US2012214806A1PendingUtilityA1
3-amino-5-phenyl-5,6-dihydro-2h-[1,4]oxazines

Assignee: ANDREINI MATTEOPriority: Aug 19, 2009Filed: May 1, 2012Published: Aug 23, 2012
Est. expiryAug 19, 2029(~3.1 yrs left)· nominal 20-yr term from priority
Inventors:Matteo Andreini David Banner Emanuele Gabellieri Wolfgang Guba Hans Hilpert Harald Mauser Alexander V. Mayweg Robert Narquizian Eoin Power Mark Rogers-Evans Massimiliano Travagli Michela Valacchi Thomas Woltering Wolfgang Wostl
A61P 3/10A61P 7/02A61P 37/02A61P 35/00A61P 43/00A61P 5/16A61P 37/06A61P 5/14A61P 37/00A61P 9/10A61P 9/00A61P 39/04A61P 29/00A61P 25/28A61P 25/00A61P 25/14A61P 3/00C07D 413/14A61P 19/02C07D 417/12A61P 17/00A61P 21/00A61P 1/00C07D 413/12C07D 265/30C07D 471/04A61P 21/02A61P 19/04A61P 1/04A61K 31/5375
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References
Claims
Abstract

The present invention relates to 3-Amino-5-phenyl-5,6-dihydro-2H-[1,4]oxazines of formula I having BACE1 and/or BACE2 inhibitory activity, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances. The active compounds of the present invention are useful in the therapeutic and/or prophylactic treatment of e.g. Alzheimer's disease and type 2 diabetes.
Claims

exact text as granted — not AI-modified
1 . A compound of formula I, 
       
         
           
           
               
               
           
         
       
       wherein 
       X is O or S, 
       R 1  is selected from the group consisting of
 i) lower alkyl, 
 ii) lower alkyl substituted by 1-5 substituents individually selected from cycloalkyl, halogen, halogen-lower alkoxy and lower alkoxy, and 
 iii) cycloalkyl, 
 
       R 2  is selected from the group consisting of
 i) aryl, 
 ii) aryl substituted by 1-4 substituents individually selected from cyano, cyano-lower alkyl, halogen, halogen-lower alkoxy, halogen-lower alkyl, heteroaryl, lower alkoxy, lower alkoxy-lower alkyl and lower alkyl, 
 iii) cycloalkyl, 
 iv) cycloalkyl substituted by 1-4 substituents individually selected from cyano, cyano-lower alkyl, halogen, halogen-lower alkoxy, halogen-lower alkyl, lower alkoxy, lower alkoxy-lower alkyl and lower alkyl, 
 v) heteroaryl, 
 vi) heteroaryl substituted by 1-4 substituents individually selected from aryl, cyano, cyano-lower alkyl, halogen, halogen-lower alkoxy, halogen-lower alkyl, cycloalkyl-lower alkoxy, lower alkenyl-lower alkoxy, aryl-lower alkoxy, heteroaryl, heterocyclyl, lower alkoxy, lower alkoxy-lower alkyl and lower alkyl, 
 vii) heterocyclyl, and 
 viii) heterocyclyl substituted by 1-4 substituents individually selected from amino, cyano, cyano-lower alkyl, halogen, halogen-lower alkoxy, halogen-lower alkyl, lower alkoxy, lower alkoxy-lower alkyl and lower alkyl, 
 
       R 3  is individually selected from the group consisting of
 i) halogen and 
 ii) lower alkyl, 
 
       R 4  is individually selected from the group consisting of
 i) H and 
 ii) lower alkyl, 
 
       R 5  is individually selected from the group consisting of
 i) H and 
 ii) lower alkyl, 
 
       R 6  is individually selected from the group consisting of
 i) H and 
 ii) lower alkyl, 
 
       R 7  is individually selected from the group consisting of
 i) H, 
 ii) aryl, and 
 iii) lower alkyl, and 
 
       n is 0, 1 or 2, 
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The compound of  claim 1 , wherein 
       X is O or S, 
       R 1  is selected from the group consisting of
 i) lower alkyl, and 
 ii) cycloalkyl, 
 
