SELECTED CGRP ANTAGONISTS, METHODS FOR THE PRODUCTION THEREOF, AND USE THEREOF AS MEDICAMENTS

ANTAGONISTES DU CGRP SELECTIONNES, PROCEDES DE PRODUCTION DE CES ANTAGONISTES ET LEUR UTILISATION COMME MEDICAMENTS

English Abstract

The invention relates to CGRP antagonists of general formula (I), wherein A,
X, Q, and R1 to R3 are defined as indicated in claim 1, the tautomers,
isomers, diastereomers, enantiomers, hydrates, mixtures, and salts thereof,
and the hydrates of the salts, especially the physiologically acceptable salts
thereof with inorganic or organic acids, medicaments containing said
compounds, the use thereof, and methods for the production thereof.

French Abstract

L'invention concerne les antagonistes du CGRP représentés par la formule générale (I), dans laquelle A, X, Q et R1 à R3 sont tels que définis dans la revendication n°1, ainsi que leurs tautomères, isomères, diastéréoisomères, énantiomères, hydrates, mélanges et sels et les hydrates de ces sels, notamment leurs sels physiologiquement tolérables contenant des acides inorganiques ou organiques. L'invention concerne également des médicaments contenant ces composés, leur utilisation et des procédés de production desdits composés.

Claims

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Patent Claims
1. CGRP antagonists of general formula
<IMG>
wherein
A denotes an oxygen or sulphur atom,
X denotes an oxygen or sulphur atom,
Q denotes a heterocycle bound via a carbon or nitrogen atom consisting of two
or
three in each case 4- to 8-membered fused rings, saturated, partially
unsaturated or
totally unsaturated independently of one another,
while the heterocycle comprises a total of one to five heteroatoms selected
independently of one another from among O, N and S,
may contain one or two carbonyl groups as ring members and
each saturated nitrogen atom as a ring member of the heterocycle may be
substituted by the group R a and one or two carbon atoms as ring members of
the
heterocycle may be substituted by the group R b,
R1 denotes a saturated, mono- or diunsaturated 5- to 7-membered aza, diaza,
triaza,
oxaza, thiaza, thiadiaza or S,S-dioxido-thiadiaza heterocycle,
while the above-mentioned heterocycles are linked to the piperidine ring in
formula I by a carbon or nitrogen atom or
are spirocyclically linked to the piperidine ring in formula I by two carbon
atoms,

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by a carbon and a nitrogen atom, by a carbon and an oxygen atom or by a
carbon and a sulphur atom,
contain one or two carbonyl or thiocarbonyl groups adjacent to a nitrogen
atom,
may be substituted at one of the nitrogen atoms by a C1-6-alkyl, C3-6-alkenyl
or
C3-6-alkenyl group,
may be substituted at one or at two carbon atoms by a C1-6-alkyl, C2-6-alkenyl
or
C2-6-alkynyl group, by a phenyl, phenylmethyl, naphthyl, biphenylyl,
pyridinyl,
diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl,
pyrazolyl,
1-(C1-3-alkyl)-pyrazolyl, imidazolyl or 1-(C1-3-alkyl)-imidazolyl group, while
the
substituents may be identical or different, and
an olefinic double bond of one of the above-mentioned unsaturated heterocycles
may be fused to a phenyl, naphthyl, pyridine, diazine, 1,3-oxazole, thienyl,
furan,
thiazole, pyrrole, N-C1-3-alkyl-pyrrole or quinoline ring, to a 1H-quinolin-2-
one
ring optionally substituted at the nitrogen atom by a C1-6-alkyl, C3-6-alkenyl
or
C3-6-alkynyl group or to an imidazole or N-C1-3-alkyl-imidazole ring or two
olefinic
double bonds of one of the above-mentioned unsaturated heterocycles may
each be fused to a phenyl or pyridine ring,
while the phenyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl,
1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-C1-3-alkyl-pyrazolyl, imidazolyl or
1--C1-3-alkyl-imidazolyl groups contained in R1 and benzo-, thieno-, pyrido-
and
diazino-fused heterocycles in the carbon skeleton may additionally be
mono-, di- or trisubstituted by halogen atoms, C1-6-alkyl, C2-6-alkenyl, C2-6-
alkynyl,
cyclo-C3-7-alkyl, cyclo-C3-7-alkenyl, cyano, hydroxy, hydroxy-C1-6-alkyl,
hydroxy-C3-6-alkenyl, hydroxy-C3-6-alkynyl, C1-6-alkoxy, C1-6-alkoxy-C1-6-
alkyl,
C1-6-alkoxy-C3-6-alkenyl, C1-6-alkoxy-C3-6-alkynyl, C3-6-alkenoxy-C1-6-alkyl,
C3-6-alkenoxy-C3-6-alkenyl, C3-6-alkenoxy-C3-6-alkynyl, C3-6-alkynoxy-
C1-6-alkyl, C3-6-alkynoxy-C3-6-alkenyl, C3-6-alkynoxy-C3-6-alkynyl,
thiohydroxy,
C1-6-alkylthio, C3-6-alkenylthio, C3-6-alkynylthio, amino, C1-6-alkyl-amino,
C3-6-alkenyl-amino, C3-6-alkynyl-amino, di-(C1-6-alkyl)-amino, di-(C3-6-
alkenyl)-

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amino, di-(C3-6-alkynyl)-amino, amino-C1-6-alkyl, C1-3-alkyl-amino-C1-6-alkyl,
di-(C1-3-alkyl)-amino-C1-6-alkyl, amino-C3-6-alkenyl, C1-3-alkyl-amino-
C3-6-alkenyl, di-(C1-3-alkyl)-amino-C3-6-alkenyl, amino-C3-6-alkynyl, C1-3-
alkyl-
amino-C3-6-alkynyl, di-(C1-3-alkyl)-amino-C3-6-alkynyl, hydroxycarbonyl,
phenylcarbonyl, pyridylcarbonyl, C1-6-alkyl-carbonyl, C2-6-alkenyl-carbonyl,
C2-6-alkynyl-carbonyl, formyl, C1-6-alkoxy-carbonyl, C3-6-alkenoxy-carbonyl,
C3-6-alkynoxy-carbonyl, aminocarbonyl, C1-6-alkyl-aminocarbonyl,
C3-6-alkenyl-aminocarbonyl, C3-6-alkynyl-aminocarbonyl, di-(C1-6-alkyl)-
aminocarbonyl, di-(C3-6-alkenyl)-aminocarbonyl, di-(C3-6-alkynyl)-
aminocarbonyl, formylamino, C1-6-alkyl-carbonylamino, C2-6-alkenyl-
carbonylamino, C2-6-alkynyl-carbonylamino, formyl-C1-6-alkyl-amino, formyl-
C3-6-alkenyl-amino, formyl-C3-6-alkynyl-amino, C1-6-alkyl-carbonyl-C1-6-alkyl-
amino, C2-6-alkenyl-carbonyl-C1-6-alkyl-amino, C2-6-alkynyl-carbonyl-
C1-6-alkyl-amino, C1-6-alkyl-carbonyl-C3-6-alkenyl-amino, C2-6-alkenyl-
carbonyl-C3-6-alkenyl-amino, C2-6-alkynyl-carbonyl-C3-6-alkenyl-amino,
C1-6-alkyl-carbonyl-C3-6-alkynyl-amino, C2-6-alkenyl-carbonyl-C3-6-alkynyl-
amino, C2-6-alkynyl-carbonyl-C3-6-alkynyl-amino, C1-6-alkyl-sulphonyl,
C2-6-alkenyl-sulphonyl, C2-6-alkynyl-sulphonyl, C1-6-alkyl-sulphinyl,
C2-6-alkenyl-sulphinyl, C2-6-alkynyl-sulphinyl, C1-6-alkyl-sulphonylamino,
C2-6-alkenyl-sulphonylamino, C2-6-alkynyl-sulphonylamino, C1-6-alkyl-
sulphonyl-C1-6-alkylamino, C1-6-alkyl-sulphonyl-C3-6-alkenylamino, C1-6-alkyl-
sulphonyl-C3-6-alkynylamino, C2-6-alkenyl-sulphonyl-C1-6-alkylamino,
C2-6-alkenyl-sulphonyl-C3-6-alkenylamino, C2-6-alkenyl-sulphonyl-
C3-6-alkynylamino, C2-6-alkynyl-sulphonyl-C1-6-alkylamino, C2-6-alkynyl-
sulphonyl-C3-6-alkenylamino, C2-6-alkynyl-sulphonyl-C3-6-alkynylamino,
aminosulphonyl, C1-6-alkylaminosulphonyl, di-(C1-6-alkyl)-aminosulphonyl,
C3-6-alkenylaminosulphonyl, di-(C3-6-alkenyl)-aminosulphonyl,
C3-6-alkynylaminosulphonyl, di-(C3-6-alkynyl)-aminosulphonyl groups, while
the substituents may be identical or different,
R2 denotes the hydrogen atom,
a phenylmethyl group or a C2-7-alkyl group which may be substituted in the
.omega. position
by a cyclo-C3-7-alkyl, cyclo-C3-7-alkenyl, phenyl, pyridinyl, diazinyl,
hydroxy, amino,

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C1-6-alkylamino, di-(C1-6-alkyl)-amino, C3-6-alkenylamino, di-(C3-6-
alkenyl)amino,
C3-6-alkynylamino, di-(C3-6-alkynyl)amino, hydroxycarbonyl, C1-6-
alkoxycarbonyl,
aminocarbonyl, aminocarbonylamino, C1-6-alkylcarbonylamino, C2-6-alkenyl-
carbonylamino, C2-6-alkynylcarbonylamino, 4-morpholinyl, [bis-(2-hydroxy-
ethyl)]amino, 4-(C1-6-alkyl)-1-piperazinyl or 4-(.omega.-hydroxy-C2-7-alkyl)-1-
piperazinyl
group,
a phenyl or pyridinyl group,
while the phenyl, pyridinyl and diazinyl groups mentioned in the above
definitions of R2 or contained as substituents may additionally be mono- di-
or
trisubstituted in the carbon skeleton by halogen, by C1-3-alkyl, C2-3-alkenyl,
C2-3-alkynyl, C1-3-alkoxy, hydroxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)-
amino,
amino-C1-3-alkyl, C1-3-alkyl-amino-C1-3-alkyl, di-(C1-3-alkyl)-amino-C1-3-
alkyl,
C1-3-alkylcarbonylamino, C1-3-alkylcarbonylamino-C1-3-alkyl, aminocarbonyl,
C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, cyano,
aminosulphonyl,
C1-3-alkyl-aminosulphonyl, di-(C1-3-alkyl)-aminosulphonyl, C1-3-alkyl-thio,
C1-3-alkyl-sulphinyl or C1-3-alkyl-sulphonyl and the substituents may be
identical
or different,
R3 denotes the hydrogen atom or a C1-3-alkyl group substituted by a phenyl or
pyridinyl group,
while the C1-3-alkyl group may be connected to an alkyl group contained in R2
or
a phenyl or pyridyl ring contained in R2 including the nitrogen atom to which
R2
and R3 are bound, forming a 4- to 7-membered ring,
or
R2 and R3 together with the enclosed nitrogen atom denote a group of general
formula

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<IMG>
wherein
Y1 denotes the carbon atom or, if R5 denotes a pair of free electrons, it may
also
denote the nitrogen atom,
q and r, if Y1 denotes the carbon atom, denote the numbers 0, 1 or 2, or
q and r, if Y1 denotes the nitrogen atom, denote the numbers 1 or 2,
R4 denotes the hydrogen atom, an amino, C1-4-alkyl-amino, di-(C1-4-alkyl)-
alkylamino, C1-6-alkyl, a cyclo-C3-7-alkyl or cyclo-C3-7-alkenyl group
optionally
substituted by a hydroxycarbonyl, C1-6-alkoxycarbonyl, hydroxycarbonyl-C1-3-
alkyl
or C1-6-alkoxycarbonyl-C1-3-alkyl group, an amino-C2-7-alkyl, Cl-4-alkyl-amino-
C2-7-alkyl, di-(C1-4-alkyl-amino)-C2-7-alkyl, aminoiminomethyl,
aminocarbonylamino, C1-4-alkyl-aminocarbonylamino, di-(C1-4-alkyl)-
aminocarbonylamino, C1-4-alkyl-aminocarbonyl-C1-4-alkyl-amino, di-(C1-4-alkyl)-
aminocarbonyl-C1-4-alkyl-amino, phenylaminocarbonylamino, aminocarbonyl,
C1-4-alkyl-aminocarbonyl, di-(C1-4-alkyl)-aminocarbonyl, aminocarbonyl-C1-3-
alkyl,
C1-4-alkyl-aminocarbonyl-C1-3-alkyl, di-(C1-4-alkyl)-aminocarbonyl-C1-3-alkyl,
aminocarbonylamino-C1-3-alkyl, C1-6-alkoxycarbonyl, C3-6-alkenoxycarbonyl, C3-
6-alkynoxycarbonyl, C1-6-alkoxycarbonyl-C1-3-alkyl, C1-6-alkenoxycarbonyl-C1-
3-alkyl, C1-6-alkynoxycarbonyl-C1-3-alkyl or hydroxycarbonyl-C1-3-alkyl group,
a phenyl, pyridinyl, diazinyl, 1-naphthyl, 2-naphthyl, pyridinylcarbonyl or
phenylcarbonyl group which may be mono- di- or trisubstituted in each case in
the carbon skeleton by halogen, by C1-3-alkyl, C2-3-alkenyl, C2-3-alkynyl,
C1-3-alkoxy, hydroxy, amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, amino-C1-
3-alkyl, C1-4-alkyl-amino-C1-3-alkyl, di-(C1-4-alkyl)-amino-C1-3-alkyl,

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C1-4-alkylcarbonylamino, C1-4-alkylcarbonylamino-C1-3-alkyl, aminocarbonyl, C1-

4-alkyl-aminocarbonyl, di-(C1-4-alkyl)-aminocarbonyl, cyano, aminosulphonyl,
C1-
4-alkyl-aminosulphonyl, di-(C1-4-alkyl)-aminosulphonyl, C1-4-alkyl-thio, C1-4-
alkyl-
sulphinyl or C1-4-alkyl-sulphonyl and the substituents may be identical or
different,
a heterocycle selected from a 4- to 10-membered azacycloalkyl group, a 6- to
10-
membered oxaza-, thiaza-, S,S-dioxothiaza- and diazacycloalkyl group as well
as
a 6- to 10-membered azabicycloalkyl group,
a 1-alkyl-4-piperidinylcarbonyl or 4-alkyl-1-piperazinylcarbonyl group,
while the above-mentioned mono- and bicyclic heterocycles are bound to Y1
in formula (II) by a nitrogen or a carbon atom,
in the above-mentioned mono- and bicyclic heterocycles a methyne group
not directly linked to a nitrogen, oxygen or sulphur atom may be substituted
by a fluorine atom and a methylene group not directly linked to a nitrogen,
oxygen or sulphur atom may be substituted by one or two fluorine atoms,
the above-mentioned mono- and bicyclic heterocycles as well as the
1-(C1-6-alkyl)-4-piperidinylcarbonyl- and 4-(C1-6-alkyl)-1-piperazinylcarbonyl
group in the ring may be mono- to tetra-substituted by hydroxy, C1-6-alkyl or
hydroxy-C1-3-alkyl groups, or, optionally additionally, may be monosubstituted
by a cyclo-C3-7-alkyl, hydroxy-C3-7-cycloalkyl, cyclo-C3-7-alkenyl, cyclo-
C3-7-alkyl-C1-3-alkyl, phenyl-C1-3-alkyl, pyridyl-C1-3-alkyl, C1-6-
alkylcarbonyl,
C1-6-alkylcarbonyl-C1-3-alkyl, hydroxy, C1-6-alkoxy, amino, C1-4-alkylamino,
di-
(C1-4-alkyl)amino, phenylcarbonyl, pyridinylcarbonyl, C1-6-alkoxycarbonyl,
hydroxycarbonyl-carbonyl, C1-6-alkoxycarbonyl-carbonyl, hydroxycarbonyl-
C1-3-alkyl, C1-6-alkoxycarbonyl-C1-3-alkyl, hydroxycarbonyl-C1-3-
alkylcarbonyl,
C1-6-alkoxycarbonyl-C1-3-alkylcarbonyl, aminocarbonyl,
C1-4-alkylaminocarbonyl, di-(C1-4-alkyl)aminocarbonyl, aminosulphonyl,
C1-4-alkylaminosulphonyl, di-(C1-4-alkyl)aminosulphonyl, C1-3-alkylsulphonyl,
cyclo-C3-7-alkylsulphonyl, aminocarbonyl-C1-3-alkyl, C1-4-alkylaminocarbonyl-
C1-3-alkyl, di-(C1-4-alkyl)aminocarbonyl-C1-3-alkyl, hydroxyaminocarbonyl-

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C1-3-alkyl, C1-3-alkoxyaminocarbonyl-C1-3-alkyl or hydroxy-(C1-3-alkyl)-
aminocarbonyl-C1-3-alkyl group, by a cyclo-C3-7-alkyl-carbonyl, azacyclo-
C4-7-alkyl-carbonyl, diazacyclo-C5-7-alkyl-carbonyl or oxazacyclo-C5-7-alkyl-
carbonyl group optionally C1-3-alkyl-substituted in the ring, while the
substituents may be identical or different and may be bound to a cyclic
carbon or cyclic nitrogen atom,
while the phenyl and pyridinyl groups contained in the groups given as
definitions of R4 hereinbefore may in turn be mono-, di- or trisubstituted
by halogen atoms, by Cl-3-alkyl, C2-3-alkenyl, C2-3-alkynyl, C1-3-alkoxy,
hydroxy, amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, amino-C1-3-alkyl,
C1-4-alkyl-amino-C1-3-alkyl, di-(C1-4-alkyl)-amino-C1-3-alkyl,
C1-4-alkylcarbonylamino, C1-4-alkylcarbonylamino-C1-3-alkyl,
aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-C1-4-alkyl-aminocarbonyl,
cyano, aminosulphonyl, C1-4-alkyl-aminosulphonyl, di-(C1-4-alkyl)-
aminosulphonyl, Cl-3-alkyl-thio, C1-3-alkyl-sulphinyl or C1-3-alkyl-
sulphonyl, while the substituents may be identical or different,
or, if Y1 denotes the carbon atom, may denote the hydroxycarbonyl,
aminomethyl, C1-4-alkyl-aminomethyl or di-(C1-4-alkyl)-aminomethyl group,
R5 denotes a hydrogen atom or a hydroxy group,
a C1-4-alkyl group, while an unbranched alkyl group in the .omega. position
may be
substituted by a phenyl, pyridinyl, diazinyl, amino, C1-4-alkylamino, di-(C1-4-
alkyl)-
amino, 4-C1-4-alkyl-1-piperazinyl or 4-morpholinyl group,
a C1-6-alkoxycarbonyl, cyano or aminocarbonyl group or, if Y1 denotes a
nitrogen
atom, R5 also denotes a pair of free electrons,
or, if Y1 denotes the carbon atom, R5 also denotes the fluorine atom, or
R4 together with R5 and Y1 denotes a 4- to 7-membered cycloaliphatic ring
wherein a methylene group may be replaced by an -NH-, -N(C1-4-alkyl)-,

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-N(C3-4-alkenyl)-, -N(C3-4-alkynyl)-, -N(cyclo-C3-7-alkyl)-, -N(C3-7-
cycloalkyl-
C1-3-alkyl)-, -N(hydroxycarbonyl-C1-3-alkyl)- or -N(C1-6-alkoxycarbonyl-C1-3-
alkyl)-
group,
while a hydrogen atom bound to a nitrogen atom in one of the groups
defined for R4 hereinbefore may be replaced by a protective group,
R6 and R7, which may be identical or different, in each case denote a hydrogen
atom, a Cl-4-alkyl group or, if Y1 denotes a carbon atom, also denote the
fluorine
atom, an amino, C1-4-alkylamino or di-(C1-4-alkyl)-amino group, while the two
C1-4-alkyl groups may be joined together to form a ring and
R8 and R9, which may be identical or different, in each case denote a hydrogen
atom or a Cl-3-alkyl group,
while
R a denotes a hydrogen atom, a straight-chain or branched C1-6-alkyl, C3-6-
alkenyl,
C3-6-alkynyl or cyclo-C3-7-alkyl group wherein each hydrogen atom, if it is
not in the .alpha.-
position to a nitrogen atom, may be replaced by fluorine,
R b denotes a halogen atom, a straight-chain or branched C1-6-alkyl, C2-6-
alkenyl,
C2-6-alkynyl, cyclo-C3-7-alkyl, cyano, hydroxy, hydroxy-C1-6-alkyl, C1-6-
alkoxy,
C1-6-alkoxy-C1-6-alkyl, amino, Cl-6-alkyl-amino or di-C1-6-alkyl-amino group,
wherein
each hydrogen atom, if it is not in the .alpha.-position to a nitrogen atom,
may be replaced
by fluorine and the two alkyl groups of the di-C1-6-alkyl-amino substituents
may be
joined together to form a 4- to 8-membered ring,
a methylene group in the .alpha.-position to a saturated nitrogen atom
substituted by the
group R a or to an oxygen or sulphur atom, as a ring member of the heterocycle
of the
group Q, is not substituted by a hydroxy, C1-6-alkoxy, amino, C1-6-alkyl-amino
or di-
Cl-6-alkyl-amino group,
the double and triple bonds of the C3-6-alkenyl or C3-6-alkynyl groups
contained in the

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groups mentioned for R a, R b, and R1 hereinbefore are also isolated from any
heteroatoms contained in these groups,
and, unless otherwise stated, all the alkyl, alkenyl and alkynyl groups
mentioned or
contained in the groups defined hereinbefore may be straight-chain or
branched,
each methyne group contained in the groups defined hereinbefore may be
substituted by a fluorine atom, each methylene group may be substituted by up
to 2
fluorine atoms and each methyl group may be substituted by up to 3 fluorine
atoms
and two alkyl and alkenyl groups bound to a nitrogen atom may be joined
together
forming a 4- to 7-membered, saturated or unsaturated heterocyclic ring,
all the aromatic and heteroaromatic groups mentioned or contained in the
groups
defined hereinbefore may additionally be mono-, di- or trisubstituted by
halogen, by
cyano or hydroxy groups and the substituents may be identical or different and
by the protective groups mentioned in the definitions above and hereinafter
are
meant the protective groups familiar from peptide chemistry, particularly
a phenylalkoxycarbonyl group with 1 to 3 carbon atoms in the alkoxy moiety
optionally substituted in the phenyl nucleus by a halogen atom, by a nitro or
phenyl
group or by one or two methoxy groups,
for example the benzyloxycarbonyl, 2-nitro-benzyloxycarbonyl, 4-nitrobenzyl-
oxycarbonyl, 4-methoxy-benzyloxycarbonyl, 2-chloro-benzyloxycarbonyl,
3-chloro-benzyloxycarbonyl, 4-chloro-benzyloxycarbonyl, 4-biphenylyl-
.alpha.,.alpha.-
dimethyl-benzyloxycarbonyl or 3,5-dimethoxy-.alpha.,.alpha.-dimethyl-
benzyloxycarbonyl
group,
an alkoxycarbonyl group with a total of 1 to 5 carbon atoms in the alkyl
moiety,
for example the methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso-
propoxycarbonyl, n-butoxycarbonyl, 1 -methyl pro poxycarbonyl, 2-methylpropoxy-
carbonyl or tert.-butyloxycarbonyl group,

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the allyloxycarbonyl, 2,2,2-trichloro-(1,1-dimethylethoxy)carbonyl or 9-
fluorenyl-
methoxycarbonyl group or
the formyl, acetyl or trifluoracetyl group,
the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates,
the
mixtures and the salts thereof, the hydrates of the salts, and those compounds
of
general formula I wherein one or more hydrogen atoms are replaced by
deuterium.
2. CGRP antagonists of general formula (I) according to claim 1, wherein
A denotes an oxygen or sulphur atom,
X denotes an oxygen or sulphur atom,
Q denotes a heterocycle bound via a carbon or nitrogen atom consisting of two
or
three in each case 4- to 8-membered fused rings, saturated, partially
unsaturated or
totally unsaturated independently of one another,
while the heterocycle comprises a total of one to five heteroatoms selected
independently of one another from among O, N and S,
may contain one or two carbonyl groups as ring members and
each saturated nitrogen atom as a ring member of the heterocycle may be
substituted by the group R a and one or two carbon atoms as ring members of
the
heterocycle may be substituted by the group R b,
R1 denotes a saturated, mono- or diunsaturated 5- to 7-membered aza, diaza,
triaza,
oxaza, thiaza, thiadiaza or S,S-dioxido-thiadiaza heterocycle,
while the above-mentioned heterocycles are linked to the piperidine ring in
formula I by a carbon or nitrogen atom or

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are spirocyclically linked to the piperidine ring in formula I by two carbon
atoms,
by a carbon and a nitrogen atom, by a carbon and an oxygen atom or by a
carbon and a sulphur atom,
contain one or two carbonyl or thiocarbonyl groups adjacent to a nitrogen
atom,
may be substituted at one of the nitrogen atoms by a Cl-6-alkyl, C3-6-alkenyl
or
C3-6-alkenyl group,
may be substituted at one or at two carbon atoms by a C1-6-alkyl, C2-6-alkenyl
or
C2-6-alkynyl group, by a phenyl, phenylmethyl, naphthyl, biphenylyl,
pyridinyl,
diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl,
pyrazolyl,
1-(C1-3-alkyl)-pyrazolyl, imidazolyl or 1-(C1-3-alkyl)-imidazolyl group, while
the
substituents may be identical or different, and
an olefinic double bond of one of the above-mentioned unsaturated heterocycles
may be fused to a phenyl, naphthyl, pyridine, diazine, 1,3-oxazole, thienyl,
furan,
thiazole, pyrrole, N-C1-3-alkyl-pyrrole or quinoline ring , to a 1H-quinolin-2-
one
ring optionally substituted at the nitrogen atom by a C1-6-alkyl, C3-6-alkenyl
or
C3-6-alkynyl group or to an imidazole or N-C1-3-alkylimidazole ring or two
olefinic
double bonds of one of the above-mentioned unsaturated heterocycles may
each be fused to a phenyl or pyridine ring,
while the phenyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl,
1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-C1-3-alkyl-pyrazolyl, imidazolyl or 1-
C1-3-alkylimidazolyl groups contained in R1 and the benzo-, thieno-, pyrido-
and diazino-fused heterocycles in the carbon skeleton may additionally be
mono-, di- or trisubstituted by halogen atoms, C1-6-alkyl, C2-6-alkenyl,
C2-6-alkynyl, cyclo-C3-7-alkyl, cyclo-C3-7-alkenyl, cyano, hydroxy, hydroxy-
C1-6-alkyl, hydroxy-C3-6-alkenyl, hydroxy-C3-6-alkynyl, C1-6-alkoxy, C1-6-
alkoxy-
C1-6-alkyl, C1-6-alkoxy-C3-6-alkenyl, C1-6-alkoxy-C3-6-alkynyl, C3-6-alkenoxy-
C1-6-alkyl, C3-6-alkenoxy-C3-6-alkenyl, C3-6-alkenoxy-C3-6-alkynyl,
C3-6-alkynoxy-C1-6-alkyl, C3-6-alkynoxy-C3-6-alkenyl, C3-6-alkynoxy-
C3-6-alkynyl, thiohydroxy, C1-6-alkylthio, C3-6-alkenylthio, C3-6-alkynylthio,

-237-
amino, C1-6-alkyl-amino, C3-6-alkenyl-amino, C3-6-alkynyl-amino, di-
(C1-6-alkyl)-amino, di-(C3-6-alkenyl)-amino, di-(C3-6-alkynyl)-amino, amino-
C1-6-alkyl, C1-3-alkyl-amino-Cl-6-alkyl, di-(C1-3-alkyl)-amino-C1-6-alkyl,
amino-
C3-6-alkenyl, C1-3-alkyl-amino-C3-6-alkenyl, di-(C1-3-alkyl)-amino-C3-6-
alkenyl,
amino-C3-6-alkynyl, C1-3-alkyl-amino-C3-6-alkynyl, di-(C1-3-alkyl)-amino-
C3-6-alkynyl, hydroxycarbonyl, phenylcarbonyl, pyridylcarbonyl, C1-6-alkyl-
carbonyl, C2-6-alkenyl-carbonyl, C2-6-alkynyl-carbonyl, formyl, Cl-6-alkoxy-
carbonyl, C3-6-alkenoxy-carbonyl, C3-6-alkynoxy-carbonyl, aminocarbonyl,
C1-6-alkyl-aminocarbonyl, C3-6-alkenyl-aminocarbonyl, C3-6-alkynyl-
aminocarbonyl, di-(C1-6-alkyl)-aminocarbonyl, di-(C3-6-alkenyl)-
aminocarbonyl, di-(C3-6-alkynyl)-aminocarbonyl, formylamino, C1-6-alkyl-
carbonylamino, C2-6-alkenyl-carbonylamino, C2-6-alkynyl-carbonylamino,
formyl-C1-6-alkyl-amino, formyl-C3-6-alkenyl-amino, formyl-C3-6-alkynyl-amino,
C1-6-alkyl-carbonyl-C1-6-alkyl-amino, C2-6-alkenyl-carbonyl-C1-6-alkyl-amino,
C2-6-alkynyl-carbonyl-C1-6-alkyl-amino, C1-6-alkyl-carbonyl-C3-6-alkenyl-
amino,
C2-6-alkenyl-carbonyl-C3-6-alkenyl-amino, C2-6-alkynyl-carbonyl-C3-6-alkenyl-
amino, C1-6-alkyl-carbonyl-C3-6-alkynyl-amino, C2-6-alkenyl-carbonyl-
C3-6-alkynyl-amino, C2-6-alkynyl-carbonyl-C3-6-alkynyl-amino, C1-6-alkyl-
sulphonyl, C2-6-alkenyl-sulphonyl, C2-6-alkynyl-sulphonyl, C1-6-alkyl-
sulphinyl,
C2-6-alkenyl-sulphinyl, C2-6-alkynyl-sulphinyl, C1-6-alkyl-sulphonylamino,
C2-6-alkenyl-sulphonylamino, C2-6-alkynyl-sulphonylamino, C1-6-alkyl-
sulphonyl-C1-6-alkylamino, C1-6-alkyl-sulphonyl-C3-6-alkenylamino, C1-6-alkyl-
sulphonyl-C3-6-alkynylamino, C2-6-alkenyl-sulphonyl-C1-6-alkylamino,
C2-6-alkenyl-sulphonyl-C3-6-alkenylamino, C2-6-alkenyl-sulphonyl-
C3-6-alkynylamino, C2-6-alkynyl-sulphonyl-C1-6-alkylamino, C2-6-alkynyl-
sulphonyl-C3-6-alkenylamino, C2-6-alkynyl-sulphonyl-C3-6-alkynylamino,
aminosulphonyl, C1-6-alkylaminosulphonyl, di-(C1-6-alkyl)-aminosulphonyl,
C3-6-alkenylaminosulphonyl, di-(C3-6-alkenyl)-aminosulphonyl,
C3-6-alkynylaminosulphonyl, di-(C3-6-alkynyl)-aminosulphonyl groups, while
the substituents may be identical or different,
R2 denotes the hydrogen atom,
a phenylmethyl group or a C2-7-alkyl group which may be substituted in the
.omega. position

-238-
by a cyclo-C3-7-alkyl, cyclo-C3-7-alkenyl, phenyl, pyridinyl, diazinyl,
hydroxy, amino,
C1-6-alkylamino, di-(C1-6-alkyl)-amino, C3-6-alkenylamino, di-(C3-6-
alkenyl)amino,
C3-6-alkynylamino, di-(C3-6-alkynyl)amino, hydroxycarbonyl, C1-6-
alkoxycarbonyl,
aminocarbonyl, aminocarbonylamino, C1-6-alkylcarbonylamino, C2-6-alkenylcarbo-
nylamino, C2-6-alkynylcarbonylamino, 4-morpholinyl, [bis-(2-
hydroxyethyl)]amino,
4-(C1-6-alkyl)-1-piperazinyl or 4-(.omega.-hydroxy-C2-7-alkyl)-1-piperazinyl
group,
a phenyl or pyridinyl group,
while the phenyl, pyridinyl and diazinyl groups mentioned in the groups
defined
for R2 hereinbefore or contained as substituents may additionally be mono-, di-
or
trisubstituted in the carbon skeleton by halogen, by C1-3-alkyl, C2-3-alkenyl,
C2-3-alkynyl, C1-3-alkoxy, hydroxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)-
amino,
amino-C1-3-alkyl, C1-3-alkyl-amino-C1-3-alkyl, di-(C1-3-alkyl)-amino-C1-3-
alkyl,
C1-3-alkylcarbonylamino, C1-3-alkylcarbonylamino-C1-3-alkyl, aminocarbonyl,
C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, cyano,
aminosulphonyl,
C1-3-alkyl-aminosulphonyl, di-(C1-3-alkyl)-aminosulphonyl, C1-3-alkylthio,
C1-3-alkylsulphinyl or C1-3-alkylsulphonyl and the substituents may be
identical or
different,
R3 denotes the hydrogen atom or a C1-3-alkyl group substituted by a phenyl or
pyridinyl group,
while the C1-3-alkyl group may be connected to an alkyl group contained in R2
or
a phenyl or pyridyl ring contained in R2 including the nitrogen atom to which
R2
and R3 are bound, forming a 4- to 7-membered ring,
or
R2 and R3 together with the enclosed nitrogen atom denote a group of general
formula

-239-
<IMG>
wherein
Y1 denotes the carbon atom or, if R5 denotes a pair of free electrons, Y1 may
also
denote the nitrogen atom,
q and r, if Y1 denotes the carbon atom, denote the numbers 0, 1 or 2, or
q and r, if Y1 denotes the nitrogen atom, denote the numbers 1 or 2,
R4 denotes the hydrogen atom, an amino, Cl-4-alkyl-amino, di-(C1-4-alkyl)-
alkylamino, C1-6-alkyl, cyclo-C3-7-alkyl, cyclo-C3-7-alkenyl, amino-C2-7-
alkyl, C1-
4-alkyl-amino-C2-7-alkyl, di-(C1-4-alkyl-amino)-C2-7-alkyl, aminoiminomethyl,
aminocarbonylamino, C1-4-alkyl-aminocarbonylamino, di-(C1-4-alkyl)-
aminocarbonylamino, C1-4-alkyl-aminocarbonyl-C1-4-alkyl-amino, di-(C1-4-alkyl)-
aminocarbonyl-C1-4-alkyl-amino, phenylaminocarbonylamino, aminocarbonyl,
C1-4-alkyl-aminocarbonyl, di-(C1-4-alkyl)-aminocarbonyl, aminocarbonyl-Cl-3-
alkyl,
C1-4-alkyl-aminocarbonyl-C1-3-alkyl, di-(C1-4-alkyl)-aminocarbonyl-C1-3-alkyl,
aminocarbonylamino-C1-3-alkyl, C1-6-alkoxycarbonyl, C3-6-alkenoxycarbonyl,
C3-6-alkynoxycarbonyl, C1-6-alkoxycarbonyl-C1-3-alkyl, C1-6-alkenoxycarbonyl-
C1-3-alkyl, C1-6-alkynoxycarbonyl-C1-3-alkyl or hydroxycarbonyl-Cl-3-alkyl
group,
a phenyl, pyridinyl, diazinyl, 1-naphthyl, 2-naphthyl, pyridinylcarbonyl or
phenylcarbonyl group which may be mono-, di- or trisubstituted in the carbon
skeleton in each case by halogen, by Cl-3-alkyl, C2-3-alkenyl, C2-3-alkynyl,
C1-3-alkoxy, hydroxy, amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, amino-C1-
3-alkyl, C1-4-alkyl-amino-C1-3-alkyl, di-(C1-4-alkyl)-amino-C1-3-alkyl,
C1-4-alkylcarbonylamino, C1-4-alkylcarbonylamino-C1-3-alkyl, aminocarbonyl, C1-

4-alkyl-aminocarbonyl, di-(C1-4-alkyl)-aminocarbonyl, cyano, aminosulphonyl,
Cl-

-240-
4-alkyl-aminosulphonyl, di-(C1-4-alkyl)-aminosulphonyl, C1-4-alkyl-thio, C1-4-
alkyl-
sulphinyl or C1-4-alkyl-sulphonyl, and the substituents may be identical or
different,
a heterocycle selected from a 4- to 10-membered azacycloalkyl group, a 6- to
10-
membered oxaza, thiaza- and diazacycloalkyl group as well as a 6- to 10-
membered azabicycloalkyl group,
a 1-alkyl-4-piperidinylcarbonyl or 4-alkyl-1-piperazinylcarbonyl group,
while the above-mentioned mono- and bicyclic heterocycles are bound to Y1
by a nitrogen or a carbon atom in formula (II),
in the above-mentioned mono- and bicyclic heterocycles a methyne group
not directly linked to a nitrogen, oxygen or sulphur atom may be substituted
by a fluorine atom and a methylene group not directly linked to a nitrogen,
oxygen or sulphur atom may be substituted by one or two fluorine atoms,
the above-mentioned mono- and bicyclic heterocycles as well as the
1-(C1-6-alkyl)-4-piperidinylcarbonyl and 4-(C1-6-alkyl)-1-piperazinylcarbonyl
group in the ring may be mono- to tetra-substituted by C1-6-alkyl groups, or
may optionally additionally be monosubstituted by a cyclo-C3-7-alkyl, cyclo-
C3-7-alkenyl, cyclo-C3-7-alkyl-C1-3-alkyl, phenyl-Cl-3-alkyl, pyridyl-C1-3-
alkyl,
C1-6-alkylcarbonyl, hydroxy, C1-6-alkoxy, amino, Cl-4-alkylamino, di-(C1-4-al-
kyl)amino, phenylcarbonyl, pyridinylcarbonyl, hydroxycarbonyl, hydroxy-
carbonyl-C1-3-alkyl, C1-6-alkoxycarbonyl, Cl-6-alkoxycarbonyl-Cl-3-alkyl,
aminocarbonyl, C1-4-alkylaminocarbonyl, di-(Cl-4-alkyl)aminocarbonyl or
C1-3-alkylsulphonyl group, by a cyclo-C3-7-alkyl-carbonyl, azacyclo-C4-7-alkyl-
carbonyl, diazacyclo-C5-7alkyl-carbonyl or oxazacyclo-C5-7alkyl-carbonyl
group optionally C1-3-alkyl-substituted in the ring, while the substituents
may
be identical or different and may be bound to a cyclic carbon or cyclic
nitrogen atom,
while the phenyl and pyridinyl groups contained in the groups mentioned

-241-
for R4 hereinbefore may in turn be mono-, di- or trisubstituted by halogen
atoms, by Cl-3-alkyl, C2-3-alkenyl, C2-3-alkynyl, C1-3-alkoxy, hydroxy,
amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, amino-C1-3-alkyl, C1-4-alkyl-
amino-C1-3-alkyl, di-(C1-4-alkyl)-amino-Cl-3-alkyl, C1-4-alkylcarbonylamino,
C1-4-alkylcarbonylamino-C1-3-alkyl, aminocarbonyl, C1-3-alkyl-
aminocarbonyl, di-C1-4-alkyl-aminocarbonyl, cyano, aminosulphonyl, C1-
4-alkyl-aminosulphonyl, di-(C1-4-alkyl)-aminosulphonyl, C1-3-alkyl-thio, C1-
3-alkyl-sulphinyl or C1-3-alkyl-sulphonyl, while the substituents may be
identical or different,
or, if Y1 denotes the carbon atom, R4 may denote the hydroxycarbonyl,
aminomethyl, C1-4-alkyl-aminomethyl or di-(C1-4-alkyl)-aminomethyl group,
R5 denotes a hydrogen atom,
a C1-4-alkyl group , while an unbranched alkyl group may be substituted in the
.omega.
position by a phenyl, pyridinyl, diazinyl, amino, Cl-4-alkylamino, di-(C1-4-
alkyl)-
amino, 4-C1-4-alkyl-1-piperazinyl or 4-morpholinyl group,
a C1-6-alkoxycarbonyl, cyano or aminocarbonyl group or, if Y1 denotes a
nitrogen
atom, R5 may denote a pair of free electrons,
or, if Y1 denotes the carbon atom, R5 may denote the fluorine atom, or
R4 together with R5 and Y1 denote a 4- to 7-membered cycloaliphatic ring
wherein a methylene group may be replaced by a -NH-, -N(C1-4-alkyl)-,
-N(C3-4-alkenyl)-, -N(C3-4-alkynyl)-, -N(cyclo-C3-7-alkyl)- or -N(C3-7-
cycloalkyl-
C1-3-alkyl) group,
while a hydrogen atom bound to a nitrogen atom in one of the groups
defined for R4 hereinbefore may be replaced by a protective group,
R6 and R7, which may be identical or different, in each case denote a hydrogen
atom, a C1-4-alkyl group or, if Y1 denotes a carbon atom, the fluorine atom, a

-242-
C1-4-alkylamino or di-(Cl-4-alkyl)-amino group, while the two C1-4-alkyl
groups may
be joined together to form a ring and
R8 and R9, which may be identical or different, in each case denote a hydrogen
atom or a C1-3-alkyl group,
while
R a denotes a hydrogen atom, a straight-chain or branched C1-6-alkyl, C3-6-
alkenyl,
C3-6-alkynyl or cyclo-C3-7-alkyl group wherein each hydrogen atom, if it is
not in the .alpha.-
position to a nitrogen atom, may be replaced by fluorine,
R b denotes a halogen atom, a straight-chain or branched C1-6-alkyl, C2-6-
alkenyl,
C2-6-alkynyl, cyclo-C3-7-alkyl, cyano, hydroxy, hydroxy-C1-6-alkyl, C1-6-
alkoxy,
C1-6-alkoxy-C1-6-alkyl, amino, C1-6-alkyl-amino or di-C1-6-alkyl-amino group,
wherein
each hydrogen atom, if it is not in the .alpha.-position to a nitrogen atom,
may be replaced
by fluorine and the two alkyl groups of the di-C1-6-alkyl-amino substituents
may be
joined together to form a 4- to 8-membered ring,
a methylene group in the .alpha.-position to a saturated nitrogen atom
substituted by the
group R a, or to an oxygen or sulphur atom, as a ring member of the
heterocycle of
the group Q, is not substituted by hydroxy, C1-6-alkoxy, amino, Cl-6-alkyl-
amino or di-
C1-6-alkyl-amino group,
the double and triple bonds of the C3-6-alkenyl or C3-6-alkynyl groups
contained in the
groups defined hereinbefore for R a, R b, and R1 are isolated from any
heteroatoms
which may be contained in these groups,
and, unless otherwise stated, all the alkyl, alkenyl and alkynyl groups
mentioned or
contained in the groups defined hereinbefore may be straight-chain or
branched,
every methyne group contained in the groups defined hereinbefore may be
substituted by a a fluorine atom, each methylene group may be substituted by
up to
2 fluorine atoms and each methyl group may be substituted by up to 3 fluorine
atoms
and two alkyl and alkenyl groups bound to a nitrogen atom may be joined
together

-243-
forming a 4- to 7-membered, saturated or unsaturated heterocyclic ring,
all the aromatic and heteroaromatic groups mentioned or contained in the
groups
defined hereinbefore may additionally be mono-, di- or trisubstituted by
halogen, by
cyano or hydroxy groups and the substituents may be identical or different and
by the protective groups mentioned in the definitions above and hereinafter
are
meant the protective groups familiar from peptide chemistry, particularly
a phenylalkoxycarbonyl group with 1 to 3 carbon atoms in the alkoxy moiety
optionally substituted in the phenyl nucleus by a halogen atom, by a nitro or
phenyl
group or by one or two methoxy groups,
for example the benzyloxycarbonyl, 2-nitro-benzyloxycarbonyl, 4-nitrobenzyl-
oxycarbonyl, 4-methoxy-benzyloxycarbonyl, 2-chloro-benzyloxycarbonyl,
3-chloro-benzyloxycarbonyl, 4-chloro-benzyloxycarbonyl, 4-biphenylyl-
.alpha.,.alpha.-
dimethyl-benzyloxycarbonyl or 3,5-dimethoxy-.alpha.,.alpha.-dimethyl-
benzyloxycarbonyl
group,
an alkoxycarbonyl group with a total of 1 to 5 carbon atoms in the alkyl
moiety,
for example the methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso-
propoxycarbonyl, n-butoxycarbonyl, 1-methylpropoxycarbonyl, 2-methylpropoxy-
carbonyl or tert.-butyloxycarbonyl group,
the allyloxycarbonyl, 2,2,2-trichloro-(1,1-dimethylethoxy)carbonyl or 9-
fluorenyl-
methoxycarbonyl group or
the formyl, acetyl or trifluoracetyl group,
the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates,
the
mixtures and the salts thereof, the hydrates of the salts, and those compounds
of
general formula I wherein one or more hydrogen atoms are replaced by
deuterium.

-244-
3. CGRP antagonists of general formula (I) according to claim 1, wherein
A, X, Q, R2 and R3 are defined as in one of claims 1 or 2 and
R1 denotes a mono- or diunsaturated 5- to 7-membered aza, diaza, triaza or
thiaza
heterocycle,
while the above-mentioned heterocycles are linked by a carbon or nitrogen atom
or
are spirocyclically linked by a carbon and a nitrogen atom, by a carbon and an
oxygen atom or by a carbon and a sulphur atom,
contain one or two carbonyl groups adjacent to a nitrogen atom,
may be substituted at a carbon atom by a phenyl, pyridinyl, diazinyl, thienyl,
pyrrolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl or 1-(C1-4-alkyl)-pyrazolyl
group and
an olefinic double bond of one of the above-mentioned unsaturated heterocycles
may be fused to a phenyl, naphthyl, pyridine, diazine, thienyl or quinoline
ring or
to a 1H-quinolin-2-one ring optionally substituted at the nitrogen atom by a
methyl group,
while the phenyl, pyridinyl, diazinyl, thienyl, pyrrolyl, 1,3-thiazolyl,
isoxazolyl,
pyrazolyl or 1-(C1-4-alkyl)-pyrazolyl groups contained in R1 as well as the
benzo-, pyrido- and diazino-fused heterocycles in the carbon skeleton may
additionally be mono-, di- or trisubstituted by halogen, by C1-6-alkyl, cyclo-
C3-7-alkyl, cyclo-C3-7-alkenyl, C1-6-alkoxy, hydroxycarbonyl,
C1-6-alkoxycarbonyl, cyano, hydroxy, amino, C1-4-alkylamino, di-
C1-4-alkylamino, C1-4-alkylcarbonylamino or C1-4-alkylcarbonyl groups, while
the substituents may be identical or different,
while, unless otherwise stated, all the alkyl, alkenyl and alkynyl groups
mentioned or
contained in the groups defined hereinbefore under R1 may be straight-chain or

-245-
branched, every methyne group contained in the groups defined hereinbefore may
be substituted by a fluorine atom, each methylene group may be substituted by
up to
2 fluorine atoms and each methyl group may be substituted by up to 3 fluorine
atoms
and two alkyl and alkenyl groups bound to a nitrogen atom may be joined
together
forming a 4- to 7-membered, saturated or unsaturated heterocyclic ring, and
all the aromatic and heteroaromatic groups mentioned or contained in the
groups
defined hereinbefore under R1 may additionally be mono-, di- or trisubstituted
by
halogen or by cyano or hydroxy groups and the substituents may be identical or
different,
the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates,
mixtures and salts thereof and the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic acids or
bases.
4. CGRP antagonists of general formula (I) according to claim 1, wherein
A, X, Q, R2 and R3 are defined as in one of claims 1 or 2 and
R1 denotes a monounsaturated 5- to 7-membered diaza or triaza heterocycle,
while the above-mentioned heterocycles are linked via a nitrogen atom or
are spirocyclically linked by a carbon and a nitrogen atom or by a carbon and
an
oxygen atom,
contain a carbonyl group adjacent to a nitrogen atom,
may additionally be substituted at a carbon atom by a phenyl group and
an olefinic double bond of one of the above-mentioned unsaturated heterocycles
may be fused to a phenyl, thienyl or quinoline ring,
while the phenyl groups contained in R1 and benzo-fused heterocycles in the

-246-
carbon skeleton may additionally be mono-, di- or trisubstituted by halogen,
by methyl, methoxy, difluoromethyl, trifluoromethyl, hydroxy, amino,
C1-4-alkylamino, di-(C1-4-alkyl)-amino, acetylamino, acetyl, hydroxycarbonyl,
C1-6-alkoxycarbonyl, cyano- difluoromethoxy or trifluoromethoxy groups,
while the substituents may be identical or different, but are preferably
unsubstituted or monosubstituted by a halogen atom or by a methyl or
methoxy group,
while, unless otherwise stated, all the alkyl groups mentioned or contained in
the
groups defined hereinbefore under R1 may be straight-chain or branched, every
methyne group contained in the groups defined hereinbefore may be substituted
by a
fluorine atom, each methylene group may be substituted by up to 2 fluorine
atoms
and each methyl group may be substituted by up to 3 fluorine atoms,
the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates,
mixtures and salts thereof and the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic acids or
bases.
5. CGRP antagonists of general formula (I) according to claim 1, wherein
A, X, Q, R2 and R3 are defined as in one of claims 1 or 2 and
R1 denotes a 1,3,4,5-tetrahydro-1,3-benzodiazepin-2-on-3-yl, 3,4-dihydro-lH-
quinazolin-2-on-3-yl, 5-phenyl-2,4-dihydro-1,2,4-triazol-3-on-2-yl, 1,3-
dihydro-
imidazo[4,5-c]quinolin-2-on-3-yl, 1,3-dihydro-naphth[1,2-d]imidazol-2-on-3-yl,
1,3-
dihydro-benzimidazol-2-on-3-yl, 4-phenyl-1,3-dihydro-imidazol-2-on-1-yl, 3,4-
dihydro-
1H-thieno[3,2-d]pyrimidin-2-on-3-yl or 3,4-dihydro-1H-thieno[3,4-d]pyrimidin-2-
on-3-yl
group or together with the piperidine ring in formula (I) denotes the 1',2'-
dihydro-2'-
oxospiro-4H-3',1-benzoxazin'-4,4'-piperidin-1-yl group,
while the heterocycles mentioned hereinbefore under R1 in the carbon skeleton
may additionally be monosubstituted by a methoxy group,
all the aromatic and heteroaromatic groups mentioned or contained in the
groups

-247-
defined hereinbefore under R1 may additionally be mono-, di- or trisubstituted
by
halogen atoms or by cyano or hydroxy groups and the substituents may be
identical
or different,
the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates,
mixtures and salts thereof and the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic acids or
bases.
6. CGRP antagonists of general formula (I) according to claim 1, wherein
A, X, R1, R 2 and R3 are defined as in one of claims 1 to 5 and
Q denotes a a heterocycle bound via a carbon or nitrogen atom consisting of a
ring A
and a ring B, which is fused by two adjacent carbon atoms or by a carbon atom
and
an adjacent nitrogen atom to the ring A, while the rings A and B are selected
independently of one another from
a 4-membered, saturated or monounsaturated carbocycle, in which a ring
member may be replaced by an > NR a group, an oxygen or sulphur atom or, in
the
case of an unsaturated ring member, by a nitrogen atom,
a 5-membered, saturated, mono- or diunsaturated carbocycle, in which one, two
or three ring members may be replaced independently of one another in each
case by an > NR a group, an oxygen or sulphur atom or, in the case of
unsaturated
ring members, may be replaced by a nitrogen atom, while in each case two or
three oxygen or sulphur atoms may not be directly linked to one another, or
a 6-membered, saturated, mono-, di- or triunsaturated carbocycle, in which
one,
two or three ring members may be replaced independently of one another in each
case by an > NR a group, an oxygen or sulphur atom or, in the case of
unsaturated
ring members, by a nitrogen atom, while in each case two or three oxygen or
sulphur atoms may not be directly linked to one another, and optionally
additionally a fourth, unsaturated ring member may be replaced by a nitrogen
atom, or

-248-
a 7-membered, saturated, mono-, di- or triunsaturated carbocycle, in which
one,
two, three or four ring members may each independently of one another be
replaced by an > NR a group, an oxygen or sulphur atom or, in the case of
unsaturated ring members, may be replaced by a nitrogen atom, while in each
case two or three oxygen or sulphur atoms may not be directly linked to one
another, or
an 8-membered, saturated, mono-, di-, tri- or tetra-unsaturated carbocycle, in
which one, two, three or four ring members may each independently of one
another be replaced by an > NR a group, an oxygen or sulphur atom or, in the
case
of unsaturated ring members, may be replaced by a nitrogen atom, while in each
case two or three oxygen or sulphur atoms may not be directly linked to one
another,
while at least one of the fused rings A and B contains at least one heteroatom
as a
ring member,
a methylene group as a ring member in the 4-membered rings A and B may in each
case be replaced independently of one another by a carbonyl group,
one or two methylene groups as ring members in the 5- to 8-membered rings A
and
B may in each case be replaced independently of one another by carbonyl
groups,
one or two carbon atoms as ring members of the rings A and B may be
substituted
by Rb, while the substituents may be identical or different,
two hydrogen atoms bound to adjacent carbon or nitrogen atoms or to a carbon
and
an adjacent nitrogen atom as ring members of the rings A or B may be replaced
by a
C3-6-n-alkylene bridge and thus form a tricyclic group, or
a hydrogen atom bound to a carbon or nitrogen atom as a ring member of the
ring A
and another hydrogen atom bound to a carbon or nitrogen atom as a ring member
of
the ring B, where the above-mentioned ring members are separated from one
another by two bonds, may be replaced by a C2-5-n-alkylene bridge and thus
form a

-249-
tricyclic group,
while in the above-mentioned C3-6-n-alkylene bridges and C2-5-n-alkylene
bridges
a methylene group may be replaced by a carbonyl group and/or one or two
methylene groups may each be replaced independently of one another by an
> NR a group, an oxygen or sulphur atom and/or a carbon atom may be
substituted
by R b, with the proviso that two oxygen and two sulphur atoms are not
directly
linked together,
R a denotes a hydrogen atom, a straight-chain or branched C1-6-alkyl, C3-6-
alkenyl,
C3-6-alkynyl or cyclo-C3-7-alkyl group, wherein each hydrogen atom, if it is
not in the
.alpha.-position to a nitrogen atom, may be replaced by fluorine,
R b denotes a halogen atom, a straight-chain or branched C1-6-alkyl, C2-6-
alkenyl,
C2-6-alkynyl, cyclo-C3-7-alkyl, cyano, hydroxy, hydroxy-Cl-6-alkyl, C1-6-
alkoxy,
C1-6-alkoxy-Cl-6-alkyl, amino, C1-6-alkyl-amino or di-C1-6-alkyl-amino group,
wherein
each hydrogen atom, if it is not in the .alpha.-position to a nitrogen atom,
may be replaced
by fluorine and the two alkyl groups of the di-C1-6-alkyl-amino substituents
may be
joined together to form a 4- to 8-membered ring,
with the provisos that
(i) the group Q contains a total of not more than five heteroatoms as ring
members,
(ii) the group Q contains a total of not more than two carbonyl groups as ring
members and
(iii) a group R b bound to a saturated carbon atom in the .alpha.-position to
a saturated
nitrogen atom substituted by the group R a, or to an oxygen or sulphur atom as
a
ring member of a bi- or tricyclic heterocycle of the group Q does not take on
the
meanings of a hydroxy, C1-6-alkoxy, amino, C1-6-alkyl-amino or di-C1-6-alkyl-
-amino group,
the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates,

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mixtures and salts thereof and the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic acids.
7. CGRP antagonists of general formula (I) according to claim 1, wherein
A, X, R1, R2 and R3 are defined as in one of claims 1 to 5 and
Q denotes a heterocycle bound via a carbon or nitrogen atom consisting of a
ring A
and a ring B, which is fused via two adjacent carbon atoms or via a carbon
atom and
an adjacent nitrogen atom to the ring A, while the rings A and B are selected
independently of one another from
a 5-membered, saturated, mono- or diunsaturated carbocycle, in which one, two
or three ring members may each be replaced independently of one another by an
> NR a group, an oxygen or sulphur atom or, in the case of unsaturated ring
members, by a nitrogen atom, while a maximum of two ring members denote
oxygen or sulphur atoms and these may not be directly linked to one another,
or
a 6-membered, saturated, mono-, di- or triunsaturated carbocycle, in which
one,
two or three ring members may each independently of one another be replaced
by an > NR a group, an oxygen or sulphur atom or, in the case of unsaturated
ring
members, by a nitrogen atom, while a maximum of two ring members denote
oxygen or sulphur atoms and these may not be directly linked to one another,
or
a 7-membered, saturated, mono-, di- or triunsaturated carbocycle, in which
one,
two or three ring members may each independently of one another be replaced
by an > NR a group, an oxygen or sulphur atom or, in the case of unsaturated
ring
members, by a nitrogen atom, while a maximum of two ring members denote
oxygen or sulphur atoms and these may not be directly linked to one another,
or
at least one of the fused rings A and B contains at least one heteroatom as a
ring
member,
one or two methylene groups as ring members in the 5- to 7-membered rings A
and

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B may each be replaced independently of one another by carbonyl groups,
one or two carbon atoms as ring members of the rings A and B may be
substituted
by R b, while the substituents may be identical or different,
two hydrogen atoms bound to adjacent carbon or nitrogen atoms or to a carbon
and
an adjacent nitrogen atom as ring members of the rings A or B may be replaced
by a
C3-5-n-alkylene bridge and thus form a tricyclic group, or
a hydrogen atom bound to a carbon or nitrogen atom as a ring member of the
ring A
and another hydrogen atom bound to a carbon or nitrogen atom as a ring member
of
the ring B, where the above-mentioned ring members are separated from one
another by two bonds, may be replaced by a C2-4-n-alkylene bridge and thus
form a
tricyclic group,
while in the above-mentioned C3-5-n-alkylene bridges and C2-4-n-alkylene
bridges
one or two methylene groups may each be replaced independently of one another
by an > NR a group or an oxygen atom and/or a carbon atom may be substituted
by R b, with the proviso that two oxygen atoms are not directly linked
together,
R a denotes a hydrogen atom, a straight-chain or branched C1-3-alkyl, C3-
alkenyl,
C3-alkynyl or cyclo-C3-6-alkyl group, wherein each hydrogen atom, if it is not
in the .alpha.-
position to a nitrogen atom, may be replaced by fluorine,
R b denotes a halogen atom, a straight-chain or branched C1-3-alkyl, C2-3-
alkenyl,
C2-3-alkynyl, cyclo-C3-6-alkyl, cyano, hydroxy, hydroxy-C1-3-alkyl, C1-3-
alkoxy,
C1-3-alkoxy-C1-3-alkyl, amino, C1-3-alkyl-amino or di-C1-3-alkyl-amino group,
wherein
each hydrogen atom, if it is not in the .alpha.-position to a nitrogen atom,
may be replaced
by fluorine and the two alkyl groups of the di-C1-3-alkyl-amino substituents
may be
joined together to form a 5- to 7-membered ring,
with the provisos that

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(i) the group Q contains a total of not more than three heteroatoms as ring
members,
(ii) the group Q contains a total of not more than two carbonyl groups as ring
members and
(iii) a group R b bound to a saturated carbon atom in the .alpha.-position to
a saturated
nitrogen atom substituted by the group R a, or to an oxygen or sulphur atom as
a
ring member of a bi- or tricyclic heterocycle of the group Q does not take on
the
meanings of a hydroxy, C1-3-alkoxy, amino, C1-3-alkyl-amino or di-C1-3-alkyl-
amino group,
the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates,
mixtures and salts thereof and the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic acids.
8. CGRP antagonists of general formula (I) according to claim 1, wherein
A, X, R1, R2 and R3 are defined as in one of claims 1 to 5 and
Q denotes a heterocycle bound via a carbon or nitrogen atom consisting of a
ring A
and a ring B, which is fused to the ring A via two adjacent carbon atoms or
via a
carbon atom and an adjacent nitrogen atom, while, with the proviso that A is a
5- or
6-membered ring and B is a 6- or 7-membered ring, the rings A and B are
selected
from
a 5-membered, saturated, mono- or diunsaturated carbocycle, in which one, two
or three ring members may each independently of one another be replaced by an
> NR a group, an oxygen or sulphur atom or, in the case of unsaturated ring
members, by a nitrogen atom, while a maximum of two ring members denote an
oxygen atom, which may not be directly linked to one another, and a maximum of
one ring member denotes a sulphur atom, or
a 6-membered, saturated, mono-, di- or triunsaturated carbocycle, in which
one,

-253-
two or three ring members may each independently of one another be replaced
by an > NR a group, an oxygen or sulphur atom or, in the case of unsaturated
ring
members, by a nitrogen atom, while a maximum of two ring members denote
oxygen atoms which may not be directly linked to one another denote and a
maximum of one ring member denotes a sulphur atom, or
a 7-membered, saturated, mono-, di- or triunsaturated carbocycle, in which
one,
two or three ring members may each independently of one another be replaced
by an > NR a group, an oxygen or sulphur atom or, in the case of unsaturated
ring
members, by a nitrogen atom, while a maximum of two ring members denote
oxygen or sulphur atoms and these may not be directly linked to one another,
or
at least one of the fused rings A and B contains at least one heteroatom as a
ring
member,
one or two methylene groups as ring members in the 5- to 7-membered rings A
and
B may each be replaced independently of one another by carbonyl groups,
one or two carbon atoms as ring members of the rings A and B may be
substituted
by R b, while the substituents may be identical or different,
two hydrogen atoms bound to adjacent carbon or nitrogen atoms or to a carbon
and
an adjacent nitrogen atom as ring members of the rings A or B may be replaced
by a
C3-4-n-alkylene bridge and thus form a tricyclic group, or
a hydrogen atom bound to a carbon or nitrogen atom as a ring member of the
ring A
and another hydrogen atom bound to a carbon or nitrogen atom as a ring member
of
the ring B, where the above-mentioned ring members are separated from one
another by two bonds, may be replaced by a C2-3-n-alkylene bridge and thus
form a
tricyclic group,
while in the above-mentioned C3-4-n-alkylene bridges and C2-3-n-alkylene
bridges
one or two methylene groups may be substituted by R b independently of one
another,

-254-
R a denotes a hydrogen atom or a straight-chain or branched C1-3-alkyl group,
wherein each hydrogen atom, if it is not in the .alpha.-position to a nitrogen
atom, may be
replaced by fluorine,
R b denotes a halogen atom or a straight-chain or branched C1-3-alkyl group,
wherein
each hydrogen atom, if it is not in the .alpha.-position to a nitrogen atom,
may be replaced
by fluorine,
with the provisos that
(i) the group Q contains a total of not more than three heteroatoms as ring
members,
(ii) the group Q contains a total of not more than two carbonyl groups as ring
members and
the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates,
mixtures and salts thereof and the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic acids.
9. CGRP antagonists of general formula (I) according to claim 1, wherein
A, X, Q and R1 are defined as in one of claims 1 to 8 and
R2 denotes the hydrogen atom or
a phenylmethyl group or a C2-7-alkyl group which may be substituted in the
.omega. position
by a cyclo-C3-7-alkyl, cyclo-C3-7-alkenyl, phenyl, pyridinyl, hydroxy, amino,
C1-6-alkylamino, di-(C1-6-alkyl)-amino, hydroxycarbonyl, C1-6-alkoxycarbonyl,
aminocarbonyl, aminocarbonylamino, C1-6-alkylamino, 4-morpholinyl group,
while the phenyl and pyridinyl groups mentioned in the groups defined
hereinbefore for R2 or contained as substituents may additionally be mono-, di-
or
trisubstituted in the carbon skeleton by halogen, by C1-3-alkyl, C1-3-alkoxy,

-255-
hydroxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, amino-C1-3-alkyl,
C1-3-alkylamino-C1-3-alkyl, di-(C1-3-alkyl)-amino-C1-3-alkyl,
C1-3-alkylcarbonylamino, C1-3-alkylcarbonyl-C1-3-alkylamino, aminocarbonyl,
C1-3-alkylaminocarbonyl or di-(C1-3-alkyl)-aminocarbonyl groups and the
substituents may be identical or different,
R3 denotes the hydrogen atom or a C1-3-alkyl group or
R2 and R3 together with the enclosed nitrogen atom denote a group of general
formula
<IMG>
wherein
Y1 denotes the carbon atom or, if R5 denotes a pair of free electrons, Y1 may
also
be the nitrogen atom,
q and r, if Y1 denotes the carbon atom, denote the numbers 0 or 1 or
q and r, if Y1 denotes the nitrogen atom, denote the numbers 1 or 2,
R4 denotes the hydrogen atom, an amino, C1-4-alkyl-amino, di-(C1-4-alkyl)-
alkylamino, C1-6-alkyl, a cyclo-C3-7-alkyl or cyclo-C3-7-alkenyl group
optionally
substituted by a hydroxycarbonyl, C1-6-alkoxycarbonyl, hydroxycarbonyl-C1-3-
alkyl
or C1-6-alkoxycarbonyl-C1-3-alkyl group, an amino-C2-7-alkyl, C1-4-alkyl-amino-
C2-7-alkyl, di-(C1-4-alkyl-amino)-C2-7-alkyl, C1-4-alkyl-aminocarbonyl, di-(C1-
4-alkyl)-
aminocarbonyl, aminocarbonyl-C1-3-alkyl, C1-4-alkyl-aminocarbonyl-C1-3-alkyl,
di-(C1-4-alkyl)-aminocarbonyl-C1-3-alkyl, aminocarbonylamino-C1-3-alkyl,
C1-6-alkoxycarbonyl, C1-6-alkoxycarbonyl-C1-3-alkyl or hydroxycarbonyl-C1-3-
alkyl
group,

-256-
a phenyl, pyridinyl or diazinyl group which may be substituted in each case by
a
halogen, by a C1-3-alkyl, C1-3-alkoxy, hydroxy, amino, C1-4-alkyl-amino, di-
(C1-
4-alkyl)-amino- amino-C1-3-alkyl, C1-4-alkyl-amino-C1-3-alkyl, di-(C1-4-alkyl)-
amino-
C1-3-alkyl group,
a heterocycle selected from a 4- to 7-membered azacycloalkyl group, a 6- to
7-membered oxaza, S,S-dioxothiaza or diazacycloalkyl group and a 7- to 9-
membered azabicycloalkyl group,
while the above-mentioned mono- and bicyclic heterocycles are bound to Y1
in formula (II) by a nitrogen or a carbon atom,
in the above-mentioned mono- and bicyclic heterocycles a methylene group
not directly linked to a nitrogen, oxygen or sulphur atom may be substituted
by one or two fluorine atoms and
the above-mentioned mono- and bicyclic heterocycles may be mono- or
disubstituted by hydroxy, C1-3-alkyl or hydroxy-C1-3-alkyl groups or may be
monosubstituted by a benzyl, cyclo-C3-6-alkyl, hydroxycyclo-C3-6-alkyl, cyclo-
C3-6-alkyl-C1-3-alkyl, C1-4-alkylcarbonyl, C1-4-alkylcarbonyl-C1-3-alkyl,
hydroxy,
C1-4-alkoxy, amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino,
C1-3-alkoxycarbonyl, hydroxycarbonyl-carbonyl, C1-3-alkoxycarbonyl-carbonyl,
hydroxycarbonyl-C1-3-alkyl, C1-3-alkoxycarbonyl-C1-3-alkyl, hydroxycarbonyl-
C1-3-alkylcarbonyl, C1-3-alkoxycarbonyl-C1-3-alkylcarbonyl, aminosulphonyl,
C1-4-alkylaminosulphonyl, di-(C1-4-alkyl)-aminosulphonyl, C1-3 alkylsulphonyl,
cyclo-C3-7-alkylsulphonyl, aminocarbonyl-C1-3-alkyl, C1-4-alkylaminocarbonyl-
C1-3-alkyl, di-(C1-4-alkyl)-aminocarbonyl-C1-3-alkyl, hydroxyaminocarbonyl-
C1-3-alkyl, C1-3-alkoxyaminocarbonyl-C1-3-alkyl or hydroxy-(C1-3-alkyl)-
aminocarbonyl-C1-3-alkyl groups,
or, if Y1 denotes the carbon atom, also denotes the hydroxycarbonyl,
aminomethyl, C1-4-alkyl-aminomethyl or di-(C1-4-alkyl)-aminomethyl group,
R5 denotes a hydrogen atom, a C1-3-alkyl group or, if Y1 denotes a nitrogen

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atom, also denotes a pair of free electrons,
R6 and R7, which may be identical or different, in each case denote a hydrogen
atom, a C1-3-alkyl group or, if Y1 denotes a carbon atom, they may also denote
an
amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group, while the two C1-3-
alkyl
groups may be joined together to form a ring and
R8 and R9, which may be identical or different, in each case denote a hydrogen
atom or a C1-3-alkyl group,
while, unless otherwise stated, all the alkyl, alkenyl and alkynyl groups
mentioned or
contained in the groups defined hereinbefore may be straight-chain or
branched,
every methyne group contained in the groups defined hereinbefore may be
substituted by a fluorine atom, each methylene group may be substituted by up
to 2
fluorine atoms and each methyl group may be substituted by up to 3 fluorine
atoms
and two alkyl and alkenyl groups bound to a nitrogen atom may be joined
together
forming a 4- to 7-membered, saturated or unsaturated heterocyclic ring,
all the aromatic and heteroaromatic groups mentioned or contained in the
groups
defined hereinbefore may additionally be mono-, di- or trisubstituted by
halogen, by
cyano or hydroxy groups and the substituents may be identical or different,
the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates,
mixtures and salts thereof and the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic acids or
bases.
10. CGRP antagonists of general formula (I) according to claim 1, wherein
A, X, Q and R1 are defined as in one of claims 1 to 8 and
R2 denotes the hydrogen atom or
a phenylmethyl group or a C2-7-alkyl group which may be substituted in the
.omega. position
by a cyclo-C3-7-alkyl, cyclo-C3-7-alkenyl, phenyl, pyridinyl, hydroxy, amino,

-258-
C1-6-alkylamino, di-(C1-6-alkyl)-amino, hydroxycarbonyl, C1-6-alkoxycarbonyl,
aminocarbonyl, aminocarbonylamino, C1-6-alkylamino, 4-morpholinyl group,
while the phenyl and pyridinyl groups mentioned in the groups defined
hereinbefore for R2 or contained as substituents may additionally be mono-, di-
or
trisubstituted in the carbon skeleton by halogen, by C1-3-alkyl, C1-3-alkoxy,
hydroxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, amino-C1-3-alkyl,
C1-3-alkylamino-C1-3-alkyl, di-(C1-3-alkyl)-amino-C1-3-alkyl,
C1-3-alkylcarbonylamino, C1-3-alkylcarbonyl-C1-3-alkylamino, aminocarbonyl,
C1-3-alkylaminocarbonyl or di-(C1-3-alkyl)-aminocarbonyl groups and the
substituents may be identical or different,
R3 denotes the hydrogen atom or a C1-3-alkyl group or
R2 and R3 together with the enclosed nitrogen atom denote a group of general
formula
<IMG>
wherein
Y1 denotes the carbon atom or, if R5 denotes a pair of free electrons, may
also
represent the nitrogen atom,
q and r, if Y1 denotes the carbon atom, denote the numbers 0 or 1 or
q and r, if Y1 denotes the nitrogen atom, denote the numbers 1 or 2,
R4 denotes the hydrogen atom, an amino, C1-4-alkyl-amino, di-(C1-4-alkyl)-
alkylamino, C1-6-alkyl, cyclo-C3-7-alkyl, cyclo-C3-7-alkenyl, amino-C2-7-
alkyl, C1-
4-alkyl-amino-C2-7-alkyl, di-(C1-4-alkyl-amino)-C2-7-alkyl, C1-4-alkyl-
aminocarbonyl,

-259-
di-(C1-4-alkyl)-aminocarbonyl, aminocarbonyl-C1-3-alkyl, C1-4-alkyl-
aminocarbonyl-
C1-3-alkyl, di-(C1-4-alkyl)-aminocarbonyl-C1-3-alkyl, aminocarbonylamino-C1-3-
alkyl,
C1-6-alkoxycarbonyl, C1-6-alkoxycarbonyl-C1-3-alkyl or hydroxycarbonyl-C1-3-
alkyl
group,
a phenyl, pyridinyl or diazinyl group which may be substituted in each case by
a
halogen, by a C1-3-alkyl, C1-3-alkoxy, hydroxy, amino, C1-4-alkylamino, di-(C1-

