Indian Patents
Title of Invention

SUBSTITUTED QUINOLONES
Abstract The invention relates to substituted quinolones and to processes for their preparation as well as to their use for the production of medicaments for the treatment and/or prophylaxis of diseases, especially for use as antiviral agents, particularly against cytomegaloviruses.
Full Text Substituted quinolones
The invention relates to substituted quinolones and to processes for their preparation
as well as to their use for the production of medicaments for the treatment and/or
prophylaxis of diseases, especially for use as antiviral agents, particularly against
cytomegaloviruses.
WO 00/040561 and US 4,959,363 describe quinolones with activity against viruses of
the herpes family. EP-A 612731 describes quinolones as antiviral agents, particularly
against HIV. WO 02/009758, WO 02/085886 and WO 03/050107 claim quinolones as
broad-spectrum antibiotics. WO 97/004775 and WO 97/004779 describe quinolones
as inhibitors of PDE4 and TNFα, among other things for the treatment of antiin-
flammatory diseases and HIV. EP-A 276700 describes 8-cyanoquinolones as antibiot-
ics. WO 02/026713 describes quinolones as antiparasitic compounds.

2
On the market there are structurally different agents having antiviral activity, but
their breadth of application is severely restricted owing to a pronounced side-effect
profile and a possible development of resistances. New agents for a better and more
effective therapy are therefore desirable.
One object of the present invention is therefore to provide new compounds with
equal or improved antiviral action for the treatment of viral infectious diseases in
humans and animals.
Surprisingly it has been found that the substituted quinolones described in the
present invention have antiviral activity.
The invention relates to compounds of formula

in which
n represents a number 1 or 2,
R1 represents fluorine, chlorine or trifluoromethyl,
R2 represents hydrogen or C1-C6-alkyl,

3
R2 represents C1-C6-alkylcarbonyl, optionally C1-C4-alkoxy-substituted C1-C6-
alkylaminocarbonyl, or C1-C6-cycloalkylaminocarbonyl,
whereby alkylcarbonyl can be substituted with a substituent, whereby the sub-
stituent is selected from the group consisting of amino, C1-C6-alkylamino, C3-
C8-cycloalkylamino, and 4- to 7-membered heterocyclyl,
R3 represents halogen, cyano, methoxy, monofluoromethoxy, difluoromethoxy,
trifluoromethoxy or ethynyl,
R4 represents C1-C6-alkyl or C1-C6-cycloalkyl,
whereby alkyl can be substituted with 1 to 3 substituents, whereby the sub-
stituents are selected independently of one another from the group consisting
of halogen, hydroxy, amino, cyano, trifluoromethyl, hydroxycarbonyl, ami-

nocarbonyl, C1-C6-alkoxy, C1-C6-alkylamino, C1-C6-alkylcarbonyl and C1-C6-
alkoxycarbonyl,
and
whereby cycloalkyl can be substituted with 1 to 3 substituents, whereby the
substituents are selected independently of one another from the group con-
sisting of halogen, hydroxy, amino, cyano, trifluoromethyl, hydroxycarbonyl,
aminocarbonyl, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylamino, C1-C6-alkyl-
carbonyl and C1-C6-alkoxycarbonyl,
R5 and R6 independently of one another represent hydrogen, methyl or ethyl,
R7 and R8 independently of one another represent halogen, hydroxy, cyano,
trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy,
C1-C3-alkyl or C1-C3-alkoxy,
R9 represents hydrogen, halogen, hydroxy, cyano, trifluoromethyl, mono-
fluoromethoxy, difluoromethoxy, trifluoromethoxy, C1-C3-Alkyl or C1-C3-
alkoxy,
and their salts, their solvates, and the solvates of their salts.
Compounds of the invention are the compounds of formula (Ic), (I), (la) and (lb) and
their salts, solvates and solvates of the salts; the compounds of the formulae given
below, encompassed by formula (Ic), (I), (la) and (lb), and their salts, solvates and
solvates of the salts, as well as the compounds specified below as exemplary em-
bodiments, encompassed by formula (Ic), (I), (la) and (lb), and their salts, solvates
and solvates of the salts, in so far as the compounds mentioned below and encom-
passed by formula (Ic), (I), (la) and (lb) are not already salts, solvates and solvates of
the salts.

The compounds of the invention may, depending on their structure, exist in stereoi-
someric forms (enantiomers, diastereomers). The invention therefore relates to the
enantiomers or diastereomers and their respective mixtures. From such mixtures of
enantiomers and/or diastereomers it is possible to isolate the stereoisomerically pure
constituents, in a known way.
Where the compounds of the invention can occur in tautomeric forms, the present
invention includes all tautomeric forms.
Salts preferred for the purposes of the present invention are physiologically accept-
able salts of the compounds of the invention. Also included, however, are salts which
are themselves not suitable for pharmaceutical applications, but can be used, for
example, for the isolation or purification of the compounds of the invention.
Physiologically acceptable salts of the compounds of the invention include acid
addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts
of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesul-
fonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphtha-
lenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid,
tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
Physiologically acceptable salts of the compounds of the invention also include salts
of usual bases, such as, by way of example and preferably, alkali metal salts (e.g.
sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium
salts) and ammonium salts derived from ammonia or organic amines having 1 to 16
carbon atoms, such as, by way of example and preferably, ethylamine, diethylamine,
triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, trietha-
nolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-
methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

Solvates for the purposes of the invention refer to those forms of the compounds of
the invention which in solid or liquid state form a complex through coordination
with solvent molecules. Hydrates are a special form of the solvates, in which the
coordination takes place with water.
For the purposes of the present invention, the substituents have the following
meaning, unless specified otherwise:
Alkyl per se and "alk" and "alkyl" in alkoxy. alkylamino, alkylcarbonyl. alkoxycarbonyl,
alkylaminocarbonyl. alkylaminocarbonylaminocarbonyl and alkylsulfonylaminocarb-
onyl represent a linear or branched alkyl radical usually having 1 to 6, preferably 1 to 4,
particularly preferably 1 to 3 carbon atoms, by way of example and preferably methyl,
ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
Alkoxy by way of example and preferably represents methoxy, ethoxy, n-propoxy,
isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
Alkylamino represents an alkylamino radical having one or two alkyl substituents
(chosen independently of one another), by way of example and preferably methyl-
amino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino,
n-hexylamino, N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-
methyl-N-n-propylamino, N-isopropyl-N-n-propylamino, N-tert-butyl-N-methylamino,
N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino. C1-C3-Alkylamino represents
for example a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino
radical having 1 to 3 carbon atoms per alkyl substituent.
Alkylcarbonyl represents by way of example and preferably acetyl and propanoyl.
Alkoxycarbonyl represents by way of example and preferably methoxycarbonyl, eth-
oxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxy-
carbonyl and n-hexoxycarbonyl.

Alkylaminocarbonyl represents an alkylaminocarbonyl radical having one or two
alkyl substituents (chosen independently of one another), by way of example and
preferably methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl,
isopropylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexyl-
aminocarbonyl, N,N-dimethylaminocarbonyl, N,N-diethylaminocarbonyl, N-ethyl-N-
methylaminocarbonyl, N-methyl-N-n-propylaminocarbonyl, N-isopropyl-N-n-propyl-
aminocarbonyl, N-tert-butyl-N-methylaminocarbonyl, N-ethyl-N-n-pentylaminocarb-
onyl and N-n-hexyl-N-methylaminocarbonyl. C1-C3-Alkylaminocarbonyl represents for
example a monoalkylaminocarbonyl radical having 1 to 3 carbon atoms or a di-
alkylaminocarbonyl radical having 1 to 3 carbon atoms per alkyl substituent.
Alkylaminocarbonylaminocarbonyl represents an alkylaminocarbonylaminocarbonyl
radical having one or two alkyl substituents (chosen independently of one another),
by way of example and preferably methylaminocarbonylaminocarbonyl, ethylamino-
carbonylaminocarbonyl, n-propylaminocarbonylaminocarbonyl, isopropylaminocarb-
onylaminocarbonyl, tert-butylaminocarbonylaminocarbonyl, n-pentylaminocarbonly-
aminocarbonyl, n-hexylaminocarbonylaminocarbonyl, N,N-dimethylaminocarbonyl-
aminocarbonyl, N,N-diethylaminocarbonylaminocarbonyl, N-ethyl-N-methylamino-
carbonylaminocarbonyl, N-methyl-N-n-propylaminocarbonylaminocarbonyl, N-iso-
propyl-N-n-propylaminocarbonylaminocarbonyl, N-tert-butyl-N-methylaminocarbonyl-
aminocarbonyl, N-ethyl-N-n-pentylaminocarbonylaminocarbonyl and N-n-hexyl-N-
methylaminocarbonylaminocarbonyl. C1-C3-alkylaminocarbonylaminocarbonyl repre-
sents for example a monoalkylaminocarbonylaminocarbonyl radical having 1 to 3
carbon atoms or a dialkylaminocarbonylaminocarbonyl radical having 1 to 3 carbon
atoms per alkyl substituent.
Alkylsulfonylaminocarbonyl represents by way of example and preferably methylsulf-
onylaminocarbonyl, ethylsulfonylaminocarbonyl, n-propylsulfonylaminocarbonyl, iso-
propylsulfonylaminocarbonyl, tert-butylsulfonylaminocarbonyl, n-pentylsulfonyl-
aminocarbonyl and n-hexylsulfonylaminocarbonyl.

Cycloalkyl represents a cycloalkyl group usually having 3 to 8, preferably 3 to 5 carbon
atoms, by way of example and preferably cycloalkyl includes cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl and cycloheptyl.
Cycloalkylamino represents by way of example and preferably cyclopropylamino,
cyclobutylamino, cyclopentylamino, cyclohexylamino and cycloheptylamino.
Cycloalkylaminocarbonyl represents by way of example and preferably cyclopropyl-
aminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl, cyclohexyl-
aminocarbonyl and cycloheptylaminocarbonyl.
Heteroaryl per se and "heteroaryl" in heteroaryloxy and heteroarylcarbonyl repre-
sents an aromatic, mono- or bicyclic radical usually having 5 to 10, preferably 5 to 6
ring atoms and up to 5, preferably up to 4 heteroatoms from the series S, O and N,
whereby heteroaryl can carry an oxo substituent, by way of example and preferably
thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, imida-
zolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, indazolyl, benzofu-
ranyl, benzothiophenyl, quinolinyl, isoquinolinyl.
Heteroaryloxy by way of example and preferably represents thienyloxy, furyloxy,
pyrrolyloxy, thiazolyloxy, oxazolyloxy, isoxazolyloxy, oxadiazolyloxy, pyrazolyloxy,
imidazolyloxy, tetrazolyloxy, pyridyloxy, pyrimidyloxy, pyridazinyloxy, pyrazinyloxy,
indolyloxy, indazolyloxy, benzofuranyloxy, benzothiophenyloxy, quinolinyloxy,
isoquinolinyloxy.
Heteroarylcarbonyl by way of example and preferably represents thienylcarbonyl,
furylcarbonyl, pyrrolylcarbonyl, thiazolylcarbonyl, oxazolylcarbonyl, isoxazolylcar-
bonyl, oxadiazolylcarbonyl, pyrazolylcarbonyl, imidazolylcarbonyl, tetrazolylcarbonyl,
pyridylcarbonyl, pyrimidylcarbonyl, pyridazinylcarbonyl, pyrazinylcarbonyl, indolyl-
carbonyl, indazolylcarbonyl, benzofuranylcarbonyl, benzothiophenylcarbonyl, quino-
linylcarbonyl, isoquinolinylcarbonyl.

Heterocyclyl per se and "heterocyclyl" in heterocyclylcarbonyl represents a mono- or
polycyclic, preferably mono- or bicyclic, heterocyclic radical usually having 4 to 10,
preferably 5 to 8 ring atoms and up to 3, preferably up to 2 heteroatoms and/or
hetero-groups from the series N, O, S, SO, SO2. The heterocyclyl radicals may be
saturated or partly unsaturated. Preference is given to 5- to 8-membered, monocyclic
saturated heterocyclyl radicals having up to two heteroatoms from the series O, N
and S, such as, by way of example and preferably, tetrahydrofuran-2-yl, tetrahydrofu-
ran-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, piperidin-1-yl, piperidin-2-yl,
piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, morpholin-2-yl, mor-
pholin-3-yl, morpholin-4-yl, thiomorpholin-2-yl, thiomorpholin-3-yl, thiomor-
pholin-4-yl, perhydroazepin-1-yl, perhydroazepin-2-yl, perhydroazepin-3-yl, perhy-
droazepin-4-yl.
Pyrrolinyl per se and "pyrrolinyl" in pyrrolinylcarbonyl represents 3,4-dihydro-2H-
pyrrol-2-yl, 3,4-dihydro-2H-pyrrol-3-yl, 3,4-dihydro-2H-pyrrol-4-yl, 3,4-dihydro-2H-
pyrrol-5-yl, 2,3-dihydro-1H-pyrrol-1-yl, 2,3-dihydro-1H-pyrrol-2-yl, 2,3-dihydro-1H-
pyrrol-3-yl, 2,3-dihydro-1H-pyrrol-4-yl, 2,3-dihydro-1H-pyrrol-5-yl, 2,5-dihydro-1H-
pyrrol-1-yl, 2,5-dihydro-1H-pyrrol-2-yl, 2,5-dihydro-1H-pyrrol-3-yl, 2,5-dihydro-1H-
pyrrol-4-yl and 2,5-dihydro-1H-pyrrol-5-yl.
Heterocyclylcarbonyl by way of example and preferably represents tetrahydrofuran-2-
ylcarbonyl, tetrahydrofuran-3-ylcarbonyl, pyrrolidin-2-ylcarbonyl, pyrrolidin-3-yl-
carbonyl, pyrrolinylcarbonyl, piperidin-1-ylcarbonyl, piperidin-2-ylcarbonyl, pipe-
ridin-3-ylcarbonyl, piperidin-4-ylcarbonyl, piperazin-1-ylcarbonyl, piperazin-2-ylcarb-
onyl, morpholin-2-ylcarbonyl, morpholin-3-ylcarbonyl, morpholin-4-ylcarbonyl,
thiomorpholin-2-ylcarbonyl, thiomorpholin-3-ylcarbonyl, thiomorpholin-4-ylcarb-
onyl, perhydroazepin-1-ylcarbonyl, perhydroazepin-2-ylcarbonyl, perhydroazepin-3-
ylcarbonyl, perhydroazepin-4-ylcarbonyl.
Halogen represents fluorine, chlorine, bromine and iodine, preferably fluorine and
chlorine.

