Azophenols as ERG Oncogene Inhibitors

Abstract

Selective azophenol inhibitors of a wild type or an altered ERG protein expression are described, where the inhibitors represent a compound of Formula (I) or Formula (II) wherein X, X 1 , X 2 , X 3 , X 4 and X 5 , R 1 through R 4 and R 9 are as described.

1 - 15 . (canceled) 
     
     
         16 . A compound of Formula (V) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 1  is selected from the group consisting of H and C 1 -C 10  alkyl; and 
         R 2  is C 2 -C 10  alkyl, 
         with the proviso that when R 1  is H, R 2  is not ethyl, isobutyl or —C(CH 3 ) 2 —CH 2 —C(CH 3 ) 3 . 
       
     
     
         17 . A method for treating a disease associated with overexpression of wild type ERG protein, an altered ERG protein, ERG gene transcription or ERG mRNA translation in a subject suffering therefrom, comprising administering to the subject a therapeutically effective amount of a compound of Formula (V) according to  claim 16  or a pharmaceutically acceptable salt thereof. 
     
     
         18 . (canceled) 
     
     
         19 . A pharmaceutical composition comprising the compound of Formula (I)
 or Formula (II)   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
       
       X is NH, O or S; 
       X 1 , X 2 , X 3 , X 4  and X 5  are independently N or CR 9 , where only one of X 1 , X 2 , X 3 , X 4  and X 5  is N; 
       R 1 , R 2  and R 4  are independently selected from the group consisting of H, aryl, halogen, C 1 -C 10  alkyl, C 1 -C 10  alkoxy, C 3 -C 7  cycloalkyl and C 3 -C 7  heterocycloalkyl, wherein the aryl, C 1 -C 10  alkyl, C 1 -C 10  alkoxy, C 3 -C 7  cycloalkyl and C 3 -C 7  heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of C 1 -C 8  alkyl, C 3 -C 7  cycloalkyl, C 3 -C 7  heterocycloalkyl, aryl, heteroaryl, halogen, hydroxyl, —CN, —COOH, —CF 3 , —OCH 2 F, —OCHF 2 , —OC 1 -C 8  alkyl, —O-aryl, —O— heteroaryl, —NR 5 R 6 , —NR 5 C(O)R 6  and —C(O)NR 5 R 6 ; 
       R 3  is selected from the group consisting of H, —OH, —NR 5 R 6 , C 1 -C 10  alkyl, C 1 -C 10  alkoxy, C 3 -C 7  cycloalkyl and C 3 -C 7  heterocycloalkyl, wherein the C 1 -C 10  alkyl, C 1 -C 10  alkoxy, C 3 -C 7  cycloalkyl and C 3 -C 7  heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of C 1 -C 8  alkyl, C 3 -C 7  cycloalkyl, C 3 -C 7  heterocycloalkyl, aryl, heteroaryl, halogen, hydroxyl, —CN, —COOH, —CF 3 , —OCH 2 F, —OCHF 2 , —OC 1 -C 8  alkyl, —O-aryl, —O-heteroaryl, —NR 5 R 6 , —NR 5 C(O)R 6  and —C(O)NR 5 R 6 ; 
       R 5  and R 6  are independently selected from the group consisting of H, C 1 -C 8  alkyl, aryl and C 3 -C 7  cycloalkyl, or R 5  and R 6  taken together form a C 3 -C 7  heterocycloalkyl wherein the C 1 -C 8  alkyl and C 3 -C 7  heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting C 1 -C 8  alkyl, C 3 -C 7  cycloalkyl, C 3 -C 7  heterocycloalkyl, aryl, heteroaryl, halogen, hydroxyl, —CN, —COOH, —CF 3 , —OCH 2 F, —OCHF 2 , —OC 1 -C 8  alkyl, —O-aryl, —O-heteroaryl, —NR 7 R 8 , —NR 7 C(O)R 8  and —C(O)NR 7 R 8 ; 
       R 7  and R 8  are independently selected from the group consisting of H and C 1 -C 8  alkyl; 
       each R 9  is independently H, halogen, —CN, —OH, COOH, —NR 10 R 11 , C 1 -C 10  alkyl, C 3 -C 7  cycloalkyl, C 1 -C 10  alkoxy and C 3 -C 7  heterocycloalkyl wherein the C 1 -C 10  alkyl, C 3 -C 7  cycloalkyl, C 1 -C 10  alkoxy and C 3 -C 7  heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of C 1 -C 8  alkyl, C 3 -C 7  cycloalkyl, C 3 -C 7  heterocycloalkyl, aryl, heteroaryl, halogen, hydroxyl, —CN, —COOH, —CF 3 , —OCH 2 F, —OCHF 2 , —OC 1 —C alkyl, —O-aryl, —O-heteroaryl, —NR 10 R 11 , —NR 10 C(O)R 11  and —C(O)NR 10 R 11 ; 
       R 10  and R 11  are independently selected from the group consisting of H, C 1 -C 8  alkyl and C 3 -C 7  cycloalkyl, or R 10  and R 11  taken together form a C 3 -C 7  heterocycloalkyl wherein the C 1 -C 8  alkyl and C 3 -C 7  heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting C 1 -C 8  alkyl, C 3 -C 7  cycloalkyl, C 3 -C 7  heterocycloalkyl, aryl, heteroaryl, halo, hydroxyl, —CN, —COOH, —CF 3 , —OCH 2 F, —OCHF 2 , —OC 1 -C 8  alkyl, —O-aryl, —O-heteroaryl, —NR 12 R 13 , —NR 12 C(O)R 13  and —C(O)NR 12 R 13 ; and 
       R 12  and R 13  are independently selected from the group consisting of H and C 1 -C 8  alkyl; 
       the pharmaceutical composition further comprising an excipient. 
     
