Pharmaceutical composition for treating bacterial infections

Abstract

The present invention addresses the problem of providing a pharmaceutical composition for treating bacterial infections, said problem being solved by means of a compound represented by general formula (I).

Description

Pharmaceutical composition for treating bacterial infections

[0001] The present invention relates to a pharmaceutical composition for treating bacterial infections.

[0002] Nontuberculous mycobacterial disease is an infectious disease caused by mycobacteria (nontuberculous mycobacteria: NTM), which are bacteria of the genus Mycobacterium, excluding Mycobacterium tuberculosis and Mycobacterium leprae, and has been increasing in recent years (Non-Patent Document 1). Pulmonary MAC disease is a respiratory infection caused by MAC bacteria, which are a type of nontuberculous mycobacterial disease and account for 70 to 80 percent of nontuberculous mycobacteria (NTM). "MAC" stands for Mycobacterium avium complex, a general term used to refer to the two bacterial species Mycobacterium avium and Mycobacterium intracellulare without distinction. Pulmonary MAC disease can be fatal when combined with aspergillosis and other diseases.

[0003] Pulmonary MAC disease is currently treated with a triple-drug combination, primarily consisting of the antibiotics azithromycin or clarithromycin (CAM), but this requires administration for 12 months or more (Non-Patent Document 2). Because of the long-term drug treatment, patients with pulmonary MAC disease are forced to bear the financial burden of purchasing therapeutic drugs and hospital visits (Non-Patent Document 3).

[0004] In recent years, clarithromycin (CAM)-resistant MAC strains have emerged (Non-Patent Document 4). Clarithromycin is not expected to be effective against CAM-resistant pulmonary MAC disease, making treatment difficult.

[0005] Furthermore, antimalarial agents (Patent Document 1), avermectin, milbemycin (Patent Document 2), and the like have been reported as pharmaceuticals for treating nontuberculous mycobacterial infections.

[0006] WO2022 / 261459CA2013 / 2813294

[0007] Steven Cowman et al. Eur Respir J 2019, 54:1900250Haworth CS et al. Thorax 2017, 72: ii1-ii64Roland Diel et al. Eur Respir J 2017, 49:1602109Heifets L. et al. Antimicrob. Agents Chemother. 1993, 37(11):2364-2370

[0008] The present invention aims to provide a compound that exhibits antibacterial effects, and a pharmaceutical for treating bacterial infections that contains the compound as an active ingredient. Another objective of the present invention is to provide a novel compound or a salt thereof.

[0009] In order to solve the above problems, the present invention includes the following inventions: [1] A compound represented by the following general formula (I) or a salt thereof: (In the formula, R １ is a halogen atom, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C ３－８ Cycloalkyl group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group, C １－６ Alkylaminoamide group, carboxyl group, amino group, nitro group, C １－６ Alkylthio group, C １－６ Haloalkylthio group, C １－６ Alkylsulfinyl group, C １－６ Haloalkylsulfinyl group, C １－６ Alkylsulfonyl group and C １－６ haloalkylsulfonyl groups; R ２ represents a hydrogen atom, a halogen atom, or C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C ３－８ Cycloalkyl group, C １－６ Haloalkyl group, C １－６Haloalkoxy group, cyano group, C(=S)NH ２ group, an amide group, or SF ５ R′ and R″ may be the same or different and are a hydrogen atom, a halogen atom, or a C １－６ alkyl groups, and R′ and R″ may be linked to form a bridge to the nitrogen-containing heterocycloalkyl ring; R ３ is a halogen atom, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C ３－８ Cycloalkyl group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group, C １－６ Alkylamino group, C １－６ R is independently selected from the group consisting of an alkoxyamino group, a carboxyl group, and an amino group; ４ is a halogen atom, C １－６ Alkyl group, C １－６ Haloalkyl group, hydroxyl group, hydroxy C １－６ Alkyl group, carboxyl group, C １－６ Alkylamino groups, amino groups and (wherein R is a halogen atom, C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－８ Cycloalkyl group, C １－６ Alkylamino group, C １－６ Haloalkylamino group, C １－６ Alkylamide group, C １－６ a haloalkylamide group or a phenyl group, and the phenyl group is selected from the group consisting of a halogen atom, C １－６ Alkyl group or C １－６ L is selected from the group consisting of -O-, -S-, -NH-, C optionally substituted with R １－６ alkylene group, C optionally substituted with R ２－６ alkenylene group, C optionally substituted with R ２－６ an alkynylene group or a chemical bond, X and Y may be the same or different and may be N, CH or CR３ wherein ring A is an aromatic hydrocarbon having 5 to 10 carbon atoms or a 5- or 6-membered aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of nitrogen atoms, sulfur atoms, and oxygen atoms, ring B is an aromatic hydrocarbon having 5 to 10 carbon atoms or a 5- or 6-membered aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of nitrogen atoms, sulfur atoms, and oxygen atoms, and the heteroatom contains at least one nitrogen atom, p is 0, 1, 2, 3, 4, or 5, q is 0, 1, or 2, and r is 0, 1, 2, or 3, and when p, q, and / or r are 2 or more, then there are 2 or more R １ , R ３ and / or R ４ may each form a ring together with the part of the ring which it substitutes, m and n may be the same or different and are 1, 2 or 3, R １ , R ３and one or more of R may be substituted with biotin or a derivative thereof). [2] The pharmaceutical composition according to [1], wherein the bacterial infection is a disease caused by infection with an intracellular parasite. [3] The pharmaceutical composition according to [1], wherein the bacterial infection is a nontuberculous mycobacterial disease. [4] The pharmaceutical composition according to [3], wherein the nontuberculous mycobacterial disease is pulmonary mycobacterial complex (MAC) disease. [5] The pharmaceutical composition according to [1], wherein the pharmaceutical composition is administered in combination with an antibacterial agent. [6] The pharmaceutical composition according to [5], wherein the antibacterial agent is a drug selected from the group consisting of macrolides, ketolides, aminoglycosides, tetracyclines, doxycycline-minocycline, rifampicin, β-lactams, lincomycins, chloramphenicols, polypeptides, glycopeptides, pyridonecarboxylic acid (quinolones), new quinolones, oxazolidinones, and sulfonamides. [7] The pharmaceutical composition according to [5], wherein the antibacterial drug is an antibacterial drug used to treat a disease caused by infection with an intracellular parasite. [8] The pharmaceutical composition according to [7], wherein the antibacterial drug is clarithromycin. [9] A compound represented by the following formula or a salt thereof:

[0010] According to the present invention, it is possible to provide a compound exhibiting antibacterial effect, a pharmaceutical for treating bacterial infections containing the compound of the present invention as an active ingredient, and a novel compound or a salt thereof.

[0011] 1 is a graph showing the ratio of viable Mycobacterium avium cells counts when macrophage cells treated with various compounds (ADI derivatives) to the viable Mycobacterium avium cells counts when untreated cells (DMSO control) were used, and the results for ADI-13 and ADI-14 are shown. 2 is a graph showing the ratio of viable Mycobacterium avium cells counts when macrophage cells treated with varying concentrations of a compound (ADI derivative) to the viable Mycobacterium avium cells counts when untreated cells (DMSO control) were used, and the results for ADI-29 and ADI-33 are shown. 1 is a graph showing the number of viable Mycobacterium avium cells obtained using macrophage cells treated with varying concentrations of a compound (ADI derivative) as a ratio to the number of viable Mycobacterium avium cells obtained using untreated cells (DMSO control), and the results are shown for ADI-46 and ADI-47. 1 is a graph showing the number of viable Mycobacterium avium cells obtained using macrophage cells treated with varying concentrations of a compound (ADI derivative) as a ratio to the number of viable Mycobacterium avium cells obtained using untreated cells (DMSO control), and the results are shown for ADI-48 and ADI-64. 1 is a graph showing the number of viable Mycobacterium avium cells obtained using macrophage cells treated with varying concentrations of a compound (ADI derivative) as a ratio to the number of viable Mycobacterium avium cells obtained using untreated cells (DMSO control), and the results are shown for ADI-79 and ADI-84. 1 is a graph showing the percentage of viable clarithromycin-resistant Mycobacterium avium cells when macrophage cells treated with a compound (ADI derivative) in combination with clarithromycin are used relative to the percentage of viable cells of the same bacterium when untreated cells (DMSO control) are used, and shows the results for ADI-46, ADI-47, and ADI-48.1 is a graph showing the effect of administration of a compound (ADI derivative) to an animal model infected with macrolide-resistant Mycobacterium avium, expressed as the ratio (%) of the number of viable bacteria in the lungs of the compound-administered group to the number of viable bacteria in the lungs of the control group (A: ADI-29, 46, 79; B: ADI-45, 47, 48).

[0012] [Compounds and Salts Used in the Present Invention] In this specification, the compounds of the present invention may be referred to as ADI derivatives or NUT compounds. They may be expressed as "ADI-X" or "NUT-X," where "X" is the same integer from about 1 to 100. For example, they may be expressed as ADI-14 (the same compound as NUT-14) or NUT-29 (the same compound as ADI-29). The hyphen before X may be omitted.

[0013] The compounds preferably used in the present invention are as described above in [1] to [9].

[0014] Furthermore, a compound represented by general formula (I) or a salt thereof: (In the formula, R １ is a halogen atom, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C ３－８ Cycloalkyl group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group, C １－６ Alkylaminoamide group, carboxyl group, amino group, nitro group, C １－６ Alkylthio group, C １－６ Haloalkylthio group, C １－６ Alkylsulfinyl group, C １－６ Haloalkylsulfinyl group, C １－６ Alkylsulfonyl group and C １－６ haloalkylsulfonyl groups; R ２ represents a hydrogen atom, a halogen atom, or C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C ３－８Cycloalkyl group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group, cyano group, C(=S)NH ２ group, an amide group, or SF ５ R′ and R″ may be the same or different and are a hydrogen atom, a halogen atom, or a C １－６ alkyl groups, and R′ and R″ may be linked to form a bridge to the nitrogen-containing heterocycloalkyl ring; R ３ is a halogen atom, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C ３－８ Cycloalkyl group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group, C １－６ Alkylamino group, C １－６ R is independently selected from the group consisting of an alkoxyamino group, a carboxyl group, and an amino group; ４ is a halogen atom, C １－６ Alkyl group, C １－６ Haloalkyl group, hydroxyl group, hydroxy C １－６ Alkyl group, carboxyl group, C １－６ Alkylamino groups, amino groups and (wherein R is a halogen atom, C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－８ Cycloalkyl group, C １－６ Alkylamino group, C １－６ Haloalkylamino group, C １－６ Alkylamide group, C １－６ a haloalkylamide group or a phenyl group, and the phenyl group is selected from the group consisting of a halogen atom, C １－６ Alkyl group or C １－６ L is selected from the group consisting of -O-, -S-, -NH-, C optionally substituted with R １－６ alkylene group, C optionally substituted with R ２－６ alkenylene group, C optionally substituted with R ２－６an alkynylene group or a chemical bond, X and Y may be the same or different and may be N, CH or CR ３ wherein ring A is an aromatic hydrocarbon having 5 to 10 carbon atoms or a 5- or 6-membered aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of nitrogen atoms, sulfur atoms, and oxygen atoms, ring B is an aromatic hydrocarbon having 5 to 10 carbon atoms or a 5- or 6-membered aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of nitrogen atoms, sulfur atoms, and oxygen atoms, and the heteroatom contains at least one nitrogen atom, p is 0, 1, 2, 3, 4, or 5, q is 0, 1, or 2, and r is 0, 1, 2, or 3, and when p, q, and / or r are 2 or more, then there are 2 or more R １ , R ３ and / or R ４ may each form a ring together with the part of the ring which it substitutes, m and n may be the same or different and are 1, 2 or 3, R １ , R ３ and one or more of R may be substituted with biotin or a derivative thereof), when p, q and / or r are 2 or more, two of R １ , R ３ and / or R ４ may form a ring together with a part of the ring in which each substituent is present (i.e., ring A, the 6-membered ring containing X and Y, and ring B).

[0015] Such an R １ , R ３ and / or R ４ Examples of the ring formed by include, but are not limited to, saturated or unsaturated 3- to 6-membered rings which may contain 1 to 3 heteroatoms selected from the group consisting of nitrogen atoms, sulfur atoms, and oxygen atoms, preferably saturated 5- to 6-membered rings which may contain 1 to 2 heteroatoms. Specific examples include, but are not limited to, the rings shown below.

[0016] X and / or Y is CR ３ When R in X and / or Y is ３ The number of is not included in q.

[0017] The symbol "Hal" in the chemical formulas herein means halogen or C １－６ It refers to a haloalkyl group, more preferably a halogen.

[0018] Furthermore, in this specification, there may be descriptions such as "a compound represented by general formula (I)" or "a compound represented by general formula (I) or a salt thereof," and these descriptions may include compounds of various embodiments shown in this specification and salts thereof, as well as compounds produced in the examples described later.

[0019] In the present invention, the term "alkyl group" preferably refers to a C １ -C ６ Examples of such alkyl groups include, but are not limited to, straight-chain or branched-chain alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, 2,3-dimethylpropyl, and benzyloxy. The above explanation also applies to the alkyl moiety in "... alkyl groups" (e.g., haloalkyl groups, alkoxyalkyl groups, hydroxyalkyl groups, and sulfanylalkyl groups) and "alkyl... groups" (e.g., alkylthio groups, alkylsulfanyl groups, alkylsulfonyl groups, alkylaminoamide groups, and alkylamino groups). The same applies to the explanations of the following terms. The term "alkenyl group" preferably refers to an alkyl group having a C ２ -C ６ Examples of alkenyl groups include, but are not limited to, straight-chain or branched alkenyl groups such as vinyl, allyl, isopropenyl, 1-butenyl, and 2-butenyl groups. The term "alkynyl group" preferably refers to a C ２ -C ６ Examples of such alkynyl groups include, but are not limited to, straight-chain or branched-chain alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, and 2-butynyl groups.

[0020] The term "halogen" preferably refers to a chlorine atom, a bromine atom, an iodine atom or a fluorine atom, more preferably a chlorine atom or a fluorine atom, but is not limited thereto.

[0021] The term "alkylene group" refers to a divalent substituent formed by removing one additional hydrogen atom at any position from an "alkyl group" defined above. The term "alkenylene group" refers to a divalent substituent formed by removing one additional hydrogen atom at any position from an "alkenyl group" defined above. The term "alkynylene group" refers to a divalent substituent formed by removing one additional hydrogen atom at any position from an "alkynyl group" defined above.

[0022] The term "cycloalkyl group" preferably refers to a C ３ -C ８ Examples of such cycloalkyl groups include, but are not limited to, cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl groups.

[0023] The term "alkoxy group" preferably refers to a C １ -C ６ Examples of such alkoxy groups include, but are not limited to, linear or branched alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertiary butoxy, pentyloxy, isopentyloxy, and neopentyloxy.

[0024] The term "alkylamino group" preferably refers to a C １ -C ６ Examples include, but are not limited to, alkylamino groups. This term refers to structures in which one or more amino groups are attached to an alkyl chain. This definition includes structures with a single amino group as well as diamino and polyamine structures with multiple amino groups. For example, -CH ２ -CH ２ -CH ２ -NH ２ In addition to primary amine structures such as -CH(NH ２ )-(CH２ ) ４ -NH ２ These may be linear or branched.

[0025] The term "aromatic hydrocarbon" preferably refers to an aromatic hydrocarbon having 5 to 10 carbon atoms, more preferably phenyl, naphthyl, and even more preferably phenyl, but is not limited thereto.

[0026] The term "aromatic heterocycle" preferably refers to a 5- or 6-membered aromatic heterocycle containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen atoms, more preferably a 5- or 6-membered aromatic heterocycle containing 2 to 3 heteroatoms, and even more preferably a 5-membered aromatic heterocycle containing 3 heteroatoms, but is not limited thereto. Examples of such aromatic hydrocarbons include oxazolyl, thiazolyl, imidazolyl, pyrrolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,4-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, and tetrazolyl. Preferred are 1,2,4-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, and 1,2,3-thiadiazolyl, and more preferred are 1,2,4-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, and 1,2,3-thiadiazolyl, but are not limited to these.

[0027] In one embodiment of the compound represented by general formula (I), ring B is selected from the group consisting of phenyl, naphthyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,4-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, and tetrazolyl.

[0028] In one embodiment of the compound represented by general formula (I), ring B has any one of the following structures: (In the formula, R ４ is as described above).

[0029] In one embodiment of the compound represented by formula (I), R ４ teeth, (R is as defined above). In this specification, this is referred to as -CH ２ Also called OCOR.

[0030] In one embodiment of the compound represented by general formula (I), ring A is phenyl. In another embodiment, ring A is pyridyl, which is a 6-membered aromatic heterocycle containing one nitrogen atom. In one embodiment of the compound represented by general formula (I), wherein Hal may be the same or different and is a halogen or C １－６ haloalkyl). １－６ The halogen atom of the haloalkyl group is preferably a chlorine atom or a fluorine atom. １－６ The haloalkyl group is preferably CF ３ For example, when p is 2, preferably one Hal is a chlorine atom and the other Hal is a fluorine atom, such as 2-chloro-5-fluorophenyl.

[0031] In the compounds of general formula (I), in one embodiment, X and Y are both CH. In this embodiment, in a further embodiment, q is 0. In another further embodiment, q is 1 and R ３ is C １ -C ６ In another embodiment, X is CH, Y is a nitrogen atom, and q is 0.

[0032] In one embodiment of the compound represented by formula (I), L is —O—.

[0033] In one embodiment of the compound represented by formula (I), R ２ is a hydrogen atom.

[0034] In the compounds represented by general formula (I), in one embodiment, m and n are each 2. In another embodiment, m is 2 and n is 1 (or vice versa).

[0035] In the compounds of general formula (I), in one embodiment, R′ and R″ are hydrogen atoms. In another embodiment, R′ and R″ are linked to form a bridge to a nitrogen-containing heterocycloalkyl ring.

[0036] In one embodiment of the compound represented by general formula (I), The structure is one of the following.

[0037] In one embodiment, the compound represented by general formula (I) has the following formula: As shown in the formula (I), a 4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl group is bonded to the 2-position, and R ４ It is a compound containing a 1,3,4-thiadiazole ring having a group. ４ The groups are as described above, but in further embodiments, R ４ The group is —CH ２ OCOR (where R is as defined above, but preferably C １－６ Alkyl group or C ３－８In yet another embodiment, R ４ The group is C １－６ It is an alkylamino group.

[0038] As the salt of the compound represented by general formula (I), a pharmaceutically acceptable salt can be preferably used. The pharmaceutically acceptable salt is not particularly limited as long as it maintains the efficacy of the active ingredient and does not have any adverse effect on the human body, and examples thereof include acetic acid, propionic acid, butyric acid, formic acid, trifluoroacetic acid, maleic acid, tartaric acid, citric acid, stearic acid, succinic acid, ethylsuccinic acid, malonic acid, lactobionic acid, gluconic acid, glucoheptonic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid (tosylic acid), Examples of the salt include salts with acids such as lauryl sulfate, malic acid, aspartic acid, glutamic acid, adipic acid, cysteine, N-acetylcysteine, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, hydroiodic acid, nicotinic acid, oxalic acid, picric acid, thiocyanic acid, undecanoic acid, acrylic acid polymers, and carboxyvinyl polymers; salts with inorganic bases such as lithium salts, sodium salts, potassium salts, and calcium salts; salts with organic amines such as morpholine and piperidine; and salts with amino acids.

[0039] [Pharmaceutical Composition for Treating Bacterial Infections] A compound represented by general formula (I) or a salt thereof can be used to treat various bacterial infections. The present invention provides a pharmaceutical composition for treating bacterial infections containing a compound represented by general formula (I) or a salt thereof. "Treatment" includes not only the cure of an existing disease and alleviation of symptoms, but also the suppression of onset. The antibacterial effect of a compound represented by general formula (I) or a salt thereof can be confirmed, for example, by a method similar to that described in the Examples below. The antibacterial effect can be confirmed, for example, by the inhibition of growth of bacteria coexisting with cells or macrophages or a reduction in the number of viable bacteria. The pharmaceutical composition of the present invention can be used to treat various bacterial infections.

[0040] The bacterial infections for which the pharmaceutical composition of the present invention is used can include a wide range of bacteria. Examples of infectious bacteria for bacterial infections include gram-positive bacteria, gram-negative bacteria, aerobic bacteria, and anaerobic bacteria, such as Mycobacterium, Staphylococcus, Lactobacillus, Streptococcus, Sarcina, Escherichia, Enterobacter, Klebsiella, Pseudomonas, Acinetobacter, Proteus, and the like. s), Campylobacter, Citrobacter, Neisseria, Bacillus, Bacteroides, Peptococcus, Clostridium, Salmonella, Shigella, Serratia, Haemophilus, Brucella, Legionella, and Listeria.

[0041] Examples of infectious bacteria for bacterial infections include Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium abscessus, Mycobacterium tuberculosis, Mycobacterium leprae, Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, and Stenotrophomonas maltophilia. maltophilia), Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Klebsiella aerogenes (or Enterobacter cloacae), Enterobacter aerogenes aerogenes, Klebsiella pneumoniae, Klebsiella oxytocaoxytoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis), Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Mannheimia haemolytica (or Pasteurella haemolytica), Moraxella catarrhaliscatarrhalis (or Branhamella catarrhalis), Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella, Gardnerella vaginalis), Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile, Corynebacterium diphtheriae, Corynebacterium ulcerans ulcerans), Streptococcus pneumoniae, Streptococcus agalactiaeagalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis or Staphylococcus saccharolyticus.

[0042] In one embodiment, the bacterial infection is a disease caused by infection with an intracellular parasite. Intracellular parasites refer to bacteria that are phagocytosed by phagocytes such as macrophages, grow therein, and cause the spread of lesions as the phagocytes spread throughout the body. Examples of intracellular parasites include Mycobacterium sp. (e.g., Mycobacterium tuberculosis, Mycobacterium leprae, nontuberculous mycobacteria, etc.), Salmonella sp., Shigella sp., Legionella sp., Listeria sp., Brucella sp., and Francisella tularensis.

[0043] In one embodiment, the bacterial infection is nontuberculous mycobacterial disease. Nontuberculous mycobacteria refer to mycobacteria (Mycobacteria of the genus Mycobacterium) other than Mycobacterium tuberculosis and Mycobacterium leprae, and examples thereof include Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium kansasii, and Mycobacterium abscessus. Nontuberculous mycobacterial disease refers to a disease caused by infection with nontuberculous mycobacteria. Examples of nontuberculous mycobacterial diseases include pulmonary mycobacterial complex (MAC) disease, pulmonary kansasii disease, and pulmonary abscessus disease. Pulmonary MAC disease is a respiratory disease caused by infection with MAC bacteria (Mycobacterium avium and / or Mycobacterium intracellulare). Pulmonary kansasii disease is a respiratory disease caused by infection with Mycobacterium kansasii. Pulmonary abscessus is a respiratory disease caused by infection with Mycobacterium abscessus. In one embodiment, the nontuberculous mycobacterial disease is pulmonary MAC disease.

[0044] The pharmaceutical composition of the present invention can be formulated according to conventional methods. Specifically, it can be formulated into oral preparations such as tablets, coated tablets, pills, powders, granules, capsules, liquids, suspensions, and emulsions; or parenteral preparations such as injections, infusions, suppositories, ointments, and patches. The proportion of carriers or additives may be appropriately determined based on the ranges commonly used in the pharmaceutical field. The carriers or additives that can be added are not particularly limited, and examples include various carriers such as water, physiological saline, other aqueous solvents, and aqueous or oily bases; and various additives such as excipients, binders, pH adjusters, disintegrants, absorption enhancers, lubricants, diluents, thickeners, wetting agents, emulsifiers, preservatives, colorants, flavorings, and fragrances.

[0045] Examples of additives that can be incorporated into tablets, capsules, etc. include binders such as gelatin, corn starch, tragacanth, and gum arabic, excipients such as crystalline cellulose, leavening agents such as corn starch, gelatin, and alginic acid, lubricants such as magnesium stearate, sweeteners such as sucrose, lactose, and saccharin, and flavors such as peppermint, saffron oil, and cherry. When the dosage unit form is a capsule, a liquid carrier such as oil or fat may be further contained in addition to the above-mentioned types of materials. Sterile compositions for injection can be formulated according to conventional pharmaceutical practices, such as dissolving or suspending the active substance and natural vegetable oils such as sesame oil and coconut oil in a vehicle such as water for injection. Aqueous solutions for injection include, for example, saline, isotonic solutions containing glucose or other adjuvants (e.g., D-sorbitol, D-mannitol, sodium chloride, etc.), and the like, which may be used in combination with appropriate solubilizers such as alcohols (e.g., ethanol), polyalcohols (e.g., propylene glycol, polyethylene glycol), and nonionic surfactants (e.g., polysorbate 80, HCO-50). Oily solutions include, for example, olive oil, sesame oil, and soybean oil, which may be used in combination with solubilizers such as benzyl benzoate and benzyl alcohol. They may also be formulated with buffers (e.g., phosphate buffer, sodium acetate buffer), soothing agents (e.g., benzalkonium chloride, procaine hydrochloride, etc.), stabilizers (e.g., human serum albumin, polyethylene glycol, etc.), preservatives (e.g., benzyl alcohol, phenol, etc.), antioxidants, etc.

[0046] The content of the compound represented by general formula (I) or a salt thereof in a composition or a single preparation may be 0.001 mg to 1000 mg, or may be 0.01 mg to 100 mg. The composition or preparation thus obtained is safe and has low toxicity, and therefore can be administered to, for example, humans or mammals (e.g., rats, mice, rabbits, sheep, pigs, cows, cats, dogs, monkeys, etc.).

