Inhibitors of the mitf molecular pathway

Abstract

Provided herein are compounds of the formula (IV): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful as MITF inhibitors, MITF pathway inhibitors and for the treatment of cancer.

What is claimed is: 
     
         1 . A compound of Formula (IV): 
       
         
           
           
               
               
           
         
         wherein: 
         (i) X is CH;
 R 1  is hydrogen, halogen, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted lower alkyl, amino, optionally substituted alkylamino, optionally substituted dialkylamino, —NHCH 2 CH═CH 2 , or CH 2 CH═CH 2 ; 
 R 2  is optionally substituted lower alkyl, optionally substituted aryl or heteroaryl, optionally substituted benzyl, —C(O)—R 4 , —S(O) 2 —R 4 , or —CH(R 5 )—R 4 , or —CH 2 CH═CH 2 ; 
 R 3  is hydrogen, optionally substituted lower alkyl, or acyl; 
 R 4  is optionally substituted aryl or heteroaryl; 
 R 5  is hydrogen or lower alkyl; and 
 pharmaceutically acceptable salts thereof, provided that compound is not 4-((1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)benzensulfonamide; or 
 
         (ii) X is N;
 R 1  is hydrogen, halogen, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted lower alkyl, amino, optionally substituted alkylamino, optionally substituted dialkylamino, or —NHCH 2 CH═CH 2 ; 
 R 2  is hydrogen, optionally substituted lower alkyl, optionally substituted aryl or heteroaryl, optionally substituted benzyl, —C(O)—R 4 , —S(O) 2 —R 4 , or —CH(R 5 )—R 4 , or —CH 2 CH═CH 2 ; 
 R 3  is hydrogen, optionally substituted lower alkyl, or acyl; 
 R 4  is optionally substituted aryl or heteroaryl; 
 R 5  is hydrogen or lower alkyl; and 
 pharmaceutically acceptable salts thereof. 
 
       
     
     
         2 . The compound of  claim 1 , wherein:
 X is CH;   R 1  is hydrogen, halogen, a 5- or 6-membered heterocycloalkyl or heteroaryl (each optionally substituted with lower alkyl or phenyl), alkoxy, phenyl, lower alkyl (optionally substituted with phenyl), —N(CH 2 CH 3 ) 2 ), —NHCH 2 CH═CH 2 , NH 2 , or —CH 2 CH═CH 2 ;   R 2  is lower alkyl, phenyl (optionally mono- or di-substituted independently with halogen, lower alkyl, —S(O) 2 NH 2  or alkoxy), —CH 2 -phenyl (said phenyl optionally substituted with halogen), C(O)-phenyl (said phenyl optionally substituted with halogen), S(O) 2 -phenyl (said phenyl optionally substituted with halogen), S(O) 2 -thiophenyl (said thiophenyl optionally substituted with halogen), thiophenyl, or —CH 2 CH═CH 2 ; and   R 3  is hydrogen, lower alkyl, or acetyl.   
     
     
         3 . The compound of  claim 1 , wherein R 1  is hydrogen, chlorine, methyl, methoxy, phenyl, piperazinyl, methylpiperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, phenyl-piperazinyl, ethyl-piperazinyl, —NHCH 2 CH═CH 2 , —CH 2 CH═CH 2 , —NH 2 , tert-butyl-piperazinyl, pyrrolidinyl, —NHCH 2 CH 2 CH 2 N(CH 2 CH 3 ) 2 , —CH 2 CH 2 CH 2 N(CH 2 CH 3 ) 2 , or —CH(CH 3 )phenyl. 
     
     
         4 . The compound of  claim 1 , wherein R 2  is methyl, —CH 2 CH═CH 2 , phenyl, —CH 2 -chlorophenyl, chlorophenyl, acetyl, —C(O)-phenyl, —C(O)-bromophenyl, —S(O) 2 -phenyl, —S(O) 2 -bromophenyl, —S(O) 2 -thiazolyl, —S(O) 2 -bromothiazolyl, difluorophenyl, methoxyphenyl or -phenyl-S(O) 2 NH 2 . 
     
     
         5 . The compound of  claim 1 , wherein R 3  is hydrogen, methyl or acetyl. 
     
     
         6 . The compound of  claim 1 , wherein:
 X is CH;   R 1  is a 5- or 6-membered heterocycloalkyl (optionally substituted with lower alkyl), or a lower alkyl (optionally substituted with —N(CH 2 CH 3 ) 2 );   R2 is methyl; and   R 3  is acetyl.   
     
     
         7 . The compound of  claim 1 , wherein:
 X is CH;   R 1  is a 5- or 6-membered heterocycloalkyl (optionally substituted with lower alkyl or phenyl), or NH 2 ;   R 2  is —C(O)R 4 ;   R 3  is H; and   R 4  is a phenyl, optionally substituted with a halogen.   
     
     
         8 . The compound of  claim 1 , wherein:
 X is CH;   R 1  is a hydrogen, alkoxy, NH 2 , or a 5- or 6-membered heterocycloalkyl (optionally substituted with lower alkyl);   R 2  is —S(O) 2 —R 4 ;   R 3  is H; and   R 4  is a phenyl or thiophenyl, each of which can be optionally substituted with halogen.   
     
     
         9 . The compound of  claim 1 , wherein:
 X is CH;   R 1  is a 5- or 6-membered heterocycloalkyl (optionally substituted with lower alkyl or phenyl);   R 2  is a phenyl, optionally substituted with one or two independently selected substituents from the group consisting of halogen and alkoxy; and   R 3  is H.   
     
     
         10 . The compound of  claim 1 , wherein:
 X is N   R 1  is hydrogen, halogen, a 5- or 6-membered heterocycloalkyl or heteroaryl (optionally substituted with lower alkyl or phenyl), alkoxy, lower alkyl (optionally substituted with phenyl or —N(CH 2 CH 3 ) 2 ), or NH 2 ;   R 2  is lower alkyl, phenyl (optionally mono- or di-substituted independently with halogen, lower alkyl, —S(O) 2 NH 2  or alkoxy), CH 2 -phenyl (said phenyl optionally substituted with halogen, C(O)-phenyl (said phenyl optionally substituted with halogen), S(O) 2 -phenyl (said phenyl optionally substituted with halogen), S(O) 2 -thiophenyl (said thiophenyl optionally substituted with halogen), or thiophenyl; and   pharmaceutically acceptable salts thereof.   
     
     
         11 . The compound of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         12 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         13 . A method for treating cancer, comprising administering a therapeutically effective amount of a compound of  claim 1  to a subject in need thereof, wherein the cancer is a MITF-dependent cancer. 
     
     
         14 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         15 . A pharmaceutical composition, comprising a compound of formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
       
     
     
         16 . A method for treating cancer, comprising administering a therapeutically effective amount of a compound of formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof to a subject in need thereof.