Pharmaceutical composition for preventing or treating viral infections

Abstract

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

Description

Pharmaceutical composition for preventing or treating viral infections

[0001] The present invention relates to a pharmaceutical composition for preventing or treating viral infections.

[0002] Viral infections affect many people worldwide, and there is a high demand for therapeutic drugs. As examples, influenza virus infection (Non-Patent Document 1), human immunodeficiency virus (HIV) infection (Non-Patent Document 2), and novel coronavirus disease (COVID-19) (Non-Patent Document 3) are described below.

[0003] Influenza, also known as the common cold, is an acute infectious disease caused by influenza viruses. Seasonal influenza, caused by influenza A or B viruses, infects people of all ages and repeatedly spreads around the world. To prevent influenza, vaccines are developed annually to match the prevalent strains. However, vaccine efficacy is not optimal and can be dramatically reduced if there is an antigenic mismatch between the vaccine and the prevalent virus strain. Various antiviral drugs have been developed, including oseltamivir (trade name Tamiflu), zanamivir (trade name Relenza), favipiravir (trade name Avigan), and baloxavir marboxil (trade name Xofluza) (Patent Document 1). Due to factors such as viral antigenic evolution and the acquisition of viral resistance, effective therapeutic agents (including vaccines) are constantly desired.

[0004] Human immunodeficiency virus (HIV) infection can lead to acquired immunodeficiency syndrome (AIDS). Anti-HIV drug treatment is generally performed using a combination therapy (Highly Active Anti-Retroviral Therapy: HAART), but a cure remains difficult, and once antiviral drug treatment is initiated, it must be continued for life.

[0005] The novel coronavirus disease (COVID-19) that emerged in 2019 is caused by human infection with SARS-CoV-2. Since the beginning of 2020, COVID-19 has spread worldwide, resulting in a global pandemic. Symptoms of COVID-19 range from mild to severe, and severe pneumonia can lead to death. Remdesivir (Patent Document 2), a known antiviral drug, has been reported to be effective in treating COVID-19 (Patent Document 3) and has been approved by the U.S. Food and Drug Administration (FDA) as the first therapeutic agent for this viral infection. While other therapeutic agents for COVID-19 have been reported, there remains a high demand for therapeutic agents.

[0006] WO2017 / 104691WO2012 / 012776WO2018 / 169946

[0007] Florian Krammer et al. Nature Reviews Disease Primers (2018),4:3Steven G. Deeks et al. Nature Reviews Disease Primers (2015),1:1Ben Hu et al. Nature Reviews Microbiology (2021),19, 141-154

[0008] The present invention aims to provide a compound exhibiting antiviral effects, and a pharmaceutical for preventing or treating viral infections containing the compound as an active ingredient, as well as 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 １－６Haloalkyl 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 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 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 ３and one or more of R may be substituted with biotin or a derivative thereof). [2] The pharmaceutical composition according to [1], wherein the viral infection is caused by a virus selected from the group consisting of influenza virus, human immunodeficiency virus, and novel coronavirus. [3] The pharmaceutical composition according to [1], wherein the viral infection is administered in combination with an antiviral drug. [4] The pharmaceutical composition according to [3], wherein the antiviral drug is selected from the group consisting of RNA polymerase inhibitors, neuraminidase inhibitors, M2 proton channel inhibitors, endonuclease inhibitors, DNA polymerase inhibitors, reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, adsorption / entry inhibitors, uncoating inhibitors, nucleic acid synthesis inhibitors, protein synthesis inhibitors, release inhibitors, and fusion inhibitors. [5] The pharmaceutical composition according to [4], wherein the antiviral drug is an RNA polymerase inhibitor. [6] 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 antiviral effects, a pharmaceutical for preventing or treating viral infections containing the compound of the present invention as an active ingredient, and a novel compound or a salt thereof.

[0011] Results of antiviral activity tests of NUT67 and NUT29 alone and in the presence of 0.3 μM favipiravir (T-705) (EC 50 1 is a graph showing the results of an anti-HIV activity test of various compounds, and is a graph showing the luciferase activity measured when added at a concentration of 10 μM. 2 is a graph showing the results of an anti-HIV activity test of various compounds, and is a graph showing the luciferase activity measured when added at a concentration of 1 μM.

