WO2004089415A2 - COMBINATIONS OF AN 11β-HYDROXYSTEROID DEHYDROGENASE TYPE 1 INHIBITOR AND A GLUCOCORTICOID RECEPTOR AGONIST - Google Patents

COMBINATIONS OF AN 11β-HYDROXYSTEROID DEHYDROGENASE TYPE 1 INHIBITOR AND A GLUCOCORTICOID RECEPTOR AGONIST Download PDF

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WO2004089415A2
WO2004089415A2 PCT/DK2004/000248 DK2004000248W WO2004089415A2 WO 2004089415 A2 WO2004089415 A2 WO 2004089415A2 DK 2004000248 W DK2004000248 W DK 2004000248W WO 2004089415 A2 WO2004089415 A2 WO 2004089415A2
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phenyl
methyl
methanone
alkyl
pyrazolo
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PCT/DK2004/000248
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French (fr)
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WO2004089415A3 (en
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Gita Camilla Tejlgaard Kampen
Henrik Sune Andersen
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Novo Nordisk A/S
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Priority to EP04725890A priority Critical patent/EP1615667A2/en
Priority to JP2006504351A priority patent/JP2006522744A/en
Publication of WO2004089415A2 publication Critical patent/WO2004089415A2/en
Publication of WO2004089415A3 publication Critical patent/WO2004089415A3/en
Priority to US11/246,814 priority patent/US20060094699A1/en
Priority to US12/491,659 priority patent/US20090264412A1/en

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Definitions

  • the instant invention involves a combination therapy comprising the administration of an 11 ?-hydroxysteroid dehydrogenase type 1 inhibitor and a glucocorticoid receptor agonist for treating some forms of cancer, diseases and disorders having inflammation as a component, and to minimize the side effects associated with glucorticoid receptor agonist therapy.
  • Glucocorticoid receptor agonists are widely used as anti-inflammatory and disease- modifying treatment in a broad spectrum of diseases with an inflammatory component. Glucocorticoid receptor agonists are also used as a component of some forms of cancer chemotherapy. However, the use of glucocorticoid receptor agonists is often limited by severe side effects caused by glucocorticoid receptor agonism in organs and tissues that are not targets for treatment. These side effects include osteoporosis, decreased linear growth (children), aseptic bone necrosis, cushingoid fat distribution, mental changes, insulin resistance, hypertension, myopathy, cataract and glaucoma (Harrison's Principles of Internal Medicine, 14 th edition, Eds. Fauci et al., McGraw-Hill, New York, USA).
  • glucocorticoid receptor agonists Like the endogenous active glucocorticoids (e.g. cortisol in humans, corticosterone in rodents), glucocorticoid receptor agonists bind to and stimulate ubiquitously expressed in- tracellular glucocorticoid receptors. Hence, the degree of receptor agonism depends on the intracellular concentration of ligand (reviewed e.g. in Yudt & Cidlowski, Mol Endocrinol; 16, 1719 (2002)).
  • 11 ?-hydroxysteroid dehydrogenase type 1 (11 ?-HSD1) is an intracellular enzyme that physiologically catalyses the conversion of biologically inactive endogenous glucocorti- coid (e.g. cortisone in man, 11-dehydrocorticosterone in rodents) to active glucocorticoid (e.g. cortisol in man, corticosterone in rodents).
  • 11 ?-HSD1 is expressed in several tissues and organs including the liver, adipose tissue, skeletal muscle, bone, pancreas, endothelium, ocular tissue and certain parts of the central nervous system.
  • 11/?-HSD1 serves to increase the local levels of active endogenous glucocorticoid in many of the tissues and or- gans that are the origin of the side effects (but not the beneficial effects) of treatment with glucocorticoid receptor agonists(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.
  • the degree of stimulation of the glucocorticoid receptor will reflect the sum of contributions from the active endogenous glucocorticoid generated locally by 11 7-HSD1, the active endogenous glucocorticoid derived from plasma and the exogenous glucocoid receptor agonist. Consequently, inhibition of 11 ?-HSD1 decreases the total stimulation of the glucocorticoid receptor. Due to the expression pattern of 11 ?-HSD1 , levels of active glucocorticoid are decreased in the tissues and organs that are negatively affected by therapy with glucocorticoid receptor agonists while the desired therapeutic effects remain intact.
  • a clinical case report demonstrates that a partial defect in/reduced activity of 11 ?-HSD1 abolishes the obesity and hypertension normally associated with Cushing's disease, i.e. increased pituitary ACTH secretion resulting in increased synthesis of cortisol in the adrenal glands (Tomlinson et al., J. Clin. Endocrinol. Metab., 87, 57 (2002).
  • the instant invention addresses the clinical problems related to side effects of treatment with glucocorticoid receptor agonists by providing a combination therapy comprised of an 11 ?-HSD1 inhibitor and a glucocorticoid receptor agonist.
  • a combination therapy comprised of an 11 ?-HSD1 inhibitor and a glucocorticoid receptor agonist.
  • the 11 ?-HSD1 inhibitor together with the glucocorticoid receptor agonist allow for control of the disease while minimizing the side effects.
  • dosage of the glucocorticoid receptor agonist can be optimized to meet the required therapeutic effect, providing improved means of achieving the desired clinical result.
  • inhibitors and/or modulators of the human 11 ?-hydroxysteroid dehydrogenase type 1 enzyme can be found in WO 01/90090, WO 01/90091 , WO 01/90092, WO 01/90093, WO 01/90094, WO 02/72084 and WO 02/076435, as well as the following patent applications under common ownership of the present application: PA 2003 00569 filed 11 April 2003 DK, PA 2003 00565 filed 11 April 2003 DK, PA 2003 00571 filed 11 April 2003 DK, PA 200300570 filed 11 April 2003 DK, PA 2003 00566 filed 11 April 2003 DK, PA 200300972 filed 27 June 2003 DK, PA 2003 00998 filed 02 July 2003 DK, PA 2003 00988 filed 30 June 2003 DK, PA 200300989 filed 30 June 2003 DK, PA 2003 00990 filed 30 June 2003 DK, and PA 200301910 filed 22 December 2003 DK, the contents of which are hereby incorporated by reference in their entirety.
  • An object of the present invention is to provide a novel combination therapy com- prised of a therapeutically effective amount of a glucocorticoid receptor agonist in combination with an 11jff-hydroxysteroid dehydrogenase type 1 (11 jff-HSDI) inhibitor for the reduction of undesirable side effects occurring during glucocorticoid receptor agonist therapy, and for treating some forms of cancer, diseases and disorders having inflammation as a component.
  • 11jff-HSDI 11jff-hydroxysteroid dehydrogenase type 1
  • halo includes fluorine, chlorine, bromine, and iodine.
  • trihalomethyl includes trifluoromethyl, trichloromethyl, tr ibromomelhyl, and triiodomethyl.
  • trihalomethoxy includes trifluorometoxy, trichlorometoxy, tribromometoxy, and triiodometoxy.
  • alkyl includes C ⁇ -C 6 straight chain saturated and methylene aliphatic hydrocarbon groups, C 3 -C 6 branched saturated hydrocarbon groups having the specified num- ber of carbon atoms.
  • this definition shall include but is not limited to methyl
  • 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, hexenyi, methylpropenyl, methylbutenyl and the like.
  • alkynyl includes C 2 -C 6 straight chain unsaturated aliphatic hydrocarbon groups and C 4 -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, pyrrolinyl, pyrrolidinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, morpholinyl, piperidinyl, thiomorpholinyl, piperazinyl, phthalimide, 1,2,3,4- tetrahydro-quinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, 1,2,3,4-tetrahydro-quinoxalinyl, and indolinyl.
  • saturated or partially saturated cyclic ring system represents but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cydoheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, tetrahydrofuranyl or tetrahydropyranyl.
  • 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]octyI, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl and the like
  • cycloalkylalkyl e.g. cyclopropylmethyl, cyclobutylethyl, adamantylmethyl and the like
  • cycloalkenyl e.g.
  • cyclobutenyl represents a partially saturated, mono-, bi-, tri- or spirocarbocyclic group having the specified number of carbon atoms.
  • heteroalkyl (tetrahydrofuranyl, tetrahydropyranyl, tertahydrothiopyranyl, 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 S0 2 .
  • 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
  • arylalkyloxy e.g. phenethyloxy, naphthylmethyloxy and the like
  • hetarylalkyloxy (e.g. 2-pyridylmethyloxy and the like) represents a hetarylalkyl group as defined below attached through an oxygen bridge.
  • alkyloxycarbonyl e.g. methylformiat, ethylformiat and the like
  • alkyloxycarbonyl represents an alkyloxy group as defined above attached through a carbonyl group.
  • aryloxycarbonyl e.g. phenylformiat, 2-thiazolylformiat and the like
  • aryloxycarbonyl represents an aryloxy group as defined above attached through a carbonyl group.
  • arylalkyloxycarbonyl e.g. benzylformiat, phenyletylformiat and the like
  • arylalkyl represents an "arylalkyloxy” group as defined above attached through a carbonyl group.
  • arylalkyl e.g. benzyl, phenylethyl, 3-phenylpropyl, 1-naphtylmethyl, 2-(1- naphtyl)ethyl and the like
  • hetarylalkyl e.g. (2-furyl)methyl, (3-furyl)methyl, (2-thienyl)methyl, (3- thienyl)methyl, (2-pyridyl)methyl, 1 -methyl-1 -(2-pyrimidyI)ethyl and the like
  • hetarylalkyl 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
  • arylcarbonyl represents an aryl group as defined below attached through a carbonyl group.
  • hetarylcarbonyl e.g. 2-thiophenylcarbonyl, 3-methoxy-anthrylcarbonyl, oxazolylcarbonyl and the like
  • hetarylcarbonyl represents a hetaryl group as defined below attached through a carbonyl group.
  • carbonylalkyl e.g. acetyl and the like
  • carbonylalkyl represents a carbonyl group attached 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
  • hetarylcarbonylalkyl e.g. 1-pyridin-2-yl-propan-1-one, 1-(1-H-imidazol-2- yl)-propan-1-one and the like
  • hetarylcarbonylalkyl represents a hetarylcarbonyl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • arylalkylcarbonyl e.g. phenylpropylcarbonyl, phenylethylcarbonyl and the like
  • hetarylalkylcarbonyl e.g. imidazolylpentylcarbonyl and the like
  • alkyl group is in turn attached through a carbonyl.
  • 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) represents an arylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
  • alkylcarboxyalkyl e.g. heptylcarboxymethyl, propylcarboxy fe/t-butyl, 3- pentylcarboxyethyl
  • arylalkylcarboxy e.g. benzylcarboxy, phenylpropylcarboxy and the like
  • arylalkylcarboxyalkyl e.g. benzylcarboxymethyl, phenylpropylcarboxypro- pyl 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 indicated number of carbon atoms.
  • hetarylcarboxy e.g. pyridine-2-carboxylic acid and the like
  • hetarylalkylcarboxy e.g. (1-H-imidazol-2-yl)-acetic acid, 3-pyrimidin-2-yl- propionic acid and the like
  • hetarylalkylcarboxy represents a hetarylalkyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
  • alkylthio e.g. methylthio, ethylthio and the like
  • arylthio e.g. benzenthiol, naphthylthiol and the like
  • 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-ethylsulfanyI-isoquinoline 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
  • aryloxyaryl represents a hetaryloxy group as defined above attached through an “aryl” group as defined below.
  • 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.
  • 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.
  • 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 sys- terns enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1 ,2,3,4-tetrahydronaphthyl, 1 ,4-dihydronaphthyl and the like.
  • 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-yI), 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-fur
  • NR 4 R 5 carbonylalkyl e.g. V, V-dimethyl- propionamide, /V-isopropyl-N-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
  • R 6 represents an alkyl group as defined above, substituted by R 6 , which is substituted by an alkyl group as defined above, wherein R 6 is as defined for Formula II herein.
  • arylR 6 alkyl e.g. ethoxy-benzene, ethyl-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, wherein R 6 is as defined for Formula II herein.
  • arylalkylR 6 alkyl e.g.
  • benzyloxymethyl, ethyl- methyl-benzyl-amine, ⁇ /-ethyl-benzylamide and the like represents an arylalkyl group as defined above, substituted by R 6 , which is substituted by an alkyl group as defined above, wherein R 6 is as defined for Formula II herein.
  • R 6 is as defined for Formula II herein.
  • hetarylR 6 alkyl e.g.
  • 2-ethoxy-1 /-/-imidazol, ethyI-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 R 6 , which is substituted by an alkyl group as defined above, wherein R 6 is as defined for Formula II herein.
  • arylcarbonylNR 15 e.g. ⁇ /-benzyl- ⁇ /-methyl- benzamide and the like
  • alkylSO n (e.g. ethylsulfonyl, ethylsulfinyl and the like) represents an alkyl group as defined above, wherein the alkyl group is in turn at- tached through a sulphur bridge wherein the sulphur is substituted with n oxygen atoms, wherein n is as defined for Formula II herein.
  • 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, wherein m is as defined for Formula II herein.
  • hetarylSO m (e.g. thiazol-2-sulfinyl, pyridine-2- sulfonyl and the like) represents 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, wherein is as defined for Formula II herein.
  • arylSO m NR 8 e.g.
  • NR 4 R 5 carbonylalkyl (e.g.
  • ⁇ /, ⁇ -dimethyl- propionamide, ⁇ /-isopropyl- ⁇ /-methyl-propionamide and the like represents NR R 5 substituted by a carbonylalkyl group as defined above, wherein R 4 and R 5 are as defined for Formula V herein.
  • arylR 8 alkyl e.g. ethoxy-benzene, N-ethyl-N- methyl-phenyl-amine, ⁇ /-ethyl-benzamide, /V-isobutyl-benzenesutfonamide and the like
  • R 8 represents an aryl group as defined above, substituted by R 8 , which is substituted by an alkyl group as defined above, wherein R 8 is as defined for Formula V herein.
  • hetaryl R 8 alkyl e.g. 2-ethoxy-1H-imidazol, ethyl-quinolin-2-yl-amine, thiazole-2-carboxylic acid, methyl-propyl-amide, pyridine-3-sulfonic acid isobutyl-amide and the like
  • R 8 represents a hetaryl group as defined above, substituted by R 8 , which is substituted by an alkyl group as defined above, wherein R 8 is as defined for Formula V herein.
  • arylcarbonylNR 15 (e.g. ⁇ /-benzyl- ⁇ /-methyl- benzamide and the like) represents an arylcarbonyl group as defined above, substituted by NR 15 , wherein R 15 is as defined for Formula V herein.
  • 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 term "combination therapy” is defined as the administration of a single pharmaceutical dosage formulation which comprises the 11 ?-HSD1 inhibitor and the glucocorticoid receptor agonist, as well as administration of each active agent in its own separate pharma- ceutical dosage formulation. Where separate dosage formulations are used, the 11 7-HSD1 inhibitor and the glucocorticoid receptor agonist can be administered to the patient at essentially the same time, i.e. concurrently, or at separate staggered times, i.e. sequentially. When given by different dosage formulations, the route of administration may be the same or different for each agent. Any route of administration known or contemplated for the individual agents is acceptable for the practice of the present invention.
  • the term "therapeutically effective amount” is defined as the amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system or a mammal that is sought by the treating individual, i.e. medical doctor or other clinician.
  • modulation are intended to include stimulation (e.g., increasing or upregulating a particular response or activity) and inhibition (e.g., decreasing or downregulating a particular response or activity).
  • agonist is intended to indicate a substance that activates the receptor(s).
  • glucocorticoid receptor agonist is intended to indicate a substance that activates glucocorticoid receptor(s) without dependence on prior modification of the substance by 11 ⁇ HSD1.
  • said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I)
  • R 6 and R 7 independently are C ⁇ -C ⁇ alkyl, C 3 -C 10 cycloalkyl, hetC 3 -C ⁇ 0 cycloalkyl, arylCrC 6 alkyl or hetarylC C 6 alkyl, wherein the alkyl, cycloalkyl, hetcycloalkyl, arylalkyl, and hetarylalkyl groups independently are optionally substituted with one or more of R 10 ; 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 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 6 alkyl, aryl, hetaryl, arylC C 6 alkyl, halo, hydroxy, oxo, C C 6 alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, d- C 6 alkyloxyCrC 6 alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrC 6 alkylcarboxy, arylcarboxy, hetarylcarboxy
  • R 8 and R 9 independently are hydrogen, halo, hydroxy, oxo, cyano, nitro, C 3 -C 10 cycloalkyl, C 3 - C 10 hetocycloalkyl, d-Cealkyl, d-Cealkyloxy, trihalomethyl, trihalomethoxy, aryld-Cealkyloxy, hetarylC C 6 alkyloxy, d-Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-C 6 alkylcarboxy, arylcarboxy, hetarylcarboxy, aryld-Ce- alkylcarboxy, hetarylCrC 6 alkylcarboxy, CrC 6 alkylcarbonylamino or arylCrC 6 alkylcarbonyl-
  • R 10 is hydrogen, halo, cyano, nitro, hydroxy, oxo, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, Ci- Cealkyl, CrC 6 aIkyloxy, trihalomethyl, trihalometh dialkylamino oxy, aryld-Cealkyloxy, hetarylCrCealkyloxy, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrC 6 alkylcarboxy, arylcarboxy or arylCrC 6 alkylcarboxy;
  • R 11 is d-Cealkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryld-Cealkyl, hetarylCrCealkyl, d-C 6 alkyl- carbonylCrC 6 alkyl, CrC 6 alkyloxy, aryloxy, CrC 6 alkyloxy, arylcarbonyl, arylCrCealkylcarbonyl, hetarylcarbonylCrC 6 alkyl, wherein the alkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 9 ;
  • R 2 is CrC 6 alkylcarbonyIaminoCrC 6 alkyl, arylcarbonylaminoCrC 6 alkyl or arylCrC 6 alkyl- carbonylaminoCrC 6 alkyl;
  • R 13 and R 14 independently are hydrogen, oxo, C 3 -C 10 cycloalkyl, CrC 6 alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC 6 alkylcarbonyl, hetarylCrCealkylcarbonyl;
  • R 15 is hydrogen, C 3 -C 10 cycloalkyl, CrC 6 alkyl, aryl, hetaryl, arylCrC 6 alkyl, hetarylCrCealkyl, CrC 6 alkyloxyalkyl or arylGrC 6 alkyloxyalkyl; 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.
  • R 3 and R 5 independently are hydrogen, NR 13 R 14 trihalomethyl, trihalomethoxy, d-Cealkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, CrC 6 alkyloxy, CrC 6 alkylthio, aryl, arylCrC 6 alkyl, hetaryl or hetarylCrCealkyl, wherein alkyl, alkynyl, alkenyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R 8 ;
  • 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 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 ⁇ alkyl, aryl, hetaryl, aryld- C 6 alkyl, halo, hydroxy, oxo, CrC 6 alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, d-C 6 - alkyloxyd-C 6 alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrC 6 alkylcarboxy, arylcarboxy, hetaryl
  • R 8 and R 9 independently are hydrogen, halo, hydroxy, oxo, cyano, nitro, C 3 -d -cycloalkyl, C 3 - dohetocycloalkyl, d-C 6 alkyl, CrC 6 alkyloxy, trihalomethyl, trihalomethoxy, arylCrCealkyloxy, hetarylCrCealkyloxy, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrC 6 aIkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetarylcarboxy, aryld- C 6 alkylcarboxy, hetarylCrC 6 alkylcarboxy, d-Cealkylcarbonylamino or arylCrC 6 alkyl- carbonylamino;
  • R 10 is hydrogen, halo, cyano, nitro, hydroxy, oxo, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, Ci- Cealkyl, CrC 6 alkyloxy, trihalomethyl, trihalometh dialkylamino oxy, arylCrCealkyloxy, hetarylCrCealkyloxy, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylC C 6 alkylcarbonyl, hetarylCrC 6 alkylcarbonyl, CrC 6 alkylcarboxy, arylcarboxy or aryld- C 6 alkylcarboxy;
  • R 11 is Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, arylCrC 6 alkyl, hetaryld-Cealkyl, C C 6 alkyl- carbonylCrC 6 alkyl, d-C 6 alkyl, arylcarbonyl, arylCrCealkylcarbonyl, hetarylcarbonylCrC 6 - alkyl, wherein the alkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 9 ;
  • R 12 is CrC 6 alkylcarbonylaminoCrC 6 alkyl, arylcarbonylaminoCrC 6 alkyl or arylCrC 6 alkyl- carbonylaminoCrC 6 alkyl;
  • R 13 and R 14 independently are hydrogen, oxo, C 3 -C 10 cycloalkyl, CrC 6 alkyl, CrC 6 alkyloxy, trihalomethyl, trihalomethoxy, arylCrCealkyloxy, hetaryld-Cealkyloxy, d-C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetarylcarboxy, arylCrCealkylcarboxy;
  • R 15 is hydrogen, C 3 -C ⁇ 0 cycloalkyl, CrCealkyl, aryl, hetaryl, arylCrCealkyl, hetarylCrC 6 alkyl, CrC 6 alkyloxyalkyl or arylCrC 6 alkyloxyalkyl; 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.
  • said substituted pyrazoIo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein R 3 and R 5 independently are hydrogen, trihalomethyl, CrC 6 alkyl, CrC 6 alkyloxy, aryl, arylCrC 6 alkyl, hetaryl or hetaryld-Cealkyl, wherein alkyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R 8 .
  • said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein R 6 and R 7 independently are CrC 6 alkyl, C 3 -C ⁇ 0 cycloalkyl, hetC 3 - Ciocycloalkyl, arylCrC 6 alkyl or hetarylCrCealkyl, wherein the alkyl, cycloalkyl, hetcycloalkyl, arylalkyl, and hetarylalkyl groups independently are optionally substituted with one or more of R 10 .
  • said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I)
  • R 6 and R 7 together with the nitrogen to which they are attached are form- ing 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 ⁇ alkyl, aryl, hetaryl, arylCrC 6 alkyl, halo, hydroxy, oxo, CrC 6 alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, d- C 6 alkyloxyCrC 6 alkyl, d-Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
  • said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein 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 4 to 10 carbon atoms and from 0 to 2 additional nitrogen atoms, the ring system optionally being substituted with at least one of CrCealkyl, aryl, hetaryl, aryld-Cealkyl, halo, hydroxy, oxo, CrC 6 alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, CrCealkyloxyCrCealkyl.
  • said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein R 8 and R 9 independently are hydrogen, halo, hydroxy, oxo, cyanoC 3 -C 10 cycloalkyl, G 3 -dohetocycloalkyl, d-Cealkyl, C C 6 alkyloxy, trihalomethyl, aryld- C 6 alkyloxy, hetarylCrCealkyloxy.
  • said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein R 10 is hydrogen, halo, cyano, nitro, hydroxy, oxo, C 3 -d 0 cyclo- alkyl, C 3 -C ⁇ 0 hetcycloalkyl, d-Cealkyl, CrC e alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-Cealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy.
  • said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein R 11 is d-Cealkyl, arylCrC 6 aIkyl, hetarylCrCealkyl, CrC 6 alkyloxy, aryloxy, CrC 6 alkyIoxy, wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 9 .
  • said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein R 12 is CrC 6 alkylcarbonylaminoCrC 6 alkyl, arylcarbonylaminod- C 6 alkyl or arylCrCealkylcarbonylaminoCrC ⁇ alkyl.
  • said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein R 13 and R 14 independently are hydrogen, C 3 -C ⁇ 0 cycloalkyl, Ci- Cealkyl, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl.
  • said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein R 15 is hydrogen, C 3 -C ⁇ 0 cycloalkyl, d-C 6 alkyl, aryl, hetaryl, aryld- Cealkyl, hetarylCrCealkyl, d-C 6 alkyloxyalkyl or aryld-C 6 alkyloxyaIkyl.
  • said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is selected from the group consisting of: (3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(2,6-dimethyl- piperidin-1 -yl-)methanone;
  • said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is selected from the group of
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II)
  • R 1 is C 3 -C ⁇ ocycloalkyl, C 3 -C 10 hetcycloalkyl, CrC 8 alkyl, aryl, hetaryl, aryld-C 6 alkyl or hetarylCrCealkyl, wherein the cycloalkyl, hetcycloalkyl, alkyl, arylalkyl and hetarylalkyl groups independently are optionally substituted with one or more of R 4 .
  • R 2 is hydrogen, d-C 8 alkyI, aryl, hetaryl, arylCrCealkyl, C 3 -C ⁇ ocycloalkylCrC 6 alkyl, d- 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 C C 8 alkyl, aryl, hetaryl, aryld- C 6 alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C 6 alkyloxy, aryld-Cealkyloxy, hetaryld- Cealkyloxy, CrCealkyloxyCrCealkyl, d-Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-Cealkylcarbox
  • R 3 is CrC 8 alkyl, d-C 6 alkenyl, C ⁇ -C 6 alkynyl, C 3 -C ⁇ 0 cycloalkyl, C 3 -C 10 hetcycloalkyl, aryl, hetaryl, arylCrC 6 alkyl, d-Cealkyloxyd-Cealkyl, hetarylCrCealkyl, aryl-R 6 -CrC 6 alkyI, hetaryl- R 6 -CrC 6 alkyl or arylCrCealkyl-R ⁇ CrCealkyl wherein the alkyl, cycloalkyl, hetcycloalkyl, alkenyl, 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 , CrC 8 alkyl, CrC 6 alkyloxy, trihalomethyl, trihalomethyloxy, C 3 -C ⁇ 0 cycloalkyl, C 3 -C ⁇ 0 hetcyclo- alkyl, C 3 -C ⁇ 0 cycloalkenyl, aryl, hetaryl, hetarylSO n , arylCrCealkyloxy, hetaryld-Cealkyloxy, CrC 6 alkyl-R 6 -C ⁇ -C 6 alkyl, arylCrC 6 alkyl-R 6 -CrC 6 alkyl, C r C 6 alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, hetarylcarbonyl, hetarylCrC
  • R° is oxygen, sulphur, SO n or NR 16.
  • R 7 is hydrogen, halo, hydroxy, cyano, nitro, COOR 17 , d-C 8 alkyl, C 3 -C ⁇ 0 cycloalkyl, C 3 -C ⁇ 0 het- cycloalkyl, methylendioxo, trihalomethyl, trihalomethyloxy, aryl, arylCrC 6 alkyl, CrCealkyloxy, CrCealkyloxyCrCealkyl, aryloxy, arylCrCealkyloxy, aryloxyd-Cealkyl, arylCrC 6 alkyloxyCr C 6 alkyl, hetaryl, hetarylCrCealkyl, hetaryloxy, hetarylCrCealkyloxy, hetaryloxyCrCealkyl, he-aryld-Ce
  • R 8 and R 9 independently are hydrogen, CrC 8 alkyl, aryl, hetaryl, aryld-C 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, CrC 8 alkyl, aryl, hetaryl, arylCrC 6 alkyl, hetaryld-Cealkyl, hydroxy, oxo, CrC 6 alkyloxy, aryld-Cealkyloxy, hetaryld- Cealkyloxy, CrC 6 alkyloxyC 1 -C 6 alkyl ) d-C 6 alkyl-carbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-C 6 alkyl
  • R 10 and R 11 independently are hydrogen, hydroxy, oxo, halo, cyano, nitro, CrC 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, 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, CrC 8 alkyl, C 3 -C ⁇ 0 cycloalkyl, C 3 -C ⁇ 0 hetcycloalkyl, aryl, arylCrC 6 alkyl, hetaryl, hetarylCrCealkyl, alkylcarbonyl, arylcarbonyl, arylCrC 6 alkylcarbonyl, aryloxyd- Cealkyl, hetaryloxyCrC 6 alkyl, arylthioCrCealkyl 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 ⁇ alkyl, aryl or arylCrCealkyl
  • R 18 is CrCealkyl, C 2 -C 6 alkenyl, aryl, arylCrC 6 alkyI, hetaryl, hetarylCrCealkyl, C 3 - Ciocycloalkyl, C 3 -C ⁇ 0 hetcycloalkyl, CrC 6 alkyloxy, aryloxy, arylCrCealkyloxy, aryld- CealkyIoxyC ⁇ -C 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 CrC 6 alkyl, C 3 -C 10 cycloalkyl, C 3 -C ⁇ 0 hetcycloalkyl, aryl, arylCrC 6 alkyl, hetaryl, hetaryld-Cealkyl;
  • n 1 or 2;
  • n 0, 1 or 2;
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein: R 1 is C 3 -Ci 0 cycloalkyl, C 3 -C ⁇ 0 hetcycloalkyl, d-C 8 alkyl, aryl, hetaryl, aryld-C 6 alkyl or hetaryld-Cealkyl, 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 C 8 alkyl, aryl, hetaryl, arylCrC 6 alkyl, C 3 -C ⁇ 0 cycloalkylCrC 6 alkyI, C C 6 - alkylcarboxyCrC 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 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, aryld- C 6 alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC 6 alkyloxy, aryld-C 6 alkyloxy, hetaryld- Cealkyloxy, CrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, aryl
  • R 3 is CrC 8 alkyl, CrC 6 alkenyl, CrC 6 alkynyl, C 3 -C ⁇ 0 cycloalkyl, C 3 -C ⁇ 0 hetcycloalkyl, aryl, hetaryl, arylCrC 6 alkyl, CrCealkyloxyCrCealkyl, hetarylCrCealkyl, aryl-R 6 -CrC 6 alkyl, hetaryl- R 6 -CrC 6 alkyl or arylC ⁇ -C6alkyl-R 6 -CrC 6 alkyl wherein the alkyl, cycloalkyl, hetcycloalkyl, alkenyl, 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 , CrC 8 alkyl, CrC 6 alkyloxy, trihalomethyl, trihalomethyloxy, C 3 -C ⁇ 0 cycloalkyl, C 3 -
  • Ciohetcycloalkyl C 3 -C ⁇ 0 cycloalkenyl, aryl, hetaryl, hetarylSO n , arylCrC 6 alkyloxy, he-aryld- C 6 alkyloxy, CrC 6 alkyl-R 6 -CrCealkyl, arylC ⁇ -C 6 alkyl-R 6 -CrC 6 alkyl, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, hetarylcarbonyl, hetarylCrC 6 alkyl-carbonyl, C ⁇ -C 6 alkylSO n , CrC 6 alkyl-carboxy, arylcarboxy, hetarylcarboxy, arylCrC 6 alkylcarboxy or hetarylCrC 6 alkyl- carboxy wherein the alkyl, cycloalkyl,
  • R 8 is oxygen, sulphur, SO n , NR 16 ;
  • R 7 is hydrogen, halo, hydroxyl, cyano, nitro, COOR 17 , CrC 8 alkyl, C 3 -C ⁇ 0 cycloalkyl, C 3 -C ⁇ 0 het- cycloalkyl, methylendioxo, trihalomethyl, trihalomethyl, trihalomethyloxy, aryl, arylCrCealkyl, CrC 6 alkyloxy, CrCealkyloxyCrCealkyl, aryloxy, aryloxyCrC 6 alkyl, arylCrCealkyloxyCrCealkyl, hetaryl, hetarylCrCealkyl, hetaryloxy, hetarylCrCealkyloxy, hetaryloxyCrCealkyl, hetarylCrCealkyloxyCrCealkyl, NR 8 R 9 , S0 2 NR 8 R 9
  • C 6 alkyIR 6 CrC 6 alkyl wherein the aryl and hetaryl groups independently are optionally substituted with one or more R 10 ;
  • R 8 and R 9 independently are hydrogen, CrC 8 alkyl, aryl, hetaryl, arylCrCealkyl 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, arylCrCealkyl, hetarylCrC 6 alkyl, hydroxy, oxo, CrC 6 alkyloxy, aryld-Cealkyloxy, hetarylCrCealkyloxy, d- CealkyloxyCrCealkyl, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrC 6 alkylcarbonyl, CrC 6 alkylcarboxy, arylcarboxy,
  • R 10 and R 11 independently are hydrogen, hydroxy, oxo, halo, cyano, nitro, d-Cealkyl, d-C 6 - alkyloxy, NR 12 R 13 , methylendioxo, trihalomethyl or trihalomethyloxy;
  • R 12 and R 13 independently are hydrogen, C ⁇ -C 8 alkyl or arylCrC 6 alkyl
  • R 14 is hydrogen, halo, hydroxy, oxo, nitro, cyano, C C 8 alkyl, CrC 6 alkyloxy or aryloxy;
  • R 15 is hydrogen, halo, hydroxy, oxo, nitro, cyano or COOR 17 ;
  • R 16 is hydrogen, CrC 8 alkyl, C 3 -C ⁇ 0 cycloalkyl, C 3 -C ⁇ 0 hetcycloalkyl, aryl, arylCrC 6 alkyl, hetaryl, hetarylCrCealkyl, alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, aryloxyd- C 6 alkyl, hetaryloxyCrCealkyl, 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, CrC 8 alkyI, aryl or aryld-C 6 alkyl
  • n 1 or 2;
  • n 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.
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R 1 is C 3 -C ⁇ 0 cycloalkyl or C 3 -C ⁇ ohetcycloalkyl wherein the cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 4 as defined above.
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R 1 is C 3 -C ⁇ 0 cycloalkyl optionally substituted with one or more of R 4 as defined above.
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R 2 is hydrogen or d-C 8 alkyl, wherein the the alkyl group is optionally substituted with one or more of R 5 as defined above.
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R 2 is d-G 8 alkyl optionally substituted with one or more of R 5 as defined above.
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is o the general formula (II) wherein R 3 is C 3 -C 10 cycloalkyl, C 3 -C ⁇ 0 hetcycloalkyl, aryl, hetaryl, arylC C 6 alkyl, hetaryld- Cealkyl, aryl-R 6 -CrC 6 alkyl, hetaryI-R 6 -CrC 6 alkyl or arylCrC 6 alkyl-R 6 -CrC 6 alkyl wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 7 .
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) 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.
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R 3 is is phenyl optionally substituted with one or more of R 7 as defined above.
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) 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.
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R 4 and R 5 independently are hydrogen, hydroxy, oxo, halo, CrC 8 alkyl, wherein the alkyl group is optionally substituted with one ore more of R 15 .
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R 6 is oxygen.
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R 7 is hydrogen, halo, hydroxy, cyano, d-C 8 alkyI, C 3 -C 10 cycloalkyl, C 3 -C 10 het- cycloalkyl, trihalomethyl, aryl, arylCrC 6 alkyl, CrC 6 alkyloxy, CrCealkyloxyCrCealkyl, aryloxy, arylCrCealkyloxy, aryloxyCrC 6 alkyl, arylCrCealkyloxyCrCealkyl, hetaryl, hetaryld-Cealkyl, hetaryloxy, hetarylCrCealkyloxy, hetaryloxyCrCealkyl, hetaryld-Cealkyl-oxy, hetaryl
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) 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 car- bon 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, aryld-Cealkyl, hetarylCrCealkyl, hydroxy, oxo, CrC 6 alkyloxy, arylCrC 6 alkyloxy, hetarylCrCealkyloxy, CrCealkyloxyd-Cealkyl, CrC 6 alkyl-carbonyl, arylcarbonyl, hetarylcarbonyl,
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R 15 is CONR 8 R 9 .
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R 18 is d-C 6 alkyl optionally substituted with R 15 .
  • said substituted amide, or a prodrug thereof, as a component of the combination therapy 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,f]azepin-5-yl)-1-[4-(3H-imidazol-4-yl)-piperidin-1-yl]-butan-1-one;
  • 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;
  • 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;
  • Acetic acid 4-(3,5-dimethyl-piperidine-1-carbonyl)-phenyl ester; (4-Chloro-3-nitro-phenyl)-(2,6-dimethyl-piperidin-1-yl)-methanone;
  • Furan-2-carboxylic acid [4-(4-methyl-piperidine-1 -sulfonyl)-phenyl]-amide;
  • Cyclohexanecarboxylic acid (2-phenylsulfanyl-phenyl)-amide; (4-Hydroxy-4-phenyl-octahydro-quinolin-1-yl)-phenyl-methanone;
  • N-Benzyl-4-bromo-N-ethyl-benzamide (3-Methyl-piperidin-1 -yl)-[4-(naphthalen-1 -yloxymethyl)-phenyl]-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;
  • Benzo[b]thiophene-3-carboxylic acid (3,3,5-trimethyl-cyclohexyl)-amide; 2-(2,6-Dimethyl-phenoxy)-N-(2-isopropyl-phenyl)-acetamide;
  • 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;

Abstract

Combination therapy comprising the administration of an 11β-hydroxysteroid dehydrogenase type 1 inhibitor and a glucocorticoid receptor agonist for treating some forms of cancer, diseases and disorders having inflammation as a component, and to minimize the side effects associated with glucorticoid receptor agonist therapy.

Description

TITLE
Combination Therapy Using an 11 ?-Hydroxysteroid Dehydrogenase Type 1 Inhibitor and a Glucocorticoid Receptor Agonist to Minimize the Side Effects Associated With Glucocorticoid Receptor Agonist Therapy
FIELD OF THE INVENTION
The instant invention involves a combination therapy comprising the administration of an 11 ?-hydroxysteroid dehydrogenase type 1 inhibitor and a glucocorticoid receptor agonist for treating some forms of cancer, diseases and disorders having inflammation as a component, and to minimize the side effects associated with glucorticoid receptor agonist therapy.
BACKGROUND OF THE INVENTION
Glucocorticoid receptor agonists are widely used as anti-inflammatory and disease- modifying treatment in a broad spectrum of diseases with an inflammatory component. Glucocorticoid receptor agonists are also used as a component of some forms of cancer chemotherapy. However, the use of glucocorticoid receptor agonists is often limited by severe side effects caused by glucocorticoid receptor agonism in organs and tissues that are not targets for treatment. These side effects include osteoporosis, decreased linear growth (children), aseptic bone necrosis, cushingoid fat distribution, mental changes, insulin resistance, hypertension, myopathy, cataract and glaucoma (Harrison's Principles of Internal Medicine, 14th edition, Eds. Fauci et al., McGraw-Hill, New York, USA).
Like the endogenous active glucocorticoids (e.g. cortisol in humans, corticosterone in rodents), glucocorticoid receptor agonists bind to and stimulate ubiquitously expressed in- tracellular glucocorticoid receptors. Hence, the degree of receptor agonism depends on the intracellular concentration of ligand (reviewed e.g. in Yudt & Cidlowski, Mol Endocrinol; 16, 1719 (2002)).
11 ?-hydroxysteroid dehydrogenase type 1 (11 ?-HSD1) is an intracellular enzyme that physiologically catalyses the conversion of biologically inactive endogenous glucocorti- coid (e.g. cortisone in man, 11-dehydrocorticosterone in rodents) to active glucocorticoid (e.g. cortisol in man, corticosterone in rodents). 11 ?-HSD1 is expressed in several tissues and organs including the liver, adipose tissue, skeletal muscle, bone, pancreas, endothelium, ocular tissue and certain parts of the central nervous system. Thus, 11/?-HSD1 serves to increase the local levels of active endogenous glucocorticoid in many of the tissues and or- gans that are the origin of the side effects (but not the beneficial effects) of treatment with glucocorticoid receptor agonists(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)).
During the course of a treatment with a glucocorticoid receptor agonist, the degree of stimulation of the glucocorticoid receptor will reflect the sum of contributions from the active endogenous glucocorticoid generated locally by 11 7-HSD1, the active endogenous glucocorticoid derived from plasma and the exogenous glucocoid receptor agonist. Consequently, inhibition of 11 ?-HSD1 decreases the total stimulation of the glucocorticoid receptor. Due to the expression pattern of 11 ?-HSD1 , levels of active glucocorticoid are decreased in the tissues and organs that are negatively affected by therapy with glucocorticoid receptor agonists while the desired therapeutic effects remain intact.
The impact of the effect of decreased 11 ?-HSD1 activity is highlighted by the 1 β- HSD1 knockout mouse that has increased plasma levels of endogenous active glucocorticoid, but inspite of this remains protected from insulin resistance, presents with an anti- atherogenic plasma lipid profile and benefits from decreased age-related cognitive impairment (Morton et al., J. Biol. Chem. 276, 41293; Kotelevtsev et al., Proc. Natl. Acad. Sci. USA, 94. 14924 (1997); Yau et al., Proc. Natl. Acad. Sci. USA, 98, 4716 (2001). In addition, a clinical case report demonstrates that a partial defect in/reduced activity of 11 ?-HSD1 abolishes the obesity and hypertension normally associated with Cushing's disease, i.e. increased pituitary ACTH secretion resulting in increased synthesis of cortisol in the adrenal glands (Tomlinson et al., J. Clin. Endocrinol. Metab., 87, 57 (2002).
The instant invention addresses the clinical problems related to side effects of treatment with glucocorticoid receptor agonists by providing a combination therapy comprised of an 11 ?-HSD1 inhibitor and a glucocorticoid receptor agonist. When administered as a part of a combination therapy, the 11 ?-HSD1 inhibitor together with the glucocorticoid receptor agonist allow for control of the disease while minimizing the side effects. Due to the drug combination, and hence the decreased severity of side effects, dosage of the glucocorticoid receptor agonist can be optimized to meet the required therapeutic effect, providing improved means of achieving the desired clinical result.
Examples of inhibitors and/or modulators of the human 11 ?-hydroxysteroid dehydrogenase type 1 enzyme can be found in WO 01/90090, WO 01/90091 , WO 01/90092, WO 01/90093, WO 01/90094, WO 02/72084 and WO 02/076435, as well as the following patent applications under common ownership of the present application: PA 2003 00569 filed 11 April 2003 DK, PA 2003 00565 filed 11 April 2003 DK, PA 2003 00571 filed 11 April 2003 DK, PA 200300570 filed 11 April 2003 DK, PA 2003 00566 filed 11 April 2003 DK, PA 200300972 filed 27 June 2003 DK, PA 2003 00998 filed 02 July 2003 DK, PA 2003 00988 filed 30 June 2003 DK, PA 200300989 filed 30 June 2003 DK, PA 2003 00990 filed 30 June 2003 DK, and PA 200301910 filed 22 December 2003 DK, the contents of which are hereby incorporated by reference in their entirety.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a novel combination therapy com- prised of a therapeutically effective amount of a glucocorticoid receptor agonist in combination with an 11jff-hydroxysteroid dehydrogenase type 1 (11 jff-HSDI) inhibitor for the reduction of undesirable side effects occurring during glucocorticoid receptor agonist therapy, and for treating some forms of cancer, diseases and disorders having inflammation as a component.
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, tr ibromomelhyl, and triiodomethyl.
The term "trihalomethoxy" includes trifluorometoxy, trichlorometoxy, tribromometoxy, and triiodometoxy.
The term "alkyl" includes Cι-C6 straight chain saturated and methylene aliphatic hydrocarbon groups, C3-C6 branched saturated hydrocarbon groups having the specified num- ber 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), tert-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, hexenyi, methylpropenyl, methylbutenyl and the like.
The term "alkynyl" includes C2-C6 straight chain unsaturated aliphatic hydrocarbon groups and C4-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, pyrrolinyl, pyrrolidinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, morpholinyl, piperidinyl, thiomorpholinyl, piperazinyl, phthalimide, 1,2,3,4- tetrahydro-quinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, 1,2,3,4-tetrahydro-quinoxalinyl, and indolinyl.
The term "saturated or partially saturated cyclic ring system" represents but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cydoheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, tetrahydrofuranyl or tetrahydropyranyl. 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]octyI, 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 "hetcycloalkyl" (tetrahydrofuranyl, tetrahydropyranyl, tertahydrothiopyranyl, 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 "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) represents an arylalkyl group as defined below attached through an oxygen bridge.
The term "hetarylalkyloxy" (e.g. 2-pyridylmethyloxy and the like) represents a hetarylalkyl 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 "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
The term "hetarylalkyl" (e.g. (2-furyl)methyl, (3-furyl)methyl, (2-thienyl)methyl, (3- thienyl)methyl, (2-pyridyl)methyl, 1 -methyl-1 -(2-pyrimidyI)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 attached 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 an hetarylalkyl group as defined above wherein the alkyl group is in turn attached through a carbonyl.
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 fe/t-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, phenylpropylcarboxypro- pyl 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 indicated 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 hetarylalkyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
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-ethylsulfanyI-isoquinoline 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 "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 "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 sys- terns enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1 ,2,3,4-tetrahydronaphthyl, 1 ,4-dihydronaphthyl and the like.
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-yI), 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-isoquinoIyl, 7-isoquinolyl, 8-isoquinolyl), ben- zo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyI, 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)), ben- zo[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]thio- phenyl (2-(2,3-dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3- dihydro-benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2, 3-di hyd ro-benzo[b]thio- phenyl), 7-(2,3-dihydro-benzo[b]thiophenyI)), 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)), 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-benz- imidazolyl), benzoxazolyl (1-benz-oxazolyl, 2-benzoxazolyl), benzothiazolyl (1 -benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothia∑olyl, 7-benzo- thiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), piperidinyl (2- piperidinyl, 3-piperidinyl, 4-piperidinyl), pyrrolidinyl (1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrro- lidinyl).
With respect to Formula II, the term "NR4R5carbonylalkyl" (e.g. V, V-dimethyl- propionamide, /V-isopropyl-N-methyl-propionamide and the like) represents NR4R5 substi- tuted by a carbonylalkyl group as defined above, wherein R4 and R5 are as defined for Formula II herein.
With respect to Formula 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, wherein R6 is as defined for Formula II herein.
With respect to Formula II, the term "arylR6alkyl" (e.g. ethoxy-benzene, ethyl-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, wherein R6 is as defined for Formula II herein. With respect to Formula II, the term "arylalkylR6alkyl" (e.g. benzyloxymethyl, ethyl- methyl-benzyl-amine, Λ/-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, wherein R6is as defined for Formula II herein. With respect to Formula II, the term "hetarylR6alkyl" (e.g. 2-ethoxy-1 /-/-imidazol, ethyI-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, wherein R6 is as defined for Formula II herein. With respect to Formula II, the term "arylcarbonylNR15" (e.g. Λ/-benzyl-Λ/-methyl- benzamide and the like) represents an arylcarbonyl group as defined above, substituted by NR15, wherein R15is as defined for Formula II herein.
With respect to Formula II, the term "alkylSOn" (e.g. ethylsulfonyl, ethylsulfinyl and the like) represents an alkyl group as defined above, wherein the alkyl group is in turn at- tached through a sulphur bridge wherein the sulphur is substituted with n oxygen atoms, wherein n is as defined for Formula II herein.
With respect to Formula II, 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, wherein m is as defined for Formula II herein.
With respect to Formula II, the term "hetarylSOm" (e.g. thiazol-2-sulfinyl, pyridine-2- sulfonyl and the like) represents 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, wherein is as defined for Formula II herein. With respect to Formula II, the term "arylSOmNR8" (e.g. /V-methyl- benzenesulfonamide 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, wherein R8 and m are as defined for Formula II herein. With respect to Formula V, the term "NR4R5carbonylalkyl" (e.g. Λ/,Λ-dimethyl- propionamide, Λ/-isopropyl-Λ/-methyl-propionamide and the like) represents NR R5 substituted by a carbonylalkyl group as defined above, wherein R4and R5 are as defined for Formula V herein.
With respect to Formula V, the term "arylR8alkyl" (e.g. ethoxy-benzene, N-ethyl-N- methyl-phenyl-amine, Λ/-ethyl-benzamide, /V-isobutyl-benzenesutfonamide and the like) represents an aryl group as defined above, substituted by R8, which is substituted by an alkyl group as defined above, wherein R8 is as defined for Formula V herein.
With respect to Formula V, the term "hetaryl R8alkyl" (e.g. 2-ethoxy-1H-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 R8, which is substituted by an alkyl group as defined above, wherein R8 is as defined for Formula V herein.
With respect to Formula V, the term "arylcarbonylNR15" (e.g. Λ/-benzyl-Λ/-methyl- benzamide and the like) represents an arylcarbonyl group as defined above, substituted by NR15, wherein R15 is as defined for Formula V herein.
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.
The term "combination therapy" is defined as the administration of a single pharmaceutical dosage formulation which comprises the 11 ?-HSD1 inhibitor and the glucocorticoid receptor agonist, as well as administration of each active agent in its own separate pharma- ceutical dosage formulation. Where separate dosage formulations are used, the 11 7-HSD1 inhibitor and the glucocorticoid receptor agonist can be administered to the patient at essentially the same time, i.e. concurrently, or at separate staggered times, i.e. sequentially. When given by different dosage formulations, the route of administration may be the same or different for each agent. Any route of administration known or contemplated for the individual agents is acceptable for the practice of the present invention. The term "therapeutically effective amount" is defined as the amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system or a mammal that is sought by the treating individual, i.e. medical doctor or other clinician.
As used herein, the various forms of the term "modulation" are intended to include stimulation (e.g., increasing or upregulating a particular response or activity) and inhibition (e.g., decreasing or downregulating a particular response or activity).
As used herein, the term "agonist" is intended to indicate a substance that activates the receptor(s).
As used herein, the term "glucocorticoid receptor agonist" is intended to indicate a substance that activates glucocorticoid receptor(s) without dependence on prior modification of the substance by 11 β HSD1.
DETAILED DECSRIPTION OF THE INVENTION
Synthetic schemes for general formula (I) through general formula (V) compounds described herein, as well as examples, are found in the following patent applications under common ownership of the present application: PA 2003 00569 filed 11 April 2003 DK, PA 2003 00565 filed 11 April 2003 DK, PA 2003 00571 filed 11 April 2003 DK, PA 2003 00570 filed 11 April 2003 DK, PA 2003 00566 filed 11 April 2003 DK, PA 2003 00972 filed 27 June 2003 DK, PA 2003 00998 filed 02 July 2003 DK, PA 2003 00988 filed 30 June 2003 DK, PA 2003 00989 filed 30 June 2003 DK, PA 2003 00990 filed 30 June 2003 DK, and PA 2003 01910 filed 22 December 2003 DK, the contents of which are hereby incorporated by reference in their entirety.
In one embodiment of the present invention said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I)
Figure imgf000013_0001
Formula (I)
wherein
R1 and R2 independently are hydrogen, halo, C(=0)NR6R7, C02R15, NR6C(=0)R1\ OR12 or R3and R5 independently are hydrogen, NR13R14 trihalomethyl, trihalomethoxy, CrC6alkyl, C2- C6alkenyl, C2-C6alkynyl, CrC6alkyloxy, CrC6alkylthio, aryl, arylCrC6alkyl, hetaryl or hetarylCrC6alkyl, wherein alkyl, alkynyl, alkenyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R8;
R4 is hydrogen, cyano, halo, C02R15, C(=0)NR6R7, d-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrC6alkyl, hydroxy, CrC6alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, or CrCealkyloxyCrCealkyl, wherein the alkyl, alkynyl, alkenyl, cycloal- kyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R9;
R6 and R7 independently are Cι-Cβalkyl, C3-C10cycloalkyl, hetC3-Cι0cycloalkyl, arylCrC6alkyl or hetarylC C6alkyl, wherein the alkyl, cycloalkyl, hetcycloalkyl, arylalkyl, and hetarylalkyl groups independently are optionally substituted with one or more of R10; 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 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 CrC6alkyl, aryl, hetaryl, arylC C6alkyl, halo, hydroxy, oxo, C C6alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, d- C6alkyloxyCrC6alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrC6alkylcarboxy, arylcarboxy, hetarylcarboxy, arylC C6alkylcarboxy or hetarylCrC6alkylcarboxy;
R8 and R9 independently are hydrogen, halo, hydroxy, oxo, cyano, nitro, C3-C10cycloalkyl, C3- C10hetocycloalkyl, d-Cealkyl, d-Cealkyloxy, trihalomethyl, trihalomethoxy, aryld-Cealkyloxy, hetarylC C6alkyloxy, d-Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-C6alkylcarboxy, arylcarboxy, hetarylcarboxy, aryld-Ce- alkylcarboxy, hetarylCrC6alkylcarboxy, CrC6alkylcarbonylamino or arylCrC6alkylcarbonyl- amino;
R10 is hydrogen, halo, cyano, nitro, hydroxy, oxo, C3-C10cycloalkyl, C3-C10hetcycloalkyl, Ci- Cealkyl, CrC6aIkyloxy, trihalomethyl, trihalometh dialkylamino oxy, aryld-Cealkyloxy, hetarylCrCealkyloxy, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrC6alkylcarboxy, arylcarboxy or arylCrC6alkylcarboxy;
R11 is d-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, aryld-Cealkyl, hetarylCrCealkyl, d-C6alkyl- carbonylCrC6alkyl, CrC6alkyloxy, aryloxy, CrC6alkyloxy, arylcarbonyl, arylCrCealkylcarbonyl, hetarylcarbonylCrC6alkyl, wherein the alkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R9;
R 2 is CrC6alkylcarbonyIaminoCrC6alkyl, arylcarbonylaminoCrC6alkyl or arylCrC6alkyl- carbonylaminoCrC6alkyl;
R13and R14 independently are hydrogen, oxo, C3-C10cycloalkyl, CrC6alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkylcarbonyl, hetarylCrCealkylcarbonyl;
R15 is hydrogen, C3-C10cycloalkyl, CrC6alkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrCealkyl, CrC6alkyloxyalkyl or arylGrC6alkyloxyalkyl; 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 said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein R1 and R2 independently are hydrogen, halo, C(=0)NR6R7, NC(=0)R11, OR12 or SR12;
R3and R5 independently are hydrogen, NR13R14 trihalomethyl, trihalomethoxy, d-Cealkyl, C2- C6alkenyl, C2-C6alkynyl, CrC6alkyloxy, CrC6alkylthio, aryl, arylCrC6alkyl, hetaryl or hetarylCrCealkyl, wherein alkyl, alkynyl, alkenyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R8;
R4 is hydrogen, cyano, halo, C02R15, C(=0)NR6R7, d-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, aryl, hetaryl, arylCrC6alkyl, hetaryld-Cealkyl, hydroxy, CrC6alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, or CrCealkyloxyCrCealkyl, wherein the alkyl, alkynyl, alkenyl, cycloalkyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R9; R6 and R7 independently are Cι-Cβalkyl, C3-C10cycloalkyl, hetC3-C10cycloalkyl, arylCrCealkyl or hetarylCrCealkyl, wherein the alkyl, cycloalkyl, hetcycloalkyl, arylalkyl, and hetarylalkyl groups independently are optionally substituted with one or more of R10; 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 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 CrCβalkyl, aryl, hetaryl, aryld- C6alkyl, halo, hydroxy, oxo, CrC6alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, d-C6- alkyloxyd-C6alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrC6alkylcarboxy, arylcarboxy, hetarylcarboxy, arylCrCealkylcarboxy or hetaryld-C6alkylcarboxy;
R8 and R9 independently are hydrogen, halo, hydroxy, oxo, cyano, nitro, C3-d -cycloalkyl, C3- dohetocycloalkyl, d-C6alkyl, CrC6alkyloxy, trihalomethyl, trihalomethoxy, arylCrCealkyloxy, hetarylCrCealkyloxy, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrC6aIkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetarylcarboxy, aryld- C6alkylcarboxy, hetarylCrC6alkylcarboxy, d-Cealkylcarbonylamino or arylCrC6alkyl- carbonylamino;
R10 is hydrogen, halo, cyano, nitro, hydroxy, oxo, C3-C10cycloalkyl, C3-C10hetcycloalkyl, Ci- Cealkyl, CrC6alkyloxy, trihalomethyl, trihalometh dialkylamino oxy, arylCrCealkyloxy, hetarylCrCealkyloxy, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylC C6alkylcarbonyl, hetarylCrC6alkylcarbonyl, CrC6alkylcarboxy, arylcarboxy or aryld- C6alkylcarboxy;
R11 is Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, arylCrC6alkyl, hetaryld-Cealkyl, C C6alkyl- carbonylCrC6alkyl, d-C6alkyl, arylcarbonyl, arylCrCealkylcarbonyl, hetarylcarbonylCrC6- alkyl, wherein the alkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R9;
R12 is CrC6alkylcarbonylaminoCrC6alkyl, arylcarbonylaminoCrC6alkyl or arylCrC6alkyl- carbonylaminoCrC6alkyl; R13 and R14 independently are hydrogen, oxo, C3-C10cycloalkyl, CrC6alkyl, CrC6alkyloxy, trihalomethyl, trihalomethoxy, arylCrCealkyloxy, hetaryld-Cealkyloxy, d-C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetarylcarboxy, arylCrCealkylcarboxy;
R15 is hydrogen, C3-Cι0cycloalkyl, CrCealkyl, aryl, hetaryl, arylCrCealkyl, hetarylCrC6alkyl, CrC6alkyloxyalkyl or arylCrC6alkyloxyalkyl; 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 said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein R1 and R2 independently are hydrogen and/or C(=0)NR6R7. In another embodiment of the present invention said substituted pyrazoIo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein R3and R5 independently are hydrogen, trihalomethyl, CrC6alkyl, CrC6alkyloxy, aryl, arylCrC6alkyl, hetaryl or hetaryld-Cealkyl, wherein alkyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R8. In another embodiment of the present invention said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein R4 is hydrogen, cyano, halo, C(=0)NR6R7, d-Cealkyl, aryl, hetaryl, arylCrC6alkyl, hetaryld-Cealkyl, hydroxy, d-Cealkyloxy, arylCrC6alkyloxy, hetarylCrC6alkyloxy, wherein the alkyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups inde- pendently are optionally substituted with one or more of R9.
In another embodiment of the present invention said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein R6 and R7 independently are CrC6alkyl, C3-Cι0cycloalkyl, hetC3- Ciocycloalkyl, arylCrC6alkyl or hetarylCrCealkyl, wherein the alkyl, cycloalkyl, hetcycloalkyl, arylalkyl, and hetarylalkyl groups independently are optionally substituted with one or more of R10.
In another embodiment of the present invention said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) R6 and R7 together with the nitrogen to which they are attached, are form- ing 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 Cι-Cβalkyl, aryl, hetaryl, arylCrC6alkyl, halo, hydroxy, oxo, CrC6alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, d- C6alkyloxyCrC6alkyl, d-Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkyl- carbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetarylcarboxy, aryld- C6alkylcarboxy or hetarylCrC6alkylcarboxy.
In another embodiment of the present invention said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein 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 4 to 10 carbon atoms and from 0 to 2 additional nitrogen atoms, the ring system optionally being substituted with at least one of CrCealkyl, aryl, hetaryl, aryld-Cealkyl, halo, hydroxy, oxo, CrC6alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, CrCealkyloxyCrCealkyl. In another embodiment of the present invention said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein R8 and R9 independently are hydrogen, halo, hydroxy, oxo, cyanoC3-C10cycloalkyl, G3-dohetocycloalkyl, d-Cealkyl, C C6alkyloxy, trihalomethyl, aryld- C6alkyloxy, hetarylCrCealkyloxy.
In another embodiment of the present invention said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein R10 is hydrogen, halo, cyano, nitro, hydroxy, oxo, C3-d0cyclo- alkyl, C3-Cι0hetcycloalkyl, d-Cealkyl, CrCealkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-Cealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy. In another embodiment of the present invention said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein R11 is d-Cealkyl, arylCrC6aIkyl, hetarylCrCealkyl, CrC6alkyloxy, aryloxy, CrC6alkyIoxy, wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R9. In another embodiment of the present invention said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein R12 is CrC6alkylcarbonylaminoCrC6alkyl, arylcarbonylaminod- C6alkyl or arylCrCealkylcarbonylaminoCrCβalkyl.
In another embodiment of the present invention said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein R13and R14 independently are hydrogen, C3-Cι0cycloalkyl, Ci- Cealkyl, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl.
In another embodiment of the present invention said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein R15 is hydrogen, C3-Cι0cycloalkyl, d-C6alkyl, aryl, hetaryl, aryld- Cealkyl, hetarylCrCealkyl, d-C6alkyloxyalkyl or aryld-C6alkyloxyaIkyl.
