Indazoles, benzothiazoles, and benzoisothiazoles, and preparation and uses thereof

Abstract

The present invention relates generally to the field of ligands for nicotinic acetylcholine receptors (nAChR), activation of nAChRs, and the treatment of disease conditions associated with defective or malfunctioning nicotinic acetylcholine receptors, especially of the brain. Further, this invention relates to novel compounds (indazoles and benzothiazoles), which act as ligands for the α7 nAChR subtype, methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.

1 . A method of treating a patient suffering from a psychotic disease, neurodegenerative disease involving a dysfunction of the cholinergic system, dementia, or memory and/or cognition impairment, alcohol withdrawal, inflammation, nicotine addiction, pain, jetlag, obesity and/or diabetes, or a method of treating a patient with anti-intoxication therapy, providing a patient with neuroprotection against damage associated with strokes and ischemia and glutamate-induced excitotoxicity, or inducing smoking cessation in a patient, comprising administering to said patient a compound of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein
 X is O or S; 
 R 1  is H, F, Cl, Br, I, OH, CN, nitro, NH 2 , alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, alkoxy having 1 to 4 carbon atoms, cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthio having 1 to 4 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein each alkyl group independently has 1 to 4 carbon atoms, Ar or Het; 
 R 2  is H, alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, or cycloalkylalkyl having 4 to 7 carbon atoms; 
 Ar is an aryl group containing 6 to 10 carbon atoms which is unsubstituted or substituted one or more times by alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, halogen, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, amino, cyano, hydroxyl, nitro, halogenated alkyl having 1 to 8 carbon atoms, halogenated alkoxy having 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms, hydroxyalkoxy having 2 to 8 carbon atoms, alkenyloxy having 3 to 8 carbon atoms, alkylthio having 1 to 8 carbon atoms, alkylsulphinyl having 1 to 8 carbon atoms, alkylsulphonyl having 1 to 8 carbon atoms, monoalkylamino having 1 to 8 carbon atoms, cycloalkylamino wherein the cycloalkyl group has 3 to 7 carbon atoms and is optionally substituted, aryloxy wherein the aryl portion contains 6 to 10 carbon atoms and is optionally substituted, arylthio wherein the aryl portion contains 6 to 10 carbon atoms and is optionally substituted, cycloalkyloxy wherein the cycloalkyl group has 3 to 7 carbon atoms and is optionally substituted, sulfo, sulfonylamino, acylamido, acyloxy or combinations thereof; and 
 Het is a heterocyclic group, which is fully saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, aryl having 6 to 10 carbon atoms and is optionally substituted, alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, cyano, trifluoromethyl, nitro, oxo, amino, monoalkylamino having 1 to 8 carbon atoms, dialkylamino wherein each alkyl group has 1 to 8 carbon atoms, or combinations thereof; or 
 a pharmaceutically acceptable salt thereof, 
 wherein if the compound exhibits chirality it can be in the form of a mixture of enantiomers such as a racemate or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer. 
 
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . (canceled) 
     
     
         6 . A method of treating a patient suffering from a psychotic disease, neurodegenerative disease involving a dysfunction of the cholinergic system, dementia, or memory and/or cognition impairment, alcohol withdrawal, inflammation, nicotine addiction, pain, jetlag, obesity and/or diabetes, or a method of treating a patient with anti-intoxication therapy, providing a patient with neuroprotection against damage associated with strokes and ischemia and glutamate-induced excitotoxicity, or inducing smoking cessation in a patient, comprising administering to said patient a compound according to Formula I′: 
       
         
           
           
               
               
           
         
       
       wherein
 A is an indazolyl according to subformula (a), 
 
       
         
           
           
               
               
           
         
