Sulfonamide compounds and uses thereof

Abstract

Compounds that modulate GHS-R are described, for examples compounds formula (I)

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein,
 R 1  is hydrogen, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cyclyl, cyclylalkyl, heterocyclyl, heterocyclylalkyl, alkyl, alkenyl, alkynyl, or R 1  can be taken together with R 2  or R 3  to form a ring; each of which is optionally substituted with 1-4 R 6 ; 
 k′ is a bond, O, C(O), C(O)O, OC(O), C(O)NR 3 , NR 3 C(O), S, SO, SO 2 , CR 2 ═CR 2 , or C≡C; 
 n is 0-6, preferably 1-3; 
 R 2  is hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; or R 2  can be taken together with R 1  to form a ring; 
 R 3  is hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl, or R 3  can be taken together with R 2 , R 4 , or R 5  to form a ring; each of which can be optionally substituted with 1-2 R 6′ ; 
 A is 
 
       
         
           
           
               
               
           
         
         x and y are each independently 0-6; 
         M is aryl, heteroaryl, cyclyl, or heterocyclyl, each of which is optionally substituted with 1-4 R 9 ; 
         R 4  and R 5  are each independently hydrogen, alkyl, alkenyl, haloalkyl, cyclyl, or heterocyclyl, or R 4  and R 5  can be taken together to form a heterocyclic ring, or R 4  and R 5  can be taken together to form an azido moiety, or one or both of R 4  and R 5  can independently be joined to one or both of R 7a  and R 7b  to form one or more bridges between the nitrogen to which the R 4  and R 5  are attached and R 7a  and R 7b , wherein each bridge contains 1 to 5 carbons; or one or both of R 4  and R 5  can independently be joined to one or both of R 7a  and R 7b  to form to form one or more heterocyclic rings including the nitrogen to which the R 4  and R 5  are attached, or one or both of R 4  and R 5  can independently be joined to R 3  to form a ring, or one or both of R 4  and R 5  can independently be joined to R 8  to form a ring; wherein each R 4  and R 5  are optionally independently substituted with 1-5 halo, 1-3 hydroxy, 1-3 alkyl, 1-3 alkoxy, 1-3 oxo, 1-3 amino, 1-3 alkylamino, 1-3 dialklyamino, 1-3 nitrile, or 1-3 haloalkyl; 
         Y is a monocyclic aryl or monocyclic heteroaryl; each of which is optionally substituted with 1-4 R 10 ; 
         each R 6  and R 6′  are independently halo, alkyl, alkenyl, alkynyl, cyclyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, haloalkyloxy, haloalkylthio, acetyl, cyano, nitro, hydroxy, oxo, C(O)OR 2 , OC(O)R 2 , N(R 3 ) 2 , C(O)N(R 3 ) 2 , NR 3 C(O)R 2 , or SR 2 ; 
         R 7a  and R 7b  are each independently hydrogen, alkyl, alkenyl, haloalkyl, cyclyl, cyclylalkyl, or heterocyclyl; or one or both of R 7a  and R 7b  can independently be joined to one or both of R 4  and R 5  to form one or more bridges between the nitrogen to which the R 4  and R 5  are attached and R 7a  and R 7b , wherein each bridge contains 1 to 5 carbons; or one or both of R 7a  and R 7b  can independently be joined to one or both of R 4  and R 5  to form to form one or more heterocyclic rings including the nitrogen to which the R 4  and R 5  are attached, or one or both of R 7a  and R 7b  can independently be joined with R 8  to form a ring; wherein each R 7a  and R 7b  can be independently optionally substituted with 1-5 halo, 1-3 hydroxy, 1-3 alkyl, 1-3 alkoxy, 1-3 amino, 1-3 alkylamino, 1-3 dialklyamino, 1-3 nitrile, or 1-3 haloalkyl; 
