NOVEL 1,2,3,4-TETRAHYDROPYRIMIDO{1,2-a}PYRIMIDIN-6-ONE
DERIVATIVES, PREPARATION THEREOF AND PHARMACEUTICAL USE
THEREOF
The present invention relates to novel chemical compounds (1,2,3,4-
tetrahydropyrimido{1,2-a}pyrimidin-6-one), derived from pyrimidinones, to the
process for the preparation thereof, to the novel intermediates obtained, to
the use thereof as medicaments, to the pharmaceutical compositions
containing them and to the novel use of such derivatives.
The present invention thus also relates to the use of said derivatives
for the preparation of a medicament for use in treating humans.
More particularly, the invention relates to novel pyrimidinone
derivatives and to the pharmaceutical use thereof for the prevention and
treatment of conditions capable of being modulated by inhibition of the
PI3K/AKT/mTOR pathway. AKT is a key participant in this signalling pathway.
A high level of AKT phosphorylation is the marker of the activation of the
pathway, which is found in many human cancers.
The products of the present invention may thus in particular be used
for the prevention or treatment of conditions capable of being modulated by
inhibition of AKT phosphorylation (P-AKT). The inhibition of P-AKT may
especially be obtained by inhibition of the PI3K/AKT/mTOR pathway, and in
particular by inhibition of kinases belonging to this pathway, for instance
receptor tyrosine kinases such as EGFR, IGFR, ErbB2, 3'-phosphoinositide-
dependent protein kinase-1 (PDK1), the PI3K phosphoinositide kinase, the
AKT serine-threonine kinase, or the mTOR kinase.
The inhibition and regulation of the PI3K/AKT/mTOR pathway
constitutes in particular a new and powerful mechanism of action for the
treatment of a large number of cancer diseases including solid and liquid
tumours.

Such conditions that can be treated by the products of the present
application are solid or liquid human tumours.
This invention also relates to novel pyrimidinone derivatives and to the
pharmaceutical use thereof for the prevention and treatment of conditions
affected by the modulation of autophagy. The inhibition and regulation of
autophagy constitutes a new mechanism of action for the treatment of a large
number of cancer diseases, including solid and liquid tumours.
This invention also relates to novel pyrimidinone derivatives and to the
pharmaceutical use thereof for the treatment of parasitic diseases such as
malaria, sleeping sickness, Chagas disease or leishmaniasis.
Role of the PI3K/AKT/mTOR pathway
The PI3K/AKT/mTOR signalling pathway is a complex network which
regulates multiple cell functions, such as growth, survival, proliferation and
cell motility, which are key processes in tumorigenesis.
This signalling pathway is an important target in the treatment of
cancer since most of its effectors are altered in human tumours. The principal
effectors contribute to the activation of the pathway are i) oncogenes, such as
ErbB1 (EGFR), ErbB2 (HER2), PIK3CA and AKT, activated by mutation,
amplification or overexpression; ii) a deficiency in tumour suppressor genes
such as PTEN, TSC1/2, LKB and PML, which are inactivated following
mutations or deletions (Jiang L-Z & Liu L-Z, Biochim Biophys Acta, 2008,
1784:150; Vivanco I & Sawyers CL, 2002, Nat Rev Cancer, 2:489; Cully M et
al., Nature Rev. Cancer, 2006, 6:184).
The activation of the oncogenes of this signalling pathway is found in
many human cancer diseases:
PIK3CA activating mutations are present in 15-30% of colon, breast,
endometrial, liver, ovarian and prostate cancers (TL Yuan and
LC Cantley, Oncogene, 2008, 27:5497; Y. Samuels et al. Science,
2004, 304:554; KE. Bachman et al. Cancer Biol Ther, 2004, 3:772;
DA Levine et al. Clin Cane Res. 2005, 11:2875; C. Hartmann et al.

Acta Neuropathol. 2005, 109:639);
amplifications, activating mutations and overexpressions of RTKs
such as EGFR and HER2 in brain, breast and lung (NSCLC)
cancers;
amplification and activating overexpression of AKT in brain, lung
(NSCLC), breast, kidney, ovarian and pancreatic cancers (Testa JR.
and Bellacosa A., Proct. Natl. Acad. Sci. USA 2001, 98:10983;
Cheng et al., Proct. Natl. Acad. Sci. USA 1992, 89: 9267; Bellacosa
et al., Int. J. Cancer, 1995, 64:280; Cheng et al., Proct. Natl. Acad.
Sci. USA 1996, 93:3636; Yuan et al., Oncogene, 2000, 19:2324).
Deficiency in the tumour suppressor genes of this signalling pathway is also
found in many human cancer diseases:
o deletion of PTEN in 50% of lung (NSCLC), liver, kidney, prostate,
breast, brain, pancreatic, endometrial and colon cancers (Maxwell GL
et al. Cane. Res. 1998, 58:2500; Zhou X-P et al. Amer. J. Pathol.,
2002, 161:439; Endersby R & Baker SJ, Oncogene, 2008, 27:5416; Li
et al. Science, 1997, 275:1943; Steack PA et al., Nat. Genet., 1997,
15:356);
o mutations in TSC1/2 in more than 50% of tuberous scleroses;
o mutations or deletions in LKB1 (or STK11) which predispose to
gastrointestinal tract cancers and to pancreatic cancer and which are
found in particular in 10-38% of lung adenocarcinomas (Shah U. et al.
Cancer Res. 2008, 68:3562);
o modifications of PML in particular by translocation in human tumours
(Gurrieri C et al, J. NAtl Cancer Inst. 2004, 96:269).
In addition, this signalling pathway is a major factor for resistance to
chemotherapy, to radiotherapy and to targeted therapies such as EGFR and
HER2 inhibitors, for example (C. Sawyers et al. Nat Rev 2002).
Role of AKT

AKT (protein kinase B; PKB) is a serine-threonine kinase which occupies a
central place in one of the major cell signalling pathways, the PI3K/AKT
pathway. AKT is in particular involved in the growth, proliferation and survival
of tumour cells. AKT activation occurs in two steps, (1) by phosphorylation of
threonine 308 (P-T308) by PDK1 and (2) by phosphorylation of serine
473 (P-S473) by mTORC2 (or mTOR-Rictor complex), resulting in complete
activation. AKT in turn regulates a large number of proteins, including mTOR
(mammalian target of Rapamycin), BAD, GSK3, p21, p27, FOXO or FKHRL1
(Manning BD & Cantley LC, Cell, 2007 129:1261). The activation of AKT
promotes the internalisation of nutrients, thereby triggering a process of
anabolising metabolisation supporting cell growth and proliferation. In
particular, AKT controls the initiation of protein synthesis through a cascade
of interactions that occurs by means of TSC1/2 (tuberous sclerosis complex),
Rheb and TOR, so as to result in two essential targets of the signalling
pathway, p70S6K and 4EBP. AKT also induces inhibiting phosphorylation of
the Forkhead transcription factor and inactivation of GSK30, which result in
the inhibition of apoptosis and in progression of the cell cycle (Franke TF,
Oncogene, 2008, 27:6473). AKT is therefore a target for anticancer therapy
and the inhibition of AKT activation by inhibition of the phosphorylation thereof
may induce apoptosis of malignant cells and, by the same token, provide a
treatment for cancer.
Receptor tyrosine kinases such as IGF1R
Abnormally high levels of protein kinase activity have been implicated in many
diseases resulting from abnormal cell functions. This may originate either
directly or indirectly from a dysfunction in the mechanisms for controlling the
kinase activity, related to for example an inappropriate mutation,
overexpression or activation of the enzyme, or owing to an overproduction or
underproduction of cytokines or of growth factors, also involved in the
transduction of upstream or downstream signals of kinases. In all these
cases, a selective inhibition of the action of kinases leads to the hope of a
beneficial effect.

The insulin-like growth factor type 1 receptor (IGF-I-R) is a transmembrane
receptor tyrosine kinase which binds firstly to IGFI, but also to IGFII and to
insulin with a weaker affinity. The binding of IGF1 to its receptor leads to
oligomerization of the receptor, activation of the tyrosine kinase,
intermolecular autophosphorylation and phosphorylation of cell substrates
(principal substrates: IRS1 and She). The receptor activated by its ligand
induces a mitogenic activity in normal cells. However, IGF-I-R plays an
important role in "abnormal" growth.
Several clinical reports underline the important role of the IGF-I pathway in
the development of human cancers:
IGF-I-R is often found overexpressed in many tumour types (breast, colon,
lung, sarcoma, prostate, multiple myeloma) and its presence is often
associated with a more aggressive phenotype.
High concentrations of circulating IGF1 are strongly correlated with a risk of
prostate, lung and breast cancer.
Furthermore, it has been widely documented that IGF-I-R is necessary for the
establishment and maintenance of the transformed phenotype in vitro just as
in vivo [Baserga R, Exp. Cell. Res., 1999, 253, pages 1-6]. The kinase activity
of IGF-I-R is essential for the transforming activity of several oncogenes:
EGFR, PDGFR, SV40 virus broad T antigen, activated Ras, Raf, and v-Src.
The expression of IGF-I-R in normal fibroblasts induces a neoplastic
phenotype, which can subsequently lead to tumour formation in vivo. IGF-I-R
expression plays an important role in substrate-independent growth. IGF-I-R
has also been shown to be a protector in chemotherapy- and radiation-
induced apoptosis and cytokine-induced apoptosis. Furthermore, the
inhibition of endogenous IGF-I-R by a dominant negative, the formation of a
triple helix or the expression of an antisense causes a suppression of the
transforming activity in vitro and a decrease in tumour growth in animal
models.
PDK1

3'-Phosphoinositide-dependent protein kinase-1 (PDK1) is one of the
essential components of the PI3K-AKT signalling pathway. It is a serine-
threonine (Ser/Thr) kinase, the role of which is to phosphorylate and activate
other Ser/Thr kinases of the AGC family that are involved in the control of cell
growth, proliferation and survival and in the regulation of the metabolism.
These kinases include protein kinase B (PKB or AKT), SGK (or serum and
glucocorticoid regulated kinase), RSK (or p90 ribosomal S6 kinase), p70S6K
(or p70 ribosomal S6 kinase) and also various isoforms of protein kinase C
(PKC) (Vanhaesebroeck B. & Alessi DR., Biochem J, 2000, 346:561). One of
the key roles of PDK1 is therefore the activation of AKT: in the presence of
PIP3, which is the second messenger generated by PI3K, PDK-1 is recruited
to the plasma membrane via its PH (pleckstrin homology) domain and
phosphorylates AKT on threonine 308 located in the activation loop, which is
an essential modification for AKT activation. PDK1 is expressed ubiquitously
and is a constitutively active kinase. PDK1 is a key element in the PI3K/AKT
signalling pathway for regulating key processes in tumorigenesis, such as cell
proliferation and survival. Since this pathway is activated in more than 50% of
human cancers, PDK1 represents a target for anticancer therapy. The
inhibition of PDK1 should result in an effective inhibition of the proliferation
and survival of cancer cells and therefore provide a therapeutic benefit for
human cancers (Bayascas JR, Cell cycle, 2008, 7:2978; Peifer C. & Alessi
DR, ChemMedChem, 2008, 3:1810).
Phosphoinositide 3-kinases (PI3Ks)
The PI3K lipid kinase is an important target in this signalling pathway
for oncology. The class I PI3Ks are divided up into class la (PI3Ka,p,5)
activated by receptor tyrosine kinases (RTKs), G protein-coupled receptors
(GPCRs), GTPases of the family Rho and p21-Ras, and class lb (PI3Ky)
activated by GPCRs and p21-Ras. The class la PI3Ks are heterodimers
which consist of a catalytic subunit p110a, p or 5 and a regulatory subunit
p85 or p55. The class lb (p110y) is monomeric. The class I PI3Ks are
lipid/protein kinases which are activated by RTKs, GPCRs or Ras after

recruitment of the membrane. These class I PI3Ks phosphorylate
phosphatidylinositol 4,5-diphosphate (PIP2) on position 3 of the inositol so as
to give phosphatidylinositol 3,4,5-triphosphate (PIP3), a key secondary
messenger in this signalling pathway. In turn, PIP3 recruits AKT and PDK1 to
the membrane, where they bind via their pleckstrin homology domain (PH
domain), resulting in activation of AKT by PDK1 phosphorylation on threonine
308. AKT phosphorylates many substrates, thus playing a key role in many
processes resulting in cell transformation, such as cell proliferation, growth
and survival, and also angiogenesis.
The class I PI3Ks are implicated in human cancers: somatic mutations
of the PIK3CA gene, which encodes PI3Ka, are found in 15-35% of human
tumours, with in particular two principal oncogenic mutations, H1047R (in the
kinase domain), and E545K/E542K (in the helical domain), (Y. Samuels et al.
Science, 2004, 304:554; TLYuan and LC Cantley, Oncogene, 2008,
27:5497). PI3K inhibitors are expected to be effective in the treatment of
many human cancers exhibiting genetic alterations resulting in the activation
of the PI3K/AKT/mTOR pathway (Vogt P. et al., Virology, 2006, 344:131;
Zhao L & Vogt PK, Oncogene, 2008, 27:5486).
mTOR
mTOR (mammalian target of rapamycin) is a serine-threonine kinase
related to the lipid kinases of the PI3K family. mTOR has been implicated in
various biological processes, including cell growth, proliferation, motility and
survival. mTOR is a multifunctional kinase which integrates both the signals
coming from growth factors and those coming from nutrients in order to
regulate protein translation, nutrient uptake, autophagy and mitochondrial
function. mTOR exists in the form of two different complexes, called mTORCI
and mTORC2. mTORCI contains the raptor subunit and mTORC2 contains
the rictor subunit. These two complexes are regulated differently: mTORCI
phosphorylates the S6 kinase (S6K) and 4EBP1, thus stimulating translation
and ribosome biogenesis so as to facilitate cell growth and progression in the
cell cycle. S6K also acts in a feedback pathway for reducing the activation of

AKT. mTORCI is sensitive to rapamycin, whereas mTORC2 is generally
insensitive to rapamycin. mTORC2 appears to modulate growth factor
signalling by phosphorylating AKT on serine residue 473. mTOR has been
implicated in various pathological conditions, including in particular cancer,
diabetes, obesity, cardiovascular diseases and neurological disorders. mTOR
modulates many biological processes, including translation, autophagy and
ribosome biogenesis by integrating intracellular and extracellular signals such
as the signals transported by growth factors, nutrients, energy levels and cell
stress (Guertin DA and Sabatini D., Cancer Cell, 2007, 12: 9; Menon S. and
Manning B.D., Oncogene, 2009, 27 :S43).
The role of autophagy
Autophagy is a lysosome-dependent intracellular degradation
mechanism (organelles, long-lived proteins, etc.). The autophagy process
involves the formation of particular vesicles called autophagosomes. The
class III PI3K lipid kinase (Vps34) is involved in the formation of
autophagosomes. This class III PI3K phosphorylates phosphatidylinositol (PI)
on position 3 of the inositol so as to give phosphatidylinositol-3-triphosphate
(PI3P). PI3P is a key second messenger in autophagosome formation via the
recruitment of proteins such as WIPI, DFCP1 and Alfy. Autophagy is a cell
survival mechanism which enables the cell to survive in a situation of stress,
for instance in the face of a metabolic stress. In the case of cancer,
autophagy is implicated in the resistance of tumour cells in the face of
environmental stresses such as: hypoxia, oxidative stresses, nutrient
deficiency, but also in the face of therapeutic stresses: treatments with
anticancer agents, ionizing radiation.
Application in antimalarial chemotherapy
Malaria is one of the primary infectious causes of mortality in the world and,
each year, affects 100 to 200 million individuals. The strong resurgence of the
disease observed over the last few years is due to several factors, including:
- the vectors, namely anopheles mosquitoes, which become resistant to the

conventional cheap insecticides,
- the increase in the population in the areas at risk, and, mainly,
- the resistance of numerous strains of Plasmodium falciparum, which is a
parasite responsible for the lethal forms of the disease, to the conventional
medicaments used, such as chloroquine and mefloquine.
The propagation of the resistance among the strains of Plasmodium, in
particular P. falciparum, to most of the antimalarial medicaments
demonstrates the urgent need to develop new compounds having a new
mode of action and thus enabling a decrease in the risk of cross resistance.
Human kinases are targets that have been validated in the treatment of many
pathological conditions, and the kinome of P. falciparum has been proposed
as a reservoir of new targets for the development of new medicaments which
have not yet been explored in the treatment of malaria.
The Plasmodium falciparum kinome is composed of 64 kinases, some of
which are orthologues of human kinases. Kinase signalling pathway inhibitors
have been tested for their ability to inhibit, in vitro and in vivo, the growth of
P. falciparum and of other pathogenic species responsible for malaria.
The molecules of the invention inhibit the growth of P. falciparum (highly
chloroquine-resistant strain Fcm29-Cameroon) at 1 uM and 0.1 uM in an in
vitro test using infected human erythrocytes, as indicated in Table 2.
Similar kinomes are present in all the Plasmodium species, such as
P. falciparum, P. vivax, P. malariae, P. ovale and P. knowlesi. The
compounds of the invention can therefore be used in the treatment of malaria
induced by all the parasites mentioned above. In addition, the kinases are
found in other parasites, such as Trypanosoma (for example, T. brucei,
T. cruzei) and Leishmania (for example, L. major, L. donovani). The
compounds of the invention can therefore be used in the treatment of
sleeping sickness, Chagas disease, the various forms of leishmaniasis and
other parasitic infections.
Kinase-inhibiting morpholino-pyrimidinone derivatives are known to

those skilled in the art.
Application WO 2008/148074 describes produces which have an
mTOR-inhibiting activity. These products are pyrido[1,2-a]pyrimidin-4-ones
which differ from the products of the present invention owing to their entirely
aromatic nature and their substitutions.
Application WO 2008/064244 describes the application of the
PI3Kp-inhibiting products TGX-221 and TGX-155 that are of use in the
treatment of cancer, and in particular of breast cancer. These products are
pyrido[1,2-a]pyrimidin-4-ones previously described in applications
WO 2004/016607 and WO 2001/053266, which differ from the products of the
present invention owing to their entirely aromatic nature and their
substitutions.
Applications WO 2006/109081, WO 2006/109084 and
WO 2006/126010 describe DNA-PK-inhibiting products that are of use in the
treatment of ATM-deficient cancers. These products are
pyrido[1,2-a]pyrimidin-4-ones which differ from the products of the present
invention owing to their entirely aromatic nature and their substitutions.
Application WO 2003/024949 describes DNA-PK-inhibiting products
that are of use in the treatment of ATM-deficient cancers. These products are
pyrido[1,2-ajpyrimidin-4-ones which differ from the products of the present
invention owing to their entirely aromatic nature and their substitutions.