[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 [6].

[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 ３－８ 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 R′ and R″ may be the same or different and are a hydrogen atom, a halogen atom, or a C１－６ 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 CR ３wherein 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 １－６It 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, C ３－８ a cycloalkyl group, a phenyl group, or C１－６ In yet another embodiment, R ４ The group is C １－６ In yet another embodiment, R ４ The group is hydroxy C １－６ In 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), pharmaceutically acceptable salts can be preferably used.The pharmaceutically acceptable salts are not particularly limited as long as they maintain the efficacy of the active ingredient and do 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 Preventing or Treating Viral Infections] Compounds represented by general formula (I) or salts thereof (collectively referred to as "compounds, etc.") can be used to treat various viral infections. "Treatment" encompasses not only the cure of disease and alleviation of symptoms, but also the suppression of onset, and may also include preventive treatment such as suppressing or preventing viral infection. The present invention provides a pharmaceutical composition for preventing or treating viral infections containing a compound represented by general formula (I) or a salt thereof ("compound, etc."). The antiviral effect of the compounds of the present invention can be confirmed by antiviral activity tests commonly used for the target virus. For example, antiviral activity can be confirmed for influenza virus, human immunodeficiency virus (HIV), and novel coronavirus (SARS-CoV-2) using the methods described in the Examples below. The antiviral effect can be confirmed, for example, by a reduction in virus-infected cells, a reduction in the amount of viral protein or nucleic acid, or the like, resulting from administration of the compounds, etc. The pharmaceutical compositions of the present invention are useful for the cure of disease that has developed after viral infection, the alleviation of symptoms, and the suppression of onset, or the suppression or prevention of viral infection. The pharmaceutical composition of the present invention can be used for the prevention or treatment of various viral infections.

[0040] Viral infections for which the pharmaceutical compositions of the present invention can be used include, for example, those caused by intracellularly infectious viruses. Examples of intracellularly infectious viruses include, but are not limited to, respiratory syncytial virus (RSV), influenza virus, parainfluenza virus, hepatitis C virus (HCV), hepatitis A virus (HAV), hepatitis B virus (HBV), Ebola virus, cytomegalovirus, adenovirus, poliovirus, Japanese encephalitis virus, measles virus, mumps virus, rubella virus, rabies virus, yellow fever virus, varicella-zoster virus, hantavirus, dengue virus, norovirus, rotavirus, parvovirus, coronavirus, novel coronavirus (SARS-CoV-2), distemper virus, adult T-cell leukemia virus (HTLV-1), human immunodeficiency virus (HIV), herpesvirus, and papillomavirus. In one embodiment, the viral infection is caused by a virus selected from the group consisting of influenza virus, human immunodeficiency virus, and novel coronavirus.

[0041] 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.

[0042] 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.

[0043] 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.).

[0044] 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.

[0045] The pharmaceutical compositions of the present invention may be administered in combination with an antiviral agent.

[0046] The pharmaceutical composition of the present invention and the antiviral drug may be administered to a subject simultaneously or at staggered times, and the order of administration does not matter. As used herein, "combination" or "administered in combination" means that the pharmaceutical composition of the present invention and the antiviral drug are administered to a subject, and does not necessarily mean that they are administered simultaneously. The pharmaceutical composition of the present invention and the antiviral drug may be administered separately, or they may be administered as a combined drug. The dosage of the antiviral drug may conform to a dosage used clinically and can be appropriately selected depending on the subject, age and weight of the subject, symptoms, administration time, dosage form, administration method, combination, etc.

