SIRTUIN MODULATING COMPOUNDS
Provided herein are novel sirtuin-modulating compounds and methods of use thereof. The sirtuin-modulating compounds may be used for increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and/or flushing as well as diseases or disorders that would benefit from increased mitochondrial activity. Also provided are compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent.
1 . A compound of the formula:
or a salt thereof, wherein
R 19 is selected from:
wherein:
each Z 10 , Z 11 , Z 12 and Z 13 is independently selected from N, CR 20 , or CR 1 ′; and
each Z 14 , Z 15 and Z 16 is independently selected from N, NR 1 ′, S, O, CR 20 , or CR 1 ′,
wherein:
zero to two of Z 10 , Z 11 , Z 12 or Z 13 are N;
at least one of Z 14 , Z 15 and Z 16 is N, NR 1 ′, O or S;
zero to one of Z 14 , Z 15 and Z 16 is S or O;
zero to two of Z 14 , Z 15 and Z 16 are N or NR 1 ′;
zero to one R 20 is a solubilizing group; and
zero to one R 1 ′ is an optionally substituted C 1 -C 3 straight or branched alkyl;
each R 20 is independently selected from H or a solubilizing group;
R 21 is selected from —NR 1 ′—C(O)—, —NR 1 ′—S(O) 2 —, —NR 1 ′—C(O)—NR 1 ′—, —NR 1 ′—C(S)—NR 1 ′—, —NR 1 ′—C(S)—NR 1 ′—CR 1 ′R 1 ′—, —NR 1 ′—C(O)—CR 1 ′R 1 ′—NR 1 ′—, —NR 1 ′—C(═NR 1 ′)—NR 1 ′—, —C(O)—NR 1 ′—, —C(O)—NR 1 ′—S(O) 2 —, —NR 1 ′—, —CR 1 ′R 1 ′—, —NR 1 ′—C(O)—CR 1 ′═CR 1 ′—, —NR 1 ′—S(O) 2 —NR 1 ′—, —NR 1 ′—C(O)—NR 1 ′—S(O) 2 —, —NR 1 ′—CR 1 ′R 1 ′—C(O)—NR 1 ′—, —CR 1 ′R 1 ′—C(O)—NR 1 ′—, —NR 1 ′—C(O)—CR 1 ′═CR 1 ′—CR 1 ′R 1 ′—, —NR 1 ′—C(═N—CN)—NR 1 ′—, —NR 1 ′—C(O)—CR 1 ′R 1 ′—O—, —NR 1 ′—C(O)—CR 1 ′R 1 ′—CR 1 ′R 1 ′—O—, —NR 1 ′—S(O) 2 —CR 1 ′R 1 ′—, —NR 1 ′—S(O) 2 —CR 1 ′R 1 ′—CR 1 ′R 1 ′—, —NR 1 ′—C(O)—CR 1 ′R 1 ′—; —NR 1 ′—C(O)—CR 1 ′R′ 1 —CR 1 ′R′ 1 —, —NR 1 ′—C(S)—NR 1 ′—CR 1 ′R′ 1 —CR 1 ′R′ 1 —, —NR 1 ′—C(O)—O—,
each R 1 ′ is independently selected from H or optionally substituted C 1 -C 3 straight or branched alkyl; and
R 31 is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the proviso that when R 21 is —NR 1 ′—C(O)—, R 31 is not 4-cyanophenyl or
and when R 21 is —NR 1 ′—S(O) 2 —, R 31 is not 4-methoxyphenyl or 4-t-butylphenyl.