Substituted triazole derivatives as gamma secretase modulators

1. A compound of Formula (I)

or a stereoisomeric form thereof, wherein

Het 1 is a heterocycle, having formula (a-1), (a-2), (a-3), or (a-4)

R 3 is C 1-4 alkyl;

R 4 , R 5 , R 6 , and R 8 each independently are hydrogen or C 1-4 alkyl optionally substituted with one or more halo substituents;

R 7a is hydrogen, halo, or C 1-4 alkyl;

R 7b and R 7c each independently are hydrogen, halo, cyano, C 1-4 alkyloxy, cycloC 3-7 alkyl, or C 1-4 alkyl optionally substituted with one or more halo substituents;

X a is CH or N;

X b is O or S;

A 1 is CR 9 ; wherein R 9 is hydrogen, halo, or C 1-4 alkyloxy;

A 2 is CH; and A 3 and A 4 are CH;

L 1 is O, carbonyl, NR 10 , NH—(C═O), or (C═O)—NH; wherein R 10 is hydrogen or C 1-4 alkyl;

R 1 is cycloC 3-7 alkyl; C 2-6 alkenyl; or C 1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, NR 11a R 12a , cycloC 3-7 alkyl, and C 1-6 alkyloxy;

wherein each cycloC 3-7 alkyl may be substituted with one or more substituents each independently selected from the group consisting of halo, C 1-4 alkyloxy, cyano, and C 1-4 alkyl optionally substituted with one or more halo substituents;

L 2 represents a direct bond; carbonyl; O; S; S(═O) p ; NR 13a ;

NR 13b —C 1-3 alkanediyl; C 1-3 alkanediyl-NR 13c ; C 1-3 alkanediyl optionally substituted with one or more halo substituents; or C 1-3 alkanediyl wherein two geminal hydrogen atoms may be replaced by C 2-6 alkanediyl;

p represents 1 or 2;

R 2 is pyrrolidinyl; tetrahydrofuranyl; piperidinyl; tetrahydropyranyl; morpholinyl; piperazinyl; cycloC 3-7 alkyl; hexahydro-1H-1,4-diazepin-1-yl; 1,3-dihydro-2H-isoindol-2-yl; 2,3-dihydro-1H-indol-1-yl; 3,4-dihydro-1(2H)-quinolinyl; 3,4-dihydro-2(1H)-isoquinolinyl; 1,2-dihydropyridinyl; indanyl; 1,3-benzodioxolyl; or Ar;

wherein pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, cycloC 3-7 alkyl, hexahydro-1H-1,4-diazepin-1-yl, 1,3-dihydro-2H-isoindol-2-yl, 2,3-dihydro-1H-indol-1-yl, 3,4-dihydro-1(2H)-quinolinyl, 3,4-dihydro-2(1H)-isoquinolinyl, 1,2-dihydropyridinyl, indanyl and 1,3-benzodioxolyl may be substituted with one or more substituents each independently selected from the group consisting of C 2-6 alkenyl, cycloC 3-7 alkyl,

C 1-4 alkylcarbonyl, hydroxyl, oxo, halo, C 1-4 alkyloxy, C 1-4 alkyloxyC 1-4 alkyl, C 1-4 alkyloxycarbonyl, Ar, and C 1-4 alkyl optionally substituted with one or more halo substituents;

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 11b R 12b , morpholinyl

C 1-4 alkyloxy substituted with one or more halo substituents,

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

or a 5- or 6-membered heteroaryl selected from the group consisting of furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl,

wherein said 5- or 6-membered heteroaryl may be substituted with one or more substituents each independently selected from the group consisting of halo, C 1-4 alkyloxy, cyano, NR 11c R 12c , morpholinyl, and C 1-4 alkyl optionally substituted with one or more halo substituents;

each R 11a , R 11b and R 11c independently is hydrogen, C 1-4 alkyl or C 1-4 alkylcarbonyl;

each R 12a , R 12b and R 12C independently is hydrogen or C 1-4 alkyl;

each R 13a , R 13b and R 13c independently is hydrogen, or C 1-4 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo and cycloC 3-7 alkyl;

or a pharmaceutically acceptable addition salt or a solvate thereof.

