KR20210033275A - Novel heteroaryl amide derivatives as MAO-B inhibitors and pharmaceutical compositions for preventing, ameliorating or treating neurodegenerative diseases comprising the same - Google Patents

Abstract

The present invention relates to: a novel heteroaryl amide derivative compound useful as an MAO-B inhibitor; a compound selected from a pharmaceutically acceptable salt thereof, a hydrate thereof or a stereoisomer thereof; a method of preparing the compound; and a pharmaceutical composition for preventing, ameliorating or treating neurodegenerative diseases comprising the compound as an active component. According to the present invention, the heteroaryl amide derivative compound has an excellent effect of inhibiting MAO-B, thereby being usefully used for preventing, ameliorating, and treating neurodegenerative diseases such as Parkinson′s disease, Alzheimer′s disease, and Huntington′s disease.

Description

Novel heteroaryl amide derivatives as MAO-B inhibitors and pharmaceutical compositions for preventing, ameliorating or treating neurodegenerative diseases comprising the novel heteroaryl amide derivative compounds useful as MAO-B inhibitors and comprising the same the same}

The present invention relates to a novel heteroaryl amide derivative compound useful as an MAO-B inhibitor, a pharmaceutically acceptable salt thereof, a compound selected from a hydrate or a stereoisomer thereof, and a method for preparing the compound, a nerve comprising the compound as an active ingredient. It relates to a pharmaceutical composition for preventing, alleviating or treating degenerative diseases.

The increase in average life expectancy causes a dramatic increase in the prevalence of age-related neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's disease. Among these neurodegenerative diseases, Parkinson's disease (PD) is the second most common disease, and is a progressive neurodegenerative motor disorder characterized by motor deficits such as tremors at rest, dyskinesia, stiffness and postural instability. These motor symptoms are largely associated with a defect in dopamine caused by the massive loss of dopamine-responsive neurons in the compact substantia nigra. However, the exact mechanism by which neurodegeneration occurs is still unknown.

Recently, several studies have reported that the expression level of monoamine oxidase B (MAO-B) in the human brain increases with age, and its activity is reported to increase significantly in the black matter of Parkinson's disease patients. . MAO (Monoamine oxidase) is located in the outer mitochondrial membrane of the liver and brain, and is known to promote oxidative deamination of monoamine neurotransmitters such as dopamine. In addition, this reaction promoted by MAO is oxidative. It has been shown to produce _{hydrogen peroxide (H 2} O ₂ ), which induces stress and neuronal cell death.

On the other hand, MAO has MAO-A and MAO-B, the two isoproteins. MAO-B is abundant in neurons and astrocytes that release serotonin, such as selegiline and rasagiline. It is known to be selectively inhibited by potent inhibitors. On the other hand, MAO-A is located in neurons that release catecholamines and is known to be selectively inhibited by low concentrations of chlorgiline. However, selegiline and rasagalin are irreversible MAO-B inhibitors and have been reported to exhibit undesirable adverse effects such as hallucinations and headaches in the long-term treatment of Parkinson's disease. In addition, recent research results exist that the irreversibility of MAO-B inhibition may contribute to short-term action.

Accordingly, in the present invention, a selective and reversible MAO-B inhibitor has been developed that can reduce undesirable adverse effects and maintain its effects in long-term use for the treatment of neurodegenerative diseases.

International Publication No. WO 2015-027324

Min-Ho Nam et. al., ACS Chem. Neurosci., 8(7):1519-1529, 2017 Yeon SK et.al., Bioorganic & Medicinal Chemistry, 26(1):232-244, 2017

An object of the present invention is a novel heteroaryl amide derivative compound having a selective inhibitory activity against monoamine oxidase B (MAO-B), a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof. To provide a compound.

Another object of the present invention is to provide a pharmaceutical composition for the prevention, alleviation or treatment of neurodegenerative diseases comprising a compound selected from a novel heteroaryl amide derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof as an active ingredient. To provide.

Another object of the present invention is to provide a health functional food for the prevention or improvement of neurodegenerative diseases comprising a compound selected from a novel heteroaryl amide derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof as an active ingredient. To provide.

Another object of the present invention is to provide a method for preparing a compound selected from novel heteroaryl amide derivative compounds, pharmaceutically acceptable salts thereof, hydrates thereof, and stereoisomers thereof.

In order to achieve the above object, the present invention provides a compound selected from a heteroaryl amide derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof, which is any one of the compounds represented by the following Formulas I to III:

[Chemical Formula Ⅰ]

[Chemical Formula Ⅱ]

[Chemical Formula Ⅲ]

In Formula I,

X is nitrogen or carbon;

R ₁ is hydrogen; Halogen atom; C ₁ -C ₁₃ alkyl group; Or a C ₃ -C ₁₀ cyclyl group;

R ₂ is a C ₃ -C ₁₀ aryl group; Or a 5- to 9-membered heteroaryl group containing 1 to 4 heteroatoms selected from boron (B), nitrogen (N), oxygen (O) and sulfur (S) atoms,

In Formula II,

Y is nitrogen or carbon;

Z is -O-; -CH ₂ -; -CH(CH ₃ )-; -C(O)O-; Or -C(O)-;

R ₃ is hydrogen; Halogen atom; C ₁ -C ₁₃ alkyl group; Or a C ₃ -C ₁₀ cyclyl group;

R ₄ is a C ₃ -C ₁₀ aryl group; Or a 5- to 9-membered heteroaryl group containing 1 to 4 heteroatoms selected from boron (B), nitrogen (N), oxygen (O) and sulfur (S) atoms,

In Formula III,

R ₅ is hydrogen; halogen; C ₁ -C ₁₃ alkyl group; Or a C ₃ -C ₁₀ cyclyl group;

R ₆ is a C ₃ -C ₁₀ aryl group; Or a 5- to 9-membered heteroaryl group containing 1 to 4 heteroatoms selected from boron (B), nitrogen (N), oxygen (O) and sulfur (S) atoms,

Each of the C ₁ -C ₁₃ alkyl group or C ₃ -C ₁₀ cyclyl group is hydrogen; Hydroxy group; Halogen group; Carbonyl group (-(C=O)R ₇ R ₈ ); _{A C 1} -C ₃ alkyl group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; _{A C 1} -C ₃ alkoxy group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; C ₆ -C ₁₀ phenoxy; Amino group (-NR ₇ R ₈ ); An amide group (-(C=O)NR ₇ R ₈ ); C ₆ -C ₁₀ aryl group; Including at least one substituent selected from the group consisting of a C ₃ -C ₁₀ heteroaryl group and a C ₃ -C _{10 heterocyclyl group,}

Each of the C ₃ -C ₁₀ aryl group or 5 to 9 membered heteroaryl group is hydrogen; Hydroxy group; Halogen group; Carbonyl group (-(C=O)R ₇ R ₈ ); _{A C 1} -C ₃ alkyl group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; _{A C 1} -C ₃ alkoxy group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; C ₆ -C ₁₀ phenoxy; Amino group (-NR ₇ R ₈ ); An amide group (-(C=O)NR ₇ R ₈ ); C ₆ -C ₁₀ aryl group; Including at least one substituent selected from the group consisting of a C ₃ -C ₁₀ heteroaryl group and a C ₃ -C _{10 heterocyclyl group,}

Each of R ₇ and R ₈ is hydrogen; C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkenyl group; C ₁ -C ₆ alkynyl group; C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; And one or more selected from the group consisting of a _{C 3} -C _{10 heterocyclyl group.}

In addition, the present invention is a neurodegenerative disease comprising as an active ingredient a compound selected from a heteroarylamide derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof, which is any one of the compounds represented by Formulas I to III. It provides a pharmaceutical composition for the prevention, alleviation or treatment of.

In addition, the present invention is a neurodegenerative disease comprising as an active ingredient a compound selected from a heteroarylamide derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof, which is any one of the compounds represented by Formulas I to III. Provides health functional foods for the prevention or improvement of

In addition, the present invention provides a method for preparing a compound selected from a heteroaryl amide derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof, which is any one of the compounds represented by Formulas I to III.

The novel heteroarylamide derivative compound according to the present invention not only plays an important role in dopamine metabolism in the brain, but also has an excellent effect of inhibiting MAO-B, which is known to inhibit brain nerve cell damage, so that the treatment of neurodegenerative diseases , It can be usefully used for the purpose of prevention and alleviation.

1 is a graph showing the inhibition rate (%) for MAO-B of compounds Nos. 1 to 36 according to the present invention showing the inhibitory effect on MAO-B.
Figure 2 is a graph showing the analysis of the inhibition rate (%) for MAO-B of compounds Nos. 37 to 45 according to the present invention showing the inhibitory effect on MAO-B.
3 is a graph showing the analysis of the inhibition rate (%) for MAO-B of compounds Nos. 46 to 48 according to the present invention showing the inhibitory effect on MAO-B.

Unless otherwise specified, all numbers, values, and/or expressions expressing ingredients, reaction conditions, and content of ingredients used herein are the various types of measurements that occur in obtaining these values, among other things in which these numbers are essentially different. Since they are approximations that reflect uncertainty, it should be understood as being modified in all cases by the term "about". In addition, when numerical ranges are disclosed herein, such ranges are continuous and, unless otherwise indicated, include all values from the minimum value of this range to the maximum value including the maximum value. Furthermore, where this range refers to an integer, all integers from the minimum to the maximum value including the maximum value are included, unless otherwise indicated.

In the present specification, where a range is described for a variable, it will be understood that the variable includes all values within the stated range, including the stated endpoints of the range. For example, a range of “5 to 10” includes values of 5, 6, 7, 8, 9, and 10, as well as any subranges such as 6 to 10, 7 to 10, 6 to 9, 7 to 9, etc. Inclusive, and it will be understood to include any values between integers that are reasonable in the scope of the stated range, such as 5.5, 6.5, 7.5, 5.5 to 8.5 and 6.5 to 9, and the like. Also, for example, the range of "10% to 30%" is 10% to 15%, 12% to 10%, 11%, 12%, 13%, etc., as well as all integers including up to 30%. It will be understood to include any subranges, such as 18%, 20% to 30%, and the like, and include any values between reasonable integers within the scope of the stated range, such as 10.5%, 15.5%, 25.5%, and the like.

In addition, terms and abbreviations used in the present specification may be interpreted as meanings commonly understood by one of ordinary skill in the art to which the present invention belongs, unless otherwise defined.

Hereinafter, the present invention will be described in detail.

The present inventors aim to develop a selective and reversible MAO-B inhibitor capable of reducing undesirable adverse effects such as hallucinations and headaches in treating neurodegenerative diseases such as Parkinson's disease and maintaining the effect even for long-term use. As a result of continuing the study, as a MAO-B inhibitor having selective inhibitory activity against MAO-B, a heteroarylamide derivative compound useful for the prevention or treatment of neurodegenerative diseases, pharmaceutically acceptable salts thereof, hydrates thereof, and stereoisomers thereof A compound selected from and a method for preparing the compound, and a pharmaceutical composition for preventing, alleviating or treating neurodegenerative diseases comprising the compound as an active ingredient were developed.

