Antiviral Pyrazolopyridine Compounds

Abstract

The present invention provides compounds of formula (I): pharmaceutical compositions containing the same, processes for preparing the same and their use as pharmaceutical agents.

1 . A compound of formula (I):  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  is H;  
 R 2  is selected from the group consisting of halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR 7 , —OAy, —OHet, —OR 10 Het, —S(O) n R 9 , —S(6) n Ay, —S(O) n Het, —S(O) n NR 7 R 8 , —NR 7 R 8 , —NHHet, —NHR 10 Het, —NHR 10 Ay, —R 10 NR 7 R 8  and —R 10 NR 7 Ay; 
 each R 7  and R 8  are the same or different and are independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, —OR 9 , —C(O)R 9 , —CO 2 R 9 , —C(O)NR 9 R 11 —C(S)NR 9 R 11 , —C(NH)NR 9 R 11 . —SO 2 R 10 , —SO 2 NR 9 R 11 , —R 10 cycloalkyl, —R 10 OR 9 , —R 10 NR 9 R 11 , —R 10 C(O)R 9 , —R 10 CO 2 R 9 , —R 10 C(O)NR 9 R 11 , —R 10 C(s)NR 9 R 11 , —R 10 NHC(NH)NR 9 R 11 , —R 10 C(NH)NR 9 R 11 , —R 10 SO 2 R 10 , —R 10 SO 2 NR 9 R 11 , —R 10 NHSO 2 R 9 , —R 10 NHCOR 9  and —R 10 SO 2 NHCOR 9 ;  
 each R 9  and R 11  are the same or different and are independently selected from the group consisting of H, alkyl, cycloalkyl, —R 10 cycloalkyl, —R 10 OH, —R 10  (OR 10 ) w  where w is 1-10, and —R 10 NR 10 R 10 :  
 each R 10  is the same or different and is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl and alkynyl;  
 n is 0, 1 or 2;  
 Ay is aryl;  
 Het is a 5- or 6-membered heterocyclic or heteroaryl group;  
 
 Y is CH;  
 R 3  and R 4  are the same or different and are each independently selected from the group consisting of H, halo, alkyl, cycloalkyl, alkenyl, Ay, Het, —OR 7 , —OAy, —C(O)R 7 , —C(O)Ay, —CO 2 R 7 , —CO 2 Ay, —SO 2 NHR 9 , —NR 7 R 8 , —NR 7 Ay, —NHHet, —NHR 10 Het, —R 10 OR 7 , —R 10 OAy, —R 10 NR 7 R 8  and —R 10 NR 7 Ay;  
 q is 0, 1, 2, 3.4 or 5;  
 each R 5  is the same or different and is independently selected from the group consisting of halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, Ay, Het, —OR 7 , —OAy, —OHet, C(O)R 9 , —CO 2 R 9 , —C(O)NR 7 R 5 , —C(O)Ay, —C(O)NR 7 Ay, —C(O)Het, —C(O)NHR 10 Het, —C(S)NR 9 R 11 , —C(NH)NR 7 R 8 , —C(NH)NR 7 Ay, —S(O) n R 9 , —S(O) 2 NR 7 R 8 , —S(O) 2 NR 7 Ay, —NR 7 R 8 , —NR 7 Ay, —NHHet, —NHR 10 Ay, —NHR 10 Het, —R 10 cycloalkyl, —R 10 OR 9 , —R 10 NR 7 R 8 , —R 10 NR 7 Ay, —R 10 C(O)R 9 , —R 10 CO 2 R 9 , —R 10 C(O)NR 9 R 11 , —R 10 C(S)NR 9 R 11 , —R 10 NHC(NH)NR 9 R 11 , —R 10 C(NH)NR 9 R 11 , —R 10 SO 2 R 9 , —R 10 SO 2 NHCOR 9 , —R 10 SO 2 NR 9 R 11 , cyano, nitro and azido; or 
 two adjacent R 5  groups together with the atoms to which they are bonded form a C 5-6  cycloalkyl or aryl  
 