4-alkyl)-amino, amino-C1-3-alkyl, C1-4-alkylamino-C1-3-alkyl, di-(C1-4-alkyl)-
amino-
C1-3-alkyl group,
a heterocycle selected from a 4- to 7-membered azacycloalkyl group, a 6- to
7-membered oxaza or diazacycloalkyl group and a 7- to 9-membered
azabicycloalkyl group,
while the above-mentioned mono- and bicyclic heterocycles are bound to Y1
in formula (II) by a nitrogen or a carbon atom,
in the above-mentioned mono- and bicyclic heterocycles a methylene group
not directly linked to a nitrogen, oxygen or sulphur atom may be substituted
by one or two fluorine atoms and
the above-mentioned mono- and bicyclic heterocycles may be mono- or
polysubstituted, for example mono- to trisubstituted, by C1-3-alkyl groups or
monosubstituted by a benzyl, cyclo-C3-6-alkyl, cyclo-C3-6-alkyl-C1-3-alkyl, C1-
4-
alkylcarbonyl, hydroxy, C1-4-alkoxy, amino, C1-4-alkylamino, di-(C1-4-alkyl)-
amino, hydroxycarbonyl, C1-3-alkoxycarbonyl, hydroxycarbonyl-C1-3-alkyl,
C1-3-alkoxycarbonyl-C1-3-alkyl or C1-3 alkylsulphonyl group,
or also, if Y1 denotes the carbon atom, the hydroxycarbonyl, aminomethyl, C1-
4-alkylaminomethyl or di-(C1-4-alkyl)-aminomethyl group,
R5 denotes a hydrogen atom, a C1-3-alkyl group or, if Y1 denotes a nitrogen
atom, also a pair of free electrons,

-260-
R6 and R7, which may be identical or different, in each case represent a
hydrogen atom, a C1-3-alkyl group or also, if Y1 denotes a carbon atom, a
C1-3-alkylamino or di-(C1-3-alkyl)-amino group, while the two C1-3-alkyl
groups may
be joined together to form a ring and
R8 and R9, which may be identical or different, in each case represent a
hydrogen atom or a C1-3-alkyl group,
while, unless otherwise stated, all the alkyl, alkenyl and alkynyl groups
mentioned or
contained in the groups defined hereinbefore may be straight-chain or
branched,
every methyne group contained in the groups defined hereinbefore may be
substituted by a fluorine atom, each methylene group may be substituted by up
to 2
fluorine atoms and each methyl group may be substituted by up to 3 fluorine
atoms
and two alkyl and alkenyl groups bound to a nitrogen atom may be joined
together
forming a 4- to 7-membered, saturated or unsaturated heterocyclic ring,
all the aromatic and heteroaromatic groups mentioned or contained in the
groups
defined hereinbefore may additionally be mono-, di- or trisubstituted by
halogen, by
cyano or hydroxy groups and the substituents may be identical or different,
the tautomers, the diastereomers, the enantiomers, the hydrates, mixtures and
salts
thereof and the hydrates of the salts, particularly the physiologically
acceptable salts
thereof with inorganic or organic acids or bases.
11.CGRP antagonists of general formula (I) according to claim 1, wherein
A, X, Q and R1 are defined as in one of claims 1 to 8 and
R2 denotes the hydrogen atom or
a phenylmethyl group or a C2-7-alkyl group which may be substituted in the
.omega. position
by a phenyl, amino, C1-6-alkylamino, di-(C1-6-alkyl)-amino group,
while the phenyl and phenylmethyl group mentioned hereinbefore may

-261-
additionally be mono- or disubstituted at an aromatic carbon atom by halogen,
by
C1-3-alkyl, C1-3-alkoxy, amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl or
di-(C1-3-alkyl)-amino-C1-3-alkyl groups and the substituents may be identical
or
different,
R3 denotes the hydrogen atom or a C1-3-alkyl group or
R2 and R3 together with the enclosed nitrogen atom denote a group of general
formula
<IMG>
wherein
Y1 denotes the carbon atom or, if R5 denotes a pair of free electrons, may
also
represent the nitrogen atom,
q and r, if Y1 denotes the carbon atom, denote the numbers 0 or 1 or
q and r, if Y1 denotes the nitrogen atom, denote the numbers 1 or 2,
R4 denotes the hydrogen atom, an amino, C1-4-alkyl-amino, di-(C1-4-alkyl)-
alkylamino, C1-6-alkyl, a cyclo-C3-7-alkyl or cyclo-C3-7-alkenyl group
optionally
substituted by a hydroxycarbonyl, C1-6-alkoxycarbonyl, hydroxycarbonyl-C1-3-
alkyl
or C1-6-alkoxycarbonyl-C1-3-alkyl group, an amino-C2-7-alkyl, C1-4-alkyl-amino-
C2-7-alkyl, di-(C1-4- alkyl-amino)-C2-7-alkyl, C1-6-alkoxycarbonyl,
C1-6-alkoxycarbonyl-C1-3-alkyl or hydroxycarbonyl-C1-3-alkyl group,
a phenyl or pyridyl group which may be substituted in each case by a halogen,
by
a C1-3-alkyl, C1-3-alkoxy, amino, C1-4-alkyl-amino, di-(C1-4-alkyl)-amino
group,

-262-
a heterocycle selected from a 6- to 7-membered azacycloalkyl group, a 6- to
7-membered S,S,dioxothiaza- and diazacycloalkyl group and a 7- to 9-membered
azabicycloalkyl group,
while the above-mentioned mono- and bicyclic heterocycles are bound to Y1
in formula (II) by a nitrogen or a carbon atom,
in the above-mentioned mono- and bicyclic heterocycles a methylene group
not directly linked to a nitrogen, oxygen or sulphur atom may be substituted
by one or two fluorine atoms and
the above-mentioned mono- and bicyclic heterocycles may be mono- or
disubstituted by a hydroxy, C1-3-alkyl or hydroxy-C1-3-alkyl group, by a
benzyl,
cyclo-C3-6-alkyl, hydroxy-C3-6-cycloalkyl, cyclo-C3-6-alkyl-C1-3-alkyl,
C1-3-alkylcarbonyl-C1-3-alkyl, amino, C1-4-alkylamino or di-(C1-4-alkyl)-
amino,
hydroxycarbonyl-carbonyl, C1-6-alkoxycarbonyl-carbonyl, hydroxycarbonyl-
C1-3-alkylcarbonyl, C1-3-alkoxycarbonyl-C1-3-alkylcarbonyl, aminosulphonyl,
C1-4-alkylaminosulphonyl, di-(C1-4-alkyl)-aminosulphonyl, cyclo-
C3-7-alkylsulphonyl, aminocarbonyl-C1-3-alkyl, C1-4-alkylaminocarbonyl-
C1-3-alkyl, di-(C1-4-alkyl)-aminocarbonyl-C1-3-alkyl, hydroxyaminocarbonyl-
C1-3-alkyl, C1-3-alkoxyaminocarbonyl-C1-3-alkyl or hydroxy-(C1-3-alkyl)-
aminocarbonyl-C1-3-alkyl groups,
or, if Y1 denotes the carbon atom, the hydroxycarbonyl, aminomethyl,
C1-4-alkyl-aminomethyl or di-(C1-4-alkyl)-aminomethyl group,
R5 denotes a hydrogen atom or, if Y1 denotes a nitrogen atom, it may also
denote
a pair of free electrons,
R6 and R7, which may be identical or different, in each case represent a
hydrogen atom, a C1-3-alkyl group or, if Y1 denotes a carbon atom, may also
represent a C1-3-alkylamino or di-C1-3-alkyl)-amino group, while the two C1-3-
alkyl
groups may be joined together to form a ring and

-263-
R8 and R9, which may be identical or different, in each case represent a
hydrogen atom or a C1-3-alkyl group,
the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates,
mixtures and salts thereof and the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic acids or
bases.
12. CGRP antagonists of general formula (I) according to claim 1, wherein
A, X, Q and R1 are defined as in one of claims 1 to 8 and
R2 denotes a phenylmethyl group or a C2-7-alkyl group which may be substituted
in
the .omega. position by a phenyl, amino, C1-6-alkylamino, di-(C1-6-alkyl)-
amino group,
while the above-mentioned phenyl and phenylmethyl group may be substituted at
an aromatic carbon atom by an amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl or
di-
(C1-3-alkyl)-amino-C1-3-alkyl group,
R3 denotes the hydrogen atom or a C1-3-alkyl group or
R2 and R3 together with the enclosed nitrogen atom denote a group of general
formula
<IMG>
wherein
R6 and R1 in each case denote a hydrogen atom or a dimethylamino group,
R8 and R9 in each case denote the hydrogen atom and

-264-
(a) Y1 denotes the carbon atom,
q and r denote the numbers 0 or 1,
R4 denotes the hydrogen atom,
a phenyl, pyridinyl or pyrimidinyl group which may be substituted in
each case by a halogen, by an amino, methylamino, dimethylamino,
methyl or methoxy group,
a hydroxy, 2-diethylamino-ethyl, amino, methylamino, dimethylamino,
diethylamino, pyrrolidin-1-yl, piperidin-1-yl, 4-amino-piperidin-1-yl, 4-
methylamino-piperidin-1-yl, 4-dimethylamino-piperidin-1-yl,
4-hydroxymethyl-piperidin-1-yl, 4-hydroxy-piperidin-1-yl, 4-methoxy-
piperidin-1-yl, 4-hydroxy-4-methyl-piperidin-1-yl, 4-hydroxy-
4-trifluoromethyl-piperidin-1-yl, 4-ethyl-4-hydroxy-piperidin-1-yl,
4,4-dimethylpiperidin-1-yl, 4-amino-4-methyl-piperidin-1-yl, 4-hydroxy-
4-hydroxymethyl-piperidin1-yl, 3-amino-piperidin-1-yl, 3-methylamino-
piperidin-1-yl, 3-dimethylamino-piperidin-1-yl, perhydro-azepin-1-yl,
perhydro-1,4-diazepin-1-yl, 4-methyl-perhydro-1,4-diazepin-1-yl, 1-
methyl-piperidin-4-yl, piperidin-4-yl, 1-ethylpiperidin-4-yl,
1-(2-hydroxyethyl)-piperidin-4-yl, 1-cyclopropyl-piperidin-4-yl, 1-
cyclopropylmethyl-piperidin-4-yl, 1-hydroxycarbonylmethyl-
piperidin-4-yl, 1-ethoxycarbonylmethyl-piperidin-4-yl,
1-hydroxycarbonylethyl-piperidin-4-yl, 1-ethoxycarbonylethyl-
piperidin-4-yl, 1-hydroxycarbonylethylcarbonyl-piperidin-4-yl,
1-ethoxycarbonylethylcarbonyl-piperidin-4-yl, 1-methylsulphonyl-
piperidin-4-yl, 1-aminosulphonyl-piperidin-4-yl,
1-hydroxycarbamoylmethyl-piperidin-4-yl, 1-(hydroxy-methyl-
carbamoyl)-piperidin-4-yl, 1-(methoxycarbamoyl-methyl)-piperidin-4-yl,
piperazin-1-yl, 4-methyl-piperazin-1-yl, 4-methylsulphonyl-
piperazin-1-yl, 4-aminosulphonyl-piperazin-1-yl, 4-cyclopropylmethyl-
piperazin-1-yl, 4-ethyl-piperazin-1-yl, 4-(2-hydroxyethyl)-piperazin-1-yl,
4-cyclopropyl-piperazin-1-yl, 4-hydroxycarbonylmethyl-piperazin-1-yl,

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4-ethoxycarbonylmethyl-piperazin-1-yl, 4-hydroxycarbonylethyl-
piperazin-1-yl, 4-ethoxycarbonylethyl-piperazin-1-yl,
4-hydroxycarbonylethylcarbonyl-piperazin-1-yl,
4-ethoxycarbonylethylcarbonyl-piperazin-1-yl, 1,2-dimethyl-piperazin-1-
yl, 3-methyl-piperazin-1-yl, 3,4,5-trimethyl-piperazin-1-yl, 3,5-dimethyl-
piperazin-1-yl, 3,3,4-trimethyl-piperazin-1-yl, 3,3-dimethyl-piperazin-1-
yl, 3,3,4,5,5-pentamethyl-piperazin-1-yl, 3,3,5,5-tetramethyl-piperazin-
1-yl, morpholin-4-yl, 4,4-difluoro-piperidin-1-yl, 8-methyl-8-aza-
bicyclo[3.2.1]oct-3-yl, 8-aza-bicyclo[3.2.1]oct-3-yl, azetidin-1-yl,
1-(methoxycarbonylmethyl)-piperidin-4-yl, 1-(ethoxycarbonylmethyl)-
piperidin-4-yl, 4-(ethoxycarbonylmethyl)-piperazin-1-yl, 1-hydroxycar-
bonylmethyl-piperidin-4-yl or 4-hydroxycarbonylmethyl-piperazin-1-yl
group, and
R5 denotes a hydrogen atom, or
(b) Y1 denotes a nitrogen atom,
q and r denote the numbers 1 or 2,
R4 denotes the hydrogen atom,
a phenyl, pyridinyl or pyrimidinyl group which may be substituted in
each case by a halogen, by an amino, methylamino, dimethylamino,
methyl or methoxy group,
a methyl, ethyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclopropylmethyl, 2-diethylamino-propyl, 1-quinuclidin-3-
yl, piperidin-4-yl, 1-methyl-piperidin-4-yl, 1-ethyl-piperidin-4-yl,
1-(2-hydroxyethyl)-piperidin-4-yl, 1-cyclopropyl-piperidin-4-yl, 1-
cyclopropylmethyl-piperidin-4-yl, 1-hydroxycarbonylmethyl-piperi-
din-4-yl, 1-ethoxycarbonylmethyl-piperidin-4-yl, 1-hydroxycarbonylethyl-
piperidin-4-yl, 1-ethoxycarbonylethyl-piperidin-4-yl,
1-hydroxycarbonylethylcarbonyl-piperidin-4-yl,

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1-ethoxycarbonylethylcarbonyl-piperidin-4-yl, 1-ethoxycarbonylmethyl-
piperidin-4-yl, 1-methylsulphonyl-piperidin-4-yl, 1-aminosulphonyl-
piperidin-4-yl, tetrahydropyran-4-yl, 8-methyl-8-aza-bicyclo[3.2.1]oct-3-
yl, 5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl or 1-aza-bicyclo[2.2.2]oct-
3-yl group and
R5 denotes a pair of free electrons,
the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates,
mixtures and salts thereof and the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic acids or
bases.
13.CGRP antagonists of general formula (I) according to claim 1, wherein
A, X, Q and R1 are defined as in one of claims 1 to 8 and
R2 denotes a phenylmethyl group or a C2-7-alkyl group which may be substituted
in
the .omega. position by a phenyl, amino, C1-6-alkylamino, di-(C1-6-alkyl)-
amino group,
while the phenyl and phenylmethyl group mentioned hereinbefore may be
substituted at an aromatic carbon atom by an amino-C1-3-alkyl, C1-3-alkylamino-
C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-alkyl group,
R3 denotes the hydrogen atom or a C1-3-alkyl group or
R2 and R3 together with the enclosed nitrogen atom denote a group of general
formula
<IMG>

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wherein
R6 and R7 in each case denote a hydrogen atom or a dimethylamino group,
R8 and R9 in each case denote the hydrogen atom and
(a) Y1 denotes the carbon atom,
q and r denote the numbers 0 or 1,
R4 denotes the hydrogen atom,
a phenyl, pyridinyl or pyrimidinyl group which may be substituted in
each case by a halogen, by an amino, methylamino, dimethylamino,
methyl or methoxy group,
a hydroxy, 2-diethylamino-ethyl, amino, methylamino, dimethylamino,
diethylamino, pyrrolidin-1-yl, piperidin-1-yl, 4-amino-piperidin-1-yl, 4-
methylamino-piperidin-1-yl, 4-dimethylamino-piperidin-1-yl, 3-amino-
piperidin-1-yl, 3-methylamino-piperidin-1-yl, 3-dimethylamino-piperidin-
1-yl, perhydro-azepin-1-yl, perhydro-1,4-diazepin-1-yl, 4-methyl-
perhydro-1,4-diazepin-1-yl, 1-methyl-piperidin-4-yl, piperidin-4-yl,
1 -ethyl piperidin-4-yl, 1-cyclopropyl-piperidin-4-yl, 1-cyclopropylmethyl-
piperidin-4-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, 4-
cyclopropylmethyl-piperazin-1-yl, 4-ethyl-piperazin-1-yl, 4-cyclopropyl-
piperazin-1-yl, 1,2-dimethyl-piperazin-1-yl, 3-methyl-piperazin-1-yl,
3,4,5-trimethyl-piperazin-1-yl, 3,5-dimethyl-piperazin-1-yl, 3,3,4-
trimethyl-piperazin-1-yl, 3,3-dimethyl-piperazin-1-yl, 3,3,4,5,5-
pentamethyl-piperazin-1-yl, 3,3,5,5-tetramethyl-piperazin-1-yl,
morpholin-4-yl, 4,4-difluoro-piperidin-1-yl, 8-methyl-8-aza-
bicyclo[3.2.1]oct-3-yl, 8-aza-bicyclo[3.2.1]oct-3-yl, azetidin-1-yl,
1-(methoxycarbonylmethyl)-piperidin-4-yl, 1-(ethoxycarbonylmethyl)-
piperidin-4-yl, 4-(ethoxycarbonylmethyl)-piperazin-1-yl, 1-hydroxycar-
bonylmethyl-piperidin-4-yl or 4-hydroxycarbonylmethyl-piperazin-1-yl

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group, and
R5 denotes a hydrogen atom, or
(b) Y' denotes a nitrogen atom,
q and r denote the numbers 1 or 2,
R4 denotes the hydrogen atom,
a phenyl, pyridinyl or pyrimidinyl group which may be substituted in
each case by a halogen, by an amino, methylamino, dimethylamino,
methyl or methoxy group,
a methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl,
2--diethylamino-propyl, 1-quinuclidin-3-yl, 1-piperidin-4-yl,
1-methyl--piperidin-4-yl, 1-ethyl-piperidin-4-yl, 1-cyclopropyl-piperidin-4-
yl,
1--cyclopropylmethyl-piperidin-4-yl, 1-hydroxycarbonylmethyl-piperidin-4-yl
or 1-ethoxycarbonylmethyl-piperidin-4-yl group and
R5 denotes a pair of free electrons,
the tautomers, the diastereomers, the enantiomers, the hydrates, mixtures and
salts
thereof and the hydrates of the salts, particularly the physiologically
acceptable salts
thereof with inorganic or organic acids or bases.
14. CGRP antagonists of general formula (I) according to claim 1, wherein
A and X in each case denote an oxygen atom,
R1 denotes a 1,3,4,5-tetrahydro-1,3-benzodiazepin-2-on-3-yl,
3,4-dihydro-1H--quinazolin-2-on-3-yl, 5-phenyl-2,4-dihydro-1,2,4-triazol-3-on-
2-yl,
1,3-dihydro--imidazo[4,5-c]quinolin-2-on-3-yl, 1,3-dihydro-naphth[1,2-
d]imidazol-2-on-3-yl,
1,3--dihydro-benzimidazol-2-on-3-yl, 4-phenyl-1,3-dihydro-imidazol-2-on-1-yl,
3,4-dihydro-

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1H-thieno[3,2-d]pyrimidin-2-on-3-yl or 3,4-dihydro-1H-thieno[3,4-d]pyrimidin-2-
on-3-yl
group or together with the piperidine ring in formula (I) denotes the 1',2'-
dihydro-2'-
oxospiro-4H-3',1-benzoxazin'-4,4'-piperidin-1-yl group,
and R2 and R3 are defined as in one of claims 1 and 2,
while the heterocycles mentioned hereinbefore under R1 may additionally be
monosubstituted in the carbon skeleton by a methoxy group,
and all the aromatic and heteroaromatic groups and parts of molecules
mentioned or
contained in the groups defined under R' may additionally be mono-, di- or
trisubstituted by halogen atoms or by cyano or hydroxy groups and the
substituents
may be identical or different,
the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates,
mixtures and salts thereof and the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic acids or
bases.
15. CGRP antagonists of general formula (I) according to claim 1, wherein
A and X in each case denote an oxygen atom,
R1 is defined as in claim 5,
Q is defined as in claim 8,
the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates,
mixtures and salts thereof and the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic acids or
bases.
16. CGRP antagonists of general formula (1) according to claim 1, wherein
A and X in each case denote an oxygen atom,

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R1 is defined as in claim 5,
Q is defined as in claim 8,
R2 and R3 are defined as in claim 12,
the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates,
mixtures and salts thereof and the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic acids or
bases.
17. The compounds of general formula (I) according to claim 1 which are
numbered progressively from (1) to (606) in the Table in the specification,
the enantiomers, the diastereomers and the salts thereof.
18. The following compounds of general formula (I) according to claim 1:
(1) (R)-1-(7-methyl-1H-indazol-5-ylmethyl)-2-[4-(4-methyl-piperazin-1-yl)-
piperidin-
1-yI]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-
piperidine-1-carboxylate,
(2) (R)-1-(4-amino-3-methyl-5-nitro-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-
piperi-
din-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-
piperidine-1-carboxylate,
(3) (R)-1-(3,4-diamino-5-methyl-benzyl)-2-[4-(4-methyl-piperazin-1 -yl)-
piperidin-
1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-
piperidine-1-carboxylate,
(4) (R)-1-(7-methyl-1H-benzimidazol-5-ylmethyl)-2-[4-(4-methyl-piperazin-1-yl)-
piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
yl)-
piperidine-1-carboxylate,
(5) (R)-2-4,4'-bipiperidinyl-1-yl-1-(7-methyl-1H-benzimidazol-5-ylmethyl)-2-
oxo-

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ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-
carboxylate,
(6) (R)-1-(7-methyl-1H-benzimidazol-5-ylmethyl)-2-oxo-2-(4-piperazin-1-yl-
piperi-
din-1-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
1-carboxylate,
(7) (R)-1-(2,7-dimethyl-1H-benzimidazol-5-ylmethyl)-2-[4-(4-methyl-piperazin-
1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-
3-yl)-piperidine-1-carboxylate,
(8) (R)-1-(7-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylmethyl)-2-[4-(4-
methyl-
piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(9) (R)-1-(2-cyclopropyl-7-methyl-1H-benzimidazol-5-ylmethyl)-2-[4-(4-methyl-
piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(10) (R)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1 -yl]-1-(7-methyl-2-
trifluoromethyl-
1H-benzimidazol-5-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(11) (R)-1-(2-methoxy-7-methyl-1H-benzimidazol-5-ylmethyl)-2-[4-(4-methyl-
piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4, 5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(12) (R)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-1-(8-methyl-quinoxalin-
6-yl-
methyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-
piperidine-1-carboxylate,
(13) (R)-1-{2-[(Z)-cyanimino]-7-methyl-2,3-dihydro-1H-benzimidazol-5-ylmethyl}-
2-
[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,

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(14) (R)-1-(7-methyl-1H-benzotriazol-5-ylmethyl)-2-[4-(4-methyl-piperazin-1-
yl)-
piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
yl)-
piperidine-1-carboxylate,
(15) (R)-2-(1'-methanesulphonyl-4,4'-bipiperidinyl-1-yl)-1-(7-methyl-1H-
benzimidazol-5-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(16) (R)-1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-[4-(4-methyl-
piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(17) (R)-1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-[4-(1-methyl-
piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(18) (R)-2-(4-amino-4-methyl-1,4'-bipiperidinyl-1'-yl)-1-(4-methyl-2-oxo-2,3-
dihydro-
benzoxazol-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(19) (R)-1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-(1'-
sulpha-
moyl-4,4'-bipiperidinyl-1-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(20) (R)-2-(1'-methanesulphonyl-4,4'-bipiperidinyl-1-yl)-1-(4-methyl-2-oxo-2,3-
dihydro-benzoxazol-6-ylmethyl )-2-oxo-ethyl 4-(2-oxo-1,2,4, 5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(21) (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-[4-(1-
methyl-
piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(22) (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-[4-(4-
methyl-
piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-

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benzodiazepin-3-yl)-piperidine-1-carboxylate,
(23) (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-(1'-methyl-
4,4'-bipiperidinyl-1-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(24) (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-(4-hydroxy-
1,4'-bipiperidinyl-1'-yI)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(25) (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-(1'-
sulphamoyl-4,4'-bipiperidinyl-1-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(26) (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-(1'-
methanesulphonyl-4,4'-bipiperidinyl-1-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,
(27) (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-[4-(8-
methyl-
8-aza-bicyclo[3.2.1]oct-3-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
tetrahydro-l,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,
(28) (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-(4-
pi-
perazin-1-yl-piperidin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl )-piperidine-1-carboxylate,
(29) (R)-2-4,4'-bipiperidinyl-1-yl-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
benzoxazol-
6-yl methyl )-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1, 3-benzodiazepin-3-yl)-
piperidine-1-carboxylate,
(30) (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-(4-
pi-
peridin-4-yl-piperazin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,

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(31) (R)-2-(4-amino-4-methyl-1,4'-bipiperidinyl-1'-yl)-1-(3,4-dimethyl-2-oxo-
2,3-
dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(32) (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-(1'-ethoxy-
carbonylmethyl-4,4'-bipiperidinyl-1-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4, 5-
tetrahydro-
1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,
(33) (R)-2-(1'-carboxymethyl-4,4'-bipiperidinyl-1-yl)-1-(3,4-dimethyl-2-oxo-
2,3-di-
hydro-benzoxazol-6-yl methyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(34) (R)-2-1,4'-bipiperidinyl-1'-yI-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
benzoxazol-
6-ylmethyl )-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-
piperidine-1-carboxylate,
(35) (R)-2-[4-(4-cyclopropyl-piperazin-1-yl)-piperidin-1-yl]-1-(3,4-dimethyl-2-
oxo-
2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,
(36) (R)-2-(4-cyclohexyl-piperazin-1-yl)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
benz-
oxazol-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
3-yI)-piperidine-1-carboxylate,
(37) (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-[4-
(tetrahydro-pyran-4-yl)-piperazin-1-yl]-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(38) (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-(4-hydroxy-
4-hydroxymethyl-1,4'-bipiperidinyl-1'-yI)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,
(39) (R)-1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-[4-(4-methyl-piperazin-1-
yl)-
piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
yl)-

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piperidine-1-carboxylate,
(40) (R)-1-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-[4-(4-methyl-
pipera-
zin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(41) (R)-2-(1'-methyl-4,4'-bipiperidinyl-1-yl)-1-(8-methyl-2,3-dihydro-1,4-
benzodioxin-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(42) (R)-2-(4-hydroxy-1,4'-bipiperidinyl-1'-yl)-1-(8-methyl-2,3-dihydro-1,4-
benzodi-
oxin-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
yl)-piperidine-1-carboxylate,
(43) (R)-1-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-(4-morpholin-4-
yl-
piperidin-1-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
yl)-
piperidine-1-carboxylate,
(44) (R)-1-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-oxo-2-[4-(5-oxo-
perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,
(45) (R)-2-(1'-ethoxycarbonylmethyl-4,4'-bipiperidinyl-1-yl)-1-(8-methyl-2,3-
dihydro-
1,4-benzodioxin-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(46) (R)-1-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-[4-(1-methyl-
piperi-
din-4-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(47) (R)-2-1,4'-bipiperidinyl-1'-yl-1-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-
yl-
methyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-
piperidine-1-carboxylate,

-276-
(48) (R)-2-[4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-piperazin-1-yl]-1-(8-
methyl-2,3-
dihydro-1,4-benzodioxin-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,
(49) (R)-2-[4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-piperidin-1-yl]-1-
(8-methyl-
2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,
(50) (R)-2-[4-(1-aza-bicyclo[2.2.2]oct-3-yl)-piperazin-1-yl]-1-(8-methyl-2,3-
dihydro-
1,4-benzodioxin-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(51) (R)-1-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-oxo-2-(4-
piperazin-
1-yl-piperidin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-
piperidine-1-carboxylate,
(52) (R)-1-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-oxo-2-(4-
piperidin-
4-yl-piperazin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-
piperidine-1-carboxylate,
(53) (R)-2-(1'-carboxymethyl-4,4'-bipiperidinyl-1-yl)-1-(8-methyl-2,3-dihydro-
1,4-
benzodioxin-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(54) (R)-2-(4-amino-4-methyl-1,4'-bipiperidinyl-1'-yl)-1-(8-methyl-2,3-dihydro-
1,4-
benzodioxin-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(55) (R)-2-(1'-methanesulphonyl-4,4'-bipiperidinyl-1-yl)-1-(8-methyl-2,3-
dihydro-1,4-
benzodioxin-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(56) (R)-2-[4-(4-methanesulphonyl-piperazin-1-yl)-piperidin-1-yl]-1-(8-methyl-
2,3-di-
hydro-1,4-benzodioxin-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-

-277-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(57) (R)-1-(8-methyl-imidazo[1,5-a]pyridin-6-ylmethyl)-2-[4-(4-methyl-
piperazin-1-
yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
3-
yl)-piperidine-1-carboxylate,
(58) (R)-2-(1'-methyl-4,4'-bipiperidinyl-1-yl)-1-(8-methyl-imidazo[1,2-
a]pyridin-6-yl-
methyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-
piperidine-1-carboxylate,
(59) (R)-1-(8-methyl-imidazo[1,2-a]pyridin-6-ylmethyl)-2-[4-(1-methyl-
piperidin-4-yl)-
piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
yl)-piperidine-1-carboxylate,
the enantiomers, the diastereomers and the salts thereof.
19. Physiologically acceptable salts of the compounds according to one of
claims
1 to 18 with inorganic or organic acids or bases.
20. Pharmaceutical compositions containing a compound according to one of
claims 1 to 18 or a physiologically acceptable salt according to claim 19,
optionally
together with one or more inert carriers and/or diluents.
21. Use of a compound according to one of claims 1 to 19 for preparing a
pharmaceutical composition for the acute and prophylactic treatment of
headaches,
particularly migraine or cluster headaches, for the treatment of non-insulin-
dependent
diabetes mellitus (NIDDM), complex regional pain syndrome (CRPS1),
cardiovascular diseases, morphine tolerance, diarrhoea caused by clostridium
toxin,
skin diseases, particularly thermal and radiation-induced skin damage
including
sunburn, inflammatory diseases, e.g. inflammatory diseases of the joints
(arthritis),
neurogenic inflammation of the oral mucosa, inflammatory lung diseases,
allergic
rhinitis, asthma, diseases accompanied by excessive vasodilatation and
resultant
reduced circulation of the blood, e.g. shock and sepsis, for alleviating pain
in general
or for preventive or acute therapeutic treatment of the symptoms of menopausal
hot

-278-
flushes caused by vasodilatation and increased blood flow in oestrogen-
deficient
women and hormone-treated patients with prostate carcinoma.
22. Process for preparing a pharmaceutical composition according to claim 20,
characterised in that a compound according to at least one of claims 1 to 19
is
incorporated in one or more inert carriers and/or diluents by a non-chemical
method.
23. Process for preparing the compounds of general formula (I) according to
one
of claims 1 to 19, characterised in that
(a) in order to prepare compounds of general formula (I) wherein all the
groups
are defined as in claim 1, a carboxylic acid of general formula
<IMG>
wherein all the groups are defined as in claim 1, is coupled with an amine of
general
formula HNR2R3, wherein R2 and R3 are defined as in claim 1, or
(b) in order to prepare compounds of general formula (I) wherein all the
groups are
defined as in claim 1, a compound of general formula
<IMG>
is coupled with an amine of general formula HNR2R3, wherein all the groups are
defined as in claim 1 and Nu denotes a leaving group,
while if desired any carboxylic acid functions, primary or secondary amino
functions
or hydroxy functions present in the starting compounds before the coupling
reactions

-279-
are protected by conventional protecting groups and any protecting groups used
are
cleaved again after the reaction,
if desired 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.

Description

CA 02565219 2006-10-17
WO 2005/103037 PCT/EP2005/004104
87076pct
Selected CGRP antagonists, methods for the production thereof, and
use thereof as medicaments
The present invention relates to the CGRP antagonists of general formula
A Q R2
~ I
N X N3
1 O
R
wherein A, Q, X, R1, R2 and R3 are defined as in claim 1, the tautomers, the
isomers,
the diastereomers, the enantiomers, the hydrates, mixtures and salts thereof
and the
hydrates of the salts, particularly the physiologically acceptable salts
thereof with
inorganic or organic acids or bases, as well as those compounds of general
formula I
in which one or more hydrogen atoms are replaced by deuterium, pharmaceutical
compositions containing these compounds, the use thereof and processes for the
1~ preparation thereof.
In the above general formula (I) in a first embodiment
A denotes an oxygen or sulphur atom,
X denotes an oxygen or sulphur atom,
Q denotes a heterocycle bound via a carbon or nitrogen atom consisting of two
or
three in each case 4- to 8-membered fused rings, saturated, partially
unsaturated or
totally unsaturated independently of one another,
while the heterocycle comprises a total of one to five heteroatoms selected
independently of one another from among 0, N and S,
may contain one or two carbonyl groups as ring members and

CA 02565219 2006-10-17
-2-
each saturated nitrogen atom as a ring member of the heterocycle may be
substituted by the group Ra and one or two carbon atoms as ring members of the
heterocycle may be substituted by the group Rb,
R' denotes a saturated, mono- or diunsaturated 5- to 7-membered aza, diaza,
triaza,
oxaza, thiaza, thiadiaza or S,S-dioxido-thiadiaza heterocycle,
while the above-mentioned heterocycles are linked to the piperidine ring in
formula I by a carbon or nitrogen atom or
are spirocyclically linked to the piperidine ring in formula I by two carbon
atoms,
by a carbon and a nitrogen atom, by a carbon and an oxygen atom or by a
carbon and a sulphur atom,
contain one or two carbonyl or thiocarbonyl groups adjacent to a nitrogen
atom,
may be substituted at one of the nitrogen atoms by a C1_6-alkyl, C3_6-alkenyl
or
C3-6-alkenyl group,
may be substituted at one or at two carbon atoms by a C1_6-alkyl, C2_6-alkenyl
or
C2_6-alkynyl group, by a phenyl, phenylmethyl, naphthyl, biphenylyl,
pyridinyl,
diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl,
pyrazolyl,
1-(C1_3-alkyl)-pyrazolyl, imidazolyl or 1-(C1_3-alkyl)-imidazolyl group, while
the
substituents may be identical or different, and
an olefinic double bond of one of the above-mentioned unsaturated heterocycles
may be fused to a phenyl, naphthyl, pyridine, diazine, 1,3-oxazole, thienyl,
furan,
thiazole, pyrrole, N-C1_3-alkyl-pyrrole or quinoline ring, to a 1H-quinolin-2-
one
ring optionally substituted at the nitrogen atom by a C1_6-alkyl, C3_6-alkenyl
or
C3-6-alkynyl group or to an imidazole or N-Cl-3-aikyl-imidazoie ring or two
olefinic
double bonds of one of the above-mentioned unsaturated heterocycles may
each be fused to a phenyl or pyridine ring,
while the phenyl, pyridinyl, diazinyl, furyl, thienyl, pyrroiyi, 1,3-oxazolyl,

= CA 02565219 2006-10-17
-3-
1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-C1_3-alkyl-pyrazolyl, imidazolyl or 1-
C1_3-alkyl-imidazolyl groups contained '+n R' and benzo-, thieno-, pyrido- and
diazino-fused heterocycles in the carbon skeleton may additionally be mono-,
di- or trisubstituted by halogen atoms, C1_6-alkyl, C2_6-alkenyi, C2_6-
alkynyl,
cyclo-C3_7-alkyl, cyclo-C3_7-alkenyl, cyano, hydroxy, hydroxy-C1_6-alkyl,
hydroxy-C3_6-alkenyl, hydroxy-C3_6-alkynyl, Cl_6-alkoxy, C1_6-alkoxy-C1_6-
a(kyl,
C1_6-alkoxy-C3_6-alkenyl, C1_6-alkoxy-C3_6-alkynyl, C3_6-aikenoxy-C1_6-aIkyI,
C3_6-alkenoxy-C3_6-alkenyl, C3_6-alkenoxy-C3_6-alkynyl, C3_6-alkynoxy-
C1_6-alkyl, C3_6-alkynoxy-C3_6-alkenyl, C3_6-alkynoxy-C3_6-alkynyl,
thiohydroxy,
CI_6-alkytthio, C3_6-alkenylthio, C3_6-alkynylthio, amino, C1_6-alkyl-amino,
C3_6-alkenyl-amino, C3_6-alkynyl-amino, di-P_6-alkyl)-amino, di-(C3_6-alkenyl)-
amino, di-(C3_6-alkynyl)-amino, amino-C1_6-alkyl, C1_3-alkyl-amino-C1_6-alkyl,
di-(C1_3-alkyl)-amino-CI-6-alkyl, amino-C3_6-alkenyl, C1_3-alkyl-amino-
C3_6-alkenyl, di-(C1_3-alkyl)-amino-C3_6-alkenyl, amino-C3_6-alkynyl, C1_3-
alkyl-
amino-C3_6-alkynyl, di-(CT_3-alkyl)-amino-C3_6-alkynyl, hydroxycarbonyl,
phenylcarbonyl, pyridylcarbonyl, C1_6-alkyl-carbonyl, C2_s-alkenyl-carbonyl,
C2_6-alkynyl-carbonyl, formyl, C1_6-alkoxy-carbonyl, C3_6-alkenoxy-carbonyl,
C3_6-alkynoxy-carbonyl, aminocarbonyl, C1_6-alkyl-aminocarbonyl,
C3_6-alkenyl-aminocarbonyl, C3_6-alkynyl-aminocarbonyl, di-(C1_6-alkyl)-
2o aminocarbonyl, di-(C3_6-alkenyl)-aminocarbonyl, di-(C3_6-alkynyl)-
aminocarbonyl, formylamino, C1_6-alkyl-carbonylamino, C2_6-alkenyl-
carbonylamino, C2_6-alkynyl-carbonylamino, formyl-Cl_6-alkyl-amino, formyl-
C3_6-alkenyl-amino, formyl-C3_6-alkynyl-amino, Cl_6-alkyl-carbonyl-C1_6-alkyl-
amino, C2_6-alkenyl-carbonyl-C1_6-alkyl-amino, C2_6-alkynyl-carbonyl-
CI_6-alkyl-amino, C1_6-alkyl-carbonyl-C3_6-alkenyl-amino, C2_6-alkenyl-
carbonyl-C3_6-alkenyl-amino, C2_6-alkynyi-carbonyl-C3_6-alkenyl-amino,
C1_6-alkyl-carbonyl-C3_6-alkynyl-amino, C2_6-alkenyl-carbonyl-C3_6-alkynyl-
amino, C2_6-alkynyl-carbonyl-C3_6-alkynyl-amino, C1_6-alkyl-sulphonyl,
C2_s-alkenyl-sulphonyl, C2_6-alkynyl-sulphonyl, Cl_6-alkyl-sulphinyl,
C2_6-alkenyl-suiphinyl, C2_6-alkynyl-sulphinyl, CT_s-alkyl-sulphonylamino,
C2_6-alkenyl-sulphonylamino, C2_6-alkynyl-sulphonylamino, C1_6-alkyl-
sulphonyl-CI_6-alkylamino, Cl_6-alkyl-sulphonyl-C3_6-aikenylamino, C1_6-alkyl-
sulphonyl-C3_6-alkynylamino, C2_6-alkenyl-sulphonyl-C1_6-alkylamino,
C2_6-alkenyl-sulphonyl-C3_6-alkenylamino, C2_6-alkenyl-sulphonyl-

CA 02565219 2006-10-17
-4-
C3_6-alkynylamino, C2_s-alkynyl-sulphonyl-C1_6-alkylamino, C2_6-alkynyl-
sulphonyl-C3_6-alkenylamino, C2_6-alkynyl-sulphonyl-C3_6-alkynylamino,
aminosulphonyl, C1_6-alkylaminosulphonyl, di-(C1_6-alkyl)-aminosulphonyl,
C3_6-alkenylaminosulphonyl, di-(C3_6-alkenyt)-aminosuiphonyl,
C3_6-aikynylaminosulphonyl, di-(C3_6-alkynyl)-aminosulphonyl groups, while
the substituents may be identical or different,
R2 denotes the hydrogen atom,
a phenylmethyl group or a C2-7-alkyl group which may be substituted in the w
position
by a cyclo-C3_7-alkyl, cyclo-C3_7-alkenyl, phenyl, pyridinyl, diazinyl,
hydroxy, amino,
C1-6-alkylamino, di-(C1_6-alkyl)-amino, C3_6-alkenylamino, di-(C3_6-
alkenyl)amino,
C3-6-alkynylamino, di-(C3_6-alkynyl)amino, hydroxycarbonyl, C1-6-
alkoxycarbonyl,
aminocarbonyl, aminocarbonylamino, C1_6-alkylcarbonylamino, C2_6-alkenyl-
carbonylamino, C2_6-alkynylcarbonylamino, 4-morpholinyl, [bis-(2-hydroxy-
ethyl)]amino, 4-(CI-6-alkyl)-1-piperazinyl or 4-((o-hydroxy-C2_7-alkyl)-1-
piperazinyl
group,
a phenyl or pyridinyl group,
while the phenyl, pyridinyl and diazinyl groups mentioned in the above
definitions of R2 or contained as substituents may additionally be mono- di-
or
trisubstituted in the carbon skeleton by halogen, by C1_3-alkyl, C2_3-alkenyl,
C2_3-alkynyl, Cl_3-alkoxy, hydroxy, amino, C1_3-alkylamino, di-(C1_3-alkyl)-
amino,
amino-CI_3-alkyl, C1_3-alkyl-amino-C1_3-alkyl, di-(C1_3-alkyl)-amino-C1_3-
alkyl,
C1_3-alkylcarbonylamino, C1-3-alkylcarbonylamino-Cl_3-alkyl, aminocarbonyl,
C1_3-alkyl-aminocarbonyl, di-(Cl_3-alkyl)-aminocarbonyl, cyano,
aminosulphonyl,
C1_3-alkyl-aminosulphonyl, di-(C1-3-alkyl)-aminosulphonyl, C1-3-alkyl-thio,
C1-3-alkyl-sulphinyl or C1_3-alkyl-sulphonyl and the substituents may be
identical
or different,
R3 denotes the hydrogen atom or a C1-3-alkyl group substituted by a phenyl or
pyridinyl group,

= CA 02565219 2006-10-17
-5-
while the C1_3-afkyl group may be connected to an alkyl group contained in R2
or
a phenyl or pyridyl ring contained in R2 including the nitrogen atom to which
R2
and R3 are bound, forming a 4- to 7-membered ring,
or
R2 and R3 together with the enclosed nitrogen atom denote a group of general
formula
R5
(CR$R9)q I
- Y
CR6R~ R4
~. (CR8R9)r, /
N CR6R7 , (II)
wherein
Y1 denotes the carbon atom or, if R5 denotes a pair of free electrons, it may
also
denote the nitrogen atom,
q and r, if Y1 denotes the carbon atom, denote the numbers 0, 1 or 2, or
q and r, if Y1 denotes the nitrogen atom, denote the numbers 1 or 2,
R4 denotes the hydrogen atom, an amino, C1-4-alkyl-amino, di-(C1-4-alkyl)-
alkylamino, C1_6-alkyl, a cyclo-C3_7-alkyl or cyclo-C3-7-alkenyl group
optionally
substituted by a hydroxycarbonyl, C1_6-alkoxycarbonyl, hydroxycarbonyl-C1_3-
alkyl
or C1-6-alkoxycarbonyl-C1_3-alkyl group, an amino-C2-7-alkyl, C1-4-alkyl-amino-
C2_7-alkyl, di-(C1_4-alkyl-amino)-C2_7-alkyl, aminoiminomethyl,
aminocarbonylamino, Cl_4-alkyl-aminocarbonylamino, di-(C1_4-alkyl)-
aminocarbonylamino, C1_4-alkyl-aminocarbonyl-C1_4- alkyl-amino, di-(C1_4-
alkyl)-
aminocarbonyl-C1-4- alkyl-amino, phenylaminocarbonylamino, aminocarbonyl,
C1-4-alkyl-aminocarbonyl, di-(C1-4-alkyl)-aminocarbonyl, aminocarbonyl-C1_3-
alkyl,
C1_4-alkyl-aminocarbonyl-C1-3-alkyl, di-(CI_4-alkyl)-aminocarbonyl-C1_3-alkyl,

CA 02565219 2006-10-17
-6-
aminocarbonylamino-Cl_3-alkyl, C1_6-alkoxycarbonyl, C3-6-alkenoxycarbonyl, C3_
6-alkynoxycarbonyl, Cl_6-alkoxycarbonyl-CI_3-alkyl, C1_6-alkenoxycarbonyl-Cl_
3-alkyl, C1_6-alkynoxycarbonyl-Cl_3-alkyl or hydroxycarbonyl-C1_3-alkyl group,
a phenyl, pyridinyl, diazinyl, 1-naphthyl, 2-naphthyl, pyridinylcarbonyl or
phenylcarbonyl group which may be mono- di- or trisubstituted in each case in
the carbon skeleton by halogen, by C1_3-alkyl, C2_3-alkenyl, C2-3-alkynyl,
C1_3-alkoxy, hydroxy, amino, C1_4-alkyiamino, di-(C1_4-alkyl)-amino, amino-Cl_
3-alkyl, C1_4-alkyl-amino-Cl_3-alkyl, di-(CI_4-alkyl)-amino-Cl_3-alkyl,
C1_4-alkylcarbonylamino, C1_4-alkylcarbonylamino-C1_3-alkyl, aminocarbonyl,
Cl_
4-alkyl-aminocarbonyl, di-(C1_4-alkyl)-aminocarbonyl, cyano, aminosulphonyl,
Cl-
4-alkyl-aminosulphonyl, di-(C1_4-alkyl)-aminosulphonyl, C1_4-alkyl-thio, C1_4-
alkyl-
sulphinyl or C1_4-alkyl-sulphonyl and the substituents may be identical or
different,
a heterocycle selected from a 4- to 10-membered azacycloalkyl group, a 6- to
10-
membered oxaza-, thiaza-, S,S-dioxothiaza- and diazacycloalkyl group as well
as
a 6- to 10-membered azabicycloalkyl group,
a 1-alkyl-4-piperidinylcarbonyl or 4-alkyl-l-piperazinylcarbonyl group,
while the above-mentioned mono- and bicyclic heterocycles are bound to Y'
in formula (II) by a nitrogen or a carbon atom,
in the above-mentioned mono- and bicyclic heterocycles a methyne group
not directly linked to a nitrogen, oxygen or sulphur atom may be substituted
by a fluorine atom and a methylene group not directly linked to a nitrogen,
oxygen or sulphur atom may be substituted by one or two fluorine atoms,
the above-mentioned mono- and bicyclic heterocycles as well as the
1-(C1_6-alkyl)-4-piperidinylcarbonyl- and 4-(CI_6-alkyl)-1-piperazinylcarbonyi
group in the ring may be mono- to tetra-substituted by hydroxy, Cl_6-alkyl or
hydroxy-C1-3-alkyl groups, or, optionally additionally, may be monosubstituted
by a cyclo-C3_7-alkyl, hydroxy-C3_7-cycloalkyl, cyclo-C3_7-alkenyl, cyclo-
C3_7-alkyl-C1_3-alkyl, phenyl-CI_3-alkyl, pyridyl-CI_3-alkyl, C1-6-
alkylcarbonyl,

CA 02565219 2006-10-17
-7-
C1-6-alkylcarbonyl-C1_3-alkyl, hydroxy, CI_6-alkoxy, amino, C1-4-alkylamino,
di-
(Cl_4-alkyl)amino, phenylcarbonyl, pyridinylcarbonyl, C1_6-alkoxycarbonyl,
hydroxycarbonyl-carbonyl, C1_6-alkoxycarbonyl-carbonyl, hydroxycarbonyl-
C1_3-alkyl, CI-6-alkoxycarbonyl-CI_3-alkyl, hydroxycarbonyl-C1_3-
alkylcarbonyl,
C1_6-alkoxycarbonyl-Cl_3-alkylcarbonyl, aminocarbonyl,
C1_4-alkylaminocarbonyl, di-(CI_4-alkyl)aminocarbonyl, aminosulphonyl,
C1_4-alkylaminosulphonyl, di-(C1_4-alkyl)aminosulphonyl, C1_3-alkylsulphonyl,
cyclo-C3_7-alkylsulphonyl, aminocarbonyl-C1_3-alkyl, C1_4-alkylaminocarbonyl-
C1-3-alkyl, di-(CI_4-alkyl)aminocarbonyl-C1_3-alkyl, hydroxyaminocarbonyl-
C1_3-alkyl, Cl_3-alkoxyaminocarbonyl-C1_3-alkyi or hydroxy-(C1-3-alkyl)-
aminocarbonyl-Cl_3-alkyl group, by a cyclo-C3-7-alkyl-carbonyl, azacyclo-
C4_7-alkyl-carbonyl, diazacyclo-C5_7-alkyl-carbonyl or oxazacyclo-C5_7-alkyl-
carbonyl group optionally C1_3-alkyl-substituted in the ring, while the
substituents may be identical or different and may be bound to a cyclic
carbon or cyclic nitrogen atom,
while the phenyl and pyridinyl groups contained in the groups given as
definitions of R4 hereinbefore may in turn be mono-, di- or trisubstituted
by halogen atoms, by C1_3-alkyl, C2_3-alkenyl, C2_3-alkynyl, C1_3-alkoxy,
hydroxy, amino, Cl_4-alkylamino, di-(Cl_4-alkyl)-amino, amino-CI_3-alkyl,
C1_4-alkyl-amino-C1-3-alkyl, di-(CI_4-alkyl)-amino-Cl_3-alkyl,
C1_4-alkylcarbonylamino, C1_4-alkylcarbonylamino-C1_3-alkyl,
aminocarbonyl, CI-3-alkyl-aminocarbonyl, di-CI_4-alkyl-aminocarbonyl,
cyano, aminosulphonyl, Cl_4-alkyl-aminosulphonyl, di-P_4-alkyl)-
aminosulphonyl, C1_3-alkyl-thio, CI_3-alkyl-sulphinyl or C1_3-alkyl-
sulphonyl, while the substituents may be identical or different,
or, if Y' denotes the carbon atom, may denote the hydroxycarbonyl,
aminomethyl, C1_4-alkyl-aminomethyl or di-(C1_4-alkyl)-aminomethyl group,
R5 denotes a hydrogen atom or a hydroxy group,
a C1_4-alkyl group, while an unbranched alkyl group in the w position may be
substituted by a phenyl, pyridinyl, diazinyl, amino, C1_4-alkylamino, di-(Cl_4-
alkyl)-

CA 02565219 2006-10-17
-8-
amino, 4-C1-4-aIkyl-l-piperazinyl or 4-morpholinyl group,
a C7_6-alkoxycarbonyl, cyano or aminocarbonyl group or, if Y' denotes a
nitrogen
atom, R5 also denotes a pair of free electrons,
or, if Y' denotes the carbon atom, R5 also denotes the fluorine atom, or
R4 together with R5 and Y' denotes a 4- to 7-membered cycloaliphatic ring
wherein a methylene group may be replaced by an -NH-, -N(C1-4-alkyl)-,
-N(C3-4-alkenyl)-, -N(C3_4-alkynyl)-, -N(cyclo-C3-7-alkyl)-, -N(C3_7-
cycloalkyl-
C1_3-alkyl)-, -N(hydroxycarbonyl-C1_3-alkyl)- or -N(Cl_s-alkoxycarbonyl-C1_3-
alkyl)-
group,
while a hydrogen atom bound to a nitrogen atom in one of the groups
defined for R4 hereinbefore may be replaced by a protective group,
R6 and R', which may be identical or different, in each case denote a hydrogen
atom, a C1_4-alkyl group or, if Y' denotes a carbon atom, also denote the
fluorine
atom, an amino, C1_4-alkylamino or di-(C1_4-alkyl)-amino group, while the two
C1-4-alkyl groups may be joined together to form a ring and
R8 and R9, which may be identical or different, in each case denote a hydrogen
atom or a CI_3-alkyl group,
while
Ra denotes a hydrogen atom, a straight-chain or branched C1-6-alkyl, C3-6-
alkenyl,
C3_6-alkynyl or cyclo-C3_7-alkyl group wherein each hydrogen atom, if it is
not in the a-
position to a nitrogen atom, may be replaced by fluorine,
Rb denotes a halogen atom, a straight-chain or branched C1_6-alkyl, C2_6-
alkenyl,
C2_6-alkynyl, cyclo-C3_7-alkyl, cyano, hydroxy, hydroxy-C1_6-alkyl, C1-6-
alkoxy,
C1-6-alkoxy-C1_6-alkyl, amino, Cl_6-alkyl-amino or di-C1_6-alkyl-amino group,
wherein
each hydrogen atom, if it is not in the a-position to a nitrogen atom, may be
replaced

CA 02565219 2006-10-17
-9-
by fluorine and the two alkyl groups of the di-C1_6-alkyl-amino substituents
may be
joined together to form a 4- to 8-membered ring,
a methylene group in the a-position to a saturated nitrogen atom substituted
by the
group Ra or to an oxygen or sulphur atom, as a ring member of the heterocycle
of the
group Q, is not substituted by a hydroxy, Cl_6-alkoxy, amino, C1_6-alkyl-amino
or di-
C1_6-alkyl-amino group,
the double and triple bonds of the C3_6-alkenyl or C3-6-alkynyl groups
contained in the
1o groups mentioned for Ra, Rb, and R' hereinbefore are also isolated from any
heteroatoms contained in these groups,
and, unless otherwise stated, all the alkyl, alkenyl and alkynyl groups
mentioned or
contained in the groups defined hereinbefore may be straight-chain or
branched,
each methyne group contained in the groups defined hereinbefore may be
substituted by a fluorine atom, each methylene group may be substituted by up
to 2
fluorine atoms and each methyl group may be substituted by up to 3 fluorine
atoms
and two alkyl and alkenyl groups bound to a nitrogen atom may be joined
together
forming a 4- to 7-membered, saturated or unsaturated heterocyclic ring,
all the aromatic and heteroaromatic groups mentioned or contained in the
groups
defined hereinbefore may additionally be mono-, di- or trisubstituted by
halogen, by
cyano or hydroxy groups and the substituents may be identical or different and
by the protective groups mentioned in the definitions above and hereinafter
are
meant the protective groups familiar from peptide chemistry, particularly
a phenylalkoxycarbonyl group with 1 to 3 carbon atoms in the alkoxy moiety
optionally substituted in the phenyl nucleus by a halogen atom, by a nitro or
phenyl
group or by one or two methoxy groups,
for example the benzyloxycarbonyl, 2-nitro-benzyloxycarbonyl, 4-nitrobenzyl-
oxycarbonyl, 4-methoxy-benzyloxycarbonyl, 2-chloro-benzyloxycarbonyl,
3-chloro-benzyloxycarbonyl, 4-chloro-benzyloxycarbonyl, 4-biphenylyl-a,a-

,. ' CA 02565219 2006-10-17
-10-
dimethyl-benzyioxycarbonyl or 3,5-dimethoxy-a,a-dimethyl-benzyloxycarbonyl
group,
an alkoxycarbonyl group with a total of 1 to 5 carbon atoms in the alkyl
moiety,
for example the methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso-
propoxycarbonyl, n-butoxycarbonyl, 1 -m ethyl propoxycarbo nyl, 2-
methylpropoxy-
carbonyl or tert.-butyloxycarbonyl group,
the allyloxycarbonyl, 2,2,2-trichloro-(1,1-dimethylethoxy)carbonyl or 9-
fluorenyi-
methoxycarbonyl group or
the formyl, acetyl or trifluoracetyl group.
In the definitions given above and hereinafter, by a group substituted in the
co position
is meant a terminally substituted group,
by a halogen atom is meant a fluorine, chlorine, bromine or iodine atom and
by a double or triple bond isolated from a heteroatom is meant a double or
triple bond
which is linked to a heteroatom via at least one saturated carbon atom.
A second embodiment of the present invention comprises the compounds of the
above general formula (I), wherein
A denotes an oxygen or sulphur atom,
X denotes an oxygen or sulphur atom,
Q denotes a heterocycle bound via a carbon or nitrogen atom consisting of two
or
three in each case 4- to 8-membered fused rings, saturated, partially
unsaturated or
totally unsaturated independently of one another,
while the heterocycle comprises a total of one to five heteroatoms selected

CA 02565219 2006-10-17
-11-
independently of one another from among 0, N and S,
may contain one or two carbonyl groups as ring members and
each saturated nitrogen atom as a ring member of the heterocycle may be
substituted by the group Ra and one or two carbon atoms as ring members of the
heterocycle may be substituted by the group Rb,
R' denotes a saturated, mono- or diunsaturated 5- to 7-membered aza, diaza,
triaza,
oxaza, thiaza, thiadiaza or S,S-dioxido-thiadiaza heterocycle,
while the above-mentioned heterocycles are linked to the piperidine ring in
formula I by a carbon or nitrogen atom or
are spirocyclically linked to the piperidine ring in formula I by two carbon
atoms,
by a carbon and a nitrogen atom, by a carbon and an oxygen atom or by a
carbon and a sulphur atom,
contain one or two carbonyl or thiocarbonyl groups adjacent to a nitrogen
atom,
may be substituted at one of the nitrogen atoms by a CI-6-alkyl, C3_6-alkenyl
or
C3_6-alkenyl group,
may be substituted at one or at two carbon atoms by a C1_6-alkyl, C2_6-alkenyl
or
C2_6-alkynyl group, by a phenyl, phenylmethyl, naphthyl, biphenylyi,
pyridinyl,
diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl,
pyrazolyl,
1-(Cl-3-alkyl)-pyrazolyl, imidazolyl or 1-(C1_3-alkyl)-imidazolyl group, while
the
substituents may be identical or different, and
an olefinic double bond of one of the above-mentioned unsaturated heterocycles
may be fused to a phenyl, naphthyl, pyridine, diazine, 1,3-oxazole, thienyl,
furan,
thiazole, pyrrole, N-C1_3-alkyl-pyrrole or quinoline ring , to a 1 H-quinolin-
2-one
ring optionally substituted at the nitrogen atom by a C1-6-alkyl, C3_6-alkenyl
or
C3_6-alkynyl group or to an imidazole or N-C1_3-alkylimidazole ring or two
olefinic

CA 02565219 2006-10-17
-12-
double bonds of one of the above-mentioned unsaturated heterocycles may
each be fused to a phenyl or pyridine ring,
while the phenyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl,
1,3-thiazolyl, isoxazolyl, pyrazolyi, 1-C1_3-alkyl-pyrazolyl, imidazolyl or 1-
C1-3-alkylimidazolyl groups contained in R' and the benzo-, thieno-, pyrido-
and diazino-fused heterocycles in the carbon skeleton may additionally be
mono-, di- or trisubstituted by halogen atoms, C1_6-alkyl, C2_6-alkenyl,
C2_6-alkynyl, cyclo-C3_7-alkyl, cyclo-C3_7-alkenyl, cyano, hydroxy, hydroxy-
C1_6-alkyl, hydroxy-C3_6-alkenyl, hydroxy-C3-6-alkynyl, C1-6-alkoxy, C1-6-
alkoxy-
C1_6-alkyl, Cl_6-alkoxy-C3-6-alkenyl, C1_6-alkoxy-C3_6-alkynyl, C3-6-alkenoxy-
CI-6-alkyl, C3_6-alkenoxy-C3_6-alkenyl, C3_6-alkenoxy-C3_6-alkynyl,
C3_6-aikynoxy-C1_6-alkyl, C3_6-alkynoxy-C3-6-alkenyl, C3_6-alkynoxy-
C3_6-alkynyl, thiohydroxy, Cl-s-alkylthio, C3_6-alkenylthio, C3-6-a(kynylthio,
amino, Cl_6-alkyl-amino, C3_6-alkenyl-amino, C3-s-alkynyl-amino, di-
(C1-6-alkyl)-amino, di-(C3_6-alkenyl)-amino, di-(C3_6-alkynyl)-amino, amino-
C1_6-alkyl, C1_3-alkyl-amino-Cl_6-alkyl, di-(C1_3-alkyl)-amino-C1_6-alkyl,
amino-
C3-6-alkenyl, C1_3-alkyl-amino-C3-6-alkenyl, di-(C1_3-alkyl)-amino-C3_6-
alkenyl,
amino-C3_6-alkynyl, Cl_3-alkyl-amino-C3_6-alkynyl, di-(C1_3-alkyl)-amino-
2o C3_6-alkynyl, hydroxycarbonyl, phenylcarbonyl, pyridylcarbonyl, C1-6-aIkyl-
carbonyl, C2_6-alkenyl-carbonyi, C2_s-alkynyl-carbonyl, formyl, Cl-6-alkoxy-
carbonyl, C3_6-alkenoxy-carbonyl, C3-6-alkynoxy-carbonyl, aminocarbonyl,
C1-6-alkyl-aminocarbonyl, C3_6-alkenyl-aminocarbonyl, C3-6-alkynyl-
aminocarbonyl, di-(Cl_6-alkyl)-aminocarbonyl, di-(C3_6-alkenyl)-
aminocarbonyl, di-(C3_6-alkynyl)-aminocarbonyl, formylamino, C1-6-alkyi-
carbonylamino, C2_6-alkenyl-carbonylamino, C2_6-alkynyl-carbonylamino,
formyl-Cl_6-alkyl-amino, formyl-C3_6-alkenyl-amino, formyl-C3_6-alkynyl-amino,
C1_6-alkyi-carbonyl-CI_6-alkyl-amino, C2-6-atkenyl-carbony!-CI_6-alkyl-amino,
C2_6-alkynyl-carbonyl-C1_6-alkyl-amino, C1_6-aikyl-carbonyl-C3_6-alkenyl-
amino,
C2_6-alkenyl-carbonyl-C3_6-alkenyl-amino, C2_6-alkynyl-carbonyl-C3-6-alkenyl-
amino, C1_6-alkyl-carbonyl-C3_6-alkynyl-amino, C2-6-alkenyl-carbonyl-
C3_6-alkynyl-amino, C2_6-alkynyl-carbonyl-C3_6-alkynyl-amino, CI.6-alkyl-
sulphonyl, C2_6-alkenyl-sulphonyl, C2_6-alkynyl-sulphonyl, Cl_s-alkyl-
sulphinyl,
C2_6-alkenyl-sulphinyl, C2_6-alkynyl-sulphinyl, C1_6-alkyl-sulphonylamino,

CA 02565219 2006-10-17
-13-
C2_6-alkenyl-sulphonylamino, C2_6-alkynyl-sulphonylamino, CI-6-alkyl-
sulphonyl-C1_6-alkylamino, C1-6-alkyl-sulphonyl-C3_6-alkenylamino, C7_6-alkyl-
suiphonyl-C3-6-alkynyiamino, C2_6-alkenyl-sulphonyl-C1_6-alkylamino,
C2_6-alkenyl-sulphonyl-C3_6-alkenylamino, C2_s-alkenyl-sulphonyl-
C3_6-alkynylamino, C2_6-alkynyl-sulphonyl-C1_6-alkylamino, C2_6-alkynyl-
sulphonyl-C3-6-alkenylamino, C2_6-alkynyl-sulphonyl-C3_6-alkynylamino,
aminosulphonyl, CI_6-alkylaminosulphonyl, di-(C1_6-alkyl)-aminosulphonyl,
C3-6-alkenylaminosulphonyl, di-(C3_6-alkenyl)-aminosulphonyl,
C3_6-alkynylaminosulphonyl, di-(C3_6-alkynyl)-aminosulphonyl groups, while
the substituents may be identical or different,
R2 denotes the hydrogen atom,
a phenylmethyl group or a C2_7-alkyl group which may be substituted in the w
position
by a cyclo-Cs_7-alkyl, cyclo-C3_7-alkenyl, phenyl, pyridinyl, diazinyl,
hydroxy, amino,
C1-6-alkylamino, di-(C1_6-alkyl)-amino, C3_6-alkenylamino, di-(C3_6-
alkenyl)amino,
C3-6-alkynylamino, di-(C3-6-alkynyl)amino, hydroxycarbonyl, C1_6-
aikoxycarbonyl,
aminocarbonyl, aminocarbonylamino, C1_6-alkylcarbonylamino, C2-6-alkenylcarbo-
nylamino, C2-6-alkynylcarbonylamino, 4-morpholinyl, [bis-(2-
hydroxyethyl)]amino,
2o 4-(C1_6-alkyl)-1-piperazinyl or 4-(w-hydroxy-C2_7-alkyl)-1-piperazinyl
group,
a phenyl or pyridinyl group,
while the phenyl, pyridinyl and diazinyl groups mentioned in the groups
defined
for R2 hereinbefore or contained as substituents may additionally be mono-, di-
or
trisubstituted in the carbon skeleton by halogen, by C1_3-alkyl, C2-3-alkenyl,
C2_3-alkynyl, C1_3-alkoxy, hydroxy, amino, C1_3-alkylamino, di-(C1_3-alkyl)-
amino,
amino-C1_3-alkyl, C1_3-alkyl-amino-CI_3-alkyl, di-(C1_3-alkyl)-amino-C1_3-
alkyl,
CI_3-alkylcarbonylamino, C1_3-alkylcarbonylamino-C1_3-alkyl, aminocarbonyl,
C1_3-alkyl-aminocarbonyl, di-(C1_3-alkyl)-aminocarbonyl, cyano,
aminosulphonyl,
Cl_3-alkyl-aminosulphonyl, di-(Cl_3-alkyl)-aminosulphonyl, C1_3-alkylthio,
C1_3-alkylsulphinyl or C1-3-alkylsulphonyl and the substituents may be
identical or
different,

CA 02565219 2006-10-17
-14-
R3 denotes the hydrogen atom or a C1_3-alkyl group substituted by a phenyl or
pyridinyl group,
while the C1_3-alkyl group may be connected to an alkyl group contained in R2
or
a phenyl or pyridyl ring contained in R2 including the nitrogen atom to which
R2
and R3 are bound, forming a 4- to 7-membered ring,
or
R2 and R3 together with the enclosed nitrogen atom denote a group of general
formula
R5
(CR8R9)q
1
6
CRR----Y
/ 4
N', (CR$Rs)r'CR R R
6 7
wherein
Y1 denotes the carbon atom or, if R5 denotes a pair of free electrons, Y1 may
also
denote the nitrogen atom,
q and r, if Y1 denotes the carbon atom, denote the numbers 0, 1 or 2, or
q and r, if Y1 denotes the nitrogen atom, denote the numbers 1 or 2,
R4 denotes the hydrogen atom, an amino, C1-4-alkyl-amino, di-(C1_4-alkyl)-
alkylamino, C1_6-alkyl, cyclo-C3_7-alkyl, cyclo-C3-7-alkenyl, amino-C2-7-
alkyl, C1_
a-alkyl-amino-C2-7-alkyl, di-(C1_4- alkyl-amino)-C2-7-alkyl, aminoiminomethyl,
aminocarbonylamino, C1_4-alkyl-aminocarbonylamino, di-(C1_4-alkyl)-
aminocarbonylamino, C1-4-alkyl-aminocarbonyl-C1_4- alkyl-amino, di-(C1_4-
alkyl)-
aminocarbonyl-C1_4- alkyl-amino, phenylaminocarbonylamino, aminocarbonyl,
C1_4-alkyl-aminocarbonyl, di-(C1_4-alkyl)-aminocarbonyl, aminocarbonyl-CI_3-
alkyl,

= CA 02565219 2006-10-17
-15-
Cl-a-aikyl-aminocarbonyi-C1_3-alkyl, di-(Cl_4-alkyl)-aminocarbonyl-C1_3-alkyl,
aminocarbonylamino-CI_3-alkyl, C1_6-alkoxycarbonyl, C3-6-alkenoxycarbonyl,
C3_6-alkynoxycarbonyl, C1_6-alkoxycarbonyl-C1_3-alkyl, Cl_6-alkenoxycarbonyl-
C1_3-alkyl, Cl_6-alkynoxycarbonyl-C1_3-alkyi or hydroxycarbonyl-CI_3-alkyl
group,
a phenyl, pyridinyl, diazinyl, 1-naphthyl, 2-naphthyl, pyridinylcarbonyl or
phenylcarbonyl group which may be mono-, di- or trisubstituted in the carbon
skeleton in each case by halogen, by C1_3-alkyl, C2_3-alkenyl, C2_3-alkynyl,
CI_3-alkoxy, hydroxy, amino, C1_4-alky(amino, di-(C1_4-alkyl)-amino, amino-Cl_
3-alkyl, CI-4-alkyl-amino-Cl_3-alkyl, di-(C1_4-alkyl)-amino-CI_3-alkyl,
Cl_4-alkylcarbonylamino, C1_4-alkylcarbonylamino-C1-3-alkyl, aminocarbonyl,
Cl_
4-alkyl-aminocarbonyl, di-(C1_4-alkyf)-aminocarbonyl, cyano, aminosulphonyl,
Cl-
4-alkyl-aminosulphonyl, di-P_4-alkyl)-aminosulphonyl, C1_4-alkyl-thio, C1-4-
alkyl-
sulphinyl or Cl_4-alkyl-sulphonyl, and the substituents may be identical or
different,
a heterocycle selected from a 4- to 10-membered azacycloalkyl group, a 6- to
10-
membered oxaza, thiaza- and diazacycloalkyl group as well as a 6- to 10-
membered azabicycloalkyl group,
a 1-alkyl-4-piperidinylcarbonyl or 4-alkyl-1-piperazinylcarbonyl group,
while the above-mentioned mono- and bicyclic heterocycles are bound to Y'
by a nitrogen or a carbon atom in formula (II),
in the above-mentioned mono- and bicyclic heterocycles a methyne group
not directly linked to a nitrogen, oxygen or sulphur atom may be substituted
by a fluorine atom and a methylene group not directly linked to a nitrogen,
oxygen or sulphur atom may be substituted by one or two fluorine atoms,
the above-mentioned mono- and bicyclic heterocycles as well as the
1-(CI_6-alkyl)-4-piperidinylcarbonyl and 4-(Cl_6-alkyl)-1-piperazinylcarbonyl
group in the ring may be mono- to tetra-substituted by C1_6-atkyi groups, or
may optionally additionally be monosubstituted by a cyclo-C3-7-alkyl, cyclo-

CA 02565219 2006-10-17
-16-
C3_7-alkenyl, cyclo-C3_7-alkyl-C1_3-alkyl, pheny!-C1_3-alkyl, pyridyl-C1_3-
alkyl,
C1_6-alkylcarbonyl, hydroxy, C1_6-alkoxy, amino, C1_4-alkylamino, di-(Ci.4-al-
kyl)amino, phenylcarbonyl, pyridinylcarbonyl, hydroxycarbonyl, hydroxy-
carbonyl-Cl_3-alkyt, CI_6-alkoxycarbonyl, C1-6-alkoxycarbonyl-CI_3-alkyl,
aminocarbonyl, Cl_4-alkylaminocarbonyl, di-(Cl_4-alkyl)aminocarbonyl or
C1_3-alkylsulphonyl group, by a cyclo-C3_7-alkyl-carbonyl, azacyclo-C4_7-alkyl-
carbonyl, diazacyclo-C5-7-alkyl-carbony! or oxazacycto-C5_7-alkyl-carbony!
group optionally C1_3-alkyl-substituted in the ring, while the substituents
may
be identical or different and may be bound to a cyclic carbon or cyclic
nitrogen atom,
while the phenyl and pyridinyl groups contained in the groups mentioned
for R4 hereinbefore may in turn be mono-, di- or trisubstituted by halogen
atoms, by C1_3-alkyl, C2_3-alkenyl, C2-3-alkynyl, CI_3-alkoxy, hydroxy,
amino, C1_4-alkylamino, di-(C1_4-alkyl)-amino, amino-C1-3-alkyl, C1_4-alkyl-
amino-C1_3-alkyl, di-(C1_4-alkyl)-amino-Cl_3-alkyl, C1_4-alkylcarbonylamino,
C1_4-alkylcarbonylamino-C1_3-alkyl, aminocarbonyl, C1_3-alkyi-
aminocarbonyl, di-Cl_4-alkyl-aminocarbonyl, cyano, aminosulphonyl, Cl-
4-alkyl-aminosulphonyl, di-(C1_4-alky!)-aminosulphonyl, C1_3-alkyl-thio, Cl_
3-alkyl-sulphinyl or C7-3-alkyl-sulphonyl, while the substituents may be
identical or different,
or, if Y' denotes the carbon atom, R4 may denote the hydroxycarbonyl,
aminomethyi, C1_4-aikyl-aminomethyl or di-(C1_4-alkyl)-aminomethyl group,
R5 denotes a hydrogen atom,
a Cl_4-alkyl group , while an unbranched alkyl group may be substituted in the
c)
position by a phenyl, pyridinyl, diazinyl, amino, C1_4-alkylamino, di-(C1_4-
alkyi)-
3o amino, 4-C1_4-alkyl-1-piperazinyl or 4-morpholinyl group,
a CI_6-alkoxycarbonyl, cyano or aminocarbonyl group or, if Y' denotes a
nitrogen
atom, R5 may denote a pair of free electrons,

