Novel oxazine derivatives and their use in the treatment of disease

Abstract

The invention relates to novel oxazine derivatives of formula (I), and pharmaceutically acceptable salts thereof, in which all of the variables are as defined in the specification, pharmaceutical compositions thereof, combinations thereof, and their use as medicaments, particularly for the treatment of Alzheimer's Disease or diabetes via inhibition of BACE-1 or BACE-2.

1 . A method of treating Alzheimer's Disease or mild cognitive impairment comprising, administering to a patient in need thereof, a compound of formula (I), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein 
         R 1  and R 2  are independently hydrogen or halogen; 
         R 3  and R 4  are independently hydrogen or C 1-3 alkyl; or R 3  and R 4  taken together are cyclopropyl; 
         or R 1  and R 4  are hydrogen and R 2  and R 3  taken together are —CH 2 —O—CH 2 —; 
         R 5  is C 1-3 alkyl, halogen-C 1-3 alkyl or C 1-3 alkoxy-C 1-3 alkyl; and 
         R 6  is phenyl or a 5- or 6-membered monocyclic heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and wherein said phenyl or heteroaryl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from halogen, cyano, amino, hydroxy, C 1-4 alkyl, halogen-C 1-4 alkyl, halogen-C 1-4 alkylthio, halogen-C 1-4 alkoxy, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkylthio, C 1-4 alkoxy-C 2-4 alkenyl, C 1-4 alkoxy-C 2-4 alkynyl, hydroxy-C 1-4 alkyl, hydroxy-C 2-4 alkenyl and hydroxy-C 2-4 alkynyl. 
       
     
     
         2 . The method according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  and R 2  are both fluoro. 
     
     
         3 . The method according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3  and R 4  are both hydrogen. 
     
     
         4 . The method according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5  is methyl. 
     
     
         5 . The method according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6  is a 6-membered monocyclic heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and wherein said phenyl or heteroaryl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from halogen, cyano, amino, hydroxy, C 1-4 alkyl, halogen-C 1-4 alkyl, halogen-C 1-4 alkylthio, halogen-C 1-4 alkoxy, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkoxy and C 1-4 alkoxy-C 1-4 alkylthio. 
     
     
         6 . The method according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6  is a pyridin-2-yl group which is substituted by 2 substituents and wherein one of the substituents is located at the para position and one of the substituents is located at the ortho position of the pyridin-2-yl group relative to the amide linker and wherein the substituents are independently selected from halogen, cyano, amino, hydroxy, methyl, trifluoromethyl, methoxy and trifluoromethoxy. 
     
     
         7 . The method according to  claim 1  which is selected from:
 5-Cyano-3-methyl-pyridine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 3-Chloro-5-cyano-pyridine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 3-Chloro-5-cyano-pyridine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 5-Cyano-3-methyl-pyridine-2-carboxylic acid {6-[(R)-2-amino-5,5-difluoro-4-(2-methoxy-ethyl)-5,6-dihydro-4H-[1,3]oxazin-4-yl]-5-fluoro-pyridin-2-yl}-amide; 
 3-Chloro-5-trifluoromethyl-pyridine-2-carboxylic acid {6-[(R)-2-amino-5,5-difluoro-4-(2-methoxy-ethyl)-5,6-dihydro-4H-[1,3]oxazin-4-yl]-5-fluoro-pyridin-2-yl}-amide; 
 3-Chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 3-Amino-5-trifluoromethyl-pyrazine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 3,5-Dichloro-pyridine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 3-Amino-5-(2,2,2-trifluoro-ethoxy)pyrazine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 3-Amino-5-(2,2-difluoro-ethoxy)-pyrazine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 3-Amino-5-(3-fluoro-propoxy)-pyrazine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 5-Methoxy-3-methyl-pyridine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 3-Amino-5-(3-methoxy-prop-1-ynyl)-pyridine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 3-Amino-5-fluoromethoxy-pyrazine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]amide; 
 3-Amino-5-(2-methoxy-ethoxy)-pyrazine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 3-Amino-5-(3-hydroxy-prop-1-ynyl)-pyridine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 3-Amino-5-fluoro-pyridine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 3-Amino-5-chloro-pyridine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 3-Chloro-pyridine-2-carboxylic acid[6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]amide; 
 3-Chloro-5-(3-methoxy-prop-1-ynyl)pyridine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 3-Amino-5-difluoromethyl-pyrazine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 3-Amino-5-(2-chloro-ethoxy)-pyrazine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 3-Chloro-5-(2,2-difluoro-ethoxy)-pyridine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 3-Amino-5-(2-fluoro-ethoxy)-pyrazine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 3-Chloro-5-fluoromethoxy-pyridine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 3-Chloro-5-ethoxy-pyridine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 3-Amino-5-(penta-deutero-ethoxy)-pyrazine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 3-Amino-5-(2-methoxy-ethyl)-pyrazine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 4-Chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 3-Amino-pyrazine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 3-Chloro-5-(3-hydroxy-prop-1-ynyl)-pyridine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 3-Amino-5-difluoromethyl-pyridine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]amide; 
 3-Amino-6-chloro-5-(1,1-difluoro-ethyl)-pyrazine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 5-Cyano-pyridine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 3-Chloro-5-(1,1-difluoro-ethyl)-pyridine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; and 
 3-Amino-5-(1,1-difluoro-ethyl)-pyrazine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide; 
 and pharmaceutically acceptable salts thereof. 
 
     
     
         8 . A method of treating Alzheimer's Disease or mild cognitive impairment comprising, administering to a patient in need thereof, 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         9 . A method of treating Alzheimer's Disease or mild cognitive impairment comprising, administering to a patient in need thereof, 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         10 . A combination comprising a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, of formula (I), 
       
         
           
           
               
               
           
         
         wherein 
         R 1  and R 2  are independently hydrogen or halogen; 
         R 3  and R 4  are independently hydrogen or C 1-3 alkyl; or R 3  and R 4  taken together are cyclopropyl; 
         or R 1  and R 4  are hydrogen and R 2  and R 3  taken together are —CH 2 —O—CH 2 —; 
         R 5  is C 1-3 alkyl, halogen-C 1-3 alkyl or C 1-3 alkoxy-C 1-3 alkyl; and 
         R 6  is phenyl or a 5- or 6-membered monocyclic heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and wherein said phenyl or heteroaryl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from halogen, cyano, amino, hydroxy, C 1-4 alkyl, halogen-C 1-4 alkyl, halogen-C 1-4 alkylthio, halogen-C 1-4 alkoxy, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkylthio, C 1-4 alkoxy-C 2-4 alkenyl, C 1-4 alkoxy-C 2-4 alkynyl, hydroxy-C 1-4 alkyl, hydroxy-C 2-4 alkenyl and hydroxy-C 2-4 alkynyl, and a second drug substance, for simultaneous or sequential administration.