(19)
(11)EP 2 870 156 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
17.06.2020 Bulletin 2020/25

(21)Application number: 13733248.2

(22)Date of filing:  21.06.2013
(51)International Patent Classification (IPC): 
A61K 31/5386(2006.01)
C07D 487/04(2006.01)
C07D 519/00(2006.01)
A61K 31/519(2006.01)
(86)International application number:
PCT/EP2013/063065
(87)International publication number:
WO 2013/190123 (27.12.2013 Gazette  2013/52)

(54)

PYRIMIDINONE DERIVATIVES AS ANTIMALARIAL AGENTS

PYRIMIDINONDERIVATE ALS ANTIMALARIAMITTEL

DÉRIVÉS DE PYRIMIDINONE EN TANT QU'AGENTS ANTI-MALARIA


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 22.06.2012 FR 1255928

(43)Date of publication of application:
13.05.2015 Bulletin 2015/20

(73)Proprietor: SANOFI
75008 Paris (FR)

(72)Inventors:
  • EL-AHMAD, Youssef
    F-75008 Paris (FR)
  • FILOCHE-ROMME, Bruno
    F-75008 Paris (FR)
  • GANZHORM, Axel
    F-75008 Paris (FR)
  • MARCINIAK, Gilbert
    F-75008 Paris (FR)
  • MUZET, Nicolas
    F-75008 Paris (FR)
  • RONAN, Baptiste
    F-75008 Paris (FR)
  • VIVET, Bertrand
    F-75008 Paris (FR)
  • ZERR, Véronique
    F-75008 Paris (FR)

(74)Representative: Nony 
11 rue Saint-Georges
75009 Paris
75009 Paris (FR)


(56)References cited: : 
WO-A1-2011/001112
WO-A2-2011/001113
  
      
    Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


    Description


    [0001] The present invention relates to pyrimidinone derivatives, and to the preparation and therapeutic use thereof.

    [0002] Malaria is one of the prime causes of infection-mediated mortality worldwide. Infection with the parasite of the type Plasmodium falciparum affects close to 225 million people, causes more than 781 000 deaths annually and predominantly concerns children under 5 years old. The substantial return of the disease observed in recent years is due to several factors, including:
    • the vectors, namely anopheles, which become resistant to the standard cheap insecticides,
    • the increase in the population in the at-risk zones and, mainly,
    • the resistance of numerous strains of Plasmodium falciparum, the parasite responsible for the mortal forms of the disease, to the medicaments conventionally used, such as chloroquine and mefloquine. Since 2001, artemisinin and derivatives thereof have been considered by the World Health Organization as the treatment of choice for Plasmodium falciparum-mediated uncomplicated malaria. However, clear signs of development of resistance to artemisinins have been observed.


    [0003] The propagation of resistance among Plasmodium strains, in particular P. falciparum, towards the majority of the antimalarial drugs demonstrates the urgent need to develop novel compounds having a novel mode of action thus enabling a decrease of the risk of cross-resistance. Human kinases are valid targets in the treatment of numerous pathologies and the kinome of P. falciparum has been proposed as a reservoir of novel targets for the development of novel medicaments, which have not yet been explored in the treatment of malaria (Doerig and Meijer (2007) Expert Opin. Ther. Targets 11, 279-290).

    [0004] The kinome of Plasmodium falciparum is composed of 64 kinases, some of which are orthologous to human kinases (Ward et al. (2004) BMC Genomics 5,79). Following this orthologous approach, a group of CF3-pyrimidinone derivatives, which are active on human phosphatidylinositol-3-kinases, has been identified as being parasite growth inhibitors in human erythrocytes. Moreover, a plasmodial phosphatidylinositol-3-kinase, known as PfPl3K, has recently been identified, and the existence of a relationship between this kinase and human phosphatidylinositol kinases has been demonstrated (Vaid et al. (2010) Blood 115, 2500-2507). PfPl3K intervenes in the mechanism of endocytosis and in trafficking the host hemoglobin and as such plays an important role in maintaining the parasite growth in the infected human erythrocyte. It might thus be thereby deduced that the plasmodial kinase PfPl3K would be a target for the compounds of the present invention.

    [0005] Human Pl3Ks play a major role in signaling and traffic in human cells (Engelman et al. (2006) Nature Rev. Genetics 7, 606-619). The Pl3K/Akt/mTOR signaling mechanism is an essential regulator of cell life, cell proliferation and protein synthesis. The insulin signaling pathway via the Pl3K/Akt axis involving class 1A of PI3Ks (Pl3Kα and β) is essential in glucose homeostasis. Downstream attenuation of insulin receptor signaling plays an important role in the development of type-2 diabetes. The other isoforms of class I Pl3K, Pl3Kγ and Pl3Kδ, are involved in the immune function and inflammation (Ihle and Povis (2010) Current Opinion in Drug Discovery & Development 13, 41-49). Inhibition of Pl3Kα or Pl3Kβ 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 Pl3Kγ or PI3Kδ show deficiences in immune functions (Okkenhaug et al. (2002) Science 297, 1031-1034). A summary of the potential and observable side effects of Pl3K 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).

    [0006] Inhibition of class III Pl3K, 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).

    [0007] In summary, non-limiting examples that may be mentioned of potential side effects due to Pl3K inhibition in man include metabolic disturbances associated with inhibition of insulin signaling with an increase of blood glucose, reduction of insulin sensitivity, diabetes, deregulation of the cerebral functions with the potential for inducing symptoms of schizophrenia and of Parkinson's disease, and neurodegeneration, and also immunosuppression. It should also be noted that nausea, diarrhea, tiredness, vomiting, skin eruptions and liver damage have been observed during clinical studies with inhibitors of the Pl3K/mTOR axis.

    [0008] On the basis of these observations, it is obvious that inhibiting human Pl3K lipid kinases may have highly undesirable effects and should be avoided when the lipid kinome of Plasmodium is targeted for the treatment of malaria.

    [0009] CF3-pyrimidinone derivatives have been described in patent applications WO 2011/001112 and WO 2011/001113 for the preparation of medicaments for treating various cancers and also for treating parasitic diseases such as malaria. These compounds are described as inhibitors of human Pl3Ks.

    [0010] The compounds of the present invention have the advantage, although being derived from inhibitors of human Pl3K and in particular Pl3Kα, they do not inhibit this class of human kinases, while nonetheless remaining inhibitors of parasite growth.

    [0011] Similar kinomes are present in all species of Plasmodium, such as P. falciparum, P. vivax, P. malariae, P. ovale and P. knowlesi. The compounds of the invention may thus be useful in the treatment of malaria induced by all the parasites mentioned above. In addition, the kinases are found in other parasites, such as Trypanosoma (for example T. brucei, T. cruzei) and Leishmania (for example L. major, L. donovani). The compounds of the invention may thus be used in the treatment of sleeping sickness, Chagas disease, the various forms of leishmaniasis and other parasitic infections.

    [0012] Other parasites, such as schistosomes, toxoplasms and Eimeria, also use kinases for their cell regulation. Consequently, the compounds of the present invention may be useful in the treatment of schistosomiasis (bilharzia), toxoplasmosis and coccidiosis.

    [0013] The present invention relates to compounds corresponding to formula (I):

    in which:



    n represents 0 or 1;



    Y represents a bridged morpholine chosen from



    L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R1, or a (C1-C2)alkyl, said alkyl being optionally substituted with one or more substituents chosen from a (C1-C3)alkyl group and a hydroxyl group;



    R1 represents:

    • a linear, branched or partially cyclic (C1-C5)alkyl group, optionally substituted with one or more substituents chosen from a hydroxyl group, an aryl group, a trifluoromethyl group and a (C3-C5)cycloalkyl group,
    • a (C3-C6)cycloalkyl group, optionally substituted with a hydroxyl group,
    • an aryl group, optionally substituted with one or more substituents chosen from a halogen atom, a hydroxyl group, a cyano group, an -NH2 group, a urea group of formula -NH-CO-NH-(C1-C4)alkyl, a morpholine group, a group of formula -SO2-(C1-C5)alkyl, a (C1-C5)alkoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

      ∘ a halogen atom,

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

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

      ∘ a group -CONR4R4' in which R4 and R4' are as defined below,

      ∘ a group -NR4R4' in which R4 and R4' are as defined below,

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

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

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

      ∘ a halogen atom,

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

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

      ∘ a group -NR5R5' in which R5 and R5', independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -CO2-(C1-C3)alkyl group, a (C3-C5)cycloalkyl group and a linear or branched (C1-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 -CO2-(C1-C4)alkyl group,
    • a group -NR6R6' in which R6 and R6', which are different, represent a (C1-C5)alkyl group and a (C1-C5)alkoxy group,



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



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

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



    [0014] 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.

    [0015] 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.

    [0016] These salts are prepared with pharmaceutically acceptable acids, but salts of other acids that are of use, for example, for purifying or isolating the compounds of formula (I) also form part of the invention. In particular, use will be made in the context of the invention of the hydrogen chloride salt.

    [0017] In the context of the present invention, and unless otherwise mentioned in the text:
    • a halogen atom: a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; in particular, the halogen atom is a fluorine atom;
    • an alkyl group: unless otherwise mentioned in the text, a linear or branched saturated aliphatic group containing from 1 to 5 carbons. Examples that may be mentioned include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl groups;
    • a partially cyclic (C1-C5)alkyl group: unless otherwise mentioned in the text, a linear saturated aliphatic group substituted with a (C3-C4)cycloalkyl group. Examples that may be mentioned include methylcyclopropyl, methylcyclobutyl and ethylcyclopropyl groups;
    • a cycloalkyl group: a cyclic (C3-C6)alkyl group. Examples that may be mentioned include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups;
    • an alkoxy group: a radical -O-alkyl in which the alkyl group is as defined previously, in particular the alkyl group is a methyl or ethyl;
    • an aryl group: a cyclic aromatic group comprising between 5 and 6 carbon atoms. An example of an aryl group that may be mentioned is the phenyl group;
    • a heteroaryl group: a monocyclic or bicyclic aromatic group comprising between 2 and 9 carbon atoms and comprising between 1 and 4 heteroatoms, such as nitrogen, oxygen or sulfur. In particular, the bicyclic aromatic groups comprise a phenyl group. Examples of monocyclic heteroaryl groups that may be mentioned include imidazolyl, pyrimidyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazolyl, oxazolyl and 1,2,4-oxadiazolyl groups. Examples of bicyclic heteroaryl groups that may be mentioned include 1H-indazolyl, benzo[1,2,3]thiadiazolyl, benzo[1,2,5]thiadiazolyl, benzothiophenyl, imidazo[1,2-a]pyridyl, quinolinyl and isoquinolinyl groups;
    • a heterocycloalkyl: a monocyclic or bicyclic alkyl group comprising from 4 to 8 atoms, 1 or 2 of which are heteroatoms, chosen from an oxygen atom and a nitrogen atom. Examples of monocyclic heterocycloalkyl groups that may especially be mentioned include piperidyl, morpholinyl and tetrahydropyranyl groups, and examples 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-azabicyclo[3.2.1]oct-8-yl.


    [0018] Among the compounds of the invention, mention may be made of a first subgroup of compounds corresponding to formula (I):

    in which:



    n represents 0 or 1, and/or



    Y represents a bridged morpholine chosen from

    and/or



    L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R1, or a (C1-C2)alkyl, said alkyl being optionally substituted with one or more substituents chosen from a (C1-C3)alkyl group and a hydroxyl group, and/or



    R1 represents:

    • a linear, branched or partially cyclic (C1-C5)alkyl group, optionally substituted with one or more substituents chosen from a hydroxyl group, an aryl group, a trifluoromethyl group and a (C3-C5)cycloalkyl group,
    • a (C3-C6)cycloalkyl group, optionally substituted with a hydroxyl group,
    • an aryl group, optionally substituted with one or more substituents chosen from a halogen atom, a hydroxyl group, a cyano group, an -NH2 group, a urea group of formula -NH-CO-NH-(C1-C4)alkyl, a morpholine group, a group of formula -SO2-(C1-C5)alkyl, a (C1-C5)alkoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

      ∘ a halogen atom,

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

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

      ∘ a group -CONR4R4' in which R4 and R4' are as defined below,

      ∘ a group -NR4R4' in which R4 and R4' are as defined below,

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

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

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

      ∘ a halogen atom,

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

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

      ∘ a group -NR5R5' in which R5 and R5', independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -CO2-(C1-C3)alkyl group, a (C3-C5)cycloalkyl group and a linear or branched (C1-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 -CO2-(C1-C4)alkyl group,
    • a group -NR6R6' in which R6 and R6', which are different, represent a (C1-C5)alkyl group and a (C1-C5)alkoxy group, and/or



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



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

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



    [0019] Among the compounds of the present 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



    L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R1, or a (C1-C2)alkyl, said alkyl being optionally substituted with one or more substituents chosen from a (C1-C3)alkyl group and a hydroxyl group;



    R1 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 (C3-C6)cycloalkyl,
    • an aryl group, optionally substituted with one or more substituents chosen from a halogen atom, a hydroxyl group, a cyano group, an -NH2 group, a urea group of formula -NH-CO-NH-(C1-C4)alkyl, a morpholine group, a group of formula -SO2-(C1-C5)alkyl, a (C1-C5)alkoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

      ∘ a halogen atom,

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

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

      ∘ a group -CONR4R4' in which R4 and R4' are as defined below,

      ∘ a group -NR4R4' in which R4 and R4' are as defined below,

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

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

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

      ∘ a halogen atom,

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

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

      ∘ a group -NR5R5' in which R5 and R5', independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -CO2-(C1-C3)alkyl group, a (C3-C5)cycloalkyl group and a linear or branched (C1-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 and an acetyl group and a -CO2-(C1-C4)alkyl group,
    • a group -NR6R6' in which R6 and R6', which are different, represent a (C1-C5)alkyl group and a (C1-C5)alkoxy group,



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



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

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

    [0020] Among the compounds of the present invention, mention may be made of a third subgroup of compounds of formula (I) in which:



    n represents 0 or 1;



    Y represents a bridged morpholine (a)



    L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R1, or (C1-C2)alkyl, said alkyl being optionally substituted with one or more substituents chosen from a (C1-C3)alkyl group and a hydroxyl group;



    R1 represents:

    • a linear, branched or partially cyclic (C1-C5)alkyl group, optionally substituted with one or more substituents chosen from a hydroxyl group, an aryl group, a trifluoromethyl group and a (C3-C5)cycloalkyl group,
    • a (C3-C6)cycloalkyl group, optionally substituted with a hydroxyl group,
    • an aryl group, optionally substituted with one or more substituents chosen from a halogen atom, a hydroxyl group, an -NH2 group, a urea group of formula -NH-CO-NH-(C1-C4)alkyl, a morpholine group, a group of formula -SO2-(C1-C5)alkyl, a (C1-C5)alkoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

      ∘ a halogen atom,

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

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

      ∘ a group -CONR4R4' in which R4 and R4' are as defined below,

      ∘ a group -NR4R4' in which R4 and R4' are as defined below,

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

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

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

      ∘ a halogen atom,

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

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

      ∘ a group -NR5R5' in which R5 and R5', independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -CO2C1-C3)alkyl group, a (C3-C5)cycloalkyl group and a linear or branched (C1-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, 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-(C1-C4)alkyl group,
    • a group -NR6R6' in which R6 and R6', which are different, represent a (C1-C5)alkyl group and a (C1-C5)alkoxy group,



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



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

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



    [0021] Among the compounds of the present invention, mention may be made of a fourth subgroup of compounds of formula (I) in which:



    n represents 0 or 1;



    Y represents a bridged morpholine (a)



    L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R1, or (C1-C2)alkyl, said alkyl being optionally substituted with one or more substituents chosen from a (C1-C3)alkyl group and a hydroxyl group;



    R1 represents:

    • a linear or branched (C1-C5) alkyl group, optionally substituted with one or more substituents chosen from a hydroxyl group and an aryl group,
    • a (C3-C6)cycloalkyl group,
    • an aryl group, optionally substituted with one or more substituents chosen from a halogen atom, a hydroxyl group, an -NH2 group, a urea group of formula -NH-CO-NH-(C1-C4)alkyl, a morpholine group, a group of formula -SO2-(C1-C5)alkyl, a (C1-C5)alkoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

      ∘ a halogen atom,

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

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

      ∘ a group -CONR4R4' in which R4 and R4' are as defined below,

      ∘ a group -NR4R4' in which R4 and R4' are as defined below,

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

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

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

      ∘ a halogen atom,

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

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

      ∘ a group -NR5R5' in which R5 and R5', independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -CO2-(C1-C3)alkyl group, a (C3-C5)cycloalkyl group and a linear or branched (C1-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, in particular a morpholinyl group, a bridged morpholinyl group and a piperidyl group, said nitrogen atom being optionally substituted with a substituent chosen from a formyl group and an acetyl group,
    • a group -NR6R6' in which R6 and R6', which are different, represent a (C1-C5)alkyl group and a (C1-C5)alkoxy group,



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



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

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



    [0022] Among the compounds of the present invention, mention may be made of a fifth subgroup of compounds of formula (I) in which:



    n represents 0 or 1;



    Y represents a bridged morpholine (a)



    L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R1, or (C1-C2)alkyl, said alkyl being optionally substituted with one or more (C1-C3)alkyl groups;



    R1 represents:

    • a linear, branched or partially cyclic (C1-C5)alkyl group, in particular an isopropyl or tert-butyl group, optionally substituted with one or more substituents chosen from a hydroxyl group, an aryl group, a trifluoromethyl group and a (C3-C5)cycloalkyl group,
    • a (C3-C6)cycloalkyl group, optionally substituted with a hydroxyl group,
    • an aryl group, in particular a phenyl group, optionally substituted with one or more substituents chosen from a halogen atom, a cyano group, an -NH2 group, a urea group of formula -NH-CO-NH-(C1-C4)alkyl, a morpholine group, a group of formula -SO2-(C1-C5)alkyl, a (C1-C5)alkoxy group, in particular a methoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

      ∘ a halogen atom, in particular a fluorine atom,

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

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

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

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

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

      ∘ a halogen atom,

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

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

      ∘ a group -NR5R5' in which R5 and R5', independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -CO2-(C1-C3)alkyl group, a (C3-C5)cycloalkyl group and a linear or branched (C1-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, 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 -CO2-(C1-C4)alkyl group,
    • a group -NR6R6' in which R6 and R6', which are different, represent an alkyl group and a (C1-C5)alkoxy group,



    R2 represents a hydrogen atom when n represents 1 and a methyl group when n represents 0; in the form of the base or of an addition salt with an acid or with a base.



    [0023] Among the compounds of the present invention, mention may be made of a sixth subgroup of compounds of formula (I) in which:



    n represents 0 or 1;



    Y represents a bridged morpholine (a)



    L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R1, or (C1-C2)alkyl, said alkyl being optionally substituted with one or more (C1-C3)alkyl groups;



    R1 represents:

    • a linear or branched (C1-C5)alkyl group, in particular an isopropyl or tert-butyl group, optionally substituted with one or more hydroxyl groups,
    • a (C3-C6)cycloalkyl group,
    • an aryl group, in particular a phenyl group, optionally substituted with one or more substituents chosen from a halogen atom, a cyano group, an -NH2 group, a urea group of formula -NH-CO-NH-(C1-C4)alkyl, a morpholine group, a group of formula -SO2-C1-C5)alkyl, a (C1-C5)alkoxy group, in particular a methoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

      ∘ a halogen atom, in particular a fluorine atom,

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

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

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

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

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

      ∘ a halogen atom,

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

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

      ∘ a group -NR5R5' in which R5 and R5', independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -CO2-(C1-C3)alkyl group, a (C3-C5)cycloalkyl group and a linear or branched (C1-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, in particular a 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine group,
    • a heterocycloalkyl group comprising one or more heteroatoms chosen from oxygen and nitrogen atoms, said nitrogen atom being optionally substituted with a substituent chosen from a formyl group and an acetyl group,
    • a group -NR6R6' in which R6 and R6', which are different, represent an alkyl group and a (C1-C5)alkoxy group,



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

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

    [0024] Among the compounds of the present invention, mention may be made of a seventh subgroup of compounds of formula (I) in which:



    Y represents a bridged morpholine (a)



    L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R1,



    R1 represents:

    • a linear or branched (C1-C5)alkyl group, in particular an isopropyl or tert-butyl group,
    • a (C3-C6)cycloalkyl group,
    • an aryl group, in particular a phenyl group, optionally substituted with one or more substituents chosen from a halogen atom, a cyano group, an -NH2 group, a urea group of formula -NH-CO-NH-(C1-C4)alkyl, a morpholinyl group, a group of formula -SO2-(C1-C5)alkyl, a (C1-C5)alkoxy group, in particular a methoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

      ∘ a halogen atom, in particular a fluorine atom,

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

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

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

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

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

      ∘ a halogen atom,

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

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

      ∘ a group -NR5R5' in which R5 and R5', independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -CO2-(C1-C3)alkyl group, a (C3-C5)cycloalkyl group and a linear or branched (C1-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, 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 -CO2-(C1-C5)alkyl group,
    • a group -NR6R6' in which R6 and R6', which are different, represent an alkyl group and a (C1-C5)alkoxy group,

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

    [0025] Among the compounds of the present invention, mention may be made of an eighth subgroup of compounds of formula (I) in which:



    Y represents a bridged morpholine (a)



    L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R1,



    R1 represents:

    • a linear or branched (C1-C5)alkyl group, in particular an isopropyl or tert-butyl group,
    • a (C3-C6)cycloalkyl group,
    • an aryl group, in particular a phenyl group, optionally substituted with one or more substituents chosen from a halogen atom, a cyano group, an -NH2 group, a urea group of formula -NH-CO-NH-(C1-C4)alkyl, a morpholinyl group, a group of formula -SO2-(C1-C5)alkyl, a (C1-C5)alkoxy group, in particular a methoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

      ∘ a halogen atom, in particular a fluorine atom,

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

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

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

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

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

      ∘ a halogen atom,

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

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

      ∘ a group -NR5R5' in which R5 and R5', independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -CO2-(C1-C3)alkyl group, a (C3-C5)cycloalkyl group and a linear or branched (C1-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, in particular a 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine group,
    • a heterocycloalkyl group comprising one or more heteroatoms chosen from oxygen and nitrogen atoms, in particular a morpholinyl group, a bridged morpholinyl group and a piperidyl group, said nitrogen atom being optionally substituted with a substituent chosen from a formyl group and an acetyl group,
    • a group -NR6R6' in which R6 and R6', which are different, represent an alkyl group and an alkoxy group,
    in the form of the base or of an addition salt with an acid or with a base.



    [0026] 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)



    L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R1, or (C1-C2)alkyl, said alkyl being optionally substituted with a hydroxyl group;



    R1 represents:

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

      ∘ a group -CONR4R4' in which R4 and R4' are as defined below,

      ∘ a group -NR4R4' in which R4 and R4' are as defined below,

    • a heteroaryl group comprising one or more heteroatoms chosen from a nitrogen atom, a sulfur atom and an oxygen atom, optionally substituted with one or more (C1-C3)alkyl groups, optionally substituted with one or more halogen atoms,
    • a group -NR6R6' in which R6 and R6', which are different, represent a (C1-C5)alkyl group and a (C1-C5)alkoxy group,



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



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

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

    [0027] A tenth subgroup of compounds of formula (I) according to the invention is such that L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R1, a methyl group or an ethyl group, in the form of the base or of an addition salt with an acid or with a base.

    [0028] An eleventh subgroup of compounds of formula (I) according to the invention is such that n represents 1, in the form of the base or of an addition salt with an acid or with a base.

    [0029] A twelfth subgroup of compounds of formula (I) according to the invention is such that n represents 0, in the form of the base or of an addition salt with an acid or with a base.

    [0030] A thirteenth subgroup of compounds of formula (I) according to the invention is such that R1 represents linear or branched (C1-C5)alkyl group, optionally substituted with a hydroxyl group, a heteroaryl group, in particular a pyridyl group, or a group - NR6R6' in which R6 and R6', which are different, represent a (C1-C5)alkyl group and a (C1-C5)alkoxy group, in the form of the base or of an addition salt with an acid or with a base.

    [0031] A fourteenth subgroup of compounds of formula (I) according to the invention is such that R1 represents linear or branched (C1-C5)alkyl group, optionally substituted with a hydroxyl group, 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-(C1-C4)alkyl group, or a group -NR6R6' in which R6 and R6', which are different, represent a (C1-C5)alkyl group and a (C1-C5)alkoxy group, in the form of the base or of an addition salt with an acid or with a base.

    [0032] 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.

    [0033] Among the compounds of formula (I) that are subjects of the invention, mention may be made especially of the following compounds:
    1. 1 (8S)-9-(2-Methyl-2-pyrid-4-ylpropyl)-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
    2. 2 (8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-oxo-2-pyrid-4-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
    3. 3 (8S)-9-[2-(6-Aminopyrid-3-yl)-2-oxoethyl]-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
    4. 4 (8S)-9-[2-(6-Methylpyrid-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
    5. 5 (8S)-9-[2-(6-Methylaminopyrid-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
    6. 6 (8S)-9-[2-(6-Dimethylaminopyrid-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
    7. 7 (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
    8. 8 1-[2-(6-Dimethylaminopyrid-3-yl)-2-oxoethyl]-2-(S)-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
    9. 9 2-(S)-Methyl-1-[2-(6-methylaminopyrid-3-yl)-2-oxoethyl]-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
    10. 10 (8S)-1-[2-(4-Methoxyphenyl)ethyl]-2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-trifluoromethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one
    11. 11 (S)-1-[2-(6-Aminopyrid-3-yl)-2-oxoethyl]-2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
    12. 12 (8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-pyrid-3-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
    13. 13 2-Methyl-7-(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. 14 (8S)-9-{2-[6-(2-Hydroxyethylamino)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
    15. 15 (8S)-9-[2-(5-Methylpyrid-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
    16. 16 2-Methyl-1-[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-dihydro-1 H-imidazo[1,2-a]pyrimidin-5-one
    17. 17 2-Methyl-1-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
    18. 18 2-Methyl-1-[2-(2-methylpyrid-3-yl)-2-oxoethyl]-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
    19. 19 (8S)-9-[2-(2-Methylpyrid-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
    20. 20 (8S)-9-[2-(4-Methylpyrid-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
    21. 21 2-Methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1-(2-oxo-2-pyrid-3-ylethyl)-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
    22. 22 (8S)-9-[2-(6-Cyclopropylaminopyrid-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
    23. 23 1-Ethyl-3-{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]phenyl}urea
    24. 24 1-Ethyl-3-{4-[2-((S)-2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-5-oxo-2-trifluoromethyl-2,3-dihydro-5H-imidazo[1,2-a]pyrimidin-1-yl)ethyl]phenyl}urea
    25. 25 (8S)-9-[2-(4-Methylthiazol-5-yl)ethyl]-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
    26. 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[1,2-a]pyrimidin-5-one
    27. 27 (8S)-9-[2-(3,5-Dimethyl-1H-pyrazol-4-yl)ethyl]-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
    28. 28 1-[2-(3,5-Dimethyl-1H-pyrazol-4-yl)ethyl]-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-a]pyrimidin-5-one
    29. 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. 30 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-1 H-imidazo[1,2-a]pyrimidin-5-one
    31. 31 (8S)-9-[2-(6-Amino-5-methylpyrid-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
    32. 32 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-1 H-imidazo[1,2-a]pyrimidin-5-one
    33. 33 (8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-oxo-2-(6-trifluoromethylpyrid-3-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
    34. 34 (8S)-9-(2-{6-[(2-Hydroxyethyl)methylamino]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
    35. 35 (8S)-9-[2-(6-Ethoxypyrid-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
    36. 36 (8S)-9-[2-(6-Amino-4,5-dimethylpyrid-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
    37. 37 (S)-9-[2-(4-Difluoromethoxyphenyl)-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
    38. 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-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
    39. 39 (8S)-9-[2-(4-Methyloxazol-5-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
    40. 40 (S)-9-[2-(3,4-Difluorophenyl)-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
    41. 41 (8S)-9-[2-(4-Morpholin-4-ylphenyl)-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
    42. 42 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]benzonitrile
    43. 43 (8S)-9-[2-(4-Methylthiazol-5-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
    44. 44 (8S)-9-[2-(5-Chloropyrid-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
    45. 45 (8S)-9-[2-(6-Methoxypyrid-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
    46. 46 (8S)-9-[2-(3-Methylisoxazol-4-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
    47. 47 (8S)-9-(2-Benzo[1,2,3]thiadiazol-5-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
    48. 48 (8S)-9-[2-(2,4-Difluorophenyl)-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
    49. 49 (8S)-9-(3-Ethyl-3-hydroxypentyl)-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
    50. 50 (8S)-9-(3-Hydroxy-3-methylbutyl)-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
    51. 51 (8S)-9-(1-Methyl-1H-indazol-3-ylmethyl)-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
    52. 52 (8S)-9-[2-(2-Cyclopropylmethoxypyrimidin-5-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
    53. 53 (8S)-9-[2-(3,5-Dimethylisoxazol-4-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
    54. 54 (8S)-9-(2-Ethyl-2-hydroxybutyl)-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
    55. 55 3-[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]benzonitrile
    56. 56 (8S)-9-(3-Methyl-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
    57. 57 {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
    58. 58 {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 methyl ester
    59. 59 (8S)-9-(5-Methyl-[1,2,4]oxadiazol-3-ylmethyl)-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
    60. 60 (8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-oxo-2-(2-trifluoromethylpyrid-3-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
    61. 61 (8S)-9-(2-Benzo[1,2,5]thiadiazol-5-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
    62. 62 (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-tetrahydropyrimido[1,2-a]pyrimidin-4-one
    63. 63 (8S)-9-{2-[6-(2-Fluoroethoxy)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
    64. 64 (8S)-9-{2-[3-Fluoro-4-(2-fluoroethoxy)phenyl]-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
    65. 65 (8S)-9-[2-(2-Methoxypyrid-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
    66. 66 (8S)-9-[2-(3-Methyl-3H-imidazol-4-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
    67. 67 (8S)-9-(2-Cyclopropyl-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
    68. 68 (8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-oxo-2-pyrid-2-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
    69. 69 (8S)-9-[2-(2-Methyl-2H-pyrazol-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
    70. 70 N,N-Dimethyl-2-(4-{2-[(S)-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-oxo-2-trifluoromethyl-2,3-dihydro-5H-imidazo[1,2-a]pyrimidin-1-yl]ethyl}phenoxy)acetamide
    71. 71 (8S)-9-[(S)-2-(4-Fluoro-2-methoxyphenyl)-2-hydroxyethyl]-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
    72. 72 (2S)-1-[2-(4-Hydroxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
    73. 73 (8S)-2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-phenylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
    74. 74 (2S)-1-{2-[4-(2-Dimethylaminoethoxy)phenyl]ethyl}-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one
    75. 75 (8S)-2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-pyrid-4-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
    76. 76 (S)-1-[2-(4-Methoxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
    77. 77 (S)-2-Methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1-(3-phenylpropyl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
    78. 78 (S)-1-{2-[4-(3-Dimethylaminopropoxy)phenyl]ethyl}-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one
    79. 79 (2S)-1-((S)-2-Hydroxy-2-phenylethyl)-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
    80. 80 (8S)-9-((S)-2-Hydroxy-2-phenylethyl)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
    81. 81 (8S)-9-[2-(4-Methoxyphenyl)ethyl]-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
    82. 82 (8S)-9-((R)-2-Benzo[b]thiophen-2-yl-2-hydroxyethyl)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
    83. 83 (8S)-9-[2-(4-Hydroxyphenyl)ethyl]-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
    84. 84 (8S)-2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(3-phenylpropyl)-8-trifluoromethylmethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
    85. 85 (8S)-2-(3-Oxa-8-azabicyclo[3.2.1]oct-8-yl)-9-(2-oxo-2-pyrid-3-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
    86. 86 (8S)-9-(1-Difluoromethyl-1H-pyrazol-3-ylmethyl)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
    87. 87 (8S)-2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-pyrid-3-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
    88. 88 (8S)-2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-pyrid-2-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
    89. 89 (S)-9-[2-(1-Acetylpiperid-4-yl)ethyl]-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
    90. 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. 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. 92 (8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-(tetrahydropyran-4-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
    93. 93 (8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(tetrahydropyran-4-ylmethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
    94. 94 (8S)-9-(1-Acetylpiperid-4-ylmethyl)-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
    95. 95 4-((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-ylmethyl)piperidine-1-carbaldehyde
    96. 96 (8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
    97. 97 (8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethylbutyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
    98. 98 (8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
    99. 99 (8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
    100. 100 (8S)-9-[2-(1-Hydroxycyclopentyl)ethyl]-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
    101. 101 (8S)-9-(1-Hydroxycyclopentylmethyl)-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
    102. 102 (8S)-9-(3,3-Dicyclopropyl-3-hydroxypropyl)-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
    103. 103 (8S)-9-(2,2-Dicyclopropyl-2-hydroxyethyl)-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
    104. 104 (8S)-9-(1-Hydroxycyclopropylmethyl)-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
    105. 105 (8S)-9-[2-(1-Hydroxycyclopropyl)ethyl]-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
    106. 106 (8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-quinolin-5-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
    107. 107 (8S)-9-[2-(3-Methylisothiazol-4-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
    108. 108 (8S)-9-[2-(4-Methanesulfonylphenyl)-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
    109. 109 (8S)-9-Isoquinolin-5-ylmethyl-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
    110. 110 (8S)-9-(2-Morpholin-4-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
    111. 111 (8S)-9-{2-[4-(2-Morpholin-4-ylethoxy)phenyl]ethyl}-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
    112. 112 N-Methoxy-N-methyl-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)acetamide
    113. 113 (8S)-9-(2-Imidazo[1,2-a]pyrid-6-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
    114. 114 (8S)-9-[2-(6-Difluoromethoxypyrid-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
    115. 115 (S)-9-{2-[4-(2-Morpholin-4-yl-2-oxoethoxy)phenyl]ethyl}-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
    116. 116 (8S)-9-(1-Methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethyl)-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
    117. 117 (8S)-9-{2-[4-(2-Dimethylaminoethoxy)phenyl]ethyl}-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
    118. 118 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-carbaldehyde
    119. 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-tetrahydropyrimido[1,2-a]pyrimidin-4-one
    in the form of the base or of an addition salt with an acid or with a base.

