NEW SUBSTITUTED IMIDAZO-PYRIDINONES AND IMIDAZO-PYRIDAZINONES, THE PREPARATION THEREOF AND THEIR USE AS PHARMACEUTICAL COMPOSITIONS

NOUVELLES IMIDAZOPYRIDINONES ET IMIDAZOPYRIDAZINONES SUBSTITUEES, LEUR PREPARATION ET LEUR UTILISATION COMME COMPOSITIONS PHARMACEUTIQUES

English Abstract

The present invention relates to substituted imidazo-pyridinones and imidazo--
pyridazinones
of general formula

(see formula I)
wherein R1 to R4 are defined as in claim 1, the tautomers, the stereoisomers,
the mixtures thereof and the salts thereof, which have valuable
pharmacological properties, particularly an inhibitory effect on the activity
of
the enzyme dipeptidylpeptidase-IV (DPP-IV).

French Abstract

Imidazo-pyridinones et imidazo-pyridazinones substituées de formule générale (I) dans laquelle R?1¿ à R?4¿ sont tels que définis dans la revendication 1, leurs tautomères, leurs stéréoisomères, leurs mélanges et leurs sels, qui possèdent des propriétés pharmacologiques précieuses, en particulier un effet inhibiteur de l'activité de l'enzyme dipeptidylpeptidase-IV (DPP-IV).

Claims

105
Claims
1. Compounds of general formula

Image
wherein

X denotes a nitrogen atom or a group of formula C-R5,

while R5 denotes a hydrogen atom or a methyl group,

R1 denotes a 5- to 7-membered cycloalkyleneimino group which is substituted
by an amino group in the carbon skeleton and may be substituted by a C1-3-
alkyl group,

a 6- to 7-membered cycloalkyleneimino group wherein the methylene group is
replaced by a -NH- group in the 4 position,

or an amino group substituted by a C5-7-cycloalkyl group,

while the C5-7-cycloalkyl group is substituted by an amino group or a
carbon atom in the 3 position of the C5-7-cycloalkyl group is replaced by
an -NH- group,

R2 denotes a benzyl group wherein the phenyl group may be substituted by
one or two fluorine, chlorine or bromine atoms or by a cyano group,

a straight-chain or branched C3-8-alkenyl group,
a C3-5-alkynyl group,


106
a C3-7-cycloalkylmethyl group,

a C5-7-cycloalkenylmethyl group,

or a furylmethyl, thienylmethyl, pyrrolylmethyl, thiazolylmethyl, imidazolyl-
methyl, pyridinylmethyl, pyrimidinylmethyl, pyridazinylmethyl or pyrazinyl-
methyl group,

R3 denotes a straight-chain or branched C1-6-alkyl group,

a phenyl-C1-3-alkyl or naphthyl-C1-3-alkyl group optionally substituted in the

aryl moiety by a halogen atom, a cyano, a C1-3-alkyl or a methoxy group,

a 2-phenyl-2-hydroxy-ethyl group,
a phenylcarbonylmethyl group,

wherein the phenyl group may be substituted by a hydroxy, C1-3-
alkyloxy, aminocarbonyl-C1-3-alkoxy, (C1-3-alkylamino)-carbonyl-C1-3-
alkoxy, [di-(C1-3-alkyl)-amino]-carbonyl-C1-3-alkoxy, amino, C1-3-alkyl-
carbonylamino, C3-6-cycloalkyl-carbonylamino, C1-3-alkoxy-
carbonylamino, C1-3-alkylsulphonylamino or aminocarbonyl group,
a (3-methyl-2-oxo-2,3-dihydro-benzoxazolyl)-carbonylmethyl group,

a thienylcarbonylmethyl group,
a heteroaryl-C1-3-alkyl group,

while by the phrase "heteroaryl group" is meant a monocyclic 5- or 6-
membered heteroaryl group optionally substituted by one or two
C1-3-alkyl groups or by a morpholin-4-yl, pyridyl or phenyl group, while


107
the 6-membered heteroaryl group contains one, two or three nitrogen
atoms and

the 5-membered heteroaryl group contains an imino group optionally
substituted by a C1-3-alkyl or phenyl-C1-3-alkyl group, or an oxygen or
sulphur atom or

an imino group optionally substituted by a C1-3-alkyl or phenyl-C1-3-alkyl
group or an oxygen or sulphur atom and additionally contains a nitrogen
atom or

an imino group optionally substituted by a C1-3-alkyl or phenyl-C1-3-alkyl
group or an oxygen or sulphur atom and additionally contains two or
three nitrogen atoms,

and additionally a phenyl ring, which may optionally be substituted by a
halogen atom, by one or two C1-3-alkyl groups or by a trifluoromethyl or
methoxy group, may be fused to the above-mentioned monocyclic
heteroaryl groups via two adjacent carbon atoms

and the bond may be formed via an atom of the heterocyclic moiety or of
the fused-on phenyl ring,

a bicyclic heteroarylmethyl group according to one of the formulae
Image


108
Image

or
a group of formula

Image
or a group of formulae

Image
wherein R6 in each case denotes a hydrogen atom or a methyl
group,

and R4 denotes a hydrogen atom or a C1-3-alkyl group,

while, unless otherwise stated, the alkyl and alkoxy groups listed in the
definitions
which have more than two carbon atoms may be straight-chain or branched,

and the hydrogen atoms of the methyl or ethyl groups listed in the definitions
may
be wholly or partly replaced by fluorine atoms,


109
the tautomers, the enantiomers, the diastereomers, the mixtures thereof and
the salts thereof.

2. Compounds of general formula I according to claim 1, wherein
X denotes a nitrogen atom or a methyne group,
R1 denotes a piperazin-1-yl, 3-amino-piperidin-1-yl, 3-amino-3-methyl-
piperidin-1-yl, 3-amino-pyrrolidin-1-yl, 1,4-diazepan-1-yl, (2-amino-
cyclohexyl)-amino or piperidin-3-yl-amino group,

R2 denotes a benzyl group wherein the phenyl group may be substituted by
one or two fluorine atoms, by a chlorine or bromine atom or by a cyano group,
a straight-chain or branched C3-8-alkenyl group,

a propyn-3-yl or but-2-yn-4-yl group,
a cyclopropylmethyl group,

a C5-7-cycloalkenylmethyl group,

or a furylmethyl or thienylmethyl group,

R3 denotes a straight-chain or branched C1-6-alkyl group,

a phenyl-C1-2-alkyl or naphthyl-C1-2-alkyl group optionally substituted in the

aryl moiety by a fluorine, chlorine or bromine atom or by a cyano, C1-3-alkyl
or
methoxy group,

a 2-phenyl-2-hydroxy-ethyl group,
a phenylcarbonylmethyl group,


110
wherein the phenyl group may be substituted by a hydroxy, C1-3-
alkyloxy, aminocarbonyl-C1-3-alkoxy, (Cl-3-alkylamino)-carbonyl-C1-3-
alkoxy, [di-(C1-3-alkyl)-amino]-carbonyl-C1-3-alkoxy, amino, C1-3-alkyl-
carbonylamino, C3-6-cycloalkyl-carbonylamino, C1-3-alkoxy-
carbonylamino, C1-3-alkylsulphonylamino or aminocarbonyl group,

a (3-methyl-2-oxo-2,3-dihydro-benzoxazolyl)-carbonylmethyl group,
a thienylcarbonylmethyl group,

a heteroaryl-methyl group,

while by the phrase a "heteroaryl group" is meant a pyridinyl,
pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, oxazolyl, isothiazolyl,
isoxazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl or thienyl group
optionally substituted by one or two methyl groups or by a pyridyl or
phenyl group,

and while additionally a phenyl ring, which may optionally be substituted
by a chlorine atom, by one or two methyl groups or by a trifluoromethyl
or methoxy group, may be fused to the above-mentioned monocyclic
heteroaryl groups via two adjacent carbon atoms

and the bond may be formed via an atom of the heterocyclic moiety or of
the fused-on phenyl ring,

an imidazo[1,2-a]pyridin-2-yl-methyl group of formulae
Image


111
Image
a 1,2,4-triazolo[4,3-a]pyridin-3-yl group of formula

Image
or a group of formulae

Image
wherein R6 in each case denotes a hydrogen atom or a methyl
group,

and R4 denotes a hydrogen atom or a methyl group,

while, unless otherwise stated, the alkyl and alkoxy groups listed in the
definitions
which have more than two carbon atoms may be straight-chain or branched,

and the hydrogen atoms of the methyl or ethyl groups listed in the definitions
may
be wholly or partly replaced by fluorine atoms,

the tautomers, the enantiomers, the diastereomers, the mixtures thereof and
the
salts thereof.


112
3. Compounds of general formula I according to claim 1, wherein
X, R2, R3 and R4 are defined as in claim 2 and

R1 denotes a 3-amino-piperidin-1-yl group,

the tautomers, the enantiomers, the diastereomers, the mixtures thereof and
the salts thereof.

4. Compounds of general formula I according to claim 1, wherein
X, R1, R3 and R4 are defined as in claim 2 or 3 and

R2 denotes a 3-methylallyl, a 3,3-dimethylallyl or a but-2-yn-4-yl group,

the tautomers, the enantiomers, the diastereomers, the mixtures thereof and
the salts thereof.

5. The following compounds of general formula I according to claim 1:

(1) 2-(3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(naphthalen-1-ylmethyl)-3,5-
dihydro-imidazo[4,5-d]pyridazin-4-one
Image

(2) 2-(3-amino-piperidin-1-yl)-3-but-2-ynyl-5-(3-methyl-isoquinolin-1-yl-
methyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,


113
Image
(3) 2-(3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(quinazolin-2-ylmethyl)-3,5-
dihydro-imidazo[4,5-d]pyridazin-4-one
Image
(4) 2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(4-methyl-quinazolin-2-
ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one
Image
(5) 2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(4-cyano-naphthalen-1-
ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one
Image
(6) 2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(4-bromonaphth-1-
ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one


114
Image

(7) 2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(benzo[1,2,5]thiadiazol-
5-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one

Image
(8) 2-((R)-3-amino-piperidin-1-yl)-3-(2-chlorobenzyl)-5-(3-methyl-
isoquinolin-1-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one

Image
(9) 2-(3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(quinoxalin-6-ylmethyl)-3,5-
dihydro-imidazo[4,5-d]pyridazin-4-one

Image
(10) 2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(2,3-dimethyl-quinoxalin-
6-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one


115
Image

(11) 2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(5-methyl-imidazo[1,2-
a]pyridin-2-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one
Image

(12) 2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(1-methyl-1H-quinolin-2-
on-6-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one

Image
(13) 2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(4-methyl-phthalazin-1-
ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one

Image
(14) 2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-([1,5]naphthyridin-2-
ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one


116
Image
and
(15) 2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(2,3,8-trimethyl-
quinoxalin-6-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one

Image
and the enantiomers and the salts thereof.

6. Physiologically acceptable salts of the compounds according to at least
one of 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.


117
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

Image
wherein X, R2, R3 and R4 are defined as in claims 1 to 5 and Z1 denotes a
nucleofugic leaving group, is reacted with an amine of general formula

H-R1 (III),
wherein R1 is defined as in claims 1 to 5, or
b) a compound of general formula

Image
wherein R2, R3 and R4 are defined as in claims 1 to 5 and

R1 denotes one of the groups mentioned for R1 hereinbefore, wherein the imino,

amino or alkylamino group is substituted by a protective group, is deprotected
and
subsequently if desired any protecting group used to protect reactive groups
during the reactions is cleaved and/or

a compound of general formula I thus obtained is resolved into its
stereoisomers
and/or


118
a compound of general formula I thus obtained is converted into the salts
thereof.
11. The process according to claim 10, wherein the nucleofugic leaving
group is a chlorine or bromine atom or a C1-3-alkylsulphanyl, C1-3-
alkylsulphinyl or
C1-3-alkylsulphonyl group.

12. The process according to claim 10 or 11, wherein a compound of
general formula I thus obtained is converted for pharmaceutical use into the
physiologically acceptable salts thereof with an inorganic or organic acid.

Description

CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 1 Foreign filing text
82541 fft
New substituted imidazo-pyridinones and imidazo-pyridazinones, the
preparation thereof and their use as pharmaceutical compositions
The present invention relates to new substituted imidazo-pyridinones and
imidazo-pyridazinones of general formula
R2
R3 O
N
X w I ~~ R1
'N
R4
(I),
the tautomers, the enantiomers, the diastereomers, the mixtures 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 tautomers, the
enantiomers, the diastereomers, the mixtures thereof and the salts thereof,
the pharmaceutical compositions containing the pharmacologically effective
compounds, the use thereof and processes for the preparation thereof.
In the above general formula I



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 2 Foreign filing text
X denotes a nitrogen atom or a group of formula C-R5,
while R5 denotes a hydrogen atom or a methyl group,
R' denotes a 5- to 7-membered cycloalkyleneimino group which is substituted
by an amino group in the carbon skeleton and may be substituted by a C~_3-
alkyl group,
a 6- to 7-membered cycloalkyleneimino group wherein the methylene group is
replaced by a -NH- group in the 4 position,
or an amino group substituted by a C5_~-cycloalkyl group,
while the C5_~-cycloalkyl group is substituted by an amino group or a
carbon atom in the 3 position of the C5_~-cycloalkyl group is replaced by
an -NH- group,
R2 denotes a benzyl group wherein the phenyl group may be substituted by
one or two fluorine, chlorine or bromine atoms or by a cyano group,
a straight-chain or branched C3_$-alkenyl group,
a C3_5-alkynyl group,
a C3_~-cycloalkylmethyl group,
a C5_~-cycloalkenylmethyl group,
or a furylmethyl, thienylmethyl, pyrrolylmethyl, thiazolylmethyl, imidazolyl-
methyl, pyridinylmethyl, pyrimidinylmethyl, pyridazinylmethyl or pyrazinyl-
methyl group,
R3 denotes a straight-chain or branched C~_6-alkyl group,



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 3 Foreign filing text
a phenyl-C~_3-alkyl or naphthyl-C~_3-alkyl group optionally substituted in the
aryl moiety by a halogen atom, a cyano, a C~_3-alkyl or a methoxy group,
a 2-phenyl-2-hydroxy-ethyl group,
a phenylcarbonylmethyl group,
wherein the phenyl group may be substituted by a hydroxy, C~-3-
alkyloxy, aminocarbonyl-C~_3-alkoxy, (C~_3-alkylamino)-carbonyl-C~_3-
alkoxy, [di-(C~_3-alkyl)-amino]-carbonyl-C~_3-alkoxy, amino, C~_3-alkyl-
carbonylamino, C3_6-cycloalkyl-carbonylamino, C~_3-alkoxy-
carbonylamino, C~_3-alkylsulphonylamino or aminocarbonyl group,
a (3-methyl-2-oxo-2,3-dihydro-benzoxazolyl)-carbonylmethyl group,
a thienylcarbonylmethyl group,
a heteroaryl-C~_3-alkyl group,
while by the phrase "heteroaryl group" is meant a monocyclic 5- or 6-
membered heteroaryl group optionally substituted by one or two
C~_3-alkyl groups or by a morpholin-4-yl, pyridyl or phenyl group, while
the 6-membered heteroaryl group contains one, two or three nitrogen
atoms and
the 5-membered heteroaryl group contains an imino group optionally
substituted by a C~_3-alkyl or phenyl-C~_3-alkyl group, or an oxygen or
sulphur atom or
an imino group optionally substituted by a C~_3-alkyl or phenyl-C~_3-alkyl
group or an oxygen or sulphur atom and additionally contains a nitrogen
atom or



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 4 Foreign filing text
an imino group optionally substituted by a C~_3-alkyl or phenyl-C~_3-alkyl
group or an oxygen or sulphur atom and additionally contains two or
three nitrogen atoms,
and additionally a phenyl ring, which may optionally be substituted by a
halogen atom, by one or two C~_3-alkyl groups or by a trifluoromethyl or
methoxy group, may be fused to the above-mentioned monocyclic
heteroaryl groups via two adjacent carbon atoms
and the bond may be formed via an atom of the heterocyclic moiety or of
the fused-on phenyl ring,
a bicyclic heteroarylmethyl group according to one of the formulae
/ ~N
/ N \ N CH2 -
I~CH2-
N CH3
N\ CH2 -
i /
N
N
N'N~CH2 -
or
a group of formula



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 5 Foreign filing text
F
F CH2 -
F ~ ~F
F
or a group of formulae
O
Rs
O Rs- N \ \
N
Rs-N ~ CH2- O ~ CH2-
CH2 -
or
wherein Rs in each case denotes a hydrogen atom or a methyl group,
and R4 denotes a hydrogen atom or a C~_3-alkyl group,
while unless otherwise stated the alkyl and alkoxy groups listed in the
definitions which have more than two carbon atoms may be straight-chain or
branched,
and the hydrogen atoms of the methyl or ethyl groups listed in the definitions
may be wholly or partly replaced by fluorine atoms.
Preferred compounds of general formula I are those wherein
X denotes a nitrogen atom or a methyne group,
R' denotes a piperazin-1-yl, 3-amino-piperidin-1-yl, 3-amino-3-methyl-
piperidin-1-yl, 3-amino-pyrrolidin-1-yl, 1,4-diazepan-1-yl, (2-amino-
cyclohexyl)-amino or piperidin-3-yl-amino group,