         R 1  is H, F, Cl, Br, I, OH, CN, nitro, NH 2 , alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, alkoxy having 1 to 4 carbon atoms, cycloalkoxy having 3 to 7 carbon atoms, alkylthio having 1 to 4 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein each alkyl group independently has 1 to 4 carbon atoms, Ar or Het; 
         R 2  is H, alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, or cycloalkylalkyl having 4 to 7 carbon atoms; 
         Ar is an aryl group containing 6 to 10 carbon atoms which is unsubstituted or substituted one or more times by alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, halogen, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, amino, cyano, hydroxyl, nitro, halogenated alkyl having 1 to 8 carbon atoms, halogenated alkoxy having 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms, hydroxyalkoxy having 2 to 8 carbon atoms, alkenyloxy having 3 to 8 carbon atoms, alkylthio having 1 to 8 carbon atoms, alkylsulphinyl having 1 to 8 carbon atoms, alkylsulphonyl having 1 to 8 carbon atoms, monoalkylamino having 1 to 8 carbon atoms, cycloalkylamino wherein the cycloalkyl group has 3 to 7 carbon atoms and is optionally substituted, aryloxy wherein the aryl portion contains 6 to 10 carbon atoms and is optionally substituted, arylthio wherein the aryl portion contains 6 to 10 carbon atoms and is optionally substituted, cycloalkyloxy wherein the cycloalkyl group has 3 to 7 carbon atoms and is optionally substituted, sulfo, sulfonylamino, acylamido, acyloxy or combinations thereof; and 
         Het is a heterocyclic group, which is fully saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, aryl having 6 to 10 carbon atoms and is optionally substituted, alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, cyano, trifluoromethyl, nitro, oxo, amino, monoalkylamino having 1 to 8 carbon atoms, dialkylamino wherein each alkyl group has 1 to 8 carbon atoms, or combinations thereof; or 
         a pharmaceutically acceptable salt thereof, 
         wherein if the compound exhibits chirality it can be in the form of a mixture of enantiomers such as a racemate or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer, and 
         wherein the indazolyl group of subformula (a) is attached to the remainder of the compound via its 3 position. 
       
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . A method according to  claim 1 , wherein R 1  is H, F, Cl, Br, 2-thiophenyl, 3-thiophenyl, 3-furyl, or phenyl. 
     
     
         12 . A method according to  claim 1 , wherein R 2  is H, methyl, 2-thiophenyl, 3-thiophenyl, 3-furyl, or phenyl. 
     
     
         13 . (canceled) 
     
     
         14 . A method according to  claim 1 , wherein R 1  is H, F, Cl, Br, methyl, methoxy, or amino. 
     
     
         15 . A method compound according to  claim 1 , wherein R 2  is H or methyl. 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . A method according to  claim 1 , wherein R 1  is H, F, Cl, Br, 2-thiophenyl, 3-thiophenyl, 3-furyl, or phenyl, and R 2  is H, methyl, 2-thiophenyl, 3-thiophenyl, 3-furyl, or phenyl. 
     
     
         20 . (canceled) 
     
     
         21 . A method compound according to  claim 1 , wherein said compound is selected from: 
       N-(1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide, 
       N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide, 
       N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide hydrochloride, 
       1-Methyl-1H-Indazole-3-carboxamide, N-1-aza-bicyclo[2,2,2]oct-3-yl, 
       (R) 1-Methyl-1H-Indazole-3-carboxamide, N-1-aza-bicyclo[2,2,2]oct-3-yl, 
       (S) 1-Methyl-1H-Indazole-3-carboxamide, N-1-aza-bicyclo[2,2,2]oct-3-yl, 
       N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(bromo)-1H-indazole-3-carboxamide, 
       N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(cyclopropyl)-1H-indazole-3-carboxamide, 
       N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(phenyl)-1H-indazole-3-carboxamide, 
       N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(phenyl)-yl)-1H-indazole-3-carboxamide, 
       N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-2-yl)-1H-indazole-3-carboxamide, 
       N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-3-yl)-1H-indazole-3-carboxamide, 
       N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(bromo)-1H-indazole-3-carboxamide, 
       N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(furan-3-yl)-1H-indazole-3-carboxamide, 
       N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(phenyl)-1H-indazole-3-carboxamide, 
       N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-2-yl)-1H-indazole-3-carboxamide, 
       N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-3-yl)-1H-indazole-3-carboxamide, 
       N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(bromo)-1H-indazole-3-carboxamide, 
       N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(furan-3-yl)-1H-indazole-3-carboxamide, 
       N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(phenyl)-1H-indazole-3-carboxamide, 
       N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-2-yl)-1H-indazole-3-carboxamide, 
       N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-3-yl)-1H-indazole-3-carboxamide, 
       N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(bromo)-1H-indazole-3-carboxamide, 
       N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(furan-3-yl)-1H-indazole-3-carboxamide, 
       N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(phenyl)-1H-indazole-3-carboxamide, 
       N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-2-yl)-1H-indazole-3-carboxamide, 
       N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-3-yl)-1H-indazole-3-carboxamide, 
       1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, N-1H-indazol-3-yl, 
       (S) 1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, N-1H-indazol-3-yl, 
       (R) 1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, N-1H-indazol-3-yl, 
       and pharmaceutically acceptable physiological salts thereof. 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . A method according to  claim 1 , wherein said patient is suffering from a psychotic disease, a neurodegenerative disease involving a dysfunction of the cholinergic system, or memory and/or cognition impairment. 
     