R1 represents an -L-aryl or -L-heteroaryl radical, such that L represents:
either a single bond,
or a linear or branched alkyl radical containing from 1 to 6 carbon atoms and
optionally substituted with a hydroxyl radical,
or a CO or -CO-Alk- group,
or an L'-X group where L' represents a linear or branched alkyl radical
containing from 1 to 6 carbon atoms, and X an oxygen or sulphur atom;
the aryl and heteroaryl radicals being optionally substituted with one or more
radicals, which may be identical or different, chosen from halogen atoms and
hydroxyl, CN, nitro, -COOH, -COOalk, -NRxRy, -CONRxRy, -NRxCORy,
-NRxCO2Rz, -CORy, alkoxy, phenoxy, alkylthio, alkyl, cycloalkyl and
heterocycloalkyl radicals;
the latter alkoxy, phenoxy, alkylthio, alkyl and heterocycloalkyl radicals being
themselves optionally substituted with one or more radicals, which may be
identical or different, chosen from halogen atoms and NRvRw;
it being possible for the heterocycloalkyl and heteroaryl radicals to additionally
contain an oxo radical;
R2 represents a hydrogen atom or an alkyl radical;
R3 represents an alkyl radical optionally substituted with one or more halogen
atoms;
R4 represents a hydrogen atom or a halogen atom;
NRxRy being such that Rx represents a hydrogen atom or an alkyl radical
and Ry represents a hydrogen atom or a cycloalkyl radical or an alkyl radical
optionally substituted with one or more radicals, which may be identical or
different, chosen from hydroxyl, alkoxy, NRvRw and heterocycloalkyl radicals;
or Rx and Ry form, with the nitrogen atom to which they are attached, a cyclic
radical containing from 3 to 10 ring members and optionally one or more other
heteroatoms chosen from O, S, NH and N-alkyl, this cyclic radical being

optionally substituted;
NRvRw being such that Rv represents a hydrogen atom or an alkyl radical
and Rw represents a hydrogen atom or a cycloalkyl radical or an alkyl radical
optionally substituted with one or more radicals, which may be identical or
different, chosen from hydroxyl, alkoxy and heterocycloalkyl radicals; or Rv
and Rw form, with the nitrogen atom to which they are attached, a cyclic
radical containing from 3 to 10 ring members and optionally one or more other
heteroatoms chosen from O, S, NH and N-alkyl, this cyclic radical being
optionally substituted;
the cyclic radicals that Rx and Ry or Rv and Rw, respectively, can form with
the nitrogen atom to which they are attached, being optionally substituted with
one or more radicals, which may be identical or different, chosen from
halogen atoms, and alkyl, hydroxyl, oxo, alkoxy, NH2, NHalk and N(alk)2
radicals;
Rz represents the values of Ry except for hydrogen;
Rx, Ry and Rz, in the -NRxCORy, -CORy and NRxCO2Rz radicals, being
chosen from the meanings indicated above for Rx, Ry and Rz;
said products of formula (I) being in all the possible racemic, enantiomeric
and diastereoisomeric isomer forms, and also the addition salts with inorganic
and organic acids or with inorganic and organic bases, of said products of
formula (I).
A subject of the present invention is thus the products of formula (I) as
defined above, in which:
R1 represents an -L-aryl or -L-heteroaryl radical, such that L represents:
either a single bond,
or a linear or branched alkyl radical containing from 1 to 6 carbon atoms and
optionally substituted with a hydroxyl radical,
or a CO group,

or an L'-X group where L' represents a linear or branched alkyl radical
containing from 1 to 6 carbon atoms, and X an oxygen or sulphur atom;
the aryl and heteroaryl radicals being optionally substituted with one or more
radicals, which may be identical or different, chosen from halogen atoms and
hydroxy!, CN, nitro, -COOH, -COOalk, -NRxRy, -CONRxRy, -NRxCORy,
-NRxCO2Rz, -CORy, alkoxy, phenoxy, alkylthio, alkyl, cycloalkyl and
heterocycloalkyl radicals;
the latter alkoxy, phenoxy, alkylthio, alkyl and heterocycloalkyl radicals being
themselves optionally substituted with one or more radicals, which may be
identical or different, chosen from halogen atoms and NRvRw;
it being possible for the heterocycloalkyl and heteroaryl radicals to also
contain an oxo radical;
R2 represents a hydrogen atom or an alkyl radical;
R3 represents an alkyl radical optionally substituted with one or more halogen
atoms;
R4 represents a hydrogen atom or a halogen atom;
NRxRy being such that Rx represents a hydrogen atom or an alkyl radical
and Ry represents a hydrogen atom or a cycloalkyl radical or an alkyl radical
optionally substituted with one or more radicals, which may be identical or
different, chosen from hydroxy, alkoxy, NRvRw or heterocycloalkyl radicals;
or Rx and Ry form, with the nitrogen atom to which they are attached, a cyclic
radical containing from 3 to 10 ring members and optionally one or more other
heteroatoms chosen from 0, S, NH and N-alkyl, this cyclic radical being
optionally substituted;
NRvRw being such that Rv represents a hydrogen atom or an alkyl radical
and Rw represents a hydrogen atom or a cycloalkyl radical or an alkyl radical
optionally substituted with one or more radicals, which may be identical or
different, chosen from hydroxyl, alkoxy and heterocycloalkyl radicals; or Rv
and Rw form, with the nitrogen atom to which they are attached, a cyclic

radical containing from 3 to 10 ring members and optionally one or more other
heteroatoms chosen from O, S, NH and N-alkyl, this cyclic radical being
optionally substituted;
the cyclic radicals that Rx and Ry or Rv and Rw, respectively can form with
the nitrogen atom to which they are attached, being optionally substituted with
one or more radicals, which may be identical or different, chosen from
halogen atoms, and alkyl, hydroxyl, oxo, alkoxy, NH2, NHalk and N(alk)2
radicals;
Rz represents the values of Ry except for hydrogen;
Rx, Ry and Rz in the -NRxCORy, -CORy and NRxCO2Rz radicals being
chosen from the meanings indicated above for Rx, Ry and Rz;
said products of formula (I) being in all the possible racemic, enantiomeric
and diastereoisomeric isomer forms, and also the addition salts with inorganic
and organic acids or with inorganic and organic bases, of said products of
formula (I).
In the products of formula (I):
- the term "alkyl (or alk) radical" denotes the linear, and where appropriate
branched, radicals methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, hexyl, isohexyl and also heptyl, octyl, nonyl and
decyl, and also the linear or branched positional isomers thereof: the alkyl
radicals containing from 1 to 6 carbon atoms and more particularly the alkyl
radicals containing from 1 to 4 carbon atoms of the above list are preferred;
-the term "alkoxy radical" denotes the linear, and where appropriate
branched, radicals methoxy, ethoxy, propoxy, isopropoxy, linear, secondary
or tertiary butoxy, pentoxy or hexoxy, and also the linear or branched
positional isomers thereof: the alkoxy radicals containing from 1 to 4 carbon
atoms of the above list are preferred;
-the term "alkylthio radical" denotes the linear, and where appropriate
branched, radicals methylthio, ethylthio, propylthio, isopropylthio, linear,

secondary or tertiary butylthio, pentylthio or hexylthio, and also the linear or
branched positional isomers thereof: the alkylthio radicals containing from 1 to
4 carbon atoms of the above list are preferred;
- the term "halogen atom" denotes chlorine, bromine, iodine or fluorine atoms,
and preferably the chlorine, bromine or fluorine atom;
-the term "cycloalkyl radical" denotes a saturated carbocyclic radical
containing 3 to 10 carbon atoms and thus denotes in particular cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl radicals, and most particularly
cyclopropyl, cyclopentyl and cyclohexyl radicals;
- in the -O-cycloalkyl radical, cycloalkyl is as defined above;
-the term "heterocycloalkyl radical" thus denotes a monocyclic or bicyclic
carbocyclic radical containing from 3 to 10 ring members, interrupted with one
or more heteroatoms, which may be identical or different, chosen from
oxygen, nitrogen or sulphur atoms: mention may, for example, be made of
morpholinyl, thiomorpholinyl, homomorpholinyl, aziridyl, azetidyl, piperazinyl,
piperidyl, homopiperazinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl,
tetrahydrofuryl, tetrahydrothienyl, tetrahydropyran, oxodihydropyridazinyl or
else oxetanyl radicals, all these radicals being optionally substituted; mention
may in particular be made of morpholinyl, thiomorpholinyl, homomorpholinyl,
piperazinyl, piperidyl, homopiperazinyl or else pyrrolidinyl radicals;
- the terms "aryl" and "heteroaryl" denote monocyclic or bicyclic, respectively
carbocyclic and heterocyclic, unsaturated or partially unsaturated radicals
containing at most 12 ring members, that may optionally contain a -C(O) ring
member, the heterocyclic radicals containing one or more heteroatoms, which
may be identical or different, chosen from 0, N, or S, with N, where
appropriate, being optionally substituted;
-the term "aryl radical" thus denotes monocyclic or bicyclic radicals
containing 6 to 12 ring members, such as, for example, phenyl, naphthyl,
biphenyl, indenyl, fluorenyl and anthracenyl radicals, more particularly phenyl
and naphthyl radicals, and even more particularly the phenyl radical. It may

be noted that a carbocyclic radical containing a -C(O) ring member is, for
example, the tetralone radical;
-the term "heteroaryl radical" thus denotes monocyclic or bicyclic radicals
containing 5 to 12 ring members: monocyclic heteroaryl radicals such as, for
example, the radicals: thienyl, such as 2-thienyl and 3-thienyl, furyl, such as
2-furyl or 3-furyl, pyranyl, pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl,
pyridyl, such as 2-pyridyl, 3-pyridyl and 4-pyridyl, pyrazinyl, pyrimidinyl,
pyridazinyl, oxazolyl, thiazolyl, isothiazolyl, diazolyl, thiadiazolyl, thiatriazolyl,
oxadiazolyl, isoxazolyl, such as 3- or 4-isoxazolyl, furazanyl, free or salified
tetrazolyl, all these radicals being optionally substituted, among which are
more particularly the radicals: thienyl, such as 2-thienyl and 3-thienyl, furyl,
such as 2-furyl, pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, oxazolyl,
isoxazolyl, pyridyl and pyridazinyl, these radicals being optionally substituted;
bicyclic heteroaryl radicals such as, for example, the radicals: benzothienyl,
such as 3-benzothienyl, benzothiazolyl, quinolyl, isoquinolyl, dihydroquinolyl,
quinolone, tetralone, adamentyl, benzofuryl, isobenzofuryl,
dihydrobenzofuran, ethylenedioxyphenyl, thianthrenyl, benzopyrrolyl,
benzimidazolyl, benzoxazolyl, thionaphthyl, indolyl, azaindolyl, indazolyl,
purinyl, thienopyrazolyl, tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl,
dihydrofuropyrazolyl, tetrahydropyrrolopyrazolyl, oxotetrahydropyrrolo-
pyrazolyl, tetrahydropyranopyrazolyl, tetrahydropyridinopyrazolyl or
oxodihydropyridinopyrazolyl, all these radicals being optionally substituted.
As examples of heteroaryl or bicyclic radicals, mention may more particularly
be made of pyrimidinyl, pyridyl, pyrrolyl, azaindolyl, indazolyl or pyrazolyl,
benzothiazolyl or benzimidazolyl radicals optionally substituted with one or
more substituents, which may be identical or different, as indicated above.
The carboxyl radical(s) of the products of formula (I) may be salified or
esterified with the various groups known to those skilled in the art, among
which mention may be made, for example of:
- among the salification compounds, inorganic bases such as, for example, an

equivalent of sodium, of potassium, of lithium, of calcium, of magnesium or of
ammonium, or organic bases such as, for example, methylamine,
propylamine, trimethylamine, diethylamine, triethylamine,
N,N-dimethylethanolamine, tris (hydroxymethyl)aminomethane,
ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine,
benzylamine, procaine, lysine, arginine, histidine and N-methylglucamine;
- among the esterification compounds, the alkyl radicals for forming
alkoxycarbonyl groups, such as, for example, methoxycarbonyl,
ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, it being possible
for these alkyl radicals to be substituted with radicals chosen, for example,
from halogen atoms and hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or
aryl radicals, as, for example, in chloromethyl, hydroxy propyl, methoxymethyl,
propionyloxymethyl, methylthiomethyl, dimethylaminoethyl, benzyl or
phenethyl groups.
The addition salts with inorganic or organic acids of the products of
formula (I) may, for example, be the salts formed with hydrochloric acid,
hydrobromic acid, hydroiodic acid, nitric acid, sulphuric acid, phosphoric acid,
propionic acid, acetic acid, trifluoroaectic acid, formic acid, benzoic acid,
maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid,
glyoxylic acid, aspartic acid, ascorbic acid, alkoylmonosulphonic acids such
as, for example, methanesulphonic acid, ethanesulphonic acid or
propanesulphonic acid, alkoyldisulphonic acids such as, for example,
methanedisulphonic acid or alpha, beta-ethanedisulphonic acid,
arylmonosulphonic acids such as benzenesulphonic acid, and aryldisulphonic
acids.
It may be recalled that stereoisomerism can be defined in its broad
sense as the isomerism of compounds having the same structural formulae,
but the various groups of which are arranged differently in space, such as in
particular in monosubstituted cyclohexanes in which the substituent may be in
the axial or equatorial position, and the various possible rotational
conformations of ethane derivatives. However, another type of

stereoisomerism exists, due to the different spatial arrangements of fixed
substituents, on double bonds or on rings, which is often referred to as
geometrical isomerism or cis-transisomerism. The term "stereoisomers" is
used in the present application in its broadest sense and therefore relates to
all the compounds indicated above.
A subject of the present invention is the products of formula (I) as defined
above, in which:
R1 represents an -L-phenyl or -L-heteroaryl radical, such that L represents:
either a single bond,
or a linear or branched alkyl radical containing from 1 to 6 carbon atoms and
optionally substituted with a hydroxyl radical,
or a CO or -CO-Alk- group,
or an L'-X group where L' represents a linear or branched alkyl radical
containing from 1 to 6 carbon atoms, and X an oxygen or sulphur atom;
the phenyl and heteroaryl radicals being optionally substituted with one or
more radicals, which may be identical or different, chosen from halogen
atoms and -NRxRy, alkoxy and alkyl radicals;
the latter alkoxy and alkyl radicals being themselves optionally substituted
with one or more radicals chosen from halogen atoms;
R2 represents an alkyl radical;
R3 represents an alkyl radical optionally substituted with one or more halogen
atoms;
R4 represents a hydrogen atom or a fluorine atom;
NRxRy being such that Rx represents a hydrogen atom or an alkyl radical
and Ry represents a hydrogen atom or an alkyl radical; or Rx and Ry form,
with the nitrogen atom to which they are attached, a morpholino radical;
all the above alkyl (alk) or alkoxy radicals being linear or branched and
containing from 1 to 6 carbon atoms,

said products of formula (I) being in all the possible racemic, enantiomeric
and diastereoisomeric forms, and also the addition salts with inorganic and
organic acids or with inorganic and organic bases, of said products of formula
CO-
ln particular, when NRxRy or NRvRw forms a ring as defined above, such an
amine ring may be chosen in particular from pyrrolidinyl, pyrazolidinyl,
pyrazolinyl, piperidyl, azepinyl, morpholinyl, homomorpholinyl, piperazinyl or
homopiperazinyl radicals, these radicals being themselves optionally
substituted as indicated above or hereinafter.
The NRxRy or NRvRw ring may more particularly be chosen from the
radicals: pyrrolidinyl, morpholinyl optionally substituted with one or two alkyl
radicals or piperazinyl optionally substituted on the second nitrogen atom with
an alkyl, phenyl or and CH2-phenyl radical, themselves optionally substituted
with one or more radicals, which may be identical or different, chosen from
halogen atoms and alkyl, hydroxyl and alkoxy radicals.
A subject of the present invention is most particularly the products of formula
(I) as defined above, corresponding to the following formulae:
-(8S)-9-[2-(4-methoxyphenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-9-[2-(4-methoxyphenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-2-(morpholin-4-yl)-9-(2-phenylethyl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-benzyl-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-
pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[(2S)-2-hydroxy-2-phenylethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[(2R)-2-hydroxy-2-phenylethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrim'do[1,2-a]pyrimidin-4-one

-(8S)-9-[(2S)-2-hydroxy-2-(4-methoxyphenyl)ethyl]-2-(morpholin-4-yl)-8-
(trifluoromethyO-e.y.S^-tetrahydro^H-pyrimidofl^-alpyrimidin-^one
- (8S)-2-(morpholin-4-yl)-9-[(1 R)-1 -phenylethyl]-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[1-(4-methoxyphenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[(1S)-1-(4-bromophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[(1R)-1-(4-bromophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-2-(morpholin-4-yl)-9-phenyl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-
pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(4-fluorophenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(3-fluorophenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(2-fluorophenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[(1R)-1-(3-fluorophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(4-fluorobenzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-2-(morpholin-4-yl)-9-(phenylcarbonyl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-2-(morpholin-4-yl)-9-(pyridin-3-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-2-(morpholin-4-yl)-9-(pyridin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

- (8S)-2-(morpholin-4-yl)-9-(pyridin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-
4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(4-methylphenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetra-
hydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(2-chlorobenzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetra-
hydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(SSJ-g-CS-fluorobenzyO^-Cmorpholin^-yO-S-CtrifluoromethyO-e.y.S.g-tetra-
hydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[2-(2-methoxyphenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[2-(3-methoxyphenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(3-methoxybenzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(4-methoxyphenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[(2-fluorophenyl)carbonyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(3,5-difluorobenzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(2,4-difluorobenzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7)8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-2-(morpholin-4-yl)-9-(2,3,4-trifluorobenzyl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[(5-chloro-1-benzothiophen-3-yl)methyl]-2-(morpholin-4-yl)-8-
(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
- (8S)-9-[(1R or 1S)-1-(4-fluorophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoro-
methyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

- (8S)-9-[(1R or 1S)-1-(4-fluorophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoro-
methyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
- (8S)-9-(3-methylphenyl)-2-(morpholin-4-yl)-8-(trifIuoromethyl)-6,7,8,9-tetra-
hydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(4-chlorophenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetra-
hydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-2-(morpholin-4-yl)-8-(trifluoromethyl)-9-[4-(trifluoromethyl)phenyl]-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
- (8S)-9-[(1R or 1S)-1-(2-fluorophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoro-
methyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
- (8S)-9-[(1R or 1S)-1-(2-fluorophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoro-
methyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[2-(3-fluorophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-benzyl-3-fIuoro-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetra-
hydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(SSJ-g-CS.S-difluorophenyO^-Cmorpholin^-yO-S-CtrifluoromethyO-ej^.g-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[(2,6-difluorophenyl)carbonyl]-2-(morphoiin-4-yl)-8-(trifluoromethyl)-
673,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[(2,4-difluorophenyl)carbonyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-2-(morpholin-4-yl)-9-(phenylacetyl)-8-(trifluoromethyl)-6,7,8,9-tetra-
hydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[2-(3-chlorophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-9-((R)-2-benzo[b]thiophen-2-yl-2-hydroxyethyl)-2-morpholin-4-yl-8-(S)-
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one

-9-[(S)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-2-morpholin-4-yl-8-(S)-
trifluoromethyl-ej.S^-tetrahydropyrimidoII^-aJpyrimidin-^one
-2-dimethylamino-N-{3-[(S)-1-hydroxy-2-((S)-8-morpholin-4-yl-6-oxo-2-
trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-
yl)ethyl]phenyl}acetamide
-9-[(S)-2-hydroxy-2-(2-methoxyphenyl)ethyl]-2-morpholin-4-yl-8-(S)-
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
-9-[(S)-2-(4-fluoro-2-methoxyphenyl)-2-hydroxyethyl]-2-morpholin-4-yl-8-(S)-
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
-9-[(S)-2-(4-chloro-2-methoxyphenyl)-2-hydroxyethyl]-2-morpholin-4-yl-8-(S)-
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
-9-[(S)-2-(2-chloro-4-methoxyphenyl)-2-hydroxyethyl]-2-morpholin-4-yl-8-(S)-
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
-9-(2-hydroxy-3-phenylpropyl)-2-morpholin-4-yl-8-(S)-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one
-9-[2-(4-hydroxyphenyl)ethyl]-2-morpholin-4-yl-8-(S)-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one
and also the addition salts with inorganic and organic acids or with inorganic
and organic bases, of said products of formula (I).
A subject of the present invention is also any process for preparing the
products of formula (I) as defined above.
The products according to the invention can be prepared using conventional
organic chemistry methods.
Preparation of compounds of formula (I)
General schemes 1 and 2 below illustrate the methods used for
preparing the products of formula (I). In this respect, they cannot constitute a
limitation of the scope of the invention, as regards the methods for preparing
the claimed compounds.

The products of formula (I) as defined above according to the present
invention may thus in particular be prepared according to the processes
described in schemes 1 and 2.
A subject of the present invention is thus also the process for preparing
products of formula (I) according to scheme 1 as defined hereinafter.
A subject of the present invention is thus also the process for preparing
products of formula (I) according to general scheme 2 as defined hereinafter.

The guanidines A are either commercially available or are prepared
according to the processes described in Lochead, A.W. et al.
(EP1460076 2002), Lochead, A.W. et al. (EP1340761 2003), Lochead, A.W.
et al. (EP1454909 2004) and Lochead, A.W. et al. (WO2005058908 2005).

The compounds C can be obtained by condensation of a guanidine A
with a dialkyl (preferably diethyl) malonate B, in the presence of a base such
as sodium methoxide, at a temperature of between 60°C and 100°C,
according to the conditions described, for example, by Badawey E.-S.A.M. et
al. (Eur J Med Chem, 1998, 33(5), 349-361).
The compounds D can be obtained from a compound C by treatment
with a chlorinating agent such as phosphorus oxychloride, in the absence of
solvent, at a temperature of between 20°C and 120°C, or in the presence of a
solvent such as dichloroethane, at a temperature of between 20°C and the
boiling point of the solvent, for instance under the conditions described by
Yamashita, A. et al. (Syn. Commun. (2004), 34(5), 795-803).
The compounds E can be obtained from a compound D by reaction
with morpholine, in the absence of solvent, at a temperature of between 20°C
and 120°C, or in the presence of a solvent such as acetonitrile, at a
temperature of between 20°C and the reflux temperature of the solvent, as
described, for example, by Aliabiev S.B. (Lett. Org. Chem. (2007), 4(4), 273-
280.
The compounds (l)-1 can be obtained by means of an alkylation or
acylation reaction, by addition of a compound F (R1-X with R1 = L-aryl or
heteroaryl as defined above and X = CI, Br, I or OTf in the case of an
alkylation and X = CI in the case of an acylation) to a mixture of a compound
E and of a base such as sodium hydride or caesium carbonate in excess, in a
solvent such as tetrahydrofuran, N,N-dimethylformamide or acetonitrile, at a
temperature of between 0°C and 80°C, as described, for example, by Ting
P.C. et al. (J. Med. Chem. (1990), 33(10), 2697-2706) in the case of the
alkylation reaction.
According to the procedure described by E. P. Seest et al., in Tet.
Assymetry 17 (2006) 2154-2182, the compounds F corresponding to chiral
1-aryl-2-chloroethanols or 1-heteroaryl-2-chloroethanols were synthesized
from the corresponding chloroketone derivatives, which are themselves

derived from the chlorination, under standard conditions, of the commercially
available acetyl derivatives.
The compounds (l)-2 can be obtained by reaction of a compound E
with an aryl or heteroaryl halide (X = CI, Br or I) or triflate G, in the presence
of a coupling agent such as copper iodide, in the presence or absence of a
copper ligand such as (+/-)-trans-1,2-diaminocyclohexane or 4,7-dimethoxy-
1,10-phenanthroline, in the presence of a base such as potassium phosphate,
in a solvent such as N-methylpyrrolidone or N,N-dimethylformamide, under
microwave irradiation, at a temperature between 100°C and 200°C, as
described, for example, by Lianbo Z. et al. (J. Org. Chem. (2009), 74(5),
2200-2202).
Alternatively, the compounds (l)-1 can be obtained according to
general scheme 2.

