Dual regulator for mglur5 and HDAC6 and use thereof

Abstract

Disclosed are a dual regulator for mGluR5 and HDAC6 and use thereof. More specifically, disclosed are a compound that simultaneously regulates mGluR5 and HDAC6, and use thereof as a therapeutic agent for movement disorders.

Description

Dual modulators of MGLUR5 and HDAC6 and their uses

[0001] Disclosed are dual modulators of mGluR5 and HDAC6 and their uses. More specifically, compounds that simultaneously modulate mGluR5 and HDAC6 and their uses as therapeutic agents for movement disorders are disclosed.

[0002] Movement disorders are a group of conditions that affect the ability to produce and control bodily movement, often associated with neurological disorders or conditions that impair neurological function. Movement disorders may manifest as abnormal fluency or speed of movement, excessive or involuntary movements, or slowing or absence of voluntary movements.

[0003] Parkinson's disease (PD), a representative example of a movement disorder, is a degenerative brain disease that causes motor dysfunction due to the gradual degeneration of dopaminergic neurons in the substantia nigra pars compacta region of the midbrain and the resulting physiological dysfunction of the basal ganglia.

[0004] The underlying cause of dopaminergic neuronal degeneration is unknown, but the main pathological features are Lewy bodies and neuroinflammation caused by synucleinopathy. Aggregated alpha-synuclein, the main component of Lewy bodies, is induced by mechanisms such as synuclein overexpression, decreased protein degradation, and accelerated aggregation, and is reported to be directly or indirectly related to dopaminergic neuronal cell death. In neurodegenerative diseases, uncontrolled neuroinflammation accelerates cell death and is reported to be a major mechanism causing extensive dopaminergic neuronal cell death in Parkinson's disease.

[0005] Decreased dopamine production and secretion due to dopamine cell death lowers dopamine levels in the basal ganglia, resulting in decreased activity of the direct pathway and increased activity of the indirect pathway. Among these, increased activity of the indirect pathway is caused by increased activity of D2 MSN (medium spiny neuron expressing D2 receptor) in the striatum, and the resulting increased activity of the STN-SNr / GPi overinhibits the thalamus, ultimately causing motor disorders. Hyperactivity of the subthalamic nucleus (STN) has been reported in PD patients, and clinical therapeutic effects on motor disorders have been reported by modulating indirect pathway activity through deep brain stimulation (DBS) in patients with end-stage PD.

[0006] HDAC6 belongs to class II histone deacetylases (HDACs). Unlike other HDACs, which regulate histone acetylation in the nucleus, it resides in the cytoplasm and regulates the acetylation of various proteins. Through acetylation regulation, HDAC6 is involved in stabilizing microtubule structure and mitochondrial transport. Furthermore, in addition to acetylation regulation, HDAC6 has been reported to participate in autophagy, mitophagy, and inflammasome formation through its unique ubiquitin-binding domain.

[0007] mGluR5 is a metabotropic glutamate receptor involved in excitatory synaptic transmission. It is highly expressed in the striatum and subthalamic nucleus (STN), key brain regions of the basal ganglia, and contributes to the activation of these brain regions.

[0008] One object of the present invention is to provide a compound that simultaneously modulates mGluR5 and HDAC6.

[0009] Another object of the present invention is to provide a use of the compound for preventing or treating movement disorders.

[0010] To achieve the above purpose, a compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof is provided:

[0011] [Chemical Formula 1]

[0012]

[0013]

[0014] In the above chemical formula 1, X 1 , X 2 , X 3 , X 4 , Y, R 1 and Ar are as defined herein.

[0015]

[0016] In addition, a pharmaceutical composition for preventing or treating movement disorders is provided, which comprises a therapeutically effective amount of a compound of the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, together with a pharmaceutically acceptable carrier or excipient.

[0017] In addition, a method for treating movement disorders is provided, comprising a step of administering a compound of the above chemical formula 1 or a pharmaceutically acceptable salt thereof to a mammal.

[0018] In addition, the present invention provides a use of the compound of the above chemical formula 1 or a pharmaceutically acceptable salt thereof in the prevention or treatment of movement disorders.

[0019] The compound of formula 1 according to the present invention or a pharmaceutically acceptable salt thereof acts as a dual modulator for mGluR5 and HDAC6 and may exhibit a preventive or therapeutic effect on movement disorders.

[0020] The present invention is described in more detail below.

[0021]

[0022] According to one aspect of the present invention, a compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof is provided:

[0023] [Chemical Formula 1]

[0024]

[0025]

[0026] In the above chemical formula 1,

[0027] Ar is aryl or heteroaryl; wherein said aryl and heteroaryl may be optionally substituted with one or more substituents selected from the group consisting of halo, cyano, hydroxy, alkyl, haloalkyl and alkoxy;

[0028] X 1 is CH, CF or N;

[0029] X 2 , X 3 and X 4 is CR 3 or N, two or more of which are CR 3 and here R 3 is -H, halo, alkyl or haloalkyl;

[0030] Y is -O- or -N(R 2 )-and; here R 2 is -H or alkyl, or R 1 It can be linked to form a 5- or 6-membered unsaturated ring structure;

[0031] R 1 is -H or R 2 It can be connected to form a 5- or 6-membered unsaturated ring structure;

[0032] The above heteroaryl has one or more heteroatoms selected from N, O and S.

[0033]

[0034] In defining the compound of chemical formula 1 throughout this specification, the following concepts defined for substituents are used.

[0035]

[0036] In the present invention, the term “halo” or “halogen”, when used alone or in combination with other additional terms (e.g., haloalkyl), means fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0037] In the present invention, the term “cyano” group means -CN.

[0038] In the present invention, the term “hydroxy” group means -OH.

[0039] As used herein, the term “alkyl”, when used alone or in combination with other additional terms (e.g., haloalkyl), means a radical of a straight or branched saturated aliphatic hydrocarbon group having, for example, 1 to 7 or 1 to 5 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.

[0040] In the present invention, the term “alkoxy” means an alkyloxy (-O-alkyl group), for example, an alkyloxy having 1 to 7 or 1 to 5 carbon atoms.

[0041] In the present invention, the term “aryl” means an aromatic hydrocarbon having, for example, 6 to 10 carbon atoms, and specific examples include, but are not limited to, phenyl and naphthyl.

[0042] In the present invention, the term “heteroaryl” means an aromatic hydrocarbon having 5 to 10 members and containing one or more heteroatoms selected from N, O and S as a reducing agent.

[0043]

[0044] According to one specific example of the present invention, in the chemical formula 1

[0045] Ar is C6-C 10 Aryl or 5 to 10 membered heteroaryl; wherein said aryl and heteroaryl may be optionally substituted with 1 to 3 substituents selected from the group consisting of halo, cyano, hydroxy, C1-C7 alkyl, halo-C1-C7 alkyl and C1-C7 alkoxy;

[0046] X 1 is CH, CF or N;

[0047] X 2 , X 3 and X 4 is CR 3 or N, two or more of which are CR 3 and here R 3 is -H, halo, C1-C7 alkyl or halo-C1-C7 alkyl;

[0048] Y is -O- or -N(R 2 )-and; here R 2 is -H or C1-C7 alkyl, or R 1 It can be linked to form a 5- or 6-membered unsaturated heterocycle;

[0049] R 1 is -H or R 2 and can be linked to form a 5- or 6-membered unsaturated heterocycle;

[0050] The above heteroaryl and heterocycle have 1 to 3 heteroatoms selected from N, O and S.

[0051]

[0052] According to another specific example of the present invention, in the chemical formula 1, Y is -O-, and R 1 may be -H. At this time, the above chemical formula 1 may be represented by the following chemical formula 2:

[0053] [Chemical Formula 2]

[0054]

[0055]

[0056]

[0057] In the above chemical formula 2, X 1 , X 2 , X 3 , X 4 and Ar 1 is as defined in chemical formula 1.

[0058]

[0059] According to another specific example of the present invention, in the chemical formula 1, Y is -O-, and X 2 , X 3 and X 4 are all CR 3 and R 1 can be -H. At this time, the above chemical formula 1 can be represented by the following chemical formula 3:

[0060] [Chemical Formula 3]

[0061]

[0062]

[0063] In the above chemical formula 3, X 1 , R 3 and Ar are as defined in chemical formula 1.

[0064]

[0065] According to another specific example of the present invention, in the chemical formula 1, Y is -N(R 2 )-and R 1 can be -H. At this time, the above chemical formula 1 can be represented by the following chemical formula 4:

[0066] [Chemical Formula 4]

[0067]

[0068]

[0069] In the above chemical formula 4,

[0070] R 2 is H or C1-C7 alkyl,

[0071] X 1 , X 2 , X 3 , X 4 and Ar are as defined in chemical formula 1.

[0072]

[0073] According to another specific example of the present invention, in the chemical formula 1, Y is -N(R 2 )-and R 2 is R 1 It can be connected to form a 5-membered unsaturated heterocycle having 1 or 2 N atoms. In this case, the chemical formula 1 can be represented by the following chemical formula 5:

[0074] [Chemical Formula 5]

[0075]

[0076]

[0077] In the above chemical formula 5,

[0078] R 2 is CH or N,

[0079] X 1 , X 2 , X 3 , X 4 and Ar are as defined in chemical formula 1.

[0080]

[0081] According to another specific embodiment of the present invention, Ar is phenyl, pyridyl, thiazolyl, imidazolyl or benzimidazolyl; and may be optionally substituted with one or two substituents selected from the group consisting of halo, cyano, C1-C5 alkyl and halo-C1-C5 alkyl.

[0082] According to another embodiment of the present invention, X 1 is CF or N; X 2 , X 3 and X 4 Go CR 3 , and here R 3 can be -H or halo.

[0083] According to another embodiment of the present invention, X 1 is CF or N; X 2 , X 3 and X 4 is CR 3 or N, two of which are CR 3 and the other one is N; where R 3 can be -H or halo.

[0084] According to another specific embodiment of the present invention,

[0085] Y is -O- or -N(R 2 )-and; here R 2 is -H or C1-C5 alkyl, or R 1 It can be linked to form a 5-membered unsaturated heterocycle having 1 or 2 N atoms;

[0086] R 1 is -H or R 2 It can be linked to form a five-membered unsaturated heterocycle having one or two N atoms.

[0087]

[0088] According to another specific example of the present invention, representative examples of the compounds of the above chemical formula 1 may include, but are not limited to, the following compounds:

[0089] 2-(6-((3-((3-chlorophenyl)ethanyl)phenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole;

[0090] 2-(Difluoromethyl)-5-(6-((3-(m-tolyleethaneyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole;

[0091] 3-((3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)phenyl)ethanyl)benzonitrile;

[0092] 2-(Difluoromethyl)-5-(3-fluoro-4-((3-(m-tolyleethaneyl)phenoxy)methyl)phenyl)-1,3,4-oxadiazole;

[0093] 3-((3-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)oxy)phenyl)ethanyl)benzonitrile;

[0094] 2-(Difluoromethyl)-5-(6-(((4-((4-fluorophenyl)ethanyl)pyridin-2-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole;

[0095] 2-(6-(((5-((3-chlorophenyl)ethanyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole;

[0096] 2-(4-(((5-((3-chlorophenyl)ethanyl)pyridin-3-yl)oxy)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole;

[0097] 2-(6-(((2-((3-chlorophenyl)ethanyl)pyridin-4-yl)oxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole;

[0098] 2-(Difluoromethyl)-5-(6-(((5-(m-tolyleethaneyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole;

[0099] 3-((5-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)pyridin-3-yl)ethanyl)benzonitrile;

[0100] 2-(6-(((5-((6-chloropyridin-2-yl)ethanyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole;

[0101] 2-(Difluoromethyl)-5-(6-(((5-((3-fluorophenyl)ethanyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole;

[0102] 2-(6-(((5-((2-chloropyridin-4-yl)ethanyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole;

[0103] 2-(6-((5-((3-chlorophenyl)ethanyl)-2-fluorophenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole;

[0104] (6-((3-((3-chlorophenyl)ethanyl)-4-fluorophenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole;

[0105] 2-(6-((3-((6-chloropyridin-2-yl)ethanyl)phenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole;

[0106] 2-(6-((3-((2-chloropyridin-4-yl)ethanyl)phenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole;

[0107] 2-(Difluoromethyl)-5-(6-((3-((2-methylthiazol-4-yl)ethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole;

[0108] 2-(Difluoromethyl)-5-(6-((3-((6-methylpyridin-2-yl)ethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole;

[0109] 2-(6-((3-((6-chloropyridin-2-yl)ethanyl)-4-fluorophenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole;

[0110] 2-(Difluoromethyl)-5-(6-((3-((2-fluoropyridin-4-yl)ethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole;

[0111] 2-(6-((4-((3-chlorophenyl)ethanyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole;

[0112] 2-(6-((4-((3-chlorophenyl)ethanyl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole;

[0113] 2-(Difluoromethyl)-5-(6-((4-(m-tolyleethaneyl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole;

[0114] 2-(Difluoromethyl)-5-(6-((3-((3-(trifluoromethyl)phenyl)ethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole;

[0115] 2-(Difluoromethyl)-5-(6-((3-((6-fluoropyridin-2-yl)ethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole;

[0116] 2-(Difluoromethyl)-5-(6-(((5-((6-methylpyridin-2-yl)ethanyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole;

[0117] 2-(Difluoromethyl)-5-(6-((3-((2-methylpyridin-4-yl)ethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole;

[0118] 2-(Difluoromethyl)-5-(6-((3-(phenylethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole;

[0119] 3-((1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)ethanyl)benzonitrile;

[0120] 2-(Difluoromethyl)-5-(6-((4-((3-fluorophenyl)ethanyl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole;

[0121] 2-(6-((4-((3-chlorophenyl)ethanyl)-1H-indol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole;

[0122] 2-(Difluoromethyl)-5-(6-((4-(m-tolylethanyl)-1H-indol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole;

[0123] 2-(6-((4-((3-chlorophenyl)ethanyl)-6-fluoro-1H-indol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole;

[0124] 2-(Difluoromethyl)-5-(6-((6-fluoro-4-(m-tolylethanyl)-1H-indol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole;

[0125] 2-(Difluoromethyl)-5-(6-((4-(m-tolyleethaneyl)-1H-indazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole;

[0126] 3-((1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-indazol-4-yl)ethanyl)benzonitrile;

[0127] 2-(6-((4-((3-chlorophenyl)ethanyl)-1H-indazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole;

[0128] 3-((3-chlorophenyl)ethanyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)aniline; and

[0129] 3-((3-chlorophenyl)ethanyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-ethylaniline.

