NEW IMIDAZOPYRIDAZINONE AND IMIDAZOPYRIDONE DERIVATIVES, THE PREPARATION THEREOF AND THEIR USE AS PHARMACEUTICAL COMPOSITIONS

NOUVEAUX DERIVES D'IMIDAZOPYRIDAZINONES ET D'IMIDAZOPYRIDONES, LEURS PREPARATIONS ET LEUR UTILISATION COMME COMPOSITIONS PHARMACEUTIQUES

English Abstract

The invention relates to substituted imidazo-pyridinones and imidazo-
pyridazinones of general formula (I), wherein Y and R1 to R4 are defined as
indicated in claim 1, the tautomers, enantiomers, diastereomers, mixtures, and
salts thereof that have valuable pharmacological properties, especially an
inhibiting effect on the activity of the dipeptidyl peptidase IV (DPP-IV)
enzyme.

French Abstract

Imidazo-pyridinones et imidazo-pyridazinones de formule générale (I) dans laquelle Y ainsi que R1 à R4 sont tels que définis dans la revendication 1. La présente invention concerne les tautomères, les énantiomères, les diastéréomères desdites substances, leurs mélanges et leurs sels. Ces substances possèdent des propriétés pharmacologiques précieuses, en particulier un effet inhibiteur sur l'activité de l'enzyme dipeptidylpeptidase-IV (DPP-IV).

Claims

67
Claims
Compounds of general formula
<IMG>
wherein
R1 denotes a C1-3-alkyl group substituted by a group R a, where
R a denotes a 3,4-dihydro-quinolinyl, 3,4-dihydro-isoquinolinyl, 1,4-dihydro-
quinazolinyl, 3,4-dihydro-quinazolinyl, 1H-benzo[d][1,2]oxazinyl, 4H-
benzo[e][1,3]oxazinyl, 4H-benzo[d][1,3]oxazinyl or 2H-benzo[1,4]oxazinyl
group, wherein in each case
in the benzo moiety one to three methyne groups may each be replaced
by a nitrogen atom and in the heterocyclyl moiety a methylene group
may be replaced by a carbonyl group,
a 4H-benzo[e][1,3]thiazinyl, 4H-benzo[d][1,3]thiazinyl or 2H-benzo [1,4]thia-
zinyl group wherein in each case
in the benzo moiety one to three methyne groups may each be replaced
by a nitrogen atom and in the heterocyclyl moiety a methylene group
may be replaced by a carbonyl group and the sulphur atom may be
replaced by a sulphinyl or sulphonyl group,

68
a 2-oxo-2H-benzo[e][1,3]oxazinyl or 2,2-dioxo-1H-benzo[c][1,2]thiazinyl group
wherein in each case in the benzo moiety
one to three methyne groups may each be replaced by a nitrogen atom,
a 2,3-dihydro-1H-benzo[e][1,4]diazepinyl, 4,5-dihydro-3H-benzo[b][1,4]diaze-
pinyl or 5-oxo-4,5-dihydro-3H-benzo[e][1,4]diazepinyl group wherein in each
case
in the benzo moiety one to three methyne groups may each be replaced
by a nitrogen atom and in the heterocyclyl moiety a methylene group
may be replaced by a carbonyl group,
a 2,3-dihydro-benzo[f][1,4]oxazepinyl or 2,3-dihydro-benzo[b][1,4]oxazepinyl
group wherein in each case
in the benzo moiety one to three methyne groups may each be replaced
by a nitrogen atom and in the heterocyclyl moiety a methylene group
may be replaced by a carbonyl group,
a 2,3-dihydro-benzo[b][1,4]thiazepinyl or 2,3-dihydro-benzo[f][1,4]thiazepinyl
group wherein in each case
in the benzo moiety one to three methyne groups may each be replaced
by a nitrogen atom and in the heterocyclyl moiety a methylene group
may be replaced by a carbonyl group and the sulphur atom may be
replaced by a sulphinyl or sulphonyl group,
a 5-oxo-4,5-dihydro-benzo[f][1,3,4]oxadiazepinyl group wherein
in the benzo moiety one to three methyne groups may each be replaced
by a nitrogen atom,

69
a 11H-dibenzo[b,e]azepinyl or 5H-dibenzo[a,d]cycloheptenyl group wherein in
each case
in the benzo moiety one to three methyne groups may each be replaced
by a nitrogen atom and the methylene group in the heterocyclyl moiety
may be replaced by an oxygen or sulphur atom, a carbonyl, sulphinyl or
sulphonyl group or by an imino group substituted by R x, where
R x denotes a hydrogen atom or a C1-4-alkyl, C2-4-alkenyl, C2-4-
alkynyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C1-3-alkyl, aryl, aryl-
C1-3-alkyl, hydroxy-C2-4-alkyl, C1-3-alkyloxy-C2-4-alkyl, C3-6-
cycloalkyloxy-C2-4-alkyl, amino-C2-4alkyl, C1-3-alkylamino-C2-4-
alkyl, di-(C1-3-alkyl)-amino-C2-4-alkyl, C1-3-alkyl-carbonyl, C1-3-
alkyloxy-carbonyl, C1-3-alkyloxy-carbonyl-C1-3-alkyl, aryl-carbonyl,
C1-3-alkyl-sulphonyl or aryl-sulphonyl group,
a phenanthridinyl group wherein
in the benzo moiety one to three methyne groups may each be replaced
by a nitrogen atom, and
a 1,2,3,4-tetrahydro-phenanthridinyl, 1,2,3,4,4a,10b-hexahydro-phenan-
thridinyl, 2,3-dihydro-1H-4-aza-cyclopenta[a]naphthyl or a 8,9,10,11-
tetrahydro-7H-6-aza-cyclohepta[a]naphthyl group wherein in each case
in the benzo moiety one to three methyne groups may each be replaced
by a nitrogen atom and one or two methylene groups may each be
replaced by an oxygen atom or a carbonyl group, while, if two
methylene groups are each replaced by an oxygen atom, the oxygen
atoms must be separated from one another by at least two methylene
units,
a phenanthrenyl group wherein

70
in each case one to three of the methyne groups in position 1 to 4 and 5
to 8 may each be replaced by a nitrogen atom,
a 1,2,3,4-tetrahydro-phenanthrenyl or a 1,2,3,4,5,6,7,8-octahydro-
phenanthrenyl group wherein
in each case one or two of the methylene groups in position 1 to 4 and
5 to 8 may each be replaced by an oxygen atom or a carbonyl group,
while, if two methylene groups are each replaced by an oxygen atom,
the oxygen atoms must be separated from one another by at least two
methylene units,
a 5H-benzo[e]pyrrolo[1,2-a][1,4]diazepinyl, thieno[3,2-b][1,4]benzoxazepinyl,
5H-dibenzo[d,f][1,3]diazepinyl or a 5-oxa-7-aza-dibenzo[a,c]cycloheptenyl
group wherein in each case
in the benzo moiety one to three methyne groups may each be replaced
by a nitrogen atom,
a naphtho[1,2-d]oxazolyl, naphtho[2,1-d]oxazolyl , naphtho[1,2-d]thiazolyl,
naphtho[2,1-d]thiazolyl, naphtho[1,2-d]imidazolyl, naphtho[1,2-b]furanyl or
naphtho[2,1-b]furanyl group wherein in each case
in the naphthyl moiety one to three methyne groups may each be
replaced by a nitrogen atom,
or a furo[3,2-c]isoquinolinyl, pyrazolo[1,5-c]quinazolinyl or 1H-perimidinyl
group,
while the methylene and methyne groups of the above mentioned radicals R a
may be substituted by the groups R10 to R13 and additionally by a C1-3-alkyl
group and the imino groups of the above mentioned radicals R a may be
substituted by the groups R x as hereinbefore defined and

71
R10 denotes a hydrogen atom,
a fluorine, chlorine, bromine or iodine atom,
a C1-4-alkyl, hydroxy, or C1-4-alkyloxy group,
a nitro, amino, C1-3-alkylamino, di-(C1-3-alkyl)amino, cyano-C1-3-
alkylamino, N-(cyano-C1-3-alkyl)-N-(C1-3-alkyl)-amino, C1-3-alkyloxy-
carbonyl-C1-3-alkylamino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl,
piperazin-1-yl, or 4-(C1-3-alkyl)-piperazin-1-yl group,
a C1-3-alkyl-carbonylamino, arylcarbonylamino, aryl-C1-3-alkyl-
carbonylamino, C1-3-alkyloxy-carbonylamino, aminocarbonylamino, C1-3-
alkylaminocarbonylamino, di-(C1-3-alkyl)aminocarbonylamino, pyrrolidin-
1-yl-carbonylamino, piperidin-1-yl-carbonylamino, morpholin-4-yl-
carbonylamino, piperazin-1-yl-carbonylamino or 4-(C1-3-alkyl)-piperazin-
1-yl-carbonylamino, C1-3-alkyl-sulphonylamino, bis-(C1-3-alkylsulphonyl)-
amino, aminosulphonylamino, C1-3-alkylamino-sulphonylamino, di-(C1-3-
alkyl)amino-sulphonylamino, pyrrolidin-1-yl-sulphonylamino, piperidin-1-
yl-sulphonylamino, morpholin-4-yl-sulphonylamino, piperazin-1-yl-
sulphonylamino or 4-(C1-3-alkyl)-piperazin-1-yl-sulphonylamino, (C1-3-
alkylamino)thiocarbonylamino, (C1-3-alkyloxy-carbonyl-
amino)carbonylamino, arylsulphonylamino or aryl-C1-3-alkyl-sulphonyl-
amino group,
an N-(C1-3-alkyl)-C1-3-alkyl-carbonylamino, N-(C1-3-alkyl)-arylcarbonyl-
amino, N-(C1-3-alkyl)-aryl-C1-3-alkyl-carbonylamino, N-(C1-3-alkyl)-C1-3-
alkyloxy-carbonylamino, N-(aminocarbonyl)-C1-3-alkylamino, N-(C1-3-
alkyl-aminocarbonyl)-C1-3-alkylamino, N-[di-(C1-3-alkyl)aminocarbonyl]-
C1-3-alkylamino, N-(C1-3-alkyl)-C1-3-alkyl-sulphonylamino, N-(C1-3-alkyl)-
arylsulphonylamino, or N-(C1-3-alkyl)-aryl-C1-3-alkyl-sulphonylamino
group,

72
a 2-oxo-imidazolidin-1-yl, 2,4-dioxo-imidazolidin-1-yl, 2,5-dioxo-
imidazolidin-1-yl or 2-oxo-hexahydropyrimidin-1-yl group wherein the
nitrogen atom in the 3 position may be substituted in each case by a
methyl or ethyl group,
a cyano, carboxy, C1-3-alkyloxy-carbonyl, aminocarbonyl, C1-3-alkyl-
aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, pyrrolidin-1-yl-carbonyl,
piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl, piperazin-1-yl-carbonyl
or 4-(C1-3-alkyl)-piperazin-1-yl-carbonyl group,
a C1-3-alkyl-carbonyl or an arylcarbonyl group,
a carboxy-C1-3-alkyl, C1-3-alkyloxy-carbonyl-C1-3-alkyl, cyano-C1-3-alkyl,
aminocarbonyl-C1-3-alkyl, C1-3-alkyl-aminocarbonyl-C1-3-alkyl, di-(C1-3-
alkyl)-aminocarbonyl-C1-3-alkyl, pyrrolidin-1-yl-carbonyl-C1-3-alkyl,
piperidin-1-yl-carbonyl-C1-3-alkyl, morpholin-4-yl-carbonyl-C1-3-alkyl,
piperazin-1-yl-carbonyl-C1-3-alkyl or 4-(C1-3-alkyl)-piperazin-1-yl-
carbonyl-C1-3-alkyl group,
a carboxy-C1-3-alkyloxy, C1-3-alkyloxy-carbonyl-C1-3-alkyloxy, cyano-
C1-3-alkyloxy, aminocarbonyl-C1-3-alkyloxy, C1-3-alkyl-aminocarbonyl-
C1-3-alkyloxy, di-(C1-3-alkyl)-aminocarbonyl-C1-3-alkyloxy, pyrrolidin-1-yl-
carbonyl-C1-3-alkyloxy, piperidin-1-yl-carbonyl-C1-3-alkyloxy, morpholin-
4-yl-carbonyl-C1-3-alkyloxy, piperazin-1-yl-carbonyl-C1-3-alkyloxy or 4-
(C1-3-alkyl)-piperazin-1-yl-carbonyl-C1-3-alkyloxy group,
a hydroxy-C1-3-alkyl, C1-3-alkyloxy-C1-3-alkyl, amino-C1-3-alkyl,
C1-3-alkylamino-C1-3-alkyl, di-(C1-3-alkyl)-amino-C1-3-alkyl, pyrrolidin-1-yl-
C1-3-alkyl, piperidin-1-yl-C1-3-alkyl, morpholin-4-yl-C1-3-alkyl, piperazin-1-
yl-C1-3-alkyl or 4-(C1-3-alkyl)-piperazin-1-yl-C1-3-alkyl group,
a hydroxy-C1-3-alkyloxy, C1-3-alkyloxy-C1-3-alkyloxy, C1-3-alkylsulphanyl-
C1-3-alkyloxy, C1-3-alkylsulphinyl-C1-3-alkyloxy, C1-3-alkylsulphonyl-C1-3-
alkyloxy, amino-C1-3-alkyloxy, C1-3-alkylamino-C1-3-alkyloxy, di-(C1-3-

73
alkyl)-amino-C1-3-alkyloxy, pyrrolidin-1-yl-C1-3-alkyloxy, piperidin-1-yl-
C1-3-alkyloxy, morpholin-4-yl-C1-3-alkyloxy, piperazin-1-yl-C1-3-alkyloxy
or 4-(C1-3-alkyl)-piperazin-1-yl-C1-3-alkyloxy group,
a mercapto, C1-3-alkylsulphanyl, C1-3-alkysulphinyl, C1-3-alkylsulphonyl,
C1-3-alkylsulphonyloxy, arylsulphonyloxy, trifluoromethylsulphanyl,
trifluoromethylsulphinyl or trifluoromethylsulphonyl group,
a sulpho, aminosulphonyl, C1-3-alkyl-aminosulphonyl, di-(C1-3-alkyl)-
aminosulphonyl, pyrrolidin-1-yl-sulphonyl, piperidin-1-yl-sulphonyl,
morpholin-4-yl-sulphonyl, piperazin-1-yl-sulphonyl or 4-(C1-3-alkyl)-
piperazin-1-yl-sulphonyl group,
a methyl or methoxy group substituted by 1 to 3 fluorine atoms,
an ethyl or ethoxy group substituted by 1 to 5 fluorine atoms,
a C2-4-alkenyl or C2-4-alkynyl group,
a C3-4-alkenyloxy or C3-4-alkynyloxy group,
a C3-6-cycloalkyl or C3-6-cycloalkyloxy group,
a C3-6-cycloalkyl-C1-3-alkyl or C3-6-cycloalkyl-C1-3-alkyloxy group or
an aryl, aryloxy, aryl-C1-3-alkyl or aryl-C1-3-alkyloxy group,
R11 and R12, which may be identical or different, in each case represent
a hydrogen atom, a fluorine, chlorine, bromine or iodine atom, a C1-3-
alkyl, trifluoromethyl, hydroxy, C1-3-alkyloxy or cyano group, or
R11 together with R12, if these are bound to adjacent carbon atoms, also
denotes a methylenedioxy, difluoromethylenedioxy, ethylenedioxy or a
straight-chain C3-5-alkylene group and

74
R13 denotes a hydrogen atom, a fluorine, chlorine or bromine atom, a
trifluoromethyl, C1-3-alkyl or C1-3-alkyloxy group,
R2 denotes a hydrogen, fluorine or chlorine atom,
a C1-6-alkyl group,
a C2-4-alkenyl group,
a C3-4-alkynyl group,
a C3-6-cycloalkyl group,
a C3-6-cycloalkyl-C1-3-alkyl group,
a tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydro-
furanylmethyl or tetrahydropyranylmethyl group,
an aryl group,
an aryl-C1-4-alkyl group,
an aryl-C2-3-alkenyl group,
an arylcarbonyl group,
an arylcarbonyl-C1-2-alkyl group,
a heteroaryl group,
a heteroaryl-C1-3-alkyl group,
a furanylcarbonyl, thienylcarbonyl, thiazolylcarbonyl or pyridylcarbonyl
group,

75
a furanylcarbonylmethyl, thienylcarbonylmethyl, thiazolylcarbonylmethyl or
pyridylcarbonylmethyl group,
a C1-4-alkyl-carbonyl group,
a C1-4-alkyl-carbonyl-C1-2-alkyl group,
a C3-6-cycloalkyl-carbonyl group,
a C3-6-cycloalkyl-carbonyl-C1-2-alkyl group,
an aryl-A or aryl-A-C1-3-alkyl group, where A denotes an oxygen or sulphur
atom, an
imino, C1-3-alkylimino, sulphinyl or sulphonyl group,
a group R b, where
R b denotes a cyano, carboxy, C1-3-alkyloxy-carbonyl, aminocarbonyl, C1-3-
alkylamino-carbonyl, di-(C1-3-alkyl)-amino-carbonyl, pyrrolidin-1-ylcarbonyl,
piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4-
methylpiperazin-1-ylcarbonyl, 4-ethylpiperazin-1-ylcarbonyl, hydroxy,
mercapto, C1-3-alkyloxy, C1-3-alkylsulphenyl, C1-3-alkylsulphinyl, C1-3-alkyl-
sulphonyl, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, pyrrolidin-1-yl,
piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl or 4-
ethyl-
piperazin-1-yl group,
or a C1-4-alkyl group substituted by a group R b, where R b is as hereinbefore
defined,
Y denotes a nitrogen atom or a group of formula C-R5,
while R5 is defined like R2 and in each case one of the two groups R2 and R5
must be a hydrogen atom or a C1-3-alkyl group,
R3 denotes a C3-8-alkyl group,

76
a C1-3-alkyl group substituted by a group R c, where
R c denotes a C3-7-cycloalkyl group optionally substituted by one or two C1-3-
alkyl groups,
a C5-7-cycloalkenyl group optionally substituted by one or two C1-3-alkyl
groups,
an aryl group or
a furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl,
pyridazinyl, pyrimidyl or pyrazinyl group, while the above mentioned
heterocyclic groups may each be substituted by one or two C1-3-alkyl groups or
by a fluorine, chlorine, bromine or iodine atom or by a trifluoromethyl, cyano
or
C1-3-alkyloxy group,
a C3-8-alkenyl group,
a C3-6-alkenyl group substituted by a fluorine, chlorine or bromine atom or by
a
trifluoromethyl group,
a C3-8-alkynyl group,
an aryl group or
an aryl-C2-4-alkenyl group,
and
R4 denotes an azetidin-1-yl or pyrrolidin-1-yl group which is substituted in
the 3
position by an amino, C1-3-alkylamino or a di-(C1-3-alkyl)amino group and may
additionally be substituted by one or two C1-3-alkyl groups,

77
a piperidin-1-yl or hexahydroazepin-1-yl group which is substituted in the 3
position
or in the 4 position by an amino, C1-3-alkylamino or a di-(C1-3-alkyl)amino
group and
may additionally be substituted by one or two C1-3-alkyl groups,
a 3-amino-piperidin-1-yl group wherein the piperidin-1-yl-moiety is
additionally
substituted by an aminocarbonyl, C1-2-alkyl-aminocarbonyl, di-(C1-2-
alkyl)aminocarbonyl, pyrrolidin-1-yl-carbonyl, (2-cyano-pyrrolidin-1-yl-
)carbonyl,
thiazolidin-3-yl-carbonyl, (4-cyano-thiazolidin-3-yl)carbonyl, piperidin-1-
ylcarbonyl or
morpholin-4-ylcarbonyl group,
a 3-amino-piperidin-1-yl group wherein the piperidin-1-yl moiety in the 4
position or in
the 5 position is additionally substituted by a hydroxy or methoxy group,
a 3-amino-piperidin-1-yl group wherein the methylene group in the 2 position
or in the
6 position is replaced by a carbonyl group,
a piperidin-1-yl or hexahydroazepin-1-yl group substituted in the 3 position
by an
amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino- group, wherein in each case
two
hydrogen atoms on the carbon skeleton of the piperidin-1-yl or hexahydroazepin-
1-yl-
group are replaced by a straight-chain alkylene bridge, this bridge containing
2 to 5
carbon atoms if the two hydrogen atoms are located on the same carbon atom, or
1
to 4 carbon atoms, if the hydrogen atoms are located on adjacent carbon atoms,
or 1
to 4 carbon atoms, if the hydrogen atoms are located on carbon atoms which are
separated by one atom, or 1 to 3 carbon atoms if the two hydrogen atoms are
located on carbon atoms separated by two atoms,
an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or hexahydroazepin-1-yl
group which is
substituted by an amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl or a di-(C1-3-
alkyl)-
amino-C1-3-alkyl group,
a piperazin-1-yl or [1,4]diazepan-1-yl group optionally substituted at the
carbon
skeleton by one or two C1-3-alkyl groups,

