Novel Gamma Secretase inhibitors

Abstract

This invention discloses novel gamma secretase inhibitors of the formula: wherein: R 1 is a substituted aryl or substituted heteroaryl group; R 2 is an R 1 group, alkyl, —X(CO)Y, or alkylene-X(CO)Y wherein X and Y are as defined herein; each R 3 and each R 3A are independently H, or alkyl; R 11 is aryl, heteroaryl, alkyl, cycloalkyl, arylalkyl, arylcycloalkyl, heteroarylalkyl, heteroarylcycloalkyl, arylheterocycloalkyl, or alkoxyalkyl. Also disclosed is a method of treating Alzheimer's Disease using one or more compounds of the invention.

1 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein: 
 (A) R 1  is selected from the group consisting of:  
 (1) unsubstituted aryl;  
 (2) aryl substituted with one or more (e.g., 1-3) R 5  groups;  
 (3) unsubstituted heteroaryl; and  
 (4) heteroaryl substituted with one or more (e.g., 1-3) R 5  groups;  
 (B) R 2  is selected from the group consisting of:  
 (1) alkyl;  
 (2) —X(CO)Y;  
 (3) —(C 1 -C 6 )alkylene-X(CO)Y;  
 (4) —(C 0 -C 6 )alkylene-(C 2 -C 6 )cycloalkylene-(CO—C 6 )alkylene-X(CO)Y;  
 (5) aryl;  
 (6) aryl substituted with one or more (e.g., 1-3) R 5  groups;  
 (7) heteroaryl;  
 (8) heteroaryl substituted with one or more (e.g., 1-3) R 5  groups;  
 (C) Each R 3  is independently selected from the group consisting of:  
 (1) H, and  
 (2) alkyl, and  
 (D) Each R 3A  and R 3B  are independently selected from the group consisting of:  
 (1) H; and  
 (2) alkyl;  
 (E) R 5  is independently selected from the group consisting of:  
 (1) halo;  
 (2) —CF 3 ;  
 (3) —OH;  
 (4)-Oalkyl;  
 (5) —OCF 3 ;  
 (6) —CN;  
 (7) —NH 2 ;  
 (8) —CO 2 alkyl;  
 (9) —CONR 6 R 7 ;  
 (10)-alkylene-NR 6 R 7 ;  
 (11) —NR 6 COalkyl;  
 (12) —NR 6 COaryl;  
 (13) —NR 6 COheteroaryl; and  
 (14) —NR 6 CONR 6 R 7 ;  
 (F) X is selected from the group consisting of:  
 (1) —O—;  
 (2) —NH—;  
 (3) -Nalkyl; and  
 (4) -Oalkylene;  
 (G) Y is selected from the group consisting of:  
 (1) —NR 6 R 7 ;  
 (2) —N(R 3 )(CH 2 ) b NR 6 R 7  wherein b is 2-6;  
 (3) unsubstituted aryl;  
 (4) unsubstituted heteroaryl;  
 (5)-alkyl;  
 (6)-cycloalkyl,  
 (7) unsubstituted arylalkyl;  
 (8) unsubstituted arylcycloalkyl;  
 (9) unsubstituted heteroarylalkyl;  
 (10) unsubstituted heteroarylcycloalkyl;  
 (11) unsubstituted arylheterocycloalkyl;  
 (12) substituted aryl;  
 (13) substituted heteroaryl;  
 (14) substituted arylalkyl;  
 (15) substituted arylcycloalkyl;  
 (16) substituted heteroarylalkyl;  
 (17) substituted heteroarylcycloalkyl; and  
 (18) substituted arylheterocycloalkyl;  
 wherein the aryl moiety in said substituted groups (12), (14), (15) and (18) of said Y group, and the heteroaryl moiety in said substituted groups (13), (16), and (17) of said Y group, are substituted with one or more (e.g., 1 to 3) substituents independently selected from the group consisting of:  
 (a) halo;  
 (b) —CF 3 ;  
 (c) —OH;  
 (d) —Oalkyl;  
 (e) —OCF 3 ;  
 (f) —CN;  
 (g) —NH 2 ;  
 (h) —CO 2 (C 1 -C 6 )alkyl;  
 (i) —C(O)NR 6 R 7 ;  
 (j) —(C 1 -C 6 )alkylene-NR 6 R 7 ;  
 (k) —NR 6 COalkyl;  
 (l) —NR 6 COaryl;  
 (m) —NR 6 COheteroaryl; and  
 (n) —NR 6 CONR 6 R 7 ;  
 or Y is selected from the group consisting of:  
                     
