PYRIMIDINONE DERIVATIVES AS AN IMALARIAL AGENTS

The present invention relates to pyrimidinone derivatives, and to the preparation and therapeutic use thereof.

Malaria is one of the prime causes of infection-mediated mortality worldwide. Infection with the parasite of the type Plasmodium falciparum affects close to 225 million people, causes more than 781 000 deaths annually and predominantly concerns children under 5 years old. The substantial return of the disease observed in recent years is due to several factors, including:

- the vectors, namely anopheles, which become resistant to the standard cheap insecticides,

- the increase in the population in the at-risk zones and, mainly,

- the resistance of numerous strains of Plasmodium falciparum, the parasite responsible for the mortal forms of the disease, to the medicaments conventionally used, such as chloroquine and mefloquine. Since 2001 , artemisinin and derivatives thereof have been considered by the World Health Organization as the treatment of choice for Plasmodium falciparum-medlated uncomplicated malaria. However, clear signs of development of resistance to artemisinins have been observed.

The propagation of resistance among Plasmodium strains, in particular P. falciparum, towards the majority of the antimalarial drugs demonstrates the urgent need to develop novel compounds having a novel mode of action thus enabling a decrease of the risk of cross-resistance. Human kinases are valid targets in the treatment of numerous pathologies and the kinome of P. falciparum has been proposed as a reservoir of novel targets for the development of novel medicaments, which have not yet been explored in the treatment of malaria (Doerig and Meijer (2007) Expert Opin. Ther. Targets 1 1 , 279-290).

The kinome of Plasmodium falciparum is composed of 64 kinases, some of which are orthologous to human kinases (Ward et al. (2004) BMC Genomics 5,79). Following this orthologous approach, a group of CF3-pyrimidinone derivatives, which are active on human phosphatidylinositol-3-kinases, has been identified as being parasite growth inhibitors in human erythrocytes. Moreover, a plasmodial phosphatidylinositol-3-kinase, known as PfPI3K, has recently been identified, and the existence of a relationship between this kinase and human phosphatidylinositol kinases has been demonstrated (Vaid et al. (2010) Blood 1 15, 2500-2507). PfPI3K intervenes in the mechanism of endocytosis and in trafficking the host hemoglobin and as such plays an important role in maintaining the parasite growth in the infected human erythrocyte. It might thus be thereby deduced that the plasmodial kinase PfPI3K would be a target for the compounds of the present invention.

Human PI3Ks play a major role in signaling and traffic in human cells (Engelman et al. (2006) Nature Rev. Genetics 7, 606-619). The PI3K/Akt/mTOR signaling mechanism is an essential regulator of cell life, cell proliferation and protein synthesis. The insulin signaling pathway via the PI3K/Akt axis involving class 1A of PI3Ks (PI3Ka and β) is essential in glucose homeostasis. Downstream attenuation of insulin receptor signaling plays an important role in the development of type-2 diabetes. The other isoforms of class I PI3K, ΡΙ3Κγ and PI3K5, are involved in the immune function and inflammation (Ihle and Povis (2010) Current Opinion in Drug Discovery & Development 13, 41 -49). Inhibition of PI3Ka or ΡΙ3Κβ in mice results in embryonic lethality (Bi et al. (1999) J. Biol. Chem. 274, 10963-10968; Bi et al. (2002) Mamm Genome 13, 169-172). Moreover, mice showing a deficiency in ΡΙ3Κγ or PI3K5 show deficiences in immune functions (Okkenhaug et al. (2002) Science 297, 1031 -1034). A summary of the potential and observable side effects of PI3K inhibition may be found in the articles by Cully et al. ((2006) Nature Rev. 6, 184-192) and Ihle and Powis ((2009) Mol. Cancer Ther. 8, 1 -9).

Inhibition of class III PI3K, PIK3C3A PS34, may also give rise to adverse side effects such as rapid neuron degeneration in mice following the conditional suppression of VPS34 in the sensory neurons (Zhou et al. (2010) PNAS 107, 9424-9429).

In summary, non-limiting examples that may be mentioned of potential side effects due to PI3K inhibition in man include metabolic disturbances associated with inhibition of insulin signaling with an increase of blood glucose, reduction of insulin sensitivity, diabetes, deregulation of the cerebral functions with the potential for inducing symptoms of schizophrenia and of Parkinson's disease, and neurodegeneration, and also immunosuppression. It should also be noted that nausea, diarrhea, tiredness, vomiting, skin eruptions and liver damage have been observed during clinical studies with inhibitors of the PI3K mTOR axis.

On the basis of these observations, it is obvious that inhibiting human PI3K lipid kinases may have highly undesirable effects and should be avoided when the lipid kinome of Plasmodium is targeted for the treatment of malaria.

CF3-pyrimidinone derivatives have been described in patent applications WO 201 1/001 1 12 and WO 201 1/001 1 13 for the preparation of medicaments for treating various cancers and also for treating parasitic diseases such as malaria. These compounds are described as inhibitors of human PI3Ks.

The compounds of the present invention have the advantage, although being derived from inhibitors of human PI3K and in particular PI3Ka, they do not inhibit this class of human kinases, while nonetheless remaining inhibitors of parasite growth.

Similar kinomes are present in all species of Plasmodium, such as P. falciparum, P. vivax, P. malariae, P. ovale and P. knowlesi. The compounds of the invention may thus be useful 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 may thus be used in the treatment of sleeping sickness, Chagas disease, the various forms of leishmaniasis and other parasitic infections.

Other parasites, such as schistosomes, toxoplasms and Eimeria, also use kinases for their cell regulation. Consequently, the compounds of the present invention may be useful in the treatment of schistosomiasis (bilharzia), toxoplasmosis and coccidiosis.

The present invention relates to compounds corresponding to formula (I):

in which:

> n represents 0 or 1 ;

> Y represents a bridged morpholine chosen from

(a) (b) (c)

> L represents a linker -CH2-CO- such that the carbonyl function is attached ubstituent R-i, or a (Ci-C2)alkyl, said alkyl being optionally substituted with one substituents chosen from a (CrC3)alkyl group and a hydroxyl group;

> Ri represents:

a linear, branched, cyclic or partially cyclic (C1-C5)alkyl group, optionally substituted with one or more substituents chosen from a hydroxyl group, an aryl group, a trifluoromethyl group and a (C3-C5)cycloalkyl group,

a (C3-C6)cycloalkyl group, optionally substituted with a hydroxyl group, an aryl group, optionally substituted with one or more substituents chosen from a halogen atom, a hydroxyl group, a cyano group, an -NH2 group, a urea group of formula -NH-CO-NH-(C1-C4)alkyl, a morpholine group, a group of formula -S02-(C1-C5)alkyl, a (C1-C5)alkoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

o a halogen atom,

o a hydroxyl group or a (CrC5)alkoxy group,

o a group -COR3, in which R3 represents a substituent chosen from a heterocycloalkyl group and a hydroxyl group,

o a group -CONR4R4' in which R4 and R4> are as defined below, o a group -NR4R4' in which R4 and R4> are as defined below,

o a heterocycloalkyl group comprising one or two heteroelements chosen from a nitrogen atom and an oxygen atom,

o a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (CrC3)alkyl group, a hydroxyl group and an -NH2 group;

a heteroaryl group, comprising one or more heteroatoms chosen from a nitrogen atom, a sulfur atom and an oxygen atom, optionally substituted with one or more substituents chosen from:

o a halogen atom,

o a (C1-C3)alkyl group optionally substituted with one or more halogen atoms,

o a (CrC5)alkoxy group, optionally substituted with one or more substituents chosen from a halogen atom, a (C3-C5)cycloalkyl group, a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (CrC3)alkyl group, a hydroxyl group and an -NH2 group,

o a group -NR5R5' in which R5 and R5', independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -C02-(C1-C3)alkyl group, a (C3-C5)cycloalkyl group and a linear or branched (CrC3)alkyl group, said alkyl group being optionally substituted with one or more hydroxyl groups,

a pyridine group bearing two linked adjacent groups forming, together with the two carbons that bear them, a heterocycle comprising a nitrogen atom and an oxygen atom,

a heterocycloalkyl group comprising one or more heteroatoms chosen from oxygen and nitrogen atoms, said nitrogen atom being optionally substituted with a substituent chosen from a formyl group, an acetyl group and a -C02-(Ci- C4)alkyl group,

a group -NR6R6' in which R6 and R6', which are different, represent a (C C5)alkyl group and a (CrC5)alkoxy group,

> R2 represents a hydrogen atom when n represents 1 and a methyl group when n represents 0;

> R4 and R4 , independently, which may be identical or different, represent a hydrogen atom or a (Ci-C3)alkyl group,

in the form of the base or of an addition salt with an acid or with a base.

The compounds of formula (I) can comprise one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers and also mixtures thereof, including racemic mixtures, are part of the invention.

The compounds of formula (I) may exist in the form of bases or salified with acids or bases, especially pharmaceutically acceptable acids or bases. Such addition salts are part of the invention.

These salts are prepared with pharmaceutically acceptable acids, but salts of other acids that are of use, for example, for purifying or isolating the compounds of formula (I) also form part of the invention. In particular, use will be made in the context of the invention of the hydrogen chloride salt.

In the context of the present invention, and unless otherwise mentioned in the text:

- a halogen atom: a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; in particular, the halogen atom is a fluorine atom;

- an alkyl group: unless otherwise mentioned in the text, a linear or branched saturated aliphatic group containing from 1 to 5 carbons. Examples that may be mentioned include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl groups;

- a partially cyclic (C-i-Cs)alkyl group: unless otherwise mentioned in the text, a linear saturated aliphatic group substituted with a (C3-C4)cycloalkyl group. Examples that may be mentioned include methylcyclopropyl, methylcyclobutyl and ethylcyclopropyl groups;

- a cycloalkyl group: a cyclic (C3-C6)alkyl group. Examples that may be mentioned include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups;

- an alkoxy group: a radical -O-alkyl in which the alkyl group is as defined previously, in particular the alkyl group is a methyl or ethyl;

- an aryl group: a cyclic aromatic group comprising between 5 and 6 carbon atoms. An example of an aryl group that may be mentioned is the phenyl group;

- a heteroaryl group: a monocyclic or bicyclic aromatic group comprising between 2 and 9 carbon atoms and comprising between 1 and 4 heteroatoms, such as nitrogen, oxygen or sulfur. In particular, the bicyclic aromatic groups comprise a phenyl group. Examples of monocyclic heteroaryl groups that may be mentioned include imidazolyl, pyrimidyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazolyl, oxazolyl and 1 ,2,4-oxadiazolyl groups. Examples of bicyclic heteroaryl groups that may be mentioned include 1 H-indazolyl, benzo[1 ,2,3]thiadiazolyl, benzo[1 ,2,5]thiadiazolyl, benzothiophenyl, imidazo[1 ,2-a]pyridyl, quinolinyl and isoquinolinyl groups;

- a heterocycloalkyi: a monocyclic or bicyclic alkyl group comprising from 4 to 8 atoms, 1 or 2 of which are heteroatoms, chosen from an oxygen atom and a nitrogen atom. Examples of monocyclic heterocycloalkyi groups that may especially be mentioned include piperidyl, morpholinyl and tetrahydropyranyl groups, and examples of bicyclic heterocycloalkyi groups that may be mentioned include groups of bridged morpholine type: 8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl, 3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl.