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 6 Foreign filing text
R2 denotes a benzyl group wherein the phenyl group may be substituted by
one or two fluorine atoms, by a chlorine or bromine atom or by a cyano group,
a straight-chain or branched C3_$-alkenyl group,
a propyn-3-yl or but-2-yn-4-yl group,
a cyclopropylmethyl group,
a C5_~-cycloalkenylmethyl group,
or a furylmethyl or thienylmethyl group,
R3 denotes a straight-chain or branched C~_6-alkyl group,
a phenyl-C~_2-alkyl or naphthyl-C~_2-alkyl group optionally substituted in the
aryl moiety by a fluorine, chlorine or bromine atom or by a cyano, C~_3-alkyl
or
methoxy group,
a 2-phenyl-2-hydroxy-ethyl group,
a phenylcarbonylmethyl group,
wherein the phenyl group may be substituted by a hydroxy, C~_3'
alkyloxy, aminocarbonyl-C~_3-alkoxy, (C~_3-alkylamino)-carbonyl-C~_3-
alkoxy, [di-(C~_3-alkyl)-amino]-carbonyl-C,_3-alkoxy, amino, C~_3-alkyl-
carbonylamino, C3_6-cycloalkyl-carbonylamino, C~_3-alkoxy-
carbonylamino, C~_3-alkylsulphonylamino or aminocarbonyl group,
a (3-methyl-2-oxo-2,3-dihydro-benzoxazolyl)-carbonylmethyl group,
a thienylcarbonylmethyl group,
a heteroaryl-methyl group,



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 7 Foreign filing text
while by the phrase a "heteroaryl group" is meant a pyridinyl,
pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, oxazolyl, isothiazolyl,
isoxazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl or thienyl group
optionally substituted by one or two methyl groups or by a pyridyl or
phenyl group,
and while additionally a phenyl ring, which may optionally be substituted
by a chlorine atom, by one or two methyl groups or by a trifluoromethyl
or methoxy group, may be fused to the above-mentioned monocyclic
heteroaryl groups via two adjacent carbon atoms
and the bond may be formed via an atom of the heterocyclic moiety or of
the fused-on phenyl ring,
an imidazo[1,2-a]pyridin-2-yl-methyl group of formulae
N
T~CH2-
,N \ N
\ N~CH2 -
CH3
or
N\ CH2-
i
N
a 1,2,4-triazolo[4,3-a]pyridin-3-yl group of formula
N
N~ ~--CH2
N
or a group of formulae



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 8 Foreign filing text
O
R6-N
Rs
CH2 -
or
wherein R6 in each case denotes a hydrogen atom or a methyl group,
and R4 denotes a hydrogen atom or a methyl group,
while unless otherwise stated the alkyl and alkoxy groups listed in the
definitions which have more than two carbon atoms may be straight-chain or
branched,
and the hydrogen atoms of the methyl or ethyl groups listed in the definitions
may be wholly or partly replaced by fluorine atoms,
the tautomers, the enantiomers, the diastereomers, the mixtures thereof and
the salts thereof,
but particularly those compounds of general formula I wherein
X, R2, R3 and R4 are as hereinbefore defined and
R' denotes a 3-amino-piperidin-1-yl group,
the tautomers, the enantiomers, the diastereomers, the mixtures thereof and
the salts thereof.
A second sub-group of preferred compounds comprises those compounds of
general formula I wherein



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 9 Foreign filing text
X, R', R3 and R4 are as hereinbefore defined and
R2 denotes a 3-methylallyl, a 3,3-dimethylallyl or a but-2-yn-4-yl group,
the tautomers, the enantiomers, the diastereomers, the mixtures thereof and
the salts thereof.
Particularly preferred are the following compounds of general formula I:
(1) 2-(3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(naphthalen-1-ylmethyl)-3,5-
dihydro-imidazo[4,5-d]pyridazin-4-one
CH3
I
N
N ~N~
/ N~ I N
NH2
(2) 2-(3-amino-piperidin-1-yl)-3-but-2-ynyl-5-(3-methyl-isoquinolin-1-yl-
methyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
O ~ CH3
N
'N
~N Nw ~ N N
CH3 NH2
(3) 2-(3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(quinazolin-2-ylmethyl)-3,5-
dihydro-imidazo[4,5-d]pyridazin-4-one
CH3
O
N~
_I N N
~N Nw I ~ N
N
NH2
(4) 2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(4-methyl-quinazolin-2-
ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 111427
55216 Ingelheim 10 Foreign filing text
~ CH3
\ N~ N
/~N
N
3 NHz
(5) 2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(4-cyano-naphthalen-1-
ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one
\ C ~ CH3
\ N
_N >-N
/ Nw
N / NHZ
(6) 2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(4-bromonaphth-1-
ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one
~ CH3
N
-N
Br I / N ~
NHZ
(7) 2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(benzo[1,2,5]thiadiazol-
5-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one
CH3
N~ ~ N N
S\ ;~ I I ~>--N
N / N~ N
NHZ
(8) 2-((R)-3-amino-piperidin-1-yl)-3-(2-chlorobenzyl)-5-(3-methyl-
isoquinolin-1-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 11 Foreign filing text
ci
o \
N
~N ~N~
iN N~ I N
CH3 NHz
(9) 2-(3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(quinoxalin-6-ylmethyl)-3,5-
dihydro-imidazo[4,5-d]pyridazin-4-one
CH3
~Nw \ N N
I /~-N
N N
NHz
(10) 2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(2,3-dimethyl-quinoxalin-
6-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one
CH3
H3C N~ \ N
N I /~--
i~~N ~ N
H3C N N
NHZ
(11) 2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(5-methyl-imidazo[1,2
a]pyridin-2-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one
(12) 2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(1-methyl-1 H quinolin-2-
on-6-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 12 Foreign filing text
~CH3
O
\ N
N ~N~
O N ~ ~ N~ I N
CH3 NH2
(13) 2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(4-methyl-phthalazin-1-
ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one
CH3
O
\ N
N ~N~
H C I N~N N~ , N
3
NHZ
(14) 2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-([1,5]naphthyridin-2-
ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one
CH3
O
\ N~ N
N ~N~
N / Nw I N
NH2
and
(15) 2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(2,3,8-trimethyl-
quinoxalin-6-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one
~CH3
O
H3C N~ \ N
N
i ~ N~ ~ N
H3C N
3 NH2
and the enantiomers and the salts thereof.



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 13 Foreign filing text
According to the invention the compounds of general formula I are obtained
by methods known per se, for example by the following methods:
a) reacting a compound of general formula
R2
R3 O
N
X w I ~~ Z1
'N
R4
(II),
wherein X, R2, R3 and R4 are as hereinbefore defined and Z~ denotes a
nucleofugic leaving group such as for example a chlorine or bromine atom or
a C~_3-alkylsulphanyl, C~_3-alkylsulphinyl or C~_3-alkylsulphonyl group,
with an amine of general formula
H-R' ( I I I ),
wherein R~ is as hereinbefore defined.
The reaction is expediently carried out in a solvent such as isopropanol,
butanol, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulphoxide,
ethyleneglycolmonomethylether, ethyleneglycoldiethylether or sulpholane,
optionally in the presence of an inorganic or tertiary organic base, e.g.
sodium
carbonate, potassium carbonate or potassium hydroxide, a tertiary organic
base, e.g. triethylamine, or in the presence of N-ethyl-diisopropylamine
(Hianig
base), while these organic bases may simultaneously also serve as solvent,
and optionally in the presence of a reaction accelerator such as an alkali
metal halide or a palladium-based catalyst at temperatures between -20 and
180°C, but preferably at temperatures between -10 and 120°C. The
reaction
may however also be carried out without a solvent or in an excess of the
amine of general formula R4'-H.



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 14 Foreign filing text
b) deprotecting a compound of general formula
R2
R3 O
N
X ~ ~ ~~ R~,
~N
R4
(IV),
wherein R2, R3 and R4 are as hereinbefore defined and
R'~ denotes one of the groups mentioned for R' hereinbefore, wherein 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. 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.
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
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 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



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 15 Foreign filing text
the carbobenzyloxycarbonyl group which can be cleaved for example by
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 with aluminium chloride/anisol at temperatures
between 0°C and ambient temperature.
If desired any protecting group used to protect reactive groups during the
reactions is subsequently 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 the salts
thereof, particularly for pharmaceutical use into the physiologically
acceptable
salts thereof with an inorganic or organic acid.
In the reactions described hereinbefore, any reactive groups present such as
hydroxy, carboxy, phosphono, O-alkyl-phosphono, amino, alkylamino or imino
groups may be protected during the reaction by conventional protecting
groups which are cleaved again after the reaction.
For example, a protecting group for a hydroxy group may be a trimethylsilyl,
acetyl, benzoyl, methyl, ethyl, tert.butyl, trityl, benzyl or
tetrahydropyranyl
group,
protecting groups for a carboxy group may be a trimethylsilyl, methyl, ethyl,
tert.butyl, benzyl or tetrahydropyranyl group,
protecting groups for a phosphono group may be an alkyl group such as a
methyl, ethyl, isopropyl or n-butyl group, a phenyl or benzyl group and



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 16 Foreign filing text
protecting groups for an amino, alkylamino or imino group may be a formyl,
acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl,
benzyloxycarbonyl,
benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the
amino group, a phthalyl group.
Any protecting group used is optionally subsequently cleaved for example by
hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, acetic
acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid
such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the
presence of an alkali metal base such as sodium hydroxide or potassium
hydroxide or aprotically, e.g. in the presence of iodotrimethylsilane, at
temperatures between 0 and 120°C, preferably at temperatures between 10
and 100°C.
However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for
example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst
such as palladium/charcoal in a suitable solvent such as methanol, ethanol,
ethyl acetate or glacial acetic acid, optionally with the addition of an acid
such
as hydrochloric acid at temperatures between 0 and 100°C, but
preferably at
temperatures between 20 and 60°C, and at a hydrogen pressure of 1 to 7
bar,
but preferably 3 to 5 bar. A 2,4-dimethoxybenzyl group, however, is preferably
cleaved in trifluoroacetic acid in the presence of anisol.
A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating
with
an acid such as trifluoroacetic acid or hydrochloric acid or by treating with
iodotrimethylsilane, optionally using a solvent such as methylene chloride,
dioxane, methanol or diethylether.
A trifluoroacetyl group is preferably cleaved by treating with an acid such as
hydrochloric acid, optionally in the presence of a solvent such as acetic
acid,
at temperatures between 50 and 120°C or by treating with sodium
hydroxide
solution, optionally in the presence of a solvent such as tetrahydrofuran at
temperatures between 0 and 50°C. .



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 17 Foreign filing text
A phthalyl group is preferably cleaved in the presence of hydrazine or a
primary amine such as methylamine, ethylamine or n-butylamine in a solvent
such as methanol, ethanol, isopropanol, toluene/water or dioxane at
temperatures between 20 and 50°C.
A single alkyl group may be cleaved from an O,O'-dialkylphosphono group
with sodium iodide, for example, in a solvent such as acetone,
methylethylketone, acetonitrile or dimethylformamide at temperatures
between 40 and 150°C, but preferably at temperatures between 60 and
100°C.
Both alkyl groups may be cleaved from an O,O'-dialkyl-phosphono group with
iodotrimethylsilane, bromotrimethylsilane or chlorotrimethylsilane/sodium
iodide, for example, in a solvent such as methyl chloride, chloroform or
acetonitrile at temperatures between 0°C and the boiling temperature of
the
reaction mixture, but preferably at temperatures between 20 and 60°C.
Moreover, the compounds of general formula I obtained may be resolved into
their enantiomers and/or diastereomers, as mentioned hereinbefore. Thus, for
example, cis/trans mixtures may be resolved into their cis and trans isomers,
and compounds with at least one optically active carbon atom may be
separated into their enantiomers.
Thus, for example, the cis/trans mixtures may be resolved by chromatography
into the cis and trans isomers thereof, the compounds of general 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 and/or fractional
crystallisation, and, if these compounds are obtained in racemic form, they
may subsequently be resolved into the enantiomers as mentioned above.



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 18 Foreign filing text
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 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 hydroxide, potassium hydroxide, arginine,
cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
The compounds of general formulae II to IV used as starting materials are
either known from the literature or may be obtained by methods known from
the literature, for example using the methods of synthesis illustrated in
Diagrams 1 to 5. The method of synthesis shown in Diagram 4 is preferred.



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1!1427
55216 Ingelheim 19 Foreign filing text
Diagram 1:
Possible method of synthesising the substituted
3,5-dihydro-imidazo[4,5-c]pyridin-4-ones



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 20 Foreign filing text
O O O
H~N NOz ~ Rs~N NOz Rs~ NOz
Rs O~H Rs \ O_ R3 Rs \ N,H
I
H
O H O H
I I
Rs~N N~H Rs~N N
\ I -~ \ I /~S-H
Rs N~H Rs N
I
H
O H Rz
Rs~N N O H O
\ I /~ Rs~N N\ R3~N N
Rs N ( /~CI \ ~ /~S CH3
i Rs \ N/ Rs N
O H
Rs~N N~
~Br Rz Rz
Rs \ N~ O I O
R3\N N R3~N N CH3
/~CI \ ~ /~i1~0
Rs N~ Rs N O
Rz
o I
Rs~N N
/~~ /rBr
Rs \ N/
Rz
o I
Rs~N N
//~ /~ R~
Rs \ N
Diagram 2:
Possible alternative method of synthesising the substituted
3, 5-d i hyd ro-i m idazo[4, 5-c] pyrid in-4-ones



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 21 Foreign filing text
O'H CI CI O
\ NOz N \ NOz N \ NOz HEN Npz
I
s NI ~ ,H Rs I ~ Rs ~ N~H Rs \ N~H
R O CI ~ I
H H
O H O H O H
H\N I N\H ~ H\N I / ~H HEN N CH
-S' 3
Rs \ NCH Rs \ N s \ I /
I R N
H
O Rz O Rz
i i
H~N I ~~S~CH3 ~ R3~N I ~~S~CH3
Rs \ Nr Rs \ rN
r
O Rz O Rz
r
R3\N I / NCH ---~ R3~N I /
-S 3 ~- R~
Rs \ N ~ Rs \ N
~O)~,z



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 22 Foreign filing text
Diagram 3:
Possible method of synthesising the substituted
3,5-dihydro-imidazo[4,5-d]pyridazin-4-ones
0 0 0
H~ CI Ra ~ Cf Ra ~ O-H
N ;( ~ N~ ,~ N
N ~~CI N \ CI N \ NOZ
R4 R4 ~ Ra
H
I
Ra ~ N N-H
I
N~
N02
Ra
H O H
Ra N-H Ra I
N
O N ~ N~N~--S.H
H N~ N-H N~
Ra . N I N' ~ R4 H R4
/,I
N~ N
Ra O O
Ra ~ N N Ra . N ~ S CHa
I /)--
O N~ I N~O N~ N
H v
Ra Ro H R
/ Br
N~ N
Rz
Ra O H O I
Ra ~ N N Ra ~ N N /CHa
I N CI N \ I N>.-S
N~
Rz Ra R4
~! N
N~ /~--Br
N~ N
Rz Rz
Ra O ~ O
Ra. N N Ra. N N /CHa
N ~ I NCI N ~ I N~l/ ~O
RQ ~ Ra
Rz
Ra N
.N~ L /~ R,
N
Ra



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 23 Foreign filing text
Diagram 4:
Possible alternative method of synthesising the substituted
3,5-dihydro-imidazo[4,5-d]pyridazin-4-ones
Rz
H3COOC NH H3COOC N H3COOC
I N>-Br -~ I N~--Br
H3COOC H3COOC H3COOC
Rz Rz
H3COOC N H3COOC
I /~Br ~ I /~Br
O N HBO N
H
Rz Rz O Rz
3
H~ O N Rs~ O N R ~ N
/~Br ~ N I /~---Br ~ N \ I /~ R'
~N ~ N N



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 24 Foreign filing text
Diagram 5:
Another possible method of synthesising the substituted
3,5-dihydro-imidazo[4,5-d]pyridazin-4-ones
H3COOC NC H H
H3COOC N H3COOC
Et0 CN ~ I /~ ~ I /~Br
Et0 'N Et0 ~N
Et0 ~ Et0 Et0
Ra Ra Ra
Rz Rz Rz
H3COOC N H~ O N R3w O N
I /~Br ~ N I /~--Br ~ N I /~Br
Et0 N N~ N N~ N
Et0
Ra Ra Ra
Rz
O
R3
~N N
/~- R'
'N
Ra



