Compounds and methods of use thereof

Abstract

Indole compounds are disclosed. Also disclosed are methods for using the compounds to treat human and animal disease, pharmaceutical compositions of the compounds, and kits including the compounds.

1 . A compound selected from the following formula: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1a  and R 2a  are each independently selected from H, optionally substituted C 1-8  alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroaralalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl; 
 R 3  is selected from H, optionally substituted C 1-8  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, halogen, or —C(O)NR d R d′ ; 
 W is 
 
       
         
           
           
               
               
           
         
       
       optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylC 2 -C 6 alkyl, optionally substituted heterocyclyl, optionally substituted cycloalkyl; optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted arylheteroalkyl, optionally substituted heteroarylheteroalkyl, optionally substituted heterocyclylheteroalkyl, optionally substituted cycloalkylheteroalkyl, -alkyl-O—C 0-2 alkyl-aryl, -alkyl-O—C 0-2 alkyl-heteroaryl, —C(O)NR d R d′ , C 1  alkyl substituted with —C(O)NR d R d′ , or C 2-8  alkyl substituted with —NR d R d′ , —C(O)NR d R d′  or —OR d ;
 A is optionally substituted C 1-4  alkylene, optionally substituted cycloalkylene, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylene, optionally substituted heteroarylene, or optionally substituted heterocycloalkylene, wherein arylene or heteroarylene are optionally substituted with 1-3 substituents, each of which is independently selected from the group consisting of halogen, C 3-8  cycloalkyl, —OR d , C 1-8  haloalkoxy, —S(O) 0-2  C 1-8  alkyl, —S(O) 0-2  aryl, —S(O) 0-2  heteroaryl, —S(O) 0-2  arylalkyl, —S(O) 0-2  heteroarylalkyl), —S(O) 0-2  cycloalkyl, —S(O) 0-2  heterocycloalkyl, —S(O) 0-2  heterocycloalkylalkyl, —S(O) 0-2  cycloalkylalkyl, —OC(O)NR d R d′ , —NR d C(O)NR d′ R d″ , —NR d C(O)OR b , —NR d S(O) 2 alkyl, —NR d S(O) 2 aryl, —NR d S(O) 2 heteroaryl, —NR d S(O) 2 cycloalkyl, —NR d S(O) 2 heterocycloalkyl, —NR d S(O) 2 -arylalkyl, —NR d S(O) 2 -heteroarylalkyl, —NR d S(O) 2 -cycloalkylalkyl, —NR d S(O) 2 -heterocycloalkyl, —SO 2 NR d R d′ , cyano, nitro, C 1-6  haloalkyl, C 1-6  haloalkoxy, —NR d R d′ , optionally substituted C 1-6  alkyl, —NR d C(O)R a , —C(O)NR d R d′ , and —C(O)OR d , wherein alkylene and cycloalkylene are optionally substituted with 1-3 substituents, each of which is independently selected from the group consisting of halogen, oxo, optionally substituted C 1-6  alkyl, —S(O) 0-2 alkyl, —OR d  and —NR d R d′ , aryl or heteroaryl, and C 3 -C 8  cycloalkyl or 4-8 membered heterocyle; 