One aspect of the present invention provides a compound selected from a heteroaryl amide derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof, which is any one of the compounds represented by the following Formulas I to III:

[Chemical Formula Ⅰ]

[Chemical Formula Ⅱ]

[Chemical Formula Ⅲ]

In Formula I,

X is nitrogen or carbon;

R ₁ is hydrogen; Halogen atom; C ₁ -C ₁₃ alkyl group; Or a C ₃ -C ₁₀ cyclyl group;

R ₂ is a C ₃ -C ₁₀ aryl group; Or a 5- to 9-membered heteroaryl group containing 1 to 4 heteroatoms selected from boron (B), nitrogen (N), oxygen (O) and sulfur (S) atoms,

In Formula II,

Y is nitrogen or carbon;

Z is -O-; -CH ₂ -; -CH(CH ₃ )-; -C(O)O-; Or -C(O)-;

R ₃ is hydrogen; Halogen atom; C ₁ -C ₁₃ alkyl group; Or a C ₃ -C ₁₀ cyclyl group;

R ₄ is a C ₃ -C ₁₀ aryl group; Or a 5- to 9-membered heteroaryl group containing 1 to 4 heteroatoms selected from boron (B), nitrogen (N), oxygen (O) and sulfur (S) atoms,

In Formula III,

R ₅ is hydrogen; halogen; C ₁ -C ₁₃ alkyl group; Or a C ₃ -C ₁₀ cyclyl group;

R ₆ is a C ₃ -C ₁₀ aryl group; Or a 5- to 9-membered heteroaryl group containing 1 to 4 heteroatoms selected from boron (B), nitrogen (N), oxygen (O) and sulfur (S) atoms,

Each of the C ₁ -C ₁₃ alkyl group or C ₃ -C ₁₀ cyclyl group is hydrogen; Hydroxy group; Halogen group; Carbonyl group (-(C=O)R ₇ R ₈ ); _{A C 1} -C ₃ alkyl group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; _{A C 1} -C ₃ alkoxy group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; C ₆ -C ₁₀ phenoxy; Amino group (-NR ₇ R ₈ ); An amide group (-(C=O)NR ₇ R ₈ ); C ₆ -C ₁₀ aryl group; Including at least one substituent selected from the group consisting of a C ₃ -C ₁₀ heteroaryl group and a C ₃ -C _{10 heterocyclyl group,}

Each of the C ₃ -C ₁₀ aryl group or 5 to 9 membered heteroaryl group is hydrogen; Hydroxy group; Halogen group; Carbonyl group (-(C=O)R ₇ R ₈ ); _{A C 1} -C ₃ alkyl group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; _{A C 1} -C ₃ alkoxy group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; C ₆ -C ₁₀ phenoxy; Amino group (-NR ₇ R ₈ ); An amide group (-(C=O)NR ₇ R ₈ ); C ₆ -C ₁₀ aryl group; Including at least one substituent selected from the group consisting of a C ₃ -C ₁₀ heteroaryl group and a C ₃ -C _{10 heterocyclyl group,}

Each of R ₇ and R ₈ is hydrogen; C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkenyl group; C ₁ -C ₆ alkynyl group; C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; And one or more selected from the group consisting of a _{C 3} -C _{10 heterocyclyl group.}

In Formula I,

X is nitrogen or carbon;

R ₁ is hydrogen; A halogen atom selected from F and Cl; Methyl group; Substituted methyl group; It is a trifluoromethyl group,

The substituted methyl group is a C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; And a C ₃ -C ₁₀ heterocyclyl group; and one or more substituents selected from the group consisting of,

R ₂ is substituted or unsubstituted benzene; Substituted or unsubstituted pyridazine; Substituted or unsubstituted pyrazine; Substituted or unsubstituted imidazole; Substituted or unsubstituted pyrazole; Substituted or unsubstituted furan; Substituted or unsubstituted pyrimidine; Substituted or unsubstituted pyrrole; Substituted or unsubstituted pyridine; Substituted or unsubstituted indole; Substituted or unsubstituted thiazole; It may be a substituted or unsubstituted benzothiazole;

In Formula II,

Y is nitrogen or carbon;

Z is -CH ₂ -or -CO-;

R ₃ is hydrogen or F;

R ₄ is substituted or unsubstituted benzene; Substituted or unsubstituted pyridazine; Substituted or unsubstituted pyrazine; Substituted or unsubstituted imidazole; Substituted or unsubstituted pyrazole; Substituted or unsubstituted furan; Substituted or unsubstituted pyrimidine; Substituted or unsubstituted pyrrole; Substituted or unsubstituted pyridine; Substituted or unsubstituted indole; Substituted or unsubstituted thiazole; It may be a substituted or unsubstituted benzothiazole;

In Formula III,

R ₅ is CH ₃ ;

R ₆ is substituted or unsubstituted benzene; Substituted or unsubstituted pyridazine; Substituted or unsubstituted pyrazine; Substituted or unsubstituted imidazole; Substituted or unsubstituted pyrazole; Substituted or unsubstituted furan; Substituted or unsubstituted pyrimidine; Substituted or unsubstituted pyrrole; Substituted or unsubstituted pyridine; Substituted or unsubstituted indole; Substituted or unsubstituted thiazole; It may be a substituted or unsubstituted benzothiazole;

In one aspect of the present invention, the heteroaryl amide derivative compound represented by Formula I provides a heteroaryl amide derivative compound selected from the group consisting of the following compound numbers 1 to 36:

(Compound No. 1) N- (3-chloro-4-(pyridin-2-ylmethoxy)phenyl)nicotinamide ( 4aa );

(Compound No. 2) N- (3-chloro-4-(pyridin-2-ylmethoxy)phenyl)picolinamide ( 4ab );

(Compound No. 3) N- (3-chloro-4-(pyridin-2-ylmethoxy)phenyl)pyridazine-3-carboxamide ( 4ac );

(Compound No. 4) N- (3-chloro-4-(pyridin-2-ylmethoxy)phenyl)pyridazine-4-carboxamide ( 4ad );

(Compound No. 5) N- (3-chloro-4-(pyridin-2-ylmethoxy)phenyl)pyrazine-2-carboxamide ( 4ae );

(Compound No. 6) N- (3-chloro-4-(pyridin-2-ylmethoxy)phenyl)isonicotinamide ( 4af );

(Compound No. 7) N- (3-chloro-4-((3-fluorobenzyl)oxy)phenyl)nicotinamide ( 4ag );

(Compound No. 8) N- (3-chloro-4-((3-fluorobenzyl)oxy)phenyl)picolinamide ( 4ah );

(Compound No. 9) N- (3-chloro-4-((3-fluorobenzyl)oxy)phenyl)pyridazine-3-carboxamide ( 4ai );

(Compound No. 10) N- (3-chloro-4-((3-fluorobenzyl)oxy)phenyl)pyridazine-4-carboxamide ( 4aj );

(Compound No. 11) N- (3-chloro-4-((3-fluorobenzyl)oxy)phenyl)pyrazine-2-carboxamide ( 4ak );

(Compound No. 12) N- (3-chloro-4-((3-fluorobenzyl)oxy)phenyl)isonicotinamide ( 4al );

(Compound No. 13) N- (3-chloro-4-((4-fluorobenzyl)oxy)phenyl)nicotinamide ( 4am );

(Compound No. 14) N- (3-chloro-4-((4-fluorobenzyl)oxy)phenyl)picolinamide ( 4an );

(Compound No. 15) N- (3-chloro-4-((4-fluorobenzyl)oxy)phenyl)pyridazine-3-carboxamide ( 4ao );

(Compound No. 16) N- (3-chloro-4-((4-fluorobenzyl)oxy)phenyl)pyridazine-4-carboxamide ( 4ap );

(Compound No. 17) N- (3-chloro-4-((4-fluorobenzyl)oxy)phenyl)pyrazine-2-carboxamide ( 4aq );

(Compound No. 18) N- (3-chloro-4-((4-fluorobenzyl)oxy)phenyl)isonicotinamide ( 4ar );

(Compound No. 19) N- (3-chloro-4-((3-chlorobenzyl)oxy)phenyl)pyridazine-4-carboxamide ( 4as );

(Compound No. 20) N- (3-chloro-4-((3-chlorobenzyl)oxy)phenyl)pyrazine-2-carboxamide ( 4at );

(Compound No. 21) N- (3-chloro-4-((3-chlorobenzyl)oxy)phenyl)nicotinamide ( 4au );

(Compound No. 22) N- (3-chloro-4-((4-chlorobenzyl)oxy)phenyl)nicotinamide ( 4av );

(Compound No. 23) N- (3-chloro-4-((4-chlorobenzyl)oxy)phenyl)picolinamide ( 4aw );

(Compound No. 24) N- (3-chloro-4-((4-chlorobenzyl)oxy)phenyl)pyridazine-3-carboxamide ( 4ax );

(Compound No. 25) N- (3-chloro-4-((4-chlorobenzyl)oxy)phenyl)pyridazine-4-carboxamide ( 4ay );

(Compound No. 26) N- (3-chloro-4-((4-chlorobenzyl)oxy)phenyl)pyrazine-2-carboxamide ( 4az );

(Compound No. 27) N- (3-chloro-4-((4-chlorobenzyl)oxy)phenyl)isonicotinamide ( 4ba );

(Compound No. 28) N- (4-(benzyloxy)-3-chlorophenyl)pyridazine-4-carboxamide ( 4bb );

(Compound No. 29) N- (4-(benzyloxy)-3-chlorophenyl)pyrazine-2-carboxamide ( 4bc );

(Compound No. 30) N- (4-(benzyloxy)-3-chlorophenyl)nicotinamide ( 4bd );

(Compound No. 31) N- (3-chloro-4-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridazine-4-carboxamide ( 4be );

(Compound No. 32) N- (3-chloro-4-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyrazine-2-carboxamide ( 4bf );

(Compound No. 33) N- (3-chloro-4-((3-(trifluoromethyl)benzyl)oxy)phenyl)nicotinamide ( 4bg );

(Compound No. 34) N- (3-(chloro-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)pyridazine-4-carboxamide ( 4bh );

(Compound No. 35) N- (3-chloro-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)pyrazine-2-carboxamide ( 4bi ); And

(Compound No. 36) N- (3-chloro-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)nicotinamide ( 4bj ).

In one aspect of the present invention, the heteroaryl amide derivative compound represented by Formula II provides a heteroaryl amide derivative compound selected from the group consisting of the following compound numbers 37 to 45:

(Compound No. 37) N- (1-(4-fluorobenzyl)-1 H -indol-5-yl)pyridazine-4-carboxamide ( 4a );

(Compound No. 38) N- (1-(4-fluorobenzyl)-1 H -indol-5-yl)pyrazine-2-carboxamide ( 4b );

(Compound No. 39) N- (1-(4-fluorobenzyl)-1 H -indol-5-yl)nicotinamide ( 4c );

(Compound No. 40) N- (1-(3-fluorobenzoyl)-1 H -indol-5-yl)pyridazine-4-carboxamide ( 4d );

(Compound No. 41) N- (1-(3-fluorobenzoyl)-1 H -indol-5-yl)pyrazine-2-carboxamide ( 4e );

(Compound No. 42) N- (1-(3-fluorobenzoyl)-1 H -indol-5-yl)nicotinamide ( 4f );

(Compound No. 43) N- (1-(pyridin-2-ylmethyl)-1 H -indol-5-yl)pyridazine-4-carboxamide ( 4g );

(Compound No. 44) N- (1-(pyridin-2-ylmethyl)-1 H -indol-5-yl)pyrazine-2-carboxamide ( 4h ); And

(Compound No. 45) N- (1-(pyridin-2-ylmethyl)-1 H -indol-5-yl)nicotinamide ( 4i ).

