New Compounds

Abstract

This invention relates to novel compounds having the structural formula I below: and to their pharmaceutically acceptable salt, compositions and methods of use. These novel compounds provide a treatment or prophylaxis of cognitive impairment, Alzheimer Disease, neurodegeneration and dementia.

1 . A compound of Formula I 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from hydrogen, nitro, cyano, -Q-C 1-6 alkyl, -Q-C 2-6 alkenyl, -Q-C 2-6 alkynyl, -Q-C 3-6 cycloalkyl, -Q-C 5-7 cycloalkenyl, -Q-C 1-6 alkylC 3-6 cycloalkyl, -Q-aryl, -Q-heteroaryl, -Q-C 1-6 alkylaryl, -Q-C 1-6 alkylheteroaryl, -Q-heterocyclyl, and -Q-C 1-6 alkylheterocyclyl, wherein said -Q-C 1-6 alkyl, -Q-C 2-6 alkenyl, -Q-C 2-6 alkynyl, -Q-C 3-6 cycloalkyl, -Q-C 5-7 cycloalkenyl, -Q-C 1-6 alkylC 3-6 cycloalkyl, -Q-aryl, -Q-heteroaryl, -Q-C 1-6 alkylaryl, -Q-C 1-6 alkylheteroaryl, -Q-heterocyclyl, or -Q-C 1-6 alkylheterocyclyl is optionally substituted by one, two or three R 7 ; 
         R 2  is (C(R 4 )(R 5 )) n R 6 , C 2-4 alkenylR 6 , C 2-4 alkynylR 6 , C 5-7 cycloalkenylR 6 , nitro or cyano and if n>1 then each C(R 4 )(R 5 ) is independent of the others; 
         R 3  is independently selected from hydrogen, halogen, C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl, C 5-7 cycloalkenyl, aryl, heteroaryl, heterocyclyl, C 1-6 alkylC 3-6 cycloalkyl, C 1-6 alkylaryl, C 1-6 alkylheteroaryl and C 1-6 alkylheterocyclyl, wherein said C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl, C 5-7 cycloalkenyl, aryl, heteroaryl, heterocyclyl, C 1-6 alkylC 3-6 cycloalkyl, C 1-6 alkylaryl, C 1-6 alkylheteroaryl or C 1-6 alkylheterocyclyl is optionally substituted with one, two or three A; 
         -Q- is a direct bond, —CONH—, —CO—, —CON(C 1-6 alkyl)-, —CON(C 3-6 cycloalkyl)-, —SO—, —SO 2 —, —SO 2 NH—, —SO 2 N(C 1-6 alkyl)-, —SO 2 N(C 3-6 cycloalkyl)-, —NHSO 2 —, —N(C 1-6 alkyl)SO 2 —, —NHCO—, —N(C 1-6 alkyl)CO—, —N(C 3-6 cycloalkyl)CO— or —N(C 3-6 cycloalkyl)SO 2 —; 
         R 4  and R 5  are independently selected from hydrogen, C 1-6 alkyl, cyano, halo or nitro; or R 4  and R 5  together form oxo, C 3-6 cycloalkyl or heterocyclyl; 
         R 6  is selected from methyl, C 3-6 cycloalkyl, heterocyclyl, aryl and heteroaryl wherein each of said methyl, C 3-6 cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with between one and four R 7 , and wherein any of the individual aryl or heteroaryl groups may be optionally fused with a 4, 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclyl group to form a bicyclic ring system where the bicyclic ring system is optionally substituted with between one and four A; 
         R 7  is independently selected from halogen, nitro, CHO, C 0-6 alkylCN, OC 1-6 alkylCN, C 0-6 alkylOR 8 , OC 2-6 alkylOR 8 , hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, C 0-6 alkylNR 8 R 9 , OC 2-6 alkylNR 8 R 9 , OC 2-6 alkylOC 2-6 alkylNR 8 R 9 , NR 8 OR 9 , C 0-6 alkylCO 2 R 8 , OC 1-6 alkylCO 2 R 8 , C 0-6 alkylCONR 8 R 9 , OC 1-6 alkylCONR 8 R 9 , OC 2-6 alkylNR 8 (CO)R 9 , C 0-6 alkylNR 8  (CO)R 9 , O(CO)NR 8 R 9 , NR 8 (CO)OR 9 , NR 8 (CO)NR 8 R 9 , O(CO)OR 8 , O(CO)R 8 , C 0-6 alkylCOR 8 , OC 1-6 alkylCOR 8 , NR 8 (CO)(CO)R 8 , NR 8 (CO)(CO)NR 8 R 9 , C 0-6 alkylSR 8 , C 0-6 alkyl(SO 2 )NR 8 R 9 , OC 1-6 alkylNR 8 (SO 2 )R 9 , OC 0-6 alkyl(SO 2 )NR 8 R 9 , C 0-6 alkyl(SO)NR 8 R 9 , OC 1-6 alkyl(SO)NR 8 R 9 , OSO 2 R 8 , SO 3 R 8 , C 0-6 alkylNR 8 (SO 2 )NR 8 R 9 , C 0-6 alkylNR 8 (SO)R 9 , OC 2-6 alkylNR 8 (SO)R 8 , OC 1-6 alkylSO 2 R 8 , C 1-6 alkylSO 2 R 8 , C 0-6 alkylSOR 8 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, C 0-6 alkylheterocyclyl, and OC 2-6 alkylheterocyclyl, wherein any C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, C 0-6 alkylheterocyclyl or OC 2-6 alkylheterocyclyl is optionally substituted by one or more R 14 , and wherein any of the individual aryl or heteroaryl groups may be optionally fused with a 4, 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclyl group to form a bicyclic ring system where the bicyclic ring system is optionally substituted with between one and four A; with the proviso that said bicyclic ring system is not an indane, benzo[1,3]dioxole or 2,3-dihydrobenzo[1,4]-dioxine ring system; 