CA 02565219 2006-10-17
-17-
or, if Y' denotes the carbon atom, R5 may denote the fluorine atom, or
R4 together with R5 and Y' denote a 4- to 7-membered cycloaliphatic ring
wherein a methylene group may be replaced by a -NH-, -N(C1-4-alkyl)-,
-N(C3-4-alkenyl)-, -N(C3_4-alkynyl)-, -N(cyclo-C3-7-alkyl)- or -N(C3_7-
cycloalkyl-
C1-3-alkyl)- group,
while a hydrogen atom bound to a nitrogen atom in one of the groups
defined for R4 hereinbefore may be replaced by a protective group,
R6 and R~, which may be identical or different, in each case denote a hydrogen
atom, a C1-4-alkyl group or, if Y' denotes a carbon atom, the fluorine atom, a
C1_4-alkytamino or di-(C1-4-alkyl)-amino group, while the two C1-4-alkyl
groups may
be joined together to form a ring and
R8 and R9, which may be identical or different, in each case denote a hydrogen
atom or a C1-3-alkyl group,
while
Ra denotes a hydrogen atom, a straight-chain or branched C1-6-alkyl, C3-6-
alkenyl,
C3_6-alkynyl or cyclo-C3_7-alkyl group wherein each hydrogen atom, if it is
not in the a-
position to a nitrogen atom, may be replaced by fluorine,
Rb denotes a halogen atom, a straight-chain or branched C1_6-alkyl, C2_6-
alkenyl,
C2_6-alkynyt, cyclo-C3-7-alkyl, cyano, hydroxy, hydroxy-C1_6-alkyl, Cl_6-
alkoxy,
CI_s-alkoxy-C1-6-alkyl, amino, CI-6-alkyl-amino or di-C1-6-alkyl-amino group,
wherein
each hydrogen atom, if it is not in the a-position to a nitrogen atom, may be
replaced
by fluorine and the two alkyl groups of the di-C1_6-alkyl-amino substituents
may be
joined together to form a 4- to 8-membered ring,
a methylene group in the a-position to a saturated nitrogen atom substituted
by the
group Ra, or to an oxygen or sulphur atom, as a ring member of the heterocycle
of
the group Q, is not substituted by hydroxy, C1_6-alkoxy, amino, C1_6-alkyl-
amino or di-

CA 02565219 2006-10-17
-18-
CI_6-alkyl-amino group,
the double and triple bonds of the C3-6-alkenyl or C3-6-alkynyl groups
contained in the
groups defined hereinbefore for Ra, Rb, and R' are isolated from any
heteroatoms
which may be contained in these groups,
the tautomers, the diastereomers, the enantiomers, the hydrates, mixtures and
salts
thereof and the hydrates of the salts, particularly the physiologically
acceptable salts
thereof with inorganic or organic acids or bases.
A third embodiment of the present invention comprises the compounds of the
above
general formula (I), wherein
A, X, Q, R2 and R3 are defined as hereinbefore in the first or second
embodiment and
R' denotes a mono- or diunsaturated 5- to 7-membered aza, diaza, triaza or
thiaza
heterocycle,
while the above-mentioned heterocycles are linked by a carbon or nitrogen atom
or
are spirocyclically linked by a carbon and a nitrogen atom, by a carbon and an
oxygen atom or by a carbon and a sulphur atom,
contain one or two carbonyl groups adjacent to a nitrogen atom,
may be substituted at a carbon atom by a phenyl, pyridinyl, diazinyl, thienyl,
pyrrolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl or 1-(C1-4-alkyl)-pyrazolyl
group and
an olefinic double bond of one of the above-mentioned unsaturated heterocycles
may be fused to a phenyl, naphthyl, pyridine, diazine, thienyl or quinoline
ring or
to a 1 H-quinolin-2-one ring optionally substituted at the nitrogen atom by a
methyl group,

, = CA 02565219 2006-10-17
-19-
while the phenyl, pyridinyl, diazinyl, thienyl, pyrrolyl, 1,3-thiazolyl,
isoxazolyl,
pyrazolyl or 1-(Cl_4-alkyl)-pyrazolyl groups contained in R' as well as the
benzo-, pyrido- and diazino-fused heterocycles in the carbon skeleton may
additionally be mono-, di- or trisubstituted by halogen, by CI-6-alkyl, cyclo-
C3_7-alkyl, cyclo-C3_7-alkenyl, Cl_6-alkoxy, hydroxycarbonyl,
C1_6-alkoxycarbonyl, cyano, hydroxy, amino, C1-4-alkylamino, di-
C1-4-alkylamino, C1_4-alkylcarbonylamino or C1_4-alkylcarbonyl groups, while
the substituents may be identical or different,
while, unless otherwise stated, all the alkyl, alkenyl and alkynyl groups
mentioned or
contained in the groups defined hereinbefore under R' may be straight-chain or
branched, every methyne group contained in the groups defined hereinbefore may
be substituted by a fluorine atom, each methylene group may be substituted by
up to
2 fluorine atoms and each methyl group may be substituted by up to 3 fluorine
atoms
and two alkyl and alkenyl groups bound to a nitrogen atom may be joined
together
forming a 4- to 7-membered, saturated or unsaturated heterocyclic ring, and
all the aromatic and heteroaromatic groups mentioned or contained in the
groups
defined hereinbefore under R' may additionally be mono-, di- or trisubstituted
by
halogen or by cyano or hydroxy groups and the substituents may be identical or
different,
the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates,
mixtures and salts thereof and the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic acids or
bases.
A fourth embodiment of the present invention comprises the compounds of the
above
general formula (I), wherein
A, X, Q, R2 and R3 are as hereinbefore defined in the first or second
embodiment and
R' denotes a monounsaturated 5- to 7-membered diaza or triaza heterocycle,
while the above-mentioned heterocycles are linked via a nitrogen atom or

CA 02565219 2006-10-17
-20-
are spirocyclically linked by a carbon and a nitrogen atom or by a carbon and
an
oxygen atom,
contain a carbonyl group adjacent to a nitrogen atom,
may additionally be substituted at a carbon atom by a phenyl group and
an olefinic double bond of one of the above-mentioned unsaturated heterocycles
may be fused to a phenyl, thienyl or quinoline ring,
while the phenyl groups contained in R' and benzo-fused heterocycles in the
carbon skeleton may additionally be mono-, di- or trisubstituted by halogen,
by methyl, methoxy, difluoromethyl, trifluoromethyl, hydroxy, amino,
C1_4-alkylamino, di-(C1_4-alkyl)-amino, acetylamino, acetyl, hydroxycarbonyl,
C1-6-alkoxycarbonyl, cyano- difluoromethoxy or trifluoromethoxy groups,
while the substituents may be identical or different, but are preferably
unsubstituted or monosubstituted by a halogen atom or by a methyl or
methoxy group,
while, unless otherwise stated, all the alkyl groups mentioned or contained in
the
groups defined hereinbefore under R' may be straight-chain or branched, every
methyne group contained in the groups defined hereinbefore may be substituted
by a
fluorine atom, each methylene group may be substituted by up to 2 fluorine
atoms
and each methyl group may be substituted by up to 3 fluorine atoms,
the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates,
mixtures and salts thereof and the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic acids or
bases.
A fifth embodiment of the present invention comprises the compounds of the
above
general formula (I), wherein
A, X, Q, R2 and R3 are as hereinbefore defined in the first or second
embodiment and

, = CA 02565219 2006-10-17
-21 -
R' denotes a 1,3,4,5-tetrahydro-1,3-benzodiazepin-2-on-3-yl, 3,4-dihydro-1 H-
quinazolin-2-on-3-yl, 5-phenyl-2,4-dihydro-1,2,4-triazol-3-on-2-yl, 1,3-
dihydro-
imidazo[4,5-c]quinolin-2-on-3-yl, 1,3-dihydro-naphth[1,2-d]imidazol-2-on-3-yl,
1,3-
dihydro-benzimidazol-2-on-3-yl, 4-phenyl-1,3-dihydro-imidazol-2-on-1-yl, 3,4-
dihydro-
1 H-thieno[3,2-d]pyrimidin-2-on-3-yi or 3,4-dihydro-1 H-thieno[3,4-d]pyrimidin-
2-on-3-yl
group or together with the piperidine ring in formula (I) denotes the 1",2"-
dihydro-2"-
oxospiro-4H-3",1-benzoxazin"-4,4"-piperidin-1-yl group,
while the heterocycles mentioned hereinbefore under R' in the carbon skeleton
may additionally be monosubstituted by a methoxy group,
all the aromatic and heteroaromatic groups mentioned or contained in the
groups
defined hereinbefore under R' may additionally be mono-, di- or trisubstituted
by
halogen atoms or by cyano or hydroxy groups and the substituents may be
identical
or different,
the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates,
mixtures and salts thereof and the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic acids or
bases.
A sixth embodiment of the present invention comprises the compounds of the
above
general formula (I), wherein
A, X, R1, R 2 and R3 are as hereinbefore defined in the first, second, third,
fourth or
fifth embodiment and
Q denotes a a heterocycle bound via a carbon or nitrogen atom consisting of a
ring A
and a ring B, which is fused by two adjacent carbon atoms or by a carbon atom
and
an adjacent nitrogen atom to the ring A, while the rings A and B are selected
independently of one another from
a 4-membered, saturated or monounsaturated carbocycle, in which a ring
member may be replaced by an >NRa group, an oxygen or sulphur atom or, in the

CA 02565219 2006-10-17
- 22 _
case of an unsaturated ring member, by a nitrogen atom,
a 5-membered, saturated, mono- or diunsaturated carbocycle, in which one, two
or three ring members may be replaced independently of one another in each
case by an >NRa group, an oxygen or sulphur atom or, in the case of
unsaturated
ring members, may be replaced by a nitrogen atom, while in each case two or
three oxygen or sulphur atoms may not be directly linked to one another, or
a 6-membered, saturated, mono-, di- or triunsaturated carbocycle, in which
one,
two or three ring members may be replaced independently of one another in each
case by an >NRa group, an oxygen or sulphur atom or, in the case of
unsaturated
ring members, by a nitrogen atom, while in each case two or three oxygen or
sulphur atoms may not be directly linked to one another, and optionally
additionally a fourth, unsaturated ring member may be replaced by a nitrogen
atom, or
a 7-membered, saturated, mono-, di- or triunsaturated carbocycle, in which
one,
two, three or four ring members may each independently of one another be
replaced by an >NRa group, an oxygen or sulphur atom or, in the case of
unsaturated ring members, may be replaced by a nitrogen atom, while in each
case two or three oxygen or sulphur atoms may not be directly linked to one
another, or
an 8-membered, saturated, mono-, di-, tri- or tetra-unsaturated carbocycle, in
which one, two, three or four ring members may each independently of one
another be replaced by an >NRa group, an oxygen or sulphur atom or, in the
case
of unsaturated ring members, may be replaced by a nitrogen atom, while in each
case two or three oxygen or sulphur atoms may not be directly linked to one
another,
while at least one of the fused rings A and B contains at least one heteroatom
as a
ring member,
a methylene group as a ring member in the 4-membered rings A and B may in each

CA 02565219 2006-10-17
-23-
case be replaced independently of one another by a carbonyl group,
one or two methylene groups as ring members in the 5- to 8-membered rings A
and
B may in each case be replaced independently of one another by carbonyl
groups,
one or two carbon atoms as ring members of the rings A and B may be
substituted
by Rb, while the substituents may be identical or different,
two hydrogen atoms bound to adjacent carbon or nitrogen atoms or to a carbon
and
an adjacent nitrogen atom as ring members of the rings A or B may be replaced
by a
C3_6-n-alkylene bridge and thus form a tricyclic group, or
a hydrogen atom bound to a carbon or nitrogen atom as a ring member of the
ring A
and another hydrogen atom bound to a carbon or nitrogen atom as a ring member
of
the ring B, where the above-mentioned ring members are separated from one
another by two bonds, may be replaced by a C2_5-n-alkylene bridge and thus
form a
tricyclic group,
while in the above-mentioned C3_6-n-alkylene bridges and C2_5-n-alkylene
bridges
a methylene group may be replaced by a carbonyl group and/or one or two
methylene groups may each be replaced independently of one another by an
>NRa group, an oxygen or sulphur atom and/or a carbon atom may be substituted
by Rb, with the proviso that two oxygen and two sulphur atoms are not directly
linked together,
Ra denotes a hydrogen atom, a straight-chain or branched CI-6-alkyl, C3-s-
alkenyl,
C3_6-alkynyl or cyclo-C3_7-alkyl group, wherein each hydrogen atom, if it is
not in the
a-position to a nitrogen atom, may be replaced by fluorine,
Rb denotes a halogen atom, a straight-chain or branched Cl_6-alkyl, C2_6-
alkenyl,
C2_6-alkynyl, cyclo-C3_7-alkyl, cyano, hydroxy, hydroxy-Ci_6-alkyl, CI_6-
alkoxy,
C1_6-alkoxy-Cl_6-alkyi, amino, Cl_6-alkyl-amino or di-C1-6-alkyl-amino group,
wherein
each hydrogen atom, if it is not in the a-position to a nitrogen atom, may be
replaced
by fluorine and the two alkyl groups of the di-C1-6-alkyl-amino substituents
may be

, = CA 02565219 2006-10-17
-24-
joined together to form a 4- to 8-membered ring,
with the provisos that
(i) the group Q contains a total of not more than five heteroatoms as ring
members,
(ii) the group Q contains a total of not more than two carbonyl groups as ring
members and
1o (iii) a group Rb bound to a saturated carbon atom in the a-position to a
saturated
nitrogen atom substituted by the group Ra, or to an oxygen or sulphur atom as
a
ring member of a bi- or tricyclic heterocycle of the group Q does not take on
the
meanings of a hydroxy, C1_6-atkoxy, amino, C1_6-alkyl-amino or di-C1_6-aikyl-
amino group,
the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates,
mixtures and salts thereof and the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic acids.
2o A seventh embodiment of the present invention comprises the compounds of
the
above general formula (I), wherein
A, X, R1, R2 and R3 are as hereinbefore defined in the first, second, third,
fourth or
fifth embodiment and
Q denotes a heterocycle bound via a carbon or nitrogen atom consisting of a
ring A
and a ring B, which is fused via two adjacent carbon atoms or via a carbon
atom and
an adjacent nitrogen atom to the ring A, while the rings A and B are selected
independently of one another from
a 5-membered, saturated, mono- or diunsaturated carbocycle, in which one, two
or three ring members may each be replaced independently of one another by an
>NRa group, an oxygen or sulphur atom or, in the case of unsaturated ring
members, by a nitrogen atom, while a maximum of two ring members denote

= ' CA 02565219 2006-10-17
-25-
oxygen or sulphur atoms and these may not be directly linked to one another,
or
a 6-membered, saturated, mono-, di- or triunsaturated carbocycle, in which
one,
two or three ring members may each independently of one another be replaced
by an >NRa group, an oxygen or sulphur atom or, in the case of unsaturated
ring
members, by a nitrogen atom, while a maximum of two ring members denote
oxygen or sulphur atoms and these may not be directly linked to one another,
or
a 7-membered, saturated, mono-, di- or triunsaturated carbocycle, in which
one,
two or three ring members may each independently of one another be replaced
by an >NRa group, an oxygen or sulphur atom or, in the case of unsaturated
ring
members, by a nitrogen atom, while a maximum of two ring members denote
oxygen or sulphur atoms and these may not be directly linked to one another,
or
at least one of the fused rings A and B contains at least one heteroatom as a
ring
member,
one or two methylene groups as ring members in the 5- to 7-membered rings A
and
B may each be replaced independently of one another by carbonyl groups,
one or two carbon atoms as ring members of the rings A and B may be
substituted
by Rb, while the substituents may be identical or different,
two hydrogen atoms bound to adjacent carbon or nitrogen atoms or to a carbon
and
an adjacent nitrogen atom as ring members of the rings A or B may be replaced
by a
C3_5-n-alkylene bridge and thus form a tricyclic group, or
a hydrogen atom bound to a carbon or nitrogen atom as a ring member of the
ring A
and another hydrogen atom bound to a carbon or nitrogen atom as a ring member
of
the ring B, where the above-mentioned ring members are separated from one
another by two bonds, may be replaced by a C2_4-n-alkylene bridge and thus
form a
tricyclic group,
while in the above-mentioned C3_5-n-alkylene bridges and C24-n-alkylene
bridges

CA 02565219 2006-10-17
-26-
one or two methylene groups may each be replaced independently of one another
by an >NRa group or an oxygen atom and/or a carbon atom may be substituted
by Rb, with the proviso that two oxygen atoms are not directly linked
together,
Ra denotes a hydrogen atom, a straight-chain or branched C1_3-alkyl, C3-
alkenyl,
C3-alkynyl or cyclo-C3_6-alkyl group, wherein each hydrogen atom, if it is not
in the a-
position to a nitrogen atom, may be replaced by fluorine,
Rb denotes a halogen atom, a straight-chain or branched CI-3-alkyl, C2-3-
alkenyl,
C2_3-alkynyl, cyclo-C3-6-alkyl, cyano, hydroxy, hydroxy-C1_3-alkyl, C1_3-
alkoxy,
C1_3-alkoxy-CT _3-alkyl, amino, CI_3-alkyl-amino or di-Cl_3-alkyl-amino group,
wherein
each hydrogen atom, if it is not in the a-position to a nitrogen atom, may be
replaced
by fluorine and the two alkyl groups of the di-Cl_3-alkyl-amino substituents
may be
joined together to form a 5- to 7-membered ring,
with the provisos that
(i) the group Q contains a total of not more than three heteroatoms as ring
members,
(ii) the group Q contains a total of not more than two carbonyl groups as ring
members and
(iii) a group Rb bound to a saturated carbon atom in the a-position to a
saturated
nitrogen atom substituted by the group Ra, or to an oxygen or sulphur atom as
a
ring member of a bi- or tricyclic heterocycle of the group Q does not take on
the
meanings of a hydroxy, Cl_3-alkoxy, amino, Cl_3-alkyl-amino or di-C1_3-alkyl-
amino group,
the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates,
mixtures and salts thereof and the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic acids.
An eighth embodiment of the present invention comprises the compounds of the

CA 02565219 2006-10-17
-27-
above general formula (I), wherein
A, X, R1, R2 and R3 are as hereinbefore defined in the first, second, third,
fourth or
fifth embodiment and
Q denotes a heterocycle bound via a carbon or nitrogen atom consisting of a
ring A
and a ring B, which is fused to the ring A via two adjacent carbon atoms or
via a
carbon atom and an adjacent nitrogen atom, while, with the proviso that A is a
5- or
6-membered ring and B is a 6- or 7-membered ring, the rings A and B are
selected
1o from
a 5-membered, saturated, mono- or diunsaturated carbocycle, in which one, two
or three ring members may each independently of one another be replaced by an
>NRa group, an oxygen or sulphur atom or, in the case of unsaturated ring
members, by a nitrogen atom, while a maximum of two ring members denote an
oxygen atom, which may not be directly linked to one another, and a maximum of
one ring member denotes a sulphur atom, or
a 6-membered, saturated, mono-, di- or triunsaturated carbocycle, in which
one,
two or three ring members may each independently of one another be replaced
by an >NRa group, an oxygen or sulphur atom or, in the case of unsaturated
ring
members, by a nitrogen atom, while a maximum of two ring members denote
oxygen atoms which may not be directly linked to one another denote and a
maximum of one ring member denotes a sulphur atom, or
a 7-membered, saturated, mono-, di- or triunsaturated carbocycle, in which
one,
two or three ring members may each independently of one another be replaced
by an >NRa group, an oxygen or sulphur atom or, in the case of unsaturated
ring
members, by a nitrogen atom, while a maximum of two ring members denote
oxygen or sulphur atoms and these may not be directly linked to one another,
or
at least one of the fused rings A and B contains at least one heteroatom as a
ring
member,

= ' CA 02565219 2006-10-17
-28-
one or two methylene groups as ring members in the 5- to 7-membered rings A
and
B may each be replaced independently of one another by carbonyl groups,
one or two carbon atoms as ring members of the rings A and B may be
substituted
by Rb, while the substituents may be identical or different,
two hydrogen atoms bound to adjacent carbon or nitrogen atoms or to a carbon
and
an adjacent nitrogen atom as ring members of the rings A or B may be replaced
by a
C3-4-n-alkylene bridge and thus form a tricyclic group, or
a hydrogen atom bound to a carbon or nitrogen atom as a ring member of the
ring A
and another hydrogen atom bound to a carbon or nitrogen atom as a ring member
of
the ring B, where the above-mentioned ring members are separated from one
another by two bonds, may be replaced by a C2_3-n-alkylene bridge and thus
form a
tricyclic group,
while in the above-mentioned C3-4-n-alkylene bridges and C2-3-n-alkylene
bridges
one or two methylene groups may be substituted by Rb independently of one
another,
Ra denotes a hydrogen atom or a straight-chain or branched C1_3-alkyl group,
wherein each hydrogen atom, if it is not in the a-position to a nitrogen atom,
may be
replaced by fluorine,
Rb denotes a halogen atom or a straight-chain or branched C1_3-alkyl group,
wherein
each hydrogen atom, if it is not in the a-position to a nitrogen atom, may be
replaced
by fluorine,
with the provisos that
(i) the group Q contains a total of not more than three heteroatoms as ring
members,
(ii) the group Q contains a total of not more than two carbonyl groups as ring

CA 02565219 2006-10-17
-29-
members and
(iii) a group Rb bound to a saturated carbon atom in the a-position to a
saturated
nitrogen atom substituted by the group Ra, or to an oxygen or sulphur atom as
a
ring member of a bi- or tricyclic heterocycle of the group Q does not take on
the
meanings of a hydroxy, C1_3-alkoxy, amino, C1_3-alkyl-amino or di-C1_3-alkyl-
amino group,
the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates,
1o mixtures and salts thereof and the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic acids.
A ninth embodiment of the present invention comprises the compounds of the
above
general formula (I), wherein
A, X, Q and R' are as hereinbefore defined in the first, second, third,
fourth, fifth,
sixth, seventh or eighth embodiment and
R2 denotes the hydrogen atom or
a phenylmethyl group or a C2_7-alkyl group which may be substituted in the w
position
by a cyclo-C3_7-alkyl, cyclo-C3_7-alkenyl, phenyl, pyridinyl, hydroxy, amino,
C1_6-alkylamino, di-(C1_6-alkyl)-amino, hydroxycarbonyl, C1_6-alkoxycarbonyl,
aminocarbonyl, aminocarbonylamino, C1-6-alkylamino, 4-morpholinyl group,
while the phenyl and pyridinyl groups mentioned in the groups defined
hereinbefore for R2 or contained as substituents may additionally be mono-, di-
or
trisubstituted in the carbon skeleton by halogen, by C1_3-alkyl, C1_3-alkoxy,
hydroxy, amino, C1-3-alkylamino, di-(C1_3-alkyl)-amino, amino-C1_3-alkyl,
C1_3-alkylamino-C1_3-alkyl, di-(C1_3-alkyl)-amino-C1_3-alkyl,
C1_3-alkylcarbonylamino, C1_3-alkylcarbonyl-C1_3-alkylamino, aminocarbonyl,
C1_3-alkylaminocarbonyl or di-(C1-3-alkyl)-aminocarbonyl groups and the
substituents may be identical or different,

CA 02565219 2006-10-17
-30-
R3 denotes the hydrogen atom or a C1_3-alkyl group or
R 2 and R3 together with the enclosed nitrogen atom denote a group of general
formula
R5
(CR$R9)q I
/c674
N ~ (CR8R9)~CR R R
6 7
wherein \ 1
Y' denotes the carbon atom or, if R5 denotes a pair of free electrons, Y' may
also
be the nitrogen atom,
q and r, if Y' denotes the carbon atom, denote the numbers 0 or 1 or
q and r, if Y' denotes the nitrogen atom, denote the numbers 1 or 2,
R4 denotes the hydrogen atom, an amino, C14-alkyl-amino, di-(C1-4-alkyl)-
alkylamino, C1_6-alkyl, a cyclo-C3_7-alkyl or cyclo-C3_7-alkenyl group
optionally
substituted by a hydroxycarbonyl, CI_6-alkoxycarbonyl, hydroxycarbonyl-C1_3-
alkyl
or C1_6-alkoxycarbonyl-C1_3-alkyl group, an amino-C2_7-alkyl, Cl-4-alkyl-amino-
2o C2_7-alkyl, di-(C1_4-alkyl-amino)-C2_7-alkyl, C1_4-alkyl-aminocarbonyl, di-
(C1_4-alkyl)-
aminocarbonyl, aminocarbonyl-C1_3-alkyl, C1-4-alkyl-aminocarbonyl-C1_3-alkyl,
di-(Cl_4-alkyl)-aminocarbonyl-Cl_3-alkyl, aminocarbonylamino-C1_3-alkyl,
C1_6-afkoxycarbonyl, Cl_6-alkoxycarbonyl-C1_3-alkyl or hydroxycarbonyl-C1-3-
alkyl
group,
a phenyl, pyridinyl or diazinyl group which may be substituted in each case by
a
halogen, by a Cl-3-alkyl, Cl_3-alkoxy, hydroxy, amino, C1_4-alkyl-amino, di-
(Cl_
4-alkyl)-amino- amino-C1_3-a{kyl, Cl_4-alkyl-amino-Cl_3-alkyl, di-(C1_4-alkyl)-
amino-
C1_3-alkyl group,

, = CA 02565219 2006-10-17
-31 -
a heterocycle selected from a 4- to 7-membered azacycloalkyl group, a 6- to
7-membered oxaza, S,S-dioxothiaza or diazacycloalkyl group and a 7- to 9-
membered azabicycloalkyl group,
while the above-mentioned mono- and bicyclic heterocycles are bound to Y'
in formula (II) by a nitrogen or a carbon atom,
in the above-mentioned mono- and bicyclic heterocycles a methylene group
not directly linked to a nitrogen, oxygen or sulphur atom may be substituted
by one or two fluorine atoms and
the above-mentioned mono- and bicyclic heterocycles may be mono- or
disubstituted by hydroxy, C1_3-alkyl or hydroxy-C1_3-alkyl groups or may be
monosubstituted by a benzyl, cyclo-C3-6-alkyl, hydroxycyclo-C3-6-alkyl, cyclo-
C3_6-alkyl-C1_3-alkyl, C1_4-alkylcarbonyl, C1_4-alkylcarbonyl-C1_3-alkyl,
hydroxy,
Cl-4-alkoxy, amino, C1-4-alkylamino, di-(C1_4-alkyl)-amino,
C1_3-alkoxycarbonyl, hydroxycarbonyl-carbonyl, C1-3-alkoxycarbonyl-carbonyl,
hydroxycarbonyl-C1_3-alkyl, C1_3-alkoxycarbonyl-C1-3-alkyl, hydroxycarbonyl-
C1_3-alkylcarbonyl, C1_3-alkoxycarbonyl-C1_3-alkylcarbonyl, aminosulphonyl,
C1_4-alkylaminosulphonyf, di-(C1_4-alkyl)-aminosulphonyl, C1_3-alkylsulphonyl,
cyclo-C3_7-alkylsulphonyl, aminocarbonyl-C1_3-alkyl, C1_4-alkylaminocarbonyl-
C1-3-afkyl, di-(C1_4-alkyl)-aminocarbonyl-C1_3-alkyl, hydroxyaminocarbonyl-
C1_3-alkyl, C1_3-alkoxyaminocarbonyl-C1_3-alkyl or hydroxy-(C1_3-alkyl)-
aminocarbonyl-C1_3-alkyl groups,
or, if Y' denotes the carbon atom, also denotes the hydroxycarbonyl,
aminomethyl, C1_4-alkyl-aminomethyl or di-(C1-4-alkyl)-aminomethyl group,
R5 denotes a hydrogen atom, a C1_3-alkyl group or, if Y' denotes a nitrogen
atom, also denotes a pair of free electrons,
R6 and R', which may be identical or different, in each case denote a hydrogen
atom, a C1_3-alkyl group or, if Y' denotes a carbon atom, they may also denote
an
amino, C1_3-alkylamino or di-(C1_3-alkyl)-amino group, while the two CI_3-
alkyl

CA 02565219 2006-10-17
-32-
groups may be joined together to form a ring and
R 8 and R9, which may be identical or different, in each case denote a
hydrogen
atom or a C1_3-alkyl group,
while, unless otherwise stated, all the alkyl, alkenyl and alkynyl groups
mentioned or
contained in the groups defined hereinbefore may be straight-chain or
branched,
every methyne group contained in the groups defined hereinbefore may be
substituted by a fluorine atom, each methylene group may be substituted by up
to 2
1o fluorine atoms and each methyl group may be substituted by up to 3 fluorine
atoms
and two alkyl and alkenyl groups bound to a nitrogen atom may be joined
together
forming a 4- to 7-membered, saturated or unsaturated heterocyclic ring,
all the aromatic and heteroaromatic groups mentioned or contained in the
groups
defined hereinbefore may additionally be mono-, di- or trisubstituted by
halogen, by
cyano or hydroxy groups and the substituents may be identical or different,
the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates,
mixtures and salts thereof and the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic acids or
bases.
A tenth embodiment of the present invention comprises the compounds of the
above
general formula (I), wherein
A, X, Q and R' are as hereinbefore defined in the first, second, third,
fourth, fifth,
sixth, seventh or eighth embodiment and
R2 denotes the hydrogen atom or
3o a phenylmethyl group or a C2_7-alkyl group which may be substituted in the
w position
by a cyclo-C3_7-alkyl, cyclo-C3_7-alkenyl, phenyl, pyridinyl, hydroxy, amino,
C1-6-alkylamino, di-(C1_6-alkyl)-amino, hydroxycarbonyl, C1_6-alkoxycarbonyl,
aminocarbonyl, aminocarbonylamino, C1_6-alkylamino, 4-morpholinyl group,

CA 02565219 2006-10-17
-33-
while the phenyl and pyridinyl groups mentioned in the groups defined
hereinbefore for R2 or contained as substituents may additionally be mono-, di-
or
trisubstituted in the carbon skeleton by halogen, by C1_3-alkyl, Cl_3-alkoxy,
hydroxy, amino, C1_3-alkylamino, di-(C1_3-alkyl)-amino, amino-C1_3-alkyl,
C1_3-alkylamino-C1_3-alkyl, di-(C1_3-alkyl)-amino-CI_3-alkyl,
C1-3-alkylcarbonylamino, C1_3-alkylcarbonyl-C1_3-alkylamino, aminocarbonyl,
C1_3-alkylaminocarbonyl or di-(C1_3-alkyl)-aminocarbonyl groups and the
substituents may be identical or different,
lo R3 denotes the hydrogen atom or a C1_3-alkyl group or
R2 and R3 together with the enclosed nitrogen atom denote a group of general
formula
R5
(CR$R9)q
ACR/674
N CR6R7 , (II)
wherein
Y' denotes the carbon atom or, if R5 denotes a pair of free electrons, may
also
represent the nitrogen atom,
q and r, if Y' denotes the carbon atom, denote the numbers 0 or 1 or
q and r, if Y' denotes the nitrogen atom, denote the numbers 1 or 2,
R4 denotes the hydrogen atom, an amino, C1_4-alkyl-amino, di-(C1_4-alkyl)-
alkylamino, C1_6-alkyl, cyclo-C3_7-alkyl, cyclo-C3_7-alkenyl, amino-C2_,-
alkyl, Cl_
4-alkyl-amino-C2_7-alkyl, di-(C1_4-a{kyl-amino)-Cz_7-alkyl, C1_4-a4kyl-
aminocarbonyl,
di-(C1_4-alkyl)-aminocarbonyl, aminocarbonyl-C1-3-alkyl, C1_4-alkyl-
aminocarbonyl-
C1_3-alkyl, di-(C1_4-alkyl)-aminocarbonyl-C1-3-alkyl, aminocarbonylamino-C1-3-
alkyl,
Cl_s-alkoxycarbonyl, C1-6-alkoxycarbonyl-C1_3-alkyl or hydroxycarbonyl-C1_3-
alkyl

, = CA 02565219 2006-10-17
-34-
group,
a phenyl, pyridinyl or diazinyl group which may be substituted in each case by
a
halogen, by a C1-3-alkyl, C1-3-alkoxy, hydroxy, amino, C1_4-alkylamino, di-(Cl-
4-alkyl)-amino, amino-C1-3-alkyl, C1-4-alkylamino-C1-3-alkyl, di-(C1-4-alkyl)-
amino-
C1-3-aIkyl group,
a heterocycle selected from a 4- to 7-membered azacycloalkyl group, a 6- to
7-membered oxaza or diazacycloalkyl group and a 7- to 9-membered
azabicycloalkyl group,
while the above-mentioned mono- and bicyclic heterocycles are bound to Y'
in formula (II) by a nitrogen or a carbon atom,
in the above-mentioned mono- and bicyclic heterocycles a methylene group
not directly linked to a nitrogen, oxygen or sulphur atom may be substituted
by one or two fluorine atoms and
the above-mentioned mono- and bicyclic heterocycles may be mono- or
polysubstituted, for example mono- to trisubstituted, by C1-3-alkyl groups or
monosubstituted by a benzyl, cyclo-C3_6-alkyl, cyclo-C3-6-alkyl-C1-3-alkyl, C1-
4-
alkylcarbonyl, hydroxy, C1-4-alkoxy, amino, C1-4-alkylamino, di-(C1-4-alkyl)-
amino, hydroxycarbonyl, C1-3-alkoxycarbonyl, hydroxycarbonyl-C1-3-alkyl,
C1-3-alkoxycarbonyl-C1-3-alkyl or C1-3-alkylsulphonyl group,
or also, if Y' denotes the carbon atom, the hydroxycarbonyl, aminomethyl, Cl-
4-alkylaminomethyl or di-(Cl-4-alkyl)-aminomethyl group,
R5 denotes a hydrogen atom, a C1-3-alkyl group or, if Y' denotes a nitrogen
atom, also a pair of free electrons,
R6 and R', which may be identical or different, in each case represent a
hydrogen atom, a C1-3-alkyl group or also, if Y' denotes a carbon atom, a
C1-3-alkylamino or di-(C1-3-alkyl)-amino group, while the two C1-3-alkyl
groups may

CA 02565219 2006-10-17
-35-
be joined together to form a ring and
R8 and R9, which may be identical or different, in each case represent a
hydrogen atom or a C1_3-alkyl group,
while, unless otherwise stated, all the alkyl, alkenyl and alkynyl groups
mentioned or
contained in the groups defined hereinbefore may be straight-chain or
branched,
every methyne group contained in the groups defined hereinbefore may be
substituted by a fluorine atom, each methylene group may be substituted by up
to 2
1 o fluorine atoms and each methyl group may be substituted by up to 3
fluorine atoms
and two alkyl and alkenyl groups bound to a nitrogen atom may be joined
together
forming a 4- to 7-membered, saturated or unsaturated heterocyclic ring,
all the aromatic and heteroaromatic groups mentioned or contained in the
groups
defined hereinbefore may additionally be mono-, di- or trisubstituted by
halogen, by
cyano or hydroxy groups and the substituents may be identical or different,
the tautomers, the diastereomers, the enantiomers, the hydrates, mixtures and
salts
thereof and the hydrates of the salts, particularly the physiologically
acceptable salts
thereof with inorganic or organic acids or bases.
An eleventh embodiment of the present invention comprises the compounds of the
above general formula (I), wherein
A, X, Q and R' are as hereinbefore defined in the first, second, third,
fourth, fifth,
sixth, seventh or eighth embodiment and
R2 denotes the hydrogen atom or
a phenylmethyl group or a CZ_7-alkyl group which may be substituted in the co
position
by a phenyl, amino, C1_6-alkylamino, di-(C1_6-alkyl)-amino group,
while the phenyl and phenylmethyl group mentioned hereinbefore may
additionally be mono- or disubstituted at an aromatic carbon atom by halogen,
by

CA 02565219 2006-10-17
-36-
C1_3-alkyl, C1_3-alkoxy, amino-Cl-3-alkyl, C1_3-alkylamino-C1_3-alkyl or
di-(C1_3-alkyl)-amino-C1_3-alkyl groups and the substituents may be identical
or
different,
R3 denotes the hydrogen atom or a C1-3-alkyl group or
R2 and R3 together with the enclosed nitrogen atom denote a group of general
formula
R5
(CRaR9)q I
Y'
CRR~-
, (CR$R9)r- / \ Ra
N CR6R7 , (Il)
wherein
Y' denotes the carbon atom or, if R5 denotes a pair of free electrons, may
also
represent the nitrogen atom,
q and r, if Y' denotes the carbon atom, denote the numbers 0 or 1 or
q and r, if Y' denotes the nitrogen atom, denote the numbers 1 or 2,
R4 denotes the hydrogen atom, an amino, Cl-4-alkyl-amino, di-(C1_4-alkyl)-
alkylamino, C1-6-alkyl, a cyclo-C3-7-alkyl or cyclo-C3_7-alkenyl group
optionally
substituted by a hydroxycarbonyl, C1_6-alkoxycarbonyl, hydroxycarbonyl-C1_3-
alkyl
or Cy_6-alkoxycarbonyl-C1_3-alkyl group, an amino-C2_7-alkyl, C1_4-alkyl-amino-
C2_7-alkyl, di-(C1_4-alkyl-amino)-C2_,-alkyl, C1_6-alkoxycarbonyl,
C1_6-alkoxycarbonyl-C1_3-alkyl or hydroxycarbonyl-C1-3-alkyl group,
a phenyl or pyridyl group which may be substituted in each case by a halogen,
by
a C1_3-alkyl, Cl_3-alkoxy, amino, C1_4-alkyl-amino, di-(C1_4-alkyl)-amino
group,

CA 02565219 2006-10-17
-37-
a heterocycle selected from a 6- to 7-membered azacycloalkyl group, a 6- to
7-membered S,S,dioxothiaza- and diazacycloalkyl group and a 7- to 9-membered
azabicycloalkyl group,
while the above-mentioned mono- and bicyclic heterocycles are bound to Y'
in formula (II) by a nitrogen or a carbon atom,
in the above-mentioned mono- and bicyclic heterocycles a methylene group
not directly linked to a nitrogen, oxygen or sulphur atom may be substituted
by one or two fluorine atoms and
the above-mentioned mono- and bicyclic heterocycles may be mono- or
disubstituted by a hydroxy, C1_3-alkyl or hydroxy-Cl_3-alkyl group, by a
benzyl,
cyclo-C3_6-alkyl, hydroxy-C3-6-cycloalkyl, cyclo-C3_6-alkyl-C1_3-alkyl,
C1-3-alkylcarbonyl-C1_3-alkyl, amino, C1_4-alkylamino or di-(C1-4-alkyl)-
amino,
hydroxycarbonyl-carbonyl, C1_6-alkoxycarbonyl-carbonyl, hydroxycarbonyl-
C1-3-alkylcarbonyl, C1_3-alkoxycarbonyl-C1_3-alkylcarbonyl, aminosulphonyl,
C1_4-alkylaminosulphonyl, di-(C1-4-alkyl)-aminosulphonyl, cyclo-
C3_7-alkylsulphonyl, aminocarbonyl-C1_3-alkyl, C1_4-alkylaminocarbonyl-
2o C1-3-alkyl, di-(C1_4-alkyl)-aminocarbonyl-C1_3-alkyl, hydroxyaminocarbonyl-
C1-3-alkyl, C1_3-alkoxyaminocarbonyl-C1_3-alkyl or hydroxy-(C1_3-alkyl)-
aminocarbonyl-C1-3-alkyl groups,
or, if Y' denotes the carbon atom, the hydroxycarbonyl, aminomethyl,
C1_4-alkyl-aminomethyl or di-(C1_4-alkyl)-aminomethyl group,
R5 denotes a hydrogen atom or, if Y' denotes a nitrogen atom, it may also
denote
a pair of free electrons,
R6 and R7, which may be identical or different, in each case represent a
hydrogen atom, a C1_3-alkyl group or, if Y' denotes a carbon atom, may also
represent a C1-3-alkylamino or di-(C1-3-alkyl)-amino group, while the two C1_3-
alkyl
groups may be joined together to form a ring and

CA 02565219 2006-10-17
-38-
R8 and R9, which may be identical or different, in each case represent a
hydrogen atom or a C1_3-alkyl group,
the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates,
mixtures and salts thereof and the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic acids or
bases.
A twelfth embodiment of the present invention comprises the compounds of the
above general formula (I), wherein
A, X, Q and R1 are as hereinbefore defined in the first, second, third,
fourth, fifth,
sixth, seventh or eighth embodiment and
R2 denotes a phenylmethyl group or a C2_7-alkyl group which may be substituted
in
the w position by a phenyl, amino, C1_6-alkylamino, di-(C1_s-alkyl)-amino
group,
while the above-mentioned phenyl and phenylmethyl group may be substituted at
an aromatic carbon atom by an amino-C1_3-a{kyl, C1_3-alkylamino-C1_3-alkyl or
di-
(C1_3-alkyl)-amino-C1_3-alkyl group,
R3 denotes the hydrogen atom or a C1_3-alkyl group or
R2 and R3 together with the enclosed nitrogen atom denote a group of general
formula
R5
(CR$R9)q (
1
CR6R~- Y
4
, (CR$R9)r R
N CR6R7 , (li)
wherein
R6 and R7 in each case denote a hydrogen atom or a dimethylamino group,

CA 02565219 2006-10-17
-39-
R8 and R9 in each case denote the hydrogen atom and
(a) Y' denotes the carbon atom,
q and r denote the numbers 0 or 1,
R4 denotes the hydrogen atom,
a pheny{, pyridinyl or pyrimidinyl group which may be substituted in
each case by a halogen, by an amino, methylamino, dimethylamino,
methyl or methoxy group,
a hydroxy, 2-diethylamino-ethyl, amino, methylamino, dimethylamino,
diethylamino, pyrrolidin-1-yl, piperidin-1-yl, 4-amino-piperidin-1-yl, 4-
methylamino-piperidin-1-yl, 4-dimethylamino-piperidin-1-yl,
4-hydroxymethyl-piperidin-1-yl, 4-hydroxy-piperidin-1-yl, 4-methoxy-
piperidin-1-yl, 4-hydroxy-4-methyl-piperidin-1-yl, 4-hydroxy-
4-trifluoromethyl-piperidin-1-yl, 4-ethyl-4-hydroxy-piperidin-1-yl,
4,4-dimethylpiperidin-1-yl, 4-amino-4-methyl-piperidin-1-yl, 4-hydroxy-
4-hydroxymethyl-piperidin1-yl, 3-amino-piperidin-1-yl, 3-methylamino-
piperidin-1-yl, 3-dimethylamino-piperidin-1-yl, perhydro-azepin-1-yl,
perhydro-1,4-diazepin-1-yl, 4-methyl-perhydro-1,4-diazepin-1-yl, 1-
methyl-piperidin-4-yl, piperidin-4-yl, 1 -ethyl piperid i n-4-yl,
1-(2-hydroxyethyl)-piperidin-4-yl, 1-cyclopropyl-piperidin-4-yl, 1-
cyclopropylmethyl-piperidin-4-yl, 1-hydroxycarbonylmethyl-
piperidin-4-y1, 1-ethoxycarbonylmethyl-piperidin-4-yl,
1-hydroxycarbonylethyl-piperidin-4-yi, 1-ethoxycarbonylethyl-
piperidin-4-yl, 1-hydroxycarbonylethylcarbonyl-piperidin-4-yl,
1-ethoxycarbonylethylcarbonyl-piperidin-4-yl, 1-methylsulphonyl-
piperidin-4-yl, 1-aminosulphonyl-piperidin-4-yl,
1-hydroxycarbamoylmethyl-piperidin-4-yl, 1-(hydroxy-methyl-
carbamoyl)-piperidin-4-yl, 1-(methoxycarbamoyl-methyl)-piperidin-4-yl,
piperazin-1-yl, 4-methyl-piperazin-1-yl, 4-methylsulphonyl-
piperazin-1-yl, 4-aminosulphonyl-piperazin-1-yl, 4-cyclopropylmethyl-

CA 02565219 2006-10-17
-40-
piperazin-l-yl, 4-ethyl-piperazin-1-yl, 4-(2-hydroxyethyl)-piperazin-1-yl,
4-cyclopropyl-piperazin-1-yl, 4-hyd roxycarbonylmethyl-piperazin-1-yl,
4-ethoxycarbonylmethyl-piperazin-1-yl, 4-hydroxycarbonylethyl-
piperazin-1-yl, 4-ethoxycarbonylethyl-piperazin-1-yl,
4-hydroxycarbonylethylcarbonyl-piperazin-1-yl,
4-ethoxycarbonylethylcarbonyl-piperazin-1-yl, 1,2-dimethyl-piperazin-l-
yl, 3-methyl-piperazin-1-yl, 3,4,5-trimethyl-piperazin-1-yl, 3,5-dimethyl-
piperazin-1-yl, 3,3,4-trimethyl-piperazin-1-yl, 3,3-dimethyl-piperazin-l-
yl, 3,3,4,5,5-pentamethyl-piperazin-1-yl, 3,3,5,5-tetramethyl-piperazin-
1-yl, morpholin-4-yl, 4,4-difluoro-piperidin-1-yl, 8-methyl-8-aza-
bicyclo[3.2.1 ]oct-3-yl, 8-aza-bicyclo[3.2.1 ]oct-3-yl, azetidin-l-yl,
1-(methoxycarbonylmethyl)-piperidin-4-yl, 1-(ethoxycarbonylmethyl)-
piperidin-4-yl, 4-(ethoxycarbonylmethyl)-piperazin-1-yl, 1-hydroxycar-
bonylmethyl-piperidin-4-yl or 4-hydroxycarbonylmethyl-piperazin-1-yl
group, and
R5 denotes a hydrogen atom, or
(b) Y' denotes a nitrogen atom,
q and r denote the numbers 1 or 2,
R4 denotes the hydrogen atom,
a phenyl, pyridinyl or pyrimidinyl group which may be substituted in
each case by a halogen, by an amino, methylamino, dimethylamino,
methyl or methoxy group,
a methyl, ethyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclopropylmethyl, 2-diethylamino-propyl, 1-quinuclidin-3-
yl, piperidin-4-yl, 1-methyl-piperidin-4-yl, 1-ethyl-piperidin-4-yl,
1-(2-hydroxyethyl)-piperidin-4-yl, 1 -cyclopropyl-pi pe rid in-4-yl, 1-
cyclopropylmethyl-piperidin-4-yl, 1-hydroxycarbonylmethyl-piperi-
din-4-yl, 1-ethoxycarbonylmethyl-piperidin-4-yl, 1-hydroxycarbonylethyl-

CA 02565219 2006-10-17
= -41 -
piperidin-4-yl, 1-ethoxycarbonylethyl-piperidin-4-yl,
1-hydroxycarbonylethylcarbonyl-piperidin-4-yl,
1-ethoxycarbonylethylcarbonyl-piperidin-4-yl, 1-ethoxycarbonylmethyl-
piperidin-4-yl, 1-methylsulphonyl-piperidin-4-yl, 1-aminosulphonyl-
piperidin-4-yl, tetrahydropyran-4-yl, 8-methyl-8-aza-bicyclo[3.2.1]oct-3-
yl, 5-methyl-2,5-diaza-bicyclo[2.2.1 ]hept-2-yl or 1-aza-bicyclo[2.2.2]oct-
3-yl group and
R5 denotes a pair of free electrons,
the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates,
mixtures and salts thereof and the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic acids or
bases.
A thirteenth embodiment of the present invention comprises the compounds of
the
above general formula (I), wherein
A, X, Q and R' are as hereinbefore defined in the first, second, third,
fourth, fifth,
sixth, seventh or eighth embodiment and
R2 denotes a phenylmethyl group or a C2-7-alkyl group which may be substituted
in
the w position by a phenyl, amino, C1-6-alkylamino, di-(C1-6-alkyl)-amino
group,
while the phenyl and phenylmethyl group mentioned hereinbefore may be
substituted at an aromatic carbon atom by an amino-C1_3-alkyl, C1-3-alkylamino-
C1_3-alkyl or di-(C1_3-alkyl)-amino-C1_3-alkyl group,
R3 denotes the hydrogen atom or a Cl_3-alkyl group or
R2 and R3 together with the enclosed nitrogen atom denote a group of general
formula

CA 02565219 2006-10-17
-42-
R5
(CR$R9)q
Y
CR6R~-
\ 4
N ~,(CR8R9)r'CR R R
6 7 (II)
wherein
R6 and R' in each case denote a hydrogen atom or a dimethylamino group,
R 8 and R9 in each case denote the hydrogen atom and
(a) Y' denotes the carbon atom,
q and r denote the numbers 0 or 1,
R4 denotes the hydrogen atom,
a phenyl, pyridinyl or pyrimidinyl group which may be substituted in
each case by a halogen, by an amino, methylamino, dimethylamino,
methyl or methoxy group,
a hydroxy, 2-diethylamino-ethyl, amino, methylamino, dimethylamino,
diethylamino, pyrrolidin-1-yl, piperidin-1-yl, 4-amino-piperidin-1-yl, 4-
methylamino-piperidin-1-yl, 4-dimethylamino-piperidin-1-yl, 3-amino-
piperidin-1-yl, 3-methylamino-piperidin-1-yl, 3-dimethylamino-piperidin-
1-yl, perhydro-azepin-1-yl, perhydro-1,4-diazepin-1-yl, 4-methyl-
perhydro-1,4-diazepin-1-yl, 1-methyl-piperidin-4-yl, piperidin-4-yl,
1-ethylpiperidin-4-yl, 1-cyclopropyl-piperidin-4-yl, 1-cyclopropylmethyl-
piperidin-4-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, 4-
cyclopropylmethyl-piperazin-1-yl, 4-ethyl-piperazin-1-yl, 4-cyclopropyl-
piperazin-1-yl, 1,2-dimethyl-piperazin-1-yl, 3-methyl-piperazin-1-yl,
3,4,5-trimethyl-piperazin-1-yl, 3,5-dimethyl-piperazin-1-yl, 3,3,4-
trimethyl-piperazin-1-yl, 3,3-dimethyl-piperazin-1-yi, 3,3,4,5,5-

CA 02565219 2006-10-17
-43-
pentamethyl-piperazin-1-yl, 3,3,5,5-tetramethyl-piperazin-1-yl,
morpholin-4-yl, 4,4-difluoro-piperidin-1-yl, 8-methyl-8-aza-
bicyclo[3.2.1]oct-3-yl, 8-aza-bicyclo[3.2.1]oct-3-yl, azetidin-1-yl,
1-(methoxycarbonylmethyl)-piperidin-4-yl, 1-(ethoxycarbonylmethyl)-
piperidin-4-yl, 4-(ethoxycarbonylmethyl)-piperazin-l-yl, 1-hydroxycar-
bonylmethyl-piperidin-4-yl or 4-hydroxycarbonylmethyl-piperazin-1-yl
group, and
R5 denotes a hydrogen atom, or
(b) Y' denotes a nitrogen atom,
q and r denote the numbers 1 or 2,
R4 denotes the hydrogen atom,
a phenyl, pyridinyl or pyrimidinyl group which may be substituted in
each case by a halogen, by an amino, methylamino, dimethylamino,
methyl or methoxy group,
a methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl, 2-
diethylamino-propyl, 1-quinuclidin-3-yl, 1-piperidin-4-yl, 1-methyl-
piperidin-4-yl, 1-ethyl-piperidin-4-yl, 1-cyclopropyl-piperidin-4-yl, 1-
cyclopropylmethyl-p.iperidin-4-yl, 1-hydroxycarbonylmethyl-piperidin-4-yl
or 1-ethoxycarbonylmethyl-piperidin-4-yi group and
R5 denotes a pair of free electrons,
the tautomers, the diastereomers, the enantiomers, the hydrates, mixtures and
salts
thereof and the hydrates of the salts, particularly the physiologically
acceptable salts
thereof with inorganic or organic acids or bases.
Other preferred embodiments of the present invention consist of the compounds
of
the above general formula (I), wherein

CA 02565219 2006-10-17
-44-
Q, R', R2 and R3 are as hereinbefore defined in the first, second, third,
fourth, fifth,
sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiment and
A and X in each case denote an oxygen atom,
the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates,
mixtures and salts thereof and the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic acids or
bases.
1o A fourteenth embodiment of the present invention comprises the compounds of
the
above general formula (I), wherein
A and X in each case denote an oxygen atom,
R' denotes a 1,3,4,5-tetrahydro-1,3-benzodiazepin-2-on-3-yl, 3,4-dihydro-1 H-
quinazolin-2-on-3-yi, 5-phenyl-2,4-dihydro-1,2,4-triazol-3-on-2-yl, 1,3-
dihydro-
imidazo[4,5-c]quinolin-2-on-3-yl, 1,3-dihydro-naphth[1,2-d]imidazol-2-on-3-yl,
1,3-
dihydro-benzimidazol-2-on-3-yl, 4-phenyl-1,3-dihydro-imidazol-2-on-1-yl, 3,4-
dihydro-
1 H-thieno[3,2-d]pyrimidin-2-on-3-yl or 3,4-dihydro-1 H-thieno[3,4-d]pyrimidin-
2-on-3-yl
group or together with the piperidine ring in formula (I) denotes the 1",2"-
dihydro-2"-
oxospiro-4H-3",1-benzoxazin"-4,4"-piperidin-1-yl group,
and R2 and R3 are as hereinbefore defined in the first or second embodiment,
while the heterocycles mentioned hereinbefore under R' may additionally be
monosubstituted in the carbon skeleton by a methoxy group,
and all the aromatic and heteroaromatic groups and parts of molecules
mentioned or
contained in the groups defined under R' may additionally be mono-, di- or
trisubstituted by halogen atoms or by cyano or hydroxy groups and the
substituents
may be identical or different,
and in this and all the embodiments mentioned previously, in each case the
compounds wherein

CA 02565219 2006-10-17
-45-
Q is defined as in the seventh embodiment
are of exceptional importance,
the compounds wherein
Q is defined as in the eighth embodiment
are of particularly outstanding importance,
the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates,
mixtures and salts thereof and the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic acids or
bases.
A fifteenth embodiment of the present invention comprises the compounds of the
above general formula (I), wherein
A and X in each case denote an oxygen atom,
2o R' is defined as in the fifth embodiment hereinbefore,
Q is defined as in the eighth embodiment hereinbefore,
and in this and all the embodiments mentioned previously, in each case the
compounds wherein
R2 and R3 are defined as in the ninth or tenth embodiment hereinbefore, are of
exceptional importance,
the compounds in which R2 and R3 are as defined in the eleventh embodiment
hereinbefore are of particularly outstanding importance,
and the compounds in which R2 and R3 are defined as in the twelfth embodiment
hereinbefore are of most particularly outstanding importance,

CA 02565219 2006-10-17
-46-
the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates,
mixtures and salts thereof and the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic acids or
bases.
A sixteenth embodiment of the present invention comprises the compounds of the
above general formula (I), wherein
A and X in each case denote an oxygen atom,
1o R' is defined as in the fifth embodiment,
Q is defined as in the eighth embodiment,
R2 and R3 are defined as in the twelfth embodiment,
the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates,
mixtures and salts thereof and the hydrates of the salts, particularly the
physiologically acceptable salts thereof with inorganic or organic acids or
bases.
Q may be, for example, the bi- and tricyclic heterocycles mentioned in Table
I, which
may be substituted at a saturated nitrogen atom by the group Ra' and,
independently
thereof, may be substituted in the carbon skeleton by the group Rb and
Ra'denotes the methyl, ethyl or 2,2,2-trifluoroethyl group and
Rb denotes the chlorine or bromine atom, the methyl, difluoromethyl,
trifluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, hydroxy, methoxy,
difluoromethoxy, trifluoromethoxy, amino, methylamino or dimethylamino group.
In all the embodiments described above Q may represent the groups shown in
Table
I, either unsubstituted as explicitly shown or optionally substituted, as
mentioned
b
above, by the groups R" and/or R.

CA 02565219 2006-10-17
-47-
Table I:
Q Name
SN-H 1 H-indol-5-yl
(1)
Rb
" 5
N
~
_R
(2) "'H 1 H-indazol-5-yl
b
H
(3) 1 H-indol-6-yi
Rb
6
H
N-N
1 H-indazol-6-yl
(4)
6 R
=~
N R
(5) "'H 1 H-benzimidazol-5-yl
b
= 5
H
(6) 1 H-benzimidazol-6-yl
/ Rb
H, 0
N4
(7) N'H 1,3-dihydro-benzimidazol-2-on-6-yI
6 R b
'
H
N-N($) 1 H-benzotriazol-6-yl
. 6 R

CA 02565219 2006-10-17
-48-
Q Name
N=N
(9)
N'" 1 H-benzotriazol-5-yl
S Rn
(10) benzofuran-5-yl
Rn
= 5
O ~
(11) benzofuran-6-yl
6 Rb
/
(12) benzothiophen-5-yl
(13) benzothiophen-6-yl
R
= 6
N=~
(14) benzothiazol-5-yl
R6
N
(15) benzothiazol-6-yl
b
6 R
N=~
benzoxazol-5-yl
(16)
Rb
' 5

CA 02565219 2006-10-17
-49-
Q Name
N
(17) 1 benzoxazol-6-yl
r Rb
s
H
(18) 2,3-dihydro-1 H-isoindol-6-yl
r Rb
H ~O
~N
4IIIRb 0 3H-benzooxazol-2-on-5-yl
(19)
O
(20) N-H 3H-benzooxazol-2-on-6-yl
6 R b
H O
N
(21) 1,3-dihydro-indol-2-on-6-yl
r 6 Rb
O
(22) CC N-H 1,3-dihydro-indol-2-on-5-yi
R
* 5
b
N H 1 H-pyrrolo[2,3-b]pyridin-5-yl
6
(23) R r iN
* 5
H
N
R b
1 H-pyrrolo[3,2-b]pyridin-6-yi
(24)
6

CA 02565219 2006-10-17
-50-
Q Name
N=\
R N-H
(25) ~N 3H-imidazo[4,5-b]pyridin-6-yl
6
H
N
(26) R6 N 1 H-imidazo[4,5-b]pyridin-6-yl
iN
' 6
_N
(27) Rb N_H 1 H-pyrazolo[3,4-b]pyridin-5-yl
iN
H
N-N
(28) R6 ~ 1 H-pyrazolo[4,3-b]pyridin-6-yl
~C, N
6
I iN
(29) I / b quinolin-6-yl
6 R
N
isoquinolin-6-yl
(30) b
6 R
\
~ quinolin-7-yl
(31) (
A' 7 R
N
(32) isoquinolin-7-yl
7

CA 02565219 2006-10-17
-51-
Q Name
(33) N, H 1,2,3,4-tetrahydroquinolin-6-yi
b
R
N H
(34) 1,2,3,4-tetrahydroisoquinolin-6-yl
Rb
6
H, N
(35) 1 1,2,3,4-tetrahydroquinolin-7-yl
7 Rb
*
H
I
N
(36) 1,2,3,4-tetrahydroisoquinolin-7-yl
7 Rb
O
6N,
(37) H 1 H-quinolin-2-on-6-yl
Ry
= 6
0
(38) ", H 1 H-quinolin-4-on-6-yl
6 Rb
=
0
H'N
(39) 1 1 H-quinolin-2-on-7-yi
)
7 R6
H, N
(40) 1 0 1 H-quinolin-4-on-7-yl
7 Rb

CA 02565219 2006-10-17
-52-
Q Name
0
(41) "'H 3,4-dihydro-1 H-quinolin-2-on-6-yl
Rb
6
0
(42) 1 "'H 2,3-dihydro-1 H-quinolin-4-on-6-yl
Rn
0
H, N
(43) I 1,--, 3,4-dihydro-1 H-quinolin-2-on-7-yl
Rn
7
H, N
(44) 0 2,3-dihydro-1 H-quinolin-4-on-7-yl
,
oy o
N, 1,4-dihydro-3,1-benzoxazin-2-on-6-
(45) yI
Rn
= 6
O
H, "A, 1,4-dihydro-3,1-benzoxazin-2-on-7-
(46) 1 yI
. 7 Rb
O
~-- o 8,9-dihydro-5H-7-oxa-5-aza-
(47) "'H benzcyclohepten-6-on-2-yl
"2 R6
=
O
H-N~-O
8,9-dihydro-5H-7-oxa-5-aza-
(48) ~ benzcyclohepten-6-on-3-yl
3 Rn

CA 02565219 2006-10-17
-53-
Q Name
H
Ny 0
(49) N\H 3,4-dihydro-1 H-quinazolin-2-on-6-yl
Rn
0
H, N'k NH
(50) 3,4-dihydro-1 H-quinazolin-2-on-7-yi
= 7 R
H
N~-- 1,3,4,5-tetrahydro-1,3-
(51) 5NH benzodiazepin-2-on-7-yl
7 Rb
O~ H
H\N N
1,3,4,5-tetrahydro-1,3-
(52) benzodiazepin-2-on-8-yl
8 Rb
0
H, N-ly O
(53) N.H 1,4-dihydro-quinoxalin-2,3-dion-6-yI
A' Rb
= 6
O
(54) 0 chroman-2-on-6-yl
R
6
=
O
(55) 0 chroman-4-on-6-yl
6 R6
=
0
chroman-2-on-7-yl
(56) O(.______
7

CA 02565219 2006-10-17
-54-
Q Name
(57) o chroman-4-on-7-yl
Rn
~
O
(58) chromen-2-on-6-yl
c
6 R
O
(59) chromen-4-on-6-yl
6 Rn
O
(60) 1 chromen-2-on-7-yl
A' R b
(61) o chromen-4-on-7-yl
Rb
7 O
\ ~ 3H-benzofuran-2-on-5-yl
(62)
Rc
O
(63) 3H-benzofuran-2-on-6-yl
6 Rb
=
~O
O
41I51Rb 0 1,3-benzodioxol-2-on-5-yl
(64)
=

CA 02565219 2006-10-17
-55-
Q Name
~ indol-3-yl
(65)
3\ N
H
\
(66) indol-1-yl
-N
s indazol-3-yl
'_
(67)
N-N
(68) indazol-1-yl
-N
N
3 1,2-benzisoxazol-3-yl
(69)
N-O
(70) benzimidazol-1-yl
-N
~=N
(71) _s I benzofuran-3-yl
~O
(72) - benzothiophen-3-yi
--s

CA 02565219 2006-10-17
-56-
Q Name
2,3-dihydro-1 H-indol-3-yl
(73)
H
(74) 2,3-dihydro-1 H-indol-1 -yl
(75) s 1,3-dihydro-indoi-2-on-3-yi
N
O H
1,3-dihydro-indol-2-on-1-yl
(76) N
O
~ 1,3-dihydro-benzimidazol-2-on-1-yi
(77) N
N
0 H
(78) N ~ 3H-benzoxazol-2-on-1-yi
o
0
3 ~ 3H-benzofuran-2-on-3-yl
(79)
0
0
) quinolin-3-yl
ON (80
3

CA 02565219 2006-10-17
-57-
Q Name
quinolin-4-yl
(81)
I iN
(82) 3 isoquinolin-3-yl
(9,
'r N
~ /
(83) z ~ quinolin-2-yl
~
(84) 2 ~ quinazolin-2-yl . N
(85) 1,2,3,4-tetrahydro-quinolin-3-yl
3 N~H
3~ \
(86) 1,2,3,4-tetrahydro-isoquinolin-3-yI
N
H
(87) H-N 1,2,3,4-tetrahydro-quinoiin-2-yl
z
(88) 3,4-dihydro-1 H-quinolin-2-on-3-yl
3
. r H
0

CA 02565219 2006-10-17
-58-
Q Name
o /
(89) 2,3-dihydro-1 H-quinolin-4-on-3-yl
3 N, H
\
/ 1 H-quinolin-2-on-3-yl
(90) 3
N, H
1Y
O
O /
1 H-quinolin-4-on-3-yl
(91) *~~ N\H
(92) 3 O chromen-2-on-3-yl
O
o /
(93) 3 chromen-4-on-3-yl
~ o
(94) chroman-2-on-3-yl
s o
.
0
(95) o
chroman-4-on-3-yl
3 ~yo ~
3 ~ 2,3-dihydro-benzofuran-3-yl
(96)
0

CA 02565219 2006-10-17
-59-
Q Name
(97) , I ~ benzotriazol-1-yi
N=N
N Br 6-bromo-3H-imidazo[4,5-b]pyridin-
(98) 3 3-yl
LN
5,6-dihydro-4H-pyrrolo[3,2,1-
(99) , 8 i~]quinolin-8-yl
1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-
(100) a I ~ i~]quinolin-8-yi
(101) o 2,3-dihydro-1,4-benzodioxin-6-yI
/N\" pyrazolo[1,5-a]pyridin-5-yl
(102) 5 ~
R b
" " imidazo[1,2-a]pyridin-6-yl
(103)
. 6 R
~ " quinoxalin-7-yl
(104)
ArI 7 Rn

CA 02565219 2006-10-17
-60-
Q Name
0")
(105) "H 3,4-dihydro-2H-1,4-benzoxazin-7-yl
R6
.
---I
(106) 0 2,3-dihydro-1,4-benzodioxin-7-yl
7 Fe
The following compounds are mentioned by way of example as most particularly
preferred compounds of the above general formula (I):
Structure Name
_r, (R)-1-(1 H-indazol-5-ylmethyl)-2-[4-(1-
~ "'" methyl-piperidin-4-yl)-piperazin-1-yl]-2-
(~ -yl]-2-
oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
\ N.~.~/ benzodiazepin-3-yl)-piperidine-1-
o
I' ~"~ O /'~" CH3 carboxylate
H O
N H (R)-1-(1H-indazol-5-ylmethyl)-2-[4-(4-
6 methyl-piperazin-1-yl)-piperidin-1-yl]-2-
(2) N Nx0 oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
~~ a '~'"i N H3 benzodiazepin-3-yl)-piperidine-1-
H 0 carboxylate
_N (R)-1 -(1 H-indazol-5-yimethyl)-2-(1'-methyl-
\ ~ "-" 4,4'-bipiperidinyl-l-yl)-2-oxo-ethyl 4-(2-
(3) oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
L'A" N-( ~ "'NCH, 3-yl)-piperidine-1-carboxylate
~1\
H 0
N H (R)-1-(1H-indazol-5-ylmethyl)-2-oxo-2-(4-
6 pipe rid i n-4-yl-pi pe razi n- 1 -yl)-ethyl 4-(2-
(4) - oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
I o a3-yl)-piperidine-l-carboxylate
H O
N H (R)-1-(1H-indazol-5-ylmethyl)-2-oxo-2-(4-
\ piperazin-1-yl-piperidin-1-yl)-ethyl 4-(2-
(5) ~ oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
~ " o "'~ ~""
N 3-yl)-piperidine-1 -carboxylate
H 0

CA 02565219 2006-10-17
-61-
Structure Name
N H (R)-2-4,4'-bipiperidinyl-l-yl-1-(1H-indazol-
\ H-indazol-
5-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(6) tetrahydro-1,3-benzodiazepin-3-yl)-
~ ~ ~
N4 piperidine-1 -carboxylate
H 0
N H (R)-2-1,4'-bipiperidinyl-1'-yI-1-(1H-indazol-
\ ~ 5-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(7) o tetrahydro-1,3-benzodiazepin-3-yl)-
\ ~'~N~
piperidine-l-carboxylate
H O
(R)-1 -(1 H-indazol-5-ylmethyl)-2-[4-(4-
N H methyl-perhydro-1,4-diazepin-1-yl)-
$ piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-
( ) , N-DI 0ly1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
H 0 yI)-piperidine-1-carboxylate
(R)-1-(1 H-indazol-5-ylmethyl )-2-oxo-2-(4-
N H perhydro-1,4-diazepin-1-yl-piperidin-1-yl)-
9 ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
( 'N~ "i~1 Nõ1''" benzodiazepin-3-y1)-piperidine-1-
H0 carboxylate
N (R)-1-(1 H-indazol-5-ylmethyl)-2-oxo-2-(4-
\ "'" perhydro-azepin-1 -yl-piperidin-1 -yl)-ethyl
(10) ;~"~ 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
~ ~" " azepin-3-yl)-piperidine-1-carboxylate
H O
(R)-1-(1 H-indazol-5-ylmethyl)-2-oxo-2-(4-
\ pyrrolidin-1-yl-piperidin-1-yl)-ethyl 4-(2-
(11) oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
I ~ "' 3-yl)-piperidine-1-carboxylate
H O
(R)-1-(1 H-indazoi-5-ylmethyi)-2-[4-(1-
N H methyl-piperidin-4-yl)-perhydro-1,4-
~
diazepin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(12) N_CNQo;~ tetrahydro-1,3-benzodiazepin-3-yl)-
H-~0 piperidine-1-carboxylate
(R)-1-(1 H-indazol-5-ylmethyl )-2-oxo-2-(4-
N H piperidin-4-yi-perhydro-1,4-diazepin-1-yl)-
6 ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
(13) N-CNJoYvN-~~N-H benzodiazepin-3-yl)-piperidine-1-
carboxylate
H-~ 0

CA 02565219 2006-10-17
-62-
Structure Name
N (R)-2-(4-dimethylamino-piperidin-1-yl)-1-
\ " " (1 H-indazol-5-ylmethyl)-2-oxo-ethyl 4-(2-
(14) ~ ;~"~, oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
~ "~ " o " 3-yI)-piperidine-1-carboxylate
H O
N H (R)-1-(1 H-indazol-5-ylmethyl)-2-(4-methy!-
~ amino-piperidin-l-yl)-2-oxo-ethyl 4-(2-oxo-
(15) N4_C 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
N
~ " " o~ ~N yl)-piperidine-1-carboxylate
H O
N H (R)-2-(4-amino-piperidin-l-yl)-1-(1H-
6 indazol-5-ylmethyl)-2-oxo-ethyl 4-(2-oxo-
(16) % ~ 10 " 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
I ~" " ~ "" yI)-piperidine-l-carboxyiate
N
H O
" (R)-2-[4-(4-fluoro-phenyi)-piperidin-1-ylj-1-
\ " " (1 H-indazol-5-ylmethyl)-2-oxo-ethyl 4-(2-
(17) ~ ~N~~F oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
~ ~ " o 3-yI)-piperidine-1 -carboxylate
H O
N (R)-2-[4-(4-fluoro-phenyl)-piperazin-1-yl]-1-
\ (1H-indazol-5-ylmethyl)-2-oxo-ethyl 4-(2-
(18) F oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
~ N~"~" o~ 3-yI)-piperidine-1-carboxylate
H O
N (R)-1-(1 H-indazol-5-ylmethyl)-2-oxo-2-(4-
~ pyridin-4-yl-piperazin-1-yl)-ethyl 4-(2-oxo-
(19) 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
I 'N~~" ~ yI)-piperidine-1-carboxylate
H 0
(R)-1-(1 H-indazol-5-ylmethyl)-2-oxo-2-
" H (3,4,5,6-tetrahydro-2H-4,4'-bipyridinyl-l-
20 ~ yI)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-l,3-
( ) "~CN~O~"c~'" benzodiazepin-3-yl)-piperidine-l-
H 0 carboxylate
N H (R)-2-[4-(4-ethyl-piperazin-1-yl)-piperidin-
6 1-yI]-1-(1H-indazol-5-ylmethyl)-2-oxo-ethyl
(21) - 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
I N~~" 0%N~ azepin-3-yl)-piperidine- 1 -carboxylate
H 0