 R 4  is selected from optionally substituted C 1-8  alkyl, optionally substituted C 1-8  heteroalkyl, optionally substituted C 2-8  alkenyl, C 2-8  alkynyl, —S(O) 2  alkyl, —S(O) 2  heteroalkyl, —S(O) 2  aryl, —S(O) 2  heteroaryl, —S(O) 2  cycloalkyl, —S(O) 2  heterocyclyl, —S(O) 2  heterocycloalkyl, —S(O) 2  arylalkyl, —S(O) 2  heteroarylalkyl, —S(O) 2  cycloalkyalkyl, formyl, —OR d , —NR d R d′ , —C(O)OR a , —C(O)NR d R d′ , —S(O) 2 NR d R d′ , amine-substituted C 2-6  alkyl, NR d′ R d″ -substituted C 2-6  alkyl, C 3-8  cycloalkyl, heterocyclyl, cycloalkylalkyl, heteocyclylalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein the alkyl, cycloalkyl and heterocyclyl are optionally substituted with 1-3 substituents, halo, alkyl, haloalkyl, heteroalkyl, —OR d , —NR d R d′ , and wherein aryl and herteroaryl are optionally substituted with 1-3 substituents, each of which is independently selected from the group consisting of halogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, —OR d , —SH, C 1-8  haloalkoxy, —S(O) 0-2  C 1-8  alkyl, —S(O) 0-2  aryl, —S(O) 0-2  heteroaryl, —S(O) 0-2 -arylalkyl, —S(O) 0-2 -heteroarylalkyl, —OC(O)NR d R d′ , —NR d C(O)NR d′ R d″ , —NR d C(O)OR b , —OR d , —NR d S(O) 2 alkyl, —NR d S(O) 2 aryl, —NR d S(O) 2 heteroaryl, —NR d S(O) 2 cycloalkyl, —NR d S(O) 2 heterocycloalkyl, —NR d S(O) 2 -arylalkyl, —NR d S(O) 2 -heteroarylalkyl, —NR d S(O) 2 -cycloalkylalkyl, —NR d S(O) 2 -heterocycloalkyl, —SO 2 NR d R d′ , optionally substituted —C 1 alkyl-C(O)NR e R f , —C 2 alkyl-O-aryl, —C 2 alkyl-O-heteroaryl, —C 1 alkyl-heterocyclyl, —C 1 alkyl-cycloalkyl, cyano, nitro, C 1-6  haloalkyl, C 1-6  haloalkoxy, —NR d R d′ , optionally substituted C 1-6  alkyl-NR d C(O)R a , —C(O)NR d R d′ , and —C(O)OR d ; 
 R 5  is selected from H, halo, and R 6 ; 
 each R 6  is independently selected from halo, C 1-8  alkyl, aryl, heteroaryl, heteroalkyl, C 3-8  cycloalkyl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, —SH, —OR d , C 1-8  haloalkoxy, C 1-8  haloalkyl, —S(O) 0-2  C 1-8  alkyl, —S(O) 0-2  aryl, —S(O) 0-2  heteroaryl, —S(O) 0-2  arylalkyl, —S(O) 0-2  heteroarylalkyl, —S(O) 0-2  cycloalkyl, —S(O) 0-2  heterocycloalkyl, —S(O) 0-2  heterocycloalkylalkyl, —S(O) 0-2  cycloalkylalkyl, —OC(O)NR d R d′ , —NR d C(O)NR d′ R d″ , —NR d C(O)OR a , —NR d S(O) 2 alkyl, —NR d S(O) 2 aryl, —NR d S(O) 2 heteroaryl, —NR d S(O) 2 cycloalkyl, —NR d S(O) 2 heterocycloalkyl, —NR d S(O) 2 —C 1-4 alkyl-aryl, —NR d S(O) 2 -heteroarylalkyl, —NR d S(O) 2 -cycloalkylalkyl, —NR a S(O) 2 -heterocycloalkyl, —SO 2 NR d R d′ , cyano, nitro, C 1-6  haloalkyl, C 1-6  haloalkoxy, —NR d R d′ , —C 1-4 alkyl-NR d R d′ , optionally substituted C 1-6  alkyl, —NR d C(O)R a , —C(O)NR d R d′ , and —C(O)OR d ; wherein alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted; 
 each of R 7  and R 8  is independently H, optionally substituted C 1-8  alkyl or fluoro; or R 7  and R 8  can, together with the carbon to which they are attached, form a ring; 
 R a , and R b  are each independently selected from optionally substituted C 1-8  alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3-8  cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl and optionally substituted heterocycloalkyl; 
 R d , R d′ , and R d″  are each independently selected from H and R a , or when taken together with the atom to which they are attached two of R d , R d′  and R d″  form a 4-8 membered heterocyclic moiety; 
 g is 1, 2 or 3; 
 m is 0, 1, 2, 3, 4 or 5; and 
 
       wherein when m is 0, at least one of R 7  or R 8  is not H. 
     