Among the compounds of the invention, mention may be made of a first subgroup of compounds corresponding to formula (I):

in which:

> n represents 0 or 1 , and/or

> Y represents a bridged morpholine chosen from

(a) (b) (c)

and/or

> L represents a linker -CH2-CO- such that the carbonyl function is attached e substituent R-i, or a (Ci-C2)alkyl, said alkyl being optionally substituted with one ore substituents chosen from a (CrC3)alkyl group and a hydroxyl group, and/or

> Ri represents:

a linear, branched, cyclic or partially cyclic (CrC5)alkyl group, optionally substituted with one or more substituents chosen from a hydroxyl group, an aryl group, a trifluoromethyl group and a (C3-C5)cycloalkyl group,

a (C3-C6)cycloalkyl group, optionally substituted with a hydroxyl group, an aryl group, optionally substituted with one or more substituents chosen from a halogen atom, a hydroxyl group, a cyano group, an -NH2 group, a urea group of formula -NH-CO-NH-(C1-C4)alkyl, a morpholine group, a group of formula -S02-(C1-C5)alkyl, a (C1-C5)alkoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

o a halogen atom,

o a hydroxyl group or a (C1-C5)alkoxy group,

o a group -COR3, in which R3 represents a substituent chosen from a

heterocycloalkyl group and a hydroxyl group,

o a group -CONR4R4' in which R4 and R > are as defined below, o a group -NR4R4' in which R4 and R > are as defined below,

o a heterocycloalkyl group comprising one or two heteroelements chosen from a nitrogen atom and an oxygen atom,

o a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (CrC3)alkyl group, a hydroxyl group and an -NH2 group;

a heteroaryl group, comprising one or more heteroatoms chosen from a nitrogen atom, a sulfur atom and an oxygen atom, optionally substituted with one or more substituents chosen from:

o a halogen atom,

o a (C1-C3)alkyl group optionally substituted with one or more halogen atoms,

o a (C1-C5)alkoxy group, optionally substituted with one or more substituents chosen from a halogen atom, a (C3-C5)cycloalkyl group, a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (CrC3)alkyl group, a hydroxyl group and an -NH2 group,

o a group -NR5R5' in which R5 and R5', independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -C02-(CrC3)alkyl group, a (C3-C5)cycloalkyl group and a linear or branched (Ci-C3)alkyl group, said alkyl group being optionally substituted with one or more hydroxyl groups,

- a pyridine group bearing two linked adjacent groups forming, together with the two carbons that bear them, a heterocyde comprising a nitrogen atom and an oxygen atom,

a heterocycloalkyl group comprising one or more heteroatoms chosen from oxygen and nitrogen atoms, said nitrogen atom being optionally substituted with a substituent chosen from a formyl group, an acetyl group and a -C02-(Ci- C4)alkyl group,

a group -NR6R6. in which R6 and R6', which are different, represent a (C C5)alkyl group and a (C1-C5)alkoxy group, and/or

> R2 represents a hydrogen atom when n represents 1 and a methyl group when n represents 0, and/or

> R4 and R , independently, which may be identical or different, represent a hydrogen atom or a (CrC3)alkyl group,

in the form of the base or of an addition salt with an acid or with a base.

Among the compounds of the present invention, mention may be made of second subgroup of compounds of formula (I) in which:

> n represents 0 or 1 ;

> Y represents a bridged morpholine chosen from

(a) (b) (c)

> L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R-i, or a (C1-C2)alkyl, said alkyl being optionally substituted with one or more substituents chosen from a (C1-C3)alkyl group and a hydroxyl group;

> Ri represents:

a linear or branched (Ci-C5) alkyl group, optionally substituted with one or more substituents chosen from a hydroxyl group and an aryl group,

a group (C3-C6)cycloalkyl,

- an aryl group, optionally substituted with one or more substituents chosen from a halogen atom, a hydroxyl group, a cyano group, an -NH2 group, a urea group of formula -NH-CO-NH-(Ci-C4)alkyl, a morpholine group, a group of formula -S02-(Ci-C5)alkyl, a (CrC5)alkoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

o a halogen atom,

o a hydroxyl group or a (C1-C5)alkoxy group,

o a group -COR3, in which R3 represents a substituent chosen from a heterocycloalkyl group and a hydroxyl group,

o a group -CONR4R4. in which R4 and R4> are as defined below, o a group -NR4R4> in which R4 and R4> are as defined below,

o a heterocycloalkyl group comprising one or two heteroelements chosen from a nitrogen atom and an oxygen atom,

o a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (CrC3)alkyl group, a hydroxyl group and an -IMH2 group,

a heteroaryl group, comprising one or more heteroatoms chosen from a nitrogen atom, a sulfur atom and an oxygen atom, optionally substituted with one or more substituents chosen from:

o a halogen atom,

o a (C1-C3)alkyl group optionally substituted with one or more halogen atoms,

o a (C1-C5)alkoxy group, optionally substituted with one or more substituents chosen from a halogen atom, a (C3-C5)cycloalkyl group, a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (C1-C3)alkyl group, a hydroxyl group and an -IMH2 group,

o a group -NR5R5. in which R5 and Rs, independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -C02-(CrC3)alkyl group, a (C3-C5)cycloalkyl group and a linear or branched (Ci-C3)alkyl group, said alkyl group being optionally substituted with one or more hydroxyl groups,

a pyridine group bearing two linked adjacent groups forming, together with the two carbons that bear them, a heterocycle comprising a nitrogen atom and an oxygen atom,

a heterocycloalkyi group comprising one or more heteroatoms chosen from oxygen and nitrogen atoms, said nitrogen atom being optionally substituted with a substituent chosen from a formyl group and an acetyl group,

a group -NR6R6. in which R6 and R6', which are different, represent a (C C5)alkyl group and a (C1-C5)alkoxy group,

> R2 represents a hydrogen atom when n represents 1 and a methyl group when n represents 0;

> R4 and R4>, independently, which may be identical or different, represent a hydrogen atom or a (CrC3)alkyl group,

in the form of the base or of an addition salt with an acid or with a base.

Among the compounds of the present invention, mention may be made of a third subgroup of compounds of formula (I) in which:

> n represents 0 or 1 ;

> Y represents a bridged morpholine (a)

(a)

> L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R-i, or (Ci-C2)alkyl, said alkyl being optionally substituted with one or more substituents chosen from a (CrC3)alkyl group and a hydroxyl group;

> Ri represents:

a linear, branched, cyclic or partially cyclic (CrC5)alkyl group, optionally substituted with one or more substituents chosen from a hydroxyl group, an aryl group, a trifluoromethyl group and a (C3-C5)cycloalkyl group,

a (C3-C6)cycloalkyl group, optionally substituted with a hydroxyl group, an aryl group, optionally substituted with one or more substituents chosen from a halogen atom, a hydroxyl group, an -NH2 group, a urea group of formula -NH- CO-NH-(C1-C4)alkyl, a morpholine group, a group of formula -S02-(C1-C5)alkyl, a (C1-C5)alkoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

o a halogen atom,

o a hydroxyl group or a (C1-C5)alkoxy group,

o a group -COR3, in which R3 represents a substituent chosen from a heterocycloalkyl group and a hydroxyl group,

o a group -CONR4R4' in which R4 and R4> are as defined below, o a group -NR4R4' in which R4 and R4> are as defined below,

o a heterocycloalkyl group comprising one or two heteroelements chosen from a nitrogen atom and an oxygen atom,

o a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (Ci-C3)alkyl group, a hydroxyl group and an -NH2 group,

a heteroaryl group, comprising one or more heteroatoms chosen from a nitrogen atom, a sulfur atom and an oxygen atom, optionally substituted with one or more substituents chosen from:

o a halogen atom,

o a (CrC3)alkyl group optionally substituted with one or more halogen atoms,

o a (CrC5)alkoxy group, optionally substituted with one or more substituents chosen from a halogen atom, a (C3-C5)cycloalkyl group, a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (CrC3)alkyl group, a hydroxyl group and an -NH2 group,

o a group -NR5R5. in which R5 and Rs, independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -C02-(C1-C3)alkyl group, a (C3-C5)cycloalkyl group and a linear or branched (CrC3)alkyl group, said alkyl group being optionally substituted with one or more hydroxyl groups,

a pyridine group bearing two linked adjacent groups forming, together with the two carbons that bear them, a heterocycle comprising a nitrogen atom and an oxygen atom,

a heterocycloalkyl group comprising one or more heteroatoms chosen from oxygen and nitrogen atoms, in particular a morpholinyl group, a bridged morpholinyl group, a tetrahydropyranyl group and a piperidyl group, said nitrogen atom being optionally substituted with a substituent chosen from a formyl group, an acetyl group and a -C02-(Ci-C4)alkyl group,

a group -NR6R6' in which R6 and R6', which are different, represent a (C C5)alkyl group and a (CrC5)alkoxy group,

> R2 represents a hydrogen atom when n represents 1 and a methyl group when n represents 0;

> R4 and R4 , independently, which may be identical or different, represent a hydrogen atom or a (CrC3)alkyl group,

in the form of the base or of an addition salt with an acid or with a base.

Among the compounds of the present invention, mention may be made of a fourth subgroup of compounds of formula (I) in which:

> n represents 0 or 1 ;

> Y represents a bridged morpholine (a)

(a)

> L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R-i, or (Ci-C2)alkyl, said alkyl being optionally substituted with one or more substituents chosen from a (CrC3)alkyl group and a hydroxyl group;

> Ri represents:

a linear or branched (C1-C5) alkyl group, optionally substituted with one or more substituents chosen from a hydroxyl group and an aryl group,

a (C3-C6)cycloalkyl group,

an aryl group, optionally substituted with one or more substituents chosen from a halogen atom, a hydroxyl group, an -NH2 group, a urea group of formula -NH- CO-NH-(C1-C4)alkyl, a morpholine group, a group of formula -S02-(C1-C5)alkyl, a (C1-C5)alkoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

o a halogen atom,

o a hydroxyl group or a (C1-C5)alkoxy,

o a group -COR3, in which R3 represents a substituent chosen from a heterocycloalkyl group and a hydroxyl group,

o a group -CONR4R4. in which R4 and R4> are as defined below, o a group -NR4R4' in which R4 and R4> are as defined below,

o a heterocycloalkyl group comprising one or two heteroelements chosen from a nitrogen atom and an oxygen atom,

o a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (Ci-C3)alkyl group, a hydroxyl group and an -NH2 group;

a heteroaryl group, comprising one or more heteroatoms chosen from a nitrogen atom, a sulfur atom and an oxygen atom, optionally substituted with one or more substituents chosen from:

o a halogen atom,

o a (C1-C3)alkyl group optionally substituted with one or more halogen atoms,

o a (C1-C5)alkoxy group, optionally substituted with one or more

substituents chosen from a halogen atom, a (C3-C5)cycloalkyl group, a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (CrC3)alkyl group, a hydroxyl group and an -NH2 group,

o a group -NR5R5' in which R5 and R5', independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -C02-(Ci-C3)alkyl group, a (C3-C5)cycloalkyl group and a linear or branched (CrC3)alkyl group, said alkyl group being optionally substituted with one or more hydroxyl groups,

a pyridine group bearing two linked adjacent groups forming, together with the two carbons that bear them, a heterocycle comprising a nitrogen atom and an oxygen atom,

a heterocycloalkyl group comprising one or more heteroatoms chosen from oxygen and nitrogen atoms, in particular a morpholinyl group, a bridged morpholinyl group and a piperidyl group, said nitrogen atom being optionally substituted with a substituent chosen from a formyl group and an acetyl group, a group -NR6R6' in which R6 and R6', which are different, represent a (C C5)alkyl group and a (CrC5)alkoxy group,

> R2 represents a hydrogen atom when n represents 1 and a methyl group when n represents 0;

> R4 and R4 , independently, which may be identical or different, represent a hydrogen atom or a (Ci-C3)alkyl group,

in the form of the base or of an addition salt with an acid or with a base.

