Heterocyclic compound and use thereof

Abstract

Disclosed are a heterocyclic compound and a use thereof. More specifically, disclosed are a heterocyclic compound acting as a dual modulator for 5-HT2A and dopamine D2 receptors and a use thereof as a therapeutic agent for mental illness.

Description

Heterocyclic compounds and their uses

[0001] A heterocyclic compound and its uses are disclosed. More specifically, 5-HT 2A A heterocyclic compound acting as a dual modulator of receptors and dopamine D2 receptors, and its use as a therapeutic agent for mental disorders are disclosed.

[0002] Schizophrenia is a complex mental illness characterized by hallucinations and delusions as primary symptoms, resulting from structural and functional abnormalities in various brain regions. It is estimated that schizophrenia affects 1–2% of the global population. The symptoms of schizophrenia are classified into positive symptoms, negative symptoms, and cognitive symptoms. Positive symptoms include hallucinations, delusions, disorganized thinking, and suspicion, while negative symptoms include illogical thinking, anhedonia, apathy, lack of desire, emotional blunting, passivity, and emotional withdrawal. Cognitive symptoms refer to attention deficit, decreased concentration, and memory impairment, and are sometimes included within the category of negative symptoms.

[0003] Atypical antipsychotics are drugs used to treat schizophrenia by binding to dopamine and serotonin receptors in the central nervous system, thereby blocking the action of brain neurotransmitters. They are called atypical antipsychotics because their pharmacological action is not limited to a single mechanism, distinguishing them from typical antipsychotics, which possess only dopamine receptor blocking action. Additionally, because they are relatively recently developed drugs among antipsychotic medications, they are also referred to as second-generation antipsychotics, whereas the earlier-developed typical antipsychotics are called first-generation antipsychotics.

[0004] In patients with schizophrenia, excessive dopamine activity in the mesolimbic pathway causes positive symptoms, while insufficient dopamine activity in the mesocortical pathway causes negative symptoms. Blocking dopamine receptors inhibits excessive dopamine activity in the mesolimbic pathway, thereby being effective against positive symptoms; conversely, blocking serotonin receptors increases dopamine secretion in the mesocortical pathway, thereby being effective against negative symptoms as well. Because atypical antipsychotics bind weakly to dopamine receptors and strongly to serotonin receptors compared to typical antipsychotics, they effectively treat positive symptoms without exacerbating or improving negative symptoms. Furthermore, they reduced extrapyramidal symptoms (EPS), which were the primary side effects caused by the inhibition of dopamine receptors in the nigrostriatal pathway.

[0005] [Prior Art Literature]

[0006] [Patent Literature]

[0007] [Reference 1] U.S. Patent No. 5,532,372

[0008] One objective of the present invention is 5-HT 2A It is to provide a compound that acts simultaneously on the receptor and the dopamine D2 receptor.

[0009] Another objective of the present invention is to provide the use of the compound as a treatment for mental disorders, particularly schizophrenia.

[0010] To achieve the above objective, a compound represented by the following chemical formula 1 or 2, or a pharmaceutically acceptable salt thereof, is provided:

[0011] [Chemical Formula 1]

[0012]

[0013] [Chemical Formula 2]

[0014]

[0015]

[0016] In the above chemical formula 1 or 2, R 1 , X 1 , X 2 , Y, Z 1 , Z 2 , Z 3 , Z 4 , l and m are as defined in this specification.

[0017]

[0018] In addition, a pharmaceutical composition for the prevention or treatment of mental illness is provided, comprising, as an active ingredient, a therapeutically effective amount of a compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.

[0019] In addition, a method for treating a mental disorder is provided, comprising the step of administering a compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof, to a mammal.

[0020] In addition, the compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof, is used in the prevention or treatment of mental illness.

[0021] The compound of Formula 1 or 2 according to the present invention, or a pharmaceutically acceptable salt thereof, maintains excellent inhibitory activity against dopamine D2 receptors while 5-HT 2A It has potent efficacy against receptors. The compound of Chemical Formula 1 or 2 exhibits excellent antipsychotic efficacy in animal models and has excellent metabolic stability. The compound of Chemical Formula 1 or 2 can be used as a treatment for schizophrenia that can improve not only positive symptoms but also negative symptoms while minimizing side effects.

[0022] The present invention will be described in more detail below.

[0023]

[0024] According to one aspect of the present invention, a compound represented by the following formula 1 or 2, or a pharmaceutically acceptable salt thereof is provided:

[0025] [Chemical Formula 1]

[0026]

[0027] [Chemical Formula 2]

[0028]

[0029]

[0030] In the above chemical formula 1 or 2,

[0031] R 1 is -H or halo;

[0032] X 1 and X 2 are each independently O or S;

[0033] Y is CH or N;

[0034] Z 1 and Z 2 Each independently N or CR 2 and; here R 2 is -H, halo, cyano, formyl, alkyl, alkoxy, haloalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, or aryl;

[0035] Z 3 and Z 4 Each independently N or CR 3 and; here R 3 is -H, halo, cyano, alkyl, alkoxy, haloalkyl, heterocycloalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aryl, unsubstituted or halo-substituted arylaminocarbonyl, heterocycloalkylcarbonyl or heteroarylaminocarbonyl, or two R 3 They are connected to each other to form an aryl or heteroaryl group together with bonding carbon atoms;

[0036] l is 1 or 2, and;

[0037] m is 0 or 1 and;

[0038] The above heterocycloalkyl and heteroaryl have one or more heteroatoms selected from N, O and S.

[0039]

[0040] In defining the compound of Formula 1 or 2 as described in this specification, the concepts defined for the following substituents are used.

[0041]

[0042] In the present invention, the terms “halo” or “halogen” refer to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I), whether used alone or in combination with other additional terms (e.g., haloalkyl).

[0043] In this invention, the term “cyano” group means -CN.

[0044] In this invention, the term “formyl” group means -C(=O)H.

[0045] In the present invention, the term “carbonyl” means -C(=O)-.

[0046] In the present invention, the term “amino” may mean a primary, secondary, or tertiary amino group bonded through a nitrogen atom, either alone or in combination.

[0047] In the present invention, the term “alkyl” refers to a radical of a saturated aliphatic hydrocarbon group having, for example, 1 to 7 or 1 to 5 carbon atoms, which is straight-chain or branch-chain, when used alone or in combination with other additional terms (e.g., haloalkyl). Examples of typical alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl, and 1,2-dimethylpropyl.

[0048] In the present invention, the term “alkoxy” means an alkyloxy (-O-alkyl group), for example, an alkyloxy having 1 to 7 or 1 to 5 carbon atoms.

[0049] In the present invention, the term “aryl” means an aromatic hydrocarbon having, for example, 6 to 10 carbon atoms, and specific examples include, but are not limited to, phenyl and naphthyl.

[0050] In the present invention, the term “heterocycloalkyl” refers to a radical of a saturated aliphatic hydrocarbon group comprising, for example, 5 to 10 members, one or more heteroatoms selected from N, O and S as a reducer.

[0051] In the present invention, the term “heteroaryl” refers to an aromatic hydrocarbon comprising, for example, one or more heteroatoms selected from N, O, and S as a reducer, and having 5 to 10 atoms.

[0052]

[0053] According to one embodiment of the present invention, in the formula 1 or 2

[0054] R 1 is -H or halo;

[0055] X 1 and X 2 are each independently O or S;

[0056] Y is CH or N;

[0057] Z 1 and Z 2 Each independently N or CR 2 and; here R 2 -H, halo, cyano, formyl, C1-C7 alkyl, C1-C7 alkoxy, halo-C1-C7 alkyl, C1-C7 alkyl carbonyl, C1-C7 alkoxycarbonyl, C1-C7 alkylaminocarbonyl, di(C1-C7 alkyl)aminocarbonyl or C6-C 10 Ariligo;

[0058] Z 3 and Z 4 Each independently N or CR 3 and; here R 3 -H, halo, cyano, C1-C7 alkyl, C1-C7 alkoxy, halo-C1-C7 alkyl, 5 to 10-membered heterocycloalkyl, C1-C7 alkyl carbonyl, C1-C7 alkoxycarbonyl, C1-C7 alkylaminocarbonyl, di(C1-C7 alkyl)aminocarbonyl, C6-C 10 Aryl, unsubstituted or halo-substituted C6-C 10 It is an arylaminocarbonyl, a 5 to 10-membered heterocycloalkylcarbonyl, or a 5 to 10-membered heteroarylaminocarbonyl, or two R3s are connected to each other to form a C6-aryl or a 5 or 6-membered heteroaryl with a carbon atom bonded to it;

[0059] l is 1 or 2, and;

[0060] m is 0 or 1 and;

[0061] The above heterocycloalkyl and heteroaryl may have one to three heteroatoms selected from N, O, and S.

[0062]

[0063] According to another embodiment of the present invention, the formula 1 may be the following formula 3:

[0064] [Chemical Formula 3]

[0065]

[0066]

[0067] In the above chemical formula 3, R 1 , X 1 , Y, Z 1 , Z 2 , Z 3 , Z 4 , l and m are as defined in Chemical Formula 1.

[0068] According to another embodiment of the present invention, the formula 2 may be the following formula 4:

[0069] [Chemical Formula 4]

[0070]

[0071]

[0072] In the above chemical formula 4, R 1 , X 1 , Y, Z 1 , Z 2 , Z 3 , Z 4 , l and m are as defined in Chemical Formula 2.

[0073] According to another embodiment of the present invention, the formula 1 may be the following formula 5:

[0074] [Chemical Formula 5]

[0075]

[0076]

[0077] In the above chemical formula 5, R 1 , X 1 , X 2 , Y, Z 1 , Z 2 , Z 3 and Z 4 It is as defined in Chemical Formula 1.

[0078] According to another embodiment of the present invention, the formula 2 may be the following formula 6:

[0079] [Chemical Formula 6]

[0080]

[0081]

[0082] In the above chemical formula 6, R 1 , X 1 , X 2 , Y, Z 1 , Z 2 , Z 3 and Z 4 It is as defined in Chemical Formula 2.

[0083] According to another embodiment of the present invention, the formula 5 may be the following formula 7:

[0084] [Chemical Formula 7]

[0085]

[0086]

[0087] In the above chemical formula 7, R 1 , X 1 , Y, Z 2 , Z 4 , R 2 and R 3 It is as defined in Chemical Formula 1.

[0088] According to another embodiment of the present invention, the formula 7 may be the following formula 8:

[0089] [Chemical Formula 8]

[0090]

[0091]

[0092] In the above chemical formula 8, R 1 , X 1 , Y and R 2 is as defined in Chemical Formula 1, and

[0093] R 3is -H, halo, cyano, alkyl, alkoxy, haloalkyl, alkyl carbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aryl, unsubstituted or halo-substituted arylaminocarbonyl, heterocycloalkylcarbonyl or heteroarylaminocarbonyl;

[0094] n is 0 or 1.

[0095] According to another embodiment of the present invention, the formula 7 may be the following formula 9:

[0096] [Chemical Formula 9]

[0097]

[0098]

[0099] In the above chemical formula 9, R 1 , X 1 , Y and R 2 is as defined in Chemical Formula 1, and

[0100] R 3 is -H, halo, cyano, alkyl, alkoxy, haloalkyl, heterocycloalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aryl, unsubstituted or halo-substituted arylaminocarbonyl, heterocycloalkylcarbonyl or heteroarylaminocarbonyl;

[0101] n is 0 or 1.

[0102] According to another embodiment of the present invention, the formula 7 may be the following formula 10:

[0103] [Chemical Formula 10]

[0104]

[0105]

[0106] In the above chemical formula 10,

[0107] R 1 It is Halo;

[0108] Y is CH or N;

[0109] Z 2is N or CR 2 And;

[0110] Z 4 is N or CR 3 is;

[0111] R 2 -H, halo, cyano, formyl, C1-C7 alkyl, C1-C7 alkoxy, halo-C1-C7 alkyl, C1-C7 alkyl carbonyl, C1-C7 alkoxycarbonyl, C1-C7 alkylaminocarbonyl, di(C1-C7 alkyl)aminocarbonyl or C6-C 10 Ariligo;

[0112] R 3 -H, halo, cyano, C1-C7 alkyl, C1-C7 alkoxy, halo-C1-C7 alkyl, 5 to 10-membered heterocycloalkyl, C1-C7 alkyl carbonyl, C1-C7 alkoxycarbonyl, C1-C7 alkylaminocarbonyl, di(C1-C7 alkyl)aminocarbonyl, C6-C 10 Aryl, unsubstituted or halo-substituted C6-C 10 It is an arylaminocarbonyl, a 5 to 10-membered heterocycloalkylcarbonyl, or a 5 to 10-membered heteroarylaminocarbonyl.

[0113] According to another embodiment of the present invention,

[0114] Z 1 and Z 2 Each independently N or CR 2 and; here R 2 is -H, halo, cyano, formyl, C1-C5 alkyl, halo-C1-C5 alkyl, C1-C5 alkylcarbonyl, C1-C5 alkylaminocarbonyl or C6 aryl;

[0115] Z 3 and Z 4 Each independently N or CR 3 and; here R 3is -H, halo, cyano, C1-C5 alkyl, C1-C5 alkoxy, halo-C1-C5 alkyl, 5 to 10-membered heterocycloalkyl, C1-C5 alkoxycarbonyl, C1-C5 alkylaminocarbonyl, di(C1-C5 alkyl)aminocarbonyl, C6 aryl, unsubstituted or halo-substituted C6 arylaminocarbonyl, 5 or 6-membered heterocycloalkylcarbonyl or 5 or 6-membered heteroarylaminocarbonyl, or two R 3 They are connected to each other to form a C6-aryl or 5- or 6-membered heteroaryl with bonded carbon atoms;

[0116] The above heterocycloalkyl and heteroaryl have one or two heteroatoms selected from N, O, and S.

[0117] According to another embodiment of the present invention, two R 3 It can form a benzene ring or a thiophene ring with carbon atoms that are connected to and bonded to it.

[0118]

[0119] According to another embodiment of the present invention, representative compounds of Formula 1 or 2 may include, but are not limited to, the following compounds:

[0120] 3-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)quinazolin-4(3H)-one;

[0121] 4-bromo-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one;

[0122] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one;

[0123] 2-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)isoquinoline-1(2H)-one;

[0124] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carbonitrile;

[0125] 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-4-methylpyridine-2(1H)-one;

[0126] 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-3-methylpyridine-2(1H)-one;

[0127] 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-5-methylpyridine-2(1H)-one;

[0128] 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-4-fluoropyridine-2(1H)-one;

[0129] 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-5-fluoropyridine-2(1H)-one;

[0130] 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-4-chloropyridine-2(1H)-one;

[0131] 6-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)thieno[2,3-c]pyridine-7(6H)-one;

[0132] 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-4-bromopyridine-2(1H)-one;

[0133] 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one;

[0134] 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-5-bromopyridine-2(1H)-one;

[0135] 5-acetyl-1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one;

[0136] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-phenylpyridine-2(1H)-one;

[0137] 3-((1r,4r)-4-(2-(4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)ethyl)cyclohexyl)quinazolin-4(3H)-one;

[0138] 5-bromo-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one;

[0139] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-5-phenylpyridine-2(1H)-one;

[0140] 3-bromo-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one;

[0141] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-3-methylpyridine-2(1H)-one;

[0142] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-5-methylpyridine-2(1H)-one;

[0143] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-methylpyridine-2(1H)-one;

[0144] 3-fluoro-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one;

[0145] 4-fluoro-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one;

[0146] 5-fluoro-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one;

[0147] 4-chloro-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one;

[0148] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-(trifluoromethyl)pyridine-2(1H)-one;

[0149] 5-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)thieno[3,2-c]pyridine-4(5H)-one;

[0150] 6-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)thieno[2,3-c]pyridin-7(6H)-one;

[0151] 5-acetyl-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one;

[0152] 4-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)thieno[3,2-b]pyridin-7(4H)-one;

[0153] methyl 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxylate;

[0154] 3-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-4(3H)-one;

[0155] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-methoxypyridine-2(1H)-one;

[0156] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-6-oxo-1,6-dihydropyridine-3-carbaldehyde;

[0157] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-5-(trifluoromethyl)pyridine-2(1H)-one;

[0158] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-N-phenyl-1,2-dihydropyridine-4-carboxamide;

[0159] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-N-(pyridine-3-yl)-1,2-dihydropyridine-4-carboxamide;

[0160] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-N-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide;

[0161] N-ethyl-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxamide;

[0162] N-ethyl-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-N-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide;

[0163] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-(morpholine-4-carbonyl)pyridine-2(1H)-one;

[0164] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-N-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-4-carboxamide;

[0165] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile;

[0166] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile;

[0167] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-6-oxo-1,6-dihydropyridine-3-carbonitrile;

[0168] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile;

[0169] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-3-methoxypyridine-2(1H)-one;

[0170] 3-bromo-5-fluoro-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one;

[0171] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-N-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide;

[0172] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide;

[0173] 1-(((1R,2R)-2-((4-(benzo[d]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carbonitrile;

[0174] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-2(1H)-one;

[0175] 3-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-6-methylpyrimidine-4(3H)-one;

[0176] 2-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridazine-3(2H)-one;

[0177] 1-(((1R,2R)-2-((4-(benzo[d]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-6-oxo-1,6-dihydropyridine-3-carbonitrile;

[0178] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-methylpyrimidine-2(1H)-one;

[0179] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-2(1H)-one;

[0180] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-4-methylpyrimidine-2(1H)-one;

[0181] N-(3-chlorophenyl)-1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxamide;

[0182] 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-iodopyridine-2(1H)-one;

[0183] 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-(piperidine-1-yl)pyridine-2(1H)-one;

[0184] methyl 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxylate;

[0185] 5-chloro-1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one;

[0186] 5-chloro-3-fluoro-1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one;

[0187] 5-bromo-1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-methylpyridine-2(1H)-one;

[0188] 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyrazine-2(1H)-one;

[0189] 3-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-5,6-dimethylpyrimidine-4(3H)-one;

[0190] 5-fluoro-3-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-4(3H)-one;

[0191] 3-(((1R,2R)-2-((4-(4-chlorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-4(3H)-one;

[0192] 3-(((1R,2R)-2-((4-(4-chlorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-6-methylpyrimidine-4(3H)-one;

[0193] 1-(((1R,2R)-2-((4-(benzo]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-2(1H)-one;

[0194] 1-(((1R,2R)-2-((4-(benzo]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile; and

[0195] 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carbonitrile.

[0196]

[0197] According to another embodiment of the present invention, representative compounds of Formula 1 or 2 may include, but are not limited to, the following compounds:

[0198] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one;

[0199] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carbonitrile;

[0200] 3-fluoro-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one;

[0201] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-(trifluoromethyl)pyridine-2(1H)-one;

[0202] 3-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-4(3H)-one;

[0203] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-2(1H)-one;

[0204] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-methylpyrimidine-2(1H)-one; and

[0205] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-4-methylpyrimidine-2(1H)-one.

[0206]

[0207] The compound of Formula 1 or 2 according to the present invention is 5-HT 2A It acts as a dual regulator of receptors (5-hydroxytryptamine receptor 2A) and dopamine D2 receptors.

[0208] According to one embodiment of the present invention, a compound of Formula 1 or 2 exhibits excellent functional activity toward a dopamine D2 receptor. In another embodiment according to the present invention, the inhibitory activity of the compound of Formula 1 or 2 toward a dopamine D2 receptor is IC 50 The value is 2.0 nM or less. In another embodiment according to the present invention, the inhibitory activity of the compound of Formula 1 or 2 against the dopamine D2 receptor is IC10 50 The value is 1.0 nM or less. In another embodiment according to the present invention, the inhibitory activity of the compound of Formula 1 or 2 against the dopamine D2 receptor is IC10 50 The value is 0.5 nM or less. In another embodiment according to the present invention, the inhibitory activity of the compound of Formula 1 or 2 against the dopamine D2 receptor is IC10 50 The value is 0.1 nM or less.

[0209] The compound of Formula 1 or 2 according to the present invention exhibits a significant effect in improving positive symptoms of antipsychotics. According to one embodiment of the present invention, the compound of Formula 1 or 2 has an ED of 0.5 mpk or less in the apomorphine-induced climbing test. 50 It indicates a value. According to another embodiment of the present invention, a compound of Formula 1 or 2 has an ED of 0.2 mpk or less in an apomorphine-induced climbing test. 50 Represents the value.

[0210] In addition, according to another embodiment of the present invention, a compound of Formula 1 or 2 exhibits excellent inhibitory activity against a D3 receptor, and 5-HT 2A The inhibitory activity against the receptor is significantly superior. In another embodiment according to the present invention, the 5-HT of the compound of Formula 1 or 2 2A Inhibitory activity against the receptor is IC 50 The value is 200 nM or less. In another embodiment according to the present invention, the 5-HT of the compound of Formula 1 or 2. 2A Inhibitory activity against the receptor is IC 50 The value is 100 nM or less. In another embodiment according to the present invention, the 5-HT of the compound of Formula 1 or 2. 2A Inhibitory activity against the receptor is IC 50 The value is 50 nM or less. In another embodiment according to the present invention, the 5-HT of the compound of Formula 1 or 2. 2A Inhibitory activity against the receptor is IC 50 The value is 20 nM or less. In another embodiment according to the present invention, the 5-HT of the compound of Formula 1 or 2. 2A Inhibitory activity against the receptor is IC 50The value is 10 nM or less. The compound of Formula 1 or 2 according to the present invention can provide a treatment for mental illness that exhibits a significant effect on the treatment of negative symptoms and / or cognitive improvement, while simultaneously reducing side effects such as extrapyramidal symptoms (EPS).

[0211] In addition, according to one embodiment of the present invention, the compound of Formula 1 or 2 does not exhibit the side effect of weight gain that commonly occurs in second-generation antipsychotic drugs.

[0212] In addition, the compound of Formula 1 or 2 according to the present invention has excellent metabolic stability. Since metabolic stability is a factor that can affect pharmacokinetic parameters (PK parameters) such as clearance, half-life, and oral bioavailability, it is one of the characteristics that drug candidates must possess.

[0213] The medicinal effect of the compound of Formula 1 or 2 according to the present invention may be maintained in the form of a pharmaceutically acceptable salt. In other embodiments according to the present invention, the pharmaceutically acceptable salt includes both the addition salt of an acid or base and the stereochemical isomer form thereof. The salt includes any salt that maintains the activity of the parent compound in the subject of administration and does not cause undesirable effects, and is not particularly limited.

[0214]

[0215] Manufacturing method

[0216] The compound of Formula 1 or 2 according to one embodiment can be prepared using known compounds or compounds that can be easily prepared from them, by a person with ordinary knowledge of compound synthesis in the art. For example, the compound of Formula 1 or 2 can be synthesized according to the methods of Reaction Schemes 1 to 4 below, but this is merely an exemplary method and the order of unit operations, etc., may be selectively changed as needed, and is not intended to limit the scope of the invention.

[0217] [Reaction Equation 1]

[0218]

[0219] Compounds 1 and 2 can be prepared from intermediate 3 by ring-opening reactions with the addition of various nucleophiles, and compound 1 can also be obtained through reaction scheme 4. Intermediate 3 can be prepared in a manner similar to reaction scheme 1a below.

[0220] [Reaction Equation 1a]

[0221]

[0222] L1 of intermediate 5 is a leaving group such as a methanesulfonate group, and intermediate 3 can be obtained through a nucleophilic substitution reaction with intermediate 4. Intermediate 4 can be prepared by various methods including the following reaction scheme 1b, and intermediate 5 can be obtained by the method of reaction scheme 1c.

[0223] [Reaction Equation 1b]

[0224]

[0225] X is a leaving group such as a halogen, and intermediate 4 can be prepared by various methods including, but not limited to, the method of reaction scheme 1b.

[0226]

[0227] [Reaction Equation 1c]

[0228]

[0229] Intermediate 5 containing a leaving group can be prepared from intermediate 14 having a diol through a methanesulfonylation reaction.

[0230]

[0231] [Reaction Equation 2]

[0232]

[0233] Compound 1-2 can be obtained from compound 1-1 containing an alkyl ester group prepared through reaction scheme 1 through a hydrolysis reaction, and compound 1-3 can be obtained through coupling with various amines.

[0234]

[0235] [Reaction Equation 3]

[0236]

[0237] R2 is an aryl group such as phenyl, and compound 1-5 can be obtained from compound 1-4 containing a halogen prepared through reaction scheme 1 via a Suzuki-Miyaura coupling reaction.

[0238]

[0239] [Reaction Equation 4]

[0240]

[0241] Compound 1 can be prepared from intermediate 16 by various methods including, but not limited to, a cyclization reaction as shown in Reaction Scheme 4. Intermediate 15 can be obtained by a method similar to Reaction Scheme 4a below.