78
a 3-imino-piperazin-1-yl, 3-imino-[1,4]diazepan-1-yl or 5-imino-[1,4]diazepan-
1-yl
group optionally substituted at the carbon skeleton by one or two C1-3-alkyl
groups,
a [1,4]diazepan-1-yl group optionally substituted by one or two C1-3-alkyl
groups,
which is substituted in the 6 position by an amino group,
a C3-7-cycloalkyl group which is substituted by an amino, C1-3-alkylamino or
di-(C1-3-
alkyl)-amino group,
a C3-7-cycloalkyl group which is substituted by an amino-C1-3-alkyl, C1-3-
alkylamino-
C1-3-alkyl or a di-(C1-3-alkyl)amino-C1-3-alkyl group,
a C3-7-cycloalkyl-C1-2-alkyl group wherein the cycloalkyl moiety is
substituted by an
amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group,
a C3-7-cycloalkyl-C1-2-alkyl group wherein the cycloalkyl moiety is
substituted by an
amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl or a di-(C1-3-alkyl)amino-C1-3-
alkyl group,
a C3-7-cycloalkylamino group wherein the cycloalkyl moiety is substituted by
an
amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group, while the two nitrogen
atoms at
the cycloalkyl moiety are separated from one another by at least two carbon
atoms,
an N-(C3-7-cycloalkyl)-N-(C1-3-alkyl)-amino group wherein the cycloalkyl
moiety is
substituted by an amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group, while
the two
nitrogen atoms at the cycloalkyl moiety are separated from one another by at
least
two carbon atoms,
a C3-7-cycloalkylamino group wherein the cycloalkyl moiety is substituted by
an
amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl or a di-(C1-3-alkyl)amino-C1-3-
alkyl group,
an N-(C3-7-cycloalkyl)-N-(C1-3-alkyl)-amino group wherein the cycloalkyl
moiety is
substituted by an amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl or a di-(C1-3-
alkyl)amino-
C1-3-alkyl group,

79
a C3-7-cycloalkyl-C1-2-alkyl-amino group wherein the cycloalkyl moiety is
substituted
by an amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group,
an N-(C3-7-cycloalkyl-C1-2-alkyl)-N-(C1-2-alkyl)-amino group wherein the
cycloalkyl
moiety is substituted by an amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino
group,
a C3-7-cycloalkyl-C1-2-alkyl-amino group wherein the cycloalkyl moiety is
substituted
by an amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl or a di-(C1-3-alkyl)amino-
C1-3-alkyl
group,
an N-(C3-7-cycloalkyl-C1-2-alkyl)-N-(C1-2-alkyl)-amino group wherein the
cycloalkyl
moiety is substituted by an amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl or a
di-(C1-3-
alkyl)amino-C1-3-alkyl group,
a R19-C2-4-alkylamino group wherein R19 is separated from the nitrogen atom of
the
C2-4-alkylamino moiety by at least two carbon atoms and
R19 denotes an amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group,
an R19-C2-4-alkylamino group wherein the nitrogen atom of the C2-4-alkylamino
moiety
is substituted by a C1-3-alkyl group and R19 is separated from the nitrogen
atom of the
C2-4-alkylamino moiety by at least two carbon atoms, while R19 is as
hereinbefore
defined,
an amino group substituted by the group R20 wherein
R20 denotes an azetidin-3-yl, azetidin-2-ylmethyl, azetidin-3-ylmethyl,
pyrrolidin-3-yl, pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, piperidin-3-yl,
piperidin-4-yl, piperidin-2-ylmethyl, piperidin-3-ylmethyl or piperidin-4-
ylmethyl
group, while the groups mentioned for R20 may each be substituted by one or
two C1-3-alkyl groups,

80
an amino group substituted by the group R20 and a C1-3-alkyl group wherein R20
is as
hereinbefore defined, while the groups mentioned for R20 may each be
substituted by
one or two C1-3-alkyl groups,
an R19-C3-4-alkyl group wherein the C3-4-alkyl moiety is straight-chained and
may
additionally be substituted by one or two C1-3-alkyl groups, while R19 is as
hereinbefore defined,
a 3-amino-2-oxo-piperidin-5-yl or 3-amino-2-oxo-1-methyl-piperidin-5-yl group,
a pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, hexahydroazepin-3-yl or
hexahydroazepin-4-yl group which is substituted in the 1 position by an amino,
C1-3-
alkylamino or di-(C1-3-alkyl)amino group,
or an azetidin-2-yl-C1-2-alkyl, azetidin-3-yl-C1-2-alkyl, pyrrolidin-2-yl-C1-2-
alkyl,
pyrrolidin-3-yl, pyrrolidin-3-yl-C1-2-alkyl, piperidin-2-yl-C1-2-alkyl,
piperidin-3-yl,
piperidin-3-yl-C1-2-alkyl, piperidin-4-yl or piperidin-4-yl-C1-2-alkyl group,
while the
above mentioned groups may each be substituted by one or two C1-3-alkyl
groups,
while by the aryl groups mentioned in the definition of the above groups are
meant
phenyl or naphthyl groups which may be mono- or disubstituted by R h, while
the
substituents may be identical or different and R h denotes a fluorine,
chlorine, bromine
or iodine atom, a trifluoromethyl, cyano, nitro, amino, aminocarbonyl,
aminosulphonyl, methylsulphonyl, acetylamino, methylsulphonylamino, C1-3-
alkyl,
cyclopropyl, ethenyl, ethynyl, hydroxy, C1-3-alkyloxy, difluoromethoxy or
trifluoromethoxy group,
by the heteroaryl groups mentioned in the definition of the above groups are
meant a
pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl,
quinolinyl or
isoquinolinyl group,
or a pyrrolyl, furanyl, thienyl or pyridyl group, wherein one or two methyne
groups are
replaced by nitrogen atoms,

81
or an indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl
group,
wherein one to three methyne groups are replaced by nitrogen atoms,
and the above mentioned heteroaryl groups may be mono- or disubstituted by
R h, while the substituents may be identical or different and R h, is as
hereinbefore defined,
while, unless otherwise stated, the above mentioned alkyl, alkenyl and alkynyl
groups
may be straight-chain or branched,
and the hydrogen atoms of the methyl or ethyl groups contained in the
definitions
may be wholly or partly replaced by fluorine atoms,
the tautomers, enantiomers, diastereomers, the mixtures thereof, the prodrugs
thereof and the salts thereof.
2. Compounds of general formula I according to claim 1, wherein
R1 denotes a methyl group substituted by a group R a, where
R a denotes a 3,4-dihydro-quinolinyl group,
a 3,4-dihydro-isoquinolinyl group,
a 1,4-dihydro-quinazolinyl or 4-oxo-1,4-dihydro-quinazolinyl group,
a 3,4-dihydro-quinazolinyl or 4-oxo-3,4-dihydro-quinazolinyl group,
a 1H-benzo[d][1,2]oxazinyl or 1-oxo-1H-benzo[d][1,2]oxazinyl group,
a 4H-benzo[e][1,3]oxazinyl or 4-oxo-4H-benzo[e][1,3]oxazinyl group,
a 4H-benzo[d][1,3]oxazinyl or 4-oxo-4H-benzo[d][1,3]oxazinyl group,

82
a 2H-benzo[1,4]oxazinyl or 2-oxo-2H-benzo[1,4]oxazinyl group,
a 4H-benzo[e][1,3]thiazinyl or 4-oxo-4H-benzo[e][1,3]thiazinyl group,
a 4H-benzo[d][1,3]thiazinyl or 2H-benzo [1,4]thiazinyl group,
a 2-oxo-2H-benzo(e][1,3]oxazinyl or 2,2-dioxo-1H-benzo[c][1,2]thiazinyl group,
a 2,3-dihydro-1H-benzo[e][1,4]diazepinyl or 2-oxo-2,3-dihydro-1H-
benzo(e][1,4]diazepinyl group,
a 4,5-dihydro-3H-benzo[b][1,4]diazepinyl or 4-oxo-4,5-dihydro-3H-
benzo[b][1,4]diazepinyl group,
a 5-oxo-4,5-dihydro-3H-benzo[e][1,4]diazepinyl group,
a 2,3-dihydro-benzo[f][1,4]oxazepinyl or 2,3-dihydro-benzo[b][1,4]oxazepinyl
group,
a 2,3-dihydro-benzo[f][1,4]thiazepinyl or 2,3-dihydro-benzo[b][1,4]thiazepinyl
group,
a 5-oxo-4,5-dihydro-benzo[f][1,3,4]oxadiazepinyl group,
a 11H-dibenzo[b,e]azepinyl or 11-oxo-11H-dibenzo[b,e]azepinyl group,
a 11H-benzo[e]pyrido[3,2-b]azepinyl or a 5H-1,9,10-triaza-dibenzo[a,d]-
cycloheptenyl group,
a 5H-dibenzo[b,e][1,4]diazepinyl or dibenzo[b,f][1,4]oxazepinyl group,
a dibenzo[b,f][1,4]thiazepinyl, 5-oxo-dibenzo[b,f][1,4]thiazepinyl or 5,5-
dioxo-
dibenzo[b,f][1,4]thiazepinyl group,

83
a 5H-dibenzo[a,d]cycloheptenyl or 5H-dibenzo[b,f]azepinyl group,
a phenanthridinyl, benzo[c](1,5]naphthyridinyl, benzo[h][1,6]naphthyridinyl,
benzo[c][1,8]naphthyridinyl, benzo[f][1,7]naphthyridinyl or 1,5,9-triaza-
phenanthrenyl group,
a 1,2,3,4-tetrahydro-phenanthridinyl, 1,2,3,4,4a,10b-hexahydro-phenan-
thridinyl, 2,3-dihydro-1H-4-aza-cyclopenta[a]naphthyl or 8,9,10,11-tetrahydro-
7H-6-aza-cyclohepta[a]naphthyl group,
a 2,3-dihydro-1H-4-oxa-10-aza-phenanthrenyl or 1-oxo-2,3-dihydro-1H-4-oxa-
10-aza-phenanthrenyl group,
a phenanthrenyl, benzo[h]quinolinyl, benzo[f]quinolinyl or
benzo[f]quinoxalinyl
group,
a 5H-benzo[a]pyrrolo[1,2-a][1,4]diazepinyl, thieno[3,2-b][1,4]benzoxazepinyl,
5H-dibenzo[d,f][1,3]diazepinyl or 5-oxa-7-aza-dibenzo[a,c]cycloheptenyl group,
a naphtho[1,2-d]oxazolyl, naphtho[2,1-d]oxazolyl, naphtho[1,2-d]thiazolyl,
naphtho[2,1-d]thiazolyl, naphtho[1,2-d]imidazolyl, naphtho[1,2-b]furanyl or
naphtho[2,1-b]furanyl group,
or a furo[3,2-c]isoquinolinyl, pyrazolo[1,5-c]quinazolinyl or 1H-perimidinyl
group,
while the benzo groups of the above mentioned radicals R a are substituted by
the groups R10 to R13 and the alkylene units of the above mentioned groups R a
may be substituted by one or two fluorine atoms or one or two C1-3-alkyl or
C1-3-alkyloxy-carbonyl groups and the imino groups of the above mentioned
radicals R a may be substituted by a C1-3-alkyl group and
R10 denotes a hydrogen atom,

84
a fluorine, chlorine, bromine or iodine atom,
a C1-3-alkyl or cyclopropyl group,
a hydroxy, C1-3-alkyloxy or cyclopropyloxy group,
a nitro, amino, C1-3-alkylamino or di-(C1-3-alkyl)amino group,
a C1-3-alkyl-carbonylamino or C1-3-alkyl-sulphonylamino group,
a cyano, carboxy, C1-3-alkyloxy-carbonyl, aminocarbonyl, C1-3-alkyl-
aminocarbonyl or di-(C1-3-alkyl)-aminocarbonyl group,
a mercapto, C1-3-alkylsulphanyl, C1-3-alkysulphinyl, C1-3-alkylsulphonyl
or aminosulphonyl group or
a difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy
group and
R11, R12 and R13, which may be identical or different, in each case
represent a hydrogen atom, a fluorine, chlorine or bromine atom, a
methyl, trifluoromethyl or methoxy group,
R2 denotes a hydrogen atom or
a C1-3-alkyl, cyclopropyl, trifluoromethyl, cyanomethyl or 2-cyano-ethyl
group,
Y denotes a nitrogen atom or a group of formula C-R5,
while R5 denotes a hydrogen atom or a C1-3-alkyl group,
R3 denotes a 2-buten-1-yl or 3-methyl-2-buten-1-yl group,

85
a 1-buten-1-yl group,
a 2-butyn-1-yl group or
a 1-cyclopenten-1-ylmethyl group
and
R4 denotes a (3-amino-piperidin-1-yl) group,
while, unless otherwise stated, the above mentioned alkyl groups may be
straight-
chain or branched,
the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts
thereof.
3. Compounds of general formula I according to claim 2, wherein
R1 denotes a methyl group substituted by a group R a, where
R a denotes a 3,4-dihydro-quinolin-2-yl group,
a 3,4-dihydro-isoquinolin-1-yl group,
a 1,4-dihydro-quinazolin-2-yl or 4-oxo-1,4-dihydro-quinazolin-2-yl group,
a 3,4-dihydro-quinazolin-2-yl or 4-oxo-3,4-dihydro-quinazolin-2-yl group,
a 1H-benzo[d][1,2]oxazin-4-yl or 1-oxo-1H-benzo[d][1,2]oxazin-4-yl group,
a 4H-benzo[e][1,3]oxazin-2-yl or 4-oxo-4H-benzo[e][1,3)oxazin-2-yl group,
a 4H-benzo[d][1,3)oxazin-2-yl or 4-oxo-4H-benzo[d][1,3]oxazin-2-yl group,


86
a 2H-benzo[1,4]oxazin-3-yl or 2-oxo-2H-benzo[1,4]oxazin-3-yl group,
a 4H-benzo(e][1,3]thiazin-2-yl or 4-oxo-4H-benzo[e][1,3]thiazin-2-yl group,
a 4H-benzo[d][1,3]thiazin-2-yl or 2H-benzo[1,4]thiazin-3-yl group,
a 2-oxo-2H-benzo[e][1,3]oxazin-4-yl or 2,2-dioxo-1H-benzo[c][1,2]thiazin-4-yl
group,
a 2,3-dihydro-1H benzo[e][1,4]diazepin-5-yl or 2-oxo-2,3-dihydro-1H-
benzo[e][1,4]diazepin-5-yl group,
a 4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl or 4-oxo-4,5-dihydro-3H-
benzo[b][1,4]diazepin-2-yl group,
a 5-oxo-4,5-dihydro-3H-benzo[e][1,4]diazepin-2-yl group,
a 2,3-dihydro-benzo[f][1,4]oxazepin-5-yl or 2,3-dihydro-benzo[b][1,4]oxazepin-
4-yl group,
a 2,3-dihydro-benzo[f][1,4]thiazepin-5-yl or 2,3-dihydro-
benzo[b][1,4]thiazepin-
4-yl group,
a 5-oxo-4,5-dihydro-benzo[f][1,3,4]oxadiazepin-2-yl group,
a 11H-dibenzo[b,e]azepin-6-yl or 11-oxo-11H-dibenzo[b,e]azepin-6-yl group,
a 11H-benzo[e]pyrido[3,2-b]azepin-6-yl or a 5H-1,9,10-triaza-dibenzo[a,d]-
cyclohepten-11-yl group,
a 5H-dibenzo[b,e][1,4]diazepin-11-yl or dibenzo[b,f][1,4]oxazepin-11-yl group,


87
a dibenzo[b,f][1,4]thiazepin-11-yl, 5-oxo-dibenzo[b,f][1,4]thiazepin-11-yl or
5,5-
dioxo-dibenzo[b,f][1,4]thiazepin-11-yl group,
a 5H-dibenzo[a,d]cyclohepten-10-yl or 5H-dibenzo[b,f]azepin-10-yl group,
a phenanthridin-6-yl, benzo[c][1,5]naphthyridin-6-yl,
benzo[h][1,6]naphthyridin-
5-yl, benzo[c][1,8]naphthyridin-6-yl, benzo[f][1,7]naphthyridin-5-yl or 1,5,9-
triaza-phenanthren-10-yl group,
a 1,2,3,4-tetrahydro-phenanthridin-6-yl, 1,2,3,4,4a,10b-hexahydro-
phenanthridin-6-yl, 2,3-dihydro-1H-4-aza-cyclopenta[a]naphth-5-yl or
8,9,10,11-tetrahydro-7H-6-aza-cyclohepta[a]naphth-5-yl group,
a 2,3-dihydro-1H-4-oxa-10-aza-phenanthren-9-yl or 1-oxo-2,3-dihydro-1H-4-
oxa-10-aza-phenanthren-9-yl group,
a phenanthren-9-yl, benzo[h]quinolin-6-yl, benzo[f]quinolin-6-yl or
benzo[f]quinoxalin-6-yl group,
a 5H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-11-yl, thieno[3,2-b][1,4]benzoxaze-
pin-9-yl, 5H-dibenzo[d,f][1,3]diazepin-6-yl or 5-oxa-7-aza-di-
benzo[a,c]cyclohepten-6-yl group,
a naphtho[1,2-d]oxazol-2-yl, naphtho[2,1-d]oxazol-2-yl, naphtho[1,2-d]thiazol-
2-yl, naphtho[2,1-d]thiazol-2-yl, naphtho[1,2-d]imidazol-2-yl, naphtho[1,2-
b]furan-2-yl or naphtho[2,1-b]furan-2-yl group,
or a furo[3,2-c]isoquinolin-5-yl, pyrazolo[1,5-c]quinazolin-5-yl or 1H-
perimidin-
2-yl group,
while the benzo groups of the above mentioned radicals R a are substituted by
the groups R10 to R13 and the alkylene units of the above mentioned groups R a
may be substituted by one or two fluorine atoms or one or two methyl groups

88
and the imino groups of the above mentioned radicals R a may be substituted
by a methyl group and
R10 denotes a hydrogen atom,
a fluorine, chlorine, bromine or iodine atom,
a methyl or ethyl group,
a hydroxy, methoxy or ethoxy group or
a difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy
group and
R11, R12 and R13, which may be identical or different, each denote a
hydrogen, fluorine, chlorine or bromine atom or a methyl, trifluoromethyl
or methoxy group,
R2 denotes a hydrogen atom or
a methyl, cyanomethyl, trifluoromethyl, ethyl, 2-cyano-ethyl, propyl,
cyclopropyl or
isopropyl group,
Y denotes a nitrogen atom or a group of formula C-R5,
while R5 denotes a hydrogen atom or a methyl, ethyl, propyl or isopropyl
group,
R3 denotes a 2-buten-1-yl or 3-methyl-2-buten-1-yl group,
a 1-buten-1-yl group,
a 2-butyn-1-yl group or

89
a 1-cyclopenten-1-ylmethyl group
and
R4 denotes a (3-amino-piperidin-1-yl) group,
the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts
thereof.
4. Compounds of general formula I according to claim 1, wherein
R1 denotes a 4-oxo-3,4-dihydro-quinazolin-2-ylmethyl group,
a dibenzo[b,f][1,4]oxazepin-11-ylmethyl group,
a phenanthridin-6-ylmethyl group,
a phenanthren-9-ylmethyl group or
a naphtho[1,2-d]oxazol-2-ylmethyl or naphtho[2,1-d]oxazol-2-ylmethyl group,
R2 denotes a hydrogen atom or a methyl group,
Y denotes a nitrogen atom,
R3 denotes a 2-butyn-1-yl group
and
R4 denotes a (3-amino-piperidin-1-yl) group,
the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts
thereof.

