MX2008005653A - Pharmaceutical use of substituted amides - Google Patents

Abstract

The use of substituted amides for modulating the activity of 11-hydroxysteroid dehydrogenase type 1 (11HSD1) and the use of these compounds as pharmaceutical compositions, are described. Also a novel class of substituted amides, their use in therapy, pharmaceutical compositions comprising the compounds, as well as their use in the manufacture of medicaments are described. The present compounds are modulators and more specifically inhibitors of the activity of 11HSD1 and may be useful in the treatment, prevention and/or prophylaxis of a range of medical disorders where a decreased intracellular concentration of active glucocorticoid is desirable.

Description

PHARMACEUTICAL USE OF SUBSTITUTE AMIDES FIELD OF THE INVENTION The present invention relates to the use of substituted amides and pharmaceutical compositions comprising the same for treating diseases wherein it is desirable to modulate the activity of dehydrogenase 11β-hydroxysteroid type 1 (11βHSD1). The present invention also relates to novel substituted amides, to their use in therapy, to pharmaceutical compositions comprising the same, to the use of said compounds in the manufacture of medicaments and to the therapeutic methods comprising the administration of the compounds. The present compounds modulate the activity of dehydrogenase 11β-hydroxysteroid type 1 (11βHSD1) and are therefore useful in the treatment of diseases in which such modulation is beneficial, such as the metabolic syndrome.

BACKGROUND OF THE INVENTION Metabolic syndrome is a global health problem. In the United States, the prevalence in the adult population is currently estimated to be approximately 25% and continues to increase both in the United States and throughout the world. The metabolic syndrome is characterized by a combination of insulin resistance, dyslipidemia, obesity and hypertension that leads to morbidity and increased mortality from cardiovascular diseases. People with metabolic syndrome are at increased risk of developing frank type 2 diabetes, the prevalence of which is increasing in the same way.

In type 2 diabetes, obesity and dyslipidemia are also highly prevalent and about 70% of people with type 2 diabetes additionally have hypertension once, again leading to increased mortality of cardiovascular diseases.

In the clinical preparation it has been widely known that glucocorticoids are capable of inducing all the cardinal features of the metabolic syndrome and type 2 diabetes. Dehydrogenase 11 β-hydroxysteroid type 1 (11βHSD1) catalyzes the local generation of the active glucocorticoid in various tissues and organs including predominantly the liver and adipose tissue, but also, for example, skeletal muscle, bones, pancreas, endothelium, ocular tissue and certain parts of the central nervous system. In addition, 11βHSD1 serves as a local regulator of glucocorticoid actions in tissues and organs where it is expressed (Tannin et al., J. Biol. Chem., 266, 16653 (1991); Bujalska et al., Endocrinology, 140; , 3188 (1999), Whorwood et al., J. Clin Endocrinol Metab., 86, 2296 (2001), Cooper et al., Bone, 27, 375 (2000), Davani et al., J. Biol. Chem. , 275, 34841 (2000), Brem et al., Hypertension, 31, 459 (1998), Rauz et al., Invest. Ophthalmol, Vis. Sci., 42, 2037 (2001), Moisan et al., Endocrinology, 127, 1450 (1990)).

The role of 11βHSD1 in the metabolic syndrome and type 2 diabetes is supported by several lines of evidence. In humans, treatment with carbenoxolone from the non-specific 11βHSD1 inhibitor improves insulin sensitivity in healthy support volunteers and people with type 2 diabetes. Also, 11βHSD1 in genetically deficient mice is resistant to insulin resistance induced by Obesity and stress. Additionally, genetically deficient mice present with an anti-atherogenic lipid profile of decreased VLDL triglycerides and increased HDL cholesterol. Conversely, mice expressing 11βHSD1 in adipocytes develop insulin resistance, hyperlipidemia, and visceral obesity, a phenotype resembling the metabolic syndrome in humans (Andrews et al., J. Clin Endocrinol, Metab., 88, 285 (2003). ), Walker et al., J. Clin Endocrinol, Metab., 80, 3155 (1995), Morton et al., J. Biol. Chem., 276, 41293 (2001), Kotelevtsev et al., Proc. Nati Acad Sci. USA, 94, 14924 (1997), Masuzaki et al., Science, 294. 2166 (2001)).

The more mechanistic aspects of 11ßHSD1 modulation and therefore the modulation of the intracellular levels of the active glucocorticoid have been investigated in several rodent models and different cellular systems. 11 ßHSD1 promotes the characteristics of the metabolic syndrome by increasing the hepatic expression of the enzymes that limit the proportion in gluconeogenesis, namely carboxykinase phosphoenolpyruvate and glucose-6-phosphatase, promoting the differentiation of preadiposites in adipocytes, also facilitating obesity, directly and indirectly by stimulating hepatic VLDL secretion, decreasing liver LDL intake and increasing vessel contractility (Kotelevtsev et al. al., Proc. Nati, Acad. Sci. USA, 94, 14924 (1997); Morton et al., J. Biol. Chem. 276, 41293 (2001); Bujalska et al., Endocrinology, 140, 3188 (1999); Souness et al., Steroids, 67, 195 (2002), Brindley & Salter, Prog. Lipid Res., 30, 349 (1991)).

Publications WO 01/90090, WO 01/90091, WO 01/90092, WO 01/90093, and WO 01/90094 describe various thiazole-sulfonamides as bitors of the dehydrogenase enzyme 11 β-hydroxysteroid type 1, and further states that said compounds may be useful in the treatment of diabetes, obesity, glaucoma, osteoporosis, cognitive diseases, immune diseases and depression.

SUMMARY OF THE INVENTION Substituted amides that modulate the activity of 11βHSD1 leading to altered intracellular concentrations of active glucocorticoid have now been found. More specifically, the present compounds bit the activity of 11βHSD1 which leads to decreased intracellular concentrations of active glucocorticoid. In addition, the present compounds can be used to treat diseases wherein the decreased level of active intracellular glucocorticoid is desirable, such as, for example, metabolic syndrome, type 2 diabetes, decreased glucose tolerance (IGT), decreased fasting glucose (IFG). ), dyslipidemia, obesity, hypertension, late diabetic complications, cardiovascular diseases, arteriosclerosis, atherosclerosis, myopathy, muscle wasting, osteoporosis, neurodegenerative and psychiatric diseases and adverse effects of treatment or therapy with glucocorticoid receptor agonists.

An object of the present invention is to provide compounds, pharmaceutical compositions and the use of compounds that modulate the activity of 11βHSD1.

DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS In the following structural formulas and throughout the specification, the following terms have the indicated meaning. The examples provided in the definitions present in this application are not inclusive unless stated otherwise. They include but are not limited to the examples mentioned.

The term "halo" includes fluorine, chlorine, bromine and iodine.

The term "trialomethyl" includes trifluoromethyl, trichloromethyl, tribromomethyl, and triiodomethyl.

The term "thhalomethoxy" includes trifluoromethoxy, trichloromethoxy, tribromomethoxy and triiodomethoxy.

The term "alkyl" includes straight chain saturated methylenes and saturated aliphatic hydrocarbon groups Cs and C3-C8 branched saturated hydrocarbon groups having the specific number of carbon atoms. For example, this definition includes methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu), pentyl, hexyl, isopropyl (i-Pr), isobutyl (i-Bu), ferf-butyl (f-Bu), sec-butyl (s-Bu), isopentyl, and neopentyl.

The term "alkenyl" includes C2-C6 straight chain unsaturated aliphatic hydrocarbon groups and C3-C6 unsaturated aliphatic hydrocarbon groups having the specific number of carbon atoms. For example, this definition includes ethenyl, propenyl, butenyl, pentenyl, hexenyl, methylpropenyl and methylbutenyl.

The term "alkynyl" includes C2-C6 straight chain unsaturated aliphatic hydrocarbon groups and C4-C6 branched unsaturated aliphatic hydrocarbon groups having the specific number of carbon atoms. For example, this definition includes ethenyl, propynyl, butynyl, pentynyl, hexynyl and methylbutynyl.

The term "monocyclic, bicyclic or tricyclic partially saturated or saturated ring system" represents but is not limited to aziridinyl, azepanyl, azocanyl, 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, indolinyl, 1,6-aza-bicyclo [3.2. 1] octane, 2-aza-bicyclo [4.1.1] octane, 2-aza-bicyclo [3.2.1] octanyl, 7-aza-bicyclo [4.1.1] octanyl, 9-aza-bicyclo [3.3.2] decanyl, 4-aza-tricyclo [4.3.1.138] undecanyl, 9-aza-tricyclo [3.3.2.03'7] decanyl.

The term "partially saturated or saturated ring" represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, tetrahydrofuranyl, and tetrahydropyranyl.

The term "partially saturated or saturated aromatic ring" means cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridyl, and pyrimidinyl.

The term "cycloalkyl" represents a saturated mono, bi-, tri or spirocarbocyclic group having the specific number of carbon atoms (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo [3.2.1] octyl, spiro [4.5] decyl, norpinyl, norbonyl, norcaryl, and adamantyl).

The term "cycloalkylalkyl" represents a cycloalkyl group as defined above linked through an alkyl group having the indicated number of carbon atoms or an alkyl group substituted as defined above for example, cyclopropylmethyl, cyclobutylmethyl, and adamantylmethyl).

The term "cycloalkenyl" represents a partially saturated mono-, bi-, tri- or spirocarbocyclic group having the specific number of carbon atoms (for example, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, and cyclodecenyl).

The term "cycloalkylcarbonyl" represents a cycloalkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group (eg, cyclopropylcarbonyl and cyclohexylcarbonyl).

The term "cycloalkylalkylcarbonyl" represents a cycloalkyl group as defined above linked through an alkyl group having the indicated number of carbon atoms or substituted alkyl group as defined above (eg, cyclohexylmethylcarbonyl and cycloheptylthylcarbonyl).

The term "hetcycloalkyl" represents a mono-, bi-, tri-, or spirocarbocyclic group having the specific number of atoms with 1-4 of the specific number being heteroatoms or groups selected from nitrogen, oxygen, sulfur and S (0) m (m = 0-2) (for example, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidine, and pyridizine).

The term "hetcycloalkylalkyl" represents a hetcycloalkyl group as defined above linked through an alkyl group having the indicated number of carbon atoms (for example, tetrahydrofuranylmethyl, tetrahydropyranylethyl, and tetrahydrothiopyranylmethyl).

The term "hetcycloalkylcarbonyl" represents a hetcycloalkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group (eg, 1-piperidin-4-yl-carbonyl and 1- (1, 2, 3,4-tetrahydro-isoquinolin-6-yl) carbonyl).

The term "alkyloxy" represents an alkyl group having the indicated number of carbon atoms attached through an oxygen bridge (e.g., methoxy, ethoxy, propyloxy, allyloxy, and cyclohexyloxy).

The term "alkyloxyalkyl" represents an alkyloxy group as defined above linked through an alkyl group having the indicated number of carbon atoms (eg, methyloxymethyl).

The term "aryl" includes a carbocyclic aromatic ring that is monocyclic, bicyclic or polycyclic such as phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl and biphenylenyl. Aryl also includes the partially hydrogenated derivatives of the carbocyclic aromatics listed above. Examples of partially hydrogenated derivatives include 1,2,3,4-tetrahydronaphthyl and 1,4-dihydronaphthyl.

The term "arylol" includes phenyl, biphenyl, naphthyl, anthracenyl, phenatrenyl and fluorenyl.

The term "aryl2" includes phenyl, biphenyl and naphthyl.

The term "hetaryl" includes 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-il 1, 2,3-triazol-4-il, 1, 2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiophenyl (2-thiophenyl, 3-thiophenyl, 4-thiophenyl, 5-thiophenyl), furanyl (2-furanyl, 3-furanyl, 4-furanyl, 5-furanyl), pyridyl (2 -pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl), 5-tetrazolyl, pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl) , 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl , 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo [b] furanyl (2-benzo [b] furanyl, 3-benzo [b] furanyl, 4-benzo [b] furanyl, 5- benzo [b] furanyl, 6-benzo [b] furanyl, 7-benzo [b] furanyl), 2,3-dihydro-benzo [b] furanyl (2- (2,3-dihydro-benzo [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)), 1,4-benzodioxin (2- (1,4-benzodioxin), 3- (1,4-benzodioxin), 5- (1, 4-benzodioxin), 6- (1,4-benzodioxin), 7- (1,4-benzodioxin), 8- (1,4-benzodioxin)), benzo [b] thiophenyl (2-benzo [b] thiophenyl), 3-benzo [b] thiophenyl, 4-benzo [b] thiophenyl, 5-benzo [b] thiophenyl, 6-benzo [b] thiophenyl, 7-benzo [b] thiophenyl), 2,3-dihydro-benzo [b] ] thiophenyl (2- (2,3-dihydro-benzo [b] thiophenyl), 3- (2,3-dihydro-benzo [b] thiophenyl), 4- (2,3-dihydrobenzo [b] thiophenyl), - (2,3-dihydro-benzo [b] thiophenyl), 6- (2,3-dihydro-benzo [b] thiophenyl), 7- (2,3-dihydro-benzo [b] thiophenyl)), 4, 5,6,7-tetrahydro-benzo [b] thiophenyl (2- (4,5,6,7-tetrahydro-benzo [b] thiophenyl), 3- (4,5,6,7-tetrahydrobenzo) [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-tetrahydro-benzo [b] thiophenyl), 7- (4,5,6,7-tetrahydro-benzo [b] thiophenyl)), thieno [2,3-b] thiophenyl, 4 ,5, 6,7-tetrahydro-thieno [2,3-c] pyridyl (4- (4,5,6,7-tetrahydro-thieno [2,3-c] pyridyl), 5-4,5,6J-tetrahydro- thieno [2,3-c] pyridyl), 6- (4,5,6,7-tetrahydro-thieno [2,3-c] pyridyl), 7- (4,5,6J-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-benzimidazolyl) , 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benz-oxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), benzo- [1, 2,5] oxadiazolyl , (4-benzo [1, 2,5] oxadiazole, 5-benzo [1, 2,5] oxadiazole), carbazolyl (1 -carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), piperidinyl (2- piperidinyl, 3-piperidinyl, 4-piperidinyl) or, and pyrrolidinyl (1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl).

The term "arylalkyl" represents an aryl group as defined above linked through an alkyl group having the indicated number of carbon atoms (eg, benzyl, phenylethyl, 3-phenylpropyl, 1-naphthylmethyl, 2- (1 -naphthyl) ethyl).

The term "hetarylalkyl" or "hetaralkylol" represents a hetaryl group as defined above linked through a group having the indicated number of carbon atoms (e.g., (2-furyl) methyl, (3-furyl) methyl, (2-thienyl) methyl, (3-thienyl) methyl, (2-pyridyl) methyl, and 1-methyl-1- (2-pyrimidyl) ethyl).

The term "aryloxyhetaryl" represents an aryloxy group as defined above linked through a hetaryl group (e.g., 2-phenoxy-pyridyl).

The term "aryloxy" represents an aryl group as defined above linked through an oxygen bridge (e.g., phenoxy and naphthyloxy).

The term "hetaryloxy" represents a hetaryl group as defined above linked through an oxygen bridge (e.g., 2-pyridyloxy).

The term "arylalkyloxy" represents an arylalkyl group as defined above linked through an oxygen bridge (for example, phenethyloxy and naphthylmethyloxy).

The term "hetarylalkyloxy" represents a hetarylalkyl group as defined above linked through an oxygen bridge (e.g., 2-pyridylmethyloxy).

The term "alkyloxycarbonyl" represents an alkyloxy group as defined above linked through a carbonyl group (e.g., methylformate and ethylformate).

The term "aryloxycarbonyl" represents an aryloxy group as defined above linked through a carbonyl group (eg, phenylformiate and 2-thiazolylformate).

The term "arylalkyloxycarbonyl" represents an "arylalkyloxy" group as defined above linked through a carbonyl group (eg, benzylformate and phenylethylformate).

The term "alkylthio" represents an alkyl group having the indicated number of carbon atoms attached through a sulfur bridge (e.g., methyl or ethylthio).

The term "arylthio" means an aryl group as defined above attached through a sulfur bridge (for example, benzothiol and naphthylthiol).

The term "hetarylthio" represents a hetaryl group as defined above linked through a sulfur bridge (e.g., pyridine-2-thiol and thiazole-2-thiol).

The term "arylthioalkyl" represents an arylthio group as defined above attached through an alkyl group having the indicated number of carbon atoms (for example, methylsulfanyl benzene and ethylsulfanyl naphthalene).

The term "hetarylthioalkyl" represents a hetarylthio group as defined above linked through an alkyl group having the indicated number of carbon atoms (for example, 2-methylsulfanyl-pyridine and 1-ethylsulfanyl-isoquinoline).

The term "hetaryloxyaryl" represents a hetaryloxy group as defined above linked through an aryl group as defined above (e.g., Ifenoxy-isoquinolyl and 2-phenoxypyridyl).

The term "hetaryloxyhetaryl" represents a hetaryloxy group as defined above linked through a hetaryl group as defined above (e.g., 1- (2-pyridyloxy-isoquinoline) and 2- (imidazol-2-yloxy-pyridine)) .

The term "aryloxyalkyl" represents an aryloxy group as defined above linked through an alkyl group having the indicated number of carbon atoms (e.g., phenoxymethyl and naphthyloxymethyl).

The term "aryloxyaryl" represents an aryloxy group as defined above linked through an aryl group as defined above (e.g., 1-phenoxy-naphthalene and phenyloxyphenyl).

The term "arylalkyloxyalkyl" represents an arylalkyloxy group as defined above linked through an alkyl group having the indicated number of carbon atoms (for example, ethoxy-methyl-benzene and 2-methoxymethyl-naphthalene).

The term "hetaryloxyalkyl" represents a hetaryloxy group as defined above attached through an alkyl group having the indicated number of carbon atoms (eg, 2-pyridyloxymethyl and 2-quinolyloxyethyl).

The term "hetarylalkyloxyalkyl" represents a hetarylalkyloxy group as defined above linked through an alkyl group having the indicated number of carbon atoms (for example, 4-methoxymethyl-pyrimidine and 2-methoxymethyl-quinoline).

The term "alkylcarbonyl" means an alkyl group as defined above having the indicated number of carbon atoms bonded through a carbonyl group (eg, octylcarbonyl, pentylcarbonyl and 3-hexenylcarbonyl).

The term "arylcarbonyl" represents an aryl group as defined above linked through a carbonyl group (eg, benzoyl).

The term "hetarylcarbonyl" represents a hetaryl group as defined above bonded through a carbonyl group (eg, 2-thiophenylcarbonyl, 3-methoxy-anthrylcarbonyl and oxazolylcarbonyl).

The term "carbonylalkyl" represents a carbonyl group bonded through an alkyl group having the indicated number of carbon atoms (eg, acetyl).

The term "alkylcarbonylalkyl" represents an alkylcarbonyl group as defined above linked through an alkyl group having the indicated number of carbon atoms (e.g., propan-2-one and 4.4, -dimethyl-pentan-2-) ona).

The term "arylcarbonylalkyl" represents an arylcarbonyl group as defined above attached through an alkyl group having the indicated number of carbon atoms (e.g., 1-phenyl-propan-1-one and 1- (3-chloro- phenyl) -2-methyl-butan-1-one).

The term "hetarylcarbonylalkyl" represents a hetarylcarbonyl group as defined above attached through an alkyl group having the indicated number of carbon atoms (e.g., 1-pyridin-2-propan-1-one and 1- (1- / - / - imidazol-2-yl) -propan-1-one).

The term "alkylcarbonyl" represents an arylalkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group (eg, phenylpropylcarbonyl and phenylethylcarbonyl).

The term "hetarylalkylcarbonyl" represents a hetarylalkyl group as defined above wherein the alkyl group is in turn linked through a carbonyl (e.g., imidazolylpentylcarbonyl).

The term "alkylcarbonylamino" represents an "alkylcarbonyl" group as defined above, wherein the carbonyl is in turn linked through the nitrogen atom of an amino group (eg, methylcarbonylamino, cyclopentylcarbonyl-aminomethyl, and methylcarbonylaminophenyl). The nitrogen atom itself can be substituted with an alkyl or aryl group.

The term "alkylcarbonylaminoalkyl" represents an "alkylcarbonylamino" group linked through an alkyl group having the indicated number of carbon atoms (for example, N-propyl-acetamide and N-butyl-propionamide).

The term "arylalkylcarbonylamino" represents an "arylalkylcarbonyl" group as defined above linked through an amino group (e.g., phenylacetamide and 3-phenyl-propionamide).

The term "arylalkylcarbonylaminoalkyl" represents an "arylalkylcarbonylamino" group linked through an alkyl group having the indicated number of carbon atoms (for example, N-ethyl-phenylacetamide and N-butyl-3-phenyl-propionamide).

The term "arylcarbonylamino" represents an "arylcarbonyl" group as defined above linked through an amino group (for example, benzamide and naphthalene-1-carboxylic acid amide).

The term "arylcarbonylaminoalkyl" represents an "arylcarbonylamino" group linked through an alkyl group having the indicated number of carbon atoms (for example, N-propyl-benzamide and N-butyl-naphthalene-1-carboxylic acid amide) .

The term "alkylcarboxy" represents an alkylcarbonyl group as defined above wherein the carbonyl is in turn linked through an oxygen bridge (for example, heptylcarboxy, cyclopropylcarboxy and 3-pentenylcarboxy).

The term "arylcarboxy" represents an arylcarbonyl group as defined above wherein the carbonyl is in turn linked through an oxygen bridge (eg, benzoic acid).

The term "alkylcarboxyalkyl" represents an alkylcarboxy group as defined above wherein the oxygen is attached via an alkyl bridge (eg, heptylcarboxymethyl, propylcarboxy-ferf-butyl and 3-pentylcarboxyethyl).

The term "arylalkylcarboxy" represents an arylalkylcarbonyl group as defined above wherein the carbonyl is in turn linked through an oxygen bridge (eg, benzylcarboxy and phenylpropylcarboxy).

The term "arylalkylcarboxyalkyl" represents an arylalkylcarboxy group as defined above wherein the carboxy group is in turn linked through an alkyl group having the indicated number of carbon atoms (eg, benzylcarboxymethyl and phenylpropylcarboxypropyl).

The term "hetarylcarboxy" represents a hetarylcarbonyl group as defined above, wherein the carbonyl is in turn linked through an oxygen bridge (e.g., pyridine-2-carboxylic acid).

The term "hetarylalkylcarboxy" represents a hetarylalkylcarbonyl group as defined above, wherein the carbonyl is in turn linked through an oxygen bridge (e.g., 1-H-imidazol-2-yl) -acetic acid and -pyrimidin-2-yl-propionic).

The term "alkyl S (0) m" represents an alkyl group having the number of carbon atoms indicated, wherein the alkyl group is in turn bound through a sulfur bridge, where the sulfur is replaced with oxygen atoms (for example, ethylsulfonyl and ethylsulfinyl).

The term "ariIS (0) m" represents an aryl group as defined above, wherein the aryl group is in turn linked through a sulfur bridge, where the sulfur is replaced by m oxygen atoms ( for example, phenylsulfinyl and naphthyl-2-sulfonyl).

The term "hetaryl (0) m" represents a hetaryl group as defined above, wherein the hetaryl group is in turn linked through a sulfur bridge where the sulfur is substituted with m carbon atoms (e.g. , thiazole-2-sulfinyl and pyridine-2-sulfonyl).

Certain of the previously defined terms may occur more than once in the structural formulas and in said occurrence each term will be defined independently of the other.

The term "optionally substituted" as used herein means that the groups in question are substituted or unsubstituted with one or more specified substituents. When the groups in question are substituted with one or more than one substituent, the substituents may be the same or different.

The term "treatment" or "treating" 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 administration of the active compound to prevent or delay the onset of symptoms or complications, alleviate (both permanently and temporarily) the symptoms or complications and / or eliminate the disease, condition or disorder. In addition, "treatment" or "treating" includes the prevention and / or prophylaxis of the disease, condition or disorder.

The term "pharmaceutically acceptable" is defined as being appropriate 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 the development of prodrugs are well known in the art.

In addition, in one embodiment, the present invention provides a novel substituted amide, a prodrug thereof or a salt thereof with a pharmaceutically acceptable base or acid or any optional optical isomer or mixture of optical isomers, including a racemic mixture of any tautomeric form, wherein the compound is of formula I: wherein: X is selected from CR and nitrogen; R1 is selected from H and C -Cβ-R6 alkyl, wherein the alkyl group is substituted with 0-3 R7; R is selected from hydrogen, halo, C6 alkyl, and -C (= 0) R13.

R8 R10, 12 alternatively, R1 and R2 are independently, R9 R Ring A is a saturated or partially saturated bicyclic or tricyclic ring consisting of the nitrogen shown, 4-10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen, and sulfur; ring A is substituted with 0-3 groups selected from alkyl halo, hydroxy, oxo, cyano, C? -C6 alkyloxy, dC6 alkylene, C6 alkyloxy, and C? Ce alkylcarbonyl, wherein each alkyl / alkylene group is substituted with 0-3 R14; R5 is selected from hydrogen, C? -C6 alkyl, -C (= 0) R13, and cyano; R6 is selected from cyano, C3-C10 cycloalkyl, 3-10 membered hetcycloalkyl, aryl, hetaryl, -C (= 0) R13, -S (= 0) nR13, -S (= 0) nNR18R19, -N (R18 ) S (= 0) nR13, -N (R23) C (= Y) NR 8R19, -C (= NR15) NR15, -N (R18) C (= 0) R13, cycloalkyl -N (R18) C (= O) -C3-C10, hetcycloalkyl -N (R18) C (= 0) - of 3-10 members, aryl -N (R18) C (= 0), hetaryl-N (R18) C (= 0) - wherein the cycloalkyl, hetcycloalkyl, aryl, and hetaryl groups are substituted with 0-3 R16; R7 is selected from halo, hydroxy, oxo, cyano, and alkyl R8, R9, R10 and R11 are independently selected from hydrogen, CrC-β, F, trihalomethyl, trihalomethoxy, hydroxy, and C alquilo alquilo alkyloxy alkyl, wherein C Cß alkyl and C?-C alquilo alquilo alkyloxy are substituted with 0-3 R1717; alternatively, R8 and R9 together with the carbon atom to which they are attached form a saturated or partially saturated ring consisting of the carbon atom shown, 2-5 additional carbon atoms and 2-0 carbon atoms selected from nitrogen, oxygen and sulfur, where this ring is substituted with 0-3 groups selected from halo, trihalomethyl, alkyl aryl, hetaryl, alkylene aryl, C6-C6 hetaryl, hydroxy, oxo, C6-alkyloxy, aryloxy, CrC6aryl or alkyloxy alkyloxy hetaryl; alternatively, R10 and R11 together with the carbon atom to which they are attached form a saturated or partially saturated ring consisting of the carbon atom shown, 2-5 carbon atoms. additional carbon and 0-2 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the ring is substituted with 0-3 groups selected from halo, trihalomethyl, CrC 6 alkyl, aryl, hetaryl, C alkylene aryl, C alkylene C6 hetaryl, hydroxy, oxo, C6 alkyloxy, aryloxy, C6 alkyloxy aryl or C6heteroyl alkyloxy; alternatively, R8 and R10 together with the two carbon atoms to which they are attached form a saturated or partially saturated ring consisting of the two carbon atoms shown, 1-4 additional carbon atoms and 0-2 heteroatoms selected from nitrogen, oxygen and sulfur where the ring is substituted with 0-3 groups selected from halo, trihalomethyl, alkyl aryl, hetaryl, alkylene aryl, alkylene hetaryl, hydroxy, oxo, C6 alkyloxy, aryloxy, alkyloxy aryl, and alkyloxy CrC6 hetaryl; R 2 is selected from H, OH, NR18R19, C3-C10 cycloalkyl, 3-10 membered hetcycloalkyl, -C (= 0) R13, -S (= 0) nR13, S (= 0) nNR18R19, -N (R18 ) S (= 0) nR13, and -C (= NR15) NR16; wherein the cycloalkyl and hetcycloalkyl groups are substituted with 0-3 R17; R13 is selected from OH, C-C-alkyl, C-C8-alkyloxy, C-C4-alkylene-C8-alkyloxy, aryl, hetaryl, aryloxy, hetaryloxy, and NR18R19; R14 is selected from halo, hydroxy, oxo, and cyano; R15 and R16 are independently selected from H, C8 alkyl, 3-10 membered cycloalkyl, halo, OH, cyano, -C (= 0) R13, -S (= 0) nR13, S (= 0) nNR18R19, - N (R18) S (= 0) nR13, aryl, and hetaryl, wherein the alkyl and cycloalkyl groups are substituted with 0-3 R20; R17 is selected from halo, OH, oxo, nitro, cyano, -C (= 0) R13, -S (= 0) nR13, S (= 0) nNR18R19, --N (R18) S (= 0) nR13, NR18R19 , C? -C? alkyl, CrC6 alkyloxy, and aryloxy; R18 and R19 are independently selected from H, C?-C8 alkyl, Ci-Cß alkyloxy, aryl, hetaryl, C Cß aryl alkylene, and C C66 alkylene hetaryl, wherein the alkyl / alkylene, aryl, and hetaryl groups are independently substituted with 0-3 R20; alternatively, R18 and R19, together with the nitrogen atom to which they are attached, form a monocyclic, bicyclic or tricyclic saturated or partially saturated ring consisting of the nitrogen shown, 4-10 carbon atoms and 0-2 additional heteroatoms selected from nitrogen , oxygen and sulfur, where this ring is substituted with 0-3 C Cß alkyl, aryl, hetaryl, alkylene Ci-Ce aryl, C6-C6-hetaryl, hydroxy, oxo, C6-alkyloxy, C6-C6-alkyloxy, C6-C6-alkyloxy hetaryl, C6-C6-alkyloxy-C-C14 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, alkylcarbonyl arylcarboxy, hetarylcarboxy, alkylcarboxy CrC6 aryl, and C6 alkylcarboxy hetaryl; R 20 is selected from H, OH, oxo, halo, cyano, nitro, C 1 Ce alkyl, C 6 alkyloxy, NR 21 R 22, methylenedioxo, dihalomethylenedioxo, trihalomethyl, and trihalomethyloxy; R21 and R22 are independently selected from H, CrC8 alkyl, and alkyl aril; R23 is selected from H and CtC6 alkyl; n is selected from 0, 1, and 2; And it is selected from O and S; 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 form.

