Substituted benzoxazole, benzimidazole, oxazolopyridine and imidazopyridine derivatives as gamma secretase modulators

1. A compound of formula (I)

or a stereoisomeric form thereof, wherein

R 1 is hydrogen, cyano, CF 3 , halo, or C 1-4 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of hydroxyl and C 1-4 alkyloxy;

R 2 is hydrogen, C 1-4 alkyl or halo;

X is CR 5 or N;

R 5 is hydrogen or halo;

A 1 is CR 6 or N;

R 6 is hydrogen, halo or C 1-4 alkyloxy;

A 2 , A 3 and A 4 each independently are CH, CF or N;

provided that no more than two of A 1 , A 2 , A 3 and A 4 are N;

Y 1 is CH

Y 2 is CR 4 ;

Y 3 is CH;

R 4 is hydrogen, halo, C 1-4 alkyloxy, cyano, cycloC 3-7 alkyl, C 2-4 alkenyl, or C 1-4 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo and C 1-4 alkyloxy;

R 3 is C 2-6 alkyl substituted with one or more halo substituents;

C 1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of piperidinyl, morpholinyl, pyrrolidinyl, Ar, C 1-6 alkyloxy, tetrahydropyranyl, cycloC 3-7 alkyloxy and cycloC 3-7 alkyl; cycloC 3-7 alkyl substituted with one or more phenyl substituents optionally substituted with one or more halo substituents;

cycloC 3-7 alkyl; piperidinyl; morpholinyl; pyrrolidinyl; tetrahydropyranyl; O—Ar; NR 7 R 8 ; C 1-6 alkyloxy; C 1-6 alkylthio; Ar; CH 2 —O—Ar; S—Ar; NCH 3 —Ar; NH—Ar; or 1,6-dihydro-1-methyl-6-oxo-3-pyridinyl;

wherein each piperidinyl, morpholinyl and pyrrolidinyl may be substituted with one or more substituents each independently selected from the group consisting of C 1-4 alkyl, C 2-6 alkenyl, C 1-4 alkylcarbonyl, halo and C 1-4 alkyloxycarbonyl;

wherein each Ar independently is

phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, C 1-4 alkyloxy, cyano, NR 7 R 8 , morpholinyl, C 1-4 alkyl, C 1-4 alkyloxy substituted with one or more halo substituents, and C 1-4 alkyl substituted with one or more halo substituents; or

a 5- or 6-membered heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, oxazolyl, furanyl, thiophenyl, pyrazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl and pyrazinyl; wherein said 5- or 6-membered heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, C 1-4 alkyloxy, cyano, C 1-4 alkyl, C 1-4 alkyloxy substituted with one or more halo substituents, and C 1-4 alkyl substituted with one or more halo substituents;

each R 7 is selected independently from hydrogen or C 1-4 alkyl;

each R 8 is selected independently from hydrogen, C 1-4 alkyl or C 1-4 alkylcarbonyl;

Z is NR 9 ;

R 9 is hydrogen, or C 1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, phenyl, cycloC 3-7 alkyl and C 1-4 alkyloxy;

or a pharmaceutically acceptable addition salt thereof.

2. The compound according to claim 1 or a stereoisomeric form thereof, wherein

R 1 is hydrogen, C 1-4 alkyl, cyano, CF 3 , or halo;

R 2 is hydrogen or C 1-4 alkyl;

X is CR 5 or N;

R 5 is hydrogen or halo;

A 1 is CR 6 or N;

R 6 is hydrogen, halo or C 1-4 alkyloxy;

A 2 , A 3 and A 4 each independently are CH, CF or N;

provided that no more than two of A 1 , A 2 , A 3 and A 4 are N;

Y 1 is CH;

Y 2 is CR 4 ;

Y 3 is CH;

R 4 is hydrogen, halo, C 1-4 alkyloxy, cyano, cycloC 3-7 alkyl, C 2-4 alkenyl, or C 1-4 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo and C 1-4 alkyloxy;

R 3 is C 2-6 alkyl substituted with one or more halo substituents; C 1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of piperidinyl, Ar, C 1-6 alkyloxy, tetrahydropyranyl, cycloC 3-7 alkyloxy and cycloC 3-7 alkyl; cycloC 3-7 alkyl; piperidinyl; morpholinyl; pyrrolidinyl; tetrahydropyranyl; O—Ar; NR 7 R 8 ; C 1-6 alkyloxy; C 1-6 alkylthio; Ar; CH 2 —O—Ar; S—Ar; NCH 3 —Ar; or NH—Ar;

wherein each piperidinyl, morpholinyl and pyrrolidinyl may be substituted with one or more substituents each independently selected from the group consisting of C 1-4 alkyl, C 2-6 alkenyl, C 1-4 alkylcarbonyl, halo and C 1-4 alkyloxycarbonyl;

wherein each Ar independently is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo,

