Novel gamma secretase inhibitors

Abstract

Novel aryl and heteroaryl sulfonamides are disclosed. The sulfonamides, which are gamma secretase inhibitors, are represented by the formula: wherein Ar 1 and Ar 2 independently represent aryl or heteroaryl and Y represents a bond or a —(C(R 3 ) 2 ) 1-3 group. Also disclosed is a method of inhibiting gamma secretase, and a method of treating Alzheimer's disease using the compounds of formula I.

1 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts or solvates thereof, wherein: 
 (A) Ar 1  and Ar 2  are independently selected from aryl or heteroaryl;  
 (B) Y is bond, or Y is a —(C(R 3 ) 2 ) 1-3 — group;  
 (C) each R 1  is independently selected from: 
 (1) —(C 1 -C 6 )alkyl;  
 (2) aryl;  
 (3) aryl substituted with one or more substituents independently selected from: halogen, CF 3 , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, OCF 3 , NH 2 , or CN;  
 (4) heteroaryl;  
 (5) heteroaryl substituted with one or more substituents independently selected from: halogen, CF 3 , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, OCF 3 , NH 2 , or CN;  
 (6) halogen;  
 (7) —CF 3 ;  
 (8) —OCF 3 ;  
 (9) —CN;  
 (10) —NO 2 ;  
 (11) —NH 2 ;  
 (12) —C(O)NH(C 1 -C 6 )alkyl;  
 (13) —C(O)N((C 1 -C 6 )alkyl) 2  wherein each (C 1 -C 6 )alkyl group is the same or different;  
 (14) —C(O)N((C 1 -C 6 )alkyl) 2  wherein each (C 1 -C 6 )alkyl group is the same or different, and said (C 1 -C 6 )alkyl groups taken together with the nitrogen to which they are bound form a ring;  
 (15) —NHC(O)(C 1 -C 6 )alkyl;  
 (16) —NHC(O)O(C 1 -C 6 )alkyl;  
 (17) —NHC(O)NH(C 1 -C 6 )alkyl;  
 (18) —NHSO 2 (C 1 -C 6 )alkyl;  
 (19) —OH;  
 (20) —OC(O)(C 1 -C 6 )alkyl;  
 (21) —O(C 1 -C 6 )alkyl,  
 (22) —Oaryl; or  
 (23) —Oar(C 1 -C 6 )alkyl;  
 
 (D) each R 2  is independently selected from: 
 (1) —(C 1 -C 6 )alkyl;  
 (2) halogen;  
 (3) —CF 3 ;  
 (4) —OCF 3 ;  
 (5) —CN;  
 (6) —NO 2 ;  
 (7) —NH 2 ;  
 (8) —C(O)O(C 1 -C 6 )alkyl;  
 (9) —C(O)NH(C 1 -C 6 )alkyl;  
 (10) —N(C 1 -C 6 alkyl) 2  wherein each C 1 -C 6 alkyl substituent is the same or different;  
 (11) —N(C 1 -C 6 alkyl) 2  wherein each C 1 -C 6 alkyl substituent is the same or different, and the C 1 -C 6 alkyl substituents together with the nitrogen atom to which they are bound form a ring;  
 (12) —NHC(O)(C 1 -C 6 )alkyl;  
 (13) —NHC(O)O(C 1 -C 6 )alkyl;  
 (14) —NHC(O)NH(C 1 -C 6 )alkyl;  
 (15) —NHSO 2 (C 1 -C 6 )alkyl;  
 (16) —OH;  
 (17) —OC(O)(C 1 -C 6 )alkyl;  
 (18) —O(C 1 -C 6 )alkyl;  
 (19) —Oaryl;  
 (20) —Oar(C 1 -C 6 )alkyl;  
 (21) -aryl;  
 (22) -aryl substituted with one or more substituents independently selected from: halogen, CF 3 , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, OCF 3 , NH 2 , or CN;  
 (23) -heteroaryl;  
 (24) -heteroaryl substituted with one or more substituents independently selected from: halogen, CF 3 , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, OCF 3 , NH 2 , or CN;  
 (25) -a group selected from:  
                     
 (26) —C(O)N((C 1 -C 6 )alkyl) 2  wherein each alkyl group is independently selected; or  
 (27) —C(O)N((C 1 -C 6 )alkyl) 2  wherein each alkyl group is independently selected and wherein the alkyl groups taken together with the nitrogen atom form a heterocycloalkyl ring;  
 