[0242]

[0243] [Reaction Equation 4a]

[0244]

[0245] Intermediate 15 can be prepared through the amine deprotection reaction of intermediate 18 obtained through a nucleophilic substitution reaction, and intermediate 17 can be obtained through the following reaction scheme 4b.

[0246]

[0247] [Reaction Equation 4b]

[0248]

[0249] Intermediate 19 can be obtained by reducing intermediate 18 as a starting material, and then intermediate 17 containing a leaving group can be prepared.

[0250]

[0251] Pharmaceutical composition

[0252] According to another aspect of the present invention, a pharmaceutical composition for the prevention or treatment of mental illness is provided, comprising, as an active ingredient, a therapeutically effective amount of a compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.

[0253] The above pharmaceutical composition may be formulated into various oral or parenteral administration forms. For example, it may be any oral administration form such as tablets, pills, hard / soft capsules, liquids, suspensions, emulsifiers, syrups, granules, elixirs, etc.

[0254] These oral formulations may include, in addition to the active ingredient, pharmaceutically acceptable carriers such as diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, or lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycol, depending on the conventional composition of each formulation.

[0255] In addition, when the above oral formulation is a tablet, it may include a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and in some cases, may additionally include a disintegrant such as starch, agar, alginic acid or its sodium salt, a boiling mixture and / or an absorbent, a coloring agent, a flavoring agent or a sweetener, etc.

[0256] The above pharmaceutical composition may be formulated into a parenteral administration form, in which case it is administered by parenteral administration methods such as subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. In order to formulate the above pharmaceutical composition into a parenteral administration form, the active ingredient, i.e., the compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof, is mixed in water with a stabilizer or buffer to prepare a solution or suspension, and such solution or suspension may be prepared into a unit dosage form in an ampoule or vial.

[0257] In addition, the above pharmaceutical composition may be sterilized or further include adjuvants such as preservatives, stabilizers, wettable powders or emulsification promoters, salts and / or buffers for osmotic pressure regulation, and further include other therapeutically useful substances, and may be formulated according to conventional methods of mixing, granulation, or coating.

[0258]

[0259] Medical utility

[0260] Another aspect of the present invention provides a method for preventing or treating a mental disorder in a subject who requires it, comprising administering a therapeutically effective amount of the compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof, to the subject who requires it. The mental disorder may be, for example, schizophrenia, but is not limited thereto.

[0261] The compound of Chemical Formula 1 or 2 above is a dopamine D2 receptor and 5-HT 2A It is a compound that simultaneously inhibits receptors. Dopamine D2 receptor and 5-HT 2A The main pharmacological characteristic of receptor inhibition is that it alleviates side effects resulting from dopamine over-inhibition as well as treats and relieves symptoms of schizophrenia by regulating excessive dopamine activity to an appropriate level.

[0262] Dopamine excess in the mesolimbic pathway, one of the major causes of schizophrenia, consequently leads to hyperactivation of dopamine receptors in medium spiny neurons (MSNs) within the striatum. Dopamine D2 receptor antagonists inhibit dopamine receptor hyperactivation in the striatum, and effective suppression of positive symptoms of schizophrenia has been reported in animal models and clinical data.

[0263] 5-HT 2A Antagonism has been reported to alleviate side effects (e.g., extrapyramidal symptoms) associated with dopamine D2 receptor inhibition (HY Meltzer, Neuropsychopharmacology, 1999). 5-HT 2A It has been reported that antagonists do not increase dopamine in the nucleus accumbens (NAc), which is associated with positive symptoms of schizophrenia, but do increase dopamine in the dorsal striatum, which is associated with extrapyramidal symptoms (J Ichikawa et al., Brain Res., 2000). This dorsal striatum-selective increase in dopamine is identified as the underlying mechanism for the reduction of extrapyramidal side effects by alleviating the decrease in dopamine signaling caused by D2 antagonism (HY Meltzer, Neuropsychopharmacology, 1999).

[0264] Also, 5-HT 2AStudies have shown that antagonists regulate dopamine in mesocortical pathways that are major in negative symptoms. Among the mesocortical pathways, 5-HT in the prefrontal cortex (PFC) 2A Antagonist administration is 5-HT 1A It amplified the increase in dopamine caused by action (J Ichikawa et al., J Neurochem., 2001).

[0265]

[0266] In another embodiment according to the present invention, a method for preventing or treating a mental disorder comprises the step of administering to an animal a pharmaceutical composition comprising an effective amount of a compound of Formula 1 or 2 and a pharmaceutically acceptable carrier. The method of the present invention is particularly suitable for use in humans, but may also be used in other animals, particularly mammals.

[0267] The specific method of administration and the therapeutically effective amount of the compound of Formula 1 or 2 or a pharmaceutically acceptable salt thereof can be obviously determined by a person skilled in the art by taking into account the type of target mammal, the type of disease, and the type of compound of Formula 1 or 2, and are not particularly limited.

[0268] For example, the compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof, may be included in the pharmaceutical composition in an effective amount of 0.1 to 500 mg / kg (body weight), preferably 0.5 to 100 mg / kg (body weight), per day for mammals including humans, and the pharmaceutical composition may be administered once or twice or more times per day via an oral or parenteral route.

[0269]

[0270] Examples

[0271] The present invention will be explained in more detail below through examples. However, the examples are intended only to illustrate the present invention and do not limit the scope of the invention.

[0272]

[0273] Example 1: Synthesis of 3-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)quinazolin-4(3H)-one

[0274] Step 1: Synthesis of ((1R,2R)-cyclohexane-1,2-diyl)bis(methylene)dimethanesulfonate

[0275]

[0276]

[0277] A solution of ((1R,2R)-cyclohexane-1,2-diyl)dimethanol (40.000 g, 277.373 mmol) and triethylamine (96.651 mL, 693.433 mmol) dissolved in dichloromethane (100 mL) was stirred at 0°C for 20 minutes, and then methanesulfonyl chloride (42.937 mL, 554.747 mmol) was added and stirred for an additional 18 hours at room temperature. The reaction mixture was filtered through a glass filter to remove the solid, water was added to the filtrate, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Hexane (100 mL) was added to the concentrate and stirred to filter the precipitated solid, wash with hexane, and dry to obtain ((1R,2R)-cyclohexane-1,2-diyl)bis(methylene)dimethanesulfonate (62.890 g, 75.5%) in the form of a white solid.

[0278]

[0279] Step 2: Synthesis of (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydrospiro[isoindole-2,1'-piperidine]-2-ium methanesulfonate

[0280]

[0281]

[0282] A solution of 6-fluoro-3-(piperidine-4-yl)benzo[d]isooxazole hydrochloride (10.000 g, 38.954 mmol), ((1R,2R)-cyclohexane-1,2-diyl)bis(methylene) dimethane sulfonate (15.211 g, 50.641 mmol), and potassium carbonate (K2CO3, 16.151 g, 116.863 mmol) dissolved in acetonitrile (50 mL) at room temperature was heated under reflux for 18 hours, after which the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was filtered through a glass filter to remove the solid, and the solvent was removed from the filtrate under reduced pressure. The concentrate was then purified and concentrated by column chromatography to obtain (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydrospiro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (11.890 g, 71.9%) as a pale yellow oil: LRMS(ES)m / z329.23 [M+H] + , calculated MW 424.53.

[0283]

[0284] Step 3: Synthesis of 3-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)quinazolin-4(3H)-one

[0285]

[0286]

[0287] (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.080 g, 0.188 mmol), quinazolin-4(3H)-one (0.033 g, 0.226 mmol), and potassium carbonate (K2CO3, 0.052 g, 0.377 mmol) were dissolved in toluene (1 mL) at room temperature and stirred at 105°C for 18 hours, after which the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography to obtain 3-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)quinazolin-4(3H)-one (0.010 g, 11.2%) as a pale yellow oil: LRMS(ES)m / z475.46 [M+H] + , calculated MW 474.58;1H-NMR(400 MHz, DMSO-d6) d 8.35 (s, 1 H), 8.12 (d,J= 7.6 Hz, 1 H), 7.97 (bs, 1 H), 7.79 (t,J= 7.8 Hz, 1 H), 7.65 (t,J= 6.6) Hz, 1 H), 7.51 (t,J= 7.6 Hz, 1 H), 7.25 (bs, 1 H), 3.45 ~ 3.44 (m, 4 H), 2.05 (m, 5 H), 1.82 ~ 1.68 (m, 4 H), 1.56 (m, 2 H), 1.39 (m, 2) H), 1.19 to 1.04 (m, 6 H).

[0288]

[0289] Example 2: Synthesis of 4-bromo-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)pyridin-2(1H)-one

[0290]

[0291]

[0292] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.100 g, 0.236 mmol), 4-bromopyridine-2(1H)-one (0.061 g, 0.353 mmol), and potassium carbonate (K2CO3, 0.065 g, 0.471 mmol) as starting materials, 4-bromo-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one (0.012 g, 10.1%) was prepared yellow in a manner similar to Step 3 of Example 1. Obtained in oil form: LRMS(ES)m / z504.32 [M+2H] + , calculated MW 502.43;1H-NMR(400 MHz, DMSO-d6) d 8.01 (s, 1 H), 7.69 (s, 1 H), 7.62 (d,J= 6.8 Hz, 1 H), 7.31 (s, 1 H), 6.68 (s, 1 H), 6.45 (s, 1 H), 3.35 (m, 4 H), 1.87 to 1.56 (m, 11 H), 1.41 (s, 1 H), 1.19 to 0.99 (m, 7 H).

[0293]

[0294] Example 3: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one hydrochloride

[0295] Step 1: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)pyridin-2(1H)-one

[0296]

[0297]

[0298] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.200 g, 0.471 mmol), pyridine-2(1H)-one (0.067 g, 0.707 mmol), and potassium carbonate (K2CO3, 0.195 g, 1.413 mmol) as starting materials, 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one (0.066 g, 33.1%) was prepared in the form of a yellow oil in a manner similar to Step 3 of Example 1. Obtained:LRMS(ES)m / z424.34 [M+H] + , calculated MW 423.53;1H-NMR(400 MHz, DMSO-d6) d 7.97 (dd,J= 8.2, 5.4 Hz, 1 H), 7.66 (d,J= 9.2 Hz, 1 H), 7.59 (d,J= 5.2 Hz, 1 H), 7.35 (t,J= 7.2 Hz, 1 H), 7.25 (t,J= 8.8 Hz, 1 H), 6.31 (d,J= 9.2 Hz, 1 H), 6.15 (t,J= 6.4 Hz, 1 H), 4.35 (d,J= 11.6 Hz, 1 H), 3.52 (t,J= 6.0 Hz, 2 H), 3.37 (m, 4 H), 2.97 (m, 2 H), 2.05 to 2.00 (m, 4 H), 1.57 (m, 2 H), 1.66 to 1.54 (m, 3 H), 1.37 (m, 2 H), 1.06 to 0.93 (m, 4 H).

[0299]

[0300] Step 2: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one hydrochloride

[0301]

[0302]

[0303] Hydrogen chloride (1.00 M solution in EtOAc, 0.130 mL, 0.130 mmol) was added to a solution of 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one (0.055 g, 0.130 mmol) dissolved in ethyl acetate (0.3 mL) / diethyl ether (5 mL) at room temperature and stirred at the same temperature. The precipitated solid was filtered, washed with diethyl ether, and dried to obtain 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one hydrochloride (0.042 g, 70.3%) in the form of a beige solid: LRMS(ES)m / z474.21 [M+H] + , calculated MW 459.99;1H-NMR(400 MHz, CD3OD) d 7.98 (q,J= 4.8 Hz, 1 H), 7.64 (dd,J= 7.0, 1.8 Hz, 1 H), 7.58 (td,J= 7.9, 2.7 Hz, 1 H), 7.42 (dd,J= 8.8, 2.0 Hz, 1 H), 7.21 (td,J= 9.1, 2.1 Hz, 1 H), 6.63 (d,J= 8.8 Hz, 1 H), 6.43 (td,J= 6.9, 1.2 Hz, 1 H), 4.20 (d,J= 10.8 Hz, 1 H), 3.93 (dd,J=13.4, 7.0 Hz, 1 H), 3.84 (d,J= 14.0 Hz, 1 H), 3.76 (d,J= 14.4 Hz, 1 H), 3.57 to 3.49 (m, 2 H), 3.28 to 3.16 (m, 3 H), 2.41 (m, 3 H), 2.32 (m, 1 H), 1.96 (m, 1 H), 1.81 to 1.70 (m, 5 H), 1.30 (m, 3 H), 1.13 (q,J= 11.1 Hz, 1 H).

[0304]

[0305] Example 4: Synthesis of 2-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)isoquinoline-1(2H)-one

[0306]

[0307]

[0308] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.200 g, 0.471 mmol), isoquinoline-1(2H)-one (0.103 g, 0.707 mmol), and potassium carbonate (K2CO3, 0.195 g, 1.413 mmol) as starting materials, 2-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)isoquinoline-1(2H)-one (0.119 g, 53.3%) was prepared as a white solid in a manner similar to Step 3 of Example 1. Obtained:LRMS(ES)m / z474.34 [M+H] + , calculated MW 473.59;1H-NMR (400 MHz, DMSO-d6) d 8.17 (d,J= 8.0 Hz, 1 H), 7.97 (dd,J= 8.6, 5.0 Hz, 1 H), 7.67 ~ 7.61 (m, 3 H), 7.45 (td,J= 5.7, 3.1 Hz, 1 H), 7.41 (d,J= 7.2 Hz, 1 H), 7.25 (t,J= 8.0 Hz, 1 H), 4.42 (d,J= 8.8 Hz, 1 H), 3.65 (t,J= 10.8 Hz, 1 H), 3.12 ~ 2.99 (m, 4 H), 2.58 (m, 1 H), 2.05 ~ 1.70 (m, 8 H), 1.54 to 1.39 (m, 4 H), 1.19 to 0.94 (m, 4 H).

[0309]

[0310] Example 5: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carbonitrile hydrochloride

[0311] Step 1: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carbonitrile

[0312]

[0313]

[0314] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.200 g, 0.471 mmol), 2-oxo-1,2-dihydropyridine-4-carbonitrile (0.085 g, 0.707 mmol), and potassium carbonate (K2CO3, 0.195 g, 1.413 mmol) as starting materials, in a manner similar to Step 3 of Example 1 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carbonitrile (0.055 g, 26.0%) was obtained in the form of a yellow oil: LRMS(ES)m / z449.31 [M+H] +, calculated MW 448.54;1H-NMR(400 MHz, DMSO-d6) d 7.97 (dd,J= 8.8, 5.6 Hz, 1 H), 7.86 (d,J= 6.8 Hz, 1 H), 7.65 (dd,J= 9.0, 2.2 Hz, 1 H), 7.24 (t,J= 8.2 Hz, 1 H), 6.96 (d,J= 1.2 Hz, 1 H), 6.49 (dd,J= 6.8, 2.0 Hz, 1 H), 4.43 (d,J= 8.8 Hz, 1 H), 3.60 (t,J= 11.2 Hz, 1 H), 3.12 ~ 2.94 (m, 4 H), 2.04 ~ 1.97 (m, 5 H), 1.83 to 1.54 (m, 6 H), 1.37 to 0.92 (m, 6 H).

[0315]

[0316] Step 2: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carbonitrile hydrochloride

[0317]

[0318]

[0319] Using 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carbonitrile (0.028 g, 0.062 mmol) as a starting material, 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carbonitrile hydrochloride (0.022 g, 72.7 %) was obtained in the form of an ivory solid by a method similar to Step 2 of Example 3: LRMS(ES)m / z449.31 [M+H] +, calculated MW 485;1H-NMR(400 MHz, CD3OD) d 7.91 (dd,J= 8.8, 5.2 Hz, 1 H), 7.80 (d,J= 7.2 Hz, 1 H), 7.42 (dd,J= 8.8, 2.4 Hz, 1 H), 7.20 (td,J= 8.8, 2.0 Hz, 1 H), 6.99 (s, 1 H), 6.55 (dd,J= 7.0, 1.8 Hz, 1 H), 4.26 (d,J= 14.0 Hz, 1 H), 3.89 (dd,J= 14.2, 7.4 Hz, 1 H), 3.69 (bs, 2) H), 3.53 (m, 2 H), 3.20 ~ 3.00 (m, 3 H), 2.42 to 2.22 (m, 4 H), 1.97 (d,J= 10.4 Hz, 1 H), 1.79 to 1.66 (m, 5 H), 1.37 to 1.23 (m, 3 H), 1.15 (m, 1 H).

[0320]

[0321] Example 6: Synthesis of 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-4-methylpyridine-2(1H)-one

[0322] Step 1: Synthesis of (3aR,7aR)-4'-(benzo[d]isothiazole-3-yl)octahydrospiro[isoindole-2,1'-piperazine]-2-yum methanesulfonate

[0323]

[0324]

[0325] (3aR,7aR)-4'-(benzo[d]isothiazole-3-yl)octahydrospiro[isoindole-2,1'-piperazine]-2-ium methanesulfonate (2.872 g, 49.6%) was obtained as a pale yellow solid in a manner similar to Step 2 of Example 1 using 3-(piperazine-1-yl)benzo[d]isothiazole-3-yl)octahydrospiro[isoindole-2,1'-piperazine]-2-ium methanesulfonate as a pale yellow solid:LRMS(ES)m / z328.17 [M+H] + , calculated MW 423.59.

[0326]

[0327] Step 2: Synthesis of 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-4-methylpyridine-2(1H)-one

[0328]

[0329]

[0330] Using (3aR,7aR)-4'-(benzo[d]isothiazole-3-yl)octahydropyro[isoindole-2,1'-piperazine]-2-ium methanesulfonate (0.200 g, 0.472 mmol), 4-methylpyridine-2(1H)-one (0.062 g, 0.567 mmol), and potassium carbonate (K2CO3, 0.196 g, 1.416 mmol) as starting materials, 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-4-methylpyridine-2(1H)-one (0.021 g, 10.2%) was prepared in the form of a yellow oil in a manner similar to Step 3 of Example 1. Obtained:LRMS(ES)m / z437.29 [M+H] +, calculated MW 436.62;1H-NMR(400 MHz, DMSO-d6) d 8.04 (d,J= 7.2 Hz, 2 H), 7.54 (t,J= 7.4 Hz, 1 H), 7.48 (d,J= 6.4 Hz, 1 H), 7.41 (t,J= 7.0 Hz, 1 H), 6.16 (s, 1 H), 6.04 (s, 1 H), 4.26 (s, 1 H), 3.40 (m, 4 H), 2.55 (m, 4 H), 2.08 (s, 3 H), 1.88 (d,J= 7.6 Hz, 1 H), 1.63 ~ 1.56 (m, 4 H), 1.38 (s, 2 H), 1.19 (m, 2 H), 1.07 to 0.95 (m, 4 H).

[0331]

[0332] Example 7: Synthesis of 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-3-methylpyridine-2(1H)-one

[0333]

[0334]

[0335] Using (3aR,7aR)-4'-(benzo[d]isothiazole-3-yl)octahydropyro[isoindole-2,1'-piperazine]-2-ium methanesulfonate (0.200 g, 0.472 mmol), 3-methylpyridine-2(1H)-one (0.062 g, 0.567 mmol), and potassium carbonate (K2CO3, 0.196 g, 1.416 mmol) as starting materials, 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-3-methylpyridine-2(1H)-one (0.071 g, 34.4%) was prepared in the form of a yellow oil in a manner similar to Step 3 of Example 1. Obtained:LRMS(ES)m / z437.29 [M+H] +, calculated MW 436.62;1H-NMR(400 MHz, DMSO-d6) d 8.02 (d,J= 7.6 Hz, 2 H), 7.52 (t,J= 7.8 Hz, 1 H), 7.44 ~ 7.38 (m, 2 H), 7.25 (d,J= 19.2 Hz, 1 H), 6.07 (t,J= 6.6 Hz, 1 H), 4.39 (d,J= 12.0 Hz, 1 H), 3.51 (t,J= 11.4 Hz, 1 H), 3.40 (m, 4 H), 2.56 (m, 4 H), 1.95 (s, 3 H), 1.86 (d,J= 13.6 Hz, 2 H), 1.72 ~ 1.55 (m, 4 H), 1.39 to 1.33 (m, 2 H), 1.19 to 0.94 (m, 4 H).

[0336]

[0337] Example 8: Synthesis of 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-5-methylpyridine-2(1H)-one

[0338]

[0339]

[0340] Using (3aR,7aR)-4'-(benzo[d]isothiazole-3-yl)octahydropyro[isoindole-2,1'-piperazine]-2-ium methanesulfonate (0.200 g, 0.472 mmol), 5-methylpyridine-2(1H)-one (0.062 g, 0.567 mmol), and potassium carbonate (K2CO3, 0.196 g, 1.416 mmol) as starting materials, 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-5-methylpyridine-2(1H)-one (0.032 g, 15.5%) was prepared in the form of a yellow oil in a manner similar to Step 3 of Example 1. Obtained:LRMS(ES)m / z437.29 [M+H] +, calculated MW 436.62;1H-NMR(400 MHz, DMSO-d6) d 8.03 (d,J= 7.6 Hz, 2 H), 7.53 (t,J= 7.8 Hz, 1 H), 7.43 (m, 2 H), 7.23 (d,J= 8.8 Hz, 1 H), 6.28 (d,J= 8.8 Hz, 1 H), 4.25 (s, 1 H), 3.56 (s, 1 H), 3.40 (m, 4 H), 2.54 (m, 4 H), 1.98 (s, 3 H), 1.66 to 1.55 (m, 4 H), 1.38 (s, 2 H), 1.19 ~ 0.97 (m, 6 H).

[0341]

[0342] Example 9: Synthesis of 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-4-fluoropyridine-2(1H)-one

[0343]

[0344]

[0345] Using (3aR,7aR)-4'-(benzo[d]isothiazole-3-yl)octahydropyro[isoindole-2,1'-piperazine]-2-ium methanesulfonate (0.150 g, 0.354 mmol), 4-fluoropyridine-2(1H)-one (0.048 g, 0.425 mmol), and potassium carbonate (K2CO3, 0.147 g, 1.062 mmol) as starting materials, 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-4-fluoropyridine-2(1H)-one (0.029 g, 18.6%) was prepared in the form of a white solid in a manner similar to Step 3 of Example 1. Obtained:LRMS(ES)m / z441.25 [M+H] +, calculated MW 440.58;1H-NMR(400 MHz, DMSO-d6) d 8.00 (d,J= 8.8 Hz, 2 H), 7.76 (t,J= 8.0 Hz, 1 H), 7.52 (t,J= 8.0 Hz, 1 H), 7.39 (t,J= 8.0 Hz, 1 H), 6.23 (td,J= 7.2, 2.8 Hz, 1 H), 6.11 (dd,J= 12.0, 2.8 Hz, 1 H), 4.36 (dd,J= 12.8, 5.2 Hz, 1 H), 3.59 (dd,J= 12.8, 9.6 Hz, 1 H), 3.41 (m, 4 H), 2.56 ~ 2.54 (m, 5 H), 2.14 to 2.12 (m, 1 H), 1.87 to 1.83 (m, 1 H), 1.67 to 1.55 (m, 3 H), 1.41 to 1.36 (m, 2 H), 1.20 (m, 2 H), 1.02 (m, 2 H).

[0346]

[0347] Example 10: Synthesis of 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-5-fluoropyridine-2(1H)-one

[0348]

[0349]

[0350] Using (3aR,7aR)-4'-(benzo[d]isothiazole-3-yl)octahydropyro[isoindole-2,1'-piperazine]-2-ium methanesulfonate (0.150 g, 0.354 mmol), 5-fluoropyridine-2(1H)-one (0.048 g, 0.425 mmol), and potassium carbonate (K2CO3, 0.147 g, 1.062 mmol) as starting materials, 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-5-fluoropyridine-2(1H)-one (0.015 g, 9.6%) was prepared in the form of a blue oil in a manner similar to Step 3 of Example 1. Obtained:LRMS(ES)m / z441.19 [M+H]+ , calculated MW 440.58;1H-NMR(400 MHz, DMSO-d6) d 8.00 (d,J= 9.2 Hz, 2 H), 7.84 (dd,J= 4.4, 3.6 Hz, 1 H), 7.53 ~ 7.46 (m, 2 H), 7.39 (t,J= 8.0 Hz, 1 H), 6.35 (dd,J= 10.0, 5.6 Hz, 1 H), 4.30 (dd,J= 12.6, 5.0 Hz, 1 H), 3.57 (dd,J= 12.8, 9.6 Hz, 1 H), 3.41 (m, 4 H), 2.58 to 2.50 (m, 5 H), 2.14 (q,J= 6.4 Hz, 1 H), 1.86 to 1.83 (m, 1 H), 1.70 (m, 1 H), 1.58 to 1.55 (m, 2 H), 1.41 to 1.39 (m, 2 H), 1.20 to 1.18 (m, 2 H), 1.03 to 0.95 (m, 2 H).

