Selective presenilin-2 gamma-secretase inhibitors

4-aminoquinolines as selective presenilin-2 γ-secretase inhibitors for use in the treatment of a disease associated with a defect leading to Notch receptor hyperactivity, such as oncogenic ligand-independent gain-of-function mutations of the Notch1 receptor or loss-of-function or gain-of-function mutations leading to hyperactivity of the Notch receptor, wherein the 4-aminoquinolines are selected from compounds of formula:

• wherein:
• X is selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, nitro, cyano, amino, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkylthio, aryl, benzyl, phenoxy, or benzoxy;
• R1 and R2 are independently selected from hydrogen, C1-4 alkyl, aryl, benzyl, C1-4 alkylol, or alkylphenol;
• R3 and R4 are independently selected from hydrogen, C1-4 alkyl, aryl, benzyl, or C1-4 alkylol;
• and
• R5 and R6 are independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, nitro, cyano, amino, or C1-4 alkyl.

Imidazole compounds as selective presenilin-2 γ-secretase inhibitors, wherein the imidazole compounds are selected from compounds of formula:

• wherein:
• R1 is selected from hydrogen, or hydroxy;
• A is selected from —CH2— or —CO—;
• and
• R2 and R3 are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, or neopentyl,
• with the proviso that when R1 is hydrogen, A is —CO—.