5- Or 6-substituted benzimidazole derivatives as inhibitors of respiratory syncytial virus replication

Abstract

The present invention concerns 5- or 6-substituted-benzimidazole derivatives having inhibitory activity on the replication of the respiratory syncytial virus and having the formula a prodrug, N-oxide, addition salt, quaternary amine, metal complex or stereochemically isomeric form thereof wherein Q is Ar 2 , R 6 , pyrrolidinyl substituted with R 6 , piperidinyl substituted with R 6 or homopiperidinyl substituted with R 6 , G is a direct bond or optionally substituted C 1-10 -alkanediyl; R 1 is Ar 1 or a monocyclic or bicyclic heterocycle; one of R 2a and R 2b is cyanoC 1-6 alkyl, cyanoC 2-6 alkenyl, Ar 3 C 1-6 alkyl, Het-C 1-6 alkyl, N(R 8a R 8b )C 1-6 alkyl, Ar 3 C 2-6 alkenyl, Het-C 2-6 alkenyl, Ar 3 aminoC 1-6 alkyl, Het-aminoC 1-6 alkyl, Ar 3 thioC 1-6 alkyl, Het-thioC 1-6 alkyl, Ar 3 sulfonylC 1-6 alkyl, Het-sulfonylC 1-6 alkyl, Ar 3 aminocarbonyl, Het-aminocarbonyl, Ar 3 (CH 2 ) n aminocarbonyl, Het-(CH 2 ) n aminocarbonyl, Ar 3 carbonylamino, Het-carbonylamino, Ar 3 (CH 2 ) n carbonylamino, Het-(CH 2 ) n carbonylamino, and the other one of R 2a and R 2b is hydrogen; in case R 2a is hydrogen, then R 3 is hydrogen; in case R 2b is hydrogen, the R 3 is hydrogen or C 1-6 alkyl. It further concerns their preparation and compositions comprising them, as well as their use as a medicine.

1 . A compound having the formula  
     
       
         
         
             
             
         
       
     
     a prodrug, N-oxide, addition salt, quaternary amine, metal complex or stereochemically isomeric form thereof wherein 
 Q is Ar 2 , R 6a , pyrrolidinyl substituted with R 6 , piperidinyl substituted with R 6  or homopiperidinyl substituted with R 6 ;  
 G is a direct bond or C 1-10 alkanediyl optionally substituted with one or more substituents individually selected from the group consisting of hydroxy, C 1-6 alkyloxy, Ar 1 C 1-6 alkyloxy, C 1-6 alkylthio, Ar 1 C 1-6 alkylthio, HO(—CH 2 —CH 2 —O) n —, C 1-6 alkyloxy(—CH 2 —CH 2 —O) n — and Ar 1 C 1-6 alkyloxy(—CH 2 —CH 2 —O) n —;  
 R 1  is Ar 1  or a monocyclic or bicyclic heterocycle being selected from piperidinyl, piperazinyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, tetrahydrofuranyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, quinolinyl, quinoxalinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, pyridopyridyl, naphthiridinyl, 1H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, imidazo[1,2-a]pyridinyl, 2,3-dihydro-1,4-dioxino[2,3-b]pyridyl or a radical of formula  
                     