[0047] The antiviral drug is, but is not limited to, a drug selected from the group consisting of RNA polymerase inhibitors, neuraminidase inhibitors, M2 proton channel inhibitors, endonuclease inhibitors, DNA polymerase inhibitors, reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, adsorption / invasion inhibitors, uncoating inhibitors, nucleic acid synthesis inhibitors, protein synthesis inhibitors, release inhibitors, and fusion inhibitors. Examples of such antiviral drugs include remdesivir (Veklury) and favipiravir (Avigan) as RNA polymerase inhibitors; zanamivir (Relenza), oseltamivir (Tamiflu), peramivir (Rapiacta), and laninamivir (Inavir) as neuraminidase inhibitors; amantadine (Symmetrel) as an M2 proton channel inhibitor; and baloxavir as an endonuclease inhibitor. Marboxil (Xofluza); DNA polymerase inhibitor, acyclovir (Zopirax); reverse transcriptase inhibitors, zidovudine and lamivudine combination preparation (Combivir), abacavir (Ziagen), tenofovir (Viread), abacavir and lamivudine combination preparation (Epzicom), tenofovir (tenofovir disoproxil fumarate: TDF) and emtricitabine combination preparation (Truvada), tenofovir Combination preparations of alafenamide fumarate (TAF) and emtricitabine (FTC) (Descovy), efavirenz, and rilpivirine; protease inhibitors include ritonavir (Norvir), pinavir and ritonavir combination (Kaletra), darunavir (Prezista), fosamprenavir (Lexiva), atazanavir (Reyataz), darunavir and cobicistat combination (Prezicobix), nilmatrervir, and ensitrervir (Zocova); and Integra. As enzyme inhibitors, raltegravir (Isentress), dolutegravir (Tevicay), cabotegravir (Vocabria); as adsorption / penetration inhibitors, maraviroc (Celsentri), enfuvirtide (Fuseon); as uncoating inhibitors, symmetrel, amantadine hydrochloride; as nucleic acid synthesis inhibitors, valacyclovir, famciclovir, remdesivir (Veklury), monurpiravir (Lagebrio); as protein synthesis inhibitors, ritonavir, lopiavir;Release inhibitors include oseltamivir (Tamiflu), zanamivir (Relenza), and peramivir (Rapiacta); and fusion inhibitors include nafamostat, amantadine, enfuvirtide (Fuseon), and maraviroc (CelCentri) (the names in parentheses are trade names). In one embodiment, the antiviral drug is an RNA polymerase inhibitor.

[0048] Any type of antiviral drug may be used as long as it can be used to treat the target viral infection. For example, antiviral drugs for influenza include, but are not limited to, favipiravir (Avigan), zanamivir (Relenza), oseltamivir (Tamiflu), peramivir (Rapiacta), laninamivir (Inavir), and baloxavir marboxil (Xofluza) (the names in parentheses are trade names). Antiviral drugs for HIV infection include, but are not limited to, reverse transcriptase inhibitors (RTIs) (nucleoside reverse transcriptase inhibitors (NRTIs) such as zidovudine, lamivudine, tenofovir, etc.; non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as efavirenz and rilpivirine), protease inhibitors (PIs) (ritonavir, darunavir, etc.), integrase inhibitors (INSTIs) (raltegravir, dolutegravir, etc.), and adsorption / entry inhibitors (maraviroc, etc.). Antiviral drugs for COVID-19 include, but are not limited to, remdesivir (Veklury), monurpiravir (Lagebrio), nilmatrellvir / ritonavir (Paquilobid), and ensitrellvir (Zocova) (the names in parentheses are trade names).

[0049] The combined administration of the pharmaceutical composition of the present invention with an antiviral drug can enhance the efficacy of treating infectious diseases due to their combined effects, and such combined administration is also useful for treating infectious diseases caused by viruses that have acquired drug resistance.

[0050] Furthermore, the pharmaceutical composition of the present invention may be administered in combination with an agent other than an antiviral agent used to treat viral infections, with or without an antiviral agent, so long as the effect of the pharmaceutical composition or its component compounds is not impaired. Examples of such agents include, but are not limited to, neutralizing antibody drugs and anti-inflammatory drugs. The dosage of such agents may conform to clinically used dosages and can be appropriately selected depending on the recipient, age and weight of the recipient, symptoms, administration time, dosage form, administration method, combination, etc.

