Novel 1,3-dihydro-2h-benzimidazol-2-one derivatives substituted with heterocycles as respiratory syncytial virus antiviral agents

Abstract

The present invention is concerned with novel 1,3-dihydro-2H-benzimidazol-2-one derivatives substituted with heterocycles having formula (I) stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, wherein R 4 , R 5 , Z and Het have the meaning defined in the claims. The compounds according to the present invention are useful as inhibitors 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 stereoisomeric form thereof, wherein 
         Het is a heterocycle having formula (b), (c), (d) or (e) 
       
       
         
           
           
               
               
           
         
         each X independently is C or N; provided that at least one X is N; 
         R 1b  is present when Het has formula (b) and X is C; each R 1b  is selected independently from the group consisting of H, halogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyloxy, N(R 6 ) 2 , CO(R 7 ), CH 2 NH 2 , CH 2 OH, CN, C(═NOH)NH 2 , C(═NOCH 3 )NH 2 , C(═NH)NH 2 , CF 3 , OCF 3 , B(OH) 2  and B(O—C 1 -C 6 alkyl) 2 ; R 1b  is absent when the X to which it is bound is N; 
         R 2b  is —(CR 8 R 9 ) m —R 10b ; 
         each R 6  is independently selected from the group consisting of H, C 1 -C 6 alkyl, COOCH 3  and CONHSO 2 CH 3 ; 
         each R 7  is independently selected from the group consisting of OH, C 1 -C 6 alkyloxy, NH 2 , NHSO 2 N(C 1 -C 6 alkyl) 2 , NHSO 2 NHCH 3 , NHSO 2 (C 1 -C 6 alkyl), NHSO 2 (C 3 -C 7 cycloalkyl) and N(C 1 -C 6 -alkyl) 2 ; 
         each R 8  and R 9  are independently chosen from the group consisting of H, C 1 -C 10 alkyl and C 3 -C 7 cycloalkyl; or R 8  and R 9  taken together form a 4 to 6 membered aliphatic ring that optionally contains one or more heteroatoms selected from the group consisting of N, S and O; 
         R 10b  is selected from the group consisting of H, R 11 , OH, CN, F, CF 2 H, CF 3 , CONR 8 R 9 , COOR 8 , CON(R 8 )SO 2 R 9 , CON(R 8 )SO 2 N(R 8 R 9 ), NR 8 R 9 , NR 8 COOR 9 , OCOR 8 , O-Benzyl, NR 8 SO 2 R 9 , SO 2 NR 8 R 9 , SO 2 R 8 , OCONR 8 R 9 , OCONR 8 R 12 , N(R 8 )CON(R 8 R 9 ), N(R 8 )COOR 12 , and a 4 to 6 membered saturated ring containing one oxygen atom; 
         m is an integer from 2 to 6; 
         R 11  is selected from the group consisting of C 1 -C 6  alkyl, C 3 -C 7 cycloalkyl, phenyl, pyridinyl and pyrazolyl; each optionally substituted with one or more substituents each independently selected from the group consisting of CF 3 , CH 3 , OCH 3 , OCF 3  and halogen; 
         R 12  is selected from the group consisting of phenyl, pyridinyl and pyrazolyl; each optionally substituted with one or more substituents each independently selected from the group consisting of CF 3 , CH 3 , OCH 3 , OCF 3  and halogen;
 or R 12  is C 1 -C 6  alkyl or C 3 -C 7 cycloalkyl; each substituted with one or more substituents each independently selected from the group consisting of CF 3 , CH 3 , OCH 3 , OCF 3  and halogen; 
 