 (E) each R 3  is independently selected from H or —(C 1 -C 3 )alkyl;  
 (F) each R 4  is independently selected from: 
 (1) —(C 1 -C 3 )alkyl;  
 (2) —OH; or  
 (3) —O(C 1 -C 3 )alkyl;  
 
 (G) R 5  is selected from: 
 (1) hydrogen;  
 (2) —(C 1 -C 6 )alkyl;  
 (3) -aryl;  
 (4) -heteroaryl;  
 (5) —(C 1 -C 3 )alkylene-O(C 1 -C 3 )alkyl;  
 (6) —(C 1 -C 6 )alkylene-S(O) 0-2 (C 1 -C 3 )alkyl;  
 (7) —(C 1 -C 6 )alkylene-S(O) 0-2 NH(C 1 -C 3 )alkyl;  
 (8) —C(O)(C 1 -C 6 )alkyl;  
 (9) —C(O)aryl;  
 (10) —C(O)ar(C 1 -C 3 )alkyl;  
 (11) —C(O)heteroaryl;  
 (12) —C(O)heteroar(C 1 -C 3 )alkyl;  
 (13) —C(O)O(C 1 -C 6 )alkyl;  
 (14) —C(O)NH(C 1 -C 6 )alkyl;  
 (15) —C(O)N((C 1 -C 6 )alkyl) 2  wherein each C 1 -C 6 alkyl group is the same or different;  
 (16) —C(O)N((C 1 -C 6 )alkyl) 2  wherein each C 1 -C 6 alkyl group is the same or different and wherein the C 1 -C 6  alkyl groups taken together with the nitrogen to which they are bound form a heterocycloalkyl ring;  
 (17) —C(O)(C 1 -C 3 )alkylene-NH(C 1 -C 3 )alkyl;  
 (18) —C(O)(C 1 -C 3 )alkylene-N((C 1 -C 3 )alkyl) 2  wherein each alkyl group is independently selected;  
 (19) —SO 2 (C 1 -C 6 )alkyl;  
 (20) —SO 2 NH(C 1 -C 6 )alkyl;  
 (21) —SO 2 N((C 1 -C 6 )alkyl) 2  wherein each C 1 -C 6 alkyl is the same or different;  
 (22) —SO 2 N((C 1 -C 6 )alkyl) 2  wherein each C 1 -C 6 alkyl is the same or different, and wherein the C 1 -C 6  alkyl groups taken together with the nitrogen to which they are bound form a heterocycloalkyl ring; or  
 (23) a group of the formula:  
                     
 
 (H) R 6  is —H or —(C 1 -C 6 ) alkyl;  
 (I) X is selected from: CH 2 , O, S, SO, SO 2 , or N—R 7 ;  
 (J) R 7  is selected from: 
 (1) —(C 1 -C 6 )alkyl;  
 (2) —(C 3 -C 6 )cycloalkyl;  
 (3) —(C1-C3)alkylene-(C3-C6)cycloalkyl;  
 (4) -aryl;  
 (5) -ar(C 1 -C 3 )alkyl;  
 (6) -heteroaryl;  
 (7) -heteroar(C 1 -C 3 )alkyl;  
 (8) —C(O)(C 1 -C 6 )alkyl;  
 (9) —C(O)aryl;  
 (10) —C(O)ar(C 1 -C 3 )alkyl;  
 (11) —C(O)heteroaryl;  
 (12) —C(O)heteroar(C 1 -C 3 )alkyl;  
 (13) —C(O)O(C 1 -C 6 )alkyl;  
 (14) —C(O)NH(C 1 -C 6 )alkyl;  
 (15) —C(O)N((C 1 -C 6 )alkyl) 2  wherein each C 1 -C 6 alkyl group is the same or different;  
 (16) —C(O)N((C 1 -C 6 )alkyl) 2  wherein each C 1 -C 6 alkyl group is the same or different, and the C 1 -C 6 alkyl groups taken together with the nitrogen to which they are bound form a heterocycloalkyl ring;  
 (17) —C(O)(C 1 -C 3 )alkylene-NH(C 1 -C 3 )alkyl;  
 (18) —C(O)(C 1 -C 3 )alkylene-N((C 1 -C 3 )alkyl) 2  wherein the C 1 -C 3 alkyl groups are the same or different; or  
 (19) —(C 1 -C 3 )alkylene-O—(C 1 -C 3 )alkyl;  
 
 (K) n and p are independently selected from 0 to 3 to form a 4 to 7 member ring;  
 (L) r is 0 to 3;  
 (M) q is 0 to 3; and  
 (N) t is 0 to 3.  
 
