THERAPEUTIC USES OF QUINAZOLINEDIONE DERIVATIVES
A subject-matter of the invention is the use of quinazolinedione derivatives as
medicaments or for manufacturing a medicament intended for the treatment and/or
prevention of disorders related to the central nervous system (abbreviated CNS) and/or
related to the peripheral nervous system (abbreviated PNS). The invention relates more
particularly to the use of quinazolinedione derivatives as medicaments or for
manufacturing a medicament intended for the treatment and/or prevention of psychiatric
disorder(s) and/or intended for the treatment and/or prevention of neurological
disorder(s).
The central nervous system or CNS comprises the brain, the spinal cord and the
cranial nerves.
The peripheral nervous system or PNS is the part of the nervous system formed
of ganglions and nerves which brings about the movement of information between the
organs and the central nervous system or CNS and which carries out the motor
commands of the latter. It comprises the somatic nervous system and the autonomic
nervous system.
The invention relates to quinazolinedione derivatives which are inhibitors of
phosphodiesterase 7 (PDE7). Some of these derivatives also inhibit phosphodiesterase 8
(PDE8).
Phosphodiesterases (PDEs) are intracellular enzymes responsible for the
hydrolysis of cAMP (cyclic adenosine 3',5'-monophosphate) and cGMP (cyclic guanosine
3',5'-monophosphate) secondary messengers to give inactive 5'-monophosphate
nucleotides. cAMP and cGMP play an essential role in cell signalling pathways and are
involved in numerous physiological processes.
The inhibition of phosphodiesterases is reflected by an increase in intracellular
concentrations of cAMP and cGMP, resulting in the specific activation of phosphorylation
pathways involved in varied functional responses. The increase in the intracellular
concentrations of cAMP or of cGMP using selective inhibitors of phosphodiesterases
appears to be a promising approach in the treatment of various diseases (Bender and
Beavo, Pharmacol. Rev., (2006) 58, 488-520). The inhibitors of phosphodiesterases are
thus of interest as therapeutic agents and as pharmacological tools.
To date, eleven families of phosphodiesterases have been identified. They are
distinguished by their primary structure, their substrate specificity and their sensitivity with
regard to various effectors and inhibitors specific for PDEs. Each family is composed of
one or more genes which are expressed in various tissues in the form of splicing variants
(Bender and Beavo, Pharmacol. Rev., (2006) 58, 488-520; Lugnier, Pharmacol.

Therapeut., (2006) 109, 366-398).
PDE4, PDE7 and PDE8 specifically hydrolyse cAMP and PDE5, PDE6 and PDE9
specifically hydrolyse cGMP.
The family PDE7 is represented by the isoforms PDE7A and PDE7B originating
from two distinct genes.
Human PDE7A (Michaeli et al., J. Biol. Chem., (1993) 268, 12925-12932; Han et
al., J. Biol. Chem., (1997) 272, 16152-16157; Wang et al., Biochem. Biophys. Res.
Commun., (2000) 276, 1271-1277) and human PDE7B (Sasaki et al., Biochem. Biophys.
Res. Commun., (2000), 271, 575-583; Gardner et al., Biochem. Biophys. Res. Commun.,
(2000) 272, 186-192) selectively hydrolyse cAMP with Michaelis constants (Km) of 0.1 to
0.2 uM and 0.13 to 0.2 µM respectively. The catalytic part of PDE7B exhibits
approximately 67% homology with that of PDE7A.
Three splicing variants are known for PDE7A. PDE7A1 and PDE7A3 are
expressed mainly in the cells of the immune system and of the lungs, while PDE7A2 is
above all expressed in the muscles of the skeleton, the heart and the kidneys. For
PDE7B, three variants have also recently been identified (Giembycz and Smith, Drugs
Future, (2006)31,207-229).
The tissue distribution profiles for PDE7A and PDE7B are very different,
suggesting that these two isoforms have distinct functions from the physiological
viewpoint. While PDE7A is copiously expressed in haematopoietic cells, the lungs, the
placenta, Leydig cells, the spleen, the collecting tubes of the kidneys, and the adrenal
glands, strong expression of PDE7B is detected in the pancreas, the heart, the thyroid
and the muscles of the skeleton (Giembycz and Smith, Drugs Future, (2006) 31, 207-
229). However, coexpression of the messenger RNAs (mRNAs) of PDE7A and PDE7B is
observed in some tissues. This is the case in the osteoblasts (Ahlstrom et al., Cell Mol.
Biol. Lett., (2005) 10, 305-319) and in some regions of the brain: several areas of the
cortex, the dentate gyrus, the majority of the components of the olfactory system, the
striatum, numerous nuclei of the thalamus and the pyrimidal cells of the hippocampus
(Miro et al., Synapse, (2001) 40, 201-214; Reyes-lrisarri et al., Neuroscience, (2005) 132,
1173-1185). In contrast, in some areas of the brain, only one of the two isoforms is
expressed. Thus, only the mRNAs of PDE7A are present in many nuclei of the brain
stem. Likewise, the mRNAs of PDE7B are present at high concentrations in the nucleus
accombens and the dorsal motor nucleus of the vagus nerve, while the mRNAs of
PDE7A are not detected there (Miro et al., Synapse, (2001) 40, 201-214; Reyes-lrisarri et
al., Neuroscience, (2005) 132, 1173-1185).
The document WO2008/119057 describes a method for the treatment of
movement anomalies associated with a neurological movement disorder pathology, such

as Parkinson's disease, the treatment method comprising the administration to a patient
of an amount of an agent which is an inhibitor of PDE7 which is effective in inhibiting the
enzymatic activity of PDE7.
A subject-matter of the present invention is in particular therapeutic applications of
quinazolinedione derivatives, which may prove to be powerful inhibitors of PDE7, or of
PDE7 and of PDE8, according to the derivatives.
The invention relates to the use of a compound corresponding to the following
general formula (I):

in which
— A represents an aryl group or a heteroaryl group;
— R1 represents:

■ a hydrogen atom,
■ -C(O)R in which R is a hydrogen atom, a (C1-C6) alkoxy group, an aryl group, a
(C3-C6) cycloalkyl group or a (C1-C6) alkyl group, the said alkyl optionally being
substituted by:
. one or more hydroxyl group(s),
. a benzyloxy group,
. a (C1-C6) alkoxy group, optionally substituted by an aryl, or
. a (C3-C6) cycloalkyl group,
■ an optionally substituted (C1-C6) alkyl group;
— R2 represents:
■ a hydrogen atom,
■ a halogen atom,

■ a cyano group,
■ a nitro group,
■ a (C1-C6) alkyl group optionally substituted by an -NH2 or else by an
-NHC(O)Rb group, with Rb as defined below,
■ an -ORa group in which Ra represents:
. a hydrogen atom,
. a (C1-C6) alkyl group optionally substituted by one or more halogen
atom(s), by one or more hydroxyl group(s), by an aryl group and/or by one or
more cyano group(s),
. a (C2-C6) alkynyl group,
. an aryl group;
— R3 represents:
■ a hydrogen atom,
■ a halogen atom,
■ a hydroxyl group,
■ a cyano group,
■ an -SCF3 group,
■ a nitro group,
■ an oxo group,

■ an -S(O)0-2-alkyl group, an -S(O)0-2-heterocycloalkyl group, an -O-SO2-aryl
group optionally substituted by one or more halogen atom(s);
■ an -alkylaminoalkyl or -cycloalkylaminoalkyl group, each optionally substituted
on the end alkyl,
■ an optionally substituted sulphonamide group,
■ an aryl group or a heteroaryl group, the said group being monocyclic or
polycyclic and in addition optionally being substituted by a (C1-C6) alkyl group, by
one or more halogen atom(s) or by a (C1-C6) alkoxy group,
■ a heterocycloalkyl group optionally substituted by a (C1-C6) alkyl group,
■ a (C1-C6) alkyl group optionally substituted by:

- one or more halogen atom(s),
- an aryl group which can be substituted by one or more halogen atom(s)
or by one or more hydroxyl group(s),
- a heteroaryl group,
- one or more hydroxyl group(s) which can be substituted by an aryl group
itself optionally substituted by one or more halogen atom(s), or
- a heterocycloalkyl group optionally substituted by a CO(O)Ra group or by

a (C1-C6) alkyl group, Ra being as defined above,
■ a -C(O)NRbRc group, with Rb and Rc being as defined below,
■ a -C(O)ORc group or an -O-C(O)ORc group, with Rc being as defined below,
■ a (C1-C6) alkoxy group, optionally substituted by

- an aminoalkyl group,
- an aminocycloalkyl group,
- a cycloalkyl group,
- a heterocycloalkyl group,
- a monocyclic or polycyclic heteroaryl group,
- one or more hydroxyl group(s),
- one or more halogen atom(s),
- a (C1-C6) alkoxy group,
- a -C(O)ORc group, with Rc being as defined below,
- a -C(O)NRbRc group, with Rb and Rc being as defined below,
- an oxo group, and/or
- an aryl group, itself optionally substituted by one or more halogen
atom(s), a cyano group, a (C1-C6) alkoxy group, an -O-haloalkyl group and/or a
haloalkyl group,
■ an -O-cycloalkyl group, an -O-aryl group or an -O-heterocycloalkyl group, each
optionally substituted by
-an aryl group, itself optionally substituted by one or more halogen
atom(s) or by a (C1-C6) alkyl group,
- an oxo group,
- one or more halogen atom(s), and/or
- a (C1-C6) alkyl group, which can itself be substituted by an aryl group
and/or an oxo group,

■ an -NH-CO-NH-aryl group, an -NH-CO-NH-heteroaryl group or an -NH-CO-
NH-(C1-C6) alkyl group, each optionally being substituted by one or more halogen
atom(s), by a cyano group, by a nitro group, by one or more hydroxyl group(s) or by a
(C1-C6) alkoxy group,
■ an -N-(C1-C6) alkyl group, it being possible for the (C1-C6) alkyl group to be
substituted by

- one or more oxo group(s), and/or
- one or more aryl group(s) optionally substituted by one or more halogen
atom(s) and/or by an SO2 group,
■ an -NH-CO-aryl group or an -NH-CO-heteroaryl group, each optionally
being substituted by one or more halogen atom(s);

or else R3 forms, with A, a polycyclic heteroaryl group optionally substituted by a (C1-C6)
alkoxy group or a (C1-C6) alkyl group optionally substituted by an aryl group which can
itself be substituted by one or more halogen atom(s);
— R4 represents a hydrogen atom, an oxo group or a (C1-C6) alkyl group;
— Rb represents:
. a hydrogen atom,
. a (C1-C6) alkyl group optionally substituted by one or more halogen atom(s), by
one or more hydroxyl, cyano, amino, heterocycloalkyl or (C1-C6) alkoxy group(s) or by an
aryl group optionally substituted by one or more halogen atom(s),
. a (C3-C6) cycloalkyl group,
. a (C2-C6) alkynyl group,
. a (C1-C6) alkoxy group,
. an aryl group optionally substituted by one or more halogen atom(s);
— Rc represents a hydrogen atom or a (C1-C6) alkyl group optionally substituted
by one or more halogen atom(s);
or then Rb and Rc form, together with the nitrogen atom to which they are attached, a
polycyclic heteroaryl group or a heterocycloalkyl group;
— m and n represent, independently of one another, the value 0, 1 or 2, it being
understood that m+n<3;
— p and p' represent, independently of one another, the value 1, 2 or 3, it being
understood that, when p is greater than or equal to 2, then the R2 groups are on separate
carbon atoms and can be different from one another and, when p' is greater than or
equal to 2, then the R3 groups are on separate carbon atoms and can be different from
one another;
— q represents the value 0 or 2, it being understood that, when q = 0, then the
nitrogenous heterocyclic group attached to the nitrogen situated in the 1 position of the
2,4-dioxo-1,2,3,4-tetrahydroquinazoline ring system is no longer bridged and is of the
type:


with R1, R4, m and n as defined above,
— r represents the value 0 or 1,
as medicament or in the preparation of a medicament intended for the treatment and/or
prevention of disorders related to the central nervous system and/or related to the
peripheral nervous system.
According to one embodiment, the said disorders are chosen from psychiatric
disorders and neurological disorders.
The compounds of general formula (I) can comprise one or more asymmetric
carbons. They can thus exist in the form of enantiomers or of diastereoisomers. These
enantiomers or diastereoisomers, and their mixtures, including racemic mixtures, come
within the invention.
Due to their structure, the compounds of general formula (I) can also exist in the
form of isomers of rotamer or atropisomer type.
The compounds of formula (I) can also exist in the form of bases or addition salts
with acids. Such addition salts come within the invention.
These salts are advantageously prepared with pharmaceutically acceptable acids
but the salts of other acids, for example of use in the purification or separation of the
compounds of general formula (I) also come within the invention.
The compounds of general formula (I) can also occur in the crystalline,
amorphous or oily form, these forms coming within the invention.
The compounds of general formula (I) can in addition occur in the form of
hydrates or of solvates, namely in the form of combinations or of associations with one or
more molecules of water or with a solvent. Such hydrates and solvates also come within
the invention.
According to the present invention, the N-oxides of the compounds comprising an
amine also come within the invention.
The compounds of formula (I) in accordance with the invention also comprise
those in which one or more hydrogen, carbon or halogen, in particular chlorine or

fluorine, atoms have been replaced by their radioactive isotopes, for example tritium, in
order to replace hydrogen, or carbon-14, in order to replace carbon-12. Such labelled
compounds are of use in research, metabolism or pharmacokinetic studies or in
biological and pharmacological assays as tools.
In the context of the invention, the following definitions apply:
- in (Ci.C6), the numerical indices determine the possible number of carbon atoms
present in a chain or a ring. Thus, by way of example, C-i-C6 represents a carbon chain
which can have from 1 to 6 carbon atoms. Likewise, by way of example, (CrC5)
represents a carbon chain which can have from 1 to 5 carbon atoms or also (C3-C6) can
represent a saturated carbon ring which can have from 3 to 6 carbon atoms;
- alkoxy: an -O-alkyl group comprising a saturated, linear or branched, aliphatic
chain;
- alkynyl: a mono- or polyunsaturated, linear or branched, aliphatic group comprising,
for example, one or two acetylenic unsaturations. For example, a (C2-C6) alkynyl group
can represent an ethynyl, propynyl, and the like;
- alkyl: a saturated, linear or branched, aliphatic group; for example, a (C1-C6) alkyl
group represents a linear or branched carbon chain of 1 to 6 carbon atoms, in particular
a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl or pentyl;
- aminoalkyl: an -NH(d-C6) alkyl or also -N((Ci-C6) alkyl)2 group;
- aryl: an optionally substituted monocyclic aromatic system comprising from 5 to
14 members per ring, preferably from 5 to 10 members per ring. Mention may be made,
as examples of monocyclic aryl groups, of phenyl or naphthyl; the aryl group can be
substituted by a group which can be one or more halogen atom(s), a hydroxyl group, a
cyano group, a trifluoromethylthio group, a nitro group, an alkyl group, an alkoxy group,
an alkylthio group, a methylsulphonyl group, an alkylaminoalkyl group or
alkylaminocycloalkyl group which is optionally substituted, an alkylaminoalkoxy or
cycloalkylaminoalkoxy group or a sulphonamide group, for example:
- polycyclic aryl: an optionally substituted polycyclic aromatic system comprising from
5 to 14 members per ring, preferably from 5 to 10 members per ring, and comprising
from 2 to 10 rings, at least one of the rings of which is aromatic. Mention may be made,
as examples of polycyclic aryl groups, of aceanthrylene, anthracene, azulene, coronene,
rubicene or naphthalene; the polycyclic aryl group can be substituted by a group which
can be one or more halogen atom(s), a hydroxyl group, a cyano group, a
trifluoromethylthio group, a nitro group, an alkyl group, an alkoxy group, an alkylthio
group, a methylsulphonyl group, an alkylaminoalkyl or alkylaminocycloalkyl group which
is optionally substituted, an alkylaminoalkoxy or cycloalkylaminoalkoxy group or a

sulphonamide group, for example;
-a bridged ring: a bicyclic structure comprising, according to the invention, a
nitrogen atom, in which at least two carbon atoms are connected via a single bond or a
carbon chain which can comprise 2 carbon atoms. By way of example, the
abovementioned ring is of the type:

with q = 1 or 2 and with the other groups and indices as defined above;
- cycloalkyl: a saturated cyclic aliphatic group comprising from 3 to 8 carbon atoms.
Mention may be made, by way of example, of a cyclopropyl, methylcyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl group;
- halogen: a fluorine, a chlorine, a bromine or an iodine;
- haloalkyl: (CrCe) alkyl substituted by one to three halogen atom(s);
- heteroaryl: a monocyclic aromatic system comprising from 5 to 14 ring members,
preferably from 5 to 10 ring members, and comprising one to several heteroatoms, such
as nitrogen, oxygen or sulphur atoms. The nitrogen atoms can be in the form of
N-oxides. For example, a monocyclic heterocycle can be a pyran, a pyrazine, a pyrazole,
a pyridazine, a pyridine, a pyrimidine, a pyrrole, an isothiazole, an isoxazole, a furan, an
imidazole, a morpholine, a thiophene, a piperazine, a diazetidine, a dihydropyrrolidine, a
piperidine, an azepine, and the like; a bicyclic heterocycle can be an isoquinoline, a
pteridine, a chroman, and the like; a tricyclic heterocycle can be a phenanthroline, a
xanthene, and the like;
- polycyclic heteroaryl: an optionally substituted polycyclic aromatic system
comprising from 5 to 14 members per ring, preferably from 5 to 10 members per ring,
and comprising from 2 to 10 rings, additionally comprising one to several heteroatoms,
such as nitrogen, oxygen or sulphur atoms, in at least one of the rings, and at least one
of the rings of which is aromatic. Mention may be made, as examples of polycyclic
heteroaryl groups, of indole, benzofuran, benzimidazole, benzothiophene, benzotriazole,
benzothiazole, benzoxazole, quinoline, isoquinoline, indazole, quinazoline, phthalazine,