         R 1c  is present when Het has formula (c); 
         each R 1c  is selected independently from the group consisting of H, halogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyloxy, N(R 6 ) 2 , CO(R 7c ), CH 2 NH 2 , CH 2 OH, CN, C(═NOH)NH 2 , C(═NOCH 3 )NH 2 , C(═NH)NH 2 , CF 3 , OCF 3 , B(OH) 2  and B(O—C 1 -C 6 alkyl) 2 ; 
         R 3c  is selected from the group consisting of H, halogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyloxy and CO(R 7c ) m —R 10c ; 
         R 2c  is —(CR 8 R 9 ) m —R 10c ; 
         R 7c  is selected from the group consisting of OH, O(C 1 -C 6 alkyl), NH 2 , NHSO 2 N(C 1 -C 6 alkyl) 2 , NHSO 2 NHCH 3 , NHSO 2 (C 1 -C 6 alkyl), NHSO 2 (C 3 -C 7 cycloalkyl), N(C 1 -C 6 -alkyl) 2 , NR 8 R 9  and NR 9 R 10c ; 
         R 10c  is selected from the group consisting of H, R 11 , OH, CN, F, CF 2 H, CF 3 , C(═NOH)NH 2 , CONR 8 R 9 , COOR 8 , CONR 8 SO 2 R 9 , CON(R 8 )SO 2 N(R 8 R 9 ), NR 8 R 9 , NR 8 COOR 9 , OCOR 8 , NR 8 SO 2 R 9 , SO 2 NR 8 R 9 , SO 2 R 8  and a 4 to 6 membered saturated ring containing one oxygen atom; 
         R 1d  is present when Het has formula (d) and X is C; each R 1d  is selected independently from the group consisting of H, OH, halogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyloxy, N(R 6 ) 2 , CO(R 7 ), CH 2 NH 2 , CH 2 OH, C(═NOH)NH 2 , C(═NOCH 3 )NH 2 , C(═NH)NH 2 , CF 3 , OCF 3 , B(OH) 2  and B(O—C 1 -C 6 alkyl) 2 ; R 1d  is absent when the X to which it is bound is N; 
         R 3d  is selected from the group consisting of H, halogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyloxy, and CO(R 7 ); 
         R 2d  is —(CR 8 R 9 ) m —R 10d ; 
         R 10d  is selected from the group consisting of H, R 11 , OH, CN, F, CF 2 H, CF 3 , CONR 8 R 9 , COOR 8 , CONR 8 SO 2 R 9 , CON(R 8 )SO 2 N(R 8 R 9 ), NR 8 R 9 , NR 8 COOR 9 , OCOR 8 , NR 8 SO 2 R 9 , SO 2 NR 8 R 9 , SO 2 R 8  and a 4 to 6 membered saturated ring containing one oxygen atom; 
         each Y independently is C or N; 
         R 1e  is present when Het has formula (e) and Y is C; each R 1e  is selected independently from the group consisting of H, halogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyloxy, N(R 6 ) 2 , CO(R 7 ), CH 2 NH 2 , CH 2 OH, CN, C(═NOH)NH 2 , C(═NOCH 3 )NH 2 , C(═NH)NH 2 , CF 3 , OCF 3 , B(OH) 2  and B(O—C 1 -C 6 alkyl) 2 ; R 1e  is absent when the Y to which it is bound is N; 