         R 8  is hydrogen or C 1 -C 6  alkyl, or R 8  can be joined with R 4 , R 5 , R 7a  or R 7b  to form a ring; 
         R 9  is halo, alkyl, cyclyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, haloalkyloxy, haloalkylthio, acetyl, cyano, nitro, hydroxy, oxo, C(O)OR 2 , OC(O)R 2 , N(R 2 ) 2 , C(O)N(R 2 ) 2 , NR 2 C(O)R 2 , SR 2 ; 
         each R 10  is independently alkyl, alkenyl, alkynyl, halo, cyano, carbonyl, aryl, arylalkyl, aryl, alkenyl, arylalkynyl, cyclyl, cyclylalkyl, alkoxy, alkoxyalkyl, aryloxy, aryloxyalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —OR 11 , —NR 11 R 11′ , —CF 3 , SOR 12 , —SO 2 R 12 , —OC(O)R 11 , —SO 2 NR 12 R 12′ , —(CH 2 ) m R 14  or R 15 ; each of which is optionally independently substituted with 1-3 R 16 ; 
         R 11  and R 11′  are each independently hydrogen, alkyl, alkenyl, alkynyl, cyclyl, heterocyclyl, aryl or heteroaryl; 
         R 12  and R 12′  are each independently hydrogen, alkyl, alkenyl, alkynyl, alkylthioalkyl, alkoxyalkyl, aryl, arylalkyl, heterocyclyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or cyclyl, cyclylalkyl, or R 12  and R 12′  taken together can be cyclized to form —(CH 2 ) q X(CH 2 ) s —; wherein each R 12  and R 12′  may independently optionally be substituted with 1 to 3 substituents selected from the group consisting of halogen, OR 11 , alkoxy, heterocycloalkyl, —NR 11 C(O)NR 11 R 11′ , —C(O)NR 11 R 11′ , —NR 11 C(O)R 11′ , —CN, oxo, —NR 11 SO 2 R 11′ , —OC(O)R 11 , —SO 2 NR 11 R 11′ , —SOR 13 , —S(O) 2 R 13 , —COOH and —C(O)OR 13 ; 
         each R 13  is independently alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which may optionally be substituted with —(CH 2 ) w OH; 
         each R 14  is independently alkoxy, alkoxycarbonyl, —C(O)NR 12 R 12′ , —NR 11 R 11′ , —C(O)R 12 , —NR 11 C(O)NR 11 R 11′  or —N-heteroaryl; 
         each R 15  is independently —(CH 2 ) p N(R 12 )C(O)R 12′ , —(CH 2 ) p CN, —(CH 2 ) p N(R 12 )C(O)OR 12′ , —(CH 2 ) p N(R 12 )C(O)NR 12 R 12′ , —(CH 2 ) p N(R 12 )SO 2 R 12 , —(CH 2 ) p SO 2 NR 12 R 12′ , —(CH 2 ) p C(O)NR 12 R 12′ , —(CH 2 ) p C(O)OR 12 , —(CH 2 ) p OX(O)OR 12 , —(CH 2 ) p OC(O)R 12 , —(CH 2 ) p OC(O)NR 12 R 12′ , —(CH 2 ) p N(R 12 )SO 2 NR 12 R 12′ , —(CH 2 ) p OR 12 , —(CH 2 ) p OC(O)N(R 12 )(CH 2 ) m OH, —(CH 2 ) p SOR 12 , —(CH 2 ) p SO 2 R 12 , —(CH 2 ) p NR 11 R 11  or —(CH 2 ) p OCH 2 C(O)N(R 12 )(CH 2 ) m OH; 
         each R 16  is independently halo, alkyl, alkenyl, alkynyl, alkoxy, —(CH 2 ) p NR 11 C(O)NR 11 R 11′ , —(CH 2 ) p C(O)NR 11 R 11′ , —(CH 2 ) p NR 11 C(O)R 11′ , —CN, —(CH 2 ) p NR 11 SO 2 R 11′ , —(CH 2 ) p OC(O)R 11 , —(CH 2 ) p SO 2 NR 11 R 11′ , —(CH 2 ) p SOR 13 , —(CH 2 ) p COOH or —(CH 2 ) p C(O)OR 13 ; 
         X is CR 11 R 11′ , O, S, S(O), S(O), or NR 11 ; 
         m is an integer between 1 and 6; 
         p is an integer from 0 to 5. 
         q and s are each independently an integer between 1 and 3; and 
         w is an integer between 0 and 5. 
       
     
     
         2 . The compound of  claim 1 , formula (I), wherein
 n is 1;   k′ is a bond or O; and   R 1  is aryl, heteroaryl, arylalkyl, or heteroarylalkyl.   
     