Among the compounds of the present invention, mention may be made of a fifth subgroup of compounds of formula (I) in which:

> n represents 0 or 1 ;

> Y represents a bridged morpholine a)

(a)

> L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R-i , or (C1-C2)alkyl, said alkyl being optionally substituted with one or more (CrC3)alkyl groups;

> Ri represents:

a linear, branched, cyclic or partially cyclic (CrC5)alkyl group, in particular an isopropyl or tert-butyl group, optionally substituted with one or more substituents chosen from a hydroxyl group, an aryl group, a trifluoromethyl group and a (C3-C5)cycloalkyl group,

a (C3-C6)cycloalkyl group, optionally substituted with a hydroxyl group, an aryl group, in particular a phenyl group, optionally substituted with one or more substituents chosen from a halogen atom, a cyano group, an -NH2 group, a urea group of formula -NH-CO-NH-(C1-C4)alkyl, a morpholine group, a group of formula -S02-(C1-C5)alkyl, a (C1-C5)alkoxy group, in particular a methoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

o a halogen atom, in particular a fluorine atom,

o a hydroxyl group or a (C1-C5)alkoxy group,

o a group -COR3, in which R3 represents a substituent chosen from a heterocycloalkyl group and a hydroxyl group,

o a heterocycloalkyl group comprising one or two heteroelements chosen from a nitrogen atom and an oxygen atom, in particular a morpholinyl group,

o a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (Ci-C3)alkyl group, a hydroxyl group and an -IMH2 group;

a heteroaryl group, comprising one or more heteroatoms chosen from nitrogen atoms, in particular a pyridyl group, and sulfur and oxygen atoms, optionally substituted with one or more substituents chosen from:

o a halogen atom,

o a (C1-C3)alkyl group optionally substituted with one or more halogen atoms,

o a (C1-C5)alkoxy group, optionally substituted with one or more substituents chosen from a halogen atom, a (C3-C5)cycloalkyl group, a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (CrC3)alkyl group, a hydroxyl group and an -IMH2 group,

o a group -NR5R5. in which R5 and Rs, independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -C02-(CrC3)alkyl group, a (C3-C5)cycloalkyl group and a linear

or branched (CrC3)alkyl group, said alkyl group being optionally substituted with one or more hydroxyl groups,

a pyridine group bearing two linked adjacent groups forming, together with the two carbons that bear them, a heterocycle comprising a nitrogen atom and an oxygen atom, in particular a 3,4-dihydro-2H-pyrido[3,2-b][1 ,4]oxazine group, a heterocycloalkyl group comprising one or more heteroatoms chosen from oxygen and nitrogen atoms, said nitrogen atom being optionally substituted with a substituent chosen from a formyl group, an acetyl group and a -C02-(Ci- C4)alkyl group,

a group -NR6R6. in which R6 and R6', which are different, represent an alkyl group and a (C1-C5)alkoxy group,

> R2 represents a hydrogen atom when n represents 1 and a methyl group when n represents 0;

in the form of the base or of an addition salt with an acid or with a base.

Among the compounds of the present invention, mention may be made of a sixth subgroup of compounds of formula (I) in which:

> n represents 0 or 1 ;

> Y represents a bridged morpholine a)

(a)

> L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R-i, or (CrC2)alkyl, said alkyl being optionally substituted with one or more (CrC3)alkyl groups;

> R-i represents:

a linear or branched (C1-C5)alkyl group, in particular an isopropyl or tert-butyl group, optionally substituted with one or more hydroxyl groups,

a (C3-C6)cycloalkyl group,

an aryl group, in particular a phenyl group, optionally substituted with one or more substituents chosen from a halogen atom, a cyano group, an -NH2 group, a urea group of formula -NH-CO-NH-(C1-C4)alkyl, a morpholine group, a group of formula -S02-(C1-C5)alkyl, a (C1-C5)alkoxy group, in particular a methoxy group, said alkoxy being optionally substituted with one or more substituents

chosen from:

o a halogen atom, in particular a fluorine atom,

o a hydroxyl group or a (CrC5)alkoxy,

o a group -COR3, in which R3 represents a substituent chosen from a heterocycloalkyl group and a hydroxyl group,

o a heterocycloalkyl group comprising one or two heteroelements chosen from a nitrogen atom and an oxygen atom, in particular a morpholinyl group,

o a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (C1-C3)alkyl group, a hydroxyl group and an -NH2 group;

a heteroaryl group, comprising one or more heteroatoms chosen from nitrogen atoms, in particular a pyridyl group, and sulfur and oxygen atoms, optionally substituted with one or more substituents chosen from:

o a halogen atom,

o a (C1-C3)alkyl group optionally substituted with one or more halogen atoms,

o a (CrC5)alkoxy group, optionally substituted with one or more substituents chosen from a halogen atom, a (C3-C5)cycloalkyl group, a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (Ci-C3)alkyl group, a hydroxyl group and an -IMH2 group,

o a group -NR5R5' in which R5 and R5', independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -C02-(CrC3)alkyl group, a (C3-C5)cycloalkyl group and a linear or branched (CrC3)alkyl group, said alkyl group being optionally substituted with one or more hydroxyl groups,

a pyridine group bearing two linked adjacent groups forming, together with the two carbons that bear them, a heterocycle comprising a nitrogen atom and an oxygen atom, in particular a 3,4-dihydro-2H-pyrido[3,2-b][1 ,4]oxazine group, a heterocycloalkyl group comprising one or more heteroatoms chosen from oxygen and nitrogen atoms, said nitrogen atom being optionally substituted with a substituent chosen from a formyl group and an acetyl group,

a group -NR6R6. in which R6 and R6', which are different, represent an alkyl group and a (CrC5)alkoxy group,

R2 represents a hydrogen atom when n represents 1 and a methyl group when n represents 0;

in the form of the base or of an addition salt with an acid or with a base.

Among the compounds of the present invention, mention may be made of a seventh subgroup of compounds of formula (I) in which:

> Y represents a bridged morpholine a)

(a)

> L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R-i ,

> R represents:

a linear or branched (C1-C5)alkyl group, in particular an isopropyl or tert-butyl group,

a (C3-C6)cycloalkyl group,

an aryl group, in particular a phenyl group, optionally substituted with one or more substituents chosen from a halogen atom, a cyano group, an -NH2 group, a urea group of formula -NH-CO-NH-(CrC4)alkyl, a morpholinyl group, a group of formula -S02-(Ci-C5)alkyl, a (CrC5)alkoxy group, in particular a methoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

a halogen atom, in particular a fluorine atom,

a hydroxyl group or a (CrC5)alkoxy group,

a group -COR3, in which R3 represents a substituent chosen from a heterocycloalkyl group and a hydroxyl group,

a heterocycloalkyl group comprising one or two heteroelements chosen from a nitrogen atom and an oxygen atom, in particular a morpholinyl group,

o a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (C1-C3)alkyl group, a hydroxyl group and an -NH2 group;

a heteroaryl group, comprising one or more heteroatoms chosen from nitrogen atoms, in particular a pyridyl group, and sulfur and oxygen atoms, optionally substituted with one or more substituents chosen from:

o a halogen atom,

o a (CrC3)alkyl group optionally substituted with one or more halogen atoms,

an alkoxy group, optionally substituted with one or more substituents chosen from a halogen atom, a (C3-C5)cycloalkyl group, a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (CrC3)alkyl group, a hydroxyl group and an -NH2 group,

a group -NR5R5. in which R5 and Rs, independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -C02-(C1-C3)alkyl group, a (C3-C5)cycloalkyl group and a linear or branched (CrC3)alkyl group, said alkyl group being optionally substituted with one or more hydroxyl groups,

a pyridine group bearing two linked adjacent groups forming, together with the two carbons that bear them, a heterocyde comprising a nitrogen atom and an oxygen atom, in particular a 3,4-dihydro-2H-pyrido[3,2-b][1 ,4]oxazine group, a heterocycloalkyl group comprising one or more heteroatoms chosen from oxygen and nitrogen atoms, said nitrogen atom being optionally substituted with a substituent chosen from a formyl group, an acetyl group and a -C02-(Ci- C5)alkyl group,

a group -NR6R6' in which R6 and R6', which are different, represent an alkyl group and a (CrC5)alkoxy group,

in the form of the base or of an addition salt with an acid or with a base.

Among the compounds of the present invention, mention may be made of eighth subgroup of compounds of formula (I) in which:

> Y represents a bridged morpholine a)

(a)

> L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R-i ,

> R represents:

a linear or branched (C1-C5)alkyl group, in particular an isopropyl or tert-butyl group,

a (C3-C6)cycloalkyl group,

an aryl group, in particular a phenyl group, optionally substituted with one or more substituents chosen from a halogen atom, a cyano group, an -NH2 group, a urea group of formula -NH-CO-NH-(CrC4)alkyl, a morpholinyl group, a group of formula -S02-(Ci-C5)alkyl, a (CrC5)alkoxy group, in particular a methoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

o a halogen atom, in particular a fluorine atom,

o a hydroxyl group or a (C1-C5)alkoxy group,

o a group -COR3, in which R3 represents a substituent chosen from a heterocycloalkyl group and a hydroxyl group,

o a heterocycloalkyl group comprising one or two heteroelements chosen from a nitrogen atom and an oxygen atom, in particular a morpholinyl group,

o a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (CrC3)alkyl group, a hydroxyl group and an -IMH2 group;

a heteroaryl group, comprising one or more heteroatoms chosen from nitrogen atoms, in particular a pyridyl group, and sulfur and oxygen atoms, optionally substituted with one or more substituents chosen from:

o a halogen atom,

o a (CrC3)alkyl group optionally substituted with one or more halogen atoms,

o an alkoxy group, optionally substituted with one or more substituents chosen from a halogen atom, a (C3-C5)cycloalkyl group, a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (CrC3)alkyl group, a hydroxyl group and an -NH2 group,

o a group -NR5R5. in which R5 and Rs, independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -C02-(C1-C3)alkyl group, a (C3-C5)cycloalkyl group and a linear or branched (CrC3)alkyl group, said alkyl group being optionally substituted with one or more hydroxyl groups,

a pyridine group bearing two linked adjacent groups forming, together with the two carbons that bear them, a heterocycle comprising a nitrogen atom and an oxygen atom, in particular a 3,4-dihydro-2H-pyrido[3,2-b][1 ,4]oxazine group, a heterocycloalkyl group comprising one or more heteroatoms chosen from oxygen and nitrogen atoms, in particular a morpholinyl group, a bridged morpholinyl group and a piperidyl group, said nitrogen atom being optionally substituted with a substituent chosen from a formyl group and an acetyl group, a group -NR6R6' in which R6 and R6', which are different, represent an alkyl group and an alkoxy group,

in the form of the base or of an addition salt with an acid or with a base.

