Dual modulators of mGluR5 and 5-HT2A receptors and their uses

Abstract

Disclosed are dual modulators of mGluR5 and 5-HT2A receptors and their uses. More specifically, disclosed are compounds that are modulators of mGluR5 and antagonists of 5-HT2A receptors and their uses as pain therapeutic agents.

Description

Technical Field

[0001] Disclosed are dual modulators of mGluR5 and 5-HT2AR (5-HT2A receptor) and their uses. More specifically, disclosed are compounds that simultaneously act as modulators of mGluR5 and antagonists of 5-HT2AR, and their uses as pain therapeutic agents. Background Art

[0002] According to the definition of the International Association for the Study of Pain (IASP), pain is an unpleasant sensation and emotional experience associated with or similar to actual or potential tissue damage. Pain can be roughly divided into physiological pain and pathological pain. Physiological pain is an adaptive response of the body to protect itself from external damage, and disappears by eliminating the cause of pain. Pathological pain is such an unadaptive state that it persists even after the noxious stimulus disappears and the damaged tissue recovers. Among pathological pain, neuropathic pain is a representative chronic pain caused by nerve damage or abnormal nerve function. It shows abnormal characteristics, such as abnormal pain manifested as pain caused by non-noxious stimulation, hyperalgesia manifested as more severe pain in the presence of noxious stimulation, spontaneous pain, other paresthesias, insensitivity, excessive pain, etc.

[0003] In the process of pain transmission, when harmful stimulation (such as heat stimulation or strong mechanical stimulation) is applied to peripheral tissues (such as skin or muscles), peripheral nerve endings are electrically stimulated, and action potentials are transmitted to the central nerves of the brain through the spinal cord. Such a process of transmitting pain signals through nerves involves the interaction of various types of neurotransmitters and receptors. Among these neurotransmitters, glutamate is a representative excitatory neurotransmitter in the central nervous system and induces signal transmission in neurons through glutamate receptors.

[0004] Glutamate receptors are mainly divided into ionotropic glutamate receptors (iGluR) and metabotropic glutamate receptors (mGluR). Metabotropic glutamate receptors are a class of G protein-coupled receptors (GPCRs) and are divided into three groups - I, II and III - according to the characteristics of the signal transduction process. Group I, composed of mGluR1 and mGluR5, regulates neuronal excitability according to their localization at the synapse and activates phospholipase C (PLC) through Gq proteins. Group II (mGluR2 and mGluR3) and Group III (mGluR4, mGluR6, mGluR7 and mGluR8) are known to inhibit the downstream signaling pathway of adenylate cyclase (AC) activated by Gi proteins as presynaptic receptors.

[0005] Serotonin (5-HT, 5-hydroxytryptamine) is also a typical neurotransmitter of the central nervous system, and is produced in the raphe nuclei of the brainstem. Serotonin plays a wide and important role in the central and peripheral nervous systems through serotonin receptors, and is closely related to various neural activities (such as emotions, cognition, diet and sleep) by greatly affecting the effects of other neurotransmitters (such as dopamine and norepinephrine). For example, by regulating the serotonin system, various drug treatments for depression, obesity, smoking cessation and irritable bowel syndrome have been developed. Serotonin receptors are divided into seven subtypes. Except as the 5-HT3 receptor of the ligand-gated ion channel, others (5-HT1-2, 5-HT4- to 7-) are all G protein coupled receptors (GPCR). These GPCR-type serotonin receptors regulate excitatory or inhibitory neurotransmission by triggering the second messenger cascade in the cell.

[0006] [Prior art documents]

[0007] [Patent Document]

[0008] International Publication No. WO 2013 / 049255

[0009] International Publication No. WO 2013 / 081400

[0010] Invention Disclosure

[0011] Technical issues

[0012] One object of the present invention is to provide compounds that act on both mGluR5 and 5-HT2AR.

[0013] Another object of the present invention is to provide the use of the compound for treating pain.

[0014] Solution to the problem

[0015] In order to achieve the above object, a compound of the following formula 1 or a pharmaceutically acceptable salt thereof is provided:

[0016] [Formula 1]

[0017]

[0018] in

[0019] X1 and X2 together with the carbon atoms to which they are attached form a 4- to 7-membered aliphatic ring or a 4- to 6-membered heteroaliphatic ring;

[0020] X3 is CH or N;

[0021] R1 is hydroxy, halogen, hydrocarbon, heterocycloalkyl or heterocycloalkyl-hydrocarbon;

[0022] R2 is hydroxy, halogen, alkyl, alkyloxy, heterocycloalkyl, hydroxyalkyl, haloalkyl, amino, alkylamino, dialkylamino, cycloalkyl-alkyl, cycloalkylamino, haloalkylamino, aminocarbonyl, alkylaminocarbonyl, alkyloxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, hydroxyaminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, or 5- or 6-membered heteroaryl;

[0023] R3 is deuterium, halogen or hydrocarbon;

[0024] R4 and R5 are each independently halogen or hydrocarbon;

[0025] m is an integer from 0 to 3;

[0026] n is 0 or 1; and

[0027] l, p and q are each independently an integer from 0 to 2;

[0028] wherein the heteroaliphatic ring, heterocycloalkyl or heteroaryl has one or more heteroatoms selected from the group consisting of N, O and S;

[0029] Provided that, when X1 and X2 together with the carbon atoms to which they are attached form a 6-membered aliphatic ring or a 5-membered heteroaliphatic ring and X3 is CH, n and q are not 0 at the same time.

[0030] In addition, a pharmaceutical composition for preventing or treating pain is provided, which comprises a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier or excipient.

[0031] In addition, provided is a method for treating pain, comprising administering a compound of Formula 1 or a pharmaceutically acceptable salt thereof to a mammal.

[0032] Advantageous Effects of the Invention

[0033] The compound of formula 1 or its pharmaceutically acceptable salt acts as a dual modulator of mGluR5 and 5-HT2AR. The dual modulatory effect on mGluR5 and 5-HT2AR can show a synergistic effect in the therapeutic effect of pain. Due to these properties, the compound of formula 1 or its pharmaceutically acceptable salt can show analgesic effect even at low doses without specific side effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 The graph shows that mGluR5 modulators and 5-HT2AR antagonists exert synergistic effects on analgesia.

[0036] Mode for the Invention

[0037] Hereinafter, the present invention is described in detail.

[0038] In metabotropic glutamate receptors (mGluR), mGluR5 belonging to group I is highly expressed in hippocampus, striatum, thalamus and cortex, and is therefore closely related to various neurological diseases. In addition, mGluR5 is also distributed in the dorsal horn of the spinal cord, and is known to play an important role in regulating somatosensory pathways and nociceptive neurotransmission. In fact, in various animal models of inflammatory pain, neuropathic pain, visceral pain, postoperative pain and orofacial pain, it is reported that the treatment with the negative allosteric modulator (that is, mGluR5 antagonist) of mGluR5 demonstrates significant analgesic effect.

[0039] Serotonin also plays an important role in the development and regulation of pain, and it can induce pain or show analgesic effects, depending on the site of action, cells and receptor types. In the trigeminal nervous system, when serotonin acts on 5-HT1B / D receptors, it relieves pain by inhibiting the release of neurotransmitters. However, when serotonin acts on the 5-HT2A receptors in the nerve endings area, it induces inflammatory and neuropathic hyperalgesia by sensitizing afferent nerve fibers. The 5-HT2A receptor is expressed not only in peripheral nerves, but also in the dorsal region of the spinal cord, and can serve as an intermediate medium for transmitting the pain signal associated with serotonin to the brain. It is reported that the expression of 5-HT2A receptors increases in dorsal root ganglia (DRG) and spinal cord dorsal horn, which are the main sites of pain pathways in animal models of neuropathic pain, and it has also been reported that ketanserin (which is a representative 5-HT2A receptor antagonist) inhibits pain induction.

[0040] Compounds that act as dual modulators of mGluR5 and 5-HT2AR are disclosed. If the compounds act synergistically by acting on both receptors simultaneously, it may be possible to maximize therapeutic and prophylactic analgesic effects while minimizing side effects by using lower dose prescriptions.

[0041] According to one aspect of the present invention, there is provided a compound of the following formula 1 or a pharmaceutically acceptable salt thereof:

[0042] [Formula 1]

[0043]

[0044] in

[0045] X1 and X2 together with the carbon atoms to which they are attached form a 4- to 7-membered aliphatic ring or a 4- to 6-membered heteroaliphatic ring;

[0046] X3 is CH or N;

[0047] R1 is hydroxy, halogen, hydrocarbon, heterocycloalkyl or heterocycloalkyl-hydrocarbon;

[0048] R2 is hydroxy, halogen, alkyl, alkyloxy, heterocycloalkyl, hydroxyalkyl, haloalkyl, amino, alkylamino, dialkylamino, cycloalkyl-alkyl, cycloalkylamino, haloalkylamino, aminocarbonyl, alkylaminocarbonyl, alkyloxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, hydroxyaminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, or 5- or 6-membered heteroaryl;

[0049] R3 is deuterium, halogen or hydrocarbon;

[0050] R4 and R5 are each independently halogen or hydrocarbon;

[0051] m is an integer from 0 to 3;

[0052] n is 0 or 1: and

[0053] l, p and q are each independently an integer from 0 to 2;

[0054] wherein the heteroaliphatic ring, heterocycloalkyl or heteroaryl has one or more heteroatoms selected from the group consisting of N, O and S;

[0055] Provided that, when x1 and x2 together with the carbon atoms to which they are attached form a 6-membered aliphatic ring or a 5-membered heteroaliphatic ring and x3 is CH, n and q are not 0 at the same time.

[0056] Herein, the following concepts defined for substituents are used to define the compounds of Formula 1.

[0057] As used herein, the term "aliphatic ring" means a non-aromatic hydrocarbon ring, and the term "heteroaliphatic ring" means a non-aromatic hydrocarbon ring having one or more heteroatoms selected from the group consisting of N, O and S, more specifically N or O. Specific examples of aliphatic rings include, but are not limited to, rings having 4 to 7 carbon atoms such as cyclobutane, cyclopropane, cyclohexane and cycloheptane. Specific examples of heteroaliphatic rings include, but are not limited to, 4- to 6-membered heterocycles such as oxetane, tetrahydrofuran, tetrahydropyran, dioxane and piperidine.

[0058] As used herein, the term "halogen" alone or in combination with another term (eg, haloalkyl) refers to a radical of fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). More specifically, the halogen may be fluorine (F).

[0059] As used herein, the term "hydrocarbyl" alone or in combination with another term (e.g., halogenated hydrocarbyl) refers to a group of a straight or branched saturated or unsaturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, preferably 1 to 5 carbon atoms, and may include a single bond, a double bond, or a triple bond. For example, the hydrocarbyl group may include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, etc., but is not limited thereto.

[0060] As used herein, the term "cycloalkyl" refers to a partially or fully saturated single or fused cyclic hydrocarbon, and can be C3-C 12 The cycloalkyl group is preferably a C3-C7 cycloalkyl group, and more specifically a C3-C6 cycloalkyl group. For example, the cycloalkyl group may include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclohexynyl group, a cycloheptyl group, etc., but is not limited thereto.

[0061] As used herein, unless otherwise indicated, the term "hydrocarbyloxy" refers to a hydrocarbyloxy group having 1 to 10 carbon atoms, preferably 1 to 5 carbon atoms.

[0062] The term "heterocycloalkyl" as used herein means a fully saturated hydrocarbon forming a ring, the ring including one or more heteroatoms selected from N, O and S, preferably 1 to 3 heteroatoms selected from N and O, and preferably a 4- to 6-membered heterocycloalkyl. Examples of heterocycloalkyl include, but are not limited to, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxane, piperidinyl, morpholinyl, and the like.

[0063] According to one embodiment of the present invention, in the above formula 1,

[0064] X1 and X2 together with the carbon atoms to which they are attached form a C4-C7 cycloalkyl or a 4- to 6-membered heterocycloalkyl group;

[0065] X3 is CH or N;

[0066] R1 is hydroxyl, halogen or C1-C5 hydrocarbon group;

[0067] R2 is hydroxy, halogen, C1-C5 alkyl, C1-C5 alkyloxy, 4- to 6-membered heterocycloalkyl, hydroxy-C1-C5 alkyl, halo-C1-C5 alkyl, C1-C5 alkylamino, C3-C6 cycloalkyl-C1-C5 alkyl, C3-C6 cycloalkylamino, halo-C1-C5 alkylamino, C1-C5 alkylaminocarbonyl, C1-C5 alkyloxycarbonyl-C1-C5 alkyl, carboxyl-C1-C5 alkyl, aminocarbonyl-C1-C5 alkyl, hydroxyaminocarbonyl-C1-C5 alkyl, C1-C5 alkylaminocarbonyl-C1-C5 alkyl, di(C1-C5 alkyl)aminocarbonyl-C1-C5 alkyl or pyridyl;

[0068] R3 is deuterium, fluorine or C1-C5 hydrocarbon group;

[0069] R4 and R5 are each independently halogen or C1-C5 hydrocarbon group;

[0070] m is an integer from 0 to 2;

[0071] n is 0 or 1; and

[0072] l, p and q are each independently an integer from 0 to 2;

[0073] The heterocycloalkyl group has 1 to 3 heteroatoms selected from the group consisting of N and O.

[0074] According to another embodiment of the present invention, examples of R1 include, but are not limited to, hydroxyl, fluorine, methyl, oxetanylmethyl, oxetanyl, and the like.

[0075] According to another embodiment of the present invention, examples of R2 include but are not limited to hydroxyl; methoxy; fluorine; methyl, ethyl, cyclopropylmethyl, fluoromethyl, hydroxymethyl, hydroxypropyl, carboxymethyl, carboxyethyl, methoxycarbonylmethyl, methoxycarbonylethyl, aminocarbonylmethyl, hydroxyaminocarbonylmethyl, methylaminocarbonylmethyl, dimethylaminocarbamoylmethyl; isopropylamino, 2,2-dimethylpropylamino, cyclopropylamino, 2,2,2-trifluoroamino, morpholinyl, methylaminocarbonyl, pyridyl, and the like.

[0076] According to another embodiment of the present invention, the 4- to 7-membered aliphatic ring is cyclobutane, cyclopentane, cyclohexane or cycloheptane.

[0077] According to another embodiment of the present invention, the 4- to 6-membered heteroaliphatic ring is oxetane, tetrahydrofuran, tetrahydropyran, dioxane or piperidine.

[0078] According to another embodiment of the present invention, in the above Formula 1, X1 and X2 together with the carbon atoms to which they are attached form oxetane, tetrahydrofuran, tetrahydropyran, cyclobutane, cyclopentane or cyclohexane.

[0079] According to another embodiment of the present invention, in the above Formula 1, p is 0.

[0080] According to another embodiment of the present invention, in the above Formula 1, X3 is CH.

[0081] According to another embodiment of the present invention, in the above Formula 1, at least one of n and q is not zero.

[0082] According to another embodiment of the present invention, in the above Formula 1, R5 is fluorine, and q is 1 or 2.

[0083] According to another embodiment of the present invention, in the above Formula 1, R5 is substituted at the ortho and / or para position of the phenyl group.

[0084] In another embodiment according to the present invention, representative examples of the compound of Formula 1 may include the following compounds, but are not limited thereto:

[0085] N-((1-(Cyclopropylamino)cycloheptyl)methyl)-4-(pyridin-2-ylethynyl)benzamide;

[0086] N-((1-(Cyclopropylamino)cyclopentyl)methyl)-4-(pyridin-4-ylethynyl)benzamide;

[0087] N-((1-(Cyclopropylamino)cyclopentyl)methyl)-4-((5-fluoropyridin-2-yl)ethynyl)benzamide;

[0088] N-((1-(Cyclopropylamino)cyclobutyl)methyl)-4-((5-fluoropyridin-2-yl)ethynyl)benzamide;

[0089] N-((1-(Cyclopropylamino)cyclobutyl)methyl)-4-(pyridin-4-ylethynyl)benzamide;

[0090] N-((1-(Cyclopropylamino)cyclobutyl)methyl)-4-((4-fluorophenyl)ethynyl)benzamide;

[0091] N-((1-(Cyclopropylamino)cyclobutyl)methyl)-3-fluoro-4-(pyridin-4-ylethynyl)benzamide:

[0092] N-((1-(Cyclopropylamino)cyclobutyl)methyl)-4-(pyridin-2-ylethynyl)benzamide;

[0093] N-((1-(Cyclopropylamino)cyclobutyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;

[0094] N-((1-(Cyclopropylamino)cyclobutyl)methyl)-2-fluoro-4-(pyridin-4-ylethynyl)benzamide;

[0095] N-((1-(Cyclopropylamino)cyclopentyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;

[0096] N-((1-(Cyclopropylamino)cycloheptyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;

[0097] N-((1-(Cyclopropylamino)cyclopentyl)methyl)-4-((4-fluorophenyl)ethynyl)benzamide;

[0098] N-((1-(Cyclopropylamino)cycloheptyl)methyl)-4-((4-fluorophenyl)ethynyl)benzamide;

[0099] N-((1-(Cyclopropylamino)cycloheptyl)methyl)-4-((5-fluoropyridin-2-yl)ethynyl)benzamide;

[0100] N-((1-(Cyclopropylamino)cycloheptyl)methyl)-4-((3-fluoropyridin-4-yl)ethynyl)benzamide;

[0101] N-((1-(Cyclopropylamino)cyclopentyl)methyl)-4-((3,4-difluorophenyl)ethynyl)benzamide;

[0102] N-((1-(Cyclopropylamino)cycloheptyl)methyl)-4-((3,4-difluorophenyl)ethynyl)benzamide;

[0103] N-((1-(Cyclopropylamino)cyclohexyl)methyl)-4-((4-fluorophenyl)ethynyl)benzamide;

[0104] N-((1-(Cyclopropylamino)cyclohexyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;

[0105] N-((1-(Cyclopropylamino)cyclopentyl)methyl)-4-((2-methylpyridin-4-yl)ethynyl)benzamide;

[0106] N-((4-(Cyclopropylamino)tetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;

[0107] 4-((2-Fluorophenyl)ethynyl)-N-((1-morpholinocyclopentyl)methyl)benzamide;

[0108] 4-((2-Fluorophenyl)ethynyl)-N-((4-(isopropylamino)tetrahydro-2H-pyran-4-yl)methyl)benzamide;

[0109] 4-((2-Fluorophenyl)ethynyl)-N-((1-(isopropylamino)cyclohexyl)methyl)benzamide;

[0110] N-((1-(Cyclopropylamino)-4-methylcyclohexyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;

[0111] 4-((2-Fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide;

[0112] 4-((2-Fluorophenyl)ethynyl)-N-((1-(neopentylamino)cyclohexyl)methyl)benzamide;

[0113] N-((4-(Cyclopropylmethyl)tetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;

[0114] 4-((2-Fluorophenyl)ethynyl)-N-((1-(isopropylamino)cyclopentyl)methyl)benzamide;

[0115] 4-(Pyridin-4-ylethynyl)-N-((1-((2,2,2-trifluoroethyl)amino)cyclohexyl)methyl)benzamide;

[0116] 4-((2-Fluorophenyl)ethynyl)-N-((1-hydroxycyclohexyl)methyl)benzamide;

[0117] 4-((4-Fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide;

[0118] 4-((2-Fluorophenyl)ethynyl)-N-((1-(pyridin-3-yl)cyclopentyl)methyl)benzamide;

[0119] 2-Fluoro-4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide;

[0120] 4-((2-Fluorophenyl)ethynyl)-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)benzamide;

[0121] 4-((2-Fluorophenyl)ethynyl)-N-((1-(hydroxymethyl)cyclohexyl)methyl)benzamide;

[0122] 4-((2-Fluorophenyl)ethynyl)-N-((4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)methyl)benzamide;

[0123] N-((4,4-difluorocyclohexyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;

[0124] 4-((2-Fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide;

[0125] 4-((2-Fluorophenyl)ethynyl)-N-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)benzamide;

[0126] 4-((2-Fluorophenyl)ethynyl)-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide;

[0127] 4-((2-Fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide;

[0128] 4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide;

[0129] (R)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide;

[0130] (S)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide;

[0131] (R)-4-((2-fluorophenyl)ethynyl)-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide;

[0132] 4-((2-Fluorophenyl)ethynyl)-N-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)benzamide;

[0133] 4-(Phenylethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide;

[0134] N-((4-(Fluoromethyl)tetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;

[0135] N-((1,4-dioxan-2-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;

[0136] 4-((2-Fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl)benzamide;

[0137] 4-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)-N-methyltetrahydro-2H-pyran-4-carboxamide;

[0138] 4-((2-Fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-2-yl)methyl)benzamide;

[0139] N-((1-(isopropylamino)cyclohexyl)methyl)-4-(phenylethynyl)benzamide;

[0140] N-((3,3-difluorocyclobutyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;

[0141] 4-((2-Fluorophenyl)ethynyl)-N-((1-hydroxycyclobutyl)methyl)benzamide;

[0142] 4-((2-Fluorophenyl)ethynyl)-N-(oxetan-2-ylmethyl)benzamide;

[0143] Methyl 3-(1-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)cyclohexyl)propanoate;

[0144] 3-(4-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)tetrahydro-2H-pyran-4-yl)propanoic acid;

[0145] 3-(1-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)cyclohexyl)propanoic acid;

[0146] 4-((2-Fluorophenyl)ethynyl)-N-((1-(3-hydroxypropyl)cyclohexyl)methyl)benzamide;

[0147] 4-((2-Fluorophenyl)ethynyl)-N-((2-hydroxycyclohexyl)methyl)benzamide;

[0148] 4-((2-Fluorophenyl)ethynyl)-N-((3-hydroxycyclohexyl)methyl)benzamide;

[0149] 4-((2-Fluorophenyl)ethynyl)-N-((1-methoxycyclohexyl)methyl)benzamide;

[0150] 4-((2-Fluorophenyl)ethynyl)-N-((4-methoxytetrahydro-2H-pyran-4-yl)methyl)benzamide;

[0151] N-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;

[0152] 4-((2-Fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl-d2)benzamide;

[0153] (R)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide;

[0154] N-((5,5-dimethyltetrahydrofuran-3-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;

[0155] 4-((2-Fluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide;

[0156] N-((3-ethyloxetan-3-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;

[0157] 4-((2,4-difluorophenyl)ethynyl)-N-((1-fluorocyclohexyl)methyl)benzamide;

[0158] Methyl 2-(1-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)cyclohexyl)acetate;

[0159] Methyl 2-(4-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)tetrahydro-2H-pyran-4-yl)acetate;

[0160] 2-(1-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)cyclohexyl)acetic acid;

[0161] N-((1-(2-amino-2-oxoethyl)cyclohexyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;

[0162] N-((4-(2-amino-2-oxoethyl)tetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;

[0163] 4-((2-Fluorophenyl)ethynyl)-N-((1-(2-(hydroxyamino)-2-oxoethyl)cyclohexyl)methyl)benzamide;

[0164] 4-((2-Fluorophenyl)ethynyl)-N-((1-(2-(methylamino)-2-oxoethyl)cyclohexyl)methyl)benzamide;

[0165] N-((1-(2-(dimethylamino)-2-oxoethyl)cyclohexyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;

[0166] 4-((2-Fluorophenyl)ethynyl)-N-((3-hydroxyoxetan-3-yl)methyl)benzamide;

[0167] 4-((4-Fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl)benzamide;

[0168] 3-Fluoro-4-((2-fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl)benzamide;

[0169] 4-((2-Fluorophenyl)ethynyl)-N-(((1s,3s)-3-hydroxycyclobutyl)methyl)benzamide;

[0170] 4-((2-Fluorophenyl)ethynyl)-N-(((1r,3r)-3-hydroxycyclobutyl)methyl)benzamide;

[0171] 4-((2-Fluorophenyl)ethynyl)-N-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)methyl)benzamide;

[0172] N-((4,4-difluorocyclohexyl)methyl)-4-(pyridin-4-ylethynyl)benzamide;

[0173] N-((3,3-difluorocyclobutyl)methyl)-4-(pyridin-4-ylethynyl)benzamide;

[0174] N-((3,3-difluorocyclobutyl)methyl)-4-(phenylethynyl)benzamide;

[0175] (S)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide;

[0176] (R)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide;

[0177] (S)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide;

[0178] 4-((4-Fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide;

[0179] 4-((2-fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl-d)benzamide;

[0180] 4-((2-Fluorophenyl)ethynyl)-N-((1-morpholinocyclobutyl)methyl)benzamide;

[0181] N-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;

[0182] 4-((2-fluorophenyl)ethynyl)-N-((2-methyltetrahydrofuran-2-yl)methyl)benzamide;

[0183] (R)-4-((4-Fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide;

[0184] (S)-4-((4-Fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide;

[0185] (R)-4-((4-Fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide;

[0186] (S)-4-((4-Fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide;

[0187] N-((3-fluorooxetan-3-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;

[0188] 4-((4-Fluorophenyl)ethynyl)-N-((1-methylcyclohexyl)methyl)benzamide;

[0189] 4-((2-Fluorophenyl)ethynyl)-N-((1-methylcyclobutyl)methyl)benzamide;

[0190] 4-((4-Fluorophenyl)ethynyl)-N-((1-methylcyclobutyl)methyl)benzamide;

[0191] 4-((2,4-difluorophenyl)ethynyl)-N-((1-methylcyclobutyl)methyl)benzamide;

[0192] 4-((2,4-difluorophenyl)ethynyl)-N-((1-methylcyclopentyl)methyl)benzamide;

[0193] (R)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide;

[0194] (R)-4-((4-Fluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide;

[0195] (S)-4-((4-Fluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide;

[0196] N-((3-ethyloxetan-3-yl)methyl)-4-((4-fluorophenyl)ethynyl)benzamide;

[0197] (S)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide;

[0198] (R)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide;

[0199] 4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-2-yl)methyl)benzamide;

[0200] 4-((4-Fluorophenyl)ethynyl)-N-((2-methyltetrahydrofuran-2-yl)methyl)benzamide;

[0201] (S)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide;

[0202] 4-((2,4-difluorophenyl)ethynyl)-N-(oxetan-2-ylmethyl)benzamide;

[0203] 4-((2,4-difluorophenyl)ethynyl)-N-((2-methyltetrahydrofuran-2-yl)methyl)benzamide;

[0204] N-((3,3-difluorocyclobutyl)methyl)-4-((2,4-difluorophenyl)ethynyl)benzamide;

[0205] N-((4,4-difluorocyclohexyl)methyl)-4-((2,4-difluorophenyl)ethynyl)benzamide;

[0206] 4-((2,4-difluorophenyl)ethynyl)-N-((3-ethyloxetan-3-yl)methyl)benzamide;

[0207] 4-((2,4-difluorophenyl)ethynyl)-N-((3-fluorooxetan-3-yl)methyl)benzamide;

[0208] (S)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide; and

[0209] 4-((2,4-difluorophenyl)ethynyl)-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)benzamide.

[0210] The compounds of Formula 1 act as dual modulators of mGluR5 and 5-HT2AR.

[0211] All compounds of Formula 1 have IC values ​​of 2 μM or less for mGluR5 and 5-HT2AR 50In another embodiment according to the present invention, the compound of Formula 1 has an IC of 1.5 μM or less for both mGluR5 and 5-HT2AR. 50 In another embodiment according to the present invention, the compound of Formula 1 has an IC of 1.0 μM or less for both mGluR5 and 5-HT2AR. 50 .

[0212] In another embodiment according to the present invention, more specific examples of the compound of Formula 1 may include the following compounds:

[0213] N-((1-(Cyclopropylamino)cyclobutyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;

[0214] N-((1-(Cyclopropylamino)cyclopentyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide;

[0215] 4-((2-Fluorophenyl)ethynyl)-N-((1-(isopropylamino)cyclohexyl)methyl)benzamide;

[0216] 4-((2-Fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide;

[0217] 4-((2-Fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide;

[0218] 4-((2-Fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide;

[0219] 4-(Phenylethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide;

[0220] 4-((2-Fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl)benzamide;

[0221] (R)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide;

[0222] 4-((2-Fluorophenyl)ethynyl)-N-((3-hydroxyoxetan-3-yl)methyl)benzamide;

[0223] 4-((4-Fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl)benzamide;

[0224] 4-((2-Fluorophenyl)ethynyl)-N-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)methyl)benzamide;

[0225] 4-((4-Fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide;

[0226] (S)-4-((4-Fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide;

[0227] (R)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide;

[0228] 4-((4-Fluorophenyl)ethynyl)-N-((2-methyltetrahydrofuran-2-yl)methyl)benzamide;

[0229] 4-((2,4-difluorophenyl)ethynyl)-N-((2-methyltetrahydrofuran-2-yl)methyl)benzamide; and

[0230] (S)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide.

[0231] The above compounds have IC values ​​of 1.0 μM or less for both mGluR5 and 5-HT2AR. 50 In addition, the compound exhibited excellent analgesic effect in the spinal nerve ligation model.

[0232] Even in the form of a pharmaceutically acceptable salt, the pharmaceutical effect of the compound according to one embodiment of the present invention can be maintained. The pharmaceutically acceptable salt includes acid or base addition salts and stereochemical isomeric forms thereof. The salt may include any salt that maintains the activity of the parent compound in the subject to be administered and does not cause any undesirable effects, but is not limited thereto. The term "additional salt" may be considered to include solvates that can be obtained from any one of the compounds of Formula 1 and their pharmaceutically acceptable salts. Examples of these solvates are hydrates or alcoholates.

[0233] Furthermore, since the compounds of Formula 1 according to the present invention may have an asymmetric carbon center, they may exist as R or S isomers, racemic mixtures or diastereomeric mixtures as well as each diastereomer, all of which are within the scope of the present invention.