[0130]

[0131] Manufacturing method

[0132] According to one specific example, the compound of formula 1 can be prepared by a person having ordinary knowledge of compound synthesis in the art using known compounds or compounds that can be easily prepared therefrom. For example, the compound of formula 1 can be synthesized according to the methods of the following reaction schemes 1 to 3, but this is only to suggest one exemplary method, and the order of unit operations, etc. can be selectively changed as needed, and is not intended to limit the scope of the invention.

[0133] [Reaction Formula 1]

[0134]

[0135]

[0136] The compound of chemical formula 1 can be prepared by a method such as the above reaction scheme 1 or the following reaction scheme 1', wherein in the above reaction scheme 1, X is a leaving group such as halogen or mesylate (MsO). Intermediate 2 can be prepared by a method such as reaction schemes 2 and 2', and intermediate 3 can be prepared by various methods including a method such as reaction scheme 3.

[0137] [Reaction Scheme 1']

[0138]

[0139]

[0140] Compounds of chemical formula 1 can be obtained from each starting material containing a halogen and an acetylene group through Sonogashira coupling. Intermediates 4 and 6 can each be prepared through reaction scheme 4.

[0141]

[0142] [Reaction Formula 2]

[0143]

[0144]

[0145] Intermediate 9 is obtained by adding hydrazine to a starting material containing an ester, and then intermediate 10 is obtained through a cyclization reaction with the addition of difluoroacetic anhydride. Intermediate 2a can then be obtained through a bromination reaction.

[0146]

[0147] [Reaction Formula 2']

[0148]

[0149]

[0150] Intermediate 12 is obtained through selective reduction from a starting material containing an ester, and then hydrazine is added to obtain intermediate 13. Subsequently, intermediate 14 is obtained through a cyclization reaction with the addition of difluoroacetic anhydride, and intermediate 2b can be obtained through a sulfonylation reaction.

[0151]

[0152] [Reaction Formula 3]

[0153]

[0154]

[0155] Intermediate 3 can be obtained from each starting material containing a halogen and an acetylene group through the Sonogashira reaction.

[0156]

[0157] [Reaction Formula 4]

[0158]

[0159]

[0160] Intermediates 4 and 6 can be obtained through a nucleophilic addition reaction from a starting material containing a leaving group X, and intermediate 16 can be prepared through the following reaction scheme 5.

[0161]

[0162] [Reaction Formula 5]

[0163]

[0164]

[0165] Intermediate 17 can be obtained through a Sonogashira reaction from a starting material containing a halogen, and then intermediate 16 can be obtained through a protecting group removal reaction.

[0166]

[0167] Pharmaceutical composition

[0168] According to another aspect of the present invention, a pharmaceutical composition for preventing or treating movement disorders is provided, comprising a therapeutically effective amount of a compound of the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, together with a pharmaceutically acceptable carrier or excipient.

[0169] The pharmaceutical composition may be formulated into various oral or parenteral dosage forms. For example, it may be any oral dosage form, such as tablets, pills, hard / soft capsules, liquids, suspensions, emulsions, syrups, granules, and elixirs.

[0170] The pharmaceutical composition may be formulated as a parenteral dosage form, in which case it is administered by parenteral administration methods such as subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. In this case, in order to formulate the pharmaceutical composition as a dosage form for parenteral administration, the active ingredient, i.e., the compound of formula 1 or a pharmaceutically acceptable salt thereof, is mixed in water with a stabilizer or buffer to prepare a solution or suspension, and this solution or suspension can be prepared in a unit dosage form of an ampoule or vial.

[0171]

[0172] Medical usefulness

[0173] Another aspect of the present invention provides a method for preventing or treating movement disorders in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the above formula 1 or a pharmaceutically acceptable salt thereof. The movement disorders may include, but are not limited to, Parkinson's disease and levodopa-induced dyskinesia (LID).

[0174] The compound of the above chemical formula 1 is a compound that simultaneously inhibits HDAC6 and mGluR5. The main pharmacological properties of HDAC6 and mGluR5 inhibition are to suppress dopaminergic neuronal degeneration and improve functional abnormalities of the basal ganglia, respectively, thereby providing fundamental treatment and symptomatic relief for Parkinson's disease.

[0175] HDAC6 plays a key role in the protein degradation pathway (macroautophagy, chaperone-mediated autophagy), and its potential therapeutic effects in Parkinson's disease through the removal of alpha-synuclein have been reported. Furthermore, a recent study reported that HDAC6 contributes to the formation of NLRP3 and pyrin inflammasomes through the same mechanism as aggresome formation. In contrast, HDAC6 inhibition inhibits NLPR3 aggregation and activity, resulting in immunosuppressive effects through the suppression of IL-1β secretion. Inhibition of NLRP3 with an antagonist or knockout of the NLRP3 gene has been shown to protect dopaminergic neurons and improve motor dysfunction in PD animal models. Therefore, HDAC6 inhibition is expected to have therapeutic effects in treating neurodegeneration by improving alpha-synuclein aggregation and neuroinflammation, key pathological features of Parkinson's disease.

[0176] mGluR5 is directly involved in excitatory synaptic signaling in the basal ganglia, and research has shown that mGluR5 inhibition can modulate the hyperactivity of the indirect pathway in the basal ganglia. Activation of mGluR5 in the subthalamic nucleus (STN) of the indirect pathway results in increased neuronal activity and increased NMDA currents, which are suppressed by mGluR5 antagonist treatment. Furthermore, in a model (haloperidol-induced catalepsy, HIC) in which the dopamine receptor 2 (D2) antagonist haloperidol induces abnormalities in indirect pathway signaling, leading to motor dysfunction, the mGluR5 antagonist improved motor function. Therefore, mGluR5 inhibition can be expected to directly modulate the mechanism of expression of the main symptoms of Parkinson's disease and improve motor function.

[0177] The compound of formula 1, which is a dual inhibitor of HDAC6 and mGluR5, can improve dopamine cell death through HDAC6 inhibition and simultaneously improve neural circuit dysfunction of the basal ganglia caused by dopamine deficiency through mGluR5 inhibition. Therefore, the compound of formula 1 can be usefully utilized as a pharmaceutical composition for the treatment of Parkinson's disease and the suppression of complications caused by levodopa.

[0178]

[0179] In another embodiment of the present invention, a method for preventing or treating a movement disorder comprises administering to an animal a pharmaceutical composition comprising an effective amount of a compound of Formula 1 and a pharmaceutically acceptable carrier or excipient. The method is particularly suitable for use in humans, but may also be used in other animals, particularly mammals.

[0180] The specific administration method and therapeutically effective amount of the compound of the above chemical formula 1 or a pharmaceutically acceptable salt thereof can be readily determined by a person skilled in the art in consideration of the type of target mammal, the type of disease, the type of the compound of the above chemical formula 1, etc., and are not particularly limited.

[0181] For example, the compound of the above chemical 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, and such pharmaceutical composition may be administered orally or parenterally once a day or in divided doses of two or more times.

[0182]

[0183] Example

[0184] The present invention will be described in more detail below through examples. However, the examples are intended to exemplify the present invention and are not intended to limit the scope of the invention.

[0185]

[0186] Example 1: Synthesis of 2-(6-((3-((3-chlorophenyl)ethanyl)phenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0187] Step 1: Synthesis of 6-methylnicotinohydrazide

[0188]

[0189]

[0190] Methyl 6-methylnicotinate (5.000 g, 33.075 mmol) and hydrazine hydrate (4.967 g, 99.226 mmol) were dissolved in ethanol (80 mL) at room temperature, stirred at 60°C for 18 hours, and then cooled to room temperature to terminate the reaction. The solvent was removed from the reaction mixture under reduced pressure, and the precipitated solid was filtered, washed with diethyl ether, and dried to obtain 6-methylnicotinohydrazide (4.850 g, 97.0%) as a white solid.

[0191]

[0192] Step 2: Synthesis of 2-(difluoromethyl)-5-(6-methylpyridin-3-yl)-1,3,4-oxadiazole

[0193]

[0194]

[0195] 6-Methylnicotinohydrazide (4.850 g, 32.083 mmol), triethylamine (13.415 mL, 96.249 mmol), and 2,2-difluoroacetic anhydride (11.966 mL, 96.249 mmol) were dissolved in tetrahydrofuran (100 mL) at room temperature, and the resulting solution was stirred at 80°C for 18 hours, after which the temperature was lowered to room temperature to terminate the reaction. The solvent was removed from the reaction mixture under reduced pressure, and water was added to the resulting concentrate, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography to obtain 2-(difluoromethyl)-5-(6-methylpyridin-3-yl)-1,3,4-oxadiazole (4.768 g, 70.4%) as a yellow solid: LRMS(ES) m / z 212.70 [M+H] + , calculated MW 211.17.

[0196]

[0197] Step 3: Synthesis of 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0198]

[0199]

[0200] 2-(Difluoromethyl)-5-(6-methylpyridin-3-yl)-1,3,4-oxadiazole (4.768 g, 22.579 mmol), 1-bromopyrrolidine-2,5-dione (NBS, 4.822 g, 27.095 mmol), and azobisisobutyronitrile (AIBN, 1.112 g, 6.774 mmol) were dissolved in acetonitrile (80 mL) at room temperature, and the resulting solution was stirred at 60°C for 4 hours, after which the temperature was lowered to room temperature to terminate the reaction. The solvent was removed from the reaction mixture under reduced pressure, and water was poured into the resulting concentrate, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography to obtain 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (4.210 g, 64.3%) as a yellow solid: LRMS(ES) m / z 292.04 [M+H] + , calculated MW 290.07.

[0201]

[0202] Step 4: Synthesis of 3-((3-chlorophenyl)ethanyl)phenol

[0203]

[0204]

[0205] 3-Iodophenol (0.500 g, 2.273 mmol), 1-chloro-3-ethynylbenzene (0.372 g, 2.727 mmol), bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2, 0.160 g, 0.227 mmol), copper iodide (CuI, 0.022 g, 0.114 mmol), and triethylamine (0.950 mL, 6.818 mmol) were dissolved in tetrahydrofuran (10 mL) at room temperature. The resulting solution was stirred at 80°C for 2 hours, and then the temperature was lowered to room temperature to terminate the reaction. A saturated aqueous ammonium chloride solution was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to obtain 3-((3-chlorophenyl)ethanyl)phenol (0.325 g, 62.5%) as an ivory solid: LRMS (ES) m / z 227.11 [MH] + , calculated MW 228.68.

[0206]

[0207] Step 5: Synthesis of 2-(6-((3-((3-chlorophenyl)ethanyl)phenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0208]

[0209]

[0210] 3-((3-Chlorophenyl)ethynyl)phenol (0.050 g, 0.219 mmol), 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.070 g, 0.241 mmol), and potassium carbonate (K2CO3, 0.091 g, 0.656 mmol) were dissolved in acetonitrile (2 mL) at room temperature, and the resulting solution was stirred at 70°C for 18 hours, after which the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography to obtain 2-(6-((3-((3-chlorophenyl)ethanyl)phenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.024 g, 25.1%) as a pale yellow solid: LRMS(ES) m / z 438.28 [M+H] + , calculated MW 437.83;1H-NMR(400 MHz, DMSO-d6) d 9.20 (dd,J= 2.4, 0.8 Hz, 1 H), 8.46 (dd,J= 8.2, 2.2 Hz, 1 H), 7.76 (d,J= 8.0 Hz, 1 H), 7.62 (t,J= 25.6 Hz, 2 H), 7.50 ~ 7.40 (m, 3 H), 7.35 (t,J= 7.6 Hz, 1 H), 7.24 (q,J= 1.2 Hz, 1 H), 7.16 (dt,J= 7.2, 1.1 Hz, 1 H), 7.12 (ddd,J=8.2, 2.8, 1.0 Hz, 1 H), 5.34 (s, 2 H).

[0211]

[0212] Example 2: Synthesis of 2-(difluoromethyl)-5-(6-((3-(m-tolyleethaneyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0213] Step 1: Synthesis of 3-(m-tolyleethaneyl)phenol

[0214]

[0215]

[0216] 3-(m-Tolyleethaneyl)phenol (0.350 g, 73.9%) was obtained as a white solid in a similar manner to Step 4 of Example 1, starting from 3-iodophenol (0.500 g, 2.273 mmol), 1-ethynyl-3-methylbenzene (0.352 mL, 2.727 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.160 g, 0.227 mmol), copper iodide (CuI, 0.022 g, 0.114 mmol) and triethylamine (0.950 mL, 6.818 mmol): LRMS(ES) m / z 207.06 [MH] + , calculated MW 208.26.

[0217]

[0218] Step 2: Synthesis of 2-(difluoromethyl)-5-(6-((3-(m-tolyleethaneyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0219]

[0220]

[0221] 2-(Difluoromethyl)-5-(6-((3-(m-tolyleethaneyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.036 g, 35.9%) was obtained as a yellow solid in a similar manner to step 5 of Example 1 using 3-(m-tolyleethaneyl)phenol (0.050 g, 0.240 mmol), 2-(6-(bromomethyl)pyridin-3-yl)-1,3,4-oxadiazole (0.073 g, 0.252 mmol) and potassium carbonate (K2CO3, 0.100 g, 0.720 mmol) as starting materials: LRMS(ES) m / z 418.33 [M+H] +, calculated MW 417.42;1H-NMR(400 MHz, DMSO-d6) d 9.22 ~ 9.17 (m, 1 H), 8.46 (dd,J= 8.2, 2.2 Hz, 1 H), 7.76 (d,J= 8.0 Hz, 1 H), 7.55 (t,J= 51.2 Hz, 1 H), 7.35 ~ 7.26 (m, 4 H), 7.21 ~ 7.19 (m, 2 H), 7.13 (d,J= 7.2 Hz, 1 H), 7.09 (ddd,J= 8.3, 2.7, 0.9 Hz, 1 H), 5.34 (s, 2 H), 2.28 (s, 3 H).