C 1-4 alkyloxy, cyano, NR 7 R 8 , morpholinyl, C 1-4 alkyl and C 1-4 alkyl substituted with one or more halo substituents; or a 5- or 6-membered heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, oxazolyl, furanyl, thiophenyl, pyrazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl and pyrazinyl; wherein said 5- or 6-membered heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, C 1-4 alkyloxy, cyano, C 1-4 alkyl and

C 1-4 alkyl substituted with one or more halo substituents;

each R 7 is selected independently from hydrogen or C 1-4 alkyl;

each R 8 is selected independently from hydrogen or C 1-4 alkyl;

Z is NR 9 ;

R 9 is hydrogen, or C 1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, phenyl and C 1-4 alkyloxy;

or a pharmaceutically acceptable addition salt thereof.

3. The compound according to claim 1 or a stereoisomeric form thereof, wherein

R 1 is hydrogen, C 1-4 alkyl, cyano, CF 3 , or halo;

R 2 is hydrogen or C 1-4 alkyl;

X is CR 5 or N;

R 5 is hydrogen or halo;

A 1 is CR 6 or N;

R 6 is hydrogen, halo or C 1-4 alkyloxy;

A 2 , A 3 and A 4 each independently are CH, CF or N;

provided that no more than two of A 1 , A 2 , A 3 and A 4 are N;

Y 1 is CH;

Y 2 is CR 4 ;

Y 3 is CH;

R 4 is hydrogen, halo, C 1-4 alkyloxy, cyano, or C 1-4 alkyl optionally substituted with one or more halo substituents;

R 3 is C 2-6 alkyl substituted with one or more halo substituents; C 1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of piperidinyl, Ar, C 1-6 alkyloxy, tetrahydropyranyl, cycloC 3-7 alkyloxy and cycloC 3-7 alkyl; cycloC 3-7 alkyl; piperidinyl; morpholinyl; pyrrolidinyl; tetrahydropyranyl; O—Ar; NR 7 R 8 ; C 1-6 alkyloxy; C 1-6 alkylthio; Ar; CH 2 —O—Ar; S—Ar; NCH 3 —Ar; or NH—Ar;

wherein each piperidinyl, morpholinyl and pyrrolidinyl may be substituted with one or more substituents each independently selected from the group consisting of C 1-4 alkyl, C 2-6 alkenyl, C 1-4 alkylcarbonyl, halo and C 1-4 alkyloxycarbonyl;

wherein each Ar independently is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo,

C 1-4 alkyloxy, cyano, NR 7 R 8 , morpholinyl, C 1-4 alkyl and C 1-4 alkyl substituted with one or more halo substituents; or a 5- or 6-membered heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, oxazolyl, furanyl, thiophenyl, pyrazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl and pyrazinyl; wherein said 5- or 6-membered heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halo,

C 1-4 alkyloxy, cyano, C 1-4 alkyl and C 1-4 alkyl substituted with one or more halo substituents;

each R 7 is selected independently from hydrogen or C 1-4 alkyl;

each R 8 is selected independently from hydrogen or C 1-4 alkyl;

Z is NR 9 ;

R 9 is hydrogen, or C 1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, phenyl and C 1-4 alkyloxy;

or a pharmaceutically acceptable addition salt thereof.

4. The compound according to claim 1 or a stereoisomeric form thereof, wherein

R 1 is hydrogen, cyano, halo, or C 1-4 alkyl optionally substituted with one or more hydroxyl radicals;

R 5 is hydrogen;

Y 1 is CH;

Y 2 is CR 4 ;

Y 3 is CH;

provided that only one of Y 1 and Y 2 may represent N;

R 4 is hydrogen, halo, C 1-4 alkyloxy, cycloC 3-7 alkyl, C 2-4 alkenyl, or

C 1-4 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo and C 1-4 alkyloxy;

R 3 is C 2-6 alkyl substituted with one or more halo substituents; C 1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of piperidinyl, Ar, C 1-6 alkyloxy, tetrahydropyranyl and cycloC 3-7 alkyl;

cycloC 3-7 alkyl substituted with one or more phenyl substituents optionally substituted with one or more halo substituents; cycloC 3-7 alkyl; piperidinyl; morpholinyl; tetrahydropyranyl;

O—Ar; C 1-6 alkyloxy; C 1-6 alkylthio; Ar; CH 2 —O—Ar; NH—Ar; or 1,6-dihydro-1-methyl-6-oxo-3-pyridinyl;

wherein each piperidinyl and morpholinyl may be substituted with one or more substituents each independently selected from the group consisting of C 1-4 alkyl,

C 1-4 alkylcarbonyl, halo and C 1-4 alkyloxycarbonyl;

wherein each Ar independently is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo,

C 1-4 alkyloxy, cyano, NR 7 R 8 , C 1-4 alkyl, C 1-4 alkyloxy substituted with one or more halo substituents, and C 1-4 alkyl substituted with one or more halo substituents; or

a 5- or 6-membered heteroaryl selected from the group consisting of pyridinyl and thiophenyl; wherein said 5- or 6-membered heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halo and C 1-4 alkyl substituted with one or more halo substituents;

each R 8 is selected independently from C 1-4 alkyl or C 1-4 alkylcarbonyl

or a pharmaceutically acceptable addition salt thereof.