     
     
         2 . The compound of  claim 1  having the formula:  
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1  having the formula:  
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1  wherein: 
 (1) Ar 1  is a 1,4-arylene;    (2) R 1  is selected from: halo, CF 3 , OCF 3 , —CN, —NO 2 , —NH 2 , —NHC(O)(C 1 -C 6 )alkyl, —NHSO 2 (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, or substituted aryl;    (3) r is 1;    (4) t is 0;    (5) n and p are selected so that a 3-piperidine, a 4-piperidine or a 3-pyrrolidine ring is formed; and    (6) Y is selected from: a bond or methylene.    
     
     
         5 . The compound of  claim 4  wherein: 
 (1) Ar 1  is phenyl;    (2) R 1  is halo, —CF 3 , —OCF 3 , or —O(C 1 -C 3 )alkyl; and    (3) n and p are selected so that a 3-piperidine ring is formed.    
     
     
         6 . The compound of  claim 5  wherein when R 1  is halo said halo is chloro.  
     
     
         7 . The compound of  claim 2  wherein: 
 (1) Ar 1  is a 1,4-arylene;    (2) R 1  is selected from: halo, CF 3 , OCF 3 , —CN, —NO 2 , —NH 2 , —NHC(O)(C 1 -C 6 )alkyl, —NHSO 2 (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, or substituted aryl;    (3) r is 1;    (4) t is 0;    (5) n and p are selected so that a 3-piperidine, a 4-piperidine or a 3-pyrrolidine ring is formed;    (6) Ar 2  is a 1,4-arylene;    (7) R 2  is selected from: 
 (a) —O(C 1 -C 3 )alkyl,  
 (b) —C(O)O(C 1 -C 6 )alkyl,  
 (c) —C(O)NH(C 1 -C 6 )alkyl,  
 (d) —C(O)N((C 1 -C 6 )alkyl) 2 ,  
 (e) —C(O)N((C 1 -C 6 )alkyl) 2  wherein the alkyl groups taken together with the nitrogen to which they are bound form a heterocycloalkyl ring,  
 (f) substituted aryl,  
 (g) substituted heteroaryl;  
   (8) q is 1;    (9) R 5  is selected from: 
 (a) —(C 1 -C 3 )alkylene-(substituted)aryl,  
 (b) substituted aryl,  
 (c) —(C 1 -C 3 )alkylene-(substituted)heteroaryl,  
 (d) substituted heteroaryl,  
 (e) —C(O)(C 1 -C 6 )alkyl,  
 (f) —C(O)-ar(C 1 -C 3 )alkyl,  
 (g) —C(O)aryl,  
 (h) —C(O)-heteroar(C 1 -C 3 )alkyl,  
 (i) —C(O)heteroaryl,  
 (j) —C(O)O(C 1 -C 6 )alkyl,  
 (k) —C(O)NH(C 1 -C 6 )alkyl,  
 (l) —C(O)N((C 1 -C 6 )alkyl) 2 ,  
 (m) —C(O)N((C 1 -C 6 )alkyl) 2  wherein the alkyl groups taken together with the nitrogen to which they are bound form a heterocycloalkyl ring,  
 (n) —C(O)(C 1 -C 3 )alkylene-NH(C 1 -C 3 )alkyl, or  
   (o) —C(O)(C 1 -C 3 )alkylene-N((C 1 -C 3 )alkyl) 2 .    
     
     
         8 . The compound of  claim 7  wherein: 
 (1) Ar 1  is phenyl;    (2) R 1  is selected from: halo, —CF 3 , —OCF 3 , or —O(C 1 -C 3 )alkyl;    (3) n and p are selected so that a 3-piperidine ring is formed;    (4) Ar 2  is phenyl;    (5) R 2  is selected from: 
 (a) —C(O)O(C 1 -C 6 )alkyl, or  
 (b) substituted heteroaryl;  
   (4) R 5  is selected from: 
 (a) —C(O)(C 1 -C 6 )alkyl,  
 (b) —C(O)-ar(C 1 -C 3 )alkyl,  
 (c) —C(O)-heteroar(C 1 -C 3 )alkyl, or  
 (d) —C(O)O(C 1 -C 6 )alkyl;  
   
     
     
         9 . The compound of  claim 8  wherein: R 2  is 4-CO 2 CH 3 ; and R 5  is selected from: (a) —C(O)-ar(C 1 -C 3 )alkyl, or (b) —C(O)-heteroar(C 1 -C 3 )alkyl.  
     
     
         10 . The compound of  claim 9  wherein when R 1  is halo said halo is chloro.  
     