quinoxaline, naphthyridine, 2,3-dihydro-1H-indole, 2,3-dihydrobenzofuran, 2,3-dihydro-
indene, tetrahydroquinoline, tetrahydroisoquinoline or tetrahydroisoquinazoline;
-a heterocycloalkyl: an optionally substituted saturated ring comprising from 3 to
8 atoms and comprising one to several heteroatoms, such as nitrogen, oxygen or sulphur
atoms, in at least one of the rings, or several heteroatoms which are identical to or
different from one another. For example, a heterocycloalkyl can be a pyrrolidine, a
morpholine, a piperazine, a diazetidine, a dihydropyrrolidine, a piperidine, a piperadine,
an azepane, an imidazolidine, a thiomorpholine, a tetrahydropyran, a tetrahydrothiopyran,
a piperazine, a diazepane, and the like;
- hydroxyl: an -OH group;
- nitro: an -N02 group;
- oxo: a -C(O)- group;
- sulphonamide: group corresponding to the formula S02-N-alkyl or S02-N-cyclo-
alkyl, alkyl and cycloalkyl being as defined above;
- trifluoromethylthio is defined by the formula -S-CF3.
Furthermore, it is understood that, in the present description, when an atom or a
group is substituted or optionally substituted by one or more defined group(s) or atom(s),
the substituents can be identical to or different from one another and may be carried, if
appropriate, by the same atom or different atoms.
Mention may be made, among the compounds which are a subject-matter of the
invention, of a group of compounds of formula (I) in which A represents an aryl group, in
particular a phenyl or heteroaryl group, in particular a pyridyl group, and ail the other
substituents and indices are as defined in the general formula (I) defined above.
Mention may be made, among the compounds in accordance with the invention, of a
group of compounds of formula (I) in which q = 0, m and n each represents 1, and all the
other substituents and indices are as defined in the general formula (I) defined above.
Mention may be made, among the compounds in accordance with the invention, of a
group of compounds of formula (I) in which R2 represents a (C1-C6) alkyl group, in
particular a methyl, substituted by an -NHC(O)Rb group in which Rb and the other
substituents and indices are as defined for the compound of general formula (I) defined
above.
Mention may be made, among the compounds in accordance with the invention, of a
group of compounds of general formula (I) in which R2 represents an -ORa group, the Ra

group and all the other substituents and indices being as defined in the general formula
(I) defined above.
Mention may be made, among the compounds in accordance with the invention, of a
group of compounds of general formula (I) in which R2 is a halogen atom or a cyano or a
hydrogen or a hydroxyl or a (CrCe) alkyl optionally substituted by an -NH2, or else by an
-NHC(O)Rb group, Rb and the other substituents and indices being as defined in the
general formula (I) defined above.
Mention may be made, among the compounds in accordance with the invention, of a
group of compounds of general formula (I) in which A is a phenyl, R^ is a -C(O)R group in
which R represents a hydrogen atom, q is equal to 0, n and m each have the value 1,
and R2 represents -ORa, Ra and the other substituents and indices being as defined in
the general formula (I) defined above.
Mention may be made, among the compounds in accordance with the invention, of a
group of compounds of general formula (I) in which A is a phenyl, Ri is a -C(O)R group in
which R represents a hydrogen atom, q is equal to 0, n and m each have the value 1, p
is equal to 2, one of the R2 groups is -ORa and the other of the R2 groups is a halogen
atom, Ra and the other substituents and indices being as defined in the general formula
(I) defined above.
Mention may be made, among the compounds in accordance with the invention, of a
group of compounds of general formula (I) in which A is a phenyl, Ri is a -C(O)R group in
which R represents a hydrogen atom, q is equal to 0, n and m each have the value 1, p =
1 and R2 is a methyl substituted by an -NH-CO-Rb group, Rb and the other substituents
and indices being as defined in the general formula (I) defined above.
Advantageously, in the compounds of formula (I), the R2 group is in the 6 position of
the 2,4-dioxo-1,2,3,4-tetrahydroquinazoline ring system. The compounds of formula (I)
can also have an R2 group in the 7 position of the 2,4-dioxo-1,2,3,4-tetrahydroquinazoline
ring system. The R2 groups in the 6 and 7 positions can be identical or different.
Advantageously, in the compounds of formula (I), p is equal to 1 or 2.
The compounds of general formula (I) can be in the base, hydrate or solvate form, in
the form of isomers or in the form of their mixtures.

In a specific form, when p' = 2, then the two R3 groups are in the 3 and 4 positions of
the ring system A and can be different from one another.
The combinations of the groups of compounds in accordance with the invention
mentioned above also come within the invention.
Mention may be made, as examples of preferred compounds in accordance with the
invention, of the following compounds:
No. 1: 2-{[3-(3,4-dimethoxybenzyl)-1-(1-formylpiperidin-4-yl)-2,4-dioxo-1,2,3,4-
tetrahydroquinazolin-6-yl]oxy}propanenitrile
No. 2: 1-(1-acetylpiperidin-4-yl)-3-(3,4-dimethoxybenzyl)-6-hydroxyquinazoline-
2,4(1 H,3H)-dione
No. 3: {[1-(1-acetylpiperidin-4-yl)-3-(3,4-dimethoxybenzyl)-2,4-dioxo-1,2,3,4-
tetrahydroquinazolin-6-yl]oxy}acetonitrile
No. 4: 2-{[1-(1-acetyipiperidin-4-yl)-3-(3,4-dimethoxybenzyl)-2,4-dioxo-1,2,3,4-
tetrahydroquinazolin-6-yl]oxy}propanenitrile
No. 5: {[3-(3,4-dimethoxybenzyl)-1-(1-formylpiperidin-4-yl)-2,4-dioxo-1,2,3,4-
tetrahydroquinazolin-6-yl]oxy}acetonitrile
No. 11: 4-[3-(3,4-dimethoxybenzyl)-6-[2-fluoro-1-(fluoromethyl)ethoxy]-2,4-dioxo-
3,4-dihydroquinazolin-1 (2H)-yl]piperidine-1 -carbaldehyde
No. 12: 1-(1-acetylpiperidin-4-yl)-3-(3,4-dimethoxybenzyl)-6-[2-fluoro-1-
(fluoromethyl)ethoxy]quinazoline-2,4(1 H,3H)-dione
No. 13: 4-[3-(3,4-dimethoxybenzyl)-2,4-dioxo-6-(2,2,2-trifluoroethoxy)-3,4-
dihydroquinazolin-1 (2H)-yl]piperidine-1 -carbaldehyde
No. 14: 1 -(1 -acetylpiperidin-4-yl)-6-(2,2-difluoroethoxy)-3-(3,4-
dimethoxybenzyl)quinazoiine-2,4(1H,3H)-dione
No. 16: 4-[6-(2,2-difluoroefhoxy)-3-(3,4-dimethoxybenzyl)-2,4-dioxo-3,4-
dihydroquinazolin-1 (2H)-yl]piperidine-1 -carbaldehyde
No. 20: N-{[3-(3,4-dimethoxybenzyl)-1-(1-formylpiperidin-4-yl)-2,4-dioxo-1,2,3,4-
tetrahydroquinazolin-6-yl]methyl}acetamide
No. 22: 1-(1-acetylpiperidin-4-yl)-6-(aminomethyl)-3-(3,4-
dimethoxybenzyl)quinazoline-2,4(1 H,3H)-dione hydrochloride
No. 23: N-{[3-(3,4-dimethoxybenzyl)-1-(1-formylpiperidin-4-yl)-2,4-dioxo-1,2,3,4-
tetrahydroquinazolin-6-yl]methyl}formamide

No. 24: N-{[1-(1-acetylpiperidin-4-yl)-3-(3,4-dimethoxybenzyl)-2,4-dioxo-1,2,3,4-
tetrahydroquinazolin-6-yl]methyl}formamide
No. 25: N-{[1-(1-acetylpiperidin-4-yl)-3-(3,4-dimethoxybenzyl)-2,4-dioxo-1,2,3,4-
tetrahydroquinazolin-6-yl]methyl}acetamide
No. 32: 4-[6-(2,2-difluoroethoxy)-2,4-dioxo-3,4-dihydroquinazolin-1 (2H)-
yl]piperidine-1-carbaldehyde
No. 33:4-[3-(3,4-dichlorobenzyl)-6-(2,2-difluoroethoxy)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 34: 4-[3-(4-chlorobenzyl)-6-(2,2-difIuoroethoxy)-2,4-dioxo-3,4-
dihydroquinazolin-1 (2H)-yl]piperidine-1 -carbaldehyde
No. 35: methyl 4-{[6-(2,2-difluoroethoxy)-1-(1-formylpiperidin-4-yl)-2,4-dioxo-1,4-
dihydroquinazolin-3(2H)-yl]methyl}benzoate
No. 36: 4-{[6-(2,2-difluoroethoxy)-1-(1-formylpiperidin-4-yI)-2,4-dioxo-1,4-
dihydroquinazolin-3(2H)-yl]methyl}benzoicacid
No. 37: 4-{[6-(2,2-difluoroethoxy)-1-(1-formylpiperidin-4-yl)-2,4-dioxo-1,4-
dihydroquinazolin-3(2H)-yl]methyl}-N-(2-methoxyethyl)benzamide
No. 38: 4-[3-(3,4-dimethoxybenzyl)-6-methyl-2,4-dioxo-3,4-dihydroquinazolin-1 (2H)-
yl]piperidine-1 -carbaldehyde
No. 39:4-[6-(2,2-difluoroethoxy)-3-(3-hydroxy-4-methoxybenzyl)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 40:4-[6-(2,2-difluoroethoxy)-3-[3-(2-hydroxyethoxy)-4-methoxybenzyl]-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 41: 4-[6-(2,2-difluoroethoxy)-3-(3-ethoxy-4-methoxybenzyl)-2,4-dioxo-3,4-
dihydroquinazolin-1 (2H)-yl]piperidine-1 -carbaldehyde
No. 42: 4-[6-(2,2-difluoroethoxy)-3-[4-methoxy-3-(2-methoxyethoxy)benzyl]-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 43: 4-[6-(2,2-difluoroethoxy)-3-(3,4-dimethoxybenzyl)-2,4-dioxo-3,4-
dihydroquinazolin-1 (2H)-yl]azepane-1 -carbaldehyde
No. 47: 4-[6-(2,2-difluoroethoxy)-3-[3-(3-hydroxypropoxy)-4-methoxybenzyl]-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 48: 4-[5-chloro-3-(3,4-dimethoxybenzyl)-2,4-dioxo-3,4-dihydroquinazolin-1 (2H)-
yl]piperidine-1 -carbaldehyde
No. 49: 4-{3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(2,2-difluoroethoxy)-2,4-dioxo-
3,4-dihydroquinazolin-1 (2H)-yl}piperidine-1 -carbaldehyde
No. 50: 2-(5-{[6-(2,2-difluoroethoxy)-1-(1-formylpiperidin-4-yl)-2,4-dioxo-1,4-

dihydroquinazolin-3(2H)-yl]methyl}-2-methoxyphenoxy)acetamide
No. 51:4-[6-(2)2-difluoroethoxy)-3-(3,4-dimethoxybenzyl)-2,4-dioxo-3,4-
dihydroquinazolin-1 (2H)-yl]-3-methylpiperidine-1 -carbaldehyde
No. 52: 3-[6-(2,2-difluoroethoxy)-3-(3,4-dimethoxybenzyl)-214-dioxo-3,4-
dihydroquinazoliri-1(2H)-yl]-8-azabicyclo[3.2.1]octane-8-carbaldehyde
No. 56: 4-{3-[4-(cyclopentyloxy)-3-methoxybenzyl]-6-[2-fluoro-1-
(fluoromethyl)ethoxy]-2,4-dioxo-3>4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 57: 4-[3-(3-chlorobenzyl)-6-[2-fluoro-1 -(fIuoromethyl)ethoxy]-2,4-dioxo-3,4-
dihydroquinazolin-1 (2H)-yl]piperidine-1 -carbaldehyde
No. 58: 4-[3-(4-chlorobenzyl)-6-[2-fluoro-1 -(fluoromethyl)ethoxy]-2,4-dioxo-3,4-
dihydroquinazotin-1 (2H)-yl]piperidine-1 -carbaldehyde
No. 59: 4-{3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-[2-fluoro-1-
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 72:4-[3-(3,4-dimethoxybenzyl)-6-(2-hydroxyethoxy)-2>4-dioxo-3,4-
dihydroquinazolin-1 (2H)-yl]piperidine-1 -carbaldehyde
No. 74:4-[3-(3,4-dichlorobenzyl)-6-[2-fluoro-1-(fluoromethyl)ethoxy]-2,4-dioxo-3,4-
dihydroquinazolin-1 (2H)-yl]piperidine-1 -carbaldehyde
No. 76: 4-{3-[(6-chloropyridin-3-yl)methyl]-6-[2-fluoro-1-(fluoromethyl)ethoxyJ-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 78: 4-[3-(3-chloro-4-methoxybenzyl)-6-[2-fluoro-1 -(fluoromethyl)ethoxy]-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 79:4-[3-(3,4-dimethoxybenzyl)-6-(2-fluoroethoxy)-2,4-dioxo-3,4-
dihydroquinazolin-1 (2H)-yl]piperidine-1 -carbaldehyde
No. 89:2-[5-({6-[2-fluoro-1-(fluoromethyl)ethoxy]-1-(1-formylpiperidin-4-yl)-2,4-
dioxo-1,4-dihydroquinazolin-3(2H)-yl}methyl)-2-methoxyphenoxy]acetamide
No. 90: 4-{6-[2-fluoro-1 -(fluoromethyl)ethoxy]-3-(3-hydroxy-4-methoxybenzyl)-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 91: 4-[3-(3,4-dimethoxybenzyl)-6-ethoxy-2,4-dioxo-3,4-dihydroquinazolin-1 (2H)-
yl]piperidine-1 -carbaldehyde
No. 97: 4-[5,7-dichloro-3-(3,4-dimethoxybenzyl)-2,4-dioxo-3,4-dihydroquinazolin-
1 (2H)-yl]piperidine-1 -carbaldehyde
No. 102: 4-[7-chloro-3-(3,4-dimethoxybenzyl)-2,4-dioxo-3,4-dihydroquinazolin-
1 (2H)-yl]piperidine-1 -carbaldehyde
No. 108: 4-{6-[2-fluoro-1 -(fluoromethyl)ethoxy]-3-(3-fluoro-4-methoxybenzyl)-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde

No. 111: 4-[6-(dtfIuoromethoxy)-3-(3,4-dimethoxybenzyl)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 112: 4-[3-(3,4-dimethoxybenzyl)-6-(1-methylethoxy)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yI]piperidine-1-carbaldehyde
No. 114: 4-{6-[2-fluoro-1-(fluoromethyl)ethoxy]-3-[4-methoxy-3-(1-
methylethoxy)benzyl]-2,4-dioxo-3,4-dihydroquinazoiin-1(2H)-yl}piperidine-1-carbaldehyde
No. 116: 4-{6-[2-fIuoro-1-(fluoromethyl)ethoxy]-3-(3-methoxybenzyl)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 117: 4-{3-[3,5-bis(trifluoromethyl)benzyl]-6-[2-fluoro-1-(fluoromethyl)ethoxy]-
2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 118: 4-[3-(3-ethoxybenzyI)-6-[2-fluoro-1-(fluoromethyl)ethoxy]-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 124: 4-{3-[3-chloro-4-(2-methoxyethoxy)benzyl]-6-[2-fluoro-1-
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 130: 4-[3-(3,4-diethoxybenzyl)-6-[2-fluoro-1 -(fluoromethyl)ethoxy]-2,4-dioxo-
3,4-dihydroquinazolin-1 (2H)-yl]piperidine-1 -carbaldehyde
No. 131: 4-[3-(4-ethoxy-3-methoxybenzyl)-6-[2-fluoro-1 -(fluoromethyl)ethoxy]-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 133: 4-{6-[2-fluoro-1 -(fluoromethyl)ethoxy]-3-(4-methoxy-3-methylbenzyl)-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 134: 4-{6-[2-fluoro-1-(fluoromethyl)ethoxy]-2,4-dioxo-3-[4-
(trifluoromethyl)benzyl]-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 135: 4-{6-[2-fluoro-1-(fluoromethyl)ethoxy]-2,4-dioxo-3-[4-
(trifluoromethyl)benzyl]-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 143: 4-{3-[4-(benzyloxy)-3-methoxybenzyl]-6-[2-fluoro-1 -(fluoromethyl)ethoxy]-
2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 145: 4-{6-[2-fluoro-1 -(fluoromethyl)ethoxy]-3-(3-methoxy-4-nitrobenzyl)-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 155: 4-[3-(4-ethoxybenzyl)-6-[2-fluoro-1-(fluoromethyl)ethoxy]-2,4-dioxo-3,4-
dihydroquinazolin-1 (2H)-yl]piperidine-1 -carbaldehyde
No. 158: 4-{6-[2-fluoro-1 -(fluoromethyl)ethoxy]-3-[4-(morpholin-4-ylmethyl)benzylJ-
2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 160: 4-{6-[2-fluoro-1 -(fluoromethyl)ethoxy]-3-(4-morpholin-4-ylbenzyl)-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 165: 4-[3-(biphenyl-4-ylmethyl)-6-[2-fluoro-1 -(fluoromethyl)ethoxy]-2,4-dioxo-
3,4-dihydroquinazolin-1 (2H)-yl]piperidine-1 -carbaldehyde

