Hepatitis b antiviral agents

Abstract

which inhibit the protein(s) encoded by hepatitis B virus (HBV) or interfere with the function of the HBV life cycle of the hepatitis B virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HBV infection. The invention also relates to methods of treating an HBV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

What is claimed: 
     
         1 . A compound represented by Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 A is optionally substituted aryl or optionally substituted heteroaryl; 
 B is selected from the group consisting of hydrogen, halo, CN, optionally substituted —C 1 -C 6  alkyl, and optionally substituted —C 3 -C 6  cycloalkyl; 
 X is optionally substituted aryl or optionally substituted heteroaryl; 
 Alternatively, B and X are taken together with the carbon atom to which they are attached to form an additional optionally substituted C 4 -C 12  cycloalkenyl or optionally substituted 4- to 12-membered heterocyclic; 
 Y is optionally substituted aryl or optionally substituted heteroaryl; 
 Z is selected from the group consisting of hydrogen, optionally substituted —C 1 -C 12  alkyl, optionally substituted —C 2 -C 12  alkenyl, optionally substituted —C 2 -C 2  alkynyl, optionally substituted —C 3 -C 8  cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl and optionally substituted heteroaryl, —C(O)NR 1 R 2 , and —C(O)OR 1 ; 
 R 1  and R 2  at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 8  alkyl, optionally substituted —C 2 -C 8  alkenyl, optionally substituted —C 2 -C 8  alkynyl, optionally substituted —C 3 -C 8  cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; 
 Alternatively, R 1  and R 2  are taken together with the nitrogen atom to which they are attached form an optionally substituted 3- to 12-membered heterocyclic; 
 R is selected from the group consisting of optionally substituted —C 1 -C 8  alkyl, optionally substituted —C 2 -C 8  alkenyl, optionally substituted —C 2 -C 8  alkynyl; 
 Alternatively, R and Z are taken together with the atoms to which they are attached to form an additional optionally substituted 4- to 12-membered heterocyclic; and 
 Alternatively, R and A are taken together with the atoms to which they are attached to form an additional optionally substituted 5- to 7-membered heterocyclic. 
 
     
     
         2 . The compound of  claim 1 , wherein A and X are each independently selected from the following by removal of one hydrogen atom: 
       
         
           
           
               
               
           
         
       
       wherein each of the above shown aryl and heteroaryl groups is optionally substituted when possible and may be connected to the dihydropyrimidine core through a carbon. 
     
     
         3 . The compound of  claim 1 , wherein R is selected from optionally substituted methyl, optionally substituted ethyl, —(CH 2 ) n OR 11 , —(CH 2 ) n OC(O)R 11 , —(CH 2 ) n C(O)OR 11 , —(CH 2 ) n C(O)NR 11 R 12 , —(CH 2 ) n OC(O)OR 11 , —(CH 2 ) n O—C(O)NR 11 R 12 , —(CH 2 ) n NR 11 R 12 , —(CH 2 ) n NR 11 C(O)R 11 , —(CH 2 ) n NR 11 C(O)OR 11 , —(CH 2 ) n NR 11 C(O)NR 11 R 12 , —(CH 2 ) n (O)R 12 , —(CH 2 ) n OS(O) 2 R 12 , —(CH 2 ) n (O) 2 OR 11 , —(CH 2 ) n NR 11 (O) 2 R 12 , —(CH 2 ) n (O) 2 NR 11 R 12 ; —(CH 2 ) n NR 11 (O) 2 NR 11 R 12 ; —(CH 2 ) n OP(O)(OR 11 ) 2 , —(CH 2 ) n P(O)(OR 11 ) 2 , —(CH 2 ) n NR 11 P(O)(OR 12 ) 2 , and —(CH 2 ) n P(O)(NR 11 R 12 ) 2 , wherein R 11  and R 12  at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 8  alkyl, optionally substituted —C 2 -C 8  alkenyl, optionally substituted —C 2 -C 8  alkynyl, optionally substituted —C 3 -C 8  cycloalkyl. 
     
     
         4 . The compound of  claim 1 , wherein Y is selected from the following 
       
         
           
           
               
               
           
         
       
       wherein each of the above shown groups is optionally substituted. 
     
