Dual regulators of mGluR5 and HDAC6, and their use

Abstract

Dual modifiers for mGluR5 and HDAC6, and their uses are disclosed. More specifically, compounds that simultaneously antagonize both mGluR5 and HDAC6, and their use as therapeutic agents for movement disorders are disclosed.

Description

[Technical Field]

[0001] Dual modifiers for mGluR5 and HDAC6, and their uses are disclosed. More specifically, compounds that simultaneously modulate mGluR5 and HDAC6, and their use as therapeutic agents for movement disorders are disclosed. [Background technology]

[0002] Movement disorders are a group of conditions that affect the ability to generate and control physical movement, and are often associated with neurological disorders or neurological dysfunctions. Movement disorders can manifest as abnormal levels of proficiency or speed in movement, excessive or involuntary movements, or delays or absences of voluntary movements.

[0003] Movement disorders are often caused by dysregulation of dopamine neurotransmission. Parkinson's disease (PD) is one example of a movement disorder associated with dysregulation of dopamine neurotransmission caused by progressive degeneration of dopamine neurons. Tardive dyskinesia is another example of a movement disorder associated with dysregulation of dopamine neurotransmission.

[0004] To compensate for the loss of dopamine, Parkinson's disease (PD) is currently treated with, for example, levodopa (L-DOPA, a dopamine precursor). Unfortunately, L-DOPA treatment for PD often causes a specific type of dyskinesia called L-DOPA-induced dyskinesia (LID), which is partly caused by excessive dopamine levels in the synapses.

[0005] Glutamate receptors are broadly classified into ion channel glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs). Of these, metabotropic glutamate receptors are a type of G protein-coupled receptor (GPCR) and are classified into three groups, I, II, and III, according to the characteristics of their signal transduction processes. Group I consists of mGluR1 and mGluR5 and functions as postsynaptic receptors that enhance the excitability of nerve cells.

[0006] Histone deacetylases (HDACs) are enzymes that remove acetyl groups from lysine residues of histone proteins that make up chromatin. In humans, 18 types of HDACs are known and are classified into Class I (HDAC1, 2, 3, 8), Class II (IIa: HDAC4, 5, 7, 9; IIb: HDAC6, 10), Class III (SIRT1-7), and Class IV (HDAC11). HDAC6, one of the Class IIb HDACs, is mainly found in the cytoplasm and plays an important role in the microtubule network by regulating the balance of acetylation and deacetylation of tubulin in addition to histones. [Overview of the project] [Problems that the invention aims to solve]

[0007] The object of the present invention is to provide a compound that simultaneously modulates mGluR5 and HDAC6.

[0008] Another object of the present invention is to provide the use of the compound for the prevention or treatment of motor disorders. [Means for solving the problem]

[0009] To achieve the above objective, the present invention relates to the following formula (1) [ka] (1) The present invention provides a compound represented by (wherein Ar, R1, R2, X1, X2, X3, Y1, Y2, Y3, and n are as defined herein) or a pharmaceutically acceptable salt thereof.

[0010] Furthermore, the present invention provides a pharmaceutical composition for the prevention or treatment of motor disorders, comprising, as an active ingredient, a therapeutically effective amount of the compound of formula (1) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.

[0011] Furthermore, the present invention provides a method for preventing or treating motor disorders, comprising the step of administering a compound of formula (1) or a pharmaceutically acceptable salt thereof to a mammal.

[0012] Furthermore, the compound of formula (1) or a pharmaceutically acceptable salt thereof is provided for use in the prevention or treatment of motor disorders. [Effects of the Invention]

[0013] The compound of formula (1) according to the present invention, or a pharmaceutically acceptable salt thereof, acts as a dual modifier for mGluR5 and HDAC6. The dual antagonistic effects on mGluR5 and HDAC6 can exert a synergistic effect in the preventive or therapeutic effects of movement disorders. Due to these properties, the compound of formula (1) or a pharmaceutically acceptable salt thereof can exert preventive or therapeutic effects of movement disorders even at low doses without causing specific side effects.

[0014] (Best mode for carrying out the invention) The present invention will be described in more detail below.

[0015] According to one aspect of the present invention, the following formula (1) [ka] (1) (wherein Ar is an aryl or heteroaryl, and the aryl and heteroaryl may be optionally substituted with one or more substituents selected from the group consisting of halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy and alkylsulfonyl; R1 is alkyl or haloalkyl; R2 is either H or alkyl; One of X1, X2, and X3 is C, and the rest are N; Y1, Y2, and Y3 are each independently CR3 or N, where R3 is H, halo, or alkyl; n is an integer between 0 and 2; The heteroaryl comprises one or more heteroatoms selected from N, O, and S. A compound represented by ( ) or a pharmaceutically acceptable salt thereof is provided.

[0016] In this specification, the following concepts defined for substituted compounds are used to define the compound of formula (1).

[0017] In the present invention, the terms "halo" or "halogen" mean fluorine (F), chlorine (Cl), bromine (Br), or iodine (I), either alone or in combination with additional terms (e.g., haloalkyl or haloalkoxy).

[0018] In this invention, the term "cyano" means -CN.

[0019] In this invention, the term "sulfonyl" means -S(=O)2-.

[0020] In the present invention, the term "alkyl" alone or in combination with additional terms (e.g., haloalkyl) refers to, for example, a linear or branched saturated aliphatic hydrocarbon radical having 1 to 7 carbon atoms. Typical examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl, and 1,2-dimethylpropyl.

[0021] In the present invention, the term "alkoxy" means an alkyloxy (-O-alkyl group), for example, an alkyloxy having 1 to 7 carbon atoms.

[0022] In this invention, the term "aryl" means, for example, an aromatic hydrocarbon having 6 to 10 carbon atoms. For example, phenyl and naphthyl are included, but are not limited to.

[0023] In the present invention, the term "heteroaryl" means a 5- to 10-membered aromatic hydrocarbon containing one or more heteroatoms selected from N, O, and S as ring members.

[0024] According to one embodiment of the present invention, in formula (1), Ar is C6-C 10 The aryl or 5-10 membered heteroaryl is optionally substituted with 1-3 substituents selected from the group consisting of halo, cyano, C1-C7 alkyl, halo-C1-C7 alkyl, C1-C7 alkoxy, halo-C1-C7 alkoxy, and C1-C7 alkylsulfonyl; R1 is a C1-C7 alkyl or halo-C1-C7 alkyl; R2 is either H or a C1-C7 alkyl group; One of X1, X2, and X3 is C, and the rest are N; Y1, Y2, and Y3 are each independently CR3 or N; where R3 is H, halo, or C1-C7 alkyl; n is an integer, either 1 or 2; The heteroaryl compound contains 1 to 3 heteroatoms selected from N, O, and S.

[0025] According to another embodiment of the present invention, X1 is C, and X2 and X3 may be N. In this case, formula (1) is the following formula (2) [ka] (2) (In the formula, Ar, R1, R2, Y1, Y2, and Y3 are the same as those defined in formula (1), and n may be an integer from 0 to 2, specifically 1 or 2, more specifically 1.)

[0026] According to another embodiment of the present invention, X2 may be and C, and X1 and X3 may be N. In this case, formula (1) is the following formula (3) [ka] (3) (In the formula, Ar, R1, R2, Y1, Y2, and Y3 are the same as those defined in formula (1), and n may be an integer from 0 to 2, specifically 1 or 2, or more specifically 1.)

[0027] According to another embodiment of the present invention, the aryl is phenyl, and the heteroaryl may be pyridyl, thienyl, imidazolyl, or benzothiazolyl.

[0028] According to another embodiment of the present invention, Ar may be phenyl or pyridyl. In this case, formula (1) is the following formula (4) [ka] (4) (wherein Z is CH or N; R4 is halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy or alkylsulfonyl; m is an integer from 0 to 3; R1, R2, X1, X2, X3, Y1, Y2, Y3 and n are the same as those defined in formula (1).)

[0029] According to another embodiment of the present invention, Y1, Y2, and Y3 may all be CR3. According to another embodiment of the present invention, R3 may be H.

[0030] In any of formulas (1) to (4), R1 may be a halo-C1 alkyl group, and more specifically, CF2H or CF3.

[0031] According to another embodiment of the present invention, representative examples of compounds of formula (1) include, but are not limited to, the following compounds: 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-phenylpropa-2-in-1-yl)pyridine-2(1H)-one; 1-(3-phenylpropa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one; 1-(3-(pyridine-4-yl)propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one; 1-(3-(pyridine-3-yl)propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one; 1-(3-(pyridine-2-yl)propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one; 1-(3-(2-fluorophenyl)propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one; 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(pyridine-4-yl)propa-2-in-1-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(pyridine-3-yl)prop-2-in-1-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(pyridine-2-yl)prop-2-in-1-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(4-fluorophenyl)propa-2-in-1-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(3-fluorophenyl)propa-2-in-1-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(2-fluorophenyl)propa-2-in-1-yl)pyridine-2(1H)-one; 1-(3-(4-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 1-(3-(2-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(p-tolyl)propa-2-in-1-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(m-tolyl)propa-2-in-1-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(3-(trifluoromethyl)phenyl)propa-2-in-1-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(3-(trifluoromethoxy)phenyl)propa-2-in-1-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(3-methoxyphenyl)propa-2-in-1-yl)pyridine-2(1H)-one; 1-(3-(6-chloropyridine-2-yl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 1-(3-(2-chloropyridine-4-yl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(6-methylpyridine-2-yl)prop-2-in-1-yl)pyridine-2(1H)-one; 1-(3-(3-bromophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(3-(difluoromethyl)phenyl)propa-2-in-1-yl)pyridine-2(1H)-one; 1-(3-(3-(difluoromethoxy)phenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(5-methylpyridine-3-yl)propa-2-in-1-yl)pyridine-2(1H)-one; 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one; 3-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-2-oxopyridine-1(2H)-yl)prop-1-in-1-yl)benzonitrile; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(3-(methylsulfonyl)phenyl)propa-2-in-1-yl)pyridine-2(1H)-one; 1-(3-(3-chloro-2-fluorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 1-(3-(3-chloro-4-fluorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 1-(3-(3-chloro-5-fluorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 1-(3-(5-chloro-2-fluorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 2-(3-(3-chlorophenyl)propa-2-in-1-yl)-5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridazine-3(2H)-one; 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyrimidine-2(1H)-one; 3-(3-(3-chlorophenyl)propa-2-in-1-yl)-6-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyrimidine-4(3H)-one; 1-(3-(benzo]thiazole-5-yl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(2-methylbenzo]thiazole-6-yl)propa-2-in-1-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(2-methyl-1H-imidazole-5-yl)propa-2-in-1-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(thiophen-3-yl)propa-2-in-1-yl)pyridine-2(1H)-one; 1-(1-(3-chlorophenyl)penta-1-in-3-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-6-methylpyridine-2(1H)-one; and 5-Bromo-1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one According to another embodiment of the present invention, more specific examples of compounds of formula (1) include the following compounds: 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one; 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(p-tolyl)propa-2-in-1-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(m-tolyl)propa-2-in-1-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(3-(trifluoromethyl)phenyl)propa-2-in-1-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(3-(trifluoromethoxy)phenyl)propa-2-in-1-yl)pyridine-2(1H)-one; 1-(3-(2-chloropyridine-4-yl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(6-methylpyridine-2-yl)prop-2-in-1-yl)pyridine-2(1H)-one; 1-(3-(3-bromophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 1-(3-(3-(difluoromethoxy)phenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one; 3-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-2-oxopyridine-1(2H)-yl)prop-1-in-1-yl)benzonitrile; 1-(3-(5-chloro-2-fluorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 1-(1-(3-chlorophenyl)penta-1-in-3-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; and 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-6-methylpyridine-2(1H)-one

[0032] Manufacturing method A compound of formula (1) according to one embodiment can be prepared by a person with ordinary skill in the synthesis of compounds in the art using known compounds or compounds readily available therefrom. For example, a compound of formula (1) can be synthesized according to the methods of reaction schemes 1 to 3 below, but this is merely an example, and the order of unit operations can be selectively changed as needed. This does not limit the scope of the present invention.

[0033] <Reaction Scheme 1> [ka] (In the formula, X is a leaving group such as mesylic acid (MsO).) Intermediate 3 can be prepared, for example, as shown in the following reaction scheme 1'.

[0034] <Reaction Scheme 1'> [ka] After adding hydrazine or hydroxylamine to each starting material containing an ester and a cyano to obtain intermediate 10 or 12, trifluoroacetic anhydride is added and intermediate 3 is obtained by a cyclization reaction. If necessary, intermediate 5 containing acetylene can also be obtained by an additional nucleophilic addition reaction.

[0035] <Reaction Scheme 2> [ka] In reaction scheme 2, compound 1 is obtained from acetylene intermediate 5 and a halogen-containing reagent by Sonogashira coupling. Intermediate 5 can be prepared by various methods, including reaction scheme 1' or reaction scheme 2' described below.

