Anti-fibrotic compound for treatment of fibrosis

Abstract

The present invention provides a compound for treating or preventing fibrosis.　The present invention relates to compounds represented by formula (I): [in the formula, the same or different, each independently, [in the formula, Y1, Y2, Y3, and X4, etc., are as defined in the specification], enantiomers or pharmaceutically acceptable salts thereof, to the use of these compounds for the treatment or prevention of fibrosis, and to pharmaceutical compositions containing these compounds.

Description

Antifibrotic compounds for the treatment of fibrosis

[0001] This patent application claims priority under the Paris Convention and the benefit of Japanese Patent Application No. 2024-057482 (filed March 29, 2024), as well as priority under Article 41 of the Japanese Patent Act, the entire contents of which are incorporated herein by reference.

[0002] Fibrosis is a pathological wound healing process that occurs in vital organs, such as the lungs, heart, liver, kidneys, and skin, where normal parenchymal tissue is replaced by connective tissue, resulting in the organ losing its elasticity and becoming stiff, preventing it from functioning normally. In fibrosis, or fibrogenesis, repair in response to repeated injury or chronic inflammation leads to the accidental overaccumulation of extracellular matrix components such as collagen, which in turn leads to the production of fibroblasts, resulting in the formation of permanent fibrous scars.

[0003] Among these, idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with progressive lung scarring and histological features resembling usual interstitial pneumonia (UIP), resulting in a significant decline in patients' quality of life due to increased cough and dyspnea. The pathogenesis of IPF has been suggested to involve genetic susceptibility and age-related repeated alveolar epithelial damage and abnormal repair responses, but the definition of susceptibility remains controversial.

[0004] Currently, two medications, pirfenidone (Pirespa, Shionogi) and nintedanib (Ofep, Boehringer Ingelheim), are available for clinical management of IPF, slowing disease progression and improving progression-free survival (Non-Patent Documents 1, 2). However, these compounds cannot reverse disease progression once it has progressed. Therefore, current efforts are focused on early detection of IPF by relying on a combination of biomarkers and on slowing disease progression with these medications.

[0005] Paul W Noble, et al., Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomized trials, Lancet (2011), vol 377, 1760-1769Luca Richeldi, et al., Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis, The new England journal of medicine (2014), vol 370, No.22:2071-2082

[0006] Thus, while current treatments can slow the progression of fibrosis, they cannot reverse fibrosis that has already occurred or restore organ function, such as the lungs. As a result, patients rely on medications that only slow disease progression to maintain survival, resulting in a seemingly endless battle. While the disease itself is life-threatening, continued medications impose economic, psychological, and social burdens on patients, creating a strong social demand for better IPF treatments. Therefore, the inventors sought to discover new fibrosis treatments that can reverse fibrosis and restore organ function, such as the lungs. They discovered compounds with the desired effects from small molecule compounds that they independently designed and synthesized.

[0007] Therefore, the present invention includes the following aspects: <Compound> [1] Formula (I): [In the formula, are the same or different and each independently: A and C are each independently a bond, or optionally substituted methylene, carbonyl, thiocarbonyl, sulfinyl, sulfonyl, phosphoryl, optionally substituted amido, or thioamido; B is a bond, or straight-chain C1-6 alkylene, C3-11 cycloalkylene, or C3-11 heterocycloalkylene, straight-chain C2-6 alkenylene, C3-8 cycloalkenylene, or C3-8 heterocycloalkenyne, straight-chain C1-6 alkynylene, optionally substituted by 1 to 3 groups selected from the group consisting of C1-6 alkyl, C3-8 cycloalkyl, trifluoromethyl, hydroxyl, amino, amido, halogen, and C1-6 alkoxy, or an arylene or heteroarylene group optionally substituted by 1 or 2 groups selected from the group consisting of C1-6 alkyl, trifluoromethyl, hydroxyl, amino, amido, halogen, and C1-6 alkoxy; Y 1 , Y 2 , Y 3 and X 4 are each independently -O-, -N=, -S-, or -NR 1 - or -CR 2 = ; where Y 1 , Y 2 , Y 3 and X 4 At least one of these is -N= or -NR 1 - and R 1 is hydrogen, optionally substituted C alkyl, optionally substituted C aryl, or optionally substituted 5-10 membered heteroaryl; R 2 is hydrogen, optionally substituted C alkyl, optionally substituted C carbonyl, optionally substituted C alkoxy, optionally substituted C alkylthio, optionally substituted C alkylamino, optionally substituted C aryl, or optionally substituted 5-10 membered heteroaryl; R 6 , R 7 , R 10 , R 11 and R 12are each independently hydrogen, optionally substituted C alkyl, optionally substituted C aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C alkoxy, hydroxy, amino, cyano, carbamoyl or halogen; n is 1, 2 or 3; where, when n is 2, one carbon atom is not substituted with R 6 and R 7 are bonded together, and the other carbon atom has R 8 and R 9 when n is 3, the two carbon atoms each independently have R 6 and R 7 are bonded together independently, and the remaining carbon atoms are 8 and R 9 are bonded together; R 8 and R 9 are each independently hydrogen, optionally substituted C alkyl, optionally substituted C aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C alkoxy, hydroxy, amino, cyano, carbamoyl or halogen; or R 6 and R 7 , R 8 and R 9 , and R 10 and R 11 each independently bridges together with the carbon to which it is bonded to form a C3-6 spiro ring, and R 6 or R 7 and R 8 or R 9 forms a double bond with the adjacent carbon atom, and R 8 or R 9 and R 10 or R 11 forms a double bond with the adjacent carbon atom, and R 8 or R 9 and R 12 forms a double bond with the adjacent carbon atom, and R 10 or R 11 and R 12forms a double bond together with the adjacent carbon atom, and the adjacent R 6 or R 7 and R 6 or R 7 are bridged together to form -CH2- or -CH2-CH2-, and adjacent R 6 or R 7 and R 8 or R 9 are bridged together to form -CH2-, -CH2-CH2-, -CH2-CH2-CH2- or -CH2-CH2-CH2-CH2-, and adjacent R 7 and R 8 and R 10 or R 11 are bridged together to form -CH2-, -CH2-CH2-, -CH2-CH2-CH2- or -CH2-CH2-CH2-CH2-, R 12 and R 6 or R 7 are bridged together to form -CH2- or -CH2-CH2-, and R 12 and R 8 or R 9 are bridged together to form -CH2- or -CH2-CH2-, or R 12 and R 10 or R 11are joined together to bridge and form -CH2- or -CH2-CH2-. Here, the substituents in "optionally substituted" are selected from the following: hydroxy, halogen, cyano, carbamoyl, amino, amidinoamino, carboxy, C6-10 aryl, 5- to 10-membered heteroaryl substituted with C1-4 alkoxycarbonyl, C6-10 aryl substituted with C1-4 alkyl, C6-10 aryl substituted with hydroxy, C6-10 aryl substituted with halogen, C6-10 aryl substituted with C1-4 alkoxy, (optionally substituted amino)-C6-10 aryl, C1-4 alkoxycarbonyl, C1-4 alkoxycarbonylamino, 5- to 6-membered heterocycloalkyl, C3-6 cycloalkyl, 5- to 10-membered heteroaryl, C6-10 aryl substituted with (C1-6 alkyl substituted with halogen), and trialkylsilyloxy, alkylarylsilyloxy, triarylsilyloxy, or a protecting group. However, the formula: ] A compound represented by the formula (I) or an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[0008] <Development of Skeletal Structure> [2] In formula (I), is a group represented by the formula: [3] The compound according to [1], its enantiomer, or a pharmaceutically acceptable salt thereof, wherein, in formula (I), is a group represented by the formula: (wherein R is hydrogen, optionally substituted C alkyl, optionally substituted C aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C alkoxy, hydroxy, optionally substituted C amino, optionally substituted C amido, cyano, carbamoyl or halogen; R is hydrogen or optionally substituted C alkyl; Z is optionally substituted C alkyl, hydroxy or halogen; and the wavy line in the above group has the formula: [4] The compound according to [2], its enantiomer, or a pharmaceutically acceptable salt thereof, wherein, in formula (I), is a group represented by the formula: (wherein R is hydrogen, optionally substituted C alkyl, optionally substituted C aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C alkoxy, hydroxy, optionally substituted C amino, optionally substituted C amido, cyano, carbamoyl or halogen; R is hydrogen or optionally substituted C alkyl; Z is optionally substituted C alkyl, hydroxy or halogen; and the wavy line in the above group has the formula: [5] The compound according to [3], its enantiomer, or a pharmaceutically acceptable salt thereof, wherein, in formula (I), is a group represented by the formula: (Here, at the end of the wavy line, there is the formula: and R is hydrogen, hydroxy, t-butyloxy, phenyl, fluorine, cyano, or carbamoyl).

[0009] <Development of Azole Structure> [6] In formula (I), the formula: is an azole ring represented by the formula: (Here, R 15 is optionally substituted C alkyl, optionally substituted C alkoxy, optionally substituted C alkylthio, optionally substituted C alkylamino, optionally substituted C aryl, optionally substituted 5-10 membered heteroaryl; R 16[7] A compound according to any one of [1] to [5], an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein, in formula (I), The azole ring represented by the formula: (Here, R 12 and R 13 are each independently hydrogen, optionally substituted C alkyl, optionally substituted C alkoxy, optionally substituted C alkylthio, optionally substituted C alkylamino, optionally substituted C aryl, or optionally substituted 5-10 membered heteroaryl; R 17 [8] The compound according to [6], an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein, in formula (I), is an azole ring represented by the formula: (Here, R 12 and R 13 are each independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C1-6 alkylthio, optionally substituted C1-6 alkylamino, optionally substituted C6-10 aryl, or optionally substituted 5- to 10-membered heteroaryl). is an azole ring represented by the formula: (wherein R is hydrogen, optionally substituted C1-6 alkyl, R 13is a group represented by the formula (I), optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C1-6 alkylthio, optionally substituted C1-6 alkylamino, optionally substituted C6-10 aryl, or optionally substituted 5- to 10-membered heteroaryl). <Development of azole side chain structure>

[10] In formula (I), R which is a side chain of the azole ring is a group represented by the formula (I), or an enantiomer thereof, or a pharmaceutically acceptable salt thereof. 2 but, (wherein X is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C1-6 alkoxy, hydroxy, amino, cyano, carbamoyl or halogen; Z is O, NH, S; and n is an integer from 1 to 5.)

[11] A compound according to any one of [1] to [9], its enantiomer, or a pharmaceutically acceptable salt thereof, wherein in formula (I), R which is a side chain of the azole ring 2 but, The compound according to

[10] , its enantiomer, or a pharmaceutically acceptable salt thereof, represented by the following formula: wherein Z is C, S, SO, SO2 or P; Y is O or S; R 3

[13] In formula (I), A and C each independently represent a group represented by the formula:

[14] The compound according to

[12] , its enantiomer, or a pharmaceutically acceptable salt thereof, wherein B is a group represented by the formula:

[15] The compound according to

[13] , its enantiomer, or a pharmaceutically acceptable salt thereof, wherein B is a group represented by the formula: The compound according to

[14] , an enantiomer thereof, or a pharmaceutically acceptable salt thereof, which is represented by the formula:

[0010] <Pharmaceutical composition>

[16] A pharmaceutical composition comprising the compound according to any one of [1] to

[15] , its enantiomer, or its pharmaceutically acceptable salt.

[17] The pharmaceutical composition according to

[16] for treating or preventing fibrosis.

[18] The pharmaceutical composition according to

[17] , wherein the fibrosis is pulmonary fibrosis.

[0011] According to the present invention, there is provided a low molecular weight compound that is expected to be useful in treating fibrosis by eliminating fibrosis and restoring the function of organs such as the lungs.

[0012] FIG. 1 shows the antifibrotic activity of the compound naphthalene-2,6-diylbis(((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) at the cellular level.

[0013] The present invention will be described in more detail below.Unless otherwise specified, the terms used in this specification are used in the meanings generally used in the relevant field.Therefore, unless otherwise defined, all technical terms and scientific terms used in this specification have the same meaning as commonly understood by those skilled in the art to which this invention belongs.

[0014] <Definitions> In this specification, the term "group" means a monovalent group unless otherwise specified. Examples of non-monovalent groups include alkylene groups (divalent). In addition, in the following explanations of substituents, etc., the term "group" may be omitted in some cases.

[0015] In the present specification, when defined as "optionally substituted" or "substituted," the number of substituents is not particularly limited as long as substitution is possible, and is one or more. Furthermore, unless otherwise specified, the description of each substituent also applies when that substituent is a part of or a substituent for another substituent.

[0016] In the present specification, any part of a group modified with "optionally substituted" or "substituted" may be substituted. For example, in "optionally substituted arylalkyl" and "substituted arylalkyl," the aryl part may be substituted, the alkyl part may be substituted, or both the aryl part and the alkyl part may be substituted.

[0017] In this specification, the substituents in the case of "optionally substituted" may be selected from substituent group α consisting of the following, and may be substituted with 1 to 5 identical or different substituents: Substituent group α: hydroxy, halogen, cyano, carbamoyl, amino, amidinoamino, carboxy, C6-10 aryl, C1-4 alkoxycarbonyl-substituted 5-10 membered heteroaryl, C1-4 alkyl-substituted C6-10 aryl, hydroxy-substituted C6-10 aryl, halogen-substituted C6-10 aryl, C1-4 alkoxy-substituted C6-10 aryl, (optionally substituted amino)-C6-10 aryl, C1-4 alkoxycarbonyl, C1-4 alkoxycarbonylamino, 5- to 6-membered heterocycloalkyl, C3-6 cycloalkyl, 5- to 10-membered heteroaryl, (halogen-substituted C1-6 alkyl)-substituted C6-10 aryl, and trialkylsilyloxy, alkylarylsilyloxy, triarylsilyloxy, or a protecting group.

[0018] These substituent groups α are optionally substituted with 1 to 5 identical or different substituents selected from substituent group β: Substituent group β: halogen, hydroxy, carboxy, cyano, C3-10 alicyclic group, C1-6 alkoxy, C3-10 alicyclicoxy, C1-6 alkylthio, 5- or 6-membered heteroarylthio, C6-10 aryl, 5- or 6-membered heteroaryl, 4- to 10-membered non-aryl heterocycle, C1-6 alkylcarbonyl, C3-10 alicyclic carbonyl, C6-10 arylcarbonyl, 5- or 6-membered heteroarylcarbonyl, 4- to 10-membered non-aryl heterocyclecarbonyl, protecting group.

[0019] In this specification, "C1-6" means that the number of carbon atoms is 1 to 6. The same applies to other numbers, for example, "C1-4" means that the number of carbon atoms is 1 to 4, and "C1-3" means that the number of carbon atoms is 1 to 3.

[0020] As used herein, the term "heteroatom" refers to an atom other than carbon or hydrogen atoms, such as an oxygen atom, nitrogen atom, or sulfur atom.

[0021] As used herein, "hydroxy" refers to the monovalent radical -OH. This group may also be referred to as a "hydroxy group" or "hydroxy."

[0022] As used herein, "halogen" refers to an atom belonging to the halogen group, such as a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. A fluorine atom or a chlorine atom is preferred. A fluorine atom is more preferred. "Halogen" may also be referred to as "halogen atom" or "halo".

[0023] As used herein, "carboxy" refers to the monovalent radical -COOH. This group is also called a "carboxy group," "carboxyl," "carboxylic acid group," or "carboxylic acid group."

[0024] As used herein, "cyano" is the monovalent radical -CN.

[0025] As used herein, "amino" refers to the monovalent radical -NH. This group may also be referred to as an "amino group."

[0026] As used herein, "alkyl" refers to a linear or branched saturated aliphatic hydrocarbon group. "C1-6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms, with preferred examples including "C1-4 alkyl," more preferably "C1-3 alkyl," and even more preferably "C1-2 alkyl." Specific examples of "C1-4 alkyl" include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, etc. Specific examples of "C1-6 alkyl" include, but are not limited to, C1-4 alkyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1,2-dimethylpropyl, n-hexyl, etc.

[0027] As used herein, "alkenyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond. "C2-6 alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms, and preferred examples include "C2-4 alkenyl." Specific examples of "C2-6 alkenyl" include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propylenyl, 2-methyl-2-propylenyl, etc.

[0028] As used herein, "alkynyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond. "C2-6 alkynyl" refers to an alkynyl group having 2 to 6 carbon atoms, and preferred examples include "C2-4 alkynyl." Specific examples of "C2-6 alkynyl" include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 3-butynyl, 1-pentynyl, 1-hexynyl, and the like.

[0029] As used herein, "aryl" refers to a monovalent group of a monocyclic or bicyclic aromatic hydrocarbon ring, and "C6-10 aryl" refers to an aryl group having 6 to 10 carbon atoms. Examples of "aryl" include, but are not limited to, C6 aryl, C10 aryl, etc. Specific examples of C6 aryl include, but are not limited to, phenyl, etc. Specific examples of C10 aryl include, but are not limited to, 1-naphthyl, 2-naphthyl, etc.

[0030] As used herein, "arylalkyl" refers to an alkyl substituted with at least one aryl. "C6-10 arylC1-6 alkyl" refers to a C1-6 alkyl substituted with at least one C6-10 aryl. Specific examples of C6-10 arylC1-6 alkyl include, but are not limited to, benzyl (phenyl-CH2-), phenethyl (phenyl-CH2CH2-), naphthalen-1-ylmethyl, naphthalen-2-ylmethyl, 2-(naphthalen-1-yl)ethyl, 2-(naphthalen-2-yl)ethyl, etc.

[0031] As used herein, "(optionally substituted amino)-arylalkyl" refers to an arylalkyl substituted with an optionally substituted amino group, wherein the alkyl group, the aryl group, or both are substituted with an amino group. The amino group of the arylalkyl group may be unsubstituted or may be substituted with one, two, or three substituents, such as an optionally substituted alkyl (e.g., unsubstituted C alkyl, C cycloalkyl-C alkyl, C cycloalkylcarbonyl, etc.). Examples of (optionally substituted amino)-C arylC alkyl include, but are not limited to, 4-(dimethylamino)benzyl, 4-((cyclopentylmethyl)amino)benzyl, 4-((cyclopentylcarbonyl)amino)benzyl, 4-((2-carbamoylethyl)carbonylamino)benzyl, etc.

[0032] As used herein, the C6-10 aryl moiety of "C6-10 arylthio" has the same meaning as the above-mentioned C6-10 aryl. Preferred examples of "C6-10 arylthio" include "C6 or C10 arylthio". Specific examples of "C6-10 arylthio" include, but are not limited to, phenylthio, 1-naphthylthio, 2-naphthylthio, etc.

[0033] As used herein, "C6-10 arylsulfonyl" refers to sulfonyl substituted with the above-mentioned "C6-10 aryl". The "C6-10 arylsulfonyl" is preferably "C6 or C10 arylsulfonyl". Specific examples of "C6-10 arylsulfonyl" include, but are not limited to, phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.

[0034] As used herein, "heteroaryl" refers to a monovalent monocyclic or bicyclic aromatic heterocyclic group containing 1 to 4 identical or different heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms.

[0035] As used herein, "5- or 6-membered heteroaryl" refers to a monovalent group of a monocyclic aromatic heterocycle consisting of 5 to 6 atoms, containing 1 to 4 identical or different heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms. Specific examples of "5- or 6-membered heteroaryl" include, but are not limited to, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0036] As used herein, the term "5- to 10-membered heteroaryl" refers to a monovalent monocyclic or bicyclic aromatic heterocyclic group consisting of 5 to 10 atoms, containing 1 to 4 identical or different heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms. Specific examples of "5- to 10-membered heteroaryl" include 5- or 6-membered heteroaryl, quinolyl, isoquinolyl, naphthyridinyl, quinoxalinyl, cinnolinyl, quinazolinyl, phthalazinyl, imidazopyridyl, imidazothiazolyl, imidazooxazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, pyrrolopyridyl, thienopyridyl, furopyridyl, benzothiadiazolyl, benzoxadiazolyl, pyridopyrimidinyl, benzofuryl, benzothienyl, benzo[1,3]dioxole, thienofuryl, chromenyl, chromanyl, coumarinyl, quinolonyl, and the like, but are not limited to these.

[0037] As used herein, "heteroarylalkyl" refers to an alkyl substituted with at least one heteroaryl. "5- to 10-membered heteroarylC1-6alkyl" refers to a C1-6 alkyl substituted with at least one 5- to 10-membered heteroaryl. Specific examples of 5- to 10-membered heteroarylC1-6alkyl include, but are not limited to, pyridin-2-ylmethyl, pyridin-4-ylmethyl, 2-(quinolin-8-yl)ethyl, 2-(quinolin-5-yl)ethyl, 2-(quinoxalin-5-yl)ethyl, 2-(1H-indol-3-yl)ethyl, etc.

[0038] As used herein, "cycloalkyl" refers to a non-aromatic saturated hydrocarbon ring group, including those having a partially bridged structure, a partially spiro-substituted structure, and one or two carbonyl structures. "C3-20 cycloalkyl" refers to a monocyclic or bicyclic cycloalkyl having 3 to 20 carbon atoms. "C3-6 cycloalkyl" refers to a monocyclic cycloalkyl having 3 to 6 carbon atoms. Specific examples of C3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0039] As used herein, "cycloalkyl" includes partially spiro-substituted, bicyclo-substituted, and pentacyclo-substituted cycloalkyls, as described above. For example, "cycloalkyl" includes cycloalkyls of the formula: The group represented by the formula:

[0040] As used herein, "cycloalkylalkyl" refers to an alkyl substituted with at least one cycloalkyl. "C3-6 cycloalkylC1-6 alkyl" refers to a C1-6 alkyl substituted with at least one C3-6 cycloalkyl. Specific examples of C3-6 cycloalkylC1-6 alkyl include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, 3-cyclopropylpropyl, 3-cyclobutylpropyl, 3-cyclopentylpropyl, 3-cyclohexylpropyl, etc.

[0041] As used herein, the term "heterocycloalkyl" refers to a non-aromatic saturated heterocycle containing one or more identical or different heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms, and includes those having a partially bridged structure and those having a partially spiro structure.

[0042] As used herein, the term "4- to 20-membered non-aryl heterocycle" refers to a monocyclic or bicyclic non-aromatic heterocycle consisting of 4 to 20 atoms, containing one or more identical or different heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms. This term includes those having partially unsaturated bonds, partially bridged structures, and partially spiro-conjugated heterocycles. The non-aryl heterocycle may form a fused ring with an aryl or heteroaryl. For example, a heterocycle fused with a C6-10 aryl or a 5- or 6-membered heteroaryl is also included. The non-aryl heterocycle may also contain one or two carbonyls, thiocarbonyls, sulfinyls, or sulfonyls. For example, cyclic groups such as lactams, thiolactams, lactones, thiolactones, cyclic imides, cyclic carbamates, and cyclic thiocarbamates are also included in the non-aryl heterocycle. Here, the oxygen atom of the carbonyl, sulfinyl, and sulfonyl and the sulfur atom of the thiocarbonyl are not included in the 4 to 20 member number (ring size) and the number of heteroatoms constituting the ring.

[0043] As used herein, the term "4- to 10-membered non-aryl heterocycle" refers to a substituent in which the "4- to 10-membered non-aryl heterocycle" is a monovalent group, among the above-mentioned "4- to 20-membered non-aryl heterocycles."

[0044] As used herein, the 4- to 10-membered non-aryl heterocyclic moiety of "4- to 10-membered non-aryl heterocyclic oxy" has the same meaning as the above-mentioned "4- to 10-membered non-aryl heterocyclic ring". The "4- to 10-membered non-aryl heterocyclic oxy" is preferably a "4- to 6-membered non-aryl heterocyclic oxy". Specific examples of "4- to 10-membered non-aryl heterocyclic oxy" include, but are not limited to, tetrahydrofuranyloxy, tetrahydropyranyloxy, azetidinyloxy, pyrrolidinyloxy, piperidinyloxy, etc.

[0045] As used herein, the 4- to 10-membered non-aryl heterocyclic moiety of "4- to 10-membered non-aryl heterocyclic thio" has the same meaning as the above-mentioned "4- to 10-membered non-aryl heterocyclic ring". The "4- to 10-membered non-aryl heterocyclic thio" is preferably a "4- to 6-membered non-aryl heterocyclic thio". Specific examples of the "4- to 10-membered non-aryl heterocyclic thio" include, but are not limited to, tetrahydropyranylthio, piperidinylthio, and the like.

[0046] As used herein, "4- to 10-membered non-aryl heterocycle carbonyl" refers to a carbonyl group substituted with the above-mentioned "4- to 10-membered non-aryl heterocycle". The "4- to 10-membered non-aryl heterocycle carbonyl" is preferably a "4- to 6-membered non-aryl heterocycle carbonyl". Specific examples of the "4- to 10-membered non-aryl heterocycle carbonyl" include, but are not limited to, azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, morpholinylcarbonyl, and the like.

