Substituted Isoindoles

Abstract

The present invention relates to novel 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 Downs 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 Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with diseases such as Alzheimer 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 . A compound according to formula (I) or a pharmaceutically acceptable salt thereof, wherein:
 formula (I) corresponds to:   
       
         
           
           
               
               
           
         
         R 1  is selected from halogen, cyano, NO 2 , SO 2 R 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NR 3 R 4 , OR 2 , C(O)R 2 , C(O)NR 3 R 4 , and COOR 2 , wherein:
 the C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with one or more R 7 ; 
 
         R 2  is selected from C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein:
 the C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with one or more R 7 ; 
 
         as to R 3  and R 4 :
 R 3  and R 4  are independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, heterocyclyl, and carbocyclyl, wherein:
 the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, heterocyclyl, or carbocyclyl is optionally substituted with one or more R 7 ; or 
 
 R 3  and R 4 , together with the atom to which they are attached, form a 4 to 7 membered ring; 
 
         Substituent A is selected from aryl and heteroaryl, wherein:
 the aryl or heteroaryl is optionally substituted with one or more R 5 ; 
 
         Substituent B is selected from aryl and heteroaryl, wherein:
 the aryl or heteroaryl is optionally substituted with one or more R 6 ; 
 
         Substituent C is selected from hydrogen, halogen, cyano, aryl, heteroaryl, heterocyclyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylC 3-6 cycloalkyl, C 1-6 alkylC 3-6 heterocyclyl, C 1-6 alkylaryl, C 1-6 alkylheteroaryl, and C 2-6 alkenylC 3-6 cycloalkyl, wherein:
 the aryl, heteroaryl, heterocyclyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylC 3-6 cycloalkyl, C 1-6 alkylC 3-6 heterocyclyl, C 1-6 alkylaryl, C 1-6 alkylheteroaryl, or C 2-6 alkenylC 3-6 cycloalkyl is optionally substituted with one to three R 7 ; 
 
         R 5  is selected from halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, OC 1-6 alkyl, and OC 1-6 alkylaryl, wherein:
 the C 1-6 alkyl, C 3-6 cycloalkyl, OC 1-6 alkyl, or OC 1-6 alkylaryl is optionally substituted with one to three R 7 ; 
 
         R 6  is selected from halogen, hydroxy, and cyano; 
         R 7  is selected from halogen, C 1-6 alkyl, SO 2 C 1-3 alkyl, OC 1-3 alkyl, OC 1-3 haloalkyl, C 1-3 alkylOH, C 1-3 alkylNR 8 R 9 , OH, cyano, C(O)OC 1-3 alkyl, and NR 8 R 9 , wherein:
 the C 1-6 alkyl, SO 2 C 1-3 alkyl, OC 1-3 alkyl, OC 1-3 haloalkyl, C 1-3 alkylOH, C 1-3 alkylNR 8 R 9 , or C(O)OC 1-3 alkyl is optionally substituted with one or more R 10 ; 
 
         as to R 8  and R 9 :
 R 8  and R 9  are independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 alkylNR 11 R 12 , C 1-3 alkylOaryl, heteroaryl, heterocyclyl, and carbocyclyl, wherein:
 the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 alkylNR 11 R 12 , C 1-3 alkylOaryl, heteroaryl, heterocyclyl, or carbocyclyl is optionally substituted with one or more R 10 ; or 
 
 R 8  and R 9 , together with the atom to which they are attached, form a 4 to 6 membered ring; 
 R 10  is selected from halo, C 1-3 alkyl, OC 1-3 alkyl, and OC 1-3 haloalkyl; 
 
         R 11  and R 12  are independently selected from hydrogen, C 1-3 alkyl, and C 1-3 haloalkyl;
 m is selected from 0, 1, and 2; and 
 when Substituent C is C 1-6 alkyl, then R 7  is not OC 1-3 alkyl or OC 1-3 haloalkyl. 
 