Preference is given to those compounds of formula (Ic) which correspond to formula

in which
n represents a number 1 or 2,
R1 represents fluorine, chlorine or trifluoromethyl,
R2 represents hydrogen or C1-C6-alkyl,
whereby alkyl can be substituted with 1 to 2 substituents, whereby the sub-
stituents are selected independently of one another from the group consisting
of hydroxy, aminocarbonyl, C1-C6-alkoxy, C1-C6-alkylcarbonyl, C1-C6-alkyl-
aminocarbonyl, C3-C8-cycloalkylaminocarbonyl, C1-C6-alkylsulfonylamino-
carbonyl, phenoxy, 5- or 6-membered heteroaryloxy, 5- to 7-membered het-
erocyclyl, 5- or 6-membered heteroaryl, 5- to 7-membered heterocyclyl-
carbonyl and 5- or 6-membered heteroarylcarbonyl,
wherein alkoxy in turn can be substituted with a substituent, whereby
the substituent is selected from the group consisting of hydroxy,
phenyl, 5- to 7-membered heterocyclyl and 5- or 6-membered hetero-
aryl,

or
R2 represents C1-C6-alkylcarbonyl, optionally C1-C4-alkoxy-substituted C1-C6-
alkylaminocarbonyl, or C3-C8-cycloalkylaminocarbonyl,
whereby alkylcarbonyl can be substituted with a substituent, whereby the sub-
stituent is selected from the group consisting of amino, C1-C6-alkylamino, C3-
C8-cycloalkylamino, and 4- to 7-membered heterocyclyl,
R3 represents halogen, cyano, methoxy, monofluoromethoxy, difluoromethoxy,
trifluoromethoxy or ethynyl,
R4 represents C1-C6-alkyl or C3-C8-cycloalkyl,
whereby alkyl can be substituted with 1 to 3 substituents, whereby the sub-
stituents are selected independently of one another from the group consisting
of halogen, hydroxy, amino, cyano, trifluoromethyl, hydroxycarbonyl, ami-
nocarbonyl, C1-C6-alkoxy, C1-C6-alkylamino, C1-C6-alkylcarbonyl and C1-C6-
alkoxycarbonyl,
and
whereby cycloalkyl can be substituted with 1 to 3 substituents, whereby the
substituents are selected independently of one another from the group con-
sisting of halogen, hydroxy, amino, cyano, trifluoromethyl, hydroxycarbonyl,
aminocarbonyl, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylamino, C1-C6-alkyl-
carbonyl and C1-C6-alkoxycarbonyl,
R5 and R6 independently of one another represent hydrogen, methyl or ethyl,

R7 and R8 independently of one another represent halogen, hydroxy, cyano,
trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy,
C1-C3-alkyl or C1-C3-alkoxy,
and their salts, their solvates and the solvates of their salts.
Preference is also given to those compounds of formula (I), in which
n represents a number 1 or 2,
R1 represents fluorine, chlorine or trifluoromethyl
R2 represents hydrogen or C1-C6-alkyl,
whereby alkyl can be substituted with 1 to 2 substituents, whereby the sub-
stituents are selected independently of one another from the group consisting
of hydroxy, aminocarbonyl, C1-C6-alkoxy, C1-C6-alkylaminocarbonyl, phen-
oxy, 5- or 6-membered heteroaryloxy, 5- to 7-membered heterocyclyl, 5- or 6-
membered heteroaryl, 5- to 7-membered heterocyclylcarbonyl and 5- or 6-
membered heteroarylcarbonyl,
wherein alkoxy in turn can be substituted with a substituent, whereby
the substituent is selected from the group consisting of hydroxy,
phenyl, 5- to 7-membered heterocyclyl and 5- or 6-membered het-
eroaryl,
R3 represents halogen, cyano, methoxy, monofluoromethoxy, difluoromethoxy,
trifluoromethoxy or ethynyl,
R4 represents C1-C6-alkyl or C3-C8-cycloalkyl,

whereby alkyl can be substituted with 1 to 3 substituents, whereby the sub-
stituents are selected independently of one another from the group consisting
of hydroxy, amino, cyano, trifluoromethyl, hydroxycarbonyl, aminocarbonyl,
C1-C6-alkoxy, C1-C6-alkylamino, C1-C6-alkylcarbonyl and C1-C6-alkoxycarb-
onyl,
and
whereby cycloalkyl can be substituted with 1 to 3 substituents, whereby the
substituents are selected independently of one another from the group con-
sisting of halogen, hydroxy, amino, cyano, trifluoromethyl, hydroxycarbonyl,
aminocarbonyl, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylamino, C1-C6-alkylcarb-
onyl and C1-C6-alkoxycarbonyl,
R5 and R6 independently of one another represent hydrogen, methyl or ethyl,
R7 and R8 independently of one another represent halogen, hydroxy, cyano,
monofluoromethoxy, difluoromethoxy, trifluoromethoxy, C1-C3-alkyl or C1-
C3-alkoxy,
and their salts, their solvates and the solvates of their salts.
Preference is also given to those compounds of formula (I) which correspond to
formula


in which
n represents a number 1 or 2,
R1 represents fluorine,
R2 represents hydrogen or C1-C6-alkyl,
whereby alkyl can be substituted with 1 to 2 substituents, whereby the sub-
stituents are selected independently of one another from the group consisting
of hydroxy, C1-C6-alkoxy, 5- or 6-membered heterocyclyl and 5- or 6-mem-
bered heterocyclylcarbonyl,
wherein alkoxy in turn can be substituted with a substituent, whereby
the substituent is selected from the group consisting of hydroxy and 5-
or 6-membered heterocyclyl,
or
R2 represents C1-C6-alkylcarbonyl,
whereby alkylcarbonyl is substituted with an amino substituent,

R3 represents fluorine, chlorine, methoxy, monofluoromethoxy, difluorometh-
oxy, trifluoromethoxy or ethynyl,
R4 represents C1-C4-alkyl or C3-C5-cycloalkyl,
whereby alkyl can be substituted with 1 to 3 substituents, whereby the sub-
stituents are selected independently of one another from the group consisting
of hydroxy, and C1-C3-alkoxy,
and
whereby cycloalkyl can be substituted with 1 to 3 substituents, whereby the
substituents are selected independently of one another from the group con-
sisting of halogen, hydroxy, trifluoromethyl, C1-C3-alkyl, C1-C3-alkoxy,
R5 and R6 independently of one another represent hydrogen or methyl,
R7 and R8 independently of one another represent fluorine, chlorine, cyano,
trifluoromethyl, difluoromethoxy, trifluoromethoxy C1-C3-alkyl or C1-C3-
alkoxy,
and their salts, their solvates and the solvates of their salts.
Preference is also given to those compounds of formula (I) which correspond to
formula


in which
n represents a number 1 or 2,
R1 represents fluorine,
R2 represents hydrogen or C1-C6-alkyl,
whereby alkyl can be substituted with 1 to 2 substituents, whereby the
substituents are selected independently of one another from the group
consisting of hydroxy, C1-C6-alkoxy, 5- or 6-membered heterocyclyl and 5- or
6-membered heterocyclylcarbonyl,
wherein alkoxy in turn can be substituted with a substituent, whereby
the substituent is selected from the group consisting of hydroxy and 5-
or 6-membered heterocyclyl,
R3 represents fluorine, chlorine, methoxy, monofluoromethoxy, difluorometh-
oxy, trifluoromethoxy or ethynyl,
R4 represents C1-C4-alkyl or C3-C5-cycloalkyl,

whereby alkyl can be substituted with 1 to 3 substituents, whereby the sub-
stituents are selected independently of one another from the group consisting
of hydroxy, and C1-C3-alkoxy,
and
whereby cycloalkyl can be substituted with 1 to 3 substituents, whereby the
substituents are selected independently of one another from the group con-
sisting of halogen, hydroxy, trifluoromethyl, C1-C3-alkyl, C1-C3-alkoxy,
R5 and R6 independently of one another represent hydrogen or methyl,
R7 and R8 independently of one another represent fluorine, chlorine, cyano,
difluoromethoxy, trifluoromethoxy C1-C3-alkyl or C1-C3-alkoxy,
and their salts, their solvates and the solvates of their salts.
Preference is given in particular to those compounds of formula (I) or (la) which
correspond to formula

R1 represents fluorine,
R2 represents hydrogen or C1-C3-alkyl,
whereby alkyl can be substituted with 1 or 2 substituents, whereby the substi-
tuents are selected independently of one another from the group consisting of
hydroxy, morpholin-2-ylcarbonyl, morpholin-3-ylcarbonyl, morpholin-4-yl-
carbonyl, piperidin-1-ylcarbonyl, piperidin-2-ylcarbonyl, piperidin-3-ylcarb-
onyl, piperidin-4-ylcarbonyl, pyrrolidin-2-ylcarbonyl, pyrrolidin-3-ylcarbonyl
and C1-C3-alkoxy which is optionally substituted with a hydroxy substituent,
or
R2 represents C1-C4-alkylcarbonyl,
whereby alkylcarbonyl is substituted with an amino substituent,
R3 represents chlorine, methoxy, difluoromethoxy or trifluoromethoxy,
R4 represents methyl, ethyl or cyclopropyl,
whereby ethyl can be substituted with 1 to 3 fluorine substituents,
and
whereby cyclopropyl can be substituted with 1 to 2 fluorine substituents,
R5 and R6 independently of one another represent hydrogen or methyl,

R7 and R8 independently of one another represent chlorine,, trifluoromethyl,
trifluoromethoxy or methyl.
and their salts, their solvates and the solvates of their salts.
Preference is given in particular to those compounds of formula (I) or (la) which
correspond to formula

in which
n represents a number 1 or 2,
R1 represents fluorine,
R2 represents hydrogen or C1-C3-alkyl,
whereby alkyl can be substituted with 1 to 2 substituents, whereby the sub-
stituents are selected independently of one another from the group consisting
of hydroxy, morpholin-2-ylcarbonyl, morpholin-3-ylcarbonyl, morpholin-4-
ylcarbonyl, piperidin-1-ylcarbonyl, piperidin-2-ylcarbonyl, piperidin-3-ylcarb-
onyl, piperidin-4-ylcarbonyl, pyrrolidin-2-ylcarbonyl, pyrrolidin-3-ylcarbonyl
and C1-C3-alkoxy which is optionally substituted with a hydroxy substituent,

R3 represents chlorine, methoxy, difluoromethoxy or trifluoromethoxy,
R4 represents methyl, ethyl or cyclopropyl,
whereby cyclopropyl can be substituted with 1 to 2 fluorine substituents,
R5 and R6 independently of one another represent hydrogen or methyl,
R7 and R8 independently of one another represent chlorine or methyl.
and their salts, their solvates and the solvates of their salts.
Preference is also given to those compounds of formula (Ic), (I), (la) and (lb) in which
R1 represents fluorine.
Preference is also given to those compounds of formula (Ic), (I), (la) and (lb) in which
R3 represents chlorine, methoxy or difluoromethoxy.
Preference is also given to those compounds of formula (Ic), (I), (la) and (lb) in which
R4 represents cyclopropyl or 2-fluorocycloprop-l-yl.
Preference is also given to those compounds of formula (Ic), (I), (la) and (lb) in which
R4 represents 2,2,2-trifluoroethyl.
Preference is also given to those compounds of formula (Ic), (I), (la) and (lb) in which
R7 and R8 represent chlorine.
Preference is also given to those compounds of formula (Ic), (I), (la) and (lb) in which
R7 represents chlorine or methyl and R8 represents trifluoromethoxy.

Preference is also given to those compounds of formula (Ic), (I), (la) and (lb) in which
R2 represents hydrogen, aminomethylcarbonyl or 2,3-dihydroxyprop-l-yl and R5 and
R6 represent methyl.
Preference is also given to those compounds of formula (Ic), (I), (la) and (lb) in which
R2 represents hydrogen and R5 and R6 represent methyl.
Preference is also given to those compounds of formula (Ic) in which R9 represents
hydrogen.
The radical definitions stated specifically in the respective combinations and pre-
ferred combinations of radicals are also replaced as desired by radical definitions of
other combinations, irrespective of the particular combinations of the radicals that
are specified.
Very particular preference is given to combinations of two or more of the abovemen-
tioned preference ranges.
The invention further relates to a process for the preparation of the compounds of
formula (Ic), whereby compounds of the formula


n, R1, R2, R3, R4, R5 and R6 have the meaning indicated above,
are reacted with compounds of formula

in which
R7, R8 and R9 have the meaning indicated above.
The reaction generally takes place in inert solvents, in the presence of a dehydrating
reagent, optionally in the presence of a base, preferably in a temperature range from
-30°C to 50°C under atmospheric pressure.
Inert solvents are for example halogenated hydrocarbons such as dichloromethane or
trichloromethane, hydrocarbon such as benzene, nitromethane, dioxane, dimethyl-
formamide or acetonitrile. It is also possible to use mixtures of the solvents. Particu-
larly preferred is dichloromethane or dimethylformamide.
Bases are for example alkali metal carbonates, such as sodium or potassium carbon-
ate, or hydrogen carbonate, or organic bases such as trialkylamines, for example
triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine
or diisopropylethylamine.
Dehydrating reagents suitable here include for example carbodiimides such as N,N'-
diethyl-, N,N, '-dipropyl-, N,N'-diisopropyl-, N,N'-dicyclohexylcarbodiimide, N-(3-
dimethylaminoisopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), N-cyclohexyl-
carbodiimide-N'-propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl com-

pounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-
phenyl-l,2-oxazolium 3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or
acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-l,2-dihydroquinoline, or
propanephosphonic anhydride, or isobutyl chloroformate, or bis(2-oxo-3-oxa-
zolidinyl)phosphoryl chloride, or 0-(benzotriazol-1-yl)-N,N,N',]N'-tetramethyluro-
nium hexafluorophosphate (HBTU), 2-(2-oxo-1-(2H)-pyridyl)-l,l,3,3-tetramethyl-
uronium tetrafluoroborate (TPTU) or O-(7-azabenzotriazol-1-yl-N,N,N',N'-tetra-
methyluronium hexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt) or
benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP),
or benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP),
or N-hydroxysuccinimide, or mixtures of these with bases.
Preferably the condensation is carried out with HATU, benzotriazol-1-yloxy-
tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) or with EDC in the
presence of HOBt.
The compounds of formula (II) are known or can be prepared by reacting compounds
of formula

in which
R1, R3 and R4 have the meaning indicated above,
with compounds of formula


in which
n, R2, R5 and R6 have the meaning indicated above.
The reaction can be carried out according to the methods described in A. Da Silva, M.
De Almeida, V. De Souza, M. Couri, Current Medicinal Chemistry, 2003, 10, 21-39 or J.
P. Sanchez, et al., Journal of Medicinal Chemistry 1995, 38(22), 4478-87.
The compounds of formula (III) and (V) are known or can be synthesized by known
methods from the corresponding starting materials.
The compounds of formula (V) optionally carry protecting groups known to a man of
the art during the reaction, which can be removed either directly after the reaction of
the compounds of formula (IV) with compounds of formula (V) to compounds of
formula (II) or after a further reaction to compounds of formula (Ic).
The compounds of formula (IV) are known or can be synthesized according to
known methods from the corresponding starting materials, as described for example
in A. Da Silva, M. De Almeida, V. De Souza, M. Couri, Current Medicinal Chemistry,
2003, 10, 21-39.
In an alternative method substituent R2 in compounds of formula (Ic) can be intro-
duced by reacting compounds of formula


in which n, R1, R3, R4, R5, R6, R7, R8 and R9 have the meaning indicated above,
with electrophiles such as carboxylic acid chlorides, optionally substituted chloro-
acetamide, optionally substituted 2-chloropropionamide, chloromethylketones or
optionally substituted 3-bromopropionamide, in the presence of a base or by reaction
with isocyanates, Michael acceptors or epoxides.
In an alternative method for the production of compounds of formula (Ic) the
nucleophilic substitution in 7-position of the quinolone and the formation of the
amide can be exchanged in the order of reaction.
The preparation of the compounds of the invention can be illustrated with the
following synthesis scheme.


The compounds of the invention show a surprising range of effects which could not
have been predicted. They show an antiviral effect on representatives of the group of
herpes viridae (herpes viruses), in particular on cytomegaloviruses (CMV) and espe-
cially on the human cytomegalovirus (HCMV).
Areas of indication which may be mentioned by way of example are:

1) Treatment and prophylaxis of HCMV infections in AIDS patients (retinitis,
pneumonitis, gastrointestinal infections).
2) Treatment and prophylaxis of cytomegalovirus infections in bone-marrow and
organ transplant patients who develop often life-threatening HCMV pneu-
monitis or encephalitis, as well as gastrointestinal and systemic HCMV infec-
tions.
3) Treatment and prophylaxis of HCMV infections in neonates and infants.
4) Treatment of an acute HCMV infection in pregnant women.
5) Treatment of an HCMV infection in immunosuppressed patients during
cancer and cancer therapy.
6) Treatment of HCMV-positive cancer patients with the aim of reducing HCMV-
mediated tumour progression (cf. J. Cinatl , et al., FEMS Microbiology Reviews
2004, 28, 59-77).
The present invention further relates to the use of the compounds of the invention
for the treatment and/or prophylaxis of diseases, in particular of infections with
viruses, especially the aforementioned viruses, and of the infectious diseases caused
thereby. A viral infection means hereinafter both an infection with a virus and a
disease caused by an infection with a virus.
The present invention further relates to the use of the compounds of the invention
for the treatment and/or prophylaxis of diseases, especially of the aforementioned
diseases.

