Modulators for amyloid beta

Abstract

The invention relates to compounds of formula wherein R 1 , R 2 , R 3 , R 4 , and Ar are as defined in the specification and claims, or to pharmaceutically active acid addition salts of such compounds. Compounds of formula I are modulators for amyloid beta and may be useful for the treatment or prevention of a disease associated with the deposition of β-amyloid in the brain, in particular Alzheimer's disease, and other diseases such as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.

1 . A compound of formula I 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is hydrogen, lower alkyl or is lower alkyl substituted by hydroxy; 
 R 2  is hydrogen, lower alkoxy or lower alkyl; 
 R 3  and R 4  are each independently hydrogen, halogen, lower alkyl, C(O)O-lower alkyl, OR′, NR″R′″, lower alkyl substituted by halogen or hydroxy, or is phenyl or benzyl, each of which is optionally substituted by one or two halogen atoms; 
 R′ is lower alkyl, or is phenyl, benzyl or pyridinyl, wherein phenyl, benzyl or pyridinyl are each optionally substituted by one or more halogen, lower alkyl or lower alkyl substituted by fluoro; 
 R″ is hydrogen or lower alkyl; 
 R′″ is lower alkyl, lower alkyl substituted by one or two hydroxy groups, CH(CH 2 OH)-phenyl, —(CH 2 ) 2 O-lower alkyl, or phenyl substituted by halogen, or 
 R″ and R′″ together with the N-atom to which they are attached form a heterocyclic ring, optionally substituted by one or more lower alkyl, CH 2 C(O)O-lower alkyl, or CH 2 C(O)OH; 
 Ar is a five-membered heteroaryl group; 
 
     or a pharmaceutically active acid addition salt thereof. 
   
   
       2 . The compound of  claim 1 , wherein Ar is imidazol-1-yl. 
   
   
       3 . The compound of  claim 2 , wherein one of R 3  or R 4  is NR″R′″ and R″ and R′″ together with the N-atom to which they are attached form a heterocyclic ring, optionally substituted by one or more lower alkyl, CH 2 C(O)O-lower alkyl or CH 2 C(O)OH. 
   
   
       4 . The compound of  claim 3 , selected from the group consisting of
 [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(4-methoxy-6-piperidin-1-yl-[1,3,5]triazin-2-yl)-amine;   (1-{4-methoxy-6-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-[1,3,5]triazin-2-yl}-piperidin-4-yl)-acetic acid ethyl ester; and   (1-{4-methoxy-6-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-[1,3,5]triazin-2-yl}-piperidin-4-yl)-acetic acid.   
   
   
       5 . The compound of  claim 2 , wherein one of R 3  or R 4  is OR′. 
   
   
       6 . The compound of  claim 5 , selected from the group consisting of
 [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[4-methoxy-6-(2-trifluoromethyl-phenoxy)-[1,3,5]triazin-2-yl]-amine;   [4-(4-fluoro-phenoxy)-6-methoxy-[1,3,5]triazin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine;   [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[4-methoxy-6-(3,4,5-trifluoro-phenoxy)-[1,3,5]triazin-2-yl]-amine;   [4-(2,4-dichloro-phenoxy)-6-methoxy-[1,3,5]triazin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine;   [4-(2-chloro-pyridin-3-yloxy)-6-methoxy-[1,3,5]triazin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine;   [4-isopropoxy-6-(2-trifluoromethyl-phenoxy)-[1,3,5]triazin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine;   (4,6-diisopropoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine;   [4,6-bis-(2-trifluoromethyl-phenoxy)-[1,3,5]triazin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine; and   [4-(4-chloro-benzyloxy)-6-methoxy-[1,3,5]triazin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine.   
   
   
       7 . The compound of  claim 2 , wherein one of R 3  or R 4  is NR″R′″ and R″ is H or lower alkyl and R′″ is lower alkyl, lower alkyl substituted by one or two hydroxy groups, —(CH 2 ) 2 OCH 3 , or phenyl substituted by halogen. 
   
   
       8 . The compound of  claim 7 , selected from the group consisting of
 N-(4-chloro-phenyl)-6-methoxy-N′-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[1,3,5]triazine-2,4-diamine;   N-(4-chloro-phenyl)-6-methoxy-N′-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-N-methyl-[1,3,5]triazine-2,4-diamine;   N-(4-chloro-phenyl)-N′-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-N-methyl-[1,3,5]triazine-2,4-diamine; and   N-(4-chloro-phenyl)-6-isopropoxy-N′-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-N-methyl-[1,3,5]triazine-2,4-diamine.   
   
   
       9 . The compound of  claim 1 , wherein one of R 3  and R 4  is halogen. 
   
   
       10 . The compound of  claim 1 , wherein one of R 3  and R 4  is lower alkyl. 
   
   
       11 . The compound of  claim 1 , wherein one of R 3  and R 4  is C(O)O-lower alkyl. 
   
   
       12 . The compound of  claim 1 , wherein one of R 3  and R 4  is OR′. 
   
   
       13 . The compound of  claim 1 , wherein one of R 3  and R 4  is NR″R′″. 
   
   
       14 . The compound of  claim 1 , wherein one of R 3  and R 4  is lower alkyl substituted by halogen or hydroxyl. 
   
   
       15 . The compound of  claim 1 , wherein one of R 3  and R 4  is phenyl optionally substituted by one or two halogen atoms. 
   
   
       16 . The compound of  claim 1 , wherein one of R 3  and R 4  is benzyl optionally substituted by one or two halogen atoms. 
   
   
       17 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is hydrogen, lower alkyl or is lower alkyl substituted by hydroxy; 
 R 2  is hydrogen, lower alkoxy or lower alkyl; 
 R 3  and R 4  are each independently hydrogen, halogen, lower alkyl, C(O)O-lower alkyl, OR′, NR″R′″, lower alkyl substituted by halogen or hydroxy, or is phenyl or benzyl, each of which is optionally substituted by one or two halogen atoms; 
 R′ is lower alkyl, or is phenyl, benzyl or pyridinyl, wherein phenyl, benzyl or pyridinyl are each optionally substituted by one or more halogen, lower alkyl or lower alkyl substituted by fluoro; 
 R″ is hydrogen or lower alkyl; 
 R′″ is lower alkyl, lower alkyl substituted by one or two hydroxy groups, CH(CH 2 OH)-phenyl, —(CH 2 ) 2 O-lower alkyl, or phenyl substituted by halogen, or 
 R″ and R′″ together with the N-atom to which they are attached form a heterocyclic ring, optionally substituted by one or more lower alkyl, CH 2 C(O)O-lower alkyl, or CH 2 C(O)OH; 
 Ar is a five-membered heteroaryl group; 
 
     or a pharmaceutically active acid addition salt thereof and a pharmaceutically acceptable carrier.