-methanone;
1-[4-(2,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-pyrrolidine-2,5-dione;
1 -(3,4-Dihydro-2H-quinolin-1 -yl)-2-(1 -naphthalen-1 -yl-1 H-tetrazol-5-ylsulfanyl)-ethanone;
[4-(2,3-Dimethyl-phenyl)-piperazin-1-yl]-o-tolyl-methanone;
(4-Benzyl-piperidin-1-yl)-(4-methyl-3-nitro-phenyl)-methanone; N-(2-Cyano-phenyl)-2-(9-ethyl-9H-1,3,4,9-tetraaza-fluoren-2-ylsulfanyl)-acetamide;
N-(2-Cyano-phenyl)-2-(9-methyl-9H-1,3,4,9-tetraaza-fluoren-2-ylsulfanyl)-acetamide;
1-(Thiophene-2-carbonyl)-2,3-dihydro-1H-quinolin-4-one;
(3-Chloro-6-nitro-benzo[b]thiophen-2-yl)-piperidin-1 -yl-methanone;
(4-Bromo-phenyl)-(3,5-dimethyl-piperidin-1-yl)-methanone; 2-Morpholin-4-yl-N-(1 -phenyl-cyclopentylmethyl)-acetamide; 9-Oxo-9H-fluorene-1 -carboxylic acid (3-methyl-butyl)-amide;
[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-(4-methyl-piperidin-1-yI)-methanone;
N-Cycloheptyl-3-diethylsulfamoyl-benzamide;
(4-Methoxy-phenyl)-(3-phenyl-piperidin-1-yl)-methanone; 3-Amino-N-cyclohexyl-N-methyl-benzamide;
N-Ethyl-3,4-dimethyl-N-phenyl-benzamide;
N-Benzyl-3,4,N-trimethyl-benzamide;
(4-Fluoro-phenyl)-(3-phenyl-piperidin-1-yl)-methanone;
[4-(2,3-Dimethyl-phenyl)-piperazin-1-yl]-(3-methoxy-phenyl)-methanone; Furan-2-carboxylic acid [4-(4-methyl-piperidine-1-sulfonyl)-phenyl]-amide;
N-(2-Cyclohex-1-enyl-ethyl)-2-o-tolyloxy-acetamide;
5-(2-Chloro-phenoxymethyl)-furan-2-carboxylic acid (1-bicyclo[2.2.1]hept-2-yl-ethyl)-amide;
3-(2-Chloro-phenyl)-1-[4-(2,3-dimethyl-phenyl)-piperazin-1-yl]-propenone;
N-[3-(Azepane-1-carbonyl)-phenyl]-benzamide; [3-(Piperidine-1 -carbonyl)-pyrazol-1 -yl]-o-tolyl-methanone;
N-(1-Phenyl-cyclopentylmethyl)-2-piperidin-1-yl-propionamide;
2-Morpholin-4-yl-N-(1-phenyl-cyclopentylmethyl)-propionamide;
N-[4-(Azepane-1-sulfonyl)-phenyI]-2,2,2-trifluoro-acetamide;
2,3-Dihydro-benzo[1 ,4]dioxine-6-carboxylic acid (1 -adamantan-1 -yl-ethyl)-amide; N-Adamantan-1 -yl-2-(3-methoxy-phenoxy)-acetamide;
3-Chloro-benzo[b]thiophene-2-carboxylic acid (2-cyano-ethyl)-phenyl-amide;
[4-(4-Nitro-benzyl)-piperidin-1-yl]-phenyl-methanone;
[4-(2-Nitro-benzyl)-piperidin-1-yl]-phenyl-methanone;
3-[5-(4-Fluoro-phenyl)-furan-2-yl]-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-propenone; 2-(3-Fluoro-benzoylamino)-4-methyl-5-(piperidine-1 -carbonyl)-thiophene-3-carboxylic acid methyl ester;
N-(2-Ethyl-phenyl)-2-(3-methyl-piperidin-1-yl)-acetamide;
2-(2-Methoxy-benzoylamino)-4-methyl-5-(piperidine-1-carbonyl)-thiophene-3-carboxylic acid methyl ester; 1-Phenyl-cyclopentanecarboxylic acid (4-phenyl-tetrahydro-pyran-4-ylmethyl)-amide;
4-(2,4-Dichloro-phenoxy)-1-(4-phenyl-piperazin-1-yl)-butan-1-one;
Naphthalene-1 -carboxylic acid cycloheptylamide;
N-lndan-5-yl-2-methyl-3-nitro-benzamide;
N-Cyclohexyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzamide; 2-Methoxy-N-(1 -phenyl-cyclopentylmethyl)-benzamide; [5-(2,5-Dichloro-phenoxymethyl)-furan-2-yl]-(2,6-dimethyl-morpholin-4-yl)-methanone;
[5-(2-Bromo-phenoxymethyl)-furan-2-yl]-(2-methyl-piperidin-1-yl)-methanone;
5-(2-Methoxy-phenoxymethyl)-furan-2-carboxylic acid cycloheptylamide;
(3,4-Dihydro-1H-isoquinolin-2-yl)-[1-(2-nitro-benzenesulfonyl)-piperidin-3-yl]-methanone; N-Cyclooctyl-2-(4-methoxy-phenoxy)-acetamide;
N-(2,3-Dimethyl-phenyl)-4-[methyl-(toluene-4-sulfonyl)-amino]-bu.yramide;
N-Phenyl-N-[4-(piperidine-1-carbonyl)-benzyl]-benzenesulfonamide;
N-[4-(3,4-Dihydro-1H-isoquinoline-2-carbonyl)-benzyl]-N-(3,4-dimethyl-phenyl)- methanesulfonamide; 2,3-Dihydro-benzo[1 ,4]dioxine-2-carboxylic acid bicyclo[2.2.1]hept-2-ylamide;
4,5,6,7-Tetrahydro-benzo[b]thiophene-3-carboxylic acid cycloheptylamide;
N-(2-Azepan-1-yl-2-oxo-ethyl)-N-benzyl-4-fluoro-benzenesulfonamide;
1 -(2,6-Dimethyl-morpholin-4-yl)-3,3-diphenyl-propan-1 -one;
N-Bicyclo[2.2.1 ]hept-2-yl-4-morpholin-4-ylmethyl-benzamide; [3-(2-Chloro-6-nitro-phenoxy)-phenyl]-piperidin-1 -yl-methanone;
N-Adamantan-1-yl-2-(4-methyl-quinolin-2-ylsulfanyl)-acetamide;
Cyclohexanecarboxylic acid (2-phenylsulfanyl-phenyl)-amide;
(4-Hydroxy-4-phenyl-octahydro-quinolin-1-yl)-phenyl-methanone;
3-Cyclohexyl-N-(3-phenyl-propyl)-propionamide; 2-[1-(2,5-Dimethyl-phenyl)-1H-tetrazol-5-ylsulfanyl]-N-isopropyl-N-phenyl-acetamide;
N-{2-[4-(3,4-Dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-ethyl}-acetamide;
N-Benzyl-N-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethyl]-benzenesulfonamide;
[4-(2-Chloro-6-nitro-phenoxy)-phenyl]-piperidin-1-yl-methanone;
N-Cycloheptyl-3-phenyl-propionamide; (3-Chloro-6-methyl-benzo[b]thiophen-2-yl)-piperidin-1-yl-methanone;
N-Cycloheptyl-2,4-dimethoxy-benzamide;
N-(3-Chloro-phenyl)-2-(8,11 ,11-trimethyl-3,4,6-triaza-tricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-
5-ylsulfanyl)-acetamide;
N-(2-Nitro-phenyl)-2-(8,11 ,11-trimethyl-3,4,6-triaza-tricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-5- ylsulfanyl)-acetamide;
N-Phenyl-2-(8,11 ,11-trimethyl-3,4,6-triaza-tricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-5- ylsulfanyl)-acetamide;
N-Ethyl-3-methyl-N-o-tolyl-benzamide;
N-[5-(2,4-Dichloro-benzylsulfanyl)-[1,3,4]thiadiazol-2-yl]-2,2-dimethyl-propionamide; 4-Bromo-1 -ethyl-1 H-pyrazole-3-carboxylic acid (2-methylsulfanyl-phenyl)-amide; i 5-Benzoyl-furan-2-carboxylic acid diisopropylamide;
N-{2-[2-(4-Bromo-phenyl)-2-oxo-ethylsulfanyl]-benzothiazol-6-yl}-acetamide;
2-(6-Amino-benzothiazol-2-ylsulfanyl)-N-cyclohexyl-acetamide;
N-(2-Cyclohexylcarbamoylmethylsulfanyl-benzothiazol-6-yl)-2-methoxy-benzamide; Benzofuran-2-yl-(4-phenyl-piperidin-1 -yl)-methanone;
1-(2-Nitro-phenyl)-piperidine-3-carboxylic acid diethylamide;
1-(4-Nitro-phenyl)-piperidine-3-carboxylic acid diethylamide;
5-Bromo-furan-2-carboxylic acid adamantan-2-ylamide;
3,3-Dimethyl-pentanedioic acid bis-[(2,4-difluoro-phenyl)-amide]; 2-(3-Bromo-benzylsulfanyl)-1 -(4-phenyl-piperazin-1 -yl)-ethanone;
N-(2-Azepan-1-yl-2-oxo-ethyl)-N-benzyl-4-bromo-benzenesulfonamide;
1-(2,3-Dihydro-indol-1-yl)-2-p-tolylsulfanyl-ethanone;
[4-(4-Bromo-benzenesulfonyl)-piperazin-1-yl]-furan-2-yl-methanone;
[5-(2-Bromo-phenoxymethyl)-furan-2-yl]-(2,6-dimethyl-morpholin-4-yl)-methanone; 5-(2-Chloro-phenoxymethyl)-furan-2-carboxylic acid diethylamide;
5-(2-Bromo-phenoxymethyl)-furan-2-carboxylic acid diethylamide;
5-(2-Chloro-phenoxymethyl)-furan-2-carboxylic acid methyl-phenyl-amide;
[5-(2-Chloro-phenoxymethyl)-furan-2-yl]-(4-methyl-piperidin-1-yl)-methanone;
[3-(2,5-Dichloro-phenoxymethyl)-phenyl]-pyrrolidin-1-yl-methanone; [5-(4-Ethoxy-phenoxymethyl)-furan-2-yl]-(4-methyl-piperidin-1-yl)-methanone;
3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-N-(2-methyl-cyclohexyl)-propionamide;
3-(3,4-Dihydro-2H-quinoline-1-carbonyl)-N-phenyl-benzenesulfonamide;
[3-(2,3-Dihydro-indole-1-sulfonyl)-phenyl]-(3,4-dihydro-2H-quinolin-1-yl)-methanone;
[3-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-(4-methyl-piperidin-1-yl)-methanone; N-Cyclohexyl-3-(2-hydroxy-4-methyl-phenyl)-3-phenyl-propionamide;
2-Diethylamino-N-(1-phenyl-cyclopentylmethyl)-propionamide;
(6-Fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-(3-trifluoromethyl-phenyl)-methanone;
(2,6-Dimethyl-morpholin-4-yl)-[4-(naphthalen-1-yloxymethyl)-phenyl]-methanone;
N-Benzyl-4-bromo-N-ethyl-benzamide; (3-Methyl-piperidin-1 -yl)-[4-(naphthalen-1 -yloxymethyl)-phenyl]-methanone;
Azepan-1 -yl-[5-(2-chloro-phenoxymethyl)-furan-2-yl]-methanone;
(4-Methyl-piperidin-1-yl)-[4-(naphthalen-1-yloxymethyl)-phenyl]-methanone;
Azepan-1-yl-[5-(2,4-dichloro-phenoxymethyl)-furan-2-yl]-methanone;
N-Cycloheptyl-4-(4-methoxy-2-methyl-phenyl)-butyramide; 2-(4-Benzothiazol-2-yl-piperazin-1-yl)-N-cyclohexyl-acetamide; N-Cycloheptyl-2-(2,6-dimethyl-phenoxy)-acetamide;
(3,4-Dihydro-2H-quinolin-1-yl)-(3-iodo-phenyl)-methanone;
N-Cycloheptyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzamide;
Azepan-1-yl-[4-(2-chloro-phenoxymethyl)-phenyl]-methanone; (2,6-Dimethyl-morpholin-4-yl)-[4-(naphthalen-2-yloxymethyl)-phenyl]-methanone;
Azepan-1 -yl-[3-(4-ethoxy-phenoxymethyl)-phenyl]-methanone;
Benzo[b]thiophene-3-carboxylic acid (1 ,2,3,4-tetrahydro-naphthalen-1-yl)-amide;
2-(4-Chloro-2-methyl-phenoxy)-N-cycloheptyl-acetamide;
2,4-Dichloro-N-cyclohexyl-N-methyl-benzamide; N-Cyclooctyl-2-p-tolyloxy-acetamide;
(3,5-Dimethyl-piperidin-1-yl)-(4-methyl-3-nitro-phenyl)-methanone;
Biphenyl-4-yl-(2,6-dimethyl-piperidin-1-yl)-methanone;
N-Cyclohexyl-4-fluoro-N-methyl-benzamide;
N-[4-(Azepane-1-carbonyl)-phenyl]-N-methyl-benzenesulfonamide; N-Cycloheptyl-2-fluoro-benzamide;
N-Cycloheptyl-4-methyl-benzamide;
(3-Methyl-piperidin-1-yl)-p-tolyl-methanone;
[2-(3,4-Dimethoxy-phenylcarbamoyl)-piperidin-1-yl]-acetic acid benzyl ester;
N-[4-(2-Methyl-piperidine-1-sulfonyl)-phenyl]-acetamide; 2-(2,4-Dichloro-phenoxy)-N-(2-methyl-butyl)-propionamide;
[4-(2-Chloro-6-nitro-phenyl)-piperazin-1-yl]-(4-methoxy-phenyl)-methanone;
N-Cyclohexyl-4-(4-methoxy-3-methyl-phenyl)-butyramide;
(3-ChIoro-6-methoxy-benzo[b]thiophen-2-yl)-(3,4-dihydro-1H-isoquinolin-2-yl)-methanone;
2-(4-Methyl-benzylsulfanyl)-1 -piperidin-1 -yl-ethanone; N-Cyclohexyl-N-[(4-phenyl-thiazol-2-ylcarbamoyl)-methyl]-benzamide;
N-(2-Azepan-1-yl-2-oxo-ethyl)-N-(4-isopropyl-phenyl)-methanesulfonamide;
N-Adamantan-1-yl-3-p-toIylsulfanyl-propionamide;
6-(2,4-Dichloro-phenylcarbamoyl)-3,4-dimethyl-cyclohex-3-enecarboxylic acid;
(4-Butyl-cyclohexyl)-morpholin-4-yl-methanone; (3,4-Dichloro-phenyl)-(3,4-dihydro-2H-quinolin-1-yl)-methanone;
N-(2-Cyclohex-1-enyl-ethyl)-3-methoxy-benzamide;
N-Adamantan-2-yl-3-(1 ,5-dimethyl-1 H-pyrazol-4-yI)-acrylamide;
N-Adamantan-1 -yl-N-methyl-4-(4-nitro-pyrazol-1-ylmethyl)-benzamide;
5-(4-Chloro-3,5-dimethyl-pyrazol-1 -ylmethyl)-furan-2-carboxylic acid adamantan-2-ylamide; 2-(4-Chloro-phenoxy)-N-(2-fluoro-5-methyl-phenyl)-2-methyl-propionamide; N-Adamantan-1-yl-2-(4-chloro-3,5-dimethyl-phenoxy)-acetamide;
2-[(3-Carboxy-bicyclo[2.2.1]heptane-2-carbonyl)-amino]-5,6-dihydro-4H- cyclopenta[b]thiophene-3-carboxylic acid propyl ester;
2-Adamantan-1-yl-N-[1-(2,5-dimethyl-phenyl)-ethyl]-acetamide; 3-Methyl-thiophene-2-carboxylic acid cyclooctylamide;
N-p-Tolyl-2-(8,11,11-trimethyl-3,4)6-triaza-tricyclo[6.2.1.027]undeca-2,4,6-trien-5-ylsulfanyl)- propionamide;
Azepan-1-yl-[5-(4-chloro-5-methyl-3-nitro-pyrazol-1-ylmethyl)-furan-2-yl]-methanone;
N-Adamantan-2-yl-3-(4-bromo-3-nitro-pyrazol-1-ylmethyl)-benzamide; N-Bicyclo[2.2.1 ]hept-2-yl-2-chloro-benzamide;
[5-(3-Chloro-phenoxymethyl)-furan-2-yl]-piperidin-1-yl-methanone;
1-(4-Ethyl-benzoyl)-6-methoxy-2-methyl-2,3-dihydro-1H-quinolin-4-one;
6-Fluoro-2-methyl-1 -{3-[4-(propane-1 -sulfonyl)-phenoxymethyl]-benzoyl}-2,3-dihydro- 1 H- quinolin-4-one; N-Cycloheptyl-2-(naphthalen-1 -yloxy)-acetamide;