[0222]

[0223] Example 3: Synthesis of 3-((3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)phenyl)ethanyl)benzonitrile

[0224] Step 1: Synthesis of 3-((3-hydroxyphenyl)ethanyl)benzonitrile

[0225]

[0226]

[0227] 3-((3-hydroxyphenyl)ethanyl)benzonitrile (0.321 g, 64.4%) was obtained as a yellow solid in a similar manner to Step 4 of Example 1, starting from 3-iodophenol (0.500 g, 2.273 mmol), 3-ethynylbenzonitrile (0.347 g, 2.727 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.160 g, 0.227 mmol), copper iodide (CuI, 0.022 g, 0.114 mmol) and triethylamine (0.950 mL, 6.818 mmol): LRMS(ES) m / z 218.06 [MH] + , calculated MW 219.24.

[0228]

[0229] Step 2: Synthesis of 3-((3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)phenyl)ethanyl)benzonitrile

[0230]

[0231]

[0232] 3-((3-hydroxyphenyl)ethanyl)benzonitrile (0.050 g, 0.228 mmol), 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.069 g, 0.239 mmol) and potassium carbonate (K2CO3, 0.095 g, 0.684 mmol) were used as starting materials in a similar manner to step 5 of Example 1, to obtain 3-((3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)phenyl)ethanyl)benzonitrile (0.055 g, 56.3%) as a pale yellow solid: LRMS(ES) m / z 429.30 [M+H] + , calculated MW 428.4;1H-NMR(400 MHz, DMSO-d6) d 9.20 (d,J= 2.4 Hz, 1 H), 8.46 (dd,J= 8.2, 2.2 Hz, 1 H), 8.03 (t,J= 1.4 Hz, 1 H), 7.86 ~ 7.84 (m, 2 H), 7.76 (d,J= 8.0 Hz, 1 H), 7.68 ~ 7.42 (m, 2 H), 7.36 (t,J= 8.0 Hz, 1 H), 7.25 (q,J= 1.3 Hz, 1 H), 7.17 (dd,J= 6.4, 1.2 Hz, 1 H), 7.13 (ddd,J=8.4, 2.6, 1.0 Hz, 1 H), 5.34 (s, 2 H).

[0233]

[0234] Example 4: Synthesis of 2-(difluoromethyl)-5-(3-fluoro-4-((3-(m-tolyleethaneyl)phenoxy)methyl)phenyl)-1,3,4-oxadiazole

[0235] Step 1: Synthesis of 3-fluoro-4-methylbenzohydrazide

[0236]

[0237]

[0238] 3-Fluoro-4-methylbenzohydrazide (4.598 g, 92.0%) was obtained as a white solid in a similar manner to Step 1 of Example 1, starting from a solution of methyl 3-fluoro-4-methylbenzoate (5.000 g, 29.732 mmol) in ethanol (80 mL) at room temperature and hydrazine hydrate (7.442 g, 148.659 mmol): LRMS(ES) m / z 169.11 [M+H] + , calculated MW 168.17.

[0239]

[0240] Step 2: Synthesis of 2-(difluoromethyl)-5-(3-fluoro-4-methylphenyl)-1,3,4-oxadiazole

[0241]

[0242]

[0243] Starting from 3-fluoro-4-methylbenzohydrazide (4.598 g, 27.341 mmol), triethylamine (11.433 mL, 82.024 mmol) and 2,2-difluoroacetic anhydride (10.197 mL, 82.024 mmol), 2-(difluoromethyl)-5-(3-fluoro-4-methylphenyl)-1,3,4-oxadiazole (5.419 g, 86.9%) was obtained as a white solid in a similar manner to step 2 of Example 1: LRMS(ES) m / z 229.10 [M+H] + , calculated MW 228.17.

[0244]

[0245] Step 3: Synthesis of 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0246]

[0247]

[0248] 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (5.419 g, 23.750 mmol), 1-bromopyrrolidine-2,5-dione (NBS, 5.072 g, 28.500 mmol) and azobisisobutyronitrile (AIBN, 1.170 g, 7.125 mmol) were used as starting materials in a similar manner to step 3 of Example 1 to obtain 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (4.300 g, 59.0%) as a pink solid: LRMS(ES) m / z 306.77 [MH] + , calculated MW 307.07.

[0249]

[0250] Step 4: Synthesis of 2-(difluoromethyl)-5-(3-fluoro-4-((3-(m-tolyleethaneyl)phenoxy)methyl)phenyl)-1,3,4-oxadiazole

[0251]

[0252]

[0253] 2-(Difluoromethyl)-5-(3-fluoro-4-((3-(m-tolyleethaneyl)phenoxy)methyl)phenyl)-1,3,4-oxadiazole (0.021 g, 20.1%) was obtained as a yellow solid in a similar manner to step 5 of Example 1 using 3-(m-tolyleethaneyl)phenol (0.050 g, 0.240 mmol), 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.088 g, 0.288 mmol) and potassium carbonate (K2CO3, 0.100 g, 0.720 mmol) as starting materials: LRMS(ES) m / z 435.31 [M+H] +, calculated MW 434.42;1H-NMR(400 MHz, DMSO-d6) d 7.91 (td,J= 10.5, 1.7 Hz, 2 H), 7.80 (t,J= 6.0 Hz, 1 H), 7.52 (t,J= 51.2 Hz, 1 H), 7.35 ~ 7.26 (m, 4 H), 7.21 to 7.19 (m, 2 H), 7.15 to 7.12 (m, 1 H), 7.10 to 7.07 (m, 1 H), 5.28 (s, 2 H), 2.28 (s, 3 H).

[0254]

[0255] Example 5: Synthesis of 3-((3-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)oxy)phenyl)ethanyl)benzonitrile

[0256]

[0257]

[0258] 3-((3-hydroxyphenyl)ethanyl)benzonitrile (0.050 g, 0.228 mmol), 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.084 g, 0.274 mmol) and potassium carbonate (K2CO3, 0.095 g, 0.684 mmol) were used as starting materials in a similar manner to step 5 of Example 1 to obtain 3-((3-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)oxy)phenyl)ethanyl)benzonitrile (0.035 g, 34.5%) as a yellow solid: LRMS(ES) m / z 446.27 [M+H] +, calculated MW 445.4;1H-NMR (400 MHz, DMSO-d6) d 8.03 (t,J= 1.4 Hz, 1 H), 7.91 (td,J= 10.0, 1.7 Hz, 2 H), 7.86 (dd,J= 7.8, 1.4 Hz, 2 H), 7.80 (t,J= 7.6 Hz, 1 H), 7.65 ~ 7.53 (m, 2 H), 7.40 ~ 7.35 (m, 1 H), 7.27 (q,J= 1.2 Hz, 1 H), 7.18 (d,J= 6.4 Hz, 1 H), 7.19 ~ 7.12 (m, 1 H), 5.29 (s, 2 H).

[0259]

[0260] Example 6: Synthesis of 2-(difluoromethyl)-5-(6-(((4-((4-fluorophenyl)ethanyl)pyridin-2-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0261] Step 1: Synthesis of 4-((4-fluorophenyl)ethanyl)pyridin-2(1H)-one

[0262]

[0263]

[0264] A similar procedure as in Step 4 of Example 1 was followed from 4-bromopyridin-2(1H)-one (0.150 g, 0.862 mmol), 1-ethynyl-4-fluorobenzene (0.155 g, 1.293 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.061 g, 0.086 mmol), copper iodide (CuI, 0.008 g, 0.043 mmol) and triethylamine (0.360 mL, 2.586 mmol) as starting materials to obtain 4-((4-fluorophenyl)ethynyl)pyridin-2(1H)-one (0.103 g, 56.0%) as a yellow solid: LRMS(ES) m / z 214.16 [M+H] + , calculated MW 213.21.

[0265]

[0266] Step 2: Synthesis of 2-(difluoromethyl)-5-(6-(((4-((4-fluorophenyl)ethanyl)pyridin-2-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0267]

[0268]

[0269] 4-((4-fluorophenyl)ethanyl)pyridin-2(1H)-one (0.030 g, 0.141 mmol), 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.049 g, 0.169 mmol) and potassium carbonate (K2CO3, 0.058 g, 0.422 mmol) were used as starting materials. In a similar manner to step 5 of Example 1, 2-(difluoromethyl)-5-(6-(((4-((4-fluorophenyl)ethanyl)pyridin-2-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.021 g, 35.3%) was obtained as an ivory solid: LRMS(ES) m / z 423.22 [M+H] + , calculated MW 422.37;1H-NMR(400 MHz, DMSO-d6) d 9.16 (d,J= 2.4 Hz, 1 H), 8.41 (dd,J= 8.2, 2.2 Hz, 1 H), 8.15 (d,J= 5.6 Hz, 1 H), 7.68 ~ 7.64 (m, 3 H), 7.48 (d,J= 50.8 Hz, 1 H), 7.32 ~ 7.27 (m, 2 H), 7.14 ~ 7.12 (m, 2 H), 5.55 (s, 2 H).

[0270]

[0271] Example 7: Synthesis of 2-(6-(((5-((3-chlorophenyl)ethanyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0272] Step 1: Synthesis of 5-((3-chlorophenyl)ethanyl)pyridin-3-ol

[0273]

[0274]

[0275] 5-Bromopyridin-3-ol (0.300 g, 1.724 mmol), 1-chloro-3-ethyleneylbenzene (0.283 g, 2.069 mmol), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4, 0.100 g, 0.086 mmol), copper iodide (CuI, 0.016 g, 0.086 mmol), and triethylamine (0.721 mL, 5.172 mmol) were mixed in N,N-dimethylformamide (10 mL) at room temperature. The resulting mixture was irradiated with microwaves, heated at 120°C for 30 min, and then cooled to room temperature to terminate the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous ammonium chloride solution was poured into the resulting concentrate, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to obtain 5-((3-chlorophenyl)ethanyl)pyridin-3-ol (0.392 g, 99.0%) as a yellow solid: LRMS(ES) m / z 230.08 [M+H] + , calculated MW 229.66.

[0276]

[0277] Step 2: Synthesis of 2-(6-(((5-((3-chlorophenyl)ethanyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0278]

[0279]

[0280] 2-(6-(((5-((3-chlorophenyl)ethanyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.011 g, 14.4%) was obtained as a brown solid in a similar manner to step 5 of Example 1 using 5-((3-chlorophenyl)ethanyl)pyridin-3-ol (0.040 g, 0.174 mmol), 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.061 g, 0.209 mmol) and potassium carbonate (K2CO3, 0.072 g, 0.523 mmol) as starting materials: LRMS(ES) m / z 439.27 [M+H] + , calculated MW 438.82;1H-NMR(400 MHz, DMSO-d6) d 9.21 (d,J= 2.4 Hz, 1 H), 8.48 (dd,J= 8.2, 2.2 Hz, 1 H), 8.44 (d,J= 2.8 Hz, 1 H), 8.38 (d,J= 1.6 Hz, 1 H), 7.79 (d,J= 8.4 Hz, 1 H), 7.73 to 7.65 (m, 2 H), 7.55 to 7.50 (m, 2 H), 7.49 to 7.43 (m, 2 H), 5.43 (s, 2 H).

[0281]

[0282] Example 8: Synthesis of 2-(4-(((5-((3-chlorophenyl)ethanyl)pyridin-3-yl)oxy)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0283]

[0284]

[0285] 5-((3-chlorophenyl)ethanyl)pyridin-3-ol (0.040 g, 0.174 mmol), 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.064 g, 0.209 mmol) and potassium carbonate (K2CO3, 0.072 g, 0.523 mmol) were used as starting materials. In a similar manner to step 5 of Example 1, 2-(4-(((5-((3-chlorophenyl)ethanyl)pyridin-3-yl)oxy)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.020 g, 25.2%) was obtained as a brown solid: LRMS(ES) m / z 456.24 [M+H] + , calculated MW 455.82;1H-NMR(400 MHz, DMSO-d6) d 8.42 (d,J= 2.8 Hz, 1 H), 8.38 (d,J= 1.2 Hz, 1 H), 7.95 ~ 7.90 (m, 2 H), 7.83 (t,J= 7.6 Hz, 1 H), 7.76 (q,J= 1.6 Hz, 1 H), 7.66 to 7.65 (m, 1 H), 7.55 to 7.41 (m, 4 H), 5.37 (s, 2 H).

[0286]

[0287] Example 9: Synthesis of 2-(6-(((2-((3-chlorophenyl)ethanyl)pyridin-4-yl)oxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0288] Step 1: Synthesis of 2-((3-chlorophenyl)ethanyl)pyridin-4-ol

[0289]

[0290]

[0291] 2-((3-chlorophenyl)ethanyl)pyridin-4-ol (0.335 g, 84.6%) was obtained as a yellow solid in a similar manner to Step 1 of Example 7, starting from 2-bromopyridin-4-ol (0.300 g, 1.724 mmol), 1-chloro-3-ethanylbenzene (0.283 g, 2.069 mmol), tetrakis(triphenylphosphine)palladium (0.100 g, 0.086 mmol), copper iodide (CuI, 0.016 g, 0.086 mmol) and triethylamine (0.721 mL, 5.172 mmol): LRMS(ES) m / z 230.15 [M+H] + , calculated MW 229.66.

[0292]

[0293] Step 2: Synthesis of 2-(6-(((2-((3-chlorophenyl)ethanyl)pyridin-4-yl)oxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0294]

[0295]

[0296] 2-((3-chlorophenyl)ethanyl)pyridin-4-ol (0.040 g, 0.174 mmol), 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.061 g, 0.209 mmol) and potassium carbonate (K2CO3, 0.072 g, 0.523 mmol) were used as starting materials in a similar manner to step 5 of Example 1 to obtain 2-(6-(((2-((3-chlorophenyl)ethanyl)pyridin-4-yl)oxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.013 g, 17.0%) as a yellow liquid: LRMS(ES) m / z 439.27 [M+H] +, calculated MW 438.82;1H-NMR(400 MHz, DMSO-d6) d 9.21 (dd,J= 2.2, 1.0 Hz, 1 H), 8.48 (dd,J= 8.0, 2.0 Hz, 1 H), 8.42 (d,J= 6.0 Hz, 1 H), 7.76 (d,J= 8.4 Hz, 1 H), 7.68 ~ 7.66 (m, 1 H), 7.59 ~ 7.51 (m, 3 H), 7.48 ~ 7.44 (m, 1 H), 7.42 ~ 7.40 (m, 1 H), 7.13 (dd,J= 5.8, 2.6 Hz, 1 H), 5.45 (s, 2 H).