In one aspect of the present invention, the heteroaryl amide derivative compound represented by Formula III provides a heteroaryl amide derivative compound selected from the group consisting of the following compound numbers 46 to 48:

(Compound No. 46) N- (1-methyl-1 H -indol-5-yl)pyridazine-4-carboxamide ( 4j );

(Compound No. 47) N- (1-methyl-1 H -indol-5-yl)pyrazine-2-carboxamide ( 4k ); And

(Compound No. 48) N- (1-methyl-1 H -indol-5-yl)nicotinamide ( 4L ).

In the present invention, the term'substitution' refers to the introduction of a hydrogen atom instead of a hydrogen atom when a derivative is formed by replacing one or more hydrogen atoms in an organic compound with another atomic group, and the'substituent' refers to the introduced atomic group.

The substituent is, for example, a halogen atom, a halogen atom, a C ₁ -C ₂₀ alkyl group _{substituted with a halogen atom (eg, CCF 3} , CHCF ₂ , CH ₂ F, CCl _3, etc.), C ₁ -C ₂₀ alkoxy, C ₂ -C ₂₀ alkoxyalkyl, hydroxy group, nitro group, cyano group, amino group, amidino group, hydrazine, hydrazone, carboxyl group or salt thereof, sulfonyl group, sulfamoyl group, sulfonic acid group or salt thereof, phosphoric acid or its Salt, or C ₁ -C ₂₀ alkyl group, C ₂ -C ₂₀ alkenyl group, C ₂ -C ₂₀ alkynyl group, C ₁ -C ₂₀ heteroalkyl group, C ₆ -C ₂₀ aryl group, C ₆ -C ₂₀ arylalkyl group, It may be a C ₆ -C ₂₀ heteroaryl group, a C ₇ -C ₂₀ heteroarylalkyl group, a C ₆ -C ₂₀ heteroaryloxy group, and a C ₆ -C ₂₀ heteroaryloxyalkyl group or a C ₆ -C ₂₀ heteroarylalkyl group. .

In the definition of a substituent in the present invention, the term'alkyl' means an aliphatic hydrocarbon radical. Alkyl may be “saturated alkyl” that does not include an alkenyl or alkynyl moiety, or may be “unsaturated alkyl” that includes at least one alkenyl or alkynyl moiety. “Alkenyl” means a group containing at least one carbon-carbon double bond, and “alkynyl” means a group containing at least one carbon-carbon triple bond. Alkyl, when used alone or in combination, may each be cyclic, branched or straight chain.

The term'aryl', alone or in combination with other radicals, is a carbocyclic containing 6 carbon atoms which may be further fused with a second 5 or 6 membered carbocyclic group which may be aromatic, saturated or unsaturated. It means an aromatic monocyclic group. Examples of aryl include, but are not limited to, phenyl, indanyl, 1-naphthyl, 2-naphthyl, teprahiadronaphthyl, and the like. Aryl can be linked with other groups at appropriate positions on the aromatic ring.

The term'alkoxy' refers to an alkyl group (ie, -O-alkyl) linked to another group through an oxygen atom. The alkoxy group may be unsubstituted or substituted with one or more suitable substituents. Examples of the alkoxy group include (C ₁ -C ₆ ) alkoxy groups such as -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-2-methyl-1-propyl, -O -2-Methyl-2-propyl, -O-2-methyl-1-butyl, -O-3-methyl-1-butyl, -O-2-methyl-3-butyl, -O-2,2-dimethyl -1-propyl, -O-2-methyl-1-pentyl, 3-O-methyl-1-pentyl, -O-4-methyl-1-pentyl, -O-2-methyl-2-pentyl, -O -3-Methyl-2-pentyl, -O-4-methyl-2-pentyl, -O-2,2-dimethyl-1-butyl, -O-3,3-dimethyl-butyl, -O-2-ethyl -1-butyl, -O-butyl, -O-isobutyl, -Ot-butyl, -O-pentyl, -O-isopentyl, -O-neopentyl and -O-hexyl .

The term'phenoxy' refers to a phenyl group (ie, -O-aryl) linked to another group through an oxygen atom. The phenoxy group is unsubstituted or one or more halogens; Alkyl group; It may be substituted with an aryl group and a hetero aryl group, but is not limited thereto.

The term'amino group' refers to an alkyl group (ie -NH- or -N-alkyl) linked to another group through a nitrogen atom. The amine group may be unsubstituted or substituted with one or more suitable substituents. Examples of alkoxy groups include (C1-C6) amino groups such as -NH-methyl, -NH-ethyl, -NH-propyl, -NH-isopropyl, -NH-2-methyl-1-propyl, -NH-2-methyl-2-propyl, -NH-2-methyl-1-butyl, -NH-3-methyl-1-butyl, -NH-2-methyl-3-butyl, -NH-2,2 -Dimethyl-1-propyl, -NH-2-methyl-1-pentyl, 3-NH-methyl-1-pentyl, -NH-4-methyl-1-pentyl, -NH-2-methyl-2-pentyl, -NH-3-methyl-2-pentyl, -NH-4-methyl-2-pentyl, -NH-2,2-dimethyl-1-butyl, -NH-3,3-dimethyl-butyl, -NH-2 -Ethyl-1-butyl, -NH-butyl, -NH-isobutyl, -NH-t-butyl, -NH-pentyl, -NH-isopentyl, -NH-neopentyl, -NH-hexyl, -N, N-dimethyl, -N-methyl-N-ethyl, -N-methyl-N-propyl, -N-methyl-isopropyl, -N-methyl-N-butyl, -N-methyl-N-isobutyl,- N-methyl-N-pentyl, -N-methyl-N-isopentyl, N-methyl-N-hexyl, N-methyl-N-isohexyl, -N,N-diethyl, -N-ethyl-N- Propyl, -N-ethyl-N-isopropyl, -N-ethyl-N-butyl, -N-ethyl-N-isobutyl, -N-ethyl-N-pentyl, -N-ethyl-N-isopentyl, -N-ethyl-N-hexyl, -N-ethyl-N-isohexyl, -N,N-dipropyl, -N-propyl-N-isopropyl, -N-propyl-N-butyl, -N-propyl -N-isobutyl, -N-propyl-N-pentyl, -N-propyl-N-isopentyl, -N-propyl-N-hexyl, -N-propyl-N-isohexyl, -N,N-di Butyl, -N-butyl-N-isobutyl, -N-butyl-N-pentyl, -N-butyl-N-isopentyl, -N-butyl-N-hexyl, -N-butyl-N-isohexyl, -N,N-dipentyl, -N-pentyl-N-hexyl, -N-pentyl-N-isohexyl, -N,N-dihexyl.

The term'halogen atom' refers to an atom of group 7 of the periodic table. Halogen atoms include fluorine (F), chlorine (Cl), bromine (Br), iodine (I), and the like.

The term'carbonyl group' means -(C=O)-, and may be substituted with hydrogen, an alkyl group, an alkoxy group and an amino group, but is not limited thereto.

The term'heterocycle group', unless otherwise stated, refers to a heteroaromatic compound containing at least one hetero atom selected from the group consisting of N, O, and S. Preferably, the heterocyclyl group may include a pyrrolidine, a furan group, a morpholine group, a piperazine and a piperidine group, more preferably a pyrrolidine group, a piperidine group, a piperazine group, and a mole It may include a foreign group, but is not limited thereto.

The term'heteroaryl group', unless otherwise stated, refers to a heteroaromatic compound containing at least one hetero atom selected from the group consisting of N, O, and S. Preferably, the heteroaryl group is a pyridine group, a pyrazine group, a pyrimidine group, a pyridazine group, a pyrazole group, an imidazole group, a triazole group, an indole group, an oxadiazole group, a thiadiazole group, a quinoline, an isoquinoline group, It may include an isoxazole group, an oxazole group, a thiazole group, and a pyrrole group, but is not limited thereto.

The term'derivative' refers to a compound obtained by substituting a part of the structure of the compound with another atom or group of atoms.

The term'stereoisomer' refers to a compound having the same molecular formula and connection method of members, but different spatial arrangements between atoms. The stereoisomer may be a diasteromer or an enantiomer. The enantiomer refers to an isomer that does not overlap with the mirror image, such as the relationship between the left hand and the right hand, and is also called an optical isomer. Enantiomers are classified into R (Rectus: clockwise) and S (sinister: counterclockwise) when four or more substituents are different on the chiral central carbon. Diastereoisomers refer to stereoisomers that are not in an enantiomeric relationship, and can be divided into cis-trans isomers due to differences in the spatial arrangement of atoms.

Specific examples of the preferred heteroaryl amide derivative compound as the compound represented by Formula I according to the present invention are as follows:

[Compound No. 1: N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)nicotinamide ];

[Compound No. 2: N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)picolinamide ];

[Compound No. 3: N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)pyridazine-3-carboxamide ];

[Compound No. 4: N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)pyridazine-4-carboxamide ];

[Compound No. 5: N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)pyrazine-2-carboxamide ];

[Compound No. 6: N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)isonicotinamide ];

[Compound No. 7: N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)nicotinamide ];

[Compound No. 8: N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)picolinamide ];

[Compound No. 9: N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)pyridazine-3-carboxamide ];

[Compound No. 10: N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)pyridazine-4-carboxamide ];

[Compound No. 11: N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)pyrazine-2-carboxamide ];

[Compound No. 12: N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)isonicotinamide ];

[Compound No. 13: N-(3-chloro-4-((4-fluorobenzyl)oxy)phenyl)nicotinamide ];

[Compound No. 14: N-(3-chloro-4-((4-fluorobenzyl)oxy)phenyl)picolinamide ];

[Compound No. 15: N-(3-chloro-4-((4-fluorobenzyl)oxy)phenyl)pyridazine-3-carboxamide ];

[Compound No. 16: N-(3-chloro-4-((4-fluorobenzyl)oxy)phenyl)pyridazine-4-carboxamide ];

[Compound No. 17: N-(3-chloro-4-((4-fluorobenzyl)oxy)phenyl)pyrazine-2-carboxamide ];

[Compound No. 18: N-(3-chloro-4-((4-fluorobenzyl)oxy)phenyl)isonicotinamide ];

[Compound No. 19: N-(3-chloro-4-((3-chlorobenzyl)oxy)phenyl)pyridazine-4-carboxamide ];

[Compound No. 20: N-(3-chloro-4-((3-chlorobenzyl)oxy)phenyl)pyrazine-2-carboxamide ];