N-Cyclohexyl-4-o-tolyloxy-butyramide;
(2-Benzylsulfanyl-phenyl)-morpholin-4-yl-methanone;
(2-Chloro-5,6-difluoro-3-methyl-phenyl)-(4-methyl-piperidin-1-yl)-methanone;
(3-Bromo-phenyl)-[4-(4-chloro-2-nitro-phenyl)-piperazin-1-yl]-methanone; 2-Bromo-N-(1 , 1 ,3,3-tetramethyl-butyl)-benzamide;
N-Adamantan-1-yl-2-(2-benzoyl-5-methoxy-phenoxy)-acetamide;
N-Cyclohexyl-3-methyl-4-p-tolyl-butyramide;
[5-(4-Methyl-2-nitro-phenoxymethyl)-furan-2-yl]-thiomorpholin-4-yl-methanone;
[5-(2,5-Dichloro-phenoxymethyl)-furan-2-yl]-thiomorpholin-4-yl-methanone; 5-(4-Chloro-2-nitro-phenoxymethyl)-furan-2-carboxylic acid adamantan-1 -ylamide;
4,5,6,7-Tetrahydro-benzo[b]thiophene-3-carboxylic acid cyclohexylamide;
4-Chloro-1 ,5-dimethyl-1 H-pyrazole-3-carboxylic acid adamantan-1 -yl-methyl-amide;
4-(4-Methoxy-3-methyl-phenyl)-N-(2-methyl-cyclohexyl)-butyramide;
3-Benzo[1 ,3]dioxol-5-yl-1 -(3,4-dihydro-1 H-isoquinolin-2-yl)-propenone; N-Bicyclo[2.2.1 ]hept-2-yl-3-phenylsulfanyl-propionamide;
Azepan-1-yl-[5-(2-nitro-phenoxymethyl)-furan-2-yl]-methanone;
N-Benzyl-2-(4-chloro-phenylsulfanyl)-N-methyl-acetamide;
1 -(4-Benzyl-piperidin-1 -yl)-2-benzylsulfanyl-ethanone;
2-(4-tert-Butyl-phenoxy)-1 -(4-ethyl-piperazin-1 -yl)-ethanone; [4-(4-Ethoxy-phenoxymethyl)-phenyl]-(4-methyl-piperidin-1-yl)-methanone; 5-(4-Bromo-3,5-dimethyl-pyrazol-1 -ylmethyl)-furan-2-carboxylic acid adamantan-2-ylamide;
1 -Azepan-1 -yl-3-(4-chloro-phenylsulfanyl)-propan-1 -one;
N-Bicyclo[2.2.1]hept-2-yl-2-(2-chloro-benzylsulfanyl)-acetamide;
2-(2-Methyl-benzylsulfanyl)-1-(4-phenyl-piperazin-1-yl)-ethanone; N-[2-(1 -Benzo[1 ,3]dioxol-5-yl-3-f uran-2-yl-3-oxo-propylsulfanyl)-phenyl]-acetamide;
(3,5-Dimethyl-piperidin-1-yl)-(3-iodo-phenyl)-methanone;
[5-(2-Bromo-phenoxymethyl)-furan-2-yl]-(6-fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)- methanone;
N-Benzyl-N-cyclohex-1-enyl-isonicotinamide; 1 -[4-(4-Fluoro-phenyl)-piperazin-1 -yl]-2-(2-methyl-benzylsulfanyl)-ethanone;
2-(2-Bromo-4-methyl-phenoxy)-N-(2-cyclohex-1-enyl-ethyl)-acetamide;
2-[5-(2-Hydroxy-phenyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-1-piperidin-1-yl-ethanone;
5-(4-Nitro-pyrazol-1-ylmethyl)-furan-2-carboxylic acid adamantan-2-ylamide;
3-Benzo[1 ,3]dioxol-5-yl-3-(2-methoxy-phenyl)-1 -pyrrolidin-1 -yl-propan-1 -one; N-Adamantan-2-yl-3,4-dichloro-benzamide;
Benzo[b]thiophen-3-yl-(6-fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-methanone;
2-Adamantan-1-yl-1-(3,4-dihydro-1H-isoquinolin-2-yl)-ethanone;
4,5,6,7-Tetrahydro-benzo[b]thiophene-3-carboxylic acid (2-cyclohex-1 -enyl-ethyl)-amide;
Benzo[b]thiophene-3-carboxylic acid (3,3,5-trimethyl-cyclohexyl)-amide; 2-(2,6-Dimethyl-phenoxy)-N-(2-isopropyl-phenyl)-acetamide;
4-Bromo-N-[3-(piperidine-1 -carbonyl)-phenyl]-benzamide;
N-Benzo[1,3]dioxol-5-ylmethyl-2-(2-cyano-phenylsulfanyl)-benzamide;
N-Adamantan-1-yl-2-(naphthalen-2-yloxy)-acetamide;
[4-(4-Chloro-phenylsulfanylmethyl)-phenyl]-morpholin-4-yl-methanone; Thiophene-2-carboxylic acid (3,3,5-trimethyl-cyclohexyl)-amide;
Benzo[1,3]dioxol-5-yl-(3,4-dihydro-2H-quinolin-1-yl)-methanone;
3-Chloro-benzo[b]thiophene-2-carboxylic acid cyclooctylamide;
2-[2-Morpholin-4-yl-1-(4-nitro-benzyl)-2-oxo-ethyl]-isoindole-1 ,3-dione;
2-Hydroxy-4,4-dimethyl-6-oxo-cyclohex-1 -enecarboxylic acid phenylamide; (2,4-Dichloro-phenyl)-(2,6-dimethyl-piperidin-1-yl)-methanone;
Adamantane-1 -carboxylic acid furan-2-ylmethyl-p-tolyl-amide;
Azocan-1-yl-(4-tert-butyl-phenyl)-methanone;
3-Chloro-benzo[b]thiophene-2-carboxylic acid benzyl-methyl-amide;
Adamantane-1 -carboxylic acid (2-fluoro-phenyl)-amide; 2-(Piperidine-1 -carbonyl)-5-piperidin-1 -yl-oxazole-4-carbonitrile; N-(4,6-Dimethyl-5-nitro-pyridin-3-yl)-benzamide;
Adamantan-1-yl-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone;
(2-Methyl-piperidin-1-yl)-o-tolyl-methanone;
N-Benzyl-4-chloro-N-isopropyl-3-nitro-benzamide; N-(3-Hexylsulfanyl-[1 ,2,4]thiadiazol-5-yl)-3-methyl-butyramide;
4,N-Dimethyl-N-[4-(piperidine-1-carbonyl)-phenyl]-benzenesulfonamide;
Azepan-1-yl-(5-tert-butyI-2H-pyrazol-3-yl)-methanone;
2-Amino-4-methyl-5-(piperidine-1-carbonyl)-thiophene-3-carboxylic acid ethyl ester;
5-Methyl-furan-2-carboxylic acid (1 -adamantan-1 -yl-ethyl)-amide; (3-Chloro-6-methyl-benzo[b]thiophen-2-yl)-(3,4-dihydro- .H-isoquinolin-2-yl)-methanone;
N-Adamantan-1-yl-2-trifluoromethyl-benzamide;
(3-Bromo-phenyl)-(2,2,4-trimethyl-4-phenyl-3,4-dihydro-2H-quinolin-1-yl)-methanone;
Benzo[1 ,3]dioxole-5-carboxylic acid dipropylamide;
N-(3,3-Diphenyl-propyl)-4-methoxy-benzamide; [4-(2-Chloro-6-nitro-phenyl)-piperazin-1 -yl]-p-tolyl-methanone;
Furan-2-yl-[4-(toluene-4-sulfonyl)-piperazin-1-yl]-methanone;
3-(2-Chloro-6-fluoro-phenyl)-1-(3,4-dihydro-2H-quinolin-1-yl)-propenone;
2-Chloro-N-cycloheptyl-benzamide;
1-[4-(4-Nitro-phenyl)-piperazin-1-yl]-3-phenyl-propan-1-one; (3,4-Dihydro-1H-isoquinolin-2-yl)-(3,4-dimethyl-phenyl)-methanone;
(1 -Adamantan-1 -yl-4-bromo-1 H-pyrazol-3-yl)-moφholin-4-yl-methanone;
2-Phenyl-cyclopropanecarboxylic acid cyclooctylamide;
3-[4-(2-Ethoxy-phenyl)-piperazine-1-carbonyl]-isochromen-1-one;
[3-(4-Bromo-pyrazol-1-ylmethyl)-phenyl]-(4-methyl-piperidin-1-yl)-methanone; 2-Azepan-1 -yl-N-biphenyl-2-yl-acetamide;
N-[5-(3,4-Dimethoxy-benzyl)-[1,3,4]thiadiazol-2-yl]-3-methyl-butyramide;
Adamantan-1 -yl-(4-phenyl-piperidin-1 -yl)-methanone;
N-(2-Azepan-1-yl-2-oxo-ethyl)-N-(4-ethoxy-phenyl)-4-methylsulfanyl-benzenesulfonamide;
1 -Adamantan-1 -yl-4-bromo-1 H-pyrazole-3-carboxylic acid diethylamide; (6-Fluoro-2-methyI-3,4-dihydro-2H-quinolin-1-yl)-(2-fluoro-phenyl)-methanone;
3-[4-(2,3-Dimethyl-phenyl)-piperazine-1-carbonyl]-isochromen-1-one;
N-Cyclooctyl-2-(2-methoxy-phenoxy)-acetamide;
N-Cyclohexyl-N-methyl-2-nitro-benzamide;
Adamantane-1 -carboxylic acid (1 ,1-dioxo-tetrahydro-thiophen-3-yl)-amide; N-Adamantan-2-yl-2-(4-chloro-phenyl)-acetamide; (2,4-Dichloro-phenyl)-(3-methyl-piperidin-1-yl)-methanone;
2-(4-tert-Butyl-phenoxy)-N-cyclooctyl-acetamide;
(10,11-Dihydro-dibenzo[b,f]azepin-5-yl)-(2-methoxy-phenyl)-methanone;
(3-Chloro-phenyl)-(2-methyl-piperidin-1-yl)-methanone; (3-Chloro-6-nitro-benzo[b]thiophen-2-yl)-(3-methyl-piperidin-1-yl)-methanone;
(2,5-Dichloro-phenyI)-(4-methyl-piperidin-1-yl)-methanone;
N-[5-(3,4-Dichloro-benzyl)-[1,3,4]thiadiazol-2-yl]-2,2-dimethyI-propionamide;
4-(4-Chloro-2-methyl-phenoxy)-1-(3,4-dihydro-2H-quinolin-1-yl)-butan-1-one;
(3,4-Dichloro-phenyl)-[4-(2,3-dimethyl-phenyl)-piperazin-1-yl]-methanone; Cyclooctanecarboxylic acid [1-(naphthaIene-2-sulfonyl)-pyrrolidin-2-yl]-amide;
1-Butyl-pyrrolidine-2-carboxylic acid benzo[1 ,3]dioxol-4-ylamide;
5-Methyl-furan-2-carboxylic acid dibenzylamide;
(3,4-Dihydro-2H-quinolin-1-yl)-[3-(4-phenyl-piperazine-1-sulfonyl)-phenyl]-methanone;
Bicyclo[2.2.1]hept-2-yl-[4-(2,3-dimethyl-phenyl)-piperazin-1-yl]-methanone; N-Adamantan-1 -yl-2-benzoyl-benzamide;
[5-(2-Chloro-phenoxymethyl)-furan-2-yl]-(3-methyl-piperidin-1-yl)-methanone;
(3,5-Dimethyl-piperidin-1-yl)-(2-iodo-phenyl)-methanone;
1-Benzenesulfonyl-pyrrolidine-2-carboxylic acid cyclooctylamide;
(3,4-Dimethoxy-phenyl)-(6-fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yI)-methanone; 3-(2,6-Dichloro-phenyl)-1 -(2-ethyI-piperidin-1 -yl)-propenone;
N-(3,4-Difluoro-phenyl)-2,6-difluoro-benzamide;
2,6-Difluoro-N-naphthalen-1-yI-benzamide;
(4-Chloro-phenyl)-(3,5-dimethyl-piperidin-1-yl)-methanone;
N-[4-(2,6-Dimethyl-piperidine-1-carbonyl)-phenyl]-2-(naphthalen-2-yloxy)-acetamide; (2-Chloro-phenyl)-(3-methyl-piperidin-1 -yl)-methanone;
N-{2-[4-(Piperidine-1-suIfonyl)-phenyl]-ethyl}-acetamide;
N-Biphenyl-2-yl-2-(pyridin-2-ylsulfanyl)-acetamide;
Azepan-1-yl-[5-(4-chloro-3,5-dimethyl-pyrazol-1-ylmethyl)-furan-2-yl]-methanone;
Acetic acid 4-(4-methyl-piperidine-1-carbonyl)-phenyl ester; Acetic acid 4-(4-benzyl-piperidine-1-carbonyl)-phenyl ester;
Benzo[1 ,3]dioxole-5-carboxylic acid cycloheptylamide;
2-(2,4-Dimethyl-phenoxy)-1-(6-fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-ethanone;
Acetic acid 4-(3,4-dihydro-2H-quinoline-1-carbonyl)-phenyl ester;
Azepan-1-yl-(3,5-dibromo-phenyl)-methanone; (3,5-Dibromo-phenyl)-[4-(2-methoxy-phenyI)-piperazin-1-yl]-methanone; N-Cyclooctyl-4-isopropyl-benzamide;
N-Cyclooctyl-2-(4-methoxy-phenyl)-acetamide;
(4-tert-Butyl-piperidin-1-yl)-phenyl-methanone;
N-(4-tert-Butyl-3-nitro-phenyl)-acetamide; (2,6-Dimethyl-piperidin-1-ylH5-(2,3,5,6-tetrafluoro-phenoxymethyl)-furan-2-yl]-methanone;
N-Cyclohexyl-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-N-methyl-propionamide;
2-(4-Chloro-3-methyl-phenoxy)-N-cyclohexyl-N-methyl-acetamide;
N-Cyclopentyl-3-(3,4-dihydro-2H-quinoline-1-carbonyl)-benzenesulfonamide;
(3,4-Dihydro-1H-isoquinolin-2-yl)-(3-dimethylamino-phenyl)-methanone; 3-Cyclohexylcarbamoyl-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid isopropyl ester;
1-(3,4-Dihydro-1H-isoquinolin-2-yl)-2-(2-methoxy-phenyl)-ethanone;
N-Benzyl-N-cyclohex-1-enyl-benzamide;
[1-(Thiophene-2-sulfonyl)-piperidin-4-yl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone; N-Adamantan-1 -yl-2-(1-phenyl-1H-tetrazol-5-ylsuIfanyl)-acetamide;
(3,4-Dihydro-2H-quinolin-1-yl)-[4-(morpholine-4-sulfonyl)-phenyl]-methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-[4-(pyrrolidine-1-sulfonyl)-phenyl]-methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-[1-(thiophene-2-sulfonyl)-piperidin-4-yl]-methanone;
(1-Benzenesulfonyl-piperidin-3-yl)-(3,4-dihydro-1H-isoquinolin-2-yl)-methanone; 6,7-Dimethyl-4-oxa-tricyclo[4.3.0.03,7]nonane-3-carboxylic acid cyclohexylamide;
6,7-Dimethyl-4-oxa-tricyclo[4.3.0.03,7]nonane-3-carboxylic acid (2-chloro-phenyl)-amide;
(6,7-Dimethyl-4-oxa-tricyclo[4.3.0.03'7]non-3-yl)-piperidin-1-yl-methanone;
2-(5,6-Dimethyl-4-oxo-3,4-dihydro-thieno[2,3-d]pyrimidin-2-ylsulfanyl)-N-furan-2-ylmethyl- acetamide; N-Allyl-2-(5,6-dimethyl-4-oxo-3,4-dihydro-thieno[2,3-d]pyrimidin-2-ylsulfanyl)-acetamide;
N-Adamantan-1-yl-2-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ylsulfanyl)- acetamide;
1-(3,4-Dihydro-2H-quinoline-1-carbonyl)-4,7,7-trimethyl-2-oxa-bicycIo[2.2.1]heptan-3-one;
1-(3,4-Dihydro-1H-isoquinoline-2-carbonyl)-4,7,7-trimethyl-2-oxa-bicyclo[2.2.1]heptan-3-one; Azepan-1-yl-(6,7-dimethyl-4-oxa-tricyclo[4.3.0.03,7]non-3-yl)-methanone;
2,5-Dimethyl-furan-3-carboxylic acid (1 -adamantan-1 -yl-ethyl)-amide;
1 -Cyclohexyl-5-oxo-pyrrolidine-3-carboxylic acid (3-cyano-4,5,6,7-tetrahydro- benzo[b]thiophen-2-yl)-amide;
2-(2-Cyano-phenylsulfanyl)-N-cyclopentyl-benzamide; [5-(2-Methoxy-4-propyl-phenoxymethyl)-furan-2-yl]-(3-methyl-piperidin-1-yl)-methanone; (4-tert-Butyl-phenyl)-(3,5-dimethyl-piperidin-1-yl)-methanone;
[4-(2-Methoxy-naphthalen-1-ylmethyl)-piperazin-1-yl]-(4-methoxy-phenyl)-methanone;
