Carboxy tetrahydropyrazolopyrazine compounds for the treatment of infectious diseases

Abstract

The present invention relates to compounds of the formula (I), or pharmaceutically acceptable salts, enantiomer or diastereomer thereof, wherein R 1 to R 3 are as described above. The compounds may be useful for the treatment or prophylaxis of hepatitis B virus infection.

1 . A compound of formula (I), 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is oxooxadiazabicyclo[3.3.1]nonanyl substituted by carboxyC 1-6 alkyl; or
 oxopyrrolidinyl, said oxopyrrolidinyl being once substituted by carboxyC 1-6 alkyl(C 1-6 alkyl)amino, carboxyphenyl, carboxypyridinyl, carboxyphenylamino, halocarboxyphenyl or carboxypyrrolidinyl; or twice substituted by carboxypyrrolidinyl and C 1-6 alkyl; 
 
         R 2  is H or C 1-6 alkyl; 
         R 3  is C 1-6 alkyl; 
         R 4  is phenyl, said phenyl being three times substituted by halogen; 
         or pharmaceutically acceptable salt, enantiomer or diastereomer thereof. 
       
     
     
         2 . A compound of formula (I) according to  claim 1 , wherein
 R 1  is carboxymethyl(methyl)aminooxopyrrolidinyl, carboxypyrrolidinyloxopyrrolidinyl, carboxypyrrolidinyl(methyl)oxopyrrolidinyl, carboxyphenyloxopyrrolidinyl, carboxypyridinyloxopyrrolidinyl, carboxyphenylaminooxopyrrolidinyl, fluorocarboxyphenyloxopyrrolidinyl or carboxymethyloxooxadiazabicyclo[3.3.1]nonanyl;   R 2  is H or methyl;   R 3  is methyl;   R 4  is trifluorophenyl;   or pharmaceutically acceptable salt, enantiomer or diastereomer thereof.   
     
     
         3 . A compound selected from:
 (2S)-1-[1-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-5-oxo-pyrrolidin-3-yl]pyrrolidine-2-carboxylic acid;   (2S)-1-[(2S)-2-methyl-1-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-5-oxo-pyrrolidin-3-yl]pyrrolidine-2-carboxylic acid;   2-[methyl-[1-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-5-oxo-pyrrolidin-3-yl]amino]acetic acid;   (2R)-1-[(2S)-2-methyl-1-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-5-oxo-pyrrolidin-3-yl]pyrrolidine-2-carboxylic acid;   1-[1-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-5-oxo-pyrrolidin-3-yl]pyrrolidine-3-carboxylic acid;   (2S)-1-[1-[(6S,7S)-6,7-dimethyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-5-oxo-pyrrolidin-3-yl]pyrrolidine-2-carboxylic acid;   2-[1-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-5-oxo-pyrrolidin-3-yl]benzoic acid;   3-[1-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-5-oxo-pyrrolidin-3-yl]benzoic acid;   (2R)-1-[1-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-5-oxo-pyrrolidin-3-yl]pyrrolidine-2-carboxylic acid;   3-fluoro-2-[1-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-5-oxo-pyrrolidin-3-yl]benzoic acid;   2-fluoro-6-[1-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-5-oxo-pyrrolidin-3-yl]benzoic acid;   2-[[1-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-5-oxo-pyrrolidin-3-yl]amino]benzoic acid;   2-[7-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-6-oxo-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl]acetic acid;   4-fluoro-2-[1-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-5-oxo-pyrrolidin-3-yl]benzoic acid;   5-fluoro-2-[1-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-5-oxo-pyrrolidin-3-yl]benzoic acid;   4-[1-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-5-oxo-pyrrolidin-3-yl]benzoic acid;   6-[1-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-5-oxo-pyrrolidin-3-yl]pyridine-2-carboxylic acid; and   2-[1-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-5-oxo-pyrrolidin-3-yl]pyridine-3-carboxylic acid.   
     
     
         4 . A process for the preparation of a compound according to any one of  claims 1  to  3  comprising the following step:
 (a) the reaction of compound of formula (V), 
 
       
         
           
           
               
               
           
         
         with an acid followed by urea formation with amine R 4 NH 2  in the presence of a phosgene equivalent; wherein R 1  and R 4  are defined as in any one of  claims 1  to  3 . 
       
     
     
         5 . A compound or pharmaceutically acceptable salts, enantiomers or diastereomers according to any one of  claims 1  to  3  for use as therapeutically active substance. 
     
     
         6 . A pharmaceutical composition comprising a compound in accordance with any one of  claims 1  to  3  and a therapeutically inert carrier. 
     
     
         7 . The use of a compound according to any one of  claims 1  to  3  for the treatment or prophylaxis of hepatitis B virus infection. 
     
     
         8 . The use of a compound according to any one of  claims 1  to  3  for the preparation of a medicament for the treatment or prophylaxis of hepatitis B virus infection. 
     
     
         9 . A compound or pharmaceutically acceptable salt, enantiomer or diastereomer according to any one of  claims 1  to  3  for the treatment or prophylaxis of hepatitis B virus infection. 
     
     
         10 . A compound or pharmaceutically acceptable salt, enantiomer or diastereomer according to any one of  claims 1  to  3 , when manufactured according to a process of  claim 4 . 
     
     
         11 . A method for the treatment or prophylaxis of hepatitis B virus infection, which method comprises administering a therapeutically effective amount of a compound as defined in any one of  claims 1  to  3 .