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 25 Foreign filing text
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 pM, were placed in black microtitre plates. 20 pl 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 pg 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 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



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 26 Foreign filing text
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]


2 13


7 5.4


182 1.2


191 14


195 17


202 9.8


205 5.4


217 10


The compounds prepared according to the invention are well tolerated, as for
example when 10 mg/kg of the compound of Example 2 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. In 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 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



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 27 Foreign filing text
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-1V 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. glibenclamid, tolbutamide, glimepiride), nateglinide,
repaglinide, thiazolidinedione (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 regulators of ABC1 or active



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 28 Foreign filing text
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
pressure such as e.g. All antagonists or ACE inhibitors, diuretics, f3-
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 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, 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:



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 29 Foreign filing text
To synthesise the compounds which contain a chiral 3-amino-piperidin-1-yl
group, the corresponding chiral reagent, namely (R)-3-(tert.-butyloxy-
carbonylamino)-piperidine, was used as starting material. (R)-3-(tert.-
butyloxy-
carbonylamino)-piperidine was obtained starting from (R)-1-benzyl-3-(tert.-
butyloxycarbonylamino)-piperidine, which was prepared analogously to the
(S)-enantiomer known from the literature (see Moon, Sung-Hwan; Lee, Sujin;
Synth.Commun.; 28; 21; 1998; 3919-3926), as follows:
About 2 g of (R)-1-benzyl-3-(tert.-butyloxycarbonylamino)-piperidine in 20 ml
of methanol are hydrogenated for 24 hours at ambient temperature at a
hydrogen pressure of 3 bar in the presence of 200 mg palladium on activated
charcoal (10% Pd). Then the catalyst is removed by suction filtering and the
filtrate is evaporated to dryness.
melting point: 119°C
Mass spectrum (ESI+): m/z = 201 [M+H]+
Example 1
2-(3-Amino-piperidin-1-yl)-3-benzyl-5-(naphthalen-1-ylmethyl)-3 5-dih dro-
imidazof4.5-dlpyridazin-4-one
0
N
N ~-N
N~ I N
NH2
1 a) 4.5-dichloro-2-naphthalen-1-ylmethyl-2H-pyridazin-3-one
o ~ o
HEN CI
N CI
I
N~ I I / N
CI CI



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 30 Foreign filing text
9.0 g (65 mmol) of potassium carbonate were added to a solution of 10.0 g
(60.61 mmol) of 4,5-dichloro-3-hydroxy-pyridazine in 50 ml
dimethylsulphoxide, then 9.42 g (63 mmol) of 1-(chloromethyl)-naphthalene
were added and the mixture was stirred for 17 hours at 50°C. The dark
solution was cooled and then combined with 300 mi of dist. water, then 300 ml
dichloromethane were stirred in, the mixture was suction filtered through
Celite, the aqueous phase was separated off and extracted another three
times with 50 ml of dichloromethane. The combined organic phases were
washed with water, dried over sodium sulphate and evaporated down. The
crude product thus obtained was dissolved in 250 ml dichloromethane, the
solution was filtered through silica gel and then evaporated down. The residue
was triturated with petroleum ether, suction filtered and dried.
Yield: 67.6% of theory.
C~SH~pCI2N2O (305.17)
Rf value: 0.71 (silica gel, dichloromethane)
Mass spectrum: (M+H)+ = 305/7 (CI)
1 b) 4-hydrox~2-naphthalen-1-ylmethyl-5-nitro-2H-ayridazin-3-one
0
OH
~N
I
/ N~
NOz
A solution of 11.04 g (160 mmol) of sodium nitrite in 40 ml of water was added
to a solution of 12 g (39.3 mmol) of 4,5-dichloro-2-naphthalen-1-ylmethyl-2H-
pyridazin-3-one in 120 ml of dimethylformamide and the mixture was stirred
for 24 hours at 85°C. Then it was evaporated down in vacuo and the
residue
was stirred with a mixture of 30 ml semiconcentrated hydrochloric acid and
30 ml of ethanol, during which time the product crystallised. It was suction
filtered, washed with ethanol and dried.
Yield: 81.7% of theory
C15H11N3~4 (297.27)



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 31 Foreign filing text
Rf value: 0.32 (silica gel, dichloromethane/ethanol 19 : 1 )
1 c) 4-amino-2-naphthalen-1-ylmethyl-5-nitro-2H-pyridazin-3-one
0
NHZ
~N
I
Nw
NOZ
9.4 g (31.6 mmol) of 4-hydroxy-2-naphthalen-1-ylmethyl-5-nitro-2H-pyridazin-
3-one were combined with 150 ml saturated methanolic ammonia solution and
heated to 130°C for 24 hours in a Roth bomb. The mixture was
concentrated
down to a volume of about 40 ml using the rotary evaporator, the product
precipitated was suction filtered and recrystallised from tetrahydrofuran.
Yield: 53.4% of theory
C15H12N4~3 (296.29)
Rf value: 0.68 (silica gel, dichloromethane/ethanol 50 : 1 )
Mass spectrum: (M + H)+ = 297
(M - H)- = 295
1 d) 4,5-diamino-2-naphthalen-1-ylmethyl-2H-pyridazin-3-one
0
NHZ
~N
I
/ N~
NH2
g (16.88 mmol) of 4-amino-2-naphthalen-1-ylmethyl-5-nitro-2H-pyridazin-3-
one, dissolved in 150 ml of tetrahydrofuran, were reduced in a Parr apparatus
with the addition of 250 mg of platinum oxide, at ambient temperature and
under 2 atm H2. The catalyst was filtered off, the filtrate was evaporated
down
and the crude product thus obtained was further processed without any more
purification.
Yield: 99% of theory
C15H14N4~ (266.3)



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 32 Foreign filing text
Rf value: 0.14 (silica gel, dichloromethane/ethanol 19 : 1 )
1 e) 2-mercapto-5-(naphthalen-1- ly methyl)-3.5-dihydro-imidazof4,5-
dlp~rridazin-4-one
0
H
N
'N~ ~~SH
N~
N
4.99 g (28.0 mmol) of N,N~-thiocarbonyldiimidazole were added to a solution
of 4.4 g (16.5 mmol) of 4,5-diamino-2-naphthalen-1-ylmethyl-2H-pyridazin-3-
one in 100 ml of tetrahydrofuran and stirred overnight at ambient temperature.
Then the mixture was concentrated by evaporation in vacuo, the residue was
combined with approx. 30 ml of water, made weakly acidic with hydrochloric
acid, the product precipitated was suction filtered, washed with water and
dried.
Yield: 98% of theory
C~gH~2N4OS (308.36)
Rf value: 0.22 (silica gel, dichloromethane/ethanol 19 : 1 )
Mass spectrum: (M - H)- = 307
1 f) 2-methylsulphanyl-5~naphthalen-1-ylmethyl)-3,5-dihydro-imidazof4.5-
dlpyridazin-4-one
0
H
N
/ N w N CH3
2.38 g (17.2 mmol) of potassium carbonate and 1.07 ml (17.20 mmol) of
iodomethane were added to a suspension of 5.3 g (17.19 mmol) of 2-
mercapto-5-(naphthalen-1-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-
one in 100 ml of dichloromethane and 100 ml of methanol and stirred
overnight at ambient temperature. Then the solvent was evaporated off, the
residue was combined with approx. 30 ml of water, acidified with 2N



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1!1427
55216 Ingelheim 33 Foreign filing text
hydrochloric acid, the product thus obtained was suction filtered, washed
again with water and dried.
Yield: 54.1 % of theory
C~7H~4NqOS (322.39)
Rf value: 0.70 (silica gel, dichloromethane/ethanol 50 : 1 )
Mass spectrum: (M + H)+ = 323
~H-NMR spectrum (ds-DMSO): b = 2.70 (s, 3H); 5.81 (s, 2H); 7.20 (dd, 1 H);
7.43 (t, 1 H); 7.57 (m, 2H); 7.86 (dd, 1 H); 7.95 (dd, 1 H); 8.29 (dd, 1 H);
8.38 (s,
1 H), 13.85 (broad s, 1 H) ppm.
1 g) 3-benzyl-2-methylsulphanyl-5-(naphthalen-1-ylmethyl)-3 5-dihydro-
imidazof4,5-~pyridazin-4-one
1
I~ o
N
I ~ N ~ I /~
N CH3
A solution of 1.0 g (3.10mmol) of 2-methylsulphanyl-5-(naphthalen-1-
ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one in 15 ml of
dimethylformamide was combined with 547 mg (3.20 mmol) of benzylbromide
and then with 442 mg (3.20 mmol) of potassium carbonate and stirred
overnight at ambient temperature. Then it was diluted with approx. 40 ml of
water and extracted three times with 15 ml of ethyl acetate. The organic
extracts were washed with water, dried over sodium sulphate and evaporated
down. The crude product thus obtained was purified by column
chromatography (silica gel; eluant: petroleum ether with 10 - 20% ethyl
acetate).
Yield: 54.7% of theory
C2aH2oN40S (412.52)
Rf value: 0.77 (silica gel, petroleum ether/ethyl acetate 1 : 1 )
Mass spectrum: (M + H)+ = 413



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 34 Foreign filing text
1 h) 3-benzyl-2-methylsulphonyl-5-(naphthalen-1-ylmeth~)-3,5-dihydro-
imidazof4,5-d]pyridazin-4-one
I
Iw
i
A solution of 395 mg (2.50 mmol) of potassium permanganate was added
dropwise to a solution of 700 mg (1.70 mmol) of 3-benzyl-2-methylsulphanyl-
5-(naphthalen-1-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one in 30 ml
concentrated acetic acid with stirring at ambient temperature and stirring was
continued for a further two hours. As the oxidation was not yet complete, a
further 150 mg potassium permanganate, dissolved in 5 ml of water, were
added and the mixture was again stirred for two hours. The reaction solution
was then combined with 0.5 g sodium hydrogen sulphite, then diluted with
approx. 40 ml of water and extracted three times with 20 ml of
dichloromethane. The organic extracts were washed with 5% sodium
hydrogen sulphite solution, then with water and dried over sodium sulphate.
The crude product obtained after evaporation was purified by column
chromatography (silica gel; eluant: dichloromethane with 1 % ethanol).
Yield: 55.7% of theory
C24H2oN4O3S (444.52)
Rf value: 0.41 (silica gel, petroleum ether/ethyl acetate 7 : 3)
Mass spectrum: (M + H)+ = 445
1 i) tert. butyl f1~1-benzyl-6-naphthalen-1- Iymethyl-7-oxo-6,7-dihydro-1H-
imidazof4 5-dlayridazin-2-y~-piperidin-3-yll-carbaminate
Iw o
N
I ~ N\ I / N ryH3
N ~ ~CH3
H CHs
O



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 35 Foreign filing text
200 mg (0.45 mmol) of 3-benzyl-2-methylsulphonyl-5-(naphthalen-1-ylmethyl)-
3,5-dihydro-imidazo[4,5-d]pyridazin-4-one and 600 mg (3.0 mmol) of tert.
butyl piperidin-3-yl-carbaminate were stirred together for 16 hours at
150°C
under nitrogen. The reaction mixture was then dissolved in 30 ml
dichloromethane, the solution was washed with 1 N sodium hydroxide solution
and dried over sodium sulphate. The crude product obtained after evaporation
was purified by column chromatography (silica gef; eluant: dichloromethane
with 1 - 2% ethanol).
Yield: 26.6% of theory
C33H36N6~3 (564.69)
Rf value: 0.59 (silica gel, dichloromethane/ethanol 19 : 1 )
Mass spectrum: (M + H)+ = 565
1 j) 2-(3-amino-aiperidin-1-yl)-3-benzLrl-5-(naphthalen-1-ylmethyl)-3,5-
dihydro-imidazof4 5-dlayridazin-4-one hydrochloride
0
N N //~~
I >--N
I / N ~ V ~1/N
NHz
A solution of 60 mg (0.106 mmol) of tert. butyl [1-(1-benzyl-6-naphthalen-1-
ylmethyl-7-oxo-6,7-dihydro-1 H-imidazo[4,5-d]pyridazin-2-yl)-piperidin-3-yl]-
carbaminate in 5 ml dichloromethane was combined with 0.5 ml trifluoroacetic
acid and stirred for two hours at ambient temperature. The mixture was
evaporated to dryness, the residue was dissolved in 5 ml dichloromethane
and the solution was washed with 1 N sodium hydroxide solution and water
and then dried over sodium sulphate. It was again concentrated by
evaporation, the residue was dissolved in a mixture of 3 ml each of diethyl
ether and acetone and the hydrochloride of the product was precipitated by
the dropwise addition of ethereal hydrochloric acid. This was suction filtered
and dried.
Yield: 37.7% of theory



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 36 Foreign filing text
C28H28N60 x HCI (501.04)
Rf value: 0.22 (silica gel, dichloromethane/ethanol 19 : 1 )
Mass spectrum: (M + H)+ = 465
Example 2
2 ~3-amino-piperidin-1-yl)-3-(but-2-~yl~(naphthalen-1-ylmethyl)-3,5-
dihydro-imidazof4,5-dlpyridazin-4-one
CH3
O
N
N ~N~
/ N~ I N
NHZ
2 a) 3-(but-2~nyl;l-2-methylsulphanyl-5-(n~hthalen-1-ylmethyl -3,5-
dihydro-imidazof4,5-d]pyridazin-4-one
CH3
O
N
/ N \ ~ />.'-'g~
N CHa
A solution of 900 mg (2.79 mmol) of 2-methylsulphanyl-5-(naphthalen-1-
ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one (Example 1f) in 15 ml of
dimethylformamide was combined with 415 mg (3.0 mmol) of potassium
carbonate and 399 mg (3.0 mmol) of 1-bromo-2-butyne and stirred at ambient
temperature for eight hours. Then the mixture was diluted with approx. 30 ml
of water and saturated with sodium chloride, whereupon the reaction product
crystallised out. It was suction filtered and purified by column
chromatography
(silica gel, eluant: petroleum ether with 10 - 50% ethyl acetate).
Yield: 71.7% of theory
C2~H~$N40S (374.47)
Rf value: 0.69 (silica gel, petroleum ether/ethyl acetate 1 : 1 )
Mass spectrum: (M + H)+ = 375



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 37 Foreign filing text
2 b) 3-(but-2-ynyl)-2-methylsulphon~rl-5-(nat~hthalen-1-ylmethyl)-3,5-
dihydro-imidazoj4,5-dlayridazin-4-one
~CH3
N N CH3
N \ ~ /~~=O
N O
A solution of 500 mg of potassium permanganate in 20 ml of water was
added dropwise to a solution of 600 mg (1.60 mmol) of 3-(but-2-ynyl)-2-
methylsulphanyl-5-(naphthalen-1-ylmethyl)-3,5-dihydro-imidazo[4,5-
d]pyridazin-4-one in 30 ml glacial acetic acid, with stirring, at ambient
temperature. After three hours at ambient temperature a sodium hydrogen
sulphite solution was added dropwise until the reaction mixture was virtually
decolourised again. Then it was diluted with approx. 50 ml of water and
saturated with sodium chloride. The crude product precipitated was suction
filtered and purified by column chromatography (aluminium oxide; eluant:
dichloromethane).
Yield: 43.0% of theory
CZ~H~gN4O3S (406.47)
Rf value: 0.70 (silica gel, dichloromethane/ethanol 19 : 1 )
Mass spectrum: (M + H)+ = 407
'H-NMR spectrum (ds-DMSO): 8 = 1.80 (s, 3H); 3.60 (s, 3H); 5.61 (s, 2H);
5.85 (s, 2H); 7.30 (dd, 1 H); 7.45 (t, 1 H); 7.58 (m, 2H); 7.90 (dd, 1 H);
7.96 (dd,
1 H); 8.30 (dd, 1 H); 8.64 (s, 1 H) ppm.
2 c) tert butyl f1-(1-(but-2-ynyl)-6-naphthalen-1-ylmethyl-7-oxo-6,7-dihydro-
1 H-imidazof4 5-dl~yridazin-2-yl)-piperidin-3-yll-carbaminate
~CH3
O
N
/ N Hs
N ~ N O CH3
CHs
O



