WO2017025695A1 - Azetidine carboxylic compounds for treating diseases involving the nurr1 nuclear receptors - Google Patents

Abstract

The invention concerns the compounds of formula (l) in which W, X, Y, Z and Het are as defined in the description. The compounds of formula (I) are modulators of the NURR1 receptor.

Description

 AZETIDINE CARBOXYLIC COMPOUNDS FOR THE TREATMENT OF DISEASES INVOLVING NURR-1 NUCLEAR RECEPTORS

The present invention relates to novel compounds of the asetidinecarboxylic type, and their method of preparation and their uiilisatkai as active ingredient of drugs, especially for the treatment or prevention of diseases involving JRR-1 nuclear receptors.

Art aterfeer

The nuclear receptor NURR-1. is expressed primarily in the central nervous system especially in the substantia nigra, the ventral zone of the integument, in the middle brain and iimbic zones where it plays an important role in the enamerican system (Law et al, 1992; S ucedo-Cardenas 1996, Zetterstrom et al., 1996a, Zetterstrom et al., 1996b). Moreover, it is also highly expressed in the olfactory bulb, hippocampus ^■ 1, temporal cortex you, the cerebellum and the posterior hypothalamus. In patients with Parkinson's disease the expression of NURR-1 is decreased in dark substance neurons that contain alpka-synueinin inclusions (Chu e al., 2006). Similarly, a decrease in the expression of NURR-Î is observed in neurons containing neurofibrillary tangles of Tau protein in patients with Aisheirner disease (Chu et al., 2006). The modulation of NURR-1 expression is also shown in other diseases of the central nervous system such as progressive supranuclear palsy, cocaine and heroin addiction, schizophrenia, bipolar disorder (Baanon et al. 2002: Xing et al., 2006; Horwath et al., 200, Nieisen et al., 2008). Of course, several genetic polymorphisms of the gene encoding NURR-I have been shown to be associated with various diseases of the nervous system. central as Farkmsom's disease schizophrenia and bipolar disorder (Buervenich et al, 2000; Chen et al, 2001, Zheng et al., 2003; Chen et al., 2007; Lia et al, 2013).

There is considerable evidence that NURR-1 is essential for the development, migration, and survival of dopaniinergic neurons (Chang et al, 2002, Im et al, 2002, Sonntag et al, 2004). The mice whose gene encoding NURR-1 was invalidated are not viable after birth, in particular due to a lack of generation of dopammergic neurons of the mesenterphalon (Zeissersrrn et al., 1986; Saucedo-Cardenas 1986). heterozygotes, expressing a reduced amount of NURR-1, show a significant decrease in the level of dopamine in the striatum and a reduction in the number of doped neurons in the substantia nigra and a decrease in the expression of certain marker genes of dopamiaergic neurons such as tyrosine hydroxylase (Imam et al., 2005, Le et al., 1999a). These heterozygous mice also show symptoms found in schizophrenia such as Iryperactiitis when they are placed in a new environment, a deficiency of emotional memory and an exaggerated response in the forced swimming test (all these symptoms being associated with "failing"). in the "dopaminergic rotransmission" (Rojas et al., 200, Ycdliermot et al., 2001). Tyrosine Hydroxylase is the emeyme responsible for the synthesis of catecholamines such as dopamine, xiorepinephrine and epinephroma. Eatechol amines in. In general, dopamine has played an important role in the mechanisms of locomotion, as well as in behavioral disorders such as learning and reward. Catastrophic deficiency is observed in many central nervous system pathologies such as Parkinson's disease. Farkiason, bipolar disorder, manic behaviors, depression, cogsitife disorders and schizophrenia.

 JRR-Ï also contributes to the maintenance and the. survival of mature dopaninergic neurons. Indeed, the mice heterozygous for the gene coding for NURR-1 are more sensitive to neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetralihydropyridine (MPTP) and the analogous hydroxylide of dopamine (6). OH-DA). to roastamphetamine psychostatinemia, to the proteasome inhibitor laciacystine (Le et al., 1999b, Li et al., 2007, Luo et al., 2010, Pan et al., 2008). On the other hand, the overexpression of NURR-1 makes it possible to protect the neurons from the death induced not only by these different stressors but also by the overexpression of ralpha-synucism (Decressao et al., 2012). It is important to note that these different stressors induce the death of neurons by mechanisms involving the alteration of myocardial function. oxidative stress, excitotoxicity and alteration of protein degradation, but these mechanisms are involved in the pathophysiology of many neurodegenerative diseases such as Parkiason's disease. Alzheimer's disease, Cre tzfeldt-Jakob disease, Hi tirsgton's disease, iysosoma diseases, progressive supranuclear palsy and amyotrophic lateral sclerosis.

NURR-1 acts not only directly on neurons to induce their survival but also acts indirectly on the cells responsible for inflammation. Indeed, the death of neurons in neirrodegenerative pathologies is most often associated with various inflammatory markers such as Faciivaiioa and the proliferation of microglia and astrocytas, a lymphocyte infiltration and an increase in the rate of pro-inflammatory mediators as per example NO, OS, TF, ILP and 11.6. in In vitro and in vivo, decreased expression of NURR-1 leads to hypersensitivity to pro-inflammatory agents, which is accompanied by an increase in immunohistochemistry (activated microglia). increased rate of mediators of Ffaxaxioni) and increased dopaurinergic neuron death (Saijo et al., 2009). This effect of URR-I on inactivation is not only observed in the central nervous system, but also in the periphery. Indeed outside the central nervous system, NURR-1 is expressed in macrophages and T lymphocytes. NURR-1 inhibits the production of mediators of inflammation by macrophages and would have a protective role against the formation of atheroma plaques seen in Atherosclerosis {Sonia et al., 2006). Recently, the role of NURR-1 in the diritentiatioa and functionality of regulatory T cells (Treg) has been demonstrated (Sekiya et al., 201, Sekiya et al., 2013), Tregs participate in immune tolerance by regulating effector T cells by their muaosuppressive action. They are essential for tolerance to self antigens, and non-dangerous antigens. Activation and / or expansion of Tregs is a promising therapeutic approach for the treatment of in -mammatory diseases such as multiple sclerosis, Crohn's disease, rheumatoid arthritis, lupus, psoriasis, Guiilain-Barre, or Addrson's disease.

NURR -1 belongs to. a family of transcription factors, called nuclear receptors. Crystal studies have put in. evidence that the hydrophobic pocket normally occupied by the ligands in the nuclear receptors was clogged with hydrophobic amino acid side chain moieties and thus would not allow the binding of endogenous ligands or. exogenous (Wang and ah, 2003). One of the modes of regulation of gene transcription by the NURR-1 receptor is through its binding to consensus sequences contained in the promoters of the genes. N URR-1 binds to these consensus sequences as monomers or hornodimers and in this case behaves as an active constitutive transcription factor (La and ah, 1992, Philips et al., 1997). However, NURR-1 can also form heterodimers with another type of nuclear receptor, the RXR receptors at the rexmoid (Perimann et al., 1995, Saecherti et al., 2002, Walién-Maekenzie et al., 2003). This receptor subfamily comprises 3 members: X ^' R-alpha, RXR-beta and RXE-gamma. These receptors are highly homologous and activated by the enteric acid derivatives (9eis retinoic acid). The interaction of NURR-1 with RXR inhibits the constitutive activity of NURR-1 and allows the creation of a complex that becomes sensitive to the action of ligands of RXR.Identification of compounds capable of modulating the activity of NURR-1 RXRa and NURE-1 RXRy complexes should result in new avenues for the treatment or prevention of diseases that duplicate the receptor.

NlJRR-.

Object of ri vemios

The invention of new compounds object is capable of modulating ^the activity of L¾.R complex - ./ B.XRa and NURR-i KXRy.