         R 14  is selected from halogen, nitro, CHO, C 0-6 alkylCN, OC 1-6 alkylCN, C 0-6 alkylOR 8 , OC 1-6 alkylOR 8 , fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, C 0-6 alkylNR 8 R 9 , OC 2-6 alkylNR 8 R 9 , OC 2-6 alkylOC 2-6 alkylNR 8 R 9 , NR 8 OR 9 , C 0-6 alkylCO 2 R 8 , OC 1-6 alkylCO 2 R 8 , C 0-6 alkylCONR 8 R 9 , OC 1-6 alkylCONR 8 R 9 , OC 2-6 alkylNR 8 (CO)R 9 , C 0-6 alkylNR 8  (CO)R 9 , O(CO)NR 8 R 9 , NR 8 (CO)OR 9 , NR 8 (CO)NR 8 R 9 , O(CO)OR 8 , O(CO)R 8 , C 0-6 alkylCOR 8 , OC 1-6 alkylCOR 8 , NR 8 (CO)(CO)R 8 , NR 8 (CO)(CO)NR 8 R 9 , C 0-6 alkylSR 8 , C 0-6 alkyl(SO 2 )NR 8 R 9 , OC 2-6 alkylNR 8 (SO 2 )R 9 , OC 0-6 alkyl(SO 2 )NR 8 R 9 , C 0-6 alkyl(SO)NR 8 R 9 , OC 1-6 alkyl(SO)NR 8 R 9 , OSO 2 R 8 , SO 3 R 8 , C 0-6 alkylNR 8 (SO 2 )NR 8 R 9 , C 0-6 alkylNR 8 (SO)R 9 , OC 2-6 alkylNR 8 (SO)R 8 , OC 1-6 alkylSO 2 R 8 , C 1-6 alkylSO 2 R 8 , C 0-6 alkylSOR 8 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, C 0-6 alkylheterocyclyl and OC 2-6 alkylheterocyclyl wherein any C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, C 0-6 alkylheterocyclyl or OC 2-6 alkylheterocyclyl is optionally substituted by between one and four A; 
         R 8  and R 9  are independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, C 0-6 alkylheterocyclyl and C 1-6 alkylNR 10 R 11 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl or C 0-6 alkylheterocyclyl is optionally substituted by between one and four A; or 
         R 8  and R 9  may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S that is optionally substituted by A; whenever two R 8  groups occur in the structure then they may optionally together form a 5 or 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, that is optionally substituted by A; 
         R 10  and R 11  are independently selected from hydrogen, C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, C 0-6 alkylheterocyclyl and C 0-6 alkylheteroaryl, wherein said C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl or C 0-6 alkylheterocyclyl is optionally substituted by A; or 
         R 10  and R 11  may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S optionally substituted by A; 
         m is 0, 1, 2 or 3; 
         n is 0, 1, 2 or 3; 
         A is independently selected from oxo, halogen, nitro, CN, OR 12 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylheterocyclyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, OC 2-6 alkylNR 12 R 13 , NR 12 , R 13 , CONR 12 R 13 , NR 12 (CO)R 13 , O(CO)C 1-6 alkyl, (CO)OC 1-6 alkyl, COR 12 , (SO 2 )NR 12 R 13 , NSO 2 R 12 , SO 2 R 12 , SOR 12 , (CO)C 1-6 alkylNR 12 R 13 , (SO 2 )C 1-6 alkylNR 12 R 13 , OSO 2 R 12  and SO 3 R 12 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, C 0-6 alkylheterocyclyl or C 0-6 alkylC 3-6 cycloalkyl is optionally substituted with halo, OSO 2 R 12 , SO 3 R 12 , nitro, cyano, OR 12 , C 1-6 alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy or trifluoromethoxy; 
         R 12  and R 13  are independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted by one, two or three hydroxy, cyano, halo or C 1-3 alkyloxy; or 
         R 12  and R 13  may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S optionally substituted by hydroxy, C 1-3 alkyloxy, cyano or halo; 
         provided that the following compounds are excluded: 
         3-amino-1-cyano-N-phenyl-1H-isoindole-1-carboxamide; 
         3-amino-1-(1H-benzimidazol-2-yl)-1H-isoindole-1-carbonitrile; 
         4,4′-(3-amino-1H-isoindole-1,1-diyl)diphenol; 
         1-phenyl-1H-isoindol-3-amine; 
         1-methyl-1H-isoindol-3-amine; 
         1,1-dimethyl-1H-isoindol-3-amine; 
         2-[3-amino-1-(4-hydroxyphenyl)-1H-isoindol-1-yl]phenol; 
         as a free base or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof. 
       
     
     
         2 . A compound according to  claim 1 , wherein R 8  and R 9  are independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, C 0-6 alkylheterocyclyl and C 1-6 alkylNR 10 R 11 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl or C 0-6 alkylheterocyclyl is optionally substituted by A; or
 R 8  and R 9  may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S that is optionally substituted by A; whenever two R 8  groups occur in the structure then they may optionally together form a 5 or 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, that is optionally substituted by A.   
     
     
         3 . A compound according to  claim 1  or  2 , wherein the following compounds are excluded:
 3-methyl-3-phenylisoindolin-1-imine; 
 3′-(3-methyl-2,3-dihydro-1H-isoindol-1-yl)biphenyl-3-carbonitrile; 
 3-(3′methoxybiphenyl-3-yl)-3 methylisoindolin-1-imine; 
 3-(3′chlorobiphenyl-3-yl)-3-methylisoindolin-1-imine; and 
 3-methyl-3-(3-pyridin-3-ylphenyl)isoindolin-1-imine; 
 as a free base or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof. 
 
     
     
         4 . A compound according to  claim 1 , wherein
 R 1  is selected from -Q-aryl and -Q-heteroaryl, wherein said -Q-aryl or -Q-heteroaryl is optionally substituted by one, two or three R 7 ;   R 2  is (C(R 4 )(R 5 )) n R 6 , and if n>1 then each C(R 4 )(R 5 ) is independent of the others;   R 3  is independently selected from hydrogen, halogen, C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl, C 5-7 cycloalkenyl, aryl, heteroaryl, heterocyclyl, C 1-6 alkylC 3-6 cycloalkyl, C 1-6 alkylaryl, C 1-6 alkylheteroaryl or C 1-6 alkylheterocyclyl, wherein the C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl, C 5-7 cycloalkenyl, aryl, heteroaryl, heterocyclyl, C 1-6 alkylC 3-6 cycloalkyl, C 1-6 alkylaryl, C 1-6 alkylheteroaryl or C 1-6 alkylheterocyclyl is optionally substituted with one, two or three A;   -Q- is a direct bond;   R 4  and R 5  are independently selected from hydrogen, C 1-6 alkyl, cyano, halo or nitro; or R 4  and R 5  together form oxo, C 3-6 cycloalkyl or heterocyclyl;   R 6  is selected from aryl or heteroaryl wherein each of the said aryl or heteroaryl is optionally substituted with between one and four R 7 , and wherein any of the individual aryl or heteroaryl groups may be optionally fused with a 4, 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclyl group to form a bicyclic ring system;   R 7  is independently selected from halogen, C 0-6 alkylOR 8 , hydroxy, OSO 2 R 8 , C 1-6 alkyl, C 0-6 alkylaryl and C 0-6 alkylheteroaryl, wherein any C 1-6 alkyl, C 0-6 alkylaryl and C 0-6 alkylheteroaryl may be optionally substituted by one or more R 14 ;   R 14  is selected from halogen, OSO 2 R 8  and C 0-6 alkylOR 8 ,   R 8  is independently selected from hydrogen, C 1-6 alkyl and trifluoromethyl.   
     
     
         5 . A compound according to  claim 1 , wherein
 R 1  is -Q-aryl, wherein said -Q-aryl is optionally substituted by one, two or three R 7 ;   R 2  is (C(R 4 )(R 5 )) n R 6 ;   -Q- is a direct bond;   R 6  is aryl wherein said aryl is optionally substituted with between one and four R 7 , and wherein the individual aryl group may be optionally fused with a 4, 5, 6 or 7 membered heterocyclyl group to form a bicyclic ring system;   R 7  is independently selected from halogen, C 0-6 alkylOR 8 , hydroxy, OSO 2 R 8 , C 1-6 alkyl, C 0-6 alkylaryl and C 0-6 alkylheteroaryl, wherein any C 1-6 alkyl, C 0-6 alkylaryl and C 0-6 alkylheteroaryl may be optionally substituted by one or more R 14 ;   R 14  is selected from halogen, OSO 2 R 8  and C 0-6 alkylOR 8 ,   R 8  is independently selected from hydrogen, C 1-6 alkyl and trifluoromethyl;   m is 0;   n is 0.   
     
     
         6 . A compound according to  claim 1 , wherein
 R 1  is selected from -Q-aryl and -Q-heteroaryl, wherein said -Q-aryl or -Q-heteroaryl is optionally substituted by one, two or three R 7 ;   R 2  is (C(R 4 )(R 5 )) n R 6 ;   R 3  is halogen;   -Q- is a direct bond;   R 6  is selected from aryl and heteroaryl wherein said aryl or heteroaryl is optionally substituted with between one and four R 7 ;   R 7  is independently selected from halogen, C 0-6 alkylCN, C 0-6 alkylOR 8 , trifluoromethyl, trifluoromethoxy, C 0-6 alkylaryl and C 0-6 alkylheteroaryl, wherein said C 0-6 alkylaryl or C 0-6 alkylheteroaryl is optionally substituted by one or more R 14 ;   R 14  is selected from halogen, CHO, C 0-6 alkylCN, C 0-6 alkylOR 8 , C 0-6 alkylCONR 8 R 9 , (CO)R 9  and C 1-6 alkyl;   R 8  and R 9  are independently selected from hydrogen, C 1-6 alkyl;   m is 0 or 1; and   n is 0.   
     
     
         7 . A compound according to  claim 1 , wherein
 R 1  is -Q-C 1-6 alkyl;   R 2  is (C(R 4 )(R 5 )) n R 6 ;   -Q- is a direct bond;   R 6  is aryl, said aryl optionally being substituted with between one or two R 7 ;   R 7  is independently selected from halogen, C 0-6 alkylCN, C 0-6 alkylOR 8 , C 0-6 alkylaryl and C 0-6 alkylheteroaryl, wherein said C 0-6 alkylaryl or C 0-6 alkylheteroaryl is optionally substituted by one or more R 14 ;   R 14  is selected from halogen, C 0-6 alkylCN and C 0-6 alkylOR 8 ;   R 8  is C 1-6 alkyl;   m is 0; and   n is 0.   
     
     
         8 . A compound according to  claim 1 , wherein
 R 1  is -Q-aryl substituted by one or two R 7 ;   R 2  is (C(R 4 )(R 5 )) n R 6 ;   -Q- is a direct bond;   R 6  is selected from aryl and heteroaryl wherein said aryl or heteroaryl is optionally substituted with between one and four R 7 ;   R 7  is independently selected from halogen, trifluoromethyl, OSO 2 R 8 , C 0-6 alkylOR 8 , C 1-6 alkyl, C 0-6 alkylaryl and C 0-6 alkylheteroaryl, wherein any C 0-6 alkylaryl or C 0-6 alkylheteroaryl is optionally substituted by one or more R 14 ;   R 14  is selected from halogen, C 0-6 alkylCN and C 0-6 alkylOR 8 ;   R 8  is selected from C 1-6 alkyl, trifluoromethyl, C 0-6 alkylaryl and C 0-6 alkylheteroaryl, wherein said C 0-6 alkylaryl or C 0-6 alkylheteroaryl or C 0-6 alkylheterocyclyl is optionally substituted by between one and four A;   M is 0;   n is 0;   A is selected halogen and C 1-6 alkyl.   
     
     
         9 . A compound according to  claim 1 , wherein
 R 1  is -Q-aryl substituted by one or two R 7 ;   R 2  is (C(R 4 )(R 5 )) n R 6 ;   -Q- is a direct bond;   R 6  is aryl substituted with between one and four R 7 ;   R 7  is independently selected from halogen, OSO 2 R 8 , C 0-6 alkylOR 8 , C 1-6 alkyl, C 0-6 alkylaryl and C 0-6  alkylheteroaryl, wherein any C 0-6 alkylaryl or C 0-6 alkylheteroaryl is optionally substituted by one or more R 14 ;   R 14  is selected from halogen, C 0-6 alkylCN and C 0-6 alkylOR 8 ;   R 8  is selected from C 1-6 alkyl, trifluoromethyl, C 0-6 alkylaryl and C 0-6 alkylheteroaryl, wherein said C 0-6 alkylaryl or C 0-6 alkylheteroaryl or C 0-6 alkylheterocyclyl is optionally substituted by between one and four A;   m is 0;   n is 0;   A is selected halogen and C 1-6 alkyl.   
     
     
         10 . A compound according to  claim 1 , wherein
 R 1  is -Q-aryl substituted by one or two R 7 ;   R 2  is (C(R 4 )(R 5 )) n R 6 ;   -Q- is a direct bond;   R 6  is heteroaryl, optionally substituted with between one and four R 7 ;   R 7  is independently selected from halogen, OSO 2 R 8 , C 0-6 alkylOR 8 , C 1-6 alkyl, C 0-6 alkylaryl and C 0-6 alkylheteroaryl, wherein any C 0-6 alkylaryl or C 0-6 alkylheteroaryl is optionally substituted by one or more R 14 ;   R 14  is selected from halogen, C 0-6 alkylCN and C 0-6 alkylOR 8 ;   R 8  is selected from C 1-6 alkyl, trifluoromethyl, C 0-6 alkylaryl and C 0-6 alkylheteroaryl, wherein said C 0-6 alkylaryl or C 0-6 alkylheteroaryl or C 0-6 alkylheterocyclyl is optionally substituted by between one and four A;   M is 0;   n is 0;   A is selected halogen and C 1-6 alkyl.   
     
     
         11 . A compound, selected from:
 3,3-Diphenyl-3H-isoindol-1-ylamine;   3-(3′-Methoxy-biphenyl-3-yl)-3-(4-methoxy-phenyl)-3H-isoindol-1-ylamine trifluoroacetate;   Trifluoro-methanesulfonic acid 5-[3-amino-1-(4-methoxy-phenyl)-1H-isoindol-1-yl]-3′-methoxy-biphenyl-2-yl ester trifluoroacetate;   5-[3-Amino-1-(4-methoxy-phenyl)-1H-isoindol-1-yl]-3′-methoxy-biphenyl-2-ol trifluoroacetate;   4,4′-(3-amino-isoindole-1,1-diyl)-bis-phenol;   4-[3-Amino-1-(4-methoxy-phenyl)-1H-isoindol-1-yl]-2-pyridin-3-yl-phenol trifluoroacetate;   4-[3-Amino-1-(4-methoxy-phenyl)-1H-isoindol-1-yl]-2-pyrimidin-5-yl-phenol trifluoroacetate;   3-(4-Methoxy-phenyl)-3-(3-pyridin-3-yl-phenyl)-3H-isoindol-1-ylamine trifluoroacetate;   3-[3-(2-Fluoro-pyridin-3-yl)-phenyl]-3-(4-methoxy-phenyl)-3H-isoindol-1-ylamine trifluoroacetate;   3-(3-Bromo-phenyl)-3-(4-methoxy-phenyl)-3H-isoindol-1-ylamine;   3-(4-Methoxy-phenyl)-3-[3-(5-methoxy-pyridin-3-yl)-phenyl]-3H-isoindol-1-ylamine trifluoroacetate;   3-(4-Methoxy-phenyl)-3-(3-pyrimidin-5-yl-phenyl)-3H-isoindol-1-ylamine trifluoroacetate;   Methanesulfonic acid 3′-[3-amino-1-(4-methoxy-phenyl)-1H-isoindol-1-yl]-5-methoxy-biphenyl-3-yl ester trifluoroacetate;   3-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-3-(3-(2-fluoropyridin-3-yl)phenyl)-3H-isoindol-1-amine trifluoroacetate;   3-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-3-(3-(5-methoxypyridin-3-yl)phenyl)-3H-isoindol-1-amine trifluoroacetate;   3-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-3-(3-(pyridin-3-yl)phenyl)-3H-isoindol-1-amine trifluoroacetate;   3-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-3-(3-(pyrimidin-5-yl)phenyl)-3H-isoindol-1-amine trifluoroacetate;   3-(3′-Methoxy-biphenyl-3-yl)-3-(4-methoxy-3-methyl-phenyl)-3H-isoindol-1-ylamine trifluoroacetate;   3-(4-Methoxy-3-methyl-phenyl)-3-[3-(5-methoxy-pyridin-3-yl)-phenyl]-3H-isoindol-1-ylamine trifluoroacetate;   3-(4-Methoxy-3-methyl-phenyl)-3-(3-pyridin-3-yl-phenyl)-3H-isoindol-1-ylamine trifluoroacetate;   3-(4-Methoxy-3-methyl-phenyl)-3-(3-pyrimidin-5-yl-phenyl)-3H-isoindol-1-ylamine trifluoroacetate;   3-[3-(2-Fluoro-pyridin-3-yl)-phenyl]-3-(4-methoxy-3-methyl-phenyl)-3H-isoindol-1-ylamine trifluoroacetate;   Methanesulfonic acid 3′-[3-amino-1-(4-methoxy-3-methyl-phenyl)-1H-isoindol-1-yl]-5-methoxy-biphenyl-3-yl ester trifluoroacetate;   5′-(3-Amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-isoindol-1-yl)-5-methoxybiphenyl-3-yl methanesulfonate trifluoroacetate;   3-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-3-(3′-methoxybiphenyl-3-yl)-3H-isoindol-1-amine trifluoroacetate;   3-Benzo[1,3]dioxol-5-yl-3-(3-pyridin-3-yl)-3H-isoindol-1-ylamine trifluoroacetate;   3-Benzo[1,3]dioxol-5-yl-3-(3-bromophenyl)-3H-isoindol-1-ylamine;   3-Benzo[1,3]dioxol-5-yl-3-(3-pyrimidin-5-ylphenyl)-3H-isoindol-1-ylamine trifluoroacetate;   3-Benzo[1,3]dioxol-5-yl-3-[3-(2-fluoropyridin-3-yl)-phenyl]-3H-isoindol-1-ylamine trifluoroacetate;   3-Benzo[1,3]dioxol-5-yl-3-[3-(5-methoxypyridin-3-yl)-phenyl]3H isoindol-1-ylamine trifluoroacetate;   as a free base or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof.   
     