[0036] <Reaction Scheme 2'> [ka] After obtaining an acetylene-containing intermediate 13 from a cyano-containing starting material 11 by a nucleophilic addition reaction, intermediate 14 is obtained by adding hydroxylamine. Subsequently, intermediate 5 can be obtained by adding trifluoroacetic anhydride and carrying out a cyclization reaction.

[0037] <Reaction Scheme 3> [ka] From the ester-containing starting material 6, an acetylene-containing intermediate 7 is obtained by a nucleophilic addition reaction, and intermediate 8 is obtained by Sonogashira coupling. Subsequently, intermediate 9 is obtained by adding hydrazine, and then compound 1 is obtained by a cyclization reaction with the addition of trifluoroacetic anhydride.

[0038] Pharmaceutical composition In another aspect of the present invention, a pharmaceutical composition for the prevention or treatment of a motor disorder is provided, comprising, as an active ingredient, a therapeutically effective amount of the compound of formula (1) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.

[0039] The aforementioned pharmaceutical composition can be formulated into various oral or parenteral dosage forms. For example, it can be formulated into any dosage form for oral administration, such as tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, and elixirs.

[0040] When the pharmaceutical composition is formulated into a parenteral dosage form, the pharmaceutical composition is administered by parenteral administration methods such as subcutaneous injection, intravenous injection, intramuscular injection, or intrapleural injection. The pharmaceutical composition can be prepared as a solution or suspension by mixing the active ingredient, i.e., the compound of formula (1) or a pharmaceutically acceptable salt thereof, with a stabilizer or buffer in water, and such a solution or suspension can be prepared as a unit dosage form in ampoules or vials.

[0041] medical utility A further aspect of the present invention is to provide a method for preventing or treating a motor disorder in a subject, comprising administering a therapeutically effective amount of the compound of formula (1) or a pharmaceutically acceptable salt thereof to the subject in need. Examples of such motor disorders include, but are not limited to, Huntington's disease, Parkinson's disease, and levodopa-induced dyskinesia (LID).

[0042] The symptoms of Parkinson's disease appear when the ion channel-type glutamate (iGlu) receptors and metabotropic glutamate (mGlu) receptors of the excitatory neurotransmitter glutamate are activated. Of these, metabotropic glutamate receptor 5 (mGluR5) is mainly expressed on the postsynaptic cell membrane (Shigemoto et al., 1997), but is also present on the presynaptic cell membrane and glial cells. Therefore, in Parkinson's disease and levodopa-induced complications (PD-LID), pharmacological inhibition of metabotropic glutamate receptor 5 (mGluR5) modulates postsynaptic excitatory synaptic transmission and glutamatergic hyperactivity, suggesting its potential as a therapeutic target (Huber et al., 2002).

[0043] Although the mechanism of action of HDAC6 (histone deacetylase 6) is not clear, it is known to have neuroprotective effects in neurological diseases such as Huntington's disease and Parkinson's disease. Generally, HDAC6 is thought to influence the development of neurological diseases through various pathways, including aggresome formation, increased autophagy, and removal of abnormally folded proteins (de Zoeten et al., 2011, d'Ydewalle et al., 2011, Fukuda et al., 2012, Govindarajan et al., 2013).

[0044] Changes in cytoprotective activity are associated with various neurodegenerative conditions, such as Parkinson's disease (Outerio et al., Science (2007), (5837), 516-519) and Huntington's disease (Dompierre et al., J. Neurosci. (2007), 27(13), 3571-3583). HDAC6 inhibition is known to have a protective effect, preventing the death of α-synuclein neurons. Simultaneously, it can protect neurons by suppressing α-synuclein aggregation and enhancing autophagy activity, which is involved in regulating α-synuclein accumulation.

[0045] The compound of formula (1) acts as a dual regulator for mGluR5 and HDAC. These compounds reduce excitatory neuronal damage and suppress microglial activity through the inhibition of metabotropic glutamate receptor (mGluR5), which is one of the mechanisms of Parkinson's disease, and exhibit neuroprotective effects through the inhibition of HDAC6. Therefore, the compound of formula (1) can be effectively used as a pharmaceutical composition for the treatment of Parkinson's disease and the suppression of levodopa-induced complications.

[0046] In another embodiment of the present invention, a method for preventing or treating a motor disorder comprises administering to an animal a pharmaceutical composition comprising an effective amount of the compound of formula (1) and a pharmaceutically acceptable carrier or excipient. The method is particularly suitable for use in humans, but can also be used in other animals, particularly mammals.

[0047] The specific method of administration and therapeutically effective dose of the compound of formula (1) or a pharmaceutically acceptable salt thereof can be determined by a person skilled in the art, taking into consideration the type of mammal, the type of disease, and the type of compound of formula (1), and is not particularly limited.

[0048] For example, the compound of formula (1) or a pharmaceutically acceptable salt thereof may be included in the pharmaceutical composition in an effective amount of 0.1 to 1,000 mg / kg (body weight), preferably 0.5 to 500 mg / kg (body weight), per day for mammals including humans. The pharmaceutical composition may be administered orally or parenterally once or in two or more divided doses per day. Examples

[0049] The present invention will be described in detail below with reference to examples. However, it should be understood that the scope of protection of the present invention is not limited to these examples. Example 1: Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-phenylpropa-2-in-1-yl)pyridine-2(1H)-one

[0050] Step 1: Synthesis of methyl 2-oxo-1-(propa-2-in-1-yl)-1,2-dihydropyridine-4-carboxylate [ka] Methyl 2-oxo-1,2-dihydropyridine-4-carboxylate (1,000 g, 6,530 mmol), 3-bromoprop-1-yin (80.00% solution in toluene, 0.618 mL, 6,530 mmol), and potassium carbonate (1,805 g, 13,060 mmol) were dissolved in N,N-dimethylformamide (30 mL) at room temperature, and the solution was stirred at the same temperature for 18 hours. Water was added to the reaction mixture, and it was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to obtain methyl 2-oxo-1-(propa-2-in-1-yl)-1,2-dihydropyridine-4-carboxylate (0.720 g, 57.7%) as a white solid.

[0051] Step 2: Synthesis of methyl 2-oxo-1-(3-phenylpropa-2-in-1-yl)-1,2-dihydropyridine-4-carboxylate [ka] Methyl 2-oxo-1-(propa-2-in-1-yl)-1,2-dihydropyridine-4-carboxylate (0.720 g, 3.766 mmol) and triethylamine (2.624 mL, 18.829 mmol) were dissolved in tetrahydrofuran (10 mL) at room temperature. Bis(triphenylphosphine)palladium(II) dichloride (0.132 g, 0.188 mmol) and copper iodide (CuI, 0.086 g, 0.452 mmol) were added, and the mixture was stirred at the same temperature for 10 minutes. Iodobenzene (0.462 mL, 4.142 mmol) was added to the reaction mixture, and the mixture was further stirred at the same temperature for 18 hours. The reaction mixture was filtered through a Celite pad to remove the solid, the filtrate was desoldered under reduced pressure, and the concentrate was purified by column chromatography and concentrated to obtain methyl 2-oxo-1-(3-phenylpropa-2-in-1-yl)-1,2-dihydropyridine-4-carboxylate (0.658 g, 65.4%) as a yellow solid.

[0052] Step 3: Synthesis of 2-oxo-1-(3-phenylpropa-2-in-1-yl)-1,2-dihydropyridine-4-carbozide [ka] Methyl 2-oxo-1-(3-phenylpropa-2-in-1-yl)-1,2-dihydropyridine-4-carboxylate (0.658 g, 2.462 mmol) and hydrazine monohydrate (1.197 mL, 24.618 mmol) were dissolved in ethanol (20 mL) at room temperature, stirred at 80°C for 5 hours, and then cooled to room temperature to terminate the reaction. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to obtain 2-oxo-1-(3-phenylpropa-2-in-1-yl)-1,2-dihydropyridine-4-carbohydrazide (0.414 g, 62.9%) as a yellow solid. LRMS (ES) m / z 268.06 [M+H]+, calculated MW 267.29.

[0053] Step 4: Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-phenylpropa-2-in-1-yl)pyridine-2(1H)-one [ka] 2-Oxo-1-(3-phenylpropa-2-in-1-yl)-1,2-dihydropyridine-4-carbohydrazide (0.414 g, 1.549 mmol), 2,2-difluoroacetic anhydride (0.578 mL, 4.647 mmol), and triethylamine (0.648 mL, 4.647 mmol) were mixed in tetrahydrofuran (10 mL) at room temperature. The resulting mixture was heated under reflux for 1 hour, then cooled to room temperature. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and it was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to obtain 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-phenylpropa-2-in-1-yl)pyridine-2(1H)-one (0.300 g, 59.2%) as a white solid. LRMS (ES) m / z 328.11 [M+H] + , calculated MW 327.29; 1 H-NMR (400 MHz, CD3OD) d 8.09 (d, J = 7.6 Hz, 1 H), 7.44 (dd, J = 7.8, 1.8 Hz, 2 H), 7.35 - 7.31 (m, 3 H), 7.22 (t, J = 51.8 Hz, 1 H), 7.21 (d, J = 1.6 Hz, 1 H), 7.03 (dd, J = 7.4, 1.8 Hz, 1 H), 5.06 (s, 2 H).

[0054] Example 2: Synthesis of 1-(3-phenylpropa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one Step 1: Synthesis of 2-oxo-1-(propa-2-in-1-yl)-1,2-dihydropyridine-4-carbonitrile [ka] 2-Oxo-1,2-dihydropyridine-4-carbonitrile (3.000 g, 24.977 mmol), 3-bromoprop-1-yin (80.00% solution in toluene, 2.366 mL, 24.977 mmol), and potassium carbonate (6.904 g, 49.954 mmol) were dissolved in N,N-dimethylformamide (30 mL) at room temperature, and the solution was stirred at the same temperature for 18 hours. Water was added to the reaction mixture, and it was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to obtain 2-Oxo-1-(propa-2-in-1-yl)-1,2-dihydropyridine-4-carbonitrile (3.000 g, 75.9%) as an ivory-colored solid.

[0055] Step 2: Synthesis of N'-hydroxy-2-oxo-1-(propa-2-in-1-yl)-1,2-dihydropyridine-4-carboxyimidamide [ka] 2-Oxo-1-(propa-2-in-1-yl)-1,2-dihydropyridine-4-carbonitrile (3.000 g, 18.968 mmol), hydroxylamine (50.00% solution, 6.265 mL, 94.841 mmol), and triethylamine (13.219 mL, 94.841 mmol) were mixed in ethanol (100 mL) at room temperature. The resulting mixture was heated under reflux for 2 hours, then cooled to room temperature. Water was added to the reaction mixture, and it was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The precipitated solid was filtered, washed with ethanol, and dried to obtain N'-hydroxy-2-oxo-1-(propa-2-in-1-yl)-1,2-dihydropyridine-4-carboxyimidamide (2.250 g, 62.0%) as a white solid.

[0056] Step 3: Synthesis of 1-(propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one [ka] N'-hydroxy-2-oxo-1-(propa-2-in-1-yl)-1,2-dihydropyridine-4-carboxyimidamide (2.250 g, 11.768 mmol), trifluoroacetic anhydride (2.493 mL, 17.653 mmol), and triethylamine (2.460 mL, 17.653 mmol) were mixed in tetrahydrofuran (50 mL) at room temperature. The resulting mixture was heated under reflux for 1 hour, then cooled to room temperature. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and it was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to obtain 1-(propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one (2.000 g, 63.1%) as an ivory-colored solid.

[0057] Step 4: Synthesis of 1-(3-phenylpropa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one [ka] 1-(propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one (0.100 g, 0.371 mmol), triethylamine (0.259 mL, 1.857 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.013 g, 0.019 mmol), and copper iodide (CuI, 0.008 g, 0.045 mmol) were dissolved in tetrahydrofuran (5 mL), stirred at room temperature for 10 minutes, then iodobenzene (0.046 mL, 0.409 mmol) was added, and the mixture was stirred additionally at the same temperature for 18 hours. The reaction mixture was filtered through a Celite pad to remove the solid, water was added to the filtrate, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to obtain 1-(3-phenylpropa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one (0.065 g, 50.7%) as a white solid. LRMS (ES) m / z 346.04 [M+H] + , calculated MW 345.28; 1 H-NMR (400 MHz, CD3OD) d 8.07 (d, J = 6.8 Hz, 1 H), 7.45 - 7.43 (m, 2 H), 7.35 - 7.28 (m, 4 H), 7.03 (dd, J = 7.2, 2.0 Hz, 1 H), 5.06 (s, 2 H).

