Imidazo[1,2-a]pyridine derivatives for treatment of herpes viral infections

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)NHR 10 Het, —C(S)NR 9 R 10 , —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 atoms to which they are bonded form a C 5-6 cycloalkyl or a 5 or 6-membered heterocyclic ring 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, 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 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  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, alkenyl, alkynyl, cycloalkyl and cycloalkenyl;  
 Ay is aryl;  
 Het is a 5- or 6-membered heterocyclic or heteroaryl group;  
 
 R 2  is selected from the group consisting of halo, alkenyl, cycloalkyl, cycloalkenyl, Ay, Het, —OR 7 , —OAy, —OHet, —OR 10 Het, —S(O) n R 9 , —S(O) n Ay, —S(O) n NR 7 R 8 , —S(O) n Het, —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;  
 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, alkenyl, cycloalkyl, 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 cycloalkyl, —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; 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, —OHet, —OR 10 Ay, —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 C 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 5  groups together with the atoms to which they are bonded form a C 5-6  cycloalkyl or aryl;  
 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 each R 1  is the same or different and is independently selected from the group consisting of halo, alkyl, cycloalkyl, Ay, Het, —OR 7 , —C(O)R 9 , —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 , —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)NR 7 Ay, —R 10 SO 2 NHCOR 9 , —R 10 NR 7 R 8 , —R 10 NR 7 Ay, cyano, nitro and azido.  
   
   
       3 . The compound according to  claim 1  wherein each R 1  is the same or different and is independently selected form the group consisting of halo, alkyl, Het, —NR 7 R 8 , —NR 7 Ay, and —NHHet.  
   
   
       4 . The compound according to  claim 1  wherein p is 1 or 2.  
   
   
       5 . The compound according to  claim 1  wherein R 2  is selected from the group consisting of Het, —OR 7 , —S(O) n R 9 , —NR 7 R 8 , —NHHet and —NHR 10 Het.  
   
   
       6 . The compound according to  claim 1  wherein R 2  is —NR 7 R 8 .  
   
   
       7 - 8 . (canceled)  
   
   
       9 . 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 .  
   
   
       10 . The compound according to  claim 1  wherein R 3  and R 4  are both H.  
   
   
       11 . The compound according to  claim 1  wherein q is 0, 1 or 2.  
   
   
       12 . 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.  
   
   
       13 . 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.  
   
   
       14 . (canceled)  
   
   
       15 . A pharmaceutical composition comprising a compound according to  claim 1 .  
   
   
       16 . The pharmaceutical composition according to  claim 15  further comprising a pharmaceutically acceptable carrier or diluent.  
   
   
       17 . The pharmaceutical composition according to  claim 15 , further comprising an antiviral agent selected from the group consisting of aciclovir and valaciclovir.  
   
   
       18 . 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 .  
   
   
       19 . (canceled)  
   
   
       20 . A method for the prophylaxis or 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 .  
   
   
       21 - 23 . (canceled)  
   
   
       24 . A process for preparing a compound according to  claim 1 , said process comprising reacting a compound of formula (XV):  
     
       
         
         
             
             
         
       
       wherein X 1  is halo;  
       with a compound of formula (XVI)  
       
         
           
           
               
               
           
         
       
       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.  
     
   
   
       25 - 32 . (canceled)  
   
   
       33 . A compound selected from the group consisting of: 
 8-chloro-2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)imidazo[1,2-a]pyridine;    4-[8-Chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-A/cyclopentyl-2-pyridinamine;    N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyridinyl]-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-8-amine;    and pharmaceutically acceptable salts thereof.