[Compound No. 21: N-(3-chloro-4-((3-chlorobenzyl)oxy)phenyl)nicotinamide ];

[Compound No. 22: N-(3-chloro-4-((4-chlorobenzyl)oxy)phenyl)nicotinamide ];

[Compound No. 23: N-(3-chloro-4-((4-chlorobenzyl)oxy)phenyl)picolinamide ];

[Compound No. 24: N-(3-chloro-4-((4-chlorobenzyl)oxy)phenyl)pyridazine-3-carboxamide ];

[Compound No. 25: N-(3-chloro-4-((4-chlorobenzyl)oxy)phenyl)pyridazine-4-carboxamide ];

[Compound No. 26: N-(3-chloro-4-((4-chlorobenzyl)oxy)phenyl)pyrazine-2-carboxamide ];

[Compound No. 27: N-(3-chloro-4-((4-chlorobenzyl)oxy)phenyl)isonicotinamide ];

[Compound No. 28: N-(4-(benzyloxy)-3-chlorophenyl)pyridazine-4-carboxamide ];

[Compound No. 29: N-(4-(benzyloxy)-3-chlorophenyl)pyrazine-2-carboxamide ];

[Compound No. 30: N-(4-(benzyloxy)-3-chlorophenyl)nicotinamide ];

[Compound No. 31: N-(3-chloro-4-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridazine-4-carboxamide ];

[Compound No. 32: N-(3-chloro-4-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyrazine-2-carboxamide ];

[Compound No. 33: N-(3-chloro-4-((3-(trifluoromethyl)benzyl)oxy)phenyl)nicotinamide ];

[Compound No. 34: N-(3-(chloro-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)pyridazine-4-carboxamide ];

[Compound No. 35: N-(3-chloro-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)pyrazine-2-carboxamide ];

[Compound No. 36: N-(3-chloro-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)nicotinamide ];

.

.

Specific examples of the preferred heteroaryl amide derivative compound as the compound represented by Formula II according to the present invention are as follows:

[Compound No. 37: N-(1-(4-fluorobenzyl)-1H-indol-5-yl)pyridazine-4-carboxamide ];

[Compound No. 38: N-(1-(4-fluorobenzyl)-1H-indol-5-yl)pyrazine-2-carboxamide ];

[Compound No. 39: N-(1-(4-fluorobenzyl)-1H-indol-5-yl)nicotinamide ];

[Compound No. 40: N-(1-(3-fluorobenzoyl)-1H-indol-5-yl)pyridazine-4-carboxamide ];

[Compound No. 41: N-(1-(3-fluorobenzoyl)-1H-indol-5-yl)pyrazine-2-carboxamide ];

[Compound No. 42: N-(1-(3-fluorobenzoyl)-1H-indol-5-yl)nicotinamide ];

[Compound No. 43: N-(1-(pyridin-2-ylmethyl)-1H-indol-5-yl)pyridazine-4-carboxamide ];

[Compound No. 44: N-(1-(pyridin-2-ylmethyl)-1H-indol-5-yl)pyrazine-2-carboxamide ];

[Compound No. 45: N-(1-(pyridin-2-ylmethyl)-1H-indol-5-yl)nicotinamide ];

.

.

Specific examples of the preferred heteroaryl amide derivative compound as the compound represented by Formula III according to the present invention are as follows:

[Compound No. 46: N-(1-methyl-1H-indol-5-yl)pyridazine-4-carboxamide ];

[Compound No. 47: N-(1-methyl-1H-indol-5-yl)pyrazine-2-carboxamide ];

[Compound No. 48: N-(1-methyl-1H-indol-5-yl)nicotinamide ];

.

.

The heteroaryl amide derivative compound represented by Formula I, Formula II, or Formula III according to the present invention may be used in the form of a pharmaceutically acceptable salt derived from an inorganic or organic acid, and preferred salts include hydrochloric acid, hydrobromic acid, and sulfuric acid. , Phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid , Hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, and may be one or more selected from the group consisting of toluenesulfonic acid.

The heteroaryl amide derivative compound represented by Formula I, Formula II, or Formula III according to the present invention or a pharmaceutically acceptable salt thereof may include hydrates and solvates. The hydrate may mean that a compound of Formula I, Formula II, or Formula III is formed by bonding with a water molecule.

Another aspect of the present invention includes a compound selected from a heteroaryl amide derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof, which is any one of the compounds represented by Formulas I to III according to the present invention as an active ingredient. It provides a pharmaceutical composition for preventing, alleviating or treating neurodegenerative diseases.

The pharmaceutical composition according to the present invention has excellent activity to inhibit monoamine oxidase B (MAO-B).

In the present invention, the term "monoamine oxidase (MAO)" is an enzyme that causes an oxidative deamination reaction of neurotransmitters such as dopamine, serotonin, adrenaline, noradrenaline, and non-biocomponent amines, and MAO-A and There are two types of MAO-B. Neurodegenerative diseases caused by Alzheimer's disease and Parkinson's disease are caused by oxidative stress caused by hydrogen peroxide due to increased MAO activity, and MAO-B inhibitors reduce oxygen radical formation and increase the amount of useful monoamines in the brain. I can make it. In addition, in brain diseases including Alzheimer's disease and brain injury, MAO-B promotes the process of metabolism of putrescine in reactive astrocytes, resulting in the production of excess GABA. Therefore, MAO-B inhibitors act as inhibitors of GABA production by astrocytes and have the effect of restoring nerve signal transduction and brain function.

Therefore, the pharmaceutical composition of the present invention is excellent in inhibiting MAO-B activity, and thus can be used for the purpose of treating, preventing and alleviating neurodegenerative diseases. Neurodegenerative diseases that can be prevented, treated or alleviated by the treatment of the pharmaceutical composition of the present invention include Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), Lou Gehrig's disease ( amyotrophic lateral sclerosis (ALS), fronto-temporal dementia, cortical-basal ganglia degeneration, and progressive supranuclear palsy (PSP). .

In the present invention, the inhibition of MAO-B may be inhibition of MAO-B activity or inhibition of biosynthesis of MAO-B. Inhibition of MAO-B activity may be reversible inhibition or irreversible inhibition. Inhibition of MAO-B activity can be selective inhibition or non-selective inhibition. Preferably, a heteroaryl amide derivative compound represented by Formula I, Formula II, or Formula III, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a stereoisomer thereof may reversibly and selectively inhibit MAO-B activity. have.

In one embodiment of the present invention, as a result of evaluating the inhibitory activity against MAO-B of a novel heteroaryl amide derivative compound designed as an inhibitor that inhibits the activity of MAO-B, the remarkable inhibitory activity against MAO-A is While not showing, it was confirmed that selectively exhibiting excellent inhibitory efficacy for MAO-B (Experimental Example 1).

As described above, the novel heteroaryl amide derivative compound according to the present invention has a high inhibitory activity against the MAO-B enzyme as a selective inhibitor of MAO-B activity, so it has been demonstrated that it can be used as a composition for the treatment of neurodegenerative diseases. I did.

The pharmaceutical composition may be applied to laboratory animals such as mice, rabbits, rats, guinea pigs, or hamsters, or primates including humans, but is not limited thereto, and may be preferably applied to primates including humans, more preferably humans.

In the present specification,'treatment' refers to relief or improvement of symptoms, reduction of the range of the disease, delay or alleviation of disease progression, improvement, alleviation or stabilization, partial or complete recovery, prolongation of survival, and other beneficial treatment results, etc. It can be used in a sense that includes all of.

The heteroaryl amide derivative compound represented by Formula I, Formula II, or Formula III, which is an active ingredient according to the use mode and method of use of the pharmaceutical composition of the present invention, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof The content of the compound selected from may be appropriately adjusted and used according to the choice of a person skilled in the art.

In one example, the pharmaceutical composition is 0.1 to the total weight of the compound selected from the heteroaryl amide derivative compound represented by Formula I, Formula II, or Formula III, pharmaceutically acceptable salts thereof, hydrates thereof, and stereoisomers thereof. It may be included in an amount of 10% by weight, more preferably 0.5 to 5% by weight.

A compound selected from the heteroaryl amide derivative compound represented by Formula I, Formula II, or Formula III, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof may be included alone in the pharmaceutical composition, or else It may also be included with a pharmacologically acceptable carrier, excipient, diluent or accessory ingredient.

Examples of the pharmaceutically acceptable carrier, excipient or diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, propylhydroxybenzoate, talc, magnesium stearate and mineral oil , Dextrin, calcium carbonate, propylene glycol, liquid paraffin, and one or more selected from the group consisting of physiological saline, but are not limited thereto, and conventional carriers, excipients, or diluents may all be used. In addition, the pharmaceutical composition may include conventional fillers, extenders, binders, disintegrants, anti-aggregating agents, lubricants, wetting agents, pH adjusters, nutrients, vitamins, electrolytes, alginic acid and salts thereof, pectic acid and salts thereof, protective colloids, glycerin , Fragrances, emulsifiers or preservatives, etc. may additionally be included.

A compound selected from a heteroarylamide derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof, which is any one of the compounds represented by the following Formulas I to III according to the present invention, is another compound for treating neurodegenerative diseases. By co-administration with an MAO-B inhibitor, the therapeutic effect of the MAO-B selective inhibitor can be enhanced.

Specifically, the pharmaceutical composition may further include one or more other MAO-B inhibitors or other therapeutic agents known to be effective in the treatment or prevention of neurodegenerative diseases in addition to the active ingredient, and can be used as a combination therapy applied at the same time or at the same time. . Other MAO-B inhibitors or other therapeutic agents that can be applied to the combination therapy include, for example, selegiline, rasagiline, safinamide, tacrine, and donepezil. , Galantamine (galantamine), rivastigmine (rivastigmine), may include one or more compounds selected from the group consisting of memantine (memantine), but is not limited thereto.

The method of administering the pharmaceutical composition may be oral or parenteral, and as an example, it may be administered through various routes including oral, transdermal, subcutaneous, intravenous, intramuscular, or intracerebroventricular injection. In addition, the formulation of the composition may vary depending on the method of use, and is formulated using a method well known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal. Can be. In general, solid preparations for oral administration include tablets, pills, soft or hard capsules (CAPSULES), pills (PILLS), powders (POWDERS), and granules (GRANULES), and such preparations include one or more. For example, it may be prepared by mixing starch, calcium carbonate, sucrose or lactose, gelatin, and the like. In addition, in addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral use include suspensions (SUSTESIONS), solvents, emulsions (EMULSIONS), and syrups (SYRUPS). In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, Sweeteners, fragrances, preservatives, and the like may be included. Forms for parenteral administration are Cream, Lotions, Ointments, PLASTERS, LIQUIDS AND SOULTIONS, Aerosols, FRUIDEXTRACTS, Elixir. It may be in the form of (ELIXIR), INFUSIONS, SACHET, PATCH, or INJECTIONS, and preferably in the form of an isotonic aqueous solution or suspension in the case of a formulation for injection. .