[0058] Example 3: Synthesis of 1-(3-(pyridine-4-yl)propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one [ka] 1-(propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one (0.100g, 0.371mmol), triethylamine (0.259mL, 1.857mmol), bis(triphenylphosphine)palladium(II) dichloride (0.013g, 0.019mmol), copper iodide (CuI, 0.00 Using 8 g, 0.045 mmol) and 4-iodopyridine (0.084 g, 0.409 mmol) as starting materials, 1-(3-(pyridine-4-yl)propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one (0.059 g, 45.9%) was obtained as a yellow solid by the same method as in step 4 of Example 2. LRMS (ES) m / z 347.02 [M+H] + , calculated MW 346.27; 1 H-NMR (400 MHz, CD3OD) d 8.51 (d, J = 4.0 Hz, 2 H), 8.03 (d, J = 7.2 Hz, 1 H), 7.44 (d, J = 6.0 Hz, 2 H), 7.28 (d, J = 2.0 Hz, 1 H), 7.01 (dd, J = 7.0, 2.2 Hz, 1 H), 5.12 (s, 2 H).

[0059] Example 4: Synthesis of 1-(3-(pyridine-3-yl)propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one [ka] 1-(Prop-2-yn-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2(1H)-one (0.100 g, 0.371 mmol), triethylamine (0.259 mL, 1.857 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.013 g, 0.019 mmol), copper(I) iodide (CuI, 0.008 g, 0.045 mmol) and 3-iodopyridine (0.084 g, 0.409 mmol) were used as starting materials, and in the same manner as in Step 4 of Example 2, 1-(3-(pyridin-3-yl)prop-2-yn-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2(1H)-one (0.030 g, 23.3%) was obtained as a yellow solid. LRMS (ES) m / z 347.13 [M+H] + , calculated MW 346.27; 1 H-NMR (400 MHz, CD3OD) d 8.62 (d, J = 1.2 Hz, 1 H), 8.49 (dd, J = 4.6, 1.4 Hz, 1 H), 8.06 (d, J = 7.2 Hz, 1 H), 7.90 (dt, J = 7.6, 2.0 Hz, 1 H), 7.41 (dd, J = 7.8, 5.0 Hz, 1 H), 7.28 (d, J = 1.2 Hz, 1 H), 7.02 (dd, J = 7.0, 2.2 Hz, 1 H), 5.12 (s, 2 H).

[0060] Example 5: Synthesis of 1-(3-(pyridin-2-yl)prop-2-yn-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2(1H)-one

Chemical formula

[0061] Example 6: Synthesis of 1-(3-(2-fluorophenyl)propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one [ka] 1-(propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one (0.100g, 0.371mmol), triethylamine (0.259mL, 1.857mmol), bis(triphenylphosphine)palladium(II) dichloride (0.013g, 0.019mmol), copper iodide (CuI, 0.008g, 0 Using 0.045 mmol) and 1-fluoro-2-iodobenzene (0.091 g, 0.409 mmol) as starting materials, 1-(3-(2-fluorophenyl)propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one (0.045 g, 33.3%) was obtained as a white solid by the same method as in step 4 of Example 2. LRMS (ES) m / z 364.03 [M+H] + , calculated MW 363.27; 1 H-NMR (400 MHz, CD3OD) d 8.07 (d, J = 6.8 Hz, 1 H), 7.47 (td, J = 7.5, 1.7 Hz, 1 H), 7.41 - 7.35 (m, 1 H), 7.29 (d, J = 1.6 Hz, 1 H), 7.16 - 7.10 (m, 2 H), 7.03 (dd, J = 7.2, 1.6 Hz, 1 H), 5.12 (s, 2 H).

[0062] Example 7: Synthesis of 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one [ka] 1-(propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one (0.100g, 0.371mmol), triethylamine (0.259mL, 1.857mmol), bis(triphenylphosphine)palladium(II) dichloride (0.013g, 0.019mmol), copper iodide (CuI, 0.008g, Using 0.045 mmol) and 1-chloro-3-iodobenzene (0.097 g, 0.409 mmol) as starting materials, 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one (0.082 g, 58.1%) was obtained as a white solid by the same method as in step 4 of Example 2. LRMS (ES) m / z 380.00 [M+H] + , calculated MW 379.72; 1 H-NMR (400 MHz, CD3OD) d 8.05 (d, J = 6.8 Hz, 1 H), 7.46 (s, 1 H), 7.38 (dd, J = 2.6, 1.4 Hz, 1 H), 7.36 (dd, J = 3.2, 1.2 Hz, 1 H), 7.32 (d, J = 7.6 Hz, 1 H), 7.28 (d, J = 2.0 Hz, 1 H), 7.02 (dd, J = 7.4, 1.8 Hz, 1 H), 5.07 (s, 2 H).

[0063] Example 8: Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(pyridine-4-yl)propa-2-in-1-yl)pyridine-2(1H)-one Step 1: Synthesis of 2-oxo-1,2-dihydropyridine-4-carbohydrazide [ka] Methyl 2-oxo-1,2-dihydropyridine-4-carboxylate (3.000 g, 19.590 mmol) and hydrazine monohydrate (1.143 mL, 23.508 mmol) were dissolved in ethanol (100 mL) at room temperature. The resulting solution was stirred at 80°C for 18 hours, and then cooled to room temperature to terminate the reaction. The precipitated solid was filtered and dried to obtain 2-oxo-1,2-dihydropyridine-4-carbohydrazide (2.610 g, 87.0%) as an ivory-colored solid. LRMS (ES) m / z 153.98 [M+H] + , calculated MW 153.14.

[0064] Step 2: Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one [ka] 2-Oxo-1,2-dihydropyridine-4-carbohydrazide (2.610 g, 17.043 mmol), 2,2-difluoroacetic anhydride (6.357 mL, 51.130 mmol), and imidazole (3.481 g, 51.130 mmol) were dissolved in dichloromethane (30 mL) at room temperature. The resulting solution was heated under reflux for 18 hours, then cooled to room temperature to terminate the reaction. The reaction mixture was filtered through filter paper to remove the solid, and saturated sodium bicarbonate aqueous solution was added to the filtrate and extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to obtain 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one (1.800 g, 49.6%) as a white solid. LRMS (ES) m / z 213.96 [M+H]+, calculated MW 213.14.

[0065] Step 3: Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(propa-2-in-1-yl)pyridine-2(1H)-one [ka] 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one (2.500 g, 11.729 mmol), 3-bromoprop-1-yne (2.093 g, 17.594 mmol), and potassium carbonate (4.863 g, 35.188 mmol) were dissolved in N,N-dimethylformamide (50 mL) at room temperature. The resulting solution was stirred at the same temperature for 18 hours. The reaction mixture was filtered through a Celite pad, and water was added to the filtrate from which the solid had been removed. The mixture was then extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to obtain 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(propa-2-in-1-yl)pyridine-2(1H)-one (2.000 g, 67.9%) as a yellow solid. LRMS (ES) m / z 293.16 [M+ACN+H] + , calculated MW 251.19.

[0066] Step 4: Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(pyridine-4-yl)propa-2-in-1-yl)pyridine-2(1H)-one [ka] 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(propa-2-in-1-yl)pyridine-2(1H)-one (0.040 g, 0.159 mmol), triethylamine (0.111 mL, 0.796 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.006 g, 0.008 mmol), copper iodide (CuI, 0.00 Using 4 g, 0.019 mmol) and 4-iodopyridine (0.033 g, 0.159 mmol) as starting materials, 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(pyridine-4-yl)propa-2-in-1-yl)pyridine-2(1H)-one (0.028 g, 53.6%) was obtained as a yellow solid by the same method as in step 4 of Example 2. LRMS (ES) m / z 329.03 [M+H] + , calculated MW 328.28; 1 H-NMR (400 MHz, CD3OD) d 8.54 (m, 2 H), 8.07 (d, J = 7.2 Hz, 1 H), 7.47 (m, 2 H), 7.23 (t, J = 51.6 Hz, 1 H), 7.23 (d, J = 2.0 Hz, 1 H), 7.03 (dd, J = 7.0, 1.8 Hz, 1H).

[0067] Example 9: Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(pyridine-3-yl)propa-2-in-1-yl)pyridine-2(1H)-one [ka] 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(propa-2-in-1-yl)pyridine-2(1H)-one (0.040 g, 0.159 mmol), triethylamine (0.111 mL, 0.796 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.006 g, 0.008 mmol), copper iodide (CuI, 0.00 Using 4 g, 0.019 mmol) and 3-iodopyridine (0.033 g, 0.159 mmol) as starting materials, 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(pyridine-3-yl)propa-2-in-1-yl)pyridine-2(1H)-one (0.030 g, 57.4%) was obtained as a yellow solid by the same method as in step 4 of Example 2. LRMS (ES) m / z 329.10 [M+H] + , calculated MW 328.28; 1 H-NMR (400 MHz, DMSO-d6) d 8.64 - 8.52 (m, 2 H), 8.09 (d, J = 7.6 Hz, 1 H), 7.91 (d, J = 6.8 Hz, 1 H), 7.42 (m, 1 H), 7.23 (t, J = 51.8 Hz, 1 H), 7.23 (m, 1 H), 7.04 (dd, J = 7.4, 1.8 Hz, 1 H), 5.11 (s, 2 H).

[0068] Example 10: Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(pyridine-2-yl)propa-2-in-1-yl)pyridine-2(1H)-one [ka] 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(propa-2-in-1-yl)pyridine-2(1H)-one (0.040 g, 0.159 mmol), triethylamine (0.111 mL, 0.796 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.006 g, 0.008 mmol), copper iodide (CuI, 0.00 Using 4 g, 0.019 mmol) and 2-iodopyridine (0.033 g, 0.159 mmol) as starting materials, 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(pyridine-2-yl)propa-2-in-1-yl)pyridine-2(1H)-one (0.020 g, 38.3%) was obtained as a yellow solid by the same method as in step 4 of Example 2. LRMS (ES) m / z 329.03 [M+H] + , calculated MW 328.28; 1 H-NMR (400 MHz, DMSO-d6) d 8.51 (m, 1 H), 8.13 (d, J = 7.2 Hz, 1 H), 7.85 (t, J = 7.8 Hz, 1 H), 7.67 - 7.56 (m, 2 H), 7.42 (dd, J = 7.8, 5.0 Hz, 1 H), 7.24 (t, J = 51.8 Hz, 1 H), 7.24 (m, 1 H), 7.05 (d, J = 6.8 Hz, 1 H), 5.14 (s, 2 H).

[0069] Example 11: Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(4-fluorophenyl)propa-2-in-1-yl)pyridine-2(1H)-one [ka] 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(propa-2-in-1-yl)pyridine-2(1H)-one (0.040 g, 0.159 mmol), triethylamine (0.111 mL, 0.796 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.006 g, 0.008 mmol), copper iodide (CuI, 0.004 g, 0 Using 0.019 mmol) and 1-fluoro-4-iodobenzene (0.035 g, 0.159 mmol) as starting materials, 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(4-fluorophenyl)propa-2-in-1-yl)pyridine-2(1H)-one (0.010 g, 18.2%) was obtained as an ivory-colored solid by the same method as in step 4 of Example 2. LRMS (ES) m / z 346.04 [M+H] + , calculated MW 345.28; 1 H-NMR (400 MHz, CD3OD) d 8.12 (dd, J = 6.8, 3.6 Hz, 1 H), 7.52 - 7.49 (m, 2 H), 7.25 (t, J = 51.8 Hz, 1 H), 7.26 - 7.23 (m, 1 H), 7.13 - 7.04 (m, 3 H), 5.08 (d, J = 3.6 Hz, 2 H).

[0070] Example 12: Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(3-fluorophenyl)propa-2-in-1-yl)pyridine-2(1H)-one [ka] 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(propa-2-in-1-yl)pyridine-2(1H)-one (0.040 g, 0.159 mmol), triethylamine (0.111 mL, 0.796 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.006 g, 0.008 mmol), copper iodide (CuI, 0.004 g, 0 Using 0.019 mmol) and 1-fluoro-3-iodobenzene (0.035 g, 0.159 mmol) as starting materials, 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(3-fluorophenyl)propa-2-in-1-yl)pyridine-2(1H)-one (0.012 g, 21.8%) was obtained as an ivory-colored solid by the same method as in step 4 of Example 2. LRMS (ES) m / z 346.04 [M+H] + , calculated MW 345.28; 1 H-NMR (400 MHz, CD3OD) d 8.11 (d, J = 7.2 Hz, 1 H), 7.40 - 7.34 (m, 1 H), 7.28 (d, J = 19.6 Hz, 1 H), 7.25 (t, J = 51.8 Hz, 1 H), 7.25 - 7.21 (m, 2 H), 7.16 - 7.11 (m, 1 H), 7.06 (dd, J = 7.4, 1.8 Hz, 1 H), 5.10 (s, 2 H).