[0234] Pharmaceutical composition

[0235] According to another aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating pain, comprising a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier or excipient.

[0236] The pharmaceutical composition can be formulated into various oral or parenteral dosage forms. For example, the pharmaceutical composition can be formulated into any dosage form for oral administration, such as tablets, pills, hard / soft capsules, solutions, suspensions, emulsions, syrups, granules or elixirs.

[0237] When the pharmaceutical composition is formulated into a parenteral dosage form, the pharmaceutical composition can be administered by a parenteral administration method such as subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection. The pharmaceutical composition can be prepared as a solution or suspension by mixing the active ingredient (i.e., a compound of Formula 1 or a pharmaceutically acceptable salt thereof) with a stabilizer or a buffer in water, and the solution or suspension can be prepared as a unit dosage form of an ampoule or a vial.

[0238] Medical usefulness

[0239] According to yet another aspect of the present invention, there is provided a method for inhibiting or treating pain in an animal, comprising administering to the animal a therapeutically effective amount of one or more compounds of Formula 1 and pharmaceutically acceptable salts thereof.

[0240] The compound of formula 1 acts as a dual modulator of mGluR5 and 5-HT2AR. Specifically, the compound of formula 1 acts as an antagonist of the 5-HT2A receptor and can act as a negative modulator (inhibitory function modulator) in the receptor sub-signaling system of mGluR5. Due to the synergistic effect between the targets, the compound of formula 1 with these characteristics can be administered to patients in small doses to minimize side effects and maximize analgesic efficacy.

[0241] The compounds of formula 1 can be used for the treatment and prevention of pain, particularly neuropathic pain. Neuropathic pain can include diabetic neuropathic pain, spinal stenosis, pain after spinal surgery, allodynia, causalgia, hyperalgesia, hyperalgesia, neuralgia, post-herpetic neuralgia, post-thoracotomy pain, trigeminal neuralgia, pain associated with multiple sclerosis, thalamic pain, phantom limb pain, anesthesia of pain, HIV-related neuropathic pain, paraplegic pain induced by spinal cord disorders or complex regional pain syndrome, pain after seizures, pain associated with neuropathy such as idiopathic or post-traumatic neuropathy and mononeuritis, cancer-related neuropathic pain, carpal tunnel-related neuropathic pain, pain associated with spinal cord injury, fibromyalgia-related neuropathic pain, back and neck pain, reflex sympathetic dystrophy, phantom limb syndrome and spontaneous pain, trauma-induced neuropathic pain, demyelination-induced pain, chemotherapy-induced neuropathy, back pain, bone pain, chronic alcoholism, hypothyroidism, neuropathic pain caused by uremia or vitamin deficiency, and central post-stroke pain.

[0242] In one embodiment, the method for inhibiting or treating pain comprises administering to an animal a pharmaceutical composition comprising an effective amount of one or more compounds of Formula 1 and a pharmaceutically acceptable carrier. The method is particularly suitable for use in humans, but can also be used in other animals, particularly mammals.

[0243] The specific administration method and therapeutically effective amount of the compound of Formula 1 or a pharmaceutically acceptable salt thereof can be determined by those skilled in the art considering the type of target mammal, the type of disease, and the type of the compound of Formula 1, and is not particularly limited.

[0244] For example, for mammals (including humans), the compound of Formula 1 or a pharmaceutically acceptable salt thereof can be included in a pharmaceutical composition at an effective dose of 0.1 to 1,000 mg / kg (body weight), preferably 0.5 to 500 mg / kg (body weight) per day. The pharmaceutical composition can be administered once a day or divided into two or more times and administered orally or parenterally.

[0245] Hereinafter, a method for preparing the compound of Formula 1 will be described. The following description is merely exemplary, and the method may be appropriately changed according to the choice of those skilled in the art.

[0246] As shown in the following Reaction Scheme 1, the compound of Formula 1 can be obtained through an amide bond reaction between the amine compound of Intermediate 4 and the carboxylic acid compound of Intermediate 5.

[0247] [Reaction Scheme 1]

[0248]

[0249] The amine compound of intermediate 4 can be prepared by various methods, including but not limited to the methods of reaction schemes 2 to 8, depending on the substituents.

[0250] [Reaction Scheme 2]

[0251]

[0252] After forming an imine compound from an amine compound 8 and a ketone compound 7 as starting materials, intermediate 6a can be obtained by a nucleophilic addition reaction using potassium nitrile (KCN), and an amine compound of intermediate 4a can be obtained by reduction.

[0253] [Reaction Scheme 3]

[0254]

[0255] The cyanohydrin compound 6b can be obtained from the ketone compound 7 by a nucleophilic addition reaction using potassium nitrile, and the amine compound of the intermediate 4b can be obtained by a reduction reaction from the compound.

[0256] [Reaction Scheme 4]

[0257]

[0258] The amine compound of the intermediate 4c can be obtained by a reduction reaction from the cyano compound 6c.

[0259] [Reaction Scheme 5]

[0260]

[0261] Compound 6d can be obtained by substitution reaction from cyano compound 6c, and the amine compound of intermediate 4d can be obtained by reduction. Intermediate 4e in the form of amine hydrochloride can be obtained under hydrochloric acid conditions.

[0262] [Reaction Scheme 6]

[0263]

[0264] The amine compound of the carboxylic acid-containing intermediate 4f can be obtained from the lactam compound 9 by cyclization under strong acid conditions. In addition, the ester-containing intermediate 4g can be obtained under acidic conditions.

[0265] [Reaction Scheme 7]

[0266]

[0267] The carboxylic acid compound 10 can be coupled with the acrylate compound 11 to obtain the compound 6e, and the amine compound of the deprotected intermediate 4h can be obtained by using a strong acid.

[0268] [Reaction Scheme 8]

[0269]

[0270] From the carboxylic acid compound 10, the fluorine-substituted compound 6f can be obtained by a coupling reaction using bis(tetrafluoroborate) under visible light, and the amine compound of the intermediate 4i can be obtained by a deprotection reaction.

[0271] [Reaction Scheme 9]

[0272]

[0273] Compound 6g containing a ring can be obtained from compound 12 by substitution reaction under alkaline conditions, and the ester and nitrile are reduced to obtain the amine compound of intermediate 4j. It is selectively protected to obtain the alcohol of 6h, and from the substitution of fluorine for the hydroxyl group, the compound of intermediate 4k can be obtained.

[0274] The carboxylic acid compound of intermediate 5 can be prepared by various methods, including but not limited to the method of reaction scheme 10 below.

[0275] [Reaction Scheme 10]

[0276]

[0277] Compound 13 can be obtained from a halogen-containing compound (14a or 15b) and an acetylene-containing compound (15a, 14b) through a Sonogashira coupling reaction, and the carboxylic acid compound of intermediate 5 can be obtained by hydrolysis. Example

[0278] Hereinafter, the present invention is explained in more detail with the following examples. However, it must be understood that the protection scope of the present disclosure is not limited to the examples.

[0279] Example 1: Synthesis of N-((1-(cyclopropylamino)cycloheptyl)methyl)-4-(pyridin-2-ylethynyl)benzamide

[0280]

[0281] Step 1: Synthesis of 4-(pyridin-2-ylethynyl)benzoic acid

[0282]

[0283] Methyl 4-ethynylbenzoate (1.500 g, 9.365 mmol), 2-iodopyridine (2.112 g, 10.302 mmol), tetrakis(triphenylphosphine)palladium (0.216 g, 0.187 mmol), cuprous iodide (0.036 g, 0.187 mmol) and piperidine (9.251 mL, 93.650 mmol) were dissolved in toluene (15 mL) at room temperature, and the resulting solution was stirred at 90 ° C for 18 hours, and then the temperature was lowered to room temperature to terminate the reaction. Saturated aqueous ammonium chloride solution was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to obtain methyl 4-(pyridin-2-ylethynyl)benzoate (1.705 g, 76.7%) as a white solid. 1.705 g (7.186 mmol) of the obtained compound and lithium hydroxide monohydrate (0.603 g, 14.372 mmol) were dissolved in methanol (5 mL) / water (5 mL) / tetrahydrofuran (5 mL) at room temperature, and the obtained mixture was stirred at the same temperature for 3 hours. After removing the solvent from the reaction mixture under reduced pressure, a 1N aqueous hydrochloric acid solution was added to the concentrate and stirred. The precipitated solid was filtered, washed with water and dried to obtain 4-(pyridin-2-ylethynyl)benzoic acid (0.695 g, 43.3)%) as a yellow solid: LRMS (ES) m / z 224.00 [M+H] + , calculated molecular weight 223.23.

[0284] Step 2: Synthesis of 1-(aminomethyl)-N-cyclopropylcycloheptane-1-amine

[0285]

[0286] Cyclopropylamine (5.700g, 99.825mmol) and cycloheptanone (11.197g, 99.825mmol) are dissolved in water (200mL) at room temperature. Sodium bisulfite (NaHSO3, 40.00% solution in water, 12.984mL, 49.912mmol) is added to the obtained solution and stirred at the same temperature for 2 hours. Potassium cyanide (9.750g, 149.737mmol) is added to the reaction mixture, and the reaction mixture is further stirred at the same temperature for 24 hours. Water is added to the reaction mixture and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate is purified by column chromatography and concentrated to obtain 1-(cyclopropylamino)cycloheptane-1-carbonitrile (12.670g, 71.2%) as a colorless oil. To a solution of the obtained product dissolved in ether (200 mL) was added lithium aluminum hydride (2.40 M solution, 88.835 mL, 213.204 mmol) at 0°C and stirred at room temperature for 16 hours. Then, water (7.684 mL, 426.408 mmol) and sodium hydroxide (1.00 M solution, 35.534 mL, 35.534 mmol) were added to the reaction mixture at 0°C, followed by stirring for 30 minutes to terminate the reaction. The reaction mixture was filtered through a celite pad to remove solids, and the solvent was removed from the filtrate under reduced pressure. The obtained product was used without further purification (1-(aminomethyl)-N-cyclopropylcycloheptane-1-amine, 12.000 g, 92.6%, colorless oil): LRMS (ES) m / z 183.16 [M+H] + , calculated molecular weight 182.31.

[0287] Step 3: Synthesis of N-((1-(cyclopropylamino)cycloheptyl)methyl)-4-(pyridin-2-ylethynyl)benzamide become

[0288]

[0289] 4-(Pyridin-2-ylethynyl)benzoic acid (0.031 g, 0.139 mmol), 1-(aminomethyl)-N-cyclopropylcycloheptane-1-amine (0.025 g, 0.139 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl, 0.040 g, 0.208 mmol), 1H-benzo[d][1,2,3]triazole-1-ol (HOBt, 0.028 g, 0.208 mmol) and N,N-diisopropylethylamine (0.121 mL, 0.694 mmol) were dissolved in M,N-dimethylformamide (2 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to give N-((1-(cyclopropylamino)cycloheptyl)methyl)-4-(pyridin-2-ylethynyl)benzamide (0.008 g, 14.9%) as a yellow solid: LRMS (ES) m / z 388.41 [M+H] + , calculated molecular weight 387.53; 1 H-NMR(400MHz, CDCl3)d 9.24 (s, 1H), 8.63 (d, J = 4.0Hz, 1H), 8.41 (t, J = 5.6Hz, 1H), 8.14 (d, J = 8.4Hz, 2H), 7.71 (t, J = 7.8Hz, 1H), 7.64 (d, J = 8.4H z, 2H), 7.54 (d, J=8.0Hz, 1H), 7.28 (m, 1H), 3.93 (d, J=5.6Hz, 2H), 2.54 (s, 1H), 2.12 (m, 2H), 1.98 (m, 2H), 1.68 (m, 12H).

[0290] Example 2: Synthesis of N-((1-(cyclopropylamino)cyclopentyl)methyl)-4-(pyridin-4-ylethynyl)benzamide

[0291]

[0292] Step 1: Synthesis of 4-(pyridin-4-ylethynyl)benzoic acid

[0293]

[0294] Using 4-iodopyridine (2.816 g, 13.735 mmol) instead of 2-iodopyridine in a manner similar to Step 1 of Example 1, methyl 4-(pyridin-4-ylethynyl)benzoate (2.500 g, 84.4%) was obtained as a white solid, followed by 4-(pyridin-4-ylethynyl)benzoic acid (2.484 g, 97.6%) as a white solid.

[0295] Step 2: Synthesis of 1-(aminomethyl)-N-cyclopropylcyclopentane-1-amine

[0296]

[0297] Cyclopentanone (10.000 mL, 112.934 mmol) was used in place of cycloheptanone in a manner similar to that in Step 2 of Example 1 to give 1-(cyclopropylamino)cyclopentane-1-carbonitrile (13.659 g, 80.5%) as a yellow liquid, followed by 1-(aminomethyl)-N-cyclopropylcyclopentane-1-amine (11.510 g, 82.1%, yellow liquid) as a yellow liquid.

[0298] Step 3: Synthesis of N-((1-(cyclopropylamino)cyclopentyl)methyl)-4-(pyridin-4-ylethynyl)benzamide become

[0299]

[0300] In a similar manner to step 3 of Example 1 using 4-(pyridin-4-ylethynyl)benzoic acid (0.100 g, 0.448 mmol) and 1-(aminomethyl)-N-cyclopropylcyclopentane-1-amine (0.083 g, 0.538 mmol) as starting materials, N-((1-(cyclopropylamino)cyclopentyl)methyl)-4-(pyridin-4-ylethynyl)benzamide (0.097 g, 60.2%) was obtained as a yellow solid: LRMS (ES) m / z 360.19 [M+H] + , calculated molecular weight 359.47; 1 H-NMR(400MHz, CDCl3)d 8.60 (d, J=9.6Hz, 2H), 7.83 (d, J=22.8Hz, 2H), 7.59~7.55 (m, 2H), 7.37 (d, J=6. 0Hz, 2H), 3.57(s, 2H), 2.27~2.20(m, 1H), 1.88~1.71(m, 8H), 0.59~0.58(m, 4H).

[0301] Example 3: Synthesis of N-((1-(cyclopropylamino)cyclopentyl)methyl)-4-((5-fluoropyridin-2-yl)ethynyl)benzamide

[0302]

[0303] Step 1: Synthesis of 4-((5-fluoropyridin-2-yl)ethynyl)benzoic acid

[0304]

[0305] Methyl 4-ethynylbenzoate (1.000 g, 6.243 mmol), 2-bromo-5-fluoropyridine (1.099 g, 6.243 mmol), cuprous iodide (0.119 g, 0.624 mmol), tetrakis(triphenylphosphine)palladium (0.433 g, 0.375 mmol) and triethylamine (8.702 mL, 62.434 mmol) were dissolved in toluene (25 mL) at room temperature. The resulting solution was stirred at 100 ° C for 16 hours, and then the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was filtered through a diatomaceous earth pad to remove solids, and water was added to the filtrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to give methyl 4-((5-fluoropyridin-2-yl)ethynyl)benzoate (0.980 g, 61.5%) as a brown solid.

[0306] Then, a solution of the obtained product and lithium hydroxide monohydrate (0.322 g, 7.679 mmol) dissolved in tetrahydrofuran (5 mL) / methanol (5 mL) / water (5 mL) was stirred at 50° C. for 6 hours at room temperature, and then the temperature was lowered to room temperature to terminate the reaction. After the solvent was removed from the reaction mixture under reduced pressure, a 1N aqueous hydrochloric acid solution was added to the concentrate and stirred. The precipitated solid was filtered, washed with water and dried to obtain 4-((5-fluoropyridin-2-yl)ethynyl)benzoic acid (0.860 g, 92.9%) as a brown solid: LRMS (ES) m / z 241.72 [M+H] + , calculated molecular weight 241.22.

[0307] Step 2: N-((1-(cyclopropylamino)cyclopentyl)methyl)-4-((5-fluoropyridin-2-yl)ethynyl)benzoyl Synthesis of amines

[0308]

[0309] In a similar manner to step 3 of Example 1 using 4-((5-fluoropyridin-2-yl)ethynyl)benzoic acid (0.156 g, 0.648 mmol) and 1-(aminomethyl)-N-cyclopropylcyclopentane-1-amine (0.100 g, 0.648 mmol) as starting materials, N-((1-(cyclopropylamino)cyclopentyl)methyl)-4-((5-fluoropyridin-2-yl)ethynyl)benzamide (0.085 g, 34.7%) was obtained as a white solid: LRMS (ES) m / z 378.18 [M+H] +, calculated molecular weight 377.46; 1 H-NMR(400MHz, CD3OD)d 8.48 (m, 1H), 7.86 (d, J=8.4Hz, 2H), 7.72~7.63 (m, 4H), 3.56 (s, 2H), 2.2 1~2.17(m,1H), 1.79~1.62(m,8H), 0.52~0.48(m,2H), 0.37~0.35(m,2H).

[0310] Example 4: Synthesis of N-((1-(cyclopropylamino)cyclobutyl)methyl)-4-((5-fluoropyridin-2-yl)ethynyl)benzamide

[0311]

[0312] Step 1: Synthesis of 1-(aminomethyl)-N-cyclopropylcyclobutane-1-amine

[0313]

[0314] In a similar manner to step 2 of Example 1, but using cyclobutanone (1.706 mL, 22.828 mmol) instead of cycloheptanone, 1-(cyclopropylamino)cyclobutane-1-carbonitrile (0.823 g, 26.5%) was obtained as a yellow liquid, followed by 1-(aminomethyl)-N-cyclopropylcyclobutane-1-amine (0.760 g, 92.3%) as a yellow solid: LRMS (ES) m / z 140.96 [M+H] + , calculated molecular weight 140.23

[0315] Step 2: N-((1-(cyclopropylamino)cyclobutyl)methyl)-4-((5-fluoropyridin-2-yl)ethynyl)benzoyl Synthesis of amines

[0316]

[0317] 4-((5-fluoropyridin-2-yl)ethynyl)benzoic acid (0.070 g, 0.290 mmol) and 1-(aminomethyl)-N-cyclopropylcyclobutane-1-amine (0.061 g, 0.435 mmol) were used in a manner similar to step 3 of Example 1 to give N-((1-(cyclopropylamino)cyclobutyl)methyl)-4-((5-fluoropyridin-2-yl)ethynyl)benzamide (0.044 g, 41.7%) as a yellow liquid: LRMS (ES) m / z 364.10 [M+H] + , calculated molecular weight 363.44; 1H-NMR(400MHz, CD3OD)d 8.48 (d, J=2.4Hz, 1H), 7.87 (d, J=6.8Hz, 2H), 7.75~7.59 (m, 4H), 3.61 (s, 2H), 2.12~2. 06 (m, 3H), 2.01 ~ 1.98 (m, 2H), 1.83 ~ 1.79 (m, 2H), 0.52 ~ 0.48 (m, 2H), 0.36 ~ 0.33 (m, 2H).

[0318] Example 5: Synthesis of N-((1-(cyclopropylamino)cyclobutyl)methyl)-4-(pyridin-4-ylethynyl)benzamide

[0319]

[0320] Step 1: Synthesis of N-((1-(cyclopropylamino)cyclobutyl)methyl)-4-(pyridin-4-ylethynyl)benzamide become

[0321]

[0322] In a similar manner to step 3 of Example 1, using 4-(pyridin-4-ylethynyl)benzoic acid (0.070 g, 0.314 mmol) and 1-(aminomethyl)-N-cyclopropylcyclobutane-1-amine (0.066 g, 0.470 mmol) as starting materials, N-((1-(cyclopropylamino)cyclobutyl)methyl)-4-(pyridin-4-ylethynyl)benzamide (0.078 g, 72.0%) was obtained as a yellow liquid: LRMS (ES) m / z 346.18 [M+H] + , calculated molecular weight 345.45; 1 H-NMR(400MHz, CD3OD)d 8.55 (d, J=6.0Hz, 2H), 7.88 (d, J=8.4Hz, 2H), 7.66 (d, J=12.0Hz, 2H), 7.53 (d, J=6.0Hz, 2H), 3.70 (s, 2H), 2.14~2.09(m, 3H), 2.07~1.97(m, 2H), 1.84~1.81(m, 2H), 0.51~0.49(m, 2H), 0.37~0.35(m, 2H).

[0323] Example 6: Synthesis of N-((1-(cyclopropylamino)cyclobutyl)methyl)-4-((4-fluorophenyl)ethynyl)benzamide

[0324]

[0325] Step 1: Synthesis of 4-((4-fluorophenyl)ethynyl)benzoic acid

[0326]

[0327] In a similar manner to step 1 of Example 3, methyl 4-bromobenzoate (0.985 g, 4.578 mmol) and 1-ethynyl-4-fluorobenzene (0.500 g, 4.162 mmol) were used as starting materials to give methyl 4-((4-fluorophenyl)ethynyl)benzoate (0.779 g, 73.6%) as a white solid followed by 4-((4-fluorophenyl)ethynyl)benzoic acid (0.672 g, 91.3%) as a pale yellow solid: LRMS (ES) m / z 239.05 [MH] + , calculated molecular weight 240.23.

[0328] Step 2: Synthesis of N-((1-(cyclopropylamino)cyclobutyl)methyl)-4-((4-fluorophenyl)ethynyl)benzamide become

[0329]

[0330] In a similar manner to step 3 of Example 1, using 4-((4-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and 1-(aminomethyl)-N-cyclopropylcyclobutane-1-amine (0.061 g, 0.437 mmol) as starting materials, N-((1-(cyclopropylamino)cyclobutyl)methyl)-4-((4-fluorophenyl)ethynyl)benzamide (0.078 g, 73.9%) was obtained as a yellow liquid: LRMS (ES) m / z 363.12 [M+H] + , calculated molecular weight 362.45; 1 H-NMR(400MHz, CD3OD)d 7.84 (dt, J=8.4, 1.9Hz, 2H), 7.60~7.53 (m, 4H), 7.12 (t, J=8.6Hz, 2H), 3.89 (s, 2H), 2.13~ 2.06 (m, 3H), 2.03 ~ 1.98 (m, 2H), 1.85 ~ 1.79 (m, 2H), 0.51 ~ 0.48 (m, 2H), 0.36 ~ 0.34 (m, 2H).

[0331] Example 7: Synthesis of N-((1-(cyclopropylamino)cyclobutyl)methyl)-3-fluoro-4-(pyridin-4-ylethynyl)benzamide

[0332]

[0333] Step 1: Synthesis of 3-fluoro-4-(pyridin-4-ylethynyl)benzoic acid

[0334]

[0335] In a similar manner to step 1 of Example 3, methyl 4-bromo-3-fluorobenzoate (1.000 g, 4.291 mmol) and 4-ethynylpyridine hydrochloride (0.493 g, 4.506 mmol) were used as starting materials to give methyl 3-fluoro-4-(pyridin-4-ylethynyl)benzoate (0.868 g, 79.2%) as a brown solid followed by 3-fluoro-4-(pyridin-4-ylethynyl)benzoic acid (0.813 g, 100.0%) as a pale yellow solid: LRMS (ES) m / z 242.09 [M+H] + , calculated molecular weight 241.22.

[0336] Step 2: N-((1-(Cyclopropylamino)cyclobutyl)methyl)-3-fluoro-4-(pyridin-4-ylethynyl)benzamide Synthesis

[0337]

[0338] In a similar manner to step 3 of Example 1, using 3-fluoro-4-(pyridin-4-ylethynyl)benzoic acid (0.070 g, 0.290 mmol) and 1-(aminomethyl)-N-cyclopropylcyclobutane-1-amine (0.061 g, 0.435 mmol) as starting materials, N-((1-(cyclopropylamino)cyclobutyl)methyl)-3-fluoro-4-(pyridin-4-ylethynyl)benzamide (0.071 g, 67.3%) was obtained as a yellow liquid: LRMS (ES) m / z 364.10 [M+H] + , calculated molecular weight 363.44; 1 H-NMR(400MHz, CD3OD)d 8.57 (dd, J=4.6, 1.8Hz, 2H), 7.73~7.68 (m, 3H), 7.55 (dd, J=4.2, 1.8Hz, 2H), 3.70 (s, 2H), 2.15~2 .07 (m, 3H), 2.03~1.97 (m, 2H), 1.85~1.77 (m, 2H), 0.50 (dt, J=8.8, 3.4Hz, 2H), 0.37~0.33 (m, 2H).

[0339] Example 8: Synthesis of N-((1-(cyclopropylamino)cyclobutyl)methyl)-4-(pyridin-2-ylethynyl)benzamide

[0340]

[0341] In a similar manner to step 3 of Example 1, 1-(aminomethyl)-N-cyclopropylcyclobutane-1-amine (0.066 g, 0.470 mmol) was used as the starting material instead of 1-(aminomethyl)-N-cyclopropylcycloheptane-1-amine to give N-((1-(cyclopropylamino)cyclobutyl)methyl)-4-(pyridin-2-ylethynyl)benzamide (0.071 g, 65.5%) as a yellow liquid: LRMS (ES) m / z 346.18 [M+H] + , calculated molecular weight 345.45; 1 H-NMR(400MHz, CD3OD)d 8.54(d, J=4.4Hz, 1H), 7.89~7.85(m, 3H), 7.69~7.65(m, 3H), 7.44~7.40(m, 1H), 3.70(s, 2H), 2 .13~2.07(m,3H), 2.03~1.97(m,2H), 1.88~1.77(m,2H), 0.53~0.49(m,2H), 0.37~0.33(m,2H).

[0342] Example 9: Synthesis of N-((1-(cyclopropylamino)cyclobutyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide

[0343]

[0344] Step 1: Synthesis of 4-((2-fluorophenyl)ethynyl)benzoic acid

[0345]

[0346] In a similar manner to step 1 of Example 3, 1-ethynyl-2-fluorobenzene (0.500 g, 4.162 mmol) and methyl 4-bromobenzoate (0.940 g, 4.370 mmol) were used as starting materials to give methyl 4-((2-fluorophenyl)ethynyl)benzoate (0.775 g, 73.2%) as a white solid, followed by 4-((2-fluorophenyl)ethynyl)benzoic acid (0.703 g, 96.0%) as a pale yellow solid: LRMS (ES) m / z 239.12 [MH] + , calculated molecular weight 240.23.

[0347] Step 2: Synthesis of N-((1-(cyclopropylamino)cyclobutyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide become

[0348]

[0349] In a similar manner to step 3 of Example 1, using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and 1-(aminomethyl)-N-cyclopropylcyclobutane-1-amine (0.061 g, 0.437 mmol) as starting materials, N-((1-(cyclopropylamino)cyclobutyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide (0.087 g, 82.4%) was obtained as a pale yellow liquid: LRMS (ES) m / z 363.12 [M+H] + , calculated molecular weight 362.45; 1 H-NMR(400MHz, CD3OD)d 7.83 (d, J=11.2Hz, 2H), 7.61 (d, J=10.0Hz, 2H), 7.55 (td, J=7.6, 1.7Hz, 1H), 7.42~7.37 (m, 1H), 7.21~7.15 (m, 2 H), 3.69(s, 2H), 2.14~2.06(m, 3H), 2.03~1.98(m, 2H), 1.85~1.79(m, 2H), 0.52~0.48(m, 2H), 0.36~0.32(m, 2H).

[0350] Example 10: Synthesis of N-((1-(cyclopropylamino)cyclobutyl)methyl)-2-fluoro-4-(pyridin-4-ylethynyl)benzamide

[0351]

[0352] Step 1: Synthesis of 2-fluoro-4-(pyridin-4-ylethynyl)benzoic acid

[0353]

[0354] In a similar manner to step 1 of Example 3, methyl 4-bromo-2-fluorobenzoate (1.000 g, 4.291 mmol) and 4-ethynylpyridine hydrochloride (0.629 g, 4.506 mmol) were used as starting materials to give methyl 2-fluoro-4-(pyridin-4-ylethynyl)benzoate (0.786 g, 71.8%) as a pale yellow solid, followed by 2-fluoro-4-(pyridin-4-ylethynyl)benzoic acid (0.568 g, 77.1%) as a yellow solid: LRMS (ES) m / z 242.16 [M+H] + , calculated molecular weight 241.22.

[0355] Step 2: N-((1-(Cyclopropylamino)cyclobutyl)methyl)-2-fluoro-4-(pyridin-4-ylethynyl)benzamide Synthesis

[0356]

[0357] In a similar manner to step 3 of Example 1, using 2-fluoro-4-(pyridin-4-ylethynyl)benzoic acid (0.070 g, 0.290 mmol) and 1-(aminomethyl)-N-cyclopropylcyclobutane-1-amine (0.061 g, 0.435 mmol) as starting materials, N-((1-(cyclopropylamino)cyclobutyl)methyl)-2-fluoro-4-(pyridin-4-ylethynyl)benzamide (0.082 g, 77.7%) was obtained as a pale yellow liquid: LRMS (ES) m / z 364.17 [M+H] + , calculated molecular weight 363.44; 1 H-NMR(400MHz, CD3OD)d 8.56 (dd, J=4.6, 1.8Hz, 2H), 7.81 (t, J=7.8Hz, 1H), 7.54 (dd, J=4.6, 1.4Hz, 2H), 7.49~7.43 (m, 2H), 3.68 (s, 2H), 2.12~2.04(m, 3H), 2.01~1.94(m, 2H), 1.85~1.77(m, 2H), 0.45~0.46(m, 2H), 0.33~0.30(m, 2H).