In another embodiment, the present invention provides the novel use of the compounds of Formula I, wherein: R 1 is selected from H and C 4 -C 6 alkyl, wherein the alkyl group is substituted with 0-1 R 7; R2 is selected from hydrogen, CrC6 alkyl, 'and -C (= 0) R13; R8 R10 alternatively, R1 and R2 are, independently, -R H9 R ~ 11R12 ring A is a saturated or partially saturated bicyclic or tricyclic ring consisting of the nitrogen shown and 7-10 carbon atoms; ring A is substituted with 0-3 groups selected from C?-C, halo, hydroxy, and C Cß alkyloxy; R5 is selected from hydrogen and C C alkyl; R6 is selected from cyano, C3-C6 cycloalkyl, 3-6 membered hetcycloalkyl, aryl, hetaryl, -C (= 0) R13, -S (= 0) nR13, -S (= 0) nNR18R19, -N (R18 ) S (0) nR13, -N (R23) C (= Y) NR18R19, -C (= NR15) NR15, -N (R18) C (= 0) R13, cycloalkyl -N (R18) C (= 0) -C3-C6, hetcycloalkyl -N (R18) C (= 0) -de 3-6 members, -aryl N (R18) C (= 0) -, hetaryl -N (R18) C (= 0) -, wherein the cycloalkyl, hetcycloalkyl, aryl, and hetaryl groups are substituted with 0-3 R16; R7 is selected from halo and C4 alkyl; R8, R9, R10 and R11 are independently selected from hydrogen and C4 alkyl; alternatively, R8 and R10 together with the two carbon atoms to which they are attached form a saturated or partially saturated ring consisting of the two carbon atoms shown and 1-4 additional carbon atoms, wherein this ring is substituted with 0 -1 groups selected from halo, trihalomethyl, hydroxyl, and alkyl R12 is selected from H, OH, and NR18R19; R 13 is selected from OH, C 1 Ct alkyl, C 1 alkyloxy, C 1-4 alkylene, CrC 4 alkyloxy, aryl, hetaryl, aryloxy, hetaryloxy, and NR 18 R 19; R15 and R16 are independently selected from H, Cr alkyl, 3-6 membered cycloalkyl, halo, OH, cyano, -C (= 0) R13, -S (= 0) nR13, S (= 0) nNR18R19, -N (R18) S (= 0) nR13, aryl, and hetaryl, wherein the alkyl and cycloalkyl groups are substituted with 0-1 R20; R18 and R19 are independently selected from H, CrC alkyl, C 1 Ct alkyloxy, aryl, hetaryl, C 1 -C 4 alkylene, and C 1 -C 4 alkylene hetaryl, wherein the alkyl / alkylene, aryl, and hetaryl groups are independently substituted with 0-1 R20; alternatively, R18 and R19, together with the nitrogen atom to which they are attached, form a monocyclic, bicyclic or tricyclic partially saturated or saturated ring consisting of the nitrogen shown, 4-5 carbon atoms, and 0-1 additional heteroatoms selected from nitrogen , oxygen and sulfur, where this ring is substituted with 0-1 alkyl CrG ,, aryl, hetaryl, alkylene alkylene, hydroxy, and C4 alkyloxy; R20 is selected from H, OH, oxo, halo, cyano, nitro, C-C4 alkyl, C? -Calkyloxy, NR21R22, trihalomethyl, and trihalomethyloxy; R21 and R22 is independently selected from H, C4 alkyl, and C4 alkyl aryl; R23 is selected from H and C Ce alkyl; n is selected from 0, 1, and 2; and Y is selected from O and S.

In another embodiment, the present invention provides the novel use of compounds wherein the substituted amide or prodrug thereof is of formula IA: IA.

In another embodiment, the present invention provides the novel use of compounds, wherein the amide or substituted prodrug thereof is of formula IB: In another embodiment, the present invention provides the novel use of the compounds wherein the amide or the prodrug thereof are of formula IC: In another embodiment, the present invention provides the novel use of compounds wherein the amide or prodrug thereof is of formula ID: ID.

In another embodiment, the present invention provides the novel use of compounds of formula I, wherein: Ring A is selected from: ring A is substituted with 0-2 R; and, R24 is selected from alkyl halo, hydroxy, oxo, cyano, and C? -C6 alkyloxy.

In another embodiment, the present invention provides the novel use of compounds of Formula I, wherein: Ring A is: In another embodiment, the present invention provides the novel use of compounds of Formula I, wherein the amide or a prodrug thereof are selected from the group: Furan-2-carboxylic acid. { 2- [5- (1,3,3-Trimethyl-6-azabicyclo [3.2.1] octane-6-carbonyl) -benzoimidazol-1-yl] -ethyl} - 1-Acetyl-piperidine-4-carboxylic acid amide. { 2- [5- (1,3,3-trimethyl-6-aza-1 bicyclo [3.2.1] octane-6-carbonyl) -benzoimidazol-1-yl] -ethyl} -amide 2-Methoxy -? / -. { 2- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -2-benzoimidazol-1-yl] -ethyl} -acetamide / -. { 2- [5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -3-benzoimidazol-1-yl] -ethyl} -isonicotinamide? / -. { 2- [5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -4-benzoimidazol-1-yl] -ethyl} -acetamide ferric acid ester. { 2- [5- (1,3,3-Trimethyl-6-aza-5-bicyclo [3.2.1] octane-6-carbonyl) -benzoimidazol-1-yl] -ethyl} -carbamic lsoxazole-5-carboxylic acid. { 2- [5- (1, 3,3-trimethyl-6-aza-6-bicyclo [3.2.1] octane-6-carbonyl) -benzoimidazol-1-yl] -ethyl} -amide ? / -. { 2- [5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -7-benzoimidazol-1-yl] -ethyl} -benzamide 3- [2-Ethyl-5- (1, 3,3-trimethyl-6-azabicyclo [3.2.1] octane-6-carbonyl) -benzimidazol-1-yl] -propyl ethyl ester ionic acid 3- [2-Ethyl-5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzimidazol-1-yl] -propionic acid ethyl ester 2 - [5- (1,3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -1 H-benzimidazol-2-yl] -cyclopropanecarboxylic acid 2- [5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -1H-benzimidazol-2-yl] -cyclopropanecarboxylic acid 3- [2-methyl-5- (1, 3,3-trimethyl-6-aza-1 bicyclo [3.2.1] octane-6-carbonyl) -benzimidazol-1-yl] -propionic 2- [1-Ethyl-5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-2-6-carbonyl) -1 H-benzimidazol-2-yl] ethyl ester -cyclopropanecarboxylic acid 3- [2-Methyl-5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -3-benzimidazol-1-yl] -propionic acid 2 - [1-Ethyl-5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -1H-4-benzimidazol-2-yl] -cyclopropanecarboxylic acid ethyl ester 3- [5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -propionic acid 3- [5- (1, 3) , 3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -propionic acid ester 5- (1, 3,3-Trimethyl-6-butyl) aza-bicyclo [3.2.1] octane-6-1-carbonyl) -indol-1-yl] -acetic acid [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane- 6-carbonyl) -indol-1-yl] -2-acetic acid 1-Morpholin-4-yl-3- [5- (1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6 -carbonyl) -3-indol-1-yl] -propan-1 -one 1-morpholin-4-yl-2- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) --4 indol-1-yl] -ethanone 2,2-Dimethyl-3- [5- (1, 3,3-trimethyl-6-aza-5-bicyclo [3.2.1] octane-6-ethyl ester -carbonyl) -indol-1-yl] -propionic acid 2,2-Dimethyl-3- [5- (1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) - -6 indole-1-yl] -propionic acid methyl ester 2-Methyl-3- [5- (1, 3,3-trimethyl-6-aza-7 bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -propionic acid methyl ester 3- [5- (1,3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6--8 carbonyl) -indol-1- il] -butyric acid 3- [5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -9-butyric acid 2-Methyl-3- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-10 1 -yl] -propionic acid 3- [ 5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1--11-ylmethyl-benzoic acid methyl ester 4- [5- (1, 3 , 3-Trimethylol-6-aza-bicyclo [3.2.1] octane-6-12-carbonyl) -indol-1-ylmethyl] -benzoic acid 4- [5- (1, 3,3-Trimethyl-6 -aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1 -13-ylmethyl-benzoic acid 3- [5- (4-Aza-tricyclo [4.3.1.1 * 3.8]] undecano-4-carbonyl) -14-indol-1-yl] -propionic acid 3- [5- (4-Aza-tricyclo [4.3.1.1 * 3,8 *] undecane-4-carbonyl) -indol-1- il] - 15 propionic 5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -1 - / - indole-2-carboxylic acid ethyl ester 5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -1H-indole-2-carboxylic acid? / - Methoxy -? / - methyl-3- [5- (1 , 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -0 indol-1-yl] -propionamide? / - Ethoxy-3- [5- (1, 3,3- trimetil-6-aza-bici clo [3.2.1] octane-6-carbonyl) -indol-1-1-yl] -propionamide? / - Hydroxy-3- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1 ] octane-6-carbonyl) -indol-1-2-yl] -propionamide. { 1- [2- (2H-Tetrazol-5-yl) -ethyl] -H-indol-5-yl} - (1, 3,3-trimethyl-6-aza-3 bicyclo [3.2.1] oct-6-yl) -methanone. { 1- [2- (3-Cyclopropyl- [1, 2,4] oxadiazol-5-yl) -ethyl] -lH-indol-5-yl} - (1,3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -metanone . { 1- [2- (3-Methyl- [1, 2,4] oxadiazol-5-yl) -ethyl] - 'H-indol-5-yl} - (1, 3,3-trimethyl-6-aza-15-bicyclo [3.2.1] oct-6-yl) -methanone? / - (IH-Tetrazol-5-yl) -3- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -propionamide. { 1- [2- (2-Methyl-2H-tetrazol-5-yl) -ethyl] -lH-indol-5-yl} - (1, 3,3-trimethyl-6-aza-17-bicyclo [3.2.1] oct-6-yl) -methanone. { 1- [2- (1-Methyl-1H-tetrazol-5-yl) -ethyl] -lH-indol-5-yl} - (1, 3,3-trimethyl-6-aza-18-bicyclo [3.2.1] oct-6-yl) -methanone. { 1- [2- (5-Methyl- [1, 2,4] oxadiazol-3-yl) -ethyl] -lH-indol-5-yl} - (1, 3,3-trimethyl-6-aza-19-bicyclo [3.2.1] oct-6-yl) -metanone 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 form.

In another embodiment, the present invention is provided for the novel preparation of a pharmaceutical composition for the treatment of conditions, diseases or disorders wherein a modulation or an inhibition of 11βHSD1 activity is beneficial.

In another embodiment, the present invention provides the novel preparation of a pharmaceutical composition, wherein conditions, disorders and diseases are influenced by intracellular glucocorticoid levels.

In another embodiment, the present invention provides the novel preparation of a pharmaceutical composition, wherein: the conditions, disorders or diseases are selected from the metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, type 2 diabetes, decreased tolerance to glucose (IGT), decreased fasting glucose (IFG), the progress of IGT to type 2 diabetes, the progress of the metabolic syndrome to type 2 diabetes, complications delayed diabetics, neurodegenerative and psychiatric diseases and the adverse effects of glucocorticoid receptor agonist treatment or therapy.

In another embodiment, the present invention provides the novel preparation of a pharmaceutical composition, wherein: the pharmaceutical composition is appropriate for a route of administration selected from oral, nasal, buccal, transdermal, pulmonary and parenteral.

In another embodiment, the present invention provides a novel method for the treatment of conditions, disorders or diseases wherein a modulation or an inhibition for the activity of 11βHSD1 is beneficial, the method comprising administering to a subject in need thereof an amount of effective of a compound of the present invention.

In another embodiment, the present invention provides a novel method wherein conditions, disorders and diseases are influenced by intracellular glucocorticoid levels.

In another embodiment, the present invention provides a novel method wherein the conditions, disorders or diseases are selected from the metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, type 2 diabetes, decreased glucose tolerance (IGT), glucose. in decreased fasting (IFG), progression of IGT to type 2 diabetes, progress of metabolic syndrome to type 2 diabetes "late diabetic complications, neurodegenerative and psychiatric disorders and adverse effects of treatment or therapy with glucocorticoid receptor agonist.

In another embodiment, the present invention provides a novel method wherein administration is via a selected route of oral, nasal, buccal, transdermal, pulmonary and parenteral.

In another embodiment, the present invention provides a novel compound of formula wherein: X is selected from CR-55 and nitrogen; R1 is selected from H and C-C6 alkyl, wherein the alkyl group is substituted with 0-3 R7; R2 is selected from hydrogen, halo, C6 alkyl, and -C (= 0) R13; R8 R10, 12 alternatively, R1 and R2 are independently, R9 R ring A is a bicyclic or tricyclic saturated or partially saturated ring consisting of the nitrogen shown, 4-10 carbon atoms and 0-2 additional heteroatoms selected from nitrogen, oxygen, and sulfur; ring A is substituted with 0-3 groups selected from C 8 alkyl, halo, hydroxy, oxo, cyano, C 6 alkyloxy, C 6 alkylene alkyloxy and C 1 -C 6 alkylcarbonyl, wherein each alkyl / alkylene group is substituted with 0-3 R: > 114 R5 is selected from hydrogen, C1-C6 alkyl, -C (= 0) R, 11.35, and cyano; R6 is selected from cyano, C3-C10 cycloalkyl, 3-10 membered hetcycloalkyl, aryl, hetaryl, -C (= 0) R13, -S (= 0) nR13, -S (= 0) nNR18R19, N (R, 1'8 °) S (= 0) nR, 1'3J, -C (= NR15) NR15, -N (R18) C (= 0) R13, cycloalkyl -N (R18) C (= O) -C3-C10, hetcycloalkyl -N (R18) C (= 0) - of 3 -10 members, aryl -N (R18) 0 (= O), hetaryl-N (R8) C (= 0) - wherein the cycloalkyl, hetcycloalkyl, aryl, and hetaryl groups are substituted with 0-3 R16; R7 is selected from halo, hydroxy, oxo, cyano, and Ci-Cß alkyl; R8, R9, R10 and R11 are independently selected from hydrogen, C-Cß alkyl, F, trihalomethyl, trihalomethoxy, hydroxy, and C Cß alkyloxy, wherein C el8 alkyl and alkyloxy they are substituted with 0-3 R17; alternatively, R8 and R9 together with the carbon atom to which they are attached form a saturated or partially saturated ring consisting of the carbon atom shown, 2-5 additional carbon atoms and 2-0 carbon atoms selected from nitrogen, oxygen and sulfur, wherein this ring is substituted with 0-3 groups selected from halo, trihalomethyl, C-rCß alkyl, aryl, hetaryl, alkylene hetaryl, hydroxy, oxo, alkyloxy aryloxy, alkyloxyCrylaryl or alkyloxy hetaryl; alternatively, R10 and R11 together with the carbon atom to which they are attached form a saturated or partially saturated ring consisting of the carbon atom shown, 2-5 additional carbon atoms and 0-2 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the ring is substituted with 0-3 groups selected from halo, trihalomethyl, C? -C6 alkyl, aryl, hetaryl, C? -C6 alkylene, aryl, C6 alkylene hetaryl, hydroxy, oxo, C6 alkyloxy, aryloxy, alkyloxy C? -C6 aryl or Ci-C-hetaryl alkyloxy; alternatively, R8 and R10 together with the two carbon atoms to which they are attached form a saturated or partially saturated ring consisting of the two carbon atoms shown, 1-4 additional carbon atoms and 0-2 heteroatoms selected from nitrogen, oxygen and sulfur wherein the ring is substituted with 0-3 groups selected from halo, trihalomethyl, C6-alkyl, aryl, hetaryl, C6-C6-alkylene, aryl, C-C-henaryl alkylene, hydroxy, oxo, alkyloxy aryl, and alkyloxy hetaryl; R 12 is selected from H, OH, NR 18 R 19, C 3 -C 0 cycloalkyl, 3-10 membered hetcycloalkyl, -C (= 0) R 13, -S (= 0) n R 13, S (= 0) nNR 18 R 19, -N ( R18) S (= 0) nR13, and -C (= NR15) NR16; wherein the cycloalkyl and hetcycloalkyl groups are substituted with 0-3 R17; R13 is selected from OH, alkyl CrC8alkyloxy, C4alkylene C4alkyloxyxy, aryl, hetaryl, aryloxy, hetaryloxy, and NR18R19; R14 is selected from halo, hydroxy, oxo, and cyano; R15 and R16 are independently selected from H, d-C8 alkyl, 3-10 membered cycloalkyl, halo, OH, cyano, -C (= 0) R13, -S (= 0) nR13, S (= 0) nNR18R19, -N (R18) S (= 0) nR13, aryl, and hetaryl, wherein the alkyl and cycloalkyl groups are substituted with 0-3 R20; R17 is selected from halo, OH, oxo, nitro, cyano, -C (= 0) R13, -S (= 0) nR13, S (= 0) nNR18R19, -N (R18) S (= 0) nR13, NR18R19 , d-C8 alkyl, d-C6 alkyloxy, and aryloxy; R18 and R19 are independently selected from H, d-C8 alkyl, d-C8 alkyloxy, aryl, hetaryl, C?-C6 alkylene aryl, and d-Cß hetaryl alkylene, wherein the alkyl / alkylene, aryl, and hetaryl groups are replace independently with 0-3 R20; alternatively, R18 and R19, together with the nitrogen atom to which they are attached, form a monocyclic, bicyclic or tricyclic saturated or partially saturated ring consisting of the nitrogen shown, 4-10 carbon atoms and 0-2 additional heteroatoms selected from nitrogen , oxygen and sulfur, wherein this ring is substituted with 0-3 d-C8 alkyl, aryl, hetaryl, C? -C6 alkylene, aryl, d-C6 alkylene, hetaryl, hydroxy, oxo, d-C? alkyloxy, d-C? alkyloxy aryl, d-C6 alkyloxy hetaryl, C6-C6alkyloxy d-C6alkyl, d-C6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, d-C6alkylcarbonyl aryl, dicarboxycarbonyl d-Cß hetaryl, dicarboxycarboxycarboxy, arylcarboxy, hetarylcarboxy, alkylcarboxy C C6 aryl, and C6-C6 hetaryl alkylcarboxy; R20 is selected from H, OH, oxo, halo, cyano, nitro, C-C-alkyl, CrC6-alkyloxy, NR21R22, methylenedioxo, dihalomethylenedioxo, trihalomethyl, and trihalomethyloxy; R21 and R22 are independently selected from H, CrC8 alkyl, and C -C aryl alkyl; R23 is selected from H and CrC6 alkyl; n is selected from 0, 1, and 2; And it is selected from O and S; 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 form.

In another embodiment, the present invention provides the novel compound of Formula I, wherein: R1 is selected from H and alkyl dC4-R6, wherein the alkyl group is substituted with 0-1 R7; R2 is selected from hydrogen, d-C6 alkyl, and -C (= 0) R13; 'R8 R10 alternatively, R1 and R2 are, independently, -R H9 R ~ 11R12 ring A is a saturated or partially saturated bicyclic or tricyclic ring consisting of the nitrogen shown and 7-10 carbon atoms; ring A is substituted with 0-3 groups selected from d-C4 alkyl, halo, hydroxy, and C6alkyloxy; R5 is selected from hydrogen and dC4 alkyl; R6 is selected from cyano, C3-C6 cycloalkyl, 3-6 membered hetcycloalkyl, aryl, hetaryl, -C (= 0) R13, -S (= 0) nR13, -S (= 0) nNR18R19, -N (R18 ) S (= 0) nR13, -N (R23) C (= Y) NR18R19, -C (= NR15) NR15, -N (R 8) C (= 0) R13, cycloalkyl -N (R18) C (= 0) -C3-C6, hetcycloalkyl -N (R18) C (= 0) -of 3-6 members, -aryl N (R18) C (= 0) -, hetaryl -N (R 8) C (= 0) -, wherein the cycloalkyl, hetcycloalkyl, aryl, and hetaryl groups are substituted with 0-3 R16; R7 is selected from halo and d-C4 alkyl; R8, R9, R10 and R11 are independently selected from hydrogen and CrC4 alkyl; alternatively, R8 and R10 together with the two carbon atoms to which they are attached form a saturated or partially saturated ring consisting of the two carbon atoms shown and 1-4 additional carbon atoms, wherein this ring is substituted with 0 -1 groups selected from halo, trihalomethyl, hydroxyl, and d-C6 alkyl; R12 is selected from H, OH, and NR18R19; R13 is selected from OH, d-C4 alkyl, CrC4 alkyloxy, CrC4 alkylene-d-C4 alkyloxy, aryl, hetaryl, aryloxy, hetaryloxy, and NR18R19; R15 and R16 are independently selected from H, dC alkyl, 3-6 membered cycloalkyl, halo, OH, cyano, -C (= 0) R13, -S (= 0) nR13, S (= 0) nNR18R19, -N (R18) S (= 0) nR13, aryl, and hetaryl, wherein the alkyl and cycloalkyl groups are substituted with 0-1 R20; R18 and R19 are independently selected from H, d-C4 alkyl, d-C4 alkyloxy, aryl, hetaryl, d-C4aryl alkylene, and d-C4 hetaryl alkylene, wherein the alkyl / alkylene, aryl, and hetaryl groups are substituted independently with 0-1 R; alternatively, R18 and R19, together with the nitrogen atom to which they are attached, form a monocyclic, bicyclic or tricyclic partially saturated or saturated ring consisting of the nitrogen shown, 4-5 carbon atoms, and 0-1 additional heteroatoms selected from nitrogen , oxygen and sulfur, where this ring is substituted with 0-1 alkyl dd, aryl, hetaryl, alkylene C? -C aryl, hetaryl d-C alkylene, hydroxy, and alkyloxy d-C; R20 is selected from H, OH, oxo, halo, cyano, nitro, d-C4 alkyl, d-C alkyloxy, NR21R22, trihalomethyl, and trihalomethyloxy; R21 and R22 is independently selected from H, d-C4 alkyl, and C4 alkyl aryl; R23 is selected from H and alkyl dC6; n is selected from 0, 1, and 2; and Y is selected from O and S.

In another embodiment, the present invention provides the novel compounds of Formula IA: In another embodiment, the present invention provides the novel compounds of Formula IB: In another embodiment, the present invention provides the novel compounds of Formula IC: In another embodiment, the present invention provides the novel compounds of Formula ID: In another embodiment, the present invention provides the novel compounds of formula I, wherein: Ring A is selected from: Ring A is substituted with 0-2 R -? 2.; and, R24 is selected from d-C8 alkyl, halo, hydroxy, oxo, cyano, and d-C6 alkyloxy.

In another embodiment, the present invention provides the novel compounds of Formula I, wherein: Ring A is: In another embodiment, the present invention provides the novel compounds of the Formula I, selected from the group: Furan-2-carboxylic acid. { 2- [5- (1, 3,3-trimethyl-6-aza-1 bicyclo [3.2.1] octane-6-carbonyl) -benzoimidazol-1-yl] -ethyl} - 1-Acetyl-piperidine-4-carboxylic acid amide. { 2- [5- (1,3,3-trimethyl-6-aza-1-1 bicyclo [3.2.1] octane-6-carbonyl) -benzoimidazol-1-yl] -ethyl} -amide 2-methoxy -? / -. { 2- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -2-benzoimidazol-1-yl] -ethyl} -acetamide? / -. { 2- [5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -1-3 benzoimidazol-1-yl] -ethyl} -isonicotinamide? / -. { 2- [5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -1,4-benzoimidazol-1-yl] -ethyl} -acetamide fert-butyl acid ester. { 2- [5- (1,3,3-Trimethyl-6-aza-1-5-bicyclo [3.2.1] octane-6-carbonyl) -benzoimidazol-1-yl] -ethyl} -carbamic lsoxazole-5-carboxylic acid. { 2- [5- (1, 3,3-trimethyl-6-aza-1-6 bicyclo [3.2.1] octane-6-carbonyl) -benzoimidazol-1-yl] -ethyl} -amide? / -. { 2- [5- (1,3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -1-7-benzoimidazol-1-yl] -ethyl} -benzamide 3- [2-Ethyl-5- (1, 3,3-trimethyl-6-aza-2-bicyclo [3.2.1] octane-6-carbonyl) -benzimidazol-1-yl] -propionic acid ethyl ester 3- [2-Ethyl-5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -3-benzimidazol-1-yl] -propionic acid 2-ethyl ester - [5- (1,3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-4-carbonyl) -1H-benzimidazol-2-yl] -cyclopropanecarboxylic acid 2- [5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -1 H-5-benzimidazol-2-yl] -cyclopropanecarboxylic acid 3- ethyl ester [2-Methyl-5- (1, 3,3-trimethyl-6-aza-5-1 bicyclo [3.2.1] octane-6-carbonyl) -benzimidazol-1-yl] -propionic acid ethyl ester 2- [1-Ethyl-5- (1, 3,3-trimethyl-6-aza-5-2 bicyclo [3.2.1] octane-6-carbonyl) -1 H -benzimidazol-2-yl] -cyclopropanecarboxylic acid 3- [2-Methyl-5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -5-3-benzimidazol-1-yl] -propionic acid 2- [ 1-Ethyl-5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -5-4 1 H-benzimidazol-2-yl] -cyclopropanecarboxylic acid ethyl ester 3- [5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-6 carbonyl) -indol-1-yl] -propionic acid 3- [5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-7-1-yl] -propionic acid ferf-butyl ester [5- (1, 3,3- Trimethyl-6-aza-7-1 bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -acetic acid [5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2 .1] octane-6-carbonyl) -indol-1-7-2-yl] -acetic acid 1-Morpholin-4-yl-3- [5- (1, 3, 3-trimethyl-6-aza-bicyclo [3.2 .1] octane-6-7-3 carbonyl) -indol-1-yl] -propan-1-one 1-Morpholin-4-yl-2- [5- (1, 3,3-trimethyl-6-aza -bicyclo [3.2.1] octane-6-7-4 carbonyl) -indol-1-yl] -ethanone 2,2-Dimethyl-3- [5- (1, 3,3-trimethyl) ethyl ester -6-aza-7-5 bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -propionic acid 2,2-Dimethyl-3- [5- (1,3,3-trimethyl-6-) aza-bicyclo [3.2.1] octane-6-7-6 carbonyl) -indol-1-yl] -propionic 2-Methyl-3- [5- (1, 3,3-trimethyl-6-aza-7-7 bicyclo [3.2.1] octane-6-carbonyl) -dole-1-yl] - methyl ester propionic 3- [5- (1,3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-7-8 carbonyl) -indol-1-yl] -butyric acid methyl ester [5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -7-9 butyric acid 2-Methyl-3- [5- (1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -7-10 indole-1-yl] -propionic acid 3- [5- (1, 3,3- Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-7-11-ilmethyl-benzoic acid 4- [5- (1, 3,3-trimethyl-6-aza) methyl ester -bicyclo [3.2.1] octane-6-7-12 carbonyl) -indol-1-ylmethyl] -benzoic acid 4- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1 -7-13-ylmethyl-benzoic acid 3- [5- (4-Aza-tricyclo [4.3.1.1 * 3,8 *] undecane-4-carbonyl) -7- ethyl ester -14 Indole-1 -yl] -propionic acid 3- [5- (4-Aza-tricyclo [4.3.1.1 * 3,8 *] undecane-4-carbonyl) -indol-1 -yl] -7-15 propionic ester et 5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-8 carbonyl) -1H-indole-2-carboxylic acid 5- (1,3,3-Trimethyl) acid -6-aza-bicyclo [3.2.1] octane-6-carbonyl) -1-indole-2-carboxylic acid? / - Methoxy -? / - methyl-3- [5- (1, 3,3-trimethyl -6-aza-bicyclo [3.2.1] octane-6-carbonyl) -10-indol-1-yl] -propionamide? / - Ethoxy-3- [5- (1, 3,3-trimethyl-6-aza- bicyclo [3.2.1] octane-6-carbonyl) -indol-1-11-yl] -propionamide / V-Hydroxy-3- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -propionamide. { 1- [2- (2H-Tetrazol-5-yl) -ethyl] -IH-indol-5-yl} - (1, 3,3-trimethyl-6-aza-13-bicyclo [3.2.1] oct-6-yl) -methanone. { 1- [2- (3-Cyclopropyl- [1, 2,4] oxadiazol-5-yl) -ethyl] -7H-indol-5-yl} - (1, 3,3-trimethyl-6- 14 aza-bicyclo [3.2.1] oct-6-yl) -methanone. { 1-t2- (3-Methyl- [1, 2,4] oxadiazol-5-yl) -ethyl] - / H-indol-5-yl} - (1,3,3-trimethyl-6-aza-15-bicyclo [3.2.1] oct-6-yl) -methanone? / - (1H-Tetrazol-5-yl) -3- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -propionamide. { 1- [2- (2-Methyl-2H-tetrazol-5-yl) -ethyl] -lH-indol-5-yl} - (1, 3,3-trimethyl-6-aza-17-bicyclo [3.2.1] oct-6-yl) -methanone. { 1- [2- (1-Methyl- / H-tetrazol-5-yl) -ethyl] -lH-indol-5-ylHl, 3,3-trimethyl-6-aza-18-bicyclo [3.2.1] oct-6-yl) -methanone. { 1- [2- (5-Methyl- [1, 2,4] oxadiazol-3-yl) -ethyl] -lH-indol-5-yl} - (1,3,3-trimethyl-6-aza-19-bicyclo [3.2.1] oct-6-yl) -metanone 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 form.

