Therapeutic compounds

Abstract

The invention provides compounds of formula (I): wherein, A, C, D, X, and Y have any of the values defined in the specification, and salts thereof. The compounds are SIRT2 inhibitors and are useful for treating SIRT2 associated conditions.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 X is CH; 
 Y is CH; 
 A is -A′-B′—, 
 A′ is 
 
       
         
           
           
               
               
           
         
         B′ is phenyl, 
         C is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         D is phenyl that is substituted with —NR a R b , or D is pyridyl that is optionally substituted with one or more groups R z  independently selected from halo, deuterium, nitro, hydroxy, cyano, carboxy, —NR a R b , —C(═O)NR a R b , —N—S(O) 2 R a , —NR a C(═O)NR a R b , (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkanoyl, (C 1 -C 4 )alkoxycarbonyl, (C 1 -C 4 )alkanoyloxy, (C 3 -C 15 )carbocycle, aryl, aryloxy, and heteroaryl, wherein any (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkanoyl, (C 1 -C 4 )alkoxycarbonyl, (C 3 -C 15 )carbocycle, and (C 1 -C 4 )alkanoyloxy of R z  is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, deuterium, —NR a R b , (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxycarbonyl, (C 1 -C 4 )alkanoyloxy, aryl, aryloxy, and heteroaryl, wherein any aryl, aryloxy, and heteroaryl of R z  is optionally substituted with one or more groups independently selected from the group consisting of halo, deuterium, halo, nitro, cyano, hydroxy, —NR a R b , (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxycarbonyl, (C 1 -C 4 )alkanoyloxy, (C 1 -C 4 )haloalkyl, R x , and (C 1 -C 4 )haloalkoxy, 
         each R a  and R b  is independently selected from the group consisting of H, (C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkanoyl, (C 1 -C 4 )alkoxycarbonyl, (C 1 -C 4 )alkanoyloxy, aryl, and heteroaryl, wherein any (C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkanoyl, (C 1 -C 4 )alkoxycarbonyl, and (C 1 -C 4 )alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of halo, deuterium, hydroxy, (C 3 -C 15 )carbocycle, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxycarbonyl, (C 1 -C 4 )alkanoyloxy, oxo (═O), aryl, and heteroaryl, and wherein any aryl and heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halo, deuterium, nitro, cyano, carboxy, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 3 -C 15 )carbocycle, —NR c R d , —C(═O)NR c R d , (C 1 -C 4 )alkoxycarbonyl, (C 1 -C 4 )haloalkyl, aryl, heteroaryl, and R e O—; or R a  and R b  together with the nitrogen to which they are attached form an azetidinyl, morpholino, piperazino, pyrrolidino or piperidino, wherein any a azetidinyl, morpholino, piperazino, pyrrolidino, 1,1-(dioxido)thio-morpholino and piperidino is optionally substituted with one or more groups independently selected from halo, oxo, and (C 1 -C 4 )alkyl; 
         each R c  and R d  is independently selected from the group consisting of H, (C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, and (C 1 -C 4 )alkoxy, wherein any (C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkanoyl, (C 1 -C 4 )alkoxycarbonyl, and (C 1 -C 4 )alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, deuterium, (C 3 -C 15 )carbocycle, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxycarbonyl, (C 1 -C 4 )alkanoyloxy, and oxo (═O); or R c  and R d  together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; 
         R e  is selected from the group consisting of H, (C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aryl, and (C 1 -C 4 )alkanoyl, wherein any (C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, and (C 1 -C 4 )alkanoyl is optionally substituted with one or more groups independently selected from halo and aryl, and wherein any aryl is optionally substituted with one or more groups independently selected from halo deuterium, nitro, cyano, hydroxy, carboxy, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxycarbonyl, and (C 1 -C 4 )alkanoyloxy; and 
         each R x  is (C 1 -C 4 )alkyl that is substituted with one or more groups independently selected from oxo, carboxy, (C 1 -C 4 )alkoxycarbonyl, and amino; or a salt thereof. 
       