[0297]

[0298] Example 10: Synthesis of 2-(difluoromethyl)-5-(6-(((5-(m-tolyleethaneyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0299] Step 1: Synthesis of 5-(m-tolylethanyl)pyridin-3-ol

[0300]

[0301]

[0302] 5-(m-Tolylethanyl)pyridin-3-ol (0.301 g, 83.4%) was obtained as a yellow solid in a similar manner to Step 1 of Example 7, starting from 5-bromopyridin-3-ol (0.300 g, 1.724 mmol), 1-ethynyl-3-methylbenzene (0.240 g, 2.069 mmol), tetrakis(triphenylphosphine)palladium (0.100 g, 0.086 mmol), copper iodide (CuI, 0.016 g, 0.086 mmol) and triethylamine (0.721 mL, 5.172 mmol): LRMS(ES) m / z 210.20 [M+H] + , calculated MW 209.25.

[0303]

[0304] Step 2: Synthesis of 2-(difluoromethyl)-5-(6-(((5-(m-tolyleethaneyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0305]

[0306]

[0307] 2-(Difluoromethyl)-5-(6-(((5-(m-tolylethanyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.017 g, 21.3%) was obtained as a brown solid in a similar manner to step 5 of Example 1 starting from 5-(m-tolylethanyl)pyridin-3-ol (0.040 g, 0.191 mmol), 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.067 g, 0.229 mmol) and potassium carbonate (K2CO3, 0.079 g, 0.573 mmol). LRMS(ES) m / z 419.32 [M+H] + , calculated MW 418.4;1H-NMR(400 MHz, DMSO-d6) d 9.21 ~ 9.20 (m, 1 H), 8.48 (dd,J= 8.4, 2.4 Hz, 1 H), 8.41 (d,J= 2.8 Hz, 1 H), 8.34 (d,J= 2.0 Hz, 1 H), 7.79 (d,J= 8.4 Hz, 1 H), 7.69 ~ 7.42 (m, 2 H), 7.38 ~ 7.23 (m, 4 H), 5.42 (s, 2 H), 2.29 (s, 3 H).

[0308]

[0309] Example 11: Synthesis of 3-((5-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)pyridin-3-yl)ethanyl)benzonitrile

[0310] Step 1: Synthesis of 3-((5-hydroxypyridin-3-yl)ethanyl)benzonitrile

[0311]

[0312]

[0313] 3-((5-hydroxypyridin-3-yl)ethanyl)benzonitrile (0.213 g, 56.1%) was obtained as a yellow solid in a similar manner to Step 1 of Example 7, starting from 5-bromopyridin-3-ol (0.300 g, 1.724 mmol), 3-ethynylbenzonitrile (0.263 g, 2.069 mmol), tetrakis(triphenylphosphine)palladium (0.100 g, 0.086 mmol), copper iodide (CuI, 0.016 g, 0.086 mmol) and triethylamine (0.721 mL, 5.172 mmol): LRMS(ES) m / z 221.29 [M+H] + , calculated MW 220.23.

[0314]

[0315] Step 2: Synthesis of 3-((5-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)pyridin-3-yl)ethanyl)benzonitrile

[0316]

[0317]

[0318] Starting from 3-((5-hydroxypyridin-3-yl)ethanyl)benzonitrile (0.050 g, 0.227 mmol), 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.072 g, 0.250 mmol) and potassium carbonate (K2CO3, 0.094 g, 0.681 mmol), 3-((5-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)pyridin-3-yl)ethanyl)benzonitrile (0.054 g, 55.4%) was prepared as a yellow solid in a similar manner to step 5 of Example 1. Obtained: LRMS(ES) m / z 430.22 [M+H] +, calculated MW 429.39;1H-NMR(400 MHz, DMSO-d6) d 9.21 (d,J= 1.6 Hz, 1 H), 8.49 ~ 8.45 (m, 2 H), 8.39 (s, 1 H), 8.07 (s, 1 H), 7.89 (dt,J= 8.0, 1.9 Hz, 2 H), 7.79 (d,J= 8.4 Hz, 1 H), 7.68 ~ 7.43 (m, 3 H), 5.43 (s, 2 H).

[0319]

[0320] Example 12: Synthesis of 2-(6-(((5-((6-chloropyridin-2-yl)ethanyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0321] Step 1: Synthesis of 5-((6-chloropyridin-2-yl)ethanyl)pyridin-3-ol

[0322]

[0323]

[0324] 5-((6-chloropyridin-2-yl)ethanyl)pyridin-3-ol (0.024 g, 12.4%) was obtained as a yellow solid in a similar manner to Step 1 of Example 7, starting from 5-ethanylpyridin-3-ol (0.100 g, 0.839 mmol), 2-chloro-6-iodopyridine (0.241 g, 1.007 mmol), tetrakis(triphenylphosphine)palladium (0.049 g, 0.042 mmol), copper iodide (CuI, 0.008 g, 0.042 mmol) and triethylamine (0.585 mL, 4.197 mmol): LRMS(ES) m / z 231.21 [M+H] + , calculated MW 230.65.

[0325]

[0326] Step 2: Synthesis of 2-(6-(((5-((6-chloropyridin-2-yl)ethanyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0327]

[0328]

[0329] Starting from 5-((6-chloropyridin-2-yl)ethanyl)pyridin-3-ol (0.024 g, 0.104 mmol), 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.036 g, 0.125 mmol) and potassium carbonate (K2CO3, 0.043 g, 0.312 mmol), 2-(6-(((5-((6-chloropyridin-2-yl)ethanyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.019 g, 41.5%) was obtained as a yellow solid in a similar manner to step 5 of Example 1. Obtained: LRMS(ES) m / z 440.13 [M+H] + , calculated MW 439.81;1H-NMR(400 MHz, DMSO-d6) d 9.20 (d,J= 1.6 Hz, 1 H), 8.49 ~ 8.43 (m, 2 H), 8.43 (d,J= 1.2 Hz, 1 H), 7.94 ~ 7.89 (m, 1 H), 7.81 to 7.79 (m, 2 H), 7.68 (d,J= 7.2 Hz, 1 H), 7.58 to 7.42 (m, 2 H), 5.44 (s, 2 H).

[0330]

[0331] Example 13: Synthesis of 2-(difluoromethyl)-5-(6-(((5-((3-fluorophenyl)ethanyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0332] Step 1: Synthesis of 5-((3-fluorophenyl)ethanyl)pyridin-3-ol

[0333]

[0334]

[0335] 5-((3-fluorophenyl)ethanyl)pyridin-3-ol (0.150 g, 40.8%) was obtained as a brown solid in a similar manner to Step 1 of Example 7, starting from 5-bromopyridin-3-ol (0.300 g, 1.724 mmol), 1-ethynyl-3-fluorobenzene (0.249 g, 2.069 mmol), tetrakis(triphenylphosphine)palladium (0.100 g, 0.086 mmol), copper iodide (CuI, 0.016 g, 0.086 mmol) and triethylamine (1.202 mL, 8.621 mmol): LRMS(ES) m / z 214.04 [M+H] + , calculated MW 213.21.

[0336]

[0337] Step 2: Synthesis of 2-(difluoromethyl)-5-(6-(((5-((3-fluorophenyl)ethanyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0338]

[0339]

[0340] 5-((3-fluorophenyl)ethanyl)pyridin-3-ol (0.050 g, 0.235 mmol), 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.082 g, 0.281 mmol) and potassium carbonate (K2CO3, 0.097 g, 0.704 mmol) were used as starting materials. In a similar manner to step 5 of Example 1, 2-(difluoromethyl)-5-(6-(((5-((3-fluorophenyl)ethanyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.024 g, 24.2%) was obtained as a yellow solid: LRMS(ES) m / z 423.15 [M+H] +, calculated MW 422.37;1H-NMR(400 MHz, DMSO-d6) d 9.20 (t,J= 1.0 Hz, 1 H), 8.49 ~ 8.43 (m, 2 H), 8.37 (d,J= 1.6 Hz, 1 H), 7.79 (d,J= 8.4 Hz, 1 H), 7.72 to 7.55 (m, 2 H), 7.48 to 7.39 (m, 3 H), 7.32 to 7.26 (m, 1 H), 5.43 (s, 2 H).

[0341]

[0342] Example 14: Synthesis of 2-(6-(((5-((2-chloropyridin-4-yl)ethanyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0343] Step 1: Synthesis of 5-((2-chloropyridin-4-yl)ethanyl)pyridin-3-ol

[0344]

[0345]

[0346] 5-((2-chloropyridin-4-yl)ethanyl)pyridin-3-ol (0.047 g, 24.3%) was obtained as a yellow solid in a similar manner to Step 1 of Example 7, starting from 5-ethanylpyridin-3-ol (0.100 g, 0.839 mmol), 2-chloro-4-iodopyridine (0.302 g, 1.259 mmol), tetrakis(triphenylphosphine)palladium (0.049 g, 0.042 mmol), copper iodide (CuI, 0.008 g, 0.042 mmol) and triethylamine (0.351 mL, 2.518 mmol): LRMS(ES) m / z 231.07 [M+H] + , calculated MW 230.65.

[0347]

[0348] Step 2: Synthesis of 2-(6-(((5-((2-chloropyridin-4-yl)ethanyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0349]

[0350]

[0351] Starting from 5-((2-chloropyridin-4-yl)ethanyl)pyridin-3-ol (0.040 g, 0.173 mmol), 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.060 g, 0.208 mmol) and potassium carbonate (K2CO3, 0.072 g, 0.520 mmol), 2-(6-(((5-((2-chloropyridin-4-yl)ethanyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.053 g, 69.5%) was obtained as a yellow solid in a similar manner to step 5 of Example 1. Obtained: LRMS(ES) m / z 440.13 [M+H] + , calculated MW 439.81;1H-NMR(400 MHz, DMSO-d6) d 9.20 (d,J= 1.6 Hz, 1 H), 8.50 ~ 8.46 (m, 3 H), 8.42 (d,J= 1.6 Hz, 1 H), 7.80 ~ 7.72 (m, 2 H), 7.68 ~ 7.42 (m, 3 H), 5.43 (s, 2 H).

[0352]

[0353] Example 15: Synthesis of 2-(6-((5-((3-chlorophenyl)ethanyl)-2-fluorophenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0354] Step 1: Synthesis of 5-((3-chlorophenyl)ethanyl)-2-fluorophenol

[0355]

[0356]

[0357] 5-((3-chlorophenyl)ethanyl)-2-fluorophenol (0.419 g, 64.9%) was obtained as a brown liquid in a similar manner to step 1 of Example 7, starting from 5-bromo-2-fluorophenol (0.500 g, 2.618 mmol), 1-chloro-3-ethynylbenzene (0.390 mL, 3.141 mmol), tetrakis(triphenylphosphine)palladium (0.151 g, 0.131 mmol), copper iodide (CuI, 0.025 g, 0.131 mmol) and triethylamine (1.095 mL, 7.853 mmol): LRMS(ES) m / z 244.86 [MH] + , calculated MW 246.67.

[0358]

[0359] Step 2: Synthesis of 2-(6-((5-((3-chlorophenyl)ethanyl)-2-fluorophenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0360]

[0361]

[0362] 5-((3-chlorophenyl)ethanyl)-2-fluorophenol (0.050 g, 0.203 mmol), 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.065 g, 0.223 mmol) and potassium carbonate (K2CO3, 0.084 g, 0.608 mmol) were used as starting materials. In a similar manner to step 5 of Example 1, 2-(6-((5-((3-chlorophenyl)ethanyl)-2-fluorophenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.047 g, 50.9%) was obtained as a yellow solid: LRMS(ES) m / z 456.38 [M+H] +, calculated MW 455.82;1H-NMR(400 MHz, DMSO-d6) d 9.21 ~ 9.20 (m, 1 H), 8.49 (dd,J= 8.2, 1.8 Hz, 1 H), 7.77 (d,J= 8.4 Hz, 1 H), 7.68 ~ 7.55 (m, 2 H), 7.49 ~ 7.40 (m, 4 H), 7.33 (q,J= 6.5 Hz, 1 H), 7.21 ~ 7.17 (m, 1 H), 5.42 (s, 2 H).

[0363]

[0364] Example 16: Synthesis of (6-((3-((3-chlorophenyl)ethanyl)-4-fluorophenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0365] Step 1: Synthesis of 3-((3-chlorophenyl)ethanyl)-4-fluorophenol

[0366]

[0367]

[0368] 3-((3-chlorophenyl)ethanyl)-4-fluorophenol (0.506 g, 78.4%) was obtained as a brown liquid in a similar manner to step 1 of Example 7, starting from 3-bromo-4-fluorophenol (0.500 g, 2.618 mmol), 1-chloro-3-ethynylbenzene (0.390 mL, 3.141 mmol), tetrakis(triphenylphosphine)palladium (0.151 g, 0.131 mmol), copper iodide (CuI, 0.025 g, 0.131 mmol) and triethylamine (1.095 mL, 7.853 mmol): LRMS(ES) m / z 244.96 [MH] + , calculated MW 246.67.

[0369]

[0370] Step 2: Synthesis of 2-(6-((3-((3-chlorophenyl)ethanyl)-4-fluorophenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0371]

[0372]

[0373] 2-(6-((3-((3-chlorophenyl)ethanyl)-4-fluorophenol (0.050 g, 0.203 mmol), 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.065 g, 0.223 mmol) and potassium carbonate (K2CO3, 0.084 g, 0.608 mmol) were used as starting materials in a similar manner to step 5 of Example 1 to obtain 2-(6-((3-((3-chlorophenyl)ethanyl)-4-fluorophenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.063 g, 68.2%) as a yellow solid: LRMS(ES) m / z 456.05 [M+H] + , calculated MW 455.82;1H-NMR(400 MHz, DMSO-d6) d 9.20 (d,J= 6.0 Hz, 1 H), 8.47 (dd,J= 8.2, 2.2 Hz, 1 H), 7.77 (d,J= 8.4 Hz, 1 H), 7.68 ~ 7.55 (m, 2 H), 7.52 to 7.47 (m, 2 H), 7.45 to 7.41 (m, 1 H), 7.13 to 7.12 (m, 1 H), 7.10 to 7.03 (m, 2 H), 5.36 (s, 2 H).