         R 3e  is selected from the group consisting of H, halogen, —(CR 8 R 9 ) m —R 10e , C≡C—CH 2 —R 10e , C≡C—R 10e  and C═C—R 10e ; 
         R 10e  is selected from the group consisting of H, R 11 , C 1 -C 6 alkyloxy, OH, CN, F, CF 2 H, CF 3 , CONR 8 R 9 , COOR 8 , CON(R 8 )SO 2 R 9 , CON(R 8 )SO 2 N(R 8 R 9 ), NR 8 R 9 , NR 8 COOR 9 , OCOR 8 , NR 8 SO 2 R 9 , SO 2 NR 8 R 9 , SO 2 R 8  and a 4 to 6 membered saturated ring containing one oxygen atom; 
         R 4  is selected from the group consisting of tert-butyl, Het 1 , aryl, Het 2 , CH(CH 3 )(CF 3 ), and C 3 -C 7 cycloalkyl substituted with one or more substituents selected from the group consisting of halo and C 1 -C 4 alkyl; 
         aryl represents phenyl or naphthalenyl; said aryl optionally being substituted with one or more substituents each independently selected from the group consisting of halo, C 1 -C 4 alkyloxy, C 1 -C 4 alkyl, OH, CN, CF 2 H, CF 3 , CF 3 O, CONR 8 R 9 , COOR 8 , CON(R 8 )SO 2 R 9 , CON(R 8 )SO 2 N(R 8 R 9 ), NR 8 R 9 , NR 8 COOR 9 , OCOR 8 , NR 8 SO 2 R 9 , SO 2 NR 8 R 9 , SO 2 R 8 , OCONR 8 R 9 , OCONR 8 R 12 , N(R 8 )CON(R 8 R 9 ), N(R 8 )COOR 12 ; or C 1-4 alkyloxyC 1-4 alkyloxy; 
         Het 1  represents a 4 to 6 membered saturated ring containing one N atom, optionally being substituted with one or more substituents each independently selected from the group consisting of halo, C 1 -C 4 alkyloxy, SO 2 R 8 , C 1 -C 4 alkylcarbonyl, CO(aryl), COHet 2 , C 1 -C 4 alkyloxycarbonyl, pyridinyl, CF 3 , SO 2 N(C 1 -C 4 alkyl) 2 , SO 2 NH(C 1 -C 4 alkyl), (C═O)NH(C 1-4  alkyl), (C═S)NH(C 1-4 alkyl), C 1 -C 4 alkyl and C 1 -C 4 alkyl substituted with one hydroxy; or
 Het 1  represents a 4 to 6 membered saturated ring containing one O atom, substituted with one or more substituents each independently selected from the group consisting of halo, C 1 -C 4 alkyloxy, CF 3 , NH(C═O)(C 1-4 alkyl), (C═O)NH(C 1-4 alkyl) and C 1 -C 4 alkyl; or 
 Het 1  represents a bicyclic 7 to 11 membered non-aromatic heterocycle containing one or two heteroatoms each independently selected from the group consisting of O, S and N, optionally substituted with one or more substituents each independently selected from the group consisting of halo, C 1 -C 4 alkyloxy, SO 2 R 8 , C 1 -C 4 alkylcarbonyl, CO(aryl), COHet 2 , C 1 -C 4 alkyloxycarbonyl, pyridinyl, CF 3 , SO 2 N(C 1 -C 4 alkyl) 2 , SO 2 NH(C 1 -C 4 alkyl), (C═O)NH(C 1-4 alkyl), (C═S)NH(C 1-4 alkyl), C 1 -C 4 alkyl and C 1 -C 4 alkyl substituted with one hydroxy; 
 
