Substituted polycyclic pyridone derivatives and prodrugs thereof

Abstract

The present invention provides the following compounds having anti-viral activity. A 1 is CR 1A R 1B , S or O; A 2 is CR 2A R 2B , S or O; A 3 is CR 3A R 3B , S or O; A 4 is CR 4A R 4B , S or O; the number of hetero atoms among atoms constituting the ring which consists of A 1 , A 2 , A 3 , A 4 , nitrogen atom adjacent to A 1 and carbon atom adjacent to A 1 , is 1 or 2; R 1A and R 1B are each independently hydrogen, halogen, alkyl, or the like; R 2A and R 2B are each independently hydrogen, halogen, alkyl, or the like; R 3A and R 3B are each independently hydrogen, halogen, alkyl, or the like; R 4A and R 4B are each independently hydrogen, halogen, alkyl, or the like; R 3A and R 3B may be taken together to form non-aromatic carbocycle or non-aromatic heterocycle; X is CH 2 , S or O; R 1 is each independently halogen, hydroxy, or the like; m is any integer of 0 to 2; and n is any integer of 1 to 2.

1 . A compound represented by formula (I): 
       
         
           
           
               
               
           
         
         or its pharmaceutically acceptable salt: 
         wherein 
         P is hydrogen or a group P R  to form a prodrug; 
         A 1  is CR 1A R 1B , S or O; 
         A 2  is CR 2A R 2B , S or O; 
         A 3  is CR 3A R 3B , S or O; 
         A 4  is each independently CR 4A R 4B , S or O; 
         the number of hetero atoms among atoms constituting the ring which consists of A 1 , A 2 , A 3 , A 4 , nitrogen atom adjacent to A 1  and carbon atom adjacent to A 4 , is 1 or 2; 
         R 1A  and R 1B  are each independently hydrogen, halogen, alkyl, haloalkyl, alkyloxy or phenyl; 
         R 2A  and R 2B  are each independently hydrogen, halogen, alkyl, haloalkyl, alkyloxy or phenyl; 
         R 3A  and R 3B  are each independently hydrogen, halogen, alkyl, haloalkyl, alkyloxy or phenyl; 
         R 4A  and R 4B  are each independently hydrogen, halogen, alkyl, haloalkyl, alkyloxy or phenyl; 
         R 3A  and R 3B  may be taken together with an adjacent carbon atom to form non-aromatic carbocycle or non-aromatic heterocycle; 
         X is CH 2 , S or O; 
         R 1  is each independently halogen, hydroxy, alkyl, haloalkyl or alkyloxy; 
         m is any integer of 0 to 2; and 
         n is any integer of 1 to 2, 
         provided that the following compounds are excluded: 
       
       
         
           
           
               
               
           
         
         wherein each definition has the same meaning as described above. 
       
     
     
         2 . The compound according to  claim 1 , wherein the group represented by formula: 
       
         
           
           
               
               
           
         
         wherein each definition has the same meaning as described in  claim 1 , 
         is a group represented by formula: 
       
       
         
           
           
               
               
           
         
         wherein R 2 , R 3 , R 4  and R 5  are each independently hydrogen atom or fluorine atom; 
         the number of fluorine atom of R 2 , R 3 , R 4  and R 5  is 1 or 2, or its pharmaceutically acceptable salt. 
       
     
     
         3 . The compound according to  claim 1 , wherein the group represented by formula: 
       
         
           
           
               
               
           
         
         wherein each definition has the same meaning as described in  claim 1 , 
         is a group represented by formula: 
       
       
         
           
           
               
               
           
         
         or its pharmaceutically acceptable salt. 
       
     
     
         4 . The compound according to any one of  claims 1  to  3 , wherein the group represented by formula: 
       
         
           
           
               
               
           
         
         wherein each definition has the same meaning as described in  claim 1 , 
         is represented by formula: 
       
       
         
           
           
               
               
           
         
         wherein each definition has the same meaning as described in  claim 1 , or its pharmaceutically acceptable salt. 
       
     
     
         5 . The compound according to  claim 1 , represented by the following formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein each definition has the same meaning as described above, or its pharmaceutically acceptable salt. 
       
     
     
         6 . The compound according to  claim 1 , represented by the following formula: 
       
         
           
           
               
               
           
         
         wherein each definition has the same meaning as described in  claim 1 , or its pharmaceutically acceptable salt. 
       
     
     
         7 . The compound according to  claim 1 , represented by the following formula: 
       
         
           
           
               
               
           
         
         wherein each definition has the same meaning as described in  claim 1 , or its pharmaceutically acceptable salt. 
       