       
     
     
         2 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein:
 R 1  is selected from halogen, cyano, NO 2 , SO 2 R 2 , C 1-6 alkyl, NR 3 R 4 , OR 2 , C(O)R 2 , C(O)NR 3 R 4 , and COOR 2 , wherein:
 the C 1-6 alkyl is optionally substituted with one or more R 7 ; 
   as to R 3  and R 4 :
 R 3  and R 4  are independently selected from hydrogen, C 1-6 alkyl, aryl, heteroaryl, heterocyclyl, and carbocyclyl, wherein:
 the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, heterocyclyl, or carbocyclyl is optionally substituted with one or more R 7 ; or 
 
 R 3  and R 4 , together with the atom to which they are attached, form a 4 to 7 membered ring; 
   Substituent C is selected from halogen, cyano, aryl, heteroaryl, heterocyclyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylC 3-6 cycloalkyl, C 1-6 alkylC 3-6 heterocyclyl, C 1-6 alkylaryl, C 1-6 alkylheteroaryl, and C 2-6 alkenylC 3-6 cycloalkyl, wherein:
 the aryl, heteroaryl, heterocyclyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylC 3-6 cycloalkyl, C 1-6 alkylC 3-6 heterocyclyl, C 1-6 alkylaryl, C 1-6 alkylheteroaryl, or C 2-6 alkenylC 3-6 cycloalkyl is optionally substituted with one to three R 7 ; and 
   as to R 8  and R 9 :
 R 8  and R 9  are independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-3 alkylNR 11 R 12 , C 1-3 alkylOaryl, heteroaryl, heterocyclyl, and carbocyclyl, wherein:
 the C 1-6 alkyl, C 1-6 haloalkyl, C 1-3 alkylNR 11 R 12 , C 1-3 alkylOaryl, heteroaryl, heterocyclyl, or carbocyclyl is optionally substituted with one or more R 10 ; or 
 
 R 8  and R 9 , together with the atom to which they are attached, form a 4 to 6 membered ring. 
   
     
     
         3 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein:
 R 1  is selected from halogen, cyano, NO 2 , SO 2 R 2 , NR 3 R 4 , OR 2 , C(O)R 2 , and COOR 2 , wherein:
 the C 1-6 alkyl is optionally substituted with one or more R 7 ; 
   R 2  is C 1-6 alkyl optionally substituted with one or more R 7 ;   R 3  and R 4  are independently selected from hydrogen, C 1-6 alkyl, aryl, heteroaryl, heterocyclyl, and carbocyclyl, wherein:
 the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, heterocyclyl, or carbocyclyl is optionally substituted with one or more R 7 ; 
   Substituent C is selected from halogen, cyano, aryl, heteroaryl, heterocyclyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 1-6 alkyl, C 1-6 alkylC 3-6 cycloalkyl, C 1-6 alkylC 3-6 heterocyclyl, C 1-6 alkylaryl, and C 1-6 alkylheteroaryl, wherein:
 the aryl, heteroaryl, heterocyclyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 1-6 alkyl, C 1-6 alkylC 3-6 cycloalkyl, C 1-6 alkylC 3-6 heterocyclyl, C 1-6 alkylaryl, or C 1-6 alkylheteroaryl is optionally substituted with one to three R 7 ; 
   R 6  is selected from halogen and hydroxy;   R 7  is selected from halogen, C 1-6 alkyl, SO 2 C 1-3 alkyl, OC 1-3 alkyl, OC 1-3 haloalkyl, C 1-3 alkylOH, cyano, C(O)OC 1-3 alkyl, and NR 8 R 9 , wherein:
 the C 1-6 alkyl, SO 2 C 1-3 alkyl, OC 1-3 alkyl, OC 1-3 haloalkyl, C 1-3 alkylOH, or C(O)OC 1-3 alkyl is optionally substituted with one or more R 10 ; 
   R 8  and R 9  are independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-3 alkylNR 11 R 12 , C 1-3 alkylOaryl, heteroaryl, heterocyclyl, and carbocyclyl, wherein:
 the C 1-6 alkyl, C 1-6 haloalkyl, C 1-3 alkylNR 11 R 12 , C 1-3 alkylOaryl, heteroaryl, heterocyclyl, or carbocyclyl is optionally substituted with one or more R 10 ; and 
   m is selected from 0 and 1.   
     
     
         4 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein Substituent A is heteroaryl. 
     
     
         5 . A compound or pharmaceutically acceptable salt thereof according to  claim 4 , wherein Substituent A is selected from pyridyl and pyrimidyl. 
     