A ninth subgroup of compounds of formula (I) according to the invention is such that:

> n represents 0 or 1 ;

> Y represents a bridged morpholine chosen from (b) and (c)

(b) (c)

> L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R-i , or (CrC2)alkyl, said alkyl being optionally substituted with a hydroxyl group;

> Ri represents:

a linear or branched (CrC5)alkyl group, optionally substituted with an aryl group,

an aryl group, optionally substituted with one or more substituents chosen from a halogen atom, a hydroxyl group and a (C1-C5)alkoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

o a group -CONR4R4. in which R4 and R4> are as defined below, o a group -NR4R4> in which R4 and R4> are as defined below,

a heteroaryl group comprising one or more heteroatoms chosen from a nitrogen atom, a sulfur atom and an oxygen atom, optionally substituted with one or more (C1-C3)alkyl groups, optionally substituted with one or more halogen atoms,

> R2 represents a hydrogen atom when n represents 1 and a methyl group when n represents 0;

> R4 and R4 , independently, which may be identical or different, represent a hydrogen atom or a (CrC3)alkyl group,

in the form of the base or of an addition salt with an acid or with a base.

A tenth subgroup of compounds of formula (I) according to the invention is such that L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R-i, in the form of the base or of an addition salt with an acid or with a base.

An eleventh subgroup of compounds of formula (I) according to the invention is such that n represents 1 , in the form of the base or of an addition salt with an acid or with a base.

A twelfth subgroup of compounds of formula (I) according to the invention is such that n represents 0, in the form of the base or of an addition salt with an acid or with a base.

A thirteenth subgroup of compounds of formula (I) according to the invention is such that R-i represents a heteroaryl group, in particular a pyridyl group, in the form of the base or of an addition salt with an acid or with a base.

A fourteenth subgroup of compounds of formula (I) according to the invention is such that Ri represents a heterocycloalkyl group comprising one or more heteroatoms chosen from oxygen and nitrogen atoms, in particular a morpholinyl group, a bridged morpholinyl group, a tetrahydropyranyl group and a piperidyl group, said nitrogen atom being optionally substituted with a substituent chosen from a formyl group, an acetyl group and a -C02-(C1-C4)alkyl group, in the form of the base or of an addition salt with an acid or with a base.

The subgroups defined above, taken separately or in combination, also form part of the invention. It should be noted that the eleventh and twelfth subgroups cannot be combined together.

Among the compounds of formula (I) that are subjects of the invention, mention may be made especially of the following compounds:

1 (8S)-9-(2-Methyl-2-pyrid-4-ylpropyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

2 (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-(2-oxo-2-pyrid-4-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

3 (8S)-9-[2-(6-Aminopyrid-3-yl)-2-oxoethyl]-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

4 (8S)-9-[2-(6-Methylpyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

5 (8S)-9-[2-(6-Methylaminopyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

6 (8S)-9-[2-(6-Dimethylaminopyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

7 (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-(2-oxo-2-pyrid-3-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

8 1-[2-(6-Dimethylaminopyrid-3-yl)-2-oxoethyl]-2-(S)-methyl-7-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-2-trifluoromethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

9 2-(S)-Methyl-1 -[2-(6-methylaminopyrid-3-yl)-2-oxoethyl]-7-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-2-trifluoromethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

10 (8S)-1 -[2-(4-Methoxyphenyl)ethyl]-2-methyl-7-(1 S,4S)-2-oxa-5-azabicyclo[2.2 ]hept-5-yl-2-trifluoromethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

1 1 (S)-1-[2-(6-Aminopyrid-3-yl)-2-oxoethyl]-2-methyl-7-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-2-trifluoromethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

12 (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-(2-pyrid-3-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

13 2-Methyl-7-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1-(2-pyrid-3-ylethyl)-2-((S)-trifluoromethyl)-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

14 (8S)-9-{2-[6-(2-Hydroxyethylamino)pyrid-3-yl]-2-oxoethyl}-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin- 4-one

15 (8S)-9-[2-(5-Methylpyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

16 2-Methyl-1-[2-(5-methylpyrid-3-yl)-2-oxoethyl]-7-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

17 2-Methyl-1-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-7-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-2-trifluoromethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

18 2-Methyl-1 -[2-(2-methylpyrid-3-yl)-2-oxoethyl]-7-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

19 (8S)-9-[2-(2-Methylpyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2 ]hept-5-yl-8-trifluoromethyl-6J,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

20 (8S)-9-[2-(4-Methylpyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

21 2-Methyl-7-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1-(2-oxo-2-pyrid-3-ylethyl)-2-((S)-trifluoromethyl)-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

22 (8S)-9-[2-(6-Cyclopropylaminopyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

23 1-Ethyl-3-{4-[2-((S)-8-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1 ,2-a]pyrimidin-1-yl)ethyl]phenyl}urea

24 1-Ethyl-3-{4-[2-((S)-2-methyl-7-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-5-oxo-2-trifluoromethyl-2,3-dihydro-5H-imidazo[1 ,2-a]pyrimidin-1 -yl)ethyl]phenyl}urea

25 (8S)-9-[2-(4-Methylthiazol-5-yl)ethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

26 2-Methyl-1 -[2-(4-methylthiazol-5-yl)ethyl]-7-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

27 (8S)-9-[2-(3,5-Dimethyl-1 H-pyrazol-4-yl)ethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2 ]hept-5-yl-8-trifluoromethyl-6J,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

28 1 -[2-(3,5-Dimethyl-1 H-pyrazol-4-yl)ethyl]-2-methyl-7-(1 S,4S)-2-oxa-5-

azabicyclo[2.2.1 ]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

29 (8S)-9-(3,3-Dimethyl-2-oxobutyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

30 1 -(3,3-Dimethyl-2-oxobutyl)-2-methyl-7-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

31 (8S)-9-[2-(6-Amino-5-methylpyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

32 1-[2-(4-Aminophenyl)ethyl]-2-methyl-7-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

33 (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-[2-oxo-2-(6-trifluoromethylpyrid-3-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

34 (8S)-9-(2-{6-[(2-Hydroxyethyl)methylamino]pyrid-3-yl}-2-oxoethyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

35 (8S)-9-[2-(6-Ethoxypyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

36 (SS^g-p-ie-Amino^.S-dimethylpyrid-S-y ^-oxoethy ^-il S^S^-oxa-S-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

37 (S)-9-[2-(4-Difluoromethoxyphenyl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

38 (8S)-9-[2-(3,4-Dihydro-2H-pyrido[3,2-b][1 ,4]oxazin-7-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

39 (8S)-9-[2-(4-Methyloxazol-5-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

40 (S)-9-[2-(3,4-Difluorophenyl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

41 (8S)-9-[2-(4-Morpholin-4-ylphenyl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-

azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

42 4-[2-((S)-8-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1 ,2-a]pyrimidin-1 -yl)acetyl]benzonitrile

43 (8S)-9-[2-(4-Methylthiazol-5-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

44 (8S)-9-[2-(5-Chloropyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

45 (8S)-9-[2-(6-Methoxypyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

46 (8S)-9-[2-(3-Methylisoxazol-4-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

47 (8S)-9-(2-Benzo[1 ,2,3]thiadiazol-5-yl-2-oxoethyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

48 (8S)-9-[2-(2,4-Difluorophenyl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

49 (8S)-9-(3-Ethyl-3-hydroxypentyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

50 (8S)-9-(3-Hydroxy-3-methylbutyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

51 (8S)-9-(1 -Methyl-1 H-indazol-3-ylmethyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

52 (8S)-9-[2-(2-Cyclopropylmethoxypyrimidin-5-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

53 (8S)-9-[2-(3,5-Dimethylisoxazol-4-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

54 (8S)-9-(2-Ethyl-2-hydroxybutyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8- trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

55 3-[2-((S)-8-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1 ,2-a]pyrimidin-1 -yl)acetyl]benzonitrile

56 (8S)-9-(3-Methyl-2-oxobutyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6, 7, 8, 9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

57 {5-[2-((S)-8-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1 ,2-a]pyrimidin-1-yl)acetyl]pyrid-2-yl}carbamic acid ethyl ester

58 {5-[2-((S)-8-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1 ,2-a]pyrimidin-1-yl)acetyl]pyrid-2-yl}carbamic acid methyl ester

59 (8S)-9-(5-Methyl-[1 ,2,4]oxadiazol-3-ylmethyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

60 (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-[2-oxo-2-(2-trifluoromethylpyrid-3-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

61 (8S)-9-(2-Benzo[1 ,2,5]thiadiazol-5-yl-2-oxoethyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

62 (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-[2-oxo-2-(tetrahydropyran-4-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

63 (8S)-9-{2-[6-(2-Fluoroethoxy)pyrid-3-yl]-2-oxoethyl}-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

64 (8S)-9-{2-[3-Fluoro-4-(2-fluoroethoxy)phenyl]-2-oxoethyl}-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

65 (8S)-9-[2-(2-Methoxypyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

66 (8S)-9-[2-(3-Methyl-3H-imidazol-4-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

67 (8S)-9-(2-Cyclopropyl-2-oxoethyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

68 (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-(2-oxo-2-pyrid-2-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

69 (8S)-9-[2-(2-Methyl-2H-pyrazol-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

70 N,N-Dimethyl-2-(4-{2-[(S)-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-oxo-2-trifluoromethyl-2,3-dihydro-5H-imidazo[1 ,2-a]pyrimidin-1-yl]ethyl}phenoxy)acetamide

71 (8S)-9-[(S)-2-(4-Fluoro-2-methoxyphenyl)-2-hydroxyethyl]-2-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-8-trifluoromethy^

one

72 (2S)-1-[2-(4-Hydroxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

73 (8S)-2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-phenylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

74 (2S)-1-{2-[4-(2-Dimethylaminoethoxy)phenyl]ethyl}-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

75 (8S)-2-(8-Oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-9-(2-oxo-2-pyrid-4-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

76 (S)-1-[2-(4-Methoxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)- 2- trifluoromethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

77 (S)-2-Methyl-7-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-1 -(3-phenylpropyl)-2-trifluoromethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

78 (S)-1-{2-[4-(3-Dimethylaminopropoxy)phenyl]ethyl}-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

79 (2S)-1-((S)-2-Hydroxy-2-phenylethyl)-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1 ]oct- 3- yl)-2-trifluoromethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

80 (8S)-9-((S)-2-Hydroxy-2-phenylethyl)-2-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

81 (8S)-9-[2-(4-Methoxyphenyl)ethyl]-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

82 (8S)-9-((R)-2-Benzo[b]thiophen-2-yl-2-hydroxyethyl)-2-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

83 (8S)-9-[2-(4-Hydroxyphenyl)ethyl]-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-

trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

84 (8S)-2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(3-phenylpropyl)-8-trifluoromethylmethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

85 (8S)-2-(3-Oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-9-(2-oxo-2-pyrid-3-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

86 (8S)-9-(1-Difluoromethyl-1 H-pyrazol-3-ylmethyl)-2-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