[0051] The present invention includes the following inventions: (1) A method for treating a viral 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 viral 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 antiviral drug. (3) A compound represented by general formula (I) or a salt thereof for use in the prevention or treatment of a viral infection. (4) A combination of a compound represented by general formula (I) or a salt thereof and an antiviral drug for use in the prevention or treatment of a viral infection. (5) A kit for preventing or treating a viral infection, comprising a compound represented by general formula (I) or a salt thereof and an antiviral drug, which are contained in separate containers and, if necessary, further comprising an instruction manual. (6) Use of a compound represented by general formula (I) or a salt thereof for producing a medicament for preventing or treating a viral infection. (7) Use of a compound represented by general formula (I) or a salt thereof and an antiviral drug for producing a medicament for preventing or treating a viral infection. (8) An antiviral agent containing a compound represented by general formula (I) or a salt thereof. (9) A compound represented by general formula (I) or a salt thereof, a composition or formulation containing the compound or the salt thereof, and a method for producing the same.

[0052] 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

[0053] [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.

[0054] <Scheme 1> (In the formula, each symbol has the same meaning as defined above.)

[0055] 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.

[0056] [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).

[0057] 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.)

[0058] 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).

[0059] [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).

[0060] [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%).

[0061] [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).

[0062] 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).

[0063] 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).

[0064] 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.

[0065] 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.)

[0066] [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).

[0067] 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).

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] Example 1: Preparation of 2-(6-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)pyridazin-3-yl)-5-methyl-1,3,4-thiadiazole (Compound Number: NUT-9)

[0073] [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.

[0074] [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).

[0075] [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).

[0076] 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)

[0077] [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%).

[0078] [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).

[0079] [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).

[0080] 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)

[0081] [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).

[0082] [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).

[0083] 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))

[0084] [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).

[0085] [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).

[0086] 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)

[0087] 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).

[0088] 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.)

[0089] 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)

[0090] [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%).

[0091] [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).

[0092] [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).

[0093] [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

[0094] [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)

[0095] [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%).

[0096] [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).

[0097] [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.

[0098] 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).

[0099] [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)

[0100] [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%).

[0101] [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).

[0102] [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).

[0103] 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)

[0104] [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%).

[0105] [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).

[0106] [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).

[0107] 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)

[0108] [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%).

[0109] [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).

[0110] [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).

[0111] 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))

[0112] [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%).

[0113] [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).

[0114] [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).

[0115] [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)

[0116] [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%).

[0117] [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).

[0118] [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).

[0119] 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)

[0120] [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%).

[0121] [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).

[0122] [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).

[0123] Example 14: Preparation of 2-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-5-butyl-1,3,4-thiadiazole (compound number: NUT-51)

[0124] 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).

[0125] 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)

[0126] (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).

[0127] 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)

[0128] 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).

[0129] 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)

[0130]

[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).

[0131] 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)

[0132] 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).

[0133] 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)

[0134] [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).

[0135] [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).

[0136] 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.

[0137] 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)

[0138] (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).

[0139] 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))

[0140] (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%). １ HNMR (500MHz, CDCl３ ) 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).

[0141] Example 22: Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methylpropionate (Compound Number: NUT-46)

[0142] (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).

[0143] 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)

[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 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).

[0145] Example 24: Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methylpentanoate (Compound Number: NUT-47)

[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 valeryl chloride (10 μL) to obtain the title compound (26 mg, yield 80%). 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=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).

[0147] 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)

[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 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).

[0149] Example 26: Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl benzoate (Compound Number: NUT-49)

[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 (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)

[0151] 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)

[0152] (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).

[0153] 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)

[0154] (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).

[0155] Example 29: Preparation of (2-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)thiazol-4-yl)methyl isobutyrate (Compound number: NUT-64)

[0156] (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).

[0157] A generalized scheme of Example 29 is as follows: <Scheme 7> (In the formula, each symbol has the same meaning as defined above.)

[0158] [Example 30] Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-oxadiazol-2-yl)methyl acetate

[0159] 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).

[0160] [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)

[0161] 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).

