Novel heterocyclic compounds having anti-hbv activity

Abstract

This application relates to novel fused tricyclic thienopyridines of Formulas I and II, which useful for treating Hepatitis B infection and other diseases. This application also relates to pharmaceutical compositions comprising thienopyridines and to the use of such compositions to treat Hepatitis B and other diseases.

1 . A compound of Formula I 
     
       
         
         
             
             
         
       
       wherein A is S, O, or N(CH 3 ); 
       R 1  and R 2  are, independently, H, CH 3 , CF 3 , or CH 3 O; 
       R 3  is H;
 or R 3  is a 5- or 6-membered ring, said ring optionally containing one or more double bonds, optionally containing 1-3 ring heteroatoms independently selected from O, N, and S, and optionally substituted with one or two groups independently selected from CH 3 , OCH 3 , CO 2 CH 3 , OC(O)CH 3 , CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms; 
 or R 3  is C 1-6  alkyl, C 1-6  alkanoyl, C 1-6  alkenyl, C 1-6  alkoxy, C 1-6  alkenoxy, wherein said alkyl groups, the alkyl moieties of said alkanoyl and said alkoxy groups, said alkenyl groups, and the alkenyl moieties of said alkenoxy groups may be straight-chain, branched, or cyclic, and can all optionally be substituted as follows:
 a) with one, two, or three halogen atoms; 
 b) with one or two substituents independently selected from hydroxy, carboxyl, cyano, benzyl, benzoyl, and benzoyloxy; 
 c) with one saturated, unsaturated, or aromatic 5- or 6-membered ring containing 0-3 heteroatoms selected from N, O, and S, said ring optionally substituted with one or two groups independently selected from CH 3 , OCH 3 , C(O)CH 3 , CO 2 CH 3 , OC(O)CH 3 , CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms; and 
 d) with one group selected from C 1-6  alkanoyl, C 1-6  alkoxycarbonyl, C 1-6  alkylcarbamoyl, ethylcarbamoylmethyl, methylcarbamoylmethyl, 2-hydroxy-2-phenyl-ethylcarbamoylmethyl, or N-phthalimido; 
 
 or R 3  is R 4 NHC(O), R 4 NHC(S), or R 4 NHCH 2 C(O), wherein R 4  is C 1-6  alkyl, wherein said alkyl group may be straight-chain, branched, or cyclic, and is optionally substituted as described for R 3  alkyl groups, or R 4  is a five- or 6-membered aromatic ring containing 0-3 heteroatoms independently selected from O, N, and S, all R 4  optionally substituted with one or two substituents independently selected from halo, methyl, and benzyl, wherein all rings are optionally substituted with one or two groups independently selected from CH 3 , OCH 3 , CO 2 CH 3 , OC(O)CH 3 , CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms; 
 
       and m and n are, independently, 1 or 2, provided that m and n are not both 2; 
       and further provided that when n=1, m=2, and R 1  and R 2  are both H, then R 3  is not methyl. 
     
   
   
       2 . The compound of  claim 1 , wherein A is S, n is 1, m is 1, R 1  is H, and R 2  is H or CH 3 . 
   
   
       3 . The compound of  claim 2 , wherein R 3  is H or C 1-6  alkyl, optionally substituted with one or two substituents independently selected from halo, hydroxy, cyano, phenyl, pyridyl, benzoyl, benzoyl methyl, benzoyloxy, C 1-6  alkoxycarbonyl, C 1-6  alkylcarbamoyl, N-phthalimido, or R 3  is a 5- or 6-membered aromatic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein all rings are optionally substituted with one or two substituents independently selected from halo, CH 3 , CH 3 O, CN, CF 3 , and CH 3 C(O), wherein all methyl groups are optionally substituted 1-3 chlorine atoms. 
   
   
       4 . The compound of  claim 3 , wherein R 3  is C 1-4  alkyl, optionally monosubstituted with halogen, hydroxy, phenyl, benzyl, pyridyl, and pyridyl methyl, wherein the phenyl and pyridyl rings are optionally further monosubstituted with methyl or halogen. 
   