No. 166: 4-{6-[2-fluoro-1-(fluoromethyl)ethoxy]-3-[4-(methylsulphanyl)benzyl]-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 167: 4-{6-[2-fluoro-1-(fluoromethyl)ethoxy]-2,4-dioxo-3-(4-(pyridin-3-yl)benzyl)-
3,4-dihydroquinazolin-1 (2H)-yl}piperidine-1 -carbaldehyde
No. 170: 4-{6-[2-fluoro-1 -(fluoromethyl)ethoxy]-3-(3-methoxy-4-methylbenzyl)-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 175: 2-[2-(cyclopentyloxy)-5-({6-[2-fluoro-1-(fluoromethyl)ethoxy]-1-(1 -
formylpiperidin-4-yl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl}methyl)phenoxy]acetamide
No. 178: 4-{6-[2-fluoro-1 -(fluoromethyl)ethoxy]-3-(3-methoxy-4-propoxybenzyl)-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 183: 2-[2-(cyclopentyloxy)-5-({6-[2-fluoro-1-(fluoromethyl)ethoxy]-1-(1-
formylpiperidin-4-yl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl}methyl)phenoxy]-N-
methylacetamide
No. 184: 2-[2-(cyclopentyloxy)-5-({6-[2-fluoro-1-(fluoromethyl)ethoxy]-1-(1-
formylpiperidin-4-yl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl}methyl)phenoxy]-N,N-
dimethylacetamide
No. 185:2-[2-(cyclopentyloxy)-5-({6-[2-fluoro-1-(fluoromethyl)ethoxy]-1-(1-
formylpiperidin-4-yl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl}methyl)phenoxy]-N-
methoxy-N-methylacetamide
No. 186: 4-{3-[4-(cyclopentyloxy)-3-ethoxybenzyl]-6-[2-fluoro-1-
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 188:4-{3-[4-(cyclopentyloxy)-3-(1-methylethoxy)benzyl]-6-[2-fIuoro-1-
(fiuoromethyi)ethoxy]-2)4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 189: 4-{3-[4-(cyclopentyloxy)-3-propoxybenzyl]-6-[2-fluoro-1-
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 190: 4-{3-[4-(cyclopentyloxy)-3-hydroxybenzyl]-6-[2-fluoro-1-
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 193: 4-{3-[4-(difluoromethoxy)-3-methoxybenzyl]-6-[2-fluoro-1-
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 194: 4-{3-[4-(difluoromethoxy)-3-ethoxybenzyl]-6-[2-fluoro-1 -
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 200: 4-{6-[2-fluoro-1 -(fluoromethyl)ethoxy]-2,4-dioxo-3-(4-(thiophen-3-yl)-
benzyl)-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 201: 4-{6-[2-fluoro-1-(fluoromethyl)ethoxy]-2,4-dioxo-3-(4-(pyridin-4-yl)benzyl)-
3,4-dihydroquinazolin-1 (2H)-yl}piperidine-1 -carbaldehyde
No. 203: 4-{6-[2-fluoro-1-(fluoromethyl)ethoxy]-3-[(1-methyl-1 H-indol-6-yl)methyl]-
2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde

No. 206: 4-{3-[4-(cyclopropylmethoxy)-3-methoxybenzyl]-6-[2-fluoro-1-
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbalclehyde
No. 207:2-[4-({6-[2-fluoro-1-(fluoromethyl)ethoxy]-1-(1-formylpiperidin-4-yl)-2,4-
dioxo-1,4-dihydroquinazolin-3(2H)-yl}methyl)-2-methoxyphenoxy]-N-methylacetamide
No. 212:4-{6-[2-fluoro-1-(fluoromethyl)ethoxy]-2,4-dioxo-3-[4-(1H-pyrazol-1-
yl)benzyl]-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 213: 4-{6-[2-fluoro-1-(fluoromethyl)ethoxy]-2,4-dioxo-3-(4-(pyridin-2-yl)benzyl)-
3,4-dihydroquinazolin-1 (2H)-yl}piperidine-1 -carbaldehyde
No. 215: 4-{6-[2-fluoro-1-(fluoromethyl)ethoxy]-2,4-dioxo-3-(4-(thiophen-2-yl)-
benzyl)-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 216: 4-{6-[2-fluoro-1 -(fluoromethyl)ethoxy]-2,4-dioxo-3-(quinolin-7-ylmethyl)-
3,4-dihydroquinazolin-1 (2H)-yl}piperidine-1 -carbaldehyde
No. 218: 4-{6-[2-fluoro-1 -(fluoromethyl)ethoxy]-3-[(6-methoxynaphthalen-2-
yl)methyl]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 223: 4-{3-[4-(1 H-benzimidazol-1 -yl)benzyl]-6-[2-fluoro-1 -(fluoromethyl)ethoxy]-
2I4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 224: 4-{6-[2-fluoro-1-(fluoromethyl)ethoxy]-3-[3-methoxy-4-(2-
methylpropoxy)benzyl]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-
carbaldehyde
No. 226: 4-{6-[2-fluoro-1-(fluoromethyl)ethoxy]-3-[3-methoxy-4-(tetrahydrofuran-3-
yloxy)benzyl]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 228:4-[3-{4-[(1-benzylpyrrolidin-3-yl)oxy]-3-methoxybenzyl}-6-[2-fluoro-1-
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 230: 4-[3-(1-benzothiophen-5-ylmethyl)-6-[2-fluoro-1-(fluoromethyl)ethoxy]-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 232: 4-{6-[2-fluoro-1 -(fluoromethyl)ethoxy]-3-[3-methoxy-4-(1 -
methylethoxy)benzyl]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 233: 4-[3-(3,4-dimethoxybenzyl)-7-fluoro-6-[2-fluoro-1 -(fluoromethyl)ethoxy]-
2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 234: 4-[3-{4-[(1 -acetylpyrrolidin-3-yl)oxy]-3-methoxybenzyl}-6-[2-fluoro-1 -
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 239: 4-[3-{4-[(4-fluorobenzyl)oxy]-3-methoxybenzyl}-6-[2-fluoro-1 -
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 240: 4-[3-{4-[(4-chlorobenzyl)oxy]-3-methoxybenzyl}-6-[2-fluoro-1 -
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 242:4-[3-{4-[(3-chlorobenzyl)oxy]-3-methoxybenzyl}-6-[2-fluoro-1-
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde

No. 243: 4-{6-[2-fluoro-1 -(fluoromethyl)ethoxy]-2,4-dioxo-3-(3-(thiophen-3-
yl)benzyl)-3>4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 245: 4-[3-(4-ethoxy-3-methoxybenzyl)-6-(2-hydroxyethoxy)-2,4-dioxo-3,4-
dihydroquinazolin-1 (2H)-yl]piperidine-1 -carbaldehyde
No. 246: 4-[3-{4-[2-(2,3-dihydro-1 H-indol-1-yl)-2-oxoethoxy]-3-methoxybenzyl}-6-[2-
fluoro-1 -(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1 (2H)-yl]piperidine-1 -
carbaldehyde
No. 250: 4-[3-{4-[(3,4-dichlorobenzyl)oxy]-3-methoxybenzyl}-6-[2-fluoro-1 -
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 251: 4-{6-[2-fluoro-1-(fluoromethyl)ethoxy]-3-[3-methoxy-4-(2-oxo-2-(piperidin-
1-yl)ethoxy)benzyl]-2,4-dioxo-3,4-dihydroquinazoIin-1(2H)-yl}piperidine-1-carbaldehyde
No. 254: 4-{3-[3-ethoxy-4-(thiophen-2-ylmethoxy)benzyl]-6-[2-fluoro-1 -
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 258: 4-[3-(3,4-dimethoxybenzyl)-6-[2-fluoro-1 -(hydroxymethyl)ethoxy]-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 263:(2R)-2-[2-(cyclopentyloxy)-5-({6-[2-fluoro-1-(fluoromethyl)ethoxy]-1-(1-
formylpiperidin-4-yl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl}methyl)phenoxy]propanoic
acid
No. 264: 4-{6-[2-fluoro-1 -(fluoromethyl)ethoxy]-3-[(1 -methyl-3-(thiophen-2-yl)-1 H-
pyrazol-5-yl)methyl]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 270: 4-{6-[2-fluoro-1-(fluoromethyl)ethoxy]-3-[4-(5-methyl-1,2,4-oxadiazol-3-
yl)benzyl]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 275: 4-{6-[2-fluoro-1 -(fluoromethyl)ethoxy]-2,4-dioxo-3-(4-(pyrimidin-5-
yl)benzyl)-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 276: 4-{6-[2-fluoro-1-(fluoromethyl)ethoxy]-3-[(1-methyl-3-phenyl-1 H-pyrazol-5-
yl)methyl]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 278: 4-{6-[2-fluoro-1 -(fluoromethyl)ethoxy]-2,4-dioxo-3-{[6-(1 H-pyrazol-1 -
yl)pyridin-3-yl]methyl}-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 279: 4-{6-[2-fluoro-1 -(fluoromethyI)ethoxy]-2,4-dioxo-3-[(2-(thiophen-2-
yl)pyrimidin-5-yl)methyl]-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1 -carbaldehyde
No. 280: 4-{6-[2-fluoro-1 -(fluoromethyl)ethoxy]-3-[4-(1-methyl-1 H-pyrazol-3-
yl)benzyl]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 282: 4-{6-[2-fluoro-1-(fluoromethyl)ethoxy]-3-[4-(3-methyl-1,2,4-oxadiazol-5-
yl)benzyl]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 283: [2-(cyclopentyloxy)-5-({6-[2-fluoro-1 -(fluoromethyl)ethoxy]-1 -(1 -
formylpiperidin-4-yl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl}methyl)phenoxy]aceticacid
No. 285:4-{6-[2-fluoro-1-(fluoromethyl)ethoxy]-2,4-dioxo-3-(thieno[2,3-b]pyridin-2-

ylmethyl)-3,4-dihydroquinazolin-1(2H)-yl>piperidine-1-carbaldehyde
No. 286: 4-{6-[2-fluoro-1 -(fluoromethyl)ethoxy]-2,4-dioxo-3-[(6-phenylpyridin-3-
yl)methyl]-3,4-dihyclroquinazolin-1(2H)-yl}pipericline-1-carbaldehycie
No. 287: 4-{6-[2-fluoro-1 -(fluoromethyl)ethoxy]-3-[(6-(morpholin-4-yl)pyridin-3-
yl)methyl]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 289: 4-{6-[2-fluoro-1 -(fluoromethyl)ethoxy]-2,4-dioxo-3-[(6-(thiophen-2-
yl)pyridin-3-yl)methyl]-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 292: 4-{6-[2-fluoro-1-(fluoromethyl)ethoxy]-3-[(1-methyl-5-phenyl-1 H-pyrazol-3-
yl)methyl]-2I4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 294: 4-({6-[2-fluoro-1-(fluoromethyl)ethoxy]-1-(1-formylpiperidin-4-yl)-2,4-dioxo-
1,4-dihydroquinazolin-3(2H)-yl}methyl)biphenyl-2-carbonitrile
No. 295:(2R)-2-[2-(cyclopentyloxy)-5-({6-[2-fluoro-1-(fluoromethyl)ethoxy]-1-(1-
formylpiperidin-4-yl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl}methyl)phenoxy]-N-
methylpropanamide
No. 297: 4-{7-fluoro-6-[2-fluoro-1 -(fluoromethyl)ethoxy]-2,4-dioxo-3-(4-(thiophen-2-
yl)benzyl)-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 298: 4-{6-[2-fluoro-1 -(fluoromethyl)ethoxy]-3-[3-methoxy-4-(morpholin-4-
ylmethyl)benzyl]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 299: 4-{6-[2-fluoro-1 -(fluoromethyl)ethoxy]-3-[3-methoxy-4-(piperidin-1 -
ylmethyl)benzyl]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 300: 4-[3-{4-[(3,4-dichlorobenzyl)oxy]-3-methoxybenzyl}-7-fluoro-6-[2-fluoro-1 -
(fluoromethyi)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yi]piperidine-1-carbaldehyde
No. 301: 2-[2-(cyclopentyloxy)-5-({6-[2-fluoro-1-(fluoromethyl)ethoxy]-1-(1-
formylpiperidin-4-yl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl}methyl)phenoxy]-N-
ethylacetamide
No. 302:(2S)-2-[2-(cyclopentyloxy)-5-({6-[2-fluoro-1-(fluoromethyl)ethoxy]-1-(1-
formylpiperidin-4-yl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl}methyl)phenoxy]propanoic
acid
No. 305: 4-{6-[2-fluoro-1 -(fIuoromethyl)ethoxy]-3-(3-methoxy-4-{[(3R)-2-oxo-1 -
phenylpyrrolidin-3-yl]oxy}benzyl)-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-
carbaldehyde
No. 306: 4-{3-[4-(cyclobutylmethoxy)-3-methoxybenzyl]-6-[2-fluoro-1 -
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H}-yI}piperidine-1-carbaldehyde
No. 307: 4-{3-[4-(benzyloxy)-3-methoxybenzyl]-7-fluoro-6-[2-fluoro-1 -
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 308: 4-{7-fluoro-6-[2-fluoro-1 -(fluoromethyl)ethoxy]-3-(4-hydroxy-3-

methoxybenzyl)-2,4-clioxo-3,4-clihydroquinazolin-1(2H)-yl}pipericline-1-carbaldehycle
No. 309: 4-{3-[4-(cyclopropylmethoxy)-3-methoxybenzyl]-7-fluoro-6-[2-fluoro-1 -
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 310: 4-{7-fluoro-6-[2-fluoro-1-(fluoromethyl)ethoxy]-3-[3-methoxy-4-
(2-methylpropoxy)benzyl]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-
carbaldehyde
No. 311: 4-{7-fluoro-6-[2-fluoro-1-(fluoromethyl)ethoxy]-3-[3-methoxy-4-
(1-methylethoxy)benzyl]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-
carbaldehyde
No. 312: 4-[3-(4-ethoxy-3-methoxybenzyl)-7-fluoro-6-[2-fluoro-1-
(fluoromethyl)ethoxy]-2,4-dioxo-3>4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 315: 4-{7-fluoro-6-[2-fluoro-1-(fluoromethyl)ethoxy]-3-{[6-(3-
methoxyphenyl)pyridin-3-yl]methyl}-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-
carbaldehyde
No. 316: 4-{7-fluoro-6-[2-fluoro-1-(fluoromethyl)ethoxy]-3-{[6-(2-
fluorophenyl)pyridin-3-yl]methyl}-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-
carbaldehyde
No. 317: 4-{7-fluoro-6-[2-fluoro-1-(fluoromethyl)ethoxy]-3-{[6-(4-
fluorophenyl)pyridin-3-yl]methyl}-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-
carbaldehyde
No. 318: 4-{7-fluoro-6-[2-fluoro-1-(fluoromethyl)ethoxy]-3-{[6-(4-
methoxyphenyl)pyridin-3-yl]methyl}-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-
carbaldehyde
No. 319: 4-{7-fluoro-6-[2-fluoro-1-(fluoromethyl)ethoxy]-2,4-dioxo-3-[(6-(thiophen-2-
yl)pyridin-3-yl)methyl]-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 320: 4-{3-[3-ethoxy-4-(thiophen-2-ylmethoxy)benzyl]-7-fluoro-6-[2-fluoro-1-
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 321: 4-{7-fluoro-6-[2-fluoro-1-(fluoromethyl)ethoxy]-3-[4-(1-methyl-1H-pyrazol-
3-yl)benzyl]-2,4-dioxo-3,4-dihydroquinazolin-1 (2H)-yl}piperidine-1 -carbaldehyde
No. 322: 4-{7-fluoro-6-[2-fluoro-1-(fluoromethyl)ethoxy]-2I4-dioxo-3-(4-(pyrimidin-5-
yl)benzyl)-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 323: 4-{7-fluoro-6-[2-fluoro-1 -(fluoromethyl)ethoxy]-3-[(1 -methyl-3-(thiophen-2-
yl)-1 H-pyrazol-5-yl)methyl]-2,4-dioxo-3,4-dihydroquinazolin-1 (2H)-yl}piperidine-1 -
carbaldehyde
No. 324: 4-{7-fluoro-6-[2-fluoro-1 -(fluoromethyl)ethoxy]-3-[3-methoxy-4-(2-oxo-2-
(piperidin-1-yl)ethoxy)benzyl]-2,4-dioxo-3I4-dihydroquinazolin-1(2H)-yl}piperidine-1-
carbaldehyde

