OA17195A

OA17195A - Pyrimidinone derivatives as antimalarial agents.

Info

Publication number: OA17195A
Application number: OA1201400571
Authority: OA
Inventors: Youssef El-Ahmad; Bruno Filoche-Romme; Axel Ganzhorm; Gilbert Marciniak; Nicolas Muzet; Baptiste Ronan; Bertrand Vivet; Véronique Zerr
Original assignee: Sanofi
Priority date: 2012-06-22
Filing date: 2013-06-21
Publication date: 2016-04-05

Abstract

The invention relates to novel pyrimidinonebased heterocyclic compounds which are parasite growth inhibitors, having the general formula (I)

Description

PYRIMIDINONE DERIVATIVES AS ANTIMALARIAL AGENTS

The présent Invention relates to pyrimidinone dérivatives, and to the préparation 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 concems children under 5 years old. The substantiel retum of the disease observed in recent years is due to several factors, including:

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

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

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

The propagation of résistance 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 kînome of P. falciparum has been proposed as a réservoir of novel targets for the development of novel médicaments, which hâve not yet been explored in the treatment of malaria (Doerig and Meijer (2007) Expert Opin. Ther. Targets 11,279-290).

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 CFj-pyrimidinone dérivatives, which are active on human phosphatidylinositol-3-kinases, has been identified as being parasite growth inhibitors in human érythrocytes. 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 • I (Vaid et al. (2010) Blood 115, 2500-2507). PfPI3K intervenes in the mechanism of endocytosis and in trafficking the host hemoglobin and as such plays an important rôle in maintaining the parasite growth in the infected human érythrocyte. It might thus be thereby deduced that the plasmodtal kinase PfPI3K would be a target for the compounds of the présent invention.

Human PI3Ks play a major rôle 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 prolifération and protein synthesis. The insulin signaling pathway via the PI3K/Akt axis involving class 1A of PI3Ks (PI3Ka and β) is essential in glucose homeostasls. Downstream atténuation of insulin receptor signaling plays an important rôle in the development of type-2 diabètes. The other isoforms of class I PI3K, ΡΙ3Κγ and PI3K5, are involved in the Immune fonction 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 déficiences In immune fonctions (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, PIK3C3/VPS34, 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, réduction of insulin sensitivity, diabètes, deregulation of the cérébral fonctions 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 éruptions and liver damage hâve been observed during clinical studles with inhibitors of the PI3K/mTOR axis.

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

CF3-pyrimidinone dérivatives hâve been described in patent applications WO 2011/001112 and WO 2011/001113 for the préparation of médicaments for treating

J various cancers and also for treating parasitic diseases such as malaria. These compounds are described as inhibitors of human PI3Ks.

The compounds of the présent invention hâve the advantage, although being derived from inhibitors of human P13K and in particular P13Ka, they do not inhibit this class of human kinases, while nonetheless remaining inhibitors of parasite growth.

Similar kinomes are présent in ail 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 ail the parasites mentioned above. In addition, the kinases are found in other parasites, such as Trypanosome (for example T. brucei, T. cruzei) and Leishmanie (for example L mejor, L donovani). The compounds ofthe 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 régulation. Consequently, the compounds of the présent invention may be useful in the treatment of schistosomiasis (bilharzia), toxoplasmosis and coccidiosis.

The présent invention relates to compounds corresponding to formula (1):

(l) in which:

> n représente 0 or 1;

> Y represents a bridged morpholine chosen from

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

> Ri represents:

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

- a (C₃'C_e)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-(CrC4)alkyl, a morpholine group, a group of formula -SO2-(Ci-Cs)alkyl, a (CrCs)alkoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

o a halogen atom, o a hydroxyl group or a (CrCs)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 R< and R*· are as defined below, o a group -NR4R4· in which R* and 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 (CrCsJalkyl group optionally substituted with one or more halogen atoms, »

I o a (Ci-Cs)alkoxy group, optionally substituted with one or more substituents chosen from a halogen atom, a (C3-Cs)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 -NH₂ group, o a group -NR5R5· in which Rs and Ry, independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -CO2-(Ci-C3)alkyl group, a (Cj-CsJcycloalkyl 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 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 -C0r(Cr C₄)alkyl group, ~ a group -NReRe* in which Re and Re·, which are different, represent a (Ci-Cs)alkyl group and a (Ci-C₅)alkoxy group, > R2 represents a hydrogen atom when n represents 1 and a methyl group when n represents 0;

> R< and R4-, independently, which may be identical or different, represent a hydrogen atom or a (Ci-Cjjalkyl group, in the form of the base or of an addition sait 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 sait.

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

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

- an alkvl group: uniess 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 groupe;

- a partiallv cvclic fCi-Cslalkvl group: unless otherwise mentioned in the text, a linear saturated aliphatic group substituted with a (CrC^cycloalkyl group. Examples that may be mentioned include methylcyclopropyl, methylcyclobutyl and ethylcyciopropyl groups;

- a cvcloalkvl group: a cyclic (Cs-Cejalkyl group. Exampies that may be mentioned include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyi 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 exampie of an aryl group that may be mentioned is the phenyl group;

- a heteroaryl group: a monocyciic 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 monocyciic heteroaryl groups that may be mentioned include imidazoiyl, pyrimidyl, isoxazolyl, thiazolyi, isothiazolyl, pyridyl, pyrazolyl, oxazolyl and 1,2,4-oxadiazolyl groups. Exampies of bicyclic heteroaryl groups that may be mentioned include 1H-indazolyl, benzo[1,2,3]thiadiazolyl, benzo[1,2,5]thiadiazolyl, benzothiophenyl, imidazo[1,2-a]pyridyl, quinolinyl and isoquinolînyl groups;

- a heterocycloalkyl: a monocyciic 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 monocyciic heterocycloalkyl groups that may especially be mentioned include piperidyl, morpholinyl and tetrahydropyranyl groups, and exampies of bicyclic heterocycloalkyl groups that may be mentioned include groups of bridged morpholine type: 8-oxa-3-azabicyclo[3.2.1]oct-3-yl, 3-oxa-8-azabicycloï3.2.1]oct-8-yl.

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

(l) in which:

> n représente 0 or 1, and/or > Y représents a bridged morpholine chosen from

(a) (b)

and/or > L représente a linker -CH2-CO- such that the carbonyl fonction is attached to the substituent Ri, or a (Ci-Cîïalkyl, said alkyl being optionally substituted with one or more substituents chosen from a (Ci-Csjalkyl group and a hydroxyl group, and/or > Ri représente:

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

- a (C3-Ce)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 -SOrfCi-CsJalkyl, a (Ci-Cs)alkoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

o a halogen atom, o a hydroxyl group or a (Ci-Csîalkoxy group, o a group -COR3, in which R3 représente a substituent chosen from a s

heterocycloalkyl group and a hydroxyl group, o a group -CONR4R4· in which R* and R*· are as defined below, o a group -NR4R4· In which R« 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 substîtuted with one or more substituents chosen from a halogen atom, a (Ci-Cajalkyl 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 substîtuted with one or more substituents chosen from:

o a halogen atom, o a (Ci-C3)alkyl group optionally substîtuted with one or more halogen atoms, o a (Ci-Cs)alkoxy group, optionally substîtuted with one or more substituents chosen from a halogen atom, a (C3-Cs)cycloalkyl group, a heteroaryl group optionally substîtuted with one or more substituents chosen from a halogen atom, a (Ci-Cjjalkyl group, a hydroxyl group and an -NH2 group, o a group -NRjRs· in which Rj and Ry, independently, which may be Identical or different, represent a substituent chosen from a hydrogen atom, a -CO2-(Ci-C3)alkyl group, a (CrCsjcycloalkyl group and a linear or branched (Ci-Csjalkyl group, said alkyl group being optionally substîtuted 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 substîtuted with a substituent chosen fforn a formyl group, an acetyl group and a -CO2-(CiC₄)alkyl group,

- a group -NReRe· In which Re and Re·, which are different, represent a (Ci-Cg)alkyi group and a (CrCs)alkoxy group, and/or > R2 represents a hydrogen atom when n represents 1 and a methyl group when n represents 0, and/or > R< and R<, independently, which may be identical or different, represent a hydrogen atom or a (Gi-C3)alkyl group, in the form of the base or of an addition sait with an acid or with a base.

Among the compounds of the présent invention, mention may be made of a 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 fonction is attached to the substituent Ri, or a (Ci-C2)alkyl, said alkyl being optionally substituted with one or more substituents chosen from a (Ci-Cajalkyl 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 group (Cs-Cejcydoalkyl,

- an aryl group, optionally substituted with one or more substituents chosen from a haiogen atom, a hydroxyl group, a cyano group, an -NH2 group, a urea group of formula -NH-CO-NH-(Ci-G₄)alkyl, a morpholine group, a group of formula -SCHCi-CsJalkyl, a (Ci-Cs)alkoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

o a haiogen atom, o a hydroxyl group or a (GrGg)alkoxy group, o a group -GOR3, in which R3 represents a substituent chosen from a heterocycloalkyl group and a hydroxyl group, o a group -CONR4R4· in which and R»· are as defined below, o a group -NRiR^ in which R< and FV 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-Csjalkyl group, a hydroxyl group and an -NH2 group,

o a halogen atom, o a (CrCaJalkyl group optionally substituted with one or more halogen atoms, o a (CrCs)alkoxy group, optionally substituted with one or more substituents chosen from a halogen atom, a (C3-Cs)cyc1oalkyl group, a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (Ci-Cj)alkyl group, a hydroxyl group and an -NH2 group, o a group -NR5R5· in which Rs and Ry, independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -CO2-(Ci-C₃)alkyl group, a (Cj-Csjcycloalkyl group and a lînear or branched (Ci-Ca)alkyl group, said alkyl group being optionally substituted with one or more hydroxyl groups,

- 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 -NReRe· in which Re and Re·, which are different, represent a (Ci-Cs)alkyl group and a (Ci-Cs)aikoxy group, > R2 represents a hydrogen atom when n represents 1 and a methyl group when n represents 0;

> R4 and Rr, independently, which may be identical or different, represent a hydrogen atom or a (Ci-Ca)alkyi group, in the form of the base or of an addition sait with an acid or with a base.

Among the compounds of the présent 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 -CHrCO- such that the carbonyl fonction is attached to the substituent Ri, or (Ci-C2)alkyl, said aikyl being optionally substituted with one or more substituent s chosen from a (Ci-C₃)alkyl group and a hydroxyl group;

> Ri represents:

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

- a (C₃-Ce)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 -NH; group, a urea group of formula -NHCO-NH-(Ci-C4)alkyl, a morpholine group, a group of formula -SO2-(Ci-C5)alkyl, a (Ci-C5)a1koxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

o a halogen atom, o a hydroxyl group or a (Ci-Cs)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 R< 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 (Ci-C₃)alkyl group, a hydroxyl group and an -NH2 group,

o a halogen atom, o a (CrCsJalkyl group optionally substituted with one or more halogen atoms, o a (Ci-Cj)alkoxy group, optionally substituted with one or more substituents chosen from a halogen atom, a (CyCsJcycloalkyl group, a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (Ci-Cajalkyl group, a hydroxyl group and an -NH2 group, o a group -NR5R5· In which R5 and Ry, independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -COHCi-CaJalkyl group, a (Ca-Csjcycloalkyl group and a linear or branched (Ci-Cajatkyl 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, 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 -CO2-(Ci-C₄)alkyl group,

- a group -NReRe· in which Re and R_e·, which are different, represent a (Ci-Cs)alkyI group and a (Ci-Cs)alkoxy group, > R2 représente a hydrogen atom when n représente 1 and a methyl group when n represents 0;

> R< and R4', independently, which may be identical or different, represent a hydrogen atom or a (Ci-Csjalkyt group, in the form of the base or of an addition sait with an acid or with a base.

Among the compounds of the présent 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 représente a linker -CH2-CO- such that the carbonyl fonction is attached to the substituent Ri, or (CiAlalkyl, said alkyl being optionally substituted with one or more substituents chosen from a (Ci-C₃)alkyl group and a hydroxyl group;

> Ri représente:

- a (C3-Ce)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 -NHCO-NH-(Ci-C4)alkyl, a morpholine group, a group of formula -SO2-(Ci-C₅)alkyl, a (Ci-Cs)alkoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

o a halogen atom, o a hydroxyl group or a (Ci-Csjalkoxy, 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 R« and R«· are as defined betow, o a group -NR4R4· in which R« 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 (Ci-C₃)alkyl group, a hydroxyl group and an -NH2 group;

o a halogen atom, o a (Ci-C₃)alkyl group optionally substituted with one or more halogen atoms, o a (CrCi)alkoxy group, optionally substituted with one or more substituents chosen from a halogen atom, a (Ca-Cs)cycloalkyl group, a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (Ci-Ca)alkyl group, a hydroxyl group and an -NH2 group, o a group -NRjRs· in which Rs and Ry, Independently, which may be Identical or different, represent a substituent chosen from a hydrogen atom, a -COzXCi-Cafolkyl group, a (CrCs)cycloalkyl group and a linear or branched (Ci-C₃)alkyl group, said alkyl group being optionally substituted with one or more hydroxyl groups,

- 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 -NR«Re· in which Re and Re·, which are different, represent a (Ci-Cj)alkyl group and a (Ci*Cs)alkoxy group, > R2 représents a hydrogen atom when n représente 1 and a methyl group when n représente 0;

> R< and Rr, Independently, which may be Identical or different, represent a hydrogen atom or a (Ci-Cs)alkyl group, in the form of the base or of an addition sait with an acid or with a base.

Among the compounds of the présent 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 -CH?-CO- such that the carbonyl fonction is attached to the substituent Ri, or (Ci-C₂)alkyl, said alkyl being optionally substituted with one or more (Ci-CjJalkyl groups;

> Ri représente:

- a linear, branched, cyclic or partially cyclic (Ci-Cs)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 (C₃Cs)cycloalkyl group,

- a (C₃-Ce)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-(Ci-C4)alkyl, a morpholine group, a group of formula -SOriCi-CjJalkyl, a (Ci-Cs)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 (Ci-Ci)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 -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, o a (Ci-Cs)alkoxy group, optionally substituted with one or more substituents chosen from a halogen atom, a (C3-C$)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 >NH₂ group, o a group -NR5R5· in which Rs and Ry, independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -CO2-(Ci-C₃)alkyl group, a (C3-Cs)cycloalkyl group and a linear or branched (CrCjJalkyl group, said alkyl group being optionaily substituted with one or more hydroxyl groups,

- a pyridine group bearing two Iinked 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 optionaily substituted with a substituent chosen from a formyl group, an acetyl group and a -CO2-(CiC^alkyl group,

- a group -NReRe· in which Re and Re·, which are different, represent an alkyl group and a (Ci-C_s)alkoxy group, > R₂ represents a hydrogen atom when n représente 1 and a methyl group when n représente 0;

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

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

> n represents 0 or 1 ;

> Y represents a bridged morpholine (a) (a) > L represents a linker -CH2-CO- such that the carbonyl fonction is attached to the substituent Ri, or (Ci-C₂)alkyl, said alkyl being optionaily substituted with one or more (Ci-C₃)alkyl groups;

> Ri represents:

- a linear or branched (Ci-C_s)alkyl group, in particular an isopropyl or tert-butyl group, optionaily substituted with one or more hydroxyl groups,

- a (CrCeJcycloalkyl group,

- an aryl group, in particular a phenyl group, optionaily 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-(Ci-C4)alkyl, a morpholine group, a group of formula -SO2-(Ci-Cs)alkyl, a (Ci-Cs)alkoxy group, in particular a methoxy group, said alkoxy being optionaily substituted with one or more substituents chosen from:

o a halogen atom, in particuiar a fluorine atom, o a hydroxyl group or a (Ci-C₅)alkoxy, o a group -CORa, in which Rj 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 particuiar a morpholinyl group, o a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (Ci-Cajalkyl group, a hydroxyl group and an -NH2 group;

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

o a halogen atom, o a (Ci-Cj)alkyl group optionally substituted with one or more halogen atoms, o a (Ci-Cï)alkoxy group, optionally substituted with one or more substituents chosen from a halogen atom, a (CrCsJcycloalkyl group, a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (CrCiJalky! group, a hydroxyl group and an -NH2 group, o a group -NR5R5· in which Rs and Ry, independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -CO2-(Ci-Cj)alkyl group, a (C3-C₅)cycloalkyl group and a linear or branched (Ci-Cj)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 particuiar a 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine group,

- a group -NReRe· in which Re and Re-, which are different, represent an alkyl group and a (CrC₅)alkoxy group, > R2 représente 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 sait with an acid or with a base.

Among the compounds of the présent 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 fonction is attached to the substituent Ri, > Ri represents:

* a linear or branched (Ci-Csjalkyl group, in particular an isopropyl or tert-butyl group,

- a (C₃-Ci)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-(Ci-C4)alkyl, a morpholiny! group, a group of formula -SO2-(Ci-Cs)alkyl, a (Ci-Cs)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 (Ci-Cs)alkoxy group, o a group -CORj, 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 heteroaryi 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 heteroaryi group, comprising one or more heteroatoms chosen from nitrogen atoms, in particular a pyridyl group, and sutfur and oxygen atoms, optionally substituted with one or more substituents chosen from:

o a halogen atom, o a (Ci-Csjalkyl 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 (Cs-Cslcycloalkyl 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 -NH₂ group, o a group -NRsRy in which Rs and Rs·, independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -CO2-(Ci-C₃)alkyl group, a (C3-C$)cycloalkyl group and a linear or branched (Ci-Cslalkyl 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 -COr(CiCs)alkyl group,

- a group -NReRe· in which Re and Re-, which are different, represent an alkyl group and a (Ci-Cs)alkoxy group,

In the form of the base or of an addition sait with an acid or with a base.

Among the compounds of the présent Invention, mention may be made of an eighth subgroup of compounds of formula (I) in which:

> Y represents a bridged morpholine (a) (a) > L represents a linker -CHrCO- such that the carbonyl function is attached to the substituent Ri, > Ri represents:

- a linear or branched (Ci-Csjalkyl group, in particular an isopropyl or tert-butyl group, * a (C₃-Ce)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-fCi-C^alkyl, a morpholinyl group, a group of formula -SO2-(Ci-Cs)alkyl, a (Ci-Cs)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 (CrCs)alkoxy group, o a group -COR3, in which Rs 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 -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 (Ci-C₃)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 (Ci-Ca)alkyl group, a hydroxyl group and an -NH₂ group, o a group -NR5R5· in which Rs and Rs·, independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -CCMCi-Cs) alkyl group, a (C₃-C₅)cycloalkyl group and a linear or branched (Ci-Cs)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 morpholtnyl 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 -NReRe* in which Re and Re·, which are different, represent an alkyl group and an alkoxy group, in the form ofthe base or of an addition sait 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 fonction is attached to the substituent Ri, or (Ci-C2)alkyl, said alkyl being optionally substituted with a hydroxyl group;

> Ri represents:

- a linear or branched (Ci-C_s)alkyl group, optionally substituted with an aryl group,

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

o a group -CONR4R4· in which Rx and R4· are as defined below, o a group -NRxRx- in which Rx and Rx· 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 (Ci-C₃)alkyl groups, optionally substituted with one or more haiogen atoms, > R2 represents a hydrogen atom when n represents 1 and a methyl group when n represents 0;

> R4 and Rx·, independentiy, which may be identical or different, represent a hydrogen atom or a (Ci-C₃)alkyl group, ίη the form of the base or of an addition sait 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 -CHî-CO- such that the carbonyl fonction is attached to the substituent Ri, in the form of the base or of an addition sait 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 sait 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 sait with an add or with a base.

A thirteenth subgroup of compounds of formula (I) according to the invention is such that Ri represents a heteroaryl group, in particular a pyridyl group, in the form of the base or of an addition sait 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 -CO2-(Ci-Cj)alkyl group, in the form of the base or of an addition sait 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 espedally of the following compounds:

(8S)-9-(2-Methyl-2-pyrid-4-ylpropyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 Jhept-5yl-e-trifluoromethyl-ej.e.SMetrahydropyrimidoil^-aJpyrimidin^-one (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-(2-oxo-2-pyrid-4-ylethyl)-8trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (8S)-9-[2-(6-Aminopyrid-3-yl)-2-oxoethyl]-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8trifluoromethyl-6,7_t8_l9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (8S)-9-[2-(6-Methy1pyrid-3-y!)-2-oxoethyl]-2-(1S,4S)-2-oxa-5- azabicyclop^.Ilhept-S-yl-e-trifluoromethyl-e.y.e.O-tetrahydropyrimîdoIl^-aJpyrimidin-

4-one (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 (8S)-9-[2-(6-Dimethy!aminopyrid-3'yl)-2-oxoethyl]-2-(1S,4S)'2-oxa-5- azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6_l7_l8_l9-tetrahydropyrimido[1_l2-a]pyrimidin-

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

1-[2-(6-Dimethylaminopyrid-3-yl)-2-oxoethyl]-2-(S)-methyl-7-(1 S,4S)-2-oxa-5azabîcyclo[2.2.1 ]hept-5-yl-2-trifluoromethyl-2_l3-dihydrO’1 H-imidazo[1,2-a]pyrimidtn-5one

2-(S)-Methy!-1-[2-(6-methylaminopyrid-3-yl)-2-oxoethy!]-7-(1S,4S)-2-oxa-5azabicydo[2.2.1]hept-5-yl-2-trifluoromethy1-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5one (8S)-1-[2-(4-Methoxyphenyl)ethyl]-2-methyl-7-(1 S,4S)-2-oxa-5- azabicyclop.Z.IJhept-S-yl^-trifluorornethyl^.S-dihydro-IH-imidazofl^-alpyrimidin-Sone (S)-1 -[2-(6-Aminopyrid-3-yl)-2-oxoethy!]-2-methyl-7-(1 S,4S)-2-oxa-5azabicyc!o[2.2.1]hept-5-yl-2-trïfluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5one (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-(2-pyrid-3-ylethyl)-8trifluoromethyl-€_l7,8_l9-tetrahydropyrimido[1,2-a]pyrimidin-4-one

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

4-one (8S)-9-[2-(5-Methylpyrid-3-yl)-2-oxoethy!]-2-(1 S,4S)-2-oxa-5azabicyclop^.Ilhept-S-yl-e-trifluoromethyl-e.y.e.Q-tetrahydropyrimidoIl^-aJpyrimidin-

4-one

2-Methyl-1 -[2-(5-methylpyrid-3-yl)-2-oxoethyl]-7-(1 S,4S)-2-oxa-517195 azabicyclo[2.2.1 ]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1 H-imidazo(1,2-

a]pyrimidin-5-one

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

2-Methyl-1 -[2-(2-methylpyrid-3-yl)-2-oxoethyl]-7-(1 S,4S)-2-oxa-5- azabtcyclo[2.2.1 ]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dÎhydro-1 H-imidazo(1,2-

a]pyrimidin-5-one (8S)-9-[2-(2-Methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5azabicyclo[2,2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-

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

4-one

2-Methyl-7-(1 S,4S)-2-oxa-5-azabicyclo(2.2.1 ]hept-5-yl-1-(2-oxo-2-pyrid-3ylethyl)-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imÎdazo[1,2-a]pyrimidin-5-one (8S)-9-[2-(6-Cyclopropylaminopyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-

4-one

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

1 -Ethyl-3-{4-[2-((S)-2-methyl-7-( 1 S,4S)-2-oxa-5-azabîcyclo[2.2.1 ] hept-5-yl-5oxo-2-trifluoromethyl-2,3-dihydro-5H-imidazo[1,2-a]pyrimidin-1-yl)ethyl]phenyl}urea (8S)-9-[2-(4-Methylthiazol-5-yl)ethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one

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

4-one

1 -(2-(3,5-Dimethyl-1 H-pyrazol-4-yl)ethyl]-2-methyl-7-(1 S,4S)-2-oxa-5azabicyclo(2.2.1 ]hept-5-yl-2-((S )-trifluorornethyl)-2,3-dihydro-1 H-imidazo(1,2-

a]pyrimidin-5-one (8S)-9-(3,3-Dimethyl-2-oxobutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one

1-(3,3-Dimethyl-2-oxobutyl)-2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-

5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimîdin-5-one (8S)-9-[2-(6-Amino-5-methylpyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5azabicyclop^.ljhept-S-yl-S-trifluoromethyl-exô.G-tetrahydropyrimidotl^-aJpyrimidin4-one

1-[2-(4-Aminophenyl)ethyl]-2-methyl-7-(1S_l4S)-2-oxa-5-azabicyc1o[2.2.1]hept-5yl-2-((S)-trifluoromethyl}-2,3-dihydro-1 H-imidazo[1,2-a]pyrimidin-5-one (8S)-2-( 1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-I2-oxo-2-(6- trifluoromethylpyrid-3-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-

a]pyrimidin-4-one (8S)-9-(2-{6-[(2-Hydroxyethyl)methylamino]pyrid-3-yl}-2-oxoethyl)-2-(1S₍4S)-2- oxa-5-azabicyclo[2.2.1]hept-5-y1-8-trifluoromethyl-6,7,8,9-tetrahydropyrimÎdo[1_l2aJpyrimidin-4-οπθ (8S)-9-[2-(6-Ethoxypyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5- azabicydo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-aJpyrimidtn4-one (8S)-9-[2-(6-Amino-4,5-dimethylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5azabicyc!o[2.2.1]hept-5-yl-8-trif!uoromethyl-6,7_l8_l9-tetrahydropyrimido[1_l2-a]pyrimidin4-one (S)-9-[2-(4-Difluoromethoxyphenyl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5azabicyclop^.lJhept-S-yl-e-trtfluoromethyl-ej.S.O-tetrahydropyrimîdofl^-alpyrimidin4-one (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-azabicyc1o[2.2.1]hept-5-y1-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2aJpyrimidin-4-one (8S)-9-[2-(4-Methyloxazol-5-yl)-2-oxœthyl]-2-(1 S,4S)-2-oxa-5azabicyclop^.ljhept-S-yl-e-trifluoromethyl-ej.S.g-tetrahydropyrimidotl^-aJpyrimidin4-one (S)-9-[2-(3,4-Difîuorophenyl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5- azabicydo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimîdin4-one (8S)-9-[2-(4-Morpholin-4-ylphenyl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5azabicyclop^.ljhept-S-yl-e-trifluoromethyl-ej.S.g-tetrahydropyrimidotl^-aJpyrimidin4-one

4-[2-((S)-8-(1S_l4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethyl3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetyl]benzonitrile (8S)-9-[2-(4-Methylthiazol-5-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5- azabicyc!o[2.2.1Ihept-S-yl-S-trifluoromethyl-e.Z.e.O-tetrahydropyrimidotl ,2-aJpyrimidin4-one (8S)-9-[2-(5-Chloropyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5azabicyc!o[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin4-one (8S)-9-[2-(6-Methoxypyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5azabicyclo^^.Ilhept-S-yl-e-trifluoromethyl-e.Z.S.iMetrahydiOpyrimidoÎI^-alpyrimidin4-one (8S)-9-[2-(3-MethylisoxazoM-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5azabicyclo(2.2.1]hept-5-yl-8-trifluoromethyl-6_l7,8,9-tetrahydiOpyrimido[1,2-a]pyrimidin4-one (8S)-9-(2-Benzo[1,2,3]thiadiazol-5-yl-2-oxoethyl)-2-(1 S,4S)-2-oxa-5azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimldin-

4-o ne (8S)-9-[2-(2,4-Difluorophenyl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5azabicyclop^.Ilhept-S-yl-e-trifluoromethyl-e.T.e.SMetrahydropyrimidotl^-aJpyrimidin4-one (8S)-9-(3-Ethyl-3-hydroxypentyl)-2-(1S,4S)-2-oxa-5-azabÎcyclo[2.2.1]hept-5-yl·

8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (8S)-9-(3-Hydroxy-3-methylbutyl)-2-( 1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ] hept-5-y Ie-trifluoromethyl-e.Z.e.O-tetrahydropyrimldoIl^-alpyrimidin^-one (8S)-9-(1 -Methyl-1 H-indazol-3-ylmethyl)-2-(1S,4S)-2-oxa-5- azabicyclo[2.2.11hept-S-yl-e-trifluoromethyl-e.T.e^-tetrahydropyrimidotl ,2-aJpyrimidin4-one (8S)-9-[2-(2-Cyclopropylmethoxypyrimidin-5-yl)-2-oxoethy1]-2-(1S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin4-one (8S)-9-[2-(3,5-Dimethylisoxazol-4-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8_l9-tetrahydropyrimido[1,2-a]pyrimidin4-one (8S)-9-(2-Ethyl-2-hydroxybutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one

3-[2-((S)-8-(1S,4S)-2-Oxa-5-azabtcyc!o[2.2.1]hept-5-yl-6-oxo-2-trifluoromethyl·

3_l4-dihydro-2H,6H-pyrimido[1,2-alpyrimidin-1-y!)aœtyllbenzonitrile (8S)-9-(3-Methyl-2-oxobutyl)-2-( 1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-y I-817195 trifluoromethyl-6,7,8₍9-tetrahydropyrimido[1,2-a]pyrimidin-4-one {5-[2-((S)-8-(1S,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 {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 (8S)-9-(5-Methyl-[1,2,4]oxadiazol-3-ylmethyl)-2-(1 S,4S)-2-oxa-5azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6₍7,8,9-tetrahydropyrimido[1,2-a]pyrimidin4-one (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-oxo-2-(2trifluoromethylpyrid-S-ylJethylj-e-trifluoromethyl-e.î.e.S-tetrahydropyrimidotl.Z-

a]pyrimidin-4-one (8S)-9-(2-Benzo[1,2,5]thiadiazol-5-yl-2-oxoethyl)-2-(1S,4S)-2-oxa-5azabicyclot^.lJhept-S-yl-e-trifluoromethyl-e.y.e^tetrahydropyrimidoIl^-ajpyrimidin4-one (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_l7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (8S)-9-{2-[6-(2-Fluoroethoxy)pyrid-3-ylI-2-oxoethyl)-2-(1 S,4S)-2-oxa-5azabicyclo[2.2.1 Jhept-5-yl-8-trifIuoromethyl-6₍7,8,9-tetrahydropyrimido[1,2-a]pyrimidin4-one (8S)-9-{2-[3-Fluoro-4-(2-fluoroethoxy)pheny l]-2-oxoethyl)-2-(1 S,4S)-2-oxa-5azabicyclop^.lJhept-S-yl-ô-trifluoromethyl-e.î.e^tetrahydropyrimidoIl^-ajpyrimidin4-one (8S)-9-I2-(2-Methoxypyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5- azablcyclo[2.2.1 Jhept-5-yl-6-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-aJpyrimidin4-one (8S)-9-[2-(3-Methyl-3H-imidazol-4-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5- aza bicyclo[2.2.1 ]hept-5-yl-8-trifluoromethy 1-6,7,8,9-tetrahydropyrim ido[1,2-a]pyrimidin4-one (8S)-9-(2-Cyclopropyl-2-oxoethyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yle-trifluoromethyl-ej.e.g-tetrahydropyrimidotl^-alpyrimidin^-one (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-(2-oxo-2-pyrid-2-ylethyl)-8trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (8S)-9-[2-(2-Methyl-2H-pyrazol-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5azabicyclo[2.2.11hept-S-yl-e-trifluoromethyl-e.T.e^tetrahydropyrimidotl ,2-a]pyrimidin17195

4-one

N,N-Dimethyl-2-(4-(2-{(S)-2-niethyl-7-(8-oxa-3-azabtcyc!o[3.2.1]oct-3-yl)-5-oxo-

2-trifluoromethyl'2_l3-dihydro-5H-imidazo[1,2-a]pyrirr)idin-1'yl]ethyl}phenoxy)acetamide (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-4one (2S)-1 -[2-(4-Hydroxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1 Joct-3yl)-2-trifluoromethyl-2,3-dihydro-1 H-imidazo[1,2-a]pyrimidin-5-one (8S)-2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-phenylethyl)-8trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (2S)-1 -f2'[4-(2-Dimethylaminoethoxy)phenyl]ethyl)-2-methyl-7-(8-oxa-3azabicyclo[3.2.1 ]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1 H-imidazo[1,2-a]pyrimidin-5one (8S)-2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-pyrid-4-ylethyl)-8trifluoramethyl-6,7,8,9-tetrahydropyrimido[1_l2-aJpyrimidin-4-one (S)-1 -[2-(4-Methoxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicycloI3.2.1 Joct-3-yl)-

2- trifluoromethyl-2,3-dihydro-1 H-imidazo[1,2-a]pyrimidin-5-one (S)-2-Methyl-7-(8-oxa-3-azabicyclo[3.2.1 Joct-3-yl)-1 -(3-phenylpropyl)-2trifluoromethyl-2,3-dihydro-1 H-imidazoI1,2-a]pyrimidin-5-one (S)-1-{2-[4-(3-Dimethylaminopropoxy)phenyl]ethyl)-2-methyl-7-(8-oxa-3azabicyclo[3.2.1]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-aJpyrimÎdin-5one (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-imldazo[1,2-a]pyrimidin-5-one (8S)-9-((S)-2-Hydroxy-2-phenylethyl)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8trifluoromethyl-6_I7_l8,9-tetrahydropyrimido(1,2-a]pyrimidin-4-one (8S)-9-[2-(4-Methoxyphenyl)ethyl]-2-(8-oxa-3-azabicyc!o[3.2.1]oct-3-yl)-8trïfluoromethyl-ej.e.O-tetrahydropyrimidoIl^-aJpyrimidin^-one (8S)-9-((R)-2-Benzo[b]thiophen-2-yl-2-hydroxyethyl)-2-(8-oxa-3azabicyc!o[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7_l8,9-tetrahydropyrimido[1_l2’a]pyrirrildin’4one (8S)-9-[2-(4-Hydroxyphenyl)ethyl]-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8trifluoromethyl-6,7,8,9-tetrahydropyrimido[1₎2-a]p^imidin-4-one (8S)-2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-y1)-9-(3-phenylpropyl)-8trifluoromethylmethyl-6,7,8_l9-tetrahydropyrimido[1_l2-a]pyrimidin-4-one (8S)-2-(3Oxa-8-azabicyclo[3.2.1]oct-8-yl)-9-(2-oxo-2-pyrid-3-ylethyl)-817195 trifluoromethyl-6,7,8_T9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (8S)-9-(1 -Difluoromethyl-1 H-pyrazol-3-ylmethyl)-2-(8-oxa-3- azabicyclo[3.2.1] oct-3-y l)-8-trifl uoromethyl-6,7,8,9-tetrahydropyrimido[ 1,2-a]pyrim id in-4one (8S)-2-(8-Oxa-3-azabicyclo[3.2.1 ]oct-3-yl)-9-(2-oxo-2-pyrid-3-y I eth y I )-8tnfluoromethyl-6,7,8,0-tetrahydrcipyrimido[1,2-a]pyrimidin-4-one (8S)-2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-pyrid-2-ylethyl)-8trifluoromethyl-6,7_T8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-[2-(1-Acetylpiperid-4-yl)ethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5yl-8-trifluoromethyl-6_T7,8,9-tetrahydropyrimido[1_T2-a]pyrimidin-4-one

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-pyrimîdo[1,2-a]pyrimidin-1 -yl)ethyl]piperidine-1 -carbaldehyde

4-[2-((S)-8-(1S,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 (8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-(tetrahydropyran-4yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (8S)-2-(1S,4S)'2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(tetrahydropyran-4y!methy!)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (8S)-9-( 1 -Acetylpiperid-4-y!methyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5yl-8-trifluoromethyl-6,7,8_T9-tetrahydropyrimido[1 ,2-a]pyrimidin-4-one

4-((S)-8-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-6-oxo-2-trifluoromethyl-3,4dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1 -ylmethyl)piperidine-1 -carbaldehyde (8S)-2-(1S_T4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(3,3,3-trifluoro-2-hydroxy-

2- trifluoromethy!propyl)-8-trifluoromethyl-6_l7,8,9-tetrahydropyrimÎdo]1_T2-a]pyrimidin-4one (8S)-2-( 1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-(4,4,4-trifIuoro-3-hydroxy-

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

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

a]pyrimidin-4-one

100 (8S)-9-i2-(1-Hydroxycyclopentyl)ethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept17195

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-azabicydo[2.2.1 Jhept-

5-yl-8-trifIuoromethyl-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-y!-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-aJpyrimidin-

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-aJpyrimidin-

4- one

104 (8S)-9-(1-Hydroxycydopropylmethyl)-2-(1 S,4S)-2-oxa-5-azabicydo[2.2.1 ]hept-

5- yl-8-trifIuoromethyl-6,7,8,9-tetrahydropyrimido[1₎2-a]pyrimidin-4-one

105 (8S)-9-[2-(1-Hydroxycydopropyl)ethyl]-2-(1 S,4S)-2-oxa-5-azabicydo[2.2.1]hept-

5-yl-8-trifluoromethyl-6,7,8,9-tetrahydiOpyrimÎdo[1,2-a]pyrimidin-4-one

106 (8S)-2-(1 S,4S)-2-Oxa-5-azabîcydo[2.2.1 ]hept-5-yl-9-quinolin-5-ylmethyl-8trifluoromethyl-6,7_l8,9-tetrahydropyrimido[1_l2-a]pyrimidin-4-one

107 (8S)-9-(2-(3-Methylisothiazol-4-yl)-2-oxoethyl]-2-(1S_I4S)-2-oxa-5azabicyclo[2.2.1 Jhept-S-yl-S-trifluoromethyl-ej.e^tetrahydropyrimidotl ,2-a]pyrimidin4-one

108 (8S)-9-[2-(4-Methane$ulfonylphenyl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5azabÎcydo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin4-one

109 (8S)-9-lsoquinolin-5-y1methy1-2-(1S,4S)-2-oxa-5-azabicydo[2.2.1]hept-5-y1-8trifluoromethyl-e.T.e^tetrahydropyrimidofl^-alpyriniidin^-one

110 (8S)-9-(2-Morpholin-4-yl-2-oxoethyl)-2-(1S_l4S)-2-oxa-5-azabicydo[2.2.1]hept-5yl-8-trifluoromethy1-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one

111 (8S)-9-{2-[4-(2-Morpho1in-4-y1ethoxy)pheny1]ethyl}-2-(1S,4S)-2-oxa-5azabicydo(2.2.1]hept-5-yl-8-trifluoromethyl-6_l7,8,9-tetrahydropyrimido[1,2-a]pyrimidin4-one

112 N-Methoxy-N-methyl-2-((S)-8-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-

2-trifIuoromethyl-3,4-dihydro-2H,6H-pyrimido[1_l2-a]pyrimidin-1-yl)acetaniide

113 (8S)-9-(2-lmidazo[1,2-a]pyrid-6-yl-2-oxoethyl)-2-(1 S,4S)-2-oxa-5azabicyclo[2.2.1 Jhept-S-yl-e-trifluorornethyl-ej.e.S-tetrahydropyrimidotl ,2-a]pyrimtdin4-one

114 (8S)-9-[2-(6-Difluoromethoxypyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6_I7_I8_l9-tetrahydropyrimido[1,2-a]pyrimidin4-one

115 (S)-9-{2-[4-(2-Morpholin-4-yl-2-oxoethoxy)phenyl]ethyl}-2-(1S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trif!uoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin4-one

116 (8S)-9-(1 -Methyl-3-trifluoromethyl-1 H-pyrazol-4-ylmethyl)-2-(1 S,4S)-2-oxa-5azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-ajpyrimidin4-one

117 (8S)-9-{2-[4-(2-Dimethylaminoethoxy)phenyl]ethyl}-2-(1S_l4S)-2-oxa-5azabicyclo[2.2.11hept-S-yl-S-trifluoromethyl-ej.S.S-tetrahydropyrimidoIl ,2-alpyrimidin4-one

118 4-[2-((S)-8-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethyl-

3_l4-dihydro-2H,6H-pyrimÎdo[1,2-a]pyrimidin-1-yl)acetyl]piperidine-1-carbaldehyde

119 (8S)-9-[2-(1-Acetylpiperid-4-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5- azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8.9-tetrahydropyrimîdo[1,2-aJpyrimidin4-one in the form of the base or of an addition sait with an acid or with a base.

It should be noted that the above compounds were named according to the IUPAC 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 ofthe intermediate compounds Ei in which n » 1 and R₂ représente 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 température 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 température between 20*C and 120*C, or in the presence of a polar solvent such as 1,2-dichloroethane, at a température 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 Ei is obtained after séparation ofthe enantiomers ofthe compound of formula D by chromatography on a chiral support.

The synthesis ofthe intermediate compounds Eo 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 reading a diamine F and cyanogen bromide in a polar solvent such as water or acetonitrile, at a température of between 0°C and the boiling point ofthe 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 température of between 60*C and 100’C.

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

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

Scheme 3

The compounds I are obtained from a compound E, in which n représente 0 or 1, and R₂represents 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 température of between 20’C and 140°C, or in the presence of a polar solvent such as methyl isobutyl ketone or butyronitrile, at a température of between 20’C and the reflux température of the solvent. The compounds (I) may then be obtained via an alkylation reaction, by addition of a compound J of formula Ri-L-Lg with Ri and L as defined above and Lg being a leaving group such as Cl, Br, I or OTf (trifluoromethanesulfonate), with compound I and a base such as sodium hydride, césium carbonate or potassium tert-butoxide In excess, In a polar solvent such as acetonitrile, Ν,Ν-dimethylformamide or tetrahydrofuran, at a température of between O’C and 150*C, as described by Tîng P.C. et al. (J. Med. Chem. (1990), 33(10), 26972706).

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 1heteroaryl-2-chloroethanols, were synthesized from the corresponding chloro ketone dérivatives, which were themselves derived from chlorinatlon of commercially available acetyl dérivatives under standard conditions.

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

The compounds K may be obtained via an alkylation reaction, by addition of a compound

J of formula Ri*L*Lg with Ri and L as defined above and Lg being a leaving group such as Cl. Br, I or OTf, with compound E and a base such as sodium hydride, césium carbonate or potassium tert-butoxide in excess, in a solvent such as acetonitrile, N,Ndimethylfoimamide or tetrahydrofuran, at a température 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, Ri is a linear or branched (Ci-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, Ri is a linear or branched (Ci-Cs)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 (!) for which the linker L is a methyl group, Ri is a group -NReRe· with Reet Re· being either different and representing an alkyl group and an alkoxy group, or Re and Re· together forming a monocyclic or bicyclic heterocycloalkyl, Y represents a bridged morpholine chosen from (a), (b) and (c), n represents 1 orO, 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.

Y N'A _Η/Λ ^CFî*R2^^ E	° 1 Michael addition	Alkylation Z-MgX O	AA ^cFr^k UM Y
base Q M	N Afcyt Y
A.	Alkylation	V S ΤλΑο -	Alkylation	. w.
	X o		Z-MgX O	^cFr^l
E	P	Q \| hytkolysjs Alkyl y φλ sAAo - ^cfi4^ s	couplng HNRjR,'	(l\|-2 A°A (1)-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 Cl or Br, in a polar solvent such as tetrahydrofuran, at a température 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-CO2Alkyl, in the presence of a base such as 1,8diazabicyclo[5.4.0]undec-7-ene, in a polar aprotic solvent such as N,Ndimethylformamide, at a température of 25C.

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 température 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-CH2COiAlkyl in which X is a halogen atom such as Cl, Br or I, to compound E and an alkaline base such as sodium hydride or césium carbonate in excess, in a polar solvent such as Ν,Ν-dimethylformamÎde or acetonitrile, at a température of 25°C.

The compounds (l)-3 may be obtained via a coupling reaction between a compound S and a compound of formula HNReRe· with Re and R? being either different and representing an alkyl group and an alkoxy group, or Re and Re· together forming a monocyclic or bicyclic heterocycloalkyl, in a polar solvent such as N,Ndimethylformamide, 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 waterftetrahydrofuran 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 fonctions in order to avoid slde 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 réactivé fonctions, the following non-exhaustive list may be mentioned:

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

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

- the acid fonctions 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 molécule by breaking a heterolytic bond, with loss of an électron 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 référencés 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

CDCh: deuterated chloroform

Cl: chlorine

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

DCM: dichloromethane

DMF: N,N-dimethylformamide

DMSO: dimethyl sulfoxide

DMSO-de: deuterated dimethyl sulfoxide HPLC: high performance liquid chromatography HCl: hydrochloric acid

K2CO3: potassium carbonate

LC/MS: liquid chromatography/mass spectrometry

MeOH: methanol

MgSO<: magnésium sulfate

MHz: Mégahertz

Na₂CO3: sodium carbonate

NaCI: sodium chloride

NaOH: sodium hydroxide

NaHCOs sodium hydrogen carbonate

Na₂SO4 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

Tn rétention time min: minutes

ESI+: positive-mode electrospray ionization

The following examples describe the préparation of certain compounds in accordance with the invention. These examples are not limiting and merely illustrate the présent 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.

It should be noted that the compounds described in the experimental section were named according to the IUPAC nomenclature by means of the Autonom software.

In the procedures and examples below:

- the microwave oven used is a Biotage, InitiatorTM Eight, 400 W max, 2450 MHz apparatus.

- the proton magnetic résonance spectre (¹H NMR), as described beiow, are recorded at a température of 300 K (exchangeable protons not recorded) at 300, 400 or 600 MHz in DMSO-de or CDCI₃₁ using the DMSO-de or CDCh peak as référencé. The chemical shifts δ are expressed in parts per million (ppm). The signais observed are expressed as follows: s = singlet, d = doublet, m = multiplet, bs » broad signal, t = triplet, q = quartet.

- the LC/MS characteristics, as described below (A, B, C, D, E, F and G) indicate, successively, the analytical method used and detailed below, the rétention time (Tr) of the compound expressed in minutes and the peak [M+HJ+ identified by mass spectrometry.

* Method A

Instrument: Acquity UPLC chain (Waters); SQD mass spectrometer (Waters) Column: Ascentis Express C18 50 x 2.1 mm 2.7 pm, T = 55’C

Solvent A: H₂O + 0.02% TFA; Solvent B: acetonitrile + 0.014% TFA

Flow rate: 1 mL/min

Gradient A/B: 10 min 2% B, 11 min 98% B, 11.3 min 98% B, 11.33 min 2% B Détection: UV 220 nm

Ionization: electrospray positive mode * Method B

Instrument: Acquity UPLC chain (Waters); LCT mass spectrometer (Waters)

Coiumn: BHE C8 50 x 2.1 mm 1.7 pm, T* = 55’C

Solvent A: H₂O + 0.02% TFA; Solvent B: acetonitrile + 0.014% TFA

Flow rate: 1 mL/min

Gradient A/B: 10 min 2% B, 11 min 98% B, 11.3 min 98% B, 11.33 min 2% B

Détection: UV 220 nm

Ionization: electrospray positive mode * Method C

Instrument: Acquity UPLC chain (Waters); SQD mass spectrometer (Waters)

Coiumn: BHE C18 50 x 2.1 mm 1.7 pm, Γ = 50’C

Solvent A: H₂O + 0.02% HCO₂H; Solvent B: acetonitrile + 0.02% HCO₂H

Flow rate: 1 mL/min

Gradient A/B: 10 min 5% B, 12 min 100% B, 12.5 min 100% B

Détection: UV 220 nm

Ionization: electrospray positive mode * Method D

Instrument: Acquity UPLC chain (Waters); SQD mass spectrometer (Waters)

Coiumn: Acquity BHE C18 50 x 2.1 mm 1.7 pm, T’ = 50’C

Solvent A: H₂O + 0.1% HCO₂H; Solvent B: acetonitrile + 0.1% HCO₂H

Flow rate: 1 mL/min

Gradient A/B: 10 min 5% B, 10.8 min 50% B, 11.2 min 100% B, 11.85 min 100% B,

11.95 min 5% B

Détection: UV 220 nm

Ionization: electrospray positive mode * Method E

Instrument: HPLC chain (Waters); ZQ mass spectrometer (Waters)

Coiumn: XBridge C18 50 x 3 mm 2.5 pm, T* = 70“C

Solvent A: H₂O + 0.1% HCO₂H; Solvent B: acetonitrile + 0.1% HCO₂H

Flow rate: 0.9 mL/min

Gradient A/B: 10 min 5% B, 15.3 min 100% B, 15.5 min 100% B, 16.3 min 5% B

Détection: UV 220 nm lonization: electrospray positive mode * Method F

Instrument: Acquity UPLC type HPLC chain (Waters); SQD mass spectrometer (Waters)

Column: BHE C18 30 x 2.1 mm 1.7 pm, T^e = 50’C

Solvent A: H2O + 0.1% HCO2H; Solvent B: acetonitrile + 0.1% HCO2H

Flow rate: 1 mL/min

Gradient A/B: 10 min 5% B, 12 min 100% B, 12.5 min 100% B

Détection: UV 220 nm lonization: electrospray positive mode • Method G

Instrument: Alliance HPLC chain (Waters); ZQ mass spectrometer (Waters)

Column: X Bridge C18 30 x 2.1 mm 2.5 pm, T’ = 55’C

Solvent A: H2O + 0.02% TFA; Solvent B: MeOH

Flow rate: 0.7 mL/min

Gradient A/B: 10 min 2% B, 13 min 100% B, 13.5 min 100% B, 13.6 min 2% B

Détection: UV 220 nm lonization: electrospray positive mode

The optical rotations [a]o²⁵ were measured on a model 341 polarimeter from PerkinElmer. Wavelength: sodium a line (589 nm).

Example 1:

(8S)-9-[2-(2,4^lfluorophenyl)-2-oxoethyl]-2-(1S_l4S)-2-oxa-5azablcyclop.2.1]hept-5-yî-8-trif1uoromethyl-6,7,8,9-tetrahydropyrimido[1,2

a]pyrimld!n-4-one (compound 48)

Step 1.1:4-trif1uoromathyî-1,4,5,6-tetrahydropyrimldln-2-ylamlne

A mixture of 6 g of 10% Pd/C and 60 g (370 mmol) of 2-amino-4(trifluoromethyl)pyrimidine dissolved in 80 mL of water, 250 mL of isopropanol and 24 mL (370 mmol) of methanesulfonic acid is hydrogenated at 5 bar, at 40°C, for 5 hours in an autoclave. The resulting mixture is then filtered and rinsed with isopropanol and with water. The filtrate is then concentrated under reduced pressure and the residue obtained is dried under vacuum to give 93.5 g of 4-trifluoromethyl-1,4,5,6-tetrahydropyrimidin-2ylamine methanesulfonate in the form of a white solid. The white solid is dissolved in 250 mL of methyl isobutyl ketone. 100 mL of 10 N sodium hydroxide are then added. The mixture is stirred at room température for 15 minutes. The phases are separated by settling and the aqueous phase is re-extracted with methyl isobutyl ketone. The organic phases are combined and then evaporated under vacuum. 59.50 g of 4-trifluoromethyl-

1,4,5,6-tetrahydropyrimidin-2-ylamine are thus obtained, the characteristics of which are as follows:

¹H NMR (300 MHz, δ in ppm, DMSO-d_e): 1.46 (m, 1H), 1.84 (m, 1H), 3.15 (m, 2H), 3.80 (m, 1H), 4.51-5.20 (bs, 2H), 5.55-6.30 (bs, 1H).

Step 1.2: 2-hydroxy-8-trifluoromethyl-6,7,8,9-tetrahydropyrlmldo[1,2-

a]pyrimidin-4-one

62.10 g (1150 mmol) of sodium methoxide are added to a mixture of 340 mL (2230 mmol) of diethyl malonate heated to 40’C. The mixture is heated at 100®C until a clear solution is obtained. 59.50 g (360 mmol) of 4-trifluoromethyl-1,4,5_l6-tetrahydropyrimidin-2ylamine dissolved in 100 mL of methanol are then added to the reaction medium. The mixture obtained is maintained at 100°C for 1 hour and then cooled to room température ovemight. The reaction mixture is evaporated to dryness under reduced pressure. The residue obtained is taken up in 250 mL of water. 12 N hydrochloric add is added to the thick suspension obtained, to pH = 5-6. The suspension obtained is filtered through a slnter funnel and the insoluble matter is rinsed with acetonitrile to give 68.10 g of 2hydroxy-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in the form of a yellow solid, the characteristics of which are as follows:

LC/MS (method D), ESI+: [M+HJ+: m/z 236; tr (min) = 0.26 ¹H NMR (300 MHz, δ in ppm, DMSO-d_e): 1.46 (m, 1H), 1.84 (m, 1H), 3.15 (m, 2H), 3.80 (m, 1H), 4.51-5.20 (bs, 2H), 5.55-6.30 (bs, 1H).

Step 1.3: 2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrlmido[1,2ajpyrim ldin-4-one

136 mL (1440 mmol) of phosphores oxychloride are added, at room température and under an argon atmosphère, to a suspension of 68.10 g (290 mmol) of 2-hydroxy-8(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 950 mL of 1,2dichloroethane. The mixture obtained is then heated at 65'C for 3 hours. After cooling, the reaction mixture is evaporated to dryness under reduced pressure. The residue obtained is taken up in 140 mL of cold water and 430 mL of ethyl acetate. 32% sodium hydroxide is added to the mixture obtained, to pH = 5. The resulting organic phase is separated out and then dried over magnésium sulfate, fîltered and concentrated under reduced pressure to give 60 g of 2-chloro-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4Hpyrimido[1,2-a]pyrimidin-4-one in the form of an orange solid, the characteristics of which are as foilows:

LC/MS (method D), ESI+: [M+H]+: m/z 254; tr (min) = 0.51 ¹H NMR (300 MHz, δ In ppm, DMSO-d_e) 2.16 (m, 2H) 3.45 (m, 1H) 4.12 (m, 1H) 4.42 (m, 1H) 5.83 (s, 1H) 9.12 (s, 1H)

Step 1.4: (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-

a]pyrimldin-4-one

The séparation of the two enantiomers of 2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydro4H-pyrimido[1_l2-a]pyrimidin-4-one (100 g) is performed by chiral chromatography: stationary phase: Chiralpak IA (250 mm x 4.6) 5 pm; température 25°C; mobile phase: methanol (100%). The levorotatory enantiomer is concentrated to give 49.10 g of (8R)-

2-chloro-8-(trifluoromethyl)-6,7_l8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one, in the form of a white powder. The dextrorotatory enantiomer is concentrated to obtain 48.5 g of (8S)-2-chloro-8-(trifluoromethyl)-6,7,8_l9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4 one, in the form of a white powder, the characteristics of which are as follows: LC/MS (method D), ESI+: [M+H]+: m/z 254; tr (min) = 0.51 ’H NMR (300 MHz, δ in ppm, DMSO-d_e): 2.14 (m, 2H), 3.47 (m, 1H), 4.12 (m, 1H), 4.36 (m, 1H), 5.81 (s, 1 H), 9.31 (s, 1H).

[a]o^2S at 589 nm = + 21.3 ± 0.5’ (MeOH)

Step 1.5: (8S)-2-f1S.4S)-2-oxa-5-azablcvclof2.2.11heDt-5-vl-8trlf1uoromethyl-6,7,8,9-tetrahydropyrimldo[1,2-a]pyrimidin-4-one

F^T

1.60 g (6.31 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9tetrahydropyrimidoî1,2-a]pyrimidin-4-one and 1.30 g (9.46 mmol) of (1S,4S)-2-oxa-5azabicyclo[2.2.1]heptane hydrochloride are mixed together. The powder obtained is placed in a tube and 2.21 mL (15.77 mmol) of triethylamine are added. The tube is sealed and heated at 130’C in an oil bath for 6 hours. After cooling, the crude product is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH). After evaporating the fractions under reduced pressure, 1.20 g of (8S)-2-(1S,4S)-2-oxa-5azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin4-one are obtained, the characteristics of which are as follows: LC/MS (method G): ESI+: [M+H]+: m/z 317 tr (min) = 1.37 ’H NMR (300 MHz, δ in ppm, CDCb): 2 (m, 2H), 2.35 (m, 2H), 3.45 (m, 2H), 3.92 (s, 1H),

3.95-4.32 (m, 4H), 4.78 (s, 1H), 4.89-5.2 <bs, 1H), 5.49-5.77 (bs, 1H).

Step 1.6: (8S)-9-[2-(2,4-dif1uorophenyl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-

a]pyrimldin-4-one

F,

A suspension of 150 mg (0.47 mmol) of (8S)-2-(1S,4S)-2-oxa-5azabicyc!o[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin4-one and 463.57 mg (1.42 mmol) of césium carbonate in 10 mL of acetonitrile is stirred for 15 minutes at room température. 222.93 mg (0.95 mmol) of 2-bromo-1-(2,4difluorophenyl)ethanone are then added. After stirring ovemight at room température, the reaction mixture is evaporated and the residue is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 130 mg of (8S)-9-[2-(2,4-difluorophenyl)-2-oxoethyl]-2(1 S,4S)-2-oxa-5-azabicydo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9tetrahydropyrimÎdo[1,2-a]pyrimidin-4-one, the characteristics of which are as foilows: LC/MS (method A): ESI+ [M+HJ+: mlz 471 tr (min) » 0.68 ¹H NMR (600 MHz. 5 in ppm, DMSO-de): 1.58-1.76 (m, 2H), 2.13-2.29 (m, 1H), 2.39-2.47 (m. 1H), 2.95-3.13 (bs, 4H), 3.16-3.29 (m. 1H), 4.34 (m, 1H), 4.41 (s, 1H). 4.51 (s, 1H), 4.58-4.71 (m, 3H), 5.38 (m. 1H). 7.3 (m. 1H), 7.51 (m, 1H), 8 (q, 1H)

Example 2:

(88)-9-[2-(4^ηβϋιγΙϋιΐ8ΖθΙ-5-γΙ)-2·οχοβΙΚγΙ]·2-(18,48)-2·οχ8-5azabîcyclo[2.2.1]hept-5-yl-8-trifluoromethyi-6,7,8,9-tetrahydropyrimldo[1,2-

a]pyrimîdin-4-one (compound 25)

Step 2.1: 5-(2-bromoethyl)-4-methylthlazole 'Br

A solution of 1 g (7 mmol) of 4-methyl-5-thiazolylethanol in 15 mL of dichloromethane is cooled to 0°C under argon. In a first stage, 1.8 g (7 mmol) of triphenylphosphine are added. Next, 1.30 g (7 mmol) of N-bromosuccinimide are added portionwise over 5 minutes. After stirring for 2 hours at 0*C, the solvent is evaporated off under vacuum. The residue obtained is purified by chromatography on silica gel (eluent: 50/50 EtOAc/heptane) to give 900 mg of 5-(2-bromoethyl)-4-methylthiazoIe, the characteristics of which are as foilows:

LC/MS (method G): ESI+ [M+H]+: m/z 207 tr (min) = 1.52

Ή NMR (300 MHz, δ in ppm, CDCb): 2.42 (s, 3H), 3.3-3.35 (t, 2H), 3.5-3.55 (t. 2H), 8.62 (s, 1H).

Step 2.2: (8S)-9-[2-(4-methylthiazol-5-yl)-2-oxoethy1]-2-{1 S,4S)-2-oxa-5azablcyclo[2.2.1]hept-5-yl-8-trifiuoromethyl-6,7,8,9-tetrahydropyrimldo[1,2-

a]pyrimldin-4-one

A suspension of 160 mg (0.50 mmol) of (8S)-2-(1S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin4-one and 415 mg (1.25 mmol) of césium carbonate in 4 mL of N.N-dimethylformamide is heated at 80’C for 15 minutes. After cooling to room température, a solution of 150 mg (0.76 mmol) of 5-(2-bromoethy1)-4-methylthiazole in 1 mL of N.N-dimethylformamide is added dropwise. The reaction medium is heated at 80’C ovemight. The reaction mixture obtained is evaporated to dryness. The residue obtained is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and evaporated to dryness.

The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 40 mg of (8S)-9-[2-(4-methylthiazol-5-yl)-2-oxoethyl]-2-(1S,4S)-2oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-

a]pyrimidin-4-one, the characteristics of which are as follows: LC/MS (method A): ESI+ [M+H]+: m/z 442 tr (min) = 0.55 ¹H NMR (600 MHz, δ in ppm, DMSO-de): 1.85 (t. 2H), 2.13 (m, 1H), 2.32 (s, 3H), 2.36 (m. 1H). 3.05-3.32 (m, 4H), 3.36 (d, 1H), 3.45 (m. 1H), 3.67 (d, 1H), 3.75 (d. 1H), 4.15-

4.22 (m, 2H), 4.57 (m, 1H), 4.63 (s. 1H). 4.71 (s, 1H), 4.8 (s. 1H), 8.8 (s, 1H).

Example 3:

(8S)-9-[2-(5-methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trlf1uoromethyl-6,7,8,9-tetrahydropyrimldo[1,2-

a]pyrimidln-4-one (compound 15)

Step 3.1:1*(5-methylpyrid~3-y1)ethanone

The following are successively introduced into a microwave tube:

484 μΙ (4.07 mmol) of 3-bromo-5-methylpyridine In 20 mL of HzO/DMF: (1/3: v/v), 2.03 mL (5.70 mmol) of tributyl(1-ethoxyvinyl)tin, 57.12 mg (0.081 mmol) of bis(triphenylphosphine)palladÎum(ll) chloride, 1.12 g (8.14 mmol) of potassium carbonate. This mixture is subjected to microwave irradiation at 110’C for 1 hour. The réaction mixture is evaporated to dryness and the residue is then taken up in water and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and evaporated to dryness. The residue obtained is taken up in 6 mL of methanol and 1 mL of 6 N HCl, and the solution is stirred ovemîght at room température. The reaction medium is evaporated to dryness and the residue is taken up in saturated aqueous NaHCOs solution and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 50/50 EtOAc/heptane) to give 300 mg of 1-(5methylpyrid-3-yl)ethanone, the characteristics of which are as follows:

LC/MS (method G): ESI+ [M+H]+: m/z 136 tr (min) - 0.78 ’H NMR (300 MHz, δ in ppm, DMSO-de): 2.37 (s, 3H), 2.62 (s, 3H), 8.1 (s, 1H), 8.63 (s, 1H), 8.93 (s, 1H).

Step 3.2: 2-bromo-1-(5-methy1pyrld-3-yl)ethanone hydrobromide

300 mg (2.22 mmol) of 1-(5-methylpyrid-3-yl)ethanone are dissolved in 15 mL of glacial acetic acid. 365 μΙ (2.22 mmol) of hydrobromic acid and 126 μΙ (2.44 mmol) of bromine are added to the medium. The reaction mixture is placed under magnetic stirrîng at room température for 2 hours. Ethyl ether Is added to the solution until a precipitate appears. The precipitate corresponding to 2-bromo-1-(5-methylpyrid-3-yl)ethanone hydrobromide is filtered off, washed with ether and dried. The 600 mg of product obtained hâve the following characteristics:

LC/MS (method G): ESI+ [M+HJ+: m/z 214 tr (min) = 1.17 ¹H NMR (300 MHz, δ in ppm, DMSO-de): 2.46 (s, 3H), 5.05 (s, 2H), 8.48 (s, 1 H), 8.82 (s, 1H), 9.12 (s, 1H).

Step 3.3: (8S)-9-[2-(5-methylpyrid-3-yl)-2-oxoethyl]-2-{1S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyi-6,7,8,9-tetrahydropyrimido[1,2-

a]pyrimidin-4-one

150 mg (0.474 mmol) of (8S)-2-(1S,4S)-2-oxa-5-azabicycloi2.2.1]hept-5-yl-8trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 5 mL of DMF are added to a suspension of 50.08 mg (1.04 mmol) of sodium hydride in 5 mL of DMF. The réaction mixture is placed under magnetic stirring at room température for 15 minutes. A solution of 153.88 mg (0.522 mmol) of 3-(bromoacetyl)pyridine hydrobromide in 5 mL of DMF is added dropwise to the reaction medium. The reaction is stirred at room température ovemight. The reaction medium is evaporated to dryness. The crude product is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 70 mg of (8S)-9-[2-(5methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-alpyrimidin-4-one, the characteristics of which are as follows:

LC/MS (method A): ESI+ [M+H]+: m/z 450 tr (min) = 0.51 ¹H NMR (600 MHz, δ in ppm. DMSO-de): 1.62-1.7 (dd, 2H), 2.25 (m. 1H), 2.4 (s, 3H),

2.43 (m. 1H), 2.96-3.2 (m. 3H), 3.2-3.33 (m. 2H). 4.37 (m, 1H), 4.42 (s, 1H), 4.47 (s, 1H),

4.57 (m. 1H), 4.63-4.7 (m, 2H), 5.6 (d, 1H), 8.16 (s, 1H), 8.67 (s, 1H), 8.98 (s, 1H).

Example 4:

(8S)-9-[2-(3,5-dimethylisoxazol-4-yl)-2-oxoethyl]-2-{1S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trlfluoromethyl-6,7,8,9-tetrahydropyrimido[1,217195

a]pyrimid1n-4-one (compound 53)

Step 4.1: N-methoxy-N-methyl-3,5-dimethylisoxazole-4-carboxamide

659 pl (8.15 mmol) of pyridine are added to a suspension of 343.07 mg (3.45 mmol) of Ν,Ο-dimethylhydroxylamine hydrochloride in 10 mL of dichloromethane. The mixture is stirred at room température until fully dissolved. A solution of 526.32 mg (3.13 mmol) of 3,5-dimethylisoxazole-4-carbonyl chloride in 5 mL of dichloromethane Is then added. After stirring for 1 hour at room température, the reaction mixture is taken up In saturated aqueous NaHCOj solution and stirred for a few minutes, and the phases are separated by settling. The organic phase Is dried over magnésium sulfate and evaporated to dryness. The residue obtained is taken up In toluene and evaporated, the operation being repeated a second time. 570 mg of N-methoxy-N-methyl-3,5dimethylisoxazole-4-carboxamide are then obtained, corresponding to the following characteristics:

LC/MS (method G): ESI+ [M+H]+: m/z 185 tr (min) = 1.08 ¹H NMR (300 MHz, δ in ppm, CDCh): 2.32 (s, 3H), 2.46 (s, 3H), 3.34 (s, 3H), 3.52 (s, 3H).

Step 4.2:143>5-dlmethyllsoxazol-4-yl)ethanone

A solution of 580 mg (3.15 mmol) of N-methoxy-N-methyl-3,5-dimethylisoxazole4-carboxamide in 20 mL of THF is cooled to 0^eC. A solution of 1.57 mL (4.72 mmol) of 3 M méthylmagnésium bromide in ether Is added. After stirring for 4 hours at room température, the reaction medium Is taken up in 10 mL of 1 N HCl and stirred for a further 1 hour at room température. The mixture is then basified with KjCOj and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and evaporated to dryness to give 420 mg of 1-(3,5-dimethylisoxazol-4-yl)ethanone, corresponding to the following characteristics:

LC/MS (method G): [M+H]+: m/z 140 tr (min) = 1.06 ’H NMR spectrum (300 MHz, δ in ppm, CDCh): 2.48 (s, 6H), 2.70 (s, 3H).

Step 4.3: 2-bromo-143.5-dlmethvlisoxazol-4-vl)ethanone

400 mg (2.87 mmol) of 1-(3,5-dimethylisoxazol-4-yl)ethanone are dissolved in 20 mL of glacial acetic acid. 1.42 mL (8.62 mmol) of hydrobromic acid and 163 pl (3.16 mmol) of bromine are added to the medium. The reaction mixture Is placed under magnetic stirring at room température for 2 hours. The solution is diluted with water, basified with saturated aqueous NaHCOa solution and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and evaporated to dryness to give 540 mg of 2-bromo-1-(3,5-dimethylisoxazol-4-yl)ethanone, corresponding to the following characteristics:

LC/MS (method G): ESI+ [M+HJ+; m/z 218 tr (min) = 1.35 ¹H NMR (300 MHz, δ in ppm, CDCI₃): 2.52 (s, 3H), 2.74 (s, 3H), 4.18 (s, 2H).

Step 4.4: (8S)-2-chloro-9-[2-(3,5-dimethylisoxazol-4-yl)-2-oxoethyl]-8trifluoromethyl-6,7,8,9-tetrahydropyrimldo[1,2-a]pyrimldin-4-one

F**]

A suspension of 150 mg (0.591 mmol) of (8S)-2-chloro-8-trifIuoromethyl-6,7,8,9tetrahydropyrimido[1,2-a]pyrimidin-4-one and 578.13 mg (1.77 mmol) of césium carbonate In 10 mL of acetonitrile Is stirred for 15 minutes at room température. 154.76 mg (0.709 mmol) of 2-bromo-1-(3,5-dimethylisoxazol-4-yl)ethanone are then added. After stim'ng ovemight at room température, the reaction mixture is evaporated and the residue is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and evaporated to dryness to give 230 mg of (8S)-2-chloro-9[2-(3,5-dimethylisoxazol-4-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9tetrahydropyrimido[1,2-a]pyrimiclin-4-one_t corresponding to the following characteristics: LC/MS (method G): ESI+ [M+H]+: m/z 391 tr (min) = 2.06 ’H NMR (300 MHz, δ in ppm. CDCh): 2.44 (s, 2H), 2.7 (s, 3H), 3.46 (m, 1H), 4 (m, 2H),

4.54 (m, 1H), 5.23 (s, 3H), 5.53 (d, 1H), 5.92 (s, 1H).

Step 4.5: (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]pyrimidln-4-one

200 mg (0.51 mmol) of (83)-2-01110110-9-(2-(3,5-dimethy1isoxazo1-4-yl)-2oxoethylJ-8-trif]uoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 83.28 mg (0.61 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1)heptane hydrochloride are mixed together. The powder obtained is placed In a tube and 178 μΙ (1.28 mmol) of triethylamine are added. The tube is sealed and heated at 130*C in an oil bath for 6 hours. The crude product obtained is taken up In water and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 130 mg of (8S)-9[2-(3,5-dimethylisoxazol-4-yl)-2-oxoethylj-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1Jhept-5-yl8-trifluoromethyl-6,7.8,9-tetrahydropyrimido[1,2-aJpyrimidin-4-one, the characteristics of which are as follows:

LC/MS (method A): ESI+ [M+HJ+: m/z 454 tr (min) = 0.58 ¹H NMR (300 MHz, δ in ppm, CDCIs): 2.44 (s, 2H), 2.7 (s, 3H), 3.46 (m, 1H), 4 (m, 2H),

4.54 (m, 1H), 5.23 (s, 3H), 5.53 (d, 1H), 5.92 (s, 1H).

Example 5:

(8S)-9-(3-methyl-2-oxobutyl)-2-(1S_l4S)-2-oxa-5-azablcyclo[2.2.1]hept-5-yl-8trifluoromBthyl-6,7,8,9-tetrahydropyrimldo[1,2-a]pyrimldin-4-one (compound 56)

F'-'T

Step 5.1:1-bromo-3-methylbutan-2-one

A solution of 1 g (11.61 mmol) of 3-methylbutan-2-one in 6 mL of methanol is cooled to a température of 10’0. When the température is reached, 597 μΙ (11.61 mmol) of bromine are added. The reaction mixture is stirred at 10’C until fully decolorized, and stirring Is then continued for 30 minutes at room température. After adding 10 mL of water to the solution, stirring is continued for 1 hour at room température. The réaction mixture is then taken up in water and extracted with ethyl ether. The organic phase is washed with aqueous 10% NaîCOj solution and then with saturated NaCi solution, dried and evaporated to give 1.50 g of 1-bromo-3-methylbutan-2-one, correspondîng to the following characteristics:

Ή NMR (300 MHz, δ in ppm, CDCh): 1.15 (s, 3H), 1.18 (s, 3H), 2.92-3.06 (m, 1H), 4 (s, 2H).

Step 5.2: (8S)-2-chloro-9-(3-methyl-2-oxobutyl)-8-trifluoromethyl-6,7,8,9tetrahydropyrimido[1,2-a]pyrimidln-4-one

A suspension of 170 mg (0.670 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9tetrahydropyrimido[1,2-aJpyrimidin-4-one and 655.21 mg (2.01 mmol) of césium carbonate in 10 mL of acetonitrile is stirred for 15 minutes at room température. 132.75 mg (0.804 mmol) of 1-bromo-3-methylbutan-2-one are then added. After stirring ovemight at room température, the reaction mixture is evaporated and the residue is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and evaporated to dryness to give 220 mg of (8S)-2-chloro-9-(3methyl-2-oxobutyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, correspondîng to the following characteristics:

LC/MS (method G): ESI+ [M+HJ+: m/z 338 tr (min) = 2.20 ¹H NMR (300 MHz, δ in ppm, CDCh): 1.13 (m, 6H), 2.38 (m, 2H), 2.68 (m, 1H). 3.41 (m, 1H), 3.87 (m. 2H), 4.51 (m, 1H), 5.2 (d, 1H). 5.9 (s, 1H).

Step 5.3: (8S)-9-(3-methyl-2-oxobutyl)-2-(1S,4S)-2-oxa-5 azabicycIo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,217195

a]pyrimidin-4-one

220 mg (0.51 mmol) of (8S)-2-chloro-9-(3-methyl-2-oxobutyl)-8-trifluoromethyl-

6.7.8.9- tetrahydropyrimido[1,2-a]pyrimidin-4-one and 105.99 mg (0.78 mmol) of (1S.4S)2*oxa-5-azabicyclo[2.2.1]heptane hydrochloride are mixed together. The powder obtained is placed in a tube and 227 μΙ (1.63 mmol) of triethylamine are added. The tube is sealed and heated at 130’C in an oil bath for 3 hours. The crude product obtained is taken up in ethyl acetate and the organic phase is washed with water, dried over magnésium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 100 mg of (8S)-9-(3methyl-2-oxobutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-

6.7.8.9- tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:

LC /MS (method A): ESI+ [M+H]+: m/z 401 tr (min) = 0.6

Ή NMR (600 MHz, δ in ppm, DMSO-d_e): 1.02 (m, 6H). 1.79 (m, 2H), 2.16 (m, 1H), 2.37 (m, 1 H), 2.68 (m, 1 H), 2.84-3.26 (bs, 3H), 3.30-3.75 (bs, 2H), 4.18 (d, 1 H), 4.30 (m, 1 H),

4.46 (m, 1H), 4.60 (s, 1H), 4.63-4.96 (bs, 2H), 5 (m, 1H).

Example 6:

(8S)-2-(1S,4S)-2-oxa-5-azablcyclo[2.2.1]hept-5-yl-9-{2-oxo-2-pyrld-3ylethyl)-8-trlfluoromethyl-6,7,8,9-tetrahydropyrlmido[1,2-a]pyrlmldln-4-one (compound 7)

Step 6.1: (8S)-2-chloro-9-{2-oxo-2-pyrid-3-yiethyl)-8-trifluoromethyl-6,7,8,9tetrahydropyrimido[1,2-a] pyrlmldin-4-one

A suspension of 750 mg (15.77 mmol) of sodium hydride in 50 mL of DMF is cooled to 0’C under argon. A solution of 2 g (7.89 mmol) of (8S)-2-chloro-8trifluoromethyl-6,7,8.9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 50 mL of DMF is added dropwise. The mixture is stirred for 10 minutes at room température. After cooling the reaction medium to 0’C, 2.92 g (9.86 mmol) of 3-(bromoacetyl)pyridine hydrobromide are added portionwise. The reaction mixture is allowed to warm to room température and is stimed ovemight The reaction medium is evaporated to dryness and the residue is taken up in water and extracted with EtOAc. The organic phase is dried over magnésium sulfate and evaporated to dryness. The crude product obtained is purified by chromatography on silica gel (eluent 100% EtOAc). After evaporating the fractions under reduced pressure, 1.90 g of (8S)-2-chloro-9-(2-oxo-2-pyrid-3-ylethyl)-8trifluoromethyl-ej.e.O-tetrahydropyrimidoIl ,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows:

LC/MS (method G): ESI+ [M+HJ+: m/z 373 tr (min) = 1.76 ¹H NMR (300 MHz, δ in ppm, CDCh): 1.66 (s, 1 H). 2.3-2.52 (m, 2H), 3.48 (m, 1 H). 4 (m, 1H), 4.37 (d, 1H), 4.56 (m, 1H), 5.92 (s. 1H), 7.45 (m. 1H). 8.22 (m, 1 H). 8.81 (s, 1H),

9.15 (s, 1H).

Step 6.2: (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-oxo-2-pyrld-

3-yiethyi)-8-trifluoromethyi-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one

>1 g (2.68 mmol) of (8S)-2-chloro-9-(2-oxo-2-pyrid-3-ylethyl)-8-trifluoromethyl-

6,7,8,9-tetrahydropyrimidoII ,2-a]pyrimidin-4-one and 545.67 mg (4.02 mmol) of (1 S,4S)-

2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride are mixed together. The powder obtained is placed in a tube and 934.86 pl (6.71 mmol) of triethylamine are added. The tube is sealed and heated at 130°C in an oil bath for 6 hours. The crude product obtained

Is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and then evaporated to dryness. The residue Is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 980 mg of (8S)-2(1S,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, the characteristics of which are as follows:

LC/MS (method A): ESI+ [M+HJ+: m/z 436 tr (min) = 0.51 ¹H NMR (600 MHz, δ in ppm, DMSO-de): 1.67 (d, 1H), 1.75 (d, 1H). 2.32 (m, 1H). 2.5 (m, 1H), 3.04 (d, 1H), 3.17-3.25 (bs, 1H), 3.25-3.4 (bs, 3H), 4.44 (dd, 1H), 4.48 (s, 1H), 4.52 (s, 1H), 4.66 (m, 1H), 4.72 (s, 1H), 4.77 (d, 1H), 5.7 (d, 1H), 7.64 (m, 1H), 8.41 (m, 1H) 8.88 (m, 1H). 9.24 (s, 1H).

Example 7:

2-methyl*1 -[2-(5-methylpyrid-3-yl)-2-oxoethy!]-7-(1 S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-lmidazo[1,2-

a]pyrimldin-5-one (compound 16)

Step 7.1: (R)-2-methvl-4-phenvl-2-trifluoromethvloxazolidlne

Ph

g (180 mmol) of (R)-phenylglycinol and then 4 g (16 mmol) of pyridinium paratoluenesulfonate are added to a solution of 25.8 g (230 mmol) of trifluoroacetone in 200 mL of toluene In a three-necked flask on which is mounted Dean-Stark apparatus. The mixture obtained is then heated at 110‘C for 5 hours. After cooling, the reaction mixture is concentrated under reduced pressure. The residue obtained is purified by filtration on silica (eluent: dichloromethane) to give 35.10 g of (R)-2-methyl-4-phenyl-2trifluoromethyloxazolidine in the form of a colorless liquid, the characteristics of which are as follows:

LC/MS (method D): ESI+ [M+H]+: m/z 232 tr (min) = 0.96 ¹H NMR (300 MHz, δ in ppm. DMSO-de): 1.55 (s, 3H), 3.58 (m, 1H), 3.80 (m. 1H). 4.28 (m. 1H), 4.42 (m, 1H), 7.34 (m, 5H).

