FR3040057A1 - AZETIDINE CARBOXYLIC COMPOUNDS - Google Patents

Abstract

The invention relates to the compounds of formula (I): wherein W, X, Y, Z and Het are as defined in the description. The compounds of formula (I) are modulators of the NURR-1 receptor.

Description

Azetidine carboxylic compounds

The present invention relates to novel compounds of the azetidinecarboxylic type, as well as to a process for their preparation and their use as active principle of medicaments, in particular for the treatment or the prevention of diseases involving the nuclear NURR-1 receptors.

Prior art

The NURR-1 nuclear receptor is expressed primarily in the central nervous system, especially in the substantia nigra, the ventral area of the integument, in the middle brain and limbic areas where it plays an important role in the neuroendocrine system (Law et al. , 1992, Saucedo-Cardenas 1996, Zetterstrom et al., 1996a, Zetterstrom et al., 1996b). In addition, it is also strongly expressed in the olfactory bulb, hippocampus, temporal cortex, cerebellum and posterior hypothalamus. In patients with Parkinson's disease the expression of NURR-1 is decreased in dark substance neurons that contain alpha-synuclein inclusions (Chu et al., 2006). Similarly, a decrease in NURR-1 expression is observed in neurons containing neurofibrillary tangles of Tau protein in patients with Alzheimer's disease (Chu et al., 2006). 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 (Bannon et al. 2002, Xing et al., 2006, Horwath et al., 2007 and Nielsen et al., 2008). Consistently, several genetic polymorphisms of the gene encoding NURR-1 have been shown to be associated with various diseases of the central nervous system such as Parkinson's disease, schizophrenia and bipolar disorder (Buervenich et al., 2000, Chen et al. 2001, Zheng et al., 2003, Chen et al., 2007, Liu et al., 2013).

There is considerable evidence that NURR-1 is essential for the development, migration and survival of dopaminergic neurons (Chung et al., 2002, Kim et al., 2002, Sonntag et al., 2004). Mice whose gene encoding NURR-1 has been invalidated are not viable after birth, in particular due to a defect in the generation of dopaminergic neurons in the midbrain (Zetterstrom et al., 1997, Saucedo-Cardenas 1998). Heterozygous mice, 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 dopaminergic neurons of the substantia nigra and a decrease in the expression of certain marker genes dopaminergic neurons such as Tyrosine Hydroxylase (Imam et al., 2005, Le et al., 1999a). These heterozygous mice also have symptoms found in schizophrenia such as hyperactivity when placed in a new environment, emotional memory deficiency, and exaggerated response in the forced swimming test (all of these symptoms being associated with a defect in the dopaminergic neurotransmission) (Rojas et al., 2007; Vuillermot et al., 2001). Tyrosine Hydroxylase is the enzyme responsible for the synthesis of catecholamines such as dopamine, norepinephrine and epinephrine. Catecholamines in general and dopamine in particular play an important role in the mechanisms of locomotion as well as in behavioral mechanisms such as learning and reward. Catecholamine deficiency is observed in many central nervous system pathologies such as Parkinson's disease, bipolar disorder, manic behavior, depression, cognitive impairment and schizophrenia. NURR-1 also contributes to the maintenance and survival of mature dopaminergic neurons. Indeed mice heterozygous for the gene encoding NURR-1 are more sensitive to neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and the hydroxylated analogue of dopamine (6-OH -DA), the psychostimulant methamphetamine, the proteasome inhibitor lactacystine (Le et al., 1999b, Li et al., 2007, Luo et al., 2010, Pan et al., 2008). On the other hand, overexpression of NURR-1 makes it possible to protect neurons from the death induced not only by these different stressors but also by the overexpression of alpha-synuclein (Decressac et al., 2012). It is important to note that these different stressors induce the death of neurons by mechanisms involving alteration of mitochondrial function, oxidative stress, excitotoxicity and alteration of protein degradation, and these mechanisms are involved. in the pathophysiology of many neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Creutzfeldt-Jakob disease, Huntington's disease, lysosomal 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 neurodegenerative pathologies is most often associated with different inflammatory markers such as the activation and proliferation of microglia and astrocytes, a lymphocyte infiltration and an increase in the rate of pro-inflammatory mediators as per example NO, ROS, TNFa, ILip and IL6. In vitro and in vivo, the decreased expression of NURR-1 leads to hypersensitivity to pro-inflammatory agents which is accompanied by an increase in markers of inflammation (activated microglia and increased rate of mediators of inflammation) and increased dopaminergic neuron death (Saijo et al., 2009). This effect of NURR-1 on inflammation 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 inflammatory mediators by macrophages and has a protective role against the formation of atheroma plaques. observed in atherosclerosis (Bonta et al., 2006). Recently, the role of NURR-1 in the differentiation and functionality of regulatory T cells (Treg) has been demonstrated (Sekiya et al., 2011, Sekiya et al., 2013). Tregs participate in immune tolerance by regulating effector T cells by their immunosuppressive action. They are essential for tolerance to self antigens, and non-dangerous antigens. Activation and / or expansion of Treg is a promising therapeutic approach for the treatment of immuno-inflammatory diseases such as multiple sclerosis, Crohn's disease, rheumatoid arthritis, lupus, psoriasis, Guillain-Barre, or Addison's disease. NURR-1 belongs to a family of transcription factors called nuclear receptors. Crystallographic studies have shown that the hydrophobic pocket normally occupied by the ligands in the nuclear receptors is clogged with hydrophobic amino acid side chain groups and thus would not allow the binding of endogenous or exogenous ligands (Wang et al. , 2003). One of the modes of regulating the transcription of genes by the NURR-1 receptor involves binding it to consensus sequences contained in the promoters of the genes. NURR-1 binds to these consensus sequences as monomers or homodimers and in this case behaves as a constitutively active transcription factor (Law et al., 1992, Philips et al., 1997). However, NURR-1 can also form heterodimers with another type of nuclear receptor, RXR receptors with rexinoids (Perlmann et al., 1995, Sacchetti et al., 2002, Wallén-Mackenzie et al., 2003). This receptor subfamily comprises 3 members: RXR-alpha, RXR-beta and RXR-gamma. These receptors are highly homologous and activated by the retinoic acid derivatives (9 cis 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 RXR ligands. The identification of compounds capable of modulating the activity of NURR-1 / RXRa and NURR-1 / RXRy complexes should therefore provide new pathways for the treatment or prevention of diseases involving the NURR-1 receptor.

OBJECT OF THE INVENTION The subject of the invention is novel compounds capable of modulating the activity of NURR-1 / RXRa and NURR-1 / RXRy complexes.

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:

wherein: W, X, Y and Z are each independently CR! or N, with the proviso that at least one and at most three of said substituents W, X, Y and Z are N;

R1 is H or (C1-C4) alkyl;

Het represents a 5- to 15-membered heterocycle optionally substituted with 1 to 4 substituents selected from: a (C 1 -C 4) alkyl optionally substituted with: 1 to 3 halogen (s), a (C 3 -C 6) cycloalkyl, a heterocycle having 7-membered phenyl or a group -NR 2 R 3, a (CrC 4) alkoxy optionally substituted with 1 to 3 halogen (s), a (C 3 -C 6) cycloalkyl, a phenyl, a halogen, a group -NR 4 R 5, a group -CONR4R5; -S02R6; and an oxo; R2 and R3 are each independently hydrogen or (C1-C4) alkyl optionally substituted with (C1-C4) alkoxy; R4 and R5 are each independently hydrogen or a (CrC4) alkyl; R6 represents a (CrC4) alkyl, a phenyl or a group -NR4R5.