The present invention further relates to the use of the compounds of the invention
for the production of a medicament for the treatment and/or prophylaxis of diseases,
especially of the aforementioned diseases.
The compounds of the invention are preferably used for the production of medica-
ments which are suitable for the prophylaxis and/or treatment of infections with a
representative of the group of herpes viridae, particularly a cytomegalovirus, in
particular the human cytomegalovirus.
The present invention further relates to a method for the treatment and/or prophy-
laxis of diseases, especially the aforementioned diseases, using an antivirally effective
amount of the compounds of the invention.
The present invention further relates to medicaments comprising at least one com-
pound of the invention and at least one or more further active ingredients, in par-
ticular for the treatment and/or prophylaxis of the aforementioned diseases. Suitable
active ingredients in the combination which may be mentioned by way of example
and preferably are: antiviral active ingredients such as valganciclovir, ganciclovir or
aciclovir.
The compounds of the invention may act systemically and/or locally. They can for
this purpose be administered in a suitable way, such as, for example, orally, parenter-
ally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, trans-
dermally, conjunctivally, otically or topically, or as implant or stent.
For these administration routes it is possible to administer the compounds of the
invention in suitable administration forms.
Suitable for oral administration are administration forms which function according
to the prior art and deliver the compounds of the invention rapidly and/or in modi-
fied fashion and which comprise the compounds of the invention in crystalline

and/or amorphicized and/or dissolved form, such as, for example, tablets (uncoated
or coated tablets, for example having coatings which are resistant to gastric juice or
dissolve with a delay or are insoluble and control the release of the compound of the
invention), tablets or films/wafers, which disintegrate rapidly in the oral cavity,
films/lyophilisates, capsules (for example hard or soft gelatin capsules), sugar-coated
tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
Parenteral administration can take place with avoidance of an absorption step (for
example intravenous, intraarterial, intracardial, intraspinal or intralumbar) or with
inclusion of an absorption (for example intramuscular, subcutaneous, intracutane-
ous, percutaneous, or intraperitoneal). Administration forms suitable for parenteral
administration are, inter alia, preparations for injection and infusion in the form of
solutions, suspensions, emulsions, lyophilisates or sterile powders.
Suitable for the other administration routes are for example pharmaceutical forms for
inhalation (including powder inhalers, nebulizers), nasal drops, solutions, sprays;
tablets, films/wafers or capsules, for lingual, sublingual or buccal administration,
suppositories, preparations for the ears or eyes, vaginal capsules, aqueous suspensions
(lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal
therapeutic systems, milk, pastes, foams, dusting powders, implants or stents.
The compounds of the invention can be converted into the stated administration
forms. This can take place in a manner known per se by mixing with inert, non-
toxic, pharmaceutically acceptable excipients. These excipients include, inter alia,
carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (for
example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents
(for example sodium dodecyl sulfate, polyoxysorbitan oleate), binders (for example
polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabi-
lizers (for example antioxidants such as ascorbic acid), colors (for example inorganic
pigments such as iron oxides) or taste- and/or odor corrigents.

The present invention further relates to medicaments which comprise at least one
compound of the invention, usually together with one or more inert, non-toxic,
pharmaceutically acceptable excipients, and to the use thereof for the aforemen-
tioned purposes.
It has generally proven advantageous on intravenous administration to administer
amounts of about 0.001 to 10 mg/kg, preferably about 0.01 to 5 mg/kg of body
weight to achieve effective results, and the dosage on oral administration is about
0.01 to 25 mg/kg, preferably 0.1 to 10 mg/kg of body weight.
It may nevertheless be necessary where appropriate to deviate from the amounts
mentioned, depending on the body weight, administration route, individual behav-
ior towards to the active ingredient, nature of the preparation and time or interval
over which administration takes place. Thus it may be sufficient in some cases to
make do with less than the aforementioned minimum amount, whereas in other
cases the stated upper limit must be exceeded. In the case of an administration of
larger amounts it may be advisable to divide these into a plurality of individual doses
over the day.
The percentage data in the following tests and examples are percentages by weight
unless otherwise indicated; parts are parts by weight. Solvent ratios, dilution ratios
and concentration data of liquid/liquid solutions are in each case based on volume.

A. Examples
Abbreviations:
BINAP 2,2'-bis(diphenylphosphino)-l,r-binaphthyl
CDCI3 deuterochloroform
DCI direct chemical ionization (in MS)
DCM dichloromethane
DIEA N,N-diisopropylethylamine
DMSO dimethyl sulfoxide
DMF N,N-dimethylformamide
EE ethyl acetate (acetic acid ethyl ester)
EI electron impact ionization (in MS)
ESI electrospray ionization (in MS)
H hour
HPLC high pressure, high performance liquid chromatography
LC-MS coupled liquid chromatography-mass spectroscopy
LDA lithium diisopropylamide
min minutes
m.p. melting point
MS mass spectroscopy
MTBE methyl tert-butyl ether
NMR nuclear magnetic resonance spectroscopy
Pd-C palladium on carbon
PyBOP 1-benzotriazolyloxytripyrrolidinophosphonium
hexafluorophosphate
RP-HPLC reverse phase HPLC
RT room temperature
Rt retention time (in HPLC)
THF tetrahydrofuran
TLC thin layer chromatography

General LC-MS and HPLC methods:
Method 1 (LC-MS): Instrument: Micromass Quattro LCZ with HPLC Agilent series
1100; column: Phenomenex Synergi 2u Hydro-RP Mercury 20 mm x 4 mm; eluent A:
11 water + 0.5 ml 50% formic acid, eluent B: 11 acetonitrile + 0.5 ml 50% formic
acid; gradient: 0.0 min 90%A -» 2.5 min 30%A → 3.0 min 5%A -» 4.5 min 5%A; flow
rate: 0.0 min 1 ml/min, 2.5 min/3.0 min/4.5 min 2 ml/min; oven: 50°C; UV detec-
tion: 208- 400 nm.
Method 2 (LC-MS): MS instrument type: Micromass ZQ; HPLC instrument type:
Waters Alliance 2795; column: Phenomenex Synergi 2u Hydro-RP Mercury 20 mm x
4 mm; eluent A: 11 water + 0.5 ml 50% formic acid, eluent B: 11 acetonitrile + 0.5 ml
50% formic acid; gradient: 0.0 min 90%A → 2.5 min 30%A -» 3.0 min 5%A →
4.5 min 5%A; flow rate: 0.0 min 1 ml/min, 2.5 min/3.0 min/4.5 min 2 ml/min; oven:
50°C; UV detection: 210 nm.
Method 3 (LC-MS): MS instrument type: Micromass ZQ; HPLC instrument type: HP
1100 series; UV DAD; column: Phenomenex Synergi 2u Hydro-RP Mercury 20 mm x
4 mm; eluent A: 11 water + 0.5 ml 50% formic acid, eluent B: 11 acetonitrile + 0.5 ml
50% formic acid; gradient: 0.0 min 90%A -» 2.5 min 30%A → 3.0 min 5%A -»
4.5 min 5%A; flow rate: 0.0 min 1 ml/min, 2.5 min/3.0 min/4.5 min 2 ml/min; oven:
50°C; UV detection: 210 nm.
Method 4 (preparative HPLC): column: RP18; gradient, with addition of 0.2%
diethylamine to the acetonitrile: 30% acetonitrile/70% water → 95% acetonitrile/5%
water.
Method 5 (preparative HPLC, formic acid): Column: Grom-Sil 120 ODS-4HE,
10 µm, SNr. 3331, 250 mm x 30 mm. Eluent A: formic acid 0.1% in water, eluent B:
acetonitrile; flow rate: 50 ml/min. Program: 0-3 min: 10% B; 3-27 min: gradient to
95% B; 27-34 min: 95% B; 34.01-38 min: 10% B.

Method 6 (preparative HPLC, hydrochloric acid): Column: Grom-Sil 120 ODS-
4HE, 10 urn, SNr. 3331, 250 mm x 30 mm. Eluent A: hydrochloric acid 0.1% in
water, eluent B: acetonitrile; flow rate: 50 ml/min. Program: 0-2 min 10% B, 3-
43 min: gradient to 100% B, 43.01-45 min: 100% B.
Method 7 (preparative HPLC): Column: Grom-Sil 120 ODS-4HE, 10 urn, SNr. 3331,
250 mm x 30 mm. Eluent A: water, Eluent B: acetonitrile, flow rate: 50 ml/min.
Program: 0-3 min: 10% B; 3-27 min: gradient to 95% B; 27-34 min: 95% B; 34.01-
38 min: 10% B.
Method 8 (preparative HPLC, trifluoroacetic acid): Column: Grom-Sil 120 ODS-
4HE, 10 urn, SNr. 3331, 250 mm x 30 mm. Eluent A: trifluoroacetic acid 0.1% in
water, eluent B: acetonitrile. Flow rate: 50 ml/min. Program: 0-3 min: 10% B;
3-27 min: gradient to 95% B; 27-34 min: 95% B; 34.01-38 min: 10% B.
Method 9 (analytical HPLC): Instrument: HP 1100 with DAD detection; column:
Kromasil 100 RP-18, 60 mm x 2.1 mm, 3.5 µm; eluent A: 5 ml perchloric acid (70%)/l
water, eluent B: acetonitrile; gradient: 0 min 2%B, 0.5 min 2%B, 4.5 min 90%B,
9 min 90%B, 9.2 min 2%B, 10 min 2%B; flow rate: 0.75 ml/min; column tempera-
ture: 30°C; UV detection: 210 nm.
Method 10 (analytical HPLC): Instrument: HP 1100 with DAD detection; column:
Kromasil 100 RP-18, 60 mm x 2.1 mm, 3.5 µm; eluent A: 5 ml perchloric acid (70%)/l
water, eluent B: acetonitrile; gradient: 0 min 2%B, 0.5 min 2%B, 4.5 min 90%B, 6.5
min 90%B, 6.7 min 2%B, 7.5 min 2%B; flow rate: 0.75 ml/min; column-temperature:
30°C; UV detection: 210 nm.
Method 11 (LC-MS): MS Instrument type: Micromass TOF (LCT); HPLC instrument
type: 2-column system, Waters 2690; column: YMC-ODS-AQ, 50 mm x 4.6 mm, 3.0
µm; eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid;

gradient: 0.0 min 100%A → 0.2 min 95%A → 1.8 min 25%A → 1.9 min 10%A → 2.0
min 5%A → 3.2 min 5%A; oven: 40°C; flow rate: 3.0 ml/min; UV detection: 210 nm.
Method 12 (preparative LC-MS): MS instrument type: Micromass Micromass ZMD;
HPLC instrument type: Waters Prep LC 4000; column: Kromasil, 50 mm x 20 mm,
100A, C18 5 µm; eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1%
formic acid; gradient: 0.0 min 70%A → 0.75 min 70%A -» 5.5 min 100%B → 6.5 min
100%B -» 7.0 min 70%A → flow rate: 40.0 ml/min.
Method 13 (LC-MS): Instrument: Micromass Platform LCZ with HPLC Agilent series
1100; column: Thermo Hypersil GOLD 3u 20 mm x 4 mm; eluent A: 1 1 water +
0.5 ml 50% formic acid, eluent B: 1 1 acetonitrile + 0.5 ml 50% formic acid; gradient:
0.0 min 100%A → 0.2 min 100%A → 2.9 min 30%A → 3.1 min 10%A -» 5.5 min
10%A; oven: 50°C; flow rate: 0.8 ml/min; UV detection: 210 nm.
The exemplary compounds which comprise a basic nitrogen can depending on the
method of their purification be isolated as a free base or in various saltforms. The
production method often describes the purification by HPLC with the addition of
formic acid (method 5) which leads to the hydroformate or with the addition of
other acids such as for example hydrochloric acid (method 6) instead of formic acid
whereby the product is isolated as the hydrochloride. Alternatively the product can
also be purified by stirring in acetonitrile or by preparative HPLC without the addi-
tion of acid (method 7) whereby the product is isolated as a free base.
From the free bases, as well as from the hydroformate, the hydrochloride of a com-
pound can be obtained by subsequent mixing with hydrochloric acid in dioxane and
evaporation on a rotary evaporator.

Starting compounds
Example 1A
8-Chloro-1-cyclopropyl-6-fluoro-7-[4-(2-hydroxyethyl)-l,4-diazepan-1-yl]-4-oxo-l,4-
dihydroquinoline-3-carboxylic acid

350 mg (1.2 mmol) of 8-Chloro-1-cyclopropyl-6,7-difluoro-4-oxo-l,4-dihydroquino-
line-3-carboxylic acid (for preparation see: DE 3420743) are dissolved according to
DE 3635218 in 3 ml of dry pyridine and heated at reflux with 202 mg (1.4 mmol) of
hexahydro-1H-l,4-diazepine-1-ethanol for 4 hours. After standing overnight the
mixture is concentrated, taken up with water and brought to pH 6 using dilute
hydrochloric acid. The solution is saturated with sodium chloride at boiling heat.
After it has cooled to room temperature, it is extracted a number of times with
dichloromethane. The organic extracts are filtered over a little silica gel and concen-
trated. 288 mg of the target compound are obtained this way. The compound is used
as a crude product in the subsequent reaction stages.
LC-MS (Method 3): Rt= 1.32 min
MS (ES+) = 424 (M+H)+
In analogy to the preparation instructions of Example 1A, Examples 2A to 12A are
prepared:

Example 2A
8-Chloro-1-cyclopropyl-6-fluoro-7-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}-4-
oxo-1,4-dihydroquinoline-3-carboxylic acid

The preparation takes place in analogy to Example 1A from 8-chloro-1-cyclopropyl-
6,7-difluoro-4-oxo-l,4-dihydroquinoline-3-carboxylic acid (for preparation see DE
3420743).
LC-MS (Method 2): Rt= 1.08 min
MS (ES+) = 454 (M+H)+
Example 3A
8-Chloro-6-fluoro-1-[(lR,2S)-2-fluorocyclopropyl]-7-{4-[2-(2-hydroxyeth-
oxy)ethyl]piperazin-1-yl}-4-oxo-l,4-dihydroquinoline-3-carboxylic acid


The Preparation takes place in analogy to Example 1A from 8-chloro-6,7-difluoro-1-
[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (for
preparation see Journal of Medicinal Chemistry (1994), 37(20), 3344-52).
LC-MS (Method 2): Rt= 1.28 min
MS (ES+) = 472 (M+H)+
Example 4A
8-Chloro-6-fluoro-1-[(lS,2R)-2-fluorocyclopropyl]-7-{4-[2-(2-hydroxyeth-
oxy)ethyl]piperazin-1-yl}-4-oxo-l,4-dihydroquinoline-3-carboxylic acid

The preparation takes place in analogy to Example 1A from 8-chloro-6,7-difluoro-1-
[(lS,2R)-2-fluorocyclopropyl]-4-oxo-l,4-dihydroquinoline-3-carboxylic acid (for
preparation see Journal of Medicinal Chemistry (1994), 37(20), 3344-52). The com-
pound is used as a crude product in the subsequent reaction stages.
LC-MS (Method 3): Rt = 1.82 min
MS (ES+) = 472 (M+H)+

Example 5A
8-Chloro-6-fluoro-1-[(lS,2R)-2-fluorocyclopropyl]-7-[4-(2-morpholin-4-yl-2-
oxoethyl)piperazin-1-yl]-4-oxo-l,4-dihydroquinoline-3-carboxylic acid

The preparation takes place in analogy to Example 1A from 4-[2-(piperazin-1-
yl)acetyl]morpholine and 8-chloro-6,7-difluoro-1-[(lS,2R)-2-fluorocyclopropyl]-4-
oxo-l,4-dihydroquinoline-3-carboxylic acid (for preparation see Journal of Medicinal
Chemistry (1994), 37(20), 3344-52). The compound is used as a crude product in the
subsequent reaction stages.
LC-MS (Method 1): R,= 1.37 min
MS(ES+) = 511(M+H)+
Example 6A
6-Fluoro-1 - [(1R, 2S)-2-fluorocyclopropyl] - 7-{4- [2-(2-hydroxyethoxy)ethyl] piperazin-1-
yl}-8-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid


The preparation takes place in analogy to Example 1A from 6,7-difluoro-1-[(lR,2S)-2-
fluorocyclopropyl]-8-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid (for
preparation see WO 96/01262). The compound is used as a crude product in the
subsequent reaction stages.
LC-MS (Method 3): R,= 1.25 min
MS (ES+) = 468 (M+H)+
Example 7 A
8-Chloro-6-fluoro-1-[(lSR,2RS)-2-fluorocyclopropyl]-7-{4-[2-(2-hydroxy-
ethyl)piperazin-1-yl]-4-oxo-l,4-dihydroquinoline-3-carboxylic acid

The preparation takes place in analogy to Example 1A from racemic 8-chloro-6,7-
difluoro-1- [cis-2-fluorocyclopropyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid

(for preparation in analogy see Journal of Medicinal Chemistry (1994), 37(20), 3344-
52). The compound is used as crude product in the subsequent reaction stages.
LC-MS (Method 1): Rt= 1.24 min
MS (ES+) = 428 (M+H)+
Example 8A
8-Chloro-6-fluoro-1-[(lSR,2RS)-2-fluorocyclopropyl]-7-(4-methylpiperazin-1-yl)-4-
oxo-l,4-dihydroquinoline-3-carboxylic acid