[0047] As used herein, "4- to 10-membered non-aryl heterocyclic sulfonyl" refers to a sulfonyl group substituted with the above-mentioned "4- to 10-membered non-aryl heterocycle". The "4- to 10-membered non-aryl heterocyclic sulfonyl" is preferably a "4- to 6-membered non-aryl heterocyclic sulfonyl". Specific examples of the "4- to 10-membered non-aryl heterocyclic sulfonyl" include, but are not limited to, azetidinylsulfonyl, pyrrolidinylsulfonyl, piperidinylsulfonyl, morpholinylsulfonyl, and the like.

[0048] As used herein, "5- to 6-membered heterocycloalkyl" refers to a heterocycloalkyl consisting of 5 to 6 ring atoms, including one or more identical or different heteroatoms selected from oxygen, nitrogen, and sulfur atoms.

[0049] As used herein, "heterocycloalkylalkyl" refers to an alkyl substituted with at least one heterocycloalkyl.

[0050] As used herein, "alkylcarbonyl" refers to a monovalent group of -C(=O)-alkyl. Preferred examples of alkylcarbonyl include C1-6 alkylcarbonyl. Specific examples of C1-6 alkylcarbonyl include acetyl (CH ３ C(=O)-), n-propanoyl (CH ３ CH ２ C(=O)-), n-butanoyl (CH ３ CH ２ CH ２ C(=O)-), n-pentanoyl (CH ３ (CH ２ ) ３ C(=O)-), n-hexanoyl (CH ３ (CH ２ ) ４ C(=O)-), n-heptanoyl (CH ３ (CH ２ ) ５ Examples include, but are not limited to, C(=O)-).

[0051] As used herein, "alkoxy" refers to a monovalent -O-alkyl group. Preferred examples of alkoxy include C1-6 alkoxy (i.e., C1-6 alkyl-O-), C1-4 alkoxy (i.e., C1-4 alkyl-O-), and the like. Specific examples of C1-4 alkoxy include methoxy (CHO-), ethoxy (CHCHO-), n-propoxy (CH(CH)O-), isopropoxy ((CH)CHO-), n-butoxy (CH(CH)O-), isobutoxy ((CH)CHCHO-), tert-butoxy ((CH)CO-), sec-butoxy (CHCHCH(CH)O-), and the like. Specific examples of C1-6 alkoxy include, but are not limited to, C1-4 alkoxy, n-pentyloxy (CH3(CH2)4O-), isopentyloxy ((CH3)2CHCH2CH2O-), neopentyloxy ((CH3)3CCH2O-), tert-pentyloxy (CH3CH2C(CH3)2O-), 1,2-dimethylpropoxy (CH3CH(CH3)CH(CH3)O-), and the like.

[0052] As used herein, "alkoxycarbonyl" refers to a monovalent group of -C(=O)-O-alkyl. Examples of alkoxycarbonyl include, but are not limited to, C1-6 alkoxycarbonyl, preferably C1-4 alkoxycarbonyl. Specific examples of C1-4 alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, isobutoxycarbonyl, and the like. Specific examples of C1-6 alkoxycarbonyl include, but are not limited to, C1-4 alkoxycarbonyl, n-pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert-pentyloxycarbonyl, 1,2-dimethylpropyloxycarbonyl, n-hexyloxycarbonyl, and the like.

[0053] As used herein, "alkoxycarbonylamino" refers to a monovalent group of -NH-C(=O)-O-alkyl. Examples of alkoxycarbonylamino include, but are not limited to, C1-6 alkoxycarbonylamino, preferably C1-4 alkoxycarbonylamino. Specific examples of C1-4 alkoxycarbonylamino include methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, n-butoxycarbonylamino, sec-butoxycarbonylamino, tert-butoxycarbonylamino, isobutoxycarbonylamino, and the like. Specific examples of C1-6 alkoxycarbonylamino include, but are not limited to, C1-4 alkoxycarbonylamino, n-pentyloxycarbonylamino, isopentyloxycarbonylamino, neopentyloxycarbonylamino, tert-pentyloxycarbonylamino, 1,2-dimethylpropyloxycarbonylamino, n-hexyloxycarbonylamino, and the like.

[0054] As used herein, "C alkylsulfonyl" refers to a sulfonyl group substituted with the above-mentioned "C alkyl". "C alkylsulfonyl" is preferably "C alkylsulfonyl". Specific examples of "C alkylsulfonyl" include, but are not limited to, methylsulfonyl, propylsulfonyl, butylsulfonyl, etc.

[0055] As used herein, the C alkyl portion of "C alkylthio" has the same meaning as the above C alkyl. Examples of "C alkylthio" include "C alkylthio", preferably "C alkylthio". Specific examples of "C alkylthio" include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, isopropylthio, isobutylthio, tert-butylthio, sec-butylthio, isopentylthio, neopentylthio, tert-pentylthio, 1,2-dimethylpropylthio, etc.

[0056] As used herein, "arylcarbonyl" refers to a monovalent group of -C(=O)-aryl. Preferred examples of arylcarbonyl include C6-10 arylcarbonyl. Specific examples of C6-10 arylcarbonyl include, but are not limited to, benzoyl (i.e., phenyl-C(=O)-), 1-naphthylcarbonyl, 2-naphthylcarbonyl, and the like.

[0057] As used herein, the C6-10 aryl moiety of "C6-10 aryloxy" has the same meaning as the above-mentioned C6-10 aryl. Preferred examples of "C6-10 aryloxy" include "C6 or C10 aryloxy". Specific examples of "C6-10 aryloxy groups" include, but are not limited to, phenoxy groups, 1-naphthyloxy groups, and 2-naphthyloxy groups.

[0058] As used herein, a "heteroarylcarbonyl" is a monovalent radical of -C(=O)-heteroaryl.

[0059] As used herein, the term "5- or 6-membered heteroarylcarbonyl group" refers to a carbonyl group substituted with the above-mentioned "5- or 6-membered heteroaryl". Specific examples of the "5- or 6-membered heteroarylcarbonyl group" include, but are not limited to, a pyrazoylcarbonyl group, a triazoylcarbonyl group, a thiazoylcarbonyl group, a thiadiazoylcarbonyl group, a pyridylcarbonyl group, and a pyridazoylcarbonyl group.

[0060] As used herein, the 5- or 6-membered heteroaryl moiety of a "5- or 6-membered heteroaryloxy group" has the same meaning as the above-mentioned "5-membered heteroaryl" or "6-membered heteroaryl." Specific examples of the "5- or 6-membered heteroaryloxy group" include, but are not limited to, a pyrazolyloxy group, a triazolyloxy group, a thiazoyloxy group, a thiadiazoyloxy group, a pyridyloxy group, and a pyridazoyloxy group.

[0061] As used herein, the 5- or 6-membered heteroaryl moiety of a "5- or 6-membered heteroarylthio group" has the same meaning as the above-mentioned "5-membered heteroaryl" or "6-membered heteroaryl." Specific examples of the "5- or 6-membered heteroarylthio group" include, but are not limited to, a pyrazoylthio group, a triazoylthio group, a thiazoylthio group, a thiadiazoylthio group, a pyridylthio group, and a pyridazoylthio group.

[0062] As used herein, the term "5- or 6-membered heteroarylsulfonyl group" refers to a sulfonyl group substituted with the above-mentioned "5- or 6-membered heteroaryl". Specific examples of the "5- or 6-membered heteroarylsulfonyl group" include, but are not limited to, a pyrazoylsulfonyl group, a triazoylsulfonyl group, a thiazoylsulfonyl group, a thiadiazoylsulfonyl group, a pyridylsulfonyl group, and a pyridazoylsulfonyl group.

[0063] As used herein, "carbamoyl" refers to the monovalent group -C(=O)-NH2.

[0064] As used herein, "amidinoamino" refers to the monovalent group -NH-C(=NH)-NH2.

[0065] As used herein, the phrase "a group substituted with a certain substituent" means that the group is substituted with at least one substituent. For example, "hydroxy-substituted C alkyl" means that the C alkyl is substituted with at least one hydroxy.

[0066] As used herein, "carbamoyl-substituted C1-6 alkyl" refers to at least one -C(=O)-NH ２ It is a C1-6 alkyl substituted with a group. Examples of "carbamoyl-substituted C1-6 alkyl" include, but are not limited to, carbamoyl-substituted C1-4 alkyl. Specific examples of "carbamoyl-substituted C1-4 alkyl" include, but are not limited to, 2-amino-2-oxoethyl (i.e., H2NC(=O)-CH2- or carbamoylmethyl), 3-amino-3-oxopropyl (i.e., H2NC(=O)-CH2CH2- or carbamoylethyl), 4-amino-4-oxobutyl (i.e., H2NC(=O)-(CH2)3- or carbamoylpropyl), 5-amino-5-oxopentyl (i.e., H2NC(=O)-(CH2)4- or carbamoylbutyl), etc. Specific examples of "carbamoyl-substituted C1-6 alkyl" include, but are not limited to, carbamoyl-substituted C1-4 alkyl, 6-amino-6-oxohexyl (i.e., H2NC(=O)-(CH2)5-, or carbamoylpentyl), 7-amino-7-oxoheptyl (i.e., H2NC(=O)-(CH2)6-, or carbamoylhexyl), and the like.

[0067] As used herein, "amidinoamino-substituted C1-6 alkyl" refers to a C1-6 alkyl substituted with at least one -NH-C(=NH)-NH2 group, wherein the nitrogen atom of the amidinoamino group may be protected with a nitrogen-protecting group (e.g., tert-butoxycarbonyl group). Examples of "amidinoamino-substituted C1-6 alkyl" include, but are not limited to, "amidinoamino-substituted C1-4 alkyl". Specific examples of "amidinoamino-substituted C1-4 alkyl" include, but are not limited to, (amidinoamino)methyl, 2-(amidinoamino)ethyl, 3-(amidinoamino)propyl, 4-(amidinoamino)butyl, etc. Specific examples of "amidinoamino-substituted C1-6 alkyl" include, but are not limited to, amidinoamino-substituted C1-4 alkyl, 5-(amidinoamino)pentyl, 6-(amidinoamino)hexyl, etc.

[0068] As used herein, "carboxy-substituted C1-6 alkyl" refers to a C1-6 alkyl substituted with at least one -COOH group. Examples of "carboxy-substituted C1-6 alkyl" include, but are not limited to, "carboxy-substituted C1-4 alkyl". Specific examples of "carboxy-substituted C1-4 alkyl" include, but are not limited to, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, etc. Specific examples of "carboxy-substituted C1-6 alkyl" include, but are not limited to, carboxy-substituted C1-4 alkyl, 5-carboxypentyl, 6-carboxyhexyl, etc.

[0069] As used herein, the term "unsubstituted carbonyl" in "unsubstituted or substituted carbonyl" refers to a carboxylic acid group, and the term "substituted carbonyl" refers to a carboxy ester or an amide thereof, a hydrocarbonyl group, an optionally substituted lower alkylcarbonyl group, an optionally substituted arylcarbonyl group, etc.

[0070] As used herein, the term "unsubstituted sulfonyl" in "unsubstituted or substituted sulfonyl" refers to a sulfonic acid group, and the term "substituted sulfonyl" refers to an ester of a sulfonic acid group or an amide thereof, a hydrosulfonyl group, an optionally substituted lower alkylsulfonyl group, an optionally substituted arylsulfonyl group, etc.

[0071] As used herein, the term "unsubstituted sulfinyl" in "unsubstituted or substituted sulfinyl" refers to a sulfinic acid group, and the term "substituted sulfinyl" refers to an ester of a sulfinic acid group or an amide thereof, a hydrosulfinyl group, an optionally substituted lower alkylsulfinyl group, an optionally substituted arylsulfinyl group, etc.

[0072] As used herein, the term "unsubstituted acyl" in "unsubstituted or substituted acyl" refers to an acyl group such as esterified carboxy, and the term "substituted acyl" refers to carbamoyl, optionally substituted lower alkylcarbamoyl, optionally substituted lower alkanoyl, aroyl, optionally substituted heteroarylcarbonyl, etc. Specific examples include trifluoroacetyl, etc.

[0073] As used herein, "alkylene" refers to a straight-chain or branched-chain divalent saturated aliphatic hydrocarbon group. "C1-6 alkylene" refers to an alkylene group having 1 to 6 carbon atoms, and preferred examples include "C1-4 alkylene," more preferably "C1-3 alkylene," and even more preferably "C1-2 alkylene." Specific examples of "C1-4 alkylene" include methylene, ethylene, propylene, isopropylene, n-butylene, etc. Specific examples of "C1-6 alkylene" include, but are not limited to, C1-4 alkylene, n-pentylene, n-hexylene, etc.

[0074] As used herein, "alkenylene" refers to a straight-chain or branched-chain divalent unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond. "C2-6 alkenylene" refers to an alkenylene group having 2 to 6 carbon atoms, and preferred examples include "C2-4 alkenylene." Specific examples of "C2-6 alkenylene" include, but are not limited to, vinylene, 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene, and 1,3-butadienylene.

[0075] As used herein, "alkynylene" refers to a straight-chain or branched-chain divalent unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond. "C2-6 alkynylene" refers to an alkynylene group having 2 to 6 carbon atoms, and preferred examples include "C2-4 alkynylene." Specific examples of "C2-6 alkynylene" include, but are not limited to, ethynylene, 1-propynylene, 2-propynylene, 1-butynylene, 1,3-butadiynylene, 1-methyl-2-propynylene, 3-butynylene, 1-pentynylene, 1-hexynylene, and the like.

[0076] As used herein, "arylene" refers to a divalent group of a monocyclic or bicyclic aromatic hydrocarbon ring, and "C6-10 arylene" refers to an arylene group having 6 to 10 carbon atoms. Examples of "arylene" include, but are not limited to, C6 arylene, C10 arylene, etc. Specific examples of C6 arylene include, but are not limited to, o-, m-, or p-phenylene, etc. Specific examples of C10 arylene include, but are not limited to, 1,3-naphthylene, etc.

[0077] As used herein, "heteroarylene" refers to a divalent monocyclic or bicyclic aromatic heterocyclic group containing 1 to 4 identical or different heteroatoms selected from the group consisting of oxygen atoms, nitrogen atoms, and sulfur atoms; and "5- to 10-membered heteroarylene" refers to a divalent monocyclic or bicyclic aromatic heterocyclic group consisting of 5 to 10 atoms containing 1 to 4 identical or different heteroatoms selected from the group consisting of oxygen atoms, nitrogen atoms, and sulfur atoms. Specific examples of "5- to 10-membered heteroarylene" include 5- or 6-membered heteroarylene, quinolylene, isoquinolylene, naphthyridinylene, quinoxalinylene, cinnolinylene, quinazolinylene, phthalazinylene, imidazopyridylene, imidazothiazolylene, imidazooxazolylene, benzothiazolylene, benzoxazolylene, benzimidazolylene, indolylene, indazolylene, pyrrolopyridylene, thienopyridylene, furopyridylene, benzothiadiazolylene, benzoxadiazolylene, pyridopyrimidinylene, benzofurylene, benzothienylene, quinolonylene, and the like, but are not limited to these.

[0078] In this specification, specific examples of "5- or 6-membered heteroarylene" include, but are not limited to, pyrrolylene, furylene, thienylene, pyrazolylene, imidazolylene, oxazolylene, oxadiazolylene, thiazolylene, thiadiazolylene, triazolylene, tetrazolylene, pyridylene, pyridazinylene, pyrimidinylene, pyrazinylene, and the like.

[0079] A "protecting group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, masks, reduces, or prevents the reactivity of the functional group. Typically, a protecting group can be selectively removed during a synthetic process, if desired. Examples of protecting groups can be found in Peter GM Wuts, "Greene's Protective Groups in Organic Synthesis", 5th Ed., John Wiley & Sons, Inc., Hoboken, New Jersey (2014) and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, John Wiley & Sons, NY, etc. As used herein, a "protecting group" may fall within the definition of substituent α. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilylethanesulfonyl ("TES"), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), and nitro-veratryloxycarbonyl ("NVOC"). Representative hydroxyl protecting groups include, but are not limited to, those in which the hydroxyl group is acylated (esterified) or alkylated, such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS, triethylsilyl, t-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS)), alkylarylsilyl ethers (e.g., t-butyldiphenylsilyl (TBDPS)), triarylsilyl ethers (e.g., triphenylsilyl), glycol ethers (e.g., ethylene glycol ether, propylene glycol ether, etc.), and allyl ethers.

[0080] <Preferred Embodiments> Preferred embodiments of the present invention are described below. The embodiments provided below are provided for a better understanding of the present invention, and the scope of the present invention should not be limited to the following description. Therefore, it is clear that those skilled in the art can make appropriate modifications within the scope of the present invention in consideration of the description in this specification.

[0081] <Compounds and compositions of the present invention> In one aspect, the present invention provides compounds of formula (I): [In the formula, are the same or different and each independently: A and C are each independently a bond, or optionally substituted methylene, carbonyl, thiocarbonyl, sulfinyl, sulfonyl, phosphoryl, optionally substituted amido, or thioamido; B is a bond, or straight-chain C1-6 alkylene, C3-11 cycloalkylene, or C3-11 heterocycloalkylene, straight-chain C2-6 alkenylene, C3-8 cycloalkenylene, or C3-8 heterocycloalkenyne, straight-chain C1-6 alkynylene, optionally substituted by 1 to 3 groups selected from the group consisting of C1-6 alkyl, C3-8 cycloalkyl, trifluoromethyl, hydroxyl, amino, amido, halogen, and C1-6 alkoxy, or an arylene or heteroarylene group optionally substituted by 1 or 2 groups selected from the group consisting of C1-6 alkyl, trifluoromethyl, hydroxyl, amino, amido, halogen, and C1-6 alkoxy; Y 1 , Y 2 , Y 3 and X 4 are each independently -O-, -N=, -S-, or -NR 1 - or -CR 2 = ; where Y 1 , Y 2 , Y 3 and X 4 At least one of these is -N= or -NR 1 - and R 1is hydrogen, optionally substituted C alkyl, optionally substituted C aryl, or optionally substituted 5-10 membered heteroaryl; R 2 is hydrogen, optionally substituted C alkyl, optionally substituted C carbonyl, optionally substituted C alkoxy, optionally substituted C alkylthio, optionally substituted C alkylamino, optionally substituted C aryl, or optionally substituted 5-10 membered heteroaryl; R 6 , R 7 , R 10 , R 11 and R 12 are each independently hydrogen, optionally substituted C alkyl, optionally substituted C aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C alkoxy, hydroxy, amino, cyano, carbamoyl or halogen; n is 1, 2 or 3; where, when n is 2, one carbon atom is not substituted with R 6 and R 7 are bonded together, and the other carbon atom has R 8 and R 9 when n is 3, the two carbon atoms each independently have R 6 and R 7 are bonded together independently, and the remaining carbon atoms are 8 and R 9 are bonded together; R 8 and R 9 are each independently hydrogen, optionally substituted C alkyl, optionally substituted C aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C alkoxy, hydroxy, amino, cyano, carbamoyl or halogen; or R 6 and R 7 , R 8 and R 9 , and R 10 and R 11each independently bridges together with the carbon to which it is bonded to form a C3-6 spiro ring, and R 6 or R 7 and R 8 or R 9 forms a double bond with the adjacent carbon atom, and R 8 or R 9 and R 10 or R 11 forms a double bond with the adjacent carbon atom, and R 8 or R 9 and R 12 forms a double bond with the adjacent carbon atom, and R 10 or R 11 and R 12 forms a double bond together with the adjacent carbon atom, and the adjacent R 6 or R 7 and R 6 or R 7 are bridged together to form -CH2- or -CH2-CH2-, and adjacent R 6 or R 7 and R 8 or R 9 are bridged together to form -CH2-, -CH2-CH2-, -CH2-CH2-CH2- or -CH2-CH2-CH2-CH2-, and adjacent R 7 and R 8 and R 10 or R 11 are bridged together to form -CH2-, -CH2-CH2-, -CH2-CH2-CH2- or -CH2-CH2-CH2-CH2-, R 12 and R 6 or R 7 are bridged together to form -CH2- or -CH2-CH2-, and R 12 and R 8 or R 9 are bridged together to form -CH2- or -CH2-CH2-, or R 12 and R 10 or R 11are joined together to bridge and form -CH2- or -CH2-CH2-. Here, the substituents in "optionally substituted" are selected from the following: hydroxy, halogen, cyano, carbamoyl, amino, amidinoamino, carboxy, C6-10 aryl, 5- to 10-membered heteroaryl substituted with C1-4 alkoxycarbonyl, C6-10 aryl substituted with C1-4 alkyl, C6-10 aryl substituted with hydroxy, C6-10 aryl substituted with halogen, C6-10 aryl substituted with C1-4 alkoxy, (optionally substituted amino)-C6-10 aryl, C1-4 alkoxycarbonyl, C1-4 alkoxycarbonylamino, 5- to 6-membered heterocycloalkyl, C3-6 cycloalkyl, 5- to 10-membered heteroaryl, C6-10 aryl substituted with (C1-6 alkyl substituted with halogen), and trialkylsilyloxy, alkylarylsilyloxy, triarylsilyloxy, or a protecting group. However, the formula: The present invention relates to a compound represented by the formula: [Excluding a compound represented by the formula:], its enantiomer, or a pharmaceutically acceptable salt thereof. The compound excluding the compound represented by the formula: is described in PCT / JP2022 / 025361 (WO 2022 / 270628).

[0082] The present invention relates to a compound of formula (I): The compounds of the present invention may be selected from the group consisting of the azole structure, the P and Q moieties, and the α-forms thereof, depending on the position of the azole structure relative to the N (nitrogen)-containing skeleton structure: and β-isomer: Thus, the compounds of the present invention may include α+α homodimers, β+β homodimers, and α+β heterodimers with respect to the P and Q moieties. The α forms in an α+α homodimer may be the same or different, as long as they are α forms. A homodimer consisting of the same α form may be referred to as a "homodimer of the same α+α form," and a homodimer consisting of different α forms may be referred to as a "homodimer of different α+α forms." Similarly, a homodimer consisting of the same β form may be referred to as a "homodimer of the same β+β form," and a homodimer consisting of different β forms may be referred to as a "homodimer of different β+β forms."

[0083] In a preferred embodiment, the present invention provides a compound represented by formula (I): is a group represented by the formula: Examples of the compound include a compound represented by formula (I), an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a group represented by formula (I):

[0084] In a further preferred embodiment, the present invention provides a compound represented by the formula (I): is a group represented by the formula: (wherein R is hydrogen, optionally substituted C alkyl, optionally substituted C aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C alkoxy, hydroxy, optionally substituted C amino, optionally substituted C amido, cyano, carbamoyl or halogen; R is hydrogen or optionally substituted C alkyl; Z is optionally substituted C alkyl, hydroxy or halogen; and the wavy line in the above group has the formula: and a pharmaceutically acceptable salt thereof, wherein the azole ring represented by the formula (I) is bonded to the compound represented by the formula (I), an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[0085] In an even more preferred embodiment, the present invention provides a compound represented by formula (I): is a group represented by the formula: (wherein R is hydrogen, optionally substituted C alkyl, optionally substituted C aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C alkoxy, hydroxy, optionally substituted C amino, optionally substituted C amido, cyano, carbamoyl or halogen; R is hydrogen or optionally substituted C alkyl; Z is optionally substituted C alkyl, hydroxy or halogen; and the wavy line in the above group has the formula: and a pharmaceutically acceptable salt thereof, wherein the azole ring represented by the formula (I) is bonded to the compound represented by the formula (I), an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[0086] In an even more preferred embodiment, the present invention provides a compound represented by the formula (I): is a group represented by the formula: (Here, at the end of the wavy line, there is the formula: and R is hydrogen, hydroxy, t-butyloxy, phenyl, fluorine, cyano, or carbamoyl), or an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[0087] In the present invention, in formula (I), In the group represented by the formula: n is 1, 2 or 3. When n is 2, one carbon atom is 6 and R 7 are bonded together, and the other carbon atom has R 8 and R 9 For example, "one carbon atom has R 6 and R 7 "Bond together" means that R 6 and R 7 When n is 3, the two carbon atoms are each independently bonded to one carbon atom. 6 and R 7 are bonded together independently, and the remaining carbon atoms are 8 and R 9The two carbon atoms are bonded together. 6 and R 7 are bonded together independently" means that one of the two carbon atoms has R 6 and R 7 is bonded to the other 6 and R 7 In this case, one of the R 6 and R 7 are the other R 6 and R 7 can be the same as or different from.

[0088] In a preferred embodiment, the present invention provides a compound represented by the formula (I): In the azole ring represented by the formula: 3 Ga-CR 2 = R 2 may be an optionally substituted C1-6 carbonyl. (wherein R is an optionally substituted C1-6 alkyl, an optionally substituted C1-6 alkoxy, an optionally substituted C1-6 alkylamino, an optionally substituted C6-10 aryl, or an optionally substituted 5- to 10-membered heteroaryl).