     
         2 . The compound of  claim 1 , wherein R 1a  and R 2a  are each independently selected from H, C 1-8  alkyl, or optionally substituted aryl. 
     
     
         3 . The compound of  claim 1 , wherein R 3  is selected from H, and optionally substituted C 1-8  alkyl. 
     
     
         4 . The compound of  claim 1 , wherein R 4  is selected from optionally substituted C 1-8  alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, amine-substituted C 2-6  alkyl, NR d′ R d″ -substituted C 2-6  alkyl, —S(O) 2  alkyl, —S(O) 2  arylalkyl, —S(O) 2  heteroarylalkyl, —S(O) 2  aryl, —S(O) 2  heteroaryl, —S(O) 2  cycloalkyl, —S(O) 2  heterocycloalkyl, —S(O) 2  heterocycloalkylalkyl, —S(O) 2  cycloalkylalkyl, optionally substituted —C 1 alkyl-C(O)NR e R f , —C 2 alkyl-O-aryl, —C 2 alkyl-O-heteroaryl, —C 1 alkyl-heterocyclyl, and —C 1 alkyl-cycloalkyl. 
     
     
         5 . The compound of  claim 1 , wherein W is arylC 2-8 alkyl optionally substituted with —OR d , —NR d R d′ , or —C(O)NR d R d′ . 
     
     
         6 . The compound of  claim 1 , wherein W is optionally substituted heteroaryl, optionally substituted heteroarylalkyl, or optionally substituted aryl. 
     
     
         7 . The compound of  claim 1 , wherein W is —(CH 2 ) 2 —O-phenyl. 
     
     
         8 . The compound of  claim 1 , wherein the compound is selected from 
       
         
           
           
               
               
           
         
       
       wherein Ar is optionally substituted aryl or optionally substituted heteroaryl. 
     
     
         9 . A compound selected from the following formula: 
       
         
           
           
               
               
           
         
       
