Substituted bicyclic triazole derivatives as gamma secretase modulators
The present invention is concerned with novel substituted bicyclic triazole derivatives of Formula (I) wherein Het 1 , R 1 , R 2 , A 1 , A 2 , A 3 , A 4 , L 1 , and L 2 have the meaning defined in the claims. The compounds according to the present invention are useful as gamma secretase modulators. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.
1. A compound of Formula (I)
or a stereoisomeric form thereof, wherein
Het 1 is a heterocycle, having formula (a-3a),
R 7a is hydrogen or C 1-4 alkyl;
R 7b and R 7c each independently are hydrogen or C 1-4 alkyl;
A 1 is CR 9 ; wherein R 9 is hydrogen, halo, or C 1-4 alkyloxy;
A 2 , A 3 , and A 4 are CH;
L 1 is NR 10 ;
wherein R 10 is hydrogen or C 1-4 alkyl;
R 1 and -L 2 -R 2 are taken together to form a bivalent radical —R 1 ‘—R 2 -L 2 -having formula (b-1) or (b-2)
—(CH 2 ) m-n —Y—(CH 2 ) n — (b-1);
—(CH 2 ) n —Y—(CH 2 ) m-n — (b-2);
wherein (b-1) or (b-2) may be substituted on one carbon atom with one aryl 1 substituent;
Y is O
m is 3
n is 1;
wherein R 1 , the nitrogen atom to which R 1 is attached, -L 2 -R 2 , and the carbon atom to which L 2 is attached together form a six-membered ring;
aryl 1 is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, C 1-4 alkyloxy, and C 1-4 alkyl optionally substituted with one or more halo substituents;
each R 11e and R 11f independently is hydrogen, C 1-4 alkyl or C 1-4 alkylcarbonyl;
each R 12e and R 12f independently is hydrogen or C 1-4 alkyl;
R 13d is hydrogen, or C 1-4 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo and cyclo C 3-7 alkyl;
or a pharmaceutically acceptable addition salt thereof.
2. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as defined claim 1 .
3. 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 said patient a therapeutically effective amount of the compound of claim 1 .
4. The method according to claim 3 wherein the disease is Alzheimer's disease.