Heterocyclylamide-substituted thiazoles, pyrroles and thiophenes
View Patent ↗The invention relates to heterocyclylamide-substituted thiazoles, pyrroles and thiophenes and processes for their preparation, to pharmaceutical compositions containing them, and to their use for the treatment and/or prophylaxis of diseases, in particular for the use as antiviral agents, especially against cytomegaloviruses.
1. A compound of the formula
in which
R 1 represents a group of the formula
where
* represents the point of attachment to the carbonyl group,
R 3 represents phenyl or 5- or 6-membered heteroaryl,
where phenyl and heteroaryl may be substituted by 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, oxo, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoromethylthio, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, hydroxycarbonyl, C 1 -C 6 -alkoxycarbonyl, amino, C 1 -C 6 -alkylamino, aminocarbonyl and C 1 -C 6 -alkylaminocarbonyl,
R 4 represents phenyl or 5- or 6-membered heteroaryl,
where phenyl and heteroaryl may be substituted by 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, oxo, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoromethylthio, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, hydroxycarbonyl, C 1 -C 6 -alkoxycarbonyl, amino, C 1 -C 6 -alkylamino, aminocarbonyl and C 1 -C 6 -alkylaminocarbonyl,
and
R 5 and R 6 independently of one another represent hydrogen, methyl or ethyl,
R 2 represents phenyl,
where phenyl may be substituted by 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoromethylthio, C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy,
A represents a group of the formula
where
* represents the point of attachment to the carbonyl group,
# represents the point of attachment to the nitrogen atom of the urea,
R 7 represents C 1 -C 6 -alkyl,
where alkyl may be substituted by one substituent, where the substituent is selected from the group consisting of C 3 -C 6 -cycloalkyl, C 6 -C 10 -aryl and 5- or 6-membered heteroaryl,
where cycloalkyl, aryl and heteroaryl may be substituted by 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, oxo, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoromethylthio, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, hydroxycarbonyl, C 1 -C 6 -alkoxycarbonyl, amino, C 1 -C 6 -alkylamino, aminocarbonyl and C 1 -C 6 -alkylaminocarbonyl,
and
R 8 and R 9 represent, independently of one another, hydrogen, halogen or C 1 -C 6 -alkyl,
where alkyl may be substituted by one substituent, where the substituent is selected from the group consisting of C 3 -C 6 -cycloalkyl, C 6 -C 1o -aryl and 5- or 6-membered heteroaryl,
in which cycloalkyl, aryl and heteroaryl may be substituted by 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, oxo, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoromethylthio, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, hydroxycarbonyl, C 1 -C 6 -alkoxycarbonyl, amino, C 1 -C 6 -alkylamino, aminocarbonyl and C 1 -C 6 -alkylaminocarbonyl,
or a salt thereof.
2. The compound according to claim 1 , characterized in that
R 1 represents a group of the formula
where
* represents the point of attachment to the carbonyl group,
R 3 represents phenyl or 5- or 6-membered heteroaryl,
where phenyl and heteroaryl may be substituted by 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, oxo, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoromethylthio, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, hydroxycarbonyl, C 1 -C 6 -alkoxycarbonyl, amino, C 1 -C 6 -alkylamino, aminocarbonyl and C 1 -C 6 -alkylaminocarbonyl,
R 2 represents phenyl,
where phenyl may be substituted by 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoromethylthio, C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy,
A represents a group of the formula
where
* represents the point of attachment to the carbonyl group,
# represents the point of attachment to the nitrogen atom of the urea,
R 7 represents C 1 -C 6 -alkyl,
where alkyl may be substituted by one substituent, where the substituent is selected from the group consisting of C 3 -C 6 -cycloalkyl, C 6 -C 10 -aryl, and 5- or 6-membered heteroaryl,
where cycloalkyl, aryl and heteroaryl may be substituted by 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, oxo, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoromethylthio, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, hydroxycarbonyl, C 1 -C 6 -alkoxycarbonyl, amino, C 1 -C 6 -alkylamino, aminocarbonyl and C 1 -C 6 -alkylaminocarbonyl,
and
R 8 and R 9 represent, independently of one another, hydrogen, halogen or C 1 -C 6 -alkyl,
or a salt thereof.
3. The compound according to claim 1 , characterized in that
R 1 represents a group of the formula
where
* represents the point of attachment to the carbonyl group,
R 3 represents phenyl or pyridyl,
where phenyl and pyridyl may be substituted by 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy,
R 2 represents phenyl,
where phenyl may be substituted by 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of fluorine, chlorine, trifluoromethoxy, difluoromethoxy, trifluoromethylthio and methyl,
A represents a group of the formula
where
* represents the point of attachment to the carbonyl group,
# represents the point of attachment to the nitrogen atom of the urea,
R 7 represents methyl, ethyl or n-butyl,
where methyl, ethyl and n-butyl may be substituted by one substituent, where the substituent is selected from the group consisting of cyclopropyl and phenyl,
where phenyl may be substituted by one trifluoromethyl substituent,
and
R 8 and R 9 represent, independently of one another, hydrogen, bromine, chlorine, methyl or ethyl,
or a salt thereof.
4. A process for preparing a compound of the formula (I) according to claim 1 or a salt thereof, characterized in that
according to process (A) a compound of the formula
in which
R 1 is as defined in claim 1 ,
is reacted in the first step with a reducing agent and in the second step in the presence of a carbonic acid derivative with a compound of the formula
H 2 N—R 2 (III)
in which
R 2 is as defined in claim 1 ,
or
according to process (B) a compound of the formula (II) is reacted in the first step with a reducing agent
and in the second step with a compound of the formula
OCN—R 2 (IV),
in which
R 2 is as defined in claim 1 ,
or
according to process (C) a compound of the formula
in which
R 2 is as defined in claim 1 , and
R 10 represents methyl or ethyl,
is reacted in the first step with a base and in the second step with a compound of the formula
R 1 —H (VI),
in which
R 1 is as defined in claim 1 ,
in the presence of a dehydrating agent.
5. A pharmaceutical composition comprising a compound according to claim 1 or a salt thereof in combination with at least one inert nontoxic, pharmaceutically acceptable auxiliary.
6. A method for controlling human cytomegalovirus (HCMV) infections in humans and animals by comprising administering an antivirally effective amount of at least one compound according to claim 1 or a salt thereof.