[0089] In a preferred embodiment, the present invention provides a compound represented by the formula (I): is an azole ring represented by the formula: (Here, R 15 is optionally substituted C alkyl, optionally substituted C alkoxy, optionally substituted C alkylthio, optionally substituted C alkylamino, optionally substituted C aryl, optionally substituted 5-10 membered heteroaryl; R 16 is an optionally substituted C1-6 alkyl, an optionally substituted C6-10 aryl, or an optionally substituted 5- to 10-membered heteroaryl), an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[0090] In a further preferred embodiment, the present invention provides a compound represented by the formula (I): The azole ring represented by the formula: (Here, R 12 and R 13 are each independently hydrogen, optionally substituted C alkyl, optionally substituted C alkoxy, optionally substituted C alkylthio, optionally substituted C alkylamino, optionally substituted C aryl, or optionally substituted 5-10 membered heteroaryl; R 17 is an optionally substituted C1-6 alkyl, an optionally substituted C6-10 aryl, or an optionally substituted 5-10 membered heteroaryl), a group represented by the formula (I), an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[0091] In a further more preferred embodiment, the present invention provides a compound of formula (I) having the formula: is an azole ring represented by the formula: (Here, R 12 and R 13 are each independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C1-6 alkylthio, optionally substituted C1-6 alkylamino, optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl), a compound represented by formula (I), an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[0092] In yet another preferred embodiment, the present invention provides a compound represented by the formula (I): is an azole ring represented by the formula: (wherein R is hydrogen, optionally substituted C1-6 alkyl, R 13is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C1-6 alkylthio, optionally substituted C1-6 alkylamino, optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl), or an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[0093] In another preferred embodiment of the present invention, in formula (I), R 2 but, (wherein X is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C5-10 membered heteroaryl, optionally substituted C1-6 alkoxy, hydroxy, amino, cyano, carbamoyl or halogen; Z is O, NH, S; and n is an integer from 1 to 5), an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[0094] In a further preferred embodiment, the present invention provides a compound in which R 1 is a side chain of the azole ring in formula (I). 2 but, The present invention also includes the compounds of formula (I) represented by the formula:

[0095] In the present invention, when A and C of the divalent group -ABC are optionally substituted amide or thioamide, it can have the following structure: (wherein each Y is independently O (oxygen) or S (sulfur), and R is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, or optionally substituted 5-10 membered heteroaryl).

[0096] In another preferred embodiment, the present invention provides a compound represented by formula (I), wherein A and C are each independently a group represented by the formula: wherein Z is C, S, SO, SO2 or P; Y is O or S; R3 is hydrogen or optionally substituted C1-6 alkyl), an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[0097] In a further preferred embodiment, the present invention relates to a compound represented by formula (I), wherein A and C are each independently a group represented by the formula: The present invention also includes the compounds of formula (I) represented by the formula:

[0098] In a more preferred embodiment of the present invention, in formula (I), B is a compound represented by the formula: The present invention also includes the compounds of formula (I) represented by the formula:

[0099] In an even more preferred embodiment, the present invention relates to a compound of formula (I), wherein B is a compound of formula: The present invention also includes the compounds of formula (I) represented by the formula:

[0100] In another embodiment, the present invention encompasses not only dimeric compounds but also monomeric compounds. That is, the monomeric compounds are represented by the formula (I): wherein either the P moiety or the Q moiety is as defined above, and the other is optionally substituted C1-6 alkyl, optionally substituted C6-10 membered aryl, optionally substituted C6-10 membered heteroaryl, optionally substituted C1-6 alkoxy, hydroxy, amino, or optionally substituted C1-6 amino, or an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[0101] Preferred monomeric entities include, for example:

[0102] The compounds of the present invention are further described below. Depending on the type of substituent, the compounds of the present invention may exist as stereoisomers such as rotational isomers, tautomers, and geometric isomers, as well as optical isomers, and the present invention includes all of these, as well as mixtures thereof. That is, when the compounds of the present invention have one or more asymmetric carbon atoms, diastereomers and enantiomers exist, and mixtures of these diastereomers and enantiomers, as well as isolated forms thereof, are also included in the compounds of the present invention.

[0103] In other embodiments, the present invention includes various hydrates, solvates and crystalline polymorphs.

[0104] Furthermore, as another embodiment, the present invention also includes prodrugs corresponding to the compounds of the present invention. In the present invention, a prodrug refers to a derivative that is hydrolyzed by acid or enzymatic decomposition in vivo to yield a compound represented by formula (I). For example, when a compound represented by formula (I) has a hydroxyl, amino, or carboxyl group, these groups can be modified using conventional methods to produce a prodrug. Prodrug technology is described, for example, in C.G. Wermuth, "The Practice of Medicinal Chemistry," 4th Ed., Academic Press, (2015), Chapter 28. For example, compounds having a carboxyl group include compounds in which the carboxyl group is an alkoxycarbonyl group, an alkylthiocarbonyl group, or an alkylaminocarbonyl group. For example, compounds having an amino group include compounds in which the amino group is substituted with an alkanoyl group to form an alkanoylamino group, compounds in which the amino group is substituted with an alkanoyl group to form an alkoxycarbonylamino group, compounds in which the amino group is substituted with an alkoxycarbonyl group to form an alkanoyloxymethylamino group, or compounds in which the amino group is hydroxylamine. Furthermore, for example, in the case of a compound having a hydroxyl, the hydroxyl may be substituted with the above-mentioned alkanoyl group to form an alkanoyloxy group, a phosphate ester, or an alkanoyloxymethyloxy group.

[0105] As used herein, the term "pharmaceutically acceptable salt" refers to an acid addition salt and a base addition salt that are acceptable for pharmaceutically use. Specific examples of "pharmaceutically acceptable salts" include acetate, propionate, butyrate, formate, trifluoroacetate, maleate, fumarate, tartrate, citrate, stearate, succinate, ethylsuccinate, malonate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, benzenesulfonate, paratoluenesulfonate (tosylate), lauryl sulfate, malate, ascorbate, mandelate, saccharate, xinafoate, pamoate, ketone ... Examples of the salts include, but are not limited to, acid addition salts such as arsenate, adipate, cysteine ​​salt, N-acetylcysteine ​​salt, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinate, oxalate, picrate, thiocyanate, undecanoate, acrylic acid polymer salt, and carboxyvinyl polymer; inorganic base addition salts such as lithium salt, sodium salt, potassium salt, and calcium salt; organic base addition salts such as morpholine and piperidine; and addition salts with amino acids such as aspartic acid and glutamic acid.

[0106] <Method for Producing the Compound of the Present Invention> General methods for producing the compound of the present invention will be explained below with examples, but the present invention is not limited to these.

[0107] The compounds of the present invention can be produced by the production methods described below. These production methods can be appropriately improved based on the knowledge of those skilled in organic synthetic chemistry. In the production methods described below, the compounds used as raw materials may be used in the form of salts, as long as they do not interfere with the reaction.

[0108] In the following production methods, even if the use of a protecting group is not specifically specified, if any functional group other than the reactive site changes under the reaction conditions or if the reaction is unsuitable for post-reaction treatment, the target compound can be obtained by protecting the functional group other than the reactive site as necessary and deprotecting it after the reaction or after a series of reactions. Protecting groups used in these processes include conventional protecting groups described in literature (Peter GM Wuts, "Greene's Protective Groups in Organic Synthesis," 5th Ed., John Wiley & Sons, Inc., Hoboken, New Jersey (2014)). The introduction and removal of protecting groups can be carried out by methods commonly used in organic synthetic chemistry (e.g., methods described in the above literature) or methods similar thereto.

[0109] The starting materials and intermediates in the following production methods are commercially available or can be obtained by synthesis from known compounds according to known methods or methods described in known literature. Furthermore, salts of these starting materials and intermediates may be used as long as they do not interfere with the reaction.

[0110] The intermediates and target compounds in the following production methods can be converted into other compounds included in the present invention by appropriately converting their functional groups. The conversion of functional groups can be carried out by a method commonly used in organic synthetic chemistry (e.g., the method described in R.C. Larock, "Comprehensive Organic Transformations," 2nd Ed., John Wiley and Sons, Inc., New York (1999)) or a method similar thereto.

[0111] In the production methods described below, the inert solvent means a solvent that does not react with the raw materials, reagents, bases, acids, catalysts, ligands, etc. used in the reaction (hereinafter, these may be referred to as "raw materials, etc. used in the reaction"). Even if the solvent used in each step reacts with the raw materials, etc. used in the reaction, it can be used as an inert solvent as long as the target reaction proceeds and the target compound is obtained.

[0112] The compound of the present invention is represented by the dimerization of a heterocycloalkyl-substituted polyheteroazole derivative. Therefore, the preparation of the compound of the present invention is based on the heteroazole ring formation reaction of a heterocycloalkyl compound and the dimerization of the heteroazole derivative. Scheme 1 (same α-form + α-form homodimer)

[0113]

[0114] Scheme 2 (identical β-form + β-form homodimer)

[0115] wherein A and C are each independently a bond, or optionally substituted methylene, carbonyl, thiocarbonyl, sulfinyl, sulfonyl, phosphoryl, optionally substituted amido, or thioamide; B is a bond, or straight-chain C1-6 alkylene, C3-11 cycloalkylene, or C3-11 heterocycloalkylene, straight-chain C2-6 alkenylene, C3-8 cycloalkenylene, or C3-8 heterocycloalkenyne, straight-chain C1-6 alkynylene, optionally substituted by 1 to 3 groups selected from the group consisting of C1-6 alkyl, C3-8 cycloalkyl, trifluoromethyl, hydroxyl, amino, amido, halogen, and C1-6 alkoxy, or an arylene or heteroarylene group optionally substituted by 1 or 2 groups selected from the group consisting of C1-6 alkyl, trifluoromethyl, hydroxyl, amino, amido, halogen, and C1-6 alkoxy; Y 1 , Y 2 , Y 3 and X 4 are each independently -O-, -N=, -S-, or -NR1 - or -CR 2 = ; where Y 1 , Y 2 , Y 3 and X 4 At least one of these is -N= or -NR 1 - and R 1 is hydrogen, optionally substituted C alkyl, optionally substituted C aryl, or optionally substituted 5-10 membered heteroaryl; R 2 is hydrogen, optionally substituted C alkyl, optionally substituted C carbonyl, optionally substituted C alkoxy, optionally substituted C alkylthio, optionally substituted C alkylamino, optionally substituted C aryl, or optionally substituted 5-10 membered heteroaryl; R 6 , R 7 , R 10 , R 11 and R 12 are each independently hydrogen, optionally substituted C alkyl, optionally substituted C aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C alkoxy, hydroxy, amino, cyano, carbamoyl or halogen; n is 1, 2 or 3; where, when n is 2, one carbon atom is not substituted with R 6 and R 7 are bonded together, and the other carbon atom has R 8 and R 9 when n is 3, the two carbon atoms each independently have R 6 and R 7 are bonded together independently, and the remaining carbon atoms are 8 and R 9 are bonded together; R 8 and R 9are each independently hydrogen, optionally substituted C alkyl, optionally substituted C aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C alkoxy, hydroxy, amino, cyano, carbamoyl or halogen; or R 6 and R 7 , R 8 and R 9 , and R 10 and R 11 each independently bridges together with the carbon to which it is bonded to form a C3-6 spiro ring, and R 6 or R 7 and R 8 or R 9 forms a double bond with the adjacent carbon atom, and R 8 or R 9 and R 10 or R 11 forms a double bond with the adjacent carbon atom, and R 8 or R 9 and R 12 forms a double bond with the adjacent carbon atom, and R 10 or R 11 and R 12 forms a double bond together with the adjacent carbon atom, and the adjacent R 6 or R 7 and R 6 or R 7 are bridged together to form -CH2- or -CH2-CH2-, and adjacent R 6 or R 7 and R 8 or R 9 are bridged together to form -CH2-, -CH2-CH2-, -CH2-CH2-CH2- or -CH2-CH2-CH2-CH2-, and adjacent R 7 and R 8 and R 10 or R 11 are bridged together to form -CH2-, -CH2-CH2-, -CH2-CH2-CH2- or -CH2-CH2-CH2-CH2-, R 12 and R6 or R 7 are bridged together to form -CH2- or -CH2-CH2-, and R 12 and R 8 or R 9 are bridged together to form -CH2- or -CH2-CH2-, or R 12 and R 10 or R 11 are bridged together to form -CH- or -CH-CH-.

[0116] The present invention can be exemplified by the following types of embodiments: * R 1 If the compound has a reactive functional group such as an amine, alcohol, carboxylic acid, or thiol, the side chain can be modified.

[0117] Step 1 of Scheme 1 and Scheme 2: Azole Formation Some embodiments of this aspect include the following reaction types: Table 2

[0118] Step 2 of Scheme 1 and Scheme 2: Deprotection １ This deprotection reaction is well known to those skilled in the art. A de-tert-butoxycarbonylation reaction and a de-9-fluorenylmethyloxycarbonylation reaction are carried out.

[0119] Step 3 in Scheme 1 and Scheme 2: Dimerization Step 3 in Scheme 1 and Scheme 2 is a substitution (or addition) reaction to effect dimerization, which is a sulfinylation reaction, sulfonylation reaction, carbonylation reaction, thiocarbonylation reaction, carbamate reaction, carbonate reaction, or alkylation reaction, which are well known to those skilled in the art.

[0120] Scheme 3 (different α-forms + α-form homodimer) (Here, A-7 is different from A-3 in Scheme 1.)

[0121] Scheme 4 (different β-forms + β-form homodimer) (Here, B-7 is different from B-3 in Scheme 2.)

[0122] Step 4 in Scheme 3 and Scheme 4: Introduction of R5 Step 4 in Scheme 3 and Scheme 4 is a substitution (or addition) reaction for introducing R5. This reaction is well known to those skilled in the art, and involves sulfinylation, sulfonylation, carbonylation, thiocarbonylation, carbamate formation, carbonate formation, or alkylation.

[0123] Step 5 of Scheme 3 and Scheme 4: Deprotection Step 2 is the deprotection of the protecting group P 2 This deprotection reaction is well known to those skilled in the art. Hydrolysis, de-tert-butoxycarbonylation, and de-9-fluorenylmethyloxycarbonylation are carried out.

[0124] Step 6 in Schemes 3 and 4: Dimerization Step 6 in Schemes 3 and 4 is a substitution (or addition) reaction to effect dimerization, which is a sulfinylation reaction, sulfonylation reaction, carbonylation reaction, thiocarbonylation reaction, carbamate reaction, carbonate reaction, or alkylation reaction, which are well known to those skilled in the art.

[0125] An example of preparation of a homodimer of different α-forms + α-forms is shown below as a reference scheme. (Reference Scheme)

[0126] As described above, Scheme 3 (different α-forms + α-form homodimers) and Scheme 4 (different β-forms + β-form homodimers) have been shown, but α-form + β-form heterodimers can be prepared by changing the combination of Compound A3 or Compound A7 and Compound B3 or B7. Furthermore, monomers can be prepared by using an amino compound or the like instead of Compound A7 and Compound B7.

[0127] The intermediates and target compounds in the above production methods can be isolated and purified by purification methods commonly used in organic synthetic chemistry (e.g., neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography, etc.). Alternatively, each intermediate can be used in the next reaction without further purification.

[0128] Optically active forms of the compounds of the present invention can be produced by using optically active starting materials or intermediates, or by optically resolving racemates of intermediates or final products. Optical resolution methods include, but are not limited to, separation methods using optically active columns and fractional crystallization. Diastereomers of the compounds of the present invention can be produced by, but are not limited to, separation methods such as column chromatography and fractional crystallization.

[0129] Pharmaceutically acceptable salts of the compound represented by formula (I) can be produced by mixing the compound represented by formula (1) with a pharmaceutically acceptable acid or base in a solvent such as, but not limited to, water, methanol, ethanol, 2-propanol, ethyl acetate, or acetone.

[0130] <Pharmaceutical Composition> In another aspect, the present invention provides a pharmaceutical composition containing the compound of the present invention, its enantiomer, or a pharmaceutically acceptable salt thereof. Specifically, the present invention provides a pharmaceutical composition for treating or preventing fibrosis, particularly pulmonary fibrosis, containing the compound of the present invention, its enantiomer, or a pharmaceutically acceptable salt thereof.

[0131] In yet another aspect, the present invention provides a pharmaceutical composition for treating or preventing fibrosis, particularly pulmonary fibrosis, containing naphthalene-2,6-diylbis(((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone). The pharmaceutical use of naphthalene-2,6-diylbis(((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) is demonstrated in Test Example 1 herein.

[0132] As used herein, "treatment" means a method or process intended to (1) delay or prevent the onset of a disease or condition; (2) slow or halt the progression, worsening, or deterioration of the symptoms of a disease or condition; (3) bring about the amelioration of the symptoms of a disease or condition; or (4) cure a disease or condition. Treatment may be administered prior to the onset of a disease or condition as a preventative measure, or alternatively, treatment may be administered after the onset of the disease.

[0133] In the present invention, "prevention" means preventing the onset of fibrosis, particularly pulmonary fibrosis.

[0134] In one embodiment, the compound of the present invention can be administered orally or parenterally, either directly or in the form of a formulation, medicament, or pharmaceutical composition using an appropriate dosage form. Specific examples of these dosage forms include, but are not limited to, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, and poultices. These formulations can be prepared by known methods using additives commonly used as pharmaceutical additives.

[0135] Depending on the purpose, these additives may include excipients, disintegrants, binders, fluidizing agents, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, sweeteners, flavors, etc. Specific examples of these additives include, but are not limited to, lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc, etc.

[0136] The dose of the compound of the present invention is appropriately selected depending on the subject to be administered, the administration route, the disease, the age, weight, and symptoms of the subject. For example, in the case of oral administration, the lower limit is 0.01 mg (preferably 100 mg) and the upper limit is 10,000 mg (preferably 6,000 mg) per day for an adult, and this amount can be administered once a day or in divided doses.

[0137] In another aspect, the present invention relates to a method for treating or preventing fibrosis, preferably pulmonary fibrosis, comprising administering a compound of the present invention, its enantiomer, or a pharmaceutically acceptable salt thereof to a subject in need of such treatment. In yet another aspect, the present invention relates to a compound of the present invention, its enantiomer, or a pharmaceutically acceptable salt thereof for treating or preventing fibrosis, preferably pulmonary fibrosis. In yet another aspect, the present invention relates to use of a compound of the present invention, its enantiomer, or a pharmaceutically acceptable salt thereof for manufacturing a medicament for treating or preventing fibrosis, preferably pulmonary fibrosis.

[0138] References, such as patent literature and non-patent literature, such as patents or patent applications, cited in this specification are incorporated herein by reference to the same extent as if each were specifically disclosed in its entirety.

[0139] As described above, the preferred embodiments of the present invention have been described to facilitate understanding of the invention. The present invention will be described in more detail below based on examples. However, it should be noted that the above description and the following examples are merely illustrative and do not limit the scope of the present invention.

[0140] Example 1 Naphthalene-2,6-diylbis(((S)-2-(3-(3-phenylpropyl)-1,2,4-oxazol-5-yl)pyrrolidin-1-yl)methanone) 1-3 Example 1-1: N'-hydroxy-4-phenylbutanimidamide

[0141] 4-Phenylbutyronitrile (500 mg, 3.44 mmol) and 50% aqueous hydroxylamine solution (2.03 ml, 34.4 mmol) were added to a recovery flask, dissolved in absolute ethanol (13.8 ml), and heated to reflux at 95°C for 4 hours. After distilling off the solvent, the residue was dried in vacuo to obtain the title compound (oil, 614 mg, yield: 100%).

[0142] Example 1-2: 3-(3-phenylpropyl)-5-[(2S)-1-tert-butoxycarbonylpyrrolidin-2-yl]-1,2,4-oxadiazole 1-1

[0143] N-Boc-L-proline (100 mg, 0.465 mmol) was dissolved in dichloromethane (3.15 ml) in a 25 ml eggplant-shaped flask. HATU (212 mg, 0.558 mmol) and diisopropylethylamine (0.162 ml, 0.929 mmol) were then added and the mixture was stirred at room temperature for 10 minutes under a nitrogen atmosphere. N'-hydroxy-4-phenylbutanimidamide (99 mg, 0.557 mmol) was then added, washing in with dichloromethane (1.5 ml), and the mixture was stirred at room temperature for 3.5 hours.

[0144] The stir bar was removed and the solvent was evaporated. The residue was purified using a silica gel column, Q-pack SI30, size 20 (hexane:ethyl acetate = 83:17 to 40:60). After evaporation, the intermediate imidamide was obtained as a mixture with the urea compound. To this mixture, pre-dried MS4Å (905 mg) was added and dissolved in ultra-dehydrated toluene (4.821 ml). A Dimroth condenser was attached and the mixture was stirred at 110 °C for 17.5 hours. After removing MS4Å by filtration through Celite, the solvent was evaporated. The resulting residue was purified using a silica gel column, Q-pack SI30, size 20 (hexane:ethyl acetate = 91:9 to 66:34). After evaporation, the desired compound 1-1 (oil) was obtained in an amount of 140 mg (0.391 mmol, 81% (after two steps)).

[0145] Example 1-3: 3-(3-phenylpropyl)-5-[(2S)-pyrrolidin-2-yl]-1,2,4-oxadiazole 1-2

[0146] Compound 1-1 (323 mg, 0.903 mmol) was added to a 25 ml eggplant-shaped flask, followed by the addition of dichloromethane (2.37 ml) and TFA (0.418 ml) and stirring at room temperature for 1 hour. The stir bar was then removed and the solvent was evaporated. The mixture was then basified with saturated aqueous sodium bicarbonate (5 ml) and extracted with ethyl acetate. The solvent was evaporated, and the resulting residue was purified on a silica gel column, Q-Pack SI30, size 20 (hexane:ethyl acetate = 50:50 to 0:100). After evaporation of the solvent, 127 mg (0.494 mmol, 55%) of the desired compound 1-2 (oil) was obtained.

[0147] Examples 1-4: Compound of Example 1 Naphthalene-2,6-diylbis(((S)-2-(3-(3-phenylpropyl)-1,2,4-oxazol-5-yl)pyrrolidin-1-yl)methanone) 1-3

[0148] To a 4 ml vial containing compound 1-2 (7.7 mg, 0.030 mmol), naphthoyl dichloride (11.6 mg, 0.045 mmol), prepared separately from 2,6-naphthalenedicarboxylic acid and oxalyl chloride, was added while washing with ultra-dehydrated THF (1.2 ml). Triethylamine (41.5 μl, 0.299 mmol) was added to this solution and stirred at room temperature for 40 min. After evaporation of the solvent, water (1 ml) and 1 M aqueous hydrochloric acid (0.1 ml) were added, followed by extraction with ethyl acetate. After evaporation of the solvent, the residue was purified on a silica gel column (Q-pack SI20 size 10) (hexane:ethyl acetate = 0:100 to chloroform:methanol = 90:10). After evaporation of the solvent, 4.3 mg (6.2 μmol, 41%) of the desired compound 1-3 (colorless amorphous solid) was obtained. At the same time, 4.2 mg (9.2 μmol, 31%) of compound 1-4 (yellowish white solid) was obtained as a by-product. The LC-MS and 1H-NMR data of the obtained compound are summarized in Table 3 below.

[0149] Example 2 (S)-6-(2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-2-naphthamide 1-5

[0150] Compound 1-4 (4.2 mg, 9.2 μmol) prepared in Example 1-4 and dichloromethane (0.922 ml) were added to a 4 ml vial, followed by HATU (21 mg, 0.055 mmol) and diisopropylethylamine (24.1 μl, 0.138 mmol). The mixture was stirred at room temperature for 5 minutes under a nitrogen atmosphere. Ammonium chloride (3.1 mg, 0.055 mmol) was then added and the mixture was stirred at room temperature for 1 hour. After evaporation of the solvent, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified on a silica gel column, Q-Pack SI30, size 10 (chloroform:methanol = 100:0 to 95:5). After evaporation of the solvent, 2.4 mg (5.3 μmol, 57%) of the desired compound 1-5 was obtained. The LC-MS and 1H-NMR data of the obtained compounds are summarized in Table 3 below.

[0151] Example 3 Naphthalene-2,6-diylbis(((S)-2-(3-(3-phenylpropyl)-1,2,4-oxazol-5-yl)piperidin-1-yl)methanone) 2-3

[0152] Example 3-1: 3-(3-phenylpropyl)-5-[(2S)-1-tert-butoxycarbonylpiperidin-2-yl]-1,2,4-oxadiazole 2-1

[0153] N-Boc-L-pipecolic acid (100 mg, 0.436 mmol) was dissolved in dichloromethane (3.36 ml) in a 25 ml eggplant-shaped flask. HATU (199 mg, 0.523 mmol) and diisopropylethylamine (0.113 ml, 0.872 mmol) were then added and stirred at room temperature for 10 minutes under a nitrogen atmosphere. N'-hydroxy-4-phenylbutanimidamide (93.3 mg, 0.523 mmol) was then added, washing with dichloromethane (1.0 ml), and the mixture was stirred at room temperature for 3 hours. The stir bar was removed and the solvent was evaporated. The residue was purified on a silica gel column, Q-Pack SI30 size 20 (hexane:ethyl acetate = 84:16 to 50:50). After evaporation of the solvent, the intermediate imidamide was obtained. To this, pre-dried MS4Å (850 mg) was added and dissolved in ultra-dehydrated toluene (4.37 ml). A Dimroth condenser was attached and the mixture was stirred at 110 °C for 17.5 hours. After removing MS4Å by filtration through Celite, the solvent was evaporated, and the resulting residue was purified on a silica gel column, Q-Pack SI30, size 20 (hexane:ethyl acetate = 93:7 to 83:17). After evaporation of the solvent, 119 mg (0.320 mmol, 73% (after two steps)) of the desired compound 2-1 (oil) was obtained.