    [0034] It should be noted that the above compounds were named according to the IUPAC nomenclature by means of the Autonom software.

    [0035] In accordance with the invention, the compounds of general formula (I) may be prepared according to the processes that follow.

    [0036] The synthesis of the intermediate compounds E1 in which n = 1 and R2 represents a hydrogen atom is described in Scheme 1:

    The guanidine A is prepared according to the processes described in patent application EP 1 460 076 by Lochead, A.W. et al.. Compound C may be obtained by condensation of a guanidine A with a dialkyl malonate B, in which R is an alkyl group, preferably an ethyl group, in the presence of a strong base such as sodium methoxide, at a temperature of between 60°C and 100°C, under the conditions described, for example, by Badawey E.-S.A.M. et al. (Eur. J. Med. Chem., 1998, 33(5), 349-361). Compound D may be obtained from a compound C by treatment with a chlorinating agent such as phosphorus oxychloride, in the absence of solvent, at a temperature between 20°C and 120°C, or in the presence of a polar solvent such as 1,2-dichloroethane, at a temperature of between 20°C and the boiling point of the solvent, as described by Yamashita, A. et al. (Syn. Commun. (2004), 34(5), 795-803). Compound E1 is obtained after separation of the enantiomers of the compound of formula D by chromatography on a chiral support.

    [0037] The synthesis of the intermediate compounds E0 in which n = 0 and R2 represents a methyl group is described in Scheme 2:

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

    [0038] The compounds E0 are obtained from a compound H by treatment with a chlorinating agent such as phosphorus oxychloride, in the absence of solvent, at a temperature between 20°C and 120°C, or in the presence of a polar solvent such as 1,2-dichloroethane, at a temperature of between 20°C and the boiling point of the solvent.

    [0039] Thereafter, the products of formula (I) as defined above according to the present invention may thus be prepared according to Scheme 3.



    [0040] The compounds I are obtained from a compound E, in which n represents 0 or 1, and R2 represents a hydrogen atom if n = 1, or a methyl group if n = 0, by reaction with a bridged morpholine Y, in the absence of solvent, at a temperature of between 20°C and 140°C, or in the presence of a polar solvent such as methyl isobutyl ketone or butyronitrile, at a temperature of between 20°C and the reflux temperature of the solvent. The compounds (I) may then be obtained via an alkylation reaction, by addition of a compound J of formula R1-L-Lg with R1 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, cesium carbonate or potassium tert-butoxide in excess, in a polar solvent such as acetonitrile, N,N-dimethylformamide or tetrahydrofuran, at a temperature of between 0°C and 150°C, as described by Ting P.C. et al. (J. Med. Chem. (1990), 33(10), 2697-2706).

    [0041] By following the procedure described by E. P. Seest et al. in Tet. Asymmetry 17 (2006) 2154-2182, the compounds J, corresponding to chiral 1-aryl-2-chloroethanols or 1-heteroaryl-2-chloroethanols, were synthesized from the corresponding chloro ketone derivatives, which were themselves derived from chlorination of commercially available acetyl derivatives under standard conditions.

    [0042] Alternatively, the compounds (I) may be obtained from a compound K by reaction with a bridged morpholine, in the absence of solvent, at a temperature of between 20°C and 140°C, or in the presence of a solvent such as methyl isobutyl ketone or butyronitrile, at a temperature of between 20°C and the reflux temperature of the solvent.

    [0043] The compounds K may be obtained via an alkylation reaction, by addition of a compound J of formula R1-L-Lg with R1 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, cesium carbonate or potassium tert-butoxide in excess, in a solvent such as acetonitrile, N,N-dimethylformamide or tetrahydrofuran, at a temperature of between 0°C and 150°C, as described, for example, by Ting P.C. et al. (J. Med. Chem. (1990), 33(10), 2697-2706).

    [0044] The compounds of formula (I) for which the linker L is an ethyl group, R1 is a linear or branched (C1-C5)alkyl group substituted with a hydroxyl group, Y represents a bridged morpholine chosen from (a), (b) and (c), n represents 1 or 0, and R2 represents a hydrogen atom when n = 1 and a methyl group when n = 0, are noted (I)-1. The compounds for which the linker L is a methyl group, R1 is a linear or branched (C1-C5)alkyl group substituted with a hydroxyl group, Y represents a bridged morpholine chosen from (a), (b) and (c), n represents 1 or 0, and R2 represents a hydrogen atom when n = 1 and a methyl group when n = 0, are noted (I)-2. The compounds of formula (I) for which the linker L is a -CH2-CO- group, R1 is a group -NR6R6' with R6 et R6' being either different and representing an alkyl group and an alkoxy 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 (I)-3. The compounds of formulae (I)-1, (I)-2 and (I)-3 may be obtained according to Scheme 4.



    [0045] The compounds (I)-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 temperature of between 0°C and 25°C, as described, for example, by Ting P.C. et al. (J. Med. Chem. (1990), 33(10), 2697-2706). The compounds N may be obtained via an addition reaction of Michael type of a compound I with a compound M, of formula CH2=CH-CO2Alkyl, in the presence of a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene, in a polar aprotic solvent such as N,N-dimethylformamide, at a temperature of 25°C.

    [0046] Similarly, the compounds (I)-2 may be obtained via an alkylation reaction, by addition of a compound O, as described above, to compound Q, in a polar solvent such as tetrahydrofuran, at a temperature of between 0°C and 25°C. The compounds Q may be obtained via an alkylation reaction, by addition of a compound P, of formula X-CH2-CO2Alkyl in which X is a halogen atom such as Cl, Br or I, to compound I and an alkaline base such as sodium hydride or cesium carbonate in excess, in a polar solvent such as N,N-dimethylformamide or acetonitrile, at a temperature of 25°C.

    [0047] The compounds (I)-3 may be obtained via a coupling reaction between a compound S and a compound of formula HNR6R6' with R6 and R6' being either different and representing an alkyl group and an alkoxy group, in a polar solvent such as N,N-dimethylformamide, in the presence of coupling agents such as 1-hydroxy benzotriazole with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Compound S is obtained by hydrolysis of compound Q, for example using lithium hydroxide monohydrate in a water/tetrahydrofuran mixture.

    [0048] It is clear to a person skilled in the art that, in order to perform the processes according to the invention described previously, it may be necessary to introduce protecting groups for the amino, carboxyl and alcohol functions in order to avoid side reactions.

    [0049] Examples of protecting groups and also of protection and deprotection methods are given in Protective Groups in Organic Synthesis, Greene et al., 3rd Edition (John Wiley & Sons, Inc., New York). As examples of protection of reactive functions, the following non-exhaustive list may be mentioned:
    • the hydroxyl groups may be protected, for example, with alkyl radicals such as tert-butyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl or acetyl,
    • the amino groups may be protected, for example, with acetyl, trityl, benzyl, tert-butoxycarbonyl, benzyloxycarbonyl or phthalimido radicals or other radicals known in peptide chemistry,
    • the acid functions may be protected, for example, in the form of esters formed with readily cleavable esters such as benzyl or tert-butyl esters or esters known in peptide chemistry.


    [0050] In the text hereinabove, the term "leaving group Lg" means a group that can be readily cleaved from a molecule by breaking a heterolytic bond, with loss of an electron pair. This group can thus be easily replaced with another group in a substitution reaction, for example. Such leaving groups are, for example, halogens or an activated hydroxyl group, such as a mesylate, tosylate, triflate, acetyl, etc. Examples of leaving groups and also references for preparing them are given in Advanced Organic Chemistry, J. March, 4th Edition, Wiley Interscience, p. 310-316.

    [0051] 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.

    [0052] 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).

    [0053] The following abbreviations and molecular formulae are used:

    EtOAc: ethyl acetate

    Br: bromine

    CDCl3: deuterated chloroform

    Cl: chlorine

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

    DCM: dichloromethane

    DMF: N,N-dimethylformamide

    DMSO: dimethyl sulfoxide

    DMSO-d6: deuterated dimethyl sulfoxide

    HPLC: high performance liquid chromatography

    HCl: hydrochloric acid

    K2CO3: potassium carbonate

    LC/MS: liquid chromatography/mass spectrometry

    MeOH: methanol

    MgSO4: magnesium sulfate

    MHz: Megahertz

    Na2CO3: sodium carbonate

    NaCl: sodium chloride

    NaOH: sodium hydroxide

    NaHCO3: 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

    Tr: retention time

    min: minutes

    ESI+: positive-mode electrospray ionization



    [0054] The following examples describe the preparation of certain compounds in accordance with the invention. These examples are not limiting and merely illustrate the present invention. The numbers of the compounds exemplified refer to those given in the table hereinafter, which shows the chemical structures and the physical properties of some compounds according to the invention.
    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 resonance spectra (1H NMR), as described below, are recorded at a temperature of 300 K (exchangeable protons not recorded) at 300, 400 or 600 MHz in DMSO-d6 or CDCl3, using the DMSO-d6 or CDCl3 peak as reference. The chemical shifts δ are expressed in parts per million (ppm). The signals 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 retention time (Tr) of the compound expressed in minutes and the peak [M+H]+ identified by mass spectrometry.

    * Method A



    [0055] 

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

    Column: Ascentis Express C18 50 x 2.1 mm 2.7 µm, T° = 55°C

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

    Flow rate: 1 mL/min

    Gradient A/B: t 0 min 2% B, t 1 min 98% B, t 1.3 min 98% B, t 1.33 min 2% B

    Detection: UV 220 nm

    Ionization: electrospray positive mode


    * Method B



    [0056] 

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

    Column: BHE C8 50 x 2.1 mm 1.7 µm, T° = 55°C

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

    Flow rate: 1 mL/min

    Gradient A/B: t 0 min 2% B, t 1 min 98% B, t 1.3 min 98% B, t 1.33 min 2% B

    Detection: UV 220 nm

    Ionization: electrospray positive mode


    * Method C



    [0057] 

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

    Column: BHE C18 50 x 2.1 mm 1.7 µm, T° = 50°C

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

    Flow rate: 1 mL/min

    Gradient A/B: t 0 min 5% B, t 2 min 100% B, t 2.5 min 100% B

    Detection: UV 220 nm

    Ionization: electrospray positive mode


    * Method D



    [0058] 

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

    Column: Acquity BHE C18 50 x 2.1 mm 1.7 µm, T° = 50°C

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

    Flow rate: 1 mL/min

    Gradient A/B: t 0 min 5% B, t 0.8 min 50% B, t 1.2 min 100% B, t 1.85 min 100% B, t 1.95 min 5% B

    Detection: UV 220 nm

    Ionization: electrospray positive mode


    * Method E



    [0059] 

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

    Column: XBridge C18 50 x 3 mm 2.5 µm, T° = 70°C

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

    Flow rate: 0.9 mL/min

    Gradient A/B: t 0 min 5% B, t 5.3 min 100% B, t 5.5 min 100% B, t 6.3 min 5% B

    Detection: UV 220 nm

    Ionization: electrospray positive mode


    * Method F



    [0060] 

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

    Column: BHE C18 30 x 2.1 mm 1.7 µm, T° = 50°C

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

    Flow rate: 1 mL/min

    Gradient A/B: t 0 min 5% B, t 2 min 100% B, t 2.5 min 100% B

    Detection: UV 220 nm

    Ionization: electrospray positive mode


    * Method G



    [0061] 

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

    Column: X Bridge C18 30 x 2.1 mm 2.5 µm, T° = 55°C

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

    Flow rate: 0.7 mL/min

    Gradient A/B: t 0 min 2% B, t 3 min 100% B, t 3.5 min 100% B, t 3.6 min 2% B

    Detection: UV 220 nm

    Ionization: electrospray positive mode



    [0062] The optical rotations [α]D25 were measured on a model 341 polarimeter from Perkin-Elmer. Wavelength: sodium α line (589 nm).

    Example 1:


    (8S)-9-[2-(2,4-difluorophenyl)-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 (compound 48)



    [0063] 


    Step 1.1: 4-trifluoromethyl-1,4,5,6-tetrahydropyrimidin-2-ylamine



    [0064] 



    [0065] 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-2-ylamine 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 temperature 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-d6): 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-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0066] 



    [0067] 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-1,4,5,6-tetrahydropyrimidin-2-ylamine 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 temperature overnight. The reaction mixture is evaporated to dryness under reduced pressure. The residue obtained is taken up in 250 mL of water. 12 N hydrochloric acid is added to the thick suspension obtained, to pH = 5-6. The suspension obtained is filtered through a sinter funnel and the insoluble matter is rinsed with acetonitrile to give 68.10 g of 2-hydroxy-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+H]+: m/z 236; tr (min) = 0.26

    1H NMR (300 MHz, δ in ppm, DMSO-d6): 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-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0068] 



    [0069] 136 mL (1440 mmol) of phosphorus oxychloride are added, at room temperature and under an argon atmosphere, 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 1,2-dichloroethane. 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 magnesium sulfate, filtered and concentrated under reduced pressure to give 60 g of 2-chloro-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in the form of an orange solid, the characteristics of which are as follows:

    LC/MS (method D), ESI+: [M+H]+: m/z 254; tr (min) = 0.51

    1H NMR (300 MHz, δ in ppm, DMSO-d6) 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]pyrimidin-4-one



    [0070] 



    [0071] The separation of the two enantiomers of 2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one (100 g) is performed by chiral chromatography: stationary phase: Chiralpak IA (250 mm x 4.6) 5 µm; temperature 25°C; mobile phase: methanol (100%). The levorotatory enantiomer is concentrated to give 49.10 g of (8R)-2-chloro-8-(trifluoromethyl)-6,7,8,9-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)-6,7,8,9-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

    1H NMR (300 MHz, δ in ppm, DMSO-d6): 2.14 (m, 2H), 3.47 (m, 1H), 4.12 (m, 1H), 4.36 (m, 1H), 5.81 (s, 1H), 9.31 (s, 1H).

    [α]D25 at 589 nm = + 21.3 ± 0.5° (MeOH)


    Step 1.5: (8S)-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



    [0072] 



    [0073] 1.60 g (6.31 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 1.30 g (9.46 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 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-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows:

    LC/MS (method G): ESI+: [M+H]+: m/z 317 tr (min) = 1.37

    1H NMR (300 MHz, δ in ppm, CDCl3): 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-difluorophenyl)-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



    [0074] 



    [0075] A suspension of 150 mg (0.47 mmol) of (8S)-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 and 463.57 mg (1.42 mmol) of cesium carbonate in 10 mL of acetonitrile is stirred for 15 minutes at room temperature. 222.93 mg (0.95 mmol) of 2-bromo-1-(2,4-difluorophenyl)ethanone are then added. After stirring overnight at room temperature, the reaction mixture is evaporated and the residue is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium 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-(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 471 tr (min) = 0.68

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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:


    (8S)-9-[2-(4-methylthiazol-5-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 (compound 25)



    [0076] 


    Step 2.1: 5-(2-bromoethyl)-4-methylthiazole



    [0077] 



    [0078] 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-methylthiazole, the characteristics of which are as follows:

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

    1H NMR (300 MHz, δ in ppm, CDCl3): 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-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



    [0079] 



    [0080] A suspension of 160 mg (0.50 mmol) of (8S)-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 and 415 mg (1.25 mmol) of cesium carbonate in 4 mL of N,N-dimethylformamide is heated at 80°C for 15 minutes. After cooling to room temperature, a solution of 150 mg (0.76 mmol) of 5-(2-bromoethyl)-4-methylthiazole in 1 mL of N,N-dimethylformamide is added dropwise. The reaction medium is heated at 80°C overnight. 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 magnesium sulfate and evaporated to dryness.

    [0081] 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)-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 442 tr (min) = 0.55

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (compound 15)



    [0082] 


    Step 3.1: 1-(5-methylpyrid-3-yl)ethanone



    [0083] 



    [0084] The following are successively introduced into a microwave tube:
    484 µl (4.07 mmol) of 3-bromo-5-methylpyridine in 20 mL of H2O/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)palladium(II) chloride, 1.12 g (8.14 mmol) of potassium carbonate. This mixture is subjected to microwave irradiation at 110°C for 1 hour. The reaction 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 magnesium sulfate and evaporated to dryness. The residue obtained is taken up in 6 mL of methanol and 1 mL of 6 N HCI, and the solution is stirred overnight at room temperature. The reaction medium is evaporated to dryness and the residue is taken up in saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic phase is dried over magnesium 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-(5-methylpyrid-3-yl)ethanone, the characteristics of which are as follows:

    LC/MS (method G): ESI+ [M+H]+: m/z 136 tr (min) = 0.78

    1H NMR (300 MHz, δ in ppm, DMSO-d6): 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-methylpyrid-3-yl)ethanone hydrobromide



    [0085] 



    [0086] 300 mg (2.22 mmol) of 1-(5-methylpyrid-3-yl)ethanone are dissolved in 15 mL of glacial acetic acid. 365 µl (2.22 mmol) of hydrobromic acid and 126 µl (2.44 mmol) of bromine are added to the medium. The reaction mixture is placed under magnetic stirring at room temperature 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 have the following characteristics:

    LC/MS (method G): ESI+ [M+H]+: m/z 214 tr (min) = 1.17

    1H NMR (300 MHz, δ in ppm, DMSO-d6): 2.46 (s, 3H), 5.05 (s, 2H), 8.48 (s,1H), 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-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0087] 



    [0088] 150 mg (0.474 mmol) of (8S)-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 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 temperature 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 temperature overnight. 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 magnesium 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-(5-methylpyrid-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, 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-d6): 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-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (compound 53)



    [0089] 


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



    [0090] 



    [0091] 659 µl (8.15 mmol) of pyridine are added to a suspension of 343.07 mg (3.45 mmol) of N,O-dimethylhydroxylamine hydrochloride in 10 mL of dichloromethane. The mixture is stirred at room temperature 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 temperature, the reaction mixture is taken up in saturated aqueous NaHCO3 solution and stirred for a few minutes, and the phases are separated by settling. The organic phase is dried over magnesium 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-3,5-dimethylisoxazole-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, CDCl3): 2.32 (s, 3H), 2.46 (s, 3H), 3.34 (s, 3H), 3.52 (s, 3H).


    Step 4.2: 1-(3,5-dimethylisoxazol-4-yl)ethanone



    [0092] 



    [0093] A solution of 580 mg (3.15 mmol) of N-methoxy-N-methyl-3,5-dimethylisoxazole-4-carboxamide in 20 mL of THF is cooled to 0°C. A solution of 1.57 mL (4.72 mmol) of 3 M methylmagnesium bromide in ether is added. After stirring for 4 hours at room temperature, the reaction medium is taken up in 10 mL of 1 N HCI and stirred for a further 1 hour at room temperature. The mixture is then basified with K2CO3 and extracted with ethyl acetate. The organic phase is dried over magnesium 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

    1H NMR spectrum (300 MHz, δ in ppm, CDCl3): 2.48 (s, 6H), 2.70 (s, 3H).


    Step 4.3: 2-bromo-1-(3,5-dimethylisoxazol-4-yl)ethanone



    [0094] 



    [0095] 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 µl (3.16 mmol) of bromine are added to the medium. The reaction mixture is placed under magnetic stirring at room temperature for 2 hours. The solution is diluted with water, basified with saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic phase is dried over magnesium 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+H]+: m/z 218 tr (min) = 1.35

    1H NMR (300 MHz, δ in ppm, CDCl3): 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]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0096] 



    [0097] A suspension of 150 mg (0.591 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 578.13 mg (1.77 mmol) of cesium carbonate in 10 mL of acetonitrile is stirred for 15 minutes at room temperature. 154.76 mg (0.709 mmol) of 2-bromo-1-(3,5-dimethylisoxazol-4-yl)ethanone are then added. After stirring overnight at room temperature, the reaction mixture is evaporated and the residue is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness to give 230 mg of (8S)-2-chloro-9-[2-(3,5-dimethylisoxazol-4-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, corresponding to the following characteristics:

    LC/MS (method G): ESI+ [M+H]+: m/z 391 tr (min) = 2.06

    1H NMR (300 MHz, δ in ppm, CDCl3): 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-(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



    [0098] 



    [0099] 200 mg (0.51 mmol) of (8S)-2-chloro-9-[2-(3,5-dimethylisoxazol-4-yl)-2-oxoethyl]-8-trifluoromethyl-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 µl (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 magnesium 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-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, the characteristics of which are as follows:

    LC/MS (method A): ESI+ [M+H]+: m/z 454 tr (min) = 0.58

    1H NMR (300 MHz, δ in ppm, CDCl3): 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,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 56)



    [0100] 


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



    [0101] 



    [0102] A solution of 1 g (11.61 mmol) of 3-methylbutan-2-one in 6 mL of methanol is cooled to a temperature of 10°C. When the temperature is reached, 597 µl (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 temperature. After adding 10 mL of water to the solution, stirring is continued for 1 hour at room temperature. The reaction mixture is then taken up in water and extracted with ethyl ether. The organic phase is washed with aqueous 10% Na2CO3 solution and then with saturated NaCl solution, dried and evaporated to give 1.50 g of 1-bromo-3-methylbutan-2-one, corresponding to the following characteristics:
    1H NMR (300 MHz, δ in ppm, CDCl3): 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-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0103] 



    [0104] A suspension of 170 mg (0.670 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 655.21 mg (2.01 mmol) of cesium carbonate in 10 mL of acetonitrile is stirred for 15 minutes at room temperature. 132.75 mg (0.804 mmol) of 1-bromo-3-methylbutan-2-one are then added. After stirring overnight at room temperature, the reaction mixture is evaporated and the residue is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness to give 220 mg of (8S)-2-chloro-9-(3-methyl-2-oxobutyl)-8-trifluoromethyl-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 338 tr (min) = 2.20

    1H NMR (300 MHz, δ in ppm, CDCl3): 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-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0105] 



    [0106] 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 µl (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 magnesium 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-(3-methyl-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

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 1.02 (m, 6H), 1.79 (m, 2H), 2.16 (m, 1H), 2.37 (m, 1H), 2.68 (m, 1H), 2.84-3.26 (bs, 3H), 3.30-3.75 (bs, 2H), 4.18 (d, 1H), 4.30 (m, 1H), 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-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 (compound 7)



    [0107] 


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



    [0108] 



    [0109] 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-8-trifluoromethyl-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 temperature. 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 temperature and is stirred overnight. 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 magnesium 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)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows:

    LC/MS (method G): ESI+ [M+H]+: m/z 373 tr (min) = 1.76

    1H NMR (300 MHz, δ in ppm, CDCl3): 1.66 (s, 1H), 2.3-2.52 (m, 2H), 3.48 (m, 1H), 4 (m, 1H), 4.37 (d, 1H), 4.56 (m, 1H), 5.92 (s, 1H), 7.45 (m, 1H), 8.22 (m, 1H), 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-pyrid-3-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0110] 



    [0111] 1 g (2.68 mmol) of (8S)-2-chloro-9-(2-oxo-2-pyrid-3-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 545.67 mg (4.02 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 934.86 µl (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 magnesium 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+H]+: m/z 436 tr (min) = 0.51

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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-oxoethyl]-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 (compound 16)



    [0112] 


    Step 7.1: (R)-2-methyl-4-phenyl-2-trifluoromethyloxazolidine



    [0113] 



    [0114] 25 g (180 mmol) of (R)-phenylglycinol and then 4 g (16 mmol) of pyridinium para-toluenesulfonate 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-2-trifluoromethyloxazolidine 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-d6): 1.55 (s, 3H), 3.58 (m, 1H), 3.80 (m, 1H), 4.28 (m, 1H), 4.42 (m, 1H), 7.34 (m, 5H).

    [α]D25 at 589 nm = -23.4 ± 0.8° (c = 1.794 mg / 0.5 mL MeOH)


    Step 7.2: (S)-3,3,3-trif)uoro-2-((R)-2-hydroxy-1-pheny)ethy)amino)-2-methylpropionitrile



    [0115] 



    [0116] 25 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 temperature. The resulting mixture is stirred at room temperature for 3 hours, followed by addition of saturated sodium bicarbonate solution to pH = 7. The organic phase is separated out and then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica (eluent A/B: pentane/EtOAc, A/B gradient: t 0 min 0% B, t 20 min 10% B, t 40 min 40% B) to give 3.50 g of (R)-3,3,3-trifluoro-2-((R)-2-hydroxy-1-phenylethylamino)-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+H]+: m/z 259 tr (min) = 0.86

    1H NMR (300 MHz, δ in ppm, DMSO-d6): 1.71 (s, 3H), 3.43 (m, 2H), 3.57 (m, 1H), 3.96 (m, 1H), 4.97 (m, 1H), 7.29 (m, 5H).

    [α]D25 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-aminomethyl-2,2,2-trifluoro-1-methylethylamino)-2-phenylethanol



    [0117] 



    [0118] 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 temperature and is then stirred overnight. The mixture obtained is cooled to 0°C, followed by very slow dropwise addition of 12 mL of water. Substantial evolution of gas and a temperature 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 filtered off and the filtrate obtained is dried over magnesium sulfate and then concentrated under reduced pressure to give 10.50 g of (R)-2-((S)-1-aminomethyl-2,2,2-trifluoro-1-methylethylamino)-2-phenylethanol, the characteristics of which are as follows:

    LC/MS (method D): ESI+ [M+H]+: m/z 263 tr (min) = 0.43

    1H NMR (300 MHz, δ in ppm, DMSO-d6): 0.90 (s, 3H), 2.48 (m, 2H), 2.72 (m, 2H), 3.31 (m, 4H), 3.95 (m, 1H), 7.27 (m, 5H).

