Compounds and their use as bace inhibitors

Abstract

The present invention relates to compounds of formula (I) and their pharmaceutical compositions. In addition, the present invention relates to therapeutic methods for the treatment and/or prevention of Aβ-related pathologies such as Down's syndrome, β-amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI (“mild cognitive impairment”), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.

1 - 25 . (canceled) 
     
     
         26 . A method of treating or reducing the risk of a disease or condition selected from hereditary cerebral hemorrhage, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as dementia of mixed vascular and degenerative origin, progressive supranuclear palsy, a disorder associated with cognitive impairment and traumatic brain injury, wherein said method comprises administering to a person suffering from, or at risk of, said disease or condition, a therapeutically effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein:
 A is —O— or —CH 2 —; 
 n is 0 or 1; 
 R 1  is C 1-6 alkyl or C 1-6 haloalkyl; 
 R 2  is hydrogen, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, C 2-6 alkynyl, C 2-6 alkenyl, C 1-6 alkyl, halogen, cyano, C 1-6 haloalkyl, NHC(O)R 9  or OR 8 , wherein: 
 
       said C 0-6 alkylaryl, C 0-6 alkylheteroaryl, C 2-6 alkynyl, C 2-6 alkenyl, C 1-6 alkyl or C 1-6 haloalkyl is optionally substituted with one to three R 7 ; 
       as to R 5  and R 6 :
 R 5  and R 6  are independently hydrogen, heterocyclyl, C 3-6 cycloalkyl, aryl, heteroaryl or C 1-6 alkyl, wherein: 
 said heterocyclyl, C 3-6 cycloalkyl, aryl, heteroaryl or C 1-6 alkyl is optionally substituted with one or two substituents independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano or OR 8 ; or 
 R 5  and R 6 , together with the carbon to which they are attached, form a ring B, wherein ring B is: 
 a 3-14 membered cycloalkyl or heterocyclyl monocyclic ring, or a 9-14 membered bicyclic cycloalkyl or heterocyclyl ring; optionally substituted by one or two substituents independently selected from oxo, halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, or OR 8 ; and optionally fused with an aryl or heteroaryl to form a bi- or polycyclic system; 
 each R 7  is independently C 1-6 alkyl, halogen, cyano, C 0-6 alkylC 3-6 cycloalkyl, C 1-6 haloalkyl, OC 1-6 alkyl, OC 1-6 haloalkyl, C 2-6 alkynyl or C 2-6 alkenyl, wherein: 
 said C 1-6 alkyl, C 0-6 alkylC 3-6 cycloalkyl, C 1-6 haloalkyl, OC 1-6 alkyl, OC 1-6 haloalkyl, C 2-6 alkynyl or C 2-6 alkenyl is optionally substituted with 1-3 substituents independently selected from halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, OC 1-6 alkyl and OC 1-6 haloalkyl; 
 each R 8  is independently hydrogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, aryl or heteroaryl, wherein: 
 said C 1-6 alkyl, C 1-6 haloalkyl, aryl or heteroaryl is optionally substituted with a group selected from halogen, cyano and C 1-6 alkyl; and 
 R 9  is a heteroaryl, wherein: 
 said heteroaryl is optionally substituted with halogen, cyano, OR 8 , C 1-6 haloalkyl or C 1-6 alkyl. 
 
     
     
         27 . The method according to  claim 26 , wherein R 1  is C 1-3 alkyl. 
     
     
         28 . The method according to  claim 27 , wherein R 1  is methyl or ethyl. 
     
     
         29 . The method according to  claim 26 , wherein R 2  is aryl, heteroaryl, C 2-6 alkynyl, halogen, NHC(O)R 9  or OR 8 , wherein:
 said aryl, heteroaryl, or C 2-6 alkynyl is optionally substituted with one to three R 7 .   
     
     
         30 . The method according to  claim 26 , wherein R 5  and R 6  are independently hydrogen or heterocyclyl, wherein:
 said heterocyclyl is optionally substituted with one or two substituents independently selected from C 1-6 alkyl or OR 8 .   
     
     
         31 . The method according to  claim 26 , wherein R 5  and R 6 , together with the carbon to which they are attached, form a ring B, wherein ring B is:
 a 3-14 membered cycloalkyl or heterocyclyl monocyclic ring, or a 9-14 membered bicyclic cycloalkyl or heterocyclyl ring; optionally substituted by one or two substituents independently selected from oxo, halogen, C 1-6 alkyl or OR 8 ; and optionally fused with an aryl or heteroaryl to form a bi- or polycyclic system.   
     