     
     
         8 . The compound according to  claim 1 , represented by the following formula: 
       
         
           
           
               
               
           
         
         wherein each definition has the same meaning as described in  claim 1 , or its pharmaceutically acceptable salt. 
       
     
     
         9 . The compound according to  claim 1 , represented by the following formula: 
       
         
           
           
               
               
           
         
         wherein each definition has the same meaning as described in  claim 1 , or its pharmaceutically acceptable salt. 
       
     
     
         10 . The compound according to  claim 1 , represented by the following formula: 
       
         
           
           
               
               
           
         
         wherein each definition has the same meaning as described in  claim 1 , or its pharmaceutically acceptable salt. 
       
     
     
         11 . The compound represented by the following formula: 
       
         
           
           
               
               
           
         
         wherein P is hydrogen or a group P R  to form a prodrug, or its pharmaceutically acceptable salt. 
       
     
     
         12 . The compound according to any one of  claims 1  to  11 , or its pharmaceutically acceptable salt,
 wherein P R  is a group selected from the following formula a) to ac):
   —C(═O)—P R0 ,  a)
 
   —C(═O)—P R1 ,  b)
 
   —C(═O)-L-P R1 ,  c)
 
   —C(═O)-L-O—P R1 ,  d)
 
   —C(═O)-L-O-L-O—P R1 ,  e)
 
   —C(═O)-L-O—C(═O)—P R1 ,  f)
 
   —C(═O)—O—P R2 ,  g)
 
   —C(═O)—N(—K)( PR2 )  h)
 
   —C(═O)—O-L-O— PR2 ,  i)
 
   —C(P R3 ) 2 —O—P R4 ,  j)
 
   —C(P R3 ) 2 —O-L-O—P R4 ,  k)
 
   —C(P R3 ) 2 —C(═O)—P R4 ,  l)
 
   —C(P R3 ) 2 —O—C(═O)—O—P R4 ,  m)
 
   —C(P R3 ) 2 —O—C(═O)N(—K)—P R4 ,  n)
 
   —C(P R3 ) 2 —O—C(═O)—O-L-O—P R4 ,  o)
 
   —C(P R3 ) 2 —O—C(═O)—O-L-N(P R4 ) 2 ,  p)
 
   —C(P R3 ) 2 —O—C(═O)—N(—K)-L-O—P R4 ,  q)
 
   —C(P R3 ) 2 —O—O—C(═O)—N(—K)-L-N(P R4 ) 2 ,  r)
 
   —C(P R3 ) 2 —O—C(═O)—O-L-O-L-O—P R4 ,  s)
 
   —C(P R3 ) 2 —O—C(═O)—O-L-N(—K)—C(═O)—P R4 ,  t)
 
   —C(P R3 ) 2 —O—P(═O)(—P R5 ) 2 ,  u)
 
   —C(P R3 ) 2 —P R6 , (except for a benzyl group)  v)
 
   —C(═N + (P R7 ) 2 )(—N(P R7 ) 2 ),  w)
 
   —C( PR3 ) 2 —C(P R3 ) 2 —C(═O)—O—P R2 ,  x)
 
   —C(P R3 ) 2 —N(—K)—C(═O)—O—P R2 ,  y)
 
   —P(═O)(—P R8 )(—P R9 ),  z)
 
   —S(═O) 2 —P R10 ,  aa)
 
   —P R11 , and  ab)
 
   —C(P R3 ) 2 —C(P R3 ) 2 —O—P R2 ,  ac)
 