[0154] Example 3-2: 3-(3-phenylpropyl)-5-[(2S)-piperidin-2-yl]-1,2,4-oxadiazole 2-2

[0155] Compound 2-1 (224.8 mg, 0.605 mmol) prepared in Example 3-1 was added to a 25 ml eggplant-shaped flask, followed by dichloromethane (1.59 ml) and TFA (0.280 ml). The mixture was stirred at room temperature for 1 hour. The stir bar was then removed and the solvent was evaporated. The mixture was then basified with saturated aqueous sodium bicarbonate (5 ml) and extracted with ethyl acetate. The solvent was evaporated, and the resulting residue was purified using a silica gel column (Q-Pack SI30, size 20) (hexane:ethyl acetate = 50:50 to 0:100). After evaporation of the solvent, 96.9 mg (0.357 mmol, 59%) of the desired compound 2-2 (oil) was obtained.

[0156] Example 3-3: Compound of Example 3 Naphthalene-2,6-diylbis(((S)-2-(3-(3-phenylpropyl)-1,2,4-oxazol-5-yl)piperidin-1-yl)methanone) 2-3

[0157] To a 4 ml vial containing compound 2-2 (7.1 mg, 0.028 mmol) prepared in Example 3-2, naphthoyl dichloride (10.7 mg, 0.041 mmol), prepared separately from 2,6-naphthalenedicarboxylic acid and oxalyl chloride, was added while washing with ultra-dehydrated THF (1.1 ml). Triethylamine (76.5 μl, 0.552 mmol) was added to this solution and stirred at room temperature for 40 minutes. After evaporation of the solvent, water (1 ml) and 1 M aqueous hydrochloric acid (0.15 ml) were added, followed by extraction with ethyl acetate. After evaporation of the solvent, the residue was purified using a silica gel column Q-pack SI20 size 10 (hexane:ethyl acetate = 30:70 to chloroform:methanol = 90:10). After distilling off the solvent, 3.3 mg (4.6 μmol, 33%) of the target compound 2-3 (colorless amorphous solid) was obtained. At the same time, 5.2 mg (11 μmol, 40%) of compound 2-4 (yellow-white solid) was also obtained as a by-product. The LC-MS and H-NMR data of the obtained compound are summarized in Table 3 below.

[0158] Example 4 (S)-6-(2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-2-naphthamide 2-5

[0159] Compound 2-4 (5.2 mg, 11 μmol) prepared in Example 3-3 and dichloromethane (0.738 ml) were added to a 4 ml vial, followed by HATU (25.3 mg, 0.066 mmol) and diisopropylethylamine (28.9 μl, 0.166 mmol). The mixture was stirred at room temperature for 5 minutes under a nitrogen atmosphere. Ammonium chloride (3.7 mg, 0.066 mmol) was then added and the mixture was stirred at room temperature for 1 hour. After evaporation of the solvent, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified on a silica gel column (Q-Pack SI30 size 10) (chloroform:methanol = 100:0 to 95:5). After evaporation of the solvent, 3.6 mg (7.7 μmol, 69%) of the desired compound 2-5 was obtained. The LC-MS and 1H-NMR data of the obtained compounds are summarized in Table 3 below.

[0160] Example 5 Naphthalene-2,6-diylbis(((1R,3S,4S)-3-(3-phenethyl-1,2,4-oxadiazol-5-yl)-2-azabicyclo[2.2.1]heptan-2-yl)methanone) 3-3 Example 5-1: Synthesis of N'-hydroxy-3-phenylpropanimidamide

[0161] 3-Phenylpropionitrile (526 mg, 4.01 mmol) and 50% aqueous hydroxylamine solution (2.36 ml, 40.1 mmol) were added to a recovery flask, dissolved in absolute ethanol (16 ml), and heated to reflux at 95°C for 4 hours. After distilling off the solvent, the residue was dried in vacuo to obtain the title compound (oil, 657 mg, yield: 100%).

[0162] Example 5-2: tert-butyl (1R,3S,4S)-3-(3-phenethyl-1,2,4-oxadiazol-5-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate 3-1

[0163] 2-Boc-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (BLD pharm) (200 mg, 0.829 mmol) was added to a 25 ml eggplant-shaped flask and dissolved in dichloromethane (4.03 ml). HATU (378 mg, 0.995 mmol) and diisopropylethylamine (0.289 ml, 1.658 mmol) were then added, and the mixture was stirred at room temperature for 10 minutes under a nitrogen atmosphere. N'-hydroxy-3-phenylpropanimidamide (163 mg, 0.995 mmol) prepared in Example 5-1 was then added while washing with dichloromethane (1.5 ml), and the mixture was stirred at room temperature for 1 hour and 30 minutes.

[0164] The stir bar was removed and the solvent was evaporated. The residue was purified using a silica gel column (Q-pack SI30 size 20) (hexane:ethyl acetate = 90:10 to 50:50). After evaporation, the intermediate imidamide was obtained. Pre-dried MS4Å (1.61 g) was added and dissolved in ultra-dehydrated toluene (4.15 ml). A Dimroth condenser was attached and the mixture was stirred at 110 °C for 7 hours and at 130 °C for 16 hours. After removing MS4Å by filtration through Celite, the solvent was evaporated. The resulting residue was purified using a silica gel column (Q-pack SI30 size 20) (hexane:ethyl acetate = 100:0 to 66:34). After evaporation, the desired compound 3-1 (oil) was obtained in an amount of 264 mg (0.716 mmol, 86% (after two steps)).

[0165] Example 5-3: 5-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-yl)-3-phenethyl-1,2,4-oxadiazole 3-2

[0166] Compound 3-1 (252 mg, 0.681 mmol) prepared in Example 5-2 was added to a 10 ml recovery flask, followed by dichloromethane (1.70 ml) and TFA (0.567 ml) and stirring at room temperature for 1 hour. The stirrer bar was then removed and the solvent was evaporated. After basifying the mixture with saturated aqueous sodium bicarbonate (5 ml), the mixture was extracted with ethyl acetate. The mixture was dried over magnesium sulfate, filtered, and the solvent was evaporated to give 171 mg (0.636 mmol, 93%) of the desired compound 3-2 (oil).

[0167] Example 5-4: Compound of Example 5 Naphthalene-2,6-diylbis(((1R,3S,4S)-3-(3-phenethyl-1,2,4-oxadiazol-5-yl)-2-azabicyclo[2.2.1]heptan-2-yl)methanone) 3-3

[0168] Compound 3-2 (10.8 mg, 0.040 mmol) prepared in Example 5-3 was placed in a 4 mL vial, and triethylamine (55.6 μL, 0.401 mmol) was added and dissolved in ultra-dehydrated THF (0.2 mL). Naphthoyl dichloride (15.5 mg, 0.060 mmol), prepared separately from 2,6-naphthalenedicarboxylic acid and oxalyl chloride, was added while washing with ultra-dehydrated THF (0.6 mL). The mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. Water (1 mL) and 1 M aqueous hydrochloric acid (0.35 mL) were added, followed by extraction with ethyl acetate. After evaporation of the solvent, the residue was purified using a silica gel column (Q-Pack SI30 size 10) (hexane:ethyl acetate = 80:20 to 25:75, followed by chloroform:methanol = 100:0 to 90:10). After distilling off the solvent, 12.8 mg (0.018 mmol, 85%) of the target compound 3-3 (colorless amorphous solid) was obtained. The LC-MS and 1H-NMR data of the obtained compound are summarized in Table 3 below.

[0169] Example 6 Naphthalene-2,6-diylbis(((2S,4R)-4-hydroxy-2-(5-(3-phenylpropyl)-4H-1,2,4-triazol-3-yl)pyrrolidin-1-yl)methanone) 4-4 Example 6-1: Ethyl 4-phenylbutanimidate

[0170] 4-Phenylbutyronitrile (0.740 ml, 5.0 mmol) was added to a recovery flask and dissolved in absolute ethanol (3.47 ml). Acetyl chloride (2.82 ml, 40 mmol) was slowly added dropwise to the mixture while cooling with cold water. The mixture was then stirred at room temperature for 2 hours and 50 minutes, the solvent was evaporated, and the mixture was dried in vacuo to obtain the title compound (oil, 928 mg, yield: 97%).

[0171] Example 6-2: tert-butyl (2S,4R)-2-(hydrazinecarbonyl)-4-hydroxypyrrolidine-1-carboxylate 4-1

[0172] N-Boc-(2S,4R)-4-hydroxyproline (300 mg, 1.30 mmol) was dissolved in dimethylformamide (2.00 ml) in a 10 ml eggplant-shaped flask. HATU (543 mg, 1.43 mmol) and diisopropylethylamine (0.452 ml, 2.60 mmol) were then added and stirred at room temperature for 8 minutes under an argon atmosphere. A solution of hydrazine-1-hydrate (0.322 ml, 6.49 mmol) in dimethylformamide (2.33 ml) was then added and stirred at room temperature for 1 hour. The stir bar was removed and the solvent was evaporated. The residue was purified on a silica gel column (Q-Pack SI30 size 20) using a chloroform:methanol mixture (chloroform:methanol = 100:0 to 95:5). After distilling off the solvent, 304 mg (1.24 mmol, 95%) of the target compound 4-1 (white solid) was obtained.

[0173] Example 6-3: tert-butyl (2S,4R)-4-hydroxy-2-(5-(3-phenylpropyl)-4H-1,2,4-triazol-3-yl)pyrrolidine-1-carboxylate 4-2

[0174] Compound 4-1 (45.4 mg, 0.185 mmol), ethyl 4-phenylbutanimidate (108 mg, 0.555 mmol), and triethylamine (38.5 μl, 0.278 mmol) were added to a 10 ml eggplant-shaped flask, dissolved in ultra-dehydrated ethanol (2.31 ml), and stirred at 110 °C for 16 hours under an argon atmosphere. After removing the stir bar and evaporating the solvent, the residue was purified on a silica gel column (Q-Pack SI30 size 20) (chloroform:methanol = 100:0 to 80:20). After evaporating the solvent, 47.7 mg (0.128 mmol, 69%) of the desired compound 4-2 (amorphous solid) was obtained.

[0175] Example 6-4 (3R,5S)-5-(5-(3-)phenylpropyl-4H-1,2,4-triazol-3-yl)pyrrolidin-3-ol 4-3

[0176] Compound 4-2 (16.4 mg, 0.044 mmol) was added to a 10 ml eggplant-shaped flask, and 4N hydrochloric acid / dioxane (0.294 ml), dioxane (0.294 ml), and water (0.029 ml) were added. The mixture was stirred at room temperature for 1 minute. The stir bar was then removed and the solvent was evaporated. A saturated aqueous solution of sodium bicarbonate was added and the mixture was washed with chloroform. The aqueous layer was dried and then extracted with chloroform:methanol (3:1). The solvent was evaporated. The residue was purified using a silica gel column (Q-Pack SI30 size 10) (chloroform:methanol = 95:5 to 75:25). After evaporation of the solvent, 10.3 mg (0.038 mmol, 86%) of the desired compound 4-3 (amorphous solid) was obtained.

[0177] Example 6-5: Compound of Example 6 Naphthalene-2,6-diylbis(((2S,4R)-4-hydroxy-2-(5-(3-phenylpropyl)-4H-1,2,4-triazol-3-yl)pyrrolidin-1-yl)methanone) 4-4

[0178] 2,6-Naphthalenedicarboxylic acid (4.2 mg, 0.019 mmol) and a 1:1 dimethylformamide:dichloromethane solution (0.256 ml) were added to a 10 ml eggplant-shaped flask, followed by HATU (21.6 mg, 0.057 mmol) and diisopropylethylamine (29.6 μl, 0.170 mmol). The mixture was stirred at room temperature for 5 min under an argon atmosphere. Compound 4-3 (10.3 mg, 0.038 mmol) was then added, washing in with a 1:1 dimethylformamide:dichloromethane solution (0.50 ml), and the mixture was stirred at room temperature for 4 h. Water was added, and the mixture was extracted with ethyl acetate and chloroform. After evaporation of the solvent, the residue was purified by silica gel column Q-pack SI30 size 10 (chloroform:methanol = 100:0 to 85:15) and preparative TLC (chloroform:methanol = 5:1). After evaporation of the solvent, 4.4 mg (6.1 μmol, 32%) of the desired compound 4-4 (white solid) was obtained. The LC-MS and 1H-NMR data of the obtained compound are summarized in Table 3 below.

[0179] Example 7 Naphthalene-2,6-diylbis(((2S,4R)-4-(tert-butoxy)-2-(3-(4-phenylbutyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) C4-5-3 Example 7-1: Synthesis of N'-hydroxy-5-phenylpentanimidamide

[0180] 5-Phenylpentanenitrile (269 mg, 1.69 mmol) and 50% aqueous hydroxylamine solution (0.449 ml, 7.61 mmol) were added to a 10 ml eggplant-shaped flask, dissolved in absolute ethanol (2.26 ml), and heated under reflux at 95°C for 7 hours and 30 minutes. After distilling off the solvent, the mixture was dried in vacuo to obtain the desired compound, N'-hydroxy-5-phenylpentanimidamide (pale black-white solid, 318 mg, yield: 98%).

[0181] Example 7-2: (9H-Fluoren-9-yl)methyl (2S,4R)-4-(tert-butoxy)-2-(3-(4-phenylbutyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate C

[0182] (2S,4R)-1-Fmoc-4-t-butoxypyrrolidine-2-carboxylic acid (150 mg, 0.366 mmol) was dissolved in dichloromethane (1.03 mL) in a 10 mL eggplant-shaped flask. HATU (153 mg, 0.403 mmol) and diisopropylethylamine (0.128 mL, 0.733 mmol) were then added and stirred at room temperature for 5 minutes under an argon atmosphere. N-hydroxy-5-phenylpentanimidamide (70.4 mg, 0.366 mmol) was then added, washing in with dichloromethane (0.8 mL), and the mixture was stirred at room temperature for 30 minutes. The stir bar was removed and the solvent was evaporated. The residue was purified using a Q-pack SI30 silica gel column (size 20 and size 10) in 50:50 hexane / ethyl acetate. After evaporation of the solvent, 150 mg (0.257 mmol, 70%) of the intermediate imidamide was obtained. 118 mg (0.202 mmol) of this intermediate was dissolved in ultra-dehydrated toluene (1.35 ml) with pre-dried MS4Å (590 mg). A Dimroth condenser was attached and the mixture was stirred at 110 °C for 14.5 hours. After removing MS4Å by filtration through Celite, the solvent was evaporated. The resulting residue was purified using a silica gel column (Q-pack SI30 size 20) (hexane:ethyl acetate = 93:7 to 75:25). After evaporation of the solvent, 109 mg (0.193 mmol, 96%) of the desired compound C4-5-1 (oil) was obtained.

[0183] Example 7-3: 5-((2S,4R)-4-(tert-butoxy)pyrrolidin-2-yl)-3-(4-phenylbutyl)-1,2,4-oxazole C4-5-2

[0184] Compound C4-5-1 (109 mg, 0.193 mmol) was added to a 25 ml eggplant-shaped flask, followed by dichloromethane (0.967 ml) and piperidine (0.118 ml, 1.16 mmol). The mixture was stirred at room temperature for 2 hours and 30 minutes. The stir bar was then removed and the solvent was evaporated. The residue was purified using a silica gel column, Q-Pack SI30, size 20 (hexane:ethyl acetate = 84:16 to 50:50). After evaporation of the solvent, 53.6 mg (0.156 mmol, 81%) of the desired compound C4-5-2 (oil) was obtained.

[0185] Example 7-4: Compound of Example 7 Naphthalene-2,6-diylbis(((2S,4R)-4-(tert-butoxy)-2-(3-(4-phenylbutyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) C4-5-3

[0186] 2,6-Naphthalenedicarboxylic acid (6.0 mg, 0.027 mmol) and dimethylformamide (0.547 ml) were added to a 10 ml eggplant-shaped flask, followed by HATU (31.2 mg, 0.082 mmol) and diisopropylethylamine (42.9 μl, 0.246 mmol). The mixture was stirred at room temperature for 5 minutes under an argon atmosphere. Compound C4-5-2 (18.8 mg, 0.055 mmol) was then added, washing with dichloromethane (0.547 ml), and the mixture was stirred at room temperature for 6 hours. Water and saturated brine were added, followed by extraction with ethyl acetate. After evaporation of the solvent, the residue was purified using two Q-pack SI30 size 10 silica gel columns (hexane:ethyl acetate = 40:60). After evaporation of the solvent, 21.7 mg (0.025 mmol, 92%) of the desired compound C4-5-3 (amorphous solid) was obtained. The LC-MS and 1H-NMR data of the obtained compounds are summarized in Table 3 below.

[0187] Example 8 Naphthalene-2,6-diylbis(((2S,4R)-4-hydroxy-2-(3-(4-phenylbutyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) C4-5-4

[0188] Compound C4-5-3 (11.3 mg, 0.013 mmol) was placed in a 4 ml vial, followed by the addition of dichloromethane (0.33 ml) and TFA (0.065 ml) and stirring at room temperature for 2 hours. After evaporation of the solvent, saturated aqueous sodium bicarbonate (1 ml) was added and the mixture was extracted with ethyl acetate. After evaporation of the solvent, the residue was purified on a silica gel column Q-Pack SI30 size 10 (chloroform:methanol = 100:0 to 93:7). After evaporation of the solvent, 9.6 mg (0.013 mmol, 98%) of the desired compound C4-5-4 (amorphous solid) was obtained. The LC-MS and 1H-NMR data of the obtained compound are summarized in Table 3 below.

[0189] Example 9 Naphthalene-2,6-diylbis(((2S,4R)-4-(tert-butoxy)-2-(3-(5-phenylpentyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) C5-5-3 Example 9-1: Synthesis of N'-hydroxy-6-phenylhexanimidamide

[0190] 6-Phenylhexanenitrile (783 mg, 4.52 mmol) and 50% aqueous hydroxylamine solution (1.20 ml, 20.3 mmol) were added to a 10 ml eggplant-shaped flask, dissolved in absolute ethanol (5.65 ml), and heated under reflux at 95°C for 7 hours and 30 minutes. After distilling off the solvent, the mixture was dried in vacuo to obtain the desired N'-hydroxy-6-phenylhexaneimidamide (pale black-white solid, 918 mg, yield: 98%).

[0191] Example 9-2: (9H-Fluoren-9-yl)methyl (2S,4R)-4-(tert-butoxy)-2-(3-(5-phenylpentyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate C

[0192] (2S,4R)-1-Fmoc-4-t-butoxypyrrolidine-2-carboxylic acid (150 mg, 0.366 mmol) was dissolved in dichloromethane (1.03 mL) in a 10 mL eggplant-shaped flask. HATU (153 mg, 0.403 mmol) and diisopropylethylamine (0.128 mL, 0.733 mmol) were then added and the mixture was stirred at room temperature for 5 minutes under an argon atmosphere. N-hydroxy-6-phenylhexaneimidamide (75.6 mg, 0.366 mmol) was then added, washing in with dichloromethane (0.8 mL), and the mixture was stirred at room temperature for 30 minutes. The stir bar was removed and the solvent was evaporated. The residue was purified using two Q-pack SI30 silica gel columns (size 20 and size 10) in series (hexane:ethyl acetate = 50:50). After evaporation of the solvent, 140 mg (0.235 mmol, 64%) of the intermediate imidamide was obtained. Pre-dried MS4Å (701 mg) was added to this and dissolved in ultra-dehydrated toluene (1.56 ml). A Dimroth condenser was attached and the mixture was stirred at 110 °C for 16 hours. After removing MS4Å by filtration through Celite, the solvent was evaporated. The resulting residue was purified using a silica gel column (Q-pack SI30 size 20) (hexane:ethyl acetate = 93:7 to 75:25). After evaporation of the solvent, 120 mg (0.207 mmol, 88%) of the desired compound C5-5-1 (oil) was obtained.

[0193] Example 9-3: 5-((2S,4R)-4-(tert-butoxy)pyrrolidin-2-yl)-3-(5-phenylpentyl)-1,2,4-oxazole C5-5-2

[0194] Compound C5-5-1 (120 mg, 0.207 mmol) was added to a 10 ml eggplant-shaped flask, followed by dichloromethane (1.03 ml) and piperidine (0.126 ml, 1.24 mmol). The mixture was stirred at room temperature for 3 hours. The stir bar was then removed and the solvent was evaporated. The residue was then purified using a silica gel column, Q-Pack SI30, size 20 (hexane:ethyl acetate = 84:16 to 50:50). After evaporation of the solvent, 58.2 mg (0.163 mmol, 79%) of the desired compound C5-5-2 (oil) was obtained.

[0195] Example 9-4: Compound of Example 9 Naphthalene-2,6-diylbis(((2S,4R)-4-(tert-butoxy)-2-(3-(5-phenylpentyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) C5-5-3

[0196] 2,6-Naphthalenedicarboxylic acid (8.7 mg, 0.039 mmol) and dimethylformamide (0.789 ml) were added to a 10 ml eggplant-shaped flask, followed by HATU (45.0 mg, 0.0118 mmol) and diisopropylethylamine (61.8 μl, 0.355 mmol). The mixture was stirred at room temperature for 5 minutes under an argon atmosphere. Compound C5-5-2 (28.2 mg, 0.079 mmol) was then added, washing with dichloromethane (0.789 ml), and the mixture was stirred at room temperature for 3 hours and 30 minutes. Water and saturated brine were added, followed by extraction with ethyl acetate. After evaporation of the solvent, the residue was purified using two Q-pack SI30 size 10 silica gel columns (hexane:ethyl acetate = 40:60). After evaporation of the solvent, 35.7 mg (0.039 mmol, 100%) of the desired compound C5-5-3 (amorphous solid) was obtained. The LC-MS and 1H-NMR data of the obtained compounds are summarized in Table 3 below.

[0197] Example 10 Naphthalene-2,6-diylbis(((2S,4R)-4-hydroxy-2-(3-(5-phenylpentyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) C5-5-4

[0198] Compound C5-5-3 (23.0 mg, 0.026 mmol) was placed in a 4 ml vial, followed by the addition of dichloromethane (0.640 ml) and TFA (0.128 ml) and stirring at room temperature for 3 hours. After evaporation of the solvent, saturated aqueous sodium bicarbonate (1 ml) was added and the mixture was extracted with ethyl acetate. After evaporation of the solvent, the residue was purified on a silica gel column Q-Pack SI30 size 10 (chloroform:methanol = 100:0 to 94:6). After evaporation of the solvent, 13.3 mg (0.017 mmol, 66%) of the desired compound C5-5-4 (amorphous solid) was obtained. LC-MS and 1H-NMR data for the obtained compound are summarized in Table 3 below.

[0199] The retention time (RT) and 1H-NMR data for the compounds of Examples 1 to 10 under the following LC / MS elution conditions are summarized in Table 3. Elution conditions: flow rate 0.9 mL / min, mobile phase A = 0.05% (v / v) formic acid aqueous solution, mobile phase B = acetonitrile containing 0.05% (v / v) formic acid; 0-0.9 min: linear gradient A:B (95:5) - A:B (10:90), 0.9-3 min: A:B (10:90).

[0200] Table 3-1

[0201] Table 3-2

[0202] Table 3-3

[0203] Table 3-4

[0204] Example 11 ((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(6-(pyrrolidine-1-carbonyl)naphthalen-2-yl)methanone 6-6-LP Example 11-1 (9H-fluoren-9-yl)methyl (2S,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate 6-1

[0205] To a 50 ml recovery flask was added a solution of (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (2.0 g, 4.88 mmol) in dichloromethane (20 ml), HATU (2.04 g, 5.37 mmol) and diisopropylethylamine (1.66 ml, 9.77 mmol), followed by stirring at room temperature for 10 minutes. N'-Hydroxy-4-phenylbutanimidamide (0.958 g, 5.37 mmol) was added to the reaction mixture while washing with dichloromethane (5 ml), followed by stirring at room temperature for 3 hours. After evaporation of the solvent, the mixture was made basic with saturated aqueous sodium bicarbonate (20 ml) and extracted with ethyl acetate (120 ml). The organic layer was washed with water (20 ml) followed by saturated brine (20 ml) and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was removed under reduced pressure. The residue was purified using a silica gel column (Q-pack SI30 size 60) (hexane:ethyl acetate = 90:10 to 20:80) to obtain 1.66 g (2.92 mmol, 60%) of the intermediate imidamide. This intermediate and toluene (30 ml) were placed in a 50 ml eggplant-shaped flask, attached to a Dean-Stark trap, and heated under reflux in an oil bath at 130 °C for 11 hours. The solvent was removed under reduced pressure, and the resulting residue was purified using a silica gel column (Q-pack SI30 size 60) (hexane:ethyl acetate = 90:10 to 70:30). After distilling off the solvent, 1.46 g (2.65 mmol, 91%) of the target compound 6-1 (oil) was obtained.