   
       5 . The compound of  claim 2 , wherein R 3  is R 4 NHC(O), R 4 NHC(S), or R 4 NHCH 2 C(O), wherein R 4  is C 1-6  alkyl, wherein said alkyl group may be straight-chain, branched, or cyclic, and is optionally substituted as described for R 3  alkyl groups, or R 4  is a five- or 6-membered aromatic ring containing 0-3 heteroatoms independently selected from O, N, and S, all R 4  optionally substituted with one or two substituents independently selected from halo, methyl, and benzyl, wherein all rings are optionally substituted with one or two groups independently selected from CH 3 , OCH 3 , CO 2 CH 3 , OC(O)CH 3 , CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms. 
   
   
       6 . The compound of  claim 1 , wherein A is S, n is 2, m is 1, R 1  is H, and R 2  is H or CH 3 . 
   
   
       7 . The compound of  claim 6 , wherein R 3  is H or C 1-4  alkyl. 
   
   
       8 . The compound of  claim 1 , wherein A is 0, n is 1, m is 1, R 1  is H, and R 2  is H or CH 3 . 
   
   
       9 . The compound of  claim 8 , wherein R 3  is H or C 1-6  alkyl, optionally substituted with one or two substituents independently selected from halo, hydroxy, cyano, phenyl, pyridyl, benzoyl, benzoyl methyl, benzoyloxy, C 1-6  alkoxycarbonyl, C 1-6  alkylcarbamoyl, N-phthalimido, or R 3  is a 5- or 6-membered aromatic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein all rings are optionally substituted with one or two substituents independently selected from halo, CH 3 , CH 3 O, CN, CF 3 , and CH 3 C(O), wherein all methyl groups are optionally substituted 1-3 chlorine atoms. 
   
   
       10 . The compound of  claim 9 , wherein R 3  is C 1-4  alkyl, optionally monosubstituted with halogen, hydroxy, phenyl, benzyl, pyridyl, and pyridyl methyl, wherein the phenyl and pyridyl rings are optionally further monosubstituted with methyl or halogen. 
   
   
       11 . The compound of  claim 8 , wherein R 3  is R 4 NHC(O), R 4 NHC(S), or R 4 NHCH 2 C(O), wherein R 4  is C 1-6  alkyl, wherein said alkyl group may be straight-chain, branched, or cyclic, and is optionally substituted as described for R 3  alkyl groups, or R 4  is a five- or 6-membered aromatic ring containing 0-3 heteroatoms independently selected from O, N, and S, all R 4  optionally substituted with one or two substituents independently selected from halo, methyl, and benzyl, wherein all rings are optionally substituted with one or two groups independently selected from CH 3 , OCH 3 , CO 2 CH 3 , OC(O)CH 3 , CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms. 
   
   
       12 . A compound of Formula II 
     
       
         
         
             
             
         
       
       wherein n is zero, 1, 2, or 3; A is S, O, or N(CH 3 ); 
       B and B′ are either both H or jointly oxo; 
       R 1  and R 2  are, independently, H, CH 3 , CF 3 , or CH 3 O; 
       R 3  is H;
 or R 3  is a 5- or 6-membered ring, said ring optionally containing one or more double bonds, optionally containing 1-3 ring heteroatoms independently selected from O, N, and S, and optionally substituted with one or two groups independently selected from CH 3 , OCH 3 , CO 2 CH 3 , OC(O)CH 3 , CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms; 
 or R 3  is C 1-6  alkyl, C 1-6  alkanoyl, C 1-6  alkenyl, C 1-6  alkoxy, C 1-6  alkenoxy, wherein said alkyl groups, the alkyl moieties of said alkanoyl and said alkoxy groups, said alkenyl groups, and the alkenyl moieties of said alkenoxy groups may be straight-chain, branched, or cyclic, and may optionally be substituted as follows:
 a) with one, two, or three halogen atoms; 
 b) with one or two substituents independently selected from hydroxy, carboxyl, cyano, benzyl, benzoyl, and benzoyloxy; 
 c) with one saturated, unsaturated, or aromatic 5- or 6-membered ring containing 0-3 heteroatoms selected from N, O, and S, said ring optionally substituted with one or two groups independently selected from CH 3 , OCH 3 , C(O)CH 3 , CO 2 CH 3 , OC(O)CH 3 , CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms; and 
 d) with one group selected from C 1-6  alkanoyl, C 1-6  alkoxycarbonyl, C 1-6  alkylcarbamoyl, ethylcarbamoylmethyl methylcarbamoylmethyl, 2-hydroxy-2-phenyl-ethylcarbamoylmethyl, or N-phthalimido; 
 