       R 2  is selected from the group consisting of
 i) aryl substituted by 1-4 substituents individually selected from cyano, halogen and heteroaryl, 
 ii) cycloalkyl, 
 iii) cycloalkyl substituted by 1-4 substituents individually selected from halogen, halogen-lower alkyl, lower alkoxy-lower alkyl and lower alkyl, 
 iv) heteroaryl, 
 v) heteroaryl substituted by 1-4 substituents individually selected from aryl, cyano, halogen, halogen-lower alkoxy, halogen-lower alkyl, cycloalkyl-lower alkoxy, lower alkenyl-lower alkoxy, aryl-lower alkoxy, heteroaryl, heterocyclyl, and lower alkyl, and 
 vi) heterocyclyl, 
 
       R 3  is halogen, 
       R 4  is H or lower alkyl, 
       R 5  is H or lower alkyl, 
       R 6  is H or lower alkyl, 
       R 7  is H, aryl or lower alkyl, and 
       n is 0 or 1 
       or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The compound of  claim 1 , having formula Ix 
       
         
           
           
               
               
           
         
       
       wherein 
       X is O or S, 
       R 1  is selected from the group consisting of
 i) lower alkyl, 
 ii) lower alkyl substituted by 1-5 substituents individually selected from cycloalkyl, halogen, halogen-lower alkoxy and lower alkoxy, and 
 iii) cycloalkyl, 
 
       R 2  is selected from the group consisting of
 i) aryl, 
 ii) aryl substituted by 1-4 substituents individually selected from cyano, cyano-lower alkyl, halogen, halogen-lower alkoxy, halogen-lower alkyl, lower alkoxy, lower alkoxy-lower alkyl and lower alkyl, 
 iii) cycloalkyl, 
 iv) cycloalkyl substituted by 1-4 substituents individually selected from cyano, cyano-lower alkyl, halogen, halogen-lower alkoxy, halogen-lower alkyl, lower alkoxy, lower alkoxy-lower alkyl and lower alkyl, 
 v) heteroaryl, 
 vi) heteroaryl substituted by 1-4 substituents individually selected from cyano, cyano-lower alkyl, halogen, halogen-lower alkoxy, halogen-lower alkyl, lower alkoxy, lower alkoxy-lower alkyl and lower alkyl, vii) heterocyclyl, and 
 viii) heterocyclyl, substituted by 1-4 substituents individually selected from cyano, cyano-lower alkyl, halogen, halogen-lower alkoxy, halogen-lower alkyl, lower alkoxy, lower alkoxy-lower alkyl and lower alkyl, 
 
       R 3  is individually selected from the group consisting of
 i) halogen and 
 ii) lower alkyl, 
 
       n is 0, 1 or 2, 
       or a pharmaceutically acceptable salt thereof. 
     
     
         4 . The compound of  claim 1 , wherein X is O. 
     
     
         5 . The compound of  claim 1 , wherein R 1  is lower alkyl or cycloalkyl. 
     
     
         6 . The compound of  claim 5 , wherein R 1  is methyl or cyclopropyl. 
     
     
         7 . The compound of  claim 1 , wherein R 2  is selected from the group consisting of
 i) aryl substituted by 1-4 substituents individually selected from cyano, halogen and heteroaryl,   ii) cycloalkyl,   iii) cycloalkyl substituted by 1-4 substituents individually selected from halogen, halogen-lower alkyl and lower alkoxy-lower alkyl,   iv) heteroaryl,   v) heteroaryl substituted by 1-4 substituents individually selected from aryl, cyano, halogen, halogen-lower alkoxy, halogen-lower alkyl, cycloalkyl-lower alkoxy, lower alkenyl-lower alkoxy, aryl-lower alkoxy, heteroaryl, heterocyclyl, and lower alkyl, and   vi) heterocyclyl.   
     
     
         8 . The compound of  claim 1 , wherein R 2  is aryl substituted by 1-4 halogens, heteroaryl or heteroaryl substituted by 1-4 substituents individually selected from halogen, halogen-lower alkoxy, halogen-lower alkyl and lower alkyl. 
     