In another embodiment of the present invention said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is selected from the group consisting of: (3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(2,6-dimethyl- piperidin-1 -yl-)methanone;
(3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yI)-(2-ethyl-piperidin-1- yl-)methanone; (5-Thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(1 ,3,3-trimethyl-6-aza- bicyclo[3.2.1]oct-6-yl)methanone;
(3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(2-methyl-piperidin-
1-yl-)methanone;
5-Methyl-7-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexylamide;
Azepan-1 -yl-(3-chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
Azepan-1 -yl-(3-chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone;
(2,6-Dimethyl-piperidin-1-yl-)-(3-chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5- ajpyrimidin-3-yl)methanone; 3-Bromo-5-furan-2-yl-7-trifluoromethyl-pyrazoIo[1 ,5-a]pyrimidin-2-carboxylic acid cyclohexylamide;
(7-Methyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(4-methyl-piperidin-1-yl)methanone; 5-(-4-Methoxy-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid benzyl- methyl amide; [5-(-4-Ethoxy-phenyl-7-methyl-pyrazolo[1 ,5-a]pyrimidine-2-yl])-piperidin-1 -yl-methanone;
Azepan-1-yl-(3-bromo-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)methanone; 5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid cyclohexyl-methyl amide; (3,4-Dihydro-1H-isoquinolin-2-yl)-[5-(-4-Methoxy-phenyl-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-3-yl]methanone; Azepan-1-yl-[5-(4-bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)methanone
Azepan-1 -yl-(5,7-diphenyl)-pyrazolo[1,5-a]pyrimidin-3-yl)methanone;
[5-(4-bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-ylj-(2-methyl-piperidin-1-yl)- methanone; (5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(2-methyl-piperidin-1 -yl)- methanone;
(2,6-Dimethyl-piperidin-1-yl-)-[7-(4-ethoxy-phenyl)-5-methyl-pyrazolo[1,5-a]pyrimidin-2-ylj methanone;
5-(4-Ethoxy-phenyl)-7-methyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl amide; Piperidin-1 -yl-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)methanone;
(5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-ajpyrimidin-3-yl)-(2-methyl-piperidin-1-yl)- methanone;
(2-Methyl-piperidin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone; Azepan-1 -yl-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-ylj- methanone;
5-Thiophen-2-yl -7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid benzyl-methyl- amide;
5-p-Tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid (1 , 3-di methyl- 1H- pyrazol-4-ylmethyl)-methyl amide;
5-Methyl-7-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl amide;
7-Methyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl amide;
(5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1-yl-methanone;
5-Naphthalen-1-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl- methyl amide;
5-Naphthalen-1-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl amide;
(5-Naphthalen-1-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone
(2-Methyl-piperidin-1-yl)-(5-naphthalen-1-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl amide;
5,7-Diphenyl-pyrazoIo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl amide;
(5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(2-methyl-piperidin-1-yl)methanone;
(5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone; 5-Methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl amide; (5-Methyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone; 5-Methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl- amide;
(2-Methyl-piperidin-1-yl)-(5-methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl amide; (5-Phenyl-7-trifluoromethyI-pyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl-methanone; 7-Phenyl-5-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl- amide; 5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid cyclohexyl amide; (5-PhenyI-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-piperidin-1 -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 said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is selected from the group of
5-Methyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester; 5-MethyI-7-phenyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester; 7-Methyl-5-phenyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester; (5-methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- (piperidin-1 -yl)methanone;
(5-methyl-7-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl amide; 7-Methyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl-amide; 7-Phenyl-5-trifluoromethyl-pyrazolo[1 ,5~a]pyrimidine-2-carboxylic acid cyclohexyl-methyl- amide; (5-Phenyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone; (2-Methyl-piperidin-1-yl)-(5-methyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)- methanone;
5-Methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl- amide; (5-Methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yI)-piperidin-1 -yl-methanone; (5,7-Diphenyl-pyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl-methanone; (5,7-Diphenyl-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-piperidin-1-yl)-methanone; 5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl-amide; (2-Methyl-piperidin-1-yl)-(5-naphthalen-1-yl-7-trifluoromethyl-pyrazolo[1,5-aJpyrimidin-2-yl)- methanone; (5-Naphthalen-1-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl-methanone;
5-Naphthalen-1-yI-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl- methyl-amide;
[7-(4-Ethoxy-phenyl)-5-methyl-pyrazolo[1 ,5-aJpyrimidin-2-yl]-(1,3,3-trimethyl-6-aza- bicydo[3.2.1 ]oct-6-yl)-methanone;
(2-Methyl-piperidin-1-yl)-(7-phenyl-5-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)- methanone;
(5-MethyI-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-(1,3,3-trimethyl-6-aza- bicyclo[3.2.1 ]oct-6-yl)-methanone; (5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(1 ,3,3-trimethyl-6-aza- bicyclo[3.2.1 ]oct-6-yl)-methanone;
(6-Bromo-3-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-morpholin-4-yl-methanone;
(5-Phenyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone;
Morpholin-4-yl-(5-phenyI-7-trifluoromethyI-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone; (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone;
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-morpholin-4-yl-methanone;
(3,6-Dibromo-pyrazolo[1,5-a]pyrimidin-2-yl)-morpholin-4-yl-methanone;
(3-Bromo-5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone;
(3-Bromo-5-phenyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-morpholin-4-yl- methanone;
(3-ChIoro-5-phenyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone;
(3-Chloro-5-phenyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-morpholin-4-yl- methanone;
(3,6-Dibromo-pyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone; [4-(4-Fluoro-phenyl)-piperazin-1 -yl]-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-2-yl)-methanone;
5-Thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl- methyl-amide;
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-methyl-piperazin- 1-yl)-methanone;
[5-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl]-(2-methyl-piperidin-1- yl)-methanone;
3-Chloro-5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl-(2-pyridin-2-yl-ethyl)-amide; [3-Chloro-5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-morpholin-4-yl- methanone;
(3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(3,4-dihydro-2/- - quinolin-1 -yl)-methanone; [5-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl]-[4-(2-methoxy- phenyl)-piperazin-1 -ylj-methanone;
(4-Benzoyl-piperazin-1-yl)-[3-chloro-5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-2-yl]-methanone;
4-(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazoIo[1 ,5-a]pyrimidine-2-carbonyl)-piperazine- 1 -carboxylic acid ethyl ester;
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(6,7-dimethoxy-1 - methyl-3,4-dihydro-1 H-isoquinolin-2-yl)-methanone;
[4-(Furan-2-carbonyl)-piperazin-1-yl]-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-2-yl]-methanone; (3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-[4-(2-methoxy- phenyl)-piperazin-1-yl]-methanone;
[5-(4-Methoxy-phenyl)-7-trifluoromethyI-pyrazolo[1 ,5-a]pyrimidin-2-yl]-piperidin-1 -yl- methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-aJpyrimidin-2-yl)- methanone;
(3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(2,6-dimethyl- piperidin-1 -yl)-methanone;
(3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(2-ethyl-piperidin-1- yl)-methanone; 3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl-amide;
[5-(4-Bromo-phenyl)-3-chloro-7-trifluoromethyl-pyrazoIo[1 ,5-a]pyrimidin-2-yl]-pyrrolidin-1-yl- methanone;
(3-Chloro-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyI)- piperazin-1 -yl]-methanone;
(3-Chloro-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-phenyl-piperazin-1- yl)-methanone;
[3-Chloro-5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(4-methyl- piperazin-1 -yl)-methanone; Azepan-1 -yl-[3-chloro-5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]- methanone;
[3-Chloro-5-(3,4-dimethoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-ylJ-pyrrolidin-
1 -yl-methanone; [5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(2-methyl-piperidin-1-yl)- methanone;
(5-Thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(1 ,3,3-trimethyl-6-aza- bicyclo[3.2.1 Joct-6-yl)-methanone;
[4-(2-ChIoro-phenyl)-piperazin-1-yl]-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-2-yl)-methanone;
(3,4-Dihydro-1 H-isoquinolin-2-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-
2-yl)-methanone;
(4-Methyl-piperazin-1-yl)-[5-(4-nitro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-ylJ- methanone; [5-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-thiomorpholin-4-yl- methanone;
(3-Bromo-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yI)-(3,4-dihydro-2 - - quinolin-1 -yl)-methanone;
(5-Furan-2-yl-7-trifluoromethyl-pyrazoIo[1 ,5-a]pyrimidin-2-yl)-pyrrolidin-1 -yl-methanone; [4-(Furan-2-carbonyl)-piperazin-1-yl]-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-2-yl]-methanone;
[5-(4-Nitro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-ylJ-piperidin-1 -yl-methanone;
(5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-pyrrolidin-1 -yl-methanone;
(4-Methyl-piperidin-1-yl)-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
(3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)- piperazin-1 -ylj-methanone;
[4-(4-Fluoro-phenyl)-piperazin-1-yl]-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-aJpyrimidin-2-yl)- methanone; [4-(4-Fluoro-phenyl)-piperazin-1 -yl]-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-2-yl)-methanone;
[3-Bromo-5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazoIo[1 ,5-a]pyrimidin-2-yl]-morpholin-4- yl-methanone;
[4-(4-Fluoro-phenyl)-piperazin-1-yl]-(7-methyl-5-phenyl-pyrazolo[1 ,5-a]pyhmidin-2-yl)- methanone; (4-Benzoyl-piperazin-1-yl)-(5-phenyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)- methanone;
(3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-phenyl-piperazin-
1-yl)-methanone; (2-Ethyl-piperidin-1-yl)-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone;
(5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-methyl-piperazin-1-yl)-methanone;
(4-Benzyl-piperazin-1-yl)-(3-chloro-5-phenyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)- methanone;
(3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-methyl-piperazin- 1-yl)-methanone;
(4-Phenyl-piperazin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)- methanone;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl]-pyrrolidin-1 -yl- methanone; (5,7-Diphenyl-pyrazolo[1,5-aJpyrimidin-2-yl)-pyrrolidin-1 -yl-methanone;
(3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-ethyl-piperidin-1- yl)-methanone;
(3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyra∑olo[1,5-a]pyrimidin-2-yl)-(2-methyl-piperidin-
1-yl)-methanone; 5-Methyl-7-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl-amide;
(3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-morpholin-4-yl- methanone;
(3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yI)-[4-(4-fluoro-phenyl)- piperazin-1 -yl]-methanone; (3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-methyl-piperazin-
1-yl)-methanone;
(7-Methyl-5-phenyl-pyrazolo[1,5-aJpyrimidin-2-yl)-piperidin-1-yl-methanone;
Azepan-1 -yl-(3-chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone; Azepan-1 -yl-[3-bromo-5-(4-bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]- methanone;
3-Bromo-5-(4-bromo-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl-amide;
(2,6-Dimethyl-piperidin-1-yl)-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin- 2-yl]-methanone; [5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-ylJ-(4-methyl-piperazin-1-yl)- methanone;
5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid benzyl-methyl-amide;
[5-(4-Ethoxy-phenyl)-7-methyl-pyrazolo[1,5-a]pyrimidin-2-yl]-(4-phenyl-piperazin-1-yl)- methanone;
(3,4-Dihydro-1H-isoquinolin-2-yl)-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1,5- a]pyrimidin-2-yl]-methanone;
Morpholin-4-yl-[5-(4-nitro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl]-methanone;
(Hexahydro-pyrrolo[1,2-aJpyrazin-2-yl)-(5-phenyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2- yl)-methanone;
(Hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-(5-p-tolyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2- yl)-methanone;
(Hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1,5- a]pyrimidin-2-yl)-methanone; (3-Chloro-5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(hexahydro-pyrrolo[1,2- a]pyrazin-2-yl)-methanone;
[5-(4-Fluoro-phenyl)-7-methyl-pyra∑olo[1,5-a]pyrimidin-2-yl]-morpholin-4-yl-methanone;
(5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(2-methyl-piperidin-1-yl)-methanone;
5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-aJpyrimidine-2-carboxylic acid (1 ,3-dimethyl-1H- pyrazol-4-ylmethyl)-methyl-amide;
5-Thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid (1 ,5-dimethyl-
1H-pyrazol-4-ylmethyl)-methyl-amide;
5-Thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid methyl-(1 ,3,5- trimethyl-1H-pyrazol-4-ylmethyl)-amide; 3-Chloro-5-(4-methoxy-phenyI)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid
(1 ,3-dimethyl-1 H-pyrazol-4-ylmethyl)-methyl-amide;
5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid (1 ,3- dimethyl-1H-pyrazol-4-ylmethyl)-methyl-amide;
5-(3,4-Dimethoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid (1 ,3- dimethyl-1 H-pyrazol-4-ylmethyl)-methyl-amide;
(2,5-Dimethyl-piperidin-1-yl)-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid methyl-(1 ,3,5- trimethyl-1H-pyrazol-4-ylmethyI)-amide; 5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid (1 ,5- dimethyl-1H-pyrazoI-4-ylmethyl)-methyl-amide;
(2,4-Dimethyl-piperidin-1-yl)-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone; (3-Bromo-5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(hexahydro-pyrrolo[1 ,2- a]pyrazin-2-yl)-methanone;
[5-(3,4-Dimethoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(hexahydro- pyrrolo[1 ,2-a]pyrazin-2-yl)-methanone;
(3-Chloro-5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(hexahydro-pyrrolo[1 ,2- a]pyrazin-2-yl)-methanone;
(3-Bromo-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1-yl- methanone;
(3-Chloro-5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-pyrrolidin-1 -yl-methanone;
(7-Methyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-methyl-piperidin-1-yl)-methanone; (4-Methyl-piperazin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
[3-Bromo-5-(4-methoxy-phenyl)-7-trifluoromethyl-pyra∑olo[1 ,5-a]pyrimidin-2-yl]-piperidin-1-yl- methanone;
(4-MethyI-pipera∑in-1-yl)-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
[4-(4-Fluoro-phenyl)-piperazin-1-yl]-(5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2- yl)-methanone;
[5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-morpholin-4-yl- methanone; (3,4-Dihydro-2/- -quinolin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2- yl)-methanone;
(3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yI)-morpholin-4-yl- methanone;
Azepan-1-yl-(3-chloro-5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone; (4-Benzoyl-piperazin-1-yl)-[5-(4-bromo-phenyI)-7-thfluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2- yl]-methanone;
(4-Benzyl-piperazin-1-yl)-[5-(4-bromo-phenyl)-3-chloro-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-2-yl]-methanone;
[5-(4-Bromo-phenyl)-3-chloro-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(4-methyI- piperazin-1 -yl)-methanone; Azepan-1-yl-[5-(4-bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-methanone;
[3-Bromo-5-(4-bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(3,4-dihydro-
2H-quinolin-1 -yl)-methanone;
[5-(3,4-Dimethoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-morphoIin-4-yl- methanone;
(3-Bromo-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-methyl-piperazin-1- yl)-methanone;
(4-Benzoyl-piperazin-1-yl)-(3-bromo-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2- yl)-methanone; (3-Bromo-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(3,4-dihydro-2/-- quinolin-1 -yl)-methanone;
[5-(4-Bromo-phenyl)-7-trifluoromethyI-pyrazolo[1 ,5-a]pyrimidin-2-yl]-piperidin-1-yl- methanone;
[5-(4-Ethoxy-phenyl)-7-methyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-piperidin-1 -yl-methanone; [5-(4-Ethoxy-phenyl)-7-methyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-morpholin-4-yl-methanone;
Azepan-1 -yl-(3-bromo-5-furan-2-yl-7-trifluoromethyI-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
(3,4-Dihydro-1 H-isoquinolin-2-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-
2-yl)-methanone; (4-Benzyl-piperazin-1-yl)-(3-bromo-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2- yl)-methanone;
A∑epan-1-yl-[5-(4-bromo-phenyl)-3-chloro-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]- methanone;
(3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(3,4-dihydro-1H- isoquinolin-2-yl)-methanone;
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yI)-piperidin-1 -yl- methanone;
Azepan-1 -yl-(5,7-diphenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone;
Azepan-1 -yl-(5-benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazoIo[1 ,5-a]pyrimidin-2-yl)- methanone;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-morpholin-4-yl- methanone;
[3-Bromo-5-(4-bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-morpholin-4-yl- methanone; [5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-thiomorpholin-4-yl- methanone;
[5-(4-Bromo-phenyl)-3-chloro-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-piperidin-1-yl- methanone; (5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(3,4-dihydro-2H- quinolin-1-yl)-methanone; >
(5-Benzo[1 ,3]dioxoI-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-benzyl-piperazin-
1-yl)-methanone;
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-morpholin-4-yl- methanone;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yI]-[4-(2-methoxy-phenyl)- piperazin-1 -yl]-methanone;
[3-Bromo-5-(4-bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(4-methyl- piperazin-1 -yl)-methanone; Azepan-1 -yl-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]- methanone;
(2,6-Dimethyl-piperidin-1-yl)-[7-(4-ethoxy-phenyl)-5-methyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]- methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-(5,7-diphenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone; (3,6-Dibromo-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone;
(3-Bromo-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1 -yl- methanone;
[5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl]-thiomorpholin-4-yl- methanone; [5-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-thiomorpholin-4-yl- methanone;
(3,4-Dihydro-1 H-isoquinolin-2-yl)-[5-(4-nitro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-2-yl]-methanone;
Azepan-1-yl-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]- methanone;
Azepan-1-yl-[5-(4-nitro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-methanone;
[5-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-morpholin-4-yl- methanone;
Azepan-1-yl-[5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]- methanone; (3,4-Dihydro-1 H-isoquinolin-2-yl)-(5-phenyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)- methanone;
[5-(4-Bromo-phenyl)-3-chloro-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-pyrrolidin-1-yl- methanone; 5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl-amide;
(3,4-Dihydro-1ry-isoquinolin-2-yl)-(5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2- yl)-methanone;
(4-Benzyl-piperazin-1-yl)-(3-chloro-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2- yl)-methanone; [3-Chloro-5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-piperidin-1-yl- methanone;
(3-Chloro-5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-methyl-piperazin-1-yl)- methanone;
(3-Chloro-5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-phenyl-piperazin-1-yl)- methanone;
[3-Chloro-5-(3,4-dimethoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-piperidin-
1 -yl-methanone;
[4-(4-Fluoro-phenyl)-piperazin-1-yl]-(5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone; (4-Phenyl-piperazin-1 -yl)-(5-p-tolyl-7-trifluoromethyI-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
Morpholin-4-yl-(5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone;
(4-Benzyl-piperazin-1-yl)-(5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone; [5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(4-methyl-piperazin-1-yl)- methanone;
[5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-morpholin-4-yl- methanone;
(4-Benzyl-piperazin-1-yl)-[5-(4-chloro-phenyl)-7-trifluoromethyI-pyrazolo[1 ,5-a]pyrimidin-2-yl]- methanone;
[5-(4-Fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-morpholin-4-yl- methanone;
[5-(4-Fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-piperidin-1-yl-methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-[5-(4-fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin- 2-yl]-methanone; Azepan-1-yl-[5-(3,4-dimethoxy-phenyI)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl]- methanone;
(4-Benzyl-piperazin-1-yl)-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2- yl]-methanone; [5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-pyrrolidin-1 -yl- methanone;
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-pyrrolidin-1 -yl- methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-[5-(4-nitro-phenyl)-7-trifluoromethyI-pyrazolo[1,5-a]pyrimidin-2- yl]-methanone;
[3-Chloro-5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl]-(4-methyl- piperidin-1 -yl)-methanone;
[3-Chloro-5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl]-(3,4-dihydro-
2H-quinolin-1 -yl)-methanone; 3-Chloro-5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl-amide;
[3-Chloro-5-(4-fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl]-(4-methyl- piperazin-1 -yl)-methanone;
(3-Chloro-5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-morpholin-4-yl-methanone; Azepan-1 -yl-(3-chloro-5-p-tolyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone;
Azepan-1 -yl-[3-chloro-5-(3,4-dimethoxy-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2- yl]-methanone;
[5-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl]-(4-methyl-piperazin-
1-yl)-methanone; 5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid benzyl-methyl-amide;
(5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-phenyl-piperazin-1-yl)-methanone;
Morpholin-4-yl-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone;
Morpholin-4-yl-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone;
Piperidin-1-yl-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone; [3-Bromo-5-(4-bromo-thiophen-2-yl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-piperidin-
1 -yl-methanone;
(3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(3,4-dihydro-2H- quinolin-1 -yl)-methanone;
(3-Chloro-5-thiophen-2-yI-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl- methanone; (7-Methyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-morpholin-4-yl-methanone; (7-Methyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-pyrrolidin-1-yl-methanone; 7-Methyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid benzyl-methyl-amide; (2,6-Dimethyl-piperidin-1-yl)-[5-(4-fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2- yl]-methanone;
Azepan-1-yl-[5-(4-fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-methanone; [5-(4-Fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(4-methyl-piperazin-1-yl)- methanone;
[5-(4-Fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(4-phenyl-piperazin-1-yl)- methanone;
(2-Ethyl-piperidin-1-yl)-[5-(4-fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]- methanone;
(5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-piperidin-1-yl-methanone; (5-Methyl-7-phenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6- yl)-methanone;
(5-Thiophen-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl)-(1 ,3,3-trimethyl-6-aza- bicyclo[3.2.1 ]oct-6-yl)-methanone;
(4-Phenyl-pipera∑in-1-yl)-pyrazolo[1 ,5-a]pyrimidin-3-yl-methanone; Pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid benzyl-(2-hydroxy-ethyl)-amide;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-(3,4-dihydro-1H- isoquinolin-2-yl)-methanone;
(5,7-Dimethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-[4-(4-methoxy-phenyl)-piperazin-1-yl]- methanone; (3,4-Dihydro-2H-quinolin-1-yl)-[5-(4-fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-
3-yl]-methanone;
(5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-piperidin-1-yl-methanone;
Azepan-1-yl-[7-trifluoromethyl-5-(3,4,5-trimethoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidin-3-yl]- methanone; (5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-pyrrolidin-1 -yl- methanone;
Azepan-1 -yl-(5,7-diphenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone;
4-(5,7-Dimethyl-pyrazolo[1 ,5-a]pyrimidine-3-carbonyl)-piperazine-1 -carboxylic acid ethyl ester; (3,4-Dihydro-1 H-isoquinolin-2-yl)-(5,7-dimethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone; [4-(3-Chloro-phenyl)-piperazin-1-yl]-(5-p-tolyI-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone;
(4-MethyI-piperidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl-methanone;
[4-(2-Methoxy-phenyl)-piperazin-1-yl]-pyrazolo[1 ,5-a]pyrimidin-3-yl-methanone; (3,4-Dihydro-2H-quinolin-1 -yl)-[5-(4-methoxy-phenyI)-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-3-yl]-methanone;
[5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-thiomorpholin-4-yl- methanone;
(5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(2-methyl-piperidin-1-yl)- methanone;
(4-Benzyl-piperazin-1-yl)-(5,7-dimethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-morpholin-4-yl- methanone;
(5,7-Dimethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-piperidin-1 -yl-methanone; (5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-[4-(2-methoxy-phenyl)- piperazin-1 -yl]-methanone;
(5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-piperidin-1 -yl-methanone;
Azepan-1 -yl-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone;
(2,6-Dimethyl-piperidin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyra∑olo[1 ,5-a]pyrimidin-3-yl)- methanone;
[5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-(4-methyl-piperazin-1- yl)-methanone;
(4-Methyl-piperazin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazoIo[1 ,5-a]pyrimidin-3-yl)- methanone; [5-(4-Bromo-phenyl)-7-trifluoromethyI-pyrazolo[1,5-a]pyrimidin-3-yl]-(4-methyI-piperazin-1-yl)- methanone;
(Hexahydro-pyrroIo[1 ,2-a]pyrazin-2-yl)-(5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3- yl)-methanone;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-(hexahydro-pyrrolo[1 ,2- a]pyrazin-2-yl)-methanone;
[5-(3,4-Dimethoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-(hexahydro- pyrrolo[1 ,2-a]pyrazin-2-yl)-methanone;
1-[5-(3-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carbonyl]-piperidine-4- carboxylic acid ethyl ester; 4-[5-(3-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carbonyl]-piperazine-1- carboxylic acid ethyl ester;
(3,4-Dihydro-2/- -quinolin-1-yl)-[5-(3-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-3-yl]-methanone; [4-(4-Fluoro-phenyl)-piperazin-1 -yl]-[5-(3-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-3-yl]-methanone;
5-p-Tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid (1 , 3-di methyl- 1H- pyrazol-4-ylmethyl)-methyl-amide;
5-p-Tolyl-7-trifluoromethyI-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid methyl-(1 ,3,5-trimethyl- 1H-pyrazol-4-ylmethyl)-amide;
[7-Difluoromethyl-5-(4-methoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidin-3-yl]-(2-ethyl-imidazol-1-yl)- methanone;
[7-Difluoromethyl-5-(4-methoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidin-3-yl]-morpholin-4-yl- methanone; 1 -[7-Difluoromethyl-5-(4-methoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidine-3-carbonyl]-1 H-indole-3- carboxylic acid methyl ester;
[4-(4-Chloro-phenyl)-piperazin-1-yl]-[7-difluoromethyl-5-(4-methoxy-phenyl)-pyrazolo[1 ,5- a]pyrimidin-3-yl]-methanone;
[7-Difluoromelhyl-5-(4-methoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidin-3-yl]-(2-ethyl-piperidin-1-yl)- methanone;
7-Difluoromethyl-5-p-tolyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid (1-ethyl-5-methyl-1H- pyra∑ol-4-ylmethyl)-methyl-amide;
1-(7-Difluoromethyl-5-methyl-pyrazolo[1 ,5-a]pyrimidine-3-carbonyl)-piperidine-4-carboxylic acid amide; (7-Difluoromethyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(2-ethyl-imidazol-1-yl)-methanone;
(7-Difluoromethyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-thiomorpholin-4-yl-methanone;
(7-Difluoromethyl-5-p-tolyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(4-pyridin-2-yl-piperazin-1-yl)- methanone;
[7-Difluoromethyl-5-(4-methoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidin-3-yl]-[4-(furan-2-carbonyl)- piperazin-1 -yl]-methanone;
7-Difluoromethyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid (1-ethyl-3-methyl-1H- pyrazol-4-ylmethyl)-methyl-amide;
[7-Difluoromethyl-5-(4-methoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidin-3-yl]-thiomorpholin-4-yl- methanone; (7-Difluoromethyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(3,4-dihydro-1H-isoquinolin-2-yl)- methanone;
(7-DifluoromethyI-5-methyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-piperidin-1-yl-methanone;
Azepan-1-yl-(7-difluoromethyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone; 7-Difluoromethyl-5-p-tolyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid methyl-(1 -methyl-1 H- pyrazol-4-ylmethyl)-amide;
(7-Difluoromethyl-5-p-tolyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(3-methyl-piperidin-1-yl)-methanone;
(7-Difluoromethyl-5-p-tolyl-pyrazolo[1,5-a]pyrimidin-3-yl)-(4-ethyl-piperazin-1-yl)-methanone;
(7-Difluoromethyl-5-p-tolyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-morpholin-4-yl-methanone; 7-Difluoromethyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid methyl-(1 ,3,5- trimethyl-1H-pyrazol-4-ylmethyl)-amide;
(7-Difluoromethyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-[4-(2-methyl-2H-pyrazole-3- carbonyl)-pipera∑in-1-yl]-methanone;
7-Difluoromethyl-5-p-tolyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid benzyl-methyl-amide; 7-Difluoromethyl-5-(4-methoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid (1-ethyl-3- methyl-1H-pyrazol-4-ylmethyl)-methyl-amide;
7-Difluoromethyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid methyl-(4-pyrazol-1-yl- benzyl)-amide;
Azepan-1-yl-(5-cyclopropyl-7-difluoromethyl-pyrazoIo[1 ,5-a]pyrimidin-3-yl)-methanone; (4-Benzyl-piperazin-1-yl)-[5-(4-methoxy-phenyl)-7-thfluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3- yl]-methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyra∑olo[1 ,5- a]pyrimidin-3-yl]-methanone;
5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidinβ-3-carboxylic acid benzyl- methyl-amide;
(5-Furan-2-yI-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(4-methyl-piperazin-1-yl)- methanone;
(5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-thiomorpholin-4-yl-methanone;
[5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-morpholin-4-yl- methanone;
(4-Benzyl-piperazin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-morpholin-4-yl- methanone; Azepan-1 -yl-(5-benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone;
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(3,4-dihydro-2H- quinolin-1 -yl)-methanone; 5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid cyclohexyl-methyl-amide;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-(3,4-dihydro-2/-.-quinoIin-
1-yl)-methanone;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-piperidin-1-yl- methanone;
Azepan-1-yl-(5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone;
(5-Benzo[1 ,3]dioxol-5-yI-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-pyrrolidin-1 -yl- methanone;
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yi)-(4-methyl-piperazin- 1-yl)-methanone;
(3,4-Dihydro-1H-isoquinolin-2-yl)-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-3-yl]-methanone;
Azepan-1 -yl-[5-(4-bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-(5,7-diphenyl-pyra∑olo[1 ,5-a]pyrimidin-3-yl)-methanone; Azepan-1 -yl-(5,7-diphenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone;
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yI)-(4-benzyl-piperazin-
1-yl)-methanone;
(4-Benzyl-piperazin-1-yl)-(5,7-diphenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone;
(5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(4-methyl-piperazin-1-yl)-methanone; [5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-(2-methyl-piperidin-1-yl)- methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-(5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone;
(5-Furan-2-yI-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(2-methyl-piperidin-1-yl)- methanone;
[5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-piperidin-1-yl- methanone;
(5-Benzo[1 ,3]dioxoI-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-morpholin-4-yl- methanone; (5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-piperidin-1 -yl- methanone;
Morpholin-4-yl-[7-trifluoromethyI-5-(3,4,5-trimethoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidin-3-yl]- methanone; (4-Benzyl-piperazin-1 -yl)-[7-trifluoromethyl-5-(3,4,5-trimethoxy-phenyl)-pyrazolo[1 ,5- a]pyrimidin-3-yl]-methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-[7-trifluoromethyl-5-(3,4,5-trimethoxy-phenyl)-pyrazolo[1 ,5- a]pyrimidin-3-yl]-methanone;
(4-Methyl-piperazin-1-yl)-[7-trifluoromethyl-5-(3,4,5-trimethoxy-phenyl)-pyrazolo[1 ,5- a]pyrimidin-3-yl]-methanone;
Azepan-1-yl-[7-trifluoromethyl-5-(3,4,5-trimethoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidin-3-yl]- methanone;
[5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-piperidin-1-yl- methanone; [5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-pyrrolidin-1 -yl- methanone;
Piperidin-1 -yl-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone;
(4-BenzyI-pipera∑in-1-yl)-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3- yl]-methanone; (3,4-Dihydro-2H-quinolin-1-yl)-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-3-yl]-methanone;
(5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(2-methyl-piperidin-1-yl)- methanone;
(5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-morpholin-4-yl-methanone; (5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-thiomorpholin-4-yl-methanone;
[4-(4-Fluoro-phenyl)-piperazin-1-yl]-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-3-yl)-methanone;
(4-Methyl-piperidin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone; (5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(4-methyl-piperazin-1 -yl)- methanone;
(4-Benzyl-piperazin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone;
[5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-morpholin-4-yl- methanone; Piperidin-1-yl-[7-trifluoromethyl-5-(3,4,5-trimethoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidin-3-yl]- methanone;
(2-Methyl-piperidin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl)- methanone; Azepan-1 -yl-[5-(4-rnethoxy-phenyl)-7-trif luoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]- methanone;
5-Thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid benzyl-methyl- amide; [5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-pyrrolidin-1-yl- methanone;
[5-(4-Chloro-phenyl)-2-methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-piperidin-1 -yl- methanone;
Azepan-1-yl-[5-(4-chloro-phenyl)-2-methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]- methanone; [5-(4-Chloro-phenyl)-2-methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-(4-methyl- piperazin-1 -yl)-methanone;
Morpholin-4-yl-(5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone; (4-Benzyl-piperazin-1-yl)-(5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone; 5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid benzyl- methyl-amide;
(4-Benzyl-piperazin-1-yl)-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone; Morpholin-4-yl-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-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 said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II)
Figure imgf000038_0001
Formula (II)
wherein R1 is C3-Cιocycloalkyl, C3-C10hetcycloalkyl, CrC8alkyl, aryl, hetaryl, aryld-C6alkyl 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-C8alkyI, aryl, hetaryl, arylCrCealkyl, C3-CιocycloalkylCrC6alkyl, d- 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 C C8alkyl, aryl, hetaryl, aryld- C6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C6alkyloxy, aryld-Cealkyloxy, hetaryld- Cealkyloxy, CrCealkyloxyCrCealkyl, d-Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-Cealkylcarboxy, arylcarboxy or aryld- Cealkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R14;
R3 is CrC8alkyl, d-C6alkenyl, Cι-C6alkynyl, C3-Cι0cycloalkyl, C3-C10hetcycloalkyl, aryl, hetaryl, arylCrC6alkyl, d-Cealkyloxyd-Cealkyl, hetarylCrCealkyl, aryl-R6-CrC6alkyI, hetaryl- R6-CrC6alkyl or arylCrCealkyl-R^CrCealkyl 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, CrC8alkyl, CrC6alkyloxy, trihalomethyl, trihalomethyloxy, C3-Cι0cycloalkyl, C3-Cι0hetcyclo- alkyl, C3-Cι0cycloalkenyl, aryl, hetaryl, hetarylSOn, arylCrCealkyloxy, hetaryld-Cealkyloxy, CrC6alkyl-R6-Cι-C6alkyl, arylCrC6alkyl-R6-CrC6alkyl, CrC6alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, hetarylcarbonyl, hetarylCrC6alkyl-carbonyl, CrC6alkylSOn, d-C6- alkyl-carboxy, 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;
R° is oxygen, sulphur, SOn or NR 16. R7 is hydrogen, halo, hydroxy, cyano, nitro, COOR17, d-C8alkyl, C3-Cι0cycloalkyl, C3-Cι0het- cycloalkyl, methylendioxo, trihalomethyl, trihalomethyloxy, aryl, arylCrC6alkyl, CrCealkyloxy, CrCealkyloxyCrCealkyl, aryloxy, arylCrCealkyloxy, aryloxyd-Cealkyl, arylCrC6alkyloxyCr C6alkyl, hetaryl, hetarylCrCealkyl, hetaryloxy, hetarylCrCealkyloxy, hetaryloxyCrCealkyl, he-aryld-Cealkyl-oxyd-Cealkyl, NR8R9, S02NR8R9, NR4R5carbonylCrC6alkyl, arylthio, hetarylthio, R18carbonylNR8, arylSOn, hetarylSOn, R19SOmNR8, arylthioCrCealkyl, hetaryl- thioCrC6alkyl or arylCι-C6alkylR6CrC6alkyl; 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- 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, CrC8alkyl, aryl, hetaryl, arylCrC6alkyl, hetaryld-Cealkyl, hydroxy, oxo, CrC6alkyloxy, aryld-Cealkyloxy, hetaryld- Cealkyloxy, CrC6alkyloxyC1-C6alkyl) d-C6alkyl-carbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-C6alkylcarboxy, arylcarboxy, hetarylcarboxy, arylCrC6alkylcarboxy or hetarylCrC6alkylcarboxy;
R10 and R11 independently are hydrogen, hydroxy, oxo, halo, cyano, nitro, CrC8alkyl, 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, d-C8alkyl, d-C6alkyloxy or aryloxy;
R15 is hydrogen, halo, hydroxy, oxo, nitro, cyano, CONR8R9 or COOR17;
R16 is hydrogen, CrC8alkyl, C3-Cι0cycloalkyl, C3-Cι0hetcycloalkyl, aryl, arylCrC6alkyl, hetaryl, hetarylCrCealkyl, alkylcarbonyl, arylcarbonyl, arylCrC6alkylcarbonyl, aryloxyd- Cealkyl, hetaryloxyCrC6alkyl, arylthioCrCealkyl or hetarylthioCrC6alkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R10;
R is hydrogen, CrCβalkyl, aryl or arylCrCealkyl;
R18 is CrCealkyl, C2-C6alkenyl, aryl, arylCrC6alkyI, hetaryl, hetarylCrCealkyl, C3- Ciocycloalkyl, C3-Cι0hetcycloalkyl, CrC6alkyloxy, aryloxy, arylCrCealkyloxy, aryld- CealkyIoxyCι-C6alkyl, hetaryloxy, hetarylCrC6alkyloxy, hetarylCrCealkyloxyCrCealkyl or R8R9NCrC6alkyl wherein the alkyl, alkenyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups are optionally substituted with R15;
R19 is CrC6alkyl, C3-C10cycloalkyl, C3-Cι0hetcycloalkyl, aryl, arylCrC6alkyl, hetaryl, hetaryld-Cealkyl;
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 o the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein: R1 is C3-Ci0cycloalkyl, C3-Cι0hetcycloalkyl, d-C8alkyl, aryl, hetaryl, aryld-C6alkyl or hetaryld-Cealkyl, 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, arylCrC6alkyl, C3-Cι0cycloalkylCrC6alkyI, C C6- alkylcarboxyCrC6alkyl wherein the alkyl, aryl and cycloalkyl groups independently are optionally 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, aryld- C6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, aryld-C6alkyloxy, hetaryld- Cealkyloxy, CrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or aryld- βalkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R14;
R3 is CrC8alkyl, CrC6alkenyl, CrC6alkynyl, C3-Cι0cycloalkyl, C3-Cι0hetcycloalkyl, aryl, hetaryl, arylCrC6alkyl, CrCealkyloxyCrCealkyl, hetarylCrCealkyl, aryl-R6-CrC6alkyl, hetaryl- R6-CrC6alkyl or arylCι-C6alkyl-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, CrC8alkyl, CrC6alkyloxy, trihalomethyl, trihalomethyloxy, C3-Cι0cycloalkyl, C3-
Ciohetcycloalkyl, C3-Cι0cycloalkenyl, aryl, hetaryl, hetarylSOn, arylCrC6alkyloxy, he-aryld- C6alkyloxy, CrC6alkyl-R6-CrCealkyl, arylCι-C6alkyl-R6-CrC6alkyl, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, hetarylcarbonyl, hetarylCrC6alkyl-carbonyl, Cι-C6alkylSOn, CrC6alkyl-carboxy, arylcarboxy, hetarylcarboxy, arylCrC6alkylcarboxy or hetarylCrC6alkyl- carboxy wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one ore more of R15;
R8 is oxygen, sulphur, SOn, NR16;
R7 is hydrogen, halo, hydroxyl, cyano, nitro, COOR17, CrC8alkyl, C3-Cι0cycloalkyl, C3-Cι0het- cycloalkyl, methylendioxo, trihalomethyl, trihalomethyloxy, aryl, arylCrCealkyl, CrC6alkyloxy, CrCealkyloxyCrCealkyl, aryloxy, aryloxyCrC6alkyl, arylCrCealkyloxyCrCealkyl, hetaryl, hetarylCrCealkyl, hetaryloxy, hetarylCrCealkyloxy, hetaryloxyCrCealkyl, hetarylCrCealkyloxyCrCealkyl, NR8R9, S02NR8R9, NR4R5carbonylalkyl, arylcarbonylNR8, arylthio, hetarylthio, arylSOn, hetarylSOn, arylSOmNR8, arylthioCrCealkyl, hetarylthioCrC6alkyl or aryld-
C6alkyIR6CrC6alkyl; wherein the aryl and hetaryl groups independently are optionally substituted with one or more R10; R8 and R9 independently are hydrogen, CrC8alkyl, aryl, hetaryl, arylCrCealkyl 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, arylCrCealkyl, hetarylCrC6alkyl, hydroxy, oxo, CrC6alkyloxy, aryld-Cealkyloxy, hetarylCrCealkyloxy, d- CealkyloxyCrCealkyl, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrC6alkylcarbonyl, CrC6alkylcarboxy, arylcarboxy, hetarylcarboxy, arylCi- Cealkyl-carboxy or hetarylCrC6alkylcarboxy;
R10 and R11 independently are hydrogen, hydroxy, oxo, halo, cyano, nitro, d-Cealkyl, d-C6- alkyloxy, NR12R13, methylendioxo, trihalomethyl or trihalomethyloxy;
R12 and R13 independently are hydrogen, Cι-C8alkyl or arylCrC6alkyl;
R14 is hydrogen, halo, hydroxy, oxo, nitro, cyano, C C8alkyl, CrC6alkyloxy or aryloxy;
R15 is hydrogen, halo, hydroxy, oxo, nitro, cyano or COOR17;
R16 is hydrogen, CrC8alkyl, C3-Cι0cycloalkyl, C3-Cι0hetcycloalkyl, aryl, arylCrC6alkyl, hetaryl, hetarylCrCealkyl, alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, aryloxyd- C6alkyl, hetaryloxyCrCealkyl, 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, CrC8alkyI, aryl or aryld-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 mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R1 is C3-Cι0cycloalkyl or C3-Cιohetcycloalkyl 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 said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R1 is C3-Cι0cycloalkyl optionally substituted with one or more of R4 as defined above.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R2 is hydrogen or d-C8alkyl, wherein the the alkyl group is optionally substituted with one or more of R5 as defined above. In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R2 is d-G8alkyl optionally substituted with one or more of R5 as defined above.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is o the general formula (II) wherein R3 is C3-C10cycloalkyl, C3-Cι0hetcycloalkyl, aryl, hetaryl, arylC C6alkyl, hetaryld- Cealkyl, aryl-R6-CrC6alkyl, hetaryI-R6-CrC6alkyl or arylCrC6alkyl-R6-CrC6alkyl wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R7.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) 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 of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R3 is is phenyl optionally substituted with one or more of R7 as defined above.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) 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 of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R4 and R5 independently are hydrogen, hydroxy, oxo, halo, CrC8alkyl, wherein the alkyl group is optionally substituted with one ore more of R15. In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R6 is oxygen.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R7 is hydrogen, halo, hydroxy, cyano, d-C8alkyI, C3-C10cycloalkyl, C3-C10het- cycloalkyl, trihalomethyl, aryl, arylCrC6alkyl, CrC6alkyloxy, CrCealkyloxyCrCealkyl, aryloxy, arylCrCealkyloxy, aryloxyCrC6alkyl, arylCrCealkyloxyCrCealkyl, hetaryl, hetaryld-Cealkyl, hetaryloxy, hetarylCrCealkyloxy, hetaryloxyCrCealkyl, hetaryld-Cealkyl-oxyCrCealkyl, NR8R9, NR R5carbonyICrC6alkyl, R18carbonylNR8, R19SOmNR8, wherein the aryl and hetaryl groups independently are optionally substituted with one or more R10.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) 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 car- bon 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, aryld-Cealkyl, hetarylCrCealkyl, hydroxy, oxo, CrC6alkyloxy, arylCrC6alkyloxy, hetarylCrCealkyloxy, CrCealkyloxyd-Cealkyl, CrC6alkyl-carbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-Cealkylcarboxy, arylcarboxy, hetarylcarboxy, aryIC C6alkylcarboxy or hetaryld-C6alkylcarboxy.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R15 is CONR8R9.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R18 is d-C6alkyl optionally substituted with R15.
In another embodiment of the present invention said substituted amide, or a prodrug thereof, as a component of the combination therapy 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,f]azepin-5-yl)-1-[4-(3H-imidazol-4-yl)-piperidin-1-yl]-butan-1-one;
2,4-Bis-benzyloxy-benzamide;
(1H-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-Cyclopen tyl-1 -(6-f luoro-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)-cyclohexyI-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-trimethyI-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; N-[1-(4-Methanesulfonyl-phenyl)-ethyl]-N-(tetrahydro-furan-2-ylmethyI)-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-cyclopentyI-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-CyclohexyI-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-benzothia∑ol-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-ben∑yl)-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-phenyI)-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-yI-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-DichIoro-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)-pipehdin-1 -yl-methanone;
2-Chloro-N-(3-trifluoromethyl-phenyl)-benzamide; N-BenzyI-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-ben∑o[b]thiophen-2-yl)-(4-methyl-pipera∑in-1-yl)-methanone;
Adamantane-1 -carboxylic acid (5-methyl-pyridin-2-yl)-amide;
3-Bromo-N-[2-methyl-1-(1 ,3,3-trimethyl-6-a∑a-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-CyclopentyI-N-[2-methyl-1 -(1 ,3,3-trimethyl-6-aza-bicyclo[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-propionyl)-piperazin-1-yl]-2-oxo-ethyl}-3-cyclopentyl- propionamide;
N-BicycIo[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-(1 H-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-phenyI)-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-ToIyl-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-rV1ethyI-N-phenyl-4-(pyrrolidine-1-sulfonyl)-ben∑amide;
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-1 H-isoquinolin-2-yl)-methanone;
2-[1-(4-Chloro-benzenesulfonyl)-1 H-ben∑oimida∑ol-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-thia∑ole-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-phenyI-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-carboxyIic acid (3-chloro-phenyl)-amide;
N-[4-(Ben∑yl-isopropyl-sulfamoyl)-phenyl]-acetamide;
N-(3,4-Dimethyl-phenyl)-N-[4-(piperidine-1-carbonyl)-ben∑yl]-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-(Benzooxa∑ol-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; (4-Chloro-3-nitro-phenyl)-(2,6-dimethyl-piperidin-1-yl)-methanone;
[1-(4-ChIoro-benzenesulfonyl)-piperidin-3-yl]-(octahydro-quinolin-1-yl)-methanone;
2,4-Dichloro-N-cyclohexyl-N-(2-hydroxy-ethyl)-benzamide;
(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-ylsuIfanyl)-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-ylmethyI-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-ylsuIfanyl)-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-1 H-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-phenyI)-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)-ben∑amide;
[5-(2,5-DichIoro-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[2.2.1]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)-1 H-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-yI)-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-trimethyI-3,4,6-triaza-tricyclo[6.2.1.02'7]undeca-2(7),3,5-trien-5- ylsulfanyl)-acetamide; N-EthyI-3-methyl-N-o-tolyl-benzamide;
N-[5-(2,4-Dichloro-benzylsulfanyl)-[1,3,4]thiadiazol-2-yl]-2,2-dimethyl-propionamide;
4-Fluoro-N-[4-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]- benzenesulfonamide;
4-Bromo-1 -ethyl-1 H-pyrazole-3-carboxylic acid (2-methylsulfanyl-phenyl)-amide; 5-Benzoyl-furan-2-carboxylic acid diisopropylamide;
2-[3-(Piperidine-1 -carbonyl)-phenyl]-isoindole-1 ,3-dione;
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-indoM -yl)-2-p-tolylsulfanyl-ethanone;
[4-(4-Bromo-benzenesulfonyl)-piperazin-1-yl]-furan-2-yI-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;
A∑epan-1-yl-[5-(2,4-dichloro-phenoxymethyl)-furan-2-yl]-methanone;
N-Cycloheptyl-4-(4-methoxy-2-methyl-phenyl)-butyramide; 2-(4-BenzothiazoI-2-yl-piperazin-1-yl)-N-cyclohexyl-acetamide;
N-CycloheptyI-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-yloxymethyI)-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-methyI-benzamide; N-Cyclooctyl-2-p-tolyloxy-acetamide; (3,5-DimethyI-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-ChIoro-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-pyra∑ol-4-yl)-acrylamide;
N-Adamantan-1 -yl-N-methyl-4-(4-nitro-pyrazol-1-ylmethyl)-benzamide;
5-(4-ChIoro-3,5-dimethyl-pyrazol-1 -ylmethyl)-f uran-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-TolyI-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-1 H- quinoIin-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-CyclohexyI-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]dioxoI-5-yl-3-furan-2-yl-3-oxo-propylsulfanyl)-phenyl]-acetamide;
(3,5-Dimethyl-piperidin-1-yl)-(3-iodo-phenyl)-methanone;
[5-(2-Bromo-phenoxymethyI)-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-carbonyI)-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-pipehdin-1-yl)-methanone;
Adamantane-1 -carboxylic acid furan-2-yImethyl-p-tolyl-amide;
Azocan-1-yl-(4-tert-butyl-phenyl)-methanone;
3-Chloro-ben∑o[b]thiophene-2-carboxylic acid ben∑yl-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-yI)-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-1H-isoquinolin-2-yl)-methanone; N-Adamantan-1 -yl-2-trifluoromethyl-benzamide;
(3-Bromo-phenyI)-(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-1 H-isoquinolin-2-yl)-(3,4-dimethyl-phenyl)-methanone;
(1 -Adamantan-1 -yl-4-bromo-1 H-pyrazol-3-yl)-morpholin-4-yI-methanone;
2-Phenyl-cyclopropanecarboxylic acid cyclooctylamide;
3-[4-(2-Ethoxy-phenyI)-piperazine-1-carbonyl]-isochromen-1-one;
[3-(4-Bromo-pyrazoI-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; i\!-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;
(4-Hydroxy-4-phenyl-octahydro-quinolin-1-yl)-phenyl-methanone;
(2-Chloro-phenyl)-(2-methyl-piperidin-1-yl)-methanone; (10,11-Dihydro-dibenzo[b,f]azepin-5-yl)-(2-methoxy-phenyI)-methanone;
(3-Chloro-phenyl)-(2-methyl-piperidin-1-yl)-methanone;
(3-Chloro-6-nitro-benzo[b]thiophen-2-yl)-(3-methyI-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-phenyI)-piperazin-1-yl]-methanone;
Cyclooctanecarboxylic acid [1 -(naphthalene-2-sulfonyl)-pyrrolidin-2-yl]-amide;
1-ButyI-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-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)-acetarnide; 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-phenyI)-acetamide; (4-tert-Butyl-piperidin-1 -yl)-phenyl-methanone;
N-(4-tert-Butyl-3-nitro-phenyI)-acetamide;
(2,6-Dimethyl-piperidin-1-yl)-[5-(2,3,5,6-tetrafluoro-phenoxymethyl)-furan-2-yl]-methanone;
2-(4-Chloro-3,5-dimethyl-phenoxy)-N-cyclohexyl-N-methyl-acetamide;
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-1 H-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-1 H-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-1 H-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-[(Adamantane-1-carbonyl)-amino]-3-(1 H-indol-3-yl)-propionic acid methyl ester;
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-1 H-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;
6-(2,4-Dichloro-phenylcarbamoyl)-3,4-dimethyl-cyclohex-3-enecarboxylic acid;
2-(2-Cyano-phenylsulfanyl)-N-cyclopentyl-benzamide; [5-(2-Methoxy-4-propyI-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-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 -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-1H-benzo[g]quinolin-4-one; 2-[(Adamantane-1-carbonyl)-amino]-3-phenyI-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-(2-oxo-4-phenyl-pyrrolidin-1-yl)-acetamide;
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-ben∑amide;
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-[(Adamantane-1-carbonyl)-amino]-3-(1 H-indol-3-yl)-propionic acid methyl ester;
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 [3-(1 H-benzoimidazol-2-ylsulfanyl)-5-nitro-phenyl]-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-thfluoromethyl-pyridin-2-ylsulfanyl)-acetamide;
2-(3-Oxo-3-phenyl-propenyl)-isoindole-1 ,3-dione;
Adamantane-1 -carboxylic acid (4-ethoxy-benzothiazol-2-yl)-amide;
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-ChIoro-phenoxy)-N-(4-chloro-3-trifluoromethyl-phenyl)-acetamide;
2,2-Dimethyl-N-(5-propyl-[1,3,4]thiadiazol-2-yI)-propionamide;
2-[2-(2,6-Dimethyl-morpholin-4-yl)-1-methyl-2-oxo-ethyl]-isoindole-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,f]azepin-5-yl)-methanone; (2-Chloro-phenyl)-(10,11-dihydro-dibenzo[b,f]azepin-5-yl)-methanone;
2-Amino-5-(azepane-1-carbonyI)-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-imida∑ol-4-yl)-piperidin-1-yl]-propan-1-one;
1 -(4-Propyl-piperazin-1 -yl)-3-(4-trifluoromethyl-phenyl)-propan-1 -one;
N-(2-Hydroxy-ben∑yl)-3-thiophen-3-yI-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-ben∑yl)-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-phenyI)-ethyl]-N-(4-hydroxy-benzyl)-2-thiophen-3-yl-acetamide;
N-(2-Chloro-benzyl)-N-(4-hydroxy-benzyl)-2-thiophen-2-yI-acetamide;
Heptanoic acid benzyl-(4-hydroxy-benzyl)-amide;
N-(4-Fluoro-benzyl)-N-(4-hydroxy-benzyI)-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-phenyIsulfanyI)-pentanoic acid (naphthalen-1 -ylmethyl)-amide;
N-(6,6-Dimethyl-bicyclo[3.1.1]hept-2-yImethyl)-4-[2-(5-methyl-1 H-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-bicycIo[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;
N-(6,6-Dimethyl-bicyclo[3.1.1]hept-2-ylmethyI)-4-[2-(5-methyl-1 H-benzoimidazol-2-ylsulfanyl)- ethyl]-benzamide;
N-(6,6-Dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-4-[2-(4-fluoro-phenylsulfanyl)-ethyl]- benzamide; 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-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-carboxyIic 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-cyclohexyI)-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-[methyI-(2-pyridin-4-yl-ethyl)-amino]-N-prop-2-ynyl- propionamide;
4-Methyl-cyclohexanecarboxylic acid {[2-(2-chloro-6-fluoro-benzylsulfanyl)-ethylcarbamoyϊ]- methyl}-prop-2-ynyl-amide; 2-Benzylsulfanyl-N-{[2-(2-chloro-6-fluoro-benzylsulfanyl)-ethylcarbamoyl]-methyl}-N-(2- methoxy-ethyl)-acetamide;
4-[2-(5-CyclopropylmethylsuIfanyl-[1 ,3,4]thiadiazol-2-yIsulfanyl)-ethyl]-N-(6,6-dimethyl- bicyclo[3.1.1]hept-2-ylmethyl)-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)-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)- ben∑amide;
3-Methoxy-N-(2-oxo-azepan-3-yl)-N-(2-piperidin-4-yI-ethyl)-5-(pyridine-2-carbonyl)- ben∑amide; 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)-benzoyl]-amino}-methyl)- ben∑oic 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- .-(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-ben∑oimidazol-2-one;
N-(2-Hydroxy-ben∑yl)-N~isobutyl-ben∑amide;
N-(2-Hydroxy-ben∑yl)-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-benzyI)-N-(3-methyI-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 of the present invention said substituted amide, or a prodrug thereof, as a component of the combination therapy is selected from the group consisting of:: (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-Ben∑yloxy-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-ben∑amide;
2-Chloro-N-cyclohexyl-N-ethyl-4-nitro-ben∑amide;
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-trimethyI-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-trimethyI-6-aza-bicyclo[3.2.1]octane-6-carbonyl)- phenyl]-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-a∑a-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-acetamide;
(4-Dimethylamino-phenyl)-(1 ,3,3-trimelhyl-6-a∑a-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-yl)-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-phenyl)-(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-yl)-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-carboxyIic 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]lhiazol-6-yl-(1 ,3,3-lrimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-melhanone; 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.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lla)
Figure imgf000071_0001
(lla) wherein
R1 is aryl, arylCrC6alkyI, hetaryl or hetaryld-Cealkyl optionally substituted with one or more of R6 independently; R2 is halo, d-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, C3-Cι0cycloalkyl, C3-CιocycloalkylCrC6- alkyl, trihalomethyl, aryl, arylCrCealkyl, CrCealkyloxyCrCealkyl, arylCrCealkyloxyCrCealkyl, Cι-C6alkylNR5CrC6alkyi, arylCrCealkylNR5CrC6alkyl, hetaryl or hetaryld-Cealkyl 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-Cι0hetcycloalkyl, Ce-CiocycloalkylCrCealkyl or C6-Cι0hetcyclo- 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 bicydic/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, hetarylCrCealkyl, hydroxy, oxo, d-Cealkyloxy, arylCrC6alkyloxy or hetarylCi -C6alkyloxy, wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R9;
R5 is d-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C3-Cιohetcycloalkyl, C3-Cι0- cycloalkyld-C6alkyl, C3-Cι0hetcycloalkylCι-C6alkyl, 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, CrC6alkyl, CrCealkyloxy, trihalomethyl, trihalomethoxy, NR10R11, aryld-Cealkyloxy, hetarylCrC6alkyloxy, d- C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkylcarbonyl, CrC6alkyloxycarbonyl, aryloxycarbonyl, arylCrCealkyloxycarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
R8 and R9 independently are hydrogen, d-Cealkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, NR10R11, d-C6alkyloxy, aryloxy, arylCrC6alkyloxy, hetaryloxy, hetarylCrCealkyloxy, CrC6alkyloxyCι-C6alkyl, d-Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkyIcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy; R10 and R11 independently are hydrogen, d-C8alkyl, aryl, hetaryl, arylCrCealkyl, C3-Cι0- cycloalkyl, C3-C10hetcycloalkyl, C3-CιocycloalkylCrC6alkyl, CrC6alkylcarbonyl, d- CealkylcarboxyCrCealkyl; 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, hetaryld-Cealkyl, hydroxy, oxo, cyano, d-C6alkyloxy, arylCrC6alkyloxy, hetaryld- Cealkyloxy, CrCealkyloxyCrCealkyl, d-Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, aryld-Cealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, 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, or any tautomeric forms.
