Substituted pyridine-piperazinyl analogues as rsv antiviral compounds

Abstract

The invention concerns novel substituted pyridine-piperazinyl analogues of formula (I) having antiviral activity, in particular, having an inhibitory activity on the replication of the respiratory syncytial virus (RSV). The invention further concerns the preparation of such novel compounds, compositions comprising these compounds, and the compounds for use in the treatment of respiratory syncytial virus infection.

1 . A compound of formula (I′) 
       
         
           
           
               
               
           
         
         or a stereochemically isomeric form thereof, wherein: 
         X and Y are each independently selected from CR 6  or N, wherein R 6  is selected from the group consisting of hydrogen, halo, hydroxy, cyano, polyhaloC 1-4 alkyl, C 1-4 alkyloxy, nitro, amino, mono- or di(C 1-4 alkyl)amino, and C 1-4 alkylcarbonyl; 
         R 1  and R 2  are each independently selected from the group consisting of hydrogen, halo, hydroxy, C 1-4 alkyl, C 1-4 alkyloxy, polyhaloC 1-4 alkyl, polyhaloC 1-4 alkyloxy, cyano, nitro, and C 1-4 alkylcarbonyl; 
         R 3  is hydrogen or C 1-6 alkyl; 
         R 4  is selected from the group consisting of hydrogen, halo, hydroxy, C 1-4 alkyl, C 1-4 alkyloxy, polyhaloC 1-4 alkyl, polyhaloC 1-4 alkyloxy, cyano, nitro, and C 1-4 alkylcarbonyl; 
         L 1  is a direct bond; oxygen; or C 1-4 alkanediyl, wherein said C 1-4 alkanediyl is optionally substituted with one or two substituents each independently selected from the group consisting of hydroxy, and phenyl optionally substituted with C 1-4 alkyloxy; 
         L 2  is a direct bond, phenyl, or piperazine optionally substituted with hydroxy; and 
         R 5  is selected from the group consisting of C 1-4 alkyl, C 3-6 cycloalkyl, heteroalkyl, aryl and heteroaryl;
 wherein said heteroalkyl is piperidinyl; 
 wherein said aryl is phenyl, or naphthalenyl; wherein each aryl is optionally substituted with one or two substituents each independently selected from the group consisting of halo, hydroxy, C 1-4 alkyl, C 1-4 alkyloxy, C 1-4 alkylthio, polyhaloC 1-4 alkyl, C 1-4 alkyloxy, cyano, nitro, amino, o- or di(C 1-4 alkyl)amino, C 1-4 alkylcarbonyl, and C 1-4 alkyl(SO 2 )—NH—; and 
 wherein said heteroaryl is selected from the group consisting of furanyl, thiophenyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 1-benzofuranyl, 2,3-dihydro-1-benzofuranyl, 1-benzothiophenyl, 1-benzopyrazolyl, 1,3-benzothiazolyl, and quinolinyl; wherein each heteroaryl is optionally substituted with one or two substituents each independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkyloxy, hydroxyC 1-4 alkyl, cyanoC 1-4 alkyl, polyhaloC 1-4 alkyl, and C 1-4 alkyloxyC 1-4 alkyl; 
 
         or a pharmaceutically acceptable acid addition salt thereof. 
       
     
     
         2 . The compound as claimed in  claim 1  wherein,
 X and Y are each independently selected from CR 6  or N, wherein R 6  is hydrogen; 
 R 1  and R 2  are each independently selected from the group consisting of hydrogen, halo, hydroxy, C 1-4 alkyl, and C 1-4 alkyloxy; 
 R 3  is hydrogen or C 1-6 alkyl; 
 R 4  is hydrogen; 
 L 1  is a direct bond; oxygen; or C 1-4 alkanediyl optionally substituted with one or two substituents each independently selected from the group consisting of hydroxy, and phenyl optionally substituted with C 1-4 alkyloxy; 
 L 2  is a direct bond, phenyl, or piperazine optionally substituted with hydroxy; and 
 R 5  is C 1-4 alkyl, C 3-6 cycloalkyl, heteroalkyl, aryl or heteroaryl;
 wherein said heteroalkyl is piperidinyl; 
 wherein said aryl is phenyl, or naphthalenyl; wherein said aryl is optionally substituted with one or two substituents each independently selected from the group consisting of halo, hydroxy, C 1-4 alkyl, C 1-4 alkyloxy, C 1-4 alkylthio, polyhaloC 1-4 alkyl, polyhaloC 1-4 alkyloxy, cyano, di(C 1-4 alkyl)-amino, C 1-4 alkylcarbonyl, and C 1-4 alkyl(SO 2 )—NH—; and 
 wherein said heteroaryl is selected from the group consisting of furanyl, pyridinyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 1-benzofuranyl, 2,3-dihydro-1-benzofuranyl, 1-benzothiophenyl, 1-benzopyrazolyl, 1,3-benzothiazolyl, and quinolinyl; wherein said heteroaryl is optionally substituted with one or two substituents each independently selected from the group consisting of: C 1-4 alkyl, C 1-4 alkyloxy, hydroxyC 1-4 alkyl, cyanoC 1-4 alkyl, polyhaloC 1-4 alkyl, and C 1-4 alkyloxyC 1-4 alkyl; 
 
 or a pharmaceutically acceptable acid addition salt thereof. 
 
     
     
         3 . The compound as claimed in  claim 1  wherein X is N, and Y is N. 
     
     
         4 . The compound as claimed in  claim 1  wherein X is N, and Y is CR 6  wherein R 6  is hydrogen. 
     