5. The compound according to claim 1 , or a stereoisomeric form thereof, wherein

R 1 is methyl;

R 2 is hydrogen;

or a pharmaceutically acceptable addition salt thereof.

6. The compound according to claim 1 , or a stereoisomeric form thereof, wherein

R 1 is C 1-4 alkyl;

R 2 is hydrogen;

X is CH or N;

A 1 is CR 6 ;

R 6 is hydrogen, methoxy or halo;

A 2 is CH or N;

A 3 and A 4 are CH;

Y 1 is CH; Y 2 is CR 4 ; Y 3 is CH;

R 4 is hydrogen, halo or C 1-4 alkyl;

R 3 is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, C 1-4 alkyloxy, NR 7 R 8 and C 1-4 alkyl substituted with one or more halo substituents;

R 7 is hydrogen;

R 8 is C 1-4 alkylcarbonyl;

Z is NR 9 ;

R 9 is C 1-6 alkyl;

or a pharmaceutically acceptable addition salt thereof.

7. The compound according to claim 1 , or a stereoisomeric form thereof, wherein

R 1 is C 1-4 alkyl;

R 2 is hydrogen;

X is CH;

A 1 is CR 6 ;

R 6 is F or methoxy;

A 2 is N or CH;

A 3 and A 4 are CH;

Y 1 is CH;

Y 2 is CR 4 ;

Y 3 is CH;

R 4 is hydrogen or methyl;

R 3 is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo and methoxy;

Z is NR 9 ;

R 9 is C 1-6 alkyl;

or a pharmaceutically acceptable addition salt thereof.

8. The compound according to claim 1 , or a stereoisomeric form thereof, wherein

R 1 is C 1-4 alkyl;

R 2 is hydrogen;

X is CH;

A 1 is COCH 3 ; A 2 is N; A 3 is CH; A 4 is CH;

Y 1 , Y 2 and Y 3 are CH;

R 3 is phenyl optionally substituted with one or more halo substituents;

Z is NR 9 ;

R 9 is C 1-6 alkyl;

or a pharmaceutically acceptable addition salt thereof.

9. The compound according to claim 1 , wherein the compound is

N-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]-2-(4-fluorophenyl)-1,6-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine,

N-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]-2-(4-fluorophenyl)-1,6-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine.2CH 3 SO 3 H,

N-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]-2-(4-fluorophenyl)-1,6-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine.2HCl,

2-(4-fluorophenyl)-N-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-2-pyridinyl]-1-methyl-1H-benzimidazol-4-amine,

2-(4-fluorophenyl)-N-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-2-pyridinyl]-1-methyl-1H-benzimidazol-4-amine.2HCl,

2-(2,3-difluorophenyl)-N-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-2-pyridinyl]-1-methyl-1H-benzimidazol-4-amine.2HCl.H 2 O,

2-(2,3-difluorophenyl)-N-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-2-pyridinyl]-1-methyl-1H-benzimidazol-4-amine,

2-(4-fluoro-3-methoxyphenyl)-N-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-2-pyridinyl]-1-methyl-1H-benzimidazol-4-amine.2HCl.H 2 O,

2-(4-fluoro-3-methoxyphenyl)-N-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-2-pyridinyl]-1-methyl-1H-benzimidazol-4-amine,

2-(3,5-dimethoxyphenyl)-N-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-2-pyridinyl]-1-methyl-1H-benzimidazol-4-amine.2HCl.H 2 O, or

2-(3,5-dimethoxyphenyl)-N-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-2-pyridinyl]-1-methyl-1H-benzimidazol-4-amine,

including any stereochemically isomeric form thereof or a pharmaceutically acceptable addition salt thereof.

10. The compound according to claim 1 , wherein the compound is

2-(4-fluorophenyl)-N-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-2-pyridinyl]-1-methyl-1H-benzimidazol-4-amine, or a pharmaceutically acceptable addition salt thereof.

11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as defined in any one of claims 1 to 10 .

12. A method for the treatment of a disease or condition selected from, traumatic brain injury, mild cognitive impairment, senility, dementia, dementia with Lewy bodies, cerebral amyloid angiopathy, multi-infarct dementia, Down's syndrome, dementia associated with Parkinson's disease and dementia associated with beta-amyloid, comprising administering to a subject a compound as defined in any one of claims 1 to 10 .