     
         9 . The compound of  claim 7 , wherein R 2  is heteroaryl substituted by 1-4 substituents individually selected from halogen, halogen-lower alkoxy, halogen-lower alkyl and lower alkyl. 
     
     
         10 . The compound of  claim 1 , wherein R 2  is 1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl; 1,1-difluoromethyl-1H-pyrazole-3-yl; 1-methoxymethyl-cycloprop-1-yl; 1-methyl-1H-indazol-3-yl; 1-trifluoromethyl-cycloprop-1-yl; 2,2-difluoro-cycloprop-1-yl; 2,4-dichloro-phenyl; 2,5-difluoro-phenyl; 2,5-dimethyl-fur-3-yl; 2,5-dimethyl-oxazol-4-yl; 2,5-dimethyl-thien-3-yl; 2-methyl-4-trifluoromethyl-thiazole-5-yl; 2-methyl-oxazol-4-yl; 2-methyl-thiazol-4-yl; 3-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl; 3,3,3-trifluoro-1-(tetrahydro-furan-2-yl)-propyl; 3,3-difluoro-cyclobut-1-yl; 3,5-dichloro-pyridin-2-yl; 3,5-difluoro-pyridin-2-yl; 3-chloro-5-cyano-pyridin-2-yl; 3-chloro-5-trifluoromethyl-pyridin-2-yl; 3-chloro-cyclobut-1-yl; 3-chloro-phenyl; 3-chloro-thiophen-2-yl; 3-fluoro-pyridin-2-yl; 3-methyl-thiophen-2-yl; 3-sec-butyl-5-chloro-pyridin-2-yl; 4-chloro-1-methyl-1H-pyrazole-3-yl; 4-chloro-2-fluoro-phenyl; 4-chloro-2-iodo-phenyl; 4-chloro-phenyl; 4-cyano-2-fluoro-phenyl; 4-oxazol-5-yl-phenyl; 5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl; 5-(2,2-difluoro-ethoxy)-pyridin-2-yl; 5-(2-fluoro-ethoxy)-pyridin-2-yl; 5-benzyloxy-pyridin-2-yl; 5-but-3-enyloxy-pyridin-2-yl; 5-butyl-pyridin-2-yl; 5-chloro-3-ethyl-pyridin-2-yl; 5-chloro-3-fluoro-pyridin-2-yl; 5-chloro-3-methyl-pyridin-2-yl; 5-chloro-pyridin-2-yl; 5-chloro-pyrimidin-2-yl; 5-chloro-thien-2-yl; 5-cyano-pyridin-2-yl; 5-cyclopropylmethoxy-pyridin-2-yl; 5-difluoromethoxy-pyridin-2-yl; 5-fluoro-pyridin-2-yl; 5-furan-2-yl-isoxazol-3-yl; 5-furan-2-yl-pyridin-2-yl; 5-methyl-pyrazin-2-yl; 5-phenyl-oxazol-4-yl; 5-pyrrolidin-1-yl-pyridin-2-yl; 5-thiophen-2-yl-isoxazol-3-yl; 5-trifluoromethyl-pyrazin-2-yl; 5-trifluoromethyl-pyrimidin-2-yl; cyclopropyl; oxazole-2-yl; pyrazin-2-yl; pyrazolo[1,5-a]pyridin-2-yl; pyrimidin-4-yl or tetrahydro-furan-3-yl. 
     
     
         11 . The compound of  claim 10 , wherein R 2  is 1-methyl-1H-indazol-3-yl; 2-methyl-oxazol-4-yl; 2-methyl-thiazol-4-yl; 3-chloro-phenyl; 4-chloro-2-fluoro-phenyl; 4-chloro-2-iodo-phenyl; 4-chloro-phenyl; 5-chloro-pyridin-2-yl; 5-chloro-thien-2-yl; 1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl; 5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl; pyrazin-2-yl, pyrazolo[1,5-a]pyridin-2-yl; 2,4-dichloro-phenyl; 2,5-difluoro-phenyl; 2,5-dimethyl-fur-3-yl; 2,5-dimethyl-oxazol-4-yl; 2,5-dimethyl-thien-3-yl; 3,5-dichloro-pyridin-2-yl or 3,5-difluoro-pyridin-2-yl. 
     