 According to a first aspect, the present invention relates to the compounds of the azetidine-3-carboxylic type of formula (I), or their pharmaceutically acceptable salts:

in which :

W, X, Y and Z are each independently CR ₅ or N, with the proviso that at least one and at most three of said substituents W, X, Y if Z represent. NOT :

R: represents H or a (C 1 -C) alkyl;

Het represents "a heterocycle having 5 to 15 members optionally substituted by 1 to 4 substituents selected from: \ (C _{r C:)} ^lk; ie optionally substituted with; I to 3 halogen (s). a cycloalkyl group, a 7-membered S-linked heterocycle, a phenyl or a group - R ₂ R _{2 .} ; a (CC ₄ ) alkoxy optionally substituted with I to 3 halogens (s); a (CC cye1 aIkyie; a phényk nn halogen; a -NE ₄ R ₅ group; a -CONB4R _5; UTI -S <¾R ₆ and oxo;

and R ;; are each independently hydrogen or a (C ₄ ) alkyloxy optionally substituted with a (C ₁ -C ₄ ) alkoxy;

R ₄ and, are each independently hydrogen or ua. (CC ₄ ) alkyl;

R ₆ represents a (C 1 R), a phenyl or a group -NR 4 R 5.

According to a second aspect, the invention relates to the compounds of formula (I) as defined above, or their pharmaceutically acceptable salts, for their use as a medicament, especially in the treatment or prevention of diseases in which the receptor URR- ^' i is involved, especially diseases neurodegenerative diseases, such as Parkinson 's disease or Alzheimer ^{' s} disease, tauopathies such as rio - leraporaia dementia. diseases of the central nervous system and in particular those involving deregulation of the dopamiaergic system. as disease For n set, the disease of restless legs, the sapraimcièaire progressive paralysis, spinal amyotrophy ^lateral, Reit syndrome, schizophrenia, bipolar disorder, manic behavior, depression and .the eognitifs disorders, inflammatory diseases such as vasculary diseases such as atherosclerosis, inflammatory diseases such as rheumatoid arthritis, Crotei's disease, psoriasis, air-immune diseases such as multiple sclerosis, lupus, psoriasis Advantageously, the compounds of the invention are particularly suitable for use in the treatment or prevention of neurodegenerative diseases such as, for example, Parkinson's disease or Alzheimer's disease.

According to the third aspect; the invention relates to a pharmaceutical composition containing fi) a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, and (ii) one or more acceptable excipients also ^a pharmaceutical point of view.

According to a fourth aspect, the invention relates to the use of a compound of formula (!) As defined above, or one of its pharmaceutically acceptable salts, as an active principle for the preparation ^of a a medicament for the treatment of diseases in which the NlJRR-1 receptor is involved, especially the above-mentioned diseases and especially neurodegenerative diseases such as, for example, Parkinson's disease or Aiz eimer's disease.

 According to a fifth aspect, the invention relates to a method of treating diseases in which the NURR-1 receptor is involved, including the aforementioned diseases and especially neurodegenerative diseases such as for example Parkinson's disease or Alzheimer's disease, said method comprising administering to a patient in need of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such a compound.

BeseriptioB detailed

By "aikyie" is meant a saturated hydrocarbon chain which may be linear or branched. For example and without limitation, an alkyl group having 1 to 4 carbon atoms carbon may be a metfryk, etbyk, propyie, baryte, I-methylethyldi, 1-ethylpropyl, 2-ethylpropyl or 1,1-dimethylethyl.

The term "halogen" means an atom of bromine, fluorine or chlorine.

The term "alkyl substituted with 1 to 3 halogen atoms" means an alkyl group as defined above in which one or more hydrogen atoms is (are) replaced by one or more stomefs). 'halogen. By way of example, mention may be made of diRuoro ethyl or trifluoromethyte groups.

 The term "aleoxy" means a group OR in which is an alkyl group as defined above. For example and without limitation, a. Alkoxy group having 1 to 4 carbon atoms may be methoxy, ethoxy, propoxy, butoxy, 1-methyl-1-methyl, 1, 1-dimethylethoxy, 1-methylpropoxy, or 2-methoxypropoxy.

The term "aleoxy substituted with 1 to 3 halogen atoms" is understood to mean an aleoxy group as defined above in which one or more hydrogen atoms is (are) replaced by a. (des) atom (s) ^halogen. By way of example, mention may be made of the rifluoromethyl group.

 The term "cycloalkyl" is intended to mean a cyclic saturated hydrocarbon chain. By way of example of a cycloalkyl group having from 3 to 6 carbon atoms, mention may be made of the hydropropyl, cyclobutyl, cyclopropyl or cyclohexyl groups.

E faétêroeycie is meant having from 5 to 7 members "monocycle saturated, unsaturated or partially insarurè eomprenaot from 1 to 3 heteroatoms, preferably 1 or 2 héteroaion are selected from the thee az, ^oxygen and sulfur. As an example of unmatured unicycle, or may be mentioned pyrrolyl groups. pyrazeiyl, imidszolyk, oxazolite, isoxazolyl, triazolite, oxadiazolyl, uranyia, tyne, thiaxolyte, isothiazolyl, tladiazolyl, pyridyl. pyridazinyl, pyriu dinyl, pyrazitryte, triazinyk, azepiayle, oxepinyie or tuiepirryle. As examples of saturated monocycle, there may be mentioned pyrrolidinyie, tetrahydrofuryl, tetralrydroihienyl, pyrrolidyl yie, hrddazolidinyk, tkiaaoildiayle. isoxazolidinyl, piperidinyl, piperaziryl, snorpholinyl, thiomorpholinyl, or hexafaydroazepiayie. As an example of a partially unsaturated unicycle, mention may be made of the di (hydroxyl) oxazole group.

By "heterocyck having 5 to 15 members" is meant a cyclic, bicyclic or heterocyclic group, optionally fused, unsaturated or partially unsaturated, comprising from 1 to 4 heteroanomas, preferably from 1 to 3 heteroatoms, and more preferably 1 or 2. heteroatoms, selected from nitrogen, oxygen and sulfur, as examples, for example, pyrrolyl, pyrazolyl, iridazolyl, oxazolyl, isoxazolyl, inazol, oxadiazolyl, furanyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl pyridyl, pyndazinyl, pyrimidazole, pyrazinyl, iriazinyl, isoquinyl, quinol, 1,4-dihydroxybutyl, 2-dihydroquinolinyk.

iH.-pvTro1o [3 _s 2-b] _pyridj.nyle? benzyl idazolyl, beozopyrazinyk, indolyl, 2,3-dihydromdolyl, indolyryl, benzofuranyl, 2,3-dihydro-hemi-muranyf, benzothiazolyl, benzothiadiazolyl, beazisoxazoly, 3,4-dihydro-1, -benzoxaayk, 2.4 ~; dÛ3ydro- l, 4- benzoxazinyl, î, 3-bena; odioxolyle _s 23 ~ _{dihydrobenzodiaxmyie;} imidazothiazolyl benzoxaiiolyk, euzoxazinyle, 4,5-dibydro 5> _s 2 enzoxa2éprnyie iihydropyrido [4,3-h} [l _s 4] oxadnyk,

## STR2 ## wherein: spiro [cyclopentan-1, 3-indol] ine] -yl, spiro-indoline-3,3'-tetrahydrofulen-1-yl, spuO [indole-33] ^; - hydropyran] -yl ₅ dibydrc ^? ciopropa [bjindol-2-yl, hexahydroearbazolyl, etfahydrocarbazolyie, dihydracarbazole or {ebabydrocycl penta [b] indol-4-yk.

 The compounds of formula (I) can be used in the form of free acids or in the form of salts or in the form of anrides or esters, said salts being obtained by combining Paeide with a mineral or organic base not toxic, preferably pharmaceutically acceptable. Among the mineral bases, it is possible to use, for example, hydroxides of sodium, potassium, magnesium or calcium. Among the organic bases, it is possible to use, for example, amines, ammoakois, basic amino acids such as lysine or arginine or compounds bearing a quaternary ammonium function such as, for example, bétasse or choline. The salts of the ibraric acid (I) with a mineral or organic base can be obtained in a conventional manner, using the methods well known to those skilled in the art, for example by mixing st &bgr; ) and the base in one. solvent, such as for example water or a hydro-icylic mixture, and then lyophilizing the solution obtained.