    [α]D25 at 589 nm = -51.2 ± 1.3° (c = 1.576 mg / 0.5 mL DMSO)


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



    [0119] 



    [0120] A mixture of 10.50 g (70 mmol) of (R)-2-((S)-1-aminomethyl-2,2,2-trifluoro-1-methylethylamino)-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 filtered 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 magnesium sulfate, filtered and then concentrated under vacuum to give 4.50 g of (S)-3,3,3-trifluoro-2-methylpropane-1,2-diamine in the form of a pale yellow oil, the characteristics of which are as follows:

    LC/MS (method E): ESI+ [M+H]+: m/z 143 tr (min) = 0.34

    1H NMR (300 MHz, DMSO-d6): 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).

    [α]D25 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-1H-imidazol-2-ylamine hydrobromide



    [0121] 



    [0122] 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-2-methylpropane-1,2-diamine in 20 mL of acetonitrile, while maintaining the temperature between 5 and 10°C. At the end of the addition, the reaction mixture is left at 5°C for 30 minutes. The mixture obtained is then stirred at room temperature overnight. The resulting mixture is then concentrated under vacuum. The residue obtained is taken up twice with ethanol 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-dihydro-1H-imidazol-2-ylamine hydrobromide in the form of a white solid, the characteristics of which are as follows:

    LC/MS (method D): ESI+ [M+H]+: m/z 168 tr (min) = 0.14

    1H NMR (300 MHz, DMSO-d6): 1.52 (s, 3 H), 3.57 (m, 1H), 3.81 (m, 1 H), 7.45 (s, 2H), 8.09 (s, 1H), 9.45 (s, 1H).

    [α]D25 at 589 nm: -5.2 ± 0.3° (c = 4.909 mg/ 0.5 mL DMSO)


    Step 7.6: (S)-7-hydroxy-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one



    [0123] 



    [0124] 36.90 g (148.76 mmol) of (S)-4-methyl-4-trifluoromethyl-4,5-dihydro-1H-imidazol-2-ylamine hydrobromide and 24.10 g (446 mmol) of sodium methoxide are added to a mixture of 29.50 g (216.43 mmol) of diethyl 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)-7-hydroxy-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-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

    1H NMR (400 MHz, DMSO-d6): 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).

    [α]D25 at 589 nm = -5.6 ± 0.6° (c = 1.789 mg/ 0.5 mL DMSO)


    Step 7.7: (S)-7-chloro-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one



    [0125] 



    [0126] 41.60 mL (446.50 mmol) of phosphorus oxychloride are added, at room temperature and under an argon atmosphere, to a suspension of 35 g (148.80 mmol) of (S)-7-hydroxy-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one in 350 mL of 1,2-dichloroethane. 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 magnesium 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+H]+: m/z 254 tr (min) = 0.51

    1H NMR (400 MHz, DMSO-d6): 1.57 (s, 3H), 4.00 (d, 1H), 4.21 (d, 1H), 5.84 (s, 1H), 9.64 (s, 1H).

    [α]D25 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-azabicyclo[2.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one



    [0127] 



    [0128] 1 g (3.84 mmol) of (S)-7-chloro-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one and 844.18 mg (5.91 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 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-5-azabicyclo[2.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1 H-imidazo[1,2-a]pyrimidin-5-one are obtained, the characteristics of which are as follows:

    LC/MS (method G): ESI+: [M+H]+: m/z 317 tr (min) =1.34

    1H NMR (300 MHz, δ in ppm, CDCl3): 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), 4.1-4.81 (bs, 3H), 8.77 (s, 1H).


    Step 7.9: 2-methyl-1-[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-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one



    [0129] 



    [0130] 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 50.08 mg (1.04 mmol) of sodium hydride in 5 mL of DMF. The reaction mixture is placed under magnetic stirring at room temperature 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 temperature overnight. 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 magnesium 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-1-[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-dihydro-1H-imidazo[1,2-a] pyrimidin-5-one, the characteristics of which are as follows:

    LC/MS (method A): ESI+ [M+H]+: m/z 450 tr (min) = 0.52

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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, 1H).


    Example 8:


    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-1H-imidazo[1,2-a]pyrimidin-5-one (compound 26)



    [0131] 


    Step 8.1: 5-(2-bromoethyl)-4-methylthiazole



    [0132] 



    [0133] 1 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 temperature 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 follows:

    LC/MS (method G): ESI+ [M+H]+: m/z 206 tr (min) = 1.52

    1H NMR (300 MHz, δ in ppm, CDCl3): 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-(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



    [0134] 



    [0135] 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 reaction medium. The reaction is heated at 80°C overnight. 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 magnesium 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-azabicyclo[2.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1 H-imidazo[1,2-a]pyrimidin-5-one, the characteristics of which are as follows:

    LC/MS (method A): ESI+ [M+H]+: m/z 442 tr (min) = 0.56

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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-[2-(2-methylpyrid-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 (compound 19)



    [0136] 


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



    [0137] 



    [0138] The following are successively introduced into a microwave tube:
    469.80 µl (4.07 mmol) of 3-bromo-5-methylpyridine in 20 mL of H2O/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(II) chloride, 1.12 g (8.14 mmol) of potassium carbonate. After irradiating with microwaves for 1 hour at 110°C, the reaction mixture is evaporated to dryness and the residue is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium 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 overnight at room temperature, the reaction mixture is evaporated to dryness and the residue is taken up in saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic phase is dried over magnesium 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

    1H NMR (300 MHz, δ in ppm, DMSO-d6): 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 hydrobromide



    [0139] 



    [0140] 150 mg (1.11 mmol) of 1-(2-methylpyrid-3-yl)ethanone are dissolved in 10 mL of glacial acetic acid. 365 µl (2.22 mmol) of hydrobromic acid and 63 µl (1.22 mmol) of bromine are added to the medium. The reaction mixture is placed under magnetic stirring at room temperature for 1 hour. Ethyl ether is added to the solution until a precipitate appears. The precipitate corresponding 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 have the following characteristics:

    LC/MS (method G): ESI+ [M+H]+: m/z 214 tr (min) = 0.72

    1H NMR (300 MHz, δ in ppm, DMSO-d6): 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-(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



    [0141] 



    [0142] 140 mg (0.474 mmol) of (8S)-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 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 temperature 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 temperature 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 magnesium 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-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 450 tr (min) = 0.48

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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-methylthiazol-5-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 (compound 43)



    [0143] 


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



    [0144] 



    [0145] 220 mg (1.56 mmol) of 1-(4-methylthiazol-5-yl)ethanone are dissolved in 10 mL of glacial acetic acid. 769 µl (4.67 mmol) of hydrobromic acid and 88 µl (1.71 mmol) of bromine are added to the medium. The reaction mixture is placed under magnetic stirring at room temperature 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 have the following characteristics:

    LC/MS (method G): ESI+ [M+H]+: m/z 220 tr (min) = 1.32

    1H NMR (300 MHz, δ in ppm, DMSO-d6): 2.67 (s, 3H), 4.79 (s, 2H), 9.31 (s, 1H).


    Step 10.2: (8S)-2-chloro-9-[2-(4-methylthiazol-5-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0146] 



    [0147] A suspension of 150 mg (0.591 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 578.13 mg (1.77 mmol) of cesium carbonate in 10 mL of acetonitrile is stirred for 15 minutes at room temperature. 213.64 mg (0.709 mmol) of 2-bromo-1-(4-methylthiazol-5-yl)ethanone hydrobromide are then added. After stirring overnight at room temperature, the reaction mixture is evaporated and the residue is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness to give 190 mg of (8S)-2-chloro-9-[2-(4-methylthiazol-5-yl)-2-oxoethyl]-8-trifluoromethyl-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 393 tr (min) = 1.95

    1H NMR (300 MHz, δ in ppm, DMSO-d6): 2.3 (m, 1H), 2.49 (s, 1H), 2.72 (s, 3H), 3.37 (m, 1H), 4.4 (m, 1H), 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-methylthiazol-5-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



    [0148] 



    [0149] 170 mg (0.511 mmol) of (8S)-2-chloro-9-[2-(4-methylthiazol-5-yl)-2-oxoethyl]-8-trifluoromethyl-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 µl (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 magnesium 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-(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 456 tr (min) = 0.55

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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-azabicyclo[2.2.1]hept-5-yl-9-[2-oxo-2-(tetrahydropyran-4-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (compound 62)



    [0150] 


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



    [0151] 



    [0152] A suspension of 150 mg (0.591 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 578.13 mg (1.77 mmol) of cesium carbonate in 10 mL of acetonitrile is stirred for 15 minutes at room temperature. 146.97 mg (0.709 mmol) of 2-bromo-1-(tetrahydropyran-4-yl)ethanone are then added. After stirring overnight at room temperature, the reaction mixture is evaporated and the residue is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium 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-tetrahydropyrimido[1,2-a]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, CDCl3): 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-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0153] 



    [0154] 220 mg (0.58 mmol) of (8S)-2-chloro-9-[2-oxo-2-(tetrahydropyran-4-yl)ethyl]-8-trifluoromethyl-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 µl (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 magnesium 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)-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-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:

    LC/MS (method A): ESI+ [M+H]+: m/z 443 tr (min) = 0.52

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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, 1H), 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-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (compound 20)



    [0155] 


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



    [0156] 



    [0157] 671 µl (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(II) 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 temperature and then basified with potassium carbonate and extracted with ethyl acetate. The organic phase is dried over magnesium 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-(4-methylpyrid-3-yl)ethanone, the characteristics of which are as follows:

    LC/MS (method G): ESI+ [M+H]+: m/z 136 tr (min) = 0.56

    1H NMR (300 MHz, δ in ppm, DMSO-d6): 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



    [0158] 



    [0159] 300 mg (2.22 mmol) of 1-(4-methylpyrid-3-yl)ethanone are dissolved in 20 mL of glacial acetic acid. 730 µl (4.44 mmol) of hydrobromic acid and 126 µl (2.44 mmol) of bromine are added to the medium. The reaction mixture is placed under magnetic stirring at room temperature 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 filtered off, washed with ethyl ether and dried. The 550 mg of product obtained have the following characteristics:

    LC/MS (method G): ESI+ [M+H]+: m/z 214 tr (min) = 1.01

    1H NMR (300 MHz, δ in ppm, DMSO-d6): 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-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0160] 



    [0161] A suspension of 100 mg (0.394 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 385.42 mg (1.18 mmol) of cesium carbonate in 10 mL of acetonitrile is stirred for 15 minutes at room temperature. 139.57 mg (0.473 mmol) of 2-bromo-1-(4-methylpyrid-3-yl)ethanone hydrobromide are then added. After stirring overnight at room temperature, the reaction mixture is evaporated and the residue is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness to give 140 mg of (8S)-2-chloro-9-[2-(4-methylpyrid-3-yl)-2-oxoethyl]-8-trifluoromethyl-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 387 tr (min) = 1.87

    1H NMR (300 MHz, δ in ppm, CDCl3): 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-methylpyrid-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



    [0162] 



    [0163] 140 mg (0.36 mmol) of (8S)-2-chloro-9-[2-(4-methylpyrid-3-yl)-2-oxoethyl]-8-trifluoromethyl-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 126 µl (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 magnesium 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-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 450 tr (min) = 0.48

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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:


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



    [0164] 


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



    [0165] 



    [0166] The reaction is performed under argon: 2 g (12.12 mmol) of ethyl pyrid-4-ylacetate 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 temperature for 30 minutes. 1.21 mL (19.39 mmol) of iodomethane are then added gently, and the solution obtained is stirred at room temperature 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 temperature 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 temperature. 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+H]+: m/z 194 tr (min) = 1.03

    1H NMR (300 MHz, δ in ppm, DMSO-d6): 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



    [0167] 



    [0168] 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 10°C. When the temperature 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 temperature and is stirred overnight. 1 N hydrochloric acid solution is added to the reaction medium, which is then extracted with ethyl acetate. The organic phase is dried over magnesium 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+H]+: m/z 152 tr (min) = 0.40

    1H NMR (300 MHz, δ in ppm, DMSO-d6): 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-pyrid-4-ylpropyl benzenesulfonate



    [0169] 



    [0170] 710 µl (4.07 mmol) of N,N-diisopropylethylamine and 33.13 mg (0.27 mmol) of 4-dimethyl amino pyridine are added to a solution of 410 mg (2.71 mmol) of 2-methyl-2-pyrid-4-ylpropan-1-ol in 10 mL of dichloromethane. The mixture is cooled to 0°C and a solution of 775.42 mg (4.07 mmol) of 4-methylbenzene-1-sulfonyl chloride in 2 mL of dichloromethane is then added. After allowing the reaction medium to warm to room temperature and stirring overnight, it is washed with water and with saturated NaCl solution. The organic phase is dried over magnesium sulfate and evaporated to dryness to give 660 mg of 2-methyl-2-pyrid-4-ylpropyl benzenesulfonate, corresponding to the following characteristics:

    LC/MS (method G): ESI+ [M+H]+: m/z 306 tr (min) = 1.49

    1H NMR (300 MHz, δ in ppm, DMSO-d6): 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-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0171] 



    [0172] The following are placed in a tube: 130 mg (0.411 mmol) of (8S)-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, 133.92 mg (0.411 mmol) of cesium carbonate, 6.16 mg (0.041 mmol) of sodium iodide and 175.74 mg (0.575 mmol) of 2-methyl-2-pyrid-4-ylpropyl benzenesulfonate in 5 mL of DMF. The reaction mixture is heated overnight at 150°C in the sealed tube. After allowing the mixture to cool to room temperature, the solvent is evaporated off. The residue is taken up in ethyl acetate, washed with water, dried over magnesium 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-ylpropyl)-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 B): ESI+ [M+H]+: m/z 450 tr (min) = 0.53

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 1.24 (s, 1H), 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-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)ethyl]phenyl}urea (compound 23)



    [0173] 


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



    [0174] 



    [0175] 5 g (35.36 mmol) of 2-(4-aminophenyl)ethanol and 6.17 mL (35.36 mmol) of N,N-diisopropylethylamine 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 temperature, 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 magnesium sulfate and evaporated to dryness to give 7.85 g of tert-butyl [4-(2-hydroxyethyl)phenyl]carbamate, the characteristics of which are as follows:
    1H NMR spectrum (300 MHz, δ in ppm, DMSO-d6): 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



    [0176] 



    [0177] 8.68 g (33.08 mmol) of triphenylphosphine are added, under an argon atmosphere, to a solution of 7.85 g (33.08 mmol) of tert-butyl [4-(2-hydroxyethyl)phenyl]carbamate in 85 mL of dichloromethane. The mixture is cooled to 0°C 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-(2-bromoethyl)phenyl]carbamate, the characteristics of which are as follows:

    LC/MS (method G): ESI+ [M+Na]+: 322 tr (min) = 2.46

    1H NMR spectrum (300 MHz, δ in ppm, DMSO-d6): 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-(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]phenyl}carbamate



    [0178] 



    [0179] 300 mg (0.95 mmol) of (8S)-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 in 3 mL of DMF are added to a suspension of 75.87 mg (1.89 mmol) of sodium hydride in 2 mL of 2-methyltetrahydrofuran. The reaction mixture is placed under magnetic stirring at room temperature for 10 minutes. A solution of 569.48 mg (1.89 mmol) of tert-butyl [4-(2-bromoethyl)phenyl]carbamate in 3 mL of DMF is added dropwise to the reaction medium. The reaction is stirred at room temperature overnight. 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 magnesium 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-(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]phenyl}carbamate, the characteristics of which are as follows:

    LC/MS (method G): ESI+ [M+H]+: m/z 536 tr (min) = 2.46

    1H NMR (300 MHz, δ in ppm, DMSO-d6): 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-aminophenyl)ethyl]-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



    [0180] 



    [0181] 4 mL (17.93 mmol of a 4 N HCl/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-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)ethyl]phenyl}carbamate. The reaction mixture is stirred for 1 hour 30 minutes at room temperature. 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-(4-aminophenyl)ethyl]-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 G): ESI+ [M+H]+: m/z 436 tr (min) = 1.60

    1H NMR (300 MHz, δ in ppm, DMSO-d6): 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-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)ethyl]phenyl}urea



    [0182] 



    [0183] 50 µl (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-(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 and 139 µl (0.79 mmol) of N,N-diisopropylethylamine in 1 mL of dichloromethane. After stirring overnight at room temperature, the solvent is evaporated off. The residue is taken up in ethyl acetate and washed with water and with saturated aqueous NaCl solution. The organic phase is dried over magnesium sulfate and evaporated to dryness. The residue is purified by reverse-phase chromatography (RP18 column) (eluent: 50/50 H2O/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-trifluoromethyl-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

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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, 1H), 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:


    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-5H-imidazo[1,2-a]pyrimidin-1-yl]ethyl}phenyl)urea (compound 24)



    [0184] 


    Step 15.1: tert-butyl (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-5H-imidazo[1,2-a]pyrimidin-1-yl]ethyl}phenyl)carbamate



    [0185] 



    [0186] A suspension of 300 mg (0.948 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-a]pyrimidin-5-one and 309.05 mg (0.948 mmol) of cesium 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-(2-bromoethyl)phenyl]carbamate is added dropwise. After reacting overnight at 85°C, the mixture is evaporated and the residue is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium 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-{2-[(1S,4S)-2-methyl-7-2-oxa-5-azabicyclo[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, the characteristics of which are as follows:

    LC/MS (method G): ESI+ [M+H]+: m/z 536 tr (min) = 2.48

    1H NMR (300 MHz, δ in ppm, CDCl3): 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, 1H), 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-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[1,2-a]pyrimidin-5-one



    [0187] 



    [0188] 1 mL of trifluoroacetic acid is added to a solution of 385 mg (0.72 mmol) of tert-butyl (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-5H-imidazo[1,2-a]pyrimidin-1-yl]ethyl}phenyl)carbamate in 4 mL of dichloromethane. After stirring for 1 hour at room temperature, the solvent is evaporated off. The residue is taken up in ethyl acetate and washed with saturated aqueous NaHCO3 solution. The organic phase is dried over magnesium 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-1 H-imidazo[1,2-a]pyrimidin-5-one, the characteristics of which are as follows:

    LC/MS (method A): ESI+ [M+H]+: m/z 436 tr (min) = 0.48

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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-[(1S,4S)-2-methyl-7-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-5-oxo-2-((S)-trifluoromethyl)-2,3-dihydro-5H-imidazo[1,2-a]pyrimidin-1-yl]ethyl}phenyl)urea



    [0189] 



    [0190] 104 µl (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[1,2-a]pyrimidin-5-one in 1 mL of dichloromethane. After stirring for 3 hours at room temperature, the solvent is evaporated off. The residue is taken up in ethyl acetate and washed with water and with saturated aqueous NaCl solution. The organic phase is dried over magnesium 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-5H-imidazo[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

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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, 1H), 3.7 (d, 1H), 3.78 (d, 1H), 3.82 (d, 1H), 4.12 (d, 1H), 4.58 (s, 1H), 4.64 (s, 1H), 4.82 (bs, 1H), 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-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 (compound 38)



    [0191] 


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



    [0192] 



    [0193] The procedure used is the same as that of step 12.1.

    [0194] 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, δ in ppm, CDCl3): 2.42 (s, 3H), 3.47 (q, 2H), 4.12 (t, 2H), 7.3 (s, 1H), 7.77 (s, 1H), 8.28 (s, 1H).


    Step 16.2: 2-bromo-1-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)ethanone hydrobromide



    [0195] 



    [0196] The procedure used is the same as that of step 12.2.

    [0197] 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 precipitation with ethyl ether and filtration, 690 mg of 2-bromo-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, CDCl3): 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]pyrimidin-4-one



    [0198] 



    [0199] The procedure used is the same as that of step 12.3.

    [0200] 200 mg (0.79 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 319.86 mg (0.95 mmol) of 2-bromo-1-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-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-a]pyrimidin-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, CDCl3): 2.27 (m, 1H), 2.44 (s, 1H), 3.17 (d, 1H), 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)-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



    [0201] 



    [0202] The procedure used is the same as that of step 12.4.

    [0203] 110 mg (0.25 mmol) 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-a]pyrimidin-4-one and 41.64 mg (0.31 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride were used in the reaction. After purification by passing through an RP18 reverse-phase column (eluent: from 100% H2O to 100% CH3CN 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-6,7,8,9-tetrahydropyrimido[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-d6): 1.65 (d, 1H), 1.72 (d, 1H), 2.25 (m, 1H), 2.4 (m, 1H), 2.99 (m, 1H), 3.13 (m, 1H), 3.2 (m, 1H), 3.26 (m, 2H), 3.49 (m, 2H), 4.13 (t, 2H) 4.36 (m, 1H), 4.41 (d, 1H), 4.48 (d, 2H) 4.52 (m, 1H), 4.63 (s, 1H), 5.52 (d, 1H), 7.36 (s, 1H), 7.57 (s, 1H), 8.37 (s, 1H).


    Example 17:


    (8S)-9-(2-benzo[1,2,3]thiadiazol-5-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 (compound 47)



    [0204] 


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



    [0205] 



    [0206] The procedure used is the same as that of step 4.1.
    500 mg (2.44 mmol) of benzo[1,2,3]thiadiazole-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, CDCl3): 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]thiadiazol-5-ylethanone



    [0207] 



    [0208] 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 basified with aqueous 1 N NaOH solution and extracted with ethyl acetate. The organic phase is dried over magnesium 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

    1H NMR (300 MHz, δ in ppm, CDCl3): 2.78 (s, 3H), 8.29 (d, 1H), 8.53 (d, 1H), 9.32 (s, 1H).


    Step 17.3: 1-benzo[1,2,3]thiadiazol-5-yl-2-bromoethanone



    [0209] 



    [0210] 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 NaHCO3 solution and with saturated NaCl solution, dried and evaporated to dryness to give 300 mg of 1-benzo[1,2,3]thiadiazol-5-yl-2-bromoethanone, corresponding to the following characteristics:

    LC/MS (method G): ESI+ [M+H]+: m/z 257 tr (min) = 1.71

    1H NMR (300 MHz, δ in ppm, CDCl3): 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-oxoethyl)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0211] 



    [0212] 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[1,2-a]pyrimidin-4-one and 167.25 mg (0.65 mmol) of 1-benzo[1,2,3]thiadiazol-5-yl-2-bromoethanone 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]thiadiazol-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 follows:

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

    1H NMR (300 MHz, δ in ppm, CDCl3): 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[1,2,3]thiadiazol-5-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



    [0213] 



    [0214] 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-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 79.50 mg (0.58 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), 100 mg of (8S)-9-(2-benzo[1,2,3]thiadiazol-5-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 are obtained, the characteristics of which are as follows:

    LC/MS (method A): ESI+ [M+H]+: m/z 493 tr (min) = 0.64

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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-methyl-1H-indazol-3-ylmethyl)-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 51)



    [0215] 


    Step 18.1: (8S)-2-chloro-9-(1-methyl-1H-indazol-3-ylmethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0216] 



    [0217] 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[1,2-a]pyrimidin-4-one and 145.39 mg (0.78 mmol) of 3-chloromethyl-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)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows:

    LC/MS (method G): ESI+ [M+H]+: m/z 398 tr (min) = 2.2

    1H NMR (300 MHz, δ in ppm, CDCl3): 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, 1H), 7.15 (t, 1H), 7.42 (t, 1H), 7.62 (d, 1H), 7.84 (d, 1H).


    Step 18.2: (8S)-9-(1-methyl-1H-indazol-3-ylmethyl)-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



    [0218] 



    [0219] 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-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows:

    LC/MS (method A): ESI+ [M+H]+: m/z 461 tr (min) = 0.68

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 1.75 (m, 2H), 2.08 (m, 1H), 2.4 (d, 1H), 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-cyclopropylmethoxypyrimidin-5-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 (compound 52)



    [0220] 


    Step 19.1: 5-bromo-2-cyclopropylmethoxypyrimidine



    [0221] 



    [0222] 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 temperature. 1 g (5.07 mmol) of 5-bromo-2-chloropyrimidine in 5 mL of THF is then added. The mixture is stirred at room temperature overnight. The reaction mixture is taken up in water and extracted with ethyl acetate. The organic phase is washed with aqueous NaHCO3 solution and with saturated aqueous NaCl 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, δ in ppm, CDCl3): 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-ethoxyvinyl)pyrimidine



    [0223] 



    [0224] The following are successively introduced into a microwave tube:
    760 mg (3.32 mmol) of 5-bromo-2-cyclopropylmethoxypyrimidine in 15 mL of dioxane, 1.36 mL (3.82 mmol) of tributyl(1-ethoxyvinyl)tin, 58.22 mg (0.08 mmol) of bis(triphenylphosphine)palladium(II) chloride, 1.12 g (7.30 mmol) of cesium fluoride. This mixture is subjected to microwave irradiation at 110°C for 1 hour. The reaction mixture is evaporated to dryness and the residue is taken up in 100 mL of ethyl ether. A solution of 2.80 g of cesium fluoride in 10 mL of water is added. After stirring for 1 hour at room temperature, the mixture is filtered through Celite. The filtrate is washed with aqueous NaHCO3 solution and then with saturated NaCl solution. The organic phase is dried over magnesium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 10/90 EtOAc/heptane) to give 480 mg of 2-cyclopropylmethoxy-5-(1-ethoxyvinyl)pyrimidine, the characteristics of which are as follows:

    LC/MS (method G): ESI+ [M+H]+: m/z 221 tr (min) = 2.34

    1H NMR (300 MHz, δ in ppm, CDCl3): 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-cyclopropylmethoxypyrimidin-5-yl)ethanone



    [0225] 



    [0226] A solution of 480 mg (2.18 mmol) of 2-cyclopropylmethoxy-5-(1-ethoxyvinyl)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 NaHCO3 solution and then with saturated NaCl solution. The organic phase is dried over magnesium 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-cyclopropylmethoxypyrimidin-5-yl)ethanone, the characteristics of which are as follows:

    LC/MS (method G): ESI+ [M+H]+: m/z 271 tr (min) = 1.87

    1H NMR (300 MHz, δ in ppm, CDCl3): 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-cyclopropylmethoxypyrimidin-5-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0227] 



    [0228] 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[1,2-a]pyrimidin-4-one and 211.66 mg (0.78 mmol) of 2-bromo-1-(2-cyclopropylmethoxypyrimidin-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-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows:

    LC/MS (method G): ESI+ [M+H]+: m/z 444 tr (min) = 2.33

    1H NMR (300 MHz, δ in ppm, CDCl3): 0.38 (m, 2H), 0.58 (m, 2H), 1.30 (m, 1H), 2.25 (m, 1H), 2.51 (m, 1H), 3.35 (m, 2H), 4.28 (d, 2H), 4.50 (m, 1H), 4.70 (m, 1H), 4.90 (d, 1H), 5.53 (d, 1H), 9.21 (s, 2H).


    Step 19.5: (8S)-9-[2-(2-cyclopropylmethoxypyrimidin-5-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



    [0229] 



    [0230] 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)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-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-cyclopropylmethoxypyrimidin-5-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 are obtained, the characteristics of which are as follows:

    LC/MS (method A): ESI+ [M+H]+: m/z 507 tr (min) = 0.65

    1H NMR spectrum (600 MHz, δ in ppm, DMSO-d6): 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-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 (compound 69)



    [0231] 


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



    [0232] 



    [0233] A suspension of 800 mg (6.03 mmol) of 2-methyl-2H-pyrazole-3-carboxylic acid in 30 mL of DCM is placed under argon and cooled to 0°C. When the temperature 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 temperature 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-pyrazole-3-carbonyl chloride, the characteristics of which are as follows:
    1H NMR (300 MHz, δ in ppm, CDCl3): 4.10 (s, 3H), 6.82 (s, 1H), 7.50 (s, 1H).

    Step 20.2: N-methoxy-N-methyl-2-methyl-2H-pyrazole-3-carboxamide



    [0234] 



    [0235] 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): ESI+ [M+H]+: m/z 170 tr (min) = 1.03

    1H NMR (300 MHz, δ in ppm, CDCl3): 3.27 (s, 3H), 3.63 (s, 3H), 3.96 (s, 3H), 6.71 (s, 1H), 7.5 (s, 1H).


    Step 20.3: 1-(2-methyl-2H-pyrazol-3-yl)ethanone



    [0236] 



    [0237] 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 magnesium 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+H]+: m/z 125 tr (min) = 0.93

    1H NMR (300 MHz, δ in ppm, CDCl3): 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 hydrobromide



    [0238] 



    [0239] 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 have the following characteristics:

    LC/MS (method G): ESI+ [M+H]+: m/z 203 tr (min) = 1.19

    1H NMR (300 MHz, δ in ppm, CDCl3): 4.78 (s, 2H), 7.19 (s, 1H), 7.56 (s, 1H).


    Step 20.5: (8S)-2-chloro-9-[2-(2-methyl-2H-pyrazol-3-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0240] 



    [0241] The procedure used is the same as that of step 12.3.

    [0242] 180 mg (0.71 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 262 mg (0.92 mmol) of 1-(2-methyl-2H-pyrazol-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-6,7,8,9-tetrahydropyrimido[1,2-a]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

    1H NMR (300 MHz, δ in ppm, CDCl3): 2.28 (m, 1H), 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-(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



    [0243] 



    [0244] 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]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-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-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows:

    LC/MS (method A): ESI+ [M+H]+: m/z 439 tr (min) = 0.54

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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).