     
         12 . A compound, selected from:
 3-Benzo[1,3]dioxol-5-yl-3-(3′-methoxy-biphenyl-3-yl)-3H-isoindol-1-ylamine trifluoroacetate;   Methanesulfonic acid 3′-(3-amino-1-benzo[1,3]dioxol-5-yl-1H-isoindol-1-yl)-5-methoxy-biphenyl-3-yl ester trifluoroacetate;   Methanesulfonic acid 4-[3-amino-1-(3-pyridin-3-yl-phenyl)-1H-isoindol-1-yl]-phenyl ester trifluoroacetate;   Methanesulfonic acid 4-[3-amino-1-(3-bromo-phenyl)-1H-isoindol-1-yl]-phenyl ester trifluoroacetate;   Methanesulfonic acid 4-{3-amino-1-[3-(2-fluoro-pyridin-3-yl)-phenyl]-1H-isoindol-1-yl}-phenyl ester trifluoroacetate;   Methanesulfonic acid 4-[3-amino-1-(3-pyrimidin-5-yl-phenyl)-1H-isoindol-1-yl]-phenyl ester trifluoroacetate;   Methanesulfonic acid 4-{3-amino-1-[3-(5-methoxy-pyridin-3-yl)-phenyl]-1H-isoindol-1-yl}-phenyl ester trifluoroacetate;   Methanesulfonic acid 4-[3-amino-1-(3′-methoxy-biphenyl-3-yl)-1H-isoindol-1-yl]-phenyl ester trifluoroacetate;   Methanesulfonic acid 4-[3-amino-1-(5′-methanesulfonyloxy-3′-methoxy-biphenyl-3-yl)-1H-isoindol-1-yl]-phenyl ester trifluoroacetate;   3-[3-(2-Fluoro-pyridin-3-yl)-phenyl]-3-pyridin-4-yl-3H-isoindol-1-ylamine trifluoroacetate;   3-Pyridin-4-yl-3-(3-pyridin-3-yl-phenyl)-3H-isoindol-1-ylamine trifluoroacetate;   3-Pyridin-4-yl-3-(3-pyrimidin-5-yl-phenyl)-3H-isoindol-1-ylamine trifluoroacetate;   3-[3-(5-Methoxy-pyridin-3-yl)-phenyl]-3-pyridin-4-yl-3H-isoindol-1-ylamine trifluoroacetate;   3-(3′-Methoxy-biphenyl-3-yl)-3-pyridin-4-yl-3H-isoindol-1-ylamine trifluoroacetate;   3-{3-[3-Amino-1-(4-methoxyphenyl)-1H-isoindol-1-yl]phenyl}thiophene-2-carbaldehyde 1.5 acetate;   4-[3-Amino-1-(3-bromophenyl)-1H-isoindol-1-yl]benzonitrile;   1-[3-(1-Isobutyl-1H-pyrazol-4-yl)phenyl]-1-(4-methoxyphenyl)-1H-isoindol-3-amine 0.5 acetate;   1-(4-Methoxyphenyl)-1-[3-(5-methyl-2-furyl)phenyl]-1H-isoindol-3-amine 0.5 acetate;   3′-[3-Amino-1-(4-methoxyphenyl)-1H-isoindol-1-yl]biphenyl-2-carboxamide 0.5 acetate;   1-[3-(5-Fluoropyridin-3-yl)phenyl]-1-[4-(trifluoromethoxy)phenyl]-1H-isoindol-3-amine 0.75 acetate;   1-(3-Pyrimidin-5-ylphenyl)-1-[4-(trifluoromethoxy)phenyl]-1H-isoindol-3-amine 0.25 acetate;   4-[3-Amino-1-(3-pyrimidin-5-ylphenyl)-1H-isoindol-1-yl]benzonitrile 0.25 acetate;   1-[3-(5-Fluoropyridin-3-yl)phenyl]-1-[4-(trifluoromethyl)phenyl]-1H-isoindol-3-amine 0.25 acetate;   1-(3-Pyrimidin-5-ylphenyl)-1-[4-(trifluoromethyl)phenyl]-1H-isoindol-3-amine 0.25 acetate;   3-[3-(3-Amino-1-pyridin-4-yl-1H-isoindol-1-yl)phenyl]thiophene-2-carbaldehyde;   1-[3-(1-Isobutyl-1H-pyrazol-4-yl)phenyl]-1-pyridin-4-yl-1H-isoindol-3-amine 0.25 acetate;   1-[3-(5-Methyl-2-furyl)phenyl]-1-pyridin-4-yl-1H-isoindol-3-amine