In another embodiment, the present invention provides a novel compound of Formula I: wherein: X is selected from CR5 and nitrogen; R1 is selected from H and alkyl dC6-R6, wherein the alkyl group is substituted with 0-3 R7; R2 is selected from hydrogen, halo, d-C6 alkyl and -C (= 0) R13; R8 R10, 12 alternatively, R1 and R2 are independently, R9 R11 ring A is a bicyclic or tricyclic saturated or partially saturated ring consisting of the nitrogen shown, 4-10 carbon atoms and 0-2 additional heteroatoms selected from nitrogen, oxygen, and sulfur; ring A is substituted with 0-3 groups selected from d-C8 alkyl, halo, hydroxy, -COOH, -CONR18R19, -S (= 0) nR13, -S (= 0) nNR18R19 oxo, cyano, d-C6 alkyloxy , alkylene dC6 alkyloxy dC6 and alkylcarbonyl CrC6, wherein each alkyl / alkylene group is substituted with 0-3 wherein R x is selected from hydrogen and d-C 6 alkyl; CONR18R19, -S (= 0) nR13, -S (= 0) nNR18R19 oxo, cyano, dyalkyloxy-d6, alkylene d-C6 alkyloxy CrC6 • and CrC6 alkylcarbonyl, wherein each alkyl / alkylene group is substituted with 0-3 R14; R5 is selected from hydrogen, CrC6 alkyl. -C (= 0) R13, and cyano; R6 is selected from cyano, aryl, hetaryl, '-oxo-C6-S alkyl (= 0) nR13, -C (= 0) R13, -S (= 0) nR13, -S (= 0) nNR18R19, -N (R18) S (= 0) nR13, -N (R23) C (= Y) NR18R19, -C (= NR15) NR15, - N (R18) C (= 0) R13, cycloalkyl -N (R18) C (= O) -C3-C10, hetcycloalkyl -N (R18) C (= 0) - of 3-10 members, wherein the cycloalkyl groups, hetcycloalkyl, aryl and hetaryl are substituted with 0-3 R16; R7 is selected from halo, hydroxy, oxo, cyano, and CrC6 alkyl; R8, R9, R10 and R11 are independently selected from hydrogen, d-C8 alkyl, F, trihalomethyl, trihalomethoxy, hydroxy, and d-C6alkyloxy, wherein the d-C8 alkyl and d-C6alkyloxy are substituted with 0-3 R17; alternatively, R8 and R9 together with the carbon atom to which they are attached form a saturated or partially saturated ring consisting of the carbon atom shown, 2-5 additional carbon atoms and 2-0 heteroatoms selected from nitrogen, oxygen and sulfur, wherein this ring is substituted with 0-3 groups selected from halo, trihalomethyl, CrC6 alkyl, aryl, hetaryl, d-C6 alkylene aryl, d-C6 alkylene hetaryl, hydroxy, oxo, CrC6 alkyloxy, aryloxy, alkylCycloalkyl or alkyloxy d- C6 hetaryl; alternatively, R10 and R11 together with the carbon atom to which they are attached form a saturated or partially saturated ring consisting of the carbon atom shown, 2-5 additional carbon atoms and 0-2 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the ring is substituted with 0-3 groups selected from halo, trihalomethyl, CrC6 alkyl, aryl, hetaryl, CrC6 alkylene aryl, d-C6 alkylene hetaryl, hydroxy, oxo, d-C6 alkyloxy, aryloxy, CrC6 alkyloxy aryl or alkyloxy d-Cßhetaryl; Alternatively, R and R together with the two carbon atoms to which they are attached form a saturated or partially saturated ring consisting of the two carbon atoms shown, 1-4 additional carbon atoms and 0-2 heteroatoms selected from nitrogen, oxygen and sulfur wherein the ring is substituted with 0-3 groups selected from halo, trihalomethyl, d-C6 alkyl, aryl, hetaryl, alkylene CrC6 aryl, alkylene CrC6 hetaryl, hydroxy, oxo, alkyloxy CrC6, aryloxy, alkyloxy d -C6 aryl, and C-C6 alkyloxy hetaryl; R12 is selected from H, OH, NR18R19, C3-C3 cycloalkyl, 3-10 membered hetcycloalkyl, -C (= 0) R13, -S (= 0) nR13, S (= 0) nNR18R19, -N ( R18) S (= 0) nR13, and -C (= NR15) NR16; wherein the cycloalkyl and hetcycloalkyl groups are substituted with 0-3 R17; R 13 is selected from OH, C C 8 alkyl, d-C 8 alkyloxy, d-C 4 alkylene d-C 8 alkyloxy, aryl, hetaryl, aryloxy, hetaryloxy, and NR 18 R 19; R14 is selected from halo, hydroxy, oxo, and cyano; R15 and R16 are independently selected from H, d-C8 alkyl, 3-10 membered cycloalkyl, halo, OH, cyano, -C (= 0) R13, -S (= 0) nR13, S (= 0) nNR 8R19 , -N (R18) S (= 0) nR13, aryl, and hetaryl, wherein the alkyl and cycloalkyl groups are substituted with 0-3 R20; R17 is selected from halo, OH, oxo, nitro, cyano, -C (= 0) R13, -S (= 0) nR13, S (= 0) nNR18R19, -N (R18) S (= 0) nR13, NR18R19 , d-C8 alkyl, d-C6 alkyloxy, and aryloxy; R18 and R9 are independently selected from H, d-C8 alkyl, d-C8 alkyloxy, aryl, hetaryl, CrC6 alkylene aryl, and CrC6 alkylene hetaryl, wherein the alkyl / alkylene, aryl, and hetaryl groups are independently substituted with 0 -3 R20; alternatively, R18 and R19, together with? the nitrogen atom to which they join, form a monocyclic, bicyclic or tricyclic saturated or partially saturated ring consisting of the nitrogen shown, 4-10 carbon atoms and 0-2 additional heteroatoms selected from nitrogen, oxygen and sulfur, wherein ring is substituted with 0-3 alkyl d-C8, aryl, hetaryl, alkylene d-C6 aryl, alkylene CrC6 hetaryl, hydroxy, oxo, C6 alkyloxy, alkyloxy d-C6 aryl, alkyloxy d-C6 hetaryl, alkyl CrC6 alkyloxy CrC6 , alkylcarbonyl d-C6, arylcarbonyl, hetarylcarbonyl, alkylcarbonyl CrC6 aryl, alkylcarbonyl CrC6 hetaryl, alkylcarboxy d-C6, arylcarboxi, hetarylcarboxi, alkylcarboxy CrC6 aryl, and alkylcarboxy d-C6 hetaryl; R20 is selected from H, OH, oxo, halo, cyano, nitro, d-C6 alkyl, d-Cß alkyloxy, NR21R22, methylenedioxo, dihalomethylenedioxo, trihalomethyl, and trihalomethyloxy; R2 and R22 are independently selected from H, d-C8 alkyl, and alkyl d-C6 aryl; R23 is selected from H and alkyl dC6; n is selected from 0, 1, and 2; And it is selected from O and S; 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 form.

In another embodiment, the present invention provides a novel compound of Formula I, wherein: wherein: X is selected from CR5 and nitrogen; R1 is selected from H and alkyl CrC6-R6, wherein the alkyl group is substituted with 0-3 R7; R2 is selected from hydrogen, halo, CrC6 alkyl and -C (= 0) R 13. R8 R10, alternatively, R1 and R2 are independently, 11 R9 R ring A is a bicyclic or tricyclic saturated or partially saturated ring consisting of the nitrogen shown, 4-10 carbon atoms and 0-2 additional heteroatoms selected from nitrogen, oxygen, and sulfur; ring A is substituted with 0-3 groups selected from d-C8 alkyl, halo, hydroxy, -COOH, -CONR18R19, -S (= 0) nR13, -S (= 0) nNR18R19 oxo, cyano, d-C6 alkyloxy , alkylene dC6 alkyloxy CrC6 and alkylcarbonyl dC6, wherein each alkyl / alkylene group is substituted with 0-3 wherein R x is selected from hydrogen and C 1 -C 6 alkyl; is substituted with 0-3 groups selected from C 8 alkyl, halo, hydroxy, -COOH, -CONR 18 R 19, -S (= 0) n R 13, -S (= 0) nNR 18 R 19 oxo, cyano, d-C 6 alkyloxy, alkylene d- C6 alkyloxy d-Ce and alkylcarbonyl CrC6, wherein each alkyl / alkylene group is substituted with 0-3 R14; R5 is selected from hydrogen, alkyl CrCe, -C (= 0) R13, and cyano; R6 is selected from cyano, aryl, hetaryl, -oxo-alkyl CrC6-S (= 0) nR13, -C (= 0) R13, -S (= 0) nR13, -S (= 0) nNR18R19, -N ( R18) S (= 0) nR13, -N (R23) C (= Y) NR18R19, -C (= NR15) NR15, -N (R18) C (= 0) R13, cycloalkyl -N (R18) C (= O) -C3-C10, hetcycloalkyl -N (R18) C (= 0) - of 3-10 members, wherein the cycloalkyl, hetcycloalkyl, aryl and hetaryl groups are substituted with 0-3 R16; R7 is selected from halo, hydroxy, oxo, cyano, and C6 alkyl; R8, R9, R10 and R11 are independently selected from hydrogen, d-C8 alkyl, F, trihalomethyl, trihalomethoxy, hydroxy, and d-C6alkyloxy, wherein the d-C8 alkyl and d-C6alkyloxy are substituted with 0-3 R17; alternatively, R8 and R9 together with the carbon atom to which they are attached form a saturated or partially saturated ring consisting of the carbon atom shown, 2-5 additional carbon atoms and 2-0 heteroatoms selected from nitrogen, oxygen and sulfur, wherein this ring is substituted with 0-3 groups selected from halo, trihalomethyl, d-C6 alkyl, aryl, hetaryl, alkylene CrC6 aryl, C6 alkylene hetaryl, hydroxy, oxo, CrC6 alkyloxy, aryloxy, alkylCycloalkyl or alkyloxy d-C6 hetaryl; alternatively, R10 and R11 together with the carbon atom to which they are attached form a saturated or partially saturated ring consisting of the carbon atom shown, 2-5 additional carbon atoms and 0-2 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the ring is substituted with 0-3 groups selected from halo, trihalomethyl, CrC6 alkyl, aryl, hetaryl, CrC6 alkylene aryl, d-C6 alkylene hetaryl, hydroxy, oxo, CrC6 alkyloxy, aryloxy, C6-C6 alkyloxy or Cry6heteroyl alkyloxy; alternatively, R8 and R10 together with the two carbon atoms to which they are attached form a saturated or partially saturated ring consisting of the two carbon atoms shown, 1-4 additional carbon atoms and 0-2 heteroatoms selected from nitrogen, Oxygen and sulfur wherein the ring is substituted with 0-3 groups selected from halo, trihalomethyl, CrC6 alkyl, aryl, hetaryl, d-C6 alkylene aryl, CrC6 alkylene hetaryl, hydroxy, oxo, d-Cß alkyloxy, aryloxy, CrC6 alkyloxy aryl, and alkyloxy d-Cß hetaryl; R 12 is selected from H, OH, NR 18 R 19, C 3 -C 0 cycloalkyl, 3-10 membered hetcycloalkyl, -C (= 0) R 13, -S (= 0) n R 13, S (= 0) nNR 18 R 19, -N ( R18) S (= 0) nR13, and -C (= NR15) NR18; wherein the cycloalkyl and hetcycloalkyl groups are substituted with 0-3 R17; R13 is selected from OH, d-C8 alkyl, d-C8 alkyloxy, dC4 alkylene, CrC8 alkyloxy, aryl, hetaryl, aryloxy, hetaryloxy, and NR18R19; R14 is selected from halo, hydroxy, oxo, and cyano; R15 and R16 are independently selected from H, d-C8 alkyl, 3-10 membered cycloalkyl, halo, OH, cyano, -C (= 0) R13, -S (= 0) nR13, S (= 0) nNR 8R19 , -N (R18) S (= 0) nR13, aryl, and hetaryl, wherein the alkyl and cycloalkyl groups are substituted with 0-3 R20; R17 is selected from halo, OH, oxo, nitro, cyano, -C (= 0) R13, -S (= 0) nR13, S (= 0) nNR18R19, -N (R18) S (= 0) nR13, NR18R19 C8 alkyl, C6 alkyloxy, and aryloxy; R18 and R19 are independently selected from H, d-C8 alkyl, d-C8 alkyloxy, aryl, hetaryl, d-C6 alkylene aryl, and d-C6 alkylene hetaryl, wherein the alkyl / alkylene, aryl, and hetaryl groups are substituted independently with 0-3 R20; alternatively, R18 and R19, together with the nitrogen atom to which they are attached, form a monocyclic, bicyclic or tricyclic saturated or partially saturated ring consisting of the nitrogen shown, 4-10 carbon atoms and 0-2 additional heteroatoms selected from nitrogen , oxygen and sulfur, wherein this ring is substituted with 0-3 alkyl d-C8, aryl, hetaryl, alkylene dd. aryl, d-C6 alkylene hetaryl, hydroxy, oxo, d-C6alkyloxy, alkyloxy dd aryl, C6alkyloxyky hetaryl, CrC6alkyloxy alkyloxy d-C6, alkylcarbonyl CrC6, arylcarbonyl, hetarylcarbonyl, alkylcarbonyl d-C6 aryl, alkylcarbonyl d-C6 hetaryl, alkylcarboxy dd, arylcarboxy, hetarylcarboxy, alkylcarboxy dd aryl, and alkylcarboxy d-C6 hetaryl; R20 is selected from H, OH, oxo, halo, cyano, nitro, d-C6 alkyl, dyalkyloxy d, NR21R22, methylenedioxo, dihalomethylenedioxo, trihalomethyl, and trihalomethyloxy; R21 and R22 are independently selected from H, d-C8 alkyl, and C1-C6 alkyl aryl; R23 is selected from H and alkyl dC6; n is selected from 0, 1, and 2; And it is selected from O and S; with the proviso that when X is CR5, then R6 is -C (= 0) R13 where R3 is OH; 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 form.

In another embodiment, the present invention provides a novel compound of Formula I, wherein: X is selected from CR5 and nitrogen; R1 is selected from H and alkyl dC6-R6, wherein the alkyl group is substituted with 0-3 R7; R2 is selected from hydrogen, halo, alkyl d-d and -C (= 0) R13; R8 R10 -R12 alternatively, R1 and R2 are independently, R9 R11 ring A is a bicyclic or tricyclic saturated or partially saturated ring consisting of the nitrogen shown, 4-10 carbon atoms and 0-2 additional heteroatoms selected from nitrogen, oxygen, and sulfur; ring A is substituted with 0-3 groups selected from alkyl Crd, halo, hydroxy, -COOH, -CONR18R19, -S (= 0) nR13, -S (= 0) nNR18R19 oxo, cyano, d-C6 alkyloxy, alkylene Cr alkyloxy d-C6 and alkylcarbonyl Crd, wherein each alkyl / alkylene group is substituted with 0-3 wherein R x is selected from hydrogen and C C 6 alkyl; is substituted with 0-3 groups selected from d-C8 alkyl, halo, hydroxy, -COOH, -C0NR18R19, -S (= 0) nR13, -S (= 0) nNR18R19 oxo, cyano, alkyloxy dd, alkylene d-C6 alkyloxy d-C6 and alkylcarbonyl dd, wherein each alkyl / alkylene group is substituted with 0-3 R14; R5 is selected from hydrogen, alkyl d-d, -C (= 0) R13, and cyano; R6 is selected from cyano, aryl, hetaryl, -oxo-C1-C6 alkyl-S (= 0) nR13, -C (= 0) R13, -S (= 0) nR13, -S (= 0) nNR18R19, - N (R18) S (= 0) nR13, -N (R23) C (= Y) NR18R19, -C (= NR15) NR15, -N (R18) C (= 0) R13, cycloalkyl -N (R18) C (= O) -C3-C10, hetcycloalkyl -N (R18) C (= 0) - of 3-10 members, wherein the cycloalkyl, hetcycloalkyl, aryl and hetaryl groups are substituted with 0-3 R16; R7 is selected from halo, hydroxy, oxo and cyano; R8, R9, R10 and R11 are independently selected from hydrogen, CrC8 alkyl, F, trihalomethyl, trihalomethoxy, hydroxy, and alkyloxy d-d, wherein the alkyl d-d and alkyloxy d- are substituted with 0-3 R17; alternatively, R8 and R9 together with the carbon atom to which they are attached form a saturated or partially saturated ring consisting of the carbon atom shown, 2-5 additional carbon atoms and 2-0 heteroatoms selected from nitrogen, oxygen and sulfur, wherein this ring is substituted with 0-3 groups selected from halo, trihalomethyl, d-C6 alkyl, aryl, hetaryl, alkylene dd aryl, d-C6 alkylene hetaryl, hydroxy, oxo, alkyloxy dd, aryloxy, alkyloxyldryl or alkyloxy hetaryl dd; alternatively, R10 and R1 together with the carbon atom to which they are attached form a saturated or partially saturated ring consisting of the carbon atom shown, 2-5 additional carbon atoms and 0-2 heteroatoms selected from nitrogen, oxygen and sulfur , wherein the ring is substituted with 0-3 groups selected from halo, trihalomethyl, dd alkyl, aryl, hetaryl, d-C6 alkylene aryl, alkylene Crd hetaryl, hydroxy, oxo, alkyloxy Crd, aryloxy, alkyloxy dd aryl or alkyloxy d -dhetarilo; alternatively, R8 and R10 together with the two carbon atoms to which they are attached form a saturated or partially saturated ring consisting of the two carbon atoms shown, 1-4 additional carbon atoms and 0-2 heteroatoms selected from nitrogen, oxygen and sulfur wherein the ring is substituted with 0-3 groups selected from halo, trihalomethyl, d-C6 alkyl, aryl, hetaryl, alkylene d-aryl, d-C6 alkylene hetaryl, hydroxy, oxo, d-C6 alkyloxy, aryloxy , alkyloxy dd aryl, and alkyloxy d-hetaryl; R12 is selected from H, OH, NR18R19, C3-C10 cycloalkyl, 3-10 membered hetcycloalkyl, -C (= 0) R13, -S (= 0) nR13, S (= 0) nNR18R19, -N (R18) S (= 0) nR13, and -C (= NR15) NR16; wherein the cycloalkyl and hetcycloalkyl groups are substituted with 0-3 R17; R13 is selected from OH, d-C8 alkyl, d-C8alkyloxy, C4alkylaminoalkyl CrC8, aryl, hetaryl, aryloxy, hetaryloxy, and NR18R19; R 4 is selected from halo, hydroxy, oxo, and cyano; R15 and R16 are independently selected from H, d-C8 alkyl, 3-10 membered cycloalkyl, halo, OH, cyano, -C (= 0) R13, -S (= 0) nR13, S (= 0) nNR18R19, -N (R18) S (= 0) nR13, aryl, and hetaryl, wherein the alkyl and cycloalkyl groups are substituted with 0-3 R20; R17 is selected from halo, OH, oxo, nitro, cyano, -C (= 0) R13, -S (= 0) nR13, S (= 0) nNR18R19, -N (R18) S (= 0) nR13, NR18R19 , d-C8 alkyl, C6 alkyloxy, and aryloxy; R18 and R19 are independently selected from H, d-C8 alkyl, CrC8 alkyloxy, aryl, hetaryl, d-C6 alkylene aryl, and C6 he6aryl alkylene, wherein the alkyl / alkylene, aryl, and hetaryl groups are independently substituted with 0 -3 R20; alternatively, R18 and R19, together with the nitrogen atom to which they are attached, form a monocyclic, bicyclic or tricyclic saturated or partially saturated ring consisting of the nitrogen shown, 4-10 carbon atoms and 0-2 additional heteroatoms selected from nitrogen , oxygen and sulfur, wherein this ring is substituted with 0-3 alkyl d-C8, aryl, hetaryl, alkylene dd aryl, d-C6 alkylene hetaryl, hydroxy, oxo, d-C6 alkyloxy, C6 alkyloxy aryl, alkyloxy Cr C6 hetaryl, d-C6 alkyloxy alkyl, dicarbonylcarbonyl, arylcarbonyl, hetarylcarbonyl, d-C6alkylcarbonyl aryl, hecarylcarbonylcarbonyl, alkylcarboxy dd, arylcarboxy, hetarylcarboxy, alkylcarboxy d-C6 aryl, and alkylcarboxy d-C6 hetaryl; R20 is selected from H, OH, oxo, halo, cyano, nitro, d-d alkyl, d-alkyloxy, NR21R22, methylenedioxo, dihalomethylenedioxo, trihalomethyl, and trihalomethyloxy; R21 and R22 are independently selected from H, d-C8 alkyl, and alkyl d-C6 aryl; R23 is selected from H and alkyl d-d; n is selected from 0, 1, and 2; And it is selected from O and S; with the proviso that when X is CR5, then R6 is -C (= 0) R13 where R13 is OH; 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 form.

In another embodiment, the present invention provides a novel compound of the formula I, wherein R1 is selected from H and alkyl dC6-R6, wherein the alkyl group is substituted with 0-1 R7; R2 is selected from hydrogen, halo, Crd alkyl and -C (= 0) R13; R8 R10, 12 alternatively, R1 and R2 are independently, R9 R11 ring A is a saturated or partially saturated bicyclic or tricyclic ring consisting of the nitrogen shown and 7-10 carbon atoms; ring A is substituted with 0-3 groups selected from d-C4 alkyl, halo, hydroxy, -COOH, -CONR 8R19, -S (= 0) nR13, -S (= 0) nNR18R19 and alkyloxy d-C6, alternatively, wherein R x is selected from hydrogen and alkyl d-d; is substituted with 0-3 groups selected from d-C8 alkyl, halo, hydroxy, -COOH, - CONR18R19, -S (= 0) nR13, -S (= 0) nNR18R19 oxo, cyano, d-C6 alkyloxy, alkylene d -C8 alkyloxy d-C6 and alkylcarbonyl dd, wherein each alkyl / alkylene group is substituted with 0-3 R14; R5 is selected from hydrogen and d-C4 alkyl R6 is selected from cyano, aryl, hetaryl, -oxo-alkyl CrC6-S (= 0) nR13, -C (= 0) R13, -S (= 0) nR13, - S (= 0) nNR18R19, -N (R18) S (= 0) nR13, -N (R23) C (= Y) NR18R19, -C (= NR15) NR15, -N (R18) C (= 0) R13 , cycloalkyl -N (R18) C (= O) -C3-C10, hetcycloalkyl -N (R18) C (= 0) - of 3-6 members, wherein the cycloalkyl, hetcycloalkyl, aryl and hetaryl groups are substituted with 0 -3 R16; R7 is selected from halo; R8, R9, R10 and R11 are independently selected from hydrogen and dC4 alkyl. alternatively, R8 and R10 together with the two carbon atoms to which they are attached form a saturated or partially saturated ring consisting of the two carbon atoms shown and 1-4 additional carbon atoms wherein this ring is substituted with 0- 1 selected group of halo, trihalomethyl, hydroxyl and alkyl dd; R12 is selected from H, OH and NR18R19, R13 is selected from OH, d-C4 alkyl, alkyloxy d-d, alkylene d-d, d-C4 alkyloxy, aryl, hetaryl, aryloxy, hetaryloxy, and NR18R19; R15 and R16 are independently selected from H, d-C4 alkyl, 3-6 membered cycloalkyl, halo, OH, cyano, -C (= 0) R13, -S (= 0) nR13, S (= 0) nNR18R19, -N (R18) S (= 0) nR13, aryl, and hetaryl, wherein the alkyl and cycloalkyl groups are substituted with 0-1 R20; R18 and R19 are independently selected from H, d-C4 alkyl, d-C4 alkyloxy, aryl, hetaryl, d-C4 alkylene aryl, and C4-4 alkylene hetaryl, wherein the alkyl / alkylene, aryl, and hetaryl groups are independently substituted with 0-1 R20; alternatively, R18 and R19, together with the nitrogen atom to which they are attached, form a monocyclic, bicyclic or tricyclic saturated or partially saturated ring consisting of the nitrogen shown, 4-5 carbon atoms and 0-1 additional heteroatom selected from nitrogen , oxygen and sulfur, wherein this ring is substituted with 0-1 alkyl Crd, aryl, hetaryl, alkylene d-C4 aryl, alkylene d-C4 hetaryl, hydroxy and alkyloxy dd R20 is selected from H, OH, oxo, halo, cyano, nitro, Crd alkyl, dyalkyloxy, NR21R22, trihalomethyl, and trihalomethyloxy; R21 and R22 are independently selected from H, d-C4 alkyl, and alkyl d-C4 aryl; R23 is selected from H and alkyl d-d; n is selected from 0, 1, and 2 and Y is selected from O and S; with the proviso that when X is CR5, then R6 is -C (= 0) R13 where R13 is OH; 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 form.

In another embodiment, the present invention provides a novel compound of Formula IA: IA. In another embodiment, the present invention provides a novel compound of Formula In another embodiment, the present invention provides a novel compound of Formula In another embodiment, the present invention provides a novel compound of Formula ID.

In another embodiment, the present invention provides a novel compound of the formula I, wherein R6 is selected from aryl, hetaryl, -C (= 0) R13, -S (= 0) nR13, -S (= 0) nNR18R19, -N (R18) S (= 0) nR13, -N (R23) C (= Y) NR18R19, -C (= NR15) NR15, -aryl N (R18) C (= 0) - or hetaryl-N (R18) ) C (= 0) -, where the cycloalkyl, hetcycloalkyl, aryl and hetaryl groups are substituted with 0-3 R 16 In another embodiment, the present invention provides a novel compound of formula I, wherein R6 is selected from aryl, hetaryl, oxo-alkyl, CrC6-S (= 0) nR13, -C (= 0) R13, -S (= 0 ) nR13, -S (= 0) nNR18R19, -N (R18) S (= 0) nR13, -N (R23) C (= Y) NR18R19 or -C (= NR 5) NR15; where the aryl and hetaryl groups are substituted with 0-3 R16 In another embodiment, the present invention provides a novel compound of Formula I, wherein R6 is selected from -C (= 0) R13, -S (= 0) nR13, -S (= 0) nNR18R19, -N (R18) S (= 0) nR13, -N (R23) C (= Y) NR18R19 or -C (= NR15) NR15.

In another embodiment, the present invention provides a novel compound of Formula I, wherein R6 is selected from -C (= 0) R13, -S (= 0) nR13, -S (= 0) nNR18R19, or -N (R23 ) C (= Y) NR18R19.

In another embodiment, the present invention provides a novel compound of Formula I, wherein R6 is selected from -N (R23) C (= Y) NR 8R19.

In another embodiment, the present invention provides a novel compound of Formula I, wherein R7 is CrC6 alkyl.

In another embodiment, the present invention provides a novel compound of Formula I, where R7 is halo.

In another embodiment, the present invention provides a novel compound of Formula I, wherein R7 is hydroxy.

In another embodiment, the present invention provides a novel compound of Formula I, wherein R7 is oxo.

In another embodiment, the present invention provides a novel compound of Formula I, wherein R7 is cyano.

In another embodiment, the present invention provides a novel compound of Formula I, where Y is oxygen (O).

In another embodiment, the present invention provides a novel compound of Formula I, wherein ring A is a saturated or partially saturated bicyclic or tricyclic ring consisting of saturated nitrogen, 4-10 carbon atoms and additional 0-2 heteroatoms selected from nitrogen, oxygen and sulfur; ring A is substituted with 0-3 groups selected from d-C8 alkyl, halo, hydroxy, -COOH, -CONR18R19, -S (= 0) nR13, -S (= 0) nNR18R19 oxo, cyano, C6alkyloxy, alkylene dd alkyloxy dd, and alkylcarbonyl d-dalkylcarbonyl, wherein each alkyl / alkylene group is substituted with 0-3 R14.

In another embodiment, the present invention provides a novel compound of Formula I, wherein ring A is a bicyclic or tricyclic partially saturated or saturated ring consisting of the nitrogen shown, 4-10 carbon atoms and 1-2 additional heteroatoms selected from nitrogen, oxygen and sulfur. ring A is substituted with 0-3 groups selected from alkyl d-d, halo, hydroxy, oxo, COOH, -C0NR18R19, -S (= 0) nR13, -S (= 0) nNR18R19 and alkyloxy d-C6.

In another embodiment, the present invention provides a novel compound of Formula I, wherein ring A is selected from: ring A is substituted with 0-2 groups selected from alkyl d-C8, halo, hydroxy, oxo, COOH, -CONR18R19, -S (= 0) nR13, -S (= 0) nNR18R19 and alkyloxy d-C6.

