Piperdine-amino-benzimidazole derivatives as inhibitors of respiratory syncytial virus replication
View Patent ↗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. A compound of formula (I)
wherein
Q is C 1−6 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 alkylcarbonyl-oxy, 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 tetrahydro-pyridyl, 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 alkyl-amino 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 1−6 alkyl, hydroxyC 1−6 alkyl, polyhaloC 1−6 alkyl, and C 1−6 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
R1 is 3-hydroxy-6-methylpyrid-2-yl.
2. A compound according to claim 1 , wherein R 3b is methyl.
3. A compound according to claim 1 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 alkoxy-carbonyl, 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 the carboxyl and C 1−6 alkyloxycarbonyl.
4. A compound according to claim 1 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.
5. A compound according to claim 1 , wherein Q is C 1−6 alkyl optionally substituted with one substituent selected from aminocarbonyl, C 1−4 alkoxy-carbonyl, 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.
6. A compound according to claim 1 , 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.
7. A compound according to claim 1 , wherein Q is
8. A compound according to claim 1 , wherein Q is