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 38 Foreign filing text
A mixture of 260 mg (0.64 mmol) of 3-(but-2-ynyl)-2-methylsulphonyl-5-
(naphthalen-1-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one and 800
mg (3.99 mmol) of tert. butyl piperidin-3-yl-carbaminate was stirred for two
hours at 150°C under nitrogen. After cooling it was dissolved in
approx. 15 ml
dichloromethane, washed with dilute ammonia solution and dried over sodium
sulphate. The crude product obtained after the evaporation was purified by
column chromatography (silica gel; eluant: dichloromethane with 1 - 5%
ethanol) .
Yield: 35.6% of theory
C30H34N603 (526.64)
Rf value: 0.53 (silica gel, dichloromethane/ethanol 19 : 1 )
Mass spectrum: (M + H)+ = 527
2 d) 2-(3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(naphthalen-1-ylmethyl -3 5-
dihydro-imidazof4,5-dlpyridazin-4-one hydrochloride
~CH3
O
N
N ~N~
/ N~ I N
NHz
A solution of 120 mg (0.23 mmol) of tert. butyl [1-(1-(but-2-ynyl)-6-
naphthalen-
1-ylmethyl-7-oxo-6,7-dihydro-1 H-imidazo[4,5-d]pyridazin-2-yl)-piperidin-3-yl]-

carbaminate and 1.0 ml of trifluoroacetic acid in 10 ml dichloromethane was
stirred for three hours at ambient temperature and then evaporated to
dryness. The residue was dissolved in 15 ml dichloromethane, the solution
was washed with 1 N sodium hydroxide solution, dried over sodium sulphate
and evaporated down. The crude product thus obtained was purified by
column chromatography (silica gel; eluant: dichloromethane with 2 - 5%
ethanol). The product was dissolved in 8 ml of ethyl acetate, and the
hydrochloride was precipitated by the dropwise addition of ethereal
hydrochloric acid, suction filtered and dried.
Yield: 66.3% of theory



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 39 Foreign filing text
C25H2sNs0 x HCI (462.99)
Rf value: 0.22 (silica gel, dichloromethane/ethanol 9 : 1 j
Mass spectrum: (M + H)+ = 427
'H-NMR spectrum (dfi-DMSO): s = 1.69 (m, 2H); 1.80 (s, 3H); 1.93 (m, 1H);
2.07 (m, 1 H); 3.20 (m, 2H); 3.40 (m, 1 H); 3.52 (m, 1 H); 3.73 (m, 1 H); 5.19
(m,
2H); 5.80 (s, 2H); 7.22 (d, 1 H); 7.45 (t, 1 H); 7.57 (m, 2H); 7.88 (dd, 1 H);
7.96
(d, 1 H); 8.29 (d, 1 H); 8.31 (s, 1 H); 8.40 (broad s, 3H) ppm.
Example 3
3 5-Dibenzy~pj~erazin-1-yl)-3,5-di~dro-imidazof4,5-clpyridin-4-one
i I
O
N N ~1
w I ~~-N~i _H
N
3 a) 2,4-dichloro-3-nitrop rid
O CI
H..N NOZ N ~ N02
I ~ I
O-H ~ CI
A solution of 30.0 g (0.192 mol) 2,4-dihydroxy-3-nitropyridine in 300 ml of
phosphorus oxychloride was refluxed for 50 hours, then approx. 200 ml of
phosphorus oxychloride was distilled off and the residue was decomposed
with ice water (approx. 300 ml). The dark solution thus obtained was extracted
twice with 150 ml of ethyl acetate, the organic phases were washed with
saturated sodium chloride solution, dried and evaporated down. The crude
product thus obtained was purified by column chromatography (silica gel,
eluant: dichloromethane).
Yield: 75% of theory.
Rf value: 0.88 (silica gel, dichloromethane/ethanol = 9:1 )



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 40 Foreign filing text
Mass spectrum: M+ = 192/4/6
3 b) 4-amino-2-chloro-3-nitropyridine
CI
N ~ N02
I ,
NHZ
A solution of 28.0 g (0.193 mol) of 2,4-dichloro-3-nitropyridine in 300 ml of
ammonia-saturated ethanol was stirred for four days at ambient temperature,
then evaporated to dryness and the crude product thus obtained was purified
by column chromatography (silica gel, eluant: dichloromethane with 0 - 5
ethanol).
Yield: 71 % of theory.
C5H4CIN3O2 (173.56)
Mass spectrum: (M + H)+ = 174/6
3 c) 4-amino-2-hydroxy-3-nitropyridine
H
N ~ NOZ
I/
NHZ
A solution of 18.0 g (104 mmol) of 4-amino-2-chloro-3-nitropyridine in 120 ml
dimethylsulphoxide and 30 ml of water was stirred for four hours at
130°C.
The solution was then cooled and left to stand overnight while cooling with
ice. The product that crystallised out was suction filtered, washed with a
little
water and dried at 50°C.
Yield: 69% of theory.
C5H5N3O3 (155.11 )
Mass spectrum: (M + H)+ = 156
(M-H)- = 154



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH 8~ Co. KG Case 1/1427
55216 Ingelheim 41 Foreign filing text
3 d) 3,4-diamino-2-hydroxypyridine
H
N ~ NH2
I
NH2
11.0 g (71 mmol) of 4-amino-2-hydroxy-3-nitropyridine were dissolved in 150
ml of dimethylformamide and reduced by catalytic hydrogenation at ambient
temperature (Pd/C 10%).
Yield: 83% of theory.
C5H~N30 (125.13)
Mass spectrum: (M + H)+ = 126
3 e) 2-Mercapto-3,5-dihydro-imidazof4,5-clp~rridin-4-one
O H
H~N N
i~--'S-H
N
A suspension of 5.0 g (39.96 mmol) of 3,4-diamino-2-hydroxypyridine and
12.82 g (80.0 mmol) of potassium-ethyl xanthogenate in 100 ml of ethanol
was refluxed for three hours. The mixture was then cooled to ambient
temperature and combined with approx. 20 ml of diethyl ether. The
precipitated product was filtered off, washed with approx. 10 ml of diethyl
ether, dried, dissolved in approx. 30 ml of water and this solution was
acidified
with concentrated hydrochloric acid. The product precipitated was suction
filtered, washed with 15 ml of water and dried at 50°C.
Yield: 82% of theory.
C6H5N30S (167.19)
Mass spectrum: (M + H)+ = 168
(M-H)-=166
3 f~ 2-methylmercapto-3.5-dihydro-imidazof4,5-clpyridin-4-one



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 42 Foreign filing text
O H
HEN N
/~S-CH3
N
4.38 g (31.7 mmol) of potassium carbonate and 1.97 ml (31.7 mmol) of methyl
iodide were added to a suspension of 5.30 g (31.7 mmol) of 2-mercapto-3,5-
dihydro-imidazo[4,5-c]pyridin-4-one in 100 ml dichloromethane and 50 ml of
methanol and the mixture was stirred overnight at ambient temperature. Then
a further 15 ml of methanol were added and undissolved ingredients were
filtered off. The filtrate was concentrated by evaporation and the crude
product thus obtained was purified by column chromatography (silica gel,
eluant: dichloromethane with 5-25% ethanol).
Yield: 96% of theory.
C~H~N30S (181.22)
Rf value: 0.53 (silica gel, dichloromethane/ethanol 9 : 1 )
Mass spectrum: (M + H)+ = 182
'H-NMR spectrum (ds-DMSO): 8 = 2.62 (s, 3H); 6.40 (broad s, 1 H); 7.03 (d,
1 H); 11.12 (broad s, 1 H); 12.95 (broad d, 1 H) ppm.
3 g) 3~5-dibenzyl-2-methylmercapto-3,5-dihydro-imidazof4,5-clpyridin-4-one
o ~ /
N
N~ ~ /~S-CH3
N
553 mg (4.0 mmol) of potassium carbonate and 0.48 ml (4.0 mmol) of benzyl
bromide were added to a solution of 362 mg (2.0 mmol) of 2-methylmercapto-
3,5-dihydro-imidazo[4,5-c]pyridin-4-one in 5.0 ml of dimethylformamide and
this mixture was stirred for three hours at ambient temperature. Then it was
diluted with 10 ml of water and extracted three times with 10 ml of ethyl
acetate. The organic extracts were dried and evaporated down, the crude



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 43 Foreign filing text
product thus obtained was purified by column chromatography (silica gel,
eluant: dichloromethane with 0-3% ethanol).
Yield: 26% of theory.
C2~H~gN3OS (361.47)
Rf value: 0.62 (silica gel, dichloromethane/ethanol 19 : 1 )
Mass spectrum: (M + H)+ = 362
'H-NMR spectrum (ds-DMSO): 8 = 2.67 (s, 3H); 5.21 (s, 2H); 5.62 (s, 2H);
6.63 (d, 1 H); 7.20 - 7.37 (m, 10 H); 7.56 (d, 1 H) ppm.
3 h) 3,5-dibenzyl-2-methanesulphonyl-3.5-dihydro-imidazof4,5-clpyridin-4-
one
o ~ /
N
N~ ~ /~~SyO Hs
N O
A solution of 190 mg (1.10 mmol) of 3-chloro-peroxybenzoic acid in 5 ml
dichloromethane was added dropwise to a solution of 181 mg (0.50 mmol) of
3,5-dibenzyl-2-methylmercapto-3,5-dihydro-imidazo[4,5-c]pyridin-4-one in 10
ml of dichloromethane at ambient temperature with stirring. After the addition
had ended the reaction mixture was stirred for a further 30 minutes, then
extracted with approx. 25 ml of 5% sodium hydrogen carbonate solution, the
organic phase was separated off, dried over sodium sulphate and
concentrated by evaporation. The crude product thus obtained, which
contained approx. 20% of the methanesulphinyl compound, was further
processed without any more purification.
Yield: approx. 75% of theory
C2~H~gN3O3S (393.47)
Rf value: 0.66 (silica gel, dichloromethane/ethanol 19 : 1 )
Mass spectrum: (M + H)+ = 394



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 44 Foreign filing text
3 i) 3,5-Dibenzyl-2-(piperazin-1-yl)-3,5-dihydro-imidazof4 5-clpyridin-4-one
0
N
\ N I /~N~ -H
\ N
660 mg (11 mmol) of glacial acetic acid were added dropwise to 860 mg (10
mmol) of piperazine with cooling, then 180 mg of 3,5-dibenzyl-2-
methanesulphonyl-3,5-dihydro-imidazo[4,5-c]pyridin-4-one (crude product
from Example 3 h) were added and the mixture was stirred for 24 hours at
150°C. After cooling approx. 10 ml of water were added, the mixture was
made alkaline with concentrated ammonia solution and the mixture was
extracted three times with 5 ml of dichloromethane. The extracts were dried
over sodium sulphate and concentrated by evaporation. The crude product
thus obtained was purified by column chromatography (silica gel; eluant:
petroleum ether with 20 - 60% ethyl acetate).
Yield: 5.5% of theory
C24H25N5~ (399.50)
Rf value: 0.28 (silica gel, petroleum ether/ethyl acetate 7 : 3)
Mass spectrum: (M + H)+ = 400
Example 4
2-(3-amino-piperidin-1-yl)-5-benzyl-3-(but-2-ynyl)-3 5-dihydro-imidazoj4 5-
clpyridin-4-one
~ CH3
N
N~ I /~N
N
NHZ



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH 8~ Co. KG Case 1/1427
55216 Ingelheim 45 Foreign filing text
4 a) 1-benzyl-4-benzyloxy-3-nitro~yridin-2-one
0
NOZ
HN
\ OH
A solution of 4.68 g (30 mmol) of 2,4-dihydroxy-3-nitro-pyridine in 100 ml of
dimethylformamide was combined batchwise at ambient temperature with
2.88 g (60 mmol) of a 50% suspension of sodium hydride in paraffin oil and
stirred for 15 minutes. Then 8.91 ml (75 mmol) of benzylbromide were added
and the mixture was stirred for 24 hours at 80°C. The solution was then
carefully stirred into approx. 250 ml of water and extracted three times with
70
ml of ethyl acetate. The extracts were washed with saturated sodium chloride
solution, dried and evaporated down in vacuo. The residue was triturated with
diethyl ether, suction filtered and dried. The product thus obtained was
further
processed without any purification.
Yield: 59% of theory.
C~sH~sN2~a (336.35)
Mass spectrum: (M+H)+ = 337
4 b) 4-amino-1-benzyl-3-nitro-pyridin-2-one
0
\ No2
N
\ I NH
2
20 ml of a saturated ethanolic ammonia solution were added to a solution of
5.5 g (16.3 mmol) of 1-benzyl-4-benzyloxy-3-nitro-pyridin-2-one in 50 ml
dichloromethane and stirred for 3 days at ambient temperature in the sealed
flask. The solution was evaporated to dryness, the residue was triturated with
diethyl ether, suction filtered and dried.
Yield: 97% of theory.



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 46 Foreign filing text
C~pH»N3O3 (245.24)
Rf value: 0.31 (silica gel; dichloromethane / ethanol 19 : 1 )
4 c) 1-benzyl-3,4-diamino-pyridin-2-one
0
N NHZ
I~ ~I
NH2
3.9 g (15.9 mmol) of 4-amino-1-benzyl-3-nitro-pyridin-2-one, dissolved in 250
ml of tetrahydrofuran, were hydrogenated over platinum oxide at 50 psi of H2
pressure and at ambient temperature. After the catalyst had been filtered off
the filtrate was concentrated by evaporation and the residue was further
processed in crude form.
Yield: 99% of theory.
C~2H~3N3O (215.26)
4 d) 5-benzyl-2-mercapto-3,5-dihydro-imidazof4 5-clpyridin-4-one
0
H
N
/ N~ I /~SH
N
A solution of 3.40 g (15.8 mmol) of 1-benzyl-3,4-diamino-pyridin-2-one and
4.99 g (28.0 mmol) of N,N~-thiocarbonyl-diimidazole in 200 ml of
tetrahydrofuran was stirred overnight at ambient temperature, then
concentrated by evaporation, the residue was combined with approx. 50 ml of
water, adjusted to pH 7 with 2N hydrochloric acid and this solution was
stirred
for approx. 30 minutes at ambient temperature. The product precipitated was
suction filtered, washed with approx. 50 ml of water and dried at 50°C.
Yield: 98% of theory.
C13H11N3~S (257.32)
Rf value:: 0.45 (silica gel; dichloromethane / ethanol 9 : 1 )



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 47 Foreign filing text
4 e) 5-benzyl-2-methylsulphanyl-3,5-dihydro-imidazof4,5-clpyridin-4-one
0
H
\ N ~ ~~ CH3
S
\ N
4.0 g (15.55 mmol) of 5-benzyl-2-mercapto-3,5-dihydro-imidazo[4,5-c]pyridin-
4-one were suspended in a mixture of 100 ml of dichloromethane and 50 ml of
methanol, then 2.15 g (15.55 mmol) of potassium carbonate and 0.97 ml
(15.55 mmol) of iodomethane were added and the mixture was stirred for 1
hour at ambient temperature. Then it was filtered, the filtrate was evaporated
down and the residue was further reacted in its crude form.
Yield: 94% of theory.
C~4H~3N3OS (271.34)
Rf value:: 0.49 (silica gel; dichloromethane / ethanol 9 : 1 )
Mass spectrum: (M+H)+ = 272
4 ~ 5-benzyl-3-(but-2-ynyl -2-methylsulphanyl-3,5-dihydro-imidazof4,5-
clpyridin-4-one
CH3
O
\ N ~ /~S CHs
\ N
2.07 g (15.0 mmol) of potassium carbonate were added to a solution of 4.0 g
(14.7 mmol) of 5-benzyl-2-methylsulphanyl-3,5-dihydro-imidazo[4,5-c]pyridin-
4-one and 1.31 ml (15.0 mmol) of 1-bromo-2-butyne in 100 ml of
dimethylformamide and stirred for one hour at ambient temperature. Then
approx. 200 ml of saturated sodium chloride solution were added and the
mixture was extracted three times with 50 ml of ethyl acetate. The extracts
were washed with saturated sodium chloride solution, dried over sodium
sulphate and evaporated down. The crude product thus obtained was purified



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 48 Foreign filing text
' by column chromatography (silica gel; eluant: dichloromethane with 0 - 2%
ethanol).
Yield: 48% of theory.
C~8H~~N30S (323.42)
Rf value:: 0.71 (silica gel; dichloromethane / ethanol 9 : 1 )
'H-NMR spectrum (ds-DMSO): b = 1.78 (s, 3H); 2.70 (s, 3H); 5.18 (s, 2H);
5.23 (s, 2H); 6.61 (d, 1 H); 7.23 - 7.38 (m, 5H); 7.53 (d, 1 H) ppm.
Mass spectrum: (M+H)+ = 324
4 g) 5-benzyl-3-(but-2-ynyl)-2-methylsulphonyl-3 5-dihydro-imidazof4 5-
c]pyridin-4-one
CH3
O
\ N N CHs
/ \ ~ /~IS.~
O
A solution of 316 mg (2.0 mmol) of potassium permanganate in 10 ml of water
was slowly added dropwise with stirring to a solution of 400 mg (1.24 mmol) of
5-benzyl-3-(but-2-ynyl)-2-methylsulphanyl-3,5-dihydro-imidazo[4,5-c]pyridin-4-
one in 10 ml of concentrated acetic acid. After three hours at ambient
temperature 400 mg of sodium bisulphite (Na2S205) were added and the
mixture was diluted with approx. 30 ml of water. It was extracted five times
with 30 ml of dichloromethane, the extracts were dried over sodium sulphate
and evaporated down. The product thus obtained was further reacted without
purification.
Yield: 50% of theory.
C~gH~7N303S (355.42)
Rf value:: 0.40 (silica gel; dichloromethane / ethanol 19 : 1 )
Mass spectrum: (M+H)+ = 356
4 h) tert-butyl f1-(5-benzyl-3-(but-2-ynyl)-4-oxo-4 5-dihydro-3H-imidazof4 5-
clayridin-2-yl)-piaeridin-3-yll-carbaminate