[a]_D ²⁵ at 589 nm = -23.4 ± 0.8’ (c = 1.794 mg / 0.5 mL MeOH)

Step 7.2: (S)-3,3,3-trlfluoro-2-((R)-2-hydroxy-1-phenylethylamino)-2methylproplonltrile

mL (200 mmol) of trimethylsilyl cyanide are added dropwise to a solution, cooled to 2’C, of 30.10 g (130 mmol) of (R)-2-methyl-4-phenyl-2-trifluoromethyloxazolidine in 300 mL of dichloromethane in a three-necked flask under argon, followed by dropwise addition of 25 mL (200 mmol) of boron trifluoride etherate. The cold bath is then removed to allow the mixture to warm to room température. The resulting mixture is stirred at room température for 3 hours, followed by addition of saturated sodium bicarbonate solution to pH = 7. The organic phase is separated out and then dried over magnésium sulfate, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica (eluent A/B: pentane/EtOAc, A/B gradient: 10 min 0% B, 120 min 10% B, t 40 min 40% B) to give 3.50 g of (R)-3,3,3-trifluoro-2-((R)-2-hydroxy-1phenylethylamino)-2-methylpropionitrile in the form of a colorless oil and 10 g of (S)-

3,3,3-trifluoro-2-((R)-2-hydroxy-1-phenylethylamino)-2-methylpropionitrile in the form of a white solid, the characteristics of which are:

LC/MS (method D): ESI+ [M+HJ+: m/z 259 tr (min) = 0.86 ’H NMR (300 MHz, δ in ppm, DMSO-de): 1.71 (s, 3H), 3.43 (m, 2H), 3.57 (m, 1H), 3.96 (m, 1H), 4.97 (m, 1H), 7.29 (m, 5H).

[a]_D ²⁵ at 589 nm = -77.6 ± 1.4’ (c =1.818 mg/ 0.5 mL DMSO) for (S)-3,3,3-trifluoro-2((R)-2-hydroxy-1-phenylethylamino)-2-methylpropionitrile

Step 7.3:	(R)-2-((S)-1-amlnomethyl-2_l2,2-trifluoro-1-fnethylethylamino)-2-
phenylethanol	Ph

65.10 mL (65.10 mmol) of a 1 M solution of lithium aluminum hydride in tetrahydrofuran are added to a solution, cooled to 2’C, of 16.80 g (65.10 mmol) of (S)-3,3,3-trifluoro-2((R)-2-hydroxy-1-phenylethylamino)-2-methylpropionitrile in 50 mL of anhydrous tetrahydrofuran in a three-necked flask under argon. At the end of the addition, the reaction mixture is allowed to warm to room température and is then stirred ovemight. The mixture obtained is cooled to 0“C, followed by very slow dropwîse addition of 12 mL of water. Substantiel évolution of gas and a température rise to 4'C are observed. 12 mL of 15% potassium hydroxide and then 25 mL of water are added to the resulting mixture, maintained at 0*C. The white precipitate formed is fîltered off and the filtrate obtained is dried over magnésium sulfate and then concentrated under reduced pressure to give

10.50 g of (R)-2-((S)-1-aminomethyl-2_l2,2-trifluoro-1-methylethylamino)-2phenylethanol, the characteristics of which are as foilows:

LC/MS (method D): ESI+ [M+H]+: m/z 263 tr (min) = 0.43 ¹H NMR (300 MHz, δ in ppm, DMSO-de): 0.90 (s, 3H), 2.48 (m, 2H), 2.72 (m, 2H), 3.31 (m, 4H), 3.95 (m, 1H), 7.27 (m, 5H).

[a]_D ²⁵ at 589 nm = -51.2 ± 1.3' (c = 1.576 mg / 0.5 mL DMSO)

Step 7.4: (S)-3_l3,3-trifluoro-2-methylpropane-1,2-dlamine

A mixture of 10.50 g (70 mmol) of (R)-2-((S)-1-aminomethyl-2,2,2-trifluoro-1methylethylamino)-2-phenylethanol in methanol, 4.5 mL (68 mmol) of methanesulfonic acid and 1.50 g of Pd(OH)₂/C (20% w/w) is hydrogenated at 25'C in an autoclave, under a hydrogen pressure of 5 bar, for 24 hours. The mixture obtained is then fîltered and the filtrate is evaporated to dryness. The oil obtained is taken up in 3 M hydrochloric acid solution (42 mL). The mixture obtained is extracted with ethyl ether. Ethyl ether and 15 mL of 35% sodium hydroxide are then added to the aqueous phase, to pH 12. The aqueous phase is then separated out by settling and extracted with 3 times 200 mL of ethyl ether. The organic phases are combined, dried over magnésium sulfate, fîltered and then concentrated under vacuum to give 4.50 g of (S)-3,3,3-trifluoro-2methylpropane-1,2-diamine in the form of a pale yellow oil, the characteristics of which are as foilows:

LC/MS (method E): ESI+ [M+H]+: m/z 143 tr (min) = 0.34 ¹H NMR (300 MHz, DMSO-de): 1.10 (s. 3 H). 1.60-1.85 (bs. 2H), 2.48 (d. 1 H), 2.72 (d, 1 H), 3.20-3.50 (bs, 2H).

[a]_D ²⁵ at 589 nm = -4.3 ± 0.6' (c = 1.778 mg/ 0.5 mL DMSO)

Step 7.5: (S)-4-methyl-4-trifluoromethyl-4,5-dihydro-1 H-imldazol-2-yiamine hydrobromide

11.60 mL (34.90 mmol) of cyanogen bromide dissolved in dichloromethane are added portionwise to a solution, cooled to 4’C, of 4.50 g (31.70 mmol) of (S)-3,3,3-trifluoro-2methylpropane-1,2-diamtne in 20 mL of acetonitrile, while maintaining the température between 5 and 10°C. At the end of the addition, the réaction mixture is left at 5°C for 30 minutes. The mixture obtained is then stirred at room température ovemight. The resulting mixture is then concentrated under vacuum. The residue obtained is taken up twice with éthanol and then twice with toluene, and evaporated to dryness each time. The solid obtained is triturated with ethyl ether and then filtered off to give 4.50 g of (S)-

4-methyl-4-trifluoromethyl-4,5-dîhydro-1H-imidazol-2-ylamine hydrobromide in the form of a white solid, the characteristics of which are as foilows:

LC/MS (method D): ESI+ [M+H]+: m/z 168 tr (min) = 0.14 ¹H NMR (300 MHz. DMSO-de): 1.52 (s, 3 H), 3.57 (m, 1 H), 3.81 (m, 1 H), 7.45 (s. 2H). 8.09 (8,1H), 9.45 (8,1H).

[a]o²⁵ at 589 nm: -5.2 ± 0.3^e (c - 4.909 mg/ 0.5 mL DMSO)

Step 7.6: (S^-hydroxy^-methyl^-trifluoromethyl^.S-dihydro-l Himidazo[1,2-a]pyrimldln-5-one

36.90 g (148.76 mmol) of (S)-4-methyl-4-trifluoromethyl-4,5-dihydro-1H-imidazol-2ylamine hydrobromide and 24.10 g (446 mmol) of sodium methoxide are added to a mixture of 29.50 g (216.43 mmol) of dîethyl malonate in 200 mL of methanol. The resulting mixture is refluxed for 18 hours. After cooling, the mixture obtained is concentrated to dryness under vacuum. 65 mL of cold water are added to the residue obtained, to obtain a thick suspension, to which is added 25% hydrochloric acid to pH 5. The resulting suspension is stirred in an ice bath for 3 hours and then filtered. The insoluble matter obtained is rinsed with water and then dried to give 37.60 g of (S)-7hydroxy-2-methyl-2-trifluoromethyl-2,3-dihydro-1 H-imidazo[1,2-a]pyrimidin-5-one in the form of a white solid, the characteristics of which are as follows:

LC/MS (method D): ESI+ [M+H]+: m/z 236 tr (min) = 0.32 ’H NMR (400 MHz, DMSO-de): 1.53 (s, 3H), 3.95 (m, 1H), 4.10 (m, 1H), 4.79 (s, 1H), 5.80-7.01 (bs, 1H), 9.09 (s, 1H).

[<x]d^2S at 589 nm = -5.6 ± 0.6* (c = 1.789 mg/ 0.5 mL DMSO)

Step 7.7: (S)-7-chloro-2-methyl-2-trlfluoromethyl-2,3-dlhydro-1 Hlmidazo[1,2-a]pyrimidin-5-one

F

41.60 mL (446.50 mmol) of phosphores oxychloride are added, at room température and under an argon atmosphère, to a suspension of 35 g (148.80 mmol) of (S)-7-hydroxy-2methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one in 350 mLof 1,2dichloroethane. The resulting mixture is then heated at 70’C for 4 hours. After cooling, the reaction mixture is evaporated to dryness under vacuum. The residue obtained is taken up in 35 mL of cold water and 500 mL of ethyl acetate. 32% sodium hydroxide is added to the mixture obtained, to pH = 6-7. The organic phase is then separated out and then dried over magnésium sulfate, filtered and concentrated under reduced pressure to give 20 g of (S)-7-chloro-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-

a]pyrimidin-5-one, the characteristics of which are as follows: LC/MS (method D): ESI+ [M+HJ+: m/z 254 tr (min) = 0.51 ’H NMR (400 MHz, DMSO-de): 1.57 (s, 3H), 4.00 (d, 1H), 4.21 (d, 1H), 5.84 (s, 1H), 9.64 (s, 1H).

[a]o²⁵ at 589 nm = -64.8 ± 1.1’ (c = 2.2 mg/ 0.5 mL DMSO)

Step 7.8: 2-methyl-7-(1S,4S)-2-oxa-5-azablcyclo[2.2.1]hept-5-yl-2-{(S)trifluoromethyl)-2,3-dlhydro-1 H-imidazo[1,2-a]pyrimidin-5-one

g (3.84 mmol) of (SÏ-ï-chloro-Z-methyl^-trifluoromethyl^.S-dihydro-IHlmidazo[1,2-a]pyrimidin-5^)ne and 844.18 mg (5.91 mmol) of (1S,4S)-2-oxa-5azabicyclo[2.2,1]heptane hydrochloride are mixed together. The powder obtained is placed In a tube and 1.38 mL (9.86 mmol) of triethylamine are added. The tube is sealed and heated at 140’C in an oil bath for 4 hours. After cooling, the crude product is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH). After evaporating the fractions under reduced pressure, 750 mg of 2-methyl-7-(1S,4S)-2-oxa-5azabicyclo[2.2.1 ]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1 H-îmidazo[1,2-

a]pyrimidin-5-one are obtained, the characteristics of which are as follows: LC/MS (method G): ESI+: [M+HJ+: m/z 317 tr (min) =1.34 ¹H NMR (300 MHz, δ in ppm, CDCI₃): 1.34 (s, 3H), 1.65 (m, 2H), 3.13 (m, 2H), 3.43 (m, 1H), 3.53 (m, 1H), 3.72 (d, 1H), 3.89 (d, 1H), 4.M.81 (bs, 3H), 8.77 (s. 1H).

Step 7.9: 2-methyl-1-[2-(5-methylpyrld-3-yl)-2-oxoethyl]-7-(1S_l4S)-2-oxa-5azablcyclo[2.2.1]hept-5-yl-2-((S)-trifluoromethyî)-2,3-dihydro-1H-îmldazo[1,2-

a]pyrimldin-5-one

150 mg (0.474 mmol) of 2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-

2-((S)-trifluoromethyl)-2,3-dihydro-1 H-imidazo[1,2-alpyrimidin-5-one in 5 mL of DMF are added to a suspension of 50.08 mg (1.04 mmol) of sodium hydride in 5 mL of DMF. The reaction mixture is placed under magnetic stirring at room température for 15 minutes. A solution of 153.88 mg (0.521 mmol) of 3-(bromoacetyl)pyridine hydrobromide in 5 mL of DMF is added dropwise to the reaction medium. The reaction is stirred at room température ovemight. The reaction medium is evaporated to dryness. The crude product is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 100 mg of 2-methyl-117195 (2-(5-methylpyrid-3-yl)-2-oxoethyl]-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-((S)trifluoromethyl)-2,3-dÎhydro-1H-imidazo[1,2-a] pyrimidin-5-one, the characteristics of which are as foilows:

LC/MS (method A): ESI+ [M+H]+: m/z 450 tr (min) = 0.52 ¹H NMR (600 MHz, δ in ppm, DMSO-d_e): 1.65 (s, 3H), 1.71 (m, 2H), 2.4 (s, 3H), 3-3.2 (m, 2H), 3.42 (s, 2H), 4 (d, 1H), 4.24 (d, 1H), 4.52 (t, 3H) 4.81 (d, 1H), 5.12 (d, 1H), 8.19 (s,1H), 8.67 (s, 1H), 8.99 (s, 1 H).

Example 8:

2-m ethyl-1 -[2-(4-methylthlazol-5-yl)ethyl]-7-(1 S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-2-((S)-trif1uoromethyl)-2,3-dihydro-1H-imidazo[1,2-

a]pyrimldin-5-one (compound 26)

Step 8.1:5-(2-bromoethyl)-4-methylthiazole g (6.98 mmol) of 2-(4-methylthiazol-5-yl)ethanol is dissolved in 15 mL of dichloromethane. The solution is cooled to 0°C. When the température is reached, 1.85 g (6.98 mmol) of triphenylphosphine are added, followed by portionwise addition of 1.30 g (6.98 mmol) of N-bromosuccinimide. After stirring for 2 hours at 0°C, the mixture is evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 50/50 EtOAc/heptane) to give 900 mg of 5-(2-bromoethyl)-4-methylthiazole, the characteristics of which are as foilows:

LC/MS (method G): ESI+ [M+HJ+: m/z 206 tr (min) = 1.52 ’H NMR (300 MHz, δ in ppm, CDCI₃): 2.42 (s, 3H) 3.3-3.35 (t, 2H) 3.5-3.55 (t, 2H) 8.62 (s. 1H)

Step 8.2: 2-methyl-1 -[2-(4-methylthiazol-5-yl)ethyl]-7-(1 S,4S)-2-oxa-5 azablcyclo[2.2.1]hept-5-yl-2-((S)-trlfluoromethyl)-2,3-dlhydro-1H-lmidazo[1,2-

a]pyrimldln-5-one

150 mg (0.474 mmol) of 2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-

2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one in 5 mL of DMF are added to a suspension of 45.53 mg (0.95 mmol) of sodium hydride in 5 mL of DMF. The reaction mixture is heated for 15 minutes at 80’C. A solution of 293.24 mg (1.42 mmol) of 5-(2-bromoethyl)-4-methylthiazole in 5 mL of DMF is added dropwise to the réaction medium. The reaction is heated at 80°C ovemight. The reaction medium is evaporated to dryness. The crude product is taken up in water and extracted with ethyi acetate. The organic phase is dried over magnésium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 45 mg of

2-methyl-1-[2-(4-methylthiazol-5-yl)ethyl]-7-(1S,4S)-2-oxa-5-azabicyc!o[2.2.1]hept-5-yl·

2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimÎdin-5-one, the characteristics of which are as foilows:

LC/MS (method A): ESI+ [M+H]+: m/z 442 tr (min) = 0.56 ¹H NMR (600 MHz, δ in ppm, DMSO-d_e): 1.55 (s, 3H), 1.86 (m, 2H), 2.34 (s. 3H), 3-3.48 (m, 7H), 3.6 (m, 1H). 3.66 (m. 1H). 3.76 (m, 1H), 3.86 (d, 1H), 4.13 (d, 1H), 4.66 (s, 1H),

8.86 (s, 1H).

Example 9:

(8S)-9-P-(2-methylpyrld-3-yl)-2-oxoethyîl-2-(1S,4S)-2-oxa-5azablcyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimldo[1,2aJpyrimidin-4-one (compound 19)

Step 9.1:1 -(2-methylpyrid-3-yl)ethanone

The following are successively Introduced into a microwave tube:

469.80 μΙ (4.07 mmol) of 3-bromo-5-methylpyridine in 20 mL of HîO/DMF: (1/3: v/v), 2.03 mL (5.70 mmol) of tributyl(1-ethoxyvinyl)tin, 57.12 mg (81.38 mmol) of bis(triphenylphosphine)palladium(ll) chloride, 1.12 g (8.14 mmol) of potassium carbonate. After irradiating with microwaves for 1 hour at 110*C, the réaction mixture is evaporated to dryness and the residue Is taken up In water and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and evaporated to dryness. The residue is taken up in a solution consisting of 6 mL of methanol and 1 mL of 1 N hydrochloric acid. After stirring ovemight at room température, the reaction mixture Is evaporated to dryness and the residue is taken up in saturated aqueous NaHCOs solution and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 50/50 EtOAc/heptane) to give 160 mg of 1-(2-methylpyrid-3-yl)ethanone, the characteristics of which are as follows:

LC/MS (method G): ESI+ [M+H]+: m/z 136 tr (min) = 0.38 ’H NMR (300 MHz, δ in ppm, DMSO-de): 2.58 (s, 3H), 2.61 (s, 3H), 7.38 (m, 1H), 8.2 (m, 1H). 8.57 (m, 1H).

Step 9.2: 2-bromo-1-(2-methylpyrid-3-yl)ethanone hydrobromlde

150 mg (1.11 mmol) of 1-(2-methylpyrid-3-yl)ethanone are dissolved in 10 mL of glacial acetic acid. 365 μΙ (2.22 mmol) of hydrobromic add and 63 μΙ (1.22 mmol) of bromine are added to the medium. The reaction mixture is placed under magnetic stirring at room température for 1 hour. Ethyl ether is added to the solution until a precipitate appears. The predpitate correspondîng to 2-bromo-1-(2-methylpyrid-3-yl)ethanone hydrobromide is filtered off, washed with ethyl ether and dried. The 280 mg of product obtained hâve the following characteristics:

LC/MS (method G): ESI+ [M+HJ+: m/z 214 tr (min) = 0.72 ¹H NMR (300 MHz, δ in ppm, DMSO-de): 2.73 (s. 3H), 5 (s, 2H), 7.86 (m, 1H). 8.76 (m, 1H), 8.86 (m, 1H).

Step 9.3: (8S)-9-{2-(2-methylpyrid>3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5azablcyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimldo[1,2-

a]pyrlmldin-4-one

140 mg (0.474 mmol) of (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8trifluoromethy1-e,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 3 mL of DMF are added to a suspension of 46.74 mg (0.97 mmol) of sodium hydride in 4 mL of DMF. The reaction mixture is placed under magnetic stirring at room température for 15 minutes. A solution of 143.62 mg (0.443 mmol) of 2-bromo-1-(2-methylpyrid-3-yl)ethanone hydrobromide in 3 mL of DMF is added dropwise to the reaction medium. The reaction Is stirred at room température for 1 hour. The reaction medium is evaporated to dryness. The crude product is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 100 mg of (8S)-9-[2-(2-methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl8-trifluoromethy!-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:

LC/MS (method A): ESI+ [M+HJ+: m/z 450 tr (min) = 0.48 ’H NMR (600 MHz, δ in ppm, DMSO-de): 1.71 (m, 2H), 2.25 (m, 1H), 2.43 (m, 1H), 2.6 (s, 3H), 3.1-3.15 (m, 2H), 3.28 (m, 1H), 3.33-3.52 (bs, 2H), 4.37 (m, 1H), 4.52 (d, 2H),

4.59 (m, 1H), 4.64 (d, 1H), 4.69 (s, 1H), 5.5 (d, 1H), 7.4 (m, 1H), 8.28 (m, 1H), 8.61 (m, 1H).

Example 10: (8S)-9-[2-(4-methylthlazol-5-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5azablcyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimldo[1,2-

a]pyrimldln-4-one (compound 43)

Step 10.1: 2-bromo-1-(4-methylthiazol-5-yl)ethanone hydrobromide

220 mg (1.56 mmol) of 1-(4-methylthlazol-5-yl)ethanone are dissolved in 10 mL of glacial acetic acid. 769 μΙ (4.67 mmol) of hydrobromic acid and 88 μΙ (1.71 mmol) of bromine are added to the medium. The reaction mixture is placed under magnetic stirring at room température for 2 hours. Ethyl ether is added to the solution until a precipitate appears. The precipitate corresponding to 2-bromo-1-(4-methylthiazol-5-yl)ethanone hydrobromide is filtered off, washed with ethyl ether and dried. The 350 mg of product obtained hâve the following characteristics:

LC/MS (method G): ESI+ [M+H]+: m/z 220 lr (min) = 1.32 ’H NMR (300 MHz, δ in ppm, DMSO-d_e): 2.67 (s, 3H), 4.79 (s, 2H), 9.31 (s, 1H).

Step 10.2:

( 8S)-2-c h lo ro-9-[2-(4-methyl thlazoi-5-yi )-2-oxoethyl]-8-

trifluoromethyl-6,7,8,9-tetrahydropyrlmido[1,2-a]pyrimidln-4-one

A suspension of 150 mg (0.591 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9tetrahydropyrimido[1,2-a]pyrimidin-4-one and 578.13 mg (1.77 mmol) of césium carbonate in 10 mL of acetonitrile is stirred for 15 minutes at room température. 213.64 mg (0.709 mmol) of 2-bromo-1-(4-methylthiazol-5-yl)ethanone hydrobromide are then added. After stirring ovemight at room température, the reaction mixture is evaporated and the residue is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and evaporated to dryness to give 190 mg of (8S)-2chloro-9-[2-(4-methylthiazol-5-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9tetrahydropyrimido[1,2-a]pyrimidin-4-one, corresponding to the following characteristics: LC/MS (method G): ESI+ [M+H]+: m/z 393 tr (min) = 1.95

Ή NMR (300 MHz, δ in ppm, DMSO-de): 2.3 (m, 1H), 2.49 (s, 1H), 2.72 (s, 3H), 3.37 (m, 1H), 4.4 (m, 1 H), 4.77 (m, 1H), 4.81 (s, 1H), 5.22 (d, 1H), 5.96 (s, 1H), 9.58 (s, 1H).

Step 10.3: (8S)-9-[2-(4-methyithiazoi-5-yI)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5azabicycio[2.2.1]hept-5-yi-8-trifluoromethyi-6,7,8,9-tetrahydropyrlmldo[1,2-

a]pyrimldin-4-one

F*j

170 mg (0.511 mmol) of (8S)-2-chloro-9-[2-(4-methylthiazol-5-yl)-2-oxoethyl]-8trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 70.42 mg (0.52 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride are mixed together. The powder obtained is placed in a tube and 151 pl (1.08 mmol) of triethylamine are added. The tube is sealed and heated at 130’C in an oil bath for 3 hours. The crude product obtained is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 120 mg of (8S)-9[2-(4-methylthiazol-5-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-y I-8trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:

LC/MS (method A): ESI+ [M+H]+: m/z 456 tr (min) = 0.55 ¹H NMR (600 MHz, δ in ppm, DMSO-de): 1.69 (m, 2H), 2.28 (m, 1H), 2.43 (m, 1H), 2.7 (s, 3H), 2.98 (d, 1H), 3.12 (d, 1H), 3.21-3.33 (m, 3H), 4.37 (m, 1H), 4.42 (s, 1H), 4.5 (s, 1H), 4.55-4.62 (m, 2H), 4.67 (s, 1H), 5.22 (d, 1H), 9.19 (s, 1H).

Example 11 ;

(8S)-2-(1S,4S)-2-Oxa-5-azabicycio[2.2.1]hept-5-yi-9-[2-oxo-2(tetrahydropyran-4-yl)ethyl]-8-trif1uoromethyl-6,7,8,9-tetrahydropyrimldo[1,2-

a]pyrlmldln-4-one (compound 62)

Step 11.1: (8S)-2-chloro-9-[2-oxo-2-(tetrahydropyran-4-yl)ethyf]-8trifluoromethyl-6,7,8,9-tetrahydropyrimldo[1,2-a]pyrimldin-4-one

A suspension of 150 mg (0.591 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9tetrahydropyrimido[1,2-a]pyrimidin-4-one and 578.13 mg (1.77 mmol) of césium carbonate in 10 mL of acetonitrile Is stirred for 15 minutes at room température. 146.97 mg (0.709 mmol) of 2-bromo-1-(tetrahydropyran-4-yl)ethanone are then added. After stirring ovemight at room température, the reaction mixture is evaporated and the residue is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and evaporated to dryness to give 220 mg of (8S)-2-chloro-9[2-oxo-2-(tetrahydropyran-4-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimidoI1,2a]pyrimidin-4-one, corresponding to the following characteristics: LC/MS (method G): ESI+ [M+H]+: m/z 380 tr (min) = 1.94 ¹H NMR (300 MHz, δ in ppm. CDCI₃): 1.58-2.04 (m. 2H). 2.37 (m. 1H). 2.5 (m. 1H). 2.76 (m, 1H), 3.5 (4H). 3.9 (d. 1H), 3.96-4.02 (m, 4H). 4.6 (m. 1H). 5.25 (d, 1H), 5.99 (s, 1H).

Step 11.2: (8S)-2-(1S,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-tetrahydropyrimldo[1,2a]pyrimldin-4-one

220 mg (0.58 mmol) of (8S)-2-chloro-9-[2-oxo-2-(tetrahydropyran-4-yl)ethyl]-8trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 94.26 mg (0.69 mmol) of (1S.4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride are mixed together. The powder obtained is placed in a tube and 202 pl (1.45 mmol) of triethylamine are added. The tube is sealed and heated at 130‘C in an oil bath for 3 hours. The crude product obtained is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and then evaporated to dryness. The residue Is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 220 mg of (8S)-217195 (1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-oxo-2-(tetrahydropyran-4-yl)ethyl]-8trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as foilows:

LC/MS (method A): ESI+ [M+H]+: m/z 443 tr (min) = 0.52 ¹H NMR (600 MHz, δ in ppm, DMSO-de): 1.49 (m, 1H), 1.52 (m, 1H), 1.7 (m, 2H), 1.79 (bs, 2H), 2.15 (m, 1H), 2.36 (m, 1H), 2.7 (m, 1H), 2.84-3.25 (bs, 3H), 3.31-3.59 (bs, 3H),

3.65 (d, 1H), 3.86 (m, 2H), 4.17 (d, 1 H), 4.3 (m, 1H), 4.35-5.3 (bs, 5H).

Example 12:

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

F

Step 12.1:1-{4-methylpyrid-3-yl)ethanone

671 μΙ (5.81 mmol) of 3-bromo-4-methylpyridine In 15 mL of H₂O/DMF (1/4: v/v), 1.93 mL (14.53 mmol) of N-butyl vinyl ether, 39.15 mg (0.17 mmol) of palladium(ll) acetate,

163.14 mg (0.38 mmol) of 1,3-bis(diphenylphosphino)propane and 973.84 mg (6.98 mmol) of potassium carbonate are placed in a microwave tube. After irradiating with microwaves at 120’C for 2 hours, 20 mL of 5% hydrochloric acid solution are added. The reaction mixture is stirred for 1 hour at room température and then basified with potassium carbonate and extracted with ethyl acetate. The organic phase ls dried over magnésium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 50/50 EtOAc/heptane) to give 320 mg of 1-(4methylpyrid-3-yl)ethanone, the characteristics of which are as foilows: LC/MS (method G): ESI+ [M+H]*: m/z 136 tr (min) = 0.56 ’H NMR (300 MHz, δ in ppm, DMSO-de): 2.46 (s, 3H), 2.62 (s, 3H), 7.35 (d, 1H), 8.56 (d, 1H),9(s, 1H).

Step 12.2: 2-bromo-1-(4-methylpyrid-3-yl)ethanone hydrobromide

300 mg (2.22 mmol) of 1-(4-methylpyrid-3-yl)ethanone are dissolved in 20 mL of glacial acetic acid. 730 μΙ (4.44 mmol) of hydrobromic acid and 126 μΙ (2.44 mmol) of bromine are added to the medium. The reaction mixture is placed under magnetic stirring at room température for 2 hours. Ethyl ether is added to the solution until a precipitate appears. The precipitate corresponding to 2-bromo-1-(4-methylpyrid-3-yl)ethanone hydrobromide is fïltered off, washed with ethyl ether and dried. The 550 mg of product obtained hâve the following characteristics:

LC/MS (method G): ESI+ [M+H]+: m/z 214 tr (min) = 1.01 ’H NMR (300 MHz, δ in ppm, DMSO-de): 2.59 (s, 3H), 5.04 (s, 2H), 7.85 (d, 1H), 8.84 (d, 1H), 9.25 (s, 1H).

Step______12.3: (8S)-2-chloro-9-[2-(4-methylpyrid-3-yl)-2-oxoethyI]-8trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimldin-4-one

A suspension of 100 mg (0.394 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9tetrahydropyrimido[1,2-alpyrimidin-4-one and 385.42 mg (1.18 mmol) of césium carbonate In 10 mL of acetonitrile is stirred for 15 minutes at room température. 139.57 mg (0.473 mmol) of 2-bromo-1-(4-methylpyrid-3-yl)ethanone hydrobromide are then added. After stirring ovemight at room température, the reaction mixture is evaporated and the residue Is taken up in water and extracted with ethyl acetate, The organic phase is dried over magnésium sulfate and evaporated to dryness to give 140 mg of (8S)-2chloro-9-[2-(4-methylpyrid-3-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9tetrahydropyrimido[1,2-a]pyrimidin-4-one, corresponding to the following characteristics: LC/MS (method G): ESI+ [M+H]+: m/z 387 tr (min) = 1.87 ’H NMR (300 MHz, δ in ppm, CDCh): 2.27 (m, 1H). 2.44 (s, 3H), 2.5 (m, 1H), 3.4 (m, 1H), 4.4 (m, 1H), 4.77 (m, 1H), 4.86 (d, 1H), 5.32 (d, 1H), 5.97 (s, 1H), 7.4 (d, 1H). 8.6 (d,1H),9(s,1H).

Step 12.4: (8S)-9-[2-(4-methylpyrld-3-yi)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5azablcyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimldo[1,2a]pyrlmidln-4-one

140 mg (0.36 mmol) of (8S)-2-chloro-9-[2-(4-methylpyrid-3-yl)-2-oxoethyl]-8trifluoromethyl-6,7,8_l9-tetrahydropyrimido[1_l2-a]pyrimidin-4-one and 94.26 mg (0.69 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride are mixed together. The powder obtained is placed in a tube and 126 pl (0.90 mmol) of triethylamine are added. The tube is sealed and heated at 120’C in an oil bath for 2 hours. The crude product obtained is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 120 mg of (8S)-9[2-(4-methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one_l the characteristics of which are as follows:

LC/MS (method A): ESI+ [M+H]*: m/z 450 tr (min) = 0.48 ’H NMR (600 MHz, δ in ppm, DMSO-d_e): 1.7 (m, 2H), 2.25 (m, 1H), 2.42 (m, 1H), 2.45 (s, 3H). 3-3.2 (m, 2H), 3.24-3.53 (bs, 3H), 3.36 (m, 1H), 4.51 (s, 1H), 4.54 (s, 1H), 4.59 (m, 1H), 4.65-4.76 (m, 2H), 5.55 (d, 1H), 7.37 (d, 1H), 8.59 (d, 1H), 9.05 (s, 1H).

Example 13:

(eSJ-Q-^-methyl^-pyrid^-ylpropylJ^-IIS^S^-oxa-Sazabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrlmldo[1,2 a]pyrimidin-4-one (compound 1)

Step 13.1: ethyl 2-methyl-2-pyrid-4-ylpropionate

The reaction is performed under argon: 2 g (12.12 mmol) of ethyl pyrid-4ylacetate are dissolved in 30 mL of DMF. After addition of 15.25 mL (15.15 mmol) of a 1 M solution of lithium bis(trimethylsilyl)amide in THF. the reaction mixture is stirred at room température for 30 minutes. 1.21 mL (19.39 mmol) of iodomethane are then added gently, and the solution obtained is stirred at room température for 1 hour 30 minutes. A second portion of 15.25 mL (15.15 mmol) of a 1 M solution of lithium bis(trimethylsilyl)amide in THF is added, and the mixture is stirred at room température for 1 hour. A second portion of 1.21 mL (19.39 mmol) of iodomethane is also added, and stirring is continued for 2 hours at room température. The precipitate formed is filtered off, the filtrate is evaporated to dryness and the residue is taken up in dichloromethane. The organic phase is washed with water and with aqueous ammonium chloride solution, dried and evaporated to dryness to give 1.80 g of ethyl 2-methyl-2-pyrid-4-ylpropionate, corresponding to the following characteristics:

LC/MS (method G): ESI+ [M+HJ+: m/z 194 tr (min) = 1.03 ¹H NMR (300 MHz, δ in ppm, DMSO-d_e): 1.11 (t, 3H), 1.49 (s, 6H), 4.09 (q, 2H), 7.31 (d, 2H), 8.52 (d, 2H).

Step 13.2: 2-methyl-2-pyrid-4-ylpropan-1-ol

A solution of 1.58 g (7.36 mmol) of ethyl 2-methyl-2-pyrid-4-ylpropionate in 30 mL of THF is cooled to 10C. When the température is reached, 22.08 mL (22.08 mmol) of 1 M diisobutylaluminum hydride solution in toluene are added dropwise. The reaction mixture is allowed to warm to room température and is stirred ovemight. 1 N hydrochloric acid solution is added to the reaction medium, which is then extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and evaporated to dryness to give

1.60 g of 2-methyl-2-pyrid-4-ylpropan-1-ol, corresponding to the following characteristics:

LC/MS (method G): ESI+ [M+HJ+: m/z 152 tr (min) » 0.40 ¹H NMR (300 MHz, δ in ppm, DMSO-de): 1.19 (s, 6H), 3.42 (d, 2H), 4.76 (t, 1H), 7.34 (d, 2H), 8.44 (d, 2H).

Step 13.3: 2-methyl-2-pyrld-4-ylpropyl benzenesulfonate

710 μΙ (4.07 mmol) of Ν,Ν-diisopropylethylamine and 33.13 mg (0.27 mmol) of 45 dimethyl amino pyridine are added to a solution of 410 mg (2.71 mmol) of 2-methyl-2pyrid-4-ylpropan-1-ol in 10 mL of dichioromethane. The mixture Is cooled to 0^eC and a solution of 775.42 mg (4.07 mmol) of 4-methylbenzene-1-sulfonyl chloride in 2 mL of dichioromethane is then added. After allowing the reaction medium to warm to room température and stirring ovemight, it is washed with water and with saturated NaCi 10 solution. The organic phase is dried over magnésium sulfate and evaporated to dryness to give 660 mg of 2-methyl-2-pyrid-4-ylpropyl benzenesulfonate, correspondîng to the following characteristics:

LC/MS (method G): ESI+ [M+HJ+: m/z 306 tr (min) = 1.49 ’H NMR (300 MHz, δ in ppm, DMSO-de): 1.22 (s, 6H), 2.43 (s, 3H), 4.11 (s, 2H), 7.27 (d,

2H), 7.42 (d, 2H), 7.66 (d, 2H), 8.43 (d, 2H).

Step 13.4:

(8S)-9-(2-methyl-2-pyrid-4-ylpropyl)-2-(1S,4S)-2-oxa-5-

azablcyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrlmldo[1,2a]pyrimidln-4-one

The following are placed in a tube: 130 mg (0.411 mmol) of (8S)-2-(1S,4S)-2oxa-S-azabicycloP^.IJhept-S-yl-e-trifluoromethyl-ej.e.S-tetrahydropyrimidoIl^a]pyrimidin-4-one. 133.92 mg (0.411 mmol) of césium carbonate, 6.16 mg (0.041 mmol) of sodium iodide and 175.74 mg (0.575 mmol) of 2-methyl-2-pyrid-4-ylpropyl 25 benzenesulfonate in 5 mL of DMF. The reaction mixture is heated ovemight at 150°C In the sealed tube. After allowing the mixture to cool to room température, the solvent is evaporated off. The residue is taken up in ethyl acetate, washed with water, dried over magnésium sulfate and evaporated to dryness. The residue Is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 18 mg of (8S)-9-(2 methyl-2-pyrid-4-ylpropy 1)-2-( 1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ] hept-5-yl-8trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as foilows:

LC/MS (method B): ESI+ [M+HJ+: m/z 450 tr (min) = 0.53

Ή NMR (600 MHz, δ in ppm, DMSO-d_s): 1.24 (s, 1 H), 1.31 (s, 3H), 1.35 (s, 3H), 1.83 (m, 2H), 2.09 (m, 1H), 2.18 (m. 1H), 3.02 (m, 1H), 3.21 (m, 2H). 3.57 (m, 1H), 3.75 (m, 2H), 3.98 (m, 1H), 4.65 (m, 2H), 4.76 (d, 1H), 4.99 (m, 1H), 7.49 (s, 2H), 8.53 (s, 2H).

Example 14:

1-ethyl-3-{4-[2-((8S)-8-(1S,4S)-2-oxa-5-azablcyclo[2.2.1]hept-5-yl-6-oxo-2trifluoromethyl-3,4-dihydro-2H,6H-pyrimldo[1,2-a]pyrlmldin-1 yl)ethyl]phenyl}urea (compound 23)

Step 14.1: tert-butyl [4-(2-hydroxyethyl)phenyî]carbamate

OH g (35.36 mmol) of 2-(4-aminophenyl)ethanol and 6.17 mL (35.36 mmol) of N,Ndiisopropylethylamine are added to a solution of 8.49 g (38.89 mmol) of di-tert-butyl dicarbonate in 10 mL of dioxane. After stirring for 4 hours at room température, the reaction mixture is evaporated to dryness. The residue is taken up in ethyl acetate and the solution is washed with 1 N hydrochloric acid solution and then with water. The organic phase is dried over magnésium sulfate and evaporated to dryness to give 7.85 g of tert-butyl [4-(2-hydroxyethyl)phenyl]carbamate, the characteristics of which are as foilows:

¹H NMR spectrum (300 MHz, δ in ppm, DMSO-de): 1.47 (s, 9H), 2.65 (t, 2H), 3.54 (q, 2H), 4.60 (t, 1H), 7.07 (d, 2H), 7.33 (d, 2H), 9.13-9.3 (bs, 1H).

Step 14.2: tert-butyl [4-(2-bromoethyl)phenyl]carbamate

8.68 g (33.08 mmol) of triphenylphosphine are added, under an argon atmosphère, to a solution of 7.85 g (33.08 mmol) of tert-butyl [4-(2hydroxyethyl)phenyl]carbamate in 85 mL of dichloromethane. The mixture is cooled to 0^eC and 5.95 g (33.08 mmol) of N-bromosuccinimide are added portionwise over 25 minutes. Stirring is continued for 3 hours at 0°C. The solvent is then evaporated off, the oil obtained is taken up in ether and the precipitate formed is filtered off and discarded. The filtrate is evaporated and the residue is purified by chromatography on silica gel (eluent: 10/90 EtOAc/heptane) to give 6.90 g of tert-butyl [4-(2bromoethyl)phenyl]carbamate, the characteristics of which are as follows: LC/MS (method G): ESI+ [M+Na]+: 322 tr (min) = 2.46 ’H NMR spectrum (300 MHz, 6 in ppm, DMSO-de): 1.47 (s, 9H), 3.04 (t, 2H), 3.68 (t, 2H),

7.15 (d, 2H), 7.38 (d, 2H), 9.29 (s, 1H).