[0162] [Example 32] Preparation of (5-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-oxadiazol-2-yl)methyl isobutyrate (Compound Number: NUT-67)

[0163] (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).

[0164] 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).

[0165] 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).

[0166] 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).

[0167] 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).

[0168] 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).

[0169] [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)

[0170] [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%).

[0171] [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).

[0172] [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).

[0173] [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).

[0174] 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)

[0175] (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).

[0176] [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)

[0177] [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%).

[0178] [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).

[0179] [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).

[0180] 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) 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).

[0181] Example 37: Preparation of 5-(4-(4-phenoxypiperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (Compound Number: NUT-68)

[0182] [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%).

[0183] [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).

[0184] [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)

[0185] 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).

[0186] [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).

[0187] Example 38: Preparation of 5-(4-(4-(2-chlorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (Compound Number: NUT-74)

[0188] 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).

[0189] Example 39: Preparation of (5-(4-(4-(2-methylphenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (Compound Number: NUT-75)

[0190] [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%).

[0191] [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).

[0192] [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)

[0193] 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).

[0194] [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).

[0195] [Example 40] Preparation of (5-(4-(4-(2-fluorophenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (Compound Number: NUT-76)

[0196] [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%).

[0197] [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).

[0198] [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)

[0199] 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).

[0200] [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).

[0201] 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)

[0202] [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).

[0203] [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).

[0204] [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).

[0205] 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)

[0206] (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).

[0207] 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)

[0208] (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).

[0209] [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)

[0210] [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%).

[0211] [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).

[0212] [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).

[0213] [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)

[0214] 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).

[0215] [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))

[0216] [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%). １ HNMR (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).

[0217] [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).

[0218] 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))

[0219] [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).

[0220] [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).

[0221] Example 48: Preparation of ethyl 2-(4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)phenyl)thiazole-4-carboxylate (Compound Number: NUT-62)

[0222] 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).

[0223] [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)

[0224] [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).

[0225] [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).

[0226] [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)

[0227] (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).

[0228] 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)

[0229] (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).

[0230] Example 52: Preparation of (5-(4-(4-phenoxypiperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl isobutyrate (compound number: NUT-70)

[0231] (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).

[0232] [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)

[0233] (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).

[0234] 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)

[0235] (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).

[0236] 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)

[0237] (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).

[0238] [Example 56] Preparation of (5-(4-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)methyl isobutyrate (Compound Number: NUT-84)

[0239] (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).

[0240] [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)

[0241] [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).

[0242] [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%).

[0243] [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).

[0244] [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).

[0245] [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)

[0246] (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).

[0247] [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)

[0248] (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).

[0249] [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)

[0250] [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).

[0251] [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 compound as a crude product (1.2 g, crude yield 99%).

[0252] [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).

[0253] [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).

[0254] 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)

[0255] (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).

[0256] 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)

[0257] (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).

[0258] [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)

[0259] [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).

[0260] [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%).

[0261] [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).

[0262] [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).

[0263] [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)

[0264]

[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).

[0265] [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)

[0266] (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).

[0267] [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)

[0268] 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).

[0269] 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)

[0270] (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).

[0271] 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)

[0272] [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).

[0273] [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).

[0274] [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).

[0275] 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)

[0276] 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).

[0277] [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)

[0278] [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).

[0279] [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%).

[0280] [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).

[0281] [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).

[0282] [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)

[0283] (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).

[0284] [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)

[0285] (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).

[0286] [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)

[0287] [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).

[0288] [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%).

[0289] [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).

[0290] [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).

[0291] 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)

[0292] (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).

[0293] [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)

[0294] (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).

[0295] 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)

[0296] [Step (a) of Example 76] 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 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. 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).

[0297] [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).

[0298] In the following test examples, the compounds (ADI derivatives, NUT compounds) produced above were also used for evaluation.