90
5. The following compounds of general formula I according to claim 1:
(1) 2-(3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-[(dibenzo[b,f][1,4]oxazepin-
11-
yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one
<IMG>
(2) 2-(3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-[(phenanthridin-6-yl)methyl]-
3,5-
dihydro-imidazo[4,5-d]pyridazin-4-one
<IMG>
(3) 2-(3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-[(phenanthren-9-yl)methyl]-
3,5-
dihydro-imidazo[4,5-d]pyridazin-4-one
<IMG>
(4) 2-((R)-3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-[(phenanthridin-6-
yl)methyl]-7-
methyl-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one
<IMG>

91
(5) 2-((R)-3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-
[(dibenzo[b,f][1,4]oxazepin-11-
yl)methyl]-7-methyl-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one
<IMG>
(6) 2-((S)-3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-
[(dibenzo[b,f][1,4]oxazepin-11-
yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one
<IMG>
(7) 2-((R)-3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-
[(dibenzo[b,f][1,4]oxazepin-11-
yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one
<IMG>
(8) 2-((R)-3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-[(naphtho[2,1-d]oxazol-2-
yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one
<IMG>
(9) 2-((R)-3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-[(naphtho[1,2-d]oxazol-2-
yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one

92
<IMG>
(10) 2-((R)-3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-[(4-oxo-3,4-dihydro-
quinazolin-
2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one
<IMG>
the enantiomers, the mixtures thereof and the salts thereof.
6. Physiologically acceptable salts of the compounds according to claims 1 to
5 with
inorganic or organic acids.
7. Pharmaceutical compositions containing a compound according to at least one
of
claims 1 to 5 or a salt according to claim 6 optionally together with one or
more inert
carriers and/or diluents.
8. Use of a compound according to at least one of claims 1 to 5 or a salt
according to
claim 6 for preparing a pharmaceutical composition which is suitable for the
treatment of type I and type II diabetes mellitus, arthritis, obesity,
allograft
transplantation and osteoporosis caused by calcitonin.
9. Process for preparing a pharmaceutical composition according to claim 7,
characterised in that a compound according to at least one of claims 1 to 5 or
a salt
according to claim 6 is incorporated in one or more inert carriers and/or
diluents by a
non-chemical method.

93
10. Process for preparing the compounds of general formula I according to
claims 1
to 6, characterised in that
a) a compound of general formula
<IMG>
wherein R1, R2, Y and R3 are as hereinbefore defined and
R4" denotes one of the groups mentioned for R4 hereinbefore which contain an
imino,
amino or alkylamino group, where the imino, amino or alkylamino group is
substituted by a protective group, is deprotected and
subsequently, if desired, a protective group used during the reactions to
protect
reactive groups is cleaved, and/or
a compound of general formula I thus obtained is resolved into its
stereoisomers
and/or
a compound of general formula I thus obtained is converted into its salts,
particularly
for pharmaceutical use into the physiologically acceptable salts thereof with
an
inorganic or organic acid.

Description

CA 02529729 2005-12-16
Boehringer Ingelheim International GmbH Case 1/1502
55216 Ingelheim foreign filing text
8431 Offt
New imidazopyridazinone and imidazopyridone derivatives, the preparation
thereof
and their use as pharmaceutical compositions
The present invention relates to new substituted imidazopyridazinones and
imidazopyridones of general formula
Rs
R1~N N
I I ~ R4
N
R2
the tautomers, the enantiomers, the diastereomers, the mixtures thereof, the
prodrugs thereof and the salts thereof, particularly the physiologically
acceptable
salts thereof with inorganic or organic acids or bases which have valuable
pharmacological properties, particularly an inhibiting effect on the activity
of the
enzyme dipeptidylpeptidase-IV (DPP-IV), the preparation thereof, the use
thereof for
the prevention or treatment of diseases or conditions associated with an
increased
DPP-IV activity or capable of being prevented or alleviated by reducing the
DPP-IV
activity, particularly type I or type II diabetes mellitus, the pharmaceutical
compositions containing a compound of general formula (I) or a physiologically
acceptable salt thereof as well as processes for the preparation thereof.
The present invention thus relates to the above compounds of general formula I
which have valuable pharmacological properties, the pharmaceutical
compositions
containing the pharmacologically effective compounds, the use thereof and
processes for the preparation thereof.
In the above general formula I
R' denotes a C~_3-alkyl group substituted by a group Ra, where

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2
Ra denotes a 3,4-dihydro-quinolinyl, 3,4-dihydro-isoquinolinyl, 1,4-dihydro-
quinazolinyl, 3,4-dihydro-quinazolinyl, 1H-benzo[dJ[1,2]oxazinyl, 4H-
benzo[e][1,3]oxazinyl, 4H-benzo[off[1,3]oxazinyl or 2H-benzo[1,4]oxazinyl
group, wherein in each case
in the benzo moiety one to three methyne groups may each be replaced
by a nitrogen atom and in the heterocyclyl moiety a methylene group
may be replaced by a carbonyl group,
a 4H-benzo[e][1,3]thiazinyl, 4H-benzo[d][1,3]thiazinyl or 2H-benzo [1,4]thia-
zinyl group wherein in each case
in the benzo moiety one to three methyne groups may each be replaced
by a nitrogen atom and in the heterocyclyl moiety a methylene group
may be replaced by a carbonyl group and the sulphur atom may be
replaced by a sulphinyl or sulphonyl group,
a 2-oxo-2H-benzo[e][1,3]oxazinyl or 2,2-dioxo-1H-benzo[c][1,2]thiazinyl group
wherein in each case in the benzo moiety
one to three methyne groups may each be replaced by a nitrogen atom,
a 2,3-dihydro-1H-benzo[e][1,4]diazepinyl, 4,5-dihydro-3H-benzo[bJ[1,4]diaze-
piny! or 5-oxo-4,5-dihydro-3H-benzo[e][1,4]diazepinyl group wherein in each
case
in the benzo moiety one to three methyne groups may each be replaced
by a nitrogen atom and in the heterocyclyl moiety a methylene group
may be replaced by a carbonyl group,
a 2,3-dihydro-benzo[~[1,4]oxazepinyl or 2,3-dihydro-benzo[b][1,4]oxazepinyl
group wherein in each case

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3
in the benzo moiety one to three methyne groups may each be replaced
by a nitrogen atom and in the heterocyclyl moiety a methylene group
may be replaced by a carbonyl group,
a 2,3-dihydro-benzo[b][1,4]thiazepinyl or 2,3-dihydro-benzo[tj[1,4]thiazepinyl
group wherein in each case
in the benzo moiety one to three methyne groups may each be replaced
by a nitrogen atom and in the heterocyclyl moiety a methylene group
may be replaced by a carbonyl group and the sulphur atom may be
replaced by a sulphinyl or sulphonyl group,
a 5-oxo-4,5-dihydro-benzo[t][1,3,4]oxadiazepinyl group wherein
in the benzo moiety one to three methyne groups may each be replaced
by a nitrogen atom,
a 11H-dibenzo[b,e]azepinyl or 5H-dibenzo[a,d]cycloheptenyl group wherein in
each case
in the benzo moiety one to three methyne groups may each be replaced
by a nitrogen atom and the methylene group in the heterocyclyl moiety
may be replaced by an oxygen or sulphur atom, a carbonyl, sulphinyl or
sulphonyl group or by an imino group substituted by RX, where
RX denotes a hydrogen atom or a C~~-alkyl, C2_4-alkenyl, C2_a-
alkynyl, C~s-cycloalkyl, C~s-cycloalkyl-C~_3-alkyl, aryl, aryl-
C~_3-alkyl, hydroxy-C2~-alkyl, C~_3-alkyloxy-C2_4-alkyl, C~s-
cycfoalkyloxy-C2_4-alkyl, amino-C2~-alkyl, C~_3-alkylamino-C2~-
alkyl, di-(C,_3-alkyl)-amino-C2~-alkyl, C~_3-alkyl-carbonyl, C,_3-
alkyloxy-carbonyl, C~_3-alkyloxy-carbonyl-C~_3-alkyl, aryl-carbonyl,
C,_3-alkyl-sulphonyl or aryl-sulphonyl group,
a phenanthridinyl group wherein

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in the benzo moiety one to three methyne groups may each be replaced
by a nitrogen atom, and
a 1,2,3,4-tetrahydro-phenanthridinyl, 1,2,3,4,4a,10b-hexahydro-phenan-
thridinyl, 2,3-dihydro-1 H-4-aza-cyclopenta[a]naphthyl or a 8,9,10,11-
tetrahydro-7H-6-aza-cyclohepta[a]naphthyl group wherein in each case
in the benzo moiety one to three methyne groups may each be replaced
by a nitrogen atom and one or two methylene groups may each be
replaced by an oxygen atom or a carbonyl group, while, if two
methylene groups are each replaced by an oxygen atom, the oxygen
atoms must be separated from one another by at least two methylene
units,
a phenanthrenyl group wherein
in each case one to three of the methyne groups in position 1 to 4 and 5
to 8 may each be replaced by a nitrogen atom,
a 1,2,3,4-tetrahydro-phenanthrenyl or a 1,2,3,4,5,6,7,8-octahydro-
phenanthrenyl group wherein
in each case one or two of the methylene groups in position 1 to 4 and
5 to 8 may each be replaced by an oxygen atom or a carbonyl group,
while, if two methylene groups are each replaced by an oxygen atom,
the oxygen atoms must be separated from one another by at least two
methylene units,
a 5H-benza[a]pyrrolo[1,2-a][1,4]diazepinyl, thieno[3,2-b][1,4]benzoxazepinyl,
5H-dibenzo[d,t][1,3]diazepinyl or a 5-oxa-7-aza-dibenzo[a,c]cycloheptenyl
group wherein in each case

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in the benzo moiety one to three methyne groups may each be replaced
by a nitrogen atom,
a naphtho[1,2-djoxazolyl, naphtho[2,1-dJoxazolyl , naphtho[1,2-dJthiazolyl,
5 naphtho[2,1-dJthiazolyl, naphtho[1,2-dJimidazolyl, naphtho[1,2-b]furanyl or
naphtho[2,1-b]furanyl group wherein in each case
in the naphthyl moiety one to three methyne groups may each be
replaced by a nitrogen atom,
or a furo[3,2-c]isoquinolinyl, pyrazolo[1,5-c]quinazolinyl or 1H-perimidinyl
group,
while the methylene and methyne groups of the above mentioned radicals Ra
may be substituted by the groups R'° to R'3 and additionally by a Ci_3-
alkyl
group and the imino groups of the above mentioned radicals Ra may be
substituted by the groups RX as hereinbefore defined and
R'° denotes a hydrogen atom,
a fluorine, chlorine, bromine or iodine atom,
a C,~-alkyl, hydroxy, or C~_4-alkyloxy group,
a nitro, amino, C,_3-alkylamino, di-(C,_3-alkyl)amino, cyano-C,_3-
alkylamino, N-(cyano-C~_3-alkyl)-N-(C~_3-alkyl)-amino, C~_3-alkyloxy-
carbonyl-C,_3-alkylamino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl,
piperazin-1-yl, or 4-(C~_3-alkyl)-piperazin-1-yl group,
a C~_3-alkyl-carbonylamino, arylcarbonylamino, aryl-C~_3-alkyl-
carbonylamino, C,_3-alkyloxy-carbonylamino, aminocarbonylamino, C~_3-
alkylaminocarbonylamino, di-(C,_3-alkyl)aminocarbonylamino, pyrrolidin-
1-yl-carbonylamino, piperidin-1-yl-carbonylamino, morpholin-4-yl-
carbonylamino, piperazin-1-yl-carbonylamino or 4-(C1_3-alkyl)-piperazin-

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1-yl-carbonyfamino, C~_3-alkyl-sulphonylamino, bis-(C~_3-alkylsulphonyl)-
amino, aminosulphonylamino, C~_3-alkylamino-sulphonylamino, di-(C~_3-
alkyl)amino-sulphonylamino, pyrrolidin-1-yl-sulphonylamino, piperidin-1-
yl-sulphonylamino, morpholin-4-yl-sulphonylamino, piperazin-1-yl-
sulphonylamino or 4-(C~_3-alkyl)-piperazin-1-yl-sulphonylamino, (C~_3-
alkylamino)thiocarbonylamino, (C~_3-alkyloxy-carbonyl-
amino)carbonylamino, arylsulphonylamino or aryl-C~_3-alkyl-sulphonyl-
amino group,
an N-(C~_3-alkyl)-C~_3-alkyl-carbonylamino, N-(C~_3-alkyl)-arylcarbonyl-
amino, N-(C~_3-alkyl)-aryl-C~_3-alkyl-carbonylamino, N-(C~_3-alkyl)-C~_3-
alkyloxy-carbonylamino, N-(aminocarbonyl)-C~_3-alkylamino, N-(C~_3-
alkyl-aminocarbonyl)-C~_3-alkylamino , N-[di-(C~_3-aikyl)aminocarbonyl]-
C~_3-alkylamino, N-(C~_3-alkyl)-C~_3-alkyl-sulphonylamino, N-(C~_3-alkyl)-
arylsulphonylamino, or N-(C~_3-alkyl)-aryl-C~_3-alkyl-sulphonylamino
group,
a 2-oxo-imidazolidin-1-yf, 2,4-dioxo-imidazolidin-1-yl, 2,5-dioxo-
imidazolidin-1-yl or 2-oxo-hexahydropyrimidin-1-yl group wherein the
nitrogen atom in the 3 position may be substituted in each case by a
methyl or ethyl group,
a cyano, carboxy, C~_3-alkyloxy-carbonyl, aminocarbonyl, C~_3-alkyl-
aminocarbonyl, di-(C~_3-alkyl)-aminocarbonyl, pyrrolidin-1-yl-carbonyl,
piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl, piperazin-1-yl-carbonyl
or 4-(C~_3-alkyl)-piperazin-1-yl-carbonyl group,
a C~_3-alkyl-carbonyl or an arylcarbonyl group,
a carboxy-Cy_3-alkyl, C~_3-alkyloxy-carbonyl-C,_3-alkyl, cyano-C,-3-alkyl,
aminocarbonyl-C~_3-alkyl, C~_3-alkyl-aminocarbonyl-C,_3-alkyl, di-(C~_3-
alkyl)-aminocarbonyl-C~_3-alkyl, pyrrolidin-1-yl-carbonyl-C~_3-alkyl,
piperidin-1-yl-carbonyl-C~_3-alkyl, morpholin-4-yl-carbonyl-C~_3-alkyl,

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piperazin-1-yl-carbonyl-C~_3-alkyl or 4-(C~_3-alkyl)-piperazin-1-yl-
carbonyl-C~_3-alkyl group,
a carboxy-C~_3-alkyloxy, C~_3-alkyloxy-carbonyl-C~_3-alkyloxy, cyano-
C~_3-alkyloxy, aminocarbonyl-C~_3-alkyloxy, C~_3-alkyl-aminocarbonyl-
C~_3-alkyloxy, di-(C~-3-alkyl)-aminocarbonyl-C~_3-alkyloxy, pyrrolidin-1-yl-
carbonyl-C~_3-alkyloxy, piperidin-1-yl-carbonyl-C~_3-alkyloxy, morpholin-
4-yl-carbonyl-C~_3-alkyloxy, piperazin-1-yl-carbonyl-C~_3-alkyloxy or 4-
(C~_3-alkyl)-piperazin-1-yl-carbonyl-C~_3-alkyloxy group,
a hydroxy-C~_3-alkyl, C~_3-alkyloxy-C,_3-alkyl, amino-G~_3-alkyl,
C~_3-alkylamino-C~_3-alkyl, di-(C~_3-alkyl)-amino-C~_3-alkyl, pyrrolidin-1-yl-
C1_3-alkyl, piperidin-1-yl-C~-3-alkyl, morpholin-4-yl-C~_3-alkyl, piperazin-1-
yl-C~_3-alkyl or 4-(C~_3-alkyl)-piperazin-1-yl-C~_3-alkyl group,
a hydroxy-C~_3-alkyloxy, C~_3-alkyloxy-C~_3-alkyloxy, C~_3-alkylsulphanyl-
C~_3-alkyloxy, C~_3-alkylsulphinyl-C~_3-alkyloxy, C~_3-alkylsufphonyl-C~_3-
alkyloxy, amino-C~_3-alkyloxy, C~_3-alkylamino-C~_3-alkyloxy, di-(C~_3-
alkyl)-amino-C~_3-alkyloxy, pyrrolidin-1-yl-C~_3-alkyloxy, piperidin-1-yl-
C~_3-alkyloxy, morpholin-4-yl-C~_3-alkyloxy, piperazin-1-yl-C~_3-alkyloxy
or 4-(C~_3-alkyl)-piperazin-1-yl-C~_3-alkyloxy group,
a mercapto, C~_3-alkylsulphanyl, C~_3-alkysulphinyl, C~_3-alkylsulphonyl,
C~_3-alkylsulphonyloxy, arylsulphonyloxy, trifluoromethylsulphanyl,
trifluoromethylsulphinyl or trifluoromethylsulphonyl group,
a sulpho, aminosulphonyl, C~_3-alkyl-aminosulphonyl, di-(C~_3-alkyl)-
aminosulphonyl, pyrrolidin-1-yl-sulphonyl, piperidin-1-yl-sulphonyl,
morpholin-4-yl-sulphonyl, piperazin-1-yl-sulphonyl or 4-(C1_3-alkyl)-
piperazin-1-yl-sulphonyl group,
a methyl or methoxy group substituted by 1 to 3 fluorine atoms,
an ethyl or ethoxy group substituted by 1 to 5 fluorine atoms,

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8
a C2~-alkenyl or Cz_4-alkynyl group,
a C3~-alkenyloxy or C3_4-alkynyloxy group,
a C3~-cycloalkyl or C~.6-cycloalkyloxy group,
a C3~-cycloalkyl-C~_3-alkyl or C3_s-cycloalkyl-C~_3-alkyloxy group or
an aryl, aryloxy, aryl-C~.3-alkyl or aryl-C~_3-alkyloxy group,
R" and R'2, which may be identical or different, in each case represent
a hydrogen atom, a fluorine, chlorine, bromine or iodine atom, a C~_3-
alkyl, trifluoromethyl, hydroxy, C~_3-alkyloxy or cyano group, or
R" together with R'2, if these are bound to adjacent carbon atoms, also
denotes a methylenedioxy, difluoromethylenedioxy, ethylenedioxy or a
straight-chain C3_5-alkylene group and
R'3 denotes a hydrogen atom, a fluorine, chlorine or bromine atom, a
trifluoromethyl, C~_3-alkyl or C~_3-alkyloxy group,
R2 denotes a hydrogen, fluorine or chlorine atom,
a C~~-alkyl group,
a C2_4-alkenyl group,
a C3~,-alkynyl group,
a C3_6-cycloalkyl group,
a C3~-cycloalkyl-C~_3-alkyl group,

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9
a tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydro-
furanylmethyl or tetrahydropyranylmethyl group,
an aryl group,
an aryl-C~_4-alkyl group,
an aryl-CZ_3-alkenyl group,
an arylcarbonyl group,
an arylcarbonyl-C~_2-alkyl group,
a heteroaryl group,
a heteroaryl-C~_3-alkyl group,
a furanylcarbonyl, thienylcarbonyl, thiazolyicarbonyl or pyridylcarbonyl
group,
a furanylcarbonylmethyl, thienylcarbonylmethyl, thiazolylcarbonylmethyl or
pyridylcarbonylmethyl group,
a C~_4-alkyl-carbonyl group,
a C~_4-alkyl-carbonyl-C~_2-alkyl group,
a C3~-cycloalkyl-carbonyl group,
a C3_fi-cycloalkyl-carbonyl-C~_2-alkyl group,
an aryl-A or aryl-A-C~_3-alkyl group, where A denotes an oxygen or sulphur
atom, an
imino, C~_3-alkylimino, sulphinyl or sulphonyl group,
a group Rb, where