[0358] Example 11: Synthesis of N-((1-(cyclopropylamino)cyclopentyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide

[0359]

[0360] 4-((2-Fluorophenyl)ethynyl)benzoic acid (0.300 g, 1.249 mmol), 1-(aminomethyl)-N-cyclopropylcyclopentane-1-amine (0.231 g, 1.499 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.712 g, 1.873 mmol) and N,N-diisopropylethylamine (1.088 mL, 6.244 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to give N-((1-(cyclopropylamino)cyclopentyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide (0.230 g, 48.9%) as a yellow solid: LRMS (ES) m / z 377.32 [M+H] + , calculated molecular weight 376.48; 1H-NMR(400MHz, CD3OD)d 7.85 (dt, J=8.0, 1.8Hz, 2H), 7.62 (d, J=6.4Hz, 2H), 7.57~7.53 (m, 1H), 7.43~7.38 (m, 1H), 7.21~ 7.15(m, 2H), 3.57(s, 2H), 2.24(m, 1H), 1.74~1.67(m, 8H), 0.59~0.51(m, 2H), 0.41~0.37(m, 2H).

[0361] Example 12: Synthesis of N-((1-(cyclopropylamino)cycloheptyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide

[0362]

[0363] In a similar manner to Example 11, 4-((2-fluorophenyl)ethynyl)benzoic acid (0.066 g, 0.274 mmol) and 1-(aminomethyl)-N-cyclopropylcycloheptane-1-amine (0.050 g, 0.274 mmol) were used as starting materials to give N-((1-(cyclopropylamino)cycloheptyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide (0.040 g, 36.1%) as a white solid: LRMS (ES) m / z 405.20 [M+H] + , calculated molecular weight 404.53; 1 H-NMR (400MHz, CD3OD) d7.84 (d, J=8.4Hz, 2H), 7.61 (d, J=8.0Hz, 3H), 7.40 (m, 1H), 7.21 ~7.15 (m, 2H), 3.47 (s, 2H), 2.17 (m, 1H), 1.77 ~ 1.49 (m, 12H), 0.49 (m, 2H), 0.34 (m, 2H).

[0364] Example 13: Synthesis of N-((1-(cyclopropylamino)cyclopentyl)methyl)-4-((4-fluorophenyl)ethynyl)benzamide

[0365]

[0366] In a similar manner to Example 11, 4-((4-fluorophenyl)ethynyl)benzoic acid (0.078 g, 0.324 mmol) was used as the starting material instead of 4-((2-fluorophenyl)ethynyl)benzoic acid to give N-((1-(cyclopropylamino)cyclopentyl)methyl)-4-((4-fluorophenyl)ethynyl)benzamide (0.045 g, 36.9%) as a white solid: LRMS (ES) m / z 377.13 [M+H] +, calculated molecular weight 376.48; 1 H-NMR(400MHz, CD3OD)d 7.84~7.82(m, 2H), 7.60~7.52(m, 4H), 7.15~7.10(m, 2H), 3.56(s, 2H), 2. 20~2.17(m,1H), 1.75~1.62(m,8H), 0.52~0.49(m,2H), 0.37~0.33(m,2H).

[0367] Example 14: Synthesis of N-((1-(cyclopropylamino)cycloheptyl)methyl)-4-((4-fluorophenyl)ethynyl)benzamide

[0368]

[0369] In a similar manner to Example 11, 4-((4-fluorophenyl)ethynyl)benzoic acid (0.066 g, 0.274 mmol) and 1-(aminomethyl)-N-cyclopropylcycloheptane-1-amine (0.050 g, 0.274 mmol) were used as starting materials to give N-((1-(cyclopropylamino)cycloheptyl)methyl)-4-((4-fluorophenyl)ethynyl)benzamide (0.035 g, 31.5%) as a yellow solid: LRMS (ES) m / z 405.20 [M+H] + , calculated molecular weight 404.53; 1 H-NMR(400MHz, CD3OD)d 7.82(dd, J=6.8, 2.0Hz, 2H), 7.60~7.53(m, 4H), 7.15~7.10(m, 2H), 3.46(s, 2H), 2.16(m, 1H), 1.78~1.45(m, 12H), 0.50~0.46(m, 2H), 0.35~0.33(m, 2H).

[0370] Example 15: Synthesis of N-((1-(cyclopropylamino)cycloheptyl)methyl)-4-((5-fluoropyridin-2-yl)ethynyl)benzamide

[0371]

[0372] In a similar manner to Example 11, 4-((5-fluoropyridin-2-yl)ethynyl)benzoic acid (0.066 g, 0.274 mmol) and 1-(aminomethyl)-N-cyclopropylcycloheptane-1-amine (0.050 g, 0.274 mmol) were used as starting materials to give N-((1-(cyclopropylamino)cycloheptyl)methyl)-4-((5-fluoropyridin-2-yl)ethynyl)benzamide (0.050 g, 45.0%) as a white solid: LRMS (ES) m / z 406.39 [M+H] + , calculated molecular weight 405.52; 1 H-NMR(400MHz, CD3OD)d 8.48 (d, J=2.8Hz, 1H), 7.86 (d, J=8.0Hz, 2H), 7.71~7.66 (m, 4H), 3.47 (s, 2 H), 2.17 (m, 1H), 1.78~1.26 (m, 12H), 0.50~0.47 (m, 2H), 0.35~0.33 (m, 2H).

[0373] Example 16: Synthesis of N-((1-(cyclopropylamino)cycloheptyl)methyl)-4-((3-fluoropyridin-4-yl)ethynyl)benzamide

[0374]

[0375] Step 1: Synthesis of 4-((3-fluoropyridin-4-yl)ethynyl)benzoic acid

[0376]

[0377] Methyl 4-ethynylbenzoate (2.000 g, 12.487 mmol) and 3-fluoro-4-iodopyridine (2.784 g, 12.487 mmol) were used in a similar manner to step 1 of Example 3 to give methyl 4-((3-fluoropyridin-4-yl)ethynyl)benzoate (2.300 g, 72.2%) as a yellow solid followed by 4-((3-fluoropyridin-4-yl)ethynyl)benzoic acid (2.150 g, 98.9%) as a beige solid: LRMS (ES) m / z 242.09 [M+H] + , calculated molecular weight 241.22.

[0378] Step 2: N-((1-(cyclopropylamino)cycloheptyl)methyl)-4-((3-fluoropyridin-4-yl)ethynyl)benzoyl Synthesis of amines

[0379]

[0380] In a similar manner to Example 11, 4-((3-fluoropyridin-4-yl)ethynyl)benzoic acid (0.066 g, 0.274 mmol) and 1-(aminomethyl)-N-cyclopropylcycloheptane-1-amine (0.050 g, 0.274 mmol)) were used as starting materials to give N-((1-(cyclopropylamino)cycloheptyl)methyl)-4-((3-fluoropyridin-4-yl)ethynyl)benzamide (0.040 g, 36.0%) as a pale yellow solid: LRMS (ES) m / z 406.18 [M+H] + , calculated molecular weight 405.52; 1 H-NMR(400MHz, CD3OD)d 8.55 (d, J=1.6Hz, 1H), 8.41 (d, J=5.2Hz, 1H), 7.88 (d, J=8.4Hz, 2H), 7.69 (d, J=8.4Hz, 2H), 7.6 3(m,1H), 3.48(s,2H), 2.19(m,1H), 1.75~1.43(m,12H), 0.52~0.48(m,2H), 0.37~0.33(m,2H).

[0381] Example 17: Synthesis of N-((1-(cyclopropylamino)cyclopentyl)methyl)-4-((3,4-difluorophenyl)ethynyl)benzamide

[0382]

[0383] Step 1: Synthesis of 4-(3,4-difluorophenyl)ethynyl)benzoic acid

[0384]

[0385] In a similar manner to step 1 of Example 3, 4-bromo-1,2-difluorobenzene (1.325 g, 6.868 mmol) was used instead of 2-bromo-5-fluoropyridine to give methyl 4-((3,4-difluorophenyl)ethynyl)benzoate (0.300 g, 17.6%) as a white solid followed by 4-((3,4-difluorophenyl)ethynyl)benzoic acid (0.280 g, 98.4%) as a white solid: LRMS (ES) m / z 257.05 [MH] + , calculated molecular weight 258.22.

[0386] Step 2: N-((1-(cyclopropylamino)cyclopentyl)methyl)-4-((3,4-difluorophenyl)ethynyl)benzamide Synthesis

[0387]

[0388] In a similar manner to Example 11, 4-((3,4-difluorophenyl)ethynyl)benzoic acid (0.084 g, 0.324 mmol) and 1-(aminomethyl)-N-cyclopropylcyclopentane-1-amine (0.050 g, 0.324 mmol) were used as starting materials to give N-((1-(cyclopropylamino)cyclopentyl)methyl)-4-((3,4-difluorophenyl)ethynyl)benzamide (0.030 g, 23.5%) as a pale yellow solid: LRMS (ES) m / z 395.19 [M+H] + , calculated molecular weight 394.47; 1 H-NMR(400MHz, CD3OD)d 7.85~7.82(m, 2H), 7.61~7.59(m, 2H), 7.47(m, 1H), 7.38~7.28(m, 2H), 3.56(s, 2 H), 2.19~2.17(m, 1H), 1.88~1.62(m, 8H), 0.51~0.49(m, 2H), 0.37~0.34(m, 2H).

[0389] Example 18: Synthesis of N-((1-(cyclopropylamino)cycloheptyl)methyl)-4-((3,4-difluorophenyl)ethynyl)benzamide

[0390]

[0391] In a similar manner to Example 11, 4-((3,4-difluorophenyl)ethynyl)benzoic acid (0.071 g, 0.274 mmol) and 1-(aminomethyl)-N-cyclopropylcycloheptane-1-amine (0.050 g, 0.274 mmol) were used as starting materials to give N-((1-(cyclopropylamino)cycloheptyl)methyl)-4-((3,4-difluorophenyl)ethynyl)benzamide (0.030 g, 25.9%) as a pale yellow solid: LRMS (ES) m / z 423.40 [M+H] + , calculated molecular weight 422.52; 1 H-NMR(400MHz, CD3OD)d 7.84~7.82(m, 2H), 7.61~7.60(m, 2H), 7.46(m, 1H), 7.34~7.28(m, 2H), 3.46(s, 2 H), 2.17~2.16(m, 1H), 1.78~1.25(m, 12H), 0.49~0.48(m, 2H), 0.35~0.33(m, 2H).

[0392] Example 19: Synthesis of N-((1-(cyclopropylamino)cyclohexyl)methyl)-4-((4-fluorophenyl)ethynyl)benzamide

[0393]

[0394] Step 1: Synthesis of 1-(aminomethyl)-N-cyclopropylcyclohexane-1-amine

[0395]

[0396] Cyclohexanone (2.112 mL, 20.377 mmol) was used in a similar manner to step 2 of Example 1 to replace cycloheptanone to give 1-(aminomethyl)-N-cyclopropylcyclohexane-1-amine (2.921 g, 96.0%, white oil): LRMS (ES) m / z 169.11 [M+H] + , calculated molecular weight 168.28.

[0397] Step 2: Synthesis of N-((1-(cyclopropylamino)cyclohexyl)methyl)-4-((4-fluorophenyl)ethynyl)benzamide become

[0398]

[0399] In a similar manner to step 3 of Example 1, using 4-((4-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and 1-(aminomethyl)-N-cyclopropylcyclohexane-1-amine (0.074 g, 0.437 mmol) as starting materials, N-((1-(cyclopropylamino)cyclohexyl)methyl)-4-((4-fluorophenyl)ethynyl)benzamide (0.078 g, 68.5%) was obtained as a white solid: LRMS (ES) m / z 391.31 [M+H] + , calculated molecular weight 390.5; 1 H-NMR (400MHz, CD3OD) d7.87~7.76(m, 2H), 7.63~7.49(m, 4H), 7.18~7.07(m, 2H), 3.55(t, J =14.8Hz, 2H), 2.22~2.12(m, 1H), 1.58~1.37(m, 10H), 0.54~0.42(m, 2H), 0.37~0.28(m, 2H).

[0400] Example 20: Synthesis of N-((1-(cyclopropylamino)cyclohexyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide

[0401]

[0402] In a similar manner to step 3 of Example 1, using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and 1-(aminomethyl)-N-cyclopropylcyclohexane-1-amine (0.074 g, 0.437 mmol) as starting materials, N-((1-(cyclopropylamino)cyclohexyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide (0.067 g, 58.9%) was obtained as a white solid: LRMS (ES) m / z 391.31 [M+H] + , calculated molecular weight 390.5; 1 H-NMR (400MHz, CD3OD) d7.85~7.79 (m, 2H), 7.63~7.60 (m, 2H), 7.57~7.53 (m, 1H), 7.41~7.39 (m, 1H), 7.25~7.1 3 (m, 2H), 3.55 (t, J=15.0Hz, 2H), 2.23~2.13 (m, 1H), 1.61~1.44 (m, 10H), 0.53~0.42 (m, 2H), 0.40~0.30 (m, 2H).

[0403] Example 21: Synthesis of N-((1-(cyclopropylamino)cyclopentyl)methyl)-4-((2-methylpyridin-4-yl)ethynyl)benzamide

[0404]

[0405] Step 1: Synthesis of 4-((2-methylpyridin-4-yl)ethynyl)benzoic acid

[0406]

[0407] In a similar manner to step 1 of Example 3, methyl 4-ethynylbenzoate (0.400 g, 2.497 mmol) and 4-bromo-2-methylpyridine (0.473 g, 2.747 mmol) were used as starting materials to give methyl 4-((2-methylpyridin-4-yl)ethynyl)benzoate (0.531 g, 84.6%) as a pale yellow solid followed by 4-((2-methylpyridin-4-yl)ethyl)benzoic acid (0.337 g, 89.2%) as a cream solid: LRMS (ES) m / z 238.06 [M+H] + , calculated molecular weight 237.26.

[0408] Step 2: N-((1-(cyclopropylamino)cyclopentyl)methyl)-4-((2-methylpyridin-4-yl)ethynyl)benzyl Synthesis of acyl wall

[0409]

[0410] In a similar manner to Example 11, 4-((2-methylpyridin-4-yl)ethyl)benzoic acid (0.046 g, 0.194 mmol) was used instead of 4-((2-fluorophenyl)ethynyl)benzoic acid to give N-((1-(cyclopropylamino)cyclopentyl)methyl)-4-((2-methylpyridin-4-yl)ethynyl)benzamide (0.020 g, 27.5%) as a yellow oil: LRMS (ES) m / z 374.21 [M+H] + , calculated molecular weight 373.5; 1 H-NMR(400MHz, CD3OD)d 8.41(d, J=4.8Hz, 1H), 7.88~7.85(m, 2H), 7.66(m, 2H), 7.42(s, 1H), 7.34~7.33(m, 1H), 3.57(s , 2H), 2.53(s, 3H), 2.21~2.20(m, 1H), 1.78~1.66(m, 8H), 0.52~0.49(m, 2H), 0.38~0.36(m, 2H).

[0411] Example 22: Synthesis of N-((4-(cyclopropylamino)tetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide

[0412]

[0413] Step 1: Synthesis of 4-(aminomethyl)-N-cyclopropyltetrahydro-2H-pyran-4-amine

[0414]

[0415] In a similar manner to Step 2 of Example 1, tetrahydro-4H-pyran-4-one (8.767 g, 87.566 mmol) was used instead of cycloheptanone to give 4-(cyclopropylamino)tetrahydro-2H-pyran-4-carbonitrile (12.000 g, 82.4%, colorless oil), and the resulting product was then used without purification to give 4-(aminomethyl)-N-cyclopropyltetrahydro-2H-pyran-4-amine (5.100 g, 91.2%) as a colorless oil: LRMS (ES) m / z 171.09 [M+H] + , calculated molecular weight 170.26.

[0416] Step 2: N-((4-(cyclopropylamino)tetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl)ethynyl) Synthesis of Benzamide

[0417]

[0418] Using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.282 g, 1.175 mmol) and 4-(aminomethyl)-N-cyclopropyltetrahydro-2H-pyran-4-amine (0.200 g, 1.175 mmol) in a manner similar to Example 11, N-((4-(cyclopropylamino)tetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide (0.230 g, 49.9%) was obtained as a white solid: LRMS (ES) m / z 393.09 [M+H] + , calculated molecular weight 392.47; 1 H-NMR (400MHz, CD3OD) d7.84 (d, J=8.4Hz, 2H), 7.61 (d, J=8.4Hz, 2H), 7.55 (m, 1H), 7.39 (m, 1H), 7.21~7.15 (m, 2H), 3.77~ 3.75(m, 2H), 3.68~3.62(m, 2H), 3.61(s, 2H), 2.23~2.20(m, 1H), 1.70~1.63(m, 4H), 0.51~0.46(m, 2H), 0.35~0.32(m, 2H).

[0419] Example 23: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((1-morpholinocyclopentyl)methyl)benzamide

[0420]

[0421] Step 1: Synthesis of (1-morpholinocyclopentyl)methylamine

[0422]

[0423] Cyclopentanone (3.000 mL, 33.880 mmol) and morpholine (3.810 mL, 44.044 mmol) were used as starting materials in a similar manner to step 2 of Example 1 to give 1-morpholinocyclopentane-1-carbonitrile (5.510 g, 90.2%) as a white solid, followed by (1-morpholinocyclopentyl)methanamine (5.500 g, 97.6%, light yellow liquid): LRMS (ES) m / z 185.09 [M+H] + , calculated molecular weight 184.28.

[0424] Step 2: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((1-morpholinocyclopentyl)methyl)benzamide

[0425]

[0426] In a similar manner to Example 11, 4-((2-fluorophenyl)ethynyl)benzoic acid (0.091 g, 0.380 mmol) and (1-morpholinocyclopentyl)methanamine (0.070 g, 0.380 mmol) were used as starting materials to give 4-((2-fluorophenyl)ethynyl)-N-((1-morpholinocyclopentyl)methyl)benzamide (0.020 g, 13.0%) as a colorless oil: LRMS (ES) m / z 407.10 [M+H] + , calculated molecular weight 406.5; 1 H-NMR(400MHz, DMSO-d6)d 8.21 (t, J=6.2Hz, 1H), 7.84 (d, J=8.4Hz, 2H), 7.65~7.63 (m, 3H), 7.48 (m, 1H), 7.3 3 (m, 1H), 7.25 (m, 1H), 3.50~3.48 (m, 4H), 3.37 (m, 2H), 2.58 (m, 4H), 1.60 (m, 8H).

[0427] Example 24: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((4-(isopropylamino)tetrahydro-2H-pyran-4-yl)methyl)benzamide

[0428]

[0429] Step 1: Synthesis of 4-(aminomethyl)-N-isopropyltetrahydro-2H-pyran-4-amine

[0430]

[0431] Propan-2-amine (2.060 mL, 23.971 mmol) and tetrahydro-4H-pyran-4-one (1.845 mL, 19.976 mmol) were used in a similar manner to step 2 of Example 1 to give 4-(isopropylamino)tetrahydro-2H-pyran-4-carbonitrile (2.108 g, 62.7%) followed by 4-(aminomethyl)-N-isopropyltetrahydro-2H-pyran-4-amine (2.100 g, 97.6%, cream solid): LRMS (ES) m / z 173.07 [M+H] + , calculated molecular weight 172.27.

[0432] Step 2: 4-((2-fluorophenyl)ethynyl)-N-((4-(isopropylamino)tetrahydro-2H-pyran-4-yl)methyl) Synthesis of Benzamide

[0433]

[0434] In a similar manner to Example 11 using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.100 g, 0.416 mmol) and 4-(aminomethyl)-N-isopropyltetrahydro-2H-pyran-4-amine (0.086 g, 0.500 mmol)) as starting materials, 4-((2-fluorophenyl)ethynyl)-N-((4-(isopropylamino)tetrahydro-2H-pyran-4-yl)methyl)benzamide (0.018 g, 11.0%) was obtained as a yellow liquid: 1 H-NMR(400MHz, CD3OD)d 7.87~7.83 (m, 2H), 7.63~7.60 (m, 2H), 7.57~7.53 (m, 1H), 7.43~7.38 (m, 1H), 7.21~7.15 (m, 2H), 3.83~3.7 9 (m, 2H), 3.74~3.71 (m, 1H), 3.69~3.63 (m, 2H), 3.55 (s, 2H), 1.65 (t, J=5.4Hz, 4H), 1.11 (d, J=6.4Hz, 6H).

[0435] Example 25: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((1-(isopropylamino)cyclohexyl)methyl)benzamide

[0436]

[0437] Step 1: Synthesis of 1-(aminomethyl)-N-isopropylcyclohexane-1-amine

[0438]

[0439] In a similar manner to step 2 of Example 1, propane-2-amine (2.000 g, 33.835 mmol) and cyclohexanone (3.321 g, 33.835 mmol) were used as starting materials to give 1-(aminomethyl)-N-isopropylcyclohexane-1-amine (3.000 g, 93.6%, colorless oil): LRMS (ES) m / z 171.09 [M+H] + , calculated molecular weight 170.3.

[0440] Step 2: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((1-(isopropylamino)cyclohexyl)methyl)benzamide become

[0441]

[0442] In a similar manner to Example 11, 4-((2-fluorophenyl)ethynyl)benzoic acid (0.099 g, 0.411 mmol) and 1-(aminomethyl)-N-isopropylcyclohexane-1-amine (0.070 g, 0.411 mmol) were used as starting materials to give 4-((2-fluorophenyl)ethynyl)-N-((1-(isopropylamino)cyclohexyl)methyl)benzamide (0.085 g, 52.7%) as a colorless oil: LRMS (ES) m / z 393.23 [M+H] + , calculated molecular weight 392.52; 1 H-NMR(400MHz, CD3OD)d 7.85(d, J=8.4Hz, 2H), 7.64~7.61(m, 2H), 7.65(m, 1H), 7.38~7.43(m, 1H), 7. 21~7.15 (m, 2H), 3.46 (s, 2H), 1.65~1.35 (m, 11H), 1.14 (s, 3H), 1.13 (s, 3H).

[0443] Example 26: Synthesis of N-((1-(cyclopropylamino)-4-methylcyclohexyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide

[0444]

[0445] Step 1: Synthesis of 1-(aminomethyl)-N-cyclopropyl-4-methylcyclohexane-1-amine

[0446]

[0447] In a similar manner to Step 2 of Example 1, 4-methylcyclohexane-1-one (1.000 mL, 6.865 mmol) was used instead of cycloheptanone to give 1-(cyclopropylamino)-4-methylcyclohexane-1-carbonitrile (1.098 g, 89.7%) as a pale yellow liquid, followed by 1-(aminomethyl)-N-cyclopropyl-4-methylcyclohexane-1-amine (0.936 g, 83.4%, pale yellow liquid): LRMS (ES) m / z 183.12 [M+H] + , calculated molecular weight 182.31.

[0448] Step 2: N-((1-(cyclopropylamino)4-methylcyclohexyl)methyl)-4-((2-fluorophenyl)ethynyl)benzoyl Synthesis of amines

[0449]

[0450] In a similar manner to step 3 of Example 1, using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.100 g, 0.416 mmol) and 1-(aminomethyl)-N-cyclopropyl-4-methylcyclohexane-1-amine (0.114 g, 0.624 mmol) as starting materials, N-((1-(cyclopropylamino)-4-methylcyclohexyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide (0.065 g, 38.6%) was obtained as a yellow solid: LRMS (ES) m / z 405.26 [M+H] + , calculated molecular weight 404.53; 1 H-NMR(400MHz, CD3OD)d 7.84 (dt, J=8.8, 2.3Hz, 2H), 7.61 (dt, J=8.0, 1.8Hz, 2H), 7.55 (td, J=7.4, 1. 5Hz, 1H), 7.53~7.38(m, 1H), 7.21~7.15(m, 2H), 3.64(s, 2H), 2.26~2.18(m, 1H) ), 1.78 (d, J=13.2Hz, 2H), 1.60 (dd, J=13.6, 3.2Hz, 2H), 1.51~1.37 (m, 3H), 1. 25~1.18 (m, 2H), 0.93 (d, J=6.4Hz, 3H), 0.52~0.47 (m, 2H), 0.35~0.31 (m, 2H).

[0451] Example 27: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide

[0452]

[0453] In a similar manner to step 3 of Example 1, using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (0.050 g, 0.437 mmol) as starting materials, 4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide (0.075 g, 76.3%) was obtained as a white solid: LRMS (ES) m / z 338.21 [M+H] + , calculated molecular weight 337.39; 1H-NMR(400MHz, CD3OD)d 7.82 (d, J=8.8Hz, 2H), 7.60 (d, J=8.8Hz, 2H), 7.55 (t, J=7.6Hz, 1H), 7.45~7.37 (m, 1H), 7.21~7.14 (m, 2H), 3.93 (dd , J=11.2, 4.0Hz, 2H), 3.39 (t, J=11.8Hz, 2H), 3.28~3.26 (m, 2H), 1.90~1.86 (m, 1H), 1.69 (s, 2H), 1.37~1.27 (m, 2H).

[0454] Example 28: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((1-(neopentylamino)cyclohexyl)methyl)benzamide

[0455]

[0456] Step 1: Synthesis of 1-(aminomethyl)-N-neopentylcyclohexane-1-amine

[0457]

[0458] Using 2,2-dimethylpropane-1-amine (2.861 mL, 24.452 mmol) and cyclohexanone (2.105 mL, 20.377 mmol) as starting materials in a manner similar to Step 2 of Example 1, 1-(neopentylamino)cyclohexane-1-carbonitrile (3.600 g, 90.9%) was obtained as a clear liquid, followed by 1-(aminomethyl)-N-neopentylcyclohexane-1-amine (3.200 g, 87.1%, white solid): LRMS (ES) m / z 199.23 [M+H]+, calculated molecular weight 198.35.

[0459] Step 2: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((1-(neopentylamino)cyclohexyl)methyl)benzamide become

[0460]

[0461] 4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and 1-(aminomethyl)-N-neopentylcyclohexane-1-amine (0.087 g, 0.437 mmol) were used in a manner similar to step 3 of Example 1 to give 4-((2-fluorophenyl)ethynyl)-N-((1-(neopentylamino)cyclohexyl)methyl)benzamide (0.119 g, 97.1%) as a pale yellow solid: LRMS (ES) m / z 421.30 [M+H] + , calculated molecular weight 420.57; 1H-NMR(400MHz, CD3OD)d 7.80~7.78(m, 2H), 7.62~7.60(m, 2H), 7.56~7.53(m, 1H), 7.42~7.38(m, 1H), 7 .21~7.14(m,2H), 3.33(s,2H), 2.30(s,2H), 1.60~1.37(m,10H), 0.91(s,9H).

[0462] Example 29: Synthesis of N-((4-(cyclopropylmethyl)tetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide

[0463]

[0464] Step 1-1: Synthesis of 4-(cyclopropylmethyl)tetrahydro-2H-pyran-4-carbonitrile

[0465]

[0466] To a solution of tetrahydro-2H-pyran-4-carbonitrile (3.333g, 29.989mmol) dissolved in tetrahydrofuran (65mL) at -78°C, bis(trimethylsilyl)lithium amide (1.30M solution in THF, 25.375mL, 32.988mmol) was added, and the reaction mixture was stirred at the same temperature for 1 hour. (Bromomethyl)cyclopropane (3.490mL, 35.987mmol) was added to the reaction mixture and further stirred at room temperature for 12 hours. Saturated aqueous ammonium chloride solution was poured into the reaction mixture and subsequently extracted with hexane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to obtain 4-(cyclopropylmethyl)tetrahydro-2H-pyran-4-carbonitrile (4.600g, 92.8%) as a pale yellow liquid: 1 H-NMR(400MHz, CDCl3)d 7.55 (d, J=3.6Hz, 2H), 7.33 (bs, 1H), 7.46 (s, 2H), 5.52 (d, J=5.2Hz, 1H), 2.08 (s, 3H), 1.4 1(s, 9H), 1.35~1.34(m, 1H), 1.34(d, J=1.6Hz, 1H), 0.88(m, 1H), 0.76(m, 1H), 0.65(m, 1H).

[0467] Step 1-2: Synthesis of (4-(cyclopropylmethyl)tetrahydro-2H-pyran-4-yl)methanamine hydrochloride

[0468]

[0469] To a solution of 4-(cyclopropylmethyl)tetrahydro-2H-pyran-4-carbonitrile (4.600 g, 27.838 mmol) dissolved in tetrahydrofuran (200 mL) at 0° C., lithium aluminum hydride (2.40 M solution in THF, 25.518 mL, 61.244 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. Then, water (3.010 mL, 167.030 mmol) was poured into the reaction mixture at room temperature and stirred for 30 minutes to terminate the reaction: 1 H-NMR (400MHz, CDCl3)d 4.24~4.23 (m, 1H), 3.12, 3.12 (ABq, J=0.7, 0.4Hz, 2H), 3.12 (q, J=0.4Hz, 2H), 1.83 (t, J=0.4Hz, 1H).

[0470] To a solution of the obtained (4-(cyclopropylmethyl)tetrahydro-2H-pyran-4-yl)methylamine (4.000 g, 23.631 mmol) dissolved in methanol (200 mL) was added hydrogen chloride (1.00 M solution in ethyl acetate, 47.262 mL, 47.262 mmol) at 0°C, and the reaction mixture was stirred at the same temperature for 10 minutes. After the solvent was removed from the reaction mixture under reduced pressure, ethyl acetate (200 mL) was added to the concentrate and stirred. The precipitated solid was filtered and washed with hexane to obtain (4-(cyclopropylmethyl)tetrahydro-2H-pyran-4-yl)methylamine hydrochloride (2.490 g, 51.2%) as a white solid.

[0471] Step 2: N-((4-(cyclopropylmethyl)tetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl)ethynyl) Synthesis of Benzamide

[0472]

[0473] In a similar manner to step 3 of Example 1, using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.100 g, 0.416 mmol) and (4-(cyclopropylmethyl)tetrahydro-2H-pyran-4-yl)methanamine hydrochloride (0.127 g, 0.624 mmol) as starting materials, N-((4-(cyclopropylmethyl)tetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide (0.010 g, 6.1%) was obtained as a white solid: LRMS (ES) m / z 392.24 [M+H] + , calculated molecular weight 391.49; 1H-NMR(400MHz, CD3OD)d 7.82 (d, J=0.4Hz, 2H), 7.61 (d, J=8.4Hz, 2H), 7.55 (td, J=7.5, 1.5Hz, 1H), 7.43~7.37 (m, 1H), 7.21~7.15 (m, 2H), 3.77~3.75 (m, 2H), 3.68~3.64(m, 2H), 1.64~1.55(m, 5H), 1.41~1.39(m, 3H), 0.82~0.76(m, 1H), 0.50~0.48(m, 2H), 0.09~0.05(m, 2H).

[0474] Example 30: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((1-(isopropylamino)cyclopentyl)methyl)benzamide

[0475]

[0476] Step 1: Synthesis of 1-(aminomethyl)-N-isopropylcyclopentane-1-amine

[0477]

[0478] In a similar manner to step 2 of Example 1, propane-2-amine (3.504 mL, 42.796 mmol) and cyclopentanone (3.155 mL, 35.663 mmol) were used as starting materials to give 1-(isopropylamino)cyclopentane-1-carbonitrile (2.618 g, 48.2%) as a white solid, followed by 1-(aminomethyl)-N-isopropylcyclopentane-1-amine (2.600 g, 96.8%, white solid): LRMS (ES) m / z 157.07 [M+H] + , calculated molecular weight 156.27.

[0479] Step 2: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((1-(isopropylamino)cyclopentyl)methyl)benzamide become

[0480]

[0481] In a similar manner to step 3 of Example 1, using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and 1-(aminomethyl)-N-isopropylcyclopentane-1-amine (0.068 g, 0.437 mmol) as starting materials, 4-((2-fluorophenyl)ethynyl)-N-((1-(isopropylamino)cyclopentyl)methyl)benzamide (0.018 g, 16.3%) was obtained as a white solid: LRMS (ES) m / z 379.30 [M+H] + , calculated molecular weight 378.49; 1H-NMR(400MHz, CD3OD)d 7.85(dd, J=8.2, 1.8Hz, 2H), 7.62(dd, J=8.2, 1.4Hz, 2H), 7.55~7.53(m, 1H), 7.43~7.38(m , 1H), 7.21~7.15(m, 2H), 3.47(s, 2H), 3.08(m, 1H), 1.74~1.65(m, 8H), 1.12~1.10(m, 6H).

[0482] Example 31: Synthesis of 4-(pyridin-4-ylethynyl)-N-((1-((2,2,2-trifluoroethyl)amino)cyclohexyl)methyl)benzamide

[0483]

[0484] Step 1: Synthesis of 1-(aminomethyl)-N-(2,2,2-trifluoroethyl)cyclohexane-1-yl

[0485]

[0486] In a similar manner to step 2 of Example 1, cyclohexanone (3.000 g, 30.565 mmol) and 2,2,2-trifluoroethane-1-amine (3.633 g, 36.679 mmol) were used as starting materials to give 1-(aminomethyl)-N-(2,2,2-trifluoroethyl)cyclohexane-1-amine (3.230 g, 94.3%, white solid): LRMS (ES) m / z 211.12 [M+H] + , calculated molecular weight 210.24.

[0487] Step 2: 4-(Pyridin-4-ylethynyl)-N-((1-((2,2,2-trifluoroethyl)amino)cyclohexyl)methyl)benzene Synthesis of formamide

[0488]

[0489] In a similar manner to step 3 of Example 1, using 4-(pyridin-4-ylethynyl)benzoic acid (0.070 g, 0.314 mmol) and 1-(aminomethyl)-N-(2,2,2-trifluoroethyl)cyclohexane-1-amine (0.099 g, 0.470 mmol) as starting materials, 4-(pyridin-4-ylethynyl)-N-((1-((2,2,2-trifluoroethyl)amino)cyclohexyl)methyl)benzamide (0.060 g, 46.1%) was obtained as a white solid: LRMS (ES) m / z 416.29 [M+H] + , calculated molecular weight 415.46; 1H-NMR(400MHz, CD3OD)d 8.56~8.54 (m, 2H), 7.83 (d, J=8.4Hz, 2H), 7.66 (d, J=8.4Hz, 2H), 7.54~7.53 (m, 2H), 3.36 (s, 2H), 3.27~3.20 (m, 2H), 1.66~1.31 (m, 10H).

[0490] Example 32: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((1-hydroxycyclohexyl)methyl)benzamide

[0491]

[0492] Step 1: Synthesis of 1-(aminomethyl)cyclohexane-1-ol

[0493]

[0494] In a similar manner to step 2 of Example 1, but using cyclohexanone alone (3.000 g, 30.565 mmol) instead of cyclopropylamine and cycloheptanone, 1-hydroxycyclohexane-1-carbonitrile (3.400 g, 88.9%, colorless oil) and then 1-(aminomethyl)cyclohexane-1-ol (2.750 g, 98.7%, colorless oil) were obtained: LRMS (ES) m / z 129.99 [M+H] + , calculated molecular weight 129.2.

[0495] Step 2: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((1-hydroxycyclohexyl)methyl)benzamide

[0496]

[0497] In a similar manner to Example 11, 1-(aminomethyl)cyclohexan-1-ol (0.200 g, 1.548 mmol) was used instead of 1-(aminomethyl)-N-cyclopropylcyclopentane-1-amine to give 4-((2-fluorophenyl)ethynyl)-N-((1-hydroxycyclohexyl)methyl)benzamide (0.350 g, 64.3%) as a yellow solid: LRMS (ES) m / z 352.15 [M+H] + , calculated molecular weight 351.42; 1 H-NMR(400MHz, DMSO-d6)d 8.27 (t, J=5.6Hz, 1H), 7.88 (m, 2H), 7.65~7.61 (m, 3H), 7.47 (m, 1H), 7.43 (t, J=23.4Hz , 1H), 7.28 (t, J=14.8Hz, 1H), 4.33 (s, 1H), 3.24 (d, J=6.0Hz, 2H), 1.53~1.15 (m, 10H).

[0498] Example 33: Synthesis of 4-((4-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide

[0499]

[0500] In a similar manner to step 3 of Example 1, 4-((4-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (0.050 g, 0.437 mmol) were used as starting materials to give 4-((4-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide (0.073 g, 74.3%) as a white solid: LRMS (ES) m / z 338.15 [M+H] + , calculated molecular weight 337.39; 1 H-NMR(400MHz, CD3OD)d 7.80 (d, J=8.4Hz, 2H), 7.58~7.53 (m, 4H), 7.12 (t, J=9.0Hz, 2H), 3.93 (dd, J=11.6, 2.8Hz, 2H), 3.39 (td, J =11.7, 2.0Hz, 2H), 3.31~3.25(m, 2H), 1.94~1.83(m, 1H), 1.66(dd, J=13.4, 1.8Hz, 2H), 1.37~1.27(m, 2H).

[0501] Example 34: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((1-(pyridin-3-yl)cyclopentyl)methyl)benzamide

[0502]

[0503] Step 1-1: Synthesis of 1-(pyridin-3-yl)cyclopentane-1-carbonitrile

[0504]

[0505] To a stirred solution of sodium hydride (NaH, 60.00%, 0.745 g, 18.622 mmol) in dimethyl sulfoxide (15 mL) / diethyl ether (5 mL) at 0°C was added 2-(pyridin-3-yl)acetonitrile (1.000 g, 8.465 mmol). The reaction mixture was stirred at the same temperature for 0.5 h, treated with 1,4-dibromobutane (1.828 g, 8.465 mmol) at room temperature, stirred for another 1 h, and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium chloride solution, separated, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed and concentrated to give 1-(pyridin-3-yl)cyclopentane-1-carbonitrile (0.387 g, 26.5%) as a pink oil: LRMS (ES) m / z 173.00 [M+H] + , calculated molecular weight 172.23.

[0506] Step 1-2: Synthesis of (1-(pyridin-3-yl)cyclopentyl)methanamine

[0507]

[0508] 1-(Pyridin-3-yl)cyclopentane-1-carbonitrile (0.378g, 2.195mmol) and lithium aluminum hydride (2.40M solution, 1.829mL, 4.389mmol) were dissolved in ether (50mL), and the resulting solution was stirred at 0°C for 0.5 hours and further stirred at room temperature for 18 hours. Then, sodium hydroxide (NaOH) (1.00M aqueous solution, 1.097mL, 1.097mmol) and water (0.237mL, 13.168mmol) were added to the reaction mixture and stirred for 30 minutes to terminate the reaction at room temperature. Water was poured into the reaction mixture and subsequently extracted with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained product was used without further purification ((1-(pyridin-3-yl)cyclopentyl)methanamine, 0.222 g, 57.4%, yellow liquid): LRMS (ES) m / z 177.02 [M+H] + , calculated molecular weight 176.26.

[0509] Step 2: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((1-(pyridin-3-yl)cyclopentyl)methyl)benzamide become

[0510]

[0511] In a similar manner to Example 11, (1-(pyridin-3-yl)cyclopentyl)methanamine (0.050 g, 0.284 mmol) and 4-((2-fluorophenyl)ethynyl)benzoic acid (0.068 g, 0.284 mmol) were used as starting materials to give 4-((2-fluorophenyl)ethynyl)-N-((1-(pyridin-3-yl)cyclopentyl)methyl)benzamide (0.055 g, 48.7%) as a beige solid: LRMS (ES) m / z 399.24 [M+H] + , calculated molecular weight 398.48; 1 H-NMR(400MHz, DMSO-d6)d 8.48 (d, J=2.4Hz, 1H), 8.32 (m, 2H), 7.70 (d, J=8.8Hz, 2H), 7.68~7.57 (m, 4H), 7.48 (m, 1H ), 7.38~7.25(m, 3H), 3.42(d, J=6.4Hz, 2H), 2.08(m, 2H), 2.08~1.74(m, 4H), 1.61(m, 2H).

[0512] Example 35: Synthesis of 2-fluoro-4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide

[0513]

[0514] Step 1: Synthesis of 2-fluoro-4-((2-fluorophenyl)ethynyl)benzoic acid

[0515]

[0516] In a similar manner to step 1 of Example 3, methyl 4-bromo-2-fluorobenzoate (2.000 g, 8.582 mmol) and 1-ethynyl-2-fluorobenzene (1.031 g, 8.582 mmol) were used as starting materials to give methyl 2-fluoro-4-((2-fluorophenyl)ethynyl)benzoate (2.000 g, 85.6%) as a white solid, followed by 2-fluoro-4-((2-fluorophenyl)ethynyl)benzoic acid (1.850 g, 97.5%) as a white solid: LRMS (ES) m / z 258.94 [M+H] + , calculated molecular weight 258.22.

[0517] Step 2: Preparation of 2-fluoro-4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide synthesis

[0518]

[0519] In a similar manner to step 3 of Example 1, using 2-fluoro-4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.271 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (0.046 mL, 0.407 mmol) as starting materials, 2-fluoro-4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide (0.077 g, 79.9%) was obtained as a white solid: LRMS (ES) m / z 356.11 [M+H] + , calculated molecular weight 355.38; 1 H-NMR(400MHz, CD3OD)d 7.68 (t, J=7.6Hz, 1H), 7.56 (td, J=7.6, 1.6Hz, 1H), 7.43~7.40 (m, 2H), 7.36 (dd, J=11.0, 1.4Hz, 1H), 7.22~7.13 (m, 2H), 3.94 (dd, J=1 1.6, 2.8Hz, 2H), 3.40 (rd, J=11.8, 1.9Hz, 2H), 3.32~3.26 (m, 2H), 1.93~1.82 (m, 1H), 1.68 (dd, J=12.8, 2.0Hz, 2H), 1.38~1.28 (m, 2H).

[0520] Example 36: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)benzamide

[0521]

[0522] In a similar manner to step 3 of Example 1, using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and (4-methyltetrahydro-2H-pyran-4-yl)methanamine (0.056 g, 0.437 mmol) as starting materials, 4-((2-fluorophenyl)ethynyl)-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)benzamide (0.045 g, 43.9%) was obtained as a white solid: LRMS (ES) m / z 352.22 [M+H] + , calculated molecular weight 351.42; 1H-NMR(400MHz, CD3OD)d 7.82 (dt, J=8.8, 1.9Hz, 2H), 7.61 (d, J=8.8Hz, 2H), 7.55 (td, J=7.5, 1.5Hz, 1H), 7.43~7.37 (m, 1H), 7.21~7.15 (m, 2H), 3.72~3.74(m, 2H), 3.67~3.61(m, 2H), 3.32(s, 2H), 1.61~1.54(m, 2H), 1.37~1.33(m, 2H), 1.05(s, 3H).

[0523] Example 37: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((1-(hydroxymethyl)cyclohexyl)methyl)benzamide

[0524]

[0525] Step 1: Synthesis of (1-(aminomethyl)cyclohexyl)methanol

[0526]

[0527] Ethyl 2-cyanoacetate (5.377 mL, 50.389 mmol) was dissolved in N, N-dimethylformamide (200 mL), and cesium carbonate (Cs2CO3, 41.044 g, 125.972 mmol) and 1,5-dibromopentane (6.816 mL, 50.389 mmol) were added thereto at 0°C, followed by stirring at the same temperature for 30 minutes and further stirring at room temperature for 12 hours. Water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 1-cyanocyclohexane-1-ethyl carboxylate (7.050 g, 77.2%, colorless liquid). At 0 ℃, the product obtained was dissolved in a solution in tetrahydrofuran (200 mL), lithium aluminum hydride (2.40 M solution in THF, 43.681 mL, 104.833 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. Then, water (4.534 mL, 251.600 mmol) was poured into the reaction mixture and stirred for 30 minutes to terminate the reaction. The reaction mixture was filtered through a diatomaceous earth pad to remove solids, and the solvent was removed from the filtrate under reduced pressure. The product obtained was used without further purification ((1-(aminomethyl)cyclohexyl)methanol, 5.260 g, 87.6%, colorless liquid).

[0528] Step 2: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((1-(hydroxymethyl)cyclohexyl)methyl)benzamide

[0529]

[0530] In a similar manner to step 3 of Example 1, using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.450 g, 1.873 mmol) and (1-(aminomethyl)cyclohexyl)methanol (0.402 g, 2.810 mmol) as starting materials, 4-((2-fluorophenyl)ethynyl)-N-((1-(hydroxymethyl)cyclohexyl)methyl)benzamide (0.461 g, 67.3%) was obtained as a white solid: LRMS (ES) m / z 366.32 [M+H] + , calculated molecular weight 365.45; 1 H-NMR(400MHz, DMSO-d6)d 8.40 (t, J=6.0Hz, 1H), 7.85 (d, J=8.4Hz, 2H), 7.64~7.61 (m, 3H), 7.50~7.45 (m, 1H) , 7.35~7.23 (m, 2H), 4.53 (t, J=6.0Hz, 1H), 3.24~3.19 (m, 4H), 1.41~1.25 (m, 10H).

[0531] Example 38: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)methyl)benzamide

[0532]

[0533] Step 1: Synthesis of (4-(aminomethyl)tetrahydro-2H-pyran-4-yl)methanol

[0534]

[0535] In a manner similar to step 1 of example 37, 1-chloro-2-(2-chloroethoxy)ethane (21.761 mL, 185.644 mmol) was used instead of 1,5-dibromopentane to give (4-(aminomethyl)tetrahydro-2H-pyran-4-yl)methanol (5.300 g, 95.5%, colorless liquid).

[0536] Step 2: 4-((2-Fluorophenyl)ethynyl)-N-((4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)methyl)benzene Synthesis of formamide

[0537]

[0538] In a similar manner to Example 11 using (4-(aminomethyl)tetrahydro-2H-pyran-4-yl)methanol (0.300 g, 2.066 mmol) and 4-((2-fluorophenyl)ethynyl)benzoic acid (0.496 g, 2.066 mmol) as starting materials, 4-((2-fluorophenyl)ethynyl)-N-((4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)methyl)benzamide (0.450 g, 59.3%) was obtained as a white solid: LRMS (ES) m / z 368.27 [M+H] + , calculated molecular weight 367.42; 1 H-NMR(400MHz, DMSO-d6)d 8.48 (t, J=6.2Hz, 1H), 7.86 (d, J=8.0Hz, 2H), 7.65~7.63 (m, 3H), 7.48 (m, 1H), 7.33 (m, 1H), 7.2 7~7.25 (m, 1H), 4.61 (t, J=6.0Hz, 1H), 3.58~3.48 (m, 4H), 3.32~3.25 (m, 4H), 1.36~1.28 (m, 4H).

[0539] Example 39: Synthesis of N-((4,4-difluorocyclohexyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide

[0540]

[0541] In a similar manner to step 3 of Example 1, using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.200 g, 0.833 mmol) and (4,4-difluorocyclohexyl)methanamine hydrochloride (0.232 g, 1.249 mmol) as starting materials, N-((4,4-difluorocyclohexyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide (0.175 g, 56.6%) was obtained as a white solid: LRMS (ES) m / z 372.23 [M+H] + , calculated molecular weight 371.4; 1 H-NMR(400MHz, DMSO-d6)d 8.63 (t, J=6.0Hz, 1H), 7.87 (d, J=8.8Hz, 2H), 7.65~7.61 (m, 3H), 7.49~7.45 (m, 1H), 7.33 (t, J=9.2Hz, 1H), 7 .25 (td, J=7.6, 1.2Hz, 1H), 3.14 (t, J=6.4Hz, 2H), 2.01~1.96 (m, 2H), 1.81~1.66 (m, 5H), 1.22~1.13 (m, 2H).

[0542] Example 40: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide

[0543]

[0544] In a similar manner to step 3 of Example 1, using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.200 g, 0.833 mmol) and (tetrahydro-2H-pyran-3-yl)methanamine (0.144 g, 1.249 mmol) as starting materials, 4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide (0.157 g, 55.9%) was obtained as a white solid: LRMS (ES) m / z 338.21 [M+H] + , calculated molecular weight 337.39; 1 H-NMR (400MHz, DMSO-d6) d8.56 (t, J=5.8Hz, 1H), 7.86 (d, J=8.8Hz, 2H), 7.65~7.61 (m, 3H), 7.48~7.45 (m, 1H), 7.33 (t, J=9.2Hz, 1H), 7.24 (td, J=14. 9, 10.1Hz, 1H), 3.75~3.65(m, 2H), 3.28~3.23(m, 1H), 3.13~3.06(m, 3H), 1 .82~1.72(m,2H), 1.57~1.52(m,1H), 1.47~1.37(m,1H), 1.25~1.16(m,1H).

[0545] Example 41: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)benzamide

[0546]

[0547] In a similar manner to step 3 of Example 1, using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and 4-(aminomethyl)tetrahydro-2H-pyran-4-ol hydrochloride (0.073 g, 0.437 mmol) as starting materials, 4-((2-fluorophenyl)ethynyl)-N-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)benzamide (0.075 g, 72.8%) was obtained as a white solid: LRMS (ES) m / z 354.20 [M+H] + , calculated molecular weight 353.39; 1H-NMR(400MHz, CD3OD)d 7.86 (d, J=8.8Hz, 2H), 7.61 (d, J=8.4Hz, 2H), 7.57~7.53 (m, 1H), 7.43~7.38 (m, 1H), 7.21 ~7.15 (m, 2H), 3.78 ~ 3.73 (m, 4H), 3.43 (s, 2H), 1.75 ~ 1.67 (m, 2H), 1.53 (d, J = 14.0Hz, 2H).

[0548] Example 42: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide

[0549]

[0550] Step 1: Synthesis of (Z)-2-methyl-N-((tetrahydro-2H-pyran-4-yl)methylene)propane-2-sulfenamide

[0551]

[0552] 2-Methylpropane-2-sulfinamide (1.000 g, 8.251 mmol), tetrahydro-2H-pyran-4-carbaldehyde (2.072 g, 18.152 mmol), magnesium sulfate (MgSO4, 5.462 g, 45.380 mmol) and pyridinium p-toluenesulfonate (0.107 g, 0.495 mmol) were dissolved in 1,2-dichloroethane (14 mL) at room temperature, and the resulting solution was stirred at the same temperature for 24 hours under visible light (blue LED, 40 W). Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to give (Z)-2-methyl-N-((tetrahydro-2H-pyran-4-yl)methylene)propane-2-sulfenamide (0.800 g, 44.6%) as a white solid.

[0553] Step 2: Synthesis of 1-(tetrahydro-2H-pyran-4-yl)ethane-1-amine hydrochloride

[0554]

[0555] (Z)-2-methyl-N-((tetrahydro-2H-pyran-4-yl)methylene)propane-2-sulfinamide (0.800 g, 3.681 mmol) and methylmagnesium bromide (1.40 M solution in THF / toluene, 5.259 mL, 7.362 mmol) were dissolved in dichloromethane (15 mL), and the resulting solution was stirred at room temperature for 1 hour and further at the same temperature for 18 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to give 2-methyl-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)propane-2-sulfinamide (0.475 g, 55.3%) as a colorless liquid. 0.400 g (1.714 mmol) of the obtained product and hydrogen chloride (4.00 M solution in 1,4-dioxane, 1.286 mL, 5.142 mmol) were dissolved in methanol (2 mL) at room temperature, and the obtained solution was stirred at the same temperature for 30 minutes. After removing the solvent from the reaction mixture under reduced pressure, ethyl acetate (1 mL) and hexane (10 mL) were added to the concentrate and stirred. The precipitated solid was filtered, washed with hexane and dried to obtain 1-(tetrahydro-2H-pyran-4-yl)ethane-1-amine hydrochloride (0.143 g, 50.4%) as a pink solid.

[0556] Step 3: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide become

[0557]

[0558] In a similar manner to Example 11, 4-((2-fluorophenyl)ethynyl)benzoic acid (0.051 g, 0.211 mmol) and 1-(tetrahydro-2H-pyran-4-yl)ethane-1-amine hydrochloride (0.035 g, 0.211 mmol) were used as starting materials to give 4-((2-fluorophenyl)ethynyl)-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide (0.045 g, 60.6%) as a white solid: LRMS (ES) m / z 352.13 [M+H] + , calculated molecular weight 351.42; 1H-NMR(400MHz, DMSO-d6)d 8.27 (d, J=8.4Hz, 1H), 7.87 (d, J=8.4Hz, 2H), 7.63~7.61 (m, 3H), 7.46 (m, 1H), 7.32 (t, J=15.4Hz, 1H), 7.26 (t, J=4 .0Hz, 1H), 3.88~3.77 (m, 3H), 3.24 (q, J=14.0Hz, 2H), 1.62~1.56 (m, 3H), 1.22~1.15 (m, 2H), 1.09 (d, J=6.8Hz, 3H).

[0559] Example 43: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide

[0560]

[0561] In a similar manner to step 3 of Example 1 using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.150 g, 0.624 mmol) and (tetrahydrofuran-3-yl)methanamine (0.098 mL, 0.937 mmol) as starting materials, 4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide (0.143 g, 70.8%) was obtained as a white solid: LRMS (ES) m / z 324.21 [M+H] + , calculated molecular weight 323.37; 1 H-NMR(400MHz, DMSO-d6)d 8.68 (t, J=5.6Hz, 1H), 7.86 (dd, J=6.8, 2.0Hz, 2H), 7.64~7.59 (m, 3H), 7.50~7.44 (m, 1H), 7.33 (t, J=8.6Hz, 1H), 7.25 ( td, J=7.6, 0.9Hz, 1H), 3.71~3.54(m, 3H), 3.45~3.36(m, 2H), 3.30~3.13(m, 2H), 1.93~1.87(m, 1H), 1.62~1.50(m, 1H).

[0562] Example 44: Synthesis of 4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide

[0563]

[0564] Step 1: Synthesis of 4-((2,4-difluorophenyl)ethynyl)benzoic acid

[0565]

[0566] Methyl 4-ethynylbenzoate (2.000 g, 12.487 mmol) and 1-bromo-2,4-difluorobenzene (2.410 g, 12.487 mmol) were used in a similar manner to step 1 of Example 1 to give methyl 4-((2,4-difluorophenyl)ethynyl)benzoate (0.780 g, 22.9%) as a white solid followed by 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.730 g, 98.7%) as a white solid: LRMS (ES) m / z 256.98 (M-1) [M+H] + , calculated molecular weight 258.22.

[0567] Step 2: Preparation of 4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide synthesis

[0568]

[0569] 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.150 g, 0.581 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (0.074 g, 0.639 mmol) were used in a manner similar to Example 11 to give 4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide (0.156 g, 75.6%) as a white solid: LRMS (ES) m / z 356.42 [M+H] + , calculated molecular weight 355.38; 1 H-NMR(400MHz, DMSO-d6)d 8.58 (t, J=5.6Hz, 1H), 7.86 (d, J=8.4Hz, 2H), 7.70 (q, J=7.9Hz, 1H), 7.61 (d, J=8.0Hz, 2H), 7.42 (td, J=9.6, 2.8Hz, 1H), 7.17 (td, J=7.8, 2.5Hz, 1H), 3.80 (dd, J=11.2, 2.4Hz, 2H), 3.22 (t, J=11.8Hz, 2H), 3.12 (t, J=6.2Hz, 2H), 1.78~1.73 (m, 1H), 1.55 (d, J=12.8Hz, 2H), 1.20~1.10 (m, 2H).

[0570] Example 45: Synthesis of (R)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide

[0571]

[0572] In a similar manner to Example 11, (R)-(tetrahydrofuran-2-yl)methanamine (0.030 g, 0.297 mmol) and 4-((2-fluorophenyl)ethynyl)benzoic acid (0.071 g, 0.297 mmol) were used as starting materials to give (R)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide (0.065 g, 67.8%) as a white solid: LRMS (ES) m / z 324.33 [M+H] + , calculated molecular weight 323.37; 1 H-NMR(400MHz, DMSO-d6)d 8.64 (t, J=6.0Hz, 1H), 7.88 (d, J=8.8Hz, 2H), 7.63 (m, 3H), 7.46 (m, 1H), 7.33 (m, 1H), 7.25 (td, J=7.6, 0.8 Hz, 1H), 3.97~3.91(m, 1H), 3.73(m, 1H), 3.60(m, 1H), 3.28(m, 2H), 1.92~1.72(m, 3H), 1.59~1.52(m, 1H).

[0573] Example 46: Synthesis of (S)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide

[0574]

[0575] In a similar manner to Example 11 using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.150 g, 0.624 mmol) and (S)-(tetrahydrofuran-2-yl)methanamine (0.095 g, 0.937 mmol) as starting materials, (S)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide (0.162 g, 80.2%) was obtained as a white solid: LRMS (ES) m / z 324.54 [M+H] + , calculated molecular weight 323.37; 1H-NMR(400MHz, DMSO-d6)d 8.65 (t, J=5.8Hz, 1H), 7.87 (dd, J=6.4, 1.6Hz, 2H), 7.65~7.61 (m, 3H), 7.50~7.44 (m, 1H), 7.33 (t, J=9.6Hz, 1H), 7.25 (td, J=7.6, 1.2Hz, 1 H), 3.94~3.91(m, 1H), 3.76~3.71(m, 1H), 3.63~3.56(m, 1H), 3.28~3.24(m, 2H), 1.90~1.85(m, 1H), 1.83~1.68(m, 2H), 1.60~1.50(m, 1H).

[0576] Example 47: Synthesis of (R)-4-((2-fluorophenyl)ethynyl)-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide

[0577]

[0578] Step 1: Synthesis of (S,E)-2-methyl-N-((tetrahydro-2H-pyran-4-yl)methylene)propane-2-sulfenamide

[0579]

[0580] Tetrahydro-2H-pyran-4-carboxaldehyde (1.000 g, 8.761 mmol), pyridinium p-toluenesulfonate (0.047 g, 0.219 mmol) and magnesium sulfate (MgSO4, 2.636 g, 21.903 mmol) were dissolved in 1,2-dichloroethane (16 mL), and the resulting solution was stirred at room temperature for 0.5 hour, and (S)-2-methylpropane-2-sulfinamide (0.531 g, 4.381 mmol) was added thereto and further stirred at the same temperature for 18 hours. Saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to give (S,E)-2-methyl-N-((tetrahydro-2H-pyran-4-yl)methylene)propane-2-sulfenamide (0.470 g, 24.7%) as a white solid: LRMS (ES) m / z 218.05 [M+H] + , calculated molecular weight 217.33.

[0581] Step 2: Synthesis of (R)-1-(tetrahydro-2H-pyran-4-yl)ethane-1-amine hydrochloride

[0582]

[0583] (S,E)-2-methyl-N-((tetrahydro-2H-pyran-4-yl)methylene)propane-2-sulfenamide (0.470 g, 2.163 mmol) was used in a manner similar to step 2 of Example 42 to give (R)-1-(tetrahydro-2H-pyran-4-yl)ethane-1-amine hydrochloride (0.310 g, 99.3%) as a yellow solid: LRMS (ES) m / z 129.97 [M+H] + , calculated molecular weight 165.66.

[0584] Step 3: (R)-4-((2-fluorophenyl)ethynyl)-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide Synthesis

[0585]

[0586] In a similar manner to Example 11, (R)-1-(tetrahydro-2H-pyran-4-yl)ethane-1-amine hydrochloride (0.050 g, 0.302 mmol) and 4-((2-fluorophenyl)ethynyl)benzoic acid (0.073 g, 0.302 mmol) were used as starting materials to give (R)-4-((2-fluorophenyl)ethynyl)-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide (0.075 g, 70.7%) as a white solid: LRMS (ES) m / z 352.20 [M+H] + , calculated molecular weight 351.42; 1 H-NMR(400MHz, DMSO-d6)d 8.27 (d, J=8.8Hz, 1H), 7.87 (d, J=8.4Hz, 2H), 7.65~7.61 (m, 3H), 7.48~7.46 (m, 1H), 7.33 (m, 1H), 7.25 (t, J=7.6 Hz, 1H), 3.85~3.79 (m, 3H), 3.20 (q, J=11.9Hz, 2H), 1.68~1.52 (m, 3H), 1.25~1.13 (m, 2H), 1.09 (d, J=6.4Hz, 3H).

[0587] Example 48: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)benzamide

[0588]

[0589] To a solution of 4-((2-fluorophenyl)ethynyl)-N-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)benzamide (0.165 g, 0.467 mmol) obtained in Example 41 dissolved in dichloromethane (10 mL) was added diethylaminosulfur trifluoride (DAST, 0.068 mL, 0.514 mmol) at 0°C, and the reaction mixture was stirred at room temperature for 0.5 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography twice and concentrated to give 4-((2-fluorophenyl)ethynyl)-N-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)benzamide (0.025 g, 15.1%) as a white solid: LRMS (ES) m / z 356.12 [M+H] + , calculated molecular weight 355.38; 1 H-NMR(400MHz, DMSO-d6)d 8.74(t, J=6.2Hz, 1H), 7.90(d, J=8.4Hz, 2H), 7.64~7.62(m, 3H), 7.45(m, 1H), 7.33(m , 1H), 7.26 (t, J=4.4Hz, 1H), 3.71~3.67 (m, 2H), 3.54~3.48 (m, 4H), 1.80~1.60 (m, 4H).

[0590] Example 49: Synthesis of 4-(phenylethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide

[0591]

[0592] Step 1: Synthesis of 4-(phenylethynyl)benzoic acid

[0593]

[0594] In a similar manner to step 1 of Example 3, methyl 4-ethynylbenzoate (0.500 g, 3.122 mmol) and iodobenzene (0.764 g, 3.746 mmol) were used as starting materials to give methyl 4-(phenylethynyl)benzoate (0.544 g, 73.8%) as a clear liquid followed by 4-(phenylethynyl)benzoic acid (0.477 g, 93.2%) as a white solid: LRMS (ES) m / z 221.25 [MH] + , calculated molecular weight 222.24.

[0595] Step 2: Synthesis of 4-(phenylethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide

[0596]

[0597] In a similar manner to step 3 of Example 1 using 4-(phenylethynyl)benzoic acid (0.070 g, 0.315 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (0.054 g, 0.472 mmol) as starting materials, 4-(phenylethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide (0.065 g, 64.6%) was obtained as a white solid: LRMS (ES) m / z 320.27 [M+H] + , calculated molecular weight 319.4; 1 H-NMR(400MHz, CD3OD)d 7.81 (dd, J=6.8, 2.0Hz, 2H), 7.59~7.56 (m, 2H), 7.56~7.50 (m, 2H), 7.38~7.35 (m, 3H), 3.93 (dd, J=11.6, 3.2Hz, 2H ), 3.39 (td, J=11.7, 2.1Hz, 2H), 3.25 (s, 2H), 1.92~1.84 (m, 1H), 1.67 (dd, J=13.2, 1.6Hz, 2H), 1.37~1.27 (m, 2H).

[0598] Example 50: Synthesis of N-((4-(fluoromethyl)tetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide

[0599]

[0600] Step 1: Synthesis of tert-butyl ((4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)methyl)carbamate

[0601]

[0602] 2.520 g (17.355 mmol) of (4-(aminomethyl)tetrahydro-2H-pyran-4-yl)methanol obtained in step 1 of Example 38 and di-tert-butyl dicarbonate (3.987 mL, 17.355 mmol) were dissolved in dichloromethane (150 mL) at room temperature, and the resulting solution was stirred at the same temperature for 24 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to give tert-butyl ((4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)methyl)carbamate (2.606 g, 61.2%) as a white solid.

[0603] Step 2: Synthesis of (4-(fluoromethyl)tetrahydro-2H-pyran-4-yl)methanamine hydrochloride

[0604]

[0605] Tert-butyl ((4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)methyl)carbamate (0.300 g, 1.223 mmol), PyFluor (0.217 g, 1.345 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (DBU, 0.366 mL, 2.446 mmol) were dissolved in toluene (3 mL) at 60 °C. The resulting solution was stirred at the same temperature for 48 hours, and the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to give tert-butyl ((4-(fluoromethyl)tetrahydro-2H-pyran-4-yl)methyl)carbamate (0.140 g, 46.3%) as a white solid: 1 H-NMR (400MHz, CDCl3)d 4.24~4.23 (m, 1H), 3.12, 3.12 (ABq, J=0.7, 0.4Hz, 2H), 3.12 (q, J=0.4Hz, 2H), 1.83 (t, J=0.4Hz, 1H).

[0606] 0.070 g (0.283 mmol) of the obtained product and hydrogen chloride (4.00 M solution in 1,4-dioxane, 0.212 mL, 0.849 mmol) were dissolved in dichloromethane (2 mL) at room temperature, and the obtained solution was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the obtained product was used without further purification ((4-(fluoromethyl)tetrahydro-2H-pyran-4-yl)methylamine hydrochloride, 0.051 g, 98.1%, white solid): LRMS (ES) m / z 148.18 [M+H] + , calculated molecular weight 147.19.

[0607] Step 3: N-((4-(Fluoromethyl)tetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzyl Synthesis of amides

[0608]

[0609] In a similar manner to step 3 of Example 1 using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.050 g, 0.208 mmol) and (4-(fluoromethyl)tetrahydro-2H-pyran-4-yl)methanamine hydrochloride (0.057 g, 0.312 mmol) as starting materials, N-((4-(fluoromethyl)tetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide (0.032 g, 41.6%) was obtained as a white solid: LRMS (ES) m / z 370.12 [M+H] + , calculated molecular weight 369.41; 1 H-NMR(400MHz, CD3OD)d 7.82 (dt, J=8.4, 1.8Hz, 2H), 7.60 (dt, J=6.8, 2.1Hz, 2H), 7.55 (td, J=7.6, 1.6Hz, 1H), 7.43~7.37 (m, 1H), 7 .21~7.15(m,2H), 4.45~4.31(m,2H), 3.81~3.76(m,2H), 3.72~3.67(m,2H), 3.55(s,2H), 1.61~1.48(m,4H).

[0610] Example 51: Synthesis of N-((1,4-dioxane-2-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide

[0611]

[0612] In a similar manner to Example 11, 4-((2-fluorophenyl)ethynyl)benzoic acid (0.100 g, 0.416 mmol) and (1,4-dioxan-2-yl)methanamine (0.054 g, 0.458 mmol) were used as starting materials to give N-((1,4-dioxan-2-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide (0.120 g, 84.9%) as a white solid: LRMS (ES) m / z 340.33 [M+H] + , calculated molecular weight 339.37; 1 H-NMR(400MHz, DMSO-d6)d 8.66~8.64 (m, 1H), 7.87 (d, J=8.4Hz, 2H), 7.64~7.61 (m, 3H), 7.50~7.45 (m, 1H), 7 .33 (t, J=9.0Hz, 1H), 7.25 (t, J=7.6Hz, 1H), 3.72~3.39 (m, 6H), 3.29~3.17 (m, 3H).

[0613] Example 52: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((3-methyloxetane-3-yl)methyl)benzamide

[0614]

[0615] In a similar manner to step 3 of Example 1, using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and (3-methyloxetan-3-yl)methanamine (0.044 g, 0.437 mmol) as starting materials, 4-((2-fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl)benzamide (0.052 g, 55.2%) was obtained as a white solid: LRMS (ES) m / z 324.33 [M+H] + , calculated molecular weight 323.37; 1 H-NMR(400MHz, DMSO-d6)d 8.71 (t, J=6.0Hz, 1H), 7.88 (dd, J=6.4, 2.0Hz, 2H), 7.66~7.61 (m, 3H), 7.50~7.45 (m, 1H), 7.33 (td, J=9.1, 1.1Hz, 1H), 7.25 (td, J=7.6, 1.1Hz, 1H), 4.44 (d, J=5.2Hz, 2H), 4.17 (d, J=5.2Hz, 2H), 3.44 (d, J=6.0Hz, 2H), 1.22 (s, 3H).

[0616] Example 53: Synthesis of 4-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)-N-methyltetrahydro-2H-pyran-4-carboxamide

[0617]

[0618] Step 1: Synthesis of ethyl 4-(aminomethyl)tetrahydro-2H-pyran-4-carboxylate

[0619]

[0620] 4-cyanotetrahydro-2H-pyran-4-carboxylic acid ethyl ester (2.000g, 10.916mmol) and cobalt chloride (CoCl2, 2.835g, 21.833mmol) were dissolved in ethanol (10mL). The resulting solution was stirred at room temperature for 1 hour, and sodium borohydride (4.130g, 109.164mmol) was added thereto, and further stirred at the same temperature for 18 hours. Then, water (0.197mL, 10.916mmol) was poured into the reaction mixture at room temperature, and the reaction was terminated by stirring for 30 minutes. The reaction mixture was filtered through a diatomaceous earth pad to remove solids, and the solvent was removed from the filtrate under reduced pressure. The resulting product was used without further purification (4-(aminomethyl)tetrahydro-2H-pyran-4-carboxylic acid ethyl ester, 1.500g, 73.4%, colorless oil): LRMS (ES) m / z 188.09 [M+H] + , calculated molecular weight 187.24.

[0621] Step 2: Ethyl 4-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)tetrahydro-2H-pyran-4-carboxylate Synthesis

[0622]

[0623] In a similar manner to Example 11, ethyl 4-(aminomethyl)tetrahydro-2H-pyran-4-carboxylate (0.450 g, 2.403 mmol) and 4-((2-fluorophenyl)ethynyl)benzoic acid (0.577 g, 2.403 mmol) were used as starting materials to give ethyl 4-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)tetrahydro-2H-pyran-4-carboxylate (0.680 g, 69.1%) as a white solid: LRMS (ES) m / z 410.38 [M+H] + , calculated molecular weight 409.46.

[0624] Step 3: 4-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)-N-methyltetrahydro-2H-pyran-4-yl Synthesis of formamide

[0625]

[0626] Ethyl 4-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)tetrahydro-2H-pyran-4-carboxylate (0.400 g, 0.977 mmol) and lithium hydroxide monohydrate (0.082 g, 1.954 mmol) were dissolved in methanol (5 mL) / tetrahydrofuran (5 mL) / water (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 16 hours. After the solvent was removed from the reaction mixture under reduced pressure, a 2N aqueous hydrochloric acid solution was added to the concentrate and stirred. The precipitated solid was filtered, washed with water and dried to give 4-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)tetrahydro-2H-pyran-4-carboxylic acid as a white solid: (0.360 g, 96.6%, LRMS (ES) m / z 382.31 [M+H] + , calculated molecular weight 381.4).

[0627] 0.040 g (0.105 mmol) of the obtained product, methylamine hydrochloride (0.007 g, 0.105 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.052 g, 0.136 mmol) and N,N-diisopropylethylamine (0.091 mL, 0.524 mmol) were dissolved in N,N-dimethylformamide (2 mL) at room temperature, and the obtained solution was stirred at the same temperature for 16 hours. The solvent was removed from the reaction mixture under reduced pressure, and a saturated sodium bicarbonate aqueous solution was poured into the obtained concentrate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to give 4-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)-N-methyltetrahydro-2H-pyran-4-carboxamide (0.035 g, 84.6%) as a white solid: LRMS (ES) m / z 395.40 [M+H] + , calculated molecular weight 394.45; 1 H-NMR(400MHz, DMSO-d6)d 8.37 (t, J=6.2Hz, 1H), 7.82 (d, J=8.4Hz, 2H), 7.77~7.61 (m, 4H), 7.48 (m, 1H), 7.35 (m, 1H), 7.28 (t, J= 10.2Hz, 1H), 3.66 (d, J = 11.2Hz, 2H), 3.35 (m, 4H), 2.58 (m, 3H), 1.95~1.92 (m, 2H), 1.49~1.45 (m, 2H).

[0628] Example 54: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-2-yl)methyl)benzamide

[0629]

[0630] In a similar manner to Example 11, 4-((2-fluorophenyl)ethynyl)benzoic acid (0.100 g, 0.416 mmol) and (tetrahydro-2H-pyran-2-yl)methanamine (0.058 g, 0.500 mmol) were used as starting materials to give 4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-2-yl)methyl)benzamide (0.120 g, 85.4%) as a cream solid: LRMS (ES) m / z 338.13 [M+H] + , calculated molecular weight 337.39; 1 H-NMR (400 MHz, DMSO-d6) 8.62(t, J=5.8Hz, 1H), 7.89~7.87(m, 2H), 7.65~7.61(m, 3H), 7.48~7.64 (m, 1H), 7.35~7.31 (m, 1H), 7.27~7.23 (m, 1H), 3.83 (dd, J=10.4, 2.4Hz, 1 H), 3.37~3.32(m, 1H), 3.25~3.24(m, 1H), 3.23~3.21(m, 2H), 1.73(d, J=3 .2Hz, 1H), 1.57 (d, J=13.2Hz, 1H), 1.45~1.34 (m, 3H), 1.17~1.06 (m, 1H).

[0631] Example 55: Synthesis of N-((1-(isopropylamino)cyclohexyl)methyl)-4-(phenylethynyl)benzamide

[0632]

[0633] In a similar manner to Example 11, 4-(phenylethynyl)benzoic acid (0.100 g, 0.450 mmol) and 1-(aminomethyl)-N-isopropylcyclohexane-1-amine (0.084 g, 0.495 mmol) were used as starting materials to give N-((1-(isopropylamino)cyclohexyl)methyl)-4-(phenylethynyl)benzamide (0.102 g, 60.5%) as a cream solid: LRMS (ES) m / z 375.17 [M+H] + , calculated molecular weight 374.53; 1H-NMR(400MHz, CD3OD)d 7.84 (d, J=7.6Hz, 2H), 7.62 (d, J=8.4Hz, 2H), 7.59~7.51 (m, 2H), 7.42 (s, 3 H), 3.40 (s, 2H), 3.11~3.03 (m, 1H), 1.58~1.36 (m, 10H), 1.08~1.05 (m, 6H).

[0634] Example 56: Synthesis of N-((3,3-difluorocyclobutyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide

[0635]

[0636] In a similar manner to Example 11 using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and (3,3-difluorocyclobutyl)methanamine hydrochloride (0.069 g, 0.437 mmol) as starting materials, N-((3,3-difluorocyclobutyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide (0.075 g, 75.0%) was obtained as a white solid: LRMS (ES) m / z 344.22 [M+H] + , calculated molecular weight 343.35; 1 H-NMR(400MHz, DMSO-d6)d 8.72 (t, J=5.6Hz, 1H), 7.86 (d, J=7.6Hz, 2H), 7.64~7.61 (m, 3H), 7.47 (q, J=6.4Hz, 1H ), 7.33 (t, J=9.2Hz, 1H), 7.25 (t, J=7.6Hz, 1H), 2.63~2.55 (m, 3H), 2.38~2.29 (m, 4H).

[0637] Example 57: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((1-hydroxycyclobutyl)methyl)benzamide

[0638]

[0639] In a similar manner to Example 11 using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and 1-(aminomethyl)cyclobutane-1-ol (0.044 g, 0.437 mmol) as starting materials, 4-((2-fluorophenyl)ethynyl)-N-((1-hydroxycyclobutyl)methyl)benzamide (0.063 g, 66.9%) was obtained as a white solid: LRMS (ES) m / z 324.21 [M+H] + , calculated molecular weight 323.37;1 H-NMR(400MHz, DMSO-d6)d 8.42 (t, J=6.8Hz, 1H), 7.90 (d, J=8.4Hz, 2H), 7.64~7.62 (m, 3H), 7.47 (q, J=6.4Hz, 1H), 7.33 (t, J=9.2Hz, 1H), 7.25 (t, J=7 .6Hz, 1H), 5.15 (s, 1H), 3.39 (d, J=5.6Hz, 2H), 2.03~1.98 (m, 2H), 1.91~1.84 (m, 2H), 1.63~1.58 (m, 1H), 1.49~1.38 (m, 1H).

[0640] Example 58: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-(oxetane-2-ylmethyl)benzamide

[0641]

[0642] In a similar manner to Example 11, 4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and oxetane-2-ylmethylamine (0.038 g, 0.437 mmol) were used as starting materials to give 4-((2-fluorophenyl)ethynyl)-N-(oxetane-2-ylmethyl)benzamide (0.065 g, 72.1%) as a white solid: LRMS (ES) m / z 310.19 [M+H] + , calculated molecular weight 309.34; 1 H-NMR(400MHz, DMSO-d6)d 8.74 (t, J=5.4Hz, 1H), 7.89 (d, J=8.0Hz, 2H), 7.64~7.62 (m, 3H), 7.47 (q, J=6.4Hz, 1H), 7.33 (t, J=9.2Hz, 1 H), 7.25 (t, J=7.6Hz, 1H), 4.78 (q, J=6.3Hz, 1H), 4.49~4.36 (m, 2H), 3.57~3.38 (m, 2H), 2.65~2.55 (m, 2H).

[0643] Example 59: Synthesis of methyl 3-(1-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)cyclohexyl)propanoate

[0644]

[0645] Step 1: Synthesis of methyl 3-(1-(aminomethyl)cyclohexyl)propionate hydrochloride

[0646]

[0647] 1-(((tert-butoxycarbonyl)amino)methyl)cyclohexane-1-carboxylic acid (0.250 g, 0.972 mmol), benzyl acrylate (0.149 mL, 0.972 mmol), [Ir{dF(CF3)ppy)2(dtbpy)]PF6 (0.011 g, 0.010 mmol) and potassium hydrogen phosphate (K2HPO4, 0.203 g, 1.166 mmol) were dissolved in N,N-dimethylacetamide (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 24 hours under visible light (blue LED, 40 W). Water was poured into the reaction mixture and subsequently extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to obtain 3-(1-(((tert-butoxycarbonyl)amino)methyl)cyclohexyl)benzyl propionate as a colorless liquid. (0.268 g, 73.5%, LRMS (ES) m / z not detected [M+H] + , calculated molecular weight 375.51)

[0648] The product obtained and hydrochloric acid (0.129g, 3.529mmol) were dissolved in methanol (10mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. After desolventizing from the reaction mixture under reduced pressure, ethyl acetate (20mL) and hexane (10mL) were added into the enriched material and stirred. The precipitated solid was filtered, washed with hexane and dried to obtain 3-(1-(aminomethyl) cyclohexyl) methyl propionate hydrochloride (0.145g, 87.2%) in the form of a colorless liquid.

[0649] Step 2: Synthesis of methyl 3-(1-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)cyclohexyl)propanoate become

[0650]

[0651] In a similar manner to Example 11, methyl 3-(1-(aminomethyl)cyclohexyl)propanoate hydrochloride (0.150 g, 0.636 mmol) and 4-((2-fluorophenyl)ethynyl)benzoic acid (0.153 g, 0.636 mmol) were used as starting materials to give methyl 3-(1-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)cyclohexyl)propanoate (0.211 g, 78.7%) as a white solid: LRMS (ES) m / z 422.36 [M+H] + , calculated molecular weight 421.51; 1H-NMR(400MHz, CD3OD)d 7.80(d, J=8.4Hz, 2H), 7.61~7.53(m, 3H), 7.41(m, 1H), 7.20~7.15(m, 2H), 3.64(s, 3H) , 2.40 (t, J=5.2Hz, 2H), 1.65 (t, J=7.4Hz, 2H), 1.55~1.47 (m, 2H), 1.44~1.26 (m, 10H).

[0652] Example 60: Synthesis of 3-(4-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)tetrahydro-2H-pyran-4-yl)propanoic acid

[0653]

[0654] Step 1: Synthesis of methyl 3-(4-(aminomethyl)tetrahydro-2H-pyran-4-yl)propanoate hydrochloride

[0655]

[0656] In a similar manner to Step 1 of Example 59, 4-(((tert-butoxycarbonyl)amino)methyl)tetrahydro-2H-pyran-4-carboxylic acid (0.130 g, 0.501 mmol) was used as the starting material to give benzyl 3-(4-(((tert-butoxycarbonyl)amino)methyl)tetrahydro-2H-pyran-4-yl)propanoate (0.165 g, 87.2%) as a pale yellow liquid, followed by methyl 3-(4-(aminomethyl)tetrahydro-2H-pyran-4-yl)propanoate hydrochloride (0.094 g, 90.5%) as a colorless liquid.

[0657] Step 2: 3-(4-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)tetrahydro-2H-pyran-4-yl)propane Synthesis of methyl ester

[0658]

[0659] In a similar manner to Example 11, methyl 3-(4-(aminomethyl)tetrahydro-2H-pyran-4-yl)propanoate hydrochloride (0.100 g, 0.421 mmol) and 4-((2-fluorophenyl)ethynyl)benzoic acid (0.101 g, 0.421 mmol) were used as starting materials to give methyl 3-(4-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)tetrahydro-2H-pyran-4-yl)propanoate (0.084 g, 47.2%) as a white solid: LRMS (ES) m / z 424.34 [M+H] + , calculated molecular weight 423.48.

[0660] Step 3: 3-(4-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)tetrahydro-2H-pyran-4-yl)propane Acid synthesis

[0661]

[0662] 3-(4-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)tetrahydro-2H-pyran-4-yl)methyl propionate (0.080g, 0.189mmol) and sodium hydroxide (NaOH, 5.00M solution, 0.189mL, 0.945mmol) were dissolved in methanol (1mL) / tetrahydrofuran (1mL) at room temperature, and the solution was stirred at the same temperature for 3 hours. Then, hydrochloric acid (0.069g, 1.889mmol) was added to the reaction mixture at room temperature and stirred for 3 minutes to terminate the reaction. Water was poured into the reaction mixture and extracted with ethyl acetate subsequently. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-(4-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)tetrahydro-2H-pyran-4-yl)propanoic acid (0.074 g, 95.7%, white solid): LRMS (ES) m / z 408.16 [MH] + , calculated molecular weight 409.46; 1 H-NMR(400MHz, CD3OD)d 7.84~7.81 (m, 2H), 7.61 (dd, J=8.6, 1.8Hz, 2H), 7.57~7.53 (m, 1H), 7.43~7.38 (m, 1H), 7.21~7.15 (m, 2H), 3.77~3.75 (m, 2H) , 3.70~3.68 (m, 2H), 3.47~3.68 (m, 2H), 2.42 (t, J=7.8Hz, 2H), 1.74 (t, J=7.8Hz, 2H), 1.51~1.50 (m, 2H), 1.47~1.45 (m, 2H).

[0663] Example 61: Synthesis of 3-(1-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)cyclohexyl)propanoic acid

[0664]

[0665] In a similar manner to step 3 of Example 60, methyl 3-(1-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)cyclohexyl)propanoate (Example 59, 0.120 g, 0.285 mmol) was used as a starting material to give 3-(1-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)cyclohexyl)propanoic acid (0.094 g, 81.0%, white solid): LRMS (ES) m / z 406.18 [MH] + , calculated molecular weight 407.49; 1H-NMR(400MHz, CD3OD)d 7.81(dt, J=8.4, 1.9Hz, 2H), 7.61~7.59(m, 2H), 7.56~7.55(m, 1H), 7.41~7.39(m, 1H), 7.21~7 .15(m, 2H), 3.30~3.29(m, 2H), 2.39~2.35(m, 2H), 1.66(t, J=8.0Hz, 2H), 1.56~1.31(m, 10H).

[0666] Example 62: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((1-(3-hydroxypropyl)cyclohexyl)methyl)benzamide

[0667]

[0668] To a solution of 3-(1-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)cyclohexyl)propanoic acid (0.050 g, 0.123 mmol) and 4-methylmorpholine (0.015 mL, 0.135 mmol) obtained in Example 61 dissolved in tetrahydrofuran (2 mL) at 0°C, isopropyl chloroformate (0.016 mL, 0.135 mmol) was added and stirred for 1 hour. Sodium borohydride (0.009 g, 0.245 mmol) was added to the reaction mixture and stirred at the same temperature for 1 hour. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to give 4-((2-fluorophenyl)ethynyl)-N-((1-(3-hydroxypropyl)cyclohexyl)methyl)benzamide (0.037 g, 76.6%) as a white solid: LRMS (ES) m / z 394.35 [M+H] + , calculated molecular weight 393.5; 1 H-NMR(400MHz, CD3OD)d 7.80 (dd, J=6.8, 2.0Hz, 2H), 7.60 (dd, J=6.8, 2.0Hz, 2H), 7.56~7.55 (m, 1H), 7.41~7.39 (m, 1H), 7.21~7.15 (m, 2H), 3.54 (t, J=6.2Hz, 2H), 1.56~1.47 (m, 8H), 1.47~1.34 (m, 8H).

[0669] Example 63: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((2-hydroxycyclohexyl)methyl)benzamide

[0670]

[0671] In a similar manner to Example 11, 4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and 2-(aminomethyl)cyclohexan-1-ol (0.056 g, 0.437 mmol) were used as starting materials to give 4-((2-fluorophenyl)ethynyl)-N-((2-hydroxycyclohexyl)methyl)benzamide (0.060 g, 58.6%) as a white solid: LRMS (ES) m / z 352.28 [M+H] + , calculated molecular weight 351.42; 1 H-NMR(400MHz, DMSO-d6)d 8.50~8.46 (m, 1H), 7.86 (d, J=8.0Hz, 2H), 7.62 (d, J=8.0Hz, 3H), 7.47 (q, J=6.4Hz, 1H), 7.33 (t, J=9.2Hz, 1H), 7.25 (t, J= 7.6Hz, 1H), 4.52(m, 1H), 3.47~3.44(m, 1H), 3.26~3.08(m, 2H), 1.80~1.53(m, 4H), 1.39~1.31(m, 2H), 1.14~0.86(m, 3H).

[0672] Example 64: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((3-hydroxycyclohexyl)methyl)benzamide

[0673]

[0674] In a similar manner to Example 11, 4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and 3-(aminomethyl)cyclohexan-1-ol (0.056 g, 0.437 mmol) were used as starting materials to give 4-((2-fluorophenyl)ethynyl)-N-((3-hydroxycyclohexyl)methyl)benzamide (0.085 g, 83.0%) as a white solid: LRMS (ES) m / z 352.22 [M+H] + , calculated molecular weight 351.42; 1H-NMR(400MHz, DMSO-d6)d 8.55~8.54 (m, 1H), 7.86 (d, J=8.4Hz, 2H), 7.62 (d, J=7.6Hz, 3H), 7.47 (q, J=6.3Hz, 1H), 7.33 (t, J=9.0Hz, 1H), 7.25 (t, J=7.6Hz, 1H), 4.48 (s , 1H), 3.12~3.06(m, 2H), 2.65~2.65(m, 4H), 1.86~1.75(m, 1H), 1.66~ 1.57(m, 2H), 1.19~1.10(m, 1H), 1.03~0.94(m, 1H), 0.81~0.72(m, 1H).

[0675] Example 65: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((1-methoxycyclohexyl)methyl)benzamide

[0676]

[0677] In a similar manner to Example 11, 4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and (1-methoxycyclohexyl)methanamine hydrochloride (0.052 g, 0.291 mmol) were used as starting materials to give 4-((2-fluorophenyl)ethynyl)-N-((1-methoxycyclohexyl)methyl)benzamide (0.085 g, 79.8%, pale yellow oil): LRMS (ES) m / z 366.29 [M+H] + , calculated molecular weight 365.45; 1 H-NMR(400MHz, CDCl3)d 7.77(m, 2H), 7.61(m, 2H), 7.58~7.50(m, 1H), 7.34(m, 1H), 7.15~7.11(m, 2H), 6 .34 (s, 1H), 3.50 (d, J=4.8Hz, 2H), 3.26 (s, 3H), 1.77 (m, 2H), 1.63~1.26 (m, 8H).

[0678] Example 66: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((4-methoxytetrahydro-2H-pyran-4-yl)methyl)benzamide

[0679]

[0680] In a similar manner to Example 11, 4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and (4-methoxytetrahydro-2H-pyran-4-yl)methanamine (0.042 g, 0.291 mmol) were used as starting materials to give 4-((2-fluorophenyl)ethynyl)-N-((4-methoxytetrahydro-2H-pyran-4-yl)methyl)benzamide (0.080 g, 74.7%) as a pale yellow oil: LRMS (ES) m / z 368.20 [M+H] + , calculated molecular weight 367.42; 1 H-NMR (400MHz, CDCl3) d7.76 (d, J=8.0Hz, 2H), 7.61 (d, J==7.6Hz, 2H), 7.52 (m, 1H), 7.35~7.33 (m, 1H) , 7.16~7.11 (m, 2H), 6.32 (bs, 1H), 3.73 (m, 4H), 3.57 (d, J=4.8Hz, 2H), 3.26 (s, 3H), 1.82~1.67 (m, 4H).

[0681] Example 67: Synthesis of N-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide

[0682]

[0683] Step 1: Synthesis of (2,2-dimethyltetrahydro-2H-pyran-4-yl)methanamine

[0684]

[0685] Using 2,2-dimethyltetrahydro-2H-pyran-4-carbonitrile (1.000 g, 7.184 mmol) as a starting material in a similar manner to step 1-2 of Example 34, (2,2-dimethyltetrahydro-2H-pyran-4-yl)methanamine (0.470 g, 45.7%, yellow oil) was obtained: LRMS (ES) m / z 144.07 [M+H] + , calculated molecular weight 143.23.