No. 325: 4-[3-{4-[2-(2,3-dihydro-1 H-indol-1 -yl)-2-oxoethoxy]-3-methoxybenzyl}-7-
fluoro-6-[2-fluoro-1-(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-
yl]piperidine-1 -carbaldehyde
No. 326: 4-{7-fluoro-6-[2-fluoro-1-(fluoromethyl)ethoxy]-3-[4-(5-methyl-1,2,4-
oxadiazol-3-yl)benzyl]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-
carbaldehyde
No. 327: 4-[3-{4-[(3-chlorobenzyl)oxy]-3-methoxybenzyl}-7-fluoro-6-[2-fluoro-1 -
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 328: 4-[3-{[6-(3,5-dichlorophenyl)pyridin-3-yl]methyl}-6-[2-fluoro-1 -
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 329: 4-({7-fluoro-6-[2-fluoro-1-(fluoromethyl)ethoxy]-1-(1-formylpiperidin-4-yl)-
2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl}methyl)biphenyl-2-carbonitrile
No. 330: 4-{7-fluoro-6-[2-fluoro-1-(fluoromethyl)ethoxy]-2,4-dioxo-3-[4-(1 H-pyrazol-
1-yl)benzyl]-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 331: 4-{7-fluoro-6-[2-fluoro-1-(fluoromethyl)ethoxy]-3-{[6-(3-
fluorophenyl)pyridin-3-yl]methyl}-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yI}piperidine-1-
carbaldehyde
No. 332: 3-[5-({7-fluoro-6-[2-fluoro-1-(fluoromethyl)ethoxy]-1-(1-formylpiperidin-4-
yl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl}methyl)pyridin-2-yl]benzonitrile
No. 333: 4-[3-(3,4-diethoxybenzyl)-7-fluoro-6-[2-fluoro-1 -(fluoromethyl)ethoxy]-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 334: 4-[3-{4-[(4-chlorobenzyl)oxy]-3-methoxybenzyl}-7-fluoro-6-[2-fluoro-1 -
(fiuoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 335: 4-{7-fluoro-6-[2-fluoro-1-(fluoromethyl)ethoxy]-3-[4-(morpholin-4-
ylmethyl)benzyl]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 336: 4-{7-fluoro-6-[2-fluoro-1-(fluoromethyl)ethoxy]-2,4-dioxo-3-{[6-(1 H-pyrazol-
1 -yl)pyridin-3-yl]methyl}-3,4-dihydroquinazolin-1 (2H)-yl}piperidine-1 -carbaldehyde
No. 337: 4-{7-fluoro-6-[2-fluoro-1 -(fluoromethyl)ethoxy]-3-(4-(morpholin-4-yl)-
benzyl)-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 338: 4-{7-fluoro-6-[2-fluoro-1 -(fluoromethyl)ethoxy]-3-(3-methoxy-4-
propoxybenzyl)-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 339:4-{3-[4-(1H-benzimidazol-1-yl)benzyl]-7-fluoro-6-[2-fluoro-1-
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 340: 5-({7-fluoro-6-[2-fluoro-1-(fluoromethyl)ethoxy]-1-(1-formylpiperidin-4-yl)-
2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl}methyl)-2-methoxybenzonitrile
No. 341: 3-(3,4-dimethoxybenzyl)-6-[2-fluoro-1-(fluoromethyl)ethoxy]-1-(1-
formylpiperidin-4-yl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carbonitrile

No. 342: 4-[3-(4-bromobenzyl)-7-fluoro-6-[2-fluoro-1 -(fluoromethyl)ethoxy]-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbalclehycle
No. 343:4-[3-{4-[(3,4-dichlorobenzyl)oxy]-3-(2-methoxyethoxy)benzyl}-7-fluoro-6-
[2-fluoro-1-(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-
carbaldehyde
No. 344: 4-{3-[4-(benzyloxy)benzyl]-7-fluoro-6-[2-fluoro-1 -(fluoromethyl)ethoxy]-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 345: 4-[3-{4-[(3,4-dichlorobenzyl)oxy]-3-ethoxybenzyl}-7-fluoro-6-[2-fluoro-1-
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 349:4-[3-{4-[(3,4-dichlorobenzyl)oxy]-3-(2-fluoroethoxy)benzyl}-7-fluoro-6-[2-
fluoro-1 -(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1 (2H)-yl]piperidine-1 -
carbaldehyde
No. 350: 4-[3-{4-[(2-chloro-4-fluorobenzyl)oxy]-3-methoxybenzyl}-7-fluoro-6-[2-
fluoro-1 -(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1 (2H)-yl]piperidine-1 -
carbaldehyde
No. 351: 4-[3-{4-[(2,4-dichlorobenzyl)oxy]-3-methoxybenzyl}-7-fluoro-6-[2-fluoro-1-
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 352:4-[3-{4-[(2-chloro-6-fluorobenzyl)oxy]-3-methoxybenzyl}-7-fluoro-6-[2-
fluoro-1 -(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1 (2H)-yl]piperidine-1 -
carbaldehyde
No. 353: 4-[3-{4-[(2,6-dichlorobenzyl)oxy]-3-methoxybenzyl}-7-fluoro-6-[2-fluoro-1 -
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 354: 4-[3-{4-[(2-chiorobenzyl)oxy]-3-methoxybenzyl}-7-fluoro-6-[2-fluoro-1 -
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 355: 4-[7-fluoro-3-{4-[(2-fluorobenzyl)oxy]-3-methoxybenzyI}-6-[2-fluoro-1 -
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 357: 2-[(3,4-dichlorobenzyl)oxy]-5-({7-fluoro-6-[2-fluoro-1 -(fluoromethyl)ethoxy]-
1-(1-formylpiperidin-4-yl)-2,4-dioxo-1>4-dihydroquinazolin-3(2H)-yl}methyl)benzonitrile
No. 358: 4-[3-{4-[(3,4-dichlorophenoxy)methyl]-3-methoxybenzyl}-7-fluoro-6-[2-
fluoro-1 -(fluoromethyOethoxyl^^-dioxo-S^-dihydroquinazolin-l (2H)-yl]piperidine-1 -
carbaldehyde
No. 360:4-{7-fluoro-6-[2-fluoro-1-(fluoromethyl)ethoxy]-2,4-dioxo-3-[4-(2-
phenylethyl)benzyl]-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 362:4-[3-{4-[(4,5-dichloro-2-fluorobenzyl)oxy]-3-methoxybenzyl}-7-fluoro-6-[2-
fluoro-1-(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-
carbaldehyde
No. 369: 4-[3-{4-[(4-chlorophenoxy)methyl]-3-methoxybenzyl}-7-fluoro-6-[2-fluoro-1 -

(fluoromethyl)ethoxy]-2l4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 371:4-[3-{3-chloro-4-[(4-chlorobenzyl)oxy]-5-ethoxybenzyl}-7-fIuoro-6-[2-fluoro-
1-(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-
carbaldehyde
No. 373:4-[3-{3-chloro-4-[(2,4-dichlorobenzyl)oxy]-5-ethoxybenzyl}-7-fluoro-6-[2-
fluoro-1-(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-
carbaldehyde
No. 375: 4-[7-fluoro-3-{4-[(4-fluorobenzyl)oxy]-3-methoxybenzyl}-6-[2-fluoro-1-
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 376: 4-[3-{4-[(3,5-dichlorobenzyl)oxy]-3-methoxybenzyl}-7-fluoro-6-[2-fluoro-1 -
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 377: 4-[3-(4-{[4-chloro-3-(trifluoromethyl)benzyl]oxy}-3-methoxybenzyl)-7-
fluoro-6-[2-fluoro-1-(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-
yl]piperidine-1 -carbaldehyde
No. 379: 4-[3-{4-[(3-chlorophenoxy)methyl]-3-methoxybenzyl}-7-fluoro-6-[2-fluoro-1 -
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 380: 4-[3-{4-[(3,5-difluorobenzyl)oxy]-3-methoxybenzyl}-7-fluoro-6-[2-fluoro-1 -
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 381:4-{3-[4-(benzyloxy)-3-methoxybenzyl]-7-fluoro-6-[2-fluoro-1-
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 382:4-[3-{4-[(3-chloro-5-fluorobenzyl)oxy]-3-methoxybenzyl}-7-fluoro-6-[2-
fluoro-1-(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-
carbaldehyde
No. 383: 4-{7-fluoro-6-[2-fluoro-1 -(fluoromethyl)ethoxy]-3-(3-methoxy-4-{[4-
(trifluoromethyl)benzyl]oxy}benzyl)-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-
carbaldehyde
No. 384: 4-[3-{4-[(2,5-dichlorobenzyl)oxy]-3-methoxybenzyl}-7-fluoro-6-[2-fluoro-1 -
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 385: 4-{[4-({7-fluoro-6-[2-fluoro-1-(fluoromethyl)ethoxy]-1-(1-formylpiperidin-4-
yl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl}methyl)-2-
methoxyphenoxy]methyl}benzonitrile
No. 386: 3-{[4-({7-fluoro-6-[2-fluoro-1 -(fluoromethyl)ethoxy]-1 -(1 -formylpiperidin-4-
yl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl}methyl)-2-
methoxyphenoxy]methyl}benzonitrile
No. 387:4-[3-{4-[(4-chloro-2-fluorobenzyl)oxy]-3-methoxybenzyl}-7-fluoro-6-[2-
fluoro-1 -(fluoromethylJethoxyJ^^dioxo-S^-dihydroquinazolin-l (2H)-yl]piperidine-1 -
carbaldehyde

No. 388:4-[3-{4-[1-(3,4-dichlorophenyl)ethoxy]-3-methoxybenzyl}-7-fluoro-6-[2-
fluoro-1 -(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1 (2H)-yl]piperidine-1 -
carbaldehyde
No. 389: 4-{7-fluoro-6-[2-fluoro-1 -(fluoromethyl)ethoxy]-3-{4-[(3-hydroxybenzyl)oxy]-
3-methoxybenzyl}-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carbaldehyde
No. 390: 4-[7-fluoro-3-{4-[(3-fluorobenzyl)oxy]-3-methoxybenzyl}-6-[2-fluoro-1 -
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 391:4-[3-{4-[(3,4-difluorobenzyl)oxy]-3-methoxybenzyl}-7-fluoro-6-[2-fluoro-1-
(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 392: 4-{3-[4-(5,6-dichloro-1 H-benzimidazol-1 -yl)-3-methoxybenzyl]-7-fluoro-6-
[2-fluoro-1-(fluoromethyl)ethoxy]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-
carbaldehyde
No. 393: 4-({7-fluoro-6-[2-fluoro-1 -(fluoromethyl)ethoxy]-1 -(1 -formylpiperidin-4-yl)-
2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl}methyl)phenyl 3,4-dichlorobenzenesulphonate
No. 394: 4-({7-fluoro-6-[2-fluoro-1-(fluoromethyl)ethoxy]-1-(1-formylpiperidin-4-yl)-
2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl}methyl)-2-methoxyphenyl 3,4-dichlorobenzene-
sulphonate
No. 403:3,4-dichloro-N-[4-({7-fluoro-6-[2-fluoro-1-(fluoromethyl)ethoxy]-1-(1-
formylpiperidin-4-yl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl}methyl)-2-
methoxyphenyl]benzamide
The compounds in accordance with the invention can be prepared by the methods
illustrated in the following Schemes 1 to 4.
In that which follows, the term "leaving group" is understood to mean a group
which can be easily substituted, with departure of an electron pair, by cleavage of a
heterolytic bond. This group can thus be easily replaced by another group, for example
during a substitution reaction. Such leaving groups are, for example, halogens or an
activated hydroxyl group, such as a mesylate, tosylate, triflate, and the like. Examples of
leaving groups and references for their preparation are given in "Advanced Organic
Chemistry", J. March, 3rd Edition, Wiley Interscience, pp. 310-316.
The term "protective group PG" is understood to mean a group which makes it
possible to prevent the reactivity of a function group or position during a chemical
reaction which may affect it and which restores the molecule after cleavage according to
methods known to a person skilled in the art.
The term "temporary protective group for amines or alcohols" is understood to
mean the protective groups such as those described in Protective Groups in Organic
Synthesis, Greene T.W. and Wuts P.G.M., published by Wiley Intersciences, 1999, and

in Protecting Groups, Kocienski P.J., 1994, Georg Thieme Verlag.
Mention may be made, for example, of temporary protective groups for amines:
benzyls or carbamates (such as terf-butoxycarbonyl, cleavable in an acid medium, or
benzyloxycarbonyl, cleavable by hydrogenolysis), temporary protective groups for
carboxylic acids*, hydrogenolysable alkyl esters (such as methyl or ethyl or tert-butyl
esters which can be hydrolysed in a basic or acid medium) and benzyl esters, temporary
protective groups for alcohols or phenols, such as tetrahydropyranyl, methyloxymethyl or
methylethoxymethyl, te/t-butyl and benzyl ethers, or temporary protective groups for
carbonyl derivatives, such as linear or cyclic acetals, such as, for example, 1,3-dioxan-2-
yl or 1,3-dioxolan-2-yl; and reference may be made to the well known general methods
described in Protective Groups, cited above.
A person skilled in the art will be in the position to choose the appropriate
protective groups according to the circumstances. The compounds of formula (I) can
comprise precursor groups for other functional groups which are generated subsequently
in one or more other stages.
In the general synthetic schemes which follow, the starting compounds and the
reactants, when their method of preparation is not described, are commercially available
or are described in the literature or else can be prepared according to methods which are
described therein or which are known to a person skilled in the art.
The pure enantiomers of the compounds in accordance with the invention can be
obtained from enantiomerically pure precursors or else by chiral phase chromatography
or else, when the compounds comprise acid or amine functional groups, by selective
crystallizations of diastereoisomeric salts obtained by reaction of the compounds (I) with
chiral amines or chiral acids respectively.
The compounds of general formula (I) can be obtained according to the following
Schemes 1 to 4. Out of concern for clarity, the group R4 has been chosen as being a
hydrogen, p and p' represent 1 and 2 respectively and the R2 and R3 groups have been
set as indicated in the schemes. However, it is to be understood that R4 can be as
defined in the general formula (I), and R2 and R3 can have the positions indicated in the
general formula (I) and that p and p' can be as defined in the general formula (I).
The synthetic routes described below serve solely as illustration and are under no
circumstances limiting. A person skilled in the art can apply without difficulty the teaching
below to the compounds of formula (I) for which R, R-i, R2, R3, R4, Ra, Rb, Re, m, n, p, p'
and q are as defined in the general formula (I).
According to Scheme 1, the compound of formula (IV) is obtained by a reductive

amination reaction by reacting a compound of formula (II), in which R' represents a
(C1-C6) alkyl group and R2 is as defined for the compound of formula (I) with a compound
of formula (III) in an acid medium and in the presence of a reducing agent, such as
sodium triacetoxyborohydride. The PG group of the compound of formula (III) is a
protective group for the amine functional group which may advantageously be tert-
butoxycarbonyl (boc). The compound of formula (IV) thus formed is subsequently
acylated, according to methods well known to a person skilled in the art, with an alkyl or
aryl chloroformate to give the compound of formula (V) in which R" represents a (C1-C6)
alkyl group or an aryl group which is substituted. A hydrolysis reaction in a basic medium
makes it possible to obtain the compounds of formula (VI) which, by a coupling reaction
with a compound of formula (VII), in which R3 is as defined for the compound of formula
(I), results in the compounds of formula (VIII). An intramolecular cyclization reaction in
the basic medium makes it possible to obtain the quinazolinedione derivatives of formula
(IX). The protective group PG for the amine functional group is subsequently cleaved, for
example in acid medium when PG is a boc, to give the compounds of formula (la) which
give, by an acylation reaction, the compounds of formula (lb).
The compounds of formula (la) are compounds of formula (I) and can act as
intermediate for other compounds of formula (I), such as the compounds of formula (lb).


The compounds of formula (I) for which R2 represents -ORa, Ra being as defined
for the compound of formula (I), correspond to the formula (Id). They can be obtained
from the compounds of formula (X) according to the following Scheme 2. The
compounds of formula (Ic), obtained by a hydrogenolysis reaction on the compounds of
formula (X), are subjected, for example, to an alkylation reaction with an alkylating agent
of type Ra-X, in which Ra is as defined for the compound of formula (I) and X represents
a leaving group (such as a halogen atom, for example), in the presence of a base, such
as caesium carbonate (Cs2C03), or also to a Mitsunobu reaction (Synthesis, 1981, 1)
with an alcohol of type Ra-OH, Ra being as defined for the compound of formula (I), to
give compounds of formula (Id).
The compounds of formula (X) and the compounds of formula (Ic) are compounds
of formula (I) and can act as intermediate for other compounds of formula (I), such as the
compounds of formula (Id).


Alternatively, the compounds of formula (Id) can be obtained by following the
procedure described in Scheme 3.
The compounds of formula (XII) are obtained by a nucleophilic aromatic
substitution reaction involving a compound of formula (XI), in which R' is as defined
above, and an alcohol of type Ra-OH, in which Ra is as defined for the compound of
formula (I), in the presence of a base. The reduction of the nitro group of the compounds
of formula (XII) results in the corresponding anilino derivatives (XIII). A reductive
amination reaction with a compound of formula (III), in which PG is a protective group for
amine functional groups, such as, for example, boc, results in the compounds of formula
(XIV). The compounds of formula (XV) are obtained by reaction of a compound of
formula (XIV) with potassium isocyanate (KNCO) in an acid medium. An intramolecular
cyclization reaction in a basic medium makes it possible to obtain the compounds of
formula (XVI). The protective group PG is cleaved by methods well known to a person
skilled in the art to give the compounds of formula (XVII). An acylation reaction results in
the compounds of formula (XVIII). Finally, the compounds of formula (Id) are obtained
either by an alkyiation reaction with a derivative of type (XIX), in which X represents a
leaving group, such as a halogen atom, in the presence of a base, such as, for example,

caesium carbonate, or also by a Mitsunobu reaction with a benzyl alcohol of type (XX). In
the compounds (XIX) and (XX), R3 is as defined above.

