Therapeutic compounds and related methods of use

Abstract

Methods of treating disorders using compounds that modulate striatal-enriched tyrosine phosphatase (STEP) are described herein. Exemplary disorders include schizophrenia and cognitive deficit.

1 . A compound represented by general formula (II): 
       
         
           
           
               
               
           
         
       
       or a salt thereof,
 wherein: 
 L is CR 4 R 5 , O, C(O), NR 6 C(O) or NR 7 ; 
 A is N; 
 each X 1 , X 2 , X 3 , X 4  and X 5  is independently CH or N, provided that at least two of X 1 , X 2 , X 3 , X 4  and X 5  are N; 
 n is 0, 1, 2, 3 or 4; 
 p is 0, 1, 2 or 3; 
 R 1  is C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl or heterocyclylalkyl, each of which is optionally substituted with 1-5 R 9 ; wherein R 1  or R 9  is optionally taken together with one of R 4 , R 5 , R 6  or R 7 , and the atoms to which they are attached to form a cyclyl, heterocyclyl, aryl or heteroaryl ring that is optionally substituted with 1-3 R 10 ; 
 each R 2  and R 3  is independently hydrogen, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO 2 , —C(O)OR a , —C(Y)NR b R b′ , —NR c C(Y)R c′ , —NR b R b′ , —OC(O)NR b R b′ , —NR c C(O)OR c′ , —SO 2 NR b R b′ , —NR c SO 2 R c′ , —NR c C(Y)NR b R b′ , —OR d , —SR d′ , —C(Y)R e  or —S(O) q R f , each of which is optionally substituted with 1-3 R 11 ; 
 each R 4 , R 5 , R 6  and R 7  is independently hydrogen, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO 2 , —C(O)OR a , —C(Y)NR b R b′ , —NR c C(Y)R c′ , —NR b R b′ , —OC(O)NR b R b′ , —NR c C(O)OR c′ , —SO 2 NR b R b′ , —NR c SO 2 R c′ , —NR c C(Y)NR b R b′ , —OR d , —SR d′ , —C(Y)R e  or —S(O) q R f ; 
 each R 9 , R 10  and R 11  is independently C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO 2 , —C(O)OR a , —C(Y)NR b R b′ , —NR c C(Y)R c′ , —NR b R b′ , —OC(O)NR b R b′ , —NR c C(O)OR c′ , —SO 2 NR b R b′ , —NR c SO 2 R c′ , —NR c C(Y)NR b R b′ , —OR d , —SR d′ , —C(Y)R e  or —S(O) q R f , each of which is optionally substituted with 1-3 R 12 ; wherein two R 9 , two R 10  or two R 11  is optionally taken together with the atoms to which they are attached to form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring; 
 R 12  is —OR d ; 
 Y is O or S; 
 q is 1 or 2; and 
 each R a , R b , R b′ , R c , R c′ , R d , R d′ , R e , R e′  and R f  is independently hydrogen, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, acyl, cyclyl, heterocyclyl, aryl, heteroaryl, cyclylalkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl. 
 
     
     
         2 . The compound according to  claim 1  represented by general formula (II) or a salt thereof,
 L is NR 7 ; 
 n is 0, 1 or 2; 
 p is 0; 
 R 1  is C 1 -C 8  alkyl, aryl or heteroaryl; 
 each R 2  and R 3  is independently hydrogen, C 1 -C 8  alkyl, aryl, halo, heterocyclylalkyl, —NR c C(Y)R c , —NR b R b′  or —OR d , each of which is optionally substituted with 1-3 R 11 ; 
 R 7  is hydrogen; and 
 each R 9 , R 10  and R 11  is independently C 1 -C 8  alkyl, heterocyclyl, halo, haloalkyl, haloalkoxy, —CN, —C(O)OR a , —C(Y)NR b R b′ , —OR d  or —C(Y)R e ; 
 Y is O; 
 each R a , R b , R b′ , R c , R c′ , R d , R d′ , R e , R e′  and R f  is independently hydrogen, C 1 -C 8  alkyl, cyclyl, heterocyclyl, aryl or heteroaryl. 
 
     
     
         3 . The compound according to  claim 2  represented by general formula (II) or a salt thereof,
 wherein: 
 R 1  is C 1 -C 8  alkyl, phenyl or benzodioxolyl; 
 each R 2  and R 3  is independently hydrogen, C 1 -C 8  alkyl, phenyl, halo, morholinylalkyl, —NR c C(Y)R c , —NR b R b′  or —OR d ; 
 R 9  is independently C 1 -C 8  alkyl, morpholinyl, tetrahydropyranyl, halo, haloalkyl, haloalkoxy, —CN, —C(O)OR a , —C(Y)NR b R b′ , —OR d  or —C(Y)R e ; and 
 each R a , R b , R b′ , R c , R c′ , R d , R d′ , R e , R e′  and R f  is independently hydrogen, C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, tetrahydropyranyl, phenyl or pyridyl. 
 
     
     
         4 . The compound according to  claim 2  represented by general formula (II) or a salt thereof,
 wherein: 
 R 1  is C 1 -C 8  alkyl, phenyl or benzodioxolyl; 
 each R 2  and R 3  is independently hydrogen, C 1 -C 8  alkyl, phenyl, halo, morholinylalkyl, —NR c C(Y)R c , —NR b R b′  or —OR d , each of which is optionally substituted with 1-3 R 11 ; 
 each R 9 , R 10  and R 11  is independently C 1 -C 8  alkyl, morpholinyl, tetrahydropyranyl, halo, haloalkyl, haloalkoxy, —CN, —C(O)OR a , —C(Y)NR b R b′ , —OR d  or —C(Y)R e ; and 
 each R a , R b , R b′ , R c , R c′ , R d , R d′ , R e , R e′  and R f  is independently hydrogen, C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, tetrahydropyranyl, phenyl or pyridyl. 
 
     
     
         5 . The compound according to  claim 4  represented by general formula (II) or a salt thereof, wherein:
 R 2  is C 1 -C 8  alkyl, phenyl, halo, morholinylalkyl, —NR c C(Y)R c′ , —NR b R b′  or —OR d , each of which is optionally substituted with 1-3 R 11 ; 
 R 3  is hydrogen; 
 R 9  is halo, haloalkoxy, —CN, —C(O)OR a  or —C(Y)NR b R b′ ; and 
 R 11  is C 1 -C 8  alkyl, morpholinyl, tetrahydropyranyl, halo, —CN, —OR d  or —C(Y)R e ; 
 
     
     
         6 . The compound according to  claim 3  or  5  represented by general formula (II) or a salt thereof, wherein:
 R 2  is C 1 -C 8  alkyl, phenyl, halo, morholinylalkyl, —NR c C(Y)R c′ , —NR b R b′  or —OR d ; 
 R 3  is hydrogen; and 
 R 9  is halo, haloalkoxy, —CN, —C(O)OR a  or —C(Y)NR b R b′ .