acetate;   3′-(3-Amino-1-pyridin-4-yl-1H-isoindol-1-yl)biphenyl-2-carboxamide 0.25 acetate;   4-{3-Amino-1-[3-(2-fluoropyridin-3-yl)phenyl]-1H-isoindol-1-yl}benzonitrile;   1-[3-(2-Fluoropyridin-3-yl)phenyl]-1-[4-(trifluoromethyl)phenyl]-1H-isoindol-3-amine;   1-[3-(5-Fluoropyridin-3-yl)phenyl]-1-pyridin-4-yl-1H-isoindol-3-amine 0.75 acetate;   1-(4-Fluoro-3-pyrimidin-5-ylphenyl)-1-pyridin-4-yl-1H-isoindol-3-amine 0.5 acetate;   1-[4-Fluoro-3-(5-fluoropyridin-3-yl)phenyl]-1-pyridin-4-yl-1H-isoindol-3-amine 0.75 acetate;   1-(3-Fluoropyridin-4-yl)-1-[3-(5-fluoropyridin-3-yl)phenyl]-1H-isoindol-3-amine 0.5 acetate;   1-(3-Fluoropyridin-4-yl)-1-(3-pyrimidin-5-ylphenyl)-1H-isoindol-3-amine 1.25 acetate;   1-(3-Fluoropyridin-4-yl)-1-[3-(2-fluoropyridin-3-yl)phenyl]-1H-isoindol-3-amine 1.25 acetate;   1-(3-Fluoropyridin-4-yl)-1-(4-fluoro-3-pyrimidin-5-ylphenyl)-1H-isoindol-3-amine 1.25 acetate;   1-[4-Fluoro-3-(5-fluoropyridin-3-yl)phenyl]-1-(3-fluoropyridin-4-yl)-1H-isoindol-3-amine 1.5 acetate;   1-[4-Fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-(3-fluoropyridin-4-yl)-1H-isoindol-3-amine 1.5 acetate;   5-[3-(3-Amino-1-pyridin-4-yl-1H-isoindol-1-yl)phenyl]nicotinonitrile acetate;   6-Fluoro-1-(4-methoxyphenyl)-1-(3-pyrimidin-5-ylphenyl)-1H-isoindol-3-amine;   6-Fluoro-1-(4-methoxyphenyl)-1-(3-pyridin-3-ylphenyl)-1H-isoindol-3-amine;   6-Fluoro-1-(3′-methoxybiphenyl-3-yl)-1-(4-methoxyphenyl)-1H-isoindol-3-amine;   6-Fluoro-1-(4-methoxyphenyl)-1-[3-(5-methoxypyridin-3-yl)phenyl]-1H-isoindol-3-amine;   6-Fluoro-1-pyridin-4-yl-1-(3-pyridin-3-ylphenyl)-1H-isoindol-3-amine;   6-Fluoro-1-pyridin-4-yl-1-(3-pyrimidin-5-ylphenyl)-1H-isoindol-3-amine;   6-Fluoro-1-[3-(5-methoxypyridin-3-yl)phenyl]-1-pyridin-4-yl-1H-isoindol-3-amine;   6-Fluoro-1-[3-(2-fluoropyridin-3-yl)phenyl]-1-pyridin-4-yl-1H-isoindol-3-amine;   1-(3′,5′-Dichlorobiphenyl-3-yl)-1-(4-methoxyphenyl)-1H-isoindol-3-amine acetate;   3′-(3-Amino-1-cyclopropyl-1H-isoindol-1-yl)-5-methoxybiphenyl-2-carbonitrile acetate;   1-Cyclopropyl-1-(3-pyrimidin-5-ylphenyl)-1H-isoindol-3-amine acetate;   3′-(3-Amino-1-methyl-1H-isoindol-1-yl)-5-methoxybiphenyl-2-carbonitrile acetate;   1-(3′,5′-Dichlorobiphenyl-3-yl)-1-methyl-1H-isoindol-3-amine hydrochloride;   1-Methyl-1-(3-pyrimidin-5-ylphenyl)-1H-isoindol-3-amine acetate;   1-[3-(2-Fluoropyridin-3-yl)phenyl]-1-methyl-1H-isoindol-3-amine acetate;   1-Isopropyl-1-(3-pyrimidin-5-ylphenyl)-1H-isoindol-3-amine acetate; and   1-[3-(5-Fluoropyridin-3-yl)phenyl]-1-methyl-1H-isoindol-3-amine acetate;   as a free base or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof.   
     