Step 14.3: tert-butyl {4-[2-((8S)-8-('IS,4S)-2-oxa-5-azablcyclo[2.2.1]hept-5-yl·

6-oxo-2-trifluoromethyi-3,4-dlhydro-2H,6H-pyrimido[1,2-a]pyrimldln-1yljethyfjphenyljcarbamate

300 mg (0.95 mmol) of (8S)-2-(1S.4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 3 mL of DMF are added to a suspension of 75.87 mg (1.89 mmol) of sodium hydride in 2 mL of 2methyltetrahydrofuran. The reaction mixture is placed under magnetic stirring at room température for 10 minutes. A solution of 569.48 mg (1.89 mmol) of tert-butyl [4-(2bromoethyl)phenyl]carbamate in 3 mL of DMF is added dropwise to the reaction medium. The reaction is stirred at room température ovemight The reaction medium is evaporated to dryness. The crude product is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 240 mg of tert-butyl {4-[2-((8S)-8-(1 S, 4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo17195

2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1 yl)ethyl]phenyl}carbamate, the characteristics of which are as follows: LC/MS (method G): ESI+ [M+H]*: m/z 536 tr (min) = 2.46 ’H NMR (300 MHz, δ in ppm, DMSO-d_fl): 1.45 (s, 9H), 1.9 (s, 3H), 2.32 (m, 1H), 2.70-

2.98 (m, 2H), 3.13 (m, 2H), 3.24-3.47 (bs, 2H), 3.7 (m, 1H), 3.77 (m, 1H), 4.17 (m, 2H), 4.47-5 (bs, 4H), 7.01 (d, 2H), 7.38 (d, 2H), 9.28 (s, 1H).

Step 14.4: (8S)-9-[2-(4-amlnophenyl)ethyl]-2-(1 S,4S)-2-oxa-5azablcyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrlmldo[1,2· a]pyrimldln-4-one

mL (17.93 mmol of a 4 N HCI/dioxane solution are added to a solution of 240 mg (0.45 mmol) of tert-butyl {4-[2-((8S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6oxo-2-trifluoromethy!-3,4-dihydro-2H_l6H-pyrimido[1,2-a]pyrimidin-1 yl)ethyl]phenyl)carbamate. The reaction mixture is stirred for 1 hour 30 minutes at room température. The solvent is evaporated off and the residue is taken up in a methanol/dichloromethane mixture and then evaporated to give 245 mg of (8S)-9-[2-(4aminophenyl)ethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-y!-8-trifîuoromethyl-

6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:

LC/MS (method G): ESI+ [M+H]+: m/z 436 tr (min) = 1.60 ’H NMR (300 MHz, δ in ppm, DMSO-d_e): 1.79-2.12 (m, 3H), 2.33 (m, 1H), 2.82-3.09 (m, 2H), 3.17 (m, 2H), 3.37 (m, 1H), 3.58 (s, 1H), 3.69 (m, 2H), 3.79 (d, 1H), 4.2 (m, 2H),

4.67 (bs, 3H), 7.33 (s, 4H), 9.8-10.6 (bs, 2H).

Step 14.5:1-ethyl-3-{4-[2-((8S)-8-(1S,4S)-2-oxa-5-azablcyclo[2.2.1]hept-5-yl-

6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimldo[1_l2-a]pyrimldln-1yl)ethyl]phenyl}urea

μΙ (0.63 mmol) of ethyl isocyanate are added to a solution of 150 mg (0.32 mmol) of (8S)-9-[2-(4-aminophenyl)ethyl]-2-(1 S.4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 139 μΙ (0.79 mmol) of Ν,Ν-diisopropylethylamine in 1 mL of dichloromethane. After stimng ovemight at room température, the solvent Is evaporated off. The residue Is taken up In ethyl acetate and washed with water and with saturated aqueous NaCI solution. The organic phase is dried over magnésium sulfate and evaporated to dryness. The residue Is purified by reverse-phase chromatography (RP18 column) (eluent: 50/50 hbO/MeOH) to give 92 mg of 1-ethyl-3-(4-[2-((8S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-

2-trifluoromethy1-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1 -yl)ethyl]phenyl)urea, the characteristics of which are as follows:

LC/MS (method A): ESI+ (M+H]+: m/z 507 tr (min) « 0.6

Ή NMR (600 MHz, δ in ppm, DMSO-de): 1.05 (t, 3H), 1.88 (m, 3H), 2.31 (m, 1H), 2.78 (m, 1H), 2.9 (m, 1H), 3.1 (m, 4H), 3.36 (m, 2H), 3.71 (d, 1 H), 3.79 (d, 1H), 4.18 (d, 2H),

4.55 (m, 1H), 4.6-5.1 (bs, 3H), 6 (t, 1H), 7 (d, 2H), 7.3 (d, 2H), 8.3 (s, 1H).

Example 15:

-ethyl-3-(4-(2-((1 S,4S)-2-methy1-7-2-oxa-5-azablcyclo[2.2.1]hept-5-yl-5oxo-2-((S)-trif1uoromethyl)-2,3-dihydro-5H-imldazo[1,2-a]pyrimidin-1yl]ethyl}phenyl)urea (compound 24)

Step 15.1: tert-butyi (4-{2-[(1S,4S)-2-mettiyl-7-2-oxa-5azablcyclo[2.2.1]hept-5-yl-5-oxo-2-((S)-tr1f1uoromethyl)-2,3-dihydro-5Hlmldazo[1,2-a]pyrimidln-1-yl]ethyl}ptienyl)carbamate

A suspension of 300 mg (0.948 mmol) of 2-methy 1-7-( 1S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2a]pyrimidin-5-one and 309.05 mg (0.948 mmol) of césium carbonate in 5 mL of DMF is stirred at 85°C for 15 minutes. A solution of 284.74 mg (0.948 mmol) of tert-butyl [4-(2bromoethyl)phenyl]carbamate is added dropwise. After reacting ovemight at 85*0, the mixture is evaporated and the residue is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 385 mg of tert-butyl (4-i2-[(1S,4S)-2-methyl-7-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-5oxo-2-((S)-trifluoromethyl)-2,3-dihydro-5H-imidazo[1,2-a]pyrimidin-1 yl]ethyl}phenyl)carbamate, the characteristics of which are as follows: LC/MS (method G): ESI+ [M+H]+: m/z 536 tr (min) = 2.48 ’H NMR (300 MHz, δ in ppm, CDCIs): 1.47 (s. 9H), 1.53 (s, 3H), 1.85 (s, 2H), 2.77 (m. 1H). 2.93 (m, 1H), 3.29-3.46 (m, 5H), 3.54 (m, 1 H), 3.68 (m, 1H), 3.81 (m, 2H), 4.13 (m, 1H), 4.66 (s, 1H). 7.11 (d, 2H), 7.39 (d, 2H), 9.29 (s, 1H).

Step 15.2: 1 -[2-{4-amlnophenyl)ethyl]-2-methy l-7-{1 S,4S)-2-oxa-5azablcyclo[2.2.1]hept-5-yl-2-((S)-tr[fluoromethyl)-2,3-dlhydro-1H-im[dazo[1,2a]pyrimidln-5-one

mL of trifluoroacetic add is added to a solution of 385 mg (0.72 mmol) of tertbutyl (4-{2-[(1S,4S)-2-methyl-7-2-oxa-5-azabicydo[2.2.1]hept-5-yl-5-oxo-2-((S)trifluoromethyl)-2,3-dihydro-5H-imidazo[1,2-a]pyrimidin-1 -yl]ethyl}phenyl)carbamate in 4 mL of dichloromethane. After stirring for 1 hour at room température, the solvent ls evaporated off. The residue is taken up in ethyl acetate and washed with saturated aqueous NaHCO_} solution. The organic phase is dried over magnésium sulfate and evaporated to dryness to give 275 mg of 1-[2-(4-aminophenyl)ethyl]-2-methyl-7-(1S,4S)-

2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2aJpyrimidin-5-one, the characteristics of which are as follows:

LC/MS (method A): ESI+ [M+HJ+: m/z 436 tr (min) = 0.48 ’H NMR (600 MHz, δ in ppm, DMSO-d_e): 1.52 (s, 3H), 1.87 (m, 2H), 2.69 (m. 1H), 2.87 (m, 1H), 3.26-3.53 (bs, 6H), 3.68 (d, 1H), 3.78 (m, 2H), 4.10 (d, 1H), 4.66 (s, 1H), 4.92 (s, 2H), 6.5 (d, 2H), 6.87 (d, 2H).

Step 15.3:1-ethyl-3-(4-{2-[(1 S,4S)-2-methyl-7-2-oxa-5azabicycio[2.2.1]hept-5-yl-5-oxo-2-((S)-trifluoromethyl)-2,3-dlhydro-5Himidazo[1,2-a]pyrimldin-1-yl]ethyl}phenyl)urea

104 pl (1.29 mmol) of ethyl isocyanate are added to a solution of 140 mg (0.32 mmol) of 1-[2-(4-aminophenyl)ethyl]-2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-

5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1_l2-a]pyrimidin-5-one in 1 mL of dichloromethane. After stirring for 3 hours at room température, the solvent is evaporated off. The residue is taken up in ethyl acetate and washed with water and with saturated aqueous NaCI solution. The organic phase is dried over magnésium sulfate and evaporated to dryness. The residue is purified by reverse-phase chromatography (RP18 column) (eluent: 50/50 H₂O/MeOH) to give 83 mg of 1-ethyl-3-(4-{2-[(1S,4S)-2-methyl-

7-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-5-oxo-2-((S)-trifluoromethyl)-2,3-dihydro-5Himidazo[1,2-a]pyrimidin-1-yl]ethyl)phenyl)urea, the characteristics of which are as follows:

LC/MS (method A): ESI+ [M+H]*: m/z 507 tr (min) = 0.6 ’H NMR (600 MHz, 8 in ppm, DMSO-d_e): 1.08 (t, 3H), 1.55 (s, 3H), 1.88 (m, 2H). 2.82 (m, 1H), 2.97 (m, 1H), 3.12 (m, 2H), 3.19 (m, 1H), 3.39 (d, 1H), 3.43 (m, 1H), 3.58 (m, 1 H), 3.7 (d, 1H), 3.78 (d, 1H), 3.82 (d, 1H), 4.12 (d, 1H), 4.58 (s, 1 H). 4.64 (s, 1H), 4.82 (bs, 1 H). 5.95 (m, 1H), 7.08 (d, 2H). 7.32 (d, 2H), 8.15 (s, 1H).

Example 16:

(8S)-9-[2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-oxoethyI]-217195 (1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9 tetrahydropyrimfdo[1,2-a]pyrimfdln-4-one (compound 38)

Step 16.1:1-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazln-7-yl)ethanone

The procedure used is the same as that of step 12.1.

800 mg (3.61 mmol) of 7-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine were used in the reaction. After purification by chromatography on silica gel (eluent: 90/10 DCM/MeOH), 320 mg of 1-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)ethanone were obtained, the characteristics of which are as follows:

LC/MS (method G): ESI+ [M+H]+: m/z 179 tr (min) = 0.66 ¹H NMR (300 MHz, 5 in ppm, CDCI₃): 2.42 (s, 3H), 3.47 (q, 2H), 4.12 (t, 2H), 7.3 (s, 1H),

7.77 (s, 1 H), 8.28 (s, 1H).

Step 16.2: 2-bromo-1-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7yljethanone hydrobromlde

The procedure used is the same as that of step 12.2.

320 mg (1.80 mmol) of 1-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)ethanone were used in the reaction. After précipitation with ethyl ether and filtration, 690 mg of 2bromo-1 -(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)ethanone hydrobromide are obtained, the characteristics of which are as follows:

LC/MS (method G): ESI+ [M+H]+: m/z 257 tr (min) =1.10 ¹H NMR (300 MHz, δ in ppm, CDCh): 3.57 (t, 2H), 4.23 (t, 2H), 4.78 (s, 2H), 7.55 (s, 1H),

8.38 (s, 1H), 8.5-9 (bs, 1H).

Step 16.3: (8S)-2-chloro-9-[2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-

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

The procedure used is the same as that of step 12.3.

200 mg (0.79 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9tetrahydropyrimido[1,2-aJpyrimidin-4-one and 319.86 mg (0.95 mmol) of 2-bromo-1-(3,4dihydro-2H-pyrido[3,2-b][1,4Joxazin-7-yl)ethanone hydrobromide were used In the reaction. After purification by chromatography on silica gel (eluent: 90/10 DCM/MeOH), 110 mg of (8S)-2-chloro-9-[2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-oxoethyl]-

8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-aJpyrimidin-4-one are obtained, the characteristics of which are as follows:

LC/MS (method G): ESI+ [M+H]+: m/z 430 tr (min) = 1.77 ¹H NMR (300 MHz, δ in ppm, CDCI₃): 2.27 (m, 1H), 2.44 (s, 1H), 3.17 (d, 1 H), 3.39 (m, 1H), 3.49 (s, 2H). 4.13 (m, 2H), 4.37 (m, 1H), 4.58-4.77 (m, 2H), 5.48 (d. 1H), 7.36 (s, 1H) 7.97 (s, 1H), 8.38 (s, 1H).

Step 16.4: (8S)-9-[2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2oxoethyl]-2-{1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9tetrahydropyrimldo[1,2-a]pyrimldin-4-one

The procedure used is the same as that of step 12.4.

110 mg (0.25 mmol) of (8S)-2-chloro-9-[2-(3,4-dihydro-2H-pyridoI3,2-

b][1,4]oxazin-7-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2a]pyrimidln-4-one and 41.64 mg (0.31 mmol) of (1 S,4S)-2-oxa-5azabicyclo[2.2.1]heptane hydrochloride were used In the réaction. After purification by passlng through an RP18 reverse-phase column (eluent: from 100% H₂O to 100% CHaCN over 30 minutes), 30 mg of (8S)-9-[2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7 yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows:

LC/MS (method A): ESI+ [M+H]+: m/z 493 tr (min) = 0.49 ¹H NMR (600 MHz, δ in ppm, DMSO-d_e): 1.65 (d, 1H), 1.72 (d, 1H), 2.25 (m, 1H), 2.4 (m, 1 H), 2.99 (m, 1 H), 3.13 (m, 1 H), 3.2 (m, 1 H), 3.26 (m, 2H), 3.49 (m, 2H), 4.13 (t, 2H) 4.36 (m, 1H), 4.41 (d, 1 H), 4.48 (d, 2H) 4.52 (m, 1H), 4.63 (s, 1H), 5.52 (d. 1 H). 7.36 (s, 1H),

7.57 (s, 1H), 8.37 (s, 1H).

Example 17:

(8S)-9-(2-benzo[1,2,3]thiadlazol-5-yl-2-oxoethyl)-2-(1S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrlmldo[1,2a]pyrlmldin-4-one (compound 47)

Step 17.1: N-methoxy-N-methylbenzo[1,2,3]thiadiazole-5-carboxamlde

The procedure used is the same as that of step 4.1.

500 mg (2.44 mmol) of benzo[1,2,3]thîadiazole-5-carbonyl chloride are used in the reaction. 620 mg of N-methoxy-N-methylbenzo[1,2,3]thiadiazole-5-carboxamide are obtained, the characteristics of which are as follows:

LC/MS (method G): ESI+ [M+H]+: m/z 224 tr (min) = 1.36 ¹H NMR (300 MHz, δ in ppm, CDCI₃): 3.34 (s, 3H), 3.57 (s, 3H), 7.99 (d, 1H), 8.5 (d, 1H),

8.9 (s, 1H).

Step 17.2:1-benzo[1,2,3]thIadlazol-5-ylethanone

The procedure used is the same as that of step 4.2.

620 mg (2.78 mmol) of N-methoxy-N-methylbenzo[1,2,3]thiadiazole-5-carboxamide were used In the reaction. The mixture Is basifîed with aqueous 1 N NaOH solution and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and evaporated to dryness to give 430 mg of 1-benzo[1,2,3]thiadiazol-5-ylethanone, corresponding to the following characteristics:

LC/MS (method G): ESI+ [M+H]+: m/z 224 tr (min) = 1.49 ’H NMR (300 MHz. δ in ppm, CDCb): 2.78 (s, 3H), 8.29 (d, 1H), 8.53 (d, 1H), 9.32 (s, 1H).

Step 17.3:1-benzof1.2.31thladlazol-5-vl-2-bromoethanone

The procedure used is the same as that of step 12.2.

430 mg (2.41 mmol) of 1-benzo[1,2,3]thiadiazol-5-ylethanone were used in the reaction. The reaction mixture is evaporated to dryness and taken up in dichloromethane. The organic phase is washed with aqueous NaHCOs solution and with saturated NaCI solution, dried and evaporated to dryness to give 300 mg of 1-benzo[1,2,3]thiadiazol-5yl'2-bromoethanone, corresponding to the following characteristics:

LC/MS (method G): ESI+ [M+H]+: m/z 257 tr (min) = 1.71 ’H NMR (300 MHz, δ in ppm, CDCb): 5.19 (s, 2H), 8.31 (d, 1H), 8.57 (d, 1H), 9.43 (s, 1H).

Step 17.4: (8S)-9-(2-benzo[1,2,3]thiadiazol-5-yl-2-oxoethyi)-2-chioro-8trif!uoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one

Cl

The procedure used is the same as that of step 12.3.

150 mg (0.59 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2a]pyrimidin-4-one and 167.25 mg (0.65 mmol) of 1-benzo[1,2,3]thiadiazol-5-yl-2bromoethanone were used in the reaction. After purification by chromatography on silica gel (eluent 90/10 DCM/MeOH), 210 mg of (8S)-9-(2-benzo[1,2,3]thiadiazo1-5-yl-2 oxoethyl)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as foilows:

LC/MS (method G): ESI+ [M+H]+: m/z 430 tr (min) = 2.29

Ή NMR (300 MHz, δ in ppm, CDC!₃): 2.32 (m, 1H), 2.42-2.62 (m, 2H), 3.36-3.48 (m, 1H),

4.42 (m, 1H), 4.8 (m, 1H), 5.14 (d, 1H), 5.76 (m, 1H), 8.35 (d, 1H), 8.61 (d, 1H), 9.51 (s, 1H).

Step 17.5: (8S)-9-(2-benzo[1 ^.SJthladlazol-S-yl-Z-oxoethyO-Z-fl S,4S)-2-oxa-

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

The procedure used is the same as that of step 12.4.

210 mg (0.49 mmol) of (8S)-9-(2-benzo[1,2,3]thiadiazol-5-yl-2-oxoethyl)-2-chloro-8trifluoromethyl-6,7,8,9-tetrahydropyrimido[1_l2-a]pyrimidin-4-one and 79.50 mg (0.58 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1Jheptane hydrochloride were used in the reaction. After purification by chromatography on silica gel (eluent: 60/40 DCM/MeOH), 100 mg of (8S)-9-(2-benzo[1,2,3]thiadiazol-5-yl-2-oxoethyl)-2-(1S₁4S)-2-oxa-5· azabîcyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7_l8,9-tetrahydropyrimido[1.2-a]pyrimidin4-one are obtained, the characteristics of which are as foilows:

LC/MS (method A): ESI+ [M+H]+: m/z 493 tr (min) = 0.64 ¹H NMR (600 MHz, δ in ppm, DMSO-de): 1.36-1.78 (bs, 2H), 2.27 (m, 1H), 2.45-2.5 (m, 2H), 2.75-3.25 (bs, 4H), 4.23-4.98 (bs, 6H), 5.9 (m, 1H), 8.34 (d, 1H), 8.58 (d, 1H). 9.5 (s, 1H).

Example 18:

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

Step_______18.1: (8S)-2-chloro-9-(1-methyl-1 H-indazol-3-ylmethyl)-8trifluoromethyl-6,7,8,9-tetrahydropyrlmido[1,2-a]pyrimldin-4-one

F

The procedure used is the same as that of step 12.3.

180 mg (0.71 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7_l8,9-tetrahydropyrimido[1,2a]pyrimidin-4-one and 145.39 mg (0.7Θ mmol) of 3-chloromethy1-1-methyl-1H-indazole were used in the reaction. After purification by chromatography on silica gel (eluent: 80/20 DCM/MeOH), 250 mg of (8S)-2-chloro-9-(1-methyl-1H-indazol-3-ylmethyl)-6trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin~4-one are obtained, the characteristics of which are as foilows:

LC/MS (method G): ESI+ [M+H]+: m/z 398 tr (min) = 2.2 ¹H NMR (300 MHz, δ in ppm, CDCb): 2.01 (m, 1H), 2.44 (m, 1H), 3.24-3.41 (m, 2H), 4.02 (s, 3H), 4.23 (m, 1H), 4.66 (d, 1H), 4.75 (m, 1H), 5.89 (d, 1 H), 7.15 (t, 1H), 7.42 (t, 1H),

7.62 (d, 1H), 7.84 (d, 1H).

Step 18.2: (8S)-9-(1 -methyl-1 H-lndazol-3-ylmethyl)-2-(1S,4S)-2-oxa-5azablcyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2a]pyrimidin-4-one

The procedure used is the same as that of step 12.4.

250 mg (0.63 mmol) of (8S)-2-chloro-9-(1-methyl-1H-indazol-3-ylmethyl)-8 trifluoromethyl-6,7,8,9-tetrahydropyrimido[1₎2-a]pyrimidin-4-one and 102.26 mg (0.75 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride were used in the reaction. After purification by chromatography on silica gel (eluent 60/40 DCM/MeOH), 230 mg of (8S)-9-(1-methyl-1H-indazol-3-ylmethyl)-2-(1S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7_l8,9-tetrahydropyrimîdo[1,2-a]pyrimidin4-one are obtained, the characteristics of which are as follows: LC/MS (method A): ESI+ [M+HJ+: m/z 461 tr (min) = 0.68

Ή NMR (600 MHz, δ in ppm, DMSO-de): 1.75 (m. 2H), 2.08 (m, 1H), 2.4 (d, 1 H), 2.6-3.3 (bs, 5H), 3.99 (s, 3H), 4.2 (m, 1H), 4.4-4.67 (t, 3H), 4.66-4.9 (bs. 2H), 5.89 (d, 1H), 7.11 (t, 1H), 7.39 (t. 1H), 7.58 (d, 1H). 7.73 (d, 1H).

Example 19: (8S)-9-[2-(2-cyclopropylmethoxypyrlmldin-5-yl)-2-oxoethyl]-2-{1S,4S)-2oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trlfluoromethyl-6,7,8,9-tetrahydropyrimido[1,2a]pyrimidin-4-one (compound 52)

F

Step 19.1: 5-bromo-2-cyclopropylmethoxypyrimldlne

A suspension of 607.92 mg (15.20 mmol) of sodium hydride in 50 mL of THF is prepared under argon. A solution of 1.10 g (15.20 mmol) of cyclopropanemethanol in 5 mL of THF is added dropwise. The mixture is stirred for 50 minutes at room température. 1 g (5.07 mmol) of 5-bromo-2-chloropyrimidine in 5 mL of THF is then added. The mixture Is stirred at room température ovemight. The réaction mixture is taken up in water and extracted with ethyl acetate. The organic phase is washed with aqueous NaHCO₃solution and with saturated aqueous NaCI solution, dried and evaporated to dryness to give 1.10 g of 5-bromo-2-cyclopropylmethoxypyrimidine, corresponding to the following characteristics:

LC/MS (method G): ESI+ [M+H]+: m/z 229 tr (min) = 2.06 ¹H NMR (300 MHz, S in ppm, CDCb): 0.33 (m, 2H), 0.55 (m, 2H). 1.23 (m, 1H), 4.12 (d,

2H), 8.74 (s, 2H).

Step 19.2: 2-cyclopropylmethoxy-5-(1 -ethoxyvinyljpyrimidine

The following are successively introduced into a microwave tube:

760 mg (3.32 mmol) of 5-bromo-2-cydopropy1methoxypyrimidine In 15 mL of dioxane, 1.36 mL (3.82 mmol) of tributyl(1-ethoxyvinyl)tin, 58.22 mg (0.08 mmol) of bis(tripheny1phosphine)palladium(ll) chloride, 1.12 g (7.30 mmol) of césium fluoride. This mixture is subjected to microwave irradiation at 110’C for 1 hour. The réaction mixture is evaporated to dryness and the residue is taken up In 100 mL of ethyl ether. A solution of 2.80 g of césium fluoride in 10 mL of water is added. After stirring for 1 hour at room température, the mixture is fïltered through Celite. The filtrate is washed with aqueous NaHCOs solution and then with saturated NaCi solution. The organic phase is dried over magnésium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 10/90 EtOAc/heptane) to give 480 mg of 2cyciopropylmethoxy-5-(1-ethoxyviny1)pyrimidine, the characteristics of which are as follows:

LC/MS (method G): ESI+ [M+H]+: m/z 221 tr (min) = 2.34 ’H NMR (300 MHz, δ in ppm, CDCh): 0.35 (m. 2H), 0.57 (m, 2H), 0.86 (m, 1H), 1.34 (t, 3H), 3.91 (q, 2H), 4.16 (d, 2H), 4.35 (s, 1H), 4.85 (s, 1H), 8.78 (s, 2H).

Step 19.3: 2-bromo-1-(2-cycîopropyîmethoxypyrimidin-5-yî)ethanone

A solution of 480 mg (2.18 mmol) of 2-cyclopropylmethoxy-5-(1ethoxyvinyl)pyrimidine in 8 mL of a THF/H₂O mixture: (6/2: v/v) is cooled to 0’C under argon. After addition of 380.02 mg (2.11 mmol) of N-bromosuccinimide, the reaction mixture is maintained at 0°C for 1 hour. The solution obtained is taken up in ethyl acetate and washed with aqueous NaHCOs solution and then with saturated NaCi solution. The organic phase is dried over magnésium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 80/20 DCM/MeOH) to give 410 mg of

2-bromo-1-(2-cyciopropylmethoxypyrimidin-5-yl)ethanone_l the characteristics of which are as follows:

LC/MS (method G): ESI+ [M+HJ+: m/z 271 tr (min) « 1.87 ’H NMR (300 MHz, δ in ppm, CDCh): 0.38 (m, 2H), 0.58 (m, 2H), 1.29 (m, 1H), 4.27 (d, 2H), 4.94 (s, 2H), 9.15 (s, 2H).

Step 19.4: (8S)-2-chloro-9-[2-(2-cyclopropylmethoxypyrimidln-5-yl)-2oxoethy!]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimldo[1,2-a]pyrimidin-4-one

The procedure used is the same as that of step 12.3.

180 mg (0.71 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2a]pyrimîdin-4-one and 211.66 mg (0.78 mmol) of 2-bromo-1-(2cyclopropylmethoxypyrimidin-5-yl)ethanone were used in the reaction. After purification by chromatography on silica gel (eluent: 80/20 DCM/MeOH), 160 mg of (8S)-2-chloro-9[2-(2-cyclopropylmethoxypyrimidin-5-yl)-2-oxoethylI-8-trifluoromethyl-6,7,8,9tetrahydropyrimido[1,2-alpyrimîdin-4-one are obtained, the characteristics of which are as follows:

LC/MS (method G): ESI+ [M+HJ+: m/z 444 tr (min) = 2.33 ¹H NMR (300 MHz, δ in ppm, CDCh): 0.38 (m, 2H), 0.58 (m, 2H), 1.30 (m, 1H), 2.25 (m,

1H), 2.51 (m, 1 H). 3.35 (m, 2H), 4.28 (d, 2H), 4.50 (m, 1H), 4.70 (m, 1H), 4.90 (d, 1H),

5.53 (d, 1 H), 9.21 (s, 2H).

Step 19.5: (8S)-9-[2-(2-cyciopropylmethoxypyrimldln-5-yl)-2-oxoethyl]-2(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9tetrahydropyrimldo[1,2-a]pyrimidin-4-one

N

The procedure used is the same as that of step 12.4.

160 mg (0.36 mmol) of (8S)-2-chloro-9-[2-(2-cyclopropylmethoxypyrimidin-5-yl)-2oxoethyll-e-trifluoromethyl-e.T.e.g-tetrahydropyrimidoIl ,2-a]pyrimidin-4-one and 58.66 mg (0.43 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride were used in the reaction. After purification by chromatography on silica gel (eluent: 60/40 DCM/MeOH), 125 mg of (8S)-9-[2-(2-cyciopropyimethoxypyrimidin-5-yl)-2-oxoethyl]-2(1S,4S)-2-oxa-5-azabicycio[2.2.1]hept-5-yl-8-trifluoromethyl-6_l7,8_I9tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characterlstics of which are as follows:

LC/MS (method A): ESI+ [M+H]+: m/z 507 tr (min) = 0.65 ¹H NMR spectrum (600 MHz, 8 in ppm, DMSO-d_e): 0.38 (m, 2H). 0.6 (m, 2H), 1.30 (m, 1H), 1.54-1.76 (m, 2H), 2.21 (m, 1H), 2.44 (m, 1H), 2.72-3.9 (bs, 5H), 4.28 (d, 2H), 4.31-

4.98 (m, 6H), 5.67 (m, 1H), 9.22 (s, 2H).

Example 20:

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

Step 20.1:2-methyl-2H-pyrazole-3-carbonyl chloride

A suspension of 800 mg (6.03 mmol) of 2-methy1-2H-pyrazoie-3-carboxylic acid In 30 mL of DCM is placed under argon and cooled to 0’C. When the température is reached, 1.32 mL (15.07 mmol) of oxalyl chloride and a catalytic amount of DMF are added. The reaction mixture is stirred at room température for 2 hours and then evaporated to dryness and the residue is taken up in DCM and evaporated again to give 850 mg of 2-methyl-2H-pyrazoie-3-carbonyl chloride, the characteristics of which are as follows:

¹H NMR (300 MHz, δ in ppm, CDCIs): 4.10 (s, 3H), 6.82 (s, 1 H), 7.50 (s, 1H).

Step 20.2: N-methoxy-N-methy1*2-methy1-2H*pyrazo1e*3-carboxamide

The procedure used is the same as that of step 4.1.

850 mg (5.88 mmol) of 2-methyl-2H-pyrazole-3-carbonyl chloride are used in the reaction. 890 mg of N-methoxy-N-methylbenzo[1,2.3]thiadiazole-5-carboxamide are obtained, the characteristics of which are as follows:

LC/MS (method G): ES1+ [M+HJ+: m/z 170 tr (min) = 1.03 ’H NMR (300 MHz, δ in ppm, CDCI₃): 3.27 (s, 3H), 3.63 (s, 3H), 3.96 (s, 3H), 6.71 (s, 1H), 7.5 (s, 1 H).

Step 20.3:1-{2-methy1-2H*pyrazol*3-y1)ethanone

The procedure used is the same as that of step 4.2.

890 mg (2.78 mmol) of N-methoxy-N-methylbenzo[1,2,3]thiadiazole-5-carboxamide were used in the reaction. The mixture is taken up in water and a few drops of 1 N HCl, basified with aqueous 1 N NaOH solution and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and evaporated to dryness to give 570 mg of 1(2-methyl-2H-pyrazol-3-yl)ethanone, corresponding to the following characteristics: LC/MS (method G): ESI+ [M+HJ+: m/z 125 tr (min) = 0.93 ’H NMR (300 MHz, δ in ppm, CDCI₃): 2.5 (s, 3H) 4.04 (s, 3H) 7.13 (s, 1H) 7.53 (s, 1H)

Step 20.4:1-{2-methyl-2H-pyrazol-3-yl)ethanone hydrobromlde

The procedure used is the same as that of step 12.2.

550 mg (4.43 mmol) of 1-(2-methyl-2H-pyrazol-3-yl)ethanone were used in the reaction. The precipitate corresponding to 1-(2-methyl-2H-pyrazol-3-yl)ethanone hydrobromide is filtered off, washed with ethyl ether and dried. The 1.15 g of product obtained hâve the following characteristics:

LC/MS (method G): ESI+ [M+H]+: m/z 203 tr (min) = 1.19 ’H NMR (300 MHz, δ in ppm, CDCh): 4.78 (s, 2H), 7.19 (s, 1H), 7,56 (s, 1H).

Step 20.5:

(8S)-2-chloro-9-[2-(2*rnethyl-2H-pyrazol-3-yl)-2-oxoethyl]-8-

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

The procedure used is the same as that of step 12.3.

180 mg (0.71 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9tetrahydropyrimido[1,2-aJpyrimidin-4-one and 262 mg (0.92 mmol) of 1-(2-methyl-2Hpyrazol-3-yl)ethanone hydrobromide were used in the reaction. After purification by chromatography on silica gel (eluent: 80/20 DCM/MeOH), 230 mg of (8S)-2-chloro-9-[2(2-methyl-2H-pyrazol-3-yl)-2-oxoethyl]-8-trifluoromethyl-6_l7,8_l9-tetrahydropyrimidoI1,2a]pyrimidin-4-one are obtained, the characteristics of which are as follows: LC/MS (method G): ESI+ [M+H]+: m/z 376 tr (min) = 1.98

Ή NMR (300 MHz, δ in ppm, CDCh): 2.28 (m, 1 H), 3.4 (m, 2H), 4.06 (s, 3H), 4.39 (m,

1H), 4.66-4.84 (m, 2H), 5.41 (d, 1H), 5.96 (s, 1H), 7.36 (s, 1H), 7.63 (s, 1H).

Step 20.6: (8S)-9-[2-(2-methyl-2H-pyrazol-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-

5-azablcyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimldo[1,2a]pyrimldin-4-one

The procedure used Is the same as that of step 12.4.

230 mg (0.61 mmol) of (8S)-2-chloro-9-[2-(2-methyl-2H-pyrazol-3-yl)-2-oxoethyl]-8trifluoromethyl-6,7_l8,9'tetrahydropyrimido[1_l2-a]pyrimidin-4-one and 107.90 mg (0.79 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride were used in the reaction. After purification by chromatography on silica gel (eluent 60/40 DCM/MeOH), 160 mg of (8S)-9-[2-(2-methyl-2H-pyrazol-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5θζβ^^οΙορ^.ΙΙΚβρί-δ-^-δ-ίπΑυοΓΟΓηβΙΐΊνΙ-βΛΘ,θ-ΙβίΓθ^^Γορ^ΓηΜοΠ^-θΐρ^ητΜίη4-one are obtained, the characteristics of which are as follows: LC/MS (method A): ESI+ [M+HJ+: m/z 439 tr (min) = 0.54

Ή NMR (600 MHz, δ in ppm, DMSO-d_e): 1.48-1.8 (bs. 2H), 2.22 (m, 1H), 2.43 (d. 1H),

2.66-3.26 (bs, 5H), 4 (s, 3H), 4.28-4.88 (bs, 6H), 5.5 (d, 1H), 7.42 (s, 1H), 7.59 (s, 1H).

Exampîe 21:

ethyl (5-[2-((S)8-(1S,4S)-2-oxa-5-azablcyclo[2.2.1]hept-5-yl-6-oxo-2trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetyl]pyrld-2yljcarbamate (compound 57)

Step 21.1; 1-(6*aminopyrid-3-yl)ethanone

g (11.57 mmol) of 1-(6-chloropyrid-3-y!)ethanone and 70 mL of ammonium hydroxide are placed in a Part reactor. The solution ts heated at 130°C ovemight. The mixture obtained is evaporated to dryness, and the residue is taken up in ethyl acetate and washed with water and with saturated NaCI solution. The organic phase is dried over sodium sulfate and evaporated to dryness to give 1.14 g of 1-(6-aminopyrid-3yljethanone, the characteristics of which are as follows: LC/MS (method G): ESI+ [M+H]+: m/z 137 tr (min) = 0.35 ¹H NMR (300 MHz, δ in ppm, CDCb): 2.41 (s, 3H), 6.45 (d, 1H), 6.88 (s, 2H), 7.86 (d, 1H), 8.58 (s, 1H).

Step 21.2: 2-bromo-1 -(6-amlnopyrld-3-yl)ethanone

The procedure used is the same as that of step 12.2.

1.14 g (8.37 mmol) of 1-(6-aminopyrid-3-yl)ethanone were used in the reaction. The reaction mixture is taken up in dichloromethane. The organic phase is washed with aqueous K2CO3 solution and with saturated NaCI solution, dried and evaporated to dryness. After purification by chromatography on silica gel (eluent 60/40 DCM/EtOAc),

530 mg of 2-bromo-1-(6-chloropyrid-3-yl)ethanone are obtained, the characteristics of which are as foilows:

LC/MS (method G): ESI+ [M+HJ+: m/z 215 tr (min) = 0.44 ’H NMR (300 MHz, δ in ppm, CDCh): 4.70 (s, 2H), 6.47 (d, 1H), 7.08 (s, 2H), 7.89 (d, 1H), 8.64 (s, 1H).

Step 21.3: (8S)-9-[2-(6-aminopyrid-3-yl)-2-oxoethy|]-2-(1 S,4S)-2-oxa-5azabicycio[2.2.1]hept-5-yl-8-trifluoromethyl'6,7,8,9-tetrahydropyrimldo[1,2· a]pyrimidin-4-one

500 mg (1.58 mmol) of (8S)-2-(1S,4S)-2-oxa-5-azablcyclo[2.2.1]hept-5-yl-8trif!uoromethyl-6,7_t8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 10 mL of DMF are added to a suspension of 69.55 mg (1.74 mmol) of sodium hydride in 10 mL of DMF. The reaction mixture is piaced under magnetic stirring at room température for 15 minutes. A solution of 373.96 mg (1.74 mmol) of 2-bromo-1-(6-chloropyrid-3-yl)ethanone in 5 mL of DMF is added dropwîse to the reaction medium. The reaction is stirred at room température for 2 hours. The reaction medium is taken up in methanol and evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 60/40 EtOAc/MeOH) to give 530 mg of (8S)-9-[2-(6-aminopyrid-3-yl)-2-oxoethylJ-2-(1S,4S)-2oxa-5-azabîcyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8_l9-tetrahydropyrimido[1,2a]pyrimidin-4-one, the characteristics of which are as foilows: LC/MS (method A): ESI+ [M+HJ+: m/z 451 tr (min) = 0.38 ¹H NMR (600 MHz, δ in ppm, CDCh): 1.5-1.81 (m, 2H), 2.23 (m, 1H), 2.41 (m, 1H), 2.74-

3.33 (bs, 5H), 4.23-4.76 (m, 6H), 5.6 (d, 1H), 6.47 (d, 1H), 6.97 (s, 2H), 7.92 (d, 1H) 8.71 (s, 1H).

Step 21.4: ethyl {5-[2-((S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yi-6oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-aJpyrimidln-l yl)acetyl]pyrld-2-yl}carbamate

168 μΙ (1 mmol) of Ν,Ν-diisopropylethylamine and 65 μΙ (0.66 mmol) of ethyl chloroformate are added to a solution of 150 mg (0.33 mmol) of (8S)-9-[2-(6-aminopyrid-

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

The heterogeneous mixture is stirred at room température for 15 minutes. The solution Is taken up in DCM and washed with water and with saturated NaCI solution. The organic phase is dried over sodium sulfate and evaporated to dryness. The residue is dissolved In 10 mL of éthanol, and aqueous 1 N NaOH solution is added. The mixture is stirred for 30 minutes at room température and then evaporated to dryness. The crude product is taken up in ethyl acetate and washed with water and with saturated NaCI solution. The organic phase is dried over sodium sulfate and evaporated to dryness. After purification by chromatography on silica gel (eluent: 60/40 DCM/MeOH), 120 mg of ethyl (5-[2-((S)8-( 1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro2H_l6H-pyrimido[1,2-a]pyrimidin-1-yl)acetyl]pyrid-2-y1}carbamate are obtained, the characteristics of which are as follows:

LC/MS (method A): ESI+ [M+H]+: m/z 523 tr (min) = 0.6

Ή NMR (600 MHz, δ in ppm, DMSO-de): 1.27 (t, 3H), 1.61 (s, 1H), 1.7 (d, 1 H), 2.24 (m, 1H), 2.44 (d, 1H), 2.57-3.17 (bs, 3H), 3.24 (m, 2H), 4.2 (q, 2H), 4.29-4.52 (m, 3H), 4.59 (m, 3H), 5.69 (d, 1H), 7.98 (d, 1H), 8.36 (d, 1H), 8.97 (s, 1H), 10.62 (s, 1H).