In another embodiment of the present invention said substituted amides, or a prodrug thereof, as a component of the combination therapy is of the general formula (lla) wherein:
R1 is aryl or hetaryl optionally substituted with one or more R6 independently;
R2is halo, d-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C10cycloalkyl, G3-CιoCycloalkylCrC6- alkyl, aryl, arylCrC6alkyl, Cι-C6alkyloxyCrC6alkyl, arylCrC6alkyloxyCrC6alkyl, CrC6- alkylNR5CrC6alkyl, aryld-CealkylNR^rCealkyl, hetaryl or hetarylCrC6alkyl wherein the al- kyl, alkenyl, alkynyl, cycloalkyl and aryl groups independently are optionally substituted with one or more R7;
R3 is Cι-C6alkyl optionally substituted with one or more of R8;
R4 is Crdocycloalkyl, C6-Cι0hetcycloalkyl, Ce-CiocycloalkylCrCealkyl 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-C6alkenyl, C2-C6alkynyl, C3-Cι0cycloalkyl, C3-Cι0hetcycloalkyl, C3-Cι0- cycloalkyld-C6alkyl, C3-CιohetcycloalkylCrC6alkyl, aryl, hetaryl, arylCrC6alkyl or hetarylCr 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, d-C6- alkyloxy, trihalomethyl, trihalomethoxy, NR10R11, arylCrCealkyloxy, hetarylCrCealkyloxy, d- C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, CrCealkyloxycarbonyl, aryloxycarbonyl, aryld-C6alkyloxycarbonyl, CrC6alkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
R8 and R9 independently are hydrogen, d-Cealkyl, aryl, hetaryl, aryICrC6aIkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, NR10R11, CrC6alkyIoxy, aryloxy, arylCrCealkyloxy, hetaryloxy, hetarylCrCealkyloxy, CrCealkyloxyCrCealkyl, CrC6alkyl-carbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrC6alkyl-carbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
R10 and R11 independently are hydrogen, CrC8alkyl, aryl, hetaryl, arylC C6alkyl, C3-C10- cycloalkyl, C3-Cι0hetcycloalkyl, Cs-CioCycloalkylCi-Cealkyl, CrC6alkylcarboxyCrCealkyl; 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-Cealkyl, aryl, hetaryl, aryld- Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, aryld-Cealkyloxy, hetaryl d-C6alkyIoxy, CrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrC6alkylcarbonyl, d-Cealkylcarboxy, 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. In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lla) wherein R1 is aryl, arylCrC6alkyl or hetaryl optionally substituted with one or more of R6.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lla) wherein R1 is aryl optionally substituted with one or more of R6. In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lla) wherein R1 is aryICrC6alkyl optionally substituted with one or more of R6.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lla) wherein R1 is hetaryl optionally substituted with one or more of R6.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lla) wherein R2 is CrC6alkyl, C3-Cι0cycloalkyl, drdocycloalkylCrCealkyl, trihalomethyl, aryld- C6alkyl, or hetaryICrC6alkyl wherein the alkyl, cycloalkyl and aryl groups independently are optionally substituted with one or more R7.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lla) wherein R2 is d-C6alkyl optionally substituted with one or more R7. In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lla) wherein R2 is trihalomethyl.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lla) wherein R3 is C C6alkyl optionally substituted with one or more of R8.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lla) wherein R4 is G6-docycloalkyl, or C6-Cι0hetcycloalkyl, wherein the cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R8. In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lla) wherein R4 is C6-Cι0cycloalkyl optionally substituted with one or more of R8.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lla) wherein R4 is C6 C6-Cι0hetcycloalkyl optionally substituted with one or more of R8.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lla) wherein R3 and R4 together with the nitrogen to which they are attached, are forming a saturated or partially saturated bicydic/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 Cι-C6alkyl, aryl, hetaryl, aryld- C6alkyl, hetaryld-Cealkyl, hydroxy, oxo, CrC6alkyloxy, aryld-C6alkyloxy 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 said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lla) wherein the saturated or partially saturated bicyclic/bridge ring system is 6-aza- bicyclo[3.2.1 joctane.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lla) wherein R6 and R7 independently are hydrogen, hydroxy, oxo, halo, cyano, CrC6alkyl, CrCealkyloxy, trihalomethyl, NR10R11, aryld-Cealkyloxy, hetarylCrCealkyloxy, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkylcarbonyl, CrCealkyloxycarbonyl, aryloxycarbonyl or arylCrCealkyloxycarbonyl. In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lla) wherein R8 and R9 independently are hydrogen, CrC6alkyl, hydroxy, oxo, CrC6alkyloxy or arylCrCealkyloxy.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lla) wherein R10 and R11 independently are hydrogen or CrC8alkyl.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is selected from the group consisting of: 1-(4-Chloro-phenyl)-5-propyI-1H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; 1-(4- Chloro-phenyl)-5-trifluoromethyl-1 H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; [1 -(4-Methoxy-phenyl)-5-methyl- 1 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. In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is 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-phenyI)-5-methyl-1 H-pyrazoIe-4-carboxylic acid cyclohexyl-methyl-amide; 1-(2-Pyridyl)-5-methyl-1 --pyrazole-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 mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (Mb)
Figure imgf000077_0001
(lib) wherein R1 is hydrogen, trihalomethyl, CrC6alkyl, CrC6alkyIoxy, CrC6alkylthio, 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, triha- lomethyl, d-Cealkyl, 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; 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 d-C6- alkyl, aryl, hetaryl, arylCrC6alkyI, hetarylCrC6alkyl, 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 CrCealkyl, aryl, hetaryl, arylCrC6alkyl, hetaryld-Cealkyl, hydroxy, oxo, C C6alkyIoxy, aryloxy, aryld-Cealkyloxy 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 CrCealkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrCealkyl, hydroxy, oxo, CrC6alkyloxy, aryloxy, arylCrCealkyloxy or hetarylCrCealkyloxy;
R6 is aryl, hetaryl, arylCrC6alkyl, C3-C10cycloalkyl, Crdohetcycloalkyl, C3-Cι0cycloalkylCr C6alkyl, CrCealkylcarboxyCrCealkyl, wherein the alkyl, aryl and cycloalkyl groups independently are optionally substituted with one or more of R11;
R7 is CrC8alkyl, aryl, hetaryl, arylCrC6alkyl, C3-d0cycloalkyl, C3-Cι0hetcycloalkyl, 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 CrC8alkyl, aryl, hetaryl, aryld- C6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrC6alkyloxy, hetaryld- C6alkyloxy, CrC6alkyloxyCrC6alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, aryl- d-Cealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R8;
R9 and R10 independently are hydrogen, CrC8alkyl, aryl, hetaryl, arylCrC6alkyl, C3-Cι0- cycloalkyl, C3-Cι0hetcycloalkyl, 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 CrC8alkyl, aryl, hetaryl, aryld- C6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrC6alkyIoxy, hetaryld- C6alkyloxy, CrCealkyloxyCrCealkyl, d-Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, aryl- CrCealkylcarbonyl, 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, CrC8alkyl, CrC6- alkyloxy or aryloxy; 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 said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lib) wherein R1 is hydrogen or CrCealkyl, wherein the alkyl group is optionally substituted with one or more of R8.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lib) wherein R1 is hydrogen.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lib) wherein R2, R3, R4 and R5 are hydrogen.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lib) wherein 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 or oxygen, the ring system optionally being substituted with at least one of CrCealkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrCealkyl, hydroxy, oxo, CrC6alkyloxy, aryloxy, arylCrC6alkyloxy or hetarylCrCealkyloxy. In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lib) wherein 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 CrCealkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrCealkyl, hydroxy, oxo, CrC6alkyloxy, aryloxy, arylCrCealkyloxy or hetarylCrCealkyloxy.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (Mb) wherein 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 CrC8alkyl, aryl, hetaryl, aryld- C6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrCealkyloxy, hetaryld- C6alkyloxy, CrC6alkyloxyCrC6aIkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R8;
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lib) wherein 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 CrC8alkyl, aryl, hetaryl, arylCrC6alkyl, hetarylC C6alkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrC6alkyloxy, hetaryld- C6alkyloxy, CrCealkyloxyd-Cealkyl, d-Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkylcarbonyl, hetarylCrC6alkylcarbonyl, d-Cealkylcarboxy, 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 said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lib) wherein 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 d-C8alkyl, aryl, hetaryl, aryld- C6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C6alkyloxy, arylCrCealkyloxy, hetaryld- C6alkyloxy, CrCealkyloxyd-Cealkyl, 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 R8.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is selected from the group consisting of: pyrazolo[1 ,5-a]pyridin-3-yl-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; (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 of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lie):
Figure imgf000081_0001
(He) wherein
R1 is hydrogen, CrC8alkyl, CrCealkyloxyCrCealkyl, aryl, hetaryl, arylCrC6alkyl, hetaryld- Cealkyl, d-C6S02, arylSOa, hetarylS02, arylCrC6alkylS02 or hetaryICrC6alkylS02 all of which is 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 R9; and
either Rd is hydrogen; and R4 is C(0)NR'R°; or Rd is C(0)NR'Ra; 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 CrC8alkyl, C3-Cι0cycloalkyl, C3-C10hetcycloalkyl, C3-Cι0cyclo- alkylCrCealkyl, 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, CrCealkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, Cι-C6alkyloxyCr C6alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetaryld- C6alkylcarbonyl, CrC6alkylcarboxy, 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, CrCealkyloxy, trihalomethyl, trihalomethoxy, NR12R13, C(0)NR12R13, arylCrC6alkyloxy, CrCealkylcarbonyl, arylcarbonyl, arylCrC6alkylcarbonyl, CrCealkylcarboxy, arylcarboxy or aryld-C6alkylcarboxy;
R10 and R11 independently are hydrogen, halo, oxo, hydroxy, CrC6alkyl, aryl, arylCrC6alkyl, hetaryl or hetarylalkyl;
R12 and R13 independently are hydrogen, CrC8alkyl, aryl, hetaryl, arylCrCealkyl, C3-Cι0- cycloalkyl, C3-Cι0hetcycloalkyl, C3-Cι0cycloalkylCrC6alkyl, d-C6alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, 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 d-C8alkyl, aryl, hetaryl, aryld- Cealkyl, hetaryld-Cealkyl, hydroxy, oxo, cyano, d-Cealkyloxy, arylCrCealkyloxy, hetaryld- C6alkyloxy, Cι-C6alkyI-oxyCrC6alkyl, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkyl-carbonyl, hetarylCrCealkylcarbonyl, d-Cealkylcarboxy, arylcarboxy or arylCr 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 of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lid)
Figure imgf000083_0001
(lid) wherein
R1 is hydrogen, d-C8alkyl, aryl, hetaryl, arylCrC-alkyl or hetarylCrCealkyl optionally substituted with one or more R8;
R2 and R5 independently are hydrogen, halo, nitro, cyano, trihalomethyl, d-Cealkyl, aryl, arylCι-C6alkyl, hetaryl or hetaryld-Cealkyl wherein the alkyl, aryl, arylalkyl, hetaryl and hetarylalkyl groups independently are substituted with one or more R8; and
either R? is hydrogen; and R4 is G(0)NRbRø or R- is C(0)NR°R'; and R4 is hydrogen;
R6 and R7 independently are Cι-C8alkyl, C3-Gι0cycloalkyl, C3-Cι0hetcycloalkyl, C3-Cι0cyclo- alkylCrC6alkyl, 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 CrC8alkyl, arylCrC6alkyl, hetarylCrCealkyl, hydroxy, cyano, CrC6alkyIoxy, 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, CrC6alkyl, CrCealkyloxy, trihalomethyl, tri- halomethoxy, NR11R12, arylCrCealkyloxy, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, d-C6alkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
R9 and R10 independently are hydrogen, halo, oxo, hydroxy, CrC6alkyl, aryl, arylCrC6alkyl, hetaryl or hetarylalkyl;
R11 and R12 independently are hydrogen, CrC8alkyl, aryl, hetaryl, arylCrC6alkyl, C3-C10- cycloalkyl, C3-Cι0hetcycloalkyl, C3-CιocycIoalkylCrC6alkyl, d-Cealkyl-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-Cealkyl, aryl, hetaryl, aryld- Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrCealkyloxy, hetaryld- Cealkyloxy, CrC6alkyl-oxyCrC6alkyl, d-C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkyl-carbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or aryld- Cealkylcarboxy; 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 said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lie) and (lid) wherein R1 is hydrogen, d-C8alkyl, aryld-Cealkyl, hetarylCrCealkyl, arylS02, hetarylS02, aryld-C6alkylS02 or hetarylCrC6alkylS02 all of which is optionally substituted with one or more R8. In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lie) and (lid) wherein R1 is hydrogen, d-C8alkyl, aryld-Cealkyl, hetaryld-Cealkyl all of which is optionally substituted with one or more R8.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lie) and (lid) wherein R1 is arylS02, hetarylS02, arylCrC6alkylS02 or hetarylC C6alkyIS02 all of which is optionally substituted with one or more R8.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lie) and (lid) wherein R2 is hydrogen.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (He) and (lid) wherein R3 is hydrogen and R4 is C(0)NR7R8.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (He) and (lid) wherein R3 is C(0)NR7R8 and R4 is hydrogen.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lie) and (lid) wherein R5 is hydrogen. In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lie) wherein R6 is hydrogen, NR12R13, d-Cealkyl, aryl or hetaryl wherein the alkyl, aryl and hetaryl independently are substituted with one or more R9.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (He) and (lid) wherein R7 and R8 independently are CrC8alkyl or Ordocycloalkyl, wherein the alkyl and cycloalkyl groups independently are optionally substituted with one or more of R10.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lie) and (lid) wherein 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 C C8alkyl, aryld-C6alkyl, hetaryld- Cealkyl, hydroxy, cyano, d-C6alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, CrC6alkyl- oxyd-C6alkyl, d-Cealkylcarbonyl, 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. In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (He) and (lid) wherein R9 is hydrogen, hydroxy, oxo, halo, nitro, cyano, d-Cealkyl, CrC6alkyloxy, triha- lomethyl, trihalomethoxy, NR12R13, C(0)NR 2R13, aryld-C6alkyloxy, d-Cealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (He) and (lid) wherein R10 and R11 independently are hydrogen, halo, oxo, hydroxy, CrC6alkyl, aryl, aryld-Cealkyl, hetaryl or hetarylalkyl.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lie) and (lid) wherein R 1 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-Cealkyl, aryl, hetaryl, aryld- C6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C6alkyloxy, arylCrC6alkyloxy, hetaryld- C6alkyloxy, CrC6alkyl-oxyCrC6alkyI, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkyl-carbonyl, hetarylCrC6alkylarbonyl, CrC6alkylcarboxy, arylcarboxy or aryld- Cealkylcarboxy.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is selected from the gropu consisting of: 1H-Benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide;
1 -Benzyl-1 H-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide; (1 H-Benzoimidazol-5-yI)-(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 said substituted amides, or a pro- drug thereof, as a component of the combination therapy is selected from the group consisting of: lsopropyl-2-trifluoromethyl-1 /-/-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-Hydroxy methyl-1 /-.-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide; 2-(4-Amino-phenyl)-1 /-/-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide; (1/.-Benzoimidazol-5-yI)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; (2-Methyl-1/-/-benzoimidazol-5-yI)-(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-./-/-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)- /-/-benzoimidazol-2-yl]-benzoic acid methyl ester; (2-Thiophen-2-yl-7H-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 mix- ture of optical isomers, including a racemic mixture, a prodrug thereof, or any tautomeric forms.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lie)
Figure imgf000087_0001
(Ne) wherein
X is oxygen or (CR1R2)n;
R\ R2, R3, and R4 independently are hydrogen, d-C6alkyl, aryl, arylCrC6alkyl, hetaryl or hetaryld-Cealkyl 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, arylCrC6alkyl or hetarylCrCealkyl; or
R1 and either R3 or R4 together with the single bond are forming a carbon-carbon double bond;
R5 is CrC8alkyl optionally substituted with one or more of R9 R6 is C3-Cιocycloalkyl, C3-Cι0hetcycloalkyl, C3-CιocycloalkyICrC6alkyI, 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, d-Cealkyloxy, arylCrCealkyloxy, hetaryld- C6alkyloxy, CrCealkyloxyCrCealkyl, d-Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or aryld- 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, arylCrCealkyl, d- 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, d-Cealkyl, d-C6- alkyloxy, trihalomethyl, trihalomethoxy, NR12R13, arylCrCealkyloxy, d-Cealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
R10 is hydrogen, d-C8alkyl, arylCrC6alkyl, hetarylCrCealkyl, Cι-C6alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy;
R11 is hydrogen, halo, hydroxy, oxo, nitro, cyano, CrC8alkyl, CrC6alkyloxy, aryloxy or hetaryloxy;
R12 and R13 independently are hydrogen, C C8alkyI, aryl, hetaryl, arylCrC6alkyl, C3-Cι0cyclo- alkyl, C3-C10hetcycloalkyl, CrCealkylcarbonyl, arylCrCealkylcarbonyl, d-CiocycloalkylCrCe- 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 d-Cealkyl, aryl, hetaryl, aryld- C6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrCealkyloxy, hetaryld- Cealkyloxy, CrCealkyloxyCrCealkyl, CrCealkylcarbonyl, 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 mix- ture of optical isomers, including a racemic mixture, a prodrug thereof, or any tautomeric forms.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (Ile) wherein X is (CR1R2)n, wherein R1, R2 and n are as defined above. In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lie) wherein n is 1.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (Ile) wherein X is oxygen.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lie) wherein R1, R2, R3, and R4 independently are hydrogen, C C6alkyl or aryld-Cealkyl, optionally substituted with one or more R8. In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (Ile) wherein 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 said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lie) wherein R5 is CrC8alkyl optionally substituted with one or more of R9.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lie) wherein R6 is C3-d0cycloalkyl or C3-C10hetcycloalkyl each of which is optionally substituted with one or more of R9. In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lie) wherein R6 is C3-Cι0cycloalkyl optionally substituted with one or more of R9.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (Ile) 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 Cι-C6alkyl, aryl, hetaryl, arylCι-C6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, CrCealkyloxyCrCealkyl, d-Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylC C6alkylcarbonyl, 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 said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (Ile) wherein R7 is hydrogen, halo, NR12R13, trihalomethyl, d-C6alkyloxy, aryloxy, aryld- Cealkyloxy or hetaryloxy optionally substituted with one or more R11 independently.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (lie) wherein R8 and R9 independently are hydrogen, hydroxy, oxo, halo, nitro, cyano, CrC6alkyl, Cι-C6alkyloxy, trihalomethyl, or NR12R13.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (Ile) wherein R10 is hydrogen or d-C8alkyl.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (Ile) wherein the bicyclic ring system is 6-aza-bicyclo[3.2.1]octane optionally substituted with one or more of d-C6alkyl. In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (Ile) wherein the bicyclic ring system is 1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is selected from the group consist- ing 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, or any tautomeric forms.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy 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 of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (llf)
Figure imgf000092_0001
(llf) wherein
R1 is hydrogen, CrC8alkyl, hetaryl, arylCrCealkyl or hetarylCi -C6alkyl 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-Cιohetcycloalkyl, N(R12R13)d- C6alkyl, CrC6alkyloxy, CrC6alkyloxyCrC6alkyl, aryl, arylCrCealkyl, aryloxy, aryloxyCr C6alkyl, arylCrC6alkyloxy, arylCrCealkyloxyCrCealkyl, CrCealkylcarboxy, arylcarboxy, arylCrCealkylcarboxy, hetaryl, hetarylCrCealkyl, hetarylCrCealkyloxy, hetaryloxyCrCealkyl or hetar lCrCealkylo yCrCeal yl wherein wherein the alkyl, aryl, arylalkyl, hetaryl and hetarylalkyl groups independently are substituted with one or more R9;
R7 is hydrogen or d-G8alkyl optionally substituted with one or more of R10;
R8 is C3-Cι0cycloalkyl, C3-Cι0hetcycloalkyl, C3-GιocycloalkylCrC6alkyl, 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 CrC8alkyl, aryl, hetaryl, arylCrCealkyl, hetarylCrC6alkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, CrCealkyloxyCrCealkyl, d-Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrC6alkyl- carboxy 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, CrC6alkyloxy, trihalomethyl, trihalomethoxy, NR12R13, arylCrC6alkyloxy, d-Cealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, CrC6aIkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
R10 and R11 independently are hydrogen, halo, oxo, hydroxy, CrC6alkyl, aryl, arylCrC6alkyl, hetaryl or hetarylalkyl;
R12 and R13 independently are hydrogen, CrC8alkyl, aryl, hetaryl, arylCrC6alkyl, C3-Cι0- cycloalkyl, C3-Cι0hetcycloalkyl, C3-C10cycloalkylCrC6alkyl, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, C3-Cι0cycloalkylcarbonyl, C3-Cι0hetcycloalkylcarbonyl 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 d-C8alkyl, aryl, hetaryl, aryld- C6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrCealkyloxy, hetarylCr C6alkyloxy, Cι-C6alkyl-oxyCι-C6alkyl, 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, or any tautomeric forms.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (llf) wherein
R1 is hydrogen, CrC8alkyl, hetaryl, aryICrC6alkyl or hetaryld-Cealkyl optionally substituted with one or more R9;
R2 and R5 independently are hydrogen, halo, nitro, cyano, trihalomethyl, CrC6alkyl, CrCealkyloxy, CrCealkyloxyCrCealkyl, aryl, arylCι~C6alkyl, aryloxy, aryIoxyCrC6alkyl, arylCrC6- alkyloxy, arylCrCealkyloxyCrCealkyl, hetaryl or hetarylCrCealkyl 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 d-Cβalkyl, C3-C10cycloalkyl, C3-C10hetcycloalkyl, N(R12R13)CrC6alkyl, d-Cealkyloxyd- C6alkyl, aryloxyCrCealkyl, arylCrCealkyloxy or arylCrCealkyloxyCrCealkyl;
R7 is CrC8alkyl optionally substituted with one or more of R10;
R8 is C3-Ci0cycloalkyl, 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 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 CrCβalkyl, aryl, hetaryl, arylCrG6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, CrCealkyloxyCrCealkyl, C C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, aryld-Ce- alkylcarbonyl, 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, tri- halomethoxy, NR12R13, arylCrCealkyloxy, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or aryld-Cealkylcarboxy;
R10 and R11 independently are hydrogen, halo, oxo, hydroxy, d-Cealkyl, aryl, arylCrC6alkyl, hetaryl or hetarylalkyl;
R12 and R13 independently are hydrogen, C C8alkyl, aryl, hetaryl, arylCrC6alkyl, C3-Cι0- cycloalkyl, C3-Cι0hetcycloalkyl, Ordocycloalkyld-Cealkyl, d-Cealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, C3-Cι0cycloalkylcarbonyl, C3-Cι0hetcycloalkylcarbonyl or C3-Cι0cyclo- 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- C6alkyl, hetarylCrC6alkyl, hydroxy, oxo, cyano, d-C6alkyloxy, aryld-Cealkyloxy, hetaryld- Cealkyloxy, CrCealkyl-oxyd-Cβalkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkyl-carbonyl, hetarylCrCealkylcarbonyl, CrC6alkylcarboxy, arylcarboxy or aryld- C6alkyIcarboxy; 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 said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (llf) wherein R2 is C(0)NR7R8 and R3 R4and R5 are hydrogen, wherein R7 and R8 are as defined above. In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (llf) wherein R3 is C(0)NR7R8 and R2 R4and R5 are hydrogen, wherein R7 and R8 are as defined above.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (llf) wherein R4 is C(0)NR7R8 and R2 R3and R5 are hydrogen, wherein R7 and R8 are as defined above.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (llf) wherein R5 is C(0)NR7R8 and R2 R3and R4are hydrogen, wherein R7 and R8 are as defined above.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (llf) wherein R6 is C(0)NR7R8, wherein R7 and R8 are as defined above. In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (llf) wherein R3 is C(0)NR7R8 and R4 is hydrogen, wherein R7 and R8 are as defined above.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (llf) wherein R3 is hydrogen and R4 is C(0)NR7R8, wherein R7 and R8 are as defined above. In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (llf) wherein R8 is C3-Cι0cycloalkyl or C3-Cι0hetcycloalkyl, each of which is optionally substituted with one or more of R10, wherein R10 is as defined above. In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (llf) wherein 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 sys- tem optionally being substituted with at least one of d-C8alkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrC6alkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrCealkyloxy, hetaryld-Cealkyloxy, CrCealkyloxyd-Cealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, aryld- C6alkylcarbonyl, hetarylCrC6alkylcarbonyl, CrCealkylcarboxy, arylcarboxy or aryld-Cealkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R11, wherein R11 is as defined above.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (llf) wherein the bicyclic ring system is 6-a∑a-bicyclo[3.2.1]octane optionally substituted with one or more d-Cealkyl. In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (llf) wherein the bicyclic ring system is 1 ,3,3-trimethyl-6-a∑a-bicyclo[3.2.1]octane.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is selected from the group consist- ing of:
(1 -.-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; (1r.-lndol-7-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; (1/-/-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 /- -lndole-6-carboxylic acid (8-methyI-8-aza-bicyclo[3.2.1]oct-3-yl)-amide;
1 H-lndole-5-carboxylic acid adamantan-2-ylamide;
(6-Aza-bicyclo[3.2.1]oct-6-yl)-(1H-indol-5-yl)-methanone; (1 H-lndol-4-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; 1H-lndoI-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; Methyl-1 H-indole-3-carboxylic acid cycloheptylamide; Methyl-1 H-indole-3-carboxylic acid adamantan-1 -ylamide;
3-Aza-bicyclo[3.2.2]non-3-yl)-(1-methyl-1/-/-indol-3-yl)-methanone;
1 -Methyl-1 H-indol-3-yl)-(4-methyl-piperazin-1 -yl)-methanone;
-Methyl-1 H-indole-3-carboxylic acid (3-hydroxy-adamantan-1-yl)-amide; 1 -Methyl-1 - -indole-3-carboxylic acid azepan-1 -ylamide;
Methyl-1 H-indoIe-3-carboxylic acid (2-oxo-azepan-3-yl)-amide;
4-Benzyl-piperidine-1 -yl)-(1 -methyl-1 /-/-indol-3-yl)-methanone; Methyl-1 H-indole-3-carboxylic acid (2,6-dimethyl-piperidin-1-yl)-amide; Methyl-1 - -indoIe-3-carboxylic acid (2-methyl-piperidin-1 -yl)-amide; (1-CyclopropylmethyI-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-1r.-indol-3-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
6-Trifluoromethyl-1 H-indol-3-yI)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1 ]oct-6-yl)-methanone;
6-Melhyl-1 W-indol-3-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-β-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-FIuoro-1 H-indol-3-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1 ]oct-6-yl)-methanone;
6-Methoxy-1 -r'-indoI-3-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
7-Nitro-1 - -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-(1/.-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-(1H-indol-3-yl)-ethanone;
(3-Aza-bicyclo[3.2.2]non-3-yl)-2-(1-methyl-1H-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)-1/- -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 - -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)-1 H-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)-1 -/-indole-3-carboxylic acid; 5-(1 ,3,3-Trimethyl-6-aza-bicydo[3.2..1]octane-6-carbonyl)-1 -/-indole-3-carboxylic acid ethyl ester;
4-(1,3,3-Trimethyl-6-aza-bicyclo[3.2. 1]octane-6-carbonyl)-1 - -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; [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)-1 H-indole-3-carboxylic acid cyanomethyl-amide;
5-(1 ,3,3-Trimethyl-6-a∑a-bicyclo[ 3: .2.1]octane-6-carbonyl)-1H-indole-3-carboxylic acid ben- zylamide;
5-(1,3,3-Thmethyl-6-aza-bicyclo[ 3; .2.1]octane-6-carbonyl)-1H-indole-3-carboxylic acid di- methylamide;
5-(1 ,3,3-Trimethyl-6-aza-bicyclo[: 3.2.1]octane-6-carbonyl)-1H-indole-3-carboxylic acid allyla- mide; 5-(1 ,3,3-Trimethyl-6-aza-bicyclo[ 3: .2.1]octane-6-carbonyl)-1H-indole-3-carboxylic acid (2- dimethylamino-ethyl)-methyl-ami iddee;;
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-TrimethyI-6-aza-bicyclo[ 3: .2.1]octane-6-carbonyl)-1 -/-indole-3-carboxylic acid 4- methoxy-benzylamide;
5-(1 ,3,3-Trimethyl-6-aza-bicyclo[ 3: .2.1]octane-6-carbonyl)-1 - -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-yI)-methanone; [3-(2,6-Dimethyl-morpholine-4-carbonyl)-1H-indol-5-yl]-(1 ,3,3-trimethyl-6-aza-bicycIo-
[3.2.1 ]oct-6-yl)-methanone;
5-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1 ]octane-6-carbonyl)-1 -/-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)-1 H-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 - -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)-1H-indole-3-carbonyl]-amino}- propionic acid ethyl ester;
5-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1 H-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-(1H-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-(1H-lndole-5-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one; (4-fert-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)-(1 -/-indol-5-yl)-methanone;
(1H-lndol-5-yl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; 1 - -lndole-5-carboxylic acid (5-hydroxy-1 ,3,3-trimethyl-cyclohexylmethyl)-amide; 1/-/-lndoIe-5carboxylic acid (3,4-dihydrospiro(1H-indene-1 ,4-piperidine)-amide;
(3-Methanesulfonylmethyl-1 -/-indol-5-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone;
(3-Dimethylaminomethyl-1/-/-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-carbonyI)-1/- -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-1 -/-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-Thmethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1 - -indole-3-carbonitrile;
6-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-carboxylic acid amide; [3-(2H-Tetrazol-5-yl)-1ry-indol-6-yl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
/V-[3-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indol-7-yl]-acetamide;
(1-Benzenesulfonyl-1/-/-indol-5-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
(1-Benzenesulfonyl-2-methyl-1H-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 -/-indol-5-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yI)-methanone;
[6-(1 ,3,3-Thmethyl-6-aza-bicyclo[3.2.1]oclane-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)-1r-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-carbonyI)-indoI-1-yl]-acetamide;
[1-(4-Trifluoromethoxy-benzyl)-1/.-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-bicycIo[3.2.1]octane-6-carbonyl)-indol-1-yImethyl]-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.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (llg)
Figure imgf000101_0001
wherein
X is NR4, S or O;
R1 and R2 independently are hydrogen, halo, cyano, trihalomethyl, CrC6alkyl or CrCealkyloxy, wherein the alkyl groups independently are optionally substituted with one or more of R7;
R3 is hydrogen, d-Cealkyl, C3-d0cycloalkyl, CrC6alkyloxy, d-C6alkylthio, 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- C6alkyl, arylCrCealkyloxyCrCealkyl, C3-Cι0cycloalkyl, C3-Cι0hetcycloalkyl, C3-Cι0cyclo- 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, 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 CrC6alkyl, aryl, hetaryl, aryld- C6alkyl, hetarylalkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrC6alkyloxy, hetaryld- Cealkyloxy, CrCealkyloxyCrCealkyl, 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 R7;
R7 are independently hydrogen, halo, hydroxy, oxo, nitro, NR9R10, cyano, COOR8, CONR9R10, CrC8alkyl, CrC6alkyloxy, aryloxy, arylCrCealkyloxy, hetaryloxy or hetaryld- C6alkyloxy;
R8 is hydrogen, CrC6alkyl, aryl, arylCrC6alkyl, hetarylalkyl, wherein the alkyl, aryl and hetarylalkyl groups independently are optionally substituted with one or more of R7;
R9 and R10 independently are hydrogen, CrC8alkyl, C3-Cιocycloalkyl, C3-Cι0hetcycloalkyl, C3- CiocycloalkylCi-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 CrC8alkyl, arylCrC6alkyl, hetarylCrC6alkyl, hydroxy, cyano, CrC6alkyloxy, arylCrCealkyloxy, hetaryld-Cealkyloxy, C C6alkyloxyCr C6alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetaryld- C6alkylcarbonyl, d-Cealkylcarboxy, arylcarboxy or aryld-Cealkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R11;
R11 is hydrogen, halo, oxo, hydroxy, CrC6alkyl, aryl, arylCrC6alkyl, hetaryl or hetarylalkyl;
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 the definitions of R4, in the above formula (llg), hetcycloalkyl cannot be 7- aza[2,2, 1 ]bicycleheptane. In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (llg) 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, 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, d-C8alkyl, CrCealkyloxyCι-C6alkyl, aryl, hetaryl, arylCι-C6alkyl, aryld- C6alkyloxyCrG-alkyl, C3-Cι0cycloalkyl, C3-C10hetcycloalkyl, C3-CιocycloalkylCrC6alkyl, d- 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, CrC6alkyloxy, aryl, aryld-Cealkyl, aryloxy, aryld-Cealkyloxy, hetaryl, hetaryloxy or hetaryld-Cealkyloxy 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 CrC6alkyl, aryl, hetaryl, aryld- Cealkyl, hetarylalkyl, hydroxy, oxo, cyano, CrCealkyloxy, arylCrCealkyloxy, hetaryld- C6aIkyloxy, CrCealkyloxyCrCealkyl, d-Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylC C6alkylcarbonyl, 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, NR5R6, cyano, COOR8, CONR5R6, CrC8alkyl, CrC6alkyloxy, aryloxy or hetaryloxy;
R8 is hydrogen, CrC6alkyl, aryl, aryld-Cealkyl, hetarylalkyl, wherein the alkyl, aryl and hetarylalkyl 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 another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (llg) wherein X is NR4 or S wherein R4 is defined as above.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (llg) wherein X is O. In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (llg) wherein X is S.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (llg) wherein is NR4 wherein R4 is defined as above.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (llg) wherein R1 and R2 independently are hydrogen, halo, trihalomethyl or d-C6alkyl, wherein the alkyl groups independently are optionally substituted with one or more of R7. In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (llg) wherein R3 is hydrogen, CrC6alkyl, aryl, arylCrCealkyl, 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 said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (llg) wherein R4 is hydrogen, CrC8alkyl, aryl, hetaryl, hetaryld-Cealkyl, arylCrC6alkyl, wherein the alkyl, aryl, hetaryl, groups independently are optionally substituted with one or more of R7. In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (llg) 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 car- bon 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, arylCrCealkyl, hetarylalkyl, hydroxy, oxo, cyano, d-C6alkyloxy, aryld-Cealkyloxy, hetaryld- Cealkyloxy, CrCealkyloxyCrCealkyl, 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.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (llg) wherein R5 and R6, together with the nitrogen to which they are attached, are azepane, azo- cane, 6-aza-bicyclo[3.2.1]octane, 8-aza-bicyclo[3.2.1]octane, 3-aza-bicyclo[3.2.1]octane, 2- a∑a-bicyclo[3.2.1]octane, 3-oxa-6-aza-bicyclo[3.2.1]octane, 6-aza-bicyclo[3.2.2]nonane, 3- a∑a-bicyclo[3.2.2]nonane, 4-aza-tricyclo[4.3.1.13,8]undecane.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is selected from the group consist- ing 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-a∑a-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-bicydo[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-thiazoI-5-yl)-methanone ; 2,4-Dimethyl-thiazoIe-5-carboxylic acid cycloheptylamide; Azepan-1-yl-(2,4-dimethyl-thiazol-5-yl)-methanone; 2,4-Dimethyl-thiazole-5-carboxyIic acid adamantan-1 -ylamide; (3-Aza-bicyclo[3.2.2]non-3-yl)-(1 H-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 mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
In another embodiment of the present invention said substituted amides, or a pro- drug thereof, as a component of the combination therapy is selected from the group consist- ing of :
(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.
In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prod- rug thereof, as a component of the combination therapy is of the general formula (III)
Figure imgf000106_0001
wherein
R1 is C5-C10cycloalkyl, C5-Cι0hetcycloalkyl, aryl, hetaryl, arylCrC6alkyl or hetarylCι-C6alkyl, wherein the cycloalkyl, hetcycloalkyl, aryl, hetaryl and arylalkyl groups independently are optionally substituted with one or more of R7;
R2 and R3 independently are hydrogen, d-C6alkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrCealkyl, aryloxy, hetaryloxy, arylCrC6alkyloxy or hetaryld-Cealkyloxy wherein the alkyl, aryl, hetaryl, arylalkyl and hetarylalkyl groups independently are optionally substituted with one or more of R8; or
R2 and R3 together with the carbon atom to which they are attached, 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-Cealkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrCealkyl, hydroxy, oxo, d-C6alkyloxy, aryloxy, aryld-Cealkyloxy or hetaryld-Cealkyloxy; R4 and R5 independently are hydrogen, halo, hydroxy, CrC6alkyl, C2-C6alkenyl, C2-C6alkynyl, CrC6alkyloxy, aryl, hetaryl, aryloxyd-Cealkyl, aryloxyaryl, hetaryloxyaryl, aryloxyhetaryl, hetaryloxyhetaryl or arylCrCealkyloxyCrCealkyl wherein the alkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R9; or
R4 and R5 together with the carbon atoms to which they are attached, are forming a saturated, partially saturated or aromatic ring system containing from 5 to 8 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, arylC C6alkyl, NR10R11, halo, trihalomethyl, trihalomethoxy, hydroxy, oxo, CrC6alkyloxy, arylCrCealkyloxy, CrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, d-Cealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy; or
R4 and either R2 or R3 together are forming a saturated or partially saturated bridge containing from 1 to 4 carbon atoms, the bridge can optionally be substituted with at least one of Ci- Cealkyl, aryl, hetaryl, arylCrCealkyl or hetarylCrCealkyl;
R6 is hydrogen, d-C6alkyl, aryl, hetaryl, arylCrC6alkyl or hetarylC C6alkyl; or
R6 and either R4 or R5 together with the carbon atoms to which they are attached, are forming a saturated, partially saturated or aromatic ring system containing from 5 to 8 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 Cι-C6alkyl, aryl, arylCι-C6alkyl, NR10R11, halo, trihalomethyl, trihalomethoxy, hydroxy, oxo, Cι-C6alkyloxy, arylCι-C6alkyloxy, CrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, arylCrC6alkylcarbonyl, C C6alkylcarboxy, arylcarboxy or aryld-Cealkylcarboxy;
R7 and R8 independently are hydrogen, halo, hydroxy, cyano, nitro, d-Cealkyl, CrC6alkyloxy, trihalomethyl, trihalomethoxy, aryloxy, hetaryloxy, aryld-Cealkyloxy, hetaryld-Cealkyloxy, CrCealkyloxyCrCealkyl, aryloxyCrC6alkyl, arylCrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetarylcarboxy, arylCrCealkylcarboxy or hetarylCrC6alkylcarboxy; R9 is hydrogen, halo, hydroxy, cyano, d-d-alky!, methylendioxo, trihalomethyl, trihalomethoxy, aryl, arylCrC6aIkyl, aryloxy, NR10R11 or aryloxyCrC6alkyl, wherein the aryl group is optionally substituted with one or more of R12;
R10 and R11 independently are hydrogen, CrC6alkyl, aryl or arylCrCealkyl wherein the alkyl and aryl groups independently are optionally substituted with one or more of R13; 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 sulfur, the ring system optionally being substituted with at least one of d-C6alkyl, aryl, hetaryl, aryld- C6alkyl, hydroxy, oxo, CrC6alkyloxy, arylCrC6alkyloxy, CrCealkyloxyCrCealkyl, d- C6alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCi-Cealkyl-carboxy;
R12 is oxo or halo;
R13 is halo, hydroxy, cyano, d-Cealkyl, CrC6alkyloxy, NR14R15, methylendioxo, trihalomethyl, or trihalomethoxy;
R14 and R15 independently are hydrogen, d-Cealkyl, aryl, hetaryl, arylCrC6alkyl or hetaryld-
A is a single, double or triple bond;
X is a chemical bond, (CR16R17)n or NR10, wherein R16 and R17 independently are hydrogen, oxo or CrC6alkyl, or
X, together with either R or R , is a double bond;
Y is CR18 or nitrogen, wherein R18 is hydrogen, d-Cealkyl, aryl, hetaryl, arylCrCealkyl or hetarylCrC6alkyl; or R18 and either R2 or R3 together are forming a saturated or partially saturated cyclic ring system containg from 1 to 4 carbon atoms, the ring system can optionally be substituted with at least one of d-Cealkyl, aryl, hetaryl, aryld-C6alkyl or hetarylCrC6alkyl; or
R18 with either R2 or R3 and either R4 or R5 together are forming a saturated or partially saturated cyclic ring system having one common carbon atom containing from 8 to 12 carbon atoms, the ring system can optionally be substituted with at least one of CrC6alkyl, aryl, hetaryl, aryICrC6alkyl or hetarylCrCealkyl;
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 of the present invention said fused 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (III) wherein R1 is C5-Cι0cycloalkyl, C5-Cι0hetcycloalkyl, aryl, hetaryl, or aryld-Cealkyl, wherein the cycloalkyl, hetcycloalkyl, aryl, hetaryl and arylalkyl groups independently are optionally substituted with one or more of R7. In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (III) wherein R1 is C5-Cιocycloalkyl, C5-Cι0hetcycloalkyl, aryl, wherein the cycloalkyl, hetcycloalkyl and aryl groups independently are optionally substituted with one or more of R7.
In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prod- rug thereof, as a component of the combination therapy is of the general formula (III) wherein R1 is C5-Ci0cycloalkyl optionally substituted with one or more of R7.
In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (III) wherein R1 is C5-C10hetcycloalkyl optionally substituted with one or more of R7. In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (III) wherein R1 is aryl, optionally substituted with one or more of R7.
In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (III) wherein R1 is hetaryl optionally substituted with one or more of R7. In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (III) wherein R1 is arylCrCealkyl optionally substituted with one or more of R7.
In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prod- rug thereof, as a component of the combination therapy is of the general formula (III) wherein R2 and R3 independently are hydrogen or d-C6alkyl.
In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (III) wherein R2 and R3 together with the carbon atom to which they are attached, 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-Cealkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrCealkyl, hydroxy, oxo, CrC6alkyIoxy, aryloxy, aryld-Cealkyloxy or hetarylCrCealkyloxy.
In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prod- rug thereof, as a component of the combination therapy is of the general formula (III) wherein R4 and R5 independently are hydrogen, CrC6alkyl, CrC6alkyloxy, aryloxyd-Cealkyl, wherein the alkyl and aryl groups independently are optionally substituted with one or more of R9.
In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (III) wherein R4 and R5 together with the carbon atoms to which they are attached, are forming a saturated or partially saturated ring system containing from 5 to 8 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-Cealkyl.
In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prod- rug thereof, as a component of the combination therapy is of the general formula (III) wherein R4 and either R2 or R3 together are forming a saturated or partially saturated bridge containing from 1 to 4 carbon atoms, the bridge can optionally be substituted with at least one of Ci- Cealkyl or arylCrCealkyl.
In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prod- rug thereof, as a component of the combination therapy is of the general formula (III) wherein R6 is hydrogen or d-Cealkyl.
In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (III) wherein R6 and either R4 or R5 together with the carbon atoms to which they are attached, are form- ing a saturated, partially saturated or aromatic ring system containing from 5 to 8 carbon at- oms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen or sulphur, the ring system optionally being substituted with at least one of CrC6alkyl, halo, trihalomethyl, Cι-C6alkyloxy or arylCrC6alkyloxy.
In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prod- rug thereof, as a component of the combination therapy is of the general formula (III) wherein R7 and R8 independently are hydrogen, halo, hydroxy, cyano, d-C6alkyl, d-C6alkyloxy, trihalomethyl, trihalomethoxy, aryloxy, hetaryloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, d- Cealkyloxyd-Cealkyl, aryloxyCrC6alkyl or arylCrCealkyloxyCrCealkyl.
In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prod- rug thereof, as a component of the combination therapy is of the general formula (III) wherein R9 is hydrogen.
In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (III) wherein A is a double or aromatic bond; X is (CR16R17)n, wherein R16 and R17 independently are hy- drogen or d-Cealkyl and n is 1; Y is CR18 wherein R18 is hydrogen, CrC6alkyl, aryl, hetaryl, arylCrC6alkyl or hetaryld-C6alkyl; R6 and either R4 or R5 together with the carbon atoms to which they are attached, are forming an aromatic ring system containing 6 carbon atoms, the ring system optionally being substituted with at least one of d-Cealkyl, aryl, arylCrC6alkyl, NR10R11, halo, trihalomethyl, trihalomethoxy, hydroxy, oxo, C C6alkyloxy, arylC C6alkyloxy, CrCealkyloxyd-Cealkyl, d-Cealkylcarbonyl, arylcarbonyl, arylCrC6alkylcarbonyl, C C6alkylcarboxy, arylcarboxy or arylCrCealkylcarboxy.
In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (III) wherein A is a double or aromatic bond. In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (III) wherein X is (CR16R17)n, wherein R16 and R17 independently are hydrogen or d-C6alkyl and n is 1.
In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (III) wherein Y is CR18 wherein R18 is hydrogen, d-C6alkyl, aryl, hetaryl, arylCrC6alkyl or hetaryld- Cealkyl.
In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is selected from the group consisting
3-(2-Bromo-phenyl)-6,7,8,9-tetrahydro-5H-[1 ,2,4]triazolo[4,3-a]azepine; 3-Phenyl-[1 ,2,4]triazolo[3,4-a]isoquinoIine;
(2-Methoxy-benzyl)-(3-phenyl-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)-amine;
3-(2-Fluoro-phenyl)-5-(4-methoxy-phenoxy)-[1 ,2,4]triazolo[4,3-c]quinazoline;
3-Phenyl-6,7,8,9-tetrahydro-5H-[1 ,2,4]triazolo[4,3-a]azepine; 3-(4-Chloro-phenyl)-6,7,8,9-tetrahydro-5H-[1 ,2,4]triazolo[4,3-a]azepine;
3-(3-Chloro-phenyI)-6,7,8,9-tetrahydro-5H-[1 ,2,4]triazolo[4,3-a]azepine;
3-(3,4-Dichloro-phenyl)-6,7,8,9-tetrahydro-5H-[1 ,2,4]triazolo[4,3-a]azepine;
5,5-Dimethyl-3-thiophen-2-yl-5,6-dihydro-[1 ,2,4]triazolo[3,4-a]isoquinoline;
3-(2-ChIoro-phenyl)-6,7,8,9-tetrahydro-5H-[1 ,2,4]triazolo[4,3-a]azepine; 5,5-Dimethyl-3-(3,4,5-trimethoxy-phenyl)-5,6-dihydro-[1 ,2,4]triazolo[3,4-a]isoquinoline;
3-Furan-2-yl-5,5-dimethyl-5,6-dihydro-[1,2,4]triazolo[3,4-a]isoquinoline;
3-(3-Bromo-phenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine;
3-(4-Bromo-phenyl)-5,5-dimethyl-5,6-dihydro-[1 ,2,4]triazolo[3,4-a]isoquinoline;
4-(5,5-Dimethyl-5,6-dihydro-[1 ,2,4]triazolo[3,4-a]isoquinolin-3-yl)-phenol; 3-(4-Methoxy-phenyl)-5,5,8,9-tetramethyl-5,6-dihydro-[1 ,2,4]triazolo[3,4-a]isoquinoline;
5,5-Dimethyl-3-phenyl-5,6-dihydro-[1 ,2,4]triazolo[3,4-a]isoquinoline;
3-(5,5-Dimethyl-5,6-dihydro-[1 ,2,4]triazolo[3,4-a]isoquinolin-3-yl)-phenol;
5,5-Dimethyl-3-p-tolyl-5,6-dihydro-[1,2,4]triazolo[3,4-a]isoquinoline;
5,5-Dimethyl-3-lhiophen-2-yl-5,6-dihydro-[1 ,2,4]triazolo[3,4-a]isoquinoline; 7,10-Dimethoxy-5,5-dimethyl-3-phenyl-5,6-dihydro-[1 ,2,4]triazolo[3,4-a]isoquinoline;
3-(2,4-Dichloro-phenyl)-6,6-dimethyl-5,6,7,8-tetrahydro-[1 ,2,4]triazolo[4,3-a]pyrimidine;
2-(6,6-Dimethyl-5,6,7,8-tetrahydro-[1 ,2,4]triazolo[4,3-a]pyrimidin-3-yl)-phenol;
3-(2-Chloro-phenyl)-6,6-dimethyl-5,6,7,8-tetrahydro-[1 ,2,4]triazolo[4,3-a]pyrimidine;
4-Benzyl-3,5-di-p-tolyl-4H-[1 ,2,4]triazole; 3-p-TolyI-6,7,8,9-tetrahydro-5H-[1 ,2,4]triazolo[4,3-a]azepine;
3-(4-Methoxy-phenyl)-6,7,8,9-tetrahydro-5H-[1 ,2,4]triazolo[4,3-a]azepine;
3-Pyridin-4-yl-6,7,8,9-tetrahydro-5H-[1 ,2,4]triazolo[4,3-a]azepine;
3-(4-Bromo-phenyl)-6,7,8,9-tetrahydro-5H-[1 ,2,4]triazolo[4,3-a]azepine;
3-Furan-2-yl-5,5,8,9-tetramethyl-5,6-dihydro-[1 ,2,4]triazolo[3,4-a]isoquinoline; 6,6-Dimethyl-3-(2-nitro-phenyl)-5,6,7,8-tetrahydro-[1 ,2,4]triazolo[4,3-a]pyrimidine;
3-(2,4-DichIoro-phenyl)-5,5-dimethyl-5,6-dihydro-[1,2,4]triazolo[3,4-a]isoquinoline; 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 said fused 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (Ilia)
Figure imgf000113_0001
wherein R1 is aryl or hetaryl, wherein the aryl and hetaryl groups independently are optionally substituted with one or more of R7;
R2 and R3 together with the atoms to which they are connected forms a C5-d0cycloalkyl or C5-Ci0hetcycloalkyl, wherein the cycloalkyl and hetcycloalkyl rings independently are option- ally substituted with one or more of R8; or
R2 and R3 are connected to one of the following ring systems at the carbon atoms marked with an asterix (*)
Figure imgf000113_0002
Figure imgf000113_0003
wherein the ring systems independently are optionally substituted with one or more R8;
R7 is hydrogen, halo, hydroxy, cyano, nitro, CrCealkyl, CrC6alkyloxy, trihalomethyl, trihalomethoxy, aryloxy, hetaryloxy, NR9R10, arylCrC6alkyloxy, hetarylCrCealkyloxy, d- CealkyloxyCι-C6alkyl, aryloxyd-C6alkyl, arylCrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetarylcarboxy, aryld-C6alkylcarboxy or hetarylCrC6alkylcarboxy;
R8 is hydrogen, CrC6alkyl, halo, aryl, hetaryl, arylCrC6alkyl, NR9R10, trihalomethyl, trihalomethoxy, hydroxy, oxo, CrC6alkyloxy, aryloxy, aryld-Cealkyloxy, hetarylCrCealkyloxy, d- CealkyloxyCrCealkyl, d-Cealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, d- C6alkylcarboxy, arylcarboxy or arylCrC6alkylcarboxy; R9 and R10 independently are hydrogen, CrC6alkyl, aryl or arylCrC8alkyl wherein the alkyl and aryl 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 sulfur, the ring system optionally being substituted with at least one of CrC6alkyl, aryl, hetaryl, aryld- C6alkyl, hydroxy, oxo, CrC6alkyloxy, arylCrC6alkyloxy, CrCealkyloxyCrCealkyl, d- C6alkylcarbonyl, arylcarbonyl, arylCrC6alkylcarbonyl, d-Cealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
R11 is CrC6alkyl, oxo or halo;
X is (CR12R13)n, wherein R12 and R13 independently are hydrogen, oxo, hydroxy or CrC6alkyl; and
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, or any tautomeric forms.
In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (Ilia) wherein R1 is aryl optionally substituted with R7 as defined above. In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (Ilia) wherein R1 is phenyl optionally substituted with R7 as defined above.
In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (Ilia) wherein R2 and R3 are connected to one of the following ring systems at the carbon atoms marked with an asterix (*)
Figure imgf000114_0001
wherein the ring systems independently are optionally substituted with one or more R8 as defined above.
In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (Ilia) wherein R7 is hydrogen, halo, hydroxy, cyano, d-d-alky!, CrC6alkyloxy, trihalomethyl, aryloxy, arylCrCealkyloxy, hetarylCrC6alkyloxy, CrCealkyloxyCrCealkyl, aryloxyd-Cealkyl or arylCrCealkyloxyCrCealkyl.
In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (Ilia) wherein R8 is hydrogen, d-C6alkyl or halo.
In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (Illb)
Figure imgf000115_0001
wherein R1 is aryl or hetaryl, wherein the aryl and hetaryl groups independently are optionally substituted with one or more of R7;
R7 is hydrogen, halo, hydroxy, cyano, nitro, d-C6alkyl, CrC6alkyloxy, trihalomethyl, trihalomethoxy, aryloxy, hetaryloxy, NR9R10, arylCrC6alkyloxy, hetarylCrCealkyloxy, d- CealkyloxyCrCealkyl, aryloxyCrC6alkyl, arylCrC6alkyloxyCrC6alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-Cealkylcarboxy, arylcarboxy, hetarylcarboxy, arylCrCealkylcarboxy or hetarylCrC6alkylcarboxy;
R9 and R10 independently are hydrogen, CrC6alkyl, aryl or arylCrC6alkyl wherein the alkyl and aryl 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 sulfur, the ring system optionally being substituted with at least one of CrC6alkyl, aryl, hetaryl, arylCrCealkyl, hydroxy, oxo, CrC6alkyloxy, arylCrCealkyloxy, CrCealkyloxyCrCealkyl, d-C6alkyl- carbonyl, arylcarbonyl, arylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or aryld-C6a- alkylcarboxy;
R11 is CrC6alkyl, oxo or halo;
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 said fused 1 ,2,4-triazole, or a prod- rug thereof, as a component of the combination therapy is of the general formula (Illb) wherein R1 is aryl optionally substituted with R7 as defined above.
In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (Illb) wherein R1 is phenyl optionally substituted with R7 as defined above. In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (Illb) wherein R1 is phenyl substituted in the ortho position.
In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (Illb) wherein R1 is phenyl substituted in both the ortho and para position.
In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (Illb) wherein R7 is halo, hydroxy, cyano, d-Cealkyl, CrC6alkyloxy, trihalomethyl, trihalomethoxy, aryloxy, hetaryloxy, NR9R10, arylCrCealkyloxy, hetarylCrCealkyloxy, CrCealkyloxyCrCealkyl, aryloxyCi-Cealkyl, aryld-Cealkyloxyd-Cealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl or hetarylCrCealkylcarbonyl; wherein R9 and R10 are defined as above.
In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (Illb) wherein R7 is CrC6alkyIoxy, trihalomethoxy, aryloxy, hetaryloxy, aryICrC6aIkyloxy, hetarylCrCealkyloxy, CrC6alkyloxyCrC6alkyl, aryloxyCrC6alkyl or arylCι-C6alkyloxyCr C6alkyl.
In another embodiment of the present invention said fused 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is selected from the group consisting of: 3-(2-Bromo-phenyl)-6,7,8,9-tetrahydro-5H-[1 ,2,4]triazolo[4,3-a]azepine; 3-(2-Phenoxymethyl-phenyl)-5,6,7,8-tetrahydro-[1 ,2,4]triazolo[4,3-a]azepin-9-one; 3-(2-Phenoxymethyl-phenyl)-6,7,8,9,10,11-hexahydro-5H-5,9:7,11-dimethano[1 ,2,4]tria- zolo[4.3-a]azonine; 3-(5-Bromo-pyridin-3-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazoIo[4,3-a]azepine; 3-(5-Hex-1-ynyl-pyridin-3-yl)-6,7,8,9-tetrahydro-5H-[1 ,2,4]triazolo[4,3-a]azepine; 3-(6-Chloro-pyridin-3-yl)-6,7,8,9-tetrahydro-5H-[1 ,2,4]triazolo[4,3-a]azepine; 3-(6-Morpholin-4-yl-pyridin-3-yl)-6,7,8,9-tetrahydro-5H-[1 ,2,4]triazolo[4,3-a]azepine; 3-Pyridin-3-yl-6,7,8,9-tetrahydro-5- -[1 ,2,4]triazolo[4,3-a]azepine; 3-(2-Benzyloxymethyl-phenyl)-6,7,8,9-tetrahydro-5H-5,9-methano[1,2,4]triazolo[4.3- a]azepine;
3-Phenyl-[1 ,2,4]triazolo[3,4-a]isoquinoline; or 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 said alpha-amino ketones, or a prodrug thereof, as a component of the combination therapy is of the general formula (IV)
Figure imgf000117_0001
Formula (IV) wherein
R1 and R2 independently are hydrogen, CrC6alkyl, C3-d0cycloalkyl, C3-Cι0 het-cycloalkyl, aryl, hetaryl, arylC C6alkyl or hetarylCrCealkyl, wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R6; or
R1 and R2 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic or bicyclic ring system containing from 4 to 8 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, arylCrC6alkyl, hetarylCrCealkyl, hydroxy, oxo, CrC6alkyl-oxy, arylCrC6alkyloxy, hetarylCrCealkyloxy, d-C6alkyl- oxyCι-C6aIkyl, CrC6alkyl-carbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, d- C6alkylcarboxy, arylcarboxy, hetarylcarboxy or arylCrCealkylcarboxy; R3 and R4 independently are hydrogen, CrC6alkyI, CrC6alkenyl, CrC6alkynyl, aryl, hetaryl, arylCrCealkyl or hetaryld-Cealkyl, wherein the alkyl, alkenyl, alkynyl, aryl, and hetaryl groups independently are optionally substituted with one or more of R7;
R5 is C3-Ci0cycloalkyl, C3~Cι0hetcycloalkyl, aryl or hetaryl, wherein the aryl, hetaryl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R8; or
R3 and R5 together with the carbon atoms 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 CrC6alkyl, aryl, hetaryl, aryld- Cealkyl, hetaryld-Cealkyl, hydroxy, oxo, CrC6alkyloxy, arylCrCealkyloxy, d-Cβalkyloxyd- C6alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, CrCealkylcarboxy, aryl-carboxy, hetarylcarboxy or aryld-Cealkylcarboxy; or
R2, R3 and R5 together with the atoms 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, oxygen or sulphur, the ring system optionally being substituted with at least one of d-Cealkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrCealkyl, hydroxy, oxo, C C6alkyl-oxy, arylCrCealkyloxy, CrCealkyloxyCrCealkyl, d-Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetaryl-carboxy or arylCrCealkylcarboxy;
R6 is hydrogen, hydroxy, oxo, halo, adamantyl, CrC6alkyl, CrCealkyloxy, trihalomethyl, triha- lomethoxy, NR9R10, arylCrCealkyloxy, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, CrC6alkylcarboxy, arylcarboxy or arylCrC6alkylcarboxy;
R7 and R8 independently are hydrogen, hydroxy, oxo, halo, cyano, nitro, NR9R10, CrC6alkyl, CrC6alkyloxy, aryl, hetaryl, arylCrCealkyloxy, hetaryld-Cealkyloxy, d-C6alkylcarbonyl, aryl- carbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, d-Cealkyl-carboxy, arylcarboxy or aryld- Cealkylcarboxy, wherein the aryl and hetaryl groups independently are optionally substituted with C3-Ci0cycloalkyl or C3-Cι0hetcycloalkyl;
R9 and R10 independently are hydrogen, CrC6alkyl, C3-Cι0cycloalkyl, C3-Cι0 hetcycloalkyl, aryl, hetaryl, arylCrC6alkyl or hetarylCrCealkyl; 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 5 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-Cealkyl, aryl, hetaryl, arylCrCealkyl, hetarylCrCealkyl, hydroxy, oxo, C C6alkyloxy, arylC C6alkyloxy, CrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetarylcarboxy or arylCrCealkylcarboxy; 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 said alpha-amino ketones, or a prodrug thereof, as a component of the combination therapy is selected from the group con- sisting of:
1 -Adamantan-1 -yl-2-morpholin-4-yl-ethanone; 1 -Adamantan-1 -yl-2-benzylamino-propan-1 -one; 1 -Adamantan-1 -yl-2-ben∑yIamino-ethanone; 2-Pyrrolidin-1 -yl-1 -(3-p-tolyl-adamantan-1 -yl)ethanone; 1 -Adamantan-1 -yl-2-morpholin-4-yl-propan-1 -one;
1 -[4-(5-Adamantan-1 -yl-[1 ,2,3]triazol-1 -yl)-phenyl]-2-phenylamino-ethanone; 6-Benzo[1 ,3]dioxol-5-yl-8-benzyl-8-a∑a-bicyclo[3.2.1 ]oclan-2-one; 2-tert-Butylamino-1 -(3-p-tolyl-adamantan-1 -yl)ethanone; 2-Morpholin-4-yl-1 -(3-p-tolyl-adamantan-1 -yl)ethanone; 1 -Adamantan-1 -yl-2-[4-(4-nitro-phenyl)-piperazin-1-yl]ethanone; 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 said substituted 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (V)
Figure imgf000119_0001
Formula (V) wherein X is O or S;
R1 is hydrogen, d-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, C3-Cι0cycloalkyl, arylCrCealkyl, hetaryld-Cealkyl, R4R5NcarbonylCrC6alkyl, arylcarbonylCrC6alkyl, hetarylcarbonyld- C6alkyl; wherein the alkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R6;
R2 is CrC6alkyl, CrC6alkenyl, arylCrC6alkyl, C3-Cι0cycloalkyl or hetaryld-C6alkyl; wherein the alkyl, alkenyl, cycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R7;
R3 is C3-Cι0cycloalkyl, C3-Cι0hetcycloalkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCi -C6alkyl, arylR8CrC6alkyl or hetarylR8CrC6alkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R9;
R4 and R5 independently are hydrogen, d-Cealkyl, C3-docycloalkyl, C5-C8hetcycloalkyl, aryl, hetaryl, arylCrC6alkyl or hetaryld-Cealkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R 1; or
R4 and R5 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-C6alkyl, aryl, arylCι-C6alkyl, hydroxy, oxo, CrC6alkyloxy, arylCrCealkyloxy, Cι-C6alkyloxyCrC6alkyl, d-Cealkylcarbonyl, arylcarbonyl, arylCrC6alkyl-carbonyl, CrC6alkylcarboxy, arylcarboxy or aryld- Cealkylcarboxy;
R6, R7, R9 and R11 independently are hydrogen, halo, N02, NH2, cyano, NR4R5, CONR4R5, trihalomethyl, trihalomethoxy, hydroxy, oxo, CrC6alkyl, C3-Cι0cycloalkyl, C3-Cι0hetcycloalkyl, aryl, hetaryl, arylCrC6alkyl, hetaryld-C6alkyl, CrC6alkylS02, R15R16NS02, CrC6alkyIoxy, aryloxy, hetaryloxy, arylCrC6alkyloxy, CrC6al kyl carbonyl, arylcarbonyl, aryld- C6alkylcarbonyl, arylcarbonyl NR15, carboxyCrC6aIkyl or carboxyaryld-C6alkyl;
R8 is oxygen, NR10, C(=0)NR10 or SOnNR10; wherein n is 1 or 2; R is hydrogen, CrC6alkyl, aryl, hetaryl, arylCrC6alkyl or hetaryld-Cealkyl;
R15 and R16 independently are hydrogen, CrC6alkyl, C3-Cι0cycloalkyl, C5-C8hetcycloalkyl, aryl or hetaryl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl or hetaryl groups independently are optionally substituted with one or more of R11; or
R15 and R16 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 8 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, arylCrCealkyl, hydroxy, oxo, Cι-C6alkyloxy, aryld-Cealkyloxy, CrC6alkyloxyCrC6alkyl, d-C6alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy; 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 said substituted 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (V) wherein X is O or S;
R1 is hydrogen, d-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, arylCrCealkyl, hetarylCrCealkyl, NR4R5carbonylCrC6alkyl, arylcarbonylCrC6alkyl, hetarylcarbonylCrC6alkyl; wherein the al- kyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R6;
R2 is CrC6alkyl, CrC6alkenyl, aryld-C6alkyl or hetarylCrC6alkyl; wherein the alkyl, alkenyl, aryl and hetaryl groups independently are optionally substituted with one or more of R7;
R3 is C5-C8cycloalkyl, C5-C8hetcycloalkyl, aryl, hetaryl, arylCrC6alkyl, hetaryld-Cealkyl, arylR8CrC6alkyl or hetaryl R8d-C6alkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R9; R4 and R5 independently are hydrogen, d-Cealkyl, C5-Cι0cycloalkyl, C5-C8hetcycloalkyl, aryl, hetaryl, arylCrC6alkyl or hetarylCrC6alkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R11; or
R4 and R5 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, arylCrC6alkyl, hydroxy, oxo, CrC6alkyloxy, arylCrCealkyloxy, CrCealkyloxyd-Cealkyl, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or aryld-Cealkylcarboxy;
R6, R7, R9 and R11 independently are hydrogen, halo, N02, NH2, cyano, trihalomethyl, trihalo- methoxy, hydroxy, oxo, CrC6alkyl, aryl, hetaryl, arylCrC6alkyl, hetaryld-Cealkyl,
S02NR15R16, Cι-C6alkyloxy, aryloxy, hetaryloxy, arylCrCealkyloxy, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, arylcarbonylNR15, carboxyCrC6alkyl or carboxyarylCrCe- alkyl;
R8 is oxygen, NR10, C(=0)NR1° or SOπNR10; wherein n is 1 or 2;
R10 is hydrogen, d-C6alkyl, aryl, hetaryl, aryld-C6alkyl or hetaryld-Cealkyl;
R15 and R16 independently are hydrogen, C C6alkyl, C5-Cι0cycloalkyl, C5-C8hetcycIoalkyl, aryl or hetaryl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl or hetaryl groups independently are optionally substituted with one or more of R 1; or
R15 and R16 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 8 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, aryICrC6alkyl, hydroxy, oxo, CrC6alkyloxy, aryld-Cealkyloxy, d-Cealkyloxyd-Cealkyl, d-Cealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or aryld-Cealkylcarboxy; 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 said substituted 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (V) wherein X is O.
In another embodiment of the present invention said substituted 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (V) wherein X is S. In another embodiment of the present invention said substituted 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (V) wherein R1 is arylCrC6alkyl, hetarylCrCealkyl, R4R5NcarbonylCrC6alkyl, arylcarbonyld- C6alkyl, hetarylcarbonylCrC6alkyl; wherein aryl and hetaryl groups independently are optionally substituted with one or more of R6. In another embodiment of the present invention said substituted 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (V) wherein R2 is d-Cealkyl, arylCrC6alkyl, C3-Cι0cycloalkyl or hetaryld-Cealkyl; all of which is optionally substituted with one or more of R7.
In another embodiment of the present invention said substituted 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (V) wherein R3 is C3-Cι0cycloalkyl, C3-Cι0hetcycloalkyl, aryl, hetaryl, arylCrC6alkyl, hetaryld- Cealkyl, arylR8CrC6alkyl or hetarylR8CrC6all.yl, wherein all groups indenpendently are optionally substituted with one or more of R9.
In another embodiment of the present invention said substituted 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (V) wherein R3 is C3-Cιohetcycloalkyl, aryl, hetaryl, aryld-C6alkyl, hetarylCrCealkyl, arylR8d- C6alkyl or hetarylR8CrC6alkyl, wherein all groups indenpendently are optionally substituted with one or more of R9.
In another embodiment of the present invention said substituted 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (V) wherein R4 and R5 independently are aryl or hetaryl wherein both groups indenpendently are optionally substituted with one or more of R11.
In another embodiment of the present invention said substituted 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (V) wherein R4 and R5 together with the nitrogen to which they are attached, are forming a satu- rated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional nitrogen atoms, the ring system optionally being substituted with at least one of d-Cβalkyl, aryl, arylCrC6alkyl, hydroxy, oxo, d-Cealkyloxy, aryld- Cealkyloxy, CrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, arylCι-C6alkyl- carbonyl, d-Cealkylcarboxy, arylcarboxy or aryld-Cealkylcarboxy.
In another embodiment of the present invention said substituted 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (V) wherein R6, R7, R9 and R11 independently are hydrogen, halo, N02, NH2, cyano, NR4R5, CONR4R5, trihalomethyl, trihalomethoxy, hydroxy, oxo, d-Cealkyl, C3-Cι0cycloalkyl, C3- Ciohetcydoalkyl, aryl, hetaryl, aryld-Cealkyl, hetaryld-Cealkyl, CrC6alkylS02, R 5R16NS02, CrCealkyloxy, aryloxy, hetaryloxy, arylCrCealkyloxy, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, arylcarbonylNR15, carboxyCrC6alkyl or carboxyarylCrC6alkyl.
In another embodiment of the present invention said substituted 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (V) wherein R8 is oxygen, NR10, C(=0)NR ° or SOnNR10; wherein n is 1 or 2.
In another embodiment of the present invention said substituted 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is of the general formula (V) wherein R10 is hydrogen, CrC6alkyl, aryl, hetaryl, arylCrC6alkyl or hetarylCrCealkyl.