     
         6 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein Substituent A is aryl. 
     
     
         7 . A compound or pharmaceutically acceptable salt thereof according to  claim 6 , wherein Substituent A is phenyl. 
     
     
         8 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein Substituent A is selected from aryl and heteroaryl. 
     
     
         9 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein Substituent A is selected from aryl and heteroaryl, wherein:
 the aryl or heteroaryl is substituted with one or more R 5 .   
     
     
         10 . A compound or pharmaceutically acceptable salt thereof according to  claim 9 , wherein R 5  is selected from cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and OC 1-6 alkyl, wherein:
 the C 1-6 alkyl is optionally substituted with one to three R 7 .   
     
     
         11 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein Substituent B is aryl. 
     
     
         12 . A compound or pharmaceutically acceptable salt thereof according to  claim 11 , wherein Substituent B is phenyl. 
     
     
         13 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein Substituent B is pyridyl. 
     
     
         14 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein Substituent B is selected from aryl and heteroaryl, wherein:
 the aryl or heteroaryl is optionally substituted with one or two fluoro atoms and/or one hydroxy group.   
     
     
         15 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein Substituent C is selected from halogen, cyano, aryl, heteroaryl, C 3-6 cycloalkyl, C 1-6 alkyl, C 1-6 alkylC 3-6 cycloalkyl, C 1-6 alkylC 3-6 heterocyclyl, C 1-6 alkylaryl, and C 1-6 alkylheteroaryl, wherein:
 the aryl, heteroaryl, C 3-6 cycloalkyl, C 1-6 alkyl, C 1-6 alkylC 3-6 cycloalkyl, C 1-6 alkylC 3-6 heterocyclyl, C 1-6 alkylaryl, or C 1-6 alkylheteroaryl is optionally substituted with one to three R 7 .   
     
     
         16 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein Substituent C is selected from aryl and heteroaryl. 
     
     
         17 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein Substituent C is selected from pyrimidyl and pyridyl. 
     
     
         18 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein Substituent C is selected from aryl, heteroaryl, heterocyclyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylC 3-6 cycloalkyl, C 1-6 alkylC 3-6 heterocyclyl, C 1-6 alkylaryl, C 1-6 alkylheteroaryl, and C 2-6 alkenylC 3-6 cycloalkyl, wherein:
 the aryl, heteroaryl, heterocyclyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkenyl, C 1-6 alkylC 3-6 cycloalkyl,   C 1-6 alkylC 3-6 heterocyclyl, C 1-6 alkylaryl, C 1-6 alkylheteroaryl, or   C 2-6 alkenylC 3-6 cycloalkyl is substituted with one to three R 7 .   
     
     
         19 . A compound or pharmaceutically acceptable salt thereof according to  claim 18 , wherein R 7  is selected from halogen, C 1-6 alkyl, SO 2 C 1-3 alkyl, OC 1-3 alkyl, OC 1-3 haloalkyl, and cyano. 
     
     
         20 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein:
 Substituent C is selected from aryl and heteroaryl, wherein:
 the aryl or heteroaryl is optionally substituted with one to three R 7 ; 
   R 5  is selected from halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and OC 1-6 alkyl, wherein:
 the C 1-6 alkyl is optionally substituted with one R 7 ; 
   R 6  is selected from halogen and hydroxy;   R 7  is selected from halogen, C 1-6 alkyl, SO 2 C 1-3 alkyl, OC 1-3 alkyl, OC 1-3 haloalkyl, and cyano; and   m is 0.   
     
     
         21 . A compound or pharmaceutically acceptable salt thereof according to  claim 20 , wherein Substituent A is selected from pyridyl, pyrimidyl, and phenyl. 
     
     
         22 . A compound or pharmaceutically acceptable salt thereof according to  claim 20 , wherein:
 Substituent A is heteroaryl substituted with one R 5 ;   Substituent B is aryl; and   Substituent C is heteroaryl.   
     