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Rb denotes a cyano, carboxy, C~_3-alkyloxy-carbonyl, aminocarbonyl, C~_3-
alkylamino-carbonyl, di-(C~_3-alkyl)-amino-carbonyl, pyrrolidin-1-ylcarbonyl,
piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4-
5 methylpiperazin-1-ylcarbonyl, 4-ethylpiperazin-1-ylcarbonyl, hydroxy,
mercapto, C~_3-alkyloxy, C~_3-alkylsulphenyl, C~_3-alkylsulphinyl, C~_3-alkyl-
sulphonyl, amino, C~_3-alkylamino, di-(C~_3-alkyl)-amino, pyrrolidin-1-yl,
piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl or 4-
ethyl-
piperazin-1-yl group,
or a C~_4-alkyl group substituted by a group Rb, where Rb is as hereinbefore
defined,
Y denotes a nitrogen atom or a group of formula C-R5,
while RS is defined like R2 and in each case one of the two groups R2 and RS
must be a hydrogen atom or a C~_3-alkyl group,
R3 denotes a C3_$-alkyl group,
a C~_3-alkyl group substituted by a group R~, where
R~ denotes a C~~-cycloalkyl group optionally substituted by one or two C~_3-
alkyl groups,
a C5_~-cycloalkenyl group optionally substituted by one or two C~_3-alkyl
groups,
an aryl group or
a furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl,
pyridazinyl, pyrimidyl or pyrazinyl group, while the above mentioned
heterocyclic groups may each be substituted by one or two C~-3-alkyl groups or
by a fluorine, chlorine, bromine or iodine atom or by a trifluoromethyl, cyano
or
C~_3-alkyloxy group,

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11
a C3_$-alkenyl group,
a C3_s-alkenyl group substituted by a fluorine, chlorine or bromine atom or by
a
trifluoromethyl group,
a C3_$-alkynyl group,
an aryl group or
an aryl-C2_4-alkenyl group,
and
R4 denotes an azetidin-1-yl or pyrrolidin-1-yl group which is substituted in
the 3
position by an amino, C~_3-alkylamino or a di-(C,_3-alkyl)amino group and may
additionally be substituted by one or two C~_3-alkyl groups,
a piperidin-1-yl or hexahydroazepin-1-yl group which is substituted in the 3
position
or in the 4 position by an amino, C~_3-alkylamino or a di-(C~_3-alkyl)amino
group and
may additionally be substituted by one or two C~_3-alkyl groups,
a 3-amino-piperidin-1-yl group wherein the piperidin-1-yl moiety is
additionally
substituted by an aminocarbonyl, C~_2-alkyl-aminocarbonyl, di-(C~_2-
alkyl)aminocarbonyl, pyrrolidin-1-yl-carbonyl, (2-cyano-pyrrolidin-1-yl-
)carbonyl,
thiazolidin-3-yl-carbonyl, (4-cyano-thiazolidin-3-yl)carbonyl, piperidin-1-
ylcarbonyl or
morpholin-4-ylcarbonyl group,
a 3-amino-piperidin-1-yl group wherein the piperidin-1-yl moiety in the 4
position or in
the 5 position is additionally substituted by a hydroxy or methoxy group,
a 3-amino-piperidin-1-yl group wherein the methylene group in the 2 position
or in the
6 position is replaced by a carbonyl group,

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12
a piperidin-1-yl or hexahydroazepin-1-yl group substituted in the 3 position
by an
amino, C~_3-alkylamino or di-(C~_3-alkyl)-amino- group, wherein in each case
two
hydrogen atoms on the carbon skeleton of the piperidin-1-yl or hexahydroazepin-
1-yl-
group are replaced by a straight-chain alkylene bridge, this bridge containing
2 to 5
carbon atoms if the two hydrogen atoms are located on the same carbon atom, or
1
to 4 carbon atoms, if the hydrogen atoms are located on adjacent carbon atoms,
or 1
to 4 carbon atoms, if the hydrogen atoms are located on carbon atoms which are
separated by one atom, or 1 to 3 carbon atoms if the two hydrogen atoms are
located on carbon atoms separated by two atoms,
an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or hexahydroazepin-1-yl
group which is
substituted by an amino-C~_3-alkyl, C~-3-alkylamino-C~_3-alkyl or a di-(C~_3-
alkyl)-
amino-C,_3-alkyl group,
a piperazin-1-yl or [1,4]diazepan-1-yl group optionally substituted at the
carbon
skeleton by one or two C~_3-alkyl groups,
a 3-imino-piperazin-1-yl, 3-imino-[1,4]diazepan-1-yl or 5-imino-[1,4]diazepan-
1-yl
group optionally substituted at the carbon skeleton by one or two C~_3-alkyl
groups,
a [1,4)diazepan-1-yl group optionally substituted by one or two C~_3-alkyl
groups,
which is substituted in the 6 position by an amino group,
a C3_~-cycloalkyl group which is substituted by an amino, C~_3-alkylamino or
di-(C~_3-
alkyl)-amino group,
a C3_~-cycloalkyl group which is substituted by an amino-C~_3-alkyl, C~_3-
alkylamino-
C,_3-alkyl or a di-(C~_3-alkyl)amino-C~_3-alkyl group,
a C3_~-cycloalkyl-C~_2-alkyl group wherein the cycloalkyl moiety is
substituted by an
amino, C,_3-alkylamino or di-(C~_3-alkyl)-amino group,
a C3_~-cycloalkyl-C~_2-alkyl group wherein the cycloalkyl moiety is
substituted by an
amino-C~_3-alkyl, C~_3-alkylamino-C~_3-alkyl or a di-(C~_3-alkyl)amino-C,_3-
alkyl group,

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13
a C3_~-cycloalkylamino group wherein the cycloalkyl moiety is substituted by
an
amino, C~_3-alkylamino or di-(C,_3-alkyl)-amino group, while the two nitrogen
atoms at
the cycloalkyl moiety are separated from one another by at least two carbon
atoms,
an N-(C3_~-cycloalkyl)-N-(C~-3-alkyl)-amino group wherein the cycloalkyl
moiety is
substituted by an amino, C~_3-alkylamino or di-(C~_3-alkyl)-amino group, while
the two
nitrogen atoms at the cycloalkyl moiety are separated from one another by at
least
two carbon atoms,
a C3_~-cycloalkylamino group wherein the cycloalkyl moiety is substituted by
an
amino-C~-3-alkyl, C~_3-alkylamino-C~_3-alkyl or a di-(C~_3-alkyl)amino-C~_3-
alkyl group,
an N-(C3_~-cycloalkyl)-N-(C~_3-alkyl)-amino group wherein the cycloalkyl
moiety is
substituted by an amino-C~_3-alkyl, C,_3-alkylamino-C~_3-alkyl or a di-(C~_3-
alkyl)amino-
C~_3-alkyl group,
a C3_~-cycloalkyl-C~_2-alkyl-amino group wherein the cycfoalkyl moiety is
substituted
by an amino, C~_3-alkylamino or di-(C~_3-alkyl)-amino group,
an N-(C3_~-cycloalkyl-C~_2-alkyl)-N-(C~_2-alkyl)-amino group wherein the
cycloalkyl
moiety is substituted by an amino, C~_3-alkylamino or di-(C~_3-alkyl)-amino
group,
a C3_~-cycloalkyl-C,_2-alkyl-amino group wherein the cycloalkyl moiety is
substituted
by an amino-C~_3-alkyl, C~_3-alkylamino-C~_3-alkyl or a di-(C~_3-alkyl)amino-
C~_3-alkyl
group,
an N-(C3_~-cycloalkyl-C~-2-alkyl)-N-(C~_2-alkyl)-amino group wherein the
cycloalkyl
moiety is substituted by an amino-C~_3-alkyl, C~_3-alkylamino-C~_3-alkyl or a
di-(C~_3
alkyl)amino-C~_3-alkyl group,
a R'9-C2_4-alkylamino group wherein R'9 is separated from the nitrogen atom of
the
C2_4-alkylamino moiety by at least two carbon atoms and

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R'9 denotes an amino, C~_3-alkylamino or di-(C~_3-alkyl)-amino group,
an R'9-C2_4-alkylamino group wherein the nitrogen atom of the C2_4-alkylamino
moiety
is substituted by a C~_3-alkyl group and R'9 is separated from the nitrogen
atom of the
C2_4-alkylamino moiety by at least two carbon atoms, while R'9 is as
hereinbefore
defined,
an amino group substituted by the group R2° wherein
R2° denotes an azetidin-3-yl, azetidin-2-ylmethyl, azetidin-3-
ylmethyl,
pyrrolidin-3-yl, pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, piperidin-3-yl,
piperidin-4-yl, piperidin-2-ylmethyl, piperidin-3-ylmethyl or piperidin-4-
yfmethyl
group, while the groups mentioned for R2° may each be substituted by
one or
two C~_3-alkyl groups,
an amino group substituted by the group R2° and a C~_3-alkyl group
wherein R2° is as
hereinbefore defined, white the groups mentioned for R2° may each be
substituted by
one or two C~_3-alkyl groups,
an R'9-C3_4-alkyl group wherein the C3_4-alkyl moiety is straight-chained and
may
additionally be substituted by one or two C~_3-alkyl groups, while R'9 is as
hereinbefore defined,
a 3-amino-2-oxo-piperidin-5-yl or 3-amino-2-oxo-1-methyl-piperidin-5-yl group,
a pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, hexahydroazepin-3-yl or
hexahydroazepin-4-yl group which is substituted in the 1 position by an amino,
C~_3-
alkylamino or di-(C~_3-alkyl)amino group,
or an azetidin-2-yl-C~_2-alkyl, azetidin-3-yl-C~_2-alkyl, pyrrolidin-2-yl-C~_2-
alkyl,
pyrrolidin-3-yl, pyrrolidin-3-yl-C~_2-alkyl, piperidin-2-yl-C~_2-alkyl,
piperidin-3-yl,
piperidin-3-yl-C~_2-alkyl, piperidin-4-yl or piperidin-4-yl-C~_2-alkyl group,
while the
above mentioned groups may each be substituted by one or two C~_3-alkyl
groups,

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while by the aryl groups mentioned in the definition of the above groups are
meant
phenyl or naphthyl groups which may be mono- or disubstituted by Rh, while the
substituents may be identical or different and R,, denotes a fluorine,
chlorine, bromine
or iodine atom, a trifluoromethyl, cyano, nitro, amino, aminocarbonyl,
5 aminosulphonyl, methylsulphonyl, acetylamino, methylsulphonylamino, C~_3-
alkyl,
cyclopropyf, ethenyl, ethynyl, hydroxy, C~_3-alkyloxy, difluoromethoxy or
trifluoromethoxy group,
by the heteroaryl groups mentioned in the definition of the above groups are
meant a
10 pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl,
benzothiophenyl, quinolinyl or
isoquinolinyl group,
or a pyrrolyl, furanyl, thienyl or pyridyl group, wherein one or two methyne
groups are
replaced by nitrogen atoms,
or an indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl
group,
wherein one to three methyne groups are replaced by nitrogen atoms,
and the above mentioned heteroaryl groups may be mono- or disubstituted by
Rh, while the substituents may be identical or different and R,, is as
hereinbefore defined,
while, unless otherwise stated, the above mentioned alkyl, alkenyl and alkynyl
groups
may be straight-chain or branched,
and the hydrogen atoms of the methyl or ethyl groups contained in the
definitions
may be wholly or partly replaced by fluorine atoms,
the tautomers, enantiomers, diastereomers, the mixtures thereof, the prodrugs
thereof and the salts thereof.
Compounds of the above general formula I which contain one or more groups that
can be cleaved in vivo are so-called prodrugs.

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The carboxy groups mentioned in the definition of the above mentioned groups
may
be replaced by a group which can be converted into a carboxy group in vivo or
by a
group which is negatively charged under physiological conditions,
and furthermore the amino and imino groups mentioned in the definition of the
above
mentioned groups may be substituted by a group which can be cleaved in vivo.
Such
groups are described for example in WO 98!46576 and by N.M. Nielsen ef al. in
International Journal of Pharmaceutics 39, 75-85 (1987).
By a group which can be converted in vivo into a carboxy group is meant, for
example, a hydroxymethyl group, a carboxy group esterified with an alcohol
wherein
the alcohol moiety is preferably a C~_6-alkanol, a phenyl-C~_3-alkanol, a
C3_9-cycloalkanol, while a C5_s-cycloaikanol may additionally be substituted
by one or
two C~_3-alkyl groups, a CS_s-cycloalkanol wherein a methylene group in the 3
or 4
position is replaced by an oxygen atom or by an imino group optionally
substituted by
a C,_3-alkyl, phenyl-C~_3-alkyl, phenyl-C~_3-alkyloxycarbonyl or C2~-alkanoyl
group
and the cycloalkanol moiety may additionally be substituted by one or two C~_3-
alkyl
groups, a C4_~-cycloalkenol, a C3_5-alkenol, a phenyl-C3_5-alkenol, a C3_5-
alkynol or
phenyl-C3_5-alkynol with the proviso that no bonds to the oxygen atom start
from a
carbon atom which carries a double or triple bond, a C3_$-cycloalkyl-C~_3-
alkanol, a
bicycloalkanol with a total of 8 to 10 carbon atoms which may additionally be
substituted in the bicycloalkyl moiety by one or two C~_3-alkyl groups, a 1,3-
dihydro-3-
oxo-1-isobenzofuranol or an alcohol of formula
Rp-CO-O-(RqCR~)-OH,
wherein
Rp denotes a C~_s-alkyl, C~~-cycloalkyl, C,_s-alkyloxy, C5_~-cycloalkyloxy,
phenyl or phenyl-C,_3-alkyl group,
Rq denotes a hydrogen atom, a C~_3-alkyl, C5_~-cycloalkyl or phenyl group and
R~ denotes a hydrogen atom or a C~_3-alkyl group,

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17
by a group which is negatively charged under physiological conditions is
meant, for
example, a tetrazol-5-yl, phenylcarbonylaminocarbonyl,
trifluoromethylcarbonylaminocarbonyl, C~_6-alkylsulphonylamino,
phenylsulphonylamino, benzylsulphonylamino, trifluoromethylsulphonylamino,
C~_6-alkylsulphonylaminocarbonyl, phenylsulphonylaminocarbonyl,
benzylsulphonylaminocarbonyl or periluoro-C~_6-alkylsulphonylaminocarbonyl
group
and by a group which can be cleaved in vivo from an imino or amino group is
meant,
for example, a hydroxy group, an acyl group such as a phenylcarbonyl group
optionally mono- or disubstituted by fluorine, chlorine, bromine or iodine
atoms, by
C,_3-alkyl or C~_3-alkyloxy groups, while the substituents may be identical or
different,
a pyridinoyl group or a C~_~s-alkanoyl group such as the formyl, acetyl,
propionyl,
butanoyl, pentanoyl or hexanoyl group, a 3,3,3-trichloropropionyl or
allyloxycarbonyl
group, a C~_~s-alkyloxycarbonyl or C~_~s-alkylcarbonyloxy group, wherein
hydrogen
atoms may be wholly or partially replaced by fluorine or chlorine atoms such
as the
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,
butoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl,
octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl,
dodecyloxycarbonyl, hexadecyloxycarbonyl, methylcarbonyloxy, ethylcarbonyloxy,
2,2,2-trichloroethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy,
butylcarbonyloxy, tert.butylcarbonyloxy, pentylcarbonyloxy, hexylcarbonyloxy,
octylcarbonyloxy, nonylcarbonyloxy, decylcarbonyloxy, undecylcarbonyloxy,
dodecylcarbonyloxy or hexadecylcarbonyloxy group, a phenyl-C~~-
alkyloxycarbonyl
group such as the benzyloxycarbonyl, phenylethoxycarbonyl or
phenylpropoxycarbonyl group, a 3-amino-propionyl group wherein the amino group
may be mono- or disubstituted by C»-alkyl or C3_~-cycloaikyl groups and the
substituents may be identical or different, a C~_3-alkylsu!phony!-C2_4-
alkyloxycarbonyl,
C,_3-alkyloxy-C2~,-alkyloxy-C2_4-alkyloxycarbonyl, RP-CO-O-(RqCR~)-O-CO, C~_s-
alkyl-
CO-NH-(RSCRt)-O-CO or C~_6-alkyl-CO-O-(RSCR, )-(RSCR~)-O-CO group, wherein Rp
to R~ are as hereinbefore defined,
RS and Rt, which may be identical or different, denote hydrogen atoms or
C~_3-alkyl groups.

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Moreover, the saturated alkyl and alkyloxy moieties which contain more than 2
carbon atoms mentioned in the foregoing definitions and those that follow,
unless
otherwise stated, also include the branched isomers thereof such as, for
example,
the isopropyl, tert.butyl, isobutyl group, etc.
Preferred compounds of the above general formula I are those wherein
R' denotes a methyl group substituted by a group Ra, where
Ra denotes a 3,4-dihydro-quinolinyl group,
a 3,4-dihydro-isoquinolinyl group,
a 1,4-dihydro-quinazolinyl or 4-oxo-1,4-dihydro-quinazolinyl group,
a 3,4-dihydro-quinazolinyl or 4-oxo-3,4-dihydro-quinazolinyl group,
a 1H-benzo[d][1,2]oxazinyl or 1-oxo-1H-benzo[dj[1,2]oxazinyl group,
a 4H-benzo[e][1,3]oxazinyl or 4-oxo-4H-benzo[e][1,3]oxazinyl group,
a 4H-benzo[dJ[1,3]oxazinyl or 4-oxo-4H-benzo[dJ[1,3]oxazinyl group,
a 2H-benzo[1,4]oxazinyl or 2-oxo-2H-benzo[1,4]oxazinyl group,
a 4H-benzo[e][1,3]thiazinyl or 4-oxo-4H-benzo[e][1,3]thiazinyl group,
a 4H-benzo[d]j1,3]thiazinyl or 2H-benzo [1,4]thiazinyl group,
a 2-oxo-2H-benzo[e](1,3]oxazinyl or 2,2-dioxo-1H-benzo[c][1,2]thiazinyl group,
a 2,3-dihydro-1 H-benzo[e][1,4]diazepinyl or 2-oxo-2,3-dihydro-1 H-
benzo[e][1,4]diazepinyl group,

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a 4,5-dihydro-3H benzo[b][1,4]diazepinyl or 4-oxo-4,5-dihydro-3H-
benzo[bJ[1,4]diazepinyl group,
a 5-oxo-4,5-dihydro-3H-benzo[e][1,4]diazepinyl group,
a 2,3-dihydro-benzo[t][1,4]oxazepinyl or 2,3-dihydro-benzo[b][1,4Joxazepinyl
group,
a 2,3-dihydro-benzo[t][1,4]thiazepinyl or 2,3-dihydro-benzo[b][1,4]thiazepinyl
group,
a 5-oxo-4,5-dihydro-benzo[tj[1,3,4]oxadiazepinyl group,
a 11H-dibenzo[b,e]azepinyi or 11-oxo-11H-dibenzo[b,e]azepinyl group,
a 11 H-benzo[e]pyrido[3,2-b]azepinyl or a 5H-1,9,10-triaza-dibenzo[a,d]-
cycloheptenyl group,
a 5H-dibenzo[b,e][1,4]diazepinyl or dibenzo[b,t][1,4]oxazepinyl group,
a dibenzo[b,f][1,4]thiazepinyl, 5-oxo-dibenzo[b,fJ[1,4Jthiazepinyl or 5,5-
dioxo-
dibenzo[b,t][1,4Jthiazepinyl group,
a 5H-dibenzo[a,dJcycloheptenyl or 5H-dibenzo[b,t]azepinyl group,
a phenanthridinyl, benzo[c][1,5]naphthyridinyl, benzo[h][1,6]naphthyridinyl,
benzo[c][1,8]naphthyridinyl, benzo[t][1,7]naphthyridinyl or 1,5,9-triaza-
phenanthrenyl group,
a 1,2,3,4-tetrahydro-phenanthridinyl, 1,2,3,4,4a,10b-hexahydro-phenan-
thridinyl, 2,3-dihydro-1H-4-aza-cyclopenta[a]naphthyl or 8,9,10,11-tetrahydro-
7H-6-aza-cyclohepta[a]naphthyl group,