 wherein each of said monocyclic or bicyclic heterocycles may optionally be substituted with 1 or where possible more, such as 2, 3, 4 or 5, substituents individually selected from the group of substituents consisting of halo, hydroxy, amino, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkyloxy, C 1-6 alkylthio, C 1-6 alkyloxyC 1-6 alkyl, Ar 1 , Ar 1 C 1-6 alkyl, Ar 1 C 1-6 alkyloxy, hydroxyC 1-6 alkyl, mono-or di(C 1-6 alkyl)amino, mono- or di(C 1-6 alkyl)aminoC 1-6 alkyl, polyhaloC 1-6 alkyl, C 1-6 alkylcarbonylamino, C 1-6 alkyl-SO 2 —NR 4a —, Ar 1 —SO 2 —NR 4a —, C 1-6 alkyloxycarbonyl, —C(═O)—NR 4a R 4b , HO(—CH 2 —CH 2 —O) n —, halo(—CH 2 —CH 2 —O) n —, C 1-6 alkyloxy(—CH 2 —CH 2 —O) n —, Ar 1 C 1-6 alkyloxy(—CH 2 —CH 2 —O) n — and mono-and di(C 1-6 alkyl)amino(—CH 2 —CH 2 —O) n —;  
 one of R 2a  and R 2b  is cyanoC 1-6 alkyl, cyanoC 2-6 alkenyl, Ar 3 C 1-6 alkyl, (Ar 3 )(OH)C 1-6 alkyl, Het-C 1-6 alkyl, N(R 8a R 8b )C 1-6 alkyl, Ar 3 C 2 - 6 alkenyl, Het-C 2-6 alkenyl, Ar 3 aminoC 1-6 alkyl, Het-aminoC 1-6 alkyl, Het-C 1-6 alkylaminoC 1-6 alkyl, Ar 3 thioC 1-6 alkyl, Het-thioC 1-6 alkyl, Ar 3 sulfonylC 1-6 alkyl, Het-sulfonylC 1-6 alkyl, Ar 3 aminocarbonyl, Het-aminocarbonyl, Ar 3 (CH 2 ) n aminocarbonyl, Het-(CH 2 ) n aminocarbonyl, Ar 3 carbonylamino, Het-carbonylamino, Ar 3 (CH 2 ) n carbonylamino, Het-(CH 2 ) n carbonylamino, Ar 3 (CH 2 ) n amino; and the other one of R 2a  and R 2b  is hydrogen;  
 in case R 2a  is hydrogen, then R 3  is hydrogen;  
 in case R 2b  is hydrogen, then R 3  is hydrogen or C 1-6 alkyl;  
 R 4a  and R 4b  can be the same or can be different relative to one another, and are each independently hydrogen or C 1-6 alkyl; or  
 R 4a  and R 4b  taken together may form a bivalent radical of formula —(CH 2 ) s — wherein s is 4 or 5;  
 R 5  is hydrogen or C 1-6 alkyl;  
 R 6  is hydrogen or C 1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of trifluoromethyl, NR 7a R 7b , C 3-7 cycloalkyl, Ar 2 , hydroxy, C 1-4 alkoxy, C 1-4 alkylthio, Ar 2 -oxy-, Ar 2 -thio-, Ar 2 (CH 2 ) n oxy, Ar 2 (CH 2 ) n thio, hydroxycarbonyl, aminocarbonyl, C 1-4 alkylcarbonyl, Ar 2 carbonyl, C 1-4 alkoxycarbonyl, Ar 2 (CH 2 ) n carbonyl, aminocarbonyloxy, C 1-4 alkylcarbonyloxy, Ar 2 carbonyloxy, Ar 2 (CH 2 ) n carbonyloxy, C 1-4 alkoxycarbonyl(CH 2 ) n oxy, mono- or di(C 1-4 alkyl)aminocarbonyl, mono- or di(C 1-4 alkyl)aminocarbonyloxy, aminosulfonyl, mono- or di(C 1-4 alkyl)aminosulfonyl or a heterocycle selected from the group consisting of pyrrolidinyl, pyrrolyl, dihydropyrrolyl, imidazolyl, triazolyl, piperidinyl, homopiperidinyl, piperazinyl, pyridyl and tetrahydropyridyl, wherein each of said heterocycle may optionally be substituted with oxo or C 1-6 alkyl;  
 R 6a  is C 1-6 alkyl substituted with one or more substituents each independently selected from the group consisting of trifluoromethyl, NR 7a R 7b , C 3-7 cycloalkyl, Ar 2 , hydroxy, C 1-4 alkoxy, C 1-4 alkylthio, Ar 2 -oxy-, Ar 2 -thio-, Ar 2 (CH 2 ) n oxy, Ar 2 (CH 2 ) n thio, hydroxycarbonyl, aminocarbonyl, C 1-4 alkylcarbonyl, Ar 2 carbonyl, C 1-4 alkoxycarbonyl, Ar 2 (CH 2 ) n carbonyl, aminocarbonyloxy, C 1-4 alkylcarbonyloxy, Ar 2 carbonyloxy, Ar 2 (CH 2 ) n carbonyloxy, C 1-4 alkoxycarbonyl(CH 2 ) n oxy, mono- or di(C 1-4 alkyl)aminocarbonyl, mono- or di(C 1-4 alkyl)aminocarbonyloxy, aminosulfonyl, mono- or di(C 1-4 alkyl)aminosulfonyl or a heterocycle selected from the group consisting of pyrrolidinyl, pyrrolyl, dihydropyrrolyl, imidazolyl, triazolyl, piperidinyl, homopiperidinyl, piperazinyl, pyridyl and tetrahydropyridyl, wherein each of said heterocycle may optionally be substituted with oxo or C 1-6 alkyl;  
