Benzimidazoles and related analogs as sirtuin modulators

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.

What is claimed is: 
     
         1 . A compound of Formula (II): 
       
         
           
           
               
               
           
         
       
       wherein:
 one of Z 11  and Z 12  is CR 13 , and the other of Z 11  and Z 12  is selected from N and CR 13 ; 
 wherein:
 R 13  is selected from hydrogen, halo, —OH, —C≡N, fluoro-substituted C 1 -C 2  alkyl, —O—(C 1 -C 2  fluoro-substituted alkyl), —S—(C 1 -C 2  fluoro-substituted alkyl), C 1 -C 4  alkyl, —(C 1 -C 2  alkyl)-N(R 14 )(R 14 ), —O—CH 2 CH(OH)CH 2 OH, —O—(C 1 -C 4 ) alkyl, —O—(C 1 -C 3 ) alkyl-N(R 14 )(R 14 ), —N(R 14 )(R 14 ), —S—(C 1 -C 4 ) alkyl and C 3 -C 7  cycloalkyl; 
 
 R is selected from hydrogen, —(C 2 -C 4 ) alkyl, —(C 1 -C 4 ) fluoro-substituted alkyl, —(C 1 -C 4 ) alkyl-N(R 7 )(R 7 ), —(C 1 -C 4 ) alkyl-C(O)—N(R 7 )(R 7 ), —(C 2 -C 4 ) alkyl —O—R 7 , and —(C 2 -C 4 ) alkyl-N(R 7 )—C(O)—R 7 ; 
 wherein:
 each R 7  is independently selected from hydrogen, and —C 1 -C 4  alkyl; or 
 two R 7  bound to the same nitrogen atom are taken together with the nitrogen atom to form a 4- to 7-membered saturated heterocycle optionally comprising one additional heteroatom selected from N, S, S(═O), S(═O) 2 , and O, 
 
 wherein:
 the saturated heterocycle is optionally substituted at a single carbon atom with —OH, —C 1 -C 4  alkyl, fluoro, —NH 2 , —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl) 2 , —NH(CH 2 CH 2 OCH 3 ), or —N(CH 2 CH 2 OCH 3 ) 2 ; 
 
 R 4  is selected from hydrogen, halo, —C≡N, fluoro-substituted C 1 -C 2  alkyl, —S—(C 1 -C 2 ) fluoro-substituted alkyl, C 1 -C 4  alkyl, —S—(C 1 -C 4 ) alkyl and C 3 -C 7  cycloalkyl; 
 X is selected from —NH—C(═O)-†, —C(═O)—NH-†, —NH—C(═S)-†, —C(═S)—NH-†, —NH—S(═O)-†, —S(═O)—NH-†, —S(═O) 2 —NH-†, —NH—S(═O) 2 -†, —NH—S(O) 2 —NR 15 -†, NR 15 —S(O) 2 —NH-†, —NH—C(═O)O-†, O—C(═O)—NH-†, —NH—C(═O)NH-†, —NH—C(═O)NR 15 -†, —NR 15 —C(═O)NH-†, —NH—NR 15 -†, —NR 15 —NH-†, —O—NH-†, —NH—O-†, —NH—CR 15 R 16 -†, —CR 15 R 16 —NH-†, —NH—C(═NR 15 )-†, —C(═NR 15 )—NH-†, —C(═O)—NH—CR 15 R 16 -†, —CR 15 R 16 —NH—C(O)-†, —NH—C(═S)—CR 15 R 16 -†, —CR 15 R 16 —C(═S)—NH-†, —NH—S(O)—CR 15 R 16 -†, —CR 15 R 16 —S(O)—NH-†, —NH—S(O) 2 —CR 15 R 16 -†, —CR 15 R 16 —S(O) 2 —NH-†, —NH—C(═O)—O—CR 15 R 16 -†, —CR 15 R 16 —O—C(═O)—NH-†, —NH—C(═O)—NR 14 —CR 15 R 16 -†, —NH—C(═O)—CR 15 R 16 -†, and —CR 15 R 16 —NH—C(═O)—O-†; 
 wherein:
 † represents where X is bound to R 11 , and: 
 R 15  and R 16  are independently selected from hydrogen, C 1 -C 4  alkyl, CF 3 , and —(C 1 -C 4  alkyl)-CF 3 ; 
 
 
       R 11  is selected from a carbocycle and a heterocycle;
 wherein:
 R 11  is optionally substituted with one to two substitutents independently selected from halo, —C≡N, C 1 -C 3  alkyl, C 3 -C 7  cycloalkyl, C 1 -C 2  fluoro-substituted alkyl, ═O, —O—C 1 -C 4  alkyl, —S—R 14 , —(C 1 -C 4  alkyl)-N(R 14 )(R 14 ), —N(R 14 )(R 14 ), —O—(C 2 -C 4  alkyl)-N(R 14 )(R 14 ), —C(O)—N(R 14 )(R 14 ), —C(O)—O—R 14 , and —(C 1 -C 4  alkyl)-C(O)—N(R 14 )(R 14 ); and 
 when R 11  is phenyl, R 11  is also optionally substituted with 3,4-methylenedioxy, fluoro-substituted 3,4-methylenedioxy, 3,4-ethylenedioxy, fluoro-substituted 3,4-ethylenedioxy, O-(saturated heterocycle), fluoro-substituted —O-(saturated heterocycle), and C 1 -C 4  alkyl-substituted O-(saturated heterocycle); 
 wherein
 each R 14  is independently selected from hydrogen, and —C 1 -C 4  alkyl; or 
 two R 14  are taken together with the nitrogen atom to which they are bound to form a 4- to 8-membered saturated heterocycle optionally comprising one additional heteroatom selected from N, S, S(═O), S(═O) 2 , and O; 
 wherein:
 when R 14  is alkyl, the alkyl is optionally substituted with one or more —OH, —O—(C 1 -C 4  alkyl), fluoro, —NH 2 , —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl) 2 , —NH(CH 2 CH 2 OCH 3 ), or —N(CH 2 CH 2 OCH 3 ) 2  and 
 
 
 when two R 14  are taken together with the nitrogen atom to which they are bound to form a 4- to 8-membered saturated heterocycle, the saturated heterocycle is optionally substituted at a carbon atom with —OH, —C 1 -C 4  alkyl, fluoro, —NH 2 , —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl) 2 , —NH(CH 2 CH 2 OCH 3 ), or —N(CH 2 CH 2 OCH 3 ) 2 ; and optionally substituted at any substitutable nitrogen atom with —C 1 -C 4  alkyl, fluoro-substituted C 1 -C 4  alkyl, or —(CH 2 ) 2 —O—CH 3 ; and 
 
 R 12  is selected from a carbocycle having at least five ring atoms; 
 wherein:
 R 12  is optionally substituted with one to two substitutents independently selected from halo, —C≡N, C 1 -C 4  alkyl, C 3 -C 7  cycloalkyl, C 1 -C 2  fluoro-substituted alkyl, —O—R 14 , —S—R 14 , —S(O)-e, —S(O) 2 —R 14 , —(C 1 -C 4  alkyl)-N(R 14 )(R 14 ), —N(R 14 )(R 14 ), —O—(C 2 -C 4  alkyl)-N(R 14 )(R 14 ), —C(O)—N(R 14 )(R 14 ), —(C 1 -C 4  alkyl)-C(O)—N(R 14 )(R 14 ), —O-phenyl, phenyl, and a second heterocycle, and 
 when R 12  is phenyl, R 12  is also optionally substituted with 3,4-methylenedioxy, fluoro-substituted 3,4-methylenedioxy, 3,4-ethylenedioxy, fluoro-substituted 3,4-ethylenedioxy, or —O-(saturated heterocycle) wherein any phenyl, saturated heterocycle or second heterocycle substituent of R 12  is optionally substituted with halo; —C≡N; C 1 -C 4  alkyl, C 1 -C 2  fluoro-substituted alkyl, —O—(C 1 -C 2  fluoro-substituted alkyl), —O—(C 1 -C 4  alkyl), —S—(C 1 -C 4  alkyl), —S—(C 1 -C 2  fluoro-substituted alkyl), —NH—(C 1 -C 4  alkyl) and —N—(C 1 -C 4  alkyl) 2 ; or 
 
 
       a pharmaceutically acceptable salt thereof. 
     
     
         2 . The compound of  claim 1 , wherein Formula (II) is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 2 , having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein R is hydrogen. 
     
     
         5 . The compound of  claim 1 , wherein X is —C(O)—NH-†. 
     
     
         6 . The compound of  claim 1 , wherein R 11  is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein:
 R 11  is optionally further substituted with substituents as defined in  claim 1 . 
 
       
     
     
         7 . The compound of  claim 1 , wherein R 12  is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein: 
         R 12  is optionally further substituted with substituents as defined in  claim 1 . 
       
