Tpk agonist and method for using same to treat neurodegenerative diseases

A method for the prophylaxis or treatment of a neurodegenerative disease or alleviating symptoms of a neurodegenerative disease, which comprises administering to a subject in need thereof a prophylactically or therapeutically effective amount of a thiamine pyrophosphokinase (TPK) agonist;

• wherein the TPK agonist is a compound of Formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof:
• wherein:
• A and B are each independently C3-10 hydrocarbon ring, 3- to 14-membered heterocycle, C6-10 aromatic ring or 5- to 14-membered heteroaromatic ring;
• L is selected from the group consisting of -Q1-, —W—, -Q1-W—, —W-Q1-, -Q1-Q2-, —W—W′—, —W-Q1-Q2-, —W-Q1-W′—, -Q1-W-Q2-, -Q1-W-Q2-W′—, —W-Q1-W′-Q2-, -Q1-Q2-W—W′— and —W-Q1-Q2-W′—;
• Q1 and Q2 are each independently selected from the group consisting of —C1-6 alkylene-, —C2-6 alkenylene-, —C2-6 alkynylene-, —C3-10 cyclic hydrocarbylene-, -(3- to 14-membered heterocyclylene)-, —C6-10 arylene- and -(5- to 14-membered heteroarylene)-, wherein the alkylene, alkenylene and alkynylene are each optionally interrupted by one group selected from the following or interrupted by multiple adjacent or non-adjacent groups independently selected from the following:
• —C3-10 cyclic hydrocarbylene-, -(3- to 14-membered heterocyclylene)-, —C6-10 arylene-, -(5- to 14-membered heteroarylene)-, —O—, —C(═O)—, —C(═O)O—, —NR—, —C(═O)NR—, —NR—C(═O)—NR′—, —NR—C(═O)O—, —(S═O)NR—, —S(═O)2NR—, —S—, —S(═O)— and —S(═O)2—;
• W and W′, at each occurrence, are each independently selected from the group consisting of —O—, —C(═O)—, —C(═O)O—, —NR—, —C(═O)NR—, —NR—C(═O)—NR′—, —NR—C(═O)O—, —(S═0)NR—, —S(═O)2NR—, —S—, —S(═O)— and —S(═O)2—;
• R and R′, at each occurrence, are each independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cyclic hydrocarbyl, 3- to 14-membered heterocyclyl, C6-10 aryl, 5- to 14-membered heteroaryl and C6-12 aralkyl;
• the above alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cyclic hydrocarbyl, cyclic hydrocarbylene, hydrocarbon ring, heterocyclyl, heterocyclylene, heterocycle, aryl, arylene, aromatic ring, heteroaryl, heteroarylene, heteroaromatic ring and aralkyl, at each occurrence, are each optionally substituted with one or more substituents independently selected from the group consisting of:
• halogen, —OH, ═O, —NH2, —CN, —NO2, C1-6 alkyl, haloC1-6 alkyl, C3-10 cyclic hydrocarbyl, 3- to 14-membered heterocyclyl, C6-10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, —C(═O)Ra, —OC(═O)Ra, —C(═O)ORa, —ORa, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRaRb, —NRaRb, —C(═O)NRaRb, —NRa—C(═O)Rb, —NRa—C(═O)ORb, —NRa—S(═O)2—Rb, —NRa—C(═O)—NRaRb, —C1-6 alkylene-ORa, —C1-6 alkylene-NRaRb and —O—C1-6 alkylene-NRaRb, the alkyl, alkylene, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl and aralkyl are further optionally substituted with one or more substituents independently selected from the group consisting of:
• halogen, —OH, ═O, —C(═O)O-tert-butyl, —NH2, —CN, —NO2, C1-6 alkyl, C1-6 haloalkyl, C3-10 cyclic hydrocarbyl, 3- to 14-membered heterocyclyl, C6-10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl, —O—C1-6 alkyl and —C1-6 alkylene-O—C1-6 alkyl;
• and
• Ra and Rb, at each occurrence, are each independently selected from the group consisting of H, C1-6 alkyl, C3-10 cyclic hydrocarbyl, 3- to 14-membered heterocyclyl, C6-10 aryl, 5- to 14-membered heteroaryl and C6-12 aralkyl, the alkyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl and aralkyl are further optionally substituted with one or more substituents independently selected from the group consisting of:
• halogen, —OH, ═O, —C(═O)O-tert-butyl, —NH2, —CN, —NO2, C1-6 alkyl, C1-6 haloalkyl, C3-10 cyclic hydrocarbyl, 3- to 14-membered heterocyclyl, C6-10 aryl, 5- to 14-membered heteroaryl, C6-12 aralkyl and —C1-6 alkylene-O—C1-6 alkyl;
• preferably, the neurodegenerative disease is Alzheimer's disease;
• more preferably, the Alzheimer's disease is one in which the subject has decreased TPK enzyme activity, decreased TPK expression level, and/or decreased TDP level.