 A first preferred family of compounds according to the invention corresponds to formula (I) in which one of the substituents W, X, Y and Z represents N, and the three others each represent CR :.

Another preferred family of compounds according to the invention corresponds to formula (I) in which two of the substituents W, X, Y and Z represent N, and the two others each represent CRj.

Another preferred family of compounds according to the invention corresponds to formula 01):

which:

W; _; Y and Z are as defined above for the compounds of formula II);

Hei represents a 5 to 15-membered heterocycle optionally substituted with 1 to 4 (C ₁ -C ₄ ) alkyl (s) optionally substituted with 1 to 3 C halogen.

 A preferred subfamily of the compounds of formula (II) is that for which ¾ is H.

 Another preferred sub-fanai of the compounds of formula (II) is that for which Het is a 5- to 12-membered, optionally substituted aryl ether having 1-4 (CrQ) alkyl (s) optionally substituted with 1 to 3 halogenated (s).

 As particularly preferred compounds, mention may be made of the following compounds:

l- 6 ~ 2,2 Hmettyl-7- (t)

pyridyloxyacetyl-3-carboxygenase;

acid l ~ [4- [2,2-Dimet yl-7 tri.fluoromét ^'hyl) -3H-1 4-benzoxazin-4-yl] "2- pyridyl] ^{azetidine-3-carbo'} xylique;

acid

pyridyijazétidiae-S-carboxylic acid;

sodium carboxylate;

] - 2- 2 _i 2 "dimetb.yi - 7.- ùifii orometh

3-sodium arboxylate;

! ^pyridyl] azéudine ~ 3 ~ carboxy ate tert-butyl ammonium;

pyridin-3-carboxylic acid-3-carboxylic acid ester;

 Sodium 1 - [2 - [2, 2, 3-methyl] -7- (trifluoromethyl) -1H-dihydro-4-benzoxazin-4-yl] -4-yl] azetidimid-3-carboxylate;

] 6-i7 ~ i60propyi-2, 2-ri: metbyi-3 ₅ 4 ~ dibydiXf-i ^ - beK20xasin - 5-yl) - 2 ^ yridyi] 3 ëîidiae-3-- sodium earboxylate; and the optional pharmaceutically acceptable salts of these compounds.

The syntheses described hereinafter, including in the preparations and examples, illustrate methods of preparing the compounds of formula (I). In these syntheses, the substituents have the meaning indicated above for the compounds of formula (1), unless otherwise indicated.

According us- first embodiment, the compounds of formula _(ί, ϊ, wherein one of the substituents W ₅ X, Y and Z and three dens represent _CR; may be prepared as described in Scheme 1 or in Scheme 2. These diagrams illustrate the case where R 1 = H, but the procedures described also apply to the case where R ₍ - (CrC).

 Mal = Ci, Br, I

Pyridine 1 is coupled by a Buchwald reaction with heterocycea 2 in the presence of a paladiura catalyst such as palladium acetate, a ligand such as Xphos and a base such as cesium carbonate. to give compound 2. This compound is then coupled with remaining 3 (obtained by conversion of azetidic acid ~ 3-oxyl car according to the procedure described in WO 2009/135842, all 36) in the presence of a base such as cesium carbonate, a palladium catalyst such as Pd (DFAa} .5 and ^a ligand such as XaniPhos. to give compound 4, compound 4 is finally saponified according to known procedure use IEA Fhoxnme the art to give ^the aœtidiae-3-oar ox.yliqoe desired acid.

Pyridine 6 is coupled by reaction with a Bnchwald stay 3 in the presence of a base such as cesium carbonate, a palladium catalyst where _I¾: .kiba) ₅ and a ligatrd as Xantphos to give the compound? This compound is then coupled with a heterocycle in the presence of a palladium catalyst such. palladium, a ligand such as Xphos and a base such as cesium carbonate, to give the compound S. The compound 8 is finally saponified according to a procedure well known to those skilled in the art to give ^acid S-azetidine-earboxylÎque sought.

According to a second embodiment, the compounds of formula (I), in which two of the substituents W, X, Y and Z represent N and the other two represent OR _: can be prepared as described in scheme 3. This scheme illustrates the case where ¾-H, but the procedure described also applies to the case where R, = (C) -C ") alkyl.

Hal ==== Cl, Br, I Pyrimidine. 9 is coupled with remaining 3 in the presence of a base such as triethylheol to give compound 10. This compound is then coupled with a heterocycle as described for scheme 2, to give compound 11. The compound 11 is finally saponified according to use procedure well known to those skilled in the art to give the desired asetidine-3-carboxylic acid.

According to a third embodiment, the compounds of formula (B), wherein one of the substituents W, X, Y represents N and the other three represent CR can be prepared known as described in Figure 4. This diagram illustrates the where R ₅ - H, but the described procedure also applies to eas or R - - (C _r C ₄ ) a! kyle.

Pyridine I is coupled with Lester 3 as described for Scheme 2 to give compound 12. This compound is then coupled with boronate 13 according to a Suzuki reaction, in the presence of a palladium catalyst such as the Pd complex ( DPPI) C! _2; C¾C.¾ _s to give the compound 14. Compound 14 is finally saponified in a well-known procedure to those skilled in the art to give the acid a2 "iklme-3- carboxylic sought.

According to another aspect, the invention relates to intermediates for preparing the compounds of formula (1). These intermediates correspond to formula (111):

wherein W, X, Y. Z and Hei are as defined for the formula (I) and R represents a (C _R C _¾ ) alk or a group - (CH _J R _Ô RT in which R ₆ and R- each independently represent hydrogen, (C _{r C,)} alkyl or

and n is 0, 1 or 2. The following examples of the preparation of compounds according to formula (I) allow to better understand rinventioa.

 In these examples, which are not limiting the scope of Finventio, the term "preparation" means the examples describing the synthesis of intermediate compounds and "examples" those describing the synthesis of compounds of formula (0) according to the invention. The following abbreviations have been used:

 AcOEt acetate (Téthyie

 AeOK potassium acetate

CHCI ₃ chloroform

CS _J CO _J cesium carbonate

 DMSO dimethylsullboxide

equivalent eq

h h

2CO ₃ potassium carbonate

 LC-MS mass spectroscopy by liquid chromatography

 LiOH lithium hydroxide

 MgS ¾ magnesium sulfate

min minute

ml milliliter

nifflol mi.llimo.le

 NaOH probe

Pd- ₂ (dba) ¾ tri.s (dibenzylidene) acetone dipalladium (0)

 Pdidppf ïCkCH, € ¾ [ï, 1 '-Bis ^ di Ké ytphos hmo} ^^^

 complex (1: 1) with dichloromethane

 PF melting point

 Yield yield

 RT ambient temperature

 THF tetrah ydrorurane

XaatPhos

 Xphos 2- (dieyclobexylphosphino) -2,4'-triisopropylbiphenyl

Nuclear magnetic resonance spectra ^(NMR): H EIA were made ^{using a} Broker Avance 400 MHz spectrometer microBay (Testas magnet 9.4), provided with a measuring probe BBFO, Muuido diameter cores 5 mm, Z gradient, and look ¾ or a 500 MHz MicroBay Avance Broker Spectrometer (1 1, 7 Tesla magnet), equipped with BEI measuring probe, with 5 mm diameter, Z gradient and iock noy cores or a Bruker soectrometer. DPX 300 MHz (7,05 Tesla magnet), equipped with B3FO measurement probe, with 5 A diameter, Z gradient and look look diameter cores. The chemical shifts (δ), calculated with respect to TMS (erythromyelysulfide), are expressed in parts per million (ppm). For each signal, the number of protons and the form of the signal (s for singular, for singulei expanded, d for doublet, dd for doublet doubled, dt for fplet split, t for triplet, q for quadrapet, m for multiplet, bep for hepiuplet). The working frequency (in MHz) and the solvent used are indicated for each compound.