The pharmaceutical composition may further contain adjuvants such as sterilizers, preservatives, stabilizers, hydrating agents or emulsification accelerators, salts and/or buffers for controlling osmotic pressure, and other therapeutically useful substances, and conventional mixing and granulation Alternatively, it may be formulated according to a coating method, and in addition, it may be formulated using a suitable method known in the art.

In addition, the dosage of the pharmaceutical composition can be determined in consideration of the method of administration, the age, sex of the taker, the severity of the patient, the condition, the absorption of the active ingredient in the body, the inactivation rate, and the drug to be used together, and can be determined once or several times. Can be administered separately. As an active ingredient of the pharmaceutical composition, it is preferably administered orally or parenterally to mammals including humans in an amount of 0.001 to 100 mg/kg body weight, preferably 0.01 to 35 mg/kg body weight, once a day or divided. It can be administered by the old route.

Another embodiment of the present invention is a therapeutically effective amount of a compound selected from a heteroarylamide derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof, which is any one of the compounds represented by the following Formulas I to III. It provides a method of treating a neurodegenerative disease, comprising the step of administering by the method.

Preferably, the treatment method may further include the step of identifying a patient in need of prevention or treatment of the neurodegenerative disease prior to the administration step.

The "therapeutically effective amount" of the present invention refers to an amount of an active ingredient for mammals that is effective in preventing or treating neurodegenerative diseases, and the therapeutically effective amount is the type of disease, the severity of the disease, the active ingredient contained in the composition, and Controls according to various factors including the type and content of other ingredients, the type of formulation and the patient's age, weight, general health status, sex and diet, administration time, route of administration and blood clearance of the composition, duration of treatment, and drugs used simultaneously However, preferably, as described above, in an amount of 0.001 to 100 mg/kg body weight, preferably 0.01 to 35 mg/kg body weight per day, once a day or divided into oral or parenteral routes Can be administered as.

The novel heteroaryl amide derivative compound according to the present invention, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a compound selected from stereoisomers thereof reversibly and selectively inhibits MAO-B, thereby effectively suppressing neurodegenerative brain disease and having side effects. Less can be prevented or cured.

Another aspect of the present invention is a compound selected from a heteroaryl amide derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof, which is any one of the compounds represented by Formulas I to III according to the present invention as an active ingredient. It provides a functional food for preventing or improving neurodegenerative diseases, including.

The health functional food is a food that emphasizes the biological regulation function of food, and is a food that has added value to act and express it for a specific purpose using physical, biochemical, and bioengineering methods. Ingredients of these health functional foods are designed and processed to sufficiently exert the body's control functions related to body defense, regulation of body rhythm, prevention and recovery of diseases to the living body, and food supplementary additives, sweeteners, or functional foods acceptable as food. It may contain raw materials.

When a compound selected from the heteroarylamide derivative compound of the present invention, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof is used as a health functional food (or a health functional beverage additive), the compound is added as it is or other food or It can be used together with food ingredients, and can be appropriately used according to a conventional method. The mixing amount of the compound may be appropriately determined according to the purpose of use (prevention, health or improvement, therapeutic treatment).

The health functional foods include various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavors and natural flavors, coloring agents and enhancers (cheese, chocolate, etc.), pectic acid and its salts, organic acids, protective colloidal growth. It may contain an agent, a pH adjuster, a stabilizer, a preservative, glycerin, alcohol, a carbonating agent used in carbonated drinks, and the like. In addition, the health functional food of the present invention may contain pulp for the manufacture of fruit and vegetable beverages. These components may be used alone or in combination, and the proportion of these additives is generally selected in the range of 0.001 to 50 parts by weight per total weight of the composition.

There is no particular limitation on the kind of the health functional food. Foods to which the above compounds can be added include sausages, meats, bread, chocolates, snacks, candies, confectionery, ramen, pizza, other noodles, gums, dairy products including ice cream, various soups, beverages, tea, drinks, alcohol Beverages and vitamin complexes. When formulated as a beverage, the liquid component added in addition to the novel lactic acid bacteria is not limited thereto, but may contain various flavoring agents or natural carbohydrates as an additional component, such as a conventional beverage. The natural carbohydrates described above are monosaccharides (e.g., glucose, fructose, etc.), disaccharides (e.g., maltose, sucrose, etc.) and polysaccharides (e.g., conventional sugars such as dextrin, cyclodextrin, etc.), and xylitol, sorbitol. And sugar alcohols such as erythritol.

Another aspect of the present invention, as shown in the following [Scheme 1],

Preparing a compound represented by [Formula 2a] by reacting a compound represented by [Formula 1a] with a benzyl bromide derivative and 2-(chloromethyl)pyridine hydrochloride (Step a);

Reducing the compound represented by [Chemical Formula 2a] prepared in step a to prepare a compound represented by [Chemical Formula 3a] (step b); And

A heteroaryl amide derivative represented by Formula I including the step of reacting the compound represented by [Formula 3a] prepared in step b with a benzoic acid derivative to prepare a compound represented by [Formula I] (step c); A method for preparing a compound selected from a compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof is provided:

(In Scheme 1,

X, R ₁ and R ₂ are as defined in Formula I of claim 1.)

The manufacturing method of the present invention shown in [Scheme 1] will be described in more detail for each step as follows.

Step a

In the step a according to the present invention, a compound represented by [Formula 1a] as a starting material is reacted with a benzyl bromide derivative and 2-(chloromethyl)pyridine hydrochloride in a base and a solvent to prepare a compound represented by [Formula 2a] It is a step to do.

The compound represented by [Chemical Formula 1a] as the starting material may be commercially available.

Specifically, heating at 95° C. using a N , N -dimethylformamide solvent in the presence of a potassium carbonate base or reaction at 135° C. using a microwave to obtain a compound represented by [Chemical Formula 2a].

Step b

Step b according to the present invention is a step of preparing a compound represented by [Chemical Formula 3a] in the presence of a solvent and a catalyst from the compound represented by [Chemical Formula 2a] as a starting material.

Specifically, the compound represented by [Chemical Formula 3a] was dissolved in ethanol and water, iron powder and ammonium chloride were added, and heated to reflux for 1 hour to obtain a compound represented by [Chemical Formula 3a].

Step c

Step c according to the present invention is a step of preparing a compound represented by [Chemical Formula I] by reacting a compound represented by [Chemical Formula 3a] as a starting material with a benzoic acid derivative under a base, HATU and a solvent.

Specifically, the compound represented by [Chemical Formula 3a] was added to tetrahydrofuran, and the benzoic acid derivative was added in the presence of HATU and N , N -diisopropylethylamine base, and then 45 minutes at 116° C. using a microwave. During the reaction, compounds represented by [Chemical Formula I] (Compound Nos. 1 to 36) were obtained.

The reactions of steps a, b, and c are generally widely known in the field of organic chemistry, and reaction conditions such as a reaction solvent, reaction temperature, and reaction time may be appropriately selected in consideration of a reaction substance and a product.

The compound prepared through the preparation method of [Reaction Scheme 1] may be subjected to a general separation and purification process, for example, diluted and washed with an organic solvent, and then the organic layer may be concentrated under reduced pressure, and, if necessary, may be purified by column chromatography.

Another aspect of the present invention, as shown in the following [Scheme 2],

Reacting a compound represented by [Formula 1b] with a benzyl bromide derivative and a benzoyl chloride derivative to prepare a compound represented by [Formula 2b] (step d);

Preparing a compound represented by [Chemical Formula 3b] by reducing the compound represented by [Chemical Formula 2b] prepared in Step d (Step e); And

A heteroaryl amide derivative represented by Formula II including the step of preparing a compound represented by [Formula II] by reacting the compound represented by [Formula 3b] prepared in Step e with a benzoic acid derivative (Step f); A method for preparing a compound selected from a compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof is provided:

(In Scheme 2,

Y, Z, R ₃ and R ₄ are as defined in Formula II of claim 1.)

The manufacturing method of the present invention shown in [Scheme 2] will be described in more detail for each step as follows.

Step d

Step d according to the present invention is a step of preparing a compound represented by [Formula 2b] by reacting a compound represented by [Formula 1b] as a starting material with a benzyl bromide derivative or a benzoyl chloride derivative in a base and a solvent.

The compound represented by [Chemical Formula 1b] as the starting material may be commercially available.

Specifically, the mixture was stirred at room temperature or 100°C in an N , N -dimethylformamide solvent in the presence of a NaH base to obtain a compound represented by [Chemical Formula 2b].

Step e

The step e according to the present invention is a step of preparing a compound represented by [Chemical Formula 3b] in the presence of a solvent and a catalyst from the compound represented by [Chemical Formula 2b] as a starting material.

Specifically, the compound represented by [Chemical Formula 2b] was dissolved in ethanol and water, iron powder and ammonium chloride were added, and heated to reflux for 1 hour to obtain a compound represented by [Chemical Formula 3b].

Step f

The step f according to the present invention is a step of preparing a compound represented by [Chemical Formula II] by reacting a compound represented by [Chemical Formula 3b] as a starting material with a benzoic acid derivative under a base, HATU, and a solvent.

Specifically, the compound represented by [Chemical Formula 3b] was added to tetrahydrofuran, and the benzoic acid derivative was added in the presence of HATU and N , N -diisopropylethylamine base, and then 45 minutes at 116° C. using a microwave. During the reaction, a compound represented by [Chemical Formula II] (Compound Nos. 37 to 45) was obtained.

The reactions of steps d, e, and f are generally widely known in the field of organic chemistry, and reaction conditions such as a reaction solvent, reaction temperature, and reaction time may be appropriately selected in consideration of a reaction substance and a product.

The compound prepared through the preparation method of [Reaction Scheme 2] may be subjected to a general separation and purification process, such as diluting and washing with an organic solvent, and then the organic layer may be concentrated under reduced pressure, and, if necessary, may be purified by column chromatography.

Another aspect of the present invention, as shown in the following [Scheme 3],

Reacting a compound represented by [Chemical Formula 1b] with dimethyl carbonate to prepare a compound represented by [Chemical Formula 2c] (step g);

Reducing the compound represented by [Chemical Formula 2c] prepared in step g to prepare a compound represented by [Chemical Formula 3c] (step h); And

A heteroaryl amide derivative represented by Formula III including the step of preparing a compound represented by [Formula III] by reacting the compound represented by [Formula 3c] prepared in Step h with a benzoic acid derivative (Step i); A method for preparing a compound selected from a compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof is provided:

(In Reaction Scheme 3,

R ₅ and R ₆ are as defined in Formula III of claim 1.)

The manufacturing method of the present invention shown in [Scheme 3] will be described in more detail for each step as follows.

Step g

Step g according to the present invention is a step of preparing a compound represented by [Chemical Formula 2c] by reacting a compound represented by [Chemical Formula 1b] as a starting material with dimethyl carbonate in a base and a solvent.

The compound represented by [Chemical Formula 1b] as the starting material may be commercially available.

Specifically, heating and refluxing for 3 hours in an N , N -dimethylformamide solvent in the presence of a potassium carbonate base to obtain a compound represented by [Chemical Formula 2c].

Step h

The step h according to the present invention is a step of preparing a compound represented by [Chemical Formula 3c] in the presence of a solvent and a catalyst from the compound represented by [Chemical Formula 2c] as a starting material.

Specifically, the compound represented by [Chemical Formula 2c] was dissolved in ethanol and water, iron powder and ammonium chloride were added, and heated to reflux for 1 hour to obtain a compound represented by [Chemical Formula 3c].

Step i

Step i according to the present invention is a step of preparing a compound represented by [Chemical Formula III] by reacting a compound represented by [Chemical Formula 3c] as a starting material with a benzoic acid derivative under a base, HATU and a solvent.

Specifically, the compound represented by [Chemical Formula 3c] was added to tetrahydrofuran, and the benzoic acid derivative was added in the presence of HATU and N , N -diisopropylethylamine base, and then 45 minutes at 116° C. using a microwave. During the reaction, a compound represented by [Chemical Formula III] (Compound Nos. 46 to 48) was obtained.

The reactions of the steps g, h and i are generally widely known in the field of organic chemistry, and reaction conditions such as a reaction solvent, reaction temperature, and reaction time may be appropriately selected in consideration of a reaction substance and a product.

The compound prepared through the preparation method of [Reaction Scheme 3] may be subjected to a general separation and purification process, such as diluting and washing with an organic solvent, and then concentrating the organic layer under reduced pressure, and, if necessary, purified by column chromatography.

Hereinafter, the present invention will be described in more detail through examples and experimental examples. However, the following examples, formulation examples, and experimental examples are merely illustrative of the present invention, and the contents of the present invention are not limited by the following examples. It will be apparent to those of ordinary skill in the art that various changes and modifications are possible within the scope of the present invention and the scope of the technical idea.

In addition, those of ordinary skill in the technical field to which the present invention pertains can prepare the target compound by various methods based on the structures of Formulas 1 to 3, and all of these methods are included in the scope of the present invention. It must be interpreted. That is, the compound of the present invention can be prepared by arbitrarily combining the synthesis methods specifically described in the following examples or various synthesis methods disclosed in the prior art, which is understood to be within the scope of the present invention, and the preparation of the compound of the present invention The method is not limited by the specific examples below.

[Example] Synthesis of MAO-B inhibitory compound

Example 1: N -(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)nicotinamide (4aa)

Step a: Preparation of 2-((2-chloro-4-nitrophenoxy)methyl)pyridine ( 2a )

Commercially available 2-chloro-4-nitrophenol (1.0 mmol, 173.6 mg) was dissolved in N , N -dimethylformamide (10 mL), and potassium carbonate (2.0 mmol, 276.4 mg) was added. A solution of 2-(chloromethyl)pyridine hydrochloride (1.0 mmol, 164.0 mg) in N, N -dimethylformamide (6 ml) was slowly added to the solution in which the starting material and base were dissolved, and then overnight at 95°C. Stirred. After the reaction was completed, the mixture was extracted with ethyl acetate, water and brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to obtain the target compound in a yield of 63%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.38 (s, 2H), 7.09 (d, J = 16.3 Hz, 1H), 7.27-7.30 (m, 1H), 7.60 (d, J = 7.8 Hz, 1H) , 7.78 (td, J = 1.4 Hz, 7.8 Hz, 1H), 8.14 (dd, J = 2.7 Hz, 9.1 Hz, 1H), 8.33 (d, J = 2.6 Hz, 1H), 8.61 (d, J = 4.6 Hz, 1H).

Step b: Preparation of 3-chloro-4-(pyridin-2-ylmethoxy)aniline ( 3a )

Compound 2a (1.0 mmol, 264.7 mg) was dissolved in ethanol (50 mL) and water (20 mL), and then ammonium chloride (5.0 mmol, 267.5 mg) and iron powder (10.0 mmol, 558.5 mg) were added. Thereafter, the mixture was heated to reflux for an hour, and after the reaction was terminated, iron powder was filtered using celite. The filtrate from which the iron powder was filtered was evaporated under reduced pressure, and extracted using ethyl acetate, water, and an aqueous sodium hydrogen carbonate solution. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and impurities were removed through column chromatography to obtain the target compound in a yield of 56%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 4.95 (s, 2H), 5.08 (s, 2H), 6.47 (dd, J = 2.1 Hz, 8.7 Hz, 1H), 6.67 (d, J = 2.1 Hz , 1H), 6.92 (d, J = 8.7 Hz, 1H), 7.34 (t, J = 5.8 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.85 (t, J = 7.3 Hz, 1H ), 8.56 (d, J = 4.2 Hz, 1H).

Step c: N Preparation of -(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)nicotinamide ( 4aa )

Compound 3a (0.1 mmol, 23.5 mg), HATU (0.11 mmol, 41.8 mg), N , N -diisopropylethylamine (0.27 mmol, 0.05 mL), and nicotinic acid (0.11 mmol, 13.5 mg) were tetra- A solution dissolved in hydrofuran (12 ml) was added and reacted at 116° C. for 45 minutes using a microwave. After the reaction was completed, the mixture was extracted using ethyl acetate, water and brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Impurities were removed using column chromatography to obtain the target compound in a yield of 53%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 5.29 (s, 2H), 7.27 (d, J = 8.8 Hz, 1H), 7.37 (t, J = 5.7 Hz, 1H), 7.58 (d, J = 7.4 Hz, 2H), 7.65 (d, J = 8.6 Hz, 1H), 7.89 (t, J = 6.8 Hz, 1H), 7.99 (s, 1H), 8.29 (d, J = 7.6 Hz, 1H), 8.60 (d, J = 3.8 Hz, 1H), 8.77 (d, J = 3.8 Hz, 1H), 9.11 (s, 1H), 10.47 (s, 1H).

Hereinafter, a heteroaryl amide compound was synthesized in the same manner as in Example 1, and its structure and ¹ H NMR data are shown in Table 1 below.

Example 37: N -(1-(4-fluorobenzyl)-1 H -Indole-5-yl)pyridazine-4-carboxamide (4a)

Step d: 1-(4-fluorobenzyl)5-nitro-1 H -Manufacturing of indole ( 2Ba )

Commercially available starting material 5-nitro-1 H -indole (1.0 mmol, 162.2 mg) was dissolved in N , N -dimethylformamide (11 ml) and sodium hydride (60% in oil, 1.2 mmol, 48.0 mg) ) Was put under the conditions of 0°C and stirred for 10 minutes. 4-fluorobenzyl bromide (1.0 mmol, 0.12 ml) was added to the solution containing the starting material and stirred at room temperature for 30 minutes. After the reaction was completed, extraction was performed using ethyl acetate, water, and an aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and impurities were removed using column chromatography to obtain the target compound in a yield of 91%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.34 (s, 2H), 6.74 (s, 1H), 7.03 (d, J = 8.1 Hz, 2H), 7.08 (s, 2H), 7.28 (d, J = 10.6 Hz, 2H), 8.08 (d, J = 8.6 Hz, 1H), 8.60 (s, 1H).

Step e: 1-(4-fluorobenzyl)-1 H -Preparation of indole-5-amine ( 3Ba )

Compound 2Ba (1.0 mmol, 270.3 mg) was dissolved in ethanol (50 ml) and water (20 ml), ammonium chloride (5.0 mmol, 267.5 mg) and iron powder (10.0 mmol, 558.5 mg) were added, and the mixture was added for 1 hour. It was heated to reflux for a while. After the reaction was completed, iron powder was filtered using Celite. The filtrate from which the iron powder was filtered was evaporated under reduced pressure, and extracted using ethyl acetate, water, and an aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and impurities were removed using column chromatography to obtain the target compound in a yield of 80%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 4.49 (s, 2H), 5.27 (s, 2H), 6.18 (d, J = 2.8 Hz, 1H), 6.49 (dd, J = 1.8 Hz, 8.6 Hz , 1H), 6.69 (d, J = 1.6 Hz, 1H), 7.12 (t, J = 9.0 Hz, 3H), 7.20 (t, J = 8.5 Hz, 2H), 7.28 (d, J = 3.0 Hz, 1H ).

Step f: N -(1-(4-fluorobenzyl)-1 H Preparation of -indol-5-yl)pyridazine-4-carboxamide ( 4a )

In a microwave vial, compound 3Ba (0.1 mmol, 24 mg), HATU (0.11 mmol, 41.8 mg), N , N -diisopropylethylamine (0.27 mmol, 0.05 mL), pyridazine-4-carboxylic acid (0.11 mmol, 13.7 mg) was dissolved in tetrahydrofuran (12 ml) and reacted at 116° C. for 45 minutes using a microwave. After the reaction was completed, extraction was performed using ethyl acetate, water and brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and impurities were removed using column chromatography to obtain the target compound in a yield of 46%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 5.42 (s, 2H), 6.52 (d, J = 2.6 Hz, 1H), 7.15 (t, J = 8.8 Hz, 2H), 7.26 (t, J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.6 Hz, 1H), 7.54 (d, J = 2.8 Hz, 1H), 8.04 (s, 1H), 8.13 (d, J = 2.9 Hz, 1H), 10.59 (s, 1H).

Hereinafter, a heteroaryl amide compound was synthesized in the same manner as in Example 37, and its structure and ¹ H NMR data are shown in Table 2 below.

Example 46: N -(1-methyl-1 H -Indole-5-yl)pyridazine-4-carboxamide (4j)

Step g: 1-methyl-5-nitro-1 H -Manufacturing of indole ( 2Cd )

A commercially available starting material 5-nitro-1 H -indole (1.0 mmol, 162.2 mg) was dissolved in N,N-dimethylformamide (5 ml), and potassium carbonate (0.24 mmol, 55.3 mg) was added. Dimethyl carbonate (2.0 mmol, 0.17 ml) was added to the mixture and heated to reflux for 3 hours. After the reaction was completed, the temperature was lowered to 4-5°C, and ice water was added to the reaction solution. The obtained solid was filtered and washed with water to obtain the target compound in a yield of 83%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.85 (s, 3H), 6.66 (d, J = 2.8 Hz, 1H), 7.21 (d, J = 2.9 Hz, 1H), 7.33 (d, J = 9.0 Hz , 1H), 8.11 (d, J = 9.0 Hz, 1H), 8.57 (s, 1H).

Step h: 1-methyl-1 H -Preparation of indole-5-amine ( 3Cd )

Compound 2Cd (1.0 mmol, 176.2 mg) was dissolved in ethanol (50 ml) and water (20 ml), ammonium chloride (5.0 mmol, 267.5 mg) and iron powder (10.0 mmol, 558.5 mg) were added, and the mixture was added for 1 hour. It was heated to reflux for a while. After the reaction was completed, iron powder was filtered using Celite. The filtrate from which iron powder was filtered was evaporated under reduced pressure, and extracted using ethyl acetate, water, and an aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. Impurities were removed using column chromatography to obtain the target compound in a yield of 78%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 3.68 (s, 3H), 4.48 (s, 2H), 6.12 (d, J = 2.7 Hz, 1H), 6.56 (dd, J = 2.0 Hz, 8.6 Hz , 1H), 6.70 (d, J = 1.8 Hz, 1H), 7.09-7.12 (m, 2H).