In another embodiment of the present invention said substituted 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is selected from the group consisting of:
3-(4-Allyl-5-mercapto-4H-[1 ,2,4]triazol-3-yl)-1 -(2,4-dichloro-ben∑yl)-1 H-pyridin-2-one; 4-Methyl-3-(4-methyI-2-phenyl-thiazol-5-yl)-5-prop-2-ynylsulfanyl-4H-[1 ,2,4]triazole; N-{1-[5-(4-ført-Butyl-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-ethyl}-4-chloro- benzenesulfonamide;
4-Methyl-3-methylsulfanyl-5-[3-(3-trifluoromethyl-benzyloxy)-thiophen-2-yl]-4H-[1 ,2,4]triazole;
N-(4-Chloro-phenyl)-2-(4-methyl-5-thiophen-3-ylmethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)- acetamide;
2-[4-Methyl-5-(2-oxo-2-phenyl-ethylsulfanyl)-4H-[1 ,2,4]triazol-3-ylmethyl]-4H- benzo[1 ,4]thiazin-3-one;
3-(4-Fluoro-benzylsulfanyl)-5-(2-fluoro-phenyl)-4-methyl-4H-[1,2,4]triazole; 3-(2-Fluoro-phenyl)-4-methyl-5-(4-methyl-benzylsulfanyl)-4H-[1 ,2,4]triazole; 4-Methyl-3-(4-methyl-benzylsulfanyl)-5-(3-trifluoromethyl-phenyl)-4H-[1 ,2,4]triazole; 3-(2,4-Dichloro-phenyl)-4-furan-2-ylmethyl-5-methylsulfanyl-4H-[1 ,2,4]triazole; 3-(4-tert-Butyl-phenyl)-5-(2,6-dichloro-benzylsulfanyl)-4-furan-2-ylmethyl-4H-[1 ,2,4]triazole; 4-Methyl-3-(4-methyl-benzylsulfanyl)-5-(5-methyl-isoxazol-3-yl)-4H-[1,2,4]triazole;
3-(3-Methoxy-benzylsulfanyl)-4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole;
3-(4-Fluoro-benzylsulfanyl)-4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazoIe;
3-(4-tert-Butyl-benzylsulfanyl)-4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole; 4-Methyl-3-(2-methyl-benzylsulfanyl)-5-thiophen-2-yl-4H-[1,2,4]triazole;
2-(5-Benzylsulfanyl-4-methyl-4H-[1,2,4]triazol-3-ylmethyl)-4H-benzo[1,4]thiazin-3-one;
2-[5-(4-Chloro-benzylsulfanyl)-4-methyl-4H-[1,2,4]triazol-3-ylmethyl]-4H-benzo[1,4]thiazin-3- one;
5-[5-(2,6-Dichloro-benzylsulfanyl)-4-methyl-4H-[1,2,4]triazol-3-yl]-benzo[1,2,5]oxadiazole; 1 -(4-Chloro-phenyl)-2-[4-methyl-5-(4-trifluoromethyl-pyridin-3-yl)-4H-[1 ,2,4]triazol-3- ylsulfanyl]-ethanone;
3-[5-(4-Chloro-benzylsulfanyI)-4-methyl-4H-[1,2,4]triazol-3-yl]-2-methyl-imidazo[1,2- a]pyridine;
3-[5-(2,4-Dichloro-benzylsulfanyl)-4-methyl-4H-[1,2,4]triazol-3-yl]-2,8-dimethyl-imidazo[1,2- ajpyridine;
4-Allyl-5-(2,4-dichloro-phenyl)-4H-[1,2,4]triazole-3-thiol;
3-(5-Allylsulfanyl-4-methyl-4H-[1 ,2,4]tria∑ol-3-yl)-1 -benzyl-1 H-pyridin-2-one;
3-(4-Allyl-5-methylsulfanyl-4H-[1,2,4]triazol-3-yl)-1-(2,4-dichloro-ben∑yl)-1H-pyridin-2-one;
3-(4-Allyl-5-mercapto-4H-[1 ,2,4]tria∑ol-3-yl)-1 -(4-chloro-benzyl)-1 H-pyridin-2-one; 3-(4-Allyl-5-prop-2-ynylsulfanyl-4H-[1 ,2,4]triazol-3-yl)-1 -(4-chloro-benzyl)-1 H-pyridin-2-one;
3-(5-Allylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-yl)-1-(2,4-dichloro-benzyl)-1H-pyridin-2-one;
1-(2,4-Dichloro-benzyl)-3-[4-ethyl-5-(2-oxo-2-phenyl-ethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-1H- pyridin-2-one;
3-(4-Allyl-5-prop-2-ynylsulfanyl-4H-[1,2,4]triazol-3-yl)-1-(3,4-dichloro-benzyl)-1H-pyridin-2- one;
4-Allyl-5-(4-methyl-2-phenyl-thiazol-5-yl)-4H-[1 ,2,4]triazole-3-thiol;
3-Allylsulfanyl-4-methyl-5-(4-methyl-2-phenyl-thiazol-5-yl)-4H-[1,2,4]triazole;
4-Allyl-5-[2-(3,4-dimethoxy-phenyl)-thiazol-4-yl]-4H-[1,2,4]triazole-3-thiol;
N-[5-(4-tert-Butyl-benzylsulfanyl)-4-methyl-4H-[1,2,4]triazol-3-ylmethyl]-4-methyl- benzenesulfonamide;
4-Methyl-3-[3-(4-methyl-benzyloxy)-thiophen-2-yl]-5-methylsulfanyl-4H-[1 ,2,4]triazole;
5-[3-(2,4-Dichloro-benzyloxy)-thiophen-2-yl]-4-methyl-4H-[1 ,2,4]triazole-3-thiol;
3-[3-(2,4-Dichloro-benzyloxy)-thiophen-2-yl]-4-methyl-5-methylsulfanyl-4H-[1,2,4]triazole;
4-Methyl-5-[3-(3-trifluoromethyl-benzyloxy)-thiophen-2-yl]-4H-[1,2,4]triazole-3-thiol; 2-(5-Benzyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(4-iodo-phenyl)-acetamide; 3-(5-Allylsulfanyl-4-methyl-4H-[1,2,4]triazol-3-yl)-2,7-dimethyl-imidazo[1 ,2-a]pyridine;
3-(5-Benzylsulfanyl-4-methyl-4H-[1 ,2,4]triazol-3-yl)-2,7-dimethyl-imidazo[1 ,2-a]pyridine;
3-(5-Benzylsulfanyl-4-methyl-4H-[1 ,2,4]triazol-3-yl)-2-methyl-imidazo[1 ,2-a]pyridine;
4-Butyl-5-(3-chloro-phenyl)-4H-[1,2,4]triazole-3-thiol; 4-Allyl-5-(3-chloro-phenyl)-4H-[1 ,2,4]triazole-3-thiol;
N-(5-{2-[5-(4-Methoxy-phenyl)-3-thiophen-2-yl-4,5-dihydro-pyrazol-1-yl]-2-oxo-ethylsulfanyl}-
4-methyl-4H-[1 ,2,4]triazol-3-ylmethyl)-benzamide;
N-(5-{2-[3,5-Bis-(4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-2-oxo-ethylsulfanyl}-4-methyl-
4H-[1 ,2,4]triazol-3-ylmethyl)-3-methoxy-benzamide; N-(5-{2-[5-(4-Methoxy-phenyl)-3-thiophen-2-yl-4,5-dihydro-pyrazol-1-yl]-2-oxo-ethylsulfanyl}-
4-methyl-4H-[1 ,2,4]triazol-3-ylmethyl)-4-(pyrrolidine-1-sulfonyl)-benzamide;
N-(5-{2-[5-(4-Methoxy-phenyl)-3-thiophen-2-yl-4,5-dihydro-pyrazol-1-yl]-2-oxo-ethylsulfanyl}-
4-methyl-4H-[1 ,2,4]triazol-3-ylmethyl)-4-(piperidine-1 -sulfonyl)-benzamide;
N-(5-{2-[5-(4-Methoxy-phenyl)-3-thiophen-2-yl-4,5-dihydro-pyrazol-1-yl]-2-oxo-ethylsulfanyl}- 4-methyl-4H-[1 ,2,4]triazol-3-ylmethyl)-4-(morpholine-4-sulfonyl)-benzamide;
4-Benzyl-3-(4-fluoro-naphthalen-1-ylmethylsulfanyl)-5-phenyl-4H-[1 ,2,4]triazole;
2-[4-Allyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1 -naphthalen-1 -yl-ethanone;
1-(4-Fluoro-phenyl)-4-(4-methyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-butan-1-one
2-(4-[_ethyl-5-phenyl-4H-[1 ,2,4]tria∑ol-3-ylsulfanyl)-1-(5,6,7,8-tetrahydro-naphthalen-2-yl)- ethanone;
5-(2-Carbazol-9-yl-ethyl)-4-(2-methyl-allyl)-4H-[1 ,2,4]triazole-3-thiol;
1-(4-r_ethoxy-phenyl)-2-[4-(2-methyl-allyl)-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-ethanone;
2-{2-[4-Allyl-5-(3-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-acetylamino}-benzoic acid methyl ester; 5-(2,4-Dichloro-phenyl)-4-(2-methyl-allyl)-4H-[1 ,2,4]triazole-3-thiol;
4-Allyl-3-(4-methoxy-benzylsulfanyl)-5-(3-methoxy-phenyl)-4H-[1,2,4]triazole;
2-[4-Allyl-5-(3-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(9H-fluoren-2-yl)-ethanone;
3-(4-Methoxy-benzylsulfanyl)-4-methyl-5-phenyl-4H-[1 ,2,4]triazole;
2-[4-AIIyl-5-(3-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-1-(4-ethyl-phenyl)-ethanone; 2-(4-Allyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-chloro-phenyl)-acetamide;
2-[4-Allyl-5-(4-tert-butyl-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(4-chloro-phenyl)-ethanone;
2-(4-Allyl-5-phenylaminomethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2,4-difluoro-phenyl)- acetamide;
2-(4-Allyl-5-phenoxymethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-methoxy-phenyl)-ethanone; 2-(4-Allyl-5-phenoxymethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -(4-bromo-phenyl)-ethanone; (4-Allyl-5-benzylsulfanyl-4H-[1,2,4]triazol-3-ylmethyl)-phenyl-amine;
2-(4-Allyl-5-benzotriazol-1 -ylmethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -(4-methoxy-phenyl)- ethanone;
2-(4-Allyl-5-phenylaminomethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(2-chloro-phenyl)-acetamide; 1-(4-Methoxy-phenyl)-2-[4-(2-methyl-allyl)-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl]-ethanone;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(4-methyl-3-nitro-phenyl)- acetamide;
[5-(2-Methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetic acid isopropyl ester;
N-(4-Chloro-phenyl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]- acetamide;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(4-methoxy-phenyl)- acetamide;
N-(3-Cyano-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-
[1,2,4]triazol-3-ylsulfanyl]-acetamide; N-(4-Acetyl-phenyl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-acetamide;
4-[5-(2,6-Dichloro-benzylsulfanyl)-4-furan-2-ylmethyl-4H-[1,2,4]triazol-3-yl]-pyridine;
N-(4-Methyl-3-nitro-phenyl)-2-[4-methyI-5-(3, .,5-trimethoxy-phenyl)-4H-[1,2, 4]triazol-3- ylsulfanylj-acetamide;
N-(3-Cyano-4,5,6,7-tetrahydro-ben∑o[b]thiophen-2-yl)-2-(4-furan-2-ylmethyl-5-pyridin-4-yl- 4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-[2-(4-Ethyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetylamino]-benzoic acid methyl ester;
2-(4-Methyl-5-phenyl- .H-[1,2,4]triazol-3-ylsulfanyl)-N-thia∑ol-2-yl-acetamide;
N-(4-Chloro-phenyl)-2-(4-ethyl-5-m-tolyl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(4-Ethoxy-phenyl)-2-(4-ethyl-5-m-tolyI-4H-[1,2,4]triazoI-3-ylsulfanyl)-acetamide; 2-(4-Ethyl-5-m-tolyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(2-nitro-phenyl)-acetamide;
2-(5-Benzyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(4-bromo-phenyl)-acetamide;
2-{5-[(2,6-Dimethyl-phenylamino)-methyl]-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl}-1-phenyl- ethanone;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(4-fluoro-phenyl)-acetamide; 2-[4-Ethyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1 -(4-methoxy-phenyl)- ethanone;
N-(4-lodo-2-methyl-phenyl)-2-[5-(2-methoxy-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]- acetamide;
2-(5-Benzyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsuifanyl)-1 -(3,4-dihydro-2H-quinolin-1 -yl)- ethanone; N-(2-Bromo-4-methyl-phenyl)-2-(4-furan-2-ylmethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3- ylsulfanyl)-acetamide;
N-(4-Chloro-phenyl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamide;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(3-trifluoromethyl-phenyl)- acetamide;
2-[5-[(4-Fluoro-phenylamino)-methyl]-4-(tetrahydro-furan-2-ylmethyl)-4H-[1,2,4]triazol-3- ylsulfanyl]-1 -p-tolyl-ethanone;
2-(5-Methyl-4-phenethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-naphthalen-1-yl-acetamide;
N-(5-Ethyl-[1,3,4]thiadiazol-2-yl)-2-(5-methyl-4-phenethyl-4H-[1,2,4]triazol-3-ylsulfanyl)- acetamide;
2-(5-Methyl-4-phenethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-phenyl-acetamide;
[5-(4-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetic acid cyclohexyl ester;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(3-chloro-phenyl)-acetamide;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(4-chloro-phenyl)-acetamide; 2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-m-tolyl-acetamide;
N-(3-Cyano-4,5,6,7-tetrahydro-ben∑o[b]thiophen-2-yl)-2-[5-(4-hydroxy-phenyl)-4-methyl-4H-
[1,2,4]triazol-3-ylsulfanyl]-acetamide;
2-(5-Benzyl-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(2-methyl-4-nitro-phenyl)-acetamide;
3-Ben∑ylsulfanyl-4-methyl-5-phenyl-4H-[1,2,4]triazole; 3-Butylsulfanyl-5-(4-methoxy-phenyl)-4-methyl-4H-[1,2,4]triazole;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-ethoxy-phenyl)-acetamide;
N-(4-Acetyl-phenyl)-2-(4-benzyl-5-pyridin-3-yl-4H-[1,2,4]lriazol-3-ylsulfanyl)-acelamide;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2,4-dimethyl-phenyl)-acetamide;
N-(3-Nitro-phenyl)-2-(4-phenethyI-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamide; 2-(4-Phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-phenyl-acetamide;
N-Naphthalen-1-yl-2-(4-phenethyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamide;
(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetic acid cyclohexyl ester;
1-(3,4-Dihydro-2H-quinolin-1-yl)-2-(4-ethyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone;
N-(3-Cyano-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-2-(4-ethyl-5-phenyl-4H-[1,2,4]triazol-3- ylsulfany -acetamide;
2-[5-(4-Methoxy-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-1-phenyl-ethanone;
3-Benzylsulfanyl-5-(4-methoxy-phenyl)-4-methyl-4H-[1,2,4]triazole;
2-(4,5-Dibenzyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-thiazol-2-yl-acetamide;
2-(4-Phenethyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-m-tolyl-acetamide; 2-(4-Phenethyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-phenyl-propionamide; 3-(5-BenzylsulfanyI-4-phenethyl-4H-[1,2,4]triazol-3-yl)-pyridine;
(4-Phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetic acid ethyl ester;
2-(4-Phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazoI-3-ylsulfanyl)-1-phenyl-ethanone;
2-(4-Phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-p-tolyl-propionamide; 1-(3,4-Dihydro-2H-quinolin-1-yl)-2-{4-ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-
[1 ,2,4]triazol-3-ylsulfanyl}-ethanone;
2-[5-(3,4-Dimethoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-p-tolyl-ethanone;
N-(3-Chloro-2-methyl-phenyl)-2-(4-methyI-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(4-Ethyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-N,N-diphenyl-propionamide; 2-(5-Cyclohexyi-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-nitro-phenyl)-acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-methyl-3-nitro-phenyl)-acetamide;
N-(2-Bromo-4-methyl-phenyl)-2-(4-ethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)- acetamide;
1-(3,4-Dihydro-2H-quinolin-1-yl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)- ethanone;
N-(4-Fluoro-phenyl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(4-Acetyl-phenyl)-2-(5-benzyl-4-elhyI-4H-[1 ,2,4]tria∑ol-3-ylsulfanyl)-acetamide;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-chloro-phenyl)-acetamide;
N-(3-Chloro-2-methyl-phenyl)-2-[4-ethyI-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(2-methyl-4-nitro-phenyl)- acetamide;
2-[5-(2-Methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-p-tolyl-propionamide;
[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetic acid ethyl ester; 2-(4-Methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-nitro-phenyl)-acetamide;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-naphthalen-1-yl- propionamide;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]tri ai zol-3-ylsulfanyl]-N-p-tolyl-propionamide;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]tri a; zol-3-ylsulfanyl]-N-phenyl-propionamide; 2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]tri a; zol-3-ylsulfanyl]-N-(4-phenyl-thiazol-2-yl)- acetamide;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-p-tolyl-acetamide;
N-(3-Chloro-4-methyl-phenyl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide; 2-[5-(4-Hydroxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-nitro-phenyl)-acetamide; 4-{2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-acetylamino}-benzoic acid ethyl ester;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-o-tolyl-acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(4-chloro-phenyl)-acetamide; 2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(4-methoxy-2-nitro-phenyl)- acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(2-methyl-4-nitro-phenyl)- acetamide;
1-(3,4-Dihydro-2H-quinolin-1-yl)-2-{5-[(2,4-dimethyl-phenylamino)-methyl]-4-ethyl-4H- [1 ,2,4]triazol-3-ylsulfanyl}-ethanone;
N-(4-Chloro-3-nitro-phenyl)-2-[5-(4-chloro-phenyl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl]- acetamide;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl]-1-(3,4-dihydro-2H-quinolin-1-yl)- ethanone; 2-(5-Benzyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -p-tolyl-ethanone;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(4-methoxy-phenyl)-acetamide;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(2-chloro-phenyl)-acetamide;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)- acelamide; 4-{2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetylamino}-benzoic acid methyl ester;
2-(5-Benzyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(2-nitro-phenyl)-acetamide;
2-(5-Benzyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(3-cyano-4,5,6,7-tetrahydro- benzo[b]thiophen-2-yl)-acetamide; 2-[5-(4-Chloro-phenyl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(2-nitro-phenyl)-acetamide;
(5-BenzylsulfanyI-4-ethyl-4H-[1 ,2,4]triazol-3-ylmethyl)-(4-chloro-phenyl)-amine;
N-(2-Methoxy-phenyl)-2-[5-(2-methoxy-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]- acetamide;
2-(4-Allyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3,4-dichloro-phenyl)-acetamide; 2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazoI-3-yisulfanyl)-N-p-toIyl-acetamide;
2-(5-Benzyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(4-chloro-phenyl)-acetamide;
2-(5-Benzyl-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(4-methoxy-phenyl)-acetamide;
N-(5-Chloro-2-methyl-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(4-Methoxy-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamide; N-(2,4-Dimethyl-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamide; N-(4-Ethoxy-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamide;
4-[2-(4-Methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetylamino]-benzoic acid methyl ester;
N-(4-ChIoro-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamide;
2-[5-(4-Hydroxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-phenyl-thiazol-2-yl)- acetamide;
2-(5-Benzyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-bromo-4-methyl-phenyl)-acetamide;
2-(5-Benzyl-4-methyl-4H-[1,2,4]triazol-3-yIsulfanyl)-1 -phenyl-ethanone;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-nitro-phenyl)-acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazoI-3-ylsulfanyl)-N-p-tolyl-acetamide; 2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(4-ethoxy-phenyI)- acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-naphthalen-1-yl-acetamide;
4-[5-(4-tert-Butyl-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-pyridine;
4-[5-(2,4-Dichloro-benzylsulfanyI)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-pyridine; 2-(5-Cydohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-methyl-4-nitro-phenyl)-acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-trifluoromethyl-phenyl)-acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-fluoro-phenyl)-acetamide;
4-{2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetylamino}-benzoic acid methyl ester; N-(3-Chloro-phenyl)-2-(5-cyclohexyl-4-ethyl-4H-[1 ,2,4]triazoI-3-ylsulfanyl)-acetamide;
2-(5-CyclohexyI-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-ethoxy-phenyl)-acetamide;
2-{5-[(4-Chloro-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4]tria∑ol-3-ylsulfanyl}-N-(2-nitro- phenyl)-acetamide;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-chloro-2-methyl-phenyl)-acetamide; 2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-phenyl-acetamide;
3-Benzyl-5-(2-chloro-6-fluoro-benzylsulfanyl)-4-methyl-4H-[1,2,4]triazole;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-nitro-phenyl)-acetamide;
2-[5-(4-Hydroxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-phenyl-ethanone;
4-[5-(4-Chloro-benzylsulfanyl)-4-methyl-4H-[1,2,4]triazol-3-yl]-phenol; 2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-fluoro-phenyl)-acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-methoxy-phenyl)-ethanone;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-bromo-phenyl)-acetamide;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-phenyl-acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-nitro-phenyl)-propionamide; 2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-trifluoromethyl-phenyl)-acetamide; {5-[(3-Chloro-4-methyl-phenylamino)-methyl]-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl}-acetic acid cyclohexyl ester;
3-[5-(2,4-Dichloro-benzylsulfanyl)-4-methyl-4H-[1,2,4]triazol-3-yl]-pyridine;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-phenyl-acetamide; N-(3-Chloro-4-methyl-phenyl)-2-[5-(4-hydroxy-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]- acetamide;
N-(4-Chloro-phenyl)-2-[5-(4-hydroxy-phenyl)-4-methyI-4H-[1,2,4]triazol-3-ylsulfanyl]- acetamide;
3-Benzyl-5-(4-chloro-benzylsulfanyl)-4-methyl-4H-[1,2,4]triazole; 2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(4-nitro-phenyl)-acetamide;
N-(4-Ethoxy-phenyl)-2-[5-(4-hydroxy-phenyl)-4-methyl-4H-[1,2,4]triazoI-3-ylsulfanyl]- acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(4-methoxy-phenyl)- acetamide; {5-[(4-Chloro-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-acetic acid cyclohexyl ester;
3-Benzylsulfanyl-5-(2-methoxy-phenyl)-4-methyl-4H-[1,2,4]triazole;
N-(2-Chloro-phenyl)-2-(4-methyl-5-m-tolyl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(2-iV1ethoxy-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide; 2-(5-Cyclohexyl-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-phenyl-acetamide;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(3-nitro-phenyl)-acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-1-(3,4-dihydro-2H-quinolin-1- yl)-ethanone;
2-(5-Benzyl-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(2-bromo-4-methyl-phenyl)-acetamide; N-(2-Chloro-phenyl)-2-[5-(2-methoxy-phenyl)-4-methyI-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
(5-Benzylsulfanyl-4-ethyl-4H-[1,2,4]triazol-3-ylmethyl)-(3-trifluoromethyl-phenyl)-amine;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-1-(4-methoxy-phenyl)- ethanone; [4-Allyl-5-(3-bromo-benzylsulfanyl)-4H-[1,2,4]triazol-3-yImethyl]-phenyl-amine;
2-(4-Furan-2-ylmethyI-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-1-(3-nitro-phenyl)- ethanone;
1-(4-Bromo-phenyl)-2-(4-furan-2-ylmethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)- ethanone; 4-{5-[2-(2-Methoxy-phenoxy)-ethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-phenyIamine; 4-[5-(4-Chloro-benzylsuIfanyl)-4-methyl-4H-[1,2,4]triazol-3-yl]-phenylamine;
[4-Allyl-5-(1,3-dioxo-1H,3H-benzo[de]isoquinolin-2-ylmethyl)-4H-[1,2,4]triazol-3-ylsulfanyl]- acetic acid ethyl ester;
2-{4-Allyl-5-[(4-chloro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1-phenyl- ethanone;
5-(3-Bromo-phenyl)-4-(2-methyl-allyl)-4H-[1,2,4]triazole-3-thiol;
2-(4-Allyl-5-benzotriazol-1-ylmethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(4-chloro-phenyl)- acetamide;
1-(4-Fluoro-phenyl)-2-(4-methyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone; 8-(4-Methyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-5-nitro-quinoline;
3-(2-Bromo-benzylsulfanyl)-4-methyl-5-(4-nitro-phenyl)-4H-[1,2,4]triazole;
2-[4-Allyl-5-(3-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-1-(2,4-dimethyl-phenyl)- ethanone;
1-(4-Bromo-phenyl)-2-(5-furan-2-yl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone; 2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(5-methyl-thiazol-2-yl)- acetamide;
2-[4-Ethyl-5-(p-tolylamino-methyl)-4H-[1,2,4]tria∑ol-3-ylsulfanyl]-1 -p-tolyl-ethanone;
2-(5-Benzyl-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(4-ethyl-phenyl)-acetamide;
2-(5-Ben∑yl-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-1-(4-methoxy-phenyl)-ethanone; 2-(5-Benzyl-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-1-p-tolyl-ethanone;
3-(2-Bromo-phenyl)-4-methyl-5-(4-nitro-benzylsulfanyl)-4H-[1,2,4]tria∑ole;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(4-phenyl-thiazol-2-yl)- acetamide; 2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(2,4-dimethyl-phenyl)- acetamide;
N-(4-Bromo-phenyl)-2-[5-(2-bromo-phenyl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl]-acetamide;
2-{5-[(2,4-Dimethyl-phenylamino)-methyl]-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl}-1-(4-methoxy- phenyl)-ethanone; 2-{5-[(2,4-Dimethyl-phenylamino)-methyl]-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl}-1-p-tolyl- ethanone;
{5-[(2,4-Dimethyl-phenylamino)-methyl]-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl}-acetic acid cyclohexyl ester;
2-{5-[(4-Fluoro-phenylamino)-methyl]-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl}-1-phenyl- ethanone; 2-{4-Ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1-(4-methoxy- phenyl)-ethanone;
[4-Ethyl-5-(4-methyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylmethyl]-(4-fluoro-phenyl)-amine; (5-Benzylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylmethyl)-(4-fluoro-phenyl)-amine; {4-Ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-acetic acid cyclohexyl ester;
N-(4-Chloro-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetamide; N-(4-Acetyl-phenyl)-2-(5-cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide; 2-[4-Ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-methyl-3-nitro-phenyl)- acetamide;
N-Cyclohexyl-2-(4-phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide; N-(2,4-Dimethyl-phenyl)-2-[4-furan-2-ylmethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3- ylsulfanylj-acetamide;
4-[2-(5-Cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetylamino]-benzoic acid ethyl ester;
2-[4-Furan-2-ylmethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-methyl-3-nitro- phenyl)-acetamide;
3-lsobutylsulfanyl-4-methyl-5-p-tolyl-4H-[1 ,2,4]triazole;
2-[2-(4-iV1ethyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetylamino]-benzoic acid methyl ester;
2-{4-Ethyl-5-[4-(morpholine-4-sulfonyl)-phenyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1-p-tolyl- ethanone; 4-Methyl-3-phenethylsulfanyl-5-p-tolyl-4H-[1 ,2,4]triazole;
2-(4-Benzyl-5-py ulfanyl)-N-p-tolyl-acetamide; 2-(4-Benzyl-5-py ulfanyl)-N-(4-nitro-phenyl)-acetamide; 2-(4-Benzyl-5-py ulfanyl)-N-phenyl-acetamide; 2-(4-Benzyl-5-py ulfanyl)-N-(3-chloro-phenyl)-acetamide; 2-(4-Benzyl-5-py ulfanyl)-N-(4-nitro-phenyl)-propionamide; 2-(4-Benzyl-5-py
Figure imgf000134_0001
ulfanyl)-N-(2,5-dichloro-phenyl)-acetamide;
N-(3-Chloro-phenyl)-2-(4-phenethyI-5-pyridin-3-yI-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(4-Nitro-phenyl)-2-(4-phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-propionamide;
N-(2-Bromo-4-methyl-phenyl)-2-[5-(3,4-dimethoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazoI-3- ylsulfanyl]-acetamide;
2-{4-Ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-N-(4-nitro-phenyl)- acetamide; 3-Benzylsulfanyl-5-cyclohexyl-4-ethyl-4H-[1,2,4]triazole;
[5-(4-Hydroxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetic acid cyclohexyl ester;
2-(5-Cyclohexyl-4-ethyI-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)- acetamide; N-(3-Chloro-4-methyl-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyI)-4H-[1,2,4]triazol-3-ylsulfanyl]- acetamide;
[4-Benzyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetic acid ethyl ester;
3-Benzylsulfanyl-4-methyl-5-(3,4,5-trimethoxy-phenyl)-4H-[1 ,2,4]triazole;
N-(2-Chloro-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-acetamide; N-(2,4-Dimethoxy-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(5-Cyclohexyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(2-methyl-4-nitro-phenyl)- acetamide;
2-(5-Cyclohexyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-1 -phenyl-ethanone;
3-Cyclohexyl-4-methyl-5-(4-methyl-benzylsulfanyl)-4H-[1,2,4]triazole; N-(2-Bromo-phenyl)-2-(5-cyclohexyI-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(5-Cyclohexyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(4-iodo-2-methyl-phenyl)- acetamide;
N-(3-Cyano-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-2-(5-cyclohexyl-4-methyl-4H-
[1,2,4]triazol-3-ylsulfanyl)-acetamide; N-(4-Acetyl-phenyl)-2-(5-cyclohexyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(5-Cyclohexyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(4-methoxy-phenyl)-acetamide;
N-(4-Chloro-phenyl)-2-(5-cyclohexyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(5-Cyclohexyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyI)-N-phenyl-acetamide;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(2-methoxy-4-nitro-phenyl)- acetamide;
N-(3-Cyano-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-2-[5-(2-methoxy-phenyl)-4-methyl-4H-
[1,2,4]triazol-3-ylsulfanyl]-acetamide;
N-(4-Bromo-phenyl)-2-(5-cyclohexyl-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamide;
2-[4-Ethyl-5-(4-hydroxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-N-phenyl-acetamide; N-(3-Chloro-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyI)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetamide;
N-(4-Acetyl-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-acetamide;
N-(4-Bromo-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-acetamide;
2-[4-Ethyl-5-(4-hydroxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(4-iodo-2-methyl-phenyl)- acetamide; N-(2,4-Dimethyl-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
4-[5-(4-Chloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-phenol;
[4-Ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetic acid cyclohexyl ester; 2-[5-(2-Methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-phenyl-thiazol-2-yl)- acetamide;
N-(3-Chloro-phenyl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(2-nitro-phenyl)-acetamide; 2-[4-Methyl-5-(4-nitro-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1 -phenyl-ethanone;
N-(4-Bromo-phenyl)-2-{4-ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1,2,4]triazol-3- ylsulfanyl}-acetamide;
N-(4-Chloro-phenyl)-2-{4-ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3- ylsulfanylj-acetamide; 2-{4-Ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1,2,4]triazol-3-ylsulfanyl}-N-(2-nitro-phenyl)- acetamide;
1-(4-Methoxy-phenyl)-2-[4-methyl-5-(4-nitro-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-ethanone;
[5-(4-Chloro-benzylsulfanyl)-4-ethyI-4H-[1 ,2,4]triazol-3-ylmethyl]-(4-fluoro-phenyl)-amine;
2-{4-Ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1,2,4]tria∑oI-3-ylsulfanyl}-1 -p-tolyl-ethanone; 2-{4-Ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-N-(4-methyl-3- nitro-phenyl)-acetamide;
N-(2-Bromo-4-methyl-phenyl)-2-{4-ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-
3-ylsulfanyl}-acetamide;
4-Allyl-5-(3-bromo-phenyl)-4H-[1 ,2,4]triazole-3-thiol; N-(2-Nitro-phenyl)-2-(4-phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyI)-acetamide;
2-{4-Ethyl-5-[4-(piperidine-1 -sulfonyl)-phenyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1 -p-tolyl- ethanone;
2-{4-Ethyl-5-[4-(piperidine-1 -sulfonyl)-phenyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1 -phenyl- ethanone; N-Biphenyl-2-yl-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-chloro-4-methyl-phenyl)- acetamide;
N-(2-Bromo-phenyl)-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
4-Benzyl-5-cyclohexyl-4H-[1 ,2,4]triazole-3-thiol; 2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -phenyl-ethanone; 2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-1-phenyl-ethanone;
(5-BenzyI-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetic acid cyclohexyl ester;
4-Methyl-3-(4-nitro-benzylsulfanyl)-5-phenyl-4H-[1 ,2,4]triazole;
2-(4-Methyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-1-p-tolyl-ethanone; 2-(4-Methyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -phenyl-ethanone;
3-Benzylsulfanyl-4-methyl-5-(naphthalen-2-yloxymethyl)-4H-[1 ,2,4]triazole;
2-(5-Cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-p-tolyl-acetamide;
3-Benzylsulfanyl-5-cyclohexyl-4-methyl-4H-[1,2,4]triazole;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-chloro-3-nitro-phenyl)-acetamide; 2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-methyl-3-nitro-phenyl)-acetamide;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-methoxy-4-nitro-phenyl)-acetamide;
N-(2-Bromo-4-methyl-phenyl)-2-(4-methyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
3-Benzylsulfanyl-4-ethyl-5-(4-nitro-phenyl)-4H-[1 ,2,4]triazole;
4-Ethyl-3-(4-methyl-benzylsulfanyl)-5-(4-nitro-phenyl)-4H-[1 ,2,4]triazole; 2-[4-Ethyl-5-(4-nitro-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-p-tolyl-ethanone;
3-(4-Chloro-benzylsulfanyl)-4-ethyl-5-(4-nitro-phenyl)-4H-[1 ,2,4]triazole;
2-[4-Ethyl-5-(4-nitro-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1 -phenyl-ethanone;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl3-N-(3,4-dimethyl-phenyl)- scΘi rπiϋΘj (2,4-Dimethyl-phenyl)-[4-ethyl-5-(4-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylmethyl]-amine
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(4-methyl-3-nitro-phenyl)- acetamide;
2-(4-Methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-trifluoromethyl-phenyl)-acetamide;
2-[5-[(2,4-DimethyI-phenylamino)-methyl]-4-(tetrahydro-furan-2-ylmethyl)-4H-[1,2,4]triazol-3- ylsulfanyl]-1 -p-tolyl-ethanone;
4-[5-(2,6-Dichloro-benzylsulfanyl)-4-(tetrahydro-furan-2-ylmethyl)-4H-[1,2,4]triazol-3-yl]- pyridine;
3-Benzylsulfanyl-5-(4-chloro-phenoxymethyl)-4-ethyl-4H-[1,2,4]triazole;
3-Butylsulfanyl-4-methyl-5-p-tolyl-4H-[1 ,2,4]triazole; 1-(5-Chloro-2-methoxy-phenyl)-2-(4-methyl-5-p-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-ethanone;
1-(4-Chloro-phenyl)-2-(4-methyl-5-p-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-ethanone;
N-(2,4-Dimethoxy-phenyl)-2-(4-ethyI-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-methyl-4-nitro-phenyl)-acetamide;
N-(4-Ethoxy-phenyl)-2-(4-ethyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamide; N-(4-Ethyl-phenyl)-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide; 2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-thiazoi-2-yl-acetamide;
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-phenyl-ethanone;
2-(4-Ethyi-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-1-p-tolyl-ethanone;
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-nitro-phenyl)-acetamide; N-(3-Chloro-phenyl)-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(2-Chloro-phenyl)-2-(4-ethyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamide;
2-[5-(2-Hydroxy-phenyl)-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-piperidin-1-yl-ethanone;
2-[5-(2-Morpholin-4-yl-ethylsulfanyI)-4-phenethyl-4H-[1 ,2,4]triazol-3-yl]-phenol;
N-(2-Methyl-4-nitro-phenyl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]tria∑ol-3-ylsulfanyl)- acetamide;
N-(2-Methyl-5-nitro-phenyl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)- acetamide;
N-(4-Bromo-phenyl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(3-Nitro-phenyl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamide; 2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-fluoro-phenyl)-acetamide;
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-methoxy-4-nitro-phenyl)-acetamide;
N-(2,5-Dichloro-phenyl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
2-(5-Cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-nitro-phenyl)-acetamide; 2-[4-Benzyl-5-(4-hydroxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(2-methyl-4-nitro-phenyl)- acetamide;
2-(4-Phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-trifluoromethyl-phenyl)- acetamide;
[4-Furan-2-ylmethyl-5-(4-hydroxy-phenyl)-4H-[1,2,4]tria∑ol-3-ylsulfanyl]-acetic acid cyclohexyl ester;
2-[4-Furan-2-ylmethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]tria∑ol-3-ylsulfanyl]-1-phenyl-ethanone;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]tria∑ol-3-ylsulfanyl]-N-(2-ethyl-phenyl)-acetamide;
2-(5-Cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3,4-dichloro-phenyl)-acetamide;
2-(5-Cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-methoxy-phenyl)-ethanone; 2-(4-Benzyl-5-phenyl-4H-[1 ,2,4]triazoI-3-ylsulfanyl)-N-(4-methoxy-2-nitro-phenyl)-acetamide;
2-(4-Benzyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(5-methyl-thiazol-2-yl)-acetamide;
2-(4-Benzyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-thiazol-2-yl-acetamide;
2-(4,5-Dibenzyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-nitro-phenyl)-acetamide;
2-(4-BenzyI-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(2-nitro-phenyI)-acetamide; 3-Benzylsulfanyl-5-(4-bromo-phenyl)-4-methyl-4H-[1 ,2,4]tria∑ole; 2-[4-Ethyl-5-(4-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(4-methyl-3-nitro-phenyl)- acetamide;
2-[4-Ethyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1 -phenyl-ethanone;
2-(4-Benzyl-5-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-1 -phenyl-ethanone; 2-(5-Methyl-4-phenethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-p-tolyl-acetamide;
2-(5-MethyI-4-phenethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(3-trifluoromethyl-phenyi)- acetamide;
N-(3-Chloro-phenyl)-2-(5-methyl-4-phenethyI-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(4-Chloro-phenyl)-2-(5-methyl-4-phenethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamide; 2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(2-methoxy-4-nitro-phenyl)- acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-nitro-phenyl)-acetamide;
N-(2,3-Dichloro-phenyl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]- acetamide; N-(2,3-DichIoro-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]- acetamide;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-1-(4-methoxy-phenyl)- ethanone;
2-[4-Ben∑yl-5-(2-hydroxy-phenyl)-4H-[1,2,4]tria∑ol-3-ylsulfanyl]-1 -piperidin-1 -yl-ethanone; 2-[4-Ben∑yl-5-(2-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-p-tolyl-acetamide;
2-{5-[(2,4-Dimethyl-phenylamino)-methyl]-4-furan-2-ylmethyl-4H-[1,2,4]triazoI-3-ylsulfanyl}-1- phenyl-ethanone;
2-(4-Methyl-5-m-tolyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-p-tolyl-acetamide;
4-{4-Ethyl-5-[4-(piperidine-1-sulfonyl)-phenyl]-4H-[1,2,4]triazol-3-ylsulfanylmethyl}- benzonitrile;
N-(2-Methoxy-phenyl)-2-(4-methyl-5-m-tolyl-4H-[1 ,2,4]tria∑ol-3-ylsulfanyl)-acetamide;
N-(4-Acetyl-phenyl)-2-(4-ethyl-5-m-tolyl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(4-Ethyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-methyl-3-nitro-phenyl)-acetamide;
2-[5-(4-Amino-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-1-(4-nitro-phenyl)-ethanone; N-{4-[5-(2-Chloro-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazol-3-yl]-phenyl}-2-methoxy- benzamide;
2-(4-Allyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-1-(4-fluoro-phenyl)-ethanone;
2-(4-Benzyl-5-pyridin-3-yI-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(4-fluoro-phenyl)-acetamide;
2-[5-(4-Amino-phenyl)-4-methyl-4H-[1,2,4]triazoI-3-ylsulfanyl]-1-(4-nitro-phenyl)-ethanone; 2-(4-Allyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(4-chloro-phenyl)-acetamide; (4-Benzyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetic acid ethyl ester;
4-[5-(4-tert-Bu-yl-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazol-3-yl]-pyridine;
2-{5-[(3-Chloro-phenylamino)-methyl]-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl}-1-phenyl- ethanone; {5-[(2-Chloro-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-acetic acid isopropyl ester;
2-[4-Ethyl-5-(4-methoxy-phenoxymethyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-1 -phenyl-ethanone;
1-(4-Chloro-phenyl)-2-{5-[(2-chloro-phenylamino)-methyl]-4-ethyl-4H-[1,2,4]triazol-3- ylsulfanylj-ethanone; 4-[5-(2-Chloro-6-fluoro-benzylsulfanyl)-4-methyl-4H-[1,2,4]triazol-3-yl]-pyridine;
3-Benzyl-5-benzylsulfanyl-4-ethyl-4H-[1 ,2,4]triazole;
3-Benzylsulfanyl-4-methyl-5-o-tolyl-4H-[1 ,2,4]triazole;
N-(4-Chloro-3-nitro-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(4-Methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-p-tolyl-ethanone; 1-(4-Methoxy-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-ethanone;
[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetonitrile;
[5-(2-Hydroxy-phenyl)-4-phenethyI-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetonitrile;
1-[5-(2-Hydroxy-phenyI)-4-phenethyl-4H-[1 ,2,4]tria∑ol-3-ylsulfanyl]-propan-2-one;
N-(2,3-Dichloro-phenyl)-2-[4-furan-2-ylmethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3- ylsulfanyl]-acetamide;
N-(3-Chloro-phenyl)-2-[4-furan-2-ylmethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3- ylsulfanyl]-acetamide;
N-(4-Chloro-phenyl)-2-[4-furan-2-ylmethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3- ylsulfanyl]-acetamide; 2-[5-(4-Methoxy-phenoxymethyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-phenyl-ethanone;
2-{5-[(2-Chloro-phenylamino)-methyl]-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl}-1-piperidin-1-yl- ethanone;
2-[5-(4-Methoxy-phenoxymethyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-1-(4-methoxy- phenyl)-ethanone; N-(2,3-Dichloro-phenyl)-2-[4-furan-2-ylmethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3- ylsulfanyl]-acetamide;
2-[4-Furan-2-yImethyl-5-(4-hydroxy-phenyl)-4H-[1,2,4]triazol-3-yIsulfanyl]-1-(4-methoxy- phenyl)-ethanone;
{5-[(2-Chloro-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-acetic acid cyclo- hexyl ester; 2-(4-Phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-thiazol-2-yl-acetamide;
2-(4-Ethyl-5-m-tolyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(4-nitro-phenyl)-acetamide;
2-(4-Ethyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(2-methoxy-phenyl)-acetamide;
2-(4-Ethyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(2-trifluoromethyI-phenyl)-acetamide; 2-[4-Furan-2-ylmethyl-5-(2-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(2-methyl-4- nitro-phenyl)-acetamide;
N-(3-Chloro-2-methyl-phenyl)-2-[4-furan-2-ylmethyl-5-(2-methoxy-phenyl)-4H-[1,2,4]triazol-3- ylsulfanylj-acetamide;
4-Allyl-5-m-toIyl-4H-[1,2,4]triazole-3-thiol; 4-(2-Methyl-allyl)-5-m-tolyl-4H-[1 ,2,4]triazole-3-thiol;
2-[4-Allyl-5-(3-bromo-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(4-ethyl-phenyl)-acetamide;
4-Allyl-3-(3-bromo-phenyl)-5-(2-nitro-benzylsulfanyl)-4H-[1,2,4]triazole;
2-[4-Allyl-5-(3-bromo-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-1-biphenyl-4-yl-ethanone;
4-(2-Methyl-allyl)-5-(3-nitro-phenyl)-4H-[1 ,2,4]triazole-3-thiol; 4-Allyl-5-(2-carbazol-9-yl-ethyl)-4H-[1,2,4]triazole-3-thiol;
5-(4-Bromo-phenyl)-4-(2-methyl-allyl)-4H-[1,2,4]triazole-3-thiol;
4-(2-Methyl-allyl)-5-(3-methyl-2-nitro-phenyl)-4H-[1,2,43triazole-3-thiol;
5-(4-Methoxy-phenyl)-4-(2-methyl-allyl)-4H-[1,2,4]triazole-3-thiol;
2-(4-Allyl-5-benzotriazol-1-ylmethyI-4H-[1 ,2,4]tria∑ol-3-ylsulfanyl)-N-(4-bromo-phenyl)- acetamide;
2-(4-Allyl-5-benzotriazol-1-ylmethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-pyridin-2-yl-acetamide;
{4-Allyl-5-[3-(1 ,3-dioxo-1 H,3H-ben∑o[de]isoquinolin-2-yl)-propyl]-4H-[1 ,2,4]triazol-3- ylsulfanyl}-acetic acid ethyl ester; and
4-Allyl-5-(4-phenyl-piperazin-1 -ylmethyl)-4H-[1 ,2,4]triazole-3-thiol; 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 said substituted 1 ,2,4-triazole, or a prodrug thereof, as a component of the combination therapy is selected from the group consisting of: 4-[2-(4-Ethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)ethyl]morpholine;
1-Benzothiazol-2-yl-2-(4-ethyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone;
Λ/-Cyclohexyl-2-(4-ethyl-5-phenyl-4 --[1,2,4]triazol-3-ylsulfanyl)-Λ/-methyl-acetamide;
2-(4-EthyI-5-phenyl-4H-[1,2,4]triazol-3-yIsulfanyl)-1-phenyl-ethanone;
2-(4-Ethyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-1-(4-methoxy-phenyl)-ethanone; 2-(4-Ethyi-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-1-pyridin-3-yl-ethanone; 2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-methanesulfonyl-phenyl)-ethanone;
2-(4-Phenethyl-5-phenyl-4 -.-[1 ,2,4]triazol-3-ylsulfanyl)-1-phenyl-ethanone;
1-(4-Methoxy-phenyl)-2-(4-phenethyl-5-phenyl-4r -[1 ,2,4]triazol-3-ylsulfanyl)-ethanone;
2-(4-Phenethyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-1-pyridin-3-yl-ethanone; 1 -(4-Methanesulfonyl-phenyl)-2-(4-phenethyl-5-phenyl-4 - -[1 ,2,4] triazol-3-ylsulfanyl)- ethanone;
2-(4-Ethyl-5-pyridin-4-yl-4 .-[1 ,2,4]triazol-3-ylsulfanyl)-1-phenyl-ethanone;
2-(4-Ethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-methoxy-phenyl)-ethanone;
2-(4-Ethyl-5-pyridin-4-yl-4 .-[1 ,2,4]triazol-3-ylsulfanyl)-1-pyridin-3-yl-ethanone; 2-(4-Ethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -(4-methanesulfonyl-phenyl)- ethanone;
2-(4-Phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-phenyl-ethanone;
1-(4-Methoxy-phenyl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone;
2-(4-Phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]tria∑ol-3-ylsulfanyl)-1-pyridin-3-yl-ethanone; 1-(4-Methanesulfonyl-phenyl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)- ethanone;
2-(4-Ethyl-5-furan-2-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-phenyl-ethanone;
2-(4-Ethyl-5-furan-2-yl-4 τ'-[1,2,4]triazol-3-ylsulfanyl)-1-(4-methoxy-phenyl)-ethanone;
2-(4-Ethyl-5-furan-2-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-pyridin-3-yl-ethanone; 2-(4-Ethyl-5-furan-2-yl-4rV-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-methanesulfonyl-phenyl)-ethanone;
2-(5-Furan-2-yl-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-phenyl-ethanone;
2-(5-Furan-2-yl-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-methoxy-phenyl)-ethanone;
2-(5-Furan-2-yl-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-pyridin-3-yl-ethanone;
2-(5-Furan-2-yl-4-phenethyl-4/-.-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-methanesulfonyl-phenyl)- ethanone;
1 -Adamantan-1 -yl-2-(4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-ethanone;
3-[5-(2-Chloro-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-yl]-propan-1-ol;
4-[4-Ethyl-5-(3-hydroxy-propyl)-4/- -[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile;
3-[5-(6-Chloro-benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-propan-1-ol; 3-[5-(3,4-Dichloro-ben∑ylsulfanyl)-4-ethyl-4H-[1 ,2,4]tria∑ol-3-yl]-propan-1 -ol;
3-(5-CyclohexylmethylsuIfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-yl)-propan-1-ol;
3-[4-Ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-propan-1-ol;
3-(5-Benzylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-yl)-propan-1-ol;
3-[4-Ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4H-t1,2,4]triazol-3-yl]-propan-1-ol; 3-[4-Ethyl-5-(3-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-propan-1 -ol; 3-[5-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-propan-1-ol;
3-[4-Ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-propan-1-ol;
N-{4-[4-Ethyl-5-(3-hydroxy-propyl)-4/- -[1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}-acetamide;
3-[4-Ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-propan-1-ol; 3-[4-Ethyl-5-(2-nitro-benzylsuIfanyl)-4H-[1 ,2,4]triazol-3-yl]-propan-1 -ol;
4-[4-Ethyl-5-(4-hydroxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile;
4-[5-(6-Chloro-benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-phenol;
4-[5-(4-Bromo-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-phenol;
4-[4-Ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol; 4-(5-Benzylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-yl)-phenol;
4-[4-Ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-phenol;
4-[4-Ethyl-5-(3-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol;
4-[4-Ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl etser; 4-[5-(4-Benzyloxy-ben∑ylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-phenol;
N-{4-[4-Ethyl-5-(4-hydroxy-phenyl)-4/-/-[1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}-acetamide;
4-[4-Ethyl-5-(4-methoxy-ben∑ylsulfanyl)-4H-[1 ,2,4]tria∑ol-3-yl]-phenol;
4-[4-Ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-[1,2,4]lriazol-3-yl]-phenol;
4-[4-Ethyl-5-(2-nitro-ben∑ylsulfanyl)-4H-[1 ,2,4]tria∑ol-3-yl]-phenol; 4-[5-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-yl]-phenol;
3-Benzo[1 ,3]dioxol-5-yl-5-(2-chloro-benzylsulfanyl)-4-ethyl-4 -/-[1 ,2,4]triazole;
4-(5-Ben∑o[1 ,3]dioxol-5-yl-4-ethyl-4H-[1 ,2,4]tria∑ol-3-ylsulfanylmethyl)-benzonitrile;
3-Ben∑o[1 ,3]dioxol-5-yl-5-(6-chloro-ben∑o[1,3]dioxol-5-ylmethylsuIfanyl)-4-ethyl-4H-
[1 ,2,4]tria∑ole; 3-Benzo[1 ,3]dioxol-5-yl-5-(4-bromo-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
4-[4-(5-Benzo[1 ,3]dioxol-5-yl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-phenyl]-
[1 ,2,3]thiadiazole;
3-Ben∑o[1 ,3]dioxol-5-yl-5-cyclohexylmethylsulfanyl-4-ethyl-4H-[1 ,2,4]triazole;
3-Benzo[1 ,3]dioxol-5-yl-4-ethyl-5-(4-trifluoromethoxy-ben∑ylsulfanyl)-4H-[1 ,2,4]tria∑ole; 3-Benzo[1 ,3]dioxol-5-yl-5-(3,5-dimethoxy-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
3-Benzo[1 ,3]dioxol-5-yl-4-ethyl-5-(4-methanesulfonyl-ben∑ylsulfanyl)-4H-[1,2,4]tria∑ole;
4-(5-Ben∑o[1 ,3]dioxol-5-yl-4-ethyl-4 - -[1 ,2,4]tria∑ol-3-ylsulfanylmethyl)-benzoic acid methyl etser;
3-Benzo[1 ,3]dioxol-5-yl-5-(2,6-dichloro-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazole; 3-Ben∑o[1 ,3]dioxol-5-yl-5-(4-benzyIoxy-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole; N-[4-(5-Benzo[1,3]dioxol-5-yl-4-ethyl-4H-[1,2,4]tria∑ol-3-ylsulfanylmethyl)-phenyl]-acetamide;
3-Benzo[1 ,3]dioxol-5-yl-4-ethyl-5-(4-methoxy-benzylsulfanyl)-4H-[1,2,4]triazole;
3-Benzo[1,3]dioxol-5-yl-4-ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4/.-[1,2,4]triazole;
3-Benzo[1,3]dioxol-5-yl-4-ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1,2,4]triazole; 3-Benzo[1 ,3]dioxol-5-yl-5-(2,4-dichloro-benzylsulfanyl)-4-ethyI-4H-[1 ,2,4]triazole;
4-[4-Ethyl-5-(2-phenoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-ben∑onitrile;
3-(6-Chloro-ben∑o[1,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-5-(2-phenoxy-phenyl)-4/-/-
[1 ,2,4]triazole;
3-(3,4-Dichloro-benzylsuIfanyl)-4-ethyl-5-(2-phenoxy-phenyl)-4H-[1,2,4]triazole; 3-(4-Bromo-benzylsulfanyl)-4-ethyl-5-(2-phenoxy-phenyl)-4H-[1,2,4]triazole;
4-{4-[4-Ethyl-5-(2-phenoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}-
[1,2,3]thiadiazole;
3-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-5-(2-phenoxy-phenyl)-4H-[1,2,4]triazole;
4-Ethyl-3-(2-phenoxy-phenyl)-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1,2,4]triazole; 4-Ethyl-3-(4-methanesulfonyl-benzylsulfanyl)-5-(2-phenoxy-phenyl)-4H-[1,2,4]tria∑ole;
4-[4-Ethyl-5-(2-phenoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyImethyl]-benzoic acid methyl etser;
3-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-5-(2-phenoxy-phenyl)-4H-[1,2,4]triazole;
3-(4-Ben∑yloxy-ben∑ylsulfanyl)-4-ethyl-5-(2-phenoxy-phenyl)-4/-.-[1,2,4]tria∑ole; 4-Ethyl-3-(4-methyl-benzylsulfanyl)-5-(2-phenoxy-phenyl)-4H-[1 ,2,4]triazole;
4-Ethyl-3-(2-phenoxy-phenyl)-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1,2,4]triazole;
4-Ethyl-3-(4-metho)cy-benzylsulfanyl)-5-(2-phenoxy-phenyl)-4/.-[1 ,2,4]triazole;
4-Ethyl-3-(2-nitro-benzylsulfanyl)-5-(2-phenoxy-phenyl)-4H-[1,2,4]triazole;
3-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-5-(2-phenoxy-phenyl)-4H-[1,2,4]triazole; 3-Cyclohexylmethylsulfanyl-4-ethyl-5-naphthalen-1 -yl-4H-[1 ,2,4]triazole;
4-Ethyl-3-naphthalen-1-yl-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1,2,4]triazole;
4-Ethyl-3-(4-methanesulfonyl-benzylsulfanyl)-5-naphthalen-1-yl-4H-[1,2,4]triazole;
4-Ethyl-3-naphthalen-1-yl-5-(3-nitro-benzylsulfanyl)-4H-[1,2,4]triazole;
4-(4-Ethyl-5-naphthalen-1-yl-4/--[1,2,4]triazol-3-ylsulfanylmethyl)-benzoic acid methyl etser; 4-Ethyl-3-naphthalen-1 -yl-5-(4-nitro-benzylsulfanyl)-4 -/-[1 ,2,4]triazole;
3-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-5-naphthalen-1-yl-4H-[1,2,4]triazole;
4-Ethyl-3-(4-methyl-benzylsuIfanyl)-5-naphthalen-1-yl-4 -/-[1,2,4]triazole;
4-Ethyl-3-(4-methoxy-benzylsulfanyl)-5-naphthalen-1-yl-4 --[1,2,4]tria∑ole;
4-Ethyl-3-(5-methyl-2-nitro-benzylsulfanyl)-5-naphthalen-1-yl-4H-[1,2,4]triazole; 3-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-5-naphthalen-1 -yl-4H-[1 ,2,4]triazole; [4-(5-Cyclohexylmethylsulfanyl-4-ethyl-4H-[1,2,4]triazol-3-yl)-phenyl]-dimethyl-amine
{4-[5-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyI-4H-[1,2,4]triazol-3-yl]-phenyl}-dimethyl-amine
{4-[4-Ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-phenyl}-dimethyl-amine
4-[5-(4-Dimethylamino-phenyl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl etser;
{4-[4-Ethyl-5-(4-nitro-benzylsulfanyl)-4/-/-[1,2,4]triazol-3-yl]-phenyl}-dimethyl-amine;
{4-[4-Ethyl-5-(4-methoxy-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-phenyl}-dimethyl-amine;
{4-[4-Ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-phenyl}-dimethyl-amine;
{4-[5-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-phenyl}-dimethyl-amine; 4-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-benzonitrile;
3-(6-Chloro-benzo[1,3]dioxol-5-ylmethylsulfanyl)-4-ethyI-5-thiophen-2-yl-4/-/-[1,2,4]triazole;
3-(3,4-Dichloro-ben∑ylsulfanyl)-4-ethyl-5-thiophen-2-yI-4/-/-[1,2,4]triazole;
3-(4-Bromo-benzylsulfanyl)-4-ethyl-5-thiophen-2-yl-4H-[1 ,2,4]triazole;
4-[4-(4-Ethyl-5-thiophen-2-yl-4/-/-[1,2,4]triazol-3-ylsulfanylmethyl)-phenyl]-[1,2,3]thiadia∑ole; 4-Ethyl-3-thiophen-2-yl-5-(4-trifluoromethoxy-ben∑ylsulfanyl)-4/--[1,2,4]triazole;
3-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-5-thiophen-2-yI-4H-[1,2,4]triazole;
4-Ethyl-3-thiophen-2-yl-5-(4 rifluoromethyl-ben∑ylsulfanyl)-4 -.-[1 ,2,43tria∑ole;
3-Benzylsulfanyl-4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazoIe;
4-Ethyl-3-(4-methanesulfonyl-ben∑ylsulfanyl)-5-thiophen-2-yl-4H-[1,2,4]tria∑ole; 4-(4-Ethyl-5-thiophen-2-yl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzoic acid methyl etser;
4-Ethyl-3-(4-nitro-benzylsulfanyl)-5-thiophen-2-yl-4H-[1 ,2,4]tria∑ole;
3-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazole;
4-Ethyl-3-(4-methyl-benzylsulfanyl)-5-thiophen-2-yl-4H-[1,2,4]triazole;
4-Ethyl-3-(4-methoxy-ben∑ylsulfanyl)-5-thiophen-2-yl-4H-[1 ,2,4]triazole; 4-Ethyl-3-(5-methyl-2-nitro-benzylsulfanyl)-5-thiophen-2-yI-4H-[1,2,4]triazole;
3-(2-Chloro-ben∑ylsulfanyl)-4-ethyl-5-(2-methoxy-phenyl)-4/-.-[1,2,4]triazole;
3-(6-Chloro-benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-5-(2-methoxy-phenyl)-4H-
[1 ,2,4]triazoIe;
4-Ethyl-3-(2-methoxy-phenyl)-5-(4-trifluoromethoxy-benzylsulfanyl)-4H-[1,2,4]triazole; 3-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-5-(2-methoxy-phenyl)-4/-/-[1,2,4]triazole;
4-Ethyl-3-(2-methoxy-phenyl)-5-(4-trifluoromethyl-benzylsulfanyl)-4 -/-[1,2,4]triazole;
3-Benzylsulfanyl-4-ethyl-5-(2-methoxy-phenyl)-4H-[1,2,4]triazole;
4-Ethyl-3-(4-methanesulfonyl-benzylsulfanyl)-5-(2-methoxy-phenyl)-4H-[1,2,4]triazole;
4-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl et- ser; 4-Ethyl-3-(2-methoxy-phenyl)-5-(4-nitro-benzylsulfanyl)-4H-[1,2,4]triazole;
3-(2,6-Dichloro-benzyIsulfanyl)-4-ethyl-5-(2-methoxy-phenyl)-4H-[1,2,4]triazole;
3-(4-Benzyloxy-benzylsulfanyl)-4-ethyl-5-(2-methoxy-phenyl)-4H-[1,2,4]triazole;
4-EthyI-3-(2-methoxy-phenyl)-5-(4-methyi-benzylsulfanyl)-4-/-[1,2,4]tria∑ole; 4-Ethyl-3-(2-methoxy-phenyl)-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1,2,4]triazole;
4-Ethyl-3-(2-methoxy-phenyl)-5-(5-methyl-2-nitro-benzylsulfanyI)-4H-[1,2,4]triazole;
4-Ethyl-3-(2-methoxy-phenyl)-5-(2-nitro-benzylsulfanyl)-4H-[1,2,4]triazole;
3-(2-Chloro-benzylsulfanyl)-4-ethyl-5-(4-methoxy-phenyl)-4/-/-[1,2,4]triazole;
4-[4-Ethyl-5-(4-methoxy-phenyl)-4 --[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile; 3-(6-Chloro-benzo[1,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-5-(4-methoxy-phenyl)-4H-
[1 ,2,4]triazole;
3-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-5-(4-methoxy-phenyl)-4/--[1 ,2,4]triazole;
3-(4-Bromo-benzylsulfanyl)-4-ethyl-5-(4-methoxy-phenyl)-4 -/-[1 ,2,4]tria∑ole;
4-{4-[4-EthyI-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}- [1 ,2,3]thiadiazole;
3-Cyclohexylmethylsulfanyl-4-ethyl-5-(4-methoxy-phenyl)-4H-[1,2,4]triazole;
4-Ethyl-3-(4-methoxy-phenyl)-5-(4-trifluoromethyl-benzylsulfanyl)-4/L.-[1,2,4]triazole;
4-Ethyl-3-(4-methanesulfonyl-benzylsulfanyl)-5-(4-methoxy-phenyl)-4H-[1,2,4]triazole;
4-[4-Ethyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]tria∑ol-3-ylsulfanylmethyl]-ben∑oic acid methyl et- ser;
3-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazole;
3-(4-Ben∑yloxy-benzylsulfanyl)-4-ethyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]tria∑ole;
4-Ethyl-3-(4-methoxy-phenyl)-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1,2,4]triazole;
N-{4-[4-Ethyl-5-(4-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-phenyl}-acetamide; 4-Ethyl-3-(4-methoxy-benzylsulfanyl)-5-(4-methoxy-phenyl)-4H-[1,2,4]triazole;
4-Ethyl-3-(4-methoxy-phenyl)-5-(2-nitro-benzylsulfanyl)-4/-.-[1,2,4]triazole;
4-(4-Ethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-benzonitrile;
4-[5-(4-Bromo-benzylsulfanyl)-4-ethyl-4/--[1,2,4]triazol-3-yl]-pyridine;
4-[5-(3,5-Dimethoxy-benzyIsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-yl]-pyridine; 4-[4-EthyI-5-(4-methanesulfonyl-benzylsulfanyl)-4 -/-[1,2,4]triazol-3-yl]-pyridine;
4-(4-Ethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzoic acid methyl etser;
4-[4-Ethyl-5-(4-methyl-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine;
4-[4-Ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4 -/-[1,2,4]triazol-3-yl]-pyridine;
4-[5-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-yl]-pyridine; 3-[5-(2-Chloro-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-yl]-pyridine; 4-(4-Ethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-yIsulfanylmethyl)-benzonitrile;
3-[5-(6-Chloro-benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-pyridine;
3-[5-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-yl]-pyridine;
3-[5-(4-Bromo-benzylsulfanyl)-4-ethyl-4/-.-[1 ,2,4]triazol-3-yl]-pyridine; 3-[4-Ethyl-5-(4-[1 ,2,3]thiadiazol-4-yl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-pyridine;
3-[4-Ethyl-5-(4-trifluoromethoxy-benzylsulfanyl)-4ry-[1 ,2,4]triazol-3-yl]-pyridine;
3-[5-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-pyridine;
3-[4-Ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-pyridine;
3-(5-Benzylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-yl)-pyridine; 3-[4-Ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4 .-[1 ,2,4]triazol-3-yl]-pyridine;
3-[4-Ethyl-5-(3-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-pyridine;
4-(4-Ethyl-5-pyridin-3-yl-4 - -[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzoic acid methyl etser;
3-[5-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-4 -/-[1 ,2,4]triazol-3-yl]-pyridine;
3-[5-(4-Benzyloxy-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazoI-3-yl]-pyridine; 3-[4-Ethyl-5-(4-methyl-benzyisulfanyl)-4H-[1 ,2,4]triazol-3-yl]-pyridine;
3-[4-Ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-pyridine;
N-[4-(4-Ethyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-phenyl]-acetamide;
3-[4-Ethyl-5-(4-methoxy-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-pyridine;
3-[4-Ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4/-/-[1 ,2,4]tria∑ol-3-yl]-pyridine; 3-[4-Ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine;
3-[5-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-4 -/-[1 ,2,4]triazol-3-yl]-pyridine;
3-(2-Chloro-ben∑ylsulfanyl)-5-(4-chloro-phenyl)-4-ethyl-4H-[1 ,2,4]tria∑ole;
4_[5-(4-Chloro-phenyl)-4-ethyl-4H-[1 ,2,4]tria∑ol-3-ylsulfanylmethyl]-ben∑onitrile;
3-(4-Chloro-phenyl)-5-(3,4-dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole; 4-{4-[5-(4-Chloro-phenyl)-4-ethyl-4H-[1 ,2,4]tria∑ol-3-ylsulfanylmethyl]-phenyl}-
[1 ,2,3]thiadia∑ole;
3-(4-Chloro-phenyl)-4-ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-(4-Chloro-phenyl)-4-ethyl-5-(3-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
4-[5-(4-Chloro-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl etser; 3-(4-Chloro-phenyl)-5-(2,6-dichloro-ben∑ylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
3-(4-BenzyIoxy-benzylsulfanyl)-5-(4-chloro-phenyl)-4-ethyl-4H-[1,2,4]tria∑ole;
3-(4-Chloro-phenyl)-4-ethyl-5-(4-methyl-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-(4-Chloro-phenyl)-4-ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]triazole;
N-{4-[5-(4-Chloro-phenyl)-4-ethyI-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-phenyl}-acetamide; 3-(4-Chloro-phenyl)-4-ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4/.-[1 ,2,4]triazole; 3-(4-Chloro-phenyl)-5-(2,4-dichloro-benzylsulfanyl)-4-ethyi-4H-[1 ,2,4]triazole;
5-[5-(2-Chloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-4-phenyl-[1 ,2,3]thiadiazole;
4-[4-Ethyl-5-(4-phenyl-[1 ,2,3]thiadiazol-5-yl)-4H-[1 ,2,4]triazol-3-ylsulfanyImethyl]-ben∑onitrile;
5-[5-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-yl]-4-phenyl-[1,2,3]thiadiazole; 5-[4-Ethyl-5-(4-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-4-phenyl-
[1,2,3]thiadiazole;
5-[5-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-yl]-4-phenyl-[1 ,2,3]thiadiazole;
5-[4-Ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4ry-[1 ,2,4]triazol-3-yl]-4-phenyl-
[1 ,2,3]thiadiazole; 5-(5-Benzylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-yl)-4-phenyl-[1 ,2,3]thiadiazole;
5-[4-Ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4 - -[1 ,2,4]triazol-3-yl]-4-phenyl-
[1 ,2,3]thiadiazole;
5-[4-EthyI-5-(4-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-4-phenyl-[1 ,2,3]thiadiazole;
5-[5-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-4-phenyl-[1 ,2,3]thiadiazole; 5-[4-Ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-4-phenyl-
[1 ,2,3]thiadiazole;
5-[4-EthyI-5-(4-methoxy-benzylsulfanyl)-4/.-[1 ,2,4]triazol-3-yl]-4-phenyl-[1 ,2,3]thiadiazole;
5-[4-Ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-4-phenyl-[1 ,2,3]thiadiazole;
4-{5-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl}- benzonitrile;
3-(6-Chloro-benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-5-[4-(2,5-dimethyl-pyrrol-1-yl)-phenyl]-4- ethyl-4H-[1 ,2,4]tria∑ole;
3-(3,4-Dichloro-ben∑ylsulfanyl)-5-[4-(2,5-dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-4H-
[1 ,2,4]tria∑ole; 3-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-5-(4-trifluoromethoxy-benzylsulfanyl)-4 - -
[1 ,2,4]triazole;
3-(3,5-Dimethoxy-benzylsulfanyl)-5-[4-(2,5-dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-4H-
[1 ,2,4]triazole;
3-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-5-(4-trifluoromethyl-benzylsulfanyI)-4H- [1 ,2,4]triazole;
3-Benzylsulfanyl-5-[4-(2,5-dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-4H-[1,2,4]triazole;
3-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyI]-4-ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4H-
[1 ,2,4]triazole;
3-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-5-(3-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole; 4-{5-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyi}-benzoic acid methyl etser;
3-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-5-(4-nitro-benzylsulfanyl)-4/--[1,2,4]triazole;
3-(4-Benzyloxy-benzylsulfanyl)-5-[4-(2,5-dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-4H- [1 ,2,4]triazole;
N-(4-{5-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl}- phenyl)-acetamide;
3-[4-(2,5-DimethyI-pyrrol-1-yl)-phenyl]-4-ethyl-5-(4-methoxy-benzylsulfanyl)-4/-/-
[1 ,2,4]triazole; 3-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-
[1 ,2,4]triazole;
3-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-5-(2-nitro-ben∑ylsulfanyl)-4H-[1 ,2,4]triazole;
3-(2,4-Dichloro-benzylsulfanyl)-5-[4-(2,5-dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-4H-
[1 ,2,4]tria∑ole; 3-Benzo[b]thiophen-2-yl-5-(2-chloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
4-(5-Benzo[b]thiophen-2-yl-4-ethyl-4H-[1 ,2,4]tria∑ol-3-ylsulfanylmethyl)-benzonitrile;
3-Benzo[b]thiophen-2-yl-5-(6-chloro-benzo[1,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-4H-
[1 ,2,4]tria∑ole;
3-Ben∑o[b]thiophen-2-yl-5-(4-bromo-ben∑ylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole; 4-[4-(5-Benzo[b]thiophen-2-yl-4-ethyl-4-.-[1,2,4]triazol-3-ylsulfanylmethyl)-phenyl]-
[1 ,2,3]thiadiazole;
3-Benzo[b]thiophen-2-yl-4-ethyl-5-(3-nitro-benzylsulfanyl)-4H-[1 ,2,4]tria∑ole;
4-(5-Ben∑o[b]thiophen-2-yl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzoic acid methyl etser; 3-Benzo[b]thiophen-2-yl-4-ethyl-5-(4-nitro-benzylsulfanyl)-4H-[1 ,2,4]tria∑ole;
3-Benzo[b]thiophen-2-yl-5-(4-benzyloxy-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
3-Benzo[b]thiophen-2-yl-4-ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]triazoIe;
N-[4-(5-Benzo[b]thiophen-2-yl-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-phenyl]- acetamide; 3-Ben∑o[b]thiophen-2-yl-4-ethyl-5-(4-methoxy-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-Benzo[b]thiophen-2-yl-4-ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1,2,4]triazole;
3-(2-Chloro-benzylsulfanyl)-4-ethyl-5-(1-phenyl-5-trifluoromethyl-1/-/-pyrazol-4-yl)-4H-
[1 ,2,4]triazole;
3-(6-Chloro-benzo[1,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-5-(1-phenyl-5-trifluoromethyl-1H- pyrazol-4-yl)-4H-[1 ,2,4]triazole; 4-{4-[4-Ethyl-5-(1 -phenyl-5-trifluoromethyl-1 tf-pyrazol-4-yl)-4/.-[1 ,2,4]triazoI-3- ylsulfanylmethyl]-phenyl}-[1,2,3]thiadiazole;
4-Ethyl-3-(1-phenyl-5-trifluoromethyl-1 -.-pyrazol-4-yl)-5-(4-trifluoromethoxy-benzylsulfanyl)-
4H-[1 ,2,4]triazole; 3-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-5-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-4H-
[1 ,2,4]triazole;
3-Benzylsulfanyl-4-ethyl-5-(1 -phenyl-5-trif luoromethyl-1 H-pyrazol-4-yl)-4H-[1 ,2,4]triazole;
4-Ethyl-3-(4-methanesulfonyl-benzylsulfanyl)-5-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-
4H-[1 ,2,4]triazole; 4-Ethyl-3-(3-nitro-benzylsulfanyl)-5-(1-phenyl-5-trif luoromethyl-1 H-pyrazol-4-yl)-4H-
[1 ,2,4]triazole;
4-[4-Ethyl-5-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]- benzoic acid methyl etser;
3-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-5-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-4H- [1 ,2,4]triazole;
3-(4-Benzyloxy-benzylsulfanyl)-4-ethyl-5-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-4H-
[1 ,2,4]triazole;
4-Ethyl-3-(4-methyl-ben∑ylsulfanyl)-5-(1-phenyl-5-trifluoromethyl-1H-pyra∑ol-4-yl)-4H-
[1 ,2,4]tria∑ole; N-{4-[4-Ethyl-5-(1 -phenyl-5-trifluoromethyl-1 H-pyra∑ol-4-yl)-4/-/-[1 ,2,4]triazol-3- ylsulfanylmethyl]-phenyl}-acetamide;
4-Ethyl-3-(5-rnethyl-2-nitro-benzylsulfanyl)-5-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-ylHH-
[1 ,2,4]tria∑ole;
4-Ethyl-3-(2-nitro-ben∑ylsulfanyl)-5-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-4H- [1 ,2,4]triazole;
3-(2,4-Dichloro-benzylsulfanyl)-4-ethyI-5-(1-phenyl-5-trifluoromethyl-1 .-pyra∑ol-4-yl)-4H-
[1 ,2,4]tria∑ole;
3-(2-Chloro-benzylsulfanyl)-5-(3-chloro-4-methyl-thiophen-2-yI)-4-ethyl-4/-/-[1 ,2,4]triazole;
4-[5-(3-Chloro-4-methyl-thiophen-2-yl)-4-ethyl-4/.-[1 ,2,4]tria∑ol-3-ylsulfanylmethyl]- benzonitrile;
3-(3-Chloro-4-methyl-thiophen-2-yl)-5-(3,4-dichloro-benzylsulfanyl)-4-ethyl-4 -/-[1 ,2,4]triazole;
4-{4-[5-(3-Chloro-4-methyl-thiophen-2-yl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]- phenyl}-[1 ,2,3]thiadiazole;
3-(3-Chloro-4-methyl-thiophen-2-yl)-5-cyclohexylmethylsulfanyl-4-ethyl-4 -/-[1 ,2,4]triazole; 3-(3-Chloro-4-methyl-thiophen-2-yl)-4-ethyl-5-(4-trifluoromethoxy-benzylsulfanyl)-4H-
[1 ,2,4]triazole;
3-(3-Chloro-4-methyl-thiophen-2-yl)-4-ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4H-
[1 ,2,4]triazoIe; 3-(3-Chloro-4-methyl-thiophen-2-yl)-4-ethyl-5-(3-nitro-benzylsulfanyl)-4-/-[1 ,2,4]triazole;
4-[5-(3-Chloro-4-methyl-thiophen-2-yI)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl etser;
3-(3-Chloro-4-methyl-thiophen-2-yl)-5-(2,6-dichloro-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazole;
3-(3-Chloro-4-methyl-thiophen-2-yl)-4-ethyl-5-(4-methyl-benzylsulfanyl)-4/-/-[1 ,2,4]triazole; 3-(3-Chloro-4-methyl-thiophen-2-yl)-4-ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-
[1 ,2,4]triazole;
3-(3-Chloro-4-methyl-thiophen-2-yl)-4-ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-
[1 ,2,4]triazole;
3-(3-Chloro-4-methyl-thiophen-2-yl)-4-ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1,2,4]triazole; 4-(4-Ethyl-5-pyridin-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-benzonitriIe;
2-[5-(6-Chloro-ben∑o[1,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-yI]-pyridine
2-[5-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-4 -/-[1,2,4]triazol-3-yl]-pyridine;
2-[5-(4-Bromo-benzylsulfanyl)-4-ethyl-4 -.-[1,2,4]triazol-3-yl]-pyridine;
2-[4-Ethyl-5-(4-[1,2,3]thiadia∑ol-4-yl-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridιne; 2-[5-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-4 -.-[1,2,4]triazol-3-yl]-pyridine;
2-[4-Ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine;
2-[4-Ethyl-5-(4-methanesulfonyl-ben∑ylsulfanyl)-4/--[1,2,4]triazol-3-yl]-pyridine;
2-[4-Elhyl-5-(3-nitro-benzylsulfanyI)-4H-[1 ,2,4]triazol-3-yl]-pyridine;
4-(4-Ethyl-5-pyridin-2-yI-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzoic acid methyl etser; 2-[4-Ethyl-5-(4-nitro-benzylsulfanyl)-4H-[1,2,4]tria∑oI-3-yl]-pyridine;
2-[5-(4-Benzyloxy-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-yl]-pyridine;
2-[4-Ethyl-5-(4-methyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-pyridine;
2-[4-Ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4ry-[1,2,4]triazol-3-yl]-pyridine;
2-[4-Ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4/--[1,2,4]tria∑ol-3-yl]-pyridine; 2-[4-Ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine;
3-[5-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-yl]-2-methylsulfanyl-pyridine;
3-[4-Ethyl-5-(4-[1,2,3]thiadiazol-4-yl-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-2-methylsuIfanyl- pyridine;
3-(5-Cyclohexylmethylsulfanyl-4-ethyl-4H-[1,2,4]triazol-3-yl)-2-methylsulfanyl-pyridine; 3-[4-Ethyl-5-(4-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-2-methylsulfanyl- pyridine;