     
         23 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein:
 the compound corresponds to formula (Ia):   
       
         
           
           
               
               
           
         
         R 1  is selected from phenyl, pyridyl, pyrimidinyl, (phenyl)phenyl, (pyridyl)phenyl, (pyrazin)phenyl, and (pyrimidinyl)phenyl, wherein:
 all such groups are optionally and independently substituted with one to three R′ groups; 
 
         R 2  is selected from hydrogen, C 3-6 cycloalkyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, pyridyl, pyrimidinyl, and phenyl, wherein:
 the phenyl, pyridyl, and pyrimidinyl are optionally and independently substituted with one to three substituents selected from R′ groups, hydroxy, SO 2 C 1-6 alkyl, and C 3-6 cycloalkyl; 
 
         R′ is selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, cyano, and cyanomethyl; 
         Y is selected from N, CH, and CF; and 
         X 1  and X 2  are independently selected from hydrogen, chloro, and fluoro. 
       
     
     
         24 . A compound or pharmaceutically acceptable salt thereof according to  claim 23 , wherein:
 R 1  is selected from phenyl, 4-pyridyl, 3-pyridyl, 2-pyridyl, pyrimidin-5-yl, pyrimidin-4-yl, 3-(phenyl)phenyl, 3-(2-pyridyl)phenyl, 3-(3-pyridyl)phenyl, 3-pyrazin-2-ylphenyl, 3-pyrimidin-5-yl-phenyl, and 3-pyrazin-2-yl-phenyl, wherein:
 all such groups are optionally and independently substituted with one to three substituents selected from R′ groups, hydroxy, SO 2 C 1-6 alkyl, and C 3-6 cycloalkyl; and 
   R 2  is selected from hydrogen, C 3-6 cycloalkyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, 3-pyridyl, pyrimidin-5-yl, phenyl, and 2-pyridyl, wherein:
 the phenyl, pyridyl, and pyrimidinyl are optionally and independently substituted with one to three R′ groups. 
   
     
     
         25 . A compound or pharmaceutically acceptable salt thereof according to  claim 23 , wherein:
 R 1  is selected from 4-methoxyphenyl, 2,6-dimethyl-4-pyridyl, 2-(difluoromethyl)-6-methyl-4-pyridyl, 3-cyano-4-methoxy-phenyl, 3-(cyanomethyl)-4-methoxy-5-methyl-phenyl, 6-methoxy-5-(trifluoromethyl)-3-pyridyl, 3-cyano-4-methoxy-5-methyl-phenyl, 2-(trifluoromethyl)-4-pyridyl, 4-pyridyl, pyrimidin-5-yl, 2-methoxy-4-pyridyl, 2-methyl-4-pyridyl, 2-(difluoromethyl)-4-pyridyl, 2-cyclopropyl-4-pyridyl, 3-(2-fluoro-3-methoxy-phenyl)phenyl, 3-(3-chlorophenyl)phenyl, 3-(4-cyano-2-pyridyl)phenyl, 3-(4-methoxy-2-pyridyl)phenyl, 3-(5-cyano-3-pyridyl)phenyl, 3-(5-fluoro-3-pyridyl)phenyl, 3-fluoro-4-methoxy-5-methyl-phenyl, 3-pyrazin-2-ylphenyl, 3-pyrimidin-5-ylphenyl, 4-hydroxy-3-pyrazin-2-yl-phenyl, 4-methoxy-3,5-dimethyl-phenyl, 4-methoxy-3-pyrimidin-5-yl-phenyl, 5-(difluoromethoxy)-4,6-dimethyl-2-pyridyl, 3,4-difluoro-5-methoxyphenyl 2,6-dimethylpyrimidin-4-yl, and 5-methoxy-4,6-dimethyl-2-pyridyl; and   R 2  is selected from hydrogen, cyclopropyl, difluoromethyl, methoxy, trifluoromethyl, 5-cyano-3-pyridyl, pyrimidin-5-yl, 2-fluoro-3-methoxy-phenyl, 4-methoxy-2-pyridyl, 5-methylsulfonyl-3-pyridyl, 5-fluoro-3-pyridyl, and 3-pyridyl.   
     
     
         26 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein:
 the compound corresponds to formula (Ib):   
       
         
           
           
               
               
           
         
         R 1  is 4-pyridyl optionally substituted with one R′ group; 
         R 2  is pyrimidin-5-yl optionally substituted with one R′ group; and 
         R′ is selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, cyano, and cyanomethyl. 
       