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a 2,3-dihydro-1H-4-oxa-10-aza-phenanthrenyl or 1-oxo-2,3-dihydro-1H-4-oxa
10-aza-phenanthrenyl group,
a phenanthrenyl, benzo[h]quinolinyl, benzo[tjquinolinyl or
benzo[t]quinoxalinyl
5 group,
a 5H-benzo[a]pyrrolo[1,2-a][1,4]diazepinyl, thieno[3,2-b][1,4]benzoxazepinyl,
5H-dibenzo[d,t][1,3]diazepinyl or 5-oxa-7-aza-dibenzo[a,c]cycloheptenyl group,
10 a naphtho[1,2-d]oxazolyl, naphtho[2,1-djoxazolyl , naphtho[1,2-d]thiazolyl,
naphtho[2,1-d]thiazolyl, naphtho[1,2-d]imidazolyl, naphtho[1,2-b]furany~ or
naphtho[2,1-b]furanyl group,
or a furo[3,2-c]isoquinolinyl, pyrazolo[1,5-c]quinazolinyl or 1H-perimidinyl
15 group,
while the benzo groups of the above mentioned radicals Ra are substituted by
the groups R'° to R'3 and the alkylene units of the above mentioned
groups Ra
may be substituted by one or two fluorine atoms or one or two C,_3-alkyl or
20 C~_3-alkyloxy-carbonyl groups and the imino groups of the above mentioned
radicals Ra may be substituted by a C~_3-alkyl group and
R'° denotes a hydrogen atom,
a fluorine, chlorine, bromine or iodine atom,
a C,_3-alkyl or cyclopropyl group,
a hydroxy, C,_3-alkyloxy or cyclopropyloxy group,
a nitro, amino, C~_3-alkylamino or di-(C~_3-alkyl)amino group,
a C~_3-alkyl-carbonylamino or C~_3-alkyl-sulphonylamino group,

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a cyano, carboxy, C~_3-alkyloxy-carbonyl, aminocarbonyl, C~_3-alkyl-
aminocarbonyl or di-(C~_3-alkyl)-aminocarbonyl group,
a mercapto, C~_3-alkylsulphanyl, C~_3-alkysulphinyl, C~_3-alkylsulphonyl
or aminosulphonyl group or
a difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy
group and
R", R'2 and R'3, which may be identical or different, in each case
represent a hydrogen atom, a fluorine, chlorine or bromine atom, a
methyl, trifluoromethyl or methoxy group,
R2 denotes a hydrogen atom or
a C~_3-alkyl, cyclopropyl, trifluoromethyl, cyanomethyl or 2-cyano-ethyl
group,
Y denotes a nitrogen atom or a group of formula C-R5,
while R5 denotes a hydrogen atom or a C~_3-alkyl group,
R3 denotes a 2-buten-1-yl or 3-methyl-2-buten-1-yl group,
a 1-buten-1-yl group,
a 2-butyn-1-yl group or
a 1-cyclopenten-1-ylmethyl group
and
R4 denotes a (3-amino-piperidin-1-yl) group,

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while, unless otherwise stated, the above mentioned alkyl groups may be
straight-
chain or branched,
the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts
thereof.
Particularly preferred are those compounds of the above general formula I
wherein
R' denotes a methyl group substituted by a group Ra, where
Ra denotes a 3,4-dihydro-quinolin-2-yl group,
a 3,4-dihydro-isoquinolin-1-yl group,
a 1,4-dihydro-quinazolin-2-yl or 4-oxo-1,4-dihydro-quinazolin-2-yl group,
a 3,4-dihydro-quinazolin-2-yl or 4-oxo-3,4-dihydro-quinazolin-2-yl group,
a 1H-benzo[dJ[1,2]oxazin-4-yl or 1-oxo-1H-benzo[dj[1,2]oxazin-4-yl group,
a 4H-benzo[e][1,3]oxazin-2-yl or 4-oxo-4H-benzo[e][1,3]oxazin-2-yl group,
a 4H-benzo[dJ[1,3]oxazin-2-yl or 4-oxo-4H-benzo[d][1,3]oxazin-2-yl group,
a 2H-benzo[1,4]oxazin-3-yl or 2-oxo-2H-benzo[1,4]oxazin-3-yl group,
a 4H-benzo[e][1,3]thiazin-2-yl or 4-oxo-4H-benzo[e][1,3]thiazin-2-yl group,
a 4H-benzo[d][1,3]thiazin-2-yl or 2H-benzo[1,4]thiazin-3-yl group,
a 2-oxo-2H-benzo[e][1,3]oxazin-4-yl or 2,2-dioxo-1H-benzo[c][1,2)thiazin-4-yl
group,

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a 2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl or2-oxo-2,3-dihydro-1H-
benzo[e](1,4]diazepin-5-yl group,
a 4,5-dihydro-3H benzo(b][1,4]diazepin-2-yl or 4-oxo-4,5-dihydro-3H-
benzo[b][1,4]diazepin-2-yl group,
a 5-oxo-4,5-dihydro-3H-benzo[e)[1,4]diazepin-2-yl group,
a 2,3-dihydro-benzo[t][1,4]oxazepin-5-yl or 2,3-dihydro-benzo[b][1,4]oxazepin-
4-yl group,
a 2,3-dihydro-benzo[tJ[1,4]thiazepin-5-yl or 2,3-dihydro-
benzo[b][1,4]thiazepin-
4-yl group,
a 5-oxo-4,5-dihydro-benzo[t][1,3,4]oxadiazepin-2-yl group,
a 11H-dibenzo[b,e]azepin-6-yl or 11-oxo-11H-dibenzo[b,e]azepin-6-yl group,
a 11 H-benzo[e]pyrido(3,2-b]azepin-6-yl or a 5H-1,9,10-triaza-dibenzo[a,d]-
cyclohepten-11-y) group,
a 5H-dibenzo[b,e][1,4]diazepin-11-yl or dibenzo[b,tJ(1,4]oxazepin-11-yl group,
a dibenzo[b,fJ[1,4]thiazepin-11-yl, 5-oxo-dibenzo[b,tJ[1,4]thiazepin-11-yl or
5,5-
dioxo-dibenzo[b,tJ[1,4]thiazepin-11-yl group,
a 5H-dibenzo[a,d]cyclohepten-10-yl or 5H-dibenzo[b,t]azepin-10-yl group,
a phenanthridin-6-yl, benzo[c][1,5]naphthyridin-6-yl,
benzo[h][1,6]naphthyridin-
5-yl, benzo[c][1,8]naphthyridin-6-yl, benzo[t][1,7]naphthyridin-5-yl or 1,5,9-
triaza-phenanthren-10-yl group,

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a 1,2,3,4-tetrahydro-phenanthridin-6-yl, 1,2,3,4,4a,10b-hexahydro-
phenanthridin-6-yl, 2,3-dihydro-1H-4-aza-cyclopenta[a]naphth-5-yl or
8,9,10,11-tetrahydro-7H-6-aza-cyclohepta[a]naphth-5-yl group,
a 2,3-dihydro-1 H-4-oxa-10-aza-phenanthren-9-yl or 1-oxo-2,3-dihydro-1 H-4-
oxa-10-aza-phenanthren-9-yl group,
a phenanthren-9-yl, benzo[h]quinolin-6-yl, benzo[t]quinolin-6-yl or
benzo[fJquinoxalin-6-yl group,
a 5H-benzo[e]pyrroto[1,2-a][1,4]diazepin-11-yl, thieno[3,2-b](1,4]benzoxaze-
pin-9-yl, 5H-dibenzo[d,t](1,3]diazepin-6-yl or 5-oxa-7-aza-di-
benzo[a,c]cyclohepten-6-yl group,
a naphtho[1,2-d]oxazol-2-yl, naphtho[2,1-d]oxazol-2-yl, naphtho[1,2-d]thiazol-
2-yl, naphtho[2,1-d]thiazol-2-yl, naphtho[1,2-d]imidazol-2-yl, naphtho(1,2-
b]furan-2-yl or naphtho[2,1-b]furan-2-yl group,
or a furo[3,2-c]isoquinolin-5-yl, pyrazolo[1,5-c]quinazolin-5-yl or 1 H-
perimidin-
2-yl group,
while the benzo groups of the above mentioned radicals Ra are substituted by
the groups R'° to R'3 and the alkylene units of the above mentioned
groups Ra
may be substituted by one or two fluorine atoms or one or two methyl groups
and the imino groups of the above mentioned radicals Ra may be substituted
by a methyl group and
R'° denotes a hydrogen atom,
a fluorine, chlorine, bromine or iodine atom,
a methyl or ethyl group,
a hydroxy, methoxy or ethoxy group or

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a difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy
group and
5 R", R'2 and R'3, which may be identical or different, each denote a
hydrogen, fluorine, chlorine or bromine atom or a methyl, trifluoromethyl
or methoxy group,
R2 denotes a hydrogen atom or
a methyl, cyanomethyl, trifluoromethyl, ethyl, 2-cyano-ethyl, propyl,
eyclopropyl or
isopropyl group,
Y denotes a nitrogen atom or a group of formula C-R5,
while R5 denotes a hydrogen atom or a methyl, ethyl, propyl or isopropyl
group,
R3 denotes a 2-buten-1-yl or 3-methyl-2-buten-1-yf group,
a 1-buten-1-yl group,
a 2-butyn-1-yl group or
a 1-cyclopenten-1-ylmethyl group
and
R4 denotes a (3-amino-piperidin-1-yl) group,
the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts
thereof.

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Most particularly preferred are those compounds of the above general formula I
wherein
R' denotes a 4-oxo-3,4-dihydro-quinazolin-2-ylmethyl group,
a dibenzo[b,fj[1,4joxazepin-11-ylmethyl group,
a phenanthridin-6-ylmethyi group,
a phenanthren-9-ylmethyl group or
a naphtho[1,2-dJoxazol-2-ylmethyl or naphtho[2,1-dJoxazol-2-ylmethyl group,
R2 denotes a hydrogen atom or a methyl group,
Y denotes a nitrogen atom,
R3 denotes a 2-butyn-1-yl group
and
R4 denotes a (3-amino-piperidin-1-yl) group,
the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts
thereof.

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The following compounds of general formula I deserve special mention:
(1) 2-(3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-[(dibenzo[b,tj[1,4]oxazepin-
11-
yl)methyl]-3,5-dihydro-imidazo[4,5-dJpyridazin-4-one
I~ o
N
i N i N, >
C N Nw I N ~~
NHZ
(2) 2-(3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-[(phenanthridin-6-yl)methyl]-
3,5-
dihydro-imidazo[4,5-djpyridazin-4-one
o
N
N
N
I ~N N~ I N
/ NHZ
(3) 2-(3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-[(phenanthren-9-yl)methyl]-
3,5-
dihydro-imidazo[4, 5-d]pyridazin-4-one
N N
I / N w I ~~N~
\N
/ NHZ
(4) 2-((R)-3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-[(phenanthridin-6-
yl)methyl]-7-
methyl-3, 5-di hydro-imidazo[4, 5-d]pyridazi n-4-one
O
I '
I N~ N
N N~N
I / NH2
(5) 2-((R)-3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-
[(dibenzo[b,t][1,4]oxazepin-11-
yl)methyl]-7-methyl-3,5-dihydro-imidazo[4,5-dJpyridazin-4-one

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O
N N
O 1N N w I ~~N~
~N
NHz
\ /
(6) 2-((S)-3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-
[(dibenzo(b,t][1,4)oxazepin-11-
yl)methyl]-3,5-dihydro-imidazo[4,5-dJpyridazin-4-one
0
N N
O ~N N ~ I ~~ N
N
/ \ ,NH2
(7) 2-((R)-3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-
[(dibenzo[b,f][1,4]oxazepin-11-
yl)methyl]-3,5-dihydro-imidazo[4,5-dJpyridazin-4-one
O
N N
O IN N w I ~~ N
N
/ \ NH2
(8) 2-((R)-3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-[(naphtho[2,1-dJoxazol-2-
yl)methyl]-3,5-dihydro-imidazo[4,5-dJpyridazin-4-one
O
\ O~N N
\ N Nw I ~~N\ /
~N
NH2
(9) 2-((R)-3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-[(naphtho[1,2-d]oxazol-2-
yl )methyl]-3, 5-di hydro-i m idazo[4, 5-dJpyridazin-4-one

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N~N N
O
I ~ ~ O N w I ~~ N
N
NHz
(10) 2-((R)-3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-[(4-oxo-3,4-dihydro-
quinazolin-
2-yl)methyl]-3,5-dihydro-imidazo[4,5-djpyridazin-4-one
O
N~N N
NH N ~ I i~N
~--~N
O NHZ
,
the enantiomers, the mixtures thereof and the salts thereof.
According to the invention the compounds of general formula I are obtained by
methods known per se, for example by the following methods:
a) deprotecting a compound of general formula
~3
R1~ N /1 _N
I I ~~---R4~,
Y~ N
R2
(II),
wherein R', R2, Y and R3 are as hereinbefore defined and
R4" denotes one of the groups mentioned for R4 hereinbefore which contain an
imino,
amino or alkylamino group, while the imino, amino or alkylamino group is
substituted
by a protective group.
The liberating of an amino group from a protected precursor is a standard
reaction in
synthetic organic chemistry. There are many examples of suitable protective
groups.

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A summary of the chemistry of protective groups can be found in Theodora W.
Greene and Peter G. M. Wuts, Protective Groups in Organic Synthesis, Second
Edition, 1991, published by John Wiley and Sons, and in Philip J. Kocienski,
Protecting Groups, published by Georg Thieme, 1994.
5
The following are examples of protective groups:
the tert.-butyloxycarbonyl group which can be cleaved by treating with an acid
such
as for example trifluoroacetic acid or hydrochloric acid or by treating with
10 bromotrimethylsilane or iodotrimethylsilane, optionally using a solvent
such as
methylene chloride, ethyl acetate, dioxane, methanol, isopropanol or
diethylether at
temperatures between 0°C and 80°C,
the 2,2,2-trichloroethoxycarbonyl group which can be cleaved by treating with
metals
15 such as for example zinc or cadmium in a solvent such as acetic acid or a
mixture of
tetrahydrofuran and a weak aqueous acid at temperatures between 0°C and
the
boiling temperature of the solvent used and
the carbobenzyloxycarbonyl group which can be cleaved for example by
20 hydrogenolysis in the presence of a noble metal catalyst such as for
example
palladium-charcoal and a solvent such as for example alcohols, ethyl acetate,
dioxane, tetrahydrofuran or mixtures of these solvents at temperatures between
0°C
and the boiling point of the solvent, by treating with boron tribromide in
methylene
chloride at temperatures between -20°C and ambient temperature, or by
treating
25 with aluminium chloride/anisol at temperatures between 0°C and
ambient
temperature.
Moreover, the compounds of general formula I obtained may be resolved into
their
enantiomers and/or diastereomers, as mentioned hereinbefore. Thus, for
example,
30 cis/trans mixtures may be resolved into their cis and trans isomers, and
compounds
with at least one stereocentre may be separated into their enantiomers.
Thus, for example, the cis/trans mixtures obtained may be resolved by
chromatography into the cis and trans isomers thereof, the compounds of
general

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formula I obtained which occur as racemates may be separated by methods known
per se (cf. Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry",
Vol. 6, Wiley
Interscience, 1971 ) into their optical antipodes and compounds of general
formula I
with at least 2 asymmetric carbon atoms may be resolved into their
diastereomers on
the basis of their physical-chemical differences using methods known per se,
e.g. by
chromatography andlor fractional crystallisation, and, if these compounds are
obtained in racemic form, they may subsequently be resolved into the
enantiomers as
mentioned above.
The enantiomers are preferably separated by column separation on chiral phases
or
by recrystallisation from an optically active solvent or by reacting with an
optically
active substance which forms salts or derivatives such as e.g. esters or
amides with
the racemic compound, particularly acids and the activated derivatives or
alcohols
thereof, and separating the diastereomeric mixture of salts or derivatives
thus
obtained, e.g. on the basis of their differences in solubility, whilst the
free antipodes
may be released from the pure diastereomeric salts or derivatives by the
action of
suitable agents. Optically active acids in common use are e.g. the D- and L-
forms of
tartaric acid or dibenzoyltartaric acid, di-O-p-toluoyltartaric acid, malic
acid, mandelic
acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An
optically
active alcohol may be for example (+)- or (-)-menthol and an optically active
acyl
group in amides, for example, may be a (+)- or (-)-menthyloxycarbonyl.
Furthermore, the compounds of formula I obtained may be converted into the
salts
thereof, particularly for pharmaceutical use into the physiologically
acceptable salts
with inorganic or organic acids. Acids which may be used for this purpose
include for
example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic
acid,
phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid,
tartaric acid or
malefic acid.
Moreover, if the new compounds of formula I thus obtained contain a carboxy
group,
they may subsequently, if desired, be converted into the salts thereof with
inorganic
or organic bases, particularly for pharmaceutical use into the physiologically
acceptable salts thereof. Suitable bases for this purpose include for example
sodium

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hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine,
diethanolamine and triethanolamine.
The compounds of general formula II used as starting materials are either
known
from the literature or may be obtained by methods known from the literature
(cf.
Examples I to XVI).
As already mentioned hereinbefore, the compounds of general formula I
according to
the invention and the physiologically acceptable salts thereof have valuable
pharmacological properties, particularly an inhibiting effect on the enzyme
DPP-IV.
The biological properties of the new compounds were investigated as follows:
The ability of the substances and their corresponding salts to inhibit the DPP-
IV
activity can be demonstrated in a test set-up in which an extract of human
colon
carcinoma cell line Caco-2 is used as the DPP IV source. The differentiation
of the
cells in order to induce the DPP-IV expression was carried out as described by
Reiher et al. in an article entitled "Increased expression of intestinal cell
line Caco-2" ,
which appeared in Proc. Natl. Acad. Sci. Vol. 90, pages 5757-5761 (1993). The
cell
extract was obtained from cells solubilised in a buffer (10mM Tris HCI, 0.15 M
NaCI,
0.04 t.i.u. aprotinin, 0.5% Nonidet-P40, pH 8.0) by centrifuging at 35,000 g
for 30
minutes at 4°C (to remove cell debris).
The DPP-IV assay was carried out as follows:
50 NI substrate solution (AFC; AFC is amido-4-trifluoromethylcoumarin), final
concentration 100 NM, were placed in black microtitre plates. 20 NI of assay
buffer
(final concentrations 50 mM Tris HCI pH 7.8, 50 mM NaCI, 1 % DMSO) was
pipetted
in. The reaction was started by adding 30 NI of solubilised Caco-2 protein
(final
concentration 0.14 Ng of protein per well). The test substances to be
investigated
were typically added prediluted in 20 NI, and the volume of assay buffer was
then
reduced accordingly. The reaction was carried out at ambient temperature,
incubating for 60 minutes. Then the fluorescence was measured in a Victor 1420
Multilabel Counter, the excitation wavelength being 405 nm and the emission

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33
wavelength being 535 nm. Blank readings (corresponding to 0 % activity) were
obtained in mixtures without any Caco-2 protein (volume replaced by assay
buffer),
control values (corresponding to 100 % activity) were obtained in mixtures
with no
substance added. The potency of the test substances in question, expressed as
ICSo
values, was calculated from dosage/activity curves consisting of 11 measuring
points
in each case. The following results were obtained:
Compound DPP IV inhibition
(Example No.) ICSO [nM]
1 14
1(1) 17
1 (2) 58
1(3) 8
1(4) 9
1(7) 3
1(8) 7
1(9) 3
The compounds prepared according to the invention are well tolerated, as for
example when 10 mg/kg of the compound of Example 1 were administered to rats
by
oral route no changes in the animals' behaviour could be detected.
In view of their ability to inhibit DPP-IV activity, the compounds of general
formula I
according to the invention and the corresponding pharmaceutically acceptable
salts
thereof are suitable for treating all those conditions or illnesses which can
be
influenced by the inhibition of the DPP-IV activity. It is therefore to be
expected that
the compounds according to the invention will be suitable for the prevention
or
treatment of diseases or conditions such as type I and type II diabetes
mellitus,
diabetic complications, metabolic acidosis or ketosis, insulin resistance,
dyslipidaemias of various origins, arthritis, atherosclerosis and related
diseases,
obesity, allograft transplantation and calcitonin-induced osteoporosis. fn
addition
these substances are capable of preventing B-cell degeneration such as e.g.
apoptosis or necrosis of pancreatic B-cells. The substances are also suitable
for

