Pyrazolopyrimidine and Pyrazolotriazine Derivatives and Pharmaceutical Compositions Containing Them

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 selected from the group consisting of H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, 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(S)NR 9 R 11 , —C(NH)NR 7 R 8 , —C(NH)NR 7 Ay, —OR 7 , —OAy, —OHet, —NR 7 R 8 , —NR 7 Ay, —NHHet, —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, —R 10 cycloalkyl, —R 10 Ay, —R 10 Het, —R 10 OR 9 , —R 10 NR 7 R 8 , —R 10 NR 7 Ay, —R 10 NHSO 2 R 9 , —R 10 C(O)R 9 , —R 10 C(O)Ay, —R 10 C(O)Het, —R 10 CO 2 R 9 , —R 10 OC(O)R 9 , —R 10 OC(O)Ay, —R 10 OC(O)Het, —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 OS(O) n R 9 , cyano, nitro and azido; 
 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, —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 Ay, —R 10 Het, —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 OR 9 , —R 10 NR 9 R 11 , —R 10 NHCOR 9 , —R 10 NHC(NH)NR 9 R 11 , —R 10 C(NH)NR 9 R 11 , —R 10 NHSO 2 R 9 , —R 10 SO 2 NR 9 R 11 , —R 10 SO 2 R 10  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 1  is N;  
       p is 0 or 1 when Y 1  is N;  
       each R 6  is the same or different and is independently selected from the group consisting of H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, 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(S)NR 9 R 11 , —C(NH)NR 7 R 8 , —C(NH)NR 7 Ay, —OR 7 , —OAy, —OHet, —NR 7 R 8 , —NR 7 Ay, —NHHet, —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, —R 10 cycloalkyl, —R 10 Ay, —R 10 Het, —R 10 OR 9 , —R 10 NR 7 R 8 , —R 10 NR 7 Ay, —R 10 NHSO 2 R 9 , —R 10 C(O)R 9 , —R 10 C(O)Ay, —R 10 C(O)Het, —R 10 CO 2 R 9 , —R 10 OC(O)R 9 , —R 10 OC(O)Ay, —R 10 OC(O)Het, —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 OS(O) n R 9 , cyano, nitro and azido;  
       Y is N or CH:  
       R 2  is selected from the group consisting of halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR 7 , —OAy, —OHet —NR 7 R 8 , —NR 7 Ay, —NHHet —S(O) n R 9 , —S(O) n Ay, —R 10 NR 7 R 8  and —R 10 NR 7 Ay;  
       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, —C(O)R 7 , C(O)Ay, —CO 2 R 7 , —CO 2 Ay, —OR 7 , —OAy, —NR 7 R 8 , —NR 7 Ay, —NHHet, —SO 2 NHR 9 , —R 10 OR 7 , —R 10 cycloalkyl, —R 10 OAy, —R 10 NR 7 R 8  and —R 10 NR 7 Ay;  
       Ring A is selected from the group consisting of aryl, 5-10 membered heterocyclic group and a 5-10 membered 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, —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(S)NR 9 R 11 , —C(NH)NR 7 R 8 , —C(NH)NR 7 Ay, —OR 7 , —OAy, —OHet, —NR 7 R 8 , —NR 7 Ay, —NHHet, —S(O) n R 9 , —S(O) 2 NR 7 R 8 , —S(O) 2 NR 7 Ay, —R 10 cycloalkyl, —R 10 Het, —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 OR 9 , —R 10 NR 7 R 8 , —R 10 NR 7 Ay, —R 10 SO 2 R 9 , —R 10 SO 2 NR 9 R 11 , —R 10 SO 2 NHCOR 9 , cyano, nitro and azido; or  
       a pharmaceutically acceptable salt thereof.  
     
   
   
       2 . The compound according to  claim 1  wherein R 1  is selected from the group consisting of halo, alkyl, cycloalkyl, Ay, Het, —OR 7 , —OAy, —NR 7 R 8 , —NR 7 Ay, —NHHet, —S(O) n R 9 , —R 10 cycloalkyl, —R 10 OR 9 , —R 10 NR 7 R 8  and —R 10 NR 7 Ay.  
   
   
       3 . The compound according to  claim 1  wherein R 1  is selected from the group consisting of alkyl, Het, —OR 7 , —NR 7 R 8 , —NR 7 Ay and —S(O) n R 9 .  
   
   
       4 - 5 . (canceled)  
   
   
       6 . The compound according to  claim 1  wherein p is 0 or 1.  
   
   
       7 . 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, alkyl, Ay, Het, —C(O)Het, —CO 2 R 9 , —C(O)NR 7 R 8 , —C(O)NR 7 Ay, —OR 7 , —OAy, —NR 7 R 8 , —NR 7 Ay, —NHHet, —S(O) n R 9 , —S(O) n Ay, —S(O) n Het, —R 10 OR 9  and cyano.  
   
   
       8 . 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, alkyl, Het, —NR 7 R 8 , —NHHet and —S(O) n R 9 .  
   