Step i: N -(1-methyl-1 H Preparation of -indol-5-yl)pyridazine-4-carboxamide ( 4j )

In a microwave vial, compound 3Cd (0.1 mmol, 14.6 mg), HATU (0.11 mmol, 41.8 mg), N , N -diisopropylethylamine (0.27 mmol, 0.05 mL), pyridazine-4-carboxylic acid (0.11 mmol, 13.7 mg) was dissolved in tetrahydrofuran (12 ml) and reacted at 116° C. for 45 minutes using a microwave. After the reaction was completed, extraction was performed using ethyl acetate, water and brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. Impurities were removed using column chromatography to obtain the target compound in a yield of 28%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 3.81 (s, 3H), 7.36 (d, J = 3.0 Hz, 1H), 7.47 (s, 2H), 8.04 (s, 1H), 8.15 (dd, J = 2.3 Hz, 5.3 Hz, 1H), 9.50 (dd, J = 1.0 Hz, 5.3 Hz, 1H), 9.69 (t, J = 1.0 Hz, 1H), 10.61 (s, 1H).

Hereinafter, a heteroaryl amide compound was synthesized in the same manner as in Example 46, and its structure and ¹ H NMR data are shown in Table 3 below.

[Experimental Example]

For 48 compounds (Compound Nos. 1 to 48) synthesized in Examples 1 to 48 of the present invention, it was confirmed whether monoamine oxidase enzyme activity was inhibited by the following Experimental Example 1.

Experimental Example 1: Monoamine oxidase enzyme assay

The inhibitory effect of MAO (Monoamine oxidase) enzymes of the compounds represented by Formulas I, II, or III synthesized in Examples 1 to 48 was measured by a conventional method known in the art. MAO activity is a fluorescence that measures the effect of a compound on the production of hydrogen peroxide from a substrate (MAO-A substrate: p -tyramine, MAO-B substrate: benzylamine) using 10-acetyl-3,7-dihydrophenoxazine. It was done in a base method.

Specifically, the compounds synthesized in Examples 1 to 48 above with recombinant hMAO-A or hMAO-B in 100 μl of 50 mM sodium phosphate buffer (pH 7.4) were incubated in advance for 15 minutes under a temperature condition of 37°C. At this time, the compounds were ^{evaluated in 4 repetitions (quatroplicate) up to the final concentration range of 10 -5} μM to 10 μM, and monoamine oxygenation was performed using a black-clear bottom 96 well assay plate. The Days Enzyme Assay was performed. In the case of hMAO-A, the assay was performed by adding 200 μM of Amplex red, 2 U/ml of mustard radish hydrogen peroxide and 2 mM of p -tyramine to 100 μl of 50 mM sodium phosphate buffer (pH 7.4). In the case of h-MAO-B, 200 μM of Amplex red, 2 U/ml of mustard radish hydrogen peroxide and 2 mM of benzylamine were added to 100 μl of 50 mM sodium phosphate buffer (pH 7.4). . After the addition, incubation was performed for 20 minutes at a temperature condition of 37°C, and the assay result was quantified using a multi-mode microplate reader based on the fluorescence of the produced resorufin. The IC ₅₀ values of the compounds were derived as mean±standard error (SEM) values from the dose response inhibition curve using Sigma-Plot software version 13.0.

As a result of evaluating the inhibitory activity against MAO-B of the heteroaryl amide derivative compound (compound Nos. 1 to 36) synthesized in Examples 1 to 36 represented by Formula I, as shown in Table 4 below, Compound Nos. 5, 7, 10, 11, 13, 16, 17, 19, 20, 21, 22, 25, 26, 28, 29, 30, 31, 32 among 36 heteroaryl amide derivative compounds represented by Formula I , 33, 34, 35, and 36 of 22 heteroaryl amide derivative compounds showed an inhibitory effect of 70% or more against MAO-B.

_{In particular, the IC 50} values of the heteroarylamide derivative compounds of Compound Nos. 11, 17, 20, 26, 32, and 35 for MAO-B are 0.03 μM, 0.0097 μM, 0.005 μM, 0.02 μM, 0.0039 μM, and 0.03, respectively. It was confirmed that the inhibitory activity of MAO-B was remarkably excellent in μM.

In addition, as a result of evaluating the inhibitory activity against MAO-B of the heteroaryl amide derivative compound represented by Formula II (compound Nos. 37 to 45) synthesized in Examples 37 to 45, as shown in Table 5 below. , Among 9 heteroaryl amide derivative compounds represented by Formula II, it was confirmed that two heteroaryl amide derivative compounds of Compound Nos. 38 and 41 showed an inhibitory effect of 60% or more against MAO-B.

_{Specifically, the IC 50} values for MAO-B of the heteroaryl amide derivative compounds of Compound Nos. 38 and 41 were found to be 1.65 μM and 0.78 μM, respectively.

On the other hand, to determine whether the heteroaryl amide derivative compounds represented by Formulas I, II, or III synthesized in Examples 1 to 48 exhibit selective inhibitory activity against MAO-B, the inhibitory efficacy against MAO-A was evaluated. As a result of doing this, as shown in Table 6 below, Compound Nos. 5, 7, 10, 11, 13, 16, 17, 19, 20, 21, 22, 25, 26, 28 showing inhibitory activity against MAO-B , 29, 30, 31, 32, 33, 34, 35, 36, 38 and 41 of the heteroaryl amide derivative compounds, except for compound Nos. 13 and 22, all except for MAO-A 50% or less inhibitory efficacy It was confirmed to show, and accordingly, it was found that the compounds exhibited MAO-B selective inhibitory activity.

[Preparation Example]

Meanwhile, the novel compounds represented by Formulas I to III according to the present invention can be formulated in various forms depending on the purpose. The following exemplifies some formulation methods in which the compounds represented by Formulas I to III according to the present invention are contained as an active ingredient, and the present invention is not limited thereto.

Formulation Example 1: Tablet (direct pressure)

After sieving 5.0 mg of the active ingredient, 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were mixed and pressed into tablets.

Formulation Example 2: Tablet (wet granulation)

After sieving 5.0 mg of the active ingredient, 16.0 mg of lactose and 4.0 mg of starch were mixed. After dissolving 800.3 mg of polysorbate in pure water, an appropriate amount of this solution was added, followed by atomization. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The fine particles were pressed into tablets.

Formulation Example 3: Powder and Capsule

After sieving 5.0 mg of the active ingredient, it was mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. Mixture using a suitable device to solid No. Filled in 5 gelatin capsules.

Formulation Example 4: Injection

An injection was prepared by containing 100 mg as an active ingredient, in addition to 180 mg of mannitol, _{26 mg of Na 2} HPO ₄ ·12H ₂ O and 2974 mg of distilled water.

The embodiments of the present invention have been described above, but those of ordinary skill in the art to which the present invention pertains will understand that the present invention can be implemented in other specific forms without changing the technical spirit or essential features. . Therefore, it should be understood that the embodiments described above are illustrative in all respects and not limiting.

Claims (15)

A compound selected from a heteroaryl amide derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof, which is any one of the compounds represented by the following formulas I to III:
[Chemical Formula Ⅰ]

[Chemical Formula Ⅱ]

[Chemical Formula Ⅲ]