The compounds (l)-1 can be obtained from a compound J by reaction
with morpholine, in the absence of solvent at a temperature of between 20°C
and 120°C, or in the presence of a solvent such as acetonitrile, at a
temperature of between 20°C and the reflux temperature of the solvent, as
described, for example, by Aliabiev S.B. (Lett. Org. Chem. (2007), 4(4), 273-
280.
The compounds J can be obtained by means of an alkylation or
acylation reaction, by addition of a compound F (R1-X with R1 = L-aryl or
heteroaryl as defined above and X = CI, Br, I or OTf in the case of an

alkylation and X = CI in the case of an acylation) to a mixture of a compound
E and of a base such as sodium hydride or caesium carbonate in excess, in a
solvent such as tetrahydrofuran, N,N-dimethylformamide or acetonitrile, at a
temperature of between 0CC and 80°C, as described, for example, by Ting
P.C. et al. (J. Med. Chem. (1990), 33(10), 2697-2706) in the case of the
alkylation reaction.
Alternatively, the compounds J can be obtained by means of a
Mitsunobu reaction between a compound D and an alcohol H, in the presence
of diethyl azodicarboxylate and of triphenylphosphine (optionally supported on
a resin), in a solvent such as tetrahydrofuran, at a temperature of between
0°C and 65°C, as described, for example, by O. Mitsunobu et al. (Synthesis
(1981), 1-28).
When R2 is different from R3 and if the synthesis is not
stereoselective, the enantiomers or the possible diastereoisomers of the
synthesis intermediates or of the compounds (H) can be separated by
chromatography on a chiral support.
The following examples of products of formula (I) illustrate the
invention without, however, limiting it.
Among the starting products of formula A or B, some are known and
can be obtained either commercially or according to the usual methods
known to those skilled in the art, for example starting from commercially
available products.
It is understood, for those skilled in the art, that, in order to implement
the processes according to the invention, described above, it may be
necessary to introduce protective groups for amino, carboxyl and alcohol
functions in order to prevent side reactions.
The following non-exhaustive list of examples of protection of reactive
functions may be mentioned:
- hydroxyl groups can be protected, for example, with alkyl radicals
such as tert-butyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl,

tetrahydropyranyl, benzyl or acetyl,
- amino groups can be protected, for example, with acetyl, trityl,
benzyl, tert-butoxycarbonyl, BOC, benzyloxycarbonyl or phthalimido radicals
or other radicals known in peptide chemistry.
Acid functions can be protected, for example, in the form of esters
formed with readily cleavable esters such as benzyl or tert-butyl esters, or
esters known in peptide chemistry.
A list of various protective groups that can be used will be found in the
manuals known to those skilled in the art, and for example in patent
BF 2 499 995.
It may be noted that it is possible, if desired and if necessary, to
subject intermediate products or products of formula (I) thus obtained by
means of the processes indicated above, in order to obtain other
intermediates or other products of formula (I), to one or more conversion
reactions known to those skilled in the art, such as, for example:
a) a reaction for esterification of an acid function,
b) a reaction for saponification of an ester function to give an acid
function,
c) a reaction for reduction of the free or esterified carboxyl function to
give an alcohol function,
d) a reaction for conversion of an alkoxy function to give a hydroxyl
function, or else of a hydroxyl function to give an alkoxy function,
e) a reaction for removal of the protective groups that the protected
reactive functions may be carrying,
f) a reaction for salification with an inorganic or organic acid or with a
base so as to obtain the corresponding salt,
g) a reaction for resolving the racemic forms to give resolved products,
said products of formula (I) thus obtained being in all the possible

racemic, enantiomeric and diastereoisomeric isomer forms.
The reactions a) to g) can be carried out under the usual conditions known to
those skilled in the art, such as, for example, those indicated hereinafter.
a) The products described above may, if desired, be the subject, on the
possible carboxyl functions, of esterification reactions which can be carried
out according to the usual methods known to those skilled in the art.
b) The possible conversions of ester functions to give acid functions of the
products described above may, if desired, be carried out under the usual
conditions known to those skilled in the art, in particular by acid or alkaline
hydrolysis, for example with sodium hydroxide or potassium hydroxide in an
alcohol medium such as, for example, in methanol, or else with hydrochloric
acid or sulphuric acid.
The saponification reaction can be carried out according to the usual methods
known to those skilled in the art, such as, for example, in a solvent such as
methanol or ethanol, dioxane or dimethoxyethane, in the presence of sodium
hydroxide or of potassium hydroxide.
c) The possible free or esterified carboxyl functions of the products described
above may, if desired, be reduced to give alcohol functions by means of the
methods known to those skilled in the art: the possible esterified carboxyl
functions may, if desired, be reduced to give alcohol functions by means of
the methods known to those skilled in the art, and in particular with lithium
aluminium hydride in a solvent such as, for example, tetrahydrofuran, or else
dioxane or ethyl ether.
The possible free carboxyl functions of the products described above may, if
desired, be reduced to give alcohol functions in particular with boron hydride.
d) The possible alkoxy functions, such as in particular methoxy functions, of
the products described above may, if desired, be converted to hydroxyl
functions under the usual conditions known to those skilled in the art, for
example with boron tribromide in a solvent such as, for example, methylene
chloride, with pyridine hydrobromide or hydrochloride or else with

hydrobromic acid or hydrochloric acid in water or trifluoroacetic acid at reflux.
e) The removal of protective groups such as, for example, those indicated
above can be carried out under the usual conditions known to those skilled in
the art, in particular by acid hydrolysis carried out with an acid such as
hydrochloric acid, benzenesulphonic acid, para-toluenesulphonic acid, formic
acid or trifluoroacetic acid, or else by catalytic hydrogenation.
The phthalimido group may be removed with hydrazine.
f) The products described above may, if desired, be the subject of salification
reactions, for example with an inorganic or organic acid or with an inorganic
or organic base, according to the usual methods known to those skilled in the
art: such a salification reaction can be carried out, for example, in the
presence of hydrochloric acid, or else of tartaric acid, citric acid or
methanesulphonic acid, in an alcohol such as, for example, ethanol or
methanol.
g) The possible optically active forms of the products described above can be
prepared by resolving the racemic mixtures according to the usual methods
known to those skilled in the art.
The products of formula (I) as defined above, and also the addition
salts thereof with acids, have advantageous pharmacological properties, in
particular due to their kinase-inhibiting properties, as is indicated above.
The products of the present invention are in particular of use in tumour
therapy.
The products of the invention may also thus increase the therapeutic
effects of commonly used antitumour agents.
These properties justify the use thereof in therapy, and a subject of the
invention is in particular, as medicaments, the products of formula (I) as
defined above, said products of formula (I) being in all the possible racemic,
enantiomeric and diastereoisomeric isomer forms, and also the
pharmaceutically acceptable addition salts with inorganic and organic acids or

with inorganic and organic bases, of said products of formula (I).
A subject of the invention is most particularly, as medicaments, the
products corresponding to the following formulae:
-(8S)-9-[2-(4-methoxyphenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-9-[2-(4-methoxyphenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-2-(morpholin-4-yl)-9-(2-phenylethyl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-benzyl-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-
pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[(2S)-2-hydroxy-2-phenylethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[(2R)-2-hydroxy-2-phenylethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[(2S)-2-hydroxy-2-(4-methoxyphenyl)ethyl]-2-(morpholin-4-yl)-8-
(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
- (8S)-2-(morpholin-4-yl)-9-[(1 R)-1 -phenylethyl]-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[1-(4-methoxyphenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[(1S)-1-(4-bromophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
- (8S)-9-[(1 R)-1 -(4-bromophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-2-(morpholin-4-yl)-9-phenyl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-
pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(4-fluorophenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-

tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(3-fluorophenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(2-fluorophenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[(1R)-1-(3-fluorophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifiuoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(4-fluorobenzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-2-(morpholin-4-yl)-9-(phenylcarbonyl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-2-(morpholin-4-yl)-9-(pyridin-3-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-2-(morpholin-4-yl)-9-(pyridin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(4-methylphenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(2-chlorobenzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(3-fluorobenzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[2-(2-methoxyphenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[2-(3-methoxyphenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
ej.S.g-tetrahydro^H-pyrimidoII^-alpyrimidin^-one
-(8S)-9-(3-methoxybenzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(4-methoxyphenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-

tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[(2-fluorophenyl)carbonyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(3,5-difluorobenzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(2,4-difluorobenzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-2-(morpholin-4-yl)-9-(2,3,4-trifluorobenzyl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[(5-chloro-1-benzothiophen-3-yl)methyl]-2-(morpholin-4-yl)-8-
(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
- (8S)-9-[(1 R or 1S)-1-(4-fluorophenyl)ethyl]-2-(morpholin-4-yl)-8-
(trifluoromethyO-ej.S^-tetrahydro^H-pyrimidoIl^^pyrimidin^-one
- (8S)-9-[(1R or 1S)-1-(4-fluorophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoro-
methyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(3-methylphenyl)-2-(morpholin-4-yl)-8-(trifluoromethyi)-6,7,8,9-tetra-
hydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(4-chlorophenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetra-
hydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-2-(morpholin-4-yl)-8-(trifluoromethyl)-9-[4-(trifluoromethyl)phenyl]-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
- (8S)-9-[(1 R or 1S)-1-(2-fluorophenyl)ethyl]-2-(morpholin-4-yl)-8-
(trifluoromethyO-ej.S.g-tetrahydro^H-pyrimidofl^-alpyrimidin^-one
- (8S)-9-[(1R or 1S)-1-(2-fluorophenyl)ethyl]-2-(morpholin-4-yl)-8-
(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[2-(3-fluorophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-benzyl-3-fluoro-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetra-

hydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(3,5-difluorophenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[(2,6-difIuorophenyl)carbonyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[(2,4-difluorophenyl)carbonyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-2-(morpholin-4-yl)-9-(phenylacetyl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[2-(3-chlorophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-9-((R)-2-benzo[b]thiophen-2-yl-2-hydroxyethyl)-2-morpholin-4-yl-8-(S)-
trifluoromethyl-ej.S.g-tetrahydropyrimidofl^-alpyrimidin^-one
-9-[(S)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-2-morpholin-4-yl-8-(S)-
trifluoromethyl-ej.S^-tetrahydropyrimidoII^-alpyrimidin^-one
-2-dimethylamino-N-{3-[(S)-1-hydroxy-2-((S)-8-morpholin-4-yl-6-oxo-2-
trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-
yl)ethyl]phenyl}acetamide
-9-[(S)-2-hydroxy-2-(2-methoxyphenyl)ethyl]-2-morpholin-4-yl-8-(S)-
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
-9-[(S)-2-(4-fluoro-2-methoxyphenyl)-2-hydroxyethyl]-2-morpholin-4-yl-8-(S)-
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
-9-[(S)-2-(4-chloro-2-methoxyphenyl)-2-hydroxyethyl]-2-morpholin-4-yl-8-(S)-
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
-9-[(S)-2-(2-chloro-4-methoxyphenyl)-2-hydroxyethyl]-2-morpholin-4-yl-8-(S)-
trifIuoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
-9-(2-hydroxy-3-phenylpropyl)-2-morpholin-4-yl-8-(S)-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one

-9-[2-(4-hydroxyphenyl)ethyl]-2-morpholin-4-yl-8-(S)-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one
and also the pharmaceutically acceptable addition salts with inorganic and
organic acids or with inorganic and organic bases, of said products of formula
(I).
The invention also relates to pharmaceutical compositions containing,
as active ingredient, at least one of the products of formula (I) as defined
above or a pharmaceutically acceptable salt of this product or a prodrug of
this product, and, where appropriate, a pharmaceutically acceptable carrier.
The invention thus extends to the pharmaceutical compositions
containing, as active ingredient, at least one of the medicaments as defined
above.
Such pharmaceutical compositions of the present invention may also,
where appropriate, contain active ingredients of other antimitotic
medicaments, such as in particular those based on taxol, cis-platin, DNA-
intercalating agents, and the like.
These pharmaceutical compositions may be administered orally,
parenterally or locally by topical application to the skin and the mucous
membranes, or by intravenous or intramuscular injection.
These compositions may be solid or liquid and may be in all the
pharmaceutical forms commonly used in human medicine, for instance simple
or sugar-coated tablets, pills, lozenges, gel capsules, drops, granules,
injectable preparations, ointments, creams or gels; they are prepared
according to the usual methods. The active ingredient may be incorporated
therein in excipients normally used in these pharmaceutical compositions,
such as talc, gum Arabic, lactose, starch, magnesium stearate, cocoa butter,
aqueous or nonaqueous carriers, fatty substances of animal or plant origin,
paraffin derivatives, glycols, various wetting agents, dispersants or
emulsifiers, or preservatives.
The usual dosage, which is variable depending on the product used,

the individual treated and the condition in question, may, for example, be from
0.05 to 5 g per day in adults, or preferably from 0.1 to 2 g per day.
A subject of the present invention is also the use of products of formula
(I) as defined above, for the preparation of a medicament for use in the
treatment or prevention of a disease characterized by the disregulation of the
activity of a protein or lipid kinase.
Such a medicament may in particular be for use in the treatment or
prevention of a disease in a mammal.
A subject of the present invention is in particular the use of a product of
formula (I) as defined above, for the preparation of a medicament for use in
the prevention or treatment of various diseases, such as cardiovascular
diseases, including in particular thrombosis.
A subject of the present invention is in particular the use of a product of
formula (I) as defined above, for the preparation of a medicament for use in
the prevention or treatment of diseases associated with an uncontrolled
proliferation.
A subject of the present invention is thus most particularly the use of a
product of formula (I) as defined above, for the preparation of a medicament
for use in the treatment or prevention of diseases in oncology, and in
particular for use in the treatment of cancers.
Among these cancers, the focus is on the treatment of solid or liquid
tumours, and on the treatment of cancers resistant to cytotoxic agents.
The cited products of the present invention may especially be used for the
treatment of primary tumours and/or of metastases, in particular in gastric,
hepatic, renal, ovarian, colon, prostate, endometrial and lung (NSCLC and
SCLC) cancers, glioblastomas, thyroid, bladder and breast cancers, in
melanoma, in lymphoid or myeloid haematopoietic tumours, in sarcomas, in
brain, larynx and lymphatic system cancers, bone and pancreatic cancers,
and in hamartomas. Also involved, in particular, are diseases which exhibit
genetic anomalies resulting in the activation of the PI3K/AKT/mTOR pathway

and/or in the activation of the MAP kinase pathway.
A subject of the present invention is also the use of the products of
formula (I) as defined above, for the preparation of medicaments for use in
cancer chemotherapy.
A subject of the present invention is thus the products of formula (I) as
defined above, for the use thereof in the treatment of cancers.
A subject of the present invention is the products of formula (I) as
defined above, for the use thereof in the treatment of solid or liquid tumours.
A subject of the present invention is therefore the products of formula
(I) as defined above, for the use thereof in the treatment of cancers resistant
to cytotoxic agents.
A subject of the present invention is therefore the products of formula
(I) as defined above, for the use thereof in the treatment of primary tumours
and/or metastases, in particular in gastric, hepatic, renal, ovarian, colon,
prostate, endometrial and lung (NSCLC and SCLC) cancers, glioblastomas,
thyroid, bladder and breast cancers, in melanoma, in lymphoid or myeloid
haematopoietic tumours, in sarcomas, in brain, larynx and lymphatic system
cancers, bone and pancreatic cancers, and in hamartomas.
A subject of the present invention is therefore the products of formula
(I) as defined above, for the use thereof in cancer chemotherapy.
A subject of the present invention is therefore the products of formula
(I) as defined above, for the use thereof in cancer chemotherapy, alone or in
combination.
Such medicaments for use in cancer chemotherapy may be used
alone or in combination.
The products of the present invention may in particular be
administered alone or in combination with chemotherapy or radiotherapy or
else in combination, for example, with other therapeutic agents.
Such therapeutic agents may be commonly used antitumour agents.

A therapeutic benefit can in particular be expected by administering the
products of the present application in combinations with varied targeted
therapies. These targeted therapies are in particular the following: i) therapies
which inhibit the MAP kinase signalling pathway, for instance therapies which
inhibit RAS, RAF.MEK or ERK; ii) targeted therapies which inhibit the kinases
or pseudokinases of the PI3K/AKT/mTOR pathway, for instance EGFR,
HER2, HER3, ALK, MET, PI3K, PDK1, AKT, mTOR and S6K.
A subject of the present invention is in particular the use of a product of
formula (I) as defined above, for the preparation of a medicament for use in
the prevention or treatment of lysosomal diseases such as glycogenosis type
II or Pompe disease. Such medicaments for use in the treatment of lysosomal
diseases can be used alone or in combination, for example, with other
therapeutic agents.
A subject of the present invention is thus the products of formula (I) as
defined above, for the prevention or treatment of lysosomal diseases such as
glycogenosis type II or Pompe disease.
A subject of the present invention is thus the use of the products of
formula (I) as defined above, for the preparation of a medicament for use in
the prevention or treatment of lysosomal diseases such as glycogenosis type
II or Pompe disease.
A subject of the present invention is thus the use as defined above, in
which said products of formula (I) are alone or in combination.
A subject of the present invention is also the use of a product of
formula (I) as defined above, for the preparation of a medicament for use in
the treatment of parasitic diseases such as malaria, sleeping sickness,
Chagas disease or leishmaniasis. Such medicaments for use in the treatment
of parasitic infections can be used alone or in combination, for example, with
other therapeutic agents.
A subject of the present invention is thus the products of formula (I) as
defined above, for the treatment of parasitic diseases such as malaria,

sleeping sickness, Chagas disease or leishmaniasis.
A subject of the present invention is thus the use of the products of
formula (I) as defined above, for the preparation of a medicament for the
treatment of parasitic diseases such as malaria, sleeping sickness, Chagas
disease or leishmaniasis.
A subject of the present invention is also, as novel industrial products,
the synthesis intermediates of formulae C, D, E and J as defined above and
recalled below:

in which R1, R2, R3 and R4 have the meanings indicated in either one of
Claims 1 and 2.
The following examples, which are products of formula (I), illustrate the
invention without, however, limiting it.
Experimental section
The nomenclature of the compounds of this present invention was
carried out with the ACDLABS software, Version 10.0.
The microwave used is a Biotage apparatus, Initiator™ 2.0, 400 W
max, 2450 MHz.
The 1H NMR spectra at 400 MHz and 1H NMR spectra at 500 MHz
were performed on a Bruker Avance DRX-400 or Bruker Avance DPX-500
spectrometer with the chemical shifts (8 in ppm) in the solvent dimethyl
sulfoxide-de (DMSO-d6) referenced at 2.5 ppm at a temperature of 303 K.
The mass spectra (MS) were obtained either by method A or by
method B or by method E:

Method A:
Waters UPLC-SQD instrument; ionization: positive and/or negative
mode electrospray (ES+/-); chromatographic conditions: column: Acquity BEH
C18 1.7 |jm - 2.1 x 50 mm; solvents: A: H20 (0.1% formic acid) B: CH3CN
(0.1% formic acid); column temperature: 50°C; flow rate: 1 ml/min;
gradient (2 min): from 5% to 50% of B in 0.8 min; 1.2 min: 100% of B;
1.85 min: 100% of B; 1.95; 5% of B; retention time = Tr (min).
Method B:
Waters ZQ instrument; ionisation: positive and/or negative mode electrospray
(ES+/-); chromatographic conditions: column: XBridge C18
2.5 urn - 3 x 50 mm; solvents: A: H20 (0.1% formic acid) B: CH3CN (0.1%
formic acid); column temperature: 70°C; flow rate: 0.9 ml/min; gradient (7
min): from 5% to 100% of B in 5.3 min; 5.5 min: 100% of B; 6.3 min: 5% of B;
retention time = Tr (min).
Method E:
Waters UPLC-SQD instrument; ionisation: positive and/or negative
mode electrospray (ES+/-); chromatographic conditions: column: Ascentis
express C18 2.7 urn - 2.1 x 50 mm; solvents: A: H2O (0.02% trifluoroacetic
acid) B: CH3CN (0.014% trifluoroacetic acid); column temperature: 55°C; flow
rate: 1 ml/min; gradient: TOmin 2%B, T1min 98%B, T1.3min 98% B, T1.33min
2%B, T1.5 min other injection; retention time = Tr (min).
The optical rotations (OR) were measured on a polarimeter model 341
from Perkin Elmer. Wavelength: a line of sodium (589 nanometres).
Purifications by preparative HPLC/MS:
■ Method C
SunFire C18 reverse phase column (Waters) 30 x 100, 5 p.
Gradient of acetonitrile (+ 0.07% TFA) in water (+ 0.07% TFA)
TO: 20% acetonitrile (+ 0.07% TFA)

T1: 20% acetonitrile (+ 0.07% TFA)
T11.5: 95% acetonitrile (+ 0.07% TFA)
T15: 95% acetonitrile (+ 0.07% TFA)
T15.5: 20% acetonitrile (+ 0.07% TFA)
Flow rate: 30 ml/min
Mass: 130_800 AMU=; ESP+, ESP
■ Method D
SunFire C18 reverse phase column (Waters) 30 x 100, 5 u.
Gradient of acetonitrile (+ 0.07% TFA) in water (+ 0.07% TFA)
TO: 40% acetonitrile (+ 0.07% TFA)
T1: 40% acetonitrile (+ 0.07% TFA)
T11: 95% acetonitrile (+ 0.07% TFA)
T14.5: 95% acetonitrile (+ 0.07% TFA)
T15: 10% acetonitrile (+ 0.07% TFA)
Flow rate: 30 ml/min
Mass: 130_800 AMU=; ESP+, ESP

Example 1: (S)-9-[2-(4-methoxyphenyl)ethyl]-2-morpholin-4-yl-8-
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one

Stage f: (S)-9-[2-(4-methoxyphenyl)ethyl]-2-morpholin-4-yl-8-
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
0.5 g of caesium carbonate, 0.23 g of 4-methoxyphenethyl bromide
and 5 mg of benzyltriethylammonium chloride (BTEAC) are added, at ambient
temperature and under an argon atmosphere, to a solution of 150 mg of (S)-
2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-
4-one in 5 ml of anhydrous dimethylformamide. The reaction mixture is
heated at 80°C for 18 hours.
After cooling, 10 ml of cold water and 50 ml of ethyl acetate are added
to the mixture obtained. The organic phase is separated and then dried over
magnesium sulphate, filtered, and concentrated under reduced pressure. The
residue obtained is purified by silica chromatography (gradient of 0% to 20%
of the eluent CH2CI2/MeOH/NH4OH 28% 38/17/2 in dichloromethane), so as
to give 160 mg of (S)-9-[2-(4-methoxyphenyl)ethyl]-2-morpholin-4-yl-8-
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the
characteristics of which are the following:
1H NMR spectrum:
1.82 to 2.05 (m, 1 H); 2.25 to 2.39 (m, 1 H); 2.73 to 2.83 (m, 1 H); 2.88
to 2.99 (m, 1 H); 3.10 to 3.21 (m, 1 H); 3.34 to 3.41 (m, 1 H); 3.43 to 3.46 (m,
4 H); 3.65 (m, 4 H); 3.72 (s, 3 H); 4.03 to 4.23 (m, 2 H); 4.47 to 4.60 (m, 1 H);