 (H)R 6  and R 7  are independently selected from the group consisting of  
 (1) H;  
 (2) alkyl;  
 (3) cycloalkyl;  
 (4) arylalkyl;  
 (5) heteroarylalkyl;  
 (6)  
 (7)  
                     
 (I) Each R 8  is independently selected from the group consisting of:  
 (1) alkyl; and  
 (2) alkyl substituted with 1 to 4 hydroxy groups;  
 (J) Each R 9  is independently selected from the group consisting of:  
 (1) H;  
 (2) alkyl;  
 (3) alkyl substituted with 1 to 4 hydroxy groups;  
 (4) cycloalkyl;  
 (5) cycloalkyl substituted with 1 to 4 hydroxy groups;  
 (6) arylalkyl;  
 (7) heteroarylalkyl;  
 (8) —C(O)Oalkyl;  
 (9) alkylene-O-alkylene-OH (preferably, —(C 2 -C 6 )alkylene-O—(C 1 -C 6 )alkylene-OH, most preferably —(CH 2 ) 2 —O—(CH 2 ) 2 —OH);  
 (10) aryl substituted with one or more (e.g., 1-3) R 5  groups; and  
 (11) heteroaryl substituted with one or more (e.g., 1-3) R 5  groups;  
 (12) unsubstituted heteroaryl;  
 (13) unsubstituted aryl; and  
 (14)-alkylene-C(O)Oalkyl (e.g., —(C 1 -C 6 )alkylene-C(O)O(C 1 -C 6 )alkyl);  
 (K) Each R 10  is independently selected from the group consisting of:  
 (1) H; and  
 (2) alkyl;  
 (L) R 11  is selected from the group consisting of:  
 (1) unsubstituted aryl;  
 (2) substituted aryl;  
 (3) unsubstituted heteroaryl,  
 (4) alkyl;  
 (5) cycloalkyl;  
 (6) unsubstituted arylalkyl;  
 (7) unsubstituted arylcycloalkyl,  
 (8) unsubstituted heteroarylalkyl;  
 (9) unsubstituted heteroarylcycloalkyl;  
 (10) unsubstituted arylheterocycloalkyl;  
 (11) alkoxyalkyl;  
 (12) substituted heteroaryl;  
 (13) substituted arylalkyl;  
 (14) substituted arylcycloalkyl;  
 (15) substituted heteroarylalkyl;  
 (16) substituted arylheterocycloalkyl;  
 wherein the aryl moiety in said substituted groups (2), (13), (14) and (16) of said R 11  group, and the heteroaryl moiety in said substituted groups (12) and (15) of said R 11  group, are substituted with one or more (e.g., 1 to 3) substituents independently selected from the group consisting of:  
 (a) halo;  
 (b) —CF 3 ;  
 (c) —OH;  
 (d) —Oalkyl;  
 (e) —OCF 3 ;  
 (f) —CN;  
 (g) —NH 2 ;  
 (h) —CO 2 (C 1 -C 6 )alkyl;  
 (i) —CONR 6 R 7 ;  
 (j) —(C 1 -C 6 )alkylene-NR 6 R 7    
 (k) —NR 6 COalkyl;  
 (l) —NR 6 COaryl;  
 (m) —NR 6 COheteroaryl; and  
 (n) —NR 6 CONR 6 R 7 ;  
 (M) m is 0 to 3, and n is 0 to 3, o is 0-3, such that m+n+o is 1, 2, 3 or 4;  
 (N) p is 0 to 4;  
 (O) r is 0 to 4;  
 (P) s is 0 to 3; and  
 (Q) Z is selected from the group consisting of:  
 (1) unsubstituted heterocycloalkyl;  
 (2) substituted heterocycloalkyl;  
 (3) —NH 2 ;  
 (4) —NH(alkyl);  
 (5) —N(alkyl) 2  wherein each alkyl is the same or different;  