[0299] Test Example 1: Evaluation of anti-influenza virus activity and cytotoxicity of compounds (NUT compounds) (1) Experimental method (1)-1. Antiviral activity test Canine kidney-derived cells (MDCK cells) were used, seeded at 3 × 10⁻⁴ cells per well in a 96-well plate. The 96-well plate was cultured for one day in a 37°C, 5% CO₂ incubator. A sample solution was prepared by dissolving the compound in 100% DMSO, which was then serially diluted with MEM + vitamin solution. The medium from the plate seeded with the cells was removed using an aspirator, and 100 μL of MEM + vitamin solution was added as a washing procedure. The medium was again removed using an aspirator, and the diluted sample solutions were added to the corresponding wells at 100 μL / well, starting with the lowest concentration. Subsequently, MEM + vitamin was added at 100 μL / well to wells with uninfected cells, and 1000 TCID 50100 μL / well of influenza virus (A / WSN / 33) solution diluted to 1 mL / mL was added. After mixing, the 96-well plate was cultured in a 37°C, 5% CO2 incubator for 2 days. The fixation and staining procedure involved removing the medium from the 96-well plate using an aspirator, adding 200 μL of 70 (v / v)% EtOH, and fixing the cells at room temperature for 5 minutes. Then, 100 μL of 0.5% crystal violet staining solution was added and stained at room temperature for 5 minutes. After washing with tap water and drying, the stain in the fixed cells was measured using a plate reader, and the median effective concentration (EC) of the compound's antiviral activity (effect) was determined. 50 ) was calculated.

[0300] (1)-2. Cytotoxicity test The 50% maximal inhibitory concentration (CC) of compounds against MDCK cells was measured according to the procedure of the antiviral activity test described above, except that virus-free MEM + vitamin was used instead of the virus solution. 50 ) was calculated.

[0301] (2) Results Antiviral activity test results of test compounds (NUT compounds) (EC 50 ) and cytotoxicity test results (CC 50 ) are shown in Table 1 below. For comparison, commercially available anti-influenza virus drugs oseltamivir (trade name "Tamiflu") and favipiravir (development code "T-705", trade name "Avigan") are also shown. "ND" in the table stands for "Not Determined," and indicates that the drug showed antiviral effect but not the median effective concentration (EC 50 ) exceeded 10 μM and could not be measured. All the tested compounds showed antiviral activity. In addition, almost all the compounds showed a median growth inhibitory concentration (CC 50 ) was confirmed to be greater than 10 μM and to have low cytotoxicity.

[0302]

[0303]

[0304]

[0305] Test Example 2: Evaluation of the combined effect of a compound (NUT compound) with an existing drug against influenza virus (1) Experimental method: A favipiravir combined group was set up, and an antiviral activity test was carried out in the same manner as in Test Example 1, except that 0.3 μM of favipiravir (T-705) was added to the wells of infected cells in the favipiravir combined group. NUT67 (Example 32) and NUT29 (Example 21) were used as test compounds (NUT compounds). A concentration of 0.3 μM of favipiravir (T-705) was found to be 0.3 μM, which is the IC 50 This is one-tenth the concentration of (3 μM).

[0306] (2) Results The results of the antiviral activity test for NUT67 and NUT29 alone and in the presence of 0.3 μM favipiravir (T-705) are shown in Figure 1. For comparison, the results of the antiviral activity test for favipiravir (T-705) alone are also shown. The horizontal axis shows the tested compound / drug, and the vertical axis shows the median effective concentration (EC 50 ) (μM) are shown.

[0307] Both NUT67 and NUT29 alone exhibit anti-influenza effects similar to or greater than those of the known drug favipiravir, but when used in combination with favipiravir, the anti-influenza effects were further enhanced.

[0308] Test Example 3: Evaluation of the Anti-SARS-CoV-2 Activity and Cytotoxicity of Compounds (NUT Compounds) (1) Experimental Materials and Methods (1)-1. Experimental Materials: VeroE6 cells derived from African green monkey kidneys were cultured in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin solution. The SARS-CoV-2 Wuhan strain (TY / WK-521, Japan, 2020) used in this experiment was provided by the National Institute of Infectious Diseases. The virus was passaged in VeroE6 cells and cultured for 3-4 days. The culture supernatant was collected and centrifuged at 2000 x g for 15 minutes. The supernatant was stored at -80°C and thawed before use. All infection experiments using this virus were performed in a BSL3 laboratory at Nagasaki University.