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improving or restoring the function of pancreatic cells and also increasing
the number
and size of pancreatic B-cells. Additionally, and on the basis of the role of
the
Glucagon-Like Peptides, such as e.g. GLP-1 and GLP-2 and their link with DPP-
IV
inhibition, it is likely that the compounds according to the invention are
suitable for
achieving, inter alia, a sedative or anxiety-relieving effect and also of
favourably
affecting catabolic states after operations or hormonal stress responses or of
reducing mortality or morbidity after myocardial infarct. They are also
suitable for
treating all conditions which are connected with the above mentioned effects
and
which are mediated by GLP-1 or GLP-2. The compounds according to the invention
may also be used as diuretics or antihypertensives and are suitable for
preventing
and treating acute renal failure. They are also suitable for the prevention
and
treatment of chronic inflammatory intestinal diseases. It is also expected
that DPP-IV
inhibitors and hence also the compounds according to the invention may be used
to
treat infertility or to improve fertility in humans or mammals, particularly
when the
infertility is connected with insulin resistance or polycystic ovary syndrome.
The
substances are also suitable for treating deficiencies of growth hormone which
are
associated with reduced stature.
The compounds according to the invention may also be used in conjunction with
other active substances. Therapeutic agents which are suitable for such
combinations include, for example, antidiabetics, such as metformin,
sulphonylureas
(e.g. glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide,
thiazolidine-
dione (e.g. rosiglitazone, pioglitazone), PPAR-gamma agonists (e.g. GI
262570),
alpha-glucosidase inhibitors (e.g. acarbose, voglibose), alpha2 antagonists,
insulin
and insulin analogues, GLP-1 and GLP-1 analogues (e.g. exendin-4) or amylin.
Also,
inhibitors of protein tyrosine phosphatase 1, substances which influence
deregulated
glucose production in the liver, such as e.g. inhibitors of glucose-6-
phosphatase, or
fructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon receptor
antagonists and inhibitors of phosphoenol pyruvate carboxykinase, glycogen
synthase kinase or pyruvate dehydrokinase, lipid lowering agents, such as HMG-
CoA-reductase inhibitors (e.g. simvastatin, atorvastatin), fibrates (e.g.
bezafibrate,
fenofibrate), nicotinic acid and its derivatives, cholesterol absorption
inhibitors such
as for example ezetimibe, bile acid-binding substances such as for example
cholestyramine, HDL-raising compounds such as for example inhibitors of CETP
or

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regulators of ABC1 or active substances for the treatment of obesity, such as
e.g.
sibutramine or tetrahydrolipostatin, or f33-agonists such as SB-418790 or AD-
9677.
It is also possible to combine the compounds with drugs for treating high
blood
5 pressure such as e.g. All antagonists or ACE inhibitors, diuretics, (3-
blockers, etc., or
combinations thereof.
The dosage required to achieve such an effect is expediently, by intravenous
route, 1
to 100 mg, preferably 1 to 30 mg, and by oral route 1 to 1000 mg, preferably 1
to 100
10 mg, in each case 1 to 4 times a day. For this purpose, the compounds of
formula I
prepared according to the invention, optionally combined with other active
substances, may be incorporated together with one or more inert conventional
carriers and/or diluents, e.g. with corn starch, lactose, glucose,
microcrystalline
cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric
acid, water,
15 water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol,
propylene
glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such
as hard
fat or suitable mixtures thereof into conventional galenic preparations such
as plain
or coated tablets, capsules, powders, suspensions or suppositories.
The Examples that follow are intended to illustrate the invention:

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Preparation of the starting compounds:
36
Example I
2-[3-(tert.-butyloxycarbonylam ino)-piperidi n-1-yl]-3-(2-butyn-1-yl )-5-
[(dibenzo[b,t][1,4]-
oxazeain-11-vl)methyll-3,5-dihvdro-imidazof4,5-dlayridazin-4-one
317 mg 11-chloromethyl-dibenzo[b,f][1,4]oxazepin are added to 400 mg 2-[3-
(tert.-
butyloxycarbonylam ino)-pi peridin-1-yl]-3-(2-butyn-1-yl )-3, 5-d ihyd ro-i
midazo[4, 5-
dJpyridazin-4-one and 276 mg potassium carbonate in 4 ml N,N-
dimethylformamide.
The reaction mixture is stirred for two hours at 80°C. For working up
it is combined
with water and the precipitate formed is suction filtered. The crude product
is purified
by chromatography over a silica gel column with methylene chloride/methanol
(100:0
to 70:30) as eluant.
Yield: 120 mg (20 % of theory)
Mass spectrum (ESI+): m/z = 594 [M+H]+
The following compounds are obtained analogously to Example I:
(1 ) 2-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-3-(2-butyn-1-yl)-5-
[(phenan-
thrid in-6-yl )methyl]-3, 5-dihyd ro-i midazo[4, 5-dj pyridazin-4-one
(2) 2-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-3-(2-butyn-1-yl)-5-
[(phenanthren-
9-yl )methyl]-3, 5-d i hyd ro-im idazo[4,5-djpyridazin-4-one
(3) 2-[(R)-3-(tert.-butyloxycarbonylamino) -piperidin-1-yl]-3-(2-butyn-1-yl)-5-
[(phenan-
thridin-6-yl)methyl]-7-methyl-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one
Rf value: 0.41 (silica gel, cyclohexane/ethyl acetate = 3:7)
Mass spectrum (ESI+): m/z = 592 [M+H]+
(4) 2-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-3-(2-butyn-1-yl)-5-
[(dibenzo[b,t][1,4]oxazepin-11-yl)methyl]-7-methyl-3,5-dihydro-imidazo[4,5-
djpyridazin-4-one
Rf value: 0.50 (silica gel, cyclohexane/ethyl acetate = 2:8)
Mass spectrum (ESI+): m/z = 608 [M+H]+

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(5) 2-bromo-3-(2-butyn-1-yl)-5-[(dibenzo[b,f][1,4]oxazepin-11-yl)methyl]-3,5-
dihydro-
imidazo[4,5-djpyridazin-4-one
Mass spectrum (ESI+): m/z = 474, 476 [M+H]+
(6) 2-bromo-3-(2-butyn-1-yl)-5-[(naphtho[2,1-d]oxazol-2-yl)methyl]-3,5-dihydro-
imidazo[4,5-dJpyridazin-4-one
Rf value: 0.80 (silica gel, methylene chloride/ethanol = 9:1 )
(7) 2-bromo-3-(2-butyn-1-yl)-5-[(naphtho[1,2-d]oxazol-2-yl)methyl]-3,5-dihydro-
imidazo[4,5-dJpyridazin-4-one
Rf value: 0.50 (silica gel, methylene chloride/methanol = 19:1 )
(8) 2-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-3-(2-butyn-1-yl)-5-
cyano-
methyl-3,5-dihydro-imidazo[4,5-djpyridazin-4-one
Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate = 1:4)
Mass spectrum (ESI+): m/z = 426 [M+H]+
Example II
2-[3-(tert.-butyloxycarbonylami no)-piperidin-1-yl]-3-(2-butyn-1-yl )-3, 5-
dihydro-
imidazoj4 5-dlpyridazin-4-one
2.50 g 3-(tert.-butyloxycarbonylamino)-piperidine are added to 2.65 g 2-bromo-
3-(2-
butyn-1-yl)-3,5-dihydro-imidazo[4,5-c~pyridazin-4-one and 2.12 g sodium
carbonate
in 5 ml dimethylsulphoxide. The reaction mixture is stirred overnight at
85°C.
After cooling to ambient temperature it is combined with water and extracted
with
ethyl acetate. The combined organic phases are dried over magnesium carbonate
and evaporated down. The crude product is further reacted without any further
purification.
Mass spectrum (ESI+): m/z = 387 [M+H]+
The following compounds are obtained analogously to Example II:
(1 ) 2-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-3-(2-butyn-1-yl)-7-
methyl-
3,5-dihydro-imidazo[4,5-dJpyridazin-4-one
Rf value: 0.15 (silica gel, cyclohexane/ethyl acetate = 3:7)

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Mass spectrum (ESI+): m/z = 401 [M+H]+
38
(2) 2-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-3-(2-butyn-1-yl)-5-
[(dibenzo[b,t][1,4]oxazepin-11-yl)methyl]-3,5-dihydro-imidazo[4,5-dJpyridazin-
4-one
Mass spectrum (ESI+): m/z = 594 [M+H]+
(3) 2-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-3-(2-butyn-1-yl)-5-
[(dibenzo[b,t][1,4]oxazepin-11-yl)methyl]-3,5-dihydro-imidazo[4,5-djpyridazin-
4-one
Mass spectrum (ESI~): m/z = 594 [M+HJ+
(4) 2-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-3-(2-butyn-1-yl)-5-
[(naphtho[2,1-d]oxazol-2-yl)methyl]-3, 5-dihyd ro-imidazo[4, 5-dJpyridazin-4-
one
Rf value: 0.70 (silica gel, methylene chloride/ethanol = 9:1 )
(5) 2-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-ylJ-3-(2-butyn-1-yl)-5-
[(naphtho[1, 2-d]oxazol-2-yl )methyl]-3, 5-d ihyd ro-imidazo[4, 5-djpyridazi n-
4-one
Rf value: 0.65 (silica gel, methylene chloride/methanol = 9:1 )
Mass spectrum (ESI+): m/z = 568 [M+H]+
(6) 2-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-3-(2-butyn-1-yl)-
3,5-dihydro-
imidazo[4,5-dJpyridazin-4-one
Mass spectrum (ESI+): m/z = 387 [M+H]+
Rf value: 0.50 (silica gel, methylene chloride/ethanol = 9:1 )
Examale III
2-bromo-3-(2-butyn-1-yl)-3,5-dihydro-imidazof4.5-dlpyridazin-4-one
0.63 ml hydrazine hydrate are added dropwise to 3.68 g methyl 2-bromo-3-(2-
butyn-
1-yl)-5-formyl-3H-imidazole-4-carboxylate in 50 ml of ethanol. The reaction
mixture is
stirred for one hour at ambient temperature, then 3 ml acetic acid are added
and the
reaction mixture is refluxed for a further hour. The precipitate formed is
suction
filtered, washed with ethanol and diethyl ether and dried.
Yield: 2.65 g (77 % of theory)
Mass spectrum (ESI+): m/z = 267, 269 [M+H]+

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39
Example IV
methyl 2-bromo-3-l2-butyn-1-vl~ 5-formyl-3H-imidazole-4-carboxylate
45 ml diisobutylaluminium hydride solution (1M in toluene) are added dropwise
to
12.45 g dimethyl 2-bromo-3-(2-butyn-1-yl)-1H-imidazole-4,5-dicarboxylate in
150 ml
of tetrahydrofuran under an argon atmosphere at -65°C. The reaction
mixture is
stirred for two hours at -65°C, then another 9 ml diisobutylaluminium
hydride solution
are added. After another hour the reaction mixture is quenched at -65°C
with a
mixture of 1 M hydrochloric acid and tetrahydrofuran (1:1 ) and stirred for
ten minutes.
Then the cooling bath is removed, the reaction mixture is diluted with water
and
extracted with ethyl acetate. The combined organic phases are dried over
magnesium sulphate and evaporated down. The crude product is purified by
chromatography over a silica gel column with cyclohexane/ethyl acetate (2:1 to
1:1 ).
Yield: 9.58 g (85 % of theory)
Mass spectrum (ESI+): m/z = 285, 287 [M+H]+
The following compounds are obtained analogously to Example IV:
(1 ) methyl 2-bromo-3-(3-methyl-2-buten-1-yl)-5-formyl-3H-imidazole-4-
carboxylate
Mass spectrum (ESI+): m/z = 301, 303 [M+H]+
Example V
dimethvl 2-bromo-3-(2-butvn-1-yl)-1 H-imidazole-4.5-dicarboxylate
4.53 ml of 1-bromo-2-butyne are added to 13.20 g dimethyl 2-bromo-1H-imidazole-
4,5-dicarboxylate and 8.57 g potassium carbonate in 70 ml N,N-
dimethylformamide
and the reaction mixture is stirred overnight at ambient temperature.
For working up it is combined with water and extracted with ethyl acetate. The
combined organic phases are dried over magnesium sulphate and evaporated down.
Yield: 14.58 g (92 % of theory)
Mass spectrum (ESI+): m/z = 315, 317 [M+H]+
The following compounds are obtained analogously to Example V:
(1) dimethyl 2-bromo-3-(3-methyl-2-buten-1-yl)-1H-imidazole-4,5-dicarboxylate
Mass spectrum (ESI+): m/z = 331, 333 [M+H]+

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Example VI
Dimethyl 2-bromo-1 H-imidazole-4,5-dicarboxvlate
6.11 ml bromine are added to 19.80 g dimethyl 1 H imidazole-4,5-dicarboxylate
and
5 14.92 g potassium carbonate in 600 ml methylene chloride. The reaction
mixture is
stirred for one hour at ambient temperature, then a mixture of saturated
sodium
sulphite solution and saturated sodium chloride solution (1:1) is added. The
organic
phase is largely separated off and the aqueous phase is extracted with ethyl
acetate
several times. The combined organic phases are dried over magnesium sulphate
10 and evaporated down, leaving about 7.40 g crude product. The aqueous phase
is
combined with ethyl acetate and extracted overnight in an extraction
apparatus. The
ethyl acetate extract is evaporated down and the flask residue is combined
with the
crude product already obtained.
Yield: 13.10 g (46 % of theory)
15 Mass spectrum (ESI+): m/z = 263, 265 [M+H]+
Example VII
2-Bromo-3-(2-but~m1-yl -7-methyl-3.5-dihydro-imidazo[4.5-dlpyridazin-4-one
0.50 ml of 1-bromo-2-butyne are added to 1.30 g 2-bromo-7-methyl-3,5-dihydro-
20 imidazo[4,5-d]pyridazin-4-one and 0.99 ml Hunig base in 30 ml of N,N-
dimethylformamide. The reaction mixture is stirred for three hours at ambient
temperature. Then the solvent is distilled off in vacuo using the rotary
evaporator.
The flask residue is stirred with 40 ml of water and 0.5 ml concentrated
aqueous
ammonia solution, suction filtered and washed with ethanol as well as diethyl
ether.
25 Yield: 1.30 g (82 % of theory)
Rf value: 0.60 (silica gel, cyclohexane/ethyl acetate = 3:7)
Mass spectrum (ESI+): m/z = 281, 283 [M+H]+

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41
Example VIII
2-bromo-7-methyl-3,5-dihydro-imidazoj4.5-d]pyridazin-4-one
5.20 ml of a 1.8 M solution of bromine in acetonitrile are slowly added
dropwise to
1.40 g of 7-methyl-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one and 1.30 g
potassium
carbonate in 40 ml acetonitrile. Then the reaction mixture is heated to
70°C,
whereupon the mixture is rapidly decolourised. More bromine solution and
potassium
carbonate are added batchwise until the reaction has ended, according to HPLC-
MS.
For working up the reaction mixture is evaporated down, stirred with 100 ml of
water
and suction filtered. The filtrate is acidified with 1 M hydrochloric acid and
extracted
with ethyl acetate. The combined extracts are dried over sodium sulphate and
evaporated down.
Yield: 1.30 g (61 % of theory)
Rf value: 0.37 (silica gel, methylene chloride/methanol = 9:1 )
Mass spectrum (ESI+): m/z = 229, 231 [M+H]+
Example IX
7-methyl-3.5-dihydro-imidazof4.5-dlpyridazin-4-one
A solution of 4.00 g sodium nitrite in 15 ml of water is added dropwise at
50°C to
2.20 g of 4-amino-7-methyl-3H-imidazo[4,5-d]pyridazine in a mixture of 30 ml
acetic
acid, 5 ml of water and 0.5 ml concentrated sulphuric acid. The reaction
mixture is
stirred for a further two hours at 50°C and then heated to 90°C
for one hour. After
cooling to ambient temperature the reaction mixture is diluted with 30 ml of
water.
The precipitate formed is suction filtered, washed with water, ethanol and
diethyl
ether and dried.
Yield: 1.00 g (45 % of theory)
Mass spectrum (ESI+): m/z = 151 [M+H]+
Example X
4-amino-7-methyl-3H-imidazo~4.5-dJpyridazine
A mixture of 2.00 g 5-acetyl-3H-imidazole-4-carbonitrile and 4.00 ml hydrazine
hydrate in 50 ml of ethanol is heated to 100 °C, until the reaction is
complete
according to HPLC-MS. After cooling to ambient temperature the reaction
mixture is
evaporated down, stirred with 20 ml of cold ethanol and suction filtered. The
filter
cake is washed with diethyl ether and dried.

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Yield: 2.10 g (95 % of theory)
Mass spectrum (ESI+): m/z = 150 [M+H]+
42
Example XI
5-acetyl-3H-imidazole-4-carbonitrile
57 ml of a 3 M solution of methylmagnesium bromide in diethyl ether are added
to
7.00 g of 4,5-dicyano-imidazole in 80 ml of tetrahydrofuran under an argon
atmosphere, while the temperature is maintained between 5°C and
15°C.
After two hours the reaction is complete according to thin layer
chromatography and
the reaction mixture is diluted with 400 ml of ethyl acetate. Then 400 ml
saturated
ammonium chloride solution are slowly added. After ten minutes the mixture is
acidified with semiconcentrated sulphuric acid and stirred for another twenty
minutes
before the organic phase is separated off. The aqueous phase is extracted with
ethyl
acetate and the combined organic phases are dried over sodium sulphate and
evaporated down. The flask residue is stirred with ethyl acetate, suction
filtered and
washed with ethyl acetate and diethyl ether.
Yield: 3.30 g (43 % of theory)
Mass spectrum (ESI+): m/z = 136 [M+H]+
Example XII
2-chloromethyl-naphthol2 1-dloxazole
Prepared by reacting 2.93 g of 2-amino-1-naphthol with 3.54 g of 2-chloro-
1,1,1-
triethoxy-ethane in 25 ml of ethanol at 60°C.
Yield: 1.90 g (58 % of theory)
Rf value: 0.55 (silica gel, petroleum ether/ethyl acetate = 9:1 )
Mass spectrum (ESI+): m/z = 218, 220 [M+H]+
The following compounds are obtained analogously to Example XII:
(1 ) 2-chloromethyl-naphtho[1,2-dJoxazole
Rf value: 0.90 (silica gel, methylene chloride/methanol = 19:1 )
Mass spectrum (ESI+): m/z = 218, 220 [M+H]+

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Example XIII
2-bromo-3-( 3-methyl-2-buten-1-yl)-3, 5-dihydro-imidazof 4.5-clpyridin-4-one
1.55 g Burgess reagent (methoxycarbonylsulphamoyl-triethylammonium-N-betaine)
are added to 1.60 g of 2-bromo-7-hydroxy-3-(3-methyl-2-buten-1-yl)-3,5,6,7-
tetrahydro-imidazo[4,5-c]pyridin-4-one in 20 ml methylene chloride and 4 ml of
tetrahydrofuran. The reaction mixture is stirred for eight hours at
60°C, then another
0.3 equivalents Burgess reagent is added. After a further two hours the cooled
reaction mixture is combined with aqueous sodium hydrogen carbonate solution
and
extracted with ethyl acetate. The combined organic phases are dried over
magnesium sulphate and evaporated down. The flask residue is chromatographed
through a silica gel column with methylene chloride/methanol (1:0 to 10:1) as
eluant.
Yield: 1.06 g (60 % of theory)
Mass spectrum (ESI+): m/z = 282, 284 [M+H]+
Example XIV
2-bromo-7-hydrox ~-L313-methyl-2-buten-1-yl~ 3,5.6,7-tetrahydro-imidaz~4,5-
,p~rridin-4-one
90 ml of water and 5.40 g iron powder are added to 4.15 g methyl 2-bromo-5-(1-
hydroxy-2-nitro-ethyl)-3-(3-methyl-2-buten-1-yl)-3H-imidazole-4-carboxylate in
270 ml
of ethanol. The mixture is refluxed, combined with 36 ml glacial acetic acid
and
stirred for one and a half hours at reflux temperature. The cooled reaction
solution is
filtered through Celite. The filtrate is evaporated down, combined with
ethanol and
made basic with solid potassium carbonate. The mixture is stirred for three
hours at
60°C. Then the ethanol is distilled off, the flask residue is combined
with water and
extracted with ethyl acetate. The combined extracts are dried over magnesium
sulphate and evaporated down. The crude product is purified by chromatography
over a silica gel column with methylene chloridelmethanol (1:1 to 7:1) as
eluant.
Yield: 1.62 g (47 % of theory)
Mass spectrum (ESI+): m/z = 300, 302 [M+H]+