The preparation takes place in analogy to Example 1A from racemic 8-chloro-6,7-
difluoro-1-[cis-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
(for preparation in analogy see Journal of Medicinal Chemistry (1994), 37(20), 3344-
52). The compound is used as a crude product in the subsequent reaction stages.
LC-MS (Method 2): Rt= 1.01 min
MS (ES+) = 398 (M+H)+

Example 9A
8-Chloro-6-fluoro-1-[cis-2-fluorocyclopropyl]-7-{4-[2-(2-hydroxyethoxy)ethyl]piper-
azin-1-yl}-4-oxo-l,4-dihydroquinoline-3-carboxylic acid

The preparation takes place in analogy to Example 1A from racemic 8-chloro-6,7-
difluoro-1-[cis-2-fluorocyclopropyl]-4-oxo-l,4-dihydroquinoline-3-carboxylic acid
(for preparation in analogy see Journal of Medicinal Chemistry (1994), 37(20), 3344-
52). The compound is used as a crude product in the subsequent reaction stages.
LC-MS (Method 2): R, = 0.99 min
MS (ES+) = 472 (M+H)+
Example 10A
l-Cyclopropyl-6-fluoro-7-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}-8-methoxy-4-
oxo-l,4-dihydroquinoline-3-carboxylic acid


The preparation takes place in analogy to Example 1A from (T-4)-(l-cyclopropyl-6,7-
difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylato-03,04)boron di-
fluoride (for preparation see Journal of Medicinal Chemistry (1995), 38(22), 4478-87).
The compound is used as a crude product in the subsequent reaction stages.
LC-MS (Method 2): Rt = 0.95 min
MS (ES+) = 450 (M+H)+
Example 11A
7- [(3RS, 5SR)-3,5-Dimethylpiperazin- 1-yl] -6-fluoro-1- [(1 R,2S)-2-fluorocyclopropyl] -8-
methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid


The preparation takes place in analogy to Example 1A from 6,7-difluoro-1-[(lR,2S)-2-
fluorocyclopropyl]-8-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid (for pre-
paration see WO 96/01262).
LC-MS (Method 3): Rt= 1.38 min
MS (ES+) = 408 (M+H)+
Example 12A
l-Cyclopropyl-8-difluoromethoxy-6-fluoro-7-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-
l-yl}-4-oxo-l,4-dihydroquinoline-3-carboxylic acid

The preparation takes place in analogy to Example 1A from (T-4)-(l-cyclopropyl-8-
difluoromethoxy-6,7-difluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylato-03,04)bor-
on difluoride (for preparation see EP 352123). The compound is used as a crude
product in the subsequent reaction stages.

Example 13A
1 -Cyclopropyl-6-fluoro-7-{4- [2-methoxy ethyl] piperazin-1 -yl}-8-methoxy-4-oxo-1,4-
dihydroquinoline-3-carboxylic acid

The preparation takes place in analogy to Example 1A from (T-4)-(l-cyclopropyl-6,7-
difluoro-l,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylato-03,04)boron difluori-
de (for preparation see Journal of Medicinal Chemistry (1995), 38(22), 4478-87). The
compound is used as a crude product in the subsequent reaction stages.
1H NMR (300 MHz, DMSO-d6): 5 = 1.05 (m, 2H), 1.13 (m, 2H), 3.10-3.90 (m, 18 H: in
there 3.82 (s, 3H)), 4.18 (m, 1H), 7.82 (d, 1H), 8.73 (s, 1H), 10.78 (bs, 1H).

Example 14A
Ethyl 3-[(2,2,2-trifluoroethyl)amino]-2-(2,4,5-trifluoro-3-methoxybenzoyl)acrylate(E
+ Z)

2.00 g (5.79 mmol) of ethyl 3-oxo-3-(2,4,5-trifluoro-3-methoxyphenyl)propanoate
are stirred in 3.8 ml (4.14 g, 40.55 mmol) of acetic anhydride and 4.82 ml (4.29 g,
28.96 mmol) of thriethylorthoformate for 2 h under reflux. The solvent is then
completely removed on a rotary evaporator and the residue is dissolved in 10 ml of
ethanol. 1.03 g (10.43 mmol) of 2,2,2-trifluoro-1-aminoethane are added dropwise to
the ice cold solution, the mixture is brought to room temperature and stirred over
night at this temperature. For the work-up the solvent is removed and the residue is
reacted further as a crude product without purification steps.
LC-MS (Method 2): Rt= 2.37 min, MS (ES+) = 386 (M+H)+.
The following Examples 15A to 22A are prepared in analogy to Example 14A from
the corresponding amines.






Under an argon atmosphere and ice cooling 0.32 g (8.11 mmol) of 60% sodium
hydride are provided in 5 ml of tetrahydrofuran and a solution of 2.23 g (5.79 mmol)
of the compound of Example 14A in 15 ml tetrahydrofuran is slowly added dropwise.
The mixture is subsequently warmed to room temperature, stirred for 2 h at this
temperature and then left standing over night. For the work-up 2 ml of acetic acid
are added dropwise and the mixture is stirred for 5 min, diluted with ethyl acetate,
washed several times with water and once with a saturated sodium hydrogen carbon-
ate solution, the organic phase is dried over magnesium sulfate, filtered and the
solvent is completely removed on a rotary evaporator. The crude product is pre-
purified by column chromatography on silica gel 60 (eluent: dichlorometh-
ane/methanol 100/1 → 100/2) and after fine purification by preparative RP-HPLC
(Method 5) 1.8 g of product are obtained.
HPLC (Method 10): R,= 4.34 min,
MS (DCI (NH3)) = 366 (M+H)+.
1H NMR (300 MHz, CDC13): 5 = 1.41 (t, 3H), 4.15 (s, 3H), 4.41 (q, 2H), 5.23 (q, 2H),
8.11 (dd, 1H), 8.33 (s, 1H).
Examples 24A to 31A listed in the table below are prepared from the corresponding
amines in analogy to Example 23A. For the preparation of 2-amino-1-fluoropropane,
see Journal of Organic Chemistry 1981, 46 (24), 4938-4948.





Example 32A
6,7-Difluoro-8-methoxy-4-oxo-1-(2,2,2-trifluoroethyl)-l,4-dihydroquinoline-3-
carboxylic acid

800 mg (2.19 mmol) of the compound of Example 23A are provided in a mixture of
25 ml of acetic acid-water-sulfuric acid 12:8:1 and stirred over night under reflux. For
the work-up the solvent is removed to a large extent on a rotary evaporator, the
residue is adjusted carefully to pH 3 while cooling with ice with a saturated sodium
hydrogen carbonate solution, the suspension is diluted with water, the precipitate is
collected by suction filtration and after drying the filter residue under high vacuum,
575 mg of the title compound are obtained.
LC-MS (Method 3): R,= 2.41 min, MS (ES+) = 338 (M+H)+.
1H NMR (300 MHz, CDC13): 5 = 4.21 (s, 3H), 5.37 (q, 2H), 8.11 (dd, 1H), 8.62 (s, 1H),
14.05 (bs, 1H).
The following Examples 33A bis 40A are prepared in analogy to Example 32A.







Example 41A
[6,7-Difluoro-8-methoxy-4-oxo-1-(2,2,2-trifluoroethyl)-l,4-dihydroquinolin-3-
yl]carbonyl difluoroborate

1.5 g (4.30 mmol) of the compound of Example 32A are provided in 10 ml of
tetrahydrofuran and then 6.81 ml (7.63 g, 53.75 mmol) of borontrifluoride di-
ethylether complex are added and the mixture is stirred at 70°C over night. For the
work-up 50 ml of diethylether are added to the reaction mixture which was cooled to
room temperature, the mixture is stirred for 20 min and the precipitate is collected
by suction filtration. After drying the residue under high vacuum, 1150 mg of the
title compound are obtained and reacted further without purification.
HPLC (Method 9): R,= 4.25 min,
MS (DCI (NH3)) = 402 (M+NH4)+.
1H NMR (300 MHz, DMSO-d6): 5 = 4.21 (s, 3H), 6.12 (q, 2H), 8.38 (dd, 1H), 9.66 (s,
1H).
The following Examples 42A to 49A are prepared in analogy to Example 41A.



Example 50A
7- [(3RS, 5SR)-3,5-Dimethylpiperazin- 1-yl] -6-fluoro-8-methoxy-4-oxo-1 -(2,2,2-
trifluoroethyl)-l,4-dihydroquinoline-3-carboxylic acid - hydroformate

300.0 mg (0.78 mmol) of the compound of Example 41A and 213.6 mg (1.87 mmol)
of cis-2,6-dimethylpiperazine are stirred over night at 50°C in 6 ml of acetonitrile.
The solvent is removed completely on a rotary evaporator and the residue is stirred
for 1 h under reflux with a mixture of 12 ml of ethanol and 6 ml of triethylamine.
For the work-up the solvent is removed on a rotary evaporator and after fine purifica-
tion by preparative RP-HPLC (method 5) 260 mg of the target compound are ob-
tained.
HPLC (Method 9): Rt= 3.76 min,
MS (ESI+) = 432 (M+H)+.
1H NMR (300 MHz, DMSO-d6): ᵹ = 1.03 (d, 6H), 2.82 (m, 2H), 3.04 (m, 2H), 3.28 (m,
2H), 3.78 (s, 3H), 5.77 (q, 2H), 7.82 (d, 1H), 8.19 (s, 1H), 8.52 (s, 1H).
The following Examples 51A to 62A are prepared in analogy to Example 50A.







A solution of 500.0 mg (1.63 mmol) of 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-4-
oxo-l,4-dihydroquinoline-3-carboxylic acid (for preparation see: DE 19854357) and
446.8 mg (3.91 mmol) of cis-2,6-dimethylpiperazine in 50 ml of acetonitrile is stirred
over night at 50°C. The solvent is removed completely on a rotary evaporator, the
residue is taken up in 50 ml of water and the pH is adjusted to pH 11 with a 1N
sodium hydroxide solution (the residue dissolves). The solution is then adjusted to
pH 7 with 1N hydrochloric acid. The precipitate is filtered off, washed with water
and diethylether and dried under high vacuum. 157 mg of the title compound are
obtained. The filtrate is extracted with dichloromethane, the organic phase is con-
centrated and the residue is purified by RP-HPLC. An additional 351 mg of the title
compound are obtained.
LC-MS (Method 2): Rt = 0.83 min
MS (ES+): m/z = 385 (M+H)+.
Example 64A
2-Chloro-4-methoxybenzonitrile

2.6 g of sodium hydride (60% in oil) are added to 2.0 g of 2-chloro-4-hydroxybenzo-
nitrile in 50 ml of THF under argon at 0°C. After 10 min 9.24 g of methyliodide are
added and the mixture is stirred over night at room temperature. For the work-up 2
ml of glacial acidic acid are added cautiously, the mixture is concentrated on a rotary
evaporator and the residue is subjected to an extractive work-up with 1N hydrochlo-
ric acid and ethyl acetate. The organic phase is dried with sodium sulfate and con-

centrated on a rotary evaporator. After HPLC purification (method 5) 0.70 g of
product are obtained.
MS (DCI / NH3): m/z = 184.9 (M+NH4)+.


1H NMR (300 MHz, CDC13): ᵹ = 7.58 (d, 1H), 7.01 (d, 1H), 6.87 (dd, 1H).
Example 65A
2-Bromo-4-chlorobenzonitrile

588 mg of 2-bromo-4-chlorobenzoic acid and 300 mg of urea are dissolved in di-
chloromethane/methanole and deposited onto 364 mg of aluminum oxide on a
rotary evaporator. The residue is irradiated for 60 min in a microwave at 150°C. After
cooling the residue is stirred with ethyl acetate and water, the mixture is filtered and
the aqueous phase is removed. The organic phase is washed with a sodium hydrogen-
carbonate solution dried over sodium sulfate, concentrated on a rotary evaporator
and then dried under high vacuum. The product is reacted further without additional
purification.
1H NMR (300 MHz, CDC13): ᵹ = 7.72 (d, 1H), 7.60 (d, 1H), 7.42 (dd, 1H).

Example 66A
2-Chloro-4-(trifluoromethoxy)phenyl trifluoromethylsulfonate

4.00 g of 2-chloro-4-trifluoromethoxyphenol are provided in 50 ml of toluene and 50
ml of a 30% solution of potassium phosphate in water at 0°C, 3.82 ml of trifluoro-
methanesulfonic anhydride are added slowly and the mixture is stirred for 1.5 h at
room temperature. The aqueous phase is removed and the organic phase is washed
with water, dried over sodium sulfate and concentrated. The crude product is reacted
onto Example 67A without purification.
Example 67A
2-Chloro-4-(trifluoromethoxy)benzonitrile

3.00 g of the compound of Example 66A are dissolved with 2.04 g of zinc cyanide
and 1.00 g of tetrakis(triphenylphosphine)palladium in 12 of ml degased DMF and
heated under argon for 2 h at 120°C. After cooling the reaction mixture is diluted
with ethyl acetate and extracted twice with a saturated sodium hydrogencarbonate

solution and then a saturated sodium chloride solution. The organic phase is dried
over sodium sulfate and concentrated. The residue is purified by silica gel chromatog-
raphy (cyclohexane/ethyl acetate 10:1).
1H NMR (300 MHz, DMSO-d6): ᵹ = 7.62 (dd, 1H), 7.95 (d, 1H), 8.18 (d, 1H).
Example 68A
2-Methyl-4-(trifluoromethoxy)benzamide

795 mg (3.61 mmol) of 2-methyl-4-(trifluoromethoxy)benzoic acid are heated with
4 ml (54.8 mmol) of thionyl chloride and a drop of DMF for 30 min under reflux.
After cooling the reaction mixture is added slowly dropwise into an ice-cooled
concentrated aqueous ammonia solution. The resulting precipitate is collected by
suction filtration, taken up in 30 ml of water and stirred for 1 h at 60°C. The reaction
mixture is left to cool, the solid is collected by filtration and dried under vacuum.
Yield: 562 mg (71% of theory)
LC-MS (Method 2): Rt = 1.61 min.
MS (ESI+): m/z = 220 (M+H)+
1H NMR (400 MHz, DMSO-d6): ᵹ = 7.79 (bs, 1H), 7.42-7.50 (m, 2H), 7.19-7.28 (m,
2H), 2.39 (s, 3H).

Example 69A
2-Methyl-4-(trifluoromethoxy)benzylamine

18.8 ml (18.8 mmol) of borane-THF-complex (1M) are provided under argon and ice
cooling. A solution of 823 mg (3.76 mmol) of 2-methyl-4-(trifluoromethoxy)benz-
amide (Example 68A) in 80 ml of THE is added dropwise and the reaction mixture is
subsequently stirred for 8 h under reflux. Under ice cooling 80 ml of 1N hydrochloric
acid are added dropwise (until the end of the evolution of gas) and the reaction
mixture is heated for 1 h under reflux. The reaction mixture is subsequently adjusted
to an alkaline pH with a 1N sodium hydroxide solution, extracted three times with
dichloromethane and the combined organic phases are dried over sodium sulfate and
the solvent is removed under vacuum. An oil is obtained which is reacted further
without further purification. Yield: 732 mg (95% of theory).
LC-MS (Method 3): R, = 1.41 min.
MS (ESI+): m/z = 206 (M+H)+
1H NMR (400 MHz, CDC13): ᵹ = 7.32-7.40 (m, 1H), 6.99-7.11 (m, 2H), 3.95-4.01 (m,
2H), 2.40 (s, 3H).