(3,4-Dichloro-phenyl)-(3,5-dimethyl-piperidin-1-yI)-methanone;
(4-Ethoxy-phenyl)-(4-methyl-piperidin-1-yl)-methanone; 2-Phenethyl-N-(tetrahydro-furan-2-ylmethyl)-benzamide;
N-Cycloheptyl-2-phenoxy-benzamide;
Adamantane-1 -carboxylic acid (2-ethoxy-phenyl)-amide;
N-Adamantan-2-yl-2-o-tolyloxy-acetamide;
(2-Chloro-phenyl)-(3,5-dimethyl-piperidin-1-yl)-methanone; 1-Morphoiin-4-yl-2-[3-(4-nitro-phenyl)-adamantan-1-yl]-ethanone;
2-Dimethylamino-N-(2-nitro-phenyl)-benzamide;
N-Benzyl-2-(4,4,6-trimethyl-1-p-tolyl-1,4-dihydro-pyrimidin-2-ylsulfanyl)-acetamide;
[4-(3,5-Dinitro-phenoxy)-phenyl]-(2-ethyl-piperidin-1-yl)-methanone;
1-(4-Chloro-benzoyI)-2,3-dihydro-1H-benzo[g]quinolin-4-one; 2-[(Adamantane-1-carbonyl)-amino]-3-phenyl-propionic acid methyl ester;
[Benzyl-(4-nitro-benzoyl)-amino]-acetic acid ethyl ester;
9-Oxo-9H-fluorene-3-carboxylic acid methyl-(4-nitro-phenyl)-amide;
Adamantane-1 -carboxylic acid [2-(4-methoxy-phenyl)-ethyl]-amide;
(10,11 -Dihydro-dibenzo[b,fJazepin-5-yl)-(4-fluoro-phenyl)-methanone; 2-Benzylsulfanyl-N-[2-(2-methoxy-phenoxy)-ethyl]-acetamide;
N-Adamantan-1-yl-2-(2-oxo-4-phenyl-pyrrolidin-1-yl)-acetamide;
2-Bromo-N-tricyclo[3.2.1.02,4]oct-6-ylmethyl-benzamide;
Adamantane-1 -carboxylic acid (2,6-dimethoxy-pyrimidin-4-yl)-amide;
Hexanedioic acid (2,7,7-trimethyl-bicyclo[2.2.1]hept-1-yI)-amide (1,7,7-trimethyl- bicyclo[2.2.1]hept-2-yl)-amide;
2-Chloro-N-(2-cyclohexyl-ethyI)-benzamide;
2-[3-(2-Ethyl-piperidin-1-yl)-3-oxo-propyl]-isoindole-1 ,3-dione;
N-Adamantan-1-yl-2-hydroxy-2,2-diphenyl-acetamide;
Adamantane-1 -carboxylic acid (naphthalen-1 -ylmethyl)-amide; Adamantane-1 -carboxylic acid (benzo[1 ,3]dioxol-5-ylmethyl)-amide;
1 -(Azepane-1 -carbonyl)-fluoren-9-one;
2-(Quinolin-2-ylsulfanyl)-N-p-tolyl-acetamide;
2,4-Dichloro-N-[3-(piperidine-1-carbonyl)-phenyl]-benzamide;
2-Chloro-4,5-difluoro-N-(3,3,5-trimethyl-cyclohexyl)-benzamide; 2-(2-Chloro-benzylsulfanyl)-N-p-toIyl-acetamide; [4-(4-Chloro-phenylsulfanylmethyl)-phenyl]-pyrrolidin-1-yl-methanone;
N-Adamantan-1 -yl-N-methyl-isonicotinamide;
Azepan-1-yl-[4-(4-chloro-phenylsulfanylmethyl)-phenyl]-methanone;
(2-Chloro-phenyl)-(1,5,7-trimethyl-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methanone; (3-Chloro-benzo[b]thiophen-2-yl)-(4-methyl-piperidin-1-yl)-methanone;
Benzoic acid 1-benzoyl-decahydro-quinoIin-4-yl ester;
2-(3-Bromo-benzylsulfanyl)-1-[4-(2-methoxy-phenyl)-piperazin-1-yl]-ethanone;
4-Methyl-N-[2-(phenoxazine-10-carbonyl)-phenyl]-benzenesulfonamide;
2-[1-(Azepane-1-carbonyl)-2-methyl-propyl]-isoindole-1 ,3-dione; 2-(3-Bromo-benzylsulfanyl)-1-piperidin-1-yl-ethanone;
1-[3-(4-Bromo-phenyl)-1-furan-2-yl-3-oxo-propyl]-pyrrolidin-2-one;
2-Chloro-N-cyclooctyl-4,5-difluoro-benzamide;
2,4-Dichloro-N-(2-furan-2-ylmethyl-cyclohexyl)-benzamide;
N-(4-Benzoyl-furazan-3-yl)-2-fluoro-benzamide; N-Adamantan-1 -yl-2-(3-cyano-4-methoxymethyl-6-methyl-pyridin-2-ylsulfanyl)-acetamide;
4-tert-Butyl-N-cyclooctyl-benzamide;
N-Adamantan-1 -yl-2-phenyl-butyramide;
(3-Chloro-6-methoxy-benzo[b]thiophen-2-yl)-piperidin-1-yl-methanone;
(3,7-Dichloro-6-methoxy-benzo[b]thiophen-2-yl)-piperidin-1-yl-methanone; Acetic acid 1-benzoyl-decahydro-quinolin-4-yl ester;
2-Bromo-N-methyl-N-phenyl-benzamide;
N-Benzo[1,3]dioxol-5-yl-2,4-dichloro-benzamide;
(3-Chloro-6-fluoro-benzo[b]thiophen-2-yl)-piperidin-1-yl-methanone;
N-(1,2,3,5,6,7-Hexahydro-s-indacen-1-yl)-2-piperidin-1-yl-acetamide; 2-[2-(1 ,3-Dioxo-1 ,3-dihydro-isoindol-2-yl)-3-phenyl-propionylamino]-3-methyl-butyric acid methyl ester;
2-(6-Oxo-6-piperidin-1-yl-hexyl)-isoindole-1 ,3-dione;
2-[2-(1 ,3-Dioxo-1 ,3-dihydro-isoindol-2-yl)-3-phenyl-propionylamino]-3-methyl-butyric acid methyl ester; Adamantane-1 -carboxylic acid (2,6-dihydroxy-pyrimidin-4-yl)-amide;
Adamantane-1 -carboxylic acid methyl-phenyl-amide;
3-Chloro-benzo[b]thiophene-2-carboxylic acid dibenzylamide;
N-Adamantan-1-yl-2-(3-cyano-6-methyl-4-trifluoromethyl-pyridin-2-ylsulfanyl)-acetamide;
2-(3-Oxo-3-phenyl-propenyl)-isoindole-1 ,3-dione; N-[5-(5-Chloro-benzooxazol-2-yl)-2-methyl-phenyl]-2-methoxy-benzamide; N-[2-(2-Bromo-phenyl)-benzooxazol-5-yl]-2-methoxy-benzamide;
2-(4-Chloro-phenoxy)-N-(4-chloro-3-trifluoromethyl-phenyl)-acetamide;
2,2-Dimethyl-N-(5-propyl-[1,3,4]thiadiazol-2-yl)-propionamide;
2-[2-(2,6-Dimethyl-morpholin-4-yl)-1-methyl-2-oxo-ethyl]-isoindole-1 ,3-dione; 2-(2-Cyano-phenylsulfanyl)-N-(2-trifIuoromethyl-phenyl)-benzamide;
Azepan-1-yI-(3,6-dichloro-benzo[b]thiophen-2-yI)-methanone;
Benzo[1 ,3]dioxol-5-yl-(4-benzyl-piperidin-1 -yl)-methanone;
Azepan-1-yl-(3-chloro-6-methyl-benzo[b]thiophen-2-yl)-methanone;
N-(5-Hexyl-[1 ,3,4]thiadiazol-2-yl)-isobutyramide; (3-Chloro-phenyl)-(10,11-dihydro-dibenzo[b,f]azepin-5-yl)-methanone;
(2-Chloro-phenyl)-(10, 11 -dihydro-dibenzo[b,f]azepin-5-yl)-methanone;
2-Amino-5-(azepane-1-carbonyl)-4-methyl-thiophene-3-carboxylic acid ethyl ester;
Adamantan-1-yl-(4-cyclopropyl-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl)-methanone;
Adamantan-1-yl-(4-trifluoromethyl-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl)-methanone; Adamantan-1 -yl-[4-(1H-benzoimidazol-2-ylsulfanyl)-piperidin-1-yl]-methanone;
Adamantan-1-yl-(1 ,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl)-methanone;
[4-(1H-lmidazol-4-yl)-piperidin-1-yl]-(4-pentyl-phenyl)-methanone;
3-Cyclohexyl-1-[4-(1H-imidazol-4-yl)-piperidin-1-yl]-propan-1-one;
1 -(4-Propyl-piperazin-1 -yl)-3-(4-trifluoromethyl-phenyl)-propan-1 -one; N-(2-Hydroxy-benzyl)-3-thiophen-3-yl-N-(2-thiophen-2-yl-ethyl)-acrylamide;
N-(1,3-Dimethyl-pentyl)-2-(3-fluoro-phenyl)-N-(4-hydroxy-benzyl)-acetamide;
N-Cyclobutyl-2-(3-fluoro-phenyl)-N-(4-hydroxy-benzyl)-acetamide;
N-Cyclobutyl-N-(4-hydroxy-benzyl)-4-trifluoromethyl-benzamide;
N-(3-Hydroxy-benzyl)-2-methyl-3-nitro-N-(4-sulfamoyl-benzyl)-benzamide; N-(4-Bromo-benzyl)-N-(4-hydroxy-benzyl)-2-naphthalen-1-yl-acetamide;
6-(2-Bromo-phenylsulfanyl)-hexanoic acid (3-amino-2,2-dimethyl-propyl)-amide;
N-(3-Amino-2,2-dimethyl-propyl)-4-[2-(2-isopropyl-phenylsulfanyl)-ethyl]-benzamide;
N-(3-Amino-2,2-dimethyl-propyl)-4-[4-(4-chloro-phenyl)-pyrimidin-2-ylsulfanylmethyl]-3-nitro- benzamide; 4-(4-Bromo-phenyl)-N-(2-hydroxy-benzyl)-4-oxo-N-thiophen-2-ylmethyl-butyramide;
N-[2-(2,4-Dichloro-phenyl)-ethyl]-N-(4-hydroxy-benzyl)-2-thiophen-3-yl-acetamide;
N-(2-Chloro-benzyl)-N-(4-hydroxy-benzyl)-2-thiophen-2-yl-acetamide;
Heptanoic acid benzyl-(4-hydroxy-benzyl)-amide;
N-(4-Fluoro-benzyl)-N-(4-hydroxy-benzyl)-2-thiophen-3-yl-acetamide; 4-Methyl-pentanoic acid (4-fluoro-benzyl)-(4-hydroxy-benzyl)-amide; N-AIIyl-2-(4-chloro-phenyl)-N-(4-hydroxy-benzyl)-acetamide;
N-Allyl-2-benzo[b]thiophen-3-yl-N-(4-hydroxy-benzyl)-acetamide;
Heptanoic acid (3-ethoxy-propyl)-(4-hydroxy-benzyl)-amide;
Dec-3-enoic acid (4-hydroxy-benzyl)-(4-trifluoromethyl-benzyl)-amide; 6-Oxo-6-phenyl-hexanoic acid (4-hydroxy-benzyl)-(4-trifluoromethyl-benzyl)-amide;
2-(3,4-Difluoro-phenyl)-N-(4-hydroxy-benzyl)-N-thiophen-2-ylmethyl-acetamide;
2-Methyl-pent-4-enoic acid (3-hydroxy-benzyl)-[2-(2-methoxy-phenyl)-ethyl]-amide;
Heptanoic acid (3-hydroxy-benzyl)-(4-isopropyl-benzyl)-amide;
5-(2,6-Dichloro-phenylsulfanyl)-pentanoic acid (naphthalen-1 -ylmethyl)-amide; N-(6,6-Dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-4-[2-(5-methyl-1H-benzoimidazol-2-ylsulfanyl)- ethyl]-benzamide;
N-(6,6-Dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-4-[2-(4-phenoxy-pyrimidin-2-ylsulfanyl)-ethyl]- benzamide;
N-(6,6-Dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-4-[2-(4-fluoro-phenylsulfanyl)-ethyI]- benzamide;
4-(2,6-Dichloro-phenylsulfanyl)-N-(6,6-dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-butyramide;
5-(3-MethylsuIfanyl-[1 ,2,4]thiadiazol-5-ylsulfanyl)-pentanoic acid (6,6-dimethyl- bicyclo[3.1.1]hept-2-ylmethyl)-amide;
5-(2,6-Dichloro-phenylsulfanyl)-pentanoic acid [2-(3-trifluoromethyl-phenyl)-ethyl]-amide; 4-[2-(2,6-Dichloro-phenylsulfanyl)-ethyl]-N-[2-(2-fluoro-phenyl)-ethyl]-benzamide;
2-Cyclohexylamino-thiazole-4-carboxylic acid (1 ,2,3,4-tetrahydro-naphthalen-1-yl)-amide;
2-Cyclohexylamino-thiazole-4-carboxylic acid (3-chloro-4-hydroxy-phenyl)-amide;
2-Cyclohexylamino-thiazole-4-carboxylic acid (1 ,2-dimethyl-propyl)-amide;
2-Cyclohexylamino-thiazole-4-carboxylic acid (1 -ethyl-propyl)-amide; 2-Cyclohexylamino-thiazole-4-carboxylic acid [3-(1-hydroxy-ethyl)-phenyl]-amide;
2-CyclohexyIamino-thiazole-4-carboxylic acid (1 -ethynyl-cyclohexyl)-amide;
2-Cyclohexylamino-thiazole-4-carboxylic acid (2-methoxy-dibenzofuran-3-yl)-amide;
2-Cyclohexylamino-thiazole-4-carboxylic acid [2-(4-hydroxy-phenyl)-ethyl]-amide;
2-Cyclohexylamino-thiazole-4-carboxylic acid (4-hydroxy-cyclohexyl)-amide; 2-(2,6-Difluoro-benzylamino)-N-[2-(3-trifluoromethyI-phenyI)-ethyl]-acetamide;
4-{4-[2-(4-Dimethylamino-phenyl)-acetyl]-piperazin-1-yl}-3-(2-phenyl-propylamino)- benzamide;
2-(2-Ethyl-phenylsulfanyl)-3-[methyl-(2-pyridin-4-yl-ethyl)-amino]-N-prop-2-ynyl- propionamide; 4-Methyl-cyclohexanecarboxylic acid {[2-(2-chloro-6-fluoro-benzylsulfanyl)-ethylcarbamoyl]- methy!}-prop-2-ynyl-amide;
2-Benzylsulfanyl-N-{[2-(2-chloro-6-fluoro-benzylsulfanyl)-ethylcarbamoyl]-methyl}-N-(2- methoxy-ethyl)-acetamide; 4-[2-(5-Cyclopropylmethylsulfanyl-[1,3,4]thiadiazol-2-ylsulfanyl)-ethyl]-N-(6,6-dimethyl- bicyclo[3.1.1 ]hept-2-ylmethyl)-benzamide;
N-(6,6-Dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-2-p-tolyloxy-acetamide;
Bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [4-(2,5-difluoro-phenoxy)-butyl]-amide;
4-Trifluoromethyl-cyclohexanecarboxylic acid [6-(2,6-difluoro-phenoxy)-hexyl]-amide; N-Cyclopropyl-3-methoxy-N-(2-piperidin-4-yl-ethyl)-5-(pyridine-2-carbonyl)-benzamide;
3-Methoxy-N-(2-methoxy-ethyl)-N-(2-piperidin-4-yl-ethyl)-5-(pyridine-2-carbonyl)-benzamide;
3-Methoxy-N-(2-piperidin-4-yl-ethyl)-5-(pyridine-2-carbonyl)-N-(tetrahydro-furan-2-ylmethyl)- benzamide;
3-Methoxy-N-(2-oxo-azepan-3-yl)-N-(2-piperidin-4-yl-ethyI)-5-(pyridine-2-carbonyl)- benzamide;
3-Methoxy-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-N-(2-piperidin-4-yl-ethyl)-5-(pyridine-2- carbonyl)-benzamide;
3-Methoxy-N-methyl-N-(2-piperidin-4-yl-ethyl)-5-(pyridine-2-carbonyl)-benzamide;
[2-({Cyclopropyl-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-methyl)-phenoxy]-acetic acid;
(2-{[[3-Methoxy-5-(pyridine-2-carbonyl)-benzoyl]-(3-methyl-butyl)-amino]-methyl}-phenoxy)- acetic acid;
[2-({Cyclopentyl-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-methyl)-phenoxy]-acetic acid; [2-({(2-Methoxy-ethyl)-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-methyl)-phenoxy]- acetic acid;
[2-({Carbamoylmethyl-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-methyl)-phenoxy]- acetic acid;