In another embodiment, the present invention provides a novel compound of Formula I, where Ring A is In another embodiment, the present invention provides a novel compound of Formula I, wherein Ring A is In another embodiment, the present invention provides a novel compound of Formula I, wherein Ring A is In another embodiment, the present invention provides a novel compound of Formula I, wherein Ring A is In another embodiment, the present invention provides a novel compound of Formula I, wherein Ring A is "In another embodiment, the present invention provides a novel compound of Formula I, where Ring A is In another embodiment, the present invention provides a novel compound of Formula I, where wherein R x is selected from hydrogen and d-C 6 alkyl; is substituted with 0-3 groups selected from d-C8 alkyl, halo, hydroxy, -COOH, -CONR18R19, -S (= 0) nR13, -S (= 0) nNR18R19 oxo, cyano, d-C6alkyloxy, alkylene dd C6 alkyloxy and alkylcarbonyl dd, wherein each alkyl / alkylene group is substituted with 0-3 R14; In another embodiment, the present invention provides a novel compound of Formula I, wherein wherein R x is selected from hydrogen and d-C 6 alkyl; is substituted with 0-3 groups selected from d-C4 alkyl, halo, hydroxy, -COOH, -CONR18R19, -S (= 0) nR13, -S (= 0) nNR18R19 and alkyloxy d-d.

In another embodiment, the present invention provides a novel compound, wherein the compound is selected from the group: Furan-2-carboxylic acid. { 2- [5- (1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzoimidazol-1-yl] -ethyl} - 1-Acetyl-piperidine-4-carboxylic acid amide. { 2- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzoimidazol-1-yl] -ethyl} -amide 2-methoxy -? / -. { 2- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzoimidazol-1-yl] -ethyl} -acetamide? / -. { 2- [5- (1,3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzoimidazol-1-yl] -ethyl} -isonicotinamide? / -. { 2- [5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzoimidazol-1-yl] -ethyl} -acetamide tert-butyl acid ester. { 2- [5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzoimidazol-1-yl] -ethyl} -carbamic lsoxazole-5-carboxylic acid. { 2- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzoimidazol-1-yl] -ethyl} -amide? / -. { 2- [5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzoimidazol-1-yl] -ethyl} -benzamide 3- [2-Ethyl-5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzimidazol-1-yl] -propionic acid ethyl ester 3- [2-Eti-5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzimidazol-1-yl] -propionic 2- [5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -1H-benzimidazol-2-yl] -cycopanecarboxylic acid ethyl ester 2- [ 5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -1 H -benzimidazol-2-yl] -cycopanecarboxylic acid ethyl ester 3- [2-Methyl- 5- (1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzimidazol-1-yl] -propionic acid ethyl ester 2- [1-Ethyl-5 - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -1 H -benzimidazol-2-yl] -cycopanecarboxylic acid 3- [2-Methyl-5- (1 , 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzimidazol-1-yl] -propionic acid 2- [1-Ethyl-5- (1,3,3-trimethyl) -6-aza-bicyclo [3.2.1] octane-6-carbonyl) -1 H -benzimidazol-2-yl] -cycopanecarboxylic acid 3- [5- (1, 3,3-Trimethyl-6-aza) ethyl ester -bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -propionic acid 3- [5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6] -carbonyl) -indol-1-yl] -propionic acid tert-butyl ester [5- (1, 3,3- Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -acetic acid [5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -acetic acid 1-Morpholin-4-yl-3- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6 -carbonyl) -indol-1-yl] -propan-1-one 1-Morpholin-4-yl-2- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -ethanone ethyl ester of 2,2-Dimethyl-3- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -propionic acid 2.2 -Dimethyl-3- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -propionic methyl ester of 2-methyl- 3- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -propionic acid methyl ester 3- [5- (1 , 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -butyric acid 3- [5- (1, 3,3-Trimethyl-6-aza -bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -butyric acid 2-Methyl-3- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1 ] octane-6-carbonyl) -indol-1-yl] -propionic acid 3- [5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol- 1-ylmethyl] -benzoic acid 4- [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-biciclot3.2.1] octane-6-carbonyl) -indol-1-ylmethyl] -benzoic acid ethyl ester of 3- [5- ( 4-Aza-tricyclo [4.3.1.1 * 3,8 *] undecane-4-carbonyl) -indol-1-yl] -propionic acid 3- [5- (4-Aza-tricyclo [4.3.1.1 * 3.8 *] undecano-4-carbonyl) -indol-1-yl] -propionic acid 5- (1,3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -1 ethyl ester - -indol-2-carboxylic acid 5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -1H-indole-2-carboxylic acid [1- (2-methanesulfonylmethoxy -ethyl) -1 H-benzoimidazol-5-yl] - (octahydro-quinolin-1-yl) -methanone (3-Hydroxy-8-aza-bicyclo [3.2.1] oct-8-yl) - [1- (2-methanesulfonylmethoxy-ethyl) -1H-benzoimidazol-5-yl] -methanone trans-1- (2-methanesulfonyl-methoxy-ethyl) -1H-benzoimidazole-5-carboxylic acid (5-hydroxy-adamantan-2) -yl) -amide Cis-1 - (2-methanesulfonyl-methoxy-ethyl) -1H-benzoimidazole-5-carboxylic acid (5-hydroxy-adamantan-2-yl) -amide (3-Hydroxy-8-aza) -bicyclo [3.2.1] oct-8-yl) - [1- (2-methanesulfonylmethoxy-ethyl) -1 H-benzoimid azol-5-yl] -methanone 1- (2-Methanesulfonyl-ethyl) -1H-benzoimidazole-5-carboxylic acid (5-hydroxy-adamantan-2-yl) -amide (3-Hydroxy-8-aza-bicyclo) [3.2.1] oct-8-yl) - [1- (2-methanesulfonyl-ethyl) -1 H -benzoimidazol-5-yl] -methanone (3-Hydroxy-8-aza-bicyclo [3.2.1] oct -8-yl) - [1- (2-methanesulfonyl-ethyl) -1 H -benzoimidazol-5-yl] -methanone [1- (2-methanesulfonyl-ethyl) -1 H -benzoimidazol-5-yl] - ( Octahydro-quinolin-1-yl) -methanone 1- (2-Methanesulfonyl-ethyl) -1H-benzoimidazole-5-carboxylic acid (5-hydroxy-adamantan-2-yl) -amide (3-Hydroxy-8-aza) -bicyclo [3.2.1] oct-8-il) -. { 1- [2- (1 H -tetrazol-5-yl) -ethyl] -1 H -benzoimidazol-5-yl} -metanone (Octahydro-quinolin-1-yl) -. { 1- [2- (1 H-tetrazol-5-yl) -ethyl] -1 H -benzoimidazol-5-yl} -methanone Trans-1- [2- (1 H-Tetrazol-5-yl) -ethyl] -1H-benzoimidazole-5-carboxylic acid (5-hydroxy-adamantan-2-yl) -amide acid Cis-1 - [2- (1 H-Tetrazol-5-yl) -ethyl] -1H-benzoimidazole-5-carboxylic acid (5-hydroxy-adamantan-2-yl) -amide 3-Hydroxy-pyrrolidine-1-carboxylic acid. { 2- [5- (3-hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzoimidazol-1-yl] -ethyl} -amide 4-Hydroxy-piperidine-1-carboxylic acid. { 2- [5- (Octahydro-quinoline-1-carbonyl) -benzoimidazol-1-yl] -ethyl} -amide acid 1-. { 2 - [(4-Hydroxy-piperidine-1-carbonyl) -amino] -ethyl} -1 H-benzoimidazole-5-carboxylic acid (5-hydroxy-adamantan-2-yl) -amide 1-. { 2 - [(1,1-Dioxo-thiomorpholine-4-carbonyl) -amino] -ethyl} -1 H-benzoimidazole-5-carboxylic acid (5-hydroxy-adamantan-2-yl) -amide 1,1-Dioxo-thiomorpholine-4-carboxylic acid. { 2- [5- (3-hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzoimidazol-1-yl] -ethyl} - Cis-1- acid amide. { 2 - [(Morpholine-4-carbonyl) -amino] -ethyl} -1H-benzo-imidazole-5-carboxylic acid (5-hydroxy-adamantan-2-yl) -amide Trans-1-. { 2 - [(Morpholine-4-carbonyl) -amino] -ethyl} -1 H-benzo-imidazole-5-carboxylic acid Cis-morpholine-4-carboxylic acid. { 2- [5- (Octahydro-quinoline-1-carbonyl) -benzoimidazol-1-yl] -ethyl} - Trans-morpholine-4-carboxylic acid amide. { 2- [5- (Octahydro-quinoline-1-carbonyl) -benzoimidazol-1-yl] -ethyl} Morpholine-4-carboxylic acid amide. { 2- [5- (3-hydroxy-8-aza-bicyclo- [3.2.1] octane-8-carbonyl) -benzoimidazol-1-yl] -ethyl} - 1,1-Dioxo-thiomorpholine-4-carboxylic acid amide. { 2- [5- (Octahydro-quinoline-1-carbonyl) -benzoimidazol-1-yl] -ethyl} 3-Hydroxy-pyrrolidine-1-carboxylic acid amide. { 2- [5- (Octahydro-quinoline-1-carbonyl) -benzoimidazol-1-yl] -ethyl} -amide acid 1-. { 2- [5- (Octahydro-quinoline-1-carbonyl) -benzoimidazol-1-yl] -ethylcarbamoyl} -piperidine-4-carboxylic acid 3-Hydroxy-pyrrolidine-1-carboxylic acid. { 2- [5- (3-hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzoimidazol-1-yl] -ethyl} Cis-4-hydroxy-piperidine-1-carboxylic acid amide. { 2- [5- (Octahydro-quinoline-1-carbonyl) -benzoimidazol-1-yl] -ethyl} -amide Trans-4-hydroxy-piperidine-1-carboxylic acid. { 2- [5- (Octahydro-quinoline-1-carbonyl) -benzoimidazol-1-yl] -ethyl} Endo-4-hydroxy-piperidine-1-carboxylic acid amide. { 2- [5- (3-hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzoimidazol-1-yl] -ethyl} -Exo-4-hydroxy-piperidine-1-carboxylic acid amide. { 2- [5- (3-hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzoimidazol-1-yl] -ethyl} -amide acid 1-. { 2 - [(1, 1-Dioxo-thiomorpholine-4-carbonyl) -amino] -ethyl} -1 H-benzoimidazole-5-carboxylic acid (1-l-Dioxo-thiomorpholine-4-carboxylic acid 5-hydroxy-adamantan-2-yl) -amide. { 2- [5- (3-hydroxy-8-aza-bicyclo [3.2.1] -octane-8-carbonyl) -benzo-imidazol-1-yl] -ethyl} -amide acid 1 -. { 2 - [(4-Hydroxy-piperidine-1 -carbonyl) -amino] -ethyl} -1 H-benzoimidazole-5-carboxylic acid (5-hydroxy-adamantan-2-yl) -amide 1 -. { 2 - [(3-Hydroxy-pyrrolidine-1 -carbonyl) -amino] -ethyl} -1H-benzoimidazole-5-carboxylic (5-hydroxy-adamantan-2-yl) -amide Morpholine-4-carboxylic acid. { 2- [5- (3-hydroxy-8-aza-bicyclo- [3.2.1] octane-8-carbonyl) -benzoimidazol-1-yl] -ethyl} - Cis-1- acid amide. { 2- [5- (5-hydroxy-adamantan-2-ylcarbamoyl) -benzoimidazol-1-yl] -ethylcarbamoyl} -piperidine- 4-carboxylic acid Trans-1 -. { 2- [5- (5-hydroxy-adamantan-2-ylcarbamoyl) -benzoimidazol-1-yl] -ethylcarbamoyl} -piperidine-4-carboxylic acid 1-. { 2- [5- (3-Hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzoimidazol-1-yl] -ethyl-carbamoyl} -piperidine-4-carboxylic acid? / - Methoxy -? - methyl-3- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1- il] -propionamide ? / - Ethoxy-3- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -propionamide? / - Hydroxy-3 - [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -propionamide. { 1- [2- (2H-Tetrazol-5-yl) -ethyl] - / H-indol-5-yl} - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -metanone . { 1- [2- (3-Cyclopropyl- [1, 2,4] oxadiazol-5-yl) -ethyl] - / H-indol-5-yl} - (1,3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -metanone . { 1- [2- (3-Methyl- [1,2,4] oxadiazol-5-yl) -ethyl] -IH-indol-5-yl} - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -methanone? / - (IH-Tetrazol-5-yl) -3- [5- (1, 3 , 3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -propionamide. { 1- [2- (2-Methyl-2H-tetrazol-5-yl) -ethyl] -IH-indol-5-ylHl, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6- il) -metanone. { 1- [2- (1-Methyl-1H-tetrazol-5-yl) -ethyl] - '/ H-indol-5-yl} - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -methanone. { 1- [2- (5-Methyl- [1, 2,4] oxadiazol-3-yl) -etl] -fV-indo-5-yl} - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -methanone; or a salt thereof with a pharmaceutically acceptable salt or acid or any optical isomer or mixture of optical isomers, including a racemic mixture or any tautomeric form.

In another embodiment, the present invention provides a novel compound of the formula I, which is a useful agent for the treatment of conditions, diseases or disorders wherein a modulation or an inhibition of the activity of 11βHSD1 is beneficial.

In another embodiment, the present invention provides a use of a novel compound of the formula I, for the preparation of a pharmaceutical composition for the treatment of conditions, diseases or disorders wherein a modulation or an inhibition of the activity of 11βHSD1 is beneficial .

In another embodiment, the present invention provides a use of a compound of formula I, for the preparation of a pharmaceutical composition for the treatment of conditions, disorders or diseases, wherein conditions, disorders and diseases are influenced by glucocorticoid levels. intracellular In another embodiment, the present invention provides a use of a compound of Formula I for the preparation of a pharmaceutical composition for the treatment of conditions, disorders or diseases wherein the conditions, disorders or diseases are selected from the metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, type 2 diabetes, decreased glucose tolerance (IGT), decreased fasting glucose (IFG), progress of IGT to type 2 diabetes, progress of the metabolic syndrome to type 2 diabetes, late diabetic complications, neurodegenerative and psychiatric diseases and the adverse effects of treatment or glucocorticoid receptor agonist therapy.

In another embodiment, the present invention provides a method for the treatment of conditions, disorders or diseases wherein a modulation or an inhibition for the activity of 11βHSD1 is beneficial, the method comprising administering to a subject in need thereof an amount effective of a compound of formula I.

In another embodiment, the present invention provides a method for the treatment of conditions, disorders or diseases, wherein conditions, disorders and diseases are influenced by intracellular glucocorticoid levels, the method comprising administration to a subject in need thereof. effective amount of a compound of formula I.

In another embodiment, the present invention provides a method for the treatment of conditions, disorders or diseases, wherein the conditions, disorders or diseases are selected from the metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, type 2 diabetes, tolerance decreased glucose (IGT), decreased fasting glucose (IFG), progression of IGT to type 2 diabetes, progression from metabolic syndrome to type 2 diabetes, late diabetic complications, neurodegenerative and psychiatric disorders and the adverse effects of treatment or therapy with the glucocorticoid receptor agonist.

In another embodiment, the present invention provides a novel compound, which is a useful agent for the treatment of conditions, disorders or diseases wherein a modulation or an inhibition of the activity of 11βHSD1 is beneficial.

In another embodiment, the present invention provides a novel method wherein conditions, disorders and diseases are influenced by intracellular glucocorticoid levels.

In another embodiment, the present invention provides a novel method wherein the conditions, disorders or diseases are selected from the metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, type 2 diabetes, impaired glucose tolerance (IGT), glucose in decreased fasting (IFG), progress of IGT to type 2 diabetes, progress of the metabolic syndrome in type 2 diabetes, late diabetic complications, psychiatric and neurodegenerative disorders and the adverse effects of treatment or glucocorticoid receptor agonist therapy.

In another embodiment, the present invention provides a pharmaceutical composition of a novel method that is understood as an active ingredient, at least one compound according to the present invention together with one or more pharmaceutically acceptable carriers or excipients.

In another embodiment, the present invention provides a novel pharmaceutical composition that is suitable for oral, nasal, transdermal, pulmonary or parenteral oral administration.

The compounds of the present invention have asymmetric centers and can occur as racemates, racemic mixtures and as individual enantiomers or distereoisomers with all isomeric forms being included in the present invention as well as mixtures thereof.

The present invention also encompasses the pharmaceutically acceptable salts of the present compounds. Said salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable basic addition salts, pharmaceutically acceptable metal salts, alkylated ammonium salts and ammonium. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of the appropriate inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric and nitric acids. Representative examples of the appropriate organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, masonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, salicylic, bismethylene, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic, sulfates, nitrates, phosphates, perchlorates, borates , acetates, benzoates, hydroxynaphthates, glycerophosphates and ketoglutarates. Additional examples of the pharmaceutically acceptable organic and inorganic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci., 66, 2 (1977), which is incorporated herein by reference. Examples of the metal salts include lithium, sodium, potassium, barium, calcium, magnesium, zinc and calcium salts. Examples of the amines and the organic amines include ammonium, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, propylamine, butylamine, tetramethylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, choline, N, N'-dibenzylethylene diamine, N -benzylphenylethylamine, N-methyl-D-glucamine and guanidine. Examples of the cationic amino acids include lysine, arginine and histidine.

In addition, some of the compounds of the present invention can form solvates in water or common organic solvents. Said solvates are 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 fert-butoxide, calcium hydroxide and magnesium hydroxide in solvents such as ether, THF, methanol, ferf-butanol, dioxane and isopropanol, ethanol. Mixtures of solvents can be used. Organic bases such as lysine, arginine, diethanolamine, choline, guandin and its derivatives, etc. they can also be used. Alternatively, the acid addition salts if applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid , salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid and tartaric acid in solvents such as ethyl acetate, ether, alcohols, acetone, THF and dioxane. The solvent mixture can also be used.

The stereoisomers of the compounds forming part of this invention can be prepared by using reagents in their simple enantiomeric form in the process where possible or by conducting the reaction in the presence of reagents or catalysts in their simple enantiomer form or by resolving the mixture. of stereoisomers by conventional methods. Some preferred methods include the use of microbial resolution, enzymatic resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid and lactic acid, where applicable or chiral bases such as brucine, (R) - or (S) - phenylethylamine, cinchona alkaloids and their derivatives. The commonly used methods are compiled by Jaques et al. in "Enantiomers, Racemates and Resolution "(Wiley Interscience, 1981) More specifically, the compound of the present invention can be converted to a 1: 1 mixture of diastereomeric amides by treating them with chiral amine, amino acids, aminoalcohols derived from amino acids, the conventional reaction conditions can be used for convert the acid to an amide, the diastereomers can be separated by fractional crystallization or chromatography and the Stereoisomers of the compound of the formula I can be prepared by hydrolyzing the pure diastereomeric amide.

Various polymorphs of the compounds forming part of this invention can be prepared by crystallizing said compounds under different conditions. For example, using different commonly used solvents or their mixtures for recrystallization, crystallizations at different temperatures; several modes of cooling, ranging from cooling very fast to very slow during crystallizations. The polymorphs can also be obtained by heating or fusing the compound followed by gradual or rapid cooling. The presence of polymorphs can be determined by solid probe NMR spectroscopy, ir spectroscopy, differential analysis calorimetry, powder X-ray diffraction or said other techniques.

The invention also encompasses the prodrugs of the present compounds, which upon administration undergo chemical conversion by metabolic processes before they become active pharmacological substances. In general, said prodrugs will be functional derivatives of the present compounds, which are rapidly convertible in vivo to the required compound of the present invention. Conventional procedures for the selection and preparation derived from appropriate prodrugs 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, can be very potent and selective in biochemical tests, even if they are inactive in vivo. This lack of so-called bioavailability can be absorbed into a number of different factors such as lack of or poor absorption in the intestine, first pass metabolism in the liver and / or poor intake in the cells. Although the factors that determine bioavailability are not fully understood, there are many examples in the scientific literature - well known to those skilled in the art - of how the compounds, which are potent and selective in biochemical tests but show slow activity or no activity in vivo, in drugs that are biologically active.

Within the scope of the invention to modify the compounds of the present invention, the "parent compound" is mentioned by linking the chemical groups that will improve the bioavailability of said compounds in such a way that ingestion in the cells or mammals is facilitated.

Examples of such modifications, which are not intended in any way to limit the scope of the invention include changing one or more carboxy groups to esters (eg, methyl esters, ethyl esters, fert-butyl, acetoxymethyl, pivaloyloxymethyl esters or other esters) acyloxymethyl). The compounds of the invention, the original compounds, such modified by linking the chemical groups are called "modified compounds" The invention also comprises the active metabolites of the present compounds.

The compounds according to the invention alter and more specifically reduce the level of active intracellular glucocorticoids and are therefore useful for the treatment of conditions, diseases and disorders in which said modulation or reduction is beneficial.

Accordingly, the present compounds may be applicable for the treatment of metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, type 2 diabetes, impaired glucose tolerance (IGT), decreased fasting glucose (IFG), Autoimmune Diabetes. Late in Adults (LADA), type 1 diabetes, late diabetic complications including cardiovascular diseases, cardiovascular disorders, disorders in lipid metabolism, neurodegenerative and psychiatric disorders, intraocular pressure dysregulation including glaucoma, immune disorders, inappropriate immune responses, musculoskeletal disorders, gastrointestinal disorders, polycystic ovary syndrome (PCOS), reduced hair growth or other diseases, disorders or conditions that are influenced by intracellular glucocorticoid levels, adverse effects of increased blood levels of glucocorticoids Exogenous or endogenous and any combination thereof, adverse effects of increased plasma levels of endogenous active glucocorticoids, Cushing's disease, Cushing's syndrome, adverse effects of treatment with glucocorticoid receptor agonists of autoimmune diseases, adverse effects of agonist treatment of the glucocorticoid receptor for inflammatory diseases, adverse effects of glucocorticoid receptor agonist treatment of diseases with an inflammatory component, adverse effects of the glucocorticoid receptor agonist treatment as a part of the cancer chemotherapy, adverse effects of glucocorticoid agonist treatment for surgery / post-surgery or other trauma, adverse effects of glucocorticoid receptor agonist therapy in the context of tissue or organ transplantation or adverse effects of treatment with the glucocorticoid receptor agonist glucocorticoid receptor in other diseases, disorders or conditions wherein the glucocorticoid receptor agonists provide clinically beneficial effects. The present compounds may also be applicable for the treatment of visceral fat accumulation and insulin resistance in HAART (highly active antiretroviral treatment) in treated patients.

More specifically, the present compounds may be applicable for the treatment of the metabolic syndrome, type 2 diabetes, diabetes as a consequence of obesity, insulin resistance, hyperglycemia, prandial hyperglycemia, hyperinsulinemia, inappropriately low insulin secretion, decreased tolerance to glucose (IGT), decreased fasting glucose (IFG), increased hepatic glucose production, type 1 diabetes, LADA; pediatric diabetes, dyslipidemia, diabetic dyslipidemia, hyperlipidemia, hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia, decreased HDL cholesterol, decreased LDUHDI ratio, other disorders of lipid metabolism, obesity, visceral obesity, obesity as a consequence of diabetes, increased food intake, hypertension, late complications of diabetes, micro / macroalbuminuria, nephropathy, retinopathy, neuropathy, diabetic ulcers, cardiovascular diseases, arteriosclerosis, atherosclerosis, coronary artery disease, cardiac hypertrophy, myocardial ischemia , coronary insufficiency, congestive coronary failure, stroke, myocardial infarction, arrhythmia, decreased blood flow, erectile dysfunction (female or male), myopathy, loss of muscle tissue, muscle wasting, muscle catabolism, osteoporosis, decreased linear growth, neurodegenerative and psychiatric disorders, Alzheimer's disease, neuronal death, decreased cognitive function, depression, anxiety, eating disorders, appetite regulation, migraine, epilepsy, addiction to chemical substances, disorders of eye pressure, glaucoma, polycystic ovary syndrome (PCOS), inappropriate immune responses, inappropriate polarization T helper-1 / T helper 2, bacterial infections, mycobacterial infections, fungal infections, viral infections, parasite infestations, sub-optimal responses immunizations, immune dysfunction, partial or complete baldness or other diseases, disorders or conditions that are influenced by intracellular glucocorticoid levels and any combination thereof, adverse effects of treatment with the glucocorticoid receptor agonist of the inflamry diseases alé such as asthma and atopic dertis, adverse effects of treatment with the glucocorticoid receptor agonist of irritable bowel disease such as Crohn's disease and ulcerative colitis; adverse effects of treatment with the glucocorticoid receptor agonist of the immune system, connective tissue and joints, for example, reactive arthritis, rheumatoid arthritis, Sjögren's syndrome, systemic lupus erythematosus, lupus nephritis, Henoch-Schonlein purpura, Wegener's granulomatosis, arthritis temporal, systemic sclerosis, vasculitis, sarcoidosis, dermatomyositis-polymyositis, pemphigus vulgaris, adverse effects of treatment with the glucocorticoid receptor agonist of endocrinological diseases such as hyperthyroidism, hypoaldosteronism, hypopituitarism, adverse effects of treatment with glucocorticoid receptor agonist of the hematological diseases, such as hemolytic anemia, thrombocytopenia, paroxysmal nocturnal hemoglobinuria, adverse effects of treatment with the glucocorticoid receptor agonist of cancer such as spinal cord diseases, Neoplastic compression of the spinal cord, brain tumors, acute lymphoblastic leukemia, Hodgkin's disease, nausea induced by chemotherapy, adverse effects treatment with the glucocorticoid receptor agonist of muscle diseases in the neuro-muscular junction, for example myasthenia gravis and hereditary myopathies (eg, Duchenne muscular dystrophy), adverse effects of treatment with glucocorticoid receptor agonist in the context of surgery and transplantation, eg, trauma, post-surgical stress, surgical stress, kidney transplantation, liver transplantation, transplantation lungs, pancreatic islet transplantation, stem cell transplantation, bone marrow transplant, heart transplant, adrenal gland transplant, tracheal transplant, intestine transplant, corneal transplant, skin graft, keratoplasty, lens implant and other procedures where the deletion with glucocorticoid receptor agonists is beneficial; adverse effects of treatment with glucocorticoid receptor agonist of brain abscess, nausea / vomiting, infections, hypercalcemia, adrenal hyperplasia, autoimmune hepatitis, spinal cord diseases, acular aneurysms or adverse effects of treatment with glucocorticoid receptor agonist in other diseases , disorders and conditions wherein the 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 component according to the invention together with one or more pharmaceutically acceptable carriers or diluents.

The pharmaceutical composition preferably in a unit dosage form, comprising from about 0.05 mg / day to about 2000 mg / day, preferably from about 0.1 mg / day to about 1000 mg / day and more preferably from about 0.5 mg / day to about 500 mg / day of a compound according to the invention.

In other embodiments, the patient is treated with a compound according to the invention 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, buccal, transdermal, pulmonary or parenteral administration.

Therefore, the invention relates to the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment of disorders and diseases wherein a modulation or an inhibition of the activity of 11βHSD1 is beneficial.

The invention also relates to a method for the treatment of disorders and diseases wherein a modulation or an inhibition of the activity of 11βHSD1 is beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound in accordance with the invention.

In a preferred embodiment of the invention the present compounds are used for the preparation of a medicament for the treatment of any disease and conditions that are influenced by intracellular glucocorticoid levels as mentioned above.

In addition, in a preferred embodiment of the invention, the present compounds are used for the preparation of a medicament for the treatment of conditions and disorders where a decreased level of active intracellular glucocorticoid is desired, such as the conditions and diseases mentioned above.

In still a preferred embodiment of the invention, the present compounds are used for the preparation of a medicament for the treatment of the metabolic syndrome, insulin resistance, dyslipidemia, hypertension due to obesity, type 2 diabetes, impaired glucose tolerance (IGT), decreased fasting glucose (IFG), progression of IGT to type 2 diabetes, progress of metabolic syndrome in diabetes type 2, late diabetic complications (for example, cardiovascular diseases, atherosclerosis and atherosclerosis), neurodegenerative and psychiatric disorders and the adverse effects of treatment or therapy with the glucocorticoid receptor agonist.

In another embodiment of the present invention, the route of administration can be any route that effectively transports a compound according to the invention to the desired or appropriate site or action, such as oral, nasal, buccal, transdermal, pulmonary or parenteral.

In yet a further aspect of the invention the present compounds are administered in combination with one or more additional active substances in any appropriate ratio. Said additional active substances may for example be selected from anti-obesity agents, antidiabetics, agents that modify lipid metabolism, antihypertensive agents, glucocorticoid receptor agonists, agents for the treatment and / or prevention of complications that result from or are associated with diabetes and agents for the treatment and / or prevention of complications and disorders that result from or are associated with obesity.

In addition, in a further aspect of the invention, the present compounds can be administered in combination with one or more anti-obesity agents or appetite regulating agents.

Said agents can be selected from the group consisting of CART agonists (cocaine-regulated amphetamine transcription), NPY antagonists (Y neuropeptides), MC4 agonists (melanocortin 4), orexin antagonists, TNF agonists (tumor necrosis factor), agonists CRF (corticotropin release factor), CRF BP antagonists (corticotropin releasing factor binding protein), urocortin agonists, β3 antagonists, MSH agonists (melanocyte-stimulating hormone), MCH (hormone-concentrating melanocyte) antagonists, CCK agonists (cholecystokinin), serotonin ingestion inhibitors, serotonin and norepinephrine re-ingestion inhibitors, mixed serotonin and noraadrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, compounds that release growth hormone, agonists TRH (hormone that releases thyrotropin), modulators UCP 2 or 3 (protein of d this linkage 2 or 3), leptin agonists, DA agonists (bromocriptine, doprexin), lipase / amylase inhibitors, PPAR modulators (peroxisome proliferator-activated receptor), RXR modulators (retinoid X receptor), TR ß agonists, AGRP inhibitors (Agouti release protein), histamine H3 antagonists, opioid antagonists (such as naltrexone), exendin-4, GLP-1 and ciliary neurotrophic factor.