 
 wherein L is straight or branched alkylene, or straight or branched alkenylene; 
 K is hydrogen, or alkyl optionally substituted by substituent group A; 
 P R0  is alkyl optionally substituted by substituent group A, or alkenyl optionally substituted by substituent group A; 
 P R1  is carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, alkylamino optionally substituted by substituent group A, or alkylsulfanyl optionally substituted by substituent group A; 
 P R2  is alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, carbocyclylalkyl optionally substituted by substituent group A, heterocyclylalkyl optionally substituted by substituent group A or trialkylsilyl; 
 P R3  is each independently hydrogen or alkyl; 
 P R4  is each independently alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, alkylamino optionally substituted by substituent group A, carbocyclylalkyl optionally substituted by substituent group A, heterocyclylalkyl optionally substituted by substituent group A, or trialkylsilyl; 
 P R5  is each independently hydroxy or OBn; 
 P R6  is carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A; 
 P R7  is each independently alkyl optionally substituted by substituent group A; 
 P R8  is alkyloxy optionally substituted by substituent group A; 
 P R9  is alkyloxy optionally substituted by substituent group A, alkylamino optionally substituted by substituent group A, carbocyclyloxy optionally substituted by substituent group A, heterocyclyloxy optionally substituted by substituent group A, carbocyclylamino optionally substituted by substituent group A or heterocyclylamino optionally substituted by substituent group A; 
 P R8  and P R9  may be taken together with an adjacent phosphorus atom to form heterocycle optionally substituted by substituent group A; 
 P R10  is alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, carbocyclylalkyl optionally substituted by substituent group A or heterocyclylalkyl optionally substituted by substituent group A; 
 P R11  is alkyl optionally substituted by substituent group A, alkenyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A; 
 Substituent group A; oxo, alkyl, hydroxyalkyl, amino, alkylamino, carbocyclyl group, heterocyclyl group, carbocyclylalkyl, alkylcarbonyl, halogen, hydroxy, carboxy, alkylcarbonylamino, alkylcarbonylaminoalkyl, alkylcarbonyloxy, alkyloxycarbonyl, alkyloxycarbonylalkyl, alkyloxycarbonyloxy, alkylaminocarbonyloxy, alkylaminoalkyl, alkyloxy, cyano, nitro, azido, alkylsulfonyl, trialkylsilyl and phospho. 
 
     
     
         13 . The compound according to  claim 12 , or its pharmaceutically acceptable salt, wherein P R  is a group selected from the following formula:
   —C(═O)—P R0 ,  a)
     —C(═O)P R1 ,  b)
     —C(═O)—O—P R2 ,  g)
     —C(═O)—N(—K)(P R2 ),  h)
     —C(═O)—O-L-O—P R2 ,  i)
     —C(P R3 ) 2 —O—C(═O)—P R4 ,  l)
     —C(P R3 ) 2 —O—C(═O)—O—P R4 ,  m)
     —C(P R3 ) 2 —O—C(═O)—O-L-O— PR4 ,  o)
     —C(P R3 ) 2 —P R6 , (except for a benzyl group)  v)
     —C(P R3 ) 2 —C(P R3 ) 2 —C(═O)—O—P R2 ,  x)
     —C(P R3 ) 2 —N(—K)—C(═O)—O—P R2 , and  y)
     —P(═O)(—P R8 )(—P R9 ),  z)
   wherein L is straight or branched lower alkylene;   K is hydrogen or alkyl optionally substituted by substituent group A;   P R0  is alkyl optionally substituted by substituent group A;   P R1  is carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A;   P R2  is alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, carbocyclylalkyl optionally substituted by substituent group A, or heterocyclylalkyl optionally substituted by substituent group A;   P R3  is each independently hydrogen or alkyl;   P R4  is alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A;   P R6  is carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A;   P R8  is alkyloxy optionally substituted by substituent group A;   P R9  is alkyloxy optionally substituted by substituent group A, alkylamino optionally substituted by substituent group A, carbocyclyloxy optionally substituted by substituent group A, heterocyclyloxy optionally substituted by substituent group A, carbocyclylamino optionally substituted by substituent group A or heterocyclylamino optionally substituted by substituent group A; and   P R8  and P R9  may be taken together with an adjacent phosphorus atom to form heterocycle optionally substituted by substituent group A,   Substituent group A; oxo, alkyl, alkylamino, carbocyclyl group, heterocyclyl group, alkylcarbonyl, halogen, hydroxy, alkylcarbonylamino, alkylcarbonyloxy, alkyloxycarbonyl, alkyloxycarbonylalkyl, alkylaminocarbonyloxy, alkyloxy, nitro, azido, alkylsulfonyl and trialkylsilyl.   
     
     
         14 . A compound represented by the following formula: 
       
         
           
           
               
               
           
         
         or its pharmaceutically acceptable salt. 
       
     
     
         15 . A compound represented by the following formula: 
       
         
           
           
               
               
           
         
         or its pharmaceutically acceptable salt. 
       
     
     
         16 . A pharmaceutical composition comprising the compound of any one of  claims 1  to  15 , or its pharmaceutically acceptable salt. 
     
     
         17 . The pharmaceutical composition according to  claim 16 , which exhibits anti influenza activity. 
     
     
         18 . The pharmaceutical composition according to  claim 16 , which exhibits cap-dependent endonuclease inhibitory activity. 
     
     
         19 . A method for treating and/or preventing disease caused by a virus having cap-dependent endonuclease characterized in administering the compound of any one of  claims 1  to  15 , or its pharmaceutically acceptable salt. 
     
     
         20 . A compound according to any one of  claims 1  to  15  or its pharmaceutically acceptable salt, for treating or preventing disease caused by a virus having cap-dependent endonuclease.