[2-({[3-Methoxy-5-(pyridine-2-carbonyl)-benzoyl]-pyridin-4-yl-amino}-methyl)-phenoxy]-acetic acid;
[2-({Cyclopropylmethyl-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-methyl)- phenoxy]-acetic acid;
[2-({[3-Methoxy-5-(pyridine-2-carbonyl)-benzoyl]-methyl-amino}-methyl)-phenoxy]-acetic acid; [4-(4-Hydroxy-benzyl)-piperazin-1-yl]-[3-methoxy-5-(pyridine-2-carbonyl)-phenyl]-methanone; {Carbamoylmethyl-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-acetic acid;
{(3-lmidazol-1-yl-propyl)-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-acetic acid;
{[3-Methoxy-5-(pyridine-2-carbonyl)-benzoyl]-pyridin-4-yl-amino}-acetic acid;
[[3-Methoxy-5-(pyridine-2-carbonyl)-benzoyl]-(2-oxo-azepan-3-yl)-amino]-acetic acid; 3-Methoxy-N-(2-methoxy-ethyl)-N-piperidin-3-ylmethyl-5-(pyridine-2-carbonyl)-benzamide;
4-[3-Methoxy-5-(pyridine-2-carbonyl)-benzoylamino]-piperidine-1 -carboxylic acid ethyl ester;
3-Methoxy-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-5-(pyridine-2-carbonyl)-benzamide; !
3-({Carbamoylmethyl-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-methyl)-benzoic acid; 3-({(3-lmidazol-1 -yl-propyl)-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyI]-amino}-methyl)- benzoic acid;
4-Amino-N-(3-hydroxy-benzyl)-N-indan-2-yl-2-propionylamino-butyramide;
5-Amino-2-propionylamino-pentanoic acid (3-hydroxy-benzyl)-indan-2-yl-amide;
N-Ethyl-2-hexylamino-N-(4-hydroxy-benzyl)-acetamide; 2-Hexylamino-N-(4-hydroxy-benzyl)-N-methyl-acetamide;
1 -[1 -(6-PhenyI-hexanoyl)-piperidin-4-yl]-1 ,3-dihydrό-benzoimidazol-2-one;
1 -[1 -(3-Cyclohexyl-propionyl)-piperidin-4-yl]-1 ,3-dihydro-benzoimidazol-2-one;
N-(2-Hydroxy-benzyl)-N-isobutyl-benzamide;
N-(2-Hydroxy-benzyl)-2-(4-hydroxy-phenyl)-N-isobutyl-acetamide; N-(2-Hydroxy-benzyl)-N-(3-methyl-butyl)-benzamide;
N-(4-Hydroxy-benzyl)-N-isobutyl-benzamide;
4-Hydroxy-N-(4-hydroxy-benzyl)-N-isobutyl-benzamide;
N-(4-Hydroxy-benzyl)-2-(4-hydroxy-phenyl)-N-isobutyl-acetamide;
N-(4-Hydroxy-benzyl)-N-(3-methyl-butyl)-benzamide; N-(2-Ethoxy-ethyl)-4-hydroxy-N-(4-hydroxy-benzyl)-benzamide;
N-(4-Hydroxy-benzyl)-N-(3-isopropoxy-propyl)-benzamide;
N-(3-Hydroxy-benzyl)-N-(4-methyl-pentyl)-benzamide;
N-(3-Hydroxy-benzyl)-2-(4-hydroxy-phenyl)-N-(4-methyl-pentyl)-acetamide;
N-(3-Hydroxy-benzyl)-N-(3-isopropoxy-propyl)-benzamide; N-(2-Hydroxy-benzyl)-N-(3-methyl-butyl)-4-propyl-benzamide;
N-(4-Hydroxy-benzyl)-N-(6-hydroxy-hexyl)-4-propyl-benzamide;
N-(4-Hydroxy-benzyl)-N-(3-methyl-butyl)-4-propyI-benzamide;
N-[2-(4-Fluoro-benzylamino)-thiazol-4-ylmethyl]-N-phenethyl-butyramide; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mix- ture of optical isomers, including a racemic mixture, or any tautomeric forms.
16. The use according to any of the claims 1 -15, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis any conditions, disorders and diseases that are influenced by intracellular glucocorticoid levels.
17. The use according to any of the claims 1-15 for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of conditions, disorders or diseases of the metabolic syndrome, insulin resistance, dyslipidemia, hypertension and obesity.
18. The use according to any of the claims 1-15, for the preparation of a composition for the treatment, prevention and/or prophylaxis of type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG).
19. The use according to any of the claims 1 -15, for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to type 2 diabetes.
20. The use according to any of the claims 1-15, for the preparation of a pharmaceutical composition for the delaying or prevention of the progression of the metabolic syndrome into type 2 diabetes.
21. The use according to any of the claims 1 -15, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of diabetic late complications including cardiovascular diseases; arteriosclerosis; atherosclerosis.
22. The use according to any of the claims 1-15, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of neurodegenerative and psychiatric disorders.
23. The use according to any of the claims 1 -15, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of adverse effects of glucocorticoid receptor agonist treatment or therapy.
24. The use according to any of the claims 1-23, wherein the pharmaceutical composition is for oral, nasal, buccal, transdermal, pulmonal or parenteral administration.
25. The use according to any of the claims 1-24, wherein the pharmaceutical composition is preferably in unit dosage form, comprising from about 0.05 mg to about 2000 mg/day, preferably from about 0.1 mg to about 1000 mg and especially preferred from about 0.5 mg to about 500 mg per day of the compound.
26. A method for the treatment, prevention and/or prophylaxis of conditions, disorders or diseases wherein a modulation or an inhibition of the activity of 11 βHSDl is beneficial, the method comprising administering to a subject in need thereof an effective amount of a com- pound according to the invention.
27. The method according to claim 26, wherein the treatment, prevention and/or prophylaxis is of any conditions, disorders and diseases that are influenced by intracellular glucocorticoid levels.
28. The method according to claim 26 or 27, wherein the condition, disorder or disease is the metabolic syndrome, insulin resistance, dyslipidemia, hypertension and obesity.
29. The method according to claim 26 or 27, wherein the condition, disorder or disease is type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG).
30. The method according to claim 26 or 27, for the delaying or prevention of the progression from IGT to type 2 diabetes.
31. The method according to claim 26 or 27, for the delaying or prevention of the progression of the metabolic syndrome into type 2 diabetes.
32. The method according to claim 26 or 27, wherein the condition, disorder or disease is diabetic late complications including cardiovascular diseases; arteriosclerosis; atherosclerosis.
33. The method according to claim 26 or 27, wherein the condition, disorder or disease is neurodegenerative and psychiatric disorders.
34. The method according to claim 26 or 27, for the treatment, prevention and/or prophy- laxis of adverse effects of glucocorticoid receptor agonist treatment or therapy.
35. A compound of the general formula (II)
Figure imgf000198_0001
wherein
R1 is C3-d -cycloalkyl or C3-C10hetcycloalkyl, wherein the cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R4;
R2 is hydrogen, CrCealkyl, aryld-Cealkyl, wherein the alkyl and aryl groups independently are optionally substituted with one or more of R5; or
R1 and R2 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-C8alkyl, aryl, hetaryl, aryid- C6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrCealkyloxy, hetaryld- C6aIkyloxy, CrC6alkyloxyCrC6alkyl, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrC6alkylcarboxy, arylcarboxy or aryld- C6alkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R14;
R3 is C3-C10cycloalkyl, C3-C10hetcycloalkyl, aryl or hetaryl, wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R7;
R4 and R5 independently are hydrogen, hydroxy, oxo, cyano, halo, methylendioxo, NR8R9, d-C-βalkyl, CrC6alkyloxy, trihalomethyl, trihalomethyloxy, C3-Cι0cycloalkyl, C3- dohetcycloalkyl, C3-Cιocycloalkenyl, aryl, hetaryl, hetarylSOn, arylCrCealkyloxy, hetaryld- C6alkyloxy, d-Cealkyl-R^d-Cealkyl, arylCrC6alkyl-R6-CrC6alkyl, CrCealkylcarbonyl, aryl- carbonyl, arylCrCealkylcarbonyl, hetarylcarbonyl, hetarylCrCealkylcarbonyl, CrC6aIkylSOn, C C6alkylcarboxy, arylcarboxy, hetarylcarboxy, arylCrCealkylcarboxy or hetaryld- C6alkylcarboxy wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one ore more of R15; R6 is oxygen, sulphur, SOn or NR16;
R7 is hydrogen, halo, hydroxy, cyano, nitro, COOR17, CrC8alkyl, C3-Cι0cycloalkyl, C3-C10het- cycloalkyl, methylendioxo, trihalomethyl, trihalomethyloxy, aryl, arylCrC6alkyl, CrC6alkyloxy, CrC6alkyloxyCrC6alkyl, aryloxy, arylCrCealkyloxy, aryloxyCrC6alkyl, arylCrC6alkyloxyCr C6alkyl, hetaryl, hetarylCrCealkyl, hetaryloxy, hetarylCrCealkyloxy, hetaryloxyCr Cealkyl, hetaryld-Cealkyl-oxyd-Cealkyl, NR8R9, SOmNR8R9, NR4R5carbonylCrC6alkyl, arylthio, hetarylthio, R18carbonylNR8, arylSOn, hetarylSOn, R19SOmNR8, arylthioCrC6alkyl, hetaryl- thiod-C6alkyl or arylCrC6alkylR6CrC6aIkyl; wherein the aryl and hetaryl groups independently are optionally substituted with one or more R10;
R8 and R9 independently are hydrogen, d-C8alkyl, aryl, hetaryl, CrC6alkyISOm, arylSOm, aryId-C6alkylSOm, aryICrC6alkyl or hetarylCrCealkyl wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R11; or
R8 and R9 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system optionally being substituted with at least one halo, cyano, d-C8aIkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrC6alkyl, hydroxy, oxo, d-C6alkyloxy, aryld-Cealkyloxy, hetaryld- C6alkyloxy, CrC6alkyloxyCrC6alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, aryld-Cealkylcarbonyl, hetarylCrC6alkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetarylcarboxy, arylCrCealkylcarboxy or hetarylCrC6alkylcarboxy;
R10 and R11 independently are hydrogen, hydroxy, oxo, halo, cyano, nitro, C C8alkyl, d- C6alkyl-oxy, NR12R13, methylendioxo, trihalomethyl or trihalomethyloxy;
R12 and R13 independently are hydrogen, d-C8alkyl or arylCrC6alkyl;
R14 is hydrogen, halo, hydroxy, oxo, nitro, cyano, d-C8alkyl, d-C6alkyloxy or aryloxy;
R15 is hydrogen, halo, hydroxy, oxo, nitro, cyano, CONR8R9 or COOR17; R16 is hydrogen, d-C8alkyl, C3-C10cycloalkyl, C3-C10hetcycloalkyl, aryl, arylCrC6alkyl, hetaryl, hetarylCrCealkyl, alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, aryloxyd- C6alkyl, hetaryloxyCrC6alkyl, arylthioCrC6alkyl or hetarylthioCrC6alkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R10;
R17 is hydrogen, C C8alkyl, aryl or aryld-Cealkyl;
R18 is CrCealkyl, C2-C6alkenyl, aryl, arylCrCealkyl, hetaryl, hetarylCrCealkyl, C3- docycloalkyl, C3-C10hetcycloalkyl, CrCealkyloxy, aryloxy, arylCrCealkyloxy, aryld-
C6alkyloxyCrC6alkyl, hetarylCrCealkyloxyCrCealkyl, hetaryloxy, hetarylCrCealkyloxy or R8R9NCrC6alkyl wherein the alkyl, alkenyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups are optionally substituted with R15;
R19 is CrC6alkyl, C3-C10cycloalkyl, C3-C10hetcycloalkyl, aryl, arylCrC6alkyl, hetaryl, hetarylCrCealkyl;
m is 1 or 2;
n is 0, 1 or 2; or
a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
36. A compound according to claim 35 wherein R1 is C3-Cιocycloalkyl or C3-C10hetcyclo- alkyl, wherein the cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R4.
