Naphthyridinone derivatives and their use in the treatment, amelioration or prevention of a viral disease

Abstract

The present invention relates to a compound having the general formula (V), optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, which are useful in treating, ameloriating or preventing a viral disease. Furthermore, specific combination therapies are disclosed.

1 . A compound having the formula (V), optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, prodrug, codrug, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, 
       
         
           
           
               
               
           
         
         wherein 
         X 51  is N; 
         X 52 —X 54  is C—R 57 ; 
         X 53  is NR 55 , N(R 55 )C(O), C(O)NR 55 , O, C(O), C(O)O, OC(O); N(R 55 )SC 2 , SO 2 N(R 55 ), S, SO, or SO 2 ; 
         R 50  is —H, -(optionally substituted C 1-6  alkyl), -(optionally substituted C 3-7  cycloalkyl), -(optionally substituted aryl), —C 1-4  alkyl -(optionally substituted C 3-7  cycloalkyl), or —C 1-4  alkyl -(optionally substituted aryl); 
         R 51  is —H, a —C 1-6  alkyl group, or a —C 1-6  alkyl group which is substituted by one or more halogen atoms; 
         R 52  is —H, a —C 1-6  alkyl group, or a —C 1-6  alkyl group which is substituted by one or more halogen atoms; or wherein R 51  and R 52  can be joined together to form a 3- to 7-membered carbo- or heterocyclic ring; 
         R 53  is —R 56 , or —X 53 —R 56 ; 
         R 55  is —H, -(optionally substituted C 1-6  alkyl), -(optionally substituted C 3-7  cycloalkyl), -(optionally substituted aryl), —C 1-4 alkyl -(optionally substituted C 3-7  cycloalkyl), or —C 1 4 alkyl -(optionally substituted aryl); 
         R 56  is -(optionally substituted hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S and which contains at least one ring); 
         R 57  is —H, -Hal or —C 1-6  alkyl; 
         R 58  is —H, —C 1-6  alkyl, or —(CH 2 CH 2 O) r H; 
         R 59  is —H, or —C 1-6  alkyl; 
         R is independently selected from —C 1  alkyl, —C(O)—C 1-6  alkyl, -Hal, —CF 3 , —CN, —COOR 58 , —OR 58 , —(CH 2 ) q NR 58 R 59 , —C(O)—NR 58 R 59 , and —NR 58 —C(O)—C 1-6  alkyl; 
         q is 0 to 4; and 
         r is 1 to 3; 
         wherein the alkyl group, aryl group, hydrocarbon group and/or cycloalkyl group can be optionally substituted with one or more substituents R. 
         with the proviso that the following compounds are disclaimed: 
       
       
         
           
           
               
               
           
         
       
       and
 ethyl 4-oxo-1-{[4-(1H-pyrazolo-1-yl)phenyl]methyl}-1,4-dihydro-1,5-naphthyridine-3-carboxylate. 
 
     
     
         2 . The compound according to  claim 1 , wherein R 53  is —R 56 . 
     
     
         3 . The compound according to  claim 1 , wherein R 53  is —X 53 —R 56  and X 53  is N(R 55 )SO 2 . 
     
     
         4 . The compound according to  claim 1 , wherein R 51  and R 52  are —H. 
     
     
         5 . The compound according to  claim 1 , wherein R 50  is —H, or -(optionally substituted C 1-6  alkyl). 
     
     
         6 . The compound according to  claim 1 , wherein R 56  is selected from 
       
         
           
           
               
               
           
         
         wherein 
         X is absent, CH 2 , NH, C(O)NH, S or O; 
         Y is CH 2 ; 
         Z is O or S; and 
         R is independently selected from —H, —C 1-6  alkyl, —CF 3 , -halogen, —CN, —OH, and —O—C 1-6  alkyl. 
       
     
     
         7 . A pharmaceutical composition comprising:
 a compound having the general formula (V) as defined in  claim 1 , optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, prodrug, codrug, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, and optionally one or more pharmaceutically acceptable excipient(s) and/or carrier(s);   with the proviso that the following compounds are disclaimed:   
       
         
           
           
               
               
           
         
       
     
     
         8 . The pharmaceutical composition according to  claim 7  further comprising at least one further medicament which is selected from the group consisting of a polymerase inhibitor which is different from the compound having the general formula (V); neuramidase inhibitor; M2 channel inhibitor; alpha glucosidase inhibitor; ligand of another influenza target; antibiotics, anti-inflammatory agents, lipoxygenase inhibitors, EP ligands, bradykinin ligands, and cannabinoid ligands. 
     
     
         9 . A compound according to formula (V) as defined in  claim 1 , optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, prodrug, codrug, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof,
 wherein the compound is for use in the treatment, amelioration or prevention of a viral disease; and   wherein the compounds disclaimed in  claim 1  are not disclaimed.   
     
     
         10 . The compound, pharmaceutical composition or method according to  claim 1 , wherein the compound according to formula (V) exhibits an IC 50  of less than about 40 μM in the FRET endonuclease activity assay disclosed herein. 
     
     
         11 . The compound according to  claim 2 , wherein R 51  and R 52  are —H. 
     
     
         12 . The compound according to  claim 2 , wherein R 50  is —H, or -(optionally substituted C 1-6  alkyl). 
     
     
         13 . The compound according to  claim 2 , wherein R 56  is selected from 
       
         
           
           
               
               
           
         
         wherein 
         X is absent, CH 2 , NH, C(O)NH, S or O; 
         Y is CH 2 ; 
         Z is O or S; and 
         R is independently selected from —H, —C 1-6  alkyl, —CF 3 , -halogen, —CN, —OH, and —O—C 1-6  alkyl. 
       
     
     
         14 . The compound according to  claim 3 , wherein R 51  and R 52  are —H. 
     
     
         15 . The compound according to  claim 3 , wherein R 50  is —H, or -(optionally substituted C 1-6  alkyl). 
     
     
         16 . The compound according to  claim 3 , wherein R 56  is selected from 
       
         
           
           
               
               
           
         
         wherein 
         X is absent, CH 2 , NH, C(O)NH, S or O; 
         Y is CH 2 ; 
         Z is O or S; and 
         R is independently selected from —H, —C 1-6  alkyl, —CF 3 , -halogen, —CN, —OH, and —O—C 1-6  alkyl. 
       
     
     
         17 . The compound according to  claim 4 , wherein R 50  is —H, or -(optionally substituted C 1-6  alkyl). 
     
     
         18 . The compound according to  claim 4 , wherein R 56  is selected from 
       
         
           
           
               
               
           
         
         wherein 
         X is absent, CH 2 , NH, C(O)NH, S or O; 
         Y is CH 2 ; 
         Z is O or S; and 
         R is independently selected from —H, —C 1-6  alkyl, —CF 3 , -halogen, —CN, —OH, and —O—C 1-6  alkyl. 
       
     
     
         19 . The compound according to  claim 5 , wherein R 56  is selected from 
       
         
           
           
               
               
           
         
         wherein 
         X is absent, CH 2 , NH, C(O)NH, S or O; 
         Y is CH 2 ; 
         Z is O or S; and 
         R is independently selected from —H, —C 1-6  alkyl, —CF 3 , -halogen, —CN, —OH, and —O—C 1-6  alkyl.