 R 7a  is hydrogen, C 1-6 alkyl, formyl or C 1-6 alkylcarbonyl;  
 R 7b  is hydrogen, C 1-6 alkyl, formyl or C 1-6 alkylcarbonyl;  
 R 8a  is Ar 3 , C 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, cyanoC 1-6 alkyl, aminoC 1-6 alkyl, mono-or di(C 1-6 alkyl)aminoC 1-6 alkyl, Ar 3 C 1-6 alkyl, Het-C 1-6 alkyl, aminocarbonyl-C 1-6 -alkyl, carboxyl-C 1-6 -alkyl;  
 R 8b  is Ar 3 , C 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, cyanoC 1-6 alkyl, aminoC 1-6 alkyl, mono-or di(C 1-6 alkyl)aminoC 1-6 alkyl, Ar 3 C 1-6 alkyl, Het-C 1-6 alkyl;  
 each n independently is 1, 2, 3 or 4;  
 each m independently is 1 or 2;  
 each p independently is 1 or 2;  
 Ar 1  is phenyl or phenyl substituted with 1 or more, such as 2, 3 or 4, substituents selected from halo, hydroxy, C 1-6 alkyl, hydroxyC 1-6 alkyl, polyhaloC 1-6 alkyl, and C 1-6 alkyloxy;  
 Ar 2  is phenyl or phenyl substituted with 1 or more, such as 2, 3 or 4, substituents selected from the group consisting of halo, hydroxy, amino, cyano, C 1-6 alkyl, hydroxyC 1-6 alkyl, polyhaloC 1-6 alkyl, aminoC 1-6 alkyl, C 1-6 alkyloxy, aminosulfonyl, aminocarbonyl, hydroxycarbonyl, C 1-4 alkylcarbonyl, mono- or di(C 1-4 alkyl)amino, mono- or di(C 1-4 alkyl)aminocarbonyl, mono- or di(C 1-4 alkyl)aminosulfonyl, mono- or di(C 1-4 alkyl)aminoC 1-6 alkyl and C 1-4 alkoxycarbonyl;  
 Ar 3  is phenyl, naphthalenyl, 1,2,3,4-tetrahydro-naphthalenyl or indanyl, wherein said phenyl, naphtyl, 1,2,3,4-tetrahydro-naphthalenyl or indanyl may optionally and each individually be substituted with one or more, such as 2, 3 or 4, substituents selected from the group consisting of halo, hydroxy, mercapto, amino, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ar 1 , hydroxyC 1-6 alkyl, polyhaloC 1-6 alkyl, aminoC 1-6 alkyl, cyanoC 1-6 alkyl, aminocarbonyl, C 1-6 alkyloxy, C 1-6 alkylthio, Ar 1 -oxy, Ar 1 -thio, Ar 1 -amino, aminosulfonyl, aminocarbonyl-C 1-6 alkyl, hydroxycarbonyl-C 1-6 alkyl, hydroxycarbonyl, C 1-4 alkylcarbonyl, mono- or di(C 1-4 alkyl)amino, mono- or di(C 1-4 alkyl)aminocarbonyl, mono- or di(C 1-4 alkyl)aminosulfonyl, mono- or di(C 1-4 alkyl)aminoC 1-6 alkyl, C 1-4 alkylcarbonylamino and C 1-4 alkoxycarbonyl;  
 Het is a heterocycle being selected from tetrahydrofuranyl, tetrahydrothienyl, dioxanyl, dioxolanyl, pyrrolidinyl, pyrrolidinonyl, furanyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, tetrahydroquinolinyl, quinolinyl, isoquinolinyl, benzodioxanyl, benzodioxolyl, indolinyl, indolyl, each of said heterocycle may optionally be substituted with oxo, amino, Ar 1 , C 1-4 alkyl, aminoC 1-4 alkyl, hydroxyC 1-6 alkyl, Ar 1 C 1-4 alkyl, mono- or di(C 1-6 alkyl)aminoC 1-6 alkyl, mono- or di(C 1-6 alkyl)amino, or with two C 1-4 alkyl radicals.  
 