 (6) —NH(unsubstituted cycloalkyl);  
 (7) —NH(substituted cycloalkyl);  
 (8) —N(alkyl)(unsubstituted cycloalkyl);  
 (9) —N(alkyl)(substituted cycloalkyl);  
 (10) —NH(unsubstituted aralkyl);  
 (11) —NH(substituted aralkyl);  
 (12) —N(alkyl)(aralkyl);  
 (13) —NH(unsubstituted heterocycloalkyl);  
 (14) —NH(substituted heterocycloalkyl);  
 (15) —N(alkyl)(unsubstituted heterocycloalkyl),  
 (16) —N(alkyl)(substituted heterocycloalkyl);  
 (17) —NH(unsubstituted heteroaralkyl);  
 (18) —NH(substituted heteroaralkyl);  
 (19) —NH-alkylene-(unsubstituted cycloalkyl);  
 (20) —NH-alkylene-(substituted cycloalkyl);  
 (21) —N(alkyl)alkylene-(unsubstituted cycloalkyl);  
 (22) —N(alkyl)alkylene-(substituted cycloalkyl);  
 (23) —NHalkylene-(unsubstituted heterocycloalkyl);  
 (24) —NHalkylene-(substituted heterocycloalkyl);  
 (25) —N(alkyl)alkylene-(unsubstituted heterocycloalkyl);  
 (26) —N(alkyl)alkylene-(substituted heterocycloalkyl);  
 (27) unsubstituted benzofused heterocycloalkyl (e.g., structures o and ab); and  
 (28) substituted benzofused heterocycloalkyl;  
 wherein said substituted heterocycloalkyl moiety of substituents (2), (14), (16), (24),  
 (26) and (27) of group Z, and said substituted cycloalkyl moiety of substituents (7), (9), (20) and (22) of group Z, and said substituted aryl moiety of substituent (11) of group Z, and said substituted heteroaryl moiety of substituent (18) of group Z, are substituted with 1 to 3 groups independently selected from the group consisting of:  
 (a) alkyl;  
 (b) —OH;  
 (c) —Oalkyl;  
 (d) —O(CO)alkyl;  
 (e) —O(CO)aryl;  
 (f) —NH 2 ;  
 (g) —NH(alkyl);  
 (h) —N(alkyl) 2  wherein each alkyl is the same or different;  
 (i) —NH(CO)alkyl;  
 (j)—N(alkyl)(CO)alkyl;  
 (k) —NH(CO)aryl;  
 (l) —N(alkyl)(CO)aryl;  
 (m) —COalkyl;  
 (n) —COaryl;  
 (O)—CONH 2 ;  
 (p) —CONH(alkyl);  
 (q) —CON(alkyl) 2  wherein each alkyl is the same or different;  
 (r) —COOalkyl;  
 (s) -alkylene-C(O)Oalkyl (e.g., —(C 1 -C 3 )alkylene-C(O)O(C 1 -C 6 )alkyl);  
 (t) piperidinyl;  
 (u) pyrrolidinyl;  
 (v) 1,1-ethylenedioxy;  
 (w) aryl;  
 (x) heteroaryl; and  
 (y) —O—CH 2 CH 2 —O— wherein both oxygen atoms are bound to the same carbon atom, and provided that the aryl and heteroaryl moieties of said Z group are not substituted with said —O—CH 2 CH 2 —O— group.  
 
     
     
         2 . The compound of  claim 1  wherein: 
 (A) R 1  is aryl substituted with one or more R 5  groups;    (B) n is 0 or 1 and m is 1, 2 or 3 such that m+n is 3;    (C) p is 0 or 1; and    (D) R 2  is —X(CO)Y, —(C 1 -C 6 )alkylene-X(CO)Y or —(C 0 -C 6 )alkylene-(C 2 -C 6 )cycloalkylene-(C 0 -C 6 )alkylene-X(CO)Y.    
     
