EP2225244A1 - Imidazoý1,2-a¨pyridine-2-carboxamide derivatives, preparation thereof and application thereof in therapeutics - Google Patents

Abstract

The invention relates to compounds of the formula (I) in which: X and Y define, together with the nitrogen atom bearing them, a saturated or partially saturated monocyclic or bicyclic amino with 5 to 10 links optionally including 1 to 2 additional heteroatoms selected from O, S, N and optionally substituted by a halogen atom, a (C₁-C₆)alkyl group, a (C₁-C₆)alkoxy group, cyano, NRaRb, COOR₈, the (C₁-C₆)alkyl and (C₁-C₆)alkoxy groups being optionally substituted by one or more halogen atoms; R₁ is a hydrogen atom, a halogen atom, a (C₁-C₆)alkoxy group, a (C₁-C₆)alkyl group; R₂ is a hydrogen atom or an optionally substituted (C₁-C₆)alkyl group, an optionally substituted (C₁-C₆)alkoxy group, a (C₂-C₆)alkenyl group, a (C₂-C₆)alkynyl group, a -CO-R₅ group, a -CO-NR₆R₇ group, a CO-O-R₈ group, a -NR₉-CO-R₁₀ group, a -N=CH-NraRb group, a halogen atom, a cyano, nitro, hydroxyiminoalkyl, alkoxyiminoalkyl group, a (C₁-C₆)alkylthio group, a (C₁-C₆)alkylsulfinyl group, a (C₁-C₆)alkylsulfonyl group, a (((C₁-C₆)alkyl)₃)silylethynyl group, a -SO₂-NR₉R₁₀ group, an optionally substituted phenyl group, an optionally substituted heterocyclic group; R₃ is a hydrogen atom, a (C₂-C₆)alkyl group, a (C₁-C₆)alkoxy group or a halogen atom; R₄ is a hydrogen atom, a (C₁-C₄)alkyl group, a (C₁-C₄)alkoxy group or a fluorine atom; wherein said compounds are in the form of a base or an addition salt to an acid. The invention can be used in therapeutics.

Description

 IMIDAZO [1,2-α] PYRIDINE-2-CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE

The present invention relates to imidazo [1,2-a] pyridine-2-carboxamide derivatives, to their preparation and to their therapeutic application in the treatment or prevention of diseases involving Nurr-1 nuclear receptors, also called NR4A2, NOT, TINUR, RNR-I, and HZF3.

The subject of the present invention is the compounds of formula (I):

in which :

X and Y form, with the nitrogen atom which carries them, a saturated or partially saturated mono- or bicyclic cyclic amine of 5 to 10 members optionally containing 1 to 4 additional heteroatoms chosen from O, S, N, optionally substituted by a halogen atom, a (C ₁ -C ₆ ) alkyl group, a (C ₁ -C ₆ ) alkoxy, cyano, NRaRb, COOR _{8 group} , the said (C ₁ -C ₆ ) alkyl and (C ₁ -C ₆ ) alkoxy groups being optionally substituted with one or more halogen atoms; R 1 represents a hydrogen atom, a halogen atom, a (C ₁ -C ₆ ) alkoxy group, a group

(Ci-C ₆₎ alkyl, NRcRd, alkyl and alkoxy being optionally substituted by one or more halogen atoms, hydroxy, amino or (Ci-Ce) alkoxy;

R ₂ represents one of the following groups:

. a hydrogen atom,

. a (C 1 -C ₆ ) alkyl group optionally substituted with one or more groups independently selected from hydroxy, halogen, NRaRb, (C ₁ -C ₆ ) alkoxy, phenyl,

. a (C ₁ -C ₆ ) alkoxy group optionally substituted with one or more groups chosen independently of one another from a hydroxy, a halogen atom, a group

NRaRb

. a (C ₂ -C ₆ ) alkenyl group, a (C ₂ -C ₆ ) alkynyl group, . a group -CO-Rs ₁ . a group -CO-NRsR ₇ ,. a group -CO-OR _8, a group -NRg-CO-Ri ₀ ,. a group -N = CH-NRaRb,

. a group NRuRn ₅ . a halogen atom,

. cyano, nitro, hydroxyiminoalkyl, alkoxyiminoalkyl, a (C ₁ -C ₆ ) alkylthio group, a (C ₁ -C ₆ ) alkylsulphinyl group,

. a (C ₁ -C ₆ ) alkylsulfonyl group, a _(((Ci-C) alkyl) ₃₎ silylethynyl,. a group -SO ₂ -NR ₉ R ₁₀ ,

. a phenyl group optionally substituted by one or more groups chosen independently of one another from the following atoms or groups: halogen, (Q-)

C ₆ ) alkoxy, cyano, NRaRb, -CO-R ₅ , -CO-NR ₆ R ₇ , -CO-OR ₈ , a (C ₁ -C ₆ ) alkyl group optionally substituted by one or more hydroxyl or NRaRb,

. a heterocyclic group optionally substituted with a halogen atom, a group

(C ₁ -C ₆ ) alkyl, a (C ₁ -C ₆ ) alkoxy, cyano, NRaRb, COOR _{8 group} , said (C ₁ -C ₆ ) alkyl and (QC ₆ ) alkoxy groups being optionally substituted with one or more carbon atoms; halogen or hydroxy; R ₃ represents a hydrogen atom, a (C ₂ -C ₆₎ alkyl, a (Ci-C _δ) alkoxy or halogen;

R _t represents a hydrogen atom, a (C ₁ -C ₄ ) alkyl group, a group or a fluorine atom;

R ₅ represents a hydrogen atom, a phenyl group or a (C 1 -C 8) alkyl group; R ₅ and R ₇ , which may be identical or different, represent a hydrogen atom or a (C ₁ -C ₆ ) alkyl group or form, with the nitrogen atom carrying them, a 4- to 7-membered ring optionally including another heteroatom selected from N, O or S; Rg is (Ci-C ₆₎ alkyl;

R ₉ and R ₁₀ , which may be identical or different, represent a hydrogen atom or a (C ₁ -C ₆ ) alkyl group;

Ru and Rn, which may be identical or different, represent a hydrogen atom or a (C ₁ -C ₆ ) alkyl group; Ra and Rb are independently of one another are hydrogen, (C _r C ₆₎ alkyl group or form with the nitrogen atom which carries them a 4- to 7-membered ring; Rc is hydrogen and Rd is (C1-C6) alkyl; with the exception of 2- (2,3-dihydro-1H-indol-1-ylcarbonyl) -5-methylimidazo [1,2-a] pyridine, and 2- (4-thiomorpholin-1-yl-carbonyl) 6-chloroimidazo [1,2-a] pyridine, in the form of a base or an acid addition salt.

2- (2,3-Dmhydro-1H-indol-1-ylcarbonyl) -5-methylimidazo [1,2-a] pyridine and 2- (4-thiomorpholin-1-ylcarbonyl) -6-chloroimidazo [ 1, 2-α] -pyridine, are respectively cited in libraries under the numbers RN = 878113-13-4 and RN = 951974-53-1. No pharmacological or therapeutic activity has been demonstrated for these compounds. They have been specifically excluded from formula (I) according to the present invention.

Document US 2006/0211747 also discloses a method for identifying Cdc34 inhibiting compounds, one of the compounds identified being an imidazo [1,2-α] pyridine derivative not included in formula (I) according to the present invention.

The following nomenclatures are considered as equivalent: - 2- (2,3-dihydro-1H-indol-1-ylcarbonyl) -5-methylimidazo [1,2-] pyridine and (2,3-dihydro-1H-indol) 1-yl) - (5-methylimidazo [1,2-a] pyridin-2-yl) methanone, and - 2- (4-thiomorpholin-1-ylcarbonyl) -6-chloroimidazo [1,2-a] pyridine, and (6-chloro-imidazo [1,2-a] pyridin-2-yl) -4-thiomorpholinylmethanone.

The compounds of formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including the racemic mixtures, form part of the invention.

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

These salts can be prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for the purification or the isolation of the compounds of formula (I) are also part of the invention.

The compounds of formula (I) may also exist in the form of hydrates or solvates, namely in the form of associations or combinations with one or more water molecules or with a solvent. Such hydrates and solvates are also part of the invention. In the context of the present invention, the following is meant: a halogen atom: a fluorine, a chlorine, a bromine or an iodine; an alkyl group: a linear, branched or cyclic saturated aliphatic group optionally substituted by a linear, branched or cyclic saturated alkyl group. By way of examples, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl and the like; an alkenyl group: a linear or branched, mono- or poly-unsaturated aliphatic group, comprising, for example, one or two ethylenic unsaturations; an alkoxy group: an -O-alkyl radical where the alkyl group is as previously defined; an alkynyl group: a linear or branched, mono- or poly-unsaturated aliphatic group, for example comprising one or two ethylenic unsaturations; a cyclic amine: a mono- or bicyclic group comprising from 5 to 10 members and comprising at least one nitrogen atom, which may additionally comprise 1 to 4 heteroatoms chosen from N, O and S, this group possibly being saturated or partially saturated. Examples of cyclic amines include benzoxazine, indoline, isoindoline, tetrahydroisoquinoline, morpholine, piperidine, pyrrolidine, pyrroline, tetrahydropyridine, tetrahydroquinoline, thiomorpholine, dihydroxybenzoxazine, tetrahydrothienopyridine; a heterocyclic group: mono or bicyclic group containing from 5 to 10 atoms, of which from 1 to 4 heteroatoms chosen from N, O and S, aromatic, unsaturated, saturated or partially saturated. As examples of heterocyclic groups, mention may be made of: pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, thiazole, isothiazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, triazine, furofuran , thienothiophene, pyrrolopyrrole, pyrroloimidazole, pyrrolopyrazole, pyrrolotriazole, imidazoimidazole, imidazopyrazole, furopyrrole, furoimidazole, furopyrazole, furotriazole, pyrrolooxazole, imidazooxazole, pyrazolooxazole, furooxazole, oxazolooxazole, oxazoloisoxazole, pyrroloisoxazole, imidazo -isoxazole, pyrazolo-isoxazole, isoxazolo-isoxazole, furo-isoxazole, isoxazolo-oxadiazole, pyrrolo-oxadiazole, furo-oxadiazole, isoxazolo-oxadiazole, thienopyrrole, thienoimidazole, thienopyrazole, thienotriazole, pyrrolo-thiazole, imidazothiazole, pyrazolo-thiazole , triazolo, thiazole, furo-thiazole, oxazolo-thiazole, oxazoloisothiazole, pyrrolo-isothiazole, imidazo-isothiazole, pyrazolo-isothiazole, isoxazolo- isothiazole, furo-isothiazole, pyrrolo-thiadiazole, imidazo-thiadiazole, furo-thiadiazole, isoxazolo-thiadiazole, oxazolo-thiadiazole, isothiazolo-thiadiazole, indole, isoindole, benzimidazole, indazole, indolizine, benzofuran, isobenzofuran, benzothiophene, benzo [c] thiophene, pyrrolopyridine ,, imidazopyridine, pyrazolopyridine, triazolopyridine, tétrazolopyridine, pyrrolopyrimidine, imidazopyrimidine, pyrazolopyrimidine, pyrrolopyrazine, imidazopyrazine, pyrazolopyrazine, pyrrolopyridazine, imidazopyridazine, pyrazolopyridazine, triazolopyridazine, pyrrolotriazine, furopyridine, furopyrimidine, furopyrazine, furopyridazine, furotriazine, oxazolopyridine , oxazolopyrimidine, oxazolopyrazine, oxazolopyridazine, isoxazolopyridine, isoxazolopyrimidine, isoxazolopyrazine, isoxazolopyridazine, oxadiazolopyridine, benzoxazole, benzisoxazole, benzoxadiazole, thienopyridine, thienopyrimidine, thiénopyrazine, thiénopyridazine, thiénotriazine, thiazolopyridine, thiazolopyrimidine, thiazolopyrazine, thiazolopyridazine, isothiazolopyridine, isothiazolopyrimidine, isothiazolopyrazine, isothiazolopyridazine, thiadiazolopyridine , thiadiazolopyrimidine, benzothiazole, benzoisothiazole, benzothiadiazole, quinoline, isoquinoline, cinnoline, phthalazin e, quinoxaline, quinazoline, naphthyridine, benzotriazine, pyridopyrimidine, pyridopyrazine, pyridopyridazine, pyridotriazine, pyrimidopyrimidine, pyrimidopyrazine, pyrimidopyridazine, pyrazinopyrazine, pyrazinopyridazine, pyrazinotriazine, pyridazinopyridazine. These groups may exist in saturated or partially saturated form.

Different subsets of compounds are defined hereinafter also forming part of the invention. Among the compounds of general formula (I) as defined above, a first group of compounds is constituted by the compounds for which R ₂ is different from a hydrogen and chlorine atom and the other substituents are as defined above, in the form of a base or an acid addition salt.

Among the compounds of general formula (I) as defined above, a second group of compounds is constituted by the compounds for which R ₂ represents one of the following groups:

. a (C 1 -C ₆ ) alkoxy group, a group NRnRn,

. a phenyl group optionally substituted with a -CO-R5 group, (C _r C ₆ ) alkyl itself optionally substituted by a hydroxyl;

. a heterocyclic group optionally substituted with a NRaRb, (C 1 -C 6) alkyl group optionally optionally substituted by a hydroxyl;

R ₅ represents a (C ₁ -C ₆ ) alkyl group,

Rn and Ri ₂ , which may be identical or different, represent a hydrogen atom or a group (C _r C ₆ ) alkyl;

Ra and Rb are independently of each other hydrogen, (C 1 -C ₆ ) alkyl; and the other substituents are as defined above, in the form of a base or an addition salt with an acid. Among the compounds of general formula (I) as defined above, a third group of compounds is constituted by the compounds for which R ₂ represents one of the following groups:

. a group (Ci-C ₆ ) alkoxy,. . a phenyl group optionally substituted with a group -CO-R ₅ , (C 1 -C 6) alkyl itself optionally substituted by a hydroxyl;

. a pyridyl group, a pyrazolyl group, a furyl group, an oxazolyl group, a triazolyl group, a pyrrolyl group or an imidazoyl group, optionally substituted by a NRaRb (Ci-C ₆ ) alkyl group, itself optionally substituted by a hydroxyl group; ; R ₅ represents a (C 1 -C 6) alkyl group,

Rn and Ri ₂ , which may be identical or different, represent a hydrogen atom or a (C 1 -C ₆ ) alkyl group;

Ra and Rb are independently of each other hydrogen, (C ₁ -C ₆ ) alkyl; and the other substituents are as defined above, in the form of a base or an addition salt with an acid.

Among the compounds of general formula (I) as defined above, a fourth group of compounds is constituted by the compounds for which R ₂ represents one of the following groups:

. a (C 1 -C 6) alkoxy group, a group NRnRi ₂ ,

. a phenyl group optionally substituted with a group -CO-R ₅ , (C ₁ -C ₆ ) alkyl itself optionally substituted with a hydroxyl;

. a pyridyl group optionally substituted by an amino group, a pyrazolyl group, a furyl group optionally substituted with a hydroxymethyl group, an oxazolyl group, a triazolyl group, a pyrrolyl group or an imidazoyl group;

R ₅ represents a group (Ci-C ₆ ) alkyl, Rn and Ri ₂ , identical or different, represent a hydrogen atom or a group (Q-

C ₆ ) alkyl; and the other substituents are as defined above, in the form of a base or as a salt of addition to an acid.

Among the compounds of general formula (I) as defined above, a fifth group of compounds is constituted by the compounds for which X and Y form, with the nitrogen atom which carries them, a cyclic mono or bicyclic amine which is saturated or partially saturated, 5 to 10 members, optionally comprising an additional heteroatom selected from O or S, optionally substituted with a group selected from a halogen atom, and the other substituents are as defined above, in the basic state or from acid addition salt.

Among the compounds of general formula (I) as defined above, a sixth group of compounds is constituted by the compounds for which -NXY represents a dihydrobenzoxazine, indoline, isoindoline, morpholine, piperidine, pyrrolidine, pyrroline, tetrahydropyridine, tetrahydroquinoline group, thiomorpholine, tetrahydrothienopyridine, optionally substituted by one or more halogen atoms; and the other substituents are as defined above, in the form of a base or an addition salt with an acid.

Among the compounds of general formula (I) as defined above, a seventh group of compounds is constituted by the compounds for which:

-NXY represents a dihydrobenzoxazine, indoline isoindoline, morpholine, piperidine, pyrrolidine, pyrroline, tetrahydropyridine, tetrahydroquinolea, thiomorpholine, tetrahydrothienopyridine group, optionally substituted with a halogen atom; R ₂ represents one of the following groups: a (C 1 -C ₆ ) alkoxy group, a group NR ₁₁ R ₁₂ ,

. a phenyl group optionally substituted with a group chosen from a halogen, a (C ₁ -C e) alkoxy group, a (C _r C ₆ ) alkyl group optionally substituted by a hydroxyl or a C (O) R _{5 group} ,

. a pyridyl group, a pyrazolyl group, a furyl group, an oxazolyl group, a triazolyl group, a pyrrolyl group or an imidazoyl group, optionally substituted by a NRaRb group, (CrC ₆ ) alkyl itself optionally substituted by a hydroxyl; R ₅ represents a (C ₁ -C ₆ ) alkyl group,

R ₁₁ and R ₁₂ , which may be identical or different, represent a hydrogen atom or a (C ₁ -C ₆ ) alkyl group;

Ra and Rb are independently of each other hydrogen, (C ₁ -C ₆ ) alkyl; R ₁ , R ₃ and R ₄ represent a hydrogen atom, in the form of a base or an addition salt with an acid. Among the compounds of general formula (I) as defined above, an eighth group of compounds is constituted by the compounds for which:

-NXY represents a dihydrobenzoxazine, indoline group optionally substituted with a fluorine atom, isoindoline, morpholine, piperidine, pyrrolidine, pyrroline, tetrahydropyridine, tetrahydroquinoline, thiomorpholine, tetrahydrothienopyridine;

R ₂ represents a methoxy group, a phenyl group substituted by a hydroxymethyl, hydroxyethyl, hydroxy-methyl-ethyl, acetyl, N-dimethyl group, a pyridyl group optionally substituted with an amino group, a pyrazolyl group, a furyl group optionally substituted with a hydroxymethyl group, an oxazolyl group, a triazolyl group, a pyrrolyl group or an imidazoyl group;

R 1, R ₃ and R ₄ represent a hydrogen atom, in the form of a base or an addition salt with an acid.

Among the compounds of general formula (I) as defined above, a ninth group of compounds is constituted by the compounds for which NXY represents a dihydrobenzoxazine, indoline, isoindoline, tetrahydroisoquinoline, morpholine, piperidine, pyrrolidine, pyrroline, tetrahydropyridine, tetrahydroquinoline group, thiomorpholine, tetrahydrothienopyridine, these groups being optionally substituted by a fluorine atom; R 1, R 3 and R ₄ represent a hydrogen atom;

R ₂ represents a methoxy group or a phenyl group substituted by a hydroxymethyl or N-dimethyl group, in the form of a base or an addition salt with an acid.

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

• {3- [2- (Piperidin-1-ylcarbonyl) imidazo [1,2-a] pyridin-6-yl] phenyl} methanol

• {3- [2- (2,3-Dihydro-4H-1,4-benzoxazin-4-ylcarbonyl) imidazo [1,2-b] pyridin-6-yl] phenyl} methanol

• {3- [2- (Morpholin-4-ylcarbonyl) imidazo [1,2-a] pyridin-6-yl] phenyl} methanol • 2- (1,2,5,6-Tetrahydropyridin-1-yl) carbonyl-N , N-dimethylimidazo [2-α] pyridin-6-amine

• {3- [2- (2,3-Dihydro-1H-indol-1-ylcarbonyl) imidazo [1,2-a] pyridin-6-yl] phenyl} methanol

(3- {2 - [(6-Fluoro-2,3-dihydro-1H-indol-1-yl) carbonyl] imidazo [1,2-a] pyridin-6-yl} phenyl) methanol

{3- [2- (2,5-Dihydro-1H-pyrrol-1-ylcarbonyl) imidazo [1,2-b] pyridin-6-yl] phenyl} methanol

• {3- [2 - [(1,2,5,6-Tetrahydropyridin-1-yl) carbonyl] imidazo [1,2-b] pyridin-6-yl] phenyl} methanol

{3- [2- (Pyrrolidin-1-ylcarbonyl) imidazo [1,2-a] pyridin-6-yl] phenyl} methanol

• {3- [2- (4,5,6,7-tetrahydro-thieno [3,2-c] pyridin-5-ylcarbonyl) imidazo [1,2-a] pyridin-6- yl] phenyl} methanol

2- (2,3-Dihydro-4H-1,4-benzoxazm-4-ylcarbonyl) -N, N-dimethylimidazo [1,2-a] pyridin-6-amine

{3- [2- (1,2,3,4-Tetrahydroquinolin-1-ylcarbonyl) imidazo [1,2-a] pyridin-6-yl] phenyl} methanol

• {3- [2- (1,3-Dihydro-2H-isoindol-2-ylcarbonyl) imidazo [1,2-a] pyridin-6-yl] phenyl} methanol

2- (2,3-Dihydro-1H-indol-1-ylcarbonyl) -N, N-dimethylimidazo [1,2-a] pyridin-6-amine • 2- (1,3-Dihydro-2H-isoindole) 2-ylcarbonyl) -N, N-dimethylimidazo [1,2-a] pyridin-6-amine N, N-dimethyl-2- (piperidin-1-ylcarbonyl) imidazo [1,2-a] pyridin-6-amine

2 - [(6-fluoro-2,3-dihydro-1H-indol-1-yl) carbonyl] -N, N-dimethylimidazo [1,2-a] pyridin-6-amine

N, N-dimethyl-2- (morphol-4-ylcarbonyl) imidazo [1,2-b] pyridin-6-amine • 2- (2,5-Dihydro-1H-pyrrol-1-ylcarbonyl) -N, N-dimethylimidazo [1,2-a] pyridin-6-amine

• {3- [2- (Thiomorpholin-4-ylcarbonyl) imidazo [1,2-a] pyridin-6-yl] phenyl} methanol • N, N-dimethyl-2- (pyrrolidin-1-ylcarbonyl) imidazo [1 , 2-α] pyridin-6-amine

2- (4,5,6,7-tetrahydro-thieno [3,2-c] pyridin-5-ylcarbonyl) -N, N-dimethylimidazo [1,2-a] pyridin-6-amine

• N, N-dimethyl-2- (thiomorpholin-4-ylcarbonyl) imidazo [l, 2-α] pyridin-6-amine

2- (1, 2, 5, 6-Tetrahydropyridin-1-yl) carbonyl-6-methoxy-5-methylimidazo [1,2-a] pyridine,

6- (Pyridin-2-yl) -2 - [(1,2,5,6-tetrahydropyridin-1-yl) carbonyl] imidazo [1,2-a] pyridine

2- (2,3-Dihydro-1H-indol-1-ylcarbonyl) -6- (pyridin-2-yl) imidazo [1,2-a] pyridine

2- (2,3-Dihydro-1H-indol-1-ylcarbonyl) -6- (1H-pyrazol-3-yl) imidazo [1,2-a] pyridine

6- (Furan-2-yl) -2 - [(1,2,5,6-tetrahydropyridin-1-yl) carbonyl] imidazo [1,2-a] pyridine

2- (2,3-Dihydro-1H-indol-1-ylcarbonyl) -6- (furan-2-yl) imidazo [1,2-a] pyridine

6- (Oxazol-2-yl) -2 - [(1, 2,5,6-tetrahydropyridin-1-yl) carbonyl] imidazo [1,2-a] pyridine

6- (Furan-3-yl) -2 - [(1,2,5,6-tetrahydropyridin-1-yl) carbonyl] imidazo [1,2-a] pyridine

• 2- (2 ₅ 3-dihydro-lH-indol-1-ylcarbonyl) -6- (furan-3-yl) imidazo [1, 2-α] pyridine

6- [5- (Hydroxymethyl) furan-2-yl] -2 - [(1,2,5,6-tetrahydropyridin-1-yl) carbonyl] imidazo [1,2-a] pyridine

[(1,2,5,6-tetrahydropyridin-1-yl) carbonyl] -6- (1H-1,2,4-triazol-3-yl) imidazo [1,2-a] pyridine

2- (2,3-Dihydro-1H-indol-1-ylcarbonyl) -6- (1H-1,2,4-triazol-3-yl) imidazo [1,2-a] pyridine

6- (6-Aminopyridin-2-yl) -2 - [(1,2,5,6-tetrahydropyridin-1-yl) carbonyl] imidazo [1,2-a] pyridine and its dihydrochloride

6- (6-Aminopyridin-2-yl) -2- (2,3-dihydro-1H-indol-1-ylcarbonyl) imidazo [1,2-a] pyridine and its dihydrochloride ## STR2 ##

2- (2,3-Dihydro-1H-indol-1-ylcarbonyl) -6- (1H-pyrrol-3-yl) imidazo [1,2-a] pyridine

2- (2,3-Dihydro-1H-indol-1-ylcarbonyl) -6- (furan-2-yl) imidazo [1,2-a] pyridine and its trifluoroecetate (1,1)

2- (2,3-Dihydro-1H-indol-1-ylcarbonyl) -6- [5- (hydroxymethyl) furan-2-yl] imidazo [1,2-a] pyridine and its trifluoroecetate (1,1)

6- (1H-Imidazol-4-yl) -2 - [(1,2,5,6-tetrahydropyridin-1-yl) carbonyl] imidazo [1,2-a] pyridine

2- (2,3-Dihydro-1H-indol-1-ylcarbonyl) -6- (1H-imidazol-4-yl) imidazo [1,2-a] pyridine

2 - [(1,2,5,6-Tetrahydropyridin-1-yl) carbonyl] -6- (1H-1,2,3-triazol-4-yl) imidazo [1,2-a] pyridine

2- (2,3-Dihydro-1H-indol-1-ylcarbonyl) -6- (1H-1,2,3-triazol-4-yl) imidazo [1,2-a] pyridine 6- (3-Acylphenyl) -2- (1, 2,5,6-tetrahydropyridin-1-yl) carbonyl-imidazo [1,2-a] pyridine

6- [3 - (1-hydroxyethyl) phenyl] -2- (1,2,5,6-tetrahydropyridin-1-yl) carbonyl imidazo [1,2-a] pyridine (RS)

6- [3- (1-Hydroxy-1-methylethyl) phenyl] -2- (1,2,5,6-tetrahydropyridin-1-yl) -carbonylimidazo [1,2-a] pyridine and their salts addition to an acid.

According to the invention, the compounds of general formula (I) can be prepared according to the process described in scheme 1.

Diagram 1

The first synthetic route (transformation A ₂ ) consists in preparing, according to methods known to those skilled in the art, a 2-amino-pyridine of formula (II), in which R ₁ , R ₂ , R ₃ and R 1 are defined as above, then to form the imidazo [1,2-α] pyridine ring by condensation of a halogenated derivative of 2-oxo-propionamide (lu) in which HaI represents a chlorine, bromine or iodine atom and X and Y are defined as previously by analogy with the methods described by JJ. Bourguignon et al. in Aust. J. Chem., 50, 719 (1997) and by JG Lombardino in J. Org. Chem., 30, 2403 (1965) for example.

The halogenated derivatives of 2-oxo-propionamide (DI) can be obtained for example according to the method described by R. Kluger et al. in J. Am. Chem. Soc., 106, 4017 (1984). The 2-amino-pyridines of formula (JI) in which R ₁ , R ₂ , R ₃ and R ₄ are defined as above can be prepared for example by transformation A ₁ , ie:

by a coupling reaction of a 2-aminopyridine derivative of formula (IV) in which R ₁ , R ₃ and R ₄ are defined as above and Z represents a boryl, stannyl or silyl group and a R ₂ -Z 'derivative (V) wherein R ₂ is defined as above and Z 'represents a halogen atom such as bromine or iodine or a sulfonyloxy group,

by a coupling reaction of a 2-aminopyridine derivative of formula (IV) in which R ₁ , R 3 and R ₄ are defined as above and Z represents a halogen atom such as bromine or iodine with a derivative R ₂ - Z '(V) in which R ₂ is defined as above and Z' represents a reactive group such as a boryl, stannyl or silyl group or a hydrogen atom, or by any other method known to those skilled in the art.

The second synthesis route (B ₂ transformation) consists in coupling an imidazopyridine-2-carboxylic acid or one of its derivatives of formula (VI) in which R ₁ , R ₂ , R 3 and R ₄ are defined as previously, W represents a hydroxy group, a halogen atom or a group (CrC ₆ ) alkoxy with a cyclic amine X-NH-Y of formula (VII), in which X and Y are defined as above, according to methods known from skilled person. Thus the acid may be converted beforehand into one of its reactive derivatives such as acid halide, anhydride, mixed anhydride or activated ester and then reacted with the amine (VII) in the presence of a base such as diisopropylethylamine, triethylamine or pyridine, in an inert solvent such as THF, DMF or dichloromethane. The coupling may also be carried out in the presence of a coupling agent such as CDI, EDCI ₃ HATU or HBTU under the same conditions without isolating a reactive intermediate. Alternatively, the amine (VII) can be reacted with an ester of the acid of formula (VI) in the presence of a catalyst such as trimethylaluminum according to the method of Weinreb, S. et al (Tet Lett. 1977), 18, 4171) or zirconium terbutylate.

The imidazopyridine-2-carboxylic acid derivatives of formula (VI) in which R ₁ , R ₂ , R ₃ and R ₄ are defined as above and W is hydroxy or halogen are prepared by condensation of a 2-aminopyridine of formula (II) wherein R ₁ , R ₂ , R ₃ and R ₄ are defined as above on a 3-halogeno-2-oxo-propionic acid ester of formula (VIU) in which HaI represents a halogen and W is (Q-C6) alkoxy, under the conditions similar to those used for the condensation of a derivative of formula (H) on a derivative of formula (ItI), followed if necessary by the conversion of the ester to acid and then to acid chloride or other reactive derivative (transformation B ₁ ).

The third synthesis route (C ₂ conversion) consists in coupling a derivative of general formula (EK) in which R ₁ , R ₃ , R ₄ , X and Y are defined as above and Z represents a halogen atom such as bromine or iodine, a sulfonyloxy group or a reactive group such as boryl, stannyl or silyl on a derivative of formula R ₂ -Z '(V) in which R ₂ is defined as above and

Z 'represents a reactive group such as a boryl, stannyl or silyl group or a hydrogen atom when Z represents a halogen atom or a sulphonyloxy group, or - Z' represents a halogen atom such as bromine or iodine when Z represents a reactive group such as a boryl, stannyl or silyl group or a hydrogen atom.

The derivatives of general formula (IX) in which R ₁ , R ₃ , R ₄ , X, Y and Z are defined as above can be prepared:

by condensation of a 2-amino-pyridine of formula (IV) in which R ₁ , R ₃ , R ₄ and Z are defined as above, on a 2-oxo-propionamide derivative (lu) in which HaI represents a chlorine, bromine or iodine atom and X and Y are defined as above (transformation Ci) according to methods cited for the conversion of a compound of formula (H) into a compound of formula (I) or

by amidation of an imidazopyridine-2-carboxylic acid or one of its derivatives of formula (X) in which R ₁ , R ₂ , R ₃ and R ₄ are defined as above, W represents a hydroxyl group, an atom of halogen or a group (Ci-Cβ) alkoxy with an amine X-NH-Y (Vu), in which X and Y are defined as above (transformation D ₂ ) according to methods cited for the conversion of a compound of formula (VI) of compound of formula (I).

Imidazopyridine-2-carboxylic acids or their derivatives of formula (X) in which R ₁ , R ₃ and R ₄ are defined as above, W is (C ₁ -C ₆ ) alkoxy, hydroxy or halogen and Z represents a boryl group, stannyl or silyl or a halogen atom can be prepared (Di transformation) by condensation of a 2-aminopyridine of formula (IV), wherein R ₁ , R ₃ and R ₄ are defined as above and Z represents a boryl group , stannyl or silyl or a halogen atom, with a 3-halo-2-oxo-propionic acid ester of formula (Vm), wherein Hal represents a halogen and W is a (Ci-C ₆ ) alkoxy group, under the conditions similar to those mentioned above for the condensation of 2-aminopyridines of formula (II) with a derivative of formula (VII), to obtain imidazopyridine-2-carboxylic acids or their derivatives of formula (VI) according to transfoπnation B ₁ , followed if necessary by the conversion of the ester to then acid chloride or other reactive derivative. Imidazopyridine-2-carboxylic acids or their derivatives of formula (VI), in which R ₁ , R ₂ , R ₃ and R ₄ are defined as above, W is (dC ₆ ) alkoxy, hydroxy or halogen may also be prepared ( transformation Ei) by coupling of a derivative of general formula (X), in which R ₁ , R ₃ and R ₄ are defined as above, W is (C ₁ -C ₆ ) alkoxy and Z represents a halogen atom such that bromine or iodine, a sulfonyloxy group or a reactive group such as boryl, stannyl or silyl on a derivative of formula R ₂ -Z '(V) in which R ₂ is defined as above and

Z ¹ represents a reactive group such as a boryl, stannyl or silyl group or a hydrogen atom when Z represents a halogen atom or a sulphonyloxy group, or - Z ¹ represents a halogen atom such as bromine or iodine when Z represents a reactive group such as a boryl, stannyl or silyl group or a hydrogen atom, optionally followed by the conversion of the ester to acid and then to acid chloride or other reactive derivative.

The couplings of the derivatives of formula (IV), (DC) or (X) with the products of formula (V) can be carried out by any method known to those skilled in the art, in particular by operating in the presence of catalysts based on copper or palladium, ligands such as phosphines, according to or by analogy with the methods described for example in the following references and references cited:

for Suzuki-type reactions: N. Miyaura, A. Suzuki, Chem. Rev., 95, 2457, (1995), for the Stille type reactions: V. Farina et al., Org. React, 50, 1 (1997),

for the Hiyama-type reactions: T. Hiyama et al., Top. Curr. Chem., 2002, 219, 61 (2002),

for Negishi-type reactions: E. Negishi et al., Chem. Rev. 103, 1979 (2003),

for Bellina type reactions: M. Miura et al., Chem. Lett, 200 (2007).

It is also possible to perform the coupling to form intermediately but without isolating organometallic derivatives such as zinc derivatives.

According to the invention, it is also possible to prepare the compounds of general formula (I), (VI) and (H) in which R ₂ is a heterocycle according to the processes described in scheme 2. construction of the cycle R ₂

Y

B ₂ NX (VII) H construction of the R ₂ ring

Figure 2

This synthetic route consists of the conversion of a compound of general formula (XI), (XII) or (Xπi), in which R 1, R ₃ , R ₄ , X, Y and W are defined as above and V represents a precursor group allowing the construction of the heterocycle of formula R ₂ according to the methods known to those skilled in the art. By way of example, V can represent:

a 2-haloacyl group such as bromoacetyl, or 1-halo-2-oxoalkyl, such as 1-bromo-2-oxoethyl, which can be converted, for example, into thiazolyl, imidazolyl or oxazolyl group by treatment; by thiourea, thioamide, guanidine, urea or amide derivatives,

an alkynyl group, such as ethynyl, which can be converted into a 1,2,3-triazol-4-yl group,

an acyl group such as formyl which can be converted, for example, to 1,3-dioxolanyl-2 or oxazolyl group;

a cyano group which can be converted, for example, to dihydroimidazolyl (2) or 1,3,4-triazol-2-yl group.

The compounds of general formula (XI) can be obtained from compounds of formula (XII), under the conditions described for the preparation of compounds (I) from derivatives of imidazopyridine-2-carboxylic acid of formula (VI) by B ₂ transformations.

The imidazopyridine-2-carboxylic acid derivatives of general formula (XII) can be obtained from amino-pyridines of formula (XIH) under the conditions described for the conversion of amino-pyridines of formula (II) into compounds of formula general (I) by transformation A ₂ .

The products of formula (I), and their precursors of formula (II) or (IV), may be subjected, if desired and if necessary, to obtain foπnule products (I) or to be converted into other products of formula (I) to one or more of the following transformation reactions, in any order: a) esterification reaction or amidification of acid function, b) ester function hydrolysis reaction in acid function, c ) an amine functional amidification reaction, d) a hydroxyl functional transformation reaction with an alkoxy function, e) an alcohol function oxidation reaction with an aldehyde or ketone function, f) a transformation reaction of the aldehyde or ketone functions. in the alcohol function by reduction or action of an organometallic such as an organomagnesium compound, g) a conversion reaction of the aldehyde or ketone functions to the oxime derivative, h) a nitrile radical conversion reaction to an aldehyde function, i) a reaction of conversion of nitrile radical to ketone function, j) an alkenyl or alkenyl group oxidation reaction, k) an aldehyde or ketone functional group olefintion reaction,

1) a hydroxyalkyl group dehydration reaction to an alkenyl group, m) a total or partial hydrogenation reaction of alkenyl or alkynyl group to an alkenyl or alkyl group, n) a catalytic coupling reaction of an organometallic derivative such as a derived from boron,

Tin or silicon with a halogenated derivative to introduce an alkyl, alkenyl, alkynyl, aryl or heteroaryl substituent, o) a reduction reaction of a nitro group into a primary amino group, p) a conversion reaction of a group primary or secondary amino to an amino, secondary or tertiary group by reductive amination or alkylation, q) a conversion reaction from a primary amino group to an amidine group, r) a reaction to protect the reactive functions, elimination of the protective groups that the protected reactive functions can carry, t) a salification reaction with a mineral or organic acid or with a base to obtain the corresponding salt, u) a resolving reaction of the racemic enantiomeric forms, said products of formula (I) thus obtained being, where appropriate, under all the possible racemic isomeric forms, enantiomers and diastereoisomers, tautomers.

In Schemes 1 and 2, the starting compounds and reagents, when their method of preparation is not described, are commercially available or described in the literature, or may be prepared according to methods described therein or which are known to those skilled in the art.

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

Example 1 (Compound No. 1): {3- [2- (Piperidin-1-ylcarbonyl) imidazo [1,2-a] pyridin-6-yl] phenyl} methanol

253 μl of a 2M solution of trimethylaluminium in toluene are added under argon and at 0 ^° C. to a solution of 40 μl of piperidine in 1 ml of xylene. The ice bath is removed and 100 mg of 6- (3-hydroxymethyl-phenyl) imidazo [1,2-a] pyridine-2-carboxylic acid (Intermediate 3) is added. The reaction mixture is stirred for 30 hours at 110 ⁰ C and then diluted with water, acidified to pH 3 with 1N hydrochloric acid and extracted with ethyl acetate and then dichloromethane. The combined organic phases are dried over magnesium sulphate and concentrated to dryness under reduced pressure. The residue is purified by chromatography on silica eluting with a gradient of hexane, ethyl acetate and methanol (47/50/3 to 0/84/16) to give 72 mg of {3- [2- (piperidine) 1-ylcarbonyl) imidazo [1,2-a] pyridin-6-yl] phenyl} methanol as a white solid.

Example 2 (Compound No. 2): {3- [2- (2,3-Dihydro-4H-1,4-benzoxazin-4-ylcarbonyl) imidazo [1,2-a] pyridin-6-yl] phenyl} methanol

To a suspension of 50 mg of 6- (3-hydroxymethyl-phenyl) -imidazo [1,2-a] pyridine-2-carboxylic acid (Intermediate 3) and 72 mg of 1- (3-dimethylaminopropyl) hydrochloride 3-ethylcarbodiimide in 2 mL of anhydrous pyridine, placed under argon, 76 mg of piperidine is added. The reaction mixture is stirred for 48 hours at 50 ⁰ C and then concentrated to dryness under reduced pressure. The residue is diluted with 3 mL of chloroform and washed with 1 mL of water. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure. The solid is triturated with methanol and filtered and dried to give 42 mg of {3- [2- (2,3-dihydro-4H-1,4-benzoxazin-4-ylcarbonyl) imidazo [1,2-t] pyridin). -6-yl] phenyl} methanol as a white solid.

Example 3 (Compound No. 3): {3- [2- (Morpholin-4-ylcarbonyl) imidazo [1,2-f] pyridin

6-yl] phenyl} methanol

To a mixture 50 mg of 6- (3-hydroxymethyl-phenyl) -imidazo [1,2-a] pyridine-2-carboxylic acid (Intermediate 3), 95.5 μl of diisopropylethylamine, 107 mg of hexafluorophosphate of 1 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium oxide (ΗATU), 38 mg of 1-hydroxy-7-azabenzotriazole (HO At) in 1 mL of N ₅ N dimethylformamide, 24.4 μL of morpholine is added. The reaction mixture is stirred at 25 ^° C. for 16 hours, diluted with 1.6 ml of a saturated aqueous solution of sodium hydrogencarbonate and 1 ml of water and then stirred for 30 minutes. The solid is drained and washed with 5 ml of a saturated aqueous solution of sodium hydrogencarbonate and then twice with 5 ml of water and twice with 5 ml of hexane to give 48 mg of {3- [2- ( morpholin-4-ylcarbonyl) imidazo [1,2-a] pyridin-6-yl] phenyl} methanol in the form of a beige-beige solid.

Example 4 (Compound No. 4): 2- (1,2,5,6-Tetrahydropyridin-1-yl) carbonyl-N-dimethyl-imidazo [1,2-a] pyridin-6-amine

To a suspension of 120 mg of 6-dimethylamino-imidazo [1,2-a] pyridine-2-carboxylic acid (Intermediate 1) and 224 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in 2 mL of anhydrous pyridine, placed under argon, 160 μL of tetrahydro-l, 2,5,6-pyridine is added. The reaction mixture is stirred for 48 hours at 50 ⁰ C and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on silica eluting with a gradient of hexane, ethyl acetate and methanol (from 47/50/3 to 0/84/16). to give 90 mg of 2- (1, 2,5,6-tetrahydropyridin-1-yl) carbonyl-N, N-dimethylimidazo [1,2-a] pyridin-6-amine as a white solid.

The intermediates described below are useful in the preparation of the compounds of the present invention. Intermediate ethyl 1: 6-dimethylamino-imidazo [1,2-a] pyridine-2-carboxylate and 6-dimethylaminoimidazo [1,2-a] pyridine-2-carboxylic acid

1.1: Ethyl 6-dimethylaminoimidazo [1,2-a] pyridine-2-carboxylate

To a solution of 19.05 g of 5-dimethylaminopyridine-2-amine (J. Chem Soc Perkin 1, 68 (1973)) in 380 mL of DME was added 26.2 mL of ethyl bromopyruvate. The reaction mixture is stirred at 20 ^° C. for 6 hours and then after adding 380 ml of ethanol for 20 hours under reflux and finally, after cooling, concentrated under reduced pressure. The solid is taken up twice in 350 ml of ethyl ether under reflux and filtered while hot and then twice in 350 ml of refluxing ethyl acetate and filtered while hot to give 39.66 g of 6-dimethylaminobromide hydrobromide. crude ethyl imidazo [1,2-a] pyridine-2-carboxylate. This salt is taken up in 800 ml of water and treated with vigorous stirring with solid sodium carbonate until pH 8-9 is reached. The aqueous phase is extracted three times with 500 ml of dichloromethane, the combined organic phases are dried over magnesium sulphate, filtered and concentrated to dryness. The residue is purified by flash chromatography on a silica column eluting with mixtures of hexane and ethyl acetate (5/1 to 1/1) to give 16.7 g of 6-dimethylaminoimidazo [ ethyl 1,2-α] pyridine-2-carboxylate in the form of a green oil.

¹ H NMR spectrum (DMSO-d6, δ in ppm): 8.35 (s, IH), 7.81 (d, J = 2.2, IH), 7.45 (d, J = 10, IH) , 7.34 (dd, J = 2.4, 10, 1H), 4.27 (q, J = 7.1, 2H), 2.84 (s, 6H), 1.31 (t, J = 7.1, 3H).

1.2: 6-Dimethylamino-imidazo [1,2-a] pyridine-2-carboxylic acid

To a suspension of 16.7 g of ethyl 6-dimethylaminoimidazo [1,2-a] pyridine-2-carboxylate in a mixture of 220 ml of tetrahydrofuran and 9.5 ml of methanol is added to ^0.degree. C 107 mL of a 2N aqueous solution of lithium hydroxide. The reaction mixture is then warmed to 20 ⁰ C and stirred for 4 hours. 2N hydrochloric acid is added dropwise to the reaction mixture cooled to 0 ^° C. until a pH of 4-5 is reached. The precipitate is filtered and washed twice with 50 ml of ethyl ether to give 14.8 g of 6-dimethylamino-imidazo [1,2-a] pyridine-2-carboxylic acid in the form of a yellow solid.

¹ H NMR spectrum (DMSO-d6, δ in ppm): 8.67 (s, IH), 8.18 (d, J = 2, IH), 7.88 (dd, J = 2.4, 10, 1H), 7.75 (d, J ≈ 10, 1H), 2.96 (s, 6H), (1H poorly visible acid). Intermediate 2: 6-Methoxy-5-methylimidazo [1,2-a] pyridine-2-carboxylic acid ethyl ester and 6-methoxy-5-methylimidazo [1,2-a] pyridine-2-carboxylic acid

2.1: Ethyl 6-methoxy-5-methylimidazo [1,2-a] pyridine-2-carboxylate This product is prepared analogously to 6-dimethylamino-imidazo [1,2-a] pyridine-2-carboxylate of ethyl using 5-methoxy-6-methylpyridine-2-amme in place of the

5-dimethylaminopyridine-2-amine.

¹ H NMR spectrum (DMSO-d6, δ in ppm): 1.37 (d, J = 6.8 Hz, 3H), 2.62 (s, 3H), 3.92

(s, 3H), 4.42 (q, J = 6.8 Hz, 2H), 7.70 (d, J = 9.8 Hz, 1H), 7.87 (d, J = 9.8). Hz, 1H), 8.73 (s large,

H).

2.2 6-Methoxy-5-methylimidazo [1,2-a] pyridine-2-carboxylic acid

This product is prepared by saponifying ethyl 6-methoxy-5-methylimidazo [1,2-a] pyridine-2-carboxylate under conditions similar to those described for the preparation of 6-dimethylamino-imidazo [1] acid. , 2-α] pyridine-2-carboxylic acid.

¹ H NMR Spectrum (DMSO-d6, δ in ppm): 2.52 (s, 3H), 3.85 (s, 3H), 7.47 (d, J = 9.8 Hz, 1H), 7, 54 (d, J = 9.8 Hz, 1H), 8.29 (s, 1H).

Intermediate ethyl 3: 6- (3-Hydroxymethyl-phenyl) -imidazo [1,2-a] pyridine-2-carboxylate and 6- (3-hydroxymethyl-phenyl) -imidazo [1,2-a] pyridine acid -2- carboxylic acid

3.1: Ethyl 6- (3-Hydroxymethyl-phenyl) -imidazo [1,2-a] pyridine-2-carboxylate To a mixture of 25 g of 6-bromo-imidazo [1,2-a] pyridine-2 ethylcarboxylate, 13 g of 3-hydroxymethylphenylboronic acid, 5 g of 2- (dicyclohexylphosphino) biphenyl, 1.6 g of palladium acetate and 19 g of potassium phosphate under an argon atmosphere are added 475 mL of a mixture of toluene and water (5/1) pre-degassed. The reaction mixture is stirred for 16 hours at 80 ^° C. and then cooled and diluted with water. After extraction with 2 times 200 ml of dichloromethane, the combined organic phases are dried over sodium sulphate, filtered and concentrated to dryness. The residue is purified by flash chromatography on a silica column eluting with mixtures of ethyl acetate and methanol (100/0 to 96/4) to give 16.1 g of 6- (3-hydroxymethyl) ethyl phenyl) imidazo [1,2-a] pyridine-2-carboxylate in the form of a light yellow solid.

¹ H NMR Spectrum (DMSO-d ₆ δ in ppm): 8.93 (s, 1H), 8.55 (s, 1H), 7.71-7.66 (m, 3H), 7.57 (d), , J = 7.7, 1H), 7.48 (t, J = 7.6, 1H), 7.39 (d, J ≈ 7.5, 1H), 5.29 (t, J = 5, 7, 1H), 4.61 (d, 5.66, 2H), 4.32 (q, J = 7.1, 2H), 1.34 (t, J = 7.1, 3H).

3.2: 6- (3-Hydroxymethyl-phenyl) -imidazo [1,2-a] pyridine-2-carboxylic acid To a suspension of 17.9 g of ethyl 6- (3-hydroxymethyl-phenyl) imidazo [1,2-a] pyridine-2-carboxylate in a mixture of 180 ml of tetrahydrofuran and 9 ml of methanol, add 90 mL of a 2N aqueous solution of lithium hydroxide. The reaction mixture is then stirred for 30 minutes at 20 ^° C. 2N hydrochloric acid is added dropwise to the reaction mixture cooled to 0 ^° C. until a pH of 4-5 is reached. The precipitate is filtered and washed twice with 50 ml of ethyl ether to give 15.3 g of 6- (3-hydroxymethyl-phenyl) -imidazo [1,2-s] pyridine-2-carboxylic acid under form of a white solid.

¹ H NMR spectrum (DMSO-d6, δ in ppm): 8.97 (s, IH), 8.52 (s, IH), 7.77 to 7.67 (m, 3H), 7.57 (d , J = 7.7, 1H), 7.48 (t, J = 7.6, 1H), 7.39 (d, J = 7.5, 1H), 5.7-4.8 (brs) , 1H), 4.60 (s, 2H), (1H poorly visible acid).

Intermediate 4: 6- (6 - {[(1,1-dimethylethoxy) carbonyl] anilino} pyridin-2-yl) imidazo [1,2-a] pyridine-2-carboxylic acid

4.1: Ethyl 6- (6-Aminopyridin-2-yl) imidazo [1,2-a] pyridine-2-carboxylate

350 mg of 2-amino-6-bromopyridine, 750 mg of 2-ethoxycarbonyl-imidazo [1,2-a] pyridine-6-boronic acid and 57 mg of [1,1-bis (diphenylphosphino) ferrocene] dichloropalladium are degassed under vacuum and then suspended under argon in 20 mL of degassed dioxane. After adding 2 mL of 2N aqueous sodium carbonate solution, the mixture is degassed under vacuum and then placed under argon and heated for 5 hours at 90 ^° C., then cooled, diluted and stirred in a mixture of

50 mL of saturated sodium bicarbonate solution and 50 mL of dichloromethane. The organic phase is dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. The residue is chromatographed on silica eluting with a mixture of ethyl acetate and hexane. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure to give 446 mg of ethyl 6- (6-aminoρyridin-2-yl) imidazo [1,2-a] pyridine-2-carboxylate.

¹ H NMR spectrum (DMSO-d6, δ in ppm): 9.13 (dd, J = 1.0, 1.6 IH), 8.61 (d, J ≈ 0.7, IH), 7.94 (dd, J = 1.8, 9.6, 1H), 7.65 (d, J = 9.6, 1H), 7.50 (t, J = 8.1, 1H) _3, 7.07 (d, J = 7.0, 1H), 6.48 (dd, J = 0.3, 8.1, 1H), 6.08 (bs, 2H), 4.33 (q, J = 7); , 1, 2H), 1.33 (t, J = 7.1, 3H). Mass Spectrum (APCI): m / z = 283 [M + H] ⁺ .

4.2: Ethyl 6- (6- {[(1,1-Dimethylethoxy) carbonyl] amino} pyridin-2-yl) imidazo [1,2-a] pyridine-2-carboxylate and 6- (6- {bis Ethyl [(1,1-dimethylethoxy) carbonyl] amino} pyridin-2-yl) imidazo [1,2-a] pyridine-2-carboxylate

To a suspension of 700 mg of ethyl 6- (6-aminopyridin-2-yl) imidazo [1,2-a] pyridine-2-carboxylate and 25 mg of 4-dimethylaminopyridine in 5 ml of acetonitrile is added 1 , 14 mL of ditertbutyledicarbonate. The mixture is stirred for 16 hours at 25 ⁰ C and then concentrated. The The residue is chromatographed on silica eluting with a gradient of ethyl acetate and hexane (50/50 to 100/0) to give 370 mg of 6- (6- {bis [(1,1-dimethylethoxy) ethylcarbonyl] amino} pyridin-2-yl) imidazo [1,2-a] pyridine-2-carboxylate

¹ H NMR spectrum (DMSO-d6, δ in ppm): 9.23 (s, IH), 8.65 (s, IH), 8.06, -7.98 (m, 2H), 7.95 ( d, J = 7.7, 1H), 7.76 (d, J = 9.6, 1H), 7.43 (d, J = 7.8, 1H), 4.33 (q, J = 7); , 0, 2H), 1.43 (s, 18H), 1.34 (t, J = 7.1, 3H).

Mass Spectrum (APCI): m / z = 483 [M + H] ⁺ , and 163 mg of 6- (6 - {[(1,1-dimethylethoxy) carbonyl] amino} pyridin-2-yl) imidazo [1 Ethyl 2-α] pyridine-2-carboxylate ¹ H NMR Spectrum (DMSO-d6, δ in ppm): 9.28 (s, 1H), 8.50 (s, 1H), 8.04-8 , 00 (m,

2H), 7.95 (d, J = 7.8, 1H), 7.70 (d, J = 9.6, 1H), 7.38 (d, J = 7.9, 1H), 4, 31 (q, J = 7.0, 2H), 1.39 (s, 9H), 1.33 (t, J = 7.1, 3H).

Mass Spectrum (APCI): m / z = 383 [M + H] ⁺ .

4.3: 6- (6 - {[(1,1-Dimethylethoxy) carbonyl] amino} pyridin-2-yl) imidazo [1,2-a] pyridine-2-carboxylic acid

0.9 ml of a 2M aqueous solution of lithium hydroxide are added to a solution of 292 mg of 6- (6- {bis [(1,1-dimethylethoxy) carbonyl] amino} pyridin-2-yl) imidazo [1] Ethyl 2-α] pyridine-2-carboxylate in 4.73 mL of a 50: 1 mixture of tetrahydrofuran and methanol. The reaction mixture is stirred for 7 hours at 25 ^° C. and then treated dropwise at 0 ^° C. with 2 N HCl hydrochloric acid until a pH of 3 is reached. The precipitate formed after 20 minutes is drained and washed. with water (20 mL) and diethyl ether (20 mL) and then dried under reduced pressure to give 195 mg of 6- (6 - {[(1,1-dimethylethoxy) carbonyl] amino} pyridine 2-yl) imidazo [1,2-a] pyridine-2-carboxylic acid in the form of a beige solid.

¹ H NMR (DMSO-d6, δ in ppm): 13.5-12.0 (br, 1H), 9.80 (s, 1H), 9.24 (s, 1H), 8.51 (s). , 1H), 8.03 (dd, J = 1.5, 9.6 1H), 7.88 (app, t, J = 8.0, 7.8, 1H), 7.77 (d, J = 8.2, 1H), 7.73 (d, J = 9.6, 1H), 7.62 (d, J = 7.5, 1H), 1.50 (s, 9H);

Intermediate 5: 6- (pyridin-2-yl) imidazo [1,2-fl] pyridine-2-carboxylic acid

5.1: Ethyl (6-pyridin-2-yl) imidazo [1,2-a] pyridine-2-carboxylate A mixture of 3.18 g of cesium carbonate, 25 ml of dioxane, 9.3 ml of water, 500 mg of 2-iodopyridine, 89 mg of [1,3-bis (diphenylphosphino) ferrocene] dichloropalladium and 848 mg of hydrobromide (1: 1) of 6- (4,4,5,5-tetramethyl-1, Ethyl 3,2-dioxaborolan-2-yl) imidazo [1,2-a] pyridine-2-carboxylate is heated for 2 hours at 110 ^° C., then partially concentrated and diluted with dichloromethane and filtered. The organic phase is washed with water and dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue is chromatographed on a silica cartridge, eluting with a mixture of dichloromethane and cyclohexane (80/20). The fractions containing the expected product are combined and concentrated to dryness under reduced pressure to give 317 mg of ethyl 6- (pyridin-2-yl) imidazo [1,2-a] pyridine-2-carboxylate in the form of a brown oil.

¹ H NMR spectrum (DMSO-d6, δ in ppm): 1.34 (t, J = 7.0 Hz, 3H), 4.33 (q, J = 7.0 Hz, 2H), 7.42 ( ddd, J = 7.5, 5.5, 2.0 Hz, 1H), 7.73 (d, J = 9.3 Hz, 1H), 7.85 - 8.02 (m, 2H), 8 , 07 (dd, J = 9.3, 2.0 Hz, 1H), 8.64 (s, 1H), 8.70 (broad d, J = 5.5Hz, 1H), 9.36 (s). broad, IH). Mass spectrum (LC-MS-DAD-ELSD): m / z 268 [M + H] ⁺ .

5.2: 6- (Pyridin-2-yl) imidazo [1,2-a] pyridine-2-carboxylic acid

317 mg of ethyl 6- (pyrid-2-yl) imidazo [1,2-a] pyridine-2-carboxylate are saponified under conditions similar to those described for the preparation of intermediate 4 (step 4.3) for give 280 mg of 6- (pyridin-2-yl) imidazo [1,2-a] pyridine-2-carboxylic acid as a pasty rosy solid.

¹ H NMR spectrum (DMSO-d6, δ in ppm): 7.47 (m, IH), 7.83 (d, J = 9.8 Hz, IH), 7.99 (dt, J = 8.5 , 2.0Hz, 1H), 8.06 (d, J = 8.5Hz, 1H), 8.31 (dd, J = 9.8Hz, 1H), 8.73 (m, 2H). ), 9.52 (bs, 1H).

Mass spectrum (LC-MS-DAD-ELSD): m / z 240 [M + H] ⁺ .

Intermediate 6: 6- (1-Triphenylmethyl-1H-imidazol-4-yl) imidazo [1,2-a] pyridine-2-carboxylic acid ethyl ester and 6- (1-triphenylmethyl-1H-imidazol-4-yl) ) imidazo [l, 2 - "] pyridine-2-carboxylic acid

6.1: Ethyl 6- (1-triphenylmethyl-1H-imidazol-4-yl) imidazo [1,2-i] pyridine-2-carboxylate 873 mg of 4-iodo-1-triphenylmethylimidazole, 750 mg. 2-ethoxycarbonylimidazo [1,2-a] pyridine-6-boronic acid, 23 mg of palladium acetate and 70 mg of (2-biphenyl) dicyclohexylphosphine are degassed under vacuum and then suspended under argon in a degassed mixture of 15 mL of toluene, 5 mL of water and 5 mL of N-methylpyrrolidone. After adding 950 mg of potassium phosphate, the mixture is degassed under vacuum then placed under argon and heated for 15 minutes at 100 ^° C. under microwave, then cooled, diluted and stirred in a mixture of 50 mL of saturated sodium bicarbonate solution. and 50 mL of dichloromethane. The organic phase is dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. The residue is chromatographed on silica eluting with a mixture of ethyl acetate and hexane. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure to give 508 mg of ethyl 6- (1-triphenylmethyl-1H-imidazol-4-yl) imidazo [1,2-a] pyridine-2-carboxylate .

¹ H NMR spectrum (DMSO-d6, δ in ppm): 8.97 (s, IH), 8.54 (s, IH), 7.76 to 7.72 (m, IH), 7.56 to 7 , 52 (m, 3H), 7.47-7.37 (m, 9H), 7.20-7.17 (m, 6H), 4.31-4.27 (m, 2H), 1.34 -1.20 (m, 3H).

Mass Spectrum (APCI): m / z = 499 [M + H] ⁺ .

6.2: 6- (1-Triphenylmethyl-1H-imidazol-4-yl) imidazo [1,2-a] pyridine-2-carboxylic acid 500 mg of 6- (1-triphenylmethyl-1H-imidazol-4-yl) imidazo ethyl [1,2-a] pyridine-2-carboxylate are saponified under conditions similar to those described for the preparation of intermediate 4 (step 4.3) to give 346 mg of 6- (1-triphenylmethyl) 1H-imidazol-4-yl) imidazo [1,2-a] pyridine-2-carboxylic acid.

¹ H NMR spectrum (DMSO-d6, δ in ppm): 9.01 (s, IH), 8.51 (s, IH), 7.83 (d, J = 9.5, IH), 7.59 -7.56 (m, 3H), 7.47-7.37 (m, 9H), 7.20-7.17 (m, 6H). Exchangeable proton not observed

Mass Spectrum (APCI): m / z = 471 [M + H] ⁺ .

Intermediate 7: 6- (1H-pyrrol-3-yl) imidazo [1,2-a] pyridine-2-carboxylic acid

7.1 Ethyl 6- [1 - (Triisopropylsilyl) -1H-pyrrol-3-yl] imidazo [1,2-a] pyridine-2-carboxylate

100 mg of ethyl 6-iodo-imidazo [1,2-a] pyridine-2-carboxylate, 135 mg of 1- (triisopropylsilyl) -pyrrole-3-boronic acid and 18 mg of tetrakis (triphenylphosphine) palladium ( 0) are degassed under vacuum and then suspended, under argon, in a degassed mixture of 1.5 mL of 1,2-dimethoxyethane, 1.5 mL of ethanol and 316 μL of aqueous 2N sodium carbonate solution. The reaction mixture is heated at reflux for 4 hours, then cooled, diluted and stirred with a mixture of 5 mL of half-saturated aqueous sodium bicarbonate solution and 5 mL of dichloromethane. The organic phase is dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. The residue is chromatographed on silica eluting with a mixture of ethyl acetate and hexane (50/50). The fractions containing the expected product are combined and concentrated to dryness under reduced pressure to give 121 mg of 6- [1- (triisopropylsilyl) -1H-pyrrol-3-yl] -imidazo [1,2-a] pyridine-2- ethyl carboxylate.

¹ H NMR spectrum (DMSO-d6, δ in ppm): 8.76 (s, IH), 8.42 (s, IH), 7.70 (dd, J = 1.9, 9.7 IH), 7.59 (d, J = 9.7H), 7.37 (bs, 1H), 6.94 (m, 1H), 6.63 (m, 1H), 4.33 (q, J = 6.9, 2H), 1.61-1.50 (m, 3H), 1.33 (t, J = 6.9, 3H), 1.10-1.03 (m, 18H). Mass Spectrum (APCI): m / z = 412 [M + H] ⁺ .

7.2: 6- (1H-Pyrrol-3-yl) imidazo [1,2-a] pyridine-2-carboxylic acid hydrochloride (1: 1) 292 mg of 6- [1- (triisopropylsilyl) -1H- Ethyl pyrrol-3-yl] imidazo [1,2-a] pyridine-2-carboxylate are saponified under conditions analogous to those described for the preparation of Intermediate 4 (step 4.3) to give 140 mg of hydrochloride ( 1: 1) 6- (1H-pyrrol-3-yl) imidazo [1,2-a] pyridine-2-carboxylic acid as a white solid.

¹ H NMR spectrum (DMSO-d6, δ in ppm): 11.07 (bs, IH), 8.73 (s, IH), 8.39 (s, IH), 7.69 (dd, J = 1.3, 9.5, 1H), 7.59 (d, J, 9.5, 1H), 7.31 (s, 1H), 6.86 (s, 1H), ₃ 6.46 (s, H). Mass Spectrum (APCI): m / z = 228 [M + H] ⁺ .

Intermediate 8: 6- (U-pyrazol-3-yl) imidazo [1,2-a] pyridine-2-carboxylic acid

8.1: Ethyl 6- (1H-pyrazol-3-yl) imidazo [1,2-b] pyridine-2-carboxylate This product is prepared under the conditions analogous to those described for the preparation of intermediate 7 (step 7.1) by replacing 1- (triisopropylsilyl) -pyrrole-3-boronic acid with pyrrazole-3-boronic acid.

¹ H NMR spectrum (MeOD-d4, δ in ppm): 8.89 (t, J = 1.2, 2.4, IH), 8.45 (d, J = 0.6, IH), 7, 89 (d, J = 9.0, 1H), 7.76 (brs, 1H), 7.67 (d, J = 9.5, 1H), 6.77 (d, J = 2.4, 1H), 4.42 (q, J = 7.1, 2H), 1.43 (t, J = 7.1, 3H).

Mass Spectrum (APCI): m / z = 257 [M + H] ⁺ .

8.2: 6- (1H-Pyrazol-3-yl) imidazo [1,2-a] pyridine-2-carboxylic acid

128 mg of ethyl 6- (1H-pyrazol-3-yl) imidazo [1,2-a] pyridine-2-carboxylate are saponified under conditions similar to those described for the preparation of intermediate 4 (step 4.3 ) to give 113 mg of 6- (1H-pyrazol-3-yl) imidazo [1,2-a] pyridine-2-carboxylic acid.

¹ H NMR (DMSO-d6, δ in ppm): 13.50-12.50 (brs, 1H), 9.03 (s, 1H), 8.40 (s, 1H), 7.83- 7.80 (m, 2H), 7.63 (d, J = 9.4, 1H), 6.74 (s, 1H).

Intermediate 9: 6- (Furan-2-yl) imidazo [1,2-a] pyridine-2-carboxylic acid 9.1: 6- (Furan-2-yl) imidazo [1,2-a] pyridine-2-carboxylate ethyl

This product is prepared under conditions similar to those described for the preparation of intermediate 7 (step 7.1) by replacing 1- (triisopropylsilyl) -pyrrole-3-boronic acid with furan-2-boronic acid.

¹ H NMR spectrum (DMSO-dό, δ in ppm): 8.78 (s, IH), 8.44 (s, IH), 7.72 (dd, J = 1.8, 9.6, IH) 7.63-7.60 (m, 2H), 6.89 (d, J = 3.4, 1H), 6.57 (dd, J = 1.8, 3.4, 1H), 4, 42 (q, J = 7.1, 2H), 1.42 (t, J = 7.1, 3H).

Mass Spectrum (APCI): m / z = 257 [M + H] ⁺ .

9.2: 6- (Furan-2-yl) imidazo [1,2-a] pyridine-2-carboxylic acid

384 mg of ethyl 6- (furan-2-yl) imidazo [1,2-a] pyridine-2-carboxylate are saponified under conditions similar to those described for the preparation of intermediate 1 (step 1.3) for give 256 mg of 6- (furan-2-yl) imidazo [1,2-a] pyridine-2-carboxylic acid.

¹ H NMR spectrum (DMSO-d6, δ in ppm): 8.86 (s, IH), 8.38 (s, IH), 7.80 (dd, J = 1.7, 9.5, IH) ,

7.67-7.64 (m, 2H), 6.90 (d, J = 3.4, 1H), 6.60 (dd, J = 1.8, 3.4, 1H).

Intermediate 10: 6- (Furan-3-yl) imidazo [1,2-a] pyridine-2-carboxylic acid

Ethyl 10.1: 6- (Furan-3-yl) imidazo [1,2-a] pyridine-2-carboxylate This product is prepared under the conditions analogous to those described for the preparation of Intermediate 7 (step 7.1) replacing 1- (triisopropylsilyl) -pyrrole-3-boronic acid with furan-3-boronic acid.

¹ H NMR spectrum (DMSO-d6, δ in ppm): 8.86 (s, IH), 8.45 (s, IH), 8.28 (s, IH), 7.82 (s, IH), 7.66 (s, 2H), 6.95 (s, 1H), 4.31 (q, J = 7.1, 2H), 1.33 (t, J = 7.1, 3H). Mass Spectrum (APCI): m / z = 257 [M + H] ⁺ .

10.2: 6- (Furan-3-yl) imidazo [1,2-a] pyridine-2-carboxylic acid

384 mg of ethyl 6- (furan-3-yl) imidazo [1,2-a] pyridine-2-carboxylate are saponified under conditions similar to those described for the preparation of intermediate 4 (step 4.3) for give 287 mg of 6- (furan-3-yl) imidazo [1,2-a] pyridine-2-carboxylic acid. ¹ H NMR Spectrum (DMSO-d6, δ in ppm): 8.86 (s, 1H), 8.38 (s, 1H), 8.27 (s, 1H) ₃ 7.81

(s, 1H), 7.64 (s, 2H), 6.95 (s, 1H).

Mass Spectrum (APCI): m / z = 229 [M + H] ⁺ .

Intermediate 11: 6- [5- (hydroxymethyl) furan-2-yl] imidazo [1,2-a] pyridine-2-carboxylic acid 11.1: 6- (5-Formylfuran-2-yl) imidazo [1, 2-α] ethyl pyridine-2-carboxylate 2 g of ethyl 6-iodo-imidazo [1,2-a] pyridine-2-carboxylate, 1.42 g of 5-formyl-furan-2-boronic acid and 231 mg of [l, r-bis (Diphenylphosphino) ferrocene] dichloropalladium are degassed under vacuum and then suspended, under argon, in a degassed mixture of 30 mL of dioxane and 9.4 mL of a 2N aqueous solution of sodium carbonate. The reaction mixture is heated for 5 hours at 90 ^° C., then stirred for 16 hours at 20 ^° C. and concentrated to dryness. The residue is chromatographed on silica eluting with a mixture of ethyl acetate and hexane (90/10), with ethyl acetate and then with a mixture (99/1) of ethyl acetate. and methanol. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure to give 884 mg of ethyl 6- (5-formylfuran-2-yl) imidazo [1,2-a] pyridine-2-carboxylate. ¹ H NMR (DMSO-d6, δ in ppm): 9.64 (s, 1H), 9.20 (s, 1H), 8.66 (s, 1H),

7.86-7.74 (m, 2H), 7.72 (d, J = 3.8, 1H), 7.37 (d, J = 3.8, 1H), 4.33 (q, J); = 7.0, 2H), 1.33 (t, J = 7.1, 3H).

Mass Spectrum (APCI): m / z = 285 [M + H] ⁺ .

11.2: 6- [5- (Hydroxymethyl) furan-2-yl] imidazo [1,2-a] pyridine-2-carboxylic acid ethyl ester To a suspension of 770 mg of 6- (5-formylfuran-2-yl) ethyl imidazo [1,2-a] pyridine-2-carboxylate in 15 ml of ethanol is added 123 mg of sodium borohydride. The reaction mixture is stirred at 25 ⁰ C for 90 minutes then diluted and stirred with 10 mL of dichloromethane and 3 mL of semi-saturated aqueous sodium carbonate. The organic phase is separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is chromatographed on silica eluting with a mixture of dichloromethane and methanol (98/2). The fractions containing the expected product are combined and concentrated to dryness under reduced pressure. The solid obtained is triturated in 5 ml of dichloromethane, filtered and dried to give 403 mg of ethyl 6- (5-formylfuran-2-yl) imidazo [1,2-a] pyridine-2-carboxylate in the form of dichloromethane. a white solid. ¹ H NMR spectrum (DMSO-d6, δ in ppm): 8.89 (s, IH), 8.60 (s, IH), 7.70 (m, 2H),

6.98 (d, J = 3.3, 1H), 6.45 (d, J = 3.3, 1H), 5.30 (t, J = 5.3, 1H), 4.47 (d. , J = 5.6, 2H), 4.32 (q, J = 7.1, 2H), 1.32 (t, J = 7.1, 3H).

Mass Spectrum (APCI): m / z = 287 [M + H] ⁺ .

11.3: 6- [5- (hydroxymethyl) furan-2-yl] imidazo [1,2-a] pyridine-2-carboxylic acid 400 mg of 6- [5- (hydroxymethyl) furan-2-yl] imidazo [1] Ethyl 2-α] pyridine-2-carboxylate are saponified under conditions similar to those described for the preparation of intermediate 4 (step 4.3) to give 346 mg of 6- [5- (hydroxymethyl) furan acid -2-yl] imidazo [1,2-a] pyridine-2-carboxylic acid in the form of a white solid.

¹ H NMR spectrum (DMSO-d6, δ in ppm): 9.06 (s, IH), 8.73 (s, IH), 8.03 (d, J = 9.5, 1H), 7.82 (d, J = 9.5, 1H), 7.09 (d, J = 3.3, 1H), 6.49 (d, J = 3.2, 1H), 4, 49 (s, 2H). Mass Spectrum (APCI): m / z = 259 [M + H] ⁺ .

Intermediate 12: 6- (oxazol-2-yl) imidazo [1,2-a] pyridine-2-carboxylic acid

Ethyl 12.1: 6- (Oxazol-2-yl) imidazo [1,2-a] pyridine-2-carboxylate

5 g of ethyl 6-iodo-imidazo [1,2-a] pyridine-2-carboxylate, 350 mg of tetrakis

(triphenylphosphine) palladium (O) and 360 mg of lithium chloride are degassed under vacuum and then suspended under argon in 15 ml of degassed dioxane. After adding 5 g of 2- (tri-n-butylstannyl) oxazole, the reaction mixture is heated at 90 ° C. for 3.5 hours, then cooled, diluted and stirred with a mixture of 100 ml of aqueous IM solution of fluoride. of potassium and 200 ml of ethyl acetate. The aqueous phase is extracted with 200 ml of ethyl acetate and the combined organic phases are washed with brine and dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. The residue is chromatographed on silica eluting with a gradient of ethyl acetate and hexane (80/20 to 100/0). The fractions containing the expected product are combined and concentrated to dryness under reduced pressure to give 530 mg of ethyl 6- (oxazol-2-yl) imidazo [1,2-a] pyridine-2-carboxylate in the form of a yellow powder.

¹ H NMR spectrum (DMSO-d6, δ in ppm): 9.30 (d, J = 0.8, IH), 8.68 (s, IH), 8.30 (s, IH), 7.85 (dd, J = 1.7, 9.5, 1H), 7.79 (d, J = 9.5, 1H), 7.44 (d, J ≈ 0.6, 1H), 4.33 ( q, J = 7.0, 2H), 1.33 (t, J = 7.1, 3H).

Mass Spectrum (APCI): m / z = 258 [M + H] ⁺ . 0 12.2: 6- (Oxazol-2-yl) imidazo [1,2-a] pyridine-2-carboxylic acid

512 mg of ethyl 6- (oxazol-2-yl) imidazo [1,2-a] pyridine-2-carboxylate are saponified under conditions similar to those described for the preparation of intermediate 4

(Step 4.3) to give 365 mg of 6- (oxazol-2-yl) imidazo [1,2-a] pyridine-2-carboxylic acid as a white solid. 5 ¹ H NMR spectrum (DMSO-d6, δ in ppm): 9.41 (s, IH), 8.73 (s, IH), 8.34 (s, IH), 8.05

(dd, J = 1.5, 9.5, 1H), 7.86 (d, J = 9.5, 1H), 7.48 (s, 1H).

Intermediate 13: 6- (1H-1,2,4-Triazol-3-yl) imidazo [1,2-] pyridine-2-carboxylic acid

Ethyl 13.1: 6- [Ethoxy (imino) methyl] imidazo [1,2-a] pyridine-2-carboxylate

470 mg of sodium ethanethiolate are added to a solution of 1 g of ethyl 6-cyanoimidazo [1,2-a] pyridine-2-carboxylate (J. Med Chem (1998), 41 (22)). , 4317) in a mixture of 15 mL of ethanol and 10 mL of dichloromethane cooled to 0 ° C. The mixture The reaction mixture is stirred for 5 hours at 25 ^° C., filtered and the filtrate evaporated to dryness. The residue is chromatographed on silica eluting with a mixture of dichloromethane and methanol (98/2) to give 625 mg of 6- [imoxy (imino) methyl] imidazo [1,2-a] pyridine-2-carboxylate. ethyl in the form of a pale yellow solid. ¹ H NMR (DMSO-d6, δ in ppm): 9.17 (s, 1H), 9.04 (s, 1H), 8.64 (s, 1H), 7.84

(m, 1H), 7.68 (m, 1H), 4.33 (q, J = 7.1, 4H), 1.34 (t = 7.2, 6H). Mass Spectrum (APCI): m / z = 262 [M + H] ⁺ .

Ethyl 13.2: 6- [Hydrazino (imino) methyl] imidazo [1,2-a] pyridine-2-carboxylate

To a solution of 625 mg of ethyl 6- [ethoxy (imino) methyl] imidazo [1,2-a] pyridine-2-carboxylate in 12 ml of ethanol is added dropwise at 0-5 ^° C. 0.2 mL of hydrazine hydrate. The reaction mixture is stirred for 2 hours, then 73 μL of hydrazine hydrate is added and stirring is continued for 2 hours, allowing the temperature to rise to 25 ^° C. The reaction mixture is concentrated to dryness under reduced pressure and the residue is dried for 600 hours. mg of

Ethyl 6- [hydrazino (imino) methyl] imidazo [1,2-a] pyridine-2-carboxylate which is used without further purification in the following synthesis.

¹ H NMR spectrum (DMSO-d6, δ in ppm): 8.77 (brs, IH), 8.49 (s, IH), 7.70 (m, IH), 7.53 (d, J = 9.6, 1H), 5.67 (s, 2H), 5.15 (bs, 2H), 4.33 (q, J = 7.1, 2H), 1.32 (t = 7.1). , 3H). Mass Spectrum (APCI): m / z = 248 [M + H] ⁺ .

Ethyl 13.3: 6- (1H-1,2,4-triazol-3-yl) imidazo [1,2-a] pyridine-2-carboxylate A suspension of 580 mg of 6- [hydrazino (imino) methyl] ethyl imidazo [1,2-a] pyridine-2-carboxylate in 6 ml of formic acid is heated for 20 hours at 85 ° C. The reaction mixture is concentrated to less than 20% of its initial volume and diluted with 20 ml of water. Solid sodium carbonate is added at 0-5 ^° C. until the pH is 8-9. The precipitate is filtered off and then purified by chromatography on silica eluting with a mixture of dichloromethane and methanol (98/2) to give 320 mg of: 6- (1H-1,2,4-triazol-3-yl) imidazo [ 1,2-α] pyridine-2-carboxylic acid ethyl ester.

¹ H NMR spectrum (DMSO-d6, δ in ppm): from 14.5 to 14.0 (br s, IH), 9.25 (s, IH), 8.69 (s, IH), 8.63 ( broad, 1H), 7.94 (dd, J = 9.5, 1.5, 1H), 7.73 (d, J = 9.5, 1H), 4.33 (q, J = 7, 0, 2H), 1.33 (t = 7.0, 3H) Mass spectrum (APCI): m / z = 258 [M + H] ⁺ .

13.4: 6- (1H-1,2,4-Triazol-3-yl) imidazo [1,2-a] pyridine-2-carboxylic acid

320 mg of ethyl 6- (1H-1,2,4-triazol-3-yl) imidazo [1,2-a] pyridine-2-carboxylate are saponified under conditions similar to those described for the preparation of intermediate 4 (step 4.3) to give 238 mg of 6- (1H-1,2,4-triazol-3-yl) imidazo [1,2-a] pyridine-2-carboxylic acid as an off-white solid.

¹ H NMR spectrum (DMSO-d6, δ in ppm): from 14.5 to 14.2 (br s, IH), 9.26 (s, IH), 8,66- 8.62 (m, 2H), 7.91 (d, J = 9.1, 1H), 7.73 (d, J = 9.6, 1H).

Intermediate 14: 6- (1H-1,2,3-triazol-4-yl) imidazo [1,2-] pyridine-2-carboxylic acid

Ethyl 14.1: 6 - [(trimethylsilyl) ethynyl] imidazo [1,2-o] pyridine-2-carboxylate

A mixture of 4 g of ethyl 6-iodo-imidazo [1,2-a] pyridine-2-carboxylate, 2.63 ml of ethynyl-trimethylsilane, 888 mg of dichloro-bis (triphenylphosphine) palladium is degassed under empty. 240 mg of degassed N, N-dimethylformamide, 3.52 ml of triethylamine are added. The reaction mixture is degassed under argon and then stirred at 50 ^° C. for 50 hours and then cooled, diluted with 20 ml of water. The precipitate is drained and washed with 5 mL of water and then chromatographed on silica eluting with mixtures of ethyl acetate and hexane (50/50 to 90/10). The fractions containing the expected product are combined and concentrated to dryness under reduced pressure to give 3.6 g of ethyl 6- [(trimethylsilyl) ethynyl] imidazo [1,2-a] pyridine-2-carboxylate in the form of d 'an off-white solid.

¹ H NMR spectrum (DMSO-d6, δ in ppm): 8.61 (s, IH), 8.22 (s, IH), 7.36 (d, J = 9.5, IH), 7.07 (dd, J = 9.5, 1.7, 1H), 4.07 (q, J = 7.1, 2H), 1.08 (t, J = 7.1, 3H), 0.01 ( s, 9H).

Mass Spectrum (APCI): m / z = 287 [M + H] ⁺ . 14.2: Ethyl-ethyl 6-ethynylimidazo [1,2-a] pyridine-2-carboxylate

To a solution of 500 mg of ethyl 6 - [(trimethylsilyl) ethynyl] imidazo [1,2-a] pyridine-2-carboxylate in 10 ml of anhydrous tetrahydrofuran, cooled to 0 ^° C., is added dropwise 1, 58 mL of an IM solution of tetrabutylammonium fluoride in tetrahydrofuran. The reaction mixture is stirred for 30 minutes then 5 ml of water are added and extracted 3 times with 20 ml of dichloromethane. The product is purified by chromatography on silica eluting with mixtures of ethyl acetate and hexane (1/3 to 1/1). The fractions containing the expected product are combined and concentrated to dryness under reduced pressure to give 280 mg of ethyl 6-ethynylimidazo [1,2-a] pyridine-2-carboxylate in the form of a yellow solid.

¹ H NMR spectrum (DMSO-d6, δ in ppm): 8.86 (d, J = 1.0, IH), 8.50 (d, J = 0.6, IH), 7.63 (d, J = 9.4, 1H), 7.37 (d, J = 1.7, 9.4, 1H), 4.32 (m, 3H), 1.32 (t, J = 7.1 Hz, 3H). Mass Spectrum (APCI): m / z = 215 [M + H] ⁺ .

14.3: Ethyl 6- (1H-1,2,3-triazol-4-yl) imidazo [1,2-a] pyridine-2-carboxylate To a solution of 220 mg of 6-ethynylimidazo [1,2- α] pyridine-2-carboxylic acid ethyl and 0.21 mL of azidotrimethylsilane in 4 ml of a mixture (9/1) of N, N-dimethylformamide and methanol is added 9.8 mg of cuprous iodide. The reaction mixture is stirred for 2 hours at 100 ^° C. and then cooled and diluted with 4 ml of dichloromethane and then filtered over alumina and concentrated to dryness. The residue is chromatographed on silica eluting with a mixture of dichloromethane and ethanol (97/3). The fractions containing the expected product are combined and concentrated to dryness under reduced pressure to give 125 mg of: 6- (1H-1,2,3-triazol-4-yl) imidazo [1,2-a] pyridine-2- ethyl carboxylate in the form of an off-white solid.

¹ H NMR spectrum (DMSO-d6, δ in ppm): from 15.5 to 15.0 (br s, IH), 9.14 (dd, J ≈ 1.1, 1.5, IH), 8.60 (d, J = 0.5, 1H), 8.40 (br s, 1H), 7.82 (dd, J = 1.7, 9.5, 1H), 7.75 (d, J = 9; , 5, 1H), 4.33 (q, J = 7.1, 2H), 1.33 (t, J = 7.1, 3H).

Mass Spectrum (APCI): m / z = 258 [M + H] ⁺ .

14.4: 6- (1H-1,2,3-Triazol-4-yl) imidazo [1,2-a] pyridine-2-carboxylic acid 125 mg of 6- (1H-1,2,3-triazol-3) ethyl (1-ethyl) imidazo [1,2-β] pyridine-2-carboxylate are saponified under conditions analogous to those described for the preparation of intermediate 4 (step 4.3) to give 72 mg of 6- ( 1H-1,2,3-triazol-3-yl) imidazo [1,2-a] pyridine-2-carboxylic acid as a white solid.

¹ H NMR spectrum (DMSO-d6, δ in ppm): from 16.0 to 15.0 (br s, IH), 9.23 (s, IH), 8.62 (s, IH), 8.46 ( broad, 1H), 7.96 (dd, J = 1.4, 9.5, 1H), 7.80 (d, J = 9.5, 1H).

The following tables illustrate the chemical structures of general formula (I)

(Table 1) and the spectroscopic characteristics (Table 2) of some examples of compounds according to the invention.

In Table 1: the column "salt", "-" represents a compound in free base form, - "HCl" represents a compound in the form of hydrochloride,

"CF ₃ COOH" represents a compound in the form of trifluoroacetate, the ratio in parentheses is the ratio (acid: base), Table 1

Table 2

characterizations

¹ H NMR spectrum (DMSO-d6, δ in ppm): from 2.10 to 2.29 (m, 2H), 3.69 to 3.78 (m, IH), 4.05 to 4.24 (m, 2H), 4.54 - 4.72 (m, 1H), 5.67 - 5.95 (m, 2H), 7.40 - 7.47 (m, 1H), 7.72 - 7.78 ( d, J = 9.5Hz, 1H), 7.80-7.85 (dd, J = 9.5, 1.7Hz, 1H), 8.29 (m, 1H), 8.48 (s); , 1H), 9.32 (bs, 1H) Mass spectrum (LC-MS-ES +/-),: m / z 295 [M + H] ⁺

¹ H NMR (DMSO-d6, δ in ppm): 2.20 (m, 2H), 3.73 (m, 1H), 4.05 - 4.26 (m, 2H), 4.67 (m). , 1H), 5.69-5.93 (m, 2H), 6.96 (dd, J = 1.9, 0.9 Hz, 1H), 7.62 (dd, J = 9.5, 1H NMR (CDCl3)? , 7Hz, 1H), 7.67 (d, J = 9.5Hz, 1H), 7.80 (t, J = 1.9Hz, 1H), 8.24 (s, 1H), 8, 26 (bs, 1H), 8.87 (bs, 1H) Mass spectrum (LC-MS-ES +/-),: m / z 294 [M + H] ⁺

¹ H NMR spectrum (DMSO-d6, δ in ppm): 3.19 (t, J = 8.5 Hz, 2H), 4.70 (t, J = 8.5 Hz, 2H), 6.98 ( dd, J = 1.9, 0.9 Hz, 1 H), 7.03 - 7.46 (m, 3H), 7.65 (dd, J = 9.5, 1.7 Hz, 1H), 7. , 70 (d, J = 9.5 Hz, 1H), 7.81 (t, J = 1.9 Hz, 1H), 8.18 (extended m, 1H), 8.28 (bs, 1H). , 8.42 (s, 1H), 8.92 (bs, 1H) Mass spectrum (LC-MS-ES +/-),: m / z 330 [M + H] ⁺

¹ H NMR spectrum (DMSO-d6, δ in ppm): from 2.13 to 2.25 (m, 2H), 3.65 to 3.79 (m, IH), 4.05 to 4.25 (m, 2H), 4.47 (d, J = 5.7Hz, 2H), 4.61-4.71 (m, 1H), 5.28 (t, J = 5.7HzH), 5.69; - 5.93 (m, 2H), 6.45 (d, J = 3.3 Hz, 1H), 6.94 (d, J = 3.3 Hz, 1H), 7.67 (m, 2H) , 8.39 (s, 1H), 8.89 (bs, 1H) Mass spectrum (LC-MS-ES +/-),: m / z 324 [M + H] ⁺

¹ H NMR spectrum (DMSO-d6, δ in ppm): from 2.10 to 2.30 (m, 2H), 3.65 to 3.82 (m, IH), 4.05 to 4.30 (m, 2H), 4.59-4.74 (m, 1H), 5.68-5.95 (m, 2H), 7.72 (d, J = 9.5Hz, 1H), 7.91 (dd; , J = 9.5, 1.7 Hz H 1), 8.47 (s, 1H), 8.61 (extended m, 1H), 9.26 (bs, 1H), 14.12-14.43. (m spread, 1H)

Mass spectrum (LC-MS-ES +/-),: m / z 293 [M + + HT, m / z 295 [M + + HT]

¹ H NMR spectrum (DMSO-d6, δ ppm): 3.22 (t, J = 8.5 Hz, 2H), 4.69 (t, J = 8.5 Hz, 2H), 7.07 ( t, J = 7.3 Hz, 1H), 7.22 (t, J = 7.3Hz, 1H), 7.32 (d, J = 7.3Hz, 1H), 7.78 (d, J = 9.5Hz, 1H), 8.01 (dd, J = 9.5, 1.7Hz, 1H), 8.19 (extended m, 1H), 8.63 (plated m, 1H), 8.72 (s, IH), 9.32 (bs, 1H) mass spectrum (LC-MS-ES +/-): m / z 329 [m + H] ^', m / z 331 [m + H] '

¹ H NMR spectrum (DMSO-d6, δ in ppm): from 2.15 to 2.33 (m, 2H), 3.70 (m masked, IH), 4.10 (m, 2H), 4.57 ( m, 1H), 5.63-5.96 (m, 2H), 6.94 (d, J = 8.6Hz, 1H), 7.23 (d, J = 7.5Hz, 1H); , 7.80 - 8.01 (m, 3H), 8.05 (spread m, 3H), 8.48 (s, 1H), 9.29 (s wide, 1H) Mass spectrum (LC-MS -ES +/-),: m / z 320 [M + Hf

¹ H NMR Spectrum (DMSO-d6, δ in ppm): 3.23 (t, J = 8.3 Hz, 2H), 4.66 (t, J = 8.3 Hz, 2H),

6.96 (d, J = 8.5 Hz, 1H), 7.06-7.13 (m, 1H), 7.20 - 7.28 (m, 2H), 7.30-7.35 (b.p. m, 1H), 7.84

- 8.03 (m, 3H), 8.05 (spread m, 2H), 8.14 - 8.29 (spread m, 1H), 8.69 (s, 1H), 9.34 (br s, 1

H)

Mass spectrum (LC-MS-ES +/-),: m / z 356 [M + H] ⁺

¹ H NMR spectrum (DMSO-d6, δ in ppm): 2.19 (m, 2H), 3.73 (m, IH), 3.95 to 4.33 (m, 2H), 4.69 (m , 1H), 5.64 - 5.95 (m, 2H), 6.45 (m, 1H), 6.85 (m, 1H), 7.28 (m, 1H), 7.56 (d, J = 9.5Hz, 1H), 7.60 (dd, J = 9.5, 1.7Hz, 1H), 8.21 (s, 1H), 8.70 (brs, 1H), , 02 (spread m, 1 H)

Mass Spectrum (LC-MS-ES +/-),: m / z 291 FM + HT, m / z 293 fM + HT

¹ H NMR spectrum (DMSO-d6, δ in ppm): 3.19 (t, J = 8.5 Hz, 2H), 4.72 (t, J = 8.5 Hz, 2H), 6.47 ( m, 1H), 6.86 (m, 1H), 7.05 (td, J = 7.9, 1.1Hz, 1H), 7.20 (broad t, J = 7.9Hz, 1H); 7.27-7.32 (m, 2H), 7.59 (d, J = 9.5Hz, 1H), 7.64 (dd, J = 9.5, 1.7Hz, 1H), 8.19 (m spread, 1H), 8.39 (s, 1H), 8.75 (bs, 1H), 11.03 (m spread, 1H) Mass spectrum (LC-MS-ES +/- ),: m / z 327 TM + HT, m / z 329 fM + H1 ⁺

The compounds according to the invention have been the subject of pharmacological tests for determining their modulatory effect on NOT.

Evaluation of in vitro activity on N2A cells The activity of the compounds according to the invention was evaluated on a cell line (N2A) endogenously expressing the Nurr1 mouse receptor and stably transfected with the NOT binding response element (NBRE) coupled to the luciferase reporter gene. EC50's are between 0.01 and 1000 nM. The tests were carried out according to the procedure

5 described below.

The Neuro-2A cell line comes from a standard commercial source (ATCC). The Neuro-2A clone was obtained from a spontaneous tumor from an albino mouse A strain by RJ Klebe et al. This Neuro-2A line is then stably transfected with 8NBRE-luciferase. N2A-8NBRE cells are cultured to confluence in culture flasks

Of 75 cm ² containing DMEM supplemented with 10% fetal calf serum, 4.5 g / L glucose and 0.4 mg / ml Geneticin. After one week of culture, the cells are recovered with 0.25% trypsin for 30 seconds and then resuspended in DMEM without phenol red containing 4.5 g / l of glucose, 10% of delipidated serum Hyclone and deposited in white plates 96 wells with transparent bottom. The cells are deposited at a rate of 60,000 per well in

75 μL for 24 hours before adding the products. The products are applied in 25 μl and incubated for a further 24 hours. On the day of the measurement, an equivalent volume (100 μL) of Steadylite is added to each well, then waited for 30 minutes to obtain a complete lysis of the cells and the maximum production of the signal. The plates are then measured in a microplate luminescence counter after being sealed with an adhesive film. The products are prepared as a stock solution at 10 ^-2 M, then diluted in 100% DMSO Each product concentration is previously diluted in culture medium before incubation with the cells thus containing 0.625% final DMSO.

For example, Compounds Nos. 7, 8, 17, 30, 35 and 43 showed an EC ₅₀ of 5 nM, 0.8 nM, 6.7 nM, 56 nM, 11 nM and 2.4 nM, respectively. It thus appears that the compounds according to the invention have a modulatory effect of NOT.

The compounds chosen from compounds of formula (I) as defined above, 2- (2,3-dihydro-1H-indol-1-ylcarbonyl) -5-methylimidazo [1,2-a] pyridine and 2- (4-thiomorpholin-1-ylcarbonyl) -6-chloroimidazo [1,2-a] pyridine, and the addition salts of these compounds with a pharmaceutically acceptable acid can therefore be used for the preparation of medicaments. for their therapeutic application in the treatment or prevention of diseases involving NOT receptors.

Thus, according to another of its aspects, the subject of the invention is a medicinal product which comprises a compound chosen from the compounds of formula (I) as defined above, 2- (2,3-dihydro-1H-indol-1 -ylcarbonyl) -5-methylimidazo [1,2-a] pyridine and the 2- (4-thiomorpholin-1-ylcarbonyl) -6-chloroimidazo [1,2-a] pyridine, and the addition salts of these compounds with a pharmaceutically acceptable acid, and more particularly which comprises a formula (I) or an addition salt thereof with a pharmaceutically acceptable acid.

These drugs find their therapeutic use, especially in the treatment and prevention of neurodegenerative diseases such as Parkinson's disease, Alzheimer's, tauopathies (eg, supranuclear progressive paralysis, fronto-temporal dementia, corticobasal degeneration, Pick's disease); brain trauma such as ischemia and head trauma and epilepsy; psychiatric illnesses such as schizophrenia, depression, substance dependence, attention deficit disorder and hyperactivity disorder; inflammatory diseases of the central nervous system such as multiple sclerosis, encephalitis, myelitis and encephalomyelitis and other inflammatory diseases such as vascular diseases, atherosclerosis, inflammation of the joints, osteoarthritis, rheumatoid arthritis; osteoarthritis, Crohn's disease, ulcerative colitis; allergic inflammatory diseases such as asthma, autoimmune diseases such as type 1 diabetes, lupus, scleroderma, Guillain-Barré Syndrome, Addison's disease and other immune-mediated diseases; osteoporosis; cancers.

Thus, the present invention relates to a compound chosen from a compound of formula (I) as defined above, 2- (2,3-dihydro-1H-indol-1-ylcarbonyl) -5-methylimidazo [1,2-α] ] pyridine and 2- (4-thiomorpholin-1-ylcarbonyl) -6-chloroimidazo [1,2-a] pyridine, and the addition salts of these compounds with a pharmaceutically acceptable acid, for the treatment and the prevention of one of the aforementioned diseases.

According to a particular embodiment, these drugs find their use in the treatment and prevention of one of the aforementioned diseases, with the exception of cancers.

According to another of its aspects, the present invention relates to the use of a compound chosen from the compounds mentioned above, for the preparation of a medicament for the treatment and prevention of one of the diseases mentioned above. above.

These compounds could also be used as a treatment associated with stem cell transplants and / or transplants. According to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as active principle, a compound chosen from the group of compounds defined above. These pharmaceutical compositions contain an effective dose of at least one compound chosen from the group of compounds defined above, or a pharmaceutically acceptable salt, of said compound, as well as at least one excipient. pharmaceutically acceptable.

Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient selected from the group of compounds defined below. The above, or its salt, can be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases. Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration. by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants. For topical application, the compounds according to the invention can be used in creams, gels, ointments or lotions.

By way of example, a unitary form of administration of a compound according to the invention in tablet form may comprise the following components:

Compound according to the invention 50.0 mg Mannitol 223.75 mg

Croscarmellose sodium 6.0 mg

Corn starch 15.0 mg

Hydroxypropyl methylcellulose 2.25 mg

Magnesium stearate 3.0 mg

There may be special cases where higher or lower dosages are appropriate; such dosages are not outside the scope of the invention. According to the usual practice, the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient. The present invention, according to another of its aspects, also relates to a method of treatment of the pathologies indicated above which comprises the administration, to a patient, of an effective dose of a compound chosen from the group of compounds defined herein. above, or a pharmaceutically acceptable salt thereof.

It is understood that all the objects of the invention defined above, in particular drug, pharmaceutical composition, method of treatment also relate more particularly to the subsets of compounds defined above.

Claims

1. Compounds of formula (I):

in which :

X and Y form, with the nitrogen atom which carries them, a saturated or partially saturated mono- or bicyclic cyclic amine of 5 to 10 members optionally comprising 1 to 4 additional heteroatoms chosen from O, S, N, optionally substituted by a halogen atom, a (Ci-C ₆₎ alkyl, a (Ci-C ₆₎ alkoxy, cyano, NRaRb, COORs, said groups (Ci-C ₆₎ alkyl and (Ci-C ₆₎ alkoxy being optionally substituted with one or more halogen atoms; R 1 represents a hydrogen atom, a halogen atom, a group (C _r C ₆ ) alkoxy, a group

(Ci-C ₆₎ alkyl, NRcRd, alkyl and alkoxy can optionally be substituted by one or more halogen atoms, hydroxy, amino or (Ci-C _O) alkoxy;

R2 represents one of the following groups:

. a hydrogen atom,

. a group _(C-e) alkyl optionally substituted with one or more groups selected independently of one another from hydroxy, a halogen atom, an NRaRb group, a (Ci-C ₆₎ alkoxy, phenyl,

. a (C ₁ -C ₆ ) alkoxy group optionally substituted with one or more groups chosen independently of one another from a hydroxy, a halogen atom, a group

NRaRb

. a (C ₂ -C ₆ ) alkenyl group, a (C ₂ -C ₆ ) alkynyl group,

. a group -CO-R _5>

. a -CO-NRsR group _? ,

. a group -CO-OR ₈ ,

. a -NR 9 -CO-R ₁ 0,. a group -N = CH-NRaRb,

. a group NRi ₁ R ₁₂

. a halogen atom,

. cyano, nitro, hydroxyiminoalkyl, alkoxyiminoalkyl,

. a (C ₁ -C ₆ ) alkylthio group, a (C ₁ -C ₆ ) alkylsulphinyl group,

. a (C ₁ -C ₆ ) alkylsulfonyl group,

. (((C ₁ -C ₆ ) alkyl) ₃ ) silylethynyl group

. a group -SOa-NRpRio,

. a phenyl group optionally substituted by one or more groups chosen independently of one another from the following atoms or groups: halogen, (Q-)

C ₆ ) alkoxy, cyano, NRaRb, -CO-R ₅ , -CO-NR ₆ R ₇ , -CO-OR ₈ , a (C ₁ -C ₆ ) alkyl group optionally substituted by one or more hydroxyl or NRaRb,

. a heterocyclic group optionally substituted with a halogen atom, a group

(Ci-C ₆ ) alkyl, a (QC ₆ ) alkoxy, cyano, NRaRb, COOR _{8 group} , the (C ₁ -C ₆ ) alkyl and (C 1 -C ₆ ) alkoxy groups being optionally substituted by one or more atoms of halogen or hydroxy; R ₃ represents a hydrogen atom, a (C ₂ -C ₆ ) alkyl group, a (C ₁ -C ₆ ) alkoxy group or a halogen atom;

R ₄ represents a hydrogen atom, a (C ₁ -C ₄ ) alkyl group, a (C ₁ -C ₄ ) alkoxy group or a fluorine atom;

R ₅ represents a hydrogen atom, a phenyl group or a (C 1 -C ₆ ) alkyl group;

R ₈ and R ₇ , which may be identical or different, represent a hydrogen atom or a (C 1 -C 6) alkyl group or form, with the nitrogen atom which bears them, a 4- to 7-membered ring optionally including another heteroatom chosen from N, O or S; R ₈ represents a (C ₁ -C ₆ ) alkyl group;

R ₉ and R ₁₀ , identical or different, represent a hydrogen atom or a group (Q-

C ₆ ) alkyl;

Rn and Ri ₂ , which may be identical or different, represent a hydrogen atom or a group (Q-

C ₆ ) alkyl; Ra and Rb are, independently of one another, hydrogen, (C ₆ ) alkyl or form with the nitrogen atom carrying them a 4- to 7-membered ring; Rc is hydrogen and Rd is (C 1 -C ₆ ) alkyl; with the exception of 2- (2,3-dihydro-1H-indol-1-ylcarbonyl) -5-methylimidazo [1,2-a] pyridine and 2- (4-thiomorpholin-1-yl-carbonyl) - 6-chloroimidazo [1,2-a] pyridine; in the form of a base or an acid addition salt.

2. Compounds of formula (I) according to claim 1, characterized in that: R. ₂ is different from a hydrogen and chlorine atom.

3. Compound of formula (I) according to any one of claims 1 or 2, characterized in that:

R. ₂ represents one of the following groups:

. a group (Ci-C ₆ ) alkoxy,. a group NRi ₁ R ₁₂ ,

. a phenyl group optionally substituted with a group selected from a group -CO-

R5, (C1-C6) alkyl itself optionally substituted with hydroxy;

. a heterocyclic group optionally substituted with a NRaRb group;

R ₅ represents a (C ₁ -C ₆ ) alkyl group; Rn and Ri ₂ , which may be identical or different, represent a hydrogen atom or a group (C ₁ -

C ₆ ) alkyl;

Ra and Rb are independently of one another, hydrogen, (Ci-C ₆₎ alkyl.

4. Compounds of formula (I) according to any one of the preceding claims, characterized in that:

X and Y form, with the nitrogen atom which carries them, a saturated or partially saturated mono- or bicyclic cyclic amine of 5 to 10 members, optionally comprising an additional heteroatom chosen from O or S, optionally substituted by a group chosen from a halogen atom.