     
         25 . A method according to  claim 1 , wherein said patient is suffering from dementia or other condition with memory loss. 
     
     
         26 . A method according to  claim 1 , wherein said patient is suffering from memory impairment due to mild cognitive impairment due to aging, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, depression, aging, head trauma, stroke, CNS hypoxia, cerebral senility, or multiinfarct dementia comprising administering an effective amount of a compound according to  claim 1 . 
     
     
         27 . A method according to  claim 1 , wherein said patient is suffering from dementia due to Alzheimer's disease. 
     
     
         28 . A method according to  claim 1 , wherein said patient is treated for alcohol withdrawal or said patient is treated with anti-intoxication therapy. 
     
     
         29 . A method according to  claim 1 , wherein said patient is treated to provide for neuroprotection against damage associated with strokes and ischemia and glutamate-induced excitotoxicity. 
     
     
         30 . A method according to  claim 1 , wherein said patient is treated for nicotine addiction, pain, jetlag, obesity and/or diabetes, or said patient is treated for of inducing smoking cessation. 
     
     
         31 . A method according to  claim 1 , wherein said patient is suffering from mild cognitive impairment (MCI), vascular dementia (VaD), age-associated cognitive decline (AACD), amnesia associated with open-heart-surgery, cardiac arrest, general anesthesia, memory deficits from exposure to anesthetic agents, sleep deprivation induced cognitive impairment, chronic fatigue syndrome, narcolepsy, AIDS-related dementia, epilepsy-related cognitive impairment, Down's syndrome, Alcoholism related dementia, drug/substance induced memory impairments, Dementia Puglistica (Boxer Syndrome), or animal dementia. 
     
     
         32 . (canceled) 
     
     
         33 . (canceled) 
     
     
         34 . (canceled) 
     
     
         35 . (canceled) 
     
     
         36 . (canceled) 
     
     
         37 . A method according to  claim 1 , wherein said patient is treated for inflammation. 
     
     
         38 . A method according to  claim 21 , wherein said compound is in the form of a hydrochloride or hydroformate salt. 
     
     
         39 . A compound according to  claim 38 , wherein said compound is: 
       N-(-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide hydrochloride, 
       N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide hydrochloride, 
       N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide hydrochloride, 
       N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(cyclopropyl)-1H-indazole-3-carboxamide hydroformate, 
       N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(furan-3-yl)-1H-indazole-3-carboxamide hydroformate, 
       N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(phenyl)-1H-indazole-3-carboxamide hydroformate, 
       N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-2-yl)-1H-indazole-3-carboxamide hydroformate, 
       N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-3-yl)-1H-indazole-3-carboxamide hydroformate, 
       N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(furan-3-yl)-1H-indazole-3-carboxamide hydroformate, 
       N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(phenyl)-1H-indazole-3-carboxamide hydroformate, 
       N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-2-yl)-1H-indazole-3-carboxamide hydroformate, 
       N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-3-yl)-1H-indazole-3-carboxamide hydroformate, 
       N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(furan-3-yl)-1H-indazole-3-carboxamide hydroformate, 
       N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(phenyl)-1H-indazole-3-carboxamide hydroformate, 
       N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-2-yl)-1H-indazole-3-carboxamide hydroformate, 
       N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-3-yl)-1H-indazole-3-carboxamide hydroformate, 
       N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(furan-3-yl)-1H-indazole-3-carboxamide hydroformate, 
       N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(phenyl)-1H-indazole-3-carboxamide hydroformate, 
       N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-2-yl)-1H-indazole-3-carboxamide hydroformate, and 
       N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-3-yl)-1H-indazole-3-carboxamide hydroformate. 
     