The compounds of formula (le) and (If), in which R2 more particularly represents a
group of type-CH2-NHC(O)Rb, Rb being defined as in the compound of formula (I), can
be prepared according to the following Scheme 4.
It is understood that, in Scheme 3, the R2 group illustrated is of -O-Ra type and is

in the 6 position of the quinoazolinedione structure (see, for example, compound (XVIII))
but that it is also possible to have a second R2 group, as defined in the general formula
(I), in the 7 position of the same quinazolinedione group.
The reduction of the nitro group of the compounds of type (XXI), in which R' and
PC are as defined above, the PC group advantageously being boc, results in the
corresponding anilino derivatives (XXII) which, by a reductive amination reaction in which
they react in an acid medium and advantageously in the presence of a reducing agent,
such as sodium triacetoxyborohydride, with a compound of formula (III), in which PG
represents a benzyloxycarbonyl protective group for amines, give compounds of formula
(XXIII). An acylation reaction with an alkyl or aryl chloroformate, in which R" represents a
(C1-C6) alkyl group or an aryl group which is substituted, results in the compounds of
formula (XXIV). The quinazolinedione analogues of formula (XXV) can be obtained by a
hydrolysis reaction in a basic medium and then by a coupling reaction with a compound
of formula (VII), in which R3 is as defined for the compound of formula (I), followed by an
intramolecular cyclization reaction in a basic medium. The PG' group (preferably a boc) is
subsequently cleaved in an acid medium to result in the compounds of formula (XXVI)
which, by acylation, give compounds of formula (XXVII), in which Rb is as defined for the
compound of formula (I). The PG protective group of (XXVII) is cleaved by a
hydrogenolysis reaction to give the compounds of formula (le). Finally, the compounds of
formula (If) are obtained by an acylation reaction on the compounds of formula (le).


It is obvious that a person skilled in the art will be in a position to choose, in the
light of his knowledge and the literature, other appropriate protective groups which make
possible the introduction of all the groups described in the general formula (I).
When the compound of formula (I) comprises a bridged ring, it can be obtained
without distinction by one of the synthetic routes described above.
The following procedures and examples describe the preparation of some

compounds in accordance with the invention. These procedures and examples are not
limiting and serve only to illustrate the present invention.
In the procedures and examples below:
- the mass spectra are produced on a quadrupole spectrometer of Platform LCZ
type (Waters) or of ZQ 4000 type (Waters) in positive electrospray ionization mode;
- the NMR (nuclear magnetic resonance) spectra are produced on a Fourier
transform spectrometer (Bruker) at a temperature of 300°C (exchangeable protons not
recorded);
- s = singlet,
- d = doublet,
- m = multiplet,

- br = broad signal
-1 = triplet,
- q = quartet
- DMSO-d6 = deuterated dimethyl sulphoxide,
- CDCb = deuterated chloroform.
The mixtures of solvents are quantified in volumetric ratios.
The NMR spectra and mass spectra confirm the structures of the compounds
obtained according to the examples below.
In the examples which follow, the following abbreviations are used:
ACN: acetonitrile
AcOEt: ethyl acetate
AcOH: acetic acid
DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene
DCM: dichloromethane
DCE: 1,2-dichloroethane
DIAD: diisopropyl azodicarboxylate
DIEA: diisopropylamine
DMF: N,N-dimethylformamide
EtOH: ethanol
HBTU: 0-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
IBCF: isobutyl chloroformate
MeOH: methanol
NaBH(OAc)3: sodium triacetoxyborohydride
AT: ambient temperature

min: minute
THF: tetrahydrofuran
NEt3: triethylamine
TFA: trifluoroacetic acid
EXAMPLES
The following examples describe the preparation of some compounds in accordance with
the invention. These examples are not limiting and serve only to illustrate the present
invention. The numbers of the compounds in the examples refer to those given in the
table below, in which the chemical structures and the physical properties of a few
compounds in accordance with the invention are illustrated.
EXAMPLE 1: Compound No.°6
Preparation of {[3-(3,4-dimethoxybenzyl)-1-(1-formylpiperidin-4-yl)-2,4-dioxo-
1,2,3,4-tetrahydroquinazolin-6-yl]oxy}acetonitriIe

Stage 1.1:
1,1 -Dimethylethyl 4-{[4-(benzyloxy)-2-(methoxycarbonyl)phenyl]ami-
no}piperidine-1-carboxylate


A mixture of 2g of methyl 2-amino-5-(benzyloxy)benzoate, 3.1 g of
1,1-dimethylethyl 4-oxopiperidine-1-carboxylate and 3.29 g of NaBH(OAc)3 in 10 ml of
AcOH is irradiated under a microwave field (Biotage Initiator Sixty) at 110°C for 20 min.
The same reaction is repeated with two other lots of 2 g of methyl 2-amino-5-
(benzyloxy)benzoate. The three reaction media are combined. The combined product is
taken up in AcOEt. The organic phase is washed with water, with a saturated NH4CI
solution and with a saturated NaHC03 solution, dried over Na2S04 and filtered, and the
solvent is evaporated under reduced pressure. The residue is chromatographed on silica
gel, elution being carried out with an AcOEt/heptane mixture, (5/95, v/v) as far as (30/70,
v/v), to give 10.2 g of the expected product.
Stage 1.2:
1,1-Dimethylethyl 4-{[4-(benzyloxy)-2-(methoxycarbonyl)phenyl][(2-methyl-
propoxy)carbonyl]amino}piperidine-1-carboxylate

A mixture of 2g of 1,1-dimethylethyl 4-{[4-(benzyloxy)-2-
(methoxycarbonyl)phenyl]amino}piperidine-1-carboxylate obtained in stage 1.1, 0.87 ml
of DIEA, 1.78 ml of IBCF and 1 g of NaOH in 10 ml of DCE is irradiated under a
microwave field at 80°C for 30 min. The same reaction is repeated with 4 other lots of 2 g
of 1,1-dimethylethyl 4-{[4-(benzyloxy)-2-(methoxycarbonyl)phenyl]amino}piperidine-1-
carboxylate. The 5 reaction media are combined. The combined product is taken up in
AcOEt and filtered, and the filtrate is evaporated under reduced pressure. The residue is
chromatographed on silica gel, elution being carried out with an AcOEt/heptane mixture,
(10/90, v/v) as far as (50/50, v/v), to give 9.3 g of the expected product.
Stage 1.3:
Sodium salt of 5-(benzyloxy)-2-({1-[(1,1-dimethylethoxy)carbonyl]-piperidin-

4-yl}[(2-methylpropoxy)carbonyl]amino)benzoicacid

A mixture of 9.3 g of 1,1-dimethylethyl 4-{[4-(benzyloxy)-2-
(methoxycarbonyl)phenyl][(2-methylpropoxy)carbonyl]amino}piperidine-1-carboxylate
obtained in stage 1.2 and 34.4 ml of 2N NaOH in 57 ml of MeOH is heated at 100°C for
3h 00. The solution is evaporated under reduced pressure and DCM is added. Drying is
carried out over Na2S04> filtration is carried out and the solvent is evaporated under
reduced pressure to give 8.7 g of the expected product.
Stage 1.4:
1,1-Dimethylethyl 4-[{4-(benzyloxy)-2-[(3,4-dimethoxybenzyl)carbamoyl]phe-
nyl}(isobutoxycarbonyl)amino]piperidine-1-carboxylate

A mixture of 6g of sodium salt of 5-(benzyloxy)-2-({1-[(1,1-
dimethylethoxy)carbonyl]piperidin-4-yl}[(2-methylpropoxy)carbonyl]amino)benzoic acid
obtained in stage 1.3 and 4.42 g of DIEA in 250 ml of DMF is stirred at AT for 15 min.
6.48 g of HBTU are added and the mixture is left stirring for 30 min. 2.48 g of
veratrylamine are added and the reaction mixture is stirred for 48h 00. It is evaporated
under reduced pressure, the residue is taken up in AcOEt, washed with a saturated

NH4CI solution and with a saturated NaHC03 solution, dried over Na2S04 and filtered,
and the solvent is evaporated under reduced pressure. The residue is chromatographed
on silica gel, elution being carried out with an AcOEt/heptane mixture, (20/80, v/v) as far
as (60/40, v/v), to give 7.5 g of expected product.
Stage 1.5:
1,1-Dimethylethyl 4-[6-(benzyloxy)-3-(3,4-dimethoxybenzyl)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]piperidine-1-carboxylate

A mixture of 2.5 g of 1,1-dimethylethyl 4-[{4-(benzyloxy)-2-[(3,4-
dimethoxybenzyl)carbamoyl]phenyl}(isobutoxycarbonyl)amino]piperidine-1-carboxylate
obtained in stage 1.4 and 7.4 g of NaOH in 18.5 ml of DCE is irradiated under a
microwave field at 110°C for 30 min. The same reaction is repeated with 2 other lots of
2.5 g of 1,1-dimethylethyl 4-[{4-(benzyloxy)-2-[(3,4-dimethoxybenzyl)carbamoyl]phenyl}-
(isobutoxycarbonyl)amino]piperidine-1-carboxylate. The 3 reaction media are combined.
The combined product is taken up in DCM, washed with water, dried over Na2S04 and
filtered, and the solvent is evaporated under reduced pressure to give 6.6 g of expected
product.
Stage 1.6:
6-(Benzyloxy)-3-(3,4-dimethoxybenzyl)-1-(piperidin-4-yl)quinazoline-
2,4(1 H,3H)-dione


A mixture of 3.5 g of 1,1-dimethylethyl 4-[6-(benzyloxy)-3-(3,4-dimethoxybenzyl)-
2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidin6-1-carboxylate obtained in stage 1.5
and 25 ml of TFA in 50 ml of DCM is stirred at AT for 2h 00. The mixture is neutralized
with K2C03. It is filtered and the filtrate is evaporated under reduced pressure. The
residue is taken up in DCM and washed with a saturated NaHC03 solution and then with
an 8% NaOH solution. The solution is dried over Na2S04 and filtered, and the solvent is
evaporated under reduced pressure to give 2.67 g of the expected product.
Stage 1.7:
4-[6-(Benzyloxy)-3-(3,4-dimethoxybenzyl)-2,4-dioxo-3,4-dihydroquinazolin-
1(2H)-yl]piperidine-1-carbaldehyde

A mixture of 0.6 g of 6-(benzyloxy)-3-(3,4-dimethoxybenzyl)-1-(piperidin-4-
yl)quinazoline-2,4(1H,3H)-dione obtained in stage 1.7 and 0.113 g of ammonium formate
in 5 ml of ACN is irradiated under a microwave field at 140°C for 1h 00. The mixture is
filtered and the filtrate is evaporated under reduced pressure to give 0.62 g of the
expected product.
Stage 1.8: Compound No. 5:
4-[3-(3,4-Dimethoxybenzyl)-6-hydroxy-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-

yl]piperidine-1-carbaldehyde

A mixture of 0.618 g of 4-[6-(benzyloxy)-3-(3,4-dimethoxybenzyl)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehycle obtained in stage 1.7, 0.44 g of
ammonium formate and 0.124 g of Pd/C (10%) in 10 ml of EtOH purged beforehand with
nitrogen is irradiated under a microwave field at 80°C for 2h 00. The mixture is filtered
and the filtrate is evaporated under reduced pressure to give 0.513 g of the expected
product.
Stage 1.9: Compound No. 6
{[3-(3,4-Dimethoxybenzyl)-1-(1-formylpiperidin-4-yl)-2,4-dioxo-1,2,3,4-
tetrahydroquinazolin-6-yl]oxy}acetonitrile

0.17 g of 4-[3-(3,4-dimethoxybenzyl)-6-hydroxy-2,4-dioxo-3,4-dihydroquinazolin-
1(2H)-yl]piperidine-1-carbaldehyde obtained in stage 1.8 and 0.25 g of Cs2C03 in 3 ml of
DMF are stirred for 15 min at AT. 0.056 g of bromoacetonitrile is added and the reaction
mixture is subsequently irradiated under a microwave field at 100°C for 15 min. It is
filtered and evaporated under reduced pressure. The residue is chromatographed on
silica gel, elution being carried out with an MeOH/DCM mixture, (1/99, v/v) as far as
(4/96, v/v), to give 0.112 g of the expected product.

EXAMPLE 2: Compound No. 3
Preparation of {[1-(1-acetylpiperidin-4-yl)-3-(3,4-dimethoxybenzyl)-2,4-dioxo-
1,2,3,4-tetrahydroquinazolin-6-yl]oxy}acetonitrile

Stage 2.1:
1-(1-Acetylpiperidin-4-yl)-6-(benzyloxy)-3-(3,4-dimethoxybenzyl)quinazoline-
2,4(1 H,3tf)-dione

0.14 g of acetyl chloride is added to a mixture of 0.6 g of 6-(benzyloxy)-3-(3,4-
dimethoxybenzyl)-1-(piperidin-4-yl)quinazoline-2l4(1H,3H)-dione obtained according to
stage 1.6 and 0.24 g of NEt3 in 10 ml of DCM cooled to 0°C. The mixture is stirred at AT
overnight. It is washed twice with a saturated NH4CI solution and filtered, and then the
filtrate is evaporated under reduced pressure to give 0.64 g of the expected product.
Stage 2.2: Compound No. 2
1-(1-Acetylpiperidin-4-yl)-3-(3,4-dimethoxybenzyl)-6-hydroxyquinazoline-
2,4(1 H,3H)-dione


A mixture of 0.64 g of 1-(1-acetylpiperidin-4-yl)-6-(benzyloxy)-3-(3,4-
dimethoxybenzyl)quinazoline-2,4(1/-/,3/-/)-dione obtained in stage 2.1, 0.44 g of
ammonium formate and 0.125 g of Pd/C (10%) in 10 ml of EtOH purged beforehand with
nitrogen is irradiated under a microwave field at 80°C for 2h 00. The mixture is filtered
and the filtrate is evaporated under reduced pressure to give 0.48 g of the expected
product.
Stage 2.3: Compound No. 3
{[1-(1-Acetylpiperidin-4-yl)-3-(3,4-dimethoxybenzyl)-2,4-dioxo-1,2,3,4-
tetrahydroquinazolin-6-yl]oxy}acetonitrile

0.12 g of 1-(1-acetylpiperidin-4-yl)-3-(3,4-dimethoxybenzyl)-6-hydroxyquinazoline-
2,4(1 H,3H)-dione obtained in stage 2.2 and 0.172 g of Cs2C03 in 3 ml of DMF are stirred
for 15min at AT. 0.038 g of bromoacetonitrile is added and the reaction mixture is
subsequently irradiated under a microwave field at 100°C for 15 min. It is filtered and the
filtrate is evaporated under reduced pressure. The residue is chromatographed on silica
gel, eiution being carried out with an MeOH/DCM mixture, (1/99, v/v) as far as (4/96, v/v),
to give 0.094 g of the expected product.
EXAMPLE 3: Compound No. 34

Synthesis of 4-[3-(4-chlorobenzyl)-6-(2,2-difluoroethoxy)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde

Stage 3.1:
Methyl 5-(2,2-difluoroethoxy)-2-nitrobenzoate

8.53 g of 2,2-difluoroethanol are added to a solution of 17.31 g of methyl 5-fluoro-
2-nitrobenzoate, 9.64 g of NEt3 and 32.71 g of 2,8,9-triisobutyl-2,5,8,9-tetra3Z3-1-
phosphabicyclo[3.3.3]undecane in 250 ml of anhydrous THF. The mixture is stirred at AT
for 30 min. The solvent is evaporated under reduced pressure. Water is added and
extraction is carried out with AcOEt. The extract is washed with a 1N aqueous HCI
solution, with water snd then with a saturated NaCI solution. It is dried over MgS04 and
filtered, and the solvent is evaporated under reduced pressure to give 21 g of the
expected product.
Stage 3.2:
Methyl 2-amino-5-(2,2-difluoroethoxy)benzoate
/VNH2
F O
21 g of methyl 5-(2,2-difluoroethoxy)-2-nitrobenzoate obtsined in stage 3.1 and
1 g of Pd/C (10%) in a mixture of 300 ml of AcOEt, 50 ml of EtOH and 5 ml of AcOH are
stirred at AT under a hydrogen atmosphere for 24h 00.
The mixture is filtered and evaporated under reduced pressure to give 18.6 g of
the expected product.