2. The compound according to claim 1 , wherein

Het 1 is a heterocycle, having formula (a-1), (a-2), (a-3a), or (a-4)

R 1 is cycloC 3-7 alkyl; or C 1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, NR 11a R 12a , cycloC 3-7 alkyl, and C 1-6 alkyloxy;

wherein each cycloC 3-7 alkyl may be substituted with one or more substituents each independently selected from the group consisting of halo, C 1-4 alkyloxy, cyano, and C 1-4 alkyl optionally substituted with one or more halo substituents;

R 2 is pyrrolidinyl; tetrahydrofuranyl; piperidinyl; tetrahydropyranyl; morpholinyl; piperazinyl;

cycloC 3-7 alkyl; 1,3-dihydro-2H-isoindol-2-yl; 2,3-dihydro-1H-indol-1-yl; 3,4-dihydro-1(2H)-quinolinyl; 3,4-dihydro-2(1H)-isoquinolinyl; 1,2-dihydropyridinyl; indanyl; 1,3-benzodioxolyl; or Ar;

wherein pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, cycloC 3-7 alkyl, 1,3-dihydro-2H-isoindol-2-yl, 2,3-dihydro-1H-indol-1-yl, 3,4-dihydro-1(2H)-quinolinyl, 3,4-dihydro-2(1H)-isoquinolinyl, 1,2-dihydropyridinyl, indanyl and 1,3-benzodioxolyl may be substituted with one or more substituents each independently selected from the group consisting of C 2-6 alkenyl, C 1-4 alkylcarbonyl, oxo, halo, C 1-4 alkyloxy,

C 1-4 alkyloxycarbonyl, Ar, and C 1-4 alkyl optionally substituted with one or more halo substituents;

or a pharmaceutically acceptable addition salt or a solvate thereof.

3. The compound according to claim 1 , wherein

Het 1 is a heterocycle, having formula (a-1), (a-2), or (a-3);

R 4 is hydrogen;

R 5 is hydrogen or C 1-4 alkyl;

R 6 is hydrogen or C 1-4 alkyl;

R 7a is hydrogen or C 1-4 alkyl;

R 7b is hydrogen, C 1-4 alkyloxy, or C 1-4 alkyl optionally substituted with one or more halo substituents;

R 7c is hydrogen or C 1-4 alkyl;

X b is O;

L 1 is carbonyl, NR 10 , NH—(C═O) or (C═O)—NH; wherein R 10 is hydrogen or C 1-4 alkyl;

R 1 is cycloC 3-7 alkyl; C 2-6 alkenyl; or C 1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of NR 11a R 12a , 1-pyrrolidinyl, and C 1-6 alkyloxy;

L 2 represents a direct bond; 0; NR 13a ; or C 1-3 alkanediyl;

R 2 is pyrrolidinyl; piperidinyl; morpholinyl; piperazinyl; hexahydro-1H-1,4-diazepin-1-yl; 1,3-dihydro-2H-isoindol-2-yl; 2,3-dihydro-1H-indol-1-yl; 3,4-dihydro-2(1H)-isoquinolinyl; 2-oxo-5-(trifluoromethyl)-1(2H)-pyridinyl; or Ar;

wherein pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and hexahydro-1H-1,4-diazepin-1-yl, may be substituted with one or more substituents each independently selected from the group consisting of cycloC 3-7 alkyl,

C 1-4 alkylcarbonyl, hydroxyl, halo, C 1-4 alkyloxy, C 1-4 alkyloxyC 1-4 alkyl, C 1-4 alkyloxycarbonyl, Ar, and C 1-4 alkyl optionally substituted with one or more halo substituents;

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

each R 11a independently is hydrogen or C 1-4 alkyl;

each R 12a independently is hydrogen or C 1-4 alkyl;

R 13a is hydrogen;

or a pharmaceutically acceptable addition salt or a solvate thereof.