87 (8S)-2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-pyrid-3-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

88 (8S)-2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-pyrid-2-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

89 (S)-9-[2-(1 -Acetylpiperid-4-yl)ethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

90 4-[2-((S)-8-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1 ,2-a]pyrimidin-1 -yl)ethyl]piperidine-1-carbaldehyde 91 4-[2-((S)-8-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1 ,2-a]pyrimidin-1 -yl)acetyl]piperidine-1 -carboxylic acid ethyl ester

92 (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-[2-(tetrahydropyran-4-yl)ethyl]-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

93 (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-(tetrahydropyran-4-ylmethyl)-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

94 (8S)-9-(1 -Acetylpiperid-4-ylmethyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6J,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

95 4-((S)-8-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1 ,2-a]pyrimidin-1 -ylmethyl)piperidine-1-carbaldehyde

96 (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5^

2- trifluoromethylpropyl)-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

97 (8S)-2-(1 S!4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-(4!4,4-trifluoro-3-hydroxy- 3- trifluoromethylbutyl)-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

98 (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-2-oxoethyl]-8-trifluoromethyl-67,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

99 (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-[2-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

100 (8S)-9-[2-(1 -Hydroxycyclopentyl)ethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

101 (8S)-9-(1-Hydroxycyclopentylmethyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

102 (8S)-9-(3,3-Dicyclopropyl-3-hydroxypropyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

103 (8S)-9-(2,2-Dicyclopropyl-2-hydroxyethyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin- 4- one

104 (8S)-9-(1 -Hydroxycyclopropylmethyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

105 (8S)-9-[2-(1 -Hydroxycyclopropyl)ethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept- 5- yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

106 (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-quinolin-5-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

107 (8S)-9-[2-(3-Methylisothiazol-4-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

108 (8S)-9-[2-(4-Methanesulfonylphenyl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

109 (8S)-9-lsoquinolin-5-ylmethyl-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

1 10 (8S)-9-(2-Morpholin-4-yl-2-oxoethyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

1 1 1 (8S)-9-{2-[4-(2-Morpholin-4-ylethoxy)phenyl]ethyl}-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

1 12 N-Methoxy-N-methyl-2-((S)-8-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1 ,2-a]pyrimidin-1 -yl)acetamide

1 13 (8S)-9-(2-lmidazo[1 ,2-a]pyrid-6-yl-2-oxoethyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin- 4-one

1 14 (8S)-9-[2-(6-Difluoromethoxypyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

1 15 (S)-9-{2-[4-(2-Morpholin-4-yl-2-oxoethoxy)phenyl]ethyl}-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

1 16 (8S)-9-(1 -Methyl-3-trifluoromethyl-1 H-pyrazol-4-ylmethyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

1 17 (8S)-9-{2-[4-(2-Dimethylaminoethoxy)phenyl]ethyl}-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

1 18 4-[2-((S)-8-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1 ,2-a]pyrimidin-1-yl)acetyl]piperidine-1 -carbaldehyde

1 19 (8S)-9-[2-(1 -Acetylpiperid-4-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

in the form of the base or of an addition salt with an acid or with a base.

It should be noted that the above compounds were named according to the lUPAC nomenclature by means of the Autonom software.

In accordance with the invention, the compounds of general formula (I) may be prepared according to the processes that follow.

The synthesis of the intermediate compounds E-i in which n = 1 and R2 represents a hydrogen atom is described in Scheme 1 :

Scheme 1

The guanidine A is prepared according to the processes described in patent application EP 1 460 076 by Lochead, A.W. et al.. Compound C may be obtained by condensation of a guanidine A with a dialkyl malonate B, in which R is an alkyl group, preferably an ethyl group, in the presence of a strong base such as sodium methoxide, at a temperature of between 60°C and 100°C, under the conditions described, for example, by Badawey E.-S.A.M. et al. (Eur. J. Med. Chem., 1998, 33(5), 349-361 ). Compound D may be obtained from a compound C by treatment with a chlorinating agent such as phosphorus oxychloride, in the absence of solvent, at a temperature between 20°C and 120°C, or in the presence of a polar solvent such as 1 ,2-dichloroethane, at a temperature of between 20°C and the boiling point of the solvent, as described by Yamashita, A. et al. (Syn. Commun. (2004), 34(5), 795-803). Compound E-, is obtained after separation of the enantiomers of the compound of formula D by chromatography on a chiral support.

The synthesis of the intermediate compounds E0 in which n = 0 and R2 represents a methyl group is described in Scheme 2:

Scheme 2

The diamine F is either commercially available or prepared according to the process described in Journal of Organic Chemistry (2006, 71 (18), 7075-7078) by Brigaud, T. et al. The guanidine G is obtained by reacting a diamine F and cyanogen bromide in a polar solvent such as water or acetonitrile, at a temperature of between 0°C and the boiling point of the solvent, according to the conditions described in patent application EP 1 340 761 by Gallet, T. et al. As previously, the compounds H may be obtained by condensation of a guanidine G with a dialkyl malonate B, in which R is an alkyl group, preferably an ethyl group, in the presence of a strong base such as sodium methoxide, at a temperature of between 60°C and 100°C.

The compounds E0 are obtained from a compound H by treatment with a chlorinating agent such as phosphorus oxychloride, in the absence of solvent, at a temperature between 20°C and 120°C, or in the presence of a polar solvent such as 1 ,2-dichloroethane, at a temperature of between 20°C and the boiling point of the solvent.

Thereafter, the products of formula (I) as defined above according to the present invention may thus be prepared according to Scheme 3.

Scheme 3

The compounds I are obtained from a compound E, in which n represents 0 or 1 , and R2 represents a hydrogen atom if n = 1 , or a methyl group if n = 0, by reaction with a bridged morpholine Y, in the absence of solvent, at a temperature of between 20°C and 140°C, or in the presence of a polar solvent such as methyl isobutyl ketone or butyronitrile, at a temperature of between 20°C and the reflux temperature of the solvent. The compounds (I) may then be obtained via an alkylation reaction, by addition of a compound J of formula R L-Lg with R-i and L as defined above and Lg being a leaving group such as CI, Br, I or OTf (trifluoromethanesulfonate), with compound I and a base such as sodium hydride, cesium carbonate or potassium tert-butoxide in excess, in a polar solvent such as acetonitrile, Ν,Ν-dimethylformamide or tetrahydrofuran, at a temperature of between 0°C and 150°C, as described by Ting P.C. et al. (J. Med. Chem. (1990), 33(10), 2697-2706).

By following the procedure described by E. P. Seest et al. in Tet. Asymmetry 17 (2006) 2154-2182, the compounds J, corresponding to chiral 1 -aryl-2-chloroethanols or 1-heteroaryl-2-chloroethanols, were synthesized from the corresponding chloro ketone derivatives, which were themselves derived from chlorination of commercially available acetyl derivatives under standard conditions.

Alternatively, the compounds (I) may be obtained from a compound K by reaction with a bridged morpholine, in the absence of solvent, at a temperature of between 20°C and 140°C, or in the presence of a solvent such as methyl isobutyl ketone or butyronitrile, at a temperature of between 20°C and the reflux temperature of the solvent.

The compounds K may be obtained via an alkylation reaction, by addition of a compound J of formula R L-Lg with R-i and L as defined above and Lg being a leaving group such as CI, Br, I or OTf, with compound E and a base such as sodium hydride, cesium carbonate or potassium tert-butoxide in excess, in a solvent such as acetonitrile, Ν,Ν-dimethylformamide or tetrahydrofuran, at a temperature of between 0°C and 150°C, as described, for example, by Ting P.C. et al. (J. Med. Chem. (1990), 33(10), 2697-2706).

The compounds of formula (I) for which the linker L is an ethyl group, R-i is a linear or branched (C1-C5)alkyl group substituted with a hydroxyl group, Y represents a bridged morpholine chosen from (a), (b) and (c), n represents 1 or 0, and R2 represents a hydrogen atom when n = 1 and a methyl group when n = 0, are noted (l)-1. The compounds for which the linker L is a methyl group, R-i is a linear or branched (C C5)alkyl group substituted with a hydroxyl group, Y represents a bridged morpholine chosen from (a), (b) and (c), n represents 1 or 0, and R2 represents a hydrogen atom when n = 1 and a methyl group when n = 0, are noted (l)-2. The compounds of formula (I) for which the linker L is a methyl group, Ri is a group -NR6R6' with R6 et R6' being either different and representing an alkyl group and an alkoxy group, or R6 and R6' together forming a monocyclic or bicyclic heterocycloalkyl, Y represents a bridged morpholine chosen from (a), (b) and (c), n represents 1 or 0, and R2 represents a hydrogen atom when n = 1 and a methyl group when n = 0, are noted (l)-3. The compounds of formulae (l)-1 , (l)-2 and (l)-3 may be obtained according to Scheme 4.

s (0-3

Scheme 4

The compounds (l)-1 may be obtained via an alkylation reaction, by addition to a compound N of a compound O, of formula Z-Mg-X in which Z represents a linear or branched alkyl radical and X is a halogen atom such as CI or Br, in a polar solvent such as tetrahydrofuran, at a temperature of between 0°C and 25°C, as described, for example, by Ting P.C. et al. (J. Med. Chem. (1990), 33(10), 2697-2706). The compounds N may be obtained via an addition reaction of Michael type of a compound E with a compound M, of formula CH2=CH2-C02Alkyl, in the presence of a base such as 1 ,8-diazabicyclo[5.4.0]undec-7-ene, in a polar aprotic solvent such as N,N-dimethylformamide, at a temperature of 25°C.

Similarly, the compounds (l)-2 may be obtained via an alkylation reaction, by addition of a compound O, as described above, to compound Q, in a polar solvent such as tetrahydrofuran, at a temperature of between 0°C and 25°C. The compounds Q may be obtained via an alkylation reaction, by addition of a compound P, of formula X-CH2-C02Alkyl in which X is a halogen atom such as CI, Br or I, to compound E and an alkaline base such as sodium hydride or cesium carbonate in excess, in a polar solvent such as Ν,Ν-dimethylformamide or acetonitrile, at a temperature of 25°C.

The compounds (l)-3 may be obtained via a coupling reaction between a compound S

and a compound of formula HNR6R6' with R6 and R6' being either different and representing an alkyl group and an alkoxy group, or R6 and R6' together forming a monocyclic or bicyclic heterocycloalkyl, in a polar solvent such as N,N-dimethylformamide, in the presence of coupling agents such as 1 -hydroxy benzotriazole with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Compound S is obtained by hydrolysis of compound Q, for example using lithium hydroxide monohydrate in a water/tetrahydrofuran mixture.

It is clear to a person skilled in the art that, in order to perform the processes according to the invention described previously, it may be necessary to introduce protecting groups for the amino, carboxyl and alcohol functions in order to avoid side reactions.

Examples of protecting groups and also of protection and deprotection methods are given in Protective Groups in Organic Synthesis, Greene et al., 3rd Edition (John Wiley & Sons, Inc., New York). As examples of protection of reactive functions, the following non-exhaustive list may be mentioned:

- the hydroxyl groups may be protected, for example, with alkyl radicals such as tert-butyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl or acetyl,

- the amino groups may be protected, for example, with acetyl, trityl, benzyl, tert-butoxycarbonyl, benzyloxycarbonyl or phthalimido radicals or other radicals known in peptide chemistry,

- the acid functions may 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.

