5,6-dihydro-2h-[1,4]oxazin-3-yl-amine derivatives useful as inhibitors of beta-secretase (bace)

Abstract

The present invention relates to novel 5,6-dihydro-2H-[1,4]oxazin-3-ylamine derivatives as inhibitors of beta-secretase, also known as beta-site amyloid cleaving enzyme, BACE, BACE1, Asp2, or memapsin2. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention and treatment of disorders in which beta-secretase is involved, such as Alzheimer's disease (AD), mild cognitive impairment, senility, dementia, dementia with Lewy bodies, Down's syndrome, dementia associated with stroke, dementia associated with Parkinson's disease and dementia associated with beta-amyloid.

1 . A compound of Formula (I) 
       
         
           
           
               
               
           
         
         or a tautomer or a stereoisomeric form thereof, wherein 
         R 1 , R 2  and R 3  are independently selected from the group consisting of hydrogen, fluoro, cyano, C 1-3 alkyl, mono- and polyhalo-C 1-3 alkyl, and C 3-6 cycloalkyl; 
         R 4  is fluoro or trifluoromethyl; or 
         R 1  and R 2 , or R 3  and R 4  taken together with the carbon atom to which they are attached may form a C 3-6 cycloalkanediyl ring; 
         R 5  is selected from the group consisting of hydrogen, C 1-3 alkyl, cyclopropyl, mono- and polyhalo-C 1-3 alkyl, homoaryl and heteroaryl; 
         X 1 , X 2 , X 3 , X 4  are independently C(R 6 ) or N, provided that no more than two thereof represent N; each R 6  is selected from the group consisting of hydrogen, halo, C 1-3 alkyl, mono- and polyhalo-C 1-3 alkyl, cyano, C 1-3 alkyloxy, mono- and polyhalo-C 1-3 alkyloxy; 
         L is a bond or —N(R 7 )CO—, wherein R 7  is hydrogen or C 1-3 alkyl; 
         Ar is homoaryl or heteroaryl; 
         homoaryl is phenyl or phenyl substituted with one, two or three substituents selected from the group consisting of halo, cyano, C 1-3 alkyl, C 1-3 alkyloxy, mono- and polyhalo-C 1-3 alkyl, mono- and polyhalo-C 1-3 alkyloxy; 
         heteroaryl is selected from the group consisting of pyridyl, pyrimidyl, pyrazyl, pyridazyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl and oxadiazolyl, each optionally substituted with one, two or three substituents selected from the group consisting of halo, cyano, C 1-3 alkyl, C 2-3 alkynyl, C 1-3 alkyloxy, mono- and polyhalo-C 1-3 alkyl, mono- and polyhalo-C 1-3 alkyloxy, and C 1-3 alkyloxy-C 1-3 alkyloxy; or 
         an addition salt or a solvate thereof. 
       
     
     
         2 . The compound according to  claim 1  wherein R 1 , R 2  and R 3  are hydrogen, R 4  is fluoro and L is —N(R 7 )CO— wherein R 7  is hydrogen. 
     
     
         3 . The compound according to  claim 2  wherein R 1 , R 2  and R 3  are hydrogen, R 4  is fluoro, L is —N(R 7 )CO— wherein R 7  is hydrogen, and R 5  is methyl, ethyl or cyclopropyl. 
     
     
         4 . The compound according to  claim 2  wherein R 1 , R 2  and R 3  are hydrogen, R 4  is fluoro, L is —N(R 7 )CO— wherein R 7  is hydrogen, and R 5  is methyl, ethyl or cyclopropyl, X 2 , X 3  and X 4  are CH, and X 1  is CH, CF or N. 
     
     
         5 . The compound according to  claim 2  wherein R 1 , R 2  and R 3  are hydrogen, R 4  is fluoro, L is —N(R 7 )CO— wherein R 7  is hydrogen, and R 5  is methyl, ethyl or cyclopropyl, and Ar is pyridyl, or pyrazyl, each optionally substituted with one or two substituents selected from halo, cyano, methoxy, trifluoroethoxy and difluoromethyl. 
     
     
         6 . The compound according to  claim 1  wherein R 1 , R 2  and R 3  are hydrogen, R 4  is trifluoromethyl and L is —N(R 7 )CO— wherein R 7  is hydrogen. 
     
     
         7 . The compound according to  claim 6  wherein R 1 , R 2  and R 3  are hydrogen, R 4  is trifluoromethyl, L is —N(R 7 )CO— wherein R 7  is hydrogen, and R 5  is methyl, ethyl or cyclopropyl. 
     
     
         8 . The compound according to  claim 6  wherein R 1 , R 2  and R 3  are hydrogen, R 4  is trifluoromethyl, L is —N(R 7 )CO— wherein R 7  is hydrogen, R 5  is methyl, ethyl or cyclopropyl, X 2 , X 3  and X 4  are CH, and X 1  is CH, CF or N. 
     
     
         9 . The compound according to  claim 6  wherein R 1 , R 2  and R 3  are hydrogen, R 4  is trifluoromethyl, L is —N(R 7 )CO— wherein R 7  is hydrogen, R 5  is methyl, ethyl or cyclopropyl, and Ar is pyridyl, or pyrazyl, each optionally substituted with one or two substituents selected from halo, cyano, methoxy, trifluoroethoxy and difluoromethyl. 
     
     
         10 . The compound according to  claim 1  wherein R 1  and R 2  are hydrogen, R 3  is fluoro, R 4  is trifluoromethyl and L is —N(R 7 )CO— wherein R 7  is hydrogen. 
     
     
         11 . A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         12 . A process for preparing a pharmaceutical composition comprising mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound as defined in  claim 1 . 
     
     
         13 . (canceled) 
     
     
         14 . A method of treating a disorder selected from the group consisting of Alzheimer's disease, mild cognitive impairment, senility, dementia, dementia with Lewy bodies, Down's syndrome, dementia associated with stroke, dementia associated with Parkinson's disease and dementia associated with beta-amyloid, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound as defined in  claim 1 .