Novel MAO-b inhibitor and use thereof

Abstract

The present invention relates to a novel MAO-B inhibitor compound and, more specifically, provides a novel compound which selectively binds to MAO-B over MAO-A and tau through modification of conventional THK5351, thereby having a remarkably improved ability to inhibit MAO-B. According to the present invention, the compound has excellent MAO-B-specific binding and MAO-B inhibitory effects, and thus can be used for the diagnosis or treatment of neurological diseases overexpressing MAO-B, and can be used as a tracer or contrast agent in PET imaging.

Description

Novel MAO-B inhibitors and uses thereof

[0001] The present invention relates to a novel MAO-B inhibitor compound and a PET contrast agent composition comprising the same as an active ingredient, a composition for treating degenerative neurological diseases, and uses thereof.

[0002] Tau protein is known to be overexpressed in patients with Alzheimer's disease, and tau protein targeting has been actively studied recently using positron emission tomography (PET) techniques. Various radiopharmaceuticals are being developed to detect tau protein expression at an early stage, and a representative substance among them is THK5351 (Ryuichi Harada et al., 18 F-THK5351: A Novel PET Radiotracer for Imaging Neurofibrillary Pathology in Alzheimer Disease, Journal of Nuclear Medicine Feb 2016, 57 (2) 208-214). According to the study published above, 18 When the brains of three normal controls (HC) and three Alzheimer's disease patients were imaged using F-labeled THK5351, the presence of tau protein accumulation in the temporal lobe could be determined through THK5351 PET imaging, allowing comparison between the normal control group and the Alzheimer's group.

[0003] The above THK5351 was known as a Tau PET tracer, but recent studies and various literature have reported that it strongly binds to MAO-B (Tetsuro Tago et al., Monoamine Oxidase B Binding of 18F-THK5351 to Visualize Glioblastoma and Associated Gliosis: An Autopsy-Confirmed Case, Clin Nucl Med. 2019 Jun;44(6):507-509.). MAO-B is also known to be overexpressed in patients with degenerative neurodegenerative diseases such as Alzheimer's disease.

[0004] The present invention provides a novel MAO-B inhibitor compound having an excellent ability to bind to and inhibit MAO-B.

[0005] However, the problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by a person having ordinary skill in the relevant technical field from the description below.

[0006] In order to solve the above problem, the present invention provides a compound represented by the following [chemical formula 1], an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:

[0007]

[0008] In the above chemical formula 1,

[0009] R 1 is a halogen,

[0010] R 2 is any one selected from an alkyl group and a substituted or unsubstituted amine group,

[0011] The above substituted amine group is substituted with an alkyl group.

[0012] According to one side, in the above chemical formula 1, the R 1can be either F or Cl.

[0013] According to one side, in the above chemical formula 1, the R 2 is any one selected from a methyl group and a substituted or unsubstituted amine group, wherein the substituted amine group may be substituted with a methyl group.

[0014] According to one aspect, the compound represented by the above [chemical formula 1] may be any one selected from the group consisting of the following compounds:

[0015]

[0016]

[0017] and

[0018]

[0019] According to another embodiment of the present invention, a contrast agent composition for positron emission tomography (PET) is provided, comprising the compound, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0020] According to one side, the contrast agent composition for positron emission tomography comprises R of the chemical formula 1 1 The element corresponding to the location may be labeled with a radioactive isotope.

[0021] According to another embodiment of the present invention, a composition for treating a neurodegenerative disease is provided, comprising the compound, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0022] According to one side, the above-mentioned degenerative neurological disease may be a MAO-B overexpression disease.

[0023] According to one side, the above-mentioned neurodegenerative disease may be at least one selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple system atrophy.

[0024] According to another embodiment of the present invention, a method for diagnosing a neurodegenerative disease is provided, comprising administering to a subject the compound, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, or a composition comprising the compound as an active ingredient.

[0025] According to another specific embodiment of the present invention, a positron emission tomography method is provided, comprising a step of administering to a subject the compound, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, or a contrast agent composition comprising the compound as an active ingredient.

[0026] The present invention provides a novel MAO-B inhibitor compound. According to the present invention, the specific binding and inhibitory effect of MAO-B compared to MAO-A is significantly improved compared to the prior art, and thus, the compound can be used for the diagnosis or treatment of neurological diseases that overexpress MAO-B, and can be used as a tracer or contrast agent in PET imaging.

[0027] Figure 1 shows the results of confirming the tau binding affinity of the compound of chemical formula 1-1 of the present invention (KDS8165) and THK5351.

[0028] The present inventors have confirmed the possibility that THK5351 can be used as a contrast agent in PET imaging or for the diagnosis and treatment of MAO-B overexpression diseases by targeting MAO-B and / or tau, and have improved this by identifying a novel substance and providing it as an invention.

[0029] In order to solve the above problem, the present invention provides a compound represented by the following [chemical formula 1], an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:

[0030]

[0031] In the above chemical formula 1,

[0032] R 1 is a halogen,

[0033] R 2 is any one selected from an alkyl group and a substituted or unsubstituted amine group,

[0034] The above substituted amine group is substituted with an alkyl group.

