Indole, azaindole and related heterocyclic pyrrolidine derivatives

Abstract

This invention provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with amido piperazine derivatives. These compounds possess unique antiviral activity, whether used alone or in combination with other antivirals, antiinfectives, immunomodulators or HIV entry inhibitors. More particularly, the present invention relates to the treatment of HIV and AIDS.

1 . A compound of Formula I, including pharmaceutically acceptable salts thereof  
       
         
           
           
               
               
           
         
       
       wherein: 
 Z is  
                     
 Q is selected from the group consisting of:  
                     
 R 1 , R 2 , R 3 , R 4 , and R 5 , are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, COOR 8 , YR 57 , and B;  
 m is 1 or 2;  
 R 7  is (CH 2 ) n R 44  wherein n is 0-6;  
 R 6  is O or does not exist;  
 — represents a carbon-carbon bond or does not exist;  
 A is selected from the group consisting of C 1-6 alkoxy, phenyl and D; wherein D is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, benzoimidazolyl and benzothiazolyl; wherein said phenyl and D are independently optionally substituted with one or two of the same or different amino, halogen or trifluoromethyl;  
 —W— is  
                     
 B is selected from the group consisting of (C 1-6 )alkyl, (C 3-6 )cycloalkyl, C(O)NR 40 R 41 , phenyl and heteroaryl; wherein said (C 1-6 )alkyl, phenyl and heteroaryl are independently optionally substituted with one to three same or different halogens or from one to three same or different substituents selected from F;  
 F is selected from the group consisting of (C 1-6 )alkyl, phenyl, hydroxy, (C 1-6 )alkoxy, halogen, benzyl, —NR 42 C(O)—(C 1-6 )alkyl, —NR 42 R 43 , COOR 54  and —CONR 42 ; wherein said (C 1-6 )alkyl is optionally substituted with one to three same or different halogen;  
 R 8  is selected from the group consisting of hydrogen and (C 1-6 )alkyl;  
 R 9  is selected from the group consisting of hydrogen and methyl;  
 X is selected from the group consisting of NR 9 , O and S;  
 R 40  and R 41  are independently selected from the group consisting of hydrogen, (C 1-6 )alkyl, (C 1-6 )alkoxy, phenyl and heteroaryl; wherein said phenyl and heteroaryl are independently optionally substituted with one to three same or different halogen, methyl, or CF 3  groups;  
 R 42  and R 43  are independently selected from the group consisting of hydrogen and (C 1-6 )alkyl;  
 R 44  is selected from the group consisting of H, (C 1-6 )alkyl, CO(C 1-6 )alkyl, C(O)-phenyl and —CONR a R b ;  
 R a  and R b  are each independently H, (C 1-6 )alkyl or phenyl;  
 R 54  is selected from the group consisting of hydrogen and (C 1-6 )alkyl;  
 R 57  is (C 1-6 )alkyl; and  
 heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl, 1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyl and triazolyl.  
 
     
     
         2 . The compound of  claim 1 , including pharmaceutically acceptable salts thereof of formula  
       
         
           
           
               
               
           
         
       
       wherein: 
 Z is  
                     
 A is selected from the group consisting of phenyl and D; wherein D is selected from the group consisting of pyridinyl, furanyl and thienyl; wherein phenyl and D are independently optionally substituted with one or two of the same or different amino or halogen;  
 W is selected from the group consisting of  
                     
 R 1  is hydrogen; and  
 Q is a member selected from groups (A) and (B) consisting of  
 (A)  
                     
  provided R 2  and R 3  are each independently hydrogen, methoxy or halogen; and R 4  and R 5  are selected from the group consisting of hydrogen, halogen, cyano, COOR 8 , C(O)NHCH 3 , C(O)NHheteroaryl, and heteroaryl; and  
 (B)  
                     
  provided R 2  is hydrogen, methoxy or halogen;  
 R 3  and R 4  are selected from the group consisting of hydrogen, halogen, methoxy, cyano, COOR 8 , C(O)NHCH 3 , C(O)NHheteroaryl and heteroaryl; and R 6  does not exist;  
 and — represents a carbon-carbon bond in (A) and (B).  
 
     
     
         3 . A pharmaceutical composition which comprises an antiviral effective amount of a compound of Formula I, including pharmaceutically acceptable salts thereof, as claimed in any of claims  1 - 2 , and one or more pharmaceutically acceptable carriers, excipients or diluents.  
     
     
         4 . The pharmaceutical composition of  claim 3 , useful for treating infection by HIV, which additionally comprises an antiviral effective amount of an AIDS treatment agent selected from the group consisting of: 
 (a) an AIDS antiviral agent;    (b) an anti-infective agent;    (c) an immunomodulator; and    (d) HIV entry inhibitors.    
     
     
         5 . A method for treating a mammal infected with a virus comprising administering to said mammal an antiviral effective amount of a compound of Formula I, including pharmaceutically accceptable salts thereof, as claimed in any of claims  1 - 2 , and one or more pharmaceutically acceptable carriers, excipients or diluents.  
     
     
         6 . The method of  claim 5 , comprising administering to said mammal an antiviral effective amount of a compound of Formula I in combination with an antiviral effective amount of an AIDS treatment agent selected from the group consisting of: an AIDS antiviral agent; an anti-infective agent; an immunomodulator; and an HIV entry inhibitor.  
     
     
         7 . The method of  claim 5  wherein said virus is HIV.  
     
     
         8 . The method of  claim 6  wherein said virus is HIV.