CA 02565219 2006-10-17
-63-
Structure Name
(R)-2-[4-(4-cyclopropylmethyl-piperazin-1-
"N H yl)-piperidin-1-yl]-1-(1H-indazol-5-
6 ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(22) ~'Nl =
~"~ N~N ~ tetrahydro-1,3-benzodiazepin-3-yl)-
H o piperidine-1-carboxylate
(R)-1 -(1 H-indazol-5-ylmethyl)-2-[4-(4-iso-
" H propyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-
ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
~
(23) " N~o~ N~N ~ ~ benzodiazepin-3-yl)-piperidine-1-
H~ ~ ~" carboxylate
(R)-2-[4-(4-cyclopropyl-piperazin-1-yl)-
" H piperidin-1-yl]-1-(1 H-indazol-5-ylmethyl)-2-
g ~ ~ oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
24 ~ 'Nxo N\ benzodiazepin-3-yl)-piperidine-l-
H o carboxylate
(R)-2-[4-(1-cyclopropyl-piperidin-4-yl)-pipe-
, N H razin-1-yl]-1-(1 H-indazol-5-ylmethyl)-2-
~ ~ oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
25) 'y "~,benzodiazepin-3-yl)-piperidine-1-
H0 carboxylate
(R)-1 -(1 H-indazol-5-ylmethyl)-2-[4-(4-
N H methoxycarbonylmethyl-piperazin-1 -yl)-
piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-
(26) N~1 ~"~ 0 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
H-~ o, yl)-piperidine-1-carboxylate
(R)-2-[4-(4-carboxymethyl-piperazi n-1-yl)-
" H piperidin-1-yl]-1-(1H-indazol-5-ylmethyl)-2-
~ ~ oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
27
( N'N 'Y~,N~N-'1o benzodiazepin-3-yl)-piperidine-1-
N
H 0 Ko carboxylate
(R)-2-[4-(2-amino-pyrimidine-5-yl)-
N H piperazin-1-yl]-1-(1H-indazol-5-ylmethyl)-
~ 2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
(28) NN1 o~N~% N~NNH 1,3-benzodiazepin-3-yl)-piperidine-1-
p~o ~~l/ carboxylate
N H (R)-2-[4-(2-diethylamino-ethyl)-piperidin-1-
6 yl]-1-(1 H-indazol-5-ylmethyl)-2-oxo-ethyl
(29) I 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
~ N~~" oazepin-3-yl)-piperidine-1-carboxylate 0 H 0

. = CA 02565219 2006-10-17
-64-
Structure Name
(R)-2-[4-(3-dimethylamino-propyl)-
N H piperazin-1-yIJ-1-(1H-indazol-5-ylmethy()-
2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
(30) ~N ~NO'~ 1,3-benzodiazepin-3-yl)-piperidine-1-
" H 0 carboxylate
SNH (R)-1-(1 H-indazof-5-ylmethyl)-2-[4-(1-
methyl-piperidin-4-yl)-pperazin-1-yl]-2-
oxo-ethyl 4-(2-oxo-2,3-dihydro-
(31) N--CNO_ H, benzimidazol-1-yl)-piperidine-l-
H --~ 0 carboxylate
N (R)-1-(1 H-indazol-5-ylmethyl)-2-[4-(4-
~ i "" methyl-piperazin-1 -yl)-piperidin-1 -yl]-2-
(32) ~ ~ oxo-ethyl 4-(2-oxo-2,3-dihydro-
N_/N~N 0 "~N~".CH, benzimidazol-1-yl)-piperidine-1-
H carboxylate
N (R)-1-(1 H-indazol-5-yimethyl)-2-(1'-methyl-
~ "'" 4,4'-bipiperidinyl-l-yl)-2-oxo-ethyl 4-(2-
(33) oxo-2,3-dihydro-benzimidazol-1-yl)-
"~~" ~ ''~ N H~ piperidine-1-carboxylate
H
N (R)-1-(1 H-indazol-5-ylmethyl)-2-[4-(1-
~ "" methyl-piperidin-4-yl)-piperazin-1-yl]-2-
(34) oxo-ethyl 4-(2-oxo-4-phenyl-2,3-dihydro-
'~ N 0 o"ii" imidazol-1-yi)-piperidine-l-carboxyiate
H
(R)-1-(1 H-indazol-5-ylmethyl)-2-[4-(4-
N H methyl-piperazin-1-yl)-piperidin-1-ylJ-2-
(35) ~ ~ oxo-ethyl 4-(2-oxo-4-phenyl-2,3-dihydro-
~ N "~N~ ~N~ ~ H3 imidazol-1-yl)-piperidine-1-carboxylate
H ~
n (R)-1-(1 H-indazol-5-ylmethyl)-2-(1'-methyl-
~ \ i "" [4,4']bipiperidinyl-1-yl)-2-oxo-ethyi 4-(2-
(36) ~ oxo-4-phenyl-2,3-dihydro-imidazol-1-yl)-
"N-Cll '~"VN'CH, piperidine-1 -carboxylate
-carboxylate
H
N (R)-1-(1 H-indazol-5-ylmethyl)-2-[4-(1-
~ methyl-piperidin-4-yl)-piperazin-1-yl]-2-
(37) ~ i ~ "~ -yl]-2-
oxo-ethyl 4-(5-oxo-3-phenyl-4,5-dihydro-
N~" ~ '~"~ H= 1,2,4-triazol-1-yl)-piperidine-l-carboxylate
H 0

CA 02565219 2006-10-17
-65-
Structure Name
NN H (R)-1-(1H-indazol-5-ylmethyl)-2-[4-(4-
~ ~ methyl-piperazin-1-yl)-piperidin-1-yl]-2-
(38) -" N-C>I CH3 oxo-ethyl 4-(5-oxo-3-phenyl-4,5-dihydro-
H="-.~ 1,2,4-triazol-1-yl)-piperidine-1-carboxylate
N (R)-1 -(1 H-indazol-5-ylmethyl)-2-(1'-methyl-
6NH 4,4'-bipiperidinyl-l-yl)-2-oxo-ethyl 4-(5-
(39) N= Q oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-
N~~" ~Na'~%'N "~ yl)-piperidine-1-carboxylate
H
( R)-1-(1 H-indazol-5-ylmethyl)-2-[4-(1-
N H methyl-piperidin-4-yl)-piperazin-1-yl]-2-
~ "~N-CNI. oxo-ethyl 4-(2-oxo-1,2-dihydro-
(40) CH3 imidazo[4,
5-c]quinolin-3-yl)-piperidine-1-
H="'~O carboxylate
(R)-1 -(1 H-indazol-5-ylmethyl)-2-[4-(4-
N "'" methyl-piperazin-1-yl)-piperidin-1-yl]-2-
I oxo-ethyl 4-(2-oxo-1,2-dihydro-
(41) ~ ~/~~
N--~;" ' o \% "CHz imidazo[4,5-c]quinolin-3-yl)-piperidine-l-
H carboxylate
(R)-1-(1 H-indazol-5-ylmethyl)-2-(1'-methyl-
I N, "-" [4,4']bipiperidinyl-1-yl)-2-oxo-ethyl 4-(2-
(42) ~ ~ oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-
!
"_ " CH, yl)-piperidine-1-carboxylate 0
H -~
N (R)-1 -(1 H-indazol-5-ylmethyl)-2-[4-(1-
"" methyl-piperidin-4-yl)-piperazin-1-yl]-2-
C ~~ N~ oxo-ethyl 4-(2-oxo-1,2-dihydro-naphth[1,2-
(43)
N N o
N O~/='"'~.~N.CH,
c~]imidazol-3-yl)-piperidine-1-carboxylate
H _1'\O
N H (R)-1-(1H-indazol-5-ylmethyl)-2-[4-(4-
~ po' methyl-piperazin-1-yl)-piperidin-1-yl]-2-
N ~("~N/~ oxo-ethyl4-(2-oxo-1,2-dihydro-naphth[1,2-
(44) H"-1~ Nx CH
' d]imidazol-3-yl)-piperidine-1-carboxylate
n (R)-1 -(1 H-indazol-5-ylmethyl)-2-(1'-methyl-
~ "" 4,4'-bipiperidinyl-1-yl)-2-oxo-ethyl 4-(2-
(45) 1~ - " oxo-1,2-dihydro-naphth[1,2-d]imidazol-3-
"~"~" ~''~NC"3 yl)-piperidine-l-carboxylate
H 0

CA 02565219 2006-10-17
-66-
Structure Name
N H (R)-1-(1H-indazol-5-ylmethyl)-2-[4-(1-
~ methyl-piperidin-4-yl)-piperazin-1-yl]-2-
(46) ~ _N~" H3 oxo-ethyl 4-(2-oxo-1,4-dihydro-2H-
N ~o( quinazolin-3-yi)-piperidine-1-carboxylate
H
(R)-1-(1H-indazol-5-ylmethyl)-2-[4-(4-
methyl-piperazin-1-yl)-piperidin-1-yl]-2-
51NH
(47) { o~"\/v~ ~N.CH3 oxo-ethyl 4-(2-oxo-1,4-dihydro-2H-
H"40 ~ quinazolin-3-yl)-piperidine-1-carboxylate
N H (R)-1-(1H-indazol-5-ylmethyl)-2-(1'-methyl-
\ i [4,4']bipiperidinyl-1-yl)-2-oxo-ethyl 4-(2-
(48) ~ ~ = " oxo-1,4-dihydro-2H-quinazolin-3-yl)-
N N o O~CH,
M -~1\ piperidine-1-carboxylate
H
( R)-1-(1 H-indazol-5-ylmethyl )-2-[4-(1-
N H methyl-piperidin-4-yl)-piperazin-1-yi]-2-
4 a~i~ oxo-ethyl 4-(7-methoxy-2-oxo-1,2,4,5-
( 9) ~N N~o~"i N~N tetrahydro-1,3-benzodiazepin-3-yl)-
~"H-fi ~ piperidine-1-carboxylate
(R)-1-(1 H-indazol-5-ylmethyl)-2-[4-(4-
\ "-" methyl-piperazin-1-yl)-piperidin-1-yl]-2-
~ N N oxo-ethyl 4-(7-methoxy-2-oxo-1,2,4,5-
I Nll 0
(50) -C
0 tetrahydro-1,3-benzodiazepin-3-yl)-
H 0 piperidine-1 -carboxylate
(R)-1-(1 H-indazol-5-ylmethyl)-2-(1'-methyl-
N H 4,4'-bipiperidinyl-l-yl)-2-oxo-ethyl 4-(7-
i methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-
(51) benzodiazepin-3-yl)-piperidine-l-
H0 carboxylate
N (R)-1-(1 H-indazol-5-ylmethyl)-2-[4-(1-
N H methyl-piperidin-4-yl)-piperazin-1-yl]-2-
s 6 oxo-ethyl 4-(2-oxo-1,4-dihydro-2H-
(52) _ N
/\
N-~No oH thieno[3,2-d]pyrimidin-3-yl)-piperidine-1-
H"~ ~N\N 3 carboxylate
_K (R)-1-(1 H-indazol-5-ylmethyl)-2-[4-(4-
~ i "-H methyl-piperazin-1-yl)-piperidin-1-yl]-2-
S -yl]-2-
oxo-ethyl 4-(2-oxo-1,4-dihydro-2H-
(53) N~o CH3 thieno[3,2-d]pyrimidin-3-yl)-piperidine-1-
H 0 carboxylate

CA 02565219 2006-10-17
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Structure Name
N H (R)-1-(1H-indazol-5-ylmethyl)-2-(1'-methyl-
\ i [4,4']bipiperidinyl-1-yl)-2-oxo-ethyl 4-(2-
(54) ;~"~ oxo-l,4-dihydro-2H-thieno[3,2-c]pyrimidin-
N N-( " o 1 3-yl)-piperidine-1 -carboxylate
H O ~J
N (R)-1-(1 H-indazol-5-ylmethyl)-2-[4-(1-
N'H methyl-piperidin-4-yl)-piperazin-1-yl]-2-
oxo-ethyl 4-(2-oxo-1,2-dihydro-4H-
(55) ;~ thieno[3,4-d]pyrimidin-3-yl)-piperidine-1 -
4 "40 carboxylate
. N H (R)-1-(1H-indazol-5-ylmethyl)-2-[4-(4-
methyl-piperazin-1 -yl)-piperidin-1-yl]-2-
(56) q__' '- N~ oxo-ethyl 4-(2-oxo-1,2-dihydro-4H-
~ -CN o o ~NCH~ thieno[3,4-d]pyrimidin-3-yl)-piperidine-1-
H" carboxylate
N (R)-1-(1 H-indazol-5-ylmethyl)-2-(1'-methyl-
~ N " [4,4']bipiperidinyl-1-yl)-2-oxo-ethyl 4-(2-
(57) ~'j~-, ~ Q N oxo-l,2-dihydro-4H-thieno[3,4-d]pyrimidin-
'"~ o H, 3-yl)-piperidine-1 -carboxylate
H O
(R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
H [4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-
~ -yl]-
2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
(58) N-CNo'~"~~--" CH 1,3-benzodiazepin-3-yl)-piperidine-1-
H-~ carboxylate
(R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
N [4-(4-methyl-piperazin-1-yl)-piperidin-1 -yl]-
\ "-H 2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
(59) 1,3-benzodiazepin-3-yl)-piperidine-l-
I ~ {J"~ '~r"~ CH, carboxylate
o
N
H 0
(R)-2-(1'-methyl-4,4'-bipiperidinyl-l-yl)-1-
N
" H (7-methyl-1 H-indazol-5-ylmethyl)-2-oxo-
ethyl ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
~ "
(60) I~ O benzodiazepin-3-yl)-piperidine-1 -
\ ~!~ .~ ~ 3
H 0 ~ ~' \j'," CM carboxylate
_N (R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
\ "" oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl
(61) /~ ~ 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
~ -{ .N o~~~"',~N.H
N4 azepin-3-yl)-piperidine-1 -carboxylate
H 0
~J

CA 02565219 2006-10-17
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Structure Name
n (R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
\ i "" oxo-2-(4-piperazin-1 -yl-piperidin-1-yl)-ethyl
(62) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
~ N\\ ~ ~"~ "" azepin-3-yl)-piperidine-1-carboxylate
H 0
H (R)-2-4,4'-bipiperidinyl-1-yl-1-(7-methyl-
H-indazol-5-ylmethyl)-2-oxo-ethyl 4-(2-
\ 1
R
(63) oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
I N4~" 3-yI)-piperidine-1 -carboxylate
H 0
H (R)-2-1,4'-bipiperidinyl-1'-yl-1-(7-methyl-
H-indazol-5-ylmethyl)-2-oxo-ethyl 4-(2-
\ 1
R
(64) " oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
I Q~"Io~"'~ ~ 3-yl)-piperidine-1-carboxylate
H O
(R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
" H [4-(4-methyl-perhydro-1,4-diazepin-1-yi)-
6 piperidin-1-y!]-2-oxo-ethyl 4-(2-oxo-
( 5) -CNI ~N~NJ'' 1,2,4,5-tetrahydro-l,3-benzodiazepin-3-
H0 yl)-piperidine-l-carboxylate
(R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
N H oxo-2-(4-perhydro-1,4-diazepin-1-yl-
~ piperidin-l-yl)-ethyl 4-(2-oxo-1,2,4,5-
(66) /NH tetra hyd ro- 1, 3-be nzod iazepi n-3-yl)-
H 0 piperidine-l-carboxylate
(R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
"N H oxo-2-(4-perhydro-azepin-l-yl-piperidin-l-
~ yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
(67)
~,/~~
benzodiazePin-3-YI)-Pi Peridine-l-
~(" H" \' N0 ~~~...///N 0 ~ "~/ carboxylate
n (R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
oxo-2-(4-pyrrolidin-1 "" -yl-piperidin-1-yt)-ethyl
(68) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
I 0azepin-3-yl)-piperidine-l-carboxylate
H 0
(R)-1-(7-methyl-1 H-indazol-5-ylmethyl )-2-
N H [4-(1-methyl-piperidin-4-yl)-perhydro-1,4-
~ ~ diazepin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(69) N-CloyN/--\N-~N tetrahydro-1,3-benzodiazepin-3-yl)-
H4 0 piperidine-l-carboxylate

CA 02565219 2006-10-17
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Structure Name
(R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
N-H oxo-2-(4-piperidin-4-yl-perhydro-1,4-
diazepin-l-yl)-ethyl 4-(2-oxo-1,2,4,5-
(70) _C" ~ tetrahydro-1,3-benzodiazepin-3-yl)-
H piperidine-l-carboxylate
(R)-2-(4-dimethylamino-piperidin-1 -yl)-1-
N H (7-methyl-1 H-indazol-5-ylmethyl)-2-oxo-
~ ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
0 71) y " benzodiazePin-3-YI)-PiPeridine-1 -
~ N
(
H 0 carboxylate
_N (R)-2-(4-methylamino-piperidin-l-yl)-1-(7-
\ "" methyl-1 H-indazol-5-ylmethyl)-2-oxo-ethyl
(72) 1 - N , 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
N~~" ~ 'N'H
azepin-3-yl)-piperidine-1 -carboxylate
H O
- N H (R)-2-(4-amino-piperidin-1-yl)-1-(7-methyl-
\ ~ 1 H-indazol-5-ylmethyl)-2-oxo-ethyl 4-(2-
(73) /~\ I oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
~ N % ~/" p "~"~" 3-yl)-piperidine-1-carboxylate
H'RO
(R)-2-[4-(4-fluoro-phenyl)-piperidin-l-yl]-1-
"N H (7-methyl-1 H-indazol-5-ylmethyl)-2-oxo-
~ ethyl 4-(2-oxo-1,2,4,5-tetrahydro-l,3-
(74) Nbenzodiazepin-3-yl)-piperidine-1-
H-~ carboxylate
(R)-2-[4-(4-fluoro-phenyl)-piperazin-l-yl]-1-
N H (7-methyl-1 H-indazol-5-ylmethyl)-2-oxo-
N ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
:~ F
(75) -( ~\NI0 ~ benzodiazepin-3-yl)-piperidine-1-
~
H~ ~/ carboxylate
N (R)- 1 -(7-methyl-1 H-indazol-5-ylmethyl)-2-
\ "" oxo-2-(4-pyridin-4-yl-piperazin-1-yl)-ethyl
J 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
(76)
~ N~~" o N'~ azepin-3-yl)-piperidine-1 -carboxylate
H O
(R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
N H oxo-2-(3,4,5,6-tetrahydro-2H-4,4'-
~ bipyridinyl-l-yl)-ethyl 4-(2-oxo-1,2,4,5-
(77) N-CNI N " tetrah dro-1,3-benzodiaze P in 3 I
H-~ ~~' piperidine-1-carboxylate Y)

CA 02565219 2006-10-17
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Structure Name
(R)-2-[4-(4-ethyl-piperazin-1-yl)-piperidin-
NN H 1-yl]-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
~ oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
(78) N N~o ~ benzodiazepin-3-yI) piperidine-l-
p 0 0N~~N~ carboxylate
(R)-2-[4-(4-cyclopropylmethyl-piperazin-1-
N H yl)-piperidin-1-yl]-1-(7-methyl-1 H-indazol-
79 5-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
( ) N-CjolyN1 N~NV tetrahydro-1,3-benzodiazepin-3-yl)-
p-~ piperidine-l-carboxylate
(R)-2-[4-(4-isopropyl-piperazin-1 -yl)-
N H piperidin-1-yl]-1-(7-methyl-1 H-indazol-5-
~ ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(80) o"\~ N~N tetrahydro-1,3-benzodiazepin-3-yl)-
Ho piperidine-l-carboxylate
(R)-2-[4-(4-cyclopropyl-piperazin-1 -yl)-
N H piperidin-1 -yl]-1-(7-methyl-1 H-indazol-5-yl-
0 methyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-
(81) N~~//~Nxo~N~~N~ tetrahydro-l,3-benzodiazepin-3-yl)-
H'~o piperidine-l-carboxylate
(R)-2-[4-(1-cyclopropyl-piperidin-4-yl)-
N H piperazin-1-yl]-1-(7-methyl-1 H-indazol-5-
ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(82 ) N~N~o~"~N ~N a tetrahydro-1,3-benzodiazepin-3-yl)-
H-~o piperidine-1 -carboxylate
(R)-2-[4-(4-methoxycarbonylmethyl-
NN H piperazin-1-yl)-piperidin-1-yl]-1-(7-methyl-
(83) o 1 H-indazol-5-ylmethyl)-2-oxo-ethyl 4-(2-
N-~Nxo'~"~ o oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
H-~( o, 3-yl)-piperidine-1 -carboxylate
(R)-2-[4-(4-carboxymethyl-piperazin-1 -yl)-
H piperidin-1-yl]-1-(7-methyl-1 H-indazol-5-yl-
(84) methyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
tetrahydro-l,3-benzodiazepin-3-yl)-
~N
N
~N O .
H-~ Ko piperidine-l-carboxylate
( R)-2-[4-( 2-a m i n o-pyri m id i n-5-yl )-
N H piperazin-1 -yl]-1-(7-methyl-1 H-indazol-5-
~ " NH ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(85) 1;~ ~N tetrahydro-1,3-benzodiazepin-3-yl)-
~ -~N o 0
piperidine-1-carboxylate

CA 02565219 2006-10-17
-71-
Structure Name
(R)-2-[4-(2-d iethylamino-ethyl)-piperidin-l-
N H yl]-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
86 oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
( ) NN -ly "\~ N benzodiazepin-3-yl)-piperidine-1-
H carboxylate
(R)-2-[4-(3-dimethylamino-propyl)-
\ N-H piperazin-1 -yl]-1 -(7-methyl-1 H-indazol-5-
ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
87
i ~ ~" ~ N tetrahydro-1,3-benzodiazepin-3-yl)-
H piperidine-1-carboxylate
(R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
I ~"'N-H [4-(1-methyl-piperidin-4-yi)-piperazin-1-yl]-
2-oxo-ethyl 4-(2-oxo-2,3-dihydro-
(88) NN" Q '0~ ~N ~NCH3 benzimidazol-l-yl)-piperidine-l-
HN"( ~~~/// 0 carboxylate
6-:1 (R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
H [4-(4-methyl-piperazin-1-yl)-piperidin-l-yl]-
(89) : 2-oxo-ethyl 4-(2-oxo-2,3-dihydro-
"-CIN o''y "' - NNCHa benzimidazol-1-yl) piperidine-l-
H carboxylate
N (R)-2-(1'-methyl-4,4'-bipiperidinyl-1-yl)-1-
~ "" (7-methyl-1 H-indazol-5-ylmethyl)-2-oxo-
(90) ~ ethyl4-(2-oxo-2,3-dihydro-benzimidazol-1-
~ N ~
" "Io~ CH'
N-, yl)-piperidine-l-carboxylate
H
N (R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
\ i "-H [4-(1-methyl-piperidin-4-yl)-piperazin-1 -yl]-
(91) /~ Qi~~ 2-oxo-ethyl 4-(2-oxo-4-phenyl-2,3-dihydro-
0\N'CH3 imidazol-1 -yl)-piperidine-1 -carboxylate
=/! ~/N p "\ N
H ~
SN-H (R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
[4-(4-methyl-piperazin-1 -yl)-piperidin-1-yl]-
(92) N~N"O2-oxo-ethyl 4-(2-oxo-4-phenyl-2,3-dihydro-
H="-~\ imidazol-l -yl)-piperidine-l -carboxylate
N (R)-2-(1'-methyl-[4,4']bipiperidinyl-l-yl)-1-
~ \ " " (7-methyl-1 H-indazol-5-ylmethyl)-2-oxo-
(93) ethyl 4-(2-oxo-4-phenyl-2,3-dihydro-
~~"I 'y"~NCH' imidazol-1 -yl)-piperidine-1-carboxylate
H

CA 02565219 2006-10-17
-72-
Structure Name
N (R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
~ \ "'" [4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-
(g4) N ~ ~ 2-oxo-ethyl 4-(5-oxo-3-phenyl-4,5-dihydro-
N~ " H3 1,2,4-triazol-l-yl)-piperidine-1-carboxylate
H
/ N-H (R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-
(95) ' I ~'=N~NO~N~- V~N~j N,CH~ 2-oxo-ethyl 4-(5-oxo-3-phenyl-4,5-dihydro-
H="-~0 1,2,4-triazol-1 -yl)-piperidine-1 -carboxylate
N~ H (R)-2-(1'-methyl-4,4'-bipiperidinyl-1-yl)-1-
~ \ (7-methyl-1 H-indazol-5-ylmethyl)-2-oxo-
(96) ~ ~ N= ethyl 4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-
N~~" ~"'~a'V NC"3 triazol-1-yl)-piperidine-1-carboxylate
H
(R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
N H [4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-
~ "~ 2-oxo-ethyl 4-(2-oxo-1,2-dihydro-
~
97 ~N~N o imidazo[4,5-c]quinolin-3-yl)-piperidine-l-
N~ ~"~~~N'~~".CH~
" carboxylate
(R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
[4-(4-methyl-piperazin-1 -yl)-piperidin-1 -yl]-
N
I !~ 2-oxo-ethyl 4-(2-oxo-l,2-dihydro-
(~~) ~J ~N Ir"'~ ' N---N'CHa imidazo[4,5-c]quinolin-3-yl)-piperidine-1 -
" o carboxylate
N (R)-2-(1'-methyl-[4,4']bipiperidinyl-1 -yl)-1-
N, (7-methyl-1 H-indazol-5-ylmethyl)-2-oxo-
(99) - ~ " /~ ~ N %~ ~ ~ ethyl 4-(2-oxo-1,2-dihydro-imidazo[4,5-c]-
N_/" L/" ~ ~~NC"' quinolin-3-yl)-piperidine-1-carboxylate
H \~
(R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
" H [4-(1-methyl-piperidin-4-yl)-piperazin-1 -ylj-
~ 2-oxo-ethyl 4-(2-oxo-1,2-dihydro-
i~
(100) -C"o H ' naphth[1,2-d]imidazol-3-yl)-piperidine-1-
H' I I ~~N N carboxylate
(R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
" H [4-(4-methyl-piperazin-1 -yl)-piperidin-1 -yl]-
(101) /~\ = N I 2-oxo-ethyl 4-(2-oxo-l,2-dihydro-
~N-{ _N o ~N~j NCH3 naphth[1,2-d]imidazol-3-yl)-piperidine-1-0 H" ~o '~/
carboxylate

CA 02565219 2006-10-17
-73-
Structure Name
N " (R)-2-(1'-methyl-4,4'-bipiperidinyl-1-yl)-1-
~ \ i (7-methyl-1 H-indazol-5-ylmethyl)-2-oxo-
(102) ~ ethyl4-(2-oxo-1,2-dihydro-naphth[1,2-d]-
H./ N-{ N o~"~:~~' CH, imidazol-3-yl)-piperidine-1-carboxylate
N H (R)-1-(7-methyl-lH-indazol-5-ylmethyl)-2-
\ i - [4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-
(103) 2-oxo-ethyl4-(2-oxo-1,4-dihydro-2H-
"4 ~" 0 H~ quinazolin-3-yl)-piperidine-1-carboxylate
H
- \ H (R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
[4-(4-methyl-piperazin-1 -yl)-piperidin-1 -yl]-
(104) 2-oxo-ethyl 4-(2-oxo-1,4-dihydro-2H-
H"4 quinazolin-3-yl)-piperidine-1 -carboxylate
N H (R)-2-(1'-methyl-[4,4']bipiperidinyl-1-yl)-1-
\ i (7-methyl-1 H-indazol-5-ylmethyl)-2-oxo-
(105) ethyl4-(2-oxo-l,4-dihydro-2H-quinazolin-
"~ o"~~N H3 3-yl)-piperidine-1-carboxylate
H 0
(R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
N H [4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-
0 2-oxo-ethyl 4-(7-methoxy-2-oxo-1,2,4,5-
(106) ~ "~NQ in-3-yl)-
I piperidine-1-carboxylate
(R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
i [4-(4-methyl-piperazin-1-yl)-piperidin-l-yl]-
(107) 2-oxo-ethyl4-(7-methoxy-2-oxo-1,2,4,5-
I ' o tetrahydro-1,3-benzodiazepin-3-yl)-
H 0 piperidine-l-carboxylate
(R)-2-(1'-methyl-4,4'-bipiperidinyl-1 -yl)-1-
N H (7-methyl-1 H-indazol-5-ylmethyl)-2-oxo-
1 $ o ethyl 4-(7-methoxy-2-oxo-1,2,4,5-
( 0 ) I "'N~otetrahydro-1,3-benzodiazepin-3-yl)-
H~ piperidine-l-carboxylate
_n (R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
H [4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-
(109) s/ ///'''''~~~N 0~~ ~ 2-oxo-ethyl 4-(2-oxo-1,4-dihydro-2H-
" thieno[3,2-d]pyrimidin-3-yl)-piperidine-1-
\ ~'N'~MCH~
"~
H carboxylate

CA 02565219 2006-10-17
-74-
Structure Name
N (R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
" [4-(4-methyl-piperazin-1-yl)-piperidin-l-yl]-
(110) S 2-oxo-ethyl4-(2-oxo-1,4-dihydro-2H-
cr
N~ ~" o " H,
thieno[3,2-d]pyrimidin-3-yl)-piperidine-l-
carboxylate
N H (R)-2-(1'-methyl-[4,4']bipiperidinyl-1 -yl)-1-
' (7-methyl-1 H-indazol-5-ylmethyl)-2-oxo-
(111) s "~" ~N\ H, ethyl4-(2-oxo-1,4-dihydro-2H-thieno[3,2-
"4 o d]pyrimidin-3-yl)-piperidine-1 -carboxylate
H
n (R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
" H [4-(1-methyl-piperidin-4-yt)-piperazin-1 -yl]-
(112) ~ 2-oxo-ethyl 4-(2-oxo-1,2-dihydro-4H-
~ /-~' thieno[3,4-d]pyrimidin-3-yl)-piperidine-1-
~l ," ~N
12r, N "'~.~"CH,
H" ~.J carboxylate
N (R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
\ i "" [4-(4-methyl-piperazin-1 -yl)-piperidin-1 -yl]-
I = N 2-oxo-ethyl4-(2-oxo-1,2-dihydro-4H-
(113) N~N o'~ N~NCH, thieno[3,4-d]pyrimidin-3-yl)-piperidine-1 -
H carboxylate
N H (R)-2-(1'-methyl-[4,4']bipiperidinyl-l-yl)-1-
\ i ' (7-methyl-1 H-indazol-5-ylmethyl)-2-oxo-
(114) ~~-, ethyl4-(2-oxo-l,2-dihydro-4H-thieno[3,4-
'-~N~~" o ~" H3 d]pyrimidin-3-yl)-piperidine-1 -carboxylate
H
(R)-1-(7-chloro-1 H-indazol-5-ylmethyl)-2-
"N H [4-(1-methyl-piperidin-4-yl)-piperazin-1 -yl]-
~ C1 2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
(115) /~N ~ 0~"\ 1,3-benzodiazepin-3-yl)-piperidine-1 -
~ % "'~,~" CH~
N--( .
H~1\ ~V1 carboxylate
N (R)-1-(7-chloro-1 H-indazol-5-ylmethyl)-2-
"" [4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-
~ 1 2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
(116) \ j NCH, 1,3-benzodiazepin-3-yl)-piperidine-l-
H 0 carboxylate
(R)-1-(7-chloro-1 H-indazol-5-ylmethyl)-2-
" H (1'-methyl-4,4'-bipiperidinyl-l-yl)-2-oxo-
117 -yl)-2-oxo-
ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
-CN O y"\ CH, benzodiazepin-3-yi)-piperidine-1 -
cc-~
H 0 0 carboxylate

CA 02565219 2006-10-17
-75-
Structure Name
N H (R)-1-(7-chloro-1H-indazol-5-ylmethyl)-2-
\ oxo-2-(4-piperidin-4-yl-piperazin-l-yi)-ethyl
(118) C1 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
N azepin-3-yl)-piperidine-1-carboxylate
~ o o N~
H 0
N (R)-1-(7-chloro-1 H-indazol-5-ylmethyl)-2-
\ "" oxo-2-(4-piperazin-1 -yl-piperidin-1-yl)-ethyl
(119) Q 01 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
~ N
" 'pN~ NH azepin-3-yl)-piperidine-1-carboxylate
H 0
N (R)-2-4,4'-bipiperidinyl-1-yI-1-(7-chloro-1 H-
\ i "" indazol-5-ylmethyl)-2-oxo-ethyl 4-(2-oxo-
(120) ~ ~C1 ~, 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
N~" o~N;~ NH yl)-piperidine-1-carboxylate
'~
H O
O
N H (R)-2-1,4'-bipiperidinyl-1'-yI-1-(7-chloro-
\ ~ 1 H-indazol-5-ylmethyl)-2-oxo-ethyl 4-(2-
(121) J_ c' oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
~ \ N~" " o~N~" 3-yI)-piperidine-1 -carboxylate
H O
(R)-1-(7-chloro-1 H-indazol-5-ylmethyl)-2-
N H [4-(4-methyl-perhydro-1,4-diazepin-1 -yl)-
~, piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-
(122) N-CN'y N,~NJ 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
H~ yI)-piperidine-l-carboxylate
(R)-1-(7-chloro-1 H-indazol-5-ylmethyl)-2-
N H oxo-2-(4-perhydro-1,4-diazepin-1-yl-
6 ~, piperidin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-
(123) ~NQo;~N~N )'H tetrahydro-l,3-benzodiazepin-3-yi)-
H~ piperidine-1 -carboxylate
(R)- 1 -(7-chloro- 1 H-indazol-5-ylmethyl)-2-
N H oxo-2-(4-perhydro-azepin-1-yl-piperidin-1-
24 ~ ~, yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
(1) ~-CN ~N~N benzodiazepin-3-yl)-piperidine-1 -
H 0 carboxylate
- N H (R)-1-(7-chloro-1H-indazol-5-ylmethyl)-2-
\ i oxo-2-(4-pyrrolidin-1 -yl-piperidin-1-yl)-ethyl
(125) 01 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
I N~~" y"'" azepin-3-yl)-piperidine-1-carboxylate
H 0

CA 02565219 2006-10-17
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Structure Name
(R)-1 -(7-chloro-1 H-indazol-5-ylmethyl)-2-
" H [4-(1-methyl-piperidin-4-yl)-perhydro-1,4-
diazepin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(126) % ~~N~ ;YNtetrahydro-1,3-benzodiazepin-3-yl)-
q o piperidine-1-carboxylate
(R)-1 -(7-chloro-1 H-indazol-5-ylmethyl)-2-
" H oxo-2-(4-piperidin-4-yl-perhydro-1,4-
~
d iazepi n-1-yl)-ethyl 4-(2-oxo-1, 2, 4, 5-
(127) % ~~"O;~vN~N,H tetrahydro-1,3-benzodiazepin-3-yl)-
piperidine-1-carboxylate
q 0
(R)-1 -(7-chloro-1 H-indazol-5-ylmethyl)-2-
, " H (4-dimethylamino-piperidin-1-yl)-2-oxo-
~ 0 ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
(128) ~N r "iN benzodiazepin-3-yl)-piperidine-1-
q0 carboxylate
N H (R)-1-(7-chloro-1H-indazol-5-ylmethyl)-2-
\ (4-methylamino-piperidin-1-yl)-2-oxo-ethyl
(129) ~ C1 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
~ N~( ~N~"'H azepin-3-yl)-piperidine-1 -carboxylate
H ~O
N H (R)-2-(4-amino-piperidin-1-yl)-1-(7-chloro-
\ 1 H-indazol-5-ylmethyl)-2-oxo-ethyl 4-(2-
(130) _CNI C1 H oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
I~ N O'~"~1 NH
4 3-yl)-p'peridine-1-carboxylate
H O
(R)-1 -(7-chloro-1 H-indazol-5-ylmethyl)-2-
"N H [4-(4-fiuoro-phenyl)-piperidin-1-yl]-2-oxo-
-~~ ~~ F ethyt 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
(131) ~-CNO o" benzodiazepin-3-yl)-piperidine-1-
q carboxylate
(R)-1 -(7-chloro-1 H-indazol-5-ylmethyl)-2-
N" H [4-(4-fluoro-phenyl)-piperazin-1-yl]-2-oxo-
132 ~~ 0 F ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
( ) N~No~"~i ~ benzodiazepin-3-yl)-piperidine-1-
H~ carboxylate
" (R)-1 -(7-chloro-1 H-indazol-5-ylmethyl)-2-
\ "" oxo-2-(4-pyridin-4-yl-piperazin-1-yl)-ethyl
(133) l- 0 C," 4-(2-oxo-1,2,4,5-tetrahydro-l,3-benzodi-
I ~" ~ " azepin-3-yl)-piperidine-1 -carboxylate
H 0

CA 02565219 2006-10-17
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Structure Name
(R)-1-(7-chloro-1 H-indazol-5-ylmethyl)-2-
N-H oxo-2-(3,4,5,6-tetrahydro-2H-4,4'-
6,-,
bipyridinyl-1-yl)-ethyl 4-(2-oxo-1,2 4,5-
i
(134) c
% N-CN1o~NN tetrahydro-1,3-benzodiazepin-3-yl)-
piperidine-1-carboxylate
p~ 0
(R)-1-(7-chloro-1 H-indazol-5-ylmethyl)-2-
"
N H [4-(4-ethYI-Pi Perazin-1-YI)-Pi Peridin-1-Y]I-2
-
C1 oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
(13 5 ) Q
~ ~N-~N ~"1 ~N ~ benzodiazepin-3-yl)-piperidine-1-
H 0 carboxylate
(R)-1-(7-chloro-1 H-indazol-5-ylmethyl)-2-
"
N 4- 4-c clo ro Imeth I-erazin-1- I
H [~ Y P PY YPi P Y)-
~ C1 piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-
(136) ~~N~o;~N~N~N~ 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
q 0 yI)-piperidine-1-carboxylate
(R)-1-(7-chloro-1 H-indazol-5-ylmethyl)-2-
/ N H [4-(4-isopropyl-piperazin-1-yl)-piperidin-1-
~ 0 yI]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
(137) C N--CN'o;~N~1 1,3-benzodiazepin-3-yl)-piperidine-1-
H~o carboxylate
(R)-1-(7-chloro-1 H-indazol-5-ylmethyl)-2-
N H [4-(4-cyclopropyl-piperazin-1-yl)-piperidin-
$ C1 1-yI]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(13 ) ~~N~oy N~ ~ tetrahydro-1,3-benzodiazepin-3-yl)-
H 0 piperidine-1 -carboxylate
(R)-1-(7-chloro-1 HI indazol-5-ylmethyl)-2-
N H [4-(1-cyclopropyl-piperidin-4-yl)-piperazin-
6C, 1-yI]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(139) N-~N1o N~~ tetrah dro-1,3-benzodiazePin-3- I
p4o ~~N~ piperidine-1-carboxylate y)
_n (R)-1-(7-chloro-1 H-indazol-5-ylmethyl)-2-
N H [4-(4-methoxycarbonylmethyl-piperazin-1-
~ N C1 yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-
(140)
(140) o'1( , _~ N~j N~o 1 ,2,4,5-tetrahydro-1,3 benzodiazepin-3-
H-~ o, yI)-piperidine-1-carboxylate
(R)-2-[4-(4-carboxymethyl-piperazin-l-yl)-
N H piperidin-1-yl]-1-(7-chloro-1H-indazol-5-yl-
5c, methyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(141) r N-CN1oyN\
~_ N,N o tetrahydro-1,3-benzodiazepin-3-yl)-
H-~o 0
~o piperidine-1-carboxylate

CA 02565219 2006-10-17
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Structure Name
( R)-2- [4-( 2-a m i n o-p yri m i d i n e-5-yl )-
N H piperazin-1-yl]-1-(7-chloro-1H-indazol-5-
6 l N ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(142) H
~N~-N tetrahydro-1,3-benzodiazepin-3-yl)-
Ho piperidine-1-carboxylate
(R)-1 -(7-chloro-1 H-indazol-5-ylmethyl)-2-
"N H [4-(2-diethylamino-ethyl)-piperidin-1-yl]-2-
oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
(143) "~N benzodiazepin-3-yl)-piperidine-1-
H carboxylate
(R)-1 -(7-chloro-1 H-indazol-5-ylmethyl)-2-
N H [4-(3-dimethylamino-propyl)-piperazin-1-
c, yI]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
(144) /~
I N-( _N N 1,3-benzodiazepin-3-yl)-piperidine-l-
p'~!\ ~/ carboxylate
(R)-1-(7-chloro-1 H-indazol-5-ylmethyl)-2-
" H [4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-
I 2-oxo-ethyl 4-(2-oxo-2,3-dihydro-
(145) ~
N-~N o~"~i N-~N H, benzimidazol-1-yl)-piperidine-1-
H carboxylate
_N (R)-1-(7-chloro-1 H-indazol-5-ylmethyl)-2-
" H [4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-
I ~ C' 2-oxo-ethyl 4-(2-oxo-2,3-dihydro-
(146) N-CINI ~~~NCH3 benzimidazol-1-yl)-piperidine-1-
H ~ carboxylate
N (R)-1-(7-chloro-1 H-indazol-5-ylmethyl)-2-
~ \ "" (1'-methyl-4,4'-bipiperidinyl-1-yl)-2-oxo-
(147) I ~ /~ ~ -C1 ethyl 4-(2-oxo-2,3-dihydro-benzimidazol-l-
N_,(N-'_./N 0 0 CH' yI)-piperidine-1-carboxylate
H ~
N (R)-1 -(7-chloro-1 H-indazol-5-ylmethyl)-2-
~ "" [4-(1 -methyl-piperidin-4-yl)-piperazin-1 -yl]-
(148) ~ ~ C1 2-oxo-ethyl 4-(2-oxo-4-phenyl-2,3-dihydro-
~~" o~ '~"~N H, imidazol-1-yl)-piperidine-1-carboxylate
H
N H (R)-1-(7-chloro-1 H-indazol-5-ylmethyl)-2-
~ ~ ~ c [4-(4-methyl-piperazin-1 -yl)-piperidin-1 -yl]-
(149) ' e N-CNIoy"\/ ~NCH, 2-oxo-ethyl 4-(2-oxo-4-phenyl-2,3-dihydro-
H"-~ 0 imidazol-1-yl)-piperidine-l-carboxylate

CA 02565219 2006-10-17
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Structure Name
n (R)-1 -(7-chloro-1 H-indazol-5-ylmethyl)-2-
~ "-" (1'-methyl-[4,4']bipiperidinyl-1-yl)-2-oxo-
(150) C1 ethyl 4-(2-oxo-4-phenyl-2,3-dihydro-
~ CN 0CH3 imidazol-1-yl)-piperidine-l-carboxylate
H
N (R)-1-(7-chloro-1 H-indazol-5-ylmethyl)-2-
~ [4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-
(151) ~N= N ~ 2-oxo-ethyl 4-(5-oxo-3-phenyl-4,5-dihydro-
N~"~" ~1,2,4-triazoi-1-yl)-piperidine-l-carboxylate
H
"N H (R)-1-(7-chloro-1H-indazol-5-ylmethyl)-2-
~ ~ . C1 [4-(4-methyl-piperazin-1-yl)-piperidin-1-yi]-
(152) " "'"o~N~ ~"CH3 2-oxo-ethyl 4-(5-oxo-3-phenyl-4,5-dihydro-
H"-~ 1,2,4-triazol-1-yl)-piperidine-1-carboxylate
n (R)-1 -(7-chloro-1 H-indazol-5-ylmethyl)-2-
~ "" (1'-methyl-4,4'-bipiperidinyl-1-yl)-2-oxo-
(153) ~ I N= 01 ethyl4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-
H3 triazol-1 -yl)-piperidine-1 -carboxylate
N~ ~" ~N''~%
H 0
0
(R)-1 -(7-chloro-1 H-indazol-5-ylmethyl)-2-
N H [4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-
~ "~ ~ ~ 2-oxo-ethyl 4-(2-oxo-1,2-dihydro-
(154) CH,
imidazo[4,5-c]quinolin-3-yl)-piperidine-1-
N~
H o carboxylate
(R)-1-(7-chloro-1 H-indazol-5-ylmethyl)-2-
" " [4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-
N
I ' Cl 2-oxo-ethyl4-(2-oxo-1,2-dihydro-
~ ~ \
NN~N ~N~~y ~NCH, (1
55) imidazo[4,5-c]quinolin-3-yl)-piperidine-1-
H carboxylate
K " (R)-1 -(7-chloro-1 H-indazol-5-ylmethyl)-2-
~ N, " (1'-methyl-[4,4']bipiperidinyl-1-yl)-2-oxo-
(156) N C1 ethyl4-(2-oxo-1,2-dihydro-imidazo[4,5-c]-
N.~"-C" 'y''a'V'NCH' q u i no lin-3-yl)-p ipe rid ine- 1 -ca rboxylate 0 H
(R)-1 -(7-chloro-1 H-indazol-5-ylmethyl)-2-
N H [4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-
2-oxo-ethyl 4-(2-oxo-1,2-dihydro-
~ ~ ~C1
i~N/\
(157) -Ci~~o H naphth[1,2-d]imidazol-3-yl)-piperidine-1-
H'O 0 I ~~N N ' carboxylate

CA 02565219 2006-10-17
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Structure Name
(R)-1-(7-chloro-1 H-indazol-5-ylmethyl)-2-
N-H [4-(4-methyl-piperazin-1-yi)-piperidin-1-yl]-
I Cl 2-oxo-ethyl 4-(2-oxo-1,2-dihydro-
(158) N ~N~ ~"~ CH3 naphth[1,2-c]imidazol-3-yl)-piperidine-1-
H ~ carboxylate
N (R)-1-(7-chloro-1 H-indazol-5-ylmethyl)-2-
~ \ ~ "-" (1'-methyl-4,4'-bipiperidinyl-1-yl)-2-oxo-
(159) ~ C1 ethyl4-(2-oxo-l,2-dihydro-naphth[1,2-d]-
/ ( ~" ~N\/NC"' imidazol-3-yl)-piperidine-1-carboxylate
H, \
N H (R)-1-(7-chloro-1H-indazol-5-ylmethyl)-2-
_ [4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-
(160) ~ N~ t _ 2-oxo-ethyl 4-(2-oxo-1,4-dihydro-2H-
\ /N~ N o \/'N'/V _'"CH3 quinazolin-3-yl)-piperidine-1-carboxylate
H
" H (R)-1 -(7-chloro-1 H-indazol-5-ylmethyl)-2-
4'
[4-(4-methyl-piperazin-1 -yl)-piperidin-1 -yl]-
(161) C, 1 oy ~ N~~ CH 2-oxo-ethyl 4-(2-oxo-1,4-dihydro-2H-
N a
H"4 0 quinazolin-3-yl)-piperidine-1 -carboxylate
N H (R)-1-(7-chloro-lH-indazol-5-ylmethyl)-2-
\ (1'-methyl-[4,4']bipiperidinyl-1-yl)-2-oxo-
(162) ~ Q= N C1 ethyl4-(2-oxo-1,4-dihydro-2H-quinazofin-
N.~~" o ~" H~ 3-yl)-piperidine-1-carboxylate
H
(R)-1-(7-chloro-1 H-indazol-5-ylmethyl)-2-
N H [4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-
~ ~, 2-oxo-ethyl 4-(7-methoxy-2-oxo-1,2,4,5-
(163) % N~N~ ;~N~N tetrahydro-1,3-benzodiazepin-3-yl)-
H~o piperidine-1-carboxylate
_K (R)-1 -(7-chloro-1 H-indazol-5-ylmethyl)-2-
"" [4-(4-methyi-piperazin-1-yi)-piperidin-1-yl]-
.~
(164) l " 2-oxo-ethyl4-(7-methoxy-2-oxo-1,2,4,5-
I Q-o,-,-Y"~ ~N- tetrahydro-1,3-benzodiazepin-3-yl)-
~ o piperidine-1-carboxylate
(R)-1 -(7-chloro-1 H-indazol-5-ylmethyl)-2-
N " (1'-methyl-4,4'-bipiperidinyl-1-yl)-2-oxo-
~ C1 ethyl 4-(7-methoxy-2-oxo-1,2,4,5-
(165) ~ N~NI ;~N\tetrahydro-1,3-benzodiazepin-3-yl)-
H~ 0 piperidine-1-carboxylate

CA 02565219 2006-10-17
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Structure Name
~ (R)-1 -(7-chloro-1 H-indazol-5-ylmethyl)-2-
N H [4-(1-methyl-piperidin-4-yi)-piperazin-1-yl]-
~ ~ 2-oxo-ethyl 4-(2-oxo-1,4-dihydro-2H-
166 S /~\ '
( ) N--( N o~N% "'~~NCH, thieno[3,2-d]pyrimidin-3-yl)-piperidine-1-
H " ! ~/ carboxylate
(R)-1 -(7-chloro-1 H-indazol-5-ylmethyl)-2-
H [4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-
S
167 ~'~ 2-oxo-ethyl 4-(2-oxo-1,4-dihydro-2H-
( ) /N~~" ~"" "/~NCH,
thieno[3,2-d]pyrimidin-3-yl)-piperidine-1-
H carboxylate
N H (R)-1-(7-chloro-111 indazol-5-ylmethyl)-2-
\ i ' (1'-methyl-[4,4']bipiperidinyl-1-yl)-2-oxo-
(168) SN~~ ~ ~N ~" ethyl 4-(2-oxo-1,4-dihydro-2H-thieno[3,2-
N N o H ~pyrimidin-3-yl)-piperidine-1-carboxylate
H
(R)-1 -(7-chloro-1 H-indazol-5-ylmethyl)-2-
N H [4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-
~ 2-oxo-ethyl 4-(2-oxo-1,2-dihydro-4H-
/ Ci
(16 9 ) 1 _ ry~/~
~N-( O /'N'~NCH, thieno[3,4-d]pyrimidin-3-yl)-piperidine-1-
H 0 carboxylate
" H (R)-1-(7-chloro-11-/-indazol-5-ylmethyl)-2-
6 [4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-
~ i
(170) N~No'~"/N~"CH3 2-oxo-ethyl4-(2-oxo-1,2-dihydro-4H-
N~ thieno[3,4-d]pyrimidin-3-yl)-piperidine-1-
H carboxylate
N H (R)-1-(7-chloro-1H-indazol-5-ylmethyl)-2-
1'-methYI-[4,4']biPi PeridinYI-1 -yl)-2-oxo-
(
~
(171) ~N~N oy "~a.-~. CH ethyl 4-(2-oxo-1,2-dihydro-4H-thieno[3,4-
H d]pyrimidin-3-yl)-piperidine-1-carboxylate
N~ ~
(R)-2-[4-(1-methyl-piperidin-4-yl)-
N H piperazin-1-yl]-2-oxo-1-(7-trifluoromethyl-
~ 1 H-indazol-5-ylmethyl)-ethyl 4-(2-oxo-
' CF,
(172) ~\ 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
I /N--( .N 0~"~N' CH3
H- 0 ~l yl)-piperidine-1-carboxylate
(R)-2-[4-(4-methyl-piperazin-1-yl)-
" H piperidin-1-yl]-2-oxo-1-(7-trifluoromethyl-
' 1 H-indazol-5-ylmethyl)-ethyl 4-(2-oxo-
(173) ~N~ j "CH 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
H 0 yl)-piperidine-1-carboxylate

CA 02565219 2006-10-17
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Structure Name
(R)-2-(1'-methyl-4,4'-bipiperidinyl-1-yl)-2-
"N oxo-1-(7-trifluoromethyl-1 H-indazol-5-
= ~ F, ylmethyl)-ethyl 4-(2-oxo-1,2,4,5-
(174) N~N ~N~.~ H tetrahydro-1,3-benzodiazepin-3-yl)-
H~0 piperidine-1-carboxylate
(R)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-
N H yl)-1-(7-trifluoromethyl-1H-indazol-5-
ylmethyl)-ethyl 4-(2-oxo-1,2,4,5-
~CF3
~
(175) /~~ tetrahydro-1,3-benzodiazepin-3-yl)-
I N-( .N O~
H" ~J piperidine-1-carboxylate
(R)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-
N H yl)-1-(7-trifluoromethyl-1H-indazol-5-
~CF~ y(methyl)-ethyl 4-(2-oxo-1,2,4,5-
(176)
~ QO
~ N, H tetrahydro-1,3-benzodiazepin-3-yl)-
I \ N~N
H-~O ~~~~J//N piperidine-1-carboxylate
(R)-2-4,4'-bipiperidinyl-1-yl-2-oxo-1-(7-
N H trifluoromethyl-1 H-indazol-5-ylmethyl)-
ethyl ~F ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
(177) --( . /~N 0 _(N ' benzodiazePin-3-YI)-Pi Peridine-l-
~\ H H0 ~/ carboxylate
(R)-2-1,4'-bipiperidinyl-1'-yl-2-oxo-1-(7-
N H trifluoromethyl-1 H-indazol-5-ylmethyl)-
6 F ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
(178) _
N N~o'y"1N~ benzodiazepin-3-yl)-piperidine-1-
H-~0 0 carboxylate
(R)-2-[4-(4-methyl-perhydro-1,4-diazepin-
N H 1-yl)-piperidin-1-yl]-2-oxo-1-(7-
\ trifluoromethyl-1 H-indazol-5-ylmethyl)-
(179) = N F, (N ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
~ N~ o~ '~ " J benzodiazepin-3-yl)-piperidine-1 -
H 0 carboxylate
(R)-2-oxo-2-(4-perhydro-1,4-diazepin-1-yl-
N H piperidin-1-yl)-1-(7-trifiuoromethyi-1H-
~ indazol-5-ylmethyl)-ethyl 4-(2-oxo-1,2,4,5-
CF3
(180) N /~ "0 ~H tetrahydro-1,3-benzodiazepin-3-yl)-
H-~o N piperidine-1 -carboxylate
(R)-2-(4-dimethylamino-piperidin-1-yl)-2-
N H oxo-1-(7-trifluoromethyl-1 H-indazol-5-
ylmethyl)-ethyl 4-(2-oxo-1,2,4,5-
6CF,
(181) I i N~N~;~~N, tetrahydro-1,3-benzodiazepin-3-yl)-
H-'o 0 piperidine-1 -carboxylate

CA 02565219 2006-10-17
-83-
Structure Name
o (R)-1-(4-methyl-2-oxo-2,3-dihydro-
4
NH benzoxazol-6-ylmethyl)-2-[4-(1-methyl-
(182) xQ piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl
_ N" ~y CH, 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
Nc
H-~ o azepin-3-yl)-piperidine-1-carboxylate
0
4 (R)-1 -(4-methyl-2-oxo-2,3-d ihyd ro-
\ " H benzoxazol-6-yl methyl)-2-[4-(4-m ethyl-
piperazin-1 -yl)-piperidin-1 -yl]-2-oxo-ethyl
(183) (~Q-CNoly "\~ ry~ NCH, 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
H O azepin-3-yl)-piperidine-1-carboxylate
~o (R)-2-(1'-methyl-4,4'-bipiperidinyl-1-yl)-1-
" H (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-
ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(184) ~ N tetrahydro-1,3-benzodiazepin-3-yl)-
N N 0~ ~NCH,
H-~C o piperidine-1 -carboxylate
o (R)-1-(4-methyl-2-oxo-2,3-dihydro-
N_H benzoxazol-6-ylmethyl)-2-oxo-2-(4-
(185) piperidin-4-yl-piperazin-1-yl)-ethyl 4-(2-
~ 1N_ oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
H-~o N ~ o ~H 3-yl)-piperidine-1 -carboxylate
o (R)-1-(4-methyl-2-oxo-2,3-dihydro-
N_H benzoxazol-6-ylmethyl)-2-oxo-2-(4-
Q piperazin-1-yl-piperidin-1-yl)-ethyl 4-(2-
(186) NNJ~o~N~/~ "/~ ,H oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
N~~~..JJ 0 ~/~ /'" 3-yl)-piperidine-1-carboxylate
o (R)-2-4,4'-bipiperidinyl-1-y1-1-(4-methyl-2-
N H oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-
(187) oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
~N,~~ benzodiazepin-3-yl)-piperidine-1-
~
N o "H carboxylate
H 0
o (R)-2-1,4'-bipiperidinyl-1'-yl-1-(4-methyl-2-
N H oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-
(188) oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
~ ~o~"~ benzodiazepin-3-yl)-piperidine-1 -
~N
o carboxylate
H O
(R)-1-(4-methyl-2-oxo-2, 3-d ihyd ro-
4 benzoxazol-6-ylmethyl)-2-[4-(4-methyl-
. "H perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-
(189) 2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-
I ~--cN ~"~ "~ 1,3-benzodiazepin-3-yl)-piperidine-1-
H 0 carboxylate

CA 02565219 2006-10-17
-84-
Structure Name
(R)-1-(4-methyl-2-oxo-2,3-dihydro-
40 benzoxazol-6-ylmethyl)-2-oxo-2-(4-
~ "H perhydro-1,4-diazepin-l-yl-piperidin-1-yl)-
(190) ~ ~ H ethyl4-(2-oxo-1,2,4,5-tetrahydro-l,3-
~ ,N o"~"~' benzodiazepin-3-yl)-piperidine-1-
H 0 carboxylate
(R)-2-(4-dimethylamino-piperidin-1-yl)-1-
N H (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-
~ i ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(191)
~ ~ : O ~/ yNN' tetrahydro-1,3-benzodiazepin-3-yl)-
H O piperidine-l-carboxylate
(R)-1-(7-methyl-1 H-benzotriazol-5-
N-H Imeth I 2-4-1-meth I-eridin-4- I
H Y Y)- [ ( YPiP Y)-
(192) _ piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-
I "I NN O~~j N ~NCH3 1,2,4,5-tetrahydro-l,3-benzodiazepin-3-
H~ ~~~/// yl)-piperidine-l-carboxylate
N,N (R)-1-(7-methyl-1 H-benzotriazol-5-
N-H "-H ylmethyl)-2-[4-(4-methyl-piperazin-1-yl)-
piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-
(193) H, 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
H yl)-piperidine-1-carboxylate
(R)-1-(7-methyl-1 H-benzotriazol-5-
N-NN H ylmethyl)-2-(1'-methyl-4,4'-bipiperidinyl-1 -
(194) ~~ yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
~
I N N '~ "CH 1,3-benzodiazepin-3-yl)-piperidine-1-
~ carboxylate
HO
(R)-1-(7-methyl-1 H-benzotriazol-5-
"" ylmethyl)-2-oxo-2-(4-piperidin-4-yl-
~ " H piperazin-l-yl)-ethyl 4-(2-oxo-1,2,4,5-
(195) ~ "'"~ ;~~" tetrahydro-l,3-benzodiazepin-3-yl)-
\ p-~o N\~ ~" H
piperidine-l-carboxylate
(R)-1-(7-methyl-1 H-benzotriazol-5-
""' ImethYI)-2-oxo-2-(4-PiPerazin-l-YI
" H Y
-
~ piperidin-l-yl)-ethyl 4-(2-oxo-1,2,4,5-
(196) I % ~NIo~ NH tetrahydro-l,3-benzodiazepin-3-yl)-
H~ piperidine-1-carboxylate
N=n (R)-2-4,4'-bipiperidinyl-l-yl-1-(7-methyl-
\ " " 1 H-benzotriazol-5-ylmethyl)-2-oxo-ethyl 4-
(197) /'~ (2-oxo-1, 2, 4, 5-tetra hyd ro-1, 3-benzod i-
~ % -( .NIo~"\=/ NH
N4 azepin-3-yl)-piperidine-1 -carboxylate
H0 ~/

CA 02565219 2006-10-17
-85-
Structure Name
N=N (R)-2-1,4'-bipiperidinyl-1'-yl-1-(7-methyl-
" H 1 H-benzotriazol-5-ylmethyl)-2-oxo-ethyl 4-
(198) I- (2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
~ ~~" oy "'~
N azepin-3-yl)-piperidine-1-carboxylate
H 0
(R)-1-(7-methyl-1 H-benzotriazol-5-
"_NN H ylmethyl)-2-[4-(4-methyl-perhydro-l,4-
diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-
(199) N'N~ ~N~ ~ (2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
H-( azepin-3-yl)-piperidine-1 -carboxylate
(R)-1-(7-methyl-1 H-benzotriazol-5-
" "' ylmethyl)-2-oxo-2-(4-perhydro-1,4-
N H diazepin-1-yl-piperidin-1-yl)-ethyl 4-(2-oxo-
(200) ~N~ /N H 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
H0 yl)-piperidine-l-carboxylate
(R)-2-(4-dimethylamino-piperidin-1-yl)-1-
"-NN H (7-methyl-1 H-benzotriazol-5-ylmethyl)-2-
4~ oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
(201) /~ "~ benzodiazepin-3- I i eridine-1-
H-~"o l "~ carboxylate y) p p
(R)-2-[4-(1-methyl-piperidin-4-yl)-
i piperazin-1 -yl]-1-(7-methyl-pyrazolo[1,5-
/~\JQ~ a]pyridin-5-ylmethyl)-2-oxo-ethyl 4-(2-oxo-
(202) N-( .N" o~ CH3 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
H- O ~J yl)-piperidine-l-carboxylate
(R)-2-[4-(4-methyl-piperazin-1 -yl)-
~ piperidin-1 -yl]-1-(7-methyl-pyrazolo[1,5-
' a]pyridin-5-ylmethyl)-2-oxo-ethyl 4-(2-oxo-
(203) ~~NI ~N~yN\jNCH, 1,2,4,5-tetrahydro-l,3-benzodiazepin-3-
H 0 yl)-piperidine-1-carboxylate
(R)-2-(1'-methyl-4,4'-bipiperidinyl-1 -yl)-1-
i N (7-methyl-pyrazolo[1,5-a]pyridin-5-
i ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(204) tetrahydro-1,3-benzodiazepin-3-yl)-
I /N-( ~N~NCH3
H- 0 ~~ll piperidine-1-carboxylate
(R)-1-(7-methyl-pyrazolo[1,5-a]pyridin-5-yl-
i :N methyl)-2-oxo-2-(4-piperidin-4-yl-pipera-
~ ~ zin-l-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
(205) ~ N~"Qo;~ H 1,3-benzodiazepin-3-yl)-piperidine-1 -
carboxylate
' H-~ 0

CA 02565219 2006-10-17
-86-
Structure Name
(R)-1-(7-methyl-pyrazolo[1,5-a]pyridin-5-yl-
~ N methyl)-2-oxo-2-(4-piperazin-1-yl-piperi-
din-l-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
(206) CQN o~N j NH 1,3-benzodiazepin-3-yl)-piperidine-1 -
H 0 ~~~/// carboxylate
(R)-2-4,4'-bipiperidinyl-1 -yl-1-(7-methyl-
I N pyrazolo[1,5-a]pyridin-5-ylmethyl)-2-oxo-
(207) ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
~NH benzodiazepin-3-yl)-piperidine-1 -
H 0 carboxylate
(R)-2-1,4'-bipiperidinyl-1'-y1-1-(7-methyl-
~ N pyrazolo[1,5-a]pyridin-5-ylmethyl)-2-oxo-
i ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
(208) ~
"~ IN
N N o'~ \~",- benzodiazepin-3-yl)-piperidine-1-
H 0 carboxylate
(R)-2-[4-(4-methyi-perhydro-1,4-diazepin-
, 1-yl)-piperidin-1-yl]-1-(7-methyl-
i " pyrazolo[1,5-a]pyridin-5-ylmethyl)-2-oxo-
(209) 1 - " "_ ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
i c" ~ " J benzodiazepin-3-yl)-piperidine-l-
H 0 carboxylate
(R)-1-(7-methyl-pyrazolo[1,5-a]pyridin-5-yl-
V "N methyl)-2-oxo-2-(4-perhydro-1,4-diazepin-
_ 1-yl-piperidin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-
(210) N_CNI tetrah dro-1,3-benzodiazepin 3 I
H~ piperidine-1-carboxylate y)
(R)-2-(4-dimethylamino-piperidin-1 -yl)-1-
(7-methyl-pyrazolo[1,5-a]pyridin-5-
ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(211) N-CNx ~"-
-,- N, tetrahydro-1,3-benzodiazepin-3-yl)-
H0 piperidine-1-carboxylate
(R)-1 -(1,7-dimethyl-1 H-indazol-5-
"N ylmethyl)-2-[4-(1-methyl-piperidin-4-yl)-
/~~ piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-
(212) ~(tJ-( NIo~"V 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
H''0 ~J yl)-piperidine-1-carboxylate
_N (R)-1-(1, 7-dimethyl-1 H-indazol-5-
\ " ylmethyl)-2-[4-(4-methyl-piperazin-1 -yl)-
piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-
(213) 4 N-Cj 'Y" NC55:~NCH3 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
H o 0 yl)-piperidine-1-carboxylate

CA 02565219 2006-10-17
-87-
Structure Name
(R)-1 -(1,7-dimethyl-1 H-indazol-5-
\ N_ ylmethyl)-2-(1'-methyl-4,4'-bipiperidinyl-1-
(214) ~ yl)-2-oxo-ethyt 4-(2-oxo-1,2,4,5-tetrahydro-
1,3-benzodiazepin-3-yl)-piperidine-1-
I N~N ~l/C/.NCH,
H~ carboxylate
(R)-1-(1,7-dimethyl-1 H-indazol-5-
"" YImethYI)-2-oxo-2-(4-Pi Peridin-4-YI
-
piperazin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-
(215)
tetrahydro-1,3-benzodiazepin-3-yl)-
-{ . /~NQ
I N~ ~N~N-H
H-~o \\JJ piperidine-1-carboxylate
(R)-1 -(1,7-dimethyl-1 H-indazol-5-
N ylmethyl)-2-oxo-2-(4-piperazin-1-yl-
. piperidin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-
(216) N-CNO~N~ j NH tetrahydro-1,3-benzodiazepin-3-yl)-
H-~ piperidine-1-carboxylate
(R)-2-4,4'-bipiperidinyl-1-yl-1-(1,7-
"N dimethyl-1 H-indazol-5-ylmethyl)-2-oxo-
. ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
(217) Nc
- NObenzodiazepin-3-yl)-piperidine-1-
H0 carboxylate
(R)-2-1,4'-bipiperidinyl-1'-y1-1-(1,7-
N dimethyl-1 H-indazol-5-ylmethyl)-2-oxo-
ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
(21$) N-CNyN,, benzodiazepin-3-yl)-piperidine-1-
H-~ carboxylate
(R)-1 -(1,7-dimethyl-1 H-indazol-5-
N ylmethyl)-2-[4-(4-methyl-perhydro-1,4-
diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-
(219) N~NQ ;~ .N~ J"- (2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
' H-~ azepin-3-yl)-piperidine-1 -carboxylate
(R)-1 -(1,7-dimethyl-1 H-indazol-5-
N- ylmethyl)-2-oxo-2-(4-perhydro-1,4-
diazepin-1-yl-piperidin-1-yl)-ethyl 4-(2-oxo-
(220) N~"1o'yN~ ~"" 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
-carboxylate
H-~ yl)-piperidine-1-carboxylate
(R)-2-(4-dimethylamino-piperidin-1-yl)-1-
"N' (1,7-dimethyl-1 H-indazol-5-ylmethyl)-2-
~ oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
(221) N~NQO;~N~ N, benzodiazepin-3-yl)-piperidine-l-
H-~ carboxylate

CA 02565219 2006-10-17
-88-
Structure Name
~ (R)-1-(2,7-dimethyl-2H-indazol-5-
I N ylmethyl)-2-[4-(1-methyl-piperidin-4-yl)-
(222) piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-
~No 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
N-
N4 H' yl)-piperidine-1 -carboxylate
H O
N (R)-1-(2,7-dimethyl-2H-indazol-5-
" ylmethyl)-2-[4-(4-methyl-piperazin-1-yl)-
N~~ o" piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-
(223)
N No1( ~"~j NCH, 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
H o yl)-piperidine-1-carboxylate
~ (R)-1-(2,7-dimethyl-2H-indazol-5-
~ N ylmethyl)-2-(1'-methyl-4,4'-bipiperidinyl-1-
(224) _ ~ yl)-2-oxo-ethyl4-(2-oxo_1,2,4,5-tetrahydro-
N-CNoYN'~~. CH3 1,3-benzodiazepin-3-yl) piperidine-1-
N~( carboxylate
H O
~ (R)-1-(2,7-dimethyl-2H-indazol-5-
i N ylmethyl)-2-oxo-2-(4-piperidin-4-yl-
(225) JQ piperazin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-
I N-CN" O tetrahydro-1,3-benzodiazepin 3 yl)
N4 piperidine-1 -carboxylate
H O
~ (R)-1-(2,7-dimethyl-2H-indazol-5-
i N ylmethyl)-2-oxo-2-(4-piperazin-1 -yl-
(226) JQ piperidin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-
N y ~N~~ H tetrahydro-1,3-benzodiazepin-3-yl)-
N" O
N~( ~ O N piperidine-1 -carboxylate
H O
~ (R)-2-4,4'-bipiperidinyl-1-yI-1-(2, 7-
"N dimethyl-2H-indazol-5-ylmethyl)-2-oxo-
(227) ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
/~ ~ benzodiazepin-3-yl)-piperidine-1-
I~ N4 --( .N O 0~NH carboxylate
H O V
(R)-2-1,4'-bipiperidinyl-1'-y1-1-(2,7-
dimethyl-2H-indazol-5-ylmethyl)-2-oxo-
i N
ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
(22$)
N benzodiazepin-3-yl)-pipendine-1-
~
N~
N4 ~/ 0 carboxylate
H O
~ (R)-1-(2,7-dimethyl-2H-indazol-5-
I "=" ylmethyl)-2-[4-(4-methyl-perhydro-1,4-
229) diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-
( N~N~o~N~ (2-oxo-1,2,4,5-tetrahydro-1,3-benzodi
N~( azepin-3-yi)-piperidine-1-carboxylate
H 0

CA 02565219 2006-10-17
-89-
Structure Name
, (R)-1 -(2,7-dimethyl-2H-indazol-5-
i "N ylmethyl)-2-oxo-2-(4-perhydro-1,4-
(230) diazepin-1-yl-piperidin-1-yl)-ethyl 4-(2-oxo-
~ o'-rN~iyN" H 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
H-~o yl)-piperidine-1-carboxylate
, (R)-2-(4-dimethylamino-piperidin-l-yl)-1-
i N (2,7-dimethyl-2H-indazol-5-ylmethyl)-2-
(231) oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
~ "~N~ y ~ N, benzodiazepin-3-yl)-piperidine-1-
H-~C carboxylate
(R)-1-(4-methyl-2-oxo-2,3-dihydro-
N H benzoxazol-6-ylmethyl)-2-[4-(1-methyl-
(232) piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl
N N~o~ ~N 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-
HN4 0 piperidine-1-carboxylate
~ (R)-1 -(4-methyl-2-oxo-2,3-d ihydro-
Qtch \ "" benzoxazol-6-ylmethyl)-2-[4-(4-methyl-
piperazin-l-yl)-piperidin-1-yl]-2-oxo-ethyl
(233) " ~ ~NI o N'',Nj" CH, 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-
~ piperidine-1-carboxylate
~ (R)-2-(1'-methyl-4,4'-bipiperidinyl-1-yl)-1-
" H (4-methyl-2-oxo-2,3-dihydro-benzoxazo1-6-
(234) ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,4-dihydro-
~ N--CNI '~N\~ ".CH3 2H-quinazolin-3-yl)-piperidine-1 -
HN-D carboxylate
N-n (R)-1-(7-methyl-1 H-benzotriazol-5-
" H ylmethyl)-2-[4-(1-methyl-piperidin-4-yl)-
(235) /~ _ piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,4-
~ N-( .N Y ~N'~~NCH, dihydro-2H-quinazolin-3-yl)-piperidine-1-
H"40 ~/ carboxylate
N=N (R)-1-(7-methyl-1 H-benzotriazol-5-
ylmethyl)-2-[4-(4-methyl-piperazin-1 -yl)-
piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,4-
(236) N ~~N~o~~ ~NCH,
dihydro-2H-quinazolin-3-yl)-piperidine-1 -
H carboxylate
N=N (R)-1-(7-methyl-1 H-benzotriazol-5-
b" H ylmethyl)-2-(1'-methyl-[4,4']bipiperidinyl-1-
(237) ~ - N yl)-2-oxo-ethyl 4-(2-oxo-1,4-dihydro-2H-
\ ~N-~ " o ~"C"' quinazolin-3-yl)-piperidine-1-carboxylate
H