     
         5 . The compound of  claim 1 , wherein Z is —(CH 2 ) n′ -M, n′ is 1, 2, or 3, M is hydrogen, —OR 11 , protected hydroxy, —CR 11 R 12 R 3 , —NR 11 R 12 , protected amino or M is selected from the groups set forth below 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein each of the above shown groups is optionally substituted when possible, R 3  is selected from the group consisting of hydrogen, optionally substituted —C 1 -C 8  alkyl, optionally substituted —C 2 -C 8  alkenyl, optionally substituted —C 2 -C 8  alkynyl, optionally substituted —C 3 -C 8  cycloalkyl, —CN, —OR 11 , and —NR 11 R 12 ; R 4  is selected from the group consisting of —NR 11 R 12 , OR 11 , optionally substituted —C 1 -C 8  alkyl, optionally substituted —C 2 -C 8  alkenyl, optionally substituted —C 2 -C 8  alkynyl, optionally substituted —C 3 -C 8  cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; R 5  is selected from the group consisting of hydrogen, optionally substituted —C 1 -C 8  alkyl, optionally substituted —C 2 -C 8  alkenyl, optionally substituted —C 2 -C 8  alkynyl, optionally substituted —C 3 -C 8  cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, —C(O)R 11 , —C(O)OR 11 , —C(O)NR 11 R 12 , —S(O) 2 R 11 , and —S(O) 2 NR 11 R 12 ; G is independently selected from CR 11 R 12 , O and NR 5 ; G′ is independently selected from CR 5  and N; m′ is 1, 2, or 3; and R 11  and R 12  at each occurrence are independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 8  alkyl, optionally substituted —C 2 -C 8  alkenyl, optionally substituted —C 2 -C 8  alkynyl, and optionally substituted —C 3 -C 8  cycloalkyl. 
     
     
         6 . The compound of  claim 1 , represented by Formula (IIa-1) or (IIb-1), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein A 1  is a 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, N, and S; A 2  is an optionally substituted phenyl, thiophenyl or 6-membered heteroaryl group including but not limited to pyridinyl, pyrazinyl, or pyrimidinyl; X 1  is optionally substituted methyl, halo, CN, OR 11 , or NR 11 R 12 ; m is 0, 1, 2, 3, 4 or 5; R 11  and R 12  at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 8  alkyl, optionally substituted —C 2 -C 8  alkenyl, optionally substituted —C 2 -C 8  alkynyl, optionally substituted —C 3 -C 8  cycloalkyl, Y and Z are as defined in  claim 1 . 
     
     
         7 . The compound of  claim 1 , represented by Formula (IIa-3) or (IIb-3), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein A 1  is a 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, N, and S; A 2  is an optionally substituted phenyl, thiophenyl or 6-membered heteroaryl group including but not limited to pyridinyl, pyrazinyl, or pyrimidinyl; X 1  is optionally substituted methyl, halo, CN, OR 11 , or NR 11 R 12 ; v is 0, 1, 2, 3, or 4; E at each occurrence is same or different and independently selected from —CR 15 R 16 —, —C(O)—, —O—, —NR 16 —, —S—, and —S(O) 2 —; u is 0, 1, 2, or 3; R 15  is hydrogen, halo, CN, —NR 11 R 12 , optionally substituted —C 1 -C 8  alkyl, optionally substituted —C 2 -C 8  alkenyl, optionally substituted —C 2 -C 8  alkynyl, optionally substituted —C 3 -C 8  cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; R 16  is hydrogen, optionally substituted —C 1 -C 8  alkyl, optionally substituted —C 2 -C 8  alkenyl, optionally substituted —C 2 -C 8  alkynyl, optionally substituted —C 3 -C 8  cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; alternatively, R 15  and R 16  are taken together with the carbon atom to which they are attached to form an optionally substituted C 3 -C 7  cycloalkyl or an optionally substituted 3- to 7-membered heterocyclic; Y and Z are as defined in  claim 1 . 
     
     
         8 . The compound of  claim 1 , represented by Formula (IIIa) or (IIIb), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein A 1  is a 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, N, and S; A 2  is an optionally substituted phenyl, thiophenyl or 6-membered heteroaryl group including but not limited to pyridinyl, pyrazinyl, or pyrimidinyl; E at each occurrence is the same or different and independently selected from —CR 15 R 16 —, —C(O)—, —O—, —NR 16 —, —S—, and —S(O) 2 —; u is 0, 1, 2, or 3; R 15  is hydrogen, halo, CN, —NR 11 R 12 , optionally substituted —C 1 -C 8  alkyl, optionally substituted —C 2 -C 8  alkenyl, optionally substituted —C 2 -C 8  alkynyl, optionally substituted —C 3 -C 8  cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; R 16  is hydrogen, optionally substituted —C 1 -C 8  alkyl, optionally substituted —C 2 -C 8  alkenyl, optionally substituted —C 2 -C 8  alkynyl, optionally substituted —C 3 -C 8  cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; alternatively, R 15  and R 16  are taken together with the carbon atom to which they are attached to form an optionally substituted C 3 -C 7  cycloalkyl or an optionally substituted 3- to 7-membered heterocyclic; and X, B, and Y are as defined in  claim 1 . 
     