     
         32 . The method according to  claim 26 , wherein R 5  and R 6 , together with the carbon to which they are attached form a cyclohexyl ring, which is substituted with OR 8 . 
     
     
         33 . The method according to  claim 26 , wherein each R 7  is independently C 1-6 alkyl, halogen, cyano, C 0-6 alkylC 3-6 cycloalkyl, C 1-6 haloalkyl, OC 1-6 alkyl or C 2-6 alkynyl, wherein:
 said C 1-6 alkyl, C 0-6 alkylC 3-6 cycloalkyl, C 1-6 haloalkyl, OC 1-6 alkyl or C 2-6 alkynyl is optionally substituted with 1-3 substituents independently selected from halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, OC 1-6 alkyl and OC 1-6 haloalkyl.   
     
     
         34 . The method according to  claim 26 , wherein R 8  is independently C 1-6 alkyl, C 2-6 alkynyl or C 1-6 haloalkyl. 
     
     
         35 . The method according to  claim 26 , wherein:
 A is —O— or —CH 2 —;   n is 0 or 1;   R 1  is C 1-6 alkyl;   R 2  is C 0-6 alkylaryl, C 0-6 alkylheteroaryl, C 2-6 alkynyl, halogen, NHC(O)R 9  or OR 8 ; wherein:   said C 0-6 alkylaryl, C 0-6 alkylheteroaryl or C 2-6 alkynyl is optionally substituted with one to three R 7 ;   
       as to R 5  and R 6 :
 R 5  and R 6  are independently hydrogen or heterocyclyl optionally substituted with one or two substituents independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano or OR 8 ; or 
 R 5  and R 6 , together with the carbon to which they are attached, form a ring B, wherein ring B is: 
 a 3-14 membered cycloalkyl or heterocyclyl monocyclic ring, or a 9-14 membered bicyclic cycloalkyl or heterocyclyl ring; optionally substituted by one or two substituents independently selected from oxo, halogen, C 1-6 alkyl or OR 8 ; and optionally fused with an aryl or heteroaryl to form a bi- or polycyclic system; 
 each R 7  is independently C 1-6 alkyl, halogen, cyano, C 0-6 alkylC 3-6 cycloalkyl, C 1-6 haloalkyl, OC 1-6 alkyl or C 2-6 alkynyl, wherein: 
 said C 1-6 alkyl, C 0-6 alkylC 3-6 cycloalkyl, C 1-6 haloalkyl, OC 1-6 alkyl or C 2-6 alkynyl is optionally substituted with 1-3 substituents independently selected from halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, OC 1-6 alkyl and OC 1-6 haloalkyl; 
 each R 8  is independently C 1-6 alkyl, C 2-6 alkynyl or C 1-6 haloalkyl, wherein: 
 said C 1-6 alkyl or C 1-6 haloalkyl is optionally substituted with a group selected from halogen, cyano or C 1-6 alkyl; and 
 R 9  is heteroaryl optionally substituted with halogen, cyano, OR 8 , C 1-6 haloalkyl or C 1-6 alkyl. 
 
     
     
         36 . The method according to  claim 26 , wherein:
 A is —O— or —CH 2 —;   n is 0 or 1;   R 1  is C 1-3 alkyl;   R 2  is aryl, heteroaryl, C 2-6 alkynyl, halogen, NHC(O)R 9  or OR 8 , wherein:   said aryl, heteroaryl or C 2-6 alkynyl is optionally substituted with one to three R 7 ;   
       as to R 5  and R 6 :
 R 5  and R 6  are independently hydrogen or heterocyclyl, wherein: 
 said heterocyclyl is optionally substituted with two substituents independently selected from C 1-6 alkyl; or 
 R 5  and R 6 , together with the carbon to which they are attached, form a ring B, wherein ring B is: 
 a 3-14 membered cycloalkyl or heterocyclyl monocyclic ring, or a 9-14 membered bicyclic cycloalkyl or heterocyclyl ring; optionally substituted by one or two substituents independently selected from oxo, halogen, C 1-6 alkyl or OR 8 ; and optionally fused with an aryl or heteroaryl to form a bicyclic system; 
 each R 7  is independently C 1-6 alkyl, halogen, cyano, C 0-6 alkylC 3-6 cycloalkyl, C 1-6 haloalkyl, OC 1-6 alkyl or C 2-6 alkynyl, wherein: 
 said C 1-6 alkyl, C 0-6 alkylC 3-6 cycloalkyl, C 1-6 haloalkyl, OC 1-6 alkyl or C 2-6 alkynyl is optionally substituted with 1-3 substituents independently selected from halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, OC 1-6 alkyl and OC 1-6 haloalkyl; 
 each R 8  is independently C 1-6 alkyl, C 2-6 alkynyl or C 1-6 haloalkyl, wherein: 
 said C 1-6 alkyl or C 1-6 haloalkyl is optionally substituted with a group selected from halogen, cyano or C 1-6 alkyl; and 
 R 9  is heteroaryl optionally substituted with halogen, cyano, OR 8 , C 1-6 haloalkyl or C 1-6 alkyl. 
 