3-[5-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-4ry-[1,2,4]triazol-3-yl]-2-methylsulfanyl-pyridine;
3-[4-Ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-2-methylsulfanyl-pyridine; 3-(5-Benzylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-yl)-2-methylsulfanyl-pyridine;
3-[4-Ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-2-methylsulfanyl- pyridine;
4-[4-Ethyl-5-(2-methylsulfanyl-pyridin-3-yl)-4/-/-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl etser; 3-[5-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-yl]-2-methylsulfanyl-pyridine;
3-[5-(4-Benzyloxy-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-yl]-2-methylsulfanyl-pyridine;
3-[4-Ethyl-5-(4-methyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-2-methylsulfanyl-pyridine;
3-[4-Ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-2-methylsulfanyl- pyridine; N-{4-[4-Ethyl-5-(2-methylsulfanyl-pyridin-3-yl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}- acetamide;
3-[4-Ethyl-5-(5-methyI-2-nitro-benzylsulfanyl)-4 -/-[1 ,2,4]tria∑ol-3-yl]-2-methylsulfanyl-pyridine;
3-[4-Ethyl-5-(2-nitro-ben∑ylsulfanyl)-4/-.-[1,2,4]triazol-3-yl]-2-methylsulfanyl-pyridine;
3-(2-Chloro-benzylsulfanyl)-4-ethyl-5-(5-methyl-thiophen-2-yl)-4H-[1 ,2,4]triazole; 4-[4-Ethyl-5-(5-methyl-thiophen-2-yl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile;
3-(6-Chloro-benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-5-(5-methyl-thiophen-2-yl)-4 -/-
[1 ,2,4]tria∑ole;
3-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-5-(5-methyl-thiophen-2-yl)-4H-[1 ,2,4]triazole;
4-{4-[4-Methyl-5-(5-methyl-thiophen-2-yl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}- [1 ,2,3]thiadiazole;
3-Cyclohexylmethylsulfanyl-4-ethyI-5-(5-methyl-thiophen-2-yl)-4 .-[1 ,2,4]triazole;
4-Ethyl-3-(5-methyl-thiophen-2-yl)-5-(4-trifluoromethoxy-benzylsulfanyl)-4H-[1,2,4]triazole;
3-(3,5-Dimethoxy-ben∑ylsulfanyl)-4-ethyl-5-(5-methyl-thiophen-2-yl)-4H-[1 ,2,4]triazole;
4-Ethyl-3-(5-methyl-thiophen-2-yl)-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1 ,2,4]triazole; 3-Ben∑ylsulfanyl-4-ethyl-5-(5-methyl-thiophen-2-yl)-4H-[1 ,2,4]tria∑ole;
4-Ethyl-3-(4-methanesulfonyl-benzylsulfanyl)-5-(5-methyl-thiophen-2-yl)-4/-/-[1,2,4]triazole;
4-EthyI-3-(5-methyl-thiophen-2-yl)-5-(3-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
4-[4-Ethyl-5-(5-methyl-thiophen-2-yl)-4ry-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl etser; 4-Ethyl-3-(5-methyl-thiophen-2-yl)-5-(4-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole; 3-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-5-(5-methyl-thiophen-2-yl)-4H-[1,2,4]triazole;
4-Ethyl-3-(4-methyl-benzylsulfanyl)-5-(5-methyl-thiophen-2-yl)-4H-[1,2,4]triazole; lS|-{4-[4-Ethyl-5-(5-methyl-thiophen-2-yl)-4H-[1,2,4]triazoI-3-ylsulfanylmethyl]-phenyl}- acetamide; 4-Ethyl-3-(4-methoxy-benzylsulfanyl)-5-(5-methyl-thiophen-2-yl)-4H-[1,2,4]triazole;
4-Ethyl-3-(5-methyl-thiophen-2-yl)-5-(2-nitro-benzylsulfanyl)-4H-[1,2,4]triazole;
3-(2,4-Dichloro-ben∑ylsulfanyl)-4-ethyl-5-(5-methyl-thiophen-2-yI)-4/--[1 ,2,4]triazole;
4-[5-(5-Chloro-thiophen-2-yl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile;
3-(5-Chloro-thiophen-2-yl)-5-(3,4-dichloro-benzylsulfanyl)-4-ethyl-4/-/-[1,2,4]triazole; 3-(4-Bromo-benzylsulfanyl)-5-(5-chloro-thiophen-2-yl)-4-ethyl-4 --[1 ,2,4]triazole;
4-{4-[5-(5-Chloro-thiophen-2-yl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}-
[1,2,3]thiadia∑ole;
3-(5-Chloro-thiophen-2-yl)-5-cyclohexylmethylsulfanyl-4-ethyl-4H-[1,2,4]triazole;
3-(5-Chloro-thiophen-2-yl)-4-ethyl-5-(4-trifluoromethoxy-benzylsulfanyl)-4H-[1,2,4]triazole; 3-(5-Chloro-thiophen-2-yl)-5-(3,5-dimethoxy-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazole;
3-(5-Chloro-thiophen-2-yl)-4-ethyI-5-(4-trifluoromethyl-benzylsulfanyl)-4 --[1 ,2,4]triazole;
3-(5-Chloro-thiophen-2-yl)-4-ethyl-5-(3-nitro-benzylsulfanyl)-4 --[1,2,4]tria∑ole;
4-[5-(5-Chloro-thiophen-2-yl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl
3-(5-Chloro-thiophen-2-yl)-5-(2,6-dichloro-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazole; 3-(5-Chloro-thiophen-2-yl)-4-ethyl-5-(4-methyl-benzylsulfanyl)-4H-[1 ,2,4]triazole; 3-(5-Chloro-thiophen-2-yl)-4-ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1,2,4]triazole; N-{4-[5-(5-Chloro-thiophen-2-yl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-phenyl}- acetamide; 3-(5-Chloro-th phen-2-yl)-4-ethyl-5-(4-methoxy-benzylsulfanyl)-4H-[1 ,2,4]triazole; 3-(5-Chloro-th ophen-2-yl)-4-ethyI-5-(5-methyl-2-nitro-benzylsulfanyl)-4 -/-[1,2,4]triazole; 3-(5-Chloro-th ophen-2-yl)-4-ethyl-5-(2-nitro-benzylsulfanyl)-4 -.-[1,2,4]triazole; 3-(5-Chloro-th ophen-2-yl)-5-(2,4-dichloro-benzylsulfanyl)-4-ethyl-4 --[1,2,4]triazole; 4-[4-Ethyl-5-(1H-indol-3-ylmethyl)-4H-[1,2,4]triazoI-3-ylsulfanylmethyl]-benzonitrile; 3-[5-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazoI-3-ylmethyl]-1 H-indole; 3-[5-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-ylmethyl]-1 -/-indole; 3-[4-Ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4H-[1,2,4]triazol-3-ylmethyl]-1H-indole; 3-[4-Ethyl-5-(3-nitro-benzylsuIfanyl)-4H-[1 ,2,4]triazol-3-ylmethyl]-1H-indole; 3-[4-Ethyl-5-(4-nitro-benzylsulfanyl)-4 .-[1,2,4]triazol-3-ylmethyl]-1H-indole; 3-[5-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylmethyl]-1 /-/-indole; 3-[5-(4-Benzyloxy-benzylsulfanyl)-4-ethyl-4/.-[1 ,2,4]triazol-3-ylmethyl]-1H-indole;
3-[4-Ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4 .-[1 ,2,4]triazol-3-ylmethyl]-1H-indole;
N-{4-[4-Ethyl-5-(1/-/-indol-3-ylmethyl)-4H-[1 ,2,4]triazoI-3-ylsulfanylmethyl]-phenyl}-acetamide;
3-[4-Ethyl-5-(4-methoxy-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylmethyl]-1H-indole; 3-[4-Ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylmethyl]-1 H-indole;
3-[4-Ethyl-5-(2-nitro-benzylsulfanyl)-4 -/-[1 ,2,4]triazol-3-yImethyl]-1H-indole;
3-[5-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-ylmethyl]-1H-indole;
2-[5-(6-Chloro-benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-4/.-[1 ,2,4]triazol-3-yl]-phenol;
2-[4-Ethyl-5-(4-[1 ,2,3]thiadiazol-4-yl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol; 2-(5-Cyclohexylmethylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-yl)-phenol;
2-[5-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-4 -.-[1 ,2,4]triazol-3-yl]-phenol;
2-[4-Ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol;
2-(5-Benzylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-yl)-phenol;
2-[4-Ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol; 2-[4-Ethyl-5-(3-nitro-benzylsulfanyl)-4/-/-[1 ,2,4]triazol-3-yl]-phenol;
4-[4-Ethyl-5-(2-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl et-
2-[4-Ethyl-5-(4-nitro-ben∑ylsulfanyl)-4H-[1 ,2,4]tria∑ol-3-yl]-phenol;
2-[5-(2,6-Dichloro-ben∑ylsulfanyl)-4-ethyl-4H-[1,2,4]tria∑ol-3-yl]-phenol; 2-[4-Ethyl-5-(4-methyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol;
2-[4-Ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol;
N-{4-[4-Ethyl-5-(2-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}-acetamide;
2-[4-Ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4/--[1 ,2,4]tria∑ol-3-yl]-phenol;
2-[4-Ethyl-5-(2-nitro-benzylsulfanyl)-4 -/-[1,2,4]triazol-3-yl]-phenol; 2-[5-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]tria∑ol-3-yl]-phenol;
5-[5-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-4-methyl-[1 ,2,3]thiadiazole;
5-[5-(4-Bromo-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-4-methyl-[1 ,2,3]thiadiazole;
5-(5-Cyclohexylmethylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-yl)-4-methyl-[1 ,2,3]thiadiazole;
5-[5-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-4H-[1,2,4]tria∑ol-3-yl]-4-methyl-[1,2,3]thiadia∑ole; 5-(5-Benzylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-yl)-4-methyl-[1 ,2,3]thiadiazole;
5-[4-Ethyl-5-(3-nitro-benzylsulfanyl)-4/-/-[1 ,2,4]triazoI-3-yl]-4-methyl-[1 ,2,3]thiadiazole;
4-[4-Ethyl-5-(4-methyl-[1 ,2,3]thiadiazol-5-yl)-4/- -[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl etser;
5-[4-Ethyl-5-(4-nitro-ben∑ylsulfanyl)-4H-[1,2,4]triazol-3-yl]-4-methyl-[1,2,3]thiadiazole; 5-[5-(4-Benzyloxy-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-4-methyl-[1 ,2,3]thiadiazole; 5-[4-Ethyl-5-(4-methyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-4-methyl-[1 ,2,3]thiadiazole;
5-[4-Ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]tria∑ol-3-yl]-4-methyl-
[1 ,2,3]thiadiazole;
5-[4-Ethyl-5-(5-methyl-2-nitro-benzylsuIfanyl)-4/-/-[1 ,2,4]triazol-3-yl]-4-methyl- [1 ,2,3]thiadiazole;
5-[5-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-4/-.-[1 ,2,4]tria∑ol-3-yl]-4-methyl-[1 ,2,3]thiadiazole;
4-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzonitrile;
3-Benzyl-5-(3,4-dichloro-benzylsulfanyl)-4-ethyl-4 - -[1 ,2,4]triazole;
4-[4-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-phenyl]-[1 ,2,3]thiadiazole; 3-Benzyl-5-(3,5-dimethoxy-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
3-Benzyl-4-ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4 - -[1 ,2,4]triazole;
3-Benzyl-5-benzylsulfanyl-4-ethyl-4ry-[1 ,2,4]triazole;
3-Benzyl-5-(2,6-dichloro-ben∑yIsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
3-Benzyl-4-ethyl-5-(4-methyl-benzylsulfanyl)-4H-[1 ,2,4]triazole; 3-Benzyl-4-ethyl-5-(4-methoxy-benzylsulfanyl)-4H-[1 ,2,4]tria∑ole;
3-Ben∑yl-4-ethyl-5-(5-methyI-2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-Ben∑yl-4-ethyl-5-(2-nitro-ben∑ylsulfanyl)-4H-[1,2,4]tria∑ole;
3-Ben∑yl-5-(2,4-dichloro-ben∑ylsulfanyl)-4-ethyl-4H-[1 ,2,4]tria∑ole;
3-(2-Bromo-phenyl)-5-(2-chloro-ben∑ylsulfanyl)-4-ethyl-4 .-[1 ,2,4]tria∑ole; 4-[5-(2-Bromo-phenyl)-4-ethyl-4ry-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile;
3-(2-Bromo-phenyI)-5-(6-chloro-benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-4H-
[1 ,2,4]tria∑ole;
3-(2-Bromo-phenyl)-5-(3,4-dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]tria∑ole;
3-(2-Bromo-phenyl)-5-cyclohexylmethylsulfanyl-4-ethyl-4H-[1,2,4]tria∑ole; 3-(2-Bromo-phenyl)-4-ethyl-5-(4-trifluoromethoxy-benzylsulfanyl)-4H-[1,2,4]triazole;
3-(2-Bromo-phenyl)-5-(3,5-dimethoxy-ben∑ylsulfanyl)-4-ethyl-4H-[1 ,2,4]tria∑ole;
3-(2-Bromo-phenyl)-4-ethyl-5-(4-trifluoromethyl-ben∑ylsulfanyl)-4H-[1 ,2,4]triazole;
3-(2-Bromo-phenyl)-4-ethyl-5-(3-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-(4-Benzyloxy-benzylsulfanyl)-5-(2-bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazole; 3-(2-Bromo-phenyl)-4-ethyl-5-(4-methoxy-benzylsulfanyl)-4 -/-[1 ,2,4]triazole;
3-(2-Bromo-phenyl)-4-ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-[1 ,2,4]tria∑ole;
3-(2-Bromo-phenyl)-5-(2,4-dichloro-benzylsulfanyl)-4-ethyl-4 - -[1 ,2,4]triazole;
2-[4-(3-Methoxy-propyl)-5-(1-methyI-piperidin-2-yl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]- benzonitrile; 2-[4-(3-Methoxy-propyl)-5-(1-methyl-piperidin-2-yl)-4 -/-[1 ,2,4]triazol-3-ylsuIfanylmethyl]- pyridine;
2-[5-(2-Methoxy-ethylsulfanyl)-4-(3-methoxy-propyl)-4H-[1 ,2,4]triazol-3-yl]-1-methyl- piperidine; 2-[4-(2-Methoxy-ethyl)-5-(1 -methyl-piperidin-2-yl)-4r -[1 ,2,4]triazol-3-ylsulfanylmethyl]- benzonitrile;
2-[4-(2-Methoxy-ethyl)-5-(1-methyI-piperidin-2-yl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]- pyridine;
2-[4-(2-Methoxy-ethyl)-5-(2-methoxy-ethylsulfanyl)-4H-[1 ,2,4]triazoI-3-yl]-1-methyl-piperidine; 2-[4-Cyclopropyl-5-(1-methyl-piperidin-2-yl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile;
2-[4-Cyclopropyl-5-(1-methyl-piperidin-2-yl)-4 - -[1 ,2,4]triazol-3-ylsulfanylmethyl]-pyridine;
2-[4-Cyclopropyl-5-(2-methoxy-ethylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-1-methyl-piperidine;
2-[5-(1-Methyl-piperidin-2-yl)-4-(2-piperidin-1-yl-ethyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]- ben∑onitrile; 2-[5-(1-Methyl-piperidin-2-yl)-4-(2-piperidin-1-yl-ethyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]- pyridine;
2-[4-Cyclopropylmethyl-5-(1-melhyl-piperidin-2-yl)-4 - -[1 ,2,4]triazol-3-ylsulfanylmethyl]- ben∑onitrile;
2-[4-Cyclopropylmethyl-5-(1-methyl-piperidin-2-yl)-4H-[1 ,2,4]triazoI-3-ylsulfanylmethyl]- pyridine;
2-[4-Cyclopropylmethyl-5-(2-methoxy-ethylsulfanyl)-4H-[1 ,2,4]tria∑ol-3-yl]-1-methyl- piperidine;
2-[5-(2-Hydroxy-phenyl)-4-(3-methoxy-propyl)-4- -[1,2,4]tria∑ol-3-ylsulfanylmethyl]- benzonitrile; 2-[4-(3-Methoxy-propyl)-5-(pyridin-2-ylmethylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol;
2-[5-(2-Methoxy-ethylsulfanyl)-4-(3-methoxy-propyI)-4H-[1 ,2,4]triazol-3-yl]-phenol;
2-[5-(2-Hydroxy-phenyl)-4-(2-methoxy-ethyl)-4 - -[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile;
2-[4-(2-Methoxy-ethyl)-5-(pyridin-2-ylmethylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenoI;
2-[4-(2-Methoxy-ethyl)-5-(2-methoxy-ethylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol; 2-[4-Cyclopropyl-5-(2-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile;
2-[4-Cyclopropyl-5-(pyridin-2-ylmethylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol;
2-[4-Cyclopropyl-5-(2-methoxy-ethylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol;
2-[5-(2-Hydroxy-phenyl)-4-(2-piperidin-1-yl-ethyl)-4ry-[1 ,2,4]triazol-3-ylsulfanylmethyl]- benzonitrile; 2-[4-(2-Piperidin-1-yl-ethyl)-5-(pyridin-2-ylmethylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol; 2-[5-(2-Methoxy-ethylsulfanyi)-4-(2-piperidin-1-yl-ethyl)-4ry-[1,2,4]triazol-3-yl]-phenol;
2-[4-Cyclopropylmethyl-5-(2-hydroxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]- benzonitrile;
2-[4-Cyclopropylmethyl-5-(pyridin-2-ylmethylsulfanyl)-4/--[1,2,4]triazol-3-yl]-phenol; 2-[4-Cyclopropylmethyl-5-(2-methoxy-ethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-phenol;
2-[5-(2-Methoxy-phenyl)-4-(3-methoxy-propyl)-4/.-[1,2,4]triazoI-3-ylsulfanylmethyl]- benzonitrile;
2-[5-(2-Methoxy-phenyl)-4-(3-methoxy-propyl)-4/.-[1,2,4]triazol-3-ylsulfanylmethyl]-pyridine;
3-(2-Methoxy-ethylsulfanyl)-5-(2-methoxy-phenyl)-4-(3-methoxy-propyl)-4H-[1,2,4]triazole; 2-[4-(2-Methoxy-ethyl)-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]- ben∑onitrile;
2-[4-(2-Methoxy-ethyl)-5-(2-methoxy-phenyl)-4H-[1,2,4]tria∑ol-3-ylsulfanylmethyl]-pyridine;
4-(2-Methoxy-ethyl)-3-(2-methoxy-ethylsulfanyl)-5-(2-methoxy-phenyl)-4H-[1,2,4]triazole;
2-[4-Cyclopropyl-5-(2-methoxy-phenyl)-4/-/-[1,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile; 2-[4-Cyclopropyl-5-(2-methoxy-phenyl)-4/-/-[1,2,4]triazol-3-ylsulfanylmethyl]-pyridine;
4-Cyclopropyl-3-(2-methoxy-ethylsulfanyl)-5-(2-methoxy-phenyl)-4H-[1,2,4]triazole;
2-[5-(2-Methoxy-phenyl)-4-(2-piperidin-1-yl-ethyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]- benzonitrile;
2-[5-(2-Methoxy-phenyl)-4-(2-piperidin-1-yl-ethyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]- pyridine;
1-{2-[3-(2-Methoxy-ethylsulfanyl)-5-(2-methoxy-phenyl)-[1 ,2,4]triazol-4-yl]-ethyl}-piperidine;
2-[4-Cyclopropylmethyl-5-(2-methoxy-phenyl)-.H-[1,2,4]triazol-3-ylsulfanylmethyl]- benzonitrile;
2-[4-Cyclopropylmethyl-5-(2-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-pyridine; 4-Cyclopropylmethyl-3-(2-methoxy-ethylsulfanyl)-5-(2-methoxy-phenyl)-4/.-[1 ,2,4]triazole;
2-[4-(3-Methoxy-propyl)-5-thiophen-2-yl-4/-/-[1,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile;
2-[4-(3-Methoxy-propyl)-5-thiophen-2-yl-4/--[1,2,4]triazol-3-ylsulfanylmethyl]-pyridine;
3-(2-Methoxy-ethylsulfanyl)-4-(3-methoxy-propyl)-5-thiophen-2-yl-4H-[1,2,4]triazole;
2-[4-(2-Methoxy-ethyl)-5-thiophen-2-yl-4/-/-[1,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile; 2-[4-(2-Methoxy-ethyl)-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-pyridine;
4-(2-Methoxy-ethyl)-3-(2-methoxy-ethylsulfanyl)-5-thiophen-2-yl-4H-[1,2,4]triazole;
2-(4-Cyclopropyl-5-thiophen-2-yl-4/-/-[1,2,4]triazol-3-ylsulfanylmethyl)-benzonitrile;
2-(4-CyclopropyI-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-pyridine;
4-Cyclopropyl-3-(2-methoxy-ethylsulfanyl)-5-thiophen-2-yl-4 --[1,2,4]triazole; 2-[4-(2-Piperidin-1-yl-ethyl)-5-thiophen-2-yl-4 .-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile; 2-[4-(2-Piperidin-1-yl-ethyl)-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-pyridine; 1-{2-[3-(2-Methoxy-ethylsulfanyl)-5-thiophen-2-yl-[1,2,4]triazol-4-yl]-ethyl}-piperidine; 2-(4-Cyclopropylmethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-benzonitrile; 2-(4-Cyclopropylmethyl-5-thiophen-2-yl-4 .-[1 ,2,4]triazol-3-ylsulfanylmethyl)-pyridine; 4-Cyclopropylmethyl-3-(2-methoxy-ethylsulfanyl)-5-thiophen-2-yl-4H-[1 ,2,4]triazole; 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 pharmaceuti- cally 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 methoxide, sodium hydride, potassium -ert-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, THF, methanol, ferf-butanol, dioxane, isopropanol, ethanol etc. Mixtures of solvents may be used. Organic bases like lysine, arginine, diethanol- amine, choline, guandine and their derivatives etc. may also be used. Alternatively, acid ad- dition 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 preferred 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 Resolu- tion" (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, aminoacids, 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; and various modes of cooling, ranging from very fast to very slow cool- ing 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, -erf-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 alters, and more specifically, reduces 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 ovary syndrome (PCOS), reduced hair growth or other diseases, disorders or c _-onditions that are influenced by intracellular glucocor- ticoid 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 ulcerative 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-Schonlein purpura, 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, comeal 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^-HSDI 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 1 "β- HSD1 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 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, pulmonal, 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 (corticotropin 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), eg NεB29-tetradecanoyl des (B30) human insulin, EP 214 826 and EP 705275 (Novo Nordisk A/S), eg AspB28 human insulin, US 5,504,188 (Eli Lilly), eg 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, PPARό 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, AspB28 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, ?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, verapamil, lacidipine, lercanidipine, aranidipine, cilnidipine, clevidipine, azelnidipine, barnidipine, efonodipine, iasidipine, iemildipine, iercanidipine, manidipine, nilvadipine, pranidipine, furnidipine, α-blockers such as doxazosin, urapidil, prazosin, terazosin, bunazosin and OPC-28326, diuretics such as thiazides/sulphonamides (e.g. bendroflumetazide, 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, prostacydin 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, moxonidine, 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 of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses as part of combination therapy comprising antihypertensive agents. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 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 ac- tive 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 sus- tained 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 pow- ders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot 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, pentaerythritol 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, led- 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, flavouring and colouring agents. 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 suspending 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 al 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 of the 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 of the 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 of the present invention.
Thus, in a further embodiment, there is provided a pharmaceutical composition comprising a compound and antihypertensive agent(s) for use according to the present invention, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and one or more pharmaceuti- cally acceptable carriers, excipients, 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
Amberlite^lRPδδ* 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. Such mammals include animals, both domestic animals, e.g. household pets, and non-domestic animals such as wildlife.
PHARMACOLOGICAL METHODS
Materials:
3H-cortisone, 3H-cortisol and scintillation proximity assay (SPA) beads were purchased from Amersham Pharmacia Biotech, /.-NADPH and yff-NAD were from Sigma Chemical Co, rabbit anti-cortisol antibodies were from Fitzgerald and sheep-anti-11-dehydrocorticosterone antibodies were from Chemicon International INC. Hepes and phosphate-buffered saline were purchased from Life Technologies. 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 radioligand bound to the SPA beads was measured on TopCount NXT, Packard.
Experimental procedures in vitro:
11ff-HSD1 enzymatic activity assay:
An extract of yeast transformed with h-11 β HSD1 (Hult et al., FEBS Lett., 441, 25 (1998)) was used as the source of enzyme. Enzyme preparation, 120 nM 3H-cortisone, 4 mM β-
NADPH, rabbit-anti cortisol antibody (1 :200), serial dilutions of test compound and anti-rabbit Ig coated 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 con- taining 500 μM carbenoxolone and 1.0 μM cortisone. Data was analysed using GraphPad Prism software.
Selectivity vs. h-11_?HSD2:
Baby hamster kidney (BHK) cells were transfected with full-length h-11^HSD2. The cells were sonicated in phosphate-buffered saline containing 10 mM HEPES (Life Technologies). The cell lysate was used as the source of enzyme. Enzyme preparation, 50 nM 3H-cortisol, 4 mM β-HAO, antibody (1 :40), serial dilutions of test compound and anti-sheep Ig coated SPA particles (1 mg/well) were added to the wells of 96-well plates. The reaction was initiated by mixing the different components and was allowed to proceed under shaking for 30 min at 30°C. The reaction was stopped be the addition of 10 fold excess of a stopping buffer containing 5 μM carbenoxolone. Data was analysed using GraphPad Prism software.
Animal studies
Pharmacological activity may be determined in an in vivo test procedure in rats as follows: Sprague-Dawley rats are allowed to acclimatise in the test facility for at least two weeks. Throughout the experiment, the rats are kept in their home cages at a standard 12 hour light - 12 hour dark cycle at 20 ± 2°C with free access to drinking water and standard rat chow containing calcium, phosphorus and vitamin D3. The combination according to the present invention or the active ingredients alone are dissolved in a vehicle appropriate for the chosen route of administration and administered in fixed amounts alone or in combination to the test animals. After predetermined time, the change in desired end-point is measured. An example of such an end-point could be the prevention by an 11 ?-HSD1 inhibitor of glucocorticoid receptor agonist induced bone loss measured by: • Total-, cortical-, and trabecular bone mineral content (BMC) and density (BMD) determined by peripheral quantitative computed tomography (pQCT) in proximal and midshaft tibia.
• Cancellous bone volume in proximal tibia determined by histomorphometry.
• Biochemical markers: Bone turnover rates assessed using the marker serum osteo- calcin (an osteoblast specific marker) and the urinary marker RatLaps (a degradation product of type I collagen derived from bone - an osteoclast specific marker). Cartilage turnover assessed using the urine marker CartiLaps (a degradation product of type II collagen).
While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. All references cited herein are hereby incorporated by reference in their entirety.

Claims

1. A combination therapy which comprises an 11 ?-hydroxysteroid dehydrogenase type 1 (11 ?-HSD1) inhibitor and a glucocorticoid receptor agonist.
2. The combination according to claim 1 wherein the 11/.-HSD1 inhibitor is of the formula (I):
Figure imgf000176_0001
Formula (I)
wherein
R1 and R2 independently are hydrogen, halo, C(=0)NR6R7, C02R15, NR6C(=0)R11, OR12 or
SR12;
R3and R5 independently are hydrogen, NR13R14 trihalomethyl, trihalomethoxy, CrC6alkyl, C2- C6alkenyl, C2-C6alkynyl, CrC6alkyloxy, CrC6alkylthio, aryl, arylC C6alkyl, hetaryl or hetarylCrCealkyl, wherein alkyl, alkynyl, alkenyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R8;
R4 is hydrogen, cyano, halo, C02R15, C(=0)NR6R7, CrC6alkyl, C2-C6alkenyl, C2-C6alkynyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrCealkyl, hydroxy, CrC6alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, or CrCealkyloxyCrCealkyl, wherein the alkyl, alkynyl, alkenyl, cycloalkyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R9;
R6 and R7 independently are C C6alkyl, C3-Cι0cycloalkyl, hetC3-C10cycloalkyl, arylCrC6alkyl or hetarylCrC6alkyl, wherein the alkyl, cycloalkyl, hetcycloalkyl, arylalkyl, and hetarylalkyl groups independently are optionally substituted with one or more of R10; 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 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 CrC6alkyl, aryl, hetaryl, aryld- C6alkyl, halo, hydroxy, oxo, CrC6alkyloxy, aryld-Cealkyloxy, hetarylCrCealkyloxy, d- C6alkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, aryld-C6alkyl- carbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetarylcarboxy, aryld- Cealkylcarboxy or hetarylCrC6alkylcarboxy;
R8 and R9 independently are hydrogen, halo, hydroxy, oxo, cyano, nitro, C3-Cι0cycloalkyl, C3- Ciohetocycloalkyl, CrC6alkyl, CrC6alkyloxy, trihalomethyl, trihalomethoxy, arylCrCealkyloxy, hetarylCrCealkyloxy, d-C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrC6alkylcarbonyl, CrC6alkylcarboxy, arylcarboxy, hetarylcarboxy, arylCrCealkylcarboxy, hetaryld-Cealkylcarboxy, CrC6alkylcarbonylamino or arylCrC6alkylcarbonyl- amino;
R10 is hydrogen, halo, cyano, nitro, hydroxy, oxo, C3-Cι0cycloalkyl, C3-C10hetcycloalkyl, Ci- Cealkyl, d-C6alkyloxy, trihalomethyl, trihalometh dialkylamino oxy, aryld-Cealkyloxy, hetarylCrCealkyloxy, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrC6alkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
R11 is Cι-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, arylCrC6alkyl, hetaryld-Cealkyl, C C6alkyl- carbonylCrC6alkyI, CrC6alkyloxy, aryloxy, CrC6alkyloxy, arylcarbonyl, arylCrCealkylcarbonyl, hetarylcarbonylCrC6alkyl, wherein the alkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R9;
R12 is Cι-C6alkylcarbonylaminoCrC6alkyl, arylcarbonylaminoCrC6alkyl or arylCrC6alkyl- carbonylaminoCrC6alkyl;
R13and R14 independently are hydrogen, oxo, C3-Cι0cycloalkyl, CrC6alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkylcarbonyl, hetarylCrCealkylcarbonyl;
R15 is hydrogen, C3-Cι0cycloalkyl, CrC6alkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrCealkyl, Cι-C6alkyloxyalkyl or aryICrC6alkyloxyalkyl; 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.
3. The combination according to claim 2 wherein the 1 β -HSD1 inhibitor is of the formula (I) wherein
R1 and R2 independently are hydrogen, halo, C(=0)NR6R7, NC(=0)R11, OR12 or SR12;
R3and R5 independenly are hydrogen, NR13R14 trihalomethyl, trihalomethoxy, CrC6alkyl, C2- C6alkenyl, C2-C6alkynyl, d-C6alkyloxy, CrC6alkylthio, aryl, arylCrC6alkyl, hetaryl or hetarylCrC6alkyl, wherein alkyl, alkynyl, alkenyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R8;
R4 is hydrogen, cyano, halo, C02R15, C(=0)NR6R7, CrC6alkyl, C2-C6alkenyl, C2-C6alkynyl, aryl, hetaryl, aryICrC6alkyl, hetarylCrC6alkyl, hydroxy, CrC6alkyloxy, arylCrCealkyloxy, hetarylCrC6alkyloxy, or Cι-C6alkyloxyCrC6alkyl, wherein the alkyl, alkynyl, alkenyl, cycloalkyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R9;
R6 and R7 independently are d-C6alkyl, C3-C 0cycloalkyl, hetC3-Cι0cycloalkyl, arylCrCealkyl or hetarylCrC6alkyl, wherein the alkyl, cycloalkyl, hetcycloalkyl, arylalkyl, and hetarylalkyl groups independently are optionally substituted with one or more of R10; 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 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 CrC6alkyl, aryl, hetaryl, aryld- C6alkyl, halo, hydroxy, oxo, d-C6alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, d- CealkyloxyCrC6aikyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetarylcarboxy, aryld- C6alkylcarboxy or hetarylCrC6alkylcarboxy;
R8 and R9 independently are hydrogen, halo, hydroxy, oxo, cyano, nitro, C3-Cι0cycloalkyl, C3- Ciohetocycloalkyl, d-C6alkyl, CrC6alkyloxy, trihalomethyl, trihalomethoxy, arylCrC6alkyIoxy, hetarylCrCealkyloxy, CrC6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrC6alkylcarboxy, arylcarboxy, hetarylcarboxy, arylCrCealkylcarboxy, hetarylCrC6alkylcarboxy, CrC6alkylcarbonylamino or aryld-C6alkyl- carbonylamino; R is hydrogen, halo, cyano, nitro, hydroxy, oxo, C3-Cι0cycloalkyl, C3-C10hetcycloalkyl, Ci- Cealkyl, CrCealkyloxy, trihalomethyl, trihalometh dialkylamino oxy, arylCrCealkyloxy, hetarylCrCealkyloxy, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, aryld- C6alkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or aryld- C6alkylcarboxy;
R11 is d-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, aryld-Cealkyl, hetarylCrCealkyl, d-C6alkyl- carbonylCrC6alkyl, CrC6alkyl, arylcarbonyl, arylCrCealkylcarbonyl, hetarylcarbonylCrC6- alkyl, wherein the alkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R9;
R12 is d-CealkylcarbonylaminoCrCealkyl; arylcarbonylaminoCrCealkyl or aryICrC6alkyl- carbonylaminoCrC6alkyl;
R13and R14 independently are hydrogen, oxo, C3-Cι0cycloalkyl, d-Cealkyl, CrC6alkyloxy, trihalomethyl, trihalomethoxy, arylCrCealkyloxy, hetaryld-Cealkyloxy, d-Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkylcarbonyl, hetarylCrC6alkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetarylcarboxy, arylCrCealkylcarboxy;
R15 is hydrogen, C3-Cι0cycloalkyl, CrC6alkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrCealkyl, CrC6alkyloxyalkyl or arylCrC6alkyloxyalkyl; or
a salt thereof with a pharmaceutically acceptable acid or base, or optical isomer, mixture of optical isomers, racemic mixture, or tautomeric form thereof.
4. The combination according to claim 2 or 3 wherein the 11 ?-HSD1 inhibitor is selected from the group:
(3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(2,6-dimethyl- piperidin-1 -yl-)-methanone;
(3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(2-ethyl-piperidin-1- yl-)-methanone;
(5-Thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(1 ,3,3-trimethyl-6-aza- bicyclo[3.2.1]oct-6-yl)-methanone; (3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-piperidin-
1-yl-)-methanone;
5-Methyl-7-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexylamide;
Azepan-1-yl-(3-chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)- methanone;
Azepan-1-yl-(3-chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl)- methanone;
(2,6-Dimethyl-piperidin-1 -yl-)-(3-chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-3-yl) methanone; 3-Bromo-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-carboxylic acid cyclohexylamide;
(7-Methyl-5-phenyl-pyrazolo[1,5-a]pyrimidin-3-yl)-(4-methyl-piperidin-1-yl-methanone;
5-(4-Methoxy-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid benzyl- methyl-amide; [5-(4-Ethoxy-phenyl-7-methyl-pyrazolo[1,5-a]pyrimidine-2-yl)]-piperidin-1-yl-methanone;
Azepan-1 -yl-(3-bromo-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)- methanone;
5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid cyclohexyl-methyl-amide; (3,4-Dihydro-1 /τ'-isoquinolin-2-yl)-[5-(-4-Methoxy-phenyl-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-3-yl]-methanone;
A∑epan-1-yl-[5-(4-bromo-phenyl)-7-trifluoromethyl-pyra∑olo[1,5-a]pyrimidin-3-yl)-methanone
Azepan-1-yl-(5,7-diphenyl)-pyrazolo[1,5-a]pyrimidin-3-yl)-methanone;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-(2-methyl-piperidin-1-yl)- methanone;
(5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl)-(2-methyl-piperidin-1-yl)- methanone;
(2,6-Dimethyl-piperidin-1-yl-)-[7-(4-ethoxy-phenyl)-5-methyl-pyrazolo[1,5-a]pyrimidin-2- yljmethanone; 5-(4-Ethoxy-phenyl)-7-methyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexylamide;
Piperidin-1-yl-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl)-methanone;
(5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl)-(2-methyl-piperidin-1-yl)- methanone;
(2-Methyl-piperidin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl)- methanone; Azepan-1 -yl-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]- methanone;
5-Thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid benzyl-methyl- amide; 5-p-Tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid (1 , 3-di methyl-1 H- pyrazol-4-ylmethyl)-methyl-amide;
5-Methyl-7-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl-amide; 7-Methyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl-amide; (5-Phenyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone; 5-Naphthalen-1-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl- methyl-amide;
5-Naphthalen-1-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexylamide; (5-Naphthalen-1-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl-methanone (2-Methyl-piperidin-1 -yl)-(5-naphthalen-1 -yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexylamide; 5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl-amide; (5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(2-methyl-piperidin-1-yl)-methanone; (5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone;
5-Methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexylamide; (5-Methyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone; 5-Methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl- amide; (2-Methyl-piperidin-1 -yl)-(5-methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a!]pyrimidine-2-carboxylic acid cyclohexylamide; (5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone; 7-Phenyl-5-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl- amide;
5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid cyclohexylamide; and (5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-piperidin-1 -yl-methanone; or
a salt thereof with a pharmaceutically acceptable acid or base, or optical isomer, mixture of optical isomers, racemic mixture, or tautomeric form thereof.
5. The combination according to claim 2 or 3 wherein the 11)--HSD1 inhibitor is selected from the group of
5-Methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid methyl ester; 5-Methyl-7-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid methyl ester;
7-Methyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid methyl ester;
(5-methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- (piperidin-1 -yl)methanone;
(5-methyl-7-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl amide;
7-Methyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl-amide; 7-Phenyl-5-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl- amide;
(5-Phenyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone;
(2-Methyl-piperidin-1-yl)-(5-methyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)- methanone; 5-Methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl- amide;
(5-Methyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl-methanone;
(5,7-Diphenyl-pyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone;
(5,7-Diphenyl-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-piperidin-1-yl)-methanone; 5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl-amide;
(2-Methyl-piperidin-1-yl)-(5-naphthalen-1-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)- methanone;
(5-Naphthalen-1-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone;
5-Naphthalen-1-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl- methyl-amide;
[7-(4-Ethoxy-phenyl)-5-methyl-pyrazolo[1,5-a]pyrimidin-2-yl]-(1,3,3-trimethyl-6-aza- bicyclo[3.2.1 ]oct-6-yl)-methanone;
(2-Methyl-piperidin-1-yl)-(7-phenyl-5-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)- methanone; (5-Methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(1 ,3,3-trimethyl-6-aza- bicyclo[3.2.1]oct-6-yl)-methanone;
(5-Phenyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-(1,3,3-trimethyl-6-aza- bicyclo[3.2.1]oct-6-yl)-methanone;
(6-Bromo-3-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-morpholin-4-yl-methanone; (5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone; Morpholin-4-yl-(5-phenyl-7-trifluoromethyl-pyrazoIo[1 ,5-a]pyrimidin-2-yl)-methanone;
(6-Bromo-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1-yl-methanone;
(6-Bromo-pyrazolo[1 ,5-a]pyrimidin-2-yl)-morpholin-4-yl-methanone;
(3,6-Dibromo-pyrazolo[1 ,5-a]pyrimidin-2-yl)-morpholin-4-yl-methanone; (3-Bromo-5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1-yl-methanone;
(3-Bromo-5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-morpholin-4-yl- methanone;
(3-Chloro-5-phenyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl-methanone;
(3-Chloro-5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-morpholin-4-yI- methanone;
(3,6-Dibromo-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1 -yl-methanone;
[4-(4-Fluoro-phenyl)-piperazin-1-yl]-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-2-yl)-methanone;
5-Thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl- methyl-amide;
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-methyl-piperazin-
1-yl)-methanone;
[5-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yI]-(2-methyl-piperidin-1- yl)-methanone; 3-Chloro-5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazoIo[1 ,5-a]pyrimidine-2-carboxylic acid methyl-(2-pyridin-2-yl-ethyl)-amide;
[3-Chloro-5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-morpholin-4-yl- methanone;
(3-Chloro-5-thiophen-2-yI-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(3,4-dihydro-2H- quinolin-1 -yl)-methanone;
[5-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-[4-(2-methoxy- phenyl)-piperazin-1-yl]-methanone;
(4-Benzoyl-piperazin-1-yl)-[3-chloro-5-(4-chloro-phenyI)-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-2-yl]-methanone; 4-(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carbonyl)-piperazine-
1 -carboxylic acid ethyl ester;
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazoIo[1 ,5-a]pyrimidin-2-yl)-(6,7-dimethoxy-1- methyl-3,4-dihydro-1 H-isoquinolin-2-yl)-methanone;
[4-(Furan-2-carbonyl)-piperazin-1-yl]-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-2-yl]-methanone; (3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazoIo[1 ,5-a]pyrimidin-2-yl)-[4-(2-methoxy- phenyl)-piperazin-1 -ylj-methanone;
[5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-piperidin-1-yl- methanone; (3,4-Dihydro-2H-quinolin-1 -yl)-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
(3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(2,6-dimethyl- piperidin-1 -yl)-methanone;
(3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(2-ethyl-piperidin-1- yl)-methanone;
3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl-amide;
[5-(4-Bromo-phenyl)-3-chIoro-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-pyrrolidin-1-yl- methanone; (3-Chloro-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)- piperazin-1 -ylj-methanone;
(3-Chloro-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-phenyl-piperazin-1- yl)-methanone;
[3-Chloro-5-(4-chloro-phenyl)-7-trifluoromelhyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(4-methyl- piperazin-1 -yl)-methanone;
Azepan-1 -yl-[3-chloro-5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]- methanone;
[3-Chloro-5-(3,4-dimethoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-pyrrolidin-
1 -yl-methanone; [5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(2-methyl-piperidin-1-yl)- methanone;
(5-Thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(1 ,3,3-trimethyl-6-aza- bicyclo[3.2.1]oct-6-yl)-methanone;
[4-(2-Chloro-phenyl)-piperazin-1-yl]-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-2-yl)-methanone;
(3,4-Dihydro-1 H-isoquinolin-2-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-
2-yl)-methanone;
(4-Methyl-piperazin-1-yl)-[5-(4-nitro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]- methanone; [5-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-thiomorphoIin-4-yl- methanone;
(3-Bromo-5-furan-2-yl-7-trifluoromethyI-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(3,4-dihydro-2H- quinolin-1 -yl)-methanone; (5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-pyrrolidin-1 -yl-methanone;
[4-(Furan-2-carbonyl)-piperazin-1-ylj-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5- ajpyrimidin-2-yl]-methanone;
[5-(4-Nitro-phenyl)-7-trifluoromethyl-pyrazoIo[1 ,5-a]pyrimidin-2-yl]-piperidin-1-yl-methanone;
(5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-pyrrolidin-1 -yl-methanone; (4-Methyl-piperidin-1-yl)-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
(3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)- piperazin-1 -ylj-methanone;
[4-(4-Fluoro-phenyl)-piperazin-1-yl]-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
[4-(4-Fluoro-phenyl)-piperazin-1-yl]-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-2-yl)-methanone;
[3-Bromo-5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-morpholin-4- yl-methanone; [4-(4-Fluoro-phenyl)-piperazin-1 -yl]-(7-methyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
(4-Ben∑oyl-piperazin-1-yl)-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
(3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-phenyl-piperazin- 1-yl)-methanone;
(2-Ethyl-piperidin-1-yl)-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone;
(5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-methyl-piperazin-1-yl)-methanone;
(4-Benzyl-piperazin-1-yl)-(3-chloro-5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone; (3-Chloro-5-thiophen-2-yI-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-methyl-piperazin-
1-yl)-methanone;
(4-Phenyl-piperazin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-pyrrolidin-1-yl- methanone; (5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-pyrrolidin-1 -yl-methanone;
(3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(2-ethyl-piperidin-1- yl)-methanone;
(3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(2-methyl-piperidin- 1-yl)-methanone;
5-Methyl-7-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl-amide;
(3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-morpholin-4-yl- methanone;
(3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)- piperazin-1 -yl]-methanone;
(3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-methyl-piperazin-
1-yl)-methanone;
(7-Methyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1-yl-methanone;
Azepan-1-yl-(3-chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
Azepan-1-yl-[3-bromo-5-(4-bromo-phenyl)-7-trifluoromethyI-pyrazolo[1 ,5-a]pyrimidin-2-yl]- methanone;
3-Bromo-5-(4-bromo-phenyI)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl-amide; (2,6-Dimethyl-piperidin-1-yl)-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-
2-yl]-methanone;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyra∑olo[1 ,5-a]pyrimidin-2-yl]-(4-methyl-piperazin-1-yl)- methanone;
5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid benzyl-methyl-amide; [5-(4-Ethoxy-phenyl)-7-methyI-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(4-phenyl-pipera∑in-1-yl)- methanone;
(3,4-Dihydro-1 /-isoquinolin-2-yl)-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-2-yl]-methanone;
Morpholin-4-yl-[5-(4-nitro-phenyl)-7-trifluoromethyl-pyrazoIo[1 ,5-a]pyrimidin-2-yl]-methanone; (Hexahydro-pyrrolo[1 ,2-a]pyrazin-2-yl)-(5-phenyl-7-trifluoromethyl-pyrazoIo[1 ,5-a]pyrimidin-2- yl)-methanone;
(Hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-(5-p-tolyI-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2- yl)-methanone;
(Hexahydro-pyrrolo[1 ,2-a]pyrazin-2-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-2-yl)-methanone; (3-Chloro-5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(hexahydro-pyrrolo[1,2- a]pyrazin-2-yl)-methanone;
[5-(4-Fluoro-phenyl)-7-methyl-pyrazolo[1,5-a]pyrimidin-2-yl]-morpholin-4-yl-methanone;
(5,7-Diphenyl-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-piperidin-1-yl)-methanone; 5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid (1 ,3-dimethyl-1 H- pyra∑ol-4-ylmethyl)-methyl-amide;
5-Thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid (1 ,5-dimethyl-
1H-pyrazol-4-ylmethyl)-methyl-amide;
5-Thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxyIic acid methyl-(1 ,3,5- trimethyl-1 H-pyrazol-4-ylmethyl)-amide;
3-Chloro-5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid
(1 ,3-dimethyl-1 H-pyrazol-4-ylmethyl)-methyl-amide;
5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid (1 ,3- dimethyl-1H-pyrazoI-4-ylmethyl)-methyl-amide; 5-(3,4-Dimethoxy-phenyl)-7-trif luoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxyIic acid (1,3- dimethyl-1H-pyrazol-4-ylmethyl)-methyl-amide;
(2,5-Dimethyl-piperidin-1-yl)-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
5-Furan-2-yl-7-trifluoromethyl-pyra∑olo[1 ,5-a]pyrimidine-2-carboxylic acid methyl-(1 ,3,5- trimethyl-1 H-pyrazol-4-ylmethyl)-amide;
5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid (1 ,5- dimethyl-1H-pyrazol-4-ylmethyl)-methyl-amide;
(2,4-Dimethyl-piperidin-1-yl)-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone; (3-Bromo-5-phenyl-7-trifluoromethyl-pyra∑olo[1 ,5-a]pyrimidin-2-yl)-(hexahydro-pyrrolo[1,2- a]pyrazin-2-yl)-methanone;
[5-(3,4-Dimethoxy-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-ylj-(hexahydro- pyrrolo[1,2-a]pyra∑in-2-yl)-methanone;
(3-Chloro-5-p-tolyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-(hexahydro-pyrrolo[1,2- a]pyrazin-2-yl)-methanone;
(3-Bromo-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1-yl- methanone;
(3-Chloro-5-phenyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-pyrrolidin-1 -yl-methanone;
(7-Methyl-5-phenyl-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-methyl-piperidin-1-yl)-methanone; (4-Methyl-piperazin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
[3-Bromo-5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazoIo[1 ,5-a]pyrimidin-2-yl]-piperidin-1-yl- methanone; (4-Methyl-piperazin-1 -yl)-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
[4-(4-Fluoro-phenyl)-piperazin-1-yl]-(5-furan-2-yl-7-trifluoromethyl-pyra∑olo[1 ,5-a]pyrimidin-2- yI)-methanone;
[5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyra∑olo[1 ,5-a]pyrimidin-2-yl]-morpholin-4-yl- methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyra∑olo[1 ,5-a]pyrimidin-2- yl)-methanone;
(3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazoIo[1 ,5-ajpyrimidin-2-yl)-morpholin-4-yl- methanone; Azepan-1 -yl-(3-chloro-5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone;
(4-Benzoyl-piperazin-1-yl)-[5-(4-bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2- yl]-methanone;
(4-Benzyl-piperazin-1-yl)-[5-(4-bromo-phenyl)-3-chloro-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-2-yl]-methanone; [5-(4-Bromo-phenyl)-3-chloro-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(4-methyl- pipera∑in-1 -yl)-methanone;
A∑epan-1-yl-[5-(4-bromo-phenyl)-7-trifluoromethyl-pyra∑olo[1 ,5-a]pyrimidin-2-yl]-methanone;
[3-Bromo-5-(4-bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(3,4-dihydro-
2H-quinolin-1-yl)-methanone; [5-(3,4-Dimethoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-morpholin-4-yl- methanone;
(3-Bromo-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-ajpyrimidin-2-yl)-(4-methyl-pipera∑in-1- yl)-methanone;
(4-Benzoyl-piperazin-1-yl)-(3-bromo-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2- yl)-methanone;
(3-Bromo-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(3,4-dihydro-2H- quinolin-1 -yl)-methanone;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-piperidin-1 -yl- methanone; [5-(4-Ethoxy-phenyl)-7-methyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-piperidin-1 -yl-methanone; [5-(4-Ethoxy-phenyl)-7-methyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-morpholin-4-yl-methanone;
Azepan-1 -yl-(3-bromo-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-ajpyrimidin-2-yI)- methanone;
(3,4-Dihydro-1H-isoquinolin-2-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazoIo[1 ,5-a]pyrimidin- 2-yl)-methanone;
(4-Benzyl-piperazin-1-yl)-(3-bromo-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2- yl)-methanone;
Azepan-1 -yl-[5-(4-bromo-phenyl)-3-chloro-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]- methanone; (3-Chloro-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(3,4-dihydro-1ry- isoquinolin-2-yl)-methanone;
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1 -yl- methanone;
Azepan-1 -yl-(5,7-diphenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone; Azepan-1 -yl-(5-benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
[5-(4-Bromo-phenyl)-7-lrifluoromethyl-pyra∑olo[1 ,5-a]pyrimidin-2-yl]-morpholin-4-yl- methanone;
[3-Bromo-5-(4-bromo-phenyl)-7-trifluoromelhyl-pyra∑olo[1 ,5-a]pyrimidin-2-yl]-morpholin-4-yl- methanone;
[5-(4-Methoxy-phenyl)-7-trifluoromethyI-pyrazolo[1 ,5-a]pyrimidin-2-yl]-thiomorpholin-4-yl- melhanone;
[5-(4-Bromo-phenyl)-3-chloro-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-piperidin-1-yl- methanone; (5-Ben∑o[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyra∑olo[1 ,5-a]pyrimidin-2-yl)-(3,4-dihydro-2H- quinolin-1 -yl)-methanone;
(5-Ben∑o[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-benzyl-piperazin-
1-yl)-methanone;
(5-Benzo[1 ,3]dioxol-5-yI-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-morpholin-4-yl- methanone;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-ajpyrimidin-2-yl]-[4-(2-methoxy-phenyl)- piperazin-1 -ylj-methanone;
[3-Bromo-5-(4-bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(4-methyl- piperazin-1 -yl)-methanone; Azepan-1-yl-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]- methanone;
(2,6-Dimethyl-piperidin-1-yl)-[7-(4-ethoxy-phenyl)-5-methyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]- methanone; (3,4-Dihydro-2H-quinolin-1-yI)-(5,7-diphenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone;
(3,6-Dibromo-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1-yl-methanone;
(3-Bromo-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1-yl- methanone;
[5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-thiomorpholin-4-yl- methanone;
[5-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-thiomorphoIin-4-yl- methanone;
(3,4-Dihydro-1 H-isoquinolin-2-yl)-[5-(4-nitro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-2-yl]-methanone; Azepan-1 -yl-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyra∑olo[1 ,5-a]pyrimidin-2-yl]- methanone;
A∑epan-1-yl-[5-(4-nitro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl]-methanone;
[5-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-morpholin-4-yl- methanone; Azepan-1 -yl-[5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-ylj- methanone;
(3,4-Dihydro-1 H-isoquinolin-2-yl)-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
[5-(4-Bromo-phenyl)-3-chloro-7-trifluoromethyl-pyra∑olo[1 ,5-a]pyrimidin-2-yl]-pyrrolidin-1-yl- methanone;
5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl-amide;
(3,4-Dihydro-1/-/-isoquinolin-2-yl)-(5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2- yl)-methanone;
(4-Benzyl-piperazin-1-yl)-(3-chloro-5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2- yl)-methanone;
[3-Chloro-5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-piperidin-1-yl- methanone;
(3-Chloro-5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-methyl-piperazin-1-yl)- methanone; (3-Chloro-5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-phenyl-pipera∑in-1-yl)- methanone;
[3-Chloro-5-(3,4-dimethoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-piperidin-
1 -yl-methanone; [4-(4-Fluoro-phenyI)-piperazin-1-yl]-(5-p-tolyI-7-trifluoromethyI-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
(4-Phenyl-piperazin-1-yl)-(5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
Morpholin-4-yl-(5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone; (4-Benzyl-piperazin-1 -yI)-(5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone;
[5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(4-methyl-piperazin-1-yl)- methanone;
[5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-morpholin-4-yl- methanone;
(4-Ben∑yl-piperazin-1-yl)-[5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]- methanone;
[5-(4-Fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-morpholin-4-yl- methanone; [5-(4-Fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-piperidin-1 -yl-methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-[5-(4-fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-
2-yl]-methanone;
A∑epan-1-yl-[5-(3,4-dimethoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]- methanone; (4-Benzyl-piperazin-1-yl)-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2- yl]-methanone;
[5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-pyrrolidin-1-yl- methanone;
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-pyrrolidin-1 -yl- methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-[5-(4-nitro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2- yl]-methanone;
[3-Chloro-5-(4-methoxy-phenyI)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-ylj-(4-methyl- piperidin-1 -yl)-methanone; [3-Chloro-5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(3,4-dihydro-
2H-quinolin-1 -yl)-methanone;
3-ChIoro-5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid cyclohexyl-methyl-amide; [3-Chloro-5-(4-fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(4-methyl- pipera∑in-1 -yl)-methanone;
(3-Chloro-5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-morpholin-4-yl-methanone;
Azepan-1-yl-(3-chloro-5-p-toIyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone;
Azepan-1-yl-[3-chloro-5-(3,4-dimethoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2- ylj-methanone;
[5-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(4-methyl-piperazin-
1-yI)-methanone;
5,7-Diphenyl-pyra∑olo[1 ,5-a]pyrimidine-2-carboxylic acid benzyl-methyl-amide;
(5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(4-phenyl-piperazin-1-yl)-methanone; Morpholin-4-yl-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone;
Morpholin-4-yl-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone;
Piperidin-1-yl-(5-thiophen-2-yl-7-trifluoromelhyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone;
[3-Bromo-5-(4-bromo-thiophen-2-yl)-7-trifluoromethyl-pyra∑olo[1 ,5-a]pyrimidin-2-yl]-piperidin-
1 -yl-methanone; (3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(3,4-dihydro-2H- quinolin-1 -yI)-methanone;
(3-Chloro-5-thiophen-2-yl-7-trifluoromelhyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1 -yl- methanone;
(7-Methyl-5-phenyI-pyrazolo[1 ,5-a]pyrimidin-2-yl)-morpholin-4-yl-methanone; (7-Methyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-pyrrolidin-1 -yl-methanone;
7-Methyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid benzyl-methyl-amide;
(2,6-Dimethyl-piperidin-1-yl)-[5-(4-fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2- yl]-methanone;
Azepan-1 -yl-[5-(4-fluoro-phenyl)-7-trifluoromethyI-pyrazolo[1 ,5-a]pyrimidin-2-yl]-methanone; [5-(4-Fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl]-(4-methyl-piperazin-1-yl)- methanone;
[5-(4-Fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-ylj-(4-phenyl-piperazin-1-yl)- methanone;
(2-Ethyl-piperidin-1-yl)-[5-(4-fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl]- methanone; (5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-piperidin-1-yl-methanone;
(5-Methyl-7-phenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6- yl)-methanone; (5-Thiophen-2-yl-7-trifluoromethyI-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(1 ,3,3-trimethyl-6-aza- bicyclo[3.2.1joct-6-yl)-methanone;
(4-Phenyl-piperazin-1-yI)-pyrazolo[1 ,5-a]pyrimidin-3-yl-methanone;
Pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid benzyl-(2-hydroxy-ethyl)-amide;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-(3,4-dihydro-1H- isoquinolin-2-yl)-methanone;
(5,7-Dimethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-[4-(4-methoxy-phenyl)-piperazin-1-yl]- methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-[5-(4-fluoro-phenyl)-7-trifluoromethyl-pyrazoIo[1,5-a]pyrimidin-
3-yl]-methanone; (5-Furan-2-yl-7-trifluoromethyI-pyrazolo[1 ,5-a]pyrimidin-3-yl)-piperidin-1 -yl-methanone;
Azepan-1-yl-[7-trifluoromethyl-5-(3,4,5-trimethoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidin-3-yl]- methanone;
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-pyrrolidin-1 -yl- methanone; Azepan-1 -yl-(5,7-diphenyl-pyrazolo[1 ,5-ajpyrimidin-3-yl)-methanone;
4-(5,7-Dimethyl-pyrazolo[1 ,5-a]pyrimidine-3-carbonyl)-piperazine-1 -carboxylic acid ethyl ester;
(3,4-Dihydro-1H-isoquinolin-2-yl)-(5,7-dimethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone;
[4-(3-Chloro-phenyl)-piperazin-1-yl]-(5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-ajpyrimidin-3-yl)- methanone;
(4-Methyl-piperidin-1-yl)-pyrazolo[1 ,5-a]pyrimidin-3-yl-methanone;
[4-(2-Methoxy-phenyl)-piperazin-1-yl]-pyrazolo[1 ,5-a]pyrimidin-3-yl-methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-3-yl]-methanone; [5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-thiomorpholin-4-yl- methanone;
(5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(2-methyl-piperidin-1-yl)- methanone;
(4-Benzyl-piperazin-1-yl)-(5,7-dimethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone; [5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazoIo[1,5-a]pyrimidin-3-yl]-morpholin-4-yl- methanone;
(5,7-Dimethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-piperidin-1-yl-methanone;
(5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-[4-(2-methoxy-phenyl)- piperazin-1 -ylj-methanone;
(5-Phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-piperidin-1 -yl-methanone;
Azepan-1-yl-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone;
(2,6-Dimethyl-piperidin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone; [5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-ylj-(4-methyl-piperazin-1 - yl)-methanone;
(4-Methyl-piperazin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-(4-methyl-piperazin-1-yl)- methanone;
(Hexahydro-pyrrolo[1 ,2-a]pyrazin-2-yl)-(5-p-tolyl-7-trifluoromethyl-pyra∑olo[1 ,5-a]pyrimidin-3- yl)-methanone;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-(hexahydro-pyrrolo[1 ,2- a]pyra∑in-2-yl)-methanone; [5-(3,4-Dimethoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-(hexahydro- pyrrolo[1 ,2-a]pyrazin-2-yl)-methanone;
1-[5-(3-Melhoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carbonyl]-piperidine-4- carboxylic acid ethyl ester;
4-[5-(3-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carbonyl]-piperazine-1- carboxylic acid ethyl ester;
(3,4-Dihydro-2H-quinolin-1-yl)-[5-(3-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-3-yl]-methanone;
[4-(4-Fluoro-phenyl)-piperazin-1-yl]-[5-(3-methoxy-phenyI)-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-3-yl]-methanone; 5-p-Tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid (1 , 3-di methyl- 1 H- pyrazol-4-ylmethyl)-methyI-amide;
5-p-Tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid methyl-(1 ,3,5-trimethyl-
1 - -pyrazol-4-ylmethyl)-amide;
[7-Difluoromethyl-5-(4-methoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidin-3-yl]-(2-ethyl-imidazol-1-yl)- methanone; [7-Difluoromethyl-5-(4-methoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidin-3-yl]-morpholin-4-yl- methanone;
1 -[7-Difluoromethyl-5-(4-methoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidine-3-carbonyl]-1 H-indole-3- carboxylic acid methyl ester; [4-(4-Chloro-phenyl)-piperazin-1-yl]-[7-difluoromethyl-5-(4-methoxy-phenyl)-pyrazolo[1 ,5- a]pyrimidin-3-yl]-methanone;
[7-Difluoromethyl-5-(4-methoxy-phenyl)-pyrazoIo[1 ,5-a]pyrimidin-3-yl]-(2-ethyl-piperidin-1-yl)- methanone;
7-Difluoromethyl-5-p-tolyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxyIic acid (1-ethyl-5-methyl-1H- pyrazol-4-ylmethyl)-methyl-amide;
1-(7-Difluoromethyl-5-methyl-pyrazolo[1 ,5-a]pyrimidine-3-carbonyl)-piperidine-4-carboxylic acid amide;
(7-Difluoromethyl-5-phenyl-pyrazoIo[1 ,5-a]pyrimidin-3-yl)-(2-ethyl-imidazol-1-yl)-methanone;
(7-Difluoromethyl-5-phenyl-pyrazoIo[1 ,5-a]pyrimidin-3-yl)-thiomorpholin-4-yl-methanone; (7-Difluoromethyl-5-p-tolyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(4-pyridin-2-yI-piperazin-1-yl)- methanone;
[7-Difluoromethyl-5-(4-methoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidin-3-yl]-[4-(furan-2-carbonyl)- piperazin-1 -ylj-methanone;
7-DifluoromethyI-5-phenyl-pyrazolo[1 ,5-ajpyrimidine-3-carboxylic acid (1-ethyl-3-methyl-1H- pyrazol-4-ylmethyl)-methyl-amide;
[7-Difluoromethyl-5-(4-methoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidin-3-yl]-thiomorpholin-4-yl- methanone;
(7-DifluoromethyI-5-phenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(3,4-dihydro-1H-isoquinolin-2-yl)- methanone; (7-Difluoromethyl-5-methyI-pyrazolo[1 ,5-a]pyrimidin-3-yl)-piperidin-1 -yl-methanone;
Azepan-1 -yl-(7-difluoromethyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone;
7-Difluoromethyl-5-p-tolyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid methyl-(1 -methyl-1 H- pyrazol-4-ylmethyl)-amide;
(7-Difluoromethyl-5-p-tolyI-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(3-methyl-piperidin-1-yl)-methanone; (7-Difluoromethyl-5-p-tolyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(4-ethyl-piperazin-1-yl)-methanone;
(7-Difluoromethyl-5-p-tolyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-morpholin-4-yl-methanone;
7-Difluoromethyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid methyl-(1 ,3,5- trimethyl-1/- -pyrazol-4-ylmethyl)-amide;
(7-Difluoromethyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-[4-(2-methyl-2H-pyrazole-3- carbonyl)-piperazin-1 -ylj-methanone; 7-Difluoromethyl-5-p-tolyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid benzyl-methyl-amide;
7-Difluoromethyl-5-(4-methoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid (1 -ethyl-3- methyl-1H-pyrazol-4-ylmethyl)-methyl-amide;
7-Difluoromethyl-5-phenyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid methyl-(4-pyrazol-1-yl- benzyl)-amide;
Azepan-1-yl-(5-cyclopropyl-7-difluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone;
(4-Benzyl-piperazin-1-yl)-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3- yl]-methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-3-yl]-methanone;
5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid benzyl- methyl-amide;
(5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(4-methyl-piperazin-1-yl)- methanone; (5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-thiomorpholin-4-yl-methanone;
[5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-morpholin-4-yl- methanone;
(4-Benzyl-piperazin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone; [5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-ajpyrimidin-3-yl]-morpholin-4-yl- methanone;
Azepan-1 -yl-(5-ben∑o[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyra∑olo[1 ,5-a]pyrimidin-3-yl)- methanone;
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(3,4-dihydro-2H- quinolin-1 -yl)-methanone;
5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid cyclohexyl-methyl-amide;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-(3,4-dihydro-2H-quinoIin-
1-yl)-methanone; [5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-piperidin-1 -yl- methanone;
Azepan-1 -yl-(5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone;
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-pyrrolidin-1 -yl- methanone; (5-Benzo[1 ,3jdioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(4-methyl-piperazin-
1-yl)-methanone;
(3,4-Dihydro-1H-isoquinolin-2-yl)-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1,5- a]pyrimidin-3-yl]-methanone; Azepan-1 -yl-[5-(4-bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-(5,7-diphenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone;
Azepan-1 -yl-(5,7-diphenyl-pyrazoIo[1,5-a]pyrimidin-3-yl)-methanone;
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyI-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(4-benzyl-piperazin-
1-yl)-methanone; (4-Benzyl-piperazin-1-yl)-(5,7-diphenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone;
(5,7-Diphenyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(4-methyl-piperazin-1-yl)-methanone;
[5-(4-Bromo-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-ajpyrimidin-3-yl]-(2-methyl-piperidin-1-yl)- methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-(5-furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone;
(5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yI)-(2-methyl-piperidin-1-yl)- methanone;
[5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-piperidin-1 -yl- methanone; (5-Benzo[1 ,3jdioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-morpholin-4-yl- methanone;
(5-Benzo[1 ,3]dioxol-5-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-piperidin-1 -yl- methanone;
Morpholin-4-yl-[7-trifluoromethyI-5-(3,4,5-trimethoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidin-3-yl]- methanone;
(4-Benzyl-piperazin-1-yl)-[7-trifluoromethyl-5-(3,4,5-trimethoxy-phenyl)-pyrazolo[1 ,5- a]pyrimidin-3-yl]-methanone;
(3,4-Dihydro-2/-/-quinolin-1-yl)-[7-trifluoromethyl-5-(3,4,5-trimethoxy-phenyl)-pyrazolo[1 ,5- a]pyrimidin-3-yl]-methanone; (4-Methyl-piperazin-1 -yl)-[7-trifluoromethyl-5-(3,4,5-trimethoxy-phenyl)-pyrazolo[1 ,5- a]pyrimidin-3-yl]-methanone;
Azepan-1-yl-[7-trifluoromethyl-5-(3,4,5-trimethoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidin-3-yl]- methanone;
[5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-piperidin-1-yl- methanone; [5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-pyrrolidin-1-yl- methanone;
Piperidin-1 -yl-(5-thiophen-2-yl-7-trifluoromethyl-pyrazoIo[1 ,5-a]pyrimidin-3-yl)-methanone;
(4-Benzyl-piperazin-1-yl)-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3- ylj-methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-3-yl]-methanone;
(5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-(2-methyl-piperidin-1-yl)- methanone; (5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-morpholin-4-yl-methanone;
(5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-thiomorpholin-4-yl-methanone;
[4-(4-Fluoro-phenyl)-piperazin-1-yl]-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5- a]pyrimidin-3-yl)-methanone;
(4-Methyl-piperidin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone;
(5-Furan-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-ajpyrimidin-3-yl)-(4-methyl-piperazin-1-yl)- methanone;
(4-Benzyl-piperazin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone; [5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-morpholin-4-yl- methanone;
Piperidin-1 -yl-[7-trifluoromethyl-5-(3,4,5-trimethoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidin-3-yl]- methanone;
(2-Methyl-piperidin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone;
Azepan-1-yl-[5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-ajpyrimidin-3-yl]- methanone;
5-Thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-ajpyrimidine-3-carboxylic acid benzyl-methyl- amide; [5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazoIo[1 ,5-a]pyrimidin-3-yl]-pyrrolidin-1 -yl- methanone;
[5-(4-Chloro-phenyl)-2-methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl]-piperidin-1 -yl- methanone;
Azepan-1 -yl-[5-(4-chloro-phenyl)-2-methyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-ylj- methanone; [5-(4-Chloro-phenyl)-2-methyl-7-trifluoromethyl-pyrazoIo[1,5-a]pyrimidin-3-yl]-(4-methyl- piperazin-1 -yl)-methanone;
Morpholin-4-yl-(5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)-methanone; (4-Benzyl-piperazin-1-yl)-(5-p-tolyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone;
5-(4-Methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid benzyl- methyl-amide;
(4-Benzyl-piperazin-1-yl)-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-yl)- methanone; Morpholin-4-yl-(5-phenyl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-3-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.