In the text hereinabove, the term "leaving group Lg" means a group that can be readily cleaved from a molecule by breaking a heterolytic bond, with loss of an electron pair. This group can thus be easily replaced with another group in a substitution reaction, for example. Such leaving groups are, for example, halogens or an activated hydroxyl group, such as a mesylate, tosylate, triflate, acetyl, etc. Examples of leaving groups and also references for preparing them are given in Advanced Organic Chemistry, J. March, 4th Edition, Wiley Interscience, p. 310-316.

In schemes 1 , 2, 3 and 4, the starting compounds and the reagents, when the method for preparing them is not described, are commercially available or described in the literature, or else can be prepared according to methods which are described therein or which are known to those skilled in the art.

According to another of its aspects, a subject of the invention is also the compounds of formulae I, N, Q and S. These compounds are useful as intermediates in the synthesis of the compounds of formula (I).

The following abbreviations and molecular formulae are used:

EtOAc: ethyl acetate

Br: bromine

CDCI3: deuterated chloroform

CI: chlorine

DBU: 1 ,8-diazabicyclo[5.4.0]undec-7-ene

DCM: dichloromethane

DMF: N,N-dimethylformamide

DMSO: dimethyl sulfoxide

DMSO-d6: deuterated dimethyl sulfoxide

HPLC: high performance liquid chromatography

HCI: hydrochloric acid

K2C03: potassium carbonate

LC/MS: liquid chromatography/mass spectrometry

MeOH: methanol

MgS04: magnesium sulfate

MHz: Megahertz

Na2C03: sodium carbonate

NaCI: sodium chloride

NaOH: sodium hydroxide

NaHC03: sodium hydrogen carbonate

Na2S04: sodium sulfate

Ph: phenyl

Pd/C: palladium-on-charcoal

Pd(OH)2/C: palladium hydroxide-on-charcoal

TFA: trifluoroacetic acid

THF: tetrahydrofuran

°C: degrees Celsius

Tr: retention time

min: minutes

ESI+: positive-mode electrospray ionization

The following examples describe the preparation of certain compounds in accordance with the invention. These examples are not limiting and merely illustrate the present invention. The numbers of the compounds exemplified refer to those given in the table hereinafter, which shows the chemical structures and the physical properties of some compounds according to the invention.

CLAIMS

1 . A compound corresponding to formula (I):

in which:

> n represents 0 or 1 ;

> Y represents a bridged morpholine chosen from

(a) (b) (c)

> L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R-i , or a (C1-C2)alkyl, said alkyl being optionally substituted with one or more substituents chosen from a (C1-C3)alkyl group and a hydroxyl group;

> R represents:

a linear, branched, cyclic or partially cyclic (C1-C5)alkyl group, optionally substituted with one or more substituents chosen from a hydroxyl group, an aryl group and a trifluoromethyl group,

- a (C3-C6)cycloalkyl group, optionally substituted with a hydroxyl group,

an aryl group, optionally substituted with one or more substituents chosen from a halogen atom, a hydroxyl group, a cyano group, an -NH2 group, a urea group of formula -NH-CO-NH-(Ci-C4)alkyl, a morpholine group, a group of formula -S02-(Ci-C5)alkyl, a (CrC5)alkoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

o a halogen atom,

o a hydroxyl group or a (CrC5)alkoxy group,

o a group -COR3, in which R3 represents a substituent chosen from a heterocycloalkyi group and a hydroxyl group,

o a group -CONR4R4' in which R4 and R > are as defined below, o a group -NR4R4' in which R4 and R > are as defined below,

o a heterocycloalkyi group comprising one or two heteroelements chosen from a nitrogen atom and an oxygen atom,

o a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (C1-C3)alkyl group, a hydroxyl group and an -NH2 group;

a heteroaryl group, comprising one or more heteroatoms chosen from a nitrogen atom, a sulfur atom and an oxygen atom, optionally substituted with one or more substituents chosen from:

o a halogen atom,

o a (C1-C3)alkyl group optionally substituted with one or more halogen atoms,

o a (C C5)alkoxy group, optionally substituted with one or more substituents chosen from a halogen atom, a (C3-C5)cycloalkyl group, a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (CrC3)alkyl group, a hydroxyl group and an -NH2 group,

o a group -NR5R5. in which R5 and Rs, independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -C02-(C1-C3)alkyl group, a (C3-C5)cycloalkyl group and a linear or branched (CrC3)alkyl group, said alkyl group being optionally substituted with one or more hydroxyl groups,

a pyridine group bearing two linked adjacent groups forming, together with the two carbons that bear them, a heterocyde comprising a nitrogen atom and an oxygen atom,

a heterocycloalkyi group comprising one or more heteroatoms chosen from oxygen and nitrogen atoms, said nitrogen atom being optionally substituted with a substituent chosen from a formyl group, an acetyl group and a -C02-(Ci-C )alkyl group,

a group -NR6R6' in which R6 and R6', which are different, represent a (C C5)alkyl group and a (C1-C5)alkoxy group,

R2 represents a hydrogen atom when n represents 1 and a methyl group when n represents 0;

> R4 and R4 , independently, which may be identical or different, represent a hydrogen atom or a (CrC3)alkyl group,

in the form of the base or of an addition salt with an acid or with a base.

2. The compound of formula (I) as claimed in claim 1 , characterized in that:

> n represents 0 or 1 ;

> Y represents a bridged morpholine chosen from

(a) (b) (c)

> L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R-i , or a (C1-C2)alkyl, said alkyl being optionally substituted with one or more substituents chosen from a (CrC3)alkyl group and a hydroxyl group;

> R represents:

a linear or branched (C-|-C5) alkyl group, optionally substituted with one or more substituents chosen from a hydroxyl group and an aryl group,

- a (C3-C6)cycloalkyl group,

- an aryl group, optionally substituted with one or more substituents chosen from a halogen atom, a hydroxyl group, a cyano group, an -NH2 group, a urea group of formula -NH-CO-NH-(C1-C4)alkyl, a morpholine group, a group of formula -S02-(C1-C5)alkyl, a (C1-C5)alkoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

o a halogen atom,

o a hydroxyl group or a (CrC5)alkoxy group,

o a group -COR3, in which R3 represents a substituent chosen from a heterocycloalkyl group and a hydroxyl group,

o a group -CONR4R4' in which R4 and R4> are as defined below, o a group -NR4R4' in which R4 and R4> are as defined below,

o a heterocycloalkyl group comprising one or two heteroelements chosen from a nitrogen atom and an oxygen atom,

o a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (CrC3)alkyl group, a hydroxyl group and an -IM H2 group;

a heteroaryl group, comprising one or more heteroatoms chosen from a nitrogen atom, a sulfur atom and an oxygen atom, optionally substituted with one or more substituents chosen from:

o a halogen atom,

o a (C1-C3)alkyl group optionally substituted with one or more halogen atoms,

o a (C1-C5)alkoxy group, optionally substituted with one or more substituents chosen from a halogen atom, a (C3-C5)cycloalkyl group, a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (C1-C3)alkyl group, a hydroxyl group and an -IM H2 group,

o a group -NR5R5. in which R5 and Rs, independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -C02-(CrC3)alkyl group, a (C3-C5)cycloalkyl group and a linear or branched (C C3)alkyl group, said alkyl group being optionally substituted with one or more hydroxyl groups,

a pyridine group bearing two linked adjacent groups forming, together with the two carbons that bear them, a heterocyde comprising a nitrogen atom and an oxygen atom,

a heterocycloalkyi group comprising one or more heteroatoms chosen from oxygen and nitrogen atoms, said nitrogen atom being optionally substituted with a substituent chosen from a formyl group and an acetyl group,

a group -NR6R6' in which R6 and R6', which are different, represent a (C C5)alkyl group and a (CrC5)alkoxy group,

> R2 represents a hydrogen atom when n represents 1 and a methyl group when n represents 0;

> R4 and R4 , independently, which may be identical or different, represent a hydrogen atom or a (Ci-C3)alkyl group,

in the form of the base or of an addition salt with an acid or with a base.

3. The compound of formula (I) as claimed in claim 1 or 2, characterized

> Y represents a bridged morpholine (a)

(a)

in the form of the base or of an addition salt with an acid or with a base.

4. The compound of formula (I) as claimed in claim 1 or 2, characterized

> n represents 0 or 1 ;

> Y represents a bridged morpholine a)

(a)

> L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R-i, or (C1-C2)alkyl, said alkyl being optionally substituted with one or more substituents chosen from a (C1-C3)alkyl group;

> Ri represents:

a linear, branched, cyclic or partially cyclic (CrC5)alkyl group, optionally substituted with one or more substituents chosen from a hydroxyl group, an aryl group, a trifluoromethyl group and a (C3-C6)cycloalkyl group,

- a (C3-C6)cycloalkyl group, optionally substituted with a hydroxyl group,

an aryl group, optionally substituted with one or more substituents chosen from a halogen atom, a hydroxyl group, an -NH2 group, a urea group of formula -NH- CO-NH-(C1-C4)alkyl, a morpholinyl group, a group of formula -S02-(C1-C5)alkyl, a (C1-C5)alkoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

o a halogen atom,

o a hydroxyl group or a (C1-C5)alkoxy,

o a group -COR3, in which R3 represents a substituent chosen from a heterocycloalkyl group and a hydroxyl group,

o a heterocycloalkyl group comprising one or two heteroelements chosen from a nitrogen atom and an oxygen atom,

o a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (Ci-C3)alkyl group, a hydroxyl group and

an -IMH2 group;

a heteroaryl group, comprising one or more heteroatoms chosen from a nitrogen atom, a sulfur atom and an oxygen atom, optionally substituted with one or more substituents chosen from:

o a halogen atom,

o a (CrC3)alkyl group optionally substituted with one or more halogen atoms,

o a (C1-C5)alkoxy group, optionally substituted with one or more substituents chosen from a halogen atom, a (C3-C5)cycloalkyl group, a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (C1-C3)alkyl group, a hydroxyl group and an -IMH2 group,

o a group -NR5R5. in which R5 and Rs, independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -C02-(C1-C3)alkyl group, a (C3-C5)cycloalkyl group and a linear or branched (CrC3)alkyl group, said alkyl group being optionally substituted with one or more hydroxyl groups,

a pyridine group bearing two linked adjacent groups forming, together with the two carbons that bear them, a heterocycle comprising a nitrogen atom and an oxygen atom,

a heterocycloalkyl group comprising one or more heteroatoms chosen from oxygen and nitrogen atoms, said nitrogen atom being optionally substituted with a substituent chosen from a formyl group, an acetyl group and a -C02-(Ci- C4)alkyl group,

a group -NR6R6. in which R6 and R6', which are different, represent a (C C5)alkyl group and a (CrC5)alkoxy group,

> R2 represents a hydrogen atom when n represents 1 and a methyl group when n represents 0;

> R4 and R4 , independently, which may be identical or different, represent a hydrogen atom or a (Ci-C3)alkyl group,

in the form of the base or of an addition salt with an acid or with a base.

