Substituted polycyclic carbamoyl pyridone derivative prodrug

Abstract

The present invention provides a compound having antiviral effects, particularly having growth inhibitory activity on influenza viruses, a preferred example of the compound being a substituted 3-hydroxy-4-pyridone derivative prodrug having cap-dependent endonuclease inhibitory activity.

1 - 24 . (canceled) 
     
     
         25 . A compound of formula (I″): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof,
 wherein: 
 “Ring” is a 5- to 7-membered ring that may be substituted by one, two or more same or different substituents selected from substituent group D; 
 P R  is a group selected from the group consisting of: 
 b) —C(═O)—P R1 , 
 c) —C(═O)-L-P R1 , 
 d) —C(═O)-L-O—P R1 , 
 e) —C(═O)-L-O-L-O—P R1 , 
 f) —C(═O)-L-O—C(═O)—P R1 , 
 g) —C(═O)—O—P R2 , 
 h) —C(═O)—N(P R2 ) 2 , 
 i) —C(═O)—O-L-O—P R2 , 
 j) —CH 2 —O—P R3 , 
 k) —CH 2 —O-L-O—P R3 , 
 l) —CH 2 —O—C(═O)—P R3 , 
 m) —CH 2 —O—C(═O)—O—P R3 , 
 n) —CH(—CH 3 )—O—C(═O)—O—P R3 , 
 o) —CH 2 —O—C(═O)—N(—K)—P R3 , 
 p) —CH 2 —O—C(═O)—O-L-O—P R3 , 
 q) —CH 2 —O—C(═O)—O-L-N(P R3 ) 2 , 
 r) —CH 2 —O—C(═O)—N(—K)-L-O—P R3 , 
 s) —CH 2 —O—C(═O)—N(—K)-L-N(P R3 ) 2 , 
 t) —CH 2 —O—C(═O)—O-L-O-L-O—P R3 , 
 u) —CH 2 —O—C(═O)—O-L-N(—K)—C(═O)—P R3 , 
 v) —CH 2 —O—P(═O)(—OH) 2 , 
 w) —CH 2 —O—P(═O)(—OBn) 2 , and 
 x) —CH 2 —P R4 , 
 wherein: 
 L is straight or branched lower alkylene, 
 K is hydrogen, or straight or branched lower alkyl, 
 P R1  is carbocyclic group optionally substituted by substituent group F, heterocyclic group optionally substituted by substituent group F, lower alkyl amino optionally substituted by substituent group F, or lower alkylthio optionally substituted by substituent group F, 
 P R2  is lower alkyl optionally substituted by substituent group F, carbocyclic group optionally substituted by substituent group F, or heterocyclic group optionally substituted by substituent group F, 
 P R3  is lower alkyl optionally substituted by substituent group F, carbocyclic group optionally substituted by substituent group F, heterocyclic group optionally substituted by substituent group F, lower alkyl amino optionally substituted by substituent group F, carbocycle lower alkyl optionally substituted by substituent group F, heterocycle lower alkyl optionally substituted by substituent group F, or lower alkylsilyl, and 
 P R4  is carbocyclic group optionally substituted by substituent group F, or heterocyclic group optionally substituted by substituent group F; 
 R 1a  is hydrogen; 
 R 2a  is hydrogen; 
 R 5a  and R 7a  are each independently selected from a substituent group consisting of hydrogen, benzhydryl, benzyl, indolylmethyl, cyclohexylmethyl, phenethyl, 3,5-dimethylisoxazolyl, 5-chloro-3-ethylbenzothiophenyl, biphenylmethyl, 4-fluorobenzyl, methylthiazolylmethyl, cyclopentylmethyl, 4-methoxybenzyl, 3-fluorobenzyl, naphthylmethyl, methyl, 3-trifluoromethylbenzyl, pyridylmethyl, 4-methylcarbonylaminobenzyl, pyrimidinyl, and the following groups: 
 
       
         
           
           
               
               
           
         