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Example XV
44
Methyl 2-bromo-5-( 1-hyd roxy-2-nitro-ethyl)-3-(3-methyl-2-buten-1-yl)-3H-
imidazole-4-
carboxvlate
35 ml nitromethane are added to 1.14 g caesium carbonate in 15 ml of methanol
at
ambient temperature. Then the mixture is combined with a solution of 3.50 g
methyl
2-bromo-3-(3-methyl-2-buten-1-yl)-5-formyl-3H-imidazole-4-carboxylate in 20 ml
of
methanol and 5 ml methylene chloride and stirred for 15 minutes at ambient
temperature. Then 0.5 ml acetic acid are added and the solution is evaporated
down
in vacuo. The flask residue is combined with aqueous sodium hydrogen carbonate
solution and extracted with ethyl acetate. The combined organic phases are
dried
over magnesium sulphate and evaporated down.
Yield: 4.15 g (99 % of theory)
Mass spectrum (ESI+): m/z = 362, 364 [M+H]+
Example XVI
2-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-3-(2-butyn-1-yl )-5-[(4-
oxo-3, 4-
dihvdro-auinazolin-2-yl)methyll-3 5-dihvdro-imidazof4 5-dlpyridazin-4-one
40 mg sodium methoxide (95 %) are added to a solution of 605 mg 2-[(R)-3-
(tert.-
butyloxycarbonylamino)-pi peridi n-1-yl]-3-(2-butyn-1-yl )-5-cyanomethyl-3, 5-
d ihyd ro-
imidazo[4,5-dJpyridazin-4-one in 9 ml of methanol. The mixture is stirred for
one hour
at ambient temperature and then neutralised with 41 pL glacial acetic acid.
Then a
solution of 195 mg anthranilic acid in 2 ml of methanol is added and the
reaction
mixture is heated to 70°C. After about two hours a white, voluminous
precipitate is
formed and the reaction mixture is cooled to ambient temperature. The
precipitate
formed is suction filtered, washed with cold methanol and dried.
Yield: 234 mg (30 % of theory)
Mass spectrum (ESI+): m/z = 545 [M+H]+

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Preparation of the final compounds:
Example 1
0
' N
i N'
G N Nw I N ~~
NHZ
5 2-(3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-[(dibenzo[b,tj[1,4]oxazepin-11-
yl)methyl]-
3 5-dih dro-imidazo 4 5- ridazin-4-one
0.33 ml trifluoroacetic acid are added to 120 mg 2-[3-(tert.-
butyloxycarbonylamino)-
pi peridin-1-yl]-3-(2-butyn-1-yl )-5-[(di benzo[b, t] [1,4]oxazepin-11-yl
)methyl]-3, 5-
dihydro-imidazo[4,5-dJpyridazin-4-one in 3 ml methylene chloride while cooling
with
10 an ice bath. The reaction mixture is stirred overnight at ambient
temperature.
For working up it is poured onto cooled saturated potassium carbonate solution
and
extracted with methylene chloride. The organic phase is separated off and
evaporated down. The crude product is purified by chromatography over a silica
gel
column with methylene chloride/methanol (100:0 to 70:30) as eluant.
15 Yield: 63 mg (63 % of theory)
Mass spectrum (ESI+): m/z = 494 [M+H]+
The following compounds are obtained analogously to Example 1:
20 (1) 2-(3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-[(phenanthridin-6-
yl)methyl]-3,5-
dihydro-imidazo[4,5-d]pyridazin-4-one
O
w N N
I
~N Nw ~ N N
NHZ
Mass spectrum (ESI+): m/z = 478 [M+H]+

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46
(2) 2-(3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-[(phenanthren-9-yl)methyl)-
3,5-
dihydro-imidazo[4,5-dJpyridazin-4-one
0
N
_N ,. I /~--N
N
/ NHz
Mass spectrum (ESI+): m/z = 477 [M+H]+
(3) 2-((R)-3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-[(phenanthridin-6-
yl)methyl]-7-
methyl-3,5-dihydro-imidazo[4,5-c~pyridazin-4-one x trifluoroacetic acid
0
~ il' N I N~-N
N N~N
I / NHZ x CF3COOH
Rf value: 0.45 (Reversed phase ready-made TLC plate (E. Merck),
acetonitrile/water/
trifluoroacetic acid = 50:50:0.1 )
Mass spectrum (ESI+): m/z = 492 [M+H]+
(4) 2-((R)-3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-
[(dibenzo[b,t][1,4]oxazepin-11-
yl)methyl]-7-methyl-3, 5-dihydro-imidazo[4, 5-dJpyridazin-4-one
0
N N
O 1N N w I ~~ N
~N
NHZ
Carried out with isopropanolic hydrochloric acid (5-6 M) in methylene
chloride.
Mass spectrum (ESI+): m/z = 508 [M+H]+

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47
(5) 2-((S)-3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-
[(dibenzo[b,tj[1,4]oxazepin-11-
yl)methyl]-3,5-dihydro-imidazo[4,5-dJpyridazin-4-one
O
I
N N
0 ,N N ~ I ~~ N
N
/ \ ~NHz
Mass spectrum (ESI+): m/z = 494 [M+H]+
(6) 2-((R)-3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-
[(dibenzo[b,f][1,4]oxazepin-11-
yl)methyl]-3,5-dihydro-imidazo[4,5-dJpyridazin-4-one
0
N N
0 1N N w I ~~ N
N
/ \ NH2
Mass spectrum (ESI+): m/z = 494 [M+H]+
(7) 2-((R)-3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-[(naphtho[2,1-dJoxazol-2-
yl)methyl]-3,5-dihydro-imidazo[4,5-dJpyridazin-4-one
0
\ G~N I N~N
\ N N~ N
N Hz
Rf value: 0.40 (silica gel, methylene chloride/ethanol/conc. aqueous ammonia =
90:10:2)
Mass spectrum (ESI+): m/z = 468 [M+H]+
(8) 2-((R)-3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-[(naphtho[1,2-d]oxazol-2-
yl )methyl]-3, 5-di hydro-i midazo[4, 5-c~pyridazin-4-one
0
N~ N
\ O N~ N
NHz

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Mass spectrum (ESI+): m/z = 468 [M+H]+
48
(9) 2-((R)-3-amino-piperidin-1-yl)-3-(2-butyn-1-yl)-5-[(4-oxo-3,4-dihydro-
quinazolin-2-
yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one
o
i N~N N
NH N ~ I ~~N~
'N
p NHz
Mass spectrum (ESI+): m/z = 445 [M+H]+
The following compounds may also be obtained analogously to the foregoing
Examples and other methods known from the literature:
No. Name Structural formula
2-(3-amino-piperidin-1-yl)-3-(2-buten-1-
0
(1) yl)-5-[(3,4-dihydro-quinolin-2-yl)methyl]- I N N
6,7-dimethyl-3,5-dihydro-imidazo[4,5- ~ N ~ N
~~-N
c]pyridin-4-one ~ ~ ~ NHZ
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- N o
(2) yl)-5-[(3,4-dihydro-isoquinolin-1- ~ \ ~N I N
N
yl)methyl]-7-cyclopropyl-3,5-dihydro- N ~ ~--(N
NHZ
imidazo[4,5-dJpyridazin-4-one
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- N o
( ) yl)-5-[(3,3-dimethyl-3,4-dihydro- ~ N
3 ~N
isoquinolin-1-yl)methyl]-3,5-dihydro- - N ~ I i~-N
~-.~N
im idazo[4, 5-dJpyridazin-4-one NHz
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- N O
( ) yl)-5-[(4,4-dimethyl-3,4-dihydro- ~ N N
4 ~ i~ N
isoquinolin-1-yl)methyl]-3,5-dihydro- ~ ~ N ~ N
imidazo[4,5-dJpyridazin-4-one NHz

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49
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- ~ o
( ) yl)-5-[(1-methyl-1,4-dihydro-quinazolin-2- / ~ N N
yl)methyl]-3,5-dihydro-imidazo[4,5- N N ~ ~ ~ N
~N
d]pyridazin-4-one NHz
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- ~ o
( ) yl)-5-[(1-methyl-4-oxo-1,4-dihydro- / ~ N N
6
quinazolin-2-yl)methyl]-3,5-dihydro- N N ~ ~ ~ N
~N
imidazo[4,5-dJpyridazin-4-one ~ NHz
2-(3-amino-piperidin-1-yl}-3-(2-buten-1- F I o
yl)-5-[(5,6,7,8-tetrafluoro-1-methyl-1,4- F ~ N
N
(7) dihydro-quinazolin-2-yl)methyl]-3,5- F ~ ~ ~ ~ ~ ~~--N~
N
dihydro-imidazo[4,5-c]pyridin-4-one F NHZ
2-(3-amino-piperidin-1-yl)-3-(2-buten-1- \ N o
(8) yl)-5-[(3,4-dihydro-quinazolin-2-yl)methyl]- / ~ NH N I N N
3,5-dihydro-imidazo[4,5-dJpyridazin-4-one N~N
NH2
2-(3-amino-piperidin-1-yl )-3-(2-butyn-1- o
(9) yl)-5-[(3-methyl-3,4-dihydro-quinazolin-2- I ~ N~ N
N
yl)methyl]-3,5-dihydro-imidazo[4,5- ~N~ N ~ ~ ~~N
~N
d]pyridazin-4-one NHZ
2-(3-amino-piperidin-1-yl )-3-(2-butyn-1- o
yl)-5-[(3-methyl-3,4-dihydro-quinazolin-2- ~ N~ N
N
(10) I meth I -3,5-dih dro-imidazo 4,5- ~ I ~ w ~ ~ N
Y ) Y ] Y [ w ~N
c]pyridin-4-one NH2
2-(3-ami no-piperidi n-1-yl )-3-( 1-buten-1-
(11) yl)-5-[(1H-benzo[dJ[1,2]oxazin-4- o-N N o
' N
yl)methyl]-3,5-dlhydro-imidazo[4,5- / \ N \ ~ i~-N
d]pyridazin-4-one N ~---(NHZ
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- o_N o
(12) yl)-5-[(1-oxo-1H-benzo[d][1,2]oxazin-4- o ~ N
yl)methyl]-3,5-dihydro-imidazo[4,5- / \ N ~ ~ i~--N
~--(N
dJpyridazin-4-one NH2

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2-( 3-ami no-piperidi n-1-yl )-3-(2-butyn-1- p
yl)-5-[(4H-benzo[e][1,3]oxazin-2- ~~N N N
(13) yl)methyl]-3,5-dihydro-imidazo[4,5- II '~ N N ~ I N~
d]pyridazin-4-one NH2
2-(3-amino-piperidin-1-yl )-3-(2-buten-1- o
(14) yl)-5 ((4,4-dimethyl-4H- I w o~ ~ N\
N~ i~N
benzo[a][1,3]oxazin-2-yl)methyl]-3,5- ~ N N
N
dihydro-imidazo[4, 5-dJpyridazin-4-one N HZ
2-( 3-amino-piperidi n-1-yl )-3-(2-butyn-1- p
(15) yl) 5 [(4-oxo-4H-benzo[e][1,3]oxazin-2- I ~ o~N I NON
I
yl)methyl]-3,5-dihydro-imidazo[4,5- ~ N N ~ N
d]pyridazin-4-one o NH2
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- \ N o
f
(16) yl)-5 ((4H-benzo[d][1,3]oxazin-2- ~ ~ ~N ~ ~-N
yl)methyl]-3,5-dihydro-imidazo[4,5- ~ N
d]pyridazin-4-one NH2
2-(3-amino-piperidin-1-yl )-3-(2-butyn-1- o
17 yl)-5 ((4H-benzo[d][1,3]oxazin-2- ~~N N
( ) yl)methyl]-7-methyl-3,5-dihydro- ~w\ ~~o ~ I N>-N
imidazo[4,5-c]pyridin-4-one NHz
2-(3-ami no-piperidi n-1-yl )-3-(2-butyn-1- o
(19) yl)-5-((4,4-dimethyl-4H- I \ N~N ~ N>-N
benzo[d][1,3]oxazin-2-yl)methyl]-3,5- ~ o N ~ N
dihydro-imidazo[4,5-dJpyridazin-4-one NHZ
2-(3-amino-piperidi n-1-yl )-3-(2-butyn-1- o
20 yl) 5 [(4-oxo-4H-benzo[dj[1,3]oxazin-2- I ~ N~N N N
( ) yl)methyl]-3,5-dihydro-imidazo[4,5- ~ o N ~ I N
dJpyridazin-4-one o NHZ
2-(3-amino-piperidi n-1-yl )-3-(2-butyn-1- o
(21 ) yl)-5-[(2H-benzo[1,4]oxazin-3-yl)methyl]- ~ j N~N \ ~ N~.-N
N
3,5-dihydro-imidazo[4,5-dJpyridazin-4-one o NH
z

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51
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- o 0
22 yl)-5-[(2-oxo-2H-benzo[1,4]oxazin-3- o~N ~ N
( ) yl)methyl]-3,5-dihydro-imidazo[4,5- / N N~N~ ~---
d]pyridazin-4-one ~ I NH2
2-( 3-a m i no-pi perid i n-1-yl )-3-( 2-butyn-1- o
yl)-5-[(2,2-dimethyl-2H-benzo[1,4]oxazin- o~N N
(23) N N ~ ~ i~N
3-yl)methyl]-3,5-dihydro-imidazo[4,5- ~ ' NN
dJpyridazin-4-one ~ NHZ
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- ~ g~ o
(24) yl)-5-[4H-benzo[e][1,3]thiazin-2-yl)methyl]- ~ ~ IN N \ ~ N)--N
~N
3,5-dihydro-imidazo[4,5-dJpyridazin-4-one NHz
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- o
25 yl)-5-[4,4-dimethyl-4H- ~ SAN N
( ) benzo[a][1,3]thiazin-2-yl)methyl]-3,5- ~ i N N~ ~ N~N
dihydro-imidazo[4,5-dJpyridazin-4-one ~ ~--~NHZ
2-( 3-a m i no-piperid i n-1-yl )-3-(2-butyn-1- o
(26) yl)-5-[4-oxo-4H-benzo[e][1,3]thiazin-2- I ~ S~N ~ NON
yl)methyl]-3,5-dihydro-imidazoj4,5- ~ N N ~ N
dJpyridazin-4-one O NH2
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- o
I -5 4H-benzo 1,3 thiazin-2-
27 y ) -[( [~lj ] W N~N N
( ) yl)methyl]-3,5-dihydro-imidazo[4,5- ~ i S N ~ ~ N N
dJpyridazin-4-one NHZ
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- o
N
(28) yl)-5-[(2H-benzo[1,4]thiazin-3-yl)methyl]- ~ ~ ~N \ ~ NON
N
3,5-dihydro-imidazo[4,5-dJpyridazin-4-one
NHZ
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- o
-N O
(29) yl)-5-[(2-oxo-2H-benzo[e][1,3]oxazin-4- o ~ N N
~ ~ i~ N
yl)methyl]-3,5-dihydro-imidazo[4,5- / \ N
N
d]pyridazin-4-one NHZ

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52
2-(3-am i no-piperid i n-1-yl )-3-(2-butyn-1-
yl)-5-[(1-methyl-2,2-dioxo-1H- NS \ o
' N
(30) benzo[c][1,2]thiazin-4-yl)methyl]-3,5- / \ N \ I N~-'N
dihydro-imidazo[4,5-d]pyridazin-4-one ~---~NH2
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- I ~ o
yl)-5-[(2,3-dihydro-1H- ~ N N
31
( ) benzo[e][1,4]diazepin-5-yl)methyl]-3,5- HN~N N~ ~ ~N
N
dihydro-imidazo[4,5-d]pyridazin-4-one NH2
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- I ~ p
32 yl)-5-[(2-oxo-2,3-dihydro-1H-benzo[e][1,4] ~ 1 N N
( ) HN N N w l ~~N~
diazepin-5-yl)methyl]-3,5-dihydro- \N
imidazo[4,5-dJpyridazin-4-one o NH2
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- I ~ o
33 yl)-5-[(1-methyl-2,3-dihydro-1H- i N N
( ) benzo[e][1,4]diazepin-5-yl)methyl]-3,5- -NON N ~. ~ N~'N
dihydro-imidazo[4,5-djpyridazin-4-one ~--~NHa
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- I ~ p
34 yl) 5 [(1-methyl-2-oxo-2,3-dihydro-1H- ~ , N N
( ) benzo[e][1,4]diazepin-5-yl)methyl]-3,5- -N N N ~ ~ N N.
dihydro-imidazo[4,5-djpyridazin-4-one O ~--(NHz
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- p
(35) yl) 5 [(4-oxo-4,5-dihydro-3H- ~ ~ N~ N I N N
benzo[b][1,4)diazepin-2-yl)methyl]-3,5- ~ N ~ N
NH
dihydro-imidazo[4,5-dJpyridazin-4-one H p z
2-(3-am i no-piperidi n-1-yl )-3-(2-butyn-1- p
(36) yl)-5-[(5-methyl-4-oxo-4,5-dihydro-3H- \ / N~ N I N N
benzo[b][1,4]diazepin-2-yl)methyl]-3,5- N N ~ N
dihydro-imidazo[4,5-dJpyridazin-4-one ~ o NH2

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5a
2-(3-amino-piperidi n-1-yl )-3-(2-butyn-1- o
yl)-5-[5-oxo-4,5-dihydro-3H- ~ N~ N N
(37) benzo[e][1,4]diazepin-2-yl)methyl]-3,5- \ / ~N ~ I NON
H NH2
dihydro-imidazo[4,5-d]pyridazin-4-one o
2-(3-am i no-piperidi n-1-yl )-3-(2-butyn-1- o
3$ yl)-5-[4-methyl-5-oxo-4,5-dihydro-3H- ~ N~ N N
I
( ) benzo[e][1,4]diazepin-2-yl)methyl]-3,5- \ / ~N ~ I NON
dihydro-imidazo[4,5-dJpyridazin-4-one p \ NH2
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1-
~N O
(39) yl)-5-[(2,3-dihydro-benzo[t][1,4]oxazepin- o ~ N N
5-yl)methyl]-3,5-dihydro-imidazo[4,5- ' / N ~ ~ ~~N~
\N
d]pyridazin-4-one \ NH2
2-(3-ami no-piperid i n-1-yl )-3-(2-butyn-1-
(40) yl)-5-[(3,3-dimethyl-2,3-dihydro- o N N o
N
benzo[f][1,4]oxazepin-5-yl)methyl]-3,5- - N \ ~ ~~-N
\ / NN
dihydro-imidazo[4,5-c~pyridazin-4-one NHz
2-(3-ami no-piperid i n-1-yl )-3-(2-butyn-1-
yl)-5-[(2,2-dimethyl-2,3-dihydro- ~N O
N
(41 ) benzo[t][1,4]oxazepin-5-yl)methyl]-7- o 'N ~ ,~N
r I
methyl-3,5-dihydro-imidazo[4,5- \ / N ~ N
NH2
dJpyridazin-4-one
2-(3-amino-piperidi n-1-yl )-3-(2-butyn-1- o
(42) YI)-5-[(2,3-dihydro-benzo[b][1,4]oxazepin- ~ N~ N N
4-yl)methyl]-7-methyl-3,5-dihydro- \ ~ N ~ ~ ~N
~N
imidazo[4,5-dJpyridazin-4-one o NHz
2-(3-amino-piperidi n-1-yl )-3-(2-butyn-1-
yl )-5-[(6, 6-di methyl-2, 3-di hyd ro- o
43 benzo b 1 4 oxaze in-4- I meth I -7- ' N~ N N
( ) [ ][ , ] p Y) Y] \ ~ N\ ~ ~~-N
- \ N
methyl-3,5-dihydro imidazo[4,5- O NH2
d]pyridazin-4-one