   
   
       2 . A compound according to  claim 1  wherein the compound has the formula (I-a-1):  
     
       
         
         
             
             
         
       
     
     wherein Q, R 5 , G and R 1  are as claimed in  claim 1;  and 
 Alk is C 1-6 alkanediyl;  
 R 8c  has the same meanings of R 8a , as claimed in  claim 1 , and also may be hydrogen;  
 R 9 , R 10 , R 11  independently from one another have the same meanings as the substituents on Ar 3  as claimed in  claim 1 .  
 
   
   
       3 . A compound according to  claim 1  wherein the compound has the formula (I-b-1):  
     
       
         
         
             
             
         
       
     
     wherein Q, R 5 , G and R 1  are as claimed in  claim 1;  and 
 Alk is C 1-6 alkanediyl;  
 R 8c  has the same meanings of R 8a , as claimed in  claim 1 , and also may be hydrogen;  
 R 9 , R 10 , R 11  independently from one another have the same meanings as the substituents on Ar 3  as claimed in  claim 1 .  
 
   
   
       4 . A compound according to  claim 1  wherein the compound has the formula (I-c):  
     
       
         
         
             
             
         
       
     
     wherein t, G, R 1 , R 2a , R 2b , R 3 , R 5  and R 6  are as claimed in  claim 1 .  
   
   
       5 . A compound according to  claim 1  wherein the compound has the formula (I-d-2):  
     
       
         
         
             
             
         
       
     
     wherein t, R 5 , R 6 , G and R 1  are as claimed in  claim 1;  and 
 Alk is C 1-6 alkanediyl;  
 R 8c  has the same meanings of R 8a , as claimed in  claim 1 , and also may be hydrogen;  
 R 9 , R 10 , R 11  independently from one another have the same meanings as the substituents on Ar 3  as claimed in  claim 1 .  
 
   
   
       6 . A compound according to  claim 1  wherein the compound has the formula (I-e-2):  
     
       
         
         
             
             
         
       
     
     wherein t, R 5 , R 6 , G and R 1  are as claimed in  claim 1;  and 
 Alk is C 1-6 alkanediyl;  
 R 8c  has the same meanings of R 8a , as claimed in  claim 1 , and also may be hydrogen;  
 R 9 , R 10 , R 11  independently from one another have the same meanings as the substituents on Ar 3  as claimed in  claim 1 .  
 
   
   
       7 . A compound according to  claim 4  wherein t is 2.  
   
   
       8 . A compound according to  claim 1 , wherein G is C 1-10 alkanediyl.  
   
   
       9 . A compound according to  claim 1 , wherein G is methylene.  
   