[0035] In the present invention, the term "substitution" refers to a reaction in which an atom or atomic group contained in a molecule of a compound is replaced with another atom or atomic group. In the above [Chemical Formula 1], the substituted amine group may be one in which one or more hydrogen atoms are replaced with a C1 to C12 chain alkyl group.

[0036] In the present invention, the term "chain-like" refers to a molecule having a chain-like structure, and the chain-like structure is a chemical structure in which carbon atoms are connected in a chain shape, and there are straight chain-like structures and branched structures.

[0037] In the present invention, the term "chain alkyl group" means a monovalent linear or branched saturated hydrocarbon residue consisting solely of carbon and hydrogen atoms, having 1 to 12 carbon atoms. Examples of such alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2-butyl, 3-butyl, pentyl, n-hexyl, and the like.

[0038] The above halogen may be fluorine (F), chloride (Cl), bromine (Br), or iodine (I), and preferably fluorine or chloride.

[0039] According to one side, in the above chemical formula 1, the R 2 is any one selected from a methyl group and a substituted or unsubstituted amine group, wherein the substituted amine group may be substituted with a methyl group.

[0040] According to one aspect, the compound represented by the above [chemical formula 1] may be any one selected from the group consisting of the following compounds:

[0041]

[0042]

[0043] and

[0044]

[0045] The compound of the present invention can bind to MAO-B specifically, and in particular selectively compared to MAO-A or tau, and inhibit its activity, and thus can be used as a composition for positron emission tomography containing the compound as an active ingredient.

[0046] According to another embodiment of the present invention, a contrast agent composition for positron emission tomography (PET) is provided, comprising the compound, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. The contrast agent may be due to the property of the compound of the present invention to strongly bind to MAO-B and / or tau protein as described above, and has the same meaning as a tracer.

[0047] According to one side, the contrast agent composition for positron emission tomography comprises R of the chemical formula 1 1 The element corresponding to the position may be labeled with a radioactive isotope. More specifically, the R 1 If the element corresponding to the position is fluorine 18 It can be marked with F.

[0048] The compound of the present invention can bind to MAO-B specifically, and in particular selectively compared to MAO-A or tau, and inhibit its activity, and thus can be used as a composition for treating a neurological disease with MAO-B overexpression, including the compound as an active ingredient.

[0049] In particular, unlike existing MAO-B inhibitory compounds that have high tau binding affinity, the compound of the present invention does not bind to tau, as verified in Example 2 below, and thus has very high MAO-B selectivity.

[0050] According to another embodiment of the present invention, a composition for treating a neurodegenerative disease is provided, comprising the compound, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0051] According to one side, the above-mentioned degenerative neurological disease may be a MAO-B overexpression disease.

[0052] According to one side, the above-mentioned neurodegenerative disease may be at least one selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple system atrophy.

[0053] According to another embodiment of the present invention, a method for diagnosing a neurodegenerative disease is provided, comprising administering to a subject the compound, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, or a composition comprising the compound as an active ingredient.

[0054] According to another specific embodiment of the present invention, a positron emission tomography method is provided, comprising a step of administering to a subject the compound, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, or a contrast agent composition comprising the compound as an active ingredient.

[0055] Hereinafter, embodiments are described in detail with reference to the attached drawings. However, the embodiments may be modified in various ways, and the scope of the patent application is not limited or restricted by these embodiments. It should be understood that all modifications, equivalents, or alternatives to the embodiments are included within the scope of the patent application.

[0056] The terms used in the examples are for illustrative purposes only and should not be construed as limiting. Singular expressions include plural expressions unless the context clearly dictates otherwise. In this specification, terms such as "comprise" or "have" are intended to specify the presence of a feature, number, step, operation, component, part, or combination thereof described in the specification, but should be understood to not preclude the presence or addition of one or more other features, numbers, steps, operations, components, parts, or combinations thereof.

[0057] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by a person of ordinary skill in the art to which the embodiments pertain. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology, and shall not be interpreted in an idealized or overly formal sense unless explicitly defined herein.

[0058]

[0059] In addition, when describing with reference to the attached drawings, identical components will be assigned the same reference numerals regardless of the drawing numbers, and redundant descriptions thereof will be omitted. When describing embodiments, if a detailed description of a related known technology is judged to unnecessarily obscure the gist of the embodiment, the detailed description will be omitted.

[0060] Components included in one embodiment and components with common functions will be described using the same names in other embodiments. Unless otherwise stated, the descriptions given in one embodiment can be applied to other embodiments, and detailed descriptions will be omitted to the extent of overlap.

[0061]

[0062] Hereinafter, the present invention will be described in detail with reference to the following examples and comparative examples. However, the technical concept of the present invention is not limited or restricted thereby.

