1,4 oxazepines as bace1 and/or bace2 inhibitors

Abstract

This invention relates to compounds of the formula wherein and R 1 to R 3 are as described herein, or to pharmaceutically acceptable salts thereof. These compounds are BACE1 and/or BACE2 inhibitors and can be used as pharmaceuticals 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 of the formula I 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is H or F; 
         R 2  is C 1-7 -alkyl; and 
         R 3  is —(C═O)—R 4  or R 5 , wherein 
         R 4  is heteroaryl substituted by one substituent selected from the group consisting of C 3-7 -cycloalkyl-C 1-7 -alkoxy-, C 3-7 -cycloalkyl-C 2-7 -alkynyl-, C 1-7 -alkoxy-C 2-7 -alkynyl-, unsubstituted heteroaryl, unsubstituted C 3-7 -cycloalkyl and C 1-7 -alkyl-S—, or 
         R 4  is heteroaryl substituted by one halogen and one amidyl; and 
         R 5  is C 3-7 -cycloalkyl-C 1-7 -alkyl-; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein R 1  is F. 
     
     
         3 . The compound of  claim 1 , wherein R 1  is H. 
     
     
         4 . The compound of  claim 1 , wherein R 2  is Me. 
     
     
         5 . The compound of  claim 1 , wherein R 2  is Et. 
     
     
         6 . The compound of  claim 1 , wherein R 3  is C 3-7 -cycloalkyl-C 1-7 -alkyl-. 
     
     
         7 . The compound of  claim 6 , wherein R 3  is cyclopropyl-CH 2 —. 
     
     
         8 . The compound of  claim 7 , which is (5R,6R)-5-[5-(Cyclopropylmethyl-amino)-2-fluoro-phenyl]-6-fluoro-5-methyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine. 
     
     
         9 . The compound of  claim 1 , wherein R 3  is —(C═O)—R 4 . 
     
     
         10 . The compound of  claim 9 , wherein R 4  is pyridinyl substituted by one halogen and one amidyl. 
     
     
         11 . The compound of  claim 10 , which is (R)—N2-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-5-yl)-4-fluorophenyl)-3-fluoropyridine-2,5-dicarboxamide formate. 
     
     
         12 . The compound of  claim 9 , wherein R 4  is pyridinyl substituted by one substituent selected from the group consisting of C 3-7 -cycloalkyl-C 1-7 -alkoxy-, C 3-7 -cycloalkyl-C 2-7 -alkynyl-, C 1-7 -alkoxy-C 2-7 -alkynyl-, unsubstituted heteroaryl and unsubstituted C 3-7 -cycloalkyl. 
     
     
         13 . The compound of  claim 12 , selected from the group consisting of
 (R)—N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-5-yl)-4-fluorophenyl)-6-(cyclopropylmethoxy)picolinamide formate,   (R)—N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-5-yl)-4-fluorophenyl)-5-(thiazol-2-yl)picolinamide formate,   (R)—N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-5-yl)-4-fluorophenyl)-5-(cyclopropylethynyl)picolinamide formate,   (R)—N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-5-yl)-4-fluorophenyl)-5-cyclopropylpicolinamide formate, and   (R)—N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-5-yl)-4-fluorophenyl)-5-β-methoxyprop-1-ynyl)picolinamide formate.   
     
     
         14 . The compound of  claim 9 , wherein R 4  is pyrazinyl substituted by C 1-7 -alkyl-S—. 
     
     
         15 . The compound of  claim 14 , which is (R)—N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-5-yl)-4-fluorophenyl)-5-(methylthio)pyrazine-2-carboxamide formate. 
     
     
         16 . The compound of  claim 9 , wherein R 4  is oxazolyl substituted by C 3-7 -cycloalkyl. 
     
     
         17 . The compound of  claim 16 , which is (R)—N-(3-(3-amino-5-ethyl-6,6-difluoro-2,5,6,7-tetrahydro-1,4-oxazepin-5-yl)-4-fluorophenyl)-5-cyclopropyloxazole-4-carboxamide. 
     
     
         18 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is H or F; 
         R 2  is C 1-7 -alkyl; and 
         R 3  is —(C═O)—R 4  or R 5 , wherein 
         R 4  is heteroaryl substituted by one substituent selected from the group consisting of C 3-7 -cycloalkyl-C 1-7 -alkoxy-, C 3-7 -cycloalkyl-C 2-7 -alkynyl-, C 1-7 -alkoxy-C 2-7 -alkynyl-, unsubstituted heteroaryl, unsubstituted C 3-7 -cycloalkyl and C 1-7 -alkyl-S—, or 
         R 4  is heteroaryl substituted by one halogen and one amidyl; and 
         R 5  is C 3-7 -cycloalkyl-C 1-7 -alkyl-; 
         or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.