 or R 3  is R 4 NHC(O), R 4 NHC(S), or R 4 NHCH 2 C(O), wherein R 4  is C 1-6  alkyl, wherein said alkyl group may be straight-chain, branched, or cyclic, and is optionally substituted as described for R 3  alkyl groups, or R 4  is a five- or 6-membered aromatic ring containing 0-3 heteroatoms independently selected from O, N, and S, all R 4  optionally substituted with one or two substituents independently selected from halo, methyl, and benzyl, wherein all rings are optionally substituted with one or two groups independently selected from CH 3 , OCH 3 , CO 2 CH 3 , OC(O)CH 3 , CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms; and 
 
       R 5  is H or C 3  alkyl; or 
       R 3  and R 5 , together with the ring carbon atoms to which they are attached, form an additional fused 5- or 6-membered cycloalkyl group; 
       provided that when A is O or S, then R 1 , R 2 , R 3 , B, and B′ are not all H, and further 
       provided that when A is S and R 1  is methyl, then R 2 , R 3 , B, and B′ are not all H. 
     
   
   
       13 . A compound according to  claim 12 , wherein A is S, R 5  is H; and wherein
 R 3  is selected from H, C 1-4  alkyl, C 1-4  alkenyl, or C 1-6  alkoxy, wherein said alkyl groups, the alkyl moieties of said alkoxy groups, and said alkenyl groups may be straight-chain, branched, or cyclic, and are optionally substituted with one or two substituents independently selected from halo, hydroxy, ethylcarbamoylmethyl methylcarbamoylmethyl, 2-hydroxy-2-phenyl-ethylcarbamoylmethyl, benzoyl, benzoyloxy, and a 5- or 6-membered ring, said ring optionally containing one or more double bonds, optionally containing 1-3 ring heteroatoms independently selected from O, N, and S, and optionally substituted with, independently, one or two groups independently selected from CH 3 , OCH 3 , CF 3 , and halo;   and n=0, 1, or 2.   
   
   
       14 . The compound of  claim 13 , wherein n=1 or 2, and R 3  is hydrogen, methyl, methoxy, ethoxy, or allyl. 
   
   
       15 . A method of treating an HBV infection, comprising providing in a person in need of treatment thereof a therapeutically effective concentration of a compound of Formula I or a compound of formula II, where formula I is 
     
       
         
         
             
             
         
       
       wherein A is S, O, or N(CH 3 ); 
       R 1  and R 2  are, independently, H, CH 3 , CF 3 , or CH 3 O; 
       R 3  is H;
 or R 3  is a 5- or 6-membered ring, said ring optionally containing one or more double bonds, optionally containing 1-3 ring heteroatoms independently selected from O, N, and S, and optionally substituted with one or two groups independently selected from CH 3 , OCH 3 , CO 2 CH 3 , OC(O)CH 3 , CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms; 
 or R 3  is C 1-6  alkyl, C 1-6  alkanoyl, C 1-6  alkenyl, C 1-6  alkoxy, C 1-6  alkenoxy, wherein said alkyl groups, the alkyl moieties of said alkanoyl and said alkoxy groups, said alkenyl groups, and the alkenyl moieties of said alkenoxy groups may be straight-chain, branched, or cyclic, and can all optionally be substituted as follows:
 a) with one, two, or three halogen atoms; 
 b) with one or two substituents independently selected from hydroxy, carboxyl, cyano, benzyl, benzoyl, and benzoyloxy; 
 c) with one saturated, unsaturated, or aromatic 5- or 6-membered ring containing 0-3 heteroatoms selected from N, O, and S, said ring optionally substituted with one or two groups independently selected from CH 3 , OCH 3 , C(O)CH 3 , CO 2 CH 3 , OC(O)CH 3 , CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms; and 
 d) with one group selected from C 1-6  alkanoyl, C 1-6  alkoxycarbonyl, C 1-6  alkylcarbamoyl, ethylcarbamoylmethyl methylcarbamoylmethyl, 2-hydroxy-2-phenyl-ethylcarbamoylmethyl, or N-phthalimido; 
 