Example 22:

(8S)-2-(8-oxa-3-azablcyclop.2.1]oct-3-yl)-9-(3-phenylpropyl)-8trifîuoromethyl-6_l7,8,9-tetrahydropyrimldo[1,2-a]pyrlmldin-4-one (compound 84)

Step 22.1: (8S)-2-(8-oxa-3-azablcyclo[3.2.1]oct-3-yl)-8-trlfluoromethyi17195

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

500 mg (1.97 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9tetrahydropyrimido[1,2-a]pyrimidin-4-one, 884 mg (5.91 mmol) of 8-oxa-3azabicyclo[3.2.1]octane and 820 pl (5.91 mmol) of triethylamine are placed in a microwave tube. The mixture is Irradiated for 10 minutes at 150'C. The reaction medium is purified directly by passing through an RP18 reverse-phase column (eluent: H₂O: 100% to CHsCN: 100%) to give 600 mg of (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:

LC/MS (method A): ESI+ [M+HJ+: mlz 331 tr (min) = 0.53 ¹H NMR (600 MHz, δ in ppm, DMSO-de): 1.66 (m, 2H). 1.81 (m, 2H), 2.09 (m, 1H), 2.2 (m, 1H). 2.89 (d. 2H), 3.34 (m, 1H), 3.75 (m, 2H), 4.14 (m. 1H), 4.26 (s, 1H), 4.37 (s, 2H),

4.84 (s, 1H), 8.17 (s, 1 H).

Step 22.2: (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(3-phenylpropyl)-8trlfluoromethyl-ej.e.S-tetrahydropyrimldotl^-alpyrlmldirM-one

A solution of 200 mg (0.61 mmol) of (8S)-2-(8-oxa-3-azabicycloI3.2.1]oct-3-yl)-8trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 790 mg (2.42 mmol) of césium carbonate in 10 mL of DMF is heated at 90’C for 10 minutes. After addition of 600 μΐ (1.21 mmol) of (3-bromopropyl)benzene, the reaction is continued for 2 hours at 90’C. The solvent is evaporated off, The residue is purified by RP18 reversephase chromatography (eluent: H₂O 100% to CH3CN 100%) to give 100 mg of (8S)-2(8-oxa-3-azabicycloI3.2.1]oct-3-yl)-9-(3-phenylpropyl)-8-trifluoromethyl-6,7,8,9tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:

» «

LC/MS (method B): ESI+ [M+HJ+: m/z 449 tr (min) = 0.85 ¹H NMR (600 MHz, δ in ppm, DMSO-de): 1.57 (m, 2H), 1.79 (m, 3H), 2 (m, 2H), 2.31 (d, 1H), 2.62 (m, 2H), 2.8 (d, 2H), 3.13 (m, 2H), 3.53 (m, 2H), 3.94 (m. 1H). 4.15 (m, 1H),

4.31 (s, 2H), 4.62 (m, 1H), 4.82 (s, 1 H), 7.18 (m, 3H), 7.27 (m, 2H).

Example 23:

(8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yi)-9-(2-oxo-2-pyrid-4-yiethyi)-8trifluoromethyi-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (compound 75)

F

A solution of 200 mg (0.61 mmol) of (8S)-2-(8-oxa-3-azabîcyc!o[3.2.1]oct-3-yl)-8trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 1.18 g (3.63 mmol) of césium carbonate in 10 mL of DMF is heated at 90’C for 10 minutes. The mixture is cooled to 0’C and 340 mg (1.21 mmol) of 2-bromo-1-pyrid-4-ylethanone are then added. The reaction is continued for 2 hours at room température. The solvent is evaporated off. The residue is purified by chromatography on a coiumn of silica (eluent: 90/10 DCM/MeOH). The isolated fraction is recrystallized from acetonitrile to give 16 mg of (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-pyrid-4-ylethyl)-8-trifluoromethyl-

LC/MS (method B): ESI+ [M+H]+: m/z 450 tr (min) = 0.55 ’H NMR (600 MHz, δ in ppm, DMSO-de): 1.32 (m, 1H) 1.5 (m, 1H) 1.62 (m, 2H) 2.2 (m, 1H) 2.42 (d, 1H) 2.51 (d, 1H) 2.69 (d, 1H) 3.2 (m, 1H) 3.38 (d, 2H) 4.05 (d, 2H) 4.31 (d, 1H) 4.61 (m, 1H) 4.85 (s, 2H) 5.45 (d, 1H) 7.89 (s, 2H) 8.85 (s, 2H)

Example 24:

(8S)-9-((S)-2-hydroxy-2-phenylethyl)-2-(8-oxa*3*azabicyclo[3.2.1]oct*3-yi)8-trif1uoromethyl-6,7,8,9-tetrahydropyrlmldo[1,2-a]pyrlmldln-4-one (compound 80) ο

F

200 mg (0.61 mmol) of (8S)-2-(8-oxa-3-azabicycloî3.2.1]oct-3-yl)-8trifluoromethyl-6_l7_l8,9’tetrahydropyrimidoi1,2-a]pyrimidin-4-one in 5 mL of DMF are added to a suspension of 60 mg (1.51 mmol) of sodium hydride in 5 mL of DMF. The reaction mixture is heated at 50*C for 10 minutes. After addition of 142 mg (0.91 mmol) of (S)-2-chloro-1-phenylethanol, the reaction is continued at 90’C ovemight. The reaction medium is evaporated to dryness. The residue is purified by chromatography on a column of silica (eluent: 90/10 DCM/MeOH). The isolated fraction is recrystallized from acetonitrile to give 33 mg of (8S)-9-((S)-2-hydroxy-2-phenylethyl)-2-(8-oxa-3azabicyclo[3.2.1]oct-3-yi)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4one, the characteristics of which are as follows:

LC/MS (method B): ESI+ [M+HJ+: m/z 451 tr (min) = 0.68 ¹H NMR (600 MHz, δ in ppm, DMSO-d_e): 1.70 (m, 2H) 1.84 (m, 2H) 2.25 (m, 1H) 2.4 (m, 1H) 3.02 (m, 3H) 3.2 (m, 1H) 3.77 (m, 2H) 4.26 (m, 2H) 4.41 (s, 2H) 4.80 (m, 1H) 4.92 (s, 1H) 5.01 (m, 1H) 5.71 (d, 1H) 7.37 (m, 5H)

Example 25:

(8S)-9-[2-{6'<fi^methylaminopyrld-3’yl)-2-oxoethyl]’2-{1S,4S)-2-oxa-5azabicyclo[2.2.1Jhept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2a]pyrimidin-4-one (compound 6)

Step 25.1:1-{G-dimethylaminopyrid-3-yl)ethanone

I

500 mg (2.89 mmol) of 1-(6-chioropyrid-3-yl)ethanone, 2 mL of éthanol and 7.23 mL (14.46 mmol) of 2 M dimethylamine in tetrahydrofuran are placed in a 20 mL microwave reactor. The solution is irradiated with microwaves for 10 minutes at 130’C. The mixture obtained is taken up in water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated to dryness to give 470 mg of 1-(6dimethylaminopyrid-3-yl)ethanone, the characteristics of which are as follows:

’H NMR (300 MHz, δ in ppm, CDCh): 2.44 (s, 3H), 3.12 (s, 6H), 6.68 (d, 1H), 7.96 (d, 1H), 8.72 (s, 1H).

Step 25.2: 2-bromo-1-(6-dlmethylamlnopyrld-3-yl)ethanone hydrobromide

The procedure used is the same as that of step 12.2.

514 mg (3.13 mmol) of 1-(e-dimethylaminopyrid-3-yl)ethanone were used in the reaction. The precipitate corresponding to 2-bromo-1-(6-dimethy1aminopyrid-3-yl)ethanone hydrobromide is fïltered off, washed with ether and dried. The 950 mg of product obtained hâve the following characteristics:

’H NMR (300 MHz, δ in ppm, CDCh): 3.22 (s, 6H), 4.80 (s, 2H), 6.95 (d, 1H), 8.10 (d, 1H), 8.68 (s, 1H).

Step 25.3: (8S)-9-[2*(6-dimethyiamlnopyrld-3-yl)-2-oxoethyl]*2*(1S_l4S)-2oxa-5-azabicyclo[2.2.1]hept-5-yi-8-trif1uoromethyl-6,7,8,9-tetrahydropyrimido[1,2a]pyrimidln-4*one

100 mg (0.32 mmol) of (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8trifluoromethyl-6_l7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 2 mL of DMF are added to a suspension of 13.91 mg (0.35 mmol) of sodium hydride in 3 mL of DMF. The reaction mixture is placed under magnetic stirring at room température for 15 minutes. A solution of 84.55 mg (0.35 mmol) of 2-bromo-1-(6-dimethylaminopyrid-3-yl)ethanone in 5 mL of DMF is added dropwise to the reaction medium. The reaction is stirred at room température for 5 minutes. The reaction medium is taken up in éthanol and evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 DCM/MeOH) to give 34 mg of (8S)-9-[2-(6-dimethylaminopyrid-3-yl)-2-oxoethyl]-2(1S, 4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifIuoromethyl-6,7,8,9tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows: LC/MS (method A): ESI+ [M+H]+: m/z 479 tr (min) = 0.48 ’H NMR (600 MHz, δ In ppm, DMSO-de): 1.62 (bs, 1 H), 1.73 (d, 1H), 2.24 (m, 1H), 2.42 (m, 1H), 2.66-3.27 (m, 11 H), 4.05-4.96 (m, 6H), 5.63 (d, 1H), 6.71 (d, 1H), 8.03 (d, 1H),

8.83 (s, 1H).

Example 26: (8S)-9-(3,3-dimethyl·2-oxobutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept·5· yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (compound 29)

Step 26.1: (eSFZ-chloro-S-p.S-dimethyl^-oxobutyO-S-trifluoromethyl·

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

F

The procedure used is the same as that of step 12.3.

150 mg (0.591 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2a]pyrimidin-4-one, 578.71 mg (1.77 mmol) of césium carbonate, 99 μΙ (0.709 mmol) of

1- bromoplnacolone and 10 mL of acetonitrile were used in the reaction. After purification by chromatography on silica gel (eluent A/B: DCM/MeOH, gradient A/B: 10 min 0% B, t 12 min 4% B, 115 min 4% B, 130 min 10% B), 188 mg of (8S)-2-chloro-9-(3,3-dimethyl-

2- oxobuty l)-8-trifIuoromethy I-6,7,8,9-tetrahyd ropy rimido[1,2-a] py ri midin-4-οπ e were obtained, corresponding to the following characteristics:

LC/MS (method G): ESI+ [M+H]+: m/z 352 tr (min) = 2.38 ’H NMR (300 MHz, δ in ppm, DMSO-d_a): 1.17 (s, 9H), 2.20 (m,1H), 2.45 (m, 1H), 3.25 (m, 2H), 4.35 (d, 1H), 4.63 (m, 1 H). 5.05 (d, 1 H). 5.92 (s, 1H).

Step 26.2: (8S)-9-(3,3-dimethyl-2-oxobutyl)-2-(1 S,4S)-2-oxa-5azablcyclop.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2a]pyrimldin-4-one

The procedure used is the same as that of step 12.4.

180 mg (0.511 mmol) of (8S)-2-chloro-9-(3,3-dimethyl-2-oxobutyl)-8-trifluoromethyl-

6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, 76.32 mg (0.563 mmol) of (1S,4S)-2oxa-5-azabicyclo[2.2.1]heptane hydrochloride and 179 pl (1.28 mmol) of triethylamine were used in the reaction. After purification by chromatography on silica gel (eluent A/B: DCM/MeOH, gradient A/B: 10 min 0% B, 115 min 4% B, 118 min 4% B, t 33 min 10% B), 130 mg of (8S)-9-(3,3-dimethyl-2-oxobutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-

5-yl-8-trifIuoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one were obtained, corresponding to the following characteristics:

LC/MS (method A): ESI+ [M+H]+: m/z 415 tr (min) = 0.67 ¹H NMR (600 MHz, δ in ppm, DMSO-d_e): 1.15 (s, 9H), 1.80 (m, 2H), 2.22 (m, 1H), 2.37 (m, 1H), 3.13 (m, 1H), 3.25 (m, 2H), 3.52 (m, 1H), 3.65 (m, 1H), 4.25 (d, 1H), 4.34 (m, 2H), 4.58 (m, 1 H), 4.67 (m, 2H), 5.32 (d, 1H).

Example 27:

(8S)-2-(1S,4S)-2-oxa-5-azablcyclo[2.2.1]hept-5-yl-9-(2-oxo-2-pyrid-4ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimldin-4-one (compound 2)

F

Step 27.1: (8S)-2-chloro-9-(2-oxo-2-pyrid-4-ylethyl)-8-trifluoromethyl·

6,7,8,9-tetrahydropyrim ido[1,2-a] py rim I di n-4-one

The procedure used is the same as that of step 12.3.

g (3.94 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2a]pyrimidin-4-one, 3.85 g (11.83 mmol) of césium carbonate, 1.33 g (4.73 mmol) of 2bromo-1-pyrid-4-ylethanone hydrobromide and 100 mL of acetonitrile were used in the reaction. After purification by chromatography on silica gel (eluent A/B: heptane/EtOAc, gradient A/B: t 0 min 60% B, t 25 min 100% B, t 30 min 100% B), 804 mg of (8S)-2chloro-9-(2-oxo-2-pyrid-4-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2a]pyrimidin-4-one were obtained, corresponding to the following characteristics: LC/MS (method G): ESI+ [M+H]+: m/z 373 tr (min) = 1.77 ’H NMR (300 MHz. δ in ppm, DMSO-de): 2.28 (m, IH), 3.36 (m, 2H), 4.40 (m, 1H), 4.73 (m. 1H). 4.98 (d, IH), 5.54 (d. 1H), 5.95 (s, 1H), 7.92 (m, 2H), 8.87 (m, 2H).

Step 27.2: (8S)-2-(1 S,4S)-2-oxa-5-azablcyclo[2.2.1]hept-5-yl-9-(2-oxo-2pyrid-4-ylethyi)-8-trifluororïiethyi-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidln-4one

The procedure used is the same as that of step 12.4.

250 mg (0.67 mmol) of (8S)-2-chloro-9’(2Oxo-2-pyrid-4-ylethyl)-8-trifluoromethyl-

6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, 109 mg (0.80 mmol) of (1S,4S)-2-oxa5-azabicyclo[2.2.1]heptane hydrochloride and 230 μΙ (1.68 mmol) of triethylamine were used in the reaction. After purification by chromatography on silica gel (eluent A/B: DCM/MeOH, gradient A/B: 10 min 0% B, 125 min 10% B, 130 min 10%) 230 mg of (8S)-

2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-oxo-2-pyrid-4-ylethyl)-8trifluoromethyl-e.T.e^tetrahydropyrimidoIl^-aJpyrimidin^l-one were obtained, corresponding to the following characteristics:

LC/MS (method A): ESI+ [M+HJ+: m/z 436 tr (min) = 0.50 ’H NMR (600 MHz, δ in ppm, DMSO-d_e): 1.65 (m, 1H), 1.72 (m, 1H), 2.25 (m, 1H), 2.45

100 (m, 1 H). 3.00 (m, 1H), 3.10 (m, 1H), 3.20 (m, 1H>, 3.30 (m, 2H), 4.38 (m, 1 H), 4.42 (m, 1H), 4.48 (m, 1H), 4.62 (m, 1H), 4.37 (m, 1 H), 4.75 (d, 1H), 5.58 (d, 1H). 7.88 (m, 2H),

8.85 (m, 2H).

Example 28:

(8S)-9-[2-(6-<nethylpyrid-3-yl)-2-oxoethyl]-2-{1S,4S)-2-oxa-5azabicyclo[2.2.1]hept*5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2

a]pyrimidin-4-one (compound 4)

Step 28.1:

2-bromo-1 -{6-<nethylpyrid-3-yl)ethanone hydrobromide

The procedure used is the same as that of step 12.2.

500 mg (3.59 mmol) of 1-(6-methylpyrid-3-yl)ethanone, 590 pl (3.59 mmol) of hydrobromic acid, 204 μΙ (3.95 mmol) of bromine and 10 mL of glacial acetic acid were used in the reaction. After précipitation with ethyl ether and filtration, 1.02 g of 2-bromo-

1-(6-methylpyrid-3-yl)ethanone hydrobromide are obtained, the characteristics of which are as follows:

LC/MS (method G): ESI+ [M+H]+: m/z 214 tr (min) = 1.00

Step______28.2: (8S)-2-chloro-9-[2-(6-fnethylpyrid-3-yl)-2-oxoethyl]-8trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimÎdin-4-one

g (3.94 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2a]pyrimidin-4-one is added to a suspension of 394.27 mg (9.86 mmol) of sodium hydride

101 in 40 mL of DMF. The reaction mixture is placed under magnetic stirring at room température for 15 minutes. A solution of 1.16 g (3.94 mmol) of 2-bromo-1-(6methylpyrid-3-yl)ethanone hydrobromide in 10 mL of DMF is added dropwise to the reaction medium at 0*C. The reaction is stined at room température ovemight. The reaction medium is evaporated to dryness. The crude product is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: heptane/EtOAc, gradient A/B: 10 min 30% B, 135 min 60% B, 140 min 60% B), 480 mg of (8S)-2-chloro-9-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9tetrahydropyrimido[1,2-a]pyrimidin-4-one were obtained, corresponding to the following characteristics:

LC/MS (method G): ESI+ [M+H]+: m/z 387 tr (min) = 1.85 ’H NMR (300 MHz, δ in ppm, DMSO-d_e); 2.30 (m, 1H), 2.58 (s. 3H), 3.29 (m, 2H), 4.40 (m, 1H), 4.75 (m, 1H), 4.93 (d, 1H). 5.55 (d, 1H), 5.94 (s, 1H), 7.46 (m, 1H), 8.26 (m. 1H), 9.09 (m, 1H).

Step 28.3: (8S)-9-[2-(6-methylpyrld-3-yl)-2-oxoethyl]-2-{1 S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trlfluoromethyl-6,7,8_l9-tetrahydropyrimldo[1,2a]pyrimidln-4-one

The procedure used is the same as that of step 12.4.

480 mg (1.24 mmol) of (8S)-2-chloro-9-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-8trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, 201.94 mg (1.49 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride and 313.97 mg (3.10 mmol) of triethylamine were used in the reaction. After purification by chromatography on silica gel (eluent A/B: heptane/EtOAc, gradient A/B: 10 min 30% B, 135 min 60% B, 140 min 60% B), 335 mg of (8S)-9-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5azabicyclo[2.2.1Jhept-5-y1-8-trifluoromethy1-6,7,8,9-tetrahydropyrimido[1,2-alpyrimidin-

4-one were obtained, corresponding to the following characteristics: LC/MS (method A): ESI+ [M+HJ+: m/z 450 tr (min) = 0,49 ’H NMR (600 MHz, δ in ppm, DMSO-de): 1.65 (m, 2H), 2.30 (m, 1H), 2.42 (m, 1 H). 2.55

102 (s, 3H), 2.70-3.10 (bs, 3H), 3.20 (m, 2H), 4.40 (m, 3H), 4.65 (m, 3H), 5.70 (m, 1H), 7.49 (m, 1H), 8.30 (m, 1H), 9.10 (m, 1H).

Example 29:

2-methyl-1 -[2-(6-methyl pyrld-3-yl)-2-oxoethyl]-7-( 1 S,4S)-2-oxa-5azablcyclop.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-lmldazo[1,2a]pyrimidin-5-one (compound 17)

F

Step 29.1: (S)-7-chloro-2-methyl-1-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-2trifluoromethyl-2,3-dihydro-1H-Imidazo[1,2-a]pyrimidIn-5-one a

500 mg (1.97 mmo!) of (S)-7-chloro-2-methyl-2-trifluoromethy!-2,3-dihydro-1Himidazo[1,2-a]pyrimidin-5-one are added to a suspension of 141.94 mg (5.91 mmol) of sodium hydride in 20 mL of DMF. The reaction mixture is placed under magnetic stirring at room température for 15 minutes. A solution of 872.32 mg (2.96 mmol) of 2-bromo-1(6-methylpyrid-3-yl)ethanone hydrobromide in 10 mL of DMF ls added dropwise to the reaction medium at 0’C. The reaction is stirred at room température ovemight. The reaction medium is evaporated to dryness. The crude product is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: heptane/EtOAc, gradient A/B: 10 min 30% B, 135 min 60% B, 140 min 60% B), 150 mg of (S)-7-chloro-2-methy!-1-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-2-trifluoromethyl-2,3dihydro-1 H-imidazo[1,2-a]pyrimidin-5-one were obtained, corresponding to the following characteristics:

LC/MS (method G): ESI+ [M+HJ+: m/z 387 tr (min) = 1.79 ’H NMR (300 MHz, δ in ppm, DMSO-de): 1.54 (s, 3H), 2.46 (s, 3H), 4.10 (d, 1 H), 4.27 (d, 1H), 4.88 (d, 1H), 5.20 (d, 1H), 5.83 (s, 1H), 7.36 (m, 1H), 7.8.17 (m, 1H), 9.00 (m, 1H).

103

Step 29.2: 2-methyM-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-7-(1 S,4S)-2-oxa-5azablcyclop.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-lmidazo[1,2a]pyrimldin-5-one

F

The procedure used is the same as that of step 12.4.

150 mg (0.388 mmol) of (S)-7-chloro-2-methyl-1-[2-(6-methylpyrid-3-yl)-2oxoethyl]-2-trifluoromethyl-2,3-djhydro-1H-imidazo[1,2-a]pyrimidin-5-one, 63.11 mg (0.465 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride and 98.61 mg (0.970 mmol) of triethylamine were used in the reaction. After purification by chromatography on silica gel (eluent A/B: DCM/MeOH, gradient A/B: 10 min 0% B, 135 min 10% B, 140 min 10% B), 65 mg of 2-methyl-1-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-7(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1Himidazo[1,2-a]pyrimidin-5-one were obtained, corresponding to the following characteristics:

LC/MS (method A): ESI+ [M+H]+: m/z 450 tr (min) = 0.49 ¹H NMR (600 MHz, δ in ppm, DMSO-de): 1.65 (s, 3H), 1.67-1.76 (bs, 2H), 2.96-3.24 (bs, 2H), 3.28 (m, 2H). 2.58 (s, 3H), 4.02 (d, 1 H), 4.24 (d, 1H), 4.48 (m, 3H), 4.85 (d, 1H),

5.20 (d, 1H), 7.49 (m, 1H), 8.30 (m, 1H), 9.10 (m, 1H).

Example 30:

2-τηβ1ΙιγΙ-7-(18,48)-2-οχ3-5-βΖ3ΐ>^εΙο[2.2.1]Κ6ρ1-5-νΙ-1-(2-οχο-2-ρνΓΕά-3ylethyl)-2-((S)-trifluoromethyl)-2,3-dihydro-1H-lmidazo[1₍2-a]pyrimldin-5-one (compound 21)

150 mg (0.474 mmol) of 2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-

2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one are added to a

104 suspension of 47.42 mg (1.19 mmol) of sodium hydride In 10 mL of DMF. The reaction mixture is placed under magnetic stirring at room température for 15 minutes. A solution of 168.31 mg (0.569 mmol) of 2-bromo-1-pyrid-3-ylethanone hydrobromide in 5 mL of DMF is added dropwise to the reaction medium at 0°C. The reaction is stirred at room température ovemight. The reaction medium is evaporated to dryness. The crude product Is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: DCM/MeOH, gradient A/B: 10 min 0% B, 135 min 10% B, t 40 min 10% B), 58 mg of 2-methyl-7-(1S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-1-(2-oxo-2-pyrid-3-yiethyi)-2-((S)-trifluoromethyl)-2,3dihydro-1H-lmidazo[1,2-a]pyrimidin-5-one were obtained, corresponding to the following characteristics:

LC/MS (method A): ESI+ [M+HJ+: m/z 436 tr (min) = 0.51

Ή NMR (600 MHz, δ In ppm, DMSO-de): 1.58 (s, 3H), 1.62 (m, 2H), 2.80-3.25 (bs, 5H)

3.95 (d, 1H), 4.15 (d, 1H), 4.50 (m, 2H), 4.80 (d, 1H), 5.15 (d, 1H), 7.51 (m, 1H), 8.30 (m, 1H), 8.78 (m, 1H), 9.20 (m, 1H).

Example 31:

(8S)-2-(1S,4S)-2-oxa-5-azablcyclo[2.2.1]hept-5-yl-9*{2-pyrid-3-ylethyl)-8trif1uoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidln-4-one (compound 12)

Step 31.1: 2-pyrld-3-ylethyl toluene-4-sulfonate

6.62 mL (47.26 mmol) of triethylamine and 8.26g (43.32 mmol) of 4methylbenzenesulfonyl chloride are added at 0*C to a solution of 5 g (39.38 mmol) of 2pyrid-3-ylethanoi in 300 mL of dichloromethane. After allowing the reaction medium to warm to room température and stirring ovemight, It Is washed with water and with saturated NaCI solution. The organic phase is dried over magnésium sulfate and evaporated to dryness. After purification by chromatography on silica gel (eluent: 4/6

105 heptane/EtOAc), 8 g of 2-pyrid-3-ylethyl toluene-4-sulfonate were obtained, corresponding to the following characteristics:

Ή NMR (300 MHz, δ in ppm, DMSO-d_e): 2.41 (s, 3H), 2.91 (m, 2H), 4.27 (m, 2H), 7.27 (m, 1H), 7.43 (m, 2H), 7.56 (m, 1H), 7.68 (m, 2H), 8.40 (m, 2H).

Step 31.2: (8S)-2-(1 S,4S)-2-oxa-5-azabicyclop.2.1]hept-5-yl-9-(2-pyrid-3ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrlmido[1,2-a]pyrimldln-4-one

A suspension of 150 mg (0.474 mmol) of (8S)-2-(1S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin4-one and 170.15 mg (0.522 mmol) of césium carbonate in 10 mL of acetonitrile is stirred for 15 minutes at 85’C. 131.53 mg (0.474 mmol) of 2-pyrid-3-ylethyl toluene-4-sulfonate are then added. After stirring ovemight at 85’C, the reaction mixture is evaporated and the residue is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: DCM/MeOH, gradient A/B: 10 min 0% B, 135 min 10% B, t40 min 10% B) 145 mg of(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5yl-9-(2-pyrid-3-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4one were obtained, the characteristics of which are as follows: LC/MS (method A): ESI+ [M+HJ+: m/z 422 tr (min) = 0.39

Ή NMR (600 MHz, δ in ppm, DMSO-d_e): 1.25 (m, 2H), 1.85 (m, 2H), 2.01 (m, 1H), 2.35 (m, 1H), 2.95 (m, 3H), 3.15 (m, 1H), 3.42 (m, 1H), 3.75 (m, 2H), 4.22 (m, 2H), 4.72 (m, 3H), 7.35 (m, 1H), 7.65 (m, 1H), 8.45 (m, 2H).

Example 32:

(8S)-9-[2-(6-methoxypyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5azabicyclop.2.1]hept-5-yl-8-trîfIuoromethyl-6,7,8_f9-tetrahydropyrlmldo[1,2a]pyrimldln-4-one (compound 45)

106

Step 32.1:1-(6-methoxypyrid-3-yl)ethanone

A mixture of 15 mL of methanol, 500 mg (2.89 mmol) of 1-(6-chloropyrid-3yl)ethanone and 1.17 g (21.69 mmol) of sodium methoxide is heated in a microwave reactor at 160’C for 4 hours. The reaction medium is evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: heptane/EtOAc, gradient A/B: t 0 min 0% B, 15 min 20% B, 130 min 40% B), 230 mg of 1-(6-methoxypyrid-3-yl)ethanone were obtained, corresponding to the following characteristics: LC/MS (method G): ESI+ [M+H]+: m/z 152 tr (min) = 1.33 ¹H NMR (300 MHz, δ in ppm, DMSO-d_e): 2.50 (s, 3H), 3.94 (s, 3H), 6.92 (m, 1 H), 8.18 (m, 1H), 8.83 (m, 1H).

Step 32.2: 2-bromo-1*(6-methoxypyrld-3-yl)ethanone hydrobromlde •HBr

The procedure used is the same as that of step 12.2.

230 mg (1.52 mmol) of 1-(6-methoxypyrid-3-yl)ethanone, 413 μΙ (7.61 mmol) of hydrobromic acid, 87 μΙ (1.67 mmol) of bromine and 5 mL of glacial acetic acid were used in the reaction. After précipitation with ethyl ether and filtration, 430 mg of 2-bromo-

1-(6-methoxypyrid-3-yl)ethanone hydrobromide are obtained, the characteristics of which are as follows:

LC/MS (method G): ESI+ [M+H]+: m/z 230 tr (min) - 1.61 ¹H NMR (300 MHz, δ in ppm, DMSO-d_e): 3.96 (s, 3H), 4.91 (s, 2H), 6.96 (m, 1H), 8.21 (m, 1H), 8.88 (m, 1H).

Step 32.3: (8S )-9-(2-(6-me thoxypyrid-3-yl)-2-oxoethy 1(-2-(1 S,4S)-2-oxa-5

107 azablcycIo[2.2.1]hept-5-yI-8'trlfluoromethyl-6_l7,8,9-tetrahydropyrlmldo[1,2a]pyrimidln-4-one

The procedure used is the same as that of step 12.3.

150 mg (0.474 mmol) of (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1Jhept-5-yl-8trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, 464.04 mg (1.42 mmol) of césium carbonate, 176.98 mg (0.569 mmol) of 2-bromo-1-(6-methoxypyrid-3yl)ethanone hydrobromide and 10 mL of acetonitrile were used in the reaction. After purification by chromatography on silica gel (eluent A/B: DCM/MeOH, gradient A/B: 10 min 0% B, 125 min 10% B, 130 min 10% B), 100 mg of (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-6,7,8,9tetrahydropyrimido[1,2-a]pyrimidin-4-one were obtained, corresponding to the following characteristics:

LC/MS (method A): ESI+ [M+H)+: m/z 466 tr (min) = 0.61 ’H NMR (600 MHz, δ in ppm, DMSO-de): 1.62 (m. 1H), 1.71 (m. 1H), 2.25 (m, 1H), 2.41 (m. 1H), 2.61-3.17 (bs, 3H), 3.25 (m, 2H), 3.95 (s, 3H), 3.38 (m, 1H), 4.48 (m, 2H), 4.62 (m, 3H), 5.70 (m, 1H), 6.97 (m, 1 H), 8.28 (m, 1H), 8.98 (s, 1H).

Example 33: (S)-9-(2-[6-{2-fluoroethoxy)pyrid-3-yl]-2-oxoethyl}-2-(1S,4S)-2-oxa-5azabicycio[2.2.1]hept-5-yi-8-trif1uoromethyi-6,7,8,9-tetrahydropyrlmido[1,2a]pyrimidin-4-one (compound 63)

F

Step 33.1:1-[6-(2-f1uoroethoxy)pyrid-3-yl]ethanone

108

530 μΙ (8.68 mmol) of 2-fluoroethanol are added to a suspension of 347.05 mg (8.68 mmol) of sodium hydride In 10 mL of DMF. The reaction mixture is placed under magnetic stirring at room température for 15 minutes. A solution of 500 mg (2.89 mmol) of 1-(6-chloropyrid-3-yl)ethanone in 3 mL of DMF is added dropwise to the réaction medium. The reaction is stirred at room température ovemight. The reaction medium is evaporated to dryness. The crude product is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: heptane/EtOAc, gradient A/B: 10 min 0% B, 15 min 10% B, 130 min 30% B), 362 mg of 1-[6-(2-fluoroethoxy)pyrid-

3-yl]ethanone were obtained, corresponding to the following characteristics: LC/MS (method G): ESI+ [M+H]+: m/z 184 tr (min) » 1.41 ¹H NMR (300 MHz. δ in ppm, DMSO-d_e): 2.57 (s, 3H), 4.56 (m, 1H), 4.67 (m, 1H), 4.86 (m. 1H), 7.00 (m, 1H), 8.21 (m, 1 H), 8.83 (m. 1H).

Step 33.2: 2-bromo-1-[6-(2*fluorœthoxy)pyrid-3-yQethanone hydrobromlde

Η0Γ

The procedure used is the same as that of step 12.2.

362 mg (1,98 mmol) of 1-[6-(2-fluoroethoxy)pyrid-3-yl]ethanone, 413 μΙ (7.61 mmol) of hydrobromic acid, 537 μΙ (9.88 mmol) of bromine and 5 mL of glacial acetic acid were used in the reaction. After précipitation with ethyl ether and filtration, 602 mg of 2bromo-1-[6-(2-fluoroethoxy)pyrid-3-y!]ethanone hydrobromide are obtained, the characteristics of which are as follows:

LC/MS (method G): ESI+ [M+HJ+: m/z 264 tr (min) = 1,69 ’H NMR spectrum (300 MHz, δ in ppm, DMSO-de): 4.56 (m, 1H), 4.69 (m. 1 H), 4.86 (m. 1H), 4.92 (s, 2H), 7.00 (m, 1H), 8.23 (m, 1H), 8.85 (m, 1H), 9.80 (bs, 1H).

Step 33.3: (8S)-9-(2-[6-(2-fluoroethoxy)pyrid-3-yn-2-oxoethyl}-2-(1 S,4S)-2oxa-5-azablcyclo[2.2.1]hept-5>yl-8-trifluoromethyl-6_l7,8_l9-tetrahydropyrimldo[1,2.· .·

109

a]pyrlmldln-4-one

F

The procedure used is the same as that of step 12.3.

150 mg (0.474 mmol) of (8S)-2-(1S,4S)-2-oxa-5-azablcyclo[2.2.1]hept-5-yl-8trifluoromethyl-ej.e.O-tetrahydropyrimidofl^-aJpyrimidin^-one, 464.04 mg (1.42 mmol) of césium carbonate, 195.20 mg (0.569 mmol) of 2-bromo-1-[6-(2-fluoroethoxy)pyrid-3yljethanone hydrobromide and 10 mL of acetonitrile were used in the reaction. After purification by chromatography on silica gel (eluent A/B: DCM/MeOH, gradient A/B: 10 min 0% B, 125 min 10% B, 130 min 10% B). 130 mg of (8S)-9-{2-[6-(2-fluoroethoxy)pyrid-

3-yl]-2-oxoethy1}-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9tetrahydropyrimido[1,2-a]pyrimidin-4-one were obtained, correspondîng to the following characteristics:

LC/MS (method A): ESI+ [M+H]*: m/z 498 tr (min) - 0.62

Ή NMR (600 MHz, δ in ppm, DMSO-d_e): 1.62 (m, 1H), 1.72 (m, 1H), 2.25 (m, 1H), 2.45 (m, 1 H), 2.61-3.17 (bs, 3H), 2.25 (m, 2H), 4.38 (m, 1H), 4.50 (m, 2H), 4.55-4.70 (m. 5H),

4.74 (m, 1H), 4.83 (m, 1H), 5.70 (m, 1H), 7.12 (m, 1H), 8.30 (m, 1H), 8.97 (m, 1H).

Example 34: (8S)-9-[(S}-2-(4-fluoro-2-methoxyphenyl)-2-hydroxyethyl]-2-(8-oxa-3azablcyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimldo[1,2a]pyrlmldln-4-one (compound 71)

F

200 mg (0.61 mmol) of (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8trifluoromethyl-e.ï.S.O-tetrahydropyrimidotl^-alpyrimidin-l-one in 5 mL of DMF are added to a suspension of 60 mg (1.51 mmol) of sodium hydride in 10 mL of DMF. The reaction mixture is heated at 50°C for 10 minutes. After addition of 162 mg (0.79 mmol)

110 of (S)-2-chloro-1-(4-fluoro-2-methoxypheny!)ethanol, the reaction is continued at room température ovemight. The reaction medium is evaporated to dryness. The residue is purified by chromatography on a coiumn of silica (eluent: 90/10 DCM/MeOH). 40 mg of (8S)-9-[(S)-2-(4-fluoro-2-methoxyphenyl)-2-hydroxyethyl]-2-(8-oxa-3azabicyclo[3.2.1 loct-S-yQ-S-trifluoromethyl-ej.S.g-tetrahydropyrimidoIl ,2-a]pyrimidin-4one were obtained, corresponding to the following characteristics:

LC/MS (method B): ESI+ [M+H]+: mfz 499 tr (min) = 0.71 ¹H NMR (600 MHz, δ in ppm, DMSO-de): 1.65 (m, 2H), 1.83 (m, 2H), 2.25 (m, 1H), 2.35 (m, 1H), 2.92 (m, 3H), 3.22 (m, 1H), 3.75 (m, 1H), 3.75 (s, 3H), 3.85 (m, 1H), 4.15 (m, 1H), 4.35 (m, 3H), 4.71 (m, 1H), 4.89 (s, 1H), 5.35 (m, 1H), 5.53 (m, 1H), 6.78 (m, 1H),

6.87 (m, 1H), 7.51 (m, 1H).

Example 35:

(S)-1-[2-{4-hydroxyphenyl)ethyl]-2-methyl-7-{8-oxa-3-azabicyclo[3.2.1]oct-

3-yl)-2-trifluoromethyl-2,3-dihydro-1H-lmidazo[1,2-a]pyrimidin-5-one (compound

72)

N

HO

Step 35.1; (S)-1 -[2-{4-benzyioxyphenyl)ethyl]-7-chloro-2-methyl-2trlf1uoromethyl-2,3-dihydro-1H-lmidazo[1,2-a]pyrimidin-5-one

A mixture of 40 mL of DMF, 2 g (7.89 mmol) of (S)-7-chloro-2-methyl-2trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one, 3.44 g (11.84 mmol) of 1benzy1oxy-4-(2-bromoethyl)benzene and 5.14 g (15.78 mmol) of césium carbonate is heated in a Biotage microwave reactor at 120°C for 20 minutes. The reaction medium is evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: heptane/EtOAc, gradient A/B: 10 min 20% B, 125 min 50% B, 135 min 50% B), 2.8 g of (S)-1-[2-(4-benzyloxypheny!)ethylI-7-chloro-2-methyl-2-trifluoromethyl-2,3-dihydro-1Himidazo[1,2-a]pyrimidin-5-one were obtained, corresponding to the following .· .*

111 characteristics:

LC/MS (method G): ESI+ [M+H]+: m/z 464 tr (min) = 2.91 ’H NMR (300 MHz, δ in ppm, CDCfc): 1.36 (s, 3H), 2.90 (m, 1H), 3.11 (m, 1 H), 3.49 (m,

1H), 3.75 (m, 1 H). 4.38 (d, 1H), 5.07 (m, 2H), 5.32 (s, 1H), 5.97 (s, 1H), 6.94 (m, 2H),

7.12 (m, 2H), 7.43 (m, 5H).

Step 35.2: (S)-1 -{2-(4-benzyIoxy phenyl)ethyî]-2-methyl-7-(8-oxa-3azabicyclo[3.2.1]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-lmldazo[1,2a]pyrimldin-5-one

O

N

The procedure used is the same as that of step 12.4.

1.40 g (3.02 mmol) of (S)-1-[2-(4-benzyloxyphenyl)ethyl)-7-chloro-2-methyl-2trifluoromethyl^.S-dihydro-IH-imidazoIl^-alpyrimîdin-S-one, 903 mg (6.04 mmol) of 8oxa-3-azabicyclo[3.2.1]octane hydrochloride and 763 mg (7.54 mmol) of triethylamine were used in the reaction. After purification by chromatography on silica gel (eluent A/B: 2/8 heptane/EtOAc), 1.2 g of (S)-1-[2-(4-benzyloxyphenyl)ethyl]-2-methyl-7-(8-oxa-3azabicyclo[3.2.1]oct-3-yl)-2-trifiuoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5one were obtained, corresponding to the following characteristics:

LC/MS (method G): ESI+ [M+HJ+: m/z 541 tr (min) = 2.84 ’H NMR (300 MHz, δ in ppm, DMSO-de): 1.49 (s, 3H), 1.66 (m, 2H), 1.83 (m, 2H), 2.79 (m, 1H), 2.96 (m, 3H), 3.45 (m, 2H), 3.86 (m, 3H), 4.10 (d, 1H), 4.39 (m, 2H), 4.78 (m, 1H), 5.08 (s, 2H), 6.96 (m, 2H), 7.15 (m, 2H), 7.41 (m, 5H).

