Diazaindole-dicarbonyl-piperazinyl antiviral agents

Abstract

The invention comprises substituted diazaindole-dicarbonyl-piperazinyl derivatives of general Formula I wherein: Q is selected from the group consisting of — may represent a bond; T is —C(O)— or —CH(CN)—; and —Y— is selected from the group consisting of compositions thereof and their use for treating HIV infection.

1 . A compound of Formula I, including pharmaceutically acceptable salts thereof,  
       
         
           
           
               
               
           
         
         wherein:  
         Q is selected from the group consisting of  
         
           
             
             
                 
                 
             
           
         
         T is —C(O)— or —CH(CN)—;  
         R 1  is hydrogen or methyl;  
         R 3  and R 5  are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, COOR 8 , XR 9  and B;  
         R 2  and R 4  are independently O or do not exist with the proviso that only one of R 2  and R 4  are O;  
         R 6  is (CH 2 ) n H, wherein n is 0-1;  
         — represents a carbon-carbon bond or does not exist;  
         —Y— is selected from the group consisting of  
         
           
             
             
                 
                 
             
           
         
         R 10 , R 11 , R 12 , R 13 , R 14 ,R 15 , R 16  and R 17  are each independently H or (C 1-6 )alkyl; wherein said (C 1-6 )alkyl may optionally be substituted with one to three same or different halogen, OH or CN;  
         R 18  is a member selected from the group consisting of C(O)-phenyl, C(O)-heteroaryl, pyridinyl, pyrimidinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, napthyridinyl, pthalazinyl, azabenzofuryl and azaindolyl; wherein said member is optionally substituted with from one to two substituents selected from the group consisting of methyl, -amino, —NHMe, —NMe 2 , methoxy, hydroxymethyl and halogen;  
         D is selected from the group consisting of hydrogen, cyano, S(O) 2 R 24 , halogen, COOR 20 , C(O)NR 21 R 22 , phenyl and heteroaryl; wherein said phenyl or heteroaryl is independently optionally substituted with one to three same or different halogens or from one to three same or different substituents selected from F (as defined below);  
         A is selected from the group consisting of phenyl, pyridinyl, furanyl, thienyl, isoxazole and oxazole; wherein said phenyl, pyridinyl, furanyl, thienyl, isoxazole or oxazole is independently optionally substituted with one to three same or different halogens or from one to three same or different substituents selected from F;  
         B is selected from the group consisting of (C 1-6 )alkyl, C(O)NR 21 R 22 , —C(O)CH 3 , —N(CH 2 CH 2 ) 2 NC(O)pyrazolyl, 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;  
         heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl and triazolyl;  
         F is selected from the group consisting of (C 1-6 )alkyl, (C 1-6 )alkenyl, phenyl, pyridinyl, hydroxy, (C 1-6 )alkoxy, halogen, benzyl, —NR 23 C(O)—(C 1-6 )alkyl, —NR 24 R 25 , —S(O) 2 NR 24 R 25 , COOR 26 , —COR 27 , and —CONR 24 R 25 ; wherein said (C 1-6 )alkyl or phenyl are each optionally substituted with hydroxy, (C 1-6 )alkoxy, (C 1-6 )alkyl, CF 3 , dimethylamino or from one to three same or different halogen;  
         R 8 , R 9  and R 26  are each independently selected from the group consisting of hydrogen and (C 1-6 )alkyl;  
         X is selected from the group consisting of NR 26 , O and S;  
         R 20 , R 21 ,R 22 , R 23 , R 24  and R 25  are independently selected from the group consisting of hydrogen, (C 1-6 )alkyl, phenyl and heteroaryl; wherein said phenyl and heteroaryl are each independently optionally substituted with one to three same or different halogen or methyl; and  
         R 27  is piperazinyl, N-methyl piperazinyl, or 3-pyrazolyl.  
       