         wherein R E6  is selected from substituent group C; 
         m is an integer 0 or 1 or more; 
         substituent group C is selected from the group consisting of halogen, cyano, hydroxy, carboxy, formyl, amino, oxo, nitro, lower alkyl, lower alkenyl, lower alkynyl, halogeno lower alkyl, lower alkyloxy, lower alkynyloxy, lower alkylthio, hydroxy lower alkyl, carbocyclic group, heterocyclic group, heterocyclic group substituted by oxo, carbocycle lower alkyloxy, carbocycleoxy lower alkyl, carbocycle lower alkyloxy lower alkyl, heterocycle lower alkyloxy, heterocycleoxy lower alkyl, heterocycle lower alkyloxy lower alkyl, halogeno lower alkyloxy, lower alkyloxy lower alkyl, lower alkyloxy lower alkyloxy, lower alkylcarbonyl, lower alkylcarbonyloxy, lower alkyloxycarbonyl, lower alkylamino, lower alkylcarbonylamino, halogeno lower alkyl carbonylamino, lower alkylaminocarbonyl, lower alkylsulfonyl, lower alkylsulfinyl, and lower alkylsulfonylamino; 
         substituent group D is selected from the group consisting of halogen, cyano, hydroxy, carboxy, formyl, amino, oxo, nitro, lower alkyl, halogeno lower alkyl, lower alkyloxy, carbocycle lower alkyloxy, heterocycle lower alkyloxy, halogeno lower alkyloxy, lower alkyloxy lower alkyl, lower alkyloxy lower alkyloxy, lower alkylcarbonyl, lower alkyloxycarbonyl, lower alkylamino, lower alkylcarbonylamino, lower alkylaminocarbonyl, lower alkylsulfonyl, lower alkylsulfonylamino, carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, and heterocycle lower alkyl optionally substituted by substituent group C; and 
         substituent group F is selected from the group consisting of oxo, lower alkyl, hydroxy lower alkyl, amino, lower alkylamino, carbocycle lower alkyl, lower alkylcarbonyl, halogen, hydroxy, carboxy, lower alkylcarbonylamino, lower alkylcarbonyloxy, lower alkyloxycarbonyl, lower alkyloxy, cyano, and nitro. 
       
     
     
         26 . The compound according to  claim 25 , or a pharmaceutically acceptable salt or solvate thereof, wherein
 P R  is selected from the group consisting of:   b) —C(═O)—P R1 ,   l) —CH 2 —O—C(═O)—P R3 ,   m) —CH 2 —O—C(═O)—O—P R3 , and   n) —CH(—CH 3 )—O—C(═O)—O—P R3 .   
     
     
         27 . The compound according to  claim 25 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a  is the following group: 
       
         
           
           
               
               
           
         
       
     
     
         28 . The compound according to  claim 27 , or a pharmaceutically acceptable salt or solvate thereof, wherein R E6  is selected from the group consisting of fluorine atom, chlorine atom, bromine atom, methyl, methoxy, and trifluoromethyl. 
     
     
         29 . The compound according to  claim 28 , or a pharmaceutically acceptable salt or solvate thereof, wherein m is an integer of 0 to 2. 
     
     
         30 . A compound of formula (III′″): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, 
       wherein:
 P R  is —CH 2 —O—C(═O)—O—P R3 , 
 P R3  is lower alkyl optionally substituted by substituent group F, carbocyclic group optionally substituted by substituent group F, heterocyclic group optionally substituted by substituent group F, lower alkyl amino optionally substituted by substituent group F, carbocycle lower alkyl optionally substituted by substituent group F, heterocycle lower alkyl optionally substituted by substituent group F, or lower alkylsilyl; 
 R 1a  is hydrogen; 
 R 2a  is hydrogen; 
 R 5a  is hydrogen; 
 R 7a  is a heterocyclic group optionally substituted by substituent group C; 
 substituent group C is selected from the group consisting of halogen, cyano, hydroxyl, carboxy, formyl, amino, oxo, nitro, lower alkyl, halogeno lower alkyl, lower alkyloxy, carbocyclic group, heterocyclic group, carbocycle lower alkyloxy, heterocycle lower alkyloxy, halogeno lower alkyloxy, lower alkyloxy lower alkyl, lower alkyloxy lower alkyloxy, lower alkylcarbonyl, lower alkyloxycarbonyl, lower alkylamino, lower alkylcarbonylamino, lower alkylaminocarbonyl, lower alkylsulfonyl, and lower alkylsulfonylamino; and 
 substituent group F is selected from the group consisting of oxo, lower alkyl, hydroxy lower alkyl, amino, lower alkylamino, carbocycle lower alkyl, lower alkylcarbonyl, halogen, hydroxy, carboxy, lower alkylcarbonylamino, lower alkylcarbonyloxy, lower alkyloxycarbonyl, lower alkyloxy, cyano, and nitro. 
 
     
     
         31 . The compound according to  claim 30 , or the pharmaceutically acceptable salt thereof or the solvate thereof, wherein P R  is 
       
         
           
           
               
               
           
         
       
     
     
         32 . A pharmaceutical composition containing a compound according to  claim 25 , or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable carrier or diluent. 
     
     
         33 . A method for treating infectious disease characterized in administering a compound according to  claim 25 , or a pharmaceutically acceptable salt or solvate thereof, to a subject in need thereof. 
     
     
         34 . A pharmaceutical composition containing a compound according to  claim 30 , or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable carrier or diluent. 
     
     
         35 . A method for treating infectious disease characterized in administering a compound according to  claim 30 , or a pharmaceutically acceptable salt or solvate thereof, to a subject in need thereof.