Example 70A
2-Bromo-4-chlorobenzylamine

13.9 ml of borane-THF complex are provided under ice cooling. A solution of 2.0 g of
2-bromo-4-chlorobenzonitrile (Example 65A) in 60 ml of THF is added slowly. The
reaction mixture is then heated for 1 h under reflux, cooled and under ice cooling 20
ml of 1N hydrochloric acid are added dropwise. The mixture is heated under reflux
for 1 h and left to cool. For the work-up the solution is adjusted to an alkaline pH
with a 1N sodium hydroxide solution and extracted with dichloromethane. The
organic phase is dried over sodium sulfate and concentrated on a rotary evaporator.
The crude product is reacted further without purification.
1H NMR (300 MHz, CDC13): ᵹ = 3.89(s, 2H), 7.35-7.45 (m [ABM], 2H), 7.55 (d, 1H).
Example 71A
4-Bromo-2-chlorobenzylamine hydrochloride

46.2 ml of borane-THF complex are provided under ice cooling. A solution of 2.0 g of
4-bromo-4-chlorobenzonitrile in 240 ml of THF is added slowly. The reaction mixture

is then heated for 1 h under reflux, cooled and 20 ml of 1N hydrochloric acid are
added dropwise while cooling on ice. The mixture is heated under reflux for 1 h and
left to cool. For the work-up the solution is adjusted to an alkaline pH with a 1N
sodium hydroxide solution and extracted with dichloromethane. The organic phase
is dried over sodium sulfate and concentrated on a rotary evaporator. 6 ml of hydro-
chloric acid in dioxane (4N) are added and the precipitated hydrochloride is collected
by suction filtration. 1.3 g of product are obtained.
1H NMR (300 MHz, DMSO-d6): ᵹ = 4.09 (s, 2H), 7.58 (dd, 1H), 7.68 (dd, 1H), 7.83 (d,
1H), 8.55 (bs, 3H).
Example 72A
4-Bromo-2-methylbenzylamine

The preparation takes place in analogy to Example 70A from 4-bromo-2-methyl-
benzonitrile.
1H NMR (300 MHz, CDC13): ᵹ = ca. 1.7 (br.s , NH2), 2.60 (s, 3H), 3.81(s, 2H), 7.19 (d,
1H), 7.28 (s, 1H), 7.30 (d, 1H).

Example 73A
2-Chloro-4-methoxybenzylamine hydrochloride

The preparation takes place in analogy to Example 71A from the compound of
Example 64A.
1H NMR (300 MHz, DMSO-d6): ᵹ = 3.80 (s, 3H), 4.04 (s, 2H), 7.01 (dd, 1H), 7.12 (d,
1H), 7.53 (d, 1H), 8.38 (bs, 3H).
Example 74A
2-Chloro-4-trifluoromethoxybenzylamine hydrochloride

The preparation takes place in analogy to Example 71A from the compound of
Example 67A.
1H NMR (300 MHz, DMSO-d6): ᵹ = 4.15 (s, 2H), 7.52 (d, 1H), 7.70 (s, 1H), 7.78 (d,
1H), 8.56 (bs, 3H).

Example 75A
2-Chloro-4-trifluoromethylbenzylamine hydrochloride

The preparation takes place in analogy to Example 71A from 2-chloro-4-
trifluoromethylbenzonitrile.
1H NMR (300 MHz, DMSO-d6): ᵹ = 4.22 (s, 2H), 7.30-7.90 (m [AB], 2H), 7.40 (s, 1H),
8.00 (s, 1H), 8.60 (bs, 3H).
Example 76A
2,4-Dichloro-6-methylbenzylamine hydrochloride

The preparation takes place in analogy to Example 71A from 2,4-dichloro-6-
methylbenzonitrile.
1H NMR (300 MHz, DMSO-d6): ᵹ = 2.5 (s, 3H), 4.10 (s, 2H), 7.40 (s, 1H), 7.60 (s, 1H),
8.40 (bs, 3H).

LC-MS (Method 13): R,= 2.44 min, MS (ES+) = 190 (M+H)+.
Example 77 A
4-Chloro- 2- trifluoromethylbenzylamine hydrochloride

The preparation takes place in analogy to Example 71A from 4-chloro-2-
trifluoromethyl-benzonitrile.
1H NMR (300 MHz, DMSO-d6): ᵹ = 4.18 (d, 2H), 7.82 (d, 1H), 7.88-7.98 (m, 2H), 8.58
(bs, 3H).
Example 78A
2-Methyl-4-trifluoromethylbenzylamine hydrochloride

The preparation takes place in analogy to Example 71A from 2-methyl-4-tri-
fluoromethylbenzonitrile.

1H NMR (400 MHz, DMSO-d6): ᵹ = 2.44 (s, 3H), 4.10 (s, 2H), 7.52 (s, 3H), 8.55 (bs,
3H).
Example 79A
8-Chloro-1-cyclopropyl-N-(2,4-dichlorobenzyl)-6,7-difluoro-4-oxo-l,4-
dihydroquinoline-3-carboxamide

15.0 g of 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carbox-
ylic acid (for preparation see DE 3420743 or Y. Kimura et al., J. Med. Chem. 1994, 37
(20), 3344) are dissolved in 500 ml of DMF and 31.3 g of PyBOP and 10.6 g of 2,4-
dichlorobenzylamine are added. After a day the solvent is removed and the residue is
purified by flash chromatography on silica gel (toluene / ethyl acetate 95:5).
LC-MS (Method 1): R,= 3.10 min, MS (ES+) = 457 (M+H)+.

Example 80A
7-[(3R,5S)-4-(Chloroacetyl)-3,5-dimethylpiperazin-1-yl]-1-cyclopropyl-N-(2,4-di-
chlorobenzyl)-6-fluoro-8-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxamide

0.17 ml (0.25 g, 2.19 mmol) of chloroacetyl chloride are provided in 5 ml of di-
chloromethane, the solution is cooled to 0°C, and subsequently 1.00 g (1.83 mmol)
of the compound of Example 12 are added, the mixture is warmed to room tempera-
ture and stirred for 1 h at this temperature. For the work-up 0.49 g of the target
compound are isolated from the solution by negative pressure column chromatogra-
phy on silica gel 60 with an eluent mixture of dichloromethane: ethanol 95:5.
LC-MS (Method 3): Rt= 3.05 min, MS (ES+) = 623 (M+H)+.
1H NMR (400 MHz, DMSO-d6): ᵹ = 0.95 (m, 2H), 1.09 (m, 2H), 1.40 (m, 6H), 3.28 (m,
2H), 3.69 (s, 3H), 4.03-4.70 (m, 9H: in there 4.58 (d, 2H)), 7.35-7.47 (m, 2H), 7.63 (d,
1H), 7.78 (d, 1H), 8.69 (s, 1H), 10.25 (t, 1H).

Example 81A
7-[(3RS,5SR)-4-(Chloroacetyl)-3,5-dimethylpiperazin-1-yl]-N-(2,4-dichlorobenzyl)-6-
fluoro-8-methoxy-1-(2,2,2-trifluoroethyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide

In analogy to Example 80A the title compound is obtained from the compound of
Example 47.
LC-MS (Method 2): Rt= 2.91 min, MS (ES+) = 666 (M+H)+.

Example 82A
7-[(3RS,5SR)-4-(Azidoacetyl)-3,5-dimethylpiperazin-1-yl]-1-cyclopropyl-N-(2,4-di-
chlorobenzyl)-6-fluoro-8-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxamide hy-
drochloride

50.0 mg of the compound of Example 80A and 15.6 mg (0.24 mmol) of sodium azide
are stirred in 3 ml of N,N-dimethylformamide in a closed reaction vessel at 90°C over
night. After fine purification by preparative RP-HPLC (Method 6) 46 mg of the target
compound are obtained.
LC-MS (Method 1): Rt= 3.03 min, MS (ES+) = 630 (M+H)+.

Example 83A
7-[(3RS,5SR)-4-(Azidoacetyl)-3,5-dimethylpiperazin-1-yl]-N-(2,4-dichlorobenzyl)-6-
fluoro-8-methoxy-1-(2,2,2-trifluoroethyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide

In analogy to Example 82A but at room temperature in the presence of 0.1 eq. of
potassium iodide the title compound is prepared from the compound of Example
81A.
LC-MS (Method 3): Rt = 3.17 min, MS (ES+): m/z = 671 (M+H)+.

Example 84A
Ethyl 4-[3-{l-cyclopropyl-[(2,4-dichlorobenzyl)amino]carbonyl}-1-fluoro-8-methoxy-
4-oxo-l,4-dihydroquinolin-7-yl]-(2RS/6SR)-2,6-dimethylpiperazin-1-yl}ethanoate
hydrochloride

1 g of the compound of Example 12 is heated with 343 mg of ethylbromoacetate,
312 mg of potassium iodide and 590 mg of potassium carbonate in 60 ml of acetoni-
trile for 2 h under reflux. After cooling the reaction mixture is separated by prepara-
tive HPLC (Method 6). 862 mg (75% of theory) of the title compound are obtained.
LC-MS (Method 2): Rt = 2.39 min, MS (ESI): m/z = 633 (M+H)+.
1H NMR (400 MHz, DMSO-d6): ᵹ = 0.98 (m, 2H), 1.12 (m, 2H), 1.29 (t, 3H), 1.33 (d,
6H), 3.35-3.69 (m, 4H), 3.72-3.90 (m, 5H: in there 3.79 (s, 3H)), 4.11 (m, 1H), 4.23-
4.51 (m, 4H: in there 4.29 (q, 2H)), 4.59 (d, 2H), 7.39 (d, 1H), 7.42 (dd, 1H), 7.53 (d,
1H), 7.78 (d, 1H), 8.69 (s, 1H), 10.22 (t, 1H).

Example 85A
4-[3-{l-Cyclopropyl-[(2,4-dichlorobenzyl)amino]carbonyl}-1-fluoro-8-methoxy-4-oxo-
l,4-dihydroquinolin-7-yl]-(2RS,6SR)-2,6-dimethylpiperazin-1-yl}ethanoicacid

200 mg of the compound of Example 84A are dissolved in 5 ml of dioxane, subse-
quently 5 ml of a 1M lithium hydroxide solution are added and the mixture is stirred
for 2 h at 50°C. For the work-up the solvent is removed on a rotary evaporator and
the residue is taken up in water and acidified with 1M hydrochloric acid (pH 3-4).
The precipitate is collected by filtration, washed with water and dried under high
vacuum. 140 mg (73% of theory) of the title compound are obtained.
LC-MS (Method 1): Rt = 2.06 min, MS (ESI): m/z = 605 (M+H)+.
1H NMR (300 MHz, DMSO-d6): ᵹ = 0.99 (m, 2H), 1.18 (m, 2H), 1.38 (d, 6H), 3.46 (m,
2H), 3.55 (m, 2H), 3.70 (s, 3H), 3.78 (m, 4H), 3.95 (m, 1H), 4.68 (d, 2H), 7.20 (dd,
1H), 7.38 (m, 2H), 7.86 (d, 1H), 1H), 8.84 (s, 1H), 10.28 (t, 1H).

Example 86A
7-[(3RS,5SR)-4-(Chloroacetyl)-3,5-dimethylpiperazin-1-yl]-6-fluoro-8-methoxy-N-[2-
methyl-4-(trifluoromethoxy)benzyl]-1-(2,2,2-trifluoroethyl)-4-oxo-l,4-dihydroquino-
line-3-carboxamide

The title compound is prepared in analogy to Example 80A from the compound of
Example 52.
LC-MS (Method 1): Rt = 3.09 min; MS (ES+): m/z = 695 (M+H)+.

Example 87A
7-[(3RS,5SR)-4-(Azidoacetyl)-3,5-dimethylpiperazin-1-yl]-6-fluoro-8-methoxy-N-[2-
methyl-4-(trifluoromethoxy)benzyl]-1-(2,2,2-trifluoroethyl)-4-oxo-l,4-dihydroquino-
line-3-carboxamide

The title compound is prepared in analogy to Example 82A from the compound of
Example 86A.
LC-MS (Method 3): Rt = 3.15 min; MS (ES+): m/z = 702 (M+H)+.
1H NMR (400 MHz, CDC13): ᵹ = 1.51 (d, 6H), 2.40 (s, 3H), 3.30 (d, 2H), 3.44 (br.d,
2H), 3.75 (s, 3H), 4.00 (br.s, 2H), 4.62 (d, 2H), 5.20 (q, 2H), 7.00-7.06 (m, 2H), 7.35
(d, 1H), 7.95 (d, 1H), 8.60 (s, 1H), 9.99 (t, 1H).

8-Chloro-1-cyclopropyl-N-(2,4-dichlorobenzyl)-6-fluoro-7-[4-(2-hydroxyethyl)-l,4-
diazepan-1-yl]-4-oxo-l,4-dihydroquinoline-3-carboxamide

110 mg (0.26 mmol) of the compound of Example 1A are dissolved in 2 ml of di-
methylformamide and 35 mg (0.26 mmol) of 1-hydroxybenzotriazole, 46 mg
(0.26 mmol) of 2,4-dichlorobenzylamine and 55 mg (0.29 mmol) of N-(3-dimethyl-
aminopropyl)-N'-ethylcarbodiimide hydrochloride are added. After two days of
stirring at room temperature the batch is diluted with 2 ml of water. The batch is
purified by preparative HPLC (Method 4). 34.5 mg of the target compound are
obtained.
LC-MS (Method 3): Rt= 1.95 min
MS (ES+) = 581 (M+H)+
In analogy to the preparation instructions of Example 1, Examples 2 to 6 are pre-
pared:

Example 2
8-Chloro-1-cyclopropyl-N-(2,4-dichlorobenzyl)-6-fluoro-7{4-[2-(2-hydroxyeth-
oxy)ethyl]piperazin-1-yl}-4-oxo-l,4-dihydroquinoline-3-carboxamide

The preparation takes place in analogy to Example 1 from Example 2A.
LC-MS (Method 2): Rt= 1.78 min
MS(ES+) = 611 (M+H)+
1H NMR (300 MHz, DMSO-d6): ᵹ = 0.9 (m, 2H), 1.2 (m, 2H), 2.6 - 2.7 (m, about 6H),
3.3 (signals under the solvent), 3.4 - 3.6 (m, about 6H), 4.3 (m, 1H), 4.5 (d, 2H), 7.4
(m, 2H), 7.65 (d, 1H), 7.9 (d, 1H), 8.8 (s, 1H), 10.1 (t, 1H).

8-Chloro-N-(2,4-dichlorobenzyl)-6-fluoro-1-[(lR,2S)-2-fluorocyclopropyl]-7-{4-[2-(2-
hydroxyethoxy)ethyl]piperazin-1-yl}-4-oxo-l,4-dihydroquinoline-3-carboxamide

The preparation takes place in analogy to Example 1 from Example 3A.
LC-MS (Method 2): Rt= 1.76 min
MS (ES+) = 629 (M+H)+
Example 4
8-Chloro-N-(2,4-dichlorobenzyl)-6-fluoro-1-[(lS,2R)-2-fluorocyclopropyl]-7-{4-[2-(2-
hydroxyethoxy)ethyl]piperazin-1-yl}-4-oxo-l,4-dihydroquinoline-3-carboxamide


The preparation takes place in analogy to Example 1 from Example 4A.
LC-MS (Method 1): Rt= 1.98 min
MS (ES+) = 629 (M+H)+
Example 5
8-Chloro-1-cyclopropyl-N-(2,4-dichlorobenzyl)-7-[(3RS,5SR)-3,5-dimethylpiperazin-1-
yl]-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxamide

The preparation takes place in analogy to Example 1 from 8-chloro-1-cyclopropyl-7-
[(3RS,5SR)-3,5-dimethylpiperazin-1-yl]-6-fluoro-4-oxo-l,4-dihydroquinoline-3-
carboxylic acid (for preparation see DE 3635218)
LC-MS (Method 2): Rt= 1.86 min
MS (ES+) = 551 (M+H)+
1H NMR (400 MHz, CDC13): ᵹ = 0.9 (m, 2H), 1.1 (d, 6H), 1.2 - 1.3 (m, 2H), 2.7 - 2.9
(m, 2H), 3.1-3.3 (m, 4H), 4.3 (m, 1H), 4.7 (d, 2H), 7.2 (dd, 2H), 7.4 (m, 2H), 8.0 (d,
1H), 8.9 (s, 1H), 10.2 (t, 1H).