[0351]

[0352] Example 11: Synthesis of 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-4-chloropyridine-2(1H)-one

[0353]

[0354]

[0355] Using (3aR,7aR)-4'-(benzo[d]isothiazole-3-yl)octahydropyro[isoindole-2,1'-piperazine]-2-ium methanesulfonate (0.150 g, 0.354 mmol), 4-chloropyridine-2(1H)-one (0.055 g, 0.425 mmol), and potassium carbonate (K2CO3, 0.147 g, 1.062 mmol) as starting materials, 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-4-chloropyridine-2(1H)-one (0.023 g, 14.2%) was prepared in the form of an ivory solid in a manner similar to Step 3 of Example 1. Obtained:LRMS(ES)m / z457.23 [M+H] + , calculated MW 457.03;1H-NMR(400 MHz, DMSO-d6) d 8.00 (d,J= 8.8 Hz, 2 H), 7.68 (d,J= 7.2 Hz, 1 H), 7.51 (t,J= 8.0 Hz, 1 H), 7.39 (t,J= 7.8 Hz, 1 H), 6.46 (d,J= 2.8 Hz, 1 H), 6.29 (dd,J= 7.2, 2.4 Hz, 1 H), 4.35 (dd,J= 13.0, 4.6 Hz, 1 H), 3.58 (dd,J= 13.0, 9.8 Hz, 1 H), 3.42 ~ 3.40 (m, 4 H), 2.58 ~ 2.50 (m, 5 H), 2.14 (q,J= 6.4 Hz, 1 H), 1.87 ~ 1.82 (m, 1 H), 1.66 ~ 1.62 (m, 1 H), 1.58 ~ 1.55 (m, 2 H), 1.40 ~ 1.33 (m, 2 H), 1.20 ~ 1.18 (m, 2 H), 1.02 to 0.99 (m, 2 H).

[0356]

[0357] Example 12: Synthesis of 6-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)thieno[2,3-c]pyridin-7(6H)-one

[0358]

[0359]

[0360] Using (3aR,7aR)-4'-(benzo[d]isothiazole-3-yl)octahydropyro[isoindole-2,1'-piperazine]-2-ium methanesulfonate (0.150 g, 0.354 mmol), thieno[2,3-c]pyridine-7(6H)-one (0.064 g, 0.425 mmol), and potassium carbonate (K2CO3, 0.147 g, 1.062 mmol) as starting materials, in a manner similar to Step 3 of Example 1, 6-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)thieno[2,3-c]pyridine-7(6H)-one (0.049 g, 28.9%) was obtained in the form of a white solid: LRMS(ES)m / z479.23 [M+H] + , calculated MW 478.67;1H-NMR(400 MHz, DMSO-d6) d 8.00 (d,J= 8.4 Hz, 2 H), 7.96 (d,J= 5.2 Hz, 1 H), 7.53 ~ 7.48 (m, 2 H), 7.39 (dd,J= 8.8, 7.2 Hz, 1 H), 7.31 (d,J= 5.2 Hz, 1 H), 6.71 (d,J= 6.8 Hz, 1 H), 4.46 (dd,J= 13.0, 4.6 Hz, 1 H), 3.73 (d,J= 9.6 Hz, 1 H), 3.41 (m, 4 H), 2.63 ~ 2.50 (m, 5 H), 2.17 (q,J= 6.4 Hz, 1 H), 1.89 ~ 1.86 (m, 1 H), 1.73 ~ 1.71 (m, 1 H), 1.57 ~ 1.55 (m, 2 H), 1.45 ~ 1.36 (m, 2 H), 1.20 (m, 2 H), 1.05 ~ 0.97 (m, 2 H).

[0361]

[0362] Example 13: Synthesis of 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-4-bromopyridine-2(1H)-one

[0363]

[0364]

[0365] Using (3aR,7aR)-4'-(benzo[d]isothiazole-3-yl)octahydropyro[isoindole-2,1'-piperazine]-2-ium methanesulfonate (0.150 g, 0.354 mmol), 4-bromopyridine-2(1H)-one (0.123 g, 0.708 mmol), and potassium carbonate (K2CO3, 0.147 g, 1.062 mmol) as starting materials, 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-4-bromopyridine-2(1H)-one (0.040 g, 22.5%) was prepared in the form of a white solid in a manner similar to Step 3 of Example 1. Obtained:LRMS(ES)m / z503.14 [M+2H] + , calculated MW 501.49;1H-NMR(400 MHz, DMSO-d6) d 8.02 (d,J= 8.4 Hz, 2 H), 7.62 (d,J= 7.2 Hz, 1 H), 7.53 (t,J= 7.8 Hz, 1 H), 7.40 (t,J= 7.8 Hz, 1 H), 6.66 (s, 1 H), 6.42 (d,J= 6.0 Hz, 1 H), 4.32 (m, 1 H), 3.59 (m, 1 H), 3.40 (m, 4 H), 2.54 (m, 5 H), 2.14 (m, 1 H), 1.85 (d,J= 15.6) Hz, 1 H), 1.64 (m, 1 H), 1.57 (d,J= 12.0 Hz, 2 H), 1.41 (m, 1 H), 1.34 (m, 1 H), 1.19 (q,J= 12.7 Hz, 1 H), 1.11 to 0.92 (m, 3 H).

[0366]

[0367] Example 14: Synthesis of 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one

[0368]

[0369]

[0370] Using (3aR,7aR)-4'-(benzo[d]isothiazole-3-yl)octahydropyro[isoindole-2,1'-piperazine]-2-ium methanesulfonate (0.180 g, 0.425 mmol), pyridine-2(1H)-one (0.081 g, 0.850 mmol), and potassium carbonate (K2CO3, 0.176 g, 1.275 mmol) as starting materials, 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one (0.076 g, 42.3%) was prepared as a pale yellow solid in a manner similar to Step 3 of Example 1. Obtained:LRMS(ES)m / z423.22 [M+H] + , calculated MW 422.59;1H-NMR(400 MHz, DMSO-d6) d 8.02 (d,J= 8.8 Hz, 2 H), 7.59 (dd,J= 6.8, 1.6 Hz, 1 H), 7.52 (t,J= 8.0 Hz, 1 H), 7.40 (t,J= 5.6) Hz, 1 H), 7.35 (t,J= 8.8 Hz, 1 H), 6.32 (d,J= 8.0 Hz, 1 H), 4.06 (m, 1 H), 3.57 (dd,J= 12.6, 9.8 Hz, 1 H), 3.43 (m, 4 H), 2.63 (m, 5 H), 2.26 (s, 1 H), 1.86 (d,J= 12.8 Hz, 1 H), 1.67 (m, 1 H), 1.56 (d,J= 10.8 Hz, 2 H), 1.44 (m, 1 H), 1.34 (d,J= 12.8 Hz, 1 H), 1.19 (q,J= 10.3 Hz, 1 H), 1.07 ~ 0.97 (m, 3 H).

[0371]

[0372] Example 15: Synthesis of 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-5-bromopyridine-2(1H)-one

[0373]

[0374]

[0375] Using (3aR,7aR)-4'-(benzo[d]isothiazole-3-yl)octahydropyro[isoindole-2,1'-piperazine]-2-ium methanesulfonate (0.200 g, 0.472 mmol), 5-bromopyridine-2(1H)-one (0.164 g, 0.944 mmol), and potassium carbonate (K2CO3, 0.196 g, 1.416 mmol) as starting materials, 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-5-bromopyridine-2(1H)-one (0.047 g, 19.8%) was prepared as a white solid in a manner similar to Step 3 of Example 1. Obtained:LRMS(ES)m / z503.14 [M+2H] + , calculated MW 501.49;1H-NMR(400 MHz, CD3OD) d 7.99 (d,J= 8.0 Hz, 1 H), 7.89 ~ 7.87 (m, 2 H), 7.56 (dd,J= 9.6, 2.8 Hz, 1 H), 7.51 (t,J= 7.4 Hz, 7 H), 7.40 (t,J= 7.0 Hz, 1 H), 6.48 (d,J= 9.6 Hz, 1 H), 4.57 ~ 4.53 (m, 2 H), 3.67 (dd,J= 13.0, 9.4 Hz, 1 H), 3.56 (m, 4 H), 2.86 (m, 1 H), 2.82 (m, 5 H), 1.94 (d,J= 13.6 Hz, 1 H), 1.76 to 1.74 (m, 1 H), 1.68 (d,J= 12.4 Hz, 2 H), 1.57 to 1.51 (m, 2 H), 1.29 (m, 1 H), 1.23 to 1.04 (m, 3 H).

[0376]

[0377] Example 16: Synthesis of 5-acetyl-1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one

[0378]

[0379]

[0380] Using (3aR,7aR)-4'-(benzo[d]isothiazole-3-yl)octahydropyro[isoindole-2,1'-piperazine]-2-ium methanesulfonate (0.200 g, 0.472 mmol), 1-(4-hydroxyphenyl)ethane-1-one (0.129 g, 0.944 mmol), and potassium carbonate (K2CO3, 0.196 g, 1.416 mmol) as starting materials, 5-acetyl-1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one (0.146 g, 66.6%) was prepared as a pale yellow solid in a manner similar to Step 3 of Example 1. Obtained:LRMS(ES)m / z465.29 [M+H] + , calculated MW 464.63;1H-NMR(400 MHz, CD3OD) d 8.22 (d,J= 2.8 Hz, 1 H), 7.99 (dd,J= 13.0, 8.6 Hz, 2 H), 7.83 (dd,J= 9.2, 2.4 Hz, 1 H), 7.51 (t,J= 7.2 Hz, 1 H), 7.38 (t,J= 7.4 Hz, 1 H), 6.78 (d,J= 8.8 Hz, 1 H), 4.32 ~ 4.21 (m, 2 H), 3.34 (m, 4 H), 2.50 (m, 8 H), 2.16 (s, 1 H), 1.86 (d,J=12.0 Hz, 1 H), 1.76 (d,J= 8.4 Hz, 1 H), 1.64 to 1.53 (m, 4 H), 1.21 (m, 3 H), 0.96 (m, 1 H).

[0381]

[0382] Example 17: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)-4-phenylpyridine-2(1H)-one

[0383]

[0384]

[0385] A mixture of 4-bromo-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one (Example 2, 0.050 g, 0.100 mmol), phenylboronic acid (0.019 g, 0.159 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2, 0.005 g, 0.007 mmol), and potassium carbonate (K2CO3, 0.055 g, 0.398 mmol) mixed in 1,4-dioxane (2 mL) / water (0.5 mL) at room temperature was microwaved at 140°C for 40 minutes. After heating, the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was filtered through a Celite pad to remove the solid, and a saturated aqueous sodium bicarbonate solution was poured into the filtrate and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, and the mixture was filtered and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography to obtain 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-phenylpyridine-2(1H)-one (0.023 g, 46.3%) as a brown solid: LRMS(ES)m / z500.23 [M+H] +, calculated MW 499.63;1H-NMR(400 MHz, DMSO-d6) d 7.96 (dd,J= 8.8, 5.2 Hz, 1 H), 7.67 (m, 4 H), 7.44 (m, 3 H), 7.23 (td,J= 8.9, 2.1 Hz, 1 H), 6.61 (m, 1 H), 6.52 (dd,J= 7.0, 2.2 Hz, 1 H), 4.40 (dd,J= 12.6, 5.0 Hz, 1 H), 3.51 (dd,J= 59.8, 69.8 Hz, 1 H), 3.10 (m, 1 H), 2.92 (dd,J= 27.0, 11.4 Hz, 2 H), 2.14 to 1.95 (m, 5 H), 1.87 to 1.70 (m, 5 H), 1.55 (m, 2 H), 1.40 (m, 2 H), 1.20 (m, 2 H), 1.05 to 0.91 (m, 2 H).

[0386]

[0387] Example 18: Synthesis of 3-((1r,4r)-4-(2-(4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)ethyl)cyclohexyl)quinazolin-4(3H)-one

[0388] Step 1: Synthesis of tert-butyl ((1r,4r)-4-(2-(4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)ethyl)cyclohexyl)carbamate

[0389]

[0390]

[0391] A solution of 2-((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)ethyl methanesulfonate (1.500 g, 4.667 mmol), 6-fluoro-3-(piperidin-4-yl)benzo[d]isooxazole hydrochloride (1.438 g, 5.600 mmol), and potassium carbonate (K2CO3, 1.935 g, 14.000 mmol) dissolved in acetonitrile (20 mL) at room temperature was heated under reflux for 18 hours, after which the temperature was lowered to room temperature to terminate the reaction. Water was added to the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography to obtain tert-butyl ((1r,4r)-4-(2-(4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)ethyl)cyclohexyl)carbamate (1.279 g, 61.5%) as an ivory solid: LRMS(ES) m / z 446.34 [M+H] + , calculated MW 445.58.

[0392]

[0393] Step 2: Synthesis of (1r,4r)-4-(2-(4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)ethyl)cyclohexane-1-amine dihydrochloride

[0394]

[0395]

[0396] Hydrogen chloride (4.00 M solution in dioxane, 2.153 mL, 8.611 mmol) was added to a solution of Tert-butyl ((1r,4r)-4-(2-(4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)ethyl)cyclohexyl)carbamate (1.279 g, 2.870 mmol) dissolved in dichloromethane (50 mL) at room temperature, and the mixture was stirred at the same temperature for 18 hours. The precipitated solid was filtered, washed with hexane, and dried to obtain (1r,4r)-4-(2-(4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)ethyl)cyclohexane-1-amine dihydrochloride (1.142 g, 95.1%) in the form of an ivory solid: LRMS(ES)m / z346.21 [M+H] + , calculated MW 418.38.

[0397]

[0398] Step 3: Synthesis of 2-amino-N-((1r,4r)-4-(2-(4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)ethyl)cyclohexyl)benzamide

[0399]

[0400]

[0401] A solution of (1r,4r)-4-(2-(4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)ethyl)cyclohexane-1-amine dihydrochloride (0.250 g, 0.598 mmol), 2-aminobenzoic acid (0.098 g, 0.717 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.341 g, 0.896 mmol) and N,N-diisopropylethylamine (0.312 mL, 1.793 mmol) dissolved in N,N-dimethylformamide (3 mL) at room temperature was stirred at the same temperature for 18 hours. The reaction mixture was solvent-removed under reduced pressure to obtain a concentrate, to which water was added and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography to obtain 2-amino-N-((1r,4r)-4-(2-(4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)ethyl)cyclohexyl)benzamide (0.100 g, 36.0%) as a white solid: LRMS(ES) m / z 465.23 [M+H] + , calculated MW 464.59.

[0402]

[0403] Step 4: Synthesis of 3-((1r,4r)-4-(2-(4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)ethyl)cyclohexyl)quinazolin-4(3H)-one

[0404]

[0405]

[0406] Triethoxymethane (0.179 mL, 1.076 mmol) was added to a solution of 2-amino-N-((1r,4r)-4-(2-(4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)ethyl)cyclohexyl)benzamide (0.050 g, 0.108 mmol) dissolved in N,N-dimethylformamide (1 mL) at 120°C, and the mixture was stirred at the same temperature for 18 hours. N,N-diisopropylethylamine (0.187 mL, 1.076 mmol) was added to the reaction mixture and stirred for an additional 4 hours at the same temperature, after which the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography to obtain 3-((1r,4r)-4-(2-(4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)ethyl)cyclohexyl)quinazoline-4(3H)-one (0.003 g, 5.9%) as a beige solid: LRMS(ES)m / z475.26 [M+H] +, calculated MW 474.58;1H-NMR(400 MHz, CD3OD) d 8.35 ~ 8.35 (m, 1 H), 8.23 ​​(d,J= 9.2 Hz, 1 H), 7.89 (dd,J= 8.4, 5.2 Hz, 1 H), 7.83 ~ 7.78 (m, 1 H), 7.68 ~ 7.66 (m, 1 H), 7.57 ~ 7.53 (m, 1 H), 7.41 (dd,J= 8.4, 2.0 Hz, 1 H), 7.19 (td,J= 8.9, 1.9 Hz, 1 H), 4.72 (m, 1 H), 4.56 (s, 1 H), 3.52 (t,J= 59.0 Hz, 1 H), 3.52 (m, 2 H), 3.07 ~ 2.96 (m, 3 H), 2.34 (d,J= 14.8 Hz, 1 H), 2.23 ~ 2.12 (m, 1 H), 2.02 ~ 1.87 (m, 7 H), 1.70 (q,J= 7.6 Hz, 1 H), 1.61 to 1.49 (m, 2 H), 1.36 to 1.26 (m, 3 H).

[0407]

[0408] Example 19: Synthesis of 5-bromo-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)pyridin-2(1H)-one

[0409]

[0410]

[0411] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.150 g, 0.353 mmol), 5-bromopyridine-2(1H)-one (0.074 g, 0.424 mmol), and potassium carbonate (K2CO3, 0.146 g, 1.060 mmol) as starting materials, 5-bromo-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one (0.020 g, 11.3%) was prepared as a white compound in a manner similar to Step 3 of Example 1. Obtained in solid form: LRMS(ES) m / z 502.15 [M] + , calculated MW 502.43;1H-NMR(400 MHz, CD3OD) d 7.88 (q,J= 4.5 Hz, 2 H), 7.55 (dd,J= 9.6, 2.8 Hz, 1 H), 7.36 (dd,J= 9.0, 2.2 Hz, 1 H), 7.14 (td,J= 9.1, 2.1 Hz, 1 H), 6.46 (d,J= 9.6 Hz, 1 H), 4.60 (dd,J= 13.0, 5.0 Hz, 1 H), 3.62 (dd,J= 13.2, 10.0 Hz, 1 H), 3.16 to 3.01 (m, 3 H), 2.65 (q,J= 6.1 Hz, 1 H), 2.22 (q,J= 6.3 Hz, 1 H), 2.17 to 2.12 (m, 2 H), 2.06 to 1.99 (m, 5 H), 1.75 to 1.65 (m, 3 H), 1.49 to 1.46 (m, 2 H), 1.31 to 1.26 (m, 2 H), 1.09 ~ 1.02 (m, 2 H).

[0412]

[0413] Example 20: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)-5-phenylpyridine-2(1H)-one

[0414]

[0415]

[0416] Using 5-bromo-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one (Example 19, 0.015 g, 0.030 mmol), phenylboronic acid (0.006 g, 0.048 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2, 0.002 g, 0.002 mmol), and potassium carbonate (K2CO3, 0.017 g, 0.119 mmol) as starting materials, in a manner similar to Example 17 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-5-phenylpyridine-2(1H)-one (0.005 g, 33.5%) was obtained in the form of a yellow oil: LRMS(ES) m / z 500.30 [M+H] + , calculated MW 499.63;1H-NMR(400 MHz, CD3OD) d 7.88 ~ 7.83 (m, 3 H), 7.50 (d,J= 8.0 Hz, 2 H), 7.41 ~ 7.34 (m, 3 H), 7.27 (t,J= 7.0 Hz, 1 H), 7.13 (td,J= 8.9, 1.6 Hz, 1 H), 6.63 (d,J= 9.2 Hz, 1 H), 4.70 (dd,J= 12.8, 5.6 Hz, 1 H), 3.73 (dd,J= 12.8, 9.6 Hz, 1 H), 3.12 to 3.02 (m, 2 H), 2.72 (dd,J= 12.6, 5.8 Hz, 1 H), 2.27 (dd,J= 12.6, 6.6 Hz, 1 H), 2.18 to 2.15 (m, 2 H), 2.02 to 1.79 (m, 6 H), 1.66 (m, 2 H), 1.58 to 1.52 (m, 2 H), 1.31 (m, 2 H), 1.21 to 1.09 (m, 3 H).

[0417]

[0418] Example 21: Synthesis of 3-bromo-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)pyridin-2(1H)-one

[0419]

[0420]

[0421] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.200 g, 0.471 mmol), 3-bromopyridine-2(1H)-one (0.098 g, 0.565 mmol), and potassium carbonate (K2CO3, 0.195 g, 1.413 mmol) as starting materials, 3-bromo-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one (0.010 g, 4.2%) was prepared as a clear oil in a manner similar to Step 3 of Example 1. Obtained in the form: LRMS(ES)m / z504.19 [M+2H] +, calculated MW 502.43;1H-NMR(400 MHz, DMSO-d6) d 7.91 ~ 7.86 (m, 2 H), 7.64 (dd,J= 6.8, 2.0 Hz, 1 H), 7.36 (dd,J= 8.8, 2.4 Hz, 1 H), 7.14 (td,J= 9.1, 2.3 Hz, 1 H), 6.26 (t,J= 6.8 Hz, 1 H), 4.71 (dd,J= 13.0, 4.2 Hz, 1 H), 3.65 (dd,J= 12.8, 10.0 Hz, 1 H), 3.16 to 3.02 (m, 3 H), 2.69 (dd,J= 12.6, 5.8 Hz, 1 H), 2.25 (dd,J= 12.4, 6.4 Hz, 1 H), 2.18 to 2.14 (m, 2 H), 2.05 to 1.99 (m, 5 H), 1.80 to 1.66 (m, 3 H), 1.49 to 1.46 (m, 2 H), 1.31 (m, 2 H), 1.15 to 1.03 (m, 2 H).

[0422]

[0423] Example 22: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)-3-methylpyridine-2(1H)-one

[0424]

[0425]

[0426] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.150 g, 0.353 mmol), 3-methylpyridine-2(1H)-one (0.046 g, 0.424 mmol), and potassium carbonate (K2CO3, 0.146 g, 1.060 mmol) as starting materials, 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-3-methylpyridine-2(1H)-one (0.026 g, 16.8%) was prepared in the form of a yellow solid in a manner similar to Step 3 of Example 1. Obtained:LRMS(ES)m / z438.28 [M+H] + , calculated MW 437.56;1H-NMR(400 MHz, CD3OD) d 7.88 (dd,J= 9.0, 5.4 Hz, 1 H), 7.44 (dd,J= 6.8, 1.6 Hz, 1 H), 7.37 ~ 7.34 (m, 2 H), 7.15 (dd,J= 9.0, 2.2 Hz, 1 H), 6.26 (t,J= 6.8 Hz, 1 H), 4.63 (dd,J= 13.4, 4.6 Hz, 1 H), 3.58 (dd,J= 12.8, 10.0 Hz, 1 H), 3.20 ~ 3.06 (m, 3 H), 2.77 ~ 2.75 (m, 1 H), 2.32 ~ 2.25 (m, 3 H), 2.09 (s, 3 H), 2.05 to 1.93 (m, 5 H), 1.80 to 1.66 (m, 3 H), 1.50 to 1.47 (m, 2 H), 1.31 (m, 2 H), 1.17 to 1.07 (m, 2 H).

[0427]

[0428] Example 23: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)-5-methylpyridine-2(1H)-one

[0429]

[0430]

[0431] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.150 g, 0.353 mmol), 5-methylpyridine-2(1H)-one (0.046 g, 0.424 mmol), and potassium carbonate (K2CO3, 0.146 g, 1.060 mmol) as starting materials, 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-5-methylpyridine-2(1H)-one (0.022 g, 14.2%) was prepared in the form of a colorless oil in a manner similar to Step 3 of Example 1. Obtained:LRMS(ES)m / z438.08 [M+H] + , calculated MW 437.56;1H-NMR(400 MHz, CD3OD) d 7.88 (dd,J= 8.6, 5.0 Hz, 1 H), 7.39 ~ 7.34 (m, 3 H), 7.14 (td,J= 9.0, 2.3 Hz, 1 H), 6.47 (d,J= 10.4 Hz, 1 H), 4.54 (dd,J= 13.2, 4.8 Hz, 1 H), 3.60 (dd,J= 12.8, 10.0 Hz, 1 H), 3.15 ~ 3.07 (m, 2 H), 3.02 ~ 2.99 (m, 1 H), 2.66 (dd,J= 12.6, 5.4 Hz, 1 H), 2.24 (dd,J= 12.4, 6.8 Hz, 1 H), 2.16 (m, 1 H), 2.10 (s, 3 H), 2.04 ~ 1.93 (m, 5 H), 1.73 (m, 3 H), 1.47 (m, 2 H), 1.27 (m, 2 H), 1.07 (m, 2 H).