4. The compound according to claim 1 , wherein

R 2 is pyrrolidinyl; tetrahydrofuranyl; piperidinyl; tetrahydropyranyl; morpholinyl; piperazinyl;

cycloC 3-7 alkyl; hexahydro-1H-1,4-diazepin-1-yl; 1,3-dihydro-2H-isoindol-2-yl; 2,3-dihydro-1H-indol-1-yl; 3,4-dihydro-1(2H)-quinolinyl; 3,4-dihydro-2(1H)-isoquinolinyl; 2-oxo-5-(trifluoromethyl)-1(2H)-pyridinyl; indanyl; 1,3-benzodioxolyl; or Ar;

wherein pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, cycloC 3-7 alkyl, hexahydro-1H-1,4-diazepin-1-yl, 1,3-dihydro-2H-isoindol-2-yl, 2,3-dihydro-1H-indol-1-yl, 3,4-dihydro-1(2H)-quinolinyl, 3,4-dihydro-2(1H)-isoquinolinyl, indanyl and 1,3-benzodioxolyl may be substituted with one or more substituents each independently selected from the group consisting of C 2-6 alkenyl, cycloC 3-7 alkyl, C 1-4 alkylcarbonyl, hydroxyl, halo, C 1-4 alkyloxy, C 1-4 alkyloxyC 1-4 alkyl, C 1-4 alkyloxycarbonyl, Ar, and C 1-4 alkyl optionally substituted with one or more halo substituents.

5. The compound according to claim 1 wherein Het 1 is a heterocycle, having formula (a-1), (a-2) or (a-3).

6. The compound according to claim 1 wherein L 1 is NH.

7. The compound according to claim 1 wherein Het 1 is a heterocycle, having formula (a-1), (a-2), (a-3a), or (a-4)

8. The compound according to claim 1 wherein the compound is

5-(2-chlorophenoxy)-N-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-1-(1-methylethyl)-1H-1,2,4-triazol-3-amine,

N-[3-methoxy-4-(2-methyl-4-pyridinyl)phenyl]-1-(1-methylethyl)-5-[3-(trifluoromethyl)-1-piperidinyl]-1H-1,2,4-triazol-3-amine,

5-(2-chlorophenoxy)-N-[3-methoxy-4-(2-methyl-4-pyridinyl)phenyl]-1-(1-methylethyl)-1H-1,2,4-triazol-3-amine,

N-[3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]-1-(1-methylethyl)-5-[3-(trifluoromethyl)-1-piperidinyl]-1H-1,2,4-triazol-3-amine,

N-[3-methoxy-4-(2-methyl-4-pyridinyl)phenyl]-1-(1-methylethyl)-5-[2-(trifluoromethyl)phenoxy]-1H-1,2,4-triazol-3-amine, or

N-[3-methoxy-4-(2-methyl-4-pyridinyl)phenyl]-1-(1-methylethyl)-5-[3-(trifluoromethyl)phenoxy]-1H-1,2,4-triazol-3-amine,

a stereoisomeric form thereof,

or a pharmaceutically acceptable addition salt.

9. The compound according to claim 1 wherein the compound is a hydrochloride addition salt of

N-[3-methoxy-4-(2-methyl-4-pyridinyl)phenyl]-1-(1-methylethyl)-5-[3-(trifluoromethyl)-1-piperidinyl]-1H-1,2,4-triazol-3-amine,

5-(2-chlorophenoxy)-N-[3-methoxy-4-(2-methyl-4-pyridinyl)phenyl]-1-(1-methylethyl)-1H-1,2,4-triazol-3-amine,

N-[3-methoxy-4-(2-methyl-4-pyridinyl)phenyl]-1-(1-methylethyl)-5-[2-(trifluoromethyl)phenoxy]-1H-1,2,4-triazol-3-amine, or

N-[3-methoxy-4-(2-methyl-4-pyridinyl)phenyl]-1-(1-methylethyl)-5-[3-(trifluoromethyl)phenoxy]-1H-1,2,4-triazol-3-amine,

or a stereoisomeric form thereof.

10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as defined in claim 1 .

11. A method for the treatment of a patient for a disease or condition selected from Alzheimer's disease, traumatic brain injury, mild cognitive impairment, senility, dementia, dementia with Lewy bodies, cerebral amyloid angiopathy, multi-infarct dementia, dementia pugilistica, Down's syndrome, dementia associated with Parkinson's disease and dementia associated with beta-amyloid comprising administering to the patient a therapeutically effective amount of the compound of claim 1 .

12. The method according to claim 11 wherein the disease is Alzheimer's disease.