7-substituted sulfonimidoylpurinone compounds for the treatment of virus infection

Abstract

The present invention relates to compounds of formula (I), wherein R 1 , R 2 and R 3 are as described herein, and their prodrugs or pharmaceutically acceptable salt, enantiomer or diastereomer thereof, and compositions including the compounds and methods of using the compounds.

1 . A compound of formula (I), 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is C 1-6 alkyl; 
         R 2  is benzyl, said benzyl being unsubstituted or substituted by one, two or three substituents independently selected from halogen and C 1-6 alkyl; 
         R 3  is —NR 4 R 5 , wherein: 
         R 4  is C 1-6 alkyl or C 1-6 alkoxyC 1-6 alkyl; 
         R 5  is (C 1-6 alkyl) 2 NCOOC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkoxycarbonyl(C 1-6 alkyl)aminoC 1-6 alkyl, C 1-6 alkoxycarbonyl(phenyl)C 1-6 alkyl, C 1-6 alkoxycarbonylC 1-6 alkyl, C 1-6 alkoxycarbonyloxyC 1-6 alkyl, C 1-6 alkyl, C 1-6 alkylcarbonyl(C 1-6 alkyl)aminoC 1-6 alkyl or pyrrolidinylcarbamoyloxyC 1-6 alkyl; or 
         R 4  and R 5  together with the nitrogen they are attached to form a heterocyclyl; 
         or pharmaceutically acceptable salt, enantiomer or diastereomer thereof; 
         with the proviso that 
         6-amino-9-benzyl-2-(propylsulfonimidoyl)-7-(pyrrolidine-1-carbonyl)purin-8-one; 
         6-amino-9-benzyl-7-(piperidine-1-carbonyl)-2-(propylsulfonimidoyl)purin-8-one; 
         6-amino-9-benzyl-7-(morpholine-4-carbonyl)-2-(propylsulfonimidoyl)purin-8-one; 
         6-amino-9-benzyl-7-(3,3-dimethylpyrrolidine-1-carbonyl)-2-(propylsulfonimidoyl)purin-8-one; 
         ethyl 1-[6-amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purine-7-carbonyl]pyrrolidine-2-carboxylate; 
         6-amino-7-(2-azaspiro[3.3]heptane-2-carbonyl)-9-benzyl-2-(propylsulfonimidoyl)purin-8-one; 
         6-amino-9-benzyl-7-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-2-(propylsulfonimidoyl)purin-8-one; 
         6-amino-9-benzyl-7-(3,3-difluoropyrrolidine-1-carbonyl)-2-(propylsulfonimidoyl)purin-8-one; 
         6-amino-9-benzyl-7-(3-fluoro-3-methyl-pyrrolidine-1-carbonyl)-2-(propylsulfonimidoyl)purin-8-one; 
         and their enantiomers or diastereomers are excluded. 
       
     
     
         2 . A compound according to  claim 1 , wherein:
 R 1  is C 1-6 alkyl;   R 2  is benzyl, said benzyl being unsubstituted or substituted by halogen or C 1-6 alkyl;   R 3  is azetidinyl;   piperazinyl substituted by C 1-6 alkyl;   piperidinyl substituted by piperidinyl;   pyrrolidinyl; or   —NR 4 R 5 , wherein:
 R 4  is C 1-6 alkyl or C 1-6 alkoxyC 1-6 alkyl; 
   R 5  is (C 1-6 alkyl) 2 NCOOC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkoxycarbonyl(C 1-6 alkyl)-aminoC 1-6 alkyl, C 1-6 alkoxycarbonyl(phenyl)C 1-6 alkyl, C 1-6 alkoxycarbonylC 1-6 alkyl, C 1-6 alkoxycarbonyloxyC 1-6 alkyl, C 1-6 alkyl, C 1-6 alkylcarbonyl(C 1-6 alkyl)aminoC 1-6 alkyl or pyrrolidinylcarbamoyloxyC 1-6 alkyl.   
     
     
         3 . A compound according to  claim 1  or  2 , wherein:
 R 1  is ethyl or propyl; 
 R 2  is benzyl, bromobenzyl, chlorobenzyl, fluorobenzyl or methylbenzyl; 
 R 3  is azetidinyl; 
 4-methylpiperazinyl; 
 piperidinylpiperidinyl; 
 pyrrolidinyl; or 
 —NR 4 R 5 , wherein:
 R 4  is methyl, ethyl, propyl or methoxyethyl; 
 R 5  is acetyl(methyl)aminoethyl, butyl, butyl(methyl)carbamoyloxyethyl, diethylcarbamoyloxyethyl, ethoxycarbonyl(methyl)aminoethyl, ethoxycarbonylethyl, ethoxycarbonylisobutyl, ethoxycarbonylisopentyl, ethoxycarbonylmethyl, ethoxycarbonyloxyethyl, ethoxycarbonyl(phenyl)ethyl, ethyl, isobutyl, isopropoxycarbonylisopentyl, isopropoxycarbonyl(phenyl)ethyl, isopropyl, methoxycarbonyl(methyl)aminoethyl, methoxyethyl, methoxypropyl, propyl, propyl(methyl)carbamoyloxyethyl, pyrrolidinylcarbamoyloxyethyl, tert-butoxycarbonyl(methyl)aminoethyl, tert-butoxycarbonylethyl, tert-butoxycarbonylisopentyl or tert-butoxycarbonyl(phenyl)ethyl. 
 
 
     
     
         4 . A compound according to  claim 3 , wherein R 3  is azetidinyl, 4-methylpiperazinyl, piperidinylpiperidinyl, pyrrolidinyl, acetyl(methyl)aminoethyl(methyl)amino, bis(methoxyethyl)amino, butyl(ethyl)amino, butyl(methyl)amino, butyl(methyl)carbamoyloxyethyl(methyl)amino, diethylcarbamoyloxyethyl(methyl)amino, ethoxycarbonyl(methyl)aminoethyl(methyl)amino, ethoxycarbonylethyl(methyl)amino, ethoxycarbonylisobutyl(methyl)amino, ethoxycarbonylisopentyl(methyl)amino, ethoxycarbonylmethyl(methyl)amino, ethoxycarbonyloxyethyl(methyl)amino, ethoxycarbonyl(phenyl)ethyl(methyl)amino, ethyl(methyl)amino, isobutyl(methyl)amino, isopropoxycarbonylisopentyl(methyl)amino, isopropoxycarbonyl(phenyl)ethyl(methyl)amino, isopropyl(methyl)amino, methoxycarbonyl(methyl)aminoethyl(methyl)amino, methoxyethyl(ethyl)amino, methoxyethyl(methyl)amino, methoxyethyl(propyl)amino, methoxypropyl(methyl)amino, propyl(ethyl)amino, propyl(methyl)amino, propyl(methyl)carbamoyloxyethyl(methyl)amino, pyrrolidinylcarbamoyloxyethyl(methyl)amino, tert-butoxycarbonyl(methyl)aminoethyl(methyl)amino, tert-butoxycarbonyl ethyl(methyl)amino, tert-butoxycarbonylisopentyl(methyl)amino or tert-butoxycarbonyl(phenyl)ethyl(methyl)amino. 
     
     
         5 . A compound according to any one of  claims 1  to  4 , wherein R 1  is ethyl. 
     
     
         6 . A compound according to  claim 1  or  2 , wherein R 2  is benzyl substituted by halogen or C 1-6 alkyl. 
     
     
         7 . A compound according to any one of  claims 2  to  6 , wherein R 2  is bromobenzyl, chlorobenzyl, fluorobenzyl or methylbenzyl. 
     
     
         8 . A compound according to  claim 7 , wherein R 2  is bromobenzyl, chlorobenzyl or fluorobenzyl. 
     
     
         9 . A compound according to  claim 1  or  2 , wherein R 3  is —NR 4 R 5 , wherein R 4  is C 1-6 alkyl, R 5  is C 1-6 alkyl. 
     
     
         10 . A compound according to  claim 9 , wherein R 3  is propyl(methyl)amino or ethyl(methyl)amino. 
     
     
         11 . A compound according to any one of  claims 1 ,  2 ,  6  and  9 , wherein:
 R 1  is C 1-6 alkyl; 
 R 2  is benzyl, said benzyl being substituted by halogen or C 1-6 alkyl; 
 R 3  is —NR 4 R 5 , wherein R 4  is C 1-6 alkyl, R 5  is C 1-6 alkyl. 
 
     
     
         12 . A compound according to  claim 11 , wherein:
 R 1  is ethyl;   R 2  is methylbenzyl, bromobenzyl, chlorobenzyl or fluorobenzyl;   R 3  is propyl(methyl)amino or ethyl(methyl)amino.   
     
     
         13 . A compound selected from:
 6-amino-9-benzyl-N-methyl-8-oxo-N-propyl-2-(propylsulfonimidoyl)purine-7-carboxamide;   6-amino-9-benzyl-N-(2-methoxyethyl)-N-methyl-8-oxo-2-(propylsulfonimidoyl)purine-7-carboxamide;   6-amino-9-benzyl-N-ethyl-8-oxo-N-propyl-2-(propylsulfonimidoyl)purine-7-carboxamide;   6-amino-9-benzyl-7-[4-(1-piperidyl)piperidine-1-carbonyl]-2-(propylsulfonimidoyl)purin-8-one;   6-amino-9-benzyl-N-ethyl-N-(2-methoxyethyl)-8-oxo-2-(propylsulfonimidoyl)purine-7-carboxamide;   6-amino-9-benzyl-N-butyl-N-ethyl-8-oxo-2-(propylsulfonimidoyl)purine-7-carboxamide;   6-amino-9-benzyl-N-(2-methoxyethyl)-8-oxo-N-propyl-2-(propylsulfonimidoyl)purine-7-carboxamide;   6-amino-9-benzyl-N,N-bis(2-methoxyethyl)-8-oxo-2-(propylsulfonimidoyl)purine-7-carboxamide;   6-amino-7-(azetidine-1-carbonyl)-9-benzyl-2-(propylsulfonimidoyl)purin-8-one;   6-amino-9-benzyl-N-isopropyl-N-methyl-8-oxo-2-(propylsulfonimidoyl)purine-7-carboxamide;   6-amino-9-benzyl-7-(4-methylpiperazine-1-carbonyl)-2-(propylsulfonimidoyl)purin-8-one;   6-amino-9-benzyl-N-(3-methoxypropyl)-N-methyl-8-oxo-2-(propylsulfonimidoyl)purine-7-carboxamide;   6-amino-9-benzyl-N-isobutyl-N-methyl-8-oxo-2-(propylsulfonimidoyl)purine-7-carboxamide;   ethyl 2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purine-7-carbonyl]-methyl-amino]acetate;   ethyl 3-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purine-7-carbonyl]-methyl-amino]propanoate;   tert-butyl 3-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purine-7-carbonyl]-methyl-amino]propanoate;   ethyl (2S)-2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purine-7-carbonyl]-methyl-amino]propanoate;   tert-butyl (2S)-2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purine-7-carbonyl]-methyl-amino]-4-methyl-pentanoate;   isopropyl (2S)-2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purine-7-carbonyl]-methyl-amino]-4-methyl-pentanoate;   ethyl (2S)-2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purine-7-carbonyl]-methyl-amino]-3-methyl-butanoate;   ethyl (2S)-2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purine-7-carbonyl]-methyl-amino]-4-methyl-pentanoate;   ethyl (2S)-2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purine-7-carbonyl]-methyl-amino]-3-phenyl-propanoate;   isopropyl (2S)-2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purine-7-carbonyl]-methyl-amino]-3-phenyl-propanoate;   tert-butyl (2S)-2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purine-7-carbonyl]-methyl-amino]-3-phenyl-propanoate;   N-[2-[acetyl(methyl)amino]ethyl]-6-amino-9-benzyl-N-methyl-8-oxo-2-(propylsulfonimidoyl)purine-7-carboxamide;   Methyl N-[2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purine-7-carbonyl]-methyl-amino]ethyl]-N-methyl-carbamate;   tert-Butyl N-[2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purine-7-carbonyl]-methyl-amino]ethyl]-N-methyl-carbamate;   ethyl N-[2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purine-7-carbonyl]-methyl-amino]ethyl]-N-methyl-carbamate;   2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purine-7-carbonyl]-methyl-amino]ethyl N-butyl-N-methyl-carbamate;   2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purine-7-carbonyl]-methyl-amino]ethyl pyrrolidine-1-carboxylate;   2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purine-7-carbonyl]-methyl-amino]ethyl N-methyl-N-propyl-carbamate;   2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purine-7-carbonyl]-methyl-amino]ethyl N,N-diethylcarbamate;   2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purine-7-carbonyl]-methyl-amino]ethyl ethyl carbonate;   6-amino-N-butyl-9-[(4-chlorophenyl)methyl]-N-methyl-8-oxo-2-[S(S)-propylsulfonimidoyl]purine-7-carboxamide;   6-amino-N-butyl-9-[(4-chlorophenyl)methyl]-N-methyl-8-oxo-2-[S(S)-propylsulfonimidoyl]purine-7-carboxamide;   6-amino-9-[(4-chlorophenyl)methyl]-N-ethyl-N-methyl-8-oxo-2-(propylsulfonimidoyl)purine-7-carboxamide;   6-amino-N-methyl-8-oxo-N-propyl-2[S(S)-propylsulfonimidoyl]-9-(p-tolylmethyl)purine-7-carboxamide;   6-amino-N-methyl-8-oxo-N-propyl-2[S(R)-propylsulfonimidoyl]-9-(p-tolylmethyl)purine-7-carboxamide;   6-amino-2-[S(S)-propylsulfonimidoyl]-9-(p-tolylmethyl)-7-(pyrrolidine-1-carbonyl)purin-8-one;   6-amino-2-[S(R)-propylsulfonimidoyl]-9-(p-tolylmethyl)-7-(pyrrolidine-1-carbonyl)purin-8-one;   6-amino-N-(2-methoxyethyl)-N-methyl-8-oxo-2-[S(S)-propylsulfonimidoyl]-9-(p-tolylmethyl)purine-7-carboxamide;   6-amino-N-(2-methoxyethyl)-N-methyl-8-oxo-2-[S(R)-propylsulfonimidoyl]-9-(p-tolylmethyl)purine-7-carboxamide;   6-amino-N-ethyl-N-methyl-8-oxo-2-(propyl sulfonimidoyl)-9-(p-tolylmethyl)purine-7-carboxamide;   6-amino-N-butyl-N-methyl-8-oxo-2-(propylsulfonimidoyl)-9-(p-tolylmethyl)purine-7-carboxamide;   6-amino-9-[(4-chlorophenyl)methyl]-2-[S(R)-ethylsulfonimidoyl]-N-methyl-8-oxo-N-propyl-purine-7-carboxamide;   6-amino-9-[(4-chlorophenyl)methyl]-2-[S(S)-ethylsulfonimidoyl]-N-methyl-8-oxo-N-propyl-purine-7-carboxamide;   6-amino-9-[(4-chlorophenyl)methyl]-N-ethyl-2[S(S)-ethylsulfonimidoyl]-N-methyl-8-oxo-purine-7-carboxamide;   6-amino-9-[(4-chlorophenyl)methyl]-N-ethyl-2-[S(R)-ethylsulfonimidoyl]-N-methyl-8-oxo-purine-7-carboxamide;   6-amino-2-[S(S)-ethylsulfonimidoyl]-N-methyl-8-oxo-N-propyl-9-(p-tolylmethyl)purine-7-carboxamide;   6-amino-2-[S(R)-ethylsulfonimidoyl]-N-methyl-8-oxo-N-propyl-9-(p-tolylmethyl)purine-7-carboxamide;   6-amino-N-ethyl-2[S(S)-ethylsulfonimidoyl]-N-methyl-8-oxo-9-(p-tolylmethyl)purine-7-carboxamide;   6-amino-N-ethyl-2-[S(R)-ethylsulfonimidoyl]-N-methyl-8-oxo-9-(p-tolylmethyl)purine-7-carboxamide;   6-amino-2-[S(S)ethylsulfonimidoyl]-9-[(4-fluorophenyl)methyl]-N-methyl-8-oxo-N-propyl-purine-7-carboxamide;   6-amino-2-[S(R)ethylsulfonimidoyl]-9-[(4-fluorophenyl)methyl]-N-methyl-8-oxo-N-propyl-purine-7-carboxamide;   6-amino-N-ethyl-2-(ethylsulfonimidoyl)-9-[(4-fluorophenyl)methyl]-N-methyl-8-oxo-purine-7-carboxamide;   6-amino-N-ethyl-2-[S(S)-(ethylsulfonimidoyl)]-9-[(4-fluorophenyl)methyl]-N-methyl-8-oxo-purine-7-carboxamide;   6-amino-N-ethyl-2-[S(R)-(ethylsulfonimidoyl)]-9-[(4-fluorophenyl)methyl]-N-methyl-8-oxo-purine-7-carboxamide;   6-amino-9-[(4-bromophenyl)methyl]-2-(ethylsulfonimidoyl)-N-methyl-8-oxo-N-propyl-purine-7-carboxamide;   6-amino-2-[S(R)-ethylsulfonimidoyl]-9-[(4-bromophenyl)methyl]-N-methyl-8-oxo-N-propyl-purine-7-carboxamide;   6-amino-2-[S(S)-ethylsulfonimidoyl]-9-[(4-bromophenyl)methyl]-N-methyl-8-oxo-N-propyl-purine-7-carboxamide;   6-amino-9-[(4-bromophenyl)methyl]-N-ethyl-2-(ethylsulfonimidoyl)-N-methyl-8-oxo-purine-7-carboxamide;   6-amino-9-[(4-bromophenyl)methyl]-N-ethyl-2-[S(S)-(ethylsulfonimidoyl)]-N-methyl-8-oxo-purine-7-carboxamide; and   6-amino-9-[(4-bromophenyl)methyl]-N-ethyl-2-[S(R)-(ethylsulfonimidoyl)]-N-methyl-8-oxo-purine-7-carboxamide;   or pharmaceutically acceptable salt, enantiomer or diastereomer thereof.   
     