Example 6
8-Chloro-N-(2,4-dichlorobenzyl)-6-fluoro-1-[(lS,2R)-2-fluorocyclopropyl]-7-[4-(2-
morpholin-4-yl-2-oxoethyl)piperazin-1-yl]-4-oxo-l,4-dihydroquinoline-3-carbox-
amide

The preparation takes place in analogy to Example 1 from Example 5A.
LC-MS (Method 1): Rt= 2.08 min
MS (ES+) = 668 (M+H)+

Example 7
N-(2,4-Dichlorobenzyl)-6-fluoro-1- [(1R, 2S)-2-fluorocyclopropyl] - 7- {4- [2-(2-hydroxy-
ethoxy)ethyl]piperazin-1-yl}-8-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxamide

140 mg (0.27 mmol) of 1-benzotriazolyloxytripyrrolidinophosphonium hexafluoro-
phosphate, 47 mg (0.27 mmol) of 2,4-dichlorobenzylamine and 35 mg (0.27 mmol)
of diisopropylethylamine are added under argon to 105 mg (0.14 mmol) of the
carboxylic acid of Example 6A in 2 ml of dimethylformamide and the mixture is
stirred at room temperature for 2 days. The reaction mixture is diluted with 2 ml of
water and without further work-up purified by preparative HPLC (Method 4). 52 mg
of the target compound are obtained.
LC-MS (Method 1): R,= 1.91 min
MS (ES+) = 625 (M+H)+
In analogy to the preparation instructions of Example 7, Examples 8 to 18 are pre-
pared:

Example 8
8-Chloro-N-(4-chloro-2-methylbenzyl)-1-cyclopropyl-6-fluoro-7-{4-[2-(2-hydroxy-
ethoxy)ethyl]piperazin-1-yl}-4-oxo-l,4-dihydroquinoline-3-carboxamide

The preparation takes place in analogy to Example 7 from Example 2A.
LC-MS (Method 3): Rt= 1.91 min
MS (ES+) = 591 (M+H)+
1H NMR (400 MHz, CDC13): ᵹ = 0.9 (m, 2H), 1.2 (m, 2H), 2.4 (s, 3H), 2.6 - 2.7 (m,
about 6H), 3.4 (m, about 4H), 3.6 - 3.8 (m, 6H), 4.2 (m, 1H), 4.6 (d, 2H), 7.2 (m, 2H),
7.35 (dd, 2H), 7.9 (d, 1H), 8.9 (s, 1H), 10.0 (t, 1H).

Example 9
8-Chloro-N-(2,4-dichlorobenzyl)-6-fluoro-1-[(lSR,2RS)-2-fluorocyclopropyl]-7-{4-[2-
(2-hydroxyethyl)piperazin-1-yl]-4-oxo-l,4-dihydroquinoline-3-carboxamide

The preparation takes place in analogy to Example 7 from Example 7A.
LC-MS (Method 2): Rt= 1.63 min
MS (ES+) = 585 (M+H)+
Example 10
8-Chloro-N-(2,4-dichlorobenzyl)-6-fluoro-1-[(lSR,2RS)-2-fluorocyclopropyl]-7-(4-
methylpiperazin-1-yl)-4-oxo-l,4-dihydroquinoline-3-carboxamide


The preparation takes place in analogy to Example 7 from Example 8A.
LC-MS (Method 2): Rt= 1.70 min
MS (ES+) = 555 (M+H)+
Example 11
8-Chloro-N-(2,4-dichlorobenzyl)-6-fluoro-1-[(lSR/2RS)-2-fluorocyclopropyl]-7-{4-[2-
(2-hydroxyethoxy)ethyl]piperazin- l-yl}-4-oxo-1,4-dihydroquinoline-3-carboxamide

The preparation takes place in analogy to Example 7 from Example 9A.
LC-MS (Method 3): Rt= 1.89 min
MS (ES+) = 629 (M+H)+
Example 12
l-Cyclopropyl-N-(2,/4-dichlorobenzyl)-7-[(3RS,5SR)-3,5-dimethylpiperazin-1-yl]-6-
fluoro-8-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxamide


The preparation takes place in analogy to Example 7 from l-cyclopropyl-7-(cis-3,5-di-
methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1;4-dihydroquinoline-3-carboxylic
acid (for preparation see Journal of Medicinal Chemistry, (1995), 38(22), 4478-87).
LC-MS (Method 2): Rt= 1.77 min
MS (ES+) = 547 (M+H)+
Example 13
l-Cyclopropyl-N-(2,4-dichlorobenzyl)-8-difluoromethoxy-7-[(3RS,5SR)-3,5-dimethyl-
piperazin-1-yl]-6-fluoro-4-oxo-l,4-dihydroquinoline-3-carboxamide


The preparation takes place in analogy to Example 7 from l-cyclopropyl-7-(cis-3,5-
dimethylpiperazin-1-yl)-8-difluoromethoxy-6-fluoro-4-oxo-l,4-dihydroquinoline-3-
carboxylic acid (for preparation see EP 352123).
LC-MS (Method 2): Rt = 2.05 min
MS (ES+) = 583 (M+H)+
Example 14
N-(4-Chloro-2-methylbenzyl)-1-cyclopropyl-6-fluoro-7-{4-[2-(2-hydroxyethoxy)eth-
yl]piperazin-1-yl}-8-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxamide

The preparation takes place in analogy to Example 7 from Example 10A.
LC-MS (Method 2): Rt = 1.70 min
MS (ES+) = 587 (M+H)+

Example 15
8-Chloro-N-(4-chloro-2-methylbenzyl)-6-fluoro-1-[(lS,2R)-2-fluorocyclopropyl]-7-[4-
(2-morpholin-4-yl-2-oxoethyl)piperazin-1-yl]-4-oxo-l,4-dihydroquinoline-3-carbox-
amide

The preparation takes place in analogy to Example 7 from Example 5A.
LC-MS (Method 2): Rt= 1.66 min
MS (ES+) = 648 (M+H)+
Example 16
N-(2,4-Dichlorobenzyl)-7-[(3RS,5SR)-3,5-dimethylpiperazin-1-yl]-6-fluoro-1-[(lR,2S)-
2-fluorocyclopropyl]-8-methoxy-4-oxo-1;4-dihydroquinoline-3-carboxamide


The preparation takes place in analogy to Example 7 from Example 11 A.
LC-MS (Method 2): Rt= 1.66 min
MS (ES+) = 565 (M+H)+
1H NMR (300 MHz, CDCl3): ᵹ = 1.1 (d, 6H), 1.4 - 1.7 (m), 2.7 - 2.9 (m, 2H), 3.0 - 3.2
(m, 2H), 3.2 - 3.4 (m, 2H), 3.7 (s, 3H), 3.8 - 3.9 (m, 1H), 4.6 - 4.9 (m, about 3H), 7.1 -
7.2 (dd, 1H), 7.3 - 7.5 (m, 2H), 7.8 - 7.9 (d, 1H), 8.8 (s, 1H), 10.3 - 10.4 (t, 1H).
Example 17
N-(4-Chloro-2-methylbenzyl)-7-[(3RS,5SR)-3,5-dimethylpiperazin-1-yl]-6-fluoro-1-
[(1R, 2S)-2-fluorocyclopropyl]-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxamide


The preparation takes place in analogy to Example 7 from Example 11 A.
LC-MS (Method 3): Rt= 1.89 min
MS (ES+) = 545 (M+H)+
1H NMR (300 MHz, CDC13): ᵹ = 1.1 (d, 6H), 1.4 - 1.7 (m), 2.4 (s, 3H), 2.7 - 2.9 (m, 2H),
3.0-3.2 (m, 2H), 3.2 - 3.4 (m, 2H), 3.7 (s, 3H), 3.8 - 3.9 (m, 1H), 4.5 - 4.65 (m, 1H),
4.65 - 5.0 (m, 2H), 7.1 - 7.2 (m, 2H), 7.3 (m, about 1H), 7.75 (d, 1H), 8.8 (s, 1H), 10.2
(t, 1H).
Example 18
l-Cyclopropyl-N-(2,4-dichlorobenzyl)-8-difluoromethoxy-6-fluoro-7-{4-[2-(2-
hydroxyethoxy)ethyl]piperazin-1-yl}-4-oxo-l,4-dihydroquinoline-3-carboxamide

The preparation takes place in analogy to Example 7 from Example 12A.
LC-MS (Method 2): Rt= 1.66 min
MS (ES+) = 643 (M+H)+

1H NMR (400 MHz, CDC13): ᵹ = 0.9 (m, 2H), 1.2 (m, 2H), 2.7 (m, about 6H), 3.4 (m,
4H), 3.6 - 3.8 (m, 6H), 4.1 (m, 1H), 4.7 (d, 2H), 6.5 (dd, 1H), 7.2 (m, 1H), 7.4 (m, 2H),
8.0 (d, 1H), 8.8 (s, 1H), 10.2 (t, 1H).
Example 19
N-(4-Bromo-2-chlorobenzyl)-1-cyclopropyl-7-[(3RS,5RS-3,5-dimethyl)piperazin-1-
yl]-6-fluoro-8-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxamide hydroformate

130 mg (0.25 mmol) of PyBOP, 78 mg (0.36 mmol) of 2-bromo-4-chlorobenzylamine
(Example 70A) and 127 mg (0.98 mmol) of N,N-diisopropylethylamine are added to
75 mg (0.19 mmol) l-cyclopropyl-7-(cis-3,5-dimethylpiperazin-1-yl)-6-fluoro-8-
methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid (for preparation see: Journal
of Medicinal Chemistry, (1995), 38(22), 4478-87) in 2 ml dimethylformamide under
argon and the mixture is stirred over night at room temperature. The reaction mix-
ture is diluted with 2 ml of water and without further work-up purified by prepara-
tive HPLC (Method 5). 92 mg of the title compound are obtained.
LC-MS (Method 1): Rt = 1.96 min, MS (ES+) = 591 (M+H)+, (79Br 35C1), 593 (M+H)+
(81Br35Cl).

1H NMR (300 MHz, CDC13): ᵹ = 0.97 (m, 2H), 1.18 (m, 2H), 1.38 (d, 6H), 3.34-3.52
(m, 6H), 3.77 (s, 3H), 3.95 (m, 1H), 4.69 (d, 2H), 4.86 (m, 1H), 7.33 (m, 2H); 7.52 (s,
2H), 7.91 (d, 1H), 8.43 (s, 1H), 8.86 (s, 1H), 10.34 (t, 1H)
From the same acid and in analogy to the preparation instructions of Example 19
Examples 20 to 27 are prepared from the corresponding amines (commercially
available or described in Examples 69A to 78A).





Example 28
N-(2,4-Dichlorobenzyl)-7-[(3RS,5RS-3,5-dimethyl)piperazin-1-yl]-6-fluoro-1-(2-flu-
oroethyl)-8-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxamide hydroformate

Preparation takes place in analogy to Example 19 from 7-(cis-3,5-dimethylpiperazin-
l-yl)-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic
acid (for preparation see: EP 0241206) and 2,4-dichlorobenzylamine.
HPLC (Method 9): Rt= 4.46 min, MS (ESI) = 553 (M+H)+ .
1H NMR (400 MHz, DMSO-d6): ᵹ = 1.15 (d, 6H), 2.88-3.07 (m, 2H), 3.11-3.56 (m, 4H
under the water signal of the DMSO), 3.78 (s, 3H), 4.59 (d, 2H), 4.76 (dd, 2H), 4.95













Example 52
7-[(3RS,5SR)-3,5-Dimethylpiperazin-1-yl]-6-fluoro-8-methoxy-N-[2-methyl-4-
(trifluoromethoxy)benzyl]-4-oxo-1-(2,2,2-trifluoroethyl)-l,4-dihydroquinoline-3-
carboxamide

212 mg (0.49 mmol) of 7-[(3RS,5SR)-3,5-dimethylpiperazin-1-yl]-6-fluoro-8-methoxy-
4-oxo-1-(2,2,2-trifluoroethyl)-l,4-dihydroquinoline-3-carboxylic acid (salt free com-
pound of Example 50A) and 366 mg (0.98 mmol) of 2-methyl-4-trifluoromethoxy-
benzylamine (Example 69A) are dissolved together with 357 mg (0.69 mmol) of
PyBOP and 30 mg (0.25 mmol) of 4-dimethylaminopyridine in 4 ml of DMF and
stirred for 12 h at room temperature. The reaction mixture is then purified by prepa-
rative HPLC (Method 7). A solid is obtained. Yield: 170 mg (56% of theory).
LC-MS (Method 1): R, = 2.00 min, MS (ES+): m/z = 619 (M+H)+
1H NMR (400 MHz, DMSO-d6): ᵹ = 10.0 (t, 1H), 8.85 (bs, 1H), 7.76 (d, 1H), 7.37 (d,
1H), 7.22 (m, 1H), 7.15-7.19 (m, 1H), 5.71 (q, 2H), 4.55 (d, 2H), 3.78 (s, 3H), 3.17-
3.24 (m, 2H), 2.92-3.06 (m, 2H), 2.70-2.83 (m, 2H), 2.37 (s, 3H), 1.00 (d, 6H).

Example 53
{(2RS,6SR)-4-[3-{[(2,4-Dichlorobenzyl)amino]carbonyl}-6-fluoro-8-methoxy-4-oxo-1-
(2,2,2-trifluoroethyl)-1,4-dihydroquinolin- 7-yl] -2,6-dimethylpiperazin-1 -yl} acetamide

243 mg (0.41 mmol) of N-(2,4-dichlorobenzyl)-7-[(3RS,5SR)-3,5-dimethylpiperazin-1-
yl]-6-fluoro-8-methoxy-4-oxo-1-(2,2,2-trifluoroethyl)-l/4-dihydroquinoline-3-carbox-
amide (released from the hydrochloride of the compound of Example 47), 46.3 mg
(0.49 mmol) of chloroacetamide, 75 mg (0.45 mmol) of potassium iodide and 143 mg
(1.03 mmol) of potassium carbonate are stirred over night under reflux in 4 ml of
acetonitrile. After cooling the mixture is filtered and separated by preparative HPLC
(Method 5). For fine purification the obtained product is stirred in hot acetonitrile,
cooled and filtered. After drying under high vacuum 46 mg (16% of theory) of the
title compound are obtained.
LC-MS (Method 3): Rt = 2.05 min, MS (ES+): m/z = 646 (M+H)+.
1H NMR (400 MHz, CDC13): ᵹ = 1.12 (d, 6H), 2.82 (m, 2H), 3.04 (m, 2H), 3.21 (m,
2H), 3.33 (m, 2H), 3.84 (s, 3H), 4.69 (d, 2H), 5.23 (m, 2H), 5.45 (s, 1H), 7.21 (m, 1H),
7.34-7.44 (m, 2H), 7.93 (d, 1H), 8.54 (s, 1H), 10.19 (m, 1H).
In analogy to the preparation of Example 53 the following Examples 54 to 75 are
prepared from the corresponding piperazines with electrophiles. As electrophiles











Example 76
N-Ethyl-{4-[l-cyclopropyl-3-{[(2,4-dichlorobenzyl)amino]carbonyl}-6-fluoro-8-
methoxy-4-oxo-l,4-dihydroquinolin-7-yl]-(2RS,6SR)-2,6-dimethylpiperazin-1-
yl}acetamide hydrochloride

50 mg of the compound of Example 84A are provided in 2 ml of DMF. An ethyl-
amine solution (2M in THF) with 103 mg of PyBOP and 35 µl of Hunig's base are
added and the mixture is left stirring for 24 h at room temperature. The complete
reaction mixture is separated by preparative HPLC (Method 6). 36 mg (69% of
theory) of the title compound are obtained.
LC-MS (Method 3): Rt = 2.17 min, MS (ES+): m/z = 632 (M+H)+
1H NMR (400 MHz, DMSO-d6): ᵹ = 0.97 (m, 2H), 1.05-1.14 (m, 5H), 1.33 (d, 6H), 3.20
(m, 2H), 3.49 (d, 2H), 3.60 (t, 2H), 3.74-3.80 (m, 5H, underneath there 3.78 (s, 3H)),
4.02-4.10 (m, 3H), 4.58 (d, 2H), 7.37-7.43 (m, 2H), 7.52 (s, 1H), 7.77 (d, 1H), 8.69 (s,
1H), 10.22 (t, 1H).
In analogy to Example 76 the following compounds are obtained with the corre-
sponding amines:


Example 79
l-Cyclopropyl-N-(2,4-dichlorobenzyl)-6-fluoro-7-[(3RS,5SR)-4-glycyl-3,5-dimethylpip-
erazin-l-yl]-8-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxamide hydrochloride

46.0 mg (0.07 mmol) of the compound of Example 82A are provided in 2 ml of
tetrahydrofuran, the solution is cooled to 0°C, 21.1 mg (0.08 mmol) of triphenyl-
phosphine, dissolved in 1 ml of tetrahydrofuran are added dropwise, the reaction
mixture is warmed to room temperature and stirred over night at this temperature.

For the work-up the solvent is removed completely on a rotary evaporator, the
residue is prepurified by preparative RP-HPLC (Method 6) and after fine purification
by column chromatography on silica gel 60 (eluent: dichloromethane:ethanol 90:10)
and concentrating the fractions with the addition of hydrochloric acid 24 mg of the
target compound are obtained.
LC-MS (Method 1): Rt = 1.86 min, MS (ES+): m/z = 604 (M+H)+
1H NMR (400 MHz, DMSO-d6): ᵹ = 0.95 (m, 2H), 1.09 (m, 2H), 1.38 (d, 3H), 1.46 (d,
3H), 3.39 (m, 2H), 3.57 (s, 2H), 3.70 (s, 3H), 3.75 (m, 1H), 4.03 (m, 1H), 4.10 (m, 2H),
4.55 (m, 1H), 4.59 (d, 2H), 7.37-7.47 (m, 2H), 7.65 (d, 1H), 7.78 (d, 1H), 8.05 (m, 2H),
8.70 (s, 1H), 10.25 (t, 1H).
Example 80
N-(2,4-Dichlorobenzyl)-6-fluoro-7-[(3RS,5SR)-4-glycyl-3,5-dimethylpiperazin-1-yl]-8-
methoxy-1-(2,2,2-trifluoroethyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide hydro-
chloride

The title compound is prepared in analogy to Example 79 from the compound of
Example 83A.
LC-MS (Method 3): Rt = 2.03 min; MS (ES+): m/z = 646 (M+H)+.

Example 81
7- [(3RS, 5SR)-4-(Azetidin-1 -ylacetyl)-3,5-dimethylpiperazin- 1-yl]- l-cyclopropyl-N-(2,4-
dichlorobenzyl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxamide

50 mg (0.08 mmol) of the compound of Example 80A and 22.9 mg (0.40 mmol) of
azetidine are stirred in 3 ml of ethanol in a closed reaction vessel over night at 90°C.
For the work-up the solvent is removed completely on a rotary evaporator and the
residue is purified by preparative RP-HPLC (Method 6). The target compound is
obtained with 24 mg.
LC-MS (Method 1): Rt = 1.97 min, MS (ES+): m/z = 644 (M+H)+
1H NMR (400 MHz, DMSO-d6): ᵹ = 0.95 (m, 2H), 1.08 (m, 2H), 1.37 (d, 3H), 1.48 (d,
3H), 2.23-2.58 (m, 2H), 3.22-3.49 (m, 4H), 3.70 (s, 3H), 3.87 (m, 1H), 3.95-4.38 (m,
6H), 4.45-4.67 (m, 4H: in there 4.58 (d, 2H)), 7.35-7.47 (m, 2H), 7.64 (d, 1H), 7.78 (d,
1H), 8.69 (s, 1H), 10.25 (t, 1H).
In analogy to Example 81 the following Examples 82 to 84 are prepared:



Example 85
8-Chloro-1-cyclopropyl-N-(2,4-dichlorobenzyl)-7-[4-acetylpiperazin-1-yl]-6-fluoro-4-
oxo-l,4-dihydroquinoline-3-carboxamide

28 µl (0.2 mmol) of triethylamine and 12.8 mg (0.1 mmol) of 1-acetylpiperazine are
added to 45.6 mg (0.1 mmol) of 8-chloro-1-cyclopropyl-N-(2,4-dichlorobenzyl)-6,7-
difluoro-4-oxo-l,4-dihydroquinoline-3-carboxamide (Example 79A) in 400 µl of
DMF. The mixture is stirred for 14 h at 100°C, filtered and purified by preparative LC-
MS (Method 12).
In analogy to Example 85 the Examples 86 to 88 listed in the following table are
prepared.



Example 89
l-Cyclopropyl-N-(2,4-dichlorobenzyl)-6-fluoro-7-[4-(2-hydroxy-2-methylpropyl)-3-
methylpiperazin-1-yl]-8-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxamide hydro-
chloride

100 mg of l-cyclopropyl-N-(2,4-dichlorobenzyl)-6-fluoro-8-methoxy-7-(3-methylpip-
erazine)-4-oxo-l,4-dihydroqumoline-3-carboxamide (free base of Example 49) are
stirred with 152 mg of isobutylene oxide (2 eq.) and 75 mg of lithium perchlorate
(4 eq.) over night in 10 ml of acetonitrile under reflux. The reaction mixture is
purified after cooling directly by preparative RP-HPLC (Method 6).
LC-MS (Method 2): R, = 1.62 min, MS (ESI): m/z = 605 (M+H)+

Example 90
l-Cyclopropyl-N-(2,4-dichlorobenzyl)-7-[(3RS,5SR)-3,5-dimethyl-4-(2-hydroxy-2-
methylpropyl)piperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-l,4-dihydroquinoline-3-
carboxamide hydrochloride

The compound is prepared in analogy to Example 89 from the compound of Exam-
ple 12 and l,2-epoxy-2-methylpropane.
LC-MS (Method 3): Rt = 1.95 min, MS (ES+): m/z = 619 (M+H)+
Example 91
l-Cyclopropyl-N-(2,4-dichlorobenzyl)-7-{(3RS,5SR)-4-[(2R)-2,3-dihydroxypropyl]-3,5-
dimethylpiperazin-1-yl}-6-fluoro-8-methoxy-4-oxo-l,4-dihydroquinoline-3-carbox-
amide hydrochloride


The title compound is prepared in analogy to Example 89 from Example 12 with
(2R)-3-butanoyloxy-l,2-epoxypropane and subsequent hydrolysis of the butyrate
with 1 equivalent of a 1M lithium hydroxide solution at 70°C for 1 h. For the work-
up the solvent is removed on a rotary evaporator, the residue is adjusted to a neutral
pH using 1N hydrochloric acid and buffer pH 7 and extracted with dichloromethane.
Purification takes place by RP-HPLC (Method 6).
LC-MS (Method 3): Rt = 1.77 min, MS (ES+): m/z = 621 (M+H)+
1H NMR (400 MHz, DMSO-d6): ᵹ = 0.96 (m, 2H), 1.12 (m, 2H), 1.39 (d, 3H), 1.45 (d,
3H), 3.22-3.38 (m, 3H), 3.39-3.78 (m, 7H), 3.80 (s, 3H), 3.85 (m, 1H), 4.02 (m, 1H),
4.11 (m, 1H), 4.58 (d, 2H), 7.38 (d, 1H), 7.42 (dd, 1H), 7.63 (d, 1H), 7.76 (d, 1H), 8.69
(s, 1H), 10.22 (t, 1H), 10.61 (bs, 1H).
In analogy to Example 91 the following Example 92 is prepared.


Example 93
7-[(3RS,5SR)-4-(3-Amino-3-oxopropyl)-3,5-dimethylpiperazin-1-yl]-6-fluoro-8-meth-
oxy-N-[2-methyl-4-(trifluoromethoxy)benzyl]-4-oxo-1-(2,2/2-trifluoroethyl)-l,4-dihy-
droquinoline-3-carboxamide hydroformate

A few drops of acetonitrile are added at room temperature to 55 mg of the compound
of Example 52, 18 mg of acrylamide and 35 mg of lithium perchlorate, so that a
stirrable suspension results. The mixture is heated to 70°C over night and left to cool.
After the addition of DMSO the whole mixture is separated by preparative HPLC
(Method 5). After concentrating the suitable fractions and drying under high vacuum
30 mg (40% of theory) of the title compound are obtained.
LC-MS (Method 1): Rt= 2.00 min, MS (ES+) = 690 (M+H)+.

Example 94
l-Cyclopropyl-7-{(3RS,5SR)-4-[(cyclopropylamino)carbonyl]-3,5-dimethylµlperazin-1-
yl}-N-(2,4-dichlorobenzyl)-6-fluoro-8-methoxy-4-oxo-l,4-dihydroquinoline-3-carb-
oxamide

30 µl (24.3 mg, 0.29 mmol) of cyclopropylisocyanate are dissolved in dichloro-
methan, 80.0 mg (0.146 mmol) of the compound of Example 12 are added and the
mixture is stirred over night at room temperature. For the work-up the solvent is
removed completely and after fine purification by preparative RP-HPLC (Method 6)
55 mg of the target compound are obtained.
LC-MS (Method 3): Rt= 2.97 min, MS (ES+) = 630 (M+H)+.
1H NMR (400 MHz, DMSO-d6): ᵹ = 0.41 (m, 2H), 0.55 (m, 2H), 0.94 (m, 2H), 1.09 (m,
2H), 1.28 (d, 6H), 3.22 (m, 2H), 3.32 (m, 2H), 3.69 (s, 3H), 4.11 (m, 4H), 4.58 (d, 2H),
6.49 (bs, 1H), 7.39 (d, 1H), 7.43 (dd, 1H), 7.63 (d, 1H), 7.74 (d, 1H), 8.68 (s, 1H),
10.25 (t, 1H).
In analogy to Example 94 the following Examples 95 to 97 are prepared.



The title compound is prepared in analogy to Example 79 from the compound of
Example 87A.
LC-MS (Method 13): Rt = 3.51 min; MS (ES+): m/z = 676 (M+H)+.
Example 99
N-(2,4-Dichlorobenzyl)-7-{(3RS,5SR)-3,5-dimethyl-4-[(5-oxo-4,5-dihydro-1H-l,2,4-
triazol-3-yl)methyl]µlperazin-1-yl}-6-fluoro-8-methoxy-4-oxo-1-(2,2,2-trifluoroethyl)-
l,4-dihydroquinoline-3-carboxamide

50.0 mg (0.09 mmol) of the free base of the compound of Example are provided in
acetonitrile, 17.0 mg (0.13 mmol) of 5-(chloromethyl)-2,4-dihydro-3H-l,2,4-triazol-3-
one (for preparation see: Cowden, Camaron J.; Tetrahedron Lett., 41 (44), 2000;
8661-8665), 16.9 mg (0.10 mmol) of potassium iodide and 35.2 mg (0.25 mmol) of
potassium carbonate are added and the mixture is stirred over night at 50°C. For the
work-up the cooled reaction mixture is filtered through silica gel, which is washed
with acetonitrile and dichloromethane/methanol (10/1), the filtrate is removed on a
rotary evaporator and from the obtained residue 23 mg (40% of theory) of the
product are obtained after fine purification on silica gel 60 (eluent: dichloro-
methane/ethanol 100/1 → 50/1 → 20/1 → 10/1).
LC-MS (Method 1): Rt = 2.10 min, MS (ES+): m/z = 686 (M+H)+;

1H NMR (400 MHz, DMSO-d6): ᵹ = 1.09 (d, 6H), 2.81 (m, 2H), 2.95 (m, 2H), 3.22 (m,
2H), 3.76 (s, 3H), 4.59 (d, 2H), 5.69 (q, 2H), 7.39 (d, 1H), 7.43 (dd, 1H), 7.64 (d, 1H),
7.76 (d, 1H), 8.82 (s, 1H), 10.12 (t, 1H), 11.22 (s, 1H), 11.28 (s, 1H).
Example 100
l-Cyclopropyl-N-(2,4-dichlorobenzyl)-6-fluoro-8-methoxy-7-[3-methyl-4-(2-
{[(methylamino)carbonyl]amino}-2-oxoethyl)µlperazin-1-yl]-4-oxo-l,4-
dihydroquinoline-3-carboxamide hydrochloride

In analogy to the instructions of Example 99 the title compound is obtained from
80.0 mg (0.14 mmol) of the compound of Example 49 and 25.4 mg (0.17 mmol) of 2-
chloro-N-[(methylamino)carbonyl]acetamide (for preparation see: patent DE 167138)
with 60 mg (62% of theory).
LC-MS (Method 1): Rt = 2.27 min, MS (ES+): m/z = 647 (M+H)+;
1H NMR (300 MHz, DMSO-d6): ᵹ = 0.95 (m, 2H), 1.11 (m, 2H), 1.32 (m, 3H), 2.72 (d,
2H), 3.27-3.95 (m, 9H: in there 3.79 (s, 3H)), 4.11 (m, 1H), 4.25 (m, 1H), 4.41 (m,
1H), 4.58 (d, 2H), 7.38 (d, 1H), 7.43 (dd, 1H), 7.64 (d, 1H), 7.71-7.98 (m, 2H: in there
7.78 (d, 1H)), 8.79 (s, 1H), 10.22 (t, 1H), 10.81 (s, 1H).
In analogy to Example 91 the following Examples 101 and 102 are prepared.



B. Assessment of the physiological activity
The in vitro effect of the compounds of the invention can be shown in the following
assays:
Anti-HCMV (anti-human cytomegalovirus) cytopathogenicity tests
The test compounds are employed as 50 millimolar (mM) solutions in dimethyl
sulfoxide (DMSO). Ganciclovir®, Foscarnet® and Cidofovir® are used as reference
compounds. After the addition of 2 µl of the 50, 5, 0.5 and 0.05 mM DMSO stock
solutions respectively to 98 µl portions of cell culture medium in row 2 A-H for
duplicate determinations, 1:2 dilutions are carried out with 50 µl portions of medium
up to row 11 of the 96-well plate. The wells in rows 1 and 12 each contain 50 µl of
medium. 150 µl of a suspension of 1 x 104 cells (human prepuce fibroblasts [NHDF])
are then plpetted into each of the wells (row 1 = cell control) and, in rows 2-12, a
mixture of HCMV-infected and uninfected NHDF cells (M.O.I. = 0.001 - 0.002), i.e. 1-
2 infected cells per 1000 uninfected cells. Row 12 (without substance) serves as virus
control. The final test concentrations are 250-0.0005 µM. The plates are incubated at
37°C/5% C02 for 6 days, i.e. until all the cells in the virus controls are infected (100%
cytopathogenic effect [CPE]). The wells are then fixed and stained by adding a
mixture of formalin and Giemsa's dye (30 minutes), washed with double-distilled
water and dried in a drying oven at 50°C. The plates are then assessed visually using
an overhead microscope (plaque multiplier from Technomara).
The following data can be obtained from the test plates:
CC50 (NHDF) = substance concentration in µM at which no visible cytostatic effects
on the cells are evident by comparison with the untreated cell control;
EC50 (HCMV) = substance concentration in µM which inhibits the CPE (cytopathic
effect) by 50% compared with the untreated virus control;



The suitability of the compounds of the invention for the treatment of HCMV
infections can be shown in the following animal model:
HCMV Xenograft Gelfoam® model
Animals:
5-6-week old immunodeficient mice (16-20 g), Fox Chase SCID.NOD or NOD.CB17-
Prkdc/J, are purchased from commercial breeders (Taconic M&B, Denmark; Jackson,
USA). The animals are kept under sterile conditions (including bedding and feed) in
isolators.
Virus growing:
Human cytomegalovirus (HCMV), Davis or AD169 strain, is grown in vitro on human
embryonic prepuce fibroblasts (NHDF cells). After the NHDF cells have been infected
with a multiplicity of infection (M.O.I.) of 0.01-0.03, the virus-infected cells are
harvested 5-10 days later and stored in the presence of minimal essential medium
(MEM), 20% foetal calf serum (FCS) (v/v), 1% glutamine (v/v), 1% Pen/Strep (v/v)
with 10% DMSO at -80°C. After serial ten-fold dilutions of the virus-infected cells,
the titer is determined on 24-well plates of confluent NHDF cells after fixing and
staining with a Giemsa formaldehyde solution.
Preparation of the sponges, transplantation, treatment and evaluation:
Collagen sponges 1x1x1 cm in size (Gelfoam®; Peasel & Lorey, order no. 407534; K.T.
Chong et al., Abstracts of 39th Interscience Conference on Antimicrobial Agents and
Chemotherapy, 1999, p. 439) are initially wetted with phosphate-buffered saline
(PBS), the trapped air bubbles are removed by degassing, and then stored in MEM,
10% FCS (v/v), 1% glutamine (v/v), 1% Pen/Strep (v/v). 1 x 106 virus-infected NHDF
cells (infection with HCMV Davis or HCMV AD169 M.O.I = 0.03) are detached

3 hours after infection and added dropwise in 20 µl of MEM, 10% PCS (v/v), 1%
glutamine (v/v), 1% Pen/Strep (v/v) to a moist sponge. The sponges are incubated for
3-4 hours to allow the cells to adhere. Then, following the addition of medium
(MEM, 10% FCS) (v/v), 1% glutamine (v/v), 1% Pen/Strep (v/v)) , the sponges are
incubated overnight. For the transplantation, the immunodeficient mice are anaes-
thetized with Avertin or a ketamine/xylazine/azepromazine mixture, the fur on the
back is removed using a shaver, the eµldermis is opened 1-2 cm, unstressed and the
moist sponges are transplanted under the dorsal skin. The surgical wound is closed
with tissue glue or clips. 4-6 hours after the transplantation, the mice can be treated
for the first time (one treatment is given on the day of the operation). On subsequent
days, oral treatment with the substance is carried out three times a day (7.00 h and
14.00 h and 19.00 h), twice a day (8 h and 18 h) or once a day (9 h) over a period of
8 days. The daily dose is for example 1 or 3 or 10 or 30 or 100 mg/kg of body weight,
the volume administered is 10 ml/kg of body weight. The substances are formulated
in the form of a 0.5% Tylose suspension/PBS with 2% DMSO or another suitable
mixture aiding solubility of the substances, e.g. 2% ethanol, 2.5% Solutol, 95.5% PBS.
10 days after transplantation and about 16 hours after the last administration of
substance, the animals are painlessly sacrificed and the sponge is removed. The virus-
infected cells are released from the sponge by collagenase digestion (330 U/1.5 ml)
and stored in the presence of MEM, 10% FCS (v/v), 1% glutamine (v/v), 1% Pen/Strep
(v/v), 10% DMSO at -140°C. Evaluation takes place after serial ten-fold dilutions of
the virus-infected cells by determining the titer on 24-well plates of confluent NHDF
cells after fixing and staining with a Giemsa formaldehyde solution. The number of
infected cells or infectious virus particles (infectious centre assay) after the substance
treatment compared with the placebo-treated control group is determined. Statistical
evaluation takes place by suitable computer programs, such as GraphPad Prism.