4.99 (s, 1 H); 6.87 (d, J=8.6 Hz, 2 H); 7.12 (d, J=8.6 Hz, 2 H).
Mass spectrometry: method A
Retention time Tr (min) = 0.93
[M+H]+: m/z 439
Optical rotation: OR= +91; C=2.426 mg/0.5 ml MeOH.
Stage e: (S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-
pyrimido[1,2-a]pyrimidin-4-one

A mixture of 1 g of (S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydro-
pyrimido[1,2-a]pyrimidin-4-one and of 15 ml of morpholine is heated at 80°C.
After one and a half hours of heating and after verification by LC/MS, the
reaction is complete. After cooling, the reaction mixture is concentrated under
reduced pressure. 10 ml of cold water and 100 ml of ethyl acetate are added
to the residue obtained. The resulting organic phase is separated and then
dried over magnesium sulphate, filtered, and concentrated under reduced
pressure so as to give 1.2 g of (S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are the
following:
Mass spectrometry: method A
Retention time Tr (min) = 0.49
[M+H]+: m/z 305; [M-H]-: m/z 303
Optical rotation: OR= +14.2+/-0.6; C=2.25mg/0.5 ml MeOH.
Stage d: (S)-2-chloro-8-trifluoromethyl-6s7,859-tetrahydropyrimido[1,2-
a]pyrimidin-4-one


The two enantiomers of (R,S)-2-chloro-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one (17 g) are separated by chiral
chromatography: stationary phase: Chiralpak AD; mobile phase: EtOH (20%)/
heptane (80%).
The laevorotary enantiomer is concentrated so as to give 8.52 g of (R)-
2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, in
the form of a white powder.
The dextrorotary enantiomer is concentrated so as to obtain 8.21 g of
(S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-
one, in the form of a white powder, the characteristics of which are the
following:
Mass spectrometry: method A
Retention time Tr (min) = 0.51
[M+H]+: m/z 254; [M-H]-: m/z 252
Optical rotation: OR = +21.3+/-0.5. MeOH.
Stage c: (R,S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-
a]pyrimidin-4-one
60 ml of phosphorus oxychloride are added, at ambient temperature
and under an argon atmosphere, to a suspension of 34 g of (R,S)-2-hydroxy-
8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 500 ml of
1,2-dichloroethane. The mixture obtained is then heated to 65°C. After stirring
for three hours at 65°C, the reaction is complete according to the verification

by LC/MS. After cooling, the reaction mixture is evaporated to dryness under
reduced pressure. The residue obtained is taken up with 100 ml of cold water
and 400 ml of ethyl acetate. 32% sodium hydroxide is added to the mixture
obtained, until pH = 6. The resulting organic phase is separated and then
dried over magnesium sulphate, filtered, and concentrated under reduced
pressure so as to give an orange residue. This residue is purified by silica
chromatography (eluent: CH2CI2/MeOH: 97/03) so as to give 20 g of (R,S)-2-
chloro-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one, in
the form of a white solid, the characteristics of which are the following:
Mass spectrometry: method A
Retention time Tr (min) = 0.51
[M+H]+: m/z 254; [M-H]-: m/z 252.
Stage b: (R,S)-2-hydroxy-8-trifluoromethyl-6,7,8,9-tetrahydro-
pyrimido[1,2-a]pyrimidin-4-one

10 g of 6-trifluoromethyl-1,4,5,6-tetrahydropyrimidin-2-ylamine
hydrochloride and 10 g of sodium methoxide are added to a mixture of 50 ml
of diethyl malonate. The mixture obtained is brought to 100°C for 75 minutes.
The heterogeneous mixture thickens and turns yellow with a small amount of
gas being given off. After cooling, the reaction mixture is evaporated to
dryness under reduced pressure. The residue obtained is triturated with ethyl
ether. The solid formed is filtered off on a sintered glass filter and then taken
up with 20 ml of cold water. 12 N hydrochloric acid is added to the thick
suspension obtained, until pH = 5-6. The suspension obtained is filtered
through sintered glass and the insoluble material is rinsed with ethyl ether so
as to give 11.5 g of (R,S)-2-hydroxy-8-trifluoromethyl-6,7,8,9-tetrahydro-
pyrimido[1,2-a]pyrimidin-4-one, in the form of a white solid, the characteristics

of which are the following:
Mass spectrometry: method A
Retention time Tr (min) = 0.26
[M+H]+: m/z 236; [M-H]-: m/z 234.
Stage a: (R,S)-6-trifluoromethyl-1,4,5,6-tetrahydropyrimidin-2-ylamine
hydrochloride
In an autoclave, a mixture of 1.1 g of Pd/C at 10%, 22 g of 2-amino-4-
(trifluoromethyl)pyrimidine dissolved in 200 ml of water, 50 ml of methanol
and 50 ml of 12N HCI are hydrogenated, under 3 bar, at 22°C, for 24 hours.
The resulting mixture is then filtered and the filtrate is concentrated under
reduced pressure. The residue obtained is oven-dried, in the presence of
P205, so as to give 27 g of (R,S)-6-trifluoromethyl-1,4,5,6-tetrahydropyrimidin-
2-ylamine hydrochloride, in the form of a grey solid, the characteristics of
which are the following:
Mass spectrometry: method A
Retention time Tr (min) = 0.17
[M+H]+: m/z 168.
Example 2: (R,S)-9-[2-(4-methoxyphenyl)ethyl]-2-morpholin-4-yl-8-
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one


Stage b: (R,S)-9-[2-(4-methoxyphenyl)ethyl]-2-morpholin-4-yl-8-trifluoro-
methyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
0.5 g of caesium carbonate, 0.23 g of 4-methoxyphenethyl bromide
and 10 mg of benzyltriethylammonium chloride (BTEAC) are added, at
ambient temperature and under an argon atmosphere, to a solution of 120 mg
of (R,S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-
a]pyrimidin-4-one in 5 ml of anhydrous dimethylformamide. The resulting
mixture is heated at 80°C for 18 hours.
After cooling, the reaction mixture is concentrated under reduced
pressure. The residue obtained is taken up with 50 ml of ethyl acetate and the
solution obtained is washed with 3 ml of water. The organic phase is
separated and then dried over magnesium sulphate, filtered, and evaporated
under reduced pressure. After purification by silica chromatography (gradient
of 0% to 20% of the eluent CH2CI2/MeOH/NH4OH 28% 38/17/2 in
dichloromethane), 80 mg of (R,S)-(9-[2-(4-methoxyphenyl)ethyl]-2-morpholin-
4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are
obtained, the characteristics of which are the following:
1H NMR spectrum:
1.85 to 2.02 (m, 1 H); 2.27 to 2.35 (m, 1 H); 2.72 to 2.84 (m, 1 H); 2.88
to 2.98 (m, 1 H); 3.09 to 3.20 (m, 1 H); 3.37 to 3.42 (m, 1 H); 3.45 (m, 4 H);
3.63 to 3.67 (m, 4 H); 3.72 (s, 3 H); 4.08 (m, 1 H); 4.14 to 4.21 (m, 1 H); 4.51
to 4.63 (m, 1 H); 5.00 (s, 1 H); 6.88 (d, J=8.6 Hz, 2 H); 7.13 (d, J=8.6 Hz, 2
H).
Mass spectrometry: method A
Retention time Tr (min) = 0.93
[M+H]+: m/z 439.
Stage a: (R,S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-
pyrimido[1,2-a]pyrimidin-4-one


A mixture of 220 mg of (R,S)-2-chloro-4-yl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one in 5 ml of morpholine is heated to
80°C. After heating for one and a half hours, the reaction is complete
according to the verification by LC/MS. After cooling, the reaction mixture is
concentrated under reduced pressure. The residue obtained is purified by
silica chromatography (gradient of 5% to 20% of the eluent
CH2CI2/MeOH/NH4OH 28% 38/17/2 in dichloromethane) so as to give 270 mg
of (R,S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-
a]pyrimidin-4-one, the characteristics of which are the following:
Mass spectrometry: method B
Retention time Tr (min) = 2.53
[M+H]+: m/z 305; [M-H]-: m/z 303.
Example 3: (S)-2-morpholin-4-yl-9-phenethyl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one

Stage a:
(R,S)-2-morpholin-4-yl-9-phenethyl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one is prepared according to the
procedure described in Example 2, using 80 mg of (R,S)-2-morpholin-4-yl-8-
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 240 mg

of (2-bromoethyl)benzene. After purification by silica chromatography (eluent:
a gradient of 5% to 20% of the eluent CH2CI2/MeOH/NH4OH 28% 38/17/2 in
dichloromethane), 75 mg of (R,S)-2-morpholin-4-yl-9-phenethyl-8-
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained,
the characteristics of which are the following:
1H NMR spectrum:
1.85 to 2.01 (m, 1 H); 2.27 to 2.35 (m, 1 H); 2.86 (m, 1 H); 2.95 to 3.05
(m, 1 H); 3.11 to 3.21 (m, 1 H); 3.39 to 3.49 (m, 5 H); 3.63 to 3.68 (m, 4 H);
4.08 to 4.23 (m, 2 H); 4.53 to 4.62 (m, 1 H); 5.00 (s, 1 H); 7.18 to 7.25 (m, 3
H); 7.29 to 7.34 (m, 2 H).
Mass spectrometry: method A
Retention time Tr (min) = 0.95
[M+H]+: m/z 409.
Stage b:
The two enantiomers of (R,S)-2-morpholin-4-yl-9-phenethyl-8-
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are separated
by chiral chromatography: Chiralpak IC 20 urn column; elution 75%
heptane/20% EtOH/5% MeOH.
The dextrorotary enantiomer is concentrated so as to obtain 27 mg of
(S)-2-morpholin-4-yl-9-phenethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido-
[1,2-a]pyrimidin-4-one, the characteristics of which are the following:
1H NMR spectrum:
1.94 (m, 1 H); 2.23 to 2.35 (m, 1 H); 2.83 to 2.91 (m, 1 H); 2.96 to 3.04
(m, 1 H); 3.16 (m, 1 H); 3.40 to 3.52 (m, 5 H); 3.65 (m, 4 H); 4.07 to 4.21 (m,
2 H); 4.50 to 4.62 (m, 1 H); 5.00 (s, 1 H); 7.18 to 7.25 (m, 3 H); 7.29 to 7.35
(m, 2 H).
Mass spectrometry: method A
Retention time Tr (min) = 0.95

[M+H]+: m/z 409
Optical rotation: OR = positive sign (+40); C=1.093 mg/0.5 ml DMSO.
The chromatographic purification also results in 30 mg of the
laevorotary enantiomer, (R)-2-morpholin-4-yl-9-phenethyl-8-trifluoromethyl-
6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one.
Example 4: (S)-9-benzyl-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one

Stage b:
The two enantiomers of (R,S)-9-benzyl-2-morpholin-4-yl-8-
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are separated
by chiral chromatography: 6 x 35 cm column; mobile phase: 60% EtOH/40%
heptane.
The dextrorotary enantiomer is concentrated so as to give 36 mg of
(S)-9-benzyl-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-
pyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are the following:
1H NMR spectrum:
2.10 to 2.25 (m, 1 H); 2.35 to 2.43 (m, 1 H); 3.19 to 3.27 (m, 5 H); 3.39
to 3.53 (m, 4 H); 4.16 to 4.27 (m, 1 H); 4.51 (d, J=15.9 Hz, 1 H); 4.57 to 4.72
(m, 1 H); 4.96 (s, 1 H); 5.23 (d, J=15.9 Hz, 1 H); 7.20 to 7.27 (m, 3 H); 7.28 to
7.34 (m, 2 H).
Mass spectrometry: method A
Retention time Tr (min) = 0.88
[M+H]+: m/z 395

Optical rotation: OR = +16.3+/-0.7. C=1.960 mg/0.5 ml DMSO.
The chromatographic purification above also results in 38 mg of the
laevorotary enantiomer, (R)-9-benzyl-2-morpholin-4-yl-8-trifluoromethyl-
6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one.
Stage a: (R,S)-9-benzyl-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one

The product is prepared according to the procedure described in
Example 2, using 140 mg of (R,S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one and 0.270 ml of benzyl bromide.
After purification by silica chromatography (gradient of 5% to 20% of the
eluent CH2CI2/MeOH/NH4OH 28% 38/17/2 in dichloromethane), 32 mg of
(R,S)-9-benzyl-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-
pyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are
the following:
1H NMR spectrum:
2.11 to 2.25 (m, 1 H); 2.35 to 2.44 (m, 1 H); 3.17 to 3.27 (m, 5 H); 3.40
to 3.53 (m, 4 H); 4.18 to 4.29 (m, 1 H); 4.51 (d, J=15.9 Hz, 1 H ); 4.58 to 4.72
(m, 1 H); 4.96 (s, 1 H); 5.22 (d, J=15.9 Hz, 1 H); 7.20 to 7.27 (m, 3 H); 7.28 to
7.36 (m, 2 H).
Mass spectrometry: method A
Retention time Tr (min) = 0.88
[M+H]+: m/z 395.
Examples: 9-((S)-2-hydroxy-2-phenylethyl)-2-morpholin-4-yl-8-(S)-
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one


The product is prepared according to the procedure described in
Example 2, using 135 mg of (R,S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one and 342 mg of (S)-2-chloro-1-
phenylethanol. After purification by silica chromatography (gradient of 5% to
20% of the eluent CH2CI2/MeOH/NH4OH 28% 38/17/2 in dichloromethane),
26 mg of 9-((S)-2-hydroxy-2-phenylethyl)-2-morpholin-4-yl-8-(R)-trifluoro-
methyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 18 mg of (S)-9-
((S)-2-hydroxy-2-phenylethyl)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of
which are the following:
1H NMR spectrum:
2.24 (m, 1 H); 2.36 to 2.46 (m, 1 H); 3.08 (dd, J=10.0 and 14.2 Hz,
1 H); 3.17 to 3.27 (m, 1 H); 3.40 to 3.48 (m, 4 H); 3.63 to 3.69 (m, 4 H); 4.17
to 4.32 (m, 2 H); 4.74 to 4.85 (m, 1 H); 4.99 (m, 1 H); 5.02 (s, 1 H); 5.67 (d,
J=5.1 Hz, 1 H); 7.22 to 7.44 (m, 5 H).
Mass spectrometry: method A
Retention time Tr (min) = 0.85
[M+H]+: m/z 425; [M-H+HCO2H]-: m/z 469
Optical rotation: OR = +7.4+/-0.6; C=1.959 mg/0.5 ml CH30H.
Example 6: 9-((R)-2-hydroxy-2-phenylethyl)-2-morpholin-4-yl-8-(S)-
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one


The product is prepared according to the procedure described in
Example 2, using 135 mg of (R,S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one and 342 mg of (R)-2-chloro-1-
phenylethanol. After purification by silica chromatography (gradient of 5% to
20% of the eluent CH2CI2/MeOH/NH4OH 28% 38/17/2 in dichloromethane),
25 mg of 9-((R)-2-hydroxy-2-phenylethyl)-2-morpholin-4-yl-8-(S)-trifluoro-
methyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the
characteristics of which are the following:
1H NMR spectrum:
1.40 to 1.56 (m, 1 H); 2.05 to 2.17 (m, 1 H); 3.05 to 3.20 (m, 2 H); 3.36
to 3.47 (m, 4 H); 3.62 to 3.67 (m, 4 H); 3.84 to 3.94 (m, 1 H); 3.96 to 4.03 (m,
1 H); 4.54 (dd, J=6.0 and 13.8 Hz, 1 H); 4.96 (s, 1 H); 4.99 to 5.04 (m, 1 H);
5.56 (broad s, 1 H); 7.18 to 7.37 (m, 5 H).
Mass spectrometry: method A
Retention time Tr (min) = 0.73
[M+H]+: m/z 425; [M-H+HCO2H]-: m/z 469
Optical rotation: OR =+63.3 +/-1.4 in MeOH.
In the purification above, 20 mg of 9-((R)-2-hydroxy-2-phenylethyl)-2-
morpholin-4-yl-8-(R)-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-
a]pyrimidin-4-one are also obtained.
Example 7: (8S)-9-[(2S)-2-hydroxy-2-(4-methoxyphenyl)ethyl]-2-
(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-
a]pyrimidin-4-one


The product is prepared according to the procedure described in
Example 2, using 135 mg of (R,S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one and 760 mg of (S)-2-chloro-1-(4-
methoxyphenyl)ethanol. After purification by silica chromatography (gradient
of 5% to 20% of the eluent CH2CI2/MeOH/NH4OH 28% 38/17/2 in
dichloromethane), 66 mg of (8S)-9-[(2S)-2-hydroxy-2-(4-methoxy-
phenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-
pyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are
the following:
1H NMR spectrum:
2.14 to 2.29 (m, 1 H); 2.35 to 2.44 (m, 1 H); 3.06 (dd, J=9.8 and
13.9 Hz, 1 H); 3.14 to 3.27 (m, 1 H); 3.37 to 3.50 (m, 4 H); 3.62 to 3.69 (m, 4
H); 3.74 (s, 3 H); 4.14 to 4.28 (m, 2 H); 4.79 (m, 1 H); 4.90 to 4.98 (m, 1 H);
5.01 (s, 1 H); 5.57 (d, J=4.9 Hz, 1 H); 6.93 (d, J=8.6 Hz, 2 H); 7.25 (d, J=8.6
Hz, 2 H).
Mass spectrometry: method A
Retention time Tr (min) = 0.84
[M+H]+: m/z 499
Optical rotation: OR = +4; C=1.397 mg/0.5 ml in CH3OH.
36 mg of (8R)-9-[(2S)-2-hydroxy-2-(4-methoxyphenyl)ethyl]-2-
(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-
a]pyrimidin-4-one sre also obtained.

Example 8: (8S)-2-(morpholin-4-yl)-9-[(1R or 1S)-1-phenylethyl]-8-
(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

The product is prepared according to the procedure described in
Example 1f, using 135 mg of (S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1d) in 5 ml of acetonitrile,
and 520 mg of (l-bromoethyl)benzene. After purification by silica
chromatography (gradient of 5% to 20% of the eluent
CH2CI2/MeOH/NH4OH 28% 38/17/2 in dichloromethane), 23 mg of (8S)-2-
(morpholin-4-yl)-9-[1-phenylethyl]-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-
pyrimido[1,2-a]pyrimidin-4-one are obtained, in the form of a single
diastereoisomer of undetermined configuration on the phenethyl chain, the
characteristics of which are the following:
1H NMR spectrum:
1.65 (d, J=7.0 Hz, 3 H); 1.72 to 1.84 (m, 1 H); 2.29 to 2.38 (m, 1 H);
3.15 to 3.26 (m, 5 H); 3.43 to 3.55 (m, 4 H); 4.08 (m, 1 H); 4.31 to 4.44 (m, 1
H); 4.96 (s, 1 H); 5.67 (q, J=7.0 Hz, 1 H); 7.23 to 7.40 (m, 5 H).
Mass spectrometry: method A
Retention time Tr (min) = 4.07
[M+H]+: m/z 409
Optical rotation: OR = +54.5+/-0.6; C=1.594 mg/0.5 ml CH30H.
Example 9: (8S)-9-[(1R and 1S)-1-(4-methoxyphenyl)ethyl]-2-(morpholin-
4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-
4-one


In a round-bottomed flask, 130 mg of (S)-2-chloro-8-trifluoromethyl-
6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1d) are introduced
into 3 ml of tetrahydrofuran, 250 mg of resin-supported triphenylphosphine
(3 mmol/g) and 116 mg of 1-(4-methoxyphenyl)ethanol. 0.12 ml of diethyl
azodicarboxylate is then added dropwise. After the addition, the reaction
mixture is stirred for 18 hours at ambient temperature. 250 mg of resin-
supported triphenylphosphine (3 mmol/g) are then added to the reaction
mixture. After stirring for a further 18 hours at ambient temperature, the
resulting mixture is filtered through a Millex filter and the filtrate obtained is
then concentrated under reduced pressure.
The residue is dissolved in 5 ml of morpholine and the resulting
mixture is heated at 80°C for 2 hours. The reaction mixture is concentrated
under reduced pressure. After purification by silica chromatography (gradient
of 0% to 20% of the eluent CH2CI2/MeOH/NH4OH 28% 38/17/2 in
dichloromethane), 40 mg of (8S)-9-[1-(4-methoxyphenyl)ethyl]-2-(morpholin-
4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
are obtained, in the form of a 60/40 mixture of the two diastereoisomers, the
characteristics of which are the following:
1H NMR spectrum:
1.61 (d, J=7.1 Hz, 1.8 H); 1.68 (d, J=7.1 Hz, 1.2 H); 2.09 to 2.47 (m,
2 H); 3.10 to 3.65 (m partially masked, 9 H); 3.72 (s, 1.2 H); 3.74 (s, 1.8 H);
3.85 to 4.34 (m, 1.6 H); 4.68 to 4.87 (m, 0.4 H); 4.93 (s, 0.4 H); 4.98 (s,
0.6 H); 5.47 (q, J=7.1 Hz, 0.4 H); 5.79 (q, J=7.1 Hz, 0.6 H); 6.86 (d, J=8.6 Hz,
0.8 H); 6.92 (d, J=8.6 Hz, 1.2 H); 7.26 (d, J=8.6 Hz, 2 H).

