Sirtuin modulating compounds

Abstract

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.