CA 02565219 2006-10-17
-90-
Structure Name
0
N H (R)-2-1,4'-bipiperidinyl-1'-yI-1-(4-methyl-2-
_ ~ ~ oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-
(238) --CN
H O~"~ N oxo-ethyl 4-(2-oxo-1,4-dihydro-2H-
N40 quinazolin-3-yl)-piperidine-1-carboxylate
N=h
N H (R)-2-[1,4']bipiperidinyl-1'-yl-1-(7-methyl-
QI\/1 ~ <) 1 H-benzotriazol-5-ylmethyl)-2-oxo-ethyl 4-
(239) N-CN o'y"\~,N (2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-
H"40 piperidine-l-carboxylate
QIQH (R)-2-[1,4']bipiperidinyl-1'-yl-1-(7-methyl-
1 H-indazol-5-ylmethyl)-2-oxo-ethyl 4-(2-
(240) ~o ooxo-1,4-dihydro-2H-quinazolin-3-yl)-
H " O piperidine-l-carboxylate
N , N H (R)-2-[1,4']bipiperidinyl-1'-yl-1-(7-chloro-
C1 1 H-indazol-5-ylmethyl)-2-oxo-ethyl 4-(2-
(241) N-CNo'y"~N~ oxo-l,4-dihydro-2H-quinazolin-3-yl)-
H"~ piperidine-l-carboxylate
N H (R)-2-[1,4']bipiperidinyl-1'-yl-1-(1H-indazol-
- 5-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,4-
(242) "~N-~N~o o dihydro-2H-quinazolin-3-yl)-piperidine-1-
H 0 carboxylate
(R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
" H [4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-
~_~ 2-oxo-ethyl 1',2"-dihydro-2"-oxospiro-4H-
(243) H-N N1 o CH, 3",1-benzoxazin'-4,4"-piperidine-l-
~ >/- o carboxylate
(R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
_N [4-(4-methyl-piperazin-1 -yl)-piperidin-1 -yl]-
(244) "" 2-oxo-ethyl 1 ",2"-dihydro-2"-oxospiro-4H-
J(~~ 3",1-benzoxazin "-4,4"-piperidine-l-
H-N N" O~ ~/v~"/~ H carboxylate
~O O /\" '
0
N (R)-2-(1'-methyl-4,4'-bipiperidinyl-l-yl)-1-
i ~ \ i " " (7-methyl-1 H-indazol-5-ylmethyl)-2-oxo-
(245) - ~ N ethyl 1 ",2"-dihydro-2"-oxospiro-4H-3',1-
" jro " o~ H' benzoxazin'-4,4"-piperidine-1-carboxylate
0

CA 02565219 2006-10-17
-91-
Structure Name
N (R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
R "" oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl
(246) Q 1 ",2"-dihydro-2'-oxospiro-4H-3",1-benz-
" ~ " ~ " oxazin"-4,4'-piperidine-1-carboxylate
0
N H (R)-1-(7-methyl-1H-indazol-5-ylmethyl)-2-
~ oxo-2-(4-piperazin-1-yl-piperidin-1 -yl)-ethyl
(247) 1',2"-dihydro-2'-oxospiro-4H-3",1-benz-
"- j " -~YNI~,,-N,%"" oxazin"-4,4'-piperidine-1-carboxylate
0
N (R)-2-4,4'-bipiperidinyl-1-yl-1-(7-methyl-
~~ "" 1 H-indazol-5-ylmethyl)-2-oxo-ethyl 1",2"-
(248) N dihydro-2'-oxospiro-4H-3',1-benzoxazin"-
" j~ o ~"" 4,4"-piperidine-1-carboxylate
0
N (R)-2-1,4'-bipiperidinyl-1'-yl-1-(7-methyl-
~
~ i "" 1H-indazol-5-ylmethyl)-2-oxo-ethyl 1 ',2'-
(249) ~ICN dihydro-2"-oxospiro-4H-3',1-benzoxazin"-
"- j~ 4,4"-piperidine-1-carboxylate
0
(R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
"" H [4-(4-methyl-perhydro-1,4-diazepin-1-yl)-
~ pipe rid i n- 1 -yl]-2-oxo-eth yl 1',2"-dihydro-2"-
(250) H-N N10"y"~"~ oxospiro-4H-3",1-benzoxazin"-4,4"-
~
0 piperidine-1-carboxylate
(R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
" H oxo-2-(4-perhydro-1,4-diazepin-1-yl-
251 ~ \ _ piperidin-1-yl)-ethyl 1 ',2"-dihydro-2'-
( ) H-N NZo"~ N.~ " oxospiro-4H-3',1-benzoxazin"-4,4"-
~
0 o piperidine-1-carboxylate
N (R)-2-(4-dimethylamino-piperidin-1-yl)-1-
~ " (7-methyl-1 H-indazol-5-ylmethyl)-2-oxo-
(252) .
" " "~o~"~N\ ethyl 1 ",2"-dihydro-2'-oxospiro-4H-3',1-
~ 0 benzoxazin"-4,4"-piperidine-1-carboxylate
0
4-(2-oxo-1,2,4,5-tetrahydro-l,3-benzodi-
NH ( R)-1-(4-methyl-2-oxo-2, 3-d ihydro-
(253) benzoxazol-6-ylmethyl)-2-(4-morpholin-4-
k " yl-piperidin-1-yl)-2-oxo-ethyl azepin-3-yl)-
I "~"~" o ~'"~~' piperidine-l-carboxylate
H 0

CA 02565219 2006-10-17
-92-
Structure Name
(R)-1-(4-methyl-2-oxo-2,3-dihydro-
o-~ benzoxazol-6-ylmethyl)-2-oxo-2-[4-
~ "H (tetrahydro-pyran-4-yl)-piperazin-1-yl]-
(254) ~ ~ ~ 0 ethyl 4-(2-oxo-1,2,4,5-tetrahydro-l,3-
I~ o benzodiazepin-3-yl)-piperidine-l-
H 0 carboxylate
o (R)-2-(4-cyclohexyl-piperazin-1-yl)-1-(4-
NH methyl-2-oxo-2,3-dihydro-benzoxazol-6-yl-
(255) o methyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
I N-( NxO~" tetrahydro-1,3-benzodiazepin-3-yl)-
N~ '-/ o piperidine-1 -carboxylate
H 0
o~ (R)-2-(4-hydroxy-1,4'-bipiperidinyl-1'-yl)-1-
NH (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-
(256) o ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
~ N~No" oH tetrahydro-1,3-benzodiazepin-3-yl)-
N~ O ~ piperidine-1-carboxylate
H O
o~ (R)-2-(4-methoxy-1,4'-bipiperidinyl-1'-yl)-1-
NH (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-
(257) ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
I -CNoy N,-- tetrahydro-1,3-benzodiazepin-3-yl)-
N4 o piperidine-1 -carboxylate
H O
o (R)-2-(4-hydroxy-4-methyl-1,4'-
o4 bipiperidinyl-1'-yl)-1-(4-methyl-2-oxo-2,3-
NH dihydro-benzoxazol-6-ylmethyl)-2-oxo-
(258) o ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
I ~N-~No"~,"oH benzodiazepin
" -3-yl)-piperidine-1-
H o 0 carboxylate
(R)-2-(4,4-dimethyl-1,4'-bipiperidinyl-1'-yl)-
NH 1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-
(259) 6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
otetrahydro-1,3-benzodiazepin-3-yl)-
GCNCNA
0 piperidine-1 -carboxylate
H O
~ (R)-2-(4-amino-4-methyl-1,4'-bipiperidinyl-
0NH 1'-yl)-1-(4-methyl-2-oxo-2,3-dihydro-benz-
(260) o oxazol-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-
I N0'y"~ N 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
N 0 \~'NHz
yl)-piperidine-1 -carboxylate
H 0
o (R)-2-(4-hydroxy-4-hydroxymethyl-1,4'-
NH bipiperidinyl-1'-yl)-1-(4-methyl-2-oxo-2,3-
~ dihydro-benzoxazol-6-ylmethyl)-2-oxo-
(261) o ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
c ~~No~'l~~ oH benzodiazepin-3-yl)-piperidine-1-
H 0 0 OH carboxylate

CA 02565219 2006-10-17
-93-
Structure Name
(R)-2-(1'-ethoxycarbonylmethyl-4,4'-
0-4 bipiperidinyl-1-yl)-1-(4-methyl-2-oxo-2,3-
/ NH dihydro-benzoxazol-6-ylmethyl)-2-oxo-
(262) ' ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
CC N- ~Nxo'y"~~i,"'~ benzodiazepin-3-yl)-piperidine-1-
H~0 o I
carboxylate
~ (R)-2-(1'-carboxymethyl-4,4'-bipiperidinyl-
NH 1-yl)-1-(4-methyl-2-oxo-2,3-dihydro-
(263) _ benzoxazol-6-ylmethyl)-2-oxo-ethyl 4-(2-
I~ N N~0'~"~'~~ o oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
~ "~ " 3-yl)-piperidine-1-carboxylate
H O
o~ (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
N benzoxazol-6-ylmethyl)-2-[4-(1-methyl-
(264) piperidin-4-yl)-piperazin-1-yl)-2-oxo-ethyl
N-CNx0'Y"~i N~ ' 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
o N azepin-3-yl)-piperidine-1-carboxylate
H O
N_ (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
~ benzoxazol-6-ylmethyl)-2-[4-(4-methyl-
(265) ~ k = N piperazin-1-yl)-piperidin-1-yIJ-2-oxo-ethyl
CC N No o 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
H o azepin-3-yl)-piperidine-1-carboxylate
(R)-1-( 3, 4-d i methyl-2-oxo-2, 3-dihyd ro-
N_ benzoxazol-6-ylmethyl)-2-(1'-methyl-4,4'-
(266) bipiperidinyl-1-yl)-2-oxo-ethyl 4-(2-oxo-
~ - N 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
I N~"~" o~ \yI)-piperidine-1-carboxylate
H O
04 0 (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
N benzoxazol-6-ylmethyl)-2-oxo-2-(4-
(267) piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-
x "~ oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
I A "~~" o~ ~"~N'" 3-yl)-piperidine-1-carboxylate
H O
4 (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
N benzoxazol-6-ylmethyl)-2-oxo-2-(4-
~ piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-
(268) CC "~Nxo~ 'H oxo-1,2,4,5-tetrahydro-l,3-benzodiazepin-
"'N 3-yl)-piperidine-1-carboxylate
H O
(R)-2-4,4'-bipiperidinyl-1-yl-1-(3,4-
N_ dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-
ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(269) CC ~ tetrahydro-1,3-benzodiazepin-3-yl)-
N~" o" piperidine-1-carboxylate
H 0

CA 02565219 2006-10-17 -94-
Structure Name
o (R)-2-1,4'-bipiperidinyl-1'-yI-1-(3,4-
N_ dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-
270 o ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
( ) "~"~lo" tetrahydro-1,3-benzodiazepin-3-yl)-
"-~ o piperidine-l-carboxylate
H O
o (R)-1 -(3,4-d imethyl-2-oxo-2, 3-d ihydro-
-K benzoxazol-6-ylmethyl)-2-[4-(4-methyl-per-
\ "- hydro-1,4-diazepin-1 -yl)-piperidin-1-yl]-2-
(271) O - - , oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
I ~-C"xo" "J" benzodiazepin-3-yl)-piperidine-1-
H o carboxylate
o (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
4 benzoxazol-6-ylmethyl)-2-oxo-2-(4-
\ perhydro-l,4-diazepin-1-yl-piperidin-1-yl)-
(272) (-".H ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
I ~ -C"o o "~" benzodiazepin-3-yl)-piperidine-1-
H o carboxylate
o (R)-1-(3,4-d imethyl-2-oxo-2, 3-dihydro-
" benzoxazol-6-ylmethyl)-2-(4-morpholin-4-
: yl-piperidin-1-yl)-2-oxo-ethyl 4-(2-oxo-
(273) "~"xo"\~"~ 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
"~ o ~'o yI)-piperidine-l-carboxylate
H O
~ (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
benzoxazol-6-ylmethyl)-2-oxo-2-[4-
~ (tetrahydro-pyran-4-yl)-piperazin-1-yl]-
(274) 0 ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
I "4N~" o_~O benzodiazepin-3-yl)-piperidine-1 -
H 0 carboxylate
~ (R)-2-(4-cyclohexyl-piperazin-1 -yl)-1-(3,4-
dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-
~ ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(275) "~"x0~ tetrahydro-1,3-benzodiazepin-3-yl)-
N4 o piperidine-1 -carboxylate
H O
o (R)-2-(4-cycloheptyl-pi perazin-1-yl)-1-(3, 4-
" dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-
(276) ~ ~ ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
~ = "~ ~ tetrahydro-1,3-benzodiazepin-3-yl)-
CQ " ~" o o ~" piperidine-1 -carboxylate
H O
04 0 (R)-2-(4-cyclopentyl-piperazin-1-yl)-1-(3,4-
" dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-
(277) o ylmethyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-
% ~ k ~"~ ~ tetrahydro-l,3-benzodiazepin-3-yl)-
I "~" " o o ~" piperidine-1-carboxylate
-carboxylate
H 0

CA 02565219 2006-10-17
-95-
Structure Name
o (R)-2-(4,4-dimethyl-1,4'-bipiperidinyl-1'-yl)-
-~( 1-(3,4-dimethyl-2-oxo-2,3-dihydro-
"' benzoxazol-6-ylmethyl)-2-oxo-ethyl 4-(2-
(278) o oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
I "~-C"xo~"1 3-yl)-piperidine-1 -carboxylate
0
H O
o (R)-1-(3,4-dimethyl-2-oxo-2, 3-d ihydro-
N, benzoxazol-6-ylmethyl)-2-(4-hydroxy-1,4'-
~ bipiperidinyl-1'-yl)-2-oxo-ethyl 4-(2-oxo-
(279) jl = " 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
I "~"~" o o ~"/" H yl)-piperidine-1 -carboxylate
H O
0 (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
benzoxazol-6-ylmethyl)-2-(4-hydroxy-4-
~ methyl-1,4'-bipiperidinyl-1'-yl)-2-oxo-ethyl
(289) % ~ ~ " 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
~ "~" " o o ~"~' H azepin-3-yl)-piperidine-1-carboxylate
H 0
o~ (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
"~ benzoxazol-6-ylmethyl)-2-(4-ethyl-4-
(281) o _ ,- 1 hydroxy-1,4'-bipiperidinyl-1'-yl)-2-oxo-ethyl
C~N-] x " " 4 -(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
~" o o~- oH azepin-3-yl)-piperidine-1-carboxylate
H O
o (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
04 benzoxazol-6-ylmethyl)-2-(4-hydroxy-4-
~
"' trifluoromethyl-1,4'-bipiperidinyl-1'-yl)-2-
(282) ' oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
ly "-C"o'y"",_~ OH benzodiazepin-3-yl)-piperidine-1-
H4o o cF, carboxylate
o ( R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
N_ benzoxazol-6-ylmethyl)-2-[1'-(2-hydroxy-
~ ~ ethyl)-4,4'-bipiperidinyl-1-yl]-2-oxo-ethyl 4-
(283) CQ x " (2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
"~" o o ~"-~OH azepin-3-yl)-piperidine-1 -carboxylate
H 0
(R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
-( benzoxazol-6-ylmethyl)-2-{4-[1-(2-hydroxy-
~ " ethyl)-piperidin-4-yl]-piperazin-1-yl}-2-oxo-
(284) ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
I al~-C"xo /~"-~OH benzodiazepin-3-yl)-piperidine-1-
H o carboxylate
o (R)-1 -(3,4-d i methyl-2-oxo-2, 3-d i hydro-
N' benzoxazol-6-ylmethyl)-2-{4-[4-(2-hydroxy-
0 ethyl)-piperazin-1-yl]-piperidin-1-yl}-2-oxo-
(285) I "-~"xo'~"1 "~~oH ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
~~ o '~"' benzodiazepin-3-yl)-piperidine-1-
carbox late

CA 02565219 2006-10-17
-96-
Structure Name
o~,o (R)-2-(4-amino-4-methyl-1,4'-bipiperidinyl-
"' 1'-yl)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
(286) o benzoxazol-6-ylmethyl)-2-oxo-ethyl 4-(2-
xo~"~"~ "" oxo-1,2,4,5-tetrahydro-l,3-benzodiazepin-
"~"
"~ o Z 3-yl)-piperidine-1 -carboxylate
H O
o (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
04 benzoxazol-6-ylmethyl)-2-(4-hydroxy-4-hy-
"' droxymethyl-1,4'-bipiperidinyl-1'-yl)-2-oxo-
(287) o ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
~ ~~"o'Ybenzodiazepin-3-yl)-piperidine-l-
H o oH o" carboxylate
o (R)-1 -(3,4-d imethyl-2-oxo-2, 3-d ihydro-
4 benzoxazol-6-ylmethyl)-2-(4-
\ hydroxymethyl-1,4'-bipiperidinyl-1'-yl)-2-
(288) _ oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
C ~ ~" o o "~ "~ ~~ benzodiazepin-3-yl)-piperidine-1-
e
H 0 carboxylate
(R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
0 benzoxazol-6-ylmethyl)-2-(1'-
~ methanesulphonyl-4,4'-bipiperidinyl-1-yl)-
~ 2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
(289) CC -~"xo'~"\os o 1,3-benzodiazepin-3-yl)-piperidine-l-
"o "' carboxylate
H O
o (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
4 benzoxazol-6-ylmethyl)-2-[4-(4-
~ methanesulphonyl-piperazin-1-yl)-
(290) \ N o piperidin-l-yl]-2-oxo-ethyl4-(2-oxo-
~ "-C" o ~ 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
H'~ yl)-piperidine-1-carboxylate
(R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
-~o benzoxazol-6-ylmethyl )-2-[4-(1-
~ methanesulphonyl-piperidin-4-yl)-
(291) CC N o piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-
~" o'~ ~"-~",s~ 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
H 0 0 yl)-piperidine-1-carboxylate

CA 02565219 2006-10-17
-97-
Structure Name
0 (R)-1-(3, 4-dimethyl-2-oxo-2, 3-d ihydro-
benzoxazol-6-ylmethyl)-2-oxo-2-(1'-
(292) sulphamoyl-4,4'-bipiperidinyl-1-yl)-ethyl4-
N~"JIo~ ;s ~ (2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
02 N
o N' "NHZ azepin-3-yl)-piperidine-l-carboxylate
H O
o (R)-1 -(3,4-d i methyl-2-oxo-2, 3-d ihydro-
N' benzoxazol-6-ylmethyl)-2-oxo-2-[4-(4-
~ i sulphamoyl-piperazin-1-yl)-piperidin-1-yl]-
(293) ' o ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
I ~ ~N~o o"~ NH benzodiazepin-3-yl)-piperidine-1-
H 0 2 carboxylate
o (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
benzoxazol-6-ylmethyl)-2-oxo-2-[4-(1-
~ sulphamoyl-piperidin-4-yl)-piperazin-1-yl]-
(294) o o ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
I ~ ~"x0 ~ ~\N=S~NHz benzodiazepin-3-yl)-piperidine-1-
H 0 carboxylate
(R)-1 -(3,4-d i methyl-2-oxo-2, 3-d ihydro-
-~ benzoxazol-6-ylmethyl )-2-(1'-
~
ethoxycarbonylmethyl-4,4'-bipiperidinyl-l-
(295) o ' yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
k N-CNx0'y"~N'y .i 1,3-benzodiazepin-3-yl)-piperidine-1-
H40 0 carboxylate
0 (R)-2-(1'-carboxymethyl-4,4'-bipiperidinyl-
1-yI )-1-(3, 4-d imethyl-2-oxo-2, 3-d ihyd ro-
(296) benzoxazol-6-ylmethyl)-2-oxo-ethyl 4-(2-
i~ N N0Y~o oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
~ O "~ H 3-yl)-piperidine-1-carboxylate
H O
o (R)-1 -(3,4-d imethyl-2-oxo-2, 3-d ihyd ro-
N benzoxazol-6-ylmethyl)-2-[4-(4-
ethoxycarbonylmethyl-piperazin-1-yl)-
(297) ~ piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-
~ N-CN o'~"~ ~N.-Yo.i 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
H'~o o yl)-piperidine-1-carboxylate
o (R)-2-[4-(4-carboxymethyl-piperazin-1-yl)-
-~(' piperidin-1-yl]-1-(3,4-dimethyl-2-oxo-2,3-
~
" dihydro-benzoxazol-6-ylmethyl)-2-oxo-
(298) '
ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
~11 ~-CINV o "~. ~No=H benzodiazepin-3-yl)-piperidine-1-
H 0 0 carboxylate

CA 02565219 2006-10-17
-98-
Structure Name
(R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
N' benzoxazol-6-ylmethyl)-2-[4-(1-
\ ethoxycarbonylmethyl-piperidin-4-yl)-
(299) piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-
I ~~Nx '~( ~i No 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
H o o yl)-piperidine-1 -carboxylate
o (R)-2-[4-(1-carboxymethyl-piperidin-4-yl)-
N' piperazin-1-yl]-1-(3,4-dimethyl-2-oxo-2,3-
~ dihydro-benzoxazol-6-ylmethyl)-2-oxo-
(300) o ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
I N-CNx -y \ N olõ benzodiazepin-3-yl)-piperidine-1-
H40 carboxylate
o (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
-(' benzoxazol-6-ylmethyl)-2-[1'-(2-
\ ethoxycarbonyl-ethyl)-4,4'-bipiperidinyl-1-
(301) yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-
I ~ -CNo'Y"~;%~i,N~L ~ 1,3-benzodiazepin-3-yl)-piperidine-l-
e
H 0 carboxylate
o (R)-2-[1'-(2-carboxy-ethyl)-4,4'-
N' bipiperidinyl-1-yl]-1-(3,4-dimethyl-2-oxo-
~ 2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-
(302) o ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
I ~~Nxo"\~N,-,,)~o=" benzodiazepin-3-yl)-piperidine-l-
carboxylate
H H
o (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
-~( benzoxazol-6-ylmethyl)-2-{4-[1-(2-
~
ethoxycarbonyl-ethyl)-piperidin-4-yl]-
(303) o o piperazin-1-yl}-2-oxo-ethyl 4-(2-oxo-
k N-( Nxo~N 1,2,4,5-tetrahydro-l,3-benzodiazepin-3-
H'~o ~/ yl)-piperidine-l-carboxylate
(R)-2-{4-[1-(2-carboxy-ethyl)-piperidin-4-
4 yl]-piperazin-1-yl}-1-(3,4-dimethyl-2-oxo-
~
2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-
(304) o ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
~ ~N-{~~//NI O~"~N ~~o H benzodiazepin-3-yl)-piperidine-1-
H 0 carboxylate
o (R)-1-( 3, 4-d i methyl-2-oxo-2, 3-d ihydro-
f( benzoxazol-6-ylmethyl)-2-{4-[4-(2-
~
ethoxycarbonyl-ethyl)-piperazin-1-yl]-
305 0
( ) o piperidin-1-yl}-2-oxo-ethyl4-(2-oxo-
I tCNxo'y"~ ~N.~_Ko"~ 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
H 0 0 yl)-piperidine-1 -carboxylate

CA 02565219 2006-10-17 -99-
Structure Name
(R)-2-{4-[4-(2-carboxy-ethyl)-piperazin-1-
-~ yl]-piperidin-1-yl}-1-(3,4-dimethyl-2-oxo-
" 2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-
(306) \ ' o ethyl 4-(2-oxo-1,2,4,5-tetrahydro-l,3-
I "~-~" o " benzodiazepin-3-yl)-piperidine-1-
" 0 carboxylate
~ (R)-1 -(3,4-dimethyl-2-oxo-2, 3-dihyd ro-
N benzoxazol-6-ylmethyl)-2-[1'-(3-
~ ' ethoxycarbonyl-propionyl)-4,4'-
N bipiperidinyl-1-yl]-2-oxo-ethyl 4-(2-oxo-
(307) ~~NXo; o yN~~ f ~ 'O
"' " 1 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
" 0 yl)-piperidine-1-carboxylate
( R)-2-[1'-( 3-carboxy-propionyf )-4, 4'-
0
bipiperidinyl-1-yl]-1-(3,4-dimethyl-2-oxo-
2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-
(308) \ ~ N~ ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
I "~-~" o ~=~" " benzodiazepin-3-y1)-piperidine-1-
" 0 carboxylate
0 (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
benzoxazol-6-ylmethyl)-2-{4-[4-(3-
~ ethoxycarbonyl-propionyl)-piperazin-1-yl]-
(309) N N' o'~"~,"~ ~o ~ 'o piperidin-1-yl}-2-oxo-ethyl4-(2-oxo-
'"' ~' o ~ 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
~ o ~
" o yl)-piperidine-l-carboxylate
o (R)-2-{4-[4-(3-carboxy-propionyl)-
-~' piperazin-1-yl]-piperidin-1-yl}-1-(3,4-
" dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-
/
(310) CQ =N ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
N-CN o'y i~1N~ " tetrahydro-1,3-benzodiazepin-3-yl)-
Ho o piperidine-1-carboxylate
o (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
N benzoxazol-6-ylmethyl)-2-{4-[1-(3-
~ ' ethoxycarbonyl-propionyl)-piperidin-4-yl]-
(311) N N '~"i N ~~_o piperazin-1-yl}-2-oxo-ethyl 4-(2-oxo-
~ o ' " lof ~ 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
" 0 yl)-piperidine-1-carboxylate
(R)-2-{4- [1 -(3-ca rboxy-p ro pio nyl)-pi perid in-
4-yl]-piperazin-1-yl}-1-(3,4-dimethyl-2-oxo-
" 2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-
(312) -Y"~ o ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
~~ N~N o'iN ~N~~ " benzodiazepin-3-yl)-piperidine-1-
q''o 0 0 carboxylate

CA 02565219 2006-10-17
-100-
Structure Name
o (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
N' benzoxazol-6-yfinethyl)-2-(1'-
H hydroxycarbamoylmethyl-4,4'-bipiperidinyl-
(313) o 1-yI)-2-oxo-ethyl4-(2-oxo-1,2,4,5-
I ~ -~"o ~N H tetrahydro-1,3-benzodiazepin-3-yl)-
H o piperidine-1-carboxylate
o (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
N' benzoxazol-6-ylmethyl)-2-{1'-[(hydroxy-
methyl-carbamoyl)-methyl]-4,4'-
(314) )' o=H bipiperidinyl-1-yi}-2-oxo-ethyl4-(2-oxo-
I ~ ~N o'1~ N'~"~ 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
H 0 yI)-piperidine-1-carboxylate
(R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
N benzoxazol-6-ylmethyl)-2-[1'-
(methoxycarbamoyl-methyl)-4,4'-
(315) \ ~ o bipiperidinyl-1-yl]-2-oxo-ethyl4-(2-oxo-
I N-CN 0~l,N'YN.H 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
H'~ 0 yI)-piperidine-l-carboxyfate
0 (R)-1-(8-methyl-2-oxo-1,2-dihydro-
NH quinolin-6-yfinethyl)-2-[4-(4-methyl-
(316) o piperazin-1 -yl)-piperidin-1 -yl]-2-oxo-ethyl
N--CNxo'yN~,N.~ 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
H-~o azepin-3-yl)-piperidine-1 -carboxylate
(R)-1-(8-methyl-2-oxo-1,2-dihydro-
, NH quinofin-6-ylmethyl)-2-[4-(1-methyl-
(317) / o piperidin-4-yf)-piperazin-1-yl]-2-oxo-ethyl
N-( Nxoj "4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
H-~o ~/ o azepin-3-yl)-piperidine-1 -carboxylate
o (R)-2-(1'-methyl-4,4'-bipiperidinyl-1-yl)-1-
NH (8-methyl-2-oxo-1,2-dihydro-quinolin-6-yl-
~ methyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
tetrahydro-1,3-benzodiazepin-3-yl)-
(318) ~ x yN~~~ N
H-~N N o o ' piperidine-1-carboxyfate
O (R)-1-(8-methyl-2-oxo-1,2-dihydro-
NH quinolin-6-yfinethyl)-2-oxo-2-(4-piperazin-
~ 1-yl-piperidin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-
(319) C ~tetrah dro-1,3-benzodiaze in-3- I
II N~NOH Y P Y)
~~ N~ o piperidine-1-carboxyfate
H O
o (R)-1-(8-methyl-2-oxo-1,2-dihydro-
NH quinofin-6-yfinethyl)-2-oxo-2-(4-piperidin-4-
(320) / 0 yl-piperazin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-
I N-( NxO~ ~N H tetrahydro-1,3-benzodiazepin-3-yl)-
"4 ~~JJ 0 piperidine-1-carboxyfate
H 0

CA 02565219 2006-10-17
-101-
Structure Name
o (R)-2-4,4'-bipiperidinyl-1-yl-1-(8-methyl-2-
NH oxo-1,2-dihydro-quinolin-6-ylmethyl)-2-
(321) oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
N4 benzodiazepin-3-yl)-piperidine-1-
I ~NJIo: o YN~-"
" carboxylate
H O
o (R)-2-1,4'-bipiperidinyl-1'-yl-1-(8-methyl-2-
/ NH oxo-1,2-dihydro-quinolin-6-ylmethyl)-2-
(322) = oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
C ~IN~N benzodiazepin-3-yl)-piperidine-1-
" o '~ carboxylate
H O
ZN o (R)-1-(8-methyl-2-oxo-1,2-dihydro-
, H quinolin-6-ylmethyl)-2-(4-morpholin-4-yl-
(323) pi peridin-1-yl)-2-oxo-ethyl 4-(2-oxo-
I\ N-( NxO~N~ N~ 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
N4 ~--~ -J1 o '~O yl)-piperidine-1 -carboxylate
H O
(R)-1-(8-methyl-2-oxo-1,2-dihydro-
~ quinolin-6-ylmethyl)-2-oxo-2-[4-
NH tetrah dro- ran-4- I i erazin-1- I
( Y pY Y)-P p Y ]-
(324) CCN N~ ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
--CN '~ /'N~benzodiazepin-3-yl)-piperidine-1-
H H 0 carboxylate
o (R)-2-(4-cyclohexyl-piperazin-1-yl)-1-(8-
NH methyl-2-oxo-1,2-dihydro-quinolin-6-yl-
(325) methyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
~ JL tetrahydro-1,3-benzodiazepin-3-yl)-
" N o
opiperidine-1 -carboxylate
CrN4
H O
o (R)-2-(4-hydroxy-1,4'-bipiperidinyl-1'-yl)-1-
NH (8-methyl-2-oxo-1,2-dihydro-quinolin-6-yl-
~ methyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(326) CC "~N~oN~N o" tetrahydro-1,3-benzodiazepin-3-yl)-
"0 ~' piperidine-1 -carboxylate
H O
o (R)-2-(4-methoxy-1,4'-bipiperidinyl-1'-yl)-1-
, NH (8-methyl-2-oxo-1,2-dihydro-quinolin-6-yl-
~ methyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(327) CQ N Nx O~"~" tetrahydro-1,3-benzodiazepin-3-yl)-
N~ o '~ piperidine-1 -carboxylate
H O
o (R)-2-(4-hydroxy-4-methyl-1,4'-
NH bipiperidinyl-1'-yl)-1-(8-methyl-2-oxo-1,2-
~ dihydro-quinolin-6-ylmethyl)-2-oxo-ethyl 4-
(32$) ~ ~l N N oH (2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
I~ N~" N o~ ~ '~' azepin-3-yl)-piperidine-1-carboxylate
H 0

. = CA 02565219 2006-10-17
-102-
Structure Name
(R)-2-(4,4-dimethyl-1,4'-bipiperidinyl-1'-yl)-
NH 1-(8-methyl-2-oxo-1,2-dihydro-quinolin-6-
. yimethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(32g) NN'x0-(N tetrahydro-1,3-benzodiazepin-3-yl)-
N~( ~~~JJJ o piperidine-1 -carboxylate
H \\O
, o (R)-2-(4-amino-4-methyl-1,4'-bipiperidinyl-
, NH 1'-yl)-1-(8-methy)-2-oxo-1,2-dihydro-
(330) ' quinolin-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-
al~-CNIO N\./'" "H2 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
N~o ''~~ yl)-piperidine-1-carboxylate
H O
o (R)-2-(4-hydroxy-4-hydroxymethyl-1,4'-
NH bipiperidinyl-1'-yl)-1-(8-methyl-2-oxo-1,2-
~ dihydro-quinolin-6-ylmethyl)-2-oxo-ethyi 4-
(331) " NxoyN~,N (2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
N4 -C 0 OHo" azepin-3-yi)-piperidine-l-carboxylate
H O
, o (R)-2-(1'-ethoxycarbonylmethyl-4,4'-
~ NH bipiperidinyl-1-y!)-1-(8-methyl-2-oxo-1,2-
(332) dihydro-quinolin-6-ylmethyl)-2-oxo-ethyI 4-
NJI:~No (2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
N
~ o azepin-3-yl)-piperidine-1-carboxylate
02)
~
H O
o (R)-2-(1'-carboxymethyl-4,4'-bipiperidinyi-
NH 1-yl)-1-(8-methyl-2-oxo-1,2-dihydro-
(333) quinolin-6-ylmethyl)-2-oxo-ethyI 4-(2-oxo-
I~ N~Nxo'~0 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
o 0 " yl)-piperidine-1-carboxylate
H O
, o (R)-1-(1,8-dimethyl-2-oxo-1,2-dihydro-
, N~ quinolin-6-ylmethyl)-2-[4-(4-methyl-
(334) piperazin-1-yl)-piperidin-1-ylJ-2-oxo-ethyl
~~N)Io;~N~yN~ 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
N o azepin-3-yl)-piperidine-1-carboxylate
H 0
(R)-1-(1,8-dimethyl-2-oxo-1,2-dihydro-
, quinolin-6-ylmethyl)-2-[4-(1-methyl-
~ piperidin-4-yl)-piperazin-1-yl}-2-oxo-ethyl
(335) % "~"xo "~ 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
H~ o ~" azepin-3-yl)-piperidine-1-carboxylate
, o (R)-1-(1,8-dimethyl-2-oxo-1,2-dihydro-
, N, quinolin-6-ylmethyl)-2-(1'-methyl-4,4'-
~ ~ bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-
(336) N-CNo'1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
N4 yl)-piperidine-l-carboxylate
" 0

CA 02565219 2006-10-17
-103-
Structure Name
~ o (R)-1-(1,8-dimethyl-2-oxo-1,2-dihydro-
~ N~ quinolin-6-ylmethyl)-2-oxo-2-(4-piperazin-
. ~ 1
N N -yl-piperidin-1-yl)-ethyf 4-(2-oxo-1,2,4,5-
(337) ~C ~~ O =~N tetrahYdro-1,3-benzodiazep in-3-YI)-
I~ ~~N~-/~
N o '~" H piperidine-1 -carboxylate
H O
~ o (R)-1-(1,8-dimethyl-2-oxo-1,2-dihydro-
~ N, quinolin-6-ylmethyl)-2-oxo-2-(4-piperidin-4-
~ ~ yi-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-
(338) N-CNxo'~ tetrahydro-1,3-benzodiazepin-3-yl)-
N~ o piperid ine- 1 -ca rboxylate
H O
~ o (R)-2-4,4'-bipiperidinyl-1-y1-1-(1,8-
~ N, dimethyl-2-oxo-1,2-dihydro-quinolin-6-
~ ~ ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(339) a,-0Y N-~ N~oN~;'~N," tetrahydro-l,3-benzodiazepin-3-yl)-
"~ piperidine-1 -carboxylate
H O
~ o (R)-2-1,4'-bipiperidinyl-1'-yI-1-(1,8-
~ N, dimethyl-2-oxo-1,2-dihydro-quinolin-6-
~ ~ ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(340) N--~N~o'yN~N tetrahydro-1,3-benzodiazepin-3-yl)-
N~ o ' piperidine-l-carboxylate
H O
~ o (R)-1-(1,8-dimethyl-2-oxo-1,2-dihydro-
~ N, quinolin-6-ylmethyl)-2-(4-morpholin-4-yl-
(341) 0 piperidin-1-yl)-2-oxo-ethyl 4-(2-oxo-
j )L N N N'~~ 1,2,4,5-tetrahydro-l,3-benzodiazepin-3-
" ~ ~ O yI)-piperidine-l-carboxylate
H O
(R)-1-(1, 8-dimethyl-2-oxo-1, 2-dihyd ro-
~ quinolin-6-ylmethyl)-2-oxo-2-[4-
" tetrahYdro-PYran-4-YI)-Pi perazin-1-YIl-
' ~ ~
(
(342) ~ ethyl4-(2-oxo-1,2,4,5-tetrahydro-l,3-
I 4N-~" benzodiazepin-3-yl)-piperidine-l-
H o carboxylate
~ o (R)-2-(4-cyclohexyl-piperazin-1-yl)-1-(1,8-
~ N, dimethyl-2-oxo-1,2-dihydro-quinolin-6-yl-
(343) methyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
I ~"JIo,yN ~" tetrahydro-1,3-benzodiazepin-3-yl)-
N~ o ~ piperidine-1 -carboxylate
H O
~ o (R)-1-(1,8-dimethyl-2-oxo-1,2-dihydro-
~ N, quinolin-6-ylmethyl)-2-(4-hydroxy-1,4'-
~ ~ bipiperidinyl-1'-yl)-2-oxo-ethyl 4-(2-oxo-
~N ~,N oH 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
(344) al]N--CNIO-~
No '~' yl)-piperidine-1-carboxylate
H 0

CA 02565219 2006-10-17
- 104 -
Structure Name
, o (R)-1-(1,8-dimethyl-2-oxo-1,2-dihydro-
~ N, quinolin-6-ylmethyl)-2-(4-methoxy-1,4'-
~ ~ bipiperidinyi-1'-yi)-2-oxo-ethyl 4-(2-oxo-
(345) N-CNo~N~ N o~ 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
N4 o yl)-piperidine-1 -carboxylate
H O
~ 0 (R)-1-(1,8-dimethyl-2-oxo-1,2-dihydro-
~ N_ quinolin-6-ylmethyl)-2-(4-hydroxy-4-
(346) methyl-1,4'2 ipiperidinyl-1'-yl)-2-oxo-ethyl
4-(2-oxo-1, ,4,5-tetrahydro-1,3-benzodi-
x N OH
I N oo ~ azepin-3-yl)-piperidine-l-carboxylate
N
H O
, 0 (R)-2-(4,4-dimethyl-1,4'-bipiperidinyl-1'-yl)-
N, 1-(1,8-dimethyl-2-oxo-1,2-dihydro-quinolin-
6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(347) ~ ~ ~N~N tetrahydro-1,3-benzodiazepin-3-yl)-
~ N~" N o 0 ' piperidine-l-carboxylate
H O
o (R)-2-(4-amino-4-methyl-1,4'-bipiperidinyl-
1'-yl )-1-(1, 8-dimethyl-2-oxo-1,2-dihyd ro-
~ quinolin-6-yfinethyl)-2-oxo-ethyl 4-(2-oxo-
(348) CC N Nxo~N~N NH2 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
~ o ~ yl)-piperidine-l-carboxylate
H O
(R)-1-(1,8-dimethyl-2-oxo-1,2-dihydro-
quinolin-6-ylmethyl)-2-(4-hydroxy-4-
~ "' hydroxymethyl-1,4'-bipiperidinyl-1'-yl)-2-
(349) ~ = N oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
N~N o'~ ~.N\,~oH benzodiazepin-3-yl)-piperidine-l-
' H'~ oH carboxylate
(R)-1-(1, 8-dimethyl-2-oxo-1, 2-dihydro-
quinolin-6-ylmethyl)-2-(1'-
~ ethoxycarbonylmethyl-4,4'-bipiperidinyl-l-
(350) o yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-
CC N~N O~"\N'~(el 1,3-benzodiazepin-3-yl)-piperidine-1-
H'o carboxylate
~ o (R)-2-(1'-carboxymethyl-4,4'-bipiperidinyl-
~ N, 1-yl)-1-(1,8-dimethyl-2-oxo-1,2-dihydro-
(351) quinolin-6-ylmethyl)-2-oxo-ethyi 4-(2-oxo-
J~ N a~ 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
''% V'N H yl)-piperidine-1 -carboxylate
I~ N,,
H \~( ~" p o
O
o (R)-1-(5-methyl-3, 4-dihydro-2H-1,4-
NH benzoxazin-7-ylmethyl)-2-[4-(4-methyl-
352 = piperazin-1 -yl)-piperidin-1-yl]-2-oxo-ethyl
( ) \ Jl N N~ , 4-(2 oxo 1,2,4,5-tetrahydro-l,3-benzodi
I' ~~ N~"~N 0 ~o '~" azepin-3-yl)-piperidine-1 -carboxylate
H 0

CA 02565219 2006-10-17
-105-
Structure Name
o (R)-1-(5-methyl-3,4-dihydro-2H-1,4-
~NH benzoxazin-7-ylmethyl)-2-[4-(1-methyl-
(353) piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl
/~ k N ~ " 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
N~ oJ" o-
azepin-3-yl)-piperidine-1-carboxylate
H 0
o,l (R)-2-(1'-methyl-4,4'-bipiperidinyl-1-yl)-1-
NH (5-methyl-3,4-dihydro-2H-1,4-benzoxazin-
~ ~ 7-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(354) C = N " tetrahydro-1,3-benzodiazepin-3-yl)-
"~" " o o ~%~''' piperidine-1 -carboxylate
H O
o--) (R)-1-(5-methyl-3,4-dihydro-2H-1,4-
, NH benzoxazin-7-ylmethyl)-2-oxo-2-(4-
355 0 piperazin-1-yl-piperidin-1-yl)-ethyl 4-(2-
( ) x~ N~ N~ H oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
N4" N o 0 3-yl)-piperidine-1 -carboxylate
H 0
o,, (R)-1-(5-methyl-3,4-dihydro-2H-1,4-
/ NH benzoxazin-7-ylmethyl)-2-oxo-2-(4-
piperidin-4-yl-piperazin-1-yl)-ethyl 4-(2-
(356) CC N~"kO;~N~N H oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
"0 = "o ~" 3-yl)-piperidine-1-carboxylate
H 0
o (R)-2-4,4'-bipiperidinyl-l-yi-1-(5-methyl-
NH 3,4-dihydro-2H-1,4-benzoxazin-7-
~ ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(357) N-CN)~0'7'YN\~ ,H tetrahydro-1,3-benzodiazepin-3-yl)-
"4 o " piperidine-1 -carboxylate
H O
o,, (R)-2-1,4'-bipiperidinyl-1'-yI-1-(5-methyl-
NH 3,4-dihydro-2H-1,4-benzoxazin-7-
~ ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(358) ;~N "~ tetrahydro-1,3-benzodiazepin-3-yl)-
N~" " o o piperidine-1 -carboxylate
H 0
(R)-1-(5-methyl-3,4-dihydro-2H-1,4-
NH benzoxazin-7-ylmethyl)-2-(4-morpholin-4-
~ ~ yl-piperidin-1-yl)-2-oxo-ethyl 4-(2-oxo-
(359) CQ ~"~"~ 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
"~" o o '''~ yl)-piperidine-l-carboxylate
H 0
(R)-1-(5-methy!-3,4-dihydro-2H-1,4-
0'1 benzoxazin-7-ylmethyl)-2-oxo-2-[4-
~ "" (tetrahydro-pyran-4-yl)-piperazin-1-yl]-
(360) ~ ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
I N-C" Z01("! N~ benzodiazepin-3-yl)-piperidine-1-
H"' carboxylate

CA 02565219 2006-10-17
-106-
Structure Name
o., (R)-2-(4-cyclohexyl-piperazin-1-yl)-1-(5-
NH methyl-3,4-dihydro-2H-1,4-benzoxazin-7-
~ ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(361) N-~Nxo N~ tetrahydro-1,3-benzodiazepin-3-yl)-
N4 o , "~ piperidine-1 -carboxylate
H O
(R)-2-(4-hydroxy-1,4'-bipiperidinyl-1'-yi)-1-
H (5-methyl-3,4-dihydro-2H-1,4-benzoxazin-
~ 7-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(362) ~~ tetrahydro-1,3-benzodiazepin-3-yI)-
N N O~ OH
N-.~ O piperidine-1-carboxylate
H O
o--) (R)-2-(4-methoxy-1,4'-bipiperidinyl-1'-yI)-1-
NH (5-methyl-3,4-dihydro-2H-1,4-benzoxazin-
~ 7-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(363) N-CNxoy NVy o\ tetrahydro-1,3-benzodiazepin-3-yi)-
N~ 0 piperidine-1 -carboxylate
H O
(R)-2-(4-hydroxy-4-methyl-1,4'-
NH bipiperidinyl-1'-yl)-1-(5-methyl-3,4-dihydro-
~ 2H-1,4-benzoxazin-7-ylmethyl)-2-oxo-ethyl
(364) N--~Nxoy"~N o" 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
N~ o '' azepin-3-yl)-piperidine-1-carboxylate
H O
o") (R)-2-(4,4-dimethyl-1,4'-bipiperidinyl-1'-yl)-
NH 1-(5-methyl-3,4-dihydro-2H-1,4-
. benzoxazin-7-ylmethyl)-2-oxo-ethyl 4-(2-
(365) N-CNxoN~ N oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
N.~ '-'~ 3-yi)-piperidine-1-carboxylate
H O
o,, (R)-2-(4-amino-4-methyl-1,4'-bipiperidinyl-
NH 1'-yI)-1-(5-methyl-3,4-dihydro-2H-1,4-
~ benzoxazin-7-ylmethyl)-2-oxo-ethyl 4-(2-
(366) N~ N oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
N o '~' NHZ 3-yi)-piperidine-1-carboxylate
H 0
(R)-2-(4-hydroxy-4-hydroxymethyl-1,4'-
NH bipiperidinyl-1'-yI)-1-(5-methyl-3,4-dihydro-
(367) ' 2H-1,4-benzoxazin-7-ylmethyl)-2-oxo-ethyi
Jl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
N
I~ o'~~o"
N azepin-3-yi)-piperidine-1-carboxylate
H O
o,l (R)-2-(1'-ethoxycarbonylmethyl-4,4'-
t NH bipiperidinyl-1-yi)-1-(4-ethylamino-3-
methoxy-5-methyl-benzyl)-2-oxo-ethyl 4-
(368) Jl N o (2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
"4"-CN o o~~,'C'''N1( azepin-3-yl)-piperidine-1-carboxylate
H 0

CA 02565219 2006-10-17
-107-
Structure Name
(R)-2-(1'-carboxymethyl-4,4'-bipiperidinyl-
~NH 1-yl)-1-(5-methyl-3,4-dihydro-2H-1,4-
. benzoxazin-7-ylmethyl)-2-oxo-ethyl 4-(2-
(369) Nx0'~"~ oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
0 3-yl)-piperidine-1 -carboxylate
H O
o (R)-1-(8-methyl-2,3-dihydro-1,4-
o benzodioxin-6-ylmethyl)-2-[4-(4-methyl-
piperazin-1 -yl)-piperidin-1 -yl]-2-oxo-ethyl
(370) 0 _
CC4 N~NJIo,y N,4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
No azepin-3-yl)-piperidine-1-carboxylate
-carboxylate
H O
(R)-1-(8-methyl-2,3-dihydro-1,4-
~ benzodioxin-6-ylmethyl)-2-[4-(1-methyl-
371 0 piperidin-4-yl)-piperazin-1-yi]-2-oxo-ethyl
( ) CC N-CNJIo N 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
No azepin-3-yl)-piperidine-1 -carboxylate
H O
l (R)-2-(1'-methyl-4,4'-bipiperidinyt-1-yl)-1-
o (8-methyl-2, 3-dihydro-1,4-benzodioxin-6-
~ ~ ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(372) N-CNxo'~N~N tetrahydro-1,3-benzodiazepin-3-yl)-
o piperidine-l-carboxylate
H O
(R)-1-(8-methyl-2,3-dihydro-1,4-
o benzodioxin-6-yimethyl)-2-oxo-2-(4-
piperazin-1-yl-piperidin-1-yl)-ethyl 4-(2-
(373) o CC N--CNxo'~N~ H oxo-1,2,4,5-tetrahydro-l,3-benzodiazepin-
"0 '~" 3-yl)-piperidine-1 -carboxylate
H O
o (R)-1-(8-methyl-2,3-dihydro-1,4-
benzodioxin-6-ylmethyl)-2-oxo-2-(4-
0 piperidin-4-yl-piperazin-1-yl)-ethyl 4-(2-
(374) NNxO N./\ N H oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
I N~ ~~~Jll o 3-yl)-piperidine-1-carboxyiate
H 0
o (R)-2-4,4'-bipiperidinyl-1-yl-1-(8-methyl-
0 2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-
375) _ oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
( N~NJIoY N\_ ,H benzodiazepin-3-yl)-piperidine-1-
~ 0 " carboxylate
H O
o (R)-2-1,4'-bipiperidinyl-1'-yl-1-(8-methyl-
0 2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-
376 0 oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
( ) N~NJIo:,yN~ benzodiazepin-3-yl)-piperidine-1-
N4 o carboxylate
H 0

CA 02565219 2006-10-17
-108-
Structure Name
(R)-1-(8-methyl-2,3-dihydro-1,4-
~~o benzodioxin-6-ylmethyl)-2-(4-morpholin-4-
(377) - ~ yl-piperidin-1-yi)-2-oxo-ethyi 4-(2-oxo- tetrahy
benz N~ ~Nx o N~ '_~O yl)-piperid ne-1~ arboxy ateodiazepin-3-
H O
(R)-1-(8-methyl-2,3-dihydro-1,4-
benzodioxin-6-ylmethyl)-2-oxo-2-[4-
~ (tetrahydro-pyran-4-yl)-piperazin-1-yl]-
(378) ~ ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
~N o' benzodiazepin-3-yl)-piperidine-1-
I ~ ~
H 0 carboxylate
,) (R)-2-(4-cyclohexyl-piperazin-1-yl)-1-(8-
o methyl-2,3-dihydro-1,4-benzodioxin-6-yl-
~ methyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(379) j~o. tetrahydro-1,3-benzodiazepin-3-yl)-
NQ -CN o piperidine-1 -carboxylate
H
,) (R)-2-(4-hydroxy-1,4'-bipiperidinyi-1'-yl)-1-
o (8-methyi-2,3-dihydro-1,4-benzodioxin-6-
~ ylmethyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-
(380) N~N~o'-N~,N oH tetrahydro-1,3-benzodiazepin-3-yl)-
N4 o '' piperidine-1 -carboxylate
H 0
(R)-2-(4-methoxy-1,4'-bipiperidinyl-1'-yl)-1-
0 (8-methyl-2,3-dihydro-1,4-benzodioxin-6-
~ ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(381) % N~N~o'~N1,N tetrahydro-1,3-benzodiazepin-3-yl)-
N~ 0 piperidine-1 -carboxylate
H O
o (R)-2-(4-hydroxy-4-methyl-1,4'-
0 bipiperidinyl-1'-yl)-1-(8-methyl-2,3-dihydro-
~. 1,4-benzodioxin-6-ylmethyl)-2-oxo-ethyl 4-
(382) CC] N~NIo~,N~N oH (2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
0 '~' azepin-3-yl)-piperidine-1-carboxylate
H 0
, ) (R)-2-(4,4-dimethyl-1,4'-bipiperidinyl-1'-yl)-
0 1-(8-methyl-2,3-dihydro-1,4-benzodioxin-
~ 6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(383) N Nxo'~N~N tetrahydro-1,3-benzodiazepin-3-yl)-
N4~ o piperidine-1 -carboxylate
H O
~ (R)-2-(4-amino-4-methyl-1,4'-bipiperidinyl-
0 1'-yl)-1-(8-methyl-2,3-dihydro-1,4-
~ benzodioxin-6-ylmethyl)-2-oxo-ethyl 4-(2-
(384) N~N)(o~~J NH= oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
N~( 0 ' 3-yl)-piperidine-1-carboxylate
H 0

CA 02565219 2006-10-17
-109-
Structure Name
.l (R)-2-(4-hydroxy-4-hydroxymethyl-1,4'-
0 bipiperidinyl-1'-yl)-1-(8-methyl-2,3-dihydro-
0- ~ 1,4-benzodioxin-6-ylmethyl)-2-oxo-ethyl 4-
(385) "~"xo;-yN~y"/~ (2-oxo-1,2,4, Y
5-tetrah dro-1,3-benzodi-
H-~o 0 OH H azepin-3-yl)-piperidine-1-carboxylate
o (R)-2-(1'-ethoxycarbonylmethyl-4,4'-
0 bipiperidinyl-1-yl)-1-(8-methyl-2,3-dihydro-
(386) 0 1,4-benzodioxin-6-ylmethyl)-2-oxo-ethyl 4-
I N NxO~"~~ 0 (2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
H~(~ o 0 azepin-3-yl)-piperidine-1-carboxylate
o") (R)-2-(1'-carboxymethyl-4,4'-bipiperidinyl-
1-yI)-1-(8-methyl-2, 3-d ihyd ro-1, 4-
~ benzodioxin-6-ylmethyl)-2-oxo-ethyl 4-(2-
(387) C~. N Nx ~"~, oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
~ 0 "~ " 3-yI)-piperidine-l-carboxylate
H 0
o (R)-1-(2,3-dihydro-1,4-benzodioxin-6-
~ o ylmethyl)-2-[4-(4-methyl-piperazin-1-yl)-
(388) o - piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-
I N~NJIo~N/yN- ~ 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
N 0 '~" yl)-piperidine-1-carboxylate
H O
o,l (R)-1-(2,3-dihydro-1,4-benzodioxin-6-
0 ylmethyl)-2-[4-(1-methyl-piperidin-4-yl)-
389 0 = piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-
( ) N~NJIo~N~",~ ~ 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
N~ 0 " yI)-piperidine-1-carboxylate
H O
o (R)-1-(2,3-dihydro-1,4-benzodioxin-6-
o ylmethyl)-2-(1'-methyl-4,4'-bipiperidinyl-1-
. yi)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
(390) CC~ ~ ~ o N 1,3-benzodiazepin-3-yl)-piperidine-l-
o ~%~ ' carboxylate
""
te
H 0
o') (R)-1-(2,3-dihydro-1,4-benzodioxin-6-
o ylmethyl)-2-oxo-2-(4-piperazin-1-yl-
(391) _ piperidin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-
I "-CN~Lo~N~N~ ,H tetrahydro-1,3-benzodiazepin-3-yl)-
N4 0 ''~" piperidine-1 -carboxylate
H 0
o,) (R)-1-(2,3-dihydro-1,4-benzodioxin-6-
~ o ylmethyl)-2-oxo-2-(4-piperidin-4-yl-
(392) _ ' piperazin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-
I "~" J2o~ N ~ tetrahydro-1,3-benzodiazepin-3-yl)-
N4 0 "~H
piperidine-1 -carboxylate
H 0

CA 02565219 2006-10-17
- 110-
Structure Name
0 0 (R)-2-4,4'-bipiperidinyl-1-yl-1-(2,3-dihydro-
\ I 1,4-benzodioxin-6-ylmethyl)-2-oxo-ethyl 4-
(393) ~ ~ (2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
I~ ~ N o o" azepin-3-yl)-piperidine-l-carboxylate
N
H O
o (R)-2-1,4'-bipiperidinyl-1'-y1-1-(2,3-dihydro-
1 1,4-benzodioxin-6-ylmethyi)-2-oxo-ethyi 4-
(394) o - (2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
I ~~No~l("~-" azepin-3-yl)-piperidine-1 -carboxylate
N 0
H
(R)-1-(2,3-dihydro-1,4-benzodioxin-6-
o ylmethyl)-2-(4-morpholin-4-yl-piperidin-1-
~ yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
(395) "~Nxo N N~ 1,3-benzodiazepin-3-yl)-piperidine-1-
N~ o ~ '~O carboxylate
H
(R)-1-(2,3-dihydro-1,4-benzodioxin-6-
Jo ylmethyl)-2-oxo-2-[4-(tetrahydro-pyran-4-
~~ yl)-piperazin-1-yl]-ethy! 4-(2-oxo-1,2,4,5-
(396) "~NxO'Y"i tetrahydro-1,3-benzodiazepin-3-yl)-
N,(, 0 piperidine-1 -carboxylate
H
(R)-2-(4-cyclohexyi-piperazin-1-yl)-1-(2,3-
~ o dihydro-1,4-benzodioxin-6-ylmethyl)-2-
397) o oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
( Jl benzodiazepm 3 yl)-piperidine-l-
I N~( ~" o ocarboxylate
H O
(R)-1-(2, 3-dihydro-1, 4-benzodioxin-6-
~ o ylmethyl)-2-(4-hydroxy-1,4'-bipiperidinyl-1'-
~ yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
(398) "~"~loy N\~N o" 1,3-benzodiazepin-3-yl)-piperidine-l-
N4 o '~' carboxylate
H
(R)-1-(2,3-dihydro-1,4-benzodioxin-6-
~,o ylmethyl)-2-(4-methoxy-1,4'-bipiperidinyl-
~ 1'-yI)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(399) "~"JIo:~N~N tetrahydro-1,3-benzodiazepin-3-y!)-
N4 o piperidine-l-carboxylate
H
(R)-1-(2,3-dihydro-1,4-benzodioxin-6-
~o ylmethyl)-2-(4-hydroxy-4-methyl-1,4'-
~ I bipiperidinyl-1'-yI)-2-oxo-ethyi 4-(2-oxo-
(400) "-CNxooH 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
N4 o yl)-piperidine-1 -carboxylate
H 0

CA 02565219 2006-10-17
-111-
Structure Name
(R)-1-(2,3-dihydro-1,4-benzodioxin-6-
~ o ylmethyl)-2-(4,4-dimethyl-1,4'-bipiperidinyl-
~ ~ 1'-y!)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(401) N-~N~o~N~ tetrahydro-l,3-benzodiazepin-3-yl)-
N {~ o piperidine-1-carboxylate
H O
o.~ (R)-2-(4-amino-4-methyl-1,4'-bipiperidinyl-
~ 0 1'-yl)-1-(2,3-dihydro-1,4-benzodioxin-6-y1-
(402) methyl)-2-oxo-ethyi 4-(2-oxo-1,2,4,5-
I "1lo~N/~" "HZ tetrahydro-1,3-benzodiazepin-3-yl)-
N4~ piperidine-l-carboxylate
H O
(R)-1-(2,3-dihydro-1,4-benzodioxin-6-
~ o ylmethyl)-2-(4-hydroxy-4-hydroxymethyl-
1,4'-bipiperidinyl-1'-yl)-2-oxo-ethyl 4-(2-
(403) ~ y N~ oxo-1,2,4,5-tetrahydro-1,
N o " 3-benzodiazepin-
"~
o o" 3-yl)-piperidine-1-carboxylate
"4
(R)-1-(2,3-dihydro-1,4-benzodioxin-6-
~, o yfinethyl)-2-(1'-ethoxycarbonylmethyl-4,4'-
~. ~ bipiperidinyl-1-yl)-2-oxo-ethyl 4-(2-oxo-
(404) N NxO"~;'~ 0 1 ,2,4,5-tetrahydro-1,3-benzodiazepin-3-
~ o "~ yl)-piperidine-1-carboxyfate
H O
o., (R)-2-(1'-carboxymethyl-4,4'-bipiperidinyl-
, 0 1-yl)-1-(2,3-dihydro-1,4-benzodioxin-6-
(405) ~I ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
N N~O~( tetrahydro-1,3-benzodiazepin-3-yl)-
~ ~ piperidine-1-carboxyiate
H O
o (R)-1-(7-methyl-2-oxo-2,3-dihydro-1 H-
"" NH benzimidazol-5-ylmethyl)-2-[4-(4-methyi-
~ iPerazin-l-YI)-PiPeridin-1-Y]I-2-oxo-ethY!
~
(406} P \ N~"x~N~N~ 4_(2_oxo-1,2,4,5-tetrahydro-1,3-benzodi-
~ "4 o azepin-3-yi)-piperidine-l-carboxylate
H o
o (R)-1-(7-methyl-2-oxo-2,3-dihydro-1 H-
"" NH benzimidazol-5-ylmethyl)-2-[4-(1-methyl-
(407) piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl
CC~"o Y ~" ~ 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
" o '" azepin-3-yi)-piperidine-1-carboxylate
" o
HN4O (R)-2-(1'-methyl-4,4'-bipiperidinyl-1-yl)-1-
NH (7-methyl-2-oxo-2,3-dihydro-1 H-
(408) benzimidazol-5-ylmethyl)-2-oxo-ethyl 4-(2-
alNN " oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
"~~o o ~N 3-yi)-piperidine-1-carboxylate
H 0

CA 02565219 2006-10-17
-112-
Structure Name
o (R)-1-( 7-methyl-2-oxo-2, 3-dihydro-1 H-
HN NH benzimidazol-5-ylmethyl)-2-oxo-2-(4-
(409) _ piperazin-1-yi-piperidin-1-yl)-ethyl 4-(2-
I ~ ~N,Lo~1,N~ oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
" O /'" 3-yl)-piperidine-1-carboxylate
H O
HN-~( (R)-1-( 7-methyl-2-oxo-2,3-dihydro-1 H-
NH benzimidazol-5-ylmethyl)-2-oxo-2-(4-
(410) piperidin-4-yl-piperazin-1-yl)-ethyl 4-(2-
k oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
I N-~ o H 3-yi)-piperidine-l-carboxylate
H O
o (R)-2-4,4'-bipiperidinyl-1-yI-1-(7-methyl-2-
HN NH oxo-2,3-dihydro-1 H-benzimidazol-5-
~ - ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(411) , ~ ~ " tetrahydro-1,3-benzodiazepin-3-yl)-
~ N~ " o ~'N " piperidine-l-carboxylate
H O
(R)-2-1,4'-bipiperidinyl-1'-yI-1-(7-methyl-2-
"" NH oxo-2,3-dihydro-1 H-benzimidazol-5-
(412) k ylmethyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-
" " tetrahydro-1,3-benzodiazepin-3-yl)-
I N~"~" o_ o~~ piperidine-1-carboxylate
H O
o (R)-1-(7-methyl-2-oxo-2,3-d ihyd ro-1 H-
HN NH benzimidazol-5-ylmethyl)-2-(4-morpholin-
(413) o 4-yl-piperidin-1-yl)-2-oxo-ethyl 4-(2-oxo-
x 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
~ N~"~" o o "~~o yI)-piperidine-1-carboxylate
H O
(R)-1-(7-methyl-2-oxo-2,3-dihydro-1 H-
HN NH benzimidazol-5-ylmethyl)-2-oxo-2-[4-(tetra-
(414) o I hydro-pyran-4-yl)-piperazin-1-yl]-ethyl 4-
k (2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
I N~~" o oazepin-3-yl)-piperidine-1-carboxyiate
H 0
O (R)-2-(4-cyclohexyl-piperazin-1-yl)-1-(7-
HN NH methyl-2-oxo-2,3-dihydro-1H-
(415) o _ benzimidazol-5-ylmethyl)-2-oxo-ethyI 4-(2-
X x N~ oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
I N"~" o o~"~ 3-yl)-piperidine-1-carboxylate
H O
O (R)-2-(4-hydroxy-1,4'-bipiperidinyl-1'-yI)-1-
HN NH (7-methyl-2-oxo-2,3-dihydro-1H-
~ benzimidazol-5-ylmethyl)-2-oxo-ethy 4-(2-
(416) 0 = N o" oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
I N4" ~" N
o ~ /" 3-yI)-piperidine-1-carboxylate
H 0

CA 02565219 2006-10-17
-113-
Structure Name
(R)-2-(4-methoxy-1,4'-bipiperidinyl-1'-yl)-1-
HN NH (7-methyl-2-oxo-2,3-dihydro-1l-/-
(417) o benzimidazol-5-ylmethyl)-2-oxo-ethyl 4-(2-
~ ,1~ oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
/~,'o' 3-yI)-piperidine-1-carboxylate
"
o o~"
CCN4
H O
(R)-2-(4-hydroxy-4-methyl-1,4'-
HN-~( bipiperidinyl-1'-yI)-1-(7-methyl-2-oxo-2,3-
/ NH dihydro-1 H-benzimidazol-5-ylmethyl)-2-
(418) o ' ~ oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
I N-CNxO o
N4 "~,N/'~,oH benzodiazepin-3-yl)-piperidine-1-
H 0 I carboxylate
o (R)-2-(4,4-dimethyl-1,4'-bipiperidinyl-1'-yl)-
HN NH 1-(7-methyl-2-oxo-2,3-dihydro-1H-
(419) o t ~ benzimidazol-5-ylmethyl)-2-oxo-ethyl 4-(2-
I N-CNxO~(",i~ oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
o 3-yl)-piperidine-1-carboxylate
H O
~ (R)-2-(4-amino-4-methyl-1,4'-bipiperidinyl-
"" NH 1'-yi)-1-(7-methyl-2-oxo-2,3-dihydro-1H-
(420) benzimidazol-5-ylmethyl)-2-oxo-ethyl 4-(2-
-~NxO'~ N~ N NH oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
CQN
o ~ z 3-yl)-piperidine-1-carboxylate
H O
o (R)-2-(4-hydroxy-4-hydroxymethyl-1,4'-
HN4 bipiperidinyl-1'-yi)-1-(7-methyl-2-oxo-2,3-
"" dihydro-1 H-benzimidazol-5-ylmethyl)-2-
(421) o oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
I \ N-{ x ~ "~,N/~o" benzodiazepin-3-yl)-piperidine-1-
H0 OH carboxylate
(R)-2-(1'-ethoxycarbonylmethyl-4,4'-
HN4 bipiperidinyl-1-yl)-1-(7-methyl-2-oxo-2,3-
" dihydro-1 H-benzimidazol-5-ylmethyl)-2-
(422) ~ N oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
I -~N o'~ ~,N'~ 1 benzodiazepin-3-yl)-piperidine-1-
H~0 o carboxylate
0 (R)-2-(1'-carboxymethyl-4,4'-bipiperidinyl-
HN NH 1-yl)-1-(7-methyl-2-oxo-2,3-dihydro-1H-
(423) o y benzimidazol-5-ylmethyl)-2-oxo-ethyI 4-(2-
CC ~ = N oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
N~" o o~'~N'~( 3-yI)-piperidine-1-carboxylate
0
H 0
o (R)-2-[4-(4-methyl-piperazin-1-yl)-
\" N_ piperidin-1-yl]-2-oxo-1-(1,3,7-trimethyl-2-
(424) o oxo-2,3-dihydro-1 H-benzimidazol-5-
(424) x - ylmethyl)-ethyl4-(2-oxo-1,2,4,5-
I N~-C" o o'~ tetrahydro-1,3-benzodiazepin-3-yl)-
H 0 i eridine-1-carbox late

= = CA 02565219 2006-10-17
- 114 -
Structure Name
(R)-2-[4-(1-methyl-piperid in-4-yl)-
piperazin-1-yl]-2-oxo-1-(1,3,7-trimethyl-2-
~ " oxo-2,3-dihydro-1H-benzimidazol-5-
(425) o ylmethyl)-ethyl4-(2-oxo-1,2,4,5-
I ~N--( NO~ tetrahydro-1,3-benzodiazepin-3-yl)-
H o V piperidine-1-carboxylate
j (R)-2-(1'-methyl-4,4'-bipiperidinyl-1-yl)-2-
oxo-1-(1,3,7-trimethyl-2-oxo-2,3-dihydro-
(426) 1 1 H-benzimidazol-5-ylmethyl)-ethyl 4-(2-
k N oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
I N~~" o ~N' 3-yI)-piperidine-1-carboxylate
H 0
"4 0 (R)-2-oxo-2-(4-piperazin-1 -yl-piperidin-1 -
1 N yl)-1-(1,3,7-trimethyl-2-oxo-2,3-dihydro-
(427) 1 H-benzimidazol-5-ylmethyl)-ethyl 4-(2-
I ~NI N\~ H oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
o ' N
N4 3-yI)-piperidine-1-carboxylate
H O
N4 0 (R)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-
N- yl)-1-(1, 3, 7-trimethyl-2-oxo-2, 3-dihydro-
(428) ~ 1 H-benzimidazol-5-ylmethyl)-ethyl 4-(2-
~ N~ oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
N~"~" o o~"~N'" 3-yI)-piperidine-1 -carboxylate
H
N~ (R)-2-4,4'-bipiperidinyl-1-yl-2-oxo-1-(1,3,7-
N trimethyl-2-oxo-2,3-dihydro-1 H-
(429) benzimidazol-5-ylmethyl)-ethyl 4-(2-oxo-
~ " 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
I "~~" 00'" yI)-piperidine-l-carboxylate
H 0
~o (R)-2-1,4'-bipiperidinyl-1'-yl-2-oxo-1-(1,3,7-
" N trimethyl-2-oxo-2,3-dihydro-1 H-
(430) benzimidazol-5-ylmethyl)-ethyl 4-(2-oxo-
~ y, " 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
I " " o o~N--_ yI)-piperidine-1-carboxylate
H O
N4 (R)-2-(4-morpholin-4-yl-piperidin-1-yl)-2-
' oxo-1-(1, 3, 7-trimethyl-2-oxo-2, 3-di hydro-
H-benzimidazol-5-ylmethyl)-ethyl 4-(2-
y
(431) 1
X N oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
I A "~~" o ~ ~o 3-yI)-piperidine-1-carboxylate
H 0

CA 02565219 2006-10-17
- 115 -
Structure Name
o (R)-2-oxo-2-[4-(tetrahydro-pyran-4-yl)-
N4 piperazin-1-yl]-1-(1,3,7-trimethyl-2-oxo-
" 2,3-dihydro-1 H-benzimidazol-5-ylmethyl)-
(432) CQ ethy! 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
N~N o'~ benzodiazepin-3-yl)-piperidine-1-
e
H~ carboxylate
~o (R)-2-(4-cyciohexyl-piperazin-1-yl)-2-oxo-
" N 1-(1,3,7-trimethyl-2-oxo-2,3-dihydro-1H-
(433) o benzimidazol-5-ylmethyl)-ethyl 4-(2-oxo-
~ 1,2,4,5-tetrahydro-l,3-benzodiazepin-3-
I "A oyl)-piperidine-1-carboxylate
H O
N4 o (R)-2-(4-hydroxy-1,4'-bipiperidinyl-1'-yl)-2-
N oxo-1-(1,3,7-trimethyl-2-oxo-2,3-dihydro-
(434) o ~ ~ 1 H-benzimidazol-5-ylmethyl)-ethyl 4-(2-
I
N~ ~"xo; 0 ~N~" oH oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
~~" 3-yi)-piperidine-1-carboxylate
H O
(R)-2-(4-methoxy-1,4'-bipiperidinyl-1'-yl)-2-
" N oxo-1-(1,3,7-trimethyl-2-oxo-2,3-dihydro-
(435) o 1 H-benzimidazol-5-ylmethyl)-ethyl 4-(2-
C2 x y N~N o oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
"~" o 0 /" 3-yl)-piperidine-1 -carboxylate
H O
(R)-2-(4-hydroxy-4-methyl-1,4'-
N-~o bipiperidinyl-1'-yl)-2-oxo-1-(1,3,7-trimethyl-
" 2-oxo-2,3-dihydro-1 H-benzimidazol-5-
(436) _ N ylmethyl)-ethyl 4-(2-oxo-1,2,4,5-
N-CN o',y \~ oH tetrahydro-1,3-benzodiazepin-3-yl)-
H4o piperidine-1-carboxylate
~o (R)-2-(4,4-dimethyl-1,4'-bipiperidinyl-1'-yl)-
" N 2-oxo-1-(1,3,7-trimethyl-2-oxo-2,3-dihydro-
(437) o 1 H-benzimidazol-5-ylmethyl)-ethyl 4-(2-
~ " Nxo oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
i ~ N4~ o ~ 3-yl)-piperidine-1-carboxylate
H O
"4 0 (R)-2-(4-amino-4-methyl-1,4'-bipiperidinyl-
N_ 1'-yl)-2-oxo-1-(1,3,7-trimethyl-2-oxo-2,3-di-
(438) o hydro-1 H-benzimidazol-5-yfinethyl)-ethyi
x " N NM 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
I N~~" o o~~" Z azepin-3-yl)-piperidine-1 -carboxylate
H O
(R)-2-(4-hydroxy-4-hydroxymethyl-1,4'-
~N bipiperidinyl-1'-yl)-2-oxo-1-(1,3,7-trimethyl-
~
2-oxo-2,3-dihydro-1 H-benzimidazol-5-
(439) \ ylmethyl)-ethyl 4-(2-oxo-1,2,4,5-
N-~N o'~ N\oH tetrahydro-1,3-benzodiazepin-3-yl)-
' H-~o oH piperidine-1 -carboxylate