5. The compound of formula (I) as claimed in any one of claims 1 to 4, characterized that:

> n represents 0 or 1 ;

> Y represents a bridged morpholine (a)

(a)

> L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R-i, or (Ci-C2)alkyl, said alkyl being optionally substituted with one or more substituents chosen from a (CrC3)alkyl group;

> Ri represents:

a linear, branched, cyclic or partially cyclic (C1-C5)alkyl group, optionally substituted with one or more substituents chosen from a hydroxyl group and an aryl group,

a (C3-C6)cycloalkyl group,

an aryl group, optionally substituted with one or more substituents chosen from a halogen atom, a hydroxyl group, an -NH2 group, a urea group of formula -NH- CO-NH-(C1-C4)alkyl, a morpholinyl group, a group of formula -S02-(C1-C5)alkyl, a (C1-C5)alkoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

o a halogen atom,

o a hydroxyl group or a (C1-C5)alkoxy,

o a group -COR3, in which R3 represents a substituent chosen from a heterocycloalkyl group and a hydroxyl group,

o a heterocycloalkyl group comprising one or two heteroelements chosen from a nitrogen atom and an oxygen atom,

o a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (CrC3)alkyl group, a hydroxyl group and an -NH2 group,

a heteroaryl group, comprising one or more heteroatoms chosen from a nitrogen atom, a sulfur atom and an oxygen atom, optionally substituted with one or more substituents chosen from:

o a halogen atom,

o a (CrC3)alkyl group optionally substituted with one or more halogen atoms,

o a (CrC5)alkoxy group, optionally substituted with one or more substituents chosen from a halogen atom, a (C3-C5)cycloalkyl group, a heteroaryl group optionally substituted with one or more substituents

chosen from a halogen atom, a (CrC3)alkyl group, a hydroxyl group and an -IMH2 group,

o a group -NR5R5' in which R5 and R5', independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -C02-(Ci-C3)alkyl group, a (C3-C5)cycloalkyl group and a linear or branched (CrC3)alkyl group, said alkyl group being optionally substituted with one or more hydroxyl groups,

a pyridine group bearing two linked adjacent groups forming, together with the two carbons that bear them, a heterocyde comprising a nitrogen atom and an oxygen atom,

a heterocycloalkyi group comprising one or more heteroatoms chosen from oxygen and nitrogen atoms, said nitrogen atom being optionally substituted with a substituent chosen from a formyl group and an acetyl group,

a group -NR6R6. in which R6 and R6', which are different, represent a (C C5)alkyl group and a (C1-C5)alkoxy group,

> R2 represents a hydrogen atom when n represents 1 and a methyl group when n represents 0;

> R4 and R4 , independently, which may be identical or different, represent a hydrogen atom or a (CrC3)alkyl group,

in the form of the base or of an addition salt with an acid or with a base.

6. The compound of formula (I) as claimed in claim 1 or 2, characterized in that:

> n represents 0 or 1 ;

> Y represents a bridged morpholine chosen from (b) and (c)

(b) (c)

> L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R-i, or (CrC2)alkyl, said alkyl being optionally substituted with a hydroxyl group;

> Ri represents:

a linear or branched (CrC5)alkyl group, optionally substituted with an aryl group,

an aryl group, optionally substituted with one or more substituents chosen from a halogen atom, a hydroxyl group and a (CrC5)alkoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

o a group -CONR4R4' in which R4 and R > are as defined below, o a group -NR4R4' in which R4 and R > are as defined below,

a heteroaryl group comprising one or more heteroatoms chosen from a nitrogen atom, a sulfur atom and an oxygen atom, optionally substituted with one or more (C1-C3)alkyl groups, optionally substituted with one or more halogen atoms,

> R2 represents a hydrogen atom when n represents 1 and a methyl group when n represents 0;

> R4 and R4>, independently, which may be identical or different, represent a hydrogen atom or a (C1-C3)alkyl group,

in the form of the base or of an addition salt with an acid or with a base.

7. The compound as claimed in any one of claims 1 to 6, characterized in that the linker L represents -CH2-CO, in the form of the base or of an addition salt with an acid or with a base.

8. The compound as claimed in any one of claims 1 to 7, characterized in that n represents 1 , in the form of the base or of an addition salt with an acid or with a base.

9. The compound as claimed in any one of claims 1 to 7, characterized in that n represents 0, in the form of the base or of an addition salt with an acid or with a base.

10. The compound as claimed in any one of claims 1 to 9, characterized in that R-i represents a heteroaryl group, in the form of the base or of an addition salt with an acid or with a base.

1 1. The compound as claimed in any one of claims 1 to 9, characterized in that R-i represents a heterocycloalkyl group comprising one or more heteroatoms chosen from oxygen and nitrogen atoms, said nitrogen atom being optionally substituted with a substituent chosen from a formyl group, an acetyl group and a -C02-(C1-C4)alkyl group, in the form of the base or of an addition salt with an acid or with a base.

12. The compound as claimed in any one of the preceding claims 1 to 1 1 , characterized in that it is chosen from:

1 (8S)-9-(2-Methyl-2-pyrid-4-ylpropyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

2 (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-(2-oxo-2-pyrid-4-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

3 (8S)-9-[2-(6-Aminopyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

4 (8S)-9-[2-(6-Methylpyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

5 (8S)-9-[2-(6-Methylaminopyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

6 (8S)-9-[2-(6-Dimethylaminopyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

7 (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-(2-oxo-2-pyrid-3-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

8 1 -[2-(6-Dimethylaminopyrid-3-yl)-2-oxoethyl]-2-(S)-methyl-7-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-2-trifluoromethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

9 2-(S)-Methyl-1-[2-(6-methylaminopyrid-3-yl)-2-oxoethyl]-7-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-2-trifluoromethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

10 (8S)-1 -[2-(4-Methoxyphenyl)ethyl]-2-methyl-7-(1 S,4S)-2-oxa-5-

azabicyclo[2.2.1 ]hept-5-yl-2-trifluoromethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

1 1 (S)-1-[2-(6-Aminopyrid-3-yl)-2-oxoethyl]-2-methyl-7-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-2-trifluoromethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

12 (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-(2-pyrid-3-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

13 2-Methyl-7-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1-(2-pyrid-3-ylethyl)-2-((S)-trifluoromethyl)-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

14 (8S)-9-{2-[6-(2-Hydroxyethylamino)pyrid-3-yl]-2-oxoethyl}-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

15 (8S)-9-[2-(5-Methylpyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

16 2-Methyl-1 -[2-(5-methylpyrid-3-yl)-2-oxoethyl]-7-(1 S,4S)-2-oxa-5-azabicyclop^.l lhept-S-yl^-iiSHrifluoromethy ^.S-dihydro-I H-imidazotl ^-a]pyrimidin-5-one

17 2-Methyl-1-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-7-(1 S,4S)-2-oxa-5-azabicyclo[2.2 ]hept-5-yl-2-trifluoromethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

18 2-Methyl-1-[2-(2-methylpyrid-3-yl)-2-oxoethyl]-7-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

19 (8S)-9-[2-(2-Methylpyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

20 (8S)-9-[2-(4-Methylpyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

21 2-Methyl-7-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1 -(2-oxo-2-pyrid-3-ylethyl)-2-((S)-trifluoromethyl)-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

22 (8S)-9-[2-(6-Cyclopropylaminopyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

23 1-Ethyl-3-{4-[2-((S)-8-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1 ,2-a]pyrimidin-1 -yl)ethyl]phenyl}urea

24 1-Ethyl-3-{4-[2-((S)-2-methyl-7-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-5-oxo-2-trifluoromethyl-2,3-dihydro-5H-imidazo[1 ,2-a]pyrimidin-1 -yl)ethyl]phenyl}urea

25 (8S)-9-[2-(4-Methylthiazol-5-yl)ethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

26 2-Methyl-1 -[2-(4-methylthiazol-5-yl)ethyl]-7-(1 S,4S)-2-oxa-5-azabicyclop^.l lhept-S-yl^-iiSHrifluoromethy ^.S-dihydro-I H-imidazotl ^-a]pyrimidin-5-one

27 (8S)-9-[2-(3,5-Dimethyl-1 H-pyrazol-4-yl)ethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

28 1-[2-(3,5-Dimethyl-1 H-pyrazol-4-yl)ethyl]-2-methyl-7-(1 S,4S)-2-oxa-5-azabicyclop^.l lhept-S-yl^-iiSHrifluoromethy ^.S-dihydro-I H-imidazotl ^-a]pyrimidin-5-one

29 (8S)-9-(3,3-Dimethyl-2-oxobutyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

30 1 -(3,3-Dimethyl-2-oxobutyl)-2-methyl-7-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

31 (8S)-9-[2-(6-Amino-5-methylpyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

32 1-[2-(4-Aminophenyl)ethyl]-2-methyl-7-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

33 (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-[2-oxo-2-(6-trifluoromethylpyrid-3-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

34 (8S)-9-(2-{6-[(2-Hydroxyethyl)methylamino]pyrid-3-yl}-2-oxoethyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

35 (8S)-9-[2-(6-Ethoxypyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

36 (SS^g-p-ie-Amino^.S-dimethylpyrid-S-y ^-oxoethy ^-il S^S^-oxa-S-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

37 (S)-9-[2-(4-Difluoromethoxyphenyl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

38 (8S)-9-[2-(3,4-Dihydro-2H-pyrido[3,2-b][1 ,4]oxazin-7-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

39 (8S)-9-[2-(4-Methyloxazol-5-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

40 (S)-9-[2-(3,4-Difluorophenyl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

41 (8S)-9-[2-(4-Morpholin-4-ylphenyl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2 ]hept-5-yl-8-trifluoromethyl-6J,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

42 4-[2-((S)-8-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1 ,2-a]pyrimidin-1 -yl)acetyl]benzonitrile

43 (8S)-9-[2-(4-Methylthiazol-5-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

44 (8S)-9-[2-(5-Chloropyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

45 (8S)-9-[2-(6-Methoxypyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

46 (8S)-9-[2-(3-Methylisoxazol-4-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

47 (8S)-9-(2-Benzo[1 ,2,3]thiadiazol-5-yl-2-oxoethyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

48 (8S)-9-[2-(2,4-Difluorophenyl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

49 (8S)-9-(3-Ethyl-3-hydroxypentyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

50 (8S)-9-(3-Hydroxy-3-methylbutyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

51 (8S)-9-(1-Methyl-1 H-indazol-3-ylmethyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1] hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

52 (8S)-9-[2-(2-Cyclopropylmethoxypyrimidin-5-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

53 (8S)-9-[2-(3,5-Dimethylisoxazol-4-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

54 (8S)-9-(2-Ethyl-2-hydroxybutyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

55 3-[2-((S)-8-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1 ,2-a]pyrimidin-1-yl)acetyl]benzonitrile

56 (8S)-9-(3-Methyl-2-oxobutyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

57 {5-[2-((S)-8-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1 ,2-a]pyrimidin-1 -yl)acetyl]pyrid-2-yl}carbamic acid ethyl ester

58 {5-[2-((S)-8-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1 ,2-a]pyrimidin-1 -yl)acetyl]pyrid-2-yl}carbamic acid methyl ester

59 (8S)-9-(5-Methyl-[1 ,2,4]oxadiazol-3-ylmethyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

60 (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-[2-oxo-2-(2-trifluoromethylpyrid-3-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