37. A compound according to claim 35 or 36 wherein R2 is hydrogen or d-C8alkyl.
38. A compound according to claim 35 wherein R1 and R2 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-C8alkyl, aryl, hetaryl, aryld-C6alkyl, hetarylCrC6alkyl, hydroxy, oxo, cyano, d-C6alkyIoxy, arylCrCealkyloxy, hetarylCrCealkyloxy, CrC6alkyloxyCrC6alkyl, d- C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-C6alkylcarboxy, arylcarboxy or arylCrCealkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R14.
39. A compound according to any of the claims 35-38 wherein R3 is aryl or hetaryl, wherein the aryl and hetaryl groups independently are optionally substituted with one or more of R7.
40. A compound according to any of the claims 35-39 wherein R4 and R5 independently are hydrogen, hydroxy, oxo, halo, d-C8alkyl, wherein the alkyl group is optionally substituted with one ore more of R15.
41. A compound according to any of the claims 35-40 wherein R7 is hydrogen, halo, hydroxy, cyano, d-C8alkyl, C3-C10cycloalkyl, C3-C10het-cycloalkyl, trihalomethyl, aryl, aryld- C6alkyl, CrC6alkyloxy, CrCealkyloxyCrCealkyl, aryloxy, arylCrCealkyloxy, aryloxyCrC6alkyl, arylCrCealkyloxyCrCealkyl, hetaryl, hetarylCrCealkyl, hetaryloxy, hetarylCrCealkyloxy, hetaryloxyd-Cealkyl, hetaryld-Cealkyl-oxyd-Cealkyl, NR8R9, R18carbonylNR8, R19SOmNR8; wherein the aryl and hetaryl groups independently are optionally substituted with one or more R10.
42. A compound according to any of the claims 35-41 wherein R8 and R9 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system optionally being substi- tuted with at least one halo, cyano, d-C8alkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrCealkyl, hydroxy, oxo, CrC6alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, CrCealkyloxyCrCealkyl, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkylcarbonyl, hetaryld- C6alkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetarylcarboxy, arylCrCealkylcarboxy or hetarylCrC6alkylcarboxy.
43. A compound according to any of the claims 35-42 wherein R15 is CONR8R9.
44. A compound according to any of the claims 35-43 wherein R18 is d-C6alkyl.
45. A compound according to any of the claims 35-44 which is: (4-Tetrazol-1-yl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
N-Cyclohexyl-N-methyl-2-phenoxymethyl- benzamide;
4-Amino-N-cyclohexyl-N-methyl-benzamide;
N-Cycloheptyl-N-methyl-2-phenoxymethyl-benzamide;
N-Cyclohexyl-N-methyl-benzamide;
2-Chloro-N-cyclohexyl-6-fluoro-N-methyl-benzamide;
N-Cyclohexyl-N-methyl-4-trifluoromethoxy-benzamide;
N-Cyclohexyl-2,3,N-trimethyl-benzamide;
3,5-Dichloro-N-cyclohexyl-N-methyl-benzamide;
N-Cyclohexyl-N-methyl-2-phenoxy-benzamide;
2,4-Bis-benzyloxy-N-cyclohexyl-N-methyl-benzamide;
2-Benzyloxy-N-cyclohexyl-N-methyl-benzamide;
N-Cyclohexyl-N-methyl-4-phenoxy-benzamide;
4-Benzyloxy-N-cyclohexyl-N-methyl-benzamide;
N-Cyclohexyl-N-methyl-4-phenoxymethyl-benzamide;
2-Chloro-N-cyclohexyl-N-ethyl-4-nitro-benzamide;
4-Chloro-N-cyclohexyl-N-ethyl-3-nitro-benzamide;
6-Fluoro-4H-benzo[1 ,3]dioxine-8-carboxylic acid cyclohexyl-methyl-amide;
Azepan-1-yl-(2-chloro-phenyl)-methanone;
Azepan-1-yl-(3-chloro-phenyl)-methanone;
Azepan-1 -yl-phenyl-methanone;
2-(Biphenyl-4-yloxy)-N-cyclohexyl-N-methyl-benzamide;
N-Cyclohexyl-2-(3,5-dimethoxy-phenoxy)-N-methyl-benzamide;
N-Cyclohexyl-2-(2,3-dimethoxy-phenoxy)-N-methyl-benzamide;
2,4-Dichloro-N-(3,3-dimethyl-1 ,5-dioxa-spiro[5.5]undec-9-yl)-N-methyl-benzamide;
2,4-Dichloro-N-methyl-N-(4-oxo-cyclohexyl)-benzamide;
N-Cyclohexyl-2-hydroxy-N-methyl-benzamide;
N-Cyclohexyl-3-methoxy-N-methyl-benzamide;
Benzo[1 ,3]dioxole-5-carboxylic acid cyclohexyl-methyl-amide;
3-Benzyloxy-N-cyclohexyl-N-methyl-benzamide;
N-Cyclohexyl-3-hydroxy-N-methyl-benzamide;
[4-(Morpholine-4-sulfonyl)-phenyl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
N-Benzyl-3-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzenesulfonamide;
[4-Fluoro-3-(morpholine-4-sulfonyl)-phenyl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone; Thiophene-2-sulfonic acid [4-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)- phenylj-amide;
N-Phenyl-4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzenesulfonamide;
(4-Phenoxy-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
N-(2,4-Dimethyl-phenyl)-3-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)- benzenesulfonamide;
(2-Phenoxymethyl-phenyl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1 ]oct- 6-yl)-methanone;
4-(3-Aza-bicyclo[3.2.2]nonane-3-carbonyl)-N,N-dipropyl-benzenesulfonamide;
2-Bromo-N-cyclohexyl-N-methyl-benzamide;
N-[4-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-acetamide;
(4-Dimethylamino-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
(4-Pyrrol-1-yl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
(4-lmidazol-1-yl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yI)-methanone;
(4-Amino-2-methoxy-phenyl)-(trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
(4-Methanesulfonyl-phenyl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1 ]oct-6-yl)-methanone;
(3-Methanesulfonyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
(4-Benzenesulfonyl-phenyi)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
Azepan-1 -yl-[4-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)-phenyl]-methanone;
Azepan-1 -yl-(4-morpholin-4-ylmethyl-phenyl)-methanone;
[4-(3-Trifluoromethyl-pyrazol-1-yl)-phenyl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone;
(4-[1 ,2,4]Triazol-1 -yl-phenyl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1 ]oct-6-yl)-methanone;
(4-Pyrazol-1 -yl-phenyl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yi)-methanone;
2-Benzyloxymethyl-N-cyclohexyl-N-methyl-benzamide;
N-Cyclohexyl-N-methyl-4-(3-methyl-5-oxo-4,5-dihydro-pyrazol-1-yl)-benzamide;
5-Methyl-2-[4-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1 ]octane-6-carbonyl)-phenyl]-2,4-dihydro- pyrazol-3-one;
(9H-Carbazol-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
[4-(3,5-Dimethyl-pyrazol-1-yl)-phenyl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone;
Phenyl-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
Azepan-1-yl-(2-bromo-phenyl)-methanone;
(3-Aza-bicyclo[3.2.2]non-3-yl)-(2-bromo-phenyl)-methanone;
(4-Benzyl-piperidin-1-yl)-quinolin-2-yl-methanone;
(2-Methyl-piperidin-1-yl)-quinolin-2-yl-methanone; (3-Aza-bicyclo[3.2.2]non-3-yl)-quinolin-2-yl-methanone;
Quinoline-2-carboxylic acid cyclohexyl-methyl-amide;
Quinolin-2-yl-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
1-[4-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-pyrrolidine-2,5-dione;
Pyridin-3-yl-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
Pyridin-4-yl-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
Pyridin-2-yl-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
(6-Pyrazol-1 -yl-pyridin-3-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1 ]oct-6-yl)-methanone;
4-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzoic acid; lmidazo[2,1-b]thiazol-6-yl-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; 8-(4-Dimethylamino-benzoyl)-8-aza-bicyclo[3.2.1]octan-3-one; (4-Dimethylamino-phenyl)-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-methanone; (4-Dimethylamino-phenyl)-(3-hydroxy-3-methyl-8-aza-bicyclo[3.2.1]oct-8-yl)-methanone; Trifluoro-acetic acid 8-(4-dimethylamino-benzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl ester; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
46. A compound of formula (III):
Figure imgf000204_0001
(III) wherein
R1 is aryl, arylCrC6alkyl, hetaryl or hetarylCrCealkyl optionally substituted with one or more of R6 independently;
R2 is halo, C C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C3-C10cycloalkylCrC6- alkyl, trihalomethyl, aryl, arylCrC6alkyl, CrCealkyloxyCrCealkyl, arylCrCealkyloxyCrCealkyl, CrC6alkylNR5CrC6alkyl, arylCrC6alkylNR5CrC6alkyl, hetaryl or hetarylCrCealkyl wherein the alkyl, alkenyl, alkynyl, cycloalkyl and aryl groups independently are optionally substituted with one or more R7;
R3 is CrC6alkyl optionally substituted with one or more of R8; R4 is Ce-Ciocycloalkyl, C6-Cι0hetcycloalkyl, C6-CιocycloalkylCrC6alkyl or C6-C10hetcyclo- alkylCrC6alkyl wherein the alkyl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R8; or
R3 and R4 together with the nitrogen to which they are attached, are forming a saturated or partially saturated bicyclic/bridge ring system containing from 7 to 12 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-Cealkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrCealkyl, hydroxy, oxo, d-C6alkyloxy, aryld-Cealkyloxy or hetarylCrCealkyloxy, wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R9;
R5 is CrC6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C.0cycloalkyl, C3-C10hetcycloalkyl, C3-C10- cycloalkyld-C6alkyl, C3-C10hetcycloalkylCrC6alkyl, aryl, hetaryl, aryld-C6alkyl or hetaryld- C6alkyl wherein the alkyl, alkenyl, alkynyl, aryl, hetaryl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R9;
R6 and R7 independently are hydrogen, hydroxy, oxo, halo, nitro, cyano, CrC6alkyl, CrCealkyloxy, trihalomethyl, trihalomethoxy, NR10R11, arylC C6alkyloxy, hetarylCrCealkyloxy, d- C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, CrCealkyloxycarbonyl, aryloxycarbonyl, arylCrC6alkyloxycarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
R8 and R9 independently are hydrogen, CrC6alkyl, aryl, hetaryl, arylCrCealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, NR10R11, CrC6alkyloxy, aryloxy, arylCrCealkyloxy, hetaryloxy, hetarylCrCealkyloxy, d-C-alkyloxyd-Cealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-C6alkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
R10 and R11 independently are hydrogen, CrC8alkyl, aryl, hetaryl, arylCrC6alkyl, C3-C 0- cycloalkyl, C3-C10hetcycloalkyl, C3-C10cycloalkylCrCealkyl, CrCealkylcarbonyl, d- C6alkylcarboxyCrC6alkyl; or
R10 and R11 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon at- oms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-C8alkyl, aryl, hetaryl, aryld- Cealkyl, hetaryld-Cealkyl, hydroxy, oxo, cyano, d-Cealkyloxy, aryld-C6alkyloxy, hetaryld- C6alkyloxy, CrCealkyloxyCrCealkyl, d-C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or aryld-e- alkylcarboxy; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
47. A compound according to claim 46 wherein R1 is aryl or hetaryl optionally substituted with one or more R6 independently;
R2 is halo, CrC6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C 0cycloalkyl, C3-C10cycloalkylCrC6- alkyl, aryl, arylCrCealkyl, CrCealkyloxyCrCealkyl, arylCrCealkyloxyCrCealkyl, d-C6- alkylNR5d-C6alkyl, aryiCrC6alkylNR5CrC6alkyl, hetaryl or hetarylC C6alkyl wherein the al- kyl, alkenyl, alkynyl, cycloalkyl and aryl groups independently are optionally substituted with one or more R7;
R3 is d-C6alkyl optionally substituted with one or more of R8;
R4 is Ce-Ciocycloalkyl, C6-C10hetcycloalkyl, Ce-docycloalkyld-Cealkyl or C6-C10hetcyclo- alkylCrC6alkyl wherein the alkyl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R8;
R5 is CrC6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C3-C10hetcycloalkyl, C3-C10- cycloalkylCrC6alkyl, C3-C10hetcycloalkylCrC6alkyl, aryl, hetaryl, arylCrC6alkyl or hetaryld- Cealkyl wherein the alkyl, alkenyl, alkynyl, aryl, hetaryl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R9;
R6 and R7 independently are hydrogen, hydroxy, oxo, halo, nitro, cyano, d-C6alkyl, d-C6- alkyloxy, trihalomethyl, trihalomethoxy, NR10R11, aryld-Cealkyloxy, hetarylCrCealkyloxy, d- C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, CrCealkyloxycarbonyl, aryloxycarbonyl, arylCrC6alkyloxycarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy; Ra and R9 independently are hydrogen, d-Cealkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, NR10R11, CrC6alkyloxy, aryloxy, arylCrC6alkyloxy, hetaryloxy, hetarylCrCealkyloxy, CrCealkyloxyCrCealkyl, d-Cealkyl-carbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrC6alkyl-carbonyl, d-C6alkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
R10 and R11 independently are hydrogen, d-C8alkyl, aryl, hetaryl, arylCrC6alkyI, C3-C10- cycloalkyl, C3-C10hetcycloalkyl, C3-C10cycloalkylCrC6alkyl, d-Cealkylcarboxyd-Cealkyl; 0r
R10 and R11 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrCealkyl, aryl, hetaryl, aryld- Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrCealkyloxy, hetaryl d-C6alkyloxy, CrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrC6aIkylcarbonyl, CrC6alkylcarboxy, arylcarboxy or aryld-e- alkylcarboxy; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, a prodrug thereof, or any tautomeric forms.
48. A compound according to claim 46 or 47 wherein R1 is aryl, arylCrC6alkyl or hetaryl optionally substituted with one or more of R6.
49. A compound according to any of the claims 46-48 wherein R2 is d-Cealkyl, C3- docycloalkyl, C3-C10cycloalkylCrCealkyl, trihalomethyl, aryld-C6alkyl, or hetarylCrCealkyl wherein the alkyl, cycloalkyl and aryl groups independently are optionally substituted with one or more R7.
50. A compound according to any of the claims 46-49 wherein R3 is d-Cealkyl optionally substituted with one or more of R8.
51. A compound according to any of the claims 46-50 wherein R4 is C6-C10cycloalkyl, or C6- dohetcycloalkyl, wherein the cycloalkyl and hetcycloalkyl groups independently are option- ally substituted with one or more of R8.
52. A compound according to any of the claims 46-51 wherein R6 and R7 independently are hydrogen, hydroxy, oxo, halo, cyano, d-C6alkyl, d-Cealkyloxy, trihalomethyl, NR10R11, aryld-Cealkyloxy, hetarylCrCealkyloxy, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, CrCealkyloxycarbonyl, aryloxycarbonyl or arylCrCealkyloxycarbonyl.