     
         3 . The compound of  claim 1 , formula (I), wherein
 n is 1;   k′ is O; and   R 1  is phenylmethyl.   
     
     
         4 . The compound of  claim 1 , formula (I), wherein
 n is 2;   k′ is a bond; and   R 1  is aryl.   
     
     
         5 . The compound of  claim 1 , formula (I), wherein
 A is   
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 5 , formula (I), wherein A is 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 6 , formula (I), wherein A is 
       
         
           
           
               
               
           
         
         R 7a  and R 7b  are H; 
         x is 1; and 
         y is 0 or 1. 
       
     
     
         8 . The compound of  claim 1 , formula (I), wherein
 A is CH 2 CH 2  or CH 2 CH 2 CH 2 ; and   each R 4  and R 5  is independently alkyl, or R 4  and R 5 , when taken together, form a heterocyclic ring.   
     
     
         9 . The compound of  claim 1 , formula (I), wherein
 R 7a  and R 7b  are each independently alkyl;   R 4  and R 5  are each independently hydrogen or alkyl; and   x and y are each independently 0 or 1.   
     
     
         10 . The compound of  claim 1 , formula (I), wherein
 Y is a monocyclic heteroaromatic moiety.   
     
     
         11 . The compound of  claim 10 , formula (I), wherein
 Y is a nitrogen containing heteraromatic moiety.   
     
     
         12 . The compound of  claim 9 , formula (I), wherein Y is a nitrogen containing 5 membered heteraromatic moiety. 
     
     
         13 . The compound of  claim 12 , formula (I), wherein Y is an oxadiazole or a triazole. 
     
     
         14 . The compound of  claim 12 , formula (I), wherein Y is substituted with 1 R 10 . 
     
     
         15 . The compound of formula (J), wherein R 10  is positioned 1,3 or 1,2, relative to the point of attachment of Y to the adjacent chain carbon. 
     
     
         16 . The compound of formula (II), 
       
         
           
           
               
               
           
         
         wherein, 
         Q 1 , Q 2 , Q 3  and Q 4  together with the carbon to which they are attached form a heteroaryl moiety, and each Q 1 , Q 2 , Q 3  and Q 4  is independently S, O, N, CR 2 , CR 10 , NR 2 , or NR 10 . 
       
     
     
         17 . The compound of  claim 16 , formula (II), wherein Q 1  and Q 4  are each independently S, O, N, or NR 10 . 
     
     
         18 . The compound of  claim 16 , formula (II) wherein Q 1  is NR 16  or O. 
     
     
         19 . The compound of  claim 16 , formula (II), Q 3  and Q 4  N. 
     
     
         20 . The compound of  claim 16 , formula (II) wherein Q 1 , Q 2 , Q 3  and Q 4  together form 
       
         
           
           
               
               
           
         
       
     
     
         21 . The compound of  claim 20 , formula (II), wherein Q 1  is O or NR 2 . 
     
     
         22 . The compound of  claim 20 , formula (II), wherein R 10  is aryl or heteroaryl, optionally substituted with up to three independent R 16 . 
     
     
         23 . The compound of  claim 22 , formula (II), wherein R 10  is a monocyclic aryl or monocyclic heteroaryl. 
     
     
         24 . The compound of  claim 22 , formula (II), wherein R 10  is a bicyclic heteroaryl. 
     
     
         25 . The compound of  claim 20 , formula (I), wherein R 10  is substituted with 1-3 R 16 . 
     
     
         26 . The compound of  claim 25 , formula (I), wherein R 16  is halo, alkyl, or alkoxy. 
     
     
         27 . The compound of  claim 26 , formula (I), wherein R 16  is chloro, fluoro, methyl, or methoxy. 
     
     
         28 . The compound of formula (I), wherein R 10  is arylalkyl or heteroarylalkyl. 
     
     
         29 . A method of treating metabolic syndrome comprising administering to a subject a compound of  claim 1 , formula (I). 
     
     
         30 . A method of treating diabetes comprising administering to a subject a compound of  claim 1 , formula (I). 
     
     
         31 . A method of treating obesity comprising administering to a subject a compound of  claim 1 , formula (I).