   
       10 . A compound according to  claim 1 , wherein R 1  is pyridyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of halo, hydroxy, amino, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkyloxy, C 1-6 alkylthio, C 1-6 alkyloxyC 1-6 alkyl, Ar 1 , Ar 1 C 1-6 alkyl, Ar 1 C 1-6 alkyloxy, hydroxyC 1-6 alkyl, mono-or di(C 1-6 alkyl)amino, mono- or di(C 1-6 alkyl)aminoC 1-6 alkyl, polyhaloC 1-6 alkyl, C 1-6 alkylcarbonylamino, C 1-6 alkyl-SO 2 —NR 4a —, Ar 1 —SO 2 —NR 4a —, C 1-6 alkyloxycarbonyl, —C(═O)—NR 4a R 4b , HO(—CH 2 —CH 2 —O) n —, halo(—CH 2 —CH 2 —O) n —, C 1-6 alkyloxy(—CH 2 —CH 2 —O) n —, Ar 1 C 1-6 alkyloxy(—CH 2 —CH 2 —O) n — and mono-or di(C 1-6 alkyl)amino(—CH 2 —CH 2 'O) n —.  
   
   
       11 . A compound according to  claim 1 , wherein R 1  is pyridyl substituted with 1 or 2 substituents independently selected from the group consisting of hydroxy and C 1-6 alkyl.  
   
   
       12 . A compound according to  claim 1 , wherein R 1  is Ar 1 , quinolinyl, benzimidazolyl, a radical of formula  
     
       
         
         
             
             
         
       
     
     or pyrazinyl; wherein each of the radicals Ar 1 , quinolinyl, benzimidazolyl, (c-4), or pyrazinyl may optionally be substituted with the substituents of said radicals as claimed in  claim 1 .  
   
   
       13 . A compound according to  claim 1 , wherein R 1  is phenyl optionally substituted with one, two or three radicals selected from the group consisting of halo, hydroxy, C 1-6 alkyl, C 1-6 alkyloxy; quinolinyl; a radical (c-4) wherein m is 2, optionally substituted with up to two radicals selected from C 1-6 alkyl; benzimidazolyl optionally substituted with C 1-6 alkyl; pyrazinyl optionally substituted with up to three radicals selected from C 1-6 alkyl.  
   
   
       14 . A compound according to  claim 1 , wherein one of R 2a  and R 3a  is selected from cyanoC 1-6 alkyl, cyanoC 2-6 alkenyl, Ar 3 C 1-6 alkyl, (Ar 3 )(OH)C 1-6 alkyl, Het-C 1-6 alkyl, N(R 8a R 8b )C 1-6 alkyl, Ar 3 C 2-6 alkenyl, Het-C 2-6 alkenyl, Ar 3 aminoC 1-6 alkyl, Het-aminoC 1-6 alkyl, Het-C 1-6 alkylaminoC 1-6 alkyl, Ar 3 thioC 1-6 alkyl, Het-thioC 1-6 alkyl, Ar 3 sulfonylC 1-6 alkyl, Het-sulfonylC 1-6 alkyl, Ar 3 aminocarbonyl, Het-aminocarbonyl, Ar 3 (CH 2 ) n aminocarbonyl, Het-(CH 2 ) n aminocarbonyl, Ar 3 carbonylamino, Ar 3 (CH 2 ) n amino; and the other one of R 2a  and R 2b  is hydrogen.  
   
   
       15 . A compound according to  claim 1 , wherein one of R 2a  and R 3a  is selected from cyanoC 1-6 alkyl, Ar 3 C 1-6 alkyl, Het-C 1-6 alkyl, N(R 8a R 8b )C 1-6 alkyl, Ar 3 C 2-6 alkenyl, Ar 3 aminoC 1-6 alkyl, Het-aminoC 1-6 alkyl, Het-C 1-6 alkylaminoC 1-6 alkyl, Ar 3 thioC 1-6 alkyl, Ar 3 aminocarbonyl, Het-aminocarbonyl, Ar 3 (CH 2 ) n aminocarbonyl, Het-(CH 2 ) n aminocarbonyl; and the other one of R 2a  and R 2b  is hydrogen.  
   
