Selective hdac8 inhibitors and their uses

Abstract

The present invention relates to small molecule compounds based on benzopyrimido- or benzoimidazo-thiazin-imine as well as their (synthesis) intermediates and their use as HDAC inhibitors, in particular HDAC8 inhibitors. The present invention also relates to the use of said compounds in the treatment of cancer and as therapeutic agents for eukaryotic parasites and respective methods of treatment.

1 - 17 . (canceled) 
     
     
         18 . A method for inhibiting an enzyme of the histone deacetylase (HDAC) family wherein said method comprises use of a compound having the general formula III 
       
         
           
           
               
               
           
         
       
       wherein
 n is an integer of 1 to 7, 
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are each independently selected from 
 hydrogen, 
 halogen, 
 NO 2 , CN, SO 3 , N(R 10 ) 2 , 
 O—X, S—X, NR R —X, —NR 10 C(═O)—X, S(═O)—X, S(═O) 2 —X, NHS(═O) 2 —X, 
 C 1 -C 6 alkyl-X, C 2 -C 6 alkenyl-X, C 2 -C 6 alkynyl-X, C 1 -C 6 heteroalkyl-X, C 1 -C 6 fluoroalkyl-X, partially fluorinated C 1 -C 6 alkyl-X, C 1 -C 6 alkyl-O—X, C 1 -C 3 alkyl-O—C 1 -C 3 alkyl-X, C 1 -C 6 alkyl-NR 8 —X, C 1 -C 3 alkyl-NR 8 —C 1 -C 3 alkyl —X, C 1 -C 6 alkyl-C(═O)NR 8 —X, C 1 -C 3 alkyl-C(═O)NR 8 —C 1 -C 3 alkyl-X, C 1 -C 6 alkyl-NR R C(═O)—X, C 1 -C 3 alkyl-NR 8 C(═O)—C 1- C 3 alkyl-X, C 1 -C 6 alkyl-S—X, C 1 -C 3 alkyl-S—C 1 -C 3 alkyl-X, C 1 -C 6 alkyl-S(═O)—X, C 1 -C 3 alkyl-S(═O)—C 1 -C 3 alkyl-X, C 1 -C 6 alkyl-S(═O) 2 —X, C 1 -C 3 alkyl-S(═O) 2 —C 1 -C 3 alkyl-X, C(═O)—X, C(═O)—NR 8 —X, C(═O)—C 1 -C 6 alkyl-X, 
 substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted aryl, heteroaryl, 
 Si 1 -Si 3 silyl-X, Si 2 -Si 4 siloxane-X; 
 X is hydrogen, or a substituted or unsubstituted group selected from aryl, heteroaryl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 fluoroalkyl, partially fluorinated C 1 -C 6 alkyl, C 1 -C 3 alkylaminoC 1 -C 3 alkoxy, hydroxyC 1 -C 3 alkylaminoC 1 -C 3 alkoxy, C 2 -C 5 heterocycloalkylC 1 -C 3 alkoxy, C 2 -C 8 heterocycloalkylC 1 -C 2 alkyl, CN, NO 2 , SO 3 , CO 2 R 9 , C(═O)R 9 , S—R 9 , S(═O)—R 9 , S(═O) 2 —R 9 , NR 10 C(═O)—R 9 , C(═O)N(R 10 ) 2 , S(═O) 2 N(R 10 ) 2 , NR 10 S(═O) 2 —R 9 , OC(═O)N(R 10 ) 2 , NR 10 C(═O)O—R 9 , —OC(═O)O—R 9 , NHC(═O)NH—R 9 , OC(═O)R 9 , N(R 10 ) 2 , C 1 -C 2 alkylN(R 10 ) 2 , C 2 -C 6 alkyne, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, C 2 -C 10 heterocycloalkyl, Si 1 -Si 3 silyl, and Si 2 —Si 4 siloxane; 
 R 8  is selected from hydrogen, C 1 -C 6 alkyl, phenyl and benzyl; 
 R 9  is a substituted or unsubstituted group selected from C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, partially fluorinated C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, and heteroaryl; and 
 R 10  and R 11  are each independently hydrogen or a substituted or unsubstituted group selected from C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, partially fluorinated C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, and heteroaryl; 
 
       or a pharmaceutically accepted salt or pharmaceutically acceptable prodrug thereof. 
     
     
         19 . The method, according to  claim 18 , wherein n is an integer from 1 to 4. 
     
     
         20 . The method according to  claim 18 , wherein the compound selectively inhibits HDAC8. 
     
     
         21 . The method of  claim 18 , wherein
 n is 1 or 2; and/or   R 3 , R 4 , R 5 , and R 6  are each hydrogen; and/or   two or three of R 3 , R 4 , R 5 , and R 6  are hydrogen; and/or   R 3 , R 4 , R 5  and R 6  are each independently selected from hydrogen; halogen; C 1 -C 6 alkyl; alkylamino; N(R 10 ) 2  with R 10  being C 1 -C 6  alkyl; and C 1 -C 6 fluoroalkyl-X with X being hydrogen.   
     
     
         22 . The method of  claim 18 , wherein the compound is selected from:
 a compound having general formula III wherein n is 1; R 3  is alkyl, and R 4 , R 5 , and R 6  are each hydrogen;   a compound having general formula III wherein n is 2; R 3 , R 4 , and R 5  are each hydrogen; and R 6  is halogen;   a compound having general formula III wherein n is 2; R 3 , R 4 , and R 6  are each hydrogen; and R 5  is halogen;   a compound having general formula III wherein n is 2; R 3 , R 4 , and R 6  are each hydrogen; and R 5  is alkyl;   a compound having general formula III wherein n is 1; R 3 , R 5 , and R 6  are each hydrogen; and R 4  is halogen.   
     