53. A compound according to any of the claims 46-52 wherein R8 and R9 independently are hydrogen, d-C6alkyl, hydroxy, oxo, C C6alkyloxy or arylCrCealkyloxy.
54. A compound according to any of the claims 46-53 wherein R10 and R11 independently are hydrogen or d-C8alkyl.
55. A compound according to any of the claims 46-54 which is 1-(4-Chloro-phenyl)-5- propyl-1H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide, or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
56. A compound according to any of the claims 46-54 selected from the group consisting of: 1-(4-Chloro-phenyl)-5-trifluoromethyl-1 H-pyrazole-4-carboxylic acid cyclohexyl-methyl- amide;
[1-(4-Methoxy-phenyl)-5-methyl- H-pyrazol-4-yl]-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6- yl)-methanone; 1 [1-(4-Chloro-phenyl)-5-propyl-1H-pyrazol-4-yl]-(1 ,3,3-trimethyl-6-aza- bicyclo[3.2.1 ]oct- 6-yl)-methanone; [1-(3,5-Dichloro-phenyl)-5-propyl-1H-pyrazol-4-yl]-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6- yl)-methanone; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
57. A compound according to any of the claims 46-54 selected from the group consisting of:
1 -(Phenyl)-5-methyl-1 H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; 1 -(4-Fluoro-phenyl)-5-methyl-1 H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; 1 -(4-Methoxy-phenyl)-5-methyl-1 H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; 1 -(4-Chloro-phenyl)-5-methyl-1 H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; 1-(2-Methyl-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; 1 -(4-Amino-phenyl)-5-methyl-1 H-pyrazole-4-carboxyϋc acid cyclohexyl-methyl-amide; 1 -(2-Pyridyl)-5-methyl-1 H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; 1-(2-Pyridyl)-5-propyl-1H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
58. A compound of the general formula (IV) :
Figure imgf000209_0001
(IV) wherein
R1 is hydrogen, trihalomethyl, d-C6alkyl, d-C6alkyloxy, d-C6alkylthio, aryl, aryld-Cealkyl, hetaryl or hetaralkyl, wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R8;
R2 , R3, R4 and R5 independently are hydrogen, halo, nitro, cyano, hydroxy, NR9R10, trihalomethyl, d-C6alkyl, CrC6alkyloxy, CrC6alkylthio, aryl, arylCrCealkyl, hetaryl or hetaralkyl, wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R8; or
R2 together with R3 are forming a saturated or partially saturated cyclic ring system containing from 3 to 6 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrCealkyl, aryl, hetaryl, arylCrCealkyl, hetarylCrCealkyl, hydroxy, oxo, CrC6alkyloxy, aryloxy, arylCrCealkyloxy or hetarylCrCealkyloxy; or
R3 together with R4are forming a saturated or partially saturated cyclic ring system containing from 3 to 6 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC6- alkyl, aryl, hetaryl, arylCrC6alkyl, hetaryld-Cealkyl, hydroxy, oxo, d-Cealkyloxy, aryloxy, arylCrCealkyloxy or hetarylCrCealkyloxy; or R4 together with R5are forming a saturated or partially saturated cyclic ring system containing from 3 to 6 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-C6- alkyl, aryl, hetaryl, arylCrCealkyl, hetaryld-Cealkyl, hydroxy, oxo, d-Cealkyloxy, aryloxy, arylCrCealkyloxy or hetarylCrCealkyloxy;
R6 is aryl, hetaryl, arylCrC6alkyl, C3-d0cycloaIkyl, C3-C10hetcycloalkyl, C3-C.0cycloalkylCr C6alkyl, CrC6alkylcarboxyCrC6alkyl, wherein the alkyl, aryl and cycloalkyl groups independ- ently are optionally substituted with one or more of R11;
R7 is C C8alkyl, aryl, hetaryl, arylCrC6alkyl, C3-C10cycloalkyl, C3-C10hetcycloalkyl, C3- C10cycloalkylCrC6alkyl, d-CealkylcarboxyCrCealkyl, wherein the alkyl, aryl and cycloalkyl groups independently are optionally substituted with one or more of R 1; or
R6 and R7, together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrCealkyl, aryl, hetaryl, arylC C6alkyl, hetarylCrC6alkyl, hydroxy, oxo, cyano, CrC6alkyloxy, aryld-Cealkyloxy, hetaryld- C6alkyloxy, CrCealkyloxyCrCeal yl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCi-6- alkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R8;
R9 and R10 independently are hydrogen, d-C8alkyl, aryl, hetaryl, arylCrC6alkyl, C3-C10- cycloalkyl, C3-C10hetcycloalkyl, C3-docycloalkylCrC6alkyl, CrC6alkylcarboxyCrC6alkyl, wherein the alkyl, aryl and cycloalkyl groups independently are optionally substituted with one or more of R11; or
R9 and R10, together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC8alkyl, aryl, hetaryl, arylC C6alkyl, hetaryld-Cealkyl, hydroxy, oxo, cyano, C C6alkyloxy, aryld-Cealkyloxy, fietaryld- C6alkyloxy, CrC6alkyloxyCrC6alkyl, d-C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R8;
R8 and R11 independently are hydrogen, halo, hydroxy, oxo, nitro, cyano, d-C8alkyl, CrCealkyloxy or aryloxy; or
a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mix- ture of optical isomers, including a racemic mixture, a prodrug thereof, or any tautomeric forms.
59. A compound according to claim 58 wherein R1 is hydrogen or d-C6alkyl, wherein the alkyl group is optionally substituted with one or more of R8.
60. A compound according to claim 58 or 59 wherein R , R , R and R are hydrogen
61. A compound according to any of the claims 58-60 wherein R6 and R7, together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bi- cyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional nitrogen or oxygen atoms, the ring system optionally being substituted with at least one of d-C8alkyl, aryl, hetaryl, aryld-Cealkyl, hetaryld-C6alkyl, hydroxy, oxo, cyano, CrC6alkyIoxy, aryld-C6alkyloxy, hetarylCrCealkyloxy, CrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-C6alkyl- carboxy, arylcarboxy or arylCrCealkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R8.
62. A compound according to any of the claims 58-61 which is: pyrazolo[1 ,5-a]pyridin-3-yl-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, a prodrug thereof, or any tautomeric forms.
63. A compound according to any of the claims 58-61 which is: (2-Methyl-pyrazolo[1,5-a]pyridin-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone;
Pyrazolo[1 ,5-a]pyridine-3-carboxylic acid cyclohexyl-methyl-amide; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
64. A compound of the general formula (V):
Figure imgf000212_0001
(V) wherein
R1 is hydrogen, d-C8alkyl, d-Cealkyloxyd-Cealkyl, aryl, hetaryl, aryld-Cealkyl, hetaryld- Cealkyl, CrC6S02, arylS02, hetarylS02, arylCrC6alkylS02 or hetarylCrC6al ylS02 optionally substituted with one or more R8;
R2 and R5 independently are hydrogen, halo, nitro, cyano, trihalomethyl, d-Cealkyl, aryl, arylCrC6alkyl, hetaryl or hetarylCrCealkyl wherein the alkyl, aryl, arylalkyl, hetaryl and hetarylalkyl groups independently are substituted with one or more R9; and
either R3 is hydrogen; and R4 is C(0)NR7R8; or R3 is C(0)NR7R8; and R4 is hydrogen;
R6 is hydrogen, halo, cyano, trihalomethyl, NR1 R13, CrC6alkyl, aryl, aryld-Cealkyl, hetaryl or hetarylCrCealkyl wherein the alkyl, aryl, arylalkyl, hetaryl and hetarylalkyl groups independ- ently are substituted with one or more R9; and
R7 and R8 independently are d-C8alkyl, C3-C10cycloalkyl, C3-Cι0hetcycloalkyl, C3-C10cyclo- alkyld-C6alkyl, wherein the alkyl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R10; or R7 and R8 together with the nitrogen to which they are attached, are forming a saturated or partially saturated bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of d-C8alkyl, arylCrCealkyl, hetaryld-Cealkyl, hy- droxy, cyano, CrCealkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, d-Cealkyloxyd-
C6alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetaryld- C6alkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R11;
R9 is hydrogen, hydroxy, oxo, halo, nitro, cyano, d-Cealkyl, d-Cealkyloxy, trihalomethyl, trihalomethoxy, NR12R13, C(0)NR12R13, aryld-C6alkyloxy, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
R10 and R11 independently are hydrogen, halo, oxo, hydroxy, d-Cβalkyl, aryl, arylCrCealkyl, hetaryl or hetarylalkyl;
R12 and R13 independently are hydrogen, d-C8alkyl, aryl, hetaryl, arylCrC6alkyl, C3-C 0- cycloalkyl, C3-C10hetcycloalkyl, C3-Cι0cycloaIkylCrC6alkyl, CrCealkylcarbonyl, arylcarbonyl, arylC C8alkylcarbonyl, hetarylcarbonyl, hetarylCrCealkylcarbonyl, CrC6alkylcarboxyCr C6alkyl; or
R12 and R13 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of C C8alkyl, aryl, hetaryl, aryld- Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C6alkyloxy, arylCrCealkyloxy, hetarylCr C6alkyloxy, CrC6alkyl-oxyCrC6alkyl, C C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkyl-carbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or aryld- dalkylcarboxy; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, a prodrug thereof, or any tautomeric forms.
65. A compound according to claim 64 having the general formula (Va):
Figure imgf000214_0001
wherein
R1 is hydrogen, C C8alkyl, aryl, hetaryl, arylCrCealkyl or hetarylCrCealkyl optionally substituted with one or more R8;
R2 and R5 independently are hydrogen, halo, nitro, cyano, trihalomethyl, d-C6alkyl, aryl, aryld-Cealkyl, hetaryl or hetarylCrCealkyl wherein the alkyl, aryl, arylalkyl, hetaryl and hetarylalkyl groups independently are substituted with one or more R8; and
either R3 is hydrogen; and R4 is C(0)NR6R7; or R3 is C(0)NR6R7; and R4 is hydrogen;
R6 and R7 independently are d-C8alkyl, C3-C10cycloalkyl, C3-C10hetcycloalkyl, C3-C10cyclo- alkylCrC6alkyl, wherein the alkyl, cycloalkyl and hetcycloalkyl groups independently are op- tionally substituted with one or more of R9; or
R6 and R7 together with the nitrogen to which they are attached, are forming a saturated or partially saturated bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system option- ally being substituted with at least one of d-C8alkyl, arylCrC6alkyl, hetarylCrCealkyl, hydroxy, cyano, d-C6alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, d-Cealkyloxyd- C6alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetaryld- C6alkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R10;
R8 is hydrogen, hydroxy, oxo, halo, nitro, cyano, d-Cealkyl, CrCealkyloxy, trihalomethyl, trihalomethoxy, NR11R12, arylCrCealkyloxy, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
R9 and R10 independently are hydrogen, halo, oxo, hydroxy, d-Cealkyl, aryl, arylCrC6alkyl, hetaryl or hetarylalkyl; R11 and R12 independently are hydrogen, CrC8alkyl, aryl, hetaryl, arylCrC6alkyl, C3-Cιo- cycloalkyl, C3-Cι0hetcycloalkyl, C3-C 0cycloalkylCrC6alkyl, CrC6alkyl-carboxyCrC6alkyl; or
R and R 2 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-C8aIkyl, aryl, hetaryl, aryld- Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, aryld-Cealkyloxy, hetaryld- C6alkyloxy, CrC-alkyl-oxyCrCealkyl, d-C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkyl-carbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylC C6alkylcarboxy; or
a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mix- ture of optical isomers, including a racemic mixture, a prodrug thereof, or any tautomeric forms.
66. A compound according to claim 64 or 65 wherein R1 is is hydrogen, CrC8alkyl, aryld- Cealkyl, hetaryld-Cealkyl, arylS02, hetarylS02, arylCrC6alkylS02 or hetarylCrC8alkylS02 all of which is optionally substituted with one or more R8.
67. A compound according to any of the claims 64-66 wherein R2 and R5 are hydrogen.
68. A compound according to any of the claims 64-67 wherein R3 is hydrogen and R4 is C(0)NR7R8.
69. A compound according to any of the claims 64-67 wherein R3 is C(O)NR7R8 and R4 is hydrogen.
70. A compound according to any of the claims 64-69 wherein R6 is hydrogen, NR12R13, d- C6alkyl, aryl or hetaryl wherein the alkyl, aryl and hetaryl independently are substituted with one or more R9.
71. A compound according to any of the claims 64-70 wherein R7 and R8 independently are d-C8alkyl or C3-C10cycloaikyl, wherein the alkyl and cycloalkyl groups independently are optionally substituted with one or more of R10.
72. A compound according to any of the claims 64-71 wherein R9 is hydrogen, hydroxy, oxo, halo, nitro, cyano, C Cβalkyl, CrCealkyloxy, trihalomethyl, trihalomethoxy, NR12R13, C(0)NR12R13, arylCrCealkyloxy, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl.
73. A compound according to any of the claims 64-72 wherein R10 and R11 independently are hydrogen, halo, oxo, hydroxy, CrCβalkyl, aryl, arylCrC6alkyl, hetaryl or hetarylalkyl.
74. A compound according to any of claims 64-73 which is: 1H-Benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide, or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mix- ture of optical isomers, including a racemic mixture, a prodrug thereof, or any tautomeric forms.
75. A compound according to any of claims 64-73 selected from the group consisting of: 1 -Benzyl-1 H-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide; (1H-Benzoimidazol-5-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, a prodrug thereof, or any tautomeric forms.
76. A compound according to any of claims 64-73 selected from the group consisting of: lsopropyl-2-trifluoromethyl-1 H-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide;
1 -Benzyl-1 H-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide;
2-Methyl-1 H-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide;
2-Hydroxymethyl-1 H-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide; 2-(4-Amino-phenyl)-1H-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide;
(1H-Benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
(2-Methyl-1H-benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
(2-Amino-1H-benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
(2-Benzo[1,3]dioxol-5-yl-.H-benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone; 3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)- H-benzoimidazol-2-yl]-benzoic acid methyl ester;
(2-Thiophen-2-yl-.H-benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone;
[2-(2-Nitro-phenyl)-.H-benzoimidazol-5-yl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanon; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, a prodrug thereof, or any tautomeric forms.
77. A compound of the general formula (VI):
Figure imgf000217_0001
(VI) wherein
X is oxygen or (CR1R2)n;
R1, R2, R3, and R4 independently are hydrogen, d-Cealkyl, aryl, arylCrC6alkyl, hetaryl or hetarylCrCealkyl optionally substituted with one or more R8 independently; or
R1 and either R3 or R4 together are forming a saturated or partially saturated ring system containing from 4 to 8 carbon atoms, the ring system optionally being substituted with at least one of CrC6alkyl, hydroxy, oxo, aryl, hetaryl, arylCrCealkyl or hetarylCrC6alkyl; or
R1 and either R3 or R4 together with the single bond are forming a carbon-carbon double bond;
R5 is C C8alkyl optionally substituted with one or more of R ; R6 is C3-C10cycloalkyl, C3-Cι0hetcycloalkyl, C3-Cι0cycloalkylCrC6alkyl, wherein the alkyl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R9; or
R5 and R6 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-C6alkyl, aryl, hetaryl, aryld- Cealkyl, hetaryld-Cealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrCealkyloxy, hetaryld- C6alkyloxy, d-Cealkyloxyd-Cealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylC C6alkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R10;
R7 is hydrogen, halo, nitro, NR12R13, cyano, trihalomethyl, d-C6alkyl, aryl, arylCrC6alkyl, C C6alkyloxy, aryloxy, arylCrCealkyloxy, hetaryl, hetarylCrC6alkyl, hetaryloxy or hetarylCrCealkyloxy optionally substituted with one or more R11 independently;
R8 and R9 independently are hydrogen, hydroxy, oxo, halo, nitro, cyano, CrC6alkyl, d-C6- alkyloxy, trihalomethyl, trihalomethoxy, NR12R13, aryld-Cealkyloxy, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
R10 is hydrogen, CrC8alkyl, arylCrC6alkyl, hetaryld-Cealkyl, CrC6alkyloxy, arylCrCealkyloxy, hetarylCrC6alkyloxy;
R11 is hydrogen, halo, hydroxy, oxo, nitro, cyano, C C8alkyl, CrC6alkyloxy, aryloxy or hetaryloxy;
R12 and R13 independently are hydrogen, CrC8alkyl, aryl, hetaryl, arylCrC6alkyl, C3-Cι0cyclo- alkyl, C3-Cι0hetcycloalkyl, CrCealkylcarbonyl, arylCrCealkylcarbonyl, C3-C10cycloalkylCrC6- alkyl, CrC6alkyloxycarbonyl; or
R12 and R13 are together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-Cealkyl, aryl, hetaryl, aryld- Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C6alkyloxy, aryld-Cealkyloxy, hetaryld- C6alkyloxy, d-Cealkyloxyd-Cealkyl, d-C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-C6alkylcarboxy, arylcarboxy or aryld- 6alkylcarboxy;
n is 1 or 2; or
a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mix- ture of optical isomers, including a racemic mixture, a prodrug thereof, or any tautomeric forms.