C. Exemplary embodiments of pharmaceutical compositions
The compounds of the invention can be converted into pharmaceutical preparations
in the following ways:
Tablet:
Composition:
100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50 mg of
com starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen,
Germany) and 2 mg of magnesium stearate.
Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.
Production:
The mixture of active ingredient, lactose and starch is granulated with a 5% solution
(m/m) of the PVP in water. The granules are then dried and mixed with the magne-
sium stearate for 5 min. This mixture is compressed using a conventional tablet press
(see above for format of the tablet). A guideline for the compressive force used for the
compression is 15 kN.
Suspension which can be administered orally:
Composition:
1000 mg of the compound of Example 1, 1000 mg of ethanol (96%), 400 mg of
Rhodigel (xanthan gum, FMC, Pennsylvania, USA) and 99 g of water.

10 ml of oral suspension are equivalent to a single dose of 100 mg of the compound
of the invention.
Production:
The Rhodigel is suspended in ethanol, and the active ingredient is added to the
suspension. The water is added while stirring. The mixture is stirred for about 6 h
until the swelling of the Rhodigel is complete.
Solution which can be administered intravenously:
Composition:
10-500 mg of the compound of Example 1, 15 g of polyethylene glycol 400 and 250 g
of water for injections.
Production:
The compound of Example 1 is dissolved together with polyethylene glycol 400 in
the water with stirring. The solution is sterilized by filtration (pore diameter 0.22 µm)
and dispensed under aseptic conditions into heat-sterilized infusion bottles. The
latter are closed with infusion stoppers and crimped caps.

WE CLAIM;
1. Compound of formula

in which
n represents a number 1 or 2,
R1 represents fluorine, chlorine or trifluoromethyl,
R2 represents hydrogen or C1-C6-alkyl,
whereby alkyl can be substituted with 1 to 2 substituents, whereby
the substituents are selected independently of one another from
the group consisting of hydroxy, aminocarbonyl, C1-C6-alkoxy, C1-
C6-alkylcarbonyl, C1-C6-alkylaminocarbonyl, C3-C8-
cycloalkylaminocarbonyl, C1-C6-alkylaminocarbonylaminocarbonyl,
C1-C6-alkylsulfonylaminocarbonyl, 5- to 7-membered heterocyclyl,
5- or 6-membered heteroaryl, and 5- to 7-membered
heterocyclylcarbonyl,
wherein alkoxy in turn can be substituted with a
substituent, whereby the substituent is hydroxyl,
or

R2 represents C1-C6-alkylcarbonyl, optionally once C1-C4-alkoxy-
substituted C1-C6-alkylaminocarbonyl, or C3-C8-
cycloalkylaminocarbonyl,
whereby alkylcarbonyl can be substituted with a
substituent, whereby the substituent is selected from the
group consisting of amino, C1-C6-alkylamino and C3-C8-
cycloalkylamino, and 4- to 7-membered heterocyclyl,
R3 represents halogen, cyano, methoxy, monofluoromethoxy,
difluoromethoxy, or trifluoromethoxy,
R4 represents C1-C6-alkyl or C3-C8-cycloalkyl,
whereby alkyl can be substituted with 1 to 3 substituents,
whereby the substituents are selected independently of one
another from the group consisting of halogen, and trifluoromethyl,
and
whereby cycloalkyl can be substituted with 1 to 3 substituents,
whereby the substituents are selected independently of one
another from the group consisting of halogen, and trifluoromethyl,
R5 and R6 independently of one another represent hydrogen, methyl or
ethyl,
R7 and R8 independently of one another represent halogen,
trifluoromethyl, monofluoromethoxy, difluoromethoxy,
trifluoromethoxy, C1-C3-alkyl or C1-C3-alkoxy,
R9 represents hydrogen, halogen, C1-C3-Alkyl or C1-C3-alkoxy,
or one of its salts.

2. Compound as claimed in claim 1, wherein it corresponds to formula

in which
n represents a number 1 or 2,
R1 represents fluorine, chlorine or trifluoromethyl,
R2 represents hydrogen or C1-C6-alkyl,
whereby alkyl can be substituted with 1 to 2 substituents, whereby
the substituents are selected independently of one another from
the group consisting of hydroxy, aminocarbonyl, C1-C6-alkoxy, C1-
C6-alkyl-carbonyl, C1-C6-alkylaminocarbonyl, C3-C8-
cycloalkylaminocarbonyl, C1-C6-alkylsulfonylaminocarbonyl,
phenoxy, 5- or 6-membered heteroaryloxy, 5- to 7-membered
heterocyclyl, 5- or 6-membered heteroaryl, 5- to 7-membered
heterocyclylcarbonyl and 5- or 6-membered heteroarylcarbonyl,
wherein alkoxy in turn can be substituted with a
substituent, whereby the substituent is selected from the
group consisting of hydroxy, phenyl, 5- to 7-membered
heterocyclyl and 5- or 6- membered heteroaryl, or
R2 represents C1-C6-alkylcarbonyl, optionally once C1-C4-alkoxy-
substituted C1-C6-alkylaminocarbonyl, or C3-C8-
cycloalkylaminocarbonyl,

whereby alkylcarbonyl can be substituted with a substituent,
whereby the substituent is selected from the group consisting of
amino, C1-C6-alkylamino, C3-C8-cycloalkylamino, and 4- to 7-
membered heterocyclyl,
R3 represents halogen, cyano, methoxy, monofluoromethoxy, difluoro-
methoxy, trifluoromethoxy or ethynyl,
R4 represents C1-C6-alkyl or C3-C8-cycloalkyl,
whereby alkyl can be substituted with 1 to 3 substituents, whereby
the substituents are selected independently of one another from
the group consisting of halogen, hydroxy, amino, cyano,
trifluoromethyl, hydroxycarbonyl, aminocarbonyl, C1-C6-alkoxy,
C1-C6-alkylamino, C1-C6-alkylcarbonyl and C1-C6-alkoxycarbonyl,
and
whereby cycloalkyl can be substituted with 1 to 3 substituents,
whereby the substituents are selected independently of one
another from the group consisting of halogen, hydroxy, amino,
cyano, trifluoromethyl, hydroxycarbonyl, aminocarbonyl, C1-C6-
alkyl, C1-C6-alkoxy, C1-C6-alkylamino, C1-C6-alkylcarbonyl and C1-
C6-alkoxycarbonyl,
R5 and R6 independently of one another represent hydrogen, methyl or
ethyl,

R7 and R8 independently of one another represent halogen, hydroxy,
cyano, trifruoromethyl, monofluoromethoxy, difluoromethoxy,
trifluoromethoxy, C1-C3-alkyl or C1-C3-alkoxy,
or one of its salts, its solvates or the solvates of its salts.
3. Compound as claimed in claim 2, wherein it corresponds to formula

in which
n represents a number 1 or 2,
R1 represents fluorine,
R2 represents hydrogen or C1-C6-alkyl,
whereby alkyl can be substituted with 1 or 2 substituents, whereby
the substituents are selected independently of one another from
the group consisting of hydroxy, C1-C6-alkoxy, 5- or 6-membered
heterocyclyl and 5- or 6-membered heterocyclylcarbonyl,
wherein alkoxy in turn can be substituted with a substituent,
whereby the substituent is selected from the group consisting
of hydroxy and 5- or 6-membered heterocyclyl,
or

R2 represents C1-C6-alkylcarbonyl,
whereby alkylcarbonyl is substituted with an amino substituent,
R3 represents fluorine, chlorine, methoxy, monofluoromethoxy,
difluoromethoxy, trifluoromethoxy or ethynyl,
R4 represents C1-C4-alkyl or C3-C5-cycloalkyl,
whereby alkyl can be substituted with 1 to 3 substituents, whereby
the substituents are selected independently of one another from
the group consisting of hydroxy and C1-C3-alkoxy,
and
whereby cycloalkyl can be substituted with 1 to 3 substituents,
whereby the substituents are selected independently of one
another from the group consisting of halogen, hydroxy,
trifluoromethyl, C1-C3-alkyl and C1-C3-alkoxy,
R5 and R6 independently of one another represent hydrogen or methyl,
R7 and R8 independently of one another represent fluorine, chlorine,
cyano, trifluoromethyl, difluoromethoxy, trifluoromethoxy,
C1-C3-alkyl or C1-C3-alkoxy.
4. Compound as claimed in claim 2 or 3, wherein it corresponds to
formula


in which
n represents a number 1 or 2,
R1 represents fluorine,
R2 represents hydrogen or C1-C3-alkyl,
whereby alkyl can be substituted with 1 or 2 substituents,
whereby the substituents are selected independently of one
another from the group consisting of hydroxy, morpholin-2-
ylcarbonyl, morpholin-3-ylcarbonyl, morpholin-4-ylcarbonyl,
µlperidin-1-ylcarbonyl, µlperidin-2-yl-carbonyl, µlperidin-3-
ylcarbonyl, µlperidin-4-ylcarbonyl, pyrrolidin-2-ylcarbonyl,
pyrrolidin-3-ylcarbonyl and C1-C3-alkoxy which is optionally
substituted with a hydroxy substituent,
or
R2 represents C1-C4-alkylcarbonyl,
whereby alkylcarbonyl is substituted with an amino substituent,
R3 represents chlorine, methoxy, difluoromethoxy or trifluoromethoxy,
R4. represents methyl, ethyl or cyclopropyl,
whereby ethyl can be substituted with 1 to 3 fluorine substituents,
and

whereby cyclopropyl can be substituted with 1 to 2 fluorine
substituents,
R5 and R6 independently of one another represent hydrogen or methyl,
R and R8 independently of one another represent chlorine,
trifluoromethyl, trifluoromethoxy or methyl.
5. Process for preparing a compound of formula (Ic) as claimed in claim
1, wherein a compound of formula

in which
n, R1, R2, R3, R4, R5 and R6 have the meaning indicated in claim 1,
is reacted with a compound of formula

in which
R7, R8 and R9 have the meaning indicated in claim 1.

Medicament comprising a compound as claimed in one of claims 1 to 4
in combination with an inert, non-toxic, pharmaceutically acceptable
excipient.
Medicament as claimed in claim 6 for the treatment and/or
prophylaxis of viral infections.



Substituted quinolones
Abstract

The invention relates to substituted quinolones and to processes for their preparation as
well as to their use for the production of medicaments for the treatment and/or prophylaxis
of diseases, especially for use as antiviral agents, particularly against cytomegaloviruses.

Documents:

00511-kolnp-2007 correspondence-1.2.pdf

00511-kolnp-2007 pct request.pdf

00511-kolnp-2007- correspondence-1.3.pdf

00511-kolnp-2007-correspondence-1.1.pdf

00511-kolnp-2007-form-26.pdf

00511-kolnp-2007-international search authority report-1.1.pdf

0511-kolnp-2007-abstract.pdf

0511-kolnp-2007-claims.pdf

0511-kolnp-2007-correspondence others.pdf

0511-kolnp-2007-description (complete).pdf

0511-kolnp-2007-form1.pdf

0511-kolnp-2007-form2.pdf

0511-kolnp-2007-form3.pdf

0511-kolnp-2007-form5.pdf

0511-kolnp-2007-international publication.pdf

0511-kolnp-2007-international search authority report.pdf

0511-kolnp-2007-others.pdf

0511-kolnp-2007-pct form.pdf

0511-kolnp-2007-priority document.pdf

511-KOLNP-2007-(02-07-2012)-CORRESPONDENCE.pdf

511-KOLNP-2007-(02-07-2012)-OTHERS.pdf

511-KOLNP-2007-(15-09-2011)-CORRESPONDENCE.pdf

511-KOLNP-2007-(15-09-2011)-OTHERS.pdf

511-KOLNP-2007-(27-01-2012)-CORRESPONDENCE.pdf

511-KOLNP-2007-(27-09-2011)-ABSTRACT.pdf

511-KOLNP-2007-(27-09-2011)-AMANDED CLAIMS.pdf

511-KOLNP-2007-(27-09-2011)-DESCRIPTION (COMPLETE).pdf

511-KOLNP-2007-(27-09-2011)-EXAMINATION REPORT REPLY RECEIVED.pdf

511-KOLNP-2007-(27-09-2011)-FORM 1.pdf

511-KOLNP-2007-(27-09-2011)-FORM 2.pdf

511-KOLNP-2007-(27-09-2011)-OTHERS.pdf

511-KOLNP-2007-(27-10-2011)-FORM 3.pdf

511-KOLNP-2007-(27-10-2011)-PETITION UNDER SECTION 8(1).pdf

511-KOLNP-2007-CORRESPONDENCE 1.1.pdf

511-KOLNP-2007-CORRESPONDENCE OTHERS 1.5.pdf

511-KOLNP-2007-CORRESPONDENCE.pdf

511-KOLNP-2007-EXAMINATION REPORT.pdf

511-KOLNP-2007-FORM 18 1.1.pdf

511-kolnp-2007-form 18.pdf

511-KOLNP-2007-FORM 26.pdf

511-KOLNP-2007-FORM 3.pdf

511-KOLNP-2007-FORM 5.pdf

511-KOLNP-2007-GRANTED-ABSTRACT.pdf

511-KOLNP-2007-GRANTED-CLAIMS.pdf

511-KOLNP-2007-GRANTED-DESCRIPTION (COMPLETE).pdf

511-KOLNP-2007-GRANTED-FORM 1.pdf

511-KOLNP-2007-GRANTED-FORM 2.pdf

511-KOLNP-2007-GRANTED-SPECIFICATION.pdf

511-KOLNP-2007-OTHERS.pdf

511-KOLNP-2007-PRIORITY DOCUMENT 1.1.pdf

511-KOLNP-2007-REPLY TO EXAMINATION REPORT.pdf

511-KOLNP-2007-TRANSLATED COPY OF PRIORITY DOCUMENT.pdf

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Patent Number 253273
Indian Patent Application Number 511/KOLNP/2007
PG Journal Number 28/2012
Publication Date 13-Jul-2012
Grant Date 10-Jul-2012
Date of Filing 12-Feb-2007
Name of Patentee AICURIS GMBH & CO. KG,
Applicant Address APRATHER WEG 18A, 42117 WUPPERTAL,GERMANY, A GERMANY COMPANY
Inventors:
# Inventor's Name Inventor's Address
1 DR. HOLGER ZIMMERMANN KATERNBERGER SCHULWEG 53, 42113 WUPPERTAL
2 DR. KERSTIN HENNINGER CLAUDIUSWEG 7, 42115 WUPPERTAL
3 DR. DANIELA PAULSEN NÜLLER STRAßE 83, 42115 WUPPERTAL
4 DR. THOMAS RÖLLE NEUENKAMP 60, 51381 LEVERKUSEN
5 DR. DIETER LANG WIMMERSBERGERSTRAßE 60, 42553 VELBERT
6 DR. KAI THEDE CLAUDIUSWEG 3, 42115 WUPPERTAL
7 DR. CHANTAL FÜRSTNER ARNOLDSTRAßE 33, 45478 MÜLHEIM AN DER RUHR
8 DR. DAVID BRÜCKNER FISCHERSTRAßE 15, 45128 ESSEN.
9 DR. JOHANNES KÖBBERLING HERZOGSTRAßE 12, 41516 GREVENBROICH
10 DR. MARCUS BAUSER CLAUDIUSWEG 3, 42115 WUPPERTAL
11 DR. RUDOLF SCHOHE-LOOP ARNDTSTRAßE 10A, 42327 WUPPERTAL
PCT International Classification Number A61K 31/47
PCT International Application Number PCT/EP2005/007601
PCT International Filing date 2005-07-13
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 102004035203.8 2004-07-21 Germany