     
     
         37 . The method according to  claim 26 , wherein said compound is selected from the group consisting of:
 6-(3,5-Dichlorophenyl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine;   6-(5-Chloropyridin-3-yl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine;   6-(3,5-Difluorophenyl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine;   6-(3,5-dimethylphenyl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine;   6-(2,5-dimethoxyphenyl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine;   6-(2,3-difluorophenyl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine;   6-(2, 5-dimethylphenyl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine;   6-(5-fluoro-2-methoxyphenyl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine;   6-(2-fluoro-3-methoxyphenyl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine;   6-(2-methoxy-5-methylphenyl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine;   6-(2-fluoro-5-methylphenyl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine;   6-(2-fluoro-5-methoxyphenyl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine;   N-(4′-amino-5′-methyl-spiro[chromane-4,2′-imidazole]-6-yl)-5-chloro-pyridine-2-carboxamide;   N-(4′-amino-5′-methyl-spiro[chromane-4,2′-imidazole]-6-yl)-5-(trifluoromethyl)pyridine-2-carboxamide;   N-(4′-amino-5′-methyl-spiro[chromane-4,2′-imidazole]-6-yl)-5-but-2-ynoxy-pyridine-2-carboxamide;   N-(4′-amino-5′-methyl-spiro[chromane-4,2′-imidazole]-6-yl)-5-but-2-ynoxy-pyrazine-2-carboxamide;   N-(4′-amino-5′-methyl-spiro[chromane-4,2′-imidazole]-6-yl)-5-methyl-thiophene-2-carboxamide;   N-(4′-amino-5′-methyl-spiro[chromane-4,2′-imidazole]-6-yl)-3,5-dichloro-pyridine-2-carboxamide;   6′-bromo-4-(difluoromethoxy)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   4-methoxy-5″-methyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   4-methoxy-5″-methyl-6′-[4-(prop-1-yn-1-yl)pyridin-2-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   5-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)benzene-1,3-dicarbonitrile;   3-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-chlorobenzonitrile;   6′-(5-chloropyridin-3-yl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   6′-(5-fluoropyridin-3-yl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   5-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-2-fluorobenzonitrile;   6′-(3,3-dimethylbut-1-yn-1-yl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   6′-(cyclopropylethynyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   N-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-bromopyrimidine-2-carboxamide;   N-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-(trifluoromethyl)pyridine-2-carboxamide;   N-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-chloro-3-methyl-1-benzofuran-2-carboxamide;   N-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-3,5-dichloropyridine-2-carboxamide;   N-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-chloropyridine-2-carboxamide;   4-methoxy-5″-methyl-6′-(2-methylpropoxy)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   4-methoxy-5″-methyl-6′-(3,3,3-trifluoropropoxy)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   6′-(3-fluoropropoxy)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   6′-bromo-5-methyl-2″,3″,5″,6″-tetrahydro-3′H-dispiro[imidazole-2, 1′-indene-2′,4″-pyran]-4-amine;   6′-(3-chlorophenyl)-5-methyl-2″,3″,5″,6″-tetrahydro-3′H-dispiro[imidazole-2, 1′-indene-2′,4″-pyran]-4-amine;   6′-(3-chloro-4-fluorophenyl)-5-methyl-2″,3″,5″,6″-tetrahydro-3′H-dispiro[imidazole-2,1′-indene-2′,4″-pyran]-4-amine;   6′-bromo-4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   6′-(5-chloropyridin-3-yl)-4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   N-(4″-amino-4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-chloropyridine-2-carboxamide;   5′-bromo-4-methoxy-5″-methyldispiro[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazol]-4″-amine;   5′-(3-chlorophenyl)-4-methoxy-5″-methyldispiro[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazol]-4″-amine;   6′-bromo-5-methyl-5″,6″-dihydro-4″H-dispiro[imidazole-2,4′-chromene-2′,3″-pyran]-4-amine;   6′-(3-chlorophenyl)-5-methyl-5″,6″-dihydro-4″H-dispiro[imidazole-2,4′-chromene-2′,3″-pyran]-4-amine;   6′-(3-chloro-4-fluorophenyl)-5-methyl-5″,6″-dihydro-4″H-dispiro[imidazole-2,4′-chromene-2′,3″-pyran]-4-amine;   6-bromo-5′-methyl-2-tetrahydropyran-3-yl-spiro[chromane-4,2′-imidazole]-4′-amine;   6-(3-chlorophenyl)-5′-methyl-2-(tetrahydro-2H-pyran-3-yl)-2,3-dihydrospiro[chromene-4,2′-imidazol]-4′-amine;   6-bromo-2-(2,2-dimethyltetrahydropyran-4-yl)-5′-methyl-spiro[chromane-4,2′-imidazole]-4′-amine;   6-(3-chlorophenyl)-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-5′-methyl-2,3-dihydrospiro[chromene-4,2′-imidazol]-4′-amine;   