HK1148016B

HK1148016B - Derivatives of 6-heterocyclic-imidazo[1,2-a]pyrroine-2-carboxamides, preparation thereof and therapeutic application thereof

Info

Publication number: HK1148016B
Application number: HK11102219.8A
Authority: HK
Inventors: Jean-François Peyronel
Original assignee: 赛诺菲-安万特
Priority date: 2008-01-02
Filing date: 2008-12-31
Publication date: 2013-11-15

Description

6-heterocyclic imidazo [1,2-a ] pyridine-2-carboxamide derivatives, preparation and therapeutic use thereof

Technical Field

The present invention relates to imidazo [1,2-a ] pyridine-2-carboxamide derivatives, methods for their preparation and their therapeutic use in the treatment or prevention of diseases in which the nuclear receptor of Nurr-1 (also known as NR4a2, NOT, TINUR, RNR-1 and HzF3) is involved.

Disclosure of Invention

One subject of the invention is a compound of formula (I) in base form or in acid addition salt form:

wherein:

x represents a phenyl group optionally substituted with one or more groups selected independently of each other from the following atoms or groups: halogen, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Alkyl, NRaRb, cyano, (C)₁-C₆) Alkoxycarbonyl group, said (C)₁-C₆) Alkyl and (C)₁-C₆) Alkoxy being optionally substitutedHaving one or more halogen atoms;

R₁represents a hydrogen atom, a halogen atom, or (C)₁-C₆) Alkoxy group, (C)₁-C₆) Alkyl or NRaRb groups; the alkyl and alkoxy groups may be substituted with one or more halogen, hydroxy, amino or (C)₁-C₆) An alkoxy group;

R₂represents an unsaturated, partially saturated or fully saturated aromatic heterocyclic radical, optionally substituted with one or more groups chosen, independently of one another, from the following atoms or groups: hydroxy, (C)₁-C₆) Alkoxy, halogen, cyano, NRaRb, -CO-R₅、-CO-NR₆R₇、-CO-O-R₈、-NR₉-CO-R₁₀(C) optionally substituted by one or more hydroxyl groups or NRaRb₁-C₆) Alkyl, oxo groups;

R₃represents a hydrogen atom or (C)₁-C₆) Alkyl, (C)₁-C₆) An alkoxy group or a halogen atom;

R₄represents a hydrogen atom or (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy or fluorine atom;

R₅represents a hydrogen atom, a phenyl group or (C)₁-C₆) An alkyl group;

R₆and R₇May be the same or different and represents a hydrogen atom or (C)₁-C₆) Alkyl or form a 4-to 7-membered ring with the nitrogen atom, said ring optionally including an additional heteroatom selected from N, O and S;

R₈is represented by (C)₁-C₆) An alkyl group;

R₉and R₁₀May be the same or different and represents a hydrogen atom or (C)₁-C₆) An alkyl group;

ra and Rb of each otherThis is independently hydrogen or (C)₁-C₆) Alkyl or form a 4-to 7-membered ring with the nitrogen atom to which they are attached, said ring optionally including an additional heteroatom selected from N, O and S;

the compounds do not include N- (4-bromophenyl) -6- (1-methylpiperidin-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide.

The compounds of formula (I) may contain one or more asymmetric carbon atoms. The compounds may thus exist in enantiomeric or diastereomeric forms. These enantiomers and diastereomers and mixtures thereof, including racemic mixtures, form part of the present invention.

The compounds of formula (I) may exist in the form of a base or in the form of an acid addition salt. Such addition salts form part of the present invention. These salts may be prepared with pharmaceutically acceptable acids, but salts of other useful acids, for example, salts for purifying or isolating compounds of formula (I) also form part of the invention.

The compounds of formula (I) may also exist in the form of hydrates or solvates, i.e. associated with or bound to one or more water molecules or solvents. Such hydrates and solvates also form part of the present invention.

N- (4-bromophenyl) -6- (1-methylpiperidin-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide is cited in the chemical library under the number RN ═ 797785-86-5, which is specifically excluded from the compounds of formula (I) according to the invention.

In the context of the present invention, the following definitions apply:

-a halogen atom: fluorine, chlorine, bromine or iodine;

-an alkyl group: a linear, branched or cyclic saturated aliphatic group, said group being optionally substituted with: a linear, branched, or cyclic saturated alkyl group. Examples which may be mentioned include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl and the like groups;

-alkenyl: linear or branched, mono-or polyunsaturated aliphatic groups containing, for example, one or two ethylenically unsaturated bonds (ethylenic unsaturations);

-an alkoxy group: -O-alkyl, wherein the alkyl is as previously defined;

-a heterocyclic group: an unsaturated, partially saturated or fully saturated monocyclic or bicyclic aryl group comprising 5 to 10 atoms including 1 to 4 heteroatoms selected from N, O and S. Examples of heterocyclic groups that may be mentioned include: pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyrrolopyrrolyl, pyrroloimidazolyl, pyrrolopyrazolyl, pyrrolotriazolyl, imidazoimidazolyl, imidazopyrazolyl, imidazotriazolyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, indolizinyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzo [ c ] thienyl, pyrrolopyridyl, imidazopyridyl, pyrazolopyridinyl, triazolopyridyl, tetrazolopyridinyl, pyrrolopyrimidyl, imidazopyrimidinyl, pyrazolopyrimidyl, triazolopyrimidinyl, tetrazolopyrimidinyl, pyrrolopyrazinyl, imidazopyridyl, pyrrolopyrazinyl, imidazopyridyl, tetrazolopyrimidyl, tetrazolopyrimidinyl, pyrrolopyrazinyl, imidazopyrazinyl, and pyrrolopyrazinyl, Pyrazolopyridinyl, triazolopyrazinyl, tetrazolopyridinyl, pyrrolopyridazinyl, imidazopyridazinyl, pyrazolopyridazinyl, triazolopyridazinyl, tetrazolopyridazinyl, pyrrolotriazinyl, imidazotriazinyl, pyrazolotriazinyl, triazolotriazinyl, tetrazolotriazinyl, furopyridinyl, furopyrimidinyl, furopyrazinyl, furopyridazinyl, furotriazinyl, oxazolopyridyl, oxazolopyrimidinyl, oxazolopyridazinyl, oxazolotriazinyl, isoxazolopyridinyl, isoxazolopyrimidinyl, isoxazolopyridazinyl, isoxazolotriazinyl, oxadiazolopyridyl, oxadiazolazinyl, oxadiazozotriazinyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, Thienopyridinyl, thienopyrimidinyl, thienopyrazinyl, thienopyridazinyl, thienotriazinyl, thiazolopyridinyl, thiazolopyrimidinyl, thiazolopyrazinyl, thiazolopyridazinyl, thiazolotriazinyl, isothiazolopyridyl, isothiazolopyrimidinyl, isothiazolopyrazinyl, isothiazolopyridazinyl, isothiazolotriazinyl, thiadiazolopyridinyl, thiadiazolopyrimidinyl, thiadiazolopyridazinyl, thiadiazolotriazinyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, benzotriazinyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, pyridotriazinyl, pyrimidopyrimidinyl, pyrimidopyridazinyl, Pyrimidotriazinyl, pyrazinopyrazinyl, pyrazinopyridazinyl, pyrazinotriazinyl, pyridazinopyridazinyl, pyridazinotriazinyl; these groups may be partially unsaturated or saturated.

Examples of heterocyclic groups which may be mentioned also include dioxolanyl and indolizoline (indolizine) groups.

If the heterocyclic group is a nitrogen-containing saturated monocyclic heterocyclic group, it is at R₂To which no nitrogen atom is attached to imidazo [1,2-a]And (4) pyridine combination.

Various subgroups of compounds are defined hereinafter which also form part of the present invention.

Among the compounds which are the subject of the present invention, a first group of compounds consists of compounds of formula (I) as defined previously, in which:

x represents a phenyl group optionally substituted with one or more halogen atoms or a cyano group;

the other groups are as defined above.

Among the compounds which are the subject of the present invention, the second group of compounds consists of compounds of formula (I) as defined previously, in which:

x represents a phenyl group optionally substituted with one or more fluorine or chlorine atoms or a cyano group;

the other groups are as defined above.

Among the compounds which are the subject of the present invention, the third group of compounds consists of compounds of formula (I) as defined previously, in which R is₂Represents an unsaturated, partially saturated or fully saturated monocyclic or bicyclic aromatic heterocyclic group, excluding piperidyl, said heterocyclic group containing 5 to 10 atoms including 1 to 4 heteroatoms selected from N, O and S; said heterocyclyl being optionally substituted with one or more groups selected independently of each other from the following atoms or groups: hydroxy, (C)₁-C₆) Alkoxy, halogen, cyano, NRaRb, -CO-R₅、-CO-NR₆R₇、-CO-O-R₈、-NR₉-CO-R₁₀Oxo, optionally substituted by one or more hydroxy groups or NRaRb groups₁-C₆) An alkyl group;

the other groups are as defined above.

Among the compounds which are the subject of the present invention, the fourth group of compounds is constituted by the compounds of formula (I) as defined previously, in which:

R₂represents pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl; said R₂Optionally substituted with one or more groups selected from the following atoms or groups: hydroxy, (C)₁-C₆) Alkoxy, oxo, halogen, -NRaRb, (C) optionally substituted by itself by hydroxy₁-C₆) An alkyl group, a carboxyl group,

ra and Rb are independent of each otherIs hydrogen or (C)₁-C₆) An alkyl group.

Among the compounds which are the subject of the present invention, a fifth group of compounds consists of compounds of formula (I) as defined previously, in which:

R₂represents a dioxolanyl, pyridyl, imidazolyl, pyrazolyl, triazolyl, pyrrolyl, furyl, oxazolyl, imidazolinyl, thienyl, pyrazinyl, pyrimidinyl or thiazolyl group; said R₂Optionally substituted with one or more groups selected from the following atoms or groups: hydroxy, (C)₁-C₆) Alkoxy, oxo, halogen, -NRaRb, (C) optionally substituted by itself by hydroxy₁-C₆) An alkyl group, a carboxyl group,

ra and Rb are each independently of the other hydrogen or (C)₁-C₆) An alkyl group, a carboxyl group,

the other groups are as defined above.

Among the compounds which are the subject of the present invention, a sixth group of compounds is constituted by compounds of formula (I) as defined previously, in which:

R₂represents indolyl, isoindolyl, benzimidazolyl, indazolyl, indolizinyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzo [ c ]]Thienyl, pyrrolopyridyl, imidazopyridyl, pyrazolopyridyl, triazolopyridyl, tetrazolopyrimidinyl, pyrrolopyrimidyl, imidazopyrimidinyl, pyrazolopyrimidinyl, triazolopyrimidinyl, pyrrolopyrazinyl, imidazopyrazinyl, pyrazolopyrimidinyl, triazolopyrazinyl, tetrazolopyridazinyl, imidazopyridazinyl, pyrazolopyridazinyl, triazolopyridazinyl, tetrazolopyridazinyl, pyrrolotriazinyl, imidazotriazinyl, pyrazolotriazinyl, triazolotriazinyl, tetrazolotriazinyl, furopyridinyl, furopyrimidinyl, furopyrazinyl, furopyridazinyl, furopyridinyl, oxazolopyridinyl, oxazolopyrimidinyl, oxazolopyridazinyl, oxazolotriazinyl, tetrazolotriazinyl, furopyridinyl, furopyrimidinyl, furopyrazinyl, furopyridazinyl, furopyridinyl, oxazolopyridyl, oxazolopyrimidyl, and pyrazolopyrimidinylAzinyl, isoxazolopyridinyl, isoxazolopyrimidinyl, isoxazolopyrazinyl, isoxazolopyridazinyl, isoxazolotriazinyl, oxadiazolidinyl, oxadiazopyrimidinyl, oxadiazolopyrazinyl, oxadiazolidizzinyl, oxadiazotriazinyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, thienopyridinyl, thienopyrimidinyl, thienopyrazinyl, thienopyridazinyl, thienotriazinyl, thiazolopyridyl, thiazolopyrimidinyl, thiazolopyridazinyl, thiazolotriazinyl, isothiazolopyridinyl, isothiazolopyrimidinyl, isothiazolopyridazinyl, isothiazolotriazinyl, thiadiazolopyridinyl, thiadiazolopyrimidinyl, thiadiazolopyridazinyl, thiadiazolotriazinyl, benzothiazolyl, oxazotriazinyl, thiazotriazinyl, thiadiazolopyridinyl, thiadiazolopyridazinyl, thia, Benzisothiazole or benzothiadiazole; said R₂Optionally substituted with one or more groups selected from the following atoms or groups: hydroxy, (C)₁-C₆) Alkoxy, oxo, halogen, -NRaRb, (C) optionally substituted by itself by hydroxy₁-C₆) An alkyl group, a carboxyl group,

ra and Rb are each independently of the other hydrogen or (C)₁-C₆) An alkyl group;

the other groups are as defined above.

Among the compounds which are the subject of the present invention, a seventh group of compounds consists of compounds of formula (I) as defined previously, in which:

R₂represents an indolyl group, optionally substituted with one or more groups selected from the following atoms or groups: hydroxy, (C)₁-C₆) Alkoxy, oxo, halogen, -NRaRb, (C) optionally substituted by itself by hydroxy₁-C₆) An alkyl group, a carboxyl group,

the other groups are as defined above.

Among the compounds which are the subject of the present invention, a eighth group of compounds is constituted by compounds of formula (I) as defined previously, in which:

R₂represents a dioxolanyl group, a pyridyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, a pyrrolyl group, a furyl group, an oxazolyl group, an indolyl group, an imidazolinyl group, a thienyl group, a pyrazinyl group, a pyrimidinyl group or a thiazolyl group, and R is₂Optionally substituted with one or more of the following groups: hydroxy, methyl, hydroxymethyl, methoxy, oxo, halogen or NH₂The radical(s) is (are),

the other groups are as defined above.

Among the compounds which are the subject of the present invention, a ninth group of compounds consists of compounds of formula (I) as defined previously, in which R is₁Represents a hydrogen atom or (C)₁-C₆) An alkyl group;

the other groups are as defined above.

Among the compounds which are the subject of the present invention, the tenth group of compounds is constituted by compounds of formula (I) as defined previously, in which R is₁Represents a hydrogen atom or a methyl group;

the other groups are as defined above.

Among the compounds which are the subject of the present invention, an eleventh group of compounds is constituted by compounds of formula (I) as defined previously, in which R is₃And R₄Represents a hydrogen atom;

the other groups are as defined above.