[0206] Example 11-2 5-((2S,4R)-4-(tert-butoxy)pyrrolidin-2-yl)-3-(3-phenylpropyl)-1,2,4-oxadiazole 6-2 Compound 6-1 (1.46 g, 2.65 mmol) prepared in Example 11-1 was added to a 25 ml eggplant-shaped flask, followed by dichloromethane (14 ml) and piperidine (3.94 ml, 39.8 mmol). The mixture was stirred at room temperature for 1 hour. After distilling off the solvent, the residue was purified using a silica gel column (Q-Pack SI30, size 60) (hexane:ethyl acetate = 65:35 to 0:100). After distilling off the solvent, 668 mg (2.03 mmol, 76.5%) of the desired compound 6-2 (oil) was obtained.

[0207] Example 11-3 Methyl 6-((2S,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-2-naphthoate 6-3

[0208] To a 25 ml eggplant-shaped flask containing 6-(methoxycarbonyl)-2-naphthoic acid (81.5 mg, 0.354 mmol), dichloromethane (2 ml), a dichloromethane (2 ml) solution of compound 6-2 (123 mg, 0.372 mmol) prepared in Example 11-2, HATU (162 mg, 0.425 mmol), and N,N-diisopropylethylamine (0.241 ml, 1.42 mmol) were added and stirred at room temperature for 2 hours. After distilling off the solvent under reduced pressure, ice chips and 5% aqueous sodium bicarbonate solution (8 mL) were added to the residue, followed by extraction with ethyl acetate (30 ml). The ethyl acetate layer was washed with water (8 ml) followed by saturated brine (8 ml) and then dried over anhydrous magnesium sulfate. After filtering off the magnesium sulfate, the ethyl acetate was evaporated under reduced pressure, and the resulting residue was purified on a silica gel column Q-pack SI30 size 20 (hexane:ethyl acetate = 100:0 to 50:50). After evaporation of the solvent, 170 mg (0.314 mmol, 89%) of the desired compound 6-3 was obtained.

[0209] Example 11-4 6-((4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-2-naphthoic acid 6-4

[0210] To a 50 ml eggplant-shaped flask containing compound 6-3 (167 mg, 0.307 mmol) prepared in Example 11-3, a methanol:tetrahydrofuran:water (3:2:1) solution (10 ml) and lithium hydroxide monohydrate (25.8 mg, 0.615 mmol) were added and stirred at room temperature for 2 hours. Lithium hydroxide monohydrate (12.9 mg, 0.307 mmol) was then added and stirred at room temperature for 2 hours. Finally, lithium hydroxide monohydrate (12.9 mg, 0.307 mmol) was added and stirred at room temperature for 1 hour. After distilling off the solvent under reduced pressure, ice chips and 1M aqueous hydrochloric acid (4 mL) were added to the residue, followed by extraction with ethyl acetate (30 ml). The ethyl acetate layer was washed with water (4 ml) and then saturated brine (4 ml) and then dried over anhydrous magnesium sulfate. After filtering off the magnesium sulfate, the ethyl acetate was evaporated under reduced pressure, and the resulting residue was purified on a silica gel column Q-pack SI30 size 20 (chloroform:methanol = 100:0 to 90:10). After evaporation of the solvent, 141 mg (0.267 mmol, 87%) of the desired compound 6-4 was obtained as a diastereomeric mixture.

[0211] Example 11-5: ((2S,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(6-(pyrrolidine-1-carbonyl)naphthalen-2-yl)methanone 6-5-LP and ((2R,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(6-(pyrrolidine-1-carbonyl)naphthalen-2-yl)methanone 6-5-P

[0212] To a 4 mL vial containing compound 6-4 (30.0 mg, 0.0568 mmol) prepared in Example 11-4, dichloromethane (0.450 mL), pyrrolidine (0.00494 mL, 0.0597 mmol), HATU (25.9 mg, 0.0682 mmol), and N,N-diisopropylethylamine (0.0387 mL, 0.227 mmol) were added and stirred at room temperature for 3 hours. After evaporation of the solvent under reduced pressure, ice chips and 5% aqueous sodium bicarbonate solution (2 mL) were added to the residue, followed by extraction with ethyl acetate (6 mL). The ethyl acetate layer was washed with water (2 mL) and then dried by passing it through a Libra tube filled with anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, the residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; eluent: ethyl acetate). The target portion of the silica gel was scraped off, and the mixture was eluted with 10% MeOH in chloroform (20 ml). The solvent was evaporated under reduced pressure to give two diastereomers.

[0213] 6-5-LP: Rf value = 0.47 (developing solvent: acetic acid acetyl), 17.8 mg (0.0307 mmol, 54%) LC-MS RT = 1.35 min m / z = 582 [M+H]+, 1H-NMR (CDCl3) δ: 8.08 (1H, s), 8.03 (1H, s), 7.92 (2H, d, J = 8.4 Hz), 7.68 (1H, d, J = 8.4 Hz), 7.66 (1H, d, J = 8.4 Hz), 7.35-7.1 (5H, m), 5.63 (1H, t, J = 7.2 Hz), 4.41 (1H, quint, J = 4.4 Hz), 3.98 and 3.96 (1H, dd, J=10.8, 5.2 Hz), 3.71 (2H, t, J=7.2 Hz), 3.49 (2H, t, J=7.2 Hz), 3.5-3.4 (1H, br s), 2.78 (2H, t, J=7.6 Hz), 2.72 (2H, t, J=7.6 Hz), 2.45-2.35 (1H, m), 2.3-2.2 (1H, m), 2.11 (2H, quint, J=7.6 Hz), 2.05-1.95 (2H, m), 1.95-1.95 (2H, m), 1.12 ppm (8H, s). 6-5-P: Rf value = 0.36 (developing solvent: acetic acid acetyl), 8.70 mg (0.0150 mmol, 26%) LC-MS RT = 1.35 min m / z = 582 [M+H]+ 1H-NMR (CDCl3) δ: 8.13 (1H, s), 7.92 (2H, d, J = 8 Hz), 7.73 (1H, d, J = 8 Hz), 7.68 (1H, d, J = 8 Hz), 7.3-7.1 (5H, m), 5.55 (1H, t, J = 7.6 Hz), 4.27 (1H, quint, J = 6.6 Hz), 3.8-3.65 (4H, m), 3.49 (2H, t, J=6.8 Hz), 2.76 (2H, t, J=7.6 Hz), 2.71 (2H, t, J=7.6 Hz), 2.7-2.6 (1H, m), 2.3-2.15 (1H, m), 2.102H, quint, J=7.6 Hz), 2.05-1.95 (2H, m), 1.95-1.85 (2H, m), 1.11 ppm (9H, s).

[0214] Example 11-6: Compound of Example 11 ((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(6-(pyrrolidine-1-carbonyl) naphthalen-2-yl)methanone 6-6-LP

[0215] Compound 6-5-LP (16.2 mg, 0.0279 mmol) prepared in Example 11-5 was placed in a 4 mL vial and water (0.011 mL) and trifluoroacetic acid (0.220 mL) were added and stirred at room temperature for 1 hour. The reaction mixture was transferred to a 10 mL recovery flask, acetonitrile (1 mL) was added, and the mixture was concentrated under reduced pressure. This procedure was repeated. Next, chloroform (1.5 mL) was added and the mixture was concentrated under reduced pressure. This procedure was also repeated. Finally, the mixture was dried under reduced pressure using a vacuum pump for one week, yielding 14.6 mg (0.0279 mmol, 100%) of the desired compound 6-6-LP. The LC-MS and 1H-NMR data for the obtained compound are summarized in Table 4 below.

[0216] Example 12: N-benzyl-6-((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-N-methyl-2-naphthamide 7-2-LP Example 12-1: N-benzyl-6-((2S,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-N-methyl-2-naphthamide 7-1-LP and N-benzyl-6-((2R,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-N-methyl-2-naphthamide 7-1-P

[0217] To a 4 mL vial containing compound 6-4 (30.0 mg, 0.0568 mmol) prepared in Example 11-4, dichloromethane (0.450 mL), N-methylbenzylamine (0.00770 mL, 0.0597 mmol), HATU (25.9 mg, 0.0682 mmol), and N,N-diisopropylethylamine (0.0387 mL, 0.227 mmol) were added and stirred at room temperature for 3 hours. After distilling off the solvent under reduced pressure, ice chips and 5% aqueous sodium bicarbonate solution (2 mL) were added to the residue, followed by extraction with ethyl acetate (6 mL). The ethyl acetate layer was washed with water (2 mL) and then dried by passing through a Libra tube filled with anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; eluent: ethyl acetate). The target silica gel was scraped off and eluted with 10% MeOH in chloroform (20 ml). The solvent was removed under reduced pressure to obtain two diastereomers.

[0218] 7-1-LP: Rf value = 0.77 (developing solvent: acetic acid acetyl) 19.1 mg (0.0303 mmol, 53%) 1H-NMR (CDCl3) δ: 8.15-8.05 (1H, br s), 8.0-7.8 (3H, m), 7.8-7.55 (2H, m), 7.45-7.0 (10H, m), 5.63 (1H, t, J = 6.8 Hz), 4.85-4.75 (1H, br s), 4.6-4.5 (1H, br s), 4.45-4.35 (1H, br s), 4.0-3.9 (1H, br s), 3.55-3.45 (1H, br s), 3.09 (1.5H, br s) and 2.92 (1.5 H, br s), 2.77 (2H, t, J=7.5 Hz), 2.72 (2H, t, J=7.5 Hz), 2.45-2.35 (1H, br s), 2.3-2.2 (1H, br s), 2.11 (2H, quint, J=7.5 Hz), 1.12 ppm (9H, s). 7-1-P: Rf value = 0.64 (developing solvent: acetic acid acetyl) 9.10 mg (0.0144 mmol, 25%) 1H-NMR (CDCl3) δ: 8.15-8.05 (1H, br s), 8.0-7.8 (3H, m), 7.8-7.6 (2H, m), 7.45-7.15 (10H, m), 5.55 (1H, t, J=7.2 Hz), 4.85-4.75 (1H, br s), 4.6-4.5 (1H, br s), 4.3-4.2 (1H, br s), 3.8-3.65 (2H, br s), 3.10 (1.5H, br s) and 2.92 (1.5H, br s), 2.74 (2H, t, J=7.5 Hz), 2.71 (2H, t, J=7.5 Hz), 2.7-2.6 (1H, m), 2.3-2.15 (1H, m), 2.09 (t, quint, J=7.5 Hz), 1.10 ppm (9H, s).

[0219] Example 12-2: Compound of Example 12 N-benzyl-6-((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-N-methyl-2-naphthamide 7-2-LP

[0220] Compound 7-1-LP (16.9 mg, 0.0267 mmol) prepared in Example 12-1 was placed in a 4 mL vial, and water (0.011 mL) and trifluoroacetic acid (0.22 mL) were added and stirred at room temperature for 1 hour. The reaction mixture was transferred to a 10 mL recovery flask, and acetonitrile (1 mL) was added and concentrated under reduced pressure. This procedure was repeated. Next, chloroform (1.5 mL) was added and concentrated under reduced pressure. This procedure was also repeated. Finally, the mixture was dried under reduced pressure using a vacuum pump for one week, yielding 15.4 mg (0.0267 mmol, 100%) of the desired compound 7-2-LP. The LC-MS and 1H-NMR data for the obtained compound are summarized in Table 4 below.

[0221] Example 13 N-benzyl-6-((2R,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-N-methyl-2-naphthamide 7-2-P

[0222] Compound 7-1-P (6.00 mg, 0.00951 mmol) prepared in Example 12-1 was placed in a 4 mL vial, and water (0.005 mL) and trifluoroacetic acid (0.1 mL) were added and stirred at room temperature for 1 hour. The reaction mixture was transferred to a 10 mL recovery flask, and acetonitrile (1 mL) was added and concentrated under reduced pressure. This procedure was repeated. Next, chloroform (1.5 mL) was added and concentrated under reduced pressure. This procedure was also repeated. Finally, the mixture was dried under reduced pressure using a vacuum pump for one week, yielding 5.47 mg (0.00951 mmol, 100%) of the desired compound 7-2-P. The LC-MS and 1H-NMR data for the obtained compound are summarized in Table 4 below.

[0223] The retention times (RT) and 1H-NMR data for the compounds of Examples 11 to 13 under the following LC / MS elution conditions are summarized in Table 4. Elution conditions: flow rate 0.9 mL / min, mobile phase A = 0.05% (v / v) formic acid aqueous solution, mobile phase B = acetonitrile containing 0.05% (v / v) formic acid; 0-0.9 min: linear gradient A:B (95:5) - A:B (10:90), 0.9-3 min: A:B (10:90).

[0224] Table 4

[0225] Example 14 1,4-phenylenebis(((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 8-2 Example 14-1 1,4-phenylenebis(((2S,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 8-1

[0226] Dichloromethane (0.800 ml), compound 6-2 (53.5 mg, 0.163 mmol) prepared in Example 11-2, HATU (70.6 mg, 0.186 mmol), and N,N-diisopropylethylamine (0.105 ml, 0.619 mmol) were added to a 4 ml vial containing terephthalic acid (12.9 mg, 0.0774 mmol) and stirred at room temperature for 4 hours. After removing the solvent under reduced pressure, ice chips and 5% aqueous sodium bicarbonate solution (2 ml) were added to the residue, followed by extraction with ethyl acetate (8 ml). The ethyl acetate layer was washed with water (2 ml) and then dried by passing through a Libra tube filled with anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; eluent: ethyl acetate:hexane = 2:1). The target silica gel was scraped off and eluted with 10% MeOH in chloroform (20 ml). The solvent was removed under reduced pressure, yielding 47.3 mg (0.0599 mmol, 77%) of the desired compound 8-1.

[0227] Example 14-2: Compound of Example 14 1,4-phenylenebis(((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone)8-2

[0228] Compound 8-1 (39.5 mg, 0.0500 mmol) prepared in Example 14-1 was placed in a 4 mL vial, and water (0.0400 mL) and trifluoroacetic acid (0.800 mL) were added and stirred at room temperature for 1 hour. The reaction mixture was transferred to a 10 mL recovery flask, acetonitrile (1 mL) was added, and the mixture was concentrated under reduced pressure. This procedure was repeated. Next, chloroform (1.5 mL) was added, and the mixture was concentrated under reduced pressure. This procedure was repeated again. Ice chips and 5% aqueous sodium bicarbonate solution (2 mL) were added to the residue, and the mixture was extracted with ethyl acetate (6 mL). The ethyl acetate layer was washed with water (2 mL) and then dried by passing it through a Libra tube filled with anhydrous sodium sulfate. The solvent was removed under reduced pressure, yielding 33.8 mg (0.0500 mmol, 100%) of the desired compound 8-2. The LC-MS and 1H-NMR data for the resulting compound are summarized in Table 5 below.

[0229] Example 15 ((1S,4S)-cyclohexane-1,4-diyl)bis(((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 9-2 Example 15-1 ((1S,4S)-cyclohexane-1,4-diyl)bis(((2S,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 9-1

[0230] To a 4 mL vial containing (1r,4r)-cyclohexane-1,4-dicarboxylic acid (13.3 mg, 0.0774 mmol), dichloromethane (0.800 mL), compound 6-2 (53.5 mg, 0.163 mmol) prepared in Example 11-2, HATU (70.6 mg, 0.186 mmol), and N,N-diisopropylethylamine (0.105 mL, 0.619 mmol) were added and stirred at room temperature for 4 hours. After removing the solvent under reduced pressure, ice chips and 5% aqueous sodium bicarbonate solution (2 mL) were added to the residue, followed by extraction with ethyl acetate (8 mL). The ethyl acetate layer was washed with water (2 mL) and then dried by passing through a Libra tube filled with anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; eluent: ethyl acetate). The target silica gel was scraped off and eluted with 10% MeOH in chloroform (20 ml). The solvent was removed under reduced pressure, yielding 40.3 mg (0.0507 mmol, 65.5%) of the desired compound 9-1.

[0231] Example 15-2: Compound of Example 15 ((1S,4S)-cyclohexane-1,4-diyl)bis(((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 9-2

[0232] To a 4 mL vial containing compound 9-1 (33.6 mg, 0.0423 mmol) prepared in Example 15-1, water (0.0330 mL) and trifluoroacetic acid (0.660 mL) were added and stirred at room temperature for 1 hour. The reaction mixture was transferred to a 10 mL eggplant-shaped flask, acetonitrile (1 mL) was added, and the mixture was concentrated under reduced pressure. This procedure was repeated. Next, chloroform (1.5 mL) was added and the mixture was concentrated under reduced pressure. This procedure was repeated again. Ice chips and 5% aqueous sodium bicarbonate solution (2 mL) were added to the residue, and the mixture was extracted with ethyl acetate (6 mL). The ethyl acetate layer was washed with water (2 mL) and then dried by passing it through a Libra tube filled with anhydrous sodium sulfate. The solvent was removed under reduced pressure, yielding 28.7 mg (0.0423 mmol, 100%) of the desired compound 9-2. The LC-MS and 1H-NMR data for the resulting compound are summarized in Table 5 below.

[0233] Example 16 Naphthalene-2,6-diylbis(((R)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)azetidin-1-yl)methanone) 10-3 Example 16-1 tert-Butyl (S)-6-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)-5-azaspiro[2.4]heptane-5-carboxylate 10-1

[0234] (6S)-5-(tert-Butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (241.3 mg, 1.0 mmol) was added to a 25 ml eggplant-shaped flask and dissolved in dichloromethane (7.0 ml). HATU (456.3 mg, 1.2 mmol) and diisopropylethylamine (0.34 ml, 2.0 mmol) were then added and stirred at room temperature for 10 minutes under a nitrogen atmosphere. N'-Hydroxy-4-phenylbutanimidamide (213.9 mg, 1.2 mmol) was then added, washing in with dichloromethane (3.0 ml), and the mixture was stirred at room temperature for 3.5 hours. The stir bar was removed, and dichloromethane (20.0 ml) and 5% aqueous sodium bicarbonate (10.0 ml) were added to the reaction mixture. The separated organic layer was washed with distilled water (10.0 ml) and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated to yield a mixture of the intermediate imidamide and urea compound (686.0 mg). The mixture (686.0 mg) was dissolved in toluene (18.0 ml) in a 25 ml eggplant-shaped flask, which was then fitted with a Dean-Stark trap and refluxed in an oil bath at 130 °C for 16 hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified using a silica gel column, Q-Pack SI30, size 20 (hexane:ethyl acetate = 90:10 to 65:35). After evaporation of the solvent, 269.2 mg (0.702 mmol, 70% (after two steps)) of the desired compound 10-1 (oil) was obtained.

[0235] Example 16-2 (S)-3-(3-phenylpropyl)-5-(5-azaspiro[2.4]heptan-6-yl)-1,2,4-oxadiazole 10-2

[0236] Compound 10-1 (443 mg, 1.155 mmol) prepared in Example 16-1 was added to a 25 ml recovery flask, followed by dichloromethane (11.55 ml) and TFA (1.77 ml), and the mixture was stirred at room temperature for 2 hours. The mixture was then made basic by adding saturated aqueous sodium bicarbonate, and extracted with dichloromethane. The mixture was dried over sodium sulfate, filtered, and the solvent was evaporated to give 324.8 mg (1.146 mmol, 99%) of the desired product 10-2 (oil).

[0237] Example 16-3: Compound of Example 16 naphthalene-2,6-diylbis(((R)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)azetidin-1-yl)methanone) 10-3

[0238] 2,6-Naphthalenedicarboxylic acid (34.8 mg, 0.161 mmol) and dichloromethane (1.0 ml) were added to a 20 ml vial, followed by HATU (146.9 mg, 0.386 mmol) and triethylamine (0.180 ml, 1.288 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 10-2 (82.2 mg, 0.338 mmol), prepared in Example 16-2, was added while washing with dichloromethane (1.10 ml). The mixture was stirred at room temperature for 4 hours. The stir bar was then removed and the solvent was evaporated. The residue was purified using a 10 g silica gel column (Chloroform:Methanol = 97:3) Renning Cartridge BK-SIL. After evaporation of the solvent, 40.3 mg (0.056 mmol, 38%) of the desired compound 10-3 (oil) was obtained. The LC-MS and 1H-NMR data of the obtained compounds are summarized in Table 5 below.

[0239] Example 17 1,4-phenylenebis(((S)-6-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)-5-azaspiro[2.4]heptan-5-yl)methanone) 11

[0240] 1,4-Benzenedicarboxylic acid (20.7 mg, 0.125 mmol) and dichloromethane (1.0 ml) were added to a 20 ml vial, followed by HATU (113.9 mg, 0.299 mmol) and triethylamine (0.139 ml, 0.997 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 10-2 (82.2 mg, 0.338 mmol) (74.2 mg, 0.262 mmol) prepared in Example 16-2 was added, washing with dichloromethane (1.10 ml). The mixture was stirred at room temperature for 4 hours. The stir bar was then removed and the solvent was evaporated. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; eluent: hexane:ethyl acetate = 1:1). The target product was removed from the silica gel and eluted with acetone (20 ml). The solvent was removed under reduced pressure to give 41.9 mg (0.060 mmol, 48%) of the target compound 11 (oil). The LC-MS and H-NMR data for the compound are summarized in Table 5.

[0241] Example 18 (trans-cyclohexane-1,4-diyl)bis(((S)-6-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)-5-azaspiro[2.4]heptan-5-yl)methanone) 12

[0242] Trans-1,4-cyclohexanedicarboxylic acid (21.5 mg, 0.125 mmol) and dichloromethane (1.0 ml) were added to a 20 ml vial, followed by HATU (113.9 mg, 0.299 mmol) and triethylamine (0.139 ml, 0.997 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 10-2 (74.2 mg, 0.262 mmol) prepared in Example 16-2 was added, washing with dichloromethane (1.10 ml). The mixture was stirred at room temperature for 4 hours. The stir bar was then removed and the solvent was evaporated. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; eluent: hexane:ethyl acetate = 1:1). The target silica gel was scraped off and eluted with acetone (20 ml). The solvent was evaporated under reduced pressure to give 21.1 mg (0.030 mmol, 24%) of the target compound 12 (oil). The LC-MS and 1H-NMR data of the obtained compound are summarized in Table 5 below.

[0243] Example 19 1,4-phenylenebis(((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 13

[0244] 1,4-Benzenedicarboxylic acid (21.0 mg, 0.126 mmol) and dichloromethane (1.0 ml) were added to a 20 ml vial, followed by HATU (115.6 mg, 0.304 mmol) and triethylamine (0.141 ml, 1.013 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 1-2 (68.5 mg, 0.266 mmol) prepared in Example 1-3 was added while washing with dichloromethane (1.0 ml). The mixture was stirred at room temperature for 4 hours. The stir bar was then removed and the solvent was evaporated. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; eluent: hexane:ethyl acetate = 1:1). The target silica gel was scraped off and eluted with acetone (20 ml). The solvent was evaporated under reduced pressure to give 68.5 mg (0.106 mmol, 84%) of the desired compound 13 (oil). The LC-MS and 1H-NMR data of the obtained compound are summarized in Table 5 below.

[0245] Example 20 (trans-cyclohexane-1,4-diyl)bis(((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 14

[0246] To a 20 ml vial, trans-1,4-cyclohexanedicarboxylic acid (21.8 mg, 0.125 mmol) and dichloromethane (1.0 ml) were added, followed by HATU (115.6 mg, 0.304 mmol) and triethylamine (0.141 ml, 1.013 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 1-2 (68.5 mg, 0.266 mmol) prepared in Example 1-3 was added while washing with dichloromethane (1.0 ml). The mixture was stirred at room temperature for 4 hours. The stir bar was then removed and the solvent was evaporated. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; eluent: hexane:ethyl acetate = 1:1). The target silica gel was scraped off and eluted with acetone (20 ml). The solvent was evaporated under reduced pressure to give 42.1 mg (0.065 mmol, 51%) of the desired compound 14 (oil). The LC-MS and 1H-NMR data of the obtained compound are summarized in Table 5 below.

[0247] Example 21 Naphthalene-2,6-diylbis(((R)-3-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 15-3 Example 21-1 tert-Butyl (R)-3-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate 15-1

[0248] (R)-1-(tert-Butoxycarbonyl)pyrrolidine-3-carboxylic acid (645.8 mg, 3.0 mmol) was added to a 50 ml eggplant-shaped flask and dissolved in dichloromethane (21 ml). Subsequently, HATU (1368.9 mg, 3.6 mmol) and triethylamine (0.836 ml, 6.0 mmol) were added and stirred at room temperature for 10 minutes. N'-Hydroxy-4-phenylbutanimidamide (641.7 mg, 3.6 mmol) was then added, washing in with dichloromethane (9.0 ml), and stirred at room temperature for 4 hours. The stir bar was removed, and dichloromethane (20.0 ml) and 5% aqueous sodium bicarbonate solution (30.0 ml) were added to the reaction mixture. The separated organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated to obtain a mixture of the intermediate imidamide and urea compound. The mixture was dissolved in toluene (63.0 ml) in a 100 ml eggplant-shaped flask. The 100 ml eggplant-shaped flask was equipped with a Dean-Stark trap and heated to reflux in an oil bath at 150 °C for 6 hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified using a silica gel column (hexane:ethyl acetate = 90:10). After evaporation of the solvent, 743.4 mg (2.08 mmol, 69% (after 2 steps)) of the desired compound 15-1 (oil) was obtained.