[0063]

[0064] Manufacturing Example 1. Synthesis of (S)-1-fluoro-3-((7-(6-(methylamino)pyridin-3-yl)quinolin-3-yl)oxy)propan-2-ol (Compound 1-1)

[0065] Manufacturing Example 1-1. Synthesis of 7-bromo-3-methoxybinoline from an aldehyde derivative

[0066]

[0067] According to the above reaction formula, 2-amino-4-bromobenzaldehyde (1.0 eq) was dissolved in toluene, and then 1,1,2-trimethoxyethane (1.2 eq) and paratoluenesulfonic acid (0.2 eq) were added and the reaction was stirred under reflux for 12 hours. After cooling the solution, the reaction was terminated with an aqueous sodium bicarbonate solution, and the organic layer was washed with ethyl acetate (EtOAc) and then additionally washed with water and brine. The organic layer was dried over anhydrous Na2SO4 and filtered. The solvent was distilled off under reduced pressure, and the residue obtained was purified by column chromatography using a mixed solvent of ethyl acetate and n-hexane to obtain 7-bromo-quinolin-3-ol.

[0068]

[0069] Manufacturing Example 1-2. Synthesis of 7-bromoquinolin-3-ol from 7-bromo-3-methoxyquinoline

[0070]

[0071] 7-Bromoquinolin-3-ol was synthesized according to the above reaction scheme. Specifically, the compound synthesized in step 1-1 (1.0 eq) was dissolved in acetic acid (AcOH), and bromine chloride (HBr, 20.0 eq) was added. The mixture was stirred at 120°C for 12 to 18 hours. Upon completion of the reaction, the pH was adjusted to neutral with ammonium hydroxide (NH4OH), diluted with ethyl acetate (EtOAc), washed with water and brine, and the organic layer was dried over anhydrous Na2SO4 and filtered. The solvent was distilled off under reduced pressure, and the residue obtained was purified by column chromatography using a mixed solvent of ethyl acetate and n-hexane to obtain 7-bromo-quinolin-3-ol.

[0072]

[0073] Manufacturing Example 1-3. Synthesis of (S)-7-bromo-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)quinoline

[0074]

[0075] According to the above reaction scheme, (S)-7-bromo-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)quinoline was synthesized. Specifically, the compound synthesized in step 1-2 (1.0 eq) was dissolved in dimethylformaldehyde (DMF), and (al)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (2.2 eq) and potassium carbonate (K2CO3, 2.2 eq) were added, followed by stirring at 110 °C with reflux for 12 hours. Upon completion of the reaction, the mixture was diluted with ethyl acetate (EtOAc), washed with water and brine, and the organic layer was dried over anhydrous Na2SO4 and filtered. The residue obtained by distilling the solvent under reduced pressure was purified by column chromatography using a mixed solvent of ethyl acetate and n-hexane to obtain (s)-7-bromo-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)quinoline.

[0076]

[0077] Manufacturing Example 1-4. Synthesis of quinoline derivatives with phenyl and pyridine

[0078]

[0079] According to the above reaction scheme, derivatives introduced with phenyl or pyridine were synthesized. Specifically, the compound synthesized in steps 1-3 (1.0 eq) was dissolved in toluene and water (H2O), and then a boronic acid pinacol ester derivative (1.1 eq) was added. Subsequently, tetrakis(triphenylphosphine)palladium (0.05 eq) and potassium carbonate (K2CO3, 3.0 eq) were added. The mixture was stirred at 100°C for 12 hours. Upon completion of the reaction, the reaction solution was diluted with ethyl acetate (EtOAc), washed with water and brine, and the organic layer was dried over anhydrous Na2SO4 and filtered. The residue obtained by distilling the solvent under reduced pressure was purified through column chromatography to obtain tert-butyl (s)-(5-(3-((2,2-dimethyl-1,3-dioxilan-4-yl)methoxy)quinolin-7-yl)pyridin-2-yl)(methyl)carbamate derivative.

[0080]

[0081] Manufacturing Example 1-5. Synthesis of tert-butyl (al)-(5-(3-(2,3-dihydroxypropoxy)quinolin-7-yl)pyridin-2-yl)(methyl)carbamate

[0082]

[0083] According to the above reaction scheme, tert-butyl (al)-(5-(3-(2,3-dihydroxypropoxy)quinolin-7-yl)pyridin-2-yl)(methyl)carbamate was synthesized. One of the derivatives synthesized in step 1-4, NHBoc compound (1.0 eq), was dissolved in methanol, and 4.0 M HCl in dioxane (1.0 eq) was slowly added dropwise to the solution, stirred for 2 hours, extracted with NaHCO3 aqueous solution and ethyl acetate, and the organic layer was removed with a small amount of water using anhydrous Na2SO4, distilled under reduced pressure to remove the solvent, and dried under vacuum. Thereafter, the residue was separated and purified by column chromatography to obtain tert-butyl (al)-(5-(3-(2,3-dihydroxypropoxy)quinolin-7-yl)pyridin-2-yl)(methyl)carbamate derivative.