5. Foπnule compounds (I) according to any one of the preceding claims, characterized in that

-NXY represents a dihydrobenzoxazine, indoline, isoindoline, morpholine, piperidine, pyrrolidine, pyrroline, tetrahydropyridine, tetrahydroquinoline, thiomorpholine or tetrahydrothienopyridine group, optionally substituted with a halogen atom; R ₂ represents one of the following groups: a (C 1 -C 6) alkoxy group, a group NRnRn,. a phenyl group optionally substituted with a group selected from a halogen, a (C ₁ -C ₆ ) alkoxy group, a (C ₁ -C ₆ ) alkyl group optionally substituted by a hydroxyl or a C (O) R _{5 group} ,

. a pyridyl group, a pyrazolyl group, a furyl group, an oxazolyl group, a triazolyl group, a pyrrolyl group or an imidazoyl group, optionally substituted by a NRaRb group, (dC ₆ ) alkyl itself optionally substituted by a hydroxyl;

R ₅ represents a (C ₁ -C ₆ ) alkyl group;

Rn and Ri ₂ , which may be identical or different, represent a hydrogen atom or a (C ₁ -C ₆ ) alkyl group;

Ra and Rb are independently of one another, hydrogen, (Ci-C ₆₎ alkyl; R ₁ , R ₃ and R ₄ . represent a hydrogen atom.

6. Compounds of formula (I) according to any one of the preceding claims, characterized in that

-NXY represents a dihydrobenzoxazine, indoline group optionally substituted with a fluorine atom, isoindoline, morpholine, piperidine, pyrrolidine, pyrroline, tetrahydropyridine, tetrahydroquinoline, thiomorpholine, tetrahydrothienopyridine;

R ₂ represents a methoxy group, a phenyl group substituted by a hydroxymethyl, hydroxyethyl, hydroxy-methyl-ethyl, acetyl, N-dimethyl group, a pyridyl group optionally substituted with an amino group, a pyrazolyl group, a furyl group optionally substituted with a hydroxymethyl group, an oxazolyl group, a triazolyl group, a pyrrolyl group or an imidazoyl group; R ₁ , R ₃ and R ₄ represent a hydrogen atom, in the form of a base or an addition salt with an acid.

7. Compound according to any one of the preceding claims, characterized in that it is chosen from:

• {3 - [2- (Piperidin-1-ylcarbonyl) imidazo [1,2-a] pyridin-6-yl] phenyl} methanol

• {3- [2- (2,3-Dihydro-4H-1,4-benzoxazin-4-ylcarbonyl) imidazo [1,2-a] pyridin-6-yl] phenyl} methanol

• {3- [2- (Morpholin-4-ylcarbonyl) imidazo [1,2-a] pyridin-6-yl] phenyl} methanol

2- (1, 2,5,6-Tetrahydropyridinyl) carbonyl-N, N-dimethylimidazo [1,2-a] pyridin-6-amine

• {3- [2- (2,3-Dihydro-1H-indol-1-ylcarbonyl) imidazo [1,2-a] pyridin-6-yl] phenyl} methanol • (3- {2 - [(6- fluoro-2,3-dihydro-lH-indol-l-yl) carbonyl] imidazo [l, 2-Uf] pyridin-6-yl} phenyl) methanol

• {3- [2- (2,5-Dihydro-1H-pyrrol-1-ylcarbonyl) imidazo [1,2-a] pyridin-6-yl] phenyl} methanol

• {3- [2 - [(1, 2,5,6-Tetrahydropyridin-1-yl) carbonyl] imidazo [1,2-a] pyridin-6-yl] phenyl} methanol

• {3- [2- (Pyrrolidin-1-ylcarbonyl) imidazo [1,2-a] pyridin-6-yl] phenyl} methanol • {3- [2- (4,5,6,7-tetrahydro-thieno [3,2-c] pyridin-5-ylcarbonyl) imidazo [1,2-a] pyridin-6-yl] phenyl} methanol

• 2- (2,3-Dihydro-4H-l, 4-benzoxazin-4-ylcarbonyl) -N, N-dimethylimidazo [2-α] pyridin-6-amine

{3- [2- (1,2,3,4-Tetrahydroquinolin-1-ylcarbonyl) imidazo [1,2-a] pyridin-6-yl] phenyl} methanol

• {3- [2- (1,3-Dihydro-2H-isoindol-2-ylcarbonyl) imidazo [1,2-a] pyridin-6-yl] phenyl} methanol • 2- (2,3-Dihydro-1H) -indol-l-ylcarbonyl) -N, N-dimethylimidazo [2-α] pyridin-6-amine

2- (1,3-Dihydro-2H-isoindol-2-ylcarbonyl) -N, N-dimethylimidazo [1,2-a] pyridin-6-amine

N, N-dimethyl-2- (piperidin-1-ylcarbonyl) imidazo [1,2-a] pyridin-6-amine

• 2 - [(6-Fluoro-2,3-dihydro-lH-indol-l-yl) carbonyl] -N, N-dimethylimidazo [2-α] pyridin-6-amine

• N, N-dimethyl-2- (morpholin-4-ylcarbonyl) imidazo [l, 2-α] pyridin-6-amine

2- (2,5-Dihydro-1H-pyrrol-1-ylcarbonyl) -N, N-dimethylimino [1,2-a] pyridin-6-amine

{3- [2- (Thiomorpholin-4-ylcarbonyl) imidazo [1,2-a] pyridin-6-yl] -penienyl} methanol • N, N-dimethyl-2- (pyrrolidin-1-ylcarbonyl) imidazo [1] , α-2] pyridin-6-amine

2- (4,5,6,7-tetrahydro-thieno [3,2-c] pyridin-5-ylcarbonyl) -N, N-dimethylidazo [1,2-a] pyridin-6-amine

• N, N-dimethyl-2- (thiomorpholin-4-ylcarbonyl) imidazo [l, 2-α] pyridin-6-amine

• 2- (2,5,6-TETRAL ydropyridin _1-yl) carbonyl-6-methoxy-5-methylimidazo [l, 2-α] pyridine,

• 6- (Pyridin-2-yl) -2 - [(l, 2,5,6-tetrahydropyridin-l-yl) carbonyl] imidazo [l, 2-α] pyridine

2- (2,3-Dihydro-1H-indol-1-ylcarbonyl) -6- (pyridin-2-yl) imidazo [1,2-a] pyridine

• 2- (2,3-Dihydro-indol-l-ylcarbonyl) -6- (lH-pyrazol-3-yl) imidazo [l, 2-α] pyridine

• 6- (Furan-2-yl) -2 - [(l, 2,5,6-tetrahydropyridin-l-yl) carbonyl] imidazo [l, 2-α] pyridine

• 2- (2,3-Dihydro-indol-l-ylcarbonyl) -6- (furan-2-yl) imidazo [l, 2-β] pyridine

• 6- (oxazol-2-yl) -2 - [(l, 2,5,6-tetrahydropyridin-l-yl) carbonyl] imidazo [l, 2-α] pyridine

• 6- (Furan-3-yl) -2 - [(l, 2,5,6-tetrahydropyridin-l-yl) carbonyl] imidazo [l, 2-α] pyridine

2- (2,3-Dihydro-1H-indol-1-ylcarbonyl) -6- (furan-3-yl) imidazo [1,2-a] pyridine

6- [5- (Hydroxymethyl) furan-2-yl] -2 - [(1,2,5,6-tetrahydropyridin-1-yl) carbonyl] imidazo [1,2-a] pyridine

[(1, 2,5,6-tetrahydropyridin-1-yl) carbonyl] -6- (1H-1,2,4-triazol-3-yl) imidazo [1,2-a] pyridine • 2- ( 2,3-Dihydro-1H-indol-1-ylcarbonyl) -6- (1H-1,2,4-triazol-3-yl) imidazo [1,2-a] pyridine

6- (6-Aminopyridin-2-yl) -2 - [(1,2,5,6-tetrahydropyridin-1-yl) carbonyl] imidazo [1,2-a] pyridine and its dihydrochloride

6- (6-Aminopyridin-2-yl) -2- (2,3-dihydro-1H-indol-1-ylcarbonyl) imidazo [1,2-a] pyridine and its dihydrochloride

6- (1H-Pyrrol-3-yl) -2 - [(1,2,5,6-tetrahydropyridin-1-yl) carbonyl] imidazo [1,2-a] pyridine • 2- (2,3- Dihydro-1H-indol-1-ylcarbonyl) -6- (1H-pyrrol-3-yl) imidazo [1,2-a] pyridine • 2- (2,3-Dihydro-1H-indol-1-ylcarbonyl) - 6- (Furan-2-yl) imidazo [1,2-a] pyridine and its trifluoroecetate (1,1)

2- (2,3-Dihydro-1H-indol-1-ylcarbonyl) -6- [5- (hydroxymethyl) furan-2-yl] imidazo [1,2-a] pyridine and its trifluoroecetate (1,1)

• 6- (lH-imidazol-4-yl) -2 - [(l, 2,5,6-tetrahydropyridin-l-yl) carbonyl] imidazo [l, 2-a] pyridine

• 2- (2,3-Dihydro-indol-l-ylcarbonyl) -6- (lH-imidazol-4-yl) imidazo [l, 2-α] pyridine

2 - [(1,2,5,6-Tetrahydropyridin-1-yl) carbonyl] -6- (1H-1,2,3-triazol-4-yl) imidazo [1,2-a] pyridine

• 2- (2,3-Dihydro-lH-indol-l-ylcarbonyl) -6- (lH-l, 2,3-triazol-4-yl) imidazo [l, 2-α] pyridine

6- (3-Acetylphenyl) -2- (1, 2,5,6-tetrahydropyridin-1-yl) carbonyl-imidazo [1,2-a] pyridine

6- [3- (1-hydroxyethyl) -phenyl] -2- (1,2,5,6-tetrahydropyridin-1-yl) -carbonyl-imidazo [1,2-a] pyridine (RS)

6- [3- (1-Hydroxy-1-methylethyl) phenyl] -2- (1,2,5,6-tetrahydropyridin-1-yl) -carbonyl-imidazo [1,2-o] pyridine and their salts; addition to an acid.

8. Medicament, characterized in that it comprises a compound chosen from the compounds of formula (I) according to any one of claims 1 to 7, 2- (2,3-dihydro-1H-indol-1-ylcarbonyl ) -5-methylimidazo [1,2-a] pyridine or 2- (4-thiomorpholin-1-ylcarbonyl) -6-chloro-imidazo [1,2-a] -pyridine, and the addition salts of these compounds to a pharmaceutically acceptable acid.

9. A medicament characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 7, or a salt of addition of these compounds to a pharmaceutically acceptable acid.

10. Pharmaceutical composition, characterized in that it comprises a compound as defined in any one of claims 6 or 7, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

11. Use of a compound as defined in any one of claims 6 or 7 for the preparation of a medicament for the treatment and prevention of neurodegenerative diseases.

12. Use of a compound as defined in any one of claims 6 or 7 for the preparation of a medicament for the treatment and prevention of cerebral trauma and epilepsy.

13. Use of a compound as defined in any one of claims 6 or 7 for the preparation of a medicament for the treatment and prevention of psychiatric diseases.

14. Use of a compound as defined in any one of claims 6 or 7 for the preparation of a medicament for the treatment and prevention of inflammatory diseases.

15. Use of a compound of formula (I) according to any one of claims 1 to 7 for the preparation of a medicament for the treatment and prevention of osteoporosis.

16. Use of a compound of formula (I) according to any one of claims 1 to 7 for the preparation of a medicament for the treatment and prevention of cancers.

17. Use of a compound of formula (I) according to any one of claims 1 to 7 for the preparation of a medicament for the treatment and prevention of Parkinson's disease, Alzheimer's disease, tauopathies, multiple sclerosis.

18. Use of a compound as defined in any one of claims 6 or

7 for the preparation of a medicament for the treatment and prevention of schizophrenia, depression, substance dependence, attention deficit disorder and hyperactivity disorder.

19.. compounds

Ethyl 6-methoxy-5-methylimidazo [1,2-n] pyridine-2-carboxylate;

6-methoxy-5-methylimidazo [1,2-a] pyridine-2-carboxylic acid;

Ethyl 6- (3-Hydroxymethyl-phenyl) imidazo [1,2-a] pyridine-2-carboxylate;

6- (3-hydroxymethyl-phenyl) -imidazo [1,2-a] pyridine-2-carboxylic acid; Ethyl 6- (6 - {[(1,1-dimethylethoxy) carbonyl] amino} pyridin-2-yl) imidazo [1,2-a] pyridine-2-carboxylate;

6- (6- {[(1,1-Dimethylethoxy) carbonyl] amino} pyridin-2-yl) imidazo [1,2-a] pyridine-2-carboxylic acid;

(6-Pyridin-2-yl) imidazo [1 ₅ 2-α] pyridine-2-carboxylic acid ethyl ester; 6- (pyridin-2-yl) imidazo [1,2-a] pyridine-2-carboxylic acid;

Ethyl 6- (1-triphenylmethyl-1H-imidazol-4-yl) imidazo [1,2-a] pyridine-2-carboxylate;

6- (1-Triphenylmethyl-1H-imidazol-4-yl) imidazo [1,2-a] pyridine-2-carboxylic acid;

Ethyl 6- [1 - (Triisopropylsilyl) -1H-pyrrol-3-yl] imidazo [1,2-a] pyridine-2-carboxylate; 6- (1H-pyrrol-3-yl) imidazo [1,2-a] pyridine-2-carboxylic acid;

Ethyl 6- (1H-pyrazol-3-yl) imidazo [1,2-a] pyridine-2-carboxylate;

6- (1H-pyrazol-3-yl) imidazo [1,2-a] pyridine-2-carboxylic acid;

6- (Furan-2-yl) ethyl imidazo [1,2-a] pyridine-2-carboxylate;

6- (Furan-2-yl) imidazo [1,2-a] pyridine-2-carboxylic acid; Ethyl 6- (Furan-3-yl) imidazo [1,2-a] pyridine-2-carboxylate;

6- (Furan-3-yl) imidazo [1,2-a] pyridine-2-carboxylic acid;

Ethyl 6- [5- (Η-hydroxymethyl) furan-2-yl] imidazo [1,2-a] pyridine-2-carboxylate;

6- [5- (hydroxymethyl) furan-2-yl] imidazo [1,2-a] pyridine-2-carboxylic acid;

6- (Oxazol-2-yl) imidazo [1,2-a] pyridine-2-carboxylic acid ethyl ester; 6- (oxazol-2-yl) imidazo [1,2-a] pyridine-2-carboxylic acid;

Ethyl 6- (1H-1,2,4-triazol-3-yl) imidazo [1,2-a] pyridine-2-carboxylate;

6- (1H-1,2,4-triazol-3-yl) imidazo [1,2-a] pyridine-2-carboxylic acid;

Ethyl 6- (1H-1,2,3-triazol-4-yl) imidazo [1,2-a] pyridine-2-carboxylate; and

6- (1H-1,2,3-Triazol-4-yl) imidazo [1,2-b] pyridine-2-carboxylic acid.

20. Use of the compounds according to claim 15 for the synthesis of the compounds as defined in claims 6 or 7.