     
     
         2 . A compound of  claim 1  wherein T is  
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound of  claim 2 , wherein: 
 R 1  is hydrogen;    — represents a carbon-carbon bond; and    R 2  and R 4  do not exist.    D is selected from the group consisting of hydrogen, cyano, S(O) 2 R 24 , halogen, COOR 20 , C(O)NH 2 , phenyl and heteroaryl; wherein said phenyl or heteroaryl is independently optionally substituted with one to three same or different halogens or a member selected from the group consisting of (C 1-6 )alkyl, (C 1-6 )alkenyl, hydroxy, (C 1-6 )alkoxy, halogen, —NR 24 R 25 , —S(O) 2 NR 24 R 25 , COOR 26  and —CONR 24 R 25 ; wherein said (C 1-6 )alkyl is optionally substituted with one to three same or different halogen or a hydroxy; and    A is selected from the group consisting of phenyl, pyridinyl, furanyl, thienyl, isoxazole and oxazole; wherein said phenyl, pyridinyl, furanyl, thienyl, isoxazole or oxazole are independently optionally substituted with one to three same or different halogens or a member selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkenyl, (C 1-3 )alkoxy, halogen and —NH 2 ; wherein said (C 1-4 )alkyl is optionally substituted with one to three same or different halogens.    
     
     
         4 . A compound of  claim 3  wherein: 
 R 6  is hydrogen; and    R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16  and R 17  are each independently H or methyl, with the proviso that a maximum of two of R 10 —R 17  is a methyl.    
     
     
         5 . A compound of  claim 4  wherein: 
 Q is a member selected from groups (A), (B), and (C) consisting of    (A)                          wherein R 3  is hydrogen, C 1 -C 3  alkoxy, —NR 26 R 9  or halogen;    (B)                          wherein R 3  is hydrogen, methoxy or halogen; and    (C)                          wherein R 3  is hydrogen, methoxy or halogen.    
     
     
         6 . A compound of  claim 5  wherein: 
 group(A) of Q is:                          wherein R 3  is hydrogen; and    group (C) of Q is:                          wherein    R 5  is hydrogen.    
     
     
         7 . A compound of  claim 5  wherein: 
 Q is selected from group (A) or (B); and    R 5  is selected from the group consisting of hydrogen, halogen, heteroaryl, phenyl, cyano, methoxy, COOR 8 , C(O)NH 2 , C(O)NHheteroaryl, and C(O)NHCH 3 ; wherein said C(O)NHheteroaryl, 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.    
     
     
         8 . A compound of  claim 7  wherein: 
 R 5  is selected from the group consisting of C(O)NH 2 , C(O)NHCH 3  and C(O)NHheteroaryl; wherein said C(O)NHheteroaryl is optionally substituted with one to three same or different halogens or from one to three same or different substituents selected from F.    
     
     
         9 . A compound of  claim 7  wherein: 
 R 5  is selected from the group consisting of phenyl and heteroaryl; wherein said 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.    
     
     
         10 . A compound of  claim 9  wherein: 
 heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazoyl, pyrazolyl, tetrazolyl and triazolyl; wherein said heteroaryl is independently optionally substituted with one to three same or different halogens or from one to three same or different substituents selected from F.    
     
     
         11 . A compound of  claim 5 , wherein: 
 R 18  is —C(O)phenyl or —C(O)heteroaryl; wherein said heteroaryl is pyridinyl, furanyl or thienyl; wherein heteroaryl is independently optionally substituted with a member selected from the group consisting of halogen, methyl, -amino, —NHMe, NMe 2  and hydroxymethyl.    
     
     
         12 . A compound of  claim 5  wherein: 
 —W— is                          R 10 , R 11 , R 12 , R 13 , R 14 ,R 15 , R 16  and R 17  are each independently H or methyl, with the proviso that not more than one is methyl; and    R 18  is selected from the group consisting of C(O)-phenyl and C(O)-heteroaryl; wherein each of C(O)-phenyl or —C(O)-heteroaryl may be optionally substituted with from one to two methyl, -amino, —NHMe, —NMe 2 , methoxy, hydroxymethyl or halogen.    
     
     
         13 . A compound of  claim 5  wherein: 
 —W— is                          R 10 , R 11 , R 12 , R 13 , R 14 ,R 15 , R 16  and R 17  are each independently H or methyl, with the proviso that not more than one is methyl; and    R 18  is selected from the group consisting of pyridinyl, pyrimidinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, napthyridinyl, pthalazinyl, azabenzofuryl and azaindolyl, each of which may be optionally substituted with from one to two substituents selected from the group consisting of methyl, -amino, —NHMe, —NMe 2 , methoxy, hydroxymethyl and halogen.    
     