[0084]

[0085] Manufacturing Example 1-6. Synthesis of (S)-3-((7-(6-((tert-butoxycarbonyl)(methyl)amino)pyridin-3-yl)quinolin-3-yl)oxy)-2 hydroxypropyl 4-methylbenzenesulfonate

[0086]

[0087] According to the above reaction formula, (S)-3-((7-(6-((tert-butoxycarbonyl)(methyl)amino)pyridin-3-yl)quinolin-3-yl)oxy)-2 hydroxypropyl 4-methylbenzenesulfonate was synthesized. The compound (1.0 eq) synthesized in the above steps 1-5 was dissolved in dichloromethane (DCM), and TsCl (1.0 eq) and triethylamine (1.5 eq) were slowly added dropwise at 0 degrees, stirred for 1 hour, and reacted at room temperature for 10 hours. After quenching the reaction with a small amount of water, the mixture was extracted with water and EA (ethyl acetate), and the organic layer was distilled under reduced pressure to remove a small amount of water using anhydrous Na2SO4, and the solvent was removed. The mixture was dried under vacuum. Afterwards, (S)-3-((7-(6-((tert-butoxycarbonyl)(methyl)amino)pyridin-3-yl)quinolin-3-yl)oxy)-2 hydroxypropyl 4-methylbenzenesulfonate was obtained by separation and purification using column chromatography.

[0088]

[0089] Manufacturing Example 1-7. Synthesis of (2S)-3-((7-(6-((tert-butoxycarbonyl)(methyl)amino)pyridin-3-yl)quinolin-3-yl)oxy)-2-((tetrahydro-2H-pyran-2-yl)oxy)propyl 4-methylbenzenesulfonate

[0090]

[0091] According to the above reaction scheme, substituted (2s)-3-((7-(6-((tert-butoxycarbonyl)(methyl)amino)pyridin-3-yl)quinolin-3-yl)oxy)-2-((tetrahydro-2H-pyran-2-yl)oxy)propyl 4-methylbenzenesulfonate was synthesized. The compound (1.0 eq) synthesized in the above step 1-6 was dissolved in chloroform (CHCl3), and then paratoluenesulfonic acid (p-TsOH, 2.29 eq) and 3,4-dihydro-2H-pyran (DHP, 20.0 eq) were slowly added dropwise, stirred for 1 hour, and adjusted to pH 9 with triethylamine. The solvent was removed by distillation under reduced pressure, and dried under vacuum. Afterwards, (2s)-3-((7-(6-((tert-butoxycarbonyl)(methyl)amino)pyridin-3-yl)quinolin-3-yl)oxy)-2-((tetrahydro-2H-pyran-2-yl)oxy)propyl 4-methylbenzenesulfonate was obtained by separation and purification using column chromatography.

[0092]

[0093] Manufacturing Example 1-8. Synthesis of tert-butyl (5-(3-((2s)-3-fluoro-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)quinolin-7-yl)pyridin-yl)(methyl)carbamate

[0094]

[0095] According to the above reaction scheme, tert-butyl (5-(3-((2s)-3-fluoro-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)quinolin-7-yl)pyridin-yl)(methyl)carbamate was synthesized. The compound synthesized in step 1-7 (1.0 eq) was dissolved in amyl alcohol, and 1.0 M TBAF in tetrahydrofuran (2.0 eq) was slowly added dropwise, followed by reaction at 80°C for 14 hours. After quenching the reaction with a small amount of water, the mixture was extracted with water and ethyl acetate, and the organic layer was distilled under reduced pressure to remove a small amount of water using anhydrous Na2SO4, and the solvent was removed. The mixture was dried under vacuum. Afterwards, tert-butyl (5-(3-((2s)-3-fluoro-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)quinolin-7-yl)pyridin-yl)(methyl)carbamate was obtained by separation and purification using column chromatography.

[0096]

[0097] Manufacturing Example 1-9. Synthesis of (S)-1-fluoro-3-((7-(6-(methylamino)pyridin-3-yl)quinolin-3-yl)oxy)propan-2-ol

[0098]

[0099] According to the above reaction formula, (S)-1-fluoro-3-((7-(6-(methylamino)pyridin-3-yl)quinolin-3-yl)oxy)propan-2-ol was synthesized. The compound (1.0 eq) synthesized in step 1-8 was dissolved in methanol, and 4 M HCl in dioxane was slowly added dropwise. The mixture was stirred at 100 degrees for 20 minutes, and the organic layer was washed with ethyl acetate and NaHCO3 aqueous solution and then extracted. The organic layer was passed through Na2SO4, distilled under reduced pressure to remove the solvent, and dried under vacuum. Thereafter, the residue was separated and purified by column chromatography to obtain (S)-1-fluoro-3-((7-(6-(methylamino)pyridin-3-yl)quinolin-3-yl)oxy)propan-2-ol in a yield of 91%, which is compound 1-1 of the present specification.

[0100] 1 H NMR (CDCl3, 400 MHz)δ8.70 (d,J= 2.4 Hz, 1H), 8.50 (s, 1H), 8.17 (s, 1H), 7.74 (d,J= 8.4 Hz, 1H), 7.78-7.71 (m, 2H), 6.53 (d,J= 8.4 Hz, 1H), 4.74-4.71 (m, 2H), 4.62-4.60 (m, 1 H), 4.41-4.33 (m, 1H), 4.42-4.23 (m, 2 H), 3.99 (d,J= 4.8 Hz, 3H), 2.01 (s, 1H).

[0101]

[0102] Manufacturing Example 2. Synthesis of (al)-1-fluoro-3-((7-(6-(methylamino)pyridin-3-yl)quinolin-3-yl)oxy)propan-2-ol (Compound 1-2)

[0103] Manufacturing Example 2-1. Synthesis of (al)-7-bromo-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)quinoline

[0104]

[0105] According to the above reaction formula, (al)-7-bromo-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)quinoline was synthesized. Specifically, the compound synthesized in step 1-2 (1.0 eq) was dissolved in dimethylformaldehyde (DMF), and then (s)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (2.2 eq) and potassium carbonate (K2CO3, 2.2 eq) were added, followed by stirring at 110 °C with reflux for 12 hours. Upon completion of the reaction, the mixture was diluted with ethyl acetate, washed with water and brine, and the organic layer was dried over anhydrous Na2SO4 and filtered. The residue obtained by distilling the solvent under reduced pressure was purified by column chromatography using a mixed solvent of ethyl acetate and n-hexane to obtain (al)-7-bromo-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)quinoline.

[0106]

[0107] Manufacturing Example 2-2. Synthesis of quinoline derivatives with phenyl and pyridine

[0108]

[0109] According to the above reaction scheme, derivatives introduced with phenyl or pyridine were synthesized. Specifically, the compound synthesized in steps 1-3 (1.0 eq) was dissolved in toluene and water (H2O), and then a boronic acid pinacol ester derivative (1.1 eq) was added. Subsequently, tetrakis(triphenylphosphine)palladium (0.05 eq) and potassium carbonate (K2CO3, 3.0 eq) were added. The mixture was stirred at 100°C for 12 hours. Upon completion of the reaction, the reaction solution was diluted with ethyl acetate (EtOAc), washed with water and brine, and the organic layer was dried over anhydrous Na2SO4 and filtered. The residue obtained by distilling the solvent under reduced pressure was purified through column chromatography to obtain tert-butyl (s)-(5-(3-((2,2-dimethyl-1,3-dioxilan-4-yl)methoxy)quinolin-7-yl)pyridin-2-yl)(methyl)carbamate derivative.

[0110]

[0111]

[0112] Manufacturing Example 2-3. Synthesis of tert-butyl (s)-(5-(3-(2,3-dihydroxypropoxy)quinolin-7-yl)pyridin-2-yl)(methyl)carbamate

[0113]

[0114] According to the above reaction formula, tert-butyl (s)-(5-(3-(2,3-dihydroxypropoxy)quinolin-7-yl)pyridin-2-yl)(methyl)carbamate was synthesized. One of the derivatives synthesized in Step 1-4, NHBoc compound (1.0 eq), was dissolved in methanol, and 4.0 M HCl (dioxane, 1.0 eq) was slowly added dropwise to the solution, stirred for 2 hours, extracted with NaHCO3 aqueous solution and ethyl acetate, and the organic layer was removed with a small amount of water using anhydrous Na2SO4, distilled under reduced pressure to remove the solvent, and dried under vacuum. Thereafter, the residue was separated and purified by column chromatography to obtain tert-butyl (s)-(5-(3-(2,3-dihydroxypropoxy)quinolin-7-yl)pyridin-2-yl)(methyl)carbamate derivative.

[0115]

[0116] Manufacturing Example 2-4. Synthesis of (al)-3-((7-(6-((tert-butoxycarbonyl)(methyl)amino)pyridin-3-yl)quinolin-3-yl)oxy)-2 hydroxypropyl 4-methylbenzenesulfonate

[0117]

[0118] 2-4. According to the above reaction formula, (al)-3-((7-(6-((tert-butoxycarbonyl)(methyl)amino)pyridin-3-yl)quinolin-3-yl)oxy)-2 hydroxypropyl 4-methylbenzenesulfonate was synthesized. The compound (1.0 eq) synthesized in step 1-5 was dissolved in dichloromethane (DCM), and TsCl (1.0 eq) and triethylamine (1.5 eq) were slowly added dropwise at 0°C, stirred for 1 hour, and reacted at room temperature for 10 hours. After quenching the reaction with a small amount of water, the organic layer was extracted with water and ethyl acetate, and a small amount of water was removed from the organic layer using anhydrous Na2SO4, distilled under reduced pressure to remove the solvent, and dried under vacuum. Afterwards, (al)-3-((7-(6-((tert-butoxycarbonyl)(methyl)amino)pyridin-3-yl)quinolin-3-yl)oxy)-2 hydroxypropyl 4-methylbenzenesulfonate was obtained by separation and purification using column chromatography.

[0119]

[0120] Manufacturing Example 2-5. Synthesis of (2-((7-(6-((tert-butoxycarbonyl)(methyl)amino)pyridin-3-yl)quinolin-3-yl)oxy)-2-((tetrahydro-2H-pyran-2-yl)oxy)propyl 4-methylbenzenesulfonate

[0121]

[0122] According to the above reaction scheme, substituted (2-((7-(6-((tert-butoxycarbonyl)(methyl)amino)pyridin-3-yl)quinolin-3-yl)oxy)-2-((tetrahydro-2H-pyran-2-yl)oxy)propyl 4-methylbenzenesulfonate was synthesized. The compound (1.0 eq) synthesized in the above step 1-6 was dissolved in chloroform (CHCl3), and then paratoluenesulfonic acid (p-TsOH, 2.29 eq) and 3,4-dihydro-2H-pyran (DHP, 20.0 eq) were slowly added dropwise, stirred for 1 hour, and adjusted to pH 9 with triethylamine. The solvent was removed by distillation under reduced pressure, and dried under vacuum. Afterwards, (2-al)-3-((7-(6-((tert-butoxycarbonyl)(methyl)amino)pyridin-3-yl)quinolin-3-yl)oxy)-2-((tetrahydro-2H-pyran-2-yl)oxy)propyl 4-methylbenzenesulfonate was obtained by separation and purification using column chromatography.

[0123]

[0124] Manufacturing Example 2-6. Synthesis of tert-butyl (5-(3-((2-fluoro-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)quinolin-7-yl)pyridin-yl)(methyl)carbamate

[0125]

[0126] According to the above reaction scheme, tert-butyl (5-(3-((2-fluoro-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)quinolin-7-yl)pyridin-yl)(methyl)carbamate was synthesized. The compound synthesized in step 1-7 (1.0 eq) was dissolved in amyl alcohol, and 1.0 M TBAF in tetrahydrofuran (2.0 eq) was slowly added dropwise, followed by reaction at 80°C for 14 hours. After quenching the reaction with a small amount of water, the mixture was extracted with water and ethyl acetate, and the organic layer was distilled under reduced pressure to remove a small amount of water using anhydrous Na2SO4, and the solvent was removed. The mixture was dried under vacuum. Afterwards, tert-butyl (5-(3-((2-fluoro-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)quinolin-7-yl)pyridin-yl)(methyl)carbamate was obtained by separation and purification using column chromatography.

[0127]

[0128] Manufacturing Example 2-7. Synthesis of (al)-1-fluoro-3-((7-(6-(methylamino)pyridin-3-yl)quinolin-3-yl)oxy)propan-2-ol

[0129]

[0130] According to the above reaction formula, (al)-1-fluoro-3-((7-(6-(methylamino)pyridin-3-yl)quinolin-3-yl)oxy)propan-2-ol was synthesized. The compound (1.0 eq) synthesized in step 1-8 was dissolved in methanol, and 4 M HCl in dioxane was slowly added dropwise. The mixture was stirred at 100°C for 20 minutes, and the organic layer was washed with ethyl acetate and NaHCO3 aqueous solution and then extracted. The organic layer was passed through Na2SO4, distilled under reduced pressure to remove the solvent, and dried under vacuum. Afterwards, the residue was separated and purified by column chromatography to obtain (al)-1-fluoro-3-((7-(6-(methylamino)pyridin-3-yl)quinolin-3-yl)oxy)propan-2-ol (compound 1-2) in a yield of 81%.

[0131] 1 H NMR (CDCl3, 400 MHz)δ8.71 (d,J= 2.9 Hz, 1H), 8.40 (d,J= 2.2 Hz, 1H), 8.16 (d,J= 1.6 Hz, 1H), 7.95-7.92 (m, 1H), 7.79-7.67 (m, 1H), 7.44-7.43 (d,J= 2.7 Hz, 1H), 6.63 (d,J= 8.8 Hz, 1 H), 5.66 (s, 1H), 4.74-4.72 (m, 1H), 4.62-4.60 (m, 1 H), 4.39-4.34 (m, 1H), 4.25-4.23 (m, 2 H), 3.02 (d,J= 5.0 Hz, 3H), 2.04 (s, 1H).

[0132]

[0133] Manufacturing Example 3. Synthesis of (S)-1-chloro-3-((7-(6-methylpyridin-3-yl)quinolin-3-yl)oxy)propan-2-ol (Compound 1-3)

[0134] Manufacturing Example 3-1. Synthesis of (al)-3-((7-(6-methylpyridin-3-yl)quinolin-3-yl)oxy)propane-1,2-diol

[0135]

[0136] According to the above reaction formula, (al)-3-((7-(6-methylpyridin-3-yl)quinolin-3-yl)oxy)propane-1,2-diol was synthesized. The compound (1.0 eq) synthesized in step 1-4 was dissolved in methanol, and 4.0 M HCl (dioxane, 3.0 eq) was slowly added dropwise to the solution, stirred for 2 hours, extracted with NaHCO3 aqueous solution and ethyl acetate, and the organic layer was removed with a small amount of water using anhydrous Na2SO4, distilled under reduced pressure to remove the solvent, and dried under vacuum. Thereafter, (al)-3-((7-(6-methylpyridin-3-yl)quinolin-3-yl)oxy)propane-1,2-diol was obtained by separation and purification using column chromatography.

[0137]

[0138] Manufacturing Example 3-2. Synthesis of (S)-1-chloro-3-((7-(6-methylpyridin-3-yl)quinolin-3-yl)oxy)propan-2-ol

[0139]

[0140] According to the above reaction formula, (S)-1-chloro-3-((7-(6-methylpyridin-3-yl)quinolin-3-yl)oxy)propan-2-ol was synthesized. The compound (1.0 eq) synthesized in the above step 3-1 was dissolved in dimethylformaldehyde, and then trimethylamine (1.5 eq) was added. After adjusting to 0°C, MsCl (1.5 eq) was slowly added dropwise to the solution, stirred for 2 hours, and extracted with NaHCO3 aqueous solution and ethyl acetate. The organic layer was distilled under reduced pressure to remove a small amount of water, and the solvent was removed, followed by vacuum drying. Afterwards, (S)-1-chloro-3-((7-(6-methylpyridin-3-yl)quinolin-3-yl)oxy)propan-2-ol (compound 1-3) was obtained in a yield of 30% by separation and purification using column chromatography.

[0141] 1 H NMR (Methanol-d4, 400 MHz)δ8.83 (d,J= 2.1 Hz, 1H), 8.69 (d,J= 2.8 Hz, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 8.17-8.15 (m, 1H), 8.03 (d,J= 8.5 Hz, 1H), 7.93-7.91 (m, 1H), 7.87-7.86 (m, 1 H), 7.47 (d,J= 3.6 Hz, 1H), 5.64-5.59 (m, 1H), 4.49 (d,J= 4.9 Hz, 2 H), 4.05-3.95 (m, 2H), 2.63 (s, 3H).

[0142]

[0143] Manufacturing Example 4. Synthesis of (S)-1-fluoro-3-((7-(6-methylpyridin-3-yl)quinolin-3-yl)oxy)propan-2-ol (Compound 1-4)

[0144] Manufacturing Example 4-1. Synthesis of (S)-2-hydroxy-3-((7-(6-methylpyridin-3-yl)quinolin-3-yl)oxy)propyl 4-methylbenzenesulfonate

[0145]

[0146] According to the above reaction formula, (S)-2-hydroxy-3-((7-(6-methylpyridin-3-yl)quinolin-3-yl)oxy)propyl 4-methylbenzenesulfonate was synthesized. The compound synthesized in step 3-1 (1.0 eq) was dissolved in dichloromethane (DCM), and then TsCl (1.0 eq), triethylamine (1.5 eq), and dibutyltin oxide (0.2 eq) were slowly added dropwise at 0 degrees, followed by reaction at room temperature for 21 hours. After the reaction was terminated with a small amount of water, the mixture was extracted with water and ethyl acetate, and the organic layer was distilled under reduced pressure to remove a small amount of water. The solvent was removed and dried under vacuum. Afterwards, (S)-2-hydroxy-3-((7-(6-methylpyridin-3-yl)quinolin-3-yl)oxy)propyl 4-methylbenzenesulfonate was obtained by separation and purification using column chromatography.

[0147]

[0148] Manufacturing Example 4-2. Synthesis of (S)-1-fluoro-3-((7-(6-methylpyridin-3-yl)quinolin-3-yl)oxy)propan-2-ol

[0149]

[0150] According to the above reaction scheme, substituted (S)-1-fluoro-3-((7-(6-methylpyridin-3-yl)quinolin-3-yl)oxy)propan-2-ol was synthesized. The compound synthesized in step 4-1 (1.0 eq) was dissolved in tert-amyl alcohol, and 1.0 M TBAF in tetrahydrofuran (2.0 eq) was slowly added dropwise. The mixture was stirred at 80°C for 14 hours and distilled under reduced pressure to remove the solvent. The mixture was extracted with water and ethyl acetate, and the organic layer was separated from the residue using anhydrous Na2SO4, distilled under reduced pressure to remove the solvent, and dried under vacuum. Afterwards, (S)-1-fluoro-3-((7-(6-methylpyridin-3-yl)quinolin-3-yl)oxy)propan-2-ol was obtained in a yield of 44% by separation and purification using column chromatography.

[0151] 1 H NMR (CDCl3, 400 MHz)δ8.88 (s, 1H), 8.73 (s, 1H), 8.25 (s, 1H), 7.99-7.97 (m, 1H), 7.83-7.81 (m, 1H), 7.76-7.74 (m, 1H), 7.46 (d,J= 2.6 Hz, 1H), 7.33 (d,J= 7.8 Hz, 1 H), 4.74-4.72 (m, 1H), 4.62-4.61 (m, 1 H), 4.43-3.33 (m, 1H), 4.26-4.24 (m, 2 H), 2.67 (s, 3H).

[0152]

[0153] Example 1. Confirmation of MAO-B selective inhibition efficacy

[0154] 10 mM of each compound and THK5351 as a control group were diluted 10-fold and prepared at five concentrations of 1 mM, 0.1 mM, 0.01 mM, and 0.001 mM. 0.05 M sodium phosphate (pH 7.4) buffer was prepared, and 5 mg / mL human monoamine oxidase type B enzyme was diluted 1 / 200 with the buffer and mixed with 2 L of compound solutions at five concentrations, and a total of 100 L of enzyme buffer was placed in a 96 plate and reacted for 1 hour. 100 uL of working buffer made by adding 20 mM Amplex red (200 L), 100 mM benzylamine substrate (200 L), and 200 U / mL horseradish peroxidase (100 L) to 0.05 M sodium phosphate (pH 7.4) buffer (9.5 mL) was mixed 1:1 with the reaction enzyme buffer, incubated for 2 hours, and then measured by absorbance (570 nm).

[0155] The experimental results are shown in Table 1 below. As shown in Table 1 below, the compound of the present invention generally exhibited a specific inhibitory effect on MAO-B, and IC 50 The value was also confirmed to be significantly lower than that of the control group. In particular, compound 1-1 of the present invention has an MAO-B inhibitory activity of IC 50 It was shown to be 0.0063uM as a reference, showing MAO-B inhibitory activity that was 18 times better than THK5351, and showed a high selectivity of 15873 times or more as a result of comparing MAO-A and MAO-B.

[0156] Compound MAO-A IC 50 (uM)MAO-B IC 50 (uM) Selectivity (MAO-A / MAO-B) Compound 1-1>1000.006315873.016 Compound 1-2>1000.178561.798 Compound 1-3>1002.245 Compound 1-4>1000.007812820.513 Comparative group (THK5351)>1000.12833.333

[0157]

[0158]

[0159] Example 2. Assay for confirmation of binding of aggregated Tau (Thioflavin T assay)

[0160] Aggregated Tau (0.5 mg / ml) was diluted in PBS buffer (pH 7.4) to prepare a stock solution with a final concentration of 0.05 mg / ml. Thioflavin T was dissolved in distilled water to prepare a 1 mM stock solution, which was then diluted in PBS buffer to prepare a final concentration of 100 μM before use. THK-5351 and the compound of formula 1-1 (KDS8165) were dissolved in DMSO to prepare a 10 mM stock, and diluted in PBS buffer to prepare a final concentration of 0.5 μM. Aggregated Tau solution (40 μL) and THK-5351 / formula 1-1 (KDS8165, 10 μL, final concentration 0.1 μM) were treated in each well of a 96-well black fluorescence microplate, and the reaction was performed at 37 oC for 20 minutes. Next, diluted Thioflavin T solution (50 μL) was treated and reacted at 37 oC for 20 minutes. The change in fluorescence intensity was measured using a SpectraMax®i3 instrument (Molecular Device) at excitation and emission wavelengths of 450 nm and 482 nm, respectively, and the results are shown in Fig. 1.

[0161] As shown in Fig. 1, THK-5351 was confirmed to bind to Tau as reported in the literature, as the fluorescence intensity was reduced by 63.85% compared to the aggregated Tau control. The compound of chemical formula 1-1 of the present invention (KDS8165) was confirmed to exhibit a fluorescence intensity similar to the control group (100.07%) and did not bind to Tau at all. In other words, it was confirmed that the compound of chemical formula 1-1 of the present invention selectively inhibits only MAO-B without binding to Tau compared to THK-5351.

[0162]

[0163] Although the embodiments described above have been described with limited drawings, those skilled in the art will appreciate that various technical modifications and variations can be applied based on the above. For example, appropriate results can still be achieved even if the described techniques are performed in a different order than described, and / or components of the described systems, structures, devices, circuits, etc. are combined or combined in a different manner than described, or are replaced or substituted with other components or equivalents.

[0164] Therefore, other implementations, other embodiments, and equivalents to the claims also fall within the scope of the claims described below.

Claims

1. A compound represented by the following [chemical formula 1], an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof: In the above chemical formula 1, R 1 is a halogen, R 2 is any one selected from an alkyl group and a substituted or unsubstituted amine group, The above substituted amine group is substituted with an alkyl group.

2. In paragraph 1, In the above chemical formula 1, the R 1 A compound selected from F or Cl, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

3. In paragraph 1, In the above chemical formula 1, the R 2 is one selected from a methyl group and a substituted or unsubstituted amine group, A compound, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, wherein the substituted amine group is substituted with a methyl group.

4. In paragraph 1, The compound represented by the above [chemical formula 1] is characterized by being any one selected from the group consisting of the following compounds, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof: and 5. A contrast agent composition for positron emission tomography (PET) comprising a compound of any one of claims 1 to 4, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

6. In the fifth paragraph, the contrast agent composition for positron emission tomography is R of the chemical formula 1. 1 A composition wherein the element corresponding to the position is labeled with a radioactive isotope.

7. A composition for treating a neurodegenerative disease, comprising a compound of any one of claims 1 to 4, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

8. A composition for treating a neurodegenerative disease, wherein the neurodegenerative disease in paragraph 7 is an MAO-B overexpression disease.

9. A composition for treating a neurodegenerative disease, wherein the neurodegenerative disease in paragraph 7 is at least one selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple system atrophy.

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