Piperidine-amino-benzimidazole derivatives as inhibitors of respiratory syncytial virus replication

Abstract

The present invention concerns piperidine-amino-benzimidazoles having inhibitory activity on the replication of the respiratory syncytial virus and having the formula their prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms wherein Q is C 1-6 alkyl optionally substituted with 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 alkyl-carbonyl, 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 alkoxy-carbonyl(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 heterocycles selected from the group consisting of pyrrolidinyl, pyrrolyl, dihydropyrrolyl, imidazolyl, triazolyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxothiomorpholinyl, pyridyl and tetrahydropyridyl, wherein each of said heterocycle may optionally be substituted with oxo or C 1-6 alkyl; 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 3a is C 1-6 alkyl and the other one of R 2a and R 3a is hydrogen; in case R 2a is different from hydrogen then R 2b is hydrogen or C 1-6 alkyl, and R 3b is hydrogen; in case R 3a is different from hydrogen then R 3b is hydrogen or C 1-6 alkyl, and R 2b is hydrogen; t is 1, 2 or 3; Ar 1 is phenyl or substituted phenyl; and Ar 2 is phenyl or substituted phenyl. It further concerns their preparation and compositions comprising them, as well as their use as a medicine.

1 .- 21 . (canceled) 
     
     
         22 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of a compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 Q is C 1-16 alkyl optionally substituted with one or more 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, pyridyl and tetrahydropyridyl, wherein each of said heterocycle may optionally be substituted with oxo or C 1-6 alkyl; or Q is C 1-6 alkyl substituted with two substituents wherein one substituent is selected from the group consisting of amino, mono- and diC 1-4 alkylamino and Ar 2 —C 1-4 alkylamino and the other substituent is selected from the group consisting of carboxyl, C 1-6 alkyloxycarbonyl, Ar 2 —C 1-4 alkyloxycarbonyl, aminocarbonyl and aminosulfonyl; wherein 
 Ar 2  is phenyl or phenyl substituted with one substituent selected from the group consisting of halo, hydroxy, C 1-16 alkyl, hydroxyC 1-6 alkyl, polyhaloC 1-16 alkyl, and C 1-16 alkyloxy; 
 each n is independently 1, 2, 3, or 4; 
 t is 2; 
 G is methylene; 
 R 3b  is C 1-6 alkyl; 
 R 5  is hydrogen; and 
 R 1  is pyridyl substituted with 1 or 2 substituents independently selected from the group consisting of hydroxy and methyl. 
 
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein R 3b  is methyl. 
     
     
         24 . The pharmaceutical composition of  claim 22 , wherein Q is C 1-6 alkyl optionally substituted with one or two substituents each independently selected from trifluoromethyl, C 3-7 cycloalkyl, Ar 2 , hydroxy, C 1-4 alkoxy, Ar 2 -oxy-, Ar 2 (CH 2 ) n oxy, hydroxycarbonyl, aminocarbonyl, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, aminocarbonyloxy, Ar 2 (CH 2 ) n carbonyloxy, C 1-4 alkoxycarbonyl(CH 2 ) n oxy, mono- or di(C 1-4 alkyl)aminocarbonyl, aminosulfonyl, mono- or di(C 1-4 alkyl)aminosulfonyl or a heterocycle selected from pyrrolidinyl, pyrrolyl, dihydropyrrolyl, imidazolyl, triazolyl, piperidinyl, homopiperidinyl, piperazinyl and tetrahydropyridyl, wherein each of said heterocycle may optionally be substituted with oxo or C 1-6 alkyl; or Q is C 1-6 alkyl substituted with two substituents wherein one substituent is selected from amino and the other substituent is selected from carboxyl and C 1-6 alkyloxycarbonyl; 
     
     
         25 . The pharmaceutical composition of  claim 22 , wherein Q is C 1-6 alkyl optionally substituted with one or two substituents each independently selected from aminocarbonyl, C 1-4 alkoxycarbonyl, aminocarbonyloxy, Ar 2 (CH 2 ) n carbonyloxy, mono- or di(C 1-4 alkyl)aminocarbonyl, aminosulfonyl, mono- or di(C 1-4 alkyl)aminosulfonyl, pyrrolidinyl, dihydropyrrolyl, piperidinyl, homopiperidinyl and tetrahydropyridyl; or Q is C 1-6 alkyl substituted with two substituents wherein one substituent is amino and the other substituent is selected from carboxyl and C 1-6 alkyloxycarbonyl. 
     
     
         26 . The pharmaceutical composition of  claim 22 , wherein Q is C 1-6 alkyl optionally substituted with one substituent selected from aminocarbonyl, C 1-14 alkoxycarbonyl, aminocarbonyloxy, Ar 2 (CH 2 ) n carbonyloxy, mono- or di(C 1-4 alkyl)aminocarbonyl, aminosulfonyl, mono- or di(C 1-4 alkyl)aminosulfonyl, pyrrolidinyl, dihydropyrrolyl, piperidinyl, homopiperidinyl and tetrahydropyridyl, and optionally with a second substituent which is hydroxy or Q is C 1-6 alkyl substituted with two substituents wherein one substituent is amino and the other substituent is selected from carboxyl and C 1-6 alkyloxycarbonyl. 
     
     
         27 . The pharmaceutical composition of  claim 22 , wherein Q is C 1-6 alkyl substituted with aminocarbonyl, C 1-4 alkoxycarbonyl, aminocarbonyloxy, mono- or di(C 1-4 alkyl)aminocarbonyl, aminosulfonyl, mono- or di(C 1-4 alkyl)aminosulfonyl, pyrrolidinyl, dihydropyrrolyl, piperidinyl, homopiperidinyl or tetrahydropyridyl. 
       
         
           
           
               
               
           
         
       
     
     
         28 . The pharmaceutical composition of  claim 22 , wherein Q is 
     
     
         29 . The pharmaceutical composition of  claim 22 , wherein Q is 
       
         
           
           
               
               
           
         
       
     
     
         30 . The pharmaceutical composition of  claim 22 , wherein R 1  is pyridyl substituted with hydroxy and C 1-6 alkyl. 
     
     
         31 . The pharmaceutical composition of  claim 22 , wherein R 1  is pyridyl substituted with hydroxy and methyl. 
     
     
         32 . The pharmaceutical composition of  claim 22 , wherein R 1  is 3-hydroxy-6-methylpyrid-2-yl. 
     
     
         33 . A process for preparing a pharmaceutical composition 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) as in the following reaction scheme: 
       
       
         
           
           
               
               
           
         
         wherein Q, G, t, R 1 , R 2a , R 2b , R 3a , R 5  are as claimed in claim  1 ; 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 method of treating in a subject a disorder related to respiratory syncytial virus (RSV) replication comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of  claim 22  and a pharmaceutically acceptable carrier. 
     
     
         35 . A method of treating in a subject a disorder related to respiratory syncytial virus (RSV) replication comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of claim  1  and a pharmaceutically acceptable carrier. 
     
     
         36 . A product made by the process of  claim 33 .