Antiviral nucleoside reverse transcriptase inhibitor

Abstract

An antiviral nucleoside reverse transcriptase inhibitor compound as shown in formula (I), and a pharmaceutically acceptable salt, a stereoisomer, a solvate, a hydrate, a crystal form or an isotopic derivative of the compound. A preparation method therefor, a pharmaceutical composition thereof, and a use thereof in the preparation of a drug for treating and/or preventing viral infectious diseases, such as human immunodeficiency virus (HIV) and hepatitis B virus (HBV).

1 . A compound of Formula (I), 
       
         
           
           
               
               
           
         
         wherein, 
         X is selected from O or S; 
         Y is selected from bond, O or S; 
         m is selected from 0 to 5; 
         A is selected from 
         1) optionally substituted C 6 -C 11  aryl or optionally substituted C 5 -C 11  heteroaryl; or 
         2) —(CH 2 ) n CH 3 , wherein n is selected from 12 to 21; or 
         3) —C(═O)R 1 , —C(═O)OR 1 , —C(═O)N(R 1 )(R 1 ), wherein each R 1  is independently selected from H, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 7  carbocyclyl, optionally substituted C 3 -C 7  heterocyclyl, or two R 1  groups together form optionally substituted C 3 -C 7  carbocyclyl or optionally substituted C 3 -C 7  heterocyclyl; 
         V is selected from O or NH; 
         B is H, or the following structure: 
       
       
         
           
           
               
               
           
         
         wherein, 
         R 2  and R 3  are each independently selected from H, optionally substituted C 1 -C 6  alkyl or a side chain of a natural or a pharmaceutically acceptable amino acid, and if the side chain contains a carboxyl group, the carboxyl group may be optionally esterified to an alkyl or aryl ester. Or, R 2 , R 3  together with the carbon atom to which they are attached may form optionally substituted C 3 -C 7  carbocyclyl or optionally substituted C 3 -C 7  heterocyclyl; 
         L is selected from —C(═O)—, —O(C═O)—, —NR 4 (C═O)—, —S(═O) p —, —NR 4 S(═O) p —, wherein each R 4  is independently selected from H, optionally substituted C 1 -C 6  acyl, optionally substituted C 1 -C 6  alkyl, optionally substituted C 3 -C 7  carbocyclyl, optionally substituted C 3 -C 7  heterocyclyl, optionally substituted C 6 -C 11  aryl or optionally substituted C 5 -C 11  heteroaryl, p is selected from 1 or 2; 
         Z is selected from O or S; 
         R 5  is selected from optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 1 -C 6  acyl, optionally substituted C 2 -C 6  alkenyl, optionally substituted C 2 -C 6  alkynyl, optionally substituted C 3 -C 7  carbocyclyl, optionally substituted C 3 -C 7  heterocyclyl, optionally substituted C 6 -C 11  aryl, or optionally substituted C 5 -C 11  heteroaryl, as valency permits; 
         provided that one and only one of X, Y, and Z is S; 
         with the proviso that the compounds do not include the compound of the following formula: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, a stereoisomer, a solvate, a hydrate, a polymorph, or an isotopic variant thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein
 X is selected from O or S;   m is selected from 0 to 5;   Y is selected from bond, O or S;   A is selected from   1) optionally substituted phenyl; or   2) —(CH 2 ) n CH 3 , wherein n is selected from 13 to 17; or   3) —C(═O)R 1  or —C(═O)OR 1 , wherein each R 1  is independently selected from optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 7  carbocyclyl, or optionally substituted C 3 -C 7  heterocyclyl;   V is selected from O or NH;   B is H, or the following structure:   
       
         
           
           
               
               
           
         
         wherein, 
         R 2  and R 3  are each independently selected from H or optionally substituted C 1 -C 6  alkyl. Or, R 2 , R 3  together with the carbon atom to which they are attached may form optionally substituted C 3 -C 7  carbocyclyl or optionally substituted C 3 -C 7  heterocyclyl; 
         L is selected from —C(═O)— or —O(C═O)—; 
         Z is selected from O or S; 
         R 5  is selected from optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 3 -C 7  carbocyclyl or optionally substituted C 3 -C 7  heterocyclyl; 
         provided that one and only one of X, Y, and Z is S; 
         with the proviso that the compounds do not include the compound of the following formula: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, a stereoisomer, a solvate, a hydrate, a polymorph, or an isotopic variant thereof. 
       
     
     
         3 . The compound of  claim 2 , which is the compound of formula (IIa) or (IIb): 
       
         
           
           
               
               
           
         
         wherein, 
         Y is selected from bond or O; 
         m, A, V, L, R 2 , R 3  and R 5  are as defined in  claim 2 ; 
         or a pharmaceutically acceptable salt, a stereoisomer, a solvate, a hydrate, a polymorph, or an isotopic variant thereof. 
       