[0309] The test compounds (NUT compounds) used were NUT29 (Example 21) and NUT61 (Example 23). For comparison, chloroquine and remdesivir were also evaluated.

[0310] (1)-2. Anti-SARS-CoV-2 Activity Test: The anti-SARS-CoV-2 activity test was performed according to the method described in J Virol. 2022;96(6):e00002-22. VeroE6 (derived from African green monkey kidney epithelial cells) were seeded at 1 x 10^4 cells per well in a 96-well plate. Sample solutions were prepared by dissolving compounds in 100% DMSO and serially diluting them with DMEM solution. After adding the NUT compound-containing sample solution, the cells were cultured at 37°C for 1 hour. They were then infected with SARS-CoV-2 in a BSL3 laboratory. After incubating the cells for an additional 2 hours, the supernatant was discarded, and the cell surface was washed twice with room-temperature PBS. The 96-well plate was then cultured at 37°C in a 5% CO2 incubator for 2 days. The supernatant (100 μL / well) of infected cells was collected, and RNA was extracted using the NX-48S Coronavirus Nucleic Acid Extraction Kit (Genolution Inc., Seoul, Korea) on a Nextractor® NX-48S (an automated nucleic acid extractor for novel coronaviruses). N gene amplification was performed on the extracted RNA (5 μL) using TaqMan®. ＴＭ Quantitative reverse transcription PCR was performed using Fast Virus 1-Step Master Mix for qPCR with TaqMan master mix (5 μL), nuclease water (7 μL), 0.5 μM reverse primer (1 μL), and 0.25 μM probe (SARS-CoV-2N primer, 1 μL). The primers and probe used for PCR were obtained from the NX-48S Coronavirus Nucleic Acid Extraction Kit (Genolution Inc., Seoul, Korea) and TaqMan Fast Virus 1-Step Master Mix (Life Technologies, CA, USA), respectively. The half-maximal inhibitory concentration (IC) for viral growth was determined using the results obtained under virus-only conditions as a negative control.50 ) was calculated.

[0311] (1)-3. Cytotoxicity Test: VeroE6 (derived from African green monkey kidney epithelial cells) were used, seeded at 1 x 10^4 cells per well in a 96-well plate. Sample solutions were prepared by dissolving compounds in 100% DMSO and then serially diluted with DMEM solution. After adding the NUT compound-containing sample solution, the 96-well plate was incubated at 37°C in a 5% CO2 incubator for 2 days. Then, 10 μL of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) solution was added and incubated at 37°C in a 5% CO2 incubator for 4 hours. The medium in the 96-well plate was removed using an aspirator, and 200 μL of PBS was added. After 1 minute, the liquid was aspirated. 200 μL of 0.04 mol / HCl / isopropyl alcohol was added to each well, and the plate was placed on a microplate mixer and shaken for 10 minutes to dissolve the formazan. The absorbance at 570 nm was measured using a plate reader, and the 50% inhibitory concentration (CC) of the compound against VeroE6 cells was determined. 50 ) was calculated.

[0312] (2) Results Anti-SARS-CoV-2 activity test results of NUT29, NUT61, chloroquine, and remdesivir (IC 50 ) and cytotoxicity test results (CC 50 ) are shown in Table 2. Anti-SARS-CoV-2 activity was confirmed in NUT29 and NUT61. 50 The value was 66.8 μM.

[0313]

[0314] Test Example 4: Evaluation of Anti-HIV Activity of Compounds (NUT Compounds) (1) Experimental Method: The anti-HIV activity test was performed as follows, based on the method described in J. Virol. 1986;59:284-291. TZM-bl cells were seeded at 2 × 10⁻⁴ cells per well in a 24-well plate. The 24-well plate was incubated at 37°C in a 5% CO₂ incubator for 1 day. NUT compounds dissolved in 100% DMSO were pre-diluted with DMEM solution to concentrations of 10 μM and 1 μM. After addition of the NUT compounds, the cells were incubated at 37°C for 2 hours. Then, in a BSL3 laboratory, the cells were infected with 30 μL of HIV-1 (NL4-3 strain). After further incubation for 48 hours, luciferase reagent (Promega) was added, and chemiluminescence was detected. Luciferase activity was measured as relative light units per second (RLU / s).