     
         11 . The compound of  claim 3  wherein: 
 (1) Ar 1  is a 1,4-arylene;    (2) R 1  is selected from: halo, CF 3 , OCF 3 , —CN, —NO 2 , —NH 2 , —NHC(O)(C 1 -C 6 )alkyl, —NHSO 2 (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, or substituted aryl;    (3) r is 1;    (4) t is 0;    (5) n and p are selected so that a 3-piperidine, a 4-piperidine or a 3-pyrrolidine ring is formed;    (6) Ar 2  is phenyl;    (2) R 2  is selected from: —O(C 1 -C 3 )alkyl or halogen; and    (3) R 5  is selected from: 
 (a) —(C 1 -C 3 )alkylene-(substituted)aryl,  
 (b) substituted aryl,  
 (c) —(C 1 -C 3 )alkylene-(substituted)heteroaryl,  
 (d) substituted heteroaryl,  
 (e) —C(O)(C 1 -C 6 )alkyl,  
 (f) —C(O)-ar(C 1 -C 3 )alkyl,  
 (g) —C(O)aryl,  
 (h) —C(O)-heteroar(C 1 -C 3 )alkyl,  
 (i) —C(O)heteroaryl,  
 (j) —C(O)O(C 1 -C 6 )alkyl,  
 (k) —C(O)NH(C 1 -C 6 )alkyl,  
 (l) —C(O)N((C 1 -C 6 )alkyl) 2 ,  
 (m) —C(O)N((C 1 -C 6 )alkyl) 2  wherein the alkyl groups taken together with the nitrogen to which they are bound form a heterocycloalkyl ring,  
 (n) —C(O)(C 1 -C 3 )alkylene-NH(C 1 -C 3 )alkyl, or  
 (o) —C(O)(C 1 -C 3 )alkylene-N((C 1 -C 3 )alkyl) 2 .  
   
     
     
         12 . The compound of  claim 11  wherein: 
 (1) Ar 1  is phenyl;    (2) R 1  is selected from: halo, —CF 3 , —OCF 3 , or —O(C 1 -C 3 )alkyl;    (3) n and p are selected so that a 3-piperidine ring is formed;    (4) R 2  is halogen;    (5) R 5  is selected from: 
 (a) —C(O)NH(C 1 -C 6 )alkyl,  
 (b) —C(O)N((C 1 -C 6 )alkyl) 2 , or  
 (c) —C(O)N((C 1 -C 6 )alkyl) 2  wherein the alkyl groups taken together with the nitrogen to which they are bound form a heterocycloalkyl ring.  
   
     
     
         13 . The compound of  claim 12  wherein: R 5  is:  
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 12  wherein: R 5  is:  
       
         
           
           
               
               
           
         
       
       wherein R 6  is methyl.  
     
     
         15 . The compound of  claim 12  wherein: R 5  is:  
       
         
           
           
               
               
           
         
       
       wherein R 6  is methyl or hydrogen, and R 7  is selected from: —(C 1 -C 3 )alkyl, —(C 1 -C 3 )alkylene-O—(C 1 -C 3 )alkyl, —(C 3 -C 6 )cycloalkyl or —(C1-C3)alkylene-(C3-C6)cycloalkyl.  
     
     
         16 . The compound of  claim 15  wherein R 6  is H.  
     
     
         17 . The compound of  claim 12  wherein when R 1  is halo said halo is chloro.  
     
     
         18 . The compound of  claim 1  selected from: a compound of Examples 1 to 230.  
     
     
         19 . The compound of  claim 1  selected from: a compound of Examples 14, 16, 17, 18, 20, 56, 62, 79, 161, 162, 180, 181, 182, 208, 209, 213, 214, 215, 216, 217, 218, 219 or 220.  
     
     
         20 . A pharmaceutical composition comprising at least one compound of  claim 1  and at least one pharmaceutically acceptable carrier.  
     
     
         21 . A method of inhibiting gamma-secretase in a patient in need of such treatment comprising administering to said patient an effective amount of a compound of  claim 1 .  
     
     
         22 . A method of treating neurodegenerative diseases in a patient in need of such treatment comprising administering to said patient an effective amount of a compound of  claim 1 .  
     
     
         23 . A method of inhibiting the deposition of beta amyloid protein in a patient in need of such treatment comprising administering to said patient an effective amount of a compound of  claim 1 .  
     
     
         24 . A method of treating Alzheimer's disease in a patient in need of such treatment comprising administering to said patient an effective amount of a compound of  claim 1.