Mass spectrometry: method A
Retention time Tr (min) = 0.94 and 0.89 (60/40 mixture of the two
diastereoisomers).
[M+H]+: m/z 439.
Example 10: (8S)-9-[(1R or 1S)-1-(4-bromophenyl)ethyl]-2-(morpholin-4-
yO-S^trifluoromethyO-ej.S.S-tetrahydro^H-pyrimidoII^-alpyrimidin^-
one

The product is prepared according to the procedure described in
Example 9, using 300 mg of (S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydro-
pyrimido[1,2-a]pyrimidin-4-one in 6 ml of tetrahydrofuran, 600 mg of resin-
supported triphenylphosphine (3 mmol/g) and 354 mg of 1-(4-
bromophenyl)ethanol. 0.28 ml of diethyl azodicarboxylate is then added
dropwise. After the addition, the reaction mixture is stirred for 18 hours at
ambient temperature. 600 mg of resin-supported triphenylphosphine (3 mmol/
g) are then added to the reaction mixture. After stirring for a further 18 hours
at ambient temperature, the resulting mixture is filtered through a Millex filter
and the filtrate obtained is then concentrated under reduced pressure.
The evaporation residue is dissolved in 5 ml of morpholine and the
mixture obtained is stirred at ambient temperature for 4 days. The reaction
mixture is then concentrated under reduced pressure. After purification by
silica chromatography (gradient of 0 to 20% of the eluent
CH2CI2/MeOH/NH4OH 28% 38/17/2 in dichloromethane), 15 mg of one of the
diastereoisomers of (8S)-9-[1 -(4-bromophenyl)ethyl]-2-(morpholin-4-yl)-8-
(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

(undetermined configuration on the phenethyl chain) are obtained, the
characteristics of which are the following:
1H NMR spectrum:
1.73 (d, J=7.1 Hz, 3 H); 2.16 to 2.31 (m, 1 H); 2.39 to 2.47 (m, 1 H);
3.12 to 3.25 (m, 5 H); 3.35 to 3.51 (m, 4 H); 4.15 (m, 1 H); 4.82 to 4.90 (m,
1 H); 4.92 (s, 1 H); 5.33 (q, J=7.1 Hz, 1 H); 7.27 (d, J=8.6 Hz, 2 H); 7.49 (d,
J=8.6 Hz, 2 H).
Mass spectrometry: method B
Retention time Tr (min) = 4.26
[M+H]+: m/z 487.
Example 11: (8S)-9-[(1S or 1R)-1-(4-bromophenyl)ethyl]-2-(morpholin-4-
yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-
one

The preceding purification also produces 60 mg of the second
diastereoisomer of (8S)-9-[1 -(4-bromophenyl)ethyl]-2-(morpholin-4-yl)-8-
(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
(undetermined configuration on the phenethyl chain), the characteristics of
which are the following:
1H NMR spectrum:
1.64 (d, J=7.1 Hz, 3 H); 1.78 to 1.94 (m, 1 H); 2.30 to 2.40 (m, 1 H);
3.08 to 3.26 (m, 5 H); 3.39 to 3.52 (m, 4 H); 4.11 (m, 1 H); 4.52 (m, 1 H); 4.95
(s, 1 H); 5.50 (q, =7.1 Hz, 1 H); 7.25 (d, J=8.6 Hz, 2 H); 7.53 (d, J=8.6 Hz,
2H).

Mass spectrometry: method B
Retention time Tr (min) = 4.37
[M+H]+: m/z 487.
Example 12: (8S)-2-(morpholin-4-yl)-9-phenyl-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

In a microwave tube, 425 mg of (S)-2-morpholin-4-yl-8-trifluoromethyl-
6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e) are introduced
into 1 ml of dimethylformamide, 422 mg of tripotassium phosphate, 380 mg of
copper iodide and 2 ml of iodobenzene. The mixture obtained is heated in a
microwave oven for 30 minutes at 150°C. The reaction mixture is then
centrifuged. The separated supernatant is then rinsed with ethyl acetate and
then evaporated to dryness. The residue is taken up with ethyl acetate and
the solution obtained is washed with water. The organic phase is separated
and then dried over magnesium sulphate, filtered, and concentrated under
vacuum. After purification by silica chromatography (gradient of 5% to 15% of
the eluent CH2CI2/MeOH/NH4OH 28% 38/17/2 in dichloromethane), 150 mg of
(8S)-2-(morpholin-4-yl)-9-phenyl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-
pyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are
the following:
1H NMR spectrum:
2.40 to 2.48 (m, 2 H); 3.00 to 3.13 (m, 4 H); 3.31 to 3.37 (m, 1 H); 3.38
to 3.48 (m, 4 H); 4.33 to 4.40 (m, 1 H); 4.93 (m, 1 H); 4.99 (s, 1 H); 7.28 to
7.37 (m, 3 H); 7.43 (t, J=7.7 Hz, 2 H).
Mass spectrometry: method A

Retention time Tr (min) = 0.83
[M+H]+:m/z381.
Example 13: (8S)-9-(4-fluorophenyl)-2-(morpholin-4-yl)-8-
(trifluoromethyO-ej.S.S-tetrahydro^H-pyrimidotl^-alpyrimidin-A-one

The product is prepared according to the procedure described in
Example 12, using 140 mg of (S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e) and 0.66 ml of 1-
fluoro-4-iodobenzene. After purification by silica chromatography (gradient of
5% to 15% of the eluent CH2CI2/MeOH/NH4OH 28% 38/17/2 in
dichloromethane), 125 mg of (8S)-9-(4-fluorophenyl)-2-(morpholin-4-yl)-8-
(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are
obtained, the characteristics of which are the following:
1H NMR spectrum:
2.41 to 2.48 (m, 2 H); 3.01 to 3.15 (m, 4 H); 3.33 to 3.37 (m, 1 H); 3.40
to 3.50 (m, 4 H); 4.35 (m, 1 H); 4.82 to 4.94 (m, 1 H); 5.00 (s, 1 H); 7.25 (t,
J=8.8 Hz, 2 H); 7.40 (dd, J=5.6 and 8.8 Hz, 2 H).
Mass spectrometry: method A
Retention time Tr (min) = 0.86
[M+H]+: m/z 399.
Example 14: (8S)-9-(3-fluorophenyl)-2-(morpholin-4-yl)-8-
(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one


The product is prepared according to the procedure described in
Example 12, using 140 mg of (S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e) and 0.66 ml of
1-fluoro-3-iodobenzene. After purification by silica chromatography (gradient
of 5% to 15% of the eluent CH2CI2/MeOH/NH4OH 28% 38/17/2 in
dichloromethane), 60 mg of (8S)-9-(3-fluorophenyl)-2-(morpholin-4-yl)-8-
(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are
obtained, the characteristics of which are the following:
1H NMR spectrum:
2.41 to 2.48 (m, 2 H); 3.03 to 3.15 (m, 4 H); 3.25 to 3.27 (m, 1 H); 3.42
to 3.49 (m, 4 H); 4.32 to 4.41 (m, 1 H); 4.93 to 5.00 (m, 1 H); 5.02 (s, 1 H);
7.14 to 7.24 (m, 2 H); 7.30 (td, J=2.2 and 10.5 Hz, 1 H); 7.46 (dt, J=6.7 and
8.1 Hz, 1 H).
Mass spectrometry: method A
Retention time Tr (min) = 0.86
[M+H]+: m/z 399.
Example 15: (8S)-9-(2-fluorophenyl)-2-(morpholin-4-yl)-8-
(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one


The product is prepared according to the procedure described in
Example 12, using 140 mg of (S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e) and 0.66 ml of
1-fluoro-2-iodobenzene. After purification by silica chromatography (gradient
of 5% to 15% of the eluent CH2CI2/MeOH/NH4OH 28% 38/17/2 in
dichloromethane), 12 mg of (8S)-9-(2-fluorophenyl)-2-(morpholin-4-yl)-8-
(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are
obtained, the characteristics of which are the following:
1H NMR spectrum:
2.37 to 2.47 (m, 2 H); 3.05 to 3.09 (m, 5 H); 3.41 to 3.47 (m, 4 H); 4.35
to 4.44 (m, 1 H); 4.89 (m, 1 H); 5.02 (s, 1 H); 7.24 to 7.33 (m, 2 H); 7.36 to
7.45 (m, 1 H);7.51 (m, 1 H).
Mass spectrometry: method A
Retention time Tr (min) = 0.83
[M+H]+: m/z 399.
Example 16: (8S)-9-[(1R or 1S)-1-(3-fluorophenyl)ethyl]-2-(morpholin-4-
yO-S-ttrifluoromethylJ-SJ.S.S-tetrahydro^H-pyrimidoII^-alpyrimidin-A-
one

Stage b:
In a round-bottomed flask, a mixture of 300 mg of (S)-2-chloro-1-[1-(3-
fluorophenyl)ethyl]-8-trifluoromethyl-1,6,7,8-tetrahydropyrimido[1,2-
a]pyrimidin-4-one and 3 ml of morpholine is heated at 80°C for 30 minutes.
After cooling, the reaction mixture is concentrated under reduced pressure.

The residue is taken up with ethyl acetate and water. The organic phase is
separated and then dried over magnesium sulphate, filtered, and
concentrated under reduced pressure. After purification by silica
chromatography (eluent: CH2CI2/MeOH 97.5/2.5), 152 mg of (8S)-9-[(1-(3-
fluorophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-
4H-pyrimido[1,2-a]pyrimidin-4-one are obtained, in the form of a single
diastereoisomer (undetermined configuration on the phenethyl chain), the
characteristics of which are the following:
1H NMR spectrum:
1.66 (d, J=7.0 Hz, 3 H); 1.80 to 1.95 (m, 1 H); 2.33 to 2.41 (m, 1 H);
3.09 to 3.28 (m, 5 H); 3.40 to 3.52 (m, 4 H); 4.06 to 4.16 (m, 1 H); 4.56 (m,
1 H); 4.95 (s, 1 H); 5.51 (q, J=7.0 Hz, 1 H); 7.00 to 7.17 (m, 3 H); 7.33 to 7.42
(m, 1 H).
Mass spectrometry: method A
Retention time Tr (min) = 0.94
[M+H]+: m/z 427.
Stage a:
In a round-bottomed flask, 400 mg of (S)-2-chloro-8-trifluoromethyl-
6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1d) are introduced
into 20 ml of tetrahydrofuran, 1.6 g of resin-supported triphenylphosphine
(3 mmol/g) and 663 mg of 1-(3-fluorophenyl)ethanol. The reaction mixture is
then stirred at ambient temperature for 5 minutes, before the addition of
0.790 ml of diethyl azodicarboxylate. After stirring for 1 hour at ambient
temperature, the reaction mixture is filtered and the filtrate is concentrated
under reduced pressure.
The residue is taken up with ethyl acetate and water. The organic
phase is separated and then dried over magnesium sulphate, filtered, and
concentrated under reduced pressure. After purification by silica
chromatography (eluent: CH2CI2/EtOAc 96/04), 150 mg of (S)-2-chloro-1-[1-

(3-fluorophenyl)ethyl]-8-trifluoromethyl-1,6,7,8-tetrahydropyrimido[1,2-
a]pyrimidin-4-one are obtained, in the form of a single diastereoisomer
(undetermined configuration on the phenethyl chain), the characteristics of
which are the following:
Mass spectrometry: method A
Retention time Tr (min) = 1.11
[M+H]+: m/z 376; [M-H]-: m/z 253 (base peak).
Example 17: (8S)-9-(4-fluorobenzyl)-2-(morpholin-4-yl)-8-
(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

0.536 g of caesium carbonate and 0.44 ml of 1-(bromomethyl)-4-
fluorobenzene are added, under an argon atmosphere, to a solution of
300 mg of (S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-
pyrimido[1,2-a]pyrimidin-4-one (Example 1e) in 3 ml of acetonitrile. The
resulting mixture is then heated at 80°C for 2 hours. The reaction mixture is
then evaporated under reduced pressure and the residue obtained is then
purified by silica chromatography (eluent: CH2CI2/MeOH 98/02) so as to give
61 mg of (8S)-9-(4-fluorobenzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one, in the form of a white solid, the
characteristics of which are the following:
1H NMR spectrum:
2.09 to 2.25 (m, 1 H); 2.34 to 2.44 (m, 1 H); 3.18 to 3.32 (m, 5 H); 3.41
to 3.53 (m, 4 H); 4.21 (m, 1 H); 4.51 (d, J=15.2 Hz, 1 H); 4.60 to 4.72 (m,
1 H); 4.96 (s, 1 H); 5.17 (d, J=15.2 Hz, 1 H); 7.13 (t, J=8.7 Hz, 2 H); 7.30 (dd,

J=5.4 and 8.7 Hz, 2 H).
Mass spectrometry: method A
Retention time Tr (min) = 0.89
[M+H]+:m/z413.
Example 18: (SJ-S-Benzoyl^-morpholin^-yl-S-trifluoromethyl-ej.S.S-
tetrahydropyrimido[1,2-a]pyrimidin-4-one

35.7 mg of sodium hydride and then, after 10 minutes of stirring,
0.135 ml de of benzoyl chloride are added, under an argon atmosphere, to a
solution of 300 mg of (S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e) in 3 ml of
tetrahydrofuran. After stirring for six hours at ambient temperature, a
saturated solution of sodium bicarbonate and ethyl acetate are added to the
reaction mixture. The organic phase is separated and then successively
washed with a saturated solution of sodium chloride, dried over magnesium
sulphate, filtered and concentrated under reduced pressure. The residue
obtained is purified by silica chromatography (eluent: CH2CI2) so as to give
74 mg of (S)-9-benzoyl-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one, in the form of a white solid, the
characteristics of which are the following:
1H NMR spectrum:
2.20 to 2.31 (m, 1 H); 2.68 to 2.82 (m, 3 H); 2.86 to 2.96 (m, 2 H); 3.15
to 3.44 (m partially masked, 4 H); 3.75 to 3.87 (m, 1 H); 4.17 to 4.30 (m, 1 H);
5.15 (s, 1 H); 5.38 to 5.53 (m, 1 H); 7.37 to 7.43 (m, 2 H); 7.45 to 7.53 (m,
3H).

Mass spectrometry: method B
Retention time Tr (min) = 3.59
[M+H]+: m/z 409
Optical rotation: OR = -15.8+/-0.8; C= 1.650 mg/0.5 ml DMSO.
Example 19: (S)-2-morpholin-4-yl-9-pyridin-3-yl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one

The product is prepared according to the procedure described in
Example 12, using 200 mg of (S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e) and 380 mg of
3-iodopyridine. After purification by silica chromatography (elution gradient of
CH2CI2 to CH2CI2/MeOH 96/04), 48 mg of (S)-2-morpholin-4-yl-9-pyridin-3-yl-
8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are
obtained, in the form of a yellow solid, the characteristics of which are the
following:
1H NMR spectrum:
2.44 to 2.48 (m, 2 H); 3.00 to 3.13 (m, 4 H); 3.31 to 3.37 (m, 1 H); 3.41
to 3.47 (m, 4 H); 4.37 (d, J=16.1 Hz, 1 H); 4.97 to 5.09 (m, 2 H); 7.48 (dd,
J=4.9 and 8.3 Hz, 1 H); 7.80 to 7.85 (m, 1 H); 8.50 (dd, J=1.4 and 4.9 Hz,
1 H); 8.57 (d, J=2.2 Hz, 1 H).
Mass spectrometry: method A
Retention time Tr (min) = 0.55
[M+H]+: m/z 382
Optical rotation: OR =-40 +/-1.6, C=0.2% in DMSO.

Example 20: (S^-morpholin^-yl-S-pyridin^-yl-S-trifluoromethyl-ej.S.S-
tetrahydropyrimido[1,2-a]pyrimidin-4-one
SAR236152
The product is prepared according to the procedure described in
Example 12, using 200 mg of (S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e) and 380 mg of 4-
iodopyridine. After purification by silica chromatography (elution gradient from
CH2CI2 to CH2CI2/MeOH 96/04), 26 mg of (S)-2-morpholin-4-yl-9-pyridin-4-yl-
8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are
obtained, in the form of a yellow solid, the characteristics of which are the
following:
1H NMR spectrum:
2.43 to 2.48 (m, 2 H); 3.07 to 3.19 (m, 4 H); 3.33 to 3.39 (m, 1 H); 3.45
to 3.50 (m, 4 H); 4.30 to 4.38 (m, 1 H); 5.06 (s, 1 H); 5.09 to 5.17 (m, 1 H);
7.45 (d, J=6.1 Hz, 2 H); 8.62 (d, J=6.1 Hz, 2 H).
Mass spectrometry: method A
[M+H]+: m/z 382; [M-H]-: m/z 380
Retention time Tr (min) = 0.42
Optical rotation: OR =-31 +/-1.3, C=0.2% in DMSO.

Example 21: (8S)-9-(4-methylphenyl)-2-(morpholin-4-yl)-8-(trifluoro-
methylJ-ej.S.S-tetrahydro^H-pyrimidoII^-alpyrimidin-^one

The product is prepared according to the procedure described in
Example 12, using 100 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e) and 100 mg of 1-iodo-
4-methylbenzene. After purification by silica chromatography (eluent: CH2CI2/
MeOH 98/02), 23 mg of (8S)-9-(4-methylphenyl)-2-(morpholin-4-yl)-8-
(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are
obtained in the form of a cream solid, the characteristics of which are the
following:
1H NMR spectrum:
2.32 (s, 3 H); 2.44 (m, 2 H); 2.97 to 3.15 (m, 4 H); 3.33 to 3.50 (m
partially masked, 5 H); 4.34 (m, 1 H); 4.86 (m, 1 H); 4.98 (s, 1 H); 7.22 (s, 4
H).
Mass spectrometry: method A
Retention time Tr (min) = 0.90
[M+H]+: m/z 395.

Example 22: (8S)-9-(2-chlorobenzyl)-2-(morpholin-4-yl)-8-(trifluoro-
methyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

214 mg of caesium carbonate and 74 mg of 1-(bromomethyl)-2-
chlorobenzene are added to a solution of 100 mg of (8S)-2-(morpholin-4-yl)-8-
(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
(Example 1e) in 2 ml of dimethylformamide. After 16 hours at a temperature
in the region of 20°C, the reaction medium is run into water. The organic
phase is separated and the aqueous phase is extracted with ethyl acetate.
The combined organic phases are concentrated to dryness under reduced
pressure. The residue is purified by preparative HPLC/MS (Method C). After
evaporation of the acetonitrile and lyophilization, 94 mg of (8S)-9-(2-chloro-
benzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-
pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of an oil, the
characteristics of which are the following:
1H NMR spectrum:
2.29 to 2.66 (m, 2 H); 3.09 to 3.18 (m, 4 H); 3.23 to 3.50 (m partially
masked, 5 H); 4.27 (m, 1 H); 4.68 (d, J=16.6 Hz, 1 H); 4.74 (m, 1 H); 4.96 (s,
1 H); 5.12 (d, J=16.6 Hz, 1 H); 7.16 to 7.22 (m, 1 H); 7.24 to 7.32 (m, 2 H);
7.41 to 7.48 (m, 1 H).
Mass spectrometry: method A
Retention time Tr (min) = 0.96
[M+H]+: m/z 429.

Example 23: (8S)-9-(3-fluorobenzyl)-2-(morpholin-4-yl)-8-
(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

The product is prepared according to the procedure described in
Example 22, using 100 mg of (8S)-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one, 214 mg of caesium
carbonate and 68 mg of 1-(bromomethyl)-3-fluorobenzene. After purification
by preparative HPLC/MS (Method C), 102 mg of (8S)-9-(3-fluorobenzyl)-2-
(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]-
pyrimidin-4-one are obtained in the form of an oil, the characteristics of which
are the following:
1H NMR spectrum:
2.17 to 2.45 (m, 2 H); 3.15 to 3.31 (m, 5 H); 3.39 to 3.49 (m, 4 H); 4.23
(m, 1 H); 4.58 (d, J=16.1 Hz, 1 H); 4.66 to 4.78 (m, 1 H); 4.97 (s, 1 H); 5.13
(d, J=16.1 Hz, 1 H); 6.98 to 7.15 (m, 3 H); 7.35 (dt, J=6.0 and 8.1 Hz, 1 H)
Mass spectrometry: method A
Retention time Tr (min) = 0.89
[M+H]+:m/z413.