     
     
         27 . A compound or pharmaceutically acceptable salt thereof according to  claim 26 , wherein:
 R 1  is selected from 2-(trifluoromethyl)-4-pyridyl and 2-methyl-4-pyridyl; and   R 2  is pyrimidin-5-yl.   
     
     
         28 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein:
 the compound corresponds to formula (Ic):   
       
         
           
           
               
               
           
         
         R 1  is selected from phenyl, pyridyl, and pyrimidinyl, wherein:
 all such groups are optionally and independently substituted with one to three substituents selected from R′ groups and SO 2 C 1-6 alkyl; 
 
         R 2  is selected from pyridyl and pyrimidinyl, wherein:
 both such groups are optionally and independently substituted with one to three R′ groups; and 
 
         R′ is selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, cyano, and cyanomethyl. 
       
     
     
         29 . A compound or pharmaceutically acceptable salt thereof according to  claim 28 , wherein:
 R 1  is selected from phenyl, 4-pyridyl, 2-pyridyl, pyrimidin-4-yl, and 3-pyridyl, wherein:
 all such groups are optionally and independently substituted with one to three substituents selected from R′ groups and SO 2 C 1-6 alkyl; 
   R 2  is selected from 3-pyridyl and pyrimidin-5-yl, wherein:
 both such groups are optionally and independently substituted with one to three R′ groups; and 
   R′ is selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, cyano, and cyanomethyl.   
     
     
         30 . A compound or pharmaceutically acceptable salt thereof according to  claim 28 , wherein:
 R 1  is selected from 4-methoxyphenyl, 2,6-dimethyl-4-pyridyl, 2-(difluoromethyl)-6-methyl-4-pyridyl, 3-cyano-4-methoxy-phenyl, 5-methoxy-4,6-dimethyl-2-pyridyl, 2,6-dimethylpyrimidin-4-yl, 3-(cyanomethyl)-4-methoxy-5-methyl-phenyl, 6-methoxy-5-(trifluoromethyl)-3-pyridyl, and 3-cyano-4-methoxy-5-methyl-phenyl; and   R 2  is selected from 5-cyano-3-pyridyl and pyrimidin-5-yl.   
     
     
         31 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein:
 the compound corresponds to formula (Id):   
       
         
           
           
               
               
           
         
         R 1  is selected from pyridyl, pyrimidinyl, and (pyrimidin)phenyl, wherein:
 all such groups are optionally and independently substituted with one to three R′ groups; 
 
         R 2  is selected from pyrimidinyl, phenyl, pyridyl, and methoxy, wherein:
 the pyrimidinyl, phenyl, and pyridyl are optionally and independently substituted with one to three R′ groups; and 
 
         R′ is selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, cyano, and cyanomethyl. 
       
     
     
         32 . A compound or pharmaceutically acceptable salt thereof according to  claim 31 , wherein:
 R 1  is selected from 4-pyridyl, pyrimidin-5-yl, and 3-pyrimidin-5-ylphenyl, wherein:
 all such groups are optionally and independently substituted with one to three R′ groups; 
   R 2  is selected from pyrimidin-5-yl, phenyl, 2-pyridyl, 3-pyridyl, and methoxy, wherein:
 the pyrimidin-5-yl, phenyl, 2-pyridyl, and 3-pyridyl are optionally and independently substituted with one to three R′ groups; and 
   R′ is selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, cyano, and cyanomethyl.   
     
     
         33 . A compound or pharmaceutically acceptable salt thereof according to  claim 32 , wherein:
 R 1  is selected from 2-(trifluoromethyl)-4-pyridyl, 4-pyridyl, pyrimidin-5-yl, 2-methoxy-4-pyridyl, and 3-pyrimidin-5-ylphenyl; and   R 2  is selected from pyrimidin-5-yl, 2-fluoro-3-methoxy-phenyl, 4-methoxy-2-pyridyl, 5-cyano-3-pyridyl, and methoxy.   
     
     
         34 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein:
 the compound corresponds to formula (Ie):   
       
         
           
           
               
               
           
         
         R 1  is pyridyl optionally substituted with one to three R′ groups; 
         R 2  is selected from pyrimidinyl and pyridyl, wherein:
 both such groups are optionally substituted with one to three R′ groups; and 
 
         R′ is selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, cyano, and cyanomethyl. 
       