[0071] Example 13: Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(2-fluorophenyl)propa-2-in-1-yl)pyridine-2(1H)-one [ka] 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(propa-2-in-1-yl)pyridine-2(1H)-one (0.040 g, 0.159 mmol), triethylamine (0.111 mL, 0.796 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.006 g, 0.008 mmol), copper iodide (CuI, 0.004 g, 0 Using 0.019 mmol) and 1-fluoro-2-iodobenzene (0.035 g, 0.159 mmol) as starting materials, 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(2-fluorophenyl)propa-2-in-1-yl)pyridine-2(1H)-one (0.010 g, 18.2%) was obtained as an ivory-colored solid by the same method as in step 4 of Example 2. LRMS (ES) m / z 346.04 [M+H] + , calculated MW 345.28; 1 H-NMR (400 MHz, CD3OD) d 8.12 (d, J = 6.8 Hz, 1 H), 7.50 - 7.49 (m, 1 H), 7.40 - 7.38 (m, 1 H), 7.25 (m, 1 H), 7.25 (t, J = 51.8 Hz, 1 H), 7.17 - 7.12 (m, 2 H), 7.08 - 7.06 (m, 1 H), 5.15 (s, 2 H).

[0072] Example 14: Synthesis of 1-(3-(4-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one [ka] 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(propa-2-in-1-yl)pyridine-2(1H)-one (0.040 g, 0.159 mmol), triethylamine (0.111 mL, 0.796 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.006 g, 0.008 mmol), copper iodide (CuI, 0.004 g, Using 0.019 mmol) and 1-chloro-4-iodobenzene (0.038 g, 0.159 mmol) as starting materials, 1-(3-(4-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one (0.010 g, 17.4%) was obtained as an ivory-colored solid by the same method as in step 4 of Example 2. LRMS (ES) m / z 362.00 [M+H] + , calculated MW 361.73; 1 H-NMR (400 MHz, CD3OD) d 8.10 (d, J = 6.8 Hz, 1 H), 7.46 - 7.44 (m, 2 H), 7.35 (m, 2 H), 7.25 (t, J = 51.8 Hz, 1 H), 7.23 (m, 1 H), 7.05 (dd, J = 6.8, 2.0 Hz, 1 H), 5.08 (s, 2 H).

[0073] Example 15: Synthesis of 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one [ka] 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(propa-2-in-1-yl)pyridine-2(1H)-one (0.040 g, 0.159 mmol), triethylamine (0.111 mL, 0.796 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.006 g, 0.008 mmol), copper iodide (CuI, 0.004 g, Using 0.019 mmol) and 1-chloro-3-iodobenzene (0.038 g, 0.159 mmol) as starting materials, 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one (0.010 g, 17.4%) was obtained as an ivory-colored solid by the same method as in step 4 of Example 2. LRMS (ES) m / z 362.00 [M+H] + , calculated MW 361.73; 1 H-NMR (400 MHz, CD3OD) d 8.11 (d, J = 7.6 Hz, 1 H), 7.50 (t, J = 1.6 Hz, 1 H), 7.41 - 7.36 (m, 2 H), 7.25 (t, J = 51.8 Hz, 1 H), 7.24 (d, J = 2.0 Hz, 2 H), 7.06 (dd, J = 7.0, 2.2 Hz, 1 H), 5.10 (s, 2 H).

[0074] Example 16: Synthesis of 1-(3-(2-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one [ka] 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(propa-2-in-1-yl)pyridine-2(1H)-one (0.040 g, 0.159 mmol), triethylamine (0.111 mL, 0.796 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.006 g, 0.008 mmol), copper iodide (CuI, 0.004 g, Using 0.019 mmol) and 1-chloro-2-iodobenzene (0.038 g, 0.159 mmol) as starting materials, 1-(3-(2-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one (0.008 g, 13.9%) was obtained as an ivory-colored solid by the same method as in step 4 of Example 2. LRMS (ES) m / z 362.00 [M+H] + , calculated MW 361.73; 1 H-NMR (400 MHz, CD3OD) d 8.17 (m, 1 H), 7.56 - 7.08 (m, 7 H), 5.16 (s, 2 H).

[0075] Example 17: Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(p-tolyl)propa-2-in-1-yl)pyridine-2(1H)-one [ka] 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(propa-2-in-1-yl)pyridine-2(1H)-one (0.040 g, 0.159 mmol), triethylamine (0.111 mL, 0.796 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.006 g, 0.008 mmol), copper iodide (CuI, 0.004 Using (g, 0.019 mmol) and 1-iodo-4-methylbenzene (0.035 g, 0.159 mmol) as starting materials, 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(p-tolyl)propa-2-in-1-yl)pyridine-2(1H)-one (0.010 g, 18.4%) was obtained as an ivory-colored solid by the same method as in step 4 of Example 2. LRMS (ES) m / z 342.19 [M+H] + , calculated MW 341.32; 1 H-NMR (400 MHz, CD3OD) d 8.12 (d, J = 7.2 Hz, 1 H), 7.25 (t, J = 51.8 Hz, 1 H), 7.34 (d, J = 7.6 Hz, 2 H), 7.25 - 7.23 (m, 1 H), 7.16 (d, J = 7.6 Hz, 2 H), 7.05 (dd, J = 7.0, 2.2 Hz, 1 H), 5.07 (s, 2 H), 2.34 (s, 3 H).

[0076] Example 18: Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(m-tolyl)propa-2-in-1-yl)pyridine-2(1H)-one [ka] 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(propa-2-in-1-yl)pyridine-2(1H)-one (0.040 g, 0.159 mmol), triethylamine (0.111 mL, 0.796 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.006 g, 0.008 mmol), copper iodide (CuI, 0.004 Using (g, 0.019 mmol) and 1-iodo-3-methylbenzene (0.035 g, 0.159 mmol) as starting materials, 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(m-tolyl)propa-2-in-1-yl)pyridine-2(1H)-one (0.015 g, 27.6%) was obtained as an ivory-colored solid by the same method as in step 4 of Example 2. LRMS (ES) m / z 342.05 [M+H] + , calculated MW 341.32; 1 H-NMR (400 MHz, CD3OD) d 8.13 (d, J = 7.2 Hz, 1 H), 7.25 (t, J = 51.6 Hz, 1 H), 7.30 - 7.21 (m, 5 H), 7.07 (d, J = 7.2 Hz, 1 H), 5.08 (s, 2 H), 2.32 (s, 3 H).

[0077] Example 19: Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(3-(trifluoromethyl)phenyl)propa-2-in-1-yl)pyridine-2(1H)-one [ka] 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(propa-2-in-1-yl)pyridine-2(1H)-one (0.050g, 0.199mmol), triethylamine (0.139mL, 0.995mmol), bis(triphenylphosphine)palladium(II) dichloride (0.007g, 0.010mmol), copper iodide (CuI, 0.005g, 0.024mmol) Using ) and 1-iodo-3-(trifluoromethyl)benzene (0.032 mL, 0.219 mmol) as starting materials, 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(3-(trifluoromethyl)phenyl)propa-2-in-1-yl)pyridine-2(1H)-one (0.030 g, 38.1%) was obtained as an ivory-colored solid by the same method as in step 4 of Example 2. LRMS (ES) m / z 396.27 [M+H] + , calculated MW 395.29; 1 H-NMR (400 MHz, DMSO-d6) d 8.12 (d, J = 6.8 Hz, 1 H), 7.79 (s, 1 H), 7.75 (d, J = 7.6 Hz, 2 H), 7.53 (t, J = 51.2 Hz, 1 H), 7.60 (t, J = 7.8 Hz, 1 H), 7.01 (d, J = 1.6 Hz, 1 H), 6.84 (dd, J = 7.4, 1.8 Hz, 1 H), 5.06 (s, 2 H).

[0078] Example 20: Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(3-(trifluoromethoxy)phenyl)propa-2-in-1-yl)pyridine-2(1H)-one [ka] 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(propa-2-in-1-yl)pyridine-2(1H)-one (0.050g, 0.199mmol), triethylamine (0.139mL, 0.995mmol), bis(triphenylphosphine)palladium(II) dichloride (0.007g, 0.010mmol), copper iodide (CuI, 0.005g, 0.024mmol) Using 1-iodo-3-(trifluoromethoxy)benzene (0.034 mL, 0.219 mmol) as a starting material, 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(3-(trifluoromethoxy)phenyl)propa-2-in-1-yl)pyridine-2(1H)-one (0.030 g, 36.6%) was obtained as an ivory-colored solid by the same method as in step 4 of Example 2. LRMS (ES) m / z 411.93 [M+H] + , calculated MW 411.29; 1 H-NMR 400 MHz, DMSO-d6) d 8.10 (d, J = 7.2 Hz, 1 H), 7.53 (t, J = 51.4 Hz, 1 H), 7.50 - 7.40 (m, 4 H), 7.01 (d, J = 2.4 Hz, 1 H), 6.84 (dd, J = 7.2, 2.0 Hz, 1 H), 5.05 (s, 2 H).

[0079] Example 21: Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(3-methoxyphenyl)propa-2-in-1-yl)pyridine-2(1H)-one [ka] 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(propa-2-in-1-yl)pyridine-2(1H)-one (0.050g, 0.199mmol), triethylamine (0.139mL, 0.995mmol), bis(triphenylphosphine)palladium(II) dichloride (0.007g, 0.010mmol), copper iodide (CuI, 0.005g, 0. Using 0.24 mmol) and 1-iodo-3-methoxybenzene (0.029 mL, 0.219 mmol) as starting materials, 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(3-methoxyphenyl)propa-2-in-1-yl)pyridine-2(1H)-one (0.013 g, 18.3%) was obtained as an ivory-colored solid by the same method as in step 4 of Example 2. LRMS (ES) m / z 358.16 [M+H] + , calculated MW 357.32; 1 H-NMR (400 MHz, DMSO-d6) d 8.10 (d, J = 7.2 Hz, 1 H), 7.53 (t, J = 51.6 Hz, 1 H), 7.26 (t, J = 7.8 Hz, 1 H), 7.01 - 6.93 (m, 4 H), 6.84 (dd, J = 7.0, 2.2 Hz, 1 H), 5.02 (s, 2 H), 3.72 (s, 3 H).

[0080] Example 22: Synthesis of 1-(3-(6-chloropyridine-2-yl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one [ka] 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(propa-2-in-1-yl)pyridine-2(1H)-one (0.050g, 0.199mmol), triethylamine (0.139mL, 0.995mmol), bis(triphenylphosphine)palladium(II) dichloride (0.007g, 0.010mmol), copper iodide (CuI, 0.005g, 0.0 Using 24 mmol) and 2-chloro-6-iodopyridine (0.026 mL, 0.219 mmol) as starting materials, 1-(3-(6-chloropyridine-2-yl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one (0.028 g, 38.8%) was obtained as a yellow solid in the same manner as in step 4 of Example 2. LRMS (ES) m / z 363.12 [M+H] + , calculated MW 362.72; 1 H-NMR (400 MHz, DMSO-d6) d 8.09 (d, J = 6.4 Hz, 1 H), 7.85 (t, J = 7.8 Hz, 1 H), 7.53 (t, J = 51.2 Hz, 1 H), 7.57 - 7.50 (m, 2 H), 7.02 (d, J = 1.6 Hz, 1 H), 6.85 (dd, J = 7.0, 2.2 Hz, 1 H), 5.08 (s, 2 H).

[0081] Example 23: Synthesis of 1-(3-(2-chloropyridine-4-yl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one [ka] 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(propa-2-in-1-yl)pyridine-2(1H)-one (0.050g, 0.199mmol), triethylamine (0.139mL, 0.995mmol), bis(triphenylphosphine)palladium(II) dichloride (0.007g, 0.010mmol), copper iodide (CuI, 0.005g, 0.0 Using 24 mmol) and 2-chloro-4-iodopyridine (0.026 mL, 0.219 mmol) as starting materials, 1-(3-(2-chloropyridine-4-yl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one (0.015 g, 20.8%) was obtained as a yellow solid in the same manner as in step 4 of Example 2. LRMS (ES) m / z 363.12 [M+H] + , calculated MW 362.72; 1 H-NMR (400 MHz, DMSO-d6) d 8.40 (d, J = 6.0 Hz, 1 H), 8.09 (d, J = 6.4 Hz, 1 H), 7.53 (t, J = 51.2 Hz, 1 H), 7.61 (m, 1 H), 7.44 (dd, J = 5.0, 1.4 Hz, 1 H), 7.02 (d, J = 1.2 Hz, 1 H), 6.84 (dd, J = 7.4, 1.8 Hz, 1 H), 5.10 (s, 2 H).