In Formula I,
X is nitrogen or carbon;
R ₁ is hydrogen; Halogen atom; C ₁ -C ₁₃ alkyl group; Or a C ₃ -C ₁₀ cyclyl group;
R ₂ is a C ₃ -C ₁₀ aryl group; Or a 5- to 9-membered heteroaryl group containing 1 to 4 heteroatoms selected from boron (B), nitrogen (N), oxygen (O) and sulfur (S) atoms,
In Formula II,
Y is nitrogen or carbon;
Z is -O-; -CH ₂ -; -CH(CH ₃ )-; -C(O)O-; Or -C(O)-;
R ₃ is hydrogen; Halogen atom; C ₁ -C ₁₃ alkyl group; Or a C ₃ -C ₁₀ cyclyl group;
R ₄ is a C ₃ -C ₁₀ aryl group; Or a 5- to 9-membered heteroaryl group containing 1 to 4 heteroatoms selected from boron (B), nitrogen (N), oxygen (O) and sulfur (S) atoms,
In Formula III,
R ₅ is hydrogen; halogen; C ₁ -C ₁₃ alkyl group; Or a C ₃ -C ₁₀ cyclyl group;
R ₆ is a C ₃ -C ₁₀ aryl group; Or a 5- to 9-membered heteroaryl group containing 1 to 4 heteroatoms selected from boron (B), nitrogen (N), oxygen (O) and sulfur (S) atoms,
Each of the C ₁ -C ₁₃ alkyl group or C ₃ -C ₁₀ cyclyl group is hydrogen; Hydroxy group; Halogen group; Carbonyl group (-(C=O)R ₇ R ₈ ); _{A C 1} -C ₃ alkyl group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; _{A C 1} -C ₃ alkoxy group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; C ₆ -C ₁₀ phenoxy; Amino group (-NR ₇ R ₈ ); An amide group (-(C=O)NR ₇ R ₈ ); C ₆ -C ₁₀ aryl group; Including at least one substituent selected from the group consisting of a C ₃ -C ₁₀ heteroaryl group and a C ₃ -C _{10 heterocyclyl group,}
Each of the C ₃ -C ₁₀ aryl group or 5 to 9 membered heteroaryl group is hydrogen; Hydroxy group; Halogen group; Carbonyl group (-(C=O)R ₇ R ₈ ); _{A C 1} -C ₃ alkyl group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; _{A C 1} -C ₃ alkoxy group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; C ₆ -C ₁₀ phenoxy; Amino group (-NR ₇ R ₈ ); An amide group (-(C=O)NR ₇ R ₈ ); C ₆ -C ₁₀ aryl group; Including at least one substituent selected from the group consisting of a C ₃ -C ₁₀ heteroaryl group and a C ₃ -C _{10 heterocyclyl group,}
Each of R ₇ and R ₈ is hydrogen; C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkenyl group; C ₁ -C ₆ alkynyl group; C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; And one or more selected from the group consisting of a _{C 3} -C _{10 heterocyclyl group.}
The method of claim 1,
In Formula I,
X is nitrogen or carbon;
R ₁ is hydrogen; A halogen atom selected from F and Cl; Methyl group; Substituted methyl group; It is a trifluoromethyl group,
The substituted methyl group is a C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; And a C ₃ -C ₁₀ heterocyclyl group; and one or more substituents selected from the group consisting of,
R ₂ is substituted or unsubstituted benzene; Substituted or unsubstituted pyridazine; Substituted or unsubstituted pyrazine; Substituted or unsubstituted imidazole; Substituted or unsubstituted pyrazole; Substituted or unsubstituted furan; Substituted or unsubstituted pyrimidine; Substituted or unsubstituted pyrrole; Substituted or unsubstituted pyridine; Substituted or unsubstituted indole; Substituted or unsubstituted thiazole; Substituted or unsubstituted benzothiazole; phosphorus, a heteroaryl amide derivative compound, any one of the compounds represented by Formulas I to III, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
The method of claim 1,
In Formula II,
Y is nitrogen or carbon;
Z is -CH ₂ -or -CO-;
R ₃ is hydrogen or F;
R ₄ is substituted or unsubstituted benzene; Substituted or unsubstituted pyridazine; Substituted or unsubstituted pyrazine; Substituted or unsubstituted imidazole; Substituted or unsubstituted pyrazole; Substituted or unsubstituted furan; Substituted or unsubstituted pyrimidine; Substituted or unsubstituted pyrrole; Substituted or unsubstituted pyridine; Substituted or unsubstituted indole; Substituted or unsubstituted thiazole; Substituted or unsubstituted benzothiazole; phosphorus, a heteroaryl amide derivative compound, any one of the compounds represented by Formulas I to III, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
The method of claim 1,
In Formula III,
R ₅ is CH ₃ ;
R ₆ is substituted or unsubstituted benzene; Substituted or unsubstituted pyridazine; Substituted or unsubstituted pyrazine; Substituted or unsubstituted imidazole; Substituted or unsubstituted pyrazole; Substituted or unsubstituted furan; Substituted or unsubstituted pyrimidine; Substituted or unsubstituted pyrrole; Substituted or unsubstituted pyridine; Substituted or unsubstituted indole; Substituted or unsubstituted thiazole; Substituted or unsubstituted benzothiazole; phosphorus, a heteroaryl amide derivative compound, any one of the compounds represented by Formulas I to III, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
The method of claim 1,
The heteroaryl amide derivative compound represented by Formula I is selected from the group consisting of the following compound numbers 1 to 36, a heteroaryl amide derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof :
(Compound No. 1) N- (3-chloro-4-(pyridin-2-ylmethoxy)phenyl)nicotinamide;
(Compound No. 2) N- (3-chloro-4-(pyridin-2-ylmethoxy)phenyl)picolinamide;
(Compound No. 3) N- (3-chloro-4-(pyridin-2-ylmethoxy)phenyl)pyridazine-3-carboxamide;
(Compound No. 4) N- (3-chloro-4-(pyridin-2-ylmethoxy)phenyl)pyridazine-4-carboxamide;
(Compound No. 5) N- (3-chloro-4-(pyridin-2-ylmethoxy)phenyl)pyrazine-2-carboxamide;
(Compound No. 6) N- (3-chloro-4-(pyridin-2-ylmethoxy)phenyl)isonicotinamide;
(Compound No. 7) N- (3-chloro-4-((3-fluorobenzyl)oxy)phenyl)nicotinamide;
(Compound No. 8) N- (3-chloro-4-((3-fluorobenzyl)oxy)phenyl)picolinamide;
(Compound No. 9) N- (3-chloro-4-((3-fluorobenzyl)oxy)phenyl)pyridazine-3-carboxamide;
(Compound No. 10) N- (3-chloro-4-((3-fluorobenzyl)oxy)phenyl)pyridazine-4-carboxamide;
(Compound No. 11) N- (3-chloro-4-((3-fluorobenzyl)oxy)phenyl)pyrazine-2-carboxamide;
(Compound No. 12) N- (3-chloro-4-((3-fluorobenzyl)oxy)phenyl)isonicotinamide;
(Compound No. 13) N- (3-chloro-4-((4-fluorobenzyl)oxy)phenyl)nicotinamide;
(Compound No. 14) N- (3-chloro-4-((4-fluorobenzyl)oxy)phenyl)picolinamide;
(Compound No. 15) N- (3-chloro-4-((4-fluorobenzyl)oxy)phenyl)pyridazine-3-carboxamide;
(Compound No. 16) N- (3-chloro-4-((4-fluorobenzyl)oxy)phenyl)pyridazine-4-carboxamide;
(Compound No. 17) N- (3-chloro-4-((4-fluorobenzyl)oxy)phenyl)pyrazine-2-carboxamide;
(Compound No. 18) N- (3-chloro-4-((4-fluorobenzyl)oxy)phenyl)isonicotinamide;
(Compound No. 19) N- (3-chloro-4-((3-chlorobenzyl)oxy)phenyl)pyridazine-4-carboxamide;
(Compound No. 20) N- (3-chloro-4-((3-chlorobenzyl)oxy)phenyl)pyrazine-2-carboxamide;
(Compound No. 21) N- (3-chloro-4-((3-chlorobenzyl)oxy)phenyl)nicotinamide;
(Compound No. 22) N- (3-chloro-4-((4-chlorobenzyl)oxy)phenyl)nicotinamide;
(Compound No. 23) N- (3-chloro-4-((4-chlorobenzyl)oxy)phenyl)picolinamide;
(Compound No. 24) N- (3-chloro-4-((4-chlorobenzyl)oxy)phenyl)pyridazine-3-carboxamide;
(Compound No. 25) N- (3-chloro-4-((4-chlorobenzyl)oxy)phenyl)pyridazine-4-carboxamide;
(Compound No. 26) N- (3-chloro-4-((4-chlorobenzyl)oxy)phenyl)pyrazine-2-carboxamide;
(Compound No. 27) N- (3-chloro-4-((4-chlorobenzyl)oxy)phenyl)isonicotinamide;
(Compound No. 28) N- (4-(benzyloxy)-3-chlorophenyl)pyridazine-4-carboxamide;
(Compound No. 29) N- (4-(benzyloxy)-3-chlorophenyl)pyrazine-2-carboxamide;
(Compound No. 30) N- (4-(benzyloxy)-3-chlorophenyl)nicotinamide;
(Compound No. 31) N- (3-chloro-4-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridazine-4-carboxamide;
(Compound No. 32) N- (3-chloro-4-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyrazine-2-carboxamide;
(Compound No. 33) N- (3-chloro-4-((3-(trifluoromethyl)benzyl)oxy)phenyl)nicotinamide;
(Compound No. 34) N- (3-(chloro-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)pyridazine-4-carboxamide;
(Compound No. 35) N- (3-chloro-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)pyrazine-2-carboxamide; And
(Compound No. 36) N- (3-chloro-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)nicotinamide.
The method of claim 1,
The heteroaryl amide derivative compound represented by Formula II is selected from the group consisting of the following compound numbers 37 to 45, a heteroaryl amide derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof :
(Compound No. 37) N- (1-(4-fluorobenzyl)-1 H -indol-5-yl)pyridazine-4-carboxamide;
(Compound No. 38) N- (1-(4-fluorobenzyl)-1 H -indol-5-yl)pyrazine-2-carboxamide;
(Compound No. 39) N- (1-(4-fluorobenzyl)-1 H -indol-5-yl)nicotinamide;
(Compound No. 40) N- (1-(3-fluorobenzoyl)-1 H -indol-5-yl)pyridazine-4-carboxamide;
(Compound No. 41) N- (1-(3-fluorobenzoyl)-1 H -indol-5-yl)pyrazine-2-carboxamide;
(Compound No. 42) N- (1-(3-fluorobenzoyl)-1 H -indol-5-yl)nicotinamide;
(Compound No. 43) N- (1-(pyridin-2-ylmethyl)-1 H -indol-5-yl)pyridazine-4-carboxamide;
(Compound No. 44) N- (1-(pyridin-2-ylmethyl)-1 H -indol-5-yl)pyrazine-2-carboxamide; And
(Compound No. 45) N- (1-(pyridin-2-ylmethyl)-1 H -indol-5-yl)nicotinamide.
The method of claim 1,
The heteroaryl amide derivative compound represented by Formula III is selected from the group consisting of the following compound numbers 46 to 48, a heteroaryl amide derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof :
(Compound No. 46) N- (1-methyl-1 H -indol-5-yl)pyridazine-4-carboxamide;
(Compound No. 47) N- (1-methyl-1 H -indol-5-yl)pyrazine-2-carboxamide; And
(Compound No. 48) N- (1-methyl-1 H -indol-5-yl)nicotinamide.
The method of claim 1,
The pharmaceutically acceptable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, Salts of inorganic or organic acids selected from the group consisting of ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid, Compounds selected from heteroaryl amide derivative compounds, pharmaceutically acceptable salts thereof, hydrates thereof and stereoisomers thereof.
A pharmaceutical composition for preventing, alleviating or treating neurodegenerative diseases, comprising the compound of any one of claims 1 to 8 as an active ingredient.
The method of claim 9,
The pharmaceutical composition is monoamine oxidase B (Monoamine oxidase B, MAO-B) that inhibits, a pharmaceutical composition for the prevention, alleviation or treatment of neurodegenerative diseases.
The method of claim 9, wherein the neurodegenerative disease is Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia. (Fronto-Temporal Dementia), cortical-basal ganglia degeneration (Cortico Basal Degeneration), and progressive supranuclear palsy (PSP), any one selected from the group consisting of neurodegenerative diseases prevention, alleviation or treatment pharmaceutical Composition.
A health functional food for preventing or improving neurodegenerative diseases, comprising the compound of any one of claims 1 to 8 as an active ingredient.
In the method for preparing the compound of any one of claims 1 to 8,
The compound is a compound represented by Formula I,
The method is as shown in the following [Scheme 1],
Preparing a compound represented by [Formula 2a] by reacting a compound represented by [Formula 1a] with a benzyl bromide derivative and 2-(chloromethyl)pyridine hydrochloride (Step a);
Reducing the compound represented by [Chemical Formula 2a] prepared in step a to prepare a compound represented by [Chemical Formula 3a] (step b); And
A method comprising: reacting the compound represented by [Chemical Formula 3a] prepared in Step b with a benzoic acid derivative to prepare a compound represented by [Chemical Formula I] (Step c):

(In the above Scheme 1,
X, R ₁ and R ₂ are as defined in Formula I of claim 1.)
In the method for preparing the compound of any one of claims 1 to 8,
The compound is a compound represented by Formula II,
The method is as shown in the following [Scheme 2],
Reacting a compound represented by [Formula 1b] with a benzyl bromide derivative and a benzoyl chloride derivative to prepare a compound represented by [Formula 2b] (step d);
Preparing a compound represented by [Chemical Formula 3b] by reducing the compound represented by [Chemical Formula 2b] prepared in Step d (Step e); And
Preparing a compound represented by [Chemical Formula II] by reacting the compound represented by [Chemical Formula 3b] prepared in Step e with a benzoic acid derivative (Step f); comprising:

(In Scheme 2,
Y, Z, R ₃ and R ₄ are as defined in Formula II of claim 1.)
In the method for preparing the compound of any one of claims 1 to 8,
The compound is a compound represented by Formula III,
The method is as shown in the following [Scheme 3],
Reacting a compound represented by [Chemical Formula 1b] with dimethyl carbonate to prepare a compound represented by [Chemical Formula 2c] (step g);
Reducing the compound represented by [Chemical Formula 2c] prepared in step g to prepare a compound represented by [Chemical Formula 3c] (step h); And
Preparing a compound represented by [Chemical Formula III] by reacting the compound represented by [Chemical Formula 3c] prepared in Step h with a benzoic acid derivative (Step i); comprising:

(In Reaction Scheme 3,
R ₅ and R ₆ are as defined in Formula III of claim 1.)

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