Among the compounds which are the subject of the present invention, a twelfth group of compounds is constituted by the compounds of formula (I) as defined previously, in which:

R₂represents a dioxolanyl group, a pyridyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, a pyrrolyl group, a furyl group, an oxazolyl group, an indolyl group, an imidazolinyl groupThienyl, pyrazinyl, pyrimidinyl or thiazolyl, said R₂Optionally substituted with one or more of the following groups: hydroxy, methyl, hydroxymethyl, methoxy, oxo, halogen or NH₂The radical(s) is (are),

R₁represents a hydrogen atom or a methyl group;

R₃and R₄Represents a hydrogen atom;

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

Among the compounds which are the subject of the present invention, a thirteenth group of compounds consists of compounds of formula (I) as defined previously, in which:

x represents a phenyl group optionally substituted with one or more fluorine atoms;

R₂represents pyridyl, furyl, dioxolanyl, imidazolyl, pyrazolyl, triazolyl, pyrrolyl, thiazolyl, oxazolyl, pyrazinyl, pyrimidinyl, thienyl, indolyl or imidazolinyl, these radicals being optionally substituted by hydroxymethyl, NH₂Methyl, methoxy, hydroxy or oxo groups or fluorine atoms;

R₁represents a hydrogen atom or a methyl group;

R₃and R₄Represents a hydrogen atom, and is represented by,

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

Among the compounds of formula (I) which are the subject of the present invention, mention may in particular be made of the following compounds and their acid addition salts:

● 6- (1, 3-dioxolan-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

● N-phenyl-6- (pyridin-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N-phenyl-6- (pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● 6- [5- (hydroxymethyl) pyridin-3-yl ] -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

● 6- [4- (hydroxymethyl) pyridin-2-yl ] -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide and its hydrochloride (1: 1)

● 6- (6-aminopyridin-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide and its hydrochloride (1: 1)

● 6- (1H-imidazol-4-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide and its hydrochloride (1: 1)

● N-phenyl-6- (1H-pyrazol-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N-phenyl-6- (1H-1, 2, 4-triazol-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N-phenyl-6- (1H-pyrrol-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● 6- (2-methyl-1H-imidazol-4-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

● 6- (furan-3-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

● 6- (1H-imidazol-1-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide and its trifluoroacetate salt (1: 1)

● 6- (oxazol-5-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

● 6- (2-aminothiazol-4-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

● 6- (2-methyl-1, 3-dioxolan-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

● 6- (4, 5-dihydro-1H-imidazol-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide and its hydrochloride (1: 1)

● 6- (6-methoxypyridin-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

● 5-methyl-N-phenyl-6- (pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● 6- (2-amino-1H-imidazol-4-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide and its trifluoroacetate salt (1: 1)

● 6- (2-aminothiazol-5-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

● 6- (6-hydroxypyridin-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

● N-phenyl-6- (1H-1, 2, 3-triazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (3, 5-difluorophenyl) -6- (furan-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (3-fluorophenyl) -6- (furan-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● 6- (furan-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

● 6- [6- (hydroxymethyl) pyridin-2-yl ] -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide and its hydrochloride (1: 1)

● 6- (1-Oxopyridin-3-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide and its hydrochloride (1: 1)

● N-phenyl-6- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● 6- (1H-imidazol-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide hydrochloride (1: 1)

● 6- (1-methyl-1H-imidazol-4-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

● 6- (oxazol-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

● N- (3, 5-difluorophenyl) -6- (pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N-phenyl-6- (pyridin-4-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● 6- (1H-indol-3-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

● N-phenyl-6- (thien-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N-phenyl-6- (pyrazin-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● 6- (1-Oxopyridin-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

● N-phenyl-6- (pyrimidin-5-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N-phenyl-6- (thien-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● 6- (5-fluoro-furan-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

● N- (3-fluorophenyl) -6- (pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2-fluorophenyl) -6- (pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2, 5-difluorophenyl) -6- (pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2, 3-difluorophenyl) -6- (pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● 6- (6-aminopyridin-2-yl) -N- (3-fluorophenyl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (3-fluorophenyl) -6- (1H-pyrrol-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (3-fluorophenyl) -6- (1H-pyrazol-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (3-fluorophenyl) -6- (furan-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (3-fluorophenyl) -6- (oxazol-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N-phenyl-6- (pyrimidin-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (3-fluorophenyl) -6- (1H-imidazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (3-fluorophenyl) -6- (1H-1, 2, 4-triazol-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● 6- (2-aminothiazol-4-yl) -N- (3-fluorophenyl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (3-fluorophenyl) -6- (1H-1, 2, 3-triazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (3-fluorophenyl) -6- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (3-fluorophenyl) -6- [5- (hydroxymethyl) furan-2-yl ] imidazo [1,2-a ] pyridine-2-carboxamide

● 6- [2- (hydroxymethyl) -1H-imidazol-4-yl ] -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

● N- (3, 5-difluorophenyl) -6- (6-methylpyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2-chlorophenyl) -6- (pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (3, 5-difluorophenyl) -6- (1H-pyrrol-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2-fluorophenyl) -6- (1H-pyrrol-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2, 5-difluorophenyl) -6- (1H-pyrrol-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2, 3-difluorophenyl) -6- (1H-pyrrol-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (3, 5-difluorophenyl) -6- (1H-pyrazol-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2-fluorophenyl) -6- (furan-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2, 5-difluorophenyl) -6- (furan-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2, 3-difluorophenyl) -6- (furan-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2-chlorophenyl) -6- (furan-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2, 5-difluorophenyl) -6- (oxazol-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2-chlorophenyl) -6- (oxazol-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2-fluorophenyl) -6- (furan-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2, 5-difluorophenyl) -6- (furan-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2, 3-difluorophenyl) -6- (furan-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2-chlorophenyl) -6- (furan-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2, 3-difluorophenyl) -6- [5- (hydroxymethyl) furan-2-yl ] imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2-fluorophenyl) -6- (1H-1, 2, 4-triazol-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2-chlorophenyl) -6- (1H-1, 2, 4-triazol-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2-cyanophenyl) -6- (pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● 6- (6-aminopyridin-2-yl) -N- (3, 5-difluorophenyl) imidazo [1,2-a ] pyridine-2-carboxamide and its dihydrochloride

● 6- (6-aminopyridin-2-yl) -N- (2-fluorophenyl) imidazo [1,2-a ] pyridine-2-carboxamide and its dihydrochloride

● 6- (6-aminopyridin-2-yl) -N- (2, 5-difluorophenyl) imidazo [1,2-a ] pyridine-2-carboxamide and its dihydrochloride

● 6- (6-aminopyridin-2-yl) -N- (2, 3-difluorophenyl) imidazo [1,2-a ] pyridine-2-carboxamide and its dihydrochloride

● 6- (6-aminopyridin-2-yl) -N- (2-chlorophenyl) imidazo [1,2-a ] pyridine-2-carboxamide and its dihydrochloride

● N- (2-chlorophenyl) -6- (1H-pyrrol-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2-fluorophenyl) -6- (1H-pyrazol-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2-chlorophenyl) -6- (1H-pyrazol-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (3, 5-difluorophenyl) -6- (furan-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (3, 5-difluorophenyl) -6- (oxazol-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2-fluorophenyl) -6- (oxazol-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2, 3-difluorophenyl) -6- (oxazol-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (3, 5-difluorophenyl) -6- [5- (hydroxymethyl) furan-2-yl ] imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2, 5-difluorophenyl) -6- [5- (hydroxymethyl) furan-2-yl ] imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2, 3-difluorophenyl) -6- (1H-imidazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2, 5-difluorophenyl) -6- (1H-1, 2, 4-triazol-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2, 3-difluorophenyl) -6- (1H-1, 2, 4-triazol-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (3, 5-difluorophenyl) -6- (1H-1, 2, 3-triazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2-fluorophenyl) -6- (1H-1, 2, 3-triazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2, 5-difluorophenyl) -6- (1H-1, 2, 3-triazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N- (2-chlorophenyl) -6- (1H-1, 2, 3-triazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxamide.

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

Scheme 1

First step synthetic route (transformation step A)₂) Is prepared according to methods known to those skilled in the art, 2-aminopyridines of formula (II) and then formed into imidazo [1,2-a ] by condensation of formula (II) with a halogenated derivative of 2-oxo-N-arylpropionamide (III)]A pyridine ring, said R in formula (II)₁、R₂、R₃And R₄Hal in said formula (III) denotes a chlorine, bromine or iodine atom and X is as defined above, the above-mentioned route being analogous, for example, to J-J.Bourguignon et al.in Aust.J.Chem.,50719(1997) and J.G.Lombardino in J.org.chem.,302403 (1965).

The halogenated derivatives of 2-oxo-N-arylpropionamide (III) can be obtained, for example, according to the following method: r. Kluger et al.in J.am.chem.Soc.,106，4017(1984)。

2-aminopyridines of formula (II) wherein R₁、R₂、R₃And R₄As previously defined, it is possible to carry out the transformation step A₁To prepare, namely:

2-aminopyridine derivatives and derivatives R via formula (IV)₂-Z' (V) coupling reaction, said R in formula (IV)₁、R₃And R₄As defined above and Z represents a boryl, stannyl or silyl group, said derivative R₂-R in Z' (V)₂As previously defined, and Z' represents a halogen atom such as a bromine atom or an iodine atom or a sulfonyloxy group,

2-aminopyridine derivatives and derivatives R via formula (IV)₂-Z' (V) coupling reaction, said R in formula (IV)₁、R₃And R₄As defined above and Z represents a halogen atom such as a bromine atom or an iodine atom, said derivative R₂-R in Z' (V)₂As previously defined, 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.

Second step synthetic route (transformation step B)₂) Is prepared by reacting an imidazopyridine-2-carboxylic acid of formula (VI) or a derivative thereof with an arylamine of formula (VII) X-NH according to methods known to those skilled in the art₂To be coupled, R in said formula (VI)₁、R₂、R₃And R₄As defined above, Y represents a hydroxyl group, a halogen atom or (C)₁-C₆) Alkoxy, wherein X in said formula (VII) is as defined above. Thus, the acid may be converted beforehand to one of its reactive derivatives, such as an acid halide, an acid anhydride, a mixed acid anhydride or an activated ester, and the derivative is then reacted with the amine (VII) in the presence of a base in an inert solvent,such as diisopropylethylamine, triethylamine or pyridine, and an inert solvent such as THF, DMF or dichloromethane. The coupling reaction can also be carried out as follows: in the presence of a coupling agent such as CDI, EDCI, HATU or HBTU under the same conditions without isolation of the reaction intermediate. Alternatively, amine (VII) may be reacted with an ester of an acid of formula (VI) in the presence of a catalyst such as trimethylaluminum (according to the following method: Weinreb, S.et al (Tet.Lett. (1977), 18, 4171)) or zirconium tert-butoxide.

The imidazopyridine-2-carboxylic acid derivatives of formula (VI) are prepared by the following route: condensation of 2-aminopyridines of formula (II) with 3-halo-2-oxopropanoic acids of formula (VIII), followed by conversion of the esters to acids and then to acid chlorides or further reactive derivatives, where appropriate (conversion step B)₁) R in said formula (VI)₁、R₂、R₃And R₄As previously defined and Y is (C)₁-C₆) Alkoxy, hydroxy or halogen, said R in formula (II)₁、R₂、R₃And R₄As previously defined, Hal in said formula (VIII) represents halogen and Y is (C)₁-C₆) Alkoxy, the above condensation reaction is carried out analogously to the conditions used in the condensation of the derivative of formula (II) with the derivative of formula (III).

Third step synthetic route (conversion step C)₂) Is a reaction of a derivative of the formula (IX) with a compound of the formula R₂-Z' (V) is coupled with a derivative of said formula (IX) R₁、R₃、R₄And X is as previously defined and Z represents a halogen atom such as a bromine atom or an iodine atom, a sulfonyloxy group or a reactive group such as a boryl group, a stannyl group or a silyl group, said formula R₂-R in Z' (V)₂As previously defined, and

-when Z represents a halogen atom or a sulfonyloxy group, Z' represents a reactive group such as a borane group, a stannane group or a silyl group or a hydrogen atom, or

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

A derivative of the general formula (IX), wherein R₁、R₃、R₄X and Z are as previously defined and can be prepared by:

condensation of 2-aminopyridines of formula (IV) with 2-oxo-N-arylpropionamide derivatives (III) (conversion step C)₁) R in said formula (IV)₁、R₃、R₄And Z is as defined above, Hal in said formula (III) represents a chlorine atom, a bromine atom or an iodine atom and X is as defined above, the above route being carried out according to the process mentioned for the conversion of the compound of formula (II) into the compound of formula (I), or

Imidazopyridine-2-carboxylic acids of formula (X) or derivatives thereof with arylamine X-NH of formula (VII)₂Amidation reaction (conversion step D)₂) R in said formula (X)₁、R₂、R₃And R₄As defined above, Y represents a hydroxyl group, a halogen atom or (C)₁-C₆) Alkoxy, said X in formula (VII) being as previously defined, the above route being carried out according to the procedures mentioned for the conversion of the compound of formula (VI) into the compound of formula (I).

The imidazopyridine-2-carboxylic acid of formula (X) or a derivative thereof can be prepared by the following route (conversion step D)₁): condensation of 2-aminopyridines of formula (IV) with 3-halo-2-oxopropanoic esters of formula (VIII) R in formula (X) followed by conversion of the ester to the acid and then to the acid chloride or another reactive derivative as appropriate₁、R₃And R₄As previously defined, Y is (C)₁-C₆) Alkoxy, hydroxy or halogen and Z represents a boryl, stannyl or silyl group or a halogen atom, R in said formula (IV)₁、R₃And R₄As defined above and Z represents a boryl, stannyl or silyl group or a halogen atom, Hal in said formula (VIII) represents a halogen and Y is (C)₁-C₆) Alkoxy group, condensation reaction of the aboveIs carried out under conditions analogous to the condensation reaction according to transformation step B₁Condensing the 2-aminopyridine of formula (II) with a derivative of formula (VIII) to give the imidazopyridine-2-carboxylic acid of formula (VI) or a derivative thereof.

The imidazopyridine-2-carboxylic acids of formula (VI) or derivatives thereof can also be prepared by reacting a derivative of formula (X) with a compound of formula R₂Preparation by coupling of a derivative of-Z' (V) (transformation step E)₁) R in said formula (VI)₁、R₂、R₃And R₄As previously defined and Y is (C)₁-C₆) Alkoxy, hydroxy or halogen, R in said formula (X)₁、R₃And R₄As previously defined, Y is (C)₁-C₆) Alkoxy and Z represents a halogen atom such as a bromine or iodine atom, a sulfonyloxy group or a reactive group such as a boryl, stannyl or silyl group, said formula R₂-R in Z' (V)₂As previously defined, and

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

the ester is then converted to the acid and then to the acid chloride or another reactive derivative, as appropriate.

The coupling reaction of the derivative of formula (IV), (IX) or (X) with the product of formula (V) can be carried out by any method known to the person skilled in the art, in particular by carrying out the reaction in the presence of copper-based or palladium-based catalysts (copper-based or palladium-based catalysts), or ligands such as phosphines, according to or analogously to the methods described, for example, in the following references or cited references:

-Suzuki-type reaction: miyaura，A.Suzuki，Chem.Rev.，95，2457，(1995)，

-Stille-type reaction: farina et al, org.fact,50，1(1997)，

-Hiyama-type reaction: t.hiyama et al, top.curr.chem., 2002, 219, 61(2002),

-Negishi-type reaction: e.negishi et al, chem.rev.,103，1979(2003)，

-Bellina-type reaction: m.miura et al, chem.lett., 200 (2007).

For carrying out the coupling reaction, it is also possible to produce organometallic derivatives such as zinc derivatives as intermediates, but without isolating the derivatives.

According to the invention, the compounds of the general formulae (I), (VI) and (II) can also be prepared according to the process described in scheme 2.

Scheme 2

The present synthetic route is the transformation of a compound of formula (XI), (XII) or (XIII), wherein R is₁、R₃、R₄X and Y are as previously defined and W represents a permissible formula R₂The above conversion reaction is carried out according to a method known to those skilled in the art.

By way of example, W may represent:

-a 2-haloacyl group such as bromoacetyl, or a 1-halo-2-oxoalkyl group such as 1-bromo-2-oxoethyl, said 2-haloacyl group or 1-halo-2-oxoalkyl group being convertible to the following by treatment with a thiourea derivative, thioamide derivative, guanidine derivative, urea derivative or amide derivative: for example, thiazolyl, imidazolyl or oxazolyl,

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

an acyl group such as formyl, which can be converted, for example, into 1, 3-dioxolan-2-yl or oxazolyl,

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

The compounds of the general formula (XI) can be obtained from compounds of the formula (XII) by carrying out the reaction under the conditions described for the preparation of the compounds of the formula (I) from imidazopyridine-2-carboxylic acid derivatives of the formula (VI) via a conversion step B₂To prepare the compound.

Imidazopyridine-2-carboxylic acid derivatives of general formula (XII) can be obtained from aminopyridines of formula (XIII) by subjecting an aminopyridine of formula (II) to a conversion step A₂Under the conditions described for the conversion into the compounds of the general formula (I).

If desired or necessary, the product of formula (I) and the precursor of formula (II), (IV), (VI), (IX) or (X) may be subjected to one or more of the following transformations in any order in order to obtain a product of formula (I) or converted to another product of formula (I):

a) esterification or amidation of the acid functions,

b) the amidation reaction of the amine functional group,

c) the hydrolysis of the ester function to an acid function,

d) the reaction of the hydroxyl function to the alkoxy function,

e) oxidation of the alcohol function to an aldehyde or ketone function,

f) the conversion of an aldehyde or ketone function into an alcohol function, by reduction or by the action of an organometallic reagent such as an organomagnesium reagent,

g) the reaction of the nitrile group to the aldehyde function,

h) the transformation of the nitrile group into a ketone functionality,

i) the reaction of an alkylene oxide to an aldehyde or ketone functional group,

j) catalytic coupling reactions of organometallic derivatives such as boron, tin or silicon derivatives with halogenated derivatives to introduce alkyl, alkenyl, alkynyl, aryl or heteroaryl substituents,

k) by reductive amination or alkylation, primary amine groups or secondary amine groups are converted into secondary amine groups or tertiary amine groups,

l) reactions for converting halogenated derivatives into secondary or tertiary amine groups, with optionally catalyzed substitution reactions with primary or secondary amines,

m) a protection reaction of the reactive functional group,

n) deprotection reactions of the protecting groups on the protected reactive functional groups,

o) salt-forming reaction of inorganic or organic acids or with bases to give the corresponding salts,

p) resolution of the racemic form to give the enantiomers,

the product of formula (I) thus obtained is in all possible isomeric forms, where appropriate: racemic mixture, enantiomeric, diastereomeric forms.

In schemes 1 and 2, when the methods of preparation of the starting materials and reagents are not described, they are either commercially available or well known from the literature or can also be prepared according to the methods described therein or known to those skilled in the art.

The following examples describe the preparation of certain compounds according to the invention. These examples are not intended to be limiting, but merely to illustrate the invention. The numbers of the exemplified compounds refer to those mentioned in the tables below, which illustrate the chemical structures and physical properties of the various compounds of the invention.

Detailed Description

Example 1: 6- (1, 3-dioxolan-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamides

To a solution of 137mg of 6-formyl-N-phenylimidazo [1,2-a ] pyridine-2-carboxamide (intermediate 8) in 5mL of toluene was added 45. mu.L of ethylene glycol, 169mg of p-toluenesulfonic acid and molecular sieves. The mixture was refluxed for 24 hours in a round bottom flask equipped with a Dean-Stark apparatus, then cooled, filtered, diluted with 100mL dichloromethane and washed with 2N sodium hydroxide and water. The organic phase was dried and concentrated to dryness to give a mixture of starting material and expected product, which was redissolved in 5mL of methanol containing 410. mu.L of ethylene glycol, 130mg of p-toluenesulfonic acid and molecular sieves. The mixture was heated at reflux for 16 h and cooled, filtered and concentrated to dryness. The residue was purified by chromatography on a silica gel column (silica cartridge) eluting with 70/30 of a mixture of dichloromethane and ethyl acetate to give 53mg of 6- (1, 3-dioxolan-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide as a white solid.

Example 2: n-phenyl-6- (pyridin-3-yl) imidazo [1,2-a ] pyridine-2-carboxamides

150mg of 6-bromo-N-phenylimidazo [1,2-a ] pyridine-2-carboxamide (intermediate 1), 0.237g of pyridine-3-boronic acid, 45mg of tetrakis (triphenylphosphine) palladium, 2mL of 2M aqueous sodium carbonate, 4mL of acetonitrile and 4mL of toluene were placed in a microwave tube. The mixture was heated in a microwave machine set at 150 ℃ for 20 minutes, then cooled and filtered, and the insoluble matter was washed with a mixture of methanol and dichloromethane. The combined filtrates were concentrated to dryness under reduced pressure. The residue was solidified with an aqueous solution of methanol (concoret) to give 73mg of N-phenyl-6- (pyridin-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide as an off-white solid.

Example 3: n-phenyl-6- (pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxamides

230mg of 6-iodo-N-phenylimidazo [1,2-a ] pyridine-2-carboxamide (intermediate 2), 690mg of 2-tributylstannylpyridine, 120mg of tetrakis (triphenylphosphine) palladium and 4mL of N, N-dimethylformamide were placed in a microwave tube. The reaction mixture was heated in a microwave machine set at 100 ℃ for 5 minutes, then heated at 150 ℃ for 5 minutes and concentrated to dryness. The residue was purified by chromatography on a silica gel column (eluting with a mixture of dichloromethane and ethyl acetate). The fractions containing the expected product were combined and evaporated to dryness under reduced pressure to give 56mg of N-phenyl-6- (pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide in the form of a white solid.

Example 4: 6- [5- (hydroxymethyl) pyridin-3-yl ] -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

163mg of 6-trimethylstannanyl-N-phenylimidazo [1,2-a ] pyridine-2-carboxamide (intermediate 4), 310mg of (5-bromopyridin-3-yl) methanol, 66mg of tetrakis (triphenylphosphine) palladium and 4mL of N, N-dimethylformamide were placed in a microwave tube. The reaction mixture was heated in a microwave machine set at 150 ℃ for 20 minutes and concentrated to dryness. The residue was purified by chromatography on a silica gel column (eluting with dichloromethane). The fractions containing the expected product were combined and evaporated to dryness under reduced pressure to give 61mg of 6- [5- (hydroxymethyl) pyridin-3-yl ] -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide as a white solid.

Example 5: 6- [4- (hydroxymethyl) pyridin-2-yl ] -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide hydrochloride (1: 1)

5.16- [4- (hydroxymethyl) pyridin-2-yl ] -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

This product was obtained in analogy to example 4, substituting (5-bromopyridin-3-yl) methanol with (2-bromopyridin-4-yl) methanol.

26- [4- (hydroxymethyl) pyridin-2-yl ] -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide hydrochloride (1: 1).

A suspension of 117mg of 6- [4- (hydroxymethyl) pyridin-2-yl ] -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide in 2mL of methanol is treated with 0.68mL of 0.5N aqueous hydrochloric acid. The mixture was stirred at room temperature for 16 hours and then evaporated to dryness under reduced pressure. The resulting solid was triturated in methanol, filtered off and dried to give 91mg of 6- [4- (hydroxymethyl) pyridin-2-yl ] -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide hydrochloride (1: 1).

Example 6: 6- (6-Aminopyridin-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide hydrochloride (1: 1)

236mg of 6-trimethylstannanyl-N-phenylimidazo [1,2-a ] pyridine-2-carboxamide (intermediate 4), 413mg of 6-bromopyridin-2-ylamine, 95mg of tetrakis (triphenylphosphine) palladium and 4mL of N, N-dimethylformamide were placed in a microwave tube. The reaction mixture was heated in a microwave machine set at 150 ℃ for 45 minutes and concentrated to dryness. The residue was purified by chromatography on a silica gel column (eluting with a mixture of dichloromethane and ethyl acetate). The fractions containing the expected product were combined and evaporated to dryness under reduced pressure to give 147mg of 6- (6-aminopyridin-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide as a yellow solid, which was taken up in a mixture of dioxane and methanol and treated with 112 μ L of a 4M solution of hydrogen chloride in dioxane. After stirring at room temperature for 1 hour, the precipitate was filtered off with suction, washed with dioxane and dried to give 156mg of 6- (6-aminopyridin-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide hydrochloride (1: 1) as a pale yellow solid.

Example 7: 6- (1H-imidazol-4-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide hydrochloride (1: 1)

7.1: 6- (1-triphenylmethyl-1H-imidazol-4-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

540mg of N-phenyl-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide (intermediate 5), 13mL of dioxane, 6.8mL of 2M sodium carbonate solution, 843mg of 4-iodo-1-triphenylmethylimidazole and 86mg of tetrakis (triphenylphosphine) palladium were placed in a microwave tube. The mixture was heated in a microwave machine set at 120 ℃ for 10 minutes, then cooled and concentrated under reduced pressure. The residue was taken up in 100mL of dichloromethane. After washing with water, the organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was purified by chromatography on a silica gel column eluting with a gradient of cyclohexane and ethyl acetate (100/0 to 60/40). The fractions containing the expected product were combined and concentrated to dryness under reduced pressure. The solid was crystallized from acetonitrile. The crystals were washed with acetonitrile followed by ether and then dried under vacuum to give 342mg of 6- (1-triphenylmethyl-1H-imidazol-4-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide as a white solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 7.09(t, J ═ 7.5Hz, 1H), 7.19(d, J ═ 8.0Hz, 6H), 7.33(t, J ═ 7.5Hz, 2H), 7.38 to 7.49(m, 9H), 7.53(d, J ═ 1.5Hz, 1H), 7.57(d, J ═ 1.5Hz, 1H), 7.59(d, J ═ 9.5Hz, 1H), 7.79(dd, J ═ 1.5 and 9.5Hz, 1H), 7.89(d, J ═ 7.5Hz, 2H), 8.50(s, 1H), 9.03 (broad singlet, 1H), 10.2(s, 1H).

Mass Spectrometry (LC-MS-DAD-ELSD): m/z 546[ M + H]⁺.

7.2: 6- (1H-imidazol-4-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide hydrochloride (1: 1)

A suspension of 270mg of 6- (1-triphenylmethyl-1H-imidazol-4-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide in 4mL of 2N hydrochloric acid is heated at 70 ℃ for 30 minutes and then diluted with 2mL of methanol, heated at reflux for 45 minutes, diluted by addition of 2mL of dichloromethane and heated at reflux for a further 2 hours. The reaction mixture was stirred at room temperature for 60 hours. The precipitate is filtered off with suction, washed with methanol, water and pentane and dried under reduced pressure to yield 96mg of 6- (1H-imidazol-4-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide hydrochloride (1: 1) in the form of a white solid.

Example 8: n-phenyl-6- (1H-pyrazol-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

300mg of 6-iodo-N-phenylimidazo [1,2-a ] pyridine-2-carboxamide (intermediate 2), 4mL of dioxane, 4mL of water, 185mg of 1H-pyrazole-3-boronic acid, 45mg of [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium and 1.077g of cesium carbonate were placed in a microwave tube. The mixture was heated in a microwave machine set at 160 ℃ for 20 minutes, then cooled, diluted with 20mL of water and extracted twice with 20mL of dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by chromatography on a silica gel column (eluting with a gradient (0 to 10%) of dichloromethane and methanol). The fractions containing the expected product were combined and concentrated to dryness under reduced pressure to give 40mg of N-phenyl-6- (1H-pyrazol-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide as a white solid.

Example 9: n-phenyl-6- (1H-1, 2, 4-triazol-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

250mg of 6-iodo-N-phenylimidazo [1,2-a ] pyridine-2-carboxamide (intermediate 2), 8mL of N, N-dimethylformamide, 7.7mg of cesium acetate, 197mg of cuprous iodide and 71.3mg of 1,2, 4-triazole were placed in a microwave tube. The reaction mixture was heated in a microwave machine set at 200 ℃ for 2.5 hours. The cooled reaction mixture was filtered, the insoluble material was washed with N, N-dimethylformamide, dichloromethane and methanol and the combined filtrates were concentrated to dryness under reduced pressure. The residue was purified by chromatography on a silica gel column (eluting with 90/10 of a mixture of dichloromethane and methanol). The fractions containing the purified desired product were combined and evaporated to dryness under reduced pressure to give 40mg of N-phenyl-6- (1H-1, 2, 4-triazol-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide as a white solid.

Example 10: n-phenyl-6- (1H-pyrrol-3-yl) imidazo [1,2-a ] pyridine-2-carboxamides

10.1: n-phenyl-6- (1-triisopropylsilyl-1H-pyrrol-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

This product was obtained in analogy to example 8, replacing 1H-pyrazole-3-boronic acid with 1-triisopropylsilyl-1H-pyrrole-3-boronic acid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 1.09(d, J ═ 7.5Hz, 18H), 1.56(m, 3H), 6.66 (broad singlet, 1H), 6.95(t, J ═ 2.0Hz, 1H), 7.09(t, J ═ 7.5Hz, 1H), 7.33(t, J ═ 7.5Hz, 2H), 7.39 (broad singlet, 1H), 7.61(d, J ═ 9.5Hz, 1H), 7.73(dd, J ═ 1.5 and 9.5Hz, 1H), 7.89(d, J ═ 7.5Hz, 2H), 8.39(s, 1H), 8.82 (broad singlet, 1H), 10.15(s, 1H).

Mass Spectrometry (LC-MS-DAD-ELSD): m/z 459[ M + H ]]⁺

10.2: n-phenyl-6- (1H-pyrrol-3-yl) imidazo [1,2-a ] pyridine-2-carboxamides

A solution of 120mg of N-phenyl-6- (1-triisopropylsilyl-1H-pyrrol-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide in 5mL of tetrahydrofuran is treated with 262. mu.L of a molar solution of tetrabutylammonium fluoride in tetrahydrofuran and stirred at room temperature for 10 minutes. It was then diluted with 15mL of dichloromethane and 20mL of water. The organic phase was dried and concentrated to dryness under reduced pressure. The residue was taken up in 2mL dichloromethane and the filtered solid was washed twice with 1mL dichloromethane and then twice with 1mL diisopropyl ether, triturated twice with 2mL water, filtered off with suction and washed again with 2mL dichloromethane and 2mL diisopropyl ether and then dried to give 40mg N-phenyl-6- (1H-pyrrol-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide as a white solid.

Example 11: 6- (2-methyl-1H-imidazol-4-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

400mg of 6-trimethylstannanyl-N-phenylimidazo [1,2-a ] pyridine-2-carboxamide (intermediate 4), 229mg of 2-methyl-4-iodo-1H-imidazole, 8mL of tetrahydrofuran, 9.1mg of bis (diphenylylideneacetone) palladium, and 4.6mg of tris (furan-2-yl) phosphine were placed in a microwave tube. The reaction mixture was heated in a microwave machine set at 130 ℃ for 50 minutes and then concentrated to dryness. The residue was taken up in 3.5mL of N, N-dimethylformamide and 150mg of 2-methyl-4-iodo-1H-imidazole, 10mg of bis (diphenylylideneacetone) palladium and 5mg of tris (furan-2-yl) phosphine were further added, followed by heating in a microwave machine set at 120 ℃ for 40 minutes. The reaction mixture was filtered, the insoluble material was washed with methanol and dichloromethane and the combined filtrates were concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluting with dichloromethane followed by 90/10 of a mixture of dichloromethane and methanol). The fractions containing the purified desired product were combined and evaporated to dryness under reduced pressure to give 28mg of 6- (2-methyl-1H-imidazol-4-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide as a light brown solid.

Example 12: 6- (furan-3-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

200mg of 6-bromo-N-phenylimidazo [1,2-a ] pyridine-2-carboxamide (intermediate 1), 10mL of dioxane, 400. mu.L of 3- (triethoxysilyl) furan, 42mg of cesium acetate, 42mg of 1, 4-diazabicyclo (2.2.2) octane (DABCO), and 1.5mL of a molar solution of tetrabutylammonium fluoride in tetrahydrofuran (molar solution) were placed in a microwave tube. The reaction mixture was heated in a microwave machine set at 120 ℃ for 3 hours, then 200. mu.L of 3- (triethoxysilyl) furan, 20mg of cesium acetate and 20mg of DABCO were added and the mixture was heated in a microwave machine set at 150 ℃ for another 1.5 hours, then cooled and filtered. The filtrate was concentrated to dryness under reduced pressure and the residue was purified by chromatography on a silica gel column (eluting with dichloromethane). The fractions containing the purified desired product were combined and evaporated to dryness under reduced pressure. The solid was dissolved hot in a mixture of dichloromethane and methanol. The hot solution was filtered and treated with diisopropyl ether. The precipitate formed is suction-filtered off and dried to yield 25mg of 6- (furan-3-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide in the form of a yellow solid.

Example 13: 6- (1H-imidazol-1-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide trifluoroacetate (1: 1)

A mixture of 0.6g of 6-iodo-N-phenylimidazo [1,2-a ] pyridine-2-carboxamide (intermediate 2), 20mL of N, N-dimethylformamide, 1.08g of cesium carbonate, 113mg of imidazole, 60mg of 1, 10-phenanthroline (phenanthroline) and 31.5mg of cuprous iodide was heated at 130 ℃ for 21 hours, and after adding 70mg of imidazole, the mixture was reacted at the same temperature for 3 hours and at room temperature for 64 hours. The reaction mixture was filtered, the insoluble material was washed with dichloromethane and the combined filtrates were concentrated under reduced pressure. The residue was purified by preparative HPLC on a Waters Sunfire 30x100, 5 μm column (elution with an acetonitrile gradient containing 0 to 60% water and 0.07% trifluoroacetic acid over 15 minutes and a flow rate of 30 mL/min). The fractions containing the purified desired product were combined and evaporated to dryness under reduced pressure. The solid was triturated in 2mL of methanol, filtered off and washed with 1mL of methanol and dried to give 110mg of 6- (1H-imidazol-1-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide trifluoroacetate (1: 1) as a pale brown solid.

Example 14: 6- (oxazol-5-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamides

To a suspension of 200mg of 6-formyl-N-phenylimidazo [1,2-a ] pyridine-2-carboxamide (intermediate 8) in 10mL of methanol were added 104mg of potassium carbonate and 147mg of p-Toluenesulfonylisobitrile (TOSMIC). The reaction mixture was refluxed for 2 hours then evaporated to dryness under reduced pressure, taken up in 300mL of dichloromethane and washed with water. The organic phase is dried and concentrated to dryness on silica gel and purified by chromatography on a silica gel column (gradient elution with 0 to 20% methanol in dichloromethane). The fractions containing the expected product were concentrated to dryness and the resulting solid was triturated with a small amount of dichloromethane, filtered off and dried to give 80mg of 6- (oxazol-5-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide as a white solid.

Example 15: 6- (2-aminothiazol-4-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

To a suspension of 60mg of crude 6- (2-bromoacetyl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide in 10mL of methanol was added 14mg of thiourea. The reaction mixture was heated at reflux for 45 minutes and then concentrated to dryness under reduced pressure. The residue was purified by chromatography on a silica gel column (eluting with a mixture of dichloromethane and methanol (gradient 100/0 to 90/10)). The fractions containing the expected product were combined and evaporated to dryness under reduced pressure to give 20mg of 6- (2-aminothiazol-4-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide as a white solid.

Example 16: 6- (2-methyl-1, 3-dioxolan-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

A mixture of 80mg of 6- (1-ethoxyvinyl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide, 2.5mL of toluene, 280. mu.L of ethylene glycol and 170mg of p-toluenesulfonic acid was placed on a molecular sieve. The mixture was refluxed for 2 hours then cooled, filtered and diluted with 20mL dichloromethane and 20mL water and neutralized with 2N sodium hydroxide solution. The aqueous phase was washed with dichloromethane and the combined organic phases were dried and concentrated to dryness. The residue was purified by chromatography on a silica gel column (eluting with a gradient of 0/30 to 70/30 of dichloromethane and ethyl acetate) to give 17mg of 6- (2-methyl-1, 3-dioxolan-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide as a white solid.

Example 17: 6- (4, 5-dihydro-1H-imidazol-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide hydrochloride (1: 1) and (1: 2)

17.12-Phenylcarbamoylimidazo [1,2-a ] pyridine-6-iminocarboxylic acid (carboximidate) ethyl ester hydrochloride (1: 1)

A suspension of 300mg of N-phenyl-6-cyanoimidazo [1,2-a ] pyridine-2-carboxamide (intermediate 2) in 25mL of ethanol containing 0.5mL of DMF is cooled to 0 ℃ and then treated with hydrogen chloride gas for 1 hour 40 minutes. The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure to a small volume. The precipitate is filtered off with suction and washed with ethanol and diethyl ether to give 296mg of ethyl 2-phenylcarbamoylimidazo [1,2-a ] pyridine-6-iminocarboxylate hydrochloride (1: 1) in the form of a white solid which is used without further purification in the remainder of the synthesis.

17.26- (4, 5-dihydro-1H-imidazol-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide hydrochloride (1: 1) and (1: 2)

A suspension of 296mg of ethyl 2-phenylcarbamoylimidazo [1,2-a ] pyridine-6-iminocarboxylate hydrochloride (1: 1) in 10mL of ethanol is cooled to 0 ℃ and 144. mu.L of ethylenediamine is added. The reaction mixture was refluxed for 16 hours and then stirred at room temperature for 60 hours. The precipitate is filtered off with suction and washed with ethanol and then recrystallised from methanol to yield 64mg of 6- (4, 5-dihydro-1H-imidazol-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide hydrochloride (1: 2) in the form of a white solid. The filtrate was concentrated to dryness and taken up in water. The insoluble material was filtered off with suction, washed with methanol and then dried to give 99mg6- (4, 5-dihydro-1H-imidazol-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide hydrochloride (1: 1) in the form of a white solid.

Example 18: 6- (6-methoxypyridin-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

To a solution of 624mg cesium carbonate, 90mg 2-bromo-6-methoxypyridine and 17.5mg [1, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride in 10mL dioxane and 4mL water was added 160mg 2-phenylcarbamoylimidazo [1,2-a ] pyridine-6-boronic acid. The mixture was refluxed for 1 hour, then cooled and concentrated to dryness under reduced pressure. The residue was taken up in 150mL of dichloromethane and washed with 100mL of water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure on silica gel and then purified by chromatography on a silica gel column (gradient elution with 0 to 35% ethyl acetate in cyclohexane). The fractions containing the purified desired product were combined and concentrated to dryness under reduced pressure to give 36mg of 6- (6-methoxypyridin-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide as an off-white solid.

Example 19: 5-methyl-N-phenyl-6- (pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

19.1: 6-iodo-5-methyl (pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester

To a suspension of 2g of 5-iodo-6-methylpyridin-2-amine in 15mL of dimethoxyethane was added 1.3mL of ethyl bromopyruvate. The reaction mixture was stirred at 20 ℃ for 16 h then concentrated to dryness, taken up in 15mL of ethanol, refluxed for 2.5 h and finally concentrated under reduced pressure. The residue was taken up in a mixture of dichloromethane and saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and concentrated to dryness under reduced pressure to give 2.77g of ethyl 6-iodo-5-methyl (pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxylate in the form of a light brown solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 1.33(t, J ═ 7.1Hz, 3H), 2.84(s, 3H), 4.33 (q)，J＝7.1Hz，2H)，7.34(d，J＝9.3Hz，1H)，7.66(d，J＝9.3Hz，1H)，8.48(s，1H).

Mass Spectrometry (LC-MS-DAD-ELSD): m/z 331[ M + H ] +.

19.2: 6-iodo-5-methyl-N-phenyl (pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

To a solution of 852. mu.L of aniline in 104mL of toluene cooled to 0 ℃ was added dropwise 6.2mL of a solution of 2M trimethylaluminum in toluene, followed by 1.5g of 6-iodo-5-methyl (pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester at 20 ℃. The reaction mixture was stirred at 20 ℃ for 2 hours. The resulting mixture was cooled to 4 ℃ and then 120mL of saturated ammonium chloride solution was added. After concentration under reduced pressure, the residue is taken up in ethyl acetate and the organic phase is washed with water, dried over magnesium sulfate, filtered through celite and evaporated to dryness under reduced pressure. The residue was triturated in methanol, filtered off and dried to give 1.15g 6-iodo-5-methyl-N-phenyl (pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide as a yellow solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 2.89(s, 3H), 7.10(tt, J ═ 1.5 and 7.5Hz, 1H), 7.33(t, J ═ 7.5Hz, 2H), 7.39(d, J ═ 9.5Hz, 1H), 7.70(d, J ═ 9.5Hz, 1H), 7.90(d, J ═ 7.5Hz, 2H), 8.49(s, 1H), 10.3(s, 1H).

Mass Spectrometry (LC-MS-DAD-ELSD): m/z 378[ M + H]⁺.

19.3: 5-methyl-N-phenyl-6- (pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

This product was obtained in analogy to the product of example 3, substituting 6-iodo-N-phenylimidazo [1,2-a ] pyridine-2-carboxamide with 6-iodo-5-methyl-N-phenyl (pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide.

Example 20: 6- (2-amino-1H-imidazol-4-yl) -N-phenylimidazo [1,2-a ] -pyridine-2-carboxamide trifluoroacetate (1: 1)

To a solution of 135mg of 6- (2-bromoacetyl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide (intermediate 9) in 10mL of N, N-dimethylformamide was added 190mg of 1-tert-butyloxycarbonylguanidine. The reaction mixture was stirred at 20 ℃ for 16 hours and then concentrated to dryness at 60 ℃ under reduced pressure. The residue was taken up in 5mL of dichloromethane and 3mL of methanol and the solution was evaporated on silica gel and then purified by chromatography on a silica gel column (eluting with dichloromethane and methanol (gradient 100/0 to 90/10)). The fractions containing the expected product were combined and evaporated to dryness under reduced pressure to yield 50mg of a mixture of 6- (2-tert-butyloxycarbonylaminothiazol-4-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide and 6- (2-amino-1-tert-butyloxycarbonylaminothiazol-4-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide as a light brown solid. The product was dissolved in 5mL dioxane and treated with 320 μ L of a 4N hydrogen chloride in dioxane solution. The mixture was heated at 60 ℃ for 4 hours, followed by addition of 200 μ L of a 4N hydrogen chloride in dioxane, and then concentrated to dryness under reduced pressure. The residue was purified by preparative LC/MS to give 18mg of 6- (2-amino-1H-imidazol-4-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide trifluoroacetate salt (1: 1) as a light brown solid.

Example 21: 6- (2-aminothiazol-5-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

21.1: 6- (2-ethoxyvinyl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamides

This product was obtained under conditions similar to those described for the first step preparation of intermediate 9, substituting tributyl (1-ethoxyvinyl) tin with tributyl (2-ethoxyvinyl) tin.

¹H NMR spectrum (DMSO-d6, δ in ppm): 1.33(t, J ═ 7.2Hz, 3H), 4.06(q, J ═ 7.2Hz, 2H), 5.26(d, J ═ 6.8Hz, 1H), 6.52(d, J ═ 6.8Hz, 1H), 7.08(t, J ═ 7.8Hz, 1H), 7.34(t,J＝7.8Hz，2H)，7.54-7.66(m，2H)，7.88(d，J＝7.8Hz，2H)，8.51(s，1H)，8.75(s，1H)，10.16(s，1H).

21.2: 6- (2-aminothiazol-5-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

To a solution of 168mg of 6- (2-ethoxyvinyl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide in 5.1mL of tetrahydrofuran is added 1.4mL of water, followed by a solution of 97mg of N-bromosuccinamide in 0.7mL of tetrahydrofuran after cooling to 0 ℃. The reaction mixture was stirred at room temperature for 3 hours. Instead of separating the 6- (1-bromo-2-oxoethyl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide formed from the reaction mixture, the reaction mixture is treated with 42mg of thiourea and stirred for a further 16 hours after the temperature has returned to 20 ℃. The solid formed is filtered off with suction, washed with water and then with methanol and dried to yield 51mg of 6- (2-aminothiazol-5-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide as a white solid.

Example 22: 6- (6-hydroxypyridin-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

22.1: 6- (6-Benzyloxypyridin-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

To a solution of 250mg of 2-benzyloxy-6-bromopyridine in 12mL of dioxane was added a solution of 1.234g cesium carbonate in 3mL water, 34.6mg [1, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride followed by 546mg of N-phenyl-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide hydrobromide (1: 1). The mixture was heated at 110 ℃ for 2 hours 45 minutes, then cooled and filtered. The solid was washed with a small amount of methanol followed by dichloromethane and then taken up in 250mL of boiled methanol containing 5mL of trifluoroacetic acid. The insoluble material was filtered off and washed with methanol and then dichloromethane and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by chromatography on a silica gel column (gradient elution with 0 to 5% methanol in dichloromethane). The fractions containing the purified desired product were combined and concentrated to dryness under reduced pressure to give 0.3g of 6- (6-benzyloxypyridin-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide as a white solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 5.54(s, 2H), 6.91(d, J ═ 8.3Hz, 1H), 7.11 (broad triplet, J ═ 7.7Hz, 1H), 7.31-7.45(m, 5H), 7.54(m, 2H), 7.63(d, J ═ 7.8Hz, 1H), 7.77(d, J ═ 9.7Hz, 1H), 7.85-7.93(m, 3H), 8.12(dd, J ═ 9.7, 2.0Hz, 1H), 8.64(s, 1H), 9.44 (broad, 1H), 10.30 (broad singlet, 1H).

Mass Spectrometry (LC-MS-DAD-ELSD): m/z 421[ M + H]⁺.

22.2: 6- (6-hydroxypyridin-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

A solution of 300mg of 6- (6-benzyloxypyridin-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide in 3mL of trifluoroacetic acid is stirred at 25 ℃ for 48 hours and then evaporated to dryness at 45 ℃ under reduced pressure. The residue was triturated with ether, filtered off and dried, then triturated with 2mL of saturated sodium bicarbonate solution, washed twice with 2mL of water and 2mL of ether and dried under reduced pressure to give 168mg of 6- (6-hydroxypyridin-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide as a pale brown solid.

Example 23: n-phenyl-6- (1H-1, 2, 3-triazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxamide

23.16-ethynyl-N-phenylimidazo [1,2-a ] pyridine-2-carboxamides

0.2g of 6-iodo-N-phenylimidazo [1,2-a ] pyridine-2-carboxamide (intermediate 2), 156. mu.L of trimethylsilylacetylene, 20mg of dichlorobis (triphenylphosphine) palladium and 2mL of piperidine were placed in a 20mL microwave tube. The mixture was heated in a microwave machine set at 130 ℃ for 15 minutes. After cooling, the mixture was poured into 50mL of saturated aqueous ammonium chloride solution. The resulting mixture was extracted twice with 70mL of diethyl ether. The combined organic phases are separated off by settling, dried and concentrated to dryness under reduced pressure. The residue was taken up in 4mL of a 1M solution of tetrabutylammonium fluoride in THF and stirred at 25 ℃ for 16 hours. After evaporation of the reaction medium to dryness, the residue is purified by chromatography on a silica gel column (elution with a mixture of cyclohexane and ethyl acetate (gradient 0 to 35%)) to yield 30mg of 6-ethynyl-N-phenylimidazo [1,2-a ] pyridine-2-carboxamide in the form of a light brown solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 4.37(s, 1H), 7.09(t, J ═ 8.0Hz, 1H), 7.34 (broad triplet, J ═ 8.0Hz, 2H), 7.39 (broad doublet, J ═ 9.5Hz, 1H), 7.67(d, J ═ 9.5Hz, 1H), 7.89 (broad doublet, J ═ 8.0Hz, 2H), 8.48(s, 1H), 8.92 (broad singlet, 1H), 10.3(s, 1H).

Mass spectrum (EI): m/z 261[ M ]]⁺(basal peak), M/z 221[ M-NHPh ═ M]⁺.

23.2: n-phenyl-6- (1H-1, 2, 3-triazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxamide

123mg of 6-ethynyl-N-phenylimidazo [1,2-a ] pyridine-2-carboxamide, 46mg of sodium azide, 38mg of ammonium chloride and 5mL of N, N-dimethylformamide were placed in a microwave tube. The reaction mixture was heated in a microwave machine set at 170 ℃ for 20 minutes and then under the same conditions for 30 minutes, followed by addition of 46mg of sodium azide and 38mg of ammonium chloride, and finally concentrated at 50 ℃ under reduced pressure. The residue was taken up in 20mL of ethyl acetate and 20mL of water. The aqueous phase was extracted twice with 20mL ethyl acetate and the combined organic phases were washed with 30mL saturated brine, then dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was purified by chromatography on a silica gel column (gradient elution with dichloromethane and methanol (100/0 to 90/10)). The fractions containing the expected product were combined and concentrated to dryness under reduced pressure to give 36mg of N-phenyl-6- (1H-1, 2, 3-triazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxamide as an off-white solid.

Example 24: n- (3, 5-difluorophenyl) -6- (furan-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

83mg of potassium carbonate and 4mL of 1, 2-dimethoxyethane were placed in a microwave tube and, after degassing with argon, 120mg of N- (3, 5-difluorophenyl) -6-iodoimidazo [1,2-a ] pyridine-2-carboxamide (intermediate 10), 40mg of furan-3-boronic acid and 21mg of dichlorobis (triphenylphosphine) palladium (II) were then added. The reaction mixture was heated in a microwave machine set at 120 ℃ for 20 minutes and then poured into a mixture of 15mL ethyl acetate and 15mL water. The aqueous phase was extracted twice with 15mL ethyl acetate and the combined organic phases were washed with 15mL saturated brine, then dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was triturated twice with 10mL of a mixture of methanol/diethyl ether (1/1) then washed with isopropanol and pentane and dried to give 22mg of N- (3, 5-difluorophenyl) -6- (furan-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide as a white solid.

Example 25: n- (3-fluorophenyl) -6- (furan-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

To a suspension of 65mg of 6- (furan-3-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid (intermediate 19) and 104mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in 2mL of anhydrous pyridine under argon was added 68mg of 3-fluoroaniline. The reaction mixture was stirred at 80 ℃ for 16 hours and then concentrated to dryness under reduced pressure. The residue was taken up in dichloromethane and washed with water. The organic phase was dried over magnesium sulfate and concentrated to dryness under reduced pressure to give 46mg of N- (3-fluorophenyl) -6- (furan-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide as a white solid.

The following intermediates are useful in the preparation of the compounds of the invention.

Intermediate 1: 6-bromo-N-phenylimidazo [1,2-a ] pyridine-2-carboxamides

To a solution of 3g aniline in 366mL toluene cooled to 0 deg.C was added dropwise 22.5mL2M trimethylaluminum in toluene followed by 5.6g ethyl 6-bromoimidazo [1,2-a ] pyridine-2-carboxylate at 20 deg.C. The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was cooled to 4 ℃ and 150mL of saturated ammonium chloride solution was added. The reaction mixture was concentrated to dryness and taken up in 400mL of water and 400mL of dichloromethane. The organic phase was dried over magnesium sulfate, filtered through celite and evaporated to dryness under reduced pressure to give 4.6g of 6-bromo-N-phenylimidazo [1,2-a ] pyridine-2-carboxamide as an off-white powder.

¹H NMR spectrum (DMSO-d6, δ in ppm): 7.09(t, J ═ 7.5Hz, 1H), 7.34(t, J ═ 7.5Hz, 2H), 7.51(d, J ═ 9.5Hz, 1H), 7.57(dd, J ═ 1.5 and 9.5Hz, 1H), 7.88(d, J ═ 8.0Hz, 2H), 8.42(s, 1H), 9.02 (broad singlet, 1H), 10.25(s, 1H).

Mass spectrum (EI): m/z 363M]⁺，m/z＝271[M-C₆H₆N]⁺，m/z＝144[m/z＝271-I]⁺.

Intermediate 2: 6-iodo-N-phenylimidazo [1,2-a ] pyridine-2-carboxamides

By the same preparation method as intermediate 1, 6-bromoimidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester was replaced with 6-iodoimidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester to give 6-iodo-N-phenylimidazo [1,2-a ] pyridine-2-carboxamide in the form of a light brown solid.

Intermediate 3: n-phenyl-6-cyanoimidazo [1,2-a ] pyridine-2-carboxamides

By the same preparation method as that of intermediate 1, 6-bromoimidazo [1,2-a ] is prepared]6-Cyanoimidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester]Pyridine-2-carboxylic acid ethyl ester (j.med.chem. (1998),41(22) 4317) to yield N-phenyl-6-cyanoimidazo [1, 2-a)]Pyridine-2-carboxamide in the form of a yellow solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 7.11(t, J ═ 7.5Hz, 1H), 7.35(t, J ═ 7.5Hz, 2H), 7.65(dd, J ═ 2.0 and 9.5Hz, 1H), 7.81(d, J ═ 9.5Hz, 1H), 7.89(d, J ═ 8.0Hz, 2H), 8.58(s, 1H), 9.41 (broad singlet, 1H), 10.4 (broad singlet, 1H)

Infrared spectrum (KBr): 3364; 2234; 1671; 1599; 1560, preparing a composition; 1527, washing the substrate; 1504; 1433 and 748cm^-1

Mass spectrum (EI): m/z 262[ M ═ M]⁺(Baseak), M/z 170[ M-C ═ M₆H₆N]⁺，m/z＝143[m/z＝170-HCN]⁺.

Intermediate 4: 6-trimethylstannyl-N-phenylimidazo [1,2-a ] pyridine-2-carboxamides

To a suspension of 160mg of 6-bromo-N-phenylimidazo [1,2-a ] pyridine-2-carboxamide in 10mL of toluene, 260. mu.L of hexamethyldisilazane and 30mg of tetrakis (triphenylphosphine) palladium (0) were added. The reaction mixture was heated at reflux for 2 hours then stirred at room temperature for 16 hours and filtered through a pad of celite. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on a silica gel column (eluting with dichloromethane). The fractions containing the expected product were combined and evaporated to dryness under reduced pressure to give 163mg of 6-trimethylstannanyl-N-phenylimidazo [1,2-a ] pyridine-2-carboxamide as a yellow solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 0.85(m, 9H), 7.09(t, J ═ 7.5Hz, 1H), 7.33(t, J ═ 7.5Hz, 2H), 7.40 (broad doublet, J ═ 9.5Hz, 1H), 7.61 (broad doublet, J ═ 9.5Hz, 1H), 7.89(d, J ═ 7.5Hz, 2H), 8.43(s, 1H), 8.53(m, 1H), 10.2(s, 1H).

Mass Spectrometry (LC-MS-DAD-ELSD): m/z 402, [ M + H ]]⁺

Intermediate 5: n-phenyl-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide and its hydrobromide salt (1: 1)

To a solution of 1g of 3-bromo-2-oxo-N-phenylpropionamide in 50mL of 1, 2-dimethoxyethane was added 1.09g of 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine. The reaction mixture was stirred at room temperature for 40 hours and then concentrated to dryness under reduced pressure. The residue was taken up in 30mL of ethanol and refluxed for 90 minutes. After concentration to dryness under reduced pressure, the solid was triturated in a small amount of ethanol, filtered off and washed with ethanol and then diethyl ether to give 0.6g N-phenyl-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide hydrobromide (1: 1) in the form of a white solid.

The hydrobromide salt was taken up in 200mL ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase was dried and concentrated to dryness under reduced pressure to give 0.53g N-phenyl-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide as a white solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 1.33(s, 12H), 7.10(t, J ═ 7.5Hz, 1H), 7.34(t, J ═ 7.5Hz, 2H), 7.46(dd, J ═ 1.5 and 9.5Hz, 1H), 7.63(d, J ═ 9.5Hz, 1H), 7.89(d, J ═ 7.5Hz, 2H), 8.58(s, 1H), 8.96 (broad singlet, 1H), 10.25(s, 1H).

Mass spectrum (EI): m/z 363[ M ]]⁺；m/z 271＝[M-NHPh]⁺；m/z 171＝[271-C6H12O]^-.

Intermediate 6: 2-Phenylcarbamoylimidazo [1,2-a ] pyridine-6-boronic acid hydrochloride (1: 1)

1 deg.) to a solution of 0.8g of 3-bromo-2-oxo-N-phenylpropionamide in 30mL of 1, 2-dimethoxyethane was added 0.87g of 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine. The reaction mixture was stirred at room temperature for 16 hours and then concentrated to dryness under reduced pressure. The residue was taken up in 15mL of ethanol and refluxed for 2 hours. After concentration to dryness under reduced pressure, the residue was crystallized from ethanol, filtered off with suction and washed with ethanol and then ether to give 0.75g N-phenyl-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide hydrobromide (1: 1) in the form of a white solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 1.34(s, 12H), 7.11(t, J ═ 7.8Hz, 1H), 7.35(t, J ═ 7.8Hz, 2H), 7.54 (broad doublet, J ═ 9.3Hz, 1H), 7.66(d, J ═ 9.3Hz, 1H), 7.87(d, J ═ 7.8Hz, 2H), 8.63(s, 1H), 9.02(s, 1H), 10.37 (broad singlet, 1H).

Mass spectrum (EI): m/z 363[ M ]]⁺.

2 deg.C A solution of 0.19g N-phenyl-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide hydrobromide (1: 1) in 9mL of acetonitrile was treated with 0.5mL of hydrochloric acid and 1g of polymer-supported benzylboronic acid (Alfa-Aesarl19459, 3 mmol/g). The reaction mixture was stirred at 25 ℃ for 16 hours and then refluxed for 1 hour. The resin was filtered off, washed with acetonitrile and then methanol and the combined filtrates were evaporated to dryness under reduced pressure to give 160mg of 2-phenylcarbamoylimidazo [1,2-a ] pyridine-6-boronic acid hydrochloride (1: 1) in the form of an orange solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 7.14(t, J ═ 7.8Hz, 1H), 7.38(t, J ═ 7.8Hz, 2H), 7.72 (broad multiplet, 1H), 7.85(d, J ═ 7.8Hz, 2H), 7.93 (broad multiplet, 1H), 7.94-8.63 (very broad multiplet, 2H), 8.81 (broad multiplet, 1H), 9.04 (broad multiplet, 1H), 10.52 (broad multiplet, 1H).

Intermediate 7: n-phenyl-6-vinylimidazo [1,2-a ] pyridine-2-carboxamides

A mixture of 0.73g 6-iodo-N-phenylimidazo [1,2-a ] pyridine-2-carboxamide, 209mg tetrakis (triphenylphosphine) palladium (0), 587. mu.L tributylvinyltin and 17mL DMF was heated in a microwave machine at 130 ℃ for 10 minutes and then concentrated to dryness. The residue was taken up in 100mL of water and extracted twice with 70mL of ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The solid is triturated in ethyl acetate, filtered off with suction, washed with ethyl acetate and then with isopropyl ether and taken up in a mixture of methanol and dichloromethane. The insoluble material was filtered off and washed with methanol. The filtrate was concentrated to dryness under reduced pressure to give 0.29g N-phenyl-6-vinylimidazo [1,2-a ] pyridine-2-carboxamide as a white solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 5.39(d, J ═ 11.0Hz, 1H), 5.92(d, J ═ 17.5Hz, 1H), 6.77(dd, J ═ 11.0 and 17.5Hz, 1H), 7.09 (broad triplet, J ═ 7.5Hz, 1H), 7.34 (broad triplet, J ═ 7.5Hz, 2H), 7.64(d, J ═ 9.5Hz, 1H), 7.70(dd, J ═ 2.0 and 9.5Hz, 1H), 7.89 (broad doublet, J ═ 8.0Hz, 2H), 8.47(s, 1H), 8.66 (broad singlet, 1H), 10.2(s, 1H).

Mass spectrum (EI): m/z 263[ M ]^+.]

Intermediate 8: 6-formyl-N-phenylimidazo [1,2-a ] pyridine-2-carboxamides

A suspension of 150mg of N-phenyl-6-vinylimidazo [1,2-a ] pyridine-2-carboxamide, 232. mu.L of osmium tetroxide and 167.5mg of sodium periodate in a mixture of 6mL of THF, 3mL of tert-butanol and 3mL of water is stirred at 20 ℃ for 20 hours and then for a further 48 hours while four 100. mu.L of osmium tetroxide and 80mg of sodium periodate are added. The reaction mixture was poured into 50mL of water and the resulting mixture was extracted twice with 50mL of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, separated by settling, dried and concentrated to dryness under reduced pressure. The residue was purified by chromatography on a silica gel column (eluting with a mixture of cyclohexane and ethyl acetate (gradient from 0 to 50%)) to give 100mg of 6-formyl-N-phenylimidazo [1,2-a ] pyridine-2-carboxamide as a white solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 7.11(t, J ═ 8.0Hz, 1H), 7.36 (broad triplet, J ═ 8.0Hz, 2H), 7.71(dd, J ═ 1.5 and 9.5Hz, 1H), 7.77 (broad doublet, J ═ 9.5Hz, 1H), 7.90 (broad doublet, J ═ 8.0Hz, 2H), 8.73(s, 1H), 9.39 (broad singlet, 1H), 10.0(s, 1H), 10.35 (broad singlet, 1H).

Mass spectrum (LC/MS): m/z 266, [ M + H ]⁺]

Intermediate 9: 6- (2-bromoacetyl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

9.1: 6- (1-ethoxyvinyl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamides

To a suspension of 1g of 6-iodo-N-phenylimidazo [1,2-a ] pyridine-2-carboxamide in 50mL of toluene was added 159mg of tetrakis (triphenylphosphine) palladium and 1.09g of tributyl (1-ethoxyvinyl) tin. The reaction mixture was heated at 150 ℃ for 9 hours and then at 130 ℃ for 16 hours and concentrated to dryness. The residue was taken up in dichloromethane and washed with 10% aqueous potassium fluoride. The organic phase was dried and concentrated to dryness and the residue was purified by chromatography on a silica gel column (eluting with a mixture of cyclohexane and ethyl acetate). The fractions containing the expected product were combined and evaporated to dryness under reduced pressure to give 0.52g of 6- (1-ethoxyvinyl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide in the form of a light brown solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 1.40(t, J ═ 7.0Hz, 3H), 3.97(q, J ═ 7.0Hz, 2H), 4.46(d, J ═ 3.0Hz, 1H), 4.90(d, J ═ 3.0Hz, 1H), 7.09(t, J ═ 8.0Hz, 1H), 7.34 (broad triplet, J ═ 8.0Hz, 2H), 7.61(d, J ═ 9.5Hz, 1H), 7.66(dd, J ═ 2.0 and 9.5Hz, 1H), 7.89 (broad doublet, J ═ 8.0Hz, 2H), 8.57(s, 1H), 8.83 (broad singlet, 1H), 10.2(s, 1H).

9.2: 6- (2-bromoacetyl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

To a solution of 123mg of 6- (1-ethoxyvinyl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide in 4mL of tetrahydrofuran, 1mL of water was added, followed by 71mg of N-bromosuccinamide after cooling to 0 ℃. The reaction mixture was stirred at room temperature for 2.5 hours and then diluted with 80mL of dichloromethane. The organic phase was washed with water and then dried and concentrated to dryness under reduced pressure to give 60mg of crude 6- (2-bromoacetyl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide as a white solid (containing a small amount of 6-acetyl derivative and dibromo derivative) and was used without further purification.

¹H NMR spectrum (DMSO-d6, δ in ppm): 4.92(s, 2H), 7.11(t, J ═ 7.5Hz, 1H), 7.36(t, J ═ 7.5Hz, 2H), 7.75(d, J ═ 9.5Hz, 1H), 7.82(dd, J ═ 1.5 and 9.5Hz, 1H), 7.90(d, J ═ 7.5Hz, 2H), 8.61(s, 1H), 9.57 (broad singlet, 1H), 10.35(s, 1H).

Mass Spectrometry (LC-MS-DAD-ELSD): m/z 358[ M + H ]]⁺，m/z 356[M-H]^-.

Intermediate 10: n- (3, 5-difluorophenyl) -6-iodoimidazo [1,2-a ] pyridine-2-carboxamide

To a solution of 980mg aniline in 100mL toluene cooled to 0 ℃ was added dropwise a solution of 5mL2M trimethylaluminum in toluene, followed by 1.5g 6-iodoimidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester at 20 ℃. The reaction mixture was stirred at 20 ℃ for 2 hours. The resulting mixture was cooled to 4 ℃ and then 100mL of saturated ammonium chloride solution was added. After concentration under reduced pressure, the residue is taken up in ethyl acetate and the organic phase is washed with water, dried over magnesium sulfate, filtered through celite and evaporated to dryness under reduced pressure. The residue was triturated in ether, filtered off and dried to yield 258mg of N- (3, 5-difluorophenyl) -6-iodoimidazo [1,2-a ] pyridine-2-carboxamide as a yellow solid.

¹H nuclear magnetic resonanceVibrational spectra (DMSO-d6, δ in ppm): 6.92(tt, J ═ 2.0 and 9.0Hz, 1H), 7.51(d, J ═ 9.5Hz, 1H), 7.59(dd, J ═ 1.5 and 9.5Hz, 1H), 7.72(m, 2H), 8.47(s, 1H), 9.02 (broad singlet, 1H), 10.75(s, 1H).

Mass Spectrometry (LC-MS-DAD-ELSD): m/z 398[ M + H]^-；m/z 400[M+H]⁺.

Intermediate 11: 6- (6- { [ (1, 1-Dimethylethoxy) carbonyl ] amino } pyridin-2-yl) imidazo- [1,2-a ] pyridine-2-carboxylic acid

11.1: 6- (6-Aminopyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester

350mg of 2-amino-6-bromopyridine, 750mg of 2-ethoxycarbonylimidazo [1,2-a ] pyridine-6-boronic acid and 57mg of [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium were degassed under vacuum and then suspended in 20mL of degassed dioxane under argon. After addition of 2mL of 2N aqueous sodium carbonate solution, the mixture is degassed under vacuum, placed under argon and heated at 90 ℃ for 5 hours, then cooled, diluted and stirred in a mixture of 50mL of saturated sodium bicarbonate solution and 50mL of dichloromethane. The organic phase is dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by chromatography on a silica gel column (eluting with a mixture of ethyl acetate and hexane). The fractions containing the expected product were combined and concentrated to dryness under reduced pressure to give 446mg of ethyl 6- (6-aminopyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxylate.

¹H NMR spectrum (DMSO-d6, δ in ppm): 9.13(dd, J ═ 1.0, 1.61H), 8.61(d, J ═ 0.7, 1H), 7.94(dd, J ═ 1.8, 9.6, 1H), 7.65(d, J ═ 9.6, 1H), 7.50(t, J ═ 8.1, 1H), 7.07(d, J ═ 7.0, 1H), 6.48(dd, J ═ 0.3, 8.1, 1H), 6.08 (broad singlet, 2H), 4.33(q, J ═ 7.1, 2H), 1.33(t, J ═ 7.1, 3H).

Mass spectrum (APCI): 283[ M + H ] M/z]⁺.

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

To 700mg of 6- (6-aminopyridin-2-yl) imidazo [1,2-a]To a suspension of pyridine-2-carboxylic acid ethyl ester and 25mg 4-dimethylaminopyridine in 5mL acetonitrile was added 1.14mL di-tert-butyl dicarbonate. The mixture was stirred at 25 ℃ for 16 hours and then concentrated. The residue was purified by chromatography on a silica gel column (gradient elution with ethyl acetate and hexane (50/50 to 100/0)) to give 370mg of 6- (6- { bis [ (1, 1-dimethylethoxy) carbonyl]Amino } pyridin-2-yl) imidazo [1,2-a]Pyridine-2-carboxylic acid ethyl ester (C)¹H NMR spectrum (DMSO-d6, δ in ppm): 9.23(s, 1H), 8.65(s, 1H), 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 163mg of 6- (6- { [ (1, 1-dimethylethoxy) carbonyl]Amino } pyridin-2-yl) imidazo [1,2-a]Pyridine-2-carboxylic acid ethyl ester (C)¹H 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): 383[ M + H ] M/z]⁺)。

11.3: 6- (6- { [ (1, 1-Dimethylethoxy) carbonyl ] amino } pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid

0.9mL of 2M aqueous lithium hydroxide solution was added to a solution of 292mg of ethyl 6- (6- { bis [ (1, 1-dimethylethoxy) carbonyl ] amino } pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxylate in 4.73mL50/l of a mixture of tetrahydrofuran and methanol. The reaction mixture was stirred at 25 ℃ for 7 hours and then treated dropwise with 2N hydrochloric acid at 0 ℃ until a pH of 3 was reached. After 20 minutes the precipitate formed was suction filtered off and washed with water (20mL) and diethyl ether (20mL) and then dried under reduced pressure to give 195mg of 6- (6- { [ (1, 1-dimethylethoxy) carbonyl ] amino } pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid in the form of a light brown solid.

¹H NMR spectrum (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, 9.61H), 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 12: 6- (pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxylic acids

12.1: (6-pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester

A mixture of 3.18g cesium carbonate, 25mL dioxane, 9.3mL water, 500mg 2-iodopyridine, 89mg [1, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride and 848mg ethyl 6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) imidazo [1,2-a ] pyridine-2-carboxylate hydrobromide (1: 1) was heated at 110 ℃ for 2 hours, then partially concentrated, 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 was purified by chromatography on a silica gel column (eluting with a mixture of dichloromethane and cyclohexane (80/20)). The fractions containing the expected product were combined and concentrated to dryness under reduced pressure to give 317mg of ethyl 6- (pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxylate in the form of a brown oil.

¹H NMR spectrum (DMSO-d6, δ in ppm): 1.34(t, J ═ 7.0Hz, 3H), 4.33(q, J ═ 7.0Hz, 2H), 7.42(ddd, J ═ 7.5, 5.5, 2.0Hz, 1H), 7.73(d, J ═ 9.3Hz, 1H), 7.85-8.02(m, 2H), 8.07(dd, J ═ 9.3, 2.0Hz, 1H), 8.64(s, 1H), 8.70 (broad doublet, J ═ 5.5Hz, 1H), 9.36 (broad singlet, 1H).

Mass Spectrometry (LC-MS-DAD-ELSD): m/z 268[ M + H]⁺.

12.2: 6- (pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxylic acids

317mg of ethyl 6- (pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxylate are saponified under conditions analogous to those described for the preparation of intermediate 11 (step 11.3) to give 280mg of 6- (pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid in the form of a pasty pink solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 7.47(m, 1H), 7.83(d, J ═ 9.8Hz, 1H), 7.99(dt, J ═ 8.5, 2.0Hz, 1H), 8.06(d, J ═ 8.5Hz, 1H), 8.31 (broad doublet, J ═ 9.8Hz, 1H), 8.73(m, 2H), 9.52 (broad singlet, 1H).

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

Intermediate 13: 6- (1-triphenylmethyl-1H-imidazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid

13.1: 6- (1-Triphenylmethyl-1H-imidazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester

873mg of 4-iodo-1-triphenylmethylimidazole, 750mg of 2-ethoxycarbonylimidazo [1,2-a ] pyridine-6-boronic acid, 23mg of cesium acetate and 70mg of 2- (dicyclohexylphosphino) biphenyl ((2-biphenyl) -dicyclohexylphosphinyl) are degassed under vacuum and then suspended under argon in a mixture of degassed 15mL of toluene, 5mL of water and 5mL of N-methylpyrrolidone. After addition of 950mg of potassium phosphate, the mixture is degassed under vacuum and then placed under argon and heated by microwaves at 100 ℃ for 15 minutes, then cooled, diluted and stirred in a mixture of 50mL of saturated sodium bicarbonate solution and 50mL of dichloromethane. The organic phase is dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by chromatography on a silica gel column (eluting with a mixture of ethyl acetate and hexane). The fractions containing the expected product were combined and concentrated to dryness under reduced pressure to give 508mg of ethyl 6- (1-triphenylmethyl-1H-imidazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxylate.

¹H NMR spectrum (DMSO-d6, δ in ppm): 8.97(s, 1H), 8.54(s, 1H), 7.76-7.72(m, 1H), 7.56-7.52(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): 499[ M + H ] M/z]⁺.

13.2: 6- (1-triphenylmethyl-1H-imidazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid

500mg of ethyl 6- (1-triphenylmethyl-1H-imidazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxylate are saponified under conditions analogous to those described for the preparation of intermediate 11 (step 11.3) to give 346mg of 6- (1-triphenylmethyl-1H-imidazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 9.01(s, 1H), 8.51(s, 1H), 7.83(d, J ═ 9.5, 1H), 7.59-7.56(m, 3H), 7.47-7.37(m, 9H), 7.20-7.17(m, 6H).

Mass spectrum (APCI): 471[ M + H ] M/z]⁺.

Intermediate 14: 6- (2- { [ (1, 1-Dimethylethoxy) carbonyl ] amino } thiazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid

14.1: 6- (2- { [ (1, 1-Dimethylethoxy) carbonyl ] amino } thiazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester

465mg of tert-butyl 4-iodothiazol-2-ylcarbamate, 434mg of 2-ethoxycarbonylimidazo [1,2-a ] pyridine-6-boronic acid and 104mg of [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium were degassed under vacuum. After addition of 10mL of degassed tetrahydrofuran and 0.66mL of 2N aqueous sodium carbonate solution, the reaction mixture is heated at 100 ℃ for 2 hours and then cooled, diluted with dichloromethane and washed with half-saturated aqueous sodium bicarbonate solution. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a dichloromethane/methanol mixture (99: 1 to 99: 2). The fractions containing the expected product were combined and concentrated to dryness under reduced pressure. The resulting solid was washed with 5mL of diethyl ether to give 125mg of ethyl 6- (2- { [ (1, 1-dimethylethoxy) carbonyl ] amino } thiazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxylate as an off-white solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 11.65(s, 1H), 8.84(s, 1H), 8.47(s, 1H), 7.84(s, 1H), 7.68-7.71(m, 2H), 4.32(q, J ═ 7.1, 2H), 1.51(s, 9H), 1.33(t, J ═ 7.1, 3H).

Mass spectrum (APCI): 389[ M + H ═ M/z]⁺.

14.2: 6- (2- { [ (1, 1-Dimethylethoxy) carbonyl ] amino } thiazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid

125mg of ethyl 6- (2- { [ (1, 1-dimethylethoxy) carbonyl ] amino } thiazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxylate are saponified under conditions analogous to those described in the preparation of intermediate 11 (step 11.3) to yield 90mg of 6- (2- { [ (1, 1-dimethylethoxy) carbonyl ] amino } thiazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid in the form of a brown solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 11.66(s, 1H), 8.86(s, 1H), 8.42(s, 1H), 7.84(s, 1H), 7.67-7.69(m, 2H), 1.51(s, 9H).

Mass spectrum (APCI): m/z 361M + H]⁺.

Intermediate 15: 6- (1H-pyrrol-3-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid

15.16- [1- (triisopropylsilyl) -1H-pyrrol-3-yl ] imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester

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

¹H NMR spectrum (DMSO-d6, δ in ppm): 8.76(s, 1H), 8.42(s, 1H), 7.70(dd, J ═ 1.9, 9.71H), 7.59(d, J ═ 9.71H), 7.37 (broad singlet, 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 ═ M]⁺.

15.2: 6- (1H-pyrrol-3-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid hydrochloride (1: 1)

292mg of ethyl 6- [1- (triisopropylsilyl) -1H-pyrrol-3-yl ] imidazo [1,2-a ] pyridine-2-carboxylate were saponified under similar conditions as described in the preparation of intermediate 11 (step 11.3) to yield 140mg of 6- (1H-pyrrol-3-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid hydrochloride (1: 1) in the form of a white solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 11.07 (broad singlet, 1H), 8.73(s, 1H), 8.39(s, 1H), 7.69(dd, J ═ 1.3, 9.5, 1H), 7.59(d, J ═ 9.5, 1H), 7.31(s, 1H), 6.86(s, 1H), 6.46(s, 1H).

Mass spectrum (APCI): 228[ M + H ] M/z]⁺.

Intermediate 16: 6- (1H-pyrazol-3-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid

16.1: 6- (1H-pyrazol-3-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester

This product was prepared under conditions similar to those described for the preparation of intermediate 15 (step 15.1), substituting 1- (triisopropylsilyl) pyrrole-3-boronic acid with pyrazole-3-boronic acid.

¹H NMR Spectroscopy (MeOD-d4, δ in ppm): 8.89(t, J ═ 1.2, 2.4, 1H), 8.45(d, J ═ 0.6, 1H), 7.89(d, J ═ 9.0, 1H), 7.76 (broad singlet, 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): 257[ M + H ] M/z]⁺.

16.2: 6- (1H-pyrazol-3-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid

128mg of ethyl 6- (1H-pyrazol-3-yl) imidazo [1,2-a ] pyridine-2-carboxylate are saponified under conditions analogous to those described in the preparation of intermediate 11 (step 11.3) to yield 113mg6- (1H-pyrazol-3-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 13.50-12.50 (broad singlet, 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 17: 6- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid

17.1: 6- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester

The product was prepared under conditions similar to those described for the preparation of intermediate 15 (step 15.1), substituting 1- (triisopropylsilyl) pyrrole-3-boronic acid with pyrazole-4-boronic acid and heating by microwave at 90 ℃ for 37 minutes.

¹H NMR spectrum (DMSO-d6, δ in ppm): 13.10 (broad singlet, 1H), 8.83(s, 1H), 8.43(s, 1H), 8.25 (broad singlet, 1H), 7.94 (broad singlet, 1H), 7.69-7.61(m, 2H), 4.31(q, J ═ 7.1, 2H), 1.32(t, J ═ 7.1, 3H).

Mass spectrum (APCI): 257[ M + H ] M/z]⁺.

17.2: 6- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid

128mg of ethyl 6- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxylate are saponified under conditions analogous to those described in the preparation of intermediate 11 (step 11.3) to yield 6- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 14.0-12.0 (broad singlet, 1H), 8.84(s, 1H), 8.36(s, 1H), 8.10(s, 2H), 7.64(s, 2H).

Intermediate 18: 6- (furan-2-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid

18.1: 6- (Furan-2-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester

This product was prepared under conditions similar to those described for the preparation of intermediate 15 (step 15.1), substituting 1- (triisopropylsilyl) pyrrole-3-boronic acid with furan-2-boronic acid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 8.78(s, 1H), 8.44(s, 1H), 7.72(dd, J ═ 1.8, 9.6, 1H), 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): 257[ M + H ] M/z]⁺.

18.2: 6- (furan-2-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid

384mg of ethyl 6- (furan-2-yl) imidazo [1,2-a ] pyridine-2-carboxylate are saponified under conditions analogous to those described in the preparation of intermediate 11 (step 11.3) to give 256mg of 6- (furan-2-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 8.86(s，1H)，8.38(s，1H)，7.80(dd，J＝1.7，9.5，1H)，7.67-7.64(m，2H)，6.90(d，J＝3.4，1H)，6.60(dd，J＝1.8，3.4，1H).

Intermediate 19: 6- (furan-3-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid

19.1: 6- (Furan-3-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester

This product was prepared under conditions similar to those described for the preparation of intermediate 15 (step 15.1), substituting 1- (triisopropylsilyl) pyrrole-3-boronic acid with furan-3-boronic acid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 8.86(s, 1H), 8.45(s, 1H), 8.28(s, 1H), 7.82(s, 1H), 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): 257[ M + H ] M/z]⁺.

19.2: 6- (furan-3-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid

384mg of ethyl 6- (furan-3-yl) imidazo [1,2-a ] pyridine-2-carboxylate are saponified under conditions analogous to those described for the preparation of intermediate 11 (step 11.3) to give 287mg of 6- (furan-3-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 8.86(s, 1H), 8.38(s, 1H), 8.27(s, 1H), 7.81(s, 1H), 7.64(s, 2H), 6.95(s, 1H).

Mass spectrum (APCI): 229[ M + H ] M/z]⁺.

Intermediate 20: 6- [5- (hydroxymethyl) furan-2-yl ] imidazo [1,2-a ] pyridine-2-carboxylic acid

20.1: 6- (5-Formylfuran-2-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester

2g of ethyl 6-iodoimidazo [1,2-a ] pyridine-2-carboxylate, 1.42g of 5-formylfuran-2-boronic acid and 231mg of [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium were degassed under vacuum and then suspended under argon in a degassed mixture of 30mL of dioxane and 9.4mL of 2N aqueous sodium carbonate solution. The reaction mixture was heated at 90 ℃ for 5 hours, then stirred at 20 ℃ for 16 hours and concentrated to dryness. The residue was purified by chromatography on a silica gel column, eluting with a mixture of ethyl acetate and hexane (90/10), then ethyl acetate, a mixture of ethyl acetate and methanol (99/1). Fractions containing the expected product were combined and concentrated to dryness under reduced pressure to give 884mg of ethyl 6- (5-formylfuran-2-yl) imidazo [1,2-a ] pyridine-2-carboxylate.

¹H NMR spectrum (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): 285M + H]⁺.

20.2: 6- [5- (hydroxymethyl) furan-2-yl ] imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester

To a suspension of 770mg of ethyl 6- (5-formylfuran-2-yl) imidazo [1,2-a ] pyridine-2-carboxylate in 15mL of ethanol was added 123mg of sodium tetrahydroborate. The reaction mixture was stirred at 25 ℃ for 90 minutes then diluted and stirred with 10mL of dichloromethane and 3mL of half-saturated aqueous sodium carbonate solution. The organic phase is separated off, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluting with a mixture of dichloromethane and methanol (98/2)). The fractions containing the expected product were combined and concentrated to dryness under reduced pressure. The resulting solid was triturated in 5mL dichloromethane, filtered off and dried to give 403mg of ethyl 6- (5-formylfuran-2-yl) imidazo [1,2-a ] pyridine-2-carboxylate as a white solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 8.89(s, 1H), 8.60(s, 1H), 7.70(m, 2H), 6.98(d, J ═ 3.3, 1H), 6.45(d, J ═ 3.3, 1H), and3.3，1H)，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): 287[ M + H ] M/z]⁺.

20.3: 6- [5- (hydroxymethyl) furan-2-yl ] imidazo [1,2-a ] pyridine-2-carboxylic acid

400mg of ethyl 6- [5- (hydroxymethyl) furan-2-yl ] imidazo [1,2-a ] pyridine-2-carboxylate are saponified under conditions analogous to those described in the preparation of intermediate 11 (step 11.3) to yield 346mg of 6- [5- (hydroxymethyl) furan-2-yl ] imidazo [1,2-a ] pyridine-2-carboxylic acid in the form of a white solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 9.06(s, 1H), 8.73(s, 1H), 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 ═ M/z]⁺.

Intermediate 21: 6- (thien-3-yl) imidazo [1,2-a ] pyridine-2-carboxylic acids

21.1: 6- (Thien-3-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester

This product was prepared under conditions analogous to those described for the preparation of intermediate 15 (step 15.1) by replacing 1- (triisopropylsilyl) pyrrole-3-boronic acid with thiophene-3-boronic acid (catalyst: dichlorobis (triphenylphosphine) palladium).

¹H NMR spectrum (DMSO-d6, δ in ppm): 1.34(d, J ═ 7.1Hz, 3H), 4.32(q, J ═ 7.1Hz, 2H), 7.56(dd, J ═ 5.0, 1.4Hz, 1H), 7.68(d, J ═ 9.8Hz, 1H), 7.73(dd, J ═ 5.0, 3.0Hz, 1H), 7.78(dd, J ═ 9.8, 1.8Hz, 1H), 7.97(dd, J ═ 3.0, 1.4Hz, 1H), 8.48(s, 1H), 8.98 (broad singlet, 1H).

Mass Spectrometry (LC-MS-DAD-ELSD): m/z 273[ M + H]⁺.

21.2: 6- (thien-3-yl) imidazo [1,2-a ] pyridine-2-carboxylic acids

310mg of ethyl 6- (thien-3-yl) imidazo [1,2-a ] pyridine-2-carboxylate are saponified under conditions analogous to those described in the preparation of intermediate 11 (step 11.3) to yield 250mg of 6- (thien-3-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 7.57(d, J ═ 5.4Hz, 1H), 7.66(d, J ═ 9.8Hz, 1H), 7.73(dd, J ═ 5.4, 2.8Hz, 1H), 7.76(dd, J ═ 9.8, 2.0Hz, 1H), 7.97 (broad doublet, J ═ 2.0Hz, 1H), 8.41(s, 1H), 8.99 (broad singlet, 1H).

Mass Spectrometry (LC-MS-DAD-ELSD): m/z 245[ M + H ]]⁺.

Intermediate 22: 6- (oxazol-2-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid

22.1: 6- (oxazol-2-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester

1g of 6-iodoimidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester, 350mg of tetrakis (triphenylphosphine) palladium (0) and 360mg of lithium chloride were degassed under vacuum and then suspended in 15mL of degassed dioxane under argon. After addition of 5g of 2- (tri-n-butylstannyl) oxazole, the reaction mixture was heated at 90 ℃ for 3.5 hours and then cooled, diluted and stirred with a mixture of 100mL of 1M aqueous potassium fluoride and 200mL of ethyl acetate. The aqueous phase was extracted with 200mL ethyl acetate and the combined organic phases were washed with brine and dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by chromatography on a silica gel column (eluting with a gradient of ethyl acetate and hexane (80/20 to 100/0)). The fractions containing the expected product were combined and concentrated to dryness under reduced pressure to give 530mg of ethyl 6- (oxazol-2-yl) imidazo [1,2-a ] pyridine-2-carboxylate in the form of a yellow powder.

¹H NMR spectrum (DMSO-d6, δ in ppm): 9.30(d, J ═ 0.8, 1H), 8.68(s, 1H), 8.30(s, 1H),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): 258[ M + H ] M/z]⁺.

22.2: 6- (oxazol-2-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid

512mg of ethyl 6- (oxazol-2-yl) imidazo [1,2-a ] pyridine-2-carboxylate are saponified under conditions analogous to those described in the preparation of intermediate 11 (step 11.3) to give 365mg of 6- (oxazol-2-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid in the form of a white solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 9.41(s, 1H), 8.73(s, 1H), 8.34(s, 1H), 8.05(dd, J ═ 1.5, 9.5, 1H), 7.86(d, J ═ 9.5, 1H), 7.48(s, 1H).

Intermediate 23: 6- (1H-1, 2, 4-triazol-3-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid

23.1: 6- [ ethoxy (imino) methyl ] imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester

470mg of sodium ethanethiol was added to 1g of 6-cyanoimidazo [1,2-a ]]Pyridine-2-carboxylic acid ethyl ester (j.med.chem. (1998),41(22) 4317) in a mixture of 15mL ethanol and 10mL dichloromethane cooled to 0 ℃. The reaction mixture was stirred at 25 ℃ for 5 hours and filtered, and the filtrate was evaporated to dryness. The residue is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol (98/2), to give 625mg of 6- [ ethoxy (imino) methyl ester]Imidazo [1,2-a ]]Pyridine-2-carboxylic acid ethyl ester in the form of a light yellow solid.

¹H NMR spectrum (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 ═]⁺.

23.2: 6- [ hydrazino (imino) methyl ] imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester

To a solution of 625mg of ethyl 6- [ ethoxy (imino) methyl ] imidazo [1,2-a ] pyridine-2-carboxylate in 12mL of ethanol is added dropwise 0.2mL of hydrazine hydrate at 0-5 ℃. The reaction mixture was stirred for 2 hours, 73. mu.L of hydrazine hydrate was added and the mixture was stirred for an additional 2 hours while the temperature rose to 25 ℃. The reaction mixture was concentrated to dryness under reduced pressure and the residue was dried to give 600mg of ethyl 6- [ hydrazino (imino) methyl ] imidazo [1,2-a ] pyridine-2-carboxylate, which was used without further purification in the rest of the synthesis.

¹H NMR spectrum (DMSO-d6, δ in ppm): 8.77 (broad singlet, 1H), 8.49(s, 1H), 7.70(m, 1H), 7.53(d, J ═ 9.6, 1H), 5.67(s, 2H), 5.15 (broad singlet, 2H), 4.33(q, J ═ 7.1, 2H), 1.32(t ═ 7.1, 3H).

Mass spectrum (APCI): 248[ M + H ] M/z]⁺.

23.3: 6- (1H-1, 2, 4-triazol-3-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester

A suspension of 580mg of ethyl 6- [ hydrazino (imino) methyl ] imidazo [1,2-a ] pyridine-2-carboxylate in 6mL of formic acid is heated at 85 ℃ for 20 hours. The reaction mixture was concentrated to less than 20% of its original volume and diluted with 20mL of water. Solid sodium carbonate was added at 0-5C to bring the pH to 8-9. The precipitate was filtered off with suction and purified by chromatography on a silica gel column (elution with a mixture of dichloromethane and methanol (98/2)) to yield 320mg of ethyl 6- (1H-1, 2, 4-triazol-3-yl) imidazo [1,2-a ] pyridine-2-carboxylate.

¹H NMR spectrum (DMSO-d6, δ in ppm): 14.5-14.0 (broad singlet, 1H), 9.25(s, 1H), 8.69(s, 1H), 8.63 (broad singlet, 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): 258[ M + H ] M/z]⁺.

23.4: 6- (1H-1, 2, 4-triazol-3-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid

320mg of ethyl 6- (1H-1, 2, 4-triazol-3-yl) imidazo [1,2-a ] pyridine-2-carboxylate are saponified under conditions analogous to those described for the preparation of intermediate 11 (step 11.3) to give 238mg of 6- (1H-1, 2, 4-triazol-3-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid in the form of an off-white solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 14.5-14.2 (broad singlet, 1H), 9.26(s, 1H), 8.66-8.62(m, 2H), 7.91(d, J ═ 9.1, 1H), 7.73(d, J ═ 9.6, 1H).

Intermediate 24: 6- (1H-1, 2, 3-triazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid

24.1: 6- [ (trimethylsilyl) ethynyl ] imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester

A mixture of 4g of ethyl 6-iodoimidazo [1,2-a ] pyridine-2-carboxylate, 2.63mL of ethynyltrimethylsilane, and 888mg of bis (triphenylphosphine) palladium dichloride was degassed under vacuum. 240mg of degassed N, N-dimethylformamide and 3.52mL of triethylamine are added. The reaction mixture was degassed under argon, stirred at 50 ℃ for 50 hours, then cooled and diluted with 20mL of water. The precipitate was suction-filtered off and washed with 5mL of water and then purified by chromatography on a silica gel column, eluting with a mixture of ethyl acetate and hexane (0/50 to 90/10). The fractions containing the expected product were combined and concentrated to dryness under reduced pressure to give 3.6g of ethyl 6- [ (trimethylsilyl) ethynyl ] imidazo [1,2-a ] pyridine-2-carboxylate in the form of an off-white solid.

¹H nuclear magnetic resonance spectroscopy (DMS0-d6, δ in ppm): 8.61(s, 1H), 8.22(s, 1H), 7.36(d, J ═ 9.5, 1H), 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): 287[ M + H ] M/z]⁺.

24.2: 6-ethynylimidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester

To a solution of 500mg of ethyl 6- [ (trimethylsilyl) ethynyl ] imidazo [1,2-a ] pyridine-2-carboxylate in 10mL of anhydrous tetrahydrofuran cooled to 0 ℃ is added dropwise 1.58mL of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran. The reaction mixture was stirred for 30 minutes, then 5mL of water was added and the resulting mixture was extracted three times with 20mL of dichloromethane. The product was purified by chromatography on a silica gel column (eluting with a mixture of ethyl acetate and hexane (1/3 to 1/1)). The fractions containing the expected product were combined and concentrated to dryness under reduced pressure to give 280mg of ethyl 6-ethynylimidazo [1,2-a ] pyridine-2-carboxylate in the form of a yellow solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 8.86(d, J ═ 1.0, 1H), 8.50(d, J ═ 0.6, 1H), 7.63(d, J ═ 9.4, 1H), 7.37(d, J ═ 1.7, 9.4, 1H), 4.32(m, 3H), 1.32(t, J ═ 7.1Hz, 3H).