CA 02565219 2006-10-17
-116-
Structure Name
(R)-2-(1'-ethoxycarbonylmethyl-4, 4'-
N-~ bipiperidinyl-1-yl)-2-oxo-1-(1,3,7-trimethyl-
" 2-oxo-2,3-dihydro-1 H-benzimidazol-5-
(440) o ylmethyl)-ethyl4-(2-oxo-1,2,4,5-
I N-~N~o'~ tetrahydro-l,3-benzodiazepin-3-yi)-
H4o 0 piperidine-l-carboxylate
(R)-2-(1'-carboxymethyl-4,4'-bipiperidinyl-
" 1-yl)-2-oxo-1-(1,3,7-trimethyl-2-oxo-2,3-
(441) dihydro-1 H-benzimidazol-5-ylmethyl)-ethyl
N NxO"\o. 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
~ ~ o N~ azepin-3-yl)-piperidine-1-carboxylate
0
H 0
N=\ (R)-1-(1,7-dimethyl-1 H-benzimidazol-5-
" ylmethyl)-2-[4-(4-methyl-piperazin-1-yl)-
0 ~ piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-
(442) N-CN O 1,2,4,5-tetrahydro-l,3-benzodiazepin-3-
~('
/
H-~o o yl)-piperidine-1-carboxylate
N~ (R)-1-(1, 7-dimethyl-1 H-benzimidazol-5-
" ylmethyl)-2-[4-(1-methyl-piperidin-4-yl)-
piperazin-1-yi]-2-oxo-ethyl 4-(2-oxo-
(443) N~NxO-~,r"% N1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
H-'o o yl)-piperidine-1-carboxylate
(R)-1-(1,7-dimethyl-1 H-benzimidazol-5-
ylmethyl)-2-(1'-methyl-4,4'-bipiperidinyl-1-
444 yI)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
( ) N~NxO~ ",~~ ' 1,3-benzodiazepin-3-yl)-piperidine-1-
o " carboxylate
H O
N=\ (R)-1-(1,7-dimethyl-1 H-benzimidazol-5-
" ylmethyl)-2-oxo-2-(4-piperazin-1 -yl-piperi-
o din-l-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
(445)
-
C N-CNo'y N~. ~",H 1,3-benzodiazepin-3-yl)-piperidine-1
N-{ o o carboxylate
H O
N=\ (R)-1-(1,7-dimethyl-1 H-benzimidazol-5-
" ylmethyl)-2-oxo-2-(4-piperidin-4-yl-
446 : piperazin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-
( ) N~Nxo'H tetrahydro-1,3-benzodiazepin-3-yl)-
~ N- o ~" piperidine-l-carboxyiate
H O
N=\ (R)-2-4,4'-bipiperidinyl-1-yl-1-(1, 7-
"l dimethyl-1 H-benzimidazol-5-ylmethyl)-2-
~ I oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
(447) N-CN O benzodiazePin-3-YI)-PiPeridine-1-
I\
"-~ 0 carboxylate
H 0

= ' CA 02565219 2006-10-17
- 117 -
Structure Name
(R)-2-1,4'-bipiperidinyl-1'-yI-1-(1,7-
dimethyl-1 H-benzimidazol-5-ylmethyl)-2-
448 0 = ~ oxo-ethy! 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
( ) I "~"xo~ benzodiazepin-3-yl)-piperidine-1-
H-~o o carboxylate
(R)-1-(1,7-dimethyl-1 H-benzimidazol-5-
ylmethyl)-2-(4-morpholin-4-yl-piperidin-1-
Al _ N yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-
(449)
I "~" o-~ \
~0 1,3-benzodiazepin-3-yl)-piperidine-1-
N-~o o carboxy(ate
(R)-1-(1,7-dimethyf-1 H-benzimidazol-5-
" ylmethyl)-2-oxo-2-[4-(tetrahydro-pyran-4-
o I yl)-piperazin-1-yi]-ethyl 4-(2-oxo-1,2,4,5-
(450)
I x~o tetrahydro-1,3-benzodiazepin-3-yl)-
H-{o o piperidine-1 -carboxylate
"=\ (R)-2-(4-cyclohexyl-piperazin-1-yl)-1-(1,7-
" dimethyl-1 H-benzimidazol-5-ylmethyl)-2-
0 oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
(451) "~"0~ benzodiazepin-3-yl)-piperidine-1-
H~o o carboxylate
"=\ (R)-1-(1,7-dimethyl-1 H-benzimidazol-5-
"' ylmethyl)-2-(4-hydroxy-1,4'-bipiperidinyl-1'-
yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-
(452) "~"lo~",i~,"~,OH 1,3-benzodiazepin-3-yl)-piperidine-1-
H-~o o carboxylate
(R)-1-(1, 7-dimethyl-1 H-benzimidazol-5-
ylmethyl)-2-(4-methoxy-1,4'-bipiperidinyl-
453 0 = ~ 1'-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-
( ) ~"X0y "~,"~tetrahydro-1,3-benzodiazepin-3-yl)-
H-(~o o piperidine-1 -carboxylate
"~~ (R)-1-(1,7-dimethyl-1 H-benzimidazol-5-
" ylmethyl)-2-(4-hydroxy-4-methyl-1,4'-
454 0 = ~ bipiperidinyl-1'-yI)-2-oxo-ethyl 4-(2-oxo-
( ) " "o'~"~,"'~, OH 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
A "-~~ o ' I yI)-piperidine-l-carboxylate
H O
"=\ (R)-1-(1,7-dimethyl-1 H-benzimidazol-5-
" yimethyl)-2-(4,4-dimethyl-1,4'-bipiperidinyl-
I 1'-yI)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(455) "~"Ioy"~,"- tetrahydro-1,3-benzodiazepin-3-yl)-
1~"-~ o piperidine-1 -carboxylate
H 0

CA 02565219 2006-10-17
- 118 -
Structure Name
(R)-2-(4-amino-4-methyl-1,4'-bipiperidinyl-
1'-yi)-1-(1, 7-dimethyl-1 H-benzimidazol-5-
ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(456)
CQ o y"/~,N NHZ tetrahydro-l,3-benzodiazepin-3-yl)-
-carboxylate
H~o ~ o ~ piperidine-1-carboxylate
(R)-1-(1,7-dimethyl-1 H-benzimidazol-5-
ylmethyl)-2-(4-hydroxy-4-hydroxymethyl-
0 = ~ 1,4'-bipiperidinyl-1'-yl)-2-oxo-ethyl4-(2-
(457) N-CNo'~-y "/.,N..~,oH oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
H-~o 0 oH 3-yl)-piperidine-1-carboxylate
N=r\ (R)-1-(1,7-dimethyl-1 H-benzimidazol-5-
"- ylmethyl)-2-(1'-ethoxycarbony(methyl-4,4'-
~ bipiperidinyi-1-yl)-2-oxo-ethyl 4-(2-oxo-
(458) CC N -CNI o'y"\N'~o 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
" o o ,
yl)-piperidine-l-carboxylate
H O
N~\ (R)-2-(1'-carboxymethyl-4,4'-bipiperidinyl-
~ ~ " 1-yl)-1-(1,7-dimethyl-1H-benzimidazol-5-
4 yimethyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-
(459) 0lo:~ ~ "o " o tetrahydro-1,3-benzodiazepin-3-yl)-
N ~ o ~N'~' "
e
piperidine-1 -carboxylate
H O
N=\ (R)-1-(7-methyl-1 H-benzimidazol-5-
, NH ylmethyl)-2-[4-(4-methyl-piperazin-1-yl)-
0 ~ ~ piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-
(460) X N-CNo;y "~ N 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
. /~/
"-~ o ~" yl)-piperidine-1 -carboxylate
H 0
N=\ "H (R)-1-(7-methyl-1 H-benzimidazol-5-
~ ylmethyl)-2-[4-(1-methyl-piperid in-4-yl )-
piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-tetrahy (461) C " ~ C '-'N1: ~ o o ~N-
yl)-piperid ne-1a arboxybateodiazepin-3-
H O
N~\ (R)-1-(7-methyl-1 H-benzimidazol-5-
/ NH ylmethyl)-2-(1'-methyl-4,4'-bipiperidinyl-1-
~ yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
(462) cc N~" o;~N\N' 1,3-benzodiazepin-3-yl)-piperidine-l-
N~ o carboxylate
H 0
N==\ (R)-1-(7-methyl-1 H-benzimidazol-5-
/ NH ylmethyl)-2-oxo-2-(4-piperazin-1-yl-
o ; ~ I piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-
(463) N--CN,~o;~N~.N~ ,H tetrahydro-l,3-benzodiazepin-3-yl)-
~ "-~ o " piperidine-1 -carboxylate
H 0

CA 02565219 2006-10-17
- 119-
Structure Name
(R)-1-(7-methyl-11-l-benzimidazol-5-
, NH ylmethyl)-2-oxo-2-(4-piperidin-4-yl-
0 piperazin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-
(464) N-CNxo",-,~N,~N,H tetrahydro-l,3-benzodiazepin-3-yl)-
H4o piperidine-1 -carboxylate
" NH (R)-2-4,4'-bipiperidinyl-l-yl-1-(7-methyl-
~ 1 H-benzimidazol-5-ylmethyl)-2-oxo-ethyl
(465) ~ ~ = N 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
N~" " o ~N.H azepin-3-yl)-piperidine-1-carboxylate
cH O
NH (R)-2-1,4'-bipiperidinyl-1'-y1-1-(7-methyl-
~ 1 H-benzimidazol-5-ylmethyl)-2-oxo-ethyl
(466) CC4 ~ N 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
" " o o '~ "~ azepin-3-yl)-piperidine-1-carboxylate
N
N
H O
N~\ (R)-1-(7-methyl-1 H-benzimidazol-5-
"H ylmethyl)-2-(4-morpholin-4-yl-piperidin-1-
(467) yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
I N-CNxo~"~,N~o 1,3-benzodiazepin-3-yl)-piperidine-l-
H-(o carboxylate
N=:\ (R)-1-(7-methyl-1 H-benzimidazol-5-
/ "H yimethyl)-2-oxo-2-[4-(tetrahydro-pyran-4-
(468) /~~ o yl)-piperazin-1-ylJ-ethy! 4-(2-oxo-1,2,4,5-
1 /N-( NxO~ tetrahydro-1,3-benzodiazepin-3-yl)-
~ l -- piperidine-1-carboxylate
H O
N=~\ (R)-2-(4-cyclohexyl-piperazin-1-yl)-1-(7-
~ ~ NH methyi-1 H-benzimidazol-5-ylmethyl)-2-
(469) ~ X = N~ oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
N N O~ benzodiazepin-3-yl)-piperidine-1 -
H--~o carboxylate
N=, (R)-2-(4-hydroxy-1,4'-bipiperidinyl-1'-yl)-1-
~ ' NH (7-methyl-1 H-benzimidazol-5-ylmethyl)-2-
(470) oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
I benzodiazepin-3-yl)-piperidine-1-
H o carboxylate
N~\ (R)-2-(4-methoxy-1,4'-bipiperidinyl-1'-yl)-1-
/ "H (7-methyl-1 H-benzimidazol-5-ylmethyl)-2-
~ oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
(471) N-~Nxobenzodiazepin-3-yl)-piperidine-l-
H-~o 0 carboxylate

CA 02565219 2006-10-17
- 12a -
Structure Name
N~\ (R)-2-(4-hydroxy-4-methyl-1,4'-
/ "H bipiperidinyl-1'-y))-1-(7-methyl-1f-I-
( ) N ~ benzimidazol-5-ylmethyl)-2-oxo-ethyl 4-(2-
472 N-{~ N o ~,N'~,,oH oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
N-~ ' ' o " 1 3-yt)-piperidine-1-carboxylate
H O
N--\ (R)-2-(4,4-dimethyl-1,4'-bipiperidinyl-1'-yl)-
, "H 1-(7-methyl-1 f-l-benzimidazol-5-ylmethyl)-
(473) 2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
N N o~~ 1,3-benzodiazepin-3-yl)-piperidine-1-
(~ carboxylate
H o
N~ (R)-2-(4-amino-4-methyl-1,4'-bipiperidinyl-
NH 1'-yl)-1-(7-methyl-1/--benzimidazol-5-
(474) r N ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
1' o 1{ "~N-~ NHZ tetrahydro-1,3-benzodiazepin-3-yl)-
H 0 o piperidine-1-carboxylate
N=\ (R)-2-(4-hydroxy-4-hyd roxymethyl-1, 4'-bi-
"H piperidinyi-1'-y!)-1-(7-methyl-1 H-
benzimidazol-5-ylmethy))-2-oxo-ethyl4-(2-
(475) "~NXoN-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
N o 3-yl)-piperidine-1-carboxylate
~ oH
H
(R)-2-(1'-ethoxycarbonylmethyl-4,4'-
"H bipiperidinyl-1-yl)-1-(7-methyl-1H-
( N benzimidazol-5-ylmethyi)-2-oxo-ethyl 4-(2-
476) 0112 NCN o''~, ~%o oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
~o o 3-yl)-piperidine-l-carboxylate
N=~\ ( R)-2-(1'-carboxymethyl-4, 4'-bipiperidinyl-
~ "H 1-yl)-1-(7-methyl-1H-benzimidazol-5-
~ ~ ylmethyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-
(477) 10 N
"~N y",Yo.H tetrahydro-l,3-benzodiazepin-3-yl)-
H -~o ~'~'V~ o piperidine-l-carboxylate
(R)-1-(2,7-dimethyi-1 H-benzimidazol-5-
"--\ NH ylmethyl )-2-[4-(4-methyl-piperazin-1-yl )-
(478) o ~ I piperidin-1-y1)-2-oxo-ethyl 4-(2-oxo-
I 4N 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
N o yl)-piperidine-1-carboxylate
H O
(R)-1-(2-cyclopropyl-7-methyl-1 H-
N benzimidazol-5-ylmethyl)-2-[4-(4-methyi-
\ NH piperazin-1-yi)-piperidin-1-yl]-2-oxo-ethyl
(479) 0 4-(2-oxo-1,2,4, 5-tetrahydro-1, 3-benzodi-
CC ~ azepin-3-yl)-piperidine-l-carboxylate
o
N
H 0

CA 02565219 2006-10-17
- 121 -
Structure Name
cF3 (R)-2-[4-(4-methyl-piperazin-1-yi)-
N NH piperidin-l-yl)-1-(7-methyl-2-
I trifluoromethyl-1 H-benzimidazol-5-
(480) ~ ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
I " 0 0 N~"~N tetrahydro-1,3-benzodiazepin-3-yl)-
H o piperidine-l-carboxylate
o- (R)-1 -(2-m ethoxy-7-m ethyl- 1 H-
N NH benzimidazol-5-ylmethyl)-2-[4-(4-methyl-
(481) o --~ piperazin-1 -yl)-piperidin-1 -yl)-2-oxo-ethyl
o;~"~ 4-(2-oxo-1,2,4,5-tetrahydro-l,3-benzodi-
~ N 0 azepin-3-yl)-piperidine-1 -carboxylate
H O
_ (R)-1-{2-[(Z)-cyanimino]-7-methyl-2,3-
HN-~N _N dihydro-1H-benzimidazol-5-ylmethyl}-2-[4-
H (4-methyl-piperazin-1 -yl)-piperidin-1-yl]-2-
(482) \ ' ~ oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-l,3-
I "~-~NIo o "~ ~N, benzodiazepin-3-yl)-piperidine-1-
H o carboxylate
_N (R)- 1 -(1 H-indazol-5-yimethy!)-2-(1'-
, ~ "H methanesulphonyl-4,4'-bipiperidinyl-l-yl)-
0 ~ 2-oxo-ethy! 4-(2-oxo-1,2,4,5-tetrahydro-
(483) "~
Nxo~,0s 1,3-benzodiazepin-3-yl)-piperidine-l-
H~ o " carboxylate
_N (R)-2-(1'-methanesulphonyl-4,4'-
" bipiperidinyl-1-yl)-1-(1-methyl-1 H-indazol-
~ ~ 5-ylmethyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-
(484) "o y N~'~ qs o tetrahydro-1,3-benzodiazepin-3-yl)-
"-{~~ o piperidine-l-carboxylate
H O
,N (R)-2-(1'-methanesulphonyl-4,4'-
/ "H bipiperidinyl-1 -yl)-1-(7-methyl-1 H-indazol-
(485) o ' 0 5-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
I N-CN-~o'~"i%~'C= "; tetrahydro-1,3-benzodiazepin-3-yl)-
H-~o piperidine-l-carboxylate
N (R)-1-(1,7-dimethyl-1 H-indazol-5-
\ "- ylmethyl)-2-(1'-methanesulphonyl-4,4'-
(486) ~ ~ ~\,o bipiperidinyi-1-yl)-2-oxo-ethyl 4-(2-oxo-
02 N N o ~ N S 1,2,4,5-tetrahydro-l,3-benzodiazepin-3-H~o " ~ yl)-piperidine-l-
carboxylate
_N (R)-1-(7-chloro-1 H-indazol-5-ylmethyl)-2-
"H (1'-methanesulphonyl-4,4'-bipiperidinyl-1-
(487) o yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
I o-~,y"\~ o 1,3-benzodiazepin-3-yl)-piperidine-l-
~ H-~o 0 "~ ~ carboxylate

CA 02565219 2006-10-17
-122-
Structure Name
," (R)-1-(7-chloro-1-methyl-1 f-l-indazol-5-yl-
, " methyl)-2-(1'-methanesulphonyl-4,4'-
(488) _ ~ o o bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-
I "~"Ioy"~;s' 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
H-~O o " yl)-piperidine-1-carboxylate
"~\ (R)-2-(1'-methanesulphonyl-4,4'-
, "H bipiperidinyl-1-yl)-1-(7-methyl-1 H-
benzimidazol-5-ylmethyl)-2-oxo-ethyl 4-(2-
(489) "~"lo-~"~;~ oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
H-'o 0 3-yl)-piperidine-l-carboxylate
"~\ (R)-1-(1,7-dimethyl-1 H-benzimidazol-5-
" ylmethyl)-2-(1'-methanesulphonyl-4,4'-
bipiperidinyl-1-yl)-2-oxo-ethyl 4-(2-oxo-
(490) "~"lo;-y"\qs o 1,2,4,5-tetrahydro- 1,3-benzodiazepin-3-
H-~o o " yl)-piperidine-l-carboxylate
"," (R)-2-(1'-methanesulphonyl-4,4'-
/ NH bipiperidinyl-1-yl)-1-(7-methyl-lH-
~~ benzotriazol-5-ylmethyl)-2-oxo-ethyl 4-(2-
(491) , "_C"Io;y"~qso oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
H-~o o 3-yl)-piperidine-1 -carboxylate
"," ( R)-1-(1, 7-d imethyl-1 H-benzotriazol-5-yl-
" methyl)-2-(1'-methanesulphonyl-4,4'-
492 04~ 0, o bipiperidinyl-1-yl)-2-oxo-ethyl 4-(2-oxo-
( ) ccio'y"\1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
H~o o yl)-piperidine-l-carboxylate
(R)-2-(1'-methanesulphonyl-4,4'-
~ o bipiperidinyl-1 -yl)-1-(8-methyl-2,3-dihydro-
~ 1,4-benzodioxin-6-ylmethyl)-2-oxo-ethyi 4-
(493) "~"Io " ~s 0 (2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
I "~( ~o ~"~ azepin-3-yl)-piperidine-1 -carboxylate
H O
o-) (R)-1-(2,3-dihydro-l,4-benzodioxin-6-
O ylmethyl)-2-(1'-methanesulphonyl-4,4'-
. bipiperidinyl-1-yl)-2-oxo-ethyl 4-(2-oxo-
(494) C "~"~o~"\os o 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
" C-] ~ o "~ ' yl)-piperidine-l-carboxylate
H O
(R)-2-(1'-methanesulphonyl-4, 4'-
NH bipiperidinyl-1-yl)-1-(5-methyl-3,4-dihydro-
~ 2H-1,4-benzoxazin-7-ylmethyl)-2-oxo-ethyl
(495) "~"~o j " ~s o 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
I "~ o ~"- ~ azepin-3-yl)-piperidine-1-carboxylate
H 0

= = CA 02565219 2006-10-17
-123-
Structure Name
(R)-1-(4,5-dimethyl-3,4-dihydro-2H-1,4-
0benzoxazin-7-ylmethyl)-2-(1'-
~ "' methanesulphonyl-4,4'-bipiperidinyl-l-yl)-
(496) ' N oo 2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-
~ ~--CN O o ~N;sII 1,3-benzodiazepin-3-yl)-piperidine-l-
H 0 carboxylate
, o (R)-2-(1'-methanesulphonyl-4,4'-
, NH bipiperidinyl-1-yl)-1-(8-methyl-2-oxo-1,2-
~ ~ dihydro-quinolin-6-ylmethyl)-2-oxo-ethyl 4-
(497) ~"x " 0s0
o (2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
N~ ~ o\='~ C~N' azepin-3-yl)-piperidine-1-carboxylate
H O
(R)-1-(1, 8-dimethyl-2-oxo-1, 2-dihydro-
quinolin-6-ylmethyl)-2-(1'-
\ methanesulphonyl-4,4'-bipiperidinyl-1-yl)-
(498) N o 0 2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-
I ~-C" o "=s 1,3-benzodiazepin-3-yl)-piperidine-1-
H 0 carboxylate
(R)-2-(1'-methanesulphonyl-4,4'-
o-'! bipiperidi nyl-1-yl)-1-(4-methyl-2-oxo-2, 3-
~" dihydro-benzoxazol-6-ylmethyl)-2-oxo-
(499) ' ~ ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
I N~Nxo'y00 benzodiazepin-3-yl)-piperidine-1-
H carboxylate
(R)-2-(1'-methanesulphonyl-4,4'-
HN-~( bipiperid inyl-1-yl )-1-(7-methyl-2-oxo-2, 3-
" dihydro-1 H-benzimidazol-5-ylmethyl)-2-
(500) oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
C~ N-CN o ~",,'~''N;s' benzodiazepin-3-yl)-piperidine-1-
carboxylate
H4o H
(R)-2-(1'-methanesulphonyl-4,4'-
bipiperidinyl-1-yi)-2-oxo-1-(1,3,7-trimethyl-
2-oxo-2,3-dihydro-1 H-benzimidazol-5-
(501) \ = N ylmethyl)-ethyl 4-(2-oxo-1,2,4,5-
~ N--CN o'~ ~;%N,s tetrahydro-1,3-benzodiazepin-3-yl)-
H~o piperidine-l-carboxylate
W~j (R)-2-(1'-methanesulphonyl-4, 4'-
N bipiperidinyl-1-yl)-1-(8-methyl-quinoxalin-
~ 6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(502) ~N qs o tetrahydro-1,3-benzodiazepin-3-yl)-
~ N~ 0 '~N_ piperidine-1 -carboxylate
H 0

CA 02565219 2006-10-17
- 124 -
Structure Name
( R)-2-(1'-methanesulphonyl-4,4'-
N bipiperidinyl-1 -yl)-2-oxo-1 -quinoxalin-6-
(503) ylmethyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
~ N-CN ~o'y N~ ~s 1, 3-benzodi azepin-3-y!)-piperidine-1-
-~ o "~ carboxylate
H o
_N (R)-1-(1 H-indazol-5-ylmethyl)-2-(1'-
~ "" methanesulphonyl-4,4'-bipiperidinyl-1-yl)-
0 2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-
(504) ! ) "_c"xo;~N~qs o 1,3-benzodiazepin-3-yl)-piperidine-1-
H-~o o carboxylate
N (R)-1-(1-methyl-1 H-indazol-5-ylmethyl)-2-
\ "- oxo-2-(1'-sulphamoy!-4,4'-bipiperidinyl-1-
yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
(505) "-C"Io~yNqs o benzodiazepin-3-yl)-piperidine-l-
H-~o o ""Z carboxylate
N (R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-
~ " oxo-2-(1'-sulphamoyl-4,4'-bipiperidinyl-1-
(506) o o o yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
I N-CNxo-~~,%~ 's benzodiazepin-3-yl)-piperidine-1-
A H-~o o "' ""= carboxylate
_N (R)-1-(1,7-dimethyl-1 H-indazol-5-
" ylmethyl)-2-oxo-2-(1'-sulphamoyl-4,4'-
(507) o-~~' o bipiperidinyl-1-yi)-ethyi 4-(2-oxo-1,2,4,5-
I ~~No'~N~ ~s- o tetrahydro-1,3-benzodiazepin-3-yl)-
piperidine-l-carboxylate
~ H o o N'NH,
_N (R)-1-(7-chloro-1 H-indazol-5-ylmethyl)-2-
~ ~ "" oxo-2-(1'-sulphamoyl-4,4'-bipiperidinyl-1-
(508) G o o yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
I N-CN'o'~"~%~'~~ 's benzodiazepin-3-yl)-piperidine-1-
-~ o "'""= carboxylate
H o
N (R)-1-(7-chloro-1-methyl-1 H-indazol-5-yl-
~ " methyl)-2-oxo-2-(1'-sulphamoyl-4,4'-
(509) ~~ _ N G o o bipiperidinyl-1-yl)-ethyl 4-(2-oxo-1,2,4,5-
S tetrahydro-1,3-benzodiazepin-3-yl)-
I~ N N o'~ ~
~ H-{o o " '""= piperidine-1 -carboxylate
-carboxylate
N-\ (R)-1-(7-methyl-1 H-benzimidazol-5-
"" ylmethyl)-2-oxo-2-(1'-sulphamoyl-4,4'-
(510) o o bipiperidinyl-1-yl)-ethyl 4-(2-oxo-1,2,4,5-
I N-CNo'~N~' s; o tetrahydro-1,3-benzodiazepin-3-yl)-
~ H-~o o "- ""= piperidine-l-carboxylate

= CA 02565219 2006-10-17
- 125 -
Structure Name
N'\ (R)-1-(1,7-dimethyl-1 H-benzimidazol-5-
" ylmethyl)-2-oxo-2-(1'-sulphamoyl-4,4'-
~
~ bipiperidinyl-1-yl)-ethyl 4-(2-oxo-1,2,4,5-
"~
(511) C
N~o~N ,s~ tetrahydro-1,3-benzodiazepin-3-yl)-
H~o o ~NHZ piperidine-1-carboxylate
N:N (R)-1-(7-methyl-1 H-benzotriazol-5-
, NH ylmethyl)-2-oxo-2-(1'-sulphamoyl-4,4'-
o bipiperidinyl-1-yl)-ethyl 4-(2-oxo-1,2,4,5-
12 07
(5 ) N-~No'y"~'~ ''~ tetrahydro-1,3-benzodiazepin-3-yl)-
~ H-(o o "H= piperidine-1 -carboxylate
",N (R)-1-(1,7-dimethyl-1 H-benzotriazol-5-yl-
" methyl)-2-oxo-2-(1'-sulphamoyl-4,4'-
513 0 o bipiperidinyl-1-yl)-ethyl4-(2-oxo-1,2,4,5-
( ) k N~NO'~"~,:s' tetrahydro-1,3-benzodiazepin-3-yl)-
AH-4o o N'NF~ piperidine-l-carboxylate
(R)-1-( 8-methyl-2, 3-d ihyd ro-1, 4-
~ o benzodioxin-6-ylmethyl)-2-oxo-2-(1'-
(514) A _ o sulphamoyl-4,4'-bipiperidinyl-l-yl)-ethyl 4-
j "~"Jlo N "S NH (2-oxo-1,2,4,5-tetrahydro-l,3-benzodi-
I "~ o ~'~ z
azepin-3-yl)-piperidine-1 -carboxylate
-carboxylate
H O
(R)-1-(2,3-dihydro-1,4-benzodioxin-6-
~,o ylmethyl)-2-oxo-2-(1'-sulphamoyl-4,4'-
,1~,~ 9 bipiperidinyl-1-yl)-ethyl 4-(2-oxo-1,2,4,5-
(515) C ~N~"~o N qs o tetrahydro-1,3-benzodiazepin-3-yl)-
N~( 'o ~N'"~ piperidine-1-carboxylate
H O
~ ( R)-1-(5-methyl-3, 4-dihydro-2H-1, 4-benz-
NH oxazin-7-ylmethyl)-2-oxo-2-(1'-sulphamoyl-
~ 4,4'-bipiperidinyl-1-yl)-ethyl 4-(2-oxo-
(516) N-CN~o'~N\N ~s NH 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
N4 o z yl)-piperidine-1-carboxylate
H O
0,1 (R)-1-(4,5-dimethyl-3,4-dihydro-2H-1,4-
N, benzoxazin-7-ylmethyl)-2-oxo-2-(1'-
_ sulphamoyl-4,4'-bipiperidinyl_1-yl)-ethyl 4-
(517) o
C " CN~o'~N\\s ~ (2-oxo-1,2,4,5-tetrahydro-1,3 benzodi
"~ 0 "' NHz azepin-3-yl)-piperidine-1 -carboxylate
H O
o (R)-1-(8-methyl-2-oxo-1,2-dihydro-
NH quinolin-6-ylmethyl)-2-oxo-2-(1'-
0 sulphamoyl-4,4'-bipiperidinyl-l-yl)-ethyl 4-
(518) ~ ~ ~, o (2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
CN~"' " o o N~S~ NHz azepin-3-yl)-piperidine-1-carboxylate
H 0

CA 02565219 2006-10-17
- 126 -
Structure Name
~ o (R)-1-(1,8-dimethyl-2-oxo-1,2-dihydro-
~ N, quinolin-6-ylmethyl)-2-oxo-2-(1'-
(519) o sulphamayl-4,4'-bipiperidinyl-1-y!)-ethyl 4-
I "-CNJIo;yN\~ "S o (2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
N4 0 "~ N+, azepin-3-yi)-piperidine-1-carboxylate
H 0 -1 -l-
~ (R)-1 -(4-methyl-2-oxo-2,3-dihydro-
NH benzoxazol-6-ylmethyl )-2-oxo-2-(1'-
~ sulphamoyl-4,4'-bipiperidinyl-l-yl)-ethyl 4-
(520) CC e No,,o (2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
N~~N~S~NHZ azepin-3-yl)-piperidine-1-carboxylate
" o o
H O
H"~ (R)-1 -(7-methyl-2-oxo-2,3-dihydro-1 H-
NH benzimidazoi-5-ylmethyl)-2-oxo-2-(1'-
(521) o sulphamoyl-4,4'-bipiperidinyl-1-yl)-ethyi 4-
~ N ;,,o (2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
I N~ ~" o~ ~'~~N'S,
NHZ azepin-3-yi)-piperidine-l-carboxylate
H 0
o (R)-2-oxo-2-(1'-sulphamoyl-4,4'-
" N_ bipiperidinyl-1-yi)-1-(1,3,7-trimethyl-2-oxo-
(522) o 2,3-dihydro-1 H-benzimidazol-5-ylmethyl)-
x= N Q o ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
C "~N-CN o o N-s;N,~ benzodiazepin-3-yl)-piperidine-1-
H H 0 carbox late
N~ (R)-1-(8-methyl-quinoxalin-6-ylmethyl)-2-
N oxo-2-(1 -sulphamoy!-4,4 bipiperidinyl-l-
~ yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
(523) ~N-~"~o~f/I qs o benzodiazepin-3-yl)-piperidine-l-
N.~ 0NH2 carboxylate
H O
"'1 (R)-2-oxo-1-quinoxalin-6-ylmethyl-2-(1'-
" sulphamoyl-4,4'-bipiperidinyl-l-yl)-ethyl 4-
(524) /~ = N o,o (2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
N-( N 0 O~,i~N~S~NH~ azepi n-3-yl)- pipe rid i ne- 1 -carboxylate
(/ N~
~J
H O
_N (R)-1-(1 H-indazol-5-ylmethyl)-2-[4-(4-
, NH methanesulphonyl-piperazin-1-yl)-
~ piperidin-1-yi]-2-oxo-ethyl 4-(2-oxo-
(525) 1 N NIo " N\ .--~ ~s 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
~ o ~ yi)-piperidine-1-carboxylate
H 0
_N (R)-2-[4-(4-methanesulphonyl-piperazin-1-
" yI)-piperidin-1-yl]-1-(1-methyl-1 H-indazol-
(526) N~ o 0 5-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
I r N--~N o'~ ~~N,s~ tetrahydro-1,3-benzodiazepin-3-yl)-
H-~ 0 piperidine-1-carboxylate

CA 02565219 2006-10-17
-127-
Structure Name
N (R)-2-[4-(4-methanesulphonyl-piperazin-1 -
/ yl)-piperidin-1-yl]-1-(7-methyl-lf-/-indazol-
~ 5-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(527) % N-~Nl O'y "1, ~N~s~ tetrahydro-1,3-benzodiazepin-3-yl)-
H-4o piperidine-l-carboxylate
_N (R)-1-(1, 7-dimethyl-1 H-indazol-5-
" ylmethyl)-2-[4-(4-methanesulphonyl-
(528) ~_ I o o piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl
N~N O~( 4-(2-oxo-1,2,4,5-tetrahydro-l,3-benzodi-
H-~o azepin-3-yl)-piperidine-1 -carboxylate
_N 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
-1-(7-chloro-1H-indazol-5-ylmethyl)-2-
0 G (R)
4- 4-methanesul hon I erazin- 1 -I
[ ( P Y -Pi P Y )-
/~~ i eridin-1- I 2 oxo-eth I aze in-3- I
(529) N -(N O~"~N . P P Y] - Y P Y)
H-4o ~1 piperidine-1-carboxylate
N (R)-1-(7-chloro-1-methyl-1 H-indazol-5-yl-
" methyl)-2-[4-(4-methanesulphonyl-
(530) 0 _ p o o piperazin-1-yi)-piperidin-1 -yl]-2-oxo-ethyl
N--CN o'~ 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
H-~o o azepin-3-yl)-piperidine-1 -carboxylate
N~\ (R)-2-[4-(4-methanesulphonyl-piperazin-1-
, NH yl)-piperidin-1 -yl]-1-(7-methyl-1 H-
531 0=~~ o benzimidazol-5-ylmethyl)-2-oxo-ethyl 4-(2-
( ) C12-) N- CNo'y"~"~";s~ oxo-1,2,4,5-tetrahydro-l,3-benzodiazepin-
Hto 0 3-yl)-piperidine-1 -carboxylate
(R)-1-(1,7-dimethyl-1 H-benzimidazol-5-
" ylmethyl)-2-[4-(4-methanesulphonyl-
532 o o piperazin-1 -yl)-piperidin-1-yl]-2-oxo-ethyl
( ) N-CNo N 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
~
H-~o azepin-3-yl)-piperidine-l-carboxylate
R (R)-2 -[4-(4-methanesulphonyl-piperazin-l-
H yl)-piperidin-l-yl]-1-(7-methyl-1H-
o benzotriazol-5-ylmethyl)-2-oxo-ethyl 4-(2-
(533) "~Nxo;~N~N~ ~s o oxo-1,2,4,5-tetrahydro-l,3-benzodiazepin-
H-~o ~" 3-yl)-piperidine-1 -carboxylate
:N (R)-1-(1,7-dimethyl-1 H-benzotriazol-5-yl-
~ methyl)-2-[4-(4-methanesulphonyl-
~ piperazin-l-yl)-piperidin-l-yl]-2-oxo-ethyl
"g,o
~, ~",S\ 4-(2-oxo-1,2,4,5-tetrahydro-l,3-benzodi-
(534) CQ N N x0
"~~ azepin-3-yl)-piperidine-1-carboxylate
-carboxylate
H 0

. = CA 02565219 2006-10-17
- 128 -
Structure Name
o,l (R)-2-[4-(4-methanesulphonyl-piperazin-1-
0 yI)-piperidin-1-yl]-1-(8-methyl-2,3-dihydro-
. 1,4-benzodioxin-6-ylmethyl)-2-oxo-ethyl 4-
(535) "~"os o (2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
N4 o azepin-3-yl)-piperidine-1-carboxylate
H O
(R)-1-(2,3-dihydro-1,4-benzodioxin-6-
~, o ylmethyl)-2-[4-(4-methanesulphonyl-
(536) ~' ~ piperazin-1 -yl)-piperidin-1 -yl]-2-oxo-ethyl
N-C"Io,YN~ N-~ s= 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
N,~ o ''' "~ ' azepin-3-yl)-piperidine-1-carboxytate
H O
l (R)-2-[4-(4-methanesulphonyl-piperazin-1-
,~~,NH yl)-piperidin-1-yl]-1-(5-methyl-3,4-dihydro-
~~ 2H-1,4-benzoxazin-7-ylmethyl)-2-oxo-ethyl
(537) 's o 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
"4 o azepin-3-yl)-piperidine-1 -carboxylate
H O
(R)-1-(4,5-dimethyl-3,4-dihydro-2H-1,4-
0') benzoxazin-7-ylmethyl)-2-[4-(4-
' ", methanesulphonyl-piperazin-1 -yl)-
(538) ~ ~ = N o~ ,o piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-
" o o ~"~N%S~ 1,2,4,5-tetrahydro-l,3-benzodiazepin-3-
H C H o yl)-piperidine-l-carboxylate
(R)-2-[4-(4-methanesulphonyl-piperazin-l-
ENH
YI)-PiPeridin-l-YI]-1-(8-methYI-2-oxo-1,2-di-
(539) ~ = N o~ ,o hydro-quinolin-6-ylmethyl)-2-oxo-ethyl 4-
I ~-CN O o ~N,s~ (2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
H 0 azepin-3-yl)-piperidine-1-carboxylate
o (R)-1-(1,8-dimethyl-2-oxo-1,2-dihydro-
N, quinolin-6-ylmethyl)-2-[4-(4-
~ methanesulphonyl-piperazin-l-yl)-
(540) "~"xoN~N~ os o piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-
N~( 0 '~" ' 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
" o I- i eridine-1-carbox late
040 (R)-2-[4-(4-methanesulphonyl-piperazin-1-
, NH yl)-piperidin-1-yl]-1-(4-methyl-2-oxo-2,3-di-
(541) o ' ~ hydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl
~N-CNoy~" 's~ 4-(2-oxo-1,2,4,5-tetrahydro-l,3-benzodi-
H 0 azepin-3-yl)-piperidine-1 -carboxylate
(R)-2-[4-(4-methanesulphonyl-piperazin-1-
HN NH yl)-piperidin-1-yl]-1-(7-methyl-2-oxo-2,3-di-
(542) o hydro-1 H-benzimidazol-5-ylmethyl)-2-oxo-
i ~~"o;~"~~"";so ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
~ " o ~ benzodiazepin-3-yl)-piperidine-1-
H H 0 carboxylate

CA 02565219 2006-10-17
- 129 -
Structure Name
"4 o (R)-2-[4-(4-methanesulphonyl-piperazin-1-
" yl)-piperidin-1-yl]-2-oxo-1-(1,3,7-trimethyl-
(543) 2-oxo-2,3-dihydro-1H-benzimidazol-5-
I ~-~"~o;~"~ ,s,o ylmethyl)-ethyl 4-(2-oxo-1,2,4,5-
~ " o tetrahydro-1,3-benzodiazepin-3-yl)-
H CH o i eridine-l-carbox late
W' I N (R)-2-[4-(4-methanesulphonyl-piperazin-l-
\ ~ yI)-piperidin-1-yl]-1-(8-methyl-quinoxalin-6-
(544) ~ o" ,o yi m ethyl)- 2-oxo-ethyl 4-(2-oxo-1,2,4,5-
I~ C" o o~"=S tetrahydro-1,3-benzodiazepin-3-yl)-
H 0 piperidine-l-carboxylate
"'1 (R)-2-[4-(4-methanesulphonyl-piperazin-1- N I yI)-piperidin-1-yl]-2-oxo-1-
quinoxalin-6-yl-
(545) ~,~ ~ ~ o,,o methyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
( " o o "~"~"=S~ 1,3-benzodiazepin-3-yl)-piperidine-1-
H 0 carboxylate
0'1 (R)-1-(4,5-dimethyl-3,4-dihydro-2H-1,4-
~ ", benzoxazin-7-ylmethyl)-2-[4-(4-methyl-
(546) -C ~ piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
" o o ~-"~"~
H 0 azepin-3-yl)-piperidine-1 -carboxylate
(R)-1-(4,5-dimethyl-3,4-dihydro-2H-1,4-
~ benzoxazin-7-ylmethyl)-2-[4-(1-methyl-
547 0 piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl
( ) % "-C"lo;y ~" 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
"4 o azepin-3-yl)-piperidine-1 -carboxylate
H 0
,, (R)-1-(4,5-dimethyl-3,4-dihydro-2H-1,4-
", benzoxazin-7-ylmethyl)-2-(1'-methyl-4,4'-
~ bipiperidinyl-1-yl)-2-oxo-ethyl 4-(2-oxo-
(548) "~"x" 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
"~ o yl)-piperidine-1 -carboxylate
H 0
o,l (R)-1-(4,5-dimethyl-3,4-dihydro-2H-1,4-
~ ", benzoxazin-7-ylmethyl)-2-oxo-2-(4-
549 - ' piperazin-1-yl-piperidin-1-yl)-ethyl 4-(2-
( ) "~"Jlo~"~"~ H oxo-1,2,4,5-tetrahydro-l,3-benzodiazepin-
I j"~ 0 o '~" 3-yl)-piperidine-1-carboxylate
H 0
o--) (R)-1-(4,5-dimethyl-3,4-dihydro-2H-1,4-
", benzoxazin-7-ylmethyl)-2-oxo-2-(4-
(550) o , piperidin-4-yl-piperazin-1-yl)-ethyi 4-(2-
I% ~~"Jlo~ ~"~"H oxo 1,2,4,5-tetrahydro-1,3 benzodiazepin-
" o 3-yl)-piperidine-1 -carboxylate
-carboxylate
H 0

CA 02565219 2006-10-17
- 130 -
Structure Name
o,l (R)-2-4,4'-bipiperidinyl-1-yI-1-(4,5-
dimethyl-3,4-dihydro-2H-1,4-benzoxazin-
0 7-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(551) "~" Jlo" H tetrahydro-1,3-benzodiazepin-3-yl)-
"~ o , piperidine-1 -carboxylate
H O
(R)-2-1,4'-bipiperidinyl-1'-yl-1-(4,5-
", dimethyl-3,4-dihydro-2H-1,4-benzoxazin-
~ 7-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(552) "~"xo_~-y "\~ " tetrahydro-1,3-benzodiazepin-3-yl)-
"-~ piperidine-1 -carboxylate
H O
O.,) (R)-1-(4,5-dimethyl-3,4-dihydro-2H-1,4-
N, benzoxazin-7-ylmethyl)-2-(4-morpholin-4-
~ yl-piperidin-l-yl)-2-oxo-ethyl 4-(2-oxo-
(553) "_C"JO"\~ 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
"4 yi)-piperidine-l-carboxylate
H 0
(R)-1-(4,5-dimethyl-3,4-dihydro-2H-1,4-
0'1 benzoxazin-7-ylmethyl)-2-oxo-2-[4-
\ (tetrahydro-pyran-4-yl)-piperazin-1-yl]-
(554) ~ ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
I ~-C" 0~1( benzodiazepin-3-yl)-piperidine-1 -
H 0 carboxylate
0,1 (R)-2-(4-cyclohexyl-piperazin-1-yl)-1-(4,5-
", dimethyl-3,4-dihydro-2H-1,4-benzoxazin-
~ 7-yimethyi)-2-oxo-ethyi 4-(2-oxo-1,2,4,5-
(555) 1 "~"xO~ tetrahydro-1,3-benzodiazepin-3-yl)-
"~ o piperidine-l-carboxylate
H O
~ (R)-1-(4,5-dimethyl-3,4-dihydro-2H-1,4-
", benzoxazin-7-ylmethyl)-2-(4-hydroxy-1,4 -
~ bipiperidinyl-1'-yi)-2-oxo-ethyl 4-(2-oxo-
(556) "~"xo"\~ oH 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
"-_~ o yl)-piperidine-1-carboxylate
H O
o") (R)-1-(4,5-dimethyl-3,4-dihydro-2H-1,4-
", benzoxazin-7-ylmethyl)-2-(4-methoxy-1,4'-
~ bipiperidinyl-1'-yI)-2-oxo-ethyl 4-(2-oxo-
(557) % "~"O~"~" 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
"~ o yl)-piperidine-l-carboxyiate
H O
o,l (R)-1-(4,5-dimethyl-3,4-dihydro-2H-1,4-
", benzoxazin-7-ylmethyl)-2-(4-hydroxy-4-
~ methyl-1,4'-bipiperidinyl-1'-yl)-2-oxo-ethyl
(558) "-C"xo-;Y"~" oH 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
"4 o ' azepin-3-yl)-piperidine-1 -carboxylate
H 0

CA 02565219 2006-10-17
-131 -
Structure Name
o,) (R)-2-(4,4-dimethyl-1,4'-bipiperidinyl-1'-yl)-
N, 1-(4,5-dimethyl-3,4-dihydro-2H-1,4-benz-
(559) o oxazin-7-ylmethyl)-2-oxo-ethyl 4-(2-oxo-
I N "ko7N~, 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
H -~ o yl)-piperidine-1-carboxylate
(R)-2-(4-amino-4-methyl-1,4'-bipiperidinyl-
~ N, 1'-yl)-1-(4,5-dimethyl-3,4-dihydro-2H-1,4-
0 benzoxazin-7-ylmethyl)-2-oxo-ethyl 4-(2-
(560) N~NxO~" N NH oxo-1,2,4,5-tetrahydro-1, p-
3-benzodiaze in
N4 o 155::I' 3-yl)-piperidine-l-carboxylate
H O
o--) (R)-1-(4,5-dimethyl-3,4-dihydro-2H-1,4-
N, benzoxazin-7-ylmethyl)-2-(4-hydroxy-4-hy-
o droxymethyl-1,4'-bipiperidinyl-1'-yl)-2-oxo-
(561) N NxO",~- ,N ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
o '~\ H benzodiazepin-3-yl)-piperidine-1-
" 0 carboxylate
(R)-1-(4,5-dimethyl-3,4-dihydro-2H-1,4-
~ benzoxazin-7-ylmethyl)-2-(1'-
(562) 0 ethoxycarbonylmethyl-4,4'-bipiperidinyl-l-
N-~NJ(o~o YI)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
H~o o N ~ 1,3-benzodiazepin-3-yl)-piperidine-1-
carbox late
(R)-2-(1'-carboxymethyl-4,4'-bipiperidinyl-
1-yl)-1-(4,5-dimethyl-3,4-dihydro-2H-1,4-
. benzoxazin-7-ylmethyl)-2-oxo-ethyl 4-(2-
(563) N Nxo NLo oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
I N o "~ '" 3-yl)-piperidine-1-carboxylate
H O
N"'), (R)-2-[4-(4-methyl-piperazin-1-yl)-
piperidin-1-yl]-1-(8-methyl-quinoxalin-6-
0 ylmethyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-
(564) "~"o~N~"~ tetrahydro-1,3-benzodiazepin-3-yl)-
~ ",(~ 0 '~" piperidine-1 -carboxylate
H O
(R)-2-[4-(1-methyl-piperidin-4-yl)-
~ piperazin-1-yl]-1-(8-methyl-quinoxalin-6-
0 ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(565) CC- x"~ tetrah dro
-1,3-benzodiaze in 3 I
N N O~( ~'~~ y p --y )-
No " piperidine-1-carboxyiate
-carboxylate
H O
(R)-2-(1'-methyl-4,4'-bipiperidinyl-1-yl)-1-
~ (8-methyl-quinoxalin-6-ylmethyl)-2-oxo-
(566) 0 ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
i Jl Nbenzodiazepin-3-yl)-piperidine-1-
I N~ (~" N
o carboxylate
H 0

CA 02565219 2006-10-17
-132-
Structure Name
" N (R)-1-(8-methyl-quinoxalin-6-yimethyl)-2-
~ oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl
(567) C 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
C o azepin-3-yl)-piperidine-1 -carboxylate
N
H O
N N (R)-1-(8-methyl-quinoxalin-6-ylmethyl)-2-
oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl
(568) CCN - N4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
-CN o1( vazepin-3-yl)-piperidine-1-carboxylate
N
N
H O
N'1 (R)-2-4,4'-bipiperidinyl-1-yl-1-(8-methyl-
~ " quinoxalin-6-ylmethyl)-2-oxo-ethyl 4-(2-
(569) oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
I ~-CN 0
~1( ~N" 3-yl)-piperidine-1 -carboxylate
N o
H O
N1 (R)-2-1,4'-bipiperidinyl-1'-y1-1-(8-methyl-
~ ~ quinoxalin-6-ylmethyl)-2-oxo-ethyl 4-(2-
(570) 0 oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
0 N~N o'1r ~ " 3-yl)-piperidine-1-carboxylate
N
H O
(R)-1-(8-methyl-quinoxalin-6-ylmethyl)-2-
N (4-morpholin-4-yl-piperidin-1-yf)-2-oxo-
0 ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
(571) N~"JIoyN~N~ benzodiazepin-3-yl)-piperidine-1-
N4 0 /\O carboxylate
H 0
(R)-1-(8-methyl-quinoxalin-6-ylmethyl)-2-
N oxo-2-[4-(tetrahydro-pyran-4-yl)-piperazin-
~ 1-yl]-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
(572) "~"JLo;~ ~" benzodiazepin-3-yl)-piperidine-1-
0 ~o carboxylate
H O
N N (R)-2-(4-cyclohexyl-piperazin-1-yl)-1-(8-
~ I methyl-quinoxalin-6-ylmethyl)-2-oxo-ethyl
(573) o ~ 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
I N-CNxo o azepin-3-yl)-piperidine-1-carboxylate
N4
H 0
N (R)-2-(4-hydroxy-1,4'-bipiperidinyl-1'-yl)-1-
~ N (8-methyl-quinoxalin-6-ylmethyl)-2-oxo-
574) _ ' ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
( CC ~ Jl ~N/y" OH benzodiazepin 3-yl)-pipendine-1-
O
N N
No o carboxylate
H 0

= ' CA 02565219 2006-10-17
- 133 -
Structure Name
(R)-2-(4-methoxy-1,4'-bipiperidinyl-1'-yi)-1-
N (8-methyl-quinoxalin-6-ylmethyl)-2-oxo-
(575) ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
I N-~No"\ " yo benzodiazepin-3-yl)-piperidine-1-
N~ 0 carboxylate
H O
N (R)-2-(4-hydroxy-4-methyl-1,4'-
N bipiperidinyl-1 yl)-1-(8-methyl-quinoxalin-
~ 6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(576) CQ tetrahYdro-1,3-benzodiaze P in-3-YI)
N OH
No '' piperidine-1 -carboxylate
H O
(R)-2-(4,4-dimethyt-1,4'-bipiperidinyl-1'-yl)-
~ 1-(8-methyl-quinoxalin-6-ylmethyl)-2-oxo-
(577) o = ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
" NJIo N~" benzodiazepin-3-yl)-piperidine-1-
N~ o '~ carboxylate
H 0
"~ (R)-2-(4-amino-4-methyl-1,4'-bipiperidinyl-
~ N 1 -yl)-1-(8-methyl-quinoxalin-6-ylmethyl)-2-
(578) ' oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
I N Nx0Y" N NHZ benzodiazepin-3-yl)-piperidine-1-
~ N~ o ~ carboxylate
H 0
carboxylate (R)-2-(4-hydroxy-4-
~N hydroxymethyl-1,4'-bipiperidinyl-1'-yl)-1-(8-
(579) methyl-quinoxalin-6-ylmethyl)-2-oxo-ethyl
I "-CNJIo y N\ ~' 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
N- ~ O ~ H azepin-3-yl)-piperidine-1-
H 0
(R)-2-(1'-ethoxycarbonylmethyl-4, 4'-
bipiperidinyl-1-yl)-1-(8-methyl-quinoxalin-
~ 6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(580) ~ _ " tetrahydro-1,3-benzodiazepin-3-yl)-
I~ N~~" o~ ~%,C'~N'1( ~ piperidine-1 -carboxylate
H 0
(R)-2-(1'-carboxymethyl-4,4'-bipiperidinyl-
~ 1-yI)-1-(8-methyl-quinoxalin-6-ylmethyl)-2-
(581) 0 oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
I ~\N JlO~N benzodiazepin-3-yl)-pipendine-1-
~-( N N H ~/ o ~IOI " carboxylate
(R)-1-(8-methyl-imidazo[1,2-a]pyridin-6-yl-
methyl)-2-[4-(4-methyl-piperazin-1-yl)-
piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-
(582) ~, 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
H-~ N J~ N yl)-piperidine-1-carboxylate

CA 02565219 2006-10-17
-134-
Structure Name
(R)-1-(8-methyl-imidazo[1, 2-a]pyridin-6-yl-
N methyl)-2-[4-(1-methyl-piperidin-4-yl)-
(583) o bIN~ piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-
(583) Nxo~ 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
H-~O '-' o yl)-piperidine-1 -carboxylate
(R)-2-(1'-methyl-4,4'-bipiperidinyl-1-yl)-1-
&N31' (8-methyl-imidazo[1,2-a]pyridin-6-
~ ylmethyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-
(584) tetrahydro-1,3-benzodiazepin-3-yl)-
N~N /~.
~ O ~' Ni
H-~o piperidine-l-carboxylate
(R)-1-(8-methyl-imidazo[1,2-a]pyridin-6-yl-
bIN methyl)-2-oxo-2-(4-piperazin-1-yl-
o J pi peridin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-
(585) % "~NXo H tetrahYdro-1,3-benzodiazePin-3-yI)-
I
H-~o o piperidine-1 -carboxylate
(R)-1-(8-methyl-imidazo[1,2-a]pyridin-6-yl-
methyl)-2-oxo-2-(4-piperidin-4-yl-
o bINJ piperazin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-
(586) "-C"xo~N-H tetrahydro-1,3-benzodiazepin-3-yl)-
H-=o o piperidine-l-carboxylate
(R)-2-4,4'-bipiperidinyl-1-yl-1-(8-methyl-
bIN N imidazo[1,2-a]pyridin-6-ylmethyl)-2-oxo-
0 J e thyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
(587) N-CNxo-;-yN~~~ " benzodiazepin-3-yl)-piperidine-l-
H-~o carboxylate
(R)-2-1,4'-bipiperidinyl-1'-y1-1-(8-methyl-
bIN imidazo[1,2-a]pyridin-6-ylmethyl)-2-oxo-
(588) o ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
I "-C"xo ~N~,N~ benzodiazepin-3-yl)-piperidine-1-
H4o o carboxylate
(R)-1-(8-methyl-imidazo[1,2-a]pyridin-6-yl-
~,N methyl)-2-(4-morpholin-4-yl-piperidin-1-yl)-
_~ INJ 2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-
(589) N-(
~\N kO " N~O 1,3-benzodiazePin-3-YI)-PiPeridine-l-
~ ~~/
02
H~o \-/ o carboxylate
(R)-1-(8-methyl-imidazo[1,2-a]pyridin-6-yl-
~N methyl)-2-oxo-2-[4-(tetrahydro-pyran-4-yl)-
piperazin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-
(590) CC N~Nx O~tetrahydro-1,3-benzodiazepin-3-yl)-
piperidine-1 -carboxylate
Ho 0 0

= ' CA 02565219 2006-10-17
-135-
Structure Name
(R)-2-(4-cyclohexyl-piperazin-1-yl)-1-(8-
~ methyl-imidazo[1,2-a]pyridin-6-ylmethyl)-2-
o NJ oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
(591)
I N-CNxO~ benzodiazepin-3-yl)-piperidine-1-
H-~o o carboxylate
(R)-2-(4-hydroxy-1,4'-bipiperidinyl-1'-yl)-1-
N (8-methyl-imidazo[1,2-a]pyridin-6-
o , NJ ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(592)
I N-CNo-y\tetrahydro-1,3-benzodiazepin-3-yl)-
H-~o o piperidine-1-carboxylate
(R)-2-(4-methoxy-1,4'-bipiperidinyl-1'-yI)-1-
~N (8-methyl-imidazo[1,2-a]pyridin-6-
o ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(593) N--CNxo'y"~.NVtetrahydro-1,3-benzodiazepin-3-yl)-
H-~o o piperidine-1 -carboxylate
(R)-2-(4-methoxy-1,4'-bipiperidinyl-1'-yl)-1-
N (8-methyl-imidazo[1,2-a]pyridin-6-
(594) o ,,"~ ylmethyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-
i N~Nxo~"~. N ~o, tetrahydro-1,3-benzodiazepin-3-yl)-
H-~o o piperidine-1 -carboxylate
(R)-2-(4-hydroxy-4-methyl-1,4'-
N bipiperidinyl-1'-yl)-1-(8-methyl-imidazo[1,2-
(595) o blN~ a]pyridin-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-
CQ N-C"o 'y"/=,N\~, oH 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
N~ o I yI)-piperidine-l-carboxylate
H O
(R)-2-(4,4-dimethyl-1,4'-bipiperidinyl-1'-yl)-
,N 1-(8-methyl-imidazo[1,2-a]pyridin-6-yl-
0 -~,N~J methyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-
(596) ~N NxO-('"~." tetrahydro-1,3-benzodiazepin-3-yl)-
'N-~ ~ o ~ piperidine-1 -carboxylate
H O
(R)-2-(4-amino-4-methyl-1,4'-bipiperidinyl-
1'-yl)-1-(8-methyl-imidazo[1,2-a]pyridin-6-
o bNJ ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
(597) N~ NO~'"~."NHZ tetrahydro-1,3-benzodiazepin-3-yl)-
H-~o ~-' o piperidine-1 -carboxylate
(R)-2-(4-hyd roxy-4-hyd roxym ethyl-1, 4'-
~ bipiperidinyl-1'-yI)-1-(8-methyl-imidazo[1,2-
(598) ~, INJ a]pyridin-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-
I ~N o~N,~ o~ 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
H-(~o 0 oH yI)-piperidine-1-carboxylate

CA 02565219 2006-10-17
- 136 -
Structure Name
( R)-2-(1'-ethoxyca rbonyl methyl-4, 4'-
bipiperidinyl-l-yl)-1-(8-methyl-imidazo[1,2-
o ~I"J a]pyridin-6-ylmethyl)-2-oxo-ethyl4-(2-oxo-
(599) "~"xo~" " ~
o 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
H-~o o ~%~'~ o I yl)-piperidine-1-carboxylate
(R)-2-(1'-carboxymethyi-4,4'-bipiperidinyl-
~" 1-yl)-1-(8-methyl-imidazo[1,2-a]pyridin-6-
o ~,1"J ylmethyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-
600
I "_C"-k o'Y o." tetrahydro-1,3-benzodiazepin-3-yl)-
H-~o 0 o piperidine-l-carboxylate
o (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
N benzoxazol-6-ylmethyl)-2-[4-(8-methyl-8-
601 o aza-bicyclo[3.2.1]oct-3-yl)-piperazin-1-yl]-
( ) "~"Xo N "~", 2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
"~ 0 1,3-benzodiazepin-3-yl)-piperidine-1-
" 0 carbox late
o (R)-2-[4-(4-cyclopropyl-piperazin-1-yl)-
4
N piperidin-1-yl]-1-(3,4-dimethyl-2-oxo-2,3-
J ' dihydro-benzoxazol-6-ylmethyl)-2-oxo-
(602) ~" o ""~ ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
" o '~" benzodiazepin-3-yl)-piperidine-1-
" 0
carbox late
(R)-2-[4-(8-methyl-8-aza-bicyclo[3.2.1 ]oct-
0 3-yl)-piperazin-1-yl]-1-(8-methyl-2,3-
~ dihydro-1,4-benzodioxin-6-ylmethyl)-2-
(603) oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
I o o '~'"~ benzodiazepin-3-yl)-piperidine-1-
H o carboxylate
l (R)-2-[4-(5-methyl-2,5-diaza-bicyclo[2.2.1 ]-
~,o hept-2-yl)-piperidin-1-yl]-1-(8-methyl-2,3-
,.~ dihydro-1,4-benzodioxin-6-ylmethyl)-2-
(604) "_C"Xo~y"~"~", oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
"-~ o benzodiazepin-3-yl)-piperidine-1-
" 0 carbox late
( R)-2-[4-(1-aza-bicyclo[2.2.2]oct-3-yl )-
o piperazin-1-yl]-1-(8-methyl-2,3-dihydro-
~~ 1,4-benzodioxin-6-ylmethyl)-2-oxo-ethyl 4-
(605) "o~~" (2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
"-~( ~~ azepin-3-yl)-piperidine-l-carboxylate
" o
(R)-1-(8-methyl-2,3-dihydro-1,4-
o benzodioxin-6-ylmethyl)-2-oxo-2-[4-(5-oxo-
. perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-
(606) r-I "" ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
"-~ benzodiazepm-3-yl) piperidine-1-
" 0 carbox late
the enantiomers, the diastereomers and the salts thereof, while the compounds

CA 02565219 2006-10-17
- 137 -
(1) (R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-[4-(4-methyl-piperazin-1-yl)-
piperidin-
1-yI]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-
piperidine-l-carboxylate,
(2) (R)-1-(4-amino-3-methyl-5-nitro-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-
piperi-
din-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-
piperidine-1-carboxylate,
1 o (3) (R)-1-(3,4-diamino-5-methyl-benzyi)-2-[4-(4-methyl-piperazin-1-yl)-
piperidin-
1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro- 1,3-benzodiazepin-3-yl)-
piperidine-1-carboxylate,
(4) (R)-1-(7-methyl-1 H-benzimidazol-5-ylmethyl)-2-[4-(4-methyl-piperazin-1 -
yl)-
piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-
piperidine-1 -carboxylate,
(5) (R)-2-4,4'-bipiperidinyl-1 -yl-1-(7-methyl-1 H-benzimidazol-5-yimethyl)-2-
oxo-
ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-
carboxylate,
(6) (R)-1-(7-methyl-1 H-benzimidazol-5-ylmethyl)-2-oxo-2-(4-piperazin-l-yl-
piperi-
din-1-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
1-carboxylate,
(7) (R)-1 -(2,7-dimethyl-1 H-benzimidazol-5-ylmethyl)-2-[4-(4-methyl-piperazin-
1-yl)-piperidin-l-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-
3-yl)-piperidine-l-carboxylate,
(8) (R)-1-(7-methyl-2-oxo-2,3-dihydro-1 H-benzimidazol-5-ylmethyl)-2-[4-(4-
methyl-
piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(9) (R)-1-(2-cyclopropyl-7-methyl-1 H-benzimidazol-5-ylmethyl)-2-[4-(4-methyl-

CA 02565219 2006-10-17
- 138 -
piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-l,3-
benzodiazepin-3-yl)-piperidine-l-carboxylate,
(10) (R)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-1-(7-methyl-2-
trifluoromethyl-
1 H-benzimidazol-5-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(11) (R)-1-(2-methoxy-7-methyl-1 H-benzimidazol-5-ylmethyl)-2-[4-(4-methyl-
piperazin-l-yl)-piperidin-l-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(12) (R)-2-[4-(4-methyl-piperazin-1-yi)-piperidin-1-yi]-1-(8-methyl-quinoxalin-
6-yl-
methyl)-2-oxo-ethyl 4-(2-oxo-1, 2, 4, 5-tetrahyd ro-1, 3-benzod iazepi n-3-yl
)-
piperidine-1-carboxylate,
(13) (R)-1-{2-[(Z)-cyanimino]-7-methyl-2,3-dihydro-lH-benzimidazol-5-ylmethyl}-
2-
[4-(4-methyl-piperazin-l-yl)-piperidin-1-yl]-2-oxo-ethy) 4-(2-oxo-1,2,4,5-
tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,
(14) (R)-1-(7-methyl-1 H-benzotriazol-5-ylmethyl)-2-[4-(4-methyl-piperazin-1 -
yl)-
pipe rid i n- 1 -yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
3-yl)-
piperidine-1-carboxylate,
(15) (R)-2-(1'-methanesulphonyl-4,4'-bipiperidinyl-1-yl)-1-(7-methyl-1H-
benzimidazol-5-ylmethyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(16) (R)-1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-[4-(4-methyl-
piperazin-l-yl)-piperidin-l-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yi)-piperidine-1-carboxylate,
(17) (R)-1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-[4-(1-methyl-
piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-l,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,

CA 02565219 2006-10-17
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(18) (R)-2-(4-amino-4-methyl-1,4'-bipiperidinyl-1'-yI)-1-(4-methyl-2-oxo-2,3-
dihydro-
benzoxazol-6-ylmethyl )-2-oxo-ethyl 4-(2-oxo-1, 2,4, 5-tetrahyd ro-1, 3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(19) (R)-1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-(1'-
sulpha-
moyl-4,4'-bipiperidinyl-l-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
1 o (20) (R)-2-(1'-methanesulphonyl-4,4'-bipiperidinyl-1-yl)-1-(4-methyl-2-oxo-
2,3-
d ihyd ro-benzoxazol-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4, 5-tetrahydro-1, 3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(21) (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-[4-(1-
methyl-
piperidin-4-yi)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(22) (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-[4-(4-
methyl-
piperazin-1-y1)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1 -carboxylate,
(23) (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyi)-2-(1'-methyl-
4,4'-bipiperidinyl-1-yi)-2-oxo-ethyi 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-l-carboxylate,
(24) (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-(4-hydroxy-
1,4'-bipiperidinyl-1'-yi)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-l-carboxylate,
(25) (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-(1'-
sulphamoyl-4,4'-bipiperidinyl-1-yl)-ethyi 4-(2-oxo-1,2,4,5-tetrahydro-l,3-
benzod iazepin-3-yl)-pi pe rid i ne-l-ca rboxylate,
(26) (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-(1'-

CA 02565219 2006-10-17
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methanesutphonyl-4,4'-bipiperidinyl-l-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,
(27) (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-[4-(8-
methyl-
8-aza-bicyclo[3.2.1 ]oct-3-yi)-piperazin-l-yi]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,
(28) (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-(4-
pi-
perazin-1-yl-piperidin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(29) (R)-2-4,4'-bipiperidinyl-1-y1-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
benzoxazol-
6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1, 3-benzodiazepin-3-yl)-
piperidine-l-carboxylate,
(30) (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-(4-
pi-
peridin-4-yl-piperazin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yi)-piperidine-1-carboxylate,
(31) (R)-2-(4-amino-4-methyl-1,4'-bipiperidinyl-1'-yI)-1-(3,4-dimethyl-2-oxo-
2,3-
dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4, 5-tetrahyd ro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(32) (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-(1'-ethoxy-
carbonylmethyl-4,4'-bipiperidinyl-l-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-
1,3-benzodiazepin-3-yl)-piperidine-1 -carboxylate,
(33) (R)-2-(1'-carboxymethyl-4,4'-bipiperidinyl-1 -yl)-1-(3,4-dimethyl-2-oxo-
2,3-di-
hyd ro-benzoxazol-6-yl methyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1 -carboxylate,
(34) (R)-2-1,4'-bipiperidinyl-1'-yI-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
benzoxazol-
6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahyd ro-1,3-benzod iazepin-3-yl)-
piperidine-1-carboxylate,

CA 02565219 2006-10-17
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(35) (R)-2-[4-(4-cyclopropyl-piperazin-1-yl)-piperidin-1-yl]-1-(3,4-dimethyl-2-
oxo-
2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4, 5-tetrahydro-
1,3-benzodiazepin-3-yl)-piperidine-l-carboxylate,
(36) (R)-2-(4-cyclohexyl-piperazin-1-yl)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
benz-
oxazol-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1, 2,4, 5-tetrahydro-1,3-benzodiazepin-
3-yI)-piperidine-l-carboxylate,
(37) (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-[4-
(tetrahydro-pyran-4-yl)-piperazin-l-yl]-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1, 3-
benzodiazepin-3-yl)-piperidine-l-carboxylate,
(38) (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-(4-hydroxy-
4-hydroxymethyl-1,4'-bipiperidinyl-1'-yI)-2-oxo-ethyl4-(2-oxo-1,2,4,5-
tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,
(39) (R)-1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-[4-(4-methyl-piperazin-l-
yl)-
piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
yl)-
piperidine-1 -carboxylate,
(40) (R)-1-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-[4-(4-methyl-
pipera-
zin-1-yl)-piperidin-l-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(41) (R)-2-(1'-methyl-4,4'-bipiperidinyl-1-yl)-1-(8-methyl-2,3-dihydro-1,4-
be nzod i oxi n-6-yl methyl )-2-oxo-ethyl 4-(2-oxo-1, 2, 4, 5-tetra hyd ro-1,
3-
benzodiazepin-3-yl)-piperidine-l-carboxylate,
(42) (R)-2-(4-hydroxy-1,4'-bipiperidinyl-1'-yI)-1-(8-methyl-2,3-dihydro-1,4-
benzodi-
oxi n-6-yimethyl )-2-oxo-ethyl 4-(2-oxo-1, 2,4, 5-tetrahyd ro-1, 3-benzod
iazepi n-3-
yI)-piperidine-1-carboxylate,
(43) (R)-1-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-(4-morpholin-4-
yl-

CA 02565219 2006-10-17
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piperidin-1-yl)-2-oxo-ethyi 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
yl)-
piperidine-1-carboxylate,
(44) (R)-1-(8-methyl-2,3-dihydro-l,4-benzodioxin-6-ylmethyl)-2-oxo-2-[4-(5-oxo-
perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-ethyl4-(2-oxo-1,2,4,5-tetrahydro-
1,3-benzodiazepin-3-yl)-piperidine-1 -carboxylate,
(45) (R)-2-(1'-ethoxycarbonylmethyl-4,4'-bipiperidinyl-1-yi)-1-(8-methyl-2,3-
dihydro-
1,4-benzodioxin-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yi)-piperidine-1 -carboxylate,
(46) (R)-1-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-[4-(1-methyl-
piperi-
din-4-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yi)-piperidine-l-carboxylate,
(47) (R)-2-1,4'-bipiperidinyl-1'-y1-1-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-
yl-
methyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yi)-
piperidine-1-carboxylate,
(48) (R)-2-[4-(8-methyl-8-aza-bicyclo[3.2.1 ]oct-3-yi)-piperazin-1-yi]-1-(8-
methyl-2,3-
d i hyd ro-1,4-benzod ioxi n-6-yl methyl)-2-oxo-ethyl 4-(2-oxo-1,2, 4, 5-
tetrahyd ro-
1,3-benzodiazepin-3-yl)-piperidine-l-carboxylate,
(49) (R)-2-[4-(5-methyl-2,5-diaza-bicyclo[2.2.1 ]hept-2-yl)-piperidin-1-yl]-1-
(8-methyl-
2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-
tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,
(50) (R)-2-[4-(1-aza-bicyclo[2.2.2]oct-3-yl)-piperazin-1 -yl]-1-(8-methyl-2,3-
dihydro-
1,4-benzodioxin-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxyiate,
(51) (R)-1-(8-methyl-2,3-dihydro-l,4-benzodioxin-6-ylmethyl)-2-oxo-2-(4-
piperazin-
1-yl-piperidin-1-yl)-ethyl 4-(2-oxo-1,2,4, 5-tetrahydro-1,3-benzodiazepin-3-
yl)-
piperidine-1-carboxylate,

CA 02565219 2006-10-17
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(52) (R)-1-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-oxo-2-(4-
piperidin-
4-yl-piperazin-1-yi)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-
piperidine-1-carboxylate,
(53) (R)-2-(1'-carboxymethyl-4,4'-bipiperidinyl-1-yl)-1-(8-methyl-2,3-dihydro-
1,4-
benzod ioxin-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahyd ro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(54) (R)-2-(4-amino-4-methyl-1,4'-bipiperidinyl-1'-yI)-1-(8-methyl-2,3-dihydro-
1,4-
benzodioxin-6-ylmethyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate,
(55) (R)-2-(1'-methanesulphonyl-4,4'-bipiperidinyl-1-yl)-1-(8-methyl-2,3-
dihydro-1,4-
be nzod ioxi n-6-yl m eth yl )-2-oxo-ethyl 4-( 2-oxo-1, 2, 4, 5-tetra hyd ro-
1, 3-
benzodiazepin-3-yi)-piperidine-1-carboxylate,
(56) (R)-2-[4-(4-methanesulphonyl-piperazin-1-yl)-piperidin-1-yl]-1-(8-methyl-
2,3-di-
hydro-1,4-benzodioxin-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-l-carboxylate,
(57) (R)-1-(8-methyl-imidazo[1,5-a]pyridin-6-ylmethyl)-2-[4-(4-methyl-
piperazin-1-
yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-l,3-benzodiazepin-
3-
yl)-piperidine-1-carboxylate,
(58) (R)-2-(1'-methyl-4,4'-bipiperidinyl-1-yl)-1-(8-methyl-imidazo[1,2-
a]pyridin-6-yl-
methyl )-2-oxo-ethyl 4-(2-oxo-1, 2, 4, 5-tetrahyd ro-1, 3-benzod iazepi n-3-
yl)-
piperidine-1-carboxylate,
(59) (R)-1-(8-methyl-imidazo[1,2-a]pyridin-6-ylmethyl)-2-[4-(1-methyl-
piperidin-4-yi)-
piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
yl)-piperidine-1 -carboxylate,
the enantiomers, the diastereomers and the salts thereof are of exceptional
importance.