     
     
         4 . The compound of  claim 3 , wherein
 m is selected from 0, 2, 3, 4 or 5;   Y is selected from bond or 0;   A is selected from   1) optionally substituted phenyl; or   2) —(CH 2 ) n CH 3 , wherein n is selected from 13 to 17;   V is selected from O or NH;   R 2  and R 3  are each independently selected from H or optionally substituted C 1 -C 6  alkyl;   L is selected from —C(═O)— or —O(C═O)—;   R 5  is selected from optionally substituted C 1 -C 6  alkyl or optionally substituted C 3 -C 7  carbocyclyl;   or a pharmaceutically acceptable salt, a stereoisomer, a solvate, a hydrate, a polymorph, or an isotopic variant thereof.   
     
     
         5 . The compound of  claim 2 , which is the compound of formula (IIIa) or (IIIb): 
       
         
           
           
               
               
           
         
         wherein, 
         m, A, V, L, R 2 , R 3  and R 5  are as defined in  claim 2 , 
         or a pharmaceutically acceptable salt, a stereoisomer, a solvate, a hydrate, a polymorph, or an isotopic variant thereof. 
       
     
     
         6 . The compound of  claim 5 , wherein,
 m is selected from 0, 2, 3, 4 or 5;   A is selected from   1) —(CH 2 ) n CH 3 , wherein n is selected from 13 to 17; or   2) —C(═O)R 1  or —C(═O)OR 1 , wherein each R 1  is independently selected from optionally substituted C 1 -C 6  alkyl or optionally substituted C 3 -C 7  carbocyclyl;   V is selected from O or NH;   R 2  and R 3  are each independently selected from H or optionally substituted C 1 -C 6  alkyl;   L is selected from —C(═O)— or —O(C═O)—;   R 5  is selected from optionally substituted C 1 -C 6  alkyl or optionally substituted C 3 -C 7  carbocyclyl;   or a pharmaceutically acceptable salt, a stereoisomer, a solvate, a hydrate, a polymorph, or an isotopic variant thereof.   
     
     
         7 . The compound of  claim 2 , which is the compound of formula (IV): 
       
         
           
           
               
               
           
         
         wherein, 
         Y is selected from bond or O; 
         m, A, V, L, R 2 , R 3  and R 5  are as defined in  claim 2 , 
         with the proviso that the compounds do not include the compound of the following formula: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, a stereoisomer, a solvate, a hydrate, a polymorph, or an isotopic variant thereof. 
       
     
     
         8 . The compound of  claim 7 , wherein,
 m is selected from 2, 3, 4 or 5;   Y is O;   A is selected from   1) —(CH 2 ) n CH 3 , wherein n is selected from 13 to 17; or   2) —C(═O)R 1  or —C(═O)OR 1 , wherein each R 1  is independently selected from optionally substituted C 1 -C 6  alkyl or optionally substituted C 3 -C 7  carbocyclyl;   V is selected from O or NH;   R 2  and R 3  are each independently selected from H or optionally substituted C 1 -C 6  alkyl;   L is selected from —C(═O)— or —O(C═O)—;   R 5  is selected from optionally substituted C 1 -C 6  alkyl or optionally substituted C 3 -C 7  carbocyclyl;   or a pharmaceutically acceptable salt, a stereoisomer, a solvate, a hydrate, a polymorph, or an isotopic variant thereof.   
     
     
         9 . The compound of  claim 1 , wherein,
 m is selected from 0, 2 or 3;   n is 15;   R 2  and R 3  are each independently selected from H or methyl;   R 5  is isopropyl.   
     
     
         10 . The compound of  claim 1 , which is selected from the following compounds: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, a stereoisomer, a solvate, a hydrate, a polymorph, or an isotopic derivatives thereof. 
       
     
     
         11 . A pharmaceutical composition, comprising the compound of  claim 1  or a pharmaceutically acceptable salt, a stereoisomer, a solvate, a hydrate, a polymorph, or an isotopic derivatives thereof, and pharmaceutically acceptable excipient(s). 
     
     
         12 . The pharmaceutical composition of  claim 11 , further containing other therapeutic agents. 
     
     
         13 . A kit, comprising
 a first container, containing the compound of  claim 1  or a pharmaceutically acceptable salt, a stereoisomer, a solvate, a hydrate, a polymorph, or an isotopic derivatives thereof; and   optionally, a second container, containing other therapeutic agents; and   optionally, a third container, containing a pharmaceutical excipient for diluting or suspending the compound and/or other therapeutic agents.   
     
     
         14 . A method of treating and/or preventing viral infections in a subject, comprising administering to the subject the compound of  claim 1  or a pharmaceutically acceptable salt, a stereoisomer, a solvate, a hydrate, a polymorph, or an isotopic derivatives thereof. 
     
     
         15 . The method of  claim 14 , wherein the viral infection is caused by HIV or HBV.