6. The combination according to claim 1 wherein the 11 ?-HSD1 inhibitor is of the For- mula (II):
Figure imgf000199_0001
Formula (II)
wherein
R1 is C3-docycloalkyl, Qrdohetcycloalkyl, CrC8alkyl, 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, arylCrCealkyl, C3-Cι0cycloalkylCrC6alkyl, d- Cealkyl-carboxyd-Cealkyl 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 d-C8alkyl, aryl, hetaryl, aryld- C6alkyl, hetaryld-Cealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, aryld-Cealkyloxy, hetaryld- Cealkyloxy, CrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrC6alkylcarbonyl, CrCealkylcarboxy, arylcarboxy or aryld- C6alkylcarboxy wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R14;
R3 is CrC8alkyl, CrC6alkenyl, CrC6alkynyl, C3-Cι0cycloalkyl, C3-Cι0hetcycloalkyl, aryl, hetaryl, aryld-Cealkyl, d-Cealkyloxyd-Cealkyl, hetarylC C6alkyl, aryl-R6-CrC6alkyl, hetaryl- R6-CrC6alkyl or arylCι-C6alkyl-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, CrC8aIkyl, CrCealkyloxy, trihalomethyl, trihalomethyloxy, C3-Cι0cycloalkyl, C3-Cι0hetcyclo- alkyl, C3-Cι0cycloalkenyl, aryl, hetaryl, hetarylSOn, arylCrCealkyloxy, hetarylCrC6alkyloxy, Cι-C6alkyl-R6-CrC6alkyl, arylCrC6alkyl-R6-CrC6alkyl, d-Cealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, hetarylcarbonyl, hetarylCrC6alkyl-carbonyl, CrC6alkylSOn, d-C6- alkyl-carboxy, 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 NR 16.
R7 is hydrogen, halo, hydroxy, cyano, nitro, COOR17, CrC8alkyl, C3-Cι0cycloalkyl, C3-Cι0het- cycloalkyl, methylendioxo, trihalomethyl, trihalomethyloxy, aryl, arylCrCealkyl, CrC6alkyloxy, CrCealkyloxyCrCealkyl, aryloxy, aryld-C6alkyloxy, aryloxyCi-Cealkyl, arylCrCealkyloxyCr C6alkyl, hetaryl, hetarylCrC6alkyl, hetaryloxy, hetarylCrCealkyloxy, hetaryloxyCrC6alkyl, hetarylCι-C6alkyl-oxyCrCealkyl, NR8R9, S02NR8R9, NR R5carbonylCrC6alkyl, arylthio, hetarylthio, R18carbonylNR8, arylSOn, hetarylSOn, R19SOmNR8, arylthioCrCealkyl, hetaryl- thioCrC6alkyI or arylCrC6alkylR6CrCealkyl; wherein the aryl and hetaryl groups independently are optionally substituted with one or more R10;
R8 and R9 independently are hydrogen, CrC8alkyl, aryl, hetaryl, arylCrC6aIkyl 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 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 halo, cyano, CrC8alkyl, aryl, hetaryl, arylCrCealkyl, hetarylCrC6alkyl, hydroxy, oxo, CrC6alkyloxy, arylCrC-alkyloxy, hetaryld- Cealkyloxy, C Cealkyloxyd-Cealkyl, CrC6alkyl-carbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetarylcarboxy, aryld-Cealkylcarboxy or hetarylCrC6alkylcarboxy;
R10 and R11 independently are hydrogen, hydroxy, oxo, halo, cyano, nitro, CrC8alkyl, 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, CrC8alkyl, d-C6alkyloxy or aryloxy;
R15 is hydrogen, halo, hydroxy, oxo, nitro, cyano, CONR8R9 or COOR17;
R16 is hydrogen, CrC8alkyl, C3-C 0cycloalkyl, C3-C10hetcycloalkyl, aryl, arylCrC6alkyl, hetaryl, hetarylCrC6alkyl, alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, aryloxyCi- Cealkyl, hetaryloxyd-Cealkyl, arylthioCrCealkyl 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 arylCrC6alkyl;
R18 is CrC6alkyl, C2-C6alkenyl, aryl, arylCrC6alkyl, hetaryl, hetarylCrCealkyl, C3- Ciocycloalkyl, C3-Cιohetcycloalkyl, CrC6alkyloxy, aryloxy, arylCrC6alkyloxy, aryld- CealkyloxyCrCealkyl, hetaryloxy, hetarylCrCealkyloxy, hetarylCrCealkyloxyCrCealkyl or R8R9NCrC6alkyl wherein the alkyl, alkenyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups are optionally substituted with R15;
R19 is d-Cβalkyl, C3-Cι0cycloalkyl, C3-Cι0hetcycloalkyl, 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.
7. The combination according to claim 6 wherein the 11β-HSD1 inhibitor is of formula (II) wherein
R1 is C3-Ci0cycloalkyl, C3-Cιohetcycloalkyl, CrC8alkyl, 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, CrC8alkyl, aryl, hetaryl, arylCrC6alkyl, C3-C10cycloalkylCrC6alkyl, d- C6alkylcarboxyCrC6alkyl wherein the alkyl, aryl and cycloalkyl groups independently are optionally 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 d-C8alkyl, aryl, hetaryl, aryld- C6alkyl, hetarylCrC6alkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrCealkyloxy, hetaryld- Cealkyloxy, CrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrC6alkylcarbonyl, CrCealkylcarboxy, 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-Cι0cycloalkyl, C3-Cι0hetcycloalkyl, aryl, hetaryl, arylCrC6alkyl, CrCealkyloxyCrCealkyl, hetarylCrCealkyl, aryl-R6-CrC6alkyl, hetaryl- R6-CrC6alkyl or arylCι-Cealkyl-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, Cι-C8alkyl, d-C6alkyloxy, trihalomethyl, trihalomethyloxy, C3-Cι0cycloalkyl, C3- C 0hetcycloalkyl, C3-Cι0cycloalkenyl, aryl, hetaryl, hetarylSOn, aryld-Cealkyloxy, hetaryld- C6alkyloxy, Ci-C6alkyl-R6-CrC6alkyl, arylCrC6alkyl-R6-CrC6alkyl, CrCealkylcarbonyl, aryl- carbonyl, arylCrCealkylcarbonyl, hetarylcarbonyl, hetarylCrC6alkyl-carbonyl, CrC6alkylSOn, CrC6alkyl-carboxy, arylcarboxy, hetarylcarboxy, aryld-Cealkylcarboxy 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, NR16;
R7 is hydrogen, halo, hydroxyl, cyano, nitro, COOR17, CrC8alkyl, C3-Cι0cycloalkyl, C3-Cι0het- cycloalkyl, methylendioxo, trihalomethyl, trihalomethyloxy, aryl, aryICrC6alkyl, CrC6alkyloxy, CrCealkyloxyCrCealkyl, aryloxy, aryloxyCrC6alkyl, arylCrCealkyloxyCrCealkyl, hetaryl, hetarylCrCealkyl, hetaryloxy, hetarylCrC6alkyloxy, hetaryloxyCrCealkyl, hetarylCrCealkyloxyCrCealkyl, NR8R9, S02NR8R9, NR4R5carbonylalkyl, arylcarbonylNR8, arylthio, hetarylthio, arylSOm, hetarylSOm, arylSOmNR8, arylthioCrCealkyl, hetarylthioCι-C6alkyl or aryld- CealkylR6Cι-C6alkyl; wherein the aryl and hetaryl groups independently are optionally substi- tuted with one or more R10;
R8 and R9 independently are hydrogen, CrC8alkyl, aryl, hetaryl, arylCrC6alkyl or hetarylC C6alkyl wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 1; 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 C C8alkyl, aryl, hetaryl, arylCrCealkyl, hetarylCrC6alkyl, hydroxy, oxo, CrC6alkyloxy, arylCrCealkyloxy, hetarylCrC6alkyloxy, C CealkyloxyCι-C6alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylC C6alkylcarbonyl, hetarylCrC6alkylcarbonyl, CrC6alkylcarboxy, arylcarboxy, hetarylcarboxy, arylCi-C6alkyl-carboxy or hetarylCrC6alkylcarboxy;
R10 and R11 independently are hydrogen, hydroxy, oxo, halo, cyano, nitro, CrC6alkyl, 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, d-C8alkyI, C C6alkyloxy or aryloxy; R15 is hydrogen, halo, hydroxy, oxo, nitro, cyano or COOR17;
R16 is hydrogen, C C8alkyl, C3-Cι0cycloalkyl, C -Cι0hetcycloalkyl, aryl, aryld-Cealkyl, hetaryl, hetaryld-Cealkyl, alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, aryloxyCi- Cealkyl, hetaryloxyCrCealkyl, arylthioCrCealkyl or hetarylthioCι-C6alkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R10;
R17 is hydrogen, CrC8alkyl, aryl or arylCrC6alkyl;
m is 1 or 2;
n is 0, 1 or 2; or
a salt thereof with a pharmaceutically acceptable acid or base, or optical isomer, mixture of optical isomers, racemic mixture, or tautomeric form thereof.
8. The combination according to claim 6 or 7 wherein the 11 ?-HSD1 inhibitor is selected from the group:
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,fja∑epin-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-bjthiophen-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 -yI]-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-FIuoro-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-yI)-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-ChIoro-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-benzothiazoI-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-phenyI-ethyl)-3-phenyl-propionamide;
4-Oxo-4-piperidin-1-yl-butyric acid 4-tert-butyl-cyclohexyl ester;
N-tert-ButyI-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-d ihydro-isoindol-2-ylmethyl)-N-(4-hydroxy-phenyl)-benzamide; Biphenyl-4-yI-piper ϊidin-1 -yl-methanone;
Azepan-1 -yl-(3,5-d lichloro-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-(1 H-lndol-3-yl)-1-methyl-ethyl]-2-(4-isobutyl-phenyl)-propionamide;
N-tert-Butyl-2-(4-isobutyl-phenyl)-propionamide;
Adamantane-1 -carboxylic acid (2-acetyI-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-cyclohexyI-acetamide;
Cyclohexanecarboxylic acid (7,7-dimethyl-5-oxo-5,6,7,δ-tetrahydro-quinazolin-2-yl)-amide;
2,4-Dichloro-N-ethyl-N-o-tolyl-benzamide;
(4-Benzyl-piperidin-1-yl)-(4-fluoro-phenyI)-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-BenzyI-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-phenyI)-benzamide;
N-Ben∑yl-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-carbonyI)-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-methyI-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)-butylj- 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-rM-[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-CycIopentyl-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-f luoro-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; 203
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-ToIyl-adamantane-1 -carboxylic acid (2,4-difluoro-phenyl)-amide;
Adamantyl-1 -carboxylic acid tert-butylamide;
2-Adamantan-1-yl-N-tert-butyI-acetamide;
N-Methyl-N-phenyl-4-(pyrrolidine-1-sulfonyI)-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-phenyI-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-yI)-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-phenyI-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-yI]-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)-pipera∑in-1-yl]-2-(2-isopropyl-5-melhyl-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-butyI)-acetamide; 2-(Naphthalen-2-ylcarbamoylmethyIsulfanyl)-N-(1 ,1 ,3,3-tetramethyl-butyl)-acetamide;
Acetic acid 4-(3,5-dimethyl-piperidine-1-carbonyl)-phenyl ester;
(4-Chloro-3-nitro-phenyl)-(2,6-dimethyl-piperidin-1-yl)-methanone;
[1-(4-Chloro-benzenesulfonyl)-piperidin-3-yl]-(octahydro-quinolin-1-yl)-methanone;
2,4-Dichloro-N-cyclohexyl-N-(2-hydroxy-ethyl)-benzamide; (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 -ylj-methanone;
N-Furan-2-ylmethyl-2-phenyI-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-1 H-isoquinolin-2-yl)-o-tolyI-methanone; (3,6-Dichloro-benzo[bjthiophen-2-yl)-(4-methyl-piperazin-1-yl)-methanone;
3-(1-Benzyl-1 H-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-yI)-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-phenyI)-piperazin-1-yl]-o-toIyl-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-methyI-9H-1,3,4,9-tetraaza-fluoren-2-ylsulfanyl)-acetamide;
1 -(Thiophene-2-carbonyl)-2,3-dihydro-1 H-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-phenyI-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)-pipera∑in-1-yl]-(3-methoxy-phenyl)-methanone;
Furan-2-carboxylic acid [4-(4-methyI-piperidine-1-sulfonyl)-phenyl]-amide; N-(2-Cyclohex-1 -enyl-ethyl)-2-o-tolyloxy-acetamide;
5-(2-Chloro-phenoxymethyI)-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-carbonyI)-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-yI-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-carboxyIic acid cycloheptylamide;
(3,4-Dihydro-1 H-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-1 H-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)-1 H-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[6.2.1.027]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-dimethyI-propionamide;
4-Fluoro-N-[4-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1joctane-6-carbonyl)-phenyl]- benzenesulfonamide;
4-Bromo-1-ethyl-1 H-pyrazole-3-carboxylic acid (2-methylsulfanyl-phenyl)-amide;
5-Benzoyl-furan-2-carboxylic acid diisopropylamide;
2-[3-(Piperidine-1 -carbonyl)-phenyl]-isoindole-1 ,3-dione;
N-{2-[2-(4-Bromo-phenyl)-2-oxo-ethyIsulfanyl]-benzothiazoI-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-carboxyIic acid adamantan-2-ylamide;
3,3-Dimethyl-pentanedioic acid bis-[(2,4-difluoro-phenyl)-amidej;
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-yI)-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-pyrroI-1-yl)-phenyl]-(4-methyl-piperidin-1-yl)-methanone;
N-Cydohexyl-3-(2-hydroxy-4-methyl-phenyl)-3-phenyl-propionamide;
2-Diethylamino-N-(1-phenyl-cyclopentylmethyl)-propionamide;
(6-Fluoro-2-methyI-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)-phenylj-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;
Ben∑o[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-yI)-(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-methyI-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-1 H-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-tolylsulfanyI-propionamide; 6-(2,4-Dichloro-phenylcarbamoyl)-3,4-dimethyI-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-ethyI)-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-pyrazoI-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[bjthiophene-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-phenoxymethyI)-furan-2-yl]-piperidin-1 -yl-methanone;
1-(4-Ethyl-benzoyl)-6-methoxy-2-methyl-2,3-dihydro-1 H-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-bulyramide; [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)-f uran-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-benzyIsuIfanyl-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-phenylsulfanyI)-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-ben∑ylsulfanyl)-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-1 H-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-ethylj-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[bjthiophene-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 -ylj-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-pyra∑ol-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-1H-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 -ylj-3-phenyl-propan-1 -one;
(3,4-Dihydro-1H-isoquinolin-2-yl)-(3,4-dimethyl-phenyl)-methanone;
(1 -Adamantan-1 -yl-4-bromo-1H-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; (4-Hydroxy-4-phenyl-octahydro-quinolin-1-yl)-phenyl-methanone;
(2-Chloro-phenyl)-(2-methyl-piperidin-1-yl)-methanone;
(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-yI)-[3-(4-phenyl-piperazine-1-sulfonyl)-phenyl]-methanone;
Bicyclo[2.2.1 ]hept-2-yl-[4-(2,3-dimethyl-phenyl)-piperazin-1 -ylj-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-methyI-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 -ylj-methanone; N-CyclooctyI-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; 2-(4-Chloro-3,5-dimethyl-phenoxy)-N-cyclohexyl-N-methyl-acetamide;
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-1 H-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-1 H-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-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-1 H-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-[(Adamantane-1-carbonyl)-amino]-3-(1 H-indol-3-yl)-propionic acid methyl ester;
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-1 H-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 -CyclohexyI-5-oxo-pyrrolidine-3-carboxylic acid (3-cyano-4,5,6,7-tetrahydro- benzo[b]thiophen-2-yl)-amide; 6-(2,4-Dichloro-phenylcarbamoyl)-3,4-dimethyl-cyclohex-3-enecarboxylic acid;
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-Metho) y-naphthalen-1-ylmethyl)-pipera∑in-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-Phenelhyl-N-(tetrahydro-furan-2-ylmethyl)-ben∑amide;
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-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-toIyl-1 ,4-dihydro-pyrimidin-2-ylsulfanyl)-acetamide; [4-(3,5-Dinitro-phenoxy)-phenyl]-(2-ethyl-piperidin-1-yI)-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,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-yImethyl-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-yI)-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-(2-oxo-4-phenyl-pyrrolidin-1 -yl)-acetamide;
N-Adamantan-1-yl-2-hydroxy-2,2-diphenyI-acetamide;
Adamantane-1 -carboxylic acid (naphthalen-1 -ylmethyl)-amide;
Adamantane-1 -carboxylic acid (benzo[1 ,3jdioxol-5-ylmethyl)-amide;
1 -(Azepane-1 -carbonyl)-fluoren-9-one; 2-(Quinolin-2-ylsulfanyl)-N-p-tolyI-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-ben∑ylsulfanyl)-N-p-tolyl-acetamide;
[4-(4-Chloro-phenylsulfanylmethyl)-phenyl]-pyrrolidin-1-yl-methanone; N-Adamantan-1 -yl-N-methyl-isonicotinamide;
A∑epan-1-yl-[4-(4-chloro-phenylsulfanylmethyl)-phenyl]-methanone;
(2-Chloro-phenyl)-(1 ,5,7-trimethyl-3,7-dia∑a-bicyclo[3.3.1]non-3-yl)-methanone;
(3-Chloro-ben∑o[b]thiophen-2-yl)-(4-methyl-piperidin-1-yl)-methanone;
Benzoic acid 1-benzoyI-decahydro-quinolin-4-yl ester; 2-(3-Bromo-benzylsuifanyl)-1 -[4-(2-methoxy-phenyl)-piperazin-1 -ylj-ethanone;
4-Methyl-N-[2-(phenoxa∑ine-10-carbonyl)-phenyl]-ben∑enesulfonamide;
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-[(Adamantane-1-carbonyl)-amino]-3-(1H-indol-3-yI)-propionic acid methyl ester;
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-hexyI)-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 [3-(1 H-benzoimidazol-2-ylsulfanyl)-5-nitro-phenyl]-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; Adamantane-1 -carboxylic acid (4-ethoxy-benzothiazol-2-yl)-amide;
N-[5-(5-Chloro-benzooxazol-2-yl)-2-methyl-phenyl]-2-methoxy-benzamide;
N-[2-(2-Bromo-phenyl)-benzooxazol-5-yl]-2-methoxy-ben∑amide;
2-(4-Chloro-phenoxy)-N-(4-chloro-3-trifluoromethyl-phenyl)-acetamide;
2,2-Dimethyl-N-(5-propyl-[1 ,3,4]thiadia∑ol-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-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-methyI-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,fjazepin-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-yI-(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 -ylj-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-trifluoromethyI-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 ben∑yl-(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-ben∑yl)-[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)-ethylj- benzamide; N-(6,6-Dimethyl-bicyclo[3.1.1jhept-2-ylmethyl)-4-[2-(4-fluoro-phenylsulfanyl)-ethylj- benzamide;
4-(2,6-Dichloro-phenylsulfanyl)-N-(6,6-dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-butyramide;
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-bicycio[3.1.1]hept-2-ylmethyl)-4-[2-(4-fluoro-phenylsulfanyl)-ethylj- ben∑amide;
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-phenylsulfanyl)-pentanoic acid [2-(3-trifluoromethyl-phenyl)-ethyl]-amide;
4-[2-(2,6-Dichloro-phenylsulfanyl)-ethyl]-N-[2-(2-fluoro-phenyl)-ethylj-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-CyclohexyIamino-thiazole-4-carboxylic acid (l-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-diben∑ofuran-3-yl)-amide;
2-Cydohexylamino-thia∑ole-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)-ethylcarbamoylj- methyl}-prop-2-ynyl-amide;
2-Benzylsulfanyl-N-{[2-(2-chloro-6-fluoro-benzylsulfanyl)-ethylcarbamoyl]-methyl}-N-(2- methoxy-ethyl)-acetamide; 4-[2-(5-Cydopropylmethylsulfanyl-[1,3,4]thiadiazol-2-ylsulfanyl)-ethyl]-N-(6,6-dimethyl- bicyclo[3.1.1]hept-2-yImethyl)-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)-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-yI-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}-methyI)-phenoxy]-acetic
3C1U|
[2-({(2-Methoxy-ethyl)-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-methyl)-phenoxyj- acetic acid;
[2-({Carbamoylmethyl-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-methyl)-phenoxyj- 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)-aminoj-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)-ben∑amide; 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-PhenyI-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)-ben∑amide;
N-(2-Ethoxy-ethyl)-4-hydroxy-N-(4-hydroxy-ben∑yl)-ben∑amide;
N-(4-Hydroxy-ben∑yl)-N-(3-isopropoxy-propyl)-ben∑amide; 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)-ben∑amide;
N-(2-Hydroxy-ben∑yl)-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; and
N-[2-(4-Fluoro-benzylamino)-thiazol-4-ylmethyl]-N-phenethyl-butyramide; or
a salt thereof with a pharmaceutically acceptable acid or base, or an optical isomer, mixture of optical isomers, racemic mixture, or tautomeric form thereof.
9. The combination according to claim 6 or 7 wherein the 11 ?-HSD1 inhibitor is selected from the group :: (4-TetrazoI-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-methyI-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-methyI-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-CycIohexyl-2-(3,5-dimethoxy-phenoxy)-N-methyl-benzamide;
N-Cyclohexyl-2-(2,3-dimethoxy-phenoxy)-N-methyl-benzamide;
2,4-Dichloro-N-(3,3-dimethyI-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-CyclohexyI-3-hydroxy-N-methyl-benzamide;
[4-(Morpholine-4-suIfonyl)-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 Joct-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-yl)-methanone;
(4-Amino-2-methoxy-phenyI)-(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-phenyl)-(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-yl)-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)-δ-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-δ-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.
10. The combination according to claim 6 or 7 wherein the 11 ?-HSD1 inhibitor is of the Formula (lla):
Figure imgf000230_0001
(Ha) wherein
R1 is aryl, arylCrCealkyl, hetaryl or hetaryld-Cealkyl optionally substituted with one or more of R6 independently;
R2 is halo, CrC6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-Cι0cycloalkyl, C3-C10cycloalkylCrC6- alkyl, trihalomethyl, aryl, arylCrCealkyl, CrCealkyloxyCrCealkyl, arylCrCealkyloxyCrCealkyl, Cι-C6alkylNR5CrC6alkyl, arylCrC6alkylNR5CrC6alkyl, hetaryl or hetaryld-Cealkyl wherein the alkyl, 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-Cι0hetcycloalkyl, Ce-CιocycloalkylCrC6alkyl or C6-Cι0hetcyclo- alkylCrCealkyl 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 bicydic/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 op- tionally being substituted with at least one of CrC6alkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrCealkyl, hydroxy, oxo, CrC6alkyloxy, 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-Cι0cycloalkyl, C3-Cι0hetcycloalkyl, C3-Cι0- cycloalkylCrC6alkyl, C3-Cι0hetcycloalkylCι-C6alkyl, 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, d-C6alkyl, d-C6- alkyloxy, trihalomethyl, trihalomethoxy, NR10R11, arylCrC6alkyloxy, hetaryld-Cealkyloxy, d- C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkylcarbonyl, CrCealkyloxycarbonyl, aryloxycarbonyl, arylCrCealkyloxycarbonyl, d-Cealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
R8 and R9 independently are hydrogen, CrC6alkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, NR10R11, CrC6alkyloxy, aryloxy, aryld-Cealkyloxy, hetaryloxy, hetarylCrCealkyloxy, CrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-C6alkylcarboxy, arylcarboxy or aryICrC6alkylcarboxy;
R10 and R11 independently are hydrogen, CrC8alkyI, aryl, hetaryl, arylCrC6alkyl, C3-do- cycloalkyl, C -Cι0hetcycloalkyl, C3-Cι0cycloalkylCι-C6alkyl, CrCealkylcarbonyl, C CealkylcarboxyCrC6alkyl; 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 CrC8alkyl, aryl, hetaryl, arylCi- Cealkyl, hetaryld-Cealkyl, hydroxy, oxo, cyano, d-dalkyloxy, aryld-C6alkyloxy, hetaryld- C-alkyloxy, CrC6alkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrC6alkylcarbonyl, CrC6alkylcarboxy, arylcarboxy or arylCπ 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.
11. The combination according to claim 10 wherein the 11 ?-HSD1 inhibitor is of the Formula (lla)wherein:
R1 is aryl or hetaryl optionally substituted with one or more R6 independently;
R2 is halo, d-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, C3-Cι0cycloalkyl, C3-Cι0cycloalkylCι-C6- alkyl, aryl, arylCrCealkyl, d-Cealkyloxyd-Cealkyl, arylCrCealkyloxyCrCealkyl, d-C6- alkylNR5CrC6alkyl, 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-Cι0cycloalkylCrC6alkyl or Ce-C10hetcyclo- alkylCrC6alkyl wherein the alkyl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R8;
R5 is CrC6aIkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C3-C10hetcycloalkyl, C3-C10- cycloalkylCrCealkyl, C3-C10hetcycloalkylCι-C6alkyl, aryl, hetaryl, arylCrC6alkyl 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, NR 0R11, aryld-Cealkyloxy, hetarylCrCealkyloxy, d- Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, d-C6alkyloxycarbonyl, aryloxycarbonyl, arylCrCealkyloxycarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
R8 and R9 independently are hydrogen, d-C6alkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrC6- alkyl, hydroxy, oxo, cyano, NR10R11, CrC6alkyloxy, aryloxy, arylCrCealkyloxy, hetaryloxy, hetarylCrCealkyloxy, CrCealkyloxyd-Cealkyl, CrC6alkyl-carbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrC6alkyl-carbonyl, CrCealkylcarboxy, arylcarboxy or arylC C6alkylcarboxy;
R10 and R11 independently are hydrogen, C C8alkyl, aryl, hetaryl, aryld-Cealkyl, C3-Cι0- cycloalkyl, C3-Cι0hetcycloalkyl, C3-CιocycloalkylCrCealkyl, CrCealkylcarboxyCrCealkyl; 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 CrC8alkyl, aryl, hetaryl, aryld- C6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrC6alkyloxy, hetaryl CrCealkyloxy, CrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-Cealkylcarboxy, 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.
12. The combination according to claim 10 or 11 wherein the 11 ?-HSD1 inhibitor is selected from:
1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; 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-1 - -pyrazol-4-yl]-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6- yl)-methanone;
1 -(Phenyl)-5-methyl-1 H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; 1-(4-Fluoro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide;
1-(4-Methoxy-phenyl)-5-methy!-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 H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; 1-(2-Pyridyl)-5-methyl-1H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; 1-(2-Pyridyl)-5-propyl-1r/-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.
13. The combination according to claim 6 or 7 wherein the 11 ?-HSD1 inhibitor is of the Formula (lib)
Figure imgf000234_0001
(lib) wherein R1 is hydrogen, 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;
R2 , R3, R4 and R5 independently are hydrogen, halo, nitro, cyano, hydroxy, NR9R10, triha- lomethyl, 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 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, arylC C6alkyl, hetaryld-Cealkyl, hydroxy, oxo, CrCealkyloxy, aryloxy, arylCrC6alkyloxy or hetarylCrC6alkyloxy; 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 CrCealkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrCealkyl, hydroxy, oxo, d-C6alkyloxy, aryloxy, arylCrCealkyloxy or hetarylCrCealkyloxy; or 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, oxygen or sulphur, the ring system optionally being substituted with at least one of CrCealkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrCealkyl, hydroxy, oxo, CrC6aIkyloxy, aryloxy, aryld-Cealkyloxy or hetarylCrC6alkyloxy;
R6 is aryl, hetaryl, arylCrC6alkyl, C3-Cι0cycloalkyl, C3-Cι0hetcycloalkyl, C3-Cι0cycloalkylCr C6alkyl, CrCealkylcarboxyCrCealkyl, wherein the alkyl, aryl and cycloalkyl groups independently are optionally substituted with one or more of R11;
R7 is CrC8alkyl, aryl, hetaryl, arylCrC6alkyl, C3-Cι0cycloalkyl, C3-Cι0hetcycloalkyl, C3- CιocycloalkylCrC6alkyI, Cι-C6alkylcarboxyCrC6alkyl, 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 CrC8alkyl, aryl, hetaryl, aryld- C6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C6alkyloxy, arylCrC6alkyloxy, hetarylCr C6alkyloxy, 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 R8;
R9 and R10 independently are hydrogen, d-C8alkyl, aryl, hetaryl, aryld-Cealkyl, C3-C10- cycloalkyl, C3-Cιohetcycloalkyl, C3-Cι0cycloalkylCrC6alkyl, 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 CrC8alkyl, aryl, hetaryl, aryld- C6alkyl, hetarylCrC6alkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrCealkyloxy, hetaryld- C6alkyloxy, CrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, aryl- CrCealkylcarbonyl, 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, CrC8aIkyl, CrCealkyloxy or aryloxy; 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.
14. The combination according to claim 13 wherein the 11 ?-HSD1 inhibitor is selected frm the group: pyrazolo[1 ,5-a]pyridin-3-yl-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1joct-6-yl)-methanone; (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.
15. The combination according to claim 6 or 7 wherein the 11 ?-HSD1 inhibitor is of the For- mula (He):
Figure imgf000236_0001
(lie) wherein
R1 is hydrogen, CrC8alkyl, CrCealkyloxyCrCealkyl, aryl, hetaryl, arylCrC6alkyl, hetaryld- C6alkyl, CrC6S02, arylS02, hetarylS02, arylCrC6alkylS02 or hetaryICrC6alkylS02 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 hetarylCrC6alkyl 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 independ- ently are substituted with one or more R9; and
R7 and R8 independently are CrC8alkyl, C3-Cι0cycloalkyl, C3-Cι0hetcycloalkyl, C3-Cι0cyclo- alkylCrC6alkyl, 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, CrC6alkyloxy, aryICrC6alkyloxy, hetaryld-Cealkyloxy, CrC6alkyloxyCr
C6alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkylcarbonyl, hetaryld- C6alkylcarbonyl, d-Cealkylcarboxy, arylcarboxy or aryld-Cealkylcarboxy 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, C(0)NR12R13, aryld-Cealkyloxy, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, d-Cealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
R10 and R11 independently are hydrogen, halo, oxo, hydroxy, d-Cealkyl, aryl, arylCrC6alkyl, hetaryl or hetarylalkyl;
R12 and R13 independently are hydrogen, d-C8alkyl, aryl, hetaryl, arylCrC6alkyl, Ca-Ciocycloalkyl, C3-Ci0hetcycloalkyl, C3-Cι0cycloalkylCrC6alkyl, d-Cealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, hetarylcarbonyl, hetarylCrCealkylcarbonyl, CrC6alkylcarboxyCr Cealkyl; 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- C6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrC6alkyloxy, hetaryld- C6alkyloxy, Cι-C6alkyl-oxyCrC6alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkyl-carbonyl, hetarylCrC6alkylcarbonyl, CrC6alkylcarboxy, arylcarboxy or aryld- Cealkylcarboxy; 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.
16. The combination according to claim 15 wherein the 11 ?-HSD1 inhibitor is of the For- mula (lid)
Figure imgf000238_0001
(lid) wherein
R is hydrogen, CrC8alkyl, aryl, hetaryl, arylC C6alkyl or hetarylCrC6alkyl optionally substi- tuted with one or more R8;
R2 and R5 independently are hydrogen, halo, nitro, cyano, trihalomethyl, d-Cealkyl, aryl, arylCrC6alkyl, hetaryl or hetaryld-Cealkyl 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-Cι0cycloalkyl, C3-C 0hetcycloalkyl, C3-Cι0cyclo- 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-C8aIkyl, aryld-Cealkyl, hetarylCrC6alkyl, hydroxy, cyano, CrC6alkyloxy, aryld-Cealkyloxy, hetaryld-Cealkyloxy, d-Cealkyloxyd- 233
C6alkyl, CrC6alkyIcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetaryld- C6alkylcarbonyl, CrC6alkylcarboxy, arylcarboxy or arylCrC6aIkylcarboxy 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, CrC6alkyloxy, trihalomethyl, trihalomethoxy, NR11R12, arylCrCealkyloxy, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
R9 and R10 independently are hydrogen, halo, oxo, hydroxy, d-C6alkyl, aryl, arylCrC6alkyl, hetaryl or hetarylalkyl;
R11 and R12 independently are hydrogen, CrC8alkyl, aryl, hetaryl, aryld-C6alkyl, C3-Cι0- cycloalkyl, C3-Cι0hetcycloalkyl, C3-CιocycloalkylCrC6alkyl, Cι-C6alkyl-carboxyCrC6alkyl; 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 CrC8alkyl, aryl, hetaryl, arylC C6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrC6alkyloxy, hetaryld- C6alkyloxy, CrCealkyl-oxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkyl-carbonyl, hetaryICrC6alkylcarbonyl, CrC6alkylcarboxy, arylcarboxy or aryld- Cealkylcarboxy; 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.
17. The combination according to claim 15 or 16 wherein the 11 ?-HSD1 inhibitor is selected from the group:
1H-Benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide; 1 -Benzyl-1 /-/-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide; (1 H-Benzoimidazol-5-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; lsopropy!-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 /-/-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide; 2-(4-Amino-phenyl)-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; , (2-Methyl-1H-benzoimidazol-5-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; (2-Amino-1ry-benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; (2-Benzo[1,3]dioxol-5-yI- .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[3.2.1joctane-6-carbonyI)-.H-benzoimidazol-2-yl]-benzoic acid methyl ester;
(2-Thiophen-2-yl-.H-benzoimidazol-5-yl)-(1,3,3-trimethyI-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.
18. The combination according to claim 6 or 7 wherein the 11 ?-HSD1 inhibitor is of the Formula (lie)
Figure imgf000240_0001
(Ne) wherein
X is oxygen or (CR1R2)n;
R1, R2, R3, and R4 independently are hydrogen, CrC6alkyl, aryl, arylCrC6alkyl, hetaryl or hetarylCrC6alkyl 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 d-C6alkyl, hydroxy, oxo, aryl, hetaryl, arylCrC6alkyl or hetarylCrCealkyl; 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 R9;
R6 is C3-Ci0cycloalkyl, C3-C ohetcycloalkyl, C3-CιocycloalkylCrC6alkyl, 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 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 CrC6aIkyl, aryl, hetaryl, aryld- C6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrCealkyloxy, hetaryld- C6alkyloxy, CrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrC6alkylcarbonyl, d-Cealkylcarboxy, arylcarboxy or aryld- 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-Cealkyl, aryl, aryld-C6alkyl, d- C6alkyloxy, aryloxy, arylCrCealkyloxy, hetaryl, hetarylCrCealkyl, hetaryloxy or hetarylCrC6- alkyloxy optionally substituted with one or more R11 independently;
R8 and R9 independently are hydrogen, hydroxy, oxo, halo, nitro, cyano, CrCealkyl, CrCealkyloxy, trihalomethyl, trihalomethoxy, NR12R13, aryld-Cealkyloxy, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrC6alkylcarboxy;
R10 is hydrogen, C C8alkyl, arylCrCealkyl, hetarylCrC6alkyl, d-C6alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy;
R11 is hydrogen, halo, hydroxy, oxo, nitro, cyano, CrC8alkyl, d-C6alkyloxy, aryloxy or hetary- loxy;
R12 and R13 independently are hydrogen, CrC8alkyl, aryl, hetaryl, arylCrC6alkyl, C3-Cι0cyclo- alkyl, C3-C10hetcycloalkyl, CrCealkylcarbonyl, arylCrC6alkylcarbonyl, C3-Ci0cycloalkylCrC6- 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 CrC6alkyl, aryl, hetaryl, aryld- C6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, aryld-Cealkyloxy, hetaryld- Cealkyloxy, CrCealkyloxyCrCealkyl, CrCealkylcarbonyl, 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.
19. The combination according to claim 18 wherein the 11 ?-HSD1 inhibitor is selected from the group:
2,3-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; 2,5-Dimethyl-3-phenyl-ben∑ofuran-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.
20. The combination according to claim 18 wherein the 11/7-HSD1 inhibitor is selected from the group:
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.
21. The combination according to claim 6 or 7 wherein the 11 ?-HSD1 inhibitor is of the For- mula (llf)
Figure imgf000243_0001
(llf) wherein
R1 is hydrogen, d-C8alkyl, hetaryl, aryld-Cealkyl or hetaryld-Cealkyl optionally substituted with one or more R9;
R , R , R\ R and R independently are hydrogen, halo, nitro, cyano, trihalomethyl, carboxy,
N(R^R1d), C(0)NR R°, CrC8alkyl, C3-C10cycloalkyl, C3-Cι0hetcycloalkyl, N(R^R1d)C C6alkyl, d-C6alkyloxy, CrCealkyloxyCrCealkyl, aryl, arylCrC6alkyl, aryloxy, aryloxyCi- Cealkyl, arylCrCealkyloxy, arylCrCealkyloxyCrCealkyl, d-C6alkylcarboxy, arylcarboxy, arylCrCealkylcarboxy, hetaryl, hetarylCrCealkyl, hetaryld-Cealkyloxy, hetaryloxyCrCealkyl 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-Ci0cycloalkyl, 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 system optionally being substituted with at least one of CrC8alkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrC6alkyloxy, hetarylCrC6alkyl- oxy, CrCealkyloxyCrCealkyl, 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;
R9 is hydrogen, hydroxy, oxo, halo, nitro, cyano, d-Cealkyl, CrC6alkyloxy, trihalomethyl, trihalomethoxy, NR12R13, arylCrCealkyloxy, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, CrC6alkylcarboxy, arylcarboxy or aryld-Cealkylcarboxy;
R10 and R11 independently are hydrogen, halo, oxo, hydroxy, CrC6alkyl, aryl, arylCrCealkyl, hetaryl or hetarylalkyl;
R12 and R13 independently are hydrogen, CrC8alkyl, aryl, hetaryl, arylCrCealkyl, Ca-Ciocycloalkyl, C3-Ci0hetcycloalkyl, C3-Cι0cycloalkylCι-C6alkyl, CrC6alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, C3-Cι0cycloalkylcarbonyl, C3-Cι0hetcycloalkylcarbonyl or C3-docyclo- 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 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, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C6alkyloxy, arylCrCealkyloxy, hetaryld- C6alkyloxy, CrCealkyl-oxyCι-C6alkyl, CrC6aIkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkyl-carbonyl, hetarylCrC6alkylcarbonyl, CrC6alkylcarboxy, 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.
22. The combination according to claim 21 wherein the 11/? -HSD1 inhibitor is of the For- mula (llf) wherein
R1 is hydrogen, CrC8alkyl, hetaryl, arylC C6alkyl or hetarylCrCealkyl optionally substituted with one or more R9;
R2 and R5 independently are hydrogen, halo, nitro, cyano, trihalomethyl, CrC6alkyl, CrCealkyloxy, CrCealkyloxyCrCealkyl, aryl, aryld-Cealkyl, aryloxy, aryloxyd-Cealkyl, arylCrCealkyloxy, arylCrCealkyloxyCrCealkyl, hetaryl or hetaryld-Cealkyl 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 Ci-CβalkyI, C3-Cι0cycloalkyl, C3-Cι0hetcycloalkyl, N(R12R13)CrC6alkyl, CrC6alkyloxyCr C6alkyl, aryloxyCi-Cealkyl, arylCrCealkyloxy or arylCrCealkyloxyCrCealkyl;
R7 is C C8alkyl optionally substituted with one or more of R10;
R8 is C3-Ci0cycloalkyl, 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 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, hetarylCrC6alkyl- oxy, CrCealkyloxyCrCealkyl, Ci -Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6- alkylcarbonyl, hetarylCrC6alkylcarbonyl, 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-d-alky!, CrC6alkyloxy, trihalomethyl, trihalomethoxy, NR12R13, arylCrCealkyloxy, d-C6alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, CrC6alkylcarboxy, arylcarboxy or aryld-Cealkylcarboxy;
R10 and R11 independently are hydrogen, halo, oxo, hydroxy, d-Cealkyl, aryl, arylCrC6alkyl, hetaryl or hetarylalkyl;
R12 and R13 independently are hydrogen, CrC8alkyl, aryl, hetaryl, arylCrC6alkyl, C3-C10- cycloalkyl, C3-Cι0hetcycloalkyl, C3-CιocycloalkylCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, C3-Cι0cycloalkylcarbonyl, C3-Cι0hetcycloalkylcarbonyl or C3-Cι0cyclo- alkylCi-C6aIkyIcarbonyl; 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, arylC C6alkyl, hetaryld-Cealkyl, hydroxy, oxo, cyano, CrC6alkyloxy, arylCrC6alkyloxy, hetaryld- C6alkyloxy, CrCealkyl-oxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkyl-carbonyl, hetarylCrCealkylcarbonyl, d-C6alkylcarboxy, 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.
23. The combination according to claim 21 or 22 wherein the 11 ?-HSD1 inhibitor is selected from the group: (1/.-lndol-5-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; 1 H-lndole-6-carboxylic acid cyclohexyl-methyl-amide; (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; 1/-/-lndole-6-carboxylic acid adamantan-2-ylamide; (6-Aza-bicyclo[3.2.1]oct-6-yl)-(1 H-indol-6-yl)-methanone; 1 H-\ ndole-6-carboxylic acid (8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amide; 1 - -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; (1 H-lndol-3-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; (1 -/-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-1H-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-1 -.-indol-3-yl)-(1 ,3,3-trimethyI-6-a∑a-bicyclo[3.2.1]oct-6-yl)- methanone;
Azepan-1 -yl-(1 -methyl-1 - -indol-3-yl)-methanone;
(5-Ben∑yloxy-1H-indol-3-yl)-(1 ,3,3-trimethyl-6-a∑a-bicyclo[3.2.1]ocl-6-yl)-methanone; (5H-[1 ,3]Dioxolo[4,5]indol-7-yl)-(1 ,3,3-trimethyl-6-a∑a-bicyclo[3.2.1]oct-6-yl)-methanone; 5-Chloro-1 -.-indol-3-yl)-(1 ,3,3-trimethyl-6-a∑a-bicyclo[3.2.1]oct-6-yl)-methanone; (6-TrifluoromethyI-1H-indol-3-yl)-(1 ,3,3-trimethyl-6-a∑a-bicyclo[3.2.1]oct-6-yl)-methanone; 6-Methyl-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-1 H-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[3.2.1joct-6-yl)-methanone; 2-(1H-lndol-3-yl)-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-ethanone; -(3-Aza-bicydo[3.2.2]non-3-yl)-2-(1H-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-1 H-indol-3-yl)-1 -(1 ,3,3-trimethyl-6-aza-bicydo[3.2.1 ]oct-6-yl)-ethanone;
[3-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1 --indoI-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-indoIe-3-carboxylic acid ethyl ester;
5-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1 joctane-6-carbonyl) •IH-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) •1H-indole-3-carboxylic acid;
4-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl) ■IH-indole-3-carboxylic acid ethyl ester;
5-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl) •1/W-indole-3-carboxylic acid;
5-(1 ,3,3-Trimethyl-6-aza-bicycIo[3.2.1]octane-6-carbonyl) ■1 H-indoIe-3-carboxylic acid ethyl ester;
4-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1 ]octane-6-carbonyl) •1f.-indole-3-carboxylic acid;
4-(1 ,3,3-Trimethyl-6-a∑a-bicyclo[3.2.1 ]octane-6-carbonyl) ■1 H-indole-3-carboxylic acid ethyl ester;
[3-(Piperidine-1-carbonyl)-1/- -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)-1 H-indole-3-carboxylic acid cyanomethyl-amide;
5-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1r.-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)-1 H-indole-3-carboxylic acid allylamide;
5-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1 joctane-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)-1 H-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)-1ry-indole-3-carboxylic acid (tetra- hydro-furan-2-ylmethyl)-amide;
[3-(2-Methoxymethyl-pyrrolidine-1 -carbonyl)-1 --indol-5-yl]-(1 ,3,3-trimethyl-6-aza-bicyclo-
[3.2.1]oct-6-yl)-methanone; [3-(2,6-Dimethyl-morpholine-4-carbonyl)-1 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)-1r -indole-3-carboxylic acid (1,1- dioxo-tetrahydro-thiophen-3-yl)-amide;
5-(1,3,3-Trimethyl-6-aza-bicydo[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)-1H-indole-3-carboxylic acid 4- trifluoromethyl-benzylamide;
5-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1r -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)-1/- -indole-3-carboxylic acid (2H- tetrazol-5-ylmethyl)-amide;
[3-(1,3,3-Trimethyl-6-a∑a-bicyclo[3.2.1]octane-6-carbonyl)-1 --indol-5-yl]-(1,3,3-trimethyl-6- a∑a-bicyclo[3.2.1]oct-6-yl)-methanone;
3-{[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-carbonyl]-amino}- propionic acid ethyl ester;
5-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1 -/-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)-(1H-indol-5-yl)-methanone;
8-(1 -/-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-(1H-lndole-5-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;
(4-fer.-Butyl-piperidin-1-yl)-(1H-indol-5-yl)-methanone; 1 -(1 H-lndole-5-carbonyl)-4-phenyl-piperidine-4-carbonitrile; (1 H-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/- -lndol-5-yl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;
1H-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-1 .-indol-5-yl)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1 ]oct-6-yl)- methanone;
(3-Dimethylaminomethyl-1 H-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-bicycIo[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)-1/- -indol-3-yl]-pyrrolidine-
2,5-dione;
(3-Thiazol-2-yl-1 -/-indol-5-yI)-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; (3-lodo-1r.-indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
6-(1,3,3-Tri methyl-6-aza-b ιicyclo[3.2.1]octane-6-carbonyl)-1H- ndole-3-carbonitrile; methyl-6-aza-b ιicyclo[3.2.1]octane-6-carbonyl)-1H- ndoIe-3-carbonitrile; 6-(1 ,3,3-Tri methyl-6-aza-b ιicyclo[3.2.1]octane-6-carbonyl)-1H- ndole-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-carbonyI)-1 /-.-indol-7-ylj-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 -j,-indol-5-yl)-(1 ,3,3-trimethyl-6-a∑a-bicyclo[3.2.1]oct-6-yl)- methanone;
(1-methyl-1 .-indol-5-yl)-(1 ,3,3-trimethyI-6-aza-bicycIo[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-a∑a-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-a∑a-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-trimethyI-6-aza-bicyclo[3.2.1 ]oct-6-yl)-methanone;
[1-(Tetrahydro-furan-2-ylmethyl)-1 -/-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 -/-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-carbonyI)-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.
24. The combination according to claim 6 or 7 wherein the 11 ?-HSD1 inhibitor is of the For- mula (llg)
Figure imgf000251_0001
wherein
X is NR4, S or O;
R1 and R2 independently are hydrogen, halo, cyano, trihalomethyl, CrC6alkyl or CrCealkyloxy, wherein the alkyl groups independently are optionally substituted with one or more of R7;
R3 is hydrogen, CrC6alkyl, C3-Cι0cycloalkyl, d-C6alkyloxy, CrC6alkylthio, aryl, arylCrC6- alkyl, 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, hetarylCi -C6alkyl, aryld- C6alkyl, arylCrCealkyloxyCrCealkyl, C3-Cι0cycloalkyl, C3-Cι0hetcycloalkyl, C3-Cι0cyclo- alkylCrCealkyl, 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, d-C6alkyloxy, aryl, arylCrC6alkyl, aryloxy, aryld-Cealkyloxy, 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, CrC6alkyloxy, arylCrCealkyloxy, hetaryld- Cealkyloxy, CrC6alkyloxyCrC6aIkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrC6alkylcarbonyl, CrCealkylcarboxy, arylcarboxy or aryld- Cealkylcarboxy 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, CrC6alkyloxy, aryloxy, arylCrCealkyloxy, hetaryloxy or hetarylC C6alkyloxy;
R8 is hydrogen, CrC6alkyl, aryl, arylCrC6alkyl, hetarylalkyl, wherein the alkyl, aryl and hetarylalkyl groups independently are optionally substituted with one or more of R7;
R9 and R10 independently are hydrogen, CrC8alkyl, C3-Cι0cycloalkyl, C3-Cι0hetcycloalkyl, C3- Ci0cycloalkylCi-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 option- ally being substituted with at least one of C C8alkyl, arylCrC6alkyl, hetaryld-Cealkyl, hydroxy, cyano, CrC6alkyloxy, aryld-Cealkyloxy, hetarylCrCealkyloxy, CrCealkyloxyd- Cealkyl, 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-Cealkyl, aryl, arylCrC6alkyl, 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 mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
25. The combination according to claim 24 wherein the 11 -HSD1 inhibitor is of the For- mula (llg) wherein
X is NR4, S or O;
R1 and R2 independently are hydrogen, halo, cyano, trihalomethyl, d-C6alkyl or CrC6- alkyloxy, 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, d-C8alkyl, CrC6alkyloxyCrC6alkyl, aryl, hetaryl, aryld-Cealkyl, arylCi- CealkyloxyCi-Cealkyl, C3-Cι0cycloalkyl, C3-dohetcycloalkyl, C3-CιocycloalkylCrC6alkyl, 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, CrC6alkyloxy, aryl, arylCrC6alkyl, aryloxy, arylCrCealkyloxy, hetaryl, hetaryloxy or hetaryld-Cealkyloxy 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- Cealkyloxy, CrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-C6alkylcarboxy, arylcarboxy or aryld- Cealkylcarboxy 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, CrC8alkyl, CrC6alkyloxy, aryloxy or hetaryloxy;
R8 is hydrogen, CrC6alkyl, aryl, arylCrC6alkyI, 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.
26. The combination according to claim 24 or 25 wherein the 11 ?-HSD1 inhibitor is selected from the group (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)-thiazoI-5-yl]-(1,3,3-lrimethyl-6-aza-bicyclo[3.2.1]ocl-6- yl)-methanone;
(3-Aza-bicyclo[3.2.2]non-3-yl)-(2,4-dimethyl-thia∑ol-5-yl)-methanone;
(1 H-lrnida∑ol-4-yl)-(1 ,3,3-trimethyl-6-a∑a-bicyclo[3.2.1]oct-6-yl)-methanone ;
(3-Aza-bicyclo[3.2.2]non-3-yl)-(4-methyl-2-phenyl-thiazol-5-yl)-melhanone ;
2,4-Dimethyl-thiazole-5-carboxylic acid cycloheptylamide; A∑epan-1 -yl-(2,4-dimethyl-thia∑ol-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;
(1 -Methyl-1 H-imidazoI-4-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; [1-(6-Methyl-pyridin-2-yl)-1 H-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 mix- ture of optical isomers, including a racemic mixture, or any tautomeric forms.
27. The combination according to claim 1 wherein the 11 ?-HSD1 inhibitor is of the Formula (III):
Figure imgf000255_0001
Formula (III) wherein
R is C5-Ci0cycloalkyl, C5-Cι0hetcycloalkyl, aryl, hetaryl, arylCrC6alkyl or hetarylCrCealkyl, wherein the cycloalkyl, hetcycloalkyl, aryl, hetaryl and arylalkyl groups independently are optionally substituted with one or more of R7;
R2 and R3 independently are hydrogen, CrC6alkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrCealkyl, aryloxy, hetaryloxy, arylCrC6alkyloxy or hetarylCrC6aIkyloxy wherein the alkyl, aryl, hetaryl, arylalkyl and hetarylalkyl groups independently are optionally substituted with one or more of R8; or
R2 and R3 together with the carbon atom to which they are attached, 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-Cβalkyl, aryl, hetaryl, arylCrCealkyl, hetaryld-Ce- alkyl, hydroxy, oxo, Cι-C6alkyloxy, aryloxy, arylCrCealkyloxy or hetarylCrC6alkyloxy;
R4 and R5 independently are hydrogen, halo, hydroxy, d-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, CrCealkyloxy, aryl, hetaryl, aryloxyCrC6alkyl, aryloxyaryl, hetaryloxyaryl, aryloxyhetaryl, hetaryloxyhetaryl or arylCrCealkyloxyCrCealkyl wherein the alkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R9; or
R4 and R5 together with the carbon atoms to which they are attached, are forming a saturated, partially saturated or aromatic ring system containing from 5 to 8 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, aryld-Cealkyl, NR10R11, halo, trihalomethyl, trihalomethoxy, hydroxy, oxo, d-C6alkyloxy, arylCrCealkyloxy, CrC6alkyloxy- d-C6alkyl, d-C6alkylcarbonyI, arylcarbonyl, arylCrC6alkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy; or
R4 and either R2 or R3 together are forming a saturated or partially saturated bridge contain- ing from 1 to 4 carbon atoms, the bridge can optionally be substituted with at least one of Ci- Cealkyl, aryl, hetaryl, arylCi-Cealkyl or hetarylCrCealkyl;
R6 is hydrogen, CrC6alkyl, aryl, hetaryl, arylCrCealkyl or hetaryld-Cealkyl; or
R6 and either R4 or R5 together with the carbon atoms to which they are attached, are forming a saturated, partially saturated or aromatic ring system containing from 5 to 8 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, arylCrCealkyl, NR10R11, halo, trihalomethyl, trihalomethoxy, hydroxy, oxo, CrC6alkyloxy, aryICrC6alkyloxy, CrCealkyloxyCrCealkyl, d-Cealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, d- C6alkylcarboxy, arylcarboxy or arylCrC6alkylcarboxy;
R7 and R8 independently are hydrogen, halo, hydroxy, cyano, nitro, d-C6alkyl, d-C6alkyloxy, trihalomethyl, trihalomethoxy, aryloxy, hetaryloxy, arylCrCealkyloxy, hetaryld-Cealkyloxy, CrCealkyloxyCrCealkyl, aryIoxyCrC6alkyl, arylCrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrC6alkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetarylcarboxy, arylCrCealkylcarboxy or hetarylCrC6alkylcarboxy;
R9 is hydrogen, halo, hydroxy, cyano, CrC6alkyl, methylendioxo, trihalomethyl, trihalo- methoxy, aryl, arylCrC6aIkyl, aryloxy, NR10R11 or aryloxyCrC6alkyl, wherein the aryl group is optionally substituted with one or more of R12;
R10 and R11 independently are hydrogen, CrC6alkyl, aryl or aryICrC6alkyl wherein the alkyl and aryl groups independently are optionally substituted with one or more of R13; 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 sulfur, the ring system optionally being substituted with at least one of CrC6alkyI, aryl, hetaryl, aryld- C6alkyl, hydroxy, oxo, CrC6alkyloxy, arylCrCealkyloxy, CrCealkyloxyCrCealkyl, d- Cealkylcarbonyl, arylcarbonyl, arylCrC6alkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCi-C6alkyl-carboxy;
R12 is oxo or halo;
R13 is halo, hydroxy, cyano, d-C6alkyl, CrC6alkyloxy, NR14R15, methylendioxo, trihalomethyl, or trihalomethoxy;
R14 and R15 independently are hydrogen, d-Cealkyl, aryl, hetaryl, arylC C6alkyl or he-aryld- Cealkyl;
A is a single, double or triple bond;
X is a chemical bond, (CR16R17)n or NR10, wherein R16 and R17 independently are hydrogen, oxo or d-Cealkyl, or
X, together with either R2 or R3, is a double bond;
Y is CR18 or nitrogen, wherein R18 is hydrogen, CrC6alkyI, aryl, hetaryl, arylCι-C6alkyl or hetaryld-Cealkyl; or
R18 and either R2 or R3 together are forming a saturated or partially saturated cyclic ring system containg from 1 to 4 carbon atoms, the ring system can optionally be substituted with at least one of d-d-alky!, aryl, hetaryl, arylCrC6alkyl or hetaryld-Cealkyl; or
R18 with either R2 or R3 and either R4 or R5 together are forming a saturated or partially saturated cyclic ring system having one common carbon atom containing from 8 to 12 carbon atoms, the ring system can optionally be substituted with at least one of CrC6alkyl, aryl, hetaryl, aryld-C6alkyl or hetaryld-Cealkyl;
n is 0, 1 or 2; or
a salt thereof with a pharmaceutically acceptable acid or base, or optical isomer, mixture of optical isomers, racemic mixture, or tautomeric form thereof.