     
         23 . The method, according to  claim 22 , wherein n is 1, R 3  is methyl, and R 4 , R 5  and R 6  are each hydrogen. 
     
     
         24 . The method, according to  claim 22 , wherein n is 2; R 3 , R 4 , and R 5  are each hydrogen; and R 6  is F. 
     
     
         25 . The method, according to  claim 22 , wherein 2; R 3 , R 4 , and R 6  are each hydrogen; and R 5  is Br. 
     
     
         26 . The method, according to  claim 22 , wherein n is 2; R 3 , R 4 , and R 6  are each hydrogen; and R 5  is methyl. 
     
     
         27 . The method, according to  claim 22 , wherein n is 1; R 3 , R 5 , and R 6  are each hydrogen; and R 4  is Br. 
     
     
         28 . The method according to  claim 18 , which is used to treat cancer. 
     
     
         29 . The method, according to  claim 28 , wherein the cancer is neuroblastoma, T-cell lymphomas, urothelial or breast cancer. 
     
     
         30 . The method according to  claim 28 , wherein said compound is used in combination with a cytostatic compound. 
     
     
         31 . The method according to  claim 18 , which is used to treat an infection caused by a eukaryotic parasite. 
     
     
         32 . The method, according to  claim 31 , wherein the eukaryotic parasite is  Schistosoma mansoni  or  Plasmodium falciparum.    
     
     
         33 . A pharmaceutical composition comprising:
 (a) at least one a compound having the general formula III   
       
         
           
           
               
               
           
         
         wherein
 n is an integer of 1 to 7, 
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are each independently selected from 
 hydrogen, 
 halogen, 
 NO 2 , CN, SO 3 , N(R 10 ) 2 , 
 O—X, S—X, NR 8 —X, —NR 10 C(═O)—X, S(═O)—X, S(═O) 2 —X, NHS(═O) 2 —X, 
 C 1 -C 6 alkyl-X, C 2 -C 6 alkenyl-X, C 2 -C 6 alkynyl-X, C 1 -C 6 heteroalkyl-X, C 1 -C 6 fluoroalkyl-X, partially fluorinated C 1 -C 6 alkyl-X, C 1 -C 6 alkyl-O—X, C 1 -C 3 alkyl-O—C 1 -C 3 alkyl-X, C 1 -C 6 alkyl-NR 8 —X, C 1 -C 3 alkyl-NR 8 —C 1 -C 3 alkyl —X, C 1 -C 6 alkyl-C(═O)NR 8 —X, C 1 -C 3 alkyl-C(═O)NR 8 —C 1 -C 3 alkyl-X, C 1 -C 6 alkyl-NR 8 C(═O)—X, C 1 -C 3 alkyl-NR 8 C(═O)—C 1 -C 3 alkyl-X, C 1 -C 6 alkyl-S—X, C 1 -C 3 alkyl-S—C 1 -C 3 alkyl-X, C 1 -C 6 alkyl-S(═O)—X, C 1 -C 3 alkyl-S(═O)—C 1 -C 3 alkyl-X, C 1 -C 6 alkyl-S(═O) 2 —X, C 1 -C 3 alkyl-S(═O) 2 —C 1 -C 3 alkyl-X, C(═O)—X, C(═O)—NR 8 —X, C(═O)—C 1 -C 6 alkyl-X, 
 substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted aryl, heteroaryl, 
 Si 1 —Si 3 silyl-X, Si 2 —Si 4 siloxane-X; 
 X is hydrogen, or a substituted or unsubstituted group selected from aryl, heteroaryl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 fluoroalkyl, partially fluorinated C 1 -C 6 alkyl, C 1 -C 3 alkylaminoC 1 -C 3 alkoxy, hydroxyC 1 -C 3 alkylaminoC 1 -C 3 alkoxy, C 2 -C 5 heterocycloalkylC 1 -C 3 alkoxy, C 2 -C 8 heterocycloalkylC 1 -C 2 alkyl, CN, NO 2 , SO 3 , CO 2 R 9 , C(═O)R 9 , S—R 9 , S(═O)—R 9 , S(═O) 2 —R 9 , NR 10 C(═O)—R 9 , C(═O)N(R 10 ) 2 , S(═O) 2 N(R 10 ) 2 , NR 10 S(═O) 2 —R 9 , OC(═O)N(R 10 ) 2 , NR 10 C(═O)O—R 9 , —OC(═O)O—R 9 , NHC(═O)NH—R 9 , OC(═O)R 9 , N(R 10 ) 2 , C 1 -C 2 alkylN(R 10 ) 2 , C 2 -C 6 alkyne, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, C 2 -C 10 heterocycloalkyl, Si 1 —Si 3 silyl, and Si 2 —Si 4 siloxane; 
 R 8  is selected from hydrogen, C 1 -C 6 alkyl, phenyl and benzyl; 
 R 9  is a substituted or unsubstituted group selected from C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, partially fluorinated C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, and heteroaryl; and 
 R 10  and R 11  are each independently hydrogen or a substituted or unsubstituted group selected from C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, partially fluorinated C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, and heteroaryl; 
 
         or a pharmaceutically accepted salt or pharmaceutically acceptable prodrug thereof, and 
         (b) a pharmaceutically acceptable excipient(s) and/or carrier.