[0315] (2) Results The results are shown in Figures 2 and 3. Figure 2 shows the luciferase activity (RLU) measured when the compound was added at a concentration of 10 μM in the anti-HIV activity test, and Figure 3 shows the luciferase activity (RLU) measured when the compound was added at a concentration of 1 μM in the same test. In Figures 2 and 3, the horizontal axis represents the test group, and the vertical axis represents the luciferase activity (RLU). As a control, the results for DMSO in which the compound was not dissolved are also shown ("DMSO" in Figures 2 and 3). The numbers of the test plots shown on the horizontal axis represent the NUT numbers of the compounds used in this test example, and are as follows: #9: NUT-9 (Example 1), #10: NUT-10 (Example 2), #11: NUT-11 (Example 15), #13: NUT-13 (Example 3), #14: NUT-14 (Example 4), #20: NUT-20 (Example 20), #27: NUT-27 (Example 8), #28: NUT-28 (Example 11), #29: NUT-29 (Example 21), #33: NUT-33 (Example 9), #45: NUT-45 (Example 18), #46: NUT-46 (Example 22), #48: NUT-48 (Example 25), #49: NUT-49 (Example 26), #50: NUT-50 (Example 27), #51: NUT-51 (Example 14), #52: NUT-52 (Example 42), #60: NUT-60 (Example 28), #61: NUT-61 (Example 23), #63: NUT-63 (Example 19), #67: NUT-67 (Example 32), #71: NUT-71 (Example 53), #79: NUT-79 (Example 41), #81: NUT-81 (Example 31), #82: NUT-82 (Example 45), and #84: NUT-84 (Example 56).

[0316] Higher luciferase activity indicates a higher proportion of HIV-infected TZM-bl cells. At 10 μM, all compounds exhibited significantly lower luciferase activity than the control (DMSO). At 1 μM, some compounds exhibited luciferase activity equivalent to that of the control, while others (#28, #29, #45, #46, #48, #49, #50, #60) exhibited activity less than 50% of that of the control. The most effective compound was NUT-28 (#28), which exhibited luciferase activity approximately 40% of that of the control. Therefore, this test confirmed the anti-HIV activity of the compounds.

[0317] Test Example 5: Evaluation of anti-influenza virus activity and cytotoxicity of compounds (NUT compounds) Antiviral activity tests and cytotoxicity tests were carried out in the same manner as in Test Example 1, except that NUT-113 (Example 76) was used as the test compound (NUT compound) and oseltamivir (trade name "Tamiflu") was used for comparison.

[0318] The results of the antiviral activity test and the cytotoxicity test are shown in Table 3 below. NUT-113 also showed antiviral activity, with a median growth inhibitory concentration (CC 50 ) exceeded 10 μM, confirming low cytotoxicity.

[0319]

[0320] 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

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 １－６ 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 ２－６ an 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).

2. The pharmaceutical composition according to claim 1, wherein the viral infection is caused by a virus selected from the group consisting of influenza virus, human immunodeficiency virus, and novel coronavirus.

3. The pharmaceutical composition according to claim 1, characterized in that it is administered in combination with an antiviral drug.

4. The pharmaceutical composition according to claim 3, wherein the antiviral drug is selected from the group consisting of RNA polymerase inhibitors, neuraminidase inhibitors, M2 proton channel inhibitors, endonuclease inhibitors, DNA polymerase inhibitors, reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, adsorption / entry inhibitors, uncoating inhibitors, nucleic acid synthesis inhibitors, protein synthesis inhibitors, release inhibitors, and fusion inhibitors.

5. The pharmaceutical composition of claim 4, wherein the antiviral drug is an RNA polymerase inhibitor.

6. A compound represented by the following formula or a salt thereof:

Images