[0686] Step 2: N-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzoyl Synthesis of amines

[0687]

[0688] In a similar manner to Example 11, 4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and (2,2-dimethyltetrahydro-2H-pyran-4-yl)methanamine (0.042 g, 0.291 mmol) were used as starting materials to give N-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide (0.035 g, 32.9%) as a pale yellow oil: LRMS (ES) m / z 366.29 [M+H] + , calculated molecular weight 365.45; 1 H-NMR(400MHz, CDCl3)d 7.76(m, 2H), 7.62(m, 2H), 7.54~7.50(m, 1H), 7.35~7.30(m, 1H), 7.18~7.11(m, 2H), 6.23(bs, 1H), 3.79~3. 75(m, 1H), 3.68~3.61(m, 1H), 3.38~3.29(m, 2H), 2.07~2.03(m, 1H), 1.66~1.55(m, 2H), 1.29~1.16(m, 8H).

[0689] Example 68: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl-d2)benzamide

[0690]

[0691] Step 1: Synthesis of tetrahydro-2H-pyran-4-yl)methane-d2-amine

[0692]

[0693] To a solution of tetrahydro-2H-pyran-4-carbonitrile (1.000 g, 8.998 mmol) dissolved in ether (12 mL) at 0°C, lithium aluminum deuteride (2.40 M solution, 7.498 mL, 17.995 mmol) was added and stirred at room temperature for 18 hours. Then, sodium hydroxide (NaOH, 1.00 M solution, 4.499 mL, 4.499 mmol) and water (0.973 mL, 53.986 mmol) were added to the reaction mixture at 0°C and stirred for 30 minutes to terminate the reaction. The reaction mixture was filtered through a celite pad to remove solids. The solvent was removed from the filtrate under reduced pressure, and the resulting product was used without further purification ((tetrahydro-2H-pyran-4-yl)methane-d2-amine, 0.370 g, 35.1%, yellow oil): LRMS (ES) m / z 118.10 [M+H] + , calculated molecular weight 117.19.

[0694] Step 2: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl-d2)benzamide become

[0695]

[0696] In a similar manner to Example 11, 4-((2-fluorophenyl)ethynyl)benzoic acid (0.720 g, 2.997 mmol) and (tetrahydro-2H-pyran-4-yl)methane-d2-amine (0.351 g, 2.997 mmol) were used as starting materials to give 4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl-d2)benzamide (0.210 g, 20.6%) as a white solid: LRMS (ES) m / z 340.33 [M+H] + , calculated molecular weight 339.41; 1 H-NMR(400MHz, DMSO-d6)d 8.57 (s, 1H), 7.86 (d, J=8.4Hz, 2H), 7.63 (m, 3H), 7.48~7.46 (m, 1H), 7.33 (t, J=9.2Hz, 1H), 7.25 (t, J=7.6H z, 1H), 3.82~3.79 (m, 2H), 3.22 (t, J=11.8Hz, 2H), 1.80~1.74 (m, 1H), 1.57~1.54 (m, 2H), 1.20~1.10 (m, 2H).

[0697] Example 69: Synthesis of (R)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide

[0698]

[0699] In a similar manner to Example 11, using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and (R)-(tetrahydrofuran-3-yl)methanamine hydrochloride (0.043 g, 0.321 mmol) as starting materials, (R)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide (0.080 g, 84.9%) was obtained as a white solid: LRMS (ES) m / z 324.23 [M+H] + , calculated molecular weight 323.37; 1H-NMR(400MHz, DMSO-d6)d 8.67 (t, J=5.4Hz, 1H), 7.86 (d, J=8.4Hz, 2H), 7.64~7.62 (m, 3H), 7.50~7.45 (m, 1H), 7.33 (t, J=9.2Hz, 1H), 7.25 (t, J=7.6H z, 1H), 3.71~3.55(m, 3H), 3.45~3.42(m, 1H), 3.27~3.19(m, 2H), 3.13~3.12(m, 1H), 1.95~1.86(m, 1H), 1.60~1.52(m, 1H).

[0700] Example 70: Synthesis of N-((5,5-dimethyltetrahydrofuran-3-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide

[0701]

[0702] In a similar manner to Example 11 using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.050 g, 0.208 mmol) and (5,5-dimethyltetrahydrofuran-3-yl)methanamine (0.030 g, 0.229 mmol) as starting materials, N-((5,5-dimethyltetrahydrofuran-3-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide (0.036 g, 49.2%) was obtained as a white solid: LRMS (ES) m / z 352.23 [M+H] + , calculated molecular weight 351.42; 1 H-NMR (400 MHz, DMSO-d6) 8.63 (t, J=5.2Hz, 1H), 7.86 (d, J=8.0Hz, 2H), 7.64~7.62 (m, 3H), 7.50~7.42 (m, 1H), 7.33 (t, J=9.2Hz, 1H), 7.25 (t, J=7.6Hz, 1H), 3.77 (t, J=8. 0Hz, 1H), 3.46 (t, J=7.8Hz, 1H), 3.25~3.20 (m, 2H), 2.59~2.52 (m, 1H), 1.83 (q, J=6.8Hz, 1H), 1.38 (q, J=6.8Hz, 1H), 1.18 (s, 3H), 1.08 (s, 3H).

[0703] Example 71: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide

[0704]

[0705] In a similar manner to Example 11 using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and (tetrahydrofuran-2-yl)methanamine (0.032 g, 0.321 mmol) as starting materials, 4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide (0.076 g, 80.7%) was obtained as a white solid: LRMS (ES) m / z 324.21 [M+H] + , calculated molecular weight 323.37; 1 H-NMR(400MHz, DMSO-d6)d 8.64 (t, J=5.6Hz, 1H), 7.87 (d, J=7.6Hz, 2H), 7.62 (d, J=7.6Hz, 3H), 7.47 (q, J=6.4Hz, 1H), 7.33 (t, J=9.2Hz, 1H), 7.25 (t, J=7 .6Hz, 1H), 3.97~3.91(m, 1H), 3.75~3.71(m, 1H), 3.61~3.56(m, 1H), 3.28~3.26(m, 2H), 1.89~1.72(m, 3H), 1.58~1.50(m, 1H).

[0706] Example 72: Synthesis of N-((3-ethyloxetan-3-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide

[0707]

[0708] In a similar manner to Example 11, 4-((2-fluorophenyl)ethynyl)benzoic acid (0.100 g, 0.416 mmol) and (3-ethyloxetan-3-yl)methanamine (0.055 g, 0.479 mmol) were used as starting materials to give N-((3-ethyloxetan-3-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide (0.091 g, 64.8%) as a white solid: LRMS (ES) m / z 338.15 [M+H] + , calculated molecular weight 337.39; 1H-NMR(400MHz, DMSO-d6)d 8.65 (t, J=6.2Hz, 1H), 7.88 (d, J=6.8Hz, 2H), 7.65~7.61 (m, 3H), 7.49~7.46 (m, 1H), 7.33 (td, J=9.1, 1.1Hz, 1H), 7.25 (td, J=7. 5, 1.2Hz, 1H), 4.40 (d, J=6.0Hz, 2H), 4.20 (d, J=5.6Hz, 2H), 3.47 (d, J=6.0Hz, 2H), 1.61 (q, J=7.5Hz, 2H), 0.86 (t, J=7.6Hz, 3H).

[0709] Example 73: Synthesis of 4-((2,4-difluorophenyl)ethynyl)-N-((1-fluorocyclohexyl)methyl)benzamide

[0710]

[0711] Step 1: Synthesis of (1-fluorocyclohexyl)methylamine hydrochloride

[0712]

[0713] 1-(((tert-Butyloxycarbonyl)amino)methyl)cyclohexane-1-carboxylic acid (0.200 g, 0.777 mmol), 1-(chloromethyl)-4-fluoro-1,4-diazainiumbicyclo[2.2.2]octanebis(tetrafluoroborate) ( 0.826g, 2.332mmol), [Ir{dF(CF3)ppy}2(dtbpy)]PF6 (0.009g, 0.008mmol) and disodium hydrogen phosphate (Na2HPO4, 0.221g, 1.554mmol) were dissolved in water (3.5mL) / acetonitrile (3.5mL), and the resulting solution was stirred at the same temperature for 18 hours under visible light (blue LED, 60W). Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to obtain tert-butyl ((1-fluorocyclohexyl)methyl)carbamate (0.095g, 52.8%) as a white solid: LRMS (ES) m / z no detection [M+H] + , calculated molecular weight 231.31.

[0714] 0.070 g (0.303 mmol) of the obtained product and 0.227 mL (0.908 mmol) of hydrogen chloride (4.00 M solution in 1,4-dioxane) were dissolved in dichloromethane (10 mL) at room temperature, and the obtained solution was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the precipitated solid was filtered, washed with ether and dried to obtain (1-fluorocyclohexyl)methylamine hydrochloride (0.057 g, 112.3%) as a white solid: LRMS (ES) m / z not detected [M+H] + , calculated molecular weight 167.73; 1 H-NMR (400MHz, DMSO-d6)d 8.03 (s, 2H), 3.01~2.96 (m, 2H), 1.87~1.76 (m, 2H), 1.50~1.41 (m, 8H).

[0715] Step 2: Synthesis of 4-((2,4-difluorophenyl)ethynyl)-N-((1-fluorocyclohexyl)methyl)benzamide

[0716]

[0717] In a similar manner to Example 11, 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.035 g, 0.136 mmol) and (1-fluorocyclohexyl)methanamine hydrochloride (0.025 g, 0.149 mmol) were used as starting materials to give 4-((2,4-difluorophenyl)ethynyl)-N-((1-fluorocyclohexyl)methyl)benzamide (0.032 g, 63.6%) as a white solid: LRMS (ES) m / z 372.23 [M+H] + , calculated molecular weight 371.4; 1 H-NMR(400MHz, DMSO-d6)d 7.03~7.02 (m, 2H), 6.80~6.78 (m, 4H), 6.29~6.18 (m, 2H), 2.72 (d, J=3.2Hz, 2H), 1.06~0.96(m, 2H), 0.78(s, 6H), 0.70~0.65(m, 1H), 0.52~0.51(m, 1H).

[0718] Example 74: Synthesis of methyl 2-(1-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)cyclohexyl)acetate

[0719]

[0720] Step 1: Synthesis of methyl 2-(1-(aminomethyl)cyclohexyl)acetate hydrochloride

[0721]

[0722] To a solution of 2-(1-(aminomethyl)cyclohexyl)acetic acid (3.000 g, 17.519 mmol) dissolved in methanol (50 mL) was added thionyl chloride (2.545 mL, 35.039 mmol) at 0°C, and stirred at 50°C for 14 hours, and the temperature was lowered to room temperature to terminate the reaction. After the solvent was removed from the reaction mixture under reduced pressure, the obtained product was used without further purification (methyl 2-(1-(aminomethyl)cyclohexyl)acetate hydrochloride, 3.850 g, 99.1%, yellow solid): LRMS (ES) m / z 185.75 [M+H] + , calculated molecular weight 221.73.

[0723] Step 2: Synthesis of methyl 2-(1-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)cyclohexyl)acetate become

[0724]

[0725] In a similar manner to Example 11, 4-((2-fluorophenyl)ethynyl)benzoic acid (0.400 g, 1.665 mmol) and methyl 2-(1-(aminomethyl)cyclohexyl)acetate hydrochloride (0.369 g, 1.665 mmol) were used as starting materials to give methyl 2-(1-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)cyclohexyl)acetate (0.450 g, 66.3%) as a yellow solid: LRMS (ES) m / z 408.29 [M+H] + , calculated molecular weight 407.49; 1 H-NMR(400MHz, DMSO-d6)d 8.30(t, J=6.4Hz, 1H), 7.86(d, J=8.8Hz, 2H), 7.64(m, 3H), 7.48(m, 1H), 7.35~7.33(m , 1H), 7.27~7.23(m, 1H), 3.53(s, 3H), 3.36(m, 2H), 2.33(s, 2H), 1.52~1.25(m, 10H).

[0726] Example 75: Synthesis of methyl 2-(4-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)tetrahydro-2H-pyran-4-yl)acetate

[0727]

[0728] Step 1: Synthesis of methyl 2-(4-(aminomethyl)tetrahydro-2H-pyran-4-yl)acetate hydrochloride

[0729]

[0730] A mixture of 8-oxa-2-azaspiro[4.5]decane-3-one (0.500 g, 3.222 mmol) and hydrochloric acid (12.00 M solution, 5.369 mL, 64.433 mmol) was heated at reflux for 8 hours at room temperature, and then the temperature was lowered to room temperature. After the solvent was removed from the reaction mixture under reduced pressure, the precipitated solid was filtered, washed with dichloromethane and dried to give 2-(4-(aminomethyl)tetrahydro-2H-pyran-4-yl)acetic acid hydrochloride (0.620 g, 91.8%) as a white solid: LRMS (ES) m / z 174.06 [M+H] + , calculated molecular weight 209.67.

[0731] To a solution of 0.514 g (2.967 mmol) of the obtained product dissolved in methanol (50 mL) was added thionyl chloride (0.431 mL, 5.935 mmol) at 0°C and stirred at 50°C for 14 hours. The temperature was lowered to room temperature to terminate the reaction. After removing the solvent from the reaction mixture under reduced pressure, the obtained product was used without further purification (2-(4-(aminomethyl)tetrahydro-2H-pyran-4-yl)acetic acid methyl ester hydrochloride, 0.660 g, 99.4%, yellow solid): LRMS (ES) m / z 188.13 [M+H] + , calculated molecular weight 223.7.

[0732] Step 2: 2-(4-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)tetrahydro-2H-pyran-4-yl)ethyl Synthesis of methyl ester

[0733]

[0734] In a similar manner to Example 11 using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.600 g, 2.498 mmol) and methyl 2-(4-(aminomethyl)tetrahydro-2H-pyran-4-yl)acetate hydrochloride (0.559 g, 2.498 mmol) as starting materials, methyl 2-(4-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)tetrahydro-2H-pyran-4-yl)acetate (0.450 g, 44.0%) was obtained as a yellow solid: LRMS (ES) m / z 410.21 [M+H] + , calculated molecular weight 409.46; 1H-NMR(400MHz, DMSO-d6)d 8.43(t, J=6.2Hz, 1H), 7.88~7.86(m, 2H), 7.64~7.62(m, 3H), 7.48(m, 1H), 7.33(m, 1H), 7.26(t, J=3.6Hz, 1H), 3.60 (m, 2H), 3.53 (m, 5H), 3.44 (d, J=6.4Hz, 2H), 2.42 (s, 2H), 1.48~1.46 (m, 4H).

[0735] Example 76: Synthesis of 2-(1-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)cyclohexyl)acetic acid

[0736]

[0737] To a solution of methyl 2-(1-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)cyclohexyl)acetate (0.300 g, 0.736 mmol) obtained in Example 74 dissolved in methanol (8 mL) / tetrahydrofuran (8 mL) / water (8 mL) was added lithium hydroxide monohydrate (0.062 g, 1.472 mmol) at room temperature and stirred at the same temperature for 5 hours. The solvent was removed from the reaction mixture under reduced pressure, and a 1N aqueous hydrochloric acid solution was added to the obtained concentrate, followed by extraction 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 by column chromatography and concentrated to obtain 2-(1-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)cyclohexyl)acetic acid (0.230 g, 79.4%) as a white solid: LRMS (ES) m / z 394.29 [M+H] + , calculated molecular weight 393.46; 1 H-NMR(400MHz, CD3OD)d 7.84~7.82(m,2H), 7.62~7.60(m,2H), 7.55(m,1H), 7.40(m,1H), 7.21~7.17(m,2H), 3.49(s,2H), 2.39(s,2H), 1.57~1.44(m,10H).

[0738] Example 77: Synthesis of N-((1-(2-amino-2-oxoethyl)cyclohexyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide

[0739]

[0740] 2-(1-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)cyclohexyl)acetic acid (0.080 g, 0.203 mmol), ammonium chloride (NH4Cl, 0.109 g, 2.033 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.101 g, 0.264 mmol) and N,N-diisopropylethylamine (0.177 mL, 1.017 mmol) obtained in Example 76 were dissolved in N,N-dimethylformamide (2 mL) at room temperature, and the resulting solution was stirred at 50°C for 16 hours. Then, the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was filtered through a celite pad to remove solids. To the concentrate obtained by removing the solvent from the filtrate under reduced pressure, a saturated aqueous sodium bicarbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give N-((1-(2-amino-2-oxoethyl)cyclohexyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide (0.055 g, 68.9%, white solid): LRMS (ES) m / z 393.30 [M+H] + , calculated molecular weight 392.47; 1 H-NMR(400MHz, DMSO-d6)d 8.95 (t, J=5.8Hz, 1H), 7.86 (d, J=8.8Hz, 2H), 7.40~7.62 (m, 4H), 7.48 (m, 1H), 7.32 (m, 1H), 7.25 (m, 1H), 7.06 (bs, 1H), 3.33 (s, 2H), 2.16 (s, 2H), 1.43~1.30 (m, 10H).

[0741] Example 78: Synthesis of N-((4-(2-amino-2-oxoethyl)tetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide

[0742]

[0743] Step 1: 2-(4-((4-((2-fluorophenyl)ethynyl)benzoyl)methyl)tetrahydro-2H-pyran-4-yl)ethyl Acid synthesis

[0744]

[0745] 2-(4-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)tetrahydro-2H-pyran-4-yl)acetic acid methyl ester (0.070 g, 0.171 mmol) obtained in Example 75 was used as a starting material in a similar manner to Example 76 to give 2-(4-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)tetrahydro-2H-pyran-4-yl)acetic acid. The obtained product was used without further purification (0.055 g, 81.4%, white solid): LRMS (ES) m / z 396.27 [M+H] + , calculated molecular weight 395.43.

[0746] Step 2: N-((4-(2-amino-2-oxoethyl)tetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl) Synthesis of (ethynyl)benzamide

[0747]

[0748] In a similar manner to Example 77 using 2-(4-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)tetrahydro-2H-pyran-4-yl)acetic acid (0.070 g, 0.177 mmol) as the starting material, N-((4-(2-amino-2-oxoethyl)tetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide (0.045 g, 64.4%, yellow oil) was obtained: LRMS (ES) m / z 395.08 [M+H] + , calculated molecular weight 394.45; 1 H-NMR(400MHz, DMSO-d6)d 8.84(t, J=6.0Hz, 1H), 7.86(m, 2H), 7.64~7.62(m, 4H), 7.51~7.43(m, 1H), 7.32(m, 1H), 7. 26 (m, 1H), 7.06 (bs, 1H), 3.62~3.52 (m, 4H), 3.41 (m, 2H), 2.23 (s, 2H), 1.45~1.40 (m, 4H).

[0749] Example 79: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((1-(2-(hydroxyamino)-2-oxoethyl)cyclohexyl)methyl)benzamide

[0750]

[0751] To a solution of methyl 2-(1-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)cyclohexyl)acetate (0.050 g, 0.123 mmol) obtained in Example 74 dissolved in methanol (2 mL) / tetrahydrofuran (1 mL) were added potassium hydroxide (KOH, 0.014 g, 0.245 mmol) and hydroxylamine (50.00% aqueous solution, 0.081 mL, 1.227 mmol) at 0° C., and stirred at room temperature for 1 hour. After removing the solvent from the reaction mixture under reduced pressure, saturated aqueous sodium bicarbonate solution was poured into the concentrate and stirred. The precipitated solid was filtered, washed with water and dried to give 4-((2-fluorophenyl)ethynyl)-N-((1-(2-(hydroxyamino)-2-oxoethyl)cyclohexyl)methyl)benzamide (0.040 g, 79.8%) as a white solid: LRMS (ES) m / z 409.15 [M+H] + , calculated molecular weight 408.47; 1 H-NMR(400MHz, CD3OD)d 7.90~7.88(m,2H), 7.63~7.61(m,2H), 7.55(m,1H), 7.40(m,1H), 7.21~7.15(m,2H), 3.47(s,2H), 2.19(s,2H), 1.56~1.37(m,10H).

[0752] Example 80: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((1-(2-(methylamino)-2-oxoethyl)cyclohexyl)methyl)benzamide

[0753]

[0754] 2-(1-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)cyclohexyl)acetic acid (0.050 g, 0.127 mmol) and methylamine hydrochloride (0.017 g, 0.254 mmol) obtained in Example 76 were used as starting materials in a similar manner to Example 77 to give 4-((2-fluorophenyl)ethynyl)-N-((1-(2-(methylamino)-2-oxoethyl)cyclohexyl)methyl)benzamide (0.045 g, 87.1%, white solid): LRMS (ES) m / z 406.97 [M+H] + , calculated molecular weight 406.5; 1H-NMR(400MHz, DMSO-d6)d 8.80 (t, J=5.6Hz, 1H), 8.06 (d, J=4.8Hz, 1H), 7.81 (d, J=48.4Hz, 2H), 7.65 (m, 3H), 7.48 (m, 1H), 7.32 (t, J =9.2Hz, 1H), 7.25 (t, J = 7.6Hz, 1H), 3.31 (s, 2H), 2.57 (d, J = 4.8Hz, 3H), 2.15 (s, 2H), 1.42~1.25 (m, 10H).

[0755] Example 81: Synthesis of N-((1-(2-(dimethylamino)-2-oxoethyl)cyclohexyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide

[0756]

[0757] 2-(1-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)cyclohexyl)acetic acid (0.050 g, 0.127 mmol) and dimethylamine hydrochloride (0.021 g, 0.254 mmol) obtained in Example 76 were used as starting materials in a similar manner to Example 77 to give N-((1-(2-(dimethylamino)-2-oxoethyl)cyclohexyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide, which was then purified by column chromatography to give the product as a white solid (0.050 g, 93.6%): LRMS (ES) m / z 421.04 [M+H] + , calculated molecular weight 420.53; 1 H-NMR(400MHz, DMSO-d6)d 8.69 (t, J=6.0Hz, 1H), 7.85 (d, J=8.8Hz, 2H), 7.65~7.62 (m, 3H), 7.48 (m, 1H), 7.33 (m, 1H), 7.26 (t , J=3.8Hz, 1H), 3.39 (d, J=6.0Hz, 2H), 2.99 (s, 3H), 2.81 (s, 3H), 2.35 (s, 2H), 1.45~1.28 (m, 10H).

[0758] Example 82: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((3-hydroxyoxetane-3-yl)methyl)benzamide

[0759]

[0760] In a similar manner to Example 11, 4-((2-fluorophenyl)ethynyl)benzoic acid (0.100 g, 0.416 mmol) and 3-(aminomethyl)oxetane-3-ol (0.052 g, 0.500 mmol) were used as starting materials to give 4-((2-fluorophenyl)ethynyl)-N-((3-hydroxyoxetane-3-yl)methyl)benzamide (0.082 g, 60.5%) as a cream solid: LRMS (ES) m / z 326.22 [M+H] + , calculated molecular weight 325.34; 1 H-NMR(400MHz, DMSO-d6)d 8.71 (t, J=6.2Hz, 1H), 7.90 (dd, J=6.8, 1.6Hz, 2H), 7.65~7.61 (m, 3H), 7.49~7.47 (m, 1H), 7.33 (t, J=8.4Hz, 1H) , 7.25 (td, J=7.5, 0.9Hz, 1H), 5.86 (s, 1H), 4.46 (d, J=6.8Hz, 2H), 4.36 (d, J=6.4Hz, 2H), 3.53 (d, J=6.0Hz, 2H).

[0761] Example 83: Synthesis of 4-((4-fluorophenyl)ethynyl)-N-((3-methyloxetane-3-yl)methyl)benzamide

[0762]

[0763] In a similar manner to Example 11, 4-((4-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and (3-methyloxetan-3-yl)methanamine (0.035 g, 0.350 mmol) were used as starting materials to give 4-((4-fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl)benzamide (0.089 g, 94.5%) as a white solid: LRMS (ES) m / z 324.11 [M+H] + , calculated molecular weight 323.37; 1 H-NMR(400MHz, DMSO-d6)d 8.69 (t, J=6.2Hz, 1H), 7.87 (d, J=8.0Hz, 2H), 7.64~7.58 (m, 4H), 7.29~7.23 (m, 2H) , 4.44 (d, J=5.6Hz, 2H), 4.17 (d, J=6.0Hz, 2H), 3.43 (d, J=6.0Hz, 2H), 1.22 (s, 3H).

[0764] Example 84: Synthesis of 3-fluoro-4-((2-fluorophenyl)ethynyl)-N-((3-methyloxetane-3-yl)methyl)benzamide

[0765]

[0766] Step 1: Synthesis of 3-fluoro-4-((2-fluorophenyl)ethynyl)benzoic acid

[0767]

[0768] In a similar manner to step 1 of Example 3, methyl 4-bromo-3-fluorobenzoate (2.000 g, 8.582 mmol) and 1-ethynyl-2-fluorobenzene (1.031 g, 8.582 mmol) were used as starting materials to give methyl 3-fluoro-4-((2-fluorophenyl)ethynyl)benzoate (1.800 g, 77.0%, LRMS (ES) m / z 272.94 [M+H]) as a white solid. + , calculated molecular weight 272.25), followed by 3-fluoro-4-((2-fluorophenyl)ethynyl)benzoic acid (1.700 g, 99.6%) as a white solid: LRMS (ES) m / z 257.03 [MH] + , calculated molecular weight 258.22.

[0769] Step 2: 3-Fluoro-4-((2-fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl)benzoyl Synthesis of amines

[0770]

[0771] In a similar manner to Example 11, 3-fluoro-4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.271 mmol) and (3-methyloxetan-3-yl)methanamine (0.036 g, 0.352 mmol) were used as starting materials to give 3-fluoro-4-((2-fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl)benzamide as a white solid: LRMS (ES) m / z 342.11 [M+H] + , calculated molecular weight 341.36; 1H-NMR(400MHz, DMSO-d6)d 8.76 (t, J=6.0Hz, 1H), 7.78~7.71 (m, 3H), 7.64 (td, J=7.5, 1.7Hz, 1H), 7.54~7.48 (m, 1H), 7.35 (t, J=8.6Hz, 1H) , 7.27 (td, J=7.5, 0.9Hz, 1H), 4.43 (d, J=6.0Hz, 2H), 4.17 (d, J=6.0Hz, 2H), 3.45 (d, J=6.4Hz, 2H), 1.22 (s, 3H).

[0772] Example 85: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-(((1s,3s)-3-hydroxycyclobutyl)methyl)benzamide

[0773]

[0774] In a similar manner to Example 11, 4-((2-fluorophenyl)ethynyl)benzoic acid (0.050 g, 0.208 mmol) and (1s,3s)-3-(aminomethyl)cyclobutane-1-ol (0.025 g, 0.250 mmol) were used as starting materials to give 4-((2-fluorophenyl)ethynyl)-N-(((1s,3s)-3-hydroxycyclobutyl)methyl)benzamide (0.059 g, 87.7%) as a cream solid: LRMS (ES) m / z 324.24 [M+H] + , calculated molecular weight 323.37; 1 H-NMR(400MHz, DMSO-d6)d 8.54 (t, J=5.8Hz, 1H), 7.87~7.85 (m, 2H), 7.65~7.61 (m, 3H), 7.48~7.44 (m, 1H), 7.33 (t, J=8.8Hz, 1H), 7.25 (td, J=7.6, 1.1Hz, 1H), 4.91 (d, J=6.4Hz, 1H), 3.88~3.79 (m, 1H), 3.23 (t, J=6.0Hz, 2H), 2.21~2.17 (m, 2H), 1.92~1.82 (m, 1H), 1.53~1.46 (m, 2H).

[0775] Example 86: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-(((1r,3r)-3-hydroxycyclobutyl)methyl)benzamide

[0776]

[0777] In a similar manner to Example 11, 4-((2-fluorophenyl)ethynyl)benzoic acid (0.050 g, 0.208 mmol) and (1r,3r)-3-(aminomethyl)cyclobutane-1-ol (0.025 g, 0.250 mmol) were used as starting materials to give 4-((2-fluorophenyl)ethynyl)-N-(((1r,3r)-3-hydroxycyclobutyl)methyl)benzamide (0.053 g, 78.7%) as a cream solid: LRMS (ES) m / z 324.14 [M+H] + , calculated molecular weight 323.37; 1 H-NMR(400MHz, DMSO-d6)d 8.58 (t, J=5.4Hz, 1H), 7.86 (dd, J=6.6, 1.8Hz, 2H), 7.65~7.61 (m, 3H), 7.48~7.45 (m, 1H), 7.33 (t, J=9.2Hz, 1H), 7.25 (td, J=7.6, 0.9Hz, 1H), 4.92 (d, J = 6.0Hz, 1H), 4.22~4.13 (m, 1H), 3.30~3.25 (m, 2H), 2.29~2.22 (m, 1H), 2.02~1.95 (m, 2H), 1.89~1.82 (m, 2H).

[0778] Example 87: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)methyl)benzamide

[0779]

[0780] In a similar manner to Example 11, 4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and (1s,3s)-3-(aminomethyl)-1-methylcyclobutane-1-ol (0.044 g, 0.379 mmol) were used as starting materials to give 4-((2-fluorophenyl)ethynyl)-N-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)methyl)benzamide (0.097 g, 98.7%) as a white solid: LRMS (ES) m / z 338.08 [M+H] + , calculated molecular weight 337.39; 1H-NMR(400MHz, DMSO-d6)d 8.53 (t, J=5.8Hz, 1H), 7.86 (dd, J=6.4, 2.0Hz, 2H), 7.65~7.61 (m, 3H), 7.53~7.44 (m, 1H), 7.33 (t, J=9.6Hz, 1H), 7 .25 (td, J=7.6, 0.9Hz, 1H), 4.84 (s, 1H), 3.24 (t, J=6.0Hz, 2H), 1.97~1.92 (m, 3H), 1.73~1.67 (m, 2H), 1.16 (s, 3H).

[0781] Example 88: Synthesis of N-((4,4-difluorocyclohexyl)methyl)-4-(pyridin-4-ylethynyl)benzamide

[0782]

[0783] In a similar manner to Example 11, 4-(pyridin-4-ylethynyl)benzoic acid (0.200 g, 0.896 mmol) and (4,4-difluorocyclohexyl)methanamine (0.160 g, 1.075 mmol) were used as starting materials to give N-((4,4-difluorocyclohexyl)methyl)-4-(pyridin-4-ylethynyl)benzamide (0.210 g, 66.1%) as a white solid: LRMS (ES) m / z 354.79 [M+H] + , calculated molecular weight 354.4; 1 H-NMR(400MHz, DMSO-d6)d 8.64 (t, J=5.8Hz, 1H), 8.62~8.60 (m, 2H), 7.88 (d, J=8.8Hz, 2H), 7.67 (d, J=6.8Hz, 2H), 7.52 (dd, J =4.4, 2.0Hz, 2H), 3.14 (t, J = 6.4Hz, 2H), 1.98~1.96 (m, 2H), 1.77~1.65 (m, 5H), 1.22~1.13 (m, 2H).

[0784] Example 89: Synthesis of N-((3,3-difluorocyclobutyl)methyl)-4-(pyridin-4-ylethynyl)benzamide

[0785]

[0786] In a similar manner to Example 11, 4-(pyridin-4-ylethynyl)benzoic acid (0.100 g, 0.448 mmol) and (3,3-difluorocyclobutyl)methanamine (0.065 g, 0.538 mmol) were used as starting materials to give N-((3,3-difluorocyclobutyl)methyl)-4-(pyridin-4-ylethynyl)benzamide (0.089 g, 60.9%) as a white solid: LRMS (ES) m / z 327.18 [M+H] + , calculated molecular weight 326.35; 1 H-NMR(400MHz, DMSO-d6)d 8.75 (t, J=5.6Hz, 1H), 8.65 (dd, J=4.4, 1.6Hz, 2H), 7.91 (d, J=8.4Hz, 2H), 7.72 (d, J=8.8Hz, 2 H), 7.56 (dd, J=4.2, 1.8Hz, 2H), 3.40 (t, J=5.0Hz, 2H), 2.67~2.62 (m, 2H), 2.42~2.33 (m, 3H).

[0787] Example 90: Synthesis of N-((3,3-difluorocyclobutyl)methyl)-4-(phenylethynyl)benzamide

[0788]

[0789] In a similar manner to Example 11, 4-(phenylethynyl)benzoic acid (0.070 g, 0.315 mmol) and (3,3-difluorocyclobutyl)methylamine hydrochloride (0.050 g, 0.315 mmol) were used as starting materials to give N-((3,3-difluorocyclobutyl)methyl)-4-(phenylethynyl)benzamide (0.080 g, 78.1%) as a white solid: LRMS (ES) m / z 326.13 [M+H] + , calculated molecular weight 325.36; 1 H-NMR(400MHz, DMSO-d6)d 8.70 (t, J=5.6Hz, 1H), 7.85 (dd, J=6.4, 2.0Hz, 2H), 7.62 (d, J=8.0Hz, 2H), 7.54 (m, 2 H), 7.42~7.40(m, 3H), 3.35(t, J=5.4Hz, 2H), 2.63~2.52(m, 2H), 2.40~2.32(m, 3H).

[0790] Example 91: Synthesis of (S)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide

[0791]

[0792] In a similar manner to Example 11, using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.050 g, 0.208 mmol) and (S)-(tetrahydro-2H-pyran-3-yl)methanamine hydrochloride (0.035 g, 0.229 mmol) as starting materials, (S)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide (0.066 g, 93.3%) was obtained as a white solid: LRMS (ES) m / z 338.13 [M+H] + , calculated molecular weight 337.39; 1 H-NMR(400MHz, DMSO-d6)d 8.58 (t, J=6.0Hz, 1H), 7.86 (d, J=8.0Hz, 2H), 7.65~7.56 (m, 3H), 7.50~7.44 (m, 1H), 7.33 (t, J=9.2Hz, 1H), 7.25 (td , J=7.6, 1.1Hz, 1H), 3.75~3.61(m, 2H), 3.31~3.28(m, 2H), 3.13~3.05(m, 3H), 1.77~1.69(m, 2H), 1.56~1.40(m, 2H).

[0793] Example 92: Synthesis of (R)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide

[0794]

[0795] In a similar manner to Example 11, 4-((2-fluorophenyl)ethynyl)benzoic acid (0.050 g, 0.208 mmol) and (R)-(tetrahydro-2H-pyran-3-yl)methanamine hydrochloride (0.035 g, 0.229 mmol) were used as starting materials to give (R)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide (0.055 g, 78.3%) as a white solid: LRMS (ES) m / z 338.20 [M+H] + , calculated molecular weight 337.39; 1H-NMR (400 MHz, DMSO-d6) 8.58 (t, J=5.8Hz, 1H), 7.86 (dd, J=6.6, 1.8Hz, 2H), 7.65~7.61 (m, 3H), 7. 44~7.35 (m, 1H), 7.33 (td, J=9.2, 0.8Hz, 1H), 7.25 (td, J=7.6, 1.1Hz, 1H), 3.75~3.72(m,1H), 3.69(s,1H), 3.30~3.25(m,1H), 3.15~3.05(m,3H), 1. 79~1.72(m,2H), 1.57~1.52(m,1H), 1.49~1.35(m,1H), 1.26~1.21(m,1H).

[0796] Example 93: Synthesis of (S)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide

[0797]

[0798] In a similar manner to Example 11 using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and (S)-(tetrahydrofuran-3-yl)methanamine (0.032 g, 0.321 mmol) as starting materials, (S)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide (0.089 g, 94.5%) was obtained as a clear liquid: LRMS (ES) m / z 324.05 [M+H] + , calculated molecular weight 323.37; 1 H-NMR (400 MHz, DMSO-d6) 8.68 (t, J=5.8Hz, 1H), 7.86 (dd, J=6.8, 2.0Hz, 2H), 7.65~7.61 (m, 3H), 7.50~7.43 (m, 1H), 7.33 (td, J=9.1, 1.1Hz, 1H), 7.25 (td, J=7.7, 1.1H z, 1H), 3.75~3.69 (m, 1H), 3.68~3.62 (m, 1H), 3.60~3.55 (m, 1H), 3.45~ 3.40 (m, 1H), 3.33~3.19 (m, 3H), 1.95~1.87 (m, 1H), 1.61~1.51 (m, 1H).

[0799] Example 94: Synthesis of 4-((4-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide

[0800]

[0801] In a similar manner to Example 11 using 4-((4-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and (tetrahydrofuran-3-yl)methanamine (0.035 g, 0.350 mmol) as starting materials, 4-((4-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide (0.079 g, 83.8%) was obtained as a cream solid: LRMS (ES) m / z 324.14 [M+H] + , calculated molecular weight 323.37; 1 H-NMR(400MHz, DMSO-d6)d 8.64 (t, J=5.8Hz, 1H), 7.85 (dd, J=6.8, 2.0Hz, 2H), 7.64~7.58 (m, 4H), 7.29~7.23 (m, 2H), 3.73~3.68 (m, 1H), 3. 65~3.63(m,1H), 3.61~3.55(m,1H), 3.45~3.42(m,1H), 3.22~3.15(m,3H), 1.95~1.86(m,1H), 1.60~1.52(m,1H).

[0802] Example 95: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((3-methyloxetane-3-yl)methyl-d)benzamide

[0803]

[0804] Step 1: Synthesis of (3-methyloxetan-3-yl)methane-d-amine

[0805]

[0806] 3-Methyloxetane-3-carboxaldehyde (2.000 g, 19.976 mmol), phenylmethylamine (2.141 g, 19.976 mmol) and acetic acid (0.114 mL, 1.998 mmol) were dissolved in tetrahydrofuran (18 mL), and the resulting solution was stirred at room temperature for 1 hour. Sodium borodeuteride (1.254 g, 29.964 mmol) was added thereto, and further stirred at the same temperature for 24 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give N-benzyl-1-(3-methyloxetane-3-yl)methane-d-amine (3.800 g, 98.9%, light yellow oil): LRMS (ES) m / z 193.15 [M+H] + , calculated molecular weight 192.28.

[0807] The obtained product, 10% Pd / C (600 mg) and ammonium formate (4.985 g, 79.051 mmol) were dissolved in methanol (20 mL) at room temperature. The obtained solution was stirred at 65 ° C for 14 hours, and then the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was filtered through a diatomaceous earth pad to remove solids, and the solvent was removed from the filtrate under reduced pressure to obtain (3-methyloxetane-3-yl)methane-d-amine (1.280 g, 63.4%, yellow oil): LRMS (ES) m / z 102.97 [M+H] + , calculated molecular weight 102.16.

[0808] Step 2: 4-((2-fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl-d)benzamide Synthesis

[0809]

[0810] In a similar manner to Example 11, 4-((2-fluorophenyl)ethynyl)benzoic acid (3.010 g, 12.529 mmol) and (3-methyloxetan-3-yl)methane-d-amine (1.280 g, 12.529 mmol) were used as starting materials to give 4-((2-fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl-d)benzamide (1.750 g, 43.1%) as a white solid: LRMS (ES) m / z 325.14 [M+H] + , calculated molecular weight 324.37; 1 H-NMR(400MHz, DMSO-d6)d 8.69 (d, J=6.0Hz, 1H), 7.88 (dd, J=7.0, 1.8Hz, 2H), 7.65~7.63 (m, 3H), 7.51~7.45 (m, 1H), 7.33 (m, 1H), 7.25 (m, 1H), 4.44 (d, J=6.0Hz, 2H), 4.17 (d, J=5.6Hz, 2H), 3.41 (d, J=6.0Hz, 1H), 1.22 (s, 3H).

[0811] Example 96: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((1-morpholinocyclobutyl)methyl)benzamide

[0812]

[0813] Step 1: Synthesis of (1-morpholinocyclobutyl)methylamine

[0814]

[0815] Cyclobutanone (2.000 g, 28.535 mmol) and morpholine (3.209 mL, 37.095 mmol) were used as starting materials in a similar manner to step 2 of Example 1 to afford 1-morpholinocyclobutane-1-carbonitrile (4.210 g, 88.8%, LRMS (ES) m / z no detected [M+H]) as a clear liquid. + , calculated molecular weight 166.22), then (1-morpholinocyclobutyl)methylamine was obtained. (2.000 g, 46.5%, clear liquid): LRMS (ES) m / z 171.02 [M+H] + , calculated molecular weight 170.26.

[0816] Step 2: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((1-morpholinocyclobutyl)methyl)benzamide

[0817]

[0818] In a similar manner to Example 11, 4-((2-fluorophenyl)ethynyl)benzoic acid (0.100 g, 0.416 mmol) and (1-morpholinocyclobutyl)methanamine (0.085 g, 0.500 mmol) were used as starting materials to give 4-((2-fluorophenyl)ethynyl)-N-((1-morpholinocyclobutyl)methyl)benzamide (0.119 g, 72.8%) as a yellow liquid: LRMS (ES) m / z 392.77 [M+H] + , calculated molecular weight 392.47; 1 H-NMR(400MHz, DMSO-d6)d 8.41 (t, J=6.2Hz, 1H), 7.86 (dd, J=7.0, 1.8Hz, 2H), 7.65~7.61 (m, 3H), 7.50~7.45 (m, 1H), 7.33 (t, J=9.2Hz, 1H), 7.25 (t, J=7.6H z, 1H), 4.08 (q, J=5.1Hz, 1H), 3.50~3.48 (m, 5H), 3.13 (d, J=5.6Hz, 3H), 2.49~2.47 (m, 2H), 1.93~1.83 (m, 3H), 1.69~1.61 (m, 2H).

[0819] Example 97: Synthesis of N-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide

[0820]

[0821] In a similar manner to Example 11 using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and (3,3-difluoro-1-methylcyclobutyl)methanamine (0.047 g, 0.350 mmol) as starting materials, N-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide (0.075 g, 72.0%) was obtained as a white solid: LRMS (ES) m / z 358.16 [M+H] + , calculated molecular weight 357.38; 1 H-NMR(400MHz, DMSO-d6)d 8.72 (t, J=6.2Hz, 1H), 7.88 (d, J=6.4Hz, 2H), 7.66~7.63 (m, 3H), 7.49~7.46 (m, 1H), 7.33 (t, J=8.8Hz, 1 H), 7.25 (td, J=7.6, 1.3Hz, 1H), 3.34~3.33(m, 2H), 2.67~2.57(m, 2H), 2.29~2.16(m, 2H), 1.17(s, 3H).

[0822] Example 98: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((2-methyltetrahydrofuran-2-yl)methyl)benzamide

[0823]

[0824] In a similar manner to Example 11, 4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and (2-methyltetrahydrofuran-2-yl)methanamine (0.045 mL, 0.350 mmol) were used as starting materials to give 4-((2-fluorophenyl)ethynyl)-N-((2-methyltetrahydrofuran-2-yl)methyl)benzamide (0.074 g, 75.3%) as a yellow solid: LRMS (ES) m / z 338.15 [M+H] + , calculated molecular weight 337.39; 1 H-NMR(400MHz, DMSO-d6)d 8.50 (t, J=6.2Hz, 1H), 7.88 (dd, J=6.4, 2.0Hz, 2H), 7.66~7.61 (m, 3H), 7.48~7.46 (m, 1H), 7.35~7.30 (m, 1H), 7.25 (td, J=7.6, 1.1Hz, 1H), 3.73~3.69(m, 2H), 3.29~3.27(m, 2H), 1.87~1.79(m, 3H), 1.57~1.46(m, 1H), 1.11(s, 3H).

[0825] Example 99: Synthesis of (R)-4-((4-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide

[0826]

[0827] In a similar manner to Example 11, using 4-((4-fluorophenyl)ethynyl)benzoic acid (0.120 g, 0.500 mmol) and (R)-(tetrahydro-2H-pyran-3-yl)methanamine hydrochloride (0.083 g, 0.549 mmol) as starting materials, (R)-4-((4-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide (0.130 g, 77.1%) was obtained as a white solid: LRMS (ES) m / z 338.21 [M+H] + , calculated molecular weight 337.39; 1 H-NMR(400MHz, DMSO-d6)d 8.55 (t, J=6.8Hz, 1H), 7.84 (d, J=8.0Hz, 2H), 7.64~7.59 (m, 4H), 7.29~7.23 (m, 2H), 3.75~3.62 (m, 2H), 3. 28(s, 1H), 3.16~3.05(m, 3H), 1.82~1.71(m, 2H), 1.57~1.52(m, 1H), 1.46~1.37(m, 1H), 1.25~1.15(m, 1H).

[0828] Example 100: Synthesis of (S)-4-((4-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide

[0829]

[0830] In a similar manner to Example 11, using 4-((4-fluorophenyl)ethynyl)benzoic acid (0.150 g, 0.624 mmol) and (S)-(tetrahydro-2H-pyran-3-yl)methanamine hydrochloride (0.104 g, 0.687 mmol) as starting materials, (S)-4-((4-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide (0.194 g, 92.1%) was obtained as a white solid: LRMS (ES) m / z 338.21 [M+H] + , calculated molecular weight 337.39; 1H-NMR(400MHz, DMSO-d6)d 8.55 (t, J=5.6Hz, 1H), 7.84 (d, J=8.0Hz, 2H), 7.64~7.56 (m, 4H), 7.31~7.21 (m, 2H), 3.75~3.62 (m, 2H), 3.32~ 3.27(m, 1H), 3.13~3.05(m, 3H), 1.83~1.68(m, 2H), 1.54~1.52(m, 1H), 1.43~1.39(m, 1H), 1.24~1.18(m, 1H).

[0831] Example 101: Synthesis of (R)-4-((4-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide

[0832]

[0833] In a similar manner to Example 11, 4-((4-fluorophenyl)ethynyl)benzoic acid (0.100 g, 0.416 mmol) and (R)-(tetrahydrofuran-3-yl)methanamine hydrochloride (0.069 g, 0.500 mmol) were used as starting materials to give (R)-4-((4-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide (0.096 g, 71.3%) as a yellow solid: LRMS (ES) m / z 324.14 [M+H] + , calculated molecular weight 323.37; 1 H-NMR(400MHz, DMSO-d6)d 8.65 (t, J=4.8Hz, 1H), 7.85 (d, J=6.8Hz, 2H), 7.64~7.58 (m, 4H), 7.29~7.23 (m, 2H), 3.73~3.68 (m, 1H), 3.66~ 3.32(m, 1H), 3.60~3.55(m, 1H), 3.45~3.42(m, 1H), 3.30~3.12(m, 3H), 1.96~1.84(m, 1H), 1.60~1.49(m, 1H).

[0834] Example 102: Synthesis of (S)-4-((4-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide

[0835]

[0836] In a similar manner to Example 11 using 4-((4-fluorophenyl)ethynyl)benzoic acid (0.150 g, 0.624 mmol) and (S)-(tetrahydrofuran-3-yl)methanamine (0.076 g, 0.749 mmol) as starting materials, (S)-4-((4-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide (0.152 g, 75.3%) was obtained as a yellow solid: LRMS (ES) m / z 324.08 [M+H] + , calculated molecular weight 323.37; 1 H-NMR(400MHz, DMSO-d6)d 8.66 (t, J=5.6Hz, 1H), 7.85 (d, J=8.4Hz, 2H), 7.63~7.60 (m, 4H), 7.29~7.24 (m, 2H), 3.73~3.68 (m, 1H), 3.66~ 3.62 (m, 1H), 3.60 ~ 3.55 (m, 1H), 3.45 ~ 3.42 (m, 1H), 3.29 ~ 3.12 (m, 3H), 1.94 ~ 1.86 (m, 1H), 1.60 ~ 1.52 (m, 1H).

[0837] Example 103: Synthesis of N-((3-fluorooxetane-3-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide

[0838]

[0839] To a solution of 4-((2-fluorophenyl)ethynyl)-NN((3-hydroxyoxetane-3-yl)methyl)benzamide (0.100 g, 0.307 mmol) obtained in Example 82 as a starting material dissolved in dichloromethane (5 mL) was added diethylaminosulfur trifluoride (DAST, 0.049 mL, 0.369 mmol) at -78°C, and stirred at the same temperature for 1 hour. The solvent was removed from the reaction mixture under reduced pressure, and a saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction 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 N-((3-fluorooxetan-3-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide (0.017 g, 16.9%) as a white solid: LRMS (ES) m / z 328.24 [M+H] + , calculated molecular weight 327.33; 1H-NMR(400MHz, DMSO-d6)d 8.88 (t, J=5.8Hz, 1H), 7.90 (dd, J=7.0, 1.8Hz, 2H), 7.66~7.60 (m, 3H), 7.50~7.45 (m, 1H) , 7.35~7.30 (m, 1H), 7.28~7.23 (m, 1H), 4.68~4.53 (m, 4H), 3.78 (dd, J=19.8, 6.2Hz, 2H).

[0840] Example 104: Synthesis of 4-((4-fluorophenyl)ethynyl)-N-((1-methylcyclohexyl)methyl)benzamide

[0841]

[0842] In a similar manner to Example 11, (1-methylcyclohexyl)methanamine (0.100 g, 0.786 mmol) and 4-((4-fluorophenyl)ethynyl)benzoic acid (0.208 g, 0.865 mmol) were used as starting materials to give 4-((4-fluorophenyl)ethynyl)-N-((1-methylcyclohexyl)methyl)benzamide (0.056 g, 20.4%) as a white solid: LRMS (ES) m / z 350.24 [M+H] + , calculated molecular weight 349.45; 1 H-NMR(400MHz, DMSO-d6)d 8.36 (t, J=6.2Hz, 1H), 7.85 (d, J=8.8Hz, 2H), 7.59~7.63 (m, 4H), 7.26 (t, J=9.0Hz, 2H), 3.12 (d, J=6.0Hz, 2H), 1.16~1.45 (m, 10H), 0.84 (s, 3H).

[0843] Example 105: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((1-methylcyclobutyl)methyl)benzamide

[0844]

[0845] In a similar manner to Example 11, (1-methylcyclobutyl)methanamine hydrochloride (0.050 g, 0.369 mmol) and 4-((2-fluorophenyl)ethynyl)benzoic acid (0.097 g, 0.405 mmol) were used as starting materials to give 4-((2-fluorophenyl)ethynyl)-N-((1-methylcyclobutyl)methyl)benzamide (0.068 g, 57.4%) as a white solid: LRMS (ES) m / z 322.16 [M+H] + , calculated molecular weight 321.4; 1H-NMR(400MHz, CDCl3)d 7.74 (d, J=8.0Hz, 2H), 7.59 (d, J=8.4Hz, 2H), 7.51 (t, J=6.8Hz, 1H), 7.32 (dd, J=13.2, 6.4Hz, 1H), 7.11 (dd, J=18.2, 8.6Hz, 2H), 6.22 (s, 1H), 3.44 (d, J=6.0Hz, 2H), 1.84~1.94 (m, 4H), 1.72~1.76 (m, 2H), 1.17 (s, 3H).

[0846] Example 106: Synthesis of 4-((4-fluorophenyl)ethynyl)-N-((1-methylcyclobutyl)methyl)benzamide

[0847]

[0848] In a similar manner to Example 11, (1-methylcyclobutyl)methanamine hydrochloride (0.050 g, 0.369 mmol) and 4-((4-fluorophenyl)ethynyl)benzoic acid (0.097 g, 0.405 mmol) were used as starting materials to give 4-((4-fluorophenyl)ethynyl)-N-((1-methylcyclobutyl)methyl)benzamide (0.070 g, 59.1%) as a white solid: LRMS (ES) m / z 322.16 [M+H] + , calculated molecular weight 321.4; 1 H-NMR(400MHz, CDCl3)d 7.74 (d, J=8.8Hz, 2H), 7.57 (d, J=8.8Hz, 2H), 7.52 (dd, J=9.0, 5.0Hz, 2H), 7.05 (t, J= 8.6Hz, 2H), 3.46 (d, J=6.0Hz, 2H), 1.89~1.93 (m, 4H), 1.71~1.78 (m, 2H), 1.19 (s, 3H).

[0849] Example 107: Synthesis of 4-((2,4-difluorophenyl)ethynyl)-N-((1-methylcyclobutyl)methyl)benzamide

[0850]

[0851] In a similar manner to Example 11, (1-methylcyclobutyl)methanamine hydrochloride (0.050 g, 0.369 mmol) and 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.095 g, 0.369 mmol) were used as starting materials to give 4-((2,4-difluorophenyl)ethynyl)-N-((1-methylcyclobutyl)methyl)benzamide (0.077 g, 61.5%) as a white solid: LRMS (ES) m / z 340.20 [M+H] + , calculated molecular weight 339.39; 1 H-NMR (400MHz, CDCl3) 7.74 (d, J=8.4Hz, 2H), 7.58 (d, J=8.8Hz, 2H), 7.47~7.52 (m, 1H), 6.84~6 .90 (m, 2H), 6.13 (bs, 1H), 3.45 (d, J=6.0Hz, 2H), 1.90~1.92 (m, 4H), 1.73 (m, 2H), 1.16 (s, 3H).

[0852] Example 108: Synthesis of 4-((2,4-difluorophenyl)ethynyl)-N-((1-methylcyclopentyl)methyl)benzamide

[0853]

[0854] In a similar manner to Example 11, (1-methylcyclopentyl)methanamine hydrochloride (0.050 g, 0.334 mmol) and 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.086 g, 0.334 mmol) were used as starting materials to give 4-((2,4-difluorophenyl)ethynyl)-N-((1-methylcyclopentyl)methyl)benzamide (0.069 g, 58.4%) as a cream solid: LRMS (ES) m / z 354.20 [M+H] + , calculated molecular weight 353.41; 1 H-NMR(400MHz, CDCl3)d 7.74(d, J=8.4Hz, 2H), 7.59(d, J=8.0Hz, 2H), 7.47~7.53(m, 1H), 6.85~6.91( m, 2H), 6.14 (bs, 1H), 3.37 (d, J=6.0Hz, 2H), 1.37~1.70 (m, 8H), 1.05 (s, 3H).

[0855] Example 109: Synthesis of (R)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide

[0856]

[0857] In a similar manner to Example 11, using 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.200 g, 0.775 mmol) and (R)-(tetrahydrofuran-3-yl)methanamine (0.086 g, 0.852 mmol) as starting materials, (R)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide (0.230 g, 87.0%) was obtained as a white solid: LRMS (ES) m / z 342.18 [M+H] + , calculated molecular weight 341.36; 1 H-NMR (400 MHz, DMSO-d6) 8.66 (t, J=5.8Hz, 1H), 7.86 (d, J=8.8Hz, 2H), 7.74~7.68 (m, 1H), 7.63 (d, J=14.8Hz, 2H), 7.47~7.38 (m, 1H), 7.19~7.15 (m, 1H), 3.73~3.69 (m, 1H), 3.67~3.63(m, 1H), 3.61~3.55(m, 1H), 3.45~3.42(m, 1H), 3.26~3. 17 (m, 2H), 3.13 (d, J=5.6Hz, 1H), 1.96~1.84 (m, 1H), 1.60~1.52 (m, 1H).

[0858] Example 110: Synthesis of (R)-4-((4-fluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide

[0859]

[0860] In a similar manner to Example 11 using 4-((4-fluorophenyl)ethynyl)benzoic acid (0.050 g, 0.208 mmol) and (R)-(tetrahydrofuran-2-yl)methanamine (0.025 g, 0.250 mmol) as starting materials, (R)-4-((4-fluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide (0.032 g, 47.5%) was obtained as a yellow solid: LRMS (ES) m / z 324.14 [M+H] + , calculated molecular weight 323.37; 1H-NMR(400MHz, DMSO-d6)d 8.65~8.63 (m, 1H), 7.86 (dd, J=6.8, 1.6Hz, 2H), 7.37~7.56 (m, 4H), 7.30~7.24 (m, 2H), 3.97~3.90 (m, 1H), 3.75 ~3.73 (m, 1H), 3.61 ~ 3.56 (m, 1H), 3.29 ~ 3.26 (m, 2H), 1.91 ~ 1.85 (m, 1H), 1.81 ~ 1.70 (m, 2H), 1.58 ~ 1.50 (m, 1H).

[0861] Example 111: Synthesis of (S)-4-((4-fluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide

[0862]

[0863] In a similar manner to Example 11 using 4-((4-fluorophenyl)ethynyl)benzoic acid (0.050 g, 0.208 mmol) and (S)-(tetrahydrofuran-2-yl)methanamine (0.025 g, 0.250 mmol) as starting materials, (S)-4-((4-fluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide (0.052 g, 77.3%) was obtained as a yellow solid: LRMS (ES) m / z 324.21 [M+H] + , calculated molecular weight 323.37; 1 H-NMR(400MHz, DMSO-d6)d 8.63 (t, J=5.8Hz, 1H), 7.91 (d, J=32.0Hz, 2H), 7.63~7.60 (m, 4H), 7.29~7.23 (m, 2H), 3.97~3.91 (m, 1H), 3.75 ~3.72 (m, 1H), 3.61 ~ 3.56 (m, 1H), 3.29 ~ 3.26 (m, 2H), 1.91 ~ 1.85 (m, 1H), 1.80 ~ 1.70 (m, 2H), 1.58 ~ 1.50 (m, 1H).

[0864] Example 112: Synthesis of N-((3-ethyloxetane-3-yl)methyl)-4-((4-fluorophenyl)ethynyl)benzamide

[0865]

[0866] In a similar manner to Example 11, 4-((4-fluorophenyl)ethynyl)benzoic acid (0.050 g, 0.208 mmol) and (3-ethyloxetan-3-yl)methanamine (0.029 g, 0.250 mmol) were used as starting materials to give N-((3-ethyloxetan-3-yl)methyl)-4-((4-fluorophenyl)ethynyl)benzamide (0.020 g, 28.5%) as a yellow liquid: LRMS (ES) m / z 338.21 [M+H] + , calculated molecular weight 337.39; 1 H-NMR(400MHz, DMSO-d6)d 8.64 (t, J=6.0Hz, 1H), 7.86 (d, J=8.4Hz, 2H), 7.67~7.56 (m, 4H), 7.30~7.24 (m, 2H), 4.39 (d, J=6.0 Hz, 2H), 4.20 (d, J=6.0Hz, 2H), 3.47 (d, J=6.0Hz, 2H), 1.61 (q, J=7.2Hz, 2H), 0.86 (t, J=7.4Hz, 3H).

[0867] Example 113: Synthesis of (S)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide

[0868]

[0869] In a similar manner to Example 11, using 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.060 g, 0.232 mmol) and (S)-(tetrahydrofuran-3-yl)methanamine (0.026 g, 0.256 mmol) as starting materials, (S)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide (0.073 g, 92.0%) was obtained as a white solid: LRMS (ES) m / z 342.18 [M+H] + , calculated molecular weight 341.36; 1 H-NMR(400MHz, DMSO-d6)d 8.66 (t, J=5.6Hz, 1H), 7.86 (dd, J=6.6, 2.2Hz, 2H), 7.71 (q, J=7.9Hz, 1H), 7.62 (d, J=8.8Hz, 2H), 7.43 (dt, J=16.4, 4.8Hz, 1 H), 7.18 (d, J = 26.0Hz, 1H), 3.73~3.63 (m, 2H), 3.61~3.42 (m, 2H), 3.26~3.16 (m, 3H), 1.95~1.86 (m, 1H), 1.61~1.52 (m, 1H).