     
     
         35 . A compound or pharmaceutically acceptable salt thereof according to  claim 34 , wherein:
 R 1  is 4-pyridyl optionally substituted with one to three R′ groups;   R 2  is selected from pyrimidin-5-yl and 3-pyridyl, wherein:
 both such groups are optionally substituted with one to three R′ groups; and 
   R′ is selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, cyano, and cyanomethyl.   
     
     
         36 . A compound or pharmaceutically acceptable salt thereof according to  claim 34 , wherein:
 R 1  is selected from 2-methyl-4-pyridyl and 2-(trifluoromethyl)-4-pyridyl; and   R 2  is selected from pyrimidin-5-yl, 5-methylsulfonyl-3-pyridyl, 5-cyano-3-pyridyl, 5-fluoro-3-pyridyl, and 3-pyridyl.   
     
     
         37 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein:
 the compound corresponds to formula (If):   
       
         
           
           
               
               
           
         
         R 1  is selected from pyridyl, (phenyl)phenyl, (pyridyl)phenyl, phenyl, pyrazinylphenyl, and pyrimidinylphenyl, wherein:
 all such groups are optionally and independently substituted by one to three R′ groups; 
 
         R 2  is selected from hydrogen, pyridyl, C 3-6 cycloalkyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, difluoromethyl, methoxy, pyrimidinyl, and trifluoromethyl, wherein:
 the pyridyl and pyrimidinyl are optionally and independently substituted by one to three R′ groups; and 
 
         R′ is selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, cyano, and cyanomethyl. 
       
     
     
         38 . A compound or pharmaceutically acceptable salt thereof according to  claim 37 , wherein:
 R 1  is selected from pyridyl, (phenyl)phenyl, (pyridyl)phenyl, phenyl, pyrazinylphenyl, and pyrimidinylphenyl, wherein:
 all such groups are optionally and independently substituted by one to three R′ groups; 
   R 2  is selected from hydrogen, pyridyl, cyclopropyl, difluoromethyl, methoxy, pyrimidinyl, and trifluoromethyl, wherein:
 the pyridyl and pyrimidinyl are optionally and independently substituted by one to three R′ groups; and 
   R′ is selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, cyano, and cyanomethyl.   
     
     
         39 . A compound or pharmaceutically acceptable salt thereof according to  claim 37 , wherein:
 R 1  is selected from 4-pyridyl, 3-(phenyl)phenyl, 3-(2-pyridyl)phenyl, 3-(3-pyridyl)phenyl, phenyl, 3-pyrazin-2-ylphenyl, 3-pyrimidin-5-ylphenyl, and 2-pyridyl, wherein:
 all such groups are optionally and independently substituted by one to three R′ groups; 
   R 2  is selected from hydrogen, 3-pyridyl, cyclopropyl, difluoromethyl, methoxy, pyrimidin-5-yl, and trifluoromethyl, wherein:
 the 3-pyridyl and pyrimidin-5-yl are optionally and independently substituted by one to three R′ groups; and 
   R′ is selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, cyano, and cyanomethyl.   
     
     
         40 . A compound or pharmaceutically acceptable salt thereof according to  claim 37 , wherein:
 R 1  is selected from 2-(difluoromethyl)-4-pyridyl, 2-(difluoromethyl)-6-methyl-4-pyridyl, 2-cyclopropyl-4-pyridyl, 3-(2-fluoro-3-methoxy-phenyl)phenyl, 3-(3-chlorophenyl)phenyl, 3-(4-cyano-2-pyridyl)phenyl, 3-(4-methoxy-2-pyridyl)phenyl, 3-(5-cyano-3-pyridyl)phenyl, 3-(5-fluoro-3-pyridyl)phenyl, 3-fluoro-4-methoxy-5-methyl-phenyl, 3-pyrazin-2-ylphenyl, 3-pyrimidin-5-ylphenyl, 4-hydroxy-3-pyrazin-2-yl-phenyl, 4-methoxy-3,5-dimethyl-phenyl, 4-methoxy-3-pyrimidin-5-yl-phenyl, 5-(difluoromethoxy)-4,6-dimethyl-2-pyridyl, and 5-methoxy-4,6-dimethyl-2-pyridyl;   R 2  is selected from hydrogen, 5-fluoro-3-pyridyl, cyclopropyl, difluoromethyl, methoxy, pyrimidin-5-yl, and trifluoromethyl.   
     
