Substituted bridged urea analogs as sirtuin modulators

Abstract

Provided herein are novel substituted bridged urea and related analogs 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.

We claim: 
     
         1 . 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 of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of formula (I) 
       
         
           
           
               
               
           
         
       
       or a salt thereof wherein:
 m is 1 or 2; 
 n is 2 or 3; 
 p is 0 to 4; 
 R 1  is selected from a carbocycle and heterocycle, 
 wherein
 R 1  is optionally substituted with one or more substituents independently, selected from halo, C 1 -C 4  alkyl, fluoro-substituted C 1 -C 4  alkyl, —C≡N, —Y, —X—C(═O)—Y, —X—O—Y, —X—OR 4 , —X—C(═O)—NR 3 R 3 , —X—NH—C(═O)—NR 3 R 3 , —X—NH—C(═O)—O—Y, —X—NR 3 R 3 , ═O, —NH—S(═O) 2 —R 3 , —S(═O) 2 —R 3 ; —S—R 3 , —(C 3 -C 7 ) cycloalkyl, —C(═N)—NR 3 R 3 , —C(═N)—NH—X—NR 3 R 3 , —X—NH—C(═O)—Y, —C(═O)—NH—X, —NH—X, phenyl, —O-phenyl, 3- to 6-membered saturated or unsaturated heterocycle and —O-(5- to 6-membered saturated heterocycle), 
 
 wherein
 any phenyl, 3- to 6-membered saturated or unsaturated heterocycle or —O-5- to 6-membered saturated heterocycle substituent of R 1  is optionally substituted at any substitutable carbon atom with one or more substituents selected from halo, —OR 4 , —X—O—Y, —CF 3 , —Y, —X—R 3 R 3 , —X—NH—C(═O)—Y—NR 3 R 3 , —X—NH—C)═O)—O—Y— (5- to 6-membered saturated heterocycle or carbocycle), —X—C(═N)—N—R 3 R 3  and —S—Y and optionally substituted at any substitutable nitrogen atom with —Y, —C(═O)—Y, —C(═O)—O—Y, —C(═O)—OR 4 , —Y—C(═O)—Y—NR 3 R 3 , —Y—NH—C(═O)—O—Y, —Y—NH—C(═O)—OR 4 , —Y—NH 2 , —C(═O)—NH—Y or —C(═O)-3- to 5-membered saturated carbocycle; 
 
 R 2  is selected from a carbocycle and a heterocycle, wherein R 2  is optionally substituted with one or more substituents independently selected from halo, C 1 -C 4  alkyl, fluoro-substituted C 1 -C 4  alkyl, —C≡N, —Y, —X—OR 4 , —X—O—Y, —SO 2 —R 3 , —X—NR 3 R 3 , —NH—S(═O) 2 R 3 , —C(═O)—NR 3 R 3 , —C(═O)—Y, —C(═O)—O—Y, —SO 2 —R y , —SO 2 —NH—R y , —SO 2 —NR 3 R 3 , 3- to 6-membered saturated carbocycle or heterocycle and phenyl, 
 wherein
 any 3- to 6-membered saturated heterocycle substituent of R 2  is optionally substituted at any carbon atom with one or more substituents selected from halo, —CF 3 , —Y, —X—O—Y, —NH—Y and —N(Y) 2 , and is optionally substituted at any nitrogen atom with one or more substituents selected from —C(═O)—O—Y, —Y and —C(═O)—Y, and 
 
 when R 2  is an N-linked 5- to 7-membered saturated or unsaturated heterocycle it is further substituted at any nitrogen atom with one or more substituents selected from —C(═O)—O—Y, —Y and —C(═O)—Y; 
 each R 3  is independently selected from hydrogen, —C(═N)—NH 2 , —C(═O)—Y, —Y, —Y—NH—C(═O)—O—Y, —Y—NH—C(═O)—OH, —Y—NH—C(═O)—CF 3 , —C(═O)—Y—3- to 5-membered saturated heterocycle, —C(═O)—O—Y-(3- to 5-membered saturated heterocycle), —C(═O)—CF 3 , —C(═O)—O—Y, —C(═O)—OH, —C(═O)—O—CF 3 , —S(═O) 2 —Y, —S(═O) 2 —OH; 
 two R 3  are taken together with the nitrogen or carbon atom to which they are bound to form a 4- to 8-membered saturated heterocycle optionally comprising one additional heteroatom selected independently front N, S, S(═O), S(═O) 2 , and O, 
 wherein
 the heterocycle formed by two R 3  is optionally substituted at any carbon atom with one or more of OH, halo, Y, NH 2 , NH—Y, N(Y) 2 , O—Y, and 
 