   
       16 . A compound according to  claim 1 , wherein one of R 2a  and R 3a  is selected from N(R 8a R 8b )C 1-6 alkyl, Ar 3 aminoC 1-6 alkyl; and the other one of R 2a  and R 2b  is hydrogen.  
   
   
       17 . A compound according to  claim 1 , wherein 
 in case R 2a  is hydrogen then R 3  is hydrogen;    in case R 2b  is hydrogen then R 3  is hydrogen or C 1-6 alkyl.    
   
   
       18 . A compound according to  claim 1 , wherein R 5  is hydrogen.  
   
   
       19 . A compound according to  claim 1 , wherein Q is R 6a , wherein R 6a  is C 1-6 alkyl substituted with one or with two substituents each independently selected from the group consisting of trifluoromethyl, NR 7a R 7b , Ar 2 , hydroxy, C 1-4 alkoxy, Ar 2 (CH 2 ) n oxy, hydroxycarbonyl, aminocarbonyl, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, Ar 2 (CH 2 ) n carbonyl, aminocarbonyloxy, C 1-4 alkylcarbonyloxy, Ar 2 carbonyloxy, mono- or di(C 1-4 alkyl)aminocarbonyl, aminosulfonyl, mono- or di(C 1-4 alkyl)aminosulfonyl or a heterocycle selected from the group consisting of pyrrolidinyl, imidazolyl, piperidinyl, homopiperidinyl, piperazinyl, dioxolanyl, dioxanyl and pyridyl, wherein each of said heterocycle may optionally be substituted with with one or two radicals selected from oxo and C 1-6 alkyl;  
   
   
       20 . A compound according to  claim 1 , wherein Q is R 6a , wherein R 6a  is C 1-6 alkyl substituted with Ar 2  or hydroxy, or C 1-6 alkyl substituted with two hydroxy radicals, or C 1-6 alkyl substituted with diC 1-6 alkyl-dioxolanyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkyl-piperazinyl.  
   
   
       21 . A compound according to  claim 1 , wherein Q is pyrrolidinyl substituted with R 6 , piperidinyl substituted with R 6  or homopiperidinyl substituted with R 6 ; wherein R 6  is hydrogen or C 1-6 alkyl optionally substituted with one or with two substituents, each independently selected from the group consisting of trifluoromethyl, NR 7a R 7b , Ar 2 , hydroxy, C 1-4 alkoxy, Ar 2 (CH 2 ) n oxy, hydroxycarbonyl, aminocarbonyl, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, Ar 2 (CH 2 ) n carbonyl, aminocarbonyloxy, C 1-4 alkylcarbonyloxy, Ar 2 carbonyloxy, mono- or di(C 1-4 alkyl)aminocarbonyl, aminosulfonyl, mono- or di(C 1-4 alkyl)aminosulfonyl or a heterocycle selected from the group consisting of pyrrolidinyl, imidazolyl, piperidinyl, homopiperidinyl, piperazinyl, dioxolanyl, dioxanyl and pyridyl, wherein each of said heterocycle may optionally be substituted with with one or two radicals selected from oxo and C 1-6 alkyl.  
   
   
       22 . A compound according to  claim 1 , wherein Q is pyrrolidinyl substituted with R 6 , piperidinyl substituted with R 6  or homopiperidinyl substituted with R 6 ; wherein R 6  is hydrogen or C 1-6 alkyl optionally substituted with NR 7a R 7b , Ar 2 , hydroxy, hydroxycarbonyl, aminocarbonyl, aminosulfonyl or C 1-6 alkyl substituted with two hydroxy radicals, or C 1-6 alkyl substituted with a heterocycle selected from dioxolanyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, wherein each of said heterocycle may optionally be substituted with oxo or with one or two C 1-6 alkyl radicals.  
   