[0374]

[0375] Example 17: Synthesis of 2-(6-((3-((6-chloropyridin-2-yl)ethanyl)phenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0376] Step 1: Synthesis of 2-(difluoromethyl)-5-(6-((3-ethanylphenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0377]

[0378]

[0379] 2-(Difluoromethyl)-5-(6-((3-ethynylphenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (1.037 g, 74.9%) was obtained as a yellow solid in a similar manner to step 5 of Example 1 starting from 3-ethynylphenol (0.500 g, 4.232 mmol), 2-(6-(bromomethyl)pyridin-3-yl)-1,3,4-oxadiazole (1.350 g, 4.655 mmol) and potassium carbonate (K2CO3, 1.755 g, 12.697 mmol): LRMS(ES) m / z 329.03 [M+H] + , calculated MW 327.29.

[0380]

[0381] Step 2: Synthesis of 2-(6-((3-((6-chloropyridin-2-yl)ethanyl)phenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0382]

[0383]

[0384] A similar method as in step 1 of Example 7 was performed using 2-(difluoromethyl)-5-(6-((3-ethynylphenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.050 g, 0.153 mmol), 2-chloro-6-iodopyridine (0.044 g, 0.183 mmol), tetrakis(triphenylphosphine)palladium (0.009 g, 0.008 mmol), copper iodide (CuI, 0.001 g, 0.008 mmol) and triethylamine (0.064 mL, 0.458 mmol) as starting materials. 2-(6-((3-((6-chloropyridin-2-yl)ethanyl)phenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.055 g, 82.0%) was obtained as a yellow solid: LRMS(ES) m / z 439.01 [M+H] +, calculated MW 438.82;1H-NMR(400 MHz, DMSO-d6) d 9.20 ~ 9.19 (m, 1 H), 8.46 (dd,J= 8.2, 2.2 Hz, 1 H), 7.90 (t,J= 7.8 Hz, 1 H), 7.76 (d,J= 7.6 Hz, 1 H), 7.68 to 7.52 (m, 3 H), 7.42 to 7.29 (m, 2 H), 7.23 to 7.21 (m, 1 H), 7.17 (ddd,J= 8.2, 2.8, 1.0 Hz, 1 H), 5.36 (s, 2 H).

[0385]

[0386] Example 18: Synthesis of 2-(6-((3-((2-chloropyridin-4-yl)ethanyl)phenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0387]

[0388]

[0389] A similar method as in step 1 of Example 7 was performed using 2-(difluoromethyl)-5-(6-((3-ethynylphenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.050 g, 0.153 mmol), 2-chloro-4-iodopyridine (0.044 g, 0.183 mmol), tetrakis(triphenylphosphine)palladium (0.009 g, 0.008 mmol), copper iodide (CuI, 0.001 g, 0.008 mmol) and triethylamine (0.064 mL, 0.458 mmol) as starting materials. 2-(6-((3-((2-chloropyridin-4-yl)ethanyl)phenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.035 g, 52.2%) was obtained as a yellow solid: LRMS(ES) m / z 439.07 [M+H] +, calculated MW 438.82;1H-NMR(400 MHz, DMSO-d6) d 9.20 ~ 9.19 (m, 1 H), 8.48 ~ 8.41 (m, 2 H), 7.76 (d,J= 8.4 Hz, 1 H), 7.68 ~ 7.68 (m, 1 H), 7.55 ~ 7.37 (m, 3 H), 7.30 to 7.30 (m, 1 H), 7.22 to 7.17 (m, 2 H), 5.35 (s, 2 H).

[0390]

[0391] Example 19: Synthesis of 2-(difluoromethyl)-5-(6-((3-((2-methylthiazol-4-yl)ethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0392]

[0393]

[0394] A similar method as in step 1 of Example 7 was used, starting from 2-(difluoromethyl)-5-(6-((3-ethynylphenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.050 g, 0.153 mmol), 4-bromo-2-methylthiazole (0.020 mL, 0.183 mmol), tetrakis(triphenylphosphine)palladium (0.009 g, 0.008 mmol), copper iodide (CuI, 0.001 g, 0.008 mmol) and triethylamine (0.064 mL, 0.458 mmol). 2-(Difluoromethyl)-5-(6-((3-((2-methylthiazol-4-yl)ethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.012 g, 18.5%) was obtained as a yellow liquid: LRMS(ES) m / z 425.13 [M+H] +, calculated MW 424.43;1H-NMR(400 MHz, DMSO-d6) d 9.37 (m, 1 H), 8.44 (d,J= 8.4 Hz, 1 H), 7.79 (m, 1 H), 7.66 (dd,J= 12.2, 8.2 Hz, 1 H), 7.56 ~ 7.44 (m, 1 H), 7.38 to 7.28 (m, 1 H), 7.21 to 7.17 (m, 1 H), 7.07 to 6.81 (m, 2 H), 5.30 (s, 2 H), 1.21 (s, 3 H).

[0395]

[0396] Example 20: Synthesis of 2-(difluoromethyl)-5-(6-((3-((6-methylpyridin-2-yl)ethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0397]

[0398]

[0399] A similar method as in step 1 of Example 7 was performed using 2-(difluoromethyl)-5-(6-((3-ethynylphenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.050 g, 0.153 mmol), 2-bromo-6-methylpyridine (0.032 g, 0.183 mmol), tetrakis(triphenylphosphine)palladium (0.009 g, 0.008 mmol), copper iodide (CuI, 0.001 g, 0.008 mmol) and triethylamine (0.064 mL, 0.458 mmol) as starting materials. 2-(Difluoromethyl)-5-(6-((3-((6-methylpyridin-2-yl)ethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.045 g, 70.4%) was obtained as a light yellow solid: LRMS(ES) m / z 419.19 [M+H] +, calculated MW 418.4;1H-NMR (400 MHz, DMSO-d6) d 9.20 ~ 9.20 (m, 1 H), 8.46 (dd,J= 8.2, 2.2 Hz, 1 H), 7.77 ~ 7.68 (m, 2 H), 7.55 ~ 7.32 (m, 3 H), 7.27 to 7.24 (m, 2 H), 7.20 to 7.18 (m, 1 H), 7.16 to 7.12 (m, 1 H), 5.36 (s, 2 H), 2.43 (s, 3 H).

[0400]

[0401] Example 21: Synthesis of 2-(6-((3-((6-chloropyridin-2-yl)ethanyl)-4-fluorophenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0402] Step 1: Synthesis of 2-(6-((3-bromo-4-fluorophenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0403]

[0404]

[0405] A similar procedure as in Step 5 of Example 1 was followed using 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.400 g, 1.379 mmol), 3-bromo-4-fluorophenol (0.290 g, 1.517 mmol) and potassium carbonate (K2CO3, 0.572 g, 4.137 mmol) as starting materials to obtain 2-(6-((3-bromo-4-fluorophenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.461 g, 83.5%) as a yellow liquid: LRMS(ES) m / z 401.95 [M+H]+, calculated MW 400.16.

[0406]

[0407] Step 2: Synthesis of 2-(difluoromethyl)-5-(6-((4-fluoro-3-((trimethylsilyl)ethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0408]

[0409]

[0410] 2-(6-((3-bromo-4-fluorophenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.300 g, 0.750 mmol), ethynyltrimethylsilane (0.124 mL, 0.900 mmol), tetrakis(triphenylphosphine)palladium (0.043 g, 0.037 mmol), copper iodide (CuI, 0.007 g, 0.037 mmol) and triethylamine (0.313 mL, 2.249 mmol) were used as starting materials in a similar manner to step 1 of Example 7. 2-(Difluoromethyl)-5-(6-((4-fluoro-3-((trimethylsilyl)ethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.136 g, 43.5%) was obtained as a yellow liquid: LRMS(ES) m / z 418.13 [M+H] + , calculated MW 417.46.

[0411]

[0412] Step 3: Synthesis of 2-(difluoromethyl)-5-(6-((3-ethynyl-4-fluorophenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0413]

[0414]

[0415] 2-(Difluoromethyl)-5-(6-((4-fluoro-3-((trimethylsilyl)ethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.131 g, 0.314 mmol) and potassium carbonate (K2CO3, 0.065 g, 0.471 mmol) were dissolved in methanol (10 mL) at room temperature, and the resulting solution was stirred at the same temperature for 4 hours. The solvent was removed from the reaction mixture under reduced pressure, and water was poured into the resulting concentrate, and the residue was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography to obtain 2-(difluoromethyl)-5-(6-((3-ethynyl-4-fluorophenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.048 g, 44.3%) as a yellow liquid.

[0416]

[0417] Step 4: Synthesis of 2-(6-((3-((6-chloropyridin-2-yl)ethanyl)-4-fluorophenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0418]

[0419]

[0420] A similar method as in step 1 of Example 7 was used, starting from 2-(difluoromethyl)-5-(6-((3-ethynyl-4-fluorophenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.024 g, 0.070 mmol), 2-chloro-6-iodopyridine (0.018 g, 0.076 mmol), tetrakis(triphenylphosphine)palladium (0.004 g, 0.003 mmol), copper iodide (CuI, 0.001 g, 0.003 mmol) and triethylamine (0.029 mL, 0.209 mmol). 2-(6-((3-((6-chloropyridin-2-yl)ethanyl)-4-fluorophenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.002 g, 6.3%) was obtained as a yellow solid: LRMS(ES) m / z 457.10 [M+H] + , calculated MW 456.81;1H-NMR(400 MHz, DMSO-d6) d 9.20 ~ 9.19 (m, 1 H), 8.46 (dd,J= 8.2, 2.2 Hz, 1 H), 8.01 (t,J= 7.6 Hz, 1 H), 7.92 (t,J= 7.8 Hz, 1 H), 7.77 (d,J= 8.4 Hz, 1 H), 7.68 to 7.65 (m, 1 H), 7.57 to 7.55 (m, 2 H), 7.38 to 7.36 (m, 2 H), 5.34 (s, 2 H).

[0421]

[0422] Example 22: Synthesis of 2-(difluoromethyl)-5-(6-((3-((2-fluoropyridin-4-yl)ethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0423]

[0424]

[0425] 2-(Difluoromethyl)-5-(6-((3-ethynylphenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.050 g, 0.153 mmol), 2-fluoro-4-iodopyridine (0.041 g, 0.183 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos, 0.007 g, 0.015 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl [2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate (0.013 g, 0.015 mmol) and cesium carbonate (Cs2CO3, 0.149 g, 0.458 mmol) was mixed in acetonitrile (5 mL) at room temperature. The resulting mixture was irradiated with microwave and heated at 110°C for 20 minutes, and then the temperature was lowered to room temperature to terminate the reaction. The solvent was removed from the reaction mixture under reduced pressure, and a saturated aqueous ammonium chloride solution was poured into the resulting concentrate, which was then extracted with ethyl acetate. The organic layer was washed with a 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 give 2-(difluoromethyl)-5-(6-((3-((2-fluoropyridin-4-yl)ethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.031 g, 48.0%) as a yellow solid: LRMS(ES) m / z 423.15 [M+H] + , calculated MW 422.37;1H-NMR(400 MHz, DMSO-d6) d 9.20 ~ 9.20 (m, 1 H), 8.46 (dd,J= 7.8, 2.2 Hz, 1 H), 8.27 (d,J= 5.2 Hz, 1 H), 7.76 (d,J= 8.4 Hz, 1 H), 7.68 to 7.39 (m, 3 H), 7.37 to 7.36 (m, 1 H), 7.31 to 7.30 (m, 1 H), 7.22 (d,J= 7.6 Hz, 1 H), 7.20 to 7.17 (m, 1 H), 5.35 (s, 2 H).

[0426]

[0427] Example 23: Synthesis of 2-(6-((4-((3-chlorophenyl)ethanyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0428] Step 1: Synthesis of 4-((3-chlorophenyl)ethanyl)-1H-pyrrolo[2,3-c]pyridine

[0429]

[0430]

[0431] A similar method as in step 1 of Example 22 was performed using 4-bromo-1H-pyrrolo[2,3-c]pyridine (0.100 g, 0.508 mmol), 1-chloro-3-ethanylbenzene (0.083 g, 0.609 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl [2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate (0.021 g, 0.025 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.024 g, 0.051 mmol) and cesium carbonate (CsCO3, 0.245 g, 1.269 mmol) as starting materials. 4-((3-chlorophenyl)ethanyl)-1H-pyrrolo[2,3-c]pyridine (0.054 g, 42.1%) was obtained as a light brown solid: LRMS(ES) m / z 253.13 [M+H] + , calculated MW 252.7.

[0432]

[0433] Step 2: Synthesis of 2-(6-((4-((3-chlorophenyl)ethanyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0434]

[0435]

[0436] Starting from 4-((3-chlorophenyl)ethanyl)-1H-pyrrolo[2,3-c]pyridine (0.025 g, 0.099 mmol), 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.034 g, 0.119 mmol) and potassium carbonate (K2CO3, 0.041 g, 0.297 mmol), 2-(6-((4-((3-chlorophenyl)ethanyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.004 g, 8.8%) was obtained as a brown solid in a similar manner to step 5 of Example 1. Obtained: LRMS(ES) m / z 462.19 [M+H] + , calculated MW 461.86;1H-NMR(400 MHz, DMSO-d6) d 9.13 ~ 9.12 (m, 1 H), 8.85 (s, 1 H), 8.38 (dd,J= 8.0, 2.4 Hz, 1 H), 8.32 (s, 1 H), 7.90 (d,J= 2.8 Hz, 1 H), 7.73 (t,J= 1.6 Hz, 1 H), 7.59 (dt,J= 7.6, 1.5 Hz, 1 H), 7.54 ~ 7.39 (m, 3 H), 7.34 (d,J= 8.4 Hz, 1 H), 6.81 (d,J= 3.2 Hz, 1 H), 5.81 (s, 2 H).