[0082] Example 24: Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(6-methylpyridine-2-yl)propa-2-in-1-yl)pyridine-2(1H)-one [ka] 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(propa-2-in-1-yl)pyridine-2(1H)-one (0.050g, 0.199mmol), triethylamine (0.139mL, 0.995mmol), bis(triphenylphosphine)palladium(II) dichloride (0.007g, 0.010mmol), copper iodide (CuI, 0.005g, 0.0 Using 24 mmol) and 2-iodo-6-methylpyridine (0.026 mL, 0.219 mmol) as starting materials, 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(6-methylpyridine-2-yl)propa-2-in-1-yl)pyridine-2(1H)-one (0.020 g, 29.4%) was obtained as a brown solid by the same method as in step 4 of Example 2. LRMS (ES) m / z 343.17 [M+H] + , calculated MW 342.31; 1 H-NMR (400 MHz, DMSO-d6) d 8.09 (d, J = 7.2 Hz, 1 H), 7.68 - 7.64 (m, 1 H), 7.53 (t, J = 51.8 Hz, 1 H), 7.31 (d, J = 7.2 Hz, 1 H), 7.23 (d, J = 8.0 Hz, 1 H), 7.02 (d, J = 1.2 Hz, 1 H), 6.85 (dd, J = 7.0, 2.2 Hz, 1 H), 5.05 (s, 2 H), 2.40 (s, 3 H).

[0083] Example 25: Synthesis of 1-(3-(3-bromophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one [ka] 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(propa-2-in-1-yl)pyridine-2(1H)-one (0.050g, 0.199mmol), triethylamine (0.139mL, 0.995mmol), bis(triphenylphosphine)palladium(II) dichloride (0.007g, 0.010mmol), copper iodide (CuI, 0.005g, Using 0.024 mmol) and 1-bromo-3-iodobenzene (0.028 mL, 0.219 mmol) as starting materials, 1-(3-(3-bromophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one (0.019 g, 23.5%) was obtained as a white solid by the same method as in step 4 of Example 2. LRMS (ES [M+2H]) m / z 408.10 [M+H] + , calculated MW 406.19; 1 H-NMR (400 MHz, DMSO-d6) d 8.10 (d, J = 6.8 Hz, 1 H), 7.65 (d, J = 1.6 Hz, 1 H), 7.59 (dt, J = 6.8, 1.3 Hz, 1 H), 7.53 (t, J = 51.4 Hz, 1 H), 7.45 (dd, J = 7.6, 1.2 Hz, 1 H), 7.31 (t, J = 8.0 Hz, 1 H), 7.01 (d, J = 1.2 Hz, 1 H), 6.84 (dd, J = 7.2, 2.0 Hz, 1 H), 5.04 (s, 2 H).

[0084] Example 26: Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(3-(difluoromethyl)phenyl)propa-2-in-1-yl)pyridine-2(1H)-one Step 1: Synthesis of 3-(3-(difluoromethyl)phenyl)propa-2-in-1-ol [ka] 3-(3-(difluoromethoxy)phenyl)propa-2-in-1-ol (0.550 g, 2.775 mmol), methanesulfonyl chloride (0.322 mL, 4.163 mmol), and triethylamine (0.774 mL, 5.551 mmol) were dissolved in dichloromethane (10 mL) at room temperature. The resulting solution was stirred at the same temperature for 1 hour. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to obtain 3-(3-(difluoromethoxy)phenyl)propa-2-in-1-ylmethanesulfonate (0.430 g, 56.1%) as a yellow liquid. LRMS (ES) m / z no detection [M+H] + , calculated MW 182.17.

[0085] Step 2: Synthesis of 3-(3-(difluoromethyl)phenyl)propa-2-in-1-ylmethanesulfonate [ka] 3-(3-(difluoromethyl)phenyl)propa-2-in-1-ol (0.750 g, 4.117 mmol), methanesulfonyl chloride (0.478 mL, 6.176 mmol), and triethylamine (1.148 mL, 8.234 mmol) were dissolved in dichloromethane (10 mL) at room temperature. The resulting solution was stirred at the same temperature for 1 hour. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to obtain 3-(3-(difluoromethyl)phenyl)propa-2-in-1-ylmethanesulfonate (0.975 g, 91.0%) as a clear liquid. LRMS (ES) m / z no detection [M+H] + , calculated MW 260.25.

[0086] Step 3: Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(3-(difluoromethyl)phenyl)propa-2-in-1-yl)pyridine-2(1H)-one [ka] 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one (0.050 g, 0.235 mmol), 3-(3-(difluoromethyl)phenyl)propa-2-in-1-ylmethanesulfonate (0.092 g, 0.352 mmol), and cesium carbonate (Cs2CO3, 0.115 g, 0.352 mmol) were dissolved in acetonitrile (2 mL) at room temperature. The resulting solution was stirred at the same temperature for 10 minutes. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to obtain 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(3-(difluoromethyl)phenyl)propa-2-in-1-yl)pyridine-2(1H)-one (0.037 g, 41.5%) as a white solid. LRMS (ES) m / z 378.17 [M+H] + , calculated MW 377.3; 1 H-NMR 400 MHz, CD3OD) d 8.09 (d, J = 7.2 Hz, 1 H), 7.61 (s, 1 H), 7.58 (d, J = 7.2 Hz, 1 H), 7.53 (d, J = 7.6 Hz, 1 H), 7.46 (t, J = 7.6 Hz, 1 H), 7.23 (t, J = 51.8 Hz, 1 H), 7.22 (s, 1 H), 7.03 (dd, J = 7.0, 1.4 Hz, 1 H), 6.73 (t, J = 56.2 Hz, 1 H), 5.08 (s, 2 H).

[0087] Example 27: Synthesis of 1-(3-(3-(difluoromethoxy)phenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one Step 1: Synthesis of 3-(3-(difluoromethoxy)phenyl)propa-2-in-1-ylmethanesulfonate [ka] Using 1-bromo-3-(difluoromethoxy)benzene (1.000 g, 4.484 mmol), 2,3,4,6,7,8,9,10-octahydropyrimide[1,2-a]azepine (DBU, 0.805 mL, 5.381 mmol), tetrakis(triphenylphosphine)palladium (0.155 g, 0.135 mmol), and copper iodide (CuI, 0.026 g, 0.135 mmol) as starting materials, 3-(3-(difluoromethoxy)phenyl)propa-2-in-1-ol (0.550 g, 61.9%) was obtained as a yellow solid in the same manner as in step 1 of Example 26. LRMS (ES) m / z no detection [M+H] + , calculated MW 198.17.

[0088] Step 2: Synthesis of 3-(3-(difluoromethoxy)phenyl)propa-2-in-1-ylmethanesulfonate [ka] Using 3-(3-(difluoromethoxy)phenyl)propa-2-in-1-ol (0.550 g, 2.775 mmol), methanesulfonyl chloride (0.322 mL, 4.163 mmol), and triethylamine (0.774 mL, 5.551 mmol) as starting materials, 3-(3-(difluoromethoxy)phenyl)propa-2-in-1-ylmethanesulfonate (0.430 g, 56.1%) was obtained as a yellow liquid in the same manner as in step 2 of Example 26. LRMS (ES) m / z no detection [M+H] +Calculated MW 276.25.

[0089] Step 3: Synthesis of 1-(3-(3-(difluoromethoxy)phenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one [ka] Using 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one (0.050 g, 0.235 mmol), 3-(3-(difluoromethoxy)phenyl)propa-2-in-1-ylmethanesulfonate (0.097 g, 0.352 mmol), and cesium carbonate (Cs2CO3, 0.153 g, 0.469 mmol) as starting materials, 1-(3-(3-(difluoromethoxy)phenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one (0.007 g, 7.6%) was obtained as a brown solid by the same method as in step 3 of Example 26. LRMS (ES) m / z 394.29 [M+H] + , calculated MW 393.3; 1 H-NMR (400 MHz, CD3OD) d 8.08 (d, J = 7.2 Hz, 1 H), 7.22 (t, J = 51.6 Hz, 1 H), 7.38 - 7.29 (m, 2 H), 7.22 (d, J = 1.6 Hz, 2 H), 7.14 (d, J = 8.0 Hz, 1 H), 7.03 (dd, J = 7.2, 2.0 Hz, 1 H), 6.82 (t, J = 73.8 Hz, 1 H), 5.07 (s, 2 H).

[0090] Example 28: Synthesis of 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one Step 1: Synthesis of 4-(5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one [ka] Using 2-oxo-1,2-dihydropyridine-4-carbohydrazide (1.730 g, 11.297 mmol), triethylamine (4.724 mL, 33.891 mmol), and trifluoroacetic anhydride (4.787 mL, 33.891 mmol) as starting materials, 4-(5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one (1.500 g, 57.4%) was obtained as a light brown solid by the same method as in step 2 of Example 8. 1 H-NMR (400 MHz, DMSO-d6) d 8.91 (s, 1 H), 7.59 (s, 2 H).

[0091] Step 2: Synthesis of 3-(3-chlorophenyl)propa-2-in-1-ol [ka] Using 1-chloro-3-iodobenzene (1.000 g, 4.194 mmol), 2,3,4,6,7,8,9,10-octahydropyrimide[1,2-a]azepine (DBU, 0.753 mL, 5.033 mmol), tetrakis(triphenylphosphine)palladium (0.145 g, 0.126 mmol), and copper iodide (CuI, 0.024 g, 0.126 mmol) as starting materials, 3-(3-chlorophenyl)propa-2-in-1-ol (0.580 g, 83.0%) was obtained as a yellow solid in the same manner as in step 1 of Example 26. LRMS (ES) m / z no detection [M+H] + , calculated MW 166.60.

[0092] Step 3: Synthesis of 3-(3-chlorophenyl)propa-2-in-1-ylmethanesulfonate [ka] Using 3-(3-chlorophenyl)propa-2-in-1-ol (0.580 g, 3.481 mmol), methanesulfonyl chloride (9.20 M solution in toluene, 0.568 mL, 5.222 mmol), and triethylamine (1.456 mL, 10.444 mmol) as starting materials, 3-(3-chlorophenyl)propa-2-in-1-ylmethanesulfonate (0.650 g, 76.3%) was obtained as a clear liquid in the same manner as in step 2 of Example 26. LRMS (ES) m / z no detection [M+H] + , calculated MW 244.69.

[0093] Step 4: Synthesis of 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one [ka] Using 4-(5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one (0.050 g, 0.216 mmol), 3-(3-chlorophenyl)propa-2-in-1-ylmethanesulfonate (0.079 g, 0.324 mmol), and cesium carbonate (Cs2CO3, 0.141 g, 0.433 mmol) as starting materials, k1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one (0.066 g, 80.3%) was obtained as a yellow solid in the same manner as in step 3 of Example 26. LRMS (ES) m / z 380.09 [M+H] + , calculated MW 379.72; 1H-NMR (400 MHz, CD3OD) d 8.09 (d, J = 6.8 Hz, 1 H), 7.46 (s, 1 H), 7.38 - 7.29 (m, 3 H), 7.23 (d, J = 1.6 Hz, 1 H), 7.03 (dd, J = 6.8, 1.6 Hz, 1 H), 5.07 (s, 2 H).

[0094] Example 29: Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(5-methylpyridine-3-yl)propa-2-in-1-yl)pyridine-2(1H)-one Step 1: Synthesis of 3-(5-methylpyridine-3-yl)propa-2-in-1-ol [ka] Using 3-bromo-5-methylpyridine (1.000 g, 5.813 mmol), 2,3,4,6,7,8,9,10-octahydropyrimide[1,2-a]azepine (DBU, 1.043 mL, 6.976 mmol), tetrakis(triphenylphosphine)palladium (0.202 g, 0.174 mmol), copper iodide (CuI, 0.033 g, 0.174 mmol), and propa-2-in-1-ol (0.391 g, 6.976 mmol) as starting materials, 3-(5-methylpyridine-3-yl)propa-2-in-1-ol (0.752 g, 87.9%) was obtained as a yellow solid by the same method as in step 1 of Example 26. LRMS (ES) m / z no detection [M+H] + , calculated MW 147.18.

[0095] Step 2: Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(5-methylpyridine-3-yl)propa-2-in-1-yl)pyridine-2(1H)-one [ka] 3-(5-methylpyridine-3-yl)propa-2-in-1-ol (0.050 g, 0.340 mmol), methanesulfonyl chloride (0.032 mL, 0.408 mmol), and triethylamine (0.057 mL, 0.408 mmol) were dissolved in acetonitrile (10 mL), stirred at room temperature for 1 hour, and 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one (0.109 g, 0.510 mmol) and cesium carbonate (Cs2CO3, 0.166 g, 0.510 mmol) were added. The mixture was stirred for an additional 0.5 hours at the same temperature. Water was poured over the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to obtain 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(5-methylpyridine-3-yl)propa-2-in-1-yl)pyridine-2(1H)-one (0.020 g, 17.2%) as a white solid. LRMS (ES) m / z 343.23 [M+H] + , calculated MW 342.31; 1 H-NMR (400 MHz, CD3OD) d 8.41 (s, 1 H), 8.35 (s, 1 H), 8.08 (d, J = 6.8 Hz, 1 H), 7.75 (s, 1 H), 7.62 - 7.56 (m, 1 H), 7.23 (t, J = 51.6 Hz, 1 H), 7.22 (d, J = 2.0 Hz, 1 H), 7.03 (dd, J = 7.2, 2.0 Hz, 1 H), 5.10 (s, 2 H), 2.32 (s, 3 H).