     
         12 . The compound of  claim 11 , wherein R 2  is 5-chloro-pyridin-2-yl; 3,5-dichloro-pyridin-2-yl; 1,1-difluoromethyl-1H-pyrazole-3-yl; 3,5-difluoro-pyridin-2-yl; 5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl; 3-chloro-5-cyano-pyridin-2-yl; 5-cyano-pyridin-2-yl; 5-difluoromethoxy-pyridin-2-yl or 5-chloro-3-fluoro-pyridin-2-yl. 
     
     
         13 . The compound of  claim 1 , wherein R 2  is 5-chloro-pyridin-2-yl. 
     
     
         14 . The compound of  claim 1 , wherein n is 1. 
     
     
         15 . The compound of  claim 1 , wherein R 3  is halogen. 
     
     
         16 . The compound of  claim 15 , wherein R 3  is F. 
     
     
         17 . The compound of  claim 1 , wherein n is 0. 
     
     
         18 . The compound of  claim 1 , selected from the group consisting of
 3,5-Difluoro-pyridine-2-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,   3,5-Dichloro-pyridine-2-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,   (RS)-N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-4-chloro-2-fluoro-benzamide,   (RS)-N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-2,4-dichloro-benzamide,   (RS)-N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-2,5-difluoro-benzamide,   (RS)-N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-3-chloro-benzamide,   5-Chloro-pyridine-2-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,   5-Chloro-thiophene-2-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,   2,5-Dimethyl-thiophene-3-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide, and   2-Methyl-thiazole-4-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide   or a pharmaceutically acceptable salt thereof.   
     
     
         19 . The compound of  claim 1 , selected from the group consisting of
 2,5-Dimethyl-oxazole-4-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,   2-Methyl-oxazole-4-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,   2,5-Dimethyl-furan-3-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,   1-(2,2,2-Trifluoro-ethyl)-1H-pyrazole-3-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,   1-Methyl-1H-indazole-3-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,   Pyrazolo[1,5-a]pyridine-2-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,   (RS)-N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-4-chloro-2-iodo-benzamide,   5-Chloro-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,   (RS)-N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-4-chloro-benzamide, and   5-Chloro-pyridine-2-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide   or a pharmaceutically acceptable salt thereof.   
     
     
         20 . The compound of  claim 1 , selected from the group consisting of
 5-Chloro-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-Chloro-pyridine-2-carboxylic acid [3-((RS)-5-amino-3-cyclopropyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid [3-((RS)-5-amino-3-cyclopropyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,   Pyrazine-2-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,   (RS)-N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-4-chloro-thiobenzamide,   5-Chloro-pyridine-2-carboxylic acid [3-((3R,6R) and (3S,6S)-5-amino-6-benzyl-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-Chloro-pyridine-2-carboxylic acid [3-((3R,6S)- and (3S,6R)-5-amino-6-benzyl-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-Chloro-pyridine-2-carboxylic acid [3-((3R,6R)-5-amino-3-methyl-6-phenyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide, and   5-Chloro-pyridine-2-carboxylic acid [3-((3R,6S)-5-amino-3-methyl-6-phenyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide   or a pharmaceutically acceptable salt thereof.   
     
     
         21 . The compound of  claim 1 , selected from the group consisting of
 5-Butyl-pyridine-2-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,   3-Chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,   3,5-Dichloro-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-Chloro-pyrimidine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-Trifluoromethyl-furan-3-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   3-Fluoro-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   3-Chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   2-Methyl-oxazole-4-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   1-Difluoromethyl-1H-pyrazole-3-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide, and   3,5-Difluoro-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide   or a pharmaceutically acceptable salt thereof.   
     