     
         14 . A compound of  claim 5  wherein: 
 —W— is                          R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16  and R 17  are each independently H or methyl, with the proviso that one is methyl;    D is selected from the group consisting of hydrogen, cyano, S(O) 2 R 24 , halogen, COOR 20 , C(O)NH 2 , phenyl and heteroaryl; wherein said phenyl or heteroaryl is independently optionally substituted with one to three same or different halogens or from one to three same or different substituents selected from the group consisting of (C 1-6 )alkyl, (C 1-6 )alkenyl, hydroxy, (C 1-6 )alkoxy, halogen, —NR 24 R 25 , —S(O) 2 NR 24 R 25 , COOR 26  and —CONR 24 R 25 ; wherein said (C 1-6 )alkyl is optionally substituted with one to three same or different halogen or a hydroxy; and    A is selected from the group consisting of phenyl, pyridinyl, furanyl, thienyl, isoxazole and oxazole; wherein said phenyl, pyridinyl, furanyl, thienyl, isoxazole or oxazole is independently optionally substituted with one to three same or different halogens or from one to three same or different substituents selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkenyl, (C 1-3 )alkoxy, halogen and —NH 2 ; wherein said (C 1-4 )alkyl is optionally substituted with one to three same or different halogens.    
     
     
         15 . A compound of  claim 7  wherein: 
 Q is selected from Group (A).    
     
     
         16 . A compound of  claim 1  including pharmaceutically acceptable salts thereof,  
       
         
           
           
               
               
           
         
         wherein:  
         Q is selected from the group consisting of  
         
           
             
             
                 
                 
             
           
         
         R 1  is hydrogen or methyl;  
         R 3  and R 5  are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, COOR 8 , XR 9  and B;  
         R 2  and R 4  are independently O or do not exist, with the proviso that only one of R 2  and R 4  are O;  
         R 6  is (CH 2 ) n H, wherein n is 0-1;  
         — represents a carbon-carbon bond or does not exist;  
         —Y— is selected from the group consisting of  
         
           
             
             
                 
                 
             
           
         
         R 10 , R 11 , R 12 , R 13 , R 14 ,R 15 , R 16  and R 17  are each independently H or (C 1-6 )alkyl; wherein said (C 1-6 )alkyl may optionally be substituted with one to three same or different halogen, OH or CN;  
         R 18  is a member selected from the group consisting of C(O)-phenyl, C(O)-heteroaryl, pyridinyl, pyrimidinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, napthyridinyl, pthalazinyl, azabenzofuryl and azaindolyl; wherein said member is optionally substituted with from one to two substituents selected from the group consisting of methyl, -amino, —NHMe, —NMe 2 , methoxy, hydroxymethyl and halogen;  
         D is selected from the group consisting of hydrogen, cyano, S(O) 2 R 24 , halogen, COOR 20 , C(O)NR 21 R 22 , phenyl and heteroaryl; wherein said phenyl or heteroaryl is independently optionally substituted with one to three same or different halogens or from one to three same or different substituents selected from F;  
         A is selected from the group consisting of phenyl, pyridinyl, furanyl, thienyl, isoxazole and oxazole; wherein said phenyl, pyridinyl, furanyl, thienyl, isoxazole or oxazole is independently optionally substituted with one to three same or different halogens or from one to three same or different substituents selected from F;  
         B is selected from the group consisting of (C 1-6 )alkyl, C(O)NR 21 R 22 , 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;  
         heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl and triazolyl;  
         F is selected from the group consisting of (C 1-6 )alkyl, (C 1-6 )alkenyl, phenyl, pyridinyl, hydroxy, (C 1-6 )alkoxy, halogen, benzyl, —NR 23 C(O)—(C 1-6 )alkyl, —NR 24 R 25 , —S(O) 2 NR 24 R 25 , COOR 26 , —COR 27 , and —CONR 24 R 25 ; wherein said (C 1-6 )alkyl or phenyl are each optionally substituted with hydroxy, (C 1-6 )alkoxy, dimethylamino or from one to three same or different halogen;  
         R 8 , R 9  and R 26  are each independently selected from the group consisting of hydrogen and (C 1-6 )alkyl;  
         X is selected from the group consisting of NR 26 , O and S;  
         R 20 , R 21 ,R 22 , R 23 , R 24  and R 25  are independently selected from the group consisting of hydrogen, (C 1-6 )alkyl, phenyl and heteroaryl; wherein said phenyl and heteroaryl are each independently optionally substituted with one to three same or different halogen or methyl; and  
         R 27  is piperazinyl, N-methylpiperazinyl or 3-pyrazolyl.  
       