    Example 21:


    ethyl {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}carbamate (compound 57)



    [0245] 


    Step 21.1: 1-(6-aminopyrid-3-yl)ethanone



    [0246] 



    [0247] 2 g (11.57 mmol) of 1-(6-chloropyrid-3-yl)ethanone and 70 mL of ammonium hydroxide are placed in a Parr reactor. The solution is heated at 130°C overnight. The mixture obtained is evaporated to dryness, and the residue is taken up in ethyl acetate and washed with water and with saturated NaCl solution. The organic phase is dried over sodium sulfate and evaporated to dryness to give 1.14 g of 1-(6-aminopyrid-3-yl)ethanone, 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, CDCl3): 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-aminopyrid-3-yl)ethanone



    [0248] 



    [0249] 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 NaCl 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 follows:

    LC/MS (method G): ESI+ [M+H]+: m/z 215 tr (min) = 0.44

    1H NMR (300 MHz, δ in ppm, CDCl3): 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-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



    [0250] 



    [0251] 500 mg (1.58 mmol) of (8S)-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 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 placed under magnetic stirring at room temperature 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 dropwise to the reaction medium. The reaction is stirred at room temperature 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-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, the characteristics of which are as follows:

    LC/MS (method A): ESI+ [M+H]+: m/z 451 tr (min) = 0.38

    1H NMR (600 MHz, δ in ppm, CDCl3): 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-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetyl]pyrid-2-yl}carbamate



    [0252] 



    [0253] 168 µl (1 mmol) of N,N-diisopropylethylamine and 65 µl (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-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 5 mL of DCM.
    The heterogeneous mixture is stirred at room temperature for 15 minutes. The solution is taken up in DCM and washed with water and with saturated NaCl solution. The organic phase is dried over sodium sulfate and evaporated to dryness. The residue is dissolved in 10 mL of ethanol, and aqueous 1 N NaOH solution is added. The mixture is stirred for 30 minutes at room temperature and then evaporated to dryness. The crude product is taken up in ethyl acetate and washed with water and with saturated NaCl 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-(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}carbamate are obtained, the characteristics of which are as follows:

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

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 1.27 (t, 3H), 1.61 (s, 1H), 1.7 (d, 1H), 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-azabicyclo[3.2.1]oct-3-yl)-9-(3-phenylpropyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (compound 84)



    [0254] 


    Step 22.1: (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0255] 



    [0256] 500 mg (1.97 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, 884 mg (5.91 mmol) of 8-oxa-3-azabicyclo[3.2.1]octane and 820 µl (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 CH3CN: 100%) to give 600 mg of (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-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 331 tr (min) = 0.53

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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, 1H).


    Step 22.2: (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(3-phenylpropyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0257] 



    [0258] A solution of 200 mg (0.61 mmol) of (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 790 mg (2.42 mmol) of cesium carbonate in 10 mL of DMF is heated at 90°C for 10 minutes. After addition of 600 µl (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 reverse-phase chromatography (eluent: H2O 100% to CH3CN 100%) to give 100 mg of (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(3-phenylpropyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:

    LC/MS (method B): ESI+ [M+H]+: m/z 449 tr (min) = 0.85

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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, 1H), 7.18 (m, 3H), 7.27 (m, 2H).


    Example 23:


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



    [0259] 



    [0260] A solution of 200 mg (0.61 mmol) of (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 1.18 g (3.63 mmol) of cesium 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 temperature. The solvent is evaporated off. 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 16 mg of (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-pyrid-4-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:

    LC/MS (method B): ESI+ [M+H]+: m/z 450 tr (min) = 0.55

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (compound 80)



    [0261] 



    [0262] 200 mg (0.61 mmol) of (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-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 overnight. 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-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:

    LC/MS (method B): ESI+ [M+H]+: m/z 451 tr (min) = 0.68

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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-dimethylaminopyrid-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 (compound 6)



    [0263] 


    Step 25.1: 1-(6-dimethylaminopyrid-3-yl)ethanone



    [0264] 



    [0265] 500 mg (2.89 mmol) of 1-(6-chloropyrid-3-yl)ethanone, 2 mL of ethanol 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-(6-dimethylaminopyrid-3-yl)ethanone, the characteristics of which are as follows:
    1H NMR (300 MHz, δ in ppm, CDCl3): 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-dimethylaminopyrid-3-yl)ethanone hydrobromide



    [0266] 



    [0267] The procedure used is the same as that of step 12.2.
    514 mg (3.13 mmol) of 1-(6-dimethylaminopyrid-3-yl)ethanone were used in the reaction. The precipitate corresponding to 2-bromo-1-(6-dimethylaminopyrid-3-yl)ethanone hydrobromide is filtered off, washed with ether and dried. The 950 mg of product obtained have the following characteristics:
    1H NMR (300 MHz, δ in ppm, CDCl3): 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-dimethylaminopyrid-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



    [0268] 



    [0269] 100 mg (0.32 mmol) of (8S)-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 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 temperature 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 temperature for 5 minutes. The reaction medium is taken up in ethanol 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-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 479 tr (min) = 0.48

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 1.62 (bs, 1H), 1.73 (d, 1H), 2.24 (m, 1H), 2.42 (m, 1H), 2.66-3.27 (m, 11H), 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)



    [0270] 


    Step 26.1: (8S)-2-chloro-9-(3,3-dimethyl-2-oxobutyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0271] 



    [0272] 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[1,2-a]pyrimidin-4-one, 578.71 mg (1.77 mmol) of cesium carbonate, 99 µl (0.709 mmol) of 1-bromopinacolone 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: t 0 min 0% B, t 12 min 4% B, t 15 min 4% B, t 30 min 10% B), 188 mg of (8S)-2-chloro-9-(3,3-dimethyl-2-oxobutyl)-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 352 tr (min) = 2.38

    1H NMR (300 MHz, δ in ppm, DMSO-d6): 1.17 (s, 9H), 2.20 (m,1H), 2.45 (m, 1H), 3.25 (m, 2H), 4.35 (d, 1H), 4.63 (m, 1H), 5.05 (d, 1H), 5.92 (s, 1H).


    Step 26.2: (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



    [0273] 



    [0274] 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)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride and 179 µl (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: t 0 min 0% B, t 15 min 4% B, t 18 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-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 415 tr (min) = 0.67

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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, 1H), 4.67 (m, 2H), 5.32 (d, 1H).


    Example 27:


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



    [0275] 


    Step 27.1: (8S)-2-chloro-9-(2-oxo-2-pyrid-4-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0276] 



    [0277] The procedure used is the same as that of step 12.3.

    [0278] 1 g (3.94 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, 3.85 g (11.83 mmol) of cesium carbonate, 1.33 g (4.73 mmol) of 2-bromo-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)-2-chloro-9-(2-oxo-2-pyrid-4-ylethyl)-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 373 tr (min) = 1.77

    1H NMR (300 MHz, δ in ppm, DMSO-d6): 2.28 (m, 1H), 3.36 (m, 2H), 4.40 (m, 1H), 4.73 (m, 1H), 4.98 (d, 1H), 5.54 (d, 1H), 5.95 (s, 1H), 7.92 (m, 2H), 8.87 (m, 2H).


    Step 27.2: (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-oxo-2-pyrid-4-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0279] 



    [0280] The procedure used is the same as that of step 12.4.
    250 mg (0.67 mmol) of (8S)-2-chloro-9-(2-oxo-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-oxa-5-azabicyclo[2.2.1]heptane hydrochloride and 230 µl (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: t 0 min 0% B, t 25 min 10% B, t 30 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)-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) = 0.50

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 1.65 (m, 1H), 1.72 (m, 1H), 2.25 (m, 1H), 2.45 (m, 1H), 3.00 (m, 1H), 3.10 (m, 1H), 3.20 (m, 1H), 3.30 (m, 2H), 4.38 (m, 1H), 4.42 (m, 1H), 4.48 (m, 1H), 4.62 (m, 1H), 4.37 (m, 1H), 4.75 (d, 1H), 5.58 (d, 1H), 7.88 (m, 2H), 8.85 (m, 2H).


    Example 28:


    (8S)-9-[2-(6-methylpyrid-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 (compound 4)



    [0281] 


    Step 28.1:


    2-bromo-1-(6-methylpyrid-3-yl)ethanone hydrobromide



    [0282] 



    [0283] The procedure used is the same as that of step 12.2.

    [0284] 500 mg (3.59 mmol) of 1-(6-methylpyrid-3-yl)ethanone, 590 µl (3.59 mmol) of hydrobromic acid, 204 µl (3.95 mmol) of bromine and 10 mL of glacial acetic acid were used in the reaction. After precipitation 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-methylpyrid-3-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0285] 



    [0286] 1 g (3.94 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one is added to a suspension of 394.27 mg (9.86 mmol) of sodium hydride in 40 mL of DMF. The reaction mixture is placed under magnetic stirring at room temperature for 15 minutes. A solution of 1.16 g (3.94 mmol) of 2-bromo-1-(6-methylpyrid-3-yl)ethanone hydrobromide in 10 mL of DMF is added dropwise to the reaction medium at 0°C. The reaction is stirred at room temperature overnight. 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 magnesium sulfate and evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: heptane/EtOAc, gradient A/B: t 0 min 30% B, t 35 min 60% B, t 40 min 60% B), 480 mg of (8S)-2-chloro-9-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-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 387 tr (min) = 1.85

    1H NMR (300 MHz, δ in ppm, DMSO-d6): 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-methylpyrid-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



    [0287] 



    [0288] 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]-8-trifluoromethyl-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: t 0 min 30% B, t 35 min 60% B, t 40 min 60% B), 335 mg of (8S)-9-[2-(6-methylpyrid-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 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-d6): 1.65 (m, 2H), 2.30 (m, 1H), 2.42 (m, 1H), 2.55 (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-methylpyrid-3-yl)-2-oxoethyl]-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 (compound 17)



    [0289] 


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



    [0290] 



    [0291] 500 mg (1.97 mmol) of (S)-7-chloro-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[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 temperature 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 is added dropwise to the reaction medium at 0°C. The reaction is stirred at room temperature overnight. 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 magnesium sulfate and evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: heptane/EtOAc, gradient A/B: t 0 min 30% B, t 35 min 60% B, t 40 min 60% B), 150 mg of (S)-7-chloro-2-methyl-1-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one were obtained, corresponding to the following characteristics:

    LC/MS (method G): ESI+ [M+H]+: m/z 387 tr (min) = 1.79

    1H NMR (300 MHz, δ in ppm, DMSO-d6): 1.54 (s, 3H), 2.46 (s, 3H), 4.10 (d, 1H), 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).


    Step 29.2: 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-1H-imidazo[1,2-a]pyrimidin-5-one



    [0292] 



    [0293] The procedure used is the same as that of step 12.4.

    [0294] 150 mg (0.388 mmol) of (S)-7-chloro-2-methyl-1-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-2-trifluoromethyl-2,3-dihydro-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: t 0 min 0% B, t 35 min 10% B, t 40 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-1H-imidazo[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-d6): 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, 1H), 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-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1-(2-oxo-2-pyrid-3-ylethyl)-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one (compound 21)



    [0295] 



    [0296] 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 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 temperature 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 temperature overnight. 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 magnesium sulfate and evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: DCM/MeOH, gradient A/B: t 0 min 0% B, t 35 min 10% B, t 40 min 10% B), 58 mg of 2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1-(2-oxo-2-pyrid-3-ylethyl)-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one were obtained, corresponding to the following characteristics:

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

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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-azabicyclo[2.2.1]hept-5-yl-9-(2-pyrid-3-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (compound 12)



    [0297] 


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



    [0298] 



    [0299] 6.62 mL (47.26 mmol) of triethylamine and 8.26g (43.32 mmol) of 4-methylbenzenesulfonyl chloride are added at 0°C to a solution of 5 g (39.38 mmol) of 2-pyrid-3-ylethanol in 300 mL of dichloromethane. After allowing the reaction medium to warm to room temperature and stirring overnight, it is washed with water and with saturated NaCl solution. The organic phase is dried over magnesium sulfate and evaporated to dryness. After purification by chromatography on silica gel (eluent: 4/6 heptane/EtOAc), 8 g of 2-pyrid-3-ylethyl toluene-4-sulfonate were obtained, corresponding to the following characteristics:
    1H NMR (300 MHz, δ in ppm, DMSO-d6): 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-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-pyrid-3-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0300] 



    [0301] A suspension of 150 mg (0.474 mmol) of (8S)-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 and 170.15 mg (0.522 mmol) of cesium 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 overnight 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 magnesium sulfate and evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: DCM/MeOH, gradient A/B: t 0 min 0% B, t 35 min 10% B, t 40 min 10% B) 145 mg of (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-pyrid-3-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one were obtained, the characteristics of which are as follows:

    LC/MS (method A): ESI+ [M+H]+: m/z 422 tr (min) = 0.39

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (compound 45)



    [0302] 


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



    [0303] 



    [0304] A mixture of 15 mL of methanol, 500 mg (2.89 mmol) of 1-(6-chloropyrid-3-yl)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, t 5 min 20% B, t 30 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-d6): 2.50 (s, 3H), 3.94 (s, 3H), 6.92 (m, 1H), 8.18 (m, 1H), 8.83 (m, 1H).


    Step 32.2: 2-bromo-1-(6-methoxypyrid-3-yl)ethanone hydrobromide



    [0305] 



    [0306] The procedure used is the same as that of step 12.2.

    [0307] 230 mg (1.52 mmol) of 1-(6-methoxypyrid-3-yl)ethanone, 413 µl (7.61 mmol) of hydrobromic acid, 87 µl (1.67 mmol) of bromine and 5 mL of glacial acetic acid were used in the reaction. After precipitation 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-d6): 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-methoxypyrid-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



    [0308] 



    [0309] 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[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, 464.04 mg (1.42 mmol) of cesium carbonate, 176.98 mg (0.569 mmol) of 2-bromo-1-(6-methoxypyrid-3-yl)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: t 0 min 0% B, t 25 min 10% B, t 30 min 10% B), 100 mg of (8S)-9-[2-(6-methoxypyrid-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 were obtained, corresponding to the following characteristics:

    LC/MS (method A): ESI+ [M+H]+: m/z 466 tr (min) = 0.61

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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, 1H), 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-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (compound 63)



    [0310] 


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



    [0311] 



    [0312] 530 µl (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 temperature 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 reaction medium. The reaction is stirred at room temperature overnight. 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 magnesium sulfate and evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: heptane/EtOAc, gradient A/B: t 0 min 0% B, t 5 min 10% B, t 30 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-d6): 2.57 (s, 3H), 4.56 (m, 1H), 4.67 (m, 1H), 4.86 (m, 1H), 7.00 (m, 1H), 8.21 (m, 1H), 8.83 (m, 1H).


    Step 33.2: 2-bromo-1-[6-(2-fluoroethoxy)pyrid-3-yl]ethanone hydrobromide



    [0313] 



    [0314] The procedure used is the same as that of step 12.2.

    [0315] 362 mg (1.98 mmol) of 1-[6-(2-fluoroethoxy)pyrid-3-yl]ethanone, 413 µl (7.61 mmol) of hydrobromic acid, 537 µl (9.88 mmol) of bromine and 5 mL of glacial acetic acid were used in the reaction. After precipitation with ethyl ether and filtration, 602 mg of 2-bromo-1-[6-(2-fluoroethoxy)pyrid-3-yl]ethanone hydrobromide are obtained, the characteristics of which are as follows:

    LC/MS (method G): ESI+ [M+H]+: m/z 264 tr (min) = 1.69

    1H NMR spectrum (300 MHz, δ in ppm, DMSO-d6): 4.56 (m, 1H), 4.69 (m, 1H), 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-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



    [0316] 



    [0317] 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[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, 464.04 mg (1.42 mmol) of cesium carbonate, 195.20 mg (0.569 mmol) of 2-bromo-1-[6-(2-fluoroethoxy)pyrid-3-yl]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: t 0 min 0% B, t 25 min 10% B, t 30 min 10% B), 130 mg of (8S)-9-{2-[6-(2-fluoroethoxy)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 were obtained, corresponding to the following characteristics:

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

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 1.62 (m, 1H), 1.72 (m, 1H), 2.25 (m, 1H), 2.45 (m, 1H), 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-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (compound 71)



    [0318] 



    [0319] 200 mg (0.61 mmol) of (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 5 mL of DMF are added to a suspension of 60 mg (1.51 mmol) of sodium hydride in 10 mL of DMF. The reaction mixture is heated at 50°C for 10 minutes. After addition of 162 mg (0.79 mmol) of (S)-2-chloro-1-(4-fluoro-2-methoxyphenyl)ethanol, the reaction is continued at room temperature overnight. The reaction medium is evaporated to dryness. The residue is purified by chromatography on a column of silica (eluent: 90/10 DCM/MeOH). 40 mg of (8S)-9-[(S)-2-(4-fluoro-2-methoxyphenyl)-2-hydroxyethyl]-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one were obtained, corresponding to the following characteristics:

    LC/MS (method B): ESI+ [M+H]+: m/z 499 tr (min) = 0.71

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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-imidazo[1,2-a]pyrimidin-5-one (compound 72)



    [0320] 


    Step 35.1: (S)-1-[2-(4-benzyloxyphenyl)ethyl]-7-chloro-2-methy)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one



    [0321] 



    [0322] A mixture of 40 mL of DMF, 2 g (7.89 mmol) of (S)-7-chloro-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one, 3.44 g (11.84 mmol) of 1-benzyloxy-4-(2-bromoethyl)benzene and 5.14 g (15.78 mmol) of cesium 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: t 0 min 20% B, t 25 min 50% B, t 35 min 50% B), 2.8 g of (S)-1-[2-(4-benzyloxyphenyl)ethyl]-7-chloro-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one were obtained, corresponding to the following characteristics:

    LC/MS (method G): ESI+ [M+H]+: m/z 464 tr (min) = 2.91

    1H NMR (300 MHz, δ in ppm, CDCl3): 1.36 (s, 3H), 2.90 (m, 1H), 3.11 (m, 1H), 3.49 (m, 1H), 3.75 (m, 1H), 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-benzyloxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one



    [0323] 



    [0324] The procedure used is the same as that of step 12.4.

    [0325] 1.40 g (3.02 mmol) of (S)-1-[2-(4-benzyloxyphenyl)ethyl]-7-chloro-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one, 903 mg (6.04 mmol) of 8-oxa-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-3-azabicyclo[3.2.1]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one were obtained, corresponding to the following characteristics:

    LC/MS (method G): ESI+ [M+H]+: m/z 541 tr (min) = 2.84

    1H NMR (300 MHz, δ in ppm, DMSO-d6): 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)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one



    [0326] 



    [0327] 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-(4-benzyloxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one in 15 mL of methanol. The mixture is refluxed for 1 hour and then allowed to cool to room temperature. 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: t 0 min 0% B, t 25 min 10% B, t 30 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-1H-imidazo[1,2-a]pyrimidin-5-one were obtained, corresponding to the following characteristics:

    LC/MS (method B): ESI+ [M+H]+: m/z 451 tr (min) = 0.68

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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:


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



    [0328] 



    [0329] 282 mg (0.87 mmol) of cesium 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-3-yl)-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-chloroethyl)dimethylamine are added. The reaction medium is heated at 80°C overnight. 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, t 25 min 10% B, t 30 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-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one were obtained, corresponding to the following characteristics:

    LC/MS (method B): ESI+ [M+H]+: m/z 522 tr (min) = 0.56

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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, 1H), 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-2-trifluoromethyl-2,3-dihydro-5H-imidazo[1,2-a]pyrimidin-1-yl]ethyl}phenoxy)acetamide (compound 70)



    [0330] 



    [0331] 235 mg (0.72 mmol) of cesium 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-3-yl)-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,N-dimethylacetamide and 43.30 mg (0.29 mmol) of sodium iodide are added. The reaction medium is heated at 80°C overnight. 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, t 25 min 10% B, t 30 min 10% B), 138 mg of N,N-dimethyl-2-(4-{2-[(S)-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-oxo-2-trifluoromethyl-2,3-dihydro-5H-imidazo[1,2-a]pyrimidin-1-yl]ethyl}phenoxy)acetamide 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-d6): 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, 1H), 3.52 (m, 1H), 3.73 (m, 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-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (compound 54)



    [0332] 


    Step 38.1: methyl ((8S)-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)acetate



    [0333] 



    [0334] 150 mg (0.474 mmol) of (8S)-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 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 temperature for 10 minutes. After addition of 45 µl (0.474 mmol) of methyl bromoacetate, the reaction is stirred at room temperature overnight. 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-(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)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-d6): 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).


    Step 38.2: (8S)-9-(2-ethyl-2-hydroxybutyl)-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



    [0335] 



    [0336] 631 µl (1.89 mmol) of a 3 M solution of ethylmagnesium bromide in ethyl ether are added at 0°C to a solution of 147 mg (0.38 mmol) of methyl ((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-1-yl)acetate in 10 mL of THF. The reaction medium is stirred at 0°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 magnesium sulfate and evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: DCM/MeOH, gradient A/B: t 0 min 0% B, t 25 min 10% B, t 30 min 10% B), 80 mg of (8S)-9-(2-ethyl-2-hydroxybutyl)-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 were obtained, corresponding to the following characteristics:

    LC/MS (method A): ESI+ [M+H]+: m/z 417 tr (min) = 0.63

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (compound 49)



    [0337] 


    Step 39.1: methyl 3-((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-1-yl)-propionate



    [0338] 



    [0339] 1 µl (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-5-azabicyclo[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 temperature overnight. 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-(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)-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-d6): 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-(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



    [0340] 



    [0341] 911 µl (2.73 mmol) of a 3 M 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-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)-propionate in 10 mL of THF. The reaction medium is stirred at 0°C 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 magnesium sulfate and evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: DCM/MeOH, gradient A/B: t 0 min 0% B, t 25 min 10% B, t 30 min 10% B), 128 mg of (8S)-9-(3-ethyl-3-hydroxypentyl)-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 were obtained, corresponding to the following characteristics:

    LC/MS (method A): ESI+ [M+H]+: m/z 431 tr (min) = 0.63

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 0.80 (m, 6H), 1.36 (m, 4H), 1.63 (m, 1H), 1.71 (m, 1H), 1.82 (m, 2H), 2.05 (m, 1H), 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,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-oxo-2-pyrid-2-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (compound 68)



    [0342] 


    Step 40.1: (8S)-2-chloro-9-(2-oxo-2-pyrid-2-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0343] 



    [0344] The procedure used is the same as that of step 12.3.

    [0345] 150 mg (0.591 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, 578.71 mg (1.77 mmol) of cesium 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: t 0 min 0% B, t 15 min 50% B, t 25 min 70% B), 218 mg of (8S)-2-chloro-9-(2-oxo-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 G): ESI+ [M+H]+: m/z 373 tr (min) = 2.14

    1H NMR (300 MHz, δ in ppm, DMSO-d6): 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-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-oxo-2-pyrid-2-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0346] 



    [0347] 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)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride and 205 µl (1.46 mmol) of triethylamine 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-(2-oxo-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

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 1.59 (m, 1H), 1.68 (m, 1H), 2.24 (m, 1H), 2.44 (m, 1H), 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, 1H), 5.70 (m, 1H), 7.73 (m, 1H), 7.98 (m, 1H), 8.07 (m, 1H), 8.78 (m, 1H).


    Example 41:


    (8S)-9-{2-[6-(2-hydroxyethylamino)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 (compound 14)



    [0348] 


    Step 41.1: (8S)-9-[2-(6-chloropyrid-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



    [0349] 



    [0350] 100 mg (0.32 mmol) of (8S)-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 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 temperature 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 temperature overnight. 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-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 G): ESI+ [M+H]+: m/z 470 tr (min) = 1.86

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 1.65 (m, 2H), 2.28 (m, 1H), 2.93 (m, 3H), 3.19 (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-hydroxyethylamino)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



    [0351] 



    [0352] A mixture of 0.50 mL of ethanol, 33 mg (0.070 mmol) of (8S)-9-[2-(6-chloropyrid-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 and 21.41 µl (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-(2-hydroxyethylamino)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 are obtained, the characteristics of which are as follows:

    LC/MS (method A): ESI+ [M+H]+: m/z 495 tr (min) = 0.40

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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, 1H).


    Example 42:


    (8S)-9-[2-(6-methylaminopyrid-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 (compound 5)



    [0353] 


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



    [0354] 



    [0355] A mixture of 2 mL of ethanol, 280 mg (1.80 mmol) of 1-(6-chloropyrid-3-yl)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 is taken up in water and extracted with EtOAc. The organic phase is dried over magnesium sulfate and evaporated to dryness. 258 mg of 1-(6-methylaminopyrid-3-yl)ethanone are obtained, the characteristics of which are as follows:
    1H NMR (300 MHz, δ in ppm, DMSO-d6): 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-methylaminopyrid-3-yl)ethanone



    [0356] 



    [0357] The procedure used is the same as that of step 12.2.

    [0358] 380 mg (2.53 mmol) of 1-(6-methylaminopyrid-3-yl)ethanone, 416 µl (2.53 mmol) of hydrobromic acid, 130 µl (2.53 mmol) of bromine and 5 mL of glacial acetic acid were used in the reaction. After precipitation with ethyl ether and filtration, the precipitate is taken up in water. The solution is basified with saturated NaHCO3 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:
    1H NMR spectrum (300 MHz, δ in ppm, DMSO-d6): 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-methylaminopyrid-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



    [0359] 



    [0360] 100 mg (0.32 mmol) of (8S)-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 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 temperature 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 temperature 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: t 0 min 0% B, t 25 min 10% B, t 30 min 15% B). 75 mg of (8S)-9-[2-(6-methylaminopyrid-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 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-d6): 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-methylaminopyrid-3-yl)-2-oxoethyl]-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 (compound 9)



    [0361] 



    [0362] 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 reaction mixture is stirred at room temperature 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 temperature 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: t 0 min 0% B, t 25 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-1H-imidazo[1,2-a]pyrimidin-5-one were obtained, corresponding to the following characteristics:

    LC/MS (method A): ESI+ [M+H]+: m/z 465 tr (min) = 0.42

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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-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 (compound 90)



    [0363] 


    Step 44.1: tert-butyl 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-1-yl)ethyl]piperidine-1-carboxylate



    [0364] 



    [0365] 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-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 2.47 g (7.59 mmol) of cesium 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 NaCl. The organic phase is dried over magnesium 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-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)ethyl]piperidine-1-carboxylate, the characteristics of which are as follows:

    LC/MS (method G): ESI+ [M+H]+: m/z 528 tr (min) = 2.57

    1H NMR spectrum (300 MHz, δ in ppm, DMSO-d6): 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, 1H), 4.18 (m, 2H), 4.63 (m, 2H).


    Step 44.2: (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-piperidin-4-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0366] 



    [0367] A solution of 250 mg (0.473 mmol) of tert-butyl 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-1-yl)ethyl]piperidine-1-carboxylate in 10 mL of formic acid is stirred for 1 hour 30 minutes at room temperature.

    [0368] 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-azabicyclo[2.2.1]hept-5-yl-9-(2-piperid-4-ylethyl)-8-trifluoromethyl-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 428 tr (min) = 1.34

    Step 44.3: 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-1-yl)ethyl]piperidine-1-carbaldehyde



    [0369] 



    [0370] 33 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-4-ylethyl)-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 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 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-1-yl)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-d6): 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-azabicyclo[2.2.1]hept-5-yl-9-[2-(tetrahydropyran-4-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (compound 92)



    [0371] 


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



    [0372] 



    [0373] 629 µL (4.47 mmol) of triethylamine 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.

    [0374] The reaction mixture is stirred at room temperature overnight. The solution is taken up in DCM, washed with aqueous NaHCO3 solution, dried over magnesium 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 4-methylbenzenesulfonate, corresponding to the following characteristics:
    1H NMR (300 MHz, δ in ppm, CDCl3): 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-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-(tetrahydropyran-4-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0375] 



    [0376] 198 mg (0.698 mmol) of 2-(tetrahydro-2H-pyran-4-yl)ethyl 4-methylbenzenesulfonate 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-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 525 mg (1.61 mmol) of cesium 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 NaCl. The organic phase is dried over magnesium 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,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-(tetrahydropyran-4-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:

    LC/MS (method A): ESI+ [M+H]+: m/z 429 tr (min) = 0.61

    1H NMR spectrum (600 MHz, δ in ppm, DMSO-d6): 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).


    Example 46:


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



    [0377] 


    Step 46.1: (8S)-2-chloro-9-(tetrahydropyran-4-ylmethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0378] 



    [0379] A suspension of 200 mg (0.788 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 771 mg (2.37 mmol) of cesium carbonate in 10 mL of acetonitrile is stirred for 15 minutes at room temperature. 187 mg (0.788 mmol) of (bromomethyl)tetrahydropyran are then added.

    [0380] 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 magnesium 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-ylmethyl)-8-trifluoromethyl-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

    1H NMR spectrum (300 MHz, δ in ppm, DMSO-d6): 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: (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(tetrahydropyran-4-ylmethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0381] 



    [0382] 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)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride are mixed together. The powder obtained is placed in a tube and 244 µL (1.75 mmol) of triethylamine are added. The tube is sealed and heated at 130°C 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 magnesium 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-5-azabicyclo[2.2.1]hept-5-yl-9-(tetrahydropyran-4-ylmethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:

    LC/MS (method A): ESI+ [M+H]+: m/z 415 tr (min) = 0.57

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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, 3H).


    Example 47:


    4-((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-1-ylmethyl)piperidine-1-carbaldehyde (compound 95)



    [0383] 


    Step 47.1: tert-butyl 4-bromomethylpiperidine-1-carboxylate



    [0384] 



    [0385] A solution of 1 g (4.41 mmol) of tert-butyl 4-hydroxymethylpiperidine-1-carboxylate in 25 mL of THF is cooled to 0°C. 1.34 g (5.07 mmol) of triphenylphosphine and 2.02 g (5.96 mmol) of carbon tetrabromide are then added.