     
         40 . A method according to  claim 21 , wherein said compound is N-(1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         41 . A method according to  claim 40 , wherein said compound is N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         42 . A method according to  claim 40 , wherein said compound is N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         43 . A method according to  claim 21 , wherein said compound is N-(1-Azabicyclo[2.2.2]oct-3-yl)-5-(bromo)-1H-indazole-3-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         44 . A method according to  claim 43 , wherein said compound is N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(bromo)-1H-indazole-3-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         45 . A method according to  claim 43 , wherein said compound is N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(bromo)-1H-indazole-3-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         46 . A method according to  claim 21 , wherein said compound is N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(cyclopropyl)-1H-indazole-3-carboxamide carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         47 . A method according to  claim 21 , wherein said compound is N-(1-Azabicyclo[2.2.2]oct-3-yl)-5-(furan-3-yl)-1H-indazole-3-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         48 . A method according to  claim 47 , wherein said compound is N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(furan-3-yl)-1H-indazole-3-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         49 . A method according to  claim 47 , wherein said compound is N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(furan-3-yl)-1H-indazole-3-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         50 . A method according to  claim 21 , wherein said compound is N-(1-Azabicyclo[2.2.2]oct-3-yl)-5-(phenyl)-1H-indazole-3-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         51 . A method according to  claim 50 , wherein said compound is N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(phenyl)-1H-indazole-3-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         52 . A method according to  claim 50 , wherein said compound is N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(phenyl)-1H-indazole-3-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         53 . A method according to  claim 21 , wherein said compound is N-(1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-2-yl)-1H-indazole-3-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         54 . A method according to  claim 53 , wherein said compound is N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-2-yl)-1H-indazole-3-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         55 . A method according to  claim 53 , wherein said compound is N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-2-yl)-1H-indazole-3-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         56 . A method according to  claim 21 , wherein said compound is N-(1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-3-yl)-1H-indazole-3-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         57 . A method according to  claim 56 , wherein said compound is N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-3-yl)-1H-indazole-3-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         58 . A method according to  claim 56 , wherein said compound is N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-3-yl)-1H-indazole-3-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         59 . A method according to  claim 39 , wherein said compound is N-(-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide hydrochloride. 
     
     
         60 . A method according to  claim 39 , wherein said compound is N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide hydrochloride. 
     
     
         61 . A method according to  claim 39 , wherein said compound is N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide hydrochloride. 
     
     
         62 . A method according to  claim 39 , wherein said compound is N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(cyclopropyl)-1H-indazole-3-carboxamide hydroformate. 
     
     
         63 . A method according to  claim 39 , wherein said compound is N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(furan-3-yl)-1H-indazole-3-carboxamide hydroformate. 
     
     
         64 . A method according to  claim 39 , wherein said compound is N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(phenyl)-1H-indazole-3-carboxamide hydroformate. 
     
     
         65 . A method according to  claim 39 , wherein said compound is N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-2-yl)-1H-indazole-3-carboxamide hydroformate. 
     
     
         66 . A method according to  claim 39 , wherein said compound is N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-3-yl)-1H-indazole-3-carboxamide hydroformate. 
     
     
         67 . A method according to  claim 39 , wherein said compound is N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(furan-3-yl)-1H-indazole-3-carboxamide hydroformate. 
     
     
         68 . A method according to  claim 39 , wherein said compound is N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(phenyl)-1H-indazole-3-carboxamide hydroformate. 
     
     
         69 . A method according to  claim 39 , wherein said compound is N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-2-yl)-1H-indazole-3-carboxamide hydroformate. 
     
     
         70 . A method according to  claim 39 , wherein said compound is N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-3-yl)-1H-indazole-3-carboxamide hydroformate. 
     
     
         71 . A method according to  claim 11 , wherein R 2  is H or methyl. 
     
     
         72 . A method according to  claim 1 , wherein Ar is substituted or unsubstituted phenyl, or naphthyl, and Het is substituted or unsubstituted tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, isoxazolinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl, or naphthyridinyl. 
     
     
         73 . A method according to  claim 1 , wherein:
 Ar is an aryl group containing 6 to 10 carbon atoms which is unsubstituted or substituted one or more times by alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, halogen, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, amino, cyano, hydroxyl, nitro, halogenated alkyl having 1 to 8 carbon atoms, halogenated alkoxy having 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms, hydroxyalkoxy having 2 to 8 carbon atoms, alkenyloxy having 3 to 8 carbon atoms, alkylthio having 1 to 8 carbon atoms, alkylsulphinyl having 1 to 8 carbon atoms, alkylsulphonyl having 1 to 8 carbon atoms, monoalkylamino having 1 to 8 carbon atoms, cycloalkylamino wherein the cycloalkyl group has 3 to 7 carbon atoms, aryloxy wherein the aryl portion contains 6 to 10 carbon atoms, arylthio wherein the aryl portion contains 6 to 10 carbon atoms, cycloalkyloxy wherein the cycloalkyl group has 3 to 7 carbon atoms, sulfo, sulfonylamino, acylamido, acyloxy or combinations thereof; and   Het is a heterocyclic group, which is fully saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, aryl having 6 to 10 carbon atoms, alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, cyano, trifluoromethyl, nitro, oxo, amino, monoalkylamino having 1 to 8 carbon atoms, dialkylamino wherein each alkyl group has 1 to 8 carbon atoms, or combinations thereof.   
     