[0096] Example 30: Synthesis of 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one Step 1: Synthesis of N'-hydroxy-2-oxo-1,2-dihydropyridine-4-carboxyimidamide [ka] Using 2-oxo-1,2-dihydropyridine-4-carbonitrile (2.000 g, 16.651 mmol) and hydroxylamine (50.00% solution in water, 3.300 mL, 49.954 mmol) as starting materials, N'-hydroxy-2-oxo-1,2-dihydropyridine-4-carboxyimidamide (2.430 g, 95.3%) was obtained as an ivory-colored solid by the same method as in step 1 of Example 8.

[0097] Step 2: Synthesis of 4-(5-(difluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one [ka] Using N'-hydroxy-2-oxo-1,2-dihydropyridine-4-carboxyimidamide (2.430 g, 15.868 mmol), triethylamine (6.635 mL, 47.604 mmol), and 2,2-difluoroacetic anhydride (5.918 mL, 47.604 mmol) as starting materials, 4-(5-(difluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one (2.000 g, 59.1%) was obtained as a white solid by the same method as in step 2 of Example 8.

[0098] Step 3: Synthesis of 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one [ka] Using 4-(5-(difluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one (0.050 g, 0.235 mmol), 3-(3-chlorophenyl)propa-2-in-1-ylmethanesulfonate (0.086 g, 0.352 mmol), and cesium carbonate (Cs2CO3, 0.153 g, 0.469 mmol) as starting materials, 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one (0.052 g, 61.3%) was obtained as a white solid by the same method as in step 3 of Example 26. LRMS (ES) m / z 362.19 [M+H] + , calculated MW 361.73; 1 H-NMR (400 MHz, CD3OD) d 8.02 (d, J = 7.2 Hz, 1 H), 7.43 (s, 1 H), 7.36 - 7.25 (m, 3 H), 7.25 (d, J = 1.2 Hz, 1 H), 7.22 (t, J = 51.4 Hz, 1 H), 6.99 (dd, J = 7.2, 1.6 Hz, 1 H), 5.06 (s, 2 H).

[0099] Example 31: Synthesis of 3-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-2-oxopyridine-1(2H)-yl)prop-1-in-1-yl)benzonitrile Step 1: Synthesis of 3-(3-hydroxyprop-1-in-1-yl)benzonitrile [ka] Using propa-2-in-1-ol (0.312 mL, 5.351 mmol), 3-iodobenzonitrile (1.226 g, 5.351 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.075 g, 0.107 mmol), copper iodide (CuI, 0.020 g, 0.107 mmol), and triethylamine (2.238 mL, 16.054 mmol) as starting materials, 3-(3-hydroxyprop-1-in-1-yl)benzonitrile (0.768 g, 91.3%) was obtained as a yellow oily substance by the same method as in step 1 of Example 26. LRMS (ES) m / z no detection [M+H] + Calculated MW 235.26.

[0100] Step 2: Synthesis of 3-(3-cyanophenyl)propane-2-in-1-ylmethanesulfonate [ka] Using 3-(3-hydroxyprop-1-in-1-yl)benzonitrile (0.768 g, 4.886 mmol), triethylamine (2.043 mL, 14.659 mmol), and methanesulfonyl chloride (0.756 mL, 9.773 mmol) as starting materials, 3-(3-cyanophenyl)prop-2-in-1-ylmethanesulfonate (0.703 g, 61.2%) was obtained as a yellow solid in the same manner as in step 2 of Example 26. LRMS (ES) m / z no detection [M+H] + Calculated MW 235.26.

[0101] Step 3: Synthesis of 3-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-2-oxopyridine-1(2H)-yl)prop-1-in-1-yl)benzonitrile [ka] 4-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2(1H)-one (0.100 g, 0.469 mmol), 3-(3-cyanophenyl)prop-2-yn-1-yl methanesulfonate (0.110 g, 0.469 mmol) and cesium carbonate (Cs2CO3, 0.459 g, 1.408 mmol) were used as starting materials, and 3-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-oxopyridin-1(2H)-yl)prop-1-yn-1-yl)benzonitrile (0.027 g, 16.3%) was obtained as a yellow solid in the same manner as in Step 3 of Example 26. LRMS (ES) m / z 353.14 [M+H] + , calculated MW 352.3; 1 1H-NMR (400 MHz, CDCl3) δ 7.82 (d, J = 6.8 Hz, 1 H), 7.74 (t, J = 1.4 Hz, 1 H), 7.69 - 7.63 (m, 2 H), 7.46 (t, J = 7.8 Hz, 1 H), 7.30 (d, J = 2.0 Hz, 2 H), 6.95 (dd, J = 7.4, 1.8 Hz, 1 H), 6.92 (t, J = 51.6 Hz, 1 H), 5.03 (s, 2 H).

[0102] Example 32: Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-1-(3-(3-(methylsulfonyl)phenyl)prop-2-yn-1-yl)pyridin-2(1H)-one Step 1: Synthesis of 3-(3-(methylsulfonyl)phenyl)prop-2-yn-1-ol

Chemical formula

[0103] Step 2: Synthesis of 3-(3-(methylsulfonyl)phenyl)propargyl methanesulfonate

Chemical formula

[0104] Step 3: Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-1-(3-(3-(methylsulfonyl)phenyl)propargyl)pyridin-2(1H)-one

Chemical formula

[0105] Example 33: Synthesis of 1-(3-(3-chloro-2-fluorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one [ka] 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(propa-2-in-1-yl)pyridine-2(1H)-one (0.100g, 0.398mmol), triethylamine (0.277mL, 1.991mmol), bis(triphenylphosphine)palladium(II) dichloride (0.014g, 0.020mmol), copper iodide (CuI, 0.009g, 0.048mm) Using 0.112 g, 0.438 mmol) and 1-chloro-2-fluoro-3-iodobenzene as starting materials, 1-(3-(3-chloro-2-fluorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one (0.080 g, 52.9%) was obtained as a yellow solid by the same method as in step 4 of Example 2. LRMS (ES) m / z 380.02 [M+H] + , calculated MW 379.72; 1H-NMR (400 MHz, DMSO-d6) d 8.08 (d, J = 6.8 Hz, 1 H), 7.52 (t, J = 51.2 Hz, 1 H), 7.62 (td, J = 7.7, 1.5 Hz, 1 H), 7.49 - 7.48 (m, 1 H), 7.21 (td, J = 8.0, 0.8 Hz, 1 H), 7.02 (d, J = 1.6 Hz, 1 H), 6.84 (dd, J = 7.0, 1.8 Hz, 1 H), 5.10 (s, 2 H).

[0106] Example 34: Synthesis of 1-(3-(3-chloro-4-fluorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one [ka] 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(propa-2-in-1-yl)pyridine-2(1H)-one (0.100g, 0.398mmol), triethylamine (0.277mL, 1.991mmol), bis(triphenylphosphine)palladium(II) dichloride (0.014g, 0.020mmol), copper iodide (CuI, 0.004g, 0.020mmol) Using 0.112 g, 0.438 mmol) and 2-chloro-1-fluoro-4-iodobenzene as starting materials, 1-(3-(3-chloro-4-fluorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one (0.092 g, 60.9%) was obtained as a yellow solid by the same method as in step 4 of Example 2. LRMS (ES) m / z 380.09 [M+H] + , calculated MW 379.72; 1H-NMR (400 MHz, DMSO-d6) d 8.09 (d, J = 7.2 Hz, 1 H), 7.72 (dd, J = 7.0, 1.8 Hz, 1 H), 7.52 (t, J = 51.2 Hz, 1 H), 7.47 - 7.46 (m, 1 H), 7.43 - 7.39 (m, 1 H), 7.01 (d, J = 2.0 Hz, 1 H), 6.83 (dd, J = 7.2, 2.0 Hz, 1 H), 5.03 (s, 2 H).

[0107] Example 35: Synthesis of 1-(3-(3-chloro-5-fluorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one [ka] 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(propa-2-in-1-yl)pyridine-2(1H)-one (0.100g, 0.398mmol), triethylamine (0.277mL, 1.991mmol), bis(triphenylphosphine)palladium(II) dichloride (0.014g, 0.020mmol), copper iodide (CuI, 0.004g, 0.020mmol) Using 0.112 g, 0.438 mmol) and 1-chloro-3-fluoro-5-iodobenzene as starting materials, 1-(3-(3-chloro-5-fluorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one (0.083 g, 54.9%) was obtained as a yellow solid by the same method as in step 4 of Example 2. LRMS (ES) m / z 380.09 [M+H] + , calculated MW 379.72; 1H-NMR (400 MHz, DMSO-d6) d 8.09 (d, J = 7.6 Hz, 1 H), 7.52 (t, J = 51.2 Hz, 1 H), 7.50 (td, J = 5.5, 2.9 Hz, 1 H), 7.41 (s, 1 H), 7.37 - 7.34 (m, 1 H), 7.01 (d, J = 1.2 Hz, 1 H), 6.83 (dd, J = 7.0, 1.8 Hz, 1 H), 5.05 (s, 2 H).

[0108] Example 36: Synthesis of 1-(3-(5-chloro-2-fluorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one [ka] 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(propa-2-in-1-yl)pyridine-2(1H)-one (0.100g, 0.398mmol), triethylamine (0.277mL, 1.991mmol), bis(triphenylphosphine)palladium(II) dichloride (0.014g, 0.020mmol), copper iodide (CuI, 0.004g, 0.020mmol) Using 0.112 g, 0.438 mmol) and 4-chloro-1-fluoro-2-iodobenzene as starting materials, 1-(3-(5-chloro-2-fluorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one (0.095 g, 62.8%) was obtained as a yellow solid by the same method as in step 4 of Example 2. LRMS (ES) m / z 380.09 [M+H] + , calculated MW 379.72; 1 H-NMR(400 MHz, DMSO-d6) d 8.08 (d, J = 7.2 Hz, 1 H), 7.52 (t, J = 51.2 Hz, 1 H), 7.63 (dd, J = 5.8, 2.6 Hz, 1 H), 7.50 - 7.49 (m, 1 H), 7.34 (t, J = 9.2 Hz, 1 H), 7.02 (d, J = 1.6 Hz, 1 H), 6.84 (dd, J = 7.0, 1.8 Hz, 1 H), 5.09 (s, 2 H).

[0109] Example 37: Synthesis of 2-(3-(3-chlorophenyl)propa-2-in-1-yl)-5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridazin-3(2H)-one Step 1: Synthesis of 6-oxo-1,6-dihydropyridazine-4-carbozide [ka] A solution of methyl 6-oxo-1,6-dihydropyridazine-4-carboxylate (1.000 g, 6.488 mmol) dissolved in ethanol (50 mL) at room temperature and hydrazine hydrate (1.532 mL, 32.440 mmol) were used as starting materials, and in the same manner as in Step 1 of Example 8, 6-oxo-1,6-dihydropyridazine-4-carbohydrazide (0.966 g, 96.6%) was obtained as a yellow solid. LRMS (ES) m / z 155.33 [M+H] + , calculated MW 154.13.

[0110] Step 2: Synthesis of 5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridazin-3(2H)-one

Chemical formula

[0111] Step 3: Synthesis of 2-(3-(3-chlorophenyl)prop-2-yn-1-yl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridazin-3(2H)-one

Chemical formula

[0112] Example 38: Synthesis of 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyrimidine-2(1H)-one Step 1: Synthesis of 2-oxo-1,2-dihydropyrimidine-4-carbohydrazide [ka] Using a solution prepared by dissolving methyl 2-oxo-1,2-dihydropyrimidine-4-carboxylate (0.500 g, 3.244 mmol) in ethanol (20 mL) at room temperature, and adding hydrazine hydrate (0.766 mL, 16.220 mmol) as a starting material, 2-oxo-1,2-dihydropyrimidine-4-carbohdrazide (0.494 g, 98.8%) was obtained as a yellow liquid in the same manner as in step 1 of Example 8. LRMS (ES) m / z 155.04 [M+H]+ , calculated MW 154.13.

[0113] Process 2: Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2(1H)-one

Chemical Structure

[0114] Process 3: Synthesis of 1-(3-(3-chlorophenyl)prop-2-yn-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2(1H)-one

Chemical Structure

[0115] Example 39: Synthesis of 3-(3-(3-chlorophenyl)propa-2-in-1-yl)-6-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyrimidine-4(3H)-one Step 1: Synthesis of 6-oxo-1,6-dihydropyrimidine-4-carbohdrazide [ka] Using a solution prepared by dissolving methyl 6-oxo-1,6-dihydropyrimidine-4-carboxylate (1,000 g, 6.488 mmol) in ethanol (50 mL) at room temperature, and hydrazine hydrate (1,624 g, 32.440 mmol) as a starting material, 6-oxo-1,6-dihydropyrimidine-4-carbohdrazide (0.996 g, 99.6%) was obtained as a white solid by the same method as in step 1 of Example 8. LRMS (ES) m / z 155.30 [M+H] +, calculated MW 154.13.