Example 24: (8S)-9-[2-(2-methoxyphenyl)ethyl]-2-(morpholin-4-yl)-8-
(trifluoromethyO-SJ.S.S-tetrahydro^H-pyrimidofl^-alpyrimidin-^one

214 mg of caesium carbonate and 78 mg of 1-(2-bromoethyl)-3-
methoxybenzene are added to a solution of 100 mg of (8S)-2-(morpholin-4-
yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
(Example 1e) in 2 ml of dimethylformamide. After 18 hours at a temperature
of 60°C, 78 mg of 1-(2-bromoethyl)-3-fluorobenzene are added. After 2 hours
at a temperature of 60°C, the reaction mixture obtained is run into water. The
organic phase is separated and the aqueous phase is extracted with ethyl
acetate. The combined organic phases are concentrated to dryness under
reduced pressure. The residue is purified by preparative HPLC/MS (Method
C). After evaporation of the acetonitrile and lyophilization, 25 mg of (8S)-9-[2-
(2-methoxyphenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetra-
hydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of an oil,
the characteristics of which are the following:
1H NMR spectrum:
1.84 to 2.00 (m, 1 H); 2.25 to 2.35 (m, 1 H); 2.83 to 3.03 (m, 2 H); 3.06 to 3.30
(m, 2 H); 3.44 (m, 4 H); 3.61 to 3.67 (m, 4 H); 3.76 (s, 3 H); 4.08 to 4.24 (m,
2H); 4.37 to 4.52 (m, 1 H); 4.99 (s, 1 H); 6.88 (dt, J=0.9 and 7.6 Hz, 1 H); 6.96
(broad d, J=7.9 Hz, 1 H); 7.14 (dd, J=1.5 and 7.6 Hz, 1 H); 7.18 to 7.26 (m, 1
H)
Mass spectrometry: method A

Retention time Tr (min) = 0.98
[M+H]+: m/z 439.
Example 25: (8S)-9-[2-(3-methoxyphenyl)ethyl]-2-(morpholin-4-yl)-8-
(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

The product is prepared according to the procedure described in
Example 24, but using 100 mg of (8S)-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one, 78 mg of 1-(2-bromo-
ethyl)-3-methoxybenzene and 214 mg of caesium carbonate in 2 ml of
dimethylformamide. After reaction for 3 days at a temperature of 60°C,
treatment as described in Example 24 and purification by preparative HPLC/
MS (Method C), 20 mg of (8S)-9-[2-(3-methoxyphenyl)ethyl]-2-(morpholin-4-
yl)-8-(trifluoromethyl)-6,7.8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
are obtained in the form of an oil, the characteristics of which are the
following:
1H NMR spectrum:
1.88 to 2.01 (m, 1 H); 2.32 (m, 1 H); 2.74 to 2.90 (m, 1 H); 2.96 (m, 1
H); 3.10 to 3.22 (m, 1 H); 3.26 to 3.39 (m partially masked, 1 H); 3.43 to 3.48
(m, 4 H); 3.62 to 3.68 (m, 4 H); 3.73 (s, 3 H); 4.02 to 4.23 (m, 2 H); 4.49 to
4.65 (m, 1 H); 5.00 (s, 1 H); 6.70 to 6.88 (m, 3 H); 7.14 to 7.26 (m, 1 H)
Mass spectrometry: method A
Retention time Tr (min) = 0.94

[M+H]+: m/z 439.
Example 26: (8S)-9-(3-methoxybenzyl)-2-(morpholin-4-yl)-8-
(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1J2-a]pyrimidin-4-one

The product is prepared according to the procedure described in
Example 22, but using 100 mg of (8S)-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one, 57 mg of 1-(chloro-
methyl)-3-methoxybenzene and 214 mg of caesium carbonate in 2 ml of
dimethylformamide. After treatment, the residue is stirred into acetonitrile. The
solid is spin-filter-dried, rinsed with diethyl ether and then dried under a
vacuum bell jar. 111 mg of (8S)-9-(3-methoxybenzyl)-2-(morpholin-4-yl)-8-
(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are
thus obtained in the form of a white solid, the characteristics of which are the
following:
1H NMR spectrum:
2.07 to 2.23 (m, 1 H); 2.35 to 2.44 (m, 1 H); 3.19 to 3.28 (m, 5 H); 3.40
to 3.55 (m, 4 H); 3.72 (s, 3 H); 4.22 (m, 1 H); 4.45 (d, J=15.9 Hz, 1 H); 4.56 to
4.70 (m, 1 H); 4.96 (s, 1 H); 5.21 (d, J=15.9 Hz, 1 H); 6.75 to 6.88 (m, 3 H);
7.19 to 7.27 (m, 1 H)
Mass spectrometry: method A
Retention time Tr (min) = 0.88

[M+H]+: m/z 425.
Example 27: (8S)-9-(4-methoxyphenyl)-2-(morpholin-4-yl)-8-
(trifluoromethyO-ej.S.S-tetrahydro^H-pyrimidoII^-alpyrimidin^-one
Chiral

The product is prepared according to the procedure described in
Example 12, using 100 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e), 108 mg of 1-iodo-4-
methoxybenzene and 79 mg of 4,7-dimethoxy-1,10-phenanthroline. After
purification by silica chromatography (eluent: CH2CI2/MeOH 98/02), 31 mg of
(8S)-9-(4-methoxyphenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of a
cream foam, the characteristics of which are the following:
1H NMR spectrum:
2.38 to 2.46 (m, 2 H); 3.04 to 3.15 (m, 4 H); 3.20 to 3.35 (m partially
masked, 1 H); 3.45 (m, 4 H); 3.77 (s, 3 H); 4.34 (m, 1 H); 4.83 (m, 1 H); 4.98
(s, 1 H); 6.95 (d, J=8.8 Hz, 2 H); 7.25 (d, J=8.8 Hz, 2 H)
Mass spectrometry: method A
Retention time Tr (min) = 0.83
[M+H]+:m/z411.

Example 28: (8S)-9-[(2-fluorophenyl)carbonyl]-2-(morpholin-4-yl)-
S^trifluoromethyO-SJ.S.S-tetrahydro^H-pyrimidoII^-alpyrimidin-^one
Chiral

The product is prepared according to the procedure described in
Example 18, using 300 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e), 47 mg of sodium
hydride and 156 mg of 2-fluorobenzoyl chloride in 5 ml of tetrahydrofuran.
After purification by silica chromatography (eluent: CH2CI2/MeOH 98/02),
35 mg of (8S)-9-[(2-fluorophenyl)carbonyl]-2-(morpholin-4-yl)-8-(trifluoro-
methyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in
the form of a white foam, the characteristics of which are the following:
1H NMR spectrum:
2.13 to 2.26 (m, 1 H); 2.65 to 2.85 (m, 3 H); 2.94 to 3.02 (m, 2 H); 3.20
to 3.40 (m partially masked, 4 H); 3.43 to 3.55 (m, 1 H); 4.42 (m, 1 H); 5.19 (s,
1 H); 5.55 to 5.69 (m, 1 H); 7.18 to 7.31 (m, 2 H); 7.49 to 7.64 (m, 2 H)
Mass spectrometry: method A
Retention time Tr (min) = 0.79
[M+H]+: m/z 427.

Example 29: (8S)-9-(3,5-difluorobenzyl)-2-(morpholin-4-yl)-8-(trifluoro-
methylJ-ej.S.S-tetrahydro-AH-pyrimidoII^-alpyrimidin-^one

The product is prepared according to the procedure described in
Example 22, using 100 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e), 214 mg of caesium
carbonate and 75 mg of 1-(bromomethyl)-3,5-difluorobenzene in 2 ml of
dimethylformamide. After purification by preparative HPLC/MS (Method C),
85 mg of (8S)-9-(3,5-difluorobenzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form
of an oil, the characteristics of which are the following:
1H NMR spectrum:
2.21 to 2.44 (m, 2 H); 3.14 to 3.33 (m, 5 H); 3.36 to 3.52 (m, 4 H); 4.23
(m, 1 H); 4.61 (d, J=16.4 Hz, 1 H); 4.68 to 4.81 (m, 1 H); 4.98 (s, 1 H); 5.07
(d, J=16.4 Hz, 1 H); 6.90 to 7.02 (m, 2 H); 7.07 (tt, J=2.3 and 9.3 Hz, 1 H)
Mass spectrometry: method B
Retention time Tr (min) = 3.93
[M+H]+:m/z431.

Example 30: (8S)-9-(2,4-difluorobenzyl)-2-(morpholin-4-yl)-8-(trifluoro-
methyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

The product is prepared according to the procedure described in
Example 22, using 100 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e), 214 mg of caesium
carbonate and 75 mg of 1-(bromomethyl)-2,4-difluorobenzene in 2 ml of
dimethylformamide. After purification by preparative HPLC/MS (Method C),
86 mg of (8S)-9-(2,4-difluorobenzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form
of an oil, the characteristics of which are the following:
1H NMR spectrum:
2.16 to 2.30 (m, 1 H); 2.35 to 2.45 (m, 1 H); 3.17 to 3.32 (m, 5 H); 3.41
to 3.49 (m, 4 H); 4.22 (dd, J=5.9 and 14.2 Hz, 1 H); 4.60 (d, J=16.1 Hz, 1 H);
4.66 to 4.76 (m, 1 H); 4.97 (s, 1 H); 5.11 (d, J=16.1 Hz, 1 H); 7.03 (ddt, J=1.1
- 2.6 and 9.0 Hz,1 H); 7.22 (ddd, J=2.6 - 9.0 and 10.9 Hz,1 H); 7.30 (dt, J=6.7
and 9.0 Hz, 1 H)
Mass spectrometry: method B
Retention time Tr (min)= 3.96
[M+H]+:m/z431.

Example 31: (8S)-2-(morpholin-4-yl)-9-(2>3,4-trifluorobenzyl)-8-(trifluoro-
methyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

The product is prepared according to the procedure described in
Example 22, using 100 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e), 214 mg of caesium
carbonate and 82 mg of 1-(bromomethyl)-2,3,4-trifluorobenzene in 2 ml of
dimethylformamide. After purification by preparative HPLC/MS (Method C),
76 mg of (8S)-2-(morpholin-4-yl)-9-(2,3,4-trifluorobenzyl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form
of an oil, the characteristics of which are the following:
1HNMR spectrum: 1H
2.15 to 2.31 (m, 1 H); 2.35 to 2.44 (m, 1 H); 3.18 to 3.32 (m, 5 H); 3.42
to 3.54 (m, 4 H); 4.22 (dd, J=5.5 and 14.3 Hz, 1 H); 4.65 (d, J=16.1 Hz, 1 H);
4.73 (m, 1 H); 4.98 (s, 1 H); 5.16 (d, J=16.1 Hz, 1 H); 7.05 to 7.17 (m, 1 H);
7.20 to 7.32 (m, 1 H)
Mass spectrometry: method B
Retention time Tr (min) = 4.08
[M+H]+: m/z 449.

Example 32: (8S)-9-[(5-chloro-1-benzothiophen-3-yl)methyl]-2-
(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-
a]pyrimidin-4-one

The product is prepared according to the procedure described in
Example 22, using 100 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e), 214 mg of caesium
carbonate and 95 mg of 3-(bromomethyl)-5-chloro-1-benzothiophene in 2 ml
of dimethylformamide. After purification by preparative HPLC/MS (Method
C), 72 mg of (8S)-9-[(5-chloro-1-benzothiophen-3-yl)methyl]-2-(morpholin-4-
yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
are obtained in the form of an oil, the characteristics of which are the
following:
1H NMR spectrum:
2.13 to 2.25 (m, 1 H); 2.34 to 2.43 (m, 1 H); 3.16 to 3.32 (m, 5 H); 3.35
to 3.48 (m, 4 H); 4.21 (dd, J=6.0 and 14.3 Hz, 1 H); 4.62 to 4.74 (m, 2 H);
5.00 (s, 1 H); 5.52 (d, J=16.1 Hz, 1 H); 7.42 (dd, J=2.0 and 8.6 Hz, 1 H); 7.67
(s, 1 H); 8.01 (d, J=2.0 Hz, 1 H); 8.03 (d, J=8.6 Hz, 1 H)
Mass spectrometry: method B
Retention time Tr (min) = 4.42
[M+H]+: m/z 485.

Example 33: (8S)-9-[(1R or 1S)-1-(4-fluorophenyl)ethyl]-2-(morpholin-4-
yl)-8-(trifluoromethyl)-6,7,8i9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-
one
Stage a:
The two diastereoisomers of (8S)-9-[(1R and 1S)-1-(4-fluoro-
phenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-
pyrimido[1,2-a]pyrimidin-4-one are separated by chiral chromatography:
Chiralpak IC 20 urn column; elution: 70% heptane 30% EtOH, using 130 mg
of a 70/30 mixture of the two diastereoisomers.
The first diastereoisomer is concentrated so as to obtain 42 mg of
(8S)-9-[(1 R or 1S)-1-(4-fluorophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoro-
methyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in the form of a
colourless solid, the characteristics of which are the following:
1H NMR spectrum (400MHz):
1.72 (d, J=6.8 Hz, 3 H); 2.22 (m, 1 H); 2.43 (m, 1 H); 3.14 to 3.27 (m, 5 H);
3.39 to 3.54 (m, 4 H); 4.13 (dd, J=5.6 and 14.4 Hz, 1 H); 4.80 to 4.88 (m, 1
H); 4.93 (s, 1 H); 5.43 (q, J=6.8 Hz, 1 H); 7.12 (t, J=8.8 Hz, 2 H); 7.36 (dd,
J=5.6 and 8.8 Hz, 2 H)
Mass spectrometry: method A
Retention time Tr (min) = 0.95
[M+H]+: m/z 427.

Stage b: (8S)-9-[(1R and 1S)-1-(4-fluorophenyl)ethyl]-2-(morpholin-4-yl)-
8-(trif!uoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

The mixture of (8S)-9-[(1 R and 1S)-1-(4-fluorophenyl)ethyl]-2-
(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]-
pyrimidin-4-one is prepared according to the procedure described in Example
24, using 500 mg of (8S)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one, 1 g of caesium carbonate and
391 mg of 1-(1-chloroethyl)-4-fluorobenzene in 20 ml of acetonitrile. After
purification by silica chromatography (eluent: CH2CI2/MeOH 97/3), 130 mg of
(8S)-9-[(1 R and 1 S)-1 -(4-fluorophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoro-
methyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in
the form of a 70/30 mixture of two diastereoisomers, the characteristics of
which are the following:
1H NMR spectrum:
It is a 70-30 mixture of two isomers, with: 1.65 (d, J=7.0 Hz, 2.1 H);
1.72 (d, J=7.0 Hz, 0.9 H); 1.75 to 1.86 (m, 0.7 H); 2.25 to 2.48 (m, 1.3 H);
3.12 to 3.27 (m, 5 H); 3.40 to 3.56 (m, 4 H); 4.00 to 4.22 (m, 1 H); 4.42 (m,
0.7 H); 4.80 to 4.87 (m, 0.3 H); 4.93 (s, 0.3 H); 4.96 (s, 0.7 H); 5.44 (q, J=7.0
Hz, 0.3 H); 5.65 (q, J=7.0 Hz, 0.7 H); 7.06 to 7.21 (m, 2 H); 7.32 to 7.40 (m, 2
H).

Example 34: (8S)-9-[(1R or 1S)-1-(4-fluorophenyl)ethyl]-2-(morpholin-4-
yO-S^trifluoromethyO-ej.S.S-tetrahydro^H-pyrimidon.Z-alpyrimidin-^
one
The previous purification (Example 33, stage a) also results in 85 mg
of (8S)-9-[(1R or 1S)-1-(4-fluorophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoro-
methyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in the form of a
colourless solid, the characteristics of which are the following:
1H NMR spectrum:
1.65 (d, J=7.0 Hz, 3 H); 1.69 to 1.86 (m, 1 H); 2.29 to 2.37 (m, 1 H);
3.14 to 3.28 (m, 5 H); 3.44 to 3.58 (m, 4 H); 4.08 (dd, J=5.9 and 14.7 Hz, 1
H); 4.42 (m, 1 H); 4.96 (s, 1 H); 5.64 (q, J=7.0 Hz, 1 H); 7.17 (t, J=8.8 Hz, 2
H); 7.35 (dd, J=5.6 and 8.8 Hz, 2 H)
Mass spectrometry: method A
Retention time Tr (min) = 0.95
[M+H]+: m/z 427.
Example 35: (8S)-9-(3-methylphenyl)-2-(morpholin-4-yl)-8-(trifluoro-
methyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

The product is prepared according to the procedure described in
Example 12, but using 250 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-

6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e) in 4 ml of
dimethylformamide, 251 mg of 1-iodo-3-methylbenzene, 349 mg of
tripotassium phosphate, 156 mg of copper iodide and 93 mg of (1S,2S)-cyclo-
hexane-1,2-diamine. After 1 hour at 150°C under microwave irradiation and
silica column purification of the resulting reaction mixture (elution gradient of
CH2CI2 to CH2CI2/MeOH 98/02), 195 mg of (8S)-9-(3-methylphenyl)-2-
(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]-
pyrimidin-4-one are obtained in the form of a green solid, the characteristics
of which are the following:
1H NMR spectrum:
2.31 (s, 3 H); 2.37 to 2.47 (m, 2 H); 3.02 to 3.16 (m, 4 H); 3.19 to 3.39
(m partially masked, 1 H); 3.40 to 3.53 (m, 4 H); 4.28 to 4.40 (m, 1 H); 4.93
(m, 1 H); 4.99 (s, 1 H); 7.13 (m, 2 H); 7.19 (broad s, 1 H); 7.29 (t, J=7.5 Hz, 1
H)
Mass spectrometry: method A
Retention time Tr (min) = 0.90
[M+H]+: m/z 395.
Example 36: (8S)-9-(4-chlorophenyl)-2-(morpholin-4-yl)-8-(trifluoro-
methyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one


The product is prepared according to the procedure described in
Example 12, but using 250 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-
6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e), 274 mg of
1-chloro-4-iodobenzene, 349 mg of tripotassium phosphate, 156 mg of
copper iodide and 93 mg of (1S,2S)-cyclohexane-1,2-diamine. After 1 hour at
150°C under microwave irradiation and silica column purification of the
resulting reaction mixture (elution gradient of CH2CI2 to CH2CI2/MeOH 98/02),
145 mg of (8S)-9-(4-chlorophenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form
of a green foam, the characteristics of which are the following:
1H NMR spectrum:
2.41 to 2.47 (m, 2 H); 3.07 to 3.12 (m, 4 H); 3.20 to 3.43 (m partially
masked, 1 H); 3.46 (m, 4 H); 4.35 (m, 1 H); 4.94 (m, 1 H); 5.01 (s, 1 H); 7.39
(d, J=8.8 Hz, 2 H); 7.49 (d, J=8.8 Hz, 2 H)
Mass spectrometry: method A
Retention time Tr (min) = 0.94;
[M+H]+:m/z415.
Example 37: (8S)-2-(morpholin-4-yl)-8-(trifluoromethyl)-9-[4-(trifluoro-
methyl)phenyl]-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

The product is prepared according to the procedure described in

Example 12, but using 250 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-
6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e), 313 mg of
1-iodo-4-(trifluoromethyl)benzene, 349 mg of tripotassium phosphate, 156 mg
of copper iodide and 93 mg of (1S,2S)-cyclohexane-1,2-diamine. After 1 hour
at 150°C under microwave irradiation and silica column purification of the
resulting reaction mixture (elution gradient of CH2CI2 to CH2CI2/MeOH 98/02),
120 mg of (8S)-2-(morpholin-4-yl)-8-(trifluoromethyl)-9-[4-(trifluoromethyl)-
phenyl]-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in
the form of a greenish solid, the characteristics of which are the following:
1H NMR spectrum (400 MHz):
2.42 to 2.53 (m partially masked, 2 H); 3.01 to 3.13 (m, 4 H); 3.22 to
3.39 (m partially masked, 1 H); 3.41 to 3.46 (m, 4 H); 4.37 (m, 1 H); 5.03 (s, 1
H); 5.05 (m, 1 H); 7.62 (d, J=8.6 Hz, 2 H); 7.81 (d, J=8.6 Hz, 2 H)
Mass spectrometry: Method A
Retention time Tr (min) = 0.98
[M+H]+: m/z 449.
Example 38: (8S)-9-[(1R or 1S)-1-(2-fluorophenyl)ethyl]-2-(morpholin-4-
yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-
one
Stage c:
The two diastereoisomers of (8S)-9-[(1R and 1S)-1-(2-fluorophenyl)-

ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido-
[1,2-a]pyrimidin-4-one are separated by chiral chromatography (Chiralpak AD
20 urn column; elution: 80% heptane 10% EtOH 10% MeOH) using 70 mg of
a 70/30 mixture of the two diastereoisomers.
41.5 mg of (8S)-9-[(1R or 1S)-1-(2-fluorophenyl)ethyl]-2-(morpholin-4-
yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
are thus obtained, the characteristics of which are the following:
1H NMR spectrum (400 MHz):
1.62 (d, J=7.2 Hz, 3 H); 1.68 to 1.85 (m, 1 H); 2.30 to 2.39 (m, 1 H);
3.20 to 3.42 (m, 5 H); 3.50 to 3.65 (m, 4 H); 4.03 (m, 1 H); 4.22 to 4.36 (m, 1
H); 4.99 (s, 1 H); 6.05 (q, J=7.2 Hz, 1 H); 7.14 to 7.29 (m, 2 H); 7.35 to 7.43
(m, 1 H); 7.47 (m, 1 H)
Mass spectrometry: method B
Retention time Tr (min) = 4.02
[M+H]+: m/z 427
Optical rotation: OR = +33; C = 2.543 mg/ml DMSO.
Stage b: (8S)-9-[(1R and 1S)-1-(2-fluorophenyl)ethyl]-2-(morpholin-4-yl)-
8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

The product can be prepared according to the procedure described in

Example 17, but using 500 mg of (8S)-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one, 1 g of caesium
carbonate and 391 mg of 1-(1-chloroethyl)-2-fluorobenzene (see stage a
below) in 22 ml of acetonitrile. After silica column purification (eluent: CH2CI2/
MeOH 97/03), 70 mg of a 70/30 mixture of the two diastereoisomers of (8S)-
9-[(1 R and 1S)-1-(2-fluorophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form
of a pale yellow powder, the characteristics of which are the following:
Retention time Tr (min) = 093 and 0.90: 70% - 30% mixture of
isomers;
[M+H]+: m/z 427.
Stage a: 1-(1-chloroethyl)-2-fluorobenzene

767 mg of thionyl chloride are added to a solution of 1 g of commercial
1-(2-fluorophenyl)ethanol in 20 ml of chloroform. After stirring overnight at a
temperature in the region of 20°C, the reaction mixture is washed with a
saturated aqueous solution of sodium bicarbonate and then dried over
anhydrous magnesium sulphate, filtered and concentrated to dryness under
reduced pressure. 780 mg of 1-(1-chloroethyl)-2-fluorobenzene are thus
obtained, said product being used as it is in the next stage.

Example 39: (8S)-9-[(1R or 1S)-1-(2-fluorophenyl)ethyl]-2-(morpholin-4-
yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-
one
The previous purification (Example 38, stage c) also results in 17.9 mg
of (8S)-9-[(1R or 1S)-1-(2-fluorophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoro-
methyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one, in the form of
an amber solid, the characteristics of which are the following:
1H NMR spectrum (400MHz):
1.69 (d, J=7.0 Hz, 3 H); 1.97 to 2.12 (m, 1 H); 2.36 to 2.46 (m, 1 H);
3.15 to 3.35 (m partially masked, 5 H); 3.43 to 3.59 (m, 4 H); 4.09 (m, 1 H);
4.72 (m, 1 H); 4.93 (s, 1 H); 5.73 (q, J=7.0 Hz, 1 H); 7.07 to 7.25 (m, 2 H);
7.28 to 7.40 (m, 1 H); 7.51 (m, 1 H)
Mass spectrometry: method B
Retention time Tr (min) = 3.93
[M+H]+: m/z 427
Optical rotation: OR = -96.3+/-1.4; C = 2.812 mg/0.5 ml DMSO.

