Novel antiviral agents against hbv infection

Abstract

including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein A, R1, R2, R3, R4, R5, R6, R7, and R8 are defined herein.

1 - 61 . (canceled) 
     
     
         62 . A compound of Formula (I), or an enantiomer, diastereoisomer, salt, hydrate, or solvate thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 A is selected from the group consisting of S(═O) 2  and C(═O); 
 R 1  is selected from the group consisting of optionally substituted C 1-6  alkyl, optionally substituted C 3-7  cycloalkyl, optionally substituted C 2-8  alkenyl, optionally substituted C 2-8  alkynyl, optionally substituted 3-7 membered cycloheteroalkyl, and optionally substituted heterocyclic; 
 R 2  is selected from the group consisting of hydrogen, optionally substituted C 1-6  alkyl, optionally substituted C 3-7  cycloalkyl, and optionally substituted heterocyclic; or
 R 1  and R 2  are taken together with the atoms to which they are bound to form optionally substituted 3-membered to 10-membered heterocyclyl; 
 
 R 3  is selected from the group consisting of optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted alkylheteroaryl; 
 R 4  is selected from the group consisting of hydrogen and optionally substituted C 1-6  alkyl; 
 R 5  is selected from the group consisting of hydrogen, halogen, optionally substituted C 1-6  alkyl, optionally substituted C 1-6  haloalkyl, OR 9 , cyano, and N(R 9 ) 2 ; 
 R 6  is H and R 8  is F, or R 6  is F and R 8  is H; 
 R 7  is selected from the group consisting of hydrogen, halogen, optionally substituted C 1-6  alkyl, OR 9 , cyano, and N(R 9 ) 2 ; 
 R 9  is independently at each occurrence selected from the group consisting of hydrogen, optionally substituted C 1-6  alkyl, optionally substituted C 3-7  cycloalkyl, optionally substituted benzyl, and optionally substituted heterocyclyl; 
 provided that, when A is SO 2 , then the compound is not selected from any of the groups (a) through (d): 
 
       (a) R 3  is optionally substituted phenyl, and R 1  or R 2 , either individually or when taken together, contain a hydroxyl group; or 
       (b) R 3  is optionally substituted phenyl, and N(R 1 )(R 2 ) is optionally substituted piperazine, 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or 
       (c) R 3  is optionally substituted aryl or alkaryl, and N(R 1 )(R 2 ) is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or 
       (d) R 3  is unsubstituted or monosubstituted aryl, unsubstituted or monosubstituted aralkyl, or unsubstituted or monosubstituted heteroaryl, and R 1  and R 2  are taken together with the atoms to which they are bound to form optionally substituted 6- to 12-membered heterocyclic. 
     
     
         63 . The compound of  claim 62 , wherein a substituted group is substituted with at least one selected from the group consisting of C 1-6  alkyl, C 1-6  haloalkyl, C 2-8 alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, —F, —Cl, —Br, —I, —CN, —NO 2 , —OR 14 , —SR 14 , —N(R 14 ) 2 , —NR 14 C(O)R 14 , —SO 2 R 14 , —SO 2 OR 14 , —SO 2 N(R 14 ) 2 , —C(O)R 14 , —C(O)OR 14 , —C(O)N(R 14 ) 2 , aryl, heterocyclyl, or heteroaryl, wherein each occurrence of R 14  is independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C 2-8  alkenyl, C 2-8  alkynyl, and C 3-6  cycloalkyl, or two R 14  units taken together with the atom(s) to which they are bound form optionally substituted 3- to 7-membered carbocyclyl or optionally substituted 3- to 7-membered heterocyclyl. 
     
     
         64 . The compound of  claim 62 , wherein the heteroaryl is selected from the group consisting of diazolyl, imidazolyl, imidazolyl, triazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolinyl, furanyl, thiophenyl, pyrimidinyl, pyridinyl, tetrazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3-(ijpyrimidinyl, 2-phenylbenzo[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H-indolyl, quinoxalinyl, quinazolinyl, quinolinyl, and isoquinolinyl. 
     
     
         65 . The compound of  claim 62 , wherein A is S(═O) 2 . 
     
     
         66 . The compound of  claim 62 , wherein A is C(═O). 
     
     
         67 . The compound of  claim 62 , wherein R 4  is hydrogen. 
     
     
         68 . The compound of  claim 62 , wherein R 3  is selected from the group consisting of optionally substituted phenyl, optionally substituted benzyl, optionally substituted benzoisoxazolyl, optionally substituted benzooxazolyl, optionally substituted furyl, optionally substituted imidazolyl, optionally substituted indoyl, optionally substituted isoxazolyl, optionally substituted isothiazolyl, optionally substituted oxazolyl, optionally substituted pyrazolyl, optionally substituted pyridin-2-on-yl, optionally substituted pyridyl, optionally substituted pyrrolyl, optionally substituted quinolinyl, optionally substituted thiazolyl optionally substituted thienyl, and optionally substituted methylpyridyl. 
     