   
       9 . The compound according to  claim 1  wherein Y is CH.  
   
   
       10 . The compound according to  claim 1  wherein Y is N.  
   
   
       11 . The compound according to  claim 1  wherein R 2  is selected from the group consisting of Ay, Het, —OR 7 , —OAy, —OHet, —NR 7 R 8 , —NR 7 Ay, —NHHet, —S(O) n R 9 , —S(O) n Ay, —R 10 NR 7 R 8  and —R 10 NR 7 Ay.  
   
   
       12 . The compound according to  claim 1  wherein R 2  is selected from the group consisting of —NR 7 R 8 , —NR 7 Ay and —NHHet.  
   
   
       13 . 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, —CO 2 R 7 , —OR 7 , —NR 7 R 8 , —R 10 OR 7  and —R 10 NR 7 R 8 .  
   
   
       14 . The compound according to  claim 1  wherein hu  3  and R 4  are both H.  
   
   
       15 . The compound according to  claim 1  wherein Ring A is selected from the group consisting of aryl, a 5-6 membered heterocyclic or heteroaryl group and a 9-membered heterocyclic or heteroaryl group.  
   
   
       16 . The compound according to  claim 1  wherein Ring A is selected from the group consisting of phenyl, naphthyl, furan, pyridine, pyrimidine, thiazol, pyrazine, pyrrole, imidazole, oxazole, benzimidazole, quinoline, isoquinoline and quinoxoline.  
   
   
       17 . The compound according to  claim 1  wherein Ring A is selected from the group consisting of phenyl, furan, pyridine and pyrimidine.  
   
   
       18 . The compound according to  claim 1  wherein Ring A is phenyl.  
   
   
       19 . The compound according to  claim 1  wherein q is 0, 1 or 2.  
   
   
       20 . 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, —CO 2 R 9 , —C(O)NR 7 R 8 , —C(O)NR 7 Ay, —OR 7 , —OAy, —NR 7 R 8 , —NR 7 Ay, —S(O) 2 NR 7 R 8 , cyano, nitro and azido.  
   
   
       21 . 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  and cyano.  
   
   
       22 . A compound selected from the group consisting of: 
 N-Cyclopentyl-8-(2-fluoro-4-pyridinyl)-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine;    N 2 ,N 4 -Dicyclopentyl-8-[2-(cyclopentylamino)-4-pyridinyl]-7-phenylpyrazolo[1,5-a][1,3,5]triazine-2,4-diamine; and    N-Cyclopentyl-8-[2-(cyclopentylamino)-4-pyrimidinyl]-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine;    a pharmaceutically acceptable salt thereof.    
   
   
       23 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier or diluent.  
   
   
       24 - 25 . (canceled)  
   
   
       26 . 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 .  
   
   
       27 . (canceled)  
   
   
       28 . 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 the compound of formula (I) according to  claim 1 .  
   
   
       29 . (canceled)  
   
   
       30 . A process for preparing a compound according to  claim 1  wherein Y is N; R 2  is selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR 7 , —OAy, —OHet —NR 7 R 8 , —NR 7 Ay, —NHHet —S(O) n R 9 , —S(O) n Ay, —R 10 NR 7 R 8  and —R 10 NR 7 Ay; R 3  is selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, Ay, Het, —C(O)R 7 , C(O)Ay, —CO 2 R 7 , —CO 2 Ay, —OR 7 , —OAy, —NR 7 R 8  (where R 7  and R 8  are not H), —NR 7 Ay (where R 7  is H), —SO 2 NHR 9 , —R 10 OR 7 , —R 10 cycloalkyl, —R 10 OAy, —R 10 NR 7 R 8  and —R 10 NR 7 Ay; and R 4  is H said process comprising reacting a compound of formula (XXV):  
     
       
         
         
             
             
         
       
     
     with a compound of formula (XXI):  
     
       
         
         
             
             
         
       
     
   
   
       31 . A process for preparing a compound according to  claim 1  wherein Y is N and R 2  is selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR 7 , —OAy, —OHet —NR 7 R 8 , —NR 7 Ay, —NHHet —S(O) n R 9 , —S(O) n Ay, —R 10 NR 7 R 8  and —R 10 NR 7 Ay, said process comprising the steps of: 
 a) reacting a compound of formula (XXVIII):                          with a compound of formula (XXI):                          to prepare an intermediate compound; and    b) oxidizing the intermediate compound.    
   
   
       32 . A process for preparing a compound according to  claim 1  comprising reacting a compound of formula (XXX).  
     
       
         
         
             
             
         
       
       wherein X 1  is chloro, bromo or iodo;  
       with a compound of formula (X):  
       
         
           
           
               
               
           
         
       
       wherein M 1  is —B(OH) 2 , —B(ORa) 2 , —B(Ra) 2 , —Sn(Ra) 3 , Zn-halide, ZnRa, or Mg-halide where Ra is alkyl or cycloalkyl and halide is halo.  
     
   
   
       33 - 40 . (canceled)