[0432]

[0433] Example 24: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)-4-methylpyridine-2(1H)-one

[0434]

[0435]

[0436] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.150 g, 0.353 mmol), 4-methylpyridine-2(1H)-one (0.046 g, 0.424 mmol), and potassium carbonate (K2CO3, 0.146 g, 1.060 mmol) as starting materials, 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-methylpyridine-2(1H)-one (0.002 g, 1.3%) was prepared in the form of a colorless oil in a manner similar to Step 3 of Example 1. Obtained:LRMS(ES)m / z438.35 [M+H] + , calculated MW 437.56;1H-NMR(400 MHz, acetone-d6) d 7.89 ~ 7.85 (m, 1 H), 7.46 (d,J= 6.8 Hz, 1 H), 7.35 (dd,J= 8.8, 2.4 Hz, 1 H), 7.13 (td,J= 9.0, 2.3 Hz, 1 H), 6.34 (s, 1 H), 6.23 (dd,J= 6.8, 1.6 Hz, 1 H), 4.53 (dd,J= 13.2, 4.8 Hz, 1 H), 3.59 (dd,J= 13.2, 10.0 Hz, 1 H), 3.11 ~ 3.01 (m, 3 H), 2.68 (dd,J= 12.6, 5.8 Hz, 1 H), 2.28 ~ 2.12 (m, 3 H), 2.19 (s, 3 H), 2.05 ~ 1.91 (m, 5 H), 1.71 (m, 3 H), 1.48 (m, 2 H), 1.29 (m, 2 H), 1.10 (m, 2 H).

[0437]

[0438] Example 25: Synthesis of 3-fluoro-1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one hydrochloride

[0439] Step 1: Synthesis of 3-fluoro-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)pyridin-2(1H)-one

[0440]

[0441]

[0442] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.150 g, 0.353 mmol), 3-fluoropyridine-2(1H)-one (0.048 g, 0.424 mmol), and potassium carbonate (K2CO3, 0.146 g, 1.060 mmol) as starting materials, 3-fluoro-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one (0.008 g, 5.1%) was prepared in the form of a brown oil in a manner similar to Step 3 of Example 1. Obtained:LRMS(ES)m / z442.24 [M+H] +, calculated MW 441.52;1H-NMR(400 MHz, CD3OD) d 7.87 (dd,J= 8.6, 5.4 Hz, 1 H), 7.44 (dt,J= 6.8, 1.6 Hz, 1 H), 7.37 (s, 2 H), 7.14 (td,J= 8.9, 2.0 Hz, 1 H), 6.31 ~ 6.26 (m, 1 H), 4.68 (dd,J= 12.8, 4.4 Hz, 1 H), 3.70 (dd,J= 12.6, 10.2 Hz, 1 H), 3.15 ~ 3.01 (m, 3 H), 2.66 (dd,J= 12.6, 5.4 Hz, 1 H), 2.23 (dd,J= 12.6, 6.6 Hz, 1 H), 2.14 (m, 2 H), 2.02 (m, 5 H), 1.76 (m, 1 H), 1.66 (m, 2 H), 1.50 ~ 1.45 (m, 2 H), 1.30 (m, 2 H), 1.12 ~ 1.02 (m, 2 H).

[0443]

[0444] Step 2: Synthesis of 3-fluoro-1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one hydrochloride

[0445]

[0446]

[0447] Using 3-fluoro-1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one (0.006 g, 0.014 mmol) as a starting material, 3-fluoro-1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one hydrochloride (0.005 g, 77.0 %) was obtained in the form of a pink solid in a manner similar to Step 2 of Example 3: LRMS(ES)m / z442.31 [M+H] +, calculated MW 477.98;1H-NMR(400 MHz, CD3OD) d 8.02 (s, 1 H), 7.48 (d,J= 6.4 Hz, 1 H), 7.42 (dd,J= 8.8, 2.0 Hz, 2 H), 7.19 (td,J= 8.9, 2.1 Hz, 1 H), 6.36 (q,J= 6.0 Hz, 1 H), 4.28 (d,J= 10.8 Hz, 1 H), 3.99 ~ 3.94 (m, 1 H), 3.84 ~ 3.76 (m, 2 H), 3.60 ~ 3.46 (m, 2 H), 3.29 ~ 3.13 (m, 3 H), 2.39 (m, 4 H), 1.98 (d,J= 10.8 Hz, 1 H), 1.79 to 1.72 (m, 5 H), 1.35 to 1.11 (m, 4 H).

[0448]

[0449] Example 26: Synthesis of 4-fluoro-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)pyridin-2(1H)-one

[0450]

[0451]

[0452] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.150 g, 0.353 mmol), 4-fluoropyridine-2(1H)-one (0.048 g, 0.424 mmol), and potassium carbonate (K2CO3, 0.146 g, 1.060 mmol) as starting materials, 4-fluoro-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one (0.007 g, 4.5%) was prepared in the form of a yellow solid in a manner similar to Step 3 of Example 1. Obtained:LRMS(ES)m / z442.24 [M+H] +, calculated MW 441.52;1H-NMR(400 MHz, CD3OD) d 7.87 (dd,J= 8.8, 5.2 Hz, 1 H), 7.72 (t,J= 7.6 Hz, 1 H), 7.36 (dd,J= 8.6, 1.8 Hz, 1 H), 7.14 (td,J= 9.0, 2.3 Hz, 1 H), 6.32 ~ 6.27 (m, 1 H), 6.18 (dd,J= 10.6, 2.6 Hz, 1 H), 4.59 (dd,J= 13.0, 4.6 Hz, 1 H), 3.63 (dd,J= 13.2, 10.0 Hz, 1 H), 3.17 ~ 3.03 (m, 3 H), 2.69 (dd,J= 12.4, 5.6 Hz, 1 H), 2.26 (dd,J= 12.8, 6.8 Hz, 1 H), 2.18 (m, 2 H), 2.07 ~ 2.03 (m, 3 H), 2.00 ~ 1.91 (m, 2 H), 1.76 ~1.65 (m, 3 H), 1.48 (m, 2 H), 1.26 (m, 2 H), 1.08 (m, 2 H).

[0453]

[0454] Example 27: Synthesis of 5-fluoro-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)pyridin-2(1H)-one

[0455]

[0456]

[0457] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.150 g, 0.353 mmol), 5-fluoropyridine-2(1H)-one (0.048 g, 0.424 mmol), and potassium carbonate (K2CO3, 0.146 g, 1.060 mmol) as starting materials, 5-fluoro-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one (0.007 g, 4.5%) was prepared in the form of a brown solid in a manner similar to Step 3 of Example 1. Obtained:LRMS(ES)m / z442.24 [M+H] + , calculated MW 441.52;1H-NMR(400 MHz, CD3OD) d 7.87 (dd,J= 8.8, 5.2 Hz, 1 H), 7.75 (t,J= 3.8 Hz, 1 H), 7.54 ~ 7.50 (m, 1 H), 7.36 (dd,J= 8.8, 2.4 Hz, 1 H), 7.14 (td,J= 9.1, 2.1 Hz, 1 H), 6.52 (q,J= 5.1 Hz, 1 H), 4.56 (dd,J= 13.0, 4.6 Hz, 1 H), 3.64 (dd,J= 13.2, 10.0 Hz, 1 H), 3.17 ~ 3.04 (m, 3 H), 2.68 (dd,J= 12.8, 6.0 Hz, 1 H), 2.25 (dd,J= 12.8, 6.8 Hz, 1 H), 2.20 to 2.15 (m, 2 H), 2.06 to 1.91 (m, 5 H), 1.79 to 1.74 (m, 1 H), 1.68 (m, 2 H), 1.51 to 1.47 (m, 2 H), 1.30 (m, 2 H), 1.15 (m, 2 H).

[0458]

[0459] Example 28: Synthesis of 4-chloro-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)pyridin-2(1H)-one

[0460]

[0461]

[0462] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.100 g, 0.236 mmol), 4-chloropyridine-2(1H)-one (0.037 g, 0.283 mmol), and potassium carbonate (K2CO3, 0.098 g, 0.707 mmol) as starting materials, 4-chloro-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one (0.020 g, 18.5%) was prepared in the form of a yellow oil in a manner similar to Step 3 of Example 1. Obtained:LRMS(ES)m / z458.29 [M+H] + , calculated MW 457.97;1H-NMR(400 MHz, CD3OD) d 7.87 (dd,J= 9.0, 5.0 Hz, 1 H), 7.63 (d,J= 7.2 Hz, 1 H), 7.36 (dd,J= 8.8, 1.6 Hz, 1 H), 7.14 (td,J= 9.2, 2.4 Hz, 1 H), 6.56 (d,J= 2.0 Hz, 1 H), 6.40 (dd,J= 7.4, 2.2 Hz, 1 H), 4.59 (dd,J= 12.8, 4.4 Hz, 1 H), 3.61 (dd,J= 13.4, 10.2 Hz, 1H), 3.15 ~ 3.02 (m, 3 H), 2.67 (dd,J= 12.2, 5.8 Hz, 1 H), 2.24 (dd,J= 12.8, 6.4 Hz, 1 H), 2.18 to 2.13 (m, 2 H), 2.07 to 1.91 (m, 5 H), 1.73 to 1.66 (m, 3 H), 1.49 to 1.46 (m, 2 H), 1.30 to 1.26 (m, 2 H), 1.11 to 1.03 (m, 2 H).

[0463]

[0464] Example 29: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-(trifluoromethyl)pyridine-2(1H)-one hydrochloride

[0465] Step 1: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)-4-(trifluoromethyl)pyridin-2(1H)-one

[0466]

[0467]

[0468] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.100 g, 0.236 mmol), 4-(trifluoromethyl)pyridine-2(1H)-one (0.046 g, 0.283 mmol), and potassium carbonate (K2CO3, 0.098 g, 0.707 mmol) as starting materials, in a manner similar to Step 3 of Example 1, 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-(trifluoromethyl)pyridine-2(1H)-one (0.010 g, 8.6%) was obtained in the form of a clear oil: LRMS(ES)m / z492.30 [M+H] +, calculated MW 491.53;1H-NMR(400 MHz, CD3OD) d 7.87 (dd,J= 8.6, 5.0 Hz, 1 H), 7.60 (d,J= 7.2 Hz, 1 H), 7.36 (dd,J= 8.6, 1.8 Hz, 1 H), 7.14 (td,J= 8.9, 2.0 Hz, 1 H), 6.77 (d,J= 8.4 Hz, 1 H), 6.50 (d,J= 7.2 Hz, 1 H), 4.65 (dd,J= 13.0, 4.2 Hz, 1 H), 3.69 (dd,J= 13.0, 9.8 Hz, 1 H), 3.18 ~ 3.07 (m, 3 H), 2.74 (dd,J= 12.4, 5.6 Hz, 1 H), 2.33 ~ 2.23 (m, 3 H), 2.09 ~ 1.91 (m, 5 H), 1.78 ~ 1.66 (m, 3 H), 1.51 ~ 1.48 (m, 2 H), 1.31 ~ 1.26 (m, 2 H), 1.16 to 1.05 (m, 2 H).

[0469]

[0470] Step 2: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-(trifluoromethyl)pyridine-2(1H)-one hydrochloride

[0471]

[0472]

[0473] Using 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-(trifluoromethyl)pyridine-2(1H)-one (0.039 g, 0.079 mmol) as a starting material, 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-(trifluoromethyl)pyridine-2(1H)-one hydrochloride (0.028 g, 66.8%) was obtained in the form of a white solid in a manner similar to Step 2 of Example 3: LRMS(ES)m / z492.24 [M+H] + , calculated MW 527.99;1H-NMR(400 MHz, CD3OD) d 7.98 (s, 1 H), 7.87 (d,J= 7.2 Hz, 1 H), 7.41 (dd,J= 8.6, 1.8 Hz, 1 H), 7.19 (td,J= 9.0, 2.1 Hz, 1 H), 6.86 (s, 1 H), 6.56 (dd,J= 6.8, 1.6 Hz, 1 H), 4.26 (d,J= 12.8 Hz, 1 H), 3.96 (q,J= 6.8 Hz, 1 H), 3.80 (dd,J= 27.4, 11.4 Hz, 2 H), 3.63 (dd,J= 13.4, 2.6 Hz, 1 H), 3.54 (m, 1 H), 3.32 to 3.14 (m, 3 H), 2.40 (m, 4 H), 2.00 (m, 1 H), 1.81 to 1.66 (m, 5 H), 1.39 to 1.12 (m, 4 H).

[0474]

[0475] Example 30: Synthesis of 5-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)thieno[3,2-c]pyridin-4(5H)-one

[0476]

[0477]

[0478] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.100 g, 0.236 mmol), thieno[3,2-c]pyridine-4(5H)-one (0.043 g, 0.283 mmol), and potassium carbonate (K2CO3, 0.098 g, 0.707 mmol) as starting materials, in a manner similar to Step 3 of Example 1, 5-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)thieno[3,2-c]pyridine-4(5H)-one (0.015 g, 13.3%) was obtained in the form of a white solid: LRMS(ES)m / z480.09 [M+H] + , calculated MW 479.61;1H-NMR(400 MHz, CD3OD) d 7.88 (dd,J= 8.6, 5.4 Hz, 1 H), 7.55 (dd,J= 5.4, 1.0 Hz, 1 H), 7.48 (d,J= 4.8 Hz, 1 H), 7.44 (d,J= 8.0 Hz, 1 H), 7.36 (dd,J= 8.6, 1.8 Hz, 1 H), 7.14 (td,J= 9.1, 2.3 Hz, 1 H), 6.92 (d,J= 7.6 Hz, 1 H), 4.65 (dd,J= 13.4, 5.0 Hz, 1 H), 3.75 (dd,J= 13.0, 9.8 Hz, 1 H), 3.16 ~ 3.01 (m, 3 H), 2.59 (dd,J= 119.4, 106.6 Hz, 1 H), 2.28 (dd,J= 12.8, 6.8 Hz, 1 H), 2.19 ~ 2.13 (m, 2 H), 2.03 ~ 1.99 (m, 5 H), 1.82 to 1.77 (m, 1 H), 1.67 to 1.65 (m, 2 H), 1.52 to 1.50 (m, 2 H), 1.32 to 1.26 (m, 2 H), 1.17 to 1.08 (m, 2 H).

[0479]

[0480] Example 31: Synthesis of 6-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)thieno[2,3-c]pyridin-7(6H)-one

[0481]

[0482]

[0483] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.100 g, 0.236 mmol), thieno[2,3-c]pyridine-7(6H)-one (0.043 g, 0.283 mmol), and potassium carbonate (K2CO3, 0.098 g, 0.707 mmol) as starting materials, in a manner similar to Step 3 of Example 1, 6-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)thieno[2,3-c]pyridine-7(6H)-one (0.015 g, 13.3%) was obtained in the form of a white solid: LRMS(ES)m / z480.28 [M+H] +, calculated MW 479.61;1H-NMR(400 MHz, CD3OD) d 7.93 (d,J= 5.6 Hz, 1 H), 7.46 (d,J= 7.2 Hz, 1 H), 7.34 (d,J= 5.2 Hz, 1 H), 7.31 (d,J= 4.8 Hz, 1 H), 7.14 (td,J= 9.2, 2.4 Hz, 1 H), 6.84 (t,J= 7.0 Hz, 2 H), 4.65 (dd,J= 13.2, 5.2 Hz, 1 H), 3.77 (dd,J= 13.2, 9.6 Hz, 1 H), 3.13 ~ 3.01 (m, 3 H), 2.71 (dd,J= 12.6, 5.4 Hz, 1 H), 2.28 (dd,J= 12.2, 6.6 Hz, 1 H), 2.19 ~ 2.13 (m, 2 H), 2.04 ~ 1.99 (m, 5 H), 1.84 ~ 1.79 (m, 1 H), 1.67 ~ 1.64 (m, 2 H), 1.55 to 1.50 (m, 2 H), 1.32 to 1.26 (m, 2 H), 1.14 to 1.08 (m, 2 H).

[0484]

[0485] Example 32: Synthesis of 5-acetyl-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)pyridin-2(1H)-one

[0486]

[0487]

[0488] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.100 g, 0.236 mmol), 5-acetylpyridine-2(1H)-one (0.039 g, 0.283 mmol), and potassium carbonate (K2CO3, 0.098 g, 0.707 mmol) as starting materials, 5-acetyl-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one (0.015 g, 13.7%) was prepared in a manner similar to Step 3 of Example 1 to produce a yellow Obtained in solid form: LRMS(ES) m / z 466.35 [M+H] + , calculated MW 465.57;1H-NMR(400 MHz, CD3OD) d 8.44 (d,J= 2.4 Hz, 1 H), 7.98 (dd,J= 9.6, 2.4 Hz, 1 H), 7.87 (dd,J= 9.0, 5.4 Hz, 1 H), 7.35 (dd,J= 8.6, 2.2 Hz, 1 H), 7.14 (td,J= 9.1, 1.7 Hz, 1 H), 6.51 (d,J= 9.6 Hz, 1 H), 4.71 (dd,J= 13.2, 4.4 Hz, 1 H), 3.70 (dd,J= 12.8, 10.0 Hz, 1 H), 3.16 to 3.03 (m, 3 H), 2.71 (dd,J= 12.6, 5.8 Hz, 1 H), 2.46 (s, 3 H), 2.27 (dd,J= 12.8, 6.4 Hz, 1 H), 2.20 to 2.15 (m, 2 H), 2.07 to 1.93 (m, 5 H), 1.79 to 1.74 (m, 1 H), 1.68 to 1.66 (m, 2 H), 1.51 to 1.45 (m, 2 H), 1.31 to 1.23 (m, 2 H), 1.13 to 1.02 (m, 2 H).

[0489]

[0490] Example 33: Synthesis of 4-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)thieno[3,2-b]pyridin-7(4H)-one

[0491]

[0492]

[0493] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.100 g, 0.236 mmol), thieno[3,2-b]pyridine-7(4H)-one (0.043 g, 0.283 mmol), and potassium carbonate (K2CO3, 0.098 g, 0.707 mmol) as starting materials, in a manner similar to Step 3 of Example 1, 4-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)thieno[3,2-b]pyridine-7(4H)-one (0.002 g, 1.8%) was obtained in the form of a white solid: LRMS(ES)m / z480.28 [M+H] +, calculated MW 479.61;1H-NMR(400 MHz, CD3OD) d 8.03 (d,J= 5.6 Hz, 1 H), 7.92 (d,J= 7.6 Hz, 1 H), 7.84 (dd,J= 8.8, 5.2 Hz, 1 H), 7.54 (d,J= 5.6 Hz, 1 H), 7.36 (dd,J= 8.6, 2.2 Hz, 1 H), 7.14 (td,J= 9.0, 2.0 Hz, 1 H), 6.31 (d,J= 7.2 Hz, 1 H), 5.05 (dd,J= 14.2, 5.0 Hz, 1 H), 3.99 (dd,J=14.0, 10.0 Hz, 1 H), 3.18 ~ 3.11 (m, 2 H), 3.06 ~ 3.03 (m, 1 H), 2.68 (dd,J= 13.4, 6.2 Hz, 1 H), 2.36 (dd,J= 12.6, 6.2 Hz, 1 H), 2.25 ~ 2.13 (m, 2 H), 2.11 to 1.86 (m, 8 H), 1.72 to 1.58 (m, 2 H), 1.34 (m, 2 H), 1.16 to 1.11 (m, 2 H).

[0494]

[0495] Example 34: Synthesis of methyl 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxylate

[0496]

[0497]

[0498] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.100 g, 0.236 mmol), methyl 2-oxo-1,2-dihydropyridine-4-carboxylate (0.043 g, 0.283 mmol), and potassium carbonate (K2CO3, 0.098 g, 0.707 mmol) as starting materials, in a manner similar to Step 3 of Example 1, methyl 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxylate (0.014 g, 12.3%) was obtained in the form of a white solid: LRMS(ES) m / z 482.27 [M+H] + , calculated MW 481.57;1H-NMR(400 MHz, CD3OD) d 7.87 (dd,J= 9.0, 5.4 Hz, 1 H), 7.71 (d,J= 6.8 Hz, 1 H), 7.36 (dd,J= 8.8, 2.4 Hz, 1 H), 7.14 (td,J= 9.0, 2.0 Hz, 1 H), 7.07 (d,J= 1.2 Hz, 1 H), 6.75 (dd,J= 6.8, 1.6 Hz, 1 H), 4.65 (dd,J= 13.0, 4.2 Hz, 1 H), 3.88 (s, 3 H), 3.66 (dd,J= 13.0, 9.8 Hz, 1 H), 3.16 ~ 3.03 (m, 3 H), 2.69 (dd,J= 12.8, 6.0 Hz, 1 H), 2.26 (dd,J= 12.6, 6.6 Hz, 1 H), 2.19 ~ 2.15 (m, 2 H), 2.07 ~ 1.92 (m, 5 H), 1.77 to 1.65 (m, 3 H), 1.53 to 1.46 (m, 2 H), 1.31 (m, 2 H), 1.20 to 1.02 (m, 2 H).

[0499]

[0500] Example 35: Synthesis of 3-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-4(3H)-one hydrochloride

[0501] Step 1: Synthesis of 3-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)pyrimidine-4(3H)-one

[0502]

[0503]

[0504] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.100 g, 0.236 mmol), pyrimidine-4(3H)-one (0.027 g, 0.283 mmol), and potassium carbonate (K2CO3, 0.098 g, 0.707 mmol) as starting materials, 3-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-4(3H)-one (0.013 g, 13.0%) was prepared as a white solid in a manner similar to Step 3 of Example 1. Obtained:LRMS(ES)m / z425.33 [M+H] +, calculated MW 424.52;1H-NMR(400 MHz, CD3OD) d 8.40 (s, 1 H), 7.93 (d,J= 6.4 Hz, 1 H), 7.88 (dd,J= 8.8, 4.8 Hz, 1 H), 7.36 (dd,J= 8.6, 2.2 Hz, 1 H), 7.14 (td,J= 9.2, 2.4 Hz, 1 H), 6.46 (d,J= 6.4 Hz, 1 H), 4.64 (dd,J= 13.2, 4.0 Hz, 1 H), 3.62 (dd,J= 13.4, 10.2 Hz, 1 H), 3.20 ~ 3.11 (m, 3 H), 2.73 (dd,J= 12.6, 5.8 Hz, 1 H), 2.31 to 2.20 (m, 3 H), 2.09 to 1.90 (m, 5 H), 1.73 to 1.66 (m, 3 H), 1.51 to 1.47 (m, 2 H), 1.30 to 1.26 (m, 2 H), 1.12 to 1.03 (m, 2 H).

[0505]

[0506] Step 2: Synthesis of 3-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-4(3H)-one hydrochloride

[0507]

[0508]

[0509] Using 3-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-4(3H)-one (0.009 g, 0.021 mmol) as a starting material, 3-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-4(3H)-one hydrochloride (0.007 g, 71.6 %) was obtained in the form of a white solid in a manner similar to Step 2 of Example 3: LRMS(ES)m / z425.33 [M+H] +, calculated MW 460.98;1H-NMR(400 MHz, CD3OD) d 8.41 (s, 1 H), 7.99 ~ 7.95 (m, 2 H), 7.42 (dd,J= 8.6, 1.8 Hz, 1 H), 7.20 (td,J= 9.0, 2.3 Hz, 1 H), 6.52 (d,J= 6.4 Hz, 1 H), 4.22 (dd,J= 13.6, 3.2 Hz, 1 H), 3.92 ~ 3.74 (m, 3 H), 3.65 (dd,J= 13.2, 3.2 Hz, 1 H), 3.57 ~ 3.51 (m, 1 H), 3.35 ~ 3.14 (m, 3 H), 2.43 to 2.22 (m, 4 H), 2.01 (m, 1 H), 1.85 (m, 5 H), 1.36 to 1.10 (m, 4 H).

[0510]

[0511] Example 36: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)-4-methoxypyridine-2(1H)-one

[0512]

[0513]

[0514] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.100 g, 0.236 mmol), 4-methoxypyridine-2(1H)-one (0.035 g, 0.283 mmol), and potassium carbonate (K2CO3, 0.098 g, 0.707 mmol) as starting materials, 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-methoxypyridine-2(1H)-one (0.035 g, 32.8%) was produced yellow in a manner similar to Step 3 of Example 1. Obtained in oil form: LRMS(ES)m / z454.00 [M+H] +, calculated MW 453.56;1H-NMR(400 MHz, CD3OD) d 7.87 (dd,J= 9.0, 5.4 Hz, 1 H), 7.45 (d,J= 7.2 Hz, 1 H), 7.35 (dd,J= 8.2, 1.4 Hz, 1 H), 7.13 (td,J= 9.2, 2.4 Hz, 1 H), 6.05 (dd,J= 7.2, 2.8 Hz, 1 H), 7.40 (d,J= 1197.2 Hz, 1 H), 4.48 (dd,J= 13.2, 4.4 Hz, 1 H), 3.77 (s, 3 H), 3.56 (dd,J=13.0, 9.8 Hz, 1 H), 3.17 ~ 3.00 (m, 3 H), 2.66 (dd,J= 12.4, 5.2 Hz, 1 H), 2.24 (dd,J= 12.8, 7.2 Hz, 1 H), 2.17 ~ 2.14 (m, 2 H), 2.04 ~ 1.91 (m, 5 H), 1.76 to 1.63 (m, 3 H), 1.48 to 1.45 (m, 2 H), 1.26 to 1.01 (m, 4 H).

