7-oxo-thiazolopyridine carbonic acid 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 (A), 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 formula (A) 
       
         
           
           
               
               
           
         
         wherein 
         R* —X 1 —R 1 ; 
         X 1  is NR 4 ; 
         X 2  is O, S or NR 4 ; 
         X 3  is O or S; 
         X 4  is O or S; 
         R 1  is —SO 2 —R 4 ; 
         R 2  is a 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, wherein the hydrocarbon group can be optionally substituted; 
         R 3  is —H, -(optionally substituted C 1-6  alkyl), -(optionally substituted C 3-7  cycloalkyl), -(optionally substituted aryl), or —C 1-4  alkyl-(optionally substituted aryl); or if X 2  is NR 4 , then R 3  can also be —OH; 
         R 4  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); or R 4  and R 1  can be joined together to form a 5- to 7-membered ring, which can optionally contain O, S or further N; or if X 2  is NR 4 , then R 4  and R 3  can be joined together to form a 5- to 7-membered ring, which can optionally contain O, S or further N; 
         R 5  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); and 
         R 6  is —H or —C 1-6  alkyl; 
         wherein the optional substituent of the alkyl group is selected from the group consisting of halogen, —CN, —NR 6 R 6 , —OH, and —O—C 1-6  alkyl; 
         wherein the optional substituent of the cycloalkyl group, the aryl group or the hydrocarbon group is selected from the group consisting of —C 1-6  alkyl, halogen, —CF 3 , —CN, —X 1 —R 5  and —C 1-4  alkyl-aryl; 
         or a pharmaceutically acceptable salt, solvate, polymorph, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof; 
         wherein, the prodrug is a compound where X 2  is O or S, and R 3  is one of the following groups: 
       
       
         
           
           
               
               
           
         
         wherein R 6  is the same or different, 
         wherein R 9  is aryl or C 3-7  cycloalkyl, 
         p is 2-8. 
       
     
     
         2 . The compound according to  claim 1 , wherein X 2  is O. 
     
     
         3 . The compound according to  claim 1 , wherein X 3  is O. 
     
     
         4 . The compound according to  claim 1 , wherein X 4  is O. 
     
     
         5 . The compound according to  claim 1 , wherein R 3  is —H, —C 1-6  alkyl or Bz. 
     
     
         6 . The compound according to  claim 1 , wherein R 4  is —H, -(optionally substituted C 1-6  alkyl), -(optionally substituted aryl), or —C 1-4  alkyl-(optionally substituted aryl). 
     
     
         7 . The compound according to  claim 1 , wherein R 2  is selected from the group consisting of 
       
         
           
           
               
               
           
         
         wherein 
         X is absent, CH 2 , NH, C(O)NH, S or O; 
         Y is CH 2 ; or 
         X and Y can be joined together to form an annulated, carbo- or heterocylic 3- to 8-membered ring which can be saturated or unsaturated; and 
         R is independently selected from H, —C 1-6  alkyl, halogen, —CN, —OH, and —O—C 1-6  alkyl. 
       
     
     
         8 . The compound according to  claim 1 , wherein R 2  is 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound according to  claim 1 , wherein R 2  is 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound according to  claim 1 , wherein R 2  is 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound according to  claim 10 , wherein X is absent and Y is CH 2 . 
     
     
         12 . The compound according to  claim 1 , wherein R is H or halogen. 
     
     
         13 . A pharmaceutical composition comprising:
 (i) a compound having formula (A) as defined in  claim 1  or a pharmaceutically acceptable salt, solvate, polymorph, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof; and   (ii) a pharmaceutically acceptable excipient.   
     
     
         14 . The pharmaceutical composition according to  claim 13 , further comprising:
 i. at least one polymerase inhibitor which is different from the compound having formula (A);   ii. at least one neuraminidase inhibitor;   iii. at least one M2 channel inhibitor;   iv. at least one alpha glucosidase inhibitor;   v. at least one ligand of another influenza target; or   vi. at least one medicament selected from an antibiotics, an anti-inflammatory agent, an lipoxygenase inhibitor, an EP ligand, an bradykinin ligand and a cannabinoid ligand.   
     
     
         15 . A method of treating or ameliorating influenza, the method comprising administering to a patient in need thereof an effective amount of a compound according to  claim 1 . 
     
     
         16 . A method of treating or ameliorating influenza, the method comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition according to  claim 13 . 
     
     
         17 . A method of treating or ameliorating influenza, the method comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition according to  claim 14 . 
     
     
         18 . A compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, polymorph, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof.