Thienopyridine derivatives for the treatment and prevention of dengue virus infections

Abstract

Methods and pharmaceutical compositions for treating viral infections, by administering certain thienopyridine derivative compounds in therapeutically effective amounts are disclosed. Methods of using the compounds and pharmaceutical compositions thereof are also disclosed. In particular, the treatment and prophylaxis of viral infections such as caused by flavivirus is disclosed, i.e., including but not limited to, Dengue virus, West Nile virus, yellow fever virus, Japanese encephalitis virus, and tick-borne encephalitis virus.

1 .- 11 . (canceled) 
     
     
         12 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the following general Formula II or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein X is selected from the groups consisting of O, S or N—R′, wherein R′ is selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl; 
         B is N or C—R 2 , wherein R 2  is selected from the groups consisting of hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, hydroxy, alkyloxy, aryloxy, heteroaryloxy, acyloxy, arylacyloxy, heteroarylacyloxy, alkylsulfonyloxy, arylsulfonyloxy, thio, alkylthio, arylthio, amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, acylamino, arylacylamino, heteroarylacylamino, alkylsulfonylamino, arylsulfonylamino, acyl, arylacyl, heteroarylacyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, substituted aminosulfonyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl, substituted carbamoyl, halogen, cyano, isocyano and nitro; 
         G is selected from the group consisting of —C(═O)—, —C(═S)—, —S(═O) 2 —, and —C(═NR 5 )—, wherein R 5  is selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl; or R 5  and R 6  or R 7 , together with the nitrogen atoms they are attached to, along with the carbon of G, or R 5  and R 8  or R 9 , together with the nitrogen atoms they are attached to, along with the carbon of G and two carbons of the X-containing 5-membered ring, may form a substituted or unsubstituted ring, which may be fused with an aromatic or aliphatic ring; 
         R 6 , R 7 , R 8 , and R 9  are independently selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl; or R 6  or R 7  and R 5 , together with the nitrogen atoms they are attached to, along with the carbon of G, or R 8  or R 9  and R 5 , together with the nitrogen atoms they are attached to, along with the carbon of G and two carbons of the X-containing 5-membered ring, or R 6  or R 7  and R 8  or R 9 , together with the nitrogen atoms they are attached to, along with the carbon or sulfur of G and two carbons of the X-containing 5-membered ring, or R 6  and R 7 , together with the nitrogen atom they are attached to, or R 8  and R 9 , together with the nitrogen atom they are attached to, may form a substituted or unsubstituted ring, which may be fused with an aromatic or aliphatic ring; and 
       
       
         
           
           
               
               
           
         
       
       is a 7 or 8-membered ring which contains one or more heteroatoms selected from N, O and S, or a 4-membered ring which may optionally contain one or more heteroatoms selected from N, O and S. The ring may be substituted or unsubstituted, or fused with another ring, which may be aromatic or non-aromatic and may include one or more heteroatoms in the ring and may be fused with an aromatic or aliphatic ring. 
     
     
         13 . The composition of  claim 12 , wherein X is S. 
     
     
         14 . The composition of  claim 12 , wherein B is CH. 
     
     
         15 . The composition of  claim 12 , wherein each of R 8  and R 9  is H. 
     
     
         16 . The composition of  claim 12 , wherein G is —C(═O)—. 
     
     
         17 . The composition of  claim 12 , wherein R 6  is a hydrogen and R 7  is a heteroaryl. 
     
     
         18 . The composition of  claim 12 , wherein 
       
         
           
           
               
               
           
         
       
       is a 7-membered ring which contains N as a heteroatom. 
     
     
         19 . The composition of  claim 12  being 3-amino-6,7,8,9-tetrahydro-5H-1-thia-6,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-yl)-amide. 
     
     
         20 . The composition of claim  1  being 3-amino-6,7,8,9-tetrahydro-5H-1-thia-7,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-yl)-amide. 
     
     
         21 .- 43 . (canceled) 
     
     
         44 . A method for the treatment or prophylaxis of a viral infection or disease associated therewith, comprising administering in a therapeutically effective amount to a mammal in need thereof, a compound of Formula II below or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein X is selected from the groups consisting of O, S or N—R′, wherein R′ is selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl; 
         B is N or C—R 2 , wherein R 2  is selected from the groups consisting of hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, hydroxy, alkyloxy, aryloxy, heteroaryloxy, acyloxy, arylacyloxy, heteroarylacyloxy, alkylsulfonyloxy, arylsulfonyloxy, thio, alkylthio, arylthio, amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, acylamino, arylacylamino, heteroarylacylamino, alkylsulfonylamino, arylsulfonylamino, acyl, arylacyl, heteroarylacyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, substituted aminosulfonyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl, substituted carbamoyl, halogen, cyano, isocyano and nitro; 
         G is selected from the group consisting of —C(═O)—, —C(═S)—, —S(═O) 2 —, and —C(═NR 5 )—, wherein R 5  is selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl; or R 5  and R 6  or R 7 , together with the nitrogen atoms they are attached to, along with the carbon of G, or R 5  and R 8  or R 9 , together with the nitrogen atoms they are attached to, along with the carbon of G and two carbons of the X-containing 5-membered ring, may form a substituted or unsubstituted ring, which may be fused with an aromatic or aliphatic ring; 
         R 6 , R 7 , R 8 , and R 9  are independently selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl; or R 6  or R 7  and R 5 , together with the nitrogen atoms they are attached to, along with the carbon of G, or R 8  or R 9  and R 5 , together with the nitrogen atoms they are attached to, along with the carbon of G and two carbons of the X-containing 5-membered ring, or R 6  or R 7  and R 8  or R 9 , together with the nitrogen atoms they are attached to, along with the carbon or sulfur of G and two carbons of the X-containing 5-membered ring, or R 6  and R 7 , together with the nitrogen atom they are attached to, or R 8  and R 9 , together with the nitrogen atom they are attached to, may form a substituted or unsubstituted ring, which may be fused with an aromatic or aliphatic ring; and 
       
       
         
           
           
               
               
           
         
       
       is a 7 or 8-membered ring which contains one or more heteroatoms selected from N, O and S, or a 4-membered ring which may optionally contain one or more heteroatoms selected from N, O and S. The ring may be substituted or unsubstituted, or fused with another ring, which may be aromatic or non-aromatic and may include one or more heteroatoms in the ring and may be fused with an aromatic or aliphatic ring. 
     
     
         45 . The method of  claim 44 , wherein X is S. 
     
     
         46 . The method of  claim 44 , wherein B is CH. 
     
     
         47 . The method of  claim 44 , wherein each of R 8  and R 9  is H. 
     
     
         48 . The method of  claim 44 , wherein G is —C(═O)—. 
     
     
         49 . The method of  claim 44 , wherein R 6  is a hydrogen and R 7  is a heteroaryl. 
     
     
         50 . The method of  claim 44 , wherein 
       
         
           
           
               
               
           
         
       
       is a 7-membered ring which contains N as a heteroatom. 
     
     
         51 . The method of  claim 44 , wherein the compound of Formula II is 3-amino-6,7,8,9-tetrahydro-5H-1-thia-6,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-yl)-amide. 
     
     
         52 . The method of  claim 44 , wherein the compound of Formula II is 3-amino-6,7,8,9-tetrahydro-5H-1-thia-7,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-yl)-amide. 
     
     
         53 . The method of  claim 44 , wherein the mammal is a human. 
     
     
         54 . The method of  claim 44 , wherein the viral infection is a flavivirus infection. 
     
     
         55 . The method of  claim 54 , wherein the flavivirus virus is selected from the group consisting of Dengue virus, West Nile virus, yellow fever virus, Japanese encephalitis virus, and tick-borne encephalitis virus. 
     
     
         56 . The method of  claim 54 , wherein said viral infection is associated with a condition selected from the group consisting of Dengue fever, Yellow fever, West Nile, St. Louis encephalitis, Hepatitis C, Murray Valley encephalitis, and Japanese encephalitis. 
     
     
         57 . The method of  claim 55 , wherein said virus is a Dengue virus. 
     
     
         58 . The method of  claim 57 , wherein said Dengue virus is selected from the group consisting of DEN-1, DEN-2, DEN-3, and DEN-4. 
     
     
         59 . The method of  claim 57 , wherein said viral infection is associated with Dengue fever. 
     
     
         60 . The method of  claim 59 , wherein said Dengue fever is selected from the group consisting of classical dengue fever, dengue hemorrhagic fever syndrome, and dengue shock syndrome. 
     
     
         61 . The method of  claim 44 , which further comprises co-administration of at least one agent selected from the group consisting of antiviral agent, vaccine, and interferon. 
     
     
         62 . The method of  claim 61 , wherein said antiviral agent is Ribavirin. 
     
     
         63 . The method of  claim 61 , wherein said antiviral agent is cidofovir. 
     
     
         64 . The method of  claim 61 , wherein said interferon is pegylated. 
     
     
         65 . A compound having the following general Formula II or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein X is selected from the groups consisting of O, S or N—R′, wherein R′ is selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl; 
         B is N or C—R 2 , wherein R 2  is selected from the groups consisting of hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, hydroxy, alkyloxy, aryloxy, heteroaryloxy, acyloxy, arylacyloxy, heteroarylacyloxy, alkylsulfonyloxy, arylsulfonyloxy, thio, alkylthio, arylthio, amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, acylamino, arylacylamino, heteroarylacylamino, alkylsulfonylamino, arylsulfonylamino, acyl, arylacyl, heteroarylacyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, substituted aminosulfonyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl, substituted carbamoyl, halogen, cyano, isocyano and nitro; 
         G is selected from the group consisting of —C(═O)—, —C(═S)—, —S(═O) 2 —, and —C(═NR 5 )—, wherein R 5  is selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl; or R 5  and R 6  or R 7 , together with the nitrogen atoms they are attached to, along with the carbon of G, or R 5  and R 8  or R 9 , together with the nitrogen atoms they are attached to, along with the carbon of G and two carbons of the X-containing 5-membered ring, may form a substituted or unsubstituted ring, which may be fused with an aromatic or aliphatic ring; 
         R 6 , R 7 , R 8 , and R 9  are independently selected from the groups consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl; or R 6  or R 7  and R 5 , together with the nitrogen atoms they are attached to, along with the carbon of G, or R 8  or R 9  and R 5 , together with the nitrogen atoms they are attached to, along with the carbon of G and two carbons of the X-containing 5-membered ring, or R 6  or R 7  and R 8  or R 9 , together with the nitrogen atoms they are attached to, along with the carbon or sulfur of G and two carbons of the X-containing 5-membered ring, or R 6  and R 7 , together with the nitrogen atom they are attached to, or R 8  and R 9 , together with the nitrogen atom they are attached to, may form a substituted or unsubstituted ring, which may be fused with an aromatic or aliphatic ring; and 
       
       
         
           
           
               
               
           
         
       
       is a 7 or 8-membered ring which contains one or more heteroatoms selected from N, O and S, or a 4-membered ring which may optionally contain one or more heteroatoms selected from N, O and S. The ring may be substituted or unsubstituted, or fused with another ring, which may be aromatic or non-aromatic and may include one or more heteroatoms in the ring and may be fused with an aromatic or aliphatic ring. 
     
     
         66 . The compound of  claim 65 , wherein X is S. 
     
     
         67 . The compound of  claim 65 , wherein B is CH. 
     
     
         68 . The compound of  claim 65 , wherein each of R 8  and R 9  is H. 
     
     
         69 . The compound of  claim 65 , wherein G is —C(═O)—. 
     
     
         70 . The compound of  claim 65 , wherein R 6  is a hydrogen and R 7  is a heteroaryl. 
     
     
         71 . The compound of  claim 65 , wherein 
       
         
           
           
               
               
           
         
       
       is a 7-membered ring which contains N as a heteroatom. 
     
     
         72 . The compound of  claim 65  being 3-amino-6,7,8,9-tetrahydro-5H-1-thia-6,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-yl)-amide. 
     
     
         73 . The compound of  claim 65  being 3-amino-6,7,8,9-tetrahydro-5H-1-thia-7,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-yl)-amide. 
     
     
         74 . A compound selected from the group consisting of: tert-butyl (4E)-4-(hydroxymethylene)-5-oxoazepane-1-carboxylate; tert-butyl (3E)-3-(hydroxymethylene)-4-oxoazepane-1-carboxylate; tert-butyl 3-cyano-2-thioxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate; tert-butyl 3-cyano-2-thioxo-1,2,5,7,8,9-hexahydro-6H-pyrido[3,2-c]azepine-6-carboxylate; and 3-amino-7-tert-butyloxycarbonyl-6,7,8,9-tetrahydro-5H-1-thia-7,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-yl)-amide; and 3-amino-6-tert-butyloxycarbonyl-6,7,8,9-tetrahydro-5H-1-thia-6,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-O-amide. 
     
     
         75 . A method for the preparation of a mixture of tert-butyl (4E)-4-(hydroxymethylene)-5-oxoazepane-1-carboxylate and tert-butyl (3E)-3-(hydroxymethylene)-4-oxoazepane-1-carboxylate, said method comprising reacting tert-butyl 4-oxoazepane-1-carboxylate with N-[tert-butoxy(dimethylamino)methyl]-N,N-dimethylamine. 
     
     
         76 . A method for the preparation of a mixture of tert-butyl 3-cyano-2-thioxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate and tert-butyl 3-cyano-2-thioxo-1,2,5,7,8,9-hexahydro-6H-pyrido[3,2-c]azepine-6-carboxylate said method comprising reacting a mixture of tert-butyl (4E)-4-(hydroxymethylene)-5-oxoazepane-1-carboxylate and tert-butyl (3E)-3-(hydroxymethylene)-4-oxoazepane-1-carboxylate in the presence of 2-cyanoethanethioamide and piperidine acetate. 
     
     
         77 . A method for the preparation of 3-amino-7-tert-butyloxycarbonyl-6,7,8,9-tetrahydro-5H-1-thia-7,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-yl)-amide comprising reacting tert-butyl 3-cyano-2-thioxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate with 2-chloro-N-(5-phenyl-1,3,4-thiadiazol-2-yl)acetamide. 
     
     
         78 . A method for the preparation of 3-amino-6,7,8,9-tetrahydro-5H-1-thia-7,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-yl)-amide comprising reacting 3-amino-7-tert-butyloxycarbonyl-6,7,8,9-tetrahydro-5H-1-thia-7,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-yl)-amide with HCl. 
     
     
         79 . A method for the preparation of 3-amino-6-tert-butyloxycarbonyl-6,7,8,9-tetrahydro-5H-1-thia-6,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-yl)-amide comprising reacting tert-butyl 3-cyano-2-thioxo-1,2,5,7,8,9-hexahydro-6H-pyrido[3,2-c]azepine-6-carboxylate with 2-chloro-N-(5-phenyl-1,3,4-thiadiazol-2-yl)acetamide. 
     
     
         80 . A method for the preparation of 3-amino-6,7,8,9-tetrahydro-5H-1-thia-6,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-yl)-amide comprising reacting 3-amino-6-tert-butyloxycarbonyl-6,7,8,9-tetrahydro-5H-1-thia-6,10-diaza-cyclohepta[f]indene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-yl)-amide with HCl.