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 NURR-1 is involved, particularly neurodegenerative diseases such as Parkinson's disease or Alzheimer's disease, tauopathies such as frontotemporal dementia, diseases of the central nervous system and especially those involving deregulation of the system. dopaminergic diseases such as Parkinson's disease, restless legs disease, progressive supranuclear palsy, lateral spinal muscular atrophy, Rett's syndrome, schizophrenia, bipolar disorder, manic behavior, depression and cognitive disorders, pathologies inflammatory diseases such as vascular pathologies such as atherosclerosis, inflammatory diseases such as rheumatoid arthritis, Crohn's disease, psoriasis, autoimmune diseases such as multiple sclerosis, lupus, psoriasis, type 1 diabetes. Advantageously the compounds of the invention are particularly indicated for their use in the treatment or prevention of neurodegenerative diseases such as for example Parkinson's disease or Alzheimer's disease.

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

According to a fourth aspect, the invention relates to the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, as an active ingredient, for the preparation of a medicament for the treatment of diseases in which the NURR-1 receptor is involved, especially the aforementioned diseases, and more particularly neurodegenerative diseases such as, for example, Parkinson's disease or Alzheimer's disease.

According to a fifth aspect, the invention relates to a method for treating diseases in which the NURR-1 receptor is involved, in particular the aforementioned diseases and more particularly 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.

detailed description

The term "alkyl" means a saturated hydrocarbon chain which may be linear or branched. For example, and without limitation, an alkyl group having 1 to 4 carbon atoms may be methyl, ethyl, propyl, butyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl, 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 atoms (s). ) of halogen. By way of example, mention may be made of difluoromethyl or trifluoromethyl groups.

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

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

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

"Heterocycle having 5 to 7 members" is understood to mean a saturated, unsaturated or partially unsaturated monocycle comprising from 1 to 3 heteroatoms, preferably 1 or 2 heteroatoms, chosen from nitrogen, oxygen and sulfur. By way of example of an unsaturated monocycle, mention may be made of pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, furanyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and azepinyl groups. oxepinyl or thiepinyl. As examples of saturated monocycle, mention may be made of pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, imidazolidinyl, thiazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or hexahydroazepinyl groups. As an example of a partially unsaturated monocycle, mention may be made of the dihydro (is) oxazole group.

"Heterocycle having 5 to 15 members" is understood to mean a monocyclic, bicyclic or tricyclic group, optionally fused, unsaturated or partially unsaturated, comprising from 1 to 4 heteroatoms, preferably from 1 to 3 heteroatoms, and more preferably 1 or 2 heteroatoms, selected from nitrogen, oxygen and sulfur. By way of examples, mention may be made of pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, furanyl, thienyl, thiazolyl, isothiazolyl, thiadiazolylpyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoquinolyl and quinolyl groups. 4-dihydroquinolinyl, 2,4-dihydroquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 1H-pyrrolo [3,2-b] pyridinyl, benzimidazolyl, benzopyrazinyl, indolyl, 2,3-dihydroindolyl, indolynyl, benzofuranyl, 2, 3-dihydrobenzofuranyl, benzothiazolyl, benzothiadiazolyl, benzisoxazolyl, 3,4-dihydro-1,4-benzoxazinyl, 2,4-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzodioxinyl, imidazothiazolyl, benzoxazolyl, benzoxazinyl, 4,5-dihydro-1,5-benzoxazepinyl, 2,3-dihydropyrido [4,3-b] [1,4] oxazinyl, 3,4-dihydropyrido [3,2-b] [1,4] oxazinyl, spiro [benzoxazine-2, 1 cyclobutane] -yl, chromanyl, chromenyl, spiro [chroman-2, r-cyclobutane], spiro [2-chromene, 1-cyclobutane], spiro [cyclopentane-1,3 ' -i ndolin] -yl, spiro [indoline-3,3'-tetrahydrofuran] -yl, spiro [indoline-3,3'-tetrahydropyran] -yl, dihydrocyclopropa [b] indol-2-yl, hexahydrocarbazolyl, tetrahydrocarbazolyl, dihydrocarbazole or tetrahydrocyclopenta [ b] indol-4-yl.

The compounds of formula (I) may be used in the form of free acids or in the form of salts or in the form of amides or esters, said salts being obtained by combining the acid with a mineral base or organic nontoxic, preferably pharmaceutically acceptable. Among the mineral bases, it is possible to use, for example, hydroxides of sodium, potassium, magnesium or calcium. Examples of organic bases which can be used are amines, amino alcohols, basic amino acids such as lysine or arginine or compounds carrying a quaternary ammonium function, such as, for example, betaine or choline. The salts of the acids of formula (I) with a mineral or organic base can be obtained in a conventional manner, using methods that are well known to those skilled in the art, for example by mixing stoichiometric quantities of compound of formula (I) and of the base in a solvent, such as for example water or a hydroalcoholic 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 other three each represent CRi. ! 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 CRi.

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

(II) wherein: W, X, Y and Z are as defined above for compounds of formula (I);

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

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

Another preferred subfamily of the compounds of formula (II) is that for which Het represents a heterocycle having from 5 to 12 ring members optionally substituted with 1 to 4 (C 1 -C 4) alkyl (s) optionally substituted with 1 to 3 halogen (s). As particularly preferred compounds, mention may be made of the following compounds: 1- [6- [2,2-dimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazin-4-yl] -2-pyridyl acid] azetidine-3-carboxylic acid; 1- [4- [2,2-dimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazin-4-yl] -2-pyridyl] azetidine-3-carboxylic acid; 1- [2- [2,2-dimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazin-4-yl] -4-pyridyl] azetidine-3-carboxylic acid; Sodium 1 - [5- [2,2-dimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazin-4-yl] -3-pyridyl] azetidine-3-carboxylate; sodium 1- [2- [2,2-dimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazin-4-yl] pyrimidin-4-yl] azetidine-3-carboxylate; Tert-butylammonium 1- [2- [2,2-dimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazin-4-yl] -6-methyl-4-pyridyl] azetidine-3-carboxylate; Tert-butylammonium 1 - [2- [2-isobutyl-7- (trifluoromethyl) -2,3-dihydro-1,4-benzoxazin-4-yl] -4-pyridyl] azetidine-3-carboxylate; sodium 1- [2- [2,2,3-trimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazin-4-yl] -4-pyridyl] azetidine-3-carboxylate; sodium 1- [6- (7-isopropyl-2,2-dimethyl-3,4-dihydro-1,4-benzoxazin-5-yl) -2-pyridyl] azetidine-3-carboxylate; and the 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 (I), unless otherwise indicated.

According to a first embodiment, the compounds of formula (I), in which one of the substituents W, X, Y and Z represents N and the other three represent CRi, can be prepared as described in Scheme 1 or in FIG. These schemes illustrate the case where R 1 = H, but the procedures described also apply to the case where R 1 = (C 1 -C 4) alkyl.