[0047] The dosage of the active ingredient of the pharmaceutical composition of the present invention is appropriately determined taking into consideration the purpose, type of disease, severity of disease, age, weight, sex, medical history, type of active ingredient, etc. For an average human weighing approximately 65 to 70 kg, the dosage is preferably approximately 0.02 mg to 5000 mg per day, more preferably approximately 0.1 mg to 200 mg. The total dosage per day may be a single dose or divided doses.

[0048] The pharmaceutical composition of the present invention may be administered in combination with an antibacterial agent, regardless of the type, as long as it can be used to treat bacterial infections.

[0049] The pharmaceutical composition of the present invention and the antibacterial agent may be administered to a subject simultaneously or at different times, and the order of administration is not important. As used herein, "combination" or "administered in combination" means that the pharmaceutical composition of the present invention and the antibacterial agent are administered to a subject, and do not necessarily have to be administered simultaneously. The pharmaceutical composition of the present invention and the antibacterial agent may be administered separately, or they may be administered as a combined drug. The dosage of the antibacterial agent may be similar to the dosage used clinically and may be appropriately selected depending on the subject, age and weight of the subject, symptoms, administration time, dosage form, administration method, combination, etc.

[0050] The antibacterial agent is selected from the group consisting of macrolides, ketolides, aminoglycosides, tetracyclines, doxycycline / minocycline, rifampicin, β-lactams, lincomycins, chloramphenicols, polypeptides, glycopeptides, pyridonecarboxylic acid (quinolones), new quinolones, oxazolidinones, and sulfonamides, and examples thereof include macrolides such as clarithromycin, erythromycin, roxithromycin, and azithromycin; ketolides such as telithromycin, cethromycin, and solithromycin; aminoglycosides such as streptomycin, tobramycin, gentamicin, kanamycin, and amikacin; tetracyclines such as tetracycline and oxytetracycline; doxycycline / minocycline; and rifampicin; and β-lactams such as benzophenone. , penicillins, cephalosporins, carbapenems, penems, monobactams; lincomycins, clindamycin; chloramphenicols, chloramphenicol; polypeptides, bacitracin, polymyxin B, colistin; glycopeptides, vancomycin, teicoplanin, dalbavancin, oritavancin, telavancin; pyridonecarboxylic acid (quinolone) compounds, nalizix Examples of new quinolones include ofloxacin, ciprofloxacin, norfloxacin, lomefloxacin, levofloxacin, tosufloxacin, gatifloxacin, moxifloxacin, garenoxacin, and sitafloxacin; oxazolidinones include linezolid and tedizolid; and sulfa drugs include ST combination drugs (a combination drug of sulfamethoxazole and trimethoprim).

[0051] In one embodiment, the antibacterial agent is an antibacterial agent used to treat diseases caused by infection with intracellular parasites. Antibacterial agents against intracellular parasites include, for example, macrolides, fluoroquinolones, rifampicin, and tetracyclines. In one embodiment, the antibacterial agent is clarithromycin. Clarithromycin is a macrolide antibacterial agent and can be used as an antibacterial agent against intracellular parasites. Clarithromycin can also be used to treat diseases caused by infection with intracellular parasites, such as pulmonary MAC disease.

[0052] The combined administration of the pharmaceutical composition of the present invention and an antibacterial agent is useful for treating, for example, infections caused by bacteria that have acquired resistance to antibacterial agents. The combined administration of the pharmaceutical composition of the present invention and clarithromycin is useful for treating, for example, infections caused by clarithromycin-resistant bacteria such as clarithromycin-resistant Mycobacterium avium.

[0053] The present invention includes the following inventions. (1) A method for treating a bacterial infection, comprising administering to a mammal an effective amount of a compound represented by general formula (I) or a salt thereof. (2) A method for treating a bacterial infection, comprising administering to a mammal an effective amount of a compound represented by general formula (I) or a salt thereof in combination with an antibacterial agent. (3) A compound represented by general formula (I) or a salt thereof for use in treating a bacterial infection. (4) A combination of a compound represented by general formula (I) or a salt thereof and an antibacterial agent for use in treating a bacterial infection. (5) A kit for treating a bacterial infection, comprising a compound represented by general formula (I) or a salt thereof and an antibacterial agent, which are contained in separate containers and, if necessary, further comprising instructions. (6) Use of a compound represented by general formula (I) or a salt thereof for producing a medicament for treating a bacterial infection. (7) Use of a compound represented by general formula (I) or a salt thereof and an antibacterial agent for producing a medicament for treating a bacterial infection. (8) An antibacterial agent comprising a compound represented by general formula (I) or a salt thereof. (9) A compound represented by formula (I) or a salt thereof, a composition or preparation containing said compound or a salt thereof, and a method for producing the same.

[0054] The present invention will be described in detail below with reference to examples, but the present invention is not limited thereto. The present invention will be further described in detail below with reference to production examples, reference examples, and test examples, but the present invention is not limited thereto. The compounds and reagents used in the production examples, examples, and test examples of the present invention are readily available commercially and can be used. For example, they can be purchased from reagent manufacturers such as Aldrich, Fujifilm Wako Pure Chemical Industries, Ltd., Kanto Chemical Co., Ltd., Nacalai Tesque, or Tokyo Chemical Industry Co., Ltd. Column chromatography was performed using silica gel (50-200 μm, Fuji Silysia Chemical). One-dimensional NMR spectra were measured using a Varian 500PS, JEOL JNM-Al400, and Varian Gemini300. Chemical shifts are reported in ppm using solvent resonance or TMS as an internal standard. Multiplicities are indicated as (s = singlet, d = doublet, t = triplet, dd = doublet of doublets, dt = doublet of triplets, m = multiplet, br = broad). The abbreviations used herein mean the following: DMF: N,N-dimethylformamide THF: tetrahydrofuran Et ３ N: Triethylamine iPr ２ NEt: Diisopropylethylamine DBU: Diazabicycloundecene DMAP: 4-dimethylaminopyridine Pd ２ (dpa) ３ : Tris(dibenzylineacetone)dipalladium(0) Xantophos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene S-phos: 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride TFA: Trifluoroacetic acid Biotin NHS: 6aR-hexahydro-2-oxo-2,5-dioxo-1-pyrrolidinyl ester-1H-thieno[3aS,4d]imidazole-4S-pentane LAH: Lithium aluminum hydride

[0055] [Production Method] Compound 3 having the following structure can be produced, for example, by the method described in the following scheme: In Compound 3, preferably, X=Y is N=C or N=N, but is not limited thereto.

[0056] <Scheme 1> (In the formula, each symbol has the same meaning as defined above.)

[0057] Compound 3 can be produced by reacting Compound 1 and Compound 2 in the presence of a base in a solvent that does not adversely affect the reaction. Examples of solvents that do not adversely affect the reaction include, but are not limited to, methanol, ethanol, acetonitrile, DMF, THF, 1,4-dioxane, etc. Examples of bases include Et ３ N, iPr ２ Examples of the base include, but are not limited to, NEt, DBU, and alkali metal (Li, Na, K, Cs) carbonates and hydroxides. The amount of base used is usually, but is not limited to, about 0.5 to about 5.0 molar equivalents, preferably about 1 to about 2 molar equivalents, relative to Compound 1. The reaction temperature is usually, but is not limited to, room temperature to about 150°C, preferably room temperature to about 120°C. In this specification, room temperature usually refers to, but is not limited to, about 10 to about 30°C. The reaction time is usually, but is not limited to, about 5 minutes to about 48 hours, preferably about 10 minutes to about 24 hours.

[0058] [Reference Production Example 1] Preparation of methyl 6-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)pyridazine-3-carboxylate Methyl 6-chloropyridazine-3-carboxylate (1.5 g) and 4-(2-(trifluoromethyl)phenoxy)piperidine (1.1 g) were dissolved in acetonitrile (80 mL) and the mixture was subjected to iPr ２NEt (1.3 mL) was added, and the mixture was stirred at 120°C for 12 hours to react. The solution after the reaction was diluted with water and then extracted with ethyl acetate. The extracted solution was washed successively with water and saturated brine, and then dried over magnesium sulfate. The solvent was then distilled off under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate:hexane = 1:2) to obtain the title target product (1.4 g, yield 63%). １ HNMR (500MHz, CDCl ３ ) δ7.89 (d, J=9.8Hz, 1H), 7.60 (d, J=8.1Hz, 1H), 7.50 (t, 8.1Hz, 1H), 7.04-7.02 (m, 2H), 6.91 (d, J=9 .8Hz, 1H), 4.84-4.81 (m, 1H), 4.12-4.08 (m, 2H), 4.00 (s, 3H), 3.86-3.81 (m, 2H), 2.08-1.99 (m, 4H).

[0059] A generalized scheme of Reference Production Example 1 is, for example, as follows: <Scheme 2> (In the formula, each symbol has the same meaning as defined above.)

[0060] Reference Production Example 2 Preparation of methyl 6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridazine-3-carboxylate Using 4-(2-chloro-5-fluorophenoxy)piperidine (1.1 g), the reaction was carried out according to the method described in Reference Production Example 1 to give the title compound (2.2 g, yield 60%). １ HNMR (500MHz, CDCl ３ ) δ7.90 (d, J=9.5Hz, 2H), 7.34 (dd, J=6.1, 8.8Hz, 1H), 6.92 (d, J=9.5Hz, 2H), 6.73 (dd, J=2.7, 10.1 Hz, 1H), 6.70-6.66 (m, 1H), 4.68 (quint., 1H), 4.12-3.93 (m, 4H), 4.00 (s, 3H), 2.06-2.00 (m, 4H).

[0061] [Reference Production Example 3] Preparation of methyl 6-(4-cyano-4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)pyridazine-3-carboxylate Methyl 6-chloropyridazine-3-carboxylate (438 mg), 4-(4-(trifluoromethyl)phenyl)piperidine-4-carbonitrile (645 mg), iPr ２ The reaction was carried out using NEt (530 μL) and acetonitrile (50 mL) according to the method described in Reference Production Example 1 to obtain the title compound (547 mg, yield 56%). １ HNMR (500MHz, CDCl ３ ) δ7.97 (d, J=9.6Hz, 2H), 7.70 (d, J=8.8Hz, 2H), 7.63 (d, J=8.6Hz, 2H), 7.00 (d, J=9.8Hz, 1H), 4.82- 4.79 (m, 2H), 4.03 (s, 3H), 3.59-3.53 (m, 2H), 2.30 (d, J = 13.7Hz, 2H), 2.14 (dt, J = 4.2, 13.2Hz, 2H).

[0062] [Reference Production Example 4] Preparation of methyl 6-(4-(2-chloro-5-fluorophenoxy)-4-cyanoperidin-1-yl)pyridazine-3-carboxylate Methyl 6-chloropyridazine-3-carboxylate (300 mg), 4-(2-chloro-5-fluorophenoxy)piperidine-4-carbonitrile (440 mg), iPr ２ The reaction was carried out using NEt (362 μL) and DMF (10 mL) according to the method described in Reference Production Example 1 to obtain the title compound (551 mg, yield 81%).

[0063] [Reference Production Example 5] Production of methyl 6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)nicotinate Methyl 6-chloronicotinate (340 mg), 4-(2-chloro-5-fluorophenoxy)piperidine (508 mg), iPr ２ The reaction was carried out using NEt (420 μL) and DMF (15 mL) according to the method described in Reference Production Example 1 to obtain the title compound (634 mg, yield 87%). 1 HNMR (500MHz, CDCl ３) δ8.81 (d, J=2.2Hz, 1H), 8.03 (dd, J=2.2, 9.1Hz, 1H), 7.33 (dd, J=6.1, 8.8Hz, 1H), 6.74 (dd, J= 3.0, 10.3Hz, 1H), 6.69-6.64 (m, 2H), 4.65-4.61 (m, 1H), 3.94-3.80 (m, 7H), 2.04-1.93 (m, 4H).

[0064] Reference Production Example 6: Preparation of methyl 6-(4-(2-chlorophenoxy)piperidin-1-yl)pyridazine-3-carboxylate Methyl 6-chloropyridazine-3-carboxylate (693 mg), 4-(2-chlorophenoxy)piperidine (850 mg), iPr ２ The reaction was carried out according to the method described in Reference Production Example 1 using NEt (1.1 mL) and acetonitrile (60 mL) to obtain the title compound (1.0 g, yield 72%). １ HNMR (500MHz, CDCl ３ ) δ7.89 (d, J=9.6Hz, 1H), 7.40 (dd, J=1.7, 8.1Hz, 1H), 7.28-7.21 (m, 1H), 7.01 (d, J=8.1Hz, 1H), 6.95 (t, J=7.8Hz, 1H), 6.92 (d, J=9.8Hz, 1H), 4.71 (quint., J=4.6Hz, 1H), 4.07-3.98 (m, 7H), 2.05-2.02 (m, 4H).

[0065] Reference Production Example 7: Preparation of methyl 6-(4-(2,6-dichlorophenoxy)piperidin-1-yl)pyridazine-3-carboxylate Methyl 6-chloropyridazine-3-carboxylate (596 mg), 4-(2,6-dichlorophenoxy)piperidine (850 mg), iPr ２ The reaction was carried out using NEt (733 μL) and acetonitrile (50 mL) according to the method described in Reference Production Example 1 to obtain the title compound (750 mg, yield 56%). 1 HNMR (500MHz, CDCl ３) δ7.90 (d, J=9.8Hz, 1H), 7.33 (d, J=8.1Hz, 2H), 7.01 (t, J=7.8Hz, 1H), 6.92 (d, J=9.5Hz, 1H), 4. 57 (quint., J=5.5Hz, 1H), 4.33-4.28 (m, 2H), 4.01 (s, 3H), 3.69-3.64 (m, 2H), 2.09-2.06 (m, 4H).

[0066] Reference Preparation Example 8: Preparation of methyl 4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)benzoate. Methyl 4-bromobenzoate (1.0 g) and 4-(2-chloro-5-fluorophenoxy)piperidine (1.0 g) were dissolved in 1,4-dioxane (25 mL), and the resulting solution was mixed with Pd ２ (dpa) ３ (39 mg), Xantphos (62 mg), and cesium carbonate (2.2 g) were added and stirred at 100°C for 12 hours. After the reaction, the reaction solution was diluted with water and extracted with ethyl acetate. The extract was washed successively with water and saturated brine and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate:hexane = 1:4) to obtain the title product (820 mg, yield 43%). １ HNMR (500MHz, CDCl ３ ) δ7.93 (d, J=9.3Hz, 2H), 7.33 (dd, J=2.7, 8.8Hz, 1H), 6.90 (d, J=9.1Hz, 2H), 6.72 (dd, J=3.0, 10.3Hz, 1H), 6.66 (dd d.

[0067] A generalized scheme of Reference Production Example 8 is as follows: <Scheme 3> (In the formula, each symbol has the same meaning as defined above.)

[0068] [Reference Production Example 9] Preparation of methyl 4-(4-(2-chlorophenoxy)piperidin-1-yl)benzoate Methyl 4-bromobenzoate (932 mg), 4-(2-chlorophenoxy)piperidine (850 mg), Pd ２ (dpa) ３ (37 mg), Xantphos (58 mg), and cesium carbonate (2.0 g) were used to carry out the reaction and treatment according to the method described in Reference Production Example 8 to obtain the title compound (762 mg, yield 55%). １ HNMR (500MHz, CDCl ３ ) δ7.93 (d, J=9.1Hz, 2H), 7.39 (dd, J=1.7, 7.8Hz, 1H), 7.24-7.20 (m, 1H), 7.00 (dd, J=1.0, 8.3Hz, 1H), 6.94 (dt, J=1.3, 7. 9Hz, 1H), 6.90 (d, J=7.1Hz, 2H), 4.63-4.59 (m, 1H), 3.88 (s, 3H), 3.69-3.64 (m, 2H), 3.41-3.37 (m, 2H), 2.09-1.98 (m, 4H).

[0069] Reference Preparation Example 10: Preparation of methyl 4-(4-(2,6-dichlorophenoxy)piperidin-1-yl)benzoate Methyl 4-bromobenzoate (932 mg), 4-(2,6-dichlorophenoxy)piperidine (850 mg), Pd ２ (dpa) ３ (37 mg), Xantphos (58 mg), and cesium carbonate (1.7 g) were used to carry out the reaction and treatment according to the method described in Reference Production Example 8 to obtain the title compound (734 mg, yield 58%). １ HNMR (500MHz, CDCl ３ ) δ7.92 (d, J=9.3Hz, 1H), 7.32 (d, J=8.1Hz, 1H), 7.00 (t, J=8.1Hz, 1H), 6.89 (d, J=9.1Hz, 2H), 4. 47 (quint., J=6.4Hz, 1H), 3.87 (s, 3H), 3.87-3.82 (m, 2H), 3.21-3.16 (m, 2H), 2.09-2.04 (m, 4H).

[0070] A generalized scheme for producing the example compounds of the present invention is shown below. <Scheme 4> (wherein each symbol has the same meaning as defined above.) Steps (a), (b) and (c) in the above scheme 4 will be described in detail below.

[0071] Step (a): Compound (4) can be produced by reacting compound (3) with hydrazine monohydrate in a solvent that does not adversely affect the reaction. Examples of solvents that do not adversely affect the reaction include, but are not limited to, methanol and ethanol. The amount of hydrazine monohydrate used relative to compound (4) is usually, but is not limited to, about 1 to about 50 molar equivalents, preferably about 10 to about 50 molar equivalents. The reaction temperature is usually, but is not limited to, room temperature to about 150°C, preferably room temperature to about 90°C. The reaction time is usually, but is not limited to, about 5 minutes to about 48 hours, preferably about 10 minutes to about 24 hours.

[0072] Step (b): Compound (5) can be produced by reacting compound (4) with a carboxylic acid halide in the presence of a base in a solvent that does not adversely affect the reaction. Examples of solvents that do not adversely affect the reaction include, but are not limited to, dichloromethane, diethyl ether, etc. Examples of carboxylic acid halides include, but are not limited to, acetyl chloride, acetoxyacetyl chloride, benzoyl chloride, etc. The amount of carboxylic acid halide used is usually 0.5 to 1.5 molar equivalents, preferably 0.8 to 1.2 molar equivalents, but is not limited to these. Examples of bases include Et ３ N, iPr ２ Examples include, but are not limited to, NEt. The amount of base used is usually about 0.5 to about 10 molar equivalents, preferably about 0.8 to about 2 molar equivalents, relative to compound (4). The reaction temperature is usually, but is not limited to, about −78° C. to about 150° C., preferably about −20° C. to about 80° C. The reaction time is usually, but is not limited to, about 5 minutes to about 48 hours, preferably about 10 minutes to about 24 hours.

[0073] Step (c): Compound (5) can be reacted with a sulfurizing agent under microwave irradiation in a solvent that does not adversely affect the reaction to produce compound (6). Examples of solvents that do not adversely affect the reaction include, but are not limited to, THF and 1,4-dioxane. Examples of sulfurizing agents include, but are not limited to, phosphorus pentasulfide and Lawesson's reagent. The amount of sulfurizing agent used is typically, but is not limited to, about 0.5 to about 10 molar equivalents, preferably about 0.8 to about 5 molar equivalents, relative to compound (5). The reaction temperature is typically, but is not limited to, room temperature to about 150°C, preferably room temperature to about 120°C. The reaction time is typically, but is not limited to, about 1 minute to about 1 hour, preferably about 5 to about 20 minutes.

[0074] Example 1: Preparation of 2-(6-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)pyridazin-3-yl)-5-methyl-1,3,4-thiadiazole (Compound No. NUT-9 (ADI-9))

[0075] [Step (a) of Example 1] Preparation of 6-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)pyridazine-3-carbohydrazide Methyl 6-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)pyridazine-3-carboxylate (572 mg) prepared in Reference Preparation Example 1 was dissolved in ethanol (8 mL), and hydrazine monohydrate (3.0 mL) was added, followed by stirring at 80°C for 12 hours. The solvent was evaporated from the reaction mixture under reduced pressure, and the mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over magnesium sulfate, and the crude product (570 mg, crude yield 99%) was used in the next reaction.

[0076] [Step (b) of Example 1] Preparation of N'-acetyl-6-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)pyridazine-3-carbohydrazide The crude product (570 mg) of 6-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)pyridazine-3-carbohydrazide obtained in the above step (a) was dissolved in dichloromethane (10 mL), and the reaction solution was cooled to 0°C. ２ NEt (522 μL) and acetyl chloride (160 μL) were added and stirred at room temperature for 10 hours. After the reaction, the reaction solution was diluted with water and extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate:methanol=95:5) to obtain the title compound (112 mg, yield 18%). １ HNMR (500MHz, CDCl ３ ) δ9.86 (br.s, NH), 8.13-8.06 (m, NH), 7.93 (d, J = 9.5Hz, 1H), 7.61 (d, J = 7.4Hz, 1H), 7.51 (t, J = 7.6Hz, 1H), 7.05-7.02 ( m, 2H), 7.99 (d, J = 9.6Hz, 1H), 4.87-4.81 (m, 1H), 4.14-4.07 (m, 2H), 3.86-3.80 (m, 2H), 2.14 (s, 3H), 2.08-2.02 (m, 4H).

[0077] [Step (c) of Example 1] Preparation of 2-(6-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)pyridazin-3-yl)-5-methyl-1,3,4-thiadiazole N'-acetyl-6-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)pyridazine-3-carbohydrazide (112 mg) obtained in step (b) above was dissolved in THF (4 mL), and phosphorus pentasulfide (124 mg) was added. The mixture was irradiated with microwaves at 150°C for 20 minutes. After the reaction, the solvent was evaporated under reduced pressure from the reaction solution, and the residue was purified by column chromatography (developing solvent: ethyl acetate:hexane=1:1) to obtain the title compound (43 mg, yield 40%). １ HNMR (500MHz, CDCl ３) δ8.15 (d, J=9.8Hz, 1H), 7.60 (d, J=7.8Hz, 1H), 7.49 (t, J=7.3Hz, 1H), 7.05-7.01 (m, 3H), 4.84-4.81 (m, 1H), 4.08-4.03 (m, 2H), 3.86-3.81 (m, 2H), 2.81 (s, 3H), 2.09-2.02 (m, 4H).

[0078] Example 2: Preparation of 2-(6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridazin-3-yl)-5-methyl-1,3,4-thiadiazole (Compound Number: NUT-10 (ADI-10))

[0079] [Step (a) of Example 2] Preparation of 6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridazine-3-carbohydrazide Methyl 6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridazine-3-carboxylate (549 mg) prepared in Reference Preparation Example 2 was reacted and treated according to the method described in Step (a) of Example 1 to give the title compound as a crude product (550 mg, crude yield 99%).

[0080] [Step (b) of Example 2] Preparation of N'-acetyl-6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridazine-3-carbohydrazide The crude product (550 mg) of 6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridazine-3-carbohydrazide obtained in the above step (a), iPr ２ The reaction was carried out according to the method described in step (b) of Example 1 using NEt (522 μL) and acetyl chloride (160 μL) to obtain the title compound (123 mg, yield 20%). １ HNMR (300MHz, CDCl ３ ) δ9.85 (br.s, NH), 8.03 (br.s, NH), 7.94 (d, J = 9.4Hz, 1H), 7.01 (d, J = 9.4Hz, 1H), 6.7 6-6.65 (m, 2H), 4.72-4.65 (m, 1H), 4.03-3.89 (m, 4H), 2.14 (s, 3H), 2.07-2.02 (m, 4H).

[0081] [Step (c) of Example 2] Preparation of 2-(6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridazin-3-yl)-5-methyl-1,3,4-thiadiazole N'-acetyl-6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridazine-3-carbohydrazide (123 mg) obtained in the above step (b) and phosphorus pentasulfide (143 mg) were reacted and treated according to the method described in step (c) of Example 1 to give the title compound (47 mg, yield 40%). １ HNMR (500MHz, CDCl ３ ) δ8.17 (d, J=9.5Hz, 1H), 7.34 (dd, J=6.1, 8.8Hz, 1H), 7.06 (d, J=9.6Hz, 1H), 6.74 (dd, J=2.7, 10Hz, 1H), 6 .68 (dt, J=2.7, 8.6Hz, 1H), 4.69 (quint.J=4.2Hz, 1H), 3.98-3.96 (m, 4H), 2.83 (s, 3H), 2.07-2.05 (m, 4H).

[0082] Example 3: Preparation of (5-(6-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)pyridazin-3-yl)-1,3,4-thiadiazol-2-yl)methyl acetate (compound number: NUT-13 (ADI-13))

[0083] [Step (1) of Example 3] Preparation of 2-(2-(6-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)pyridazine-3-carbonyl)hydrazinyl)2-oxoethyl acetate: 6-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)pyridazine-3-carbohydrazide (572 mg) obtained in Step (a) of Example 1, iPr ２ The reaction was carried out according to the method described in step (b) of Example 1 using NEt (452 ​​μL) and acetoxyacetyl chloride (244 μL) to obtain the title compound (385 mg, yield 63%). １ HNMR (500MHz, CDCl ３) δ9.84 (br.s, NH), 8.61 (br.s, NH), 7.94 (d, J=9.6Hz, 1H), 7.61 (d, J=7.6Hz, 1H), 7.51 (d, J=7.4Hz, 1H), 7.05-7. 00 (m, 2H), 4.87-4.83 (m, 1H), 4.73 (s, 2H), 4.12-4.08 (m, 2H), 3.86-3.82 (m, 2H), 2.22 (s, 3H), 2.11-2.08 (m, 4H).