Step 35.3: (S)-1 -[2-(4-hydroxyphenyl)ethyî]-2-methyl-7-(8-oxa-3azabicycloP^.IJoct-S-yl^-trlfluoromethyl^t.S-dihydro-IH-imldazon^a]pyrimidin-5-one · .·

112 ο (A N

700 mg (11.10 mmol) of ammonium formate and 156 mg (0.22 mmol) of 20% palladium hydroxide are added at 0°C to a solution of 1.20 g (2.22 mmol) of (S)-1-[2-(4benzyloxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-trifluoromethyl-

2,3-dihydro-1H-imidazo[1_l2-a]pyrimidin-5-one in 15 mL of methanol. The mixture is refluxed for 1 hour and then allowed to cool to room température. The reaction medium is filtered through Celite and the filtrate is then evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: DCM/MeOH, gradient A/B: 10 min 0% B, t 25 min 10% B, 130 min 10% B), 732 mg of (S)-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[1,2a]pyrimidin-5-one were obtained, corresponding to the following characteristics: LC/MS (method B): ESI+ [M+HJ+: m/z 451 tr (min) - 0.68 ¹H NMR (600 MHz, δ in ppm, DMSO-de): 1.48 (s, 3H), 1.64 (m, 2H). 1.80 (m, 2H), 2.72 (m. 1H), 2.87 (m, 1H), 3.00 (m, 2H). 3.35 (m, 1H), 3.52 (m, 1H), 3.78 (m, 3H), 4.09 (d, 1H), 4.39 (m, 2H), 4.77 (s, 1H), 6.68 (m, 2H), 6.97 (m, 2H), 9.16 (s, 1H).

Example 36: (SJ-l-P-ft-^-dimethylamlnoethoxyJphenylJethylJ^-methyl-T-ie-oxa-Sazablcyclop^.IJoct-S-yn^-trlfluoromethyl^.S-dlhydro-IH-imldazon^a]pyrlmidin-5-one (compound 74)

282 mg (0.67 mmol) of césium carbonate are added to a solution of 130 mg (0.29 mmol) of (S)-1 -[2-(4-hydroxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1 ]oct-3yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one in 10 mL of DMF. After heating at 80*C for 20 minutes, 62.40 mg (0.43 mmol) of (2.* .·

113 chloroethyl)dimethylamine are added. The reaction medium is heated at80°C ovemight. The reaction medium is evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: DCM/MeOH, gradient A/B: 10 min 0% B, 125 min 10% B, 130 min 10% B), 116 mg of (S)-1-{2-[4-(2-dimethylaminoethoxy)phenyl]ethyl}-2-methyl-7-(8-oxa-

3-azabicyclo[3.2.1]oct-3-yl)-2-trifluoromethyl-2_l3-dihydro-1H-im!dazo[1,2-a]pyrimidin-5one were obtained, corresponding to the following characteristics: LC/MS (method B): ESI+ [M+HJ+: m/z 522 tr (min) = 0.56 ¹H NMR (600 MHz, δ in ppm, DMSO-d_e): 1.48 (s, 3H), 1.62 (m, 2H), 1.77 (m, 2H), 2.77 (m, 7H), 2.88 (m, 1H), 2.93 (m, 2H), 3.40 (m, 4H), 3.57-378 (bs, 2H), 3.82 (m, 1 H). 4.06 (m, 1H), 4.26 (m, 2H), 4.33 (m, 2H), 4.72 (s, 1H), 6.90 (m, 2H), 7.12 (m, 2H), 10.2 (bs,

1H).

Example 37: N,N-dimethyl-2-(4-{2-[(S)-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-oxo-2trifluoromethyl^S-dihydro-SH-imldazotl ,2-a]pyrimidln-1yl]ethyl}phenoxy)acetamlde (compound 70)

235 mg (0.72 mmol) of césium carbonate are added to a solution of 130 mg (0,29 mmol) of (S)-1-{2-(4-hydroxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one in 10 mL of DMF. After heating at 80*C for 20 minutes, 52.60 mg (0.43 mmol) of 2-chloro-N,Ndimethylacetamide and 43.30 mg (0.29 mmol) of sodium lodide are added. The reaction medium is heated at 80*C ovemight. The reaction medium is evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: DCM/MeOH, gradient A/B: t 0 min 0% B, 125 min 10% B, 130 min 10% B), 138 mg of N,N-dimethyl-2-(4-{2-î(S)-2methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-oxo-2-trifluoromethyl-2_l3xiihydro-5Himidazoî1,2-a]pyrimidin-1-yHethyl}phenoxy)acetamide were obtained, corresponding to the following characteristics:

LC/MS (method B): ESI+ [M+H]+: m/z 536 tr (min) = 0.69 ¹H NMR (600 MHz, δ in ppm, DMSO-de): 1.53 (s, 3H), 1.68 (m, 2H), 1.82 (m, 2H), 2.75 (m, 1H), 2.81 (s, 3H), 2.95 (m, 3H), 2.97 (s, 3H), 3.38 (m, 1 H). 3.52 (m, 1H), 3.73 (m,

114

2H), 3.82 (d, 1H), 4.13 (d, 1H), 4.41 (m, 2H), 4.74 (s, 2H), 4.76 (s, 1H), 6.85 (m, 2H),

7.12 (m, 2H).

Example 38:

(8S)'9-(2-ethyl-2-hydroxybutyl)-2-(1S,4S)-2-oxa-5-azablcyclo[2.2.1]hept-5yi-e-trifluoromethyl-ej.e.g-tetrahydropyrimldofl^-ajpyrimldin^-one (compound 54)

Step 38,1: methyl ((8S)-8-(1S,4S)-2-oxa-5-azablcyclo[2.2.1]hept-5-yl-6-oxo-

2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimldo[1,2-a]pyrimldln-1-yl)acetate

F

150 mg (0.474 mmol) of (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 3 mL of DMF are added to a suspension of 18.97 mg (0.474 mmol) of sodium hydride in 7 mL of DMF. The reaction mixture is stirred at room température for 10 minutes. After addition of 45 pl (0.474 mmol) of methyl bromoacetate, the reaction is stirred at room température ovemight. The reaction medium Is evaporated to dryness. The residue is purified by chromatography on a column of silica (eluent 95/5 DCM/MeOH). 147 mg of methyl ((2S)~ 8-( 1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetate were obtained, corresponding to the following characteristics:

LC/MS (method G): ESI+ [M+H]+: m/z 389 tr (min) = 1.70 ¹H NMR (300 MHz, δ in ppm, DMSO-de): 1.81 (m, 2H), 2.11 (m, 1H), 2.40 (m, 1H), 3.13 (m, 3H), 3.50 (m, 1H), 3.57 (s, 3H), 3.69 (m, 1H), 4.16 (m, 1H), 4.27 (m, 1H), 4.50 (m, 1H), 4.68 (m, 4H).

.· .·

115

Step

38.2:

(8S)-9-(2-ethyl-2-hydroxybutyl)-2-(1S,4S)-2-oxa-5azablcyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimldo[1,2a]pyrimldin-4-one

HO

631 μΙ (1.89 mmol) of a 3 M solution of ethylmagnesium bromide in ethyl ether are added at O’C to a solution of 147 mg (0.38 mmol) of methyl ((2S)-8-(1S,4S)-2-oxa5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2a]pyrimidin-1-yl)acetate in 10 mL of THF. The reaction medium is stirred at O’C for 4 hours, followed by addition of 10 mL of saturated ammonium chloride solution. The resulting mixture is extracted with ethyl acetate and the organic phase is then dried over magnésium sulfate and evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: DCM/MeOH, gradient A/B: 10 mîn 0% B, 125 min 10% B, 130 min 10% B), 80 mg of (8S)-9-(2-ethyl-2-hydroxybutyl)-2-(1S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-

4-one were obtained, corresponding to the following characteristics: LC/MS (method A): ESI+ [M+H]+: m/z 417 tr (min) = 0.63 ’H NMR (600 MHz, δ in ppm, DMSO-de): 0.76 (m, 3H), 0.83 (m, 3H), 1.30 (m, 1H), 1.36 (m, 1H), 1.42 (m, 2H), 1.83 (m, 2H), 2.25 (m, 1H), 2.39 (m, 1H), 2.99 (m, 1H), 3.24 (m, 1H), 3.30 (m, 2H), 3.57 (m, 1H), 3.70 (m, 1H), 4.13 (m, 1H), 4.61 (m, 3H), 4.72 (m, 1H),

4.98 (m, 1H).

Example 39:

(8S)-9-(3-ethyl-3-hydroxypentyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5yl-8-trif1uoromethyl-6,7,8,9-tetrahydropyrlmido[1,2-a]pyrimldin-4-one (compound 49)

116

F

Step 39.1: methyl 3-((2S)-8-(1S,4S)-2-oxa-5-azabîcycio[2.2.1]hept-5-yl-6oxo-2-trlfluoromethyl*3,4-dihydro-2H,6H-pyrlmIdo[1,2-a]pyrimldin-1-yl)propionate

pl (0.006 mmol) of DBU and 274.94 mg (3.16 mmol) of methyl acrylate are added to a solution of 200 mg (0.632 mmol) of (8S)-2-(1S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-

4-one in 5 mL of DMF. The reaction mixture is stirred at room température ovemight. The reaction medium is evaporated to dryness. The residue is purified by chromatography on a column of silica (eluent: 95/5 DCM/MeOH). 245 mg of methyl 3((2S)-8-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)-propionate were obtained, corresponding to the following characteristics:

LC/MS (method G): ESI+ [M+H]+: m/z 403 tr (min) = 1.83 ¹H NMR (300 MHz, δ in ppm, DMSO-de): 1.61 (m, 2H). 1.85 (m, 1H), 2.11 (m, 1H), 2.43 (m, 1H), 2.61 (m, 1H), 2.88 (m, 2H), 3.09 (m, 2H), 3.35 (m, 4H), 3.48 (m, 1H), 3.95 (m, 2H), 4.45 (m, 4H).

Step 39.2: (8S)-9-(3-ethyl-3-hydroxypentyl)-2-(1 S,4S)-2-oxa-5azabÎcyclo[2.2.1]hept-5-yl*8-trifluoromethyl-6,7,8_l9-tetrahydropyrimldo[1,2aJpyrimIdln-4-one .· .·

117

911 μΙ (2.73 mmol) of a 3 Μ solution of ethylmagnesium bromide in ethyl ether are added at 0*C to a solution of 220 mg (0.55 mmol) of methyl 3-((2S)-8-(1S,4S)-2-oxa5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifIuoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2a]pyrimidin-1-yl)-propionate in 10 mL of THF. The reaction medium is stined at 0^eC for 2 hours. 10 mL of saturated ammonium chloride solution are added to the reaction medium. The resulting mixture is extracted with ethyl acetate and the organic phase is then dried over magnésium sulfate and evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: DCM/MeOH, gradient A/B: 10 min 0% B, 125 min 10% B, t 30 min 10% B), 128 mg of (8S)-9-(3-ethyl-3-hydroxypentyl)-2-(1S,4S)-2oxa-5-azabicyclo[2.2.1 ]hept-5-yi-8-trifluoromethyi-6,7,8,9-tetrahydropyrimido[1,2a]pyrimidin-4-one were obtained, corresponding to the following characteristics: LC/MS (method A): ESI+ [M+H]+: m/z 431 tr (min) = 0.63 ’H NMR (600 MHz, δ in ppm, DMSO-de): 0.80 (m, 6H), 1.36 (m, 4H), 1.63 (m, 1H), 1.71 (m, 1 H), 1.82 (m, 2H), 2.05 (m, 1 H), 2.34 (m, 1H), 3.15 (m, 1H), 3.23 (m, 1H), 3.62 (m, 1H), 3.70 (m, 1H), 3.99 (m, 1H), 4,19 (m, 2H), 4.51 (m, 2H), 4.64 (m, 2H), 5.01-5.12 (bs, 1H).

Example 40:

(8S)-2-(1S_l4S)-2-oxa-5-azablcyclo[2.2.1]hept-5-yl-9-(2-oxo-2-pyrid-2ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrlmido[1,2-a]pyrlmidin-4-one (compound 68)

Step 40.1: (8S)-2-chloro-9-(2-oxo-2-pyrid-2-ylethyl)-8-trifluoromethyl-

6,7,8,9-tetrahydropyrimldo[1,2-a]pyrimidln-4-one .·

118

The procedure used is the same as that of step 12.3.

150 mg (0.591 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7.8.9tetrahydropyrimido[1,2-aJpyrimidin-4-one, 578.71 mg (1.77 mmol) of césium carbonate,

199.40 mg (0.709 mmol) of 2-bromo-1-pyrid-2-ylethanone hydrobromide and 10 mL of acetonitrile were used in the reaction. After purification by chromatography on silica gel (eluent A/B: heptane/EtOAc, gradient A/B: 10 min 0% B, 115 min 50% B, 125 min 70% B), 218 mg of (8S)-2-ch!oro-9-(2-oxo-2-pyrid-2-ylethyl)-8-trifluoromethy!-6,7.8,9- tetrahydropyrimido[1,2-a]pyrimidin-4-one were obtained, corresponding to the following characteristics:

LC/MS (method G): ESI+ [M+HJ+: m/z 373 tr (min) = 2.14 ¹H NMR (300 MHz, δ in ppm, DMSO-d_e): 2.28 (m, 1H), 3.40 (m. 1H). 4.40 (m. 1H), 4.80 (m, 1H), 5.11 (d, 1H), 5.61 (d, 1H), 5.77 (m, 1H). 5.93 (s, 1H), 7.76 (m. 1H), 8.00 (m, 1H), 8.08 (m, 1H), 8.79 (m, 1H).

Step 40.2: (8S}-2-(1 S,4S)-2-oxa-5-azablcyclo[2.2.1]hept-5-yl-9-(2-oxo-2pyrld-2-yiethyi)-8-trlf1uoromethyi-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidln-4one

The procedure used is the same as that of step 12.4.

218 mg (0.58 mmol) of (8S)-2-chloro-9-(2-oxo-2-pyrid-2-ylethyl)-8-trifluoromethyl-

6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, 95.17 mg (0.702 mmol) of (1S,4S)-2oxa-5-azabicyclo[2.2.1]heptane hydrochloride and 205 μΙ (1.46 mmol) of triethylamlne were used in the reaction. After purification by chromatography on silica gel (eluent A/B: 95/5 DCM/MeOH), 103 mg of (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2oxo-2-pyrid-2-ylethyl)-8-trifluoromethyl-6₍7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one were obtained, corresponding to the following characteristics: LC/MS (method A): ESI+ [M+H]+: m/z 436 tr (min) = 0.59 ·· .·

119

Ή NMR (600 MHz, δ in ppm, DMSO-de): 1.59 (m, 1 H), 1.68 (m, 1 H), 2.24 (m, 1 H). 2.44 (m. 1 H). 2.90 (m. 2H), 3.08-3.20 (bs, 2H), 3.25 (m, 1H), 4.26 (m. 1H), 4.37 (m, 1H). 4.47 (m, 1H), 4.62 (m, 1H), 4.72 (m, 1H), 4.82 (m, 1 H). 5.70 (m, 1H), 7.73 (m, 1H), 7.98 (m, 1H), 8.07 (m, 1H), 8.78 (m, 1 H).

Example 41: (8S)-9-{2-[6-(2-hydroxyethylamlno)pyrid-3-yl]-2-oxoethyl}-2-(1S,4S)-2-oxa5-azablcycio[2.2.1]hept-5-yl-8-trifluoromethyi-6,7,8,9-tetrahydropyrimldo[1,2a]pyrimldln-4-one (compound 14)

F

Step 41.1: (8S)-9-[2-(6-chloropyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimldo[1,2a]pyrimldin-4-one

F

100 mg (0.32 mmol) of (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 3 mL of DMF are added to a suspension of 41.73 mg (1.04 mmol) of sodium hydride in 5 mL of DMF. The reaction mixture is stirred at room température for 10 minutes. After addition of 244.65 mg (1.04 mmol) of 2-bromo-1-(6-chloropyrid-3-yl)ethanone, the reaction Is continued at room température ovemight. The reaction medium is evaporated to dryness. The residue is purified by chromatography on a column of silica (eluent: 90/10 DCM/MeOH). 85 mg of (8S)-9-[2-(6-chloropyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one were obtained, corresponding to the following characteristics:

LC/MS (method G): ESI+ [M+H]+: m/z 470 tr (min) = 1.86 ¹H NMR (600 MHz, δ in ppm, DMSO-de): 1.65 (m. 2H), 2.28 (m, 1H), 2.93 (m, 3H), 3.19 .· .·

120 (m, 3H), 4.45 (m, 3H), 4.71 (m, 3H). 5.74 (m, 1H), 7.78 (m, 1H), 8.41 (m, 1H), 9.10 (m, 1H).

Step 41.2: (8S)-9-{2-[6-(2-hydroxyethylamlno)pyrid-3-yî]-2-oxoethyl}-2(1S,4S)-2-oxa-5-azabicyclop.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9tetrahydropyrimldo[1,2-a]pyrimidin-4-one

A mixture of 0.50 mL of éthanol, 33 mg (0.070 mmol) of (8S)-9-p-(6-chloropyrid-

3-yl)-2-oxoethy1]-2-(1S, 4S)-2-oxa-5-azabicyclop.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9tetrahydropyrimido[1,2-a]pyrimidin-4-one and 21.41 pi (0.352 mmol) of ethanolamine is heated in a Biotage microwave reactor at 130*C for 30 minutes. The reaction mixture is evaporated to dryness and the residue is then taken up in 10 mL of water. The precipitate is filtered off and then dried under vacuum. 17 mg of (8S)-9-{2-[6-(2hydroxyethylamino)pyrid-3-yl]-2-oxoethyl}-2-(1 S,4S)-2-oxa-5-azabicyc1op.2.1 ]hept-5yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as foilows:

LC/MS (method A): ESI+ [M+H]+: m/z 495 tr (min) = 0.40 ’H NMR (600 MHz, δ in ppm, DMSO-de): 1.62 (m, 1H), 1.73 (m, 1H), 2.23 (m, 1H), 2.41 (m. 1H), 2.91-3.12 (bs, 3H), 3.23 (m, 1H), 3.42 (m, 2H), 3.54 (m, 2H), 4.36 (m, 2H), 4.49 (m, 2H), 4.60 (m, 2H), 4.74 (m, 1H), 5.60 (d, 1H), 6.58 (d, 1H), 7.53 (m, 1H), 7.88 (m, 1H), 8.77 (m, 1 H).

Example 42:

(8S)-9-[2-(6-methylamInopyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5azabIcyclop.2.1]hept-5-yi-8-trifluoromethyl-6,7,8_l9-tetrahydropyrimido[1,2a]pyrimIdin-4-one (compound 5) ·* .

121

Step 42.1:1 -(6-methylamlnopyrid-3-yl)ethanone

A mixture of 2 mL of éthanol, 280 mg (1.80 mmol) of 1-(6-chloropyrid-3yl)ethanone and 4.50 mL (9 mmol) of a 2 M solution of methylamine in THF is heated in a Biotage microwave reactor at 130*C for 30 minutes. The reaction medium is evaporated to dryness. The crude product ls taken up in water and extracted with EtOAc. The organic phase is dried over magnésium sulfate and evaporated to dryness. 258 mg of 1-(6-methylaminopyrid-3-yl)ethanone are obtained, the characteristics of which are as follows:

’H NMR (300 MHz. δ in ppm. DMSO-d_e): 2.42 (s. 3H), 2.84 (s. 3H), 6.47 (m, 1H), 7.42 (m. 1H). 7.85 (m, 1H), 8.65 (m, 1H).

Step 42.2: 2-bromo-1*(6-methylamlnopyrid-3-yl)ettianone

The procedure used is the same as that of step 12.2.

380 mg (2.53 mmol) of 1-(6-methylaminopyrid-3-yl)ethanone, 416 pl (2.53 mmol) of hydrobromlc acid, 130 μΙ (2.53 mmol) of bromine and 5 mL of glacial acetic acid were used in the reaction. After précipitation with ethyl ether and filtration, the precipitate is taken up in water. The solution is basified with saturated NaHCOs solution. The precipitate formed is filtered off, washed with water and then dried under vacuum. 370 mg of 2-bromo-1-(6-methylaminopyrid-3-yl)ethanone are obtained. the characteristics of which are as follows:

’H NMR spectrum (300 MHz. δ in ppm, DMSO-de): 2.85 (s, 3H), 4.70 (s, 2H), 6.50 (m, 1H), 7.62 (m, 1H), 7.87 (m, 1H), 8.71 (m, 1H).

Step 42.3: (8S)-9-[2-(6-mettiylamlnopyrid-3-yl)-2-oxoethyl]-2*(1 S,4S)-2-oxa-5 ·’ .

122 azablcyclo[2.2.1]hept-5-yl-8-tfifluoromethyl-6_l7,8,9-tetrahydropyrimldo[1,2a]pyrimidln-4-one

100 mg (0.32 mmol) of (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8trifluoromethyl-6.7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 3 mL of DMF are added to a suspension of 13.91 mg (0.35 mmol) of sodium hydride in 5 mL of DMF. The reaction mixture is stirred at room température for 15 minutes. After dropwise addition of

79.67 mg (0.35 mmol) of 2-bromo-1-(6-methylaminopyrid-3-yl)ethanone dissolved in 3 mL of DMF, the reaction is continued at room température for 1 hour. The réaction medium is evaporated to dryness. The residue is purified by chromatography on a column of silica (eluent A/B: DCM/MeOH, gradient A/B: 10 min 0% B, 125 min 10% B, t 30 min 15% B). 75 mg of (8S)-9-[2-(6-methylaminopyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2oxa-S-azabicyclop^.Ilhept-S-yl-e-trifluoromethyl-ôXS.O-tetrahydropyrimidoIl^a]pyrimidin-4-one were obtained, corresponding to the following characteristics: LC/MS (method A): ESI+ [M+H]+: m/z 465 tr (min) = 0.41 ¹H NMR spectrum (600 MHz, δ in ppm, DMSO-de): 1.62 (m, 1H), 1.73 (m, 1H), 2.23 (m, 1H), 2.42 (m, 1H), 2.86 (s, 3H), 2.92-3.16 (bs, 3H), 3.23 (m, 2H), 4.37 (m, 2H), 4.49 (m, 2H), 4.60 (m, 2H), 5.60 (m, 1H), 6.51 (m, 1H). 7.47 (m, 1H), 7.92 (m, 1H), 8.78 (m, 1H).

Example 43:

2-methyl-1-[2-(6-methylamlnopyrid-3-yl)-2-oxoethyl]-7-(1S,4S)-2-oxa-5azablcyclop.2.1]hept-5-yl*2-((S)-trifluoromethyl)-2,3-dlhydro-1H-lmldazo[1,2-

100 mg (0.32 mmol) of 2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one in 3 mL of DMF are added to a suspension of 13.91 mg (0.35 mmol) of sodium hydride in 5 mL of DMF. The .· .·

123 reaction mixture is stirred at room température for 15 minutes. After dropwise addition of

79.67 mg (0.35 mmol) of 2-bromo-1-(6-methylaminopyrid-3-yl)ethanone dissolved in 3 mL of DMF, the reaction is continued at room température for 1 hour. The reaction medium is evaporated to dryness. The residue is purified by chromatography on a column of silica (eluent A/B: DCM/MeOH, gradient A/B: 10 min 0% B, 125 min 10% B, t 30 min 15% B). 100 mg of 2-methyl-1-[2-(6-methylaminopyrid-3-yl)-2-oxoethyl]-7- (1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1Himidazo[1,2-a]pyrimidin-5-one were obtained, corresponding to the following characteristics:

LC/MS (method A): ESI+ [M+H]+: mlz 465 tr (min) ~ 0.42 ’H NMR (600 MHz, δ in ppm, DMSO-d_e): 1.61 (s, 3H), 1.70 (m, 1H), 1.75 (m, 1H), 2.86 (d, 3H), 2.93-3.26 (bs, 3H), 3.35 (m, 1H), 3.98 (m, 1H), 4.22 (m, 1H), 4.53 (m, 3H), 4.64 (d, 1H), 5.05 (d, 1H), 6.51 (m, 1H), 7.50 (m, 1H), 7.91 (m, 1H). 8.79 (m, 1H).

Example 44:

4-[2-((2S)-8-(1S,4S)-2-oxa-5-azablcyclo[2.2.1]hept-5-yl-6-oxo-2trlfluoromethyl-3,4-dlhydro-2H,6H-pyrlmido[1,2-a]pyrimldln-1-yl)ethyl]plperidlne-

1-carbaldehyde (compound 90)

Step 44.1: tert-butyi 4-[2-((2S)-8-(1S,4S)-2-oxa-5-azabicycio[2.2.1]hept-5-yl-6-oxo

Z-trifluoromethyl-S^ihydro-îH.eH-pyrimidoIl^-aJpyrimldln-lyl)ethyl]plperidine-1-carboxyiate .·

124

1.03 g (3.54 mmol) of tert-butyl 4-(2-bromoethyl)piperidine-1-carboxylate and 530 mg (3.54 mmol) of sodium iodide are added to a solution of 800 mg (2.53 mmol) of (8S)-

2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9tetrahydropyrimido[1,2-a]pyrimidin-4-one and 2.47 g (7.59 mmol) of césium carbonate in 15 mL of acetonitrile. The reaction mixture is heated in a Biotage microwave reactor at 100’C for 1 hour 15 minutes. The reaction medium Is evaporated to dryness and the residue is taken up in EtOAc and washed with water and with saturated NaCI. The organic phase is dried over magnésium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 90/10 DCM/MeOH) to give 730 mg of tert-butyl 4-[2-((2S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2- trifluoromethyi-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)ethyl]piperidine-1carboxylate, the characteristics of which are as follows: LC/MS (method G): ESI+ [M+H]+: m/z 528 tr (min) = 2.57 ’H NMR spectrum (300 MHz, δ in ppm, DMSO-de): 0.98 (m, 2H), 1.24 (m, 1H), 1.38 (s, 9H), 1.47 (m, 1H), 1.61 (m, 3H), 1.84 (m, 2H), 2.03 (m, 1H), 2.33 (m, 1H), 2.68 (m, 2H),

3.13 (m, 3H), 3.32 (m, 3H), 3.57-3.75 (dd, 2H), 3.88 (m, 2H), 7.92 (m, 1 H), 4.18 (m, 2H),

4.63 (m, 2H).

Step 44.2: (eS^-ÎIS^J^-oxa-S-azabicyclop^.lJhept-S-yl-iî-p-pIperidin^ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one

A solution of 250 mg (0.473 mmol) of tert-butyl 4-[2-((2S)-8-(1S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2a]pyrimidin-1-yl)ethyl]piperidine-1-carboxylate in 10 mL of formic acid is stirred for 1 hour 30 minutes at room température.

The reaction mixture is evaporated to dryness and the residue Is taken up in DCM and evaporated to give 224 mg of (8S)-2-(1S,4S)-2-oxa-5-azabicyclop.2.1]hept-5-yl-9.· /

125 (2-piperid-4-ylethyl)-8-trifluoromethyl-6,7₍8_l9-tetrahydropyrimido[1,2-aJpyrimidin-4-one_lthe characteristics of which are as follows:

LC/MS (method G): ESI+ [M+HJ+: m/z 428 tr (min) = 1.34

Step 44.3:4-[2-((2S)-8-(1 S,4S)-2-oxa-5-azablcycio[2.2.1]hept-5-yl-6-oxo-2trifluoromethyi-3,4-dihydro-2H,6H-pyrimldo[1,2-a]pyrimidln-1-yi)ethyl]piperidlne-

1-carbaidehyde

F mg (0.521 mmol) of ammonium formate are added to a suspension of 224 mg (0.474 mmol) of (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-piperid-4ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 10 mL of

1,4-dioxane. The reaction mixture is heated at 100’C for 4 hours and then evaporated to dryness. The residue is taken up in DCM and the solution is washed with water and with saturated NaCI. The organic phase is dried over sodium sulfate and evaporated to dryness. The product obtained is purified by chromatography on silica gel (eluent: 90/10 DCM/MeOH) to give 85 mg of 4-[2-((2S)-8-(1S,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-1yl)ethyl]piperidine-1-carbaldehyde, the characteristics of which are as follows: LC/MS (method A): ESI+ [M+H]+: m/z 456 tr (min) = 0.54 ¹H NMR (600 MHz, δ in ppm, DMSO-d_e): 0.83-1.11 (m, 2H), 1.5 (m, 2H), 1.58-1.77 (m. 3H), 1.85 (m, 2H), 2.04 (m, 1H), 2.34 (m, 1H), 2.57 (m, 1H), 2.99 (m, 1H), 3.02-3.23 (m, 3H), 3.33 (m, 1H). 3.59-3.75 (m, 3H), 4.07-4.21 (m, 3H). 4.55-4.99 (m, 4H), 7.95 (s, 1H).

Example 45: (8S)-2-(1S,4S)-2-oxa-5-azablcycio[2.2.'l]hept-5-yl-9-[2-(tetrahydropyran-4-yi)ethyl]8-trifluoromethyl-6,7,8,9-tetrahydropyrimldo[1,2-a]pyrimidin-4-one (compound 92) ·· .

126

F

Step 45.1: 2-(tetrahydro-2H-pyran-4-yl)ethyl 4-methylbenzenesulfonate

629 pL (4.47 mmol) oftriethylamine and 813 mg (4.10 mmol) of p-toluenesulfonyl chloride are added to a solution of 500 mg (3.73 mmol) of 2-(tetrahydropyran-4-yl)ethanol in 15 mL of DCM previously cooled to 0’C.

The reaction mixture is stirred at room température ovemight. The solution is taken up in DCM, washed with aqueous NaHCOs solution, dried over magnésium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 20/80 EtOAc/heptane) to give 840 mg of 2-(tetrahydro-2H-pyran-4-yl)ethyl 4methylbenzenesulfonate, corresponding to the following characteristics:

¹H NMR (300 MHz, δ in ppm, CDCh): 1.15-1.32 (m, 2H), 1.45-1.74 (m, 5H). 2.47 (s, 3H),

3.33 (td, 2H), 3.88-3.96 (m, 2H), 4.09 (t, 2H), 7.37 (d. 2H). 7.82 (d, 2H).

Step 45.2: (8S)-2-(1 S,4S)-2-oxa-5-azablcyclo[2.2.1]hept-5-yl-9-[2-(tetrahydropyran

4-yl)ethylJ-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimldln-4-one

198 mg (0.698 mmol) of 2-(tetrahydro-2H-pyran-4-yl)ethyl 4methylbenzenesulfonate and 104 mg (0.698 mmol) of sodium iodide are added to a solution of 170 mg (0.537 mmol) of (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8trifluoromethyl-ej.e.O-tetrahydropyrimidotl^-aJpyrimidin^-one and 525 mg (1.61

-· .

127 mmol) of césium carbonate In 5 mL of acetonitrile. The reaction mixture is heated in a Biotage microwave reactor at 100°C for 1 hour 15 minutes. The reaction medium is evaporated to dryness and the residue Is taken up in EtOAc and washed with water and with saturated NaCi. The organic phase is dried over magnésium sulfate and evaporated to dryness. The residue Is purified by chromatography on silica gel (eluent: 95/5 DCM/MeOH) to give 140 mg of (8S)-2-(1S_l4S)-2-oxa-5-azabicycîo[2.2.1]hept-5-yl-9-[2(tetrahydropyran-l-yOethyll-e-trifluoromethyl-e.T.e.G-tetrahydropyrimidotl^a]pyrimidin-4-one, the characteristics of which are as follows: LC/MS (method A): ESI+ [M+H]+: m/z 429 tr (min) = 0.61

Ή NMR spectrum (600 MHz, δ in ppm, DMSO-de): 1.09-1.25 (m, 2H), 1.46-1.57 (m, 3H), 1.58-1.67 (m, 2H), 1.82-1.89 (m, 2H), 2.04 (m, 1H), 2.34 (m, 1H), 2.96-2-3.22 (m, 3H), 3,23-3.37 (m, 4H), 3.63 (m, 1H), 3.73 (m, 1H), 3.82 (m, 2H), 4.11 (m, 1H), 4.21 (m, 1H), 4.57-5.01 (m, 3H).

Exemple 46: (8S)-2-(1S,4S)-2-oxa-5-azablcyclo[2.2.1]hept-5-yl-9-(tetrahydropyran-4ylmethyl)-8-tr1fluoromethyl-6,7,8,9-tetrahydropyrimldo[1,2-a]pyrimidin-4-one (compound 93)

Step 46.1: (8S)-2-chloro-9-(tetrahydropyran-4-ylmethyl)-8-trlfluoromethyl-6,7,8,9tetrahydropyrlmido[1,2-a]pyrimldln-4-one

A suspension of 200 mg (0.788 mmol) of (eS^-chloro-e-trifluoromethyl-ej.e.OtetrahydropyrimÎdo[1,2-a]pyrimidin-4-one and 771 mg (2.37 mmol) of césium carbonate in 10 mL of acetonitrile is stirred for 15 minutes at room température. 187 mg (0,788 ·· .

128 mmol) of (bromomethyl)tetrahydropyran are then added.

The reaction mixture Is heated in a Biotage microwave reactor at 100’C for 50 minutes. The crude product is evaporated and the residue Is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 DCM/MeOH) to give 220 mg of (8S)-2-chloro-9-(tetrahydropyran-4-yimethyi)-8trifluoromethyi-6,7,8,9-tetrahydropyrimido[1.2-a]pyrimidin-4-one, corresponding to the following characteristics:

LC/MS (method G): ESI+ [M+H]+: m/z 352 tr (min) = 2.08 ’H NMR spectrum (300 MHz, δ in ppm, DMSO-d_e): 1.04-1.42 (m. 2H), 1.42-1.57 (m. 2H), 2.04-2.33 (m, 2H). 2.34-2.46 (m. 1H), 2.95-3.07 (m, 1H), 3.17-3.30 (m, 3H), 3.79-3.89 (m, 2H), 4.04-4.21 (m, 2H), 4.72 (m, 1H), 5.89 (s, 1H).

Step 46.2: (8S1-241 S.4S)-2-oxa-5-azablcvclor2.2.1lhept-5-yl-9-(tetrahydropyran-4ylmethyl)-8-trifluoromethyl-e,7₁8_l9-tetrahydropyrimldo[1,2-a]pyrimldin-4-one

F

220 mg (0.62 mmol) of (8S)-2-chloro-9-(tetrahydropyran-4-ylmethyl)-8-trifluoromethyl-

6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 127 mg (0.93 mmol) of (1S,4S)-2oxa-5-azabicycio[2.2.1]heptane hydrochloride are mixed together. The powder obtained is placed in a tube and 244 pL (1.75 mmol) of triethylamine are added. The tube Is sealed and heated at 130^eC in an oil bath for 4 hours. The crude product obtained is taken up in ethyl acetate and the organic phase is washed with water, dried over magnésium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 DCM/MeOH) to give 180 mg of (8S)-2-(1S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-9-(tetrahydropyran-4-ylmethyl)-8-trifluoromethyl-6,7,8,9tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows: LC/MS (method A): ESI+ [M+HJ+: m/z 415 tr (min) = 0.57 ’H NMR (600 MHz, δ In ppm, DMSO-de): 1.10-1.38 (m. 2H), 1.40-1.56 (m, 2H), 1.79-1.89 (m, 2H), 2.06-2.22 (m, 2H), 2.32 (m, 1H), 2.89 (m. 1H), 2.95-3.14 (m, 2H), 3.20 (m, 3H),

3.61 (m, 1H), 3.73 (m. 1H). 3.83 (m. 2H), 4.07-4.17 (m, 2H), 4.56 (m. 1H), 4.60-4.96 (m,

129

3H).

Example 47:

4-((2S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2trifluoromethyl-3,4-dlhydro-2H,6H-pyrimido[1,2-a]pyrimidin-1ylmethyl)plperidine-1-carbaldehyde (compound 95)

Step 47.1: tert-butvl 4-bromomethylplperidlne-1 -carboxylate

A solution of 1 g (4.41 mmol) of tert-butyl 4-hydroxymethylpiperidine-1carboxylate in 25 mL of THF is cooled to 0^eC. 1.34 g (5.07 mmol) of triphenylphosphine and 2.02 g (5.96 mmol) of carbon tetrabromide are then added.

The réaction mixture is stirred at room température over the weekend.

The solution is taken up in ethyl ether. the insoluble matter is filtered off and the organic phase is evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 80/20 EtOAc/heptane) to give 960 mg of tert-butyl 4-bromomethylpiperidine-1carboxylate, the characteristics of which are as follows:

LC/MS (method G): ESI+ [M+H]+: m/z 279 tr (min) = 2.13 ’HNMR (300 MHz. δ in ppm.CDCh): 1.09-1.29 (m. 2H). 1.47 (s. 9H). 1.71-1.88 (m, 3H), 2.62-2.78 (m. 2H). 3.31 (d. 2H). 4.07-4.25 (m. 2H).

Step 47.2: tert-butyl 4-((2S)-8-(1S,4S)-2-oxa-5-azabicyclop.2.1]hept-5-yi-6-oxo-2trifluoromethyl-3,4-dihydro-2H,6H-pyrlmldo[1,2-a]pyrimidin-1ylmethyl)plperidine-1-carboxylate

130

788 mg (2.84 mmol) of tert-butyl 4-bromomethylpiperidine-1 -carboxylate and 425 mg (2.84 mmol) of sodium iodide are added to a solution of 690 mg (2.18 mmol) of (8S)-2(1 S, 4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9tetrahydropyrimido[1,2-a]pyrimidin-4-one and 2.13 g (6.54 mmol) of césium carbonate in 10 mL of acetonitrile. The reaction mixture is heated in a Biotage microwave reactor at 100“C for 3 hours. The reaction medium is evaporated to dryness and the residue is taken up in EtOAc and washed with water and with saturated NaCI. The organic phase is dried over magnésium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 DCM/MeOH) to give 510 mg of tert-butyl 4((2S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro2H,6H-pyrimido[1,2-a]pyrimidin-1-ylmethyl)piperidine-1-carboxylate, the characteristics of which are as follows:

LC/MS (method G): ESI+ [M+H]+: m/z 514 tr (min) = 2.45 ’H NMR (300 MHz, δ in ppm, DMSO-de): 0.93-1.03 (m, 1H), 1.11-1.32 (m, 3H), 1.38 (s, 9H), 1.44-1.64 (m, 2H), 1.76-1.91 (m, 2H). 1.99-2.39 (m, 3H), 2.78-3.32 (m, 5H), 3.60 (m, 1H), 3.71 (m, 1H), 3.86-3.99 (m, 2H), 4.06-4.19 (m, 2H), 4.48-4.92 (m, 3H).