     
     
         8 . A compound of Formula (IIb): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 13  is hydrogen, halo, —OH, —C≡N, fluoro-substituted C 1 -C 2  alkyl, —O—(C 1 -C 2  fluoro-substituted alkyl), —S—(C 1 -C 2  fluoro-substituted alkyl), C 1 -C 4  alkyl, —(C 1 -C 2  alkyl)-N(R 14 )(R 14 ), —O—CH 2 CH(OH)CH 2 OH, —O—(C 1 -C 4 ) alkyl, —O—(C 1 -C 3 ) alkyl-N(R 14 )(R 14 ), —N(R 14 )(R 14 ), —S—(C 1 -C 4 ) alkyl or C 3 -C 7  cycloalkyl; 
 R is hydrogen, —(C 2 -C 4 ) alkyl, —(C 1 -C 4 ) fluoro-substituted alkyl, —(C 1 -C 4 ) alkyl-N(R 7 )(R 7 ), —(C 1 -C 4 ) alkyl-C(O)—N(R 7 )(R 7 ), —(C 2 -C 4 ) alkyl —O—R 7  or —(C 2 -C 4 ) alkyl-N(R 7 )—C(O)—R 7 ; 
 wherein:
 each R 7  is independently selected from hydrogen, and —C 1 -C 4  alkyl; or 
 two R 7  bound to the same nitrogen atom are taken together with the nitrogen atom to form a 4- to 7-membered saturated heterocycle optionally comprising one additional heteroatom selected from N, S, S(═O), S(═O) 2 , and O, 
 wherein:
 the saturated heterocycle is optionally substituted at a single carbon atom with —OH, —C 1 -C 4  alkyl, fluoro, —NH 2 , —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl) 2 , —NH(CH 2 CH 2 OCH 3 ), or —N(CH 2 CH 2 OCH 3 ) 2 ; 
 
 
 R 4  is selected from hydrogen, halo, —C≡N, fluoro-substituted C 1 -C 2  alkyl, —S—(C 1 -C 2 ) fluoro-substituted alkyl, C 1 -C 4  alkyl, —S—(C 1 -C 4 ) alkyl and C 3 -C 7  cycloalkyl; 
 X is selected from —NH—C(═O)-†, —C(═O)—NH-†, —NH—C(═S)-†, —C(═S)—NH-†, —NH—S(═O)-†, —S(═O)—NH-†, —S(═O) 2 —NH-†, —NH—S(═O) 2 -†, —NH—S(O) 2 —NR 15 -†, —NR 15 —S(O) 2 —NH-†, —NH—C(═O)O-†, O—C(═O)—NH-†, —NH—C(═O)NH-†, —NH—C(═O)NR 15 -†, —NR 15 —C(═O)NH-†, —NH—NR 15 -†, —NR 15 —NH-†, —O—NH-†, —NH—O-†, —NH—CR 15 R 16 -†, —CR 15 R 16 —NH-†, —NH—C(═NR 15 )-†, —C(═NR 15 )—NH-†, —C(═O)—NH—CR 15 R 16 -†, —CR 15 R 16 —NH—C(O)-†, —NH—C(═S)—CR 15 R 16 -†, —CR 15 R 16 —C(═S)—NH-†, —NH—S(O)—CR 15 R 16 -†, —CR 15 R 16 —S(O)—NH-†, —NH—S(O) 2 —CR 15 R 16 -†, —CR 15 R 16 —S(O) 2 —NH-†, —NH—C(═O)—O—CR 15 R 16 -†, —CR 15 R 16 —O—C(═O)—NH-†, —NH—C(═O)—NR 14 —CR 15 R 16 -†, —NH—C(═O)—CR 15 R 16 -†, and —CR 15 R 16 —NH—C(═O)—O-†; 
 wherein:
 † represents where X is bound to R 11 , and: 
 R 15  and R 16  are independently selected from hydrogen, C 1 -C 4  alkyl, CF 3 , and —(C 1 -C 4  alkyl)-CF 3 ; 
 