N-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-chloro-3-methylpyridine-2-carboxamide;   N-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-fluoropyridine-2-carboxamide;   4-methoxy-5″-methyl-6′-[2-(prop-1-yn-1-yl)pyridin-4-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   4-methoxy-5″-methyl-6′-[3-(prop-1-yn-1-yl)phenyl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   6′-(5-bromopyridin-3-yl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   4,4-difluoro-5″-methyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   5′-(5-chloropyridin-3-yl)-4-methoxy-5″-methyldispiro[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazol]-4″-amine;   4-methoxy-5″-methyl-5′-[5-(prop-1-yn-1-yl)pyridin-3-yl]dispiro[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazol]-4″-amine;   7′-bromo-5-methyl-3′,4′-dihydro-2′H-spiro[imidazole-2,1′-naphthalen]-4-amine;   7′-(5-chloropyridin-3-yl)-5-methyl-3′,4′-dihydro-2′H-spiro[imidazole-2, 1′-naphthalen]-4-amine;   5-methyl-7′-(5-(prop-1-ynyl)pyridin-3-yl)-3′,4′-dihydro-2′H-spiro[imidazole-2, 1′-naphthalen]-4-amine;   6′-bromo-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amine;   6′-(5-chloropyridin-3-yl)-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amine;   5″-methyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amine;   6′-(cyclopropylethynyl)-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amine;   6′-(3, 3-dimethylbut-1-yn-1-yl)-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amine;   6′-(5-chloro-6-methylpyridin-3-yl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   6′-(5-chloro-2-methylpyridin-3-yl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   4-methoxy-5″-methyl-6′-[4-methyl-5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   6′-bromo-5″-ethyl-4-methoxy-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   6′-(5-chloropyridin-3-yl)-5″-ethyl-4-methoxy-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   5″-ethyl-4-methoxy-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   5-(4″-amino-5″-ethyl-4-methoxy-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)pyridine-3-carbonitrile;   3-(4″-amino-5″-ethyl-4-methoxy-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)benzonitrile;   6′-[5-(but-1-yn-1-yl)pyridin-3-yl]-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   4″-amino-5″-methyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4-ol;   3-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-methylbenzonitrile;   3-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-fluorobenzonitrile;   6′-bromo-5″-methyl-3′H-dispiro[cyclopropane-1,2′-indene-1′,2″-imidazol]-4″-amine;   3-(4″-amino-5″-methyl-3′H-dispiro[cyclopropane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-chlorobenzonitrile;   4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-6′-carbonitrile;   4-methoxy-6′-[3-(methoxymethyl)phenyl]-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   6′-[3-fluoro-5-(methoxymethyl)phenyl]-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   4-methoxy-5″-methyl-6′-{5-[(2,2,2-trifluoroethoxy)methyl]pyridin-3-yl}-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   4-methoxy-5″-methyl-6′-(5-methylpyridin-3-yl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   4-methoxy-5″-methyl-6′-[5-(trifluoromethyl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   3-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-(trifluoromethyl)benzonitrile;   3-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-(difluoromethyl)benzonitrile;   5-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-2-fluoro-3-methoxybenzonitrile;   6′-(3,5-difluorophenyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   6′-(2-fluoro-3-methoxyphenyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   4-methoxy-5″-methyl-6′-phenyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   3-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-methoxybenzonitrile;   3-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-bromobenzonitrile;   3-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-ethylbenzonitrile;   3-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-(methoxymethyl)benzonitrile;   6′-(2-fluoro-5-methoxyphenyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   6′-(2,5-difluorophenyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   5-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-3-chloro-2-fluorobenzonitrile;   6′-(2,3-difluorophenyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   3-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-4-fluorobenzonitrile;   6′-(2,4-difluorophenyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   6′-(2,3-dichlorophenyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   