       wherein 
       g is 1, 2 or 3; 
       R 1a  is selected from H, optionally substituted C 1-8  alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl; 
       Q is selected from aryl, heteroaryl, arylalkyl, heterocycloalkyl, heteroarylalkyl, alkyl-C(O)NR e R f , alkyl-C(O)-heterocyclyl, heterocycloalkyl-alkyl, cycloalkyl, cycloalkylaryl, cycloalkylalkyl, arylheteroalkyl, and heteroarylheteroalkyl, wherein Q is optionally substituted with 1-3 substituents, each of which is independently selected from the group consisting of optionally substituted —C 1-6 heteroalkyl, halogen, C 3-8  cycloalkyl, —OR d , C 1-8  haloalkoxy, —S(O) 0-2  C 1-8  alkyl, —S(O) 0-2  aryl, —S(O) 0-2  heteroaryl, —S(O) 0-2  arylalkyl, —S(O) 0-2  heteroarylalkyl), —S(O) 0-2  cycloalkyl, —S(O) 0-2  heterocycloalkyl, —S(O) 0-2  heterocycloalkylalkyl, —S(O) 0-2  cycloalkylalkyl, —OC(O)NR d R d′ , —NR d C(O)NR d′ R d″ , —NR d C(O)OR b , —NR d S(O) 2 alkyl, —NR d S(O) 2 aryl, —NR d S(O) 2 heteroaryl, —NR d S(O) 2 cycloalkyl, —NR d S(O) 2 heterocycloalkyl, —NR d S(O) 2 -arylalkyl, —NR d S(O) 2 -heteroarylalkyl, —NR d S(O) 2 -cycloalkylalkyl, —SO 2 NR d R d′ , cyano, nitro, C 1-6  haloalkyl, —NR d R d′ , aryl, heteroaryl, heterocyclyl, -alkyl-OR d , optionally substituted —C 1-6  alkyl, —NR d C(O)R a , —C(O)NR d R d′ , and —C(O), wherein R e  and R f  are selected from the same groups as R 1  and R 2 , respectively; 
       R 3  is selected from H, optionally substituted C 1-8  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, halogen, or C(O)NR d R d′ ; 
       W 2  is hydrogen, optionally substituted C 1-8  alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, or —C(O)NR d R d′ ; 
       A is optionally substituted C 1-4  alkylene, optionally substituted cycloalkylene, optionally substituted arylene, optionally substituted heteroarylene, wherein arylene or heteroarylene are optionally substituted with 1-3 substituents, each of which is independently selected from the group consisting of halogen, optionally substituted aryl, optionally substituted heteroaryl, C 3-8  cycloalkyl, —OR d , C 1-8  haloalkoxy, —S(O) 0-2  C 1-8  alkyl, —S(O) 0-2  aryl, —S(O) 0-2  heteroaryl, —S(O) 0-2  arylalkyl, —S(O) 0-2  heteroarylalkyl), —OC(O)NR d R d′ , —NR d C(O)NR d′ R d″ , —NR d C(O)OR a , —NR d S(O) 2 alkyl, —NR d S(O) 2 aryl, —NR d S(O) 2 heteroaryl, —NR d S(O) 2 cycloalkyl, —NR d S(O) 2 heterocycloalkyl, —NR d S(O) 2 -arylalkyl, —NR d S(O) 2 —C 1-4 alkyl-heteroaryl, —NR d S(O) 2 —C 1-4 alkyl-cycloalkyl, —NR d S(O) 2 —C 1-4 alkyl-heterocycloalkyl, —SO 2 NR d R d′ , cyano, nitro, C 1-6  haloalkyl, C 1-6  haloalkoxy, —NR d R d′ , optionally substituted C 1-6  alkyl, —NR d C(O)R a , —C(O)NR d R d′ , and —C(O)OR d , wherein alkylene and cycloalkylene are optionally substituted with 1-3 substituents, each of which is independently selected from the group consisting of halogen, oxo, optionally substituted C 1-6  alkyl, —S(O) 0-2 alkyl, —OR d  and —NR d R d′ , aryl or heteroaryl, and C 3 -C 8  cycloalkyl or 4-8 membered heterocyle; 