In one embodiment of the invention, the anti-obesity agent is leptin, dexamfetamine or amphetamine, fenfluramine or dexfenfluramine, sibutramine, orlistat, mazindol or phentermine.

Suitable anti-diabetic agents include insulin, insulin analogs and derivatives such as those described in EP 792 290 (Novo Nordisk A / S), for example, NcB29-tetradecanoyl des (B30) human insulin, EP 214 826. and EP 705 275 (Novo Nordisk A / S), for example, AspB28 human insulin, US 5,504,188 (Eli Lilly), for example, LysB28 Pro829 human insulin, EP 368 187 (Aventis), for example Lantus, which are all incorporated in this document for reference, GLP-1 (glucagon as peptide-1) and GLP-1 derivatives such as those described in WO 98/08871 of Novo Nordisk A / S, which is incorporated herein by reference as well as orally active hypoglycemic agents .

Orally active hypoglycemic agents preferably comprise sulfonylureas, biguanides, meglitinides, glucosidase inhibitors, glucagon antagonists such as those described in WO 99/01423 of Novo Nordisk A / S and Agouron Pharmaceuticals, Inc., GLP-1 agonists, channel openers. calcium such as those described in WO 97/26265 and WO 99/03861 of Novo Nordisk A / S which are incorporated herein by reference, DPP-IV (dipeptidyl peptidase-IV) inhibitors, inhibitors of the liver enzymes involved in the stimulation of gluconeogenesis and / or glycogenolysis, modulators of glucose intake, compounds that modify the metabolism of lipids such as antihyperlipidemic agents and antilipidemic agents such as PPARa modulators, PPARd modulators, cholesterol absorption inhibitors, HSL (lipase sensitive hormone) inhibitors and HMG CoA inhibitors (statins), nicotinic acid, fibrates , anion exchangers, compounds that decrease food intake, bile acid resins, RXR agonists and agents that act on the ATP-dependent potassium channel of ß-cells.

In one embodiment, the present compounds are administered in combination with insulin or an analogue or derivative of insulin, such as NeB29-tetradecanoyl des (B30) human insulin, AspB28 human insulin, Lys828 ProB29 human insulin, Lantus®, or a mixed preparation which comprises one or more of these.

In an additional embodiment, the present compounds are administered in combination with a sulfonylurea, for example, toibutamide, glibenclamide, glipizide or glycoside.

In another embodiment, the present compounds are administered in combination with a biguanide, for example metformin.

In yet another embodiment, the present compounds are administered in combination with a meglitinide for example, repaglinide or senaglinide.

In yet another embodiment, the present compounds are administered in combination with a thiazolidinedione, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds described in WO 97/41097 such as 5 - [[4- [3-Methyl-4-oxo] -3,4-dihydro-2-quinazolinyl] 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 described in WO 99/19313 such as (-) 3- [4- [2-phenoxazin-10-yl] ethoxy] phenyl] -2 acid. -ethoxypropanoic acid or a pharmaceutically acceptable salt thereof, preferably the arginine salt.

In a further embodiment, the present compounds are administered together with an α-glucosidase inhibitor, for example, miglitol or acarbose.

In another embodiment, the present compounds are administered in combination in combination with an agent acting on the ATP-dependent potassium channel of the β-cells for example, toibutamide, glibenclamide, glipizide, glycoside or repaglinide.

Therefore, the present compounds can be administered in combination with nateglinide.

In yet another embodiment, the present compounds are administered in combination with an antihyperlipidemic agent or antilipidemic agent, for example, cholestyramine, colestipol, clofibrate, gemfibrozil, fenofibrate, bezafibrate, tesaglitazar, EML-4156, LY-818, MK-767, atorvastatin , fluvastatin, lovastatin, pravastatin, simvastatin, acipimox, probucol, ezetimibe or dextrotyrosine.

In one embodiment, the present compounds are administered in combination with more than one of the aforementioned compounds, for example, in combination with a sulfonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin, insulin and lovastatin, etc.

In addition, the present compounds are administered in combination with one or more anti-hypertensive agents. Examples of anti-hypertensive 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, ß2 receptor blockers eg S-atenolol, OPC-1085, ACE inhibitors (angiotensin-converting enzyme) inhibitors such as quinapril, lisinopril, enalapril, captopril, benazepril, perindopril, triolapril, fosinopril, ramipril, cilazapril, delapril , imidapril, moexipril, espirapril, 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, lacidoipine, lercanidipine, aranidipine, cilnidipine, clevidipine, azelnidipine, barnidipine, efonodipin a, iasidipine, iemildipine, iercanidipine, manidipine, nilvadipine, pranidipine, fumidipine, blockers such as doxazosin, urapidil, prazosin, terazosin, bunazosin and OPC-28326, diuretics such as thiazides / sulfonamides (e.g., bendro-flumetazide, chlorothalidone, hydrochlorothiazide, and clopamide), loop diuretics (eg, bumetanide, furosemide, and torasemide) and potassium-sparing diuretics (eg, amiloride, spironolactone), endothelin ET-A antagonists such as ABT-546, ambrisetan, atrasentan, SB-234551, CI-1034, S-0139 and YM-598, endothelin antagonists for example, bosentan and J-104133, renin inhibitors such as alisquiren, vasopressin V1 antagonists for example, OPC-21268, antagonists of vasopressin V2 such as tolvaptan, SR-121463 and OPC-31260, B-type natriuretic peptide agonists eg Nesiritide, angiotensin II antagonists such as irbesartan, ciesartancilexetil, losartan, valsartan, telmisartan, eprosartan, ciesartan, CL-329167, eprosartan, iosartan, olmesartan, pratosartan, TA-606, and agonists YM-358, 5-HT2 for example, phenoldopam and quetanserin, adenosine A1 antagonists such as naftopidil, N-0861 and FK-352, thromboxane A2 antagonists such as KT2- 962, endopeptidase inhibitors for example, ecadotril, agonists nitric oxide oxide such as LP-805, dopamine D1 antagonists for example, MYD-37, dopamine D2 agonists such as nolomirola, n-3 fatty acids for example, omacor, prostacyclin agonists such as treprostinil, beraprost, PGE1 agonists for example, ecraprost , Na + / K + ATPase modulators eg PST-2238, potassium channel activators for example, KR-30450, vaccines such as PMD-3117, Indapamides, CGRP-unigen, guanylate cyclase stimulators, hydralazines, methyldopa, docarpamine, moxonidine, CoAprovel, MondoBiotech-811.

Additional reference may be made to Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.

Therefore, the present compounds can be administered in combination with one or more glucocorticoid receptor agonists. Examples of such glucocorticoid receptor agonists are betamethasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, beclomethasone, butixicort, clobetasol, flunisolide, flucatisone (and the like), mometasone, 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 combination of the compounds according to the invention with one or more above-mentioned compounds and optionally one or more additional pharmacologically active substances are considered within the scope of the present invention.

PHARMACEUTICAL COMPOSITIONS The compounds of the present invention can be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in multiple or simple doses. The pharmaceutical compositions according to the invention can be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients. in accordance with the conventional techniques described in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.

The pharmaceutical compositions can be formulated specifically for the administration of any appropriate route such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal), the oral route being preferred. It will be appreciated that the preferred route will depend on the general conditions and age of the subject to be treated, the nature of the condition to be treated and the active ingredient selected.

Pharmaceutical compositions for oral administration include solid dosage forms such as soft or hard capsules, capsules, tablets, troches, lozenges, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release in accordance with methods well known in the art.

Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution in sterile injectable solutions or dispersions before use. Slow-release injectable formulations (depot) are also contemplated as being within the scope of the present invention.

Other appropriate forms of administration include suppositories, syrups, sprays, ointments, creams, gels, inhalants, skin patches, implants, etc.

A typical oral dose 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 in body weight per day administered in one or more doses such as 1 to 3 doses. The exact dose will depend on the frequency and mode of administration, sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant disease to be treated and other factors evident to those experts in the technique.

The formulations may conveniently be present in unit dosage forms 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, for example, 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, for example, about 100 mg.

For parenteral routes, such as intravenous, intrathecal, intramuscular and the like, typical doses are in the order of about half the dose used for oral administration.

The compounds of this invention are generally used 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 basic salt and a basic addition salt of a compound having the utility of a free acid. The term "pharmaceutically acceptable salts" refers to non-toxic salts of the compounds for use in accordance with the present invention which are generally prepared by reacting the free base with an appropriate organic and inorganic acid or by reacting the acid with an organic or inorganic appropriate. When a compound to be used in accordance with the present invention, contains a free base said 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 compound to be used in accordance with the present invention contains a free acid said salts are prepared in a conventional manner by treating a solution or suspension of the compound with a chemical equivalent or a pharmaceutically acceptable base. Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with an appropriate cation such as sodium or ammonium ion. Other salts that are not pharmaceutically acceptable may be useful in the preparation of compounds for use in accordance with the present invention and these form a further aspect of the present invention.

For parenteral administration, solutions of the compounds present in sterile solution, aqueous propylene glycol or peanut or safflower oil can be used. Said aqueous solutions should be properly stabilized if necessary and the liquid diluent first becomes isotonic with sufficient saline or glucose. Saline solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous medium employed is 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 the suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, syrup, phospholipids, gelatin, lactose, terra alba, sucrose, cyclodextrin, amylase, magnesium stearate talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, monoglycerides and diglycerides of the fatty acid, fatty acid esters pentaerythritol, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any prolonged release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or mixed with a wax. The formulations can also include wetting agents, emulsifiers and suspending agents, preservatives, sweetening agents or flavoring agents.

Pharmaceutical compositions formed by the combination of the compounds of the invention and pharmaceutically acceptable carriers are then rapidly administered in a variety of dosage forms appropriate for the described routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the pharmacy art.

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 an appropriate 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 a liquid emulsion of oil in water or water in oil.

The compositions intended for oral use can be prepared according to any known method, and said compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives to provide flavorful and pharmaceutically elegant preparations. . The tablets may contain the active ingredient in admixture with pharmaceutically acceptable non-toxic excipients which are suitable for the manufacture of tablets. These excipients can be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, disintegrating and granulating agents, for example corn starch or alginic acid, binding agents, for example starch. , gelatin or acacia and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be covered or may not be covered 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 delay time material such as monostearate of glyceryl or glyceryl distearate can be used. They may also be covered 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 can also be prepared as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or a soft gelatin capsule wherein the ingredient active is mixed with water or an oily medium, for example peanut oil, liquid paraffin or olive oil.

The aqueous suspensions may contain the active compounds in admixture with excipients suitable for the manufacture of aqueous suspensions. Said excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum, the dispersing or wetting agents can be a naturally occurring phosphatide such as lecithin or condensation products of an alkyl oxide with fatty acids, for example polyoxyethylene stearate or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example, heptadecathyl-eneoxyketanol or condensation products of ethylene oxide with derived partial esters of the 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 coloring agents, one or more flavoring 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, peanut oil, olive oil, safflower oil or coconut oil or in a mineral oil such as a liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above and flavoring agents may be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

Powders and dispersible granules suitable for the preparation of an aqueous suspension by the addition of water provide the active compound in admixture with a wetting or dispersing agent, the suspending agent and one or more preservatives. Wetting or dispersing agents and suspending agents are exemplified by those previously mentioned. Additional excipients, for example, coloring agents, flavors and sweeteners may also be present.

Pharmaceutical compositions comprising a compound for use in accordance with the present invention may also be in the form of water-in-oil emulsions. The oily phase can be a vegetable oil, for example olive oil or peanut oil or a mineral oil, for example a liquid paraffin or a mixture thereof. Suitable emulsifying agents can be naturally occurring gums, for example acacia gum or tragacanth gum, naturally occurring phosphatides, for example soy, lecithin 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 flavoring agents.

The syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Said formulations may also contain a demulcent, preservative or coloring and flavoring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated in accordance with known methods using appropriate wetting or dispersing agents and the suspension agents described above. The sterile injectable preparation can 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 vehicles and acceptable solvents that may be employed are water, Ringer's solution and suspension solution or isotonic solvent. For this purpose, any soft fixed oil can be used using 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 that is solid at ordinary temperatures but liquid at the rectal temperature and will further melt in the rectum to release the drug. Such materials include, for example, cocoa butter and polyethylene glycols.

For topical use, creams, ointments, gelatins, suspensions solutions, etc. are contemplated. containing the compounds of the present invention. For the purpose of this application, topical applications will include mouth rinses and liquids for gargling.

Compounds for use in accordance with the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

In addition, some of the compounds for use in accordance with the present invention can form solvates with water or common organic solvents. Said solvates are also contemplated within the scope of the present invention.

In addition, in a further embodiment, there is provided a pharmaceutical composition comprising a compound for use in accordance with the present invention or a pharmaceutically acceptable salt, solvate or prodrug thereof and one or more pharmaceutically acceptable carriers, excipients or diluents.

If a solid carrier is used for oral administration, the preparation may be packaged in a hard gelatin capsule in powder or granule form or it may 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, emulsion, soft gelatin capsule or sterile injectable liquid such as a non-aqueous or aqueous liquid solution or suspension.

A typical tablet that can be prepared by conventional tabletting techniques can contain: Center: Actcompound (as free compound or salt thereof) 5.0 mg Lactosum PH. Eur. 67.8 mg Cellulose, microcrist. (Avicel) 31.4 mg Amberlite®IRP88 * 1.0 mg Magnesii stearas PH. Enough quantity Coating: Hydroxypropyl methylcellulose approx. 9 mg My acett 9-40 T "approx 0.9 mg Potassium polyacrylline NF, disintegrating tablet, Rohm and Haas. ** Monoglyceride used as a plasticizer for film coating.

The compounds of the invention can be administered to a patient who is a mammal, especially a human in need thereof. Said mammals also include animals, both domestic animals, for example house pets and non-domestic animals, such as wildlife.

Any novel feature or combination of features described in this document is considered essential for this invention.

The present invention also relates to the subsequent methods for the preparation of the compounds of the invention.

The present invention is further illustrated in the following representatexamples which are, however, not intended to limit the scope of the invention in any way.

EXAMPLES The following examples and the general procedures refer to intermediate compounds and final products for the general formula (I) previously identified. The preparation of the compounds of the general formula (I) of the present invention is described in detail using the following examples. Occasionally, the reaction may not be applicable as described for each compound included within the disclosed scope of the invention. The compounds for which this occurs will be readily recognized by those skilled in the art. In these cases, the reactions can be successfully performed by modifications known to those skilled in the art, which is, by appropriate protection of interference groups, by switching to other conventional reagents or by routine modification of the reaction conditions. Alternaty, other reactions described herein or otherwise conventional will be applicable to the preparation of the corresponding compounds of the invention. In all the preparatmethods, all the starting materials are known or can be easily prepared from known starting materials. The structures of the compounds are confirmed by elemental analysis or nuclear magnetic resonance (NMR), where the peaks assigned to the characteristic protons in the title compounds are presented where appropriate. The 1 H NMR (dH) exchanges are provided in parts per million (ppm) in downfield of tetramethylsilane as an internal reference standard. M.p .: is the melting point (for its acronym in English) and is provided in in ° C and is not corrected. Column chromatography was carried out using the technique described by W.C. Still et al., J. Org. Chem. 43: 2923 (1978) on Merck 60 silica gel (Art. 9385). HPLC analyzes were performed using 5 μm C18 4 x 250 mm column eluted with various mixtures of water and acetonitrile, flow = 1 ml / min, as described in the experimental section.

Microwave oven synthesis: The reaction was heated by microwave oven irradiation in sealed microwave glasses in an Emrys Optimizer Simple Emrys Optimizer EXP from PersonalChemistry®.

Preparative HPLC: Column: 1.9 x 15 cm Waters XTerra RP-18. Stabilizer: linear gradient 5 - 95% in 15 min, MeCN, 0.1% TFA, flow rate of 15 ml / min. The pooled fractions were evaporated to dryness under vacuum or evaporated in vacuo until the MeCN was removed and subsequently frozen and freeze-dried.

ABBREVIATIONS d = day (s) g = gram (s) h = hour (s) Hz = hertz L = liter (s) M = molar mg = milligram (s) min = minute (s) mL = milliliter (s) mmol = millimole (s) mol = mole (s) ppm = parts per million psi = pounds per square inch ESI = electrode dew ionization m / z = mass for the load radius mp = melting point MS = HPLC mass spectrometry = high pressure liquid chromatography RP = reverse phase HPLC-MS = mass spectrometry - high pressure liquid chromatography NMR = nuclear magnetic resonance spectroscopy rt = room temperature TLC = thin layer chromatography DCM = dichloromethane, CH2Cl2, methylene chloride DIPEA = A,? -diisopropylethylamine DMF =? /,? / - dimethylformamide DMSO = dimethylsulfoxide EDAC = 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride Et20 = diethyl ether EtOAc = ethyl acetate HOBt = 1-hydroxybenzotriazole MeCN = acetonitrile MeOH = methanol NMP =? / - methylpyrrolidin-2-one TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran CDCI3 = chloroform deuterium CD3OD = chloroform tetradeuterium DMSO-cfe = dimethylsulfoxide hexadeuterio NMR ANALYSIS The NMR spectrum was recorded at 300 and 400 MHz on a Bruker DRX300 instrument, DRX400 or AV400 equipped with reverse-selective 5 mm probe heads (SEI, 1H and 13C), reverse wideband 5mm (BBI, 1H, broadband) and 5mm nuclear box (QNP, 1H, 13C) respectively . Changes (d) were provided in parts per million (ppm) in downfield of tetramethylsilane as the internal reference standard.

HPLC-MS HPLC-MS Method RP analysis was performed on an Agilent HPLC system (vacuum degasser 1100, pump 1100, 1100 injector and a DAD 1100) fitted with a MS Model VL detector system (MW 0-1000) and a system SEDERE detector Model Sedex 55 ELS using a Waters X-terra MS C18 column (5 μm, 3.0 mm x 50 mm) with elution gradient, 5% to 95% solvent B (0.05% TFA in acetonitrile) in solvent A (0.05% TFA in water) within 3 min, 2.7 mL / min, temperature 40 ° C.

PREPARATION TECHNIQUES HPLC ZLC HPLC method RP purification was performed in a Gilson system (3 Gilson 306 pumps, Gilson 170 DAD detector and a Gilson 215 liquid handle) using a RP Waters X-terra (10 μm, 30 mm x 150 mm) with elution gradient, 5% to 95% solvent B (0.05% TFA in acetonitrile) in solvent A (0.05) % TFA in water) within 15 min, 40 mUmin, detection at 210 nm, temperature rt. The pooled fractions were evaporated to dryness under vacuum or evaporated in vacuo until the acetonitrile was removed and then frozen and the freeze dried.

GENERAL The following examples and general procedures refer to intermediate compounds and final products for the general formula (I) identified in the specification and in the synthesis schemes. The preparation of the compounds of the general formula (I) of the present invention are described in detail using the following examples. Occasionally, the reaction may not be applicable as described for each compound included within the disclosed scope of the invention. The compounds for which it occurs will be readily recognized by those skilled in the art. In these cases, the reactions can be successfully performed by conventional modifications known to those skilled in the art, which is by appropriate protection of interference groups, by switching to other conventional agents, or by routine modification of reaction conditions. Alternatively, other reactions described herein or otherwise conventional will be applicable to the preparation of the corresponding compounds of the invention. In all preparative methods, all of the starting materials are known or can be prepared by a person skilled in the art in analogy with the preparation of similar known compounds or by the General Procedures A through D described herein. The structures of the compounds are formed by elemental analysis or nuclear magnetic resonance (NMR), where the peaks assigned to the characteristic protons in the title compounds are presented where appropriate.

GENERAL PROCEDURES General Procedure (A) The compounds of Formula (Ia) according to the invention wherein R1, R3, and R4 are as defined for formula (I), with NR3R4 corresponding to ring A, can be prepared as notes later: A benzimidazole of formula (II) wherein NR3R4 corresponds to ring A defined above can be reacted with a carboxylic acid in the presence of coupling reagents (eg, EDAC and HOBt) or an activated carboxylic acid of formula (III) in where R1 is as defined above. This reaction can be carried out in a suitable solvent (for example, dichloromethane) in the presence of a base (e.g., DIPEA) at room temperature.

General Procedure (B) The compounds of the Formula (Ib) according to the invention wherein R2, R3, R4, R8, R9, R10, R11, and R12 are as defined by Formula (I), with NR3R4 corresponding to ring A, can be prepared as follows: (HIV) (Ib) The acid -Fluoro-3-nitrobenzoic acid can be reacted with an amine of the formula (IV) wherein R8, R9, R10, R11 and R12 are as defined above. This reaction can be carried out in a suitable solvent (e.g., ethanol) in the presence of a base (e.g., DIPEA) at room temperature to form the secondary aniline of the formula (V). The carboxylic acid of the formula (V) can then be activated with HOBT and EDAC and reacts with an amine of the formula (VI) wherein NR3R4 is the ring A as defined above. This reaction can be carried out in an appropriate solvent (for example, THF) in the presence of a base (for example, DIPEA) at room temperature to form the compound of the formula (VII). The nitro group of the compounds of the formula (VII) can be reduced by hydrogen under pressure in an appropriate solvent (eg, methanol / dichloromethane) in the presence of a catalyst (eg, palladium on activated carbon) at room temperature to form the diamine of the formula (VIII). The compounds of the Formula (VIII) can be reacted with an aldehyde of the formula (IX) wherein R 2 is as defined above. This reaction can be carried out in an appropriate solvent (for example, NMP) in the presence of a drying agent (for example, 4 A molecular sieve) at 50 ° C to form the compounds of the formula (Ib).

General Procedure (C) The compounds of the Formula (le) according to the invention wherein R2, R3, and R4 are as defined for the formula (I), with NR3R4 corresponding to the ring A, can be prepared as outlined continuation: 4-Amino-3-nitrobenzoic acid can be activated with HOBT and EDAC and reacted with an amine of formula (VI) wherein NR3R4 is ring A as defined above. This reaction can be carried out in an appropriate solvent (for example, THF) in the presence of a base (for example, DIPEA) at room temperature to form the compound of the formula (X). The nitro group of the formula (X) can be reduced by hydrogen under pressure in a mixture of methanol and dichloromethane in the presence of a catalyst (eg, palladium on activated carbon) at room temperature to form the diamine of the formula (XI) . (XI) can be reacted with an aldehyde of the formula (IX) wherein R2 is as defined above. This reaction can be carried out in NMP in the presence of a drying agent (e.g., 4 A molecular sieve) at 50 ° C to form the white product (le).

General Procedure (D) The compounds of the formula (Id) according to the invention wherein R1, R3, R4, and R5 are as defined for the formula (I), with NR3R4 corresponding to the ring A, can be prepared as notes later: An indole of formula (XII) wherein R3, R4, and R5 are as defined above, with NR3R4 corresponding to ring A, can be reacted with an alkyl / benzyl halide of the Formula (XIII) wherein R1 is as defined above in the presence of a base (e.g., sodium hydride). This reaction can be carried out in a suitable solvent (e.g., DMF) at a temperature of more than reflux.

Example 1 (General Procedure (A)) Furan-2-carboxylic acid. { 2- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzoimidazol-1-yl] -ethyl} -amide To a solution of 2-furoic acid (37 mg, 0.33 mmol) in dry THF (2 mL) at room temperature under an inert atmosphere of nitrogen was added HOBt (49 mg, 0.36 mmol) and EDAC (82 mg, 0.43 mmol) , and the resulting solution was stirred for 30 minutes. [1- (2-Amino-etl) -1H-benzoimidazol-5-yl] - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl tricluoroacetate was added. ) -metanone (150 mg, 0.33 mmol) to the solution followed by TEA (0.184 mL, 1.32 mmol), and the reaction mixture was stirred for 16 h at room temperature. The volatiles were evaporated in vacuo and the resulting solid was purified by preparative HPL, dried under vacuum at 50 ° C yielding 100 mg (70%) of the title compound as a solid. MS-ESI m / z 435; 1 H NMR (400 MHz, DMSO-d 6) d 0.88-0.99 (m, 6H), 1.07 (d, 3H), 1.29-1.41 (m, 4H), 1.50-1.52 (m) and 2.10-2.11 (m, 1 H), 1.76-1.79 (m, 1 H), 3.02 (d), 3.13 (d), 3.32 (d) and 3.47 (d, 2H), 3.69 (t, 2H), 3.87-3.89 (m) and 4.39 -4.41 (m, 1 H), 4.56 (t, 2H), 6.58 (s, 1 H), 6.98 (d, 1 H), 7.48 (dd, 1 H), 7.77-7.82 (m, 2H), 7.89 (t, 1H), 8.54-8.58 (m, 1 H), 9.07 (d, 1 H).

The following compounds were synthesized using a method similar to that described in Example 1 above. MS- Ex. Structure MW Name IUPAC ESI m / z MS- Ex. Structure MW Name IUPAC Yam ESI m / z 1-4 acid-butyl ester of acid. { 2- [5- (1, 3,3-Trimethyl-6-aza-440.59 bicyclo [3.2.1] octane-6- 441 carbonyl) - benzoimidazol-1-yl] -ethyl} -carbamic lsoxazole-5-carboxylic acid. { 2- [5- (1, 3,3-trimethyl-6-aza- 1-6 435.53 bicyclo [3.2.1] octane-6- 436 carbonyl) -benzoimidazol-1-yl] - ethyl} -amide 1-7 Example 2 (General procedure (B)) Ethyl 3- [2-Ethyl-5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzimidazole ethyl ester 1-il] -propionic To a solution of 3- [2-amino-4- (1, 3,3-trimethyl-6-azabicyclo [3.2.1] octane-6-carbonyl) -phenylamino] -propionic acid ethyl ester (250 mg , 0.645 mmol) in dry NMP (10 mL) at room temperature under an inert atmosphere of nitrogen was added approx. 200 mg of 4 A molecular sieve followed by acetaldehyde (93 uL, 1.29 mmol). The mixture was stirred for 16 hrs at 50CC. The reaction was warmed by the addition of water (100 mL) followed by extraction with diethyl ether (3 x 100 mL). The combined organic phases were washed with brine (4 x 200 mL), dried (MgSO 4), filtered and evaporated in vacuo. The resulting oil was purified by preparative HPLC, dried under vacuum at 50 ° C yielding 104 mg (38%) of the title compound as brown oil. MS-ESI m / z 426; 1 H NMR (400 MHz, CDCl 3) d 0.88-1.06 (m, 6H), 1.11-1.23 (m, 7H), 1.24-1.28 (m) and 1.55-1.65 (m, 1 H), 1.36-1.45 (m, 2H), 1.50 (t, 3H), 1.74-1.81 (m, 1 H), 2.23-2.30 (m) and 3.12-3.20 (m, 1 H), 2.81 (t, 2H), 2.96 (q, 2H) , 3.22-3.35 (m, 1 H), 3.32 (dd) and 3.62 (dd, 1 H), 4.03-4.07 (m) and 4.63-4.67 (m, 1 H), 4.13 (q, 2H), 4.45 ( dt, 2H), 7.32-7.46 (m, 2H), 7.84 (d, 1 H).

Example 3 3- [2-Ethyl-5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzimidazol-1-yl] -propionic acid To a solution of 3- [2-ethyl-5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzimidazol-1-yl] ethyl ester] -propionic (104 mg, 0.244 mmol) in 96% ethanol (5 mL) at room temperature At room temperature under an inert atmosphere of nitrogen, 1 N NaOH (aq) (0.3 mL, 0.3 mmol) was added. The mixture was stirred for 2 hrs at room temperature. The reaction was quenched by the addition of water (5 mL) and acidified to pH 2 with 1 HCl followed by extraction with ether (2 x 10 mL). The combined organic phases were washed with water (2 x 10 mL), brine (10 mL), dried (MgSO), filtered and evaporated in vacuo yielding 11 mg (11%) of the title compound as a yellow oil. MS-ESI m / z 398; 1 H NMR (400 MHz, CDCl 3) d 0.83-1.06 (m, 6H), 1.12-1.22 (m, 7H), 1.24-1.28 (m) and 1.46-1.54 (m, 1 H), 1.30-1.39 (m, 2H), 1.33 (t, 3H), 1.63-1.74 (m, 1H), 2.22-2.32 (m) and 3.15-3.27 (m, 1H), 2.26 (t, 2H), 2.85 (t, 2H), 3.51 (q, 2H), 7.25-7.35 (m, 2H), 7.56 (d) and 7.74 (d, 1H).

Example 4 (General procedure (C)) 2- [5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -1H-benzimidazole-2-ethyl ester il] -cyclopropanecarboxylic acid To a solution of (3,4-diaminophenyl) - (1,3,3-trimethyl-6-azabicyclo [3.2.1] oct-6-yl) -methanone (500 mg, 1.74 mmol) in dry NMP (25 mL ) at room temperature under an inert atmosphere of nitrogen was added approx. 500 mg of 4 A molecular sieve followed by ethyl 2-formyl-1-cyclopropanecarboxylate (0.51 mL, 3.86 mmol). The mixture was stirred for 16 hrs at 50 ° C. The reaction was warmed by the addition of water (100 mL) followed by extraction with diethyl ether (3 x 100 mL). The combined organic phases were washed with water (3 x 100 mL), brine (100 mL), dried (MgSO), filtered and evaporated in vacuo. The resulting oil was purified by preparative HPLC, dried under vacuum at 50 ° C yielding 60 mg (8%) of the title compound as a solid. MS-ESI m / z 410; 1 H NMR (400 MHz, CDCl 3) d 0.88-1.06 (m, 6H), 1.07-1.20 (m, 4H), 1.25 (t, 3H), 1.27-1.34 (m) and 1.49-1.66 (m, 3H), 1.36-1.48 (m, 2H), 1.72-1.84 (m, 2H), 2.36-2.48 (m, 1 H), 2.66-2.76 (m, 1 H), 3.18-3.27 (m, 1 H), 3.30 (d) and 3.65 (d, 1 H), 4.00-4.06 (m) and 4.57-4.65 (m, 1 H), 4.14 (q, 2H), 7.18-7.30 (m, 2H), 7.57 (d, 1 H), 10.37 (br s, 1 H).