[0515]

[0516] Example 37: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-6-oxo-1,6-dihydropyridine-3-carbaldehyde

[0517]

[0518]

[0519] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.100 g, 0.236 mmol), 6-oxo-1,6-dihydropyridine-3-carbaldehyde (0.035 g, 0.283 mmol), and potassium carbonate (K2CO3, 0.098 g, 0.707 mmol) as starting materials, in a manner similar to Step 3 of Example 1 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-6-oxo-1,6-dihydropyridine-3-carbaldehyde (0.026 g, 24.4%) was obtained in the form of a yellow oil: LRMS(ES)m / z452.35 [M+H] + , calculated MW 451.54;1H-NMR(400 MHz, CD3OD) d 9.61 (s, 1 H), 8.37 (d,J= 2.4 Hz, 1 H), 7.89 ~ 7.86 (m, 2 H), 7.36 (dd,J= 8.6, 2.2 Hz, 1 H), 7.14 (td,J= 9.1, 2.3 Hz, 1 H), 6.56 (d,J= 9.2 Hz, 1 H), 4.74 (dd,J= 13.0, 4.6 Hz, 1 H), 3.69 (dd,J= 13.0, 10.2 Hz, 1 H), 3.17 ~ 3.04 (m, 3 H), 2.70 (dd,J= 12.8, 6.0 Hz, 1 H), 2.28 ~ 2.15 (m, 3 H), 2.05 ~ 1.88 (m, 5 H), 1.81 ~ 1.67 (m, 3 H), 1.50 ~ 1.48 (m, 2 H), 1.30 ~ 1.26 (m, 2 H), 1.21 ~ 1.04 (m, 2 H).

[0520]

[0521] Example 38: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)-5-(trifluoromethyl)pyridin-2(1H)-one

[0522]

[0523]

[0524] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.100 g, 0.236 mmol), 5-(trifluoromethyl)pyridine-2(1H)-one (0.046 g, 0.283 mmol), and potassium carbonate (K2CO3, 0.098 g, 0.707 mmol) as starting materials, in a manner similar to Step 3 of Example 1, 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-5-(trifluoromethyl)pyridine-2(1H)-one (0.015 g, 13.0%) was obtained in the form of a yellow oil: LRMS(ES)m / z492.30 [M+H] + , calculated MW 491.53;1H-NMR(400 MHz, CD3OD) d 8.14 (s, 1 H), 7.87 (dd,J= 8.8, 4.8 Hz, 1 H), 7.65 (dd,J= 9.8, 2.6 Hz, 1 H), 7.35 (dd,J= 8.6, 2.2 Hz, 1 H), 7.13 (td,J= 9.1, 2.3 Hz, 1 H), 6.61 (d,J= 7.6 Hz, 1 H), 4.69 (dd,J= 12.8, 4.4 Hz, 1 H), 3.66 (dd,J= 13.0, 10.2 Hz, 1 H), 3.16 ~ 3.03 (m, 3 H), 2.68 (dd,J= 12.6, 5.8 Hz, 1 H), 2.25 (dd,J= 12.6, 6.6 Hz, 1 H), 2.19 to 2.13 (m, 2 H), 2.06 to 1.91 (m, 5 H), 1.80 to 1.66 (m, 3 H), 1.52 ~ 1.42 (m, 2 H), 1.30 ~ 1.05 (m, 4 H).

[0525]

[0526] Example 39: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-N-phenyl-1,2-dihydropyridine-4-carboxamide

[0527] Step 1: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid

[0528]

[0529]

[0530] A solution of methyl 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxylate (Example 34, 0.135 g, 0.280 mmol) and lithium hydroxide monohydrate (0.024 g, 0.561 mmol) dissolved in methanol (5 mL) / tetrahydrofuran (5 mL) / water (5 mL) at room temperature was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, an aqueous 1N hydrochloric acid solution was added to the concentrate and stirred; the precipitated solid was filtered, washed with water, and dried to obtain 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid (0.089 g, 67.9%) as a yellow solid: LRMS(ES) m / z 466.15 [MH] + , calculated MW 467.54.

[0531]

[0532] Step 2: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-N-phenyl-1,2-dihydropyridine-4-carboxamide

[0533]

[0534]

[0535] A solution of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid (0.030 g, 0.064 mmol), aniline (0.007 mL, 0.077 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.037 g, 0.096 mmol), and N,N-diisopropylethylamine (0.034 mL, 0.192 mmol) dissolved in N,N-dimethylformamide (1 mL) at room temperature was left at the same temperature for 18 hours. The mixture was stirred. Water was added to the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography to obtain 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-N-phenyl-1,2-dihydropyridine-4-carboxamide (0.003 g, 8.6%) as a pale yellow solid: LRMS(ES) m / z 543.36 [M+H] +, calculated MW 542.66;1H-NMR(400 MHz, CD3OD) d 7.92 (dd,J= 8.8, 5.2 Hz, 1 H), 7.76 (d,J= 7.2 Hz, 1 H), 7.65 (d,J= 7.6 Hz, 2 H), 7.40 (dd,J= 8.8, 2.0 Hz, 2 H), 7.34 (t,J= 8.0 Hz, 2 H), 7.17 (m, 2 H), 7.04 (d,J= 2.0 Hz, 1 H), 6.78 (dd,J= 7.0, 1.8 Hz, 1 H), 4.37 (d,J= 13.2 Hz, 1 H), 3.89 (dd,J= 13.6, 8.0 Hz, 1 H), 3.59 ~ 3.46 (m, 3 H), 2.95 (bs, 2 H), 2.35 ~ 2.21 (m, 4 H), 1.97 (d,J= 15.6 Hz, 1 H), 1.79 ~ 1.67 (m, 5 H), 1.35 ~ 1.14 (m, 6 H).

[0536]

[0537] Example 40: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-N-(pyridine-3-yl)-1,2-dihydropyridine-4-carboxamide

[0538]

[0539]

[0540] Using 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid (0.060 g, 0.128 mmol), pyridine-3-amine (0.014 g, 0.154 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.073 g, 0.192 mmol), and N,N-diisopropylethylamine (0.067 mL, 0.385 mmol) as starting materials, in a manner similar to Step 2 of Example 39 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-N-(pyridine-3-yl)-1,2-dihydropyridine-4-carboxamide (0.019 g, 27.2%) was obtained in the form of a yellow solid: LRMS(ES) m / z 544.35 [M+H] + , calculated MW 543.64;1H-NMR(400 MHz, CD3OD) d 8.85 (d,J= 2.4 Hz, 1 H), 8.32 (dd,J= 5.0, 1.0 Hz, 1 H), 8.22 (d,J= 9.6 Hz, 1 H), 7.91 ~ 7.87 (m, 1 H), 7.78 (d,J= 6.8 Hz, 1 H), 7.43 ~ 7.40 (m, 2 H), 7.19 (td,J= 8.9, 1.9 Hz, 2 H), 7.09 (d,J= 1.6 Hz, 1 H), 6.80 (dd,J= 7.2, 2.4 Hz, 1 H), 4.34 (d,J= 13.2 Hz, 1 H), 4.00 (dd,J= 12.0, 6.4 Hz, 1 H), 3.61 to 3.42 (m, 3 H), 3.17 to 2.97 (m, 3 H), 2.38 (m, 4 H), 2.27 (q,J= 13.6 Hz, 1 H), 1.72 (m, 5 H), 1.24 (m, 5 H).

[0541]

[0542] Example 41: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-N-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide

[0543]

[0544]

[0545] Using 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid (0.040 g, 0.086 mmol), methanolamine hydrochloride (0.007 g, 0.103 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.049 g, 0.128 mmol), and N,N-diisopropylethylamine (0.045 mL, 0.257 mmol) as starting materials, in a manner similar to Step 2 of Example 39 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-N-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (0.020 g, 48.6%) was obtained in the form of an ivory solid: LRMS(ES)m / z481.41 [M+H] +, calculated MW 480.58;1H-NMR(400 MHz, CD3OD) d 7.92 (dd,J= 8.8, 4.8 Hz, 1 H), 7.71 (d,J= 6.8 Hz, 1 H), 7.42 (dd,J= 8.8, 1.6 Hz, 1 H), 7.20 (td,J= 9.0, 1.9 Hz, 1 H), 6.93 (d,J= 1.6 Hz, 1 H), 6.68 (dd,J= 7.2, 1.6 Hz, 1 H), 4.27 (d,J= 12.0 Hz, 1 H), 3.89 (dd,J= 12.8, 7.6 Hz, 1 H), 3.63 (bs, 2H), 3.50 ~ 3.43 (m, 2 H), 3.07 (d,J= 26.4 Hz, 2 H), 2.87 (s, 3 H), 2.35 (m, 3 H), 2.33 ~ 2.25 (m, 1 H), 1.96 (d,J= 11.2 Hz, 1 H), 1.78 ~ 1.68 (m, 5 H), 1.34 to 1.21 (m, 4 H), 1.13 (q,J= 10.9 Hz, 1 H).

[0546]

[0547] Example 42: Synthesis of N-ethyl-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxamide

[0548]

[0549]

[0550] A method similar to Step 2 of Example 39 using 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid (0.060 g, 0.128 mmol), ethanolamine hydrochloride (0.013 g, 0.154 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.073 g, 0.192 mmol), and N,N-diisopropylethylamine (0.067 mL, 0.385 mmol) as starting materials. N-ethyl-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxamide (0.024 g, 37.8%) was obtained in the form of an ivory solid: LRMS(ES)m / z495.41 [M+H] + , calculated MW 494.61;1H-NMR(400 MHz, CD3OD) d 7.92 (dd,J= 8.8, 4.8 Hz, 1 H), 7.71 (d,J= 6.4 Hz, 1 H), 7.41 (dd,J= 7.6, 3.2 Hz, 1 H), 6.19 (td,J= 608.8, 802.0 Hz, 1 H), 6.92 (d,J= 1.6 Hz, 1 H), 6.68 (dd,J= 7.0, 1.8 Hz, 1 H), 4.31 (d,J= 11.6 Hz, 1 H), 3.87 (dd,J= 13.0, 8.2 Hz, 1 H), 3.52 (bs, 3 H), 3.35 (q,J= 7.3 Hz, 2 H), 2.97 (bs, 3 H), 2.35 ~ 2.20 (m, 4 H), 1.95 (m, 1 H), 1.78 ~ 1.66 (m, 5 H), 1.33 ~ 1.22 (m, 4 H), 1.18 (t,J= 7.2 Hz, 3 H), 1.13 (q,J= 9.9 Hz, 1 H).

[0551]

[0552] Example 43: Synthesis of N-ethyl-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-N-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide

[0553]

[0554]

[0555] A method similar to Step 2 of Example 39 using 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid (0.060 g, 0.128 mmol), N-methyl ethanolamine (0.013 mL, 0.154 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.073 g, 0.192 mmol), and N,N-diisopropylethylamine (0.067 mL, 0.385 mmol) as starting materials. N-ethyl-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-N-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (0.036 g, 55.2%) was obtained as a yellow solid: LRMS(ES) m / z 509.41 [M+H] +, calculated MW 508.64;1H-NMR(400 MHz, CD3OD) d 7.95 (q,J= 4.5 Hz, 1 H), 7.75 (d,J= 7.2 Hz, 1 H), 7.44 (dd,J= 8.8, 1.6 Hz, 1 H), 7.22 (td,J= 9.1, 2.0 Hz, 1 H), 6.56 (s, 1 H), 6.39 (d,J= 7.2 Hz, 1 H), 4.30 (d,J= 13.6 Hz, 1 H), 3.92 (d,J= 8.8 Hz, 1 H), 3.71 to 3.61 (m, 2 H), 3.55 (q,J=6.9 Hz, 2 H), 3.48 (d,J= 13.2 Hz, 1 H), 3.17 (bs, 3 H), 3.02 (d,J= 21.2 Hz, 3 H), 2.42 to 2.24 (m, 4 H), 2.00 (d,J= 9.6 Hz, 1 H), 1.84 to 1.69 (m, 5 H), 1.37 ~ 1.22 (m, 5 H), 1.18 (t,J= 7.2 Hz, 3 H).

[0556]

[0557] Example 44: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)-4-(morpholine-4-carbonyl)pyridin-2(1H)-one

[0558]

[0559]

[0560] Using 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid (0.060 g, 0.128 mmol), morpholine (0.013 mL, 0.154 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.073 g, 0.192 mmol), and N,N-diisopropylethylamine (0.067 mL, 0.385 mmol) as starting materials, in a manner similar to Step 2 of Example 39 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-(morpholine-4-carbonyl)pyridine-2(1H)-one (0.039 g, 56.6%) was obtained as a white solid: LRMS(ES)m / z537.41 [M+H] + , calculated MW 536.65;1H-NMR(400 MHz, CD3OD) d 7.92 (dd,J= 8.8, 5.2 Hz, 1 H), 7.73 (d,J= 6.4 Hz, 1 H), 7.41 (dd,J= 8.8, 2.4 Hz, 1 H), 7.19 (td,J= 9.0, 2.3 Hz, 1 H), 6.57 (d,J= 1.6 Hz, 1 H), 6.39 (dd,J= 6.8, 1.6 Hz, 1 H), 4.27 (d,J= 12.8 Hz, 1 H), 3.89 (dd,J= 13.2, 6.4 Hz, 1 H), 3.70 (bs, 4H), 3.62 (bs, 3 H), 3.59 ~ 3.48 (m, 2 H), 3.45 (m, 2 H), 3.16 (q,J= 15.1 Hz, 2 H), 3.05 (dd,J= 13.6, 6.4 Hz, 1 H), 2.40 ~ 2.36 (m, 2 H), 2.34 ~ 2.25 (m, 2 H), 1.98 (d,J= 17.7 Hz, 1 H), 1.73 (m, 5 H), 1.37 to 1.24 (m, 4 H), 1.15 (q,J= 10.8 Hz, 1 H).

[0561]

[0562] Example 45: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-N-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-4-carboxamide

[0563]

[0564]

[0565] Using 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid (0.060 g, 0.128 mmol), 4-fluoroaniline (0.017 g, 0.154 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.073 g, 0.192 mmol), and N,N-diisopropylethylamine (0.067 mL, 0.385 mmol) as starting materials, in a manner similar to Step 2 of Example 39 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-N-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-4-carboxamide (0.029 g, 40.3 %) was obtained in the form of a white solid: LRMS(ES) m / z 561.39 [M+H] +, calculated MW 560.65;1H-NMR(400 MHz, CD3OD) d 7.90 (dd,J= 8.8, 4.8 Hz, 1 H), 7.76 (d,J= 7.2 Hz, 1 H), 7.66 (dd,J= 8.8, 4.8 Hz, 2 H), 7.39 (dd,J= 8.8, 2.0 Hz, 1 H), 7.18 (td,J= 9.1, 2.1 Hz, 1 H), 7.08 (t,J= 8.8 Hz, 2 H), 7.03 (d,J= 1.6 Hz, 1 H), 6.76 (dd,J= 7.0, 1.8 Hz, 1 H), 4.43 (d,J=13.2 Hz, 1 H), 3.85 (dd,J= 13.6, 8.4 Hz, 1 H), 3.40 (bs, 3 H), 2.79 (bs, 3 H), 2.33 ~ 2.11 (m, 4 H), 1.96 (d,J= 12.4 Hz, 1 H), 1.80 ~ 1.67 (m, 5 H), 1.34 to 1.13 (m, 5 H).

[0566]

[0567] Example 46: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile

[0568]

[0569]

[0570] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.100 g, 0.236 mmol), 4-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (0.038 g, 0.283 mmol), and potassium carbonate (K2CO3, 0.098 g, 0.707 mmol) as starting materials, in a manner similar to Step 3 of Example 1 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (0.022 g, 20.2%) was obtained in the form of a brown oil: LRMS(ES)m / z463.24 [M+H] + , calculated MW 462.57;1H-NMR(400 MHz, CD3OD) d 7.88 (dd,J= 8.8, 5.2 Hz, 1 H), 7.80 (d,J= 6.8 Hz, 1 H), 7.36 (dd,J= 9.0, 2.2 Hz, 1 H), 7.14 (td,J= 9.9, 2.1 Hz, 1 H), 6.38 (d,J= 6.8 Hz, 1 H), 4.67 (dd,J= 13.0, 4.6 Hz, 1 H), 3.61 (dd,J= 13.2, 10.4 Hz, 1 H), 3.16 to 3.03 (m, 3 H), 2.67 (dd,J= 12.6, 5.8 Hz, 1 H), 2.43 (s, 3 H), 2.26 to 2.13 (m, 3 H), 2.07 to 1.87 (m, 5 H), 1.75 to 1.66 (m, 3 H), 1.48 to 1.45 (m, 2 H), 1.31 to 1.20 (m, 2 H), 1.17 ~ 1.02 (m, 2 H).

[0571]

[0572] Example 47: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile

[0573]

[0574]

[0575] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.100 g, 0.236 mmol), 4-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile (0.038 g, 0.283 mmol), and potassium carbonate (K2CO3, 0.098 g, 0.707 mmol) as starting materials, in a manner similar to Step 3 of Example 1 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile (0.017 g, 15.6%) was obtained in the form of a yellow oil: LRMS(ES)m / z463.38 [M+H] +, calculated MW 462.57;1H-NMR(400 MHz, CD3OD) d 8.31 (s, 1 H), 7.87 (dd,J= 8.6, 5.0 Hz, 1 H), 7.36 (dd,J= 9.0, 2.2 Hz, 1 H), 7.14 (td,J= 9.0, 1.9 Hz, 1 H), 6.43 (s, 1 H), 4.65 (dd,J= 13.0, 4.6 Hz, 1 H), 3.61 (dd,J= 12.8, 10.0 Hz, 1 H), 3.16 ~ 3.06 (m, 3 H), 2.65 (dd,J= 12.4, 6.0 Hz, 1 H), 2.32 (s, 3 H), 2.24 to 2.13 (m, 3 H), 2.05 to 1.87 (m, 5 H), 1.74 to 1.66 (m, 3 H), 1.47 to 1.44 (m, 2 H), 1.31 to 1.20 (m, 2 H), 1.17 to 1.01 (m, 2 H).

[0576]

[0577] Example 48: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-6-oxo-1,6-dihydropyridine-3-carbonitrile

[0578]

[0579]

[0580] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.100 g, 0.236 mmol), 6-oxo-1,6-dihydropyridine-3-carbonitrile (0.034 g, 0.283 mmol), and potassium carbonate (K2CO3, 0.098 g, 0.707 mmol) as starting materials, in a manner similar to Step 3 of Example 1 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-6-oxo-1,6-dihydropyridine-3-carbonitrile (0.012 g, 11.4%) was obtained in the form of a yellow oil: LRMS(ES)m / z449.31 [M+H] + , calculated MW 448.54;1H-NMR(400 MHz, CD3OD) d 8.37 (d,J= 2.4 Hz, 1 H), 7.87 (dd,J= 8.6, 5.0 Hz, 1 H), 7.61 (dd,J= 9.4, 2.6 Hz, 1 H), 7.36 (dd,J= 8.8, 2.0 Hz, 1 H), 7.14 (td,J= 9.0, 2.4 Hz, 1 H), 6.55 (d,J= 9.2 Hz, 1 H), 4.69 (dd,J= 13.0, 4.2 Hz, 1 H), 3.63 (dd,J= 13.6, 10.0 Hz, 1 H), 3.15 to 3.04 (m, 3 H), 2.66 (dd,J= 12.4, 6.0 Hz, 1 H), 2.25 to 2.13 (m, 3 H), 2.07 to 1.88 (m, 5 H), 1.76 to 1.66 (m, 3 H), 1.48 to 1.45 (m, 2 H), 1.31 ~ 1.26 (m, 2 H), 1.21 ~ 1.02 (m, 2 H).

[0581]

[0582] Example 49: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile

[0583]

[0584]

[0585] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.100 g, 0.236 mmol), 2-oxo-1,2-dihydropyridine-3-carbonitrile (0.034 g, 0.283 mmol), and potassium carbonate (K2CO3, 0.098 g, 0.707 mmol) as starting materials, similar to Step 3 of Example 1 By this method, 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (0.021 g, 19.9%) was obtained in the form of a yellow oil: LRMS(ES)m / z449.31 [M+H] +, calculated MW 448.54;1H-NMR(400 MHz, CD3OD) d 8.03 (dd,J= 7.4, 2.2 Hz, 1 H), 7.96 (dd,J= 6.6, 2.2 Hz, 1 H), 7.88 (dd,J= 8.8, 5.2 Hz, 1 H), 7.36 (dd,J= 8.8, 2.0 Hz, 1 H), 7.14 (td,J= 9.0, 2.1 Hz, 1 H), 6.44 (t,J= 7.0 Hz, 1 H), 4.73 (dd,J= 13.0, 4.2 Hz, 1 H), 3.65 (dd,J= 13.0, 10.2 Hz, 1 H), 3.17 ~ 3.04 (m, 3 H), 2.68 (dd,J= 12.4, 6.0 Hz, 1 H), 2.25 (dd,J= 12.8, 6.4 Hz, 1 H), 2.20 ~ 2.15 (m, 2 H), 2.07 ~ 1.91 (m, 5 H), 1.79 ~ 1.66 (m, 3 H), 1.49 to 1.42 (m, 2 H), 1.34 to 1.26 (m, 2 H), 1.21 to 1.03 (m, 2 H).

[0586]

[0587] Example 50: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)-3-methoxypyridine-2(1H)-one

[0588]

[0589]

[0590] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.100 g, 0.236 mmol), 3-methoxypyridine-2(1H)-one (0.035 g, 0.283 mmol), and potassium carbonate (K2CO3, 0.098 g, 0.707 mmol) as starting materials, 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-3-methoxypyridine-2(1H)-one (0.011 g, 10.3%) was prepared in a manner similar to Step 3 of Example 1 to produce a yellow Obtained in oil form: LRMS(ES)m / z454.33 [M+H] + , calculated MW 453.56;1H-NMR(400 MHz, CD3OD) d 7.88 (dd,J= 8.6, 5.0 Hz, 1 H), 7.36 (dd,J= 8.6, 1.8 Hz, 1 H), 7.17 ~ 7.12 (m, 2 H), 6.89 (d,J= 7.2 Hz, 1 H), 6.28 (t,J= 7.2 Hz, 1 H), 4.61 (dd,J= 12.8, 4.4 Hz, 1 H), 3.78 (s, 3 H), 3.65 (dd,J= 12.8, 10.0 Hz, 1 H), 3.11 ~ 3.08 (m, 2 H), 3.03 ~ 3.01 (m, 1 H), 2.72 to 2.67 (m, 1 H), 2.27 to 2.23 (m, 1 H), 2.18 (m, 2 H), 2.04 to 1.92 (m, 5 H), 1.78 to 1.74 (m, 1 H), 1.65 (m, 2 H), 1.49 to 1.46 (m, 2 H), 1.31 (m, 2 H), 1.17 to 1.07 (m, 2 H).

[0591]

[0592] Example 51: Synthesis of 3-bromo-5-fluoro-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)pyridin-2(1H)-one

[0593]

[0594]

[0595] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.120 g, 0.283 mmol), 3-bromo-5-fluoropyridine-2(1H)-one (0.065 g, 0.339 mmol), and potassium carbonate (K2CO3, 0.117 g, 0.848 mmol) as starting materials, in a manner similar to Step 3 of Example 1, 3-bromo-5-fluoro-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one (0.010 g, 6.8%) was obtained in the form of a brown solid: LRMS(ES)m / z520.31 [M] + , calculated MW 520.42;1H-NMR(400 MHz, CD3OD) d 8.05 (dd,J= 6.8, 3.2 Hz, 1 H), 7.89 (dd,J= 8.8, 5.2 Hz, 1 H), 7.84 (t,J= 3.6 Hz, 1 H), 7.37 (dd,J= 8.8, 2.4 Hz, 1 H), 7.15 (td,J= 9.1, 2.1 Hz, 1 H), 4.57 (dd,J= 12.8, 4.0 Hz, 1 H), 3.73 (dd,J= 13.2, 9.6 Hz, 1 H), 3.24 (m, 2 H), 2.90 (d,J= 12.8 Hz, 1 H), 2.45 (bs, 3 H), 2.14 (m, 2 H), 2.09 (m, 1 H), 1.92 (m, 2 H), 1.76 (m, 1 H), 1.69 (d,J= 12.0 Hz, 2 H), 1.56 (d,J= 7.2 Hz, 2 H), 1.35 ~ 1.26 (m, 2 H), 1.21 to 1.07 (m, 3 H).