     
         22 . The compound of  claim 1 , selected from the group consisting of
 N-[3-((R)-5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-4-cyano-2-fluoro-benzamide,   4-Chloro-1-methyl-1H-pyrazole-3-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   3-Methyl-thiophene-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-Phenyl-oxazole-4-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   3-Chloro-thiophene-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   2-Methyl-4-trifluoromethyl-thiazole-5-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   3-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-Chloro-pyridine-2-carboxylic acid [3-((R)-5-amino-2,2,3-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid [3-((R)-5-amino-2,2,3-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide, and   5-Chloro-pyridine-2-carboxylic acid [3-((R)-5-amino-3,6,6-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide   or a pharmaceutically acceptable salt thereof.   
     
     
         23 . The compound of  claim 1 , selected from the group consisting of
 (RS)-N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-4-oxazol-5-yl-benzamide,   (RS)-2,2-Difluoro-cyclopropanecarboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   Cyclopropanecarboxylic acid [3-((R)-5-amino-2,2,3-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   1-Trifluoromethyl-cyclopropanecarboxylic acid [3-((R)-5-amino-2,2,3-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   (RS)-2,2-Difluoro-cyclopropanecarboxylic acid [3-((R)-5-amino-2,2,3-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   1-Trifluoromethyl-cyclopropanecarboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   3-Chloro-cyclobutanecarboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   3,3-Difluoro-cyclobutanecarboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-Cyclopropylmethoxy-pyridine-2-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide, and   5-(2-Fluoro-ethoxy)-pyridine-2-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide   or a pharmaceutically acceptable salt thereof.   
     
     
         24 . The compound of  claim 1 , selected from the group consisting of
 5-(2,2-Difluoro-ethoxy)-pyridine-2-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,   Pyrimidine-4-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,   5-But-3-enyloxy-pyridine-2-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,   5-Methyl-pyrazine-2-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,   5-Benzyloxy-pyridine-2-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,   3-Chloro-5-cyano-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-Chloro-3-fluoro-pyridine-2-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,   5-Cyano-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-Chloro-3-ethyl-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide, and   3 (RS)-sec-Butyl-5-chloro-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide   or a pharmaceutically acceptable salt thereof.   
     
     
         25 . The compound of  claim 1 , selected from the group consisting of
 5-Cyano-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-Difluoromethoxy-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-Chloro-3-fluoro-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-Furan-2-yl-isoxazole-3-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-Furan-2-yl-pyridine-2-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-Pyrrolidin-1-yl-pyridine-2-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-Thiophen-2-yl-isoxazole-3-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   Oxazole-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-Trifluoromethyl-pyrazine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide, and   5-Trifluoromethyl-pyrimidine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide   or a pharmaceutically acceptable salt thereof.   
     
     
         26 . The compound of  claim 1 , selected from the group consisting of
 1-Methoxymethyl-cyclopropanecarboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   (RS)-Tetrahydro-furan-3-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-Chloro-3-methyl-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-Fluoro-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-Chloro-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-Chloro-pyridine-2-carboxylic acid [3-(5-amino-3-cyclopropyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-Chloro-pyridine-2-carboxylic acid [3-((3R,6R) and (3S,6S)-5-amino-6-benzyl-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-Chloro-pyridine-2-carboxylic acid [3-((3R,6S)- and (3S,6R)-5-amino-6-benzyl-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   3,5-Dichloro-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide, and   1-Difluoromethyl-1H-pyrazole-3-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   or a pharmaceutically acceptable salt thereof.   
     
     
         27 . The compound of  claim 1 , selected from the group consisting of
 1-Difluoromethyl-1H-pyrazole-3-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-Chloro-pyridine-2-carboxylic acid [3-((R)-5-amino-2,2,3-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid [3-((R)-5-amino-2,2,3-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-Chloro-pyridine-2-carboxylic acid [3-((R)-5-amino-3,6,6-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,   3-Chloro-5-cyano-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-Cyano-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-Difluoromethoxy-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   5-Chloro-3-fluoro-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,   1-(2,2,2-Trifluoro-ethyl)-1H-pyrazole-3-carboxylic acid [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide, and   1-Methyl-1H-indazole-3-carboxylic acid [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide   or a pharmaceutically acceptable salt thereof.   
     