61 (8S)-9-(2-Benzo[1 ,2,5]thiadiazol-5-yl-2-oxoethyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

62 (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-[2-oxo-2-(tetrahydropyran-4-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

63 (8S)-9-{2-[6-(2-Fluoroethoxy)pyrid-3-yl]-2-oxoethyl}-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin- 4-one

64 (8S)-9-{2-[3-Fluoro-4-(2-fluoroethoxy)phenyl]-2-oxoethyl}-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

65 (8S)-9-[2-(2-Methoxypyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

66 (8S)-9-[2-(3-Methyl-3H-imidazol-4-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

67 (8S)-9-(2-Cyclopropyl-2-oxoethyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

68 (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-(2-oxo-2-pyrid-2-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

69 (8S)-9-[2-(2-Methyl-2H-pyrazol-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

70 N,N-Dimethyl-2-(4-{2-[(S)-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-oxo-2-trifluoromethyl-2,3-dihydro-5H-imidazo[1 ,2-a]pyrimidin-1 -yl]ethyl}phenoxy)acetami

71 (8S)-9-[(S)-2-(4-Fluoro-2-methoxyphenyl)-2-hydroxyethyl]-2-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

72 (2S)-1-[2-(4-Hydroxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

73 (8S)-2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-phenylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

74 (2S)-1-{2-[4-(2-Dimethylaminoethoxy)phenyl]ethyl}-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

75 (8S)-2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-pyrid-4-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

76 (S)-1-[2-(4-Methoxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)- 2- trifluoromethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

77 (S)-2-Methyl-7-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-1-(3-phenylpropyl)-2-trifluoromethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

78 (S)-1-{2-[4-(3-Dimethylaminopropoxy)phenyl]ethyl}-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-2-trifluoromethyl-2,^^

one

79 (2S)-1-((S)-2-Hydroxy-2-phenylethyl)-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1 ]oct- 3- yl)-2-trifluoromethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one

80 (8S)-9-((S)-2-Hydroxy-2-phenylethyl)-2-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

81 (8S)-9-[2-(4-Methoxyphenyl)ethyl]-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

82 (8S)-9-((R)-2-Benzo[b]thiophen-2-yl-2-hydroxyethyl)-2-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

83 (8S)-9-[2-(4-Hydroxyphenyl)ethyl]-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

84 (8S)-2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(3-phenylpropyl)-8-trifluoromethylmethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

85 (8S)-2-(3-Oxa-8-azabicyclo[3.2.1]oct-8-yl)-9-(2-oxo-2-pyrid-3-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

86 (8S)-9-(1 -Difluoromethyl-1 H-pyrazol-3-ylmethyl)-2-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

87 (8S)-2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-pyrid-3-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

88 (8S)-2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-pyrid-2-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

89 (S)-9-[2-(1 -Acetylpiperid-4-yl)ethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

90 4-[2-((S)-8-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1 ,2-a]pyrimidin-1 -yl)ethyl]piperidine-1-carbaldehyde

91 4-[2-((S)-8-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1 ,2-a]pyrimidin-1 -yl)acetyl]piperidine-1-carboxylic acid ethyl ester

92 (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-[2-(tetrahydropyran-4-yl)ethyl]-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

93 (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-(tetrahydropyran-4-ylmethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

94 (8S)-9-(1 -Acetylpiperid-4-ylmethyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6J,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

95 4-((S)-8-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1 ,2-a]pyrimidin-1 -ylmethyl)piperidine-1-carbaldehyde

96 (SS^-il S^S^-Oxa-S-azabicycloP^.l lhept-S-yl-g-iS.S.S-trifluoro^-hydroxy- 2- trifluoromethylpropyl)-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

97 (8S)-2-(1 S!4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-(4!4,4-trifluoro-3-hydroxy- 3- trifluoromethylbutyl)-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

98 (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-[2-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

99 (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-[2-(3-oxa-8-azabicyclo[3.2.1 ]oct-8-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

100 (8S)-9-[2-(1 -Hydroxycyclopentyl)ethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

101 (8S)-9-(1 -Hydroxycyclopentylmethyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

102 (8S)-9-(3,3-Dicyclopropyl-3-hydroxypropyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

103 (8S)-9-(2,2-Dicyclopropyl-2-hydroxyethyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin- 4- one

104 (8S)-9-(1 -Hydroxycyclopropylmethyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

105 (8S)-9-[2-(1 -Hydroxycyclopropyl)ethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept- 5- yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

106 (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-quinolin-5-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

107 (8S)-9-[2-(3-Methylisothiazol-4-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

108 (8S)-9-[2-(4-Methanesulfonylphenyl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

109 (8S)-9-lsoquinolin-5-ylmethyl-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

1 10 (8S)-9-(2-Morpholin-4-yl-2-oxoethyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5- yl-8-trifluoromethyl-6J,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

1 1 1 (8S)-9-{2-[4-(2-Morpholin-4-ylethoxy)phenyl]ethyl}-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

1 12 N-Methoxy-N-methyl-2-((S)-8-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1 ,2-a]pyrimidin-1 -yl)acetamide

1 13 (8S)-9-(2-lmidazo[1 ,2-a]pyrid-6-yl-2-oxoethyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

1 14 (8S)-9-[2-(6-Difluoromethoxypyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

1 15 (S)-9-{2-[4-(2-Morpholin-4-yl-2-oxoethoxy)phenyl]ethyl}-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

1 16 (8S)-9-(1 -Methyl-3-trifluoromethyl-1 H-pyrazol-4-ylmethyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

1 17 (8S)-9-{2-[4-(2-Dimethylaminoethoxy)phenyl]ethyl}-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

1 18 4-[2-((S)-8-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1 ,2-a]pyrimidin-1 -yl)acetyl]piperidine-1 -carbaldehyde

1 19 (8S)-9-[2-(1 -Acetylpiperid-4-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6 ,7,8,9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

in the form of the base or of an addition salt with an acid or with a base.

13. A process for preparing a compound of formula (I) as claimed in any one of claims 1 to 12, comprising the reaction of a compound of formula E

in which n represents 0 or 1 and R2 represents a hydrogen atom when n = 1 or a methyl group when n = 0, with a bridged morpholine Y, chosen from (a), (b) and (c) as defined in claim 1 , to obtain a compound of formula I

and the alkylation reaction by addition to I of a compound of formula J = R L-Lg in which Ri and L are as defined in any one of the preceding claims and Lg is a leaving group.

14. A process for preparing a compound of formula (I) as claimed in any one of claims 1 to 12, comprising the alkylation reaction of a compound of formula E

in which n represents 0 or 1 and R2 represents a hydrogen atom when n = 1 or a methyl group when n = 0, by addition of a compound of formula J = R L-Lg in which R-i and L are as defined in any one of claims 1 to 8 and Lg is a leaving group, to obtain a compound of formula K

in which R-i , R2, L and n are as defined in one of claims 1 to 8, and a reaction on a compound K with a compound of formula Y being a bridged morpholine chosen from (a), (b) and (c) as defined in claim 1 .

15. A process for preparing a compound of formula (I) as claimed in any one of claims 1 to 12, in which the linker L is an ethyl group, Ri is a linear or branched (CrC5)alkyl group substituted with a hydroxyl group, Y represents a bridged morpholine chosen from (a), (b) and (c) as defined in claim 1 , n represents 1 or 0, and R2 represents a hydrogen atom when n = 1 and a methyl group when n = 0, comprising a Michael addition reaction of a compound of formula E

in which n represents 0 or 1 and R2 represents a hydrogen atom when n = 1 or a methyl group when n = 0, on a compound of formula M = CH2=CH2-C02Alkyl, to obtain a compound of formula N,

in which n represents 0 or 1 and R2 represents a hydrogen atom when n = 1 or a methyl group when n = 0, and Y is a bridged morpholine chosen from (a), (b) and (c) as defined in claim 1 ,

and a reaction of alkyl on a compound of formula N with a compound of formula O = Z-Mg-X in which Z represents a linear or branched alkyl radical and X is a halogen atom.

16. A process for preparing a compound of formula (I) as claimed in any one of claims 1 to 12, in which the linker L is a methyl group, Ri is a linear or branched (CrC5)alkyl group substituted with a hydroxyl group, Y represents a bridged morpholine chosen from (a), (b) and (c) as defined in claim 1 , n represents 1 or 0, and R2 represents a hydrogen atom when n = 1 and a methyl group when n = 0, comprising an addition reaction of a compound of formula E

in which n represents 0 or 1 and R2 represents a hydrogen atom when n = 1 or a methyl group when n = 0, with a compound of formula P = X-CH2-C02Alkyl with X being a halogen atom, to obtain a compound of formula Q

in which Y is a bridged morpholine chosen from (a), (b) and (c), n represents 0 or 1 and R2 represents a hydrogen atom when n = 1 or a methyl group when n = 0,

and an alkylation reaction on a compound of formula Q with a compound of formula O = Z-Mg-X in which Z represents a linear or branched alkyl radical and X is a halogen atom.

17. A process for preparing a compound of formula (I) as claimed in any one of claims 1 to 12, in which the linker L is a methyl group, Ri is a group -NR6R6' with R6 et R6' being either different and representing an alkyl group and an alkoxy group, or R6 and R6' together forming a monocyclic or bicyclic heterocycloalkyl, Y represents a bridged morpholine chosen from (a), (b) and (c) as defined in claim 1 , n represents 1 or O, and R2 represents a hydrogen atom when n = 1 and a methyl group when n = 0, comprising a hydrolysis reaction of a compound of formula Q

in which Y is a bridged morpholine chosen from (a), (b) and (c), n represents 0 or 1 and R2 represents a hydrogen atom when n = 1 or a methyl group when n = 0, to obtain a compound of formula S

in which Y represents a bridged morpholine chosen from (a), (b) and (c) as defined in claim 1 , n represents 1 or 0 and R2 represents a hydrogen atom when n = 1 or a methyl group when n = 0,

and a coupling reaction between a compound of formula S and a compound of formula HNR6R6' with R6 and R6' being either different and representing an alkyl group and an alkoxy group, or R6 and R6' together forming a monocyclic or bicyclic heterocycloalkyl.

18. Compounds of formulae I, N, Q and S:

in which n, R2 and Y are as defined in claim 1 .

19. A medicament, characterized in that it comprises a compound as claimed in any one of claims 1 to 12, or an addition salt of this compound with a pharmaceutically acceptable acid or base.

20. The compound as claimed in any one of claims 1 to 12, as a medicament.

21. A pharmaceutical composition, characterized in that it comprises a compound as claimed in any one of claims 1 to 12, or a pharmaceutically acceptable salt of this compound, and also at least one pharmaceutically acceptable excipient.

22. The use of a compound as claimed in any one of claims 1 to 12, for the preparation of a medicament for treating parasite-induced malaria.

23. The compound as claimed in any one of claims 1 to 12, for its use in the treatment of malaria induced by all species of Plasmodium, such as P. falciparum, P. vivax, P. malariae, P. ovale and P. knowlesi, by all species of Trypanosoma and by all species of Leishmania, in the treatment of sleeping sickness, the treatment of Chagas disease, the various forms of leishmaniasis and the treatment of other parasitic infections, such as schistosomiasis (bilharzia), toxoplasmosis and coccidiosis.