         Het 2  represents a monocyclic 5 to 6 membered aromatic heterocycle containing one or more heteroatoms each independently selected from the group consisting of O, S and N; or a bicyclic 8 to 12 membered aromatic heterocycle containing one or more heteroatoms each independently selected from the group consisting of O, S and N; said Het 2  optionally being substituted with one or more substituents each independently selected from the group consisting of halo, C 1 -C 4 alkyloxy, C 1 -C 4 alkyl, OH, CN, CF 2 H, CF 3 , CONR 8 R 9 , COOR 8 , CON(R 8 )SO 2 R 9 , CON(R 8 )SO 2 N(R 8 R 9 ), NR 8 R 9 , NR 8 COOR 9 , OCOR 8 , NR 8 SO 2 R 9 , SO 2 NR 8 R 9 , SO 2 R 8 , OCONR 8 R 9 , OCONR 8 R 12 , N(R 8 )CON(R 8 R 9 ), N(R 8 )COOR 12 ; 
         Z is C or N; R 5  is present where Z is C, whereby R 5  is selected form the group consisting of hydrogen, CF 3  and halogen; R 5  is absent where Z is N;
 or a pharmaceutically acceptable addition salt or a solvate thereof. 
 
       
     
     
         2 . The compound according to  claim 1 , wherein
 Het is a heterocycle having formula (b), (c), (d) or (e);   each X independently is C or N; provided that at least one X is N;   R 1b  is present when Het has formula (b) and X is C; each R 1b  is selected independently from the group consisting of H, halogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyloxy, CF 3  and OCF 3 ; R 1b  is absent when the X to which it is bound is N;   R 2b  is —(CR 8 R 9 ) m —R 10b ;   each R 8  and R 9  are independently chosen from the group consisting of H and C 1 -C 10 alkyl;   R 10b  is selected from the group consisting of H, R 11 , OH, CN, F, CF 2 H, CF 3 , NR 8 R 9 , SO 2 NR 8 R 9 , SO 2 R 8 ;   m is an integer from 2 to 6;   R 11  is selected from the group consisting of C 1 -C 6  alkyl, C 3 -C 7 cycloalkyl, phenyl, pyridinyl and pyrazolyl; each optionally substituted with one or more substituents each independently selected from the group consisting of CF 3 , CH 3 , OCH 3 , OCF 3  and halogen;   R 12  is selected from the group consisting of phenyl, pyridinyl and pyrazolyl; each optionally substituted with one or more substituents each independently selected from the group consisting of CF 3 , CH 3 , OCH 3 , OCF 3  and halogen;
 or R 12  is C 1 -C 6  alkyl or C 3 -C 7 cycloalkyl; each substituted with one or more substituents each independently selected from the group consisting of CF 3 , CH 3 , OCH 3 , OCF 3  and halogen; 
   R 1c  is present when Het has formula (c);   each R 1c  is selected independently from the group consisting of H, halogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyloxy, CF 3  and OCF 3 ;   R 3c  is selected from the group consisting of H, halogen, C 1 -C 6 alkyl;   R 2c  is —(CR 8 R 9 ) m —R 10c ;   R 10c  is selected from the group consisting of H, C 1 -C 6 alkyl, OH, CN, F, CF 2 H, CF 3 , NR 8 R 9 , SO 2 NR 8 R 9 , SO 2 R 8 ;   R 1d  is present when Het has formula (d) and X is C; each R 1d  is selected independently from the group consisting of H, halogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyloxy, CF 3  and OCF 3 ; R 1d  is absent when the X to which it is bound is N;   R 3d  is selected from the group consisting of H, halogen, C 1 -C 6 alkyl;   R 2d  is —(CR 8 R 9 ) m —R 10d ;   R 10d  is selected from the group consisting of H, C 1 -C 6 alkyl, OH, CN, F, CF 2 H, CF 3 , NR 8 R 9 , SO 2 NR 8 R 9 , SO 2 R 8 ;   each Y independently is C or N;   R 1e  is present when Het has formula (e) and Y is C; each R 1e  is selected independently from the group consisting of H, halogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyloxy, CF 3  and OCF 3 ; R 1e  is absent when the Y to which it is bound is N;   R 3e  is selected from the group consisting of H, halogen;   R 4  is selected from the group consisting of tert-butyl, Het′, aryl, Het 2 , CH(CH 3 )(CF 3 ), and C 3 -C 7 cycloalkyl substituted with one or more substituents selected from the group consisting of halo and C 1 -C 4 alkyl;   aryl represents phenyl or naphthalenyl; said aryl optionally being substituted with one or more substituents each independently selected from the group consisting of halo, C 1 -C 4 alkyloxy, C 1 -C 4 alkyl, OH, CN, CF 2 H, CF 3 , CONR 8 R 9 , NR 8 R 9 , NR 8 COOR 9 , SO 2 NR 8 R 9 , SO 2 R 8 , OCONR 8 R 9 , OCONR 8 R 12 , N(R 8 )COOR 12 ;   Het 1  represents a 4 to 6 membered saturated ring containing one N atom, optionally being substituted with one or more substituents each independently selected from the group consisting of halo, C 1 -C 4 alkyloxy, CF 3 , SO 2 R 8 , C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkyloxycarbonyl, pyridinyl, SO 2 N(C 1 -C 4 alkyl) 2 , SO 2 NH(C 1 -C 4 alkyl), (C═O)NH(C 1-4 alkyl), (C═S)NH(C 1-4 alkyl), C 1 -C 4 alkyl and C 1 -C 4 alkyl substituted with one hydroxy; or   Het 1  represents a 4 to 6 membered saturated ring containing one O atom, substituted with one or more substituents each independently selected from the group consisting of halo, C 1 -C 4 alkyloxy, CF 3 , NH(C═O)(C 1-4 alkyl), (C═O)NH(C 1 -4alkyl) and C 1 -C 4 alkyl;   Het 2  represents a monocyclic 5 to 6 membered aromatic heterocycle containing one or more heteroatoms each independently selected from the group consisting of O, S and N; or a bicyclic 8 to 12 membered aromatic heterocycle containing one or more heteroatoms each independently selected from the group consisting of O, S and N; said Het 2  optionally being substituted with one or more substituents each independently selected from the group consisting of halo, C 1 -C 4 alkyloxy, C 1 -C 4 alkyl, OH, CN, CF 2 H, CF 3 , CONR 8 R 9 , NR 8 R 9 , NR 8 COOR 9 , SO 2 NR 8 R 9 , SO 2 R 8 , OCONR 8 R 9 , OCONR 8 R 12 , N(R 8 )COOR 12 ;   Z is C or N; R 5  is present where Z is C, whereby R 5  is selected form the group consisting of hydrogen, CF 3  and halogen; R 5  is absent where Z is N;   and the pharmaceutically acceptable addition salts, and the solvates thereof.   
     