     
         28 . The compound of  claim 1 , selected from the group consisting of
 2,5-Dimethyl-furan-3-carboxylic acid [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,   2,5-Dimethyl-oxazole-4-carboxylic acid [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,   2,5-Dimethyl-thiophene-3-carboxylic acid [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,   2-Methyl-oxazole-4-carboxylic acid [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,   2-Methyl-thiazole-4-carboxylic acid [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,   3,5-Dichloro-pyridine-2-carboxylic acid [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,   3,5-Difluoro-pyridine-2-carboxylic acid [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,   3-Chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide   5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid [3-(5-amino-3-cyclopropyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide, and   5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide hydrochloride   or a pharmaceutically acceptable salt thereof.   
     
     
         29 . The compound of  claim 1  selected from the group consisting of
 5-Chloro-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide, 
 5-Chloro-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide, 
 5-Chloro-pyridine-2-carboxylic acid [3-(5-amino-3-cyclopropyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide, 
 5-Chloro-pyridine-2-carboxylic acid [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide, 
 5-Chloro-pyridine-2-carboxylic acid [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide, 
 5-Chloro-thiophene-2-carboxylic acid [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide, 
 N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-4-chloro-thiobenzamide, 
 N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-4-chloro-2-fluoro-benzamide, 
 N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-2,4-dichloro-benzamide, and 
 N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-2,5-difluoro-benzamide 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         30 . The compound of  claim 1  selected from the group consisting of
 N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-3-chloro-benzamide, 
 N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-4-chloro-2-iodo-benzamide, 
 N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-4-chloro-benzamide, 
 Pyrazine-2-carboxylic acid [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide hydrochloride, 
 Pyrazolo[1,5-a]pyridine-2-carboxylic acid [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide, 
 5-Chloro-pyridine-2-carboxylic acid [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide, and 
 5-Chloro-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         31 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I 
       
         
           
           
               
               
           
         
       
       wherein 
       X is O or S, 
       R 1  is selected from the group consisting of
 i) lower alkyl, 
 ii) lower alkyl substituted by 1-5 substituents individually selected from cycloalkyl, halogen, halogen-lower alkoxy and lower alkoxy, and 
 iii) cycloalkyl, 
 
       R 2  is selected from the group consisting of
 i) aryl, 
 ii) aryl substituted by 1-4 substituents individually selected from cyano, cyano-lower alkyl, halogen, halogen-lower alkoxy, halogen-lower alkyl, heteroaryl, lower alkoxy, lower alkoxy-lower alkyl and lower alkyl, 
 iii) cycloalkyl, 
 iv) cycloalkyl substituted by 1-4 substituents individually selected from cyano, cyano-lower alkyl, halogen, halogen-lower alkoxy, halogen-lower alkyl, lower alkoxy, lower alkoxy-lower alkyl and lower alkyl, 
 v) heteroaryl, 
 vi) heteroaryl substituted by 1-4 substituents individually selected from aryl, cyano, cyano-lower alkyl, halogen, halogen-lower alkoxy, halogen-lower alkyl, cycloalkyl-lower alkoxy, lower alkenyl-lower alkoxy, aryl-lower alkoxy, heteroaryl, heterocyclyl, lower alkoxy, lower alkoxy-lower alkyl and lower alkyl, 
 vii) heterocyclyl, and 
 viii) heterocyclyl substituted by 1-4 substituents individually selected from amino, cyano, cyano-lower alkyl, halogen, halogen-lower alkoxy, halogen-lower alkyl, lower alkoxy, lower alkoxy-lower alkyl and lower alkyl, 
 
       R 3  is individually selected from the group consisting of
 i) halogen and 
 ii) lower alkyl, 
 
       R 4  is individually selected from the group consisting of
 i) H and 
 ii) lower alkyl, 
 
       R 5  is individually selected from the group consisting of
 i) H and 
 ii) lower alkyl, 
 
       R 6  is individually selected from the group consisting of
 i) H and 
 ii) lower alkyl, 
 
       R 7  is individually selected from the group consisting of
 i) H, 
 ii) aryl, and 
 iii) lower alkyl, and 
 
       n is 0, 1 or 2, 
       or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
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