[0596]

[0597] Example 52: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-N-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide

[0598] Step 1: Synthesis of methyl 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

[0599]

[0600]

[0601] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.300 g, 0.707 mmol), methyl 6-oxo-1,6-dihydropyridine-3-carboxylate (0.130 g, 0.848 mmol), and potassium carbonate (K2CO3, 0.293 g, 2.120 mmol) as starting materials, in a manner similar to Step 3 of Example 1, methyl 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (0.027 g, 7.9%) was obtained in the form of a white solid: LRMS(ES) m / z 482.36 [M+H] +, calculated MW 481.57;1H-NMR(400 MHz, CD3OD) d 8.40 (d,J= 2.8 Hz, 1 H), 7.94 (dd,J= 9.4, 2.2 Hz, 2 H), 7.37 (dd,J= 8.6, 1.8 Hz, 1 H), 7.16 (td,J= 9.1, 2.3 Hz, 1 H), 6.53 (d,J= 9.2 Hz, 1 H), 4.58 ~ 4.55 (m, 1 H), 3.83 (s, 3 H), 3.81 ~ 3.76 (m, 1 H), 3.11 (m, 1 H), 2.63 ~ 2.60 (m, 3 H), 2.17 ~ 2.13 (m, 5 H), 1.96 (m, 1 H), 1.80 to 1.67 (m, 5 H), 1.54 (m, 1 H), 1.33 to 1.31 (m, 2 H), 1.23 to 1.08 (m, 3 H).

[0602]

[0603] Step 2: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid

[0604]

[0605]

[0606] Using methyl 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (0.200 g, 0.415 mmol) and lithium hydroxide monohydrate (0.087 g, 2.077 mmol) as starting materials, 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.150 g, 77.3%) was prepared in the form of a yellow solid in a manner similar to Step 1 of Example 39. Obtained:LRMS(ES)m / z468.40 [M+H] +, calculated MW 467.54.

[0607]

[0608] Step 3: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-N-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide

[0609]

[0610]

[0611] 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.100 g, 0.214 mmol), methanolamine hydrochloride (0.029 g, 0.428 mmol), N,N-diisopropylethylamine (0.112 mL, 0.642 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl, 0.082 g, 0.428 mmol) and 1H-benzo[d][1,2,3]triazole-1-ol (HOBt, 0.058 g, 0.428 mmol) Using the starting material, 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-N-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (0.032 g, 31.1%) was obtained in the form of a yellow solid in a manner similar to Step 2 of Example 39: LRMS(ES) m / z 480.58 [M+H] +, calculated MW 480.58;1H-NMR(400 MHz, DMSO-d6) d 8.20 (d,J= 2.4 Hz, 1 H), 8.18 (m, 1 H), 7.97 (dd,J= 8.6, 5.4 Hz, 1 H), 7.78 (dd,J= 9.4, 2.6 Hz, 1 H), 7.65 (dd,J= 9.0, 2.2 Hz, 1 H), 7.24 (td,J= 9.0, 2.0 Hz, 1 H), 6.35 (d,J= 9.6 Hz, 1 H), 4.41 to 4.39 (m, 1 H), 3.66 to 3.60 (m, 1 H), 3.09 (m, 1 H), 2.96 (m, 1 H), 2.85 (m, 1 H), 2.69 (d,J= 2.4 Hz, 3 H), 2.67 (m, 1 H), 2.16 to 1.95 (m, 5 H), 1.87 to 1.77 (m, 2 H), 1.66 (m, 1 H), 1.54 (m, 2) H), 1.39 (m, 1 H), 1.31 (m, 1 H), 1.19 (m, 2 H), 1.06 to 0.93 (m, 3 H).

[0612]

[0613] Example 53: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

[0614] Step 1: Synthesis of methyl 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxylate

[0615]

[0616]

[0617] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (1.500 g, 3.533 mmol), methyl 2-oxo-1,2-dihydropyridine-3-carboxylate (1.082 g, 7.067 mmol), and potassium carbonate (K2CO3, 1.465 g, 10.600 mmol) as starting materials, in a manner similar to Step 3 of Example 1, methyl 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (0.178 g, 10.5%) was obtained in the form of a pale yellow solid: LRMS(ES) m / z 482.40 [M+H] + , calculated MW 481.57.

[0618]

[0619] Step 2: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid

[0620]

[0621]

[0622] Using methyl 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (0.268 g, 0.557 mmol) and lithium hydroxide monohydrate (0.047 g, 1.113 mmol) as starting materials, 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.201 g, 77.3%) was prepared in the form of a beige solid in a manner similar to Step 1 of Example 39. Obtained:LRMS(ES)m / z466.35 [MH] +, calculated MW 467.54.

[0623]

[0624] Step 3: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

[0625]

[0626]

[0627] Using 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.050 g, 0.107 mmol), methanolamine hydrochloride (0.009 g, 0.128 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.061 g, 0.160 mmol), and N,N-diisopropylethylamine (0.056 mL, 0.321 mmol) as starting materials, in a manner similar to Step 2 of Example 39 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (0.016 g, 31.1%) was obtained in the form of an ivory solid: LRMS(ES)m / z481.41 [M+H] +, calculated MW 480.58;1H-NMR(400 MHz, CD3OD) d 8.43 (dd,J= 7.4, 1.8 Hz, 1 H), 7.90 ~ 7.86 (m, 2 H), 7.41 (dd,J= 8.8, 2.4 Hz, 1 H), 7.18 (td,J= 9.0, 2.1 Hz, 1 H), 6.54 (t,J= 6.8 Hz, 1 H), 4.48 (dd,J= 13.0, 3.4 Hz, 1 H), 3.82 (dd,J= 13.2, 8.8 Hz, 1 H), 3.57 to 3.41 (m, 2 H), 3.35 (d,J= 14.8 Hz, 1 H), 2.98 ~ 2.87 (m, 3 H), 2.92 (d,J= 3.6 Hz, 3 H), 2.30 (m, 2 H), 2.20 (m, 2 H), 1.97 (d,J= 13.2 Hz, 1 H), 1.79 (m, 1 H), 1.71 (d,J= 9.2 Hz, 3 H), 1.62 (d,J= 12.8 Hz, 1 H), 1.35 to 1.13 (m, 4 H).

[0628]

[0629] Example 54: Synthesis of 1-(((1R,2R)-2-((4-(benzo[d]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carbonitrile

[0630] Step 1: Synthesis of 3-(piperazine-1-yl)benzo[d]isooxazole

[0631]

[0632]

[0633] A solution of 3-chlorobenzo[d]isooxazole (1.000 g, 6.512 mmol), piperazine (1.683 g, 19.535 mmol), and potassium carbonate (K2CO3, 0.900 g, 6.512 mmol) dissolved in acetonitrile (30 mL) at room temperature was stirred at 140°C for 48 hours, after which the temperature was lowered to room temperature to terminate the reaction. Water was added to the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography to obtain 3-(piperazine-1-yl)benzo[d]isooxazole (0.677 g, 51.2%) as a pale yellow liquid: LRMS(ES)m / z204.18 [M+H] + , calculated MW 203.25.

[0634]

[0635] Step 2: Synthesis of (3aR,7aR)-4'-(benzo[d]isooxazole-3-yl)octahydrospiro[isoindole-2,1'-piperazine]-2-yum methanesulfonate

[0636]

[0637]

[0638] (3aR,7aR)-4'-(benzo[d]isooxazole-3-yl)octahydrospiro[isoindole-2,1'-piperazine]-2-ium methanesulfonate (0.370 g, 27.3%) was obtained in the form of a yellow oil using 3-(piperazine-1-yl)benzo[d]isooxazole (0.677 g, 3.331 mmol), ((1R,2R)-cyclohexane-1,2-diyl)bis(methylene)dimethanesulfonate (1.501 g, 4.996 mmol), and potassium carbonate (K2CO3, 1.381 g, 9.993 mmol) as starting materials in a manner similar to Step 2 of Example 1:LRMS(ES)m / z312.32 [M+H] +, calculated MW 407.53.

[0639]

[0640] Step 3: Synthesis of 1-(((1R,2R)-2-((4-(benzo[d]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carbonitrile

[0641]

[0642]

[0643] Using (3aR,7aR)-4'-(benzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperazine]-2-ium methanesulfonate (0.180 g, 0.442 mmol), 2-oxo-1,2-dihydropyridine-4-carbonitrile (0.106 g, 0.883 mmol), and potassium carbonate (K2CO3, 0.183 g, 1.325 mmol) as starting materials, in a manner similar to Step 3 of Example 1, 1-(((1R,2R)-2-((4-(benzo[d]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carbonitrile (0.015 g, 7.9%) was obtained in the form of a light brown solid: LRMS(ES)m / z432.40 [M+H] +, calculated MW 431.54;1H-NMR(400 MHz, CD3OD) d 7.85 (d,J= 7.6 Hz, 1 H), 7.77 (d,J= 6.4 Hz, 1 H), 7.19 (td,J= 207.6, 267.9 Hz, 1 H), 7.44 (d,J= 8.0 Hz, 1 H), 7.26 (t,J= 7.0 Hz, 1 H), 5.40 (d,J= 1202.4 Hz, 1 H), 6.48 (dd,J= 6.8, 2.0 Hz, 1 H), 4.72 (dd,J= 13.2, 4.4 Hz, 1 H), 3.63 (dd,J=13.0, 10.2 Hz, 1 H), 3.53 (t,J= 5.0 Hz, 4 H), 2.67 (t,J= 6.2 Hz, 1 H), 2.63 (t,J= 5.0 Hz, 4 H), 2.23 (dd,J= 12.4, 6.0 Hz, 1 H), 1.91 (dd,J= 13.0, 3.0 Hz, 1 H), 1.78 to 1.72 (m, 1 H), 1.66 (m, 2 H), 1.46 (m, 2 H), 1.34 to 1.25 (m, 1 H), 1.17 to 1.02 (m, 3 H).

[0644]

[0645] Example 55: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-2(1H)-one hydrochloride

[0646] Step 1: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)pyrimidine-2(1H)-one

[0647]

[0648]

[0649] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.150 g, 0.353 mmol), pyrimidine-2(1H)-one (0.068 g, 0.707 mmol), and potassium carbonate (K2CO3, 0.146 g, 1.060 mmol) as starting materials, 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-2(1H)-one (0.034 g, 22.7%) was prepared as a pale yellow solid in a manner similar to Step 3 of Example 1. Obtained:LRMS(ES)m / z425.40 [M+H] + , calculated MW 424.52;1H-NMR(400 MHz, CD3OD) d 8.55 (dd,J= 3.8, 3.0 Hz, 1 H), 8.13 (dd,J= 6.8, 2.8 Hz, 1 H), 7.87 (dd,J= 8.8, 5.2 Hz, 1 H), 7.35 (dd,J= 8.8, 2.0 Hz, 1 H), 7.14 (td,J= 9.1, 2.1 Hz, 1 H), 6.50 (dd,J= 6.0, 4.4 Hz, 1 H), 4.67 (dd,J= 13.2, 4.4 Hz, 1 H), 3.57 (dd,J= 12.8, 10.0 Hz, 1 H), 3.16 ~ 3.04 (m, 3 H), 2.67 (dd,J= 12.8, 6.0 Hz, 1 H), 2.24 (dd,J= 12.6, 6.6 Hz, 1 H), 2.17 (t,J= 11.0 Hz, 2 H), 2.07 ~ 1.90 (m, 5 H), 1.78 (m, 1 H), 1.68 (m, 2 H), 1.48 (m, 2 H), 1.28 (m, 1 H), 1.19 (m, 1 H), 1.10 (m, 2 H).

[0650]

[0651] Step 2: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-2(1H)-one hydrochloride

[0652]

[0653]

[0654] Using 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-2(1H)-one (0.030 g, 0.071 mmol) as a starting material, 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-2(1H)-one hydrochloride (0.028 g, 86.0 %) was obtained in the form of an ivory solid in a manner similar to Step 2 of Example 3: LRMS(ES) m / z 425.40 [M+H] + , calculated MW 460.98;1H-NMR(400 MHz, CD3OD) d 8.62 (q,J= 2.4 Hz, 1 H), 8.15 (dd,J= 6.4, 2.8 Hz, 1 H), 7.94 (m, 1 H), 7.42 (dd,J= 8.6, 1.8 Hz, 1 H), 7.20 (td,J= 9.1, 2.0 Hz, 1 H), 6.57 (q,J= 3.5 Hz, 1 H), 4.21 (d,J= 13.2 Hz, 1 H), 3.89 (dd,J= 19.8, 19.8 Hz, 1 H), 3.73 (bs, 1 H), 3.60 ~ 3.50 (m, 3 H), 3.25 ~ 3.06 (m, 3 H), 2.45 ~ 2.22 (m, 4 H), 1.98 (d,J= 12.8 Hz, 1 H), 1.80 ~ 1.69 (m, 5 H), 1.37 ~ 1.24 (m, 3 H), 1.14 (q,J= 9.7 Hz, 1 H).

[0655]

[0656] Example 56: Synthesis of 3-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)-6-methylpyrimidine-4(3H)-one

[0657]

[0658]

[0659] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.150 g, 0.353 mmol), 6-methylpyrimidine-4(3H)-one (0.078 g, 0.707 mmol), and potassium carbonate (K2CO3, 0.146 g, 1.060 mmol) as starting materials, 3-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-6-methylpyrimidine-4(3H)-one (0.017 g, 11.0%) was prepared in the form of a white solid in a manner similar to Step 3 of Example 1. Obtained:LRMS(ES)m / z439.40 [M+H] + , calculated MW 438.55;1H-NMR(400 MHz, CD3OD) d 8.32 (s, 1 H), 7.92 (dd,J= 8.8, 5.6 Hz, 1 H), 7.37 (dd,J= 8.8, 2.0 Hz, 1 H), 7.16 (td,J= 9.0, 2.0 Hz, 1 H), 6.32 (s, 1 H), 4.50 (d,J= 14.4 Hz, 1 H), 3.68 (dd,J= 13.4, 9.4 Hz, 1 H), 3.25 (m, 3 H), 2.93 (bs, 1 H), 2.48 (bs, 2 H), 2.27 (s, 3 H), 2.14 (s, 4 H), 1.94 (d,J= 13.2 Hz, 1 H), 1.75 to 7.67 (m, 3 H), 1.54 (m, 2 H), 1.29 (t,J= 12.0 Hz, 2 H), 1.20 to 1.07 (m, 3 H).

[0660]

[0661] Example 57: Synthesis of 2-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridazine-3(2H)-one

[0662]

[0663]

[0664] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.180 g, 0.424 mmol), pyridazine-3(2H)-one (0.081 g, 0.848 mmol), and potassium carbonate (K2CO3, 0.176 g, 1.272 mmol) as starting materials, 2-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridazine-3(2H)-one (0.143 g, 79.4%) was prepared in the form of a yellow oil in a manner similar to Step 3 of Example 1. Obtained:LRMS(ES)m / z425.33 [M+H] +, calculated MW 424.52;1H-NMR(400 MHz, CD3OD) d 7.95 (dd,J= 4.0, 1.6 Hz, 1 H), 7.90 (dd,J= 8.4, 5.2 Hz, 1 H), 7.44 ~ 7.39 (m, 2 H), 7.18 (td,J= 9.1, 2.3 Hz, 1 H), 7.00 (dd,J= 9.2, 1.6 Hz, 1 H), 4.41 (dd,J= 13.2, 4.4 Hz, 1 H), 4.13 (dd,J= 13.2, 7.6 Hz, 1 H), 3.54 (dd,J= 25.0, 11.0 Hz, 2 H), 3.45 (m, 1 H), 3.37 (dd,J= 12.6, 3.8 Hz, 1 H), 3.00 (m, 2 H), 2.89 (dd,J= 12.8, 8.0 Hz, 1 H), 2.30 (m, 2 H), 2.28 ~ 2.15 (m, 2 H), 1.97 (d,J= 16.0 Hz, 1 H), 1.87 to 1.74 (m, 2 H), 1.70 (d,J= 8.8 Hz, 3 H), 1.36 to 1.11 (m, 4 H).

[0665]

[0666] Example 58: Synthesis of 1-(((1R,2R)-2-((4-(benzo[d]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-6-oxo-1,6-dihydropyridine-3-carbonitrile

[0667]

[0668]

[0669] Using (3aR,7aR)-4'-(benzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperazine]-2-ium methanesulfonate (0.100 g, 0.245 mmol), 6-oxo-1,6-dihydropyridine-3-carbonitrile (0.035 g, 0.294 mmol), and potassium carbonate (K2CO3, 0.102 g, 0.736 mmol) as starting materials, in a manner similar to Step 3 of Example 1, 1-(((1R,2R)-2-((4-(benzo[d]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-6-oxo-1,6-dihydropyridine-3-carbonitrile (0.037 g (34.9%) was obtained in the form of a pale yellow solid: LRMS(ES)m / z432.40 [M+H] + , calculated MW 431.54;1H-NMR(400 MHz, CD3OD) d 8.36 (d,J= 2.4 Hz, 1 H), 7.85 (d,J= 8.0 Hz, 1 H), 7.60 (dd,J= 9.4, 2.6 Hz, 1 H), 7.55 ~ 7.51 (m, 1 H), 7.44 (d,J= 8.4 Hz, 1 H), 7.26 (td,J= 7.6, 0.8 Hz, 1 H), 6.54 (d,J= 9.6 Hz, 1 H), 4.74 (dd,J= 13.0, 4.6 Hz, 1 H), 3.62 (dd,J= 12.8, 10.0 Hz, 1 H), 3.53 (m, 4 H), 2.69 ~ 2.62 (m, 5 H), 2.22 (dd,J= 12.8, 6.0 Hz, 1 H), 1.92 ~ 1.87 (m, 1 H), 1.77 ~ 1.67 (m, 3 H), 1.50 ~ 1.44 (m, 2 H), 1.30 (m, 1 H), 1.17 to 1.00 (m, 3 H).

[0670]

[0671] Example 59: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-methylpyrimidine-2(1H)-one hydrochloride

[0672] Step 1: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)-4-methylpyrimidine-2(1H)-one

[0673]

[0674]

[0675] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (4.000 g, 9.422 mmol), 4-methylpyrimidine-2(1H)-one (2.386 g, 21.671 mmol), and cesium carbonate (Cs2CO3, 9.210 g, 28.267 mmol) as starting materials, 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-methylpyrimidine-2(1H)-one (1.800 g, 43.6%) was prepared in a manner similar to Step 3 of Example 1. Obtained in the form of an ivory solid: LRMS(ES)m / z439.40 [M+H] +, calculated MW 438.55;1H-NMR(400 MHz, CD3OD) d 7.96 (d,J= 6.4 Hz, 1 H), 7.87 (dd,J= 8.6, 5.0 Hz, 1 H), 7.37 (dd,J= 8.6, 2.2 Hz, 1 H), 7.14 (td,J= 8.9, 2.3 Hz, 1 H), 6.42 (d,J= 6.4 Hz, 1 H), 4.60 (dd,J= 13.0, 4.3 Hz, 1 H), 3.52 (dd,J= 13.0, 9.8 Hz, 1 H), 3.15 to 3.02 (m, 3 H), 2.65 (dd,J=12.4, 6.0 Hz, 1 H), 2.35 (s, 3 H), 2.24 to 2.18 (m, 1 H), 2.17 to 2.11 (m, 2 H), 2.06 to 1.90 (m, 5 H), 1.80 to 1.66 (m, 3 H), 1.51 to 1.42 (m, 2 H), 1.33 to 1.24 (m, 1 H), 1.21 to 1.02 (m, 3 H).

[0676]

[0677] Step 2: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-methylpyrimidine-2(1H)-one hydrochloride

[0678]

[0679]

[0680] Using 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-methylpyrimidine-2(1H)-one (0.100 g, 0.228 mmol) as a starting material, 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-methylpyrimidine-2(1H)-one hydrochloride (0.091 g, 84.0 %) was obtained in the form of a yellow solid by a method similar to Step 2 of Example 3: LRMS(ES)m / z439.34 [M+H]+ , calculated MW 475.01;1H-NMR(400 MHz, CD3OD) d 7.99 (d,J= 6.8 Hz, 1 H), 7.97 (dd,J= 8.2, 4.2 Hz, 1 H), 7.42 (dd,J= 8.6, 1.8 Hz, 1 H), 7.20 (td,J= 9.1, 2.8 Hz, 1 H), 6.50 (d,J= 6.8 Hz, 1 H), 4.12 (d,J= 13.6 Hz, 1 H), 3.89 (dd,J= 13.0, 6.2 Hz, 1 H), 3.80 (dd,J= 23.6, 12.4 Hz, 2 H), 3.63 (d,J= 14.4 Hz, 1 H), 3.53 (t,J= 11.8 Hz, 1 H), 3.31 ~ 3.20 (m, 2 H), 3.15 (q,J= 6.8 Hz, 1 H), 2.43 (m, 2 H), 2.39 (s, 3 H), 2.29 (q,J= 14.5 Hz, 2 H), 1.98 (d,J= 12.4 Hz, 1 H), 1.75 (m, 5 H), 1.29 (m, 3 H), 1.13 (q,J= 11.2 Hz, 1 H).

[0681]

[0682] Example 60: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-2(1H)-one

[0683] Step 1: Synthesis of (2-chloro-4-fluorophenyl)(piperazine-1-yl)methanone oxime

[0684]

[0685]

[0686] 2-chloro-4-fluoro-N-hydroxybenzimidyl chloride (2.700 g, 12.980 mmol) was added to a solution of piperazine (1.677 g, 19.470 mmol) and triethylamine (5.428 mL, 38.940 mmol) dissolved in tetrahydrofuran (20 mL) at 0°C, and the mixture was stirred at room temperature for 2 hours. Water was added to the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography to obtain (2-chloro-4-fluorophenyl)(piperazine-1-yl)methanone oxime (2.040 g, 61.0%) as an ivory solid: LRMS(ES) m / z 258.09 [M+H] + , calculated MW 257.69.

[0687]

[0688] Step 2: Synthesis of (6-fluoro-3-(piperazine-1-yl)benzo[d]isooxazole

[0689]

[0690]

[0691] A solution of (2-chloro-4-fluorophenyl)(piperazine-1-yl)methanone oxime (2.040 g, 7.916 mmol) and potassium tert-butoxide (0.977 g, 8.708 mmol) dissolved in 1,4-dioxane (20 mL) at room temperature was heated under reflux for 18 hours, after which the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was filtered through a glass filter to remove the solid, and the solvent was removed from the filtrate under reduced pressure; the resulting product was used without further purification. (6-fluoro-3-(piperazine-1-yl)benzo[d]isooxazole, 1.700 g, 97.1%, yellow solid):LRMS(ES)m / z222.15 [M+H] + , calculated MW 221.24.

[0692]

[0693] Step 3: Synthesis of (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydrospiro[isoindole-2,1'-piperazine]-2-yum methanesulfonate

[0694]

[0695]

[0696] (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperazine]-2-ium methanesulfonate (0.954 g, 29.2%) was obtained in the form of a yellow oil using 6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperazine]-2-ium methanesulfonate in a manner similar to Step 2 of Example 1, using 6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperazine]-2-ium methanesulfonate as starting materials:LRMS(ES)m / z330.22 [M+H] + , calculated MW 425.52.

[0697]

[0698] Step 4: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-2(1H)-one

[0699]

[0700]

[0701] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperidine]-2-ium methanesulfonate (0.150 g, 0.353 mmol), pyrimidine-2(1H)-one (0.051 g, 0.530 mmol), and potassium carbonate (K2CO3, 0.146 g, 1.060 mmol) as starting materials, 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-2(1H)-one (0.025 g, 16.6%) was prepared in the form of a yellow solid in a manner similar to Step 3 of Example 1. Obtained:LRMS(ES)m / z426.39 [M+H] + , calculated MW 425.51;1H-NMR(400 MHz, CD3OD) d 8.54 (dd,J= 4.0, 2.8 Hz, 1 H), 8.11 (dd,J= 6.0, 2.8 Hz, 1 H), 7.87 (dd,J= 8.8, 4.8 Hz, 1 H), 7.22 (dd,J= 8.8, 2.4 Hz, 1 H), 7.06 (td,J= 9.1, 2.1 Hz, 1 H), 6.50 (dd,J= 6.4, 4.4 Hz, 1 H), 4.71 (dd,J= 12.8, 4.0 Hz, 1 H), 3.54 (dd,J= 11.2, 8.4 Hz, 1 H), 3.51 (t,J= 5.0 Hz, 4 H), 2.67 (dd,J= 12.8, 6.4 Hz, 1 H), 2.62 (t,J= 4.6 Hz, 4 H), 2.23 (dd,J= 12.4, 6.0 Hz, 1 H), 1.90 (d,J= 13.2 Hz, 1 H), 1.83 to 1.76 (m, 1 H), 1.68 (m, 2 H), 1.48 (m, 2 H), 1.28 (m, 1 H), 1.21 to 1.02 (m, 3 H).