3-(4″-amino-4-(difluoromethoxy)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-fluorobenzonitrile;   3-(4″-amino-4-(difluoromethoxy)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-methoxybenzonitrile;   4-(difluoromethoxy)-5″-methyl-6′-[5-(trifluoromethyl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   3-(4″-amino-4-(difluoromethoxy)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-chlorobenzonitrile;   4-(difluoromethoxy)-6′-(3,5-difluorophenyl)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   5-(4″-amino-4-(difluoromethoxy)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-2-fluoro-3-methoxybenzonitrile;   4-methoxy-4, 5″-dimethyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   6′-(cyclobutylethynyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   4-methoxy-5″-methyl-6′-(3-methylbut-1-yn-1-yl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   4-methoxy-5″-methyl-6′-{5-[( 2 H 3 )prop-1-yn-1-yl]pyridin-3-yl}-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   3-(4″-amino-5″-methyl-4-oxodispiro[cyclohexane-1,2′-[1H]indene-1′(3′H),2″-[2H]imidazol]-6′-yl)-5-fluorobenzonitrile;   4-methoxy-5″-methyl-6′-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   6′-bromo-5″-methyl-4-[( 2 H 3 )methyloxy]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   3-(4″-amino-5″-methyl-4-[( 2 H 3 )methyloxy]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-fluorobenzonitrile;   6′-(5-chloropyridin-3-yl)-5″-methyl-4-[( 2 H 3 )methyloxy]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   6′-[5-(difluoromethyl)pyridin-3-yl]-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   4-methoxy-5″-methyl-6′-(3-methyl-1H-indol-5-yl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   5″-methyl-4-[( 2 H 3 )methyloxy]-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   6′-[2-chloro-3-(prop-1-yn-1-yl)phenyl]-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   6′-bromo-5″-methyl-4-(trifluoromethyl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   3-(4″-amino-5″-methyl-4-[( 2 H 3 )methyloxy]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-chlorobenzonitrile;   6′-(cyclobutylmethoxy)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   5-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-2-fluoro-3-(methoxymethyl)benzonitrile;   6′-bromo-4-(difluoromethyl)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   6′-(5-chloropyridin-3-yl)-4-(difluoromethyl)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   6′-bromo-4-ethoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   4-ethoxy-5″-methyl-6′[5-(trifluoromethyl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   3-(4″-amino-4-ethoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-fluorobenzonitrile;   6′-(5-chloropyridin-3-yl)-4-ethoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;   3-(4″-amino-4-ethoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-(difluoromethyl)benzonitrile; and   4-ethoxy-5″-methyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine,   
       or a pharmaceutically acceptable salt of any foregoing compound. 
     
     
         38 . The method according to  claim 26 , wherein said compound is (1r, 1′R,4R)-4-methoxy-5″-methyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         39 . The method according to  claim 26 , wherein said compound is 3-[(1r,1′R,4R)-4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-chlorobenzonitrile: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         40 . A method of treating or reducing the risk of a disease or condition selected from hereditary cerebral hemorrhage, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as dementia of mixed vascular and degenerative origin, progressive supranuclear palsy, a disorder associated with cognitive impairment and traumatic brain injury, wherein said method comprises administering to a person suffering from, or at risk of, said disease or condition, a therapeutically effective amount of a compound which is (1r,1′R,4R)-4-methoxy-5″-methyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine: 
       
         
           
           
               
               
           
         
       
     
     
         41 . A method of treating or reducing the risk of a disease or condition selected from hereditary cerebral hemorrhage, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as dementia of mixed vascular and degenerative origin, progressive supranuclear palsy, a disorder associated with cognitive impairment and traumatic brain injury, wherein said method comprises administering to a person suffering from, or at risk of, said disease or condition, a therapeutically effective amount of a compound which is a pharmaceutically acceptable salt of (1r, 1′R,4R)-4-methoxy-5″-methyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine: