Pyrrolopyridine derivatives and their use as bace inhibitors

Abstract

This invention relates to novel compounds having the structural formula I below: (I) 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 according to Formula I or a pharmaceutically acceptable salt thereof, wherein:
 Formula I corresponds to:   
       
         
           
           
               
               
           
         
         R 1  is selected from aryl and heteroaryl, wherein:
 the aryl or heteroaryl is optionally substituted with one or more R 4 ; and 
 the aryl or heteroaryl is optionally fused with a 4, 5, 6, or 7 membered cycloalkyl, cycloalkenyl, or heterocyclyl group to form a bicyclic ring system, wherein:
 the bicyclic ring system is optionally substituted with one or more R 4 ; 
 
 
         R 2  is selected from aryl and heteroaryl, wherein:
 the aryl or heteroaryl is optionally substituted with one or more R 4 ; and 
 the aryl or heteroaryl is optionally fused with a 4, 5, 6, or 7 membered cycloalkyl, cycloalkenyl, or heterocyclyl group to form a bicyclic ring system, wherein:
 the bicyclic ring system is optionally substituted with one or more R 4 ; 
 
 
         R 3  is independently selected from halogen, nitro, CHO, C 0-6 alkylCN, OC 1-6 alkylCN, C 0-6 alkylOR 5 , OC 2-6 alkylOR 5 , C 0-6 alkylNR 5 R 6 , OC 2-6 alkylNR 5 R 6 , OC 2-6 alkylOC 2-6 alkylNR 5 R 6 , C 0-6 alkylCO 2 R 5 , OC 1-6 alkylCO 2 R 5 , C 0-6 alkylCONR 5 R 6 , OC 1-6 alkylCONR 5 R 6 , OC 2-6 alkylNR 5 (CO)R 6 , C 0-6 alkylNR 5 (CO)R 6 , O(CO)NR 5 R 6 , NR 5 (CO)OR 6 , NR 5 (CO)NR 5 R 6 , O(CO)OR 5 , O(CO)R 5 , C 0-6 alkylCOR 5 , OC 1-6 alkylCOR 5 , NR 5 (CO)(CO)R 5 , NR 5 (CO)(CO)NR 5 R 6 , C 0-6 alkylSR 5 , C 0-6 alkyl(SO 2 )NR 5 R 6 , OC 1-6 alkylNR 5 (SO 2 )R 6 , OC 0-6 alkyl(SO 2 )NR 5 R 6 , C 0-6 alkyl(SO)NR 5 R 6 , OC 1-6 alkyl(SO)NR 5 R 6 , C 0-6 alkylOSO 2 R 5 , C 0-6 alkylSO 3 R 5 , C 0-6 alkylNR 5 (SO 2 )NR 5 R 6 , C 0-6 alkylNR 5 (SO)R 6 , OC 2-6 alkylNR 5 (SO)R 6 , OC 1-6 alkylSO 2 R 5 , C 0-6 alkylSO 2 R 5 , C 0-6 alkylSOR 5 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylC 3-6 cycloalkenyl, C 0-6 alkylC 6 cycloalkynyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, C 0-6 alkylheterocyclyl, and OC 2-6 alkylheterocyclyl, wherein:
 the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylC 3-6 cycloalkenyl, C 0-6 alkylC 6 cycloalkynyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, C 0-6 alkylheterocyclyl, or OC 2-6 alkylheterocyclyl is optionally substituted with one or more R 11 , and 
 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, wherein:
 the bicyclic ring system is optionally substituted with one or more A; 
 
 
         W is C or N; 
         X is C or N; 
         Y is C or N; 
         Z is C or N; 
         when W and X are N, Y and Z are C; 
         when W and Y are N, X and Z are C; 
         when W and Z are N, X and Y are C; 
         when X and Y are N, W and Z are C; 
         when X and Z are N, W and Y are C; 
         when Y and Z are N, W and X are C; 
         when W, X, and Y are C, Z is N; 
         when W, X, and Z are C, Y is N; 
         when W, Y, and Z are C, X is N; 
         when X, Y, and Z are C, W is N; 
         m is 0, 1, 2, or 3; 
         R 4  is independently selected from halogen, nitro, SF S , OSF 5 , CHO, C 0-6 alkylCN, OC 1-6 alkylCN, C 0-6 alkylOR 5 , OC 2-6 alkylOR 5 , C 0-6 alkylNR 5 R 6 , OC 2-6 alkylNR 5 R 6 , OC 2-6 alkylOC 2-6 alkylNR 5 R 6 , C 0-6 alkylCO 2 R 5 , OC 1-6 alkylCO 2 R 5  C 0-6 alkylCONR 5 R 6 , OC 1-6 alkylCONR 5 R 6 , OC 2-6 alkylNR 5 (CO)R 6 , C 0-6 alkylNR 5 (CO)R 6 , O(CO)NR 5 R 6 , NR 5 (CO)OR 6 , NR 5 (CO)NR 5 R 6 , O(CO)OR 5 , O(CO)R 5 , C 0-6 alkylCOR 5 , OC 1-6 alkylCOR 5 , NR 5 (CO)(CO)R 5 , NR 5 (CO)(CO)NR 5 R 6 , C 0-6 alkylSR 5 , C 0-6 alkyl(SO 2 )NR 5 R 6 , OC 1-6 alkylNR 5 (SO 2 )R 6 , OC 0-6 alkyl(SO 2 )NR 5 R 6 , C 0-6 alkyl(SO)NR 5 R 6 , OC 1-6 alkyl(SO)NR 5 R 6 , C 0-6 alkylOSO 2 R 5 , SO 3 R 5 , C 0-6 alkylNR 5 (SO 2 )NR 5 R 6 , C 0-6 alkylNR 5 (SO)R 6 , OC 2-6 alkylNR 5 (SO)R 6 , OC 1-6 alkylSO 2 R 5 , C 0-6 alkylSO 2 R 5 , C 0-6 alkylSOR 5 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylC 3-6 cycloalkenyl, C 0-6 alkylC 6 cycloalkynyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, C 0-6 alkylheterocyclyl and OC 2-6 alkylheterocyclyl, wherein:
 the 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 with one or more R 11 , and 
 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, wherein:
 the bicyclic ring system is optionally substituted with one or more A; 
 
 
         as to R 5  and R 6 :
 R 5  and R 6  are independently selected substituents such that:
 R 5  is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylC 3-6 cycloalkenyl, C 0-6 alkylC 6 cycloalkynyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, C 0-6 alkylheterocyclyl, and C 1-6 alkylNR 7 R 8 , wherein:
 the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylC 3-6 cycloalkenyl, C 0-6 alkylC 6 cycloalkynyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, or C 0-6 alkylheterocyclyl is optionally substituted with one or more A; 
 
 R 6  is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylOR 7 , C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylC 3-6 cycloalkenyl, C 0-6 alkylC 6 cycloalkynyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, C 0-6 alkylheterocyclyl, and C 1-6 alkylNR 7 R 8 , wherein:
 the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylC 3-6 cycloalkenyl, C 0-6 alkylC 6 cycloalkynyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, or C 0-6 alkylheterocyclyl is optionally substituted with one or more A; or 
 
 
 R 5  and R 6 , together with the atom(s) to which they are attached, form a 4 to 6 membered heterocyclic ring, wherein the ring:
 the ring contains one or more heteroatoms selected from N, O, and S; and 
 the ring is optionally substituted with A; or 
 
 whenever two R 5  groups occur in the structure, they may, together with the atom(s) to which they are attached, form a 5 or 6 membered heterocyclic ring, wherein:
 the ring contains one or more heteroatoms selected from N, O, and S, and 
 the ring is optionally substituted with one or more A; 
 
 
         as to R 7  and R 8 :
 R 7  and R 8  are independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylC 3-6 cycloalkenyl, C 0-6 alkylC 6 cycloalkynyl, C 0-6 alkylaryl, C 0-6 alkylheterocyclyl and C 0-6 alkylheteroaryl, wherein:
 the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylC 3-6 cycloalkenyl, C 0-6 alkylC 6 cycloalkynyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, or C 0-6 alkylheterocyclyl is optionally substituted with one or more A; or 
 
 R 7  and R 8  may together form a 4 to 6 membered heterocyclic ring, wherein:
 the ring contains one or more heteroatoms selected from N, O; and S; and 
 the ring is optionally substituted with one or more A; 
 
 
         A is selected from oxo, halogen, nitro, SF S , OSF 5 , CN, OR 9 , 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 9 R 10 , NR 9 R 10 , CONR 9 R 10 , NR 9 (CO)R 10 , O(CO)C 1-6 alkyl, (CO)OC 1-6 alkyl, COR 9 , (SO 2 )NR 9 R 10 , NSO 2 R 9 , SO 2 R 9 , SOR 9 , (CO)C 1-6 alkylNR 9 R 10 , (SO 2 )C 1-6 alkylNR 9 R 10 , OSO 2 R 9 , and SO 3 R 9 , wherein:
 the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, C 0-6 alkylheterocyclyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylC 3-6 cycloalkenyl, or C 0-6 alkylC 6 cycloalkynyl is optionally substituted with halo, OSO 2 R 9 , SO 3 R 9 , nitro, cyano, OR 9 , C 1-6 alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy or trifluoromethoxy; 
 
         as to R 9  and R 10 :
 R 9  and R 10  are independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 6 cycloalkynyl, aryl, heteroaryl and heterocyclyl, wherein:
 the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 6 cycloalkynyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one, two or three hydroxy, cyano, halogen, or C 1-3 alkyloxy; or 
 
 R 9  and R 10  may together with the atom(s) to which they are attached, form a 4 to 6 membered heterocyclic ring, wherein:
 the ring contains one or more heteroatoms selected from N, O, and S; and 
 the ring is optionally substituted with hydroxy, C 1-3 alkyloxy, cyano, or halogen; and 
 
 
         R 11  is independently selected from halogen, nitro, SF S , OSF 5 , CHO, C 0-6 alkylCN, OC 1-6 alkylCN, C 0-6 alkylOR 8 , OC 1-6 alkylOR 8 , fluoromethoxy, difluoromethoxy, trifluoromethoxy, C 0-6 alkylNR 5 R 6 , OC 2-6 alkylNR 5 R 6 , OC 2-6 alkylOC 2-6 alkylNR 5 R 6 , NR 5 OR 6 , C 0-6 alkylCO 2 R 5 , OC 1-6 alkylCO 2 R 5 , C 0-6 alkylCONR 5 R 6 , OC 1-6 alkylCONR 5 R 6 , OC 2-6 alkylNR 5 (CO)R 6 , C 0-6 alkylNR 5 (CO)R 6 , O(CO)NR 5 R 6 , NR 5 (CO)OR 6 , NR 5 (CO)NR 5 R 6 , O(CO)OR 5 , O(CO)R 5 , C 0-6 alkylCOR 5 , OC 1-6 alkylCOR 5 , NR 5 (CO)(CO)R 6 , NR 5 (CO)(CO)NR 5 R 6 , C 0-6 alkylSR 5 , C 0-6 alkyl(SO 2 )NR 5 R 6 , OC 2-6 alkylNR 5 (SO 2 )R 6 , OC 0-6 alkyl(SO 2 )NR 5 R 6 , C 0-6 alkyl(SO)NR 5 R 6 , OC 1-6 alkyl(SO)NR 5 R 6 , OSO 2 R 5 , SO 3 R 5 , C 0-6 alkylNR 5 (SO 2 )NR 5 R 6 , C 0-6 alkylNR 5 (SO)R 6 , OC 2-6 alkylNR 5 (SO)R 6 , OC 1-6 alkylSO 2 R 5 , C 0-6 alkylSO 2 R 5 , C 0-6 alkylSOR 5 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylC 3-6 cycloalkenyl, C 0-6 alkylC 6 cycloalkynyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, C 0-6 alkylheterocyclyl, and OC 2-6 alkylheterocyclyl, wherein:
 the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylC 3-6 cycloalkenyl, C 0-6 alkylC 6 cycloalkynyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, C 0-6 alkylheterocyclyl, or OC 2-6 alkylheterocyclyl is optionally substituted with one or more A. 
 
       
     
     
         2 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein:
 R 1  is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R 4 ;   R 2  is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R 4 ;   R 3  is independently selected from halogen, nitro, CHO, C 0-6 alkylCN, OC 1-6 alkylCN, C 0-6 alkylOR 5 , OC 2-6 alkylOR 5 , C 0-6 alkylNR 5 R 6 , OC 2-6 alkylNR 5 R 6 , OC 2-6 alkylOC 2-6 alkylNR 5 R 6 , C 0-6 alkylCO 2 R 5 , OC 1-6 alkylCO 2 R 5 , C 0-6 alkylCONR 5 R 6 , OC 1-6 alkylCONR 5 R 6 , OC 2-6 alkylNR 5 (CO)R 6 , C 0-6 alkylNR 5 (CO)R 6 , O(CO)NR 5 R 6 , NR 5 (CO)OR 6 , NR 5 (CO)NR 5 R 6 , O(CO)OR 5 , O(CO)R 5 , C 0-6 alkylCOR 5 , OC 1-6 alkylCOR 5 , NR 5 (CO)(CO)R 5 , NR 5 (CO)(CO)NR 5 R 6 , C 0-6 alkylSR 5 , C 0-6 alkyl(SO 2 )NR 5 R 6 , OC 1-6 alkylNR 5 (SO 2 )R 6 , OC 0-6 alkyl(SO 2 )NR 5 R 6 , C 0-6 alkyl(SO)NR 5 R 6 , OC 1-6 alkyl(SO)NR 5 R 6 , C 0-6 alkylOSO 2 R 5 , C 0-6 alkylSO 3 R 5 , C 0-6 alkylNR 5 (SO 2 )NR 5 R 6 , C 0-6 alkylNR 5 (SO)R 6 , OC 2-6 alkylNR 5 (SO)R 6 , OC 1-6 alkylSO 2 R 5 , C 0-6 alkylSO 2 R 5 , C 0-6 alkylSOR 5 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylC 3-6 cycloalkenyl, C 0-6 alkylC 6 cycloalkynyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, C 0-6 alkylheterocyclyl, and OC 2-6 alkylheterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylC 3-6 cycloalkenyl, C 0-6 alkylC 6 cycloalkynyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, C 0-6 alkylheterocyclyl, or OC 2-6 alkylheterocyclyl is optionally substituted with one or more R 11 , 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 one or more A;   W is C or N;   X is C or N;   Y is C or N;   Z is C or N;   when W and X are N, Y and Z are C;   when W and Y are N, X and Z are C;   when W and Z are N, X and Y are C;   when X and Y are N, W and Z are C;   when X and Z are N, W and Y are C;   when Y and Z are N, W and X are C;   when W, X, and Y are C, Z is N;   when W, X, and Z are C, Y is N;   when W, Y, and Z are C, X is N;   when X, Y, and Z are C, W is N;   m is 0, 1, 2, or 3;   R 4  is independently selected from halogen, nitro, SF S , OSF 5 , CHO, C 0-6 alkylCN, OC 1-6 alkylCN, C 0-6 alkylOR 5 , OC 2-6 alkylOR 5 , C 0-6 alkylNR 5 R 6 , OC 2-6 alkylNR 5 R 6 , OC 2-6 alkylOC 2-6 alkylNR 5 R 6 , C 0-6 alkylCO 2 R 5 , OC 1-6 alkylCO 2 R 5  C 0-6 alkylCONR 5 R 6 , OC 1-6 alkylCONR 5 R 6 , OC 2-6 alkylNR 5 (CO)R 6 , C 0-6 alkylNR 5 (CO)R 6 , O(CO)NR 5 R 6 , NR 5 (CO)OR 6 , NR 5 (CO)NR 5 R 6 , O(CO)OR 5 , O(CO)R 5 , C 0-6 alkylCOR 5 , OC 1-6 alkylCOR 5 , NR 5 (CO)(CO)R 5 , NR 5 (CO)(CO)NR 5 R 6 , C 0-6 alkylSR 5 , C 0-6 alkyl(SO 2 )NR 5 R 6 , OC 1-6 alkylNR 5 (SO 2 )R 6 , OC 0-6 alkyl(SO 2 )NR 5 R 6 , C 0-6 alkyl(SO)NR 5 R 6 , OC 1-6 alkyl(SO)NR 5 R 6 , C 0-6 alkylOSO 2 R 5 , SO 3 R 5 , C 0-6 alkylNR 5 (SO 2 )NR 5 R 6 , C 0-6 alkylNR 5 (SO)R 6 , OC 2-6 alkylNR 5 (SO)R 6 , OC 1-6 alkylSO 2 R 5 , C 0-6 alkylSO 2 R 5 , C 0-6 alkylSOR 5 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylC 3-6 cycloalkenyl, C 0-6 alkylC 6 cycloalkynyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, C 0-6 alkylheterocyclyl, and OC 2-6 alkylheterocyclyl, 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, C 0-6 alkylheterocyclyl, or OC 2-6 alkylheterocyclyl is optionally substituted with one or more R 11 , 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 one or more A;   R 5  is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylC 3-6 cycloalkenyl, C 0-6 alkylC 6 cycloalkynyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, C 0-6 alkylheterocyclyl, and C 1-6 alkylNR 7 R 8 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylC 3-6 cycloalkenyl, C 0-6 alkylC 6 cycloalkynyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, or C 0-6 alkylheterocyclyl is optionally substituted with one or more A;   R 6  