 p is 1, 2 or 3; and  
 each R 6  is the same or different and is independently selected from the group consisting of halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, Ay, Het, —OR 7 , —OAy, —OHet, —OR 10 Ay, —OR 10 Het, —C(O)R 9 , —CO 2 R 9 , —C(O)NR 1 R 8 , —C(O)Ay, —C(O)NR 7 Ay, C(O)NHR 10 Ay, —C(O)Het, —C(O)NHR 10 Het, —C(S)NR 9 R 11 , —C(NH)NR 7 R 8 , —C(NH)NR 7 Ay, —S(O) n R 9 , —S(O) n Ay, —S(O) n Het, —S(O) 2 NR 7 R 8 , —S(O) 2 NR 7 Ay, —NR 7 R 8 , —NR 7 Ay, —NHR 10 Ay, —NHHet, —NHR 10 Het, —R 10 cycloalkyl, —R 10 Ay, —R 10 Het, —R 10 OR 9 , —R 10 —O—C(O)R 9 , —R 10 —O—C(O)Ay —R 10 —O—C(O)Het, —R 10 —O—S(O) n R 10 , —R 10 NR 7 R 8 , —R 10 NR 7 Ay, —R 10 (O)R 9 R 9 , —R 10 CO 2 R 9 , —R 10 C(O)NR 9 R 11 , —R 10 C(S)NR 9 R 11 , —R 10 NHC(NH)NR 9 R 11 , —R 10 C(NH)NR 9 R 11 , —R 10 SO 2 R 9 , —R 10 SO 2 NHCOR 9 , —R 10 SO 2 NR 9 R 11 , cyano, nitro and azido; or 
 two adjacent R 6  groups together with the atoms to which they are bonded form a C 5 -cycloalkyl or a 5- or 6-membered heterocyclic group containing 1 or 2 heteroatoms;  
 
 wherein at least one R 6  is selected from the group consisting of —NR 7 R 8 , —NR 7 Ay, —NHHet, —NHR 10 Ay and —NHR 10 Het; and  
 wherein when Y is OH, R 3  is not —NR 7 Ay;  
 or a pharmaceutically acceptable salt or solvate thereof.  
 
   
   
       2 . The compound according to  claim 1  wherein R 2  is selected from the group consisting of Ay, Het, —OR 77 —OAy, —OHet, —OR 10 Het —S(O) n R 9 , —S(O) n Ay, —NR 7 R 6 , —NHHet, —NHR 10 Het, —R 10 NR 7 R 8  and —R 10 NR 7 Ay.  
   
   
       3 . The compound according to  claim 1  wherein R 2  is —NR 7 R 8 .  
   
   
       4 - 6 . (canceled)  
   
   
       7 . The compound according to  claim 1  wherein R 3  and R 4  are each H.  
   
   
       8 . The compound according to  claim 1  wherein q is 0, 1 or 2.  
   
   
       9 . (canceled)  
   
   
       10 . The compound according to  claim 1 , wherein each R 5  is the same or different and is independently selected from the group consisting of halo, alkyl, —OR 7  and cyano.  
   
   
       11 . (canceled)  
   
   
       12 . The compound according to  claim 1  wherein p is 1.  
   
   
       13 - 15 . (canceled)  
   
   
       16 . The compound according to  claim 1  wherein each R 6  is the same or different and is independently selected from the group consisting of halo, —NR 7 R 8 , —NR 7 Ay, —NHHet, —NHR 11 )Het and —NHR 10 Ay.  
   
   
       17 . (canceled)  
   
   
       18 . A pharmaceutical composition comprising a compound according to  claim 1 .  
   
   
       19 - 20 . (canceled)  
   
   
       21 . A method for the treatment of a herpes viral infection selected from HSV-1 and HSV-2 in an animal, said method comprising administering to the animal a therapeutically effective amount of a compound according to  claim 1 .  
   