[0084] [Step (2) of Example 3] Preparation of (5-(6-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)pyridazin-3-yl)-1,3,4-thiadiazol-2-yl)methyl acetate. 2-(2-(6-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)pyridazine-3-carbonyl)hydrazinyl)2-oxoethyl acetate (340 mg) obtained in step (1) above and phosphorus pentasulfide (345 mg) were reacted and treated according to the method described in step (c) of Example 1 to give the title compound (155 mg, yield 46%). １ HNMR (500MHz, CDCl ３ ) δ8.18 (d, J=9.6Hz, 1H), 7.62 (d, J=7.8Hz, 1H), 7.51 (d, J=7.6Hz, 1H), 7.64-7.03 (m, 2H), 5.53 (s, 2H) , 4.86-4.83 (m, 1H), 4.09 (dt, J=4.4, 13.7Hz, 2H), 3.88-3.82 (m, 2H), 2.18 (s, 3H), 2.11-2.02 (m, 4H).

[0085] Example 4: Preparation of (5-(6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridazin-3-yl)-1,3,4-thiadiazol-2-yl)methyl acetate (compound number: NUT-14 (ADI-14))

[0086] [Step (1) of Example 4] Preparation of 2-(2-(6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridazine-3-carbonyl)hydrazinyl)2-oxoethyl acetate: 6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridazine-3-carbohydrazide (250 mg) obtained in Step (a) of Example 2, iPr ２ The reaction was carried out according to the method described in step (b) of Example 1 using NEt (238 μL) and acetoxyacetyl chloride (111 μL) to obtain the title compound (137 mg, yield 43%). １ HNMR (500MHz, CDCl ３ ) δ9.84 (br.s, NH), 8.58 (br.s, NH), 7.95 (d, J = 9.6Hz, 1H), 7.35 (dd, J = 6.1, 8.8Hz, 1H), 7.01 (d, J = 9.5Hz, 1H), 7.64 (dd, J =2.7, 10.0Hz, 1H), 6.71-6.67 (m, 1H), 4.76 (s, 2H), 4.70-4.69 (m, 1H), 4.03-3.92 (m, 4H), 2.22 (s, 3H), 2.07-2.04 (m, 4H).

[0087] [Step (2) of Example 4] Preparation of (5-(6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridazin-3-yl)-1,3,4-thiadiazol-2-yl)methyl acetate. 2-(2-(6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridazine-3-carbonyl)hydrazinyl)2-oxoethyl acetate (137 mg) obtained in Step (1) above and phosphorus pentasulfide (143 mg) were reacted and treated according to the method described in Step (c) of Example 1 to give the title compound (73 mg, yield 54%). １ HNMR (500MHz, CDCl ３) δ8.19 (d, J=9.5Hz, 1H), 7.35 (dd, J=6.2, 8.8Hz, 1H), 7.06 (d, J=9.6Hz, 1H), 6.74 (dd, J=2.7, 10.0Hz, 1H), 6 70-6.67 (m, 1H), 5.53 (s, 2H), 4.69 (quint., 4.4Hz, 1H), 4.02-3.96 (m, 4H), 2.19 (s, 3H), 2.06-2.05 (m, 4H).

[0088] Example 5: Preparation of (5-(6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl acetate (compound number: NUT-19)

[0089] Phosphoryl chloride (4 mL) was added to 2-(2-(6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridazine-3-carbonyl)hydrazinyl)2-oxoethyl acetate (230 mg) obtained in step (1) of Example 4, and the mixture was stirred at 100°C for 6 hours. Ice was added to the reaction mixture, which was then diluted with an aqueous potassium carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate:methanol = 95:5) to obtain the title compound (92 mg, yield 42%). １ HNMR (500MHz, CDCl ３ ) δ8.03 (d, J=9.5Hz, 1H), 7.32 (dd, J=5.9, 8.8Hz, 1H), 7.03 (d, J=9.8Hz, 1H), 6.72 (dd, J=3.0, 10.3Hz, 1H ), 6.70-6.67 (m, 1H), 5.36 (s, 2H), 4.69-4.67 (m, 1H), 4.04-3.92 (m, 4H), 2.16 (s, 3H), 2.06-2.03 (m, 4H).

[0090] A generalized scheme of Example 5 is, for example, as follows: <Scheme 5> (In the formula, each symbol has the same meaning as defined above.)

[0091] Example 6: Preparation of (5-(6-(4-cyano-4-(trifluoromethyl)phenyl)piperidin-1-yl)pyridazin-3-yl)-1,3,4-thiadiazol-2-yl)methyl acetate (compound number: NUT-21)

[0092] [Step (a) of Example 6] Preparation of 6-(4-cyano-4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)pyridazine-3-carbohydrazide Methyl 6-(4-cyano-4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)pyridazine-3-carboxylate (547 mg) obtained in Reference Preparation Example 3 was reacted and treated according to the method described in Step (a) of Example 1 to give the title compound as a crude product (545 mg, crude yield 99%).

[0093] [Step (b) of Example 6] Preparation of 2-(2-(6-(4-cyano-4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)pyridazine-3-carbonyl)hydrazinyl)-2-oxoethyl acetate. The crude product (545 mg) of 6-(4-cyano-4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)pyridazine-3-carbohydrazide prepared in the above step (a), iPr ２ The reaction was carried out according to the method described in step (b) of Example 1 using NEt (489 μL) and acetoxyacetyl chloride (228 μL) to obtain the title compound (56 mg, yield 8%). １ HNMR (500MHz, CDCl ３ ) δ9.58 (br.d, NH), 8.00 (d, J = 9.6Hz, 1H), 7.71 (d, J = 8.3Hz, 2H), 7.64 (d, J = 8.6Hz, 2H), 7.08 (d, J = 9.6Hz, 1H), 5.14 (b r.s, 2H), 5.04 (br.s, NH), 4.89 (d, J=14.0Hz, 2H), 3.60 (t, J=13.5Hz, 2H), 2.32 (d, J=13.2Hz, 2H), 2.21-2.14 (m, 5H).

[0094] [Step (c) of Example 6] Preparation of (5-(6-(4-cyano-4-(trifluoromethyl)phenyl)piperidin-1-yl)pyridazin-3-yl)-1,3,4-thiadiazol-2-yl)methyl acetate. 2-(2-(6-(4-cyano-4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)pyridazine-3-carbonyl)hydrazinyl)-2-oxoethyl acetate (56 mg) prepared in step (b) above and phosphorus pentasulfide (56 mg) were reacted and treated according to the method described in step (c) of Example 1 to give the title compound (22 mg, yield 40%). １ HNMR (500MHz, CDCl ３ ) δ8.24 (d, J=9.6Hz, 1H), 7.70 (d, J=8.3Hz, 2H), 7.63 (d, J=8.3Hz, 2H), 7.13 (d, J=9.6Hz, 1H), 5. 54 (s, 2H), 4.77 (d, J = 14.2Hz, 2H), 3.60-3.54 (m, 2H), 2.31 (d, J = 13.7Hz, 2H), 2.19-2.13 (m, 5H).

[0095] [Example 7] Preparation of (5-(6-(4-(2-chloro-5-fluorophenoxy)-4-cyanopiperidin-1-yl)pyridazin-3-yl)-1,3,4-thiadiazol-2-yl)methyl acetate (compound number: NUT-25), and

[0096] [By-product of Example 7] Preparation of (5-(6-(4-carbamothioyl-4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridazin-3-yl)-1,3,4-thiadiazol-2-yl)methyl acetate (Compound No.: NUT-26)

[0097] [Step (a) of Example 7] Preparation of 6-(4-(2-chloro-5-fluorophenoxy)-4-cyanopiperidin-1-yl)pyridazine-3-carbohydrazide Methyl 6-(4-(2-chloro-5-fluorophenoxy)-4-cyanoperidin-1-yl)pyridazine-3-carboxylate (508 mg) prepared in Reference Preparation Example 4 was reacted and treated according to the method described in Step (a) of Example 1 to give the title compound as a crude product (300 mg, crude yield 59%).

[0098] [Step (b) of Example 7] Preparation of 2-(2-(6-(4-(2-chloro-5-fluorophenoxy)-4-cyanopiperidin-1-yl)pyridazine-3-carbonyl)hydrazinyl)-2-oxoethyl acetate. A portion (195 mg) of the crude product of 6-(4-(2-chloro-5-fluorophenoxy)-4-cyanopiperidin-1-yl)pyridazine-3-carbohydrazide prepared in the above step (a), iPr ２ The reaction was carried out according to the method described in step (b) of Example 1 using NEt (100 μL) and acetoxyacetyl chloride (54 μL) to obtain the title compound (158 mg, yield 64%). １ HNMR (500MHz, CDCl ３ ) δ9.84 (br.s, NH), 8.60 (br.s, NH), 8.02 (d, J = 9.5Hz, 1H), 7.42 (dd, J = 5.9, 8.8Hz, 1H), 7.34 (dd, J = 3.0, 9.3Hz, 1H), 7.04 (d, J = 9 .6Hz, 1H), 6.90 (ddd, J=2.7, 7.6, 8.8Hz, 1H), 4.76 (s, 2H), 4.24-4.19 (m, 2H), 3.84-3.80 (m, 2H), 2.38-2.33 (m, 4H), 2.23 (s, 3H).

[0099] [Step (c) of Example 7] Preparation of (5-(6-(4-(2-chloro-5-fluorophenoxy)-4-cyanoperidin-1-yl)pyridazin-3-yl)-1,3,4-thiadiazol-2-yl)methyl acetate. 2-(2-(6-(4-(2-chloro-5-fluorophenoxy)-4-cyanopiperidin-1-yl)pyridazine-3-carbonyl)hydrazinyl)-2-oxoethyl acetate (157 mg) prepared in step (b) above and phosphorus pentasulfide (156 mg) were reacted and treated according to the method described in step (c) of Example 1 to give the title compound (41 mg, yield 26%). １ HNMR (500MHz, CDCl ３ ) δ8.24 (d, J=9.6Hz, 1H), 7.41 (dd, J=5.9, 8.8Hz, 1H), 7.33 (dd, J=2.7, 9.3Hz, 1H), 7.09 (d, J=9.8Hz, 1H), 6.89 ( ddd.

[0100] Furthermore, (5-(6-(4-carbamothioyl-4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridazin-3-yl)-1,3,4-thiadiazol-2-yl)methyl acetate (20 mg, yield 12%) was also obtained as a by-product of the reaction in step (c) above. １ HNMR (500MHz, CDCl ３ ) δ8.17 (d, J=9.8Hz, 1H), 7.88 (br.d, NH), 7.11 (br.d, NH), 7.38 (dd, J= 5.6, 8.8Hz, 1H), 7.01 (d, J = 9.8Hz, 1H), 6.79-6.75 (m, 1H), 6.72 (dd, J = 2 7, 9.5Hz, 1H), 5.52 (s, 2H), 4.42 (d, J=13.5Hz, 2H), 3.39 (t, J=13.5Hz, 2H), 2.68 (dt, J=4.7, 14.2Hz, 2H), 2.34 (d, J=13.0Hz, 2H), 2.18 (s, 3H).

[0101] [Example 8] (5-(6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)methyl acetate (Compound number: NUT-27)

[0102] [Step (a) of Example 8] Preparation of 6-(4-cyano-(2-chloro-5-fluorophenyl)piperidin-1-yl)nicotinohydrazide Methyl 6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)nicotinate (547 mg) prepared in Reference Preparation Example 5 was reacted and treated according to the method described in Step (a) of Example 1 to give the title compound as a crude product (85 mg, crude yield 16%).

[0103] [Step (b) of Example 8] Preparation of 2-(2-(6-(4-(2-chloro-5-fluorophenyl)piperidin-1-yl)nicotinoyl)hydrazinyl-2-oxoethyl acetate] The crude product (85 mg) of 6-(4-cyano-(2-chloro-5-fluorophenyl)piperidin-1-yl)nicotinohydrazide prepared in the above step (a), iPr ２ The reaction was carried out according to the method described in step (b) of Example 1 using NEt (49 μL) and acetoxyacetyl chloride (258 μL) to obtain the title compound (56 mg, yield 52%). １ HNMR (500MHz, CDCl ３ ) δ8.93 (br.s, NH), 8.66 (d, J=2.2Hz, 1H), 7.89 (dd, J=2.7, 9.1Hz, 1H), 7.34 (dd, J=5.6, 8.8Hz, 1H), 6.73 (dd, J=3.0, 10.3Hz, 1H), 6.69-6.65 (m, 2H), 4.74 (s, 2H), 4.66-4.62 (m, 1H), 3.93-3.82 (m, 4H), 2.22 (s, 3H), 2.02-1.97 (m, 4H).

[0104] [Step (c) of Example 8] Preparation of (5-(6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)methyl acetate. 2-(2-(6-(4-(2-chloro-5-fluorophenyl)piperidin-1-yl)nicotinoyl)hydrazinyl-2-oxoethyl acetate (56 mg) prepared in step (b) above, phosphorus pentasulfide (56 mg), and THF (2 mL) were reacted and treated according to the method described in step (c) of Example 1 to give the title compound (32 mg, yield 49%). １ HNMR (500MHz, CDCl ３ ) δ8.65 (d, J=2.4Hz, 1H), 8.10 (dd, J=2.5, 9.0Hz, 1H), 7.33 (dd, J=6.1, 8.8Hz, 1H), 6.76-6.72 (m, 2H), 6.68-6.6 5 (m, 1H), 5.50 (s, 2H), 4.66-4.62 (m, 1H), 3.92-3.88 (m, 2H), 3.84-3.80 (m, 1H), 2.17 (s, 3H), 2.05-1.97 (m, 4H).

[0105] Example 9: Preparation of (5-(6-(4-(2-chlorophenoxy)piperidin-1-yl)pyridazin-3-yl)-1,3,4-thiadiazol-2-yl)methyl acetate (compound number: NUT-33 (ADI-33))

[0106] [Step (a) of Example 9] Preparation of 6-(4-(2-chlorophenoxy)piperidin-1-yl)pyridazine-3-carbohydrazide Methyl 6-(4-(2-chlorophenoxy)piperidin-1-yl)pyridazine-3-carboxylate (1.0 g) prepared in Reference Preparation Example 6 and hydrazine monohydrate (5 mL) were reacted and treated according to the method described in Step (a) of Example 1 to give the title compound as a crude product (347 mg, crude yield 80%).

[0107] [Step (b) of Example 9] Preparation of 2-(2-(6-(4-(2-chlorophenoxy)piperidin-1-yl)pyridazine-3-carbonyl)hydrazinyl)2-oxoethyl acetate

[0049] The crude product (347 mg) of 6-(4-(2-chlorophenoxy)piperidin-1-yl)pyridazine-3-carbohydrazide prepared in the above step (a), iPr ２ The reaction was carried out according to the method described in step (b) of Example 1 using NEt (210 μL) and acetoxyacetyl chloride (119 μL) to obtain the title compound (348 mg, yield 78%). １ HNMR (500MHz, CDCl ３ ) δ9.83 (br.s, NH), 8.60 (br.s, NH), 7.94 (d, J = 9.6Hz, 1H), 7.41 (dd, J = 1.7, 7.8Hz, 1H), 7.23 (dt, J = 1.7, 8.3Hz, 1H), 7.01 (d, J = 8.8 Hz, 2H), 6.96 (dt, J=1.5, 8.1Hz, 1H), 4.76 (s, 2H), 4.73 (quint., J=4.4Hz, 1H), 4.02-3.94 (m, 4H), 2.22 (s, 3H), 2.06-2.02 (m, 4H).

[0108] [Step (c) of Example 9] Preparation of (5-(6-(4-(2-chlorophenoxy)piperidin-1-yl)pyridazin-3-yl)-1,3,4-thiadiazol-2-yl)methyl acetate. 2-(2-(6-(4-(2-chlorophenoxy)piperidin-1-yl)pyridazine-3-carbonyl)hydrazinyl)2-oxoethyl acetate (143 mg) prepared in step (b) above and phosphorus pentasulfide (156 mg) were reacted and treated according to the method described in step (c) of Example 1 to give the title compound (45 mg, yield 29%). １ HNMR (500MHz, CDCl ３) δ8.16 (d, J=9.5Hz, 1H), 7.39 (dd, J=1.5, 7.8Hz, 1H), 7.22 (dt, J = 1.5, 7.9Hz, 1H), 7.05 (d, J = 9.8Hz, 1H), 6.99 (dd, J = 1.2, 8.3Hz , 1H), 6.94 (dt, J = 1.0, 7.6Hz, 1H), 5.51 (s, 2H), 4.71 (quint., J = 4.7Hz, 1H), 4.00-3.94 (m, 4H), 2.17 (s, 3H), 2.05-2.02 (m, 4H).

[0109] Example 10: Preparation of (5-(6-(4-(2,6-dichlorophenoxy)piperidin-1-yl)pyridazin-3-yl)-1,3,4-thiadiazol-2-yl)methyl acetate (compound number: NUT-34)

[0110] [Step (a) of Example 10] Preparation of 6-(4-(2,6-dichlorophenoxy)piperidin-1-yl)pyridazine-3-carbohydrazide Methyl 6-(4-(2,6-dichlorophenoxy)piperidin-1-yl)pyridazine-3-carboxylate (750 mg) prepared in Reference Preparation Example 7 and hydrazine monohydrate (4 mL) were reacted and treated according to the method described in Step (a) of Example 1 to give the title compound as a crude product (591 mg, crude yield 79%).

[0111] [Step (b) of Example 10] Preparation of 2-(2-(6-(4-(2,6-dichlorophenoxy)piperidin-1-yl)pyridazine-3-carbonyl)hydrazinyl)2-oxoethyl acetate A portion (382 mg) of the crude product of 6-(4-(2,6-dichlorophenoxy)piperidin-1-yl)pyridazine-3-carbohydrazide prepared in the above step (a), iPr ２ The reaction was carried out according to the method described in step (b) of Example 1 using NEt (210 μL) and acetoxyacetyl chloride (119 μL) to obtain the title compound (271 mg, yield 56%). １ HNMR (500MHz, CDCl ３) δ9.84 (br.s, NH), 8.63 (br.s, NH), 7.95 (d, J = 9.5Hz, 1H), 7.35 (d, J = 8.3Hz, 2H), 7.03-7.00 (m, 2H), 4.76 ( s, 2H), 4.58 (quint., J=5.2Hz, 1H), 4.30-4.25 (m, 2H), 3.71-3.66 (m, 2H), 2.22 (s, 3H), 2.11-2.05 (m, 4H).

[0112] [Step (c) of Example 10] Preparation of (5-(6-(4-(2,6-dichlorophenoxy)piperidin-1-yl)pyridazin-3-yl)-1,3,4-thiadiazol-2-yl)methyl acetate. 2-(2-(6-(4-(2,6-dichlorophenoxy)piperidin-1-yl)pyridazine-3-carbonyl)hydrazinyl)2-oxoethyl acetate (154 mg) prepared in step (b) above and phosphorus pentasulfide (156 mg) were reacted and treated according to the method described in step (c) of Example 1 to give the title compound (45 mg, yield 29%). １ HNMR (500MHz, CDCl ３ ) δ8.18 (d, J=9.6Hz, 1H), 7.33 (dd, J=8.1Hz, 2H), 7.06 (d, J=9.8Hz, 1H), 7.02 (t, J=8.1Hz, 1H), 5.53 (s , 2H), 4.58 (quint., 5.6Hz, 1H), 4.02-4.27 (m, 2H), 3.69-3.64 (m, 2H), 2.19 (s, 3H), 2.11-2.08 (m, 4H).

[0113] Example 11: Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (compound number: NUT-28 (ADI-28))

[0114] [Step (a) of Example 11] Preparation of 4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)benzohydrazide Methyl 4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)benzoate (546 mg) prepared in Reference Preparation Example 8 and hydrazine monohydrate (2 mL) were reacted and treated according to the method described in Step (a) of Example 1 to give the title compound as a crude product (476 mg, crude yield 87%).

[0115] [Step (b) of Example 11] Preparation of 2-(2-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)benzoyl)hydrazinyl)-2-oxoethyl acetate A portion (400 mg) of the crude product of 4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)benzohydrazide prepared in the above step (a), iPr ２ The reaction was carried out according to the method described in step (b) of Example 1 using NEt (143 μL) and acetoxyacetyl chloride (108 μL) to give the title compound (366 mg). １ HNMR (500MHz, CDCl ３ ) δ9.12 (br.s, NH), 8.77 (br.s, NH), 7.75 (d, J=8.6Hz, 2H), 7.33 (dd , J=6.1, 8.8Hz, 1H), 6.92 (d, J=8.8Hz, 2H), 6.72 (dd, J=2.7, 10.3Hz, 1H), 6.66 (dt, J=2.7, 8.8Hz, 1H), 4.72 (s, 2H), 4.61-4.56 (m, 1H), 3. 66-3.61 (m, 2H), 3.43-3.39 (m, 2H), 2.21 (s, 3H), 2.09-1.99 (m, 4H).

[0116] [Step (c) of Example 11] Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate. 2-(2-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)benzoyl)hydrazinyl)-2-oxoethyl acetate (296 mg) prepared in step (b) above, phosphorus pentasulfide (313 mg), and THF (8 mL) were reacted and treated according to the method described in step (c) of Example 1 to give the title compound (258 mg, yield 87%). １ HNMR (500MHz, CDCl ３ ) δ7.86 (d, J=8.8Hz, 2H), 7.33 (dd, J=6.1, 8.8Hz, 1H), 7.00 (d, J=8.8Hz, 1H), 6.73 (dd, J=2.7, 10.3Hz, 1H), 6.67 (dt, J= 2.5, 8.1Hz, 1H), 5.50 (s, 2H), 4.62-4.57 (m, 1H), 3.66-3.61 (m, 2H), 3.43-3.38 (m, 2H), 2.18 (s, 3H), 2.12-2.02 (m, 4H).

[0117] [Example 12] Preparation of (5-(4-(4-(2-chlorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (compound number: NUT-31)

[0118] [Step (a) of Example 12] Preparation of 4-(4-(2-chlorophenoxy)piperidin-1-yl)benzohydrazide Methyl 4-(4-(2-chlorophenoxy)piperidin-1-yl)benzoate (690 mg) prepared in Reference Preparation Example 9 and hydrazine monohydrate (2.5 mL) were reacted and treated according to the method described in Step (a) of Example 1 to give the title compound as a crude product (345 mg, crude yield 48%).

[0119] [Step (b) of Example 12] Preparation of 2-(2-(4-(4-(2-chlorophenoxy)piperidin-1-yl)benzoyl)hydrazinyl)-2-oxoethyl acetate. The crude product (345 mg) of 4-(4-(2-chlorophenoxy)piperidin-1-yl)benzohydrazide prepared in the above step (a), iPr ２ The reaction was carried out according to the method described in step (b) of Example 1 using NEt (210 μL) and acetoxyacetyl chloride (119 μL) to obtain the title compound (248 mg, yield 56%). 1 HNMR (500MHz, CDCl ３ ) δ9.25 (br.s, NH), 8.89 (br.s, NH), 7.75 (d, J = 9.1Hz, 2H), 7.39 (d, J = 7.8Hz, 1H), 7.22 (t, J = 8.3Hz, 1H), 6.99 (d, J = 8.3Hz, 1H) ), 6.95-6.89 (m, 3H), 4.71 (s, 2H), 4.63-4.60 (m, 1H), 3.67-3.63 (m, 2H), 3.41-3.37 (m, 2H), 2.20 (s, 3H), 2.08-1.95 (m, 4H).

[0120] [Step (c) of Example 12] Preparation of (5-(4-(4-(2-chlorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate. 2-(2-(4-(4-(2-chlorophenoxy)piperidin-1-yl)benzoyl)hydrazinyl)-2-oxoethyl acetate (143 mg) prepared in step (b) above, phosphorus pentasulfide (156 mg), and THF (4 mL) were reacted and treated according to the method described in step (c) of Example 1 to give the title compound (76 mg, yield 54%). １ HNMR (500MHz, CDCl ３ ) δ7.85 (d, J=9.1Hz, 2H), 7.40 (dd, J=1.7, 8.1Hz, 1H), 7.00 (dt, J=1.7, 7.6Hz, 1H), 7.01-6.93 (m, 4H), 5.50 (s, 2H), 4.64-4.60 (m, 1H), 3.68-3.63 (m, 2H), 3.41-3.36 (m, 2H), 2.17 (s, 3H), 2.11-2.01 (m, 4H).

[0121] Example 13: Preparation of (5-(4-(4-(2,6-dichlorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (compound number: NUT-32)

[0122] [Step (a) of Example 13] Preparation of 4-(4-(2,6-dichlorophenoxy)piperidin-1-yl)benzohydrazide Methyl 4-(4-(2,6-dichlorophenoxy)piperidin-1-yl)benzoate (734 mg) prepared in Reference Preparation Example 10 and hydrazine monohydrate (2.5 mL) were reacted and treated according to the method described in Step (a) of Example 1 to give the title compound as a crude product (343 mg, crude yield 47%).

[0123] [Step (b) of Example 13] Preparation of 2-(2-(4-(4-(2,6-dichlorophenoxy)piperidin-1-yl)benzoyl)hydrazinyl)-2-oxoethyl acetate. The crude product (340 mg) of 4-(4-(2,6-dichlorophenoxy)piperidin-1-yl)benzohydrazide prepared in the above step (a), iPr ２ The reaction was carried out according to the method described in step (b) of Example 1 using NEt (188 μL) and acetoxyacetyl chloride (106 μL) to obtain the title compound (348 mg, yield 81%). １ HNMR (500MHz, CDCl ３ ) δ9.30 (br.s, NH), 8.96 (br.s, NH), 7.75 (d, J = 9.1Hz, 2H), 7.32 (d, J = 8.1Hz, 2H), 7.00 (t, J = 8.1Hz, 1H), 6.90 (d, J = 9.1H) z, 1H), 4.70 (s, 2H), 4.48 (quint., J=6.4Hz, 1H), 3.85-3.80 (m, 2H), 3.22-3.16 (m, 2H), 2.19 (s, 3H), 2.08-2.05 (m, 4H).