Example 40: (8S)-9-[2-(3-fluorophenyl)ethyl]-2-(morpholin-4-yl)-8-
(trifluoromethyO-ej.S.S-tetrahydro^H-pyrimidoII^-alpyrimidin^-one

296 mg of sodium hydroxide in 2.5 ml of water, 33 mg of
tetrabutylammonium hydrogen sulphate and 200 mg of 1-(2-bromoethyl)-3-
fluorobenzene are added to a solution of 150 mg of (8S)-2-(morpholin-4-yl)-8-
(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in
2.5 ml of toluene. After one hour under microwave irradiation (power 100
watts on a CEM discover apparatus) at 60°C and then one hour again at
60°C and twice six hours at 70°C, the reaction mixture is diluted with ethyl
acetate. The resulting mixture is washed with water. The organic phase is
separated and then concentrated to dryness under reduced pressure. After
purification of the resulting residue by preparative HPLC/MS (method D),
43 mg of (8S)-9-[2-(3-fluorophenyl)ethyl]-2-(morpholin-4-yl)-8-
(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are
obtained, the characteristics of which are the following:
1H NMR spectrum (400 MHz):
1.87 to 2.05 (m, 1 H); 2.29 to 2.38 (m, 1 H); 2.82 to 3.24 (m, 3 H); 3.38
to 3.50 (m, 5 H); 3.60 to 3.66 (m, 4 H); 4.11 to 4.25 (m, 2 H); 4.50 to 4.69 (m,
1 H); 4.99 (s, 1 H); 6.96 to 7.15 (m, 3 H); 7.28 to 7.41 (m, 1 H)
Mass spectrometry: method B
Retention time Tr (min) = 4.10

[M+H]+: m/z 427.
Example 41: (8S)-9-benzyl-3-fluoro-2-(morpholin-4-yl)-8-(trifluoro-
methyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

Stage e:
4 g of caesium carbonate and 796 mg of benzyl bromide are added to a
suspension of 1 g of (8S)-3-fluoro-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 11.8 ml of acetonitrile.
After stirring overnight at a temperature in the region of 20°C, the suspension
obtained is filtered and the resulting filtrate is concentrated to dryness under
reduced pressure. The oily yellow residue is purified on a silica column
(eluent: CH2CI2/MeOH 98/02). The fractions of interest are combined and
concentrated to dryness under reduced pressure. The residue is taken up
with diethyl ether, spin-filter-dried and then dried under vacuum. 600 mg of
(8S)-9-benzyl-3-fluoro-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetra-
hydro-4H-pyrimido[1,2-a]pyrimidin-4-one are thus obtained in the form of a
white powder, the characteristics of which are the following:
1H NMR spectrum (400 MHz):
2.17 to 2.30 (m, 1 H); 2.39 to 2.46 (m, 1 H); 3.31 to 3.52 (m, 9 H); 4.23
(m, 1 H); 4.55 (d, J=16.1 Hz, 1 H); 4.61 to 4.73 (m, 1 H); 5.13 (d, J=16.1 Hz, 1
H); 7.20 to 7.26 (m, 3 H); 7.28 to 7.36 (m, 2 H)

Mass spectrometry: method B
Retention time Tr (min) = 4.01
[M+H]+:m/z413.
Stage d: (8S)-3-fluoro-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetra-
hydro-4H-pyrimido[1,2-a]pyrimidin-4-one

The product can be prepared according to the procedure described in
Example 16, stage b, but using 1 g of (8S)-2-chloro-3-fluoro-8-
(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 5 ml
of acetonitrile, and 1.6 ml of morpholine. After a period overnight at 65°C,
1.1 g of (8S)-3-fluoro-2-(morpholin-4-yl)-3-(trifluoromethyl)-6,7,8,9-tetrahydro-
4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of a beige powder,
the characteristics of which are the following:
Mass spectrometry: Method A
Retention time Tr (min) = 0.56
[M+H]+: m/z 323; [M-H]-: m/z 321.

Stage c: (8S)-3-fluoro-2-chloro-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-
pyrimido[1,2-a]pyrimidin-4-one

The enantiomers of (8R,8S)-2-chloro-3-fluoro-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are separated by chiral
chromatography (Chiralpak AD 20 urn 80 * 350 mm 250 ml/min 254 nm; 5%
EtOH 5% MeOH 90% heptane + 0.1% TEA), using 6.8 g of a racemic
mixture.
The dextrorotary enantiomer is concentrated so as to obtain 3.13 g of
(8S)-2-chloro-3-fluoro-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-
a]pyrimidin-4-one, in the form of a white solid, the characteristics of which are
the following:
Mass spectrometry: Method A
Retention time Tr (min) = 0.62
[M+H]+: m/z 272; [M-H]-: m/z 270
Optical rotation: OR = +19.6+/-0.6; C = 2.488 mg/0.5 ml CH3OH.
Stage b: (8R, 8S)-2-chloro-3-fluoro-8-(trifluoromethyl)-6,7,8,9-tetrahydro-
4H-pyrimido[1,2-a]pyrimidin-4-one

8 ml of phosphorus trichloride are added to a solution of 6.5 g of (8R,

8S)-3-fluoro-2-hydroxy-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-
a]pyrimidin-4-one in 20 ml of 1,2-dichloroethane. After stirring for 4 hours at a
temperature of 65°C and a return to a temperature in the region of 20°C, the
reaction mixture is concentrated to dryness under reduced pressure. The
residue is diluted in 150 ml of ethyl acetate and 10 ml of ice-cold water. A
concentrated sodium hydroxide solution is added, at a temperature of
between 0°C and 10°C, until a pH of between 6 and 7 is obtained. The solid
formed is filtered off so as to give 3.5 g of a beige solid S1. The filtrate is
separated by settling out, and the organic phase is dried over anhydrous
magnesium sulphate, filtered and concentrated to dryness under reduced
pressure. After silica column purification of the residue (eluent: CH2CI2/MeOH
97/03), 3.3 g of a pale yellow solid S2 are obtained. The two solids S1 and S2
are combined so as to give 6.8 g of (8R,8S)-2-chloro-3-fluoro-8-
(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one, in the
form of a pale yellow powder, the characteristics of which are the following:
Mass spectrometry: Method B
Retention time Tr (min) = 2.90
[M+H]+: m/z 272; [M-H]-: m/z 270.
Stage a: (8R,8S)-3-fluoro-2-hydroxy-8-(trifluoromethyl)-6,7,8,9-tetra-
hydro-4H-pyrimido[1,2-a]pyrimidin-4-one

5.6 g of sodium methoxide are added to a suspension of 7 g of
6-(trifluoromethyl)-1,4,5,6-tetrahydropyrimidin-2-amine hydrochloride
(Example 1, stage a) in 35 ml of dimethyl fluoropropanedioate. After the
suspension has been stirred for 3 hours at a temperature of 100°C, the

medium obtained is concentrated to dryness under reduced pressure. The
residue is taken up in diethyl ether and then spin-filter-dried under vacuum.
The solid obtained is taken up in 14 ml of water and the resulting mixture is
cooled in ice before acidification to pH 5-6 through the addition of
concentrated hydrochloric acid (25%). After stirring for 2 hours at a
temperature of 0°C and then overnight at a temperature in the region of 20°C,
the suspension is filtered and then the solid is spin-filter-dried and vacuum-
dried over P205. 6.5 g of (8R,8S)-3-fluoro-2-hydroxy-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form
of a yellow powder, the characteristics of which are the following:
Mass spectrometry: Method A
Retention time Tr (min) = 0.28
[M+H]+: m/z 254; [M-H]-: m/z 252.
Example 42: (8S)-9-(3,5-difluorophenyl)-2-(morpholin-4-yl)-8-(trifIuoro-
methyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

The product is prepared according to the procedure described in
Example 12, but using 250 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-
6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e), 276 mg of
1,3-difluoro-5-iodobenzene, 349 mg of tripotassium phosphate, 156 mg of
copper iodide and 93 mg of (1S,2S)-cyclohexane-1,2-diamine. After 1 hour at

150°C under microwave irradiation and silica column purification of the
reaction mixture (elution gradient of CH2CI2 to CH2CI2/MeOH 98/02), 91 mg of
(8S)-9-(3,5-difluorophenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetra-
hydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of an ochre
foam, the characteristics of which are the following:
1H NMR spectrum (400 MHz):
2.45 (m, 2 H); 3.07 to 3.16 (m, 4 H); 3.32 to 3.37 (m, 1 H); 3.45 to 3.55
(m, 4 H); 4.36 (m, 1 H); 5.01 (m, 1 H); 5.04 (s, 1 H); 7.18 to 7.34 (m, 3 H)
Mass spectrometry: method A
Retention time Tr (min) = 0.95
[M+H]+: m/z417; [M-H+HCO2H]-: m/z461.
Example 43: (8S)-9-[(2,6-difluorophenyl)carbonyl]-2-(morpholin-4-yl)-8-
(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

The product is prepared according to the procedure described in
Example 18, using 300 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e), 47 mg of sodium
hydride and 174 mg of 2,6-difluorobenzoyl chloride in 4 ml of tetrahydrofuran.
After three successive purifications by silica chromatography (eluent: CH2CI2/
MeOH; gradient of 100/0 to 98/02 then 98/1 and 98/2), 22 mg of (8S)-9-[(2,6-
difluorophenyl)carbonyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of a

white solid, the characteristics of which are the following:
1H NMR spectrum (400 MHz):
2.06 to 2.23 (m, 1 H); 2.69 to 2.79 (m, 1 H); 2.91 (m, 2 H); 3.06 (m, 2
H); 3.18 to 3.34 (m partially masked, 1 H); 3.37 to 3.50 (m, 4 H); 4.52 to 4.61
(m, 1 H); 5.23 (s, 1 H); 5.62 to 5.86 (m, 1 H); 7.04 to 7.35 (m, 2 H); 7.50 to
7.67 (m, 1 H)
Mass spectrometry: method A
Retention time Tr (min) = 0.93
[M+H]+: m/z 445.
Example 44: (8S)-9-[(2,4-difluorophenyl)carbonyl]-2-(morpholin-4-yl)-8-
(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

The product is prepared according to the procedure described in
Example 18, using 300 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e), 47 mg of sodium
hydride and 174 mg of 2,4-difluorobenzoyl chloride in 4 ml of tetrahydrofuran.
After two successive purifications by silica chromatography (eluent:
CH2CI2/MeOH; gradient of 100/0 to 98/02 then 99/01), 24 mg of (8S)-9-[(2,4-
difluorophenyl)carbonyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetra-
hydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of a
colourless lacquer, the characteristics of which are the following:

1H NMR spectrum (400 MHz):
2.20 (m, 1 H); 2.67 to 2.77 (m, 1 H); 2.81 to 2.91 (m, 2 H); 3.03 (m, 2
H); 3.24 to 3.45 (m partially masked, 2 H); 3.37 to 3.46 (m, 2 H); 3.52 (m, 1
H); 4.30 to 4.48 (m, 1 H); 5.21 (s, 1 H); 5.53 to 5.67 (m, 1 H); 7.18 (dt, J=2.5
and 8.6 Hz, 1 H); 7.35 (ddd, J=2.5 and 9.3 and 11.2 Hz, 1 H); 7.61 to 7.71 (m,
1 H)
Mass spectrometry: method A
Retention time Tr (min) = 0.94
[M+H]+: m/z 445.
Example 45: (8S)-2-(morpholin-4-yl)-9-(phenylacetyl)-8-(trifluoromethyi)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

The product is prepared according to the procedure described in
Example 18, using 300 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e), 47 mg of sodium
hydride and 152 mg of phenylacetyl chloride in 4 ml of tetrahydrofuran. After
two successive purifications by silica chromatography (eluent: CH2CI2/MeOH;
gradient of 100/0 to 98/02 then CH2CI2/EtOAc 95/05), 12 mg of (8S)-2-
(morpholin-4-yl)-9-(phenylacetyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-
pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of a colourless
lacquer, the characteristics of which are the following:

1H NMR spectrum (400 MHz):
1.91 (m, 1 H); 2.59 to 2.69 (m, 1 H); 2.88 (m, 1 H); 3.33 to 3.45 (m, 4
H); 3.60 (m, 4 H); 4.07 (d, J=16.0 Hz, 1 H); 4.16 (d, J=16.0 Hz, 1 H); 4.43 to
4.52 (m, 1 H); 5.30 (s, 1 H); 5.48 to 5.61 (m, 1 H); 7.11 (d, J=7.7 Hz, 2 H);
7.17 to 7.23 (t, J=7.7 Hz, 1 H); 7.28 (t, J=7.7 Hz, 2 H)
Mass spectrometry: method A
Retention time Tr (min) = 0.99;
[M+H]+: m/z 423;
[M-H]-: m/z 421; base peak: m/z 303.
Example 46: (8S)-9-[2-(3-chlorophenyl)ethyl]-2-(morpholin-4-yl)-8-
(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

The product is prepared according to the procedure described in
Example 40, using 150 mg of (8S)-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 2.5 ml of toluene are
added 296 mg of sodium hydroxide in 2.5 ml of water, 33 mg of
tetrabutylammonium hydrogen sulphate and 216 mg of 1-(2-bromoethyl)-3-
chlorobenzene. After 44 hours at 60°C. After cooling, the reaction mixture is
diluted with ethyl acetate. The organic phase is separated and the aqueous
phase is extracted with ethyl acetate. The combined organic phases are
concentrated to dryness under reduced pressure and the residue is purified

by preparative HPLC/MS (Method D). 42 mg of (8S)-9-[2-(3-chloro-
phenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-
pyrimido[1,2-a]pyrimidin-4-one are thus obtained, the characteristics of which
are the following:
1H NMR spectrum (400 MHz):
1.91 to 2.05 (m, 1 H); 2.34 (m, 1 H); 2.81 to 2.92 (m, 1 H); 2.94 to 3.04
(m, 1 H); 3.17 (m, 1 H); 3.38 to 3.50 (m, 5 H); 3.65 (m, 4 H); 4.09 to 4.22 (m,
2 H); 4.57 to 4.71 (m, 1 H); 4.99 (s, 1 H); 7.17 (d, J=7.8 Hz, 1 H); 7.25 to 7.38
(m, 3 H)
Mass spectrometry: method A
Retention time Tr (min) = 1.03
[M+H]+: m/z 443; [M-H+HCO2H]-: m/z 487.
Example 47 pharmaceutical composition
Tablets corresponding to the following formulation were prepared:
Product of Example 1 0.2 g
Excipient for a tablet having a final weight of 1 g
(details of the excipient: lactose, talc, starch, magnesium stearate).
Example 1 is taken by way of example of a pharmaceutical preparation, it
being possible for this preparation to be carried out, if desired, with other
products of formula (I) according to the present invention, and in particular as
examples in the present application, among Examples 2 to 46 and 48 to 56.
The products of the table below are products of formula (I) as defined above,
and constitute examples 48 to 56 of the present invention. These products
from 48 to 56 are prepared as indicated above in the experimental section.



Pharmacological section:
Experimental protocols
In vitro experimental procedures
The inhibitory activity of the molecules on AKT phosphorylation is
measured either by western blotting using the technique described below, or
by the MSD Multi-spot Biomarker detection technique from Meso Scale
Discovery also described below. It was demonstrated, on one set of

molecules, that both techniques give compatible results.
Study of pAKT expression in PC3 human prostate carcinoma cells
measured bv western blotting (test A):
This test is based on measuring the expression of the AKT protein
phosphorylated on serine 473. The phosphorylation of AKT (pAKT) is
measured by western blotting in the PC3 human prostate carcinoma line
(ATCC CRL-1435), using an antibody that specifically recognises
pAKT-S473.
On day 1, the PC3 cells are seeded into 6-well plates (TPP, # 92006)
at the concentration of 0.8x106 cells/well in 1800 ul of DMEM medium (DMEM
Gibco #11960-044) containing 10% of foetal calf serum (SVF Gibco,
# 10500-056) and 1% glutamine (L-Glu Gibco # 25030-024), and incubated at
37°C, 5% CO2, overnight.
On day 2, the cells are incubated in the presence or absence of the
test products for 1 to 2 hours at 37°C in the presence of 5% CO2. The
molecules, diluted in dimethyl sulphoxide (DMSO Sigma #D2650), are added
from a 10-times concentrated stock solution, the final percentage of DMSO
being 0.1%. The molecules are tested either at a single concentration of less
than or equal to 10 uM, or at increasing concentrations in a range that can
extend from less than 1 nM to 10 uM.
After this incubation, the cells are lysed for the preparation of the
proteins. After the culture medium has been drawn off, the cells are rinsed
with 1 ml of PBS (DPBS Gibco, #14190-094), recovered by scraping in 200 ul
of complete HNTG buffer and transferred into a 96-well plate (Greiner
#651201), and lysed for 1 h on ice. The HNTG buffer is composed of the
following mixture: 50 mM hepes, 150 mM NaCI, 1% triton, 10% glycerol, with
extemporaneous addition of one Mini Protease Inhibitor Cocktail tablet
(Roche 1836153) and of one Phosphatase Inhibitor Cocktail tablet
(Rochel 04906837001) per 10 ml of buffer.
The lysate is centrifuged fcr 10 min at 6000 rpm. 155 pi of supernatant

are recovered. 150 ul are incubated for denaturation for 5 min at 95°C in the
presence of 4X NuPAGE LDS Sample Buffer diluted 4-fold (InVitrogen ref
NP0007) and of 10X NuPAGE Sample Reducing Agent diluted 10-fold
(InVitrogen ref NP0009). These samples are then frozen at -20°C. 5 ul are
assayed by the microBCA technique according to the technical bulletin of the
MicroBCA Protein Assay Kit (Pierce #23235).
For protein separation, 20 ug of proteins are loaded on to a NU-PAGE
4-12% Bis Tris Gel, 12 well (InVitrogen ref NP0322BOX) and the migration is
carried out for 1 h 30 in 20X NU-PAGE MOPS SDS Running Buffer diluted
20-fold (InVitrogen ref NP0001), at 150 volts.
The gel is then transferred on to an Invitrolon PVDF membrane
(Invitrogen #LC2007) permeabilised beforehand for a few seconds in ethanol
(Ethanol Fischer Scientific #E/0600DF/15).
The transfer is carried out in a Biorad tank at 30 volts overnight or at
60 volts for 3 hours, in the presence of 20X NUPAGE Transfer Buffer diluted
20-fold (InVitrogen ref NP0006).
The membrane is then saturated in saturating solution composed of
TBS (10x Tris Buffered Saline, Sigma #T5912, diluted 10-fold), 0.1% Tween
20 (Sigma #P5927) and 3% BSA (Bovine Serum Albumin Fraction V, Sigma
#A4503) for 6 h after overnight transfer or else for 1 h after transfer for a
period of 3 h.
The primary antibodies are diluted to 1/1000th for the anti-phospho
AKT-Ser473 antibody (193H2, rabbit monoclonal, cat#4058 from Cell
Signaling Technology) Abeam), in saturating solution composed of PBS, 0.1%
Tween 20 and 3% BSA, and then shaken overnight at 4°C.
Two rinses for 5 min in washing solution composed of TBS and 0.1%
Tween 20 are carried out before hybridisation of the secondary antibodies.
The secondary antibodies are diluted to 1/10000th for the rabbit
anti-Mouse IgG HRP antibody (W402 Promega) and to 1/10000th for the goat
anti-Rabbit IgG HRP antibody (W401 Promega) in saturating solution, and

then shaken for 1 h at ambient temperature.
Two rinses for 30 min in washing solution are carried out and then a
rinse for 5 min in H20 is carried out in order to eliminate the remaining Tween
20.
The revealing solution is prepared volume-for-volume according to the
technical bulletin of the Western Lightning Chemiluminescence Reagent Plus
(Western Lightning Chemiluminescence Reagent Plus Perkin Elmer
#NEL104).
The membrane is placed in the revealing solution for 1 min, drained,
inserted between two transparent plates and then placed in the measuring
device for reading the luminescence and the quantification of the signal. The
luminescence is read with the FujiFilm device (Ray Test).
The FUJI device measures the total luminescence signal obtained
(AU) for each band selected. It then subtracts the background noise (BG)
proportional to the size of the band selected (Area), said background noise
being calculated from a specific background noise band, with a view to
obtaining the specific signal (AU-BG) for each band. The band obtained in the
absence of product and in the presence of 0.1% DMSO is considered to be
the 100% signal. The software calculates the % specific activity (Ratio)
obtained for each band selected as a function of this 100% signal. The
percentage inhibition is calculated for each concentration according to the
formula (100%-Ratio).
Two independent experiments make it possible to calculate the mean
of the percentages of inhibition obtained at a given concentration for the
products tested only at one concentration.
Where appropriate, the activity of the products is translated into
approximate IC50, obtained from a dose-response curve of various
concentrations tested and representing the dose giving 50% of specific
inhibition (absolute IC5o). Two independent experiments make it possible to
calculate the mean of the IC5o values.