Stage 3.3:
1,1-Dimethylethyl 4-{[4-(2,2-difluoroethoxy)-2-(methoxycarbonyl)phenyl]ami-
no}piperidine-1 -carboxylate

A mixture of 4 g of methyl 2-amino-5-(2,2-difluoroethoxy)benzoate and 6.88 g of
1,1-dimethylethyl 4-oxopiperidine-1-carboxylate obtained in stage 3.2 in 15 ml of AcOH is
heated at 90°C for 10min. It is allowed to cool to AT and 7.3 g of NaBH(OAc)3 are
added. The mixture is left stirring at AT for 12h 00. It is extracted with AcOEt and the
extract is washed with a saturated K2C03 solution and then with water. It is dried over
MgS04, filtered and evaporated under reduced pressure to give 6.63 g of the expected
product.
Stage 3.4:
1,1-Dimethylethyl 4-{carbamoyl[4-(2,2-difluoroethoxy)-2-(methoxycarbonyl)-
phenyl]amino}piperidine-1-carboxylate

1.95 g of potassium isocyanate in solution of 4 ml of water are added to a solution
of 6.63 g of 1,1-dimethyiethyl 4-{[4-(2,2-difluoroethoxy)-2-(methoxycarbonyl)phenyl]
amino}piperidine-1-carboxylate obtained in stage 3.3 in 40 ml of AcOH. The mixture is

stirred at AT for 12h 00. It is extracted with AcOEt and the extract is washed with a
saturated K2C03 solution and then with water. It is dried over MgS04l filtered and
evaporated under reduced pressure to give 6.95 g of the expected product.
Stage 3.5:
1,1-Dimethylethyl 4-[6-(2,2-difluoroethoxy)-2,4-dioxo-3,4-dihydroquinazolin-
1 (2H)-yt]piperidine-1-carboxylate

2.5 g of 1,1-dimethylethyl 4-{carbamoyl[4-(2,2-difluoroethoxy)-2-(methoxy-
carbonyl)phenyl]amino}piperidine-1-carboxylate obtained in stage 3.4 in solution in a
mixture of 10 ml of dioxane and 5 ml of a 1N aqueous NaOH solution are irradiated
under a microwave field at 130°C for 30 min. Extraction is carried out with AcOEt and the
extract is neutralized with a 1N aqueous HCI solution, washed with water, dried over
MgS04) filtered and evaporated under reduced pressure. The residue obtained is
triturated in an AcOEt/pentane mixture to give the expected product. The same reaction
is reproduced with 2 other lots of 2.5 g of 1,1-dimethylethyl 4-{carbamoyl[4-(2,2-
difluoroethoxy)-2-(methoxycarbonyl)phenyl]amino}piperidine-1 -carboxylate obtained in
stage 3.4 to give, in total, 5.63 g of expected product.
Stage 3.6:
6-(2,2-DifIuoroethoxy)-1-(piperidin-4-yl)quinazoline-2,4(1H,3H)-dione


A solution of 5.63 g of 1,1-dimethylethyl 4-[6-(2,2-difluoroethoxy)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]piperidine-1-carboxylate obtained in stage 3.5 in 70 ml of
formic acid is stirred at AT for 2h 00. The solvent is evaporated under reduced pressure
to give 6.13 g of the expected product in the form of the formic acid salt.
Stage 3.7:
4-[6-(2,2-Difluoroethoxy)-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-
yl]piperidine-1 -carbaldehyde

A mixture of 6.13 g of 6-(2,2-difluoroethoxy)-1-(piperidin-4-yl)quinazoline-
2,4(1 H,3H)-dione obtained in stage 3.6 and 3.12 g of ammonium formate in 28 ml of
ACN and 28 ml of dioxane is irradiated under a microwave field at 140°C for 1h 00. The
reaction mixture is run into water. The mixture is filtered and the precipitate is washed
with water and then with ether to give 4.47 g of the expected product.
Stage 3.8: Compound No. 34
4-[3-(4-Chlorobenzyl)-6-(2,2-difluoroethoxy)-2,4-dioxo-3,4-dihydroquinazolin-
1 (2W)-yl]piperidine-1 -carbaldehyde


A mixture of 0.15 g of 4-[6-(2,2-difluoroethoxy)-2,4-dioxo-3,4-dihydroquinazolin-
1(2W)-yl]piperidine-1-carbaldehyde obtained in stage 3.7, 0.096 g of 1-(bromomethyl)-4-
chlorobenzene and 0.3 g of Cs2C03 in 3 ml of DMF is stirred at AT for 1h 00. AcOEt is
added and washing is carried out with water and then with a saturated NaCI solution. The
organic phase is dried over MgS04> filtered and evaporated under reduced pressure. The
residue is chromatographed on silica gel, elution being carried out with AcOEt, to give
0.116 g of the expected product.
EXAMPLE 4: Compound No. 49
Synthesis of 4-{3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(2,2-difluoro-
ethoxy)-2,4-dioxo-3,4-dihydroquinazolin-1(2W)-yl}piperidine-1-carbaldehyde

0.172 g of DIAD is added to a solution of 0.15 g of 4-[6-(2,2-difluoroethoxy)-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde obtained in stage 3.7,
0.142 g of [4-(cyclopentyloxy)-3-methoxyphenyl]methanol and 0.223 g of PPh3 in 3 ml of
anhydrous THF. The mixture is stirred at AT for 12h 00 and then at 60°C for 1h 00. It is
evaporated under reduced pressure and the residue is purified on silica gel, elution being
carried out with AcOEt, to give 0.083 g of the expected product.
EXAMPLE 5: Compound No. 20
Synthesis of /V-{[3-(3,4-dimethoxybenzyl)-1-(1-formylpiperidin-4-yl)-2,4-
dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]methyl}acetamide


Stage 5.1:
Methyl 2-amino-5-({[(1,1-dimethylethoxy)carbonyl]amino}methyl)benzoate

A mixture of 0.273 g of methyl 5-{[(tert-butoxycarbonyl)amino]methyl}-2-
nitrobenzoate, 0.166 g of ammonium formate and 0.094 g of Pd/C (10%) in 10 ml of
EtOH purged beforehand with nitrogen is irradiated under a microwave field at 120°C for
5 min. The mixture is filtered and the filtrate is evaporated under reduced pressure. The
residue is chromatographed on silica gel, elution being carried out with an
AcOEt/heptane mixture, (5/95, v/v) as far as (30/70, v/v), to give 0.2 g of the expected
product.
Stage 5.2:
Benzyl 4-{[4-({[(1,1-dimethylethoxy)carbonyl]amino}methyl)-2-(methoxy-
carbonyl)phenyl]amino}piperidine-1-carboxylate


A solution of 1.66 g of benzyl 4-oxopiperidine-1-carboxylate and 1 g of methyl
2-amino-5-({[(1,1-dimethylethoxy)carbonyl]amino}methyl)benzoate obtained in stage 5.1
in 20 ml of DCM is added dropwise at AT to a suspension of 2.04 g of NaBH(OAc)3 in a
mixture of 20 ml of DCM and 0.41 ml of AcOH. The mixture is stirred at AT for 15h 00
and then a further 2.04 g of NaBH(OAc)3 are added. After stirring for 6h 00, 1.66 g of
benzyl 4-oxopiperidine-1-carboxylate are added and the mixture is stirred at AT for
48h 00. A saturated NaHC03 solution is added and extraction is carried out with DCM.
The organic phase is washed with a saturated NaHC03 solution and twice with a
saturated NH4CI solution. It is dried over Na2S04 and filtered, and the filtrate is
evaporated under reduced pressure. The residue is chromatographed on silica gel,
elution being carried out with an AcOEt/heptane mixture, (5/95, v/v) as far as (40/60, v/v),
to give 1.6 g of the expected product.
Stage 5.3:
Benzyl 4-{[4-({[(1,1-dimethylethoxy)carbonyl]amino}methyl)-2-
(methoxycarbonyl)phenyl](ethoxycarbonyl)amino}piperidine-1-carboxylate

2.08 g of DIEA and then 1.745 g of ethyl chloroformate are added to a solution of
1.6 g of benzyl 4-{[4-({[(1,1-dimethylethoxy)carbonyl]amino}methyl)-2-(methoxy-
carbonyl)phenyl]amino}piperidine-1-carboxylate obtained in stage 5.2 in 11 ml of DCM.
The mixture is stirred at AT for 4 days. It is evaporated under reduced pressure. The
residue is taken up in 10 ml of pyridine (10 ml) and 0.7 g of ethyl chloroformate is added.
The mixture is stirred at AT for 4h 00. It is evaporated under reduced pressure. The
residue is chromatographed on silica gel, elution being carried out with an
AcOEt/heptane mixture, (10/90, v/v) as far as (30/70, v/v), to give 0.875 g of the
expected product.

Stage 5.4:
Benzyl 4-[3-(3,4-dimethoxybenzyl)-6-({[(1,1-dimethylethoxy)carbonyl]amino}-
methyl)-2,4-dioxo-3,4-dihydroquinazolin-1(2W)-yl]piperidine-1-carboxylate

A mixture of 0.165 g of benzyl 4-{[4-({[(1,1-dimethylethoxy) carbonyl]amino}-
methyl)-2-(methoxycarbonyl)phenyl](ethoxycarbonyl)amino}piperidine-1-carboxylate
obtained in stage 5.3 and 0.028 g of LiOH in 5 ml of THF/H20 (70/30) is stirred at AT for
15h00. The mixture is subsequently irradiated under a microwave field at 100°C for
1 h 00. It is filtered and the filtrate is evaporated under reduced pressure. The residue is
taken up in 5 ml of DMF. 0.108 g of DIEA is added and the mixture is stirred at AT for
10 min. 0.159 g of HBTU is added and the mixture is stirred at AT for 30 min. 0.061 g of
veratrylamine is subsequently added and the mixture is stirred at AT for 1 h 00. 0.5 ml of
DBU is added and the mixture is stirred at AT for 48h 00. It is evaporated under reduced
pressure and the residue is taken up in AcOEt. The solution is washed 3 times with a
saturated NH4CI solution and twice with water. It is dried over Na2S04 and filtered, and
the filtrate is evaporated under reduced pressure. The residue is chromatographed on
silica gel, elution being carried out with an AcOEt/DCM mixture, (10/90, v/v) as far as
(20/80, v/v), to give 0.104 g of the expected product.
Stage 5.5:
Benzyl 4-[6-(aminomethyl)-3-(3,4-dimethoxybenzyl)-2,4-dioxo-3,4-dihydro-
quinazolin-1(2H)-yl]piperidine-1-carboxylate


A solution of 0.102 g of benzyl 4-[3-(3,4-dimethoxybenzyl)-6-({[(1,1-
dimethylethoxy)carbonyl]amino}methyl)-2,4-dioxo-3,4-dihydroquinazoiin-1(2/7)-
yl]piperidine-1-carboxylate obtained in stage 5.4 and 0.5 ml of TFA in 9.5 ml of DCM is
stirred at AT for 2h 00. A saturated NaHC03 solution is added. The organic phase is
dried over Na2S04 and filtered, and the filtrate is evaporated under reduced pressure to
give 0.09 g of the expected product.
Stage 5.6:
Benzyl 4-{6-[(acetylamino)methyl]-3-(3,4-dimethoxybenzyl)-2,4-dioxo-3,4-di-
hydroquinazolin-1(2H)-yl}piperidine-1-carboxylate

0.049 g of acetic anhydride is added to a solution of 0.09 g of benzyl 4-[6-
(aminomethyl)-3-(3,4-dimethoxybenzyl)-2,4-dioxo-3,4-dihydroquinazolin-1(2/-/)-
yl]piperidine-1-carboxylate obtained in stage 5.5 and 0.09 ml of NEt3 in 3 ml of DCM and
the mixture is stirred at AT for 1h 00. DCM is added and the solution is washed with a
saturated NH4CI solution, then with a 1N HCI solution, then with a 2N NaOH solution and
then with water. The organic phase is dried over Na2S04 and filtered, and the filtrate is
evaporated under reduced pressure to give 0.104 g of the expected product.

Stage 5.7:
/V-{[3-(3,4-Dimethoxybenzyl)-2,4-dioxo-1-(piperidin-4-yl)-1,2,3,4-tetrahydro-
quinazolin-6-yl]methyl}acetamide

A mixture of 0.1 g of benzyl 4-{6-[(acetylamino)methyr]-3-(3,4-dimethoxybenzyl)-
2,4-dioxo-3,4-dihydroquinazolin-1(2/V)-yl}piperidine-1-carboxylate obtained in stage 5.6,
0.016 g of ammonium formate and 0.018 g of Pd/C (10%) in 2 ml of EtOH purged
beforehand with nitrogen is irradiated under a microwave field at 80°C for 30 min. The
mixture is filtered and the filtrate is evaporated under reduced pressure to give 0.077 g of
the expected product.
Stage 5.8: Compound No. 20
/V-{[3-(3>4-Dimethoxybenzyl)-1-(1-formylpiperidin-4-yl)-2,4-dioxo-1,2,3,4-
tetrahydroquinazolin-6-yl]methyl}acetamide

A mixture of 0.070 g of /V-{[3-(3,4-dimethoxybenzyl)-2,4-dioxo-1-(piperidin-4-yl)-
1,2,3,4-tetrahydroquinazolin-6-yl]methyl}acetamide obtained in stage 5.7 and 0.028 g of
ammonium formate in 2 ml of ACN is irradiated under a microwave field at 140°C for
1h 00. The mixture is filtered and the filtrate is evaporated under reduced pressure. The
residue is chromatographed on silica gel, elution being carried out with an MeOH/DCM
mixture, (0.5/99.5, v/v) as far as (7/93, v/v), to give 0.035 g of the expected product.

The chemical structures and the physical properties of compounds corresponding to the
general formula (I) according to the invention, and also of some of their intermediates (in
particular compounds 32, 55, 120 and 257), are illustrated in the following table.

The compounds in accordance with the invention form the subject of
pharmacological trials which have shown their advantage as therapeutically active
substances.
1) Measurement of the inhibitory activity of the compounds in accordance with
the invention with regard to PDE7
The ability of the compounds of formula (I) to inhibit PDE7 is measured using an
enzymatic assay based on the separation of radioactive cAMP (substrate of PDE7) from
the radioactive 5'-AMP (product of the enzymatic reaction) by thin layer chromatography
on polyethyleneimine (PEI) cellulose, after halting the enzymatic reaction. The 5'-AMP is
extracted quantitatively from the PEI cellulose and its radioactivity is measured using a
liquid scintillation counter.
The inhibitory activity of the compounds of formula (I) with regard to PDE7 is
represented by the inhibition constant IC50) defined as the concentration of the compound
(inhibitor) tested in the assay which makes it possible to reduce the enzymatic activity of
PDE7 by 50%. The lower the ICso values, the greater the inhibitory power of the
compounds.
Materials
The [3H]-cAMP (NET 275; 25 to 40 Ci/mmol) was purchased from Perkin-Elmer
(NEN Life Sciences, Boston, United States), the rolipram was purchased from Sigma (St
Louis, Mo, United States) and the sheets of polyethyleneimine cellulose F made of plastic
for thin layer chromatography were purchased from Merck (Darmstadt, Germany). All the
other products used are of commercial origin.
Enzyme
Human PDE7 was partially purified from the HUT-78 cell line by following a
method analogous to that described by Bloom and Beavo (Proc. Natl. Acad. Sci. USA,
(1996) 93, 14188-14192). The enzyme preparation obtained is stored at -80°C in a buffer
comprising 20 mM of Tris-HCI (pH 7.0), 5 mM of MgCI2, 4mM of EDTA, 1 mM of
dithiothreitol and 20% of glycerol. As the partially purified PDE7 is contaminated by
PDE4, it is necessary to add 10 uM of rolipram (selective inhibitor of PDE4) in the
enzymatic assay in order to completely inhibit the PDE4 activity. The Michaelis constant
(Km) of PDE7 for cAMP, measured using the radiochemical assay described below, is
21 nM.
Solutions of compounds in accordance with the invention
The compounds of formula (I) to be tested as PDE7 inhibitors are dissolved in

DMSO at a concentration of 10 mM. These solutions are subsequently diluted in cascade
in DMSO in order to obtain solutions with the desired concentrations. The latter are
subsequently diluted to one-twentieth in the assay buffer to give 5% DMSO solutions.
The latter are finally diluted to one-fifth in the enzymatic assay.
The solution of rolipram (added in the assay in order to completely inhibit the
contaminating PDE4 activity) is prepared in an identical way and contributes 1% of
DMSO to the enzymatic assay.
PDE7 Enzymatic assay
The assay is carried out in 1.5 ml Eppendorf tubes comprising 40 mM of Tris-HCI
(pH 7.5), 15 mM of MgCI2, 1 mM of EGTA, 0.5 mg/ml of bovine serum albumin, 0.063
uCi of [3H]-cAMP (corresponding to a cAMP concentration of between 15 and 25 nM),
10 uM of rolipram and PDE7 in a final volume of 100 ul. The assay is carried out in the
absence (control sample) or in the presence (treated sample) of the compounds tested
as PDE7 inhibitors. The final concentration of DMSO in the assay is 2%. The reaction is
initiated by addition of enzyme and the samples are maintained at ambient temperature
for 30 minutes. The enzymatic dilution is adjusted so as to obtain a degree of conversion
of 10 to 15%. The enzymatic reaction is halted by immersion of the stoppered Eppendorf
tubes in a water bath at 100°C for 3 minutes. Blanks (reaction halted immediately after
addition of the enzyme) are included in each experiment. The samples are subsequently
centrifuged at 10 000xg for 1 minute and an aliquot portion of 10 ul of supernatant is
deposited 2 cm from the bottom edge of a sheet of PEI cellulose on which 10 ug of
cAMP and 10 ug of 5'-AMP have been deposited beforehand, in order to facilitate the
migration and to make it easier to cut out the strips of PEI cellulose comprising the
5'-AMP, which take place subsequently, 18 migration lanes with a width of 1 cm are
delimited per plate by scraping the cellulose with a spatula over a width of 1 mm. The
plates are developed over their entire length with a 0.30 M solution of LiCI in water by
ascending chromatography. The 5'-AMP (Rf = 0.20) and the cAMP (Rf = 0.47) are
visualized under UV light at 254 nm. The strips of PEI cellulose comprising the 5'-AMP
are cut out and the nucleotide is quantitatively extracted in counting flasks with 2 ml of a
solution which is 16M in formic acid and 2M in ammonium formate in water (rotary stirrer
for 15 min). After addition of 10 ml of scintillation liquid (OptiPhase HiSafe 3 from Perkin-
Elmer/Wallac), the radioactivity is counted using a liquid scintillation counter (model
1414, Perkin-Elmer/Wallac). Each assay is carried out in duplicate. The radioactivity
specifically associated with the 5'-AMP formed in the enzymatic reaction is obtained by
subtracting the mean value of blanks from the mean value of the controls (or treated
samples).