The mass spectra (LC-MS) were performed using a Waters brand Aequity UPLC-UV-MS spe- ctor equipped with a BEH CI 8 Aequity UPLC column having the following characteristics: 50x2.1 m 1, 7 μm; 0.8 mL / min - 45 ° C; 210 260 drew; eluent H, 0 ÷ CH ₅ COOH 0, 1 (A) / acetonitrile (CO) 0.1 CB); gradient 5-95% in B in 2.5 min then 95% in B up to 3 min 5 min.

 Melting points were measured on iOptiMelt MPÀ 100.

The ambient temperature is 20 * C ± 5 ^'3 C.

Prepgratjos 1: 4- ^ çj pro-2 ~ Tidyl) -¾2-dlm ^

In a Q-to.be reactor, 250 rag of 2-chloro-6-chloropyridine (3 mmol) were introduced; 1 eq) in 7.5 rnl of toluene under nitrogen, then 300 rag _2} 2-dimethyl-7- (tritluorQmétbyi) -3 _s 4-dibydro-l. _> 4-benzo [oxa] (preparation of PCT application F.R2015 / 050398) (1.3 mmol, 1 eq.), 5.8 mg of palladium acetate (0.03 mmol, 0.02 g); eq), 25 mg of Xohos (0.05 mmol, 0, Q4 eq), 7.9 mg of phenylboronic acid (0.06 simol, 0.05 eq) and 846 mg of C¾C € (2.60 mole; eq) have been added. The Q-tube was sealed and the reaction was heated overnight at 120 ° C. The reaction medium was diluted with water and with AcOEt. The aqueous phase was extracted 3 times with EtOEt, the organics were dried over MgSO 4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on EPIS silica using 60% to 80% acetomyril / water eluent to give 151 mg of the title compound as a yellow resin.

liât: 34%.

¾ KMN (300 MHz, CHCl rf) δ .1.31 (s, 6 H) 3.S6 (s, 2 H) 6.86 (d.7-7.6 Hz, 1H) 7.07 (dd,, 7-8.4, 2.0 Hz 7.17 (d, 1, Hz, 1H) 7.20 (d, 7-8.4 ¾ 1H) 7.44 (d, 7-8.4 Hz, 1H) 7.49 (dd, r-8.4, 7.6 Hz, i H). LC-MS: ταίζ (M + H) ^- : 343. mnM In a Q-tube reactor under nitrogen, 150 mg of 4- (6-dichloro-2-pyrklyl) -2,2-dimethyl-7- ⁽ Ruifluoromethyl) -3H-1 _> 4-benzoxidine (Preparation 1) (0.44 ml to 1 eq) in 2.25 ml of toluene and then 79 ml of methylmethacrylate hydrobromide (0.53 g). mol: 12 eq), 20 mg of Pd2 (dba) 3 (0.02 mmol, 0.05 eq), 25 μg of XantPhos (0.04 mmol, 0.1 eq) and 570 mg of Cs ₂ CO (1, 75 mmol, 4 eq) were added The Q-tube was sealed and the reaction was heated overnight at 1 K C. The reaction medium was diluted with water and PAcOEt. aqueous phase was extracted 3 times with PAcOEt, the organics were dried over MgS0 _4, filtered and concentrated under reduced pressure, the residue was purified by flash ehroma ograpfaie on silica with eluant eyciohexane -A / AcOEl of 0% to 15% to give 121 mg of the title compound as a yellow resin.

Rdi: 65%.

¾ NMR (300 MHz, CHCW) δ ppm I .30 (s, 6 H) 3.47 - 3.65 (m, 1H) 3.77 (s, 3H) 3.78 (s, 2H) 4.11 - 4.26 (m, 4H) ) 5.89 (d, J = 7.9 Hz, 1H) 6.60 (d, 7-7.9 Rz, 1H) 7.02 (dd, 8.7, 2.2 Hz, 1H) 7.13 (d, J = 2.2 Hz _, 1H) 7.35 11, J = 7.9 Hz, 1H) 7.49 (d, J-8.7 Hz, 1H).

LC - MS; / z (M÷H) ^÷ : 422.

 To a solution of 120 mg of i - [6- [2,2-dimethylvinyl] -7- (triilorone sthyl)

4-ylj-2-p-idyl] azehyde-3-carboxyethylene (preparation 2) (0.28 mmol, 1 eq) in 3.6 ml of THF were added to 1.0 mg. LiOH (0.43 mm at 1, 50 eq) dissolved in 2.4 mL of water The mixture was stirred for 2 h at RT and then concentrated under reduced pressure to remove THF. Acetic acid 10% in water has been added up to The obiesu precipitate was filtered and dried in an oven to give 105 mg of the title compound as a beige solid.

Yield: 90%.

NMR (400 MHz, DMSO -? / ₆ ) 6 ppm 1.26 (s, 6H) 3.44 - 3.56 (m, 1 H) 3.74 (s, 2H) 3.97 (d <J-7.8, 6.1 Hz, 2H) ) 4.05 - 4J4 (m, 2H) 6.01 (d, J-7.SHz, iH) 6.55 (d.7 = 8.0 Hz, 1H) 7.06 - 7.14 (, 2H) 7.42-7.52 (m, 1H) 7.60 (d, J-9.0 Hz, 1H).

LC-MS: m / z (M + H) ^; : 408.

FF: 66-75 C,

The comp was synthesized according to the protocol described in the preparation! from 2-chloro-4-iodopyridipine and 1H-trifluoromethyl-1-hydroxy-1-benzoxazioe (preparation of application PCT / FR2015 / 050398) to give 245 mg of the compound title in the form of a pale yellow solid.

Yield: 29%.

1H NMR (300 MHz, CHCU-d) δ ppm 1.33 (s, 6H) 3.52 (s, 2H) 7.04 (dd, J = 5.8, 2.2Hz, 1H) 7.06- ^" .13 (m) 7.19 (d, J¾.2 ¾ 1H) 7.35 (d, 7 = 8Hz, 1H) 8.20 (d, 7-S.8 Hz, 1H).

LC-MS: m / z (M + R) ^'! : 343.

The compound was synthesized according to the procedure described in Preparation 2, starting from 4- (2-chloro-4-pyridyl) -2,2-diinyl (Preparation 3) to give 208 mg of the title compound as the title compound. a yellow mule.

Yield: 71%.

 Ή NMR (300 MHz, CTCi 7) S ppm 1.33 (s, 6H) 3.48 (s, 2H) 3.51 ~ 3.66 (m, 1H) 3.76 (s, 3H) 4, 15 - 4.27 (m, 4) H) 6.03 (d, 7-1.9 Hz, 1H) 6.50 (dd, .7-5.8, L9 Hz, 1H) 7.03 (dd, 7-S.6, 1.9 Hz, 1H) 7.14 (d , 7-1.9 Hz, 1H) 7.32 (d,, 3-8.6 Hz, 1H) 8.03 (d, 7 = 5.8 Hz, 1H).

LC-MS: m / z (M + HV: 422.

The compound was svinbéîisé by piotocole déexit in Example 1, starting from 1 - [4 "[2,2 DIIT éthyi ^■ 7- (t ifn uoron XET yl) -3H-i .4 ^ eîizoxazin ^! Methyl-2-pyridyl-azetidine-3-carboxylate (Preparation 4) to give 144 mg of the title compound as a yellow solid.

Rdi: 80%,

¾ NMR (400 MHz, ΩMSQ ~ cL) δ ppxn 1, 28 (s, 6 H) 3.42 - 3.54 (m, 1H) 3.60 (s, 2H) 3.90 - 4.02 (m, 2H) 4.03 - 4.14 ( m, 2 H) 6.12 ^■■ 6.21 (m, 1 H) 6.60 (dd,, -5.8, 1.8 Hz, .1 H) 7.06 - 7.16 (m, 2H) 7.36 (d, J = 8.8 Hz, 1H ) 7.95 (d, .7 = 5.8 Hz, 1H).