   
       23 . A compound according to  claim 1 , wherein Q is pyrrolidinyl substituted with R 6 , piperidinyl substituted with R 6  or homopiperidinyl substituted with R 6 ; wherein R 6  is hydrogen or C 1-6 alkyl substituted with Ar 2  or C 1-6 alkyl substituted with piperidinyl or with piperazinyl.  
   
   
       24 . A compound according to  claim 21 , wherein Q is piperidinyl substituted with R 6 .  
   
   
       25 . A compound according to  claim 1 , wherein R 8a  is Ar 3 , C 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, cyanoC 1-6 alkyl, aminoC 1-6 alkyl, mono-or di(C 1-6 alkyl)aminoC 1-6 alkyl, Ar 3 C 1-6 alkyl, Het-C 1-6 alkyl, aminocarbonyl-C 1-6 alkyl, carboxyl-C 1-6 -alkyl; and R 8b  is Ar 3 .  
   
   
       26 . A compound according to  claim 1 , wherein R 8a  is C 1-6 alkyl, hydroxyC 1-6 alkyl, Ar 3 C 1-6 alkyl, Het-C 1-6 alkyl, aminocarbonyl-C 1-6 -alkyl; and R 8b  is C 1-6 alkyl, hydroxyC 1-6 alkyl, Ar 3 C 1-6 alkyl, Het-C 1-6 alkyl.  
   
   
       27 . A compound according to  claim 1 , wherein Ar 3  is phenyl optionally substituted with one, two or three substituents selected from halo, hydroxy, mercapto, amino, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ar 1 , hydroxyC 1-6 alkyl, CF 3 , aminoC 1-6 alkyl, cyanoC 1-6 alkyl, aminocarbonyl, C 1-6 alkyloxy, C 1-6 alkylthio, Ar 1 -oxy, Ar 1 -thio, Ar 1 -amino, aminosulfonyl, aminocarbonyl-C 1-6 alkyl, hydroxycarbonyl-C 1-6 alkyl, hydroxycarbonyl, C 1-4 alkylcarbonyl, C 1-4 alkylcarbonylamino or C 1-4 alkoxycarbonyl.  
   
   
       28 . A compound according to  claim 1 , wherein Ar 3  is phenyl substituted with one, two or three substituents selected from halo, C 1-6 alkyl or hydroxyC 1-6 alkyl.  
   
   
       29 . A compound as claimed in  claim 1  for use as a medicine.  
   
   
       30 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of a compound as claimed in  claim 1 .  
   
   
       31 - 32 . (canceled)  
   
   
       33 . A process for preparing a compound as claimed in  claim 1 , said process comprising 
 (a) reacting an intermediate of formula (II) with a reagent (III) as in the following reaction scheme:                          (b) reacting an intermediate of formula (IV) with a reagent (V) thus obtaining a compound of formula (I-c-1) as in the following reaction scheme:                          (c) reducing an intermediate (VII-a) or (VII-b) to obtain an intermediate (VIII-a) or (VIII-b) and subsequently oxidizing the alcohol group in (VIII-a) or (VIII-b) with a mild oxidant to obtain an intermediate (IX-a) or (IX-b) and subsequently alkylating (IX-a) or (IX-b) to obtain (I-f-1) or (I-f-2), which is further alkylated to obtain (I-g-1) or (I-g-2) as in the following reaction schemes:                                            (d) converting the alcohol group in (VIII-a) or (VIII-b) to a leaving group and subsequently reacting the thus obtained products with an amine thus obtaining (I-g-1) or (I-g-2);                          (e) converting an intermediate (IX-a) or (IX-b) to a compound (I-g-1) or (I-g-2) using a Wittig or Wittig-Horner procedure; selectively reducing the double bond in (I-g-1) or (I-g-2) thus obtaining compounds (I-i-1) or (I-i-2); reducing the cyano group in (I-i-1) or (I-i-2) to a methyleneamine group thus obtaining (I-j-1) or (I-j-2); mono- or dialkylating the latter thus obtaining compounds (I-k-1) or (I-k-2); (I-l-1) or (I-l-2):                                                              and optionally converting the thus obtained compounds of formula (I) into their pharmaceutically acceptable base-addition or acid addition salt form by treatment with a suitable base or acid and conversely treating the base-addition or acid addition salt form with an acid or a base to obtain the free form of the compound of formula (I).    
   