     
         14 . A compound according to  claim 13 , selected from:
 6-amino-9-benzyl-N-methyl-8-oxo-N-propyl-2-(propylsulfonimidoyl)purine-7-carboxamide;   6-amino-9-[(4-chlorophenyl)methyl]-2-[S(R)-ethylsulfonimidoyl]-N-methyl-8-oxo-N-propyl-purine-7-carboxamide;   6-amino-9-[(4-chlorophenyl)methyl]-2-[S(S)-ethylsulfonimidoyl]-N-methyl-8-oxo-N-propyl-purine-7-carboxamide;   6-amino-9-[(4-chlorophenyl)methyl]-N-ethyl-2[S(S)-ethylsulfonimidoyl]-N-methyl-8-oxo-purine-7-carboxamide;   6-amino-9-[(4-chlorophenyl)methyl]-N-ethyl-2-[S(R)-ethylsulfonimidoyl]-N-methyl-8-oxo-purine-7-carboxamide;   6-amino-2-[S(S)-ethylsulfonimidoyl]-N-methyl-8-oxo-N-propyl-9-(p-tolylmethyl)purine-7-carboxamide;   6-amino-2-[S(R)-ethylsulfonimidoyl]-N-methyl-8-oxo-N-propyl-9-(p-tolylmethyl)purine-7-carboxamide;   6-amino-N-ethyl-2[S(S)-ethylsulfonimidoyl]-N-methyl-8-oxo-9-(p-tolylmethyl)purine-7-carboxamide;   6-amino-N-ethyl-2-[S(R)-ethylsulfonimidoyl]-N-methyl-8-oxo-9-(p-tolylmethyl)purine-7-carboxamide;   6-amino-2-(ethylsulfonimidoyl)-9-[(4-fluorophenyl)methyl]-N-methyl-8-oxo-N-propyl-purine-7-carboxamide;   6-amino-2-[S(S)ethylsulfonimidoyl]-9-[(4-fluorophenyl)methyl]-N-methyl-8-oxo-N-propyl-purine-7-carboxamide; and   6-amino-2-[S(R)ethylsulfonimidoyl]-9-[(4-fluorophenyl)methyl]-N-methyl-8-oxo-N-propyl-purine-7-carboxamide;   or pharmaceutically acceptable salt, enantiomer or diastereomer thereof.   
     