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54
2-(3-am i no-piperidi n-1-yl )-3-(2-butyn-1- o
44 yl)-5 [(2,3-dihydro-benzo[b][1,4]thiazepin- ~ N~ N N
( ) 4-yl)methyl]-7-methyl-3,5-dihydro- ~ / N ~ ~ ~ N
~N
imidazo[4,5-dJpyridazin-4-one S NHZ
2-(3-amino-piperidi n-1-yl )-3-(2-butyn-1-
yl )-5-[(2, 2-d imethyl-2, 3-di hyd ro- o
' N N N
(45) benzo[b][1,4]thiazepin-4-yl)methyl]-7- ~ / ~ ~ ~ ,~-N
N~N
methyl-3, 5-di hyd ro-i m idazo[4, 5- S NHZ
dJpyridazin-4-one
2-(3-am i no-piperidin-1-yl )-3-(2-butyn-1-
/ o
(46) yl) 5 [(2,3-dihydro-benzo[t][1,4]thiazepin- ~ N N
5-yl)methyl]-7-methyl-3,5-dihydro- SAN N ~ ~ NON
imidazo[4,5-dJpyridazin-4-one ~---(NH2
2-( 3-amino-piperidi n-1-yl )-3-(2-butyn-1-
yl )-5-[(5-oxo-4, 5-d i hyd ro- _ o
O~ N
(47) benzo[tj[1,3,4]oxadiazepin-2-yl)methyl]-7- \ / II N ~ ~~-N
,N N w N
methyl-3, 5-dihyd ro-i midazo(4, 5 N
O H NH2
d]pyridazin-4-one
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- / ~ o
4$ yl)-5-[(11H-dibenzo[b,e]azepin-6- ~ I N N
I
( ) yl)methyl]-7-ethyl-3,5-dihydro- N N ~ ~ N N
imidazo[4,5-dJpyridazin-4-one \ / NH2
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- / ~ o
(49) yl)-5-[(11H-dibenzo[b,e]azepin-6- ~~N ~ N~-N
yl)methyl]-7-cyanomethyl-3,5-dihydro- N N ~ N
imidazo[4,5-djpyridazin-4-one \ / ~~ NH2
N
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- / \
_ o
(50) yl) 5 [(11,11-difluoro-11H-dibenzo- FF ~ N N
[b,e]azepin-6-yl)methyl]-3,5-dihydro- , N ~ N
Y\~~~N
imidazo[4,5-c]pyridin-4-one \ / NHZ

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\ O
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- ~ N
-N
(51 ) yl) 5 [(11-oxo-11 H-dibenzo[b,e]azepin-6- o N N ~ I N~N
yl)methyl]-7-(2-cyanoethyl)-3,5-dihydro- \ / NH2
im idazo[4, 5-dJ pyridazi n-4-one
II
N
2-(3-amino-piperidin-1-yl)-3-(1-buten-1- ~ \ o
(52) yl)-5-[(11H-benzo[e]pyrido(3,2-b]azepin-6- ~ I N N
yl)methyl]-7-methyl-3,5-dihydro-imidazo- _~ N ~ N
~~-N
[4,5-d]pyridazin-4-one N NHZ
2-(3-amino-piperidin-1-yl-(2-butyn-1-yl)-5- / ~~N o
(53) ((5H-1,9,10-triaza-dibenzo[a,dJcyclo- I I N N
i~ N
hepten-11-yl)methyl]-3,5-dihydro- ~ N ~ N
imidazo[4,5-c]pyridin-4-one \ , N NHZ
2-(3-amino-piperidin-1-yl)-3-(2-buten-1- ~ ~ p
(54) yl)-5 ((5-methyl-5H-dibenzo[b,e][1,4]- ~ ~ N I N~N
diazepin-11-yl)methyl]-7-methyl-3,5- -N N N~N
dihydro-imidazo[4,5-djpyridazin-4-one \ ~ NHz
2-(3-amino-piperidin-1-yl)-3-(1-buten-1- / \ o
(55) yl)-5-[(dibenzo[b,f][1,4]oxazepin-11- o - I N N
yl)methyl]-3,5-dihydro-imidazo[4,5- N ~ I ~~N~
N
c]pyridin-4-one ~ NHz
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- ~ ~ o
N
(56) yl)-5-[(dibenzo[b,t][1,4]thiazepin-11- ~ ~ N I ,~--N
N N~N
yl )methyl]-7-methyl-3, 5-dihyd ro- _
N H2
imidazo[4,5-dJpyridazin-4-one \

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2-(3-amino-piperidin-1-yl)-3-(1-buten-1- / \ o
(57) yl) 5 [(dibenzo(b,t][1,4]thiazepin-11- S ~ I N N
yl)methyl]-3,5-dihydro-imidazo[4,5- N ~ I N~-N
c]pyridin-4-one \ / NH2
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- ~ ~ O
yl)-5-[(5-oxo-dibenzo[b,f][1,4]thiazepin-11- ~ N N
58 0 ~ ' ~ ~~-N
( ) yl)methyl]-7-methyl-3,5-dihydro- =S N N ~ N
NHZ
imidazo[4,5-dJpyridazin-4-one \ /
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- ~ ~ o
yl)-5-[(5,5-dioxo-dibenzo[b,tj[1,4]- ~ N N
(59) thiazepin-11-yl)methyl]-7-methyl-3,5- o .S ~N N ~ ~ ~~N~
O - ,N
N Hz
dihydro-imidazo[4,5-dJpyridazin-4-one \ /
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- ~ ~ O
(60) yl)-5-[(5H-dibenzo[a,dJcyclohepten-10- ' 1 N ~ N
N~ i N
yl)methyl]-7-methyl-3,5-dihydro- N
NHZ
imidazo[4,5-dJpyridazin-4-one \ /
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- ~ ~ o
61 yl) 5 [(5-methyl-5H-dibenzo[b,t]azepin-10- ~ 1 N ~ N N
'
( ) yl)methyl]-7-trifluoromethyl-3,5-dihydro- ~N N ~ N
NHz
imidazo[4,5-dJpyridazin-4-one \ / F F F
2-( 3-amino-piperidi n-1-yl )-3-(3-methyl-2-
I
(62) buten-1-yl)-5-[(phenanthridin-6-yl)methyl]- I ~ ~N o /
7-methyl-3,5-dihydro-imidazo[4,5- N N
dJpyridazin-4-one Iv ~ ~ ~~N~
'N
NH2

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I~
2-(3-amino-piperidi n-1-yl )-3-(2-buten-1-
(63) YI)-5-[(phenanthridin-6-yl)methyl]-7- I ~ ~ N o /
meth I-3 5-dih dro-i
y , y midazo[4,5- N N
dJpyridazin-4-one N ~ I i~--N'
~N
NH2
I~
2-(3-am i no-piperidin-1-yl )-3-( 1-buten-1-
I T
(64) YI)-5-[(phenanthridin-6-yl)methyl]-7- ~ 'N o
methyl-3,5-dihydro-imidazo[4,5- N N
dJpyridazin-4-one N ~ I ~~N~
'---(N
NHz
2-(3-amino-piperidin-1-yl)-3-[(1- ~ I i
(65) cyclopenten-1-yl)methyl]-5- I / ~nl o /
[(phenanthridin-6-yl)methyl]-7-meth I-3 5-
Y ~ N N
dihydro-imidazo[4,5-d]pyridazin-4-one N ~ ~ ~~N~
'N
N H2
2-(3-amino-piperidin-1-yl)-3-(1-buten-1- o
(66) yl)-5-[(phenanthridin-6-yl)methyl]-3,5- I ~ N~ N I N~--N
dihydro-imidazo[4,5-c]pyridin-4-one ~ v 'N
NHz
2-(3-amino-piperidi n-1-yl )-3-(2-butyn-1-
0
yl)-5-[(benzo[c][1,5]naphthyridin-6- I
(67) yl)methyl]-7-cyclopropyl-3,5-dihydro- I ~ N \ I ~~-N
N~ _N
imidazo[4,5-dJpyridazin-4-one ~ NHZ
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- I ~ o
(6$) yl)-5-[(benzo[h][1,6]naphthyridin-5- N ~ N N
yl)methyl]-3,5-dihydro-imidazo[4,5- I ~ N N~N N
d]pyridazin-4-one I / ~--~NHZ

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2-(3-amino-piperidi n-1-yl )-3-(2-butyn-1- p
(69) yl)-5-[(benzo[c][1,8]naphthyridin-6- N I N' N I N~N
yl)methyl]-3,5-dihydro-imidazo[4,5- ~ i N ~ N
dJpyridazin-4-one ~ I NH2
2-( 3-amino-piperidi n-1-yl )-3-(2-butyn-1- p
(70) yl)-5-[(5-benzo[t][1,7]naphthyridin-5- ~ ~ N' N I NON
yl)methyl]-3,5-dihydro-imidazo[4,5- ~ 'N ~N
c]pyridin-4-one I ~ NHZ
2-(3-amino-piperidi n-1-yl )-3-(2-butyn-1- p
( ) yl)-5-[(1,5,9-triaza-phenanthren-10- ~ ~ N' N I NON
71
yl)methyl]-3,5-dihydro-imidazo[4,5- N~ 'N ~N
c]pyridin-4-one I ~ NH2
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- p
(72) yl)-5-[(1,2,3,4-tetrahydrophenanthridin-6- I N' N ( NON
yl)methyl]-3,5-dihydro-imidazo[4,5- w
NH2
c]pyridin-4-one
2-(3-ami no-piperid i n-1-yl )-3-(2-butyn-1- p
(73) yl)-5-[(1,2,3,4,4a,10b-hexahydro- N' N ( NON
phenanthridin-6-yl)methyl]-3,5-dihydro- ~ ~N
NHZ
imidazo[4,5-c]pyridin-4-one
2-( 3-ami no-piperidin-1-yl )-3-(2-butyn-1- p
(74) yl) 5 ((2,3-dihydro-1H-4-aza- ~ N' N I NON
cyclopenta[a]naphth-5-yl)methyl]-3,5- I ~ ~ N
NH2
dihyd ro-i midazo(4, 5-c]pyrid i n-4-one
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- p
(75) yl)-5-[(8,9,10,11-tetrahydro-7H-6-aza- I N' N I NON
cyclohepta[a]naphth-5-yl )methyl]-3, 5- w
NHZ
dihydro-imidazo[4,5-c]pyridin-4-one

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2-( 3-amino-pi peridi n-1-yl )-3-(2-butyn-1- o
(76) yl)-5 [(2,3-dihydro-1H-4-oxa-10-aza- I N' N I NON
phenanthren-9-yl)methyl]-3,5-dihydro- o
imidazo[4,5-c]pyridin-4-one I ~ NH2
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- o 0
(77) yl)-5 [(1-oxo-2,3-dihydro-1H-4-oxa-10- I N' N I N
N
aza-phenanthren-9-yl)methyl]-3,5- o ~ ~N
dihydro-imidazo[4,5-c]pyridin-4-one I ~ NH2
N
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- I i o
(78) yl)-5-[(10-cyanophenanthren-9-yl)methyl]- ~ ~ ~ N N
N~ N
3, 5-di hydro-i midazo[4, 5-c] pynd in-4-one
NHZ
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- ~ \ o '
(79) yl)-5-[(benzo[h]quinolin-6-yl)methyl]-3,5- ~ \ N ~ N~-N
_ N / \ \ N
dlhydro Imidazo[4,5-c]pyndin-4-one I ~ NH
2
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- ~ \ o '
(80) yl)-5-[(benzo[tJquinolin-6-yl)methyl]-3,5- ~ \ N ~ NON
N' N
_ _
dihydro imidazo[4,5 dJpyridazin-4-one ~ ~~ NHz
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- ~ \ o '
(81 ) yl)-5-[(benzo[t]quinoxalin-6-yl)methyl]-3,5- ~ ~ N I NON
_ _ __
dihydro imidazo[4,5 dJpyridazin 4 one N ~ / N ' N NH
N 2
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- / ~ o
(82) yl)-5-[(5H-benzo[e]pyrrolo[1,2- N I N I NON
a][1,4]diazepin-11-yl)methyl]-7-methyl- ~ N N '
NHZ
3,5-dihydro-imidazo[4,5-dJpyridazin-4-one ~ /

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2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- / \ o
(83) YI)-5-[(thieno[3,2-b][1,4]benzoxazepin-9- o ~ N N
yl)methyl]-7-trifluoromethyl-3,5-dihydro- N N ' I NON
imidazo[4,5-d]p ridazin-4-one \ s F NHZ
Y F F
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- / \
(84) YI)-5-[(thieno[3,2-b][1,4]benzoxazepin-9- O - I N N
yl)methyl]-3,5-dihydro-imidazo[4,5- N ~ ~ ~~N~
N
c]pyridin-4-one \ S NHZ
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- _ H o
(85) YI)-5-[(5H-dibenzo[d,t][1,3]diazepin-6- \ ~ N~N I N~-N
yl)methyl]-7-methyl-3,5-dihydro- ~ N N ' N ~-~-
NHZ
imidazo[4,5-d]pyridazin-4-one ~
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- _ / p
(86) YI)-5-[(5-methyl-5H- \ / N~NI_ ~~ N~-N
dibenzo[d,t][1,3]diazepin-6-yl)methyl]-3,5- _ N ~N
NHZ
dihydro-imidazo[4,5-c]pyridin-4-one ~
2-( 3-amino-piperidi n-1-yl )-3-(3-methylbut-
2-en-1-yl)-5-[(5-oxa-7-aza- o /
(87) dibenzo[a,c]cyclohepten-6-yl)methyl]-7- \ / ~~N N ~
methyl-3,5-dihydro-imidazo[4,5-c]pyridin- ~ N N
w I ~~-N
4-one \ ~ NHZ
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- ~
(88) yl)-5-[(naphtho[1,2-d]thiazol-2-yl)methyl]- ~ ~ \N~N \ ~ NON
3 5-dih dro-imidaz 4 N
y o[ ,5-d]pyndazin-4-one
NHz
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- ~
N
(89) yl)-5-[(naphtho[2,1-d]thiazol-2-yl)methyl]-
3,5-dih dro-imidazo 4 5- ridazin-4-on N
Y [ ~ dIPY a NHz

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2-(3-amino-piperid i n-1-yl )-3-(2-butyn-1- o
(90) yl)-5-[(3H-naphtho[1,2-c~imidazol-2 ~ ~ N~N N
NH N ~ I ~~N~
-yl )methyl]-3, 5-d ihyd ro-im idazo[4, 5- NN
dJpyridazin-4-one NHz
2-(3-amino-piperidi n-1-yl )-3-(2-butyn-1-
(91) yl)-5-[(naphtho[1,2-b]furan-2-yl)methyl]- ~ ~ ~ ~ N ~ NON
\N w N
3, 5-di hyd ro-im idazo[4, 5-d]pyndazi n-4-one NHZ
2-( 3-amino-piperidi n-1-yl )-3-(2-butyn-1-
(92) yl)-5-[(naphtho[2,1-b]furan-2-yl)methyl]- ~ ~ ~ N N
O \N w I ~~N~
3,5-dihydro-imidazo[4,5-d]pyridazin-4-one \N
NHZ
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- \ I o %
(93) yl)-5-[(2-methyl-furo[3,2-c]isoquinolin-5- ~N I NON
N
yl)methyl]-3,5-dihydro-imidazo[4,5- p N
c]pyridin-4-one NH2
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- _N O
(94) yl)-5-[(pyrazolo[1,5-c]quinazolin-5- ~ N~N ~ N~N
yl)methyl]-3,5-dihydro-imidazo[4,5- ~ N NON
dJpyridazin-4-one I i NHz
2-(3-amino-piperidin-1-yl)-3-(2-butyn-1- H
N
(95) yl)-5-[(1H-perimidin-2-yl)methyl]-3,5- ~ \\ ~N~ I N>--N
dihydro-imidazo[4,5-dJpyridazin-4-one ~ ~ NHz

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Example 2
Coated tablets containing 75 mq of active substance
1 tablet core contains:
active substance 75.0 mg
calcium phosphate 93.0 mg
corn starch 35.5 mg
polyvinylpyrrolidone 10.0 mg
hydroxypropylmethylcellulose 15.0 mg
magnesium stearate 1.5 mg
230.0 mg
Preparation:
The active substance is mixed with calcium phosphate, corn starch, polyvin-
ylpyrrolidone, hydroxypropylmethylcellulose and half the specified amount of
magnesium stearate. Blanks 13 mm in diameter are produced in a tablet-making
machine and these are then rubbed through a screen with a mesh size of 1.5 mm
using a suitable machine and mixed with the rest of the magnesium stearate.
This
granulate is compressed in a tablet-making machine to form tablets of the
desired
shape.
Weight of core: 230 mg
die: 9 mm, convex
The tablet cores thus produced are coated with a film consisting essentially
of
hydroxypropylmethylcellulose. The finished film-coated tablets are polished
with
beeswax.
Weight of coated tablet: 245 mg.

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Example 3
63
Tablets containinct 100 mct of active substance
Composition:
1 tablet contains:
active substance 100.0 mg
lactose 80.0 mg
corn starch 34.0 mg
polyvinylpyrrolidone 4.0 mg
magnesium stearate 2.0 mp
220.0 mg
Method of Preparation:
The active substance, lactose and starch are mixed together and uniformly
moistened
with an aqueous solution of the polyvinylpyrrolidone. After the moist
composition has
been screened (2.0 mm mesh size) and dried in a rack-type drier at 50°C
it is
screened again (1.5 mm mesh size) and the lubricant is added. The finished
mixture
is compressed to form tablets.
Weight of tablet: 220 mg
Diameter: 10 mm, biplanar, facetted on both sides and notched on one side.
Example 4
Tablets containing 150 mq of active substance
Composition:
1 tablet contains:
active substance 150.0 mg
powdered lactose 89.0 mg
corn starch 40.0 mg
colloidal silica 10.0 mg
polyvinylpyrrolidone 10.0 mg
magnesium stearate 1.0 ma
300.0 mg

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Preparation:
The active substance mixed with lactose, corn starch and silica is moistened
with a
20% aqueous polyvinylpyrrolidone solution and passed through a screen with a
mesh
size of 1.5 mm. The granules, dried at 45°C, are passed through the
same screen
again and mixed with the specified amount of magnesium stearate. Tablets are
pressed from the mixture.
Weight of tablet: 300 mg
die: 10 mm, flat
Example 5
Hard gelatine capsules containing 150 ma of active substance
1 capsule contains:
active substance 150.0 mg
corn starch (dried) approx. 80.0 mg
lactose (powdered) approx. 87.0 mg
magnesium stearate 3.0 ma
approx. 420.0 mg
Preparation:
The active substance is mixed with the excipients, passed through a screen
with a
mesh size of 0.75 mm and homogeneously mixed using a suitable apparatus. The
finished mixture is packed into size 1 hard gelatine capsules.
Capsule filling: approx. 320 mg
Capsule shell: size 1 hard gelatine capsule.

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Example 6
Suppositories containing 150 mg of active substance
1 suppository contains:
5 active substance 150.0 mg
polyethyleneglycol 1500 550.0 mg
polyethyleneglycol 6000 460.0 mg
polyoxyethylene sorbitan monostearate 840.0 mg
2,000.0 mg
Preparation:
After the suppository mass has been melted the active substance is
homogeneously
distributed therein and the melt is poured into chilled moulds.
Example 7
Suspension containing 50 mg of active substance
100 ml of suspension contain:
active substance 1.00 g
carboxymethylcellulose-Na-salt 0.10 g
methyl p-hydroxybenzoate 0.05 g
propyl p-hydroxybenzoate 0.01 g
glucose 10.00 g
glycerol 5.00 g
70% sorbitol solution 20.00 g
flavouring 0.30 g
dist. water ad 100 ml
Preparation:
The distilled water is heated to 70°C. The methyl and propyl p-
hydroxybenzoates
together with the glycerol and sodium salt of carboxymethylcellulose are
dissolved
therein with stirring. The solution is cooled to ambient temperature and the
active
substance is added and homogeneously dispersed therein with stirring. After
the

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sugar, the sorbitol solution and the flavouring have been added and dissolved,
the
suspension is evacuated with stirring to eliminate air.
ml of suspension contain 50 mg of active substance.
5 Example 8
Ampoules containing 10 ma active substance
Composition:
active substance 10.0 mg
0.01 N hydrochloric acid q.s.
double-distilled water ad 2.0 ml
Preparation:
The active substance is dissolved in the necessary amount of 0.01 N HCI, made
isotonic with common salt, filtered sterile and transferred into 2 ml
ampoules.
Example 9
Ampoules containing 50 mgr of active substance
Composition:
active substance 50.0 mg
0.01 N hydrochloric acid q.s.
double-distilled water ad 10.0 ml
Preparation:
The active substance is dissolved in the necessary amount of 0.01 N HCI, made
isotonic with common salt, filtered sterile and transferred into 10 ml
ampoules.

Representative Drawing