Mass spectrum (APCI): 215[ M + H ] M/z]⁺.

24.3: 6- (1H-1, 2, 3-triazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester

To a solution of 220mg of 6-ethynylimidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester and 0.21mL of azidotrimethylsilane in 4mL of a mixture of N, N-dimethylformamide and methanol (9/1) was added 9.8mg of cuprous iodide. The reaction mixture was stirred at 100 ℃ for 2 hours then cooled, diluted with 4mL of dichloromethane, filtered through alumina and concentrated to dryness. The residue was purified by chromatography on a silica gel column (eluting with a mixture of dichloromethane and ethanol (97/3)). The fractions containing the expected product were combined and concentrated to dryness under reduced pressure to give 125mg of ethyl 6- (1H-1, 2, 3-triazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxylate in the form of an off-white solid.

¹H nuclear magnetic resonanceSpectrum (DMSO-d6, δ in ppm): 15.5-15.0 (broad singlet, 1H), 9.14(dd, J ═ 1.1, 1.5, 1H), 8.60(d, J ═ 0.5, 1H), 8.40 (broad singlet, 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): 258[ M + H ] M/z]⁺.

24.4: 6- (1H-1, 2, 3-triazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid

125mg of ethyl 6- (1H-1, 2, 3-triazol-3-yl) imidazo [1,2-a ] pyridine-2-carboxylate are saponified under conditions analogous to those described for the preparation of intermediate 11 (step 11.3) to give 72mg of 6- (1H-1, 2, 3-triazol-3-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid in the form of a white solid.

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

Intermediate 25: ethyl 6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) imidazo [1,2-a ] pyridine-2-carboxylate hydrobromide (1: 1)

To a solution of 4g 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine in 40mL 1, 2-dimethoxyethane was added 4.26g ethyl 3-bromo-2-oxopropanoate. The reaction mixture was stirred at 20 ℃ for 40 hours. The precipitate is filtered off with suction, washed with a small amount of 1, 2-dimethoxyethane and pentane and taken up in 50mL of ethanol and refluxed for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure. The resulting oil was redissolved in ether and the solution was concentrated under reduced pressure. The solid was filtered off with suction and washed with a little ether to give 3.78g of ethyl 6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) imidazo [1,2-a ] pyridine-2-carboxylate hydrobromide salt (1: 1) as a white solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 1.27-1.38(m, 15H), 4.36(q, J ═ 7.3Hz, 2H), 7.59(d, J ═ 9.3Hz, 1H), 7.67(d, J ═ 9.3Hz, 1H), 8.68(s, 1H), 8.97(s, 1H).

Mass spectrum (EI): m/z 316[ M ]]⁺，244[M-CO₂Et+H]⁺.

Intermediate 26: 2-ethoxycarbonylimidazo [1,2-a ] pyridine-6-boronic acid

To a solution of 2.5g 2-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine in 50mL 1, 2-dimethoxyethane was added 2.14mL ethyl 3-bromo-2-oxopropionate. The reaction mixture was stirred at 25 ℃ for 3.5 hours, then 50mL of ethanol were added and the resulting mixture was refluxed for 16 hours. The reaction mixture was cooled and concentrated to dryness. The residue was suspended in 100mL of water at 0C and treated with solid sodium carbonate while stirring vigorously until the pH reached 8-9. The precipitate is filtered off with suction and washed with 100mL of water at 0 ℃ and then dissolved in 150mL of methanol. The solution was dried over magnesium sulfate, filtered, concentrated and dried in vacuo to give 2.36g of 2-ethoxycarbonylimidazo [1,2-a ] pyridine-6-boronic acid as a cream-colored solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 8.82(d, J ═ 0.9, 1H), 8.58(s, 1H), 8.35(s, 2H)7.61(m, 2H), 4.33(m, 2H), 1.32(m, 3H)

Mass spectrum (APCI): 235[ M + H ] M/z]⁺.

The chemical structures (table 1), spectral characterization, and synthetic methods (table 2) of some examples of compounds of the invention are illustrated in the following tables.

In these tables:

-the ratio in brackets is the acid/base ratio, "HCl" represents the hydrochloride form of the compound, "TFA" represents the trifluoroacetate form of the compound and the ratio indicated in brackets is the acid/base ratio, the symbol "-" represents the compound in base form;

-“-CH₃"represents a methyl group, or a salt thereof,

TABLE 1

TABLE 2

Pharmacological assays were performed on the compounds of the invention to determine their regulatory effect on NOT.

Evaluation of in vivo Activity on N2A cells

The activity of the compounds of the invention was evaluated on a cell line (N2A) that endogenously expresses the murine Nurrl receptor and was stably transfected with a NOT Binding Response Element (NBRE) coupled to a luciferase reporter gene (luciferase reporter gene). EC50 values were between 0.01 and 1000 nM. The test was carried out according to the following method.

The Neuro-2A cell line was from a standard commercial source (ATCC). The Neuro-2A clone was obtained from a spontaneous tumor (spontaneous tumor) derived from albino mouse A line (a strain of albino mouse A) according to R.J Klebe et al. Neuro-2A cell lines were subsequently used with 8 NBRE-fireflyThe luciferase was stably transfected. N2A-8NBRE cells at 75cm²The flask of (4) containing DMEM supplemented with 10% fetal bovine serum, 4.5g/l glucose and 0.4mg/ml geneticin, until confluent. After one week of culture, the cells were reconstituted with 0.25% trypsin for 30 seconds, then resuspended in phenol red free DMEM containing 4.5g/l glucose and 10% Hyclone skim serum and plated in white, clear-bottomed 96-well plates. Before adding the product, 75. mu.l of cells were left for 24 hours at a ratio of 60000 cells per well. 25 μ l of product was added and incubated for an additional 24 hours. On the day of measurement, an equal volume (100. mu.l) of Steadylite was added to each well and the wells were allowed to stand for 30 minutes for complete lysis of the cells and maximum production of signal. After sealing with an adhesive film, the cell plates were measured on a microplate luminometer. The product is as follows 10^-2M was prepared as a stock solution and then diluted in 100% DMSO. Each product concentration was diluted in culture broth beforehand before incubation with cells, thus containing a final concentration of 0.625% DMSO.

For example, compounds numbered 3, 17, 24, 29, 45 and 53 showed EC of 0.9nM, 26.8nM, 0.9nM, 1.1nM, 1.2nM and 0.4nM, respectively₅₀The value is obtained.

Thus, the compounds according to the invention have a modulating effect on NOT.

Accordingly, the compounds of the present invention are useful in the preparation of medicaments for the therapeutic use in the treatment or prevention of diseases in which the NOT receptor is involved.

Thus, according to another aspect, one subject of the present invention is a medicament containing a compound of formula (I) or an addition salt thereof with a pharmaceutically acceptable acid.

These drugs have therapeutic uses, in particular in the treatment and prevention of the following diseases: neurodegenerative diseases such as parkinson's disease, alzheimer's disease, tauopathies (e.g., progressive supranuclear palsy, frontotemporal dementia, corticobasal degeneration), pick's disease); brain trauma, such as ischemia and cranial trauma and epilepsy; psychoses, such as schizophrenia, depression, psychoactive substance dependence (substance dependency) and attention deficit hyperactivity disorder; inflammatory diseases of the central nervous system, such as multiple sclerosis, encephalitis, myelitis and encephalomyelitis, and other inflammatory diseases, such as vascular pathologies (vascularides), atherosclerosis, joint inflammation (jointingformations), arthropathy, rheumatoid arthritis; osteoarthritis, crohn's disease, ulcerative colitis; allergic inflammatory diseases such as asthma, autoimmune diseases, e.g. type 1 diabetes, lupus, scleroderma (scleroderma), Guillain-barre syndrome, addison's syndrome and other immune mediated diseases; osteoporosis; cancer.

Accordingly, one subject of the present invention relates to compounds of formula (I) as defined above for the treatment or prevention of the diseases, symptoms and conditions mentioned above.

According to another aspect, the present invention relates to the use of a compound selected from formula (I) as defined above for the preparation of a medicament for the treatment or prevention of one of the diseases, symptoms or conditions mentioned above.

These compounds may also be used as a therapy in conjunction with transplant and/or stem cell transplantation.

According to another aspect, the present invention relates to a pharmaceutical composition comprising as an active ingredient a compound of the present invention. These pharmaceutical compositions contain an effective dose of at least one compound of the invention, or a pharmaceutically acceptable salt of said compound, and at least one pharmaceutically acceptable excipient.

The excipients are selected from the usual excipients known to the person skilled in the art, depending on the pharmaceutical form and the desired method of administration.

In the pharmaceutical composition of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical (local), intratracheal, intranasal, transdermal or rectal administration, the active ingredient of the above formula (I) or a salt thereof may be administered as a unit administration form, as a mixture with standard pharmaceutical excipients, to humans and animals for the prevention or treatment of the above symptoms or diseases.

Suitable unit administration forms include oral administration forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal or inhalation administration forms, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants (implants). For topical administration, the compounds according to the invention may be used in creams, gels, ointments or lotions (deposition).

By way of example, a unit dosage form of a compound of the invention in the form of a tablet may comprise the following components:

compound of the invention 50.0mg

Mannitol 223.75mg

Croscarmellose sodium 6.0mg

Corn starch 15.0mg

Hydroxypropyl methylcellulose 2.25mg

Magnesium stearate 3.0mg

For special cases, either high or low doses are applicable; these dosages do not exceed the content of the present invention. According to conventional practice, the dosage suitable for each patient is determined by a physician according to the method of administration and the weight and response of the patient in question.

According to another aspect, the present invention also relates to the above-indicated method for treating a condition, which comprises administering to a patient an effective dose of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

It is understood that all the subject-matters of the invention as defined above, in particular the medicaments, pharmaceutical compositions and methods of treatment, also apply more particularly to the subgroups of compounds as defined above.

Claims

1. A compound of formula (I) in base form or in acid addition salt form:

wherein:

x represents a phenyl group optionally substituted with one or more fluorine or chlorine atoms, or with a cyano group;

R₂represents a dioxolanyl group, a pyridyl group, an imidazolyl group, a pyrazole groupA group selected from the group consisting of phenyl, triazolyl, pyrrolyl, furyl, oxazolyl, indolyl, imidazolinyl, thienyl, pyrazinyl, pyrimidinyl, and thiazolyl, and R₂Optionally substituted with one or more of the following groups: hydroxy, methyl, hydroxymethyl, methoxy, halogen, NH₂Or an oxo group, or a pharmaceutically acceptable salt thereof,

R₁represents a hydrogen atom or a methyl group;

R₃and R₄Represents a hydrogen atom.

2. Compounds of formula (I) according to claim 1, characterized in that they are selected from:

● 6- (1, 3-dioxolan-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

● N-phenyl-6- (pyridin-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N-phenyl-6- (pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N-phenyl-6- (1H-pyrazol-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N-phenyl-6- (1H-pyrrol-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● 6- (furan-3-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

● 6- (oxazol-5-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

● 6- (2-aminothiazol-4-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

● 6- (6-methoxypyridin-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

● 5-methyl-N-phenyl-6- (pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● 6- (2-aminothiazol-5-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

● 6- (6-hydroxypyridin-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

● 6- (furan-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

● N-phenyl-6- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● 6- (oxazol-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

● N-phenyl-6- (pyridin-4-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● 6- (1H-indol-3-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

● N-phenyl-6- (thien-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N-phenyl-6- (pyrazin-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● 6- (1-Oxopyridin-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

● N-phenyl-6- (pyrimidin-5-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● N-phenyl-6- (thien-3-yl) imidazo [1,2-a ] pyridine-2-carboxamide

● 6- (5-fluoro-furan-2-yl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

● N-phenyl-6- (pyrimidin-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide

3. Pharmaceutical, characterized in that it comprises a compound of formula (I) according to any one of claims 1 or 2, or an addition salt of this compound with a pharmaceutically acceptable acid.

4. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of claims 1 or 2, or a pharmaceutically acceptable salt of this compound, and at least one pharmaceutically acceptable excipient.

5. Use of a compound of formula (I) according to any one of claims 1 or 2 in the manufacture of a medicament for the treatment or prevention of a neurodegenerative disease.

6. Use of a compound of formula (I) according to any one of claims 1 or 2 in the manufacture of a medicament for the treatment or prevention of brain trauma and epilepsy.

7. Use of a compound of formula (I) according to any one of claims 1 or 2 in the manufacture of a medicament for the treatment or prophylaxis of psychosis.

8. Use of a compound of formula (I) according to any one of claims 1 or 2 in the manufacture of a medicament for the treatment or prevention of inflammatory diseases.

9. Use of a compound of formula (I) according to any one of claims 1 or 2 in the manufacture of a medicament for the treatment or prevention of osteoporosis.

10. Use of a compound of formula (I) according to any one of claims 1 or 2 in the manufacture of a medicament for the treatment or prevention of cancer.

11. Use of a compound of formula (I) according to any one of claims 1 or 2 in the manufacture of a medicament for the treatment or prevention of parkinson's disease, alzheimer's disease, tauopathies and multiple sclerosis.

12. Use of a compound of formula (I) according to any one of claims 1 or 2 for the preparation of a medicament for the treatment or prevention of schizophrenia, depression, psychoactive substance dependence and attention deficit disorder with hyperactivity.

13. A compound:

6-bromo-N-phenylimidazo [1,2-a ] pyridine-2-carboxamides

6-iodo-N-phenylimidazo [1,2-a ] pyridine-2-carboxamides

N-phenyl-6-cyanoimidazo [1,2-a ] pyridine-2-carboxamides

6-trimethylstannyl-N-phenylimidazo [1,2-a ] pyridine-2-carboxamides

N-phenyl-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) imidazo [1,2-a ] pyridine-2-carboxamide and its hydrobromide salt (1: 1)

2-Phenylcarbamoylimidazo [1,2-a ] pyridine-6-boronic acid hydrochloride (1: 1)

N-phenyl-6-vinylimidazo [1,2-a ] pyridine-2-carboxamides

6-formyl-N-phenylimidazo [1,2-a ] pyridine-2-carboxamides

6- (2-bromoacetyl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamide

6- (1-ethoxyvinyl) -N-phenylimidazo [1,2-a ] pyridine-2-carboxamides

N- (3, 5-difluorophenyl) -6-iodoimidazo [1,2-a ] pyridine-2-carboxamide

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

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

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

6- (6- { bis [ (1, 1-dimethylethoxy) carbonyl ] amino } pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester

6- (pyridin-2-yl) imidazo [1,2-a ] pyridine-2-carboxylic acids

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

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

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

6- (2- { [ (1, 1-Dimethylethoxy) carbonyl ] amino } thiazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid

6- (2- { [ (1, 1-Dimethylethoxy) carbonyl ] amino } thiazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester

6- (1H-pyrrol-3-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid and its hydrochloride (1: 1)

6- [1- (triisopropylsilyl) -1H-pyrrol-3-yl ] imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester

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

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

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

6- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester

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

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

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

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

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

6- (5-Formylfuran-2-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester

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

6- (thien-3-yl) imidazo [1,2-a ] pyridine-2-carboxylic acids

6- (Thien-3-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester

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

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

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

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

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

Ethyl 6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) imidazo [1,2-a ] pyridine-2-carboxylate hydrobromide (1: 1).

14. Use of a compound according to claim 13 for the preparation of a compound of general formula (I) as defined in any one of claims 1 or 2.