 
       R 11  is selected from a carbocycle and a heterocycle;
 wherein:
 R 11  is optionally substituted with one to two substitutents independently selected from halo, —C≡N, C 1 -C 3  alkyl, C 3 -C 7  cycloalkyl, C 1 -C 2  fluoro-substituted alkyl, ═O, —O—C 1 -C 4  alkyl, —S—R 14 , —(C 1 -C 4  alkyl)-N(R 14 )(R 14 ), —N(R 14 )(R 14 ), —O—(C 2 -C 4  alkyl)-N(R 14 )(R 14 ), —C(O)—N(R 14 )(R 14 ), —C(O)—O—R 14 , and —(C 1 -C 4  alkyl)-C(O)—N(R 14 )(R 14 ); and 
 when R 11  is phenyl, R 11  is also optionally substituted with 3,4-methylenedioxy, fluoro-substituted 3,4-methylenedioxy, 3,4-ethylenedioxy, fluoro-substituted 3,4-ethylenedioxy, O-(saturated heterocycle), fluoro-substituted —O-(saturated heterocycle), and C 1 -C 4  alkyl-substituted O-(saturated heterocycle); 
 wherein
 each R 14  is independently selected from hydrogen, and —C 1 -C 4  alkyl; or 
 two R 14  are taken together with the nitrogen atom to which they are bound to form a 4- to 8-membered saturated heterocycle optionally comprising one additional heteroatom selected from N, S, S(═O), S(═O) 2 , and O; 
 wherein:
 when R 14  is alkyl, the alkyl is optionally substituted with one or more —OH, —O—(C 1 -C 4  alkyl), fluoro, —NH 2 , —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl) 2 , —NH(CH 2 CH 2 OCH 3 ), or —N(CH 2 CH 2 OCH 3 ) 2  and 
 when two R 14  are taken together with the nitrogen atom to which they are bound to form a 4- to 8-membered saturated heterocycle, the saturated heterocycle is optionally substituted at a carbon atom with —OH, —C 1 -C 4  alkyl, fluoro, —NH 2 , —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl) 2 , —NH(CH 2 CH 2 OCH 3 ), or —N(CH 2 CH 2 OCH 3 ) 2 ; and optionally substituted at any substitutable nitrogen atom with —C 1 -C 4  alkyl, fluoro-substituted C 1 -C 4  alkyl, or —(CH 2 ) 2 —O—CH 3 ; and 
 
 
 
 R 12  is selected from a carbocycle having at least five ring atoms; 
 wherein:
 R 12  is optionally substituted with one to two substitutents independently selected from halo, —C≡N, C 1 -C 4  alkyl, C 3 -C 7  cycloalkyl, C 1 -C 2  fluoro-substituted alkyl, —O—R 14 , —S—R 14 , —S(O)—R 14 , —S(O) 2 —R 14 , —(C 1 -C 4  alkyl)-N(R 14 )(R 14 ), —N(R 14 )(R 14 ), —O—(C 2 -C 4  alkyl)-N(R 14 )(R 14 ), —C(O)—N(R 14 )(R 14 ), —(C 1 -C 4  alkyl)-C(O)—N(R 14 )(R 14 ), —O-phenyl, phenyl, and a second heterocycle, and 
 when R 12  is phenyl, R 12  is also optionally substituted with 3,4-methylenedioxy, fluoro-substituted 3,4-methylenedioxy, 3,4-ethylenedioxy, fluoro-substituted 3,4-ethylenedioxy, or —O-(saturated heterocycle) wherein any phenyl, saturated heterocycle or second heterocycle substituent of R 12  is optionally substituted with halo; —C≡N; C 1 -C 4  alkyl, C 1 -C 2  fluoro-substituted alkyl, —O—(C 1 -C 2  fluoro-substituted alkyl), —O—(C 1 -C 4  alkyl), —S—(C 1 -C 4  alkyl), —S—(C 1 -C 2  fluoro-substituted alkyl), —NH—(C 1 -C 4  alkyl) and —N—(C 1 -C 4  alkyl) 2 ; or 
 
 
       a pharmaceutically acceptable salt thereof. 
     
     
         9 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 
     
     
         10 . The pharmaceutical composition of  claim 9 , further comprising an additional active agent. 
     
     
         11 . A pharmaceutical composition comprising a compound of  claim 8 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 
     
     
         12 . A method for treating a subject suffering from or susceptible to insulin resistance, a metabolic syndrome, diabetes, or complications thereof, or for increasing insulin sensitivity in a subject, comprising administering to the subject in need thereof a compound of  claim 1 . 
     
     
         13 . A method for treating a subject suffering from or susceptible to insulin resistance, a metabolic syndrome, diabetes, or complications thereof, or for increasing insulin sensitivity in a subject, comprising administering to the subject in need thereof a composition of  claim 9 .