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 49 Foreign filing text
CH3
O
N
I / N~ I / N CH3
N ~~ O-~CH3
H \\ CH3
O
A mixture of 220 mg (0.62 mmol) of 5-benzyl-3-(but-2-ynyl)-2-
methylsulphonyl-3,5-dihydro-imidazo[4,5-c]pyridin-4-one and 781.1 mg (3.90
mmol) of tert-butyl piperidin-3-yl-carbaminate was heated to 170°C
under
nitrogen for 5 hours. After cooling to ambient temperature the crude product
thus obtained was purified by column chromatography (silica gel; eluant:
dichloromethane with 0 - 3% ethanol).
Yield: 23% of theory
C27H33N5O3 (475.60)
Rf value:: 0.32 (silica gel; dichloromethane / ethanol 19 : 1 )
Mass spectrum: M+ = 475
(M + H)+ = 476
4 i) 2-(3-amino-piperidin-1-yl)-5-benzyl-3-(but-2-ynyl -3 5-dih
imidazof4,5-clpyridin-4-one
~CH3
O
N
~ ~ I /~-N
N ~
NHZ
A solution of 70.0 mg (0.147 mmol) of tert-butyl [1-(5-benzyl-3-(but-2-ynyl)-4-

oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl)-piperidin-3-yl]-carbaminate and
0.5 ml trifluoroacetic acid in 3.0 ml dichloromethane was stirred for one hour
at ambient temperature. The mixture was then concentrated by evaporation in
vacuo and the residue was dissolved in approx. 5 ml dichloromethane. This
solution was washed with approx. 5 ml of 1 N sodium hydroxide solution, then
dried over sodium sulphate and concentrated by evaporation. The residue



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 50 Foreign filing text
was dissolved in approx. 3 ml of ethyl acetate, and the product was
precipitated as the hydrochloride by the dropwise addition of ethereal
hydrochloric acid, suction filtered and dried.
Yield: 41 % of theory.
C22H25N5O x HCI (411.94)
Rf value: 0.22 (silica gel; dichloromethane / ethanol 9 : 1 )
Mass spectrum: M+ = 375
(M+H)+=376
Example 6
2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl -~(1 2 4ltriazolof4 3-alayridin-3-

ylmethyl~-3,5-dihydro-imidazoj4 5-dlpYridazin-4-one hydrochloride
\ O i CHs
N N
~~N
N_N Nw N
NHz
Prepared analogously to Example 1j by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 72% of theory.
C2~ H23N9O (417.48)
Mass spectrum: (M + H)+ = 418
'H-NMR spectrum (ds-DMSO): 8 = 1.70 (m, 2H); 1.80 (s, 3H); 1.93 (m, 1H);
2.02 (m, 1 H); 3.20 (m, 2H); 3.38 (m, 1 H); 3.50 (m, 1 H); 3.74 (m, 1 H); 5.17
(m,
2H); 5.98 (s, 2H); 7.45 (t, 1 H); 7.90 (dd, 1 H); 8.02 (d, 1 H); 8.33 (s, 1
H); 8.50
(broad s, 3H); 8.98 (d, 1 H) ppm.



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH 8~ Co. KG Case 1/1427
55216 Ingelheim 51 Foreign filing text
Example 7
2-(3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(3-methyl-isoguinolin-1-ylmethy~-
3,5-dihydro-imidazof4,5-d~pyridazin-4-one
I ~ O ~ CH3
N
~N ~N~
I iN N~
CH3 NHz
Prepared analogously to Example ~ from tert-butyl {1-[1-(but-2-ynyl)-6-(3-
methyl-isoquinolin-1-ylmethyl)-7-oxo-6,7-dihydro-1 H-imidazo[4,5-d]pyridazin-
2-yl]-piperidin-3-yl}-carbaminate and trifluoroacetic acid in dichloromethane.
Yield: 57% of theory.
C25H2~N~0 x HCI (477.99)
Rf value: 0.13 (silica gel; dichloromethane / ethanol 9 : 1 )
Mass spectrum: (M + H)+ = 442
Example 35
2-(3-amino-piperidin-1-yl)-3-(but-2-ynyll-5-(naphthalen-1-ylmethyl)-3 5-
dihydro-imidazof4,5-clpyridin-4-one
i_ CH3
I
N
N~ I ~~N
N
N HZ
Prepared analogously to Example ~ by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 92% of theory.
C26H2~N50 (425.54)
Mass spectrum: (M + H)+ = 426
Rf value: 0.54 (silica gel; dichloromethane / methanol / conc. ammonia 8 : 2
0.1 )



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 52 Foreign filing text
Example 86
2-(3-a mino-piperidin-1-yl)-3-(3-methyl-but-2-enyl)-5-(3-methyl-isoguinolin-1-
ylmethyl)-3,5-dihydro-imidazof4 5-clpyridin-4-one
H_C
Prepared analogously to Example 1i by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 84% of theory.
C2~H32N60 (456.59)
Mass spectrum: (M + H)+ = 457
'H-NMR spectrum (ds-DMSO): 8 = 1.11 - 1.25 (m, 1 H); 1.57 - 1.90 (m, 9H);
2.50 - 2.65 (m, 1 H); 2.75 - 2.88 (m, 2H); 3.25 - 3.45 (m, 2H); 4.81 (d, 2H);
5.33 (t, 1 H); 5.78 (s, 2H); 6,48 (d, 1 H); 7.40 (d, 1 H); 7.58 - 7.65 (m,
2H); 7.72
(t, 1 H); 7.89 (d, 1 H); 8.40 (d, 1 H) ppm.
Example 136
2-((R)-3-a mino-piperid in-1-yl)-3-(but-2-ynyl)-5-(4-methyl-auinazolin-2-
ylmethyl)-3,5-dihydro-imidazof4 5-dlpyridazin-4-one
~ CH3
N~ N N
/~N
N
CH3 NHZ
136 a) dimethyl 2-bromo-1-(but-2-ynyl)-1H-imidazol-4 5-dicarboxylate



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 111427
55216 Ingelheim 53 Foreign filing text
H3C~0 i
O N
I ~>--gr
H CEO ~N
3
O
A solution of 15.0 g (57.0 mmol) of dimethyl 2-bromo-imidazole-4,5-
dicarboxylate, 5.15 ml (57.0 mmol) of 1-bromo-2-butyne and 50 ml of N,N-
diisopropylethylamine in 280 ml of tetrahydrofuran was refluxed for one hour.
The mixture was concentrated by evaporation, the residue combined with
approx. 100 ml of water and extracted three times with 70 ml of ethyl acetate.
The extracts were washed with 50 ml of water, dried and evaporated down.
The crude product thus obtained was purified by column chromatography
(silica gel; eluant: dichloromethane with 0 - 2% ethanol).
Yield: 75% of theory.
C»H~~BrN2O4 (315.13)
Rf value:: 0.82 (silica gel; dichloromethane / ethanol 9 : 1 )
Mass spectrum: (M + H)+ = 315/317
136 b) methyl 2-bromo-3-(but-2- rLnyl)-5-formyl-3H-imidazol-4-carboxylate
CH3
O N
~~-Br
~N
O
43 ml (43 mmol) of a 1 molar solution of diisobutyl-aluminium hydride in
tetrahydrofuran within 20 minutes were added dropwise to a solution of 13.5 g
(42.84 mmol) of dimethyl 2-bromo-1-(but-2-ynyl)-1H-imidazol-4,5-
dicarboxylate in 220 ml of tetrahydrofuran under an argon atmosphere at
-70°C. The mixture was stirred for a further 4 hours at -70°C,
then 20 ml of a
mixture of 1 M hydrochloric acid and tetrahydrofuran were added dropwise.
After heating to ambient temperature approx. 200 ml of water were added and



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG ~ Case 1/1427
55216 Ingelheim 54 Foreign filing text
the mixture was extracted three times with 70 ml of ethyl acetate. The
extracts
were dried and evaporated down, and the crude product thus obtained was
purified by column chromatography (silica gel; eluant: petroleum ether with 20
- 50% ethyl acetate).
Yield: 52% of theory.
C~oH9BrN203 (285.10)
Mass spectrum: (M+H)+ = 285/287
'H-NMR spectrum (ds-DMSO): 8 = 1.80 (s, 3H); 3.93 (s, 3H); 5.11 (s, 2H);
10.12 (s, 1 H) ppm.
136 c) 2-bromo-3-(but-2-ynyl)-3,5-dihydro-imidazof4,5-dlp~iridazin-4-one
~ CH3
N
HN ~ ~~Br
N~ N
0.31 ml of hydrazine hydrate (99%, 6.31 mmol), dissolved in 1 ml of ethanol,
were added dropwise at ambient temperature to a solution of 1.80 g (6.31
mmol) of methyl 2-bromo-3-(but-2-ynyl)-5-formyl-3H-imidazol-4-carboxylate in
25 ml of ethanol. Five minutes later, 1.5 ml of concentrated acetic acid were
added and the mixture was refluxed for 30 minutes. After cooling the
precipitated solid was suction filtered, washed with 10 ml of ethanol and 20
ml
of diethyl ether and dried.
Yield: 74% of theory.
C9H~BrN40 (267.09)
Mass spectrum: (M+H)+ = 267/269
H-NMR spectrum (ds-DMSO): 8 = 1.80 (s, 3H); 5.28 (s, 2H); 8.38 (s, 1 H);
12.99 (s, 1 H) ppm.



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 ingelheim 55 Foreign filing text
136 d) 2-bromo-3-(but-2-ynyl~-5-(4-methyl-auinazolin-2-ylmethyl)-3,5-
dihydro-imidazo~4.5-dlpyridazin-4-one
489 mg (1.5 mmol) of caesium carbonate were added to a solution of 300 mg
(1.12 mmol) of 2-bromo-3-(but-2-ynyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-
one and 260.1 mg (1.35 mmol) of 2-chloromethyl-4-methyl-quinazoline in 4.0
ml of dimethylformamide and this mixture was stirred for 2 hours under an
argon atmosphere at 80°C. Then it was diluted with 10 ml of water and
stirred
for 30 minutes at ambient temperature. The crude product precipitated was
suction filtered and purified by column chromatography (silica gel; eluant:
petroleum ether with 20 - 50% ethyl acetate).
Yield: 51 % of theory.
C~9H~5BrNs0 (423.28)
136 e) tert-butyl {1-f1- but-2-~~6-j4-methyl-auinazolin-2-ylmethyl)-7-oxo-
6 7-dihydro-1 H-imidazof4 5-dlp~rridazin-2-yll-piperidin-3-yl~carbaminate
O ~ CH3
\ Nw N
~N ~N
/ iN N~ ~ / CH3
N ~--~ O'-'~CH3
CH3 H"~ CH3
O
A solution of 240 mg (0.567 mmol) of 2-bromo-3-(but-2-ynyl)-5-(4-methyl-
quinazolin-2-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one and 140.2
mg (0.70 mmol) of tert-butyl (R)-piperidin-3-yl-carbaminate in 4 ml
dimethylsulphoxide was combined with 95 mg (0.9 mmol) of sodium
carbonate and stirred for 3 hours at 80°C. Then another 50 mg of tert-
butyl



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 56 Foreign filing text
piperidin-3-yl-carbaminate were added and the mixture was stirred for a
further 2 hours at 80°C. After cooling to ambient temperature it was
combined
with 10 ml of water and stirred for 30 minutes. The product precipitated was
suction filtered, washed with 5 ml of water and dried.
Yield: 81 % of theory.
C2gH34NgO3 (542.65)
136 f] 2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl~5-(4-methyl-auinazolin-2-
ylmethyl)-3,5-dihydro-imidazof4,5-dlayridazin-4-one
O i CHs
N~N N
I / iN N~ I /~N~
N
3 NHz
Prepared analogously to 11 from 240 mg (0.442 mmol) of tert-butyl f1-[1-(but-
2-ynyl)-6-(4-methyl-quinazolin-2-ylmethyl)-7-oxo-6,7-dihydro-1 H-imidazo[4,5-
d]pyridazin-2-yl]-piperidin-3-yl}-carbaminate with trifluoroacetic acid in
dichloromethane.
Yield: 56% of theory.
C2aH2sNs0 (442.53)
Rf value:: 0.42 (silica gel; dichloromethane / ethanol 9 : 1 with the addition
of
1 drop of conc. ammonia solution)
Mass spectrum: (M+H)+ = 443
'H-NMR spectrum (ds-DMSO): 8 = 1.23 - 1.37 (m, 1 H); 1.60 - 1.95 (m, 6H);
2.75 - 3.10 (m, 6H); 3.58 - 3.72 (m, 2H); 5.10 (s, 2H); 5.61 (s, 2H); 7.70 (t,
1 H); 7.82 (d, 1 H); 7.93 (t, 1 H); 8.28 (d, 1 H); 8.30 (s, 1 H); ppm
(exchangeable
protons not visible).
Example 138
2-((R)-3-amino-piperidin-1-yl)-3-(but-2- ny~(benzofdlisothiazol-3-ylmethyl)-
3,5-dihydro-imidazof4.5-dlpyridazin-4-one



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 57 Foreign filing text
CH3
0
I N I N~N
g-N N ~ N
NH2
Prepared analogously to Example 1,i by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 83% of theory.
C22H23N~OS (433.54)
Mass spectrum: (M + H)+ = 434
Rf value: 0.15 (silica gel; dichloromethane / methanol 9 : 1 )
Example 139
2-((R)-3-amino-piperid in-1-yl)-3-(but-2-ynyl ~benzof dlisoxazol-3-ylmethyl )-
3,5-dihydro-imidazol4,5-dlpyridazin-4-one
~CH3
O
I N I N~N
O-N N ~ N
NHZ
Prepared analogously to Example ~ by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 67% of theory.
C22H23N702 (417.47)
Mass spectrum: (M + H)+ = 418
Rf value: 0.40 (silica gel; dichloromethane / methanol / conc. ammonia 9 : 1
0.1 )
Example 140
2-((R)-3-amino-piperidin-1-yl -(but-2-yn rLl)-5-(1-methyl-1H-indazol-3-
ylmeth~)-3,5-dihydro-imidazof4,5-dlpyridazin-4-one



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 58 Foreign filing text
" CH3
O
N N
I i ~ ~~N
N-N N w N
i
HsC NH2
Prepared analogously to Example 1j by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 90% of theory.
C2sH2sNs0 (430.52)
Mass spectrum: (M + H)+ = 431
Rf value: 0.15 (silica gel; dichloromethane / methanol 9 : 1 )
Example 178
2-(3-amino-piaeridin-1-yl)-3-(but-2-ynyl)-5- 2-oxo-2-phenyl-ethyl)-3 5-dihydro-

imidazo(4,5-dlpyridazin-4-one
O ~ CH3
N N
O
N
NHz
Prepared analogously to Example 11 by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 79% of theory.
C2sH2sNs02 (420.51 )
Mass spectrum: (M+H)+ = 421
~H-NMR spectrum (d6-DMSO): 8 = 1.16 -1.27 (m, 1 H); 1.60 - 1.95 (m, 9H);
2.65 (dd, 1 H); 2.88 (m, 2H); 3.35 - 3.54 (m, 2H); 4.87 (d, 2H); 5.33 (t, 1
H);
5.70 (s, 2H); 7.60 (t, 2H); 7.72 (t, 1 H); 8.07 (d, 2H); 8.30 (s, 1 H) ppm.