[0249] Example 21-2 (R)-3-(3-phenylpropyl)-5-(pyrrolidin-2-yl)-1,2,4-oxadiazole 15-2

[0250] Compound 15-1 (629.9 mg, 1.762 mmol) prepared in Example 21-1 was added to a 25 ml recovery flask, followed by dichloromethane (17.62 ml) and TFA (2.7 ml), and the mixture was stirred at room temperature for 2 hours. The mixture was then made basic by adding saturated aqueous sodium bicarbonate, and extracted with dichloromethane. The mixture was dried over sodium sulfate, filtered, and the solvent was evaporated to give 438.4 mg (1.703 mmol, 97%) of the desired product 15-2 (oil).

[0251] Example 21-3: Compound of Example 21 naphthalene-2,6-diylbis(((R)-3-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 15-3

[0252] 2,6-Naphthalenedicarboxylic acid (30.0 mg, 0.139 mmol) and dichloromethane (1.0 ml) were added to a 20 ml vial, followed by HATU (126.6 mg, 0.333 mmol) and triethylamine (0.155 ml, 1.11 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 15-2 (75.1 mg, 0.292 mmol) prepared in Example 21-2 was added while washing with dichloromethane (1.0 ml). The mixture was stirred at room temperature for 4 hours. The stir bar was then removed and the solvent was evaporated. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:methanol = 30:1). The target silica gel was scraped off and eluted with acetone (20 ml). The solvent was evaporated under reduced pressure to give 40.3 mg (0.058 mmol, 42%) of the desired compound 15-3 (oil). The LC-MS and 1H-NMR data of the obtained compound are summarized in Table 5 below.

[0253] Example 22 1,4-phenylenebis(((R)-3-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 16

[0254] 1,4-Benzenedicarboxylic acid (23.1 mg, 0.139 mmol) and dichloromethane (1.0 ml) were added to a 20 ml vial, followed by HATU (126.6 mg, 0.333 mmol) and triethylamine (0.155 ml, 1.11 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 15-2 (75.1 mg, 0.292 mmol) prepared in Example 21-2 was added while washing with dichloromethane (1.0 ml). The mixture was stirred at room temperature for 4 hours. The stir bar was then removed and the solvent was evaporated. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; eluent: dichloromethane:methanol = 40:1). The target silica gel was scraped off and eluted with acetone (20 ml). The solvent was evaporated under reduced pressure to give 28.4 mg (0.044 mmol, 32%) of the desired compound 16 (oil). The LC-MS and 1H-NMR data of the obtained compound are summarized in Table 5 below.

[0255] Example 23 (trans-cyclohexane-1,4-diyl)bis(((R)-3-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 17

[0256] To a 20 ml vial, trans-1,4-cyclohexanedicarboxylic acid (22.2 mg, 0.129 mmol) and dichloromethane (1.0 ml) were added, followed by HATU (117.7 mg, 0.310 mmol) and triethylamine (0.144 ml, 1.03 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 15-2 (69.6 mg, 0.292 mmol), prepared in Example 21-2, was added while washing with dichloromethane (1.0 ml). The mixture was stirred at room temperature for 4 hours. The stir bar was then removed and the solvent was evaporated. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:methanol = 40:1). The target silica gel was scraped off and eluted with acetone (20 ml). The solvent was evaporated under reduced pressure to give 25.8 mg (0.040 mmol, 31%) of the target compound 17 (oil). The LC-MS and 1H-NMR data of the obtained compound are summarized in Table 5 below.

[0257] Example 24 Naphthalene-2,6-diylbis(((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)azetidin-1-yl)methanone) 18-3 Example 24-1 tert-Butyl (S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate 18-1

[0258] (S)-1-(tert-Butoxycarbonyl)azetidine-2-carboxylic acid (603.7 mg, 3.0 mmol) was added to a 50 ml eggplant-shaped flask and dissolved in dichloromethane (21.0 ml). Subsequently, HATU (1368.7 mg, 3.6 mmol) and triethylamine (0.836 ml, 6.0 mmol) were added and stirred at room temperature for 10 minutes. N'-Hydroxy-4-phenylbutanimidamide (641.7 mg, 3.6 mmol) was then added, washing in with dichloromethane (9.0 ml), and stirred at room temperature for 4 hours. The stir bar was removed, and dichloromethane (20.0 ml) and 5% aqueous sodium bicarbonate (30.0 ml) were added to the reaction mixture. The separated organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated to yield a mixture of the intermediate imidamide and urea compound. The mixture was dissolved in toluene (63.0 ml) in a 100 ml eggplant-shaped flask. The 100 ml eggplant-shaped flask was equipped with a Dean-Stark trap and heated to reflux in an oil bath at 150 °C for 6 hours. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified using a silica gel column (hexane:ethyl acetate = 90:10). After distillation, the desired compound 18-1 (oil) was obtained in an amount of 760.9 mg (2.22 mmol, 74% (after two steps)).

[0259] Example 24-2 (S)-5-(azetidin-2-yl)-3-(3-phenylpropyl)-1,2,4-oxadiazole 18-2

[0260] Compound 18-1 (760.9 mg, 2.22 mmol) prepared in Example 24-1 was added to a 50 ml recovery flask, followed by dichloromethane (22.2 ml) and TFA (3.4 ml), and the mixture was stirred at room temperature for 2 hours. The mixture was then made basic by adding saturated aqueous sodium bicarbonate, and extracted with dichloromethane. The mixture was dried over sodium sulfate, filtered, and the solvent was evaporated to give 539.0 mg (2.21 mmol, 99%) of the desired compound 18-2 (oil).

[0261] Example 24-3: Compound of Example 24 naphthalene-2,6-diylbis(((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)azetidin-1-yl)methanone) 18-3

[0262] 2,6-Naphthalenedicarboxylic acid (34.8 mg, 0.161 mmol) and dichloromethane (1.0 ml) were added to a 20 ml vial, followed by HATU (146.9 mg, 0.386 mmol) and triethylamine (0.180 ml, 1.288 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 18-2 (82.2 mg, 0.338 mmol), prepared in Example 24-2, was added while washing with dichloromethane (1.0 ml). The mixture was stirred at room temperature for 4 hours. The stir bar was then removed and the solvent was evaporated. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:methanol = 30:1). The target silica gel was scraped off and eluted with acetone (20 ml). The solvent was evaporated under reduced pressure to give 40.3 mg (0.056 mmol, 38%) of the desired compound 18-3 (oil). The LC-MS and 1H-NMR data of the obtained compound are summarized in Table 5 below.

[0263] Example 25 1,4-phenylenebis(((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)azetidin-1-yl)methanone) 19

[0264] 1,4-Benzenedicarboxylic acid (26.8 mg, 0.161 mmol) and dichloromethane (1.0 ml) were added to a 20 ml vial, followed by HATU (146.9 mg, 0.386 mmol) and triethylamine (0.180 ml, 1.288 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 18-2 (82.2 mg, 0.338 mmol), prepared in Example 24-2, was added while washing with dichloromethane (1.0 ml). The mixture was stirred at room temperature for 4 hours. The stir bar was then removed and the solvent was evaporated. The residue was purified using a silica gel column (Q-Pack SI30, size 10) (hexane:ethyl acetate = 33:67). After evaporation of the solvent, 38.3 mg (0.056 mmol, 39%) of the desired compound 19 (oil) was obtained. The LC-MS and 1H-NMR data of the obtained compounds are summarized in Table 5 below.

[0265] Example 26 (trans-cyclohexane-1,4-diyl)bis(((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)azetidin-1-yl)methanone) 20

[0266] Trans-1,4-cyclohexanedicarboxylic acid (27.7 mg, 0.161 mmol) and dichloromethane (1.0 ml) were added to a 20 ml vial, followed by HATU (146.9 mg, 0.386 mmol) and triethylamine (0.180 ml, 1.288 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 18-2 (82.2 mg, 0.338 mmol), prepared in Example 24-2, was added while washing with dichloromethane (1.0 ml). The mixture was stirred at room temperature for 4 hours. The stir bar was then removed and the solvent was evaporated. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:methanol = 40:1). The target silica gel was scraped off and eluted with acetone (20 ml). The solvent was evaporated under reduced pressure to give 58.4 mg (0.094 mmol, 58%) of the desired compound 20 (oil). The LC-MS and H-NMR data of the obtained compound are summarized in Table 5 below.

[0267] Example 27 1,4-phenylenebis(((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)methanone) 21

[0268] 1,4-Benzenedicarboxylic acid (19.8 mg, 0.119 mmol) and dichloromethane (1.0 ml) were added to a 20 ml vial, followed by HATU (108.6 mg, 0.286 mmol) and triethylamine (0.133 ml, 0.952 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 2-2 (67.8 mg, 0.250 mmol) prepared in Example 3-2 was added while washing with dichloromethane (1.10 ml). The mixture was stirred at room temperature for 4 hours. The stir bar was then removed and the solvent was evaporated. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:methanol = 40:1). The target silica gel was scraped off and eluted with acetone (20 ml). After distilling off the solvent, 32.9 mg (0.049 mmol, 41%) of the target compound 21 (oil) was obtained. The LC-MS and 1H-NMR data of the obtained compound are summarized in Table 5 below.

[0269] Example 28 (trans-cyclohexane-1,4-diyl)bis(((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)methanone) 22

[0270] Trans-1,4-cyclohexanedicarboxylic acid (20.5 mg, 0.119 mmol) and dichloromethane (1.0 ml) were added to a 20 ml vial, followed by HATU (108.6 mg, 0.286 mmol) and triethylamine (0.133 ml, 0.952 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 2-2 (67.8 mg, 0.250 mmol) prepared in Example 3-2 was added, washing with dichloromethane (1.10 ml). The mixture was stirred at room temperature for 4 hours. The stir bar was then removed and the solvent was evaporated. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:methanol = 40:1). The target silica gel was scraped off and eluted with acetone (20 ml). After distilling off the solvent, 44.2 mg (0.065 mmol, 55%) of the target compound 22 (oil) was obtained. The LC-MS and 1H-NMR data of the obtained compound are summarized in Table 5 below.

[0271] Example 29 Naphthalene-2,6-diylbis(((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)-2,5-dihydro-1H-pyrrol-1-yl) methaneone) 23-3 Example 29-1 tert-Butyl (S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 23-1

[0272] (S)-1-(tert-Butoxycarbonyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (639.7 mg, 3.0 mmol) was added to a 50 ml eggplant-shaped flask and dissolved in dichloromethane (21.0 ml). HATU (1368.9 mg, 3.6 mmol) and triethylamine (0.836 ml, 6.0 mmol) were then added and stirred at room temperature for 10 minutes. N'-Hydroxy-4-phenylbutanimidamide (641.7 mg, 3.6 mmol) was then added, washing in with dichloromethane (9.0 ml), and the mixture was stirred at room temperature for 4 hours. The stir bar was removed, and dichloromethane (20.0 ml) and 5% aqueous sodium bicarbonate (30.0 ml) were added to the reaction mixture. The separated organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off to obtain a mixture of the intermediate imidamide and urea compound. The mixture was dissolved in toluene (63.0 ml) in a 100 ml eggplant-shaped flask. The 100 ml eggplant-shaped flask was equipped with a Dean-Stark trap and heated to reflux in an oil bath at 150 °C for 6 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified using a silica gel column (hexane:ethyl acetate = 80:20). After distilling off the solvent, 468.6 mg (1.32 mmol, 44% (after two steps)) of the desired compound 23-1 (oil) was obtained.

[0273] Example 29-2 (S)-5-(2,5-dihydro-1H-pyrrol-2-yl)-3-(3-phenylpropyl)-1,2,4-oxadiazole 23-2

[0274] Compound 23-1 (468.6 mg, 1.32 mmol) prepared in Example 29-1 was added to a 50 ml recovery flask, followed by dichloromethane (13.2 ml) and TFA (2.0 ml), and the mixture was stirred at room temperature for 2 hours. The mixture was then made basic by adding saturated aqueous sodium bicarbonate, and extracted with dichloromethane. The mixture was dried over sodium sulfate, filtered, and the solvent was evaporated to give 326.8 mg (1.28 mmol, 97%) of the desired product 23-2 (oil).

[0275] Example 29-3: Compound of Example 29 naphthalene-2,6-diylbis(((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)-2,5-dihydro-1H-pyrrol-1-yl) methanone) 23-3

[0276] 2,6-Naphthalenedicarboxylic acid (27.2 mg, 0.126 mmol) and dichloromethane (1.0 ml) were added to a 20 ml vial, followed by HATU (115.0 mg, 0.302 mmol) and triethylamine (0.141 ml, 1.01 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 23-2 (67.4 mg, 0.266 mmol) prepared in Example 29-2 was added while washing with dichloromethane (1.0 ml). The mixture was stirred at room temperature for 4 hours. The stir bar was then removed and the solvent was evaporated. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:methanol = 40:1). The target silica gel was scraped off and eluted with acetone (20 ml). The solvent was evaporated under reduced pressure to give 59.4 mg (0.095 mmol, 76%) of the desired compound 23-3 (oil). The LC-MS and 1H-NMR data of the obtained compound are summarized in Table 5 below.

[0277] Example 30 1,4-phenylenebis(((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)-2,5-dihydro-1H-pyrrol-1-yl)methaneone) 24

[0278] 1,4-Benzenedicarboxylic acid (20.9 mg, 0.126 mmol) and dichloromethane (1.0 ml) were added to a 20 ml vial, followed by HATU (115.0 mg, 0.302 mmol) and triethylamine (0.141 ml, 1.01 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 23-2 (67.7 mg, 0.264 mmol) prepared in Example 29-2 was added while washing with dichloromethane (1.0 ml). The mixture was stirred at room temperature for 4 hours. The stir bar was then removed and the solvent was evaporated. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:methanol = 50:1). The target silica gel was scraped off and eluted with acetone (20 ml). The solvent was evaporated under reduced pressure to give 57.1 mg (0.089 mmol, 71%) of the desired compound 24 (oil). The LC-MS and 1H-NMR data of the obtained compound are summarized in Table 5 below.

[0279] Example 31 (trans-cyclohexane-1,4-diyl)bis(((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)-2,5-dihydro-1H-pyrrol-1-yl) methanone) 25

[0280] Trans-1,4-cyclohexanedicarboxylic acid (21.7 mg, 0.126 mmol) and dichloromethane (1.0 ml) were added to a 20 ml vial, followed by HATU (115.0 mg, 0.302 mmol) and triethylamine (0.141 ml, 1.01 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 23-2 (67.7 mg, 0.264 mmol), prepared in Example 29-2, was added while washing with dichloromethane (1.0 ml). The mixture was stirred at room temperature for 4 hours. The stir bar was then removed and the solvent was evaporated. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; eluent: hexane:ethyl acetate = 1:1). The target silica gel was scraped off and eluted with acetone (20 ml). The solvent was evaporated under reduced pressure to give 19.0 mg (0.029 mmol, 23%) of the desired compound 25 (oil). The LC-MS and 1H-NMR data of the obtained compound are summarized in Table 5 below.

[0281] Example 32 Naphthalene-2,6-diylbis(((2S,4R)-4-fluoro-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 26-3 Example 32-1 tert-Butyl (2S,4R)-4-fluoro-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate 26-1

[0282] (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoro-2-pyrrolidinecarboxylic acid (233.2 mg, 1.0 mmol) was dissolved in dichloromethane (7.0 ml) in a 25 ml eggplant-shaped flask. HATU (456.3 mg, 1.2 mmol) and diisopropylethylamine (0.34 ml, 2.0 mmol) were then added and stirred at room temperature for 10 minutes under a nitrogen atmosphere. N'-Hydroxy-4-phenylbutanimidamide (213.9 mg, 1.2 mmol) was then added, washing in with dichloromethane (3.0 ml), and the mixture was stirred at room temperature for 3.5 hours. The stir bar was removed, and dichloromethane (20.0 ml) and 5% aqueous sodium bicarbonate (10.0 ml) were added to the reaction mixture. The separated organic layer was washed with distilled water (10.0 ml) and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated to yield a mixture of the intermediate imidamide and urea compound (740.0 mg). The mixture (740.0 mg) was dissolved in toluene (18.0 ml) in a 25 ml eggplant-shaped flask, which was then fitted with a Dean-Stark trap and heated to reflux in an oil bath at 130 °C for 16 hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified using a silica gel column, Q-Pack SI30, size 20 (hexane:ethyl acetate = 90:10 to 35:65). After evaporation of the solvent, 308.6 mg (0.82 mmol, 82% (after two steps)) of the desired compound 26-1 (oil) was obtained.

[0283] Example 32-2 5-((2S,4R)-4-fluoropyrrolidin-2-yl)-3-(3-phenylpropyl)-1,2,4-oxadiazole 26-2

[0284] Compound 26-1 (259.1 mg, 0.69 mmol) prepared in Example 32-1 was added to a 50 ml recovery flask, followed by dichloromethane (6.9 ml) and TFA (1.06 ml), and the mixture was stirred at room temperature for 2 hours. The mixture was then made basic by adding saturated aqueous sodium bicarbonate, and extracted with dichloromethane. The mixture was dried over sodium sulfate, filtered, and the solvent was evaporated to give 190.0 mg (0.69 mmol, 100%) of the desired compound 26-2 (oil).

[0285] Example 32-3: Compound of Example 32 naphthalene-2,6-diylbis(((2S,4R)-4-fluoro-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 26-3

[0286] 2,6-Naphthalenedicarboxylic acid (23.1 mg, 0.107 mmol) and dichloromethane (1.0 ml) were added to a 20 ml vial, followed by HATU (97.7 mg, 0.257 mmol) and triethylamine (0.119 ml, 0.856 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 26-2 (67.4 mg, 0.266 mmol) prepared in Example 32-2 was added while washing with dichloromethane (1.0 ml). The mixture was stirred at room temperature for 4 hours. The stir bar was then removed and the solvent was evaporated. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; eluent: dichloromethane:ethyl acetate = 1:1). The target silica gel was scraped off and eluted with acetone (20 ml). The solvent was evaporated under reduced pressure to give 36.7 mg (0.050 mmol, 47%) of the desired compound 26-3 (oil). The LC-MS and 1H-NMR data of the obtained compound are summarized in Table 5 below.

[0287] Example 33 1,4-phenylenebis(((2S,4R)-4-fluoro-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 27

[0288] 1,4-Benzenedicarboxylic acid (16.9 mg, 0.102 mmol) and dichloromethane (1.0 ml) were added to a 20 ml vial, followed by HATU (92.8 mg, 0.244 mmol) and triethylamine (0.114 ml, 0.815 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 26-2 (67.7 mg, 0.264 mmol) prepared in Example 32-2 was added while washing with dichloromethane (1.0 ml). The mixture was stirred at room temperature for 4 hours. The stir bar was then removed and the solvent was evaporated. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; eluent: dichloromethane:ethyl acetate = 1:1). The target product was scraped off from the silica gel and eluted with acetone (20 ml). The solvent was evaporated under reduced pressure to give 30.7 mg (0.045 mmol, 44%) of the desired compound 27 (oil). The LC-MS and H-NMR data of the obtained compound are summarized in Table 5 below.

[0289] Example 34 (trans-cyclohexane-1,4-diyl)bis(((2S,4R)-4-fluoro-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 28

[0290] To a 20 ml vial, trans-1,4-cyclohexanedicarboxylic acid (20.7 mg, 0.120 mmol) and dichloromethane (1.0 ml) were added, followed by HATU (109.5 mg, 0.288 mmol) and triethylamine (0.134 ml, 0.96 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 26-2 (69.0 mg, 0.251 mmol), prepared in Example 32-2, was added while washing with dichloromethane (1.0 ml). The mixture was stirred at room temperature for 4 hours. The stir bar was then removed and the solvent was evaporated. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; eluent: dichloromethane:ethyl acetate = 1:1). The target silica gel was scraped off and eluted with acetone (20 ml). The solvent was evaporated under reduced pressure to give 35.8 mg (0.052 mmol, 43%) of the desired compound 28 (oil). The LC-MS and 1H-NMR data of the obtained compound are summarized in Table 5 below.

[0291] The retention time (RT) and 1H-NMR data for the compounds of Examples 14 to 34 under the following LC / MS elution conditions are summarized in Table 5. Elution conditions: flow rate 0.9 mL / min, mobile phase A = 0.05% (v / v) formic acid aqueous solution, mobile phase B = acetonitrile containing 0.05% (v / v) formic acid; 0-0.9 min: linear gradient A:B (95:5) - A:B (10:90), 0.9-3 min: A:B (10:90).

[0292] Table 5-1

[0293] Table 5-2

[0294] Table 5-3

[0295] Table 5-4

[0296] The following is a list of preferred compounds of the present invention:

[0297] The following lists another group of preferred compounds of the present invention:

[0298] Example 35 tert-butyl (S)-2-(5-(3-phenylpropyl)-4H-1,2,4-triazol-3-yl)azetidine-1-carboxylate 29-2 Example 35-1 tert-butyl (S)-2-(hydrazinecarbonyl)azetidine-1-carboxylate 29-1

[0299] N-Boc-(2S)-azetidine-2-carboxylic acid (500 mg, 2.49 mmol) was dissolved in dimethylformamide (2.50 ml) in a 10 ml eggplant-shaped flask. HATU (1.039 mg, 2.73 mmol) and diisopropylethylamine (0.866 ml, 4.97 mmol) were then added and stirred at room temperature for 8 minutes under an argon atmosphere. This solution was then added to a 25 ml eggplant-shaped flask containing a solution of hydrazine-1-hydrate (0.616 ml, 12.4 mmol) in dimethylformamide (1.5 ml), washing with DMF (0.97 ml), and stirred at room temperature for 1.5 hours. The mixture was basified with saturated aqueous sodium bicarbonate (10 ml) and extracted with ethyl acetate. The solvent was evaporated, and the resulting residue was purified on a silica gel column Q-pack SI30 size 60 (hexane:ethyl acetate = 0:100 and chloroform:methanol 100:0 to 95:5) to obtain 407 mg (1.89 mmol, 76%) of the desired product 29-1 (oil).

[0300] Example 35-2: Compound of Example 35 tert-butyl (S)-2-(5-(3-phenylpropyl)-4H-1,2,4-triazol-3-yl)azetidine-1-carboxylate 29-2

[0301] Compound 29-1 (169 mg, 0.787 mmol), ethyl 4-phenylbutanimidate (169 mg, 0.866 mmol), and triethylamine (546 μl, 3.94 mmol) were added to a 25 ml eggplant-shaped flask, dissolved in ultra-dehydrated toluene (3.94 ml) and ultra-dehydrated THF (1.97 ml), and stirred at 60 °C for 6 h under an argon atmosphere. After removing the stir bar and evaporating the solvent, the residue was purified on a silica gel column (Q-Pack SI30 size 20) (chloroform:methanol = 100:0 to 95:5). After evaporating the solvent, 180 mg (0.525 mmol, 67%) of the desired compound 29-2 (amorphous solid) was obtained.

[0302] Example 36 (trans-cyclohexane-1,4-diyl)bis(((R)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)azetidin-1-yl)methanone) 30-3 Example 36-1 (9H-fluoren-9-yl)methyl (R)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate 30-1

[0303] (R)-1-Fmoc-azetidine-2-carboxylic acid (300 mg, 0.928 mmol) was dissolved in dichloromethane (2.64 ml) in a 25 ml eggplant-shaped flask. HATU (388 mg, 1.02 mmol) and diisopropylethylamine (0.356 ml, 2.04 mmol) were added, followed by N'-hydroxy-4-phenylbutanimidamide (182 mg, 1.02 mmol) while washing with dichloromethane (2.0 ml). The mixture was stirred at room temperature for 1 hour and 15 minutes. The stir bar was removed and the solvent was evaporated. The residue was purified on a silica gel column (Q-Pack SI30 size 60) using a 34:66 hexane:ethyl acetate mixture. The resulting intermediate (161 mg, 0.332 mmol) was transferred to a 30 ml eggplant-shaped flask, pre-dried MS4Å (804 mg) was added, and the mixture was dissolved in toluene (2.77 ml). A Dimroth condenser was attached, and the mixture was stirred at 110 °C for 15 hours. After removing MS4Å by filtration through Celite, the solvent was evaporated, and the resulting residue was purified on a silica gel column Q-Pack SI30 size 20 (hexane:ethyl acetate = 90:10 to 60:40). After evaporation of the solvent, 132 mg (0.284 mmol, 31% (after two steps)) of the desired 30-1 (amorphous solid) was obtained.