The percentage of inhibition of PDE7 at a given concentration of the compound
tested (inhibitor) is calculated using the equation: 1% = [mean value of the controls -
mean value of the treated samples] x 100/[mean value of the controls - mean value of
the blanks].
The IC50 is the concentration of the compound (inhibitor) tested in the assay which
makes it possible to reduce the enzymatic activity of PDE7 by 50%.
Results
As illustrative and nonlimiting examples, the following quinazolinediones inhibit PDE7
with the ICM values indicated below :
Compound IC50
(MM)
No. 16: 4-[6-(2,2-difluoroethoxy)-3-(3,4-dimethoxybenzyl)-2,4-dioxo-3,4- Q Q15
dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 11: 4-[3-(3,4-dimethoxybenzyl)-6-[2-fluoro-1 -(fluoromethyl)ethoxy]-2,4- 0.039
dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 72: 4-[3-(3,4-dimethoxybenzyl)-6-(2-hydroxyethoxy)-2,4-dioxo-3,4- 0.089
dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde
No. 77: N-{[3-(3,4-dimethoxybenzyl)-1-(1-formylpyrrolidin-3-yl)-2,4-dioxo- 0.82
1,2,3,4-tetrahydroquinazolin-6-yl]methyl}acetamide
No. 97: 4-[5,7-dichloro-3-(3,4-dimethoxybenzyl)-2,4-dioxo-3,4- 0.061
dihydroquinazolin-1 (2H)-yl]piperidine-1 -carbaldehyde
No. 111: 4-[6-(difluoromethoxy)-3-(3,4-dimethoxybenzyl)-2,4-dioxo-3,4- 0.0067
dihydroquinazolin-1 (2H)-yl]piperidine-1 -carbaldehyde
2) Measurement of the inhibitory activity of the compounds in accordance with
the invention with regard to PDE8
By using for PDE8 an enzymatic assay equivalent to that described for PDE7, the
following IC50 values are obtained :
Compound IC50 PDE7 (uM) IC50 PDE8 (uM)
No. 11 0.039 0.14
No. 251 0.046 0.39
No. 294 0.037 0.015

3) Evaluation of the compounds in accordance with the invention in an in
vitro model of microglial activation
The glial cells actively participate in the neurodegenerative mechanism by the
production of neurotoxic factors. The production of these mediators forms part of the
neuroinflammatory process observed in neurodegenerative diseases and in particular in
Parkinson's disease and Alzheimer's disease.
Numerous studies have demonstrated that the inhibition of glial activation and
consequently the reduction in the production of proinflammatory factors, such as
interleukin-1, released by activated glial cells significantly reduces neuronal
degeneration.
The compounds according to the invention have been evaluated in an in vitro
model of microglial activation. After activation by lipopolysaccharide (LPS), the microglial
cells secrete large amounts of interleukin-1, which amounts can be quantified by specific
assaying in the cell supernatants.
Cultures of microglial cells of the MG7 line derived from the mouse cortex are
incubated in the presence of variable concentrations of compounds according to the
invention. After incubating at 37°C for 1 hour, the cells are brought together with LPS,
which induces the production of interleukin-1. After treating for 24 h, the amounts of
interleukin-1 p are measured in the culture supernatants by ELISA assay.
Compound No. 297 significantly decreases, in a concentration-dependent fashion,
the secretion of interleukin-1 (3 by MG7 microglial cells activated by LPS. The maximum
inhibitory effect observed is 47% at 3 uM.
According to the invention, the compound of formula (I) defined above in
accordance with the invention can be used as medicament or in the preparation of a
medicament intended for the treatment and/or prevention of disorder(s) related to the
central nervous system and/or related to the peripheral nervous system.
According to the invention, the compound of formula (I) in accordance with the
invention can be used as medicament or in the preparation of a medicament intended for
the treatment and/or prevention of psychiatric disorders) and/or neurological disorder(s).
According to the invention, the compounds of formula (I) in accordance with the
invention can be used as medicaments or in the preparation of a medicament intended
for the treatment or prevention of psychiatric disorders chosen from anxiety, depression,
mood disorders, insomnia, delusion disorders, obsessive disorders, psychoses, disorders
related to schizophrenia, attention deficit hyperactivity disorders (ADHD) in hyperkinetic
children, disorders related to the use of psychotropic substances, in particular in the case

of abuse of a substance and/or of dependency on a substance, including alcohol
dependence and/or nicotine dependence, migraine, stress, disorders related to illnesses
of psychosomatic origin, panic attacks, epilepsy, memory disorders, cognitive disorders,
in particular senile dementia or disorders related to Alzheimer's disease, and disorders of
attention or of vigilance, ischaemia, disorders related to brain trauma or disorders related
to acute or chronic neurodegenerative diseases, including chorea and Huntington's
chorea.
According to the invention, the compounds of formula (I) in accordance with the
invention can be used as medicaments or in the preparation of a medicament intended
for the treatment and/or prevention of neurological disorders which may be reflected by
movement anomalies or motor disorders associated with a pathology chosen from
dyskinesia, Parkinson's disease, postencephalitic parkinsonism, dopa-sensitive dystonia,
Shy-Drager syndrome, periodic limb movement disorder (PLMD) syndrome, periodic limb
movements in sleep (PLMS) syndrome, Tourette's syndrome or restless legs syndrome
(RLS).
According to one embodiment, the compounds of formula (I) in accordance with the
invention can be used as medicaments or to manufacture a medicament intended for the
treatment of at least one movement anomaly or motor disorder related to Parkinson's
disease; in particular, the said movement anomaly or the said motor disorder is chosen
from resting tremor, rigidity, bradykinesia and deficiency in postural reflexes.
According to one embodiment, the compounds of formula (I) in accordance with
the invention can be used as medicaments or for manufacturing a medicament intended
for the prevention and/or treatment of neurological disorders reflected by movement
anomalies or motor disorders associated with trauma of the spinal cord, in particular in
the treatment of spinal trauma. Within the meaning of the present invention, the term
"trauma of the spinal cord" is understood to mean acute or chronic pathologies which
have an external origin and which destroy the spinal tract and/or spinal neurones, and
which occur, for example, during a fall, impact, crushing episode or road crash.
Advantageously, the compounds of formula (I) in accordance with the invention
can be used as medicaments or to manufacture a medicament intended for the
prevention and/or treatment of disorders:
- related to schizophrenia, in particular (i) in the prevention and/or treatment of
positive or negative symptoms and/or (ii) in the prevention and/or treatment of memory

deficiency;
- associated with Parkinson's disease, in particular (i) in the symptomatic
prevention and/or treatment of motor disorders, depression and/or cognitive disorders
and/or (ii) in its basic (neuroprotective) treatment and/or
- related to Alzheimer's disease, in particular (i) in the symptomatic prevention
and/or treatment of cognitive disorders and/or behavioural disorders (aggression,
depression) and/or (ii) in its basic (neuroprotective) treatment.
The use of the compounds of general formula (I) in accordance with the invention
as medicaments or to manufacture a medicament intended to treat and/or prevent the
abovementioned disorders or pathologies forms an integral part of the invention, and in
particular compounds of formula (I) chosen from compounds Nos. 1 to 6, 11 to 14, 16,
20, 22 to 25, 32 to 43, 47 to 52, 55 to 59, 72, 74, 76, 78, 79, 89 to 91, 97, 102, 108, 111,
112, 114, 116 to 118, 124, 130, 131, 133 to 135, 143, 145, 155, 158, 160, 165 to 167,
170, 175, 178, 183 to 186, 188, 189, 190, 193, 194, 200, 201, 203, 206, 207, 212, 213,
215, 216, 218, 223, 224, 226, 228, 230, 232 to 234, 239, 240, 242, 243, 245, 246, 250,
251, 254, 258, 263, 264, 270, 275, 276, 278 to 280, 282, 283, 285 to 287, 289, 292, 294,
295, 287 to 302, 305 to 312, 315 to 345, 349 to 355, 357, 358, 360, 362, 369, 371, 373,
375 to 377, 379 to 394 and 403.
Another subject-matter of the invention is a compound corresponding to the
general formula (I) as defined above in the treatment and/or prevention of disorders
related to the central nervous system and/or related to the peripheral nervous system,
the said disorder(s) advantageously being chosen from psychiatric disorders and
neurological disorders.
Pharmaceutical compositions comprising, as active principle, at least one
compound in accordance with the invention are of use in the present invention. These
pharmaceutical compositions comprise an effective dose of at least one compound of
formula (I) in accordance with the invention and also at least one pharmaceutically
acceptable excipient.
The said excipients are chosen, according to the pharmaceutical form and the
method of administration desired, from the usual excipients which are known to a person
skilled in the art.
In the pharmaceutical compositions of use in the present invention for oral,
sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal,
intranasal, transdermal or rectal administration, the active principle of formula (I) above

or its optional salt, solvate or hydrate can be administered in unit administration form, as
a mixture with conventional pharmaceutical excipients, to animals and human beings for
the prophylaxis or treatment of the above disorders or diseases.
The appropriate unit administration forms comprise forms by the oral route, such
as tablets, soft or hard gelatin capsules, powders, granules and oral solutions or
suspensions, sublingual, buccal, intratracheal, intraocular or intranasal administration
forms, forms for administration by inhalation, topical, transdermal, subcutaneous,
intramuscular or intravenous administration forms, rectal administration forms and
implants. Use may be made, for topical application, of the compounds according to the
invention in creams, gels, ointments or lotions.
By way of example, a unit administration form of a compound in accordance with
the invention in the form of a tablet can comprise the following components :
Compound No. 1 (2-{[3-(3,4-dimethoxybenzyl)-1-(1-formylpiperidin-
4-yl)~2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]oxy}propanenitrile) 50.0 mg
Mannitol 223.75 mg
Croscarmellose sodium 6.0 mg
Maize starch 15.0 mg
Hydroxypropylmethylcellulose 2.25 mg
Magnesium stearate 3.0 mg
The said unit forms comprise doses in order to make possible daily
administration of 0.5 mg to 800 mg of active principle per individual, more particularly of
0.5 mg to 200 mg, according to the pharmaceutical dosage form.
There may be cases where higher or lower dosages are appropriate; such
dosages do not depart from the scope of the invention. According to the usual practice,
the dosage appropriate to each patient is determined by the physician according to the
method of administration and the weight and response of the said patient.
A method for the treatment and/or prevention of the pathologies indicated above
comprises the administration, to a patient, of an effective dose of a compound in
accordance with the invention or of one of its hydrates or solvates.

CLAIMS
1. Use of a compound corresponding to the general formula (I)

in which
— A represents an aryl group or a heteroaryl group;
— R1 represents:

■ a hydrogen atom,
■ -C(O)R in which R is a hydrogen atom, a (C1-C6) alkoxy group, an aryl group, a
(C3-C6) cycloalkyl group or a (C1-C6) alkyl group, the said alkyl optionally being
substituted by:
. one or more hydroxyl group(s),
. a benzyloxy group,
. a (C1-C6) alkoxy group, optionally substituted by an aryl, or
. a (C3-C6) cycloalkyl group,
■ an optionally substituted (C1-C6) alkyl group;
— R2 represents:
■ a hydrogen atom,
■ a halogen atom,
■ a cyano group,
■ a nitro group,
■ a (C1-C6) alkyl group optionally substituted by an -NH2 or else by an
-NHC(O)Rb group, with Rb as defined below,
■ an -ORa group in which Ra represents:
. a hydrogen atom,

. a (C1-C6) alkyl group optionally substituted by one or more halogen
atom(s), by one or more hydroxyl group(s), by an aryl group and/or by one or
more cyano group(s),
. a (C2-C6) alkynyl group,
. an aryl group;
— R3 represents:
■ a hydrogen atom,
■ a halogen atom,
■ a hydroxyl group,
■ a cyano group,
■ an -SCF3 group,
■ a nitro group,
■ an oxo group,
■ an -S(O)0-2-alkyl group, an -S(O)0-2-heterocycloalkyl group, an -O-SO2-aryl
group optionally substituted by one or more halogen atom(s);
■ an -alkylaminoalkyl or -cycloalkylaminoalkyl group, each optionally substituted
on the end alkyl,
■ an optionally substituted sulphonamide group,
■ an aryl group or a heteroaryl group, the said group being monocyclic or
polycyclic and in addition optionally being substituted by a (C1-C6) alkyl group, by
one or more halogen atom(s) or by a (C1-C6) alkoxy group,
■ a heterocycloalkyl group optionally substituted by a (C1-C6) aikyl group,
■ a (C1-C6) alkyl group optionally substituted by:

- one or more halogen atom(s),
- an aryl group which can be substituted by one or more halogen atom(s)
or by one or more hydroxyl group(s),
- a heteroaryl group,
- one or more hydroxyl group(s) which can be substituted by an aryl group
itself optionally substituted by one or more halogen atom(s), or
- a heterocycloalkyl group optionally substituted by a CO(O)Ra group or by
a (C1-C6) alkyl group, with Ra as defined above,

■ a -C(O)NRbRc group, with Rb and Rc as defined below,
■ a -C(O)ORc group or an -O-C(O)ORc group, with Rc as defined below,
■ a (C1-C6) alkoxy group, optionally substituted by

- an aminoalkyl group,
- an aminocycloalkyl group,

- a cycloalkyl group,
- a heterocycloalkyl group,
- a monocyclic or polycyclic heteroaryl group,
- one or more hydroxyl group(s),
- one or more halogen atom(s),
- a (C1-C6) alkoxy group,
- a -C(O)ORc group, with Rc as defined below,
- a -C(O)NRbRc group, with Rb and Rc as defined below,
- an oxo group, and/or
- an aryl group, itself optionally substituted by one or more halogen
atom(s), a cyano group, a (C1-C6) alkoxy group, an -O-haloalkyl group and/or a
haloalkyl group,
■ an -O-cycloalkyl group, an -O-aryl group or an -O-heterocycloalkyl group, each
optionally substituted by
- an aryl group, itself optionally substituted by one or more halogen
atom(s) or by a (C1-C6) alkyl group,
- an oxo group,
- one or more halogen atom(s), and/or
- a (C1-C6) alkyl group, which can itself be substituted by an aryl group
and/or an oxo group,

■ an -NH-CO-NH-aryl group, an -NH-CO-NH-heteroaryl group or an -NH-CO-
NH-(C1-C6) alkyl group, each optionally being substituted by one or more halogen
atom(s), by a cyano group, by a nitro group, by one or more hydroxyl group(s) or by a
(C1-C6) alkoxy group,
■ an -N-(C1-C6) alkyl group, it being possible for the (C1-C6) alkyl group to be
substituted by

- one or more oxo group(s), and/or
- one or more aryl group(s) optionally substituted by one or more halogen
atom(s) and/or by an SO2 group,
■ an -NH-CO-aryl group or an -NH-CO-heteroaryl group, each optionally
being substituted by one or more halogen atom(s);
or else R3 forms, with A, a polycyclic heteroaryl group optionally substituted by a (C1-C6)
alkoxy group or a (C1-C6) alkyl group optionally substituted by an aryl group which can
itself be substituted by one or more halogen atom(s);
— R4 represents a hydrogen atom, an oxo group or a (C1-C6) alkyl group;

— Rb represents:
. a hydrogen atom,
. a (C1-C6) alkyl group optionally substituted by one or more halogen atom(s), by
one or more hydroxyl, cyano, amino, heterocycloalkyl or (C1-C6) alkoxy group(s) or by an
aryl group optionally substituted by one or more halogen atom(s),
. a (C3-C6) cycloalkyl group,
. a (C2-C6) alkynyl group,
. a (C1-C6) alkoxy group,
. an aryl group optionally substituted by one or more halogen atom(s);
— Rc represents a hydrogen atom or a (C1-C6) alkyl group optionally substituted
by one or more halogen atom(s);
or then Rb and Rc form, together with the nitrogen atom to which they are attached, a
polycyclic heteroaryl group or a heterocycloalkyl group;
— m and n represent, independently of one another, the value 0, 1 or 2, it being
understood that m+n≤3;
— p and p' represent, independently of one another, the value 1, 2 or 3, it being
understood that, when p is greater than or equal to 2, then the R2 groups are on separate
carbon atoms and can be different from one another and, when p' is greater than or
equal to 2, then the R3 groups are on separate carbon atoms and can be different from
one another;
— q represents the value 0 or 2, it being understood that, when q = 0, then the
nitrogenous heterocyclic group attached to the nitrogen situated in the 1 position of the
2,4-dioxo-1,2,3,4-tetrahydroquinazoline ring system is no longer bridged and is of the
type:

with R1, R4, m and n as defined above,

— r represents the value 0 or 1;
in the form of the base or of an addition salt with an acid;
in the preparation of a medicament intended for the treatment and/or prevention
of disorder(s) related to the central nervous system and/or related to the peripheral
nervous system.
2. Use of a compound corresponding to the general formula (I)

in which
— A represents an aryl group or a heteroaryl group;
— R1 represents:

■ a hydrogen atom,
■ -C(O)R in which R is a hydrogen atom, a (C1-C6) alkoxy group, an aryl group, a
(C3-C6) cycloalkyl group or a (C1-C6) alkyl group, the said alkyl optionally being
substituted by:
. one or more hydroxyl group(s),
. a benzyloxy group,
. a (C1-C6) alkoxy group, optionally substituted by an aryl, or
. a (C3-C6) cycloalkyl group,
■ an optionally substituted (C1-C6) alkyl group;
— R2 represents:
■ a hydrogen atom,
■ a halogen atom,
■ a cyano group,
■ a nitro group,

■ a (C1-C6) alkyl group optionally substituted by an -NH2 or else by an
-NHC(O)Rb group, with Rb as defined below,
■ an -ORa group in which Ra represents:
. a hydrogen atom,
. a (C1-C6) alkyl group optionally substituted by one or more halogen
atom(s), by one or more hydroxyl group(s), by an aryl group and/or by one or
more cyano group(s),
• a (C2-C6) alkynyl group,
. an aryl group;
— R3 represents:
■ a hydrogen atom,
■ a halogen atom,
■ a hydroxyl group,
■ a cyano group,
■ an -SCF3 group,
■ a nitro group,
■ an oxo group,