     
         3 . The compound of  claim 2  wherein: 
 (A) R 1  is phenyl substituted with one or more R 5  groups; and    (B) n is 0 and m is 3.    
     
     
         4 . The compound of  claim 1 , wherein R 2  is  
       
         
           
           
               
               
           
         
       
       wherein X and Y are as defined.  
     
     
         5 . The compound of  claim 3  wherein R 11  is phenyl substituted with one or more halo atoms.  
     
     
         6 . The compound of  claim 1  wherein: 
 (A) R 11  is aryl substituted with one or more R 5  groups;    (B) n is 0 or 1 and m is 1, 2 or 3 such that m+n is 3;    (C) p is 0 or 1;    (D) R 2  is —X(CO)Y, —(C 1 -C 6 )alkylene-X(CO)Y or —(CO—C 6 )alkylene-(C 2 -C 6 )cycloalkylene-(CO—C 6 )alkylene-X(CO)Y;    (E) X is O;    (F) Y is —NR 6 R 7 ; or Y is selected from the group consisting of:                          (G) R 6  and R 7  are independently selected from the group consisting of: H, methyl, ethyl, —(C 3 -C 8 )cycloalkyl, -aryl(C 1 -C 6 )alkyl, 4-pyridylmethyl, and                          
     
     
         7 . The compound of  claim 6  wherein: 
 (A) R 11  is phenyl substituted with one or more R 5  groups;    (B) n is 0 and m is 3;    (C) said group                          is a group of the formula:                          (D) said group                          is a group of the formula:                          (E) R 11  is selected from the group consisting of: —(C 1 -C 6 )alkyl, (C 3 -C 8 )-cycloalkyl, aryl, aryl(C 1 -C 6 )alkyl and —(C 1 -C 6 )alkoxyalkyl.    
     
     
         8 . The compound of  claim 7  wherein said R 11  is selected from the group consisting of: methyl, ethyl, cyclohexyl, phenyl, benzyl, —(CH 2 ) 2 phenyl, and —CH 2 OCH 3 .  
     
     
         9 . The compound of  claim 7  wherein R 1  is phenyl substituted with one or more halo atoms.  
     
     
         10 . The compound of  claim 8  wherein R 11  is phenyl substituted with one or more halo atoms.  
     
     
         11 . The compound of  claim 6  wherein Y is selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 1  selected from a final compound of Examples 1-29, 31-33, 35-48, 50-61, 63-67, 67A-67BR, 68,69,71-74, 74A, 74B, 74C, 75, 76, 78-83, 85-99,101-159, 159A, 159B, 159C, 160, 160A-160AA, 161, 161A-161G, 162, 162A, 162B, 162C, 164, 164A, 164B, 164C, 165-167, 167A, 167B, 167C, 168, 168A, 169, 169A-169D, 170, 170A-170AD, 171-173, 173A-173T, and 174.  
     
     
         13 . The compound of  claim 1  selected from a final compound of Examples 67B, 67E, 67N, 67P, 67U, 67AG, 67AT, 67AW, 67AY, 67BA, 67BD, 67BE, 67BG, 67BH, 67BL, 160B, 160K, 161, 161A, 161E, 161F, 173, 173A, 173B, 173C, 173E, 173G, 1731, 173J, 173K, 173L and 173N.  
     
     
         14 . The compound of  claim 1  selected from a final compound of Examples 7-B, 7-AT, 7-BG, 61-A, 73, 73-A, 73-C, 73-E, 73-J, and 73-N.  
     
     
         15 . A pharmaceutical composition comprising at least one compound of  claim 1  and at least one pharmaceutically acceptable carrier.  
     
     
         16 . A method of inhibiting gamma-secretase in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of one or more compounds of  claim 1 .  
     
     
         17 . A method of treating one or more neurodegenerative diseases in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of one or more compounds of  claim 1 .  
     
     
         18 . A method of inhibiting the deposition of beta amyloid protein in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of one more compounds of  claim 1 .  
     
     
         19 . A method of treating Alzheimer's disease in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of one or more compounds of  claim 1.