[0124] [Step (c) of Example 13] Preparation of (5-(4-(4-(2,6-dichlorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate. 2-(2-(4-(4-(2,6-dichlorophenoxy)piperidin-1-yl)benzoyl)hydrazinyl)-2-oxoethyl acetate (154 mg) prepared in step (b) above, phosphorus pentasulfide (156 mg), and THF (8 mL) were reacted and treated according to the method described in step (c) of Example 1 to give the title compound (258 mg, yield 52%). １ HNMR (500MHz, CDCl ３ ) δ7.82 (d, J=8.6Hz, 2H), 7.30 (d, J=8.1Hz, 2H), 7.02-6.94 (m, 3H), 5.48 (s, 2H), 4.46 (qui nt., J=5.4Hz, 1H), 3.85-3.79 (m, 2H), 3.21-3.14 (m, 2H), 2.16 (s, 3H), 2.09-2.07 (m, 4H).

[0125] Example 14: Preparation of 2-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-5-butyl-1,3,4-thiadiazole (Compound No. NUT-51 (ADI-51))

[0126] The reaction was carried out according to the method described in step (c) of Example 1 using 4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)benzoyl)hydrazin-1-yl)-N'-pentanoyl hydrazide (50 mg), phosphorus pentasulfide (52 mg), and THF (2 mL) to obtain the title compound (21 mg, yield 43%). １ HNMR (500MHz, CDCl ３) δ7.82 (d, J=7.1Hz, 2H), 7.34-7.31 (m, 1H), 6.97 (d, J=7.6Hz, 2H), 6. 72 (d, J=10.1Hz, 1H), 6.68-6.64 (m, 1H), 4.61-4.54 (m, 1H), 3.63-3.60 (m, 2H), 3.39-3.35 (m, 2H), 3.11 (t, J=7.1Hz, 2H), 2.14-2.03 (m, 4H), 1.80 (quint., J=7.4Hz, 2H), 1.51-1.43 (m, 2H), 0.98 (t, J=7.6Hz, 3H).

[0127] Example 15: Preparation of (5-(6-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)pyridazin-3-yl)-1,3,4-thiadiazol-2-yl)methanol (Compound Number: NUT-11 (ADI-11))

[0128] (5-(6-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)pyridazin-3-yl)-1,3,4-thiadiazol-2-yl)methyl acetate (80 mg) produced in Example 3 was suspended in a mixture of THF (3 mL) and water (3 mL), and lithium hydroxide monohydrate (35 mg) was added, followed by stirring at room temperature for 12 hours. After the reaction, the reaction solution was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dried under reduced pressure to obtain the title product (48 mg, yield 66%). １ HNMR (500MHz, CDCl ３ ) δ8.18 (d, J=9.8Hz, 1H), 7.62 (d, J=7.8Hz, 1H), 7.51 (t, J=8.6Hz, 1H), 7.07-7.03 (m, 3H), 5.13 (s, 2H), 4.86-4.83 (m, 1H), 4.10-4.06 (m, 2H), 3.88-3.82 (m, 2H), 2.11-2.02 (m, 4H).

[0129] Example 16: Preparation of (5-(6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridazin-3-yl)-1,3,4-thiadiazol-2-yl)methanol (Compound Number: NUT-12 (ADI-12))

[0130] The title compound (125 mg, yield 93%) was obtained using (5-(6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridazin-3-yl)-1,3,4-thiadiazol-2-yl)methyl acetate (130 mg) prepared in Example 4 and lithium hydroxide monohydrate (66 mg) in accordance with the method described in Example 15. １ HNMR (500MHz, CDCl ３ ) δ8.18 (d, J=9.5Hz, 1H), 7.35 (dd, J=5.9, 8.8Hz, 1H), 7.07 (d, J=9.8Hz, 1H), 6.74 (dd, J=2.7, 10.0Hz, 1H), 6.68 (dt, J=2.7, 7.8Hz, 1H), 5.14 (s, 2H), 4.69 (quint., J=4.2Hz, 1H), 4.02-3.93 (m, 4H), 2.86 (br.s, OH), 2.08-2.04 (m, 4H).

[0131] Example 17 Preparation of (5-(6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridazin-3-yl)-1,3,4-thiadiazol-2-yl)methyl 3-(5-((3aS,4S,6aR)-2-oxooctahydrocyclopenta[d]imidazol-4-yl)pentanamide)propanoate (Compound Number: NUT-38)

[0132]

[0111] (5-(6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridazin-3-yl)-1,3,4-thiadiazol-2-yl)methanol (60 mg), produced in the same manner as in Example 16, was dissolved in DMF (3 mL), and 3-((tert-butoxycarbonyl)amino)propanoic acid (40 mg), DMAP (26 mg), and EDCI (41 mg) were added, followed by stirring at room temperature for 12 hours. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate) to obtain a condensate (75 mg). This was dissolved in dichloromethane (1 mL), and TFA (150 μL) was added, followed by stirring at room temperature for 6 hours. After the reaction, a saturated aqueous solution of sodium bicarbonate was added to make the reaction solution basic, and then the solution was extracted with dichloromethane. The extract was washed successively with water and saturated brine, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure and then dried under reduced pressure to obtain (5-(6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridazin-3-yl)-1,3,4-thiadiazol-2-yl)methyl 3-aminopropanoate (63 mg). This was dissolved in DMF (1 mL), and Biotin NHS (46 mg) was added thereto, followed by stirring at room temperature for 12 hours. After the reaction, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography (developing solvent: dichloromethane:methanol=95:5) to obtain the title compound (29 mg, yield 34%). １ HNMR (500MHz, CDCl ３) δ8.16 (d, J=9.6Hz, 1H), 7.34 (dd, J=6.2, 8.8Hz, 1H), 7.06 (d, J=9.8Hz, 1H), 6.96 (br.t, 1H), 6.73 (dd, J=2.4, 10. 0Hz, 1H), 6.69-6.66 (m, 1H), 6.51 (br.s, 1H), 5.66 (br.s, 1H), 5.55 (s, 2H), 4.69-4.68 (m, 1H), 4.52-4.50 (m, 1H), 4 .. 32-4.30 (m, 1H), 3.99-3.94 (m, 4H), 3.57-3.54 (m, 2H), 3.15-3.11 (m, 1H), 2.90 (dd, J = 4.6, 12.7Hz, 1H), 2.73 (d, J = 12.9Hz, 1H), 2.70-2.67 (m, 2H), 2.21 (t, J = 7.4Hz, 2H), 2.09-2.01 (m, 4H), 1.72-1.63 (m, 4H), 1.42-1.39 (m, 2H).

[0133] Example 18: Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (Compound Number: NUT-45 (ADI-45))

[0134] The reaction and treatment of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (258 mg) prepared in Example 11 and lithium hydroxide monohydrate (117 mg) were carried out according to the method described in Example 15 to obtain the title compound (190 mg, yield 81%). １ HNMR (400MHz, DMSO-d ６ ) δ7.78 (d, J=8.9Hz, 2H), 7.47 (dd, J=6.2, 8.9Hz, 1H), 7.28 (dd, J=2.8, 11.0Hz, 1H), 7.08 (d, J=9.2Hz, 2H), 6.83 (dt , J=3.0, 8.2Hz, 1H), 4.85-4.80 (m, 3H), 3.65-3.69 (m, 2H), 3.39-3.28 (m, 2H), 2.05-1.98 (m, 2H), 1.78-1.73 (m, 2H).

[0135] Example 19: Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3-thiazol-2-yl)methanol (Compound Number: NUT-63 (ADI-63))

[0136] [Step (a) of Example 19] Preparation of ethyl 2-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)thiazole-4-carboxylate Ethyl 2-(4-bromophenyl)thiazole-4-carboxylate (600 mg) and 4-(2-chloro-5-fluorophenoxy)piperidine (440 mg) were dissolved in 1,4-dioxane (15 mL), and the resulting solution was heated to 100°C for 1 hour. ２ (dpa) ３ (18 mg), Xantphos (28 mg), and cesium carbonate (963 mg) were added and stirred at 100°C for 12 hours. After the reaction, the reaction solution was diluted with water and extracted with ethyl acetate. The extract was washed successively with water and saturated brine and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate:hexane = 1:4) to obtain the title compound (124 mg, yield 14%). １ HNMR (500MHz, CDCl ３ ) δ8.06 (s, 1H), 7.91 (d, J=8.8Hz, 2H), 7.33 (dd, J=6.1, 8.8Hz, 1H), 6.96 (d, J=8.8Hz, 2H), 6.72 (dd, J=2.7, 10.3Hz, 1H), 6.66 (dt, J=2.7 , 7.8Hz, 1H), 4.59-4.55 (m, 1H), 4.45 (q, J=7.1Hz, 2H), 3.64-3.59 ( m, 2H), 3.39-3.34 (m, 2H), 2.13-2.01 (m, 4H), 1.44 (t, J=7.1Hz, 3H).

[0137] [Step (b) of Example 19] Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3-thiazol-2-yl)methanol. Ethyl 2-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)thiazole-4-carboxylate (100 mg) obtained in Step (a) above was dissolved in THF (2 mL), and the reaction solution was cooled to 0°C. LAH (12 mg) was added and stirred at room temperature for 1 hour. After the reaction, the reaction solution was quenched with a 10% aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with saturated saline, and the residue was purified by column chromatography (developing solvent: ethyl acetate:hexane=1:1) and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title product (80 mg, yield 88%). １ HNMR (500MHz, CDCl ３ ) δ7.82 (d, J=8.8Hz, 2H), 7.33 (dd, J=6.1, 8.6Hz, 1H), 7.06 (s, 1H), 6.95 (d, J=8.8Hz, 2H), 6.72 (dd, J=2.7, 10.0Hz, 1H) , 6.66 (dt, J=2.7, 8.1Hz, 1H), 4.80 (s, 2H), 4.57-4.54 (m, 1H), 3.61-3.54 (m, 2H), 3.35-3.30 (m, 2H), 2.10-2.01 (m, 4H).

[0138] Below, from compounds having a B ring such as a thiadiazole group substituted with methanol, "R(C=O)O-CH ２ A generalized scheme for producing a compound having a B ring, such as a thiadiazole group, substituted with a - group is shown below. <Scheme 6> (In the formula, each symbol has the same meaning as defined above.) Details and specific examples of this will be explained with reference to the following Examples 20 to 29.

[0139] Example 20: Preparation of (5-(6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridazin-3-yl)-1,3,4-thiadiazol-2-yl)methyl isobutyrate (Compound Number: NUT-20 (ADI-20))

[0140] (5-(6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridazin-3-yl)-1,3,4-thiadiazol-2-yl)methanol (125 mg) prepared in the same manner as in Example 16 was dissolved in dichloromethane (3 mL), and the reaction solution was cooled to 0° C. and subjected to iPr ２ NEt (78 μL), DMAP (4 mg), and isobutyl chloride (37 μL) were added and stirred at room temperature for 10 hours. After the reaction, the reaction solution was diluted with water and extracted with ethyl acetate. The extract was washed sequentially with saturated brine and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate:hexane = 1:1) to obtain the title compound (92 mg, yield 62%). 1 HNMR (500MHz, CDCl ３ ) δ8.18 (d, J=9.6Hz, 1H), 7.34 (dd, J=6.1, 8.8Hz, 1H), 7.06 (d, J=9 .8Hz, 1H), 6.73 (dd, J=2.7, 10.0Hz, 1H), 6.67 (dt, J=2.7, 8.6Hz, 1H) ), 5.54 (s, 2H), 4.69 (quint., J=4.4Hz, 1H), 4.02-3.93 (m, 4H), 2. 62 (sept., J=6.9Hz, 1H), 2.09-2.02 (m, 4H), 1.23 (d, J=7.1Hz, 6H).

[0141] Example 21: Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl isobutyrate (Compound No. NUT-29 (ADI-29))

[0142] (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (140 mg), prepared in the same manner as in Example 18, iPr ２ The reaction was carried out according to the method described in Example 20 using NEt (81 μL), DMAP (10 mg), and isobutyl chloride (81 μL) to obtain the title compound (148 mg, yield 97%). １HNMR (500MHz, CDCl ３ ) δ7.86 (d, J=8.8Hz, 2H), 7.33 (dd, J=6.4, 8.8Hz, 1H), 6.98 (d, J=8 .8Hz, 2H), 6.73 (dd, J=3.0, 10.3Hz, 1H), 6.69-6.65 (m, 1H), 5.51 (s , 2H), 4.61-4.56 (m, 1H), 3.66-3.61 (m, 2H), 3.42-3.38 (m, 2H), 2.67 (sept., J = 7.1Hz, 1H), 2.12-2.01 (m, 4H), 1.23 (d, J = 6.9Hz, 6H).

[0143] Example 22: Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methylpropionate (Compound No. NUT-46 (ADI-46))

[0144] (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (27 mg), prepared in the same manner as in Example 18, iPr ２ The reaction was carried out according to the method described in Example 20 using NEt (18 μL), DMAP (2 mg), and propionyl chloride (7 μL) to obtain the title compound (24 mg, yield 78%). １ HNMR (500MHz, CDCl ３ ) δ7.85 (d, J=8.6Hz, 2H), 7.33 (dd, J=6.1, 8.6Hz, 1H), 6.97 (d, J=8. 6Hz, 2H), 6.73 (dd, J = 2.7, 10.3Hz, 1H), 6.66 (dt, J = 2.4, 8.6Hz, 1H), 5.51 (s, 2H), 4.61-4.57 (m, 1H), 3.65-3.60 (m, 2H), 3.42-3.37 (m, 2H) H), 2.45 (q, J=7.6Hz, 2H), 2.11-2.00 (m, 4H), 1.20 (t, J=7.6Hz, 3H).

[0145] Example 23: Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl butyrate (Compound Number: NUT-61 (ADI-61))

[0146] (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (27 mg), prepared in the same manner as in Example 18, iPr ２ The reaction was carried out according to the method described in Example 20 using NEt (18 μL), DMAP (2 mg), and butyric acid chloride (7 μL) to obtain the title compound (21 mg, yield 71%). １ HNMR (500MHz, CDCl ３ ) δ7.84 (d, J=8.8Hz, 2H), 7.33 (dd, J=6.1, 8.8Hz, 1H), 6.97 (d, J=9.0Hz, 2 H), 6.72 (dd, J = 2.7, 10.0Hz, 1H), 6.66 (dt, J = 2.7, 8.3Hz, 1H), 5.50 (s, 2H ), 4.59-4.57 (m, 1H), 3.65-3.60 (m, 2H), 3.41-3.37 (m, 2H), 2.40 (t, J=7. 3Hz, 2H), 2.11-2.01 (m, 4H), 1.71 (q, J=7.6Hz, 2H), 0.98 (t, J=7.4Hz, 3H).

[0147] Example 24: Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl pentanoate (Compound No. NUT-47 (ADI-47))

[0148] (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (27 mg), prepared in the same manner as in Example 18, iPr ２ The reaction was carried out according to the method described in Example 20 using NEt (18 μL), DMAP (2 mg), and valeryl chloride (10 μL) to obtain the title compound (26 mg, yield 80%). １HNMR (500MHz, CDCl ３ ) δ7.85 (d, J=8.8Hz, 2H), 7.33 (dd, J=6.1, 8.8Hz, 1H), 6.97 (d, J=8.6Hz, 2H), 6.72 (dd, J=2.7, 10.3Hz, 1H), 6.66 (dt, J=3.0, 8.8Hz, 1H), 5.50 (s, 2H), 4.60- 4.54 (m, 1H), 3.65-3.60 (m, 2H), 3.41-3.37 (m, 2H), 2.42 (t, J=7.4Hz, 2H), 2. 11-1.99 (m, 4H), 1.78-1.63 (m, 2H), 1.40-1.34 (m, 2H), 0.93 (t, J=7.4Hz, 3H).

[0149] Example 25: Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methylcyclobutanecarboxylate (Compound Number: NUT-48 (ADI-48))

[0150] (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (27 mg), prepared in the same manner as in Example 18, iPr ２ The reaction was carried out according to the method described in Example 20 using NEt (18 μL), DMAP (2 mg), and cyclobutanoyl chloride (9 μL) to obtain the title compound (24 mg, yield 75%). １ HNMR (500MHz, CDCl ３ ) δ7.85 (d, J=8.8Hz, 2H), 7.32 (dd, J=6.4, 8.8Hz, 1H), 6.97 (d, J=8.6Hz, 2 H), 6.72 (dd, J = 2.7, 10.3Hz, 1H), 6.66 (dt, J = 2.5, 7.9Hz, 1H), 5.50 (s, 2H ), 4.59-4.57 (m, 1H), 3.65-3.60 (m, 2H), 3.42-3.38 (m, 2H), 3.24 (quint. , J=8.6Hz, 1H), 2.36-2.32 (m, 2H), 2.26-2.24 (m, 2H), 2.09-1.93 (m, 6H).

[0151] Example 26: Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl benzoate (Compound No. NUT-49 (ADI-49))

[0152] (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (27 mg), prepared in the same manner as in Example 18, iPr ２ The reaction was carried out according to the method described in Example 20 using NEt (29 μL), DMAP (2 mg), and benzoyl chloride (16 μL) to obtain the title compound (29 mg, yield 88%). １ HNMR (500MHz, CDCl ３ ) δ8.10 (d, J=8.1Hz, 2H), 7.85 (d, J=8.6Hz, 2H), 7.61 (t, J=7.6Hz, 1H), 7. 48 (t, J=7.8Hz, 2H), 7.32 (dd, J=6.1, 8.6Hz, 1H), 6.96 (d, J=8.6Hz, 2H), 6 .72 (dd, J=2.7, 10.3Hz, 1H), 6.66 (dt, J=2.2, 7.8Hz, 1H), 5.75 (s, 2H), 4. 60-4.56 (m, 1H), 3.65-3.60 (m, 2H), 3.41-3.36 (m, 2H), 2.12-2.00 (m, 4H)

[0153] Example 27 Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methylcyclopropanecarboxylate (Compound Number: NUT-50)

[0154] (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (30 mg), prepared in the same manner as in Example 18, iPr ２ The reaction was carried out according to the method described in Example 20 using NEt (18 μL), DMAP (2 mg), and cyclopropanecarbonyl chloride (8 μL) to obtain the title compound (24 mg, yield 70%).１ HNMR (500MHz, CDCl ３ ) δ7.85 (d, J=8.8Hz, 2H), 7.33 (dd, J=6.1, 8.8Hz, 1H), 6.97 (d, J=9.1 Hz, 2H), 6.72 (dd, J=2.7, 10.3Hz, 1H), 6.68-6.65 (m, 1H), 5.50 (s, 2H) ), 4.62-4.55 (m, 1H), 3.65-3.60 (m, 2H), 3.42-3.37 (m, 2H), 2.10-2.07 (m, 4H), 1.75-1.69 (m, 1H), 1.11-1.08 (m, 2H), 0.98-0.94 (m, 2H).

[0155] Example 28: Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl cyclopentanecarboxylate (Compound Number: NUT-60 (ADI-60))

[0156] (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (27 mg), prepared in the same manner as in Example 18, iPr ２ The reaction was carried out according to the method described in Example 20 using NEt (16 μL), DMAP (2 mg), and cyclopentanecarbonyl chloride (9 μL) to obtain the title compound (25 mg, yield 81%). １ HNMR (500MHz, CDCl ３ ) δ7.85 (d, J=8.6Hz, 2H), 7.33 (dd, J=6.4, 8.8Hz, 1H), 6.97 (d, J=8.8Hz, 2H), 6.73 (dd, J=2.7, 10.3Hz, 1H), 6.66 (dt, J=3.0, 8.1Hz, 1H), 5.50 (s, 2H), 4.60- 4.57 (m, 1H), 3.65-3.60 (m, 2H), 3.42-3.38 (m, 2H), 3.84 (quint, J=7.8Hz, 1H) , 2.11-2.00 (m, 4H), 1.96-1.83 (m, 4H), 1.76-1.71 (m, 2H), 1.64-1.59 (m, 2H).

[0157] Example 29: Preparation of (2-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)thiazol-4-yl)methyl isobutyrate (Compound No. NUT-64 (ADI-64))

[0158] (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (25 mg) prepared in the same manner as in Example 18 was dissolved in dichloromethane (3 mL), and the reaction solution was cooled to 0° C. and subjected to iPr ２ NEt (16 μL), DMAP (2 mg), and isobutyl chloride (8 μL) were added and stirred at room temperature for 10 hours. After the reaction, the reaction solution was diluted with water and extracted with ethyl acetate. The extract was washed sequentially with saturated brine and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate:hexane = 1:2) to obtain the title compound (22 mg, yield 74%). １ HNMR (500MHz, CDCl ３ ) δ7.84 (d, J=8.3Hz, 2H), 7.32 (dd, J=6.1, 8.8Hz, 1H), 7.14 (s, 1H), 6. 96 (d, J=8.6Hz, 2H), 6.72 (dd, J=2.7, 10.1Hz, 1H), 6.68-6.64 (m, 1H), 5.27 (s, 2H), 4.57-4.54 (m, 1H), 3.62-3.57 (m, 2H), 3.36-3.31 (m, 2H) , 2.66 (sept. J = 6.8 Hz, 1H), 2.12-2.00 (m, 4H), 1.22 (d, J = 6.8Hz, 6H).

[0159] A generalized scheme of Example 29 is as follows: <Scheme 7> (In the formula, each symbol has the same meaning as defined above.)

[0160] [Example 30] Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-oxadiazol-2-yl)methyl acetate

[0161] The reaction and treatment was carried out according to the method described in Example 5 using 2-(2-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)benzoyl)hydrazinyl)-2-oxoethyl acetate (200 mg) prepared in step (b) of Example 11 and phosphoryl chloride (4 mL) to obtain the title compound (160 mg, yield 83%). 1 HNMR (500MHz, CDCl ３ ) δ7.92 (d, J=9.1Hz, 2H), 7.32 (dd, J=6.1, 8.8Hz, 1H), 6.98 (d, J=8.8Hz, H), 6.72 (dd, J=3.6, 10.3Hz, 1H), 6.66 (dt, J=2 7, 8.1Hz, 1H), 5.32 (s, 2H), 4.61-4.56 (m, 1H), 3.66-3.61 (m, 2H), 3.44-3.39 (m, 2H), 2.18 (s, 3H), 2.09-2.00 (m, 4H).

[0162] Example 31: Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-oxadiazol-2-yl)methanol (Compound Number: NUT-81 (ADI-81))

[0163] The title compound (101 mg, yield 86%) was obtained by reacting and treating 2-(2-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)benzoyl)hydrazinyl)-2-oxoethyl acetate (130 mg) prepared in step (b) of Example 11 and lithium hydroxide monohydrate (61 mg) according to the method described in Example 15. 1 HNMR (500MHz, CDCl ３ ) δ7.92 (d, J=8.8Hz, 2H), 7.33 (dd, J=6.1, 8.6Hz, 1H), 6.98 (d, J=8.8Hz, H), 6.72 (dd, J=2.7, 10.1Hz, 1H), 6.66 (dt, J=2.9, 8. 1Hz, 1H), 4.92 (d, J=6.6Hz, 2H), 4.60-4.57 (m, 1H), 3.65-3.61 (m, 2H), 3.44-3.40 (m, 2H), 3.11 (br.s, OH), 2.09-1.99 (m, 4H).

[0164] Example 32: Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-oxadiazol-2-yl)methyl isobutyrate (Compound No. NUT-67 (ADI-67))

[0165] (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-oxadiazol-2-yl)methanol (70 mg), prepared in a similar manner to Example 31, ２ The reaction was carried out according to the method described in Example 20 using NEt (45 μL), DMAP (5 mg), and isobutyl chloride (22 μL) to obtain the title compound (68 mg, yield 83%). 1 HNMR (500MHz, CDCl ３ ) δ7.93 (d, J=9.1Hz, 2H), 7.33 (dd, J=6.1, 8.8Hz, 1H), 6.99 (d, J=8.8 Hz, 2H), 6.73 (dd, J=2.7, 10.0Hz, 1H), 6.67 (dt, J=2.7, 8.6Hz, 1H), 5. 33 (s, 2H), 4.61-4.58 (m, 1H), 3.67-3.62 (m, 2H), 3.45-3.40 (m, 2H), 2.68 (sept., J=7.1Hz, 1H), 2.12-1.99 (m, 4H), 1.23 (d, J=6.9Hz, 6H).

[0166] Reference Preparation Example 11: Preparation of methyl 4-(4-(2-methylphenoxy)piperidin-1-yl)benzoate Methyl 4-bromobenzoate (1.0 g), 4-(2-methylphenoxy)piperidine (918 mg), Pd ２ (dpa) ３ (44 mg), Xantphos (69 mg), and cesium carbonate (2.4 g) were used to carry out the reaction and treatment according to the method described in Reference Production Example 8 to obtain the title compound (797 mg, yield 51%). １ HNMR (400MHz, CDCl ３) δ7.93 (d, J=9.1Hz, 2H), 7.18-7.14 (m, 2H), 6.92-6.86 (m, 4H), 4.60-4.55 (m, 1H), 3.88 (s, 3 H), 3.64-3.59 (m, 2H), 3.41-3.35 (m, 2H), 2.25 (s, 3H), 2.11-2.04 (m, 2H), 2.00-1.94 (m, 2H).

