Pyrazolo-Pyridine Derivatives As Antiherpes Agents

Abstract

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

1 . A compound of formula (I):  
     
       
         
         
             
             
         
       
     
     wherein 
 p is 0, 1, 2, 3 or 4;  
 each R 1  is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, —OR 7 , —OAy, —OR 10 Ay, —OHet, —OR 10 Het, —C(O)R 9 , —C(O)Ay, —C(O)Het, —CO 2 R 9 , —C(O)NR 7 R 8 , —C(O)NR 7 Ay, —C(O)NHR 10 Ay, —C(O)NH R 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, —NHHet, —NHR 10 Ay, —NHR 10 Het, —R 10 cycloalkyl, —R 10 Ay, —R 10 Het, —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 OR 9 , —R 10 C(O)R 9 , —R 10 CO 2 R 9 , —R 10 C(O)NR 9 R 11 , —R 10 C(O)NR 7 Ay, —R 10 C(O)NHR 10 Het, —R 10 C(S)NR 9 R 11 , —R 10 C(NH)NR 9 R 11 , —R 10 SO 2 R 9 , —R 10 SO 2 NR 9 R 11 , —R 10 SO 2 NHCOR 9 , —R 10 NR 7 R 8 , —R 10 NR 7 Ay, —R 10 NHC(NH)NR 9 R 11 , cyano, nitro and azido; 
 or two adjacent R 1  groups together with the carbon atoms to which they are bonded form a cycloalkyl or a 5- or 6-membered heterocyclic group containing 1 or 2 heteroatoms;  
 each R 7  and R 8  are the same or different and are independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkenyl, —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 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 C(NH)NR 9 R 11 , —R 10 SO 2 R 10 , —R 10 SO 2 NR 9 R 11 , —R 10 SO 2 NHCOR 9 , —R 10 NR 9 R 11 , —R 10 NHCOR 9 , —R 10 NHSO 2 R 9  and —R 10 NHC(NH)NR 9 R 11 ;  
 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  wherein 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, alkenyl, alkynyl, cycloalkyl and cycloalkenyl;  
 Ay is aryl;  
 Het is a 5- or 6-membered heterocyclic or heteroaryl group;  
 
 Y is CH;  
 R 2  is selected from the group consisting of halo, alkyl, alkenyl, cycloalkyl, cycloalkenyl, Ay, Het, —OR 7 , —OAy, —OHet, —OR 10 Het, —S(O) n R 9 , —S(O) n Ay, —S(O) n Het, —S(O) n NR 7 R 8 , —NR 7 R 8 , —NHHet, —NHR 10 Ay, —NHR 10 Het, —R 10 NR 7 R 8  and —R 10 NR 7 Ay;  
 n is 0, 1 or 2;  
 R 3  and R 4  are the same or different and are each independently selected from the group consisting of H, halo, alkyl, alkenyl, cycloalkyl, Ay, Het, —OR 7 , —OAy, —C(O)R 7 , (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 cycloalkyl, —R 10 OR 7 , —R 10 OAy, —R 10 NR 7 R 8  and —R 10 NR 7 Ay;  
 Ring A is a 5-10 membered heterocyclic or heteroaryl group;  
 q is 0, 1, 2, 3, 4 or 5; and  
 each R 5  is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, —OR 7 , —OAy, —OR 10 Ay, —OHet, —OR 10 Het, —C(O)R 9 , —C(O)Ay, —C(O)Het, —CO 2 R 9 , —C(O)NR 7 R 8 , —C(O)NR 7 Ay, —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 Het, —R 10 OR 9 , —R 10 C(O)R 9 , —R 10 CO 2 R 9 , —R 10 C(O)NR 9 R 11 , —R 10 C(O)NR 7 Ay, —R 10 C(O)NHR 10 Het, —R 10 C(S)NR 9 R 11 , —R 10 C(NH)NR 9 R 11 , —R 10 SO 2 R 9 , —R 10 SO 2 NR 9 R 11 , —R 10 SO 2 NHCOR 9 , —R 10 NR 7 R 8 , —R 10 NR 7 Ay, —R 10 NHC(NH)NR 9 R 11 , cyano, nitro and azido;  
 wherein when Y is CH, R 3  is not —NR 7 Ay;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       2 . The compound according to  claim 1  wherein p is 0, 1 or 2.  
   
   
       3 . The compound according to  claim 1  wherein p is 1.  
   