is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylOR 7 , C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylC 3-6 cycloalkenyl, C 0-6 alkylC 6 cycloalkynyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, C 0-6 alkylheterocyclyl, and C 1-6 alkylNR 7 R 8 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylC 3-6 cycloalkenyl, C 0-6 alkylC 6 cycloalkynyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, or C 0-6 alkylheterocyclyl is optionally substituted with one or more A; or   R 5  and R 6  may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O, and S that is optionally substituted with A; whenever two R 5  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, and S, that is optionally substituted with one or more A;   R 7  and R 8  are independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylC 3-6 cycloalkenyl, C 0-6 alkylC 6 cycloalkynyl, C 0-6 alkylaryl, C 0-6 alkylheterocyclyl, and C 0-6 alkylheteroaryl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylC 3-6 cycloalkenyl, C 0-6 alkylC 6 cycloalkynyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, or C 0-6 alkylheterocyclyl is optionally substituted with one or more A; or   R 7  and R 8  may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O, and S optionally substituted with one or more A;   A is selected from oxo, halogen, nitro, SF S , OSF 5 , CN, OR 9 , 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 9 R 10 , NR 9 R 10 , CONR 9 R 10 , NR 9 (CO)R 10 , O(CO)C 1-6 alkyl, (CO)OC 1-6 alkyl, COR 9 , (SO 2 )NR 9 R 10 , NSO 2 R 9 , SO 2 R 9 , SOR 9 , (CO)C 1-6 alkylNR 9 R 10 , (SO 2 )C 1-6 alkylNR 9 R 10 , OSO 2 R 9 , and SO 3 R 9 , 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, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylC 3-6 cycloalkenyl, or C 0-6 alkylC 6 cycloalkynyl is optionally substituted with halo, OSO 2 R 9 , SO 3 R 9 , nitro, cyano, OR 9 , C 1-6 alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, or trifluoromethoxy;   R 9  and R 10  are independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 6 cycloalkynyl, aryl, heteroaryl, and heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 6 cycloalkynyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one, two, or three hydroxy, cyano, halogen, or C 1-3 alkyloxy; or   R 9  and R 10  may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O and S optionally substituted with hydroxy, C 1-3 alkyloxy, cyano, or halogen; and   R 11  is independently selected from halogen, nitro, SF S , OSF 5 , CHO, C 0-6 alkylCN, OC 1-6 alkylCN, C 0-6 alkylOR 8 , OC 1-6 alkylOR 8 , fluoromethoxy, difluoromethoxy, trifluoromethoxy, C 0-6 alkylNR 5 R 6 , OC 2-6 alkylNR 5 R 6 , OC 2-6 alkylOC 2-6 alkylNR 5 R 6 , NR 5 OR 6 , C 0-6 alkylCO 2 R 5 , OC 1-6 alkylCO 2 R 5 , C 0-6 alkylCONR 5 R 6 , OC 1-6 alkylCONR 5 R 6 , OC 2-6 alkylNR 5 (CO)R 6 , C 0-6 alkylNR 5 (CO)R 6 , O(CO)NR 5 R 6 , NR 5 (CO)OR 6 , NR 5 (CO)NR 5 R 6 , O(CO)OR 5 , O(CO)R 5 , C 0-6 alkylCOR 5 , OC 1-6 alkylCOR 5 , NR 5 (CO)(CO)R 6 , NR 5 (CO)(CO)NR 5 R 6 , C 0-6 alkylSR 5 , C 0-6 alkyl(SO 2 )NR 5 R 6 , OC 2-6 alkylNR 5 (SO 2 )R 6 , OC 0-6 alkyl(SO 2 )NR 5 R 6 , C 0-6 alkyl(SO)NR 5 R 6 , OC 1-6 alkyl(SO)NR 5 R 6 , OSO 2 R 5 , SO 3 R 5 , C 0-6 alkylNR 5 (SO 2 )NR 5 R 6 , C 0-6 alkylNR 5 (SO)R 6 , OC 2-6 alkylNR 5 (SO)R 6 , OC 1-6 alkylSO 2 R 5 , C 0-6 alkylSO 2 R 5 , C 0-6 alkylSOR 5 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylC 3-6 cycloalkenyl, C 0-6 alkylC 6 cycloalkynyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, C 0-6 alkylheterocyclyl, and OC 2-6 alkylheterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylC 3-6 cycloalkenyl, C 0-6 alkylC 6 cycloalkynyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, C 0-6 alkylheterocyclyl, or OC 2-6 alkylheterocyclyl is optionally substituted with one or more A.   
     
     
         3 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein:
 X is C or N;   Y is C;   Z is C or N; and   W is C.   
     
     
         4 . A compound or pharmaceutically acceptable salt thereof according to  claim 3 , wherein:
 X is C;   Y is C;   Z is N; and   W is C.   
     
     
         5 . A compound or pharmaceutically acceptable salt thereof according to  claim 4 , wherein m is 0. 
     
     
         6 . A compound or pharmaceutically acceptable salt thereof according to  claim 4 , wherein R 1  is aryl optionally substituted with one R 4 . 
     
     
         7 . A compound or pharmaceutically acceptable salt thereof according to  claim 6 , wherein R 1  is phenyl substituted with one R 4 . 
     
     
         8 . A compound or pharmaceutically acceptable salt thereof according to  claim 4 , wherein R 4  is C 0-6 alkylheteroaryl optionally substituted with one or more R 11 . 
     
     
         9 . A compound or pharmaceutically acceptable salt thereof according to  claim 8 , wherein R 4  is pyrimidyl. 
     
     
         10 . A compound or pharmaceutically acceptable salt thereof according to  claim 8 , wherein R 4  is pyridyl. 
     
     
         11 . A compound or pharmaceutically acceptable salt thereof according to  claim 8 , wherein R 4  is pyridyl substituted with one halo. 
     
     
         12 . A compound or pharmaceutically acceptable salt thereof according to  claim 8 , wherein R 4  is pyridyl substituted with one methoxy. 
     
     
         13 . A compound or pharmaceutically acceptable salt thereof according to  claim 4 , wherein R 4  is C 0-6 alkylaryl optionally substituted with one or more R 11 . 
     
     
         14 . A compound or pharmaceutically acceptable salt thereof according to  claim 13 , wherein R 4  is phenyl substituted with one halo and one methoxy. 
     
     
         15 . A compound or pharmaceutically acceptable salt thereof according to  claim 4 , wherein R 2  is heteroaryl. 
     
     
         16 . A compound or pharmaceutically acceptable salt thereof according to  claim 15 , wherein R 2  is pyridyl. 
     
     
         17 . A compound or pharmaceutically acceptable salt thereof according to  claim 4 , wherein R 2  is aryl substituted with one R 11 . 
     
     
         18 . A compound or pharmaceutically acceptable salt thereof according to  claim 17 , wherein R 11  is methoxy. 
     
     
         19 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein:
 X is N;   W is C;   Y is C; and   Z is C.   
     
     
         20 . A compound or pharmaceutically acceptable salt thereof according to  claim 19 , wherein m is 0. 
     
     
         21 . A compound or pharmaceutically acceptable salt thereof according to  claim 19 , wherein R 1  is C 0-6 alkylaryl optionally substituted with one R 4 . 
     
     
         22 . A compound or pharmaceutically acceptable salt thereof according to  claim 21 , wherein R 1  is phenyl substituted with one R 4 . 
     
     
         23 . A compound or pharmaceutically acceptable salt thereof according to  claim 22 , wherein R 4  is C 0-6 alkylheteroaryl optionally substituted with one or more R 11 . 
     
     
         24 . A compound or pharmaceutically acceptable salt thereof according to  claim 23 , wherein R 4  is pyrimidyl. 
     
     
         25 . A compound or pharmaceutically acceptable salt thereof according to  claim 23 , wherein R 4  is pyridyl substituted with one halo. 
     
     
         26 . A compound or pharmaceutically acceptable salt thereof according to  claim 19 , wherein R 2  is heteroaryl. 
     
     
         27 . A compound or pharmaceutically acceptable salt thereof according to  claim 26 , wherein R 2  is pyridyl. 
     
     
         28 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein:
 R 1  is aryl substituted with one R 4 ;   R 2  is selected from aryl and heteroaryl, wherein:
 the aryl or heteroaryl is optionally substituted with one R 4 ; 
   W is C;   X is C or N;   Y is C;   Z is C or N;   m is 0;   R 4  is selected from C 0-6 alkylOR 5 , C 0-6 alkylaryl, and C 0-6 alkylheteroaryl, wherein:
 the C 0-6 alkylaryl or C 0-6 alkylheteroaryl is optionally substituted with one or more R 11 ; 
   R 5  is C 1-6 alkyl;   R 8  is C 1-6 alkyl; and   each R 11  is independently selected from halogen and C 0-6 alkylOR 8 .   
     
     
         29 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein:
 X is C;   W is N;   Y is C; and   Z is C.   
     
     
         30 . A compound or pharmaceutically acceptable salt thereof according to  claim 29 , wherein m is 0. 
     
     
         31 . A compound or pharmaceutically acceptable salt thereof according to  claim 29 , wherein R 1  is C 0-6 alkylaryl optionally substituted with one R 4 . 
     
     
         32 . A compound or pharmaceutically acceptable salt thereof according to  claim 29 , wherein R 1  is phenyl substituted with one R 4 . 
     
     
         33 . A compound or pharmaceutically acceptable salt thereof according to  claim 29 , wherein R 4  is C 0-6 alkylheteroaryl or C 0-6 alkylaryl, wherein:
 the C 0-6 alkylheteroaryl or C 0-6 alkylaryl is optionally substituted with one or more R 11 .   
     
     
         34 . A compound or pharmaceutically acceptable salt thereof according to  claim 29 , wherein R 4  is C 0-6 alkylheteroaryl optionally substituted with one or more R 11 . 
     
     
         35 . A compound or pharmaceutically acceptable salt thereof according to  claim 29 , wherein R 4  is pyrimidyl. 
     