Example 5 2- [5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -1-r7-benzimidazol-2-yl] -cyclopropanecarboxylic acid To a solution of 2- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -1 / - / - benzimidazol-2-yl] ethyl ester] Cyclopropanecarboxylic acid (60 mg, 0.147 mmol) in 96% ethanol (3 mL) at room temperature under an inert atmosphere of nitrogen was added 1 N NaOH (aq) (0.36 mL, 0.36 mmol). The mixture was stirred for 16 hrs at 50 ° C. The reaction was quenched by the addition of water (3 mL) and acidified to pH 2 with 1N HCl followed by extraction with diethyl ether (2 x 5 mL). The combined organic phases were washed with water (2 x 5 mL), brine (5 mL), dried (MgSO), filtered and evaporated in vacuo yielding 49 mg (88%) of the title compound as a solid. MS-ESI m / z 382; 1 H NMR (400 MHz, CDCl 3) d 0.87-1.06 (m, 6H), 1.08-1.20 (m, 4H), 1.30-1.38 (m, 1H), 1.39-1.45 (m) and 1.48-1.64 (m, 3H ), 1.70-1.90 (m, 2H), 1.91-2.01 (m, 1 H), 2.18-2.30 (m) and 2.43-2.61 (m) and 2.85-3.02 (m, 2H), 3.15 (t) and 3.66 (t, 1 H), 3.20-3.34 (m, 1 H), 3.88-4.01 (m) and 4.54-4.65 (m, 1 H), 7.39-7.50 (m, 1 H), 7.69-7.85 (m, 2H).

The following compounds were synthesized using a method similar to those described in Examples 2, 3, 4 and 5 above: MS- Ex. MW Structure Name IUPAC Yam ESI m / z 3-ethyl ester 1-yl] -propionic acid ethyl ester 2- [1-Ethyl-5- (1, 3,3-trimethyl-6-aza-bicyclo- 5-2 437.58 [3.2.1] octane-6- 438 carbonyl) -1 H- benzimidazol-2-yl] -cyclopropanecarboxylic acid 3- [2-Methyl-5- (1, 3,3-trimethyl-6-aza- 5-3 383.49 bicyclo- [3.2.1] octane- 6-384 carbonyl) -benzimidazole- 1-yl] -propionic acid 2- [1-Ethyl-5- (1, 3,3- cyclopropanecarboxylic Example 6 (General procedure (D)) 3- [5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] ethyl ester] -propionic To a solution of (1 / - -indol-5-yl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -methanone (250 mg, 0.84 mmol) in dry DMF (5 mL) at room temperature under an inert nitrogen atmosphere was added sodium hydride (30 mg, 1.26 mmol, 60% dispersion in oil), and after stirring for 30 min ethyl bromopropionate was added (168 mg, 0.93 mmol) and the reaction mixture was stirred for 16 h at 60 ° C. The reaction was quenched by the addition of water (20 mL) followed by extraction with DCM (3 x 100 mL). The combined organic phases were dried (MgSO4), filtered and evaporated in vacuo. The resulting solid was purified by silica gel chromatography using a mixture of ethyl acetate and heptane (1: 1) as eluent. The pure fractions were collected, the solvent was evaporated in vacuo and dried under vacuum at 50 ° C yielding 125 mg (37%) of the title compound as a solid. MS-ESI m / z 397; 1 H NMR (400 MHz, CDCl 3) d 0.95 (d, 3 H), 1.03 (d, 3 H), 1.13-1.22 (m, 7 H), 1.25-1.43 (m, 2 H), 1.45 (s, 1 H), 1.62- 1.68 (m, 1 H), 1.76-1.80 (m, 1 H), 2.29-2.33 (m, 1 H), 2.82 (t, 2H), 3.28-3.35 (m) and 3.63 (d), 1 H) , 4.12-4.14 and 4.64-4.66 (m, 1 H), 4.11 (q, 2H), 4.47 (t, 2H), 6.52 (d, 1 H), 7.18 (d, 1 H), 7.32-7.39 (m , 2H), 7.74 (d, 1 H).

Example 7 3- [5- (1,3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -propionic acid To a solution of 3- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -propionic acid ethyl ester (80 mg , 0.2 mmol) in ethanol (2 mL) was added 1N of aqueous sodium hydroxide solution (2 mL), and the resulting solution was stirred for 2 h. The solution was acidified with 1N hydrochloric acid solution before the organic volatiles were removed in vacuo, and the aqueous residues were extracted with DCM (3 x 5 mL). The combined organic phases were dried (MgSO4), filtered and evaporated in vacuo. The resulting solid was purified by preparative HPLC, dried under vacuum at 50 ° C yielding 55 mg (74%) of the title compound as a solid. MS-ESI m / z 369; 1 H NMR (400 MHz, DMSO-d 6) d 0.94 (d, 3 H), 1.04 (d, 3 H), 1.13-1.17 (m, 4 H), 1.28-1.38 (m, 2 H), 1.43-1.45 (m, 1 H), 1.60-1.63 (m, 1H), 1.75-1.79 (m, 1 H), 2.24-2.32 and 3.25-3.26 (m, 1 H), 2.74 (t, 2H), 3.27-3.35 (m) and 3.62-3.65 (m), 1 H), 4.08-4.10 and 4.62-4.63 (m, 1 H), 4.39 (t, 2H), 6.47-6.48 (m, 1H), 7.17-7.23 (m, 3H), 7.70 (d, 1 H).

The following compounds were synthesized using a method similar to those described in Examples 6 and 7 above: MS-Ex. MW Structure Name IUPAC ESI m / z [5- (1,3,3-Trimethyl-) butyl butyl ester 6-aza- 7-1 410.56 bicyclo-411 [3.2.1] octane-6-carbonyl) -indol-1-yl] -acetic acid [5- (1, 3,3-Trimethyl-6-aza- 7- 2 354.45 bicyclo [3.2.1] octane 355 -6-carbonyl) -indol-1- il] -acetic il] -propan-1-one 7-4 MS- Ex. Structure MW Name IUPAC ESI m / z ethyl ester of -6-carbonyl) -indol-1- il] -propionic acid 2,2-Dimethyl-3- il] -propionic methyl ester of il] -propionic methyl ester of il] -butyric acid 3- [5- (1, 3,3-Trimethyl-6-aza- 7-9 382.50 bicyclo [3.2.1] octane 383 -6-carbonyl) -indol-1- il] -butyric MS- Ex. Structure MW Name IUPAC ESI m / z acid 2-Methyl-3- [5- il] -propionic acid 3- [5- (1, 3,3-Trimethyl-6-aza-430.55 bicyclo [3.2.1] octane 431 -6-carbonyl) -indol-1- ilmetilj-benzoic methyl ester of ilmetilj-benzoic acid 4- [5- (1, 3,3-Trimethyl-6-aza-13 430.55 bicyclo [3.2.1] octane 431 -6-carbonyl) -indol-1- ilmetilj-benzoic ethyl ester the -14 propionic MS- Ex. Structure MW Name IUPAC ESI m / z acid 3- [5- (4-Azatricyclo [4.3.1.1 * 3.8 *] 7-15 366.46 undecano-4- 367 carbonyl) -indol-1- il] - propionic Example 8 5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -1H-indole-2-carboxylic acid ethyl ester To a solution of 1 H-lndol-2,5-dicarboxylic acid 2-ethyl ester (890 mg, 3.8 mmol) in dry DMF (10 mL) at room temperature under an inert nitrogen atmosphere was added HOBt (570 mg, 4.2 mmol) and EDAC (951 mg, 4.9 mmol), and the resulting solution was stirred for 30 min. 1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane hydrochloride (796 mg, 4.2 mmol) was added to the solution followed by DIPEA (1.98 mL, 11.4 mmol), and the reaction mixture was stirred for 16 h at room temperature. The reaction was quenched by the addition of water (20 mL) followed by extraction with DCM (3 x 50 mL). The combined organic phases were dried (MgSO4), filtered and evaporated in vacuo. The resulting solid was purified by silica gel chromatography using a mixture of ethyl acetate and heptane (1: 2) as eluent. The pure fractions were collected, the solvent was evaporated in vacuo and dried under vacuum at 50 ° C yielding 800 mg (57%) of the title compound as a solid. MS-ESI m / z 369; 1 H NMR (300 MHz, CDCl 3) d 0.94 (d, 3 H), 1.04 (d, 3 H), 1.14-1.19 (m, 4 H), 1.24-1.29 (m, 2 H), 1.39-1.45 (m, 4 H), 1.58-1.63 (m, 1 H), 1.76-1.79 (m, 1 H), 3.25-3.30 (m, 1 H), 3.35 (d) and 3.65 (d, 1 H), 4.06-4.09 (m) and 4.64-4.67 (m, 1 H), 4.42 (q) , 2H), 7. 27 (s, 1 H), 7.39-7.46 (m, 2H), 7.82 (d, 1 H), 9.05 (s, 1 H).

Example 9 5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -1 - / - indole-2-carboxylic acid To a solution of 5- (1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -1H-indole-2-carboxylic acid ethyl ester (500 mg, 1.35 mmol) in ethanol (10 mL) was added 1 N of aqueous sodium hydroxide solution (10 mL), and the resulting solution was stirred for 16 h. The solution was acidified with 1 N hydrochloric acid before the organic volatiles were removed in vacuo and the aqueous residues were extracted with DCM (3 x 5 mL). The combined organic phases were dried (MgSO4), filtered and evaporated in vacuo. The resulting solid was dried under vacuum at 50 ° C yielding 460 mg (100%) of the title compound as a solid. MS-ESI m / z 341; 1 H NMR (300 MHz, DMSO-de) d 0.88-0.99 (m, 6H), 1.07 (d, 3H), 1.16-1.19 (m, 1 H), 1.27-1.50 (m, 4H), 1.74-1.77 ( m, 1 H), 3.10-3.19 (m, 1 H), 3.40 -3.48 (m, 1 H), 3.99-4.07 (m) and 4.38-4.40 (m, 1 H), 7.16 (s, 1 H) , 7.32-7.37 (m, 1 H), 7.42-7.48 (m, 1 H), 7.77 (d, 1 H), 11.93 (s, 1 H), 13.04 (s, 1 H).

Example 10 [1- (2-Methanesulfonylmethoxy-ethyl) -1 H -benzoimidazol-5-yl] - (octahydro-quinolin-1-yl) -metanone Step-A: 4- (2-Hydroxyethylamino) -3-nitro-benzoic acid methyl ester The methyl ester of 4-Fluoro-3-nitro-benzoic acid (3 g, 15.64 mmol) was dissolved in DMF (20 ml) and DIPEA (5.8 g, 18.07 mmol) was added. Then 2-Aminoethanol (1.1 g, 18. 07mmol) slowly by maintaining the temperature < 20 ° C. It was stirred continuously at room temperature for 1 h. After checking the completion of the reaction by TLC, the reaction mixture was added in the cold ice water.

The yellow solid was filtered off, washed with cold water and finally washed with hexane yielding 3.3 g (92%) of 4- (2-hydroxyethylamino) -3-nitro-benzoic acid methyl ester. 1 H NMR (300 MHz, CDCl 3) d 3.5 (q, 2 H), 3.7 (q, 2 H), 3.9 (s, 3 H), 5.1 (t, 1 H), 7.2 (d, 1 H), 8.0 (d, 1 H), 8.6 (s, 1 H).

Step-B: 3-Amino-4- (2-hydroxy-ethylamino) -benzoic acid methyl ester: To a solution of 4- (2-hydroxy-ethylamino) -3-nitro-benzoic acid methyl ester (3.0 g , 12.4 mmol) in methanol was added 10% Pd / C (800 mg). The mixture was hydrogenated at 1 atmospheric pressure for 2 h. The catalyst was filtered off and the methanol was evaporated to give 2.6 g (99%) of 3-amino-4- (2-hydroxyethylamino) -benzoic acid methyl ester.

Step-C: 1- (2-Hydroxyethyl) -1H-benzoimidazole-5-carboxylic acid methyl ester: 3-Amino-4- (2-hydroxy-ethylamino) -benzoic acid methyl ester (2.6 g, 12.0 mmol) in formic acid (20 mL). The solution was heated at 45 ° C for 1 h. After checking the completion of the reaction by TLC, the formic acid was evaporated at < 40 ° C under reduced pressure and the resulting solid was recrystallized from EtOAc. The above solid was dissolved in 3N HCl, stirred at room temperature for 1 h, basified again with saturated sodium bicarbonate solution and extracted with EtOAc. The organic layer was evaporated to give 2.1g (78%) of 1- (2-hydroxy-ethyl) -1H-benzoimidazole-5-carboxylic acid methyl ester. MS-ESI m / z 221 (M + 1): 1 H NMR (300 MHz, DMSO-d6) d 3.7 (q, 2H), 3.9 (s, 3H), 4.3 (t, 3H), 5.0 (t, 1 H), 7.7 (d, 1 H), 7.9 (dd, 1 H), 8.25 (s, 1 H), 8.35 (s, 1 H) Step-D: 1- (2-Methylsulfanylmethoxy-ethyl) -1 / - / - benzoimidazole-5-carboxylic acid methyl ester: A solution of 1- (2-hydroxyethyl) -1H-benzimidazole-5-methyl ester -carboxylic (0.5 g, 2.27 mmol) in a mixture of THF: dry DME (25 mL: 15 mL) was cooled to 5 ° C. NaH (0.081 g, 3.4 mmol) was added and stirred for 30 min at the same temperature . A mixture of chloromethyl methyl sulfide (0.285 g, 2.95 mmol) and Nal (0.408 g, 2.95 mmol) was subsequently added slowly followed by TBAl (0.087 g, 0.22 mmol). The reaction was stirred overnight at room temperature. It was then quenched with saturated ammonium chloride solution and extracted with EtOAc. The organic layer was evaporated to give 0.53 g (83%) of 1- (2-methylsulfanylmethoxyethyl) -1H-benzimidazole-5-carboxylic acid methyl ester. 1 H NMR (300 MHz, CDCl 3) d 1.9 (s, 3 H), 3.9 (t, 2 H), 3.95 (s, 3 H), 4.4 (t, 2 H), 4.6 (s, 2 H), 7.45 (d, 1 H ), 8.05 (m, 2H), 8.5 (d, 1H) Step-E: 1- (2-Methanesulfonylmethoxy-ethyl) -1H-benzoimidazole-5-carboxylic acid methyl ester: A solution of 1- (2-methylsulfanylmethoxyethyl) -1H-benzimidazole-5-carboxylic acid methyl ester (3.0 g, 10.7 mmol) in methanol (30 mL) was cooled to 0 ° C and for this an oxone solution (4.88 g, 7.94 mmol) in water was added. The solution was stirred at room temperature for 12 h. It was warmed with 5% sodium bicarbonate solution and extracted with EtOAc. Removal of the solvent afforded 2.0 g (60%) of 1- (2-methanesulfonylmethoxy-ethyl) -1H-benzoimidazole-5-carboxylic acid methyl ester. MS-ESI m / z 313 (M + 1): 1 H NMR (300 MHz, DMSO-d 6) d 2.9 (s, 3 H), 4.0 (s, 3 H), 4.25 (t, 2 H), 4.65 (t, 2 H) ), 4.75 (s, 2H), 7.85 (d, 2H), 8.0 (dd, 1H), 8.35 (s, 1H), 8.5 (s, 1 H) Step-F: 1- (2-Methanesulfonylmethoxy-ethyl) -1H-benzoimidazole-5-carboxylic acid: 1- (2-Methanesulfonylmethoxyethyl) -1-H-benzimidazole-5-carboxylic acid methyl ester (1.0 g, 3.2 mmol) was dissolved in THF (5 mL). A solution of LiOH (0.38 g, 16 mmol) in water was added and the mixture was stirred vigorously for 1 h. The reaction was acidified with 2N HCl at pH 2 at 5-10 ° C. It was then filtered to give 0.8 g (84%) of 1- (2-methanesulfonylmethoxy-ethyl) -1- -benzoimidazole-5-carboxylic acid. 1 H NMR (300 MHz, DMSO-d 6) d 2.9 (s, 3 H), 4.2 (t, 2 H), 4.5 (t, 2 H), 4.65 (s, 2 H), 7.75 (d, 1 H), 7.9 (dd) , 1 H), 8.25 (d, 1 H), 8.35 (s, 1 H), 12.7 (s, 1 H) Step-G: [1- (2-Methanesulfonylmethoxy-ethyl) -1- -benzoimidazol-5-yl] - (octahydro-quinolin-1-yl) -methanone: To a solution of 1- (2-methanesulfonylmethoxyethyl) - 1 H-benzimidazole-5-carboxylic acid (0.5 g, 1677 mmol) in DMF (5 mL) was added decahydroquinoline (0.257 g, 1845 mmol) followed by HOBt (0.25 g, 1845 mmol) and DIPEA (0.65 g, 5 mmol). The reaction mixture was cooled to 0 ° C and EDCI.HCl (0.354 g, 1845 mmol) was added. It gradually rose to room temperature and was stirred continuously for 12 h. The solvent was subsequently evaporated, the residue was diluted with water (5 mL) and extracted with CH2Cl2 (3x25 mL). The combined organic phases were washed with brine solution, dried (Na2SO4) and the solvent evaporated to yield the crude amide which was purified by preparative HPLC to provide 0.3 g (43%) of [1- (2-methanesulfonylmethoxy-ethyl) - 1H-benzimidazol-5-yl] - (octahydroquinolin-1-yl) -methanone. MS-ESI m / z 420 (M + 1): 1 H NMR (300 MHz, DMSO-d 6) d 1.1-1.9 (br, 13 H), 2.8 (s, 3 H), 3.0-3.3 (m, 2 H), 4.15 (t, 2H), 4.5 (t, 2H), 4.65 (s, 2H), 7.3 (m, 1 H), 7.6 (m, 1 H), 7.7 (d, 1 H), 8.3 (s, 1 H) ) The following compounds were synthesized using a method similar to those described in Example 10 above: MS- Ex. Structure MW Name IUPAC ESI m / z (3-Hydroxy-8-azabicyclo [3.2.1] oct-8- -1 nilmet 408 benzoimidazol-5-yl] -methanone trans- (2-) acid acid amide Cis-1 - (2- amide (3-Hydroxy-8-aza- -4 408 il] -metanone Example 11 1- (2-Methanesulfonyl-ethyl) -1 H -benzoimidazole-5-carboxylic acid (5-hydroxy-adamantan-2-yl) -amide Step A: 2- (2-Methylsulfanylethyl) isoindol-1,3-dione: To a solution of N-bromoethyltrhalimido (1g, 3.953 mmol) in methanol (25 mL), was added NaSMe (0.415 g, 5.929 mmol) under N2 at 0 ° C. The reaction mixture was stirred at room temperature for 2 h. The reaction mass was concentrated, diluted with water and extracted with EtOAc (3x25 mL). The organic layer was washed with brine solution over anhydrous Na2SO4 and concentrated to give 2- (2-Methylsulfanylethyl) isoindol-1,3-dione (0.88 g, 80%). MS-ESI m / z 222 (M + 1); 1 H NMR (300 MHz, CDCl 3) d 7.7 (m, 2 H), 7.9 (m, 2 H), 3.9 (t, 1 H), 2.8 (t, 2 H), 2.2 (s, 3 H).

Step-B: 2- (2-Methanesulfonyl-ethyl) -isoindole-1,3-dione: To a solution of 2- (2-methylsulfanylethyl) -isoindole-1,3-dione (2.5 g, 11.30 mmol) in acid acetic acid (10 mL) was added 30% hydrogen peroxide (6 mL) at 0 ° C. The reaction mixture was produced at room temperature and stirred for 2 h. The excess hydrogen peroxide in the reaction mixture was warmed with a saturated solution of sodium sulfite and the resulting solution was extracted with CHCl3. The organic layer was washed with brine, dried over Na 2 SO 4 and evaporated to give 2- (2-methanesulfonyl-ethyl) -isoindole-1,3-dione (2.3 g, 83%). 1 H NMR (300 MHz, CDCl 3) d 7.9 (m, 2H), 7.8 (m, 2H), 4.2 (t, 1 H), 3.4 (t, 1 H), 3.1 (s, 3H).

Step-C: 2-Methanesulfonyl-ethylamine: Hydrazine hydrate (15 mL) was added to a solution of 2- (2-methanesulfonylethyl) -isoindole-1,3-dione (3.123 g, 12.344 mmol) in a mixture of CHCl3-ethanol (: 1) at 0 ° C. . Subsequently, it was stirred overnight at room temperature. It was filtered and the filtrate was concentrated to give 2-methanesulfonylethylamine (1.2 g, 80%). H NMR (300 MHz, CDCl 3) d 3.05 (t, 2H), 3.15 (t, 2H), 3.0 (s, 3H).

Step-D: 4- (2-Methanesulfonyl-ethylamino) -3-nitro-benzoic acid methyl ester: To a solution of 2-methanesulfonylethylamine (1.3 g, 10.56 mmol) and DIPEA (3.5 mL, 31.69 mmol) in DMF ( 15 mL) was added 4-fluoro-3-nitro-benzoic acid methyl ester (1.2 g, 15.84 mmol) in portions. The reaction mixture was allowed to stir for 15 h at room temperature. Subsequently, it was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine and concentrated to give 4- (2-methanesulfonyl-ethylamino) -3-nitro-benzoic acid methyl ester (83%). H NMR (300 MHz, CDCl 3) d 8.9 (d, 1 H), 8.6 (t, 1 H), 8.2 (d, 1 H), 6.9 (d, 1 H), 4.0 (q, 2 H), 3.9 ( s, 3H), 3.4 (t, 2H), 3.0 (s, 3H).

Step-E: 1- (2-Methanesulfonyl-ethyl) -1H-benzoimidazole-5-carboxylic acid methyl ester: 4- (2-Methanesulfonyl-ethylamino) -3-nitro-benzoic acid methyl ester (1.63 g) , 5.40 mmol) was dissolved in methanol, and 10% Pd / C (150 mg) was added under N2 atmosphere. The reaction mixture was subsequently hydrogenated at 1 atmospheric pressure at room temperature for 2 h.

It was filtered through celite and the filtrate was concentrated to provide the desired product. The crude material (1.32 g, 4.85 mmol) was taken in formic acid (10 mL) and allowed to stir at 50 ° C for 4 h. The reaction mass was concentrated, diluted with water and extracted with EtOAc. The organic layers were washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to give 1- (2-methanesulfonylethyl) -1H-benzoimidazole-5-carboxylic acid methyl ester (77%). 1H NMR (300 MHz, DMSO-d6). d 8.45 (s, 1H), 8.3 (s, 1H), 7.9 (d, 1 H), 7.8 (d, 1 H), 4.75 (t, 2H), 3.9 (s, 3H), 3.8 (t, 2H) ), 3.0 (s, 3H).

Step F: 1- (2-Methanesulfonyl-ethyl) -1H-benzoimidazole-5-carboxylic acid: To a solution of 1- (2-methanesulfonylethyl) -1H-benzoimidazole-5-carboxylic acid methyl ester (0.2 g) , 7.09 mmol) in methanol was added LiOH (50mg) followed by water (1mL). The reaction mixture was allowed to stir at room temperature for 2 h. Subsequently, the methanol was removed and the aqueous layer was acidified with citric acid. The precipitated product was filtered to give 1- (2-methanesulfonyl-ethyl) -1H-benzoimidazole-5-carboxylic acid (90%). MS-ESI m / z 269 (M + 1); 1 H NMR (300 MHz, DMSO-d 6) d 12.6 (br, 1 H), 8.4 (s, 1 H), 8.2 (s, 1 H), 7.9 (d, 1 H), 7.8 (d, 1 H) , 4.8 (t, 2H), 3.8 (t, 2H), 3.0 (s, 3H).

Step G: 1- (2-Methanesulfonyl-ethyl) -1H-benzoimidazole-5-carboxylic acid (5-hydroxy-adamantan-2-yl) -amide: To a solution of 1- (2-methanesulfonylethyl) -1 H-benzoimidazole-5-carboxylic acid (0.2 g, 0.74 mmol) in DMF (5 mL) was added HOBt (0.15 g, 0.89 mmol), DIPEA (0.4 mL, 2.23 mmol), 4-aminoadamantan-1-ol (0.15 g) 0.89 mmol) and EDCI (0.21 g, 1.11 mmol) successively under N2 atmosphere. The reaction mixture was allowed to stir overnight at room temperature. It was diluted with water and extracted with CHCl3. The organic layer was washed with saturated NaHCO 3 solution, brine and dried over anhydrous Na 2 SO 4. Concentration of the organic layer afforded 1- (2-methanesulfonylethyl) -1H-benzoimidazole-5-carboxylic acid (5-hydroxiadamantan-2-yl) -amide (0.05 g). MS-ESI m / z 418 (M + 1); 1 H NMR (300 MHz, CDCl 3) d 8.2 (s, 1 H), 8.1 (s, 1 H), 7.9 (d, 1 H), 7.5 (d, 1 H), 6.4 (d, 1 H), 4.8 ( t, 2H), 4.2 (m, 1H), 3.6 (t, 2H), 2.7 (s, 3H), 2.4 (s, 2H), 2.3 (m, 1 H), 1.8 (m, 11 H).

The following compounds were synthesized using a method similar to those described in Example 11 above: MS- Ex. Structure MW Name IUPAC ESI m / z (3-Hydroxy-8- -yl] -methanone (3-H-droxy-8- -yl] -metanone [1- (2- 11-3 390 Methanone 1- (2- Methanesulfonyl- adamantan-2-yl) -amide Example 12 (3-Hydroxy-8-aza-bicyclo [3.2.1] oct-8-yl) -. { 1- [2- (1 H-tetrazol-5-yl) -ethyl] -1 H -benzoimidazol-5-yl} -metanone Step-A: 4- (2-Cyano-ethylamino) -3-nitro-benzoic acid ethyl ester: To a solution of 4-fluoro-3-nitro-benzoic acid methyl ester (4.95 g, 24.8 mmol) in DMF (25 ml) was added 3-aminopropionitrile fumarate (3.18 g, 12.4 mmol) and DIPEA (15 ml, 84.3 mmol). The mixture was stirred at room temperature for 2 h. The solvent was evaporated under vacuum and the residue was diluted in water (50 mL). It was extracted with EtOAc (3x100 mL) and the organic phase was washed with brine solution and dried (Na 2 SO 4). Removal of the solvent afforded 4- (2-cyanoethylamino) -3-nitro-benzoic acid methyl ester (6.19 g, 98.5%). MS-ESI m z 250 (M + 1); 1 H NMR (300 MHz, CDCl 3) d 2.8 (t, 2 H), 3.8 (m, 2 H), 6.9 (d, 1 H), 8.2 (m, 1 H), 8.5 (t, 1 H), 8.9 (s) , 1 HOUR) Step-B: 3-Amino-4- (2-cyanoethylamino) -benzoic acid methyl ester: To a solution of ammonium chloride (21.7 g, 406.3 mmol) in water (200 mL) was added 4-methyl ester. (2-cyanoethylamino) -3-nitro-benzoic acid (6.1 g, 24.5 mmol) followed by zinc powder (42.8 g, 655.9 mmol). The mixture was heated at 60 ° C for 3 h. It was filtered hot and washed with EtOAc. The filtrate was further extracted with EtOAc and the combined phase was washed with brine solution. The organic layer was evaporated to give 4.1 g (75%) of 3-amino-4- (2-cyano-ethylamino) -benzoic acid methyl ester. MS-ESI m / z 220 (M + 1); 1 H NMR (300 MHz, CDCl 3) d 2.7 (t, 2 H), 3.6 (m, 2 H), 3.8 (s, 3 H), 4.3 (bs, 1 H), 6.6 (d, 1 H), 7.45 (d, 1 H), 7.6 (d, 1 H) Step-C: 1- (2-Cyano-ethyl) -1H-benzoimidazole-5-carboxylic acid methyl ester: To the 3-amino-4- (2-cyano-ethylamino) -benzoic acid methyl ester (4. 0 g) formic acid (25 ml) was added and the mixture was heated at 50 ° C for 3 h. Subsequently it was concentrated and the residue was recrystallized from EtOAc to yield 4.0 g (95%) of 1- (2-cyanoethyl) -1H-benzimidazole-5-carboxylic acid methyl ester. MS-ESI m / z 230 (M + 1); 1 H NMR (300 MHz, CDCl 3) d 2.95 (t, 2 H), 4.0 (s, 3 H), 4.55 (t, 2 H), 7.4 (d, 1 H), 8.1 (m, 1 H), 8.15 (s, 1 H), 8.55 (s, 1 H) Step-D: 1- (2-Cyanoethyl) -1H-benzoimidazole-5-carboxylic acid: To a solution of 1- (2-cyanoethyl) -1H-benzimidazole-5-carboxylic acid methyl ester (4.0 g, 17.4 mmol) in THF (30 mL) was added LiOH (1.67 g, 69.79 mmol) in water (8 mL) followed by MeOH (2 mL). Stirring was continued at room temperature for 1 h. It was then concentrated and acidified with 2N HCl. The formed solids were filtered and dried, which yielded 1- (2-cyanoethyl) -1H-benzoimidazole-5-carboxylic acid (3.5 g, 95%). 1 H NMR (300 MHz, DMSO-d 6) d 3.1 (t, 2 H), 4.6 (t, 2 H), 7.8 (d, 1 H), 7.9 (dd, 1 H), 8.25 (d, 1 H), 8.42 (s, 1 H) Step-E: 3- [5- (3-Hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzoimidazol-1-yl] -propionitrile: To a solution of 1- (2-) acid cyanoethyl) -1 H-benzoimidazole-5-carboxylic acid (0.25 g, 1.16 mmol) in DMF (2.5 mL) was added with stirring HOBt (0.17 g, 1.27 mmol) followed by exo-nortropinol hydrochloride (0.21 g, 1.27 mmol) , DIPEA (0.45 g, 3.48 mmol). EDCI.HCI was previously added and stirred at room temperature for 12 h. The solvent was subsequently evaporated and the residue was diluted with water (5 mL) and extracted with CH2Cl2. The organic phase was washed with brine solution, dried (Na 2 SO 4) and the solvent was evaporated. The residue was purified by preparative HPLC which yielded 0.26 g (67%) of 3- [5- (3-Hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzoimidazol-1-yl] - propionitrile. MS-ESI m z 325 (M + 1).