   
       4 . The compound according to  claim 1  wherein each R 1  is the same or different and is independently selected from the group consisting of halo, alkyl, Ay, Het, —OR 7 , —OAy, —C(O)Het, —CO 2 R 9 , —C(O)NR 7 R 8 , —C(O)NR 7 Ay, —C(O)NHR 10 Het, —S(O) n R 9 , —NR 7 R 8 , —NR 7 Ay, —NHHet, —NHR 10 Ay, —NHR 10 Het, —R 10 OR 9 , cyano, nitro and azido.  
   
   
       5 . The compound according to  claim 1  wherein each R 1  is the same or different and is independently selected from the group consisting of halo, alkyl, Het, —OR 7 , —C(O)NR 7 R 8 , —S(O) n R 9 , —NR 7 R 8 , —NR 7 Ay and —NHHet.  
   
   
       6 . The compound according to  claim 1  wherein R 2  is selected from the group consisting of Ay, Het, —OR 7 , —OHet, —OR 10 Het, —S(O) n R 9 , —NR 7 R 8 , —NHHet, —NHR 10 Het and —R 10 NR 7 R 8 .  
   
   
       7 . The compound according to  claim 1  wherein R 2  is selected from the group consisting of —NR 7 R 8  and Het.  
   
   
       8 - 9 . (canceled)  
   
   
       10 . The compound according to  claim 1  wherein R 3  and R 4  are the same or different and are each independently selected from the group consisting of H, halo, alkyl, Ay, —OR 7 , —CO 2 R 7 , —NR 7 R 8 , —R 10 OR 7  and —R 10 NR 7 R 8 .  
   
   
       11 . The compound according to  claim 1  wherein R 3  and R 4  are each H.  
   
   
       12 . The compound according to  claim 1  wherein Ring A is selected from the group consisting of furan, pyridine, pyrimidine, thiazol, pyrazine, pyrrole, imidazole, oxazole, benzimidazole, quinoline, isoquinoline and quinoxoline.  
   
   
       13 . The compound according to  claim 1  wherein Ring A is selected from the group consisting of furan, thiazole, pyridine and pyrimidine.  
   
   
       14 . The compound according to  claim 1  wherein q is selected from the group consisting of 0, 1 and 2.  
   
   
       15 . The compound according to  claim 1  wherein q is 1.  
   
   
       16 . 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, alkenyl, Ay, Het, —OR 7 , —OAy, —CO 2 R 9 , —C(O)NR 7 R 8 , —C(O)NR 7 Ay, —S(O) 2 NR 7 R 8 , —NR 7 R 8 , —NR 7 Ay, —NHR 10 Ay, cyano, nitro and azido.  
   
   
       17 . 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 , —NR 7 R 8 , cyano, nitro and azido.  
   
   
       18 . A compound selected from the group consisting of: 
 N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyridinyl]-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amine;    N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyridinyl]-2-(2-methyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyridin-7-amine; 
 or a pharmaceutically acceptable salt thereof.  
   
   
   
       19 . A pharmaceutical composition comprising a compound according to  claim 1 .  
   
   
       20 . A pharmaceutical composition according to  claim 19  further comprising a pharmaceutically acceptable carrier or diluent.  
   
   
       21 . A pharmaceutical composition according to  claim 19  further comprising an antiviral agent selected from the group consisting of aciclovir and valaciclovir.  
   
   
       22 . A method for the treatment of a herpes viral infection selected from herpes simplex virus 1 and herpes simplex virus 2 in an animal, said method comprising administering to the animal a therapeutically effective amount of a compound according to  claim 1 .  
   
   
       23 . (canceled)  
   
   
       24 . A method for the treatment of a condition or disease associated with a herpes viral infection selected from herpes simplex virus 1 and herpes simplex virus 2 in an animal, comprising administering to the animal a therapeutically effective amount of a compound according to  claim 1 .  
   
   
       25 - 27 . (canceled)  
   
   
       28 . A process for preparing the compound according to  claim 1 , said process comprising reacting a compound of formula (XXII):  
     
       
         
         
             
             
         
       
       wherein 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.  
     
   
   
       29 . A process for preparing the compound according to  claim 1 , said process comprising reacting a compound of formula (XXIX):  
     
       
         
         
             
             
         
       
       with a 1-aminopyridinium salt of formula (XXX):  
       
         
           
           
               
               
           
         
         wherein Z- is a counter ion.  
       
     
   
   
       30 . A process for preparing the compound according to  claim 1 , said process comprising reacting a compound of formula (XXXVI):  
     
       
         
         
             
             
         
       
       with a suitable ring forming reagent.  
     
   
   
       31 - 38 . (canceled)