[0437]

[0438] Example 24: Synthesis of 2-(6-((4-((3-chlorophenyl)ethanyl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0439] Step 1: Synthesis of 2-(6-((4-bromo-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0440]

[0441]

[0442] 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.100 g, 0.345 mmol), 4-bromo-1H-pyrrolo[3,2-c]pyridine (0.082 g, 0.414 mmol) and potassium carbonate (K2CO3, 0.143 g, 1.034 mmol) were used as starting materials in a similar manner to step 5 of Example 1 to obtain 2-(6-((4-bromo-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.116 g, 82.8%) as an ivory solid: LRMS(ES) m / z 407.95 [M+H] + , calculated MW 406.19.

[0443]

[0444] Step 2: Synthesis of 2-(6-((4-((3-chlorophenyl)ethanyl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0445]

[0446]

[0447] 2-(6-((4-bromo-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.123 mmol), 1-chloro-3-ethaneylbenzene (0.020 g, 0.148 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl [2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate (0.005 g, 0.006 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.006 g, 0.012 mmol) and carbonic acid Using cesium (CsCO3, 0.071 g, 0.369 mmol) as a starting material, a similar method to step 1 of Example 22 was used to obtain 2-(6-((4-((3-chlorophenyl)ethanyl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.023 g, 40.5%) as a yellow solid: LRMS(ES) m / z 462.12 [M+H] + , calculated MW 461.86;1H-NMR(400 MHz, DMSO-d6) d 9.13 ~ 9.12 (m, 1 H), 8.36 (dd,J= 8.2, 2.2 Hz, 1 H), 8.20 (d,J= 6.0 Hz, 1 H), 7.78 (t,J= 1.6 Hz, 1 H), 7.74 (d,J= 3.2 Hz, 1 H), 7.65 ~ 7.62 (m, 1 H), 7.55 ~ 7.40 (m, 4 H), 7.25 (d,J= 8.4 Hz, 1 H), 6.87 (dd,J= 3.2, 1.2 Hz, 1 H), 5.73 (s, 2 H).

[0448]

[0449] Example 25: Synthesis of 2-(difluoromethyl)-5-(6-((4-(m-tolyleethaneyl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0450]

[0451]

[0452] 2-(6-((4-Bromo-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.123 mmol), 1-Ethynyl-3-methylbenzene (0.020 g, 0.148 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl [2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate (0.005 g, 0.006 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.006 g, 0.012 mmol) and carbonic acid Using cesium (CsCO3, 0.071 g, 0.369 mmol) as a starting material, a similar method to step 1 of Example 22 was used to obtain 2-(difluoromethyl)-5-(6-((4-(m-tolylethanyl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.036 g, 66.3%) as a yellow solid: LRMS(ES) m / z 442.18 [M+H] + , calculated MW 441.44;1H-NMR(400 MHz, DMSO-d6) d 9.13 ~ 9.12 (m, 1 H), 8.36 (dd,J= 8.2, 2.2 Hz, 1 H), 8.18 (d,J= 6.0 Hz, 1 H), 7.72 (d,J= 3.2 Hz, 1 H), 7.52 to 7.39 (m, 4 H), 7.33 (t,J= 7.6 Hz, 1 H), 7.27 to 7.23 (m, 2 H), 6.81 (dd,J= 3.2, 0.8 Hz, 1 H), 5.72 (s, 2 H), 2.32 (s, 3 H).

[0453]

[0454] Example 26: Synthesis of 2-(difluoromethyl)-5-(6-((3-((3-(trifluoromethyl)phenyl)ethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0455]

[0456]

[0457] A similar method as in step 1 of Example 7 was carried out using 2-(difluoromethyl)-5-(6-((3-ethynylphenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.050 g, 0.153 mmol), 1-iodo-3-(trifluoromethyl)benzene (0.050 g, 0.183 mmol), tetrakis(triphenylphosphine)palladium (0.009 g, 0.008 mmol), copper iodide (CuI, 0.001 g, 0.008 mmol) and triethylamine (0.064 mL, 0.458 mmol) as starting materials. 2-(Difluoromethyl)-5-(6-((3-((3-(trifluoromethyl)phenyl)ethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.044 g, 61.1%) was obtained as a yellow solid: LRMS(ES) m / z 472.83 [M+H] + , calculated MW 471.39;1H-NMR (400 MHz, DMSO-d6) d 9.20 (d,J= 2.4 Hz, 1 H), 8.47 (dd,J= 8.0, 2.4 Hz, 1 H), 7.89 (s, 1 H), 7.83 (d,J= 8.0 Hz, 1 H), 7.76 (d,J= 8.4 Hz, 2 H), 7.68 ~ 7.62 (m, 1 H), 7.55 ~ 7.34 (m, 2 H), 7.28 ~ 7.27 (m, 1 H), 7.20 ~ 7.18 (m, 1 H), 7.14 ~ 7.11 (m, 1 H), 5.34 (s, 2 H).

[0458]

[0459] Example 27: Synthesis of 2-(difluoromethyl)-5-(6-((3-((6-fluoropyridin-2-yl)ethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0460]

[0461]

[0462] A similar method as in step 1 of Example 7 was performed using 2-(difluoromethyl)-5-(6-((3-ethynylphenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.050 g, 0.153 mmol), 2-bromo-6-fluoropyridine (0.032 g, 0.183 mmol), tetrakis(triphenylphosphine)palladium (0.009 g, 0.008 mmol), copper iodide (CuI, 0.001 g, 0.008 mmol) and triethylamine (0.064 mL, 0.458 mmol) as starting materials. 2-(Difluoromethyl)-5-(6-((3-((6-fluoropyridin-2-yl)ethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.038 g, 58.9%) was obtained as a light brown solid: LRMS(ES) m / z 423.15 [M+H] + , calculated MW 422.37;1H-NMR (400 MHz, DMSO-d6) d 9.20 (d,J= 1.2 Hz, 1 H), 8.47 (dd,J= 8.0, 2.4 Hz, 1 H), 8.03 (q,J= 8.1 Hz, 1 H), 7.77 ~ 7.74 (m, 1 H), 7.68 to 7.42 (m, 2 H), 7.40 to 7.35 (m, 1 H), 7.29 to 7.28 (m, 1 H), 7.24 to 7.21 (m, 2 H), 7.18 to 7.15 (m, 1 H), 5.36 (s, 2 H).

[0463]

[0464] Example 28: Synthesis of 2-(difluoromethyl)-5-(6-(((5-((6-methylpyridin-2-yl)ethanyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0465] Step 1: Synthesis of 2-(6-(((5-bromopyridin-3-yl)oxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0466]

[0467]

[0468] 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.180 g, 0.621 mmol), 5-bromopyridin-3-ol (0.119 g, 0.683 mmol) and potassium carbonate (K2CO3, 0.257 g, 1.862 mmol) were used as starting materials in a similar manner to step 5 of Example 1 to obtain 2-(6-(((5-bromopyridin-3-yl)oxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.056 g, 23.6%) as a brown solid: LRMS(ES) m / z 385.24 [M+H] + , calculated MW 383.15.

[0469]

[0470] Step 2: Synthesis of 2-(difluoromethyl)-5-(6-(((5-((6-methylpyridin-2-yl)ethanyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0471]

[0472]

[0473] 2-(6-(((5-bromopyridin-3-yl)oxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.130 mmol), 2-ethynyl-6-methylpyridine (0.017 g, 0.144 mmol), tetrakis(triphenylphosphine)palladium (0.008 g, 0.007 mmol), copper iodide (CuI, 0.001 g, 0.007 mmol) and triethylamine (0.055 mL, 0.391 mmol) were used as starting materials in a similar manner to step 1 of Example 7. 2-(Difluoromethyl)-5-(6-(((5-((6-methylpyridin-2-yl)ethanyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.015 g, 27.4%) was obtained as a light brown solid: LRMS(ES) m / z 420.18 [M+H] +, calculated MW 419.39;1H-NMR(400 MHz, CDCl3) d 9.34 (s, 1 H), 8.46 (dd,J= 8.2, 1.8 Hz, 1 H), 7.77 (d,J= 8.4 Hz, 1 H), 7.68 ~ 7.64 (m, 3 H), 7.55 ~ 7.51 (m, 1 H), 7.48 ~ 7.43 (m, 2 H), 6.94 (t,J= 51.6 Hz, 1 H), 5.37 (s, 2 H), 2.76 (s, 3 H).

[0474]

[0475] Example 29: Synthesis of 2-(difluoromethyl)-5-(6-((3-((2-methylpyridin-4-yl)ethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0476]

[0477]

[0478] A similar method as in step 1 of Example 7 was performed using 2-(difluoromethyl)-5-(6-((3-ethynylphenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.050 g, 0.153 mmol), 4-bromo-2-methylpyridine (0.035 g, 0.183 mmol), tetrakis(triphenylphosphine)palladium (0.009 g, 0.008 mmol), copper iodide (CuI, 0.001 g, 0.008 mmol) and triethylamine (0.064 mL, 0.458 mmol) as starting materials. 2-(Difluoromethyl)-5-(6-((3-((2-methylpyridin-4-yl)ethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.056 g, 87.6%) was obtained as a yellow solid: LRMS(ES) m / z 419.19 [M+H] +, calculated MW 418.4;1H-NMR(400 MHz, DMSO-d6) d 9.20 ~ 9.19 (m, 1 H), 8.48 ~ 8.45 (m, 2 H), 7.76 (d,J= 8.4 Hz, 1 H), 7.68 ~ 7.43 (m, 1 H), 7.39 ~ 7.35 (m, 2 H), 7.29 to 7.26 (m, 2 H), 7.19 to 7.17 (m, 1 H), 7.16 to 7.14 (m, 1 H), 5.35 (s, 2 H), 2.43 (s, 3 H).

[0479]

[0480] Example 30: Synthesis of 2-(difluoromethyl)-5-(6-((3-(phenylethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0481]

[0482]

[0483] 2-(Difluoromethyl)-5-(6-((3-ethyneylphenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.050 g, 0.153 mmol), iodobenzene (0.037 g, 0.183 mmol), tetrakis(triphenylphosphine)palladium (0.009 g, 0.008 mmol), copper iodide (CuI, 0.001 g, 0.008 mmol) and triethylamine (0.064 mL, 0.458 mmol) were used as starting materials in a similar manner to step 1 of Example 7 to prepare 2-(difluoromethyl)-5-(6-((3-(phenylethyneyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.015 g, 24.3%) was obtained as a bright yellow solid: LRMS(ES) m / z 404.20 [M+H] +, calculated MW 403.39;1H-NMR(400 MHz, DMSO-d6) d 9.20 ~ 9.20 (m, 1 H), 8.46 (dd,J= 8.2, 2.2 Hz, 1 H), 7.76 (d,J= 8.4 Hz, 1 H), 7.68 ~ 7.50 (m, 3 H), 7.42 to 7.39 (m, 3 H), 7.34 (t,J= 8.0 Hz, 1 H), 7.22 to 7.21 (m, 1 H), 7.15 to 7.13 (m, 1 H), 7.11 to 7.08 (m, 1 H), 5.34 (s, 2 H).

[0484]

[0485] Example 31: Synthesis of 3-((1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)ethanyl)benzonitrile

[0486]

[0487]

[0488] A similar method as in step 1 of Example 7 was performed using 2-(6-((4-bromo-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.123 mmol), 3-ethynylbenzonitrile (0.019 g, 0.148 mmol), tetrakis(triphenylphosphine)palladium (0.007 g, 0.006 mmol), copper iodide (CuI, 0.001 g, 0.006 mmol) and triethylamine (0.051 mL, 0.369 mmol) as starting materials. 3-((1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)ethanyl)benzonitrile (0.036 g, 64.6%) was obtained as a yellow solid: LRMS(ES) m / z 453.27 [M+H] +, calculated MW 452.42;1H-NMR(400 MHz, DMSO-d6) d 9.13 ~ 9.12 (m, 1 H), 8.36 (dd,J= 8.2, 2.2 Hz, 1 H), 8.23 ​​~ 8.21 (m, 2 H), 8.00 ~ 7.98 (m, 1 H), 7.92 ~ 7.90 (m, 1 H), 7.76 ~ 7.75 (m, 1 H), 7.66 (d,J= 8.0 Hz, 1 H), 7.63 ~ 7.40 (m, 2 H), 7.25 (d,J= 8.4 Hz, 1 H), 6.91 ~ 6.90 (m, 1 H), 5.73 (s, 2 H).

[0489]

[0490] Example 32: Synthesis of 2-(difluoromethyl)-5-(6-((4-((3-fluorophenyl)ethanyl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0491]

[0492]

[0493] 2-(6-((4-Bromo-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.123 mmol), 1-ethynyl-3-fluorobenzene (0.018 g, 0.148 mmol), tetrakis(triphenylphosphine)palladium (0.007 g, 0.006 mmol), copper iodide (CuI, 0.001 g, 0.006 mmol) and triethylamine (0.051 mL, 0.369 mmol) were used as starting materials in a similar manner to step 1 of Example 7. 2-(Difluoromethyl)-5-(6-((4-((3-fluorophenyl)ethanyl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.032 g, 58.4%) was obtained as a yellow solid: LRMS(ES) m / z 446.27 [M+H] +, calculated MW 445.41;1H-NMR(400 MHz, DMSO-d6) d 9.12 (d,J= 2.4 Hz, 1 H), 8.36 (dd,J= 8.2, 2.2 Hz, 1 H), 8.20 (d,J= 6.0 Hz, 1 H), 7.74 (d,J= 3.2 Hz, 1 H), 7.57 to 7.47 (m, 5 H), 7.33 to 7.29 (m, 1 H), 7.24 (d,J= 8.4 Hz, 1 H), 6.86 to 6.85 (m, 1 H).

[0494]

[0495] Example 33: Synthesis of 2-(6-((4-((3-chlorophenyl)ethanyl)-1H-indol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0496] Step 1: Synthesis of 2-(6-((4-bromo-1H-indol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0497]

[0498]

[0499] 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.300 g, 1.034 mmol), 4-bromo-1H-indole (0.213 g, 1.086 mmol) and potassium carbonate (K2CO3, 0.429 g, 3.103 mmol) were used as starting materials in a similar manner to step 5 of Example 1 to obtain 2-(6-((4-bromo-1H-indol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.251 g, 59.9%) as a yellow solid: LRMS(ES) m / z 406.84 [M+H] + , calculated MW 405.2.