[0304] Example 36-2 (R)-5-(azetidin-2-yl)-3-(3-phenylpropyl)-1,2,4-oxadiazole 30-2

[0305] Compound 30-1 (132 mg, 0.284 mmol) prepared in Example 36-1 was added to a 10 ml eggplant-shaped flask, followed by dichloromethane (1.42 ml) and piperidine (0.145 ml, 1.42 mmol). The mixture was stirred at room temperature for 2 hours. The stir bar was then removed and the solvent was evaporated. The residue was purified using a silica gel column (Q-Pack SI30, size 20) (hexane:ethyl acetate = 50:50 and chloroform:methanol 100:0 to 95:5). After evaporation of the solvent, 58.9 mg (0.242 mmol, 85%) of the desired compound 30-2 (oil) was obtained.

[0306] Example 36-3: Compound of Example 36 (trans-cyclohexane-1,4-diyl)bis(((R)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)azetidin-1-yl)methanone) 30-3

[0307] To a 10 ml eggplant-shaped flask, trans-1,4-cyclohexanedicarboxylic acid (10.6 mg, 0.06 mmol) and dichloromethane (0.993 ml) were added, followed by HATU (54.6 mg, 0.144 mmol) and diisopropylethylamine (0.094 ml, 0.538 mmol). The mixture was stirred at room temperature for 5 minutes. Compound 30-2 (29.1 mg, 0.120 mmol), prepared in Example 36-2, was then added, washing with dichloromethane (1.0 ml). The mixture was stirred at room temperature for 3 hours. The stir bar was then removed and the solvent was evaporated. The residue was purified using a silica gel column (Q-Pack SI30, size 10) (chloroform:methanol = 98:2). After evaporation, 34.4 mg (0.055 mmol, 93%) of the desired product 30-3 (oil) was obtained.

[0308] Example 37 N-benzyl-6-((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-2-naphthamide 31-2-LP Example 37-1 N-benzyl-6-((2S,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-2-naphthamide 31-1-LP and N-benzyl-6-((2R,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-2-naphthamide 31-1-P

[0309] To a 4 mL vial containing compound 6-4 (36.5 mg, 0.0692 mmol) prepared in Example 11-4, dichloromethane (0.550 mL), benzylamine (0.00794 mL, 0.0726 mmol), HATU (31.6 mg, 0.0830 mmol), and N,N-diisopropylethylamine (0.0471 mL, 0.277 mmol) were added and stirred at room temperature for 3 hours. After the solvent was removed under reduced pressure, ice chips and 5% aqueous sodium bicarbonate solution (2 mL) were added to the residue, followed by extraction with ethyl acetate (6 mL). The ethyl acetate layer was washed with water (2 mL) and then dried by passing through a Libra tube filled with anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: ethyl acetate:hexane = 2:1). The target silica gel was scraped off, and the mixture was eluted with 10% MeOH in chloroform (20 ml). The solvent was removed under reduced pressure, yielding two diastereomers.

[0310] 31-1-LP: Rf value=0.69, 18.8 mg (0.0305 mmol, 44%) NMR(CDCl3) δ: 8.29 (1H, s), 8.02 (1H, s), 7.95-7.8 (3H, m), 7.63 (1H, d, J=8.4 Hz), 7.4-7.1 (10H, m), 6.81 (1H, t, J=5.6 Hz), 5.61 (1H, t, J=6.8 Hz), 4.69 (2H, d, J=5.6 Hz), 4.40 (1H, quint, J=4.4 Hz), 3.98-3.9 (1H, m), 3.49 and 3.46 (1H, dd, J=10.8, 3.6 Hz), 2.77 (2H, t, J=7.5 Hz), 2.71 (2H, t, J=7.5 Hz), 2.45-2.35 (1H, m), 2.3-2.2 (1H, m), 2.10 (2H, quint, J=7.5 Hz), 1.11 ppm (9H, s). 31-1-P: Rf value=0.48, 9.24 mg (0.0150 mmol, 21.5%) NMR(CDCl3) δ: 8.31 (1H, s), 8.10 (1H, s), 8.0-7.85 (3H, m), 7.71 (1H, d, J=8 Hz), 7.4-7.1 (10H, m), 6.69 (1H, t, J=5.6 Hz), 5.53 (1H, t, J=7.6 Hz), 4.71 (2H, d, J=5.6 Hz), 4.27 (1H, quint, J=6.4 Hz), 3.8-3.6 (2H, m), 2.76 (2H, t, J=7.6 Hz), 2.71 (2H, t, J=7.6 Hz), 2.7-2.55 (1H, m), 2.3-2.15 (1H, m), 2.10 (2H, quint, J=7.6 Hz), 1.10 ppm (9H, s).

[0311] Example 37-2: Compound N-ベンジル-6-((2S,4R)-4-ヒドロキシ-2-(3-(3-フェニル) in Example 37プロピル)-1,2,4-オキサジアール-5-イル)ピロリジン-1-カルボニル)-2-ナフトアミド31-2-LP

[0312] To a 4 mL vial containing compound 31-1-LP (18.8 mg, 0.0305 mmol) prepared in Example 37-1, water (0.012 mL) and trifluoroacetic acid (0.240 mL) were added and stirred at room temperature for 1 hour. The reaction mixture was transferred to a 10 mL recovery flask, acetonitrile (1 mL) was added, and the mixture was concentrated under reduced pressure. This procedure was repeated. Next, chloroform (1.5 mL) was added and the mixture was concentrated under reduced pressure. This procedure was also repeated. Finally, the mixture was dried under reduced pressure using a vacuum pump for one week to obtain 16.5 mg (0.0294 mmol, 96%) of the desired compound 31-2-LP.

[0313] Example 38 N-benzyl-6-((2R,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-2-naphthamide 31-2-P

[0314] Compound 31-1-P (9.24 mg, 0.0150 mmol) prepared in Example 38-1 was placed in a 4 mL vial, and water (0.006 mL) and trifluoroacetic acid (0.120 mL) were added and stirred at room temperature for 1 hour. The reaction mixture was transferred to a 10 mL recovery flask, and acetonitrile (1 mL) was added and concentrated under reduced pressure. This procedure was repeated. Next, chloroform (1.5 mL) was added and concentrated under reduced pressure. This procedure was also repeated. Finally, the mixture was dried under reduced pressure using a vacuum pump for one week, yielding 18.15 mg (0.0145 mmol, 97%) of the desired compound 31-2-P.

[0315] Example 39 Methyl 4-((2S,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)benzoate 32-1

[0316] To a 25 ml eggplant-shaped flask containing 4-(methoxycarbonyl)benzoic acid (80.3 mg, 0.446 mmol), dichloromethane (3 ml), a dichloromethane (2 ml) solution of compound 6-2 (154 mg, 0.468 mmol) prepared in Example 11-2, HATU (203 mg, 0.534 mmol), and N,N-diisopropylethylamine (0.303 ml, 1.78 mmol) were added and stirred at room temperature for 2 hours. After removing the solvent under reduced pressure, ice chips and 5% aqueous sodium bicarbonate solution (8 ml) were added to the residue, followed by extraction with ethyl acetate (30 ml). The ethyl acetate layer was washed with water (8 ml) followed by saturated brine (8 ml) and then dried over anhydrous magnesium sulfate. After filtering off the magnesium sulfate, the ethyl acetate was evaporated under reduced pressure, and the resulting residue was purified on a silica gel column Q-pack SI30 size 20 (hexane:ethyl acetate = 100:0 to 55:45). After evaporation of the solvent, 176 mg (0.357 mmol, 76%) of the desired compound 32-1 was obtained.

[0317] Example 40 4-((4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)benzoic acid 32-2

[0318] To a 50 ml eggplant-shaped flask containing compound 32-1 (169 mg, 0.344 mmol) prepared in Example 39, a methanol:tetrahydrofuran:water (3:2:1) solution (5 ml) and lithium hydroxide monohydrate (28.9 mg, 0.689 mmol) were added and stirred at room temperature for 3 hours. Lithium hydroxide monohydrate (12.9 mg, 0.307 mmol) was then added and stirred at room temperature for 2 hours. Finally, lithium hydroxide monohydrate (7.2 mg, 0.172 mmol) was added and stirred at room temperature for 0.5 hours. After distilling off the solvent under reduced pressure, ice chips and 1M aqueous hydrochloric acid (4 mL) were added to the residue, followed by extraction with ethyl acetate (30 ml). The ethyl acetate layer was washed with water (4 ml) followed by saturated brine (4 ml) and then dried over anhydrous magnesium sulfate. After filtering off the magnesium sulfate, the ethyl acetate was evaporated under reduced pressure, and the resulting residue was purified on a silica gel column Q-pack SI30 size 20 (chloroform:methanol = 100:0 to 90:10). After evaporation of the solvent, 142 mg (0.298 mmol, 87%) of the desired compound 32-2 was obtained as a diastereomeric mixture.

[0319] Example 41 6-((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-N-methyl-N-phenethyl-2-naphthamide 33-2-LP Example 41-1 6-((2S,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-N-methyl-N-phenethyl-2-naphthamide 33-1-LP and 6-((2R,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-N-methyl-N-phenethyl-2-naphthamide 33-1-P

[0320] To a 4 mL vial containing compound 6-4 (36.5 mg, 0.0692 mmol) prepared in Example 11-4, dichloromethane (0.550 mL), N-methylphenethylamine (0.0106 mL, 0.0726 mmol), HATU (31.6 mg, 0.0830 mmol), and N,N-diisopropylethylamine (0.0471 mL, 0.277 mmol) were added and stirred at room temperature for 3 hours. After removing the solvent under reduced pressure, ice chips and 5% aqueous sodium bicarbonate solution (2 mL) were added to the residue, followed by extraction with ethyl acetate (6 mL). The ethyl acetate layer was washed with water (2 mL) and then dried by passing through a Libra tube filled with anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: ethyl acetate:hexane = 2:1). The target silica gel was scraped off, and the mixture was eluted with 10% MeOH in chloroform (20 ml). The solvent was removed under reduced pressure, yielding two diastereomers.

[0321] 33-1-LP: Rf value = 0.49, 21.7 mg (0.0336 mmol, 49%) NMR(CDCl3) δ: 8.05 (1H, br), 7.88 (1H, br s), 7.85 - 7.7 (2H, br s), 7.67 (1H, br s), 7.5 - 7.1 (11H, m), 6.92 (1H, br s), 5.64 (1H, t, J = 6.8 Hz), 4.41 (1H, quint, J = 4.4 Hz), 4.0 - 3.9 (1H, m), 3.9 - 3.75 (1H, br s), 3.6 - 3.45 (2H, m), 3.21 (1.5H, s) and 2.87 (1.5H, s), 3.1 - 3.0 (1H, br s), 2.85 - 2.7 (1H, br s), 2.78 (2H, t, J = 7.6 Hz), 2.72 (2H, t, J = 7.6 Hz), 2.45 - 2.35 (1H, m), 2.3 - 2.2 (1H, m), 2.11 (2H, quint, J = 7.6 Hz), 1.12 and 1.11 ppm (9H, s). 33-1-P: Rf value = 0.30, 9.60 mg (0.0149 mmol, 22%) NMR(CDCl3) δ: 8.11 (1H, br s), 7.95 - 7.8 (3H, m), 7.73 (1H, br s), 7.5 - 7.1 (10, m), 6.92 (1H, br s), 5.55 (1H, t, J = 4.4 Hz), 4.27 (1H, quint, J = 5.6 Hz), 3.9 - 3.8 (1H, br s), 3.8 - 3.65 (2H, m), 3.55 - 3.45 (1H, br s), 3.21 (1.5H, s) and 2.87 (1.5H, s), 3.1 - 3.0 (1H, br s), 2.85 - 2.7 (1H, br s), 2.76 (2H, t, J = 7.2 Hz), 2.71 (2H, t, J = 7.2 Hz), 2.7 - 2.6 (1H, m), 2.3 - 2.2 (1H, m), 2.08 (2H, quint, J = 7.2 Hz), 1.11 ppm (9H, s).

[0322] Example 41-2: Compound of Example 41 6-((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-N-methyl-N-phenethyl-2-naphthamide 33-2-LP

[0323] To a 4 mL vial containing compound 33-1-LP (21.1 mg, 0.0328 mmol) prepared in Example 41-1, water (0.0125 mL) and trifluoroacetic acid (0.250 mL) were added and stirred at room temperature for 1 hour. The reaction mixture was transferred to a 10 mL recovery flask, acetonitrile (1 mL) was added, and the mixture was concentrated under reduced pressure. This procedure was repeated once more. Next, chloroform (1.5 mL) was added, and the mixture was concentrated under reduced pressure. This procedure was also repeated once more. Finally, the mixture was dried under reduced pressure using a vacuum pump for one week, yielding 19.3 mg (0.0328 mmol, 100%) of the desired compound 33-2-LP.

[0324] Example 42 6-((2R,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-N-methyl-N-phenethyl-2-naphthamide 33-2-P

[0325] To a 4 mL vial containing compound 33-1-P (7.91 mg, 0.0123 mmol) prepared in Example 41-1, water (0.005 mL) and trifluoroacetic acid (0.1 mL) were added and stirred at room temperature for 1 hour. The reaction mixture was transferred to a 10 mL recovery flask, acetonitrile (1 mL) was added, and the mixture was concentrated under reduced pressure. This procedure was repeated once more. Next, chloroform (1.5 mL) was added and the mixture was concentrated under reduced pressure. This procedure was also repeated once more. Finally, the mixture was dried under reduced pressure using a vacuum pump for one week to obtain 7.22 mg (0.0128 mmol, 100%) of the desired compound 33-2-P.

[0326] Example 43 ((2S,4R)-4-Hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(6-((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)naphthalen-2-yl)methanone 34-2-LP Example 43-1 ((2S,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(6-((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)naphthalen-2-yl)methanone 34-1-LP and ((2R,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(6-((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)naphthalen-2-yl)methanone 34-1-P

[0327] To a 4 mL vial containing compound 6-4 (31.2 mg, 0.0593 mmol) prepared in Example 11-4, dichloromethane (0.450 mL), a dichloromethane (0.050 mL) solution of compound 1-2 (16.0 mg, 0.0622 mmol) prepared in Example 1-3, HATU (27.0 mg, 0.0711 mmol), and N,N-diisopropylethylamine (0.0403 mL, 0.237 mmol) were added and stirred at room temperature for 3 hours. After removing the solvent under reduced pressure, ice chips and 5% aqueous sodium bicarbonate solution (2 mL) were added to the residue, followed by extraction with ethyl acetate (6 mL). The ethyl acetate layer was washed with water (2 mL) and then dried by passing through a Libra tube filled with anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; eluent: ethyl acetate:hexane = 2:1). The target silica gel was scraped off and eluted with 10% MeOH in chloroform (20 ml). The solvent was removed under reduced pressure to obtain two diastereomers.

[0328] 34-1-LP: Rf value = 0.51 (developing solvent: ethyl acetate:hexane = 2:1) 20.7 mg (0.0270 mmol, 45.5%) 1H-NMR (CDCl3) δ: 8.09 (2H, br s), 7.92 (2H, br s), 7.71 (2H, br s), 7.3-7.1 (10H, m), 5.63 (1H, t, J = 6.8 Hz), 5.55 (1H, br s), 4.41 (1H, br s), 3.95 (1H, br s), 3.85 (1H, br s), 3.67 (1H, br s), 3.48 (1H, br s), 2.78 (4H, t, J = 7.6 Hz), 2.72 (4H, t, J=7.6 Hz), 2.45-2.35 (1H, m), 2.3-2.2 (1H, m), 2.2-1.95 (4H, m), 2.11 (4H, quint, J=7.6 Hz), 1.12 ppm (9H, s). 34-1-P: Rf value = 0.36 (developing solvent: ethyl acetate:hexane = 2:1) 11.6 mg (0.0151 mmol, 45.5%) 1H-NMR(CDCl3) δ: 8.13 (1H, br s), 8.10 (1H, br s), 7.94 (1H, br s), 7.73 (1H, br s), 7.35-7.1 (10H, m), 5.6-5.5 (1H, br s), 5.56 (1H, t, J=7.2 Hz), 4.26 (1H, br s), 3.9-3.6 (4H, m), 2.76 (4H, t, J=7.6 Hz), 2.71 (4H, t, J=7.6 Hz), 2.7-2.6 (1H, m), 2.3-1.8 (5H, m), 2.10 (4H, quint, J=7.6 Hz), 1.11 ppm (9H, s).

[0329] Example 43-2: Compound of Example 43 ((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(6-((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)naphthalen-2-yl)methanone 34-2-LP

[0330] Compound 34-1-LP (20.2 mg, 0.0263 mmol) prepared in Example 43-1 was placed in a 4 mL vial, and water (0.0100 mL) and trifluoroacetic acid (0.200 mL) were added and stirred at room temperature for 1 hour. The reaction mixture was transferred to a 10 mL eggplant-shaped flask, acetonitrile (1 mL) was added, and the mixture was concentrated under reduced pressure. This procedure was repeated. Next, chloroform (1.5 mL) was added, and the mixture was concentrated under reduced pressure. This procedure was also repeated. Ice chips and 5% aqueous sodium bicarbonate solution (2 mL) were added to the residue, and the mixture was extracted with ethyl acetate (6 mL). The ethyl acetate layer was washed with water (2 mL) and then dried by passing it through a Libra tube filled with anhydrous sodium sulfate. The solvent was removed under reduced pressure, yielding 18.7 mg (0.0263 mmol, 100%) of the desired compound 34-2-LP.

[0331] Example 44 (2R,4R)-4-Hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(6-((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)naphthalen-2-yl)methanone 34-2-P

[0332] Compound 34-1-P (10.6 mg, 0.0138 mmol) prepared in Example 43-1 was placed in a 4 mL vial and water (0.00550 mL) and trifluoroacetic acid (0.110 mL) were added and stirred at room temperature for 1 hour. The reaction mixture was transferred to a 10 mL eggplant-shaped flask, acetonitrile (1 mL) was added, and the mixture was concentrated under reduced pressure. This procedure was repeated. Next, chloroform (1.5 mL) was added and the mixture was concentrated under reduced pressure. This procedure was also repeated. Ice chips and 5% aqueous sodium bicarbonate solution (2 mL) were added to the residue, and the mixture was extracted with ethyl acetate (6 mL). The ethyl acetate layer was washed with water (2 mL) and then dried by passing it through a Libra tube filled with anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 9.80 mg (0.0138 mmol, 100%) of the desired compound 34-2-P.

[0333] Example 45 ((2S,4R)-4-Hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(6-((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)naphthalen-2-yl)methanone 35-2-LP Example 45-1 ((2S,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(6-((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)naphthalen-2-yl)methanone 35-1-LP and ((2R,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(6-((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)naphthalen-2-yl)methanone 35-1-P

[0334] To a 4 mL vial containing compound 6-4 (31.2 mg, 0.0593 mmol) prepared in Example 11-4, dichloromethane (0.450 mL), a dichloromethane (0.050 mL) solution of compound 2-2 (16.9 mg, 0.0622 mmol) prepared in Example 3-2, HATU (27.0 mg, 0.0711 mmol), and N,N-diisopropylethylamine (0.0403 mL, 0.237 mmol) were added and stirred at room temperature for 3 hours. After distilling off the solvent under reduced pressure, ice chips and 5% aqueous sodium bicarbonate solution (2 mL) were added to the residue, followed by extraction with ethyl acetate (6 mL). The ethyl acetate layer was washed with water (2 mL) and then dried by passing through a Libra tube filled with anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; eluent: ethyl acetate:hexane = 2:1). The target silica gel was scraped off and eluted with 10% MeOH in chloroform (20 ml). The solvent was removed under reduced pressure to obtain two diastereomers.

[0335] 35-1-LP: Rf value = 0.79 (developing solvent: acetic acid acetyl: hexane = 2:1) 24.6 mg (0.0315 mmol, 53%) 1H-NMR (CDCl3) δ: 8.07 (1H, s), 8.0 (1H, s), 8.0-7.85 (2H, br s), 7.70 (1H, d, J = 7.6 Hz), 7.61 (1H, d, J = 7.6 Hz), 7.35-7.1 (10H, m), 6.28 (1H, br s), 5.64 (1H, t, J = 6.8 Hz), 4.41 (1H, br s), 3.95 (1H, br s), 3.75 (1H, br s), 3.48 (1H, br s), 3.31 (1H, br s), 2.79 (4H, t, J=7.6 Hz), 2.72 (4H, t, J=7.6 Hz), 2.45-2.35 (1H, m), 2.3-2.2 (1H, m), 2.11 (4H, quint, J=7.6 Hz), 2.1-2.0 (1H, m), 1.9-1.4 (5H, m), 1.12 ppm (9H, s). 35-1-P: Rf value = 0.62 (developing solvent: acetic acid acetyl: hexane = 2:1) 11.5 mg (0.0147 mmol, 24%) 1H-NMR(CDCl3) δ: 8.13 (1H, s), 8.05-7.85 (2H, m), 8.0 (1H, s), 7.74 (1H, d, J=7.6 Hz), 7.61 (1H, d, J=7.6 Hz), 7.35-7.1 (10H, m), 6.28 (1H, br s), 5.55 (1H, t, J=8 Hz), 4.27 (1H, quint, J=6.4 Hz), 3.85-3.75 (3H, m), 3.9 (1H, br s), 2.81 (4H, t, J=7.6 Hz), 2.74 (4H, t, J=7.6 Hz), 2.7-2.6 (1H, m), 2.3-2.2 (1H, m), 2.11 (4H, quint, J=7.6 Hz), 2.05-1.95 (1H, m), 1.9-1.4 (5H, m), 1.11 ppm (9H, s).

[0336] Example 45-2: Compound of Example 45 ((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(6-((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)naphthalen-2-yl)methanone 35-2-LP

[0337] To a 4 mL vial containing compound 35-1-LP (23.9 mg, 0.0306 mmol) prepared in Example 45-1, water (0.0120 mL) and trifluoroacetic acid (0.240 mL) were added and stirred at room temperature for 1 hour. The reaction mixture was transferred to a 10 mL recovery flask, acetonitrile (1 mL) was added, and the mixture was concentrated under reduced pressure. This procedure was repeated. Next, chloroform (1.5 mL) was added and the mixture was concentrated under reduced pressure. This procedure was also repeated. Ice chips and 5% aqueous sodium bicarbonate solution (2 mL) were added to the residue, and the mixture was extracted with ethyl acetate (6 mL). The ethyl acetate layer was washed with water (2 mL) and then dried by passing it through a Libra tube filled with anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 19.9 mg (0.0274 mmol, 89.5%) of the desired compound 35-2-LP.

[0338] Example 46 ((2R,4R)-4-Hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(6-((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)naphthalen-2-yl)methanone 35-2-P

[0339] Compound 35-1-P (11.6 mg, 0.0148 mmol) prepared in Example 45-1 was placed in a 4 mL vial and water (0.006 mL) and trifluoroacetic acid (0.120 mL) were added and stirred at room temperature for 1 hour. The reaction mixture was transferred to a 10 mL eggplant-shaped flask, acetonitrile (1 mL) was added, and the mixture was concentrated under reduced pressure. This procedure was repeated. Next, chloroform (1.5 mL) was added and the mixture was concentrated under reduced pressure. This procedure was also repeated. Ice chips and 5% aqueous sodium bicarbonate solution (2 mL) were added to the residue, and the mixture was extracted with ethyl acetate (6 mL). The ethyl acetate layer was washed with water (2 mL) and then dried by passing it through a Libra tube filled with anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 10.8 mg (0.0148 mmol, 100%) of the desired compound 35-2-P.

[0340] Example 47 ((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(6-((2S,4R)-4-(tert-butoxy)-2-(3-phenethyl-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)naphthalen-2-yl)methanone 36-4-LP Example 47-1: (9H-fluoren-9-yl)methyl (2S,4R)-4-(tert-butoxy)-2-(3-phenethyl-1,2,4-oxazol-5-yl)pyrrolidine-1-carboxylate 36-1

[0341] A 50 ml recovery flask was charged with a solution of (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (1.53 g, 3.74 mmol) in dichloromethane (9 ml), a solution of N'-hydroxy-3-phenylpropanimidamide (0.675 g, 4.11 mmol) in dichloromethane (10 ml), HATU (1.56 g, 4.11 mmol), and diisopropylethylamine (1.27 ml, 7.48 mmol), and the mixture was stirred at room temperature for 2 hours. After evaporation of the solvent, the mixture was made basic with saturated aqueous sodium bicarbonate (15 ml) and then extracted with ethyl acetate (90 ml). The organic layer was washed with water (15 ml) and then saturated brine (15 ml) and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified using a silica gel column, Q-pack SI30 size 60 (hexane:ethyl acetate = 90:10 to 20:80) to obtain 1.23 g (2.21 mmol, 59%) of the intermediate imidamide. This intermediate and toluene (22 ml) were placed in a 50 ml eggplant-shaped flask, attached to a Dean-Stark trap, and heated under reflux in an oil bath at 130 °C for 15 hours. The solvent was removed under reduced pressure, and the resulting residue was purified using a silica gel column, Q-pack SI30 size 60 (hexane:ethyl acetate = 65:35 to 0:100). After distillation, 0.457 g (0.850 mmol, 39%) of the desired compound 36-1 (oil) was obtained.