Step-F: 3-Hydroxy-8-aza-bicyclo [3.2.1] oct-8-yl) -. { 1- [2- (1 H-tetrazol-5-yl) -ethyl] -1 H -benzoimidazol-5-yl} -Metanone: To a solution of 3- [5- (3-Hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzoimidazol-1-yl] -propionitrile (250 mg, 0.7 mmol) in DMF (5%). mL) was added sodium azide (184 mg, 2.83 mmol) and Ammonium chloride (152 mg, 2.83 mmol) and heated at 100 ° C for 12 h. The solvent was completely evaporated, methanol (20 mL) was added and filtered. The filtrate was concentrated and the residue was purified by preparative HPLC to provide 36 mg (13%) of 3-hydroxy-8-aza-bicyclo [3.2.1] oct-8-yl) -. { 1- [2- (1 H-tetrazol-5-yl) -eti I] -1 H-benzoimidazol-5-yl} -Metanone. MS-ESI m / z 368 (M + 1); 1 H NMR (300 MHz, DMSO-d 6) d 1.3-2.0 (m, 8 H), 3.15 (s, 1 H), 3.5 (t, 2 H), 3.9-4.0 (m, 2 H), 4.6 (br, 1 H ), 4.75 (t, 2H), 7.4 (dd, 1 H), 7.6-7.7 (m, 2H), 8.25 (s, 1 H).

The following compounds were synthesized using a method similar to those described in Example 11 above: MS-Ex. Structure MW Name IUPAC ESI m / z (Octahydro- il} -metanone acid Trans-1- [2- (1 H-Tetrazol-5-yl) - adamantan-2-yl) - amide acid Cis-1 - [2- (1 H-Tetrazol-5-yl) - adamantan-2-yl) - amide Example 13 3-Hydroxy-pyrrolidine-1-carboxylic acid. { 2- [5- (3-hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzoimidazol-1-yl] -ethyl} -amide V HO JO Stage-A: 4-Fluoro-3-nitro-benzoic acid methyl ester: To a solution of 4-fluoro-3-nitrobenzoic acid (16.0 g, 0.0864 mol) in dry DMF (100 mL) was added with stirring potassium carbonate (59.0 g, 0.43 mol) followed by methyl iodide (24.5 g, 0.173 mol) and the mixture was stirred for 3 h at room temperature. The reaction mixture was diluted with ice water (500 mL), extracted with EtOAc (3x100 mL) and the combined organic phases were washed with water (3x100 mL) and saturated brine solution (100 mL). The organic phase was dried (Na 2 SO 4) and the solvent was evaporated yielding 17.0 g (99%) of 4-fluoro-3-nitro-benzoic acid methyl ester.

Step-B: 4- (2-Chloroethylamino) -3-nitro-benzoic acid methyl ester: To a solution of 4-fluoro-3-nitro-benzoic acid methyl ester (10.0 g, 0.0502 mol) in dry DMF ( 100 mL) was added with stirring potassium carbonate (59.0 g, 0.43 mol) followed by 2-chloroethylamine hydrochloride (8.7 g, 0.075 mol) and the mixture was stirred for 15 h at room temperature. The reaction mixture was diluted with ice water (500 mL) and the solid precipitate was filtered, washed with water and dried under vacuum to obtain a yellow solid (12.7 g, 98%). MS-ESI m / z 259 (M + 1).

Stage-C: 3-Amino-4- (2-chloroethylamino) -benzoic acid methyl ester: To a solution of 4- (2-chloroethylamino) -3-nitro-benzoic acid methyl ester (12.7 g, 0. 0492 mol) in methanol (500 mL) was added 10% Pd / C (1.3 g) under an atmosphere of N2 The reaction mixture was hydrogenated in a Parr apparatus at 3 kg pressure for 2 h. The catalyst was filtered over celite and the filtrate was concentrated affording 1.0 g (98%) of 3-amino-4- (2-chloroethylamino) -benzoic acid methyl ester as a solid.

Step-D: 1- (2-Chloroethyl) -1H-benzimidazole-5-carboxylic acid methyl ester: To 3-amino-4- (2-chloroethylamino) -benzoic acid methyl ester (11.0 g, 0.0482 mol) HC02H (30 mL) was added and heated to 100 ° C for 1 h. The reaction was cooled to room temperature and diluted with ice water (100 mL). The pH of the reaction mixture was adjusted to 7 with NaHCO 3 and the solid precipitate was filtered, washed with water and dried under vacuum to obtain a light green solid (9.9 g, 86%) of methyl ester of acid 1- ( 2-Chloroethyl) -1H-benzimidazole-5-carboxylic acid. MS-ESI m / z 239 (M + 1).

Step-E: 1- (2-Azidoethyl) -1H-benzimidazole-5-carboxylic acid methyl ester: To a solution of 1- (2-chloroethyl) -1H-benzimidazole-5-carboxylic acid methyl ester ( 9.9 g, 0.0416 mol) in dry DMSO (90 mL) was added with stirring NaN3 (5.4 g, 0.0832 mol) and the mixture was stirred for 15 h at 75 ° C. The reaction mixture was cooled to room temperature and diluted with ice water (500 mL) and the solid precipitate was filtered, washed with water and dried under vacuum yielding 9.3 g (91%) of 1- (2-azidoethyl) -1H-benzimidazole-5-carboxylic acid methyl ester as a solid. MS-ESI m / z 246 (M + 1); 1 H NMR (300 MHz, DMSO-d 6) d 3.8 (t, 2 H), 3.9 (s, 3 H), 4.5 (t, 2 H), 7.8 (d, 1 H), 7.9 (dd, 1 H), 8.25 ( s, 1 H), 8.4 (s, 1 H).

Step-F: 1- (2-Azido-ethyl) -1H-benzimidazole-5-carboxylic acid: To a solution of 1- (2-azidoethyl) -1H-benzimidazole-5-carboxylic acid methyl ester (5.0 g, 0.0204 mol) in THF / water 1: 1 (100 mL) was added with stirring LiOH (0.73 g) , 0.0306 mol) and the mixture was stirred for 5 h at room temperature. The solvent was evaporated and ice water (100 mL) was added to the residue. The pH of the reaction mixture was adjusted to 5 with 1N HCl and the mixture was extracted with EtOAc (5x100 mL). The combined organic phases were washed with saturated brine solution (100 mL), dried (Na2SO4) and the evaporated solvent yielded 4.2 g (89%) of 1- (2-azidoethyl) -1H-benzimidazole-5-carboxylic acid. as a solid colored ash. MS-ESI m / z 232 (M + 1); 1 H NMR (300 MHz, DMSO-d 6) d 3.8 (t, 2 H), 4.5 (t, 2 H), 7.8 (d, 1 H), 7.9 (d, 1 H), 8.25 (s, 1 H), 8.4 (s) , 1 HOUR).

Step-G: [1- (2-Azidoethyl) -1H-benzimidazol-5-yl] - (3-hydroxy-8-azabicyclo [3.2.1] oct-8-yl) methanone: To a solution of acid 1 (2-azidoethyl) -1 H-benzimidazole-5-carboxylic acid (0.82 g, 0.00357 mol) in dry DMF (8.0 mL) was added with stirring HOBt (0.578 g, 0.00428 mol), DIPEA (1.9 mL, 0.0107 mol), 8-azabicyclo [3.2.1] octan-3-ol (0.5 g, 0.00393 mol) and the mixture was cooled to 0 ° C. To the resulting mixture was added EDCI (0.82 g, 0.00428 mol) and stirred for 15 h room temperature. The reaction mixture was subsequently diluted with ice water (100 mL), extracted with EtOAc (3x50 mL) and the combined organic phases were washed with water (3x50 mL) and saturated brine solution (50 mL). The organic phase was dried (Na 2 SO 4) and the solvent was evaporated yielding (1.1 g, 98%) of [1- (2-azidoethyl) -1 H -benzimidazol-5-yl] - (3-hydroxy-8-) azabicyclo [3.2.1] oct-8-yl) methanone. MS-ESI m / z 341 (M + 1).

Step-H: [1- (2-Amino-ethyl) -1 H -benzoimidazol-5-yl] - (3-hydroxy-8-aza-bicyclo [3.2.1] oct-8-yl) -methanone: A a solution of [1- (2-azidoethyl) -1H-benzimidazol-5-yl] - (3-hydroxy-8-aza-bicyclo [3.2.1] oct-8-yl) methanone (1.1 g, 0.0035 mol) in methanol (15 mL) 10% Pd / C (0.17 g) was added and the mixture was hydrogenated at 3 kg pressure for 1 h. The catalyst was filtered over celite and the filtrate was concentrated to give [1- (2-aminoethyl) -1 H -benzimidazol-5-yl] - (3-hydroxy-8-aza-bicyclo [3.2.1] oct-8-yl) methanone (0.87 g, 86%) . MS-ESI m / z 315 (M + 1).

Step-I: 3-Hydroxypyrrolidine-1-carboxylic acid. { 2- [5- (3-hydroxy-8-azabicyclo [3.2.1] octane-8-carbonyl) -benzoimidazol-1-yl] -ethyl} amide: A) 3-Hydroxypyrrolidine-1-carbonyl chloride: To a solution of pyrrolidin-3-ol (0.083 g, 0.955 mmol) in dry THF (5 mL) was added DIPEA (0.3 mL, 1.91 mmol) and cooled at 0 ° C. To the resulting mixture was added triphosgene (0.127 g, 0.429 mmol) and the mixture was stirred for 2 h at room temperature.

B) To a solution of [1- (2-aminoethyl) -1 H -benzimidazol-5-yl] - (3-hydroxy-8-aza-bicyclo [3.2.1] oct-8-yl) methanone (0.25 g , 0.79 mmol) in dry THF (5 mL) was added DIPEA (0.3 mL, 1.91 mmol) at 0 ° C. Compound A was slowly added to this reaction mixture and stirred for 3 days at room temperature. The solvent was evaporated and the residue was purified by preparative HPLC to yield 175 mg (54%) of 3-hydroxy-pyrrolidine-1-carboxylic acid. { 2- [5- (3-hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzoimidazol-1-yl] -ethyl} -amide. MS-ESI m / z 428 (M + 1); 1 H-NMR (300 MHz, CD3OD) d 1.5 (t, 1 H), 1.9 (m, 6H), 2.1 (m, 3H), 3.2 (m, 2H), 3.5 (t, 2H), 4.2 (m , 2H), 4.4 (m, 1 H), 4.5 (t, 2H), 4.8 (s, 1 H), 7.45 (dd, 1 H), 7.7 (d, 1 H), 7.8 (s, 1 H) , 8.25 (s, 1 H), Example 14 4-Hydroxy-piperidine-1-carboxylic acid. { 2- [5- (Octahydro-quinoline-1-carbonyl) -benzoimidazol-1-yl] -ethyl} -amide H Stages A-F is similar to those used in example 13 above.

Step-G: [1- (2-Azidoethyl) -1 H -benzimidazol-5-yl] - (octahydroquinolin-1-yl) methanone: To a solution of 1- (2-azidoethyl) -1 H -benzimidazole- 5-carboxylic acid (1 g, 0.00433 mol) in dry DMF (7.0 mL) was added with stirring HOBt (0.876 g, 0.00649 mol), DIPEA (2.25 mL, 0.0129 mol), decahydroquinoline (0.902 g, 0.00649 mol) at 0 ° C. EDCI (1.24 g, 0.00649 mol) was added to the resulting mixture and stirred for 15 h at room temperature. The reaction mixture was diluted with ice water (100 mL) and extracted with EtOAc (3x50 mL). The combined organic phases were washed with water, dried (Na 2 SO 4) and the solvent was evaporated to [1- (2-azidoethyl) -1 H -benzimidazol-5-yl] - (octahydroquinolin-1-yl) methanone (1.5 g, 98%).

Step-H: [1- (2-Aminoethyl) -1 H -benzimidazol-5-yl] - (octahydroquinolin-1-yl) methanone: To a solution of [1- (2-azidoethyl) -1 H -benzimidazole- 5-yl] - (octahydroquinolin-1-yl) methanone (1.8 g, 0.0051 mol) in methanol (10 mL) was added 10% Pd / C (0.2 g). The reaction mixture was hydrogenated at 3 kg pressure for 2 h. The catalyst was filtered over celite and the filtrate was concentrated to give [1- (2-aminoethyl) -1 H -benzimidazol-5-yl] - (octahydroquinolin-1-yl) methanone (1.5 g, 90%).

Step-I: 4-Hydroxypiperidine-1-carboxylic acid. { 2- [5- (Octahydroquinoline-1-carbonyl) benzimidazol-1-yl] ethyl} amida: A) 4-Hydroxypiperidine-1-carbonyl chloride: To a solution of piperidin-4-ol (0.074 g, 0.73 mmol) in dry THF (5 mL) was added DIPEA (0.3 mL, 1.91 mmol) at 0 ° C. To the resulting mixture was added triphosgene (0.076 g, 2.1 mmol) and stirred for 2 h at room temperature.

B) To a solution of [1- (2-aminoethyl) -1 H -benzimidazol-5-yl] - (octahydroquinolin-1-yl) methanone (0.2 g, 0.613 mmol) in dry THF (5 mL) was added DIPEA (0.3 mL, 1.91 mmol) at 0 ° C. Compound A was slowly added to this reaction mixture and stirred for 2 h at room temperature. The solvent was evaporated and the residue was purified by preparative HPLC to yield cis and trans isomers of 4-hydroxypiperidine-1-carboxylic acid. { 2- [5- (Octahydroquinoline-1-carbonyl) -benzimidazol-1-yl] ethyl} amide. Isomer I (12 mg): MS-ESI m / z 454 (M + 1); 1 H-NMR (300 MHz, CD 3 OD) d 1.30-1.80 (m, 13 H), 2.0 (m, 3 H), 2.9 (m, 2 H), 3.2 (m, 2 H), 3.55 (t, 2 H), 3.7 (m , 3H), 4.5 (t, 2H), 7.35 (d, 1 H), 7.7 (m, 2H), 8.25 (s, 1H). HPLC (VERYPOL.M): tr = 7.73 min (95%).

Isomer II (8 mg): MS-ESI m / z 454 (M + 1); 1 H-NMR (300 MHz, CD 3 OD) d 1.2 (m, 3 H), 1.4 (m, 8 H), 1.7 (m, 6 H), 3.0 (m, 2 H), 3.6 (t, 2 H), 3.7 (m, 3 H) ), 4.4 (t, 2H), 7.4 (dd, 1 H), 7.65 (d, 1 H), 7.7 (s, 1 H), 8.3 (s, 1 H). HPLC (VERYPOL.M): tr = 7.86 min (94%).

Example 15 1 - acid. { 2 - [(4-Hydroxy-piperidine-1 -carbonyl) -amino] -ethyl} -1 H-benzoimidazole-5-carboxylic acid (5-hydroxy-adamantan-2-yl) -amide Steps A-F are similar to those used in Example 14 above.

Step-G: 1- (2-Azidoethyl) -1H-benzimidazole-5-carboxylic acid (5-hydroxydiamantan-2-yl) -amide: To a solution of 1- (2-azidoethyl) -1H-benzimidazole -5-carboxylic acid (0.65 g, 0.0028 mol) in dry DMF (5.0 mL) was added with stirring HOBt (0.46 g, 0.0034 mol), DIPEA (2.5 mL, 0.014). mol), 4-aminoadamantan-1-ol (0.685 g, 0.0034 mol) at 0 ° C. EDCI (0.65 g, 0.0034 mol) was added to the resulting mixture and stirred for 15 h at room temperature. The reaction mixture was diluted with ice water (100 mL) and extracted with EtOAc (3x50 mL) and the combined organic phases were washed with water, dried (Na2SO) and the solvent was evaporated yielding (1.0 g, 93.5%) of 1- (2-azidoethyl) -1 H-benzimidazole-5-carboxylic acid (5-hydroxiadamantan-2-yl) -amide. MS-ESI / z 381 (M + 1).

Step-H: 1 - [(2-Aminoethyl) -1H-benzimidazole-5-carboxylic acid (5-hydroxy-adamantan-2-yl)] - amide: To a solution of 1- (2-azidoethyl) - 1 H-benzimidazole-5-carboxylic acid (5-hydroxydiamantan-2-yl) -amide (1.0 g, 0.00263 mol) in methanol (20 mL) was added 10% Pd / C (200 mg). The reaction mixture was hydrogenated at 3 kg of pressure for 1 h. The catalyst was filtered over celite and the filtrate was concentrated to give 1- (2-aminoethyl) -1 H -benzimidazole-5-carboxylic acid (5-hydroxy-adamantan-2-yl) -amide (0.7 g, 75%) .

Stage-I: acid 1-. { 2 - [(4-Hydroxypiperidine-1-carbonyl) -amino] -ethyl} -1 H-benzoimidazole-5-carboxylic (5-hydroxy-adamantan-2-yl) -amide: To a solution of 1- (2-aminoethyl) -1 H-benzimidazole-5-carboxylic acid (5-hydroxy-adamantan -2-yl) -amide (0.35 g, 0.988 mmol) in dry THF (5 mL) was added DIPEA (0.3 mL, 1.91 mmol) at 0 ° C. To this reaction mixture was added 4-hydroxypiperidine-1-carbonyl chloride slowly and stirred for 2 h at room temperature. The solvents were evaporated and the residue was purified by preparative HPLC of cis and trans isomers of 1- acid. { 2 - [(4-hydroxypiperidine-1-carbonyl) -amino] -ethyl} -1H-benzimidazole-5-carboxylic acid (5-hydroxiadamantan-2-yl) -amide.

Isomer I (0.008 g): MS-ESI m / z 482 (M + 1); 1H-NMR (300 MHz, CD3OD): d 1.4 (m, 3H), 1.6 (d, 3H), 1.8 (m, 9H), 2.0 (d, 2H), 2.2 (s, 1 H), 2.4 (s) , 2H), 2.9 (m, 2H), 3.5-3.8 (m, 5H), 4.0 (s, 1 H), 4.5 (t, 2H), 7.65 (d, 1 H), 7.8 (d, 1 H), 7.95 (d, 1 H), 8.15 (s, 1 H), 8.25 (s, 1 H). HPLC (VERYPOL.M): tr = 6.59 min (95%).

Isomer II (0.022 g): MS-ESI miz 482 (M + 1); 1 H-NMR (300 MHz, CD3OD): d 1.4 (m, 3H), 1.5 (d, 2H), 1.8 (m, 5H), 1.9 (d, 2H), 2.1 (d, 2H), 2.2 (brs , 1 H), 2.3 (d, 2H), 2.9 (m, 2H), 3.55 (t, 2H), 3.7 (m, 3H), 4.1 (s, 1 H), 4.4 (t, 2H), 4.6 ( s, 1 H), 7.65 (d, 1 H), 7.8 (dd, 1 H), 8.15 (d, 1 H), 8.25 (s, 1 H). HPLC (VERYPOL.M): tr = 6.12 min (98%).

Example 16 1 - acid. { 2 - [(1,1-Dioxo-thiomorpholine-4-carbonyl) -amino] -ethyl} -1 H-benzoimidazole-5-carboxylic acid (5-hydroxy-adamantan-2-yl) -amide Steps A-F are similar to those used in Example 15 above.

Step-I: A) 1,1-Dioxo-thiomorpholine-4-carbonyl chloride: To a solution of 1.1 thiomorpholine dioxide (0.181 g, 0.00105 mol) in dry THF (5 mL) was added DIPEA (0.3 mL, 0.00191 mol) at 0 ° C. To the resulting mixture was added triphosgene (0.11 g, 0.00037 mol) and the mixture was stirred for 2 h at room temperature.

B) To a solution of 1- (2-aminoethyl) -1H-benzimidazole-5-carboxylic acid (5-hydroxiadamantan-2-yl) -amide (0.25 g, 0.706 mmol) in dry THF (5 mL) was added DIPEA (0.3 mL, 1.91 mmol) at 0 ° C. Compound A was slowly added to this reaction mixture and stirred for 2 h at room temperature. The solvents were evaporated and the residue was purified by preparative HPLC producing the cis and trans isomers of acid 1-. { 2 - [(1,1-dioxo-thiomorpholine-4-carbonyl) -amino] -ethyl} -1H-benzimidazole-5-carboxylic acid (5-hydroxiadamantan-2-yl) -amide.

Isomer I (15 mg): MS-ESI m / z 516 (M + 1); 1 H-NMR (300 MHz, CD 3 OD) d 1.5 (d, 2 H), 1.8 (d, 4 H), 1.9 (d, 2 H), 2.1 (m, 3 H), 2.3 (s, 2 H), 2.7 (t, 4 H) ), 3.6 (t, 2H), 4.1 (s, 1 H), 4.5 (t, 2H), 7.6 (d, 1 H), 7.8 (d, 1H), 8.2 (s, 1 H), 8.35 (s) , 1 HOUR). HPLC (VERYPOL.M): tr = 6.54 min (98%).

Isomer II (17 mg): MS-ESI m / z 516 (M + 1); H-NMR (300 MHz, CD3OD) d 1.6 (d, 2H), 1.8 (d, 6H), 2.1 (d, 2H), 2.2 (m, 1H), 2.4 (s, 2H), 2.7 (t, 4H) ), 3.6 (t, 2H), 3.7 (t, 4H), 4.0 (s, 1 H), 4.5 (t, 2H), 7.6 (d, 1 H), 7.8 (dd, 1 H), 8.2 (s) , 1 H), 8.3 (s, 1H). HPLC (VERYPOL.M): tr = 6.84 min (94%).

Example 17 1,1-Dioxo-thiomorpholine-4-carboxylic acid. { 2- [5- (3-hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzoimidazol-1-yl] -ethyl} -amide Steps A-F are similar to those used in Example 16 above.

Step-I: To a solution of [1- (2-aminoethyl) -1 H -benzimidazol-5-yl] - (3-hydroxy-8-azabicyclo [3.2.1] oct-8-yl) -methanone (0.2 g, 0.636 mmol) in dry THF (5 mL) was added DIPEA (0.3 mL, 1.91 mmol) at 0 ° C. To this reaction mixture was added 1,1-dioxo-thiomorpholine-4-carbonyl chloride slowly and stirred for 2 h at room temperature. The solvents were evaporated and the residue was purified by preparative HPLC to produce 1,1-dioxo-thiomorpholine-4-carboxylic acid. { 2- [5- (3-hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzoimidazol-1-yl] -ethyl} -amide (0.007 g, 2.3%). MS-ESI m / z 476 (M + 1); 1 H-NMR (300 MHz, CD 3 OD) d 1.5 (t, 1 H), 1.8 (m, 4 H), 2.1 (brs, 3 H), 2.8 (s, 4 H), ), 3.8 (s, 4H), 4.2 (m, 2H), 4.5 (t, 2H), 4.7 (s, 1 H), 7.5 (d, 1 H), 7.7 (d, 1 H), 7.85 (s) , 1 H), 8.3 PLC (VERYPOL.M): tr = 6.24 min (97%).

The following compounds were synthesized using a method similar to those described in the previous 13-17: MS-Ex. Structure MW Name IUPAC ESI m / z acid Cis-1 -. { 2- [(morpholine-4-carbonyl) - 1 467.57 «" "fr-M» * "» - 458 imidazole-5-carboxylic acid (5-hydroxy-adamantan-2-yl) -amide (Cis-morpholine-4-carboxylic acid 5-hydroxy-adamantan-2-yl) -amide. { 2- [5--3 439.56 (octahydro-quinoline-1- 440 carbonyl) -benzoimidazole- 1-yl] -ethyl} - Trans-morpholine-4-carboxylic acid amide. { 2- [5--4 r1 439.56 (octahydro-quinoline-1- 440 carbonyl) -benzoimidazol-1-yl] -ethyl} -amide MS- Ex. Structure MW Name IUPAC ESI m / z Morpholine-4-carboxylic acid. { 2- [5- (3- 'A hydroxy-8-aza-bicyclo- 17-5 - 427,51 [3.2.1] octane-8- 428 H O carbonyl) -benzoimidazol-o-1-yl] -ethyl} -amido 1, 1-Dioxo- 1-yl] -ethyl} -3-Hydroxy acid amide acid amide 1-. { 2- [5- (Octahydroquinoline-1-carbonyl) -17-8481, 60-benzoimidazol-1-yl] -482 ethylcarbamoyl} -piperidine- 4-carboxylic acid 3-Hydroxy-Aa, pyrrolidine-1-carboxylic acid. { 2- [5- (3-hydroxy-8-aza-17-9 or r1 427.51, 428-N bicyclo [3.2.1] octane-8-, -G carbonyl) -benzoimidazol-1-yl] - ethyl} -amide MS- Ex. Structure MW Name IUPAC ESI m / z Cis-4-hydroxy acid Trans-4-hydroxy acid amide Endo-4-hydroxypiperidine-1-carboxylic acid amide, -. { 2- [5- (3-hydroxy-8-aza-12-N ^ r 441.53 442 -N- "• bicyclo [3.2.1] octane-8-carbonyl) -benzoimidazol-1-yl] -ethyl.} .-Exo-4-hydroxy acid amide 1-yl] -ethyl} -amide acid 1-. { 2 - [(1, 1-Dioxo- adamantan-2-yl) -amide MS- Ex. MW Structure Name IUPAC ESI m / z 1,1-Dioxo-thiomorpholine-4-carboxylic acid. { 2- [5- (3- 17-15 475.57 hydroxy-8-aza- 476 bicyclo [3.2.1] -octane-8-carbonyl) -benzoimidazol-1-yl] -ethyl} -amide acid 1-. { 2 - [(4-Hydroxy-ppi? Ppeerpiddi? Nnaa-11 -ccaarbonyl) -amino] -ethyl} -1 H 17-16 448811,, 6600 * '482 benzoimidazole-5- carboxylic (5-hydroxy-adamantan-2-yl) -amide Morpholine-4-carboxylic acid. { 2- [5- (3- CCr * Q? »Hydroxy-8-aza-bicyclo-17-18 or r1 427.51 428 -« [3.2.1] octane-8- O-carbonyl) -benzoimidazole-1-yl ] -ethyl} - Cis-1 acid amide -. { 2- [5- (5- 4-carboxylic MS- Ex. MW Structure Name IUPAC ESI m / z Trans-1 acid. { 2- [5- (5- ethylcarbamoyl} -piperidine- 4-carboxylic acid 1-. { 2- [5- (3-Hydroxy- piperidine-4-carboxylic PHARMACOLOGICAL METHODS 11βHSD1 enzyme test Materials Beds for the scintillation proximity test coated with 3H-cortisone and Ig anti-rabbit (SPA) were purchased from Amersham Pharmacia Biotech, ß-NADPH was from Sigma and the rabbit anti-cortisol antibodies were Fitzgerald. A yeast extract transformed with h-11βHSD1 (Hult ef al., FEBS Lett., 441, 25 (1998)) was used as the enzyme source. The test compounds were dissolved in DMSO (10 mM). All dilutions were performed in a stabilizer 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. The 96-well Optiplate 96 plates were supplied by Packard. The amount of 3H-cortisol bound to the SPA beds was measured in TopCount NXT, Packard.

Methods H-11βHSD1, 120 nM 3H-cortisone, 4 mM ß-NADPH, antibody (1: 200), serial dilutions of the test compound and SPA particles (2 mg / well) were added to the wells. The reaction was inhibited by mixing the different components and allowed to proceed under stirring for 60 min at 30 ° C. The reaction was stopped by the addition of 10 times the excess of the stop stabilizer containing 500 μM of carbenoxolone and 1 μM of cortisone. The data was analyzed using the GraphPad Prism program.