28. The combination according to claim 27 wherein the 11yff-HSD1 inhibitor is selected from the group:
3-(2-Bromo-phenyl)-6,7,8,9-tetrahydro-5H-[1 ,2,4]triazolo[4,3-a]azepine; 3-Phenyl-[1 ,2,4]triazolo[3,4-ajisoquinoline;
(2-Methoxy-benzyl)-(3-phenyl-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)-amine;
3-(2-Fluoro-phenyl)-5-(4-methoxy-phenoxy)-[1 ,2,4]triazolo[4,3-c]quinazoline;
3-Phenyl-6,7,8,9-tetrahydro-5H-[1 ,2,4]triazolo[4,3-a]azepine;
3-(4-Chloro-phenyl)-6,7,8,9-tetrahydro-5H-[1 ,2,4]triazolo[4,3-a]azepine; 3-(3-Chloro-phenyl)-6,7,δ,9-tetrahydro-5H-[1 ,2,4]triazolo[4,3-a]azepine;
3-(3,4-Dichloro-phenyl)-6,7,δ,9-tetrahydro-5H-[1 ,2,4]triazolo[4,3-a]azepine;
5,5-Dimethyl-3-thiophen-2-yl-5,6-dihydro-[1,2,4]triazolo[3,4-a]isoquinoline;
3-(2-Chloro-phenyl)-6,7,δ,9-tetrahydro-5H-[1 ,2,4]triazolo[4,3-a]azepine;
5,5-Dimethyl-3-(3,4,5-trimethoxy-phenyl)-5,6-dihydro-[1 ,2,4]triazolo[3,4-a]isoquinoline; 3-Furan-2-yl-5,5-dimethyl-5,6-dihydro-[1 ,2,4]triazolo[3,4-a]isoquinoline;
3-(3-Bromo-phenyl)-6,7,8,9-tetrahydro-5H-[1 ,2,4]triazolo[4,3-a]a∑epine;
3-(4-Bromo-phenyl)-5,5-dimethyl-5,6-dihydro-[1,2,4]tria∑olo[3,4-a]isoquinoline;
4-(5,5-Dimethyl-5,6-dihydro-[1 ,2,4]triazolo[3,4-a]isoquinolin-3-yl)-phenol;
3-(4-Methoxy-phenyl)-5,5,8,9-tetramethyl-5,6-dihydro-[1 ,2,4]triazolo[3,4-a]isoquinoline; 5,5-Dimethyl-3-phenyl-5,6-dihydro-[1 ,2,4]tria∑olo[3,4-a]isoquinoline;
3-(5,5-Dimethyl-5,6-dihydro-[1 ,2,4]tria∑olo[3,4-a]isoquinolin-3-yl)-phenol;
5,5-Dimethyl-3-p-tolyl-5,6-dihydro-[1 ,2,4]tria∑olo[3,4-a]isoquinoline;
5,5-Dimethyl-3-thiophen-2-yl-5,6-dihydro-[1 ,2,4]tria∑olo[3,4-a]isoquinoline;
7,10-Dimethoxy-5,5-dimethyl-3-phenyl-5,6-dihydro-[1,2,4]triazolo[3,4-a]isoquinoline; 3-(2,4-Dichloro-phenyl)-6,6-dimethyl-5,6,7,8-tetrahydro-[1 ,2,4]triazolo[4,3-a]pyrimidine;
2-(6,6-Dimethyl-5,6,7,8-tetrahydro-[1 ,2,4]triazolo[4,3-a]pyrimidin-3-yl)-phenol;
3-(2-Chloro-phenyl)-6,6-dimethyl-5,6,7,8-tetrahydro-[1 ,2,4]triazolo[4,3-a]pyrimidine;
4-Benzyl-3,5-di-p-tolyl-4H-[1 ,2,4]triazole;
3-p-Tolyl-6,7,8,9-tetrahydro-5H-[1 ,2,4]triazolo[4,3-ajazepine; 3-(4-Methoxy-phenyl)-6,7,8,9-tetrahydro-5H-[1 ,2,4]triazolo[4,3-a]azepine;
3-Pyridin-4-yl-6,7,8,9-tetrahydro-5H-[1 ,2,4jtriazolo[4,3-a]azepine;
3-(4-Bromo-phenyl)-6,7,8,9-tetrahydro-5H-[1 ,2,4]triazolo[4,3-a]azepine;
3-Furan-2-yl-5,5,8,9-tetramethyl-5,6-dihydro-[1 ,2,4]triazolo[3,4-a]isoquinoline;
6,6-Dimethyl-3-(2-nitro-phenyl)-5,6,7,8-tetrahydro-[1,2,4jtriazolo[4,3-a]pyrimidine; and 3-(2,4-Dichloro-phenyl)-5,5-dimethyl-5,6-dihydro-[1 ,2,4jtriazolo[3,4-a]isoquinoline; or a salt thereof with a pharmaceutically acceptable acid or base, or optical isomer, mixture of optical isomers, racemic mixture, or tautomeric form thereof.
29. The combination according to claim 27 wherein the 11 ?-HSD1 inhibitor is of the Formula (Ilia)
Figure imgf000259_0001
wherein R1 is aryl or hetaryl, wherein the aryl and hetaryl groups independently are optionally substituted with one or more of R7;
R2 and R3 together with the atoms to which they are connected forms a C5-Cι0cycloalkyl or C5-Cι0hetcycloalkyl, wherein the cycloalkyl and hetcycloalkyl rings independently are option- ally substituted with one or more of R8; or
R2 and R3 are connected to one of the following ring systems at the carbon atoms marked with an asterix (*)
Figure imgf000259_0002
Figure imgf000259_0003
wherein the ring systems independently are optionally substituted with one or more R8;
R7 is hydrogen, halo, hydroxy, cyano, nitro, CrC6alkyl, CrC6alkyloxy, trihalomethyl, trihalomethoxy, aryloxy, hetaryloxy, NR9R10, arylCrCealkyloxy, hetarylCi -C6alkyloxy, d- CealkyloxyCι-C6alkyl, aryloxyd-Cealkyl, arylCrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkylcarbonyl, hetarylCrC6alkylcarbonyI, CrCealkylcarboxy, arylcarboxy, hetarylcarboxy, arylCrCealkylcarboxy or hetarylCι-C6alkylcarboxy; R8 is hydrogen, CrC6alkyi, halo, aryl, hetaryl, arylCι-C6alkyl, NR9R10, trihalomethyl, trihalomethoxy, hydroxy, oxo, CrC6alkyloxy, aryloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, d- C6alkyloxyCrC6alkyl, CrC6alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, d- C6alkyIcarboxy, arylcarboxy or arylCrCealkylcarboxy;
R9 and R10 independently are hydrogen, CrC6alkyl, aryl or arylCrC6alkyl wherein the alkyl and aryl 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 sulfur, the ring system optionally being substituted with at least one of CrC6alkyl, aryl, hetaryl, aryld- C6alkyl, hydroxy, oxo, CrC6aIkyloxy, arylCrCealkyloxy, CrCealkyloxyCrCealkyl, C C6alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, d-Cealkylcarboxy, arylcarboxy or arylCrC6alkylcarboxy;
R11 is CrC6alkyl, oxo or halo;
X is (CR12R13)π, wherein R12 and R13 independently are hydrogen, oxo, hydroxy or C C6alkyI; and
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, or any tautomeric forms.
30. The combination according to claim 27 wherein the 11 ?-HSD1 inhibitor is of the Formula (Illb)
Figure imgf000260_0001
wherein R1 is aryl or hetaryl, wherein the aryl and hetaryl groups independently are optionally substituted with one or more of R7;
R7 is hydrogen, halo, hydroxy, cyano, nitro, CrC6alkyl, CrC6alkyloxy, trihalomethyl, triha- lomethoxy, aryloxy, hetaryloxy, NR9R10, arylCrCealkyloxy, hetarylCrCealkyloxy, d- Cealkyloxyd-Cealkyl, aryloxyCrC6alkyl, arylCrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrC6alkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetarylcarboxy, arylCrCealkylcarboxy or hetarylCrC6alkylcarboxy;
R9 and R10 independently are hydrogen, CrC6alkyl, aryl or arylCrC6alkyl wherein the alkyl and aryl 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 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 of CrC6alkyl, aryl, hetaryl, arylCrCealkyl, hydroxy, oxo, d-C6alkyloxy, aryld-Cealkyloxy, CrCealkyloxyCrCealkyl, d-Cealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, d-Cealkylcarboxy, arylcarboxy or arylCrC6a-
R .11 is CrC6alkyl, oxo or halo;
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.
31. The combination according to claim 29 or 30 wherein the 11 ?-HSD1 inhibitor is selected from the group:
3-(2-Bromo-phenyl)-6,7,8,9-tetrahydro-5H-[1 ,2,4]triazolo[4,3-a]azepine;
3-(2-Phenoxymethyl-phenyl)-5,6,7,8-tetrahydro-[1 ,2,4]triazolo[4,3-a]azepin-9-one; 3-(2-Phenoxymethyl-phenyl)-6,7,8,9,10,11-hexahydro-5/.-5,9:7,11-dimethano[1 ,2,4]tria- zo!o[4.3-a]azonine;
3-(5-Bromo-pyridin-3-yl)-6,7,8,9-tetrahydro-5H-[1 ,2,4]triazolo[4,3-ajazepine;
3-(5-Hex-1-ynyl-pyridin-3-yl)-6,7,8,9-tetrahydro-5H-[1 ,2,4]triazoIo[4,3-a]azepine;
3-(6-Chloro-pyridin-3-yl)-6,7,8,9-tetrahydro-5H-[1 ,2,4]triazolo[4,3-a]azepine; 3-(6-Morpholin-4-yl-pyridin-3-yl)-6,7,8,9-tetrahydro-5H-[1 ,2,4]triazolo[4,3-a]azepine; 3-Pyridin-3-yl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine;
3-(2-Benzyloxymethyl-phenyl)-6,7,8,9-tetrahydro-5H-5,9-methano[1 ,2,4]triazolo[4.3- ajazepine;
3-Phenyl-[1 ,2,4]triazolo[3,4-a]isoquinoline; or 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.
32. The combination according to claim 1 wherein the 11 ?-HSD1 inhibitor is of the Formula (IV):
Figure imgf000262_0001
wherein
R1 and R2 independently are hydrogen, CrC6alkyl, C3-Cι0cycloalkyl, C3-Cι0 het-cycloalkyl, aryl, hetaryl, arylCrC6aIkyl or hetarylCrCealkyl, wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R6; or
R1 and R2 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic or bicyclic ring system containing from 4 to 8 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system op- tionally being substituted with at least one of CrC6alkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrCealkyl, hydroxy, oxo, CrC6alkyl-oxy, arylCrCealkyloxy, hetarylCrC6aIkyloxy, CrCealkyloxyd-Cealkyl, CrC6alkyl-carbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, d- C6alkylcarboxy, arylcarboxy, hetarylcarboxy or aryld-C6alkylcarboxy;
R3 and R4 independently are hydrogen, d-Cealkyl, CrC6alkenyl, CrC6alkynyl, aryl, hetaryl, arylCrC6alkyl or hetarylCrCealkyl, wherein the alkyl, alkenyl, alkynyl, aryl, and hetaryl groups independently are optionally substituted with one or more of R7;
R5 is C3-Cιocycloalkyl, C3-Cιohetcycloalkyl, aryl or hetaryl, wherein the aryl, hetaryl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R8; or
R3 and R5 together with the carbon atoms 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, hetaryld-Cealkyl, hydroxy, oxo, CrC6alkyloxy, arylCrCealkyloxy, Cι-C6alkyloxyCr C6alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, d-C6alkyl- carboxy, aryl-carboxy, hetarylcarboxy or arylCrCealkylcarboxy; or
R2, R3 and R5 together with the atoms 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, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC6alkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrCealkyl, hydroxy, oxo, CrC6alkyl-oxy, arylCrCealkyloxy, CrCealkyloxyCrCealkyl, d-Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, CrC6alkylcarboxy, arylcarboxy, hetaryl-carboxy or arylCrC6alkylcarboxy;
R6 is hydrogen, hydroxy, oxo, halo, adamantyl, CrC6alkyI, CrC6alkyloxy, trihalomethyl, trihalomethoxy, NR9R10, arylCrCealkyloxy, d-C6alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, CrC6alkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
R7 and R8 independently are hydrogen, hydroxy, oxo, halo, cyano, nitro, NR9R10, CrC6alkyl, Cι-C6alkyloxy, aryl, hetaryl, arylCrCealkyloxy, hetarylCrCealkyloxy, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC6alkylcarbonyl, d-C6alkyl-carboxy, arylcarboxy or aryld- C6alkylcarboxy, wherein the aryl and hetaryl groups independently are optionally substituted with Qrdocycloalkyl or C3-d0hetcycloalkyl;
R9 and R10 independently are hydrogen, CrC6alkyl, C3-Cι0cycloalkyl, C3-Cι0 hetcycloalkyl, aryl, hetaryl, arylC C6alkyl or hetarylCrCealkyl; 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 5 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 CrC6alkyl, aryl, hetaryl, arylCrC6alkyl, hetaryld-Cealkyl, hydroxy, oxo, CrC6alkyloxy, arylCrCealkyloxy, CrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, d-Cealkylcarboxy, arylcarboxy, hetarylcarboxy or arylCrCealkylcarboxy; or a salt thereof with a pharmaceutically acceptable acid or base, or optical isomer, mixture of optical isomers, racemic mixture, or tautomeric form thereof.
33. The combination according to claim 32 wherein the 110-HSD1 inhibitor is selected from the group:
1 -Adamantan-1 -yl-2-morpholin-4-yl-ethanone;
1 -Adamantan-1 -yl-2-benzylamino-propan-1 -one;
1 -Adamantan-1 -yl-2-benzylamino-ethanone;
2-Pyrrolidin-1 -yl-1 -(3-p-tolyl-adamantan-l -yl)ethanone; 1 -Adamantan-1 -yl-2-morpholin-4-yl-propan-1 -one;
1 -[4-(5-Adamantan-1 -yl-[1 ,2,3]triazol-1 -yl)-phenyl]-2-phenylamino-ethanone;
6-Benzo[1 ,3]dioxol-5-yl-8-benzyl-8-aza-bicyclo[3.2.1 ]octan-2-one;
2--er--Butylamino-1 -(3-p-tolyl-adamantan-1 -yl)ethanone;
2-Morpholin-4-yl-1 -(3-p-tolyI-adamantan-1 -yl)ethanone; and 1 -Adamantan-1 -yl-2-[4-(4-nitro-phenyl)-piperazin-1 -yljethanone; or
a salt thereof with a pharmaceutically acceptable acid or base, or optical isomer, mixture of optical isomers, racemic mixture, or tautomeric form thereof.
34. The combination according to claim 1 wherein the 11/ff-HSD1 inhibitor is of the Formula (V):
Figure imgf000264_0001
Formula (V) wherein X is O or S;
R1 is hydrogen, CrC6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-Cι0cycloalkyl, arylCrC6alkyl, hetarylCrCealkyl, R4R5NcarbonylCrC6alkyl, arylcarbonylCrC6alkyl, hetarylcarbonyld- C6alkyl; wherein the alkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are option- ally substituted with one or more of R6; R2 is d-Cealkyl, d-C6aIkenyl, arylCrCealkyl, C3-Cι0cycloalkyl or hetarylCrCealkyl; wherein the alkyl, alkenyl, cycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R7;
R3 is C3-Ci0cycloalkyl, C3-Cι0hetcycloalkyl, aryl, hetaryl, arylCrCealkyl, hetarylCrC6alkyl, arylR8CrC6alkyl or hetarylR8CrC6alkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R9;
R4 and R5 independently are hydrogen, d-Cealkyl, C3-Cι0cycloalkyl, C5-C8hetcycloalkyl, aryl, hetaryl, arylCrC6alkyl or hetarylCrCealkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R11; or
R4 and R5 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, arylCrC6alkyl, hydroxy, oxo, CrC6alkyIoxy, arylCrCealkyloxy, CrCealkyloxyCrCealkyl, d-Cealkylcarbonyl, arylcarbonyl, arylCrC6alkyl-carbonyl, GrC6alkylcarboxy, arylcarboxy or aryld- C6alkylcarboxy;
R6, R7, R9 and R11 independently are hydrogen, halo, N02, NH2, cyano, NR4R5, CONR4R5, trihalomethyl, trihalomethoxy, hydroxy, oxo, d-Cealkyl, C3-Cι0cycloalkyl, C3-Cι0hetcycloalkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrCealkyl, CrC6alkylS02, R15R16NS02, CrC6alkyloxy, aryloxy, hetaryloxy, arylCrCealkyloxy, CrCealkylcarbonyl, arylcarbonyl, arylC C6alkylcarbonyl, arylcarbonylNR15, carboxyC Cealkyl or carboxyaryICrC6alkyl;
R8 is oxygen, NR10, C(=0)NR10 or SOnNR10; wherein n is 1 or 2;
R10 is hydrogen, CrC6alkyl, aryl, hetaryl, arylCrC6alkyl or hetarylCrCealkyl;
R15 and R16 independently are hydrogen, CrC6alkyl, C3-Cι0cycloalkyl, C5-C8hetcycloalkyl, aryl or hetaryl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl or hetaryl groups independently are optionally substituted with one or more of R11; or R15 and R16 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 8 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, aryld-Cealkyl, hydroxy, oxo, CrC6alkyloxy, aryld-Cealkyloxy, Cι-C6alkyloxyCrC6alkyl, CrCealkylcarbonyl, arylcarbonyl, arylCrC6alkylcarbonyl, CrC6alkylcarboxy, arylcarboxy or arylCrCealkylcarboxy; 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.
35. The combination according to claim 34 wherein the 11 ?-HSD1 inhibitor is of the Formula (V) wherein X is O or S;
R1 is hydrogen, CrC6alkyl, C2-C6alkenyl, C2-C6alkynyl, arylCrC6alkyl, hetarylCrCealkyl, NR4R5carbonylCr C6alkyl, arylcarbonylCrC6alkyl, hetarylcarbonylCrC6alkyl; wherein the alkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R6;
R2 is CrC6alkyl, d-C6alkenyl, arylCrC6alkyl or hetarylCrCealkyl; wherein the alkyl, alkenyl, aryl and hetaryl groups independently are optionally substituted with one or more of R7;
R3 is C5-C8cycloalkyl, C5-C8hetcycloalkyl, aryl, hetaryl, arylCrCealkyl, hetarylCrC6aIkyl, arylR8CrC6alkyl or hetarylR8CrC6alkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R9;
R4 and R5 independently are hydrogen, d-Cealkyl, C5-Cι0cycloalkyl, C5-C8hetcycloalkyl, aryl, hetaryl, arylCrC6alkyl or hetarylCrC6alkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R11; or
R4 and R5 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 CrC6alkyl, aryl, arylCrC6alkyl, hydroxy, oxo, d-Cealkyloxy, aryld-Cealkyloxy, CrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or aryld-Cealkylcarboxy;
R6, R7, R9 and R11 independently are hydrogen, halo, N02, NH2, cyano, trihalomethyl, trihalomethoxy, hydroxy, oxo, d-Cealkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrC6alkyl, S02NR15R16, CrCealkyloxy, aryloxy, hetaryloxy, aryld-Cealkyloxy, C C6alkylcarbonyl, arylcarbonyl, arylCrC6alkylcarbonyl, arylcarbonylNR15, carboxyCrC6alkyl or carboxyarylCi -Cealkyl;
R8 is oxygen, NR10, C(=0)NR1° or SOnNR10; wherein n is 1 or 2;
R10 is hydrogen, C Cealkyl, aryl, hetaryl, aryld-C6alkyl or hetarylCrCealkyl;
R15 and R16 independently are hydrogen, CrC6alkyl, C5-Cι0cycloalkyl, C5-C8hetcycloalkyl, aryl or hetaryl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl or hetaryl groups independently are optionally substituted with one or more of R11; or
R15 and R16 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 8 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, arylCι-C6alkyl, hydroxy, oxo, CrC6alkyloxy, arylCrCealkyloxy, CrCealkyloxyCrCealkyl, d-Cealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, CrC6alkylcarboxy, arylcarboxy or arylCrC6alkyl- carboxy; or
a salt thereof with a pharmaceutically acceptable acid or base, optical isomer, mixture of optical isomers, racemic mixture, or tautomeric form thereof.
36. The combination according to claim 34 or 35 wherein the 11 ?-HSD1 inhibitor is selected from the group:
3-(4-Allyl-5-mercapto-4H-[1 ,2,4]triazol-3-yl)-1 -(2,4-dichloro-benzyl)-1 H-pyridin-2-one; 4-Methyl-3-(4-methyl-2-phenyl-thiazol-5-yl)-5-prop-2-ynylsulfanyl-4H-[1,2,4]triazole; N-{1-[5-(4-tert-Butyl-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-ethyl}-4-chloro- benzenesulfonamide; 4-Methyl-3-methylsulfanyl-5-[3-(3-trifluoromethyl-benzyloxy)-thiophen-2-yl]-4H-[1,2,4]triazole;
N-(4-Chloro-phenyl)-2-(4-methyl-5-thiophen-3-ylmethyI-4H-[1,2,4]triazoI-3-ylsulfanyl)- acetamide;
2-[4-Methyl-5-(2-oxo-2-phenyl-ethylsulfanyl)-4H-[1,2,4]triazol-3-ylmethyl]-4H- benzo[1 ,4]thiazin-3-one;
3-(4-Fluoro-benzylsulfanyl)-5-(2-fluoro-phenyl)-4-methyl-4H-[1,2,4]triazole;
3-(2-Fluoro-phenyl)-4-methyl-5-(4-methyl-benzylsulfanyl)-4H-[1,2,4]triazole;
4-Methyl-3-(4-methyl-benzylsulfanyl)-5-(3-trifluoromethyl-phenyl)-4H-[1,2,4]triazole;
3-(2,4-Dichloro-phenyl)-4-furan-2-yImethyl-5-methylsulfanyl-4H-[1,2,4]triazole; 3-(4-tert-Butyl-phenyl)-5-(2,6-dichloro-benzylsulfanyl)-4-furan-2-ylmethyl-4H-[1,2,4]triazole;
4-Methyl-3-(4-methyl-benzylsulfanyl)-5-(5-methyl-isoxazol-3-yl)-4H-[1,2,4]triazole;
3-(3-Methoxy-benzylsulfanyl)-4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole;
3-(4-Fluoro-benzylsulfanyl)-4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole;
3-(4-tert-Butyl-benzylsulfanyl)-4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole; 4-Methyl-3-(2-methyl-benzylsulfanyl)-5-thiophen-2-yl-4H-[1,2,4]triazole;
2-(5-Benzylsulfanyl-4-methyl-4H-[1,2,4]triazol-3-ylmethyl)-4H-benzo[1,4]thiazin-3-one;
2-[5-(4-Chloro-ben∑ylsulfanyl)-4-methyl-4H-[1,2,4]tria∑ol-3-ylmethyl]-4H-ben∑o[1,4]thia∑in-3- one;
5-[5-(2,6-Dichloro-benzylsulfanyl)-4-methyl-4H-[1,2,4]tria∑ol-3-yl]-ben∑o[1 ,2,5]oxadia∑ole; 1 -(4-Chloro-phenyl)-2-[4-methyl-5-(4-trifluoromethyI-pyridin-3-yl)-4H-[1 ,2,4]triazol-3- ylsulfanylj-ethanone;
3-[5-(4-Chloro-benzylsulfanyl)-4-methyl-4H-[1,2,4]triazol-3-yl]-2-methyl-imidazo[1 ,2- ajpyridine;
3-[5-(2,4-Dichloro-benzylsulfanyl)-4-methyl-4H-[1,2,4]triazol-3-yl]-2,8-dimethyl-imidazo[1,2- ajpyridine;
4-Allyl-5-(2,4-dichloro-phenyl)-4H-[1,2,4]triazole-3-thiol;
3-(5-Allylsulfanyl-4-methyl-4H-[1 ,2,4]triazol-3-yl)-1 -benzyl-1 H-pyridin-2-one;
3-(4-Allyl-5-methylsulfanyl-4H-[1,2,4]triazol-3-yl)-1-(2,4-dichloro-benzyl)-1H-pyridin-2-one;
3-(4-Allyl-5-mercapto-4H-[1 ,2,4]triazol-3-yl)-1 -(4-chloro-benzyl)-1 H-pyridin-2-one; 3-(4-Allyl-5-prop-2-ynylsulfanyl-4H-[1 ,2,4]tria∑ol-3-yl)-1 -(4-chloro-ben∑yl)-1 H-pyridin-2-one;
3-(5-Allylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-yl)-1-(2,4-dichloro-benzyl)-1H-pyridin-2-one;
1-(2,4-Dichloro-benzyl)-3-[4-ethyl-5-(2-oxo-2-phenyl-ethylsulfanyl)-4H-[1,2,4jtriazol-3-yl]-1H- pyridin-2-one;
3-(4-Allyl-5-prop-2-ynylsulfanyl-4H-[1,2,4]triazol-3-yl)-1-(3,4-dichloro-benzyl)-1H-pyridin-2- one; 4-Allyl-5-(4-methyl-2-phenyl-thiazoI-5-yl)-4H-[1 ,2,4]triazole-3-thiol;
3-Allylsulfanyl-4-methyl-5-(4-methyl-2-phenyl-thiazol-5-yl)-4H-[1 ,2,4]triazole;
4-Allyl-5-[2-(3,4-dimethoxy-phenyl)-thiazol-4-yl]-4H-[1 ,2,4]triazole-3-thiol;
N-[5-(4-tert-Butyl-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylmethyl]-4-methyl- benzenesulfonamide;
4-Methyl-3-[3-(4-methyl-benzyloxy)-thiophen-2-yl]-5-methylsulfanyl-4H-[1 ,2,4]triazole;
5-[3-(2,4-Dichloro-benzyloxy)-thiophen-2-ylj-4-methyl-4H-[1 ,2,4]triazole-3-thiol;
3-[3-(2,4-Dichloro-benzyloxy)-thiophen-2-yl]-4-methyl-5-methylsulfanyI-4H-[1 ,2,4jtriazole;
4-Methyl-5-[3-(3-trifluoromethyl-benzyloxy)-thiophen-2-yl]-4H-[1 ,2,4]triazole-3-thiol; 2-(5-Benzyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-iodo-phenyl)-acetamide;
3-(5-Allylsulfanyl-4-methyl-4H-[1 ,2,4]triazol-3-yl)-2,7-dimethyl-imidazo[1 ,2-a]pyridine;
3-(5-Benzylsulfanyl-4-methyl-4H-[1 ,2,4]triazol-3-yl)-2,7-dimethyl-imidazo[1 ,2-a]pyridine;
3-(5-BenzyIsulfanyl-4-methyl-4H-[1 ,2,4]triazol-3-yl)-2-methyl-imidazo[1 ,2-a]pyridine;
4-Butyl-5-(3-chloro-phenyl)-4H-[1 ,2,4]triazole-3-thiol; 4-Allyl-5-(3-chloro-phenyl)-4H-[1 ,2,4]triazole-3-thiol;
N-(5-{2-[5-(4-Methoxy-phenyl)-3-thiophen-2-yl-4,5-dihydro-pyrazol-1-yl]-2-oxo-ethylsulfanyl}-
4-methyl-4H-[1,2,4]tria∑ol-3-ylmethyl)-ben∑amide;
N-(5-{2-[3,5-Bis-(4-methoxy-phenyl)-4,5-dihydro-pyra∑ol-1-yl]-2-oxo-ethylsulfanyl}-4-methyl-
4H-[1 ,2,4]triazol-3-ylmethyl)-3-methoxy-ben∑amide; N-(5-{2-[5-(4-Methoxy-phenyl)-3-thiophen-2-yl-4,5-dihydro-pyrazol-1-yl]-2-oxo-ethylsulfanyl}-
4-methyl-4H-[1 ,2,4]triazol-3-ylmethyl)-4-(pyrrolidine-1-sulfonyl)-benzamide;
N-(5-{2-[5-(4-Methoxy-phenyl)-3-thiophen-2-yl-4,5-dihydro-pyra∑ol-1-yl]-2-oxo-ethylsulfanyl}-
4-methyl-4H-[1 ,2,4]triazol-3-ylmethyl)-4-(piperidine-1-sulfonyl)-benzamide;
N-(5-{2-[5-(4-Methoxy-phenyl)-3-thiophen-2-yl-4,5-dihydro-pyrazol-1-yl]-2-oxo-ethylsulfanyl}- 4-methyl-4H-[1 ,2,4]triazol-3-ylmethyl)-4-(morpholine-4-sulfonyl)-benzamide;
4-Benzyl-3-(4-fluoro-naphthalen-1-ylmethylsulfanyl)-5-phenyl-4H-[1 ,2,4]triazole;
2-[4-Allyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1 -naphthalen-1 -yl-ethanone;
1 -(4-Fluoro-phenyl)-4-(4-methyl-5-phenyI-4H-[1 ,2,4]triazol-3-ylsulfanyl)-butan-1 -one
2-(4-Methyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(5,6,7,8-tetrahydro-naphthalen-2-yl)- ethanone;
5-(2-Carbazol-9-yl-ethyl)-4-(2-methyl-allyl)-4H-[1,2,4]triazole-3-thiol;
1-(4-Methoxy-phenyl)-2-[4-(2-methyl-allyl)-5-phenyl-4H-[1 ,2,4jtriazol-3-ylsulfanyl]-ethanone;
2-{2-[4-Allyl-5-(3-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetylamino}-benzoic acid methyl ester; 5-(2,4-DichIoro-phenyl)-4-(2-methyl-allyl)-4H-[1 ,2,4]triazole-3-thiol; 4-Allyl-3-(4-methoxy-benzylsulfanyl)-5-(3-methoxy-phenyl)-4H-[1,2,4]triazole;
2-[4-Allyl-5-(3-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsuIfanyl]-1-(9H-fluoren-2-yl)-ethanone;
3-(4-Methoxy-benzylsulfanyl)-4-methyl-5-phenyl-4H-[1 ,2,4]triazoIe;
2-[4-Allyl-5-(3-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(4-ethyl-phenyl)-ethanone; 2-(4-Allyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-chloro-phenyl)-acetamide;
2-[4-AIIyl-5-(4-tert-butyl-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(4-chloro-phenyl)-ethanone;
2-(4-Allyl-5-phenylaminomethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2,4-difluoro-phenyl)- acetamide;
2-(4-Allyl-5-phenoxymethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-methoxy-phenyl)-ethanone; 2-(4-Allyl-5-phenoxymethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-bromo-phenyl)-ethanone;
(4-Allyl-5-benzylsulfanyl-4H-[1 ,2,4]triazol-3-ylmethyl)-phenyl-amine;
2-(4-Allyl-5-ben∑otria∑ol-1 -ylmethyl-4H-[1 ,2,4]tria∑ol-3-ylsulfanyl)-1 -(4-methoxy-phenyl)- ethanone;
2-(4-Allyl-5-phenylaminomethyI-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-chloro-phenyl)-acetamide; 1-(4-Methoxy-phenyl)-2-[4-(2-methyl-allyl)-5-phenyl-4H-[1 ,2,4]triazol-3-yIsulfanyl]-ethanone;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]tria∑ol-3-ylsulfanyl]-N-(4-methyl-3-nitro-phenyl)- acetamide;
[5-(2-Methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetic acid isopropyl ester;
N-(4-Chloro-phenyl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylj- acetamide;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-methoxy-phenyl)- acetamide;
N-(3-Cyano-4,5,6,7-tetrahydro-ben∑o[b]thiophen-2-yl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-
[1 ,2,4]tria∑ol-3-ylsulfanyl]-acetamide; N-(4-AcetyI-phenyl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-acetamide;
4-[5-(2,6-Dichloro-benzylsulfanyl)-4-furan-2-ylmethyl-4H-[1 ,2,4]triazol-3-yl]-pyridine;
N-(4-Methyl-3-nitro-phenyl)-2-[4-methyi-5-(3,4,5-trimethoxy-phenyl)-4H-[1 ,2,4]triazol-3- ylsulfanylj-acetamide;
N-(3-Cyano-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-2-(4-furan-2-ylmethyl-5-pyridin-4-yl- 4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-[2-(4-Ethyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetylamino]-benzoic acid methyl ester;
2-(4-Methyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-thiazoI-2-yl-acetamide;
N-(4-Chloro-phenyl)-2-(4-ethyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(4-Ethoxy-phenyl)-2-(4-ethyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide; 2-(4-Ethyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-nitro-phenyl)-acetamide; 2-(5-Benzyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyI)-N-(4-bromo-phenyl)-acetamide;
2-{5-[(2,6-Dimethyl-phenylamino)-methyl]-4-methyI-4H-[1 ,2,4]triazol-3-yIsulfanyl}-1-phenyl- ethanone;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-fluoro-phenyl)-acetamide; 2-[4-Ethyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1 -(4-methoxy-phenyl)- ethanone;
N-(4-lodo-2-methyl-phenyl)-2-[5-(2-methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanylj- acetamide;
2-(5-BenzyI-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyI)-1-(3,4-dihydro-2H-quinolin-1-yl)- ethanone;
N-(2-Bromo-4-methyl-phenyl)-2-(4-furan-2-ylmethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3- ylsulfanyl)-acetamide;
N-(4-Chloro-phenyl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(3-trifluoromethyl-phenyl)- acetamide;
2-[5-[(4-Fluoro-phenylamino)-methyl]-4-(tetrahydro-furan-2-ylmethyl)-4H-[1 ,2,4]triazol-3- ylsulfanyl]-1 -p-tolyl-ethanone;
2-(5-Methyl-4-phenethyI-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-naphthalen-1-yl-acetamide;
N-(5-Ethyl-[1 ,3,4]thiadiazol-2-yl)-2-(5-methyl-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyI)- acetamide;
2-(5-Methyl-4-phenethyl-4H-[1 ,2,4]tria∑ol-3-ylsulfanyl)τN-phenyl-acetamide;
[5-(4-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]tria∑ol-3-ylsulfanyl]-acetic acid cyclohexyl ester;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]tri ai zol-3-ylsulfanyl]-N-(3-chloro-phenyl)-acetamide;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]tri ai zol-3-ylsulfanyl]-N-(4-chloro-phenyl)-acetamide; 2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]tri ai zol-3-ylsulfanyl]-N-m-tolyl-acetamide;
N-(3-Cyano-4,5,6,7-tetrahydro-benzo[b]thi oι phen-2-yl)-2-[5-(4-hydroxy-phenyl)-4-methyl-4H-
[1 ,2,4]triazol-3-ylsulfanyl]-acetamide;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-methyl-4-nitro-phenyl)-acetamide;
3-Ben∑ylsulfanyl-4-methyl-5-phenyl-4H-[1 ,2,4]triazole; 3-Butylsulfanyl-5-(4-methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazole;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-ethoxy-phenyl)-acetamide;
N-(4-Acetyl-phenyl)-2-(4-benzyl-5-pyridin-3-yl-4H-[1 ,2,4]tria∑oI-3-ylsulfanyl)-acetamide;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2,4-dimethyl-phenyl)-acetamide;
N-(3-Nitro-phenyl)-2-(4-phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide; 2-(4-Phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazoI-3-ylsulfanyl)-N-phenyl-acetamide; N-Naphthalen-1-yl-2-(4-phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetic acid cyclohexyl ester;
1-(3,4-Dihydro-2H-quinolin-1-yl)-2-(4-ethyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone;
N-(3-Cyano-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3- ylsulfanyl)-acetamide;
2-[5-(4-Methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-phenyl-ethanone;
3-Benzylsulfanyl-5-(4-methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazole;
2-(4,5-Dibenzyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-thiazol-2-yl-acetamide;
2-(4-Phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-m-tolyl-acetamide; 2-(4-Phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-phenyl-propionamide;
3-(5-Benzylsulfanyl-4-phenethyl-4H-[1 ,2,4]triazol-3-yl)-pyridine;
(4-Phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetic acid ethyl ester;
2-(4-Phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -phenyl-ethanone;
2-(4-PhenethyI-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-p-tolyl-propionamide; 1-(3,4-Dihydro-2H-quinolin-1-yl)-2-{4-ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-
[1 ,2,4]tria∑ol-3-ylsulfanyl}-ethanone;
2-[5-(3,4-Dimethoxy-phenyl)-4-methyl-4H-[1 ,2,4]tria∑ol-3-ylsulfanyl]-1 -p-tolyl-ethanone;
N-(3-Chloro-2-methyl-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(4-Ethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N,N-diphenyl-propionamide; 2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-nitro-phenyl)-acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-methyl-3-nitro-phenyI)-acetamide;
N-(2-Bromo-4-methyl-phenyl)-2-(4-ethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)- acetamide;
1-(3,4-Dihydro-2H-quinolin-1-yl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)- ethanone;
N-(4-Fluoro-phenyl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(4-Acetyl-phenyl)-2-(5-benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-chloro-phenyl)-acetamide;
N-(3-Chloro-2-methyl-phenyl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylj- acetamide;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(2-methyl-4-nitro-phenyl)- acetamide;
2-[5-(2-Methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-p-tolyl-propionamide;
[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetic acid ethyl ester; 2-(4-Methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-nitro-phenyl)-acetamide; 2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-naphthalen-1-yl- propionamide;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4jtriazol-3-ylsulfanyl]-N-p-tolyl-propionamide;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-N-phenyl-propionamide; 2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-phenyl-thiazol-2-yl)- acetamide;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-p-tolyl-acetamide;
N-(3-Chloro-4-methyl-phenyl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide; 2-[5-(4-Hydroxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-nitro-phenyl)-acetamide;
4-{2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetylamino}-benzoic acid ethyl ester;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-o-tolyl-acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-chIoro-phenyl)-acetamide; 2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(4-methoxy-2-nitro-phenyl)- acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(2-methyl-4-nitro-phenyl)- acetamide;
1-(3,4-Dihydro-2H-quinolin-1-yl)-2-{5-[(2,4-dimethyl-phenylamino)-methyl]-4-ethyl-4H- [1 ,2,4]triazol-3-ylsulfanyl}-ethanone;
N-(4-Chloro-3-nitro-phenyl)-2-[5-(4-chloro-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylj- acetamide;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(3,4-dihydro-2H-quinolin-1-yl)- ethanone; 2-(5-Benzyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -p-tolyl-ethanone;
2-(4-Benzyl-5-pyri d( in-3-yl-4H-[1 ,2,4]tri azol-3-ylsulfanyl)-N-(4-methoxy-phenyl)-acetamide;
2-(4-Benzyl-5-pyri dι in-3-yl-4H-[1 ,2,4]tri azol-3-ylsulfanyl)-N-(2-chloro-phenyl)-acetamide;
2-(4-Benzyl-5-pyri d( in-3-yl-4H-[1 ,2,4]tri azol-3-ylsulfanyl)-N-(5-ethyl-[1 ,3,4]thiadiazol-2-yl)- acetamide; 4-{2-[5-(2-Bromo-phenyl)-4-ethyI-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetylamino}-ben∑oic acid methyl ester;
2-(5-Ben∑yl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(2-nitro-phenyl)-acetamide;
2-(5-Benzyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-cyano-4,5,6,7-tetrahydro- benzo[b]thiophen-2-yl)-acetamide; 2-[5-(4-Chloro-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(2-nitro-phenyl)-acetamide; (5-Benzylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylmethyl)-(4-chloro-phenyl)-amine;
N-(2-Methoxy-phenyl)-2-[5-(2-methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
2-(4-Allyl-5-pyridin-4-yI-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3,4-dichloro-phenyl)-acetamide; 2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-p-tolyl-acetamide;
2-(5-Benzyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(4-chloro-phenyl)-acetamide;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-methoxy-phenyl)-acetamide;
N-(5-Chloro-2-methyl-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4]tria∑ol-3-ylsulfanyl)-acetamide;
N-(4-Methoxy-phenyl)-2-(4-methyI-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide; N-(2,4-Dimethyl-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(4-Ethoxy-phenyl)-2-(4-methyl-5-o-tolyI-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
4-[2-(4-Methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetylamino]-ben∑oic acid methyl ester;
N-(4-Chloro-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-[5-(4-Hydroxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-phenyl-thiazol-2-yl)- acetamide;
2-(5-Benzyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-bromo-4-methyl-phenyl)-acetamide;
2-(5-Ben∑yl-4-methyl-4H-[1 ,2,4]tria∑ol-3-ylsulfanyl)-1-phenyI-ethanone;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-nitro-phenyl)-acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4jtriazol-3-ylsulfanyl)-N-p-tolyl-acetamide; 2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-ethoxy-phenyl)- acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-naphthalen-1-yl-acetamide;
4-[5-(4-tert-Butyl-ben∑ylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-yl]-pyridine;
4-[5-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-pyridine; 2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-methyl-4-nitro-phenyl)-acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]tria∑ol-3-ylsulfanyl)-N-(3-trifluoromethyl-phenyl)-acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-fluoro-phenyl)-acetamide;
4-{2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetylamino}-benzoic acid methyl ester; N-(3-Chloro-phenyl)-2-(5-cyclohexyI-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4jtriazol-3-ylsulfanyl)-N-(4-ethoxy-phenyl)-acetamide;
2-{5-[(4-Chloro-phenylamino)-methyl]-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl}-N-(2-nitro- phenyl)-acetamide;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-chloro-2-methyl-phenyl)-acetamide; 2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-phenyl-acetamide; 3-Benzyl-5-(2-chloro-6-fluoro-benzylsulfanyl)-4-methyI-4H-[1 ,2,4]triazole;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-nitro-phenyl)-acetamide;
2-[5-(4-Hydroxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-phenyl-ethanone;
4-[5-(4-Chloro-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazol-3-yl]-phenol; 2-(5-Ben∑yl-4-ethyl-4H-[1 ,2,4]triazol-3-yIsulfanyl)-N-(4-fluoro-phenyl)-acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-methoxy-phenyl)-ethanone;
2-(5-Benzyl-4-ethyI-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-bromo-phenyl)-acetamide;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-phenyl-acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-nitro-phenyl)-propionamide; 2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-trifluoromethyl-phenyl)-acetamide;
{5-[(3-Chloro-4-methyl-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4jtriazol-3-ylsulfanyl}-acetic acid cyclohexyl ester;
3-[5-(2,4-Dichloro-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazol-3-yl]-pyridine;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-phenyl-acetamide; N-(3-Chloro-4-methyl-phenyl)-2-[5-(4-hydroxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanylj- acetamide;
N-(4-Chloro-phenyl)-2-[5-(4-hydroxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
3-Benzyl-5-(4-chloro-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazole; 2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-nitro-phenyl)-acetamide;
N-(4-Ethoxy-phenyl)-2-[5-(4-hydroxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-methoxy-phenyl)- acetamide; {5-[(4-Chloro-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-acetic acid cyclohexyl ester;
3-BenzyIsuIfanyl-5-(2-methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazole;
N-(2-Chloro-phenyl)-2-(4-methyl-5-m-tolyl-4H-[1 ,2,4]tria∑ol-3-ylsulfanyl)-acetamide;
N-(2-Methoxy-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4]tria∑ol-3-ylsulfanyl)-acetamide; 2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]tria∑ol-3-ylsulfanyl)-N-phenyl-acetamide;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(3-nitro-phenyl)-acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-1-(3,4-dihydro-2H-quinolin-1- yl)-ethanone;
2-(5-Benzyl-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(2-bromo-4-methyl-phenyl)-acetamide; N-(2-Chloro-phenyl)-2-[5-(2-methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
(5-Benzylsulfanyl-4-ethyl-4H-[1,2,4]triazol-3-yImethyl)-(3-trifluoromethyl-phenyl)-amine;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-1-(4-methoxy-phenyl)- ethanone;
[4-Allyl-5-(3-bromo-ben∑ylsulfanyl)-4H-[1,2,4]triazol-3-ylmethyl]-phenyl-amine;
2-(4-Furan-2-ylmethyl-5-pyridin-4-yl-4H-[1,2,4]triazoI-3-ylsulfanyl)-1-(3-nitro-phenyl)- ethanone;
1-(4-Bromo-phenyl)-2-(4-furan-2-ylmethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)- ethanone;
4-{5-[2-(2-Methoxy-phenoxy)-ethylsulfanyl]-4-methyl-4H-[1 ,2,4]triazol-3-yl}-phenylamine;
4-[5-(4-Chloro-benzylsulfanyl)-4-methyl-4H-[1,2,4]triazol-3-yl]-phenylamine;
[4-Allyl-5-(1,3-dioxo-1H,3H-benzo[de]isoquinolin-2-ylmethyl)-4H-[1,2,4]triazol-3-ylsulfanylj- acetic acid ethyl ester; 2-{4-Allyl-5-[(4-chloro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1 -phenyl- ethanone;
5-(3-Bromo-phenyl)-4-(2-methyl-allyl)-4H-[1,2,4]lriazole-3-thiol;
2-(4-Allyl-5-ben∑otriazol-1-ylmethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(4-chloro-phenyl)- acetamide; 1 -(4-Fluoro-phenyl)-2-(4-methyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-ethanone;
8-(4-Methyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-5-nitro-quinoline;
3-(2-Bromo-benzylsulfanyl)-4-methyI-5-(4-nitro-phenyl)-4H-[1,2,4]triazole;
2-[4-Allyl-5-(3-methoxy-phenyl)-4H-[1,2,4]tria∑ol-3-ylsulfanyl]-1-(2,4-dimethyl-phenyl)- ethanone; 1 -(4-Bromo-phenyl)-2-(5-furan-2-yl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-ethanone;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(5-methyl-thiazol-2-yl)- acetamide;
2-[4-Ethyl-5-(p-tolylamino-methyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-1-p-tolyl-ethanone;
2-(5-Benzyl-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(4-ethyl-phenyl)-acetamide; 2-(5-Benzyl-4-ethyI-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -(4-methoxy-phenyl)-ethanone;
2-(5-Benzyl-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(5-ethyI-[1,3,4]thiadiazol-2-yl)-acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-1 -p-tolyl-ethanone;
3-(2-Bromo-phenyl)-4-methyl-5-(4-nitro-benzylsulfanyl)-4H-[1,2,4]triazole;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]tria∑ol-3-ylsulfanyl]-N-(4-phenyl-thiazol-2-yl)- acetamide; 2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(2,4-dimethyl-phenyl)- acetamide;
N-(4-Bromo-phenyl)-2-[5-(2-bromo-phenyl)-4-ethyl-4H-[1,2,4]tria∑ol-3-ylsulfanyl]-acetamide;
2-{5-[(2,4-Dimethyl-phenylamino)-methyl]-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl}-1-(4-methoxy- phenyl)-ethanone;
2-{5-[(2,4-Dimethyl-phenylamino)-methyl]-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl}-1-p-tolyl- ethanone;
{5-[(2,4-Dimethyl-phenylamino)-methyl]-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl}-acetic acid cyclohexyl ester; 2-{5-[(4-Fluoro-phenylamino)-methyl]-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl}-1 -phenyl- ethanone;
2-{4-Ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1-(4-methoxy- phenyl)-ethanone;
[4-Ethyl-5-(4-methyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylmethylj-(4-fluoro-phenyl)-amine; (5-Benzylsulfanyl-4-ethyl-4H-[1,2,4]triazol-3-ylmethyl)-(4-fluoro-phenyl)-amine;
{4-Ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-acetic acid cyclohexyl ester;
N-(4-Chloro-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-acetamide; iSI-(4-Acetyl-phenyl)-2-(5-cyclohexyl-4-ethyl-4H-[1 ,2,4]tria∑ol-3-ylsulfanyl)-acetamide; 2-[4-Ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-methyl-3-nitro-phenyl)- acetamide;
N-Cyclohexyl-2-(4-phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(2,4-Dimethyl-phenyl)-2-[4-furan-2-ylmethyl-5-(4-hydroxy-phenyl)-4H-[1,2,4]triazol-3- ylsulfanylj-acetamide; 4-[2-(5-Cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetylamino]-ben∑oic acid ethyl ester;
2-[4-Furan-2-ylmethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]tria∑ol-3-ylsulfanyl]-N-(4-methyl-3-nitro- phenyl)-acetamide;
3-lsobutylsulfanyl-4-methyl-5-p-tolyl-4H-[1,2,4]tria∑ole; 2-[2-(4-Methyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetylamino]-benzoic acid methyl ester;
2-{4-Ethyl-5-[4-(morpholine-4-sulfonyl)-phenyl]-4H-[1 ,2,4]triazol-3-ylsulfanyi}-1-p-tolyl- ethanone;
4-Methyl-3-phenethylsulfanyl-5-p-tolyl-4H-[1,2,4]triazole; 2-(4-Benzyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-p-tolyl-acetamide; 2-(4-Benzyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(4-nitro-phenyl)-acetamide;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-phenyl-acetamide;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(3-chloro-phenyl)-acetamide;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-yIsulfanyl)-N-(4-nitro-phenyl)-propionamide; 2-(4-Benzyl-5-pyridin-3-yl-4H-[1,2,4jtriazol-3-ylsulfanyl)-N-(2,5-dichloro-phenyl)-acetamide;
N-(3-ChIoro-phenyl)-2-(4-phenethyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(4-Nitro-phenyl)-2-(4-phenethyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-propionamide;
N-(2-Bromo-4-methyl-phenyI)-2-[5-(3,4-dimethoxy-phenyl)-4-methyl-4H-[1,2,4]triazol-3- ylsulfanylj-acetamide; 2-{4-Ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1,2,4]triazol-3-ylsulfanyl}-N-(4-nitro-phenyl)- acetamide;
3-Benzylsulfanyl-5-cydohexyl-4-ethyl-4H-[1,2,4]triazole;
[5-(4-Hydroxy-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-acetic acid cyclohexyl ester;
2-(5-Cyclohexyl-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)- acetamide;
N-(3-Chloro-4-methyl-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-
3Cθl3mi θ
[4-Benzyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetic acid ethyl ester;
3-Ben∑ylsulfanyl-4-methyl-5-(3,4,5-trimethoxy-phenyl)-4H-[1,2,4]tria∑ole; N-(2-Chloro-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetamide;
N-(2,4-Dimethoxy-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(5-Cyclohexyl-4-methyl-4H-[1,2,4]tria∑ol-3-ylsulfanyl)-N-(2-methyl-4-nitro-phenyl)- acetamide;
2-(5-CyclohexyI-4-methyl-4H-[1,2,4jtriazol-3-ylsulfanyl)-1-phenyl-ethanone; 3-Cyclohexyl-4-methyl-5-(4-methyl-ben∑ylsulfanyl)-4H-[1,2,4]triazole;
N-(2-Bromo-phenyl)-2-(5-cyclohexyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(5-Cyclohexyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(4-iodo-2-methyI-phenyl)- acetamide;
N-(3-Cyano-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-2-(5-cyclohexyl-4-methyl-4H- [1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(4-Acetyl-phenyl)-2-(5-cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(5-Cyclohexyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(4-methoxy-phenyl)-acetamide;
N-(4-Chloro-phenyl)-2-(5-cyclohexyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(5-Cyclohexyl-4-methyl-4H-[1,2,4jtriazol-3-ylsulfanyl)-N-phenyl-acetamide; 2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4jtriazol-3-ylsulfanyl]-N-(2-methoxy-4-nitro-phenyl)- acetamide;
N-(3-Cyano-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-2-[5-(2-methoxy-phenyl)-4-methyl-4H-
[1 ,2,4]triazol-3-ylsulfanyl]-acetamide; N-(4-Bromo-phenyl)-2-(5-cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-[4-Ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-phenyl-acetamide;
N-(3-Chloro-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetamide;
N-(4-Acetyl-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetamide;
N-(4-Bromo-phenyl)-2-[4-ethyI-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetamide; 2-[4-Ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-iodo-2-methyl-phenyl)- acetamide;
N-(2,4-Dimethyl-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylj- acetamide;
4-[5-(4-Chloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-phenol; [4-Ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetic acid cyclohexyl ester;
2-[5-(2-Methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-phenyl-thiazol-2-yl)- acetamide;
N-(3-Chloro-phenyl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acelamide; 2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(2-nitro-phenyl)-acetamide;
2-[4-Methyl-5-(4-nitro-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-phenyl-ethanone;
N-(4-Bromo-phenyl)-2-{4-ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3- ylsulfanylj-acetarnide;
N-(4-Chloro-phenyl)-2-{4-ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1,2,4]triazol-3- ylsulfanylj-acetamidβ;
2-{4-Ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-N-(2-nitro-phenyl)- acetamide;
1-(4-Methoxy-phenyl)-2-[4-methyl-5-(4-nitro-phenyl)-4H-[1 ,2,4jtria∑ol-3-ylsulfanyl]-ethanone;
[5-(4-Chloro-ben∑ylsulfanyl)-4-ethyl-4H-[1 ,2,4]tria∑ol-3-ylmethyl]-(4-fluoro-phenyl)-amine; 2-{4-Ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1-p-tolyl-ethanone;
2-{4-EthyI-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-N-(4-methyl-3- nitro-phenyl)-acetamide;
N-(2-Bromo-4-methyl-phenyl)-2-{4-ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-
3-ylsulfanyl}-acetamide; 4-Allyl-5-(3-bromo-phenyl)-4H-[1 ,2,4]triazole-3-thiol; N-(2-Nitro-phenyl)-2-(4-phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-{4-Ethyl-5-[4-(piperidine-1 -sulfonyl)-phenylj-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1 -p-tolyl- ethanone;
2-{4-Ethyl-5-[4-(piperidine-1 -sulfonyl)-phenyl]-4H-[1 ,2,4]triazoI-3-ylsulfanyl}-1 -phenyl- ethanone;
N-Biphenyl-2-yl-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-chloro-4-methyl-phenyl)- acetamide;
N-(2-Bromo-phenyl)-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide; 4-Benzyl-5-cyclohexyl-4H-[1 ,2,4]triazole-3-thiol;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -phenyl-ethanone;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-1 -phenyl-ethanone;
(5-Benzyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetic acid cyclohexyl ester;
4-Methyl-3-(4-nitro-benzylsulfanyl)-5-phenyl-4H-[1 ,2,4jtriazole; 2-(4-Methyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -p-tolyl-ethanone;
2-(4-Methyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-phenyl-ethanone;
3-Benzylsulfanyl-4-methyl-5-(naphthalen-2-yloxymethyl)-4H-[1 ,2,4]lriazole;
2-(5-Cyclohexyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-p-tolyl-acetamide;
3-Benzylsulfanyl-5-cyclohexyl-4-methyl-4 H-[1 ,2, .jtria∑ole; 2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-chloro-3-nitro-phenyl)-acetamide;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-methyl-3-nitro-phenyl)-acetamide;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]tria∑ol-3-ylsulfanyl)-N-(2-methoxy-4-nitro-phenyl)-acetamide;
N-(2-Bromo-4-methyl-phenyl)-2-(4-methyl-5-phenyl-4H-[1 ,2,4jtriazol-3-ylsulfanyl)-acetamide;
3-BenzyIsulfanyl-4-ethyl-5-(4-nitro-phenyl)-4H-[1,2,4jtria∑ole; 4-Ethyl-3-(4-methyl-ben∑ylsulfanyl)-5-(4-nitro-phenyl)-4H-[1 ,2,4]triazole;
2-[4-Ethyl-5-(4-nitro-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-p-tolyl-ethanone;
3-(4-Chloro-benzylsulfanyl)-4-ethyl-5-(4-nitro-phenyl)-4H-[1 ,2,4]triazole;
2-[4-Ethyl-5-(4-nitro-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylj-1-phenyl-ethanone;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(3,4-dimethyl-phenyl)- acetamide;
(2,4-Dimethyl-phenyl)-[4-ethyl-5-(4-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylmethyl]-amine
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(4-methyl-3-nitro-phenyl)- acetamide;
2-(4-Methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-trifluoromethyl-phenyl)-acetamide; 2-[5-[(2,4-Dimethyl-phenylamino)-methyl]-4-(tetrahydro-furan-2-ylmethyl)-4H-[1,2,4]triazol-3- ylsulfanyl]-1 -p-tolyl-ethanone;
4-[5-(2,6-Dichloro-benzylsulfanyl)-4-(tetrahydro-furan-2-ylmethyl)-4H-[1 ,2,4]triazol-3-yl]- pyridine; 3-Benzylsulfanyl-5-(4-chloro-phenoxymethyl)-4-ethyl-4H-[1 ,2,4]triazole;
3-Butylsulfanyl-4-methyl-5-p-tolyl-4H-[1 ,2,4]triazole;
1-(5-Chloro-2-methoxy-phenyl)-2-(4-methyl-5-p-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-ethanone;
1-(4-Chloro-phenyI)-2-(4-methyl-5-p-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-ethanone;
N-(2,4-Dimethoxy-phenyl)-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide; 2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-methyl-4-nitro-phenyl)-acetamide;
N-(4-Ethoxy-phenyl)-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(4-Ethyl-phenyl)-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-thiazol-2-yl-acetamide;
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -phenyl-ethanone; 2-(4-Ethyl-5-phenyl-4H-[1 ,2,4jtriazol-3-ylsulfanyl)-1 -p-tolyl-ethanone;
2-(4-EthyI-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-nitro-phenyl)-acetamide;
N-(3-Chloro-phenyl)-2-(4-ethyl-5-phenyl- _H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(2-Chloro-phenyl)-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-[5-(2-Hydroxy-phenyl)-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-piperidin-1-yl-ethanone; 2-[5-(2-Morpholin-4-yl-ethyIsulfanyl)-4-phenethyl-4H-[1 ,2,4]triazol-3-yl]-phenol;
N-(2-Methyl-4-nitro-phenyl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)- acetamide;
N-(2-Methyl-5-nitro-phenyl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)- acetamide; N-(4-Bromo-phenyl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(3-Nitro-phenyl)-2-(4-phenethyl-5-pyridin-4-yI-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-fluoro-phenyl)-acetamide;
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-methoxy-4-nitro-phenyl)-acetamide;
N-(2,5-Dichloro-phenyl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
2-(5-Cyclohexyl-4-methyl-4H-[1 ,2,4jtriazol-3-ylsulfanyl)-N-(3-nitro-phenyl)-acetamide;
2-[4-Benzyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(2-methyl-4-nitro-phenyl)- acetamide;
2-(4-Phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-trifluoromethyl-phenyl)- acetamide; [4-Furan-2-ylmethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazoI-3-ylsulfanyl]-acetic acid cyclohexyl ester;
2-[4-Furan-2-ylmethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-phenyl-ethanone;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanylj-N-(2-ethyl-phenyl)-acetamide; 2-(5-Cyclohexyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(3,4-dichloro-phenyl)-acetamide;
2-(5-Cyclohexyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-1-(4-methoxy-phenyl)-ethanone;
2-(4-Benzyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyI)-N-(4-methoxy-2-nitro-phenyI)-acetamide;
2-(4-Benzyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(5-methyI-thiazol-2-yl)-acetamide;
2-(4-Benzyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-thiazoI-2-yl-acetamide; 2-(4,5-Dibenzyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(4-nitro-phenyl)-acetamide;
2-(4-Benzyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(2-nitro-phenyl)-acetamide;
3-Benzylsulfanyl-5-(4-bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazole;
2-[4-Ethyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4jtriazol-3-ylsulfanyl]-N-(4-methyl-3-nitro-phenyl)- acetamide; 2-[4-Ethyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1 -phenyl-ethanone;
2-(4-Benzyl-5-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-1 -phenyl-ethanone;
2-(5-Methyl-4-phenethyl-4H-[1 ,2,4]tria∑ol-3-ylsulfanyl)-N-p-tolyl-acetamide;
2-(5-Methyl-4-phenethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(3-trifluoromethyl-phenyl)- acetamide; N-(3-Chloro-phenyl)-2-(5-methyl-4-phenethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(4-Chloro-phenyl)-2-(5-methyl-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyI)-acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]tria∑ol-3-ylsulfanyl]-N-(2-methoxy-4-nitro-phenyl)- acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-nitro-phenyl)-acetamide; N-(2,3-Dichloro-phenyl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanylj- acetamide;
N-(2,3-Dichloro-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanylj- acetamide;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(4-methoxy-phenyl)- ethanone;
2-[4-Benzyl-5-(2-hydroxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyI]-1 -piperidin-1 -yl-ethanone;
2-[4-Benzyl-5-(2-hydroxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-N-p-tolyl-acetamide;
2-{5-[(2,4-Dimethyl-phenylamino)-methyl]-4-furan-2-ylmethyl-4H-[1,2,4]triazol-3-ylsulfanyl}-1- phenyl-ethanone; 2-(4-Methyl-5-m-tolyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-p-tolyl-acetamide; 4-{4-Ethyl-5-[4-(piperidine-1-sulfonyl)-phenyl]-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl}- benzonitrile;
N-(2-Methoxy-phenyl)-2-(4-methyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(4-Acetyl-phenyl)-2-(4-ethyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide; 2-(4-Ethyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-methyl-3-nitro-phenyl)-acetamide;
2-[5-(4-Amino-phenyl)-4-methyI-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(4-nitro-phenyl)-ethanone;
N-{4-[5-(2-Chloro-benzylsulfanyl)-4-methyI-4H-[1 ,2,4]triazol-3-yl]-phenyl}-2-methoxy- benzamide;
2-(4-Allyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-fluoro-phenyl)-ethanone; 2-(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-fluoro-phenyl)-acetamide;
2-[5-(4-Amino-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-1-(4-nitro-phenyl)-ethanone;
2-(4-Allyl-5-thiophen-2-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-chloro-phenyl)-acetamide;
(4-Benzyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetic acid ethyl ester;
4-[5-(4-tert-Butyl-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazoI-3-yl]-pyridine; 2-{5-[(3-Chloro-phenylamino)-methylj-4-ethyl-4H-[1,2,4jtriazol-3-ylsulfanyl}-1 -phenyl- ethanone;
{5-[(2-ChIoro-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-acetic acid isopropyl ester;
2-[4-Ethyl-5-(4-methoxy-phenoxymethyl)-4H-[1 ,2,4]tria∑ol-3-ylsulfanyl]-1 -phenyl-ethanone; 1 -(4-Chloro-phenyl)-2-{5-[(2-chloro-phenylamino)-methyl]-4-ethyI-4H-[1 ,2,4]triazol-3- ylsulfanyl}-ethanone;
4-[5-(2-Chloro-6-fluoro-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazol-3-yl]-pyridine
3-Benzyl-5-benzylsulfanyl-4-ethyl-4H-[1 ,2,4]triazole;
3-Benzylsulfanyl-4-methyl-5-o-tolyl-4H-[1 ,2,4]triazole; N-(4-Chloro-3-nitro-phenyl)-2-(4-methyl-5-o-toIyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(4-Methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-p-tolyl-ethanone;
1-(4-Methoxy-phenyl)-2-(4-methyI-5-o-toIyl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone;
[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetonitrile;
[5-(2-Hydroxy-phenyl)-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetonitrile; 1 -[5-(2-Hydroxy-phenyl)-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-propan-2-one;
N-(2,3-Dichloro-phenyl)-2-[4-furan-2-ylmethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazoi-3- ylsulfanylj-acetamide;
N-(3-Chloro-phenyl)-2-[4-furan-2-ylmethyl-5-(2-methoxy-phenyl)-4H-[1,2,4]triazol-3- ylsulfanylj-acetamide; N-(4-Chloro-phenyl)-2-[4-furan-2-ylmethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3- ylsulfanylj-acetamide;
2-[5-(4-Methoxy-phenoxymethyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1 -phenyl-ethanone;
2-{5-[(2-Chloro-phenylamino)-methyl]-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl}-1-piperidin-1-yl- ethanone;
2-[5-(4-Methoxy-phenoxymethyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(4-methoxy- phenyl)-ethanone;
N-(2,3-Dichloro-phenyl)-2-[4-furan-2-ylmethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3- ylsulfanylj-acetamide; 2-[4-Furan-2-ylmethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(4-methoxy- phenyl)-ethanone;
{5-[(2-Chloro-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-acetic acid cyclohexyl ester;
2-(4-Phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-thiazol-2-yl-acetamide; 2-(4-Ethyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-nitro-phenyl)-acetamide;
2-(4-EthyI-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-methoxy-phenyl)-acetamide;
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-trifluoromethyl-phenyl)-acetamide;
2-[4-Furan-2-ylmethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]tria∑ol-3-ylsulfanyl]-N-(2-methyl-4- nitro-phenyl)-acetamide; N-(3-Chloro-2-methyl-phenyl)-2-[4-furan-2-ylmethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3- ylsulfanylj-acetamide;
4-AIIyl-5-m-tolyl- 4 H-[1 ,2,4]tria∑ole-3-thiol;
4-(2-Methyl-allyl)-5-m-tolyl-4H-[1 ,2,4]tria∑ole-3-thiol;
2-[4-Allyl-5-(3-bromo-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-ethyl-phenyl)-acetamide; 4-Allyl-3-(3-bromo-phenyl)-5-(2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
2-[4-Allyl-5-(3-bromo-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-biphenyl-4-yl-ethanone;
4-(2-Methyl-allyl)-5-(3-nitro-phenyl)-4H-[1 ,2,4jtriazole-3-thiol;
4-AllyI-5-(2-carbazol-9-yl-ethyl)-4H-[1 ,2,4]triazole-3-thiol;
5-(4-Bromo-phenyl)-4-(2-methyl-allyl)-4H-[1 ,2,4]tria∑ole-3-thiol; 4-(2-Methyl-allyl)-5-(3-methyl-2-nitro-phenyl)-4H-[1 ,2,4]triazole-3-thiol;
5-(4-Methoxy-phenyl)-4-(2-methyI-allyl)-4H-[1 ,2,4]triazole-3-thiol;
2-(4-Allyl-5-benzotriazol-1-ylmethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-bromo-phenyl)- acetamide;
2-(4-Allyl-5-benzotriazol-1-ylmethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-pyridin-2-yl-acetamide; {4-Aliyl-5-[3-(1 ,3-dioxo-1 H,3H-benzo[de]isoquinolin-2-yl)-propyl]-4H-[1 ,2,4]triazol-3- ylsulfanyl}-acetic acid ethyl ester; and 4-Allyl-5-(4-phenyl-piperazin-1 -ylmethyl)-4H-[1 ,2,4]triazole-3-thiol; or
a salt thereof with a pharmaceutically acceptable acid or base, or optical isomer, mixture of optical isomers, racemic mixture, or tautomeric form thereof.