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 59 Foreign filing text
The following compounds may be prepared analogously to the foregoing
Examples and other methods known from the literature:
Ex. Structure Ex~ Structure
) ~ (2) / CH3
O \ / O
N w I N~ N I \ N \ I N>-- N
I ~ N NHZ I i N NH2
(g) ~ (4) / CH3
O ~ / o
w I N~ ~/ H I / w I NON
N N
NH2
(5) H C O ~_ CHs (6) O i CHs
sN II N N ~~N N N
N N w I N~N N-~N w I ~~N
N
NHZ NHZ
O ~ CH3 ($) / CH3
N N O
I ~ N 'N w I N~N / \ N I N~N
CH NH2 / \ \ N
NH2
(g) ~CH2 (~ Q) CH2
N O ~ N o ~CH3
I v N N I v N N
I \ W I N~ N~ \ _ ~ I N~ N
NHz / ~ NHZ



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 60 Foreign filing text
(11 ) I CH3 (12) H3C I CH3
N O ~CH3 N O CH3
w
N ~ N
I \ ~ I ~~-N I ~ I ~~-N
' ~N \ ~N
I ~ /
NHz ~ NHZ
(13) H3C I CH3 (14) ~CH
I//O
N
N
I N~ N N I \ ~ I ~~ N
N~N I ~ ~N
I NHz
NHZ
(15) / CH3 (16)
N O ~ N O
I \ w I N~-N I v ~ I N~-N
/ N ~ / \ N
NH2 ~ NH2
(1~) ~ (18)
I
O
I N~ N N N' > I N~ N O N
I \ ~ IN~~ \ ~ I ~~-N
I N
NH2 ~ NH2
(19) ~ (2~) F
N o I~
N O
I \ \ I /~ N I N\ N N F
I U,N ~ ~ i~N
NHz I \ W N
NHz
(21 ) O \ (22) S \
O ~ O w
I Nv N I N N I Nv N N
\ \ ~N~ \ ~ I ~~-N
/ ~--~ / N
NH2 ~ NH2



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 61 Foreign filing text
(23) 0 (24)
~/ o ~/
N ~ N
I ~ N N I ~ N N
I \ \ I N~--N~ I \ ~ I N~-N
NHz ~ NHz
o /CH3
H3C. ~ I N~N H3C~ \ I N>--N
~N ~N
NHz NHz
o /'cH3 (2g) o ~ CH3
H3C~N N N~ N
l IV~ N~-~- I / ~ I ~~-N
N
NHz NHz
g) C ~ CH3 (3p) o 'CH3
~'N
I / ~ I N~ N N / ~ I N~ N
N N
NHz NHz
(3~ ) ~ ~ CH3 (32) ~ ~ CH3
N~N N / ~ I N~N
N N
NHz NHz
(33) ~ ~ CH3 (34) p ~ CH3
H3C I / w I N~ N I / ~ I N~ N
N
N HsC
NHz NHz
(35) C ~ CH3 (3g) 0 //CH3
~'N
~ ~ I N~'N I ~ ~ I N?-N
/ N NHz I / NHz



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 62 Foreign filing text
(37) p ~ CH3 (3$) p //CH3
H3C I N~ N I N~--N I N~ N I Iv~-N
\ \ N H3C \ \ N
I , NH2 I , NH2
(39) o ~ CH3 (40) o ~ CH3
\ N N
\ I rv~-N ni \ \ I rv>-N
\ N
I , NHZ I , NH2
(41 ) ~ ~ CH3 (42) p ~ CH3
\ N N
N ~ \ I ~~N N w N I N~N
\ N ~ \ \ N
I , NHz I , NH2
(43) p /CH3 (44) p ~ CH3
0
N
I \~ \ I N~N HN \ \ I N~N
I / NHZ I / N NH2
(45) G ~ CH3 (46) p 'CH3
\ N N \ Nw N NN
H C ~ N \ \ I N~ N'---~ I ~ / \ I N~ N
3
I , NH2 NHZ
(47) 0 ~ CH3 (48) p ~ CH3
\ N~N I N N I \ N~N N
i ~N \ ~ ~ ~N \ I i~N
N ~( N
NH2 CH3 NHZ



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 63 Foreign filing text
(4g) O //CH3 (50) ' O ~ CH3
N>--N S~N~ \ I N~-N
N '~ ~ N
NHZ \ / NHz
(51 ) N O i CHa (52) N O i CHs
N N N
i w N
N~N~ H3C N I /~-N
N
\ I NHZ \ I NH2
(53) \ I O ~ CH3 (54) \ I O /CH3
N C~~ ~'N
~~-N\ > ~ I ~~-N
N '~ N
NH2 NH2
(55) / I O ~ CH3 (5g) ~ I O
~N N ~ N ~N
~ I ~~N OH ~ I ~~N
N ~--~ N
NHZ NHZ
(57) \ I O ~ CH3 (5$) \ I O ~ CH3
N N N N
O W I N~ N~ O ~ I N~ N
NHZ \NHz
(5g) OMe (60) OH
I O ~ CH3 / I O //CH3
~/N
O W I N~N \ O ~ I ~~N
N ~ N
NHZ NH2



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 64 Foreign filing text
1) / O ~ CHs (62) O N-CHs
N
N
NHz O ~ I N~N O
NH / I O ! CHs
z
N N
O ~ I ~~ N
N
NHz
(63) NHZ (64) O-CHs
O ~ CHs
HN ~O
O w I N~N / ~ O / CHs
N ~ N
NHz N
O ~ I /~ N
N
NHz
H3C~ .,O (66) O NHz
HN'S.
O / I O ~ CHs
/ I O "CHs
N N
N N ~ i~-N
O ~ I ~~N O \ N
N NHz
NHz
(67) \ I OH O ~CH3 (g$) NHz
N N ~O
O W I ~~ N~ / I O O i CHs
N
NHz ~ N N
O ~ I ~~ N
\N
NHz
) H3C~NH (7~) HsC.N.CHs
1 0 ~O
O O i CHs / I O O ~_ CHs
N
O ~ I N~ N \ O ~ I N~ N
N '-( N
NHz NHz



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 65 Foreign filing text
!7~ ) H3C' O O (72) O~CH3
I NH O ~CH3
NH O ~ CH3 / N
N
O ~. I i N~ O \ N
N N~ \ , ~ /~ N
NHZ NHz
(73) HN~CH3 (74) CH3
OJ
O
O ~ CH NH O i CH3
o ~ 3 ~
\ N N N N
~~N O \ I ~~N~
O ~ N \N
NH2 NHZ
(75) CH3 (76)
O~CH3 O
NH ~ CH NH i CH
\ I O ~ s \ I O ~ s
O \ I N~ N~ O ~. I N~ N
~NHZ NHZ
(77) O ~ CH3 (7$) , CH3
O
N I N
Me0 / \ N\ I i~N \ NI' ~I ~>--N
N O ~N
NHZ NHZ
(79) HN'CH3 ($~) HN~CH
3
O CH3 1 0 CH3
O O ~ ~ I O O
N \ N
O \ I ~~ N O \ I ~~ N
N N
NHz NH2



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 66 Foreign filing text
~$~ ) O~CH3 CH (82) CH3
3 O v
NH ~ l CH
O / NH ~ s
N
\ O NI' ~I ,~-N \ I N O N
~N N
NHz O \ N
NHz
(83) / CH3 (84) NW i
I
\ N~ N O \
i N \ I ~~N HsC~N N
N ~ ~~ N
Hz \ N
NHz
(85) H3C CH (86) H3C CH
/ 3 O / 3
N~ \ I N~N HsC I Nw \ I N~N
\ N
N
NHz I / NHz
(87) (88) H3C,N
O
NH H3 / CH3 ~O H3C CH3
0 , O O /
N N \
O \ I ,~N~ N I N N
N O \ N
NHz
NHz
(89) \ I (90) \ I
O a O
N>--N I / N w I N~N~ H
N N
NHz



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 67 Foreign filing text
(g1 ) H3C CHI (g2) H3C CH3
I I
O O
N
N\ N I ~~N NH I N~ N I N>---N NH2
~N y/ ~N w
N N
(g3) H3C CH3 (g4) H3C CH3
I I
O O
N I NJ-N I ~ N w I N~N
N N NH2
NH
(g5) H3C CH3 (g6) H3C CH3
I I
O O
I / N w I N~N I / N w I N~N NH
N
N
H3C NH2
(97) H3C CH3 (g$) CH3
o I o
I N\ N w I N~ N I N\ N w I N~ N
I , N NH2 I , N NHZ
g) CH2 (100) CHZ
O ~ O ~CH3
I N\ N w I N~ N I N\ N w I N~ N
N ~ N
I , NH2 I , NH2
(101) CH3 (102) H3C CH3
I I
O CHs O CHs
N
I N\ N w I ~~ N I N\ N w I N~ N
~ N NH2 I / N NH2



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 68 Foreign filing text
O ~ O ~ CH3
(103) ~~H (104)
N
N
~ 'N w I N~ N~ N
N I ~ 'N w I N~N
I / NHZ I / NHZ
(105) (106)
O
N O
I N\ N ~ I ~~ N I N\ N I N~ N
N ~--( \ N ~ N
I , NHZ I / NHZ
(107)
I (108)
O O
N
I N\ N w I ~~ N I N\ N w I N~ N
/ N NH2 I / N NH2
(109) F (110)
O
O
I
N p N / F I N\ N w I N~ N
~N ~ '~ N
~ N w I N N I , NH2
I , NH2
(111 ) g ~ (112)
O ~ O ~ O
N
N\ N I i~ N I N~ N I N~- N
N~ N \ N~ N
I , NHZ I / NHZ
(113) ~ (114) / CH3
~ S O
O
N~ N HsC~N N
I ~ N ~ I N~ N~ N w I ~~ N
\N
NH2 NHZ



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 69 Foreign filing text
(115) / CH3 (116) / CH3
O ~ CH3 O /
N
H3C CH N w I N~N H3C N I i~N
s ~N N w
N
NHZ NHZ
(117) CH3 (118) CH3
~N
I/NwIN~N ~\NIN~N
N / N~
N
N
NHZ NH2
(119) ~ CH3 (120) / CH3
o ~ O /
N / Nw I N~N N / Nw I N~N
N
N
NHZ NHZ
(121 ) / CH3 (122) / CH3
O ~ O /
HC N
N
Nw I N~N I / Nw I N N
~N
'~ HsC N
NHZ NHz
(123) \ I (124) o ~ CH3
O
_ Nw N
I / N w I N~ NU H I ~ 'N w I N N
N
/ NHz
(125) \ I (126) O / CH3
O
N~ N
N N~ ~ I 'N I i~ N
I / W I ~ N NH HC ~ Nw N
N ~ s
I / NH2



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 70 Foreign filing text
_ _
O / (128) O ~ CH3
(127) / ~H3
N ~ N N ~ N N
~ N w I N~ N~ N ~ N w I N~ N
I / \NH2 I , NHZ
O / O / CH3
(129) / ~H3 (130)
N
N ~ N
N
N ~ Nw I N~N N ~ Nw I N
I , NH2 I / NH2
(131 ) O / CH3 (132) O / CH3
O
I N~N \ N I N~N
~N Nw N HN ~ Nw N
I / NHZ ~ / NH2
O / O / CH3
(133) / ~H3 (134)
O .N \ N w I N~N I ~ / N w I N~N
H3C I ~ N a N
/ NH2 NHz
(135) O / CH3 (136) O / CH3
N~N I N~-N I ~ N~N I N~-N
~N N~ / ~N N~
N ~ N
NHZ CH3 NHZ
(137) O / CH3 (138) O / CH3
~~N N ~Nw N N
N~
N N w I N~ N~ S ~ I I N N
NHZ \ ~ NH2



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 71 Foreign filing text
(139) O / CH3 1140) O / CH3
N N
p/N\ N w I N~N H3C N/ ~ N I /~N
N Nw N
\ / NH2 \ ~ NH2
(141 ) / O / CH3 (142) S O / CHs
N \ I N
Nw N Nw N
N~ /~N N v /~N~
NH2 NH2
( 144) / ~H3
(143) / ~H3
/ S O ~ ~ I O
~~N N ~ N N
N w I N~N~ OH N w I N~N
NH2 NH2
(145) / CH3 (146) OMe CH
p ~ / p / s
I I
\ N N \ N
O N w I /~ N~ O N w I /~ N
N \ '---~N
NH2 NHZ
(147) OH CH (148) CH3
3 / NHZ p
I O ~ I
N ~ N N
N~ /~N~ ~ ~ /~N~
O Nw N O Nw N
NH2 NH2
(149) H (150) NHz CH
O~N.CH3 p ~ s
O~ CHs ~ I N N
i O ~ O N w I /~ N
N
I N~N NH
z
N
O Nw N
NH2



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 72 Foreign filing text
(151 ) o.CH3 (152) H3~ .O
HN~O HN/S'O CHs
CH3
/I O % ~I O
N N N N
~ ~ ~~-N O N w I ~~N~
O N~ N NN
NH2 NH2
(153) 0 NHZ (154) CH3
O / CH3 / I OH O
~ N
N N~ N~ /~N
N~ O N w N
O N w ~--~N
NH2 NHz
(155) NHZ (156) H3C'NH
O CH3
O / ~O CH3
/I O ~ / O O
N
O N w I N~N \ N I N~-N
O N~N
NHZ
NHz
(157) H3C.N.CH3 (158) H C, ~~
3
O CH3 / NHO O / CH3
o ~ I
/ I O ~ ~ N N
N I N~N O Nw I N N
O N~N NH2
NHZ
(159) O~CH3 CH (160)
HN CH3
/ N H O % ~O
I CHs
N I N~ / I O O
O N~ ~ N
N ~ N N
NHZ O N w I ~~N~
~--~N
NHZ



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 73 Foreign filing text
(161 ) CH3 (162) CH3
O
CH3 ~CH3 CH3
NH p ~ , NH p
\I N \I
N N N
O Nw I N~N O Nw I ~ N
N
NHZ NH2
(163) (164) / CH3
CH3
O O
/ NH / \ N
I ~ ~ I N I ~~N
\ N N Me0 \ N ~ N
O N w I N~N I , NH2
NHZ
(165) CH3 (166) HN.CH3
I
i ~ O 1 0 CHa
\ N N ~ O
O N w I ~~ N~ I p
N \ \ N
NH2 N~ ~~N
O Nw N
NHZ
(167) HN~CH3 (168) O~CH3 CH
NH p I
p CH3
I I
p p \ N N
\ N N O N w I N~ N
O N w I N~N~ NH2
\NH2
(169) CH3 (170) CH3
O~ CH3 I
I o
NH
O \ N~N N
i)-N
\ N N I ~ ~N N~ I
O N w I ~~N~ ~ 'N
N NH2
NH2



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 74 Foreign filing text
(171 ) H3C.NH (172) H3C CH3
O H3C CH3 O I
N
O O ~ N
I ~ ~ N
\ I / ~N N~ I N
N N
O N ~ I ~~N~ NHZ
~--~N
NH2
(173) H3C CH3 (174)
I O H3C CH3
H3C O
I N\ N N / I NH O
~~ N~ \
\ N~ N N N
I ~ ~ ~~--N
NH2 O N w N
NH2
(175) H3C.NH (176) H3C CH3
O H3C CH3 O I
O O I I I N\ N I N~ N
\ N N \ Nw N
N
O N w I ~~N~ I / NH2
N
NH2
(177) N~~ (178) / CH3
) o
O \ I \ N N.
H3C'N I N~ O N w I N~N
N~ i N
N NH2
NH2
(179)
(180)
i
o \ / o \
\ I N~N I \ N I N~N
N
H N NH2



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 75 Foreign filing text
(181)
O
~ ~ I N~-N
N
H3C NHz
Example 182
2-(3-amino-piperidin-1-yl -3-(but-2-ynyl)-5-(auinoxalin-6-ylmethyl)-3 5-
dihydro-
imidazof4,5-dlayridazin-4-one
CH3
~Nw \ N N
I ~~-N
N N
NHZ
Prepared analogously to Example ~ by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 69% of theory.
C23H2aNs0 (428.50)
Mass spectrum: (M + H)+ = 429
'H-NMR spectrum (ds-DMSO): 8 = 1.22 -1.33 (m, 1 H); 1.60 - 1.94 (m 5H);
2.75 - 3.08 (m, 3H); 3.53 - 3.70 (m, 2H); 5.10 (s, 2H); 5.60 (s, 2H); 7.79
(dd,
1 H); 7.90 (s, 1 H); 8.08 (d, 1 H); 8.32 (s, 1 H); 8.92 (s, 2H) ppm
(exchangeable
protons not visible).
Example 183
2-(3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(4-methyl-pyridin-2-ylmethyl)-3 5-
dihydro-imidazoj4,5-dlpyridazin-4-one



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 76 Foreign filing text
~ CH3
HsC \ N N
\~~ I ~-N
iN N~ ~ N
NH2
Prepared analogously to Example ~ by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 90% of theory.
C2~ H25N~0 x 2 HCI (464.40)
Rf value:: 0.43 (silica gel; dichloromethane / methanol 7 : 3)
Mass spectrum: (M + H)+ = 392
'H-NMR spectrum (ds-DMSO): 8 = 1.65 -1.80 (m, 2H); 1.80 (s, 3H); 1.90 -
2.10 (m, 2H); 3.15 - 3.43 (m, 3H); 3.45 - 3.55 (m, 1 H); 3.72 - 3.82 (m, 1 H);
5.18 (q, 2H); 5.70 (s, 2H); 7.58 (s, 1 H); 7.79 (d, 1 H); 8.39 (s, 1 H); 8.60
(broad
s; 2H); 8.73 (d, 1 H) ppm.
Example 184
~~R~-3-amino-piperidin-1-yl~(but-2-yny~-5-(4-phenyl-auinazolin-2-
ylmethyl)-3.5-dihydro-imidazof4.5-dlpyridazin-4-one
Prepared analogously to Example 11 by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 63% of theory.
C29H28N80 (504.60)
Mass spectrum: (M + H)+ = 505
H-NMR spectrum (d6-DMSO): 8 = 1.22 -1.33 (m, 1 H); 1.60 - 1.95 (m, 5H);
2.78 (dd, 1 H); 2.85 - 3.06 (m, 2H); 3.56 - 3.72 (m, 2H); 5.11 (s, 2H); 5.72
(s,
2H); 7.56 - 7.75 (m, 6H); 7.90 - 8.03 (m, 2H); 8.08 (d, 1 H); 8.30 (s, 1 H)
ppm.