     
         9 . The compound of  claim 1 , represented by Formula (IIIa) or (IIIb), or a pharmaceutically acceptable salt thereof, wherein the heterocyclic ring 
       
         
           
           
               
               
           
         
       
       is selected from the groups below: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein each of the above shown groups is optionally substituted; each R 3  is selected from the group consisting of hydrogen, optionally substituted —C 1 -C 8  alkyl, optionally substituted —C 2 -C 8  alkenyl, optionally substituted —C 2 -C 8  alkynyl, optionally substituted —C 3 -C 8  cycloalkyl, —CN, —OR 11 , and —NR 11 R 12 ; R 5  is selected from the group consisting of hydrogen, optionally substituted —C 1 -C 8  alkyl, optionally substituted —C 2 -C 8  alkenyl, optionally substituted —C 2 -C 8  alkynyl, optionally substituted —C 3 -C 8  cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, —C(O)R 11 , —C(O)OR 11 , —C(O)NR 11 R 12 , —S(O) 2 R 11 , —S(O) 2 NR 11 R 12 ; R 11  and R 12  at each occurrence are independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 8  alkyl, optionally substituted —C 2 -C 8  alkenyl, optionally substituted —C 2 -C 8  alkynyl, optionally substituted —C 3 -C 8  cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; and m′ is 1, 2, or 3. 
     
     
         10 . The compound of  claim 1 , represented by Formula (IV) or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein E at each occurrence is the same or different and independently selected from —CR 15 R 16 —, —C(O)—, —O—, —NR 16 —, —S—, and —S(O) 2 —; u is 0, 1, 2, or 3; R 15  is hydrogen, halo, CN, —NR 11 R 12 , optionally substituted —C 1 -C 8  alkyl, optionally substituted —C 2 -C 8  alkenyl, optionally substituted —C 2 -C 8  alkynyl, optionally substituted —C 3 -C 8  cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl or optionally substituted heteroaryl; R 16  is hydrogen, optionally substituted —C 1 -C 8  alkyl, optionally substituted —C 2 -C 8  alkenyl, optionally substituted —C 2 -C 8  alkynyl, optionally substituted —C 3 -C 8  cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl or optionally substituted heteroaryl; alternatively, R 15  and R 16  are taken together with the carbon atom to which they are attached to form an optionally substituted C 3 -C 7  cycloalkyl or an optionally substituted 3- to 7-membered heterocyclic; and X, B, Y and Z are as defined in  claim 1 . 
     
     
         11 . The compound of  claim 1 , selected from the compounds set forth below or a pharmaceutically acceptable salt thereof: 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   Compound 
                   Structure 
                 
                     
                     
                 
                     
                 
                 
                 
                 
               
                     
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         12 . A pharmaceutical composition, comprising a compound according to  claim 1  or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient. 
     
     
         13 . A method of treating or preventing an HBV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a combination of compounds of Formula (I). 
     
     
         14 . The method of  claim 13 , further comprising administering to the subject at least one additional therapeutic agent selected from the group consisting of a HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, literature-described capsid assembly modulator, reverse transcriptase inhibitor, TLR-agonist, inducer of cellular viral RNA sensor, therapeutic vaccine, and agents of distinct or unknown mechanism, and a combination thereof. 
     
     
         15 . The method of  claim 14 , wherein the compound and the at least one additional therapeutic agent are co-formulated. 
     
     
         16 . The method of  claim 14 , wherein the compound and the at least one additional therapeutic agent are co-administered. 
     
     
         17 . The method of  claim 14 , wherein administering the compound allows for administering of the at least one additional therapeutic agent at a lower dose or frequency as compared to the administering of the at least one additional therapeutic agent alone that is required to achieve similar results in prophylactically treating an HBV infection in an individual in need thereof. 
     
     
         18 . The method of  claim 14 , wherein before administering the therapeutically effective amount of the compound of Formula (I), the individual is known to be refractory to a compound selected from the group consisting of a HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, inducer of cellular viral RNA sensor, therapeutic vaccine, antiviral compounds of distinct or unknown mechanism, and combination thereof. 
     
     
         19 . The method of  claim 14 , wherein the administering of the compound reduces viral load in the individual to a greater extent compared to the administering of a compound selected from the group consisting of a HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, inducer of cellular viral RNA sensor, therapeutic vaccine, antiviral compounds of distinct or unknown mechanism, and combination thereof. 
     
     
         20 . The method of  claim 14 , wherein the administering of the compound causes a lower incidence of viral mutation and/or viral resistance than the administering of a compound selected from the group consisting of a HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, inducer of cellular viral RNA sensor, therapeutic vaccine, antiviral compounds of distinct or unknown mechanism, and combination thereof.