78. A compound according to claim 77 wherein X is (CR1R2)n.
79. A compound according to claim 77 wherein X is oxygen.
80. A compound according to any one of the claims 77-79 wherein R1, R2, R3, and R4 independently are hydrogen, d-C6alkyl or arylCrC6alkyl, optionally substituted with one or more R8.
81. A compound according to any one of the claims 77-79 wherein R1 and either R3 or R4 together with the single bond are forming a carbon-carbon double bond.
82. A compound according to any one of the claims 77-81 wherein R5 is CrC8alkyl option- ally substituted with one or more of R9.
83. A compound according to any one of the claims 77-82 wherein R6 is C3-Cι0cycloalkyl or C3-Ci0hetcycloalkyl, each of which is optionally substituted with one or more of R9.
84. A compound according to any one of the claims 77-81 wherein R5 and R6 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC6alkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, aryld-Cealkyloxy, hetarylCrCealkyloxy, d-Cealkyl- oxyd-C6alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or aryld-Cealkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R10.
85. A compound according to any one of the claims 77-84 wherein R7 is hydrogen, halo, NR12R13, trihalomethyl, d-Cealkyloxy, aryloxy, arylC C6alkyloxy, hetaryloxy optionally substituted with one or more R11 independently.
86. A compound according to any one of the claims 77-85 wherein R8 and R9 independently are hydrogen, hydroxy, oxo, halo, nitro, cyano, d-Cβalkyl, d-C6alkyloxy, trihalomethyl or
NR12R13.
87. A compound according to any one of the claims 77-86 wherein R1Q is hydrogen or C C8alkyl.
88. A compound according to any one of the claims 77-87 selected from the group consisting of:
2,3-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide;
2,5-Dimethyl-3-phenyl-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; 2,2-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide;
2-Methyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide;
(2,3-Dimethyl-2,3-dihydro-benzofuran-7-yl)-(2,4,4-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone;
4-Methoxy-2-methyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; 2-Methyl-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide;
(2-Methyl-2,3-dihydro-benzofuran-7-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1 ]oct-6-yl)- methanone;
Benzofuran-7-carboxylic acid cyclohexyl-methyl-amide;
2,3-Dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; 3,3-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide;
Chroman-8-carboxylic acid cyclohexyl-methyl-amide; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, a prodrug thereof, or any tautomeric forms.
89. A compound according to any one of the claims 77-87 selected from the group consisting of: 2,3-Dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; Benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; 2-Methyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; 2-Methyl-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide;
3,3-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide;
(2,3-Dimethyl-2,3-dihydro-benzofuran-7-yl)-(2,4,4-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone;
4-Methoxy-2-methyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; 2,2-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide;
(2-Methyl-2,3-dihydro-benzofuran-7-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone;
Chroman-8-carboxylic acid cyclohexyl-methyl-amide; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mix- ture of optical isomers, including a racemic mixture, a prodrug thereof, or any tautomeric forms.
90. A compound of the general formula (VII):
Figure imgf000221_0001
(VII) wherein
R1 is hydrogen, C C8alkyl, hetaryl, aryld-Cealkyl or hetarylCrCealkyl optionally substituted with one or more R9;
R2, R3, R4, R5 and R6 independently are hydrogen, halo, nitro, cyano, trihalomethyl, carboxy, N(R12R13), C(0)NR7R8, d-C8alkyl, C3-Cιocycloalkyl, C3-C10hetcycloalkyl, N(R12R13)d-C6alkyl, CrCealkylcarboxy, arylcarboxy, arylCrCealkylcarboxy, CrC6alkyloxy, d-Cealkyloxyd- C6alkyl, aryl, arylCrCealkyl, aryloxy, aryloxyCrC6alkyl, arylCrCealkyloxy, arylCrCealkyloxyCrCealkyl, hetaryl, hetarylCrCealkyl, hetarylCrCealkyloxy, hetaryloxyd-Cealkyl or hetarylCrCealkyloxyCrCealkyl wherein the alkyl, aryl, arylalkyl, hetaryl and hetarylalkyl groups independently are substituted with one or more R9; R7 is hydrogen or d-C8alkyl optionally substituted with one or more of R10;
R8 is C3-C10cycloalkyl, C3-Cι0hetcycloalkyl, C3-CιocycloalkylCrC6alkyl, wherein the cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R10; or
R7 and R8 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring sys- tem optionally being substituted with at least one of d-C8alkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCι-C6alkyl, hydroxy, oxo, cyano, CrC6alkyloxy, aryld-Cealkyloxy, hetarylCrCealkyloxy, CrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, aryld- C6alkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R11;
R9 is hydrogen, hydroxy, oxo, halo, nitro, cyano, C Cβalkyl, d-Cealkyloxy, trihalomethyl, trihalomethoxy, NR12R13, arylCrCealkyloxy, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
R10 and R11 independently are hydrogen, halo, oxo, hydroxy, CrC6alkyl, aryl, aryld-Cealkyl, hetaryl or hetarylalkyl;
R12 and R13 independently are hydrogen, d-C8alkyl, aryl, hetaryl, arylCrC6alkyl, C3-C10- cycloalkyl, C3-Cιohetcycloalkyl, C3-C10cycloalkylCrC6alkyl, d-C6alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, C3-Cι0cycloalkylcarbonyl, C3-Cι0hetcycloalkylcarbonyl or C3- C10cycloalkylCι-C6alkylcarbonyl wherein the alkyl and aryl groups independently are optionally substituted with one or more of R11, wherein R11is as defined above; or
R12 and R13 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC8alkyl, aryl, hetaryl, aryld- Cealkyl, hetaryld-Cealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrCealkyloxy, hetaryld- C6alkyloxy, d-Cealkyl-oxyd-Cealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkyl-carbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or aryld- C6alkylcarboxy; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, a prodrug thereof, or any tautomeric forms.
91. A compound according to claim 90 wherein
R1 is hydrogen, CrC8alkyl, hetaryl, aryld-Cealkyl or hetarylCrCealkyl optionally substituted with one or more R9;
R2 and R5 independently are hydrogen, halo, nitro, cyano, trihalomethyl, C Cβalkyl, CrCealkyloxy, CrCealkyloxyCrCealkyl, aryl, arylCrC6alkyl, aryloxy, aryloxyCrC6alkyl, arylCrCealkyloxy, arylCrCealkyloxyCrCealkyl, hetaryl or hetaryl d-C6al kyl wherein the alkyl, aryl, arylalkyl, hetaryl and hetarylalkyl groups independently are substituted with one or more R9; and
either R3 is C(0)NR7R8, and R4 is hydrogen; or R3 is hydrogen, and R4 is C(0)NR7R8;
R6 is C C8alkyl, C3-d0cycloalkyl, C3-Cι0hetcycloalkyl, N(R12R13)CrC6alkyl, CrC6alkyloxyCr C6alkyl, aryloxyCrC6alkyl, arylCrCealkyloxy or arylCrCealkyloxyCrCealkyl;
R7 is CrC8alkyl optionally substituted with one or more of R10;
R8 is C3-Cιocycloalkyl, C3-C10hetcycloalkyl, C3-CιocycloalkylCrC6alkyl, wherein the cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R10; or
R7 and R8 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of CrC8alkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, aryld-Cealkyloxy, hetarylCrCealkyloxy, CrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R11; R9 is hydrogen, hydroxy, oxo, halo, nitro, cyano, CrC6alkyl, C C6alkyloxy, trihalomethyl, trihalomethoxy, NR12R13, arylCrCealkyloxy, d-C6alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, d-Cealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
R10 and R11 independently are hydrogen, halo, oxo, hydroxy, CrC6alkyl, aryl, arylCrCealkyl, hetaryl or hetarylalkyl;
R12 and R13 independently are hydrogen, d-C8alkyl, aryl, hetaryl, arylCrC6alkyl, C3-C10- cycloalkyl, C3-C 0hetcycloalkyl, C3-Cι0cycloalkylCι-C6alkyl, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, C3-C10cycloalkylcarbonyl, C3-C10hetcycloalkylcarbonyl or C3-C10cyclo- alkyld-C6alkylcarbonyl; or
R12 and R13 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon at- oms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC8alkyl, aryl, hetaryl, aryld- C6alkyl, hetaryld-Cealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrCealkyloxy, hetaryld- C6alkyloxy, CrC6alkyl-oxyCrC6alkyl, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkyl-carbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or aryld- C6alkylcarboxy; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
92. A compound according to claim 90 or 91 wherein R2 is C(0)NR7R8 and R3, R4, and R5 are hydrogen.
93. A compound according to claim 90 or 91 wherein R3 is C(0)NR7R8 and R4 is hydrogen.
94. A compound according to claim 90 or 91 wherein R4 is C(0)NR7R8 and R3 is hydrogen.
95. A compound according to claim 90 or 91 wherein R5 is C(0)NR7R8 and R2, R3, and R4 are hydrogen.
96. A compound according to claim 90 or 91 wherein R6 is C(0)NR7R .'8
97. A compound according to any one of the claims 90-96 selected from the group consisting of:
(1H-lndol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; 1H-lndole-6-carboxylic acid cyclohexyl-methyl-amide; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, a prodrug thereof, or any tautomeric forms.
98. A compound according to any one of the claims 90-96 selected from the group consist- ing of:
(1H-lndol-7-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
(1H-lndol-6-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
1H-lndole-6-carboxylic acid adamantan-2-ylamide;
(6-Aza-bicyclo[3.2.1 ]oct-6-yl)-(1 H-indol-6-yl)-methanone; 1 H-lndole-6-carboxylic acid (8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amide;
1H-lndole-5-carboxylic acid adamantan-2-ylamide;
(6-Aza-bicyclo[3.2.1]oct-6-yl)-(1H-indol-5-yl)-methanone;
(1H-lndol-4-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
(1H-lndol-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; (1H-lndol-2-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
(1 -Methyl-1 H-indol-3-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
(3-Aza-bicyclo[3.2.2]non-3-yl)-(1H-indol-3-yl)-methanone;
1 -Methyl-1 H-indole-3-carboxylic acid cycloheptylamide;
1 -Methyl-1 H-indole-3-carboxylic acid adamantan-1 -ylamide; (3-Aza-bicyclo[3.2.2]non-3-yl)-(1 -methyl-1 H-indol-3-yl)-methanone;
(1 -Methyl-1 H-indol-3-yl)-(4-methyl-piperazin-1 -yl)-methanone;
1 -Methyl-1 H-indole-3-carboxylic acid (3-hydroxy-adamantan-1 -yl)-amide;
1 -Methyl-1 H-indole-3-carboxylic acid azepan-1 -ylamide;
1 -Methyl-1 H-indole-3-carboxylic acid (2-oxo-azepan-3-yl)-amide; (4-Benzyl-piperidine-1 -yl)-(1 -methyl-1 H-indol-3-yl)-methanone;
1 -Methyl-1 H-indole-3-carboxylic acid (2,6-dimethyl-piperidin-1-yl)-amide;
1 -Methyl-1 H-indole-3-carboxylic acid (2-methyl-piperidin-1 -yl)-amide;
(1-Cyclopropylmethyl-6-fluoro-1H-indol-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone; Azepan-1 -yl-(1 -methyl-1 H-indol-3-yl)-methanone; (5-Benzyloxy-1H-indol-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
(5H-[1 ,3]Dioxolo[4,5]indol-7-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
(5-Chloro-1H-indol-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
(6-Trifluoromethyl-1H-indol-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; (6-MethyI-1H-indol-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
(6-Nitro-1H-indol-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
(5-Methoxy-1H-indol-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
(6-Fluoro-1 H-indol-3-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1 ]oct-6-yl)-methanone;
(6-Methoxy-1H-indol-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; (7-Nitro-1H-indol-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
(1H-lndol-4-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
2-(1H-lndol-3-yl)-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-ethanone;
1 -(3-Aza-bicyclo[3.2.2]non-3-yl)-2-(1 H-indol-3-yl)-ethanone;
1 -(3-Aza-bicyclo[3.2.2]non-3-yl)-2-(1 -methyl-1 H-indol-3-yl)-ethanone; 2-(1-Methyl-1H-indol-3-yl)-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-ethanone;
[3-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indol-6-yloxy]-acetic acid tert- butyl ester;
6-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-carboxylic acid;
6-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-carboxylic acid ethyl ester;
5-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1 H-indole-3-carboxylic acid;
5-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1 ]octane-6-carbonyl)-1 H-indole-3-carboxylic acid ethyl ester;
4-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-carboxylic acid; 4-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-carboxylic acid ethyl ester;
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-carboxylic acid;
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-carboxylic acid ethyl ester; 4-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1 H-indole-3-carboxylic acid;
4-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1 ]octane-6-carbonyl)-1 H-indole-3-carboxylic acid ethyl ester;
[3-(Piperidine-1-carbonyl)-1H-indol-5-yl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone; 5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-carboxylic acid cyanomethyl-amide;
5-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-carboxylic acid benzylamide; 5-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-carboxylic acid dimethylamide;
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-carboxylic acid allylamide;
5-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-carboxylic acid (2- dimethylamino-ethyl)-methyl-amide;
5-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-carboxylic acid (2- methoxy-ethyl)-amide;
5-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-carboxylic acid 4- methoxy-benzylamide; 5-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1 ]octane-6-carbonyl)-1 H-indole-3-carboxylic acid (tetra- hydro-furan-2-ylmethyl)-amide;
[3-(2-Methoxymethyl-pyrrolidine-1 -carbonyl)-1 H-indol-5-yl]-(1 ,3,3-trimethyl-6-aza-bicyclo-
[3.2.1 ]oct-6-yl)-methanone;
[3-(2,6-Dimethyl-morpholine-4-carbonyl)-1H-indol-5-yl]-(1 ,3,3-trimethyl-6-aza-bicyclo- [3.2.1]oct-6-yl)-methanone;
5-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-carboxylic acid (1,1- dioxo-tetrahydro-thiophen-3-yl)-amide;
5-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-carboxylic acid [3-(4- methyl-piperazin-1 -yl)-propyl]-amide; 5-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1 H-indole-3-carboxylic acid 4- trifluoromethyl-benzylamide;
5-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-carboxylic acid (furan-
2-ylmethyl)-amide;
[3-(2,3,5,6-Tetrahydro-[1,2']bipyrazinyl-4-carbonyl)- .H-indol-5-yl]-(1,3,3-trimethyl-6-aza- bicyclo[3.2.1 ]oct-6-yl)-methanone;
5-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-carboxylic acid (2H- tetrazol-5-ylmethyl)-amide;
[3-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indol-5-yl]-(1,3,3-trimethyl-6- aza-bicyclo[3.2.1]oct-6-yl)-methanone; 3-{[5-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1 H-indole-3-carbonyl]-amino}- propionic acid ethyl ester;
5-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-carboxylic acid (4- methoxy-phenyl)-amide; 3-{[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-carbonyl]-amino}- propionic acid;