 or R 3  is R 4 NHC(O), R 4 NHC(S), or R 4 NHCH 2 C(O), wherein R 4  is C 1-6  alkyl, wherein said alkyl group may be straight-chain, branched, or cyclic, and is optionally substituted as described for R 3  alkyl groups, or R 4  is a five- or 6-membered aromatic ring containing 0-3 heteroatoms independently selected from O, N, and S, all R 4  optionally substituted with one or two substituents independently selected from halo, methyl, and benzyl, wherein all rings are optionally substituted with one or two groups independently selected from CH 3 , OCH 3 , CO 2 CH 3 , OC(O)CH 3 , CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms; 
 
       and m and n are, independently, 1 or 2, provided that m and n are not both 2. 
       and where formula II is 
     
     
       
         
         
             
             
         
       
       wherein n is zero, 1, 2, or 3; A is S, O, or N(CH 3 ); 
       B and B′ are either both H or jointly oxo; 
       R 1  and R 2  are, independently, H, CH 3 , CF 3 , or CH 3 O; 
       R 3  is H;
 or R 3  is a 5- or 6-membered ring, said ring optionally containing one or more double bonds, optionally containing 1-3 ring heteroatoms independently selected from O, N, and S, and optionally substituted with one or two groups independently selected from CH 3 , OCH 3 , CO 2 CH 3 , OC(O)CH 3 , CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms; 
 or R 3  is C 1-6  alkyl, C 1-6  alkanoyl, C 1-6  alkenyl, C 1-6  alkoxy, C 1-6  alkenoxy, wherein said alkyl groups, the alkyl moieties of said alkanoyl and said alkoxy groups, said alkenyl groups, and the alkenyl moieties of said alkenoxy groups may be straight-chain, branched, or cyclic, and may optionally be substituted as follows:
 a) with one, two, or three halogen atoms; 
 b) with one or two substituents independently selected from hydroxy, carboxyl, cyano, benzyl, benzoyl, and benzoyloxy; 
 c) with one saturated, unsaturated, or aromatic 5- or 6-membered ring containing 0-3 heteroatoms selected from N, O, and S, said ring optionally substituted with one or two groups independently selected from CH 3 , OCH 3 , C(O)CH 3 , CO 2 CH 3 , OC(O)CH 3 , CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms; and 
 d) with one group selected from C 1-6  alkanoyl, C 1-6  alkoxycarbonyl, C 1-6  alkylcarbamoyl, ethylcarbamoylmethyl methylcarbamoylmethyl, 2-hydroxy-2-phenyl-ethylcarbamoylmethyl, or N-phthalimido; 
 
 
       or R 3  is R 4 NHC(O), R 4 NHC(S), or R 4 NHCH 2 C(O), wherein R 4  is C 1-6  alkyl, wherein said alkyl group may be straight-chain, branched, or cyclic, and is optionally substituted as described for R 3  alkyl groups, or R 4  is a five- or 6-membered aromatic ring containing 0-3 heteroatoms independently selected from O, N, and S, all R 4  optionally substituted with one or two substituents independently selected from halo, methyl, and benzyl, wherein all rings are optionally substituted with one or two groups independently selected from CH 3 , OCH 3 , CO 2 CH 3 , OC(O)CH 3 , CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms; and 
       R 5  is H or C 3  alkyl; or 
       R 3  and R 5 , together with the ring carbon atoms to which they are attached, form an additional fused 5- or 6-membered cycloalkyl group. 
     
   
   
       16 . The method of  claim 15 , wherein a compound of formula I is provided, where A is S, n is 1, m is 1, R 1  is H, and R 2  is H or CH 3 . 
   
   
       17 . The method of  claim 16 , wherein R 3  is H or C 1-6  alkyl, optionally substituted with one or two substituents independently selected from halo, hydroxy, cyano, phenyl, pyridyl, benzoyl, benzoyl methyl, benzoyloxy, C 1-6  alkoxycarbonyl, C 1-6  alkylcarbamoyl, N-phthalimido, or R 3  is a 5- or 6-membered aromatic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein all rings are optionally substituted with one or two substituents independently selected from halo, CH 3 , CH 3 O, CN, CF 3 , and CH 3 C(O), wherein all methyl groups are optionally substituted 1-3 chlorine atoms. 
   