       R 4  is selected from optionally substituted C 1-8  alkyl, optionally substituted C 1-8  heteroalkyl, C 2-8  alkenyl, C 2-8  alkynyl, —S(O) 2  alkyl, —S(O) 2  heteroalkyl, —S(O) 2  aryl, —S(O) 2  heteroaryl, —S(O) 2  cycloalkyl, —S(O) 2  heterocyclyl, —S(O) 2  heterocycloalkyl, —S(O) 2  arylalkyl, —S(O) 2  heteroarylalkyl, —S(O) 2  cycloalkyalkyl, formyl, —OR d , —NR d R d′ , —C(O)OR a , —C(O)NR d R d′ , —S(O) 2 NR d R d′ , C 3-8  cycloalkyl, heterocyclyl, cycloalkylalkyl, heteocyclylalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein the alkyl, cycloalkyl and heterocyclyl are optionally substituted with 1-3 substituents, halo, alkyl, haloalkyl, heteroalkyl, —OR d , —NR d R d′ , and wherein aryl and herteroaryl are optionally substituted with 1-3 substituents, each of which is independently selected from the group consisting of halogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, —OR d , —SH, C 1-8  haloalkoxy, —S(O) 0-2  C 1-8  alkyl, —S(O) 0-2  aryl, —S(O) 0-2  heteroaryl, —S(O) 0-2 -arylalkyl, —S(O) 0-2 -heteroarylalkyl, —OC(O)NR d R d′ , —NR d C(O)NR d′ R d″ , —NR d C(O)OR b , —OR d , —NR d S(O) 2 alkyl, —NR d S(O) 2 aryl, —NR d S(O) 2 heteroaryl, —NR d S(O) 2 cycloalkyl, —NR d S(O) 2 heterocycloalkyl, —NR d S(O) 2 -arylalkyl, —NR d S(O) 2 -heteroarylalkyl, —NR d S(O) 2 -cycloalkylalkyl, —NR d S(O) 2 — heterocycloalkyl, —SO 2 NR d R d′ , optionally substituted —C 1 alkyl-C(O)NR e R f , —C 1 alkyl-O-aryl, —C 1 alkyl-O-heteroaryl, —C 1 alkyl-heterocyclyl, —C 1 alkyl-cycloalkyl, cyano, nitro, C 1-6  haloalkyl, C 1-6  haloalkoxy, —NR d R d′ , optionally substituted C 1-6  alkyl, —NR d C(O)R a , —C(O)NR d R d′ , and —C(O)OR d ; 
       each R 6  is independently selected from halo, C 1-8  alkyl, aryl, heteroaryl, heteroalkyl, C 3-8  cycloalkyl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, —SH, —OR d , C 1-8  haloalkoxy, C 1-8  haloalkyl, —S(O) 0-2  C 1-8  alkyl, —S(O) 0-2  aryl, —S(O) 0-2  heteroaryl, —S(O) 0-2  arylalkyl, —S(O) 0-2  heteroarylalkyl, —S(O) 0-2  cycloalkyl, —S(O) 0-2  heterocycloalkyl, —S(O) 0-2  heterocycloalkylalkyl, —S(O) 0-2  cycloalkylalkyl, —OC(O)NR d R d′ , —NR d C(O)NR d′ R d″ , —NR d C(O)OR a , —NR d S(O) 2 alkyl, —NR d S(O) 2 aryl, —NR d S(O) 2 heteroaryl, —NR d S(O) 2 cycloalkyl, —NR d S(O) 2 heterocycloalkyl, —NR d S(O) 2 -arylalkyl, —NR d S(O) 2 -heteroarylalkyl, —NR d S(O) 2 -cycloalkylalkyl, —NR a S(O) 2 -heterocycloalkyl, —SO 2 NR d R d′ , cyano, nitro, C 1-6  haloalkyl, C 1-6  haloalkoxy, —NR d R d′ , —C 1-4 alkyl-NR d R d′ , optionally substituted C 1-6  alkyl, —NR d C(O)R a , —C(O)NR d R d′ , and —C(O)OR d ; wherein alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted; 
       R a , and R b  are each independently selected from optionally substituted C 1-8  alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3-8  cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl and optionally substituted heterocycloalkyl; 
       R d , R d′ , and R d″  are each independently selected from H and R a , or when taken together with the atom to which they are attached two of R d , R d′  and R d″  form a 4-8 membered heterocyclic moiety. 
     
     
         10 . The compound of  claim 9 , wherein R 1a  is selected from H, optionally substituted C 1-8  alkyl, and optionally substituted aryl. 
     
     
         11 . The compound of  claim 9 , wherein A is optionally substituted C 1-4  alkylene, wherein the C 1-4  alkylene is optionally substituted with 1-3 substituents, each of which is independently selected from the group consisting of halogen, hydroxyl, optionally substituted C 1-6  alkyl, C 1-8  alkoxy, —SO 2  alkyl, and —NR d R d′ . 
     
     
         12 . A method for the treatment of obesity in a subject, the method comprising administering to the subject a compound of formulae I or VII, such that obesity is treated in the subject. 
     
     
         13 - 16 . (canceled)