[0702]

[0703] Example 61: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-4-methylpyrimidine-2(1H)-one hydrochloride

[0704] Step 1: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-4-methylpyrimidine-2(1H)-one

[0705]

[0706]

[0707] Using (3aR,7aR)-4'-(6-fluorobenzo[d]isooxazole-3-yl)octahydropyro[isoindole-2,1'-piperazine]-2-ium methanesulfonate (0.120 g, 0.282 mmol), 4-methylpyrimidine-2(1H)-one hydrochloride (0.062 g, 0.423 mmol), and potassium carbonate (K2CO3, 0.117 g, 0.846 mmol) as starting materials, in a manner similar to Step 3 of Example 1, 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-4-methylpyrimidine-2(1H)-one (0.027 g, 21.8%) was obtained in the form of a brown solid: LRMS(ES)m / z440.26 [M+H] +, calculated MW 439.54;1H-NMR(400 MHz, CD3OD) d 7.95 (d,J= 6.8 Hz, 1 H), 7.88 (dd,J= 9.2, 5.2 Hz, 1 H), 7.25 (dd,J= 8.8, 2.4 Hz, 1 H), 7.08 (td,J= 9.0, 2.0 Hz, 1 H), 6.45 (d,J= 6.4 Hz, 1 H), 4.46 (dd,J= 13.4, 4.2 Hz, 1 H), 3.65 (m, 1 H), 3.62 (t,J= 4.0 Hz, 4 H), 2.99 (dd,J= 13.2, 5.6 Hz, 1 H), 2.93 (m, 4 H), 2.54 (dd,J= 12.6, 6.6 Hz, 1 H), 2.36 (s, 3 H), 1.93 (d,J= 10.0 Hz, 1 H), 1.75 (m, 1 H), 1.70 (d,J= 11.6 Hz, 2 H), 1.56 (m, 2 H), 1.29 (m, 1 H), 1.14 (m, 3 H).

[0708]

[0709] Step 2: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-4-methylpyrimidine-2(1H)-one hydrochloride

[0710]

[0711]

[0712] Using 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-4-methylpyrimidine-2(1H)-one (0.009 g, 0.020 mmol) as a starting material, 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-4-methylpyrimidine-2(1H)-one hydrochloride (0.008 g, 82.1%) was obtained in the form of a beige solid in a manner similar to Step 2 of Example 3: LRMS(ES)m / z440.33 [M+H] +, calculated MW 475.99;1H-NMR(400 MHz, CD3OD) d 8.04 (d,J= 7.2 Hz, 1 H), 7.91 (dd,J= 8.8, 5.2 Hz, 1 H), 7.31 (dd,J= 8.8, 2.0 Hz, 1 H), 7.13 (td,J= 9.1, 2.3 Hz, 1 H), 6.53 (d,J= 6.4 Hz, 1 H), 4.19 (bs, 2 H), 4.12 (dd,J= 14.0, 2.4 Hz, 1 H), 3.90 (dd,J= 13.6, 6.8 Hz, 1 H), 3.73 (bs, 2 H), 3.67 (dd,J= 13.4, 2.6 Hz, 1 H), 3.61 ~ 3.37 (m, 4 H), 3.20 (dd,J= 13.2, 7.6 Hz, 1 H), 2.41 (s, 3 H), 1.98 (d,J= 12.0 Hz, 1 H), 1.81 ~ 1.73 (m, 5 H), 1.35 ~ 1.23 (m, 3 H), 1.14 (q,J= 11.7 Hz, 1 H).

[0713]

[0714] Example 62: Synthesis of N-(3-chlorophenyl)-1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxamide

[0715]

[0716]

[0717] Using 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid (0.060 g, 0.128 mmol), 3-chloroaniline (0.016 mL, 0.154 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.073 g, 0.192 mmol), and N,N-diisopropylethylamine (0.067 mL, 0.385 mmol) as starting materials, a method similar to Step 2 of Example 39 N-(3-chlorophenyl)-1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxamide (0.021 g, 28.4%) was obtained in the form of a beige solid: LRMS(ES) m / z 577.37 [M+H] + , calculated MW 577.1;1H-NMR(400 MHz, CD3OD) d 7.92 (dd,J= 8.8, 4.8 Hz, 1 H), 5.84 (t,J= 1200.0 Hz, 1 H), 7.77 (d,J= 7.2 Hz, 1 H), 7.56 (d,J= 9.2 Hz, 1 H), 7.41 (dd,J= 8.4, 2.0 Hz, 1 H), 7.32 (t,J= 8.0 Hz, 1 H), 7.22 ~ 7.14 (m, 2 H), 7.05 (d,J= 1.6 Hz, 1 H), 6.78 (dd,J= 6.8, 2.0 Hz, 1 H), 4.34 (d,J= 14.8 Hz, 1 H), 3.90 (dd,J= 13.6, 8.0 Hz, 1 H), 3.64 ~ 3.39 (m, 3 H), 3.00 (m, 3 H), 2.33 (m, 2 H), 2.25 (m, 2 H), 1.97 (d,J= 14.8 Hz, 1 H), 1.80 to 1.68 (m, 5 H), 1.27 (td,J= 23.8, 11.5 Hz, 4 H), 1.23 to 1.19 (m, 1 H).

[0718]

[0719] Example 63: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)-4-iodopyridine-2(1H)-one

[0720]

[0721]

[0722] Using (3aR,7aR)-4'-(6-fluorobenzo]isooxazole-3-yl)octahydropyroisoindole-2,1'-piperidine]-2-ium methanesulfonate (3.000 g, 7.067 mmol), 4-iodopyridine-2(1H)-one (3.123 g, 14.133 mmol), and potassium carbonate (K2CO3, 2.930 g, 21.200 mmol) as starting materials, 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-iodopyridine-2(1H)-one (0.580 g, 14.9%) was prepared in the form of a yellow liquid in a manner similar to Step 3 of Example 1. Obtained:LRMS(ES)m / z550.22 [M+H] +, calculated MW 549.43;1H-NMR(400 MHz, CD3OD) d 7.87 (dd,J= 8.8, 4.8 Hz, 1 H), 7.35 (dd,J= 8.8, 2.0 Hz, 1 H), 7.33 (d,J= 8.0 Hz, 1 H), 7.14 (td,J= 8.8, 2.4 Hz, 1 H), 7.02 (d,J= 1.6 Hz, 1 H), 6.67 (dd,J= 7.0, 1.8 Hz, 1 H), 4.56 (dd,J= 13.2, 4.8 Hz, 1 H), 3.58 (dd,J= 13.2, 10.0 Hz, 1 H), 3.15 ~ 3.01 (m, 3 H), 2.65 (q,J= 6.0 Hz, 1 H), 2.22 (q,J= 6.4 Hz, 1 H), 2.16 ~ 2.12 (m, 2 H), 2.06 ~ 2.01 (m, 3 H), 1.98 ~ 1.89 (m, 2 H), 1.75 ~ 1.65 (m, 3 H), 1.48 to 1.45 (m, 2 H), 1.29 (q,J= 12.0 Hz, 1 H), 1.18 (m, 1 H), 1.06 (q,J= 10.5 Hz, 2 H).

[0723]

[0724] Example 64: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)-4-(piperidin-1-yl)pyridin-2(1H)-one

[0725]

[0726]

[0727] 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-iodopyridine-2(1H)-one (0.100 g, 0.182 mmol), piperidine (0.022 mL, 0.218 mmol), sodium tert-butoxide (0.021 g, 0.218 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (Ruphos, 0.008 g, 0.018 mmol) and 2-dicyclohexylphosphino-2',4',6'-diisopropoxy-1,1'-biphenyl [2-(2'-amino-1,1'-biphenyl)]palladium(II) A solution of methanesulfonate (Ruphos Pd G3, 0.015 g, 0.018 mmol) dissolved in tetrahydrofuran (3 mL) at room temperature was stirred at 85°C for 18 hours, after which the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography to obtain 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-(piperidine-1-yl)pyridine-2(1H)-one (0.049 g, 53.1%) as a beige solid: LRMS(ES)m / z507.36 [M+H] +, calculated MW 506.67;1H-NMR(400 MHz, CD3OD) d 7.97 (dd,J= 8.8, 4.8 Hz, 1 H), 7.42 (dd,J= 8.8, 2.0 Hz, 1 H), 7.34 (t,J= 7.0 Hz, 1 H), 7.19 (td,J= 9.0, 2.0 Hz, 1 H), 6.24 (dd,J= 7.6, 3.2 Hz, 1 H), 5.75 ~ 5.73 (m, 1 H), 3.94 ~ 3.92 (m, 2 H), 3.70 (m, 2 H), 3.55 (bs, 1 H), 3.39 (t,J= 5.6 Hz, 4 H), 3.22 (bs, 2 H), 3.01 (td,J= 17.1, 5.9 Hz, 1 H), 2.38 (m, 2 H), 2.35 (m, 1 H), 2.14 (m, 1 H), 1.93 (m, 1 H), 1.79 ~ 1.67 (m, 7 H), 1.63 ~ 1.58 (m, 4 H), 1.26 (m, 3 H), 1.11 (m, 1 H).

[0728]

[0729] Example 65: Synthesis of methyl 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxylate

[0730]

[0731]

[0732] Using (3aR,7aR)-4'-(6-fluorobenzo]isooxazole-3-yl)octahydropyroisoindole-2,1'-piperidine]-2-ium methanesulfonate (1.500 g, 3.533 mmol), methyl 2-oxo-1,2-dihydropyridine-3-carboxylate (1.082 g, 7.067 mmol), and potassium carbonate (K2CO3, 1.465 g, 10.600 mmol) as starting materials, in a manner similar to Step 3 of Example 1, methyl 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (0.178 g, 10.5%) was obtained in the form of a pale yellow solid: LRMS(ES) m / z 482.40 [M+H] + , calculated MW 481.57;1H-NMR(400 MHz, CD3OD) d 8.18 (dd,J= 7.2, 2.0 Hz, 1 H), 7.93 ~ 7.82 (m, 2 H), 7.35 (dd,J= 8.8, 2.4 Hz, 1 H), 7.14 (td,J= 9.1, 2.3 Hz, 1 H), 6.39 (t,J= 6.8 Hz, 1 H), 4.74 (dd,J= 12.8, 4.4 Hz, 1 H), 3.81 (m, 3 H), 3.61 (dd,J= 13.0, 10.2 Hz, 1 H), 3.11 ~ 3.01 (m, 3 H), 2.70 (dd,J= 12.2, 5.8 Hz, 1 H), 2.24 (dd,J= 12.6, 6.6 Hz, 1 H), 2.16 (m, 2 H), 2.04 ~ 1.92 (m, 5 H), 1.77 (bs, 1 H), 1.66 (bs, 2 H), 1.48 (d,J= 6.0 Hz, 2 H), 1.29 (q,J= 10.3 Hz, 1 H), 1.17 to 1.03 (m, 3 H).

[0733]

[0734] Example 66: Synthesis of 5-chloro-1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)pyridin-2(1H)-one

[0735]

[0736]

[0737] Using (3aR,7aR)-4'-(6-fluorobenzo]isooxazole-3-yl)octahydropyroisoindole-2,1'-piperidine]-2-ium methanesulfonate (0.200 g, 0.471 mmol), 5-chloropyridine-2(1H)-one (0.122 g, 0.942 mmol), and potassium carbonate (K2CO3, 0.195 g, 1.413 mmol) as starting materials, 5-chloro-1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one (0.058 g, 26.9%) was prepared in the form of a beige solid in a manner similar to Step 3 of Example 1. Obtained:LRMS(ES)m / z458.41 [M+H] +, calculated MW 457.97;1H-NMR(400 MHz, CD3OD) d 7.91 (dd,J= 8.8, 5.6 Hz, 1 H), 7.81 (d,J= 2.8 Hz, 1 H), 7.54 (dd,J= 9.2, 2.8 Hz, 1 H), 7.41 (dd,J= 8.8, 1.6 Hz, 1 H), 7.19 (td,J= 8.9, 1.9 Hz, 1 H), 6.58 (d,J= 9.6 Hz, 1 H), 4.27 (dd,J= 13.6, 3.6 Hz, 1 H), 3.83 (dd,J= 13.2, 8.0 Hz, 1 H), 3.60 ~ 3.51 (m, 2 H), 3.46 (m, 1 H), 3.33 (d,J= 13.2 Hz, 1 H), 3.02 (m, 2 H), 2.92 (q,J= 6.5 Hz, 1 H), 2.31 (m, 2 H), 2.28 ~ 2.16 (m, 2 H), 1.95 (d,J= 13.2 Hz, 1 H), 1.77 to 1.65 (m, 5 H), 1.36 to 1.20 (m, 3 H), 1.12 (q,J= 10.5 Hz, 1 H).

[0738]

[0739] Example 67: Synthesis of 5-chloro-3-fluoro-1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)pyridin-2(1H)-one

[0740]

[0741]

[0742] Using (3aR,7aR)-4'-(6-fluorobenzo]isooxazole-3-yl)octahydropyroisoindole-2,1'-piperidine]-2-ium methanesulfonate (0.200 g, 0.471 mmol), 5-chloro-3-fluoropyridine-2(1H)-one (0.139 g, 0.942 mmol), and potassium carbonate (K2CO3, 0.195 g, 1.413 mmol) as starting materials, 5-chloro-3-fluoro-1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one (0.060 g, 26.8%) was prepared in a manner similar to Step 3 of Example 1. Obtained in the form of brown oil: LRMS(ES)m / z476.39 [M+H] + , calculated MW 475.96;1H-NMR(400 MHz, CD3OD) d 7.94 (dd,J= 8.6, 4.6 Hz, 1 H), 7.69 (s, 1 H), 7.52 (dd,J= 9.4, 2.2 Hz, 1 H), 7.40 (dd,J= 8.8, 2.4 Hz, 1 H), 7.18 (td,J= 9.1, 2.0 Hz, 1 H), 4.31 (d,J= 13.2 Hz, 1 H), 3.91 (dd,J= 13.2, 7.2 Hz, 1 H), 3.64 to 3.60 (m, 1 H), 3.56 (dd,J= 10.8, 4.4 Hz, 1 H); 3.51 to 3.46 (m, 1 H), 3.42 (d,J= 14.0 Hz, 1 H), 3.14 to 3.04 (m, 3 H), 3.00 to 2.97 (m, 1 H), 2.36 to 2.20 (m, 4 H), 1.97 (d,J= 11.6 Hz, 1 H), 1.74 (m, 4 H), 1.65 (d,J= 12.0 Hz, 1 H), 1.36 to 1.23 (m, 3 H), 1.14 (q,J= 10.9 Hz, 1 H).

[0743]

[0744] Example 68: Synthesis of 5-bromo-1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)-4-methylpyridine-2(1H)-one

[0745]

[0746]

[0747] Using (3aR,7aR)-4'-(6-fluorobenzo]isooxazole-3-yl)octahydropyroisoindole-2,1'-piperidine]-2-ium methanesulfonate (0.200 g, 0.471 mmol), 5-bromo-4-methylpyridine-2(1H)-one (0.177 g, 0.942 mmol), and potassium carbonate (K2CO3, 0.195 g, 1.413 mmol) as starting materials, in a manner similar to Step 3 of Example 1, 5-bromo-1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-methylpyridine-2(1H)-one (0.070 g, 28.8%) was obtained in the form of a yellow solid: LRMS(ES)m / z516.31 [M+H] +, calculated MW 516.46;1H-NMR(400 MHz, CD3OD) d 7.91 (dd,J= 8.8, 4.8 Hz, 1 H), 7.88 (s, 1 H), 7.40 (dd,J= 8.8, 2.4 Hz, 1 H), 7.19 (td,J= 9.1, 2.3 Hz, 1 H), 6.54 (s, 1 H), 4.23 (dd,J= 13.2, 3.2 Hz, 1 H), 3.84 (dd,J= 13.4, 7.4 Hz, 1 H), 3.55 (dd,J= 23.0, 13.0 Hz, 2 H), 3.46 (m, 1 H), 3.32 (d,J= 13.2 Hz, 1 H), 3.01 (q,J= 12.9 Hz, 2 H), 2.92 (dd,J= 13.2, 6.8 Hz, 1 H), 2.31 (m, 3 H), 2.27 (s, 3 H), 2.21 (m, 1 H), 1.95 (d,J= 12.4 Hz, 1 H), 1.77 to 1.64 (m, 5 H), 1.32 to 1.20 (m, 3 H), 1.10 (q,J= 10.7 Hz, 1 H).

[0748]

[0749] Example 69: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)pyrazine-2(1H)-one

[0750]

[0751]

[0752] Using (3aR,7aR)-4'-(6-fluorobenzo]isooxazole-3-yl)octahydropyroisoindole-2,1'-piperidine]-2-ium methanesulfonate (0.150 g, 0.353 mmol), pyrazine-2(1H)-one (0.068 g, 0.707 mmol), and potassium carbonate (K2CO3, 0.146 g, 1.060 mmol) as starting materials, 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyrazine-2(1H)-one (0.035 g, 23.3%) was prepared in the form of a yellow solid in a manner similar to Step 3 of Example 1. Obtained:LRMS(ES)m / z425.33 [M+H] + , calculated MW 424.52;1H-NMR(400 MHz, CD3OD) d 8.02 (s, 1 H), 7.87 (dd,J= 8.8, 4.8 Hz, 1 H), 7.54 (dd,J= 4.4, 0.8 Hz, 1 H), 7.38 ~ 7.37 (m, 2 H), 7.14 (td,J= 9.0, 2.4 Hz, 1 H), 4.60 (dd,J= 13.2, 4.4 Hz, 1 H), 3.64 (dd,J= 12.8, 10.0 Hz, 1 H), 3.18 to 3.05 (m, 3 H), 2.70 (dd,J= 12.8, 5.6 Hz, 1 H), 2.27 (dd,J= 13.0, 6.2 Hz, 1 H), 2.21 (t,J= 10.4 Hz, 2 H), 2.08 to 1.90 (m, 5 H), 1.78 to 1.73 (m, 1 H), 1.67 (m, 2 H), 1.53 to 1.46 (m, 2 H), 1.28 (m, 1 H), 1.18 (m, 1 H), 1.10 (m, 2 H).

[0753]

[0754] Example 70: Synthesis of 3-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-5,6-dimethylpyrimidine-4(3H)-one

[0755]

[0756]

[0757] Using (3aR,7aR)-4'-(6-fluorobenzo]isooxazole-3-yl)octahydropyroisoindole-2,1'-piperidine]-2-ium methanesulfonate (0.100 g, 0.236 mmol), 5,6-dimethylpyrimidine-4(3H)-one (0.029 g, 0.236 mmol), and potassium carbonate (K2CO3, 0.098 g, 0.707 mmol) as starting materials, 3-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-5,6-dimethylpyrimidine-4(3H)-one (0.015 g, 14.1%) was prepared in a manner similar to Step 3 of Example 1. Obtained in the form of a yellow oil: LRMS(ES) m / z 453.40 [M+H]+, calculated MW 452.57; 1H-NMR (400 MHz, DMSO-d6) d 8.17 (s, 1 H), 7.86 (dd,J= 8.6, 5.0 Hz, 1 H), 7.34 (dd,J= 8.6, 2.2 Hz, 1 H), 7.12 (td,J= 9.1, 2.3 Hz, 1 H), 4.59 (dd,J= 13.2, 4.0 Hz, 1 H), 3.56 (dd,J= 13.2, 10.0 Hz, 1 H), 3.17 ~ 3.06 (m, 3 H), 2.73 (dd,J= 12.6, 5.8 Hz, 1 H), 2.30 to 2.17 (m, 6 H), 2.08 to 2.00 (m, 6 H), 1.94 to 1.89 (m, 2 H), 1.74 to 1.65 (m, 3 H), 1.51 to 1.44 (m, 2 H), 1.32 to 1.24 (m, 2 H), 1.09 ~ 1.00 (m, 2 H).

[0758]

[0759] Example 71: Synthesis of 5-fluoro-3-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)pyrimidine-4(3H)-one

[0760]

[0761]

[0762] Using (3aR,7aR)-4'-(6-fluorobenzo]isooxazole-3-yl)octahydropyroisoindole-2,1'-piperidine]-2-ium methanesulfonate (0.100 g, 0.236 mmol), 5-fluoropyrimidine-4(3H)-one (0.027 g, 0.236 mmol), and potassium carbonate (K2CO3, 0.098 g, 0.707 mmol) as starting materials, 5-fluoro-3-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-4(3H)-one (0.007 g, 6.7%) was prepared in the form of a yellow oil in a manner similar to Step 3 of Example 1. Obtained: LRMS(ES)m / z443.43 [M+H]+, calculated MW 442.51;1H-NMR(400 MHz, DMSO-d6) d 8.26 (s, 1 H), 7.97 (d,J= 2.4 Hz, 1 H), 7.88 (dd,J= 9.0, 5.4 Hz, 1 H), 7.37 (dd,J= 8.8, 2.0 Hz, 1 H), 7.15 (td,J= 8.9, 2.5 Hz, 1 H), 4.64 (dd,J= 13.6, 4.0 Hz, 1 H), 3.74 (dd,J= 13.2, 10.0 Hz, 1 H), 3.23 ~ 3.17 (m, 2 H), 2.87 ~ 2.84 (m, 1 H), 2.41 (m, 2 H), 2.21 to 2.02 (m, 5 H), 1.94 to 1.90 (m, 1 H), 1.80 to 1.68 (m, 4 H), 1.56 to 1.52 (m, 2 H), 1.29 (m, 2 H), 1.15 ~ 1.05 (m, 2 H).

[0763]

[0764] Example 72: Synthesis of 3-(((1R,2R)-2-((4-(4-chlorobenzo]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)pyrimidine-4(3H)-one

[0765] Step 1: Synthesis of 4-(2,6-dichlorobenzoyl)piperidine-1-carbaldehyde

[0766]

[0767]

[0768] Aluminum chloride (AlCl3, 8.352 g, 62.639 mmol) was added to a solution of 1-formylpiperidine-4-carbonyl chloride (5.500 g, 31.319 mmol) dissolved in 1,2-dichloroethane (30 mL) at 0°C, and the mixture was stirred for 30 minutes at the same temperature. 1,3-dichlorobenzene (5.366 mL, 46.979 mmol) was added to the reaction mixture and stirred for an additional 18 hours at 80°C, after which the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a 1N aqueous hydrochloric acid solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 25 g cartridge; ethyl acetate / hexane = 50% to 100%) to obtain 4-(2,6-dichlorobenzoyl)piperidine-1-carbaldehyde (3.733 g, 41.7%) in the form of a brown oil: LRMS(ES) m / z 286.10 [M+H] + , calculated MW 286.15.

[0769]

[0770] Step 2: Synthesis of 4-chloro-3-(piperidine-4-yl)benzo]isooxazole

[0771]

[0772]

[0773] A solution of 4-(2,6-dichlorobenzoyl)piperidine-1-carbaldehyde (3.000 g, 10.484 mmol) and hydroxylamine hydrochloride (1.457 g, 20.968 mmol) dissolved in methanol (30 mL) at room temperature was heated and refluxed for 3 hours. Then, potassium hydroxide (KOH, 50.00% solution in water, 11.764 mL, 104.840 mmol) was added and heated and refluxed again for 18 hours, after which the temperature was lowered to room temperature to terminate the reaction. Water was added to the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 25 g cartridge; methanol / dichloromethane = 0% to 40%) to obtain 4-chloro-3-(piperidin-4-yl)benzo]isooxazole (2.219 g, 89.4%) in the form of a brown oil: LRMS(ES)m / z237.15 [M+H] + , calculated MW 236.7.

[0774]

[0775] Step 3: Synthesis of (3aR,7aR)-4'-(4-chlorobenzo]isooxazole-3-yl)octahydropyroisoindole-2,1'-piperidine]-2-yum methanesulfonate

[0776]

[0777]

[0778] Using 4-chloro-3-(piperidine-4-yl)benzo]isooxazole (2.200 g, 9.294 mmol), ((1R,2R)-cyclohexane-1,2-diyl)bis(methylene) dimethanesulfonate (4.188 g, 13.942 mmol), and potassium carbonate (K2CO3, 3.854 g, 27.883 mmol) as starting materials, (3aR,7aR)-4'-(4-chlorobenzo]isooxazole-3-yl)octahydropyroisoindole-2,1'-piperidine]-2-ium methanesulfonate (1.100 g, 26.8%) was obtained in the form of a yellow oil in a manner similar to Step 2 of Example 1: LRMS(ES)m / z345.28 [M+H] + , calculated MW 440.98.