     
         20 . The pharmaceutical composition according to  claim 19 , wherein the compound of Formula (I) is a compound of Formula (III) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 1  and R 2  are as defined. 
       
     
     
         21 . The pharmaceutical composition according to  claim 19 , wherein the compound of Formula (II) is a compound of Formula (IV) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein R 3  and R 9  are as defined. 
       
     
     
         22 . A pharmaceutical composition comprising the compound of Formula (V) according to  claim 16  and an excipient. 
     
     
         23 . A method for treating a disease associated with overexpression of wild type ERG protein, an altered ERG protein, ERG gene transcription or ERG mRNA translation in a subject suffering therefrom, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to  claim 19 . 
     
     
         24 . A method for treating a disease associated with overexpression of wild type ERG protein, an altered ERG protein, ERG gene transcription or ERG mRNA translation in a subject suffering therefrom, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to  claim 20 . 
     
     
         25 . A method for treating a disease associated with overexpression of wild type ERG protein, an altered ERG protein, ERG gene transcription or ERG mRNA translation in a subject suffering therefrom, comprising co-administering to the subject a therapeutically effective amount of a pharmaceutical composition according to  claim 21 . 
     
     
         26 . A method for treating a disease associated with overexpression of wild type ERG protein, an altered ERG protein, ERG gene transcription or ERG mRNA translation in a subject suffering therefrom, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to  claim 22 . 
     
     
         27 . The method according to  claim 23 , wherein the disease is selected from the group consisting of Ewing's sarcoma, acute myeloid leukemia, acute T-lymphoblastic leukemia, and endothelial cancer. 
     
     
         28 . The pharmaceutical composition according to  claim 19 , wherein R 3  and R 4  in Formula (I) and Formula (II) are each H and at least one of R 1  and R 2  is not H. 
     
     
         29 . The pharmaceutical composition according to  claim 19 , wherein R 1 , R 3  and R 4  in Formula (I) and Formula (II) are each H and R 2  is not H. 
     
     
         30 . The pharmaceutical composition according to  claim 19 , wherein R 3  in Formula (I) and Formula (II) is —OH. 
     
     
         31 . The pharmaceutical composition according to  claim 19 , wherein R 3  in Formula (I) and Formula (II) is —NR 5 R 6 .