     
         13 . A compound, selected from:
 1-(2′-Fluoro-5′-methoxybiphenyl-3-yl)-1-(3-fluoropyridin-4-yl)-1H-isoindol-3-amine;   1-(2′-Fluoro-3′-methoxybiphenyl-3-yl)-1-(3-fluoropyridin-4-yl)-1H-isoindol-3-amine;   1-(2′,6-Difluoro-3′-methoxybiphenyl-3-yl)-1-(3-fluoropyridin-4-yl)-1H-isoindol-3-amine;   5-{3-[3-Amino-1-(3-fluoropyridin-4-yl)-1H-isoindol-1-yl]phenyl}nicotinonitrile;   1-(2′-Fluoro-5′-methoxybiphenyl-3-yl)-1-pyridin-4-yl-1H-isoindol-3-amine;   1-(2′-Fluoro-3′-methoxybiphenyl-3-yl)-1-pyridin-4-yl-1H-isoindol-3-amine;   1-[4-Fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-pyridin-4-yl-1H-isoindol-3-amine;   1-[3-(2-Fluoropyridin-3-yl)phenyl]-1-(2-methoxypyrimidin-5-yl)-1H-isoindol-3-amine;   1-(2-Methoxypyrimidin-5-yl)-1-(3-pyrimidin-5-ylphenyl)-1H-isoindol-3-amine;   1-(2′-Fluoro-3′-methoxybiphenyl-3-yl)-1-(2-methoxypyrimidin-5-yl)-1H-isoindol-3-amine;   1-(2-Ethylpyridin-4-yl)-1-(3-pyrimidin-5-ylphenyl)-1H-isoindol-3-amine;   1-(2-Ethylpyridin-4-yl)-1-[3-(2-fluoropyridin-3-yl)phenyl]-1H-isoindol-3-amine;   1-(2-Isopropylpyridin-4-yl)-1-(3-pyrimidin-5-ylphenyl)-1H-isoindol-3-amine;   1-[3-(2-Fluoropyridin-3-yl)phenyl]-1-(2-isopropylpyridin-4-yl)-1H-isoindol-3-amine;   1-(2-Fluoropyridin-4-yl)-1-[3-(2-fluoropyridin-3-yl)phenyl]-1H-isoindol-3-amine;   1-[3-(2-Fluoropyridin-3-yl)phenyl]-1-(2-methoxypyridin-4-yl)-1H-isoindol-3-amine;   1-(2-Chloropyridin-4-yl)-1-[3-(2-fluoropyridin-3-yl)phenyl]-1H-isoindol-3-amine;   1-(2-Chloropyridin-4-yl)-1-(3-pyrimidin-5-ylphenyl)-1H-isoindol-3-amine;   1-(5-Fluoropyridin-3-yl)-1-[3-(2-fluoropyridin-3-yl)phenyl]-1H-isoindol-3-amine;   1-(5-Fluoropyridin-3-yl)-1-(3-pyrimidin-5-ylphenyl)-1H-isoindol-3-amine;   1-(4-Fluoro-3-pyrimidin-5-ylphenyl)-1-(4-methoxy-3-methylphenyl)-1H-isoindol-3-amine;   1-[4-Fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-(4-methoxy-3-methylphenyl)-1H-isoindol-3-amine;   6-Chloro-1-pyridin-4-yl-1-(3-pyrimidin-5-ylphenyl)-1H-isoindol-3-amine;   1-(3-Pyrimidin-5-ylphenyl)-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-isoindol-3-amine 0.66 acetate;   3-[3-Amino-1-(2,6-dichloropyridin-4-yl)-1H-isoindol-1-yl]phenyl 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonate;   3-[3-Amino-1-(2,6-dichloropyridin-4-yl)-1H-isoindol-1-yl]phenyl 6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonate;   3-[3-Amino-1-(2,6-dichloropyridin-4-yl)-1H-isoindol-1-yl]phenyl 2,6-difluorobenzenesulfonate;   3-[3-Amino-1-(4-fluoro-3-pyrimidin-5-ylphenyl)-1H-isoindol-1-yl]phenyl trifluoromethanesulfonate;   3-[3-Amino-1-(4-fluoro-3-pyrimidin-5-ylphenyl)-1H-isoindol-1-yl]phenyl trifluoromethanesulfonate; and   4-[3-Amino-1-(4-fluoro-3-pyrimidin-5-ylphenyl)-1H-isoindol-1-yl]phenyl trifluoromethanesulfonate;   as a free base or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof.   
     
     
         14 . A compound according to  claim 1  for use in therapy. 
     
     
         15 . A pharmaceutical formulation comprising as active ingredient a therapeutically effective amount of a compound according to  claim 1  in association with pharmaceutically acceptable excipients, carriers or diluents. 
     
     
         16 . A method of inhibiting activity of BACE comprising contacting said BACE with a compound according to  claim 1 . 
     
     
         17 . A method of treating or preventing an Aβ-related pathology in a mammal, comprising administering to said patient a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         18 . The method of  claim 17 , wherein said Aβ-related pathology is Downs syndrome, a β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI (“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 or cortical basal degeneration. 
     
     
         19 . The method of  claim 17 , wherein said mammal is a human. 
     
     
         20 . A method of treating or preventing an Aβ-related pathology in a mammal, comprising administering to said patient a therapeutically effective amount of a compound according to  claim 1 , and at least one cognitive enhancing agent, memory enhancing agent, or choline esterase inhibitor. 
     
     
         21 . A method according to  claim 20 , wherein said Aβ-related pathology is Downs syndrome, a β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI (“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 or cortical basal degeneration. 
     
     
         22 . A method according to  claim 20 , wherein said mammal is a human.