[0500]

[0501] Step 2: Synthesis of 2-(6-((4-((3-chlorophenyl)ethanyl)-1H-indol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0502]

[0503]

[0504] 2-(6-((4-bromo-1H-indol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.123 mmol), 1-chloro-3-ethanylbenzene (0.020 g, 0.148 mmol), tetrakis(triphenylphosphine)palladium (0.007 g, 0.006 mmol), copper iodide (CuI, 0.001 g, 0.006 mmol) and triethylamine (0.052 mL, 0.370 mmol) were used as starting materials in a similar manner to step 1 of Example 7. 2-(6-((4-((3-chlorophenyl)ethanyl)-1H-indol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.023 g, 40.4%) was obtained as a yellow solid: LRMS(ES) m / z 461.26 [M+H] + , calculated MW 460.87;1H-NMR(400 MHz, DMSO-d6) d 9.14 (d,J= 1.6 Hz, 1 H), 8.33 (dd,J= 8.4, 2.4 Hz, 1 H), 7.69 ~ 7.65 (m, 2 H), 7.58 ~ 7.56 (m, 1 H), 7.52 to 7.39 (m, 4 H), 7.26 (d,J= 7.2 Hz, 1 H), 7.14 to 7.10 (m, 2 H), 6.75 (d,J= 3.6 Hz, 1 H), 5.69 (s, 2 H).

[0505]

[0506] Example 34: Synthesis of 2-(difluoromethyl)-5-(6-((4-(m-tolylethanyl)-1H-indol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0507]

[0508]

[0509] 2-(6-((4-bromo-1H-indol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.123 mmol), 1-ethynyl-3-methylbenzene (0.017 g, 0.148 mmol), tetrakis(triphenylphosphine)palladium (0.007 g, 0.006 mmol), copper iodide (CuI, 0.001 g, 0.006 mmol) and triethylamine (0.052 mL, 0.370 mmol) were used as starting materials in a similar manner to step 1 of Example 7. 2-(Difluoromethyl)-5-(6-((4-(m-tolylethanyl)-1H-indol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.021 g, 38.6%) was obtained as a brown solid: LRMS(ES) m / z 441.25 [M+H] + , calculated MW 440.45;1H-NMR(400 MHz, DMSO-d6) d 9.14 (d,J= 2.4 Hz, 1 H), 8.33 (dd,J= 8.4, 2.4 Hz, 1 H), 7.66 (d,J= 7.2 Hz, 1 H), 7.52 ~ 7.37 (m, 4 H), 7.30 (t,J= 7.8 Hz, 1 H), 7.22 to 7.19 (m, 2 H), 7.11 (t,J= 7.8 Hz, 2 H), 6.70 (d,J= 3.2 Hz, 1 H), 5.69 (s, 2 H), 2.31 (s, 3 H).

[0510]

[0511] Example 35: Synthesis of 2-(6-((4-((3-chlorophenyl)ethanyl)-6-fluoro-1H-indol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0512] Step 1: Synthesis of 2-(6-((4-bromo-6-fluoro-1H-indol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0513]

[0514]

[0515] 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.300 g, 1.034 mmol), 4-bromo-6-fluoro-1H-indole (0.232 g, 1.086 mmol) and potassium carbonate (K2CO3, 0.429 g, 3.103 mmol) were used as starting materials in a similar manner to step 5 of Example 1 to obtain 2-(6-((4-bromo-6-fluoro-1H-indol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.250 g, 57.1%) as a brown liquid: LRMS(ES) m / z 424.23 [M+H] + , calculated MW 423.19.

[0516]

[0517] Step 2: Synthesis of 2-(6-((4-((3-chlorophenyl)ethanyl)-6-fluoro-1H-indol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0518]

[0519]

[0520] 2-(6-((4-Bromo-6-fluoro-1H-indol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.118 mmol), 1-chloro-3-ethaneylbenzene (0.019 g, 0.142 mmol), tetrakis(triphenylphosphine)palladium (0.007 g, 0.006 mmol), copper iodide (CuI, 0.001 g, 0.006 mmol) and triethylamine (0.049 mL, 0.354 mmol) were used as starting materials in a similar manner to step 1 of Example 7. 2-(6-((4-((3-chlorophenyl)ethanyl)-6-fluoro-1H-indol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.017 g, 30.0%) was obtained as a yellow solid: LRMS(ES) m / z 479.23 [M+H] + , calculated MW 478.86;1H-NMR(400 MHz, DMSO-d6) d 9.13 (d,J= 1.2 Hz, 1 H), 8.35 (dd,J= 8.2, 2.2 Hz, 1 H), 7.72 ~ 7.71 (m, 1 H), 7.65 ~ 7.65 (m, 1 H), 7.59 ~ 7.57 (m, 1 H), 7.53 ~ 7.40 (m, 4 H), 7.19 (d,J= 8.4 Hz, 1 H), 7.14 (dd,J= 10.2, 2.2 Hz, 1 H), 6.76 (dd,J= 3.2, 0.8 Hz, 1 H), 5.67 (s, 2 H).

[0521]

[0522] Example 36: Synthesis of 2-(difluoromethyl)-5-(6-((6-fluoro-4-(m-tolylethanyl)-1H-indol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0523]

[0524]

[0525] 2-(6-((4-Bromo-6-fluoro-1H-indol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.118 mmol), 1-ethynyl-3-methylbenzene (0.016 g, 0.142 mmol), tetrakis(triphenylphosphine)palladium (0.007 g, 0.006 mmol), copper iodide (CuI, 0.001 g, 0.006 mmol) and triethylamine (0.049 mL, 0.354 mmol) were used as starting materials in a similar manner to step 1 of Example 7. 2-(Difluoromethyl)-5-(6-((6-fluoro-4-(m-tolylethanyl)-1H-indol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.023 g, 42.5%) was obtained as a yellow solid: LRMS(ES) m / z 459.22 [M+H] + , calculated MW 458.44;1H-NMR(400 MHz, DMSO-d6) d 9.14 (d,J= 1.6 Hz, 1 H), 8.35 (dd,J= 8.2, 2.2 Hz, 1 H), 7.65 ~ 7.52 (m, 2 H), 7.46 ~ 7.43 (m, 2 H), 7.41 ~ 7.39 (m, 1 H), 7.31 (t,J= 7.6 Hz, 1 H), 7.22 (d,J= 7.6 Hz, 1 H), 7.18 (d,J= 8.4 Hz, 1 H), 7.10 (dd,J= 10.0, 2.4 Hz, 1 H), 6.70 (dd,J= 3.2, 0.8 Hz, 1 H), 5.66 (s, 2 H), 2.31 (s, 3 H).

[0526]

[0527] Example 37: Synthesis of 2-(difluoromethyl)-5-(6-((4-(m-tolyleethaneyl)-1H-indazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0528] Step 1: Synthesis of methyl 6-(hydroxymethyl)nicotinate

[0529]

[0530]

[0531] Dimethyl pyridine-2,5-dicarboxylate (25,000 g, 128.093 mmol) and calcium chloride (CaCl2, 56.862 g, 512.374 mmol) were dissolved in tetrahydrofuran (300 mL) / ethanol (300 mL), and the resulting solution was stirred at 0°C for 30 minutes. Sodium borohydride (8.238 g, 217.759 mmol) was added, and the mixture was further stirred at the same temperature for 18 hours. Ammonium chloride (NH4Cl, 3.00 M solution in water, 426.978 mL, 1.281 mol) was added to the reaction mixture at room temperature, and the reaction was terminated by stirring for 30 minutes. The reaction mixture was filtered through a pad of Celite to remove solids, and water was poured into the filtrate, which was then extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was dissolved in dichloromethane, passed through a silica gel plug (methanol / dichloromethane = from 0% to 5%), and concentrated to obtain methyl 6-(hydroxymethyl)nicotinate (11.090 g, 51.8%) as a white solid: LRMS(ES) m / z 168.18 [M+H] + , calculated MW 167.16.

[0532]

[0533] Step 2: Synthesis of 6-(hydroxymethyl)nicotinohydrazide

[0534]

[0535]

[0536] Starting from methyl 6-(hydroxymethyl)nicotinate (11.090 g, 66.344 mmol) and hydrazine hydrate (16.122 mL, 331.718 mmol), 6-(hydroxymethyl)nicotinohydrazide (10.875 g, 98.1%) was obtained as an ivory solid in a similar manner to Step 1 of Example 1: LRMS(ES) m / z 168.11 [M+H] + , calculated MW 167.17.

[0537]

[0538] Step 3: Synthesis of (5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methanol

[0539]

[0540]

[0541] 6-(Hydroxymethyl)nicotinohydrazide (10.875 g, 65.054 mmol), 2,2-difluoroacetic anhydride (24.263 mL, 195.161 mmol), and triethylamine (27.202 mL, 195.161 mmol) were dissolved in tetrahydrofuran (250 mL) at room temperature, and the resulting solution was stirred at 70°C for 3 hours and then cooled to room temperature. Potassium carbonate (K2CO3, 3.00 M solution in water, 216.845 mL, 650.535 mmol) was added to the reaction mixture at room temperature, and the reaction was terminated by stirring for 1 hour. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 3 M aqueous potassium carbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography to obtain (5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methanol (4.000 g, 27. %) as a pale yellow solid: LRMS(ES) m / z 228.10 [M+H] +, calculated MW 227.17.

[0542]

[0543] Step 4: Synthesis of (5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl methanesulfonate

[0544]

[0545]

[0546] (5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methanol (5.200 g, 22.890 mmol), methanesulfonyl chloride (2.126 mL, 27.468 mmol), and N,N-diisopropylethylamine (5.980 mL, 34.336 mmol) were dissolved in dichloromethane (50 mL) at 0°C, and the resulting solution was stirred at room temperature for 18 h. After removing the solvent from the reaction mixture under reduced pressure, the precipitated solid was filtered, washed with methanol and dried to obtain (5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl methanesulfonate (4.010 g, 57.4%) as a pale yellow solid: LRMS(ES) m / z 306.24 [M+H] + , calculated MW 305.26.

[0547]

[0548] Step 5: Synthesis of 2-(6-((4-bromo-1H-indazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0549]

[0550]

[0551] A similar procedure as in Step 5 of Example 1 was followed from (5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl methanesulfonate (0.300 g, 0.983 mmol), 4-bromo-1H-indazole (0.203 g, 1.032 mmol) and potassium carbonate (K2CO3, 0.407 g, 2.948 mmol) as starting materials to obtain 2-(6-((4-bromo-1H-indazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.206 g, 51.6%) as a yellow liquid: LRMS(ES) m / z 407.80 [M+H] + , calculated MW 406.19.

[0552]

[0553] Step 6: Synthesis of 2-(difluoromethyl)-5-(6-((4-(m-tolyleethaneyl)-1H-indazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0554]

[0555]

[0556] 2-(6-((4-bromo-1H-indazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.123 mmol), 1-chloro-3-ethanylbenzene (0.022 g, 0.160 mmol), tetrakis(triphenylphosphine)palladium (0.007 g, 0.006 mmol), copper iodide (CuI, 0.001 g, 0.006 mmol) and triethylamine (0.051 mL, 0.369 mmol) were used as starting materials in a similar manner to step 1 of Example 7. 2-(Difluoromethyl)-5-(6-((4-(m-tolylethanyl)-1H-indazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.048 g, 88.3%) was obtained as a brown solid: LRMS(ES) m / z 442.10 [M+H] +, calculated MW 441.44;1H-NMR (400 MHz, DMSO-d6) d 9.12 (d,J= 2.0 Hz, 1 H), 8.36 ~ 8.32 (m, 2 H), 7.76 (d,J= 8.8 Hz, 1 H), 7.65 ~ 7.40 (m, 4 H), 7.36 to 7.28 (m, 2 H), 7.24 (d,J= 7.6 Hz, 1 H), 7.16 (d,J= 8.0 Hz, 1 H), 5.93 (s, 2 H), 2.32 (s, 3 H).

[0557]

[0558] Example 38: Synthesis of 3-((1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-indazol-4-yl)ethanyl)benzonitrile

[0559]

[0560]

[0561] 2-(6-((4-bromo-1H-indazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.123 mmol), 1-ethynyl-3-methylbenzene (0.017 g, 0.148 mmol), tetrakis(triphenylphosphine)palladium (0.007 g, 0.006 mmol), copper iodide (CuI, 0.001 g, 0.006 mmol) and triethylamine (0.051 mL, 0.369 mmol) were used as starting materials in a similar manner to step 1 of Example 7. 3-((1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-indazol-4-yl)ethanyl)benzonitrile (0.030 g, 53.9%) was obtained as a yellow solid: LRMS(ES) m / z 453.21 [M+H] +, calculated MW 452.42;1H-NMR(400 MHz, DMSO-d6) d 9.11 (d,J= 1.2 Hz, 1 H), 8.43 (d,J= 0.8 Hz, 1 H), 8.34 (dd,J= 8.2, 2.2 Hz, 1 H), 8.23 ​​~ 8.22 (m, 1 H), 7.98 (dt,J= 8.0, 1.4 Hz, 1 H), 7.89 (dt,J= 8.0, 2.2 Hz, 1 H), 7.81 (d,J= 8.0 Hz, 1 H), 7.66 to 7.52 (m, 2 H), 7.44 to 7.40 (m, 2) H), 7.17 (d,J= 8.0 Hz, 1 H), 5.94 (s, 2 H).

[0562]

[0563] Example 39: Synthesis of 2-(6-((4-((3-chlorophenyl)ethanyl)-1H-indazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0564]

[0565]

[0566] 2-(6-((4-bromo-1H-indazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.123 mmol), 1-chloro-3-ethanylbenzene (0.022 g, 0.160 mmol), tetrakis(triphenylphosphine)palladium (0.007 g, 0.006 mmol), copper iodide (CuI, 0.001 g, 0.006 mmol) and triethylamine (0.051 mL, 0.369 mmol) were used as starting materials in a similar manner to step 1 of Example 7. 2-(6-((4-((3-chlorophenyl)ethanyl)-1H-indazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.046 g, 80.9%) was obtained as a brown solid: LRMS(ES) m / z 462.55 [M+H] +, calculated MW 461.86;1H-NMR(400 MHz, DMSO-d6) d 9.11 (d,J= 2.0 Hz, 1 H), 8.40 (d,J= 1.2 Hz, 1 H), 8.34 (dd,J= 8.2, 2.2 Hz, 1 H), 7.80 ~ 7.78 (m, 2 H), 7.65 to 7.61 (m, 1 H), 7.52 to 7.51 (m, 1 H), 7.50 to 7.44 (m, 2 H), 7.43 to 7.37 (m, 2 H), 7.16 (d,J= 8.4 Hz, 1 H), 5.94 (s, 2 H).