LC-MS; AV2 (M-I-H) ^+: 40S.

FF: 100-107%.

The compound was synthesized according to the protocol described in Preparation 2, to be coated with 2-ethyl oropyrimidine and hydrochloride salt ^. Azetidine-3'-methylcarboxylate to give 1.42 g of the title compound under the ibnae of a pale yellow solid.

Rut: 30%.

NMR (300 MHz, CHCW) δ ppm 3.50 - 3.68 (br, 1H) 3.78 (s, 3H) 4.09 - 4.24 (br 4 II) 6.18 (dd.2 Hz, 1 RI 6.26 id _; J ~ 2 ¾ 1H) 7.99 (d, 7 = 5.8 Hz, i H).

LC'-MS: nx K (M-H) ^' : 227.

The compound was synthesized according to the protocol described in Preparation 1, starting from methyl 1- (2-cbloro-4-pyridyl) -2-butyl-3-carboxylate (5-epoxionization) and 2 _: 2-Dimethyl-7- (trifluoro (ethyl) -3,4-dihydro-1,4-hexoxane (preparation of the application) PC17FR20I 5/050398) to give 174 mg of the title compound the foxme of a yellow oil pays.

Kilt: 66%.

^! HR (300 MHz, CHCI ₃ -I) δ ppm 1.31 (s, 6H) 3.51 ~ 3.65 (m, 1H) 3.7? (s 3 H) 3.78 (s ₅ 2 H) 4.05 - 4.1 S (s, 4 H) 5.98 (dd, J-5.9, 1 .S Hz, 1H) 6.19 (d, J ^¾ = l .8 H , 1 H) 7.03 (dd,, / - 8.6, 2.1 Hz, 1H) 7.14 (d, J = L8 Hz, 1H) 7.45 (d, J = 8.6 Hz, 1H) 8.02 (d, / = 5.9 Hz, 1H).

 LC-MS: mlz - ΛΗ .Η}: 422. E mgte 3? .. ^

 The compound was synthesized according to the protocol described in Example 1, from ~ [2- [2,2-dimethyl] -1- (triilothinothiyl) -3 H -1,4-benzo-4-diol 4-methyl-3-carboxyalkylcarbonylis (6) to give 138 mg of the title compound as a white solid.

* Η NMR (400 MHz, DMStW ₆ ) 5 ppm 1 .26 (s _s 6 H) 3.49 - 3.58 (m, 1 H) 3.71 (s, 2 H) 3.96 (dd, 7.8, 5.9 Hz, 2 11 ) 4.03 - 4.12 (m, 2H) 6.12 (dd, 7 = 5.7, 13 Hz, 1H) 6.18 (d, .9 Hz, 1H) 7.06 ^■ · 7.12 (m, 2H) 7 , 54 (d,, -8.6 Hz, 1H) 7.93 (d, 7 = 5.7 1 -1 H).

LC-MS; m / z (M + H) ⁺ : 408,

FF: 1 15-12! "VS.

The compound was synthesized according to the protocol described in la. Preparation 2, from 3,3 dibromopyridi: ow and cblodiydrate <l¾zé idine-3-carbQxykte of méihyle to give 1050 mg of the title compound in the form of a ^"one oil ja?.

Yield: 52%. ¹ NMR (300 MHz, DMSO-) δ ppm 3.60 - 3.74 (m, HH) 3.68 (a, 3 H) 3.99 (dd, #-7.9, 5.8 Hz, 2H) 4.08 - 4.17 (m, 2) H) 7.12 (d, 7-2.2 Hz,! H) 7.82 (d, 7-2.2 Hz, 1H) 7.99 (d, 7-2.2 Hz, 1H).

LC-MS: fz (M÷H) ^÷ : 271.

 S p rid] I am already under the control of myself

 The compound was synthesized according to the procedure described in Preparation 2, starting from methyl 1- (5-bioiso-3-pyridyl) azetidium-3-carboxyate (Preparation 7) and 2,2-dimethyl-7 (trifluoro (methyl) -3,4-dihydro-1,4-benzoxazkie (panel 65 of PCT Application F 2,15 / 050398) to give 360 mg of the title compound as a yellow resin.

 Rd: 66%.

^{May 5} RRMMNN HH ((440000 M MHHzz ,, D-iQ DMMSSOW ₆₎ δ δ ppppmm 11 ..3333 ((ss ,, 66 HH)) 33..3322 ((ss ,, 33 HH)) 33..5544 ((ss ,, 22HH)) 33..6699 ■■ - 1155 33..7744 ((mm ,, ii HH)) 33..9977 ((dddd ,, 77--77..66 ,, 55 ## EQU1 ## where ## EQU1 ## -22.33 HHz13, 11HH)) 66..9944 ((dd, 77 == 88..11 HHz, 11MM)) 77..0011 - 77..0077 ((mm, 22HH)) 77.6677 ((dd), 77-22..33 H Hz, 11HH)) 77..9955 ((dd, J 7-22..33 HHz) \\ HH)) ..

LLCC - MMSS :: mm / zz ((MM ÷÷ HH)) ^"" :: 442222 ..

2i i SIIlH he Hm ^ ¾H; ^

Methyl pyridylsulfate-3-carboxyate (Preparation 8) (0.66 mmol, 1 eq) was dissolved in 2.8 ml. THF. A solution of 24 mg (0.6 mmol, 0.9 eq) of NaOH in 1.4 g of water was added and the mixture was stirred at room temperature. The medium was concentrated under reduced pressure to remove THF. The medium was diluted in diethyl ether and in water. The aqueous phase was extracted at Diethyl ether. The aqueous phase was lyophilized to give 258 mg of the title compound as an off-white powder.

Yield: 98%.

 ¾ RM (400 MHz, DMSO-) δ ppm 1.33 (s, 6H) 3.03 - 3.15 (m, 1H) 3.54 (s, 2H) 3.81 - 3.8S (m, 2H) 3.93 (dd, J) -8.4, 7.3 Hz, 2H) 6.68 (L Hz, 1 μl) 6.91 (d, J-9.0 Hz, 1H) 7.0 ± 7.06 (m, 2H) 7.59 (d,, 7 = 2.3 H¾ 1 H) 7.86 (d, J-2.3 Hz, 1.H).

LC-MS: m / z (M + H) ^~: 408.

M.p. 57-160 ° C. l S loa ^ * fe roethyk

1 g of 2,4-dichlorophenylidia (6.71 molesol), 1.02 g of rheihyl azetidine hydride-diisocyanate (6.71 mmol, 1 eq), and 2.34 ml of Triketynaphysis (16.78 mmol, 2.5 eq) was dissolved in 10 mL of 1,4-dioxane and stirred for 24 h at RT. The reaction medium was diluted in water and extracted 3 ibis with PAcQEt. The organic phases were washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash silica chromatography ^on a 1% dichloromethane-ethanol eluent to give 640 g of the title compound as spent white powder.

 Yield: 42%.

¹ NMR (300 MHz, DMSO-) δ ppm 3.62 - 3.74 (m, 1H) 3.68 (s, 3H) 4.13 (dd, J-, 4, 5.8 Hz, 2H) 4.23 ^■■ 4.31 (m, 2H) 6.43 (d, Hz, 1H) 8.07 (d, J-5.9 Hz, 1H).

LC-MS: m Z (M + H 2: 228.

¾¾¾ t ¾ 1.0 ,,; Iri ^' 2d2.3- ^

The compound was synthesized according to the protocol described in Preparation 2, starting from the methyl 1 - (2 "thioropyiimidix-4-yl) azetidine-3-carboxylate (Preparation 9) and 2,2-

(Preparation 65 of the application

FCT / FE2015 / 050398) to give 136 mg of. compound of the title in the form of a colorless resin,

IMI: 50%.