     
     
         17 . A compound of  claim 6  wherein: 
 Q is                          R 5  is selected from the group consisting of hydrogen, halogen, cyano, XR 9 , heteroaryl, —N(CH 2 CH 2 ) 2 NC(O)pyrazolyl, and —C(O)CH 3 , wherein said heteroaryl is optionally substituted with one substituent selected from F;    heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, isoxazolyl, isoxazolyl, pyrazolyl, and triazolyl;    —Y— is selected from the group consisting of                          R 10 , R 11 , R 12 , R 13 , R 14 ,R 15 , R 16  and R 17  are each hydrogen;    A is phenyl or pyridinyl;    R 18  is C(O)-phenyl, isoquinolyl or quinazolyl;    D is cyano or oxadiazolyl;    F is selected from the group consisting of (C 1-6 )alkyl, phenyl, pyridinyl, (C 1-2 )alkoxy, —COOR 26 —COR and —CONR 24 R 25 ; wherein said phenyl is optionally substituted with one group selected from methyl, methoxy, fluoro, or trifluoromethyl;    X is selected from the group consisting of O;    R 9  is (C 1-2 )alkyl;    R 26  is hydrogen, methyl, or ethyl;    R 24  and R 25  are independently selected from the group consisting of hydrogen and methyl; and    R 27  is piperazinyl, N-methyl piperazinyl, or 3-pyrazolyl.    
     
     
         18 . A compound of  claim 17  wherein: 
 R 5  is heteroaryl optionally substituted with one halogen or one substituent selected from F;    —Y— is                          R 18  is C(O)-phenyl, isoquinolyl or quinazolyl; and    F is (C 1-6 )alkyl.    
     
     
         19 . A compound of  claim 18  wherein R 18  is C(O)-phenyl.  
     
     
         20 . A compound of  claim 18  wherein R 18  is isoquinolyl or quinazolyl.  
     
     
         21 . A compound of  claim 17  wherein: 
 R 5  is heteroaryl optionally substituted with one substituent selected from F;    heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, isoxazolyl, isoxazolyl, pyrazolyl and triazolyl; and    —Y— is                          
     
     
         22 . A compound of  claim 17  wherein: 
 Q is                          R 5  is heteroaryl optionally substituted with one substituent selected from F; and    heteroaryl is selected from the group consisting of pyrazolyl and triazolyl.    
     
     
         23 . A compound of  claim 22  wherein: 
 F is selected from the group consisting of methyl and —CONR 24 R 25 ; and    R 24  and R 25  are independently selected from the group consisting of hydrogen and methyl.    
     
     
         24 . A compound of  claim 23  wherein: 
 F is methyl.    
     
     
         25 . A pharmaceutical composition which comprises an antiviral effective amount of a compound of Formula I, including pharmaceutically acceptable salts thereof, as claimed in  claim 1 , and one or more pharmaceutically acceptable carriers, excipients or diluents.  
     
     
         26 . The pharmaceutical composition of  claim 25  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.    
     
     
         27 . A method for treating a mammal infected with the HIV virus comprising administering to said mammal an antiviral effective amount of a compound of Formula I, including pharmaceutically accceptable salts thereof, as claimed in  claim 1 , and one or more pharmaceutically acceptable carriers, excipients or diluents.  
     
     
         28 . The method of  claim 27  comprising administering to said mammal an antiviral effective amount of a compound of Formula I, including pharmaceutically accceptable salts thereof, as claimed in  claim 1 , 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.