Step 47.3: (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-piperid-4-ylmethyl· 8-trifluorom ethyl-6,7,8,9-tetrahydropyri m ido[1,2-a] pyri m idin-4-one

A solution of 280 mg (0.545 mmol) of tert-butyl 4-((S)-8-(1S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2a]pyrimidin-1-ylmethyl)piperidine-1-carboxylate in 10 mL of formic acid is stirred for 2 hours at room température. The reaction mixture is evaporated to dryness and the residue is taken up in DCM and evaporated to give 250 mg of (8S)-2-(1S,4S)-2-oxa-5azabicyclo[2.2,1]hept-5-yl-9-piperid-4-ylmethyl-8-trifluoromethyl-6,7,8,917195

131 tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as foilows: LC/MS (method G): ESI+ [M+HJ+: m/z 414 tr (min) * 1.31

Step 47.4:4-((2S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2trifIuoromethyl-3,4-dlhydro-2H,6H-pyrimldo[1,2-a]pyrlmldln-1ylmethyl)plperidlne-1-carbaldehyde

F mL (0.817 mmol) of ammonium formate are added to a suspension of 250 mg (0.545 mmol) of (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-piperid-4-ylmethyl8-trifiuoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one In 10 mL of 1,4dioxane. The reaction mixture is heated at 100’C for 2 hours and then evaporated to dryness. The residue Is taken up in EtOAc and washed with aqueous NaHCOs solution and with saturated NaCl. The organic phase is dried over sodium sulfate and evaporated to dryness. The product obtained Is purified by chromatography on silica gel (eluent: 90/10 DCM/MeOH) to give 120 mg of4-((2S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-

5-yl-6-oxo-2-trifIuoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1ylmethyl)piperidine-1-carbaldehyde, the characteristics of which are as foilows: LC/MS (method D): ESI+ [M+HJ+: m/z 442 tr (min) - 0.82 ¹H NMR (600 MHz, δ in ppm, DMSO-de): 0.91-1.24 (m, 2H), 1.56-1.75 (m, 2H), 1.81-1.91 (m, 2H), 2.14-2.29 (m, 2H), 2.36 (m, 1H), 2.54 (m, 1H), 2.96 (m, 2H), 3.15 (m, 1H), 3.21-

3.40 (m, 2H), 3.66 (m, 2H), 3.74 (m, 1H), 4.10-4.23 (m, 3H), 4.51 (m, 1H), 4.58-4.84 (m, 3H), 7.99 (m, 1H).

Example 48:

(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-{3,3,3-trifluoro-2hydroxy-2-trifluoromethylpropyl)-8-trifluoromethyl-6,7,8,9tetrahydropyrimldo[1,2-a]pyrimidin-4-one (compound 96) ·· .

132

F

264 mg (1.42 mmol) of bis(trifluoromethyl)oxirane are added to a solution of 300 mg (0.948 mmol) of (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl'8-tnfluoromethyl' e.y.e^tetrahydropyrimidofl^-alpyrimidin^-oneand 1.66 ml (1.66 mmol) of 1 M sodium hydroxide in 5 mL of 1,4-dioxane. The reaction mixture is heated in a Biotage microwave reactor at 130°C for 2 hours. The reaction medium is evaporated to dryness and the residue is taken up in EtOAc and washed with water and with saturated NaCI. The organic phase is dried over magnésium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 DCM/MeOH) to give 250 mg of (8S)-2-(1S_l4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(3₍3_l3-trifluoro-2-hydroxy-2trifluoromethylpropyD-B-trifluoromethyl-e.T.S.g-tetrahydropyrimidoil^-aJpyrimidin^one, the characteristics of which are as follows:

LC/MS (method A): ESI+ [M+H]+: m/z 497 tr (min) - 0.71 ¹H NMR (600 MHz, δ in ppm, DMSO-d_e): 1.81-1.95 (m, 2H), 2.21 (m, 1H), 2.44 (m, 1 H).

2.95-3.36 (m, 3H), 3.47-3.64 (m, 2H), 3.69 (m, 1H), 4.08 (m, 1H), 4.57-5.05 (m, 4H), 5.40 (m,1H), 8.74 (m, 1H).

Example 49:

(8S)-2-(1S,4S)-2-oxa-5-azabIcyclop.2.1]hept-5-yl-9-p-(3-oxa-8azabicyclop.2.1]oct-8-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9tetrahydropyrimldo[1,2-a]pyrimldln-4-one (compound 99)

Step 49.1: ((2S)-8-(1 S,4S)-2-oxa-5-azablcyclo[2.2.1]hept-5-yl-6-oxo-2trifluoromethyl-3,4-dihydro-2H,6H-pyrlmido[1,2-a]pyrimidln-1-yl)acetic acid .· .·

133

mg (2.22 mmol) of lithium hydroxide monohydrate are added to a solution of 720 mg (1.85 mmol) of methyl ((2S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1lhept-5-yl-6-oxo-

2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetate (préparation described In Step 38.1) in 20 mL of THF/water (1/1: v/v). The reaction mixture is stirred at room température for 2 hours, after which the THF is evaporated off and the solution is acidified with 1 N HCl and extracted with EtOAc. The organic phase is washed with water and with saturated NaCI, dried over magnésium sulfate and then evaporated to dryness to give 690 mg of ((2S)-8-(1S,4S)-2-oxa-5-azabicydo[2.2.1]hept-5-yl-6-oxo-2trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1 -yl)acetic acid, the characteristics of which are as follows:

LC/MS (method A): ESI+ [M+H]+: m/z 375 tr (min) = 1.63 ’H NMR (300 MHz, δ in ppm, DMSO-de): 1.81 (m, 2H), 2.02-2.18 (m, 1H), 2.32-2.43 (m, 1H), 3.10-3.32 (m, 3H), 3.49-3.59 (m, 1H), 3.68 (m, 1H), 3.98-4.08 (m, 1 H), 4.24-4.35 (m, 1H), 4.37-4.47 (m, 1H), 4.57-4.86 (m, 4H), 12.71 (m, 1H).

Step 49.2: (8S)-2-(1S,4S)-2-oxa-5-azablcyclo[2.2.1]hept-5-yl-9-[2-(3-oxa-8azablcyclop.Z.IJoct-e-ylJ^-oxoethyn-e-trifluoromethyl-ej.e.Stetra hydropyrimldo[1,2-a]pyrlmldln-4-one

pL (0.881 mmol) of N-methylmorpholine, 86 mg (0.44 mmol) of 1-(3dimethylaminopropyl)-3-ethy1carbodiimÎde hydrochloride and 69 mg (0.44 mmol) of 1hydroxybenzotriazole hydrate are added to a solution of 150 mg (0.4 mmol) of ((2S)-8(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H ·· .

134 pyrimido[1,2-a]pyrimidin-1-yl)acetic acid in 10 mL of DMF. The reaction mixture is stirred for 10 minutes at room température, followed by addition of 66 mg (0.44 mmol) of (1R,5S)-3-oxa-8-azabicyclo[3.2,1]octane hydrochloride. The reaction is continued at room température for 5 hours. The DMF Is evaporated off and the residue obtained is purified by chromatography on silica gel (eluent: 95/5 DCM/MeOH) to give 130 mg of (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-(3-oxa-8-azabicyc!o[3.2.1]oct-8yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8₍9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:

LC/MS (method A): ESI+ [M+H]+: m/z 470 tr (min) - 0.5 ¹H NMR (600 MHz, δ in ppm, DMSO-de) performed at 140^eC: 1.77-1.95 (m, 6H), 2.21-

2.43 (m, 2H), 3.14-3.38 (m, 3H), 3.53-3.72 (m. 6H), 3.98 (d, 1H), 4.27-4.48 (m, 4H), 4.62 (s, 1H), 4.71 (s, 1H), 4.76 (s, 1H), 5.11 (d, 1H).

Example SO: (8S)-9-(3-hydroxy-3-methylbutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept5-yl-8-trlfluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrlmldin-4-one (compound 50)

430 pL (1.29 mmol) of a 3 M solution of méthylmagnésium bromide in ethyl ether are added at 0°C to a solution of 173 mg (0.43 mmol) of methyl 3-((2S)-8-(1S,4S)-2-oxa5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2a]pyrimidin-1-y1)-propionate (préparation described in Step 39.1) in 10 mL of THF. The reaction medium is stirred at 0^eC for 2 hours. 10 mL of saturated ammonium chloride solution are added to the reaction medium. The resulting mixture is extracted with ethyl acetate and the organic phase is dried over magnésium sulfate and evaporated to dryness. After purification by chromatography on silica gel (eluent: 95/5 DCM/MeOH), 128 mg of (8S)-9-(3-hydroxy-3-methylbutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, corresponding to the following characteristics:

LC/MS (method A): ESI+ [M+H]+: m/z 403 tr (min) = 0.53

135 ’H NMR (600 MHz, δ in ppm, DMSO-d_e): 1.09 (s, 3H), 1.12 (s, 3H), 1.64-1.76 (m, 2H),

1.78-1.87 (m, 2H), 2.02 (m, 1H), 2.33 (m, 1H), 3.13 (m, 1H), 3.24-3.35 (m, 2H), 3.63 (m, 1H), 3.69 (m, 1H), 4.12 (m, 1H), 4.20 (m, 1H), 4.25 (s, 1H), 4.53 (m, 1H), 4.59-5.03 (m, 4H).

Example 51:

(8S)-9-(1-hyd roxycyclopropy Imethyl )-2-(1 S,4S)-2-oxa-5azablcyclo[2.2.1]hept-5-yl-8-trlfIuoromethyl-6,7,8,9-tetrahydropyrimldo[1,2a]pyrlmldln-4-one (compound 104)

F

146 mg (0.515 mmol) of titanium (IV) isopropoxide are added to a solution of 200 mg (0.515 mmol) of methyi ((2S)-8-(1S,4S)-2-oxa-5-azabicycloI2.2.1]hept-5-yl-6-oxo-2trifluoromethyl-3,4-dihydro-2H_l6H-pyrimido[1_I2-a]pyrimidin-1-yl)acetate (préparation described in Step 38.1) in 3 mL of THF. The solution is cooled to 0*C, followed by dropwise addition of 858 pL (2.58 mmol) of 3 M ethylmagnesium bromide in ethyl ether. The reaction mixture is stirred for 30 minutes at room température. 10 mL of saturated ammonium chloride solution are added to the reaction medium. The resulting mixture is extracted with ethyl acetate and the organic phase is dried over magnésium sulfate and evaporated to dryness. After purification by chromatography on silica gel (eluent: 95/5 DCM/MeOH), 80 mg of (8S)-9-(1-hydroxycyclopropylmethyl)-2-(1S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin4-one are obtained, corresponding to the following characteristics:

LC/MS (method A): ESI+ [M+H]+: m/z 387 tr (min) = 0.52 ’H NMR (600 MHz, δ in ppm, DMSO-de): 0.52-0.71 (m, 4H), 1.77-1.86 (m, 2H), 2.27 (m, 1H), 2.40 (m, 1H), 3.20-3.29 (m, 3H), 3.45 (d, 1H), 3.59 (m, 1H), 3.72 (m, 1H), 4.18 (m, 1 H), 4.37 (m, 1H), 4.59-5.01 (m, 4H), 5.54 (s, 1H).

Example 52:

(8S)-2-(1S,4S)-2-oxa-5-azablcyclo[2.2.1]hept-5-yl-9-qulnolln-5-ylmethyl-8·· .

136 trif1uoromethyl-6,7,8,9-tetrahydropyrimldo[1,2-a]pyrimldln-4-one (compound 106)

Step 52.1: Qulnolln-5-ylmethanol

HO

A suspension of 171 mg (4.49 mmol) of lithium aluminum hydride in 20 ml of THF is cooled to 0*C. A solution of 700 mg (3.74 mmol) of methyl quinoline-5-carboxylate in 5 ml of THF is then added dropwise. The reaction mixture is stirred at 0’C for 1 hour and then hydrolysed with, in this order, 0.17 ml of H₂O, 0.17 ml of NaOH and 3 « 0.17 ml of H₂O. The precipitate formed is fïltered off and washed with THF and then with EtOAc. The organic phase is washed with saturated NaCi solution, dried and evaporated. After purification by chromatography on silica gel (eluent: 95/5 DCM/MeOH), 190 mg of quinolin-5-ylmethanol are obtained, corresponding to the following characteristics: LC/MS (method G): ESI+ [M+H]+: m/z 160 tr (min) = 0.43 ’H NMR (300 MHz, δ in ppm, DMSO-de): 4.97 (d, 2H), 5.40 (t, 1H), 7.51-7.65 (m, 2H),

7.72 (t, 1H), 7.93 (d, 1 H), 8.53 (d, 1H), 8.88-8.93 (m, 1H).

Step 52.2: 5-chloromethylquinoline hydrochlorlde ci

A solution of 190 mg (1.19 mmol) of quinolin-5-ylmethanoi in 5 ml of thionyl chloride is stirred for 10 minutes at room température and then refluxed for 2 hours. The reaction mixture Is evaporated, the solid obtained is taken up in ethyl ether and the solution is fïltered, washed with ethyl ether and dried to give 255 mg of 5chloromethylquinoline hydrochloride, corresponding to the following characteristics: LC/MS (method G): ESi+ [M+H]+: m/z 178 tr (min) = 1.07 ’H NMR (300 MHz, δ in ppm, DMSO-de): 5.40 (s, 2H), 7.96-8.10 (m, 3H), 8.34 (m, 1H),

9.17 (m, 1H), 9.27 (m, 1H).

·· .

137

Step 52.3: (8S)-2-Chloro-9-qulnoiln-5-yimethyl-8-trifluoromethyf-6,7,8_t9tetrahydropyrimido[1,2-a]pyrlmidin-4-one

A suspension of 180 mg (0.709 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9tetrahydropyrimido[1,2-a]pyrimidin-4-one and 693 mg (2,13 mmol) of césium carbonate in 10 mL of acetonitrile is stirred for 15 minutes at room température. 182 mg (0.851 mmol) of 5-chloromethylquinolîne hydrochloride are then added, along with a catalytic amount of sodium iodide.

The reaction mixture is stirred at room température for 5 hours. The crude product is evaporated and the residue is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnésium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 DCM/MeOH) to give 160 mg of (8S)-2-chloro-9-quinolin-5-ylmethyl-8-trif!uoromethyl-6,7,8,9-tetrahydropyrimido[1,2a]pyrimidin-4-one, corresponding to the following characteristics: LC/MS (method G): ESI+ [M+H]+: mlz 395 tr (min) = 2.00

Ή NMR spectrum (300 MHz, δ in ppm, DMSO-de): 2.24-2.46 (m, 2H), 3.35-3.47 (m, 1H), 4.26-4.36 (m, 1H), 4.66-4.80 (m. 1H), 5.04 (d, 1H), 5.83 (d, 1H), 5.98 (s, 1H), 7.42 (d, 1H), 7.61 (m, 1H), 7.73 (t, 1H), 7.97 (d, 1H), 8.57 (d, 1H), 8.95 (m, 1H).

Step 52.4: (8S)-2-(1S,4S)-2-oxa-5-azablcyclo[2.2.1]hept-5-yl-9-quinoiin-5yimethyl-8-trifluoromethyi-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one

160 mg (0.40 mmol) of (8S)-2-chloro-9-quino!in-5-ylmethyl-8-trifluoromethyl-

6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 82 mg (0.60 mmoi) of (1S,4S)-2oxa-5-azabicyclo[2.2.1]heptane hydrochloride are mixed together. The powder obtained ·· .

138 is placed in a tube and 158 pL (1.13 mmol) oftriethylamine are added. The tube is sealed < and heated at 130’C in an oil bath for 7 hours. The crude product obtained is taken up in DCM and the organic phase is washed with water, dried over magnésium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 DCM/MeOH) to give 125 mg of (8S)-2-(1S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-9-quinolin-5-ylmethy l-8-trifluoromethyl-6,7,8,9tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows: LC/MS (method A): ESI+ [M+H]+: m/z 458 tr (min) = 0.47 ’H NMR (600 MHz, δ in ppm, DMSO-d_e): 1.42-1.67 (bm, 2H), 2.29-2.46 (m, 2H), 2.74-

3.20 (bm, 4H), 3.27-3.36 (m, 1H), 4.27 (m, 2H), 4.42 (m, 1H), 4.52-4.80 (bm, 2H), 4.85 (m, 1H), 5.91 (d, 1H), 7.39 (d, 1H), 7.56 (m, 1H), 7.71 (t, 1H), 7.93 (d, 1H), 8.62 (m, 1H),

8.92 (m, 1H).

Example 53: (S)-9-[2-(6-difluoromethoxypyrid-3-yl)-2-oxoethyn-2-(1S,4S)-2-oxa-5azabicycio[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimldo[1,2a]pyrlmldin-4-one (compound 114)

Step 53.1: 5-bromo-2-difluoTomethoxypyridine

Br

5.42 g (34.48 mmol) of sodium chlorodifluoroacetate are added to a solution of 5 g (28.74 mmol) of 5-bromo-1 H-pyrid-2-one in 120 ml of acetonitrile, under argon.

The white suspension obtained is refluxed ovemight and then evaporated to dryness. The residue is taken up in aqueous ammonium chloride solution and extracted with EtOAc. The organic phase is dried over magnésium sulfate and then evaporated to dryness. The crude product is purified by chromatography on silica gel (eluent: 0/100 EtOAc/heptane to 20/80 EtOAc/heptane over 35 minutes) to give 2.2 g of 5-bromo-2difluoromethoxypyridine, corresponding to the following characteristics:

·· .·

139

LC/MS (method G): ESI+ [M+H]+: m/z 226 tr (min) = 2.08 ’H NMR spectrum (300 MHz, δ in ppm, DMSO-d_e): 7.12 (d, 1H), 7.67 (t, 1 H), 8.15 (dd, 1H), 8.43 (d, 1 H).

Step 53.2: 5-(1-butoxyvlnyl)-2-difluoromethoxypyrldine

g (4.46 mmol) of 5-bromo-2-difluoromethoxypyridine in 20 mL of H2O/DMF (1/4: v/v), 1.46 mL (11.16 mmol) of N-butyl vinyl ether, 30.68 mg (0.13 mmol) of palladium(ll) acetate, 125 mg (0.29 mmol) of 1,3-bis(diphenylphosphino)propane and 746 mg (5.36 mmol) of potassium carbonate are placed in a microwave tube. After microwave irradiation for 1 hour at 120'C, the crude product is taken up in water and extracted with DCM. The organic phase is dried over magnésium sulfate and then evaporated to dryness. The crude product is purified by chromatography on silica gel (eluent: 0/100 EtOAc/heptane to 20/80 EtOAc/heptane over 35 minutes) to give 110 mg of 5-(1butoxyvinyl)-2-difluoromethoxypyridine, corresponding to the following characteristics: LC/MS (method G): ESI+ [M+H]+: m/z 244 tr (min) = 2.74 ’H NMR spectrum (300 MHz, δ in ppm, DMSO-de): 0.94 (t, 3H), 1.38-1.53 (m. 2H). 1.66-

1.78 (m, 2H), 3.86 (t, 2H), 4.38 (d, 1H), 4.85 (d, 1H), 7.09 (d, 1 H), 7.71 (t, 1H), 8.09 (dd, 1H), 8.49 (d, 1 H).

Step 53.3: 2-bromo-1 -(6-dlfluoromethoxypyrid-3-yi)ethanone

A solution of 100 mg (0.41 mmol) of 5-(1-butoxyvinyl)-2-dif!uoromethoxypyridine in 4 mL of THF/H2O (3/1 : v/v) ls cooled to 0’C. 74 mg (0.41 mmol) of N-bromosuccinimide are then added in a single portion. The yellow solution is stirred at 0’C for 1 hour and then taken up in water and extracted with EtOAc. The organic phase is washed with saturated aqueous NaHCOj solution and then with saturated NaCI solution, dried over magnésium sulfate and then evaporated to dryness. The crude product is purified by chromatography on silica gel (eluent: 20/80 EtOAc/heptane to 40/60 EtOAc/heptane •· .·

140 over 15 minutes) to give 82 mg of 2-bromo-1-(6-difluoromethoxypyrid-3-yl)ethanone_lcorresponding to the following characteristics:

LC/MS (method G): ESI+ [M+HJ+: m/z 266 tr (min) = 1.84 ¹H NMR spectrum (300 MHz, δ in ppm, DMSO-de): 4.91 (s, 2H), 7.19 (d, 1H), 7.75 (t, 1H), 8.36 (dd, 1H), 8.85 (d, 1H).

Step 53.4: (8S)-9-[2-(fr-difluoromethoxypyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2a]pyrimldin-4-one

The procedure used is the same as that of step 12.3.

120 mg (0.38 mmoi) of (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8trifluoromethyl-ej.S.g-tetrahydropyrimidonÆ-aJpyrimidin^-one, 371 mg (1.42 mmol) of césium carbonate, 121 mg (0.45 mmol) of 2-bromo-1-(6-difluoromethoxypyrid-3yl)ethanone and 15 mL of acetonitrile were used in the reaction. After purification by chromatography on silica gel (eluent A/B: DCM/MeOH, gradient A/B: 10 min 0% B, 125 min 10% B, t 30 min 10% B), 38 mg of (8S)-9-[2-(6-difluoromethoxypyrid-3-yl)-2oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yi-8-trif1uoromethyl-6,7,8,9tetrahydropyrimido[1,2-a]pyrimidin-4-one were obtained, corresponding to the following characteristics:

LC/MS (method A): ESI+ [M+H]*: m/z 502 tr (min) = 0.67 ¹H NMR (600 MHz, δ in ppm, DMSO-de): 1.56-1.74 (m, 2H), 2.21 (m, 1 H), 2.44 (m, 1H),

2.78-3.09 (m, 3H), 3.23 (m, 1H), 3.47-3.85 (m, 1H), 4.37 (m, 1 H), 4.41-4.53 (m, 2H), 4.53-4.71 (m, 3H), 5.66-5.78 (m, 1H), 7.26 (d, 1H), 7.82 (t, 1H), 8.48 (dd, 1H), 9.01 (m, 1H).

The table which follows illustrâtes the chemical structures and the physical properties of some examples of compounds according to the invention. In this table:

- in the Sait column, represents a compound in free base form, whereas HCI represents a compound In hydrochloride form;

141

-the Data’ column successively indicates the LC/MS analytical method used (A, B, C or F) and detailed in the experimental section, the rétention time (tr) of the compound expressed in minutes, and the peak [M+H]* identified by mass spectrometry.

Table

(D

142

The asterisk * on Ri and L indicates the atom of attachment of Ri to L.

No.	n	Y	Ri	L	Sait	Data
1 Ex. 13	1	b?	O·	*-C(CH₃)2-CH2~	-	Method B: tr (min) ^c 0.53 [M+HJ+: 450
2 Ex. 27	1	^H/p	o·	*-C0-CH2-	-	Method A: tr (min) = 0.50 [M+HJ+: 436

£ϊί

No.	n	Y	Ri	L	Sait	Data
3	1	Y--	N=/	•-CO-CHz-	-	Method A: tr (min) = 0.38 [M+HJ+: 451
4 Ex. 28	1			‘-CO-CHz-	-	Method A: tr (min) = 0.49 [M+HJ+: 450
5 Ex. 42	1	^Η,ίΛ°		•-CO-CH2-	-	Method A: tr (min) = 0X1 [M+H]+: 465
6 Ex. 25	1	^Η,ίΛ°	m	‘-CO-CH2-	-	Method A: tr (min) = 0.48 [M+HJ+: 479
7 Ex. 6	1		o-	-CO-CH2-	-	Method A: tr (min) = 0.51 [M+HJ+: 436

No.	n	Y	Ri	L	Sait	Data
8	0	J?	\ γχ / N⁼/	•-CO-CH2-	-	Method A: tr (min) = 0.49 [M+HJ+: 479
9 Ex. 43	0		K)*	•-CO-CH2-	-	Method A: tr (min) = 0.42 [M+HJ+: 465
10	0	^Η';Λ^Ο		•-CH2-CH2-	-	* Method C tr (min)-1.19 [M+HJ+: 451
11	0	^H'iT°	η,ν-^Ά· _N=/	•-CO-CH2-	-	Method A: tr (min) = 0.38 [M+HJ+: 451
12 Ex. 31	1	*·	o- N^⁷	•-CH2-CH2-	-	Method A: tr (min) = 0.39 [M+HJ+: 422

Slrl

No.	n	Y	Ri	L	Sait	Data
13	0	'A	o- N^⁷	•-CHrCHz-	-	Method A: tr (min) = 0.39 [M+Hl+:422
14 Ex. 41	1		j—OH KJ·	*-CO-CHz-	-	Method A: tr (min) = 0.40 [M+H]+:495
15 Ex. 3	1	A	b·	*-CO-CHz-	-	Method A: tr (min) = 0.51 [M+HJ+: 450
16 Ex. 7	0	-ft-	b- N^⁷	-CO-CHz-	-	Method A: tr (min)= 0.52 [M+HJ+: 450
17 Ex. 29	0	A	AJN^=/	•-CO-CH2-	-	Method A: tr (min) = 0.49 [M+HJ+: 450

146

No.	n	Y	Ri	L	Sait	Data
18	0		Q	•-CO-CH2-	-	Method A: tr (min) = 0.48 [M+H]+: 450
19 Ex. 9	1		Q-	•-CO-CH2-	-	Method A: tr (min) = 0.48 [M+H]+: 450
20 Ex. 12	1		0- N=/	•-CO-CHz-	-	Method A: tr (min) = 0.50 [M+HJ+: 450
21 Ex. 30	0		O· N^⁷	•-CO-CH2-	-	Method A: tr (min) = 0.51 [M+HJ+: 436
22	1	4t	νηΓΛ· ^H \=/	•-CO-CH2-	-	Method A: tr (min) = 0.45 [M+HJ+: 491

No.	n	Y	Ri	L	Sait	Data
23 Ex. 14	1		M °^·	•-CHz-CHz-	-	Method A: tr (min) = 0.60 [M+HJ+: 507
24 Ex. 15	0		M	•-CHî-CHî^-	-	Method A: tr (min) = 0.60 [M+HJ+: 507
25 Ex. 2	1		“6-	-CH2-CH2-	-	Method A: tr (min) = 0.55 [M+HJ+: 442
26 Ex. 8	0	-ff-	6-	•-CH2-CH2—	-	Method A: tr (min) = 0.56 [M+HJ+: 442
27	1			•-CHî-CHî^-	-	Method A: tr (min) = 0.46 [M+HJ+: 439

90 :+[H+«] 870 = (uiw) a *V poyisim	-		•O-ⁿ'^h	•4V OV''H	0	ζε
997 :+[H+hJ Z70 = (u\|uj) a :y poqiaw	-	^HO-OO-·	/=N •O-^N'^H	4v Oj-H	L	ιε
90 :+Ih+W] Ζ9Ό = (u\|ui) fl :y ροφβη	-	^HO-OO-·	k	4V oJ^'H	0	οε
90 :+ÏH*H] Ζ9Ό = (u\|ui) fl :V poiflBH	-	^HO-OO-·		„-FV OjH	L	9Z •xg 6Z
60 :+[H+Wl 970 = (ujui) fl :y poqpvn	-			^H4y OJ-H	0	8Z
nea	lies	Ί	’H	λ	u	•ON

8trl

149

No.	η	Y	Ri	L	Sait	Data
33	1	^Η,ίΛ°	R> F N^=/	•-CO-CH2-	-	Method A: tr (min) = 0.67 [M+HJ+: 504
34	1	--ft-	/—OH /^nhO	•-CO-CH2—	-	Method A: tr (min)^c 0.47 [M+H]+: 509
35	1			•-CO-CH2—	-	Method A: tr (min) = 0.67 [M+H]+: 480
36	1	H.J^O	H^-X· N^=/	•-CO-CH2-	-	Method A: tr (min) = 0.43 [M+H]+: 479
37	1		4^.	•-CO-CH2-	-	Method A: tr (min) = 0.69 [M+HJ+: 501

150

No.	n	Y	Ri	• L	Sait	Data
38 Ex. 16	1			•-CO-CH2-	-	Method A: tr (min) = 0.49 [M+HJ+: 439
39	1	fr	à'	•-C0-CH2-	-	Method A: tr (min) = 0.52 [M+H]+: 440
40	1	-ft-	'-p- F	•-CO-CHs-	-	Method A: tr (min) = 0.68 [M+H]+: 471
41	1		OO	•-CO-CH2-	-	Method A: tr (min) = 0.64 [M+HJ+: 520
42	1		N=—	*-CO-CHî-	-	Method A: tr(min) = 0.62 [M+HJ+: 460

1S1

152

No.	n	Y	Ri	L	Sait	Data
48 Ex. 1	1	it.	^f-0·	•-CO-CH2—	-	Method A: tr (min) = 0.68 [M+H]+: 471
49 Ex. 39	1	it.	T HO	-CHî-CHz-	-	Method A: tr (min) = 0.63 [M+H]+: 431
50 Ex. 50	1	it-	S· HO	•-CHt-CHz-	-	Method A: tr (min) = 0.53 [M+H]+: 403
51 Ex. 18	1	it-	Q, /N-N	*-CHz~	-	Method A: tr (min) = 0.68 [M+H]+: 461
52 Ex. 19	1	it.		-CO-CHz-	-	Method A: tr (min) s 0.65 [M+H]+: 507
53 Ex. 4	1	it.	0¼.	-CO-CHz-	-	Method A: tr (min) = 0.58 [M+H]+: 454

153

No.	n	Y	Ri	L	Sait	Data
54 Ex. 38	1		% HO	•-CHj-	-	Method A: tr (min) = 0.63 [M+HJ+: 417
55	1	U	N. b-	•-CO-CHz-	-	Method A: tr (min) = 0.61 [M+H]+: 460
56 Ex. 5	1	if-		«-CO-CHj-	-	Method A: tr (min) = 0.60 [M+HJ+: 401
57 Ex. 21	1			•-CO-CHj-	-	Method A: tr (min) = 0.60 [M+HJ+: 523
58	1	Η.ΪΌ	%	«-CO-CHi-	-	Method A: tr (min) = 0.55 [M+H]+: 509
59	1		0 y N	•-CHj-	-	Method C tr (min) = 0.85 [M+H]+: 413

No.	n	Y	Ri	L	Sait	\| Data
60	1	H.J^O	TJ II n	•-CO-CHî-	-	Method A: tr (min) = 0.62 [M+H]+: 504
61	1	H.J^O	b·	•-CO-CH2-	-	Method A: tr (min) = 0.64 [M+H]+: 493
62 Ex. 11	1	«	O·	•-CO-CH2-	-	Method A: tr (min) = 0.52 [M+HJ+: 443
63 Ex. 33	1	Ύ-	r^f °-fy·	•-CO-CH2-	-	Method A: tr (min) - 0.62 [M+H]+: 498
64	1	<	Æ^F F	•-CO-CH2-	-	Method A: tr (min) = 0.65 [M+H]+:515
65	1		Q- O—	•-CO-CH2-	-	Method A: tr (min)= 0.63 [M+H]+: 466

155

No.	n	Y	Ri	L	Sait	Data
66	1		o* A	•-CO-CHj-	-	Method A: tr (min) = 0.40 [M+H]+:439
67	1			•-CO-CHr-	-	Method C tr (min) = 0.88 [M+H]+: 399
68 Ex. 40	1		o·	•-CO-CHr-	-	Method A: tr (min) = 0.59 [M+HJ+: 436
69 Ex. 20	1		A· N-N\	•-CO-CHr-	-	Method A: tr (min) “ 0.54 [M+HJ+: 439
70 Ex. 37	0	o N	Æ'^;- ”-O>·	•-CH2-CH2-	-	Method B: tr (min) = 0.69 [M+HJ+: 536
71 Ex. 34	1	O A N	^e~0·	*-CHOH-CHz- OH abs. conf. (S)	-	Method B: tr (min) b 0.71 [M+H]+:499

156

3	Μ ο*	Μ [Π Μ G» χ <η	W [Π Μ σ> χ 4».	Μ C4	W [Π Μ W X Μ	I No. \|
ο	ο		ο		Ο	3
Ο Ν		ο <Λ Ν	Ο <Λ Ν	ο <Λ Ν	Ο Ν	-<
•	ο ό •	0 *	ν'Ί ό^Λ *	0 •	I Ο ό •	50
A X ο X Ί	A X A X Ί	A ? X Ί	A X ?, X Ί	ό g X Ί	δ X A X Ί	1“
1	1	1	δ	4	1	ω « ί?
£ 5 = 3 1 5 Λ 7 â fe « œ CO N	·= ’ΐ ? λ π a fe £ ο <η ~ W	Method Β: tr (min) = 0.55 (Μ+Η]+: 450	?3 ? 3 ϊ ? * ιι α. 8 p m β « <η	Method F tr (min) = 0.84 [M+H]+: 449	Method Β: tr (min) = 0.68 [M+HJ+: 451	ο ω ΕΓ

No.	n	Y	Rt	L	Sait	Data
78	0	0 A N	\ °O	•-CH2-CH2-	HCl	Method B: tr (min) = 0.58 [M+H]+: 536
79	0	0 N	O·	‘-CHOH-CHz- OH abs. conf. (S)	-	Method B: tr (min) = 0.65 [M+HJ+: 451
80 Ex. 24	1	0 N	O-	*-CH0H-CHzOH abs. conf. (S)	-	Method B: tr (min) = 0.68 [M+HJ+: 451
81	1	0 N		•-CHî-CHr-	-	Method B: tr (min) = 0.81 [M+HJ+: 465
82	1	0 A N	00·	*-CH0H-CH2- OH abs. conf. (R)	-	Method B: tr (min) = 0.85 [M+HJ+: 507
83	1	0 A N	HQ—y>~‘	•-CH2-CH2—	-	Method B: tr (min) = 0.68 [M+H]+: 451

158

No.	n	Y	Ri	L	Sait	Data
84 Ex. 22	1	A N	qa-	•-CH2-CH2-	-	Method B: tr (min) » 0.85 [M+H]+: 449
85	1	0 N	0·	•-CO-CH2—	-	Method B: tr (min) = 0.52 (M+HJ+: 450
86	1	A N	fl· F^/^N'N F	•-CH2—	-	Method F tr (min) = 0.83 [M+HJ+: 461
87	1	A N	o·	•-CO-CH2—	-	Method F tr (min) - 0.83 [M+HJ+: 450
88	1	0 A N	Q-	•-CO-CH2-	-	Method F tr (min) -1.01 [M+HJ+: 450
89	1			•-CH2-CH2-	-	Method A: tr (min)= 0.55 [M+HJ+: 470

OS* :+lH+Hl 10*1 = (u\|tu)j) a poqiaw	-	-^ïHO*·	<X	4V	t	Z* •*3 SB
9S* :+(H+Wl W0 = (u]uj)j1 apomen	-	^HO-·	•CM	^Hïy	t	*6
St* :+[H+H] ZSO =1 (u\|ui) J1 :y potnaim	-	^HD-·	O	OJ'-H	t	9* *3 CB
62* i+lH+Hl t9’0s(u\|iu)Jî :y poinaim	-		O	Mv' OjH	t	S* *3 26
tS MH+hI 29‘0 = (u\|iu) Jl :y poipayn	-	-*HO-O0-	•05	OjH	t	tB
99* :+[H+W) W0=*(u\|uj)ji :y poinaw	-		<x	^h4V OJH	t	** •xg 06
eieg	lies	1		λ	U	©N

651 ο *Ο

Νο.	η	Y	Ri	L	Sait	Data
96 Εχ. 48	1	^ΗΆ°		*-CHz-	-	Method A: tr (min) = 0.71 [M+HJ+: 497
97	1	^ΗΆ°		•-CHî-CHj-	-	Method A: tr (min) = 0.68 [M+HJ+: 511
98	1	ïft.	0.	•-CO-CHj-	-	Method A: tr (min) “ 0.51 [M+HJ+: 470
99 Εχ. 49	1	-if-		•-CO-CHj-	-	Method A: tr (min) “ 0.5 [M+H]*: 470
100	1		A	•-CH2-CH2—	-	Method A: tr (min) = 0.6 [M+HJ+: 429
101	1	^-4f.	X o	*-CHz~	-	Method D tr (min) = 0.95 [M+H]+: 415

No.	n	Y	Ri	L	Sait	Data
102	1			•-CHî-CHî-	-	Method A: tr (min) = 0.68 [M+H]+: 455
103	1	^Η'ίΛ° At^h		•-CH2-	-	Method D tr (min) = 1.13 [M+HJ+: 441
104 Ex. 51	1	^h>Tp	O X	•-CH2-	-	Method A: tr (min) = 0.52 [M+H]+: 387
105	1	Hj^O At^h	V HO----	•-CHj-CHî—	-	Method A: tr (min) = 0.53 [M+H]+: 401
106 Ex. 52	1	4f	O O·	•-CH2-	-	Method A: tr (min) = 0.47 [M+HJ+: 458

162

No.	η	Y	Ri	L	Sait	Data
107	1	fe	0	•-CO-CH?-	-	Method A: tr (min) = 0.S7 [M+H]+: 456
108	1		'fe-	•-CO-CHî-	-	Method A: tr (min) = 0.54 [M+H]+: 513
109	1			*-CHz-	-	Method A: tr (min) = 0.53 [M+HJ+: 458
110	1	^Hfep fe	O·	*-CO-CHî-	-	Method A: tr (min)= 0.56 [M+HJ+: 444
111	1	^Hfep fe	<o ⁰O·	•-CHrCHi-	-	Method A: tr (min)= 0.49 [M+H]+: 550

163

No.	n	Y	Ri	L	Sait	Data
112	1		\ —0	•-CO-CHz-	-	Method A: tr (min) = 0.53 [M+HJ+: 418
113	1	-ft-	ib «	•-CO-CH?-	-	Method A: tr (min) = 0.38 [M+HJ+: 475
114 Ex. 53	1	4f-	N—^J	*-CO-CH?-	-	Method A: tr (min)^a 0.67 [M+HJ+: 502
115	1	H.J^O	°vO °-Q-	•-CHî-CHz—	-	Method A: tr (min) = 0.61 [M+HJ+: 564
116	1	4f-	A F Q ^F \ F		-	Method A: tr (min) = 0.67 [M+HJ+: 479

No.	n	Y	Ri	L	Sait	Data
117	1	υλ°	A _ °O	•-CHrCHz-	-	Method A: tr (min)= 0.49 [M+HJ+: S08
118	1	^Η>Λ°		•-CO-CH2-	-	Method A: tr (mln)^c 0.79 [M+HJ+: 567
119	1	Hj\>		•-CO-CH2-	-	Method A: tr (min) = 0.48 [M+H]+: 484

165

The compounds according to the invention underwent pharmacologîcal trials to détermine their inhibitory effect on the growth of Plasmodium falciparum.

Antimalarial activity test

The compounds according to the invention underwent pharmacologîcal trials to détermine their inhibitory effect on the growth of Plasmodium falciparum (strain NF54 sensitive to inhibition with chloroquine) in an in vitro test using infected human érythrocytes. The growth of the parasites is measured via the incorporation of tritiated hypoxanthine compared with the incorporation in the absence of drug. The tests are performed in 96-well microplates (Falcon™ 96-well microtiter plates, ref. No. 353072) in RPMI1640 solutions (10.44 g/l) (without hypoxanthine) with HEPES (5.94 g/l), NaHCOa (2.1 g/l), neomycin (100 g/mL)+ AlbumaxR II (5 g/l) supplemented with human érythrocytes with a final hematocrit of 1.25% and a final parasitemia of 0.15%.

The stock solution of the compounds Is prepared at 10 mg/mL in DMSO. For the test, fresh solutions atthe desired concentrations are prepared In RPMI medium. For the test, 100 pl of compound are mixed with 100 μΙ of infected blood. For the détermination of the IC» values, the compounds are tested in twofold serial dilution.

The plates are incubated at 37^eC under a humid atmosphère with 93% N₂, 4% CO2 and 3% O2. After 48 hours, 50 μ! of ³H-hypoxanthine (= 0.5 pCi) in RPMI medium are added to each well and incubation is continued for a further 24 hours. Next, the plates are washed with distilled water and the cell lyzate is transférred onto fiberglass filters. The filters are dried and the radioactivity is determined by liquid scintillation. The results in cpm are converted into percentages of inhibition. The inhibitory activity is given by the concentration that inhibits 50% of the growth of the parasite relative to a control without compound.

The IC» values are between 3 nM and 4000 nM, in particular between 3 nM and 384 nM and even more particularly less than or equal to 200 nM.