     
         15 . A process for preparing a compound according to any one of  claims 1  to  14 , the process comprising the following step:
 the reaction of a compound of formula (II), 
 
       
         
           
           
               
               
           
         
         with carbamoyl chloride in the presence of a mixed base; 
         wherein the mixed base is pyridine and triethylamine, pyridine and DIPEA, DMAP and triethylamine, or DMAP and DIPEA; R 1  and R 2  are defined as in any one of  claims 1  to  14 . 
       
     
     
         16 . A compound or pharmaceutically acceptable salt, enantiomer or diastereomer according to any one of  claims 1  to  14  for use as therapeutically active substance. 
     
     
         17 . A pharmaceutical composition comprising a compound in accordance with any one of  claims 1  to  14  and a therapeutically inert carrier. 
     
     
         18 . The use of a compound according to any one of  claims 1  to  14  for the treatment or prophylaxis of hepatitis B virus infection. 
     
     
         19 . The use of a compound according to any one of  claims 1  to  14  for the preparation of a medicament for the treatment or prophylaxis of hepatitis B virus infection. 
     
     
         20 . The use of a compound according to any one of  claims 1  to  14  as the TLR7 agonist. 
     
     
         21 . The use of a compound according to any one of  claims 1  to  14  to induce production of interferon-α. 
     
     
         22 . A compound or pharmaceutically acceptable salt, enantiomer or diastereomer according to any one of  claims 1  to  14  for the treatment or prophylaxis of hepatitis B virus infection. 
     
     
         23 . A compound or pharmaceutically acceptable salt, enantiomer or diastereomer according to any one of  claims 1  to  14 , when manufactured according to a process of  claim 15 . 
     
     
         24 . 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  14 .