     
         41 . A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
 4-Fluoro-1-(2-fluoro-5-(pyrimidin-5-yl)phenyl)-1-(2-methylpyridin-4-yl)-1H-isoindol-3-amine;   5-(3-(3-Amino-4-fluoro-1-(2-methylpyridin-4-yl)-1H-isoindol-1-yl)-4-fluorophenyl)nicotinonitrile;   4-Fluoro-1-(2-fluoro-5-(5-fluoropyridin-3-yl)phenyl)-1-(2-methylpyridin-4-yl)-1H-isoindol-3-amine;   4-Fluoro-1-(2-fluoro-5-(pyridin-3-yl)phenyl)-1-(2-methylpyridin-4-yl)-1H-isoindol-3-amine;   4-Fluoro-1-(2-fluoro-5-(pyrimidin-5-yl)phenyl)-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine;   5-(3-(3-Amino-4-fluoro-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-1-yl)-4-fluorophenyl)nicotinonitrile;   4-Fluoro-1-(2-fluoro-5-(5-(methylsulfonyl)pyridin-3-yl)phenyl)-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine;   1-(3′-Chlorobiphenyl-3-yl)-4-fluoro-1-(pyridin-4-yl)-1H-isoindol-3-amine;   4-Fluoro-1-(pyridin-4-yl)-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine;   (R) and (S) 4-Fluoro-1-(pyridin-4-yl)-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine,   4-Fluoro-1-(4-fluoro-3-(pyrimidin-5-yl)phenyl)-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine;   (R) and (S) 4-Fluoro-1-(4-fluoro-3-(pyrimidin-5-yl)phenyl)-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine;   4-Fluoro-1-(2′-fluoro-3′-methoxybiphenyl-3-yl)-1-(pyridin-4-yl)-1H-isoindol-3-amine;   4-Fluoro-1-(3-(5-fluoropyridin-3-yl)phenyl)-1-(pyridin-4-yl)-1H-isoindol-3-amine;   4-Fluoro-1-(4-fluoro-3-(pyrimidin-5-yl)phenyl)-1-(pyridin-4-yl)-1H-isoindol-3-amine;   4-Fluoro-1-(4-methoxyphenyl)-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine;   1-(2′,6-Difluoro-3′-methoxybiphenyl-3-yl)-4-fluoro-1-(pyrimidin-5-yl)-1H-isoindol-3-amine;   4-Fluoro-1-(4-fluoro-3-(4-methoxypyridin-2-yl)phenyl)-1-(pyrimidin-5-yl)-1H-isoindol-3-amine;   4-Fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine;   1-(2′,6-Difluoro-3′-methoxybiphenyl-3-yl)-4-fluoro-1-(pyrimidin-5-yl)-1H-isoindol-3-amine;   5-(3-(3-Amino-1-(2,6-dimethylpyridin-4-yl)-4-fluoro-1H-isoindol-1-yl)phenyl)nicotinonitrile;   5-(3-(3-Amino-4-fluoro-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-1-yl)phenyl)nicotinonitrile;   4-Fluoro-1-(4-fluoro-3-(pyrimidin-5-yl)phenyl)-1-(2-methoxypyridin-4-yl)-1H-isoindol-3-amine;   5-(5-(3-Amino-4-fluoro-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-1-yl)-2-fluorophenyl)nicotinonitrile;   5-(5-(3-Amino-4-fluoro-1-(pyridin-4-yl)-1H-isoindol-1-yl)-2-fluorophenyl)nicotinonitrile;   4-Fluoro-1-(2-methoxypyridin-4-yl)-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine;   5-(3-(3-amino-4-fluoro-1-(2-methoxypyridin-4-yl)-1H-isoindol-1-yl)phenyl)nicotinonitrile;   4-Fluoro-1-(2-methoxypyridin-4-yl)-1-(3-(pyrazin-2-yl)phenyl)-1H-isoindol-3-amine;   4-Fluoro-1-(3-(pyrazin-2-yl)phenyl)-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine;   1-(2-Cyclopropylpyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine;   1-(2-(Difluoromethyl)-6-methylpyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine;   1-(2-(Difluoromethyl)-6-methylpyridin-4-yl)-4-fluoro-1-(2-(pyrimidin-5-yl)pyridin-4-yl)-1H-isoindol-3-amine;   4-Fluoro-1-(3-fluoro-4-methoxy-5-methylphenyl)-1-(2-(pyrimidin-5-yl)pyridin-4-yl)-1H-isoindol-3-amine;   4-Fluoro-1-(4-methoxy-3,5-dimethylphenyl)-1-(2-(pyrimidin-5-yl)pyridin-4-yl)-1H-isoindol-3-amine;   4-Fluoro-1-(5-methoxy-4,6-dimethylpyridin-2-yl)-1-(2-(pyrimidin-5-yl)pyridin-4-yl)-1H-isoindol-3-amine;   1-(2-Cyclopropylpyridin-4-yl)-4-fluoro-1-(3-(pyrazin-2-yl)phenyl)-1H-isoindol-3-amine trifluoroacetate;   4-Fluoro-1-(3-(4-methoxypyridin-2-yl)phenyl)-1-(2-methoxypyridin-4-yl)-1H-isoindol-3-amine;   2-(3-(3-Amino-4-fluoro-1-(2-methoxypyridin-4-yl)-1H-isoindol-1-yl)phenyl)isonicotinonitrile;   1-(2-(Difluoromethyl)pyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine;   (R) and (S) 1-(2-(Difluoromethyl)pyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine;   1-(2-(Difluoromethyl)pyridin-4-yl)-4-fluoro-1-(2-(pyrimidin-5-yl)pyridin-4-yl)-1H-isoindol-3-amine;   5-(3-Amino-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-1-yl)-2-methoxybenzonitrile;   4-Fluoro-1-(5-methoxy-4,6-dimethylpyridin-2-yl)-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine;   1-(2,6-Dimethylpyrimidin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine;   1-(3,4-Difluoro-5-methoxyphenyl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine;   2-(5-(3-Amino-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-1-yl)-2-methoxy-3-methylphenyl)acetonitrile;   4-Fluoro-1-(4-fluoro-3-methoxyphenyl)-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine;   4-Fluoro-1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine;   4-(3-Amino-4-fluoro-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-1-yl)-2-(pyrazin-2-yl)phenol;   4-Fluoro-1-(4-methoxy-3-(pyrimidin-5-yl)phenyl)-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine;   1-(2-Cyclopropylpyridin-4-yl)-4-fluoro-1-(2-(pyrimidin-5-yl)pyridin-4-yl)-1H-isoindol-3-amine;   3-(5-Difluoromethoxy-4,6-dimethyl-pyridin-2-yl)-7-fluoro-3-(5′-fluoro-[2,3]bipyridinyl-4-yl)-3H-isoindol-1-ylamine;   5-(3-Amino-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-1-yl)-2-methoxy-3-methylbenzonitrile;   6-Chloro-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine; and   6-Chloro-4-fluoro-1-(2-methylpyridin-4-yl)-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine.   
     
     
         42 . A pharmaceutical composition comprising, wherein the composition comprises:
 a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof according to  claim 1 ; and   a pharmaceutically acceptable excipient, carrier, or diluent.   
     
     
         43 - 46 . (canceled) 
     
     
         47 . A method of treating or preventing an Aβ-related pathology in a mammal, wherein the method comprises administering to the mammal a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof according to  claim 1 . 
     
     
         48 . The method of  claim 47 , wherein the Aβ-related pathology is selected from Downs syndrome, a β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, mild cognitive impairment, Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy, and cortical basal degeneration. 
     
     
         49 . A method of treating or preventing Alzheimer's Disease in a mammal, wherein the method comprises administering to the mammal a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof according to  claim 1 . 
     
     
         50 . The method of  claim 48 , wherein the mammal is a human. 
     
     
         51 . A method of treating or preventing an Aβ-related pathology in a mammal, wherein the method comprises administering to the mammal:
 a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof according to  claim 1 ; and 
 a cognitive enhancing agent, memory enhancing agent, or choline esterase inhibitor.