   
       34 . A compound of formula (VII-a), (VII-b), (VIII-a), (VIII-b), (IX-a), (IX-b), (I-f-1), (I-f-2), (I-g-1) or (I-g-2) said formula being as in  claim 33 , wherein G, R 1 , R 2a , R 2b , R 3 , R 5 , R 8a , R 8b , R 12  are as claimed in  claim 33 , and wherein Q is pyrrolidinyl, piperidinyl or homopiperidinyl, substituted on their nitrogen with a radical R 6  which is C 1-6 alkyl optionally substituted with one or two, substituents each independently selected from the group consisting of trifluoromethyl, C 3-7 cycloalkyl, Ar 2 , hydroxy, C 1-4 alkoxy, C 1-4 alkylthio, Ar 2 -oxy-, Ar 2 -thio-, Ar 2 (CH 2 ) n oxy, Ar 2 (CH 2 ) n thio, hydroxycarbonyl, aminocarbonyl, C 1-4 alkylcarbonyl, Ar 2 carbonyl, C 1-4 alkoxycarbonyl, Ar 2 (CH 2 ) n carbonyl, aminocarbonyloxy, C 1-4 alkylcarbonyloxy, Ar 2 carbonyloxy, Ar 2 (CH 2 ) n carbonyloxy, C 1-4 alkoxycarbonyl(CH 2 ) n oxy, mono- or di(C 1-4 alkyl)aminocarbonyl, mono- or di(C 1-4 alkyl)aminocarbonyloxy, aminosulfonyl, mono- or di(C 1-4 alkyl)aminosulfonyl or a heterocycle selected from the group consisting of pyrrolidinyl, pyrrolyl, dihydropyrrolyl, imidazolyl, triazolyl, piperidinyl, homopiperidinyl, piperazinyl, dioxolanyl, dioxanyl, pyridyl and tetrahydropyridyl, wherein each of said heterocycle may optionally be substituted with one or two substituents selected from oxo or C 1-6 alkyl; and wherein said R 6  can be represented by R 6b , as well as the pharmaceutically acceptable salt forms thereof, and the possible stereoisomeric forms thereof.  
   
   
       35 . A compound according to  claim 34  wherein R 6b  is C 1-6 alkyl optionally substituted with Ar 2 , hydroxy, aminocarbonyl, aminosulfonyl, or C 1-6 alkyl substituted with two hydroxy radicals, or C 1-6 alkyl substituted with pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkyl-piperazinyl.  
   
   
       36 . A compound according to  claim 34  wherein R 6b  is C 1-6 alkyl.  
   
   
       37 . A compound formula (VII-a), (VII-b), (VIII-a), (VIII-b), (IX-a), (IX-b), (I-f-1), (I-f-2), (I-g-1) or (I-g-2) said formula being as in  claim 33 , wherein G, R 1 , R 2a , R 2b , R 3 , R 5 , R 8a , R 8b  and R 12  are as claimed in  claim 1  and wherein Q is R 6b  wherein R 6b  is as claimed in  claim 33 .  
   
   
       38 . A compound according to  claim 37  wherein R 6b  is C 1-6 alkyl optionally substituted with Ar 2 , hydroxy, aminocarbonyl, aminosulfonyl, or C 1-6 alkyl substituted with two hydroxy radicals, or C 1-6 alkyl substituted with pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkyl-piperazinyl.  
   
   
       39 . A compound according to  claim 37  wherein R 6b  is C 1-6 alkyl.