¾ RM (300 MHz, DMSÛ-) δ ppm L25 (s _s. 6 H) 3.59 ^■■ 3.73 (m, 1 H) 3.68 (s, 3H) 4.02 (s. 2H) 4.10 (dd, .7 = 8.9, 5.8 Hz, 2H) 4.1 S - 4.28 (, 2H) 6.02 (d, 7 = 5.7 Hz, 1H) 7.1 (d, ./¾ Hz, 1H) 7.16 (dd,, 7-8.6 , 2 Hz, 1H) 8.04 (d, .7-5.7 Hz, 1H) 8.27 (d, 7-8.6 Hz, 1H). LC-MS: ra / z (Μ · Π): 423.

Example S: H2- | 2,2 dIra ^^

^ lpwtoidia ^ -yttoétiâtee-S-ca box ^' yj.ate sodium

 The compound was synthesized according to the protocol described in Example 4, starting from - [2- [2,2-- di: rheihyl ~? - tà: .oo ^

methyl carboxylate (Preparation 10) to give 120 mg of the title compound as a white powder.

Yield: 89%.

 ¹ NMR (400 MHz, DMSO ^) δ ppm 1.25 (s, 6H) 2.95 - 3.10 (m, 1H) 3.87 - 4.12 (m, 6H) 5.91 (d, 5.7Hz, 1H) 7.09 (d, J = 2Hz, 1H) 7.15 (dd, i-8.7, 2Hz, 1H) 7.95 (d, .7-5.7! ¾Hi) 8.30 (d, 7-8.7 Hz, 1H).

FF; 71-97 ^C. C.

The compound was synthesized according to the protocol described in preparation 2. ia from 2,4 dihrom.o-6 ~ methylpyridl you and 2,2-dinièthyl ~ - (trifl "Oromë ^{: hy]) - 3 _4- Benzoxazine-4-diltidyl (Preparation of PCT Application No. 15/050398) to give 391 mg of the title compound as a pale yellow oil.

Rai: 27%,

⁵ H NMR (300 MHz, DMSC δ 1.27 (s, 6 H) 2.39 (s, 3H) 3.79 (s, 2H} 7.10 ~ 7.1 (m, 3 H) 7.28 - 7.33 (m, _1H). 7.62 (d, J 9.2 E 1, 1H).

LC-MS: m / 2 (M + HL: 401.

E ^ gM s _{.. 6i.} ¾fc of l-f2-} J ^

 The compound was synthesized according to the protocol described in Preparation 2, starting from 4- (4-bremo-6-x-methyl-2-pyridyl) -2,2- (Hn)

 (Preparation 11) and inert azetidine-3-carboxyate hydrochloride in THF at 13CPC to give 124 rag of the compound of. title under the ton of a colorless resin. Edt: 59%.

¾ RM (300 MHz, DMSO ~; 4) δ ppm 1.2? (s, 6 M) 2.2? (s, 3M 3.48 - 3.60 (m, HH) 3.69 (s, 2H) 3.94 (dd, .7-7.8, 5.9 Hz, 2H) 4.02 - 4.1 1 (m, 2H) 6.00 ( d, J = .1 .6 Hz, 1 H) 6.04 (d, J = 1.6 Hz, 1 H) 7.03 _-. 7.12 n, 2H) 7.53 (d, / -8.4 Hz, H!).

LC-MS: vaf (M + H) ^- : 422.

Exempt 7: H2 12 ~ dlmét¾yl-7-CtrffiaQrero ^

75 rng of acid! - [[2,2-dimethyl-? - (i ^

 4-pyridyl] -3-carboxy (example 6) (0.18 mol, 1 eq) were dissolved in 5 mL of THF, 56 μL of tert-butylamia (0.53 molo, 3 eq) were added together. if the mixture was stirred at RT, then concentrated under reduced pressure. The solid obtained was triturated in 10 ml of petroleum ether and filtered. The solid was washed with petroleum ether, dried under vacuum at 95 ° C to give 31 mg. composed of the title in the form of a white powder.

Yield: 22%. ^{: ί} Μ m (400 MHz, DMSO ~ i) δ ppm 1 .26 (s ₅ 6 H) 2.25 (s, 3 H) 3.18 - 3.29 (m, 1 μl) 3.82 - 3.90 (m, 2 H) 3.91 - 3.99 (m, 2H) 5.95 (s, 1H) 5.9? (s, i H) 7.03 - 7.1! (m, 2H) 7.51 (d, 8.1 H + H).

1 .21 (5, 7 11 0.8 eq of IBuNB $.

LC-MS: m / z (M-H) ^- : 422.

FF 111-120 ° C.

Preparation,, H, LH2-i¾b¾ty ^ In a. Q-tube reactor, 192 mg of ethyl 2- (2-c oro-4-pyridyl) azetid-3-carboxyethylene (preparation 5) (0.85 mmol, 1.1 eq) and 200 mg of 2-sobutyl were introduced. (7-trifluoromethyl) -3,4-dihydro-2H-1-b-oxazazine (preparation 135 of application PCT / FR2015 / 050398) in 4 μl of toluene under argon and then 34 mg of palladium acetate ( 0.15 mmol, 0.2 eq, 77 mg of Xpbos 0.16 mmol, 0.21 eq), 4.7 mg of phenylboronic acid (0.04 mmol, 0.05 eq), 502 mg of Cs _: CC¾ (1.54 mmol, 2 eq) and 100 μl of water were added. Q-Iube was sealed and the reaction heated s é é follows a 120 ^S C. The medium, réactioiniei was diluted with water and æœ The organic phase was dried over MgS0 _4, filtered and concentrated Ei under reduced pressure. The residue was purified by preparative LC-MS (Cl 8 column Kinetex 2L2 * 150m * ^'5pm) to the side of an IO / aeétonitrile gradient with 0.1% ibrmique acid of 10 to 90% to give 30 mg of the title compound as an off-white powder.

Yield: 9%,

¾ RM (300 MHz, CHCl d) δ ppm 0.95 (m, 6H) 1.30 ·· 1 .41 ia, i H) 1.58 - 1.70 (m, i) 1.85 - 1.99 (m, 1H) 3.40 (m, 1H) dd, J = 12, 7.8 Hz, 1H) 3.54 - 3.64 (m, 1H) 3.76 (s, 3 M) 4.06 - 413 (m, 4H) 4.14 - 4.23 (m, 1H) 4.23 - 4.30 (ru, 1H) 6.00 (dd, J = 57, 1, 9Hz, 1H) 6.14 (d,, M, 9Hz, 1H) 6.99 - 7.05 (m, 1H) 7.1.6 (d) , J = 2.0 Hz, 1H) 7.42 (d, MHz, 1H) 8.03 (d, ^::: 5.7 Hz, 1H). Example ë: 1 ¾ -i ^

The compound was synthesized according to the protocol described in Example 1 using NaOH instead of LiOH, from 1 - [2- [2-methyl-7- (trifluoromethyl) -2,3-dihydro-1 _s beîizoxazin 4- ~ 4-yi-4-pyridyl] methyl-3-a2éiidine earboxylâie (preparation 12) to give 21 nig of the title compound per ton of oil.

Rut: 72%.

 This compound was used directly for the formation of the leri-bui laroine salt according to the protocale described in Example 7 to give 9 rag of the title compound as a white powder.

RdI: 39%.

NMR (400 MHz, DMSO-) δ ppm 0.90 (at, J-4.SH, 3H) 0.92 (d, ds * 4.8 Hz, 3H) 1.20 (s, 9H) 1.34 - 1.45 (m) , 1H) 1.50 - ^■ 1.59 (m, 1H) 1.78 - 1.91 (m, 1H) 3.12 - 3.24 (TU, 1H) 3.42 - 3.50 (in, 1H) 3.83 - 3.91 (m , 2 H) 3. 1. ■ _-. 3.99 (m, 2 H) 4.0? (dd, J-13.2, 2.6 Hz, 1H) 4.20 - 4.28 (m, 1H) 6.0? (dd, J * 5.7, 1.8 Hz. 1H) 6.09 (d, g, Hz) 7.06 - 7.12 ta, 2H) 7.51 (d, J-7.9 Hz, 1H) 7.90 (d , J-5.7H, 1H).