    [0386] The reaction mixture is stirred at room temperature 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-1-carboxylate, the characteristics of which are as follows:

    LC/MS (method G): ESI+ [M+H]+: m/z 279 tr (min) = 2.13

    1H NMR (300 MHz, δ in ppm, CDCl3): 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-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-ylmethyl)piperidine-1-carboxylate



    [0387] 



    [0388] 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-(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 and 2.13 g (6.54 mmol) of cesium 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 NaCl. The organic phase is dried over magnesium 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-dihydro-2H,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

    1H NMR (300 MHz, δ in ppm, DMSO-d6): 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-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0389] 



    [0390] A solution of 280 mg (0.545 mmol) of tert-butyl 4-((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-ylmethyl)piperidine-1-carboxylate in 10 mL of formic acid is stirred for 2 hours at room temperature. 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-5-azabicyclo[2.2.1]hept-5-yl-9-piperid-4-ylmethyl-8-trifluoromethyl-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 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-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-ylmethyl)piperidine-1-carbaldehyde



    [0391] 



    [0392] 41 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-ylmethyl-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 2 hours and then evaporated to dryness. The residue is taken up in EtOAc and washed with aqueous NaHCO3 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 of 4-((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-1-ylmethyl)piperidine-1-carbaldehyde, the characteristics of which are as follows:

    LC/MS (method D): ESI+ [M+H]+: m/z 442 tr (min) = 0.82

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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-2-hydroxy-2-trifluoromethylpropyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (compound 96)



    [0393] 



    [0394] 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-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 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 NaCl. The organic phase is dried over magnesium 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,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropyl)-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 497 tr (min) = 0.71

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 1.81-1.95 (m, 2H), 2.21 (m, 1H), 2.44 (m, 1H), 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-azabicyclo[2.2.1]hept-5-yl-9-[2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (compound 99)



    [0395] 


    Step 49.1: ((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-1-yl)acetic acid



    [0396] 



    [0397] 95 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[2.2.1]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetate (preparation described in Step 38.1) in 20 mL of THF/water (1/1: v/v). The reaction mixture is stirred at room temperature 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 NaCl, dried over magnesium sulfate and then evaporated to dryness to give 690 mg of ((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-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

    1H NMR (300 MHz, δ in ppm, DMSO-d6): 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, 1H), 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-azabicyclo[2.2.1]hept-5-yl-9-[2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0398] 



    [0399] 98 µL (0.881 mmol) of N-methylmorpholine, 86 mg (0.44 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 69 mg (0.44 mmol) of 1-hydroxybenzotriazole hydrate are added to a solution of 150 mg (0.4 mmol) of ((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-1-yl)acetic acid in 10 mL of DMF. The reaction mixture is stirred for 10 minutes at room temperature, 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 temperature 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-azabicyclo[3.2.1]oct-8-yl)-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-d6) performed at 140°C: 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 50:


    (8S)-9-(3-hydroxy-3-methylbutyl)-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 50)



    [0400] 



    [0401] 430 µL (1.29 mmol) of a 3 M solution of methylmagnesium 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-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)-propionate (preparation described in Step 39.1) in 10 mL of THF. The reaction medium is stirred at 0°C 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 magnesium 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-5-yl-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

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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-hydroxycyclopropylmethyl)-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 104)



    [0402] 



    [0403] 146 mg (0.515 mmol) of titanium (IV) isopropoxide are added to a solution of 200 mg (0.515 mmol) of methyl ((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-1-yl)acetate (preparation described in Step 38.1) in 3 mL of THF. The solution is cooled to 0°C, followed by dropwise addition of 858 µL (2.58 mmol) of 3 M ethylmagnesium bromide in ethyl ether. The reaction mixture is stirred for 30 minutes at room temperature. 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 magnesium 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-5-azabicyclo[2.2.1]hept-5-yl-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 387 tr (min) = 0.52

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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, 1H), 4.37 (m, 1H), 4.59-5.01 (m, 4H), 5.54 (s, 1H).


    Example 52:


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



    [0404] 


    Step 52.1: Quinolin-5-ylmethanol



    [0405] 



    [0406] 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 x 0.17 ml of H2O. The precipitate formed is filtered off and washed with THF and then with EtOAc. The organic phase is washed with saturated NaCl 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

    1H NMR (300 MHz, δ in ppm, DMSO-d6): 4.97 (d, 2H), 5.40 (t, 1H), 7.51-7.65 (m, 2H), 7.72 (t, 1H), 7.93 (d, 1H), 8.53 (d, 1H), 8.88-8.93 (m, 1H).


    Step 52.2: 5-chloromethylquinoline hydrochloride



    [0407] 



    [0408] A solution of 190 mg (1.19 mmol) of quinolin-5-ylmethanol in 5 ml of thionyl chloride is stirred for 10 minutes at room temperature and then refluxed for 2 hours. The reaction mixture is evaporated, the solid obtained is taken up in ethyl ether and the solution is filtered, washed with ethyl ether and dried to give 255 mg of 5-chloromethylquinoline hydrochloride, corresponding to the following characteristics:

    LC/MS (method G): ESI+ [M+H]+: m/z 178 tr (min) = 1.07

    1H NMR (300 MHz, δ in ppm, DMSO-d6): 5.40 (s, 2H), 7.96-8.10 (m, 3H), 8.34 (m, 1H), 9.17 (m, 1H), 9.27 (m, 1H).


    Step 52.3: (8S)-2-Chloro-9-quinolin-5-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0409] 



    [0410] A suspension of 180 mg (0.709 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 693 mg (2.13 mmol) of cesium carbonate in 10 mL of acetonitrile is stirred for 15 minutes at room temperature. 182 mg (0.851 mmol) of 5-chloromethylquinoline hydrochloride are then added, along with a catalytic amount of sodium iodide.

    [0411] The reaction mixture is stirred at room temperature 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 magnesium 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-trifluoromethyl-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 395 tr (min) = 2.00

    1H NMR spectrum (300 MHz, δ in ppm, DMSO-d6): 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-azabicyclo[2.2.1]hept-5-yl-9-quinolin-5-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one



    [0412] 



    [0413] 160 mg (0.40 mmol) of (8S)-2-chloro-9-quinolin-5-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 82 mg (0.60 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 158 µL (1.13 mmol) of triethylamine 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 magnesium 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-5-azabicyclo[2.2.1]hept-5-yl-9-quinolin-5-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:

    LC/MS (method A): ESI+ [M+H]+: m/z 458 tr (min) = 0.47

    1H NMR (600 MHz, δ in ppm, DMSO-d6): 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-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 (compound 114)



    [0414] 


    Step 53.1: 5-bromo-2-difluoromethoxypyridine



    [0415] 



    [0416] 5.42 g (34.48 mmol) of sodium chlorodifluoroacetate are added to a solution of 5 g (28.74 mmol) of 5-bromo-1H-pyrid-2-one in 120 ml of acetonitrile, under argon.

    [0417] The white suspension obtained is refluxed overnight 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 magnesium 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-2-difluoromethoxypyridine, corresponding to the following characteristics:

    LC/MS (method G): ESI+ [M+H]+: m/z 226 tr (min) = 2.08

    1H NMR spectrum (300 MHz, δ in ppm, DMSO-d6): 7.12 (d, 1H), 7.67 (t, 1H), 8.15 (dd, 1H), 8.43 (d, 1H).


    Step 53.2: 5-(1-butoxyvinyl)-2-difluoromethoxypyridine



    [0418] 



    [0419] 1 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(II) 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 magnesium 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-(1-butoxyvinyl)-2-difluoromethoxypyridine, corresponding to the following characteristics:

    LC/MS (method G): ESI+ [M+H]+: m/z 244 tr (min) = 2.74

    1H NMR spectrum (300 MHz, δ in ppm, DMSO-d6): 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, 1H), 7.71 (t, 1H), 8.09 (dd, 1H), 8.49 (d, 1H).


    Step 53.3: 2-bromo-1-(6-difluoromethoxypyrid-3-yl)ethanone



    [0420] 



    [0421] A solution of 100 mg (0.41 mmol) of 5-(1-butoxyvinyl)-2-difluoromethoxypyridine in 4 mL of THF/H2O (3/1: v/v) is 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 NaHCO3 solution and then with saturated NaCl solution, dried over magnesium 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 over 15 minutes) to give 82 mg of 2-bromo-1-(6-difluoromethoxypyrid-3-yl)ethanone, corresponding to the following characteristics:

    LC/MS (method G): ESI+ [M+H]+: m/z 266 tr (min) = 1.84

    1H NMR spectrum (300 MHz, δ in ppm, DMSO-d6): 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-(6-difluoromethoxypyrid-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



    [0422] 



    [0423] The procedure used is the same as that of step 12.3. 120 mg (0.38 mmol) of (8S)-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, 371 mg (1.42 mmol) of cesium carbonate, 121 mg (0.45 mmol) of 2-bromo-1-(6-difluoromethoxypyrid-3-yl)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: t 0 min 0% B, t 25 min 10% B, t 30 min 10% B), 38 mg of (8S)-9-[2-(6-difluoromethoxypyrid-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 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-d6): 1.56-1.74 (m, 2H), 2.21 (m, 1H), 2.44 (m, 1H), 2.78-3.09 (m, 3H), 3.23 (m, 1H), 3.47-3.85 (m, 1H), 4.37 (m, 1H), 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).



    [0424] The table which follows illustrates the chemical structures and the physical properties of some examples of compounds according to the invention. In this table:
    • in the "Salt" column, "-" represents a compound in free base form, whereas "HCl" represents a compound in hydrochloride form;
    • the "Data" column successively indicates the LC/MS analytical method used (A, B, C or F) and detailed in the experimental section, the retention time (tr) of the compound expressed in minutes, and the peak [M+H]+ identified by mass spectrometry.
    Table


    The asterisk * on R1 and L indicates the atom of attachment of R1 to L.
    No.nYR1LSaltData
    1 Ex. 13 1



    *-C(CH3)2-CH2- - Method B:
    tr (min) = 0.53 [M+H]+: 450
    2 Ex. 27 1  

    *-CO-CH2- - Method A:
    tr (min) = 0.50 [M+H]+: 436
    3 1



    *-CO-CH2- - Method A:
    tr (min) = 0.38 [M+H]+: 451
    4 Ex. 28 1



    *-CO-CH2- - Method A:
    tr (min) = 0.49 [M+H]+: 450
    5 Ex. 42 1



    *-CO-CH2- - Method A:
    tr (min) = 0.41 [M+H]+: 465
    6 Ex. 25 1



    *-CO-CH2- - Method A:
    tr (min) = 0.48 [M+H]+: 479
    7 Ex. 6 1



    *-CO-CH2- - Method A:
    tr (min) = 0.51 [M+H]+: 436
    8 0



    *-CO-CH2- - Method A:
    tr (min) = 0.49 [M+H]+: 479
    9 Ex. 43 0



    *-CO-CH2- - Method A:
    tr (min) = 0.42 [M+H]+: 465
    10 0



    *-CH2-CH2- - * Method C
    tr (min) = 1.19 [M+H]+: 451
    11 0



    *-CO-CH2- - Method A:
    tr (min) = 0.38 [M+H]+: 451
    12 Ex. 31 1



    *-CH2-CH2- - Method A:
    tr (min) = 0.39 [M+H]+: 422
    13 0



    *-CH2-CH2- - Method A:
    tr (min) = 0.39 [M+H]+: 422
    14 Ex. 41 1



    *-CO-CH2- - Method A:
    tr (min) = 0.40 [M+H]+: 495
    15 Ex. 3 1



    *-CO-CH2- - Method A:
    tr (min) = 0.51 [M+H]+: 450
    16 Ex. 7 0



    *-CO-CH2- - Method A:
    tr (min) = 0.52 [M+H]+: 450
    17 Ex. 29 0



    *-CO-CH2- - Method A:
    tr (min) = 0.49 [M+H]+: 450
    18 0



    *-CO-CH2- - Method A:
    tr (min) = 0.48 [M+H]+: 450
    19 Ex. 9 1



    *-CO-CH2- - Method A:
    tr (min) = 0.48 [M+H]+: 450
    20 Ex. 12 1



    *-CO-CH2- - Method A:
    tr (min) = 0.50 [M+H]+: 450
    21 Ex. 30 0



    *-CO-CH2- - Method A:
    tr (min) = 0.51 [M+H]+: 436
    22 1



    *-CO-CH2- - Method A:
    tr (min) = 0.45 [M+H]+: 491
    23 Ex. 14 1



    *-CH2-CH2- - Method A:
    tr (min) = 0.60 [M+H]+: 507
    24 Ex. 15 0



    *-CH2-CH2- - Method A:
    tr (min) = 0.60 [M+H]+: 507
    25 Ex. 2 1



    *-CH2-CH2- - Method A:
    tr (min) = 0.55 [M+H]+: 442
    26 Ex. 8 0



    *-CH2-CH2- - Method A:
    tr (min) = 0.56 [M+H]+: 442
    27 1



    *-CH2-CH2- - Method A:
    tr (min) = 0.46 [M+H]+: 439
    28 0



    *-CH2-CH2- - Method A:
    tr (min) = 0.45 [M+H]+: 439
    29 Ex. 26 1



    *-CO-CH2- - Method A:
    tr (min) = 0.67 [M+H]+: 415
    30 0



    *-CO-CH2- - Method A:
    tr (min) = 0.67 [M+H]+: 415
    31 1



    *-CO-CH2- - Method A:
    tr (min) = 0.42 [M+H]+: 465
    32 0



    *-CH2-CH2- - Method A:
    tr (min) = 0.48 [M+H]+: 436
    33 1



    *-CO-CH2- - Method A:
    tr (min) = 0.67 [M+H]+: 504
    34 1



    *-CO-CH2- - Method A:
    tr (min) = 0.47 [M+H]+: 509
    35 1



    *-CO-CH2- - Method A:
    tr (min) = 0.67 [M+H]+: 480
    36 1



    *-CO-CH2- - Method A:
    tr (min) = 0.43 [M+H]+: 479
    37 1



    *-CO-CH2- - Method A:
    tr (min) = 0.69 [M+H]+: 501
    38 Ex. 16 1



    *-CO-CH2- - Method A:
    tr (min) = 0.49 [M+H]+: 439
    39 1



    *-CO-CH2- - Method A:
    tr (min) = 0.52 [M+H]+: 440
    40 1



    *-CO-CH2- - Method A:
    tr (min) = 0.68 [M+H]+: 471
    41 1



    *-CO-CH2- - Method A:
    tr (min) = 0.64 [M+H]+: 520
    42 1



    *-CO-CH2- - Method A:
    tr (min) = 0.62 [M+H]+: 460
    43 Ex. 10 1



    *-CO-CH2- - Method A:
    tr (min) = 0.55 [M+H]+: 456
    44 1



    *-CO-CH2- - Method A:
    tr (min) = 0.61 [M+H]+: 470
    45 Ex. 32 1



    *-CO-CH2- - Method A:
    tr (min) = 0.61 [M+H]+: 466
    46 1



    *-CO-CH2- - Method A:
    tr (min) = 0.55 [M+H]+: 440
    47 Ex. 17 1



    *-CO-CH2- - Method A:
    tr (min) = 0.64 [M+H]+: 493
    48 Ex. 1 1



    *-CO-CH2- - Method A:
    tr (min) = 0.68 [M+H]+: 471
    49 Ex. 39 1



    *-CH2-CH2- - Method A:
    tr (min) = 0.63 [M+H]+: 431
    50 Ex. 50 1



    *-CH2-CH2- - Method A:
    tr (min) = 0.53 [M+H]+: 403
    51 Ex. 18 1



    *-CH2- - Method A:
    tr (min) = 0.68 [M+H]+: 461
    52 Ex. 19 1



    *-CO-CH2- - Method A:
    tr (min) = 0.65 [M+H]+: 507
    53 Ex. 4 1



    *-CO-CH2- - Method A:
    tr (min) = 0.58 [M+H]+: 454
    54 Ex. 38 1



    *-CH2- - Method A:
    tr (min) = 0.63 [M+H]+: 417
    55 1



    *-CO-CH2- - Method A:
    tr (min) = 0.61 [M+H]+: 460
    56 Ex. 5 1



    *-CO-CH2- - Method A:
    tr (min) = 0.60 [M+H]+: 401
    57 Ex. 21 1



    *-CO-CH2- - Method A:
    tr (min) = 0.60 [M+H]+: 523
    58 1



    *-CO-CH2- - Method A:
    tr (min) = 0.55 [M+H]+: 509
    59 1



    *-CH2- - Method C
    tr (min) = 0.85 [M+H]+: 413
    60 1



    *-CO-CH2- - Method A:
    tr (min) = 0.62 [M+H]+: 504
    61 1



    *-CO-CH2- - Method A:
    tr (min) = 0.64 [M+H]+: 493
    62 Ex. 11 1



    *-CO-CH2- - Method A:
    tr (min) = 0.52 [M+H]+: 443
    63 Ex. 33 1



    *-CO-CH2- - Method A:
    tr (min) = 0.62 [M+H]+: 498
    64 1



    *-CO-CH2- - Method A:
    tr (min) = 0.65 [M+H]+: 515
    65 1



    *-CO-CH2- - Method A:
    tr (min) = 0.63 [M+H]+: 466
    66 1



    *-CO-CH2- - Method A:
    tr (min) = 0.40 [M+H]+: 439
    67 1



    *-CO-CH2- - Method C
    tr (min) = 0.88 [M+H]+: 399
    68 Ex. 40 1



    *-CO-CH2- - Method A:
    tr (min) = 0.59 [M+H]+: 436
    69 Ex. 20 1



    *-CO-CH2- - Method A:
    tr (min) = 0.54 [M+H]+: 439
    70 Ex. 37 0



    *-CH2-CH2- - Method B:
    tr (min) = 0.69 [M+H]+: 536
    71 Ex. 34 1



    *-CHOH-CH2-OH abs. conf. (S) - Method B:
    tr(min) = 0.71 [M+H]+: 499
    72 Ex. 35 0



    *-CH2-CH2- - Method B:
    tr(min) = 0.68 [M+H]+: 451
    73 1



    *-CO-CH2- - Method F
    tr(min) = 0.84 [M+H]+: 449
    74 Ex. 36 0



    *-CH2-CH2- HCl Method B:
    tr(min) = 0.56 [M+H]+: 522
    75 Ex. 23 1



    *-CO-CH2- - Method B:
    tr(min) = 0.55 [M+H]+: 450
    76 0



    *-CH2-CH2- - Method C
    tr (min) = 1.26 [M+H]+: 465
    77 0



    *--CH2-CH2- - Method B:
    tr(min) = 82 [M+H]+: 449
    78 0



    *-CH2-CH2- HCl Method B:
    tr (min) = 0.58 [M+H]+: 536
    79 0



    *-CHOH-CH2-OH abs. conf. (S) - Method B:
    tr(min) = 0.65 [M+H]+: 451
    80 Ex. 24 1



    *-CHOH-CH2-OH abs. conf. (S) - Method B:
    tr(min) = 0.68 [M+H]+: 451
    81 1



    *-CH2-CH2- - Method B:
    tr(min) = 0.81 [M+H]+: 465
    82 1



    *-CHOH-CH2-OH abs. conf. (R) - Method B:
    tr (min) = 0.85 [M+H]+: 507
    83 1



    *-CH2-CH2- - Method B:
    tr(min) = 0.68 [M+H]+: 451
    84 Ex. 22 1



    *-CH2-CH2- - Method B:
    tr(min) = 0.85 [M+H]+: 449
    85 1



    *-CO-CH2- - Method B:
    tr(min) = 0.52 [M+H]+: 450
    86 1



    *-CH2- - Method F
    tr(min) = 0.83 [M+H]+: 461
    87 1



    *-CO-CH2- - Method F
    tr(min) = 0.83 [M+H]+: 450
    88 1



    *-CO-CH2- - Method F
    tr(min) = 1.01 [M+H]+: 450
    89 1



    *-CH2-CH2- - Method A:
    tr (min) = 0.55 [M+H]+: 470
    90 Ex. 44 1



    *-CH2-CH2- - Method A:
    tr (min) = 0.54 [M+H]+: 456
    91 1



    *-CO-CH2- - Method A:
    tr (min) = 0.62 [M+H]+: 514
    92 Ex. 45 1



    *-CH2-CH2- - Method A:
    tr (min) = 0.61 [M+H]+: 429
    93 Ex. 46 1



    *-CH2- - Method A:
    tr (min) = 0.57 [M+H]+: 415
    94 1



    *-CH2- - Method D
    tr (min) = 0.84 [M+H]+: 456
    95 Ex. 47 1



    *-CH2- - Method D
    tr (min) = 1.01 [M+H]+: 450
    96 Ex. 48 1



    *-CH2- - Method A:
    tr (min) = 0.71 [M+H]+: 497
    97 1



    *-CH2-CH2- - Method A:
    tr (min) = 0.68 [M+H]+: 511
    98 1



    *-CO-CH2- - Method A:
    tr (min) = 0.51 [M+H]+: 470
    99 Ex. 49 1



    *-CO-CH2- - Method A:
    tr (min) = 0.5 [M+H]+: 470
    100 1



    *-CH2-CH2- - Method A:
    tr (min) = 0.6 [M+H]+: 429
    101 1



    *-CH2- - Method D
    tr (min) = 0.95 [M+H]+: 415
    102 1



    *-CH2-CH2- - Method A:
    tr (min) = 0.68 [M+H]+: 455
    103 1



    *-CH2- - Method D
    tr (min) = 1.13 [M+H]+: 441
    104 Ex. 51 1



    *-CH2- - Method A:
    tr (min) = 0.52 [M+H]+: 387
    105 1



    *-CH2-CH2- - Method A:
    tr (min) = 0.53 [M+H]+: 401
    106 Ex. 52 1



    *-CH2- - Method A:
    tr (min) = 0.47 [M+H]+: 458
    107 1



    *-CO-CH2- - Method A:
    tr (min) = 0.57 [M+H]+: 456
    108 1



    *-CO-CH2- - Method A:
    tr (min) = 0.54 [M+H]+: 513
    109 1



    *-CH2- - Method A:
    tr (min) = 0.53 [M+H]+: 458
    110 1



    *-CO-CH2- - Method A:
    tr (min) = 0.56 [M+H]+: 444
    111 1



    *-CH2-CH2- - Method A:
    tr (min) = 0.49 [M+H]+: 550
    112 1



    *-CO-CH2- - Method A:
    tr (min) = 0.53 [M+H]+: 418
    113 1



    *-CO-CH2- - Method A:
    tr (min) = 0.38 [M+H]+: 475
    114 Ex. 53 1



    *-CO-CH2- - Method A:
    tr (min) = 0.67 [M+H]+: 502
    115 1



    *-CH2-CH2- - Method A:
    tr (min) = 0.61 [M+H]+: 564
    116 1



    *-CH2- - Method A:
    tr (min) = 0.67 [M+H]+: 479
    117 1



    *-CH2-CH2- - Method A:
    tr (min) = 0.49 [M+H]+: 508
    118 1



    *-CO-CH2- - Method A:
    tr (min) = 0.79 [M+H]+: 567
    119 1



    *-CO-CH2- - Method A:
    tr (min) = 0.48 [M+H]+: 484


    [0425] The compounds according to the invention underwent pharmacological trials to determine their inhibitory effect on the growth of Plasmodium falciparum.

    Antimalarial activity test



    [0426] The compounds according to the invention underwent pharmacological trials to determine their inhibitory effect on the growth of Plasmodium falciparum (strain NF54 sensitive to inhibition with chloroquine) in an in vitro test using infected human erythrocytes. 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 RPMI 1640 solutions (10.44 g/l) (without hypoxanthine) with HEPES (5.94 g/l), NaHCO3 (2.1 g/l), neomycin (100 g/mL)+ AlbumaxR II (5 g/l) supplemented with human erythrocytes with a final hematocrit of 1.25% and a final parasitemia of 0.15%.

    [0427] The stock solution of the compounds is prepared at 10 mg/mL in DMSO. For the test, fresh solutions at the desired concentrations are prepared in RPMI medium. For the test, 100 µl of compound are mixed with 100 µl of infected blood. For the determination of the IC50 values, the compounds are tested in twofold serial dilution.

    [0428] The plates are incubated at 37°C under a humid atmosphere with 93% N2, 4% CO2 and 3% O2. After 48 hours, 50 µl of 3H-hypoxanthine (= 0.5 µCi) 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 transferred 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.

    [0429] The IC50 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.

    [0430] The table of results for the antimalarial activity test is given below:
    Compound No.IC50 Plasmodium falciparum 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 9 nM
    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 3 nM
    24 8 nM
    25 <3.4 nM
    26 10 nM
    27 <4.5 nM
    28 9 nM
    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
    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 6 nM
    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 9 nM
    83 10 nM
    84 110 nM
    85 150 nM
    86 170 nM
    88 140 nM
    89 3.4 nM
    90 2 nM
    91 25 nM
    92 4 nM
    93 4 nM
    94 9 nM
    95 7 nM
    96 170 nM
    97 30 nM
    98 140 nM
    99 170 nM
    100 9 nM
    101 10 nM
    102 5 nM
    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 3 nM
    116 117 nM
    117 6 nM
    118 15 nM
    119 30 nM

    Human PI3Kα activity test



    [0431] The compounds according to the invention underwent pharmacological trials to measure the selectivity toward human lipid kinases and especially human PI3Kα. The test uses a luciferin/luciferase system to measure the concentration of ATP and its consumption during the enzymatic reaction. The test is performed in 96-well format (Corning/Costar 96 black flat-bottomed half-wells plate, ref. 3694) in a total volume of 30 µl.

    [0432] To 1 µl of inhibitor in 100% DMSO are added (final concentrations) 50 µM of the substrate PIP2 ((L-α-phosphatidyl-D-myoinositol 4,5-bisphosphate, Calbiochem 524644), 2 µM of ATP and 1.7 µg/mL of PI3Kα (p110α/p85α, Invitrogen PV4788) in a buffer of Tris/HCI 50 mM pH 7.5, EGTA 1 mM, MgCl2 10 mM, Chaps 0.03%, 1 mM DTT). After 90 minutes, the reaction is quenched by adding 20 µl/well of KinaseGlo reagent (Promega V6713). After 10 minutes in the dark, the luminescence is read using a PHERAStar microplate reader (reading at 0.8 sec/well).

    [0433] The IC50 values are determined by the preparation of successive threefold dilutions on at least a scale of more than 10 000. The IC50 values are between 190 nM and more than 10 000 nM, in particular between 1040 nM and more than 10 000 nM and even more particularly greater than 2000 nM.

    [0434] The activity of the other isoforms of human PI3K may be measured in the same manner.

    [0435] The table of results for the activity of human PI3Kα test is given below:
    No.IC50 Human PI3Kα
    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
    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
    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 nM
    84 200 nM
    85 >10000 nM
    86 7300 nM
    87 10000 nM
    88 1300 nM
    89 2800 nM
    90 2400 nM
    91 >10000 nM
    92 450 nM
    93 780 nM
    94 130 nM
    95 180 nM
    96 8500 nM
    97 440 nM
    98 >10000 nM
    99 >10000 nM
    100 1980 nM
    101 450 nM
    102 2500 nM
    103 840 nM
    104 930 nM
    105 1900 nM
    106 >10000 nM
    107 >10000 nM
    108 >10000 nM
    109 7800 nM
    110 >10000 nM
    111 330 nM
    112 >10000 nM
    113 >10000 nM
    114 >10000 nM
    115 590 nM
    116 >10000 nM
    117 380 nM
    118 >10000 nM
    119 >10000 nM


    [0436] The table below shows the human PI3Kα activity test results for known compounds derived from the applications mentioned above WO 2011/001 112 and WO 2011/001 113.
    COMPOUNDSSTRUCTUREIC50 Human PI3Kα
    Example 1 (p. 39, WO 2011/001 112)

    15 nM
    Example 10 (p. 61, WO 2011/001 112)

    17 nM
    Example 5 (p. 54, WO 2011/001 113)

    6 nM
    Example 1 (p. 44, WO 2011/001 113)

    9 nM


    [0437] It may be seen that although the compounds of the present 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 from the already-known CF3 pyrimidinones, described in patent applications WO 2011/001 112 and WO 2011/001 113, which are powerful inhibitors of human PI3Kα, which may be used for the treatment of malaria but above all for various cancers in man.

    [0438] Similar kinomes are present in all species of Plasmodium, such as P. falciparum, P. vivax, P. malariae, P. ovale and P. knowlesi. The compounds of the invention may thus be useful in the treatment of malaria induced by all the parasites mentioned above. In addition, 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.

    [0439] The compounds according to the invention may thus be used for the preparation of medicaments, in particular medicaments for inhibiting parasite growth.

    [0440] Thus, according to another of its aspects, a subject of the invention is medicaments that comprise a compound of formula (I), or an addition salt of the compound of formula (I) with a pharmaceutically acceptable acid or base.

    [0441] These medicaments find their use in therapeutics, especially in the treatment of malaria induced by all 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 medicaments 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), toxoplasmosis and coccidiosis which are caused by other parasites, respectively schistosomes, toxoplasma and Eimeria.

    [0442] According to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as active ingredient, 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 salt of said compound, and also at least one pharmaceutically acceptable excipient.

    [0443] 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.

    [0444] In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above, or its salt, can be administered in unit administration form, as a mixture with conventional pharmaceutical excipients, to animals or to human beings for the treatment of the above disorders or diseases.

    [0445] 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.

    [0446] 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 50.0 mg
    Mannitol 223.75 mg
    Croscaramellose sodium 6.0 mg
    Corn starch 15.0 mg
    Hydroxypropylmethylcellulose 2.25 mg
    Magnesium stearate 3.0 mg


    [0447] There may be particular cases where higher or lower dosages are appropriate; such dosages do not depart from the context of the invention. According to the usual practice, the dosage appropriate for each patient is determined by the physician according to the method of administration and the weight and response of said patient.

    [0448] According to another of its aspects, the present 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 salt thereof.


    Claims

    1. A compound corresponding to formula (I):

    in which:



    n represents 0 or 1;



    Y represents a bridged morpholine chosen from



    L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R1, or a (C1-C2)alkyl, said alkyl being optionally substituted with one or more substituents chosen from a (C1-C3)alkyl group and a hydroxyl group;



    R1 represents:

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

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

    - an aryl group, optionally substituted with one or more substituents chosen from a halogen atom, a hydroxyl group, a cyano group, an -NH2 group, a urea group of formula -NH-CO-NH-(C1-C4)alkyl, a morpholine group, a group of formula -SO2-(C1-C5)alkyl, a (C1-C5)alkoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

    ∘ a halogen atom,

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

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

    ∘ a group -CONR4R4' in which R4 and R4' are as defined below,

    ∘ a group -NR4R4' in which R4 and R4' are as defined below,

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

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

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

    ∘ a halogen atom,

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

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

    ∘ a group -NR5R5' in which R5 and R5', independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -CO2-C1-C3)alkyl group, a (C3-C5)cycloalkyl group and a linear or branched (C1-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 -CO2-(C1-C4)alkyl group,

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



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



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

    in the form of the base or of an addition salt with an acid or with a base.
     
    2. The compound of formula (I) as claimed in claim 1, characterized in that:



    n represents 0 or 1;



    Y represents a bridged morpholine chosen from



    L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R1, or a (C1-C2)alkyl, said alkyl being optionally substituted with one or more substituents chosen from a (C1-C3)alkyl group and a hydroxyl group;



    R1 represents:

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

    - a (C3-C6)cycloalkyl group,

    - an aryl group, optionally substituted with one or more substituents chosen from a halogen atom, a hydroxyl group, a cyano group, an -NH2 group, a urea group of formula -NH-CO-NH-(C1-C4)alkyl, a morpholine group, a group of formula -SO2-(C1-C5)alkyl, a (C1-C5)alkoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

    ∘ a halogen atom,

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

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

    ∘ a group -CONR4R4' in which R4 and R4' are as defined below,

    ∘ a group -NR4R4' in which R4 and R4' are as defined below,

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

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

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

    ∘ a halogen atom,

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

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

    ∘ a group -NR5R5' in which R5 and R5', independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -CO2-(C1-C3)alkyl group, a (C3-C5)cycloalkyl group and a linear or branched (C1-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 and an acetyl group and a -CO2-(C1-C4)alkyl group,

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



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



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

    in the form of the base or of an addition salt with an acid or with a base.
     
    3. The compound of formula (I) as claimed in claim 1 or 2, characterized in that:


    Y represents a bridged morpholine (a)

    in the form of the base or of an addition salt with an acid or with a base.
     
    4. The compound of formula (I) as claimed in claim 1 or 2, characterized in that:



    n represents 0 or 1;



    Y represents a bridged morpholine (a)



    L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R1, or (C1-C2)alkyl, said alkyl being optionally substituted with one or more substituents chosen from a (C1-C3)alkyl group;



    R1 represents:

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

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

    - an aryl group, optionally substituted with one or more substituents chosen from a halogen atom, a hydroxyl group, an -NH2 group, a urea group of formula -NH-CO-NH-(C1-C4)alkyl, a morpholinyl group, a group of formula - SO2-(C1-C5)alkyl, a (C1-C5)alkoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

    ∘ a halogen atom,

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

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

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

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

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

    ∘ a halogen atom,

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

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

    ∘ a group -NR5R5' in which R5 and R5', independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -CO2-(C1-C3)alkyl group, a (C3-C5)cycloalkyl group and a linear or branched (C1-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 -CO2-(C1-C4)alkyl group,

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



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



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

    in the form of the base or of an addition salt with an acid or with a base.
     
    5. The compound of formula (I) as claimed in claim 1 or 2, characterized in that:



    n represents 0 or 1;



    Y represents a bridged morpholine (a)



    L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R1, or (C1-C2)alkyl, said alkyl being optionally substituted with one or more substituents chosen from a (C1-C3)alkyl group;



    R1 represents:

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

    - a (C3-C6)cycloalkyl group,

    - an aryl group, optionally substituted with one or more substituents chosen from a halogen atom, a hydroxyl group, an -NH2 group, a urea group of formula -NH-CO-NH-(C1-C4)alkyl, a morpholinyl group, a group of formula - SO2-(C1-C5)alkyl, a (C1-C5)alkoxy group, said alkoxy being optionally substituted with one or more substituents chosen from:

    ∘ a halogen atom,

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

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

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

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

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

    ∘ a halogen atom,

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

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

    ∘ a group -NR5R5' in which R5 and R5', independently, which may be identical or different, represent a substituent chosen from a hydrogen atom, a -CO2-(C1-C3)alkyl group, a (C3-C5)cycloalkyl group and a linear or branched (C1-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 and an acetyl group,

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



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



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

    in the form of the base or of an addition salt with an acid or with a base.
     
    6. The compound of formula (I) as claimed in claim 1 or 2, characterized in that:



    n represents 0 or 1;



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



    L represents a linker -CH2-CO- such that the carbonyl function is attached to the substituent R1, or (C1-C2)alkyl, said alkyl being optionally substituted with a hydroxyl group;



    R1 represents:

    - a linear or branched (C1-C5)alkyl group, optionally substituted with an aryl group, or a hydroxyl group,

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

    ∘ a group -CONR4R4' in which R4 and R4' are as defined below,

    ∘ a group -NR4R4' in which R4 and R4' are as defined below,

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

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



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



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

    in the form of the base or of an addition salt with an acid or with a base.
     
    7. The compound as claimed in claim 1 or 2, characterized in that the linker L represents -CH2-CO, a methyl group or an ethyl group, in the form of the base or of an addition salt with an acid or with a base.
     
    8. The compound as claimed in claim 1 or 2, characterized in that n represents 1, in the form of the base or of an addition salt with an acid or with a base.
     
    9. The compound as claimed in claim 1 or 2, characterized in that n represents 0, in the form of the base or of an addition salt with an acid or with a base.
     
    10. The compound as claimed in claim 1 or 2, characterized in that R1 represents a linear or branched (C1-C5)alkyl group, optionally substituted with a hydroxyl group, a heteroaryl group or a group -NR6R6' in which R6 and R6', which are different, represent a (C1-C5)alkyl group and a (C1-C5)alkoxy group, in the form of the base or of an addition salt with an acid or with a base.
     
    11. The compound as claimed in claim 1 or 2, characterized in that R1 represents a linear or branched (C1-C5)alkyl group, optionally substituted with a hydroxyl group, 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 -CO2-(C1-C4)alkyl group, or a group -NR6R6' in which R6 and R6', which are different, represent a (C1-C5)alkyl group and a (C1-C5)alkoxy group, in the form of the base or of an addition salt with an acid or with a base.
     
    12. The compound as claimed in claim 1 or 2, characterized in that it is chosen from:

    1 (8S)-9-(2-Methyl-2-pyrid-4-ylpropyl)-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

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

    3 (8S)-9-[2-(6-Aminopyrid-3-yl)-2-oxoethyl]-2-(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

    4 (8S)-9-[2-(6-Methylpyrid-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

    5 (8S)-9-[2-(6-Methylaminopyrid-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

    6 (8S)-9-[2-(6-Dimethylaminopyrid-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

    7 (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

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

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

    10 (8S)-1-[2-(4-Methoxyphenyl)ethyl]-2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one

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

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

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

    14 (8S)-9-{2-[6-(2-Hydroxyethylamino)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

    15 (8S)-9-[2-(5-Methylpyrid-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

    16 2-Methyl-1-[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-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one

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

    18 2-Methyl-1-[2-(2-methylpyrid-3-yl)-2-oxoethyl]-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

    19 (8S)-9-[2-(2-Methylpyrid-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

    20 (8S)-9-[2-(4-Methylpyrid-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

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

    22 (8S)-9-[2-(6-Cyclopropylaminopyrid-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

    23 1-Ethyl-3-{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]phenyl}urea

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

    25 (8S)-9-[2-(4-Methylthiazol-5-yl)ethyl]-2-(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

    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-1H-imidazo[1,2-a]pyrimidin-5-one

    27 (8S)-9-[2-(3,5-Dimethyl-1H-pyrazol-4-yl)ethyl]-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

    28 1-[2-(3,5-Dimethyl-1H-pyrazol-4-yl)ethyl]-2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-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-(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

    31 (8S)-9-[2-(6-Amino-5-methylpyrid-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

    32 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[1,2-a]pyrimidin-5-one

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

    34 (8S)-9-(2-{6-[(2-Hydroxyethyl)methylamino]pyrid-3-yl}-2-oxoethyl)-2-(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

    35 (8S)-9-[2-(6-Ethoxypyrid-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

    36 (8S)-9-[2-(6-Amino-4,5-dimethylpyrid-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

    37 (S)-9-[2-(4-Difluoromethoxyphenyl)-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

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

    39 (8S)-9-[2-(4-Methyloxazol-5-yl)-2-oxoethyl]-2-(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

    40 (S)-9-[2-(3,4-Difluorophenyl)-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

    41 (8S)-9-[2-(4-Morpholin-4-ylphenyl)-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

    42 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]benzonitrile

    43 (8S)-9-[2-(4-Methylthiazol-5-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

    44 (8S)-9-[2-(5-Chloropyrid-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

    45 (8S)-9-[2-(6-Methoxypyrid-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

    46 (8S)-9-[2-(3-Methylisoxazol-4-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

    47 (8S)-9-(2-Benzo[1,2,3]thiadiazol-5-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

    48 (8S)-9-[2-(2,4-Difluorophenyl)-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

    49 (8S)-9-(3-Ethyl-3-hydroxypentyl)-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

    50 (8S)-9-(3-Hydroxy-3-methylbutyl)-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

    51 (8S)-9-(1-Methyl-1H-indazol-3-ylmethyl)-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

    52 (8S)-9-[2-(2-Cyclopropylmethoxypyrimidin-5-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

    53 (8S)-9-[2-(3,5-Dimethylisoxazol-4-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

    54 (8S)-9-(2-Ethyl-2-hydroxybutyl)-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

    55 3-[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]benzonitrile

    56 (8S)-9-(3-Methyl-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

    57 {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

    58 {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 methyl ester

    59 (8S)-9-(5-Methyl-[1,2,4]oxadiazol-3-ylmethyl)-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

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

    61 (8S)-9-(2-Benzo[1,2,5]thiadiazol-5-yl-2-oxoethyl)-2-(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

    62 (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-tetrahydropyrimido[1,2-a]pyrimidin-4-one

    63 (8S)-9-{2-[6-(2-Fluoroethoxy)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

    64 (8S)-9-{2-[3-Fluoro-4-(2-fluoroethoxy)phenyl]-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

    65 (8S)-9-[2-(2-Methoxypyrid-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

    66 (8S)-9-[2-(3-Methyl-3H-imidazol-4-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

    67 (8S)-9-(2-Cyclopropyl-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

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

    69 (8S)-9-[2-(2-Methyl-2H-pyrazol-3-yl)-2-oxoethyl]-2-(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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    89 (S)-9-[2-(1-Acetylpiperid-4-yl)ethyl]-2-(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

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

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

    94 (8S)-9-(1-Acetylpiperid-4-ylmethyl)-2-(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

    95 4-((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-ylmethyl)piperidine-1-carbaldehyde

    96 (8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one

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

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

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

    100 (8S)-9-[2-(1-Hydroxycyclopentyl)ethyl]-2-(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

    101 (8S)-9-(1-Hydroxycyclopentylmethyl)-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

    102 (8S)-9-(3,3-Dicyclopropyl-3-hydroxypropyl)-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

    103 (8S)-9-(2,2-Dicyclopropyl-2-hydroxyethyl)-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

    104 (8S)-9-(1-Hydroxycyclopropylmethyl)-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

    105 (8S)-9-[2-(1-Hydroxycyclopropyl)ethyl]-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

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

    107 (8S)-9-[2-(3-Methylisothiazol-4-yl)-2-oxoethyl]-2-(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

    108 (8S)-9-[2-(4-Methanesulfonylphenyl)-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

    109 (8S)-9-Isoquinolin-5-ylmethyl-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

    110 (8S)-9-(2-Morpholin-4-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

    111 (8S)-9-{2-[4-(2-Morpholin-4-ylethoxy)phenyl]ethyl}-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

    112 N-Methoxy-N-methyl-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)acetamide

    113 (8S)-9-(2-Imidazo[1,2-a]pyrid-6-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

    114 (8S)-9-[2-(6-Difluoromethoxypyrid-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

    115 (S)-9-{2-[4-(2-Morpholin-4-yl-2-oxoethoxy)phenyl]ethyl}-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

    116 (8S)-9-(1-Methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethyl)-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

    117 (8S)-9-{2-[4-(2-Dimethylaminoethoxy)phenyl]ethyl}-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

    118 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-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-tetrahydropyrimido[1,2-a]pyrimidin-4-one

    in the form of the base or of an addition salt with an acid or with a base.
     
    13. A process for preparing a compound of formula (I) as claimed in any one of claims 1 to 12, comprising the reaction of a compound of formula E

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

    and the alkylation reaction by addition to I of a compound of formula J = Ri-L-Lg in which R1 and L are as defined in any one of the preceding claims and Lg is a leaving group.
     
    14. A process for preparing a compound of formula (I) as claimed in any one of claims 1 to 12, comprising the alkylation reaction of a compound of formula E

    in which n represents 0 or 1 and R2 represents a hydrogen atom when n = 1 or a methyl group when n = 0, by addition of a compound of formula J = Ri-L-Lg in which R1 and L are as defined in any one of claims 1 to 8 and Lg is a leaving group, to obtain a compound of formula K

    in which R1, R2, L and n are as defined in one of claims 1 to 8, and a reaction on a compound K with a compound of formula Y being a bridged morpholine chosen from (a), (b) and (c) as defined in claim 1.
     
    15. A process for preparing a compound of formula (I) as claimed in any one of claims 1 to 12, in which the linker L is an ethyl group, R1 is a linear or branched (C1-C5)alkyl group substituted with a hydroxyl group, Y represents a bridged morpholine chosen from (a), (b) and (c) as defined in claim 1, n represents 1 or 0, and R2 represents a hydrogen atom when n = 1 and a methyl group when n = 0, comprising a Michael addition reaction of a compound of formula I

    in which n represents 0 or 1 and R2 represents a hydrogen atom when n = 1 or a methyl group when n = 0, on a compound of formula M = CH2=CH-CO2Alkyl, to obtain a compound of formula N,

    in which n represents 0 or 1 and R2 represents a hydrogen atom when n = 1 or a methyl group when n = 0, and Y is a bridged morpholine chosen from (a), (b) and (c) as defined in claim 1,
    and a reaction of alkyl on a compound of formula N with a compound of formula O = Z-Mg-X in which Z represents a linear or branched alkyl radical and X is a halogen atom.
     
    16. A process for preparing a compound of formula (I) as claimed in any one of claims 1 to 12, in which the linker L is a methyl group, R1 is a linear or branched (C1-C5)alkyl group substituted with a hydroxyl group, Y represents a bridged morpholine chosen from (a), (b) and (c) as defined in claim 1, n represents 1 or 0, and R2 represents a hydrogen atom when n = 1 and a methyl group when n = 0, comprising an addition reaction of a compound of formula I

    in which n represents 0 or 1 and R2 represents a hydrogen atom when n = 1 or a methyl group when n = 0, with a compound of formula P = X-CH2-CO2Alkyl with X being a halogen atom, to obtain a compound of formula Q

    in which Y is a bridged morpholine chosen from (a), (b) and (c), n represents 0 or 1 and R2 represents a hydrogen atom when n = 1 or a methyl group when n = 0,
    and an alkylation reaction on a compound of formula Q with a compound of formula O = Z-Mg-X in which Z represents a linear or branched alkyl radical and X is a halogen atom.
     
    17. A process for preparing a compound of formula (I) as claimed in any one of claims 1 to 12, in which the linker L is a OCH2-CO-group, R1 is a group -NR6R6' with R6 et R6' being either different and representing an alkyl group and an alkoxy group, Y represents a bridged morpholine chosen from (a), (b) and (c) as defined in claim 1, n represents 1 or 0, and R2 represents a hydrogen atom when n = 1 and a methyl group when n = 0, comprising a hydrolysis reaction of a compound of formula Q

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

    in which Y represents a bridged morpholine chosen from (a), (b) and (c) as defined in claim 1, n represents 1 or 0 and R2 represents a hydrogen atom when n = 1 or a methyl group when n = 0,
    and a coupling reaction between a compound of formula S and a compound of formula HNR6R6' with R6 and R6' being either different and representing an alkyl group and an alkoxy group.
     
    18. Compounds of formulae I, N, Q and S:

    and

    in which n, R2 and Y are as defined in claim 1.
     
    19. A medicament, characterized in that it comprises a compound as claimed in any one of claims 1 to 12, or an addition salt of this compound with a pharmaceutically acceptable acid or base.
     
    20. The compound as claimed in claim 1 or 2, as a medicament.
     
    21. A pharmaceutical composition, characterized in that it comprises a compound as claimed in any one of claims 1 to 12, or a pharmaceutically acceptable salt of this compound, and also at least one pharmaceutically acceptable excipient.
     
    22. The use of a compound as claimed in any one of claims 1 to 12, for the preparation of a medicament for treating parasite-induced malaria.
     
    23. The compound as claimed in claim 1 or 2, for its use in the treatment of malaria induced by all species of Plasmodium, such as P. falciparum, P. vivax, P. malariae, P. ovale and P. knowlesi, by all species of Trypanosoma and by all species of Leishmania, in the treatment of sleeping sickness, the treatment of Chagas disease, the various forms of leishmaniasis and the treatment of other parasitic infections, such as schistosomiasis (bilharzia), toxoplasmosis and coccidiosis.
     


    Ansprüche

    1. Verbindung, die der Formel (I) entspricht:

    in der:



    n für 0 oder 1 steht;



    Y für ein verbrücktes Morpholin steht, das aus

    ausgewählt ist;



    L für einen derartigen Linker -CH2-CO-, dass die Carbonylfunktion an den Substituenten R1 gebunden ist, oder ein (C1-C2)Alkyl steht, wobei das Alkyl gegebenenfalls durch einen oder mehrere Substituenten, die aus einer (C1-C3)Alkylgruppe und einer Hydroxylgruppe ausgewählt sind, substituiert ist;



    R1 für

    - eine lineare, verzweigte oder teilweise cyclische (C1-C5)Alkylgruppe, die gegebenenfalls durch einen oder mehrere Substituenten, die aus einer Hydroxylgruppe, einer Arylgruppe und einer Trifluormethylgruppe und einer (C3-C5)Cycloalkylgruppe ausgewählt sind, substituiert ist,

    - eine (C3-C6)Cycloalkylgruppe, die gegebenenfalls durch eine Hydroxylgruppe substituiert ist,

    - eine Arylgruppe, die gegebenenfalls durch einen oder mehrere Substituenten, die aus einem Halogenatom, einer Hydroxylgruppe, einer Cyanogruppe, einer -NH2-Gruppe, einer Harnstoffgruppe der Formel -NH-CO-NH-(C1-C4)Alkyl, einer Morpholingruppe, einer Gruppe der Formel -SO2-(C1-C5)Alkyl und einer (C1-C5)Alkoxygruppe ausgewählt sind, substituiert ist, wobei die Alkoxygruppe gegebenenfalls durch einen oder mehrere Substituenten, die aus:

    ∘ einem Halogenatom,

    ∘ einer Hydroxylgruppe oder einer (C1-C5) Alkoxygruppe,

    ∘ einer Gruppe -COR3, in der R3 für einen Substituenten, der aus einer Heterocycloalkylgruppe und einer Hydroxylgruppe ausgewählt ist, steht,

    ∘ einer Gruppe -CONR4R4', in der R4 und R4' wie nachstehend definiert sind,

    ∘ einer Gruppe -NR4R4' in der R4 und R4' wie nachstehend definiert sind,

    ∘ einer Heterocycloalkylgruppe mit einem oder zwei Heteroelementen, die aus einem Stickstoffatom und einem Sauerstoffatom ausgewählt sind,

    ∘ einer Heteroarylgruppe, die gegebenenfalls durch einen oder mehrere Substituenten, die aus einem Halogenatom, einer (C1-C3)Alkylgruppe, einer Hydroxylgruppe und einer -NH2-Gruppe ausgewählt sind, substituiert ist;

    ausgewählt sind, substituiert ist;

    - eine Heteroarylgruppe mit einem oder mehreren Heteroatomen, die aus einem Stickstoffatom, einem Schwefelatom und einem Sauerstoffatom ausgewählt sind, die gegebenenfalls durch einen oder mehrere Substituenten, die aus:

    ∘ einem Halogenatom,

    ∘ einer (C1-C3) Alkylgruppe, die gegebenenfalls durch ein oder mehrere Halogenatome substituiert ist,

    ∘ einer (C1-C5)Alkoxygruppe, die gegebenenfalls durch einen oder mehrere Substituenten, die aus einem Halogenatom, einer (C3-C5)Cycloalkylgruppe und einer Heteroarylgruppe, die gegebenenfalls durch einen oder mehrere Substituenten, die aus einem Halogenatom, einer (C1-C3)Alkylgruppe, einer Hydroxylgruppe und einer -NH2-Gruppe ausgewählt sind, substituiert ist, ausgewählt sind, substituiert ist,

    ∘ einer Gruppe -NR5R5', in der R5 und R5' unabhängig gleich oder verschieden sein können und für einen Substituenten, der aus einem Wasserstoffatom, einer -CO2-(C1-C3)Alkylgruppe, einer (C3-C5) Cycloalkylgruppe und einer linearen oder verzweigten (C1-C3)Alkylgruppe ausgewählt ist, stehen, wobei die Alkylgruppe gegebenenfalls durch eine oder mehrere Hydroxylgruppen substituiert ist,

    ausgewählt sind, substituiert ist;

    - eine Pyridingruppe mit zwei verknüpften benachbarten Gruppen, die zusammen mit den beiden Kohlenstoffatomen, die sie tragen, einen Heterocyclus mit einem Stickstoffatom und einem Sauerstoffatom bilden,

    - eine Heterocycloalkylgruppe mit einem oder mehreren Heteroatomen, die aus Sauerstoff- und Stickstoffatomen ausgewählt sind, wobei das Stickstoffatom gegebenenfalls durch einen Substituenten, der aus einer Formylgruppe, einer Acetylgruppe und einer -CO2-(C1-C4)Alkylgruppe ausgewählt ist, substituiert ist,

    - eine Gruppe -NR6R6', in der R6 und R6', die verschieden sind, für eine (C1-C5)Alkylgruppe und eine (C1-C5)Alkoxygruppe stehen,
    steht;



    R2 für ein Wasserstoffatom steht, wenn n für 1 steht, und für eine Methylgruppe steht, wenn n für 0 steht;



    R4 und R4' unabhängig gleich oder verschieden sein können und für ein Wasserstoffatom oder eine (C1-C3)Alkylgruppe stehen,

    in Form der Base oder eines Additionssalzes mit einer Säure oder mit einer Base.


     
    2. Verbindung der Formel (I) nach Anspruch 1, dadurch gekennzeichnet, dass:



    n für 0 oder 1 steht;



    Y für ein verbrücktes Morpholin steht, das aus

    ausgewählt ist;



    L für einen derartigen Linker -CH2-CO-, dass die Carbonylfunktion an den Substituenten R1 gebunden ist, oder ein (C1-C2)Alkyl steht, wobei das Alkyl gegebenenfalls durch einen oder mehrere Substituenten, die aus einer (C1-C3)Alkylgruppe und einer Hydroxylgruppe ausgewählt sind, substituiert ist;



    R1 für

    - eine lineare, verzweigte oder teilweise cyclische (C1-C5)Alkylgruppe, die gegebenenfalls durch einen oder mehrere Substituenten, die aus einer Hydroxylgruppe und einer Arylgruppe ausgewählt sind, substituiert ist,

    - eine (C3-C6)Cycloalkylgruppe,

    - eine Arylgruppe, die gegebenenfalls durch einen oder mehrere Substituenten, die aus einem Halogenatom, einer Hydroxylgruppe, einer Cyanogruppe, einer -NH2-Gruppe, einer Harnstoffgruppe der Formel -NH-CO-NH-(C1-C4)Alkyl, einer Morpholingruppe, einer Gruppe der Formel -SO2-(C1-C5)Alkyl und einer (C1-C5)Alkoxygruppe ausgewählt sind, substituiert ist, wobei die Alkoxygruppe gegebenenfalls durch einen oder mehrere Substituenten, die aus:

    ∘ einem Halogenatom,

    ∘ einer Hydroxylgruppe oder einer (C1-C5) Alkoxygruppe,

    ∘ einer Gruppe -COR3, in der R3 für einen Substituenten, der aus einer Heterocycloalkylgruppe und einer Hydroxylgruppe ausgewählt ist, steht,

    ∘ einer Gruppe -CONR4R4', in der R4 und R4' wie nachstehend definiert sind,

    ∘ einer Gruppe -NR4R4', in der R4 und R4' wie nachstehend definiert sind,

    ∘ einer Heterocycloalkylgruppe mit einem oder zwei Heteroelementen, die aus einem Stickstoffatom und einem Sauerstoffatom ausgewählt sind,

    ∘ einer Heteroarylgruppe, die gegebenenfalls durch einen oder mehrere Substituenten, die aus einem Halogenatom, einer (C1-C3)Alkylgruppe, einer Hydroxylgruppe und einer -NH2-Gruppe ausgewählt sind, substituiert ist;

    ausgewählt sind, substituiert ist;

    - eine Heteroarylgruppe mit einem oder mehreren Heteroatomen, die aus einem Stickstoffatom, einem Schwefelatom und einem Sauerstoffatom ausgewählt sind, die gegebenenfalls durch einen oder mehrere Substituenten, die aus:

    ∘ einem Halogenatom,

    ∘ einer (C1-C3) Alkylgruppe, die gegebenenfalls durch ein oder mehrere Halogenatome substituiert ist,

    ∘ einer (C1-C5)Alkoxygruppe, die gegebenenfalls durch einen oder mehrere Substituenten, die aus einem Halogenatom, einer (C3-C5)Cycloalkylgruppe und einer Heteroarylgruppe, die gegebenenfalls durch einen oder mehrere Substituenten, die aus einem Halogenatom, einer (C1-C3)Alkylgruppe, einer Hydroxylgruppe und einer -NH2-Gruppe ausgewählt sind, substituiert ist, ausgewählt sind, substituiert ist,

    ∘ einer Gruppe -NR5R5', in der R5 und R5' unabhängig gleich oder verschieden sein können und für einen Substituenten, der aus einem Wasserstoffatom, einer -CO2-(C1-C3)Alkylgruppe, einer (C3-C5) Cycloalkylgruppe und einer linearen oder verzweigten (C1-C3)Alkylgruppe ausgewählt ist, stehen, wobei die Alkylgruppe gegebenenfalls durch eine oder mehrere Hydroxylgruppen substituiert sein kann, ausgewählt sind, substituiert ist;

    - eine Pyridingruppe mit zwei verknüpften benachbarten Gruppen, die zusammen mit den beiden Kohlenstoffatomen, die sie tragen, einen Heterocyclus mit einem Stickstoffatom und einem Sauerstoffatom bilden,

    - eine Heterocycloalkylgruppe mit einem oder mehreren Heteroatomen, die aus Sauerstoff- und Stickstoffatomen ausgewählt sind, wobei das Stickstoffatom gegebenenfalls durch einen Substituenten, der aus einer Formylgruppe, einer Acetylgruppe und einer -CO2-(C1-C4)Alkylgruppe ausgewählt ist, substituiert ist,

    - eine Gruppe -NR6R6', in der R6 und R6', die verschieden sind, für eine (C1-C5)Alkylgruppe und eine (C1-C5)Alkoxygruppe stehen,
    steht;



    R2 für ein Wasserstoffatom steht, wenn n für 1 steht, und für eine Methylgruppe steht, wenn n für 0 steht;



    R4 und R4' unabhängig gleich oder verschieden sein können und für ein Wasserstoffatom oder eine (C1-C3)Alkylgruppe stehen,

    in Form der Base oder eines Additionssalzes mit einer Säure oder mit einer Base.


     
    3. Verbindung der Formel (I) nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass:


    Y für ein verbrücktes Morpholin (a)

    steht;
    in Form der Base oder eines Additionssalzes mit einer Säure oder mit einer Base.
     