     
         74 . A method according to  claim 6 , wherein:
 Ar is an aryl group containing 6 to 10 carbon atoms which is unsubstituted or substituted one or more times by alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, halogen, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, amino, cyano, hydroxyl, nitro, halogenated alkyl having 1 to 8 carbon atoms, halogenated alkoxy having 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms, hydroxyalkoxy having 2 to 8 carbon atoms, alkenyloxy having 3 to 8 carbon atoms, alkylthio having 1 to 8 carbon atoms, alkylsulphinyl having 1 to 8 carbon atoms, alkylsulphonyl having 1 to 8 carbon atoms, monoalkylamino having 1 to 8 carbon atoms, cycloalkylamino wherein the cycloalkyl group has 3 to 7 carbon atoms, aryloxy wherein the aryl portion contains 6 to 10 carbon atoms, arylthio wherein the aryl portion contains 6 to 10 carbon atoms, cycloalkyloxy wherein the cycloalkyl group has 3 to 7 carbon atoms, sulfo, sulfonylamino, acylamido, acyloxy or combinations thereof; and   Het is a heterocyclic group, which is fully saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, aryl having 6 to 10 carbon atoms, alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, cyano, trifluoromethyl, nitro, oxo, amino, monoalkylamino having 1 to 8 carbon atoms, dialkylamino wherein each alkyl group has 1 to 8 carbon atoms, or combinations thereof.   
     
     
         75 . A method according to  claim 1 , wherein:
 Ar is an aryl group containing 6 to 10 carbon atoms which is unsubstituted or substituted one or more times by alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, halogen, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, amino, cyano, hydroxyl, nitro, halogenated alkyl having 1 to 8 carbon atoms, halogenated alkoxy having 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms, hydroxyalkoxy having 2 to 8 carbon atoms, alkenyloxy having 3 to 8 carbon atoms, alkylthio having 1 to 8 carbon atoms, alkylsulphinyl having 1 to 8 carbon atoms, alkylsulphonyl having 1 to 8 carbon atoms, monoalkylamino having 1 to 8 carbon atoms, cycloalkylamino wherein the cycloalkyl group has 3 to 7 carbon atoms and is optionally substituted by C 1-4 -alkyl, C 1-4 -alkoxy, hydroxyl, amino, monoalkylamino having 1 to 4 carbon atoms, and/or dialkylamino in which each alkyl group has 1 to 4 carbon atoms, aryloxy wherein the aryl portion contains 6 to 10 carbon atoms and is optionally substituted by halogen, C 1-4 -alkyl, hydroxy, C 1-4 -alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C 1-4 -alkylamino, dialkylamino in which each alkyl group has 1 to 4 carbon atoms, C 1-4 -hydroxyalkyl, C 1-4 -hydroxyalkoxy, carboxy, cyano, or C 1-4 -alkoxy-carbonyl, arylthio wherein the aryl portion contains 6 to 10 carbon atoms and is optionally substituted by halogen, C 1-4 -alkyl, hydroxy, C 1-4 -alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C 1-4 -alkylamino, dialkylamino in which each alkyl group has 1 to 4 carbon atoms, C 1-4 -hydroxyalkyl, C 1-4 -hydroxyalkoxy, carboxy, cyano, or C 1-4 -alkoxy-carbonyl, cycloalkyloxy wherein the cycloalkyl group has 3 to 7 carbon atoms and is optionally substituted by C 1-4 -alkyl, C 1-4 -alkoxy, hydroxyl, amino, monoalkylamino having 1 to 4 carbon atoms, and/or dialkylamino in which each alkyl group has 1 to 4 carbon atoms, sulfo, sulfonylamino, or combinations thereof; and   Het is a heterocyclic group, which is fully saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, aryl having 6 to 10 carbon atoms and is optionally substituted by halogen, C 1-4 -alkyl, hydroxy, C 1-4 -alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C 1-4 -alkylamino, dialkylamino in which each alkyl group has 1 to 4 carbon atoms, C 1-4 -hydroxyalkyl, C 1-4 -hydroxyalkoxy, carboxy, cyano, or C 1-4 -alkoxy-carbonyl, alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, cyano, trifluoromethyl, nitro, oxo, amino, monoalkylamino having 1 to 8 carbon atoms, dialkylamino wherein each alkyl group has 1 to 8 carbon atoms, or combinations thereof.   
     