[0167] Reference Preparation Example 12: Preparation of methyl 4-(4-(2-fluorophenoxy)piperidin-1-yl)benzoate Methyl 4-bromobenzoate (959 mg), 4-(2-fluorophenoxy)piperidine (870 mg), Pd ２ (dpa) ３ (41 mg), Xantphos (65 mg), and cesium carbonate (2.2 g) were used to carry out the reaction and treatment according to the method described in Reference Production Example 8 to obtain the title compound (1.1 g, yield 77%). １ HNMR (500MHz, CDCl ３ ) δ7.92 (d, J=8.8Hz, 2H), 7.12-7.02 (m, 3H), 6.98-6.95 (m, 1H), 6.90 (d, J=8.8Hz, 2H), 4.53-4.50 (m, 1H), 3.88 (s, 3H), 3.72-3.67 (m, 2H), 3.33-3.28 (m, 2H), 2.10-2.06 (m, 2H), 1.98-1.93 (m, 2H).

[0168] Reference Preparation Example 13: Preparation of methyl 4-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)benzoate. Methyl 4-bromobenzoate (758 mg) and 4-(2-(trifluoromethyl)phenoxy)piperidine (1.2 g) were dissolved in 1,2-dimethoxyethane (18 mL), and the resulting solution was mixed with Pd ２ (dpa) ３ (160 mg), S-phos (144 mg), and tripotassium phosphate (1.6 g) were added and stirred at 80°C for 12 hours. After the reaction, the reaction solution was diluted with water and extracted with ethyl acetate. The extract was washed successively with water and saturated brine and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate:hexane = 1:4) to obtain the title product (334 mg, yield 25%).１ HNMR (500MHz, CDCl ３ ) δ7.92 (d, J=8.8Hz, 2H), 7.59 (d, J=7.9Hz, 1H), 7.48 (t, J=7.6Hz, 1H), 7.02-6.99 (m, 2H), 6.69 (d, J= 8.8Hz, 2H), 4.74-4.69 (m, 1H), 3.86 (s, 3H), 3.59-3.54 (m, 2H), 3.46-3.42 (m, 2H), 2.06-1.99 (m, 4H).

[0169] Reference Preparation Example 14: Preparation of methyl 4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-2-(methoxymethoxy)benzoate. Methyl 4-bromo-2-(methoxymethoxy)benzoate (1.43 g), 2-chloro-5-fluorophenoxy)piperidine (1.0 g), Pd ２ (dpa) ３ (39 mg), Xantphos (62 mg), and cesium carbonate (2.2 g) were used to carry out the reaction and treatment according to the method described in Reference Production Example 8 to obtain the title compound (887 mg, yield 48%). １ HNMR (500MHz, CDCl ３ ) δ7.80 (d, J=8.8Hz, 1H), 7.33 (dd, J=6.2, 8.8Hz, 1H), 6.72 (dd, J=2.7, 10.3Hz, 1H), 6.67-6.57 (m, 2H), 5.25 ( s, 2H), 4.61-4.54 (m, 1H), 3.85 (s, 3H), 3.63-3.59 (m, 2H), 3.54 (s, 3H), 3.41-3.36 (m, 2H), 2.11-1.96 (m, 4H).

[0170] Reference Preparation Example 15: Preparation of methyl 4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-2-methoxybenzoate Methyl 4-bromo-2-methoxybenzoate (1.15 g), 2-chloro-5-fluorophenoxy)piperidine (900 mg), Pd ２ (dpa) ３ (39 mg), Xantphos (62 mg), and cesium carbonate (2.2 g) were used to carry out the reaction and treatment according to the method described in Reference Production Example 8 to obtain the title compound (511 mg, yield 33%). １HNMR (500MHz, CDCl ３ ) δ7.81 (d, J=8.8Hz, 1H), 7.33 (dd, J=6.1, 8.8Hz, 1H), 6.72 (dd, J= 2.7, 10.1Hz, 1H), 6.66 (dt, J=2.7, 8.1Hz, 1H), 6.50 (dd, J=2.2, 8.8 Hz, 1H), 6.41 (d, J=2.2Hz, 1H), 4.60-4.57 (m, 1H), 3.91 (s, 3H), 3.8 5 (s, 3H), 3.65-3.60 (m, 2H), 3.42-3.38 (m, 2H), 2.11-1.98 (m, 4H).

[0171] [Example 33] Preparation of (5-(2-(2-aminoethoxy)-4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (compound number: NUT-39)

[0172] [Step (a) of Example 33] Preparation of 4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-2-(methoxymethoxy)benzohydrazide Methyl 4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-2-(methoxymethoxy)benzoate (887 mg) prepared in Reference Preparation Example 14 and hydrazine monohydrate (2.7 mL) were reacted and treated according to the method described in Step (a) of Example 1 to give the title compound as a crude product (770 mg, crude yield 87%).

[0173] [Step (b) of Example 33] Preparation of 2-(2-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-2-(methoxymethoxy)benzoyl)hydrazinyl)-2-oxoethyl acetate. A portion (700 mg) of the crude product of 4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-2-(methoxymethoxy)benzohydrazide prepared in the above step (a) was added to iPr ２ The reaction was carried out according to the method described in step (b) of Example 1 using NEt (346 μL) and acetoxyacetyl chloride (180 μL) to obtain the title compound (700 mg). １ HNMR (500MHz, CDCl ３) δ10.50 (d, J=6.7Hz, 1H), 9.99 (d, J=7.1Hz, 1H), 8.03 (d, J=8.8Hz, 1H), 7.32 (dd, J=6.1, 8.8Hz, 1H), 6.73-6.64 (m, 4H) ), 5.40 (s, 2H), 4.77 (s, 2H), 4.60-4.55 (m, 1H), 3.64-3.58 (m, 5H), 3.42-3.38 (m, 2H), 2.18 (s, 3H), 2.10-1.98 (m, 4H).

[0174] [Step (c) of Example 33] Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-2-hydroxyphenyl)-1,3,4-thiadiazol-2-yl)methyl acetate 2-(2-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-2-(methoxymethoxy)benzoyl)hydrazinyl)-2-oxoethyl acetate (168 mg) prepared in step (b) above was reacted and treated using THF (25 mL), phosphorus pentasulfide (313 mg), and THF (4 mL) according to the method described in step (c) of Example 1 to give the title compound (67 mg, yield 44%). １ HNMR (300MHz, CDCl ３ ) δ7.60 (d, J=9.4Hz, 0.5H), 7.35-7.30 (m, 1.5H), 6.73-6.56 (m, 4H), 5.46 (s, 1H), 5.33 (s, 1H), 4.63- 4.53 (m, 1H), 3.68-3.60 (m, 2H), 3.46-3.37 (m, 2H), 2.18 (s, 1.5H), 2.17 (s, 1.5H), 2.11-1.93 (m, 4H).

[0175] [Step (d) of Example 33] Preparation of (5-(2-(2-aminoethoxy)-4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-2-hydroxyphenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (64 mg) prepared in step (c) above was dissolved in DMF (3 mL), and tert-butyl (2-bromoethyl)carbamate (36 mg) and potassium carbonate (55 mg) were added, followed by stirring at room temperature for 24 hours. The solution after the reaction was diluted with water and then extracted with ethyl acetate. The extracted solution was washed successively with water and saturated brine, and then dried over magnesium sulfate. The solvent was then evaporated under reduced pressure, and the residue was dissolved in dichloromethane (1 mL). TFA (150 μL) was added and the mixture was stirred at room temperature for 6 hours. After the reaction, saturated aqueous sodium bicarbonate solution was added to make the reaction mixture basic, and the mixture was then extracted with dichloromethane. The extract was washed successively with water and saturated brine, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the mixture was dried under reduced pressure to obtain the title compound (58 mg, yield 83%). １ HNMR (500MHz, CDCl ３ ) δ8.34 (d, J=8.8Hz, 1H), 7.33 (dd, J=5.9, 8.8Hz, 1H), 6.72 (dd, J=2. 7, 10.3Hz, 1H), 6.68-6.65 (m, 2H), 6.48 (d, J=2.2Hz, 1H), 5.50 (s, 2H) ), 4.61-4.58 (m, 1H), 4.21 (t, J=5.2Hz, 2H), 3.65-3.60 (m, 2H), 3.43 -3.38 (m, 2H), 3.28 (t, J=5.2Hz, 2H), 2.16 (s, 3H), 2.10-2.00 (m, 4H).

[0176] Example 34 Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridazin-3-yl)-2-(2-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentamido)ethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (Compound Number: NUT-40)

[0177] (5-(2-(2-aminoethoxy)-4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (55 mg), produced in the same manner as in Example 33, was dissolved in DMF (1 mL), and Biotin NHS (46 mg) was added thereto, followed by stirring at room temperature for 12 hours. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (developing solvent: dichloromethane:methanol=95:5) to obtain the title product (25 mg, yield 32%). １ HNMR (500MHz, CDCl ３ ) δ8.23 (d, J=8.8Hz, 1H), 7.33 (dd, J=6.1, 8.8Hz, 1H), 6.73 (dd, J=2.7, 10.3Hz, 1H), 6.68-6.58 (m, 3H), 5.50 (s, 2H), 4.64-4.58 (m, 1H), 4.43-4.40 (m, 1H), 4.31-4.24 (m, 2H), 4.20-4.16 (m, 1H), 3.80-3.77 (m , 2H), 3.67-3.61 (m, 2H), 3.44-3.40 (m, 2H), 3.05-3.01 (m, 1H), 2.84 (dd, J = 4.9, 12.9Hz, 1H), 2.68 (d, J = 12.9Hz, 1H), 2.36-2.26 (m, 4H), 2.15 (s, 3H), 2.05-2.00 (m, 4H), 1.70-1.58 (m, 4H), 1.43-1.35 (m, 2H).

[0178] [Example 35] Preparation of (5-4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-2-methoxyphenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (compound number: NUT-53)

[0179] [Step (a) of Example 35] Preparation of 4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-2-methoxybenzohydrazide Methyl 4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-2-methoxybenzoate (510 mg) prepared in Reference Preparation Example 15 and hydrazine monohydrate (1.0 mL) were reacted and treated according to the method described in Step (a) of Example 1 to give the title compound as a crude product (500 mg, crude yield 98%).

[0180] [Step (b) of Example 35] Preparation of 2-(2-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-2-methoxybenzoyl)hydrazinyl)-2-oxoethyl acetate. A portion (400 mg) of the crude product of 4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-2-methoxybenzohydrazide prepared in the above step (a), iPr ２ The reaction was carried out according to the method described in step (b) of Example 1 using NEt (262 μL) and acetoxyacetyl chloride (130 μL) to obtain the title compound (182 mg). １ HNMR (500MHz, CDCl ３ ) δ10.4 (d, J=6.9Hz, NH), 9.29 (d, J=6.6Hz, NH), 8.05 (d, J=8.8Hz, 1H), 7.33 (dd, J=5.9, 8.6Hz, 1H), 6.73-6.62 (m, 3H), 6.41 (s, 1H), 4.74 (s, 2H), 4.63-4.58 (m, 1H), 4.03 (s, 3H), 3.65-3.61 (m, 2H), 3.45-3.41 (m, 2H), 2.21 (s, 3H), 2.11-2.01 (m, 4H).

[0181] [Step (c) of Example 35] Preparation of (5-4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-2-methoxyphenyl)-1,3,4-thiadiazol-2-yl)methyl acetate. 2-(2-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-2-methoxybenzoyl)hydrazinyl)-2-oxoethyl acetate (182 mg) prepared in step (b) above, phosphorus pentasulfide (180 mg), and THF (4 mL) were reacted and treated according to the method described in step (c) of Example 1 to give the title compound (33 mg, yield 18%). １ HNMR (500MHz, CDCl ３ ) δ8.35 (d, J=8.8Hz, 1H), 7.33 (dd, J=6.1, 8.8Hz, 1H), 6.73 (dd, J=2.7, 10.3Hz, 1H), 6.68-6.64 (m, 2H), 6.49 (s, 1H), 5.52 (s, 2H), 4.63-4.56 (m, 1H), 4.00 (s, 3H), 3.66-3.61 (m, 2H), 3.43-3.39 (m, 2H), 2.16 (s, 3H), 2.13-2.02 (m, 4H).

[0182] [Example 36] Preparation of (5-4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-2-methoxyphenyl)-1,3,4-thiadiazol-2-yl)methanol (Compound Number: NUT-54)

[0183] The title compound (20 mg, yield 78%) was obtained using (5-4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-2-methoxyphenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (28 mg) prepared in step (c) of Example 35 above and lithium hydroxide monohydrate (6 mg) in accordance with the method described in Example 15. １ HNMR (500MHz, CDCl ３) δ8.29 (d, J=8.8Hz, 1H), 7.33 (dd, J=2.7, 8.8Hz, 1H), 6.72 (dd, J=2.7, 10.0Hz, 1H), 6.68-6.63 (m, 2H), 6.47 ( s, 1H), 5.09 (s, 2H), 4.59-4.57 (m, 1H), 3.97 (s, 3H), 3.64-3.59 (m, 2H), 3.41-3.37 (m, 2H), 2.10-2.02 (m, 4H).

[0184] Example 37: Preparation of 5-(4-(4-phenoxypiperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (Compound Number: NUT-68)

[0185] [Step (a) of Example 37] Preparation of 4-(4-phenoxypiperidin-1-yl)benzohydrazide Methyl 4-(4-phenoxy)piperidin-1-yl)benzoate (800 mg) and hydrazine monohydrate (2.5 mL) were reacted and treated according to the method described in Step (a) of Example 1 to give the title compound as a crude product (482 mg, crude yield 60%).

[0186] [Step (b) of Example 37] Preparation of 2-(2-(4-(4-phenoxypiperidin-1-yl)benzoyl)hydrazinyl)-2-oxoethyl acetate A portion (465 mg) of the crude product of 4-(4-phenoxypiperidin-1-yl)benzohydrazide prepared in the above step (a), iPr ２ The reaction was carried out according to the method described in step (b) of Example 1 using NEt (312 μL) and acetoxyacetyl chloride (194 μL) to give the title compound (466 mg). １ HNMR (500MHz, CDCl ３) δ9.23 (d, J=5.6Hz, 1H), 8.88 (d, J=5.6Hz, 2H), 7.75 (d, 8.6Hz, 2H), 7.3 0 (t, 7.30 (t, J = 7.6 Hz, 2H), 6.97 (t, J = 7.3 Hz, 1H), 6.94 (d, J = 8.6 Hz, 2H), 6.91 (d, J=8.8Hz, 2H), 4.70 (s, 2H), 4.56-4.54 (m, 1H), 3.67-3.62 (m, 2H ), 3.34-3.29 (m, 2H), 2.20 (s, 3H), 2.10-2.06 (m, 2H), 1.97-1.92 (m, 2H).

[0187] [Step (c) of Example 37] Preparation of (5-(4-(4-phenoxypiperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (Compound No.: NUT-69)

[0188] 2-(2-(4-(4-phenoxypiperidin-1-yl)benzoyl)hydrazinyl)-2-oxoethyl acetate (411 mg) produced in step (b) above was dissolved in THF (25 mL), Lawesson's reagent (445 mg) was added, and the mixture was stirred at 80°C for 12 hours. After the reaction, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography (developing solvent: ethyl acetate:hexane=1:1) to obtain the title product (121 mg, yield 29%). １ HNMR (500MHz, CDCl ３ ) δ7.85 (d, J=8.3Hz, 2H), 7.31 (t, J=7.6Hz, 2H), 6.99-6.94 (m, 5H), 5.50 (s, 2H), 4.58-4.53 (m, 1H), 3.67-3.63 (m, 2H), 3.34-3.29 (m, 2H), 2.17 (s, 3H), 2.13-2.08 (m, 2H), 1.98-1.94 (m, 2H).

[0189] [Step (d) of Example 37] Preparation of (5-(4-(4-phenoxypiperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol The (5-(4-(4-phenoxypiperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (100 mg) prepared in Step (c) above and lithium hydroxide monohydrate (51 mg) were reacted and treated according to the method described in Example 15 to give the title compound (88 mg, yield 99%). １ HNMR (500MHz, CDCl ３ ) δ7.84 (d, J=8.8Hz, 2H), 7.31 (t, J=7.6Hz, 1H), 6.98-6.94 (m, 5H), 5.09 (s, 2H), 4.57-4.54 (m, 1 H), 3.67-3.62 (m, 2H), 3.33-3.28 (m, 2H), 2.83 (br.s, OH), 2.12-2.08 (m, 2H), 1.99-1.93 (m, 2H).

[0190] Example 38: Preparation of 5-(4-(4-(2-chlorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (Compound Number: NUT-74)

[0191] The title compound (50 mg, yield 74%) was obtained by reacting (5-(4-(4-(2-chlorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (75 mg) prepared in step (c) of Example 12 and lithium hydroxide monohydrate (36 mg) in accordance with the method described in Example 15. １ HNMR (500MHz, CDCl ３ ) δ7.84 (d, J=8.1Hz, 2H), 7.40 (dd, J=1.5, 7.9Hz, 1H), 7.22 (dt, J=1.3, 8.6Hz, 1H), 7.01-6.92 ( m, 4H), 5.09 (s, 2H), 3.68-3.63 (m, 2H), 3.39-3.35 (m, 2H), 2.82 (br.s, OH), 2.10-2.02 (m, 4H).

[0192] Example 39: Preparation of (5-(4-(4-(2-methylphenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (Compound Number: NUT-75)

[0193] [Step (a) of Example 39] Preparation of 4-(4-(2-methylphenoxy)piperidin-1-yl)benzohydrazide Methyl 4-(4-(2-methylphenoxy)piperidin-1-yl)benzoate (750 mg) prepared in Reference Preparation Example 11 and hydrazine monohydrate (2.5 mL) were reacted and treated according to the method described in Step (a) of Example 1 to give the title compound as a crude product (485 mg, crude yield 65%).

[0194] [Step (b) of Example 39] Preparation of 2-(2-(4-(4-(2-methylphenoxy)piperidin-1-yl)benzoyl)hydrazinyl)-2-oxoethyl acetate. A portion (485 mg) of the crude product of 4-(4-(2-methylphenoxy)piperidin-1-yl)benzohydrazide prepared in the above step (a), iPr ２ The reaction was carried out according to the method described in step (b) of Example 1 using NEt (312 μL) and acetoxyacetyl chloride (194 μL) to obtain the title compound (380 mg). １ HNMR (500MHz, CDCl ３ ) δ9.16 (br.s, NH), 8.80 (br.s, NH), 7.75 (d, J = 8.8Hz, 2H), 7.18-7.15 (m, H), 6.92 (d, J = 9.1Hz, 2H), 6.89-6.86 (m, 2H), 4.72 (s, 2H), 4.59-4.57 (m, 1H), 3.63-3.58 (m, 2H), 3.39-3.35 (m, 2H), 2.25 (s, 3H), 2.21 (s, 3H), 2.09-2.04 (m, 2H), 1.99-1.95 (m, 2H).

[0195] [Step (c) of Example 39] Preparation of (5-(4-(4-(2-methylphenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (Compound No.: NUT-72)

[0196] The reaction and treatment was carried out according to the method described in step (c) of Example 37 using 2-(2-(4-(4-(2-methylphenoxy)piperidin-1-yl)benzoyl)hydrazinyl)-2-oxoethyl acetate (340 mg) prepared in the above step (b) and Lawesson's reagent (355 mg) to obtain the title compound (380 mg, yield 18%). １ HNMR (400MHz, CDCl ３ ) δ7.85 (d, J = 9.0Hz, 2H), 7.18-7.15 (m, 2H), 6.98 (d, J = 9.0Hz, 2H), 6.91-6.87 (m, 2H) 5.50 (s, 2H), 4.60-4.57 ( m, 1H), 3.63-3.58 (m, 2H), 3.40-3.35 (m, 2H), 2.25 (s, 3H), 2.18 (s, 3H), 2.12-2.06 (m, 2H), 2.03-1.96 (m, 2H).

[0197] [Step (d) of Example 39] Preparation of (5-(4-(4-(2-methylphenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol Using 5-(4-(4-(2-methylphenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (60 mg) prepared in Step (c) above and lithium hydroxide monohydrate (30 mg), a reaction was carried out in accordance with the method described in Example 15 to afford the title compound (48 mg, yield 89%). １ HNMR (400MHz, CDCl ３ ) δ7.85 (d, J = 8.2Hz, 2H), 7.18-7.15 (m, 2H), 6.98 (d, J = 8.8Hz, 2H), 6.90-6.87 (m, 2H), 5.09 (s, 2H), 4.60-4.57 (m , 1H), 3.62-3.57 (m, 2H), 3.39-3.33 (m, 2H), 2.63 (br.s, OH), 2.25 (s, 3H), 2.12-2.06 (m, 2H), 2.03-1.96 (m, 2H).

[0198] [Example 40] Preparation of (5-(4-(4-(2-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (Compound Number: NUT-76)

[0199] [Step (a) of Example 40] Preparation of 4-(4-(2-fluorophenoxy)piperidin-1-yl)benzohydrazide Methyl 4-(4-(2-fluorophenoxy)piperidin-1-yl)benzoate (1.0 g) prepared in Reference Preparation Example 12 and hydrazine monohydrate (3.5 mL) were reacted and treated according to the method described in Step (a) of Example 1 to give the title compound as a crude product (510 mg, crude yield 51%).

[0200] [Step (b) of Example 40] Preparation of 2-(2-(4-(4-(2-fluorophenoxy)piperidin-1-yl)benzoyl)hydrazinyl)-2-oxoethyl acetate. A portion (494 mg) of the crude product of 4-(4-(2-fluorophenoxy)piperidin-1-yl)benzohydrazide prepared in the above step (a), iPr ２ The reaction was carried out according to the method described in step (b) of Example 1 using NEt (312 μL) and acetoxyacetyl chloride (194 μL) to give the title compound (537 mg). １ HNMR (500MHz, CDCl ３ ) δ9.09 (br.s, NH), 8.73 (br.s, NH), 7.74 (d, J = 8.8Hz, 2H), 7.12-7.02 (m, 3H), 6.99-6.94 (m, 1H), 6.92 (d, J = 6.9Hz, 2H), 4 .72 (s, 2H), 4.54-4.50 (m, 1H), 3.70-3.66 (m, 2H), 3.33-3.29 (m, 2H), 2.21 (s, 3H), 2.09-2.05 (m, 2H), 1.99-1.92 (m, 2H).

[0201] [Step (c) of Example 40] Preparation of (5-(4-(4-(2-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (Compound No.: NUT-77)

[0202] The reaction and treatment was carried out according to the method described in step (c) of Example 37 using 2-(2-(4-(4-(2-fluorophenoxy)piperidin-1-yl)benzoyl)hydrazinyl)-2-oxoethyl acetate (500 mg) prepared in the above step (b) and Lawesson's reagent (518 mg) to obtain the title compound (130 mg, yield 26%). １ HNMR (500MHz, CDCl ３ ) δ7.84 (d, J=8.8Hz, 2H), 7.13-7.03 (m, 3H), 7.00-6.93 (m, 3H), 5.50 (s, 3H), 4.55-4.49 (m, 1 H), 3.71-3.66 (m, 2H), 3.23-3.27 (m, 2H), 2.17 (s, 3H), 2.12-2.08 (m, 2H), 2.01-1.96 (m, 2H).

[0203] [Step (d) of Example 40] Preparation of (5-(4-(4-(2-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol The 5-(4-(4-(2-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (100 mg) prepared in Step (c) above and lithium hydroxide monohydrate (49 mg) were reacted and treated according to the method described in Example 15 to give the title compound (73 mg, yield 82%). １ HNMR (500MHz, CDCl ３ ) δ7.82 (d, J=8.4Hz, 2H), 7.11-7.01 (m, 3H), 7.03-6.89 (m, 3H), 5.07 (s, 2H), 3.68-3.65 (m, 2H), 3.29-3.25 (m, 2H), 2.12-2.04 (m, 2H), 2.01-1.91 (m, 2H).

[0204] Example 41: Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanamine (Compound Number: NUT-79 (ADI-79))

[0205] [Step (a) of Example 41] Preparation of tert-butyl (2-(2-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)carbonyl)hydrazinyl)-2-oxoethyl)carbamate. 4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)benzohydrazide (1.0 g) prepared in Step (a) of Example 11 and (tert-butoxycarbonyl)glycine (480 mg) were dissolved in DMF (8 mL), and the resulting mixture was diluted with Et ３ N (760 μL) and HATU (1.0 g) were added, and the mixture was stirred at room temperature for 24 hours. The solution after the reaction was diluted with water and extracted with ethyl acetate. The extracted solution was washed successively with water and saturated brine, and then dried over magnesium sulfate. The solvent was then distilled off under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate) to obtain the title compound (1.2 g, yield 85%). １ HNMR (500MHz, CDCl ３ ) δ9.09 (br.s, NH), 8.68 (br.s, NH), 7.74 (d, J=8.8Hz, 2H), 7.33 (dd, J=6. 4, 8.8Hz, 1H), 6.90 (d, J = 8.3Hz, 2H), 6.71 (d, J = 10.3Hz, 1H), 6.67 (dt, J = 2.7, 8.6Hz, 1H), 5.25 (br.d, NH), 4.61-4.54 (m, 1H), 3.98 (d, J=5.6Hz, 2H ), 3.64-3.60 (m, 2H), 3.40-3.37 (m, 2H), 2.11-1.94 (m, 4H), 1.48 (s, 9H).