LOMS: m / z (M + Hf: 436.

M.p. 162-166 ° C.

The compound was synthesized according to the protocol described in Preparation L using K 2 CO 3; at the plate of Cs; CO $ _> from i - (2-methyl-4-chlorophenyl) azetidine-3-arboxylate (preparation 5) and 2,2-methylmethyl (HFluorometethyl); 3,4-dikydro-1,4-benzoxazine (preparation 277 of application PCTVFR2015 Ό50398) to give 87 mg of the title compound as a pale yellow solid.

Yield: 1? .

¾. NMR (300 ML¾ DMSO-¾) δ ppm. 1 .08 - 1 .14 (m, 6H) 1.37 (s, 3H) 3.5? - 3.74 (m, 1H) 3.68 (s, 3H) 3.9S (dd, J-7.9, 5.8 Hz, 2H) 4.05 - 4.1? (m, 2H) 4.32 (q,, / - 6.6 Hz, 1 HH)) 66..1122 ((dddd .. 77 == 55..66 ,, 11..99 HHzz ,, 11 HH)) 66..117 ((a), 7 = 11.99 HHz ,, 11 HH)) 77..0022 - - 77, 414 ((mm, 22 HH)) 77..4488 ({ad ,, 77- * 77..99 HHzz ,, 1.1 HH)) 77..9944 ( (dd, 77--55.66 HHz11, 11HH)) ..

LLCC - MMSS :: ¾¾ ·· {(M-÷ HIî ^{} '} f} ^" :: 443366 ..

The compound was synthesized according ie protocol described in ^Example 4, from l- [2- ~ 2.23 triœèt¾yî-7 ~ (triiluoro3î3étliyl) -3H-l, 4-ben2oxazia-4-yl] -4- Methyl pyridyl] azetidine-3-carboxylate (Preparation 13) to give 56 mg of the title compound as a blaache powder.

 Yield 76%.

 ¾ RM (400 MHz, DMSO- <¾} δ ppm 1.11 (d, J-6.6 Hz, 3H) 1 .13 (s, 3H) 1.36 (s, 3H) 2.96 - 3.08 (m, 1H) 3.78 - 3.9S (m, 4H) 4.29 (q, 7-6.6 Hz, 1H) 6.03 (dd, 7 = 5.7, 1.7 Hz, 1H) 6.07 (d, 7 -7) Hz, 1H) 7.05 - 7.14 A, 2H) 7.44 (d, 7-9.2Hz, 1H) 7.88 (d, 7 = 5.7Hz, 1H).

LC-MS: m / z (MH) ^÷ ; 422.

 FF: 137-153 X. i ^ a »& ^

The compound was synthesized according to the protocol described in the preparation. 2, from 2,6-dihydropyridine and methyl azetidio-5-carboxyate hydrochloride to give 730 mg.

liter in the form of a yellow oil.

 Yield: 49%.

 ¾ RM (300 MHz, DMSO-4) δ ppm 3.60 - 3.70 (m, 1 H) 3.68 (s, 3 H) 4.01 (dd, 7 = 8.4, 5.8 Hz, 2 H) 4.12 - 4.19 (m, 2H) 6.37 (d, 7-8.3 Hz. 1H) 6.69 (d, 7-7.4 Hz, 1H) 7.54 (dd, 7-8.3, 7.4 Hz, 1H).

LC-MS: m 2 (M + H) +: 227. De 880 mg of 5-bromo-7-isopropyl] -2,2-dimethyl ^'l -3 Wiliiydro- 1, 4-benzoxazine (preparation 253 of the application KT / FR2015 / 050398) (3.1 Ramoi; 1eq) were dissolved in 13.2 mL of DiVISO. 252 mg of M (dppi) CkCK _; Cb (0.3 nanol; 0 _: 1 eq), i, 2 g cLAcQ (i 2.4 mmol, 4 eq) and 3.14 g of bis (pinacol) boraae (12.4 mmol; 4 eq) were added the mixture was stirred overnight under argon at 85 ^C réaciionnei C. the medium was diluted with water and extracted with ΓΑο-ΟΕί the organic phase was washed.. with brine, séekée on GSCL, filtered and concentrated under reduced pressure. the residue was purified by flash chromatography on silica ^using a gradient cyclohexaîte / dichlo.roi¾éiha "e of 40 to 100% to give L33 g of the title compound as spent orange powder (75% molar of his (pi: aeoi) borane),

Yield: 32%.

 ¾ 00 MHz NMR, DMSO-O δ ppm .10 (d, J = 6.9 Hz, 6H) 1.22 (s, 6H) 1.29 (s, 12H) 2.61 - 2.76 (m, 1H) 3.06 (d, ---- 2.) Hz, 2H) 5.60 (se, NH) 6.61 {d,, 7 = 2.1 Hz, 1H) 6.85 (d, J = 2.1 Hz, 1H),

LC-MS: m / z (Μ + Η) ^': 332

Preparation 16: H6- (7-iso?> Ropy ^^

448 mg of methyl [2-pyridin-3-aryl] -3-methoxy arboxylate (Preparation 14) (1.98 mmol, 1.9 eq), 1.33 g of 7-isopropyl ether were added to the reaction mixture. ~ 2 ₅ 2-dimé l-5- (4A5 _s 5H ^

dioxaboroloyl) -2-yl) -3,4-dihydra-1, 44 benzoxime (preparation 15) (1 mmol), 4 mg of potassium carbonate (3 mmol, 3 eq) and 50 mg of Pd ( dppf) Ci _2! C¾Ci ₂ (0.06 mmol, 0.06 eq) dissolved in 3.33 mL of 1,4-dioxane and 1 mL of water. The mixture was heated at 120 ° C. for 2.5 hours under nitrogen. The reaction medium was diluted to. Water and LAcOEt. The aqueous phase was extracted 3 times at 80 ° C., the organics were washed with brine, dried over MgSO 4, filtered and concentrated under reduced pressure. The residue was purified by preparative LC-MS (Cl 8 column Lima 18.5 * 250mm * 10 m) Ugly ^a gradient .ï¾0 / aceto Trile with 0.1% of fo acid nape of 10 to 90% to give 145 mg of the title compound as a yellow oil.

Yield: 37%.

¾ RM (300 MHz, D SO-) δ ppm 1.16 (d, J-6.8 Hz, 6 II) 1.25 (s, 6 H) 2.75 (hept,, / = 6.8 Hz, 1 II) 3.12 (d, 7 = 2.5 Hz, 2H) 3.60 - 3.74 (m, i II) 3.69 (s, 3H) 4.06 (dd, J-7.8, 5.8 Hz. 2H) 4.15-4.24 (m, 2H) 6.34 (d,, 7-1.9 Hz, 1H) 6.34 (br, J = 8, i Hz,! H) 6.97 (d, = 19.9 Hz, H) 7.0? (d, J 7.6 Hz, 1H) 7.62 (m, 1H) 7.93 (se, NH).

LC-MS: m¾ (M + LiF: 396. Example ^10: H <7 * ^^ w¾

 The compound was synthesized according to the protocol described in Example 4, at. from 1 ~ [6- (7-isopropyl) -2,2-dimethyl-3,4-di]

Methyl carboxylate (prepaiton 16) to give 120 mg of the title compound as a white powder.

3 1; 87%.

 NMR (400 MHz, DMSO-) δ Ppm. 1, 16 (d,, 7-6.8 Hz, 6H) 1.25 (s, 6H) 2.74 (hept, JN5.8H¾1H) 3.00 - 3.10 (m, 1H) 3, 12 ( d, J¾, 4 Hz, 2 H) 3.89 - 4.02 (m, 4H) 6.22 (d, J = 7.9 Hz. 1H) 6.56 (d, J = 1.8 Hz, 1H) 6.94 - 7.02 (m, 2 H) 7.54 (t J-7.9 Hz, 1H) 8.31 (se, NH).