166

The table of results for the antimalarial activity test is given below:

Compound No.	ICeo Plasmodium falclparum NF54
1	20 nM
2	15 nM
3	13 nM
4	58 nM
5	95 nM
6	>200 nM
7	10 nM
8	>200 nM
9	>200 nM
10	11 nM
11	40 nM
12	9nM
13	21 nM
14	70 nM
15	150 nM
16	>200 nM
17	160 nM
18	93 nM
19	24 nM
20	35 nM
21	82 nM
22	>200 nM
23	3nM
24	8nM
25	<3.4 nM
26	10 nM
27	<4.5 nM
28	9nM
29	46 nM
30	>240 nM
31	75 nM
32	4 nM
33	4000 nM
34	>200 nM
35	>210 nM
36	240 nM
37	230 nM
38	140 nM
39	98 nM
40	80 nM

Compound No.	ICso Plasmodium falclparum NF54
41	930 nM
42	80 nM
43	42 nM
44	106 nM
45	112 nM
46	398 nM
47	13 nM
48	27 nM
49	6nM
50	8 nM
51	65 nM
52	130 nM
53	870 nM
54	10 nM
55	28 nM
56	45 nM
57	65 nM
58	53 nM
59	87 nM
60	19 nM
61	130 nM
62	11 nM
63	384 nM
64	39 nM
65	21 nM
66	73 nM
67	43 nM
68	27 nM
69	96 nM
70	12 nM
71	23 nM
72	37 nM
73	44 nM
74	68 nM
75	80 nM
76	93 nM
77	160 nM
78	360 nM
79	640 nM
82	9nM

167

Compound No.	ICeo Plasmodium falclparum NF54
83	10 nM
84	110nM
85	150 nM
86	170 nM
88	140 nM
89	3.4 nM
90	2nM
91	25 nM
92	4 nM
93	4 nM
94	9nM
95	7nM
96	170 nM
97	30 nM
98	140 nM
99	170 nM
100	9nM
101	10 nM

Compound No.	IC» Plasmodium falclparum NF54
102	5nM
103	75 nM
104	12 nM
105	24 nM
106	13 nM
107	100 nM
108	86 nM
109	79 nM
110	330 nM
111	5 nM
112	200 nM
113	430 nM
114	245 nM
115	3nM
116	117nM
117	6 nM
118	15 nM
119	30 nM

Human ΡΙ3Κα activity test

The compounds according to the invention underwent pharmacological trials to measure the selectivity toward human lipid kinases and espedally human PI3Ka. The test uses a ludferin/luciferase System to measure the concentration of ATP and its consumption during the enzymatic reaction. The test is performed in 96-well format 10 (Coming/Costar 96 black flat-bottomed half-wells plate, ref. 3694) in a total volume of 30 μίτο 1 μΙ of inhibitor in 100% DMSO are added (final concentrations) 50 μΜ of the substrate PIP2 ((L-a-phosphatidyl-D-myoinositol 4,5-bisphosphate, Calbiochem 524644), 2 μΜ of ATP and 1.7 μg/mL of ΡΙ3Κα (ρ110α/ρ85α, Invitrogen PV4788) in a 15 buffer of Tris/HCI 50 mM pH 7.5, EGTA1 mM, MgCb 10 mM, Chaps 0.03%, 1 mM DTT).

After 90 minutes, the reaction Is quenched by adding 20 μΙ/well of KinaseGIo reagent (Promega V6713). After 10 minutes in the dark, the luminescence is read using a PHERAStar microplate reader (reading at 0.8 sec/well).

The ICso values are determined by the préparation of successive threefold

168 dilutions on at least a scale of more than 10 000. The ICso values are between 190 nM and more than 10 000 nM, in particuiar between 1040 nM and more than 10 000 nM and even more particularly greater than 2000 nM.

The activity of the other isoforms of human PI3K may be measured in the same 5 manner.

The table of results for the activity of human PI3Ka test is given below:

No.	IC» Human PI3Ka
1	3130 nM
2	10000 nM
3	7200 nM
4	>10000 nM
5	8200 nM
6	>10000 nM
7	10000 nM
8	>10000 nM
9	>10000 nM
10	7200 nM
11	10000 nM
12	2900 nM
13	5750 nM
14	>10000 nM
15	>7200 nM
16	>7200 nM
17	10000 nM
18	>10000 nM
19	>10000 nM
20	>10000 nM
21	>10000 nM
22	>10000 nM
23	1040 nM
24	2440 nM
25	1000 nM
26	2000 nM
27	1530 nM
28	2260 nM
29	7930 nM
30	>10000 nM
31	6350 nM
32	3700 nM

No.	ICw Human PI3Ka
33	>10000 nM
34	>10000 nM
35	>10000 nM
36	>10000 nM
37	>10000 nM
38	5770 nM
39	>10000 nM
40	>10000 nM
41	4200 nM
42	>10000 nM
43	>10000 nM
44	>10000 nM
45	>10000 nM
46	>10000 nM
47	>10000 nM
48	>10000 nM
49	2740 nM
50	4300 nM
51	>10000 nM
52	>10000 nM
53	>10000 nM
54	2210 nM
55	>10000 nM
56	>10000 nM
57	>10000 nM
58	6400 nM
59	>10000 nM
60	>10000 nM
61	>10000 nM
62	>10000 nM
63	>7200 nM
64	>10000 nM

169

No.	IC_mHuman PI3Ka
65	>10000 nM
66	>10000 nM
67	4000 nM
68	6600 nM
69	>10000 nM
70	1000 nM
71	810 nM
72	730 nM
73	2500 nM
74	820 nM
75	10000 nM
76	950 nM
77	820 nM
78	250 nM
79	1600 nM
80	1600 nM
81	2000 nM
82	340 nM
83	190 ηΜ
84	200 ηΜ
85	>10000 ηΜ
86	7300 ηΜ
87	10000 ηΜ
88	1300 ηΜ
89	2800 ηΜ
90	2400 ηΜ
91	>10000 ηΜ
92	450 ηΜ
93	780 ηΜ
94	130 ηΜ
95	180 ηΜ
96	8500 ηΜ
97	440 ηΜ
98	>10000 ηΜ
99	>10000 ηΜ
100	1980 ηΜ
101	450 ηΜ
102	2500 ηΜ
103	840 ηΜ

Νο.	ICso Human ΡΙ3Κα
104	930 ηΜ
105	1900 ηΜ
106	>10000 ηΜ
107	>10000 ηΜ
108	>10000 ηΜ
109	7800 ηΜ
110	>10000 ηΜ
111	330 ηΜ
112	>10000 ηΜ
113	>10000 ηΜ
114	>10000 ηΜ
115	590 ηΜ
116	>10000 ηΜ
117	380 ηΜ
118	>10000 ηΜ
119	>10000 ηΜ

170

The table below shows the human P!3Ka activity test results for known compounds derived from the applications mentioned above WO 2011/001 112 and WO 2011/001 113.

COMPOUNDS	STRUCTURE	ICsa Human PI3Ka
Example 1 (p. 39, WO 2011/001 112)	û OM	15 nM
Example 10 (p. 61, WO 2011/001 112)	Γ J CNrat	17 nM
Example 5 (p. 54, WO 2011/001 113)	„ 9-	6nM
Example 1 (p. 44, WO 2011/001 113)		9nM

It may be seen that although the compounds of the présent invention are derived from inhibitors of human PI3K and in particular PI3K, such compounds no longer inhibit, or only sparingly inhibit, this class of human kinases. Thus, they are clearly distinguished 10 from the already-known CF3 pyrimidinones, described in patent applications WO 2011/001 112 and WO 2011/001 113, which are powerfu! inhibitors of human PI3Ka, which may be used for the treatment of malaria but above ail for various cancers in man.

Similar kinomes are présent in ali species of Plasmodium, such as P. falciparum, 15 P. vivax, P. malarias, P. ovale and P. knowlesi. The compounds of the invention may thus be useful in the treatment of malaria induced by ail the parasites mentioned above.

171

In addition, these 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.

The compounds according to the invention may thus be used for the préparation of médicaments, in particular médicaments for inhibiting parasite growth.

Thus, according to another of rts aspects, a subject of the invention is médicaments that comprise a compound of formula (I), or an addition sait of the compound of formula (!) with a pharmaceutically acceptable acid or base.

These médicaments find their use in therapeutics, especially in the treatment of malaria induced by ail species of Plasmodium such as P. falciparum, P. vivax, P. malariae, P. ovale and P. knowlesi, but also induced by other species of parasites, for instance Trypanosoma such as T. brucei, T. cruzei and Leishmania, for instance L major, L donovani.

These médicaments also find their use in therapeutics In the treatment of sleeping sickness, Chagas disease, the various forms of leishmaniasis and infections such as schistosomiasis (bilharzia), toxopiasmosis and coccidiosis which are caused by other parasites, respectively schistosomes, toxoplasma and Eimeria.

According to another of its aspects, the présent invention relates to pharmaceutical compositions comprising, as active ingrédient, a compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable sait of said compound, and also at least one pharmaceutically acceptable excipient.

Said excipients are chosen, according to the pharmaceutical form and the mode of administration desired, from the usual excipients which are known to those skilled in the art.

In the pharmaceutical compositions of the présent invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or recta! administration, the active ingrédient of formula (I) above, or its sait, can be administered in unit administration form, as a mixture with conventiona!

172 pharmaceutical excipients, to animais or to human beings for the treatment of the above disorders or dîseases.

The appropriate unit administration forms include oral-route forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal administration forms, inhalation forms, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants. For topical application, the compounds according to the invention can be used in creams, gels, ointments or lotions.

By way of example, a unit administration form of a compound according to the invention in tablet form may comprise the following components:

Compound according to the invention Mannitol Croscaramellose sodium Com starch Hydroxypropylmethylcellulose Magnésium stéarate

50.0 mg 223.75 mg 6.0 mg 15.0 mg 2.25 mg 3.0 mg

There may be particular cases where higher or lower dosages are appropriate: such dosages do not départ from the context of the invention. According to the usual practice, the dosage appropriate for each patient is determined by the physicien according to the method of administration and the weight and response of said patient.

According to another of its aspects, the présent invention also relates to a method for treating the pathological conditions indicated above, which comprises the administration, to a patient, of an effective dose of a compound according to the invention, or a pharmaceutically acceptable sait thereof.

Claims

1. A compound corresponding to formula (I):

Y 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 fonction Is attached to the substituent Ri, or a (Ci-C₂)alkyl, said alkyl being optionaily substituted with one or more substituents chosen from a (Ci-C₃)alkyl group and a hydroxyl group;

> Ri represents:

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

- a (Ci-C<j)cycloa!kyl group, optionaily substituted with a hydroxyl group,

- an aryl group, optionaily 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 -SO2-(Ci-C_s)alkyl, a (Ci-C_s)alkoxy group, said alkoxy being optionaily substituted with one or more substituents chosen from:

o a halogen atom,

174 o a hydroxyl group or a (Ci-Cs)alkoxy group, o a group -CORj, in which Rj 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 Rx and Rx· 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;

o a halogen atom, o a (CrCjJalkyl group optionally substituted with one or more halogen atoms, o a (Ci-Cs)alkoxy group, optionally substituted with one or more substituents chosen from a halogen atom, a (C3-Cs)cycloalkyl group, a heteroaryl group optionally substituted with one or more substituents chosen from a halogen atom, a (Ci-Ca)alkyt group, a hydroxyl group and an -NH2 group, o a group -NR5R5· in which Rs and Rs·, independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -CO2-(Ci-C₃)alkyl group, a (C₃-Cs)cycloalkyl group and a linear or branched (CrC₃)alkyl group, said aikyl group being optionally substituted with one or more hydroxyl groups,

- 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 -CCHCr C₄)alkyl group,

- a group -NReRe· in which Re and R«·, which are different, represent a (Ci-Cs)alkyl group and a (Ci-Cs)alkoxy group, > R2 represents a hydrogen atom when n represents 1 and a methyl group when n

175 represents 0;

> Rx and R<·, independently, which may be identical or different, represent a hydrogen atom or a (Ci-C₃)a1ky1 group, in the form of the base or of an addition sait with an acid or with a base.

2. The compound of formula (1) 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 fonction is attached to the substituent Ri, or a (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 (0,-0$) alkyl group, optionally substituted with one or more substituents chosen from a hydroxyl group and an aryl group,

- a (C3-Ce)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-(Ci-C₄)alkyl, a morpholine group, a group of formula -SOHCi-Csïalkyl, a (CrCs)alkoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

o a halogen atom, o a hydroxyl group or a (Ci-Cs)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 R» and Rr are as defined below, o a group -NFURx· in which R* and R*· are as defined below, o a heterocycloalkyl group comprisïng one or two heteroelements chosen from a nitrogen atom and an oxygen atom,

176 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 suffur atom and an oxygen atom, optionally substituted with one or more substituents chosen from:

o a halogen atom, o a (Ci-Cs)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 -NH₂ group, o a group -NRsRs- in which Rs and Rs·, independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -CO2-(Ci-C₃)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 groupe,

- a group -NReRe· in which Re and Rr, which are different, represent a (Ci-Cs)alkyI group and a (CrCs)alkoxy group, > R₂ represents a hydrogen atom when n represents 1 and a methyl group when n represents 0;

> R< and Rr, 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 sait with an acid or with a base.

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

> Y represents a bridged morpholine (a)

177 (a) in the form of the base or of an addition sait with an acid or with a base.

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

> n représente 0 or 1 ;

> Y représente a bridged morpholine (a) (a) > L représente a linker -CH2-CO- such that the carbonyl fonction is attached to the substituent Ri, or (Ci-C₂)alkyl, said alkyl being optionally substituted with one or more substituents chosen from a (Ci-Cajalkyl group;

> Ri représente:

- a linear, branched, cyclic or partially cyclic (Ci-Cs)alkyl group, optionally substituted with one or more substituents chosen from a hydroxyl group, an aryl group, a trifluoromethyl group and a (C3-Ce)cycloalky| group,

- a (C3-Ce)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 -NHCO-NH-(Ci-C₄)alkyi, a morpholinyl group, a group of formula -SOriCrCsJalkyl, a (Ci-Cj)alkoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

o a halogen atom, o a hydroxyl group or a (Ci-Cs)alkoxy, o a group -COR3, in which Ra représente a substituent chosen fforn 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

178 an -NH₂ group;

o a halogen atom, o a (CrC₃)alkyl group optionally substituted with one or more halogen atoms, o a (Ci-Cs)alkoxy group, optionally substituted with one or more substituents chosen from a halogen atom, a (C3-C₅)cydoalkyl 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 -NH₂ group, o a group -NR₅R₅· In which Rs and Rs·, independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -CO2-(Ci-C₃)alkyl group, a (Cj-CsJcycloaikyl group and a linear or branched (Ci-C₃)alkyi group, said alkyl group being optionally substituted with one or more hydroxyl groups,

- 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 fonnyl group, an acetyl group and a -COfeCr C₄)alkyl group,

- a group -NReRe· in which Re and Re·, which are different, represent a (Ci-Cs)alkyi group and a (Ci-Cs)alkoxy group, > R₂ represents a hydrogen atom when n represents 1 and a methyl group when n represents 0;

> R< and R4·, independently, which may be identical or different, represent a hydrogen atom or a (Ci-Csjalkyl group, in the form of the base or of an addition sait with an acid or with a base.

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

>n represents 0 or 1;

> Y represents a bridged morpholine (a)

179 (a) > L represents a linker -CHj-CO- such that the carbonyl fonction is attached to the substituent Ri, or (Ci-C₂)alkyl, said alkyl being optionally substituted with one or more substituents chosen from a (Ci-C₃)alky! group;

> Ri represents:

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

- a (C₃-C_e)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 -NHCO-NH-(Ci-C4)alkyl, a morpholinyl group, a group of formula -SO^Ci-Csîalkyl, a (Ci-Cs)alkoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

o a halogen atom, o a hydroxyl group or a (Ci-Csjalkoxy, o a group -CORj, 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-Cîjalkyl group, a hydroxyl group and an -NH₂ group,

o a halogen atom, o a (Ci-C₃)alkyl group optionally substituted with one or more halogen atoms, o a (Ci*Cs)alkoxy group, optionally substituted with one or more substituents chosen from a halogen atom, a (Cs-Csîcycloalkyl group, a heteroaryl group optionally substituted with one or more substituents

180 chosen from a halogen atom, a (Ci-Cs)alkyl group, a hydroxyl group and an -NH2 group, o a group -NRsRy in which Rs and Ry, independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -CCMCi-CaJalkyl group, a (Cs-Csjcycloalkyl group and a linear or branched (Ci-Cajalkyl group, said alkyl group being optionally substîtuted with one or more hydroxyl groups,

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

- a group -NReRy in which Re and Ry, which are different, represent a (CrCsîalkyl group and a (Ci-Cs)alkoxy group, > R2 represents a hydrogen atom when n represents 1 and a methyl group when n represents 0;

> R< and Ri*, independently, which may be identical or different, represent a hydrogen atom or a (Ci-Csjalkyl group, in the form of the base or of an addition sait 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 fonction is attached to the substituent Ri, or (Ci-C2)alkyl, sald alkyl being optionally substîtuted with a hydroxyl group;

> Ri represents:

181

- a linear or branched (Ct-Csjalkyl 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 (Ci-Cgjalkoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

o a group -CONR4R4· in which R« and R< are as defined below, o a group -NR4R4 in which R« 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 (Ci-Ca)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;

> R< and R«, independently, which may be identical or different, represent a hydrogen atom or a (Ci-Cs)alkyl group, in the form of the base or of an addition sait with an acid or with a base.

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

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

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

10. The compound as daimed in any one of daims 1 to 9, characterized in that Ri represents a heteroaryl group, in the form of the base or of an addition sait with an acid or with a base.

11. The compound as daimed in any one of daims 1 to 9, characterized in that Ri represents a heterocycioalkyl 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 -COHCi-CiJalkyl group, in the form of the base or of an addition sait with an acid or with a base.

182

12. The compound as claimed in any one of the preceding claims 1 to 11, 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-5yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one

2 (BS )-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-(2-oxo-2-pyrid-4-y!ethyl)-8trifluoromethyl-6_l7,8,9-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]pyrimidin4-one

4 (8S)-9-[2-(6-Methylpyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin4-one

5 (8S)-9-[2-(6-Methylaminopyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5azabicyclop^.Ilhept-S-yl-S-trifluoromethyl-ej.e.iMetrahydropyrimidon.Z-aJpyrimidin4-one

6 (8S)-9-[2-(6-Dimethylaminopyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5azabicyclo^.Z.IJhept-S-yl-B-trifluoromethyl-SJ.e.S-tetrahydropyrimidon^-alpyrimidin4-one

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

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

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

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-5one

183

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

12 (8S)-2-(1S_l4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-pyrid-3-ylethyl)-8trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one

13 2-Methyk7-(1S,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-Hydroxyethylaniino)pyrid-3-yl]-2-oxoethyl}-2-(1 S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trif!uoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin4-one

15 (8S)-9-[2-(5-Methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5azabicyclo(2.2.1]hept-5-yl-8-trifIuoromethyl-6,7,8,9-tetrahydropyriniido[1,2-a]pyriniidin4-one

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

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

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)-trffluoromethyl)-2,3-dihydro-1 H-imidazo[1,2a]pyrimidin-5-one

19 (8S)-9-[2-(2-Methylpyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5a2abicyc!o[2.2.1]hept-5-yl-8-trifluoromethyl-6_l7,8,9-tetrahydropyrimido[1,2-a]pyrimidin4-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-trifIuoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin4-one

21 2-Methy 1-7-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1 -(2-oxo-2-pyrid-317195

184 ylethyl)-2-((S)-trifluoromethyl)-2_i3-di hydro-1 H-imidazo[1,2-a]pyrimidin-5-one

22 (8S)-9-[2-(6-Cyclopropylaminopyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin4-one

23 1 -Et hy l-3-{4-[2-((S)-e-( 1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-6-oxo-2trifluoromethy^3,4-dihydro-2H,6H-pyrimίdo[1,2-a]pyriπlidin-1-yl)ethyl]pheπyl}urea

24 1-Ethyl-3-{4-[2-((S)-2-methyl-7-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl-5oxcH2-tnfluoromethyl-2_l3-dihydro-5H-imidazo[1,2-a]pyrimidin-'l-yl)ethyl]phenyl}urea

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

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

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

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-y!-2-((S)-trifluoroniethyl)-2,3-dihydro-1 H-imidazoï1,2aJpyrimidin-5-one

29 (8S)-9-(3,3-Dimethyl-2-oxobutyl)-2-(1S,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-azabicycloï2.2.1 Jhept-

5- yk2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one

31 (8S)-9-[2-(6-Amino-5-methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin4-one

32 1-[2-(4-Aminophenyl)ethy1]-2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidÎn-5-one

185

33 (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-oxo-2-(S- trifluoromethylpyrid-S-ynethylj-e-trifluoromethyl-e.T.e.S-tetrahydropyrimidotl^a]pyrimidin«4-one

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

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

4-one

36 (8S)-9-[2-(6-Amino-4,5-dimethylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trifIuoromethyl-6_l7,8_l9-tetrahydropyrimido[1_l2-a]pyrimidin4-one

37 (S)-9-[2-(4-Difluoromethoxyphenyl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5azabicydo[22.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin4-one

38 (8S)-9-[2-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-oxoethyl]-2-(1S,4S)-

2-oxa-5-azabicydo[2.2.1]hept-5-yl-8-trifluoromethyl-6_l7_l8_l9-tetrahydropyrimido[1₍2a]pyrimidin-4-one

39 (8S)-9-[2-(4-Methyloxazo1-5-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5- azabicydo[2.2.1]hept-5-yl-8-trifluoromethy1-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin4-one

40 (S)-9-[2-(3,4-Difluorophenyl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5azabicydo[2.2.1]hept-5-yl-8-trifIuoromethyl-6_l7,8,9-tetrahydropyrimido[1_l2-a]pyrimidin4-one

41 (8S)-9-[2-(4-Morpholin-4-ylphenyl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5azabicydo[2.2.1]hept-5-yl-8-trifluoromethy!-6₎7,8,9-tetrahydropyrimido[1,2-a]pyrimidin4-one

42 4-[2-((S)-6-( 1 S,4S)-2-Oxa-5-azabicydo[2.2.1 ]hept-5-yl-6-oxo-2-trifluoromethyl-

3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1 -yl)acetyl]benzonitrile

186

43 (8S)-9-[2-(4-Methy lthiazol-5-y l)-2-oxoethy l]-2-( 1 S,4S)-2-oxa-5azabicycloP^.Ilhept-S-yl-e-trifluoromethyl-e.y.e.G-tetrahydropyrimidotl^-alpyrimidin4-one

44 (8S)-9-[2-(5-Chloropyrid-3-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6_l7_l8,9-tetrahydropyrimido[1,2-a]pyrimidin4-one

45 (8S)-9-[2-(6-Methoxypyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8_l9-tetrahydropyrimido[1,2-a]pyr1midin4-one

46 (8S)-9-[2-(3-Methylisoxazol-4-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin4-one

47 (8S)-9-(2-Benzo[1,2,3]thiadiazol-5-yl-2-oxoethyl)-2-( 1 S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trif!uoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin4-one

48 (8S)-9-[2-(2,4-Difluoropheny1)-2-oxoethyl]-2-(1S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7_l8,9-tetrahydropyrimido[1,2-a]pyrimidin4-one

49 (8S)-9-(3-Ethy1-3-hydroxypenty!)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl8-trifIuoromethyl-6_l7,8_l9-tetrahydropyrimÎdo[1_l2-a]pyrimîdin-4-one

50 (8S)-9-(3-Hydroxy-3-methy1butyl)-2-(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-y1-

8-trifluoromethyl-6,7,8,9-tetrahydropyrimidon,2-a]pyrimidin-4-one

51 (8S)-9-(1-Methyl-1H-indazo1-3-ylmethyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1] hept-5-yl-8-trifIuoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidÎn-4-one

52 (8S)-9-(2-(2-Cyclopropylmethoxypyrimidin-5-yl)-2-oxoethyl]-2-( 1 S,4S)-2-oxa-5azabîcyclo[2.2.1 ]hept-5-yl-8-trifIuoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin4-one

53 (8S)-9-[2-(3,5-Dimethylisoxazol-4-y1)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin17195

187

4-one

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

55 3-[2-((S)-8-(1 S_l4S)-2-Oxa-5-azablcyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethyl-

3.4- dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-y!)acetyl]benzonitrile

56 (8S)-9-(3-Methyl-2-oxobutyl)-2-(1 S,4S)-2-oxa-5-azabicydo[2.2.1 ]hept-5-yl-8trifluoromethyl-6_l7₎8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one

57 {5-[2-((S)-8-(1S,4S)-2-Oxa-5-azabicydo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethyl-

3.4- dihydre-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetyl]pyrid-2-yl}carbamîc add ethyl ester

58 {5-[2-((S)-8-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-y!-6-oxo-2-trifluoromethyl-

3.4- dihydro-2H_l6H-pyrimido[1,2-a]pyrimidin-1 -yl)acetyl]pyrid-2-y!}carbamic add methyl ester

59 (8S)-9-(5-Methyl-[1,2,4]oxadiazol-3-y!methy!)-2-(1 S,4S)-2-oxa-5azabicydoP^.IJhept-S-yl-e-trifluoromethyl-ej.e.g-tetrahydropyrimidotl^-aJpyrimidin4-one

60 (8S)-2-(1S,4S)-2-Oxa-5-azabicyclo(2.2.1]hept-5-yl-9-[2-oxo-2-(2trifluoromethylpyrid-S-ylJethyll-e-trifluoromethyl-ej.e.O-tetrahydropyrimidotl.Za]pyrimidin-4-one

61 (8S)-9-(2-Benzo[1,2,5lthiadiazol-5-yl-2-oxoethyl)-2-(1 S,4S)-2-oxa-5azabicyclo[2.2.1 Jhept-S-yl-e-trifluoromethyl-ej^.O-tetrahydropyrimidotl ,2-a]pyrimidin4-one

62 (8S)-2-(1S,4S)-2-Oxa-5-azabicydo[2.2.1]hept-5-y!-9-[2-oxo-2-(tetrahydropyran4-y!)ethyl]-8-trifluoromethyl-6,7_l8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one

63 (8S)-9-{2-[6-(2-Fluoroethoxy)pyrid-3-yl]-2-oxoethy!}-2-(1 S,4S)-2-oxa-5azabicydo[2.2.1]hept-5-yl-6-trifluoromethyl-6_l7₍8_l9-tetrahydropyrimido[1_l2-a]pyrimidin4-one

64 (8S)-9-{2-[3-Fluoro-4-(2-fluoroethoxy)pheny!]-2-oxoethyl}-2-(1 S,4S)-2-oxa-517195

188 azabicydop^.lJhept-S-yl-e-trifluoromethyl-e.T.e.O-tetrahydropyrimidoil^-aJpyrimidin4-one

65 (8S)-9-[2-(2-Methoxypyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7_l8,9-tetrahydropyrimido[1,2-a]pyrinriidin4-o ne

66 (8S)-9-[2-(3-Methyl-3H-imidazol-4-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6₍7,8,9-tetrahydropyrimido[1,2-a]pyrimidin4-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_l7,8,9-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)-8trifluoromethyl-ej.e.G-tetrahydropyrimidoIl^-aJpyrimÎdin^-one

69 (8S)-9-[2-(2-Methyl-2H-pyrazol-3-yl)-2-oxoethyl]-2-( 1 S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trifluoromethy1-6,7_t8,9-tetrahydropyrimÎdo[1,2-a]pyrimidin4-one

70 N,N-Dimethyl-2-(4-{2-[(S)-2-methyl-7-(8-oxa-3-azabicycloï3.2.1]oct-3-yl)-5-oxo-

2-trifluoromethyl-2_l3-dihydro-5H-imidazo[1,2-a]pyrimidin-1-yl]ethyl}phenoxy)acetamide

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

72 (2S)-1 -[2-(4-Hydroxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicycloï3.2.1 ]oct-3yl)-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)-8trifIuoromethyl-6,7,8,9-tetrahydropyrimidoï1_l2-a]pyrimidin-4-one

74 (2S)-1-{2-ï4-(2-Dimethylaminoethoxy)phenyl]ethyl}-2-methyl-7-(8-oxa-3azabicyclo[3.2.1 ]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1 H-lmidazo[1,2-a]pyrimidin-5one

75 (8S)-2-(8-Oxa-3-azabicydo[3.2.1]oct-3-yl)-9-(2-oxo-2-pyrid-4-ylethyl)-817195

189 trifluoromethy1-6,7,8,9-tetrahydropyrimido[1,2-aÎpyrimidin-4-one

76 (S)-1-[2-(4-Methoxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1îoct-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-y1)-1-(3-phenylpropyl)-2trifluoromethyl-2,3-dihydro-1 H-irnidazo[1,2-a]pyrimidin-5-one

78 (S)-1-{2-[4-(3-Dimethylaminopropoxy)phenyl]ethyl}-2-methyl-7-(8-oxa-3azabicyclo[3.2.1]oct-3-y1)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5one

79 (2S)-1-((S)-2-Hydroxy-2-phenylethyl)-2-methy1-7-(8-oxa-3-azabicyc1o[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)-8trifluoromethyl-e^.e^tetrahydropyrimidofl^-ajpyrimidirHl-one

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

82 (eSj-O-GR^-BenzoIbJthiophen^-y^-hydroxyethyl^-fS-oxa-SazabicyclotS^.IJod-S-yO-e-trinuoromethyl-eze.g-tetrahydropyrimidoIV-alpyrimidirHl· one

83 (8S)-9-[2-(4-Hydroxyphenyl)ethyl]-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8trifluoromethyl-OJ.e^tetrahydropyrimtdoil^-ajpyrimidin^-one

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

85 (8S)-2-(3-Oxa-8-azabicyclo[3.2.1]oct-8-y1)-9-(2-oxo-2-pyrid-3-y1ethyl)-8trifluoromethyl-6_I7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one

86 (SSl-g-tl-Difluoromethyl-l H-pyrazol-3-y1methyl)-2-(8-oxa-3azabicycloIS^.IJoct-S-ylî-e-trifluoromethyl-ej.e^tetrahydropyrimidoIl^-aJpyrimidîn^one

87 (8S)-2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-y1)-9-(2-oxo-2-pyrid-3-ylethyl)-817195

190 trifluoromethyl-6,7,8_l9-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)-8trifluoromethyl-6,7,8,9-tetrahydropyrinnido[1 ^-alpyrimidirM-one

89 (S>9-[2-(1-Acetylpiperid-4-yt)ethy1]-2-(1S_I4S)’2-oxa-5-azabÎcyclo[2.2.1]hept-5yl-8-trifluoromethyt-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one

90 4-[2-((S)-8-(1S,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-(1S,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-4yl)ethyl]-8-trifluoromethyl-6_l7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one

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

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

96 (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1 ]hept-5-yl-9-(3₁3,3-trifluoro-2-hydroxy-

2-trifluoromethylpropyl)-8-trifluoromethyl-6,7_l8,9-tetrahydropyrimido[1_l2-a]pyrimidin-4one

97 (8S)-2-(1 S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(4,4,4-trifluoro-3-hydroxyS-trifluoromethylbutylJ-e-trifluoromethyl-e.T.e.g-tetrahydropyrimidofl^-alpyrimidin^one

98 (8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-(8-oxa-3azabicyclo[3.2.1]oct-3-yl)-2-oxoethyl]-8-trifluoromethyl-6_l7,8,9-tetrahydropyrimido[1,2a]pyrimidin-4-one

191

99 (8S)-2-(1 S,4S)-2-Oxa-5-azabicydo[2.2.1]hept-5-yl-9-[2-(3-oxa-8- azabicydo[3.2.1]oct-8-yl)-2-oxoethyl]-8-trifluoromethyl-6_l7,8,9-tetrahydropyrimido[1_l2a]pyrimidin-4-one

100 (8S)-9-[2-( 1 -Hydroxycydopentyl)ethyl]-2-(1 S,4S)-2-oxa-5-azabicydo[2.2.1 Jhept-

S-yl-S-trifluoromethyl-e.î.e.O-tetrahydropyrimidoIl^-aJpyrimidin^-one

101 (8S)-9-(1-Hydroxycydopentylmethyl)-2-(1S,4S)-2-oxa-5-azabicydo[2.2.1]hept-

S-yl-S-trifluoromethyl-e.î.e.O-tetrahydropyrimidoIl^-aJpyrimidirM-one

102 (8S)-9-(3,3-Dicydopropyl-3-hydroxypropyl)-2-(1 S,4S)-2-oxa-5- azabicydop^JJhept-S-yl-S-trffluoromethyl-e.T.e.g-tetrahydropyrimidoIV-aJpyrimidin-

4-one

103 (8S)-9-(2,2-Dicydopropyl-2-hydroxyethyl)-2-(1 S,4S)-2-oxa-5- azabicydo^.lJhept-S-yl-e-trifluoromethyl-e.y.S.O-tetrahydropyrimidoIl^-ajpyrimidin-

4- one

104 (8S)-9-( 1-Hydroxycydopropylmethyl)-2-(1 S,4S)-2-oxa-5-azabicydo[2.2.1 Jhept-

5- yl-8-trifluoromethy|-6,7.8_l9-tetrahydropyrimido[1_l2-a]pyrimidin-4-one

105 (8S)-9-[2-(1-Hydroxycydopropyl)ethyl]-2-(1 S,4S)-2-oxa-5-azabicydo[2.2.1 Jhept-

S-yl-S-trifluoromethyl-e.y.e.O-tetrahydropyrimidoni-aJpyrimidin^-one

106 (8S)-2-(1 S,4S)-2-Oxa-5-azabicydo[2.2.1]hept-5-yl-9-<iuinolin-5-ylmethyl-8trifluoromethyl-6,7_l8_l9-tetrahydropyrimÎdo[1_l2-a]pyrimidin-4-one

107 (8S)-9-[2-(3-Methylisothiazol-4-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5azabicydo[2.2.1 ]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyri mido[ 1,2-aJpyrimidin4-one

108 (8S)-9-[2-(4-Methanesulfonylphenyl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5azabicydo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-aJpyrimidin4-o ne

109 (8S)-9-lsoquinolin-5-ylmethyl-2-(1S_l4S)-2-oxa-5-azabicydo[2.2.1]hept-5-yl-8- trifluoromethyl-ej.S.g-tetrahydropyrimidotl^-aJpyrimidin^ne

110 (8S)-9-(2-Morpholin-4-yl-2-oxoethyl)-2-( 1 S,4S)-2-oxa-5-azabicydo[2.2.1 ]hept-517195

192 γΙ-δ-ΙπίΙυοωΜβίηγ^,Τ,β,θ-ΙβίΏΚγάωρτήΓηϊάοΙΙ^-θΪρχπΓηΪάΪΓΜ-οηβ

111 (8S)-9-{2-[4-(2-Morpholin-4-ylethoxy)phenyl Jethyl}-2-(1 S,4S)-2-oxa-5azabicydoP^JJhept-S-yl-e-trifluoromethyl-e.y.e^tetrahydropyrimidoIl^-aJpyrimidin4-one

112 N-Methoxy-N-methyl-2-((S)-8-(1 S,4S)-2-oxa-5-azabicydo[2.2.1 ]hept-5-yl-6-oxo-

2-trifluoromethyl-3,4^1^^)-21-1,61-1^111^011,2-3^01^10-1^1)306131^6

113 (8S)-9-(2-lmidazo[1,2-a]pyrid-6-yl-2-oxoethyl)-2-(1 S,4S)-2-oxa-5azabicydoI2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin4-one

114 (8S)-9-[2-(6-Difluoromethoxypyrid-3-yl)-2-oxoethylï-2-(1 S,4S)-2-oxa-5azabÎcyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin4-one

115 (S)-9-{2-[4-(2-Morpholin-4-yl-2-oxoethoxy)phenyl]ethyl)-2-(1 S,4S)-2-oxa-5azabicyclo[2.2.1Jhept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-aÏpyrimidin4-one

116 (8S)-9-(1-Methyl-3-trifluoromethyl-1 H-pyrazol-4-ylmethyl)-2-(1 S,4S)-2-oxa-5azabicyclo[2.2.1]hept-5-yl-8-trinuoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimÎdin4-one

117 (8S)-9-{2-[4-(2-Dimethylamînoethoxy)phenylïethyl)-2-(1 S,4S)-2-oxa-5azabicydo[2.2.1]hept-5-yl-8-tnfluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin4-one

3,4-dihydro-2H,6H-pyrimido[1,2-aJpyrimidin-1 -yl)acetyl]piperidine-1 -carbaldehyde

119 (8S)-9-[2-(1-Acetylpiperid-4-yl)-2-oxoethyl]-2-(1 S,4S)-2-oxa-5azabicyclo[2.2.1ïhept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin4-one in the form of the base or of an addition sait with an add or with a base.

13. A process for preparing a compound of formula (I) as claimed in any one of daims 1

193 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 5 in claim 1, to obtain a compound of formula I

Y

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

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

CF

O 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 = Ri-L-Lg in which Ri and L 15 are as defined in any one of daims 1 to 8 and Lg is a leaving group, to obtain a compound of formula K

K in which Ri, Rï, L and n are as defined in one of daims 1 to 8, and a reaction on a compound K with a compound of formula Y being a bridged morpholine chosen from (a),

194 (b) and (c) as defined in daim 1.

15. A process for preparing a compound of formula (I) as clalmed in any one of daims 1 to 12, in which the linker L is an ethyl group, Ri Is a linear or branched (Ci-Cs)alkyl group substituted with a hydroxyl group, Y represents a bridged morpholine chosen from (a), (b) and (c) as defined In daim 1, n represents 1 or 0, and Rî represents a hydrogen atom when n = 1 and a methyl group when n = 0, comprising a Michael addition readion of a compound of formula E

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 = CI-^CHz-COjAlkyl, to obtain a compound of formula N,

R2

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 daim 1, and a readion of aikyl on a compound of formula N with a compound of formula O = ZMg-X in which Z represents a linear or branched aikyl radical and X is a halogen atom.

16. A process for preparing a compound of formula (I) as claimed in any one of daims 1 to 12, in which the linker L is a methyl group, Ri îs a linear or branched (Ci-Csjalkyl group substituted with a hydroxyl group, Y represents a bridged morpholine chosen from (a), (b) and (c) as defined in daim 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 readion of a compound of formula E

195 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-CH^CCfeAlkyl with X being a halogen atom, to obtain a compound of formula Q

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 daims 1 to 12, in which the linker L is a methyl group, Ri is a group -NReRe· with ReetRe· being either different and representing an alkyl group and an alkoxy group, or Re and Re· together forming a monocydic or bicydic heterocydoalkyl, Y represents a bridged morpholine chosen from (a), (b) and (c) as defined in daim 1, n represents 1 or 0, 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

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 ’v *

196 compound of formula S

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 HNReRe· with Re and Re- being either different and representing an alkyl group and an alkoxy group, or Re and Re· together forming a monocyclic or bicyclic heterocycloalkyl.

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

N , Q and

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

19. A médicament, characterized in that it comprises a compound as claimed in any one of daims 1 to 12, or an addition sait of this compound with a pharmaceutically acceptable add or base.

20. The compound as claimed in any one of daims 1 to 12, as a médicament.

•·» ^; 197

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

5 22. The use of a compound as daimed In any one of daims 1 to 12, for the préparation of a médicament for treating parasrte-înduced malaria.

23. The compound as claimed In any one of daims 1 to 12, for its use in the treatment of malaria induced by all species of Plasmodium, such as P. falciparum, P. vivax, P.

10 malariae, P. ovale and P. knowlesi, by all species of Trypanosome 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 coccidiosls.