[0206] [Step (b) of Example 41] Preparation of tert-butyl ((5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl))-1,3,4-thiadiazol-2-yl)methyl)carbamate. The tert-butyl (2-(2-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)carbonyl)hydrazinyl)-2-oxoethyl)carbamate (1.0 g) prepared in step (a) above and Lawesson's reagent (850 mg) were reacted and treated according to the method described in step (c) of Example 37 to afford the title compound (587 mg, yield 59%). １HNMR (500MHz, CDCl ３ ) δ7.83 (d, J=8.8Hz, 2H), 7.33 (t, J=6.6Hz, 1H), 6.97 (d, J=8.6Hz, 2H), 6.72 (d, J=10.0Hz, 1H), 6.67 (t, J=8.3Hz, 1H), 6.30 ( br.s, NH), 4.72 (d, J=5.2Hz, 1H), 4.62-4.52 (m, 1H), 3.68-3.57 (m, 2H), 3.42-3.32 (m, 2H), 2.15-1.97 (m, 4H), 1.49 (s, 9H).

[0207] [Step (c) of Example 41] Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanamine. tert-Butyl ((5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl))-1,3,4-thiadiazol-2-yl)methyl)carbamate (580 mg) prepared in step (b) above was dissolved in dichloromethane (5 mL), and TFA (216 μL) was added, followed by stirring at room temperature for 8 hours. After the reaction, a saturated aqueous solution of sodium bicarbonate was added to make the reaction solution basic, and then the solution was extracted with dichloromethane. The extract was washed successively with water and saturated brine and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dried under reduced pressure to obtain the title compound (339 mg, yield 72%). １ HNMR (500MHz, CDCl ３ ) δ7.81 (d, J=8.8Hz, 2H), 7.31 (t, J=8.6Hz, 1H), 6.95 (d, J=8.6Hz, 2H), 6.71 (d, J=10.3Hz, 1H), 6.64 (dt, J= 2.5, 8.8Hz, 1H), 4.61-4.52 (m, 1H), 4.28 (s, 2H), 3.61-3.57 (m, 2H), 3.42-3.34 (m, 2H), 2.13-1.87 (m, 4H).

[0208] Example 42: Preparation of N-((5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)isobutyramide (Compound Number: NUT-52 (ADI-52))

[0209] (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanamine (42 mg), iPr ２ The reaction was carried out according to the method described in Example 20 using NEt (21 μL) and isobutyl chloride (81 μL) to obtain the title compound (8 mg, yield 17%). １ HNMR (500MHz, CDCl ３ ) δ7.82 (d, J=8.6Hz, 2H), 7.33 (dd, J=6.4, 8.8Hz, 1H), 6.96 (d, J=8.8Hz, 2H), 6.72 (dd, J=2.5, 10.0Hz, 1H), 6.66 (dt, J=2.7, 8.1Hz, 1H), 6.46 (t, J=5.2Hz, NH), 4.83 (d, J = 5.9Hz, 2H), 4.62-4.55 (m, 1H), 3.65-3.60 (m, 2H), 3.41-3.36 (m, 2H), 2.46 (sept, J=6.9Hz, 1H), 2.11-2.00 (m, 4H), 1.20 (d, J=6.9Hz, 6H).

[0210] Example 43: Preparation of N-((5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)aceamide (Compound Number: NUT-80)

[0211] (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanamine (42 mg), which was produced in the same manner as in Example 41, was dissolved in dichloromethane (4.0 mL), and acetic anhydride (11 μL) was added thereto, followed by stirring at room temperature for 12 hours. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate) to obtain the title product (16 mg, yield 35%). １ HNMR (500MHz, CDCl ３) δ7.79 (d, J=8.8Hz, 2H), 7.1 (dd, J=5.9, 8.6Hz, 1H), 6.94 (d, J=8.8Hz, 2H), 6.80 (t, J=5.2Hz, NH), 6.70 (dd, J=2.7, 10.0Hz, 1H), 6.66-6.63 (m, 1H), 4.80 (d, J=5.9Hz, 2H), 4.59-4.53 (m, 1H), 3.63-3.58 (m, 2H), 3.39-3.34 (m, 2H), 2.10-1.99 (m, 7H).

[0212] [Example 44] Preparation of (5-(4-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (compound number: NUT-83)

[0213] [Step (a) of Example 44] Preparation of 4-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)benzohydrazide Methyl 4-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)benzoate (334 g) prepared in Reference Preparation Example 13 and hydrazine monohydrate (1.5 mL) were reacted and treated according to the method described in Step (a) of Example 1 to give the title compound as a crude product (273 mg, crude yield 82%).

[0214] [Step (b) of Example 44] Preparation of 2-(2-(4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)benzoyl)hydrazinyl)-2-oxoethyl acetate. A portion (270 mg) of the crude product of 4-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)benzohydrazide prepared in the above step (a), iPr ２ The reaction was carried out according to the method described in step (b) of Example 1 using NEt (148 μL) and acetoxyacetyl chloride (93 μL) to obtain the title compound (300 mg). １ HNMR (500MHz, CDCl ３) δ9.41 (br.s, NH), 9.12 (br.s, NH), 7.76 (d, J = 8.3Hz, 2H), 7.59 (d, J = 7.4Hz, 1H), 7.48 (t, J = 7.6Hz, 1H), 7.04-7.00 (m, 2H), 6.87 (d, J=8.6Hz, 2H), 4.75-4.69 (m, 1H), 4.68 (s, 2H), 3.58-3.50 (m, 2H), 3.47-3.39 (m, 2H), 2.17 (s, 3H).

[0215] [Step (c) of Example 44] Preparation of (5-(4-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate 2-(2-(4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)benzoyl)hydrazinyl)-2-oxoethyl acetate (300 mg) prepared in step (b) above and Lawesson's reagent (278 mg) were reacted and treated according to the method described in step (c) of Example 37 to give the title compound (168 mg, yield 56%). １ HNMR (500MHz, CDCl ３ ) δ7.85 (d, J=8.6Hz, 2H), 7.60 (d, J=7.8Hz, 1H), 7.50 (t, J=8.1Hz, 1H), 7.03-7.00 (m, 4H), 5.50 ( s, 2H), 4.80-4.71 (m, 1H), 3.59-3.54 (m, 2H), 3.47-3.43 (m, 2H), 2.17 (s, 3H), 2.14-2.03 (m, 4H).

[0216] Example 45: Preparation of (5-(4-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (Compound Number: NUT-82 (ADI-82))

[0217] The title compound (100 mg, yield 74%) was obtained by reacting (5-(4-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (148 mg) prepared in Example 44 and lithium hydroxide monohydrate (65 mg) in accordance with the method described in Example 15. １ HNMR (500MHz, CDCl ３ ) δ7.84 (d, J=8.8Hz, 2H), 7.60 (d, J=7.1Hz, 1H), 7.50 (t, J=7.6Hz, 1H), 7.04-7.00 (m, 2H), 6.97 (d, J=8.8Hz, 2 H), 5.09 (s, 2H), 4.76-4.71 (m, 1H), 3.59-3.53 (m, 2H), 3.46-3.41 (m, 2H), 2.75 (br.s, OH), 2.14-2.01 (m, 2H).

[0218] [Example 46] Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl glycinate hydrochloride (compound number: NUT-88 (ADI-88))

[0219] [Step (a) of Example 46] Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl (tert-butoxycarbonyl)glycinate. (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (80 mg), prepared in the same manner as in Example 18, was dissolved in DMF (3 mL), and (tert-butoxycarbonyl)glycine (57 mg), DMAP (41 mg), and EDCI (61 mg) were added thereto, followed by stirring at room temperature for 24 hours. The solution after the reaction was diluted with water and then extracted with ethyl acetate. The extracted solution was washed successively with water and saturated brine and then dried over magnesium sulfate. The solvent was then distilled off under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate:hexane=1:1) to obtain the title compound (87 mg, yield 79%). １HNMR (500MHz, CDCl ３ ) δ7.83 (d, J=9.1Hz, 2H), 7.32 (dt, J=6.1, 8.8Hz, 1H), 6.97 (d, J=8.8Hz, 2H), 6.72 (dd, J=2.7, 10.3Hz, 1H), 4. 62-4.54 (m, 1H), 4.02 (d, J=5.7Hz, 2H), 3.64-3.60 (m, 2H), 3.42-3.37 (m, 2H), 2.10-2.01 (m, 4H), 1.46 (s, 9H).

[0220] [Step (b) of Example 46] Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl glycinate hydrochloride. A solution of hydrogen chloride in 1,4-dioxane (4 M, 1.0 mL) was added to (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl (tert-butoxycarbonyl)glycinate (87 mg) prepared in Step (a) above, and the mixture was stirred at room temperature for 2 hours. After the reaction, the solvent was evaporated under reduced pressure and the residue was dried under reduced pressure to obtain the title product (76 mg, yield 99%). １ HNMR (500MHz, DMSO-d ６ ) δ8.42 (br.s, 3H), 7.80 (d, J = 8.8Hz, 2H), 7.47 (dd, J = 6.4, 8.3Hz, 1H), 7.28 (d, J = 10.5Hz, 1H), 7.12 (d, J = 8.8Hz, 2H), 6.83 (t, J = 8.1Hz, 1H), 5.65 (s, 2H), 4.86-4.78 (m, 1H), 3.93 (d, J = 5.4Hz, 2H), 3.37-3.33 (m, 4H), 2.08-1.99 (m, 2H), 1.80-1.70 (m, 2H).

[0221] Example 47 Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl L-valine ester hydrochloride (Compound No. NUT-89 (ADI-89))

[0222] [Step (a) of Example 47] Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl (tert-butoxycarbonyl)-L-valine ester. (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (160 mg), prepared in a similar manner to that in Example 18, was dissolved in DMF (6 mL), and (tert-butoxycarbonyl)L-valine (140 mg), DMAP (82 mg), and EDCI (122 mg) were added thereto, followed by stirring at room temperature for 24 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The extracted solution was washed successively with water and saturated brine and then dried over magnesium sulfate. The solvent was then distilled off under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate:hexane=1:1) to obtain the title compound (185 mg, yield 79%). １ HNMR (500MHz, CDCl ３ ) δ7.85 (d, J=8.6Hz, 2H), 7.33 (dt, J=6.4, 8.8Hz, 1H), 6.98 (d, J=8.6Hz, 2H), 6.73 (dd, J=2.5, 1 0.3Hz, 1H), 6.67 (dt, J = 2.5, 7.8Hz, 1H), 5.61 (d, J = 13.0Hz, 1H), 5.52 (d, J = 13.5Hz, 1H), 5.00 ( d, J=8.8Hz, NH), 4.62-4.56 (m, 1H), 4.35-4.30 (m, 1H), 3.67-3.60 (m, 2H), 3.44-3.37 (m, 2H), 2 .25-2.15 (m, 1H), 2.12-1.98 (m, 4H), 1.46 (s, 9H), 0.99 (d, J = 6.9Hz, 3H), 0.91 (d, J = 6.9Hz, 3H).

[0223] [Step (b) of Example 47] Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl L-valine ester hydrochloride. To (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl (tert-butoxycarbonyl)-L-valine ester (185 mg) prepared in Step (a) above was added a solution of hydrogen chloride in 1,4-dioxane (4 M, 2.5 mL), and the mixture was stirred at room temperature for 2 hours. After the reaction, the solvent was evaporated under reduced pressure and the residue was dried under reduced pressure to obtain the title product (150 mg, yield 98%). １ HNMR (500MHz, DMSO-d ６ ) δ8.62 (br.s, 3H), 7.82 (d, J = 8.6Hz, 2H), 7.47 (t, J = 6.9Hz, 1H), 7.28 (d, J = 11.0Hz, 1 H), 7.14 (d, J = 8.1 Hz, 2H), 6.83 (t, J = 8.4 Hz, 1H), 5.72 (d, J = 13.2 Hz, 1H), 5.65 (d, J = 13 .. 4Hz, 1H), 4.85-4.78 (m, 1H), 4.04-3.97 (m, 1H), 3.41-3.33 (m, 2H), 2.27-2.16 (m, 1H) , 2.09-2.00 (m, 2H), 1.82-1.72 (m, 2H), 0.99 (d, J=6.9Hz, 3H), 0.95 (d, J=6.9Hz, 3H).

[0224] Example 48: Preparation of ethyl 2-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)thiazole-4-carboxylate (Compound Number: NUT-62)

[0225] Ethyl 2-(4-bromophenyl)thiazole-4-carboxylate (600 mg), 4-(2-chlorophenoxy)piperidine (440 mg), Pd ２ (dpa) ３ (18 mg), Xantphos (28 mg), and cesium carbonate (963 mg) were used to carry out the reaction and treatment according to the method described in Reference Production Example 8 to obtain the title compound (124 mg, yield 14%). １ HNMR (500MHz, CDCl３ ) δ8.06 (s, 1H), 7.91 (d, J=8.8Hz, 2H), 7.33 (dd, J=6.1, 8.8Hz, 1H), 6.96 (d, J=8.8Hz, 2H), 6.73 (dd, J=2.7, 10.3Hz, 1H), 6.66 (dt, J=7.8 , 10.5Hz, 1H), 4.59-4.55 (m, 1H), 4.44 (q, J=7.1Hz, 2H), 3.64-3.59 ( m, 2H), 3.39-3.34 (m, 2H), 2.13-2.01 (m, 4H), 1.44 (t, J=7.1Hz, 3H).

[0226] [Example 49] Preparation of 2-butyl-5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-2-methoxyphenyl)-1,3,4-thiadiazole (Compound Number: NUT-55)

[0227] [Step (a) of Example 49] Preparation of (4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-2-methoxy)-N'-pentanoylbenzohydrazide. A portion (100 mg) of the crude product of 4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-2-methoxybenzohydrazide prepared in the same manner as in Step (a) of Example 35, iPr ２ The reaction was carried out according to the method described in step (b) of Example 1 using NEt (65 μL) and valeryl chloride (37 μL) to obtain the title compound (70 mg). １ HNMR (500MHz, CDCl ３) δ10.5 (d, J=7.4Hz, NH), 9.11 (br.s, NH), 8.05 (d, J=8.8Hz, 1H), 7.33 (dd, J=6.1, 8.8Hz, 1H ), 6.72 (dd, J=2.7, 10.3Hz, 1H), 6.69-6.65 (m, 1H), 6.61 (d, J=8.8Hz, 1H), 6.41 (s, 1H), 4.62 -4.57 (m, 1H), 4.02 (s, 3H), 3.65-3.60 (m, 2H), 3.43-3.39 (m, 2H), 2.33 (t, J=7.6Hz, 2H), 2.1 1-2.00 (m, 4H), 1.70 (quint., J=7.6Hz, 2H), 1.40 (sext., 7.4Hz, 2H), 0.94 (t, J=7.3Hz, 3H).

[0228] [Step (b) of Example 49] Preparation of 2-butyl-5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-2-methoxyphenyl)-1,3,4-thiadiazole. (4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-2-methoxy)-N'-pentanoylbenzohydrazide (70 mg) prepared in step (a) above, phosphorus pentasulfide (72 mg), and THF (2 mL) were reacted and treated according to the method described in step (c) of Example 1 to give the title compound (14 mg, yield 18%). １ HNMR (500MHz, CDCl ３ ) δ8.32 (d, J=8.8Hz, 1H), 7.33 (dd, J=6.1, 8.8Hz, 1H), 6.73 (dd, J=2.7, 10.3H z, 1H), 6.68-6.65 (m, 2H), 6.50 (s, 1H), 4.62-4.55 (m, 1H), 3.99 (s, 3H), 3.65 -3.60 (m, 2H), 3.41-3.37 (m, 2H), 3.11 (t, J=7.6Hz, 2H), 2.13-2.02 (m, 4H), 1 .82 (quint., J=7.4Hz, 2H), 1.47 (sext., J=7.4Hz, 2H), 0.98 (t, J=7.4Hz, 3H).

[0229] [Example 50] Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-2-methoxyphenyl)-1,3,4-thiadiazol-2-yl)methyl isobutyrate (Compound Number: NUT-56)

[0230] (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-2-methoxyphenyl)-1,3,4-thiadiazol-2-yl)methanol (27 mg), iPr ２ The reaction was carried out according to the method described in Example 20 using NEt (16 μL), DMAP (2 mg), and isobutyl chloride (8 μL) to obtain the title compound (23 mg, yield 75%). １ HNMR (500MHz, CDCl ３ ) δ8.34 (d, J=2.5Hz, 1H), 7.33 (dd, J=6.2, 8.8Hz, 1H), 6.73 (dd, J=2.7, 10.3H z, 1H), 6.68-6.64 (m, 2H), 6.48 (d, J = 2.7, 10.3Hz, 2H), 6.49 (d, J = 2.2Hz, 1H) , 5.53 (s, 2H), 4.62-4.57 (m, 1H), 4.00 (s, 3H), 3.66-3.61 (m, 2H), 3.43-3.39 (m, 2H), 2.66 (sept., J=6.8Hz, 1H), 2.12-2.02 (m, 4H), 1.22 (d, J=6.9Hz, 6H).

[0231] Example 51 Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-2-methoxyphenyl)-1,3,4-thiadiazol-2-yl)methyl benzoate (Compound Number: NUT-57)

[0232] (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-2-methoxyphenyl)-1,3,4-thiadiazol-2-yl)methanol (27 mg), iPr ２The reaction was carried out according to the method described in Example 20 using NEt (16 μL), DMAP (2 mg), and benzoyl chloride (8 μL) to obtain the title compound (25 mg, yield 75%). １ HNMR (500MHz, CDCl ３ ) δ8.37 (d, J=9.0Hz, 1H), 8.10 (d, J=7.6Hz, 2H), 7.60 (t, J=7.3Hz, 1H), 7.4 7 (t, J=7.6Hz, 2H), 7.33 (dd, J=6.2, 8.8Hz, 1H), 6.73 (dd, J=2.7, 10.0Hz, 1 H), 6.68-6.64 (m, 2H), 6.48 (d, J = 2.2Hz, 1H), 5.78 (s, 2H), 4.62-4.55 (m, 1 H), 3.99 (s, 3H), 3.66-3.61 (m, 2H), 3.43-3.39 (m, 2H), 2.12-2.02 (m, 4H).

[0233] Example 52: Preparation of (5-(4-(4-phenoxypiperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl isobutyrate (compound number: NUT-70)

[0234] (5-(4-(4-phenoxypiperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (25 mg), iPr ２ The reaction was carried out according to the method described in Example 20 using NEt (24 μL), DMAP (2 mg), and isobutyl chloride (12 μL) to obtain the title compound (25 mg, yield 77%). １ HNMR (500MHz, CDCl ３ ) δ7.85 (d, J=8.6Hz, 2H), 7.31 (t, J=8.1Hz, 2H), 6.99-6.94 (m, 5H), 5.50 (s, 2H), 4.58-4.51 (m, 1H), 3.67-3.62 (m , 2H), 3.33-3.28 (m, 2H), 2.67 (sept., J = 7.1Hz, 1H), 2.12-2.08 (m, 2H), 1.97-1.95 (m, 2H), 1.23 (d, J = 7.1Hz, 6H).

[0235] [Example 53] Preparation of (5-(4-(4-(2-chlorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl isobutyrate (Compound Number: NUT-71)

[0236] (5-(4-(4-(2-chlorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (26 mg), prepared in a similar manner to Example 38, iPr ２ The reaction was carried out according to the method described in Example 20 using NEt (17 μL), DMAP (2 mg), and isobutyl chloride (8 μL) to obtain the title compound (29 mg, yield 93%). １ HNMR (500MHz, CDCl ３ ) δ7.84 (d, J=9.0Hz, 2H), 7.29 (dd, J=1.5, 7.9Hz, 1H), 7.73-7.20 (m, 1H), 7.01-6.94 (m, 4H), 5.50 (s, 2H), 4.64-4.57 (m, 1H), 3.68-3.63 (m, 2H), 3.39-3.35 (m, 2H), 2.66 (sept., J=6.9Hz, 1H), 2.08-2.01 (m, 4H), 1.22 (d, J=6.9Hz, 6H).

[0237] Example 54: Preparation of (5-(4-(4-(2-methylphenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl isobutyrate (Compound Number: NUT-73)

[0238] (5-(4-(4-(2-methylphenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (25 mg), prepared in a similar manner to Example 39, iPr ２ The reaction was carried out according to the method described in Example 20 using NEt (17 μL), DMAP (2 mg), and isobutyl chloride (8 μL) to obtain the title compound (30 mg, yield 99%). １ HNMR (400MHz, CDCl ３) δ7.85 (d, J = 8.9Hz, 2H), 7.18-7.15 (m, 2H), 6.98 (d, J = 8.9Hz, 2H), 6.90-6.87 (m, 2H), 5.51 (s, 2H), 4.61-4.57 (m, 1H), 3.63-3.58 (m, 2H), 3.40-3.34 (m, 2H), 2.67 (sept., J=8.6Hz, 1H), 2.25 (s, 3H), 2.11-2.07 (m, 2H), 2.02-1.98 (m, 2H), 1.22 (d, J=8.6Hz, 6H).

[0239] Example 55: Preparation of (5-(4-(4-(2-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl isobutyrate (Compound Number: NUT-78)

[0240] (5-(4-(4-(2-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (27 mg), iPr ２ The reaction was carried out according to the method described in Example 20 using NEt (18 μL), DMAP (2 mg), and isobutyl chloride (8 μL) to obtain the title compound (27 mg, yield 84%). １ HNMR (500MHz, CDCl ３ ) δ7.84 (d, J=8.8Hz, 2H), 7.12-7.02 (m, 3H), 6.98-6.96 (m, 2H), 5.50 (s, 2H), 4.53-4.50 (m, 1H), 3.69-3.66 (m, 2 H), 3.31-3.27 (m, 2H), 2.66 (sept., J = 7.1Hz, 1H), 2.11-2.07 (m, 2H), 2.01-1.94 (m, 2H), 1.22 (d, J = 7.1Hz, 6H).

[0241] Example 56: Preparation of (5-(4-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl isobutyrate (Compound No. NUT-84 (ADI-84))

[0242] (5-(4-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (40 mg), prepared in a similar manner to Example 44, iPr ２ The reaction was carried out according to the method described in Example 20 using NEt (18 μL), DMAP (2 mg), and isobutyl chloride (8 μL) to obtain the title compound (42 mg, yield 92%). １ HNMR (500MHz, CDCl ３ ) δ7.85 (d, J=9.0Hz, 2H), 7.60 (d, J=6.9Hz, 1H), 7.49 (t, J=7.8Hz, 1H), 7.03-7.00 (m, 2H), 6.97 (d, J=9.0Hz, 2H), 5.51 (s, 2H), 4.75-4.70 (m, 1H), 3.59-3.54 (m, 2H), 3.46-3.42 (m, 2H), 2.67 (sept., J=7.1Hz, 1H), 2.11-2.20 (m, 4H), 1.22 (d, J=7.1Hz, 6H).

[0243] [Example 57] Preparation of (S)-(5-(4-(3-(2-chloro-5-fluorophenoxy)pyrrolidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (Compound number: NUT-86)

[0244] [Step (a) of Example 57] Preparation of methyl (S)-3-(2-chloro-5-fluorophenoxy)pyrrolidin-1-yl)benzoate Methyl 4-bromobenzoate (720 mg), (S)-3-(2-chloro-5-fluorophenoxy)pyrrolidine (716 mg), Pd ２ (dpa) ３ (30 mg), Xantphos (48 mg), and cesium carbonate (1.6 g) were used and reacted according to the method described in Reference Production Example 8 to obtain the title compound (610 mg, yield 52%). １ HNMR (400MHz, CDCl ３) δ7.93 (d, J=8.9Hz, 2H), 7.32 (dd, J=7.5, 10.9Hz, 1H), 6.72-6.66 (m, 2H), 6.55 (d, J=8.9Hz, 2H), 5.08-5.06 (m, 1H), 3.87 (s, 3H), 3.77 (dd, J=4.8, 11.4Hz, 1H), 3.68-3.55 (m, 3H), 2.46-2.41 (m, 1H), 2.37-2.28 (m, 1H).

[0245] [Step (b) of Example 57] Preparation of (S)-3-(2-chloro-5-fluorophenoxy)pyrrolidin-1-yl)benzohydrazide Methyl (S)-3-(2-chloro-5-fluorophenoxy)pyrrolidin-1-yl)benzoate (610 mg) prepared in the above step (a) and hydrazine monohydrate (2.5 mL) were reacted and treated according to the method described in step (a) of Example 1 to give the title compound as a crude product (402 mg, crude yield 66%).

[0246] [Step (c) of Example 57] Preparation of (S)-2-(2-(4-(3-(2-chloro-5-fluorophenoxy)pyrrolidin-1-yl)benzoyl)hydrazinyl)-2-oxoethyl acetate. A portion (383 mg) of the crude product of (S)-3-(2-chloro-5-fluorophenoxy)pyrrolidin-1-yl)benzohydrazide prepared in the above step (b), iPr ２ The reaction was carried out according to the method described in step (b) of Example 1 using NEt (229 μL) and acetoxyacetyl chloride (140 μL) to obtain the title compound (340 mg). １ HNMR (500MHz, CD ３ OD) δ7.77 (d, J=8.8Hz, 2H), 7.36 (dd, J=5.9, 8.6Hz, 1H), 7.02 (dd, J=2.7, 10.5Hz, 1H), 6.73 (dt, J=3.0, 8.6Hz, 1H), 6.62 (d, J= 8.8Hz, 2H), 5.25-5.21 (m, 1H), 4.70 (s, 2H), 3.76 (dd, J=4.4, 11.8Hz, 1H), 3.57-3.53 (m, 3H), 2.38-2.32 (m, 2H), 2.15 (s, 3H).