[0567]

[0568] Example 40: Synthesis of 3-((3-chlorophenyl)ethanyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)aniline

[0569] Step 1: Synthesis of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-iodoaniline

[0570]

[0571]

[0572] Starting from (5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl methanesulfonate (0.300 g, 0.983 mmol), 3-iodoaniline (0.258 g, 1.179 mmol) and potassium carbonate (K2CO3, 0.204 g, 1.474 mmol), N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-iodoaniline (0.205 g, 48.7%) was obtained as a yellow liquid in a similar manner to step 5 of Example 1.

[0573]

[0574] Step 2: Synthesis of 3-((3-chlorophenyl)ethanyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)aniline

[0575]

[0576]

[0577] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-iodoaniline (0.205 g, 0.479 mmol), 1-chloro-3-ethanylbenzene (0.078 g, 0.575 mmol), tetrakis(triphenylphosphine)palladium (0.028 g, 0.024 mmol), copper iodide (CuI, 0.005 g, 0.024 mmol) and triethylamine (0.100 mL, 0.718 mmol) were used as starting materials in a similar manner to step 1 of Example 7. 3-((3-chlorophenyl)ethanyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)aniline (0.100 g, 47.8%) was obtained as a brown liquid: LRMS(ES) m / z 437.22 [M+H] + , calculated MW 436.85;1H-NMR(400 MHz, DMSO-d6) d 9.15 (d,J= 1.2 Hz, 1 H), 8.37 (dd,J= 8.4, 2.4 Hz, 1 H), 7.57 ~ 7.53 (m, 3 H), 7.46 ~ 7.37 (m, 3 H), 7.08 (t,J= 7.8 Hz, 1 H), 6.74 to 6.65 (m, 3 H), 6.63 (dd,J= 8.4, 1.6 Hz, 1 H), 4.49 (d,J= 6.4 Hz, 2 H).

[0578]

[0579] Example 41: Synthesis of 3-((3-chlorophenyl)ethanyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-ethylaniline

[0580]

[0581]

[0582] 3-((3-Chlorophenyl)ethanyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)aniline (0.030 g, 0.069 mmol) was dissolved in dichloromethane (2 mL) at room temperature. Acetaldehyde (0.003 g, 0.076 mmol) and acetic acid (0.004 g, 0.069 mmol) were added to the resulting solution, and the mixture was stirred at the same temperature for 1 h. Sodium cyanoborohydride (0.006 g, 0.103 mmol) was added to the reaction mixture, and the mixture was further stirred at the same temperature for 18 h. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a 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-((3-chlorophenyl)ethanyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-ethylaniline (0.021 g, 65.8%) as a brown solid: LRMS(ES) m / z 465.29 [M+H] + , calculated MW 464.9;1H-NMR(400 MHz, DMSO-d6) d 9.17 (d,J= 2.0 Hz, 1 H), 8.35 (dd,J= 8.2, 2.2 Hz, 1 H), 7.66 ~ 7.53 (m, 2 H), 7.46 ~ 7.37 (m, 4) H), 7.14 (t,J= 8.2 Hz, 1 H), 6.79 ~ 6.76 (m, 2 H), 6.69 (dd,J= 8.4, 2.0 Hz, 1 H), 4.71 (s, 2 H), 3.56 (q,J= 6.9 Hz, 2 H), 1.14 (t,J= 9.0 Hz, 3 H).

[0583]

[0584] Experimental Example 1: Fluorescence-based enzyme activity assay

[0585] To measure the inhibitory effect of compounds on histone deacetylase 6 (HDAC6) activity, an experiment was conducted to confirm the enzyme activity by reacting the substrate with the human HDAC6 enzyme, which was conjugated with a fluorescent peptide of p53 residues 379-382. The test compounds were dissolved in 100% DMSO at a concentration of 10 mM to make a stock solution, and each compound was serially diluted by 1 / 3 in the test buffer solution to make the final concentration 30 μM as the peak concentration point. Trichostatin A (TSA), a reference compound used to confirm the completeness of the experiment, was serially diluted by 1 / 3 in the test buffer solution to make the peak concentration 1 μM. The test compounds and TSA prepared in the test buffer were dispensed together into a 96-well black plate and spun down to react with the HDAC6 enzyme. And the reaction was carried out at room temperature for 10 minutes, and after 10 minutes, the substrate was dispensed, sealed, and reacted at 30℃ for 1 hour in a light-blocking state. The fluorescence value was measured using a plate reader using a wavelength of Excitation / Emission = 360 / 460 nm. The fluorescence measurement value was standardized by setting the values ​​of the HDAC6 enzyme-treated and untreated groups as 100% and 0%, respectively, and the activity of the compound calculated for each concentration was calculated as IC 50 The values ​​were calculated and displayed in Table 1 (+++: less than 0.1 μM, ++: 0.1 to 1.0 μM, +: greater than 1.0 to 20 μM).

[0586] [Table 1]

[0587]

[0588]

[0589] Experimental Example 2: Fluorescence-based Ca2+ mobilization assay

[0590] To measure the activity of antagonists against mGluR5 receptors, intracellular Ca was measured using HEK293 cells overexpressing mGluR5 receptors. 2+ An experiment was conducted to confirm the change in the level. The cells prepared in the cell culture medium were dispensed into a 384-well plate coated with poly-D-lysine and cultured in an incubator at 37°C with 5% CO2. The next day, the cell culture medium was removed and Ca 2+ After adding dye loading buffer containing reagents capable of measuring the concentration, the cells were incubated at 37°C for 60 minutes. The compounds were dissolved in 100% DMSO to make a stock solution at a concentration of 10 mM, and each compound was sequentially diluted by 1 / 3 in the test buffer, with the highest concentration point being 10 μM as the final concentration. The compound solutions diluted by concentration were added to the cells after incubation in dye loading buffer and incubated at room temperature for 30 minutes in a light-shielded state. After incubation, EC 80 Ca upon addition of L-glutamate at a concentration 2+ Level changes were measured for 2 minutes using FLIPR Tetra (MDS). The measured values ​​were normalized based on the results of the maximum-minimum fluorescence response values, and L-glutamate EC 80 The activity value was calculated by taking the fluorescence value of the vehicle treatment group as 100% and the fluorescence value of the vehicle treatment group as 0%. The antagonistic efficacy of the test compound was calculated by taking the IC 50 The values ​​were calculated and shown in Table 2 (+++: less than 0.1 μM, ++: 0.1 to 1.0 μM, +: greater than 1.0 to 20 μM).

[0591] [Table 2]

[0592]

Claims

1. A compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, Ar is aryl or heteroaryl; wherein said aryl and heteroaryl may be optionally substituted with one or more substituents selected from the group consisting of halo, cyano, hydroxy, alkyl, haloalkyl and alkoxy; X 1 is CH, CF or N; X 2 , X 3 and X 4 is CR 3 or N, two or more of which are CR 3 and here R 3 is -H, halo, alkyl or haloalkyl; Y is -O- or -N(R 2 )-and; here R 2 is -H or alkyl, or R 1 It can be linked to form a 5- or 6-membered unsaturated ring structure; R 1 is -H or R 2 It can be connected to form a 5- or 6-membered unsaturated ring structure; The above heteroaryl has one or more heteroatoms selected from N, O and S.

2. In paragraph 1, Ar is C6-C 10 Aryl or 5 to 10 membered heteroaryl; wherein said aryl and heteroaryl may be optionally substituted with 1 to 3 substituents selected from the group consisting of halo, cyano, hydroxy, C1-C7 alkyl, halo-C1-C7 alkyl and C1-C7 alkoxy; X 1 is CH, CF or N; X 2 , X 3 and X 4 is CR 3 or N, two or more of which are CR 3 and here R 3 is -H, halo, C1-C7 alkyl or halo-C1-C7 alkyl; Y is -O- or -N(R 2 )-and; here R 2 is -H or C1-C7 alkyl, or R 1 It can be linked to form a 5- or 6-membered unsaturated heterocycle; R 1 is -H or R 2 and can be linked to form a 5- or 6-membered unsaturated heterocycle; A compound or a pharmaceutically acceptable salt thereof, wherein the heteroaryl and heterocycle have 1 to 3 heteroatoms selected from N, O and S.

3. In the first paragraph, a compound characterized in that the compound of the chemical formula 1 is a compound of the following chemical formula 2, or a pharmaceutically acceptable salt thereof: [Chemical Formula 2] In the above chemical formula 2, X 1 , X 2 , X 3 , X 4 and Ar are as defined in paragraph 1.

4. In the first paragraph, a compound characterized in that the compound of the chemical formula 1 is a compound of the following chemical formula 3 or a pharmaceutically acceptable salt thereof: [Chemical Formula 3] In the above chemical formula 3, X 1 , R 3 and Ar are as defined in paragraph 1.

5. In the first paragraph, a compound characterized in that the compound of the chemical formula 1 is a compound of the following chemical formula 4 or a pharmaceutically acceptable salt thereof: [Chemical Formula 4] In the above chemical formula 4, R 2 is H or C1-C7 alkyl, X 1 , X 2 , X 3 , X 4 and Ar are as defined in paragraph 1.

6. In the first paragraph, a compound characterized in that the compound of the chemical formula 1 is a compound of the following chemical formula 5 or a pharmaceutically acceptable salt thereof [Chemical Formula 5] In the above chemical formula 5, R 2 is CH or N, X 1 , X 2 , X 3 , X 4 and Ar are as defined in paragraph 1.

7. A compound or a pharmaceutically acceptable salt thereof, characterized in that, in paragraph 1, Ar is phenyl, pyridyl, thiazolyl, imidazolyl or benzimidazolyl; and may be optionally substituted with one or two substituents selected from the group consisting of halo, cyano, C1-C5 alkyl and halo-C1-C5 alkyl.

8. In paragraph 1, X 1 is CF or N; X 2 , X 3 and X 4 Go CR 3 , and here R 3 A compound characterized by being -H or halo, or a pharmaceutically acceptable salt thereof.

9. In paragraph 1, X 1 is CF or N; X 2 , X 3 and X 4 is CR 3 or N, two of which are CR 3 and the other one is N; where R 3 A compound characterized by being -H or halo, or a pharmaceutically acceptable salt thereof.

10. In paragraph 1, Y is -O- or -N(R 2 )-and; here R 2 is -H or C1-C5 alkyl, or R 1 It can be linked to form a 5-membered unsaturated heterocycle having 1 or 2 N atoms; R 1 is -H or R 2 A compound or a pharmaceutically acceptable salt thereof, characterized in that it is capable of forming a five-membered unsaturated heterocycle having one or two N atoms by being linked to .

11. In the first paragraph, a compound characterized in that the compound of the chemical formula 1 is selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof: 2-(6-((3-((3-chlorophenyl)ethanyl)phenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((3-(m-tolyleethaneyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 3-((3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)phenyl)ethanyl)benzonitrile; 2-(Difluoromethyl)-5-(3-fluoro-4-((3-(m-tolyleethaneyl)phenoxy)methyl)phenyl)-1,3,4-oxadiazole; 3-((3-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)oxy)phenyl)ethanyl)benzonitrile; 2-(Difluoromethyl)-5-(6-(((4-((4-fluorophenyl)ethanyl)pyridin-2-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(6-(((5-((3-chlorophenyl)ethanyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(4-(((5-((3-chlorophenyl)ethanyl)pyridin-3-yl)oxy)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(6-(((2-((3-chlorophenyl)ethanyl)pyridin-4-yl)oxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-(((5-(m-tolyleethaneyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 3-((5-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)pyridin-3-yl)ethanyl)benzonitrile; 2-(6-(((5-((6-chloropyridin-2-yl)ethanyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-(((5-((3-fluorophenyl)ethanyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(6-(((5-((2-chloropyridin-4-yl)ethanyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(6-((5-((3-chlorophenyl)ethanyl)-2-fluorophenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole; (6-((3-((3-chlorophenyl)ethanyl)-4-fluorophenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(6-((3-((6-chloropyridin-2-yl)ethanyl)phenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(6-((3-((2-chloropyridin-4-yl)ethanyl)phenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((3-((2-methylthiazol-4-yl)ethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((3-((6-methylpyridin-2-yl)ethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(6-((3-((6-chloropyridin-2-yl)ethanyl)-4-fluorophenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((3-((2-fluoropyridin-4-yl)ethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(6-((4-((3-chlorophenyl)ethanyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(6-((4-((3-chlorophenyl)ethanyl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-(m-tolyleethaneyl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((3-((3-(trifluoromethyl)phenyl)ethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((3-((6-fluoropyridin-2-yl)ethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-(((5-((6-methylpyridin-2-yl)ethanyl)pyridin-3-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((3-((2-methylpyridin-4-yl)ethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((3-(phenylethanyl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 3-((1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)ethanyl)benzonitrile; 2-(Difluoromethyl)-5-(6-((4-((3-fluorophenyl)ethanyl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(6-((4-((3-chlorophenyl)ethanyl)-1H-indol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-(m-tolylethanyl)-1H-indol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(6-((4-((3-chlorophenyl)ethanyl)-6-fluoro-1H-indol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((6-fluoro-4-(m-tolylethanyl)-1H-indol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 2-(Difluoromethyl)-5-(6-((4-(m-tolyleethaneyl)-1H-indazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole; 3-((1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-indazol-4-yl)ethanyl)benzonitrile; 2-(6-((4-((3-chlorophenyl)ethanyl)-1H-indazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole; 3-((3-chlorophenyl)ethanyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)aniline; and 3-((3-chlorophenyl)ethanyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-ethylaniline.

12. A pharmaceutical composition for preventing or treating movement disorders, comprising a therapeutically effective amount of a compound of formula 1 according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.

13. A pharmaceutical composition according to claim 12, characterized in that the movement disorder is Parkinson's disease.

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