    4. Verbindung der Formel (I) nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass:



    n für 0 oder 1 steht;



    Y für ein verbrücktes Morpholin (a)

    steht;



    L für einen derartigen Linker -CH2-CO-, dass die Carbonylfunktion an den Substituenten R1 gebunden ist, oder ein (C1-C2)Alkyl steht, wobei das Alkyl gegebenenfalls durch einen oder mehrere Substituenten, die aus einer (C1-C3)Alkylgruppe ausgewählt sind, substituiert ist;



    R1 für

    - eine lineare, verzweigte oder teilweise cyclische (C1-C5)Alkylgruppe, die gegebenenfalls durch einen oder mehrere Substituenten, die aus einer Hydroxylgruppe, einer Arylgruppe, einer Trifluormethylgruppe und einer (C3-C5)Cycloalkylgruppe ausgewählt sind, substituiert ist,

    - eine (C3-C6)Cycloalkylgruppe, die gegebenenfalls durch eine Hydroxylgruppe substituiert ist,

    - eine Arylgruppe, die gegebenenfalls durch einen oder mehrere Substituenten, die aus einem Halogenatom, einer Hydroxylgruppe, einer -NH2-Gruppe, einer Harnstoffgruppe der Formel -NH-CO-NH-(C1-C4)Alkyl, einer Morpholinylgruppe, einer Gruppe der Formel -SO2-(C1-C5)Alkyl und einer (C1-C5)Alkoxygruppe ausgewählt sind, substituiert ist, wobei die Alkoxygruppe gegebenenfalls durch einen oder mehrere Substituenten, die aus:

    ∘ einem Halogenatom,

    ∘ einer Hydroxylgruppe oder einem (C1-C5)Alkoxy,

    ∘ einer Gruppe -COR3, in der R3 für einen Substituenten, der aus einer Heterocycloalkylgruppe und einer Hydroxylgruppe ausgewählt ist, steht,

    ∘ einer Heterocycloalkylgruppe mit einem oder zwei Heteroelementen, die aus einem Stickstoffatom und einem Sauerstoffatom ausgewählt sind,

    ∘ einer Heteroarylgruppe, die gegebenenfalls durch einen oder mehrere Substituenten, die aus einem Halogenatom, einer (C1-C3)Alkylgruppe, einer Hydroxylgruppe und einer -NH2-Gruppe ausgewählt sind, substituiert ist;

    ausgewählt sind, substituiert ist;

    - eine Heteroarylgruppe mit einem oder mehreren Heteroatomen, die aus einem Stickstoffatom, einem Schwefelatom und einem Sauerstoffatom ausgewählt sind, die gegebenenfalls durch einen oder mehrere Substituenten, die aus:

    ∘ einem Halogenatom,

    ∘ einer (C1-C3)Alkylgruppe, die gegebenenfalls durch ein oder mehrere Halogenatome substituiert ist,

    ∘ einer (C1-C5)Alkoxygruppe, die gegebenenfalls durch einen oder mehrere Substituenten, die aus einem Halogenatom, einer (C3-C5)Cycloalkylgruppe und einer Heteroarylgruppe, die gegebenenfalls durch einen oder mehrere Substituenten, die aus einem Halogenatom, einer (C1-C3)Alkylgruppe, einer Hydroxylgruppe und einer -NH2-Gruppe ausgewählt sind, substituiert ist, ausgewählt sind, substituiert ist,

    ∘ einer Gruppe -NR5R5', in der R5 und R5' unabhängig gleich oder verschieden sein können und für einen Substituenten, der aus einem Wasserstoffatom, einer -CO2-(C1-C3)Alkylgruppe, einer (C3-C5) Cycloalkylgruppe und einer linearen oder verzweigten (C1-C3)Alkylgruppe ausgewählt ist, stehen, wobei die Alkylgruppe gegebenenfalls durch eine oder mehrere Hydroxylgruppen substituiert sein kann,

    ausgewählt sind, substituiert ist;

    - eine Pyridingruppe mit zwei verknüpften benachbarten Gruppen, die zusammen mit den beiden Kohlenstoffatomen, die sie tragen, einen Heterocyclus mit einem Stickstoffatom und einem Sauerstoffatom bilden,

    - eine Heterocycloalkylgruppe mit einem oder mehreren Heteroatomen, die aus Sauerstoff- und Stickstoffatomen ausgewählt sind, wobei das Stickstoffatom gegebenenfalls durch einen Substituenten, der aus einer Formylgruppe, einer Acetylgruppe und einer -CO2-(C1-C4)Alkylgruppe ausgewählt ist, substituiert ist,

    - eine Gruppe -NR6R6', in der R6 und R6', die verschieden sind, für eine (C1-C5)Alkylgruppe und eine (C1-C5)Alkoxygruppe stehen,
    steht;



    R2 für ein Wasserstoffatom steht, wenn n für 1 steht, und für eine Methylgruppe steht, wenn n für 0 steht;



    R4 und R4' unabhängig gleich oder verschieden sein können und für ein Wasserstoffatom oder eine (C1-C3)Alkylgruppe stehen,

    in Form der Base oder eines Additionssalzes mit einer Säure oder mit einer Base.


     
    5. Verbindung der Formel (I) nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass:



    n für 0 oder 1 steht;



    Y für ein verbrücktes Morpholin (a)

    steht;



    L für einen derartigen Linker -CH2-CO-, dass die Carbonylfunktion an den Substituenten R1 gebunden ist, oder ein (C1-C2)Alkyl steht, wobei das Alkyl gegebenenfalls durch einen oder mehrere Substituenten, die aus einer (C1-C3)Alkylgruppe ausgewählt sind, substituiert ist;



    R1 für

    - eine lineare, verzweigte oder teilweise cyclische (C1-C5)Alkylgruppe, die gegebenenfalls durch einen oder mehrere Substituenten, die aus einer Hydroxylgruppe und einer Arylgruppe ausgewählt sind, substituiert ist,

    - eine (C3-C6)Cycloalkylgruppe,

    - eine Arylgruppe, die gegebenenfalls durch einen oder mehrere Substituenten, die aus einem Halogenatom, einer Hydroxylgruppe, einer -NH2-Gruppe, einer Harnstoffgruppe der Formel -NH-CO-NH-(C1-C4)Alkyl, einer Morpholinylgruppe, einer Gruppe der Formel -SO2-(C1-C5)Alkyl und einer (C1-C5)Alkoxygruppe ausgewählt sind, substituiert ist, wobei die Alkoxygruppe gegebenenfalls durch einen oder mehrere Substituenten, die aus:

    ∘ einem Halogenatom,

    ∘ einer Hydroxylgruppe oder einem (C1-C5)Alkoxy,

    ∘ einer Gruppe -COR3, in der R3 für einen Substituenten, der aus einer Heterocycloalkylgruppe und einer Hydroxylgruppe ausgewählt ist, steht,

    ∘ einer Heterocycloalkylgruppe mit einem oder zwei Heteroelementen, die aus einem Stickstoffatom und einem Sauerstoffatom ausgewählt sind,

    ∘ einer Heteroarylgruppe, die gegebenenfalls durch einen oder mehrere Substituenten, die aus einem Halogenatom, einer (C1-C3)Alkylgruppe, einer Hydroxylgruppe und einer -NH2-Gruppe ausgewählt sind, substituiert ist;

    ausgewählt sind, substituiert ist;

    - eine Heteroarylgruppe mit einem oder mehreren Heteroatomen, die aus einem Stickstoffatom, einem Schwefelatom und einem Sauerstoffatom ausgewählt sind, die gegebenenfalls durch einen oder mehrere Substituenten, die aus:

    ∘ einem Halogenatom,

    ∘ einer (C1-C3) Alkylgruppe, die gegebenenfalls durch ein oder mehrere Halogenatome substituiert ist,

    ∘ einer (C1-C5)Alkoxygruppe, die gegebenenfalls durch einen oder mehrere Substituenten, die aus einem Halogenatom, einer (C3-C5)Cycloalkylgruppe und einer Heteroarylgruppe, die gegebenenfalls durch einen oder mehrere Substituenten, die aus einem Halogenatom, einer (C1-C3)Alkylgruppe, einer Hydroxylgruppe und einer -NH2-Gruppe ausgewählt sind, substituiert ist, ausgewählt sind, substituiert ist,

    ∘ einer Gruppe -NR5R5', in der R5 und R5' unabhängig gleich oder verschieden sein können und für einen Substituenten, der aus einem Wasserstoffatom, einer -CO2-(C1-C3)Alkylgruppe, einer (C3-C5) Cycloalkylgruppe und einer linearen oder verzweigten (C1-C3)Alkylgruppe ausgewählt ist, stehen, wobei die Alkylgruppe gegebenenfalls durch ein oder mehrere Hydroxylgruppen substituiert sein kann, ausgewählt sind, substituiert ist;

    - eine Pyridingruppe mit zwei verknüpften benachbarten Gruppen, die zusammen mit den beiden Kohlenstoffatomen, die sie tragen, einen Heterocyclus mit einem Stickstoffatom und einem Sauerstoffatom bilden,

    - eine Heterocycloalkylgruppe mit einem oder mehreren Heteroatomen, die aus Sauerstoff- und Stickstoffatomen ausgewählt sind, wobei das Stickstoffatom gegebenenfalls durch einen Substituenten, der aus einer Formylgruppe und einer Acetylgruppe ausgewählt ist, substituiert ist,

    - eine Gruppe -NR6R6', in der R6 und R6', die verschieden sind, für eine (C1-C5)Alkylgruppe und eine (C1-C5)Alkoxygruppe stehen,
    steht;



    R2 für ein Wasserstoffatom steht, wenn n für 1 steht, und für eine Methylgruppe steht, wenn n für 0 steht;



    R4 und R4' unabhängig gleich oder verschieden sein können und für ein Wasserstoffatom oder eine (C1-C3)Alkylgruppe stehen,

    in Form der Base oder eines Additionssalzes mit einer Säure oder mit einer Base.


     
    6. Verbindung der Formel (I) nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass:



    n für 0 oder 1 steht;



    Y für ein verbrücktes Morpholin steht, das aus (b) und (c)

    ausgewählt ist;



    L für einen derartigen Linker -CH2-CO-, dass die Carbonylfunktion an den Substituenten R1 gebunden ist, oder ein (C1-C2)Alkyl steht, wobei das Alkyl gegebenenfalls durch eine Hydroxylgruppe substituiert ist;



    R1 für

    - eine lineare oder verzweigte (C1-C5)Alkylgruppe, die gegebenenfalls durch eine Arylgruppe substituiert ist,

    - eine Arylgruppe, die gegebenenfalls durch einen oder mehrere Substituenten, die aus einem Halogenatom, einer Hydroxylgruppe und einer (C1-C5)Alkoxygruppe ausgewählt sind, substituiert ist, wobei die Alkoxygruppe gegebenenfalls durch einen oder mehrere Substituenten, die aus:

    ∘ einer Gruppe -CONR4R4' , in der R4 und R4' wie nachstehend definiert sind,

    ∘ einer Gruppe -NR4R4', in der R4 und R4' wie nachstehend definiert sind,

    ausgewählt sind, substituiert ist,

    - eine Heteroarylgruppe mit einem oder mehreren Heteroatomen, die aus einem Stickstoffatom, einem Schwefelatom und einem Sauerstoffatom ausgewählt sind, die gegebenenfalls durch eine oder mehrere (C1-C3)Alkylgruppen, die gegebenenfalls durch ein oder mehrere Halogenatome substituiert sind, substituiert ist,

    - eine Gruppe -NR6R6', in der R6 und R6', die verschieden sind, für eine (C1-C5)Alkylgruppe und eine (C1-C5)Alkoxygruppe stehen,



    R2 für ein Wasserstoffatom steht, wenn n für 1 steht, und für eine Methylgruppe steht, wenn n für 0 steht;



    R4 und R4' unabhängig gleich oder verschieden sein können und für ein Wasserstoffatom oder eine (C1-C3)Alkylgruppe stehen,

    in Form der Base oder eines Additionssalzes mit einer Säure oder mit einer Base.


     
    7. Verbindung nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass der Linker L für -CH2-CO, eine Methylgruppe oder eine Ethylgruppe steht, in Form der Base oder eines Additionssalzes mit einer Säure oder mit einer Base.
     
    8. Verbindung nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass n für 1 steht, in Form der Base oder eines Additionssalzes mit einer Säure oder mit einer Base.
     
    9. Verbindung nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass n für 0 steht, in Form der Base oder eines Additionssalzes mit einer Säure oder mit einer Base.
     
    10. Verbindung nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass R1 für eine lineare oder verzweigte (C1-C5) Alkylgruppe, die gegebenenfalls durch eine Hydroxylgruppe substituiert ist, eine Heteroarylgruppe oder eine Gruppe -NR6R6', in der R6 und R6', die verschieden sind, für eine (C1-C5)Alkylgruppe und eine (C1-C5)Alkoxygruppe stehen, steht, in Form der Base oder eines Additionssalzes mit einer Säure oder mit einer Base.
     
    11. Verbindung nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass R1 für eine lineare oder verzweigte (C1-C5)Alkylgruppe, die gegebenenfalls durch eine Hydroxylgruppe substituiert ist, eine Heterocycloalkylgruppe mit einem oder mehreren Heteroatomen, die aus Sauerstoff- und Stickstoffatomen ausgewählt sind, wobei das Stickstoffatom gegebenenfalls durch einen Substituenten, der aus einer Formylgruppe, einer Acetylgruppe und einer -CO2-(C1-C4)Alkylgruppe ausgewählt ist, substituiert ist, oder eine Gruppe -NR6R6', in der R6 und R6', die verschieden sind, für eine (C1-C5)Alkylgruppe und eine (C1-C5)Alkoxygruppe stehen, steht, in Form der Base oder eines Additionssalzes mit einer Säure oder mit einer Base.
     
    12. Verbindung nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass sie aus:

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

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

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

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

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

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

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

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

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

    (8S)-1-[2-(4-Methoxyphenyl)ethyl]-2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-trifluormethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-on

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    (8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-oxo-2-(6-trifluormethylpyrid-3-yl)ethyl]-8-trifluormethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-on

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

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

    (8S)-9-[2-(6-Amino-4,5-dimethylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluormethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-on

    (S)-9-[2-(4-Difluormethoxyphenyl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluormethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-on

    (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-trifluormethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-on

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

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

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

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

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

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

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

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

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

    (8S)-9-[2-(2,4-Difluorphenyl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluormethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-on

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

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

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

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

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

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

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

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

    {5-[2-((S)-8-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluormethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetyl]pyrid-2-yl}carbamidsäureethylester

    {5-[2-((S)-8-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluormethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetyl]pyrid-2-yl}carbamidsäuremethylester

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

    (8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-oxo-2-(2-trifluormethylpyrid-3-yl)ethyl]-8-trifluormethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-on

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

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

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

    (8S)-9-{2-[3-Fluor-4-(2-fluorethoxy)phenyl]-2-oxoethyl}-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluormethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-on

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

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

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

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

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

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

    (8S)-9-[(S)-2-(4-Fluor-2-methoxyphenyl)-2-hydroxyethyl]-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluormethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-on

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    (8S)-9-(1-Difluormethyl-1H-pyrazol-3-ylmethyl)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluormethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-on

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

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

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

    4-[2-((S)-8-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluormethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)ethyl]piperidin-1-carbaldehyd

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

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

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

    (8S)-9-(1-Acetylpiperid-4-ylmethyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluormethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-on

    4-((S)-8-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluormethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-ylmethyl)piperidin-1-carbaldehyd

    (8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(3,3,3-trifluor-2-hydroxy-2-trifluormethylpropyl)-8-trifluormethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-on

    (8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(4,4,4-trifluor-3-hydroxy-3-trifluormethylbutyl)-8-trifluormethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-on

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

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

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

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

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

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

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

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

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

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

    (8S)-9-[2-(4-Methansulfonylphenyl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluormethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-on

    (8S)-9-Isoquinolin-5-ylmethyl-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluormethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-on

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

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

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

    (8S)-9-(2-Imidazo[1,2-a]pyrid-6-yl-2-oxoethyl)-2-(lS,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluormethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-on

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

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

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

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

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

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

    ausgewählt ist, in Form der Base oder eines Additionssalzes mit einer Säure oder mit einer Base.
     
    13. Verfahren zur Herstellung einer Verbindung der Formel (I) nach einem der Ansprüche 1 bis 12, umfassend die Umsetzung einer Verbindung der Formel E

    in der n für 0 oder 1 steht und R2 für ein Wasserstoffatom steht, wenn n = 1, oder für eine Methylgruppe steht, wenn n = 0, mit einem verbrückten Morpholin Y, das aus (a), (b) und (c) gemäß Anspruch 1 ausgewählt wird, zum Erhalt einer Verbindung der Formel I

    und die Alkylierungsreaktion durch Addition einer Verbindung der Formel J = R1-L-Lg, in der R1 und L wie in einem der vorhergehenden Ansprüche definiert sind und Lg für eine Abgangsgruppe steht, an I.
     
    14. Verfahren zur Herstellung einer Verbindung der Formel (I) nach einem der Ansprüche 1 bis 12, umfassend die Alkylierungsreaktion einer Verbindung der Formel E

    in der n für 0 oder 1 steht und R2 für ein Wasserstoffatom steht, wenn n = 1, oder für eine Methylgruppe steht, wenn n = 0, durch Addition einer Verbindung der Formel J = R1-L-Lg, in der R1 und L wie in einem der Ansprüche 1 bis 8 definiert sind und Lg für eine Abgangsgruppe steht, zum Erhalt einer Verbindung der Formel K

    in der R1, R2, L und n wie in einem der Ansprüche 1 bis 8 definiert sind, und eine Umsetzung an einer Verbindung K mit einer Verbindung der Formel Y, bei der es sich um ein verbrücktes Morpholin handelt, das aus (a), (b) und (c) gemäß Anspruch 1 ausgewählt wird.
     
    15. Verfahren zur Herstellung einer Verbindung der Formel (I) nach einem der Ansprüche 1 bis 12, in der der Linker L für eine Ethylgruppe steht, R1 für eine lineare oder verzweigte (C1-C5) Alkylgruppe, die durch eine Hydroxylgruppe substituiert ist, steht, Y für ein verbrücktes Morpholin, das aus (a), (b) und (c) gemäß Anspruch 1 ausgewählt ist, steht, n für 1 oder 0 steht und R2 für ein Wasserstoffatom steht, wenn n = 1, und für eine Methylgruppe steht, wenn n = 0, umfassend eine Michael-Additionsreaktion einer Verbindung der Formel I

    in der n für 0 oder 1 steht und R2 für ein Wasserstoffatom steht, wenn n = 1, oder für eine Methylgruppe steht, wenn n = 0, an einer Verbindung der Formel M = CH2=CH-CO2-Alkyl zum Erhalt einer Verbindung der Formel N,

    in der n für 0 oder 1 steht und R2 für ein Wasserstoffatom steht, wenn n = 1, oder für eine Methylgruppe steht, wenn n = 0 und Y für ein verbrücktes Morpholin steht, das aus (a), (b) und (c) gemäß Anspruch 1 ausgewählt ist,
    und eine Umsetzung von Alkyl an einer Verbindung der Formel N mit einer Verbindung der Formel O = Z-Mg-X, in der Z für einen linearen oder verzweigten Alkylrest steht und X für ein Halogenatom steht.
     
    16. Verfahren zur Herstellung einer Verbindung der Formel (I) nach einem der Ansprüche 1 bis 12, in der der Linker L für eine Methylgruppe steht, R1 für eine lineare oder verzweigte (C1-C5) Alkylgruppe, die durch eine Hydroxylgruppe substituiert ist, steht, Y für ein verbrücktes Morpholin steht, das aus (a), (b) und (c) gemäß Anspruch 1 ausgewählt ist, n für 1 oder 0 steht und R2 für ein Wasserstoffatom steht, wenn n = 1, und für eine Methylgruppe steht, wenn n = 0, umfassend eine Additionsreaktion einer Verbindung der Formel I

    in der n für 0 oder 1 steht und R2 für ein Wasserstoffatom steht, wenn n = 1, oder für eine Methylgruppe steht, wenn n = 0, mit einer Verbindung der Formel P = X-CH2-CO2-Alkyl, wobei X für ein Halogenatom steht, zum Erhalt einer Verbindung der Formel Q

    in der Y für ein verbrücktes Morpholin steht, das aus (a), (b) und (c) ausgewählt ist, n für 0 oder 1 steht und R2 für ein Wasserstoffatom steht, wenn n = 1, und für eine Methylgruppe steht, wenn n = 0,
    und eine Alkylierungsreaktion an einer Verbindung der Formel Q mit einer Verbindung der Formel O = Z-Mg-X, in der Z für einen linearen oder verzweigten Alkylrest steht und X für ein Halogenatom steht.
     
    17. Verfahren zur Herstellung einer Verbindung der Formel (I) nach einem der Ansprüche 1 bis 12, in der der Linker L für eine CH2-CO-Gruppe steht, R1 für eine Gruppe -NR6R6' steht, wobei R6 und R6' entweder verschieden sind und für eine Alkylgruppe und eine Alkoxygruppe stehen, Y für ein verbrücktes Morpholin steht, das aus (a), (b) und (c) gemäß Anspruch 1 ausgewählt ist, n für 1 oder 0 steht und R2 für ein Wasserstoffatom steht, wenn n = 1, und für eine Methylgruppe steht, wenn n = 0, umfassend eine Hydrolysereaktion einer Verbindung der Formel Q

    in der Y für ein verbrücktes Morpholin steht, das aus (a), (b) und (c) ausgewählt ist, n für 0 oder 1 steht und R2 für ein Wasserstoffatom steht, wenn n = 1, oder für eine Methylgruppe steht, wenn n = 0, zum Erhalt einer Verbindung der Formel S

    in der Y für ein verbrücktes Morpholin steht, das aus (a), (b) und (c) gemäß Anspruch 1 ausgewählt ist, n für 1 oder 0 steht und R2 für ein Wasserstoffatom steht, wenn n = 1, oder für eine Methylgruppe steht, wenn n = 0, und eine Kupplungsreaktion zwischen einer Verbindung der Formel S und einer Verbindung der Formel HNR6R6', wobei R6 und R6' entweder verschieden sind und für eine Alkylgruppe und eine Alkoxygruppe stehen.
     
    18. Verbindungen der Formeln I, N, Q und S:

    und

    in denen n, R2 und Y wie in Anspruch 1 definiert sind.
     
    19. Medikament, dadurch gekennzeichnet, dass es eine Verbindung nach einem der Ansprüche 1 bis 12 oder ein Additionssalz dieser Verbindung mit einer pharmazeutisch akzeptablen Säure oder Base umfasst.
     
    20. Verbindung nach Anspruch 1 oder 2 als Medikament.
     
    21. Pharmazeutische Zusammensetzung, dadurch gekennzeichnet, dass sie eine Verbindung nach einem der Ansprüche 1 bis 12 oder ein pharmazeutisch akzeptables Salz dieser Verbindung sowie mindestens einen pharmazeutisch akzeptablen Exzipienten umfasst.
     
    22. Verwendung einer Verbindung nach einem der Ansprüche 1 bis 12 zur Herstellung eines Medikaments zur Behandlung von durch Parasiten induzierter Malaria.
     
    23. Verbindung nach Anspruch 1 oder 2 zur Verwendung bei der Behandlung von durch alle Arten von Plasmodium, wie P. falciparum, P. vivax, P. malariae, P. ovale und P. knowlesi, durch alle Arten von Trypanosoma und durch alle Arten von Leishmania induzierter Malaria, bei der Behandlung von Schlafkrankheit, bei der Behandlung von Chagas-Krankheit, der verschiedenen Formen von Leishmaniase und der Behandlung anderer parasitischer Infektionen, wie Schistosomiasis (Bilharziose), Toxoplasmose und Kokzidiose.
     


    Revendications

    1. Composé correspondant à la formule (I) :

    dans laquelle :



    n représente 0 ou 1 ;



    Y représente une morpholine pontée choisie parmi



    L représente un linker -CH2-CO- tel que la fonction carbonyle est liée au substituant R1, ou C1-2-alkyle, ledit alkyle étant éventuellement substitué par un ou plusieurs substituants choisis parmi un groupe C1-3-alkyle et un groupe hydroxyle ;



    R1 représente :

    - un groupe C1-5-alkyle linéaire, ramifié ou partiellement cyclique, éventuellement substitué par un ou plusieurs substituants choisis parmi un groupe hydroxyle, un groupe aryle et un groupe trifluorométhyle et un groupe C3-5-cycloalkyle,

    - un groupe C3-6-cycloalkyle, éventuellement substitué par un groupe hydroxyle,

    - un groupe aryle, éventuellement substitué par un ou plusieurs substituants choisis parmi un atome d'halogène, un groupe hydroxyle, un groupe cyano, un groupe -NH2, un groupe urée de formule -NH-CO-NH-C1-4-alkyle, un groupe morpholine, un groupe de formule -SO2-C1-5-alkyle, un groupe C1-5-alcoxy, ledit alcoxy étant éventuellement substitué par un ou plusieurs substituants choisis parmi :

    ∘ un atome d'halogène,

    ∘ un groupe hydroxyle ou un groupe C1-5-alcoxy,

    ∘ un groupe -COR3, dans lequel R3 représente un substituant choisi parmi un groupe hétérocycloalkyle et un groupe hydroxyle,

    ∘ un groupe -CONR4R4, dans lequel R4 et R4' sont tels que définis ci-dessous,

    ∘ un groupe -NR4R4' dans lequel R4 et R4' sont tels que définis ci-dessous,

    ∘ un groupe hétérocycloalkyle comprenant un ou deux hétéroéléments choisis parmi un atome d'azote et un atome d'oxygène,

    ∘ un groupe hétéroaryle éventuellement substitué par un ou plusieurs substituants choisis parmi un atome d'halogène, un groupe C1-3-alkyle, un groupe hydroxyle et un groupe -NH2;

    - un groupe hétéroaryle, comprenant un ou plusieurs hétéroatomes choisis parmi un atome d'azote, un atome de soufre et un atome d'oxygène, éventuellement substitué par un ou plusieurs substituants choisis parmi :

    ∘ un atome d'halogène,

    ∘ un groupe C1-3-alkyle éventuellement substitué par un ou plusieurs atomes d'halogène,

    ∘ un groupe C1-5-alcoxy, éventuellement substitué par un ou plusieurs substituants choisis parmi un atome d'halogène, un groupe C3-5-cycloalkyle, un groupe hétéroaryle éventuellement substitué par un ou plusieurs substituants choisis parmi un atome d'halogène, un groupe C1-3-alkyle, un groupe hydroxyle et un groupe -NH2,

    ∘ un groupe -NR5R5' dans lequel R5 et R5', indépendamment, identiques ou différents, représentent un substituant choisi parmi un atome d'hydrogène, un groupe -CO2-C1-3-alkyle, un groupe C3-5-cycloalkyle et un groupe C1-3-alkyle linéaire ou ramifié, ledit groupe alkyle étant éventuellement substitué par un ou plusieurs groupes hydroxyle,

    - un groupe pyridine portant deux groupes adjacents liés formant, conjointement avec les deux carbones qui les portent, un hétérocycle comprenant un atome d'azote et un atome d'oxygène,

    - un groupe hétérocycloalkyle comprenant un ou plusieurs hétéroatomes choisis parmi des atomes d'oxygène et d'azote, ledit atome d'azote étant éventuellement substitué par un substituant choisi parmi un groupe formyle, un groupe acétyle et un groupe-CO2-C1-4-alkyle,

    - un groupe -NR6R6' dans lequel R6 et R6', qui sont différents, représentent un groupe C1-5-alkyle et un groupe C1-5-alcoxy,



    R2 représente un atome d'hydrogène lorsque n représente 1 et un groupe méthyle lorsque n représente 0 ;



    R4 et R4', indépendamment, identiques ou différents, représentent un atome d'hydrogène ou un groupe C1-3-alkyle,

    à l'état de base ou de sel d'addition avec un acide ou avec une base.


     
    2. Composé de formule (I) selon la revendication 1, caractérisé en ce que :



    n représente 0 ou 1 ;



    Y représente une morpholine pontée choisie parmi



    L représente un linker -CH2-CO- tel que la fonction carbonyle est fixée au substituant R1, ou un C1-2-alkyle, ledit alkyle étant éventuellement substitué par un ou plusieurs substituants choisis parmi un groupe C1-3-alkyle et un groupe hydroxyle ;



    R1 représente :

    - un groupe C1-5-alkyle linéaire, ramifié ou partiellement cyclique, éventuellement substitué par un ou plusieurs substituants choisis parmi un groupe hydroxyle et un groupe aryle,

    - un groupe C3-6-cycloalkyle,

    - un groupe aryle, éventuellement substitué par un ou plusieurs substituants choisis parmi un atome d'halogène, un groupe hydroxyle, un groupe cyano, un groupe -NH2, un groupe urée de formule -NH-CO-NH-C1-4-alkyle, un groupe morpholine, un groupe de formule -SO2-C1-5-alkyle, un groupe C1-5-alcoxy, ledit alcoxy étant éventuellement substitué par un ou plusieurs substituants choisis parmi :

    ∘ un atome d'halogène,

    ∘ un groupe hydroxyle ou un groupe C1-5-alcoxy,

    ∘ un groupe -COR3, dans lequel R3 représente un substituant choisi parmi un groupe hétérocycloalkyle et un groupe hydroxyle,

    ∘ un groupe -CONR4R4, dans lequel R4 et R4' sont tels que définis ci-dessous,

    ∘ un groupe -NR4R4' dans lequel R4 et R4' sont tels que définis ci-dessous,

    ∘ un groupe hétérocycloalkyle comprenant un ou deux hétéroéléments choisis parmi un atome d'azote et un atome d'oxygène,

    ∘ un groupe hétéroaryle éventuellement substitué par un ou plusieurs substituants choisis parmi un atome d'halogène, un groupe C1-3-alkyle, un groupe hydroxyle et un groupe -NH2 ;

    - un groupe hétéroaryle, comprenant un ou plusieurs hétéroatomes choisis parmi un atome d'azote, un atome de soufre et un atome d'oxygène, éventuellement substitué par un ou plusieurs substituants choisis parmi :

    ∘ un atome d'halogène,

    ∘ un groupe C1-3-alkyle éventuellement substitué par un ou plusieurs atomes d'halogène,

    ∘ un groupe C1-5-alcoxy, éventuellement substitué par un ou plusieurs substituants choisis parmi un atome d'halogène, un groupe C3-5-cycloalkyle, un groupe hétéroaryle éventuellement substitué par un ou plusieurs substituants choisis parmi un atome d'halogène, un groupe C1-3-alkyle, un groupe hydroxyle et un groupe -NH2,

    ∘ un groupe -NR5R5' dans lequel R5 et R5', indépendamment, identiques ou différents, représentent un substituant choisi parmi un atome d'hydrogène, un groupe -CO2-C1-3-alkyle, un groupe C3-5-cycloalkyle et un groupe C1-3-alkyle linéaire ou ramifié, ledit groupe alkyle étant éventuellement substitué par un ou plusieurs groupes hydroxyle,

    - un groupe pyridine portant deux groupes adjacents liés formant, conjointement avec les deux carbones qui les portent, un hétérocycle comprenant un atome d'azote et un atome d'oxygène,

    - un groupe hétérocycloalkyle comprenant un ou plusieurs hétéroatomes choisis parmi des atomes d'oxygène et d'azote, ledit atome d'azote étant éventuellement substitué par un substituant choisi parmi un groupe formyle, un groupe acétyle et un groupe-CO2-C1-4-alkyle,

    - un groupe -NR6R6' dans lequel R6 et R6', qui sont différents, représentent un groupe C1-5-alkyle et un groupe C1-5-alcoxy,



    R2 représente un atome d'hydrogène lorsque n représente 1 et un groupe méthyle lorsque n représente 0 ;



    R4 et R4', indépendamment, identiques ou différents, représentent un atome d'hydrogène ou un groupe C1-3-alkyle,

    à l'état de base ou de sel d'addition avec un acide ou avec une base.
     