[0247] [Step (d) of Example 57] Preparation of (S)-(5-(4-(3-(2-chloro-5-fluorophenoxy)pyrrolidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (S)-2-(2-(4-(3-(2-chloro-5-fluorophenoxy)pyrrolidin-1-yl)benzoyl)hydrazinyl)-2-oxoethyl acetate (340 mg) prepared in step (c) above and Lawesson's reagent (305 mg) were reacted and treated according to the method described in step (c) of Example 37 to give the title compound (380 mg, yield 36%). １ HNMR (500MHz, CDCl ３ ) δ7.84 (d, J=8.8Hz, 2H), 7.33 (dd, J=6.4, 8.8Hz, 1H), 6.72-6.65 (m, 2H), 6.62 (d, J=8.8Hz, 2H), 5.49 (s, 2H), 5.11 -5.07 (m, 1H), 3.79 (dd, J=4.7, 11.3Hz, 1H), 3.67-3.59 (m, 3H), 2.49-2.41 (m, 1H), 2.38-2.30 (m, 1H), 2.17 (s, 3H).

[0248] [Example 58] Preparation of (S)-(5-(4-(3-(2-chloro-5-fluorophenoxy)pyrrolidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (Compound Number: NUT-85)

[0249] (S)-(5-(4-(3-(2-chloro-5-fluorophenoxy)pyrrolidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (45 mg), prepared in a similar manner to Example 57, and lithium hydroxide monohydrate (21 mg) were used for the reaction and treatment according to the method described in Example 15 to obtain the title compound (38 mg, yield 94%). １ HNMR (400MHz, DMSO-d ６) δ7.76 (d, J=8.9Hz, 2H), 7.47 (dd, J=6.2, 8.9Hz, 1H), 7.27 (dd, J=2.8, 1 0.8Hz, 1H), 6.86 (dt, J = 2.8, 8.2Hz, 1H), 6.69 (d, J = 9.0Hz, 2H), 6.15 (t, J = 5.7Hz, OH), 5.37-5.30 (m, 1H), 4.81 (d, J = 6.0Hz, 2H), 3.76 (dd, J = 4.6 , 11.9Hz, 1H), 3.57-3.46 (m, 3H), 2.40-2.31 (m, 1H), 2.28-2.20 (m, 1H).

[0250] [Example 59] Preparation of (S)-(5-(4-(3-(2-chloro-5-fluorophenoxy)pyrrolidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (Compound number: NUT-87)

[0251] (S)-(5-(4-(3-(2-chloro-5-fluorophenoxy)pyrrolidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (26 mg), prepared in a similar manner to Example 58, iPr ２ The reaction was carried out according to the method described in Example 20 using NEt (16 μL), DMAP (2 mg), and isobutyl chloride (8 μL) to obtain the title compound (28 mg, yield 98%). １ HNMR (500MHz, CDCl ３ ) δ 7.84 (d, J = 8.8 Hz, 2H), 7.33 (dd, J = 6.1, 8.6 Hz, 1H), 6.72-6.65 ( m, 3H), 6.62 (d, J=8.8Hz, 2H), 5.45 (s, 2H), 5.11-5.07 (m, 1H), 3.79 (dd, J=5.2, 11.3Hz, 1H), 3.67-3.57 (m, 3H), 2.66 (sept., J=6.9Hz , 1H), 2.48-2.40 (m, 1H), 2.38-2.33 (m, 1H), 1.22 (d, J=6.9Hz, 6H).

[0252] [Example 60] Preparation of (R)-(5-(4-(3-(2-chloro-5-fluorophenoxy)pyrrolidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (Compound number: NUT-91)

[0253] [Example 60, Step (a)] Preparation of methyl (R)-(3-(2-chloro-5-fluorophenoxy)pyrrolidin-1-yl)benzoate Methyl 4-bromobenzoate (1.2 g), (R)-3-(2-chloro-5-fluorophenoxy)pyrrolidine (1.8 g), Pd ２ (dpa) ３ (53 mg), Xantphos (84 mg), and cesium carbonate (2.8 g) were used to react and treat according to the method described in Reference Production Example 8 to obtain the title compound (1.4 g, yield 70%). １ HNMR (500MHz, CDCl ３ ) δ7.98 (d, J=8.8Hz, 2H), 7.32 (dd, J=5.9, 8.6Hz, 1H), 6.72-6.66 (m, 3H), 6.55 (d, J=9.0Hz, 2H), 5.11-5.01 ( m, 1H), 3.87 (s, 3H), 3.77 (dd, J=4.9, 11.5Hz, 1H), 3.68-3.56 (m, 3H), 2.45-2.42 (m, 1H), 2.35-2.31 (m, 1H).

[0254] [Step (b) of Example 60] Preparation of (R)-(3-(2-chloro-5-fluorophenoxy)pyrrolidin-1-yl)benzohydrazide Methyl (R)-3-(2-chloro-5-fluorophenoxy)pyrrolidin-1-yl)benzoate (1.2 g) prepared in the above step (a) and hydrazine monohydrate (5 mL) were reacted and treated according to the method described in step (a) of Example 1 to give the title target product as a crude product (1.2 g, crude yield 99%).

[0255] [Step (c) of Example 60] Preparation of (R)-2-(2-(4-(3-(2-chloro-5-fluorophenoxy)pyrrolidin-1-yl)benzoyl)hydrazinyl)-2-oxoethyl acetate

[0112] A portion (1.2 g) of the crude product of (R)-(3-(2-chloro-5-fluorophenoxy)pyrrolidin-1-yl)benzohydrazide prepared in the above step (b), iPr ２The reaction was carried out according to the method described in step (b) of Example 1 using NEt (687 μL) and acetoxyacetyl chloride (420 μL) to obtain the title compound (680 mg). １ HNMR (500MHz, DMSO-d ６ ) δ10.0 (br.s, NH), 7.73 (d, J=8.8Hz, 2H), 7.46 (dd, J=6.4, 8.8Hz, 1H), 7.25 (dd, J=2.5, 10.8Hz, 1H), 6.84 (dt, J=2.5, 8.3Hz, 1H), 6.60 (d, J=8. 6Hz, 2H), 5.33-5.27 (m, 1H), 4.56 (s, 2H), 3.74 (dd, J=4.4, 11.8Hz, 1H) , 3.49-3.39 (m, 3H), 2.36-2.32 (m, 1H), 2.26-2.20 (m, 1H), 2.10 (s, 3H).

[0256] [Step (d) of Example 60] Preparation of (R)-(5-(4-(3-(2-chloro-5-fluorophenoxy)pyrrolidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (R)-2-(2-(4-(3-(2-chloro-5-fluorophenoxy)pyrrolidin-1-yl)benzoyl)hydrazinyl)-2-oxoethyl acetate (680 mg) prepared in step (c) above and Lawesson's reagent (610 mg) were reacted and treated according to the method described in step (c) of Example 37 to give the title compound (209 mg, yield 31%). １ HNMR (500MHz, CDCl ３ ) δ7.84 (d, J=8.6Hz, 2H), 7.33 (dd, J=6.1, 8.6Hz, 1H), 6.72-6.65 (m, 2H), 6.62 (d, J=8.6Hz, 2H), 5.49 (s, 2H), 5.11 -5.07 (m, 1H), 3.79 (dd, J=4.7, 11.3Hz, 1H), 3.69-3.57 (m, 3H), 2.48-2.43 (m, 1H), 2.38-2.31 (m, 1H), 2.17 (s, 3H).

[0257] Example 61 Preparation of (R)-(5-(4-(3-(2-chloro-5-fluorophenoxy)pyrrolidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (Compound Number: NUT-90)

[0258] (R)-(5-(4-(3-(2-chloro-5-fluorophenoxy)pyrrolidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (200 mg), prepared in a similar manner to Example 60, and lithium hydroxide monohydrate (94 mg) were used in the reaction and treatment according to the method described in Example 15 to obtain the title compound (120 mg, yield 67%). １ HNMR (400MHz, DMSO-d ６ ) δ7.76 (d, J=8.7Hz, 2H), 7.47 (dd, J=6.2, 8.7Hz, 1H), 7.27 (dd, J=2.8, 10 .8Hz, 1H), 6.86 (dt, J=2.7, 8.2Hz, 1H), 6.69 (d, J=8.7Hz, 2H), 6.15 (br.s, OH), 5.35-5.30 (m, 1H), 4.82 (d, J = 4.4Hz, 2H), 3.76 (dd, J = 4.6, 11.9Hz, 1H), 3.55-3.44 (m, 3H), 2.40-2.29 (m, 1H), 2.28-2.19 (m, 1H).

[0259] Example 62: Preparation of (R)-(5-(4-(3-(2-chloro-5-fluorophenoxy)pyrrolidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl isobutyrate (Compound Number: NUT-92)

[0260] (R)-(5-(4-(3-(2-chloro-5-fluorophenoxy)pyrrolidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (41 mg), prepared in the same manner as in Example 61, iPr ２ The reaction was carried out according to the method described in Example 20 using NEt (27 μL), DMAP (2 mg), and isobutyl chloride (12 μL) to obtain the title compound (28 mg, yield 98%). １ HNMR (500MHz, CDCl ３) δ 7.84 (d, J = 8.8 Hz, 2H), 7.33 (dd, J = 6.1, 8.6 Hz, 1H), 6.72-6.65 ( m, 3H), 6.62 (d, J=8.8Hz, 2H), 5.49 (s, 2H), 5.11-5.07 (m, 1H), 3.78 (dd, J=4.7, 11.3Hz, 1H), 3.67-3.58 (m, 3H), 2.66 (sept., J=6.9Hz , 1H), 2.46-2.42 (m, 1H), 2.38-2.30 (m, 1H), 1.22 (d, J=7.1Hz, 6H).

[0261] [Example 63] Preparation of (5-(4-(3-(2-chloro-5-fluorophenoxy)-8-azabicyclo[3,2,1]octan-8-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (compound number: NUT-95)

[0262] [Example 63, Step (a)] Preparation of methyl 4-(3-(2-chloro-5-fluorophenoxy)-8-azabicyclo[3,2,1]octan-8-yl)benzoate Methyl 4-bromobenzoate (1.0 g), 3-(2-chloro-5-fluorophenoxy)-8-azabicyclo[3,2,1]octane (1.2 g), Pd ２ (dpa) ３ (43 mg), Xantphos (68 mg), and cesium carbonate (2.3 g) were used and reacted according to the method described in Reference Production Example 8 to obtain the title compound (510 g, yield 28%). １ HNMR (500MHz, CDCl ３ ) δ7.96 (d, J=8.3Hz, 2H), 7.29-7.20 (m, 1H), 6.86-6.79 (m, 2H), 6.69 (d, J=10.3Hz, 1H), 6. 65 (t, J=7.6Hz, 1H), 4.77-4.69 (m, 1H), 4.48-4.42 (m, 2H), 3.68 (s, 3H), 2.24-1.88 (m, 8H).

[0263] [Step (b) of Example 63] Preparation of (4-(3-(2-chloro-5-fluorophenoxy)-8-azabicyclo[3,2,1]octan-8-yl)phenyl)benzohydrazide Methyl 4-(3-(2-chloro-5-fluorophenoxy)-8-azabicyclo[3,2,1]octan-8-yl)benzoate (510 mg) prepared in the above step (a) and hydrazine monohydrate (2.5 mL) were reacted and treated according to the method described in step (a) of Example 1 to give the title compound as a crude product (372 g, crude yield 73%).

[0264] [Step (c) of Example 63] Preparation of 2-(2-(4-(3-(2-chloro-5-fluorophenoxy)-8-azabicyclo[3,2,1]octan-8-yl)benzoyl)hydrazinyl)-2-oxoethyl acetate. A portion (372 mg) of the crude product of (4-(3-(2-chloro-5-fluorophenoxy)-8-azabicyclo[3,2,1]octan-8-yl)phenyl)benzohydrazide prepared in the above step (b) was added to iPr ２ The reaction was carried out according to the method described in step (b) of Example 1 using NEt (200 μL) and acetoxyacetyl chloride (4124 μL) to obtain the title compound (330 mg). １ HNMR (500MHz, CDCl ３ ) δ9.10 (br.s, NH), 7.79 (8.3Hz, 2H), 6.90-6.80 (m, 2H), 6.69 (d, J = 10.0Hz, 1H), 6.6 5 (t, J=6.4Hz, 1H), 4.72 (s, 2H), 4.48-4.40 (m, 1H), 2.21 (s, 3H), 2.14-1.85 (m, 8H).

[0265] [Step (d) of Example 63] Preparation of (5-(4-(3-(2-chloro-5-fluorophenoxy)-8-azabicyclo[3,2,1]octan-8-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate: 2-(2-(4-(3-(2-chloro-5-fluorophenoxy)-8-azabicyclo[3,2,1]octan-8-yl)benzoyl)hydrazinyl)-2-oxoethyl acetate (330 mg) prepared in step (c) above and Lawesson's reagent (340 mg) were reacted and treated according to the method described in step (c) of Example 37 to give the title compound (133 mg, yield 41%). １ HNMR (500MHz, CDCl ３ ) δ7.94-7.89 (m, 2H), 7.29-7.27 (m, 1H), 6.93-6.86 (m, 2H), 6.70 (d, J = 10.3Hz, 1H), 6.65 (t, J = 8.1Hz, 1H ), 5.51 (s, 2H), 4.74-4.73 (m, 1H), 4.8-4.43 (m, 2H), 2.25-2.20 (m, 2H), 2.18 (s, 3H), 2.13-1.90 (m, 6H).

[0266] [Example 64] Preparation of (5-(4-(3-(2-chloro-5-fluorophenoxy)-8-azabicyclo[3,2,1]octan-8-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (Compound Number: NUT-94)

[0267]

[0111] (5-(4-(3-(2-chloro-5-fluorophenoxy)-8-azabicyclo[3,2,1]octan-8-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (100 mg), prepared in a similar manner to that of Example 63, and lithium hydroxide monohydrate (42 mg) were used for the reaction and treatment according to the method described in Example 15 to obtain the title compound (120 mg, yield 91%). １ HNMR (400MHz, DMSO-d ６) δ7.79 (d, J=8.7Hz, 2H), 7.39 (dd, J=6.4, 9.0Hz, 1H), 7.32 (dd, J=2.8, 11.0Hz, 1H), 6.97 (d, J=8.9Hz, 2H), 6.79 (dt, J=2.8, 8.2H) z, 1H), 6.18 (t, J = 5.7Hz, OH), 5.05-4.94 (m, 1H), 4.84 (d, J = 5.5Hz, 2H), 4.50-4.41 (m, 2H), 2.07-1.93 (m, 6H), 1.67-1.62 (m, 2H).

[0268] [Example 65] Preparation of (5-(4-(3-(2-chloro-5-fluorophenoxy)-8-azabicyclo[3,2,1]octan-8-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl isobutyrate (Compound Number: NUT-96)

[0269] (5-(4-(3-(2-chloro-5-fluorophenoxy)-8-azabicyclo[3,2,1]octan-8-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (40 mg), prepared in a similar manner to Example 64, iPr ２ The reaction was carried out according to the method described in Example 20 using NEt (24 μL), DMAP (2 mg), and isobutyl chloride (11 μL) to obtain the title compound (47 mg, yield 99%). １ HNMR (500MHz, CDCl ３ ) δ7.91 (d, J=7.6Hz, 2H), 7.29-7.27 (m, 1H), 6.88 (d, J=7.8Hz, 2H), 6.70 (d, J=10.0Hz, 1H), 6.65 (t, J=8.1Hz, 1H), 5.5 0 (s, 2H), 4.78-4.70 (m, 1H), 4.48-4.42 (m, 2H), 2.67 (sept., J = 6.8Hz, 1H), 2.25-1.84 (m, 8H), 1.23 (d, J = 7.1Hz, 6H).

[0270] [Example 66] Preparation of (5-(6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)methanol (Compound Number: NUT-97)

[0271] The title compound (80 mg, yield 73%) was obtained using (5-(6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)methyl acetate (120 mg), which was prepared in a similar manner to that of Example 8, and lithium hydroxide monohydrate (52 mg) in accordance with the method described in Example 15. １ HNMR (500MHz, CDCl ３ ) δ8.60 (s, 1H), 8.24-8.16 (m, 1H), 7.34 (dd, J = 6.1, 8.6Hz, 1H), 6.85 (d, J = 7.8Hz, 1H), 6.73 (dd, J = 2.2, 10.1 Hz, 1H), 6.86 (dt, J=2.2, 8.1Hz, 1H), 5.10 (s, 2H), 4.71-4.64 (m, 1H), 3.98-3.84 (m, 4H), 2.11-1.96 (m, 4H).

[0272] Example 67 Preparation of (5-(6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)methyl isobutyrate (Compound Number: NUT-98)

[0273] (5-(6-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)methanol (50 mg), prepared in a similar manner to Example 66, ２ The reaction was carried out according to the method described in Example 20 using NEt (25 μL), DMAP (2 mg), and isobutyl chloride (14 μL) to obtain the title compound (43 mg, yield 73%). １ HNMR (500MHz, CDCl ３) δ8.66 (s, 1H), 8.24-8.09 (m, 1H), 7.34 (dd, J = 6.1, 8.6Hz, 1H), 6.84-6.77 (m, 1H), 6.73 (dd, J = 2.2, 10.1Hz, 1H), 6.68 (dt, J=2.2, 8.9Hz, 1H), 5.52 (s, 2H), 4.69-4.61 (m, 1H), 3.97-3.77 (m, 4H), 2.09-1.97 (m, 8H), 1.23 (d, J=7.1Hz, 6H).

[0274] Example 68: Preparation of ethyl 5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazole-2-carboxylate (Compound Number: NUT-99)

[0275] [Step (a) of Example 68] Preparation of 1-(4-bromophenyl)-4-(2-chloro-5-fluorophenoxy)piperidine 1,4-Dibromobenzene (944 mg), 4-(2-chlorophenoxy)piperidine (1.1 g), Pd ２ (dpa) ３ (37 mg), Xantphos (58 mg), and cesium carbonate (2.6 g) were used to carry out the reaction and treatment according to the method described in Reference Production Example 8 to obtain the title compound (1.3 g, yield 83%). １ HNMR (500MHz, CDCl ３ ) δ, 7.32 (dd, J = 6.4, 8.8 Hz, 1H), 7.11-6.85 (m, 4H), 6.72 (dd, J = 2.7, 10.3 Hz, 1H), 6.94 (dt, J = 2.7, 8.3Hz, 1H), 4.62-4.40 (m, 1H), 3.60-3.28 (m, 2H), 3.23-2.92 (m, 2H), 2.33-1.88 (m, 4H).

[0276] [Step (b) of Example 68] Preparation of 4-(2-chloro-5-fluorophenoxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine. The mixture of 1-(4-bromophenyl)-4-(2-chloro-5-fluorophenoxy)piperidine (prepared in Step (a) above) (769 mg), bis(pinacolato)diboron (559 mg), Pd(dppf)Cl ２(146 mg) and potassium carbonate (589 mg) were reacted without solvent at 110°C for 12 hours with stirring. After the reaction, the mixture was diluted with ethyl acetate and filtered through Celite. The filtrate was diluted with water and extracted with ethyl acetate. The extracted solution was washed successively with water and saturated brine and then dried over magnesium sulfate. The solvent was then distilled off under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate:hexane = 1:9) to obtain the title compound (476 mg, yield 55%). １ HNMR (500MHz, CDCl ３ ) δ7.72 (d, J=7.4Hz, 2H), 7.32 (t, J=7.1Hz, 1H), 6.93 (d, J=6.9Hz, 2H), 6.71 (d, J=10.3Hz, 1H), 6.65 (t, J =6.9Hz, 1H), 4.59-4.48 (m, 1H), 3.66-3.54 (m, 2H), 3.36-3.26 (m, 2H), 2.13-1.95 (m, 4H), 1.34 (s, 12H).

[0277] [Step (c) of Example 68] Preparation of ethyl 5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazole-2-carboxylate. 4-(2-chloro-5-fluorophenoxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (107 mg) prepared in Step (b) above and ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate (130 mg) were dissolved in toluene (1.5 mL) and ethanol (750 μL), and the resulting mixture was treated with Pd(OAc). ２ (7 mg), Xantphos (17 mg), and potassium phosphate (127 mg) were added and stirred at 60°C for 10 hours. After the reaction, the reaction solution was diluted with water and extracted with ethyl acetate. The extract was washed successively with water and saturated brine and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate:hexane = 1:2) to obtain the title compound (96 mg, yield 63%). １ HNMR (500MHz, CDCl ３) δ9.11 (s, 1H), 7.92 (d, J=8.6Hz, 2H), 7.34 (dd, J=6.1, 8.8Hz, 1H) , 7.06-6.95 (m, 2H), 6.73 (dd, J=2.5, 10.3Hz, 1H), 6.67 (dt, J=2.5, 8.3Hz, 1H), 4.62-4.58 (m, 1H), 4.53 (q, J=7.1Hz, 2H), 3.70-3.62 (m , 2H), 3.47-3.42 (m, 2H), 2.19-1.99 (m, 4H), 1.48 (t, J=7.1Hz, 3H).

[0278] Example 69: Preparation of 5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazole-2-carboxylic acid (compound number: NUT-100)

[0279] Ethyl 5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazole-2-carboxylate (20 mg), prepared in a similar manner to Example 68, and lithium hydroxide monohydrate (9 mg) were used for the reaction and treatment according to the method described in Example 15 to obtain the title compound (16 mg, yield 86%). １ HNMR (500MHz, CDCl ３ ) δ9.02 (s, 1H), 7.91 (d, J = 7.6Hz, 2H), 7.34 (t, J = 7.3Hz, 1H), 7.12-6.93 (m, 2H), 6.76 (d, J = 10.3Hz, 1H ), 6.67 (t, J=7.6Hz, 1H), 4.64-4.52 (m, 1H), 3.70-3.57 (m, 2H), 3.46-3.33 (m, 2H), 2.24-1.91 (m, 4H).

[0280] [Example 70] Preparation of (5-(4-(4-((3-chloropyridin-2-yl)oxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (compound number: NUT-101)

[0281] [Step (a) of Example 70] Preparation of methyl (4-(4-(3-chloropyridin-2-yl)oxy)piperidin-1-yl)benzoate Methyl 4-bromobenzoate (1.0 g), 3-chloro-2-(piperidin-4-yloxy)pyridine (993 mg), Pd ２ (dpa) ３ (43 mg), Xantphos (68 mg), and cesium carbonate (2.4 g) were used to carry out the reaction and treatment according to the method described in Reference Production Example 8 to obtain the title compound (1.2 g, yield 74%). １ HNMR (500MHz, CDCl ３ ) δ8.04 (dd, J=1.7, 4.9Hz, 1H), 7.93 (d, J=8.4Hz, 2H), 7.65 (dd, J=1.8, 7.6Hz, 1H), 6.98-6.87 (m, 2H), 6.85 (dd, J=4.9, 7 .6Hz, 1H), 5.47-5.35 (m, 1H), 3.88 (s, 3H), 3.71-3.66 (m, 2H), 3.42-3.38 (m, 2H), 2.20-2.08 (m, 2H), 2.04-1.94 (m, 2H).

[0282] [Step (b) of Example 70] Preparation of (4-(4-(3-chloropyridin-2-yl)oxy)piperidin-1-yl)benzohydrazide Methyl (4-(4-(3-chloropyridin-2-yl)oxy)piperidin-1-yl)benzoate (1.0 g) prepared in the above step (a) and hydrazine monohydrate (2.0 mL) were reacted and treated according to the method described in step (a) of Example 1 to give the title compound as a crude product (659 mg, crude yield 66%).

[0283] [Step (c) of Example 70] Preparation of 2-(2-(4-(4-((3-chloropyridin-2-yl)oxy)piperidin-1-yl)benzoyl)hydrazinyl)-2-oxoethyl acetate. A portion (659 mg) of the crude product of (4-(4-(3-chloropyridin-2-yl)oxy)piperidin-1-yl)benzohydrazide prepared in the above step (b) was added to iPr ２ The reaction was carried out according to the method described in step (b) of Example 1 using NEt (402 μL) and acetoxyacetyl chloride (247 μL) to obtain the title compound (459 mg).１ HNMR (500MHz, DMSO-d ６ ) δ10.1 (br.s, NH), 10.0 (br.s, NH), 8.15-8.11 (m, 1H), 7.89 (d, J = 7.4Hz, 1H), 7.76 (d, J = 8.3Hz, 2H), 7.04-7.01 (m, 3H), 5 .37-5.29 (m, 1H), 4.59 (s, 2H), 3.69-3.61 (m, 2H), 3.40-3.34 (m, 2H), 2.11 (s, 3H), 2.11-2.02 (m, 2H), 1.81-1.72 (m, 2H).

[0284] [Step (d) of Example 70] Preparation of (5-(4-(4-((3-chloropyridin-2-yl)oxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate. 2-(2-(4-(4-((3-chloropyridin-2-yl)oxy)piperidin-1-yl)benzoyl)hydrazinyl)-2-oxoethyl acetate (446 mg) prepared in step (c) above and Lawesson's reagent (404 mg) were reacted and treated according to the method described in step (c) of Example 37 to give the title compound (400 mg, yield 90%). １ HNMR (500MHz, CDCl ３ ) δ8.05-8.04 (m, 1H), 7.86 (d, J = 8.6Hz, 2H), 7.65-7.63 (m, 1H), 7.19 (d, J = 8.3Hz, 1H), 6.90-6.79 (m, 2H) , 5.50 (s, 2H), 3.72-3.59 (m, 2H), 3.52-3.39 (m, 2H), 2.35-2.23 (m, 2H), 2.16 (s, 3H), 2.10-2.01 (m, 2H).