[0342] Example 47-2: 5-((2S,4R)-4-(tert-butoxy)pyrrolidin-2-yl)-3-phenethyl-1,2,4-oxadiazole 36-2

[0343] Compound 36-1 (0.451 g, 0.839 mmol) prepared in Example 47-1 was added to a 25 ml eggplant-shaped flask, followed by dichloromethane (4.5 ml) and piperidine (1.25 ml, 12.6 mmol). The mixture was stirred at room temperature for 1 hour. After evaporation of the solvent, the residue was purified on a silica gel column (Q-Pack SI30, size 20) (hexane:ethyl acetate = 65:35 to 0:100). After evaporation of the solvent, 190 mg (0.601 mmol, 71.5%) of the desired compound 36-2 (oil) was obtained.

[0344] Example 47-3 ((2S,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(6-((2S,4R)-4-(tert-butoxy)-2-(3-phenethyl-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)naphthalen-2-yl)methanone 36-3-LP and ((2R,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(6-((2S,4R)-4-(tert-butoxy)-2-(3-phenethyl-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)naphthalen-2-yl)methanone 36-3-P

[0345] To a 4 ml vial containing compound 6-4 (31.2 mg, 0.0593 mmol) prepared in Example 11-4, dichloromethane (0.450 ml), a dichloromethane (0.050 ml) solution of compound 36-2 (19.6 mg, 0.0622 mmol) prepared in Example 47-2, HATU (27.0 mg, 0.0711 mmol), and N,N-diisopropylethylamine (0.0403 ml, 0.237 mmol) were added and stirred at room temperature for 3 hours. After the solvent was evaporated under reduced pressure, ice chips and a 5% aqueous solution of sodium bicarbonate (2 mL) were added to the residue, followed by extraction with ethyl acetate (6 ml). The ethyl acetate layer was washed with water (2 ml) and then dried by passing it through a Libra tube filled with anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was separated by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, The product was purified using a 20 x 20 cm column (eluent: ethyl acetate:hexane = 2:1). The target product was removed from the silica gel and eluted with 10% MeOH in chloroform (20 ml). The solvent was removed under reduced pressure to obtain two diastereomers.

[0346] 36-3-LP: Rf value = 0.76 (developing solvent: acetic acid acetyl: hexane = 2:1) 4.5 mg (0.0297 mmol, 50%) 1H-NMR (CDCl3) δ: 8.09 (2H, s), 7.94 (2H, d, J = 8.4 Hz), 7.71 (2H, d, J = 8.4 Hz), 7.35-7.1 (10H, m), 5.64 (1H, br s), 4.41 (2H, br s), 4.0-3.9 (2H, br s), 3.55-3.45 (2H, br s), 3.15-3.05 (4H, m), 2.78 (2H, t, 3-P: Rf value = 0.58 (developing solvent: acetic acid acetyl: hexane = 2:1) 12.9 mg (0.0156 mmol, 26%) 1H-NMR (CDCl3) δ: 8.14 (1H, s), 8.10 (1H, s), 7.96 (2H, d, J = 7.2 Hz), 7.75 (1H, d, J=7.2 Hz), 7.72 (1H, d, J=7.2 Hz), 7.35-7.1 (10H, m), 5.65 (1H, t, J=6.8 Hz), 5.55 (1H, t, J=8 Hz), 4.41 (1H, br s), 4.27 (1H, br s), 3.95 (1H, br s), 3.8-3.65 (2H, m), 3.50 (1H, br s), 3.15-3.0 (4H, br s), 2.76 (2H, t, J=7.6 Hz), 2.71 (2H, t, J=7.6 Hz), 2.7-2.6 (1H, m), 2.45-2.35 (1H, m), 2.3-2.15 (2H, m), 2.10 (2H, quint, J=7.6 Hz), 1.13 (8H, s), 1.11 ppm (9H, s).

[0347] Example 47-4: Compound of Example 47 (2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(6-((2S,4R)-4-hydroxy-2-(3-phenethyl-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)naphthalen-2-yl)methanone 36-4-LP

[0348] Compound 36-3-LP (24.7 mg, 0.0299 mmol) prepared in Example 47-3 was placed in a 4 mL vial and water (0.0230 mL) and trifluoroacetic acid (0.460 mL) were added and stirred at room temperature for 1 hour. The reaction mixture was transferred to a 10 mL eggplant-shaped flask, acetonitrile (1 mL) was added, and the mixture was concentrated under reduced pressure. This procedure was repeated. Next, chloroform (1.5 mL) was added and the mixture was concentrated under reduced pressure. This procedure was also repeated. Ice chips and 5% aqueous sodium bicarbonate solution (2 mL) were added to the residue, and the mixture was extracted with ethyl acetate (6 mL). The ethyl acetate layer was washed with water (2 mL) and then dried by passing it through a Libra tube filled with anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 21.3 mg (0.0299 mmol, 100%) of the desired compound 36-4-LP.

[0349] Example 48 ((2R,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(6-((2S,4R)-4-hydroxy-2-(3-phenethyl-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)naphthalen-2-yl)methanone 36-4-P

[0350] Compound 36-3-P (12.8 mg, 0.0156 mmol) prepared in Example 47-3 was placed in a 4 mL vial and water (0.0120 mL) and trifluoroacetic acid (0.240 mL) were added and stirred at room temperature for 1 hour. The reaction mixture was transferred to a 10 mL eggplant-shaped flask, acetonitrile (1 mL) was added, and the mixture was concentrated under reduced pressure. This procedure was repeated. Next, chloroform (1.5 mL) was added and the mixture was concentrated under reduced pressure. This procedure was also repeated. Ice chips and 5% aqueous sodium bicarbonate solution (2 mL) were added to the residue, and the mixture was extracted with ethyl acetate (6 mL). The ethyl acetate layer was washed with water (2 mL) and then dried by passing it through a Libra tube filled with anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 11.1 mg (0.0156 mmol, 100%) of the desired compound 36-4-P.

[0351] Example 49 ((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(4-(pyrrolidine-1-carbonyl)phenyl)methanone 37-2-LP Example 49-1 ((2S,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(4-(pyrrolidine-1-carbonyl)phenyl)methanone 37-1-LP and ((2R,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(4-(pyrrolidine-1-carbonyl)phenyl)methanone 37-1-P

[0352] To a 4 mL vial containing compound 32-2 (30.9 mg, 0.0647 mmol) prepared in Example 40, dichloromethane (0.5 mL), pyrrolidine (0.00562 mL, 0.0679 mmol), HATU (29.5 mg, 0.0777 mmol), and N,N-diisopropylethylamine (0.0440 mL, 0.259 mmol) were added and stirred at room temperature for 3 hours. After evaporation of the solvent under reduced pressure, ice chips and 5% aqueous sodium bicarbonate solution (2 mL) were added to the residue, followed by extraction with ethyl acetate (6 mL). The ethyl acetate layer was washed with water (2 mL) and then dried by passing through a Libra tube filled with anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, the residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; eluent: ethyl acetate). The target portion of the silica gel was scraped off, and the mixture was eluted with 10% MeOH in chloroform (20 ml). The solvent was evaporated under reduced pressure to give two diastereomers.

[0353] 37-1-LP: Rf value = 0.37 (developing solvent: acetic acid acetyl) 19.0 mg (0.0358 mmol, 55%) 1H-NMR (CDCl3) δ: 7.60 (2H, d, J = 8.4 Hz), 7.55 (2H, d, J = 8.4 Hz), 7.3-7.1 (5H, m), 5.6-5.5 (1H, dd, J = 8.6, 4 Hz), 4.38 (1H, quint, J = 4.4 Hz), 3.87 and 3.85 (1H, dd, J = 10.8, 4.4 Hz), 3.65 (2H, t, J = 6.8 Hz), 3.5-3.4 (1H, m), 3.38 (2H, d, J=8 Hz), 7.64 (2H, d, J=8 Hz), 7.70 (2H, d, J=8 Hz), 7.96 (2H, d, J=8 Hz), 1.20 (2H, s), 1.43 (9H, s), 1.20 (2H, t, J=6.8 Hz), 2.76 (2H, t, J=7.6 Hz), 2.71 (2H, t, J=7.6 Hz), 2.45-2.35 (1H, m), 2.28-2.18 (1H, m), 2.09 (2H, quint, J=7.6 Hz), 2.05-1.95 (2H, m), 1.95-1.85 (2H, m), 1.13 ppm (9H, s). 37-1-P: Rf value = 0.24 (developing solvent: acetic acid acetyl) 6.80 mg (0.0128 mmol, 20%) 1H-NMR (CDCl3) δ: 7.65 (2H, d, J=8 Hz), 7.56 (2H, d, J=8 Hz), 7.35-7.15 (5H, m), 5.49 (1H, t, J=8 Hz), 4.25 (1H, quint, J=6.8 Hz), 3.75-3.55 (5H, m), 3.38 (2H, t, J=6.6 Hz), 2.74 (2H, t, J=7.6 Hz), 2.70 (2H, t, J=7.6 Hz), 2.65-2.55 (1H, m), 2.25-2.15 (1H, m), 2.08 (2H, quint, J=7.6 Hz), 2.05-1.95 (2H, m), 1.95-1.85 (2H, m), 1.11 ppm (9H, s).

[0354] Example 49-2: Compound of Example 49 ((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(4-(pyrrolidine-1-carbonyl)phenyl)methanone 37-2-LP

[0355] To a 4 mL vial containing compound 37-1-LP (18.5 mg, 0.0348 mmol) prepared in Example 49-1, water (0.014 mL) and trifluoroacetic acid (0.280 mL) were added and stirred at room temperature for 1 hour. The reaction mixture was transferred to a 10 mL recovery flask, acetonitrile (2 mL) was added, and the mixture was concentrated under reduced pressure. This procedure was repeated once more. Next, chloroform (3 mL) was added and the mixture was concentrated under reduced pressure. This procedure was also repeated once more. Finally, the mixture was dried under reduced pressure using a vacuum pump for one week to obtain 16.5 mg (0.0348 mmol, 100%) of the desired compound 37-2-LP.

[0356] Example 50 ((2R,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(4-(pyrrolidine-1-carbonyl)phenyl)methanone 37-2-P

[0357] To a 4 mL vial containing compound 37-1-P (6.58 mg, 0.0124 mmol) prepared in Example 49-1, water (0.005 mL) and trifluoroacetic acid (0.1 mL) were added and stirred at room temperature for 1 hour. The reaction mixture was transferred to a 10 mL recovery flask, acetonitrile (2 mL) was added, and the mixture was concentrated under reduced pressure. This procedure was repeated. Next, chloroform (3 mL) was added and the mixture was concentrated under reduced pressure. This procedure was also repeated. Finally, the mixture was dried under reduced pressure using a vacuum pump for one week to obtain 5.88 mg (0.0124 mmol, 100%) of the desired compound 37-2-P.

[0358] The retention time (RT) and 1H-NMR data for the compounds of Examples 35 to 50 under the following LC / MS elution conditions are summarized in Table 6. Elution conditions: flow rate 0.9 mL / min, mobile phase A = 0.05% (v / v) formic acid aqueous solution, mobile phase B = acetonitrile containing 0.05% (v / v) formic acid; 0-0.9 min: linear gradient A:B (95:5) - A:B (10:90), 0.9-3 min: A:B (10:90).

[0359] Table 6-1

[0360] Table 6-2

[0361] Table 6-3

[0362] Table 6-4

[0363] Table 6-5

[0364] Table 6-6

[0365] Example 51 N-benzyl-4-((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-N-methylbenzamide 38-2-LP Example 51-1 N-benzyl-4-((2S,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-N-methylbenzamide 38-1-LP and N-benzyl-4-((2R,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-N-methylbenzamide 38-1-P

[0366] To a 4 mL vial containing compound 32-2 (30.9 mg, 0.0647 mmol) prepared in Example 40, dichloromethane (0.5 mL), N-methylbenzylamine (0.00876 mL, 0.0679 mmol), HATU (29.5 mg, 0.0777 mmol), and N,N-diisopropylethylamine (0.0440 mL, 0.259 mmol) were added and stirred at room temperature for 3 hours. After removing the solvent under reduced pressure, ice chips and 5% aqueous sodium bicarbonate solution (2 mL) were added to the residue, followed by extraction with ethyl acetate (6 mL). The ethyl acetate layer was washed with water (2 mL) and then dried by passing through a Libra tube filled with anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: ethyl acetate:hexane = 2:1). The target silica gel was scraped off, and the mixture was eluted with 10% MeOH in chloroform (20 ml). The solvent was removed under reduced pressure, yielding two diastereomers.

[0367] 38-1-LP: Rf value = 0.39 (developing solvent: acetic acid acetyl: hexane = 2:1) 20.4 mg (0.0303 mmol, 54%) 1H-NMR (CDCl3) δ: 7.58 (1H, d J = 8 Hz), 7.56 (1H, d, J = 8 Hz), 7.50 (2H, d, J = 8 Hz), 7.4-7.1 (10, m), 5.56 (1H, br s), 4.76 (1H, br s), 4.47 (1H, br s), 4.38 (1H, br s), 3.85 (1H, br s), 3.41 (1H, br s), 3.06 (1.5H, s) and 2.84 (1.5H, s), 2.73 (2H, t, J=7.2 Hz), 2.70 (2H, t, J=7.2 Hz), 2.45-2.35 (1H, br s), 2.25-2.15 (1H, br s) 2.09 (2H, quint, J=7.2 Hz), 1.13 ppm (9H, s). 38-1-P: Rf value = 0.20 (developing solvent: acetic acid acetyl: hexane = 2:1) 7.40 mg (0.0127 mmol, 20%) 1H-NMR (CDCl3) δ: 7.66 (1H, d, J=8 Hz), 7.62 (1H, d, J=8 Hz), 7.51 (2H, d, J=8 Hz), 7.4-7.1 (10H, m), 5.47 (1H, br s), 4.47 (1H, br s), 4.25 (1H, br s), 3.67 (1H, br s), 3.61 (1H, br s), 3.06 (1.5H, s) and 2.84 (1.5H, s), 2.71 (2H, t, J=7.2 Hz), 2.69 (2H, t, J=7.2 Hz), 2.65-2.55 (1H, br s), 2.25-2.15 (1H, br s), 2.07 (2H, quint, J=7.2 Hz), 1.11 ppm (9H, s).

[0368] Example 51-2: Compound of Example 51 N-benzyl-4-((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-N-methylbenzamide 38-2-LP

[0369] To a 4 mL vial containing compound 38-1-LP (19.0 mg, 0.0328 mmol) prepared in Example 51-1, water (0.0125 mL) and trifluoroacetic acid (0.250 mL) were added and stirred at room temperature for 1 hour. The reaction mixture was transferred to a 10 mL recovery flask, acetonitrile (2 mL) was added, and the mixture was concentrated under reduced pressure. This procedure was repeated once more. Next, chloroform (3 mL) was added and the mixture was concentrated under reduced pressure. This procedure was also repeated once more. Finally, the mixture was dried under reduced pressure using a vacuum pump for one week to obtain 13.0 mg (0.0248 mmol, 76%) of the desired compound 38-2-LP.

[0370] Example 52 N-benzyl-4-((2R,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-N-methylbenzamide 38-2-P

[0371] To a 4 mL vial containing compound 38-1-P (6.2 mg, 0.0107 mmol) prepared in Example 51-1, water (0.005 mL) and trifluoroacetic acid (0.1 mL) were added and stirred at room temperature for 1 hour. The reaction mixture was transferred to a 10 mL recovery flask, acetonitrile (2 mL) was added, and the mixture was concentrated under reduced pressure. This procedure was repeated once more. Next, chloroform (3 mL) was added and the mixture was concentrated under reduced pressure. This procedure was also repeated once more. Finally, the mixture was dried under reduced pressure using a vacuum pump for one week to obtain 4.54 mg (0.00865 mmol, 82%) of the desired compound 38-2-P.

[0372] Example 53 N-benzyl-4-((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)benzamide 39-2-LP Example 53-1 N-benzyl-4-((2S,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)benzamide 39-1-LP and N-benzyl-4-((2R,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)benzamide 39-1-P

[0373] To a 4 mL vial containing compound 32-2 (30.9 mg, 0.0647 mmol) prepared in Example 40, dichloromethane (0.5 mL), benzylamine (0.00743 mL, 0.0679 mmol), HATU (29.5 mg, 0.0777 mmol), and N,N-diisopropylethylamine (0.0440 mL, 0.259 mmol) were added and stirred at room temperature for 3 hours. After distilling off the solvent under reduced pressure, ice chips and 5% aqueous sodium bicarbonate solution (2 mL) were added to the residue, followed by extraction with ethyl acetate (6 mL). The ethyl acetate layer was washed with water (2 mL) and then dried by passing through a Libra tube filled with anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: ethyl acetate:hexane = 2:1). The target silica gel was scraped off, and the mixture was eluted with 10% MeOH in chloroform (20 ml). The solvent was removed under reduced pressure, yielding two diastereomers.

[0374] 39-1-LP: Rf value = 0.43 (developing solvent: ethyl acetate:hexane = 2:1) 21.7 mg (0.0383 mmol, 59%) 1H-NMR(CDCl3) δ: 7.80 (1H, d, J=8 Hz), 7.55 (1H, d, J=8 Hz), 7.4-7.0 (10H, m), 6.73 (1H, t, J=5.6 Hz), 5.53 (1H, t, J=7.2 Hz), 4.63 (2H, d, J=5.6 Hz), 4.37 (1H, quint, J=4.4 Hz), 3.84 and 3.82 (1H, dd, J=10.8, 5.2 Hz), 3.38 and 3.35 (1H, dd, 2.75 (2H, t, J=7.6 Hz), 2.71 (2H, t, J=7.6 Hz), 2.4-2.3 (1H, m), 2.25-2.15 (1H, m), 2.08 (2H, quint, J=7.6 Hz), 1.12 ppm (9H, s). 39-1-P: Rf value = 0.31 (Developing solvent: ethyl acetate:hexane = 2:1) 8.90 mg (0.0157 mmol, 24%) 1H-NMR(CDCl3) δ: 7.83 (2H, d, J=8 Hz), 7.63 (2H, d, J=8 Hz), 7.4-7.1 (H, t, J=5.6 Hz), 4.65 (2H, d, J=5.6 Hz), 4.24 (1H, quint, J=6.4 Hz), 3.7-3.55 (2H, m), 2.74 (2H, t, J=7.6 Hz), 2.70 (2H, t, J=7.6 Hz), 2.65-2.55 (1H, m), 2.25-2.15 (1H, m), 2.07 (2H, quint, J=7.6 Hz), 1.10 ppm (9H, s).

[0375] Example 53-2: Compound of Example 53 N-benzyl-4-((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)benzamide 39-2-LP

[0376] To a 4 mL vial containing compound 39-1-LP (20.0 mg, 0.0353 mmol) prepared in Example 53-1, water (0.014 mL) and trifluoroacetic acid (0.280 mL) were added and stirred at room temperature for 1 hour. The reaction mixture was transferred to a 10 mL recovery flask, acetonitrile (2 mL) was added, and the mixture was concentrated under reduced pressure. This procedure was repeated once more. Next, chloroform (3 mL) was added and the mixture was concentrated under reduced pressure. This procedure was also repeated once more. Finally, the mixture was dried under reduced pressure using a vacuum pump for one week to obtain 18.0 mg (0.0353 mmol, 100%) of the desired compound 39-2-LP.

[0377] Example 54 N-benzyl-4-((2R,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)benzamide 39-2-P

[0378] To a 4 mL vial containing compound 39-1-P (6.55 mg, 0.0116 mmol) prepared in Example 53-1, water (0.005 mL) and trifluoroacetic acid (0.1 mL) were added and stirred at room temperature for 1 hour. The reaction mixture was transferred to a 10 mL recovery flask, acetonitrile (2 mL) was added, and the mixture was concentrated under reduced pressure. This procedure was repeated once more. Next, chloroform (3 mL) was added and the mixture was concentrated under reduced pressure. This procedure was also repeated once more. Finally, the mixture was dried under reduced pressure using a vacuum pump for one week to obtain 5.56 mg (0.0109 mmol, 94%) of the desired compound 39-2-P.

[0379] Example 55 4-((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-N-methyl-N-phenethylbenzamide 40-2-LP Example 55-1 4-((2S,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-N-methyl-N-phenethylbenzamide 40-1-LP and 4-((2R,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-N-methyl-N-phenethylbenzamide 40-1-P

[0380] To a 4 mL vial containing compound 32-2 (30.9 mg, 0.0647 mmol) prepared in Example 40, dichloromethane (0.5 mL), N-methylphenethylamine (0.00988 mL, 0.0679 mmol), HATU (29.5 mg, 0.0777 mmol), and N,N-diisopropylethylamine (0.0440 mL, 0.259 mmol) were added and stirred at room temperature for 3 hours. After removing the solvent under reduced pressure, ice chips and 5% aqueous sodium bicarbonate solution (2 mL) were added to the residue, followed by extraction with ethyl acetate (6 mL). The ethyl acetate layer was washed with water (2 mL) and then dried by passing through a Libra tube filled with anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; eluent: ethyl acetate). The target silica gel was scraped off and eluted with 10% MeOH in chloroform (20 ml). The solvent was removed under reduced pressure to obtain two diastereomers.

[0381] 40-1-LP: Rf value = 0.61 (developing solvent: acetic acid acetyl) 22.7 mg (0.0382 mmol, 59%) 1H-NMR (CDCl3) δ: 7.57 (1H, d, J = 7.6 Hz), 7.48 (1H, d, J = 7.6 Hz), 7.4-7.1 (10H, m), 7.03 (1H, d, J = 7.6 Hz), 6.94 (1H, d, J = 7.6 Hz), 5.56 (1H, t, J = 7.2 Hz), 4.4-4.3 (1H, br s), 3.9-3.75 (2H, m), 3.5-3.35 (2H, m), 3.15 (1.5H,s) and δ: 2.79 (1.5H, s), 3.05-2.95 (1H, m), 2.76 (2H, t, J=7.6 Hz), 2.71 (2H, t, J=7.6 Hz), 3.7-3.6 (1H, m), 2.43-2.33 (1H, m), 2.28-2.18 (1H, m), 2.10 (2H, quint, J=7.6 Hz), 1.13 ppm (9H, s). 40-1-P: Rf value = 0.44 (developing solvent: acetic acid acetyl) 10.3 mg (0.0173 mmol, 27%) 1H-NMR (CDCl3) δ: 7.63 (1H, d, J=7.6 Hz), 7.53 (1H, d, J=7.6 Hz), 7.4-7.1 (10H, m), 7.05 (1H, d, J=7.6 Hz), 6.95 (1H, d, J=7.6 Hz), 5.48 (1H, t, J=8 Hz), 4.3-4.2 (1H, br s), 3.85-3.75 (1H, m), 3.75-3.55 (2H, m), 3.5-3.4 (1H, m), 3.16 (1.5H, s) and 2.79 (1.5H, s), 3.05-2.95 (1H, m), 2.8-2.65 (1H, m), 2.75 (2H, t, J=8 Hz), 2.70 (2H, t, J=8 Hz), 2.65-2.55 (1H, m), 2.25-2.15 (1H, m), 2.08 (2H, quint, J=8 Hz), 1.11 ppm (9H, s).

[0382] Example 55-2: Compound of Example 55 4-((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-N-methyl-N-phenethylbenzamide 40-2-LP

[0383] To a 4 mL vial containing compound 40-1-LP (21.3 mg, 0.0358 mmol) prepared in Example 55-1, water (0.014 mL) and trifluoroacetic acid (0.280 mL) were added and stirred at room temperature for 1 hour. The reaction mixture was transferred to a 10 mL recovery flask, acetonitrile (2 mL) was added, and the mixture was concentrated under reduced pressure. This procedure was repeated once more. Next, chloroform (3 mL) was added and the mixture was concentrated under reduced pressure. This procedure was also repeated once more. Finally, the mixture was dried under reduced pressure using a vacuum pump for one week to obtain 19.3 mg (0.0358 mmol, 100%) of the desired compound 40-2-LP.

[0384] Example 56 4-((2R,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-N-methyl-N-phenethylbenzamide 40-2-P

[0385] To a 4 mL vial containing compound 40-1-P (7.92 mg, 0.0133 mmol) prepared in Example 55-1, water (0.006 mL) and trifluoroacetic acid (0.120 mL) were added and stirred at room temperature for 1 hour. The reaction mixture was transferred to a 10 mL recovery flask, acetonitrile (2 mL) was added, and the mixture was concentrated under reduced pressure. This procedure was repeated once more. Next, chloroform (3 mL) was added and the mixture was concentrated under reduced pressure. This procedure was also repeated once more. Finally, the mixture was dried under reduced pressure using a vacuum pump for one week to obtain 5.53 mg (0.0103 mmol, 77%) of the desired compound 40-2-P.

[0386] Example 57 tert-Butyl (S)-2-(4-methyl-5-(3-phenylpropyl)-4H-1,2,4-triazol-3-yl)azetidine-1-carboxylate 41

[0387] Ethyl N-methyl-4-phenylbutanimidothioate (59 mg, 0.264 mmol) was added to a 10 ml eggplant-shaped flask, and compound 29-1 (14.7 mg, 0.066 mmol) prepared in Example