[0870] Example 114: Synthesis of (R)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide

[0871]

[0872] In a similar manner to Example 11, using 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.060 g, 0.232 mmol) and (R)-(tetrahydrofuran-2-yl)methanamine (0.026 g, 0.256 mmol) as starting materials, (R)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide (0.075 g, 94.6%) was obtained as a white solid: LRMS (ES) m / z 342.11 [M+H] + , calculated molecular weight 341.36; 1 H-NMR(400MHz, DMSO-d6)d 8.63 (t, J=6.0Hz, 1H), 7.87 (d, J=8.8Hz, 2H), 7.74~7.68 (m, 1H), 7.62 (d, J=8.8Hz, 2H), 7.45~7.40 (m , 1H), 7.21~7.14(m, 1H), 3.96~3.91(m, 1H), 3.75~3.56(m, 2H), 3.28~3.26(m, 2H), 1.92~1.50(m, 4H).

[0873] Example 115: Synthesis of 4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-2-yl)methyl)benzamide

[0874]

[0875] In a similar manner to Example 11, 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.060 g, 0.232 mmol) and (tetrahydro-2H-pyran-2-yl)methanamine (0.029 g, 0.256 mmol) were used as starting materials to give 4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-2-yl)methyl)benzamide (0.051 g, 61.8%) as a white solid: LRMS (ES) m / z 356.25 [M+H] + , calculated molecular weight 355.38; 1H-NMR (400 MHz, DMSO-d6) 8.57 (t, J=18.8Hz, 1H), 7.87 (dd, J=6.4, 1.6Hz, 2H), 7.74~7.68 (m, 1H), 7 .61 (dd, J=6.4, 1.6Hz, 2H), 7.42 (td, J=9.6, 2.8Hz, 1H), 7.21~7.14 (m, 1H ), 3.83 (d, J=11.2Hz, 1H), 3.42~3.33 (m, 1H), 3.25~3.20 (m, 3H), 1.74~1. 74 (m, 1H), 1.58 (d, J=12.8Hz, 1H), 1.42~1.34 (m, 3H), 1.17~1.08 (m, 1H).

[0876] Example 116: Synthesis of 4-((4-fluorophenyl)ethynyl)-N-((2-methyltetrahydrofuran-2-yl)methyl)benzamide

[0877]

[0878] In a similar manner to Example 11 using 4-((4-fluorophenyl)ethynyl)benzoic acid (0.060 g, 0.250 mmol) and (2-methyltetrahydrofuran-2-yl)methanamine (0.032 g, 0.275 mmol) as starting materials, 4-((4-fluorophenyl)ethynyl)-N-((2-methyltetrahydrofuran-2-yl)methyl)benzamide (0.025 g, 29.7%) was obtained as a yellow solid: LRMS (ES) m / z 338.21 [M+H] + , calculated molecular weight 337.39; 1H-NMR (400 MHz, DMSO-d6) d 8.46 (t, J = 6.4 Hz, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.64-7.56 (m, 4H), 7.29-7.23 (m, 2H), 3.73-3.69 (m, 2H), 3.37-3.22 (m, 2H), 1.89-1.79 (m, 3H), 1.56-1.46 (m, 1H), 1.11 (s, 3H).

[0879] Example 117: Synthesis of (S)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide

[0880]

[0881] In a similar manner to Example 11 using 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.060 g, 0.232 mmol) and (S)-(tetrahydrofuran-2-yl)methanamine (0.026 g, 0.256 mmol) as starting materials, (S)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide (0.073 g, 92.0%) was obtained as a white solid: LRMS (ES) m / z 342.18 [M+H] + , calculated molecular weight 341.36; 1 H-NMR(400MHz, DMSO-d6)d 8.63 (t, J=5.8Hz, 1H), 7.87 (d, J=8.8Hz, 2H), 7.74~7.68 (m, 1H), 7.62 (d, J=8.8Hz, 2H), 7.45~7.40 (m , 1H), 7.21~7.14(m, 1H), 3.96~3.91(m, 1H), 3.75~3.56(m, 2H), 3.27~3.21(m, 2H), 1.92~1.50(m, 4H).

[0882] Example 118: Synthesis of 4-((2,4-difluorophenyl)ethynyl)-N-(oxetane-2-ylmethyl)benzamide

[0883]

[0884] In a similar manner to Example 11, 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.060 g, 0.232 mmol) and oxetane-2-ylmethylamine (0.022 g, 0.256 mmol) were used as starting materials to give 4-((2,4-difluorophenyl)ethynyl)-N-(oxetane-2-ylmethyl)benzamide (0.064 g, 84.1%) as a cream solid: LRMS (ES) m / z 328.17 [M+H] + , calculated molecular weight 327.33; 1 H-NMR(400MHz, DMSO-d6)d 8.73 (t, J=5.8Hz, 1H), 7.89 (d, J=8.4Hz, 2H), 7.74~7.61 (m, 1H), 7.62 (d, J=8.8Hz, 2H), 7.45~7.40 (m, 1H), 7.2 1~7.15(m,1H), 4.82~4.76(m,1H), 4.48~4.38(m,2H), 3.55~3.42(m,2H), 2.61~2.57(m,1H), 2.41~2.34(m,1H).

[0885] Example 119: Synthesis of 4-((2,4-difluorophenyl)ethynyl)-N-((2-methyltetrahydrofuran-2-yl)methyl)benzamide

[0886]

[0887] In a similar manner to Example 11, 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.060 g, 0.232 mmol) and (2-methyltetrahydrofuran-2-yl)methanamine (0.029 g, 0.256 mmol) were used as starting materials to give 4-((2,4-difluorophenyl)ethynyl)-N-((2-methyltetrahydrofuran-2-yl)methyl)benzamide (0.064 g, 77.5%) as a white solid: LRMS (ES) m / z 356.25 [M+H] + , calculated molecular weight 355.38; 1 H-NMR(400MHz, DMSO-d6)d 8.48 (t, J=6.4Hz, 1H), 7.88 (dd, J=6.4, 2.0Hz, 2H), 7.72~7.68 (m, 1H), 7.61 (d, J=8.4Hz, 2H), 7.42 (td, J=9.6, 2.4H z, 1H), 7.21~7.13(m, 1H), 3.75~3.67(m, 2H), 3.33~3.24(m, 2H), 1.87~1.79(m, 3H), 1.54~1.49(m, 1H), 1.11(s, 3H).

[0888] Example 120: Synthesis of N-((3,3-difluorocyclobutyl)methyl)-4-((2,4-difluorophenyl)ethynyl)benzamide

[0889]

[0890] In a similar manner to Example 11, (3,3-difluorocyclobutyl)methanamine hydrochloride (0.050 g, 0.317 mmol) and 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.098 g, 0.381 mmol) were used as starting materials to give N-((3,3-difluorocyclobutyl)methyl)-4-((2,4-difluorophenyl)ethynyl)benzamide (0.049 g, 42.7%) as a white solid: LRMS (ES) m / z 362.19 [M+H] + , calculated molecular weight 361.34; 1H-NMR (400MHz, CD3OD) d 7.75~7.81 (m, 2H), 7.54~7.59 (m, 3H), 7.02 (m, 2H), 3.48 (d, J=6.0Hz, 2H), 3.28~3.29 (m, 1H), 2.62 (m, 2H), 2.32 (m, 2H).

[0891] Example 121: Synthesis of N-((4,4-difluorocyclohexyl)methyl)-4-((2,4-difluorophenyl)ethynyl)benzamide

[0892]

[0893] In a similar manner to Example 11, (4,4-difluorocyclohexyl)methylamine hydrochloride (0.050 g, 0.269 mmol) and 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.083 g, 0.323 mmol) were used as starting materials to give N-((4,4-difluorocyclohexyl)methyl)-4-((2,4-difluorophenyl)ethynyl)benzamide (0.048 g, 63.7%) as a white solid: LRMS (ES) m / z 390.26 [M+H] + , calculated molecular weight 389.39; 1 H-NMR(400MHz, CD3OD)d 8.58 (t, J=5.2Hz, 1H), 7.81 (d, J=8.4Hz, 2H), 7.55~7.65 (m, 3H), 6.97~7.08 (m, 2 H), 3.28~3.29(m, 3H), 2.01~2.05(m, 2H), 1.69~1.85(m, 4H), 1.25~1.33(m, 2H).

[0894] Example 122: Synthesis of 4-((2,4-difluorophenyl)ethynyl)-N-((3-ethyloxetane-3-yl)methyl)benzamide

[0895]

[0896] In a similar manner to Example 11, (3-ethyloxetan-3-yl)methanamine (0.050 g, 0.434 mmol) and 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.135 g, 0.521 mmol) were used as starting materials to give 4-((2,4-difluorophenyl)ethynyl)-N-((3-ethyloxetan-3-yl)methyl)benzamide (0.070 g, 45.4%) as a white solid: LRMS (ES) m / z 356.18 [M+H] + , calculated molecular weight 355.38; 1H-NMR(400MHz, CD3OD)d 7.82 (d, J=8.4Hz, 2H), 7.58 (d, J=8.4Hz, 2H), 7.54~7.60 (m, 1H), 6.96~7.07 (m, 2H), 4.56 (d, J =6.4Hz, 2H), 4.39 (d, J=6.0Hz, 2H), 3.59 (s, 2H), 1.74 (q, J=7.5Hz, 2H), 0.97 (t, J=7.4Hz, 3H).

[0897] Example 123: Synthesis of 4-((2,4-difluorophenyl)ethynyl)-N-((3-fluorooxetane-3-yl)methyl)benzamide

[0898]

[0899] In a similar manner to Example 11, (3-fluorooxetane-3-yl)methanamine (0.050 g, 0.476 mmol) and 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.147 g, 0.571 mmol) were used as starting materials to give 4-((2,4-difluorophenyl)ethynyl)-N-((3-fluorooxetane-3-yl)methyl)benzamide (0.090 g, 54.8%) as a white solid: LRMS (ES) m / z 346.21 [M+H] + , calculated molecular weight 345.32; 1 H-NMR(400MHz, CD3OD)d 7.83 (d, J=8.0Hz, 2H), 7.58 (d, J=8.4Hz, 2H), 7.54~7.60 (m, 1H), 7.04 (td, J=9.4, 2.4H z, 1H), 6.99 (td, J=8.6, 2.0Hz, 1H), 4.74 (s, 2H), 4.69 (s, 2H), 3.90 (d, J=20.0Hz, 2H).

[0900] Example 124: Synthesis of (S)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide

[0901]

[0902] In a similar manner to Example 11, (S)-(tetrahydro-2H-pyran-3-yl)methanamine hydrochloride (0.050 g, 0.330 mmol) and 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.102 g, 0.396 mmol) were used as starting materials to give (S)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide (0.050 g, 42.7%) as a white solid: LRMS (ES) m / z 356.18 [M+H] + , calculated molecular weight 355.38; 1 H-NMR(400MHz, CD3OD)d 8.54 (bs, 1H), 7.81 (d, J=6.4Hz, 2H), 7.58 (d, J=7.2Hz, 3H), 6.98~7.05 (m, 2H), 3.79~3. 88(m, 2H), 3.42(m, 1H), 3.25(m, 2H), 1.89(m, 2H), 1.56~1.64(m, 2H), 1.30~1.32(m, 2H).

[0903] Example 125: Synthesis of 4-((2,4-difluorophenyl)ethynyl)-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)benzamide

[0904]

[0905] In a similar manner to Example 11, (4-methyltetrahydro-2H-pyran-4-yl)methanamine (0.050 g, 0.387 mmol) and 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.120 g, 0.464 mmol) were used as starting materials to give 4-((2,4-difluorophenyl)ethynyl)-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)benzamide (0.042 g, 29.4%) as a white solid: LRMS (ES) m / z 370.25 [M+H] + , calculated molecular weight 369.41; 1 H-NMR(400MHz, CD3OD)d 7.82 (d, J=8.0Hz, 2H), 7.59 (d, J=8.8Hz, 2H), 7.55~7.61 (m, 1H), 6.97~7.09 (m, 2H), 3.58~3.76(m, 4H), 3.26~3.35(m, 2H), 1.52~1.57(m, 2H), 1.34(m, 2H), 1.02(s, 3H).

[0906] Experimental Example 1: Confirmation of synergistic analgesic effect through dual action

[0907] By using the representative mGluR5 antagonist MPEP (2-methyl-6-(phenylethynyl)pyridine) and the 5-HT2AR antagonist MDL11,939 in the "spinal nerve ligation model", which is a neuropathic pain model, the synergistic analgesic effect through the dual action of mGluR5 and 5-HT2AR was confirmed.

[0908] In order to measure the analgesic effect of MPEP and MDL11,939 when administered alone or together, the reversibility rate (% reversal) of the pain relief parameter was calculated according to the method of Experimental Example 4, and the results are presented in Figure 1 In. As in Figure 1 As shown in , MPEP or MDL11,939 alone did not show a significant analgesic effect at a sub-effective dose (sub-effective dose: a dose lower than the effective dose that induces a significant pain relief effect). However, when they were administered simultaneously, a significant analgesic effect was evident. The results clearly demonstrated that MPEP and MDL11,939 act synergistically to relieve pain.

[0909] Experimental Example 2: Fluorescence-based Ca 2+ Mobilization assay

[0910] To measure activity on mGluR5, experiments were performed using a HEK293 cell line permanently overexpressing mGluR5 to examine intracellular Ca 2+ The cells in the cell culture medium were aliquoted into 384-well plates coated with poly-D-lysine and cultured in a 37°C incubator supplied with 5% CO2. The next day, the culture medium was removed and dye loading buffer (containing a dye capable of measuring Ca2+) was added. 2+ The test compound was dissolved in 100% DMSO at a final concentration of 10 mM to prepare a stock solution. A starting concentration of 10 μM was prepared from the stock solution, and then serially diluted to prepare a working solution (test compound working solution). The test compound working solution was added to cells incubated in dye loading buffer, which were maintained at room temperature in a light-shielded state for 30 minutes before measurement. EC was measured using FLIPR Tetra (MDS Analysis Technology). 80 The concentration of L-glutamate induces Ca 2+ The level changes for 2 minutes. The fluorescent Ca 2+ Signal values ​​were normalized to the EC 80 The % inhibition of the test compound was estimated by taking the fluorescence signal induced by L-glutamate at a concentration of 100% and the fluorescence signal induced by the vehicle as 0%. The potency of the test compound was calculated as IC 50The values ​​were compared and are presented in Table 1. (+: 1,000-2,000 nM, ++: 500-1,000 nM, +++: 100-500 nM, ++++: less than 100 nM).

[0911] Experimental Example 3: HTRF-based IP1 accumulation assay

[0912] The 5-HT2AR antagonism of the test compounds was confirmed by measuring the production of IP1 using a HEK293 cell line permanently overexpressing human 5-HT2AR. The test compounds were dissolved in 100% DMSO to a final concentration of 10 mM. A starting concentration of 10 μM was prepared from the stock solution and then serially diluted in a buffer containing lithium chloride (LiCl) to prepare the working solution. The cells and compounds prepared in the assay buffer were placed in a 96-well plate and incubated at room temperature for 10 minutes. EC was added 80 Concentration of serotonin was added, and then incubated at 37°C for 30 minutes in a light-shielded state. To measure IP1 accumulation in cells, IP1-d2 receptors and IP1-Cryptate donors (which are HTRF-based substances for fluorescent signals) were added and incubated for 1 hour at room temperature in a light-shielded state. The fluorescence emission signals of the receptors and donors were detected, and the HTRF ratio values ​​were subtracted from the average of the serotonin control. The percentage of activation was calculated by normalization of the serotonin control (0%) and the IP1 control (100%). IC of the test compound 50 The values ​​are presented in Table 1. (+: 1,000-2,000 nM, ++: 500-1,000 nM, +++: 100-500 nM, ++++: less than 100 nM).

[0913] [Table 1]

[0914]

[0915]

[0916]

[0917] Experimental Example 4: Analgesic efficacy experiment using an animal model (Chung model)

[0918] The Chung model (spinal nerve ligation model) is a representative animal model for studying neuropathic pain and is widely accepted by global pharmaceutical companies around the world as the gold standard for animal pain models.

[0919] In this experiment, male Sprague-Dawley rats (100-120 g) purchased from Koatech (Pyeongtaek-si, Gyeonggi-do) were used. The rats were placed in a room maintained at a constant temperature and humidity with a 12-hour light-dark cycle. The rats were allowed to eat and drink freely during the experiment.

[0920] For the Chung surgery, rats were anesthetized by isoflurane inhalation according to the article (Kim and Chung (1992), Pain 50 (3): 355-63), and the left lumbar nerves L5 and L6 were tied with sutures (6-0 silk) at the end of the dorsal ganglion and in front of the entrance to the sciatic nerve. After suturing the incision, the rats were allowed to recover in a controlled maintenance room for 2 weeks to induce physical allodynia in the left hind paw of the rats. To measure physical (tactile) allodynia, the rats were placed in a cage with a wire mesh bottom. Stimuli of increasing intensity (von Frey filaments ranging from 0.41 to 15.8 g were used) were placed on the plantar surface of the foot on the side of the nerve injury. While applying the gradually increasing stimulation, the intensity of the stimulation when a pain response (sudden lifting, licking or sucking of the foot) was induced was recorded. As described in the study of Chaplan et al. (1994) (Chaplan et al. (1994) J. Neurosci. Methods 53 (1): 55-63), the paw withdrawal threshold (PWT) was determined by increasing or decreasing the intensity of the continuous stimulation, and the results were analyzed by applying Dixon's up-and-down method. Only rats that did not show behavioral dysfunction (e.g., foot dragging or falling) were selected and included in the study, and the rats used had a PWT of 3.16 g or less.

[0921] After measuring the basal response extent before drug injection, each compound and solvent were injected by oral administration (12.5-100 mg / kg), and the measurements were repeated at constant time intervals (60 and 120 min) after drug injection.

[0922] The experimenter performed PWT measurement under blind conditions and did not know which drug was administered to which rat. The control group was administered gabapentin (65 mg / kg, intraperitoneal administration) and randomly mixed during the measurement. The measured pain response thresholds were statistically analyzed by calculating the reversal rate (% reversal) of pain in the following equation 1. A high reversal rate means that abnormal pain is greatly reduced after drug administration.

[0923] [Equation 1]

[0924] Pain reversal rate (% reversal) = [(PWT after drug administration) - (PWT before drug administration)] * 100 / [(15 g, estimated PWT in normal animals) - (PWT before drug administration)]

[0925] The PWT used at this time is a value obtained by multiplying gram (a unit of measurement for "force") by 10,000 and taking the logarithm, which is a method commonly used in academia. The results are presented in Table 2.

[0926] Each experiment consisted of a compound group, a solvent group for the compound, and a gabapentin (GBP) group as a positive control group. 0.5% HPMC (hydroxypropyl methylcellulose) was used as a solvent for the compound.

[0927] [Table 2]

[0928]

[0929] As can be seen from Table 2, it was confirmed that the compound according to one embodiment of the present invention has an excellent analgesic effect.

Claims

1. A compound of the following formula 1 or a pharmaceutically acceptable salt thereof: [Formula 1] in X1 and X2 together with the carbon atoms to which they are attached form a 4- to 6-membered heteroaliphatic ring, wherein the 4- to 6-membered heteroaliphatic ring is oxetane, tetrahydrofuran, tetrahydropyran, dioxane or piperidine; X3 is CH or N; R1 is hydroxyl, halogen or C1-C5 hydrocarbon group; R2 is hydroxy, methoxy, fluorine, methyl, ethyl, cyclopropylmethyl, fluoromethyl, hydroxymethyl, hydroxypropyl, carboxymethyl, carboxyethyl, methoxycarbonylmethyl, methoxycarbonylethyl, aminocarbonylmethyl, hydroxyaminocarbonylmethyl, methylaminocarbonylmethyl, dimethylaminocarbamoylmethyl; isopropylamino, 2,2-dimethylpropylamino, cyclopropylamino, 2,2,2-trifluoroamino, morpholinyl, methylaminocarbonyl or pyridine; R3 is deuterium, halogen or methyl; R4 is halogen; R5 is fluorine; m is an integer from 0 to 3; n is 0 or 1; and l and p are each independently an integer from 0 to 2; q is 1 or 2.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R3 is deuterium, fluorine or methyl; and m is an integer from 0 to 2.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X1 and X2 together with the carbon atoms to which they are attached form oxetane, tetrahydrofuran or tetrahydropyran.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein p is 0.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X3 is CH.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein n is not 0.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R5 is substituted at the ortho and / or para position of the phenyl group.

8. A compound selected from the group consisting of: N-((1-(Cyclopropylamino)cycloheptyl)methyl)-4-(pyridin-2-ylethynyl)benzamide; N-((1-(Cyclopropylamino)cyclopentyl)methyl)-4-(pyridin-4-ylethynyl)benzamide; N-((1-(Cyclopropylamino)cyclopentyl)methyl)-4-((5-fluoropyridin-2-yl)ethynyl)benzamide; N-((1-(Cyclopropylamino)cyclobutyl)methyl)-4-((5-fluoropyridin-2-yl)ethynyl)benzamide; N-((1-(Cyclopropylamino)cyclobutyl)methyl)-4-(pyridin-4-ylethynyl)benzamide; N-((1-(Cyclopropylamino)cyclobutyl)methyl)-4-((4-fluorophenyl)ethynyl)benzamide; N-((1-(Cyclopropylamino)cyclobutyl)methyl)-3-fluoro-4-(pyridin-4-ylethynyl)benzamide; N-((1-(Cyclopropylamino)cyclobutyl)methyl)-4-(pyridin-2-ylethynyl)benzamide; N-((1-(Cyclopropylamino)cyclobutyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide; N-((1-(Cyclopropylamino)cyclobutyl)methyl)-2-fluoro-4-(pyridin-4-ylethynyl)benzamide; N-((1-(Cyclopropylamino)cyclopentyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide; N-((1-(Cyclopropylamino)cycloheptyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide; N-((1-(Cyclopropylamino)cyclopentyl)methyl)-4-((4-fluorophenyl)ethynyl)benzamide; N-((1-(Cyclopropylamino)cycloheptyl)methyl)-4-((4-fluorophenyl)ethynyl)benzamide; N-((1-(Cyclopropylamino)cycloheptyl)methyl)-4-((5-fluoropyridin-2-yl)ethynyl)benzamide; N-((1-(Cyclopropylamino)cycloheptyl)methyl)-4-((3-fluoropyridin-4-yl)ethynyl)benzamide; N-((1-(Cyclopropylamino)cyclopentyl)methyl)-4-((3,4-difluorophenyl)ethynyl)benzamide; N-((1-(Cyclopropylamino)cycloheptyl)methyl)-4-((3,4-difluorophenyl)ethynyl)benzamide; N-((1-(Cyclopropylamino)cyclohexyl)methyl)-4-((4-fluorophenyl)ethynyl)benzamide; N-((1-(Cyclopropylamino)cyclohexyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide; N-((1-(Cyclopropylamino)cyclopentyl)methyl)-4-((2-methylpyridin-4-yl)ethynyl)benzamide; N-((4-(Cyclopropylamino)tetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((1-morpholinocyclopentyl)methyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((4-(isopropylamino)tetrahydro-2H-pyran-4-yl)methyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((1-(isopropylamino)cyclohexyl)methyl)benzamide; N-((1-(Cyclopropylamino)-4-methylcyclohexyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((1-(neopentylamino)cyclohexyl)methyl)benzamide; N-((4-(Cyclopropylmethyl)tetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((1-(isopropylamino)cyclopentyl)methyl)benzamide; 4-(Pyridin-4-ylethynyl)-N-((1-((2,2,2-trifluoroethyl)amino)cyclohexyl)methyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((1-hydroxycyclohexyl)methyl)benzamide; 4-((4-Fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((1-(pyridin-3-yl)cyclopentyl)methyl)benzamide; 2-Fluoro-4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((1-(hydroxymethyl)cyclohexyl)methyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)methyl)benzamide; N-((4,4-difluorocyclohexyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide; 4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide; (R)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide; (S)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide; (R)-4-((2-fluorophenyl)ethynyl)-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)benzamide; 4-(Phenylethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide; N-((4-(Fluoromethyl)tetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide; N-((1,4-dioxan-2-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl)benzamide; 4-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)-N-methyltetrahydro-2H-pyran-4-carboxamide; 4-((2-Fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-2-yl)methyl)benzamide; N-((1-(isopropylamino)cyclohexyl)methyl)-4-(phenylethynyl)benzamide; N-((3,3-difluorocyclobutyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((1-hydroxycyclobutyl)methyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-(oxetan-2-ylmethyl)benzamide; Methyl 3-(1-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)cyclohexyl)propanoate; 3-(4-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)tetrahydro-2H-pyran-4-yl)propanoic acid; 3-(1-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)cyclohexyl)propanoic acid; 4-((2-Fluorophenyl)ethynyl)-N-((1-(3-hydroxypropyl)cyclohexyl)methyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((2-hydroxycyclohexyl)methyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((3-hydroxycyclohexyl)methyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((1-methoxycyclohexyl)methyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((4-methoxytetrahydro-2H-pyran-4-yl)methyl)benzamide; N-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl-d2)benzamide; (R)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide; N-((5,5-dimethyltetrahydrofuran-3-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide; N-((3-ethyloxetan-3-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide; 4-((2,4-difluorophenyl)ethynyl)-N-((1-fluorocyclohexyl)methyl)benzamide; Methyl 2-(1-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)cyclohexyl)acetate; Methyl 2-(4-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)tetrahydro-2H-pyran-4-yl)acetate; 2-(1-((4-((2-fluorophenyl)ethynyl)benzamido)methyl)cyclohexyl)acetic acid; N-((1-(2-amino-2-oxoethyl)cyclohexyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide; N-((4-(2-amino-2-oxoethyl)tetrahydro-2H-pyran-4-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((1-(2-(hydroxyamino)-2-oxoethyl)cyclohexyl)methyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((1-(2-(methylamino)-2-oxoethyl)cyclohexyl)methyl)benzamide; N-((1-(2-(dimethylamino)-2-oxoethyl)cyclohexyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((3-hydroxyoxetan-3-yl)methyl)benzamide; 4-((4-Fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl)benzamide; 3-Fluoro-4-((2-fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-(((1s,3s)-3-hydroxycyclobutyl)methyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-(((1r,3r)-3-hydroxycyclobutyl)methyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)methyl)benzamide; N-((4,4-difluorocyclohexyl)methyl)-4-(pyridin-4-ylethynyl)benzamide; N-((3,3-difluorocyclobutyl)methyl)-4-(pyridin-4-ylethynyl)benzamide; N-((3,3-difluorocyclobutyl)methyl)-4-(phenylethynyl)benzamide; (S)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide; (R)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide; (S)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide; 4-((4-Fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide; 4-((2-fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl-d)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((1-morpholinocyclobutyl)methyl)benzamide; N-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide; 4-((2-fluorophenyl)ethynyl)-N-((2-methyltetrahydrofuran-2-yl)methyl)benzamide; (R)-4-((4-Fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide; (S)-4-((4-Fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide; (R)-4-((4-Fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide; (S)-4-((4-Fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide; N-((3-fluorooxetan-3-yl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide; 4-((4-Fluorophenyl)ethynyl)-N-((1-methylcyclohexyl)methyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((1-methylcyclobutyl)methyl)benzamide; 4-((4-Fluorophenyl)ethynyl)-N-((1-methylcyclobutyl)methyl)benzamide; 4-((2,4-difluorophenyl)ethynyl)-N-((1-methylcyclobutyl)methyl)benzamide; 4-((2,4-difluorophenyl)ethynyl)-N-((1-methylcyclopentyl)methyl)benzamide; (R)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide; (R)-4-((4-Fluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide; (S)-4-((4-Fluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide; N-((3-ethyloxetan-3-yl)methyl)-4-((4-fluorophenyl)ethynyl)benzamide; (S)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide; (R)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide; 4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-2-yl)methyl)benzamide; 4-((4-Fluorophenyl)ethynyl)-N-((2-methyltetrahydrofuran-2-yl)methyl)benzamide; (S)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydrofuran-2-yl)methyl)benzamide; 4-((2,4-difluorophenyl)ethynyl)-N-(oxetan-2-ylmethyl)benzamide; 4-((2,4-difluorophenyl)ethynyl)-N-((2-methyltetrahydrofuran-2-yl)methyl)benzamide; N-((3,3-difluorocyclobutyl)methyl)-4-((2,4-difluorophenyl)ethynyl)benzamide; N-((4,4-difluorocyclohexyl)methyl)-4-((2,4-difluorophenyl)ethynyl)benzamide; 4-((2,4-difluorophenyl)ethynyl)-N-((3-ethyloxetan-3-yl)methyl)benzamide; 4-((2,4-difluorophenyl)ethynyl)-N-((3-fluorooxetan-3-yl)methyl)benzamide; (S)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide; and 4-((2,4-difluorophenyl)ethynyl)-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)benzamide, or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: N-((1-(Cyclopropylamino)cyclobutyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide; N-((1-(Cyclopropylamino)cyclopentyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((1-(isopropylamino)cyclohexyl)methyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide; 4-(Phenylethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl)benzamide; (R)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-((3-hydroxyoxetan-3-yl)methyl)benzamide; 4-((4-Fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl)benzamide; 4-((2-Fluorophenyl)ethynyl)-N-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)methyl)benzamide; 4-((4-Fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide; (S)-4-((4-Fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide; (R)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide; 4-((4-Fluorophenyl)ethynyl)-N-((2-methyltetrahydrofuran-2-yl)methyl)benzamide; 4-((2,4-difluorophenyl)ethynyl)-N-((2-methyltetrahydrofuran-2-yl)methyl)benzamide; and (S)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide.

10. A pharmaceutical composition for preventing or treating pain, comprising a therapeutically effective amount of a compound as defined in any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier or excipient.

11. The pharmaceutical composition according to claim 10, wherein the pain is neuropathic pain.

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