[0285] [Example 71] Preparation of (5-(4-(4-((3-chloropyridin-2-yl)oxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (Compound Number: NUT-102)

[0286] (5-(4-(4-((3-chloropyridin-2-yl)oxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (300 mg), prepared in a similar manner to Example 70, and lithium hydroxide monohydrate (140 mg) were used for the reaction and treatment according to the method described in Example 15 to obtain the title compound (270 mg, yield 99%). １ HNMR (500MHz, DMSO-d ６ ) δ8.15-8.14 (m, 1H), 7.92-7.88 (m, 1H), 7.78 (d, J = 7.1Hz, 2H), 7.09 (d, J = 7.4Hz, 2H), 7.04-7.02 (m, 1H), 6 .24-6.18 (m, 1H), 4.84 (s, 2H), 3.68-3.65 (m, 2H), 3.44-3.38 (m, 2H), 2.12-2.04 (m, 2H), 1.88-1.72 (m, 2H).

[0287] [Example 72] Preparation of (5-(4-(4-((3-chloropyridin-2-yl)oxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl isobutyrate (Compound Number: NUT-103)

[0288] (5-(4-(4-((3-chloropyridin-2-yl)oxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (150 mg), prepared in a similar manner to Example 71, ２ The reaction was carried out according to the method described in Example 20 using NEt (97 μL), DMAP (12 mg), and isobutyl chloride (44 μL) to obtain the title compound (44 mg, yield 25%). １ HNMR (500MHz, CDCl ３) δ8.05-8.04 (m, 1H), 7.85 (d, J = 8.1Hz, 2H), 7.66-7.64 (m, 1H), 7.04-6.98 (m, 2H), 6.87-6.84 (m, 2H), 5.51 (s, 2H), 5.43-5.36 (m, 1 H), 3.73-3.61 (m, 2H), 3.44-3.34 (m, 2H), 2.66 (sept., J = 7.1Hz, 1H), 2.20-2.10 (m, 2H), 2.06-1.96 (m, 2H), 1.22 (d, J = 7.1Hz, 6H).

[0289] [Example 73] Preparation of (5-(4-(4-((3-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (compound number: NUT-104)

[0290] [Example 73, Step (a)] Preparation of methyl (4-(4-(3-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)benzoate Methyl 4-bromobenzoate (1.0 g), 3-trifluoromethyl-2-(piperidin-4-yloxy)pyridine (1.2 g), Pd ２ (dpa) ３ (43 mg), Xantphos (68 mg), and cesium carbonate (2.4 g) were used to carry out the reaction and treatment according to the method described in Reference Production Example 8 to obtain the title compound (854 mg, yield 48%). １ HNMR (500MHz, CDCl ３ ) δ8.31 (d, J=4.2Hz, 1H), 7.94 (d, J=7.8Hz, 2H), 7.88 (d, J=7.3Hz, 1H), 6.99-6.87 (m, 3H), 5.54-5.45 (m, 1H), 3.88 (s, 3H), 3.61-3.57 (m, 2H), 3.49-3.44 (m, 2H), 2.15-1.95 (m, 4H).

[0291] [Step (b) of Example 73] Preparation of (4-(4-(3-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)benzohydrazide Methyl (4-(4-(3-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)benzoate (854 mg) prepared in the above step (a) and hydrazine monohydrate (2.0 mL) were reacted and treated according to the method described in step (a) of Example 1 to give the title compound as a crude product (570 mg, crude yield 54%).

[0292] [Step (c) of Example 73] Preparation of 2-(2-(4-(4-((3-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)benzoyl)hydrazinyl)-2-oxoethyl acetate. A portion (570 mg) of the crude product of 4-(4-(3-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)benzohydrazide prepared in the above step (b) was added to iPr ２ The reaction was carried out according to the method described in step (b) of Example 1 using NEt (313 μL) and acetoxyacetyl chloride (195 μL) to give the title compound (562 mg). １ HNMR (500MHz, CDCl ３ ) δ9.20 (d, J=5.2Hz, NH), 8.93 (br.s, NH), 8.32 (d, J=4.9Hz, 1H), 7.88 (d, J=7.9Hz, 1H), 7.77 (d, J=7.8Hz, 2H), 7.00- 6.97 (m, 3H), 5.55-5.48 (m, 1H), 4.72 (s, 2H), 3.61-3.57 (m, 2H), 3.48-3.46 (m, 2H), 2.20 (s, 3H), 2.16-1.99 (m, 4H).

[0293] [Step (d) of Example 73] Preparation of (5-(4-(4-((3-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate. 2-(2-(4-(4-((3-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)benzoyl)hydrazinyl)-2-oxoethyl acetate (480 mg) prepared in step (c) above and Lawesson's reagent (404 mg) were reacted and treated according to the method described in step (c) of Example 37 to afford the title compound (367 mg, yield 77%). １ HNMR (500MHz, CDCl ３ ) δ8.33 (d, J = 4.0Hz, 1H), 7.97-7.86 (m, 3H), 7.34-7.30 (m, 2H), 7.00 (dd, J = 5.6, 7.3Hz, 1H), 5.60-5.54 (m, 1H), 5.52 (s, 2H), 3.65-3.61 (m, 2H), 3.55-3.52 (m, 2H), 2.46-2.36 (m, 2H), 2.18 (s, 3H), 2.15-2.09 (m, 2H).

[0294] Example 74: Preparation of (5-(4-(4-((3-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (Compound Number: NUT-105)

[0295] (5-(4-(4-((3-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl acetate (280 mg), prepared in a similar manner to Example 73, and lithium hydroxide monohydrate (123 mg) were used for the reaction and treatment according to the method described in Example 15 to obtain the title compound (189 mg, yield 73%). １ HNMR (500MHz, DMSO-d ６) δ8.45 (dd, J=1.3, 4.9Hz, 1H), 8.11 (dd, J=1.5, 7.6Hz, 1H), 7.78 (d, J=8.8Hz, 2H), 7.18 (dd, J=5.2, 7.4Hz, 1H), 7.08 (d, J=9.2Hz, 2H), 5.49-5.42 (m, 1H), 4.84 (s, 2H), 3.58-3.46 (m, 4H), 2.08-2.04 (m, 2H), 1.82-1.78 (m, 2H).

[0296] [Example 75] Preparation of (5-(4-(4-((3-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl isobutyrate (Compound Number: NUT-106)

[0297] (5-(4-(4-((3-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (80 mg), iPr ２ The reaction was carried out according to the method described in Example 20 using NEt (47 μL), DMAP (4 mg), and isobutyl chloride (22 μL) to obtain the title compound (84 mg, yield 92%). １ HNMR (500MHz, CDCl ３ ) δ8.31 (d, J = 4.6Hz, 1H), 7.93-7.83 (m, 3H), 7.04-6.93 (m, 3H), 5.53-5.48 (m, 3H), 3.63-3.52 ( m, 2H), 3.50-3.39 (m, 2H), 2.66 (sept., J=7.1Hz, 1H), 2.15-1.99 (m, 4H), 1.23 (d, J=6.9Hz, 6H).

[0298] Example 76 Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl L-lysine ester hydrochloride (Compound Number: NUT-113)

[0299] Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl (tert-butoxycarbonyl)-L-lysine ester (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (100 mg) was dissolved in DMF (4 mL), and (tert-butoxycarbonyl)L-lysine (141 mg), DMAP (49 mg), and EDCI (76 mg) were added, followed by stirring at room temperature for 24 hours. The solution after the reaction was diluted with water and then extracted with ethyl acetate. The extracted solution was washed successively with water and saturated brine, and then dried over magnesium sulfate. Furthermore, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate:hexane=1:2) to obtain the title compound (135 mg, yield 75%). 1 HNMR (400MHz, CDCl ３ ) δ7.85 (d, J=8.4Hz, 2H), 7.33 (dd, J=6.2, 8.7Hz, 1H), 7.03-6.94 (m, 2H), 6.72 (dd, J=3.0, 10.3Hz, 1H), 6.69-6.64 (m, 1H), 5.60 (d, J = 13.3Hz, 1H), 5.52 (d, J = 13.3Hz, 1H), 5.20-5.09 (m, 1H), 4.64-4.55 (m, 2H), 4.39-4.31 (m, 1H), 3.68-3.60 (m, 2H), 3.44-3.38 (m, 2H), 3.13- 3.09 (m, 2H), 2.14-1.99 (m, 4H), 1.90-1.81 (m, 1H), 1.77-1.67 (m, 1H), 1.52-1.40 (m, 23H).

[0300] [Step (b) of Example 76] To (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl (tert-butoxycarbonyl)-L-lysine ester (135 mg) prepared in Step (a) above, a solution of hydrogen chloride in 1,4-dioxane (4 M, 2.0 mL) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction, the solvent was evaporated under reduced pressure, and the residue was dried under reduced pressure to obtain the title product (95 mg, yield 96%).1 HNMR (500MHz, CD ３ OD) δ8.21-8.04 (m, 2H), 7.77-7.61 (m, 1H), 7.54-7.37 (m, 2H), 7.12-7.05 (m, 1H), 6.80-6.73 (m, 1H), 5.80-5.71 (m, 2H), 4.26-4.18 (m, 1H) , 3.93-3.77 (m, 2H), 3.75-3.57 (m, 2H), 2.95 (t, J=7.1Hz, 2H), 2.46-2 .15 (m, 4H), 2.09-1.93 (m, 2H), 1.78-1.69 (m, 2H), 1.67-1.50 (m, 2H).

[0301] In the following test examples, the compounds (ADI derivatives, NUT compounds) produced above were also used for evaluation.

[0302] Test Example 1: Evaluation of antibacterial effect of compound (ADI derivative) treatment (1) Experimental method RAW 264 (derived from mouse macrophages) cells were used. The cells were cultured at 1.0 x 10 5 The concentration was adjusted to 1.0x10 cells / mL, and 100 μL was seeded into a 96-well plate and incubated overnight at 37°C and 5% CO2. The supernatant was discarded, and Mycobacterium avium was added by vortexing with beads and thoroughly mixed, and then 1.0x10 cells / mL was added. 6 The CFU / mL concentration was adjusted, and 100 μL of the solution was applied to each well and incubated for 4 hours at 37°C in 5% CO2. The supernatant was discarded, and the cell surface was washed twice with room-temperature PBS. After further incubation for 42 hours, the cells were incubated in medium containing the compound (ADI derivative) at the adjusted concentration. As a control, medium containing DMSO without the compound was used. DMEM (high glucose, pyruvate; Life Technologies Japan) was used as the medium. The supernatant was discarded, and the cell surface was washed twice with room-temperature PBS. 100 μL of 0.1% saponin was added, and the plate was incubated on ice for 10 minutes. 100 μL of room-temperature PBS was added, and the plate was centrifuged (3000 rpm, 15 minutes, 4°C). The supernatant was discarded, and 200 μL of 4°C PBS was applied and the cells were suspended and collected with a pipette. A dilution series was prepared, and CFU / mL was counted and evaluated 7 days after the start of incubation.

[0303] (2) Results The results are shown in Figure 1. The results are expressed as the ratio of the number of viable Mycobacterium avium cells obtained using compound-treated macrophage cells to the number of viable Mycobacterium avium cells obtained using compound-untreated cells (DMSO control). The horizontal axis shows the compound (ADI derivative), and the vertical axis shows the CFU / mL ratio (compound / DMSO control). For each compound, the results at a compound concentration of 10 μM were plotted. The results of two experiments for each compound are plotted, and the average value is shown in the center between the plots. The compounds shown in Figure 1 are as follows:"DV9": Compound of Example 1 (NUT-9 (ADI-9)) "DV10": Compound of Example 2 (NUT-10 (ADI-10)) "DV11": Compound of Example 15 (NUT-11 (ADI-11)) "DV12": Compound of Example 16 (NUT-12 (ADI-12)) "DV13": Compound of Example 3 (NUT-13 (ADI-13)) "DV14": Compound of Example 4 (NUT-14 (ADI-14)) "DV20": Compound of Example 20 (NUT-20 (ADI-20)) "DV28": Compound of Example 11 (NUT-28 (ADI-28)) "DV29": Compound of Example 21 (NUT-29 (ADI-29)) "DV33": Compound of Example 9 (NUT-33 (ADI-33)) "DV45": Compound of Example 18 (NUT-45 (ADI-45)) "DV46": Compound of Example 22 (NUT-46 (ADI-46)) "DV47": Compound of Example 24 (NUT-47 (ADI-47)) "DV48": Compound of Example 25 (NUT-48 (ADI-48)) "DV49": Compound of Example 26 (NUT-49 (ADI-49)) "DV51": Compound of Example 14 (NUT-51 (ADI-51)) "DV52": Compound of Example 42 (NUT-52 (ADI-52)) "DV60": Compound of Example 28 (NUT-60 (ADI-60)) "DV61": Compound of Example 23 (NUT-61 (ADI-61)) "DV63": Compound of Example 19 (NUT-63 (ADI-63)) "DV64": Compound of Example 29 (NUT-64 (ADI-64)) "DV67": Compound of Example 32 (NUT-67 (ADI-67)) "DV79": Compound of Example 41 (NUT-79 (ADI-79)) "DV81": Compound of Example 31 (NUT-81 (ADI-81)) "DV82": Compound of Example 45 (NUT-82 (ADI-82)) "DV84": The compound of Example 56 (NUT-84 (ADI-84)).

[0304] Compounds for which the average ratio was 0.5 or less were screened. Compounds (ADI derivatives) selected by this screening, such as ADI-13, 14, 29, 33, 46, 47, 48, 64, 79, and 84, were used in subsequent tests.

[0305] Test Example 2: Evaluation of antibacterial effect by treatment with compounds (ADI derivatives) at various concentrations (1) Experimental method This test example was carried out in the same manner as Test Example 1, except that ADI-13, 14, 29, 33, 46, 47, 48, 64, 79 and 84 were used as test compounds.

[0306] (2) Results The results are shown in Figures 2 to 6 (Figure 2: ADI-13, ADI-14; Figure 3: ADI-29, ADI-33; Figure 4: ADI-46, ADI-47; Figure 5: ADI-48, ADI-64; Figure 6: ADI-79, ADI-84). The results are expressed as the ratio of viable Mycobacterium avium cells obtained using compound-treated macrophage cells to the viable count of the same bacteria obtained using compound-untreated cells (DMSO control). The horizontal axis shows the compound (ADI derivative) concentration (μM), and the vertical axis shows the CFU / mL ratio (compound / DMSO control). For each compound, the results were plotted at compound concentrations of 0.098 μM, 0.195 μM, 0.391 μM, 0.781 μM, 1.563 μM, 3.125 μM, and 6.25 μM. In the graphs showing the results for each compound, the horizontal solid line represents the CFU / mL ratio of the DMSO control, and the vertical dashed line represents the compound concentration that corresponds to that CFU / mL ratio. A decrease in the viable bacterial count in macrophage cells treated with each compound was observed for all compounds, but ADI-29, 46, 47, and 48 in particular showed a concentration-dependent decrease in viable bacterial count upon compound treatment of macrophage cells, thereby demonstrating a more effective bacterial growth inhibitory effect.

[0307] Test Example 3: Evaluation of antibacterial effect against clarithromycin-resistant bacteria by combined treatment with clarithromycin and compounds (ADI derivatives) (1) Experimental method This test example was conducted in the same manner as Test Example 1, except that clarithromycin (CAM)-resistant Mycobacterium avium (CAM_MIC>32 μg / mL) was used as the test bacteria, a total of 200 μL of medium containing 8 μg / mL of CAM and the compound (ADI derivative) with an adjusted concentration was used as the test medium, a medium containing DMSO but without CAM and compound (ADI derivative) was used as the control medium, and ADI-46, 47, and 48 were used as the test compounds.

[0308] (2) Results The results are shown in Figure 7. The results are expressed as a ratio of the number of CAM-resistant bacteria surviving when macrophage cells were treated with CAM and compounds to the number of bacteria surviving when untreated cells (DMSO control) were used. The horizontal axis shows the compound (ADI derivative) concentration (μM), and the vertical axis shows the CFU / mL ratio (compound / DMSO control). For each compound, the results were plotted at compound concentrations of 0 μM, 0.781 μM, and 3.125 μM. Coadministration of 8 μg / mL of CAM with an ADI derivative against CAM-resistant Mycobacterium avium (CAM_MIC > 32 μg / mL) resulted in a concentration-dependent reduction in the number of viable bacteria within macrophage cells. This coadministration to macrophage cells demonstrated an inhibitory effect on the growth of CAM-resistant Mycobacterium avium.

[0309] Test Example 4: Verification of the Effect of Compound (ADI Derivative) Administration on Macrolide-Resistant Mycobacterium avium-Infected Animal Models (1) Experimental Method (1-1) Preparation of Dosing Solutions Each of the ADI derivatives, ADI-29, 45, 46, 47, 48, and 79, was tested. 12 mg of the ADI derivative was dissolved in 3 mL of 0.5 w / v% methylcellulose 400 (Fujifilm Corporation) to prepare a 4 mg / mL stock solution. Since 400 μL of solution was required for one dose, six 500 μL bottles of solution were prepared and stored at -30°C. 12 mg of clarithromycin (CAM, Sigma-Aldrich Japan LLC) was dissolved in 6 mL of DMSO to prepare a 2 mg / mL stock solution. Since 300 μL of solution was required for one dose, fourteen 400 μL bottles of solution were prepared and stored at -30°C. On the day of administration, the mixture was returned to room temperature and then administered.

[0310] (1-2) Preparation of Bacterial Solution: Mycobacterium avium 230 (a macrolide-resistant (clarithromycin-resistant: CAM MIC > 32) clinical isolate) was used. It was cultured on Middlebrook 7H10 agar medium (Nippon Becton Dickinson Co., Ltd.) containing 10% oleic acid albumin dextrose catalase (OADC) for 7 days at 37°C and 5% CO2. It was then subcultured on Middlebrook 7H9 liquid medium (Nippon Becton Dickinson Co., Ltd.) containing 0.5% Tween 80 (Tokyo Chemical Industry Co., Ltd.) and cultured at 37°C for 3–5 days (until the Mycobacterium avium reached the logarithmic phase of growth). The culture was then dispensed into 300 μL aliquots and stored at −80°C. When infecting model animals with the bacteria, a stock of Mycobacterium avium was suspended in Middlebrook 7H9 liquid medium and cultured at 37°C for 3-5 days (until the logarithmic phase of the Mycobacterium avium growth curve). The bacterial suspension was centrifuged at 1690g for 10 minutes (KUBOTA 6200), the supernatant was removed, and the suspension was resuspended in phosphate-buffered saline (PBS, Thermo Fisher Scientific) with glass beads. The concentration of Mycobacterium avium in the suspension was measured using a McFarland turbidimeter to determine a concentration of 1.0 x 10 7 The concentration was adjusted to CFU / mL.

[0311] (1-3) Macrolide-Resistant Mycobacterium avium Infection Model Animals C57BL / 6J mice (Jackson Laboratory Japan) were used as macrolide-resistant Mycobacterium avium infection model animals.

[0312] (1-4) Administration Schedule C57BL / 6J mice were administered Mycobacterium avium solution (1.0 × 10 7 CFU / mL) was administered intratracheally in 100 μL. Starting two weeks after infection, 100 μL of the above-mentioned ADI dosing solution was administered intratracheally under inhalation anesthesia three days a week (ADI-29, 45, 46, 47, 48, and 79 administration groups, n = 3-4). The CAM administration group (n = 3) received 100 μL of the above-mentioned CAM dosing solution once daily forcibly into the stomach using an oral tube. The control group (n = 4) received 100 μL of 0.5 w / v% methylcellulose 400 intratracheally under inhalation anesthesia three days a week. The administration period was two weeks for all groups.

[0313] (1-5) Detection of viable Mycobacterium avium counts in the lungs Two days after the final administration, mice were euthanized, and the left lungs were removed and homogenized with 1 mL of PBS. Serial dilutions were made with PBS and inoculated onto 7H10 agar plates coated with Middlebrook PANTA (a combination antibiotic consisting of polymyxin B, amphotericin B, nalidixic acid, trimethoprim, and azlocillin). Colony counts were performed on day 7, and the viable Mycobacterium avium counts in the lungs were evaluated in terms of colony-forming units (CFU).

[0314] (2) Results The percentage of bacterial inhibition compared to the control group was calculated by dividing the number of viable bacteria in the lungs of the CAM-administered group and the ADI-29, 45, 46, 47, 48, and 79-administered groups by the average number of viable bacteria in the lungs of the control group. The percentage inhibition results for the ADI derivatives are shown in Figure 8 (A: ADI-29, 46, and 79; B: ADI-45, 47, and 48). The horizontal axis represents the type of compound (ADI derivative), and the vertical axis represents the ratio of CFU counts (ADI derivative-administered group / control group) expressed as a percentage (×100%). In the CAM-administered group (not shown) and the ADI-45-administered group, the group average was over 100%, indicating no bacterial growth inhibition effect. In the ADI-29-administered group, the group average was approximately 100%, but this is thought to be due to individual differences, and bacterial growth inhibition was observed in some individuals. In the ADI-46, 47, 48, and 79 groups, the group average was below 100%, demonstrating an inhibitory effect on proliferation. These results indicate that ADI-46, 47, 48, and 79 suppress the number of viable Mycobacterium avium bacteria in the lungs and are effective in treating macrolide-resistant Mycobacterium avium. Although the inhibitory effect of ADI-29 was not clear on group average, a tendency toward inhibition was observed in some individuals due to individual differences, providing evidence supporting its therapeutic efficacy.

[0315] The present invention is not limited to the above-described embodiments, test examples, and examples, and various modifications are possible within the scope of the claims. The technical scope of the present invention also includes embodiments obtained by appropriately combining the technical means disclosed in different embodiments. Furthermore, all academic literature and patent documents described in this specification are incorporated herein by reference.

Claims

A compound represented by the following general formula (I) or a salt thereof: (In the formula, R １ is a halogen atom, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C ３－８ Cycloalkyl group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group, C １－６ Alkylaminoamide group, carboxyl group, amino group, nitro group, C １－６ Alkylthio group, C １－６ Haloalkylthio group, C １－６ Alkylsulfinyl group, C １－６ Haloalkylsulfinyl group, C １－６ Alkylsulfonyl group and C １－６ haloalkylsulfonyl groups; R ２ represents a hydrogen atom, a halogen atom, or C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C ３－８ Cycloalkyl group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group, cyano group, C(=S)NH ２ group, an amide group, or SF ５ It is the basis, R′ and R″ may be the same or different and are each a hydrogen atom, a halogen atom, or C １－６ alkyl groups, and R′ and R″ may be linked to form a bridge to the nitrogen-containing heterocycloalkyl ring; R ３ is a halogen atom, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C ３－８ Cycloalkyl group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group, C １－６ Alkylamino group, C １－６ are independently selected from the group consisting of an alkoxyamino group, a carboxyl group, and an amino group; R ４ is a halogen atom, C １－６ Alkyl group, C １－６ Haloalkyl group, hydroxyl group, hydroxy C １－６ Alkyl group, carboxyl group, C １－６ Alkylamino groups, amino groups and (wherein R is a halogen atom, C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－８ Cycloalkyl group, C １－６ Alkylamino group, C １－６ Haloalkylamino group, C １－６ Alkylamide group, C １－６ a haloalkylamide group or a phenyl group, and the phenyl group is selected from the group consisting of a halogen atom, C １－６ Alkyl group or C １－６ optionally substituted with haloalkyl groups; L is a C group optionally substituted with —O—, —S—, —NH—, or R. １－６ alkylene group, C optionally substituted with R ２－６ alkenylene group, C optionally substituted with R ２－６ an alkynylene group or a chemical bond; X and Y may be the same or different and are N, CH or CR ３ and Ring A is an aromatic hydrocarbon having 5 to 10 carbon atoms or a 5- or 6-membered aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom, Ring B is an aromatic hydrocarbon ring having 5 to 10 carbon atoms or a 5- or 6-membered aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of nitrogen atoms, sulfur atoms, and oxygen atoms, and the heteroatoms include at least one nitrogen atom; p is 0, 1, 2, 3, 4 or 5; q is 0, 1 or 2; r is 0, 1, 2 or 3; When p, q and / or r are 2 or more, 2 or more R １ , R ３ and / or R ４ may form a ring together with the part of the ring which each substitutes, m and n may be the same or different and are 1, 2 or 3; R １ , R ３ and one or more of R may be substituted with biotin or a derivative thereof). 　 The pharmaceutical composition according to claim 1, wherein the bacterial infection is a disease caused by infection with an intracellular parasite. 　 The pharmaceutical composition according to claim 1, characterized in that the bacterial infection is nontuberculous mycobacterial infection. 　 The pharmaceutical composition according to claim 3, wherein the nontuberculous mycobacterial disease is pulmonary MAC disease.

10. The pharmaceutical composition of claim 1, which is administered in combination with an antibacterial agent.

6. The pharmaceutical composition according to claim 5, wherein the antibacterial agent is selected from the group consisting of macrolides, ketolides, aminoglycosides, tetracyclines, doxycycline / minocycline, rifampicin, β-lactams, lincomycins, chloramphenicols, polypeptides, glycopeptides, pyridonecarboxylic acid (quinolones), new quinolones, oxazolidinones, and sulfonamides.

6. The pharmaceutical composition according to claim 5, wherein the antibacterial agent is an antibacterial agent used to treat a disease caused by infection with an intracellular parasite.

8. The pharmaceutical composition according to claim 7, wherein the antibacterial agent is clarithromycin. 　 A compound represented by the following formula or a salt thereof:

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