Withanolides useful for the treatment of neurodegenerative diseases

A method of treating or preventing a disease characterized by TDP-43 proteinopathy in a patient comprising administering to the patient a therapeutically or prophylactically effective amount of a compound Formula (I):

• wherein:
• R1 is hydrogen, alkyl, alkenyl, haloalkyl, aralkyl, heterocyclylalkyl, —Ra—ORb, —C(O)Rb, cycloalkylalkyl or —P(O)2O2−;
• R2 is hydrogen, alkyl, alkenyl, haloalkyl, —ORb or —OC(O)Rb;
• R3 is hydrogen, alkyl, alkenyl, haloalkyl, aralkyl, heterocyclylalkyl, —Ra—ORb, —C(O)Rb, cycloalkylalkyl or —P(O)2O2−;
• R4 is hydrogen, alkyl, alkenyl, haloalkyl, —ORb or —OC(O)Rb;
• Ra is an alkylene or alkenylene chain;
• and
• Rb is hydrogen, alkyl, alkenyl, haloalkyl, aralkyl, cycloalkylalkyl or heterocyclylalkyl,
• as an isolated stereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, provided that,
• when R2 and R4 are each hydrogen, R1 and R3 cannot both be selected from the group consisting of hydrogen and —C(O)CH3;
• or
• when R1 and R3 are each —C(O)CH3, R2 or R4 cannot both be selected from the group consisting of hydrogen and —OC(O)CH3.