 optionally substituted at any substitutable nitrogen atom with C(═O)—O—Y, Y or C(═O)—Y; 
 each R 4  is independently selected from hydrogen, Y, —CF 3 , —C(═O)—Y, —C(═O)—O—Y, —Y—C(═O)—Y or —Y—C(═O)—O—Y; 
 R 5  and R 6  are independently selected from hydrogen, —OH, —OCF 3 , —O—Y, —O—C(═O)—Y, —O—C(═O)—O—Y, —O—C(═O)—NH—Y, —O—C(═O)—N(Y) 2 , —O—C(═O)-5- to 6-membered saturated or unsaturated heterocycle or carbocycle, 
 wherein
 only one of R 5  and R 6  is O—C(═O)-5- to 6-membered saturated or unsaturated heterocycle or carbocycle, and 
 when R 5  or R 6  is O—C(═O)-5- to 6-membered saturated or unsaturated heterocycle or carbocycle it is further substituted with halo, —OH, Y, —O—Y, —OCF 3  or —O—C(═O)—Y; or 
 R 5  and R 6  can be taken together to the carbon atom to which they are bound to form ═O; 
 R 7  and R 8  are independently selected from hydrogen, halo, —OH, —O—Y and Y, 
 R 9  is selected from hydrogen, halo, —OH, —OCF 3 , —O—Y, Y, —O—C(═O)—Y, —NH—Y and —N(Y) 2 ; 
 
 each X is C 0 -C 5  straight chain or branched alkyl, alkenyl or alkynyl; and 
 each Y is C 1 -C 5  straight chain or branched alkyl, alkenyl or alkynyl; 
 wherein
 any Y or X is optionally substituted with one or more of —OH, —C 1 -C 4  straight chain or branched alkyl, —C 1 -C 4  alkene, —C 1 -C 4  alkynyl, —O—(C 1 -C 4  alkyl), —O—(C 1 -C 4  alkene), —O—(C 1 -C 4  alkynyl), —C(═O)—C 1 -C 4  straight chain or branched alkyl, —C(═O)—C 1 -C 4  alkene, —C(═O)—C 1 -C 4  alkynyl, —C(═O)—O—C 1 -C 4  straight chain or branched alkyl, —C(═O)—O—C 1 -C 4  alkene, —C(═O)—O—C 1 -C 4  alkynyl, halo, —NH 2 , —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl) 2 , —(C 1 -C 3  straight chain or branched alkyl)-NH—(═NH)—NH 2 , —NH(alkoxy-substituted C 1 -C 4  alkyl), —NH(hydroxy-substituted C 1 -C 4  alkyl), —N(alkoxy-substituted C 1 -C 4  alkyl)(hydroxy-substituted C 1 -C 4  alkyl), —N(hydroxy-substituted C 1 -C 4  alkyl) 2  or —N(alkoxy-substituted C 1 -C 4  alkyl) 2 ; or 
 
 
       a pharmaceutically acceptable salt thereof. 
     
     
         2 . The method of  claim 1 , wherein p is 0. 
     
     
         3 . The method of  claim 1 , wherein p is 1 to 4. 
     
     
         4 . The method of  claim 1 , wherein —(CH 2 )p-R 1  is selected from any one of: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The method of  claim 1 , wherein R 1  is selected from phenyl, a saturated or unsaturated 5- to 6-membered heterocycle and a fused bicyclic 8- to 11-membered saturated or unsaturated carbocycle or heterocycle. 
     
     
         6 . The method of  claim 1 , wherein R 1  is a fused bicyclic 8- to 11-membered saturated or unsaturated heterocycle. 
     
     
         7 . The method of  claim 1 , wherein R 1  is selected from any one of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         8 . The method of  claim 7 , wherein R 1  is selected from any one of: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The method of  claim 1 , wherein R 2  is selected from a 5- to 7-membered saturated carbocycle or heterocycle, an N-linked heterocycle, and an 8- to 11-membered saturated or unsaturated heterocycle. 
     
     
         10 . The method of  claim 1 , wherein R 2  is an N-linked 5- to 7-membered saturated or unsaturated heterocycle. 
     
     
         11 . The method of  claim 1 , wherein R 2  is a fused bicyclic 8- to 11-membered saturated or unsaturated heterocycle. 
     
     
         12 . The method of  claim 1 , wherein R 2  is selected from any one of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         13 . The method of  claim 12 , wherein R 2  is selected from any one of: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The method of  claim 1 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The method of  claim 1 , wherein the pharmaceutical composition further comprises an additional active agent.