, = CA 02565219 2006-10-17
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The compounds of general formula (I) are prepared by methods known in
principle.
The following processes have proved particularly suitable for preparing the
compounds of general formula (I) according to the invention:
(a) In order to prepare compounds of general formula (I) wherein all the
groups are
as hereinbefore defined:
coupling a carboxylic acid of general formula
Q
A
N'11~ X O, H
O
R , (III)
wherein all the groups are as hereinbefore defined, with an amine of general
formula
HNR2R3, wherein R2 and R3 are as hereinbefore defined. Before the reaction,
any
carboxylic acid functions, primary or secondary amino functions or hydroxy
functions
present in a compound of formula (III) and/or in the groups R2 and R3 of the
amine of
formula HNR2R3 may be protected by conventional protecting groups and after
the
reaction any protecting groups used may be cleaved using methods familiar to
those
skilled in the art.
2o The coupling is preferably carried out using methods known from peptide
chemistry
(cf. e.g. Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for
example
using carbodiimides such as e.g. dicyclohexylcarbodiimide (DCC), diisopropyl
carbodiimide (DIC) or ethyl-(3-dimethylaminopropyl)-carbodiimide,
O-(1H-benzotriazol-1-yl)- N,N-N',N'tetramethyluronium hexafluorophosphate
(HBTU)
or tetrafluoroborate (TBTU) or 1 H-benzotriazol-1 -yl-oxy-
tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP). By adding
1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-
benzotriazine
(HOObt) the reaction speed can be increased. The couplings are normally
carried out
with equimolar amounts of the coupling components as well as the coupling
reagent
in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethyl
formamide (DMF), dimethyl acetamide (DMA), N-methylpyrrolidone (NMP) or

CA 02565219 2006-10-17
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mixtures thereof and at temperatures between -30 and +30 C, preferably -20 and
+25 C. If necessary, N-ethyl-diisopropylamine (Hunig base) is preferably used
as an
additional auxiliary base.
The so-called anhydride process is used as a further coupling method for
synthesising compounds of general formula (I) (cf. also: M. Bodanszky,
"Peptide
Chemistry", Springer-Veriag 1988, p. 58-59; M. Bodanszky, "Principles of
Peptide
Synthesis", Springer-Verlag 1984, p. 21-27). The Vaughan variant of the mixed
anhydride process is preferred (J.R. Vaughan Jr., J. Amer. Chem. Soc. 73, 3547
1o (1951)), in which the mixed anhydride of the carboxylic acid of general
formula (III)
which is to be coupled and monoisobutyl carbonate is obtained, using isobutyl
chlorocarbonate in the presence of bases such as 4-methylmorpholine or
4-ethylmorpholine. The preparation of this mixed anhydride and the coupling
with
amines are carried out in a one-pot process, using the above-mentioned
solvents
and at temperatures between -20 and +25 C, preferably 0 C and +25 C.
(b) In order to prepare compounds of general formula (I) wherein all the
groups are
as hereinbefore defined:
coupling a compound of general formula
Q
A
Nu
N X
1
R ~
(IV)
with an amine of general formula HNR2R3,
wherein all the groups are as hereinbefore defined and Nu denotes a leaving
group,
for example a halogen atom, such as the chlorine, bromine or iodine atom, an
alkylsulphonyloxy group with 1 to 10 carbon atoms in the alkyl moiety, a
phenylsulphonyloxy or naphthylsulphonyloxy group optionally mono-, di- or
trisubstituted by chlorine or bromine atoms, by methyl or nitro groups, while
the

CA 02565219 2006-10-17
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substituents may be identical or different, a 1H-imidazol-1 -yi, a 1H-pyrazol-
1 -yl
optionally substituted by one or two methyl groups in the carbon skeleton, a
1 H-1,2,4-triazol-1-yl, 1 H-1,2,3-triazol-1 -yl, 1 H-1,2,3,4-tetrazol-1 -yl, a
vinyl, propargyl,
p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl,
pentafluorophenyl, pyranyl or pyridinyl, a dimethylaminyloxy, 2(1H)-oxopyridin-
1 -yl-
oxy, 2,5-dioxopyrrolidin-1 -yloxy, phthalimidyloxy, 1H-benzo-triazol-1 -yloxy
or azide
group. Before the reaction any carboxylic acid functions, primary or secondary
amino
functions or hydroxy functions present in a compound of formula (IV) and/or in
the
groups R2 and R3 of the amine of formula HNR2R3 may be protected by
conventional
1o protecting groups and after the reaction any protecting groups used may be
cleaved
again using methods familiar to those skilled in the art.
The reaction is carried out under Schotten-Baumann or Einhorn conditions, i.e.
the
components are reacted in the presence of at least one equivalent of an
auxiliary
base at temperatures between -50 C and +120 C, preferably -10 C and +30 C, and
optionally in the presence of solvents. The auxiliary bases used are
preferably alkali
metal and alkaline earth metal hydroxides, e.g. sodium hydroxide, potassium
hydroxide or barium hydroxide, alkali metal carbonates, e.g. sodium carbonate,
potassium carbonate or caesium carbonate, alkali metal acetates, e.g. sodium
or
potassium acetate, as well as tertiary amines, e.g. pyridine, 2,4,6-
trimethylpyridine,
quinoline, triethylamine, N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine,
1,4-diazabicyclo[2,2,2]octane or 1,8-diazabicyclo[5,4,0]undec-7-ene, the
solvents
used may be, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane,
acetonitrile, dimethyl formamide, dimethyl acetamide, N-methyl-pyrrolidone or
mixtures thereof; if alkali metal or alkaline earth metal hydroxides, alkali
metal
carbonates or acetates are used as the auxiliary bases, water may also be
added to
the reaction mixture as cosolvent.
The new compounds of general formula (I) according to the invention contain
one or
more chiral centres. If for example there are two chiral centres the compounds
may
occur in the form of two pairs of diastereomeric antipodes. The invention
covers the
individual isomers as well as the mixtures thereof.

CA 02565219 2006-10-17
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The diastereomers may be separated on the basis of their different physico-
chemical
properties, e.g. by fractional crystallisation from suitable solvents, by high
pressure
liquid or column chromatography, using chiral or preferably non-chiral
stationary
phases.
Racemates covered by general formula (I) may be separated for example by HPLC
on suitable chiral stationary phases (e.g. Chiral AGP, Chiralpak AD).
Racemates
which contain a basic or acidic function can also be separated via the
diastereomeric,
optically active salts which are produced on reacting with an optically active
acid, for
example (+) or (-)-tartaric acid, (+) or (-)-diacetyl tartaric acid, (+) or (-
)-monomethyl
tartrate or (+)-camphorsulphonic acid, or an optically active base, for
example with
(R)-(+)-1-phenylethylamine, (S)-(-)-1-phenylethylamine or (S)-brucine.
According to a conventional method of separating isomers, the racemate of a
compound of general formula (I) is reacted with one of the above-mentioned
optically
active acids or bases in equimolar amounts in a solvent and the resulting
crystalline,
diastereomeric, optically active salts thereof are separated using their
different
solubilities. This reaction may be carried out in any type of solvent provided
that it is
sufficiently different in terms of the solubility of the salts. Preferably,
methanol,
ethanol or mixtures thereof, for example in a ratio by volume of 50:50, are
used.
Then each of the optically active salts is dissolved in water, carefully
neutralised with
a base such as sodium carbonate or potassium carbonate, or with a suitable
acid,
e.g. dilute hydrochloric acid or aqueous methanesulphonic acid, and in this
way the
corresponding free compound is obtained in the (+) or (-) form.
The (R) or (S) enantiomer alone or a mixture of two optically active
diastereomeric
compounds covered by general formula I may also be obtained by performing the
syntheses described above with a suitable reaction component in the (R) or (S)
configuration.
The needed as starting compounds hydroxycarboxylic acids of general formula
(III)
are obtained by reacting piperidines of general formula

CA 02565219 2006-10-17
- 148 -
R~
NH , (V)
wherein R' is as hereinbefore defined, with carbonic acid derivatives of
general
formula
A
Y~Y
~ 2 , (VI)
wherein Y, and Y2 represent nucleofugic groups which may be identical or
different,
preferably the chlorine atom, the p-nitrophenoxy or trichloromethoxy group, if
A
denotes the oxygen atom, or the chlorine atom, if A denotes the sulphur atom,
and with compounds of general formula
Q
H\X ---(; O\Zi
0 , (VII)
wherein X and Q are as hereinbefore defined and Z, denotes a protective group
for a
carboxy group, for example a Cl-6-alkyl or benzyl group, while the alkyl
groups may
be straight-chain or branched and the benzyl group may be substituted by one
or two
methoxy groups. Preferably Z, is the methyl, ethyl, tert-butyl or benzyl
group. Before
the reaction any carboxylic acid functions, primary or secondary amino
functions or
hydroxy functions present in the group R' of a compound of formula (V) and/or
in a
compound of formula (VII) may be protected by conventional protecting groups
and
after the reaction any protecting groups used may be cleaved again by methods
familiar to those skilled in the art.
In a first step the compounds of general formula (V) are reacted in a solvent,
for
example in dichloromethane, THF, pyridine or mixtures thereof, at a
temperature
from -20 to 50 C in the presence of a base, for example triethylamine,
pyridine or
ethyldiisopropylamine, with the carbonic acid derivatives of general formula
(VI). The

CA 02565219 2006-10-17
-149-
resulting intermediate may be purified or reacted further without
purification.
The reaction of these intermediates with compounds of general formula (V1I) is
also
carried out in one of the above-mentioned solvents, and at the temperatures
specified above, in the presence of a base, such as triethylamine or pyridine,
with or
without the addition of an activating reagent, such as e.g. 4-
dimethylaminopyridine.
To activate them the compounds of general formula (Vii) may also be
deprotonated
using a metal hydride, such as e.g. NaH or KH, while in this case the base or
the
activating reagent may be omitted.
The starting compounds of formula (V) and (VI) are either commercially
obtainable,
known from the literature or may be prepared by methods known from the
literature.
If the group X in compounds of general formula (VII) denotes the oxygen atom,
the
hydroxycarboxylic acids of general formula
Q
H., O O, H
O ,(VIII)
which are needed for the synthesis may be obtained from compounds of general
formula
Q
H, N O" H (IX)
H O
while Q in both formulae is as hereinbefore defined.
By diazotising compounds of general formula (IX) with a suitable diazotising
reagent,
preferably sodium nitrite in an acid medium, it is possible to obtain the
compounds of
general formula (VIII). If enantiomerically pure compounds are used the
corresponding enantiomerically pure hydroxycarboxylic acid compounds are
obtained, the configuration being retained as the reaction proceeds.

CA 02565219 2006-10-17
- 150 -
An alternative method of obtaining compounds of general formula (VIII), if Q
is not
bound by a nitrogen atom, comprises reacting aldehydes of general formula (X)
with
N-acetylglycine in acetic anhydride as solvent in the presence of alkali metal
acetate,
preferably sodium or potassium acetate, at a suitable temperature, preferably
at 80-
130 C.
Q
O O~
H Q
~ AN H ,(XI)
I-r
O I(X) H O
The aziactones obtained as primary product are hydrolysed without being
isolated to
form the compounds of general formula (XI). By further reaction in the
presence of
aqueous inorganic acids, such as sulphur, phosphorus or hydrochloric acid, but
preferably hydrochloric acid, compounds of general formula (XII) are obtained.
These
are then converted with suitable reducing agents into the compounds of general
formula (VIII).
Q
O O, H
0
,(XII)
Suitable reducing agents are alkali metal borohydrides, such as sodium or
potassium
borohydride. Other suitable reducing agents are chlorodialkylboranes, such as
chlorodicyclohexylborane. If chiral chlorodialkylboranea, such as e.g. B-
chlorodiisopinocampheylborane, are used, the compounds of general formula
(VIII)
may be isolated in enantiomerically pure form.
If Q is not bound by a nitrogen atom, another method of obtaining compounds of
general formula (VIII) comprises alkylating compounds of formula

CA 02565219 2006-10-17
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O O
O,,-N /~ O
(XIII)
with compounds of general formula
C Q
Hal (XIV)
wherein Hal denotes a chlorine, bromine or iodine atom, and Q is as
hereinbefore
defined, analogously to methods known from the literature (Michael T.
Crimmins,
Kyle A. Emmitte and Jason D. Katz, Org. Lett. 2, 2165-2167 [20001). The
diastereomeric products formed may then be separated by physicochemical
methods, preferably by chromatographic methods or recrystallisation. The
hydrolytic
cleaving of the chiral auxiliary and cleaving of the benzyl protective group
also
provides a way of obtaining enantiomerically pure hydroxycarboxylic acid
compounds
of general formula (VII). The further reaction of compounds of general formula
(VIII)
5 to compounds of general formula (VII) is carried out in an alcoholic medium,
preferably in methanol or ethanol, in the presence of a suitable acid, such as
hydrochloric acid. Alternatively, the reaction may be carried out by reaction
in
alcoholic solvents, preferably methanol, with thionylchloride.
If the group X in compounds of general formula (VII) denotes the sulphur atom,
the
thiocarboxylic acids of general formula
Q
H, S O" Z
1
0 ,(XV)

CA 02565219 2006-10-17
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needed for the synthesis, wherein Q is as hereinbefore defined and Z, denotes
a
protective group for a carboxy group as described in process (a), are obtained
from
compounds of general formula (VII) wherein X denotes the oxygen atom.
The corresponding alkylthiocarboxylic acid esters of these compounds may be
obtained by Mitsunobu reaction of the compounds of general formula (VII) with
C1_6-
alkylthiocarboxylic acids, while the alkyl chain may be straight-chain or
branched but
preferably denotes the methyl group. They may be hydrolysed by known methods
to
form the compounds of general formula (XV) (Bert Strijtveen and Richard M.
Kellogg,
J.Org. Chem. 51, 3664-3671 [1986]).
All the compounds of general formula (I) which contain primary or secondary
amino,
hydroxy or hydroxycarbonyl functions, are preferably obtained from precursors
with
protective groups. Examples of protective groups for amino functions include
the
benzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitro-benzyloxycarbonyl,
4-methoxy-benzyloxycarbonyl, 2-chloro-benzyloxycarbonyl, 3-chloro-
benzyloxycarbonyl, 4-chloro-benzyloxycarbonyl, 4-biphenylyl-a,a-dimethyi-
benzyl-
oxycarbonyl or 3,5-dimethoxy-a,a-dimethyl-benzyloxycarbonyl group, a
alkoxycarbonyl group with a total of 1 to 5 carbon atoms in the alkyl moiety,
for
2o example the methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso-
propoxycarbonyl, n-butoxycarbonyl, 1-methylpropoxycarbonyl, 2-methylpropoxy-
carbonyl or tert-butyloxycarbonyl group, the allyloxycarbonyl, 2,2,2-trichloro-
(1, 1 -dimethylethoxy)carbonyl or 9-fluorenylmethoxycarbonyl group or a
formyl, acetyl
or trifluoracetyl group.
Examples of protective groups for hydroxy functions include the
trimethylsilyl,
triethylsilyl, triisopropyl, tert-butyldimethylsilyl or tert-
butyldiphenylsilyl group, a tert-
butyl, benzyl, 4-methoxybenzyl or 3,4-dimethoxybenzyl group.
3o Examples of protective groups for hydroxycarbonyl functions include an
alkyl group
with a total of 1 to 5 carbon atoms, for example the methyl, ethyl, n-propyl,
isopropyl,
n-butyl, tert-butyl, allyl, 2,2,2-trichloroethyl, benzyl or 4-methoxybenzyl
group.

CA 02565219 2006-10-17
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The compounds of general formula I obtained may, if they contain suitable
basic
functions, be converted, particularly for pharmaceutical use, into their
physiologically
acceptable salts with inorganic or organic acids. Suitable acids include for
example
hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric
acid,
methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid,
p-toluenesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic
acid, mandelic
acid, malic acid, citric acid, tartaric acid or maleic acid.
Moreover, if they contain a carboxylic acid function, the new compounds of
formula
1o (I) may be converted into the addition salts thereof with inorganic or
organic bases,
particularly, for pharmaceutical use, into their physiologically acceptable
addition
salts. Suitable bases for this include for example sodium hydroxide, potassium
hydroxide, ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine,
diethanolamine and triethanolamine.
The present invention relates to racemates if the compounds of general formula
(I)
have only one chiral element. However, the application also includes the
individual
diastereomeric pairs of antipodes or mixtures thereof which are obtained if
there is
more than one chiral element in the compounds of general formula (I), as well
as the
individual optically active enantiomers of which the above-mentioned racemates
are
made up.
Also included in the subject matter of this invention are the compounds
according to
the invention, including the salts thereof, in which one or more hydrogen
atoms, for
example one, two, three, four or five hydrogen atoms, are replaced by
deuterium.
The new compounds of general formula (I) and the physiologically acceptable
salts
thereof have valuable pharmacological properties, based on their selective
CGRP-
antagonistic properties. The invention further relates to pharmaceutical
compositions
containing these compounds, their use and the preparation thereof.
The new compounds mentioned above and the physiologically acceptable salts
thereof have CGRP-antagonistic properties and exhibit good affinities in CGRP
receptor binding studies. The compounds display CGRP-antagonistic properties
in

CA 02565219 2006-10-17
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the pharmacological test systems described hereinafter.
The following experiments were carried out to demonstrate the affinity of the
above-
mentioned compounds for human CGRP-receptors and their antagonistic
properties:
A. Binding studies with SK-N-MC cells (expressing the human CGRP receptor)
SK-N-MC cells are cultivated in "Dulbecco's modified Eagle medium". The medium
is
removed from confluent cultures. The cells are washed twice with PBS buffer
(Gibco
1o 041-04190 M), detached by the addition of PBS buffer mixed with 0.02% EDTA,
and
isolated by centrifuging. After resuspension in 20 ml of "Balanced Salts
Solution"
[BSS (in mM): NaCI 120, KCI 5.4, NaHCO3 16.2, MgSO4 0.8, NaHPO4 1.0, CaC12
1.8,
D-glucose 5.5, HEPES 30, pH 7.40] the cells are centrifuged twice at 100 x g
and
resuspended in BSS. After the number of cells has been determined, the cells
are
homogenised using an Ultra-Turrax and centrifuged for 10 minutes at 3000 x g.
The
supernatant is discarded and the pellet is recentrifuged in Tris buffer (10 mM
Tris, 50
mM NaCI, 5 mM MgCI2, 1 mM EDTA, pH 7.40) enriched with 1% bovine serum
albumin and 0.1 % bacitracin, and resuspended (1 ml / 1000000 cells). The
homogenised product is frozen at -80 C. The membrane preparations are stable
for
more than 6 weeks under these conditions.
After thawing, the homogenised product is diluted 1:10 with assay buffer (50
mM
Tris, 150 mM NaCI, 5 mM MgCI2, 1 mM EDTA, pH 7.40) and homogenised for 30
seconds with an Ultra-Turrax. 230 pl of the homogenised product are incubated
for
180 minutes at ambient temperature with 50 pM 125 1-iodotyrosyl-Calcitonin-
Gene-
Related Peptide (Amersham) and increasing concentrations of the test
substances in
a total volume of 250 pl. The incubation is ended by rapid filtration through
GF/B-
glass fibre filters treated with polyethyleneimine (0.1 %) using a cell
harvester. The
protein-bound radioactivity is measured using a gamma counter. Non-specific
binding
is defined as the bound radioactivity in the presence of 1 pM human CGRP-alpha
during incubation.
The concentration binding curves are analysed using computer-aided non-linear
curve matching.

CA 02565219 2006-10-17
-155-
The compounds mentioned hereinbefore show IC50 values <_ 10000 nM in the test
described.
B. CGRP Antagonism in SK-N-MC cells
SK-N-MC cells (1 million cells) are washed twice with 250 pl incubation buffer
(Hanks' HEPES, 1 mM 3-isobutyl-l-methylxanthine, 1% BSA, pH 7.4) and pre-
incubated at 37 C for 15 minutes. After the addition of CGRP (10 pl) as
agonist in
increasing concentrations (10-11 to 10"6 M), or additionally the substance in
3 to 4
different concentrations, the mixture is incubated for another 15 minutes.
Intracellular cAMP is then extracted by the addition of 20 pl of 1 M HCI and
centrifugation (2000 x g, 4 C, for 15 minutes). The supernatants are frozen in
liquid
nitrogen and stored at -20 C.
The cAMP contents of the samples are determined by radioimmunoassay (Messrs.
Amersham) and the pA2 values of antagonistically acting substances are
determined
graphically.
The compounds of general formula I exhibit CGRP-antagonistic properties in the
in
vitro test model described, in a dosage range between 10"12 and 10"5 M.
In view of their pharmacological properties the compounds of general formula I
and
the salts thereof with physiologically acceptable acids are thus suitable for
the acute
and prophylactic treatment of headaches, particularly migraine or cluster
headaches.
Moreover, the compounds of general formula I also have a positive effect on
the
following diseases: non-insulin-dependent diabetes mellitus ("NIDDM"), complex
regional pain syndrome (CRPS1), cardiovascular diseases, morphine tolerance,
diarrhoea caused by clostridium toxin, skin diseases, particularly thermal and
radiation-induced skin damage including sunburn, inflammatory diseases, e.g.
inflammatory diseases of the joints (arthritis), neurogenic inflammation of
the oral
mucosa, inflammatory lung diseases, allergic rhinitis, asthma, diseases
accompanied
by excessive vasodilatation and resultant reduced blood supply to the tissues,
e.g.

CA 02565219 2006-10-17
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shock and sepsis. In addition, the compounds according to the invention have a
general pain-relieving effect.
The symptoms of menopausal hot flushes caused by vasodilatation and increased
blood flow in oestrogen-deficient women and hormone-treated patients with
prostate
carcinoma are favourably affected by the CGRP antagonists of the present
application in a preventive and acute-therapeutic capacity, this therapeutic
approach
being distinguished from hormone replacement by the absence of side effects.
1o The dosage required to achieve a corresponding effect is conveniently
0.0001 to 3
mg/kg of body weight, preferably 0.01 to 1 mg/kg of body weight, when
administered
intravenously or subcutaneously, and 0.01 to 10 mg/kg of body weight,
preferably 0.1
to 10 mg/kg of body weight when administered orally, nasally or by inhalation,
1 to 3
x a day in each case.
If the treatment with CGRP antagonists and/or CGRP release inhibitors is given
as a
supplement to conventional hormone replacement, it is advisable to reduce the
doses specified above, in which case the dosage may be from 1/5 of the lower
limits
mentioned above up to 1/1 of the upper limits specified.
The compounds prepared according to the invention may be administered either
on
their own or optionally in combination with other active substances for the
treatment
of migraine by intravenous, subcutaneous, intramuscular, intrarectal,
intranasal route,
by inhalation, transdermally or orally, while aerosol formulations are
particularly
suitable for inhalation. The combinations may be administered either
simultaneously
or sequentially.
Categories of active substance which may be used in the combination include
e.g.
antiemetics, prokinetics, neuroleptics, antidepressants, neurokinin
antagonists,
angiotensin receptor blockers (angiotensin II antagonists), iNOS inhibitors,
AMPA
antagonists, anticonvulsants, histamine-H1-receptor antagonists,
antimuscarinics,
(3-blockers, a-agonists and a-antagonists, ergot alkaloids, mild analgesics,
non-
steroidal antiphlogistics, corticosteroids, calcium antagonists, 5-HT,Bilo-
agonists or
other anti-migraine agents which may be formulated together with one or more
inert

CA 02565219 2006-10-17
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conventional carriers and/or diluents, e.g. with corn starch, lactose,
glucose,
microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone, 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,
solutions, metered dose aerosols or suppositories.
Thus other active substances which may be used for the combinations mentioned
1o above include for example the non-steroidal antiinflammatories aceclofenac,
acemetacin, acetylsalicylic acid, azathioprine, diclofenac, diflunisal,
fenbufen,
fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, leflunomide,
lornoxicam,
mefenamic acid, naproxen, phenylbutazone, piroxicam, sulphasalazine,
tenoxicam,
zomepirac or the pharmaceutically acceptable salts thereof as well as
meloxicam and
other selective COX2-inhibitors, such as for example rofecoxib and celecoxib.
It is also possible to use ergotamine, dihydroergotamine, metoclopramide,
domperidone, diphenhydramine, cyclizine, promethazine, chlorpromazine,
vigabatrin,
timolol, isometheptene, pizotifen, botox, gabapentin, topiramate, riboflavin,
montelukast, lisinopril, prochloroperazine, dexamethasone, flunarizine,
dextropropoxyphene, meperidine, metoprolol, propranolol, nadolol, atenolol,
clonidine, indoramin, carbamazepine, phenytoin, valproate, amitryptiline,
lidocaine or
diltiazem and other 5-HTlBilD-agonists such as, for example, almotriptan,
avitriptan,
donitriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan
and
zolmitriptan.
The dosage of these active substances is expediently 1/5 of the lowest
recommended dose to 1/1 of the normally recommended dose, i.e. for example 20
to
100 mg of sumatriptan.
The invention further relates to the use of the compounds according to the
invention
as valuable adjuvants for the production and purification (by affinity
chromatography)
of antibodies as well as in RIA and ELISA assays, after suitable radioactive
labelling,
for example by tritiation of suitable precursors, for example by catalytic

. = CA 02565219 2006-10-17
- 158 -
hydrogenation with tritium or replacing halogen atoms with tritium, and as a
diagnostic or analytical adjuvant in neurotransmitter research.
Experimental section
As a rule, IR, 1 H-NMR and/or mass spectra have been obtained for the
compounds
prepared.
Unless otherwise stated, the acid, base and salt solutions used for working up
the
reaction solutions are aqueous systems of the specified concentrations.
1o Unless otherwise stated, Rf values are obtained using ready-made silica gel
TLC
plates 60 F254 (E. Merck, Darmstadt, Item no. 1.05714) without chamber
saturation.
The Rf values determined under the heading Polygram are obtained using ready-
made Polygram SIL G/UV254 TLC films (coated with 0.2 mm silica gel) made by
Messrs Macherey-Nagel (Duren, Item no. 805 021).
The Rf values determined under the heading Polygram-Alox are obtained using
ready-made Polygram Alox N/UV254 TLC films (coated with 0.2 mm aluminium
oxide)
made by Messrs Macherey-Nagel (Duren, Item no. 802 021).
The ratios given for the eluants relate to units by volume of the solvent in
question.
The units by volume specified for NH3 refer to a concentrated solution of NH3
in
water.
For chromatographic purification, silica gel made by Millipore (MATREXTM, 35-
70 m)
is used.
For chromatographic purification, aluminium oxide 90 (standardised, E. Merck,
Darmstadt, Item no. 1.01097) is used.
The HPLC data provided are measured using the parameters specified below:

CA 02565219 2006-10-17
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Method A:
Analytical column: Zorbax column (Agilent Technologies), SB (Stable Bond) C18;
3.5
pm; 4.6 x 75 mm; column temperature: 30 C; flow: 0.8 mL / min; injection
volume: 5
pL; detection at 254 nm
time (min) percent by volume of water percent by volume of acetonitrile
(with 0.1% formic acid) (with 0.1% formic acid)
0 95 5
9 10 90
10 90
11 95 5
Method B:
Analytical column: Zorbax column (Agilent Technologies), SB (Stable Bond) C18;
3.5
pm; 4.6 x 75 mm; column temperature: 30 C; flow: 1.6 mL / min; injection
volume: 5
10 pL; detection at 254 nm
time (min) percent by volume of water percent by volume of acetonitrile
(with 0.1 % formic acid) (with 0.1 % formic acid)
0 95 5
4.5 10 90
5 10 90
5.5 90 10
In preparative HPLC purifications as a rule the same gradients are used as
were
used to collect the analytical HPLC data.
The products are collected under mass controi and the fractions containing the
product are combined and freeze-dried.
If no detailed information is given as to the configuration, it is not clear
whether it is a
pure enantiomer or whether partial or even complete racemisation has occurred.

CA 02565219 2006-10-17
- 160 -
The following abbreviations are used in the description of the experiments:
abs. absolute
Boc tert.-butoxycarbonyl
CDI N,M-carbonyidiimidazole
CDT 1,1'-carbonyldi-(1,2,4-triazol)
Cyc cyclohexane
DCM dichloromethane
DMF N,N-dimethylformamide
1 o EtOAc ethyl acetate
EtOH ethanol
semiconc. semiconcentrated
HCI hydrochloric acid
HOAc acetic acid
i. vac. in vacuo (in vacuo)
conc. concentrated
LiOH lithium hydroxide
MeOH methanol
NaCI sodium chloride
2o NaOH sodium hydroxide
NMP N-methyl-2-pyrrolidinone
PE petroleum ether
RT ambient temperature
TBME tert.-butylmethylether
TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate
TFA trifluoroacetic acid
THF tetrahydrofuran

CA 02565219 2006-10-17
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A Preparation of the intermediate products
Amine component Al:
3-piperazin-1 -yl-l -aza-bicyclo[2.2.2]octane
H \/'N AN
A1 a) 3-(4-benzyl-Qiperazin-l-yl)-1-aza-bicyclof2.2.21octane
'o A solution of 5.0 g(30.0 mmol) 1-aza-bicyclo[2.2.2]octan-3-one (used as the
hydrochloride salt) and 5.9 mL (33.3 mmol) N-benzylpiperazine in 300 mL DCM
was
stirred for 1 h at RT. While cooling with ice 10.0 g (65.9 mmol) sodium
triacetoxyborohydride were added batchwise within 1 h and the reaction mixture
was
stirred overnight at RT. 15% K2CO3 solution was added and the mixture was
stirred
for 1 h at RT. The aqueous phase was separated off and the organic phase was
dried over MgSO4. After the desiccant and solvent had been eliminated the
residue
was purified by chromatography (silica gel, gradient DCM to MeOH/NH3 9:1).
Yield: 2.0 g(23 /a of theory)
ESI-MS: (M+H)+ = 286
2o Rf = 0.35 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2)
A1 b) 3-piperazin-l-yl-1-aza-bicyclof2.2.21octane
A solution of 2.0 g (7.0 mmol) 3-(4-benzyl-piperazin-1-yl)-1-aza-
bicyclo[2.2.2]octane
in 30 mL MeOH was combined with 400 mg 10% Pd/C and hydrogenated at 50 C
and 3 bar hydrogen pressure until the theoretical hydrogen uptake had
occurred. The
catalyst was filtered off and the filtrate was evaporated down i.vac. .
Yield: 1.0 g (73% of theory)
ESI-MS: (M+H)+ = 196
Rf = 0.13 (silica gel, DCM/MeOH/NH3 75:25:5)

CA 02565219 2006-10-17
-162-
Amine component A2:
[4,4']bipiperidinyl-1-sulphonic acid amide
HN OO
N/S\NHz
A2a) carbobenzyloxysulphamoyl chloride
0 OO
O H' S, cI
Under a nitrogen atmosphere a solution of 3.63 mL (35.0 mmol) benzylalcohol in
20
mL DCM was added dropwise to a solution of 5.0 g (35.3 mmol) chlorosulphonyl
isocyanate in 20 mL DCM cooled to -10 C and the reaction mixture was stirred
for 1
h at this temperature. The reaction solution was evaporated down i.vac. , the
residue
triturated with PE, suction filtered and dried.
Yield: 6.0 g (69% of theory)
A2b)
0 OO
O NN+J
Under a nitrogen atmosphere a solution of 7.67 mL (55.0 mmol) triethylamine in
30
mL EtOAc was added dropwise at RT to a solution of 6.0 g (24.0 mmol)
carbobenzyloxysulphamoyl chloride in 60 mL EtOAc and the reaction mixture was
stirred for 2 h at RT. The precipitate was filtered and the filtrate was
evaporated to
dryness. The product was obtained as an oil, which was further reacted without
purification.
Yield: 7.8 g (98% of theory)

CA 02565219 2006-10-17
-163-
A2c)
4 0
OA o
N
NH O I ~
/
3.5 g (13.0 mmol) tert-butyl [4,4']bipiperidinyl-1-carboxylate were added to a
solution
of 6.2 g (18.7 mmol) of the crude product from Example A2b in 40 mL dry THF
and
the reaction mixture was refluxed for 3 h. It was evaporated down i.vac. and
the
residue was purified by chromatography (silica gel, gradient DCM/MeOH 50:1 to
30:1).
Yield: 4.5 g (72% of theory)
1o ESI-MS: (M+H)+ = 482
Rf = 0.39 (Polygram-Alox, DCM/MeOH 50:1)
A2d)
O~~O
HN O
N~O ~
H ~
/
3.2 mL methanolic HCI (1.25 M) were added to a suspension of 1.68 g (3.49
mmol)
Example A2c in 50 mL MeOH and the reaction mixture was stirred overnight at RT
and for 2 h at 60 C. To complete the reaction a further 1 mL methanolic HCI
were
added and the mixture was again heated to 60 C for 1 h. It was evaporated down
i.vac. , the residue was triturated with diethyl ether, the diethyl ether was
decanted
and the residue was dried. The product was obtained as the hydrochloride salt.
Yield: 1.51 g (98% of theory)
ESI-MS: (M+H)+ = 382
A2e) L4 4'lbipiperidinyl-1-sulphonic acid amide
0.20 g 10% Pd/C were added to a suspension of 1.5 g (3.41 mmol) Example A2d in
40 mL MeOH and the reaction mixture was hydrogenated (for 3 h) at 50 C and 3
bar
hydrogen pressure until the theoretical hydrogen uptake had occurred. The
catalyst
was filtered off and the filtrate was evaporated to dryness. The product was
obtained

CA 02565219 2006-10-17
- 164 -
as the hydrochloride salt.
Yield: 0.85 g (88% of theory)
ESI-MS: (M+H)+ = 248
Amine component A3:
4-hydroxymethyl-[1,4')bipiperidinyl-4-ol
H N\/~N\'-~OH
OH
''0
A3a) 1-benzyl-4-hydroxymethyl-piperidin-4-ol
A solution of 200 g AD-Mix-Alpha (Messrs Aldrich, Item no. 39,275-8) in 500 mL
water and 300 mL tert-butanol was stirred for 20 min at RT, cooled to 0 C,
combined
with 13.7 g (144 mmol) methanesulphonic acid amide and 27.0 g (144 mmol) of
1-benzyl-4-methylene-piperidine and, after removal of the cooling bath,
stirred for 22
h at RT. 59 g Na2SO3 were added to the reaction mixture and it was stirred for
1 h at
RT. 2 L EtOAc and 500 mL saturated NaHCO3 solution were added, the organic
phase was separated off and dried over Na2SO4 . After the desiccant and
solvent had
been eliminated the residue was dissolved in 150 mL EtOAc and filtered through
Alox. The filtrate was discarded and the product was eluted from the Alox with
1 L
MeOH. After the solvent had been eliminated the product was reacted further
without
purification.
Yield: 26.0 g(82% of theory)
ESI-MS: (M+H)+ = 222
retention time (HPLC): 1.4 min (method B)
A3b) 4-hydroxymethyl-piperidin-4-ol
A suspension of 26.0 g(117 mmol) 1-benzyl-4-hydroxymethyl-piperidin-4-ol and
5.0
g 10% Pd/C in 500 mL MeOH was hydrogenated at 50 C and 3 bar hydrogen
pressure until the theoretical hydrogen uptake had occurred (4 h). The
catalyst was
filtered off and washed with MeOH. After the solvent had been eliminated the
residue
was reacted further without purification.
Yield: 15.4 g(100% of theory)

CA 02565219 2006-10-17
-165-
ESI-MS: (M+H)+ = 132
retention time (HPLC): 0.5 min (method B)
A3c) 1'-benzyl-4-hydroxymethyl-[1 4']bipiperidinyl-4-oI
Under a nitrogen atmosphere a solution of 19.9 mL (111 mmol) 1 -benzyl-
piperidin-4-
one, 14.6 g (111 mmol) 4-hydroxymethyl-piperidin-4-ol and 12.2 mL (222 mmol)
AcOH in 300 mL of a THF/MeOH mixture (2:1) was cooled to 0 C and at this
temperature 5.87 g (89 mmol) sodium cyanoborohydride was added batchwise.
After
the addition had ended the cooling bath was removed and the reaction mixture
was
stirred overnight at RT. 30 mL of 4 M HCI were added, the mixture was stirred
for 1 h
at RT and evaporated down i.vac.. The residue was combined with 200 mL water
and 100 mL 15% K2CO3 solution and extracted with 300 mL EtOAc. The organic
phase was concentrated by evaporation, the residue was dissolved in 150 mL
EtOH
and acidified with methanolic HCI (1.25 M). The precipitate formed was
filtered,
washed with 100 mL EtOH and 100 mL diethyl ether and dried. The product was
obtained as the bis-hydrochloride salt.
Yield: 9.6 g (23% of theory)
ESI-MS: (M+H)+ = 305
Rf = 0.25 (silica gel, DCM/MeOH/NH3 70:30:3)
A3d) 4-hydroxymethyl-[1,4']bipiperidinyl-4-ol
A suspension of 9.6 g (25.4 mmol, used as the bis-hydrochloride salt) of 1'-
benzyl-4-
hydroxymethyl-[1,4']bipiperidinyl-4-ol and 2.0 g 10% Pd/C in 300 mL MeOH was
hydrogenated at 50 C and 3 bar hydrogen pressure until the theoretical
hydrogen
uptake had occurred (2.5 h). The catalyst was filtered off, the filtrate was
evaporated
down Lvac. , the residue was triturated with 200 mL diethyl ether, suction
filtered,
washed with 100 mL diethyl ether and dried. The product was obtained as the
bis-
hydrochloride salt.
Yield: 7.0 g (96% of theory)
3o ESI-MS: (M+H) + = 215

= CA 02565219 2006-10-17
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Examgle 1
(R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-[4-(4-methyl-piperazin-l-yl)-
piperidin-1-yl]-
2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-
carboxylate
O -H
N\~ ~\N'CH3
N NO~
O
NO
H
1 a) 7-methyl-1 H-indazol-5-carbaldehyde
1o Under an argon atmosphere 2.8 g (70 mmol, 55% in mineral oil) NaH were
added
batchwise to a solution of 13.5 g (64 mmol) 5-bromo-7-methyl-1 H-indazole in
120 mL
dry THF, while the temperature rose to approx 35 C. After 15 min the reaction
mixture was cooled to -78 C and within 30 min 100 mL sec. BuLi (140 mmol, 1.4
M in
Cyc) were added dropwise. The mixture was kept for a further hour at this
temperature, before a solution of 20 mL DMF in 20 mL dry THF was added
(strongly
exothermic reaction). The reaction mixture was stirred overnight at RT, cooled
to 0 C
and 140 mL 2 M HCI was added dropwise under argon (strongly exothermic
reaction). The acid solution was adjusted to pH 7-8 with solid NaHCO3,
combined
with 500 mL water and extracted with 500 mL EtOAc. The organic phase was
separated off, filtered through activated charcoal and evaporated down i.vac.
. The
residue obtained was recrystallised from 70 mL EtOAc; the mother liquor
obtained
was evaporated down and the residue was purified by chromatography (silica
gel,
PE/EtOAc 2:1).
Yield: 6.9 g(67% of theory)
ESI-MS: (M+H) + = 161
Rf = 0.5 (silica gel, PE/EtOAc 1:1)
1 b) 7-methyl-1 -(2-trimethylsilanyl-ethanesulphonyl)-1 H-indazol-5-
carbaldehyde
22.5 mL (160 mmol) triethylamine were added to a solution of 8.5 g (53.07
mmol) 7-

CA 02565219 2006-10-17
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methyl-1 H-indazol-5-carbaldehyde in 250 mL DCM and then a solution of 15.96 g
(79.5 mmol) 2-trimethylsilanyl-ethanesulphonyl chloride in 50 mL DCM was
slowly
added dropwise and the reaction solution was then stirred overnight at RT. It
was
evaporated down i.vac. and the residue was purified by chromatography (silica
gel,
PE/EtOAc 8:2).
Yield: 14.0 g(81 % of theory)
ESI-MS: (M+H)+ = 325
Rf = 0.35 (silica gel, PE/EtOAc 8:2)
1 c) (Z,E)-2-acetylamino-3-(7-methyl-1 H-indazol-5-yl -acrylic acid
A mixture of 14 g (43.15 mmol) 7-methyl-1-(2-trimethylsilanyl-ethanesulphonyl)-
1H-
indazol-5-carbaldehyde, 10.12 g (86.4 mmol) N-acetylglycine and 7.09 g (86.4
mmol)
NaOAc in 60 mL acetic anhydride was refluxed for 3 h. The reaction mixture was
cooled to approx 60 C and combined dropwise with 40 mL water, stirred for 10
min
at this temperature and then heated for 1 h to 95 C. The reaction solution was
poured onto 500 mL water, extracted three times with in each case 300 mL
EtOAc,
the combined organic phases were extracted twice with in each case 200 mL of
7%
K2CO3 solution, the combined aqueous phases were acidified with conc. HCI and
extracted three times more with 200 mL EtOAc. The combined organic phases were
filtered through activated charcoal and evaporated down i.vac. .
A mixture of the desired product and (Z,E)-2-acetylamino-3-(1-acetyl-7-methyl-
1 H-
indazol-5-yl)-acrylic acid was obtained, which was further reacted without
purification.
Yield: 2.1 g(19% of theory)
ESI-MS: (M+H) = 260
retention time (HPLC): 4.2 min (method A)
(Z,E)-2-acetylamino-3-(1-acetyl-7-methyl-1 H-indazol-5-yl)-acrylic acid
Yield: 2.1 g(16% of theory)
ESI-MS: (M+H)+ = 302
retention time (HPLC): 5.8 min (method A)
1 d) 3-(7-methyl-1 H-indazol-5-yl)-2-oxo-propionic acid
70 mL 4 M HCI were added to a solution of 4.25 g of the above crude product in
40
mL NMP and the reaction mixture was heated for 3 h to a bath temperature of
100 C.
The reaction solution was poured onto 400 mL water, extracted five times with
in

, = CA 02565219 2006-10-17
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each case 200 mL EtOAc, the combined organic phases were washed twice with 300
mL water, dried over Na2SO4 and concentrated by evaporation i.vac..
Yield: 1.3 g (36% of theory)
El-MS: (M)+ = 218
retention time (HPLC): 5.4 min (method A)
1 e) ethyl (R)-2-hydroxy-3-(7-methyl-1 H-indazol-5-yl)-propionate
A solution of 2.31 g (7.2 mmol) (1R)-B-chlorodiisopinocampheylborane in 20 mL
THF
was added dropwise within 30 min to a solution of 1.3 g (5.96 mmol) 3-(7-
methyl-1 H-
1o indazol-5-yl)-2-oxo-propionic acid and 0.84 mL (7.2 mmol) triethylamine in
50 mL
THF cooled to approx. -25 C and the reaction mixture was kept for 1.5 h at
this
temperature and then heated to RT within another hour. The mixture was
evaporated
down i.vac., the residue was taken up in 100 mL 4 M ethanolic HCI and stirred
overnight at RT. 200 mL EtOAc and 200 mL 15% K2CO3 solution were added, the
organic phase was separated off and dried over Na2SO4. After the desiccant and
solvent had been eliminated the residue was purified chromatographically by
HPLC.
Yield: 0.45 g (30% of theory)
ESI-MS: (M+H)+ = 249
retention time (HPLC): 5.8 min (method A)
1f) tert.-butyl 5-((R)-2-ethoxycarbonyl-2-hydroxy-ethyl -7-methyl-indazol-1-
carboxylate
A solution of 397 mg (1.82 mmo) Boc-anhydride in 5 mL DCM was slowly added
dropwise to a solution of 450 mg (1.81 mmol) ethyl (R)-2-hydroxy-3-(7-methyl-
1H-
indazol-5-yl)-propionate, 55 mg (0.45 mmol) DMAP and 0.27 mL (1.82 mmol)
triethylamine in 15 mL DCM and the reaction solution was stirred overnight at
RT.
The mixture was diluted with 50 mL DCM, washed with 10% citric acid and 15%
K2CO3 solution and dried over Na2SO4. After the desiccant and solvent had been
eliminated the residue was reacted further without purification.
Yield: 0.63 g (100% of theory)
ESI-MS: (2M+Na)+ = 719
retention time (HPLC): 8.3 min (method A)

CA 02565219 2006-10-17
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1 g) 4-(2-oxo-1,2,4,5-tetrahYdro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl
chloride
6 g (12.1 mmol) phosgene (20 percent by weight in toluene) were added to a
solution
of 2.5 g (10.2 mmol) 3-piperidin-4-y1-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-
one and
2.6 mL (14.9 mmol) ethyldiisopropylamine in 75 mL DCM cooled to 0 C and the
reaction mixture was stirred for 30 min at this temperature . It was allowed
to warm
up to RT, evaporated down i.vac. to approx. 50 mL and filtered through silica
gel, the
latter was washed with 200 mL DCM/EtOAc (1:1) and the combined filtrates were
again evaporated down i.vac. . The residue was stirred with diisopropylether,
suction
filtered and dried i.vac..
Yield: 2.42 g (77% of theory)
Rf = 0.43 (silica gel, DCM/EtOAc 1:1)
1 h) tert.-butyl 5-{(R)-2-ethoxycarbonyl-2-f4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-Qperidine-l-carbonyloxy)-ethyl)-7-methyl-indazol-1-
carboxylate
Under a nitrogen atmosphere 92 mg (2.1 mmol, 55% in mineral oil) NaH were
added
batchwise to a solution of 632 mg (1.81 mmol) tert.-butyl 5-((R)-2-
ethoxycarbonyl-2-
hydroxy-ethyl)-7-methyl-indazol-1-carboxylate in 60 mL dry THF cooled to 0 C
and
stirred for a further hour at this temperature. Subsequently 800 mg (1.82
mmol) 4-(2-
oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl chloride
were
added batchwise while cooling and the reaction mixture was stirred overnight
at RT.
It was evaporated down i.vac., combined with 200 mL 10% citric acid solution,
extracted twice with 200 mL EtOAc, the combined organic phases were washed
with
200 mL 15% K2C03 solution and dried over Na2SO4. After the desiccant and
solvent
had been eliminated the residue was purified by chromatography (silica gel,
EtOAc/PE 2:1).
Yield: 330 mg (29% of theory)
ESI-MS: (M+H) + = 620
3o Rf = 0.45 (silica gel, EtOAc/PE 2:1)
1 i) tert.-butyl 5-{(R)-2-carboxy-2-f4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-
3-yl)-piperidine-l-carbonyloxy]-ethyl)-7-methyl-indazol-1-carboxylate
A solution of 19.2 mg (0.8 mmol) lithium hydroxide hydrate in 10 mL water was

= CA 02565219 2006-10-17
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added at RT to a solution of 330 mg (0.53 mmol) tert.-butyl 5-{(R)-2-
ethoxycarbonyl-
2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-l-
carbonyloxy]-
ethyl}-7-methyl-indazol-l-carboxylate in 30 mL THF and the reaction mixture
was
stirred for 30 min at RT . It was evaporated down i.vac. , the residue was
taken up in
100 mL water, combined with 10% citric acid with stirring, extracted twice
with 100
mL DCM and the combined organic phases were dried over Na2SO4. After the
desiccant and solvent had been eliminated the residue was reacted further
without
purification.
Yield: 440 mg (crude)
1o ESI-MS: (M+H)+ = 592
retention time (HPLC): 8.2 min (method A)
1 k) tert.-butyl 7-methyl-5-{(R)-3-[4-(4-methyl-piperazin-1 -yl)-piperidin-1-
yll-3-oxo-2-
14-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxyl-
propyl}-indazol-1-carboxylate
A solution of 440 mg tert.-butyl 5-{(R)-2-carboxy-2-[4-(2-oxo-1,2,4,5-
tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-l-carbonyloxy]-ethyl}-7-methyl-indazol-1-
carboxylate,
256 mg (0.8 mmol) TBTU, 146 pL (1.0 mmol) triethylamine and 147 mg (0.8 mmol)
1-
methyl-4-piperidin-4-yl-piperazine in 8 mL DMF was stirred for 2 h at RT. The
reaction solution was filtered through an injection filter and purified
directly by HPLC
without any further working up. The fractions containing the product were
combined,
evaporated down i.vac. , made alkaline with 15% K2CO3 solution, extracted
three
times with 30 mL DCM, the combined organic phases were dried over Na2SO4 and
the solvent was eliminated i. vac.:
Yield: 160 mg (28% of theory)
ESI-MS: (M+H)+ = 757
retention time (HPLC): 6.6 min (method A)
11) (R)-1-(7-methyl-1 H-indazol-5-ylmethyl)-2-[4-(4-methyl-piperazin-1 -yl)-
piperidin-
1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-l,3-benzodiazepin-3-yl)-
piperidine-l-carboxylate
A solution of 160 mg (0.21 mmol) tert.-butyl 7-methyl-5-{(R)-3-[4-(4-methyl-
piperazin-
1-yl)-piperidin-1 -yl]-3-oxo-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
3-yl)-
piperidine-1-carbonyloxy]-propyl}-indazol-1-carboxylate in 10 mL 1 M HCI was
stirred

, = CA 02565219 2006-10-17
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for 1 h at RT. To complete the reaction the mixture was heated to 50 C for 10
min
and stirred for a further hour at RT. The mixture was combined with 15% K2CO3
solution, extracted three times with in each case 30 mL DCM and the combined
organic phases were dried over Na2SO4. After the desiccant and solvent had
been
eliminated the residue was triturated with 30 mL diisopropylether, suction
filtered,
washed with 10 mL diisopropylether again and dried in the air.
Yield: 100 mg (72% of theory)
ESI-MS: (M+H)+ = 657
retention time (HPLC): 4.9 min (method A)
Example 2
(R)-1-(4-amino-3-methyl-5-nitro-benzyl)-2-[4-(4-methyl-piperazin-l-yl)-
piperidin-1-yl]-
2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-l-
carboxylate
o . ,.o
'N
~11 NHz
o
/0~~ ~% N~
N~ O
0
H
2a) methyl (Z,E)-2-acetylamino-3-(4-amino-methyl-5-nitro-phenyl)-acrylate
0.7 g (2.9 mmol) Pd(OAc)2 and 0.9 g (2.9 mmol) tri-o-tolyl-phosphane were
added
under an argon atmosphere to a solution of 9.0 g (39.0 mmol) 4-bromo-2-
methyl-6-nitro-phenylamine and 10.0 g (69.9 mmol) methyl 2-acetylamino-
acrylate in
100 mL acetonitrile and 100 mL triethylamine. The reaction mixture was stirred
for 24
h at a bath temperature of 90 C, evaporated down i.vac., the residue was
combined
with 200 mL water and 200 mL EtOAc and the precipitate was filtered off. The
crystals were dissolved by refluxing in 500 mL MeOH, filtered off hot and the
filtrate
was evaporated to dryness i.vac..
Yield: 8.0 g (70% of theory)
ESI-MS: (M+H)+ = 294

CA 02565219 2006-10-17
- 172 -
2b) 3-(4-amino-3-methyl-5-nitro-phenyi)-2-oxo-propionic acid
60 mL of a 4 M HCI were metered into a solution of 8.0 g (53.1 mmol) methyl
(Z,E)-2-
acetylamino-3-(4-amino-methyl-5-nitro-phenyl)-acrylate in 60 mL 1,4-dioxane,
refluxed for 3 h with stirring, the reaction solution was evaporated down
i.vac. and the
residue was combined with ice. The precipitate was filtered off, washed with
ice
water and dried.
Yield: 6.5 g (95% of theory)
El-MS: (M)+ = 238
1o 2c) (R)-3-(4-amino-3-methyl-5-nitro-phenyl)-2-hydroxy-propionic acid
Under a nitrogen atmosphere a solution of 12.0 g (37.4 mmol) (1 R)-B-
chlorodiisopinocampheylborane in 40 mL THF was added dropwise within 15 min to
a solution of 6.5 g (26.0 mmol) 3-(4-amino-3-methyl-5-nitro-phenyl)-2-oxo-
propionic
acid and 4.5 mL (32.4 mmol) triethylamine in 100 mL THF cooled to -35 C and
the
reaction solution was stirred overnight at RT. Then the reaction solution was
carefully
combined with 60 mL of 1 M NaOH and 150 mL diethyl ether at 5 C and stirred
for 15
min. The organic phase was separated off, extracted three times with 40 mL 1 M
NaOH and once with 40 mL water. The combined aqueous phases were acidified
with semiconc. HCI while cooling with an ice bath and extracted twice with in
each
case 120 mL EtOAc. The combined organic phases were dried over Na2SO4 and
evaporated down i.vac. . The crude product was obtained, which was further
reacted
without purification.
Yield: 6.0 g (67% of theory)
2d) methyl (R)-3-(4-amino-3-meth rLl-5-nitro-phenyl)_2-hydroxy-propionate
While cooling with ice/acetone, 4.0 mL (54.8 mmoi) SOCI2 and at 0 C 6.0 g
(17.5
mmol) (R)-3-(4-amino-3-methyl-5-nitro-phenyl)-2-hydroxy-propionic acid in 10
mL
MeOH were slowly added dropwise to 90 mL MeOH. The reaction solution was
stirred for 1 h at 0 C and for 1 h at RT and then evaporated down i.vac. . The
residue
was combined with EtOAc, washed with saturated NaHSO4 solution and dried over
Na2SO4 . After the desiccant and solvent had been eliminated the residue was
purified by chromatography (silica gel, gradient DCM/MeOH 100:1 to 50:1).
Yield: 3.4 g (76% of theory)
ESI-MS: (M+H)+ = 255

CA 02565219 2006-10-17
- 173 -
Rf = 0.43 (Polygram, DCM/MeOH 50:1)
2e) (R)-2-(4-amino-3-methyl-5-nitro-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-
1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate
Under a nitrogen atmosphere 1.8 g (14.7 mmol) 4-dimethylaminopyridine in 25 mL
pyridine were first combined with 2.7 g (13.4 mmol) 4-nitro-phenyl
chloroformate
while cooling with an ice bath, stirred for 30 min at RT, then combined with
3.4 g
(13.2 mmol) methyl (R)-3-(4-amino-3-methyl-5-nitro-phenyl)-2-hydroxy-
propionate in
mL pyridine, stirred again for 2 h at RT, and then combined with 3.5 g (14.3
mmol)
10 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and stirred for
5 h at RT.
After the reaction had ended the reaction mixture was evaporated down i.vac.,
the
residue was combined with EtOAc, the organic phase was washed with 10% KHSO4
solution and saturated NaHSO4 solution and dried over Na2SO4. After the
desiccant
and solvent had been eliminated the residue was purified by chromatography
(silica
15 gel, DCM/MeOH 25:1).
Yield: 3.7 g (50% of theory)
ESI-MS: (M+H)+ = 526
Rf = 0.42 (Polygram, DCM/MeOH 25:1)
2o 2f) (R)-2-(4-amino-3-methyl-5-nitro-phenyl -1-carboxy-ethyl 4-(2-oxo-1 2 4
5-
tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate
A solution of 120 mg (5.0 mmol) LiOH in 5 mL water was metered into a solution
of
1.0 g (1.8 mmol) (R)-2-(4-amino-3-methyl-5-nitro-phenyl)-1-methoxy-carbonyl-
ethyl 4-
(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in
10 mL
THF, the reaction solution was stirred for 4 h at RT and then evaporated down
i.vac..
The residue was combined with 30 mL water, washed with 30 mL diethyl ether,
acidified with 4 M HCI while cooling with an ice bath and stirred for 30 min
at RT. The
precipitate was filtered off, washed with water and dried.
Yield: 0.79 g(81 % of theory)
3o ESI-MS: (M-H)" = 510
2g) (R)-1-(4-amino-3-methyl-5-nitro-benzyl)-2-f4-(4-methyl-piperazin-1-yl)-
piperi-
din-1-yll-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-
piperidine-1-carbox late

CA 02565219 2006-10-17
- 174 -
A solution of 780 mg (1.5 mmol) (R)-2-(4-amino-3-methyl-5-nitro-phenyl)-1-
carboxy-
ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-l-
carboxylate,
520 mg (1.6 mmol) TBTU, 350 pL (2.1 mmol) ethyldiisopropylamine in 30 mL THF
and 5 mL DMF was stirred for 1 h at RT, then combined with 300 mg (1.6 mmol) 1-
methyl-4-piperidin-4-yl-piperazine and stirred for 4 h at RT. The reaction
solution
was combined with 100 mL semisaturated NaHCO3 solution and extracted twice
with
50 mL EtOAc. The organic phases were dried over Na2SO4, filtered and
evaporated
down i.vac. . The residue was dissolved in a little DCM, combined with diethyl
ether,
the precipitate was suction filtered and dried.
1 o Yield: 1.0 g (97% of theory)
ESI-MS: (M+H)+ = 677
Rf = 0.46 (Polygram-Alox, DCM/MeOH 25:1)
Example 2.1
(R)-1-(3,4-diamino-5-methyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-
yl]-2-
oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-l-
carboxylate
NH2
NHZ
O
\ I ~ N,~ N~
~N
O
H
260 mg (0.37 mmol) (R)-1-(4-amino-3-methyl-5-nitro-benzyl)-2-[4-(4-methyl-
piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyi 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-l-carboxylate were dissolved in 25 mL THF and
combined with 130 mg 10% Pd/C. The mixture was hydrogenated for 4.5 h in a
Parr
apparatus at 50 C under 50 psi hydrogen pressure. Then the catalyst was
filtered off,
the filtrate was evaporated down i.vac. , the residue was dissolved in a
little DCM,
combined with diethyl ether, the precipitate was suction filtered and dried.
Yield: 180 mg (75% of theory)
3o ESI-MS: (M+H) + = 647
retention time (HPLC): 4.3 min (method A)

= = CA 02565219 2006-10-17
-175-
Example 2.2
(R)-1-(7-methyl-1 H-benzimidazol-5-ylmethyl)-2-[4-(4-methyl-piperazin-1-yl)-
piperidin-
1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-
piperidine-1-
carboxylate
N='1
NH
O
N
OX-]),
~NONO
H O
I
110 mg (0.16 mmol) (R)-1-(4-amino-3-methyl-5-nitro-benzyl)-2-[4-(4-methyl-
1o piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyi 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate were dissolved in 10 mL THF,
combined with 1 mL formic acid and 30 mg 10% Pd/C. The mixture was
hydrogenated for 1 h in a Parr apparatus at RT and 50 psi hydrogen pressure
and for
1.75 h at 50 C and 50 psi hydrogen pressure. Then the catalyst was filtered
off, the
filtrate was evaporated down i.vac. , the residue was dissolved in 5 mL formic
acid,
refluxed for 1 h and then evaporated down i.vac. The residue was combined with
water, made alkaline with Na2CO3 solution, extracted with DCM and the organic
phase was dried over Na2SO4 . After the desiccant and solvent had been
eliminated
the residue was purified by chromatography (Alox, gradient DCM/MeOH 30:1 to
20:1).
Yield: 40 mg (39% of theory)
ESI-MS: (M+H)+ = 655
Rf = 0.28 (Polygram-Alox, DCM/MeOH 25:1)
Example 2.3
(R)-2-4,4'-bipiperidinyl-l-yl-1-(7-methyl-1 H-benzimidazol-5-ylmethyl)-2-oxo-
ethyl 4-
(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

= ' CA 02565219 2006-10-17
-176-
N=\
NH
O
kOH
, ~N
01~"-)
N ~ ~ 0
1 O
H
2.3a) (R)-1-methoxycarbonyl-2-(7-methyl-1 H-benzimidazol-5-yl)-ethyl 4-(2-oxo-
1,2 4 5-tetrahydro-1 3-benzodiazepin-3-yl)-piperidine-1-carboxylate
1.2 g (2.3 mmol) (R)-2-(4-amino-3-methyl-5-nitro-phenyl)-1 -methoxycarbonyl-
ethyl 4-
(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate
were
dissolved in 50 mL formic acid and combined with 300 mg 10% Pd/C. The mixture
was hydrogenated for 2 h in a Parr apparatus at 60 C and 50 psi hydrogen
pressure.
Then the catalyst was filtered off, the filtrate was evaporated down i.vac.
and the
residue was purified by chromatography (Alox, gradient DCM/MeOH 40:1 to 30:1).
Yield: 880 mg (76% of theory)
ESI-MS: (M+H)+ = 506
Rf = 0.40 (Polygram-Alox, DCM/MeOH 25:1)
2.3b) (R)-1-carboxy-2-(7-methyl-1 H-benzimidazol-5-yl)-ethyl 4-(2-oxo-1,2,4,5-
tetrahydro-1 3-benzodiazepin-3-yl)-piperidine-1-carboxylate
A solution of 96 mg (4.0 mmol) LiOH in 5 mL water was added dropwise to a
solution
of 910 mg (1.8 mmol) (R)-1-methoxycarbonyl-2-(7-methyl-1H-benzimidazol-5-yi)-
ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-
carboxylate in
12 mL THF and the reaction solution was stirred overnight at RT. The residue
was
combined with 1 mL 4 M HCI and evaporated to dryness i.vac..
Yield: 980 g (100% of theory)
ESI-MS: (M+H)+ = 492
2.3c) (R)-2-(1'-benzyl-4 4'-bipiperidinyl-1-yl)-1-(7-methyl-1H-benzimidazol-5-
ylmethyl)-2-oxo-ethyl 4-(2-oxo-1 2 4 5-tetrahydro-l,3-benzodiazepin-3-yl)-
piperidine-1-carboxylate
A solution of 120 mg (0.22 mmol) (R)-1-carboxy-2-(7-methyl-1H-benzimidazol-5-
yl)-
ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-l-
carboxylate,
85 mg (0.27 mmol) TBTU and 50 pL (0.36 mmol) triethylamine in 10 mL THF and 1
mL DMF was stirred for 1 h at RT, then combined with 80 mg (0.31 mmol) 1-
benzyl-

CA 02565219 2006-10-17
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[4,4']bipiperidinyl and stirred overnight at RT. The reaction solution was
combined
with 1 mL saturated Na2CO3 solution and extracted with 100 mL EtOAc. The
organic
phase was dried over Na2SO4 , filtered and evaporated down i.vac. . The
residue was
purified via HPLC, the fractions containing the product were combined and
evaporated to dryness i.vac..
Yield: 75 mg (42 % of theory)
ESI-MS: (M+H)+ = 732
2.3d) (R)-2-4 4'-bipiperidinyl-1-vl-1-(7-methyl-1 H-benzimidazol-5-ylmethyl)-2-
oxo-
1o ethyl 4-(2-oxo-1 2 4 5-tetrahydro-1 3-benzodiazepin-3-yl)-piperidine-1-
carboxylate
75 mg (0.09 mmol) (R)-2-(1'-benzyl-4,4'-bipiperidinyl-1-yl)-1-(7-methyl-1H-
benzimidazol-5-ylmethyl)-2-oxo-ethyi 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-
3-yl)-piperidine-1-carboxylate were dissolved in 10 mL MeOH and combined with
30
mg 10% Pd/C. The mixture was hydrogenated for 2 h in a Parr apparatus at 50 C
and 50 psi hydrogen pressure. Then the catalyst was filtered off and the
filtrate was
evaporated down i.vac. .
Yield: 48 mg (81 % of theory)
ESI-MS: (M+H)+ = 642
retention time (HPLC): 4.6 min (method A)
Example 2.4
(R)-1-(7-methyl-1 H-benzimidazol-5-ylmethyl)-2-oxo-2-(4-piperazin-l-yl-
piperidin-1-yl)-
ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-
carboxylate
N=~
NH
OII ~
N Iol
H
2.4a) (R)-2-[4-(4-benz rLl-piperazin-l-yl)-piperidin-l-yll-1-(7-methyl-lH-
benzimidazol-
5-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1 2 4 5-tetrahydro-l,3-benzodiazepin-3-yl)-
piperidine-l-carboxyiate

= ' CA 02565219 2006-10-17
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A solution of 120 mg (0.22 mmol) (R)-1-carboxy-2-(7-methyl-1H-benzimidazol-5-
yl)-
ethyl 4-(2-oxo-1,2,4,5-tetrahydro-l,3-benzodiazepin-3-yl)-piperidine-1-
carboxylate,
85 mg (0.27 mmol) TBTU and 120 pL (0.86 mmol) triethylamine in 10 mL THF and 1
mL DMF was stirred for 1 h at RT, then combined with 90 mg (0.27 mmol) 1-
benzyl-
4-piperidin-4-yl-piperazine (used as the bishydrochloride salt) and stirred
overnight at
RT. The reaction solution was combined with 1 mL semisaturated NaHCO3 solution
and extracted with 100 mL EtOAc. The organic phase was dried over Na2SO4,
filtered and evaporated down i.vac. .
Yield: 67 mg (42% of theory)
2.4b) (R)- 1-(7-methyl-1 H-benzimidazol-5-ylmethyl)-2-oxo-2-(4-piperazin-1-yl-
piperi-
din-1-yi)-ethyl 4-(2-oxo-1 2 4 5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
1-carboxylate
67 mg (0.08 mmol) (R)-2-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-1-(7-
methyl-1 H-
benzimidazol-5-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5,-tetrahydro-1,3-
benzodiazepin-
3-yl)-piperidine-1-carboxylate were dissolved in 10 mL MeOH and combined with
30
mg 10% Pd/C. The mixture was hydrogenated for 3 h in a Parr apparatus at 50 C
and 50 psi hydrogen pressure. Then the catalyst was filtered off and the
filtrate was
evaporated down i.vac.. The residue was purified by HPLC, the fractions
containing
the product were combined and lyophilised.
Yield: 18 mg (34% of theory)
ESI-MS: (M-H)- = 641
retention time (HPLC): 4.1 min (method A)
Example 2.5
(R)-1-(2,7-dimethyl-1 H-benzimidazol-5-ylmethyl)-2-[4-(4-methyl-piperazin-1-
yl)-
piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-l,3-benzodiazepin-3-
yl)-
piperidine-l-carboxylate
H
\
OII N
01_11~1'_) ~N~O/\~N~
lol O
H

CA 02565219 2006-10-17
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A solution of 120 mg (0.16 mmol) (R)-1-(3,4-diamino-5-methyl-benzyl)-2-[4-(4-
methyl-
piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-l-carboxylate were refluxed in 2 mL AcOH for 2
h and
then evaporated down i.vac. . The residue was purified by HPLC, the fractions
containing the product were combined and lyophilised.
Yield: 59 mg (56% of theory)
ESI-MS: (M+H)+ = 671
retention time (HPLC): 4.3 min (method A)
Example 2.6
(R)-1 -(7-methyl-2-oxo-2,3-dihydro-1 H-benzimidazol-5-ylmethyl)-2-[4-(4-methyl-
piperazin-l-yl)-piperidin-l-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-l-carboxylate
H
& N
>=0
0 = H
N~~O-~y~
120 mg (0.17 mmol) (R)-1-(4-amino-3-methyl-5-nitro-benzyl)-2-[4-(4-methyl-
piperazin-1-yl)-piperidin-l-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
2o benzodiazepin-3-yl)-piperidine-1-carboxylate were dissolved in 10 mL THF
and
combined with 30 mg 10% Pd/C. The mixture was hydrogenated for 2 h in a Parr
apparatus at 50 C and 50 psi hydrogen pressure, the catalyst was filtered off
and the
filtrate was evaporated down i.vac. . The residue was dissolved in 10 mL 1,4-
dioxane, combined with 30 mg (0.18 mmol) CDT, refluxed for 2 h and then
evaporated to dryness i.vac.. The residue was purified by chromatography
(Alox,
DCM/MeOH 9:1), the fractions containing the product were combined, evaporated
down i.vac. , dissolved in MeOH, combined with diethyl ether, the precipitate
was
suction filtered and dried.
Yield: 95 mg (82% of theory)
3o ESI-MS: (M+H) + = 673
Rf = 0.57 (Polygram-Alox, DCM/MeOH 9:1)

CA 02565219 2006-10-17
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Examgle 2.7
(R)-1 -(2-cyclopro pyl-7-m ethyl- 1 H-benzimidazol-5-ylmethyl)-2-[4-(4-methyl-
piperazin-
1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-
piperidine-1 -carboxylate
H
N\
Q N
~N4 C
1 O
H
A solution of 120 mg (0.16 mmol) (R)-1-(3,4-diamino-5-methyl-benzyl)-2-[4-(4-
methyl-
1 o piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
1,3-
benzodiazepin-3-yl)-piperidine-l-carboxylate in 1 mL DMF was combined with 20
pL
(0.27 mmol) cyclopropanecarbaldehyde and stirred for 2 days at RT. The residue
was purified by HPLC, the fractions containing the product were combined and
lyophilised.
Yield: 85 mg (73% of theory)
ESI-MS: (M+H) + = 697
retention time (HPLC): 4.4 min (method A)
Example 2.8
,o
(R)-2-[4-(4-methyl-piperazin-l-yl)-piperidin-1-yl]-1-(7-methyl-2-
trifluoromethyl-1 H-
be nzi m id azo l-5-yl m ethyl )-2-oxo-ethyl 4-( 2-oxo-1, 2, 4, 5-tetra hyd ro-
1, 3-be nzod iazep i n-
3-yl)-piperidine-1-carboxylate
H
N
/CF3
N~
N
0 0Q)
~NN~\ \ C
i p
H
A solution of 120 mg (0.16 mmol) (R)-1-(3,4-diamino-5-methyl-benzyl)-2-[4-(4-
methyl-
piperazin-1-yl)-piperidin-l-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-

CA 02565219 2006-10-17
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benzodiazepin-3-yl)-piperidine-l-carboxylate in 1 mL DMF was combined with 30
mg
(0.26 mmol) trifluoroacetaldehyde and 3 drops of TFA and stirred for 2 h at
100 C.
The residue was purified by HPLC, the fractions containing the product were
combined and lyophilised.
Yield: 39 mg (34% of theory)
ESI-MS: (M+H)+ = 725
retention time (HPLC): 5.5 min (method A)
Example 2.9
(R)- 1 -(2-methoxy-7-methyl- 1 M benzimidazol-5-ylmethyl)-2-[4-(4-methyl-
piperazin-1-
yl)-piperidin-l-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
3-yl)-
piperidine-1-carboxylate
H
N
/> \
/~N0~N/
/ I N-(~J
~ /
N-\O 0
H
A solution of 115 mg (0.15 mmol) (R)-1-(3,4-diamino-5-methyl-benzyl)-2-[4-(4-
methyl-
p i pe razi n-1-y I)- p i pe ri d i n-1-y I]- 2-o xo-ethyl 4-( 2-oxo-1, 2, 4,
5-tetra hyd ro-1, 3-
benzodiazepin-3-yi)-piperidine-l-carboxylate in 0.5 mL MeOH was combined with
zo 200 mg (1.47 mmol) tetramethoxymethane and 10 mg p-toluenesulphonic acid
and
refluxed for 4 h. The residue was purified by HPLC, the fractions containing
the
product were combined and lyophilised. The product was obtained as the formate
salt.
Yield: 50 mg (45% of theory)
ESI-MS: (M+H) + = 687
retention time (HPLC): 4.8 min (method A)

CA 02565219 2006-10-17
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Example 2.10
(R)-2-[4-(4-methyl-piperazin-1 -yl)-piperidin-1 -yl]-1 -(8-methyl-quinoxalin-6-
ylmethyl)-
2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-
carboxylate
I
N4
H O
I
Under a nitrogen atmosphere a solution of 120 mg (0.16 mmol) 4-(2-oxo-1,2,4,5-
1o tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (R)-1-(3,4-
diamino-5-
methyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl in
20 mL THF
was combined with 20 pL (40% in water, 0.78 mmol) Glyoxal and 300 mg Na2SO4,
stirred for 20 h at RT, filtered and evaporated down i.vac. . The residue was
purified
by HPLC, the fractions containing the product were combined and lyophilised.
Yield: 72 mg (68% of theory)
ESI-MS: (M+H)+ = 669
retention time (HPLC): 5.3 min (method A)
Example 2.11
(R)-1-{2-[(Z)-cyanimino]-7-methyl-2,3-dihydro-1 H-benzimidazol-5-ylmethyl}-2-
[4-(4-
methyl-piperazin-1-yl)-piperidin-l-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
1,3-
benzod iazepi n-3-yl )-p i perid i ne-l-carboxylate
N N
& N>=N
0II H
A solution of 120 mg (0.16 mmol) (R)-1-(3,4-diamino-5-methyl-benzyl)-2-[4-(4-
methyl-
piperazin-1-yl)-piperidin-l-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-

