Macrocyclic flu endonuclease inhibitors

Abstract

The present invention relates to macrocyclic pyridotriazine derivatives and the prodrugs thereof, and the pharmaceutically acceptable salts, solvates or polymorph thereof, and the use of such compounds as a medicament, in particular in the prevention and/or treatment of viral infections caused by viruses belonging to the Orthomyxoviridae family. The present invention furthermore relates to pharmaceutical compositions or combination preparations of the compounds, and to the compositions or preparations for use as a medicament, more preferably for the prevention or treatment of viral infections caused by viruses belonging to the Orthomyxoviridae family.

1 .- 16 . (canceled) 
     
     
         17 . A method of treating an influenza viral infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound having Formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof and one or more pharmaceutically acceptable excipients, diluents, or carriers 
       
         
           
           
               
               
           
         
         or any possible stereoisomeric form thereof, 
         wherein: 
         R 1  is CH 2 , —CH 2 —CH 2 —O—, C 3-6 cycloalkyl, oxetanyl, C 1-3 alkyl-cyclopropyl, or C 1-3 alkyl-cyclobutyl, each optionally substituted by one or more substituents independently selected from, halo, oxo, CH 2 -methoxy, C 1-4 alkyl, C 1-6 cycloalkyl, and tetrahydrofuran; 
         R 2  is C 1-6 alkyl, C 1-6 alkyl-O—, C 1-6 alkyl-N—, C 2-6 alkenyl, C 2-6 alkenyl-O—, or C 2-6 alkenyl-N—, each optionally substituted by one or more substituents independently selected from halo, oxo, and C 1-4 alkyl; 
         R 3  is CH 2  or O, wherein the CH 2  is optionally substituted by one or more substituents independently selected from halo, oxo, and methyl; 
         or, R 2  and R 3  together form C 2-8 alkenyl optionally substituted by one or more substituents independently selected from halo, oxo, and methyl; 
         X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8  and X 9  are each independently N or CH and wherein any of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8  and X 9  is CH, said CH is optionally substituted by one or more substituents independently selected from C 1-4 alkyl, C 3-6 cycloalkyl, CHF 2 , CH 2 F, CF 3 , OCF 3 , SCF 3 , OCH 3 , SCH 3 , S—(O) 2 —CH 3 , and halogen; 
         the dotted lines are each an optional bond; 
         R 4  is absent, or is —CH 2 —CH 2 —, —O—CH 2 —, —S—CH 2 —, S—(O) 2 —CH 2 , or cyclopropyl, each optionally substituted by one or more substituents independently selected from halo, oxo, and methyl; 
         R 5  is H, —C(═O)Y, —(CH 2 )—O—(C═O)—Y, —(CH 2 )—O—(C═O)—O—Y, —(CHCH 3 )—O—(C═O)—Y, —(CHCH 3 )—O—(C═O)—O—Y, —(CH 2 )—O—(C═O)—NH—Y, or —(CH 2 )—O—(C═O)C(R 7 )—NH—(R 8 ); 
         Y is C 1-6 alkyl, C 3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, C 1-4 alkyl-(O—R 7 ), C 1-4 alkyl-N—(R 7 )(R 8 ), or R 7 —O—R 8 —O—CH 2 ;
 wherein R 7  and R 8  are independently hydrogen or C 1-4 alkyl; and 
 
         R 6  is H, methyl, or CH 2 —O—CH 3 ; 
         or a pharmaceutically acceptable salt, polymorph, or solvate thereof. 
       
     
     
         18 . The method according to  claim 17 , wherein:
 R 1  is CH 2 , —CH 2 —CH 2 —O—, C 3-6 cycloalkyl, C 1-3 alkyl-cyclopropyl, or C 1-3 alkyl-cyclobutyl, each optionally substituted by one or more substituents independently selected from, halo, oxo, CH 2 -methoxy, C 1-4 alkyl, and C 1-6 cycloalkyl;   R 2  is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkenyl-O—, or C 2-6 alkenyl-N—, each optionally substituted by one or more substituents independently selected from halo, oxo, and C 1-4 alkyl;   R 3  is CH 2  or O, wherein the CH 2  is optionally substituted by one or more substituents independently selected from halo, oxo, and methyl;   or, R 2  and R 3  together form C 2-8 alkenyl optionally substituted by one or more substituents independently selected from halo, oxo, and methyl;   X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8  and X 9  are each independently N or CH and wherein any of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8  and X 9  is CH, said CH is optionally substituted by one or more substituents independently selected from C 1-4 alkyl, C 3-6 cycloalkyl, CHF 2 , CH 2 F, CF 3 , OCF 3 , SCF 3 , OCH 3 , SCH 3 , S—(O) 2 —CH 3  or halogen;   the dotted lines are each an optional bond;   R 4  is absent, or is —CH 2 —CH 2 —, —O—CH 2 —, or —S—CH 2 —, each optionally substituted by one or more substituents independently selected from halo, oxo, and methyl;   R 5  is H, —C(═O)Y, —(CH 2 )—O—(C═O)—Y, —(CH 2 )—O—(C═O)—O—Y, —(CHCH 3 )—O—(C═O)—Y, —(CHCH 3 )—O—(C═O)—O—Y, —(CH 2 )—O—(C═O)—NH—Y, or —(CH 2 )—O—(C═O)C(R 7 )—NH—(R 8 );   Y is C 1-6 alkyl, C 3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, C 1-4 alkyl-(O—R 7 ), C 1-4 alkyl-N—(R 7 )(R 8 ), or R 7 —O—R 8 —O—CH 2 ;
 wherein R 7  and R 8  are independently hydrogen or C 1-4 alkyl; and 
   R 6  is H or methyl.   
     