[0116] Step 2: Synthesis of 6-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyrimidine-4(3H)-one [ka] Using 6-oxo-1,6-dihydropyrimidine-4-carbohydrazide (0.996 g, 6.462 mmol), imidazole (1.320 g, 19.386 mmol), and 2,2-difluoroacetic anhydride (2.410 mL, 19.386 mmol) as starting materials, 6-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyrimidine-4(3H)-one (0.231 g, 16.7%) was obtained as a brown liquid in the same manner as in step 2 of Example 8. LRMS (ES) m / z 215.08 [M+H] + , calculated MW 214.13.

[0117] Step 3: Synthesis of 3-(3-(3-chlorophenyl)propa-2-in-1-yl)-6-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyrimidine-4(3H)-one [ka] Using 6-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyrimidine-4(3H)-one (0.100 g, 0.467 mmol), 3-(3-chlorophenyl)propa-2-in-1-ylmethanesulfonate (0.120 g, 0.490 mmol), and cesium carbonate (Cs2CO3, 0.228 g, 0.701 mmol) as starting materials, 3-(3-(3-chlorophenyl)propa-2-in-1-yl)-6-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyrimidine-4(3H)-one (0.021 g, 12.4%) was obtained as a brown solid by the same method as in step 3 of Example 26. LRMS (ES) m / z no detection [M+H] + , calculated MW 362.72; 1 H-NMR (400 MHz, DMSO-d6) δ 7.74 (s, 1 H), 7.53 - 7.53 (m, 1 H), 7.47 - 7.36 (m, 3 H), 7.27 (s, 1 H), 6.92 (s, 1 H), 5.16 (s, 2 H).

[0118] Example 40: Synthesis of 1-(3-(benzothiazol-5-yl)prop-2-yn-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2(1H)-one Step 1: Synthesis of 3-(benzothiazol-5-yl)prop-2-yn-1-ol [Chemical Structure] Propargyl alcohol (0.100 g, 1.784 mmol), 5-bromobenzothiazole (0.401 g, 1.873 mmol), tetrakis(triphenylphosphine)palladium (0.103 g, 0.089 mmol), copper(I) iodide (CuI, 0.017 g, 0.089 mmol) and triethylamine (0.746 mL, 5.351 mmol) were mixed with N,N-dimethylformamide (4 mL) at room temperature. The resulting mixture was irradiated with microwave and heated at 120 °C for 30 minutes, then cooled to room temperature to terminate the reaction. The solvent was removed from the reaction mixture under reduced pressure, saturated aqueous ammonium chloride solution was poured into the obtained concentrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to obtain 3-(benzothiazol-5-yl)prop-2-yn-1-ol (0.052 g, 15.4%) as a yellow solid. LRMS (ES) m / z 190.21 [M+H] + , calculated MW 189.23.

[0119] Step 2: Synthesis of 1-(3-(benzo]thiazole-5-yl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one [ka] Using 3-(benzo]thiazole-5-yl)propa-2-in-1-ol (0.052 g, 0.275 mmol), triethylamine (0.046 mL, 0.330 mmol), 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one (0.070 g, 0.330 mmol), and cesium carbonate (Cs2CO3, 0.134 g, 0.412 mmol) as starting materials, 1-(3-(benzo]thiazole-5-yl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one (0.016 g, 15.1%) was obtained as a brown solid by the same method as in step 2 of Example 29. LRMS (ES) m / z 385.18 [M+H] + , calculated MW 384.36; 1 H-NMR (400 MHz, DMSO-d6) d 9.43 (s, 1 H), 8.19 - 8.14 (m, 3 H), 7.66 - 7.40 (m, 1 H), 7.53 (s, 1 H), 7.02 (d, J = 2.0 Hz, 1 H), 6.85 (dd, J = 7.0, 2.2 Hz, 1 H), 5.08 (s, 2 H). Example 41: 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-

[0120] Synthesis of (yl)-1-(3-(2-methylbenzo]thiazole-6-yl)propa-2-in-1-yl)pyridine-2(1H)-one Step 1: Synthesis of 3-(2-methylbenzo]thiazole-6-yl)propa-2-in-1-ol [ka] Propa-2-in-1-ol (0.025 g, 0.446 mmol), 6-bromo-2-methylbenzothiazole (0.107 g, 0.468 mmol), tetrakis(triphenylphosphine)palladium (0.026 g, 0.022 mmol), copper iodide (CuI, 0.004 g, 0.022 mmol), and triethylamine (0.186 mL, 1.338 mmol) were mixed in the same manner as in Step 1 of Example 40 to obtain 3-(2-methylbenzothiazole-6-yl)propa-2-in-1-ol (0.068 g, 75.0%) as a brown liquid. LRMS (ES) m / z 204.05 [M+H] + , calculated MW 203.26.

[0121] Step 2: Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(2-methylbenzo]thiazole-6-yl)propa-2-in-1-yl)pyridine-2(1H)-one [ka] 3-(2-methylbenzo]thiazole-6-yl)propa-2-in-1-ol (0.060 g, 0.295 mmol), triethylamine (0.049 mL, 0.354 mmol), methanesulfonyl chloride (0.027 mL, 0.354 mmol), 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one (0.075 g, 0.354 mmol) Using mol) and cesium carbonate (Cs2CO3, 0.144 g, 0.443 mmol) as starting materials, 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(2-methylbenzo]thiazole-6-yl)propa-2-in-1-yl)pyridine-2(1H)-one (0.005 g, 4.3%) was obtained as a brown solid by the same method as in step 2 of Example 29. LRMS (ES) m / z 399.18 [M+H] + , calculated MW 398.39; 1H-NMR (400 MHz, DMSO-d6) d 8.43 (d, J = 5.2 Hz, 1 H), 8.00 (d, J = 2.0 Hz, 1 H), 7.81 (d, J = 8.4 Hz, 1 H), 7.63 (dd, J = 5.4, 1.4 Hz, 1 H), 7.52 - 7.49 (m, 2 H), 7.23 (t, J = 51.8 Hz, 1 H), 5.29 (s, 2 H), 2.80 (s, 3 H).

[0122] Example 42: Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(2-methyl-1H-imidazole-5-yl)propa-2-in-1-yl)pyridine-2(1H)-one [ka] 5-Iodo-2-methyl-1H-imidazole (0.050g, 0.240mmol), 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(propa-2-in-1-yl)pyridine-2(1H)-one (0.078g, 0.313mmol), copper iodide (CuI, 0.005g, 0.024mmol), 1,1'-bis(diphenylphosphin)ferrocene (0.013g, 0.024mmol), and methanesulfonate 1,1-ferrocene Using diyl-bis(diphenylphosphin)(2'-amino-1,1'-biphenyl-2-yl)palladium(II, 0.022g, 0.024 mmol) as a starting material, 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(2-methyl-1H-imidazole-5-yl)propa-2-in-1-yl)pyridine-2(1H)-one (0.022g, 27.6%) was obtained as a brown solid by the same method as in step 4 of Example 2. LRMS (ES) m / z 332.20 [M+H] + , calculated MW 331.28; 1H-NMR (400 MHz, DMSO-d6) d 11.92 (s, 1 H), 8.04 (d, J = 6.8 Hz, 1 H), 7.65 - 7.29 (m, 2 H), 6.99 (d, J = 2.0 Hz, 1 H), 6.83 (dd, J = 6.8, 1.6 Hz, 1 H), 4.96 (s, 2 H), 2.18 (s, 3 H).

[0123] Example 43: Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(thiophen-3-yl)propa-2-in-1-yl)pyridine-2(1H)-one [ka] 3-iodothiophene (0.030g, 0.143mmol), 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(propa-2-in-1-yl)pyridine-2(1H)-one (0.047g, 0.186mmol), copper iodide (CuI, 0.003g, 0.014mmol), 1,1'-ferrocenediylbis(diphenylphosphine, 0.008g, 0.014mmol), and methanesulfonate 1,1-phenylphosphine. Using rosendiyl-bis(diphenylphosphin)(2'-amino-1,1'-biphenyl-2-yl)palladium(II, 0.013g, 0.014 mmol) as a starting material, 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(thiophen-3-yl)propa-2-in-1-yl)pyridine-2(1H)-one (0.017g, 36.5%) was obtained as a brown solid by the same method as in step 4 of Example 2. LRMS (ES) m / z 334.12 [M+H] + , calculated MW 333.31; 1H-NMR (400 MHz, DMSO-d6) d 8.07 (d, J = 7.2 Hz, 1 H), 7.81 (dd, J = 3.0, 1.0 Hz, 1 H), 7.65 - 7.40 (m, 1 H), 7.59 - 7.57 (m, 1 H), 7.14 (dd, J = 5.2, 1.2 Hz, 1 H), 7.00 (d, J = 2.0 Hz, 1 H), 6.83 (dd, J = 7.2, 2.0 Hz, 1 H), 5.00 (s, 2 H).

[0124] Example 44: Synthesis of 1-(1-(3-chlorophenyl)penta-1-in-3-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one Step 1: Synthesis of 1-(3-chlorophenyl)penta-1-in-3-ol [ka] Using 1-chloro-3-iodobenzene (0.500 g, 2.097 mmol), penta-1-in-3-ol (0.229 g, 2.726 mmol), tetrakis(triphenylphosphine)palladium (0.121 g, 0.105 mmol), copper iodide (CuI, 0.020 g, 0.105 mmol), and triethylamine (0.877 mL, 6.291 mmol) as starting materials, 1-(3-chlorophenyl)penta-1-in-3-ol (0.190 g, 46.5%) was obtained as a yellow liquid in the same manner as in step 1 of Example 40. LRMS (ES) m / z no detection [M+H] + , calculated MW 194.66; 1 H-NMR (400 MHz, DMSO-d6) d 7.42 - 7.39 (m, 2 H), 7.38 - 7.32 (m, 2 H), 5.44 (d, J = 5.6 Hz, 1 H), 4.34 (q, J = 6.0 Hz, 1 H), 1.67 - 1.56 (m, 2 H), 0.93 (t, J = 7.4 Hz, 3 H).

[0125] Step 2: Synthesis of 1-(3-bromopenta-1-in-1-yl)-3-chlorobenzene [ka] 1-(3-chlorophenyl)penta-1-in-3-ol (0.200 g, 1.027 mmol) was dissolved in dichloromethane (4 mL), phosphorus tribromide (0.105 mL, 1.110 mmol) was added at 0°C, and the mixture was stirred at the same temperature for 1 hour, followed by further stirring at room temperature for 3 hours. Water (0.555 mL, 30.823 mmol) was added to the reaction mixture at room temperature and stirred for 5 minutes to terminate the reaction. Saturated sodium bicarbonate aqueous solution was poured over the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to obtain 1-(3-bromopenta-1-in-1-yl)-3-chlorobenzene (0.165 g, 62.4%) as a brown solid. R f 0.4; LRMS (ES) m / z no detection [M+H] + Calculated MW 257.56.

[0126] Step 3: Synthesis of 1-(1-(3-chlorophenyl)penta-1-in-3-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one [ka] Using 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one (0.050 g, 0.235 mmol), 1-(3-bromopenta-1-in-1-yl)-3-chlorobenzene (0.066 g, 0.258 mmol), and potassium carbonate (0.097 g, 0.704 mmol) as starting materials, 1-(1-(3-chlorophenyl)penta-1-in-3-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one (0.029 g, 31.7%) was obtained as a brown solid by the same method as in step 3 of Example 26. LRMS (ES) m / z 390.20 [M+H] + , calculated MW 389.79; 1 H-NMR (400 MHz, DMSO-d6) d 8.46 (d, J = 6.0 Hz, 1 H), 7.67 - 7.54 (m, 2 H), 7.45 - 7.40 (m, 3 H), 7.36 - 7.33 (m, 2 H), 5.88 (t, J = 6.4 Hz, 1 H), 2.00 - 1.93 (m, 2 H), 1.07 (t, J = 7.2 Hz, 3 H).

[0127] Example 45: Synthesis of 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-6-methylpyridine-2(1H)-one Step 1: Synthesis of 6-methyl-2-oxo-1,2-dihydropyridine-4-carbohydrazide [ka] Using methyl 6-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate (2.000 g, 11.965 mmol) and hydrazine monohydrate (0.756 mL, 15.554 mmol) as starting materials, 6-methyl-2-oxo-1,2-dihydropyridine-4-carbohradide (1.731 g, 86.5%) was obtained as a beige solid by the same method as in step 1 of Example 8. LRMS (ES) m / z 168.05 [M+H] + , calculated MW 167.17.

[0128] Step 2: Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-6-methylpyridine-2(1H)-one [ka] Using 6-methyl-2-oxo-1,2-dihydropyridine-4-carbohydrazide (1.731 g, 10.355 mmol), imidazole (1.719 mL, 31.064 mmol), and 2,2-difluoroacetic anhydride (2.832 mL, 22.780 mmol) as starting materials, 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-6-methylpyridine-2(1H)-one (1.821 g, 77.4%) was obtained as an ivory-colored solid by the same method as in step 2 of Example 8. LRMS (ES) m / z 228.16 [M+H] + , calculated MW 227.17.