Azepan-1 -yl-(1 H-indol-5-yl)-methanone;
1H-lndole-5-carboxylic acid dibenzylamide;
(3-Aza-bicyclo[3.2.2]non-3-yl)-( .H-indol-5-yl)-methanone; (4-Benzyl-piperidin-1 -yl)-(1 H-indol-5-yl)-methanone;
8-(1 H-lndole-5-carbonyl)-1 -phenyl-1 ,3,8-triaza-spiro[4.5]decan-4-one;
[4-(4-Chloro-phenyl)-4-hydroxy-piperidin-1-yl]-(1H-indol-5-yl)-methanone;
1 -[1 -(1 H-lndole-5-carbonyl)-piperidin-4-yl]-1 ,3-dihydro-benzoimidazol-2-one;
(4--et -Butyl-piperidin-1 -yl)-(1 H-indol-5-yl)-methanone; 1-(1H-lndole-5-carbonyl)-4-phenyl-piperidine-4-carbonitrile;
(1H-lndol-5-yl)-(4-phenyl-piperidin-1-yl)-methanone;
(5-Benzyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-(1H-indol-5-yl)-methanone;
(1 H-lndol-5-yl)-(4-pyrrolidin-1 -yl-piperidin-1 -yl)-methanone;
1 H-lndole-5-carboxylic acid (5-hydroxy-1 ,3,3-trimethyl-cyclohexylmethyl)-amide; 1 H-lndole-5carboxylic acid (3,4-dihydrospiro(1 H-indene-1 ,4-piperidine)-amide;
(3-Methanesulfonylmethyl-1H-indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone;
(3-Dimethylaminomethyl-1H-indol-6-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone; 1-{3-Acetyl-2-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indol-3-yl]-2,3- dihydro-imidazol-1-yl}-ethanone;
1-Ethyl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indol-3-yl]-pyrrolidine-
2,5-dione;
(3-Thiazol-2-yl-1H-indol-5-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; (3-lodo-1H-indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
6-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-carbonitrile;
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-carbonitrile;
6-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1 H-indole-3-carboxylic acid amide;
[3-(2H-Tetrazol-5-yl)-1H-indol-6-yl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; Λ/-[3-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indol-7-yl]-acetamide; (1-Benzenesulfonyl-1H-indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
(1 -Benzenesulfonyl-2-methyl-1 H-indol-5-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1 ]oct-6-yl)- methanone;
(1 -methyl-1 H-indol-5-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; (1 -Benzyl-1 H-indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
[6-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-acetic acid ethyl ester;
[1-(2-Ethoxy-ethyl)-1H-indol-6-yl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
{1-[2-(2-Methoxy-ethoxy)-ethyl]-1H-indol-6-yl}-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone; 3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-propionic acid ethyl ester;
(1 -Phenethyl-1 H-indol-5-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1 ]oct-6-yl)-methanone;
[1-(Tetrahydro-furan-2-ylmethyl)-1H-indol-5-yl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone; 2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-acetamide;
[1 -(4-Trifluoromethoxy-benzyl)-1 H-indol-5-yl]-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1 ]oct-6-yl)- methanone;
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-ylmethyl]-benzoic acid methyl ester; 4-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-ylmethyl]-benzonitrile; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
99. A compound of the general formula (VIII):
Figure imgf000229_0001
wherein X is NR4, S or O;
R1 and R2 independently are hydrogen, halo, cyano, trihalomethyl, d-C6alkyl or d-d-alky!- oxy, wherein the alkyl groups independently are optionally substituted with one or more of R .7 ;. R3 is hydrogen, CrC6alkyl, C3-C10cycloalkyl, CrC6alkyloxy, CrC6alkylthio, aryl, arylCrCealkyl, hetaryl or hetarylalkyl, wherein the alkyl, cycloalkyl, aryl, hetaryl and hetarylalkyl groups independently are optionally substituted with one or more of R7;
R4 is hydrogen, d-C8alkyl, CrCealkyloxyCrCealkyl, aryl, hetaryl, hetarylCrCealkyl, aryld- Cealkyl, arylCrCealkyloxyCrCealkyl, C3-C10cycloalkyl, C3-C10hetcycloalkyl, C3-C10cyclo- alkylCrC6alkyl, CrC6alkylcarboxyCrC6alkyl wherein the alkyl, aryl, hetaryl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R7;
R5 is hydrogen, and R6 is adamantyl optionally substituted with hydroxy, d-C6alkyloxy, aryl, arylCi-C6alkyl, aryloxy, arylCrC6alkyloxy, hetaryl, hetaryloxy or hetarylCrCealkyloxy wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R7; or
R5 and R6 are together with the nitrogen to which they are attached, forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-C6alkyl, aryl, hetaryl, aryld- Cealkyl, hetarylalkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrCealkyloxy, hetaryld-Ce- alkyloxy, CrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, aryld- C6alkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R7;
R7 are independently hydrogen, halo, hydroxy, oxo, nitro, NR9R10, cyano, COOR8,
CONR9R10, CrC8alkyl, d-C6alkyloxy, aryloxy, arylCrCealkyloxy, hetaryloxy or hetaryld- C6alkyloxy;
R8 is hydrogen, d-Cealkyl, aryl, arylCrCealkyl, hetarylalkyl, wherein the alkyl, aryl and het- arylalkyl groups independently are optionally substituted with one or more of R7;
R9 and R10 independently are hydrogen, CrC8alkyl, C3-Cι0cycloalkyl, C3-Cι0hetcycloalkyl, C3- Cι0cycloalkylCι-C6alkyl, wherein the alkyl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R7; or R9 and R10 together with the nitrogen to which they are attached, are forming a saturated or partially saturated bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of d-C8alkyl, aryld-Cealkyl, hetaryld-Cealkyl, hy- droxy, cyano, CrC6alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, CrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrC6alkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R11;
R11 is hydrogen, halo, oxo, hydroxy, d-C6alkyl, aryl, arylCrCealkyl, hetaryl or hetarylalkyl;
provided that hetcycloalkyl is not 7-aza[2,2,1]bicycleheptane; or
a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mix- ture of optical isomers, including a racemic mixture, or any tautomeric forms.
100. A compound according to claim 99 wherein X is NR4, S or O;
R1 and R2 independently are hydrogen, halo, cyano, trihalomethyl, d-C6alkyl or CrCealkyloxy, wherein the alkyl groups independently are optionally substituted with one or more of R7;
R3 is hydrogen, d-C6alkyl, C3-Cι0cycloalkyl, CrC6alkyloxy, d-Cealkylthio, aryl, arylCrCealkyl, hetaryl or hetarylalkyl, wherein the alkyl, cycloalkyl, aryl, hetaryl and hetarylalkyl groups independently are optionally substituted with one or more of R7;
R4 is hydrogen, CrC8alkyl, CrCealkyloxyCrCealkyl, aryl, hetaryl, arylCrC6alkyl, arylCrCealkyloxyCrCealkyl, C3-Cι0cycloalkyl, C3-C10hetcycloalkyl, C3-C10cycloalkylCι-C6alkyl, d-C6- alkylcarboxyCι-C6alkyl wherein the alkyl, aryl, hetaryl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R7;
R5 is hydrogen, and R6 is adamantyl optionally substituted with hydroxy, CrC6alkyloxy, aryl, arylCrC6alkyl, aryloxy, arylCrCealkyloxy, hetaryl, hetaryloxy or hetarylCrCealkyloxy wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R7; or R5 and R6 are together with the nitrogen to which they are attached, forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC6alkyl, aryl, hetaryl, aryld- C6alkyl, hetarylalkyl, hydroxy, oxo, cyano, d-C6alkyloxy, aryld-Cealkyloxy, hetarylCrCealkyloxy, CrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, aryld- C6alkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R7;
R7 are independently hydrogen, halo, hydroxy, oxo, nitro, NR5R6, cyano, COOR8, CONR5R6, C C8alkyl, d-C6alkyloxy, aryloxy or hetaryloxy;
R8 is hydrogen, CrC6alkyl, aryl, arylCrC6alkyl, hetarylalkyl, wherein the alkyl, aryl and hetarylalkyl groups independently are optionally substituted with one or more of R7;
provided that hetcycloalkyl is not 7-aza[2,2,1]bicycleheptane; or
a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
101. A compound according to claim 99 or 100 wherein X is NR4 or S.
102. A compound according to any of the claims 99-101 wherein R1 and R2 independently are hydrogen, halo, trihalomethyl or d-Cealkyl, wherein the alkyl group is optionally substituted with one or more of R7 wherein R7 is as defined in claim 1.
103. A compound according to any of the claims 99-102 wherein R3 is hydrogen, d- C6alkyl, aryl, arylCrC6alkyl, hetaryl or hetarylalkyl, wherein the alkyl, cycloalkyl, aryl, hetaryl and hetarylalkyl groups independently are optionally substituted with one or more of R7 wherein R7 is as defined in claim 1.
104. A compound according to any of the claims 99-103 wherein R4 is hydrogen, d- C8alkyl, aryl, hetaryl, hetarylCrCealkyl, arylCrC6alkyl, wherein the alkyl, aryl, hetaryl, groups independently are optionally substituted with one or more of R7 wherein R7 is as defined in claim 1.
105. A compound according to any of the claims 99-104 wherein R5 and R6 are together with the nitrogen to which they are attached, forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of d-Cealkyl, aryl, hetaryl, arylCrC6alkyl, hetarylalkyl, hydroxy, oxo, cyano, CrC6alkyloxy, aryld-Cealkyloxy, hetarylCrCealkyloxy, d-Cealkyloxyd- C6alkyl, d-C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCι-C6alkylcarbonyl, hetaryld- C6alkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R7.
106. A compound according to any of the claims 99-105 which is: (4-Methyl-2-phenyl-thiazol-5-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone ;
(2,4-Dimethyl-thiazol-5-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1 ]oct-6-yl)-methanone;
(4-Methyl-2-pyrazin-2-yl-thiazol-5-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1 ]oct-6-yl)- methanone; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mix- ture of optical isomers, including a racemic mixture, a prodrug thereof, or any tautomeric forms.
107 A compound according to any of the claims 99-105 selected from the group consisting of: [4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1 ]oct-6- yl)-methanone ;
(3-Aza-bicyclo[3.2.2]non-3-yl)-(2,4-dimethyl-thiazol-5-yl)-methanone;
(1H-lmidazol-4-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
(3-Aza-bicyclo[3.2.2]non-3-yl)-(4-methyl-2-phenyl-thiazol-5-yl)-methanone; 2,4-Dimethyl-thiazole-5-carboxylic acid cycloheptylamide;
Azepan-1 -yl-(2,4-dimethyl-thiazol-5-yl)-methanone;
2,4-Dimethyl-thiazole-5-carboxylic acid adamantan-1 -ylamide;
(3-Aza-bicyclo[3.2.2]non-3-yl)-(1H-imidazol-4-yl)-methanone;
2,4-Dimethy!-thiazole-5-carboxylic acid (3-hydroxy-adamantan-1 -yl)-amide; (1 -Methyl-1 H-imidazol-4-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; [1-(6-Methyl-pyridin-2-yl)-1H-imidazol-4-yl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone;
[1-(4-Chloro-benzyl)-5-methyl-1H-imidazol-4-yl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
108. A compound according to any one of the preceding compound claims 35-107, which is an agent useful for the treatment, prevention and/or prophylaxis of any conditions, disor- ders and diseases wherein a modulation or an inhibition of the activity of 11 βHSDl is beneficial.
109. A compound according to any one of the claims 35-107, which is an agent useful for the treatment, prevention and/or prophylaxis of any conditions, disorders and diseases that are influenced by intracellular glucocorticoid levels.
110. A compound according to any one of the claims 35-107, which is an agent useful for the treatment, prevention and/or prophylaxis of conditions, disorders or diseases selected from the group consisting of the metabolic syndrome, insulin resistance, dyslipidemia, hyper- tension and obesity.
111. A compound according to any one of the claims 35-107, which is an agent useful for the treatment, prevention and/or prophylaxis of type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG).
112. A compound according to any one of the claims 35-107, which is an agent useful for the delaying or prevention of the progression from IGT into type 2 diabetes.
113. A compound according to any one of the claims 35-107, which is an agent useful for delaying or prevention of the progression of the metabolic syndrome into type 2 diabetes.
114. A compound according to any one of the claims 35-107, which is an agent useful for the treatment, prevention and/or prophylaxis of adverse effects of glucocorticoid receptor agonist treatment or therapy.
115. A pharmaceutical composition comprising, as an active ingredient, at least one compound according to any one of the claims 35-107 together with one ore more pharmaceutically acceptable carriers or excipients.
116. The pharmaceutical composition according to claim 115 which is for oral, nasal, buc- cal, transdermal, pulmonal or parenteral administration.
117. The pharmaceutical composition according to claim 115 or 116 in unit dosage form, comprising from 0.05 mg to 2000 mg/day, from 0.1 mg to 1000 mg or from 0.5 mg to 500 mg per day of the compound according to anyone of the claims 35-107.
118. A use of a compound according to any of the claims 35-107, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of any conditions, disorders and diseases wherein a modulation or an inhibition of the activity of 11 βHSDl is beneficial.
119. A use of a compound according to any of the claims 35-107, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of any conditions, disorders and diseases that are influenced by intracellular glucocorticoid levels.
120. A use of a compound according to any of the claims 35-107, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of conditions, disorders or diseases selected from the group consisting of the metabolic syndrome, insulin resistance, dyslipidemia, hypertension and obesity.
121. A use of a compound according to any of the claims 35-107, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG).
122. A use of a compound according to any of the claims 35-107, for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to type 2 diabetes.
123. A use of a compound according to any of the claims 35-107, for the preparation of a pharmaceutical composition for the delaying or prevention of the progression of the metabolic syndrome into type 2 diabetes.
124. A use of a compound according to any of the claims 35-107, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of adverse effects of glucocorticoid receptor agonist treatment or therapy.
125. A method for the treatment, prevention and/or prophylaxis of any conditions, disorders or diseases wherein a modulation or an inhibition of the activity of 11 βHSDl is beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound according to the invention.
126. The method according to claim 125 wherein the conditions, disorders or diseases are selected from the group consisting of the metabolic syndrome, insulin resistance, dyslipidemia, hypertension and obesity.
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US11/265,794 US20060111366A1 (en) 2003-04-11 2005-10-11 Pharmaceutical use of substituted amides
US12/006,765 US20080108598A1 (en) 2003-02-07 2008-01-03 Pharmaceutical use of substituted amides
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JP2006522746A (en) 2006-10-05
WO2004089470A3 (en) 2004-12-23
EP1615698A2 (en) 2006-01-18
EP2239012A2 (en) 2010-10-13
DE602004027171D1 (en) 2010-06-24
JP2006522748A (en) 2006-10-05
US20090264414A1 (en) 2009-10-22
EP1615698B1 (en) 2010-09-29
JP4629657B2 (en) 2011-02-09
EP2239012A3 (en) 2011-06-15
EP1787982B1 (en) 2010-05-12
WO2004089896A1 (en) 2004-10-21
EP1787982A2 (en) 2007-05-23

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