     
         19 . The method according to  claim 17 , wherein:
 R 1  is CH 2 , C 3-6 cycloalkyl, C 1-3 alkyl-cyclopropyl, or C 1-3 alkyl-cyclobutyl, each optionally substituted by one or more substituents independently selected from, halo, and C 1-4 alkyl;   R 2  is C 1-6 alkyl or C 2-6 alkenyl, each optionally substituted by one or more substituents independently selected from halo and C 1-4 alkyl;   R 3  is CH 2  or O, wherein the CH 2  is optionally substituted by one or more substituents independently selected from halo and methyl;   or, R 2  and R 3  together form C 2-8 alkenyl optionally substituted by one or more substituents independently selected from halo, oxo, and methyl;   X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8  and X 9  are each independently N or C and wherein any of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8  and X 9  is CH, said CH is optionally substituted by one or more substituents independently selected from C 1-4 alkyl, C 3-6 cycloalkyl, CHF 2 , CH 2 F, CF 3 , OCF 3 , SCF 3 , OCH 3 , SCH 3 , S—(O) 2 —CH 3 , and halogen;   the dotted lines are each an optional bond;   R 4  is absent or is —S—CH 2 — optionally substituted by one or more substituents independently selected from halo and methyl;   R 5  is H; and   R 6  is H or methyl.   
     
     
         20 . The method according to  claim 17 , wherein:
 R 1  is CH 2 , C 3-6 cycloalkyl, or C 1-3 alkyl-cyclopropyl, each optionally substituted by one or more substituents independently selected from halo and C 1-4 alkyl;   R 2  is C 1-6 alkyl or C 2-6 alkenyl, each optionally substituted by one or more substituents independently selected from halo and C 1-4 alkyl;   R 3  is CH 2  or O, wherein the CH 2  is optionally substituted by one or more substituents independently selected from halo and methyl;   X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8  and X 9  are each independently N or CH and wherein any of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8  and X 9  is CH, said CH is optionally substituted by one or more substituents independently selected from C 1-4 alkyl, C 3-6 cycloalkyl, CHF 2 , CH 2 F, CF 3 , OCF 3 , SCF 3 , OCH 3 , SCH 3 , S—(O) 2 —CH 3 , and halogen;   the dotted lines are each an optional bond;   R 4  is absent or is —S—CH 2 — optionally substituted by one or more substituents independently selected from halo and methyl;   R 5  is H; and   R 6  is H or methyl.   
     
     
         21 . The method according to  claim 17 , wherein:
 R 1  is CH 2 , C 3-6 cycloalkyl, or C 1-3 alkyl-cyclopropyl, each optionally substituted by one or more substituents independently selected from halo and C 1-4 alkyl;   R 2  is C 1-6 alkyl or C 2-6 alkenyl, each optionally substituted by one or more substituents independently selected from halo and C 1-4 alkyl;   R 3  is CH 2  or O, wherein the CH 2  is optionally substituted by one or more substituents independently selected from halo and methyl;   X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8  and X 9  are each CH which is optionally substituted by one or more substituents independently selected from C 1-4 alkyl, C 3-6 cycloalkyl, and halogen;   the dotted lines are each an optional bond;   R 4  is absent or is —S—CH 2 — optionally substituted by one or more substituents independently selected from halo and methyl;   R 5  is H; and   R 6  is H.   
     
     
         22 . The method according to  claim 17 , wherein R 1  is CH 2 , C 3-6 cycloalkyl, or C 1-3 alkyl-cyclopropyl, each optionally substituted by one or more substituents independently selected from halo and C 1-4 alkyl. 
     
     
         23 . The method according to  claim 17 , wherein R 2  is C 1-6 alkyl or C 2-6 alkenyl, each optionally substituted by one or more substituents independently selected from halo and C 1-4 alkyl. 
     
     
         24 . The method according to  claim 17 , wherein R 3  is CH 2  or O, wherein the CH 2  is optionally substituted by one or more substituents independently selected from halo and methyl. 
     
     
         25 . The method according to  claim 17 , wherein X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8  and X 9  are each CH which is optionally substituted by one or more substituents independently selected from C 1-4 alkyl, C 3-6 cycloalkyl, and halogen. 
     
     
         26 . The method according to  claim 17 , wherein R 4  is absent or is —S—CH 2 — optionally substituted by one or more substituents independently selected from halo and methyl. 
     
     
         27 . The method according to  claim 17 , wherein R 5  is H. 
     
     
         28 . The method according to  claim 17 , wherein R 6  is H. 
     
     
         29 . A method of treating an influenza viral infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, solvate or polymorph thereof selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and one or more pharmaceutically acceptable excipients, diluents, or carriers. 
       
     
     
         30 . The method according to  claim 17 , wherein the influenza viral infection is an influenza A viral infection, and influenza B viral infection, or a combination thereof. 
     
     
         31 . The method according to  claim 18 , wherein the influenza viral infection is an influenza A viral infection, and influenza B viral infection, or a combination thereof. 
     
     
         32 . The method according to  claim 19 , wherein the influenza viral infection is an influenza A viral infection, and influenza B viral infection, or a combination thereof. 
     
     
         33 . The method according to  claim 23 , wherein the influenza viral infection is an influenza A viral infection, and influenza B viral infection, or a combination thereof. 
     
     
         34 . The method according to  claim 24 , wherein the influenza viral infection is an influenza A viral infection, and influenza B viral infection, or a combination thereof. 
     
     
         35 . The method according to  claim 25 , wherein the influenza viral infection is an influenza A viral infection, and influenza B viral infection, or a combination thereof. 
     
     
         36 . The method according to  claim 29 , wherein the influenza viral infection is an influenza A viral infection, and influenza B viral infection, or a combination thereof.