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 77 Foreign filing text
Example 185
~~R)-3-amino-piperid in-1-yl)-3-(but-2-ynyl)-5-(auinoxalin-2-ylmethyl)-3,5-
dihydro-imidazo14,5-dlpyridazin-4-one
CH3
N N
~~N
N N
NHz
Prepared analogously to Example 11 by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 88% of theory.
C2sH2aNa0 x HCI (464.96)
Mass spectrum: (M + H)+ = 429
'H-NMR spectrum (ds-DMSO): 8 = 1.63 -1.75 (m, 2H); 1.77 (s, 3H); 1.88 -
2.10 (m, 2H); 3.13 - 3.26 (m, 2H); 3.35 - 3.56 (m, 2H); 3.75 (dd, 1 H); 5.15
(q,
2H); 5.71 (s, 2H); 7.80 - 7.86 (m, 2H); 7.99 (m, 1 H); 8.09 (m, 1 H); 8.33 (s,
1 H); 8.45 (broad s, 2H); 8.92 (s, 1 H) ppm.
Example 186
2-((R)-3-amino-aiperidin-1-yl)-3-(but-2-ynyl)-5-(2,3-dimethyl-auinoxalin-6-
I~thyl)-3,5-dihydro-imidazof4,5-dlpyridazin-4-one
CH3
H3C N~ ~ N
~ '~N ~N
H C" ~'~~ N ~ I N
3 N
NH2
Prepared analogously to Example 1i by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 52% of theory.
C25H28N80 (456.56)
Mass spectrum: (M + H)+ = 457



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 78 Foreign filing text
'H-NMR spectrum (ds-DMSO): 8 = 1.18 - 1.31 (m, 1 H); 1.58 - 1.72 (m, 1 H);
1.73 -1.93 (m, 5H); 2.66 (s, 3H); 2.68 (s, 3H); 2.75 (dd, 1 H); 2.83 - 3.05
(m,
1 H); 3.55 - 3.68 (m, 2H); 5.10 (s, 2H); 5.53 (s, 2H); 7.62 (dd, 1 H); 7.70
(s,
1 H); 7.92 (d, 1 H); 8.31 (s, 1 H) ppm.
Example 187
2-((R)-3-amino-piperid in-1-yl)-3-(but-2-ynyl)-5-(4-cyano-naphthalen-1-
ly meths -3,5-dihydro-imidazof4,5-dlayridazin-4-one
O ~ CH3
N
~N
/ Nw I N
N / NHZ
Prepared analogously to Example 1j by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 62% of theory.
C2sH2sN70 (451.53)
Mass spectrum: (M + H)+ = 452
' H-NMR spectrum (ds-DMSO): 8 = 1.22 -1.32 (m, 1 H); 1.58 - 1.71 (m, 1 H);
1.75 -1.93 (m, 5H); 2.77 (dd, 1 H); 2.83 - 3.05 (m, 2H); 3.55 - 3.70 (m, 2H);
5.60 (s, 2H); 5.88 (s, 2H); 7.28 (d, 1 H); 7.76 - 7.88 (m, 2H); 8.10 (d, 1 H);
8.17
(d, 1 H); 8.30 (s, 1 H); 8.47 (d, 1 H) ppm.
Example 188
2-(3-amino-piperidin-1-yl)-3-(3-methyl-but-2-enyl)-5-(2-oxo-2-phen I-a
3, 5-d i hyd ro-i m idazof4, 5-cl pyrid i n-4-o ne
HsC CHa
O
N N
p
N
NHz



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 79 Foreign filing text
Prepared analogously to Example 11 by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 69% of theory.
C24H29N02 (419.53)
Mass spectrum: (M + H)+ = 420
~H-NMR spectrum (ds-DMSO): b = 1.15 -1.27 (m, 1 H); 1.57 - 1.92 (m, 9H);
2.55 - 2.70 (m, 2H); 2.76 - 2.92 (m, 2H); 3.41 (dt, 1 H); 4.80 (d, 2H); 5.32
(t,
1 H); 5.04 (s, 2H); 6.51 (d, 1 H); 7.34 (d, 1 H); 7.60 (t, 2H); 7.70 (t, 1 H);
8.08 (d,
2H) ppm.
Example 189
2-~-amino-piperidin-1-yl)-3-(3-methyl-but-2-enyl)-5-(2-oxo-2-phenyl-ethyl)-
3.5-dihydro-imidazof4.5-dlpyridazin-4-one
Prepared analogously to Example ~ by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 88% of theory.
C22H24Ns02 (404.47)
Mass spectrum: (M + H)+ = 405
H-NMR spectrum (ds-DMSO): 8 = 1.55 (m, 1 H); 1.70 (m, 1 H); 1.88 (m, 1 H);
1.99 (m, 1 H); 3.05 - 3.22 (m, 3H); 3.57 (m, 1 H); 3.71 (dt, 1 H); 5.11 (s,
2H);
5.70 (s, 2H); 7.60 (t, 2H); 7.72 (t, 1 H); 8.08 (d, 2H); 8.32 (s, 1 H) ppm.
Example 190
2-(3-amino-piperidin-1-yl -~(3-methyl-but-2-eny~-~naphthalen-1-ylmethyl~
3,5-dihydro-imidazof4.5-clayridin-4-one



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 80 Foreign filing text
Prepared analogously to Example ~ by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 86% of theory.
C27H31N5~ (441.58)
Mass spectrum: (M + H)+ = 442
~H-NMR spectrum (ds-DMSO): 8 = 1.13 -1.75 (m,1 H); 1.57 - 1.95 (m, 9H);
2.57 (dd, 1 H); 2.83 (m, 2H); 3.30 - 3.47 (m, 2H); 4.87 (d, 2H); 5.39 (t, 1
H);
5.68 (s, 2H); 6.50 (d, 1 H); 7.09 (d, 1 H); 7.32 (d,1 H); 7.42 (t, 1 H); 7.58
(m, 2H);
7.89 (d, 1 H); 7.98 (d, 1 H); 8.21 (d, 1 H) ppm.
Example 191
2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl~4-fluoronaphthalen-1-
ylmethyl)-3,5-dihydro-imidazof4 5-dlpyridazin-4-one hydrochloride
\ O i CHs
\ N
--N
/ Nw
NHz
Prepared analogously to Example 11 by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 88% of theory.
C2sH25FNs0 (444.52)
Mass spectrum: (M + H)+ = 445
'H-NMR spectrum (ds-DMSO): 8 = 1.70 (m, 2H); 1.81 (s, 3H); 1.94 (m, 1 H);
2.03 (m, 1 H); 3.19 (m, 2H); 3.40 (m, 1 H); 3.50 M, 1 H); 3.74 (m, 1 H); 5.19
(m,



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 81 Foreign filing text
2H); 5.77 (s, 2H); 7.28 (d, 2H); 7.76 (m, 2H); 8.10 (d, 1 H); 8.31 (s, 1 H);
8.38
(d, 1 H); 8.47 (broad s, 3H) ppm.
Example 192
2-((R)-3-amino-piperid in-1-yl)-3-(but-2-~nyl)-5-(6-methylbenzoxazol-2-
ylmethyl)-3 5-dihydro-imidazof4,5-dlpyridazin-4-one hydrochloride
//CH3
O ~i
~O~N~ ~ N~N
H C ~N
3
NHZ
Prepared analogously to Example ~ by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 81 % of theory.
C23H25N~02 (431.50)
Mass spectrum: (M + H)+ = 432
'H-NMR spectrum (ds-DMSO): 8 = 1.70 (m, 2H); 1.80 (s, 3H); 1.94 (m, 1 H);
2.04 (m, 1 H); 2.43 (s, 3H); 3.21 (m, 2H); 3.40 (m, 1 H); 3.51 (m, 1 H); 3.75
(m,
1 H); 5.15 (dd, 2H); 5.63 (s, 2H); 7.17 (d, 1 H); 7.50 (s, 1 H); 7.56 (d, 1
H); 8.35
(s, 1 H); 8.46 (broad s, 3H) ppm.
Example 193
2-((R)-3-amino-pJ~erid in-1-yl)-3-(but-2-yn~)-5-( 1-phen~ilbenzimidazol-2-
ly methyl)-3,5-dihydro-imidazof4,5-dlayridazin-4-one hydrochloride
/ ~CH3
O i
N~N w ( /~N
N
NHZ
Prepared analogously to Example 11 by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH 8~ Co. KG Case 1/1427
55216 Ingelheim 82 Foreign filing text
Yield: 62% of theory.
C2aH2$N80 (492.59)
Mass spectrum: (M + H)+ = 493
'H-NMR spectrum (ds-DMSO): 8 = 1.72 (m, 2H); 1.80 (s, 3H); 1.95 (m, 1H);
2.03 (m, 1 H); 3.21 (m, 2H); 3.40 (m, 1 H); 3.49 (m, 1 H); 5.08 (dd, 2H); 5.75
(s,
2H); 7.31 (d, 1 H); 7.45 - 7.66 (m, 7H); 7.86 (d, 1 H); 8.22 (s, 1 H); 8.54
(broad
s, 3H) ppm.
Example 194
~~R)-3-amino-piperidin-1-yl)-3-(but-2-~yl)-5-(4-methylbenzoxazol-2-
~methyl)-3 5-dihydro-imidazof4 5-dlpyridazin-4-one hydrochloride
Prepared analogously to Example ~ by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 83% of theory.
C23H25N~02 (431.50)
Mass spectrum: (M + H)+ = 432
H-NMR spectrum (d6-DMSO): S = 1.71 (m, 2H); 1.80 (s, 3H); 1.93 (m, 1 H);
2.05 (m, 1 H); 3.22 (m, 2H); 3.41 (m, 1 H); 3.53 (m, 1 H); 3.75 (m, 1 H); 5.16
(dd,
2H); 5.66 (s, 2H); 7.20 (d, 1 H); 7.27 (t, 1 H); 7.48 (d, 1 H); 8.35 (s, 1 H);
8.44
(broad s, 3H) ppm.
Example 195
2-((R)-3-amino-piperidin-1-y~-abut-2-ynyl)-5-(5-trifluoromethylbenzothiazol-
2-ylmethyl)-3 5-dihydro-imidazof4 5-dlpyridazin-4-one hydrochloride



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 83 Foreign filing text
/'CH3
O
N
S~N w I /~N
N
NHZ
F3C
Prepared analogously to Example ~ by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 98% of theory.
C23H22 FsN70S (501.54)
Mass spectrum: (M + H)+ = 502
'H-NMR spectrum (d6-DMSO): 8 = 1.70 (m, 2H); 1.80 (s, 3H); 1.95 (m, 1 H);
2.05 (m, 1 H); 3.22 (m, 2H); 3.40 (m, 1 H); 3.52 (m, 1 H); 3.77 (m, 1 H); 5.19
(dd,
2H); 5.82 (s, 2H); 7.77 (d, 1 H); 8.31 (d, 1 H); 8.35 (s, 1 H); 8.41 (s, 1 H);
8.50
(broad s, 3H) ppm.
Example 196
2-((RBI-3-amino_pi~peridin-1- Iy )-3-(but-2-ynyl)-5-y5-chlorobenzoxazol-2-
ylmethyl)-3.5-dihydro-imidazof4.5-dlpxridazin-4-one hydrochloride
O ~ CH3
O~N N
N N ~ I /~' N
N
NHz
CI
Prepared analogously to Example 1 j by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 77% of theory.
C22H22CIN~02 (451.92)
Mass spectrum: (M + H)+ = 452
~H-NMR spectrum (ds-DMSO): b = 1.71 (m, 2H); 1.80 (s, 3H); 1.94 (m, 1 H);
2.05 (m, 1 H); 3.22 (m, 2H); 3.41 (m, 1 H); 3.53 (m, 1 H); 3.75 (m, 1 H); 5.16
(dd,
2H); 5.69 (s, 2H); 7.43 (d, 1 H); 7.75 (d, 1 H); 7.83 (s, 1 H); 8.39 (s, 1 H);
8.97
(broad s, 3H) ppm.



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH 8~ Co. KG Case 1/1427
55216 Ingelheim 84 Foreign filing text
Example 197
~(R)-3-amino-piperidin-1-yl -3-(but-2-ynyl)-5-(5-methylbenzoxazol-2-
ylmethyl)-3 5-dihydro-imidazof4 5-dlpyridazin-4-one hydrochloride
H3
NHz
H3C
Prepared analogously to Example 1~ by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 57% of theory.
C23H25N~02 (431.50)
Mass spectrum: (M + H)+ = 432
~H-NMR spectrum (ds-DMSO): 8 = 1.71 (m, 2H); 1.80 (s, 3H); 1.93 (m, 1 H);
2.04 (m, 1 H); 2.41 (s, 3H); 3.21 (m, 2H); 3.40 (m, 1 H); 3.53 (m, 1 H); 3.75
(m,
1 H); 5.16 (dd, 2H); 5.64 (s, 2H); 7.20 (d, 1 H); 7.49 (s, 1 H); 7.57 (d, 1
H); 8.38
(s, 1 H); 8.92 (broad s, 3H) ppm.
Example 198
2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-f1- pyridin-3-yl)-benzimidazol-
2-
Ylmethyll-3 5-dihydro-imidazof4,5-dlpyridazin-4-one hydrochloride
~N
/ ~CH3
O i
N~N N
/ ~ N N ~ I /~"N~
N
NHZ
Prepared analogously to Example ~ by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 ingelheim 85 Foreign filing text
Yield: 37°!0 of theory.
C2~H2~N90 (493.58)
Mass spectrum: (M + H)+ = 494
'H-NMR spectrum (ds-DMSO): 8 = 1.71 (m, 2H); 1.81 (s, 3H); 1.95 (m, 1H);
2.02 (m, 1 H); 3.22 (m, 2H); 3.40 (m, 1 H); 3.48 (m, 1 H); 3.73 (m, 1 H); 5.08
(dd,
2H); 5.67 (s, 2H); 7.28 (d, 1 H); 7.41 (m, 2H); 7.70 (dd, 1 H); 7.28 (d, 1 H);
8.17
(d, 1 H); 8.22 (s, 1 H); 8.43 (broad s, 3H); 8.78 (d, 1 H); 8.88 (s, 1 H) ppm.
Example 199
~~R)-3-amino-piperidin-1-yl)-3-(but-2-yn~)-5-(5.7-dimethylbenzoxazol-2-
ylmethyl~3.5-dih~dro-imidazo(4.5-dlpyridazin-4-one hydrochloride
Prepared analogously to Example 1~ by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 86% of theory.
C24H2~N~02 (445.53)
Mass spectrum: (M + H)+ = 446
'H-NMR spectrum (ds-DMSO): 8 = 1.71 (m, 2H); 1.80 (s, 3H); 1.94 (m, 1 H);
2.05 (m, 1 H); 2.36 (s, 3H); 2.42 (s, 3H); 3.22 (m, 2H); 3.41 (m, 1 H); 3.54
(m,
1 H); 3.75 (m, 1 H); 5.16 (dd, 2H); 5.63 (s, 2H); 7.02 (s, 1 H); 7.28 (s, 1
H); 8.34
(s, 1 H); 8.41 (broad s, 3H) ppm.
Example 200
2 ~(R)-3-amino-piperidin-1-yl -~3-(but-2-ynyl)-5-(4-chlorona~~hth-1- I~ethyl~
3.5-dihydro-imidazo(4.5-dlpyridazin-4-one



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 86 Foreign filing text
/'CH3
N~/
N~ ~N
CI ~ / N~ ~ N
NHZ
Prepared analogously to Example ~ by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 54% of theory.
C2sH2sCIN60 (460.97)
Mass spectrum: (M + H)+ = 461/3
'H-NMR spectrum (ds-DMSO): 8 = 1.22 (m, 1 H); 1.62 (m, 1 H); 1.73 (m, 1 H);
1.80 (s, 3H); 1.87 (m, 1 H); 2.73 (m, 1 H); 2.99 (m, 1 H); 3.60 (m, 2H); 5.12
(s,
2H); 5.80 (s, 2H); 7.22 (d, 1 H); 7.65 (d, 1 H) 7.72 (m, 2H); 8.23 (d, 1 H);
8.30
(s, 1 H); 8.39 (d, 1 H) ppm.
Example 201
2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5- 4-bromonaphth-1-ylmethyl)-
3,5-dihydro-imidazof4,5-dlpyridazin-4-one hydrochloride
~ CH3
\ N
%'~~N ~--N
Br I / N ~ I N
NHZ
Prepared analogously to Example ~ by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 67% of theory.
C25H2sBrN60 (505.42)
Mass spectrum: (M + H)+ = 505/7
'H-NMR spectrum (d6-DMSO): 8 = 1.70 (m, 2H); 1.80 (s, 3H); 1.93 (m, 1H);
2.04 (m, 1 H); 3.20 (m, 2H); 3.40 (m, 1 H); 3.51 (m, 1 H); 3.74 (m, 1 H); 5.17
(dd,
2H); 5.78 (s, 2H); 7.16 (d, 1 H); 7.70 (m, 2H); 7.83 (d, 1 H); 8.20 (d, 1 H);
8.32
(s, 1 H); 8.37 (d, 1 H); 8.47 (broad s, 3H) ppm.



