2-aryl imidazo[1,2-a]pyridine-3-acetamide derivatives, preparation methods and uses thereof

1. A compound of Formula I, its tautomer, its racemic or optical isomer, its pharmaceutically acceptable salt (which is water soluble), or its solvate,

wherein:

R 1 is selected from ethyl, propyl, butyl, and methoxyethyl;

R 2 is selected from 2-pyridinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl, 2-morpholinylethyl, and 3-morpholinylpropyl;

R 3 is 6-methyl or 7-methyl;

R 4 is 1-3 substituents selected from H, halogen, alkyl, substituted hydrocarbonyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, C 1 -C 6 alkoxyl, C 5 -C 10 aryloxy, substituted aryloxy, C 1 -C 6 alkylamino, C 5 -C 1  arylamino, substituted arylamino, di-(C 1 -C 6 alkyl)amino, di-(C 5 -C 10 aryl)amino, di-(substituted aryl)amino, C 1-10 hydrocarbonylacyloxy, C 6-10 arylacyloxy, C 1-10 hydrocarbonylacylamino, C 6-10 arylacylamino, carboxyl, C 1-10 hydrocarbonyloxyformyl, C 6-10 aryloxyformyl, aminoformyl, C 1-10 hydrocarbonylaminoformyl, or C 6-10 arylaminoformyl; wherein the heteroaromatic cycle is a monocyclic or fused aromatic hydrocarbonyl having 1-3 heteroatoms selected from N, O or S, each of the substituents of groups having substituents is selected from halogen, hydroxyl, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxyl, C 1-6 alkylthio, mono- or di- or tri-halogenated C 1-6 alkyl, amino, C 1-6 alkylamino, C 1-10 hydrocarbonylacyloxy, C 1-10 hydrocarbonylacylamino, C 6-10 arylacyloxy, and C 6-10 arylacylamino.

2. The compound of Formula I according to claim 1 , its tautomer, its racemic or optical isomer, its pharmaceutically acceptable salt, or its solvate, wherein R 3 is at 4-, 5-, 6-, or 7-position of imidazo[1,2-a]pyridine ring; R 4 is at ortho-, meta- or para-position of benzene ring.

3. The compound of Formula I according to claim 1 , its tautomer, its racemic or optical isomer, its pharmaceutically acceptable salt, or its solvate, wherein, R 3 and R 4 are independently selected from F, Cl, Br, I, C 1 -C 6 alkyl, C 1 -C 3 alkoxylethyl, and C 1 -C 6 alkoxyl, wherein R 3 has 1-2 substituents, and R 4 has 1-3 substituents.

4. The compound of Formula I according to claim 1 , its tautomer, its racemic or optical isomer, its pharmaceutically acceptable salt, or its solvate, wherein R 1 is ethyl or methoxyethyl.

5. A compound of Formula I, its tautomer, its racemic or optical isomer, its pharmaceutically acceptable salt (which is water soluble), or its solvate,

wherein:

R 1 is selected from ethyl, propyl, butyl, and methoxyethyl;

R 2 is selected from 2-pyridinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl, 2-morpholinylethyl, and 3-morpholinylpropyl;

R 3 is 1-2 substituents selected from H, halogen, alkyl, substituted hydrocarbonyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, C 1 -C 6 alkoxyl, C 5 -C 10 aryloxy, substituted aryloxy, C 1 -C 6 alkylamino, C 5 -C 10 arylamino, substituted arylamino, di-(C 1 -C 6 alkyl)amino, di-(C 5 -C 1  aryl)amino, di-(substituted aryl)amino, C 1-10 hydrocarbonylacyloxy, C 6-10 arylacyloxy, C 1-10 hydrocarbonylacylamino, C 6-10 arylacylamino, carboxyl, C 1-10 hydrocarbonyloxyformyl, C 6-10 aryloxyformyl, aminoformyl, C 1-10 hydrocarbonylaminoformyl, or C 6-10 arylaminoformyl; wherein the heteroaromatic cycle is a monocyclic or fused aromatic hydrocarbonyl having 1-3 heteroatoms selected from N, O or S, each of the substituents of groups having substituents is selected from halogen, hydroxyl, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxyl, C 1-6 alkylthio, mono- or di- or tri-halogenated C 1-6 alkyl, amino, C 1-6 alkylamino, C 1-10 hydrocarbonylacyloxy, C 1-10 hydrocarbonylacylamino, C 6-10 arylacyloxy, and C 6-10 arylacylamino; and

R 4 is 4-chloro, 3,4-dichloro, 4-methyl, or 4-methoxy.