     
         5 . The compound as claimed in  claim 1  wherein X is CR 6 , wherein R 6  is hydrogen; and Y is N. 
     
     
         6 . The compound as claimed in  claim 1  wherein X is CR 6 , wherein R 6  is hydrogen; and Y is CR 6 , wherein R 6  is hydrogen. 
     
     
         7 . The compound as claimed in  claim 1  wherein X is CR 6 , wherein R 6  is hydrogen; Y is N; L 1  is a direct bond; and L 2  is a direct bond. 
     
     
         8 . The compound as claimed in  claim 1  wherein X is N; Y is N; L 1  is a direct bond; and L 2  is a direct bond. 
     
     
         9 . The compound as claimed in  claim 1  wherein X is CR 6 , wherein R 6  is hydrogen; Y is N; L 1  is a direct bond; L 2  is a direct bond; and R 5  is aryl. 
     
     
         10 . The compound as claimed in  claim 1  wherein X is N, Y is N, L 1  is a direct bond, L 2  is a direct bond and R 5  is aryl. 
     
     
         11 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound as claimed in  claim 1 . 
     
     
         12 . A process for preparing a pharmaceutical composition as claimed in  claim 11  wherein a therapeutically active amount of a compound as claimed in  claim 1  is intimately mixed with a pharmaceutically acceptable carrier. 
     
     
         13 . (canceled) 
     
     
         14 . A method of treating a respiratory syncytial virus infection comprising administering a therapeutically effective amount of at least one compound of  claim 1 . 
     
     
         15 . A compound according to  claim 1 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof. 
     
     
         16 . A compound of formula (II): 
       
         
           
           
               
               
           
         
         including any stereochemically isomeric form thereof, wherein: 
         X and Y are each independently CR 6  or N, wherein R 6  is selected from the group consisting of hydrogen, halo, hydroxy, C 1-4 alkyl, C 1-4 alkyloxy, cyano, polyhaloC 1-4 alkyl, polyhaloC 1-4 alkyloxy, nitro, amino, mono- or di(C 1-4 alkyl)amino, and C 1-4 alkylcarbonyl; 
         R 1  and R 2  are each independently selected from the group consisting of hydrogen, halo, hydroxy, C 1-4 alkyl, C 1-4 alkyloxy, polyhaloC 1-4 alkyl, polyhaloC 1-4 alkyloxy, cyano, nitro, and C 1-4 alkylcarbonyl; 
         R 3  is hydrogen or C 1-6 alkyl; and 
         R 4  is selected from the group consisting of hydrogen, halo, hydroxy, C 1-4 alkyloxy, polyhaloC 1-4 alkyl, C 1-4 alkyloxy, cyano, nitro, and C 1-4 alkylcarbonyl. 
       
     
     
         17 . A compound of formula (IV): 
       
         
           
           
               
               
           
         
         including any stereochemically isomeric form thereof, wherein: 
         X is CR 6  or N, wherein R 6  is selected from the group consisting of hydrogen, halo, hydroxy, C 1-4 alkyl, C 1-4 alkyloxy, cyano, polyhaloC 1-4 alkyl, polyhaloC 1-4 alkyloxy, nitro, amino, mono- or di(C 1-4 alkyl)amino, and C 1-4 alkylcarbonyl; 
         L a  is selected from the group consisting of bromo, iodo, trifluoromethylsulfonate, tri(C 1-4 alkyl) tin, B(OH) 2 , alkylboronates and cyclicboronate esters; 
         R 3  is hydrogen or C 1-6 alkyl; 
         R 4  is selected from the group consisting of: hydrogen, halo, hydroxy, C 1-4 alkyloxy, polyhaloC 1-4 alkyl, C 1-4 alkyloxy, cyano, nitro, and C 1-4 alkylcarbonyl; 
         L 1  is selected from the group consisting of a direct bond; oxygen; and C 1-4 alkanediyl optionally substituted with one or two substituents each independently selected from the group consisting of: hydroxy, and phenyl optionally substituted with C 1-4 alkyloxy; 
         L 2  is selected from the group consisting of a direct bond, phenyl, and piperazine optionally substituted with hydroxy; and 
         R 5  is selected from the group consisting of C 1-4 alkyl, C 3-6 cycloalkyl, heteroalkyl, aryl and heteroaryl;
 wherein heteroalkyl is piperidinyl;
 wherein said aryl is phenyl, or naphthalenyl; wherein each aryl is optionally substituted with one or two substituents each independently selected from the group consisting of: halo, hydroxy, C 1-4 alkyl, C 1-4 alkyloxy, C 1-4 alkylthio, polyhaloC 1-4 alkyl, polyhaloC 1-4 alkyloxy, cyano, nitro, amino, o- or di(C 1-4 alkyl)amino, C 1-4 alkylcarbonyl, and C 1-4 alkyl(SO 2 )—NH—; and 
 
 wherein said heteroaryl is selected from the group consisting of: furanyl, thiophenyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 1-benzofuranyl, 2,3-dihydro-1-benzofuranyl, 1-benzothiophenyl, 1-benzopyrazolyl, 1,3-benzothiazolyl, and quinolinyl; wherein each heteroaryl is optionally substituted with one or two substituents each independently selected from the group consisting of: C 1-4 alkyl, C 1-4 alkyloxy, hydroxyC 1-4 alkyl, cyanoC 1-4 alkyl, polyhaloC 1-4 alkyl, and C 1-4 alkyloxyC 1-4 alkyl.