■ an -S(O)0-2-alkyl group, an -S(O)0-2-heterocycloalkyl group, an -O-SO2-aryl
group optionally substituted by one or more halogen atom(s);
■ an -alkylaminoalkyl or -cycloalkylaminoalkyl group, each optionally substituted
on the end alkyl,
■ an optionally substituted sulphonamide group,
■ an aryl group or a heteroaryl group, the said group being monocyclic or
polycyclic and in addition optionally being substituted by a (C1-C6) alkyl group, by
one or more halogen atom(s) or by a (C1-C6) alkoxy group,
■ a heterocycloalkyl group optionally substituted by a (C1-C6) alkyl group,
■ a (C1-C6) alkyl group optionally substituted by:

- one or more halogen atom(s),
- an aryl group which can be substituted by one or more halogen atom(s)
or by one or more hydroxyl group(s),
- a heteroaryl group,
- one or more hydroxyl group(s) which can be substituted by an aryl group
itself optionally substituted by one or more halogen atom(s), or
- a heterocycloalkyl group optionally substituted by a CO(O)Ra group or by
a (C1-C6) alkyl group, with Ra as defined above,
■ a -C(O)NRbRc group, with Rb and Rc as defined below,

■ a -C(O)ORc group or an -O-C(O)ORc group, with Rc as defined below,
■ a (C1-C6) alkoxy group, optionally substituted by

- an aminoalkyl group,
- an aminocycloalkyl group,
- a cycloalkyl group,
- a heterocycloalkyl group,
- a monocyclic or polycyclic heteroaryl group,
- one or more hydroxyl group(s),
- one or more halogen atom(s),
- a (C1-C6) alkoxy group,
- a -C(O)ORc group, with Rc as defined below,
- a -C(O)NRbRc group, with Rb and Rc as defined below,
- an oxo group, and/or
- an aryl group, itself optionally substituted by one or more halogen
atom(s), a cyano group, a (C1-C6) alkoxy group, an -O-haloalkyl group and/or a
haloalkyl group,
■ an -O-cycloalkyl group, an -O-aryl group or an -O-heterocycloalkyl group, each
optionally substituted by
- an aryl group, itself optionally substituted by one or more halogen
atom(s) or by a (C1-C6) alkyl group,
- an oxo group,
- one or more halogen atom(s), and/or
- a (C1-C6) aikyl group, which can itseif be substituted by an aryl group
and/or an oxo group,

■ an -NH-CO-NH-aryl group, an -NH-CO-NH-heteroaryl group or an -NH-CO-
NH-(C1-C6) alkyl group, each optionally being substituted by one or more halogen
atom(s), by a cyano group, by a nitro group, by one or more hydroxyl group(s) or by a
(C1-C6) alkoxy group,
■ an -N-(C1-C6) alkyl group, it being possible for the (C1-C6) alkyl group to be
substituted by

- one or more oxo group(s), and/or
- one or more aryl group(s) optionally substituted by one or more halogen
atom(s) and/or by an SO2 group,
■ an -NH-CO-aryl group or an -NH-CO-heteroaryl group, each optionally
being substituted by one or more halogen atom(s);
or else R3 forms, with A, a polycyclic heteroaryl group optionally substituted by a (C1-C6)

alkoxy group or a (C1-C6) alkyl group optionally substituted by an aryl group which can
itself be substituted by one or more halogen atom(s);
— R4 represents a hydrogen atom, an oxo group or a (C1-C6) alkyl group;
— Rb represents:
. a hydrogen atom,
. a (C1-C6) alkyl group optionally substituted by one or more halogen atom(s), by
one or more hydroxyl, cyano, amino, heterocycloalkyl or (C1-C6) alkoxy group(s) or by an
aryl group optionally substituted by one or more halogen atom(s),
. a (C3-C6) cycloalkyl group,
. a (C2-C6) alkynyl group,
. a (C1-C6) alkoxy group,
. an aryl group optionally substituted by one or more halogen atom(s);
— Rc represents a hydrogen atom or a (C1-C6) alkyl group optionally substituted
by one or more halogen atom(s);
or then Rb and Rc form, together with the nitrogen atom to which they are attached, a
polycyclic heteroaryl group or a heterocycloalkyl group;
— m and n represent, independently of one another, the value 0, 1 or 2, it being
understood that m+n≤3;
— p and p' represent, independently of one another, the value 1, 2 or 3, it being
understood that, when p is greater than or equal to 2, then the R2 groups are on separate
carbon atoms and can be different from one another and, when p' is greater than or
equal to 2, then the R3 groups are on separate carbon atoms and can be different from
one another;
— q represents the value 0 or 2, it being understood that, when q = 0, then the
nitrogenous heterocyclic group attached to the nitrogen situated in the 1 position of the
2,4-dioxo-1,2,3,4-tetrahydroquinazoline ring system is no longer bridged and is of the
type:


with R1, R4, m and n as defined above,
— r represents the value 0 or 1;
in the form of the base or of an addition salt with an acid;
as medicament.
3. Use according to either of the preceding claims, characterized in that the
disorder(s) is or are chosen from psychiatric disorders and neurological disorders.
4. Use according to Claim 3, characterized in that the psychiatric disorders are
chosen from anxiety, depression, mood disorders, insomnia, delusion disorders,
obsessive disorders, psychoses, disorders related to schizophrenia, attention deficit
hyperactivity disorders (ADHD) in hyperkinetic children, disorders related to the use of
psychotropic substances, in particular in the case of abuse of a substance and/or of
dependency on a substance, including alcohol dependence and/or nicotine dependence,
migraine, stress, disorders related to illnesses of psychosomatic origin, panic attacks,
epilepsy, memory disorders, cognitive disorders, in particular senile dementia or
disorders related to Alzheimer's disease, and disorders of attention or of vigilance,
ischaemia, disorders related to brain trauma or disorders related to acute or chronic
neurodegenerative diseases, including chorea and Huntington's chorea.
5. Use according to Claim 3, characterized in that the neurological disorders are
reflected by movement anomalies or motor disorders associated with a pathology chosen
from dyskinesia, Parkinson's disease, postencephalitic parkinsonism, dopa-sensitive
dystonia, Shy-Drager syndrome, periodic limb movement disorder (PLMD) syndrome,
periodic limb movements in sleep (PLMS) syndrome, Tourette's syndrome or restless
legs syndrome (RLS).
6. Use according to Claim 5, characterized in that the movement anomalies or
motor disorders are associated with Parkinson's disease.
7. Use according to Claim 6, characterized in that the anomalies or motor
disorders are chosen from resting tremor, rigidity, bradykinesia and deficiency in postural
reflexes.

8. Use according to one of Claims 4 to 7, (a) in the treatment and/or prevention of
disorders related to schizophrenia, in particular (i) in the prevention and/or treatment of
positive or negative symptoms and/or (ii) in the prevention and/or treatment of memory
deficiency, (b) in the treatment and/or prevention of disorders associated with
Parkinson's disease, in particular (i) in the symptomatic prevention and/or treatment of
motor disorders, depression and/or cognitive disorders and/or (ii) in its basic treatment,
and/or (c) in the treatment and/or prevention of disorders related to Alzheimer's disease,
in particular (i) in the symptomatic prevention and/or treatment of cognitive disorders
and/or behavioural disorders and/or (ii) in its basic treatment.
9. Use according to Claim 3, characterized in that the neurological disorders are
reflected by movement anomalies or motor disorders associated with trauma of the spinal
cord, in particular spinal trauma.

10. Use according to any one of the preceding claims, characterized in that A
represents a phenyl group or a pyridyl group.
11. Use according to any one of the preceding claims, characterized in that q = 0,
and m and n each represents 1.
12. Use according to any one of the preceding claims, characterized in that R2
represents a (C1-C6) alkyl group, in particular a methyl, substituted by an -NH-C(O)-Rb
group, Rb being as defined in Claim 1 or Claim 2.
13. Use according to any one of Claims 1 to 11, characterized in that R2
represents an -ORa group, Ra being as defined in Claim 1 or Claim 2.
14. Use according to any one of Claims 1 to 11, characterized in that R2 is a
halogen atom or a cyano or a hydrogen or a hydroxyl or a (C1-C6) alkyl optionally
substituted by an -NH2 or else by an -NHC(O)Rb group, Rb being as defined in Claim 1
or Claim 2.
15. Use according to any one of Claims 1 to 11, characterized in that A is a
phenyl, R1 is a -C(O)R group in which R represents a hydrogen atom, q is equal to 0, n
and m each have the value 1 and R2 represents -ORa, Ra being as defined in Claim 1 or
Claim 2.

16. Use according to any one of Claims 1 to 11, characterized in that A is a
phenyl, R1 is a -C(O)R group in which R represents a hydrogen atom, q is equal to 0, n
and m each have the value 1, p = 1 and R2 represents a methyl substituted by an
-NH-CO-Rb group, Rb being as defined in Claim 1 or Claim 2.
17. Use according to any one of Claims 1 to 11, characterized in that A is a
phenyl, R1 is a -C(O)R group in which R represents a hydrogen atom, q is equal to 0, n
and m each have the value 1, p is equal to 2, one of the R2 groups is -ORa, Ra being as
defined in Claim 1 or Claim 2, and the other of the R2 groups is a halogen atom.
18. Use according to any one of the preceding claims, characterized in that the R2
group is in the 6 position of the 2,4-dioxo-1,2,3,4-tetrahydroquinazoline ring system and
in that there may additionally be an R2 group, identical to or different from the said
abovementioned R2 group, in the 7 position of the 2,4-dioxo-1,2,3,4-
tetrahydroquinazoline ring system, the said compound of formula (I) being in the base,
hydrate or solvate form, in the form of isomers or in the form of their mixtures.
19. Use according to any one of Claims 1 to 9, characterized in that the
compound of formula (I) is chosen from compounds Nos. 1 to 6, 11 to 14, 16, 20, 22 to
25, 32 to 43, 47 to 52, 55 to 59, 72, 74, 76, 78, 79, 89 to 91, 97, 102, 108, 111, 112, 114,
116 to 118, 124, 130, 131, 133 to 135, 143, 145, 155, 158, 160, 165 to 167, 170, 175,
178, 183 to 186, 188, 189, 190, 193, 194, 200, 201, 203, 206, 207, 212, 213, 215, 216,
218, 223, 224, 226, 228, 230, 232 to 234, 239, 240, 242, 243, 245, 246, 250, 251, 254,
258, 263, 264, 270, 275, 276, 278 to 280, 282, 283, 285 to 287, 289, 292, 294, 295, 287
to 302, 305 to 312, 315 to 345, 349 to 355, 357, 358, 360, 362, 369, 371, 373, 375 to
377, 379 to 394 and 403, in the form of the base or of an addition salt with an acid.
20. Compound corresponding to the general formula (I)


in which
— A represents an aryl group or a heteroaryl group;
— R1 represents:

■ a hydrogen atom,
■ -C(O)R in which R is a hydrogen atom, a (C1-C6) alkoxy group, an aryl group, a
(C3-C6) cycloalkyi group or a (C1-C6) alkyl group, the said alkyl optionally being
substituted by:
. one or more hydroxyl group(s),
. a benzyloxy group,
. a (C1-C6) alkoxy group, optionally substituted by an aryl, or
. a (C3-C6) cycloalkyi group,
■ an optionally substituted (C1-C6) alkyl group;
— R2 represents:
■ a hydrogen atom,
■ a halogen atom,
■ a cyano group,
■ a nitro group,
■ a (C1-C6) alkyl group optionally substituted by an -NH2 or else by an
-NHC(O)Rb group, with Rb as defined below,
■ an -ORa group in which Ra represents:
. a hydrogen atom,
. a (C1-C6) alkyl group optionally substituted by one or more halogen
atom(s), by one or more hydroxyl group(s), by an aryl group and/or by one or
more cyano group(s),
. a (C2-C6) alkynyl group,

. an aryl group;
— R3 represents:
■ a hydrogen atom,
■ a halogen atom,
■ a hydroxyl group,
■ a cyano group,
■ an -SCF3 group,
■ a nitro group,
■ an oxo group,
■ an -S(O)0-2-alkyl group, an -S(O)0-2-heterocycloalkyl group, an -O-SO2-aryl
group optionally substituted by one or more halogen atom(s);
■ an -alkylaminoalkyl or -cycloalkylaminoalkyl group, each optionally substituted
on the end alkyl,
■ an optionally substituted sulphonamide group,
■ an aryl group or a heteroaryl group, the said group being monocyclic or
polycyclic and in addition optionally being substituted by a (C1-C6) alkyl group, by
one or more halogen atom(s) or by a (C1-C6) alkoxy group,
■ a heterocycloalkyl group optionally substituted by a (C1-C6) alkyl group,
■ a (C1-C6) alkyl group optionally substituted by:

- one or more halogen atom(s),
- an aryl group which can be substituted by one or more halogen atom(s)
or by one or more hydroxyl group(s),
- a heteroaryl group,
- one or more hydroxyl group(s) which can be substituted by an aryl group
itself optionally substituted by one or more halogen atom(s), or
- a heterocycloalkyl group optionally substituted by a CO(O)Ra group or by
a (C1-C6) alkyl group, with Ra as defined above,

■ a -C(O)NRbRc group, with Rb and Rc as defined below,
■ a -C(O)ORc group or an -O-C(O)ORc group, with Rc as defined below,
■ a (C1-C6) alkoxy group, optionally substituted by

- an aminoalkyl group,
- an aminocycloalkyl group,
- a cycloalkyl group,
- a heterocycloalkyl group,
- a monocyclic or polycyclic heteroaryl group,
- one or more hydroxyl group(s),

- one or more halogen atom(s),
- a (C1-C6) alkoxy group,
- a -C(O)ORc group, with Rc as defined below,
- a -C(O)NRbRc group, with Rb and Rc as defined below,
- an oxo group, and/or
- an aryl group, itself optionally substituted by one or more halogen
atom(s), a cyano group, a (C1-C6) alkoxy group, an -O-haloalkyl group and/or a
haloalkyl group,
■ an -O-cycloalkyl group, an -O-aryl group or an -O-heterocycloalkyl group, each
optionally substituted by
-an aryl group, itself optionally substituted by one or more halogen
atom(s) or by a (C1-C6) alkyl group,
- an oxo group,
- one or more halogen atom(s), and/or
- a (C1-C6) alkyl group, which can itself be substituted by an aryl group
and/or an oxo group,

■ an -NH-CO-NH-aryl group, an -NH-CO-NH-heteroaryl group or an -NH-CO-
NH-(C1-C6) alkyl group, each optionally being substituted by one or more halogen
atom(s), by a cyano group, by a nitro group, by one or more hydroxyl group(s) or by a
(C1-C6) alkoxy group,
■ an -N-(C1-C6) alkyl group, it being possible for the (C1-C6) alkyl group to be
substituted by

- one or more oxo group(s), and/or
- one or more aryl group(s) optionally substituted by one or more halogen
atom(s) and/or by an SO2 group,
■ an -NH-CO-aryl group or an -NH-CO-heteroaryl group, each optionally
being substituted by one or more halogen atom(s);
or else R3 forms, with A, a polycyclic heteroaryl group optionally substituted by a (C1-C6)
alkoxy group or a (C1-C6) alkyl group optionally substituted by an aryl group which can
itself be substituted by one or more halogen atom(s);
— R4 represents a hydrogen atom, an oxo group or a (C1-C6) alkyl group;
— Rb represents:
. a hydrogen atom,
. a (C1-C6) alkyl group optionally substituted by one or more halogen atom(s), by

one or more hydroxyl, cyano, amino, heterocycloalkyl or (C1-C6) alkoxy group(s) or by an
aryl group optionally substituted by one or more halogen atom(s),
. a (C3-C6) cycloalkyl group,
. a (C2-C6) alkynyl group,
. a (C1-C6) alkoxy group,
. an aryl group optionally substituted by one or more halogen atom(s);
— Rc represents a hydrogen atom or a (C1-C6) alkyl group optionally substituted
by one or more halogen atom(s);
or then Rb and Rc form, together with the nitrogen atom to which they are attached, a
polycyclic heteroaryl group or a heterocycloalkyl group;
— m and n represent, independently of one another, the value 0, 1 or 2, it being
understood that m+n≤3;
— p and p' represent, independently of one another, the value 1, 2 or 3, it being
understood that, when p is greater than or equal to 2, then the R2 groups are on separate
carbon atoms and can be different from one another and, when p' is greater than or
equal to 2, then the R3 groups are on separate carbon atoms and can be different from
one another;
- q represents the value 0 or 2, it being understood that, when q = 0, then the
nitrogenous heterocyclic group attached to the nitrogen situated in the 1 position of the
2,4-dioxo-1,2,3,4-tetrahydroquinazoline ring system is no longer bridged and is of the
type:

with R1, R4, m and n as defined above,
— r represents the value 0 or 1;
in the form of the base or of an addition salt with an acid;
in the treatment and/or prevention of disorder(s) related to the central nervous

system and/or related to the peripheral nervous system, the said disorder(s) being
advantageously chosen from psychiatric disorders and neurological disorders.
21. Compound according to the preceding claim, characterized in that it is defined
according to any one of Claims 9 to 19.

The subject matter of the present invention is the use of compounds of formula (I) in the form of a base, a hydrate
or a solvate, or of mixtures thereof as a medicament or for preparing a medicament intended for the treatment and/or prevention
of disorders associated with the central nervous system (abbreviated to CNS) and/or associated with the peripheral nervous system
(abbreviated to PNS).