   
       18 . The method of  claim 17 , wherein R 3  is C 1-4  alkyl, optionally monosubstituted with halogen, hydroxy, phenyl, benzyl, pyridyl, and pyridyl methyl, wherein the phenyl and pyridyl rings are optionally further monosubstituted with methyl or halogen. 
   
   
       19 . The method of  claim 16 , wherein R 3  is R 4 NHC(O), R 4 NHC(S), or R 4 NHCH 2 C(O), wherein R 4  is C 1-6  alkyl, wherein said alkyl group may be straight-chain, branched, or cyclic, and is optionally substituted as described for R 3  alkyl groups, or R 4  is a five- or 6-membered aromatic ring containing 0-3 heteroatoms independently selected from O, N, and S, all R 4  optionally substituted with one or two substituents independently selected from halo, methyl, and benzyl, wherein all rings are optionally substituted with one or two groups independently selected from CH 3 , OCH 3 , CO 2 CH 3 , OC(O)CH 3 , CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms. 
   
   
       20 . The method of  claim 15 , wherein a compound of formula I is provided, and A is S, n is 2, m is 1, R 1  is H, and R 2  is H or CH 3 . 
   
   
       21 . The method of  claim 20 , wherein R 3  is H or C 1-4  alkyl. 
   
   
       22 . The method of  claim 15 , wherein a compound of formula I is provided, and A is O, n is 1, m is 1, R 1  is H, and R 2  is H or CH 3 . 
   
   
       23 . The method of  claim 22 , wherein R 3  is H or C 1-6  alkyl, optionally substituted with one or two substituents independently selected from halo, hydroxy, cyano, phenyl, pyridyl, benzoyl, benzoyl methyl, benzoyloxy, C 1-6  alkoxycarbonyl, C 1-6  alkylcarbamoyl, N-phthalimido, or R 3  is a 5- or 6-membered aromatic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein all rings are optionally substituted with one or two substituents independently selected from halo, CH 3 , CH 3 O, CN, CF 3 , and CH 3 C(O), wherein all methyl groups are optionally substituted 1-3 chlorine atoms. 
   
   
       24 . The method of  claim 23 , wherein R 3  is C 1-4  alkyl, optionally monosubstituted with halogen, hydroxy, phenyl, benzyl, pyridyl, and pyridyl methyl, wherein the phenyl and pyridyl rings are optionally monosubstituted with methyl or halogen. 
   
   
       25 . The method of  claim 22 , wherein R 3  is R 4 NHC(O), R 4 NHC(S), or R 4 NHCH 2 C(O), wherein R 4  is C 1-6  alkyl, wherein said alkyl group may be straight-chain, branched, or cyclic, and is optionally substituted as described for R 3  alkyl groups, or R 4  is a five- or 6-membered aromatic ring containing 0-3 heteroatoms independently selected from O, N, and S, all R 4  optionally substituted with one or two substituents independently selected from halo, methyl, and benzyl, wherein all rings are optionally substituted with one or two groups independently selected from CH 3 , OCH 3 , CO 2 CH 3 , OC(O)CH 3 , CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms. 
   
   
       26 . The method  claim 15 , wherein a compound of formula II is provided. 
   
   
       27 . The method of  claim 26 , wherein A is S, R 5  is H; and wherein R 3  is selected from H, C 1-4  alkyl, C 1-4  alkenyl, or C 1-6  alkoxy, wherein said alkyl groups, the alkyl moieties of said alkoxy groups, and said alkenyl groups may be straight-chain, branched, or cyclic, and are optionally substituted with one or two substituents independently selected from halo, hydroxy, ethylcarbamoylmethyl, methylcarbamoylmethyl, 2-hydroxy-2-phenyl-ethylcarbamoylmethyl, benzoyl, benzoyloxy, and a 5- or 6-membered ring, said ring optionally containing one or more double bonds, optionally containing 1-3 ring heteroatoms independently selected from O, N, and S, and optionally substituted with, independently, one or two groups independently selected from CH 3 , OCH 3 , CF 3 , and halo;
 and n=0, 1, or 2.   
   
   
       28 . The method of  claim 26 , wherein n=1 or 2, and R 3  is H, methyl, methoxy, ethoxy or allyl.