Diagram 1

Hal = Cl, Br, I

The pyridine 1 is coupled by a Buchwald reaction with the heterocycle 2 in the presence of a palladium 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 ester 3 (obtained by conversion of azetidine-3-carboxylic acid according to the procedure described in WO 2009/135842, route 36) in the presence of a base such as cesium carbonate, a palladium catalyst such as Pd2 (dba) 3 and a ligand such as XantPhos, to give compound 4. Compound 4 is finally saponified according to a procedure well known to man of the art to give the desired azetidine-3-carboxylic acid.

Figure 2

Hal = Cl, Br, I

The pyridine 6 is coupled by a Buchwald reaction with the ester 3 in the presence of a base such as cesium carbonate, a palladium catalyst such as Pd2 (dba) 3 and a ligand such as XantPhos for give the compound 7. This compound is then coupled with a heterocycle in the presence of a palladium catalyst such as palladium acetate, a ligand such as Xphos and a base such as cesium carbonate, to give compound 8. Compound 8 is finally saponified according to a procedure well known to those skilled in the art to give the desired azetidine-3-carboxylic acid.

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 CRi, can be prepared as described in diagram 3. This diagram illustrates the where R = H, but the procedure described also applies to the case where R! = (C 1 -C 4) alkyl.

Figure 3

Hal = Cl, Br, I

Pyrimidine 9 is coupled with Tester 3 in the presence of a base such as triethylamine to give compound 10. This compound is then coupled with a heterocycle as described for Scheme 2, to give compound 11. Compound 11 is finally saponified according to a procedure well known to those skilled in the art to give the desired azetidine-3-carboxylic acid.

According to a third embodiment, the compounds of formula (I), in which one of the substituents W, X, Y and Z represents N and the other three represent CRi, can be prepared as described in scheme 4. This scheme illustrates the case where R 1 = H, but the procedure described also applies to the case where R 1 = (C 1 -C 4) alkyl.

Figure 4

Hal = Cl, Br, I

Pyridine 1 is coupled with ester 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 Pd complex. (dppf) Cl 2, CH 2 Cl 2, to give compound 14. Compound 14 is finally saponified according to a procedure well known to those skilled in the art to give the desired azetidine-3-carboxylic acid.

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

wherein W, X, Y, Z and Het are as defined for formula (I) and R represents a (CrC6) alkyl or a - (CH2) - NR6R7 group in which R6 and R7 each independently represent hydrogen , (C1-C4) alkyl or (C3-C6) cycloalkyl, and n is 0.1 or 2.

The following examples of preparation of compounds according to formula (I) will allow a better understanding of the invention.

In these examples, which are not limiting to the scope of the invention, the term "preparation" means the examples describing the synthesis of intermediate compounds and "examples" those describing the synthesis of compounds of formula (I) according to invention.

The following abbreviations have been used:

AcOEt ethyl acetate

AcOK Potassium Acetate! CHCI3 chloroform

Cs2C03 cesium carbonate DMSO dimethylsulfoxide eq equivalent h hour! K2C03 potassium carbonate LC-MS mass spectroscopy by liquid chromatography

LiOH lithium hydroxide

MgSCL magnesium sulfate min minute I mL milliliter mmol millimole

NaOH soda

Pd2 (dba) 3 tris (dibenzylideneacetone) dipalladium (0)

Pd (dppf) Cl2, CH2Cl2 [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II), complex (1: 1) with dichloromethane PF mp

Yield at RT room temperature THF tetrahydrofuran) XantPhos 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene

Xphos 2- (dicyclohexylphosphino) -2 ', 4', 6'-triisopropylbiphenyl

The nuclear magnetic resonance (NMR) * H spectra were made using a Bruker Avance 400 MHz microBay spectrometer (9.4 Tesla magnet), equipped with a> BBFO measurement probe, multi diameter nuclei 5 mm, Z gradient and lock 2H or a Bruker Avance 500 MHz microBay spectrometer (11.7 Tesla magnet), equipped with a BBI measuring probe, multi-core diameter 5 mm, Z-gradient and 2H lock, or a 300 MHz Bruker DPX spectrometer (7.05 Tesla magnet), equipped with a BBFO measurement probe, multi-core diameter 5 mm, Z gradient and lock 2H. The chemical shifts (δ), calculated with respect to TMS (tetramethylsilane), are expressed in parts per million (ppm). For each signal, the number of protons and the form of the signal are indicated (s for singlet, for singlet widened, d for doublet, dd for doublet split, dt for triplet split, t for triplet, q for quadruplet, m for multiplet, hept for heptuplet). The working frequency (in MHz) and the solvent used are indicated for each compound.

The mass spectra (LC-MS) were performed using a Waters-branded Acquity UPLC-UV-MS spectrometer equipped with a BEH C18 Acquity UPLC column with the following characteristics: 50x2.1mm 1.7 pm ; 0.8 mL / min - 45 ° C; 210 260 nm; eluent H20 + CH3COOH 0.1 (A) / acetonitrile + CH3COOH 0.1 (B); gradient 5-95% in B in 2.5 min then 95% in B up to 3 min / 5 min.

Melting points were measured on the OptiMelt MP Al 00.

The ambient temperature is 20 ° C + 5 ° C.

Preparation 1: 4- (6-Chloro-2-pyridv) -2,2-dimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazine

In a Q-tube reactor, 250 mg of 2-bromo-6-chloropyridine (1.3 mmol, 1 eq) in 7.5 ml of toluene under nitrogen and 300 mg of 2,2-dimethyl-7 were introduced. - (trifluoromethyl) -3,4-dihydro-1,4-benzoxazine (preparation 65 of application PCT / FR2015 / 050398) (1.3 mmol, 1 eq.), 5.8 mg of palladium acetate (0 , 03 mmol, 0.02 eq), 25 mg of Xphos (0.05 mmol, 0.04 eq), 7.9 mg of phenylboronic acid (0.06 mmol, 0.05 eq) and 846 mg of Cs2CO3 (2.60 mmol, 2 eq) were 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 AcOEt, the organics were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by RP18 silica flash chromatography using 60% to 80% acetonitrile / water eluent to give 151 mg of the title compound as a yellow resin.

Yield: 34%. Ή NMR (300 MHz, CHCl 3 -d) δ 1.31 (s, 6H) 3.86 (s, 2H) 6.86 (d, 7 = 7.6 Hz, 1H) 7.07 (dd, 7 = 8.4, 2.0 Hz, 1H) ) 7.17 (d, / = 2.0 Hz, 1H) 7.20 (d, 7 = 8.4 Hz, 1H) 7.44 (d, 7 = 8.4 Hz, 1H) 7.49 (dd, 7 = 8.4.7.6 Hz, 1H) ). LC-MS: m / z (M + H) +: 343.

Preparation 2: Methyl 1-r6-r2.2-dimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazin-4-yl-2-pyridinazetidine-3-carboxymate

In a Q-tube reactor under nitrogen, 150 mg of 4- (6-chloro-2-pyridyl) -2,2-dimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazine (Preparation 1) were introduced. (0.44 mmol, 1 eq) in 2.25 mL of toluene, then 79 mg of methyl azetidine-3-carboxylate hydrochloride (0.53 mmol, 1.2 eq), 20 mg of Pd2 (dba 3 (0.02 mmol, 0.05 eq), 25 mg of XantPhos (0.04 mmol, 0.1 eq) and 570 mg of CS2CO3 (1.75 mmol, 4 eq) were added. The Q-tube was sealed and the reaction was heated overnight at 110 ° C. The reaction medium was diluted with water and with AcOEt. The aqueous phase was extracted 3 times with AcOEt, the organics were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica using 0% to 15% cyclohexane / AcOEt eluent to give 121 mg of the title compound as a yellow resin.