     
         3 . The compound according to  claim 1 , wherein Het is a heterocycle having formula (b), (d) or (e). 
     
     
         4 . The compound according to  claim 1 , wherein Het is a heterocycle having formula (c). 
     
     
         5 . The compound according to  claim 1 , wherein Z is N and R 5  is absent. 
     
     
         6 . The compound according to  claim 1 , wherein Z is C and R 5  is halogen. 
     
     
         7 . The compound according to  claim 1 , wherein R 4  is selected from the group consisting of Het % aryl, Het 2 , and C 3 -C 7 cycloalkyl substituted with one or more substituents selected from the group consisting of halo and C 1 -C 4 alkyl. 
     
     
         8 . The compound according to  claim 7  wherein R 4  is Het 1 . 
     
     
         9 . The compound according to  claim 7  wherein R 4  is Het 2 . 
     
     
         10 . The compound according to  claim 7  wherein R 4  is aryl. 
     
     
         11 . The compound according to  claim 10  wherein aryl is phenyl optionally being substituted with one or more substituents each independently selected from the group consisting of halo, C 1 -C 4 alkyloxy, C 1 -C 4 alkyl, CN, CONR 8 R 9 , COOR 8 , SO 2 R 8 . 
     
     
         12 . The compound according to  claim 11  wherein aryl is phenyl substituted with two substituents each independently selected from the group consisting of halo, C 1 -C 4 alkyloxy or C 1 -C 4 alkyl. 
     
     
         13 . The compound according to  claim 12  wherein Het is of formula (c-1a) 
       
         
           
           
               
               
           
         
         wherein R 3c  is H and R 2c  is —(CR 8 R 9 ) m —R 10c  wherein R 8  and R 9  are each H, m is 3 and R 10c  represents CN or SO 2 CH 3 . 
       
     
     
         14 . The compound according to  claim 1  wherein aryl is phenyl optionally being substituted with one or more substituents each independently selected from the group consisting of halo, C 1 -C 4 alkyloxy, C 1 -C 4 alkyl, CN, CONR 8 R 9 , COOR 8 , SO 2 R 8 , CF 3  0 or C 1-4 alkyloxyC 1-4 alkyloxy. 
     
     
         15 . The compound according to  claim 1  wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         16 . (canceled) 
     
     
         17 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of a compound as defined in  claim 1 . 
     
     
         18 . (canceled) 
     
     
         19 . A method of treating a respiratory syncytial viral (RSV) infection comprising administering to a subject in need of treatment an anti-virally effective amount of a compound as claimed in  claim 1 .