    3. Composé de formule (I) selon la revendication 1 ou 2, caractérisé en ce que :


    Y représente une morpholine pontée (a)

    à l'état de base ou de sel d'addition avec un acide ou avec une base.
     
    4. Composé de formule (I) selon la revendication 1 ou 2, caractérisé en ce que :



    n représente 0 ou 1 ;



    Y représente une morpholine pontée (a)



    L représente un linker -CH2-CO- tel que la fonction carbonyle est fixée au substituant R1, ou C1-2-alkyle, ledit alkyle étant éventuellement substitué par un ou plusieurs substituants choisis parmi un groupe C1-3-alkyle ;



    R1 représente :

    - un groupe C1-5-alkyle linéaire, ramifié ou partiellement cyclique, éventuellement substitué par un ou plusieurs substituants choisis parmi un groupe hydroxyle, un groupe aryle, un groupe trifluorométhyle et un groupe C3-5-cycloalkyle,

    - un groupe C3-6-cycloalkyle, éventuellement substitué par un groupe hydroxyle,

    - un groupe aryle, éventuellement substitué par un ou plusieurs substituants choisis parmi un atome d'halogène, un groupe hydroxyle, un groupe -NH2, un groupe urée de formule -NH-CO-NH-C1-4-alkyle, un groupe morpholinyle, un groupe de formule -SO2-C1-5-alkyle, un groupe C1-5-alcoxy, ledit alcoxy étant éventuellement substitué par un ou plusieurs substituants choisis parmi :

    ∘ un atome d'halogène,

    ∘ un groupe hydroxyle ou un C1-5-alcoxy,

    ∘ un groupe -COR3, dans lequel R3 représente un substituant choisi parmi un groupe hétérocycloalkyle et un groupe hydroxyle,

    ∘ un groupe hétérocycloalkyle comprenant un ou deux hétéroéléments choisis parmi un atome d'azote et un atome d'oxygène,

    ∘ un groupe hétéroaryle éventuellement substitué par un ou plusieurs substituants choisis parmi un atome d'halogène, un groupe C1-3-alkyle, un groupe hydroxyle et un groupe -NH2 ;

    - un groupe hétéroaryle, comprenant un ou plusieurs hétéroatomes choisis parmi un atome d'azote, un atome de soufre et un atome d'oxygène, éventuellement substitué par un ou plusieurs substituants choisis parmi :

    ∘ un atome d'halogène,

    ∘ un groupe C1-3-alkyle éventuellement substitué par un ou plusieurs atomes d'halogène,

    ∘ un groupe C1-5-alcoxy, éventuellement substitué par un ou plusieurs substituants choisis parmi un atome d'halogène, un groupe C3-5-cycloalkyle, un groupe hétéroaryle éventuellement substitué par un ou plusieurs substituants choisis parmi un atome d'halogène, un groupe C1-3-alkyle, un groupe hydroxyle et un groupe -NH2,

    ∘ un groupe -NR5R5' dans lequel R5 et R5', indépendamment, identiques ou différents, représentent un substituant choisi parmi un atome d'hydrogène, un groupe -CO2-C1-3-alkyle, un groupe C3-5-cycloalkyle et un groupe C1-3-alkyle linéaire ou ramifié, ledit groupe alkyle étant éventuellement substitué par un ou plusieurs groupes hydroxyle,

    - un groupe pyridine portant deux groupes adjacents liés formant, conjointement avec les deux carbones qui les portent, un hétérocycle comprenant un atome d'azote et un atome d'oxygène,

    - un groupe hétérocycloalkyle comprenant un ou plusieurs hétéroatomes choisis parmi des atomes d'oxygène et d'azote, ledit atome d'azote étant éventuellement substitué par un substituant choisi parmi un groupe formyle, un groupe acétyle et un groupe-CO2-C1-4-alkyle,

    - un groupe -NR6R6' dans lequel R6 et R6', qui sont différents, représentent un groupe C1-5-alkyle et un groupe C1-5-alcoxy,



    R2 représente un atome d'hydrogène lorsque n représente 1 et un groupe méthyle lorsque n représente 0 ;



    R4 et R4', indépendamment, identiques ou différents, représentent un atome d'hydrogène ou un groupe C1-3-alkyle,

    à l'état de base ou de sel d'addition avec un acide ou avec une base.
     
    5. Composé de formule (I) selon la revendication 1 ou 2, caractérisé en ce que :



    n représente 0 ou 1 ;



    Y représente une morpholine pontée (a)



    L représente un linker -CH2-CO- tel que la fonction carbonyle est fixée au substituant R1, ou C1-2-alkyle, ledit alkyle étant éventuellement substitué par un ou plusieurs substituants choisis parmi un groupe C1-3-alkyle ;



    R1 représente :

    - un groupe C1-5-alkyle linéaire, ramifié ou partiellement cyclique, éventuellement substitué par un ou plusieurs substituants choisis parmi un groupe hydroxyle et un groupe aryle,

    - un groupe C3-6-cycloalkyle,

    - un groupe aryle, éventuellement substitué par un ou plusieurs substituants choisis parmi un atome d'halogène, un groupe hydroxyle, un groupe -NH2, un groupe urée de formule -NH-CO-NH-C1-4-alkyle, un groupe morpholinyle, un groupe de formule -SO2-C1-5-alkyle, un groupe C1-5-alcoxy, ledit alcoxy étant éventuellement substitué par un ou plusieurs substituants choisis parmi :

    ∘ un atome d'halogène,

    ∘ un groupe hydroxyle ou un C1-5-alcoxy,

    ∘ un groupe -COR3, dans lequel R3 représente un substituant choisi parmi un groupe hétérocycloalkyle et un groupe hydroxyle,

    ∘ un groupe hétérocycloalkyle comprenant un ou deux hétéroéléments choisis parmi un atome d'azote et un atome d'oxygène,

    ∘ un groupe hétéroaryle éventuellement substitué par un ou plusieurs substituants choisis parmi un atome d'halogène, un groupe C1-3-alkyle, un groupe hydroxyle et un groupe -NH2 ;

    - un groupe hétéroaryle, comprenant un ou plusieurs hétéroatomes choisis parmi un atome d'azote, un atome de soufre et un atome d'oxygène, éventuellement substitué par un ou plusieurs substituants choisis parmi :

    ∘ un atome d'halogène,

    ∘ un groupe C1-3-alkyle éventuellement substitué par un ou plusieurs atomes d'halogène,

    ∘ un groupe C1-5-alcoxy, éventuellement substitué par un ou plusieurs substituants choisis parmi un atome d'halogène, un groupe C3-5-cycloalkyle, un groupe hétéroaryle éventuellement substitué par un ou plusieurs substituants choisis parmi un atome d'halogène, un groupe C1-3-alkyle, un groupe hydroxyle et un groupe -NH2,

    ∘ un groupe -NR5R5' dans lequel R5 et R5', indépendamment, qui peuvent être identiques ou différents, représentent un substituant choisi parmi un atome d'hydrogène, un groupe -CO2-C1-3-alkyle, un groupe C3-5-cycloalkyle et un groupe C1-3-alkyle linéaire ou ramifié, ledit groupe alkyle étant éventuellement substitué par un ou plusieurs groupes hydroxyle,

    - un groupe pyridine portant deux groupes adjacents liés formant, conjointement avec les deux carbones qui les portent, un hétérocycle comprenant un atome d'azote et un atome d'oxygène,

    - un groupe hétérocycloalkyle comprenant un ou plusieurs hétéroatomes choisis parmi des atomes d'oxygène et d'azote, ledit atome d'azote étant éventuellement substitué par un substituant choisi parmi un groupe formyle et un groupe acétyle,

    - un groupe -NR6R6' dans lequel R6 et R6', qui sont différents, représentent un groupe C1-5-alkyle et un groupe C1-5-alcoxy,



    R2 représente un atome d'hydrogène lorsque n représente 1 et un groupe méthyle lorsque n représente 0 ;



    R4 et R4', indépendamment, identiques ou différents, représentent un atome d'hydrogène ou un groupe C1-3-alkyle,

    sous forme de la base ou d'un sel d'addition avec un acide ou avec une base.
     
    6. Composé de formule (I) selon la revendication 1 ou 2, caractérisé en ce que :



    n représente 0 ou 1 ;



    Y représente une morpholine pontée choisie parmi (b) et (c)



    L représente un linker -CH2-CO- tel que la fonction carbonyle est fixée au substituant R1, ou C1-2-alkyle, ledit alkyle étant éventuellement substitué par un groupe hydroxyle ;



    R1 représente :

    - un groupe C1-5-alkyle linéaire ou ramifié, éventuellement substitué par un groupe aryle, ou un groupe hydroxyle,

    - un groupe aryle, éventuellement substitué par un ou plusieurs substituants choisis parmi un atome d'halogène, un groupe hydroxyle et un groupe C1-5-alcoxy, ledit alcoxy étant éventuellement substitué par un ou plusieurs substituants choisis parmi :

    ∘ un groupe -CONR4R4, dans lequel R4 et R4' sont tels que définis ci-dessous,

    ∘ un groupe -NR4R4' dans lequel R4 et R4' sont tels que définis ci-dessous,

    - un groupe hétéroaryle, comprenant un ou plusieurs hétéroatomes choisis parmi un atome d'azote, un atome de soufre et un atome d'oxygène, éventuellement substitué par un ou plusieurs groupes C1-3-alkyle, éventuellement substitués par un ou plusieurs atomes d'halogène,

    - un groupe -NR6R6' dans lequel R6 et R6', qui sont différents, représentent un groupe C1-5-alkyle et un groupe C1-5-alcoxy,



    R2 représente un atome d'hydrogène lorsque n représente 1 et un groupe méthyle lorsque n représente 0 ;



    R4 et R4', indépendamment, identiques ou différents, représentent un atome d'hydrogène ou un groupe C1-3-alkyle,

    à l'état de base ou de sel d'addition avec un acide ou avec une base.
     
    7. Composé selon la revendication 1 ou 2, caractérisé en ce que le linker L représente -CH2-CO, un groupe méthyle ou un groupe éthyle, à l'état de base ou de sel d'addition avec un acide ou avec une base.
     
    8. Composé selon la revendication 1 ou 2, caractérisé en ce que n représente 1, à l'état de base ou de sel d'addition avec un acide ou avec une base.
     
    9. Composé selon la revendication 1 ou 2, caractérisé en ce que n représente 0, à l'état de base ou de sel d'addition avec un acide ou avec une base.
     
    10. Composé selon la revendication 1 ou 2, caractérisé en ce que R1 représente un groupe C1-5-alkyle linéaire ou ramifié, éventuellement substitué par un groupe hydroxyle, un groupe hétéroaryle ou un groupe -NR6R6' dans lequel R6 et R6', qui sont différents, représentent un groupe C1-5-alkyle et un groupe C1-5-alcoxy, à l'état de base ou de sel d'addition avec un acide ou avec une base.
     
    11. Composé selon la revendication 1 ou 2, caractérisé en ce que R1 représente un groupe C1-5-alkyle linéaire ou ramifié, éventuellement substitué par un groupe hydroxyle, un groupe hétérocycloalkyle comprenant un ou plusieurs hétéroatomes choisis parmi des atomes d'oxygène et d'azote, ledit atome d'azote étant éventuellement substitué par un substituant choisi parmi un groupe formyle, un groupe acétyle et un groupe -CO2-C1-4-alkyle, ou un groupe -NR6R6' dans lequel R6 et R6', qui sont différents, représentent un groupe C1-5-alkyle et un groupe C1-5-alcoxy, à l'état de base ou de sel d'addition avec un acide ou avec une base.
     
    12. Composé selon la revendication 1 ou 2, caractérisé en ce qu'il est choisi parmi :

    1 (8S)-9-(2-méthyl-2-pyridin-4-ylpropyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    2 (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-oxo-2-pyridin-4-yléthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    3 (8S)-9-[2-(6-aminopyridin-3-yl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    4 (8S)-9-[2-(6-méthylpyridin-3-yl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    5 (8S)-9-[2-(6-méthylaminopyridin-3-yl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    6 (8S)-9-[2-(6-diméthylaminopyridin-3-yl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    7 (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-oxo-2-pyridin-3-yléthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    8 1-[2-(6-diméthylaminopyridin-3-yl)-2-oxoéthyl]-2-(S)-méthyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-trifluorométhyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one

    9 2-(S)-méthyl-1-[2-(6-méthylaminopyridin-3-yl)-2-oxoéthyl]-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-trifluorométhyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one

    10 (8S)-1-[2-(4-méthoxyphényl)éthyl]-2-méthyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-trifluorométhyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one

    11 (S)-1-[2-(6-aminopyridin-3-yl)-2-oxoéthyl]-2-méthyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-trifluorométhyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one

    12 (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-pyridin-3-yléthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    13 2-méthyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1-(2-pyridin-3-yléthyl)-2-((S)-trifluorométhyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one

    14 (8S)-9-{2-[6-(2-hydroxyéthylamino)pyridin-3-yl]-2-oxoéthyl}-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    15 (8S)-9-[2-(5-méthylpyridin-3-yl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    16 2-méthyl-1-[2-(5-méthylpyridin-3-yl)-2-oxoéthyl]-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-((S)-trifluorométhyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one

    17 2-méthyl-1-[2-(6-méthylpyridin-3-yl)-2-oxoéthyl]-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-trifluorométhyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one

    18 2-méthyl-1-[2-(2-méthylpyridin-3-yl)-2-oxoéthyl]-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-((S)-trifluorométhyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one

    19 (8S)-9-[2-(2-méthylpyridin-3-yl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    20 (8S)-9-[2-(4-méthylpyridin-3-yl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    21 2-méthyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1-(2-oxo-2-pyridin-3-yléthyl)-2-((S)-trifluorométhyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one

    22 (8S)-9-[2-(6-cyclopropylaminopyridin-3-yl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    23 1-éthyl-3-{4-[2-((S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluorométhyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)éthyl]phényl}urée

    24 1-éthyl-3-{4-[2-((S)-2-méthyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-5-oxo-2-trifluorométhyl-2,3-dihydro-5H-imidazo[1,2-a]pyrimidin-1-yl)éthyl]phényl}urée

    25 (8S)-9-[2-(4-méthylthiazol-5-yl)éthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    26 2-méthyl-1-[2-(4-méthylthiazol-5-yl)éthyl]-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-((S)-trifluorométhyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one

    27 (8S)-9-[2-(3,5-diméthyl-1H-pyrazol-4-yl)éthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    28 1-[2-(3,5-diméthyl-1H-pyrazol-4-yl)éthyl]-2-méthyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-((S)-trifluorométhyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one

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

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

    31 (8S)-9-[2-(6-amino-5-méthylpyridin-3-yl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    32 1-[2-(4-aminophényl)éthyl]-2-méthyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-((S)-trifluorométhyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one

    33 (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-oxo-2-(6-trifluorométhylpyridin-3-yl)éthyl]-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    34 (8S)-9-(2-{6-[(2-hydroxyéthyl)méthylamino]pyridin-3-yl}-2-oxoéthyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    35 (8S)-9-[2-(6-éthoxypyridin-3-yl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    36 (8S)-9-[2-(6-amino-4,5-diméthylpyridin-3-yl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    37 (S)-9-[2-(4-difluorométhoxyphényl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    38 (8S)-9-[2-(3,4-dihydro-2H-pyrido[3,2-b] [1,4]oxazin-7-yl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    39 (8S)-9-[2-(4-méthyloxazol-5-yl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    40 (S)-9-[2-(3,4-difluorophényl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    41 (8S)-9-[2-(4-morpholin-4-ylphényl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    42 4-[2-((S)-8-(lS,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluorométhyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acétyl]benzonitrile

    43 (8S)-9-[2-(4-méthylthiazol-5-yl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    44 (8S)-9-[2-(5-chloropyridin-3-yl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    45 (8S)-9-[2-(6-méthoxypyridin-3-yl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    46 (8S)-9-[2-(3-méthylisoxazol-4-yl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    47 (8S)-9-(2-benzo[1,2,3]thiadiazol-5-yl-2-oxoéthyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    48 (8S)-9-[2-(2,4-difluorophényl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

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

    50 (8S)-9-(3-hydroxy-3-méthylbutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    51 (8S)-9-(1-méthyl-1H-indazol-3-ylméthyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    52 (8S)-9-[2-(2-cyclopropylméthoxypyrimidin-5-yl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    53 (8S)-9-[2-(3,5-diméthylisoxazol-4-yl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

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

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

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

    57 {5-[2-((S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluorométhyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acétyl]pyridin-2-yl}carbamate d'éthyle

    58 {5-[2-((S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluorométhyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acétyl]pyridin-2-yl}carbamate de méthyle

    59 (8S)-9-(5-méthyl-[1,2,4]oxadiazol-3-ylméthyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    60 (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-oxo-2-(2-trifluorométhylpyridin-3-yl)éthyl]-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    61 (8S)-9-(2-benzo[1,2,5]thiadiazol-5-yl-2-oxoéthyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    62 (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-oxo-2-(tétrahydropyran-4-yl)éthyl]-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    63 (8S)-9-{2-[6-(2-fluoroéthoxy)pyridin-3-yl]-2-oxoéthyl}-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    64 (8S)-9-{2-[3-fluoro-4-(2-fluoroéthoxy)phényl]-2-oxoéthyl}-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    65 (8S)-9-[2-(2-méthoxypyridin-3-yl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    66 (8S)-9-[2-(3-méthyl-3H-imidazol-4-yl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    67 (8S)-9-(2-cyclopropyl-2-oxoéthyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    68 (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-oxo-2-pyridin-2-yléthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    69 (8S)-9-[2-(2-méthyl-2H-pyrazol-3-yl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    70 N,N-diméthyl-2-(4-{2-[(S)-2-méthyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-oxo-2-trifluorométhyl-2,3-dihydro-5H-imidazo[1,2-a]pyrimidin-1-yl]éthyl}phénoxy)acétamide

    71 (8S)-9-[(S)-2-(4-fluoro-2-méthoxyphényl)-2-hydroxyéthyl]-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    72 (2S)-1-[2-(4-hydroxyphényl)éthyl]-2-méthyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-trifluorométhyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one

    73 (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-phényléthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    74 (2S)-1-{2-[4-(2-diméthylaminoéthoxy)phényl]éthyl}-2-méthyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-trifluorométhyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one

    75 (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-pyridin-4-yléthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    76 (S)-1-[2-(4-méthoxyphényl)éthyl]-2-méthyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-trifluorométhyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one

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

    78 (S)-1-{2-[4-(3-diméthylaminopropoxy)phényl]éthyl}-2-méthyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-trifluorométhyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one

    79 (2S)-1-((S)-2-hydroxy-2-phényléthyl)-2-méthyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-trifluorométhyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one

    80 (8S)-9-((S)-2-hydroxy-2-phényléthyl)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    81 (8S)-9-[2-(4-méthoxyphényl)éthyl]-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    82 (8S)-9-((R)-2-benzo[b]thiophén-2-yl-2-hydroxyéthyl)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    83 (8S)-9-[2-(4-hydroxyphényl)éthyl]-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    84 (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(3-phénylpropyl)-8-trifluorométhylméthyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    85 (8S)-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-9-(2-oxo-2-pyridin-3-yléthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    86 (8S)-9-(1-difluorométhyl-1H-pyrazol-3-ylméthyl)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    87 (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-pyridin-3-yléthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    88 (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-pyridin-2-yléthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    89 (S)-9-[2-(1-acétylpipéridin-4-yl)éthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[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-trifluorométhyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)éthyl]pipéridine-1-carbaldéhyde

    91 4-[2-((S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluorométhyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acétyl]pipéridine-1-carboxylate d'éthyle

    92 (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-(tétrahydropyran-4-yl)éthyl]-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    93 (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(tétrahydropyran-4-ylméthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    94 (8S)-9-(1-acétylpipéridin-4-ylméthyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[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-trifluorométhyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-ylméthyl)pipéridine-1-carbaldéhyde

    96 (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(3,3,3-trifluoro-2-hydroxy-2-trifluorométhylpropyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    97 (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(4,4,4-trifluoro-3-hydroxy-3-trifluorométhylbutyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    98 (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-oxoéthyl]-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    99 (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoéthyl]-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    100 (8S)-9-[2-(1-hydroxycyclopentyl)éthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

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

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

    103 (8S)-9-(2,2-dicyclopropyl-2-hydroxyéthyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

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

    105 (8S)-9-[2-(1-hydroxycyclopropyl)éthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    106 (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-quinoléin-5-ylméthyl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    107 (8S)-9-[2-(3-méthylisothiazol-4-yl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    108 (8S)-9-[2-(4-méthanesulfonylphényl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    109 (8S)-9-isoquinoléin-5-ylméthyl-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    110 (8S)-9-(2-morpholin-4-yl-2-oxoéthyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    111 (8S)-9-{2-[4-(2-morpholin-4-yléthoxy)phényl]éthyl}-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    112 N-méthoxy-N-méthyl-2-((S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluorométhyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acétamide

    113 (8S)-9-(2-imidazo[1,2-a]pyridin-6-yl-2-oxoéthyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    114 (8S)-9-[2-(6-difluorométhoxypyridin-3-yl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    115 (S)-9-{2-[4-(2-morpholin-4-yl-2-oxoéthoxy)phényl]éthyl}-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    116 (8S)-9-(1-méthyl-3-trifluorométhyl-1H-pyrazol-4-ylméthyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    117 (8S)-9-{2-[4-(2-diméthylaminoéthoxy)phényl]éthyl}-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    118 4-[2-((S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluorométhyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acétyl]pipéridine-1-carbaldéhyde

    119 (8S)-9-[2-(1-acétylpipéridin-4-yl)-2-oxoéthyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one

    à l'état de base ou de sel d'addition avec un acide ou avec une base.
     
    13. Procédé pour la préparation d'un composé de formule (I) selon l'une quelconque des revendications 1 à 12, comprenant la réaction d'un composé de formule E

    dans laquelle n représente 0 ou 1 et R2 représente un atome d'hydrogène lorsque n = 1 ou un groupe méthyle lorsque n = 0, avec une morpholine pontée Y, choisie parmi (a), (b) et (c) telle que définie dans la revendication 1, pour obtenir un composé de formule I

    et la réaction d'alkylation par addition à I d'un composé de formule J = R1-L-Lg dans laquelle R1 et L sont tels que définis selon l'une quelconque des revendications précédentes et Lg est un groupe partant.
     
    14. Procédé pour la préparation d'un composé de formule (I) selon l'une quelconque des revendications 1 à 12, comprenant la réaction d'alkylation d'un composé de formule E

    dans laquelle n représente 0 ou 1 et R2 représente un atome d'hydrogène lorsque n = 1 ou un groupe méthyle lorsque n = 0, par addition d'un composé de formule J = R1-L-Lg dans laquelle R1 et L sont tels que définis selon l'une quelconque des revendications 1 à 8 et Lg est un groupe partant, pour obtenir un composé de formule K

    dans laquelle R1, R2, L et n sont tels que définis selon l'une des revendications 1 à 8, et une réaction sur un composé K avec un composé de formule Y qui est une morpholine pontée choisie parmi (a), (b) et (c) telle que définie dans la revendication 1.
     
    15. Procédé pour la préparation d'un composé de formule (I) selon l'une quelconque des revendications 1 à 12, dans lequel le linker L est un groupe éthyle, R1 est un groupe C1-5-alkyle linéaire ou ramifié substitué par un groupe hydroxyle, Y représente une morpholine pontée choisie parmi (a), (b) et (c) telle que définie dans la revendication 1, n représente 1 ou 0, R2 représente un atome d'hydrogène lorsque n = 1 et un groupe méthyle lorsque n = 0, comprenant une réaction d'addition de Michael d'un composé de formule I

    dans laquelle n représente 0 ou 1 et R2 représente un atome d'hydrogène lorsque n = 1 ou un groupe méthyle lorsque n = 0, sur un composé de formule M = CH2=CH-CO2Alkyl, pour obtenir un composé de formule N,

    dans laquelle n représente 0 ou 1 et R2 représente un atome d'hydrogène lorsque n = 1 ou un groupe méthyle lorsque n = 0, et Y est une morpholine pontée choisie parmi (a), (b) et (c) telle que définie dans la revendication 1,
    et une réaction d'alkyle sur un composé de formule N avec un composé de formule O = Z-Mg-X dans laquelle Z représente un radical alkyle linéaire ou ramifié et X est un atome d'halogène.
     
    16. Procédé pour la préparation d'un composé de formule (I) selon l'une quelconque des revendications 1 à 12, dans lequel le linker L est un groupe méthyle, R1 est un groupe C1-5-alkyle linéaire ou ramifié substitué par un groupe hydroxyle, Y représente une morpholine pontée choisie parmi (a), (b) et (c) telle que définie dans la revendication 1, n représente 1 ou 0, et R2 représente un atome d'hydrogène lorsque n = 1 et un groupe méthyle lorsque n = 0, comprenant une réaction d'addition d'un composé de formule I

    dans laquelle n représente 0 ou 1 et R2 représente un atome d'hydrogène lorsque n = 1 ou un groupe méthyle lorsque n = 0, avec un composé de formule P = X-CH2-CO2Alkyl, X étant un atome d'halogène, pour obtenir un composé de formule Q

    dans laquelle Y est une morpholine pontée choisie parmi (a), (b) et (c), n représente 0 ou 1 et R2 représente un atome d'hydrogène lorsque n = 1 ou un groupe méthyle lorsque n = 0,
    et une réaction d'alkylation sur un composé de formule Q avec un composé de formule O = Z-Mg-X dans laquelle Z représente un radical alkyle linéaire ou ramifié et X est un atome d'halogène.
     
    17. Procédé pour la préparation d'un composé de formule (I) selon l'une quelconque des revendications 1 à 12, dans lequel le linker L est un groupe CH2-CO-, R1 est un groupe -NR6R6', R6 et R6' étant soit différents et représentant un groupe alkyle et un groupe alcoxy, Y représente une morpholine pontée choisie parmi (a), (b) et (c) telle que définie dans la revendication 1, n représente 1 ou 0, et R2 représente un atome d'hydrogène lorsque n = 1 et un groupe méthyle lorsque n = 0, comprenant une réaction d'hydrolyse d'un composé de formule Q

    dans laquelle Y est une morpholine pontée choisie parmi (a), (b) et (c), n représente 0 ou 1 et R2 représente un atome d'hydrogène lorsque n = 1 ou un groupe méthyle lorsque n = 0, pour obtenir un composé de formule S

    dans laquelle Y représente une morpholine pontée choisie parmi (a), (b) et (c) telle que définie dans la revendication 1, n représente 1 ou 0 et R2 représente un atome d'hydrogène lorsque n = 1 ou un groupe méthyle lorsque n = 0, et une réaction de couplage entre un composé de formule S et un composé de formule HNR6R6', R6 et R6' étant soit différents et représentant un groupe alkyle et un groupe alcoxy.
     
    18. Composés de formules I, N, Q et S :

    et

    dans lesquelles n, R2 et Y sont tels que définis dans la revendication 1.
     
    19. Médicament, caractérisé en ce qu'il comprend un composé selon l'une quelconque des revendications 1 à 12, ou un sel d'addition de ce composé avec un acide ou une base pharmaceutiquement acceptable.
     
    20. Composé selon la revendication 1 ou 2, en tant que médicament.
     
    21. Composition pharmaceutique, caractérisée en ce qu'elle comprend un composé selon l'une quelconque des revendications 1 à 12, ou un sel pharmaceutiquement acceptable de ce composé, et également au moins un excipient pharmaceutiquement acceptable.
     
    22. Utilisation d'un composé selon l'une quelconque des revendications 1 à 12, pour la préparation d'un médicament pour le traitement de la malaria induite par un parasite.
     
    23. Composé selon la revendication 1 ou 2, pour son utilisation dans le traitement de la malaria induite par toutes les espèces de Plasmodium, telles que P. falciparum, P. vivax, P. malariae, P. ovale et P. knowlesi, par toutes les espèces de Trypanosoma et par toutes les espèces de Leishmania, dans le traitement de la maladie du sommeil, le traitement de la maladie de Chagas, les diverses formes de leishmaniose et le traitement d'autres infections parasitaires, telles que la schistosomiase (bilharziose), la toxoplasmose et la coccidiose.
     






    Cited references

    REFERENCES CITED IN THE DESCRIPTION



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    Patent documents cited in the description




    Non-patent literature cited in the description