Claims (33)

1. A compound of the formula I: wherein: X is selected from CR5 and nitrogen; R1 is selected from H and C -Cβ-R6 alkyl, wherein the alkyl group is substituted with 0-3 R7; R2 is selected from hydrogen, halo, C6 alkyl, and -C (= 0) R13; R8 R10, 12 alternatively, R1 and R2 are independently, 11 R9 R ring A is a bicyclic or tricyclic saturated or partially saturated ring consisting of the nitrogen shown, 4-10 carbon atoms and 0-2 additional heteroatoms selected from nitrogen, oxygen, and sulfur; ring A is substituted with 0-3 groups selected from d-Cß alkyl, halo, hydroxy, -COOH, -CONR18R19, -S (= 0) nR13, -S (= 0) nNR18R19 oxo, cyano, alkyloxy d-Ce , d-C6 alkylene dC6 alkyloxy and C6 alkylcarbonyl, wherein each alkyl / alkylene group is substituted with 0-3 or 14. alternatively, wherein Rx is selected from hydrogen and CrC6 alkyl; is substituted with 0-3 groups selected from CrC8 alkyl, halo, hydroxy, -COOH, - CONR18R19, -S (= 0) nR13, -S (= 0) nNR18R19 oxo, cyano, C-alkyloxyC, alkyleneC-C-alkyloxyC C6 and alkylcarbonyl CrC6, wherein each alkyl / alkylene group is substituted with 0-3 R14; R5 is selected from hydrogen, CrC6 alkyl, -C (= 0) R13, and cyano; R6 is selected from cyano, aryl, hetaryl, -oxo-C1-C6 alkyl-S (= 0) nR13, -C (= 0) R13, -S (= 0) nR13, -S (= 0) nNR18R19, - N (R 8) S (= 0) nR 13, -N (R 23) C (= Y) NR 18 R 19, -C (= NR 15) NR 15, -N (R 18) C (= 0) R 13, cycloalkyl -N (R 18) C (= O) -C3-C10, hetcycloalkyl -N (R18) C (= 0) - of 3-10 members, wherein the cycloalkyl, hetcycloalkyl, aryl and hetaryl groups are substituted with 0-3 R16; R7 is selected from halo, hydroxy, oxo, cyano, and d-C6 alkyl; R8, R9, R10 and R11 are independently selected from hydrogen, d-C8 alkyl, F, trihalomethyl, trihalomethoxy, hydroxy, and d-C6alkyloxy, wherein the d-C8 alkyl and d-C6alkyloxy are substituted with 0-3 R17; alternatively, R8 and R9 together with the carbon atom to which they are attached form a saturated or partially saturated ring consisting of the carbon atom shown, 2-5 additional carbon atoms and 2-0 heteroatoms selected from nitrogen, oxygen and sulfur, wherein this ring is substituted with 0-3 groups selected from halo, trihalomethyl, d-C6 alkyl, aryl, hetaryl, d-C6 alkylene aryl, d-Cß hetaryl alkylene, hydroxy, oxo, d-C6 alkyloxy, aryloxy, cycloalkyl or heteroaryl d-C6 hetaryl; alternatively, R10 and R11 together with the carbon atom to which they are attached form a saturated or partially saturated ring consisting of the carbon atom shown, 2-5 additional carbon atoms and 0-2 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the ring is substituted with 0-3 groups selected from halo, trihalomethyl, d-C6 alkyl, aryl, hetaryl, alkylene CrC6 aryl, alkylene CrC6 hetaryl, hydroxy, oxo, alkyloxy CrC6, aryloxy, alkyloxy d-Cß aryl or alkyloxy d-Cehetaryl; alternatively, R8 and R10 together with the two carbon atoms to which they are attached form a saturated or partially saturated ring consisting of the two carbon atoms shown, 1-4 additional carbon atoms and 0-2 heteroatoms selected from nitrogen, oxygen and sulfur where the ring is replaced with 0-3 selected groups of halo, trihalomethyl, d-C6 alkyl, aryl, hetaryl, d-C6 alkylene aryl, d-C6 alkylene hetaryl, hydroxy, oxo, d-C6 alkyloxy, aryloxy, d-C6 alkyloxy aryl, and d-C6 alkyloxy hetaryl; R12 is selected from H, OH, NR18R19, C3-C10 cycloalkyl, 3-10 membered hetcycloalkyl, -C (= 0) R13, -S (= 0) nR13, S (= 0) nNR18R19, -N (Rt8) S (= 0) nR13, and -C (= NR15) NR16; wherein the cycloalkyl and hetcycloalkyl groups are substituted with 0-3 R17; R13 is selected from OH, CrC8 alkyl, d-C8 alkyloxy, d-C4 alkylene C8 alkyloxy, aryl, hetaryl, aryloxy, hetaryloxy, and NR18R19; R14 is selected from halo, hydroxy, oxo, and cyano; R15 and R16 are independently selected from H, CrC8 alkyl, 3-10 membered cycloalkyl, halo, OH, cyano, -C (= 0) R13, -S (= 0) nR13, S (= 0) nNR18R19, -N (R18) S (= 0) nR13, aryl, and hetaryl, wherein the alkyl and cycloalkyl groups are substituted with 0-3 R20; R17 is selected from halo, OH, oxo, nitro, cyano, -C (= 0) R13, -S (= 0) nR13, S (= 0) nNR18R19, -N (R18) S (= 0) nR13, NR18R19 , CrC8 alkyl, d-C6 alkyloxy, and aryloxy; R18 and R19 are independently selected from H, d-C8 alkyl, d-C8 alkyloxy, aryl, hetaryl, CrC6 alkylene aryl, and CrC6 alkylene hetaryl, wherein the alkyl / alkylene, aryl, and hetaryl groups are independently substituted with 0- 3 R20; alternatively, R18 and R19, together with the nitrogen atom to which they are attached, form a monocyclic, bicyclic or tricyclic saturated or partially saturated ring consisting of the nitrogen shown, 4-10 carbon atoms and 0-2 additional heteroatoms selected from nitrogen , oxygen and sulfur, wherein this ring is substituted with 0-3 alkyl d-C8, aryl, hetaryl, C6 alkylene aryl, C6 alkylene hetaryl, hydroxy, oxo, CrC6 alkyloxy, dyalkoxy d-C6 aryl, C6 alkyloxy hetaryl, CrC6 alkylCycloxy alkyl, CrC6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, CrC6 alkylcarbonyl aryl, d-C6 alkylcarbonyl hetaryl, alkylcarboxy dC6, arylcarboxy, hetarylcarboxy, alkylcarboxy dC6 aryl, and alkylcarboxy dC6 hetaryl; R20 is selected from H, OH, oxo, halo, cyano, nitro, d-C6 alkyl, C? -C6 alkyloxy, NR21R22, methylenedioxo, dihalomethylenedioxo, trihalomethyl, and trihalomethyloxy; R21 and R22 are independently selected from H, d-C8 alkyl, and alkyl d-C6 aryl; R23 is selected from H and alkyl dC6; n is selected from 0, 1, and 2; And it is selected from O and S; 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 form.

2. A compound according to claim 1, wherein: X is selected from CR5 and nitrogen; R1 is selected from H and alkyl CrC6-R6, wherein the alkyl group is substituted with 0-3 R7; R2 is selected from hydrogen, halo, d-C6 alkyl, and -C (= 0) R R8 R10 R12 alternatively, R 1 and DR ^ s "rn, ¡in" d.Jerp, ern "dj; i" e "n * te, m, en, tte, R f- »9 R r-» 1 ring A is a bicyclic or tricyclic saturated or partially saturated ring consisting of the nitrogen shown, 4-10 carbon atoms and 0-2 additional heteroatoms selected from nitrogen, oxygen, and sulfur; ring A is substituted with 0-3 groups selected from d-C8 alkyl, halo, hydroxy, -COOH, -CONR 8R19, -S (= 0) nR13, -S (= 0) nNR 8R19 oxo, cyano, alkyloxy d -C6, alkylene dCyCycloxy CrC6 and alkylcarbonyl CrC6, wherein each alkyl / alkylene group is substituted with 0-3 wherein R x is selected from hydrogen and d-C 6 alkyl; is substituted with 0-3 groups selected from C 8 alkyl, halo, hydroxy, -COOH, - CONR18R19, -S (= 0) nR13, -S (= 0) nNR18R19 oxo, cyano, d-C6alkyloxy, d-C6alkyloxy C6alkyloxyxy and C6alkylcarbonyl, wherein each alkyl / alkylene group is substituted with 0- 3 R14; R5 is selected from hydrogen, d-C6 alkyl, -C (= 0) R13, and cyano; R6 is selected from cyano, aryl, hetaryl, -oxo-alkyl CrC6-S (= 0) nR13, -C (= 0) R13, -S (= 0) nR13, -S (= 0) nNR18R19, -N ( R18) S (= 0) nR13, -N (R23) C (= Y) NR18R19, -C (= NR15) NR15, -N (R18) C (= 0) R13, cycloalkyl -N (R18) C (= O) -C3-C10, hetcycloalkyl -N (R18) C (= 0) - of 3-10 members, wherein the cycloalkyl, hetcycloalkyl, aryl and hetaryl groups are substituted with 0-3 R16; R7 is selected from halo, hydroxy, oxo, cyano, and CrC6 alkyl; R8, R9, R10 and R1 are independently selected from hydrogen, d-C8 alkyl, F, trihalomethyl, trihalomethoxy, hydroxy, and d-C6alkyloxy, wherein the C8 alkyl and d6C6 alkyloxy are substituted with 0-3 R17; alternatively, R8 and R9 together with the carbon atom to which they are attached form a saturated or partially saturated ring consisting of the carbon atom shown, 2-5 additional carbon atoms and 2-0 heteroatoms selected from nitrogen, oxygen and sulfur, wherein this ring is substituted with 0-3 groups selected from halo, trihalomethyl, CrC6 alkyl, aryl, hetaryl, d-C6 alkylene aryl, d-Cß hetaryl alkylene, hydroxy, oxo, CrC6 alkyloxy, aryloxy, alkylCycloalkyl or alkyloxy d- C6 hetaryl; alternatively, R10 and R11 together with the carbon atom to which they are attached form a saturated or partially saturated ring consisting of the carbon atom shown, 2-5 additional carbon atoms and 0-2 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the ring is substituted with 0-3 groups selected from halo, trihalomethyl, CrC6 alkyl, aryl, hetaryl, d-C6 alkylene aryl, d-C6 alkylene hetaryl, hydroxy, oxo, CrC6 alkyloxy, aryloxy, CrC6 alkyloxy aryl or alkyloxy CrC6hetaryl; alternatively, R8 and R10 together with the two carbon atoms to which they are attached form a saturated or partially saturated ring consisting of the two carbon atoms shown, 1-4 additional carbon atoms and 0-2 heteroatoms selected from nitrogen, oxygen and sulfur wherein the ring is substituted with 0-3 groups selected from halo, trihalomethyl, d-C6 alkyl, aryl, hetaryl, alkylene CrC6 aryl, alkylene d-C6 hetaryl, hydroxy, oxo, alkyloxy CrC6, aryloxy, alkyloxy CrC6 aryl, and heteroaryl d-C6 hetaryl; R12 is selected from H, OH, NR18R19, C3-C10 cycloalkyl, 3-10 membered hetcycloalkyl, -C (= 0) R13, -S (= 0) nR13, S (= 0) nNR 8R19, -N (R18 ) S (= 0) nR13, and -C (= NR15) NR16; wherein the cycloalkyl and hetcycloalkyl groups are substituted with 0-3 R17; R 13 is selected from OH, C C 8 alkyl, C 1 -C 8 alkyloxy, C 4 C alkyleneoxy CrC 8, aryl, hetaryl, aryloxy, hetaryloxy, and NR 18 R 19; R14 is selected from halo, hydroxy, oxo, and cyano; R15 and R16 are independently selected from H, d-C8 alkyl, 3-10 membered cycloalkyl, halo, OH, cyano, -C (= 0) R13, -S (= 0) nR13, S (= 0) nNR18R19, -N (R18) S (= 0) nR13, aryl, and hetaryl, wherein the alkyl and cycloalkyl groups are substituted with 0-3 R20; R17 is selected from halo, OH, oxo, nitro, cyano, -C (= 0) R13, -S (= 0) nR13, S (= 0) nNR18R19, -N (R18) S (= 0) nR13, NR18R19 , CrC8 alkyl, d-C6 alkyloxy, and aryloxy; R18 and R19 are independently selected from H, d-C8 alkyl, d-C8 alkyloxy, aryl, hetaryl, d-C6 alkylene, aryl, and CrC6 alkylene hetaryl, wherein the alkyl / alkylene, aryl, and hetaryl groups are independently substituted with 0-3 R20; alternatively, R18 and R19, together with the nitrogen atom to which they are attached, form a monocyclic, bicyclic or tricyclic saturated or partially saturated ring consisting of the nitrogen shown, 4-10 carbon atoms and 0-2 additional heteroatoms selected from nitrogen , oxygen and sulfur, wherein this ring is substituted with 0-3 alkyl d-C8, aryl, hetaryl, alkylene d-C6 aryl, alkylene CrC6 hetaryl, hydroxy, oxo, alkyloxy CrC6, alkyloxy d-C6 aryl, alkyloxy d- C6-hetaryl, d-C6-alkyloxy-d6-C6 alkyl, CrC6-alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, CrC6-alkylcarbonyl aryl, CrC6-alkylcarbonyl hetaryl, C-C6-alkylcarboxy, arylcarboxy, hetarylcarboxy, alkylcarboxy-d-C6-aryl, and alkylcarboxy d-C6-hetaryl; R20 is selected from H, OH, oxo, halo, cyano, nitro, CrC6 alkyl, d-C6 alkyloxy, NR21R22, methylenedioxo, dihalomethylenedioxo, trihalomethyl, and trihalomethyloxy; R2 and R22 are independently selected from H, CrC8 alkyl, and CrC6 alkyl aryl; R23 is selected from H and CrC6 alkyl; n is selected from 0, 1, and 2; And it is selected from O and S; with the proviso that when X is CR5, then R6 is -C (= 0) R13 where R3 is OH; 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 form.

3. The compound according to claim 1, wherein the compound is of Formula IA:

4. The compound according to claim 1, wherein the compound is of Formula IB: IB.

5. The compound according to claim 1, wherein the compound is of the Formula IC: IC.

6. The compound according to claim 1, wherein the compound is of the Formula ID: ID.

7. The compound according to claim 1, wherein R6 is selected from -C (= 0) R13, -S (= 0) nR13, -S (= 0) nNR18R19, -N (R18) S (= 0) nR13 , -N (R23) C (= Y) NR18R19 or -C (= NR15) NR15.

8. The compound according to claim 1, wherein R6 is selected from -C (= 0) R13, -S (= 0) nR13, -S (= 0) nNR18R19, or

9. The compound according to claim 1, wherein R is selected from N (R23) C (= Y) NR18R19.

10. The compound according to claim 1, wherein Y is oxygen (O).

11. The compound according to claim 1, wherein ring A is selected from: ring A is substituted with 0-2 groups selected from alkyl d-C8, halo, hydroxy, oxo, cyano, COOH, -CONR18R19, -S (= 0) nR13, -S (= 0) nNR18R19 and alkyloxy d-C6 .

12. The compound according to claim 11, wherein ring A is

13. The compound according to claim 11, wherein ring A is

14. The compound according to claim 11, wherein ring A is

15. The compound according to claim 11, wherein ring A is

HNT 16. The compound according to claim 11, wherein ring A is

17. The compound according to claim 11, wherein ring A is

18. The compound according to claim 1, wherein I, wherein wherein R x is selected from hydrogen and d-C 6 alkyl; is substituted with 0-3 groups selected from d-C8 alkyl, halo, hydroxy, -COOH, -CONR18R19, -S (= 0) nR13, -S (= 0) nNR18R19 oxo, cyano, d-C6 alkyloxy, alkylene d -C6 C6 alkyloxy and C6 alkylcarbonyl, wherein each alkyl / alkylene group is substituted with 0-3 R14;

19. A compound selected from the group: Furan-2-carboxylic acid. { 2- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzoimidazol-1-yl] -ethyl} - 1-Acetyl-piperidine-4-carboxylic acid amide. { 2- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzoimidazol-1-yl] -ethyl} -amide 2-methoxy -? / -. { 2- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzoimidazol-1-yl] -ethyl} -acetamide? / -. { 2- [5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzoimidazol-1-yl] -etl} -isonicotinamide? / -. { 2- [5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzoimidazol-1-yl] -ethyl} -acetamide tert-butyl acid ester. { 2- [5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzoimidazol-1-yl] -ethyl} -carbamic lsoxazole-5-carboxylic acid. { 2- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzoimidazol-1-yl] -ethyl} -amide? -. { 2- [5- (1,3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzoimidazol-1-yl] -ethyl} -benzamide 3- [2-Ethyl-5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzimidazol-1-yl] -propionic acid ethyl ester 3- [2-Ethyl-5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzimidazol-1-yl] -propionic acid ethyl ester 2- [ 5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -1 H -benzimidazol-2-yl] -cyclopropanecarboxylic acid 2- [5- (1, 3, 3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -1 H -benzimidazol-2-yl] -cyclopropanecarboxylic acid Ethyl 3- [2-Methyl-5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzimidazol-1-yl] -propionic acid ethyl ester of 2- [1-Ethyl-5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -1 H -benzimidazol-2-yl] -cyclopropanecarboxylic acid 3- [2-Methyl-5- (1,3, 3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzimidazol-1-yl] -propionic acid 2- [1-Ethyl-5- (1, 3,3-trimethyl-6- aza-bicyclo [3.2.1] octane-6-carbonyl) -1 H -benzimidazol-2-yl] -cyclopropanecarboxylic acid 3- [5- (1, 3,3-Trimethyl-6-aza-bicyclo [] 3.2.1] octane-6-carbonyl) -indol-1-yl] -propionic acid 3- [5- (1,3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -propionic acid [5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -feronic acid ester -acetic acid [5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -acetic 1-Morpholin-4-yl-3- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -propan-1-one 1-Morpholin-4-yl-2 - [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -ethanone ethyl ester of 2,2-Dimethyl-3- acid [5- (1, 3,3-trimethyl-6-aza- bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -propionic acid 2,2-Dimethyl-3- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2. 1] octane-6-carbonyl) -indol-1-yl] -propionic acid methyl ester 2-Methyl-3- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane] -6-carbonyl) -indol-1-yl] -propionic acid methyl ester 3- [5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indole -1-yl] -butyric acid 3- [5- (1,3,3-Trimetl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -butyric acid 2-Methyl-3- [5- (1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -propionic acid 3- [5- ( 1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-ylmethyl] -benzoic acid methyl ester 4- [5- (1, 3, 3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-ylmethyl] -benzoic acid 4- [5- (1,3,3-Trimethyl-6-aza-bicyclo [ 3.2.1] octane-6-carbonyl) -indol-1-ylmethyl] -benzoic acid ethyl ester 3- [5- (4-Aza-tricyclo [4.3.1.1 * 3,8 *] undecane-4-carbonyl) -indol-1-yl] -propionic acid 3 - [5- (4-Aza-tricyclo [4.3.1.1 * 3,8 *] undecane-4-carbonyl) -indol-1-yl] -propionic acid 5- (1,3,3-Trimethyl-) ethyl ester 6-aza-bicyclo [3.2.1] octane-6-carbonyl) -1H-indole-2-carboxylic acid 5- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -1 - -indole-2-carboxylic acid / - Methoxy -? / - methyl-3- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -propionamide? / - Ethoxy-3- [5- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -propionamide? / - Hydroxy-3- [5- (1, 3,3-trimethyl- 6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -propionamide. { 1- [2- (2H-Tetrazol-5-yl) -ethyl] - / H-indol-5-yl} - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -metanone . { 1- [2- (3-Cyclopropyl- [1, 2,4] oxadiazol-5-yl) -ethyl] -lH-indol-5-yl} - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -methanone. { 1- [2- (3-Methyl- [1, 2,4] oxadiazol-5-yl) -etl] - / rV-indol-5-yl} - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -methanone? / - (IH-Tetrazol-5-yl) -3- [5- (1, 3 , 3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -indol-1-yl] -propionamide. { 1- [2- (2-Met.l-2H-tetrazol-5-yl) -ethyl] - / H-indol-5-yl} - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -methanone. { 1- [2- (1-Methyl-fH-tetrazol-5-yl) -ethyl] -lH-indol-5-yl} - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -methanone. { 1- [2- (5-Methyl- [1, 2,4] oxadiazol-3-yl) -ethyl] -lH-indol-5-ylHl, 3,3-trimethyl-6-aza-bicyclo [3.2.1 ] oct-6-yl) -methanone; or a salt thereof with a pharmaceutically acceptable salt or acid or any optical isomer or mixture of optical isomers, including a racemic mixture or any tautomeric form.

20. A compound selected from the group: [1- (2-methanesulfonylmethoxy-ethyl) -1 H -benzoimidazol-5-yl] - (octahydro-quinolin-1-yl) -methanone (3-hydroxy-8-aza-bicyclo [3.2 .1] oct-8-yl) - [1- (2-methanesulfonylmethoxy-ethyl) -1 H -benzoimidazol-5-yl] -methanone trans-1 - (2-methanesulfonyl-methoxy-ethyl) -1 H- benzoimidazole-5-carboxylic acid (5-hydroxy-adamantan-2-yl) -amide Cis-1 - (2-methanesulfonyl-methoxy-ethyl) -1H-benzoimidazole-5-carboxylic acid (5-hydroxy-adamantan- 2-yl) -amide (3-Hydroxy-8-aza-bicyclo [3.2.1] oct-8-yl) - [1- (2-methanesulfonylmethoxy-ethyl) -1 H -benzoimidazol-5-yl] -methanone 1- (2- Methanesulfonyl-ethyl) -1H-benzoimidazole-5-carboxylic acid (5-hydroxy-adamantan-2-yl) -amide (3-Hydroxy-8-aza-bicyclo [3.2.1] oct-8-yl) - [1- (2-methanesulfonyl-ethyl) -1 H -benzoimidazol-5-yl] -methanone (3-Hydroxy-8) -aza-bicyclo [3.2.1] oct-8-yl) - [1 - (2-methanesulfonyl-ethyl) -1 H -benzoimidazol-5-yl] -methanone [1- (2-Methanesulfonyl-ethyl) -1 H -benzoimidazol-5-yl] - (octahydro-quinolin-1-yl) -methanone 1- (2-methanesulfonyl-ethyl) -1 H -benzoimidazole-5- acid carboxylic (5-hydroxy-adamantan-2-yl) -amide (3-Hydroxy-8-aza-bicyclo [3.2.1] oct-8-yl) -. { 1- [2- (1 H -tetrazol-5-yl) -ethyl] -1 H -benzoimidazol-5-yl} -metanone (Octahydro-quinolin-1-yl) -. { 1- [2- (1 H-tetrazol-5-yl) -ethyl] -1 H -benzoimidazol-5-yl} -methanone Trans-1- [2- (1 H-Tetrazol-5-yl) -ethyl] -1H-benzoimidazole-5-carboxylic acid (5-hydroxy-adamantan-2-yl) -amide acid Cis-1 - [2- (1 H-Tetrazol-5-yl) -ethyl] -1H-benzoimidazole-5-carboxylic acid (5-hydroxy-adamantan-2-yl) -amide 3-Hydroxy-pyrrolidine-1-carboxylic acid. { 2- [5- (3-hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzoimidazol-1-yl] -ethyl} 4-Hydroxy-piperidine-1-carboxylic acid amide. { 2- [5- (Octahydro-quinoline-1-carbonyl) -benzoimidazol-1-yl] -ethyl} -amide acid 1-. { 2 - [(4-Hydroxy-piperidine-1-carbonyl) -amino] -ethyl} -1 H-benzoimidazole-5-carboxylic acid (5-hydroxy-adamantan-2-yl) -amide 1-. { 2 - [(1,1-Dioxo-thiomorpholine-4-carbonyl) -amino] -ethyl} -1 H-benzoimidazole-5-carboxylic acid (5-hydroxy-adamantan-2-yl) -amide 1,1-Dioxo-thiomorpholine-4-carboxylic acid. { 2- [5- (3-hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzoimidazol-1-yl] -ethyl} - Cis-1 acid amide -. { 2 - [(Morpholine-4-carbonyl) -amino] -ethyl} -1H-benzo-imidazole-5-carboxylic acid (5-hydroxy-adamantan-2-yl) -amide Trans-1 - acid. { 2 - [(Morpholine-4-carbonyl) -amino] -ethyl} -1 H-benzo-imidazole-5-carboxylic acid (5-hydroxy-adamantan-2-yl) -amide Cis-morpholine-4-carboxylic acid. { 2- [5- (Octahydro-quinoline-1-carbonyl) -benzoimidazol-1-yl] -ethyl} - Trans-morpholine-4-carboxylic acid amide. { 2- [5- (Octahydro-quinoline-1-carbonyl) -benzoimidazol-1-yl] -ethyl} Morpholine-4-carboxylic acid amide. { 2- [5- (3-hydroxy-8-aza-bicyclo- [3.2.1] octane-8-carbonyl) -benzoimidazol-1-yl] -ethyl} -amide acid 1, 1-Dioxo-thiomorpholine-4-carboxylic acid. { 2- [5- (Octahydro-quinoline-1-carbonyl) -benzoimidazol-1-yl] -ethyl} 3-Hydroxy-pyrrolidine-1-carboxylic acid amide. { 2- [5- (Octahydro-quinoline-1-carbonyl) -benzoimidazol-1-yl] -ethyl} -amide acid 1-. { 2- [5- (Octahydro-quinoline-1-carbonyl) -benzoimidazol-1-yl] -ethylcarbamoyl} -piperidine-4-carboxylic acid 3-Hydroxy-pyrrolidine-1-carboxylic acid. { 2- [5- (3-hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzoimidazol-1-yl] -ethyl} Cis-4-hydroxy-piperidine-1-carboxylic acid amide. { 2- [5- (Octahydro-quinoline-1-carbonyl) -benzoimidazol-1-yl] -ethyl} - Trans-4-hydroxy-piperidine-1-carboxylic acid amide. { 2- [5- (Octahydro-quinoline-1-carbonyl) -benzoimidazol-1-yl] -ethyl} Endo-4-hydroxy-piperidine-1-carboxylic acid amide. { 2- [5- (3-hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzoimidazol-1-yl] -ethyl} -Exo-4-hydroxy-piperidine-1-carboxylic acid amide. { 2- [5- (3-hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzoimidazol-1-yl] -ethyl} -amide acid 1-. { 2 - [(1,1-Dioxo-thiomorpholine-4-carbonyl) -amino] -ethyl} -1 H-benzoimidazole-5-carboxylic acid (1-l-Dioxo-thiomorpholine-4-carboxylic acid 5-hydroxy-adamantan-2-yl) -amide. { 2- [5- (3-hydroxy-8-aza-bicyclo [3.2.1] -octane-8-carbonyl) -benzo-imidazol-1-yl] -ethyl} -amide acid 1 -. { 2 - [(4-Hydroxy-piperidine-1 -carbonyl) -amino] -ethyl} -1 H-benzoimidazole-5-carboxylic acid (5-hydroxy-adamantan-2-yl) -amide acid 1-. { 2 - [(3-Hydroxy-pyrrolidine-1-carbonyl) -amino] -ethyl} -1H-benzoimidazole-5-carboxylic (5-hydroxy-adamantan-2-yl) -amide Morpholine-4-carboxylic acid. { 2- [5- (3-hydroxy-8-aza-bicyclo- [3.2.1] octane-8-carbonyl) -benzoimidazol-1-yl] -ethyl} - Cis-1- acid amide. { 2- [5- (5-hydroxy-adamantan-2-ylcarbamoyl) -benzoimidazol-1-yl] -ethylcarbamoyl} -piperidine- 4-carboxylic acid Trans-1-. { 2- [5- (5-hydroxy-adamantan-2-ylcarbamoyl) -benzoimidazol-1-yl] -ethylcarbamoyl} -piperidine-4-carboxylic acid 1-. { 2- [5- (3-Hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzoimidazol-1-yl] -ethyl-carbamoyl} -piperidine-4-carboxylic acid 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 form.

21. A compound according to any one of claims 1-20, which is a useful agent for the treatment of conditions, disorders or diseases wherein a modulation or an inhibition of the activity of 11βHSD1 is beneficial.

22. The compound according to claim 21, wherein the conditions, disorders and diseases are influenced by intracellular glucocorticoid levels.

23. The compound according to claim 21, wherein the conditions, disorders or diseases are selected from metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, type 2 diabetes, impaired glucose tolerance (IGT), glucose in decreased fasting (IFG), progression of IGT to type 2 diabetes, progress of the metabolic syndrome in type 2 diabetes, late diabetic complications, neurodegenerative and psychiatric disorders and the adverse effects of treatment or therapy of the glucocorticoid receptor agonist.

24. A pharmaceutical composition comprising, as an active ingredient, at least one compound according to any of claims 1-20 together with one or more pharmaceutically acceptable carriers or excipients.

25. The pharmaceutical composition according to claim 24, which is suitable for oral, nasal, buccal, transdermal, pulmonary or parenteral administration.

26. The use of a compound according to any of claims 1-20, for the preparation of a pharmaceutical composition for the treatment of conditions, disorders or diseases wherein a modulation or an inhibition of the activity of 11βHSD1 is beneficial.

27. The use according to claim 26, wherein the conditions, disease disorders are influenced by intracellular glucocorticoid levels.

28. The use according to claim 26, wherein the conditions, disorders or diseases are selected from metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, type 2 diabetes, impaired glucose tolerance (IGT), fasting glucose decreased (IFG), progression of IGT to type 2 diabetes, progress of the metabolic syndrome in type 2 diabetes, late diabetic complications, neurodegenerative and psychiatric disorders and the adverse effects of treatment or therapy of glucocorticoid receptor agonist.

29. The use according to any of claims 26-28, wherein the pharmaceutical composition is appropriate for a route of administration selected from oral, nasal, buccal, transdermal, pulmonary and parenteral.

30. A method for the treatment of conditions, disorders or diseases wherein a modulation or inhibition of the activity of 11βHSD1 is beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound according to any of claims 1-20.

31. The method according to claim 30, wherein the conditions, disorders and diseases are influenced by the intracellular glucocorticoid levels.

32. The method according to claim 30, where the conditions, disorders or diseases are selected from metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, type 2 diabetes, decreased glucose tolerance (IGT), decreased fasting glucose (IFG), IGT progress to type 2 diabetes, progression of the metabolic syndrome in type 2 diabetes, late diabetic complications, neurodegenerative and psychiatric disorders and the adverse effects of glucocorticoid receptor agonist treatment or therapy.

33. The method according to any of claims 30-32, wherein the administration is via a selected route of oral, nasal, buccal, transdermal, pulmonary and parenteral.