Yield: 65%. 1H NMR (300 MHz, CHCl3-rf) δ ppm 1.30 (s, 6H) 3.47 - 3.65 (m, 1H) 3.77 (s, 3H) 3.78 (s, 2H) 4.11 - 4.26 (m, 4H) H) 5.89 (d, 7 = 7.9 Hz, 1H) 6.60 (d, 7 = 7.9 Hz, 1H) 7.02 (dd, 7 = 8.7, 2.2Hz, 1H) 7.13 (d, 7 = 2.2Hz, 1H) H) 7.35 (t, 7 = 7.9 Hz, 1H) 7.49 (d, 7 = 8.7 Hz, 1H). LC-MS: m / z (M + H) +: 422.

Example 1: 1- (6H-2,2-dimethyl-7-trifluoromethyl) -3H-1,4-benzoxazin-4-yl-2-pyridaznazetidine-3-carboxy acid

To a solution of methyl 1- [6- [2,2-dimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazin-4-yl] -2-pyridyl] azetidine-3-carboxylate (120 mg) ( Preparation 2) (0.28 mmol, 1 eq) in 3.6 mL of THF were added 10.2 mg of LiOH (0.43 mmol, 1.50 eq) dissolved in 2.4 mL of water. The mixture was stirred for 2 h at RT, then concentrated under reduced pressure to remove THF. A solution of 10% acetic acid in water was added until precipitation. The precipitate obtained was filtered and dried in an oven to give 105 mg of the title compound as a beige solid.

Yield: 90%. 2H NMR (400MHz, DMSO-rf6) δ ppm 1.26 (s, 6H) 3.44 - 3.56 (m, 1H) 3.74 (s, 2H) 3.97 (dd, / = 7.8, 6.1Hz, 2H) 4.05 - 4.14 (m, 2H) 6.01 (d, / = 7.8 Hz, 1H) 6.55 (d, / = 8.0.0 Hz, 1H) 7.06 - 7.14 (m, 2H) 7.42-7.52 (m, 1H) 7.60 (d, / = 9.0 Hz, 1H). LC-MS: m / z (M + H) +: 408. mp: 66-75 ° C.

Preparation 3: 4- (2-chloro-4-pyridyl) -2,2-dimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazine

The compound was synthesized according to the procedure described in Preparation 1, starting from 2-chloro-4-iodopyridine and 2,2-dimethyl-7- (trifluoromethyl) -3,4-dihydro-1,4-benzoxazine ( Preparation 65 of PCT / FR2015 / 050398) to give 245 mg of the title compound as a pale yellow solid.

Yield: 29%. 1H NMR (300 MHz, CHCl 3 -Z) δ ppm 1.33 (s, 6H) 3.52 (s, 2H) 7.04 (dd, / = 5.8, 2.2Hz, 1H) 7.06 - 7.13 (m, 2H) 7.19 (d, / = 2.2 Hz, 1H) 7.35 (d, / = 8.4 Hz, 1H) 8.20 (d, / = 5.8 Hz, 1H). LC-MS: m / z (M + H) +: 343.

Preparation 4: 1- (4-Amyl) -2-dimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazin-4-yl-2-pyridylazetidine-3-methyl carboxymate

The compound was synthesized according to the protocol described in Preparation 2, starting from 4- (2-chloro-4-pyridyl) -2,2-dimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazine (preparation 3) to give 208 mg of the title compound as a yellow oil.

Yield: 71%. ι NMR (300 MHz, CHCl 3 -Z) δ ppm 1.33 (s, 6H) 3.48 (s, 2H) 3.51 - 3.66 (m, 1H) 3.76 (s, 3H) 4.15 - 4.27 (m, 4H) ) 6.03 (d, / = 1.1.9 Hz, 1H) 6.50 (dd, / = 5.8, 1.9 Hz, 1H) 7.03 (dd, / = 8.6,1.9 Hz, 1H) 7.14 (d, / = 1.9 Hz, 1H) 7.32 (d, / = 8.6 Hz, 1H) 8.03 (d, / = 5.8 Hz, 1H). LC-MS: m / z (M + H) +: 422.

Example 2: 1- (4R) -2-Dimethyl-7-fluorifluoromethyl) -3H-1,4-benzoxazin-4-yl-2-pyridyl-azetidine-3-carboxy acid

The compound was synthesized according to the protocol described in Example 1, starting from 1- [4- [2,2-dimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazin-4-yl] -2 methylpyridyl] azetidine-3-carboxylate (Preparation 4) to give 144 mg of the title compound as a yellow solid.

Yield: 80%. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (s, 6H) 3.42 - 3.54 (m, 1H) 3.60 (s, 2H) 3.90 - 4.02 (m, 2H) 4.03 - 4.14 (m) , 1H) 6.12 - 6.21 (m, 1H) 6.60 (dd, 7 = 5.8,1.8 Hz, 1H) 7.06 - 7.16 (m, 2H) 7.36 (d, 7 = 8.8 Hz, 1H) 7.95 ( d, 7 = 5.8 Hz, 1H). LC-MS: m / z (M + H) +: 408. MP: 100-107 ° C.

Preparation 5: Methyl 1- (2-chloro-4-pyridyl) azetidine-3-carboxylate

The compound was synthesized according to the procedure described in Preparation 2, from 2-chloro-4-iodopyridine and methyl azetidine-3-carboxylate hydrochloride to give 142 mg of the title compound as a pale yellow solid.

Yield: 30%. NMR (300 MHz, CHCl3-7) δ ppm 3.50 - 3.68 (m, 1H) 3.78 (s, 3H) 4.09 - 4.24 (m, 4H) 6.18 (dd, 7 = 5.8, 2Hz, 1H) 6.26 (d, 7 = 2 Hz, 1H) 7.99 (d, 7 = 5.8 Hz, 1H). LC-MS: m / z (M + H) +: 227.

Preparation 6: Methyl-1-methyl-2,2-dimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazin-4-yl-4-pyridyl-11-azetidin-3-carboxymate

The compound was synthesized according to the protocol described in Preparation 1, starting from methyl 1- (2-chloro-4-pyridyl) azetidine-3-carboxylate (Preparation 5) and 2,2-dimethyl-7- ( trifluoromethyl) -3,4-dihydro-1,4-benzoxazine (Preparation 65 of PCT / FR2015 / 050398) to give 174 mg of the title compound as a pale yellow oil.

Yield: 66%. 1H NMR (300 MHz, CHCl3-d) δ ppm 1.31 (s, 6H) 3.51 - 3.65 (m, 1H) 3.77 (s, 3H) 3.78 (s, 2H) 4.05 - 4.18 (m, 4H) ) 5.98 (dd, 7 = 5.9, 1.8 Hz, 1H) 6.19 (d, 7 = 1.8 Hz, 1H) 7.03 (dd, 7 = 8.6, 2.1 Hz, 1H) 7.14 (d, 7 = 1.8 Hz, 1H) 7.45 (d, 7 = 8.6 Hz, 1H) 8.02 (d, 7 = 5.9 Hz, 1H). LC-MS: m / z (M + H) +: 422.