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH 8 Co. KG Case 1/1427
55216 Ingelheim 87 Foreign filing text
Example 202
~R)-3-amino-piperidin-1-yl)-3-(but-2-yn,~l~(benzof 1,2,51oxadiazol-5-
ylmethyl)-3,5-dihydro-imidazof4.5-dlpyridazin-4-one
~ CH3
N~ ~ N N
O ~ I I ~>--N
N / Nw N
NHZ
Prepared analogously to Example ~ by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 83% of theory.
C2~ H22N802 (418.46)
Mass spectrum: (M + H)+ = 419
'H-NMR spectrum (ds-DMSO): 8 = 1.41 (m, 1 H); 1.67 (m, 1 H); 1.80 (s, 3H);
1.82 (m, 1 H); 1.93 (m, 1 H); 2.42 (dd, 1 H); 3.10 (m, 2H); 3.57 (m, 1 H);
3.68
(dd, 1 H); 5.11 (s, 2H); 5.47 (s, 2H); 7.53 (d, 1 H); 7.76 (s, 1 H); 8.04 (d,
1 H); 8.3
(s, 1 H); ppm.
Example 203
2-((R)-3-amino-piperidin-1-yl)-3-(but-2-~yl~(benzo(1 2 5lthiadiazol-4-
ylmethyl)-3,5-dihydro-imidazof4,5-dlpyridazin-4-one
S_ i_ CH3
O
N~ N
~~ N
N
NHZ
Prepared analogously to Example ~ by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 73% of theory.
C2~H22N$OS (434.53)
Mass spectrum: (M + H)+ = 435



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 88 Foreign filing text
'H-NMR spectrum (ds-DMSO): 8 = 1.30 (m, 1 H); 1.65 (m, 1 H); 1.79 (s, 3H);
1.82 (m, 1 H); 1.90 (m, 1 H) 2.82 (dd, 1 H); 2.96 (m, 1 H); 3.04 (m, 1 H);
3.61 (m,
1 H); 3.66 (dd, 1 H); 5.12 (s, 2H); 5.84 (s, 2H); 7.22 (d, 1 H); 7.64 (t, 1
H); 8.01
(d, 1 H); 8.30 (s, 1 H); ppm.
Example 204
~~,R)-3-amino-piperidin-1-yl -3-(but-2-ynyl)-5-(benzof1.2,51thiadiazol-5-
ylmethyl)-3,5-dihydro-imidazoL4.5-dlpyridazin-4-one
/'CH3
O
N' ~ N N
S\ ;~ I ~ ~~N
N ~ N~ N
NHz
Prepared analogously to Example 1i by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 81 % of theory.
C2~ H22N$OS (434.53)
Mass spectrum: (M + H)+ = 435
' H-NMR spectrum (ds-DMSO): 8 = 1.30 (m, 1 H); 1.65 (m, 1 H); 1.79 (s, 3H);
1.81 (m, 1 H); 1.90 (m, 1 H); 2.32 (dd, 1 H); 2.95 (m, 1 H); 3.03 (m, 1 H);
3.57 (m,
1 H); 3.65 (dd, 1 H); 5.11 (s, 2H); 5.54 (s, 2H); 7.66 (d, 1 H); 7.85 (s, 1
H); 8.07
(d, 1 H); 8.31 (s, 1 H) ppm.
Example 205
2-((R~-3-amino-piperidin-1-Y~-~2-chlorobenzyl)-5-(3-methyl-isoauinolin-1-
ylmethyl)-3,5-dihydro-imidazof4.5-dlpyridazin-4-one
a
0
w
N
N
I iN N~ I N
CH3 NHZ



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 89 Foreign filing text
Prepared analogously to Example 1 j, by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 70% of theory.
C28H28CIN~0 (514.03)
Mass spectrum: (M + H)+ = 514/6
'H-NMR spectrum (ds-DMSO): 8 = 1.14 (m, 1 H), 1.46 (m, 1 H); 1.64 (m, 1 H);
1.79 (m, 1 H); 2.44 (s, 3H); 2.62 (dd, 1 H); 2.70 )m, 1 H); 2.85 (m, 1 H);
3.20 -
3.44 (m, 2H); 5.63 (s, 2H); 5.88 (s, 2H); 6.70 (d, 1 H); 7.25 (t, 1 H); 7.32
(t, 1 H);
7.52 (m, 3H); 7.71 (t, 1 H); 7.85 (d, 1 H); 8.18 (d, 1 H); 8.30 (s, 1 H) ppm.
Example 206
~f R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(2-methyl-naphthalen-1-
ylmethyl)-3,5-dihydro-imidazo[4.5-dlpyridazin-4-one
CH3
0
N
N ~N~
/ N~ I N
CH3
NHZ
Prepared analogously to Example ,1~' by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 56% of theory.
C26H2sN60 (440.55)
Mass spectrum: (M + H)+ = 441
Rf value: 0.29 (silica gel; dichloromethane/methanol 9 : 1 )
Example 207
2-((R)-3-amino-piperid in-1-~)-3-(but-2-ynyl)-5-(5-methyl-imidazof 1 2-
alayridin-
2-ylmethyl)-3,5-dihydro-imidazo~4.5-dlpyridazin-4-one



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH ~ Co. KG Case 1/1427
55216 Ingelheim 90 Foreign filing text
Prepared analogously to Example J, by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 86% of theory.
C23H2sNa0 (430.52)
Mass spectrum: (M + H)+ = 431
Rf value: 0.37 (silica gel; dichloromethane / methanol / conc. ammonia 9 : 1
0.1 )
Example 208
2-((R)-3-amino-piperidin-1-yl)-3-(but-2-yny~-~isoauinolin-3-ylmeth~)-3 5-
dihydro-imidazof4.5-dlpyridazin-4-one
Prepared analogously to Example 11 by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 97% of theory.
C24H25N~0 (427.51 )
Mass spectrum: (M + H)+ = 428
Rf value: 0.15 (silica gel; dichloromethane / methanol 9 : 1 )
Example 209
2-( ( R)-3-a m i n o-a i pe rid i n-1-yl )-3-( but-2-yn yl )-5-( 1-m ethyl-1 H-
p a i no I i n-2-o n-6-
ylmethyl)-3.5-dihydro-imidazof4 5-dlpyridazin-4-one



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 91 Foreign filing text
CH3
O
~ N
IV ~N~
O N I ~ N ~ I j~ ~~--~)N
CH3 NHZ
Prepared analogously to Example ,1~' by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 32% of theory.
C25H27N7O2 (457.54)
Mass spectrum: (M + H)+ = 458
Rf value: 0.11 (silica gel; dichloromethane / methanol 9 : 1 )
Example 210
~R~-3-amino-aiperidin-1-y1~3-(but-2-ynyl)-5-(2-methyl-2H-indazol-3-
ylmethy_I)-3.5-dihydro-imidazof4.5-dlpyridazin-4-one
Prepared analogously to Example ,1~' by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 84% of theory.
C2sH2sNs0 (430.52)
Mass spectrum: (M + H)+ = 431
Rf value: 0.18 (silica gel; dichloromethane / methanol 9 : 1 )
Example 211
~(R)-3-a m i no-pJ~erid i n-1-yl)-3~but-2~rnY~-7-methyl-5-(4-phenyl-q
uinazolin-
2-ylmethyl)-3.5-dihydro-imidazof4.5-dlpyridazin-4-one



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 92 Foreign filing text
,~cH~
Prepared analogously to Example 1j by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 29% of theory.
C3oH3oNs0 (518.63)
Mass spectrum: (M + H)+ = 519
Rf value: 0.26 (silica gel; dichloromethane / methanol 8 : 2)
Example 212
2-((R)-3-amino-aiperidin-1-yl -~3-(but-2-ynyl)-7-methyl-5-(4-methyl-auinazolin-

2-ylmethyl)-3.5-dihydro-imidazof4 5-dlayridazin-4-one
CH3
\ N~ N
~N
I / ~N N\ ( / N
~N
CH3 CH3 NHZ
Prepared analogously to Example 11 by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 61 % of theory.
C25H2sNa0 (456.55)
Mass spectrum: (M + H)+ = 457
Rf value: 0.27 (silica gel; dichloromethane / methanol 9 : 1 )
Example 213
2-((R)-3-amino-piperidin-1-LrIZ 3-(but-2-ynyl)-7-methyl-5-(3-methyl-
isoauinolin-
1-ylmethyl)-3.5-dihydro-imidazof4 5-dlpyridazin-4-one



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 93 Foreign filing text
I \ O ~ CH3
\ N
iN N~ I N
'N ~N~
CH3 CH3 NHZ
Prepared analogously to Example 1 j by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 56% of theory.
C2gH2gN7O (455.57)
Mass spectrum: (M + H)+ = 456
Rf value: 0.53
(silica gel RP-8; water / acetonitrile / trifluoroacetic acid 50 : 50 : 0.1 )
Example 214
2-((R~-3-amino-aiperidin-1-yl~3~but-2-ynyl)-5-( 1-meth~rl-1 H-indazol-4-
Ir~methyl~-3,5-dihydro-imidazof4,5-dlpyridazin-4-one
~CH3
N_ p
H3C_N \ N N //~~
I ~-N )
I / N ~ I \~JN
NHZ
Prepared analogously to Example ~ by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 45% of theory.
C23H2sNs0 (430.52)
Mass spectrum: (M + H)+ = 431
HPLC analysis:
The HPLC analysis was carried out under the following experimental
conditions:
column: Xterra MS18; 3.5Nm; 4.6 x 50 mm
flow: 1 mL/min
eluant A: water / 0.1 % trifluoroacetic acid
eluant B: acetonitrile / 0.1 % trifluoroacetic acid



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 94 Foreign filing text
~ a
gradient: 5% B -~ 98% B within 5 min.; maintain 98% B to 7.5 min.
A retention time of 3.13 min. was observed for this substance.
Example 215
2-((R)-3-amino-piperidin-1-yl)-3-(but-2-yn~l)-5~- 4-methyl-phthalazin-1-
ylmethyl)-3,5-dihydro-imidazof4 5-dlpyridazin-4-one
Hz
Prepared analogously to Example 11 by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 48% of theory.
C2aH2sN80 (442.53)
Mass spectrum: (M + H)+ = 433
HPLC analysis (see Example 214):
retention time: 2.53 min.
Example 216
2-((R)-3-amino-piperidin-1-yl)-3-(but-2-yn rLl -5-f2- 3-methyl-2-oxo-2 3-dih
benzoxazol-4-yl)-2-oxo-ethyll-3 5-dihydro-imidazof4 5-dlpyridazin-4-one
CH3
I O
N
O N I />--N~
~N~ O N ~ N
O CH3 NHz
Prepared analogously to Example ~ by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 36% of theory.
C24H25N7Oa (475.51 )



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 95 Foreign filing text
Mass spectrum: (M + H)+ = 476
HPLC analysis (see Example 214):
retention time: 3.30 min.
Example 217
21(R)-3-amino-piperidin-1-yl -3-(but-2- rLnyl)-5-(2-methyl-2H isoduinolin-1-on-

4-ylmethyl)-3,5-dihydro-imidazo[4,5-dlpyridazin-4-one
c
HZ
Prepared analogously to Example ~ by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 18% of theory.
C25H2~N~02 (457.54)
Mass spectrum: (M + H)+ = 458
HPLC analysis (see Example 214):
retention time: 2.67 min.
Example 218
2-((R)-3-amino-piaeridin-1-yl)-3-(but-2-yn~)-5-(8-methoxy-cluinolin-5-
ylmethyl)-3,5-dihydro-imidazof4 5-dlayridazin-4-one
CH3
I O
N ~ N
N ~N~
H3C~0 \ ~ N ~ I N
NH2
Prepared analogously to Example ~ by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 33% of theory



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 96 Foreign filing text
C25H2~N~02 (457.54)
Mass spectrum: (M + H)+ = 458
HPLC analysis (see Example 214):
retention time: 3.18 min.
Example 219
2-((R)-3-amino-piperidin-1-yl)-3-(but-2-yn Iy )-5~,L5~naahth rider in-2-
ylmethyl~
3,5-dihydro-imidazof4,5-dlpyridazin-4-one
CH3
O
\ N~ N
N ~N~
N~ I N
NHZ
Prepared analogously to Example 11 by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 25% of theory.
C23H24N8~ (428.50)
Mass spectrum: (M + H)+ = 429
HPLC analysis (see Example 214):
retention time: 2.06 min.
Example 220
2-((R)-3-amino-aiperidin-1-yl~-3-(but-2-ynyl)-5-(2,3.8-trimet~l-ctuinoxalin-6-
ylmethyl)-3,5-dihydro-imidazof4,5-dlp~ridazin-4-one
~CH3
O
H3C N~ \ N
N
i / N~
H3C N
C NHZ
Prepared analogously to Example 11 by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH 8~ Co. KG Case 1/1427
55216 Ingelheim 97 Foreign filing text
Yield: 76% of theory.
C2sHsoNsO (470.58)
Mass spectrum: (M + H)+ = 471
HPLC analysis (see Example 214):
retention time: 3.44 min.
Example 221
~~R)-3-amino-aiperidin-1-yl)-3~but-2-ynyl)-5-(4-morpholin-4-~auinazolin-2-
ylmethyl -3.5-dihydro-imidazof4,5-dhyridazin-4-one
~CH3
O~ O
N N~ N
~N ~N
iN N~ ~ N
NI-f2
Prepared analogously to Example 1j by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 71 % of theory.
C2~H3~ N902 (513.61 )
Mass spectrum: (M + H)+ = 514
HPLC analysis (see Example 214):
retention time: 1.76 min.
Example 222
2-~~R)-3-amino-piperidin-1-yl -3-(but-2-ynLrl)-~3-aentafluorophenyl-allyl)-3,5-

d ihyd ro-imidazor4, 5-dlpyridazin-4-one
CH3
F O
F \ \ N
_N ~N~
F ~ ~ F N~ ~ N
F NH2
Prepared analogously to Example 11 by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 98 Foreign filing text
Yield: 89% of theory.
CzsH2~ FsNs~ (492.46)
Mass spectrum: ~ (M + H)+ = 493
Rf value: 0.18 (silica gel; dichloromethane / ethanol 9 : 1 )
Example 223
~~R)-3-amino-aiperidin-1-Yl~but-2-ynyl -7-methyl-5-(4-cyano-naphthalen-
1-ylmethyl)-3.5-dihydro-imidazof4.5-dlpyridazin-4-one
\ o ~ CH3
N
~N
/ N ~.
N~
CH3 NHZ
Prepared analogously to Example 1j by cleaving the Boc protective group with
trifluoroacetic acid in dichloromethane.
Yield: 66% of theory.
C27H2~N~0 (465.56)
Mass spectrum: (M + H)+ = 466
Rf value: 0.62
(silica gel RP-8; water / acetonitrile / trifluoroacetic acid 50 : 50 : 0.1 )
Example 224
Coated tablets containin~75-mg 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


hydroxypropylmethylcellulose15.0 mg


magnesium stearate 1._ 5 mg


230.0 mg





CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 111427
55216 Ingelheim 99 Foreign filing text
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.
Example 225
Tablets containing 100 mgi 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 ma
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



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 100 Foreign filing text
Diameter: 10 mm, biplanar, facetted on both sides and notched on one
side.



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH ~ Co. KG Case 1/1427
55216 Ingelheim 101 Foreign filing text
Example 226
Tablets containing 150 mg 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 mg


300.0 mg
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 227
Hard Gelatine capsules containing 150 mq"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



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 102 Foreign filing text
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.
Example 228
Suppositories containing 150 ma of active substance
1 suppository contains:
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 229
Suspension containing 50 ma 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





CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH 8~ Co. KG Case 1/1427
55216 Ingelheim 103 Foreign filing text
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 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.
Example 230
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 231
Ampoules containing 50 mg of active substance
Composition:
active substance 50.0 mg
0.01 N hydrochloric acid q.s.
double-distilled water ad 10.0 ml



CA 02508233 2005-06-O1
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1427
55216 Ingelheim 104 Foreign filing text
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