CA 02565219 2006-10-17
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benzodiazepin-3-yl)-piperidine-l-carboxylate in 10 mL THF was combined with 60
mg (0.25 mmol) diphenylcyanocarbonimidate and refluxed for 2 h with stirring.
Then
EtOAc and saturated NaHCO3 solution was added, the phases were separated and
the organic phase was dried over Na2SO4. After the desiccant and solvent had
been
eliminated the residue was purified by chromatography (Alox, DCM/MeOH 25:1 to
8:1). The fractions containing the product were combined, evaporated down
i.vac.,
dissolved in a little MeOH, combined with diethyl ether, and the precipitate
was
suction filtered and dried.
Yield: 28 mg (22% of theory)
1o ESI-MS: (M+H)+ = 697
Rf = 0.24 (Polygram-Alox, DCM/MeOH 25:1)
Example 2.12
(R)-1-(7-methyl-1 H-benzotriazol-5-ylmethyl)-2-[4-(4-methyl-piperazin-1-yl)-
piperidin-
1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-
piperidine-1-
carboxylate
H
K
I ~
O ~ N N
IN -CNO~N/
O
H 0
J
120 mg (0.17 mmol) (R)-1-(4-amino-3-methyl-5-nitro-benzyl)-2-[4-(4-methyl-
piperazin-1-yl)-piperidin-1 -yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-l,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate were dissolved in 10 mL MeOH and
combined with 30 mg 10% Pd/C. The mixture was hydrogenated for 1 h in a Parr
apparatus at 50 C at 50 psi hydrogen pressure. Then the catalyst was filtered
off, the
filtrate was combined with 2.5 mL 20% AcOH and 15 mg (0.22 mmol) sodium
nitrite
in 0.5 mL water and stirred for 2 h at RT. The reaction solution was made
alkaline
with NaHCO3 solution, extracted with DCM and the organic phase was dried over
Na2SO4. After the desiccant and solvent had been eliminated the residue was
purified by chromatography (Alox, gradient DCM/MeOH 25:1 to 5:1).
Yield: 22 mg (19% of theory)

CA 02565219 2006-10-17
- 184 -
ESI-MS: (M+H)+ = 658
Rf = 0.25 (Polygram-Alox, DCM/MeOH 25:1)
Example 2.13
(R)-2-(1'-methanesulphonyl-4,4'-bipiperidinyl-1-yl)-1-(7-methyl-1 H-
benzimidazol-5-
ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4, 5-tetrahyd ro-1,3-benzod iazepin-3-yl)-
piperidine-
1-carboxylate
H
~ N
0 N
OSO
\ I N ~/ ' 'O~ N~ ~
N'~
1 O
H
A solution of 120 mg (0.22 mmol) (R)-1-carboxy-2-(7-methyl-1H-benzimidazol-5-
yl)-
ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-
carboxylate,
80 mg (0.25 mmol) TBTU, 40 pL (0.29 mmol) triethylamine and 80 mg (0.33 mmol)
1-
methanesulphonyl-[4,4']bipiperidinyl in 1.5 mL DMF was stirred overnight at
RT. The
reaction mixture was purified by HPLC without working up. The fractions
containing
the product were combined and lyophilised.
Yield: 67 mg (42% of theory)
ESI-MS: (M+H)+ = 720
.0 retention time (HPLC): 5.9 min (method A)
Example 3
(R)-1 -(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-[4-(4-methyl-
piperazin-1 -
yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-l,3-benzodiazepin-
3-yl)-
piperidine-1-carboxylate
H
~ / O O
O
~N~ O

CA 02565219 2006-10-17
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3a) 4-methyl-3H-benzoxazol-2-one
76.0 g (0.45 mol) CDI in 1 L DCM were added dropwise at 0 C to a solution of
50.0 g
(0.39 mol) 5-amino-m-cresol and 210 mL (1.2 mol) in 1 L DCM. After the end of
the
reaction the reaction mixture was combined with 250 mL water, the organic
phase
was separated off and washed twice with 250 mL 1 M KHSO4 solution and 250 mL
water and dried over MgSO4. After the desiccant and solvent had been
eliminated the
residue obtained was dissolved in 200 mL EtOAc, refluxed, combined with 100 mL
PE, slowly cooled to RT, the precipitate formed was suction filtered and
dried.
Yield: 39.2 g (67% of theory)
1o ESI-MS: (M+H) + = 150
Rf = 0.65 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2)
3b) 6-bromo-4-methyl-3H-benzoxazol-2-one
35.8 g (199.1 mmol) N-bromosuccinimide were added to a solution of 29.5 g
(197.8
mmol) 4-methyl-3H-benzoxazol-2-one in 200 mL AcOH and stirred overnight at RT.
The reaction solution was combined with 800 mL water, stirred for 15 min at
RT, the
precipitate was suction filtered, washed with water and dried at 60 C in the
vacuum
drying cupboard.
Yield: 43.0 g (95% of theory)
2o ESI-MS: (M+H)+ = 226/228 (Br)
Rf = 0.35 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2)
3c) methyl (Z,E)-2-acetylamino-3-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-yl)-
acrylate
Under a nitrogen atmosphere 5.4 g (23.9 mmol) Pd(OAc)2 and 7.5 g (24.0 mmol)
tri-
o-tolyl-phosphane were added to a solution of 38.3 g (168.0 mmol) 6-bromo-4-
methyl-3H-benzoxazol-2-one and 28.0 g (191.7 mmol) methyl 2-acetylamino-
acrylate
in 800 mL acetonitrile and 480 mL triethylamine, the reaction mixture was
stirred for
18 h at 80 C and then evaporated down i.vac. . The residue was combined with
100
mL water and 50 mL EtOAc and the precipitate was filtered off. The crystals
were
dissolved in MeOH/DCM 1:1 at reflux temperature, combined with activated
charcoal,
filtered off and the filtrate was evaporated to dryness.
Yield: 31.2 g (64% of theory)
ESI-MS: (M+H)+ = 291

CA 02565219 2006-10-17 -186-
Rf = 0.38 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2)
3d) 3-(4-methyl-2-oxo-2 3-dihvdro-benzoxazot-6-yl)-2-oxo-propionic acid
160 mL 4 M HCI were added to a solution of 31.2 g (107.5 mmol) methyl (Z,E)-2-
acetylamino-3-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-yl)-acrylate in 320 mL
1,4-
dioxane and the reaction solution was refluxed for 5 h. The mixture was
evaporated
down i. vac., the precipitate was filtered off, washed with water and dried at
60 C in
the vacuum drying cupboard.
Yield: 24.9 g (98% of theory)
1o ESI-MS: (M+H)+ = 236
Rf = 0.38 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2)
3e) (R)-2-hydroxy-3-(4-methyl-2-oxo-2 3-dihydro-benzoxazol-6-yl)-propionic
acid
Under a nitrogen atmosphere a solution of 60.0 g (187.1 mmol) (1 R)-B-
chlorodiisopinocampheylborane in 200 mL THF was added dropwise within 15 min
to
a solution of 24.9 g (105.9 mmol) 3-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-
yl)-2-
oxo-propionic acid and 20.0 mL (143.9 mmol) triethylamine in 400 mL THF cooled
to
-35 C and the reaction solution was stirred overnight at RT. Then the reaction
solution was carefully made alkaline with 1 M NaOH at 50C, combined with 400
mL
EtOAc and stirred for 15 min. The organic phase was separated off, extracted
twice
with 100 mL 1 M NaOH and with 100 mL water. The combined aqueous phases were
acidified with semiconc. HCI and extracted twice with 150 mL EtOAc. The
combined
organic phases were dried over MgSO4 and evaporated down i.vac. .
Yield: 20.8 g (83% of theory)
ESI-MS: (M+H)+ = 238
Rf = 0.10 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2)
3f) methyl (R)-2-hydroxy-3-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-yl)-
propionate
23.0 g (97.0 mmol) (R)-2-hydroxy-3-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-
yl)-
propionic acid were dissolved in 200 mL methanolic HCI (1.3 M), stirred
overnight at
RT and then evaporated down i.vac. . The residue was combined with 200 mL
EtOAc, washed with 15% K2CO3 solution and the organic phase was dried over
Na2SO4 . After the desiccant and solvent had been eliminated the residue was

CA 02565219 2006-10-17
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combined with DIPE, the crystals were filtered off and dried at 50 C in the
vacuum
drying cupboard.
Yield: 14.6 g(60% of theory)
ESI-MS: (M+H)+ = 252
Rf = 0.44 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2)
3g) (R)-l-carboxy-2-(4-methyl-2-oxo-2 3-dihydro-benzoxazol-6-yl)-ethyl 4-(2-
oxo-
1 2 4 5-tetrahydro-1 3-benzodiazepin-3-yl)-piperidine-1-carboxylate
Under a nitrogen atmosphere 4.1 g (20.1 mmol) 4-nitrophenyl chloroformate in
20 mL
THF were metered into 40 mL pyridine at a bath temperature of 60 C within 10
min,
stirred for 5 min, then 5.0 g (19.9 mmol) methyl (R)-2-hydroxy-3-(4-methyl-2-
oxo-2,3-
dihydro-benzoxazol-6-yl)-propionate and 20 mL pyridine were added and the
reaction
mixture was stirred for 1.5 h at 60 C. The reaction solution was combined with
4.9 g
(20.0 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and
stirred
for 2 h at 100 C. After the reaction had ended 150 mL EtOAc was added, the
mixture
was washed three times with 70 mL 1 M KHSO4 solution and 12 times with 50 mL
15% K2CO3 solution and the organic phase was dried over MgSOa. After the
desiccant and solvent had been eliminated the residue was dissolved in 60 mL
THF,
combined with 250 mg LiOH in 10 mL water and the reaction mixture was stirred
for
2o 3 h at RT. The THF was eliminated Lvac., the aqueous residue was mixed with
60
mL TBME, insoluble constituents were filtered off, the organic phase was
separated
off and the aqueous phase was acidified with 1 M HCI. After 1 h at RT the
precipitate
formed was suction filtered, washed with water and dried at 60 C in the vacuum
drying cupboard.
Yield: 2.5 g (25% of theory)
ESI-MS: (M-H)" = 507
Rf = 0.10 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2)
3h) (R)-1-(4-methyl-2-oxo-2 3-dihydro-benzoxazol-6-ylmethyl)-2-f4-(4-methyl-
piperazin-1-yl)-piperidin-1-yll-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzod iazepin-3-yl )-pi perid i ne-1-carboxylate
A solution of 510 mg (1.0 mmol) (R)-1-carboxy-2-(4-methyl-2-oxo-2,3-
dihydrobenz-
oxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5,-tetrahydro-l,3-benzodiazepin-3-yl)-
piperidine-1-
carboxylate, 365 mg (1.12 mmol) TBTU, 230 NL (1.31 mmol) ethyldiisopropylamine
in

CA 02565219 2006-10-17
- 188 -
80 mL THF was stirred for 30 min at RT , then combined with 210 mg (1.12 mmol)
1-methyl-4-piperidin-4-yl-piperazine and stirred for 22 h at RT. To complete
the
reaction the mixture was again combined with 100 mg (0.3 mmol) TBTU and 50 mg
(0.27 mmol) 1-methyl-4-piperidin-4-yl-piperazine and 40 mL THF and stirred for
a
further 4 h at RT. The reaction solution was diluted with 250 mL EtOAc and
extracted
twice with 60 mL saturated NaHCO3 solution. The organic phase was dried over
Na2SO4, filtered and evaporated down i.vac. . The residue was purified by
chromatography (Alox, DCM/MeOH 50:1 to 25:1), the fractions containing the
product were combined, evaporated down i.vac., combined with diethyl ether,
filtered
off and dried.
Yield: 440 mg (65% of theory)
ESI-MS: (M+H) + = 674
Rf = 0.46 (Polygram-Alox, DCM/MeOH 25:1)
Example 3.1
(R)-1-(4-methyl-2-oxo-2, 3-di hydro-benzoxazol-6-ylmethyl)-2-[4-(1-methyl-
piperidin-4-
yl)-piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
3-yl)-
piperidine-1-carboxylate
H
6 O O
N4 O
H ~
A solution of 510 mg (1.0 mmol) (R)-1-carboxy-2-(4-methyl-2-oxo-2,3-dihydro-
benz-
oxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5,-tetrahydro-1,3-benzodiazepin-3-yl)-
piperidine-l-
carboxylate, 370 mg (1.11 mmol) TBTU, 230 pL (1.31 mmol) ethyldiisopropylamine
in
60 mL THF was stirred for 30 min at RT, then combined with 210 mg (1.12 mmol)
1-
(1-methyl-piperidin-4-yl)-piperazine and stirred for 22 h at RT. To complete
the
reaction the mixture was again combined with 80 mg (0.24 mmol) TBTU, 50 pL
(0.28
mmol) ethyidiisopropylamine, 50 mg (0.27 mmol) 1-(1-methyl-piperidin-4-yl)-
piperazine and 40 mL THF and stirred for a further 2 days at RT. The reaction
solution was combined with 10 mL LiOH solution (0.5 M) and stirred for 30 min
at RT.

CA 02565219 2006-10-17
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Then it was diluted with 250 mL EtOAc and extracted twice with 60 mL saturated
NaHCO3 solution. The organic phase was dried over Na2SO4, filtered and
evaporated
down i.vac. . The residue was purified by chromatography (Alox, DCM/MeOH 50:1
to
25:1), the fractions containing the product were combined, evaporated down
i.vac.,
combined with diethyl ether, filtered off and dried.
Yield: 420 mg (62% of theory)
ESI-MS: (M+H)+ = 674
Rf = 0.40 (Polygram-Alox, DCM/MeOH 25:1)
Example 3.2
(R)-2-(4-amino-4-methyl-1,4'-bipiperidinyl-1'-yl)-1-(4-methyl-2-oxo-2,3-
dihydro-
benzoxazol-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-
yl)-piperidine-1-carboxylate
H
I / O O
N~N~O~N~N~NHZ
O
1 O
H
A solution of 80 mg (0.16 mmol) (R)-1-carboxy-2-(4-methyl-2-oxo-2,3-dihydro-
benzoxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-
piperidine-1-carboxylate, 58 mg (0.18 mmol) TBTU, 140 pL (1.0 mmol)
triethylamine
and 59 mg (0.16 mmol) tert.-butyl (4-methyl-[1,4')bipiperidinyl-4-yl)-
carbamate (used
as the bis-hydrochloride salt) in 1.8 mL DMF was stirred overnight at RT. The
reaction mixture was purified by HPLC, the fractions containing the product
were
combined and lyophilised.
The coupling product was taken up in 4 mL DCM, combined with 0.5 mL TFA and
the
reaction mixture was shaken for 5 h at RT and overnight without a seal, during
which
time the DCM evaporated off. The residue was combined with 2 mL 15% K2CO3
solution and extracted twice with 2 mL DCM. The solvent from the combined
organic
phases was allowed to evaporate off overnight, the residue was taken up in 1
mL
3o DMF and the crude product was purified by HPLC. The fractions containing
the
product were combined and lyophilised.

CA 02565219 2006-10-17
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Yield: 42 mg (36% of theory)
ESI-MS: (M+H)+ = 688
retention time (HPLC): 4.5 min (method A)
Example 3.3
(R)-1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-(1'-
sulphamoyl-
4,4'-bipiperidinyl-1-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
yl)-
piperidine-1-carboxylate
H
O O
O
/ O\l
N---( N O~ N-S-NH2
N~\ ~/ ~\ ~/ O
1 O
H
A solution of 73 mg (0.14 mmol) (R)-1-carboxy-2-(4-methyl-2-oxo-2,3-dihydro-
benz-
oxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-
piperidine-1-
carboxylate, 51 mg (0.16 mmol) TBTU, 42 pL (0.3 mmol) triethylamine and 41 mg
(0.14 mmol) [4,4']bipiperidinyl-1-sulphonic acid amide (used as the
hydrochloride
salt) in 1.8 mL DMF was stirred overnight at RT. The reaction mixture was
purified by
HPLC, the fractions containing the product were combined and lyophilised.
Yield: 22 mg (21 % of theory)
o ESI-MS: (M+H) + = 738
retention time (HPLC): 3.5 min (method B)
Example 3.4
(R)-2-(1'-methanesulphonyl-4,4'-bipiperidinyl-1-yl)-1-(4-methyl-2-oxo-2,3-
dihydro-
benzoxazo l-6-yl methyl )-2-oxo-ethyl 4-(2-oxo-1, 2,4, 5-tetrahyd ro-1, 3-
benzod iazepi n-3-
yl)-piperidine-1-carboxylate

CA 02565219 2006-10-17
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H
O O
OO
-~~JJ( N O N~S
No 0
H
A solution of 110 mg (0.22 mmol) (R)-1-carboxy-2-(4-methyl-2-oxo-2,3-dihydro-
benz-
oxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-
piperidine-l-
carboxylate, 80 mg (0.25 mmol) TBTU and 50 pL (0.29 mmol)
ethyldiisopropylamine
in 10 mL THF was stirred for 50 min at RT. Then 60 mg (0.24 mmol) 1-
methanesulphonyl-[4,4']bipiperidinyl was added. The reaction mixture was
stirred
overnight at RT. It was diluted with 50 mL EtOAc, extracted twice with 30 mL
15%
K2CO3 solution and the organic phase was dried over MgSO4. After the desiccant
and solvent had been eliminated the residue was triturated with water, suction
filtered
and purified by chromatography (silica gel, gradient DCM to DCM/MeOH/NH3
50:45:5).
Yield: 80 mg (50% of theory)
ESI-MS: (M+H) + = 737
Rf = 0.38 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2)
Example 4
(R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-[4-(1-methyl-
/-o piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
1,3-
benzod iazepin-3-yl)-pipe ridine- 1 -carboxylate
N
O
0 O
~ ~~0~ / N~~N~
N
1 O
H
4a) 3,4-dimethyl-3H-benzoxazol-2-one
A solution of 10.0 g (67.0 mmol) 4-methyl-3H-benzoxazol-2-one in 200 mL THF
was
combined with 8.0 g (70.6 mmol) potassium-tert.-butoxide, stirred for 30 min
at RT,
then combined with 7.0 mL (110.3 mmol) iodomethane and stirred overnight at
RT.

CA 02565219 2006-10-17
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The reaction mixture was combined with 100 mL EtOAc, washed twice with 50 mL
saturated NaCi solution, the organic phase was dried over MgSO4, filtered and
evaporated to dryness i.vac.. The residue was combined with PE/EtOAc 2:1, the
precipitate was suction filtered and dried at 60 C in the vacuum drying
cupboard.
Yield: 9.0 g (82% of theory)
ESI-MS: (M+H) + = 164
Rf = 0.56 (silica gel, PE/ EtOAc 2:1)
4b) 6-bromo-3,4-dimethyl-3H-benzoxazol-2-one
To a solution of 9.0 g (55.2 mmol) 3,4-dimethyl-3H-benzoxazol-2-one in 50 mL
AcOH
were added 11.0 g (60.0 mmol) N-bromosuccinimide and the reaction mixture was
stirred overnight at RT. The reaction solution was combined with 300 mL water,
stirred for 15 min at RT, the precipitate was suction filtered, washed with
water and
dried at 60 C in the vacuum drying cupboard.
Yield: 12.7 g (95% of theory)
ESI-MS: (M+H)+ = 242/244 (Br)
Rf = 0.52 (silica gel, PE/ EtOAc 2:1)
4c) methyl (Z,E)-2-acetylamino-3-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-
2o yl)-acrylate
Under a nitrogen atmosphere 1.8 g (8.0 mmol) Pd(OAc)2 and 2.5 g (8.0 mmol) tri-
o-
tolyi-phosphane were added to a solution of 13.2 g (54.5 mmol) 6-bromo-3,4-
dimethyl-3H-benzoxazol-2-one and 9.0 g (61.6 mmol) methyl 2-acetylamino-
acrylate
in 250 mL acetonitrile and 160 mL triethylamine and the reaction mixture was
stirred
for 18 h at 80 C. The reaction solution was evaporated down i.vac., the
residue was
combined with 100 mL water and 50 mL EtOAc and the precipitate was filtered
off.
The latter was dissolved in MeOH/DCM (1:1), combined with activated charcoal,
filtered off and the filtrate was evaporated to dryness.
Yield: 8.7 g (52% of theory)
3o ESI-MS: (M+H)+ = 305
Rf = 0.47 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2)
4d) 3-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-oxo-propionic acid
40 mL 4 M HCI were added to a solution of 8.7 g (28.6 mmol) methyl (Z,E)-2-

CA 02565219 2006-10-17
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acetylamino-3-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-yl)-acrylate in 80
mL
1,4-dioxane and the reaction solution was refluxed for 5 h and then left
overnight at
RT. It was evaporated down i.vac. , the precipitated product was filtered off,
washed
with water and dried at 60 C in the vacuum drying cupboard.
Yield: 6.6 g (93% of theory)
ESI-MS: (M+H)+ = 250
Rf = 0.13 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2)
4e) (R)-3-(3 4-dimethyl-2-oxo-2 3-dihydro-benzoxazol-6-yl)-2-hydroxy-propionic
acid
Under a nitrogen atmosphere a solution of 15.0 g (46.8 mmol) (1 R)-B-
chlorodiisopinocampheylborane in 50 mL THF was added dropwise within 15 min to
a solution of 6.6 g (26.5 mmol) 3-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-
yl)-2-
oxo-propionic acid and 5.0 mL (36.0 mmol) triethylamine in 100 mL THF cooled
to -
35 C and the reaction solution was stirred overnight at RT. Then at 5 C the
mixture
was combined with 60 mL 1 M NaOH and 100 mL EtOAc, stirred for 15 min, the
organic phase was separated off and extracted twice with 30 mL 1 M NaOH and
with
40 mL water. The combined aqueous phases were acidified with semiconc. HCI and
extracted twice with 100 mL EtOAc. The combined organic phases were dried over
MgSOa and evaporated down i.vac. .
Yield: 3.4 g(51 % of theory)
ESI-MS: (M+H) + = 252
Rf = 0.13 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2)
4f) methyl (R)-3-(3 4-dimethyl-2-oxo-2 3-dihydro-benzoxazol-6-yl)-2-hydroxy-
propionate
3.4 g (13.5 mmol) (R)-3-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-
hydroxy-
propionic acid were dissolved in 40 mL methanolic HCI (1.3 M) and the reaction
mixture was stirred overnight at RT. It was evaporated down i.vac., the
residue was
taken up in 200 mL EtOAc, washed with 15% K2CO3 solution and the organic phase
was dried over Na2SO4. After the desiccant and solvent had been eliminated the
residue was reacted further without purification.
Yield: 2.5 g (70% of theory)
ESI-MS: (M+H)+ = 266

CA 02565219 2006-10-17
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Rf = 0.54 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2)
4g) (R)-1-carboxy-2-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-yl)-ethyl 4-
(2-
oxo-1,2,4,5,-tetrahydro-1,3-benzodiazepin-3 yl)-piperidine-1-carboxylate
Under a nitrogen atmosphere a solution of 2.0 g (10.0 mmol) 4-nitrophenyl
chloroformate in 10 mL THF was added at 60 C within 10 min to 20 mL pyridine
and
stirred for 10 min. Then a solution of 2.5 g (9.4 mmol) methyl (R)-3-(3,4-
dimethyl-2-
oxo-2,3-dihydro-benzoxazol-6-yl)-2-hydroxy-propionate in 10 mL pyridine was
added,
the mixture was stirred for a further 2.5 h at 60 C and then combined with 2.5
g (10.0
mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one. The
reaction
solution was stirred for 3 h at 100 C. After the end of the reaction the
reaction
mixture was evaporated down i.vac., combined with 150 mL EtOAc, the organic
phase was washed three times with 40 mL 1 M KHSO4 solution and 12 times with
30
mL 15% K2CO3 solution and dried over MgSO4. After the desiccant and solvent
had
been eliminated the residue was dissolved in 60 mL THF, combined with 250 mg
LiOH in 10 mL water and the reaction mixture was stirred for 3 h at RT. The
THF was
eliminated i.vac., the aqueous phase was diluted with 60 mL EtOAc, filtered to
remove the insoluble constituents and the organic phase was separated off. The
aqueous phase was acidified with 15 mL 1 M HCI, extracted three times with 50
mL
EtOAc and the combined organic phases were dried over MgSO4. After the
desiccant
and solvent had been eliminated the residue was dissolved at 80 C in 30 mL
isopropanol. The solution was left to cool slowly overnight, the precipitate
was
suction filtered, washed with isopropanol and dried at 60 C in the vacuum
drying
cupboard.
Yield: 1.1 g (22% of theory)
ESI-MS: (M+H)+ = 523
Rf = 0.31 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2)
4h) (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-f4-(1-
methyl-
piperidin-4-yl)-piperazin-1-yll-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-Lrl)-piperidine-l-carboxylate
A solution of 80 mg (0.15 mmol) (R)-1-carboxy-2-(3,4-dimethyl-2-oxo-2,3-
dihydro-
benz-oxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5,-tetrahydro-1, 3-benzod iazepin-3-yl)-
piperidine-l-carboxylate, 52 mg (0.16 mmol) TBTU, 24 pL (0.17 mmol)
triethylamine

CA 02565219 2006-10-17
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and 30 mg (0.16 mmol) 1 -(1 -m ethyl pipe rid i n-4-yl)-pi perazi ne in 1.5 mL
DMF was
stirred overnight at RT. The reaction mixture was purified by HPLC, the
fractions
containing the product were combined and lyophilised.
Yield: 70 mg (66% of theory)
ESI-MS: (M+H)+ = 688
Rf = 0.36 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2)
The following compounds were prepared analogously from in each case 80 mg
(Examples 4.1 and 4.2) or in each case 100 mg (Examples 4.3 to 4.6) of (R)-1-
carboxy-2-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-yl)-ethyl 4-(2-oxo-
1,2,4,5-
tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and the
corresponding
amount of amine:
&o 0
R
NO
N4 O
H
Example R Yield (%) Mass Rf
spectrum (silica gel,
DCM/MeOH/Cyc/NH3
70:15:15:2)
4.1 62 688 0.32
[M+H]+
4.2 52 687 0.33
N/ IM+HI+
4.3 44 764 0.43
[M+H]+
29 763 0.49
4.4 . q
[M+H]
N

CA 02565219 2006-10-17
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4.5 44 764 0.38
[M+H]+
4.6 49 689 0.43
[M+H]+
Example 4.7
(R)-1 -(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-(1'-
sulphamoyl-4,4'-bipiperidinyl-l-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yi)-piperidine-l-carboxylate
o
o
0110
0~ /S\"Hz
N o
1 p
H
A solution of 75 mg (0.14 mmol) (R)-1-carboxy-2-(3,4-dimethyl-2-oxo-2,3-
dihydro-
benzoxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5,-tetrahyd ro-1,3-benzod iazepin-3-yl)-
piperidine-1-carboxylate, 51 mg (0.16 mmol) TBTU, 42 pL (0.30 mmol)
triethylamine
and 41 mg (0.14 mmol) [4,4']bipiperidinyl-l-sulphonic acid amide (used as the
hydrochloride salt) in 2 mL DMF were stirred overnight at RT. The reaction
mixture
was purified by HPLC, the fractions containing the product were combined and
lyophilised.
Yield: 31 mg (29% of theory)
ESI-MS: (M+H)+ = 752
retention time: 3.7 min (method B)
The following compounds were prepared analogously from in each case 83 mg (R)-
1-ca rboxy-2-( 3, 4-d i m ethyl-2-oxo-2, 3-d i hyd ro-benzoxazo l-6-yl )-ethyl
4-( 2-oxo-1, 2, 4, 5-
tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-l-carboxylate and the
corresponding
amount of amine:

CA 02565219 2006-10-17
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~ ~ o 0
O~R
N O
H O
I
Example R Yield (%) Mass retention time
spectrum HPLC
(method)
4.8 =~ 72 751 3.9 min
oõo
[M+H]+ (B)
4.9 52 714 2.5 min
[M+H]+ (B)
Example 4.10
(R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-(4-
piperazin-1 -
yl-piperidin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-
piperidine-
1-carboxylate
~ ~ o
0 0
\
N(~ O
O
H
60 mg (0.08 mmol) (R)-2-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-1-(3,4-
dimethyl-2-
oxo-2 , 3-d i hyd ro-benzoxazo l-6-yl m ethyl )-2-o xo-ethyl 4-(2-oxo-1, 2, 4,
5-tetra hyd ro-1, 3-
benzodiazepin-3-yl)-piperidine-l-carboxylate (Example 4.3) were dissolved in
20 mL
MeOH and combined with 10 mg 10% Pd/C. The mixture was hydrogenated at 50 C
and 3 bar hydrogen pressure until the theoretical hydrogen uptake had
occurred.
Then the catalyst was filtered off, the filtrate was evaporated to dryness i.
vac., the
residue was combined with MeOH and water and lyophilised.
Yield: 50 mg (94% of theory)

CA 02565219 2006-10-17
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ESI-MS: (M+H)+ = 674
Rf = 0.33 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2)
Example 4.11
(R)-2-4,4'-bipiperidinyl-1-yl-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-
ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4, 5-tetrahydro-1,3-benzodiazepin-3-yl)-
piperidine-
1-carboxylate
~ ~ o
0 0
H
O
O
H
Analogously to Example 4.10 the product was obtained from 40 mg (0.05 mmol)
(R)-
2-(1'-benzyl-4,4'-bipiperidinyl-1-yl)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-
benzoxazol-6-
ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahyd ro- 1, 3-benzod iazepin-3-yl )-
piperidine-
1-carboxylate (Example 4.4).
Yield: 35 mg (99% of theory)
ESI-MS: (M+H)+ = 673
Rf = 0.29 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2)
2o Example 4.12
(R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazo1-6-yimethyl)-2-oxo-2-(4-
piperidin-4-
yl-piperazin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-
piperidine-1-carboxylate
~ ~ o
0 o
/N~NO~ H
N'"p O
i O
H
Analogously to Example 4.10 the product was obtained from 60 mg (0.08 mmol)
(R)-

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2-[4-(1-benzyl-piperidin-4-yl)-piperazin-1-yl]-1-(3,4-dimethyl-2-oxo-2,3-
dihydro-
benzoxazol-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-
yl)-piperidine-1-carboxylate (Example 4.5) .
Yield: 45 mg (85% of theory)
ESI-MS: (M+H)+ = 674
Rf = 0.22 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2)
Example 4.13
io (R)-2-(4-amino-4-methyl-1,4'-bipiperidinyl-1'-yl)-1-(3,4-dimethyl-2-oxo-2,3-
dihydro-
be nzoxazol-6-yimethyl)-2-oxo-ethyl 4-(2-oxo-1, 2,4, 5-tetrahyd ro-1, 3-benzod
iazep in-3-
yl)-piperidine-1-carboxylate
&o 0
\
N~N O~N~/ "' N tVHZ
IOI \~
1 O
H
A solution of 80 mg (0.15 mmol) (R)-1-carboxy-2-(3,4-dimethyl-2-oxo-2,3-
dihydro-
benz-oxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5,-tetrahydro-1,3-benzod iazepin-3-yl )-
piperidine-l-carboxylate, 58 mg (0.18 mmol) TBTU, 140 pL (1.00 mmol)
triethylamine
and 59 mg (0.16 mmol) tert.-butyl (4-methyl-[1,4']bipiperidinyl-4-y1)-
carbamate in 1.8
zo mL DMF were stirred overnight at RT. The reaction mixture was purified by
HPLC,
the fractions containing the product were combined and lyophilised. The
residue
obtained was dissolved in 4 mL DCM, combined with 0.5 mL TFA and the reaction
solution was stirred for 5 h at RT. The DCM was left to evaporate off
overnight, the
residue was combined with 2 mL 15% K2CO3 solution and extracted twice with 2
mL
DCM. After the solvent had been eliminated the residue was taken up in 1 mL
DMF
and purified by HPLC. The fractions containing the product were combined and
lyophilised.
Yield: 40 mg (35% of theory)
ESI-MS: (M+H)+ = 702
retention time (HPLC): 4.6 min (method A)

CA 02565219 2006-10-17
- 200 -
Example 4.14
( R)-1-( 3, 4-d i m ethyl-2-oxo-2 , 3-d i hyd ro-be nzoxazo I-6-yl m et hyl )-
2-(1 '-
ethoxycarbonylmethyl-4,4'-bipiperidinyl-1-yl)-2-oxo-ethyl 4-(2-oxo-1, 2,4,5-
tetrahydro-
1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate
6o 0
OX !N~NO~ N O'
N~O O ~
H
Analogously to Example 4h the product was obtained from 200 mg (0.38 mmol) (R)-
1o 1-carboxy-2-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-yl)-ethyl 4-(2-oxo-
1,2,4,5-
tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 110 mg (0.43
mmol)
ethyl [4,4']bipiperidinyl-1-yl-acetate.
Yield: 60 mg (21 % of theory)
ESI-MS: (M+H) + = 759
Rf = 0.54 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2)
Example 4.15
(R)-2-(1'-carboxymethyl-4,4'-bipiperidinyl-1-yl)-1-(3,4-dimethyl-2-oxo-2,3-
dihydro-
1o benzoxazol-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-
yl)-piperidine-l-carboxylate
I ~ o
0 0
O~H
O/N
N C/ 'O O O
H
A solution of 4 mg (0.16 mmol) LiOH in 3 mL water was added to a solution of
60 mg
(0.08 mmol) (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-(1'-
ethoxyca rbo nyl m ethyl-4, 4'-bipiperid i nyl-l-yl )-2-oxo-ethyl 4-(2-oxo-1,
2,4, 5-tetrahyd ro-
1,3-benzodiazepin-3-yl)-piperidine-l-carboxylate (Example 4.14) in 6 mL THF
and

.a
CA 02565219 2006-10-17
- 201 -
the reaction mixture was stirred for 14 h at RT. The mixture was combined with
1 M
HCI until an acid reaction was produced, evaporated down i.vac., the residue
was
taken up in a little DMF and the crude product was purified by HPLC. The
fractions
containing the product were combined and lyophilised.
Yield: 20 mg (35% of theory)
ESI-MS: (M-H)- = 729
Rf = 0.43 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2)
Example 4.16
(R)-2-1,4'-bipiperidinyl-1'-y1-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-
ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4, 5-tetrahydro-1, 3-benzod iazepin-3-yl)-
piperid i ne-
1 -carboxylate
~o
/N~N'o~~NV
O,X-
O 0
H
A solution of 70 mg (0.13 mmol) (R)-1-carboxy-2-(3,4-dimethyl-2-oxo-2,3-
dihydro-
benzoxazol-6-yl)-ethyl 4-(2-oxo-1,2,4, 5,-tetrahydro-1,3-benzod iazepin-3-yl)-
piperidine-1-carboxylate, 50 mg (0.16 mmol) TBTU, 25 pL (0.18 mmol)
triethylamine
and 59 mg (0.16 mmol) [1,4']bipiperidinyl in 1.0 mL DMF were shaken overnight
at
RT. The reaction mixture was purified by HPLC without any further working up,
the
fractions containing the product were combined and lyophilised.
Yield: 68 mg (75% of theory)
ESI-MS: (M+H)+ = 673
Rf = 0.78 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2)
The following compounds were prepared analogously from in each case 70 mg (R)-
1-carboxy-2-(3,4-dimethyl-2-oxo-2,3-d ihydro-benzoxazol-6-yl)-ethyl 4-(2-oxo-
1,2,4, 5,-
tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and the
corresponding
amount of amine:

CA 02565219 2006-10-17
- 202 -
/
~o
O
0~"'4~,R
~ O
H
Example R Yield (%) Mass Rf
spectrum (silica gel,
DCM/MeOH/Cyc/NH3
70:15:15:2)
4.17 37 714 0.32
-~N [M+H]+
4.18 50 673 0.65
N[M+H]+
4.19 77 675 0.63
[M+H]+
4.20a 31 719 0.49
oH [M+H]+
OH
a use of 4 eq. of triethylamine, as the amine component was used as the bis-
hydrochloride salt
Example 5
(R)-1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-[4-(4-methyl-piperazin-1 -yl)-
piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
yl)-
piperidine-1-carboxylate

CA 02565219 2006-10-17
-203-
~ O
I
o ~ o)
N-C~ON
O
1 O
H
5a) (Z,E)-2-acetylamino-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-acrylic acid
A suspension of 15.0 g (91.4 mmol) 2,3-dihydro-1,4-benzodioxin-6-carbaldehyde,
16.0 g (137 mmol) N-acetylglycine and 11.2 g(137 mmol) NaOAc in 50 mL acetic
anhydride was heated to 120 C in the oil bath for 4 h. After cooling 35 mL
water were
slowly added and the reaction mixture was stirred for 1 h at 80 C. The cooled
solution was poured onto 350 mL water and combined with 150 mL toluene. A
further
200 mL water were added, the phases were separated and the aqueous phase was
again extracted with toluene. The aqueous phase was combined with 500 mL DCM
and the phases were again separated. After standing for some time at RT a
precipitate was deposited from the aqueous phase, and it was filtered off and
dried.
The organic phase was evaporated down to approx. 100 mL and left at RT. The
precipitate formed was also filtered and dried. The two product fractions were
combined.
Yield: 9.3 g (38% of theory)
ESI-MS: (M+H)+ = 264
5b) 3-(2 3-dihydro-1 4-benzodioxin-6-yl)-2-oxo-propionic acid
.0 110 mL 4 M HCI were added to a boiling solution of 9.25 g (35.1 mmol) (Z,E)-
2-
acetylamino-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-acrylic acid in 100 mL
isopropanol,
the reaction mixture was refluxed for 2 h, combined with another 40 mL of 4 M
HCI,
refluxed for a further 4 h and left overnight at RT. The precipitate formed
was filtered
and dried at 60 C. The product was reacted further without purification.
Yield: 4.6 g (59% of theory)
ESI-MS: (M-H)" = 221
5c) (R)-3-(2 3-dih rLdro-1 4-benzodioxin-6-yl)-2-hydroxy-propionic acid
A solution of 12.4 g(23.0 mmol) (1 R)-B-chlorodiisopinocampheylborane in 50 mL
3o THF was added dropwise within 30 min to a solution of 4.6 g (20.7 mmol) 3-
(2,3-
dihydro-1,4-benzodioxin-6-yl)-2-oxo-propionic acid and 3.14 mL (23.0 mmol)

CA 02565219 2006-10-17
- 204 -
triethylamine in 150 mL THF cooled to -35 C and the reaction mixture was kept
for 1
h at this temperature and for 4 h at RT. To complete the reaction a solution
of 5.0 g
(9.3 mmol) (1 R)-B-chlorodiisopinocampheylborane in 50 mL THF was added and
the
reaction mixture was stirred overnight at RT. THF was removed i.vac. and the
crude
product (2.0 g) was reacted further without purification.
ESI-MS: (M+H)+ = 225
retention time (HPLC): 5.1 min (method A)
5d) methyl (R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-hydroxy-propionate
1o 2.0 g of the crude product from Example 5c were dissolved in 150 mL
methanolic
HCI (1.25 M) and the reaction mixture was stirred for 70 h at RT. The solvent
was
eliminated i.vac., the residue was taken up in 50 mL EtOAc and 50 mL saturated
K2CO3 solution, the organic phase was separated off and the solvent was
removed.
The crude product was then purified by HPLC.
Yield: 0.23 g (5% of theory over 2 steps)
ESI-MS: (M+H)+ = 239
retention time (HPLC): 6.0 min (method A)
5e) (R)-1-carboxy-2-(2 3-dihydro-1,4-benzodioxin-6-yl)-ethyl 4-(2-oxo-1,2,4,5-
tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate
Under a nitrogen atmosphere 55 mg (55% in mineral oil, 1.2 mmol) sodium
hydride
were added to a solution of 230 mg (0.97 mmol) methyl (S)-3-(2,3-dihydro-1,4-
benzodioxin-6-yl)-2-hydroxy-propionate in 25 mL THF at 0 C, the reaction
mixture
was stirred for 30 min, then combined with 424 mg (0.97 mmol) 4-(2-oxo-1,2,4,5-
tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl chloride and stirred
overnight at RT. The reaction mixture was evaporated to dryness i.vac. and the
residue was combined with 20 mL EtOAc and 20 mL 10% citric acid solution. The
phases were separated, the aqueous phase was extracted again with 20 mL EtOAc
and the combined organic phases were washed with 15% K2CO3 solution. The
3o aqueous phase was separated off, combined with 4 M HCL, the precipitate
formed
was suction filtered and dried.
Yield: 35 mg (7% of theory)
ESI-MS: (M+H)+ = 496
retention time (HPLC): 7.3 min (method A)

CA 02565219 2006-10-17
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5f) (R)-1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-[4-(4-methyl-piperazin-1-
yl)-
piperidin-1-yll-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
yl)-
piperidine-1-carboxylate
A solution of 35 mg (0.07 mmol) (R)-1-carboxy-2-(2,3-dihydro-1,4-benzodioxin-6-
yl)-
ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-
carboxyfate,
25 mg (0.08 mmol) TBTU, 11 pL (0.08 mmol) triethylamine and 14 mg (0.08 mmol)
1-
methyl-4-piperidin-4-yl-piperazine in 1 mL DMF was stirred overnight at RT.
The
reaction mixture was purified by HPLC, the fractions containing the product
were
combined and lyophilised.
1o Yield: 30 mg (64% of theory)
ESI-MS: (M+H)+ = 661
retention time (HPLC): 5.4 min (method A)
Example 6
(R)-1-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-[4-(4-methyl-
piperazin-1-
yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
3-yl)-
piperidine-1-carboxylate
o
o o
~
N 0
r p
H
6a) 3,4-dihydroxy-5-methyl-benzoic acid
Under a nitrogen atmosphere 50.0 g (0.25 mol) 3,4-dimethoxy-5-methyl-benzoic
acid
and 170 g pyridine-hydrochloride were stirred for 2 h at a bath temperature of
160 C.
The reaction mixture was poured onto 1 L citric acid solution and extracted
with 1 L
EtOAc. The organic phase was washed with 1 L water, dried and evaporated down
i.vac. .
Yield: 38.5 g (90% of theory)
ESI-MS: (M-H)- = 167
3o retention time (HPLC): 4.2 min (method A)

CA 02565219 2006-10-17
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6b) methyl 3,4-dihydroxy-5-methyl-benzoate
A solution of 41.5 g (0.25 mol) 3,4-dihydroxy-5-methyl-benzoic acid in 500 mL
methanolic HCI (1.25 M) was stirred overnight at RT. It was evaporated down
i.vac. ,
the residue was combined with DIPE, the precipitate was filtered off and dried
in the
vacuum drying cupboard.
Yield: 36.0 g (80% of theory)
ESI-MS: (M+H)+ = 183
retention time (HPLC): 5.9 min (method A)
6c) methyl 8-methyl-2,3-dihydro-1,4-benzodioxin-6-carboxylate
A mixture of 34.0 g (0.19 mol) methyl 3,4-dihydroxy-5-methyl-benzoate, 77.12 g
(0.56
mol) K2CO3 and 32.1 mL (0.37 mol) dibromoethane in 500 mL acetonitrile was
refluxed for 6 h. The solid was filtered off, washed with 100 mL acetonitrile
and the
filtrate was evaporated to dryness i.vac.. The residue was combined with 500
mL
water and 500 mL EtOAc, the phases were separated, the organic phase was dried
and evaporated to dryness i. vac.. The residue was combined with 120 mL DIPE,
the
precipitate was suction filtered, washed with 50 mL DIPE and dried.
Yield: 32.5 g (84% of theory)
ESI-MS: (M+H) + = 209
retention time (HPLC): 4.2 min (method B)
6d) 8-methyl-2,3-dihydro-1,4-benzodioxin-6-carboxylic acid
A solution of 6.65 g (0.28 mol) LiOH in 100 mL water was metered into a
solution of
33.60 g (0.16 mol) methyl 8-methyl-2,3-dihydro-1,4-benzodioxin-6-carboxylate
in 200
mL THF and the reaction solution was stirred overnight at RT. To complete the
reaction 150 mL 6 M NaOH were added and the mixture was stirred for a further
2 h
at 50 C. The reaction mixture was evaporated down i.vac, the residue was
combined
with THF, acidified with conc. HCI while cooling with ice, the precipitate was
filtered
off, washed with 150 mL water and dried at 60 C in the circulating air dryer.
Yield: 31.1 g (99% of theory)
ESI-MS: (M+H)+ = 195
retention time (HPLC): 3.3 min (method B)

CA 02565219 2006-10-17
- 207 -
6e) (8-methyl-2,3-dihydro-1,4-benzodioxin-6-yl)-methanol
A solution of 31.0 g (0.16 mol) 8-methyl-2,3-dihydro-1,4-benzodioxin-6-
carboxylic
acid in 500 mL THF was combined with 29.2 g(0.18 mol) CDI, stirred for 2 h at
40 C
and then added dropwise to a solution of 18.14 g (0.48 mol) sodium borohydride
in
200 mL water at approx. 20 C. After the addition had ended the mixture was
stirred
for 2 h at RT, then acidified with semiconc. HCI while being cooled, combined
with
300 mL water and 600 mL EtOAc, the phases were separated and the organic phase
was dried. After the desiccant and solvent had been eliminated the residue was
purified by chromatography (silica gel, PE/EtOAc 2:1).
Yield: 25.8 g (90% of theory)
ESI-MS: (M-H20+H) + = 163
Rf = 0.55 (silica gel, PE/EtOAc 1:1)
6f) 8-methyl-2,3-dihydro-1,4-benzodioxin-6-carbaldehyde
73.9 g (0.85 mol) manganese dioxide were added batchwise to a solution of 25.8
g
(0.14 mol) (8-methyl-2,3-dihydro-1,4-benzodioxin-6-yl)-methanol in 300 mL DCM
while cooling with an ice bath and the reaction solution was stirred overnight
at RT.
The precipitate was filtered off, washed with 100 mL DCM and the filtrate was
evaporated to dryness i.vac..
Yield: 23.6 g (93% of theory)
ESI-MS: (2M+Na)+ = 179
Rf = 0.75 (silica gel, PE/EtOAc 1:1)
6g) (Z,E)-2-acetylamino-3-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-yl)-acrylic
acid
A mixture of 15.0 g (0.08 mol) 8-methyl-2,3-dihydro-1,4-benzodioxin-6-
carbaldehyde,
14.9 g(0.13 mol) N-acetylglycine and 10.4 g(0.13 mol) NaOAc in 60 mL acetic
anhydride was stirred for 5 h at a bath temperature of 120 C. The reaction
mixture
was cooled to 60 C and combined dropwise with 40 mL water, then heated to 80
C
again for 1.5 h. The reaction solution was poured onto 200 mL water and 100 mL
toluene, combined with 200 mL EtOAc, stirred for 30 min at RT, the precipitate
was
suction filtered, washed with 100 mL EtOAc and dried.
Yield: 11.0g (47% of theory)
ESI-MS: (M-H)" = 276
Rf = 0.1 (silica gel, DCM/MeOH/NH3 80:20:2)

CA 02565219 2006-10-17
-208-
6h) 3-(8-methyl-2 3-dihydro-1 4-benzodioxin-6-yl)-2-oxo-propionic acid
60 mL 4 M HCI were metered into a solution of 11.0 g (39.7 mmol) (Z,E)-2-
acetylamino-3-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-yl)-acrylic acid in 120
mL 1,4-
dioxane and the reaction solution was refluxed for 2 h. Then it was evaporated
down
i.vac, the residue was combined with 100 mL water, the precipitate was
filtered off,
washed with water and dried at 50 C in the vacuum drying cupboard.
Yield: 9.2 g (98% of theory)
ESI-MS: (M-H)- = 235
retention time (HPLC): 3.5 min (method B)
6i) (R)-2-hydroxy-3-(8-methyl-2 3-dihydro-1,4-benzodioxin-6-yl)-propionic acid
Under a nitrogen atmosphere a solution of 15.1 g (47.0 mmol) (1 R)-B-
chlorodiisopinocampheylborane in 50 mL THF was added dropwise within 15 min to
a solution of 9.2 g (38.9 mmol) 3-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-yl)-
2-oxo-
propionic acid and 5.4 mL (39.0 mmol) triethylamine in 100 mL THF cooled to -
35 C
and the reaction mixture was stirred for 1 h at RT. After the end of the
reaction the
reaction solution was evaporated down i.vac., combined with 200 mL 1 M NaOH
and
150 mL TBME, stirred, the aqueous phase was separated off, acidified with 2 M
HCI
and extracted twice with 250 mL EtOAc. The combined organic phases were dried,
filtered through activated charcoal and evaporated down i.vac.
Yield: quantitative
ESI-MS: (M-H)- = 237
retention time (HPLC): 2.8 min (method B)
6j) methyl (R)-2-hydroxy-3-(8-methyl-2 3-dihydro-1 4-benzodioxin-6-yl)-
propionate
11.3 g (47.4 mmol) (R)-2-hydroxy-3-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-yl)-
propionic acid were dissolved in 250 mL methanolic HCI (1.3 M), stirred
overnight at
RT and then evaporated down i.vac.. The product was reacted further without
purification.
Yield: 10.3 g (86% of theory)
ESI-MS: (M+H) + = 253
retention time (HPLC): 3.4 min (method B)

CA 02565219 2006-10-17
-209-
6k) (R)-1-(methoxycarbonyi-2-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-yl)-ethyl
4-
(2-oxo-1 2 4 5-tetrahydro-1 3-benzodiazepin-3-yl)-piperidine-1-carboxyiate
Under a nitrogen atmosphere 4.0 g (19.8 mmol) 4-nitrophenyl chloroformate in
10 mL
THF was added dropwise to a solution of 2.7 g (21.8 mmol) dimethyl-
aminopyridine
in 20 mL pyridine while cooling with an ice bath, the cooling bath was removed
and
the mixture was stirred for 30 min at RT. While cooling again to 0 C, 5.0 g
(19.8
mmol) methyl (R)-2-hydroxy-3-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-yl)-
propionate in 10 mL pyridine were added, the cooling bath was removed and the
mixture was stirred for 2 h at RT. The reaction solution was combined with 5.3
g
1o (21.8 mmol) 3-piperidin-4-y1-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and
stirred
for 20 h at RT. After the end of the reaction the reaction mixture was
evaporated
down i.vac. , combined with 150 mL EtOAc, the organic phase was washed with 1
M
KHSO4 and saturated K2CO3 solution and dried over Na2SO4. After the desiccant
and solvent had been eliminated the residue was purified by chromatography
(silica
gel, EtOAc).
Yield: 5.2 g (50% of theory)
ESI-MS: (M+H) + = 524
retention time (HPLC): 4.4 min (method B)
2o 61) (R)-1-carboxy-2-(8-methyl-2 3-dihydro-1 4-benzodioxin-6-yl)-ethyl 4-(2-
oxo-
1 2 4 5-tetrahydro-1 3-benzodiazepin-3-yl)-piperidine-1-carboxylate
151 mg (6.3 mmol) LiOH in 50 mL water were metered into a solution of 2.2 g
(4.2
mmol) (R)-1-(methoxycarbonyl-2-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-yl)-
ethyl 4-
(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in
50 mL
THF and the reaction mixture was stirred for 2 h at RT. After the end of the
reaction
the mixture was evaporated to dryness i.vac.. The residue was combined with
100
mL water and 100 mL EtOAc, the aqueous phase was separated off, acidified with
2
M HCI, extracted with 200 mL EtOAc and the organic phase was dried. After the
desiccant and solvent had been eliminated the residue was evaporated to
dryness
i.vac. and reacted further without purification.
Yield: 1.9 g (86% of theory)
ESI-MS: (M+H)+ = 510
retention time (HPLC): 3.9 min (method A)

CA 02565219 2006-10-17
-210-
6m) (R)-1-(8-methyl-2 3-dihydro-1 4-benzodioxin-6-yimethyl)-2-[4-(4-methyl-
pipera-
zin-1-yl)-piperidin-1-yll-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-l,3-
benzodiazepin-3-yl)-piperidine-l-carboxylate
A solution of 80 mg (0.16 mmol) (R)-1-carboxy-2-(8-methyl-2,3-dihydro-1,4-
benzodioxin-6-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-l,3-benzodiazepin-3-yl)-
piperidine-1-carboxylate, 51 mg (0.16 mmol) TBTU, 42 pL (0.30 mmol)
triethylamine
and 29 mg (0.16 mmol) 1-methyl-4-piperidin-4-yl-piperazine in 1 mL DMF was
stirred
overnight at RT. The reaction mixture was purified by HPLC, the fractions
containing
the product were combined and lyophilised.
1o Yield: 60 mg (57% of theory)
ESI-MS: (M+H)+ = 675
retention time (HPLC): 5.0 min (method A)
The following compounds were prepared analogously from in each case 80 mg (R)-
1-carboxy-2-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-yl)-ethyl 4-(2-oxo-1,2,4,5-
tetra-
hydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and the corresponding
amount of amine:
~ o
~ i ~
~
N
H
Example R Yield (%) Mass HPLC
spectrum retention time
(method)
6.1 72 674 5.4 min
[M+H]+ (A)
6.2 68 676 5.2 min
[M+H]+ (A)
6.3 67 662 5.2 min
~~~o [M+HI+ (A)

CA 02565219 2006-10-17
- 211 -
Example R Yield (%) Mass HPLC
spectrum retention time
(method)
6.4 =~ ~N 69 689 5.2 min
N~" [M+H]+ (A)
6.5 44 746 5.6 min
N~ 1 [M+H]+ (A)
0
6.6 68 675 4.6 min
[M+HI+ (A)
6.7 77 660 5.4 min
[M+H]+ (A)
6.8 =~ 65 701 2.7 min
[M+H]+ (B)
6.9 =~ 74 687 3.0 min
"~N
[M+H]+ (B)
6.10 20 687 4.2 min
N [M+H]+ (B)
6.11 72 795 6.1 min
[M+H]+ (A)
6.12 33 795 6.0 min
[M+H]+ (A)

CA 02565219 2006-10-17
-212-
Example 6.13
(R)-1 -(8-methyl-2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-oxo-2-(4-piperazin-
1 -yl-
piperidin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-
piperidine-1-
carboxylate
o
I
o o
0
0
H
35 mg (0.04 mmol) benzyl 4-(1-{(R)-3-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-
yl)-2-
1o [4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-
carbonyloxy]-
propionyl}-piperidin-4-yl)-piperazin-1-carboxylate (Example 6.12) were
dissolved in
mL MeOH and combined with 50 mg 10% Pd/C. The mixture was hydrogenated
at 50 C and 3 bar hydrogen pressure until the theoretical hydrogen uptake had
occurred (for 3 h). Then the catalyst was filtered off, the filtrate was
evaporated to
dryness i.vac., the residue was taken up in 2 mL DMF and purified by HPLC. The
fractions containing the product were combined and lyophilised.
Yield: 15 mg (52% of theory)
ESI-MS: (M+H)+ = 661
retention time (HPLC): 2.8 min (method A)
Example 6.14
(R)-1-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-oxo-2-(4-piperidin-4-
yl-
piperazin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yi)-
piperidine-1-
carboxylate
o
~~o
0:12 N--C ,N~O~ N/~N'H
~/ 0
N
1 0
H

CA 02565219 2006-10-17
-213-
Analogously to Example 6.13 the product was obtained from 85 mg (0.11 mmol)
(R)-
1-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-[4-(1-benzyloxy-carbonyl-
piperidin-4-yl)-piperazin-1 -yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 6.11).
Yield: 50 mg (52% of theory)
ESI-MS: (M+H) + = 661
retention time (HPLC): 2.6 min (method A)
Example 6.15
(R)-2-(1'-carboxymethyl-4,4'-bipiperidinyl-1-yl)-1-(8-methyl-2,3-dihydro-1,4-
benzodioxin-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahyd ro-1,3-
benzodiazepin-
3-yl)-piperidine-1-carboxylate
~ o
I
o _ ~ o
\ I N~ -CN'k 0 0 OH
O O
H
A solution of 1.4 mg (0.06 mmol) LiOH in 0.5 mL water was added to a solution
of 28
mg (0.04 mmol) (R)-2-(1'-ethoxycarbonylmethyl-4,4'-bipiperidinyl-1-yl)-1-(8-
methyl-
2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-l-carboxylate (Example 6.5) in 0.5 mL THF and
the
reaction solution was stirred for 3 h at RT. The reaction mixture was purified
by
HPLC without any further working up. The fractions containing the product were
combined and lyophilised.
Yield: 23 mg (85% of theory)
ESI-MS: (M+H)+ = 718
retention time (HPLC): 3.2 min (method B)
Example 6.16
(R)-2-(4-amino-4-methyl-1,4'-bipiperidinyl-1'-yl)-1-(8-methyl-2,3-dihydro-1,4-
benzodioxin-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-
3o 3-yl)-piperidine-1-carboxylate

CA 02565219 2006-10-17
-214-
0
O~NV N NHZ
I N~N 0
N~
~ 0
H
Analogously to Example 3.2 the product was obtained from 80 mg (0.16 mmol) (R)-
1-
carboxy-2-(8-methyl-2,3-d ihyd ro-1,4-benzodioxin-6-yl)-ethyl 4-(2-oxo-1,2,4,5-
tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 59 mg (0.16
mmol)
tert.-butyl (4-methyl-[1,4']bipiperidinyl-4-yl)-carbamate (used as the bis-
hydrochloride
salt).
Yield: 50 mg (43% of theory)
ESI-MS: (M+H)+ = 689
1o retention time (HPLC): 4.9 min (method A)
Example 6.17
(R)-2-(1'-methanesulphonyl-4,4'-bipiperidinyl-1-yl)-1-(8-methyl-2,3-dihydro-
1,4-
benzod ioxi n-6-yl methyl)-2-oxo-ethyl 4-(2-oxo-1, 2,4, 5-tetrahyd ro-1, 3-
benzod iazepi n-
3-yl)-piperidine-1-carboxylate
0
' - 0
s
a-c~ pN' ~
0
CC
H 0
Analogously to Example 6m the product was obtained from 80 mg (0.16 mmol) (R)-
1-
carboxy-2-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-yl)-ethyl 4-(2-oxo-1,2,4,5-
tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 39 mg (0.16
mmol)
1-methanesulphonyl-[4,4']bipiperidinyl.
Yield: 90 mg (78% of theory)
ESI-MS: (M+H)+ = 738
retention time (HPLC): 4.2 min (method B)

CA 02565219 2006-10-17
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Example 6.18
(R)-2-[4-(4-methanesulphonyl-piperazin-1-yl)-piperidin-1-yl]-1-(8-methyl-2,3-
dihydro-
1,4-benzodioxin-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-
benzodiazepin-3-yl)-piperidine-l-carboxylate
' ~)
'-o
oõo
I o~N~/ NlSl~
N't!\ o
O
H
Analogously to Example 6m the product was obtained from 80 mg (0.16 mmol) (R)-
1-
ca rboxy-2-(8-methyl-2, 3-d i hyd ro-1, 4-benzod ioxin-6-yl )-ethyl 4-(2-oxo-
1,2,4, 5-
1o tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 40 mg 1-
methanesulphonyl-4-piperidin-4-yl-piperazine.
Yield: 52 mg (45% of theory)
ESI-MS: (M+H)+ = 739
retention time (HPLC): 3.1 min (method B)
Example 7
(R)-1-(8-methyl-imidazo[1,5-a]pyridin-6-ylmethyl)-2-[4-(4-methyl-piperazin-1 -
yl)-
piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
yl)-
piperidine-1-carboxylate
rN
N /
~
~~ \ ~N~N0~NV N
v' - O
H O
7a) methyl (Z, E)-2-acetylamino-3-(6-amino-5-methyl-pyridin-3-yl)-acrylate
Under a nitrogen atmosphere 6.58 g (7.19 mmol) tris-(dibenzylideneacetone)-
palladium were added to a mixture of 33.6 g (180 mmol) 5-bromo-3-methyl-
pyridin-2-
ylamine, 28.9 g (198 mmol) methyl 2-acetylamino-acrylate, 4.42 g (14.4 mmol)
tri-o-
tolyl-phosphane and 30.9 mL (180 mmol) ethyldiisopropylamine in 500 mL

CA 02565219 2006-10-17
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butyronitrile and the reaction mixture was heated to 110 C for 17 h. The
reaction
solution was evaporated down i.vac. and the residue was stirred with approx.
500
mL water. The precipitate was filtered, recrystallised from acetonitrile and
dried. The
aqueous mother liquor was evaporated down and the residue was purified by
chromatography (silica gel, EtOAc/MeOH/NH3 90:10:1). The fractions containing
the
product were evaporated down, the residue was triturated with a little
acetonitrile,
filtered, dried and combined with the above product fraction.
Yield: 16.6 g (37% of theory)
ESI-MS: (M+H)+ = 250
1o Rf = 0.46 (silica gel, EtOAc/MeOH/NH3 90:10:1)
7b) 3-(6-amino-5-methyl-pyridin-3-yl)-2-oxo-propionic acid
230 mL 4 M HCI were added to a solution of 15.57 g (62.46 mmol) methyl (Z,E)-2-
acetylamino-3-(6-amino-5-methyl-pyridin-3-yl)-acrylate in 250 mL 1,4-dioxane,
the
reaction mixture was refluxed for 1.5 h and stirred for a further 16 h at RT.
It was
evaporated down i.vac., the residue was triturated with EtOAc/DIPE (1:1),
filtered
and dried in the circulating air dryer. The product was obtained as the
hydrochloride
salt.
Yield: 14.4 g (100% of theory)
2o ESI-MS: (M+H)+ = 195
retention time (HPLC): 2.7 min (method A)
7c) methyl (R)-3-(6-amino-5-methyl-pyridin-3-yi)-2-hydroxy-propionate
A mixture of 13.8 g (59.9 mmol) 3-(6-amino-5-methyl-pyridin-3-yl)-2-oxo-
propionic
acid and 17.5 mL (125.7 mmol) triethylamine in 140 mL THF was cooled to -35 C
under an argon atmosphere. Then a solution of 40.3 g (126 mmol) (1R)-B-
chlorodiisopinocampheylborane in 210 mL THF was added dropwise so that the
reaction temperature remained between -35 C and -25 C; the reaction mixture
was
kept for 3 h at this temperature before being combined at 0-5 C with 150 mL of
1 M
NaOH and being stirred for 2 h at RT. 200 mL TBME were added, the organic
phase
was separated off and acidified with 200 mL 2 M HCI. The aqueous phase was
separated off, evaporated down, the residue was taken up in THF/MeOH (1:1),
filtered and the filtrate was then evaporated down. The crude product thus
obtained
(12.5 g) was dissolved in 300 mL MeOH, combined dropwise with 4.3 mL (59.3

= CA 02565219 2006-10-17
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mmol) SOCI2 while cooling with ice and stirred for a further 2 h at RT. The
mixture
was evaporated down i. vac. and the residue was purified by chromatography
(silica
gel, EtOAc/MeOH/NH3 90:10:1).
Yield: 5.62 g (45% of theory)
ESI-MS: (M+H) + = 211
retention time (HPLC): 2.4 min (method A)
7d) methyl (R)-2-hydroxy-3-(8-methyl-imidazo[1,5-alpyridin-6-yl)-propionate
A solution of 800 mg (3.81 mmol) methyl (R)-3-(6-amino-5-methyl-pyridin-3-yl)-
2-
hydroxy-propionate and 1.6 mL (12.6 mmol, 50% in water) chloroacetaldehyde in
16
mL MeOH was refluxed for 2 h under a nitrogen atmosphere. It was evaporated
down i.vac. , the residue was taken up in 100 mL DCM, extracted with 10 mL
saturated NaHCO3 solution, the organic phase was separated off and dried over
Na2SO4. After the desiccant and solvent had been eliminated the residue was
purified by chromatography (Alox, DCM/MeOH 40:1).
Yield: 610 mg (68% of theory)
ESI-MS: (M+H)+ = 235
Rf = 0.57 (Polygram-Alox, DCM/MeOH 25:1)
7e) (R)-1-methoxycarbonyl-2-(8-methyl-imidazo[1,5-alpyridin-6-yl)-ethyl 4-(2-
oxo-
1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-l-carboxylate
Analogously to Example 6k the product was obtained from 685 mg (2.92 mmol)
methyl (R)-2-hydroxy-3-(8-methyl-imidazo[1,5-a]pyridin-6-yl)-propionate and
800 mg
(3.26 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, and
purified
by chromatography (first purification: Alox, gradient DCM/MeOH 50:1 to 40:1;
second
purification: silica gel, DCM/MeOH 15:1).
Yield: 570 mg (39% of theory)
ESI-MS: (M+H)+ = 506
7f) (R)-1-carboxy-2-(8-methyl-imidazo[1,5-alpyridin-6-yl)-ethyl 4-(2-oxo-
1,2,4,5-
tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 -carboxylate
A solution of 40.0 mg (1.67 mmol) LiOH in 15 mL water was added to a solution
of
560 mg (1.11 mmol) (R)-1-methoxycarbonyl-2-(8-methyl-imidazo[1,5-a]pyridin-6-
yl)-
ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-l-
carboxylate in

CA 02565219 2006-10-17
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20 mL THF and the reaction mixture was stirred for 1 h at RT. It was
evaporated
down i.vac. , the residue was taken up in 30 mL water auf and acidified with
AcOH.
The precipitate was filtered and dried.
Yield: 700 mg (100% of theory, product contained AcOH)
ESI-MS: (M+H)+ = 492
7g) (R)-1-(8-methyl-imidazo[1,5-alpyridin-6-ylmethyl)-2-f4-(4-methyl-piperazin-
1-
yl)-piperidin-1-yll-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
3-
yl)-piperidine-1-carboxylate
1 o A solution of 115 mg (0.18 mmol) (R)-1-carboxy-2-(8-methyl-imidazo[1,5-
a]pyridin-6-
yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-
carboxylate, 70 mg (0.22 mmol) TBTU and 40 pL (0.29 mmol) triethylamine in 10
mL
THF and 1 mL DMF was stirred for 1 h at RT. Then 50 mg (0.27 mmol) 1-methyl-4-
piperidin-4-yl-piperazine were added and the reaction mixture was stirred
overnight
at RT. To complete the reaction another 70 mg TBTU and 50 mg 1-methyl-4-
piperidin-4-yl-piperazine were added, the mixture was stirred for a further 65
h at RT
and again combined with 70 mg TBTU, 50 mg 1-methyl-4-piperidin-4-yl-
piperazine,
40 pL triethylamine and 1 mL DMF and stirred overnight at RT. 10 mL
semisaturated
NaHCO3 solution were added to the reaction mixture, it was extracted twice
with 30
mL EtOAc and the combined organic phases were dried over Na2SO4. After the
desiccant and solvent had been eliminated the residue was purified by HPLC.
The
fractions containing the product were combined and lyophilised.
Yield: 49 mg (29% of theory)
ESI-MS: (M+H) = 657
retention time (HPLC): 2.0 min (method B)
The following compounds were prepared analogously from in each case 115 mg of
(R)-1-carboxy-2-(8-methyl-imidazo[1,5-a]pyridin-6-yl)-ethyl 4-(2-oxo-1,2,4,5-
tetra-
hydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and the corresponding
3o amount of amine:
r-N
IN
N O~R
N~
~--C/ 0
O
H

CA 02565219 2006-10-17
-219-
Example R Yield (%) Mass HPLC
spectrum retention time
(method)
7.1 33 656 2.2 min
N
N'- IM+HI+ (B)
7.2 41 657 1.9 min
IM+HI+ (B)
The following Examples describe the preparation of pharmaceutical formulations
which contain as active substance any desired compound of general formula (I):
Example I
Capsules for powder inhalation containing 1 mg of active ingredient
1o Composition:
1 capsule for powder inhalation contains:
active ingredient 1.0 mg
lactose 20.0 mg
hard gelatine capsules 50.0 mg
71.0 mg
Method of preparation:
The active ingredient is ground to the particle size required for inhaled
substances.
The ground active ingredient is homogeneously mixed with the lactose. The
mixture
is transferred into hard gelatine capsules.

CA 02565219 2006-10-17
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Example lI
Inhalable solution for Respimat containing 1 mg of active ingredient
Composition:
1 puff contains:
active ingredient 1.0 mg
benzalkonium chloride 0.002 mg
disodium edetate 0.0075 mg
1o purified water ad 15.0 pi
Method of preparation:
The active ingredient and benzalkonium chloride are dissolved in water and
transferred into Respimat cartridges.
Example III
lnhalable solution for nebulisers containing 1 mg of active ingredient
Composition:
1 vial contains:
active ingredient 0.1 g
sodium chloride 0.18 g
benzalkonium chloride 0.002 g
purified water ad 20.0 ml
Method of preparation:
The active ingredient, sodium chloride and benzalkonium chloride are dissolved
in
water.

CA 02565219 2006-10-17
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Example IV
Propellant gas-operated metering aerosol containing 1 mg of active ingredient
Composition:
1 puff contains:
active ingredient 1.0 mg
lecithin 0.1 %
propellant gas ad 50.0 pl
Method of preparation:
The micronised active ingredient is homogeneously suspended in the mixture of
lecithin and propellant gas. The suspension is transferred into a pressurised
container with a metering valve.
Example V
Nasal spray containing 1 mg of active ingredient
Composition:
active ingredient 1.0 mg
sodium chloride 0.9 mg
benzalkonium chloride 0.025 mg
disodium edetate 0.05 mg
purified water ad 0.1 ml
Method of preparation:
The active ingredient and the excipients are dissolved in water and
transferred into a
suitable container.

CA 02565219 2006-10-17
- 222 '
Example VI
Injectable solution containing 5 mg of active substance per 5 ml
Composition:
active substance 5 mg
glucose 250 mg
human serum aibumin 10 mg
glycofurol 250 mg
1o water for injections ad 5 ml
Preparation:
Glycofurol and glucose are dissolved in water for injections (Wfl); human
serum
albumin is added; active ingredient is dissolved with heating; made up to
specified
volume with Wfl; transferred into ampoules under nitrogen gas.
Example VII
Iniectable solution containing 100 mg of active substance per 20 ml
Composition:
active substance 100 mg
monopotassium dihydrogen phosphate = KH2PO4 12 mg
disodium hydrogen phosphate = Na2HPO4=2H2O 2 mg
sodium chloride 180 mg
human serum albumin 50 mg
Polysorbate 80 20 mg
water for injections ad 20 ml

CA 02565219 2006-10-17
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Preparation:
Polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate and
disodium hydrogen phosphate are dissolved in water for injections (Wfl); human
serum albumin is added; active ingredient is dissolved with heating; made up
to
specified volume with Wfl; transferred into ampoules.
Example Vili
Lyophilisate containing 10 mg of active substance
Composition:
Active substance 10 mg
Mannitol 300 mg
human serum albumin 20 mg
Preparation:
Mannitol is dissolved in water for injections (Wfl); human serum albumin is
added;
active ingredient is dissolved with heating; made up to specified volume with
Wfl;
transferred into vials; freeze-dried.
Solvent for lyophilisate:
Polysorbate 80 = Tween 80 20 mg
mannitol 200 mg
water for injections ad 10 ml
Preparation:
Polysorbate 80 and mannitol are dissolved in water for injections (WfI);
transferred
into ampoules.

CA 02565219 2006-10-17
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Example IX
Tablets containing 20 mg of active substance
Composition:
active substance 20 mg
lactose 120 mg
maize starch 40 mg
magnesium stearate 2 mg
Povidone K 25 18 mg
Preparation:
Active substance, lactose and maize starch are homogeneously mixed; granulated
with an aqueous solution of Povidone; mixed with magnesium stearate;
compressed
in a tablet press; weight of tablet 200 mg.
Example X
Capsules containing 20 mg active substance
Composition:
active substance 20 mg
maize starch 80 mg
highly dispersed silica 5 mg
magnesium stearate 2.5 mg
Preparation:
Active substance, maize starch and silica are homogeneously mixed; mixed with
magnesium stearate; the mixture is packed into size for 3 hard gelatine
capsules in a
capsule filling machine.

CA 02565219 2006-10-17
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Example XI
Suppositories containing 50 mg of active substance
Composition:
active substance 50 mg
hard fat (Adeps solidus) q.s. ad 1700 mg
Preparation:
Hard fat is melted at about 38 C; ground active substance is homogeneously
dispersed in the molten hard fat; after cooling to about 35 C it is poured
into chilled
moulds.
Example XII
Iniectable solution containing 10 mg of active substance per 1 ml
Composition:
active substance 10 mg
mannitol 50 mg
human serum albumin 10 mg
water for injections ad 1 ml
Preparation:
Mannitol is dissolved in water for injections (Wfl); human serum albumin is
added;
active ingredient is dissolved with heating; made up to specified volume with
Wfl;
transferred into ampoules under nitrogen gas.

Representative Drawing