Piperazine thiazole derivatives useful in the treatment of tauopathies such as Alzheimer's disease

A method for reducing TAU-induced cytotoxicity, which method comprises contacting a cell with an effective amount of a compound of formula IA or a pharmaceutically active salt thereof, a stereoisomeric form, including an individual diastereoisomer or enantiomer of the compound of formula IA as well as a racemic or non-racemic mixture thereof;

• wherein
• G1 is lower alkyl;
• lower alkyl substituted by one or more halogens;
• cycloalkyl;
• tetrahydropyran-4-yl;
• phenethyl;
• phenethyl substituted by one or more halogens;
• phenoxymethyl;
• phenoxymethyl substituted by one or more halogens;
• benzyloxy-ethyl;
• benzyloxy-ethyl substituted by one or more halogens;
• or is —NR2R3;
• R2 is hydrogen or lower alkyl;
• R3 is lower alkyl, tetrahydropyran-4-yl, —CH2-cycloalkyl or cycloalkyl optionally substituted by lower alkyl substituted by one or more halogens;
• or R2 and R3 form together with the N-atom to which they are attached a heterocycloalkyl group with 4 or 5 carbon atoms, which is optionally substituted by one or more substituents selected from halogen or lower alkyl substituted by one or more halogens;
• X is —CH2— or —(CH2)2—;
• Ar is phenyl or pyridinyl;
• R4 is halogen;
• lower alkyl;
• lower alkyl substituted by one or more halogens;
• or lower alkoxy;
• n is 1 or 2;
• with the proviso that said compound is not:
• 5-(4-(3-fluorobenzyl)piperazin-1-yl)-3-methyl-1,2,4-thiadiazole, or
• 3-isopropyl-5-(4-(3-(trifluoromethyl)benzyl)piperazin-1-yl)-1,2,4-thiadiazole;
• wherein the cell is a human neuron.

A method for reducing human neuronal cell death and/or degeneration, which method comprises contacting a human neuron with an effective amount of a compound of formula IA or a pharmaceutically active salt thereof, a stereoisomeric form, including an individual diastereoisomer or enantiomer of the compound of formula IA as well as a racemic or non-racemic mixture thereof;

• wherein
• G1 is lower alkyl;
• lower alkyl substituted by one or more halogens;
• cycloalkyl;
• tetrahydropyran-4-yl;
• phenethyl;
• phenethyl substituted by one or more halogens;
• phenoxymethyl;
• phenoxymethyl substituted by one or more halogens;
• benzyloxy-ethyl;
• benzyloxy-ethyl substituted by one or more halogens;
• or is —NR2R3;
• R2 is hydrogen or lower alkyl;
• R3 is lower alkyl, tetrahydropyran-4-yl, —CH2-cycloalkyl or cycloalkyl optionally substituted by lower alkyl substituted by one or more halogens;
• or R2 and R3 form together with the N-atom to which they are attached a heterocycloalkyl group with 4 or 5 carbon atoms, which is optionally substituted by one or more substituents selected from halogen or lower alkyl substituted by one or more halogens;
• X is —CH2— or —(CH2)2—;
• Ar is phenyl or pyridinyl;
• R4 is halogen;
• lower alkyl;
• lower alkyl substituted by one or more halogens;
• or lower alkoxy;
• n is 1 or 2;
• with the proviso that said compound is not:
• 5-(4-(3-fluorobenzyl)piperazin-1-yl)-3-methyl-1,2,4-thiadiazole or
• 3-isopropyl-5-(4-(3-(trifluoromethyl)benzyl)piperazin-1-yl)-1,2,4-thiadiazole.