     
         69 . The compound of  claim 62 , wherein:
 R 3  is selected from the group consisting of:   
       
         
           
           
               
               
           
         
         R S  is independently at each occurrence selected from the group consisting of bromo, chloro, fluoro, cyano, hydroxyl, optionally fluorinated C 1-6  alkyl, and —O(C 1-6  alkyl), or two R S  are taken with the atoms with which they bind to form a fused cyclic or heterocyclic moiety; 
         x is 0, 1, 2, or 3; and 
         R 4  is hydrogen. 
       
     
     
         70 . The compound of  claim 62 , wherein R 3  is substituted with at least one halo or C 1-6  alkyl. 
     
     
         71 . The compound of  claim 62 , wherein R 3  is substituted with at least one halo. 
     
     
         72 . The compound of  claim 62 , wherein R 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         73 . The compound of  claim 62 , wherein R 5  and R 7  are independently at each occurrence H or F. 
     
     
         74 . The compound of  claim 62 , wherein R 3  is 
       
         
           
           
               
               
           
         
       
       and R 4  is hydrogen. 
     
     
         75 . The compound of  claim 62  wherein R 5 , R 7 , and R 8  are each H. 
     
     
         76 . The compound of  claim 62 , wherein:
 R 1  is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, optionally substituted benzyl, optionally substituted methylpyridyl,   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and
 R 2  is H. 
 
     
     
         77 . The compound of  claim 62 , wherein
 R 1  is isopropyl, t-butyl,   
       
         
           
           
               
               
           
         
       
       and
 R 2  is H. 
 
     
     
         78 . The compound of  claim 62 , wherein 
       
         
           
           
               
               
           
         
       
       is 
       
         
           
           
               
               
           
         
       
     
     
         79 . The compound of  claim 62 , wherein
 R 1  is   
       
         
           
           
               
               
           
         
       
       and
 R 3  is 
 
       
         
           
           
               
               
           
         
         R S  is independently selected at each occurrence from the group consisting of bromo, chloro, fluoro, cyano, hydroxyl, optionally fluorinated C 1-6  alkyl, and —O—(C 1-6  alkyl), or two R S  taken together with the carbon atom(s) to which they are bound form a fused cyclic or heterocyclyl moiety; and 
         x is 0, 1, 2, or 3. 
       
     
     
         80 . The compound of  claim 62 , wherein —N(R 1 )(R 2 ) does not contain hydroxyl. 
     
     
         81 . The compound of  claim 62 , wherein R 1  is not cyclopentane. 
     
     
         82 . The compound of  claim 62 , wherein 
       
         
           
           
               
               
           
         
       
       is 
       
         
           
           
               
               
           
         
       
     
     
         83 . The compound of  claim 62 , which is: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is 
 
       
         
           
           
               
               
           
         
       
       and
 R 3  is 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         84 . The compound of  claim 62 , which is: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is 
 
       
         
           
           
               
               
           
         
       
       and
 R 3  is 
 
       
         
           
           
               
               
           
         
         
           R S  is independently selected at each occurrence from the group consisting of bromo, chloro, fluoro, cyano, hydroxyl, optionally fluorinated C 1-6  alkyl, and —O—(C 1-6  alkyl), or when two R S  are taken with the atom(s) to which they bind to form a fused cyclic or heterocyclic moiety; and 
         
         x is 0, 1, 2, or 3. 
       
     
     
         85 . The compound of  claim 62 , which is: 
       
         
           
           
               
               
           
         
       
       wherein R 1  is isopropyl, t-butyl, 
       
         
           
           
               
               
           
         
       
     
     
         86 . The compound of  claim 62 , which is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein
 R 1  is isopropyl, t-butyl, 
 
       
         
           
           
               
               
           
         
       
       and
 R 2  is H. 
 
     
     
         87 . A pharmaceutical composition comprising a compound of  claim 62  and a pharmaceutically acceptable excipient. 
     
     
         88 . A method of treating or preventing a disease that involves pregenomic RNA encapsidation in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of at least one compound of  claim 62 . 
     
     
         89 . The method of  claim 88 , wherein the disease that involves pregenomic RNA encapsidation is Hepatitis B virus infection. 
     
     
         90 . A method of treating or preventing a Hepatitis B viral infection in a patient in need thereof, wherein the method comprising administering to the patient a therapeutically effective amount of at least one compound of  claim 62 . 
     
     
         91 . The method of  claim 90 , wherein the treatment controls or ameliorates a condition associated with liver disease. 
     
     
         92 . The method of  claim 91 , wherein the condition associated with liver disease comprises cirrhosis or hepatocellular carcinoma. 
     
     
         93 . A method of repressing at least one selected from the group consisting of viral replication and morphogenesis in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of at least one compound of  claim 62 .