37. The combination according to claim 34 or 35 wherein the 11 ?-HSD1 inhibitor is selected from the group: 4-[2-(4-Ethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)ethyl]morpholine;
1-Benzothiazol-2-yl-2-(4-ethyl-5-phenyl-4/- -[1 ,2,4]triazol-3-ylsulfanyl)-ethanone;
Λ/-Cyclohexyl-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-Λ/-methyl-acetamide;
2-(4-Ethyl-5-phenyl-4 -/-[1 ,2,4]triazol-3-ylsulfanyl)-1-phenyl-ethanone;
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-methoxy-phenyl)-ethanone; 2-(4-Ethyl-5-phenyl-4 - -[1 ,2,4]triazoI-3-ylsulfanyl)-1-pyridin-3-yl-ethanone;
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-methanesulfonyl-phenyl)-ethanone;
2-(4-Phenethyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-1 -phenyl-ethanone;
1-(4-Methoxy-phenyl)-2-(4-phenethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-ethanone;
2-(4-Phenethyl-5-phenyl-4H-[1 ,2,4]tria∑oI-3-ylsulfanyl)-1-pyridin-3-yl-ethanone; 1 -(4-MethanesulfonyI-phenyl)-2-(4-phenethyl-5-phenyI-4H-[1 ,2,4]triazol-3-ylsulfanyl)- ethanone;
2-(4-Ethyl-5-pyri« n-4-yl-4H-[1 ,2,4]tri a∑ol-3-ylsulfanyl)-1-phenyl-ethanone;
2-(4-Ethyl-5-pyri« n-4-yl-4H-[1 ,2,4] a∑ol-3-ylsulfanyl)-1-(4-methoxy-phenyl)-ethanone;
2-(4-Ethyl-5-pyriι n-4-yl-4H-[1 ,2,4]tri azol-3-ylsulfanyl)-1-pyridin-3-yl-ethanone; 2-(4-Ethyl-5-pyriι n-4-yl-4H-[1 ,2,4]tri azol-3-ylsulfanyl)-1-(4-methanesulfonyl-phenyl)- ethanone;
2-(4-Phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-phenyl-ethanone;
1-(4-Methoxy-phenyl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-ethanone;
2-(4-Phenethyl-5-pyridin-4-yl-4/-/-[1 ,2,4]triazol-3-ylsulfanyl)-1-pyridin-3-yl-ethanone; 1-(4-Methanesulfonyl-phenyl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)- ethanone;
2-(4-Ethyl-5-furan-2-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-phenyl-ethanone;
2-(4-Ethyl-5-furan-2-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-methoxy-phenyl)-ethanone;
2-(4-Ethyl-5-furan-2-yl-4H-[1)2,4]triazol-3-ylsulfanyl)-1-pyridin-3-yI-ethanone; 2-(4-Ethyl-5-furan-2-yl-4H-[1 ,2,4]tria∑ol-3-ylsulfanyl)-1-(4-methanesulfonyl-phenyl)-ethanone; 2-(5-Furan-2-yI-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -phenyl-ethanone;
2-(5-Furan-2-yl-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-methoxy-phenyl)-ethanone;
2-(5-Furan-2-yl-4-phenethyI-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-pyridin-3-yl-ethanone;
2-(5-Furan-2-yl-4-phenethyI-4 -.-[1 ,2,4jtriazol-3-ylsulfanyl)-1-(4-methanesulfonyI-phenyl)- ethanone;
1 -Adamantan-1 -yl-2-(4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-ethanone;
3-[5-(2-Chloro-ben∑ylsulfanyl)-4-ethyl-4H-[1 ,2,4]tria∑ol-3-yl]-propan-1-ol;
4-[4-Ethyl-5-(3-hydroxy-propyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile;
3-[5-(6-Chloro-benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-propan-1-ol; 3-[5-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-propan-1 -ol;
3-(5-Cyclohexylmethylsulfanyl-4-ethyl-4/--[1 ,2,4]triazol-3-yl)-propan-1-ol;
3-[4-Ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-propan-1-ol;
3-(5-Benzylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-yl)-propan-1-ol;
3-[4-Ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-propan-1-ol; 3-[4-Ethyl-5-(3-nitro-benzylsulfanyl)-4/.-[1 ,2,4]triazol-3-yl]-propan-1-ol;
3-[5-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-propan-1-ol;
3-[4-Ethyl-5-(3-trifluoromethoxy-ben∑ylsulfanyl)-4H-[1 ,2,4]tria∑ol-3-yl]-propan-1-ol;
N-{4-[4-Ethyl-5-(3-hydroxy-propyI)-4H-[1 ,2,4]tria∑ol-3-yIsulfanylmethyl]-phenyl}-acetamide;
3-[4-Ethyl-5-(5-methyl-2-nitro-ben∑ylsulfanyl)-4H-[1 ,2,4]tria∑ol-3-yl]-propan-1-ol; 3-[4-Ethyl-5-(2-nitro-ben∑ylsulfanyl)-4/-/-[1 ,2,4]triazol-3-yl]-propan-1-ol;
4-[4-Ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile;
4-[5-(6-Chloro-ben∑o[1 ,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-4H-[1 ,2,4]tria∑ol-3-yl]-phenol;
4-[5-(4-Bromo-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-phenol;
4-[4-Ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1 ,2,4]triazoI-3-yl]-phenol; 4-(5-Benzylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-yl)-phenol;
4-[4-Ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol;
4-[4-Ethyl-5-(3-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol;
4-[4-Ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazoI-3-ylsulfanylmethyl]-benzoic acid methyl etser; 4-[5-(4-Benzyloxy-benzylsulfanyl)-4-ethyl-4 -/-[1 ,2,4]triazol-3-yl]-phenol;
N-{4-[4-Ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazoI-3-ylsulfanylmethyI]-phenyl}-acetamide;
4-[4-Ethyl-5-(4-methoxy-ben∑ylsulfanyl)-4/- -[1 ,2,4]tria∑ol-3-yl]-phenoI;
4-[4-Ethyl-5-(5-methyl-2-nitro-ben∑ylsulfanyl)-4H-[1 ,2,4]tria∑ol-3-yl]-phenol;
4-[4-Ethyl-5-(2-nitro-benzylsulfanyI)-4 -.-[1 ,2,4]triazol-3-yl]-phenol; 4-[5-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-yl]-phenol; 3-Benzo[1 ,3]dioxol-5-yl-5-(2-chloro-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazole;
4-(5-Benzo[1 ,3]dioxol-5-yl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzonitrile;
3-Benzo[1,3]dioxol-5-yl-5-(6-chloro-benzo[1,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-4H-
[1 ,2,4]triazole; 3-Benzo[1 ,3]dioxol-5-yl-5-(4-bromo-benzyIsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
4-[4-(5-Benzo[1,3]dioxol-5-yl-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-phenylj-
[1 ,2,3]thiadiazole;
3-Benzo[1 ,3]dioxol-5-yl-5-cyclohexylmethylsulfanyl-4-ethyl-4H-[1,2,4]triazole;
3-Benzo[1 ,3]dioxol-5-yl-4-ethyl-5-(4-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]triazole; 3-Benzo[1 ,3]dioxol-5-yl-5-(3,5-dimethoxy-benzylsulfanyl)-4-ethyl-4 .-[1 ,2,4]triazole;
3-Benzo[1 ,3]dioxol-5-yl-4-ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4 - -[1 ,2,4]triazole;
4-(5-Benzo[1 ,3]dioxol-5-yl-4-ethyl-4 -/-[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzoic acid methyl etser;
3-Ben∑o[1 ,3]dioxol-5-yl-5-(2,6-dichloro-ben∑ylsulfanyl)-4-ethyl-4H-[1,2,4]triazole; 3-Benzo[1 ,3]dioxol-5-yl-5-(4-benzyloxy-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
N-[4-(5-Benzo[1 ,3]dioxol-5-yl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-phenyl]-acetamide;
3-Benzo[1 ,3]dioxol-5-yl-4-ethyl-5-(4-methoxy-benzylsulfanyl)-4H-[1 ,2,4]tria∑ole;
3-Ben∑o[1 ,3]dioxol-5-yl-4-ethyl-5-(5-methyl-2-nitro-ben∑ylsulfanyl)-4H-[1 ,2,4]tria∑ole;
3-Ben∑o[1 ,3]dioxol-5-yl-4-ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole; 3-Benzo[1 ,3]dioxol-5-yl-5-(2,4-dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
4-[4-Ethyl-5-(2-phenoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile;
3-(6-Chloro-benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-5-(2-phenoxy-phenyl)-4H-
[1 ,2,4]tria∑ole;
3-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-5-(2-phenoxy-phenyl)-4H-[1 ,2,4]triazole; 3-(4-Bromo-ben∑ylsulfanyl)-4-ethyl-5-(2-phenoxy-phenyl)-4H-[1 ,2,4]triazole;
4-{4-[4-Ethyl-5-(2-phenoxy-phenyl)-4 .-[1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}-
[1 ,2,3]thiadiazole;
3-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-5-(2-phenoxy-phenyl)-4 y-[1 ,2,4]triazole;
4-Ethyl-3-(2-phenoxy-phenyl)-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1 ,2,4]triazole; 4-Ethyl-3-(4-methanesulfonyl-benzylsulfanyl)-5-(2-phenoxy-phenyl)-4 - -[1 ,2,4jtriazole;
4-[4-Ethyl-5-(2-phenoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl etser;
3-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-5-(2-phenoxy-phenyl)-4H-[1 ,2,4]triazole;
3-(4-Benzyloxy-benzylsulfanyl)-4-ethyl-5-(2-phenoxy-phenyl)-4 -/-[1,2,4]triazole; 4-Ethyl-3-(4-methyl-benzylsulfanyl)-5-(2-phenoxy-phenyl)-4H-[1 ,2,4]triazole; 4-Ethyl-3-(2-phenoxy-phenyl)-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1,2,4]triazole;
4-Ethyl-3-(4-methoxy-benzylsulfanyl)-5-(2-phenoxy-phenyl)-4H-[1,2,4]triazole;
4-Ethyl-3-(2-nitro-benzylsulfanyl)-5-(2-phenoxy-phenyl)-4/- -[1,2,4jtriazole;
3-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-5-(2-phenoxy-phenyl)-4H-[1,2,4]triazole; 3-CyclohexyImethylsulfanyl-4-ethyl-5-naphthalen-1 -yl-4/-/-[1 ,2,4]triazole;
4-Ethyl-3-naphthalen-1-yl-5-(4-trifluoromethyl-benzylsulfanyl)-4 --[1,2,4]triazole;
4-Ethyl-3-(4-methanesulfonyl-benzylsulfanyl)-5-naphthalen-1-yl-4 -.-[1,2,4]triazole;
4-Ethyl-3-naphthalen-1-yl-5-(3-nitro-benzylsulfanyl)-4H-[1,2,4]triazole;
4-(4-Ethyl-5-naphthalen-1-yl-4 -/-[1,2,4]triazol-3-ylsulfanylmethyl)-benzoic acid methyl etser; 4-Ethyl-3-naphthalen-1-yl-5-(4-nitro-benzylsulfanyl)-4H-[1,2,4jtriazole;
3-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-5-naphthalen-1-yl-4H-[1,2,4]triazole;
4-Ethyl-3-(4-methyI-benzylsulfanyl)-5-naphthalen-1-yl-4H-[1,2,4]tria∑ole;
4-Ethyl-3-(4-methoxy-ben∑ylsulfanyl)-5-naphthalen-1-yl-4H-[1,2,4]triazole;
4-Ethyl-3-(5-methyl-2-nitro-benzylsulfanyl)-5-naphthalen-1-yl-4H-[1,2,4]triazole; 3-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-5-naphthalen-1 -yl-4H-[1 ,2,4]triazole;
[4-(5-Cyclohexylmethylsulfanyl-4-ethyl-4H-[1,2,4]triazol-3-yl)-phenyl]-dimethyl-amine
{4-[5-(3,5-Dimethoxy-ben∑ylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-yl]-phenyl}-dimethyl-amine
{4-[4-Ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1 ,2,4]tria∑ol-3-yl]-phenyl}-dimethyl-amine
4-[5-(4-Dimethylamino-phenyl)-4-ethyl-4H-[1,2,4]tria∑ol-3-ylsulfanylmethyl]-ben∑oic acid methyl etser;
{4-[4-Ethyl-5-(4-nitro-benzylsulfanyl)-4H-[1,2,4]tria∑oI-3-yl]-phenyl}-dimethyl-amine;
{4-[4-Ethyl-5-(4-methoxy-benzylsulfanyl)-4H-[1,2,4]tria∑ol-3-yl]-phenyl}-dimethyl-amine;
{4-[4-Ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-phenyl}-dimethyl-amine;
{4-[5-(2,4-Dichloro-benzylsulfanyl)-4-ethyI-4H-[1,2,4]triazol-3-ylj-phenyl}-dimethyl-amine; 4-(4-Ethyl-5-thiophen-2-yl-4H-[1 ,2,4]tria∑ol-3-ylsulfanylmethyl)-ben∑onitrile;
3-(6-Chloro-benzo[1,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazole;
3-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazole;
3-(4-Bromo-benzylsulfanyl)-4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazole;
4-[4-(4-Ethyl-5-thiophen-2-yl-4H-[1 ,2,4]tria∑ol-3-ylsulfanylmethyl)-phenyl]-[1,2,3]thiadia∑ole; 4-Ethyl-3-thiophen-2-yl-5-(4-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-5-thiophen-2-yI-4f.-[1,2,4jtriazole;
4-Ethyl-3-thiophen-2-yl-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-Benzylsulfanyl-4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazole;
4-Ethyl-3-(4-methanesulfonyl-benzylsulfanyl)-5-thiophen-2-yl-4H-[1,2,4]triazole; 4-(4-Ethyl-5-thiophen-2-yl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzoic acid methyl etser; 4-Ethyl-3-(4-nitro-benzylsulfanyl)-5-thiophen-2-yl-4 --[1,2,4]triazole;
3-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-5-thiophen-2-yl-4/--[1,2,4]triazole;
4-Ethyl-3-(4-methyl-benzylsulfanyl)-5-thiophen-2-yl-4/-/-[1,2,4]triazole;
4-Ethyl-3-(4-methoxy-benzylsulfanyl)-5-thiophen-2-yl-4H-[1,2,4]triazole; 4-Ethyl-3-(5-methyl-2-nitro-benzylsulfanyl)-5-thiophen-2-yl-4H-[1,2,4]triazole;
3-(2-Chloro-benzylsulfanyl)-4-ethyI-5-(2-methoxy-phenyI)-4H-[1,2,4]triazole;
3-(6-ChIoro-benzo[1,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-5-(2-methoxy-phenyl)-4H-
[1 ,2,4]triazole;
4-Ethyl-3-(2-methoxy-phenyl)-5-(4-trifluoromethoxy-benzylsulfanyl)-4H-[1,2,4]triazole; 3-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-5-(2-methoxy-phenyl)-4H-[1,2,4jtriazole;
4-Ethyl-3-(2-methoxy-phenyl)-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1,2,4]triazole;
3-Benzylsulfanyl-4-ethyl-5-(2-methoxy-phenyI)-4H-[1,2,4]triazole;
4-Ethyl-3-(4-methanesulfonyl-benzylsulfanyl)-5-(2-methoxy-phenyl)-4H-[1,2,4]triazole;
4-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl et- ser;
4-Ethyl-3-(2-methoxy-phenyl)-5-(4-nitro-benzylsulfanyl)-4H-[1,2,4]tria∑ole;
3-(2,6-DichIoro-ben∑ylsulfanyl)-4-ethyl-5-(2-methoxy-phenyl)-4H-[1,2,4]tria∑ole;
3-(4-Benzyloxy-benzylsulfanyl)-4-ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazole;
4-Ethyl-3-(2-methoxy-phenyl)-5-(4-methyl-ben∑ylsulfanyl)-4H-[1,2,4]tria∑ole; 4-Ethyl-3-(2-methoxy-phenyl)-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1,2,4]triazole;
4-Ethyl-3-(2-methoxy-phenyl)-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-[1,2,4]triazole;
4-Ethyl-3-(2-methoxy-phenyl)-5-(2-nitro-benzylsulfanyl)-4H-[1,2,4]tria∑ole;
3-(2-Chloro-ben∑ylsulfanyl)-4-ethyl-5-(4-methoxy-phenyl)-4 -/-[1,2,4]tria∑ole;
4-[4-Ethyl-5-(4-methoxy-phenyl)-4H-[1,2,4]tria∑ol-3-ylsulfanylmethyl]-ben∑onitrile; 3-(6-Chloro-ben∑o[1,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-5-(4-methoxy-phenyl)-4H-
[1 ,2,4]triazole;
3-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]tria∑ole;
3-(4-Bromo-benzylsulfanyl)-4-ethyl-5-(4-methoxy-phenyl)-4/--[1,2,4]triazole;
4-{4-[4-Ethyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}- [1,2,3]thiadiazole;
3-Cyclohexylmethylsulfanyl-4-ethyl-5-(4-methoxy-phenyl)-4H-[1,2,4]triazole;
4-Ethyl-3-(4-methoxy-phenyl)-5-(4-trifluoromethyl-benzylsulfanyl)-4/-/-[1,2,4]triazole;
4-Ethyl-3-(4-methanesulfonyl-benzylsulfanyl)-5-(4-methoxy-phenyl)-4H-[1,2,4]triazole;
4-[4-Ethyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethylj-benzoic acid methyl et- ser; 3-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazole;
3-(4-Benzyloxy-benzylsulfanyl)-4-ethyl-5-(4-methoxy-phenyl)-4/-/-[1 ,2,4]triazole;
4-Ethyl-3-(4-methoxy-phenyl)-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]tria∑ole;
N-{4-[4-Ethyl-5-(4-methoxy-phenyl)-4 - -[1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}-acetamide; 4-Ethyl-3-(4-methoxy-benzylsulfanyl)-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazole;
4-Ethyl-3-(4-methoxy-phenyl)-5-(2-nitro-benzylsulfanyl)-4 -/-[1 ,2,4]triazole;
4-(4-Ethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzonitrile;
4-[5-(4-Bromo-benzylsulfanyl)-4-ethyl-4/-/-[1 ,2,4]triazol-3-yl]-pyridine;
4-[5-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-yl]-pyridine; 4-[4-Ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-pyridine;
4-(4-Ethyl-5-pyridin-4-yl-4/- -[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzoic acid methyl etser;
4-[4-Ethyl-5-(4-methyl-benzylsuIfanyl)-4H-[1 ,2,4]triazol-3-yl]-pyridine;
4-[4-Ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4 - -[1 ,2,4]triazol-3-ylj-pyridine;
4-[5-(2,4-Dichloro-benzyIsulfanyl)-4-ethyI-4 -/-[1 ,2,4]triazol-3-yl]-pyridine; 3-[5-(2-Chloro-benzylsulfanyl)-4-ethyl-4r -[1 ,2,4]triazol-3-yl]-pyridine;
4-(4-Ethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzonitrile;
3-[5-(6-Chloro-benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-4H-[1 ,2,4]tria∑ol-3-yl]-pyridine;
3-[5-(3,4-DichIoro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-pyridine;
3-[5-(4-Bromo-ben∑ylsulfanyl)-4-ethyl-4H-[1 ,2,4]lria∑ol-3-yl]-pyridine; 3-[4-Ethyl-5-(4-[1 ,2,3]thiadiazol-4-yl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-pyridine;
3-[4-Ethyl-5-(4-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-pyridine;
3-[5-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]tria∑ol-3-yl]-pyridine;
3-[4-Ethyl-5-(4-trifluoromethyl-ben∑ylsulfanyl)-4f.-[1 ,2,4]tria∑ol-3-yl]-pyridine;
3-(5-Ben∑ylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-yl)-pyridine; 3-[4-Ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-pyridine;
3-[4-Ethyl-5-(3-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-pyridine;
4-(4-EthyI-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzoic acid methyl etser;
3-[5-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4jtriazol-3-yl]-pyridine;
3-[5-(4-Benzyloxy-ben∑ylsulfanyl)-4-ethyl-4H-[1 ,2,4]tria∑ol-3-yl]-pyridine; 3-[4-Ethyl-5-(4-methyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-pyridine;
3-[4-Ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]tria∑ol-3-ylj-pyridine;
N-[4-(4-Ethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-phenyl]-acetamide;
3-[4-Ethyl-5-(4-methoxy-benzylsulfanyl)-4ry-[1 ,2,4]triazoI-3-yl]-pyridine;
3-[4-Ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-pyridine; 3-[4-Ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-pyridine; 3-[5-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-4/.-[1,2,4]triazol-3-ylj-pyridine;
3-(2-Chloro-benzylsulfanyl)-5-(4-chloro-phenyl)-4-ethyl-4/-/-[1 ,2,4]triazole;
4-[5-(4-Chloro-phenyl)-4-ethyl-4f -[1 ,2,4]triazol-3-ylsulfanylmethylj-benzonitrile;
3-(4-Chloro-phenyl)-5-(3,4-dichloro-benzylsulfanyl)-4-ethyl-4 - -[1 ,2,4]triazole; 4-{4-[5-(4-Chloro-phenyl)-4-ethyl-4/.-[1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}-
[1,2,3]thiadiazoIe;
3-(4-Chloro-phenyl)-4-ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4/-/-[1,2,4]triazole;
3-(4-Chloro-phenyl)-4-ethyl-5-(3-nitro-benzylsulfanyl)-4W-[1 ,2,4]triazole;
4-[5-(4-Chloro-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl etser; 3-(4-Chloro-phenyI)-5-(2,6-dichloro-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazole;
3-(4-Benzyloxy-benzylsulfanyl)-5-(4-chloro-phenyl)-4-ethyl-4 -/-[1,2,4]triazole;
3-(4-ChIoro-phenyl)-4-ethyl-5-(4-methyl-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-(4-Chloro-phenyl)-4-ethyl-5-(3-trifluoromethoxy-ben∑ylsulfanyl)-4H-[1,2,4]triazole;
N-{4-[5-(4-Chloro-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyImethyl]-phenyl}-acetamide; 3-(4-Chloro-phenyl)-4-ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-(4-Chloro-phenyl)-5-(2,4-dichloro-ben∑ylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
5-[5-(2-ChIoro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-4-phenyl-[1 ,2,3]thiadiazole;
4-[4-Ethyl-5-(4-phenyl-[1 ,2,3]thiadiazol-5-yl)-4/-.-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile;
5-[5-(3,4-Dichloro-ben∑ylsulfanyl)-4-ethyl-4 -/-[1 ,2,4]lriazol-3-yl]-4-phenyl-[1 ,2,3]thiadiazole; 5-[4-Ethyl-5-(4-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-4-phenyl-
[1 ,2,3]thiadiazole;
5-[5-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]tria∑ol-3-yl]-4-phenyl-[1 ,2,3]thiadia∑ole;
5-[4-Ethyl-5-(4-trifluoromethyl-ben∑ylsulfanyl)-4/-.-[1 ,2,4]tria∑oi-3-yl]-4-phenyl-
[1 ,2,3]thiadia∑ole; 5-(5-Benzylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-yI)-4-phenyl-[1 ,2,3]thiadiazole;
5-[4-Ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-4-phenyl-
[1 ,2,3]thiadiazole;
5-[4-Ethyl-5-(4-nitro-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-4-phenyl-[1 ,2,3]thiadiazoIe;
5-[5-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-4 -/-[1,2,4]triazol-3-yl]-4-phenyl-[1 ,2,3]thiadiazole; 5-[4-Ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-4-phenyl-
[1 ,2,3]thiadiazole;
5-[4-Ethyl-5-(4-methoxy-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-4-phenyl-[1 ,2,3]thiadiazole;
5-[4-Ethyl-5-(2-nitro-benzylsulfanyl)-4 -/-[1 ,2,4]triazol-3-yl]-4-phenyl-[1 ,2,3]thiadiazole;
4-{5-[4-(2,5-Dimethyl-pyrroI-1-yl)-phenyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl}- benzonitrile; 3-(6-Chloro-benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-5-[4-(2,5-dimethyl-pyrrol-1-yl)-phenyl]-4- ethyl-4H-[1 ,2,4]triazole;
3-(3,4-Dichloro-benzylsulfanyl)-5-[4-(2,5-dimethyI-pyrrol-1-yl)-phenyl]-4-ethyl-4/- -
[1 ,2,4]triazole; 3-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-5-(4-trifluoromethoxy-benzylsulfanyl)-4H-
[1 ,2,4]triazole;
3-(3,5-Dimethoxy-benzylsulfanyl)-5-[4-(2,5-dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-4 - -
[1 ,2,4]triazole;
3-[4-(2,5-Dimethyl-pyrrol-1-yI)-phenyl]-4-ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4/- - [1 ,2,4jtriazole;
3-Benzylsulfanyl-5-[4-(2,5-dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-4 - -[1 ,2,4]triazole;
3-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4-ethyI-5-(4-methanesulfonyI-benzylsulfanyl)-4H-
[1 ,2,4]tria∑ole;
3-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenylj-4-ethyl-5-(3-nitro-benzylsulfanyl)-4 - -[1 ,2,4]triazole; 4-{5-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-4 --[1 ,2,4]triazol-3-ylsulfanylmethyl}-benzoic acid methyl etser;
3-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-5-(4-nitro-benzylsulfanyl)-4H-[1 ,2,4]tria∑ole;
3-(4-Ben∑yloxy-ben∑ylsulfanyl)-5-[4-(2,5-dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-4H-
[1 ,2,4]triazole; N-(4-{5-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl}- phenyl)-acetamide;
3-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-5-(4-methθ)cy-ben∑ylsulfanyl)-4H-
[1 ,2,4]tria∑ole;
3-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-5-(5-methyl-2-nitro-ben∑ylsulfanyl)-4H- [1 ,2,4jtriazole;
3-[4-(2,5-Dimethyl-pyrroI-1-yl)-phenyl]-4-ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-(2,4-Dichloro-benzylsulfanyl)-5-[4-(2,5-dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-4H-
[1 ,2,4]triazole;
3-Benzo[b]thiophen-2-yI-5-(2-chloro-benzylsulfanyl)-4-ethyl-4 - -[1 ,2,4]triazole; 4-(5-Benzo[b]thiophen-2-yl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzonitrile;
3-Benzo[b]thiophen-2-yl-5-(6-chloro-benzo[1 ,3jdioxol-5-ylmethyIsulfanyl)-4-ethyl-4H-
[1 ,2,4]triazole;
3-Benzo[b]thiophen-2-yl-5-(4-bromo-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
4-[4-(5-Benzo[b]thiophen-2-yl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-phenylj- [1 ,2,3]thiadiazole; 3-Benzo[bjthiophen-2-yl-4-ethyl-5-(3-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
4-(5-Benzo[b]thiophen-2-yl-4-ethyI-4H-[1 ,2,4]triazol-3-ylsulfanylmethyI)-benzoic acid methyl etser;
3-Ben∑o[b]thiophen-2-yl-4-ethyl-5-(4-nitro-ben∑yIsulfanyl)-4H-[1 ,2,4]tria∑ole; 3-Benzo[b]thiophen-2-yl-5-(4-benzyloxy-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]tria∑ole;
3-Benzo[b]thiophen-2-yl-4-ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]triazole;
N-[4-(5-Benzo[b]thiophen-2-yl-4-ethyl-4/.-[1,2,4]triazol-3-ylsulfanylmethyl)-phenyl]- acetamide;
3-Benzo[b]thiophen-2-yl-4-ethyl-5-(4-methoxy-ben∑ylsulfanyl)-4H-[1 ,2,4]triazole; 3-Benzo[b]thiophen-2-yl-4-ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-(2-Chloro-benzyIsulfanyl)-4-ethyl-5-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-4H-
[1 ,2,4]triazole;
3-(6-Chloro-benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-5-(1 -phenyl-5-trifluoromethyl-1 H- pyrazol-4-yl)-4H-[1,2,4]triazole; 4-{4-[4-Ethyl-5-(1 -phenyl-5-trifluoromethyl-1 H-pyrazol-4-yl)-4H-[1 ,2,4]triazol-3- ylsulfanylmethyl]-phenyl}-[1 ,2,3]thiadia∑ole;
4-Ethyl-3-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-5-(4-trifluoromethoxy-benzylsulfanyl)-
4H-[1 ,2,4]tria∑ole;
3-(3,5-Dimethoxy-ben∑ylsulfanyl)-4-ethyl-5-(1-phenyl-5-trifluoromethyl-1H-pyra∑ol-4-yl)-4H- [1 ,2,4]tria∑ole;
3-Benzylsulfanyl-4-ethyl-5-(1 -phenyl-5-trifluoromethyl-1 H-pyrazol-4-yl)-4H-[1 ,2,4]triazole;
4-Ethyl-3-(4-methanesulfonyl-benzylsulfanyl)-5-(1-phenyl-5-trifluoromethyl-1H-pyra∑ol-4-yl)-
4H-[1 ,2,4]tria∑ole;
4-Ethyl-3-(3-nitro-ben∑ylsulfanyl)-5-(1-phenyl-5-trifluoromethyl-1H-pyra∑ol-4-yl)-4H- [1 ,2,4]triazole;
4-[4-Ethyl-5-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-4H-[1 ,2,4]triazol-3-ylsuIfanylmethylj- ben∑oic acid methyl etser;
3-(2,6-Dichloro-benzylsulfanyI)-4-ethyl-5-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-4H-
[1 ,2,4]triazole; 3-(4-Benzyloxy-benzylsulfanyl)-4-ethyl-5-(1 -phenyl-5-trifluoromethyl-1 - -pyrazol-4-yl)-4 --
[1 ,2,4]triazole;
4-Ethyl-3-(4-methyl-benzylsulfanyl)-5-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-4H-
[1 ,2,4]triazole;
N-{4-[4-Ethyl-5-(1 -phenyl-5-trif luoromethyl-1 H-pyrazol-4-yl)-4H-[1 ,2,4]triazoI-3- ylsulfanylmethylj-phenylj-acetamide; 4-Ethyl-3-(5-methyI-2-nitro-benzylsulfanyl)-5-(1-phenyl-5-trifluoromethyl-1 .-pyrazol-4-yl)-4H-
[1 ,2,4]triazole;
4-Ethyl-3-(2-nitro-benzylsulfanyl)-5-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-4ry-
[1 ,2,4]triazole; 3-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-5-(1 -phenyI-5-trifluoromethyl-1 - -pyrazol-4-yl)-4H-
[1 ,2,4]triazole;
3-(2-Chloro-benzylsulfanyl)-5-(3-chIoro-4-methyl-thiophen-2-yl)-4-ethyl-4H-[1 ,2,4]triazole;
4-[5-(3-Chloro-4-methyl-thiophen-2-yl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethylj- benzonitrile; 3-(3-Chloro-4-methyl-thiophen-2-yl)-5-(3,4-dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
4-{4-[5-(3-Chloro-4-methyl-thiophen-2-yl)-4-ethyl-4H-[1 ,2,4]triazol-3-yIsulfanylmethyl]- phenyl}-[1 ,2,3]thiadiazole;
3-(3-Chloro-4-methyl-thiophen-2-yl)-5-cyclohexylmethylsulfanyl-4-ethyl-4H-[1 ,2,4]triazole;
3-(3-Chloro-4-methyl-thiophen-2-yI)-4-ethyl-5-(4-trifluoromethoxy-benzylsulfanyl)-4H- [1 ,2,4]triazole;
3-(3-Chloro-4-methyl-thiophen-2-yl)-4-ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4H-
[1 ,2,4]triazole;
3-(3-Chloro-4-methyl-thiophen-2-yl)-4-ethyl-5-(3-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
4-[5-(3-Chloro-4-methyl-thiophen-2-yl)-4-ethyl-4/- -[1 ,2,4]tria∑ol-3-ylsulfanylmethyl]-ben∑oic acid methyl etser;
3-(3-Chloro-4-methyl-thiophen-2-yl)-5-(2,6-dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
3-(3-Chloro-4-methyl-thiophen-2-yl)-4-ethyI-5-(4-methyl-ben∑ylsulfanyl)-4H-[1 ,2,4]tria∑ole;
3-(3-Chloro-4-methyl-thiophen-2-yI)-4-ethyl-5-(3-trifluoromethoxy-ben∑ylsulfanyl)-4H-
[1 ,2,4]triazole; 3-(3-Chloro-4-methyI-thiophen-2-yl)-4-ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-
[1 ,2,4]triazole;
3-(3-Chloro-4-methyl-thiophen-2-yl)-4-ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
4-(4-Ethyl-5-pyridin-2-yl-4/- -[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzonitrile;
2-[5-(6-Chloro-ben∑o[1 ,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-pyridine 2-[5-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-4/.-[1,2,4]triazol-3-ylj-pyridine;
2-[5-(4-Bromo-benzylsulfanyl)-4-ethyl-4ry-[1 ,2,4]triazol-3-yl]-pyridine;
2-[4-Ethyl-5-(4-[1,2,3]thiadiazol-4-yI-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-pyridine;
2-[5-(3,5-Dimethoxy-benzylsulfanyI)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-pyridine;
2-[4-Ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4ry-[1,2,4]triazol-3-yl]-pyridine; 2-[4-Ethyl-5-(4-methanesulfonyl-benzyIsulfanyl)-4 - -[1 ,2,4]triazol-3-yl]-pyridine; 2-[4-Ethyl-5-(3-nitro-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine;
4-(4-Ethyl-5-pyridin-2-yl-4/--[1,2,4]triazol-3-ylsulfanylmethyl)-benzoic acid methyl etser;
2-[4-Ethyl-5-(4-nitro-benzylsulfanyl)-4r-[1,2,4]triazol-3-yl]-pyridine;
2-[5-(4-Benzyloxy-ben∑ylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-yl]-pyridine; 2-[4-Ethyl-5-(4-methyl-benzylsulfanyI)-4H-[1,2,4]triazol-3-yl]-pyridine;
2-[4-Ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine;
2-[4-Ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-pyridine;
2-[4-Ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine;
3-[5-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-yl]-2-methylsulfanyl-pyridine; 3-[4-Ethyl-5-(4-[1,2,3]thiadiazol-4-yl-benzylsulfanyl)-4H-[1,2,4]triazoI-3-yl]-2-methylsulfanyl- pyridine;
3-(5-Cyclohexylmethylsulfanyl-4-ethyl-4/-/-[1,2,4]triazol-3-yl)-2-methylsulfanyl-pyridine;
3-[4-Ethyl-5-(4-trifluoromethoxy-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-2-methylsulfanyl- pyridine; 3-[5-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-4/--[1,2,4]triazol-3-yl]-2-methylsulfanyl-pyridine;
3-[4-Ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4f.-[1 ,2,4]triazol-3-yl]-2-methylsulfanyl-pyridine;
3-(5-Benzylsulfanyl-4-ethyl-4H-[1,2,4]triazol-3-yl)-2-methylsulfanyl-pyridine;
3-[4-Ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-2-methylsulfanyl- pyridine; 4-[4-Ethyl-5-(2-methylsulfanyl-pyridin-3-yl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl etser;
3-[5-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-yl]-2-methylsulfanyl-pyridine;
3-[5-(4-Benzyloxy-benzylsulfanyl)-4-ethyl-4H-[1,2,4]tria∑ol-3-yl]-2-methylsulfanyl-pyridine;
3-[4-EthyI-5-(4-methyl-ben∑ylsulfanyl)-4/-/-[1,2,4]triazol-3-yl]-2-methylsulfanyl-pyridine; 3-[4-Ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-2-methylsulfanyl- pyridine;
N-{4-[4-Ethyl-5-(2-methylsulfanyI-pyridin-3-yl)-4/--[1,2,4]triazol-3-ylsulfanylmethyl]-phenyl}- acetamide;
3-[4-Ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4 -/-[1,2,4]triazol-3-yl]-2-methylsulfanyl-pyridine; 3-[4-Ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-2-methylsulfanyl-pyridine;
3-(2-Chloro-benzylsulfanyl)-4-ethyl-5-(5-methyl-thiophen-2-yl)-4/--[1,2,4]triazole;
4-[4-Ethyl-5-(5-methyl-thiophen-2-yl)-4 --[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile;
3-(6-Chloro-benzo[1,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-5-(5-methyI-thiophen-2-yl)-4H-
[1 ,2,4]triazole; 3-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-5-(5-methyl-thiophen-2-yl)-4H-[1 ,2,4]triazole; 4-{4-[4-Methyl-5-(5-methyl-thiophen-2-yl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}-
[1 ,2,3]thiadiazole;
3-Cyclohexylmethylsulfanyl-4-ethyl-5-(5-methyl-thiophen-2-yl)-4ry-[1 ,2,4]triazole;
4-Ethyl-3-(5-methyl-thiophen-2-yl)-5-(4-trifluoromethoxy-benzylsulfanyl)-4ry-[1 ,2,4]triazole; 3-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-5-(5-methyl-thiophen-2-yl)-4H-[1 ,2,4]triazole;
4-Ethyl-3-(5-methyl-thiophen-2-yl)-5-(4-trifluoromethyl-benzylsulfanyl)-4 - -[1 ,2,4]triazole;
3-Benzylsulfanyl-4-ethyl-5-(5-methyl-thiophen-2-yl)-4H-[1 ,2,4]triazoIe;
4-Ethyl-3-(4-methanesulfonyl-benzylsulfanyl)-5-(5-methyl-thiophen-2-yl)-4 - -[1 ,2,4]triazole;
4-Ethyl-3-(5-methyl-thiophen-2-yl)-5-(3-nitro-benzylsulfanyl)-4ry-[1 ,2,4]triazoIe; 4-[4-Ethyl-5-(5-methyl-thiophen-2-yl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl etser;
4-Ethyl-3-(5-methyl-thiophen-2-yl)-5-(4-nitro-benzyIsulfanyl)-4H-[1 ,2,4]triazole;
3-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-5-(5-methyl-thiophen-2-yl)-4H-[1 ,2,4]triazole;
4-Ethyl-3-(4-methyl-benzylsulfanyl)-5-(5-methyl-thiophen-2-yl)-4H-[1,2,4]triazole; N-{4-[4-Ethyl-5-(5-methyl-thiophen-2-yl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-phenyl}- acetamide;
4-Ethyl-3-(4-methoxy-benzylsulfanyl)-5-(5-methyl-thiophen-2-yl)-4H-[1 ,2,4]triazole;
4-Ethyl-3-(5-methyl-thiophen-2-yl)-5-(2-nitro-benzylsulfanyl)-4 -.-[1 ,2,4]triazole;
3-(2,4-Dichloro-ben∑ylsulfanyl)-4-ethyl-5-(5-methyl-thiophen-2-yl)-4H-[1 ,2,4]tria∑ole; 4-[5-(5-Chloro-thiophen-2-yl)-4-ethyl-4/-/-[1 ,2,4]triazoI-3-ylsuIfanylmethyl]-benzonitrile;
3-(5-Chloro-thiophen-2-yl)-5-(3,4-dichloro-benzylsulfanyl)-4-ethyl-4ry-[1 ,2,4]triazole;
3-(4-Bromo-benzylsulfanyl)-5-(5-chloro-thiophen-2-yl)-4-ethyl-4H-[1,2,4]tria∑ole;
4-{4-[5-(5-Chloro-thiophen-2-yl)-4-ethyl-4/-.-[1 ,2,4]tria∑ol-3-ylsulfanylmethyI]-phenyl}-
[1 ,2,3]thiadia∑ole; 3-(5-Chloro-th iophen-2-yl)-5-cyclohexylmethylsulfanyl-4-ethyl-4H-[1 ,2,4]triazole; 3-(5-Chloro-th iophen-2-yl)-4-ethyl-5-(4-trifluoromethoxy-benzylsulfanyl)-4 - -[1 ,2,4]triazole; 3-(5-Chloro-th iophen-2-yl)-5-(3,5-dimethoxy-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole; 3-(5-Chloro-th ιiophen-2-yl)-4-ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4 -/-[1 ,2,4]triazole; 3-(5-Chloro-th ιiophen-2-yl)-4-ethyl-5-(3-nitro-benzylsulfanyl)-4 -/-[1 ,2,4]triazole; 4-[5-(5-Chloro-thiophen-2-yl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl etser;
3-(5-Chloro-thiophen-2-yl)-5-(2,6-dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole; 3-(5-Chloro-thiophen-2-yl)-4-ethyl-5-(4-methyI-benzylsulfanyl)-4H-[1 ,2,4]triazole; 3-(5-Chloro-thiophen-2-yl)-4-ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4/-.-[1 ,2,4]triazole; N-{4-[5-(5-Chloro-thiophen-2-yl)-4-ethyl-4-/-[1,2,4]triazol-3-ylsulfanylmethyl]-phenyl}- acetamide;
3-(5-Chloro-thiophen-2-yl)-4-ethyl-5-(4-methoxy-benzylsulfanyl)-4 -/-[1,2,4]triazole;
3-(5-Chloro-thiophen-2-yl)-4-ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4r/-[1,2,4]triazole; 3-(5-Chloro-thiophen-2-yl)-4-ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1,2,4]triazole;
3-(5-Chloro-thiophen-2-yl)-5-(2,4-dichloro-benzylsulfanyl)-4-ethyl-4/--[1,2,4]triazole;
4-[4-Ethyl-5-(1H-indol-3-ylmethyl)-4H-[1,2,4]triazol-3-ylsulfanyImethyl]-benzonitrile;
3-[5-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-ylmethyl]-1H-indole;
3-[5-(3,5-Dimethoxy-benzylsulfanyI)-4-ethyl-4H-[1,2,4]triazoI-3-ylmethyl]-1H-indole; 3-[4-Ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylmethyl]-1 H-indole;
3-[4-Ethyl-5-(3-nitro-benzylsulfanyI)-4H-[1 ,2,4]triazol-3-ylmethyl]-1H-indole;
3-[4-Ethyl-5-(4-nitro-benzylsulfanyI)-4H-[1,2,4]triazol-3-ylmethyl]-1/-/-indole;
3-[5-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-ylmethylj-1H-indole;
3-[5-(4-Benzyloxy-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-ylmethyl]-1 H-indole; 3-[4-Ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylmethyl]-1 H-indole;
N-{4-[4-EthyI-5-(1H-indol-3-ylmethyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}-acetamide;
3-[4-Ethyl-5-(4-methoxy-benzylsulfanyl)-4H-[1,2,4]triazol-3-yImethyl]-1 H-indole;
3-[4-Ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-[1,2,4]triazol-3-ylmethyl]-1 H-indole;
3-[4-EthyI-5-(2-nitro-benzylsulfanyl)-4H-[1,2,4]tria∑ol-3-ylmethyl]-1H-indole; 3-[5-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazoI-3-ylmethyl]-1 H-indole;
2-[5-(6-Chloro-benzo[1,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazoI-3-yl]-phenol;
2-[4-Ethyl-5-(4-[1,2,3]thiadiazol-4-yl-ben∑ylsulfanyl)-4H-[1,2,4]tria∑ol-3-yl]-phenol;
2-(5-Cyclohexylmethylsulfanyl-4-ethyl-4H-[1,2,4]triazol-3-yl)-phenol;
2-[5-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-yl]-phenol; 2-[4-Ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-phenol;
2-(5-Benzylsulfanyl-4-ethyl-4H-[1,2,4]triazol-3-yl)-phenol;
2-[4-Ethyl-5-(4-methanesulfonyl-ben∑ylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol;
2-[4-Ethyl-5-(3-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol;
4-[4-Ethyl-5-(2-hydroxy-phenyI)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl et- ser;
2-[4-Ethyl-5-(4-nitro-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-phenol;
2-[5-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-yl]-phenol;
2-[4-Ethyl-5-(4-methyl-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-phenol;
2-[4-EthyI-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1,2,4]triazol-3-ylj-phenol; N-{4-[4-Ethyl-5-(2-hydroxy-phenyl)-4H-[1,2,4jtriazol-3-ylsulfanylmethyl]-phenyl}-acetamide; 2-[4-Ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-phenol;
2-[4-Ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-phenol;
2-[5-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-yl]-phenol;
5-[5-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-yl]-4-methyl-[1,2,3]thiadiazole; 5-[5-(4-Bromo-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-4-methyl-[1 ,2,3]thiadiazole;
5-(5-Cyclohexylmethylsulfanyl-4-ethyl-4H-[1,2,4]triazol-3-yl)-4-methyl-[1,2,3]thiadiazole;
5-[5-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-yl]-4-methyl-[1,2,3]thiadiazole;
5-(5-Benzylsulfanyl-4-ethyl-4H-[1,2,4]triazol-3-yl)-4-methyl-[1,2,3jthiadiazole;
5-[4-Ethyl-5-(3-nitro-benzylsulfanyl)-4H-[1,2,4]triazol-3-ylj-4-methyl-[1,2,3]thiadiazoie; 4-[4-EthyI-5-(4-methyl-[1 ,2,3]thiadiazol-5-yl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethylj-benzoic acid methyl etser;
5-[4-Ethyl-5-(4-nitro-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-4-methyl-[1,2,3]thiadiazole;
5-[5-(4-Benzyloxy-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-yl]-4-methyl-[1,2,3]thiadiazole;
5-[4-Ethyl-5-(4-methyl-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-4-methyl-[1,2,3jthiadiazole; 5-[4-Ethyl-5-(3-trifluoromethoxy-benzyIsulfanyl)-4H-[1,2,4]triazol-3-yl]-4-methyl-
[1 ,2,3]thiadiazole;
5-[4-Ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-4-methyl-
[1 ,2,3]thiadiazole;
5-[5-(2,4-Dichloro-benzylsulfanyI)-4-ethyl-4H-[1,2,4]tria∑ol-3-yl]-4-methyl-[1,2,3jthiadia∑ole; 4-(5-Benzyl-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-benzonitrile;
3-Benzyl-5-(3,4-dichloro-ben∑ylsulfanyl)-4-ethyl-4H-[1,2,4]triazole;
4-[4-(5-Benzyl-4-ethyl-4H-[1,2,4]tria∑ol-3-ylsulfanylmethyl)-phenyl]-[1,2,3]thiadia∑ole;
3-Ben∑yl-5-(3,5-dimethoxy-ben∑ylsulfanyl)-4-ethyl-4H-[1 ,2,4]tria∑ole;
3-Benzyl-4-ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1,2,4]triazole; 3-Benzyl-5-benzylsulfanyl-4-ethyl-4H-[1 ,2,4]triazole;
3-Ben∑yl-5-(2,6-dichloro-ben∑ylsulfanyl)-4-ethyl-4H-[1,2,4]triazole;
3-Ben∑yl-4-ethyl-5-(4-methyl-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-Benzyl-4-ethyl-5-(4-methoxy-benzyIsulfanyl)-4H-[1,2,4]triazole;
3-Benzyl-4-ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-[1,2,4jtriazole; 3-Benzyl-4-ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1,2,4]triazole;
3-Benzyl-5-(2,4-dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
3-(2-Bromo-phenyl)-5-(2-chloro-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazole;
4-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile;
3-(2-Bromo-phenyl)-5-(6-chloro-benzo[1,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-4H- [1,2,4]triazole; 3-(2-Bromo-phenyl)-5-(3,4-dichloro-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazole;
3-(2-Bromo-phenyl)-5-cyclohexylmethylsulfanyl-4-ethyl-4H-[1,2,4]triazoIe;
3-(2-Bromo-phenyl)-4-ethyI-5-(4-trifluoromethoxy-benzylsulfanyl)-4H-[1,2,4jtriazole;
3-(2-Bromo-phenyl)-5-(3,5-dimethoxy-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazole; 3-(2-Bromo-phenyl)-4-ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1,2,4]triazole;
3-(2-Bromo-phenyl)-4-ethyl-5-(3-nitro-benzylsulfanyl)-4H-[1,2,4]triazole;
3-(4-Benzyloxy-benzylsulfanyl)-5-(2-bromo-phenyl)-4-ethyl-4H-[1,2,4]triazole;
3-(2-Bromo-phenyl)-4-ethyl-5-(4-methoxy-benzylsulfanyl)-4H-[1,2,4]triazole;
3-(2-Bromo-phenyl)-4-ethyl-5-(5-methyl-2-nitro-benzylsuIfanyl)-4H-[1 ,2,4jtriazole; 3-(2-Bromo-phenyl)-5-(2,4-dichloro-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazole;
2-[4-(3-Methoxy-propyl)-5-(1-methyI-piperidin-2-yl)-4H-[1 ,2,4jtriazol-3-ylsulfanylmethyl]- benzonitrile;
2-[4-(3-Methoxy-propyl)-5-(1-methyl-piperidin-2-yl)-4H-[1,2,4]triazol-3-ylsulfanylmethylj- pyridine; 2-[5-(2-Methoxy-ethylsulfanyl)-4-(3-methoxy-propyl)-4H-[1,2,4]triazol-3-yl]-1-methyI- piperidine;
2-[4-(2-Methoxy-ethyl)-5-(1-methyl-piperidin-2-yl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]- benzonitrile;
2-[4-(2-Methoxy-ethyl)-5-(1-methyl-piperidin-2-yl)-4H-[1,2,4]tria∑ol-3-ylsulfanylmethyl]- pyridine;
2-[4-(2-Methoxy-ethyl)-5-(2-methoxy-ethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-1-methyl-piperidine;
2-[4-Cyclopropyl-5-(1-methyl-piperidin-2-yl)- .H-[1 ,2,4]tria∑ol-3-ylsulfanylmethyl]-ben∑onitrile;
2-[4-Cyclopropyl-5-(1-methyl-piperidin-2-yl)-4H-[1,2,4]tria∑ol-3-ylsulfanylmethyl]-pyridine;
2-[4-Cyclopropyl-5-(2-methoxy-ethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-1-methyl-piperidine; 2-[5-(1-Methyl-piperidin-2-yI)-4-(2-piperidin-1-yI-ethyl)-4H-[1,2,4]tria∑ol-3-ylsulfanyImethyl]- ben∑onitrile;
2-[5-(1-Methyl-piperidin-2-yl)-4-(2-piperidin-1-yl-ethyl)-4H-[1,2,4]triazol-3-ylsulfanylmethylj- pyridine;
2-[4-CycIopropylmethyl-5-(1-methyl-piperidin-2-yl)-4H-[1,2,4]triazol-3-ylsulfanylmethylj- benzonitrile;
2-[4-Cyclopropylmethyl-5-(1-methyl-piperidin-2-yl)-4H-[1,2,4]triazol-3-ylsulfanylmethylj- pyridine;
2-[4-Cyclopropylmethyl-5-(2-methoxy-ethylsulfanyI)-4H-[1,2,4]triazol-3-yl]-1-methyl- piperidine; 2-[5-(2-Hydroxy-phenyl)-4-(3-methoxy-propyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]- benzonitrile;
2-[4-(3-Methoxy-propyl)-5-(pyridin-2-ylmethylsulfanyl)-4H-[1,2,4jtriazol-3-yl]-phenol;
2-[5-(2-Methoxy-ethylsulfanyl)-4-(3-methoxy-propyl)-4H-[1,2,4]triazol-3-yl]-phenol; 2-[5-(2-Hydroxy-phenyl)-4-(2-methoxy-ethyl)-4H-[1,2,4jtriazol-3-ylsulfanylmethyl]-benzonitrile;
2-[4-(2-Methoxy-ethyl)-5-(pyridin-2-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-phenoI;
2-[4-(2-Methoxy-ethyl)-5-(2-methoxy-ethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-phenol;
2-[4-Cyclopropyl-5-(2-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile;
2-[4-Cyclopropyl-5-(pyridin-2-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-ylj-phenol; 2-[4-Cyclopropyl-5-(2-methoxy-ethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-phenol;
2-[5-(2-Hydroxy-phenyl)-4-(2-piperidin-1-yl-ethyl)-4H-[1,2,4]triazol-3-yIsulfanylmethylj- benzonitrile;
2-[4-(2-Piperidin-1-yl-ethyl)-5-(pyridin-2-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-phenol;
2-[5-(2-Methoxy-ethylsulfanyl)-4-(2-piperidin-1-yl-ethyl)-4H-[1,2,4]triazol-3-yl]-phenol; 2-[4-Cyclopropylmethyl-5-(2-hydroxy-phenyl)-4H-[1,2,4]triazol-3-ylsuIfanylmethylj- ben∑onitrile;
2-[4-Cyclopropylmethyl-5-(pyridin-2-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-phenol;
2-[4-Cyclopropylmethyl-5-(2-methoxy-ethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-phenol;
2-[5-(2-Methoxy-phenyl)-4-(3-methoxy-propyl)-4H-[1,2,4]tria∑ol-3-ylsulfanylmethylj- benzonitrile;
2-[5-(2-Methoxy-phenyl)-4-(3-methoxy-propyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-pyridine;
3-(2-Metho)cy-ethylsulfanyl)-5-(2-methoxy-phenyl)-4-(3-methoxy-propyl)-4H-[1 ,2,4]triazole;
2-[4-(2-Methoxy-ethyl)-5-(2-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanylmethylj- ben∑onitrile; 2-[4-(2-Methoxy-ethyl)-5-(2-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-pyridine;
4-(2-Methoxy-ethyl)-3-(2-methoxy-ethylsulfanyl)-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazole;
2-[4-Cyclopropyl-5-(2-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-ben∑onitrile;
2-[4-Cyclopropyl-5-(2-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-pyridine;
4-Cyclopropyl-3-(2-methoxy-ethylsulfanyl)-5-(2-methoxy-phenyl)-4H-[1,2,4]triazole; 2-[5-(2-Methoxy-phenyl)-4-(2-piperidin-1 -yl-ethyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethylj- benzonitrile;
2-[5-(2-Methoxy-phenyl)-4-(2-piperidin-1-yl-ethyl)-4H-[1,2,4]triazol-3-ylsulfanylmethylj- pyridine;
1-{2-[3-(2-Methoxy-ethylsulfanyl)-5-(2-methoxy-phenyl)-[1,2,4]triazol-4-yl]-ethyl}-piperidine; 2-[4-Cyclopropylmethyl-5-(2-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]- benzonitrile;
2-[4-Cyclopropylmethyl-5-(2-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanylmethylj-pyridine;
4-Cyclopropylmethyl-3-(2-methoxy-ethylsulfanyl)-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazole; 2-[4-(3-Methoxy-propyl)-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile;
2-[4-(3-Methoxy-propyl)-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-pyridine;
3-(2-Methoxy-ethylsulfanyl)-4-(3-methoxy-propyl)-5-thiophen-2-yl-4H-[1,2,4]triazole;
2-[4-(2-Methoxy-ethyl)-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile;
2-[4-(2-Methoxy-ethyl)-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-pyridine; 4-(2-Methoxy-ethyl)-3-(2-methoxy-ethylsulfanyl)-5-thiophen-2-yl-4H-[1,2,4]triazole;
2-(4-Cyclopropyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-benzonitrile;
2-(4-Cyclopropyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-pyridine;
4-Cyclopropyl-3-(2-methoxy-ethylsulfanyl)-5-thiophen-2-yl-4H-[1,2,4]triazole;
2-[4-(2-Piperidin-1-yl-ethyl)-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile; 2-[4-(2-Piperidin-1-yl-ethyl)-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-pyridine;
1-{2-[3-(2-Methoxy-ethylsulfanyl)-5-thiophen-2-yl-[1,2,4]triazol-4-yl]-ethyl}-piperidine;
2-(4-Cyclopropylmethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-ben∑onitrile;
2-(4-Cyclopropylmethyl-5-thiophen-2-yl-4H-[1,2,4]lriazol-3-ylsulfanylmethyl)-pyridine;
4-Cyclopropylmethyl-3-(2-methoxy-ethylsulfanyl)-5-thiophen-2-yl-4H-[1,2,4]triazole; 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.
38. A pharmaceutical composition which comprises the combination according to any of the claims 1-37 and a pharmaceutically acceptable carrier.
39. A pharmaceutical composition made by combining an 1 .β -HSD1 inhibitor, a glucocorticoid receptor agonist and a pharmaceutically acceptable carrier.
40. A process for making a pharmaceutical composition comprising: combining an 1 β- HSD1 inhibitor, a glucocorticoid receptor agonist and a pharmaceutically acceptable carrier.
41. The use of the combination according to any of the claims 1-37, for the preparation of a pharmaceutical composition for treating or preventing diseases or disorders where modulation or reduction of the level of active intracellular glucorticoid is beneficial
42. The use of the combination according to any of the claims 1-37, for the preparation of a pharmaceutical composition for reducing the adverse effects of glucocorticoid receptor agonist therapy in indications of Cushing's disease, Cushing's syndrome, allergic-inflammatory diseases, adverse effects of glucocorticoid receptor agonist treatment of disorders of the respiratory system, adverse effects of glucocorticoid receptor agonist treatment of inflammatory bowel disease; adverse effects of glucocorticoid receptor agonist treatment of disorders of the immune system, connective tissue and joints; adverse effects of glucocorticoid receptor agonist treatment of endocrinological diseases; adverse effects of glucocorticoid receptor agonist treatment of hematological diseases; adverse effects of glucocorticoid receptor ago- nist treatment of cancer, chemotherapy-induced nausea, adverse effects of glucocorticoid receptor agonist treatment of diseases of muscle and at the neuro-muscular joint; adverse effects of glucocorticoid receptor agonist treatment in the context of surgery & transplantation; adverse effects of glucocorticoid receptor agonist treatment of brain absess, nausea/vomiting, infections, hypercalcemia, adrenal hyperplasia, autoimmune hepatitis, spinal cord diseases, saccular aneurysms.
43. The use according to claim claim 42, wherein the indication is selected from the following group: Cushing's disease, Cushing's syndrome, asthma, atopic dermatitis, cystic fibrosis, emphysema, bronchitis, hypersensitivity, pneumonitis, eosinophilic pneumonias, pulmonary fibrosis, Crohn's disease, Ulcerative colitis, reactive arthritis, rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus, lupus nephritis, Henoch-Schδnlein purpura, Wegener's granulomatosis, temporal arteritis, systemic sclerosis, vasculitis, sarcoidosis, dermalomyositis-polymyositis, pemphigus vulgaris, hyperthyroidism, hypoaldosteronism, hy- popituitarism, hemolytic anemia, thrombocytopenia, paroxysmal nocturnal hemoglobinuria, neoplastic compression of the spinal cord, brain tumours, acute lymphoblastic leukemia, Hodgkin's disease, chemotherapy-induced nausea, myasthenia gravis, heriditary myopathies, Duchenne muscular dystrophy, 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, tracheal transplantation, intestinal transplantation, comeal transplantation, skin grafting, keratoplasty, lens implantation, brain absess, nausea/vomiting, infections, hypercalcemia, adrenal hyperplasia, autoimmune hepatitis, spinal cord diseases, and saccular aneurysms.
44. A method of treating or preventing diseases or disorders where modulation or reduction of the level of active intracellular glucorticoid is beneficial comprising: administering to a patient in need of such treatment a therapeutically effective amount of the combination of any of the claims 1-37.
45. A method of reducing the adverse effects of glucocorticoid receptor agonist therapy in indications of Cushing's disease, Cushing's syndrome, allergic-inflammatory diseases, adverse effects of glucocorticoid receptor agonist treatment of disorders of the respiratory system, adverse effects of glucocorticoid receptor agonist treatment of inflammatory bowel dis- ease; adverse effects of glucocorticoid receptor agonist treatment of disorders of the immune system, connective tissue and joints; adverse effects of glucocorticoid receptor agonist treatment of endocrinological diseases; adverse effects of glucocorticoid receptor agonist treatment of hematological diseases; adverse effects of glucocorticoid receptor agonist treatment of cancer, chemotherapy-induced nausea, adverse effects of glucocorticoid recep- tor agonist treatment of diseases of muscle and at the neuro-muscular joint; adverse effects of glucocorticoid receptor agonist treatment in the context of surgery & transplantation; adverse effects of glucocorticoid receptor agonist treatment of brain absess, nausea/vomiting, infections, hypercalcemia, adrenal hyperplasia, autoimmune hepatitis, spinal cord diseases, saccular aneurysms comprising: administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of claim 39.
46. The method of claim 45, wherein the indication is selected from the following group: Cushing's disease, Cushing's syndrome, asthma, atopic dermatitis, cystic fibrosis, emphysema, bronchitis, hypersensitivity, pneumonitis, eosinophilic pneumonias, pulmonary fibrosis, Crohn's disease, Ulcerative colitis, reactive arthritis, rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus, lupus nephritis, Henoch-Schδnlein purpura, Wegener's granulomatosis, temporal arteritis, systemic sclerosis, vasculitis, sarcoidosis, dermatomyositis-polymyositis, pemphigus vulgaris, hyperthyroidism, hypoaldosteronism, hy- popituitarism, hemolytic anemia, thrombocytopenia, paroxysmal nocturnal hemoglobinuria, neoplastic compression of the spinal cord, brain tumours, acute lymphoblastic leukemia, Hodgkin's disease, chemotherapy-induced nausea, myasthenia gravis, heriditary myopathies, Duchenne muscular dystrophy, 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, tracheal transplantation, intestinal transplantation, corneal transplanta- tion, skin grafting, keratoplasty, lens implantation, brain absess, nausea/vomiting, infections, hypercalcemia, adrenal hyperplasia, autoimmune hepatitis, spinal cord diseases, and saccu- lar aneurysms.
47. The combination according to claim 1 wherein the glucocorticoid receptor agonist is selected from the group consisting of: betametasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, predni- sone, 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.
48. The combination according to any of the claims 2-5 wherein the glucocorticoid receptor agonist is selected from the group consisting of: betametasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, predni- sone, 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.
49. The combination according lo any of the claims 6-26 wherein the glucocorticoid recep- tor agonist is selected from the group consisting of: betametasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, predni- sone, 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.
50. The combination according to any of the claims 27-31 wherein the glucocorticoid receptor agonist is selected from the group consisting of: betametasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, predni- sone, 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.
51. The combination according to claims 32 or 33 wherein the glucocorticoid receptor agonist is selected from the group consisting of: betametasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, predni- sone, 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.
52. The combination according to any of the claims 34-37 wherein the glucocorticoid receptor agonist is selected from the group consisting of: betametasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, predni- sone, 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.
53. A kit comprising an amount of an 11 ?-HSD1 inhibitor and a pharmaceutically acceptable carrier, vehicle, or diluent in a first unit dosage form; an amount of a glucocorticoid re- ceptor agonist and a pharmaceutically acceptable carrier, vehicle, or diluent in a second unit dosage form; and a container.
54. The use of the combination according to any of the claims 1-37, for the preparation of a pharmaceutical composition for preventing diseases or disorders where modulation or reduction of the level of active intracellular glucorticoid is beneficial, said use comprising adminis- tering to a patient in need of said treatment (i) a first amount of an 11 ?-HSD1 inhibitor and (ii) a second amount of a glucocorticoid receptor agonist, wherein said first and second amounts together are effective for said treatment.
55. A method for treating or preventing diseases or disorders where modulation or reduc- tion of the level of active intracellular glucorticoid is beneficial, said method comprising administering to a patient in need of said treatment (i) a first amount of an 11 ?-HSD1 inhibitor and (ii) a second amount of a glucocorticoid receptor agonist, wherein said first and second amounts together are effective for said treatment.
PCT/DK2004/000248 2003-04-11 2004-04-06 COMBINATIONS OF AN 11β-HYDROXYSTEROID DEHYDROGENASE TYPE 1 INHIBITOR AND A GLUCOCORTICOID RECEPTOR AGONIST WO2004089415A2 (en)

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