     
         76 . A method according to  claim 1 , wherein:
 Ar is an aryl group containing 6 to 10 carbon atoms which is unsubstituted or substituted one or more times by alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, halogen, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, amino, cyano, hydroxyl, nitro, halogenated alkyl having 1 to 8 carbon atoms, halogenated alkoxy having 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms, hydroxyalkoxy having 2 to 8 carbon atoms, alkenyloxy having 3 to 8 carbon atoms, alkylthio having 1 to 8 carbon atoms, alkylsulphinyl having 1 to 8 carbon atoms, alkylsulphonyl having 1 to 8 carbon atoms, monoalkylamino having 1 to 8 carbon atoms, cycloalkylamino wherein the cycloalkyl group has 3 to 7 carbon atoms and is optionally substituted by C 1-4 -alkyl, C 1-4 -alkoxy, hydroxyl, amino, monoalkylamino having 1 to 4 carbon atoms, and/or dialkylamino in which each alkyl group has 1 to 4 carbon atoms, aryloxy wherein the aryl portion contains 6 to 10 carbon atoms and is optionally substituted by halogen, C 1-4 -alkyl, hydroxy, C 1-4 -alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C 1-4 -alkylamino, dialkylamino in which each alkyl group has 1 to 4 carbon atoms, C 1-4 -hydroxyalkyl, C 1-4 -hydroxyalkoxy, carboxy, cyano, or C 1-4 -alkoxy-carbonyl, arylthio wherein the aryl portion contains 6 to 10 carbon atoms and is optionally substituted by halogen, C 1-4 -alkyl, hydroxy, C 1-4 -alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C 1-4 -alkylamino, dialkylamino in which each alkyl group has 1 to 4 carbon atoms, C 1-4 -hydroxyalkyl, C 1-4 -hydroxyalkoxy, carboxy, cyano, or C 1-4 -alkoxy-carbonyl, cycloalkyloxy wherein the cycloalkyl group has 3 to 7 carbon atoms and is optionally substituted by C 1-4 -alkyl, C 1-4 -alkoxy, hydroxyl, amino, monoalkylamino having 1 to 4 carbon atoms, and/or dialkylamino in which each alkyl group has 1 to 4 carbon atoms, sulfo, sulfonylamino, or combinations thereof; and   Het is a heterocyclic group, which is fully saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, aryl having 6 to 10 carbon atoms and is optionally substituted by halogen, C 1-4 -alkyl, hydroxy, C 1-4 -alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C 1-4 -alkylamino, dialkylamino in which each alkyl group has 1 to 4 carbon atoms, C 1-4 -hydroxyalkyl, C 1-4 -hydroxyalkoxy, carboxy, cyano, or C 1-4 -alkoxy-carbonyl, alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, cyano, trifluoromethyl, nitro, oxo, amino, monoalkylamino having 1 to 8 carbon atoms, dialkylamino wherein each alkyl group has 1 to 8 carbon atoms, or combinations thereof.   
     
     
         77 . A method according to  claim 1 , wherein R 1  is H, F, Cl, Br, methyl, methoxy, or amino, and R 2  is H or methyl. 
     
     
         78 . A method according to  claim 1 , wherein R 1  is H, F, Cl, Br, 2-thiophenyl, 3-thiophenyl, 3-furyl, or phenyl, and R 2  is H, methyl 2-thiophenyl, 3-thiophenyl, 3-furyl, or phenyl. 
     
     
         79 . A method according to  claim 1 , wherein R 1  is H, F, Cl, Br, I, OH, CN, nitro, NH 2 , alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, alkoxy having 1 to 4 carbon atoms, cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthio having 1 to 4 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms, or dialkylamino wherein each alkyl group independently has 1 to 4 carbon atoms. 
     
     
         80 . A method according to  claim 1 , wherein R 1  is alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, or hydroxyalkoxy having 2 to 4 carbon atoms