LC-MS: m / z (M + H) ⁺ : 382.

FF: 167474 ^B C. phsrmacoíoglqae activity

 The compounds of the invention have been subjected to biological tests in order to evaluate their potential. treat cm prevent certain pathogens ueurodegeneralives.

The ability of compounds according to the iayemion to act as an enhancer of the heterodimeras formed by the UK.R.-1 nuclear receptor and the RXR nuclear receptors was measured by in vitro testing.

A riva lion bag test was used as a primary screeaing test. Cos-7 cells were eo-exchanged with a plasmid expressing a chimera of the human Nt1RR-HGaM receptor, a plasmid expressing the human RXR receptor. (RXRa or RXRy receptor) and a reporter plasmid 5Gal.4pGL3-TK-L c. Transfections were performed using a chemical agent (Jet FBI).

The transfected cells were distributed in 384 well plates and. left standing for 24 hours,

At 24 hour time the culture medium was changed. The test products were added (final concentration of between 10 ^"* and 3.10" ° M) in the culture medium. After a night of incubation, the lucifer expression was measured after addition of "SeadyGio" according to the manufacturer's instructions (Promega).

The 4 - [[6-mét¾yl ^"2-phenyl-5 ^^ (nonuné XCT0135908 described by Watien Mackex-ie ^ et al, 2003, Genes & Development 17: 3036-3047) to 2.1 ^{G" 5M} (ago ste RXR) was used as reference.

Induction levels (Emax) were calculated based on the basal activity of each heterodirnere. The results were expressed in. percentage of the induction level compared to the induction level obtained with the reference (the induction level of the reference is arbitrarily equal to 100%).

For example, among the compounds according to the invention, one obtains the following results expressed as a percentage relative to a reference compound busily ^'U' RR-1 / RXR (XCT0Î 35908).

Tables »1

 kNralJ XKaFL hNisrrtJiX gFL

Example EC _{5 (;} (nM) EIRSX {%) EC _¾ (nM) Exnax {¾)

 IV! 585372-01 33 114 109 O l

608507-0! 18? 93. 525 92

3 I 1608 12- 1 47 108 86 102

4 1608748-01 353 95 237 1

5 IV 1609012-01 543 1 19 993 133

8 1V1609037-01 81 63 129 6

9 TVl 609040-01 596 86 915 82

I 0 IV 1609042-01 428 72 788 58

The compounds according to ^the invention have an induction rate ranging up to 1 19% (1 URR / RXRo) and 133% (ikj Rl RXRy) and EC ₅₀ of up to 33 nM (NlOUU RXR) and. NM {NURR1 ¾Χ¾.γ). 1 / invention also relates to a pharmaceutical composition containing, as active principle, at least one compound of formula (I), one of its salts acuaceutiqueraememem acceptable.

 The pharmaceutical compositions according to the invention can be prepared in a conventional manner, using pharmaceutically acceptable excipients in order to obtain forms that can be administered parentally or, preferably, orally, for example tablets or capsules. .

 In the case of injectable forms, the compounds of formula (I) will advantageously be used in the form of solid surface salts in an aqueous medium. As previously indicated, the salts are preferably formed between a compound of formula (I) and a pharmaceutically acceptable, non-toxic base. The formulation may be either a solution of the compound in an isotonic aqueous medium in the presence of soluble excipients or a lyophilizate. of the compound to which the diluting solvent is extemporaneously added. The preparations may be injected as an infusion or as a form of injection depending on the patient's needs.

 In practice, in the case of administration of the compound parenterally, the daily dosage in humans will preferably be between 2 and 250 rag.

The orally administrable preparations will preferably be presented in the form of a capsule or a tablet containing the compound of the invention, finely ground or better, micromated, and mixed with excipients known to those skilled in the art, such as for example lactose, amido pregelatinized and magnesium stearate.

Claims

Compound of formula (I):

in which :

W, X, Y and Z are each independently CR ₅ or N, with the proviso that at least one and at most three substituent W, X, Y and Z represent N;

Ri is H oit a _(Ci-C;) aikyle;

Het represents im héterocyeie having S to 15 membered heterocycle optionally substituted by 1 to 4 substituents selected from: (Q -C _¾) aîkyie optionally substituted by 1-3 halogen (s), a (CQ} cycloalky] e, in hétéroeycie having from 5 to 7 ring members, phenyl or a group - ¾ j; iC a C _r;} aieoxy optionally substituted by 1 to 3 halogen (s); a (C, -C _ft) cycloalkyl; phenyl; halogen; group - ¾ _S : a group ···· CON ₄ , a group -S0 ₂ R _' : and an oxo;

R; _Î and R .; each independently represent hydrogen or (C _R -C _4> aikyie optionally substituted by a (CRQ) alkoxy;

¾ and R _¾ each independently represent hydrogen or (CrQ) alkyl;

R represents a (C _r C ₄ ) alkyl. a henyl on a group - ^; N¾R _¾ ,

or a pharmaceutically acceptable salt of the compound of formula (I).

A compound of formula (1) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein one, W, X, Y and Z substituents represent N, and the other three each represents CRj.

A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein two of the substituents W, X, Y and Z are N, and the other two are each CR _; . Compound according to Fane of claims 1 to 3, of formula (II _.

in which ;

 , X, Y and Z are as defined in one of claims 1 to 3;

Het represents a 5- to 15-membered ring of electronically substituted phenyl substituted with 1 to 4 (C ₁ -C ₄ ) alkyl (s) optionally substituted with 3-pendenes;

or a pharmaceutically acceptable salt of said compound of formula (II).

5. A compound of formula 01) according to revendicatiou 4, or an acceptable pharmaceutiqnemeat salt thereof, wherein Het represents a hétérocyeie having 5 to 12 ring members optionally substituted by 1 to 4 iC _r C _4} aikyle (s} optionally substied with 1 to 3 halogens).

A compound of formula (II) according to claim 4 or claim 5, or a pharmaceutically acceptable salt thereof, wherein R _t is H.

7. Compound of formula (I) according to claim 1 which is chosen from:

acid 1 - [6- [2 -dimétii> d-7- {trifluoromé l) -3.Hl _t ^ 4-benzoxazin-2-pyridyl yij} aséiidme-3 -earboxyiiq ue;

acid 1

pyridyl] azéridine-3-carboxylic

acid

pyridyl] azét.idine-3-earboxylique .;

sodium carboxylate;

l- [2 ~ [2 ~ 2 _s dirnéthyi-7- (trifluoromethyl) -3H-l, 4 ~ benzoxazb

 Sodium 3-carboxylate;

l- [2- [2,2-diniéthyl-7- (trifluoromémy!) ~ 3H ~? _^

pyridyl] azetid; tert-butylammonium ne-3-carboxylate; tert-binylsmmonium pyridine;

sodium carboxylate;

sodium carboxylate;

and the pharmaceutically acceptable salts of these compounds.

8. A compound according to one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for use as a medicament.

9. A compound according to one of claims 1 to 7, or a pharmaceutically acceptable salt thereof. for its use in the prevention or treatment of neurodegenerative diseases.

10. A compound according to claim 9, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of Parkinson's disease, 1. A compound according to any of claims 1 to 7, or a pharmaceutically acceptable salt thereof. It is acceptable for use in the prevention or treatment of tacopaihias, diseases of the central nervous system, restless leg disease, progressive upranuclear paralysis, lateral spinal papyrism, Rett's syndrome, schizophrenia, bipolar disorder, manic behavior, depression and eognitive disorders, inflammatory diseases, or autoimmune diseases.

12. A pharmaceutical composition comprising as active substance a compound of formula (I) as defined in any of claims 1-7, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. .

13. intermediate of formula (III):

wherein W. X, Y, Z and Het are as defined in one of claims 1 to 6 and R represents a (C _r C ₆ ) alkyl or a group ~ (t¾) _u -NR ₆ y in which s and R _? are each independently hydrogen.

or a (C _$ - Q) cycloaÎkyîe, and n is 0. 1 to 2.