[0779]

[0780] Step 4: Synthesis of 3-(((1R,2R)-2-((4-(4-chlorobenzo]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)pyrimidine-4(3H)-one

[0781]

[0782]

[0783] Using (3aR,7aR)-4'-(4-chlorobenzo]isooxazole-3-yl)octahydropyroisoindole-2,1'-piperidine]-2-ium methanesulfonate (0.100 g, 0.227 mmol), pyrimidine-4(3H)-one (0.026 g, 0.272 mmol), and potassium carbonate (K2CO3, 0.094 g, 0.680 mmol) as starting materials, 3-(((1R,2R)-2-((4-(4-chlorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-4(3H)-one (0.028 g, 28.0%) was prepared as a pale yellow oil in a manner similar to Step 3 of Example 1. Obtained: LRMS(ES)m / z441.32 [M+H]+, calculated MW 440.97;1H-NMR(400 MHz, CD3OD) d 8.40 (s, 1 H), 7.93 (d,J= 6.8 Hz, 1 H), 7.87 (d,J= 8.0 Hz, 1 H), 7.68 (d,J= 1.2 Hz, 1 H), 7.36 (dd,J= 8.4, 1.6 Hz, 1 H), 6.46 (d,J= 6.8 Hz, 1 H), 4.63 ~ 4.59 (m, 1 H), 3.65 (dd,J= 13.2, 9.6 Hz, 1 H), 3.19 ~ 3.13 (m, 3 H), 2.84 ~ 2.80 (m, 1 H), 2.34 (m, 3 H), 2.13 to 1.91 (m, 5 H), 1.76 to 1.67 (m, 3 H), 1.52 to 1.49 (m, 2 H), 1.32 to 1.26 (m, 2 H), 1.10 to 1.04 (m, 2H).

[0784]

[0785] Example 73: Synthesis of 3-(((1R,2R)-2-((4-(4-chlorobenzo]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)-6-methylpyrimidine-4(3H)-one

[0786]

[0787]

[0788] Using (3aR,7aR)-4'-(4-chlorobenzo]isooxazole-3-yl)octahydropyroisoindole-2,1'-piperidine]-2-ium methanesulfonate (0.100 g, 0.227 mmol), 6-methylpyrimidine-4(3H)-one (0.030 g, 0.272 mmol), and potassium carbonate (K2CO3, 0.094 g, 0.680 mmol) as starting materials, 3-(((1R,2R)-2-((4-(4-chlorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-6-methylpyrimidine-4(3H)-one (0.043 g, 41.7%) was prepared as a pale yellow solid in a manner similar to Step 3 of Example 1. Obtained in the form of: LRMS(ES) m / z 455.39 [M+H]+, calculated MW 455; 1H-NMR (400 MHz, CD3OD) d 8.32 (s, 1 H), 7.85 (d,J= 8.4 Hz, 1 H), 7.67 (d,J= 1.2 Hz, 1 H), 7.34 (dd,J= 8.6, 1.8 Hz, 1 H), 6.31 (s, 1 H), 4.63 (m, 1 H), 3.59 (dd,J= 13.2, 10.0 Hz, 1 H), 3.17–3.04 (m, 3 H), 2.68 (dd,J= 12.4, 6.0 Hz, 1 H), 2.26 (s, 3 H), 2.18 (m, 3 H), 2.06 to 1.90 (m, 5 H), 1.71 to 1.66 (m, 3 H), 1.49 to 1.44 (m, 2 H), 1.33 to 1.04 (m, 4 H).

[0789]

[0790] Example 74: Synthesis of 1-(((1R,2R)-2-((4-(benzo]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-2(1H)-one

[0791]

[0792]

[0793] 1-(((1R,2R)-2-((4-(benzo]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-2(1H)-one (0.020 g, 20.0 %) was obtained in the form of a yellow oil using (3aR,7aR)-4'-(benzo]isooxazole-3-yl)octahydropyroisoindole-2,1'-piperazine]-2-yum methanesulfonate (0.100 g, 0.245 mmol), pyrimidine-2(1H)-one (0.028 g, 0.294 mmol), and potassium carbonate (K2CO3, 0.102 g, 0.736 mmol) as starting materials in a manner similar to Step 3 of Example 1: LRMS(ES)m / z408.29 [M+H]+, calculated MW 407.52;1H-NMR(400 MHz, CD3OD) d 8.55 (dd,J= 4.4, 2.8 Hz, 1 H), 8.12 (dd,J= 6.4, 2.8 Hz, 1 H), 7.85 (d,J= 8.4 Hz, 1 H), 7.55 ~ 7.51 (m, 1 H), 7.44 (d,J= 8.8 Hz, 1 H), 7.26 (td,J= 7.5, 0.9 Hz, 1 H), 6.50 (dd,J= 6.4, 4.4 Hz, 1 H), 4.72 (dd,J= 13.0, 4.6 Hz, 1 H), 3.57 ~ 3.52 (m, 5 H), 2.70 ~ 2.62 (m, 5 H), 2.23 (dd,J= 13.0, 5.8 Hz, 1 H), 1.90 (m, 1 H), 1.80 (m, 1 H), 1.68 (m, 2 H), 1.50 ~ 1.44 (m, 2 H), 1.31 (m, 1) H), 1.12 to 1.03 (m, 3 H).

[0794]

[0795] Example 75: Synthesis of 1-(((1R,2R)-2-((4-(benzo]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile

[0796]

[0797]

[0798] Using (3aR,7aR)-4'-(benzo]isooxazole-3-yl)octahydropyroisoindole-2,1'-piperazine]-2-ium methanesulfonate (0.100 g, 0.245 mmol), 2-oxo-1,2-dihydropyridine-3-carbonitrile (0.035 g, 0.294 mmol), and potassium carbonate (K2CO3, 0.102 g, 0.736 mmol) as starting materials, in a manner similar to Step 3 of Example 1, 1-(((1R,2R)-2-((4-(benzo]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (0.020 g, 18.9%) was obtained in the form of a yellow solid: LRMS(ES) m / z 432.40 [M+H]+, calculated MW 431.54; 1H-NMR (400 MHz, CD3OD) d 8.01 (dd,J= 7.2, 2.0 Hz, 1 H), 7.93 (dd,J= 7.0, 1.8 Hz, 1 H), 7.84 (d,J= 8.0 Hz, 1 H), 7.52 (m, 1 H), 7.43 (d,J= 8.4 Hz, 1 H), 7.25 (t,J= 7.4 Hz, 1 H), 6.42 (t,J= 6.8 Hz, 1 H), 4.77 (dd,J= 13.0, 4.2 Hz, 1 H), 3.61 (dd,J= 13.0, 10.2 Hz, 1 H), 3.51 (m, 4 H), 2.67 ~ 2.60 (m, 5 H), 2.21 (dd,J= 12.4, 6.0 Hz, 1 H), 1.88 (m, 1 H), 1.74 ~ 1.65 (m, 3 H), 1.50 to 1.42 (m, 2 H), 1.32 to 1.25 (m, 2 H), 1.07 to 0.99 (m, 2 H).

[0799]

[0800] Example 76: Synthesis of 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carbonitrile

[0801]

[0802]

[0803] Using (3aR,7aR)-4'-(6-fluorobenzo]isooxazole-3-yl)octahydropyroisoindole-2,1'-piperidine]-2-ium methanesulfonate (0.150 g, 0.353 mmol), 2-oxo-1,2-dihydropyridine-4-carbonitrile (0.064 g, 0.530 mmol), and potassium carbonate (K2CO3, 0.146 g, 1.060 mmol) as starting materials, in a manner similar to Step 3 of Example 1, 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carbonitrile (0.042 g, 26.4%) was obtained in the form of a yellow solid. LRMS(ES)m / z450.37 [M+H] + , calculated MW 449.53;1H-NMR(400 MHz, CD3OD) d 7.87 (dd,J= 9.0, 5.0 Hz, 1 H), 7.77 (d,J= 6.8 Hz, 1 H), 7.23 (dd,J= 8.8, 2.4 Hz, 1 H), 7.06 (td,J= 8.8, 2.0 Hz, 1 H), 6.90 (s, 1 H), 6.48 (dd,J= 7.0, 1.8 Hz, 1 H), 4.70 (dd,J= 12.8, 4.0 Hz, 1 H), 3.63 (dd,J= 12.8, 10.0 Hz, 1 H), 3.52 (t,J= 5.0 Hz, 4 H), 2.69 (m, 1 H), 2.64 (t,J= 4.4 Hz, 4 H), 2.25 (dd,J= 12.8, 6.0 Hz, 1 H), 1.91 (d,J= 13.6 Hz, 1 H), 1.74 (m, 1 H), 1.68 (m, 2 H), 1.48 (m, 2 H), 1.30 (q,J= 12.8 Hz, 1 H), 1.19 ~ 1.02 (m, 3 H).

[0804]

[0805] Regarding the compound of the example, 5-HT2A In order to measure the inhibitory effect on the receptor and the binding ability to the dopamine D2 receptor, Experimental Examples 1 and 2 were performed as follows.

[0806]

[0807] Experimental Example 1: HTRF-based IP1 accumulation assay

[0808] Human 5-HT 2A The 5-HT of the test compound was determined by measuring the production of IP1 (inositol monophosphate) using the HEK293 cell line overexpressing the receptor. 2A Receptor antagonistic effects were confirmed. Stock solutions were prepared by dissolving the compounds in 100% DMSO at a concentration of 10 mM. Each compound was sequentially diluted 1 / 3 in test buffer containing lithium chloride (LiCl), with the maximum concentration point set at 10 μM relative to the final concentration. The cells and compounds prepared in the test buffer were placed in multiwell plates and incubated at room temperature for 10 minutes, after which the EC 80 Serotonin was added to achieve the required concentration, and the cells were incubated at 37°C for 30 minutes in the dark. To measure the intracellular accumulation of IP1, IP1-d2 receptors and IP1-Cryptate donors, which are HTRF-based fluorescent substances, were added, and the cells were incubated at room temperature in the dark for 1 hour. The fluorescence measurements were converted into the HTRF ratio, and the serotonin-treated group (EC 80 After standardizing the values ​​in the ) and untreated groups to 0% and 100%, respectively, the activity of the compound calculated for each concentration was IC 50 The values ​​were calculated and the results are shown in Table 1 (+: greater than 100 nM and less than or equal to 200 nM, ++: greater than 10 nM and less than or equal to 100 nM, +++: less than or equal to 10 nM).

[0809] [Table 1]

[0810]

[0811]

[0812]

[0813] Experimental Example 2: PathHunter® Chemiluminescence-based β-Arrestin Recruitment Assay

[0814] The antagonistic effect of the test compound on the D2 receptor was confirmed by measuring β-Arrestin recruitment using the PathHunter® Detection Kit and the PathHunter® CHO-K1 DRD2L β-Arrestin cell line. 24 hours prior to the test, cells were AssayComplete TM Cell Plating 2 Reagent was diluted and dispensed into multiwell plates, and incubated at 37°C under 5% CO2 conditions. Stock solutions were prepared by dissolving the compounds in 100% DMSO at a concentration of 10 mM, and each compound was prepared such that the maximum concentration point was 1 μM, based on the maximum concentration standard, and AssayComplete TM The compounds were sequentially diluted by 1 / 3 with Cell Plating 2 Reagent. The diluted test compounds were added to a multiwell plate containing cultured cells, and the reaction was carried out at 37°C for 30 minutes. Subsequently, EC 80 Dopamine of a certain concentration was added, and the reaction was carried out at 37°C for 90 minutes. PathHunter ® The Detection Kit mixture was dispensed into each well and reacted at 25°C for 60 minutes. The chemiluminescence measurements generated by the enzymatic reaction were compared to the dopamine-treated group (EC 80 After standardizing the values ​​in the ) and untreated groups to 0% and 100%, respectively, the activity of the compound calculated for each concentration was IC 50 The values ​​were calculated and the results are shown in Table 2 (+: greater than 1.0 nM and less than or equal to 2.0 nM, ++: greater than 0.5 nM and less than or equal to 1.0 nM, +++: greater than 0.1 nM and less than or equal to 0.5 nM, ++++: less than or equal to 0.1 nM).

[0815] [Table 2]

[0816]

[0817]

[0818]

[0819] Experimental Example 3: Apomorphine-induced climbing test in mice

[0820] When well-known dopamine agonists such as apomorphine are administered to mice, they induce unique motor behaviors such as standing or climbing along the walls of the cage (Hester et al., J. med. Chem., 1970; Gouret, J. Pharmacol., 1973). Climbing behavior in mice induced by apomorphine has been suggested as a method to evaluate the effects of antipsychotic drugs (Brenda et al., EJ Pharmacol., 1978), and a reduction in this climbing behavior can be predicted as antipsychotic activity.

[0821] Male ICR mice weighing 30–40 g, purchased from Coatec Co., Ltd. (Pyeongtaek, South Korea), were used as experimental animals. The mice were housed in a temperature- and humidity-controlled room under a 12-hour light-dark cycle. During the experiment, feed and water were provided for free consumption.

[0822] All animals were acclimatized to the laboratory environment at least one hour prior to the experiment. Excipients or the test compound were administered orally according to the mouse's body weight. Thirty minutes or one hour after oral administration, 1 mg / kg of apomorphine was administered subcutaneously, after which the mice were placed in a circular wire mesh cage (diameter 12 cm, height 14 cm). Climbing behavior of each mouse was observed starting 10 minutes after apomorphine administration, and scores were assigned according to the behavioral evaluation method below.

[0823] - 0: When all four feet are on the floor

[0824] - 1: One foot leaning against the cage

[0825] - 2: When leaning both feet against the cage

[0826] - 3: When leaning three paws against the cage

[0827] - 4: When leaning all four paws against the cage

[0828]

[0829] Climbing behavior was observed a total of five times at 5-minute intervals from 10 minutes after apomorphine administration to 30 minutes, and the sum of the scores evaluated at the five evaluation points was calculated (maximum score = 20). The results for each test group were expressed as a percentage (%) relative to the control group. From the inhibition percentage data, ED was determined by simple linear regression analysis based on the dose-response curve. 50 Calculate or the observed maximum effective dose ED max We calculated the values ​​and presented them in Table 3.

[0830] [Table 3]

[0831]

[0832]

[0833] All test compounds showed a strong inhibitory effect on apomorphine, and showed an inhibitory effect up to 60 times stronger than lurasidone used as a comparative example.

[0834]

[0835] Experimental Example 4: Evaluation of Human Liver Metabolic Stability

[0836] To predict the extent of drug metabolism by the liver, a major organ for drug metabolism, through in vitro experiments, the metabolic stability of the drug was evaluated using liver microsomes.

[0837] Specifically, human liver microsomes and the test compound were added to a reaction solution composed of 0.5 M potassium phosphate buffer (pH 7.4), distilled water, NADPH Regenerating System Solution A (26 mM NADP+, 66 mM glucose-6-phosphate, and 66 mM MgCl2in H2O), and NADPH Regenerating System Solution B (40 U / mL glucose-6-phosphate dehydrogenase in 5 mM sodium citrate), and incubated at 37°C. Metabolic stability was evaluated by the retention rate after 30 minutes relative to the initial reaction time. The concentration of the test compound was 1 μM, the protein content of the human liver microsomes was 0.5 mg / mL, and the reaction time was 30 minutes. The results are shown in Table 4.

[0838] [Table 4]

[0839]

[0840]

[0841]

[0842] It was confirmed that the metabolic stability of all test compounds was significantly improved compared to lurasidone, which was used as a reference drug.

Claims

1. A compound represented by the following chemical formula 1 or 2, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] [Chemical Formula 2] In the above chemical formula 1 or 2, R 1 is -H or halo; X 1 and X 2 are each independently O or S; Y is CH or N; Z 1 and Z 2 Each independently N or CR 2 and; here R 2 is -H, halo, cyano, formyl, alkyl, alkoxy, haloalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, or aryl; Z 3 and Z 4 Each independently N or CR 3 and; here R 3 is -H, halo, cyano, alkyl, alkoxy, haloalkyl, heterocycloalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aryl, unsubstituted or halo-substituted arylaminocarbonyl, heterocycloalkylcarbonyl or heteroarylaminocarbonyl, or two R 3 They are connected to each other to form an aryl or heteroaryl group together with bonding carbon atoms; l is 1 or 2, and; m is 0 or 1 and; The above heterocycloalkyl and heteroaryl have one or more heteroatoms selected from N, O and S.

2. In Paragraph 1, R 1 is -H or halo; X 1 and X 2 are each independently O or S; Y is CH or N; Z 1 and Z 2 Each independently N or CR 2 and; here R 2 -H, halo, cyano, formyl, C1-C7 alkyl, C1-C7 alkoxy, halo-C1-C7 alkyl, C1-C7 alkyl carbonyl, C1-C7 alkoxycarbonyl, C1-C7 alkylaminocarbonyl, di(C1-C7 alkyl)aminocarbonyl or C6-C 10 Ariligo; Z 3 and Z 4 Each independently N or CR 3 and; here R 3 -H, halo, cyano, C1-C7 alkyl, C1-C7 alkoxy, halo-C1-C7 alkyl, 5 to 10-membered heterocycloalkyl, C1-C7 alkyl carbonyl, C1-C7 alkoxycarbonyl, C1-C7 alkylaminocarbonyl, di(C1-C7 alkyl)aminocarbonyl, C6-C 10 Aryl, unsubstituted or halo-substituted C6-C 10 It is an arylaminocarbonyl, a 5 to 10-membered heterocycloalkylcarbonyl, or a 5 to 10-membered heteroarylaminocarbonyl, or two Rs 3 is connected to form a C6-aryl or 5- or 6-membered heteroaryl with carbon atoms bonded together; l is 1 or 2, and; m is 0 or 1 and; A compound or a pharmaceutically acceptable salt thereof characterized in that the above heterocycloalkyl and heteroaryl have one to three heteroatoms selected from N, O and S.

3. A compound or a pharmaceutically acceptable salt thereof, characterized in that, in claim 1, the compound of Formula 1 is a compound of Formula 3 below: [Chemical Formula 3] In the above chemical formula 3, R 1 , X 1 , Y, Z 1 , Z 2 , Z 3 , Z 4 , l and m are as defined in Paragraph 1.

4. A compound or a pharmaceutically acceptable salt thereof, characterized in that, in claim 1, the compound of formula 2 is a compound of formula 4 below: [Chemical Formula 4] In the above chemical formula 4, R 1 , X 1 , Y, Z 1 , Z 2 , Z 3 , Z 4 , l and m are as defined in Paragraph 1.

5. A compound or a pharmaceutically acceptable salt thereof, characterized in that, in claim 1, the compound of Formula 1 is a compound of Formula 5 below: [Chemical Formula 5] In the above chemical formula 5, R 1 , X 1 , X 2 , Y, Z 1 , Z 2 , Z 3 and Z 4 is as defined in Paragraph 1.

6. A compound or a pharmaceutically acceptable salt thereof, characterized in that, in claim 1, the compound of formula 2 is a compound of formula 6 below: [Chemical Formula 6] In the above chemical formula 6, R 1 , X 1 , X 2 , Y, Z 1 , Z 2 , Z 3 and Z 4 is as defined in Paragraph 1.

7. A compound or a pharmaceutically acceptable salt thereof, characterized in that, in claim 5, the compound of formula 5 is a compound of formula 7 below: [Chemical Formula 7] In the above chemical formula 7, R 1 , X 1 , Y, Z 2 , Z 4 , R 2 and R 3 is as defined in Paragraph 1.

8. In Paragraph 2, Z 1 and Z 2 Each independently N or CR 2 and; here R 2 is -H, halo, cyano, formyl, C1-C5 alkyl, halo-C1-C5 alkyl, C1-C5 alkylcarbonyl, C1-C5 alkylaminocarbonyl or C6 aryl; Z 3 and Z 4 Each independently N or CR 3 and; here R 3 is -H, halo, cyano, C1-C5 alkyl, C1-C5 alkoxy, halo-C1-C5 alkyl, 5 to 10-membered heterocycloalkyl, C1-C5 alkoxycarbonyl, C1-C5 alkylaminocarbonyl, di(C1-C5 alkyl)aminocarbonyl, C6 aryl, unsubstituted or halo-substituted C6 arylaminocarbonyl, 5 or 6-membered heterocycloalkylcarbonyl or 5 or 6-membered heteroarylaminocarbonyl, or two R 3 They are connected to each other to form a C6-aryl or 5- or 6-membered heteroaryl with bonded carbon atoms; A compound or a pharmaceutically acceptable salt thereof characterized in that the above heterocycloalkyl and heteroaryl have one or two heteroatoms selected from N, O and S.

9. In paragraph 8, two Rs 3 A compound or a pharmaceutically acceptable salt thereof characterized by forming a benzene ring or a thiophene ring with carbon atoms that are connected to and bonded to each other.

10. A compound or a pharmaceutically acceptable salt thereof, characterized in that, in claim 1, the compound of formula 1 or 2 is selected from the group consisting of the following compounds: 3-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)quinazolin-4(3H)-one; 4-bromo-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one; 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one; 2-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)isoquinoline-1(2H)-one; 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carbonitrile; 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-4-methylpyridine-2(1H)-one; 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-3-methylpyridine-2(1H)-one; 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-5-methylpyridine-2(1H)-one; 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-4-fluoropyridine-2(1H)-one; 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-5-fluoropyridine-2(1H)-one; 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-4-chloropyridine-2(1H)-one; 6-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)thieno[2,3-c]pyridine-7(6H)-one; 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-4-bromopyridine-2(1H)-one; 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one; 1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-5-bromopyridine-2(1H)-one; 5-acetyl-1-(((1R,2R)-2-((4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one; 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-phenylpyridine-2(1H)-one; 3-((1r,4r)-4-(2-(4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)ethyl)cyclohexyl)quinazolin-4(3H)-one; 5-bromo-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one; 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-5-phenylpyridine-2(1H)-one; 3-bromo-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one; 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-3-methylpyridine-2(1H)-one; 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-5-methylpyridine-2(1H)-one; 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-methylpyridine-2(1H)-one; 3-fluoro-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one; 4-fluoro-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one; 5-fluoro-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one; 4-chloro-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one; 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-(trifluoromethyl)pyridine-2(1H)-one; 5-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)thieno[3,2-c]pyridine-4(5H)-one; 6-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)thieno[2,3-c]pyridin-7(6H)-one; 5-acetyl-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one; 4-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)thieno[3,2-b]pyridin-7(4H)-one; methyl 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxylate; 3-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-4(3H)-one; 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-methoxypyridine-2(1H)-one; 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-6-oxo-1,6-dihydropyridine-3-carbaldehyde; 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-5-(trifluoromethyl)pyridine-2(1H)-one; 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-N-phenyl-1,2-dihydropyridine-4-carboxamide; 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-N-(pyridine-3-yl)-1,2-dihydropyridine-4-carboxamide; 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-N-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide; N-ethyl-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxamide; N-ethyl-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-N-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide; 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-(morpholine-4-carbonyl)pyridine-2(1H)-one; 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-N-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-4-carboxamide; 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile; 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile; 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-6-oxo-1,6-dihydropyridine-3-carbonitrile; 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile; 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-3-methoxypyridine-2(1H)-one; 3-bromo-5-fluoro-1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one; 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-N-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide; 1-(((1R,2R)-2-((4-(benzo[d]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carbonitrile; 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-2(1H)-one; 3-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-6-methylpyrimidine-4(3H)-one; 2-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridazine-3(2H)-one; 1-(((1R,2R)-2-((4-(benzo[d]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-6-oxo-1,6-dihydropyridine-3-carbonitrile; 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-methylpyrimidine-2(1H)-one; 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-2(1H)-one; 1-(((1R,2R)-2-((4-(6-fluorobenzo[d]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-4-methylpyrimidine-2(1H)-one; N-(3-chlorophenyl)-1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxamide; 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-iodopyridine-2(1H)-one; 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-(piperidine-1-yl)pyridine-2(1H)-one; methyl 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxylate; 5-chloro-1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one; 5-chloro-3-fluoro-1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyridine-2(1H)-one; 5-bromo-1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-4-methylpyridine-2(1H)-one; 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyrazine-2(1H)-one; 3-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-5,6-dimethylpyrimidine-4(3H)-one; 5-fluoro-3-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-4(3H)-one; 3-(((1R,2R)-2-((4-(4-chlorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-4(3H)-one; 3-(((1R,2R)-2-((4-(4-chlorobenzo]isooxazole-3-yl)piperidine-1-yl)methyl)cyclohexyl)methyl)-6-methylpyrimidine-4(3H)-one; 1-(((1R,2R)-2-((4-(benzo]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)pyrimidine-2(1H)-one; 1-(((1R,2R)-2-((4-(benzo]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile; and 1-(((1R,2R)-2-((4-(6-fluorobenzo]isooxazole-3-yl)piperazine-1-yl)methyl)cyclohexyl)methyl)-2-oxo-1,2-dihydropyridine-4-carbonitrile.

11. A pharmaceutical composition for the prevention or treatment of mental illness, comprising, as an active ingredient, a therapeutically effective amount of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.

12. A pharmaceutical composition according to claim 11, characterized in that the mental illness is schizophrenia.

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