[0129] Step 3: Synthesis of 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-6-methylpyridine-2(1H)-one [ka] Using 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-6-methylpyridine-2(1H)-one (0.100 g, 0.440 mmol), 3-(3-chlorophenyl)propa-2-in-1-ylmethanesulfonate (0.118 g, 0.484 mmol), and potassium carbonate (0.122 g, 0.880 mmol) as starting materials, 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-6-methylpyridine-2(1H)-one (0.036 g, 21.8%) was obtained as a beige solid by the same method as in step 3 of Example 26. LRMS (ES) m / z 376.19 [M+H] + , calculated MW 375.76; 1 H-NMR (400 MHz, DMSO-d6) d 7.51 (t, J = 52.2 Hz, 1 H), 7.52 (m, 1 H), 7.46 - 7.43 (m, 1 H), 7.39 - 7.36 (m, 2 H), 6.90 (s, 1 H), 6.78 (s, 1 H), 5.14 (s, 2 H), 2.63 (s, 3 H).

[0130] Example 46: Synthesis of 5-bromo-1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one Step 1: Synthesis of 5-bromo-2-oxo-1,2-dihydropyridine-4-carbohydrazide [ka] Using methyl 5-bromo-2-oxo-1,2-dihydropyridine-4-carboxylate (2.000 g, 8.620 mmol) and hydrazine monohydrate (0.545 mL, 11.205 mmol) as starting materials, 5-bromo-2-oxo-1,2-dihydropyridine-4-carbohydrazide (1.619 g, 80.9%) was obtained as a beige solid by the same method as in step 1 of Example 8. LRMS (ES) m / z 232.06 / 234.04 [M+H] + , calculated MW 232.04.

[0131] Step 2: Synthesis of 5-bromo-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one [ka] Using 5-bromo-2-oxo-1,2-dihydropyridine-4-carbohydrazide (1.619 g, 6.977 mmol), imidazole (1.159 mL, 20.932 mmol), and 2,2-difluoroacetic anhydride (1.908 mL, 15.350 mmol) as starting materials, 5-bromo-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one (0.589 g, 28.9%) was obtained as a pale yellow solid by the same method as in step 2 of Example 8. LRMS (ES) m / z 292.04 [M+H] + , calculated MW 292.04.

[0132] Step 3: Synthesis of 5-bromo-1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one [ka] Using 5-bromo-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one (0.100 g, 0.342 mmol), 3-(3-chlorophenyl)propa-2-in-1-ylmethanesulfonate (0.092 g, 0.377 mmol), and potassium carbonate (0.095 g, 0.685 mmol) as starting materials, 5-bromo-1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one (0.027 g, 17.9%) was obtained as a brown solid by the same method as in step 3 of Example 26.

[0133] LRMS (ES) m / z no detection [M+H] + , calculated MW 440.63; 1 H-NMR (400 MHz, DMSO-d6) d 8.28 (s, 1 H), 7.50 (s, 1 H), 7.44 (t, J = 21.4 Hz, 1 H), 7.46 - 7.43 (m, 1 H), 7.39 - 7.37 (m, 2 H), 6.78 (s, 1 H), 4.95 (s, 2 H).

[0134] Experimental Example 1: Fluorescence-based enzyme activity assay To measure the inhibitory effect of compounds on the activity of histone deacetylase 6 (HDAC6), an oxygen activity assay was performed to evaluate enzyme activity by reacting human HDAC6 enzyme with a substrate conjugated with a fluorescent peptide at p53 residues 379-382. The test compound was dissolved in 100% DMSO at a concentration of 10 mM to prepare a stock solution. A starting concentration of 30 μM was prepared from the stock solution, and then serially diluted by 1 / 3 to prepare the test buffer solution. Trichostatin A (TSA), the reference compound used to validate the experiment, was started at the highest concentration of 1 μM and serially diluted by 1 / 3 in the test buffer solution. To react the test compound and TSA prepared in the test buffer with the HDAC6 enzyme, these were dispensed into 96-well black plates and the plates were spun down. The reaction was then allowed to proceed at room temperature for 10 minutes. After 10 minutes, the substrate was dispensed and the plates were sealed. The reaction was carried out at 30°C for 1 hour in a light-shielded environment. Fluorescence values ​​were measured using a plate reader (wavelength: excitation / emission = 360 / 460 nm). Fluorescence values ​​were normalized, with the HDAC6 enzyme-treated group set to 100% and the untreated group to 0%. Compound activity was measured using IC50. 50 The values ​​were calculated and shown in Table 1 (+: 500 to 1,000 nM, ++: 100 to 500 nM, +++: less than 100 nM).

[0135] [Table 1]

[0136] Experimental Example 2: Fluorescence-based Ca2+ recruitment assay To measure the activity of antagonists against mGluR5, we used the HEK293 cell line, which constitutively overexpresses mGluR5, to measure intracellular Ca 2+ An experiment was conducted to confirm the change in levels. Cells from cell culture medium were dispensed into 384-well plates coated with poly-D-lysine and cultured in a 37°C incubator supplied with 5% CO2. The next day, the medium was removed and Ca was added. 2+After adding a dye loading buffer containing reagents capable of measuring EC, the cells were incubated at 37°C for 60 minutes. The test compound was dissolved in 100% DMSO to prepare a stock solution at a final concentration of 10 mM. A starting concentration of 10 μM was prepared from this stock solution, and then the standard solution (test compound standard solution) was prepared by serial dilution. The test compound standard solution (compound working solutions) was added to cells cultured in the dye loading buffer and maintained at room temperature for 30 minutes under light-shielding conditions before measurement. 80 Ca induced by L-glutamate concentration 2+ Changes in levels were measured for 2 minutes using FLIPR Tetra (MDS Analytical Technologies). Fluorescence Ca was detected in the presence of the test compound. 2+ The signal value is the EC of L-glutamate. 80 The fluorescence signal induced by the test compound was normalized to 100%, and the fluorescence signal of the solvent-treated group was normalized to 0%, and the inhibition rate of the test compound was estimated. The antagonistic efficacy of the test compound was determined by IC. 50 The values ​​were calculated and shown in Table 2 (+: 500 to 1,000 nM, ++: 100 to 500 nM, +++: less than 100 nM).

[0137] [Table 2]

Claims

1. The following formula (1) 【Chemistry 1】 （１） (wherein Ar is an aryl or heteroaryl, where the aryl and heteroaryl may be optionally substituted with one or more substituents selected from the group consisting of halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy and alkylsulfonyl; R 1 is alkyl or haloalkyl; R 2 is H or alkyl; X 1 , X 2 and X 3 One of them is C, and the rest is N; Y 1 、 Y 2 and Y 3 each independently is CR 3 or N, where R 3 is H, halo or alkyl; n is an integer between 0 and 2; The heteroaryl compound comprises one or more heteroatoms selected from N, O, and S.) or a pharmaceutically acceptable salt thereof.

2. Ar is C 6 -C 10 The aryl or 5-10 membered heteroaryl is, where the aryl and heteroaryl are halo, cyano, and C 1 -C 7 Alkyl, Halo-C 1 -C 7 Alkyl, C 1 -C 7 Alkoxy, Halo-C 1 -C 7 Alkoxy and C 1 -C 7 It may be optionally substituted with one to three substituents selected from the group consisting of alkylsulfonyls; R 1 C 1 -C 7 Alkyl or Halo-C 1 -C 7 It is alkyl; R 2 is H or C 1 -C 7 It is alkyl; X 1 , X 2 and X 3 One of them is C, and the rest is N; Y 1 , Y 2 and Y 3 Each of them operates independently, CR 3 Or N, where R 3 is H, halo, or C 1 -C 7 It is alkyl; n is an integer, either 1 or 2; The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that the heteroaryl comprises one to three heteroatoms selected from N, O, and S.

3. The compound of formula (1) above is the compound of formula (2) below 【Chemistry 2】 （２） (In the formula, n is an integer of 1 or 2, and Ar, R 1 , R 2 , Y 1 , Y 2 and Y 3 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that it is a compound represented by (the same as defined in claim 1).

4. The compound of formula (1) above is the compound of formula (3) below 【Transformation 3】 （３） (In the formula, n is an integer of 1 or 2, and Ar, R 1 , R 2 , Y 1 , Y 2 and Y 3 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that it is a compound represented by (the same as defined in claim 1).

5. The aryl is phenyl; The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that the heteroaryl is pyridyl, thienyl, imidazolyl, or benzothiazolyl.

6. Y 1 , Y 2 and Y 3 All of the above is CR 3 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

7. R 3 The compound according to claim 6, or a pharmaceutically acceptable salt thereof, characterized in that it is H.

8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, is characterized in that the compound of formula (1) is selected from the following group: 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-phenylpropane-2-in-1-yl)pyridine-2(1H)-one; 1-(3-phenylpropane-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one; 1-(3-(pyridine-4-yl)propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one; 1-(3-(pyridine-3-yl)propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one; 1-(3-(pyridine-2-yl)propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one; 1-(3-(2-fluorophenyl)propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one; 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(pyridine-4-yl)propa-2-in-1-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(pyridine-3-yl)propa-2-in-1-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(pyridine-2-yl)propa-2-in-1-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(4-fluorophenyl)propa-2-in-1-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(3-fluorophenyl)propa-2-in-1-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(2-fluorophenyl)propa-2-in-1-yl)pyridine-2(1H)-one; 1-(3-(4-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 1-(3-(2-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(p-tolyl)propa-2-in-1-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(m-tolyl)propa-2-in-1-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(3-(trifluoromethyl)phenyl)propa-2-in-1-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(3-(trifluoromethoxy)phenyl)propa-2-in-1-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(3-methoxyphenyl)propa-2-in-1-yl)pyridine-2(1H)-one; 1-(3-(6-chloropyridine-2-yl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 1-(3-(2-chloropyridine-4-yl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(6-methylpyridine-2-yl)propa-2-in-1-yl)pyridine-2(1H)-one; 1-(3-(3-bromophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(3-(difluoromethyl)phenyl)propa-2-in-1-yl)pyridine-2(1H)-one; 1-(3-(3-(difluoromethoxy)phenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(5-methylpyridine-3-yl)propa-2-in-1-yl)pyridine-2(1H)-one; 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one; 3-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-2-oxopyridine-1(2H)-yl)prop-1-in-1-yl)benzonitrile; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(3-(methylsulfonyl)phenyl)propa-2-in-1-yl)pyridine-2(1H)-one; 1-(3-(3-chloro-2-fluorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 1-(3-(3-chloro-4-fluorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 1-(3-(3-chloro-5-fluorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 1-(3-(5-chloro-2-fluorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 2-(3-(3-chlorophenyl)propa-2-in-1-yl)-5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridazine-3(2H)-one; 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyrimidine-2(1H)-one; 3-(3-(3-chlorophenyl)propa-2-in-1-yl)-6-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyrimidine-4(3H)-one; 1-(3-(benzo]thiazole-5-yl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(2-methylbenzo]thiazole-6-yl)propa-2-in-1-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(2-methyl-1H-imidazole-5-yl)propa-2-in-1-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(thiophen-3-yl)propa-2-in-1-yl)pyridine-2(1H)-one; 1-(1-(3-chlorophenyl)penta-1-in-3-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-6-methylpyridine-2(1H)-one; and 5-bromo-1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one.

9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, characterized in that the compound of formula (1) is selected from the following group: 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one; 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(p-tolyl)propa-2-in-1-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(m-tolyl)propa-2-in-1-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(3-(trifluoromethyl)phenyl)propa-2-in-1-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(3-(trifluoromethoxy)phenyl)propa-2-in-1-yl)pyridine-2(1H)-one; 1-(3-(2-chloropyridine-4-yl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-1-(3-(6-methylpyridine-2-yl)propa-2-in-1-yl)pyridine-2(1H)-one; 1-(3-(3-bromophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 1-(3-(3-(difluoromethoxy)phenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,2,4-oxadiazole-3-yl)pyridine-2(1H)-one; 3-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-2-oxopyridine-1(2H)-yl)prop-1-in-1-yl)benzonitrile; 1-(3-(5-chloro-2-fluorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; 1-(1-(3-chlorophenyl)penta-1-in-3-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2(1H)-one; and 1-(3-(3-chlorophenyl)propa-2-in-1-yl)-4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-6-methylpyridine-2(1H)-one.

10. A pharmaceutical composition for the prevention or treatment of motor disorders, comprising, as an active ingredient, a therapeutically effective amount of a compound of formula (1) described in any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.

11. The pharmaceutical composition according to claim 10, characterized in that the motor disorder is Huntington's disease, Parkinson's disease, or levodopa-induced dyskinesia (LID).

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