Study of pAKT expression in PC3 human prostate carcinoma cells
measured bv the MSP Multi-spot Biomarker Detection technique from Meso
Scale Discovery (Test B):
This test is based on measuring the expression of the AKT protein
phosphorylated on serine 473 (P-AKT-S473), in the PC3 human prostate
carcinoma line, by means of the technique based on a sandwich
immunoassay using the MSD Multi-spot Biomarker Detection kit from Meso
Scale Discovery: phospho-Akt (Ser473) whole cell lysate kit (#K151CAD) or
phospho-Akt (Ser473)/Total Akt whole cell lysate kit (#K15100D). The
primary antibody specific for P-AKT-S473 (Kit #K151CAD) is coated onto an
electrode in each well of the 96-well plates of the MSD kit: after the addition of
a protein lysate to each well, the signal is visualised by adding a secondary
detection antibody labelled with an electrochemiluminescent compound. The
procedure followed is that described in the kit.
On day 1, the PC3 cells are seeded into 96-well plates (TPP, #92096)
at the concentration of 35 000 cells/well in 200 ul of DMEM medium (DMEM
Gibco #11960-044) containing 10% of foetal calf serum (FCS Gibco,
#10500-056) and 1% glutamine (L-Glu Gibco #25030-024), and incubated at
37°C, 5% CO2, overnight.
On day 2, the cells are incubated in the presence or absence of the
test products for 1 to 2 h at 37°C in the presence of 5% of CO2. The
molecules, diluted in dimethyl sulphoxide (DMSO Sigma #D2650), are added
from a 20-times concentrated stock solution, the final percentage of DMSO
being 0.1%. The molecules are tested either at a single concentration of less
than or equal to 10uM, or at increasing concentrations in a range that can
extend from less than 1nM to 10uM.
After this incubation, the cells are lysed for the preparation of the
proteins. For this, after the culture medium has been drawn off, 50 pi of
complete Tris Lysis Buffer of the MSD kit containing the protease and
phosphatase inhibitor solutions are added to the wells and the cells are lysed

for 1 h at 4°C with shaking. At this stage, the plates containing the lysates can
be frozen at -20°C or at -80°C.
The wells of the 96-well plates of the MSD kit are saturated for 1 h at
ambient temperature with the blocking solution of the MSD kit. Four washes
are carried out with 150 ul of Tris Wash Buffer of the MSD kit. The lysates
previously prepared are transferred into the 96-well multi-spot plates of the
MSD kit and incubated for 1 h at ambient temperature, with shaking. Four
washes are carried out with 150 pi of Tris Wash Buffer of the MSD kit. 25 pi of
the MSD sulfo-tag detection antibody solution are added to the wells and
incubated for 1 h at ambient temperature, with shaking. Four washes are
carried out with 150 pi of Tris Wash Buffer of the MSD kit. 150 pi of Read
Buffer of the MSD kit are added to the wells and the plates are read
immediately on the S12400 instrument from Meso Scale Discovery.
The instrument measures a signal for each well. Wells without cells
and containing the lysis buffer serve to determine the background noise that
will be subtracted from all the measurements (min). The wells containing cells
in the absence of product and in the presence of 0.1% DMSO are considered
to be the 100% signal (max). The percentage inhibition is calculated for each
concentration of test product according to the following formula: (1-((test-min)/
(max-min)))x100.
The activity of the product is translated to IC5o, obtained from a dose-
response curve of the various concentrations tested and representing the
dose giving 50% specific inhibition (absolute IC50). 2 independent experiments
make it possible to calculate the mean of the IC50 values.
The inhibitory activity of the molecules on autophagy is measured by
the translocation of the LC3 protein from the cytoplasm to the
autophagosomes. For this, Hela cells were transfected with a vector encoding
the chimeric protein GFP-LC3. A Hela clone stably expressing the GFP-LC3
protein was selected. The translocation of the LC3 protein is determined by
measuring the number of cells exhibiting LC3 granulations after a metabolic

stress, using an iCyte automatic image analysis cytometer (Compucyte).
Study of the translocation of the LC3 protein in Hela human cells,
measured bv image analysis cytometry (Test C):
On day 1, the Hela GFP-LC3 cells are seeded into 96-well plates
coated with poly-D-lysine (Greiner, #655946) at the concentration of
15 000 cells/well in 200 ul of DMEM medium (DMEM Gibco #11960-044)
containing 10% of foetal calf serum (FCS Gibco, #10500-056) and 1%
glutamine (L-Glu Gibco #25030-024), and incubated at 37°C, 5% CO2,
overnight.
On day 2, the cells are washed twice with EBSS (Sigma #E3024). The
cells are then incubated in EBSS, 10 uM of hydroxychloroquine and test
products for 2h at 37°C in the presence of 5% CO2. The molecules are diluted
in dimethyl sulphoxide (DMSO Sigma #D2650), the final DMSO percentage
being 0.1%. The molecules are tested at increasing concentrations in a range
that can extend from 10 nM to 1 uM.
After this incubation, the cells are fixed with 4% paraformaldehyde
(Sigma #HT501128 4L) for 10 min. The cells are then washed twice with PBS
and then the nuclei are stained with 2 ug/ml of Hoechst 33342 (Invitrogen
#H3570). The 96-well plates are then read with the iCyte image analysis
cytometer (Compucyte). The analyser quantifies the number of cells
exhibiting LC3 granulations. A cell is considered to be positive when it
exhibits at least 4 LC3 granulations. The percentage of cells exhibiting more
than 4 granulations is calculated relative to the total number of cells.
The activity of the product is translated to IC5o, obtained from a dose-
response curve of the various concentrations tested and representing the
dose giving 50% specific inhibition (absolute IC50). Two independent
experiments make it possible to calculate the mean of the IC50 values.
The results obtained for the products as examples in the experimental
section are given in the pharmacological results table below:
Pharmacological results Table 1:

Antimalarial activity test
The antimalarial activity tests are carried out according to the
radioactive micromethod of Desjardins (R.E. Desjardins, C.J. Canfield,
J.D. Haynes, J.D. Chulay, Antimicrob. Agents Chemother., 1979, 16, 710-
718). The assays are carried out in 96-well microplates (Test Plates Ref.
92696, Techno Plastic Products Ag, Zollstrasse 155, CH-8219 Trasadingen).
The P. falciparum strains are cultured in solutions of RPMI 1640
supplemented with 5% of human serum with a haematocrit at 2% and a blood
parasite concentration at 1.5%. For each assay, the parasites are incubated
with selected concentrations of drugs for 48 h at 37°C in a humid atmosphere
and at 5% CO2. Artemisinin, artesunate and also chloroquine diphosphate are
used as reference molecules. The first dilution of the drug is prepared at
1 mg/ml in dimethyl sulphoxide. The range of successive daughter solution
dilutions is also prepared in dimethyl sulphoxide. Each daughter dilution is
then diluted to 1 /50th in RPMI 1640 supplemented with 5% of human serum,
all of the dilutions being carried out at 37°C. These dilutions are then added to
the parasites in culture in the microplates. After addition of the drug, the
parasites are in culture in RPMI 1640 containing 5% of human serum and 1%
of dimethyl sulphoxide. The growth of the parasites is measured by

incorporation of tritiated hypoxanthine (added 24 h after the beginning of the
exposure to the drug) compared with the incorporation in the absence of drug.
The activity of the product is translated to % inhibition of the growth of
P. falciparum (highly chloroquine-resistant strain Fcm29-Cameroon) at 1 uM
and 0.1 uM in an in vitro test using infected human erythrocytes.
The results obtained for the products as examples in the experimental
section are given in pharmacological results Table 2 below:


CLAIMS
1) Products of formula (I):
in which:
R1 represents an -L-aryl or -L-heteroaryl radical, such that L represents:
either a single bond,
or a linear or branched alkyl radical containing from 1 to 6 carbon atoms and
optionally substituted with a hydroxyl radical,
or a CO or -CO-Alk- group,
or an L'-X group where L' represents a linear or branched alkyl radical
containing from 1 to 6 carbon atoms, and X an oxygen or sulphur atom;
the aryl and heteroaryl radicals being optionally substituted with one or more
radicals, which may be identical or different, chosen from halogen atoms and
hydroxyl, CN, nitro, -COOH, -COOalk, -NRxRy, -CONRxRy, -NRxCORy,
-NRxCO2Rz, -CORy, alkoxy, phenoxy, alkylthio, alkyl, cycloalkyl and
heterocycloalkyl radicals;
the latter alkoxy, phenoxy, alkylthio, alkyl and heterocycloalkyl radicals being
themselves optionally substituted with one or more radicals, which may be
identical or different, chosen from halogen atoms and NRvRw;
it being possible for the heterocycloalkyl and heteroaryl radicals to additionally
contain an oxo radical;
R2 represents a hydrogen atom or an alkyl radical;

R3 represents an alkyl radical optionally substituted with one or more halogen
atoms;
R4 represents a hydrogen atom or a halogen atom;
NRxRy being such that Rx represents a hydrogen atom or an alkyl radical
and Ry represents a hydrogen atom or a cycloalkyl radical or an alkyl radical
optionally substituted with one or more radicals, which may be identical or
different, chosen from hydroxy!, alkoxy, NRvRw and heterocycloalkyl radicals;
or Rx and Ry form, with the nitrogen atom to which they are attached, a cyclic
radical containing from 3 to 10 ring members and optionally one or more other
heteroatoms chosen from 0, S, NH and N-alkyl, this cyclic radical being
optionally substituted;
NRvRw being such that Rv represents a hydrogen atom or an alkyl radical
and Rw represents a hydrogen atom or a cycloalkyl radical or an alkyl radical
optionally substituted with one or more radicals, which may be identical or
different, chosen from hydroxyl, alkoxy and heterocycloalkyl radicals; or Rv
and Rw form, with the nitrogen atom to which they are attached, a cyclic
radical containing from 3 to 10 ring members and optionally one or more other
heteroatoms chosen from O, S, NH and N-alkyl, this cyclic radical being
optionally substituted;
the cyclic radicals that Rx and Ry or Rv and Rw, respectively, can form with
the nitrogen atoms to which they are attached, being optionally substituted
with one or more radicals, which may be identical or different, chosen from
halogen atoms, and alkyl, hydroxyl, oxo, alkoxy, NH2, NHalk and N(alk)2
radicals;
Rz represents the values of Ry except for hydrogen;
Rx, Ry and Rz, in the -NRxCORy, -CORy and NRxCO2Rz radicals, being
chosen from the meanings indicated above for Rx, Ry and Rz;
all the above alkyl (alk), alkoxy and alkylthio radicals being linear or branched
and containing from 1 to 6 carbon atoms,

said products of formula (I) being in all the possible racemic, enantiomeric
and diastereoisomeric isomer forms, and also the addition salts with inorganic
and organic acids or with inorganic and organic bases, of said products of
formula (I).
2) Products of formula (I) as defined in Claim 1, in which:
R1 represents an -L-phenyl or -L-heteroaryl radical, such that L represents:
either a single bond,
or a linear or branched alkyl radical containing from 1 to 6 carbon atoms and
optionally substituted with a hydroxyl radical,
or a CO or -CO-Alk- group,
or an L'-X group where L' represents a linear or branched alkyl radical
containing from 1 to 6 carbon atoms, and X an oxygen or sulphur atom;
the phenyl and heteroaryl radicals being optionally substituted with one or
more radicals, which may be identical or different, chosen from halogen
atoms and -NRxRy, alkoxy and alkyl radicals;
the latter alkoxy and alkyl radicals being themselves optionally substituted
with one or more radicals chosen from halogen atoms;
R2 represents an alkyl radical;
R3 represents an alkyl radical optionally substituted with one or more halogen
atoms;
R4 represents a hydrogen atom or a fluorine atom;
NRxRy being such that Rx represents a hydrogen atom or an alkyl radical
and Ry represents a hydrogen atom or an alkyl radical; or Rx and Ry form,
with the nitrogen atom to which they are attached, a morpholino radical;
all the above alkyl (alk) or alkoxy radicals being linear or branched and
containing from 1 to 6 carbon atoms,

said products of formula (I) being in all the possible racemic, enantiomeric
and diastereoisomeric isomer forms, and also the addition salts with inorganic
and organic acids or with inorganic and organic bases, of said products of
formula (I).
3) Products of formula (I) as defined in either one of Claims 1 and 2,
corresponding to the following formulae:
-(8S)-9-[2-(4-methoxyphenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-9-[2-(4-methoxyphenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-2-(morpholin-4-yl)-9-(2-phenylethyl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-benzyl-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-
pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[(2S)-2-hydroxy-2-phenylethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[(2R)-2-hydroxy-2-phenylethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[(2S)-2-hydroxy-2-(4-methoxyphenyl)ethyl]-2-(morpholin-4-yl)-8-
(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
- (8S)-2-(morpholin-4-yl)-9-[(1 R)-1 -phenylethyl]-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[1-(4-methoxyphenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
- (8S)-9-[(1 S)-1 -(4-bromophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[(1R)-1-(4-bromophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-

6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-2-(morpholin-4-yl)-9-phenyl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-
pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(4-fluorophenyl)-2-(morpholin-4-yl)-8-(trifIuoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(3-fluorophenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(2-fluorophenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
- (8S)-9-[(1 R)-1 -(3-fluorophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(4-fluorobenzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-2-(morpholin-4-yl)-9-(pyridin-3-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-2-(morpholin-4-yl)-9-(pyridin-3-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
- (8S)-2-(morpholin-4-yl)-9-(pyridin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-
4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(4-methylphenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetra-
hydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(2-chlorobenzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetra-
hydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(3-fluorobenzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetra-
hydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[2-(2-methoxyphenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[2-(3-methoxyphenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-

6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(3-methoxybenzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(4-methoxyphenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[(2-fluorophenyl)carbonyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(3,5-difluorobenzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(2,4-difluorobenzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-2-(morpholin-4-yl)-9-(2,3,4-trifluorobenzyl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[(5-chloro-1-benzothiophen-3-yl)methyl]-2-(morpholin-4-yl)-8-
(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
- (8S)-9-[(1R or 1S)-1-(4-fluorophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoro-
methyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
- (8S)-9-[(1 R or 1 S)-1 -(4-fluorophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoro-
methyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
- (8S)-9-(3-methylphenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetra-
hydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(4-chlorophenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetra-
hydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-2-(morpholin-4-yl)-8-(trifluoromethyl)-9-[4-(trifluoromethyl)phenyl]-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
- (8S)-9-[(1R or 1S)-1-(2-fluorophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoro-
methyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
- (8S)-9-[(1R or 1S)-1-(2-fluorophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoro-

methyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[2-(3-fluorophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-benzyl-3-fluoro-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetra-
hydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-(3,5-difluorophenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[(2,6-difluorophenyl)carbonyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[(2,4-difluorophenyl)carbonyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-2-(morpholin-4-yl)-9-(phenylacetyl)-8-(trifluoromethyl)-6,7,8,9-tetra-
hydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-(8S)-9-[2-(3-chlorophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-
tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-9-((R)-2-benzo[b]thiophen-2-yl-2-hydroxyethyl)-2-morpholin-4-yl-8-(S)-
6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-9-[(S)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-2-morpholin-4-yl-8-(S)-
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
-2-dimethylamino-N-{3-[(S)-1-hydroxy-2-((S)-8-morpholin-4-yl-6-oxo-2-
trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-
yl)ethyl]phenyl}acetamide
-9-[(S)-2-hydroxy-2-(2-methoxyphenyl)ethyl]-2-morpholin-4-yl-8-(S)-
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
-9-[(S)-2-(4-fluoro-2-methoxyphenyl)-2-hydroxyethyl]-2-morpholin-4-yl-8-(S)-
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
-9-[(S)-2-(4-chloro-2-methoxyphenyl)-2-hydroxyethyl]-2-morpholin-4-yl-8-(S)-
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one

-9-[(S)-2-(2-chloro-4-methoxyphenyl)-2-hydroxyethyl]-2-morpholin-4-yl-8-(S)-
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
-9-(2-hydroxy-3-phenylpropyl)-2-morpholin-4-yl-8-(S)-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one
-9-[2-(4-hydroxyphenyl)ethyl]-2-morpholin-4-yl-8-(S)-trifluoromethyl-6,7,8,9-
tetrahydropyrimido[1,2-a]pyrimidin-4-one
and also the addition salts with inorganic and organic acids or with inorganic
and organic bases, of said products of formula (I).
4) Process for preparing the products of formula (I) as defined in any one of
Claims 1 to 3, according to scheme 1 as defined hereinafter.


in which the substituents R1, R2, R3 and R4 have the meanings indicated in
either one of Claims 1 and 2 and in which R represents alkyl, and X
represents a chlorine, bromine or iodine atom or a sulphonyloxy group such
as trifluoromethylsulphonyloxy.
5) Process for preparing the products of formula (I) as defined in any one of
Claims 1 to 3, according to scheme 2 as defined hereinafter.

in which the substituents R1, R2, R3 and R4 have the meanings indicated in
either one of Claims 1 and 2, and X represents a chlorine, bromine or iodine
atom or a sulphonyloxy group such as trifluoromethylsulphonyloxy.
6) As medicaments, the products of formula (I) as defined in any one of
Claims 1 to 3, and also the pharmaceutically acceptable addition salts with .
inorganic and organic acids or with inorganic and organic bases, of said
products of formula (I).
7) As medicaments, the products of formula (I) as defined in Claim 3, and
also the pharmaceutically acceptable addition salts with inorganic and organic
acids or with inorganic and organic bases, of said products of formula (I).
8) Pharmaceutical compositions containing, as active ingredient, at least one

of the products of formula (I) as defined in any one of Claims 1 to 3, or a
pharmaceutically acceptable salt of this product or a prodrug of this product,
and a pharmaceutically acceptable carrier.
9) Use of a product of formula (I) as defined in any one of Claims 1 to 3, for
the preparation of a medicament for use in the treatment of cancers.
10) Use according to Claim 9, for the treatment of solid or liquid tumours.
11) Use according to Claim 9 and 10, for the treatment of cancers resistant to
cytotoxic agents.
12) Use according to one or more of Claims 9 to 11, for the treatment of
primary tumours and/or of metastases, in particular in gastric, hepatic, renal,
ovarian, colon, prostate, endometrial and lung (NSCLC and SCLC) cancers,
glioblastomas, thyroid, bladder and breast cancers, in melanoma, in lymphoid
or myeloid haematopoietic tumours, in sarcomas, in brain, larynx and
lymphatic system cancers, bone and pancreatic cancers, and in hamartomas.
13) Use of the products of formula (I) as defined in Claims 1 to 3, for the
preparation of medicaments for use in cancer chemotherapy.
14) Use of the products of formula (I) as defined in Claims 1 to 3, for the
preparation of medicaments for use in cancer chemotherapy alone or in
combination.
15) Products of formula (I) as defined in any one of Claims 1 to 3, as
inhibitors of AKT(PKB) phosphorylation.

16) As novel industrial products, the synthesis intermediates of formulae C, D,
E and J as defined in Claims 4 and 5 above and recalled below:

in which R1, R2, R3 and R4 have the definitions indicated in either one of
Claims 1 and 2.
17) Products of formula (I) as defined in any one of Claims 1 to 3, for the use
thereof in the treatment of cancers.
18) Products of formula (I) as defined in any one of Claims 1 to 3, for the use
thereof in the treatment of solid or liquid tumours.
19) Products of formula (I) as defined in any one of Claims 1 to 3, for the use
thereof in the treatment of cancers resistant to cytotoxic agents.
20) Products of formula (I) as defined in any one of Claims 1 to 3, for the use
thereof in the treatment of primary tumours and/or metastases, in particular in
gastric, hepatic, renal, ovarian, colon, prostate, endometrial and lung (NSCLC
and SCLC) cancers, glioblastomas, thyroid, bladder and breast cancers, in
melanoma, in lymphoid or myeloid haematopoietic tumours, in sarcomas, in
brain, larynx and lymphatic system cancers, bone and pancreatic cancers,
and in hamartomas.

21) Products of formula (I) as defined in any one of Claims 1 to 3, for the use
thereof in cancer chemotherapy.
22) Products of formula (I) as defined in any one of Claims 1 to 3, for the use
thereof in cancer chemotherapy, alone or in combination.
23) Products of formula (I) as defined in any one of Claims 1 to 3, for the
prevention or treatment of lysosomal diseases such as glycogenosis type II or
Pompe disease.
24) Use of the products of formula (I) as defined in any one of Claims 1 to 3,
for the preparation of a medicament for use in the prevention or treatment of
lysosomal diseases such as glycogenosis type II or Pompe disease.
25) Use as defined in Claim 23 or 24, in which said products of formula (I) are
alone or in combination.
26) Products of formula (I) as defined in any one of Claims 1 to 3, for the
treatment of parasitic diseases such as malaria, sleeping sickness, Chagas
disease or leishmaniasis.
27) Use of the products of formula (I) as defined in any one of Claims 1 to 3
for the preparation of a medicament for the treatment of parasitic diseases
such as malaria, sleeping sickness, Chagas disease or leishmaniasis.



(54) Title : NOVEL l,2,3,4-TETRAHYDRO-PYRIMIDO(1,2-A)PYRIMIDIN-6-ONE DERIVATIVES, PREPARATION
THEREOF, AND PHARMACEUTICAL USE THEREOF
(57) Abstract : The invention relates to the novel materials of formula (I), where: R1 is an optionally substituted L-aryl or □L-
heteroaryl, such that L is a single bond, alkyl, CO, or CO-alk, or L□X, with L□being an alkyl and X being O or S; R2 is H or alkyl;
R3 is an alkyl optionally substituted by Hal; and R4 is Hou Hal, wherein said materials are in any isomeric form and the salts
thereof, to be used as drugs.
(57) Abrege : L'invention concerne les nouveaux produits de formule (I): dans laquelle Rl represente L-aryle ou -L-heteroaryle
eventuellement substitues, tel que L represente simple liaison, alkyle,CO ou CO-alk ou L'-X avec L' represente alkyle et X
represente O ou S; R2 represente H ou alkyle; R3 represente alkyle eventuellement substitue par Hal; R4 represente Hou Hal; ces
produits etant sous toutes les formes isomeres et les sels, a litre de medicaments.

ABSTRACT

The invention relates to the novel materials of formula (I), where: R1 is an optionally substituted L-aryl or □L-
heteroaryl, such that L is a single bond, alkyl, CO, or CO-alk, or L□X, with L□being an alkyl and X being O or S; R2 is H or alkyl;
R3 is an alkyl optionally substituted by Hal; and R4 is Hou Hal, wherein said materials are in any isomeric form and the salts
thereof, to be used as drugs.