Example 3: 1- (2,2-Dimethyl) -7- (trifluoromethyl) -3H-1,4-benzoxazin-4-yl-4-pyridyl-11-azetidine-3-carboxylic acid

The compound was synthesized according to the protocol described in Example 1, starting from 1- [2- [2,2-dimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazin-4-yl] -4 methylpyridyl] azetidine-3-carboxylate (Preparation 6) to give 138 mg of the title compound as a white solid.

Yield: 86%. 1H NMR (400MHz, DMSO-d6) δ ppm 1.26 (s, 6H) 3.49 - 3.58 (m, 1H) 3.71 (s, 2H) 3.96 (dd, 7 = 7.8, 5.9Hz, 2H) 4.03 - 4.12 (m, 2H) 6.12 (dd, 7 = 5.7, 1.9 Hz, 1H) 6.18 (d, 7 = 1.9 Hz, 1H) 7.06 - 7.12 (m, 2H) 7.54 (d, 7 = 8.6) Hz, 1H) 7.93 (d, 7 = 5.7 Hz, 1H). LC-MS: m / z (M + H) +: 408. Mp 115-121 ° C.

Preparation 7: Methyl 1- (5-bromo-3-pyridyl) azetidine-3-carboxymate

The compound was synthesized according to the protocol described in Preparation 2, from 3,3-dibromopyridine and methyl azetidine-3-carboxylate hydrochloride to give 1050 mg of the title compound as a yellow oil. .

Yield: 52%. 1H NMR (300 MHz, DMSO- / 6) δ ppm 3.60 - 3.74 (m, 1H) 3.68 (s, 3H) 3.99 (dd, / = 7.9, 5.8 Hz, 2H) 4.08 - 4.17 (m, 2H) 7.12 (t, / = 2.2 Hz, 1H) 7.82 (d, / = 2.2 Hz, 1H) 7.99 (d, / = 2.2 Hz, 1H). LC-MS: m / z (M + H) +: 271.

Preparation 8: 1- (5-Amino-2,2-dimethyl-7-trifluoromethyl) -3H-1,4-benzoxazin-4-yl-3-methylpyridylazetidine-3-carboxymate

The compound was synthesized according to the protocol described in Preparation 2, starting from methyl 1- (5-bromo-3-pyridyl) azetidine-3-carboxylate (Preparation 7) and 2,2-dimethyl-7- ( trifluoromethyl) -3,4-dihydro-1,4-benzoxazine (Preparation 65 of PCT / FR2015 / 050398) to give 360 mg of the title compound as a yellow resin.

Yield: 66%. 1H NMR (400 MHz, DMSO-Z6) δ ppm 1.33 (s, 6H) 3.32 (s, 3H) 3.54 (s, 2H) 3.69 -3.74 (m, 1H) 3.97 (dd, / = 7.6 , 5.9 Hz, 2H) 4.12 (dt, / = 8.6, 7.6 Hz, 2H) 6.81 (t, / = 2.3 Hz, 1H) 6.94 (d, / = 8.1 Hz, 1H) 7.01 - 7.07 (m , 2H) 7.67 (d, / = 2.3 Hz, 1H) 7.95 (d, / = 2.3 Hz, 1H). LC-MS: m / z (M + H) +: 422.

Example 4: sodium 1-r5-r2.2-dimethyl-7- (trifluoromethyl-3H-1,4-benzoxazin-4-yl) -3-pyridaznazetidine-3-carboxymate

280 mg of methyl 1- [5- [2,2-dimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazin-4-yl] -3-pyridyl] azetidine-3-carboxylate (preparation 8) ( 0.66 mmol, 1 eq) were dissolved in 2.8 mL of THF. A solution of 24 mg (0.6 mmol, 0.9 eq) of NaOH in 1.4 mL of water was added and the mixture was stirred for one hour 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 with diethyl ether. The aqueous phase was lyophilized to give 258 mg of the title compound as an off-white powder.

Yield: 98%. 1H NMR (400 MHz, DMSO-4) δ ppm 1.33 (s, 6H) 3.03 - 3.15 (m, 1H) 3.54 (s, 2H) 3.81 - 3.88 (m, 2H) 3.93 (dd, .7 = 8.4, 7.3 Hz, 2H) 6.68 (t, 7 = 2.3 Hz, 1H) 6.91 (d, 7 = 9.0 Hz, 1H) 7.01 - 7.06 (m, 2H) 7.59 (d, 7 = 2.3 Hz , 1H) 7.86 (d, 7 = 2.3 Hz, 1H). LC-MS: m / z (M + H) +: 408. MP: 157-160 ° C.

Preparation 9: Methyl 1- (2-chloropyrimidin-4-vPazetidine-3-carboxymate) 1 g of 2,4-dichloropyrimidine (6.71 mmol, leq), 1.02 g of azetidine-3-carboxylic acid hydrochloride. methyl (6.71 mmol, 1 eq), and 2.34 mL of triethylamine (16.78 mmol, 2.5 eq) were dissolved in 10 mL of 1,4-dioxane and stirred for 24 h at RT. The reaction mixture was diluted with water and extracted 3 times with EtOAc.The organic phases were washed with brine, dried over MgSCL, filtered and concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel. using a 1% dichloromethane / methanol eluent to give 640 mg of the title compound as a white powder.

Yield: 42%. 1 H NMR (300 MHz, DMSO-rf 6) δ ppm 3.62 - 3.74 (m, 1H) 3.68 (s, 3H) 4.13 (dd, 7 = 9.4, 5.8 Hz, 2H) 4.23 - 4.31 (m, 2H) H) 6.43 (d, 7 = 5.9 Hz, 1H) 8.07 (d, 7 = 5.9 Hz, 1H). LC-MS: m / z (M + H) +: 228.

Preparation 10: 1- (2-Amino-2,2-dimethyl) -7- (trifluoromethyl) -3H-1,4-benzoxazin-4-ylpyrimidin-4-ylazetidine-3-methyl carboxymate

The compound was synthesized according to the protocol described in Preparation 2, starting from methyl 1- (2-chloropyrimidin-4-yl) azetidine-3-carboxylate (Preparation 9) and 2,2-dimethyl-7- (trifluoromethyl) -3,4-dihydro-1,4-benzoxazine (Preparation 65 of PCT / FR2015 / 050398) to give 136 mg of the title compound as a colorless resin.

Yield: 50%. 1H NMR (300 MHz, DMSO-76) δ ppm 1.25 (s, 6H) 3.59 - 3.73 (m, 1H) 3.68 (s, 3H) 4.02 (s, 2H) 4.10 (dd, 7 = 8.9 , 5.8 Hz, 2H) 4.18 - 4.28 (m, 2H) 6.02 (d, 7 = 5.7 Hz, 1H) 7.10 (d, 7 = 2 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: m / z (M + H) +: 423.

Example 5α1-β2-r2.2-dimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazin-4-ylpyrimidin-4-ylazetidine-3-sodium carboxilate

The compound was synthesized according to the protocol described in Example 4, starting from 1- [2- [2,2-dimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazin-4-yl] pyrimidine. Methyl 4-yl] azetidine-3-carboxylate (Preparation 10) to give 120 mg of the title compound as a white powder.

Yield: 89%. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (s, 6H) 2.95 - 3.10 (m, 1H) 3.87 - 4.12 (m, 6H) 5.91 (d, .7 = 5.7 Hz, 1H ) 7.09 (d, / = 2Hz, 1H) 7.15 (dd, / = 8.7, 2Hz, 1H) 7.95 (d, / = 5.7Hz, 1H) 8.30 (d, / = 8.7 Hz, 1H) ). LC-MS: m / z (M + H) +: 409 mp: 71-97 ° C.

Preparation 11: 4- (4-Bromo-6-methyl-2-pyridyl) -2,2-dimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazine

The compound was synthesized according to the protocol described in Preparation 2, starting from 2,4-dibromo-6-methylpyridine and 2,2-dimethyl-7- (trifluoromethyl) -3,4-dihydro-1,4-4. Benzoxazine (Preparation 65 of PCT / FR2015 / 050398) to give 391 mg of the title compound as a pale yellow oil.

Yield: 27%. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.27 (s, 6H) 2.39 (s, 3H) 3.79 (s, 2H) 7.10 -7.19 (m, 3H) 7.28 - 7.33 (m, 1H) H) 7.62 (d, / = 9.2 Hz, 1H). LC-MS: m / z (M + H) +: 401.

Example 6: 1- [2,2-Dimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazin-4-yl] -6-methyl-4-pyridyl] azetidine-3-carboxylic acid

The compound was synthesized according to the protocol described in Preparation 2, starting from 4- (4-bromo-6-methyl-2-pyridyl) -2,2-dimethyl-7- (trifluoromethyl) -3H-1,4 benzoxazine (preparation 11) and methyl azetidine-3-carboxylate hydrochloride in THF at 130 ° C to give 124 mg of the title compound as a colorless resin.

Yield: 59%. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.27 (s, 6H) 2.27 (s, 3H) 3.48 - 3.60 (m, 1H) 3.69 (s, 2H) 3.94 (dd, / = 7.8, 5.9 Hz, 2H) 4.02 - 4.11 (m, 2H) 6.00 (d, / = 1.6 Hz, 1H) 6.04 (d, / = 1.6 Hz, 1H) 7.03 - 7.12 (m, 2H) 7.53 ( d, / = 8.4 Hz, 1H). LC-MS: m / z (M + H) +: 422.

Example 7: tert-Butyl ammonium 1H-2,2-dimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazin-4-yl-6-methyl-4-pyridvllazetidine-3-carboxymate

75 mg of 1- [2- [2,2-dimethyl-7- (trifhioromethyl) -3H-1,4-benzoxazin-4-yl] -6-methyl-4-pyridyl] azetidine-3-carboxylic acid ( Example 6) (0.18 mmol, 1 eq) were dissolved in 5 mL of THF. 56 μl of tert-butylamine (0.53 mmol, 3 eq) were added and the mixture was stirred at RT for 1 hour and 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 of the title compound as a white powder.

Yield: 22%. 1 H NMR (400 MHz, DMSO- / 6) δ ppm 1.26 (s, 6H) 2.25 (s, 3H) 3.18 - 3.29 (m, 1H) 3.82 - 3.90 (m, 2H) 3.91 - 3.99 ( m, 2H) 5.95 (s, 1H) 5.97 (s, 1H) 7.03 - 7.11 (m, 2H) 7.51 (d, / = 8.1 Hz, 1H). 1.21 (s, 7H, 0.8 eq of tBiiNH2). LC-MS: m / z (M + H) +: 422. mp: 111-120 ° C.

Preparation 12: Methyl 1-r 2 -F 2 -isobutyl-7- (trifluoromethyl) -2,3-dihydro-1,4-benzoxazin-4-yl-4-pyridyl-11-azetidin-3-carboxymate

In a Q-tube reactor, 192 mg of methyl 1- (2-chloro-4-pyridyl) azetidine-3-carboxylate (preparation 5) (0.85 mmol, 1.1 eq) and 200 mg of 2-isobutyl-7- (trifluoromethyl) -3,4-dihydro-2H-1,4-benzoxazine (preparation 135 of application PCT / FR2015 / 050398) in 4 mL of toluene under argon, followed by 34 mg of acetate of palladium (0.15 mmol, 0.2 eq), 77 mg of Xphos (0.16 mmol, 0.21 eq), 4.7 mg of phenylboronic acid (0.04 mmol, 0.05 eq), 502 mg Cs 2 CO 3 (1.54 mmol, 2 eq) and 100 μL water were 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 organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by preparative LC-MS (Kinetex C18 column 21.2 * 150mm * 5pm) using an H 2 O / acetonitrile gradient with 0.1% formic acid of 10-90% to give 30 mg of composed of the title in the form of an off-white powder.

Yield: 9%. NMR (300 MHz, CHCl3-Z) δ ppm 0.95 (m, 6H) 1.30 -1.41 (m, 1H) 1.58 -1.70 (m, 1H) 1.85 - 1.99 (m, 1H) 3.40 (dd, / = 12.9, 7.8 Hz, 1H) 3.54 - 3.64 (m, 1H) 3.76 (s, 3H) 4.06 - 4.13 (m, 4H) 4.14 - 4.23 (m, 1H) 4.23 - 4.30 (m, 1 H) 6.00 (dd, / = 5.7, 1.9 Hz, 1H) 6.14 (d, / = 1.9 Hz, 1H) 6.99 - 7.05 (m, 1H) 7.16 (d, / = 2.0 Hz, 1H) 7.42 (d, / = 8.6 Hz, 1H) 8.03 (d, / = 5.7 Hz, 1H).

Example 8: tert-Butylammonium 1- (2-r 2 -isobutyl) -7- (trifluoromethyl) -2,3-dihydro-1,4-benzoxazin-4-yl-4-pyridaznitidine-3-carboxymate

The compound was synthesized according to the protocol described in Example 1 using NaOH in place of LiOH, from 1- [2- [2-isobutyl-7- (trifluoromethyl) -2,3-dihydro-1, Methyl 4-benzoxazin-4-yl] -4-pyridyl] azetidine-3-carboxylate (Preparation 12) to give 21 mg of the title compound as an oil.

Yield: 72%.

This compound was used directly for the formation of the tert-butylamine salt according to the protocol described in Example 7 to give 9 mg of the title compound in the form of a white powder.

Yield: 39%. 1H NMR (400MHz, DMSO-c / e) δppm 0.90 (d, / = 4.8Hz, 3H) 0.92 (d, / = 4.8Hz, 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 (m, 1H) 3.42 - 3.50 (m, 1H) 3.83 - 3.91 (m, 2H) 3.91 - 3.99 (m, 2H) 4.07 (dd, / = 13.2, 2.6Hz, 1H) 4.20 - 4.28 (m, 1H) 6.07 (dd, / = 5.7,1.8 Hz, 1H) 6.09 (d, / = 1.8 Hz, 1H) 7.06 -7.12 (m, 2H) 7.51 (d, / = 7.9 Hz, 1H) 7.90 (d, / = 5.7 Hz, 1H). LC-MS: m / z (M + H) +: 436. MP: 162-166 ° C.

Preparation 13: Methyl-1-methyl-2-methyl-7- (trifluoromethyl) -3H-1,4-benzoxazin-4-yl-4-pyridaznazetidine-3-methyl carboxymate

The compound was synthesized according to the procedure described in Preparation 1, using K 2 CO 3 instead of CS 2 CO 3, from methyl 1- (2-chloro-4-pyridyl) azetidine-3-carboxylate (Preparation 5) and from 2,2,3-trimethyl-7- (trifluoromethyl) -3,4-dihydro-1,4-benzoxazine (preparation 277 of PCT / FR2015 / 050398) to give 87 mg of the title compound in the form of a pale yellow solid.

Yield: 17%. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.08 -1.14 (m, 6H) 1.37 (s, 3H) 3.57 - 3.74 (m, 1H) 3.68 (s, 3H) 3.98 (dd, / = 7.9, 5.8 Hz, 2H) 4.05 - 4.17 (m, 2H) 4.32 (q, / = 6.6 Hz, 1H) 6.12 (dd, / = 5.6, 1.9 Hz, 1H) 6.17 (d, / = 1.9 Hz, 1H) 7.02 - 7.14 (m, 2H) 7.48 (d, / = 7.9 Hz, 1H) 7.94 (d, / = 5.6 Hz, 1H). LC-MS: m / z (M + H) +: 436.

Example 9: 1-Al-2,2,2,3-trimethyl-7-trifluoromethyl (3H-1,4-benzoxazin-4-yl) -4

Sodium dvridvnazetidine-3-carboxymate

Na +

The compound was synthesized according to the protocol described in Example 4, starting from 1- [2- [2,2,3-trimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazin-4-yl] Methyl 4-pyridyl] azetidine-3-carboxylate (Preparation 13) to give 56 mg of the title compound as a white powder.

Yield: 76%. 1H NMR (400 MHz, DMSO-Zfi) δ ppm 1.11 (d, / = 6.6 Hz, 3H) 1.13 (s, 3H) 1.36 (s, 3H) 2.96 - 3.08 (m, 1H) 3.78 - 3.95 (m, 4H) 4.29 (q, / = 6.6 Hz, 1H) 6.03 (dd, / = 5.7,1.7 Hz, 1H) 6.07 (d, / = 1.7 Hz, 1H) 7.05 - 7.14 (m, 2H) 7.44 (d, / = 9.2 Hz, 1H) 7.88 (d, / = 5.7 Hz, 1H). LC-MS: m / z (M + H) +: 422. mp: 137-153 ° C.

Preparation 14: Methyl 1- (6-chloro-2-pyridyl) azetidine-3-carboxymate

The compound was synthesized according to the procedure described in Preparation 2, from 2,6-dichloropyridine and methyl azetidine-3-carboxylate hydrochloride to give 730 mg of the title compound as a yellow oil. .

Yield: 49%. 1H NMR (300 MHz, DMSO-d 5) δ ppm 3.60 - 3.70 (m, 1H) 3.68 (s, 3H) 4.01 (dd, / = 8.8, 5.8 Hz, 2H) 4.12 - 4.19 (m, 2) H) 6.37 (d, / = 8.3 Hz, 1H) 6.69 (d, / = 7.4 Hz, 1H) 7.54 (dd, / = 8.3, 7.4 Hz, 1H). LC-MS: m / z (M + H) +: 227.

Preparation 15: 7-Isopropyl-2,2-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaboroan-2-yl) -3,4-dihydro-1,4-benzoxazine 880 mg of 5-bromo-7-isopropyl-2 2-dimethyl-3,4-dihydro-1,4-benzoxazine (preparation 253 of PCT / FR2015 / 050398) (3.1 mmol, 1 eq) was dissolved in 13.2 mL of DMSO. 252 mg of Pd (dppf) Cl 2, CH 2 Cl 2 (0.3 mmol, 0.1 eq), 1.2 g of AcOK (12.4 mmol, 4 eq) and 3.14 g of bis (pinacol) borane ( 12.4 mmol, 4 eq) were added. The medium was stirred overnight under argon at 85 ° C. The reaction medium was diluted with water and extracted with AcOEt. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica using a cyclohexane / dichloromethane gradient of 40 to 100% to give 1.33 g of the title compound as an orange powder (containing 75 mol% of bis). (pinacol) borane).

Yield: 32%. ¹ NMR (300 MHz, DMSO-/ β) δ ppm 1.10 (d, / = 6.9 Hz, 6H) 1.22 (s, 6H) 1.29 (s, 12H) 2.61 - 2.76 (m, 1H) 3.06 (d, / = 2.1 Hz, 2H) 5.60 (se, NH) 6.61 (d, / = 2.1 Hz, 1H) 6.85 (d, / = 2.1 Hz, 1H). LC-MS: m / z (M + H) +: 332

Preparation 16: 1- (6- (7-Isopropyl-2,2-dimethyl-3,4-dihydro-1,4-benzoxazin-5-yl) -2-pyridylazetidine-3-carboxylate 448 mg of 1- (6-chloro-2-pyridyl) methyl azetidine-3-carboxylate (Preparation 14) (1.98 mmol, 1.97 eq), 1.33 g of 7-isopropyl-2,2-dimethyl-5- (4,4,5,5-dichloroethane). tetramethyl-1,3,2-dioxaborolan-2-yl) -3,4-dihydro-1,4-benzoxazine (Preparation 15) (1 mmol, 1 eq), 416 mg of potassium carbonate (3 mmol, 3 eq. and 50 mg of Pd (dppf) Cl 2, CH 2 Cl 2 (0.06 mmol, 0.06 eq) were dissolved in 3.33 mL of 1,4-dioxane and 1 mL of water. 120 ° C. for 2 hours under nitrogen The reaction medium was diluted with water and with AcOEt The aqueous phase was extracted 3 times with AcOEt, the organics were washed with brine, dried over MgSO 4 The residue was purified by preparative LC-MS (Luna C18 column 18.5 * 250mm * 10μιη) using an H 2 O / acetonitrile gradient. 0.1% formic acid 10% to 90% to give 145 mg of the title compound as a yellow oil.

Yield: 37%. 1H NMR (300 MHz, DMSO-rf6) δ ppm 1.16 (d, / = 6.8 Hz, 6H) 1.25 (s, 6H) 2.75 (hept, / = 6.8 Hz, 1H) 3.12 (d, / = 2.5 Hz, 2H) 3.60 - 3.74 (m, 1H) 3.69 (s, 3H) 4.06 (dd, / = 7.8, 5.8 Hz, 2H) 4.15 - 4.24 (m, 2H) 6.34 (d, 7 = 8.1 Hz, 1H) 6.57 (d, 7 = 1.9 Hz, 1H) 6.97 (d, 7 = 1.9 Hz, 1H) 7.07 (d, 7 = 7.6 Hz, 1H) 7.62 (m, 1H) 7.93 (se, NH). LC-MS: m / z (M + H) +: 396.

Example 10: sodium 1-r 6 -f7-isopropyl [-2,2-dimethyl-3,4-dihydro-1,4-benzoxazin-5-yl] -2-pyridylazetidine-3-carboxymate

The compound was synthesized according to the protocol described in Example 4, starting from 1- [6- (7-isopropyl-2,2-dimethyl-3,4-dihydro-1,4-benzoxazin-5-yl) Methyl 2-pyridyl] azetidine-3-carboxylate (Preparation 16) to give 120 mg of the title compound as a white powder.

Yield: 87%. 1 H NMR (400 MHz, DMSO-4) δ ppm 1.16 (d, 7 = 6.8 Hz, 6H) 1.25 (s, 6H) 2.74 (hept, 7 = 6.8 Hz, 1H) 3.00 - 3.10 (m, 1H) 3.12 (d, 7 = 2.4 Hz, 2H) 3.89 - 4.02 (m, 4H) 6.22 (d, 7 = 7.9 Hz, 1H) 6.56 (d, 7 = 1.8 Hz, 1H) 6.94 - 7.02 (m, 2H) 7.54 (t, 7 = 7.9 Hz, 1H) 8.31 (se, NH). LC-MS: m / z (M + H) +: 382. mp: 167-174 ° C.

Pharmacological activity

The compounds of the invention have been subjected to biological tests so as to evaluate their potential to treat or prevent certain neurodegenerative pathologies.

The ability of the compounds according to the invention to act as an activator of the heterodimers formed by the nuclear receptor NURR-1 and the nuclear receptors RXR was measured by an in vitro test.

A transactivation test was used as a primary screening test. Cos-7 cells were co-transfected with a plasmid expressing a human NURR-1-Gal4 receptor chimera, a plasmid expressing the human RXR receptor (RXRα or RXRγ receptor) and a 5Gal4pGL3-TK-Luc reporter plasmid. Transfections were performed using a chemical agent (Jet PEI).

The transfected cells were dispensed into 384-well plates and allowed to stand for 24 hours.

At 24 hour time the culture medium was changed. The products to be tested were added (final concentration between 10 -4 and 3.10-10 M) in the culture medium. After a night of incubation, luciferase expression was measured after addition of "SteadyGlo" according to the manufacturer's instructions (Promega). 4 - [[6-methyl-2-phenyl-5- (2-propenyl) -4-pyrimidinyl] amino] -benzoic acid (named XCT0135908, described by Wallen-Mackenzie et al., 2003, Genes & Development 17 : 3036-3047) at 2.10'5 M (RXR agonist) was used as a reference.

Induction levels (Emax) were calculated based on the basal activity of each heterodimer. The results were expressed as a percentage of the induction level relative to the induction level obtained with the reference (the induction level of the reference is arbitrarily equal to 100%). By way of example, among the compounds according to the invention, the following results expressed as a percentage relative to a reference compound NURR-1 / RXR activator (XCT0135908) are obtained.

Table 1

The compounds according to the invention have an induction level of up to 119% (NURR1 / RXRa) and 133% (NURR1 / RXRy) and EC50s up to 33nM (NURR1 / RXRa) and 86nM (NURR1). / RXRy). The invention also relates to a pharmaceutical composition containing, as active ingredient, at least one compound of formula (I), or a pharmaceutically acceptable salt thereof.

The pharmaceutical compositions in accordance with the invention may be prepared conventionally using pharmaceutically acceptable excipients in order to obtain parenterally or, preferably, orally administrable forms, for example tablets or capsules. .

In the case of injectable forms, the compounds of formula (I) will advantageously be used in the form of soluble salts in an aqueous medium. As indicated above, the salts are preferably formed between a compound of formula (I) and a non-toxic pharmaceutically acceptable 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 dilution solvent is extemporaneously added. These preparations can be injected as an infusion or bolus depending on the needs of the patient.

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

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

Claims (13)

1. Compound of formula (I): wherein: W, X, Y and Z are each independently CR 1 or N, with the proviso that at least one and at most three of said substituents W, X, Y and Z are N; R 1 represents H or a (CrC 4) alkyl; Het represents a heterocycle having from 5 to 15 members optionally substituted with 1 to 4 substituents chosen from: a (C 1 -C 4) alkyl optionally substituted by: 1 to 3 halogen (s), a (C 3 -C 6) cycloalkyl, a heterocycle having 5-7 membered phenyl or -NR2R3 group; a (C1-C4) alkoxy optionally substituted with 1 to 3 halogen (s); (C3-C6) cycloalkyl; phenyl; a halogen; a group -NRjRs; a group -CONI ^ Rs; a group -SO2R6; and an oxo; R2 and R3 are each independently hydrogen or (C1-C4) alkyl optionally substituted with (C1-C4) alkoxy; R4 and R5 are each independently hydrogen or (C1-C4) alkyl; R6 represents a (C1-C4) alkyl, a phenyl or a group -N1 ^ Rs. 1 or a pharmaceutically acceptable salt of said compound of formula (I). A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein one of the substituents W, X, Y and Z is N, and the other three are each CR 1. 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 two others each represent CR 1. 4. Compound according to one of claims 1 to 3, of formula (II): a) wherein: W, X, Y and Z are as defined in one of claims 1 to 3; Het represents a heterocycle having 5 to 15 members optionally substituted with 1 to 4 (CrC4) alkyl (s) optionally substituted with 1 to 3 halogen (s); or a pharmaceutically acceptable salt of said compound of formula (II). 5. A compound of formula (II) according to claim 4, or a pharmaceutically acceptable salt thereof, wherein Het represents a 5- to 12-membered heterocycle optionally substituted with 1 to 4 (C 1 -C 4) alkyl (s). optionally substituted with 1 to 3 halogen (s). A compound of formula (II) according to claim 4 or claim 5, or a pharmaceutically acceptable salt thereof, wherein R1 is H. 7. Compound of formula (I) according to claim 1 which is chosen from: 1- [6- [2,2-dimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazin-4-yl] -2 acid pyridyl azetidine-3-carboxylic acid; 1- [4- [2,2-dimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazin-4-yl] -2-pyridyl] azetidine-3-carboxylic acid; 1- [2- [2,2-dimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazin-4-yl] -4-pyridyl] azetidine-3-carboxylic acid; sodium 1- [5- [2,2-dimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazin-4-yl] -3-pyridyl] azetidine-3-carboxylate; sodium 1- [2- [2,2-dimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazin-4-yl] pyrimidin-4-yl] azetidine-3-carboxylate; tert-butylammonium 1- [2- [2,2-dimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazin-4-yl] -6-methyl-4-pyridyl] azetidine-3-carboxylate; tert-butylammonium 1- [2- [2-isobutyl-7- (trifluoromethyl) -2,3-dihydro-1,4-benzoxazin-4-yl] -4-pyridyl] azetidine-3-carboxylate; sodium 1- [2- [2,2,3-trimethyl-7- (trifluoromethyl) -3H-1,4-benzoxazin-4-yl] -4-pyridyl] azetidine-3-carboxylate; sodium 1- [6- (7-isopropyl-2,2-dimethyl-3,4-dihydro-1,4-benzoxazin-5-yl) -2-pyridyl] azetidine-3-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. The compound of claim 9, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of Parkinson's disease. 11. Compound according to one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for its use in the prevention or treatment of tauopathies, diseases of the central nervous system, restless leg disease, progressive supranuclear palsy, lateral spinal muscular atrophy, Rett's syndrome, schizophrenia, bipolar disorder, manic behavior, depression and cognitive disorders, inflammatory diseases, or autoimmune diseases. A pharmaceutical composition comprising as active substance a compound of formula (I) as defined in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 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 (CrC6) alkyl or a - (CH2) n-NR6R7 group wherein R6 and R7 each independently represent hydrogen, a (C 1 -C 4) alkyl or a (C 3 -C 6) cycloalkyl, and n is 0.1 or 2.