5,6-DIHYDRO-2H-[1,4]OXAZIN-3-YL-AMINE DERIVATIVES USEFUL AS INHIBITORS OF BETA-SECRETASE (BACE)

摘要

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.

主权项

1. A compound of Formula (I) or a tautomer or a stereoisomeric form thereof, wherein R1, R2 and R3 are independently selected from the group consisting of hydrogen, fluoro, cyano, C1-3alkyl, mono- and polyhalo-C1-3alkyl, and C3-6cycloalkyl R4 is trifluoromethyl; or R1 and R2, or R3 and R4 taken together with the carbon atom to which they are attached may form a C3-6cycloalkanediyl ring; R5 is selected from the group consisting of hydrogen, C1-3alkyl, cyclopropyl, mono- and polyhalo-C1-3alkyl, homoaryl and heteroaryl; X1, X2, X3, X4 are independently C(R6) or N, provided that no more than two thereof represent N; each R6 is selected from the group consisting of hydrogen, halo, C1-3alkyl, mono- and polyhalo-C1-3alkyl, cyano, C1-3alkyloxy, mono- and polyhalo-C1-3alkyloxy; L is a bond or —N(R7)CO—, wherein R7 is hydrogen or C1-3alkyl; 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, C1-3alkyl, C1-3alkyloxy, mono- and polyhalo-C1-3alkyl, mono- and polyhalo-C1-3alkyloxy; 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, C1-3alkyl, C2-3alkynyl, C1-3alkyloxy, mono- and polyhalo-C1-3alkyl, mono- and polyhalo-C1-3alkyloxy, and C1-3alkyloxy-C1-3alkyloxy; or an addition salt or a solvate thereof.