   
       22 - 24 . (canceled)  
   
   
       25 . A process for preparing a compound according to  claim 1 , said process comprising the steps of: 
 (a) reacting the compound of formula (XXXII)                        wherein p′ is 0, 1 or 2;      with diphenylphosphoryl azide in tert-butanol to give the compound of formula (I-X)                          (b) optionally cleaving the compound of formula (I-X) to give the compound of formula (I-Y)                          and    (c) optionally converting the compound of formula (I-Y) to a compound of formula (I-Z)                        where R 6x  is selected form the group consisting of —NR 7 R 8  where R 7  and R 8      are not both H, —NR 7 Ay, —NHHet, —NHR 10 Ay and —NHR 10 Het;      using conditions selected from the group consisting of cross coupling, reductive amination, alkylation, acylation and sulfonylation.    
   
   
       26 - 27 . (canceled)  
   
   
       28 . A process for preparing a compound according to  claim 1  wherein at least one R 6  is selected from the group consisting of —NR 7 R 8 , —NR 7 Ay, —NHHet, —NHR 10 Ay and —NHR 10 Het, said process comprising the steps of: 
 a) reacting a compound of formula (XXII):                        wherein each R 6  is the same or different and is independently selected from the group consisting of halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, Ay, Het, —OR 7 , —OAy, —OHet, —OR 10 Ay, —OR 10 Het, —C(O)R 9 , —CO 2 R 9 , —C(O)NR 7 R 8 , —C(O)Ay, —C(O)NR 7 Ay, —C(O)NHR 10 Ay, —C(O)Het, —C(O)NHR 10 Het, —C(S)NR 9 R 11 , —C(NH)NR 7 R 8 , —C(NH)NR 7 Ay, —S(O) n R 9 , —S(O) n Ay, —S(O) n Het, —S(O) 2 NR 7 R 8 , —S(O) 2 NR 7 Ay, —NR 7 R 9 , —NR 7 Ay, —NHR 10 Ay, —NHHet, —NHR 10 Het, —R 10 cycloalkyl, —R 10 Ay, —R 10 Het, —R 10 OR 9 , —R 10 —O—C(O)R 9 , —R 10 —O—C(O)Ay, —R 10 —O—C(O)Het, —R 10 —O—S(O) n R 9 , —R 10 NR 7 R 8 , —R 10 NR 7 Ay, —R 10 C(O)R 9 , —R 10 CO 2 R 9 , —R 10 C(O)NR 9 R 11 , —R 10 C(S)NR 9 R 11 , —R 10 NHC(NH)NR 9 R 11 , —R 10 C(NH)NR 9 R 11 , —R 10 SO 2 R 9 , —R 10 SO 2 NHCOR 9 , —R 10 SO 2 NR 9 R 11 , cyano, nitro and azido; or    two adjacent R 6  groups together with the atoms to which they are bonded form a C 5-6 cycloalkyl or a 5- or 6-membered heterocyclic group containing 1 or 2 heteroatoms;    wherein, at least one R 6  is selected from the group consisting of halo, —NR 7 R 8 , —NR 7 Ay, —NHHet, —NHR 10 Ay and —NHR 10 Het; and    X 1  is chloro, bromo or iodo;      with a compound of formula (XXIV):                        wherein M 2  is selected from the group consisting of —B(OH) 2 , —B(ORa) 2 , —B(Ra) 2 , —Sn(Ra) 3  Zn-halide, ZnRa, and Mg-halide where Ra is alkyl or cycloalkyl and halide is halo;      to prepare a compound of formula (XVII):                        wherein at least one R 5  is selected from the group consisting of halo, —NR 7 R 8 , —NR 7 Ay, —NHHet, —NHR 10 Ay and —NHR 10 Het; and      b) in the embodiment wherein no R 6  is —NR 7 R 8 , —NR 7 Ay, —NHHet, —NHR 10 Ay or —NHR 10 Het, replacing R 8  halo of the compound of formula (XVII) with an amine substituent selected from the group consisting of —NR 7 R 8 , —NR 7 Ay, —NHHet, —NHR 10 Ay and —NHR 10 Het;    to prepare a compound of formula (I).    
   
   
       29 - 36 . (canceled)