     
     
         2 . (canceled) 
     
     
         3 . The compound of  claim 1  which is a compound of formula (Ia): 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         4 . The compound of  claim 1  which is a compound of formula (Ib): 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         5 . The compound of  claim 1  which is a compound of formula (Ic): 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         6 . The compound of  claim 1  which is a compound of formula (Id): 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         7 - 9 . (canceled) 
     
     
         10 . The compound of  claim 1  which is a compound of formula (Ig): 
       
         
           
           
               
               
           
         
       
       wherein:
 R is selected from F, Cl, deuterium, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; or a salt thereof. 
 
     
     
         11 . The compound of  claim 1  which is a compound of formula (Ih): 
       
         
           
           
               
               
           
         
       
       wherein:
 R is selected from F, Cl, deuterium, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; or a salt thereof. 
 
     
     
         12 . The compound of  claim 1  which is a compound of formula (Ii): 
       
         
           
           
               
               
           
         
       
       wherein:
 R is selected from F, Cl, deuterium, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; or a salt thereof. 
 
     
     
         13 - 17 . (canceled) 
     
     
         18 . A pharmaceutical composition comprising a compound as described in  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. 
     
     
         19 . (canceled) 
     
     
         20 . A method for inhibiting the activity of SIRT2 in an animal comprising administering to the animal a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in  claim 1 . 
     
     
         21 - 28 . (canceled) 
     
     
         29 . The compound of  claim 1  wherein D is phenyl that is substituted with —NR a R b . 
     
     
         30 . The compound of  claim 29  wherein R a  and R b  together with the nitrogen to which they are attached form an azetidinyl, morpholino, piperazino, pyrrolidino or piperidino, wherein any a azetidinyl, morpholino, piperazino, pyrrolidino, 1,1-(dioxido)thio-morpholino and piperidino is optionally substituted with one or more groups independently selected from halo, oxo, and (C 1 -C 4 )alkyl. 
     
     
         31 . The compound of  claim 29  wherein R a  and R b  together with the nitrogen to which they are attached form an morpholino, piperazino, pyrrolidino or piperidino, 2-oxomorpholino, 2-oxopyrrolidino, 2-oxopiperidino, 4-methylpiperazino, or 1,1-(dioxido)thio-morpholino. 
     
     
         32 . The compound of  claim 1  wherein D is pyridyl that is optionally substituted with one or more groups R z  independently selected from halo, deuterium, nitro, hydroxy, cyano, carboxy, —NR a R b , —C(═O)NR a R b , —N—S(O) 2 R a , —NR a C(═O)NR a R b , (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkanoyl, (C 1 -C 4 )alkoxycarbonyl, (C 1 -C 4 )alkanoyloxy, (C 3 -C 15 )carbocycle, aryl, aryloxy, and heteroaryl, wherein any (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkanoyl, (C 1 -C 4 )alkoxycarbonyl, (C 3 -C 15 )carbocycle, and (C 1 -C 4 )alkanoyloxy of R z  is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, deuterium, —NR a R b , (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxycarbonyl, (C 1 -C 4 )alkanoyloxy, aryl, aryloxy, and heteroaryl, wherein any aryl, aryloxy, and heteroaryl of R z  is optionally substituted with one or more groups independently selected from the group consisting of halo, deuterium, halo, nitro, cyano, hydroxy, —NR a R b , (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxycarbonyl, (C 1 -C 4 )alkanoyloxy, (C 1 -C 4 )haloalkyl, R x , and (C 1 -C 4 )haloalkoxy. 
     
     
         33 . The compound of  claim 1  wherein D is pyridyl that is optionally substituted with one or more groups R z  independently selected from aryl and heteroaryl, wherein any aryl and heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halo, deuterium, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, and (C 1 -C 4 )haloalkyl. 
     
     
         34 . The compound of  claim 1  wherein D is pyridyl that is substituted with one or more groups R z  independently selected from phenyl, furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or its N-oxide) and quinolyl (or its N-oxide), wherein any R z  is optionally substituted with one or more groups independently selected from the group consisting of halo, deuterium, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, and (C 1 -C 4 )haloalkyl. 
     
     
         35 . The compound of  claim 1  wherein D is pyridyl that is substituted with one or more groups R z  independently selected from phenyl, furyl, pyrazolyl, pyrrolyl, and thienyl, wherein any R z  is optionally substituted with one or more groups independently selected from the group consisting of halo, deuterium, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, and (C 1 -C 4 )haloalkyl. 
     
     
         36 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         37 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a salt thereof.