2,5,6,7-Tetrahydro-[1,4]oxazepin-3-ylamine or 2,3,6,7-tetrahydro-[1,4]oxazepin-5-ylamine compounds

Abstract

This invention relates to compounds of the formula wherein A, B and R 1 to R 7 are as described below, or to pharmaceutically acceptable salts thereof. These compounds are BACE1 and/or BACE2 inhibitors and can be used as medicaments for the therapeutic and/or prophylactic treatment of diseases such as Alzheimer's disease, diabetes, particularly type 2 diabetes, and other metabolic disorders.

1 . A compound according to formula I, 
       
         
           
           
               
               
           
         
         wherein 
         A is O and B is —CR 8 R 9 —; or 
         B is O and A is —CR 8 R 9 —; 
         R 1  is selected from the group consisting of hydrogen, C 1-7 -alkyl and C 3-7 -cycloalkyl; 
         R 2  is selected from the group consisting of hydrogen, C 1-7 -alkyl and C 3-7 -cycloalkyl; 
         R 3  is selected from the group consisting of hydrogen, halogen, C 1-7 -alkyl and C 3-7 -cycloalkyl; 
         R 4  is selected from the group consisting of hydrogen, halogen, C 1-7 -alkyl and C 3-7 -cycloalkyl; 
         R 5  is C 1-7 -alkyl or C 3-7 -cycloalkyl; 
         or R 3  and R 5  together with the C atom to which they are attached form a cyclopropyl ring; 
         R 6a , R 6b , R 6c  and R 6d  independently from each other are selected from the group consisting of hydrogen, C 1-7 -alkyl, halogen and halogen-C 1-7 -alkyl; 
         R 7  is —(CO)—R 10  or R 11 , wherein 
         R 10  is selected from the group consisting of 
         aryl, said aryl being unsubstituted or substituted by one, two or three groups selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkoxy, halogen-C 1-7 -alkoxy, cyano, hydroxy-C 1-7 -alkyl, oxo and phenyl, 
         heteroaryl, said heteroaryl being unsubstituted or substituted by one, two or three groups selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkoxy, halogen-C 1-7 -alkoxy, cyano, hydroxy-C 1-7 -alkyl, oxo and phenyl, and 
         C 3-7 -cycloalkyl, said cycloalkyl being unsubstituted or substituted by one, two, three or four groups selected from the group consisting of C 1-7 -alkyl, halogen and halogen-C 1-7 -alkyl; 
         R 11  is selected from the group consisting of 
         C 1-7 -alkyl, and 
         C 3-7 -cycloalkyl, said cycloalkyl being unsubstituted or substituted by one, two, three or four groups selected from the group consisting of C 1-7 -alkyl, halogen and halogen-C 1-7 -alkyl, and 
         R 8  and R 9  are independently from each other selected from hydrogen, C 1-7 -alkyl and C 3-7 -cycloalkyl; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A compound according to  claim 1 , wherein A is O and B is —CR 8 R 9 —. 
     
     
         3 . A compound according to  claim 1 , wherein B is O and A is —CR 8 R 9 —. 
     
     
         4 . A compound according to  claim 1 , wherein R 1  and R 2  are independently from each other hydrogen or C 1-7 -alkyl. 
     
     
         5 . A compound according to  claim 1 , wherein R 1  and R 2  are hydrogen. 
     
     
         6 . A compound according to  claim 1 , wherein R 3  and R 4  are independently from each other selected from the group consisting of hydrogen, halogen, and C 1-7 -alkyl. 
     
     
         7 . A compound according to  claim 1 , wherein R 3  and R 4  are independently from each other hydrogen or fluoro. 
     
     
         8 . A compound according to  claim 1 , wherein R 3  and R 4  are fluoro. 
     
     
         9 . A compound according to  claim 1 , wherein R 5  is methyl or ethyl. 
     
     
         10 . A compound according to  claim 1 , wherein R 3  and R 5  together with the C atom to which they are attached form a cyclopropyl ring. 
     
     
         11 . A compound according to  claim 1 , wherein R 6a  is hydrogen or fluoro and R 6b , R 6c  and R 6d  are hydrogen. 
     
     
         12 . A compound according to  claim 1 , wherein R 7  is —(CO)—R 10  and R 10  is selected from the group consisting of
 aryl, said aryl being unsubstituted or substituted by one, two or three groups selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkoxy, halogen-C 1-7 -alkoxy, cyano, hydroxy-C 1-7 -alkyl, oxo and phenyl, 
 heteroaryl, said heteroaryl being unsubstituted or substituted by one, two or three groups selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkoxy, halogen-C 1-7 -alkoxy, cyano, hydroxy-C 1-7 -alkyl, oxo and phenyl, and 
 C 3-7 -cycloalkyl, said cycloalkyl being unsubstituted or substituted by one, two, three or four groups selected from the group consisting of C 1-7 -alkyl, halogen and halogen-C 1-7 -alkyl. 
 
     
     
         13 . A compound according to  claim 12 , wherein R 10  is selected from the group consisting of
 heteroaryl, said heteroaryl being unsubstituted or substituted by one, two or three groups selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkoxy, halogen-C 1-7 -alkoxy, cyano, hydroxy-C 1-7 -alkyl, oxo and phenyl, and   C 3-7 -cycloalkyl, said cycloalkyl being unsubstituted or substituted by one, two, three or four groups selected from the group consisting of C 1-7 -alkyl, halogen and halogen-C 1-7 -alkyl.   
     
     
         14 . A compound according to  claim 12 , wherein R 10  is heteroaryl, said heteroaryl being unsubstituted or substituted by one, two or three groups selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkoxy, halogen-C 1-7 -alkoxy, cyano, hydroxy-C 1-7 -alkyl, oxo and phenyl. 
     
     
         15 . A compound according to  claim 12 , wherein R 10  is C 3-7 -cycloalkyl, said cycloalkyl being unsubstituted or substituted by one, two, three or four groups selected from the group consisting of C 1-7 -alkyl, halogen and halogen-C 1-7 -alkyl. 
     
     
         16 . (canceled) 
     
     
         17 . A compound according to  claim 1 , wherein R 7  is R 11  and R 11  is selected from the group consisting of C 1-7 -alkyl and C 3-7 -cycloalkyl, said cycloalkyl being unsubstituted or substituted by one, two, three or four groups selected from the group consisting of C 1-7 -alkyl, halogen and halogen-C 1-7 -alkyl. 
     
     
         18 . A compound according to  claim 17 , wherein R 11  is C 3-7 -cycloalkyl, said cycloalkyl being unsubstituted or substituted by one, two, three or four groups selected from the group consisting of C 1-7 -alkyl, halogen and halogen-C 1-7 -alkyl. 
     
     
         19 . A compound according to  claim 1 , wherein R 8  and R 9  are hydrogen. 
     
     
         20 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier and/or adjuvant.