6. The compound of Formula I according to claim 5 , its tautomer, its racemic or optical isomer, its pharmaceutically acceptable salt, or its solvate, wherein, R 3 is at 4-, 5-, 6-, or7 -position of imidazo[1,2-a]pyridine ring; R 4 is at ortho-, meta- or para-position of benzene ring.

7. The compound of Formula I according to claim 6 , its tautomer, its racemic or optical isomer, its pharmaceutically acceptable salt, or its solvate, wherein, R 3 and R 4 are independently selected from F, Cl, Br, I, C 1 -C 6 alkyl, C 1 -C 3 alkoxylethyl, and C 1 -C 6 alkoxyl, wherein R 3 has 1-2 substituents, and R 4 has 1-3 substituents.

8. The compound of Formula I according to claim 6 , its tautomer, its racemic or optical isomer, its pharmaceutically acceptable salt, or its solvate, wherein R 1 is ethyl or methoxyethyl.

9. A compound, its tautomer, its racemic or optical isomer, its pharmaceutically acceptable salt, or its solvate, which is selected from the following compounds:

N-benzyl-N-ethyl-2-(4-chlorophenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide;

N-ethyl-N-(2-pyridinylmethyl)-2-(4-chlorophenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride;

N-ethyl-N-(3-pyridinylmethyl)-2-(4-chlorophenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride;

N-ethyl-N-(4-pyridinylmethyl)-2-(4-chlorophenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride;

N-(2-methoxyethyl)-N-(2-pyridinylmethyl)-2-(4-chlorophenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride;

N-(2-methoxyethyl)-N-(3-pyridinylmethyl)-2-(4-methylphenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride;

N-benzyl-N-ethyl-2-(3,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide;

N-ethyl-N-(2-pyridinylmethyl)-2-(3,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride;

N-ethyl-N-(3-pyridinylmethyl)-2-(3,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide-hydrochloride;

N-ethyl-N-(4-pyridinylmethyl)-2-(3,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide-hydrochloride;

N-(2-methoxyethyl)-N-(2-pyridinylmethyl)-2-(3,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide-hydrochloride;

N-(2-methoxyethyl)-N-(3-pyridinylmethyl)-2-(3,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride;

N-benzyl-N-ethyl-2-(4-methylphenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide;

N-ethyl-N-(2-pyridinylmethyl)-2-(4-methylphenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride;

N-ethyl-N-(3-pyridinylmethyl)-2-(4-methylphenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride;

N-ethyl-N-(4-pyridinylmethyl)-2-(4-methylphenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride;

N-(2-methoxyethyl)-N-(2-pyridinylmethyl)-2-(4-methylphenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride;

N-(2-methoxyethyl)-N-(3-pyridinylmethyl)-2-(4-methylphenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride;

N-benzyl-N-ethyl-2-(4-methoxyphenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide;

N-ethyl-N-(2-pyridinylmethyl)-2-(4-methoxyphenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride;

N-ethyl-N-(3-pyridinylmethyl)-2-(4-methoxyphenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide-hydrochloride;

N-ethyl-N-(4-pyridinylmethyl)-2-(4-methoxyphenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride;

N-(2-methoxyethyl)-N-(2-pyridinylmethyl)-2-(4-methoxyphenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride;

N-(2-methoxyethyl)-N-(3-pyridinylmethyl)-2-(4-methoxyphenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride;

N-(2-methoxyethyl)-N-(2-morpholinylethyl)-2-(4-methylphenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride;

N-(2-methoxyethyl)-N-(2-morpholinylethyl)-2-(4-methylphenyl)-6-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride;

N-ethyl-N-(4-pyridinylmethyl)-2-(4-methylphenyl)-6-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride; and

N-ethyl-N-(4-pyridinylmethyl)-2-(4-chlorophenyl)-6-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride.

10. A pharmaceutical composition comprising at least one compound of Formula I according to claim 3 , its tautomer, its racemic or optical isomer, its pharmaceutically acceptable salt, or its solvate, and optionally a pharmaceutically acceptable carrier or adjuvant.

11. The compound of Formula I according to claim 3 , its racemic or optical isomer, its pharmaceutically acceptable salt, or its solvate, wherein R 3 , R 4 are independently selected from F, Cl, methyl, ethyl, methoxyethyl, methoxy, and ethoxy.

12. The compound of Formula I according to claim 3 , its racemic or optical isomer, its pharmaceutically acceptable salt, or its solvate, wherein R 2 is 2-pyridinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl, or 2-morpholinylethyl.

13. A pharmaceutical composition, comprising at least one compound of Formula I according to claim 7 , its tautomer, its racemic or optical isomer, its pharmaceutically acceptable salt, or its solvate, and optionally a pharmaceutically acceptable carrier or adjuvant.

14. The compound of Formula I according to claim 7 , its racemic or optical isomer, its pharmaceutically acceptable salt, or its solvate, wherein R 3 , R 4 are independently selected from F, Cl, methyl, ethyl, methoxyethyl, methoxy, and ethoxy.

15. The compound of Formula I according to claim 7 , its racemic or optical isomer, its pharmaceutically acceptable salt, or its solvate, wherein R 2 is 2-pyridinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl, or 2-morpholinylethyl.

16. A method for preparing the compound of Formula I, its tautomer, its racemic or optical isomer, its pharmaceutically acceptable salt, or its solvate according to claims 1 , comprising the following steps:

a) converting an aromatic hydrocarbon compound of Formula VIII:

via Friedel-Crafts acetylation to form a ketone compound of Formula VII:

b) reacting the ketone compound VII with bromine under the catalysis of aluminum trichloride to form a bromide, not being separated, reacting with an aminopyridine compound of Formula VI,

under heating and in the presence of an alkali or alkaline compound to form an imidazopyridine compound of Formula V:

C) reacting the imidazopyridine compound V with dimethylamine and formaldehyde aqueous soltuion in acetic acid to form a Mannich base, separating via filtration, then reacting with iodomethane to form a quaternary ammonium salt of Formula IV:

d) reacting the quaternary ammonium salt IV with a cyanide to form a corresponding nitrile, then hydrolyzing in the presence of a strong base, and acidifying to form a carboxylic compound of Formula II

e) in the presence or absence of a catalyst, such as 4-dimethylaminopyridine, reacting the carboxylic compound of Formula II as obtained in step d) with an amine compound of Formula III in the presence of a condensing agent:

to obtain a compound of Formula I

wherein:

R 1 is selected from ethyl, propyl, butyl, and methoxyethyl;

R 2 is selected from 2-pyridinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl, 2-morpholinylethyl, and 3-morpholinylpropyl;

R 3 is 6-methyl or 7-methyl:

R 4 is 1-3 substituents selected from H, halogen, alkyl, substituted hydrocarbonyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, C 1 -C 6 alkoxyl, C 5 -C 10 aryloxy, substituted aryloxy, C 1 -C 6 alkylamino, C 5 -C 10 arylamino, substituted arylamino, di-(C 5 -C 10 alkyl)amino, di-(C 5 -C 10 aryl)amino, di-(substituted aryl)amino, C 1 -C 10 hydrocarbonylacyloxy, C 6 -C 10 arylacyloxy, C 1 -C 10 hydrocarbonylacylamino, C 6 -C 10 arylacylamino, carboxyl, C 1 -C 10 hydrocarbonyloxyformyl, C 6 -C 10 aryloxyformyl, aminoformyl, C 1 -C 10 hydrocarbonylaminoformyl, or C 6 -C 10 arylaminoformyl; wherein the heteroaromatic cycle is a monocyclic or fused aromatic hydrocarbonyl having 1-3 heteroatoms selected from N, O or S, each of the substituents of groups having substituents is selected from halogen, hydroxyl, cyano, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 alkylthio, mono- or di- or tri-halogenated C 1 -C 6 alkyl, amino, C 1 -C 6 alkylamino, C 1 -C 10 hydrocarbonylacyloxy, C 1 -C 10 hydrocarbonylacylamino, C 6 -C 10 arylacyloxy, and C 6 -C 10 arylacylamino; or a tautomer, racemic or optical isomer, pharmaceutically acceptable salt (which is water soluble), or solvate thereof.

17. A method for preparing the compound of Formula I, its tautomer, its racemic or optical isomer, its pharmaceutically acceptable salt, or its solvate according to claim 1 , comprising the following steps:

a) converting an aromatic hydrocarbon compound of Formula VIII:

via Friedel-Crafts acetylation using succinic anhydride to form a ketonic acid compound of Formula VIII′:

b) subjecting the above ketonic acid compound of Formula VIII′ to bromination with bromine to form a brominated acid compound of Formula VII′:

c) reacting the above brominated acid compound of Formula VII′ with a chloroformate (such as ethyl chloroformate or isobutyl chloroformate) to form a mixed acid anhydride, then reacting with an amine of Formula III:

in the presence or absence of a catalyst, and in the presence of an alkali to form a bromonated amide compound of Formula II′:

d) subjecting the above bromonated amide compound of Formula I1′ and an aminopyridine compound of Formula VI:

to condensation in the presence of an alkali to prepare a compound of Formula I:

wherein:

R 1 is selected from ethyl, propyl, butyl, and methoxyethyl;

R 2 is selected from 2-pyridinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl, 2-morpholinylethyl, and 3-morpholinylpropyl;

R 3 is 6-methyl or 7-methyl:

R 4 is 1-3 substituents selected from H, halogen, alkyl, substituted hydrocarbonyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, C 1 -C 6 alkoxyl, C 5 -C 10 aryloxy, substituted aryloxy, C 1 -C 6 alkylamino, C 5 -C 10 arylamino, substituted arylamino, di-(C 5 -C 10 alkyl)amino, di-(C 5 -C 10 aryl)amino, di-(substituted aryl)amino, C 1 -C 10 hydrocarbonylacyloxy, C 6 -C 10 arylacyloxy, C 1 -C 10 hydrocarbonylacylamino, C 6 -C 10 arylacylamino, carboxyl, C 1 -C 10 hydrocarbonyloxyformyl, C 6 -C 10 aryloxyformyl, aminoformyl, C 1 -C 10 hydrocarbonylaminoformyl, or C 6 -C 10 arylaminoformyl; wherein the heteroaromatic cycle is a monocyclic or fused aromatic hydrocarbonyl having 1-3 heteroatoms selected from N, O or S, each of the substituents of groups having substituents is selected from halogen, hydroxyl, cyano, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 alkylthio, mono- or di- or tri-halogenated C 1 -C 6 alkyl, amino, C 1 -C 6 alkylamino, C 1 -C 10 hydrocarbonylacyloxy, C 1 -C 10 hydrocarbonylacylamino, C 6 -C 10 arylacyloxy, and C 6 -C 10 arylacylamino; or a tautomer, racemic or optical isomer, pharmaceutically acceptable salt (which is water soluble), or solvate thereof.

18. A method of treating a translocator protein (TSPO)-associated condition selected from the group consisting of anxiety and depression comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula I:

wherein:

R 1 is selected from ethyl, propyl, butyl, and methoxyethyl;

R 2 is selected from, 2-pyridinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl, 2-morpholinylethyl, and 3-morpholinylpropyl;

R 3 , R 4 are independently selected from H, halogen, alkyl, substituted hydrocarbonyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, C 1 -C 6 alkoxyl, C 5 -C 10 aryloxy, substituted aryloxy, C 1 -C 6 alkylamino, C 5 -C 10 arylamino, substituted arylamino, di-(C 5 -C 10 alkyl)amino, di-(C 5 -C 10 aryl)amino, di-(substituted aryl)amino, C 1 -C 10 hydrocarbonylacyloxy, C 6 -C 10 arylacyloxy, C 1 -C 10 hydrocarbonylacylamino, C 6 -C 10 arylacylamino, carboxyl, C 1 -C 10 hydrocarbonyloxyformyl, C 6 -C 10 aryloxyformyl, aminoformyl, C 1 -C 10 hydrocarbonylaminoformyl, or C 6 -C 10 arylaminoformyl; wherein the heteroaromatic cycle is a monocyclic or fused aromatic hydrocarbonyl having 1-3 heteroatoms selected from N, O or S, each of the substituents of groups having substituents is selected from halogen, hydroxyl, cyano, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 alkylthio, mono- or di- or tri-halogenated C 1 -C 6 alkyl, amino, C 1 -C 6 alkylamino, C 1 -C 10 hydrocarbonylacyloxy, C 1 -C 10 hydrocarbonylacylamino, C 6 -C 10 arylacyloxy, and C 6 -C 10 arylacylamino; or a tautomer, racemic or optical isomer, pharmaceutically acceptable salt, or solvate thereof.

19. The method according to claim 18 wherein the compound is a TSPO ligand.