     
         36 . A compound or pharmaceutically acceptable salt thereof according to  claim 29 , wherein R 4  is pyridyl substituted with one halo. 
     
     
         37 . A compound or pharmaceutically acceptable salt thereof according to  claim 29 , wherein:
 R 4  is phenyl substituted with two R 11 , and   each R 11  is independently selected from halogen and C 0-6 alkylOR 8 .   
     
     
         38 . A compound or pharmaceutically acceptable salt thereof according to  claim 29 , wherein R 2  is pyridyl. 
     
     
         39 . A compound or pharmaceutically acceptable salt thereof according to  claim 29 , wherein:
 R 1  is aryl substituted with one R 4 ;   R 2  is heteroaryl;   W is N;   X is C;   Y is C;   Z is C;   m is 0;   R 4  is selected from C 0-6 alkylaryl and C 0-6 alkylheteroaryl, wherein:
 the C 0-6 alkylaryl or C 0-6 alkylheteroaryl is optionally substituted with one or more R 11 ; and 
   each R 11  is independently selected from halogen and C 0-6 alkylOR 8 .   
     
     
         40 . A compound or pharmaceutically acceptable salt thereof, wherein the compound is selected from:
 5-(4-Methoxyphenyl)-5-(3-pyrimidin-5-ylphenyl)-5H-pyrrolo[3,4-b]pyridin-7-amine;   5-[3-(2-Fluoropyridin-3-yl)phenyl]-5-(4-methoxyphenyl)-5H-pyrrolo[3,4-b]pyridin-7-amine;   5-(4-Methoxyphenyl)-5-[3-(5-methoxypyridin-3-yl)phenyl]-5H-pyrrolo[3,4-b]pyridin-7-amine;   5-(4-Methoxyphenyl)-5-(3-pyridin-3-ylphenyl)-5H-pyrrolo[3,4-b]pyridin-7-amine;   5-[3-(2-Fluoropyridin-3-yl)phenyl]-5-pyridin-4-yl-5H-pyrrolo[3,4-b]pyridin-7-amine;   5-Pyridin-4-yl-5-(3-pyrimidin-5-ylphenyl)-5H-pyrrolo[3,4-b]pyridin-7-amine;   5-(2′-Fluoro-5′-methoxybiphenyl-3-yl)-5-pyridin-4-yl-5H-pyrrolo[3,4-b]pyridin-7-amine 0.25 acetate;   5-(2′-Fluoro-3′-methoxybiphenyl-3-yl)-5-pyridin-4-yl-5H-pyrrolo[3,4-b]pyridin-7-amine 0.5 acetate;   3-Pyridin-4-yl-3-(3-pyrimidin-5-ylphenyl)-3H-pyrrolo[3,4-c]pyridin-1-amine;   3-[3-(2-Fluoropyridin-3-yl)phenyl]-3-pyridin-4-yl-3H-pyrrolo[3,4-c]pyridin-1-amine;   7-[3-(2-Fluoropyridin-3-yl)phenyl]-7-pyridin-4-yl-7H-pyrrolo[3,4-b]pyridin-5-amine;   7-Pyridin-4-yl-7-(3-pyrimidin-5-ylphenyl)-7H-pyrrolo[3,4-b]pyridin-5-amine; and   7-(2′-Fluoro-3′-methoxybiphenyl-3-yl)-7-pyridin-4-yl-7H-pyrrolo[3,4-b]pyridin-5-amine.   
     
     
         41 . A pharmaceutical formulation, wherein the formulation 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.   
     
     
         42 - 46 . (canceled) 
     
     
         47 . A method of inhibiting activity of BACE, wherein the method comprises contacting BACE with a compound or pharmaceutically acceptable salt thereof according to  claim 1 . 
     
     
         48 . 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 . 
     
     
         49 . The method of  claim 48 , wherein said Aβ-related pathology is 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, or cortical basal degeneration. 
     
     
         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. 
 
     
     
         52 . The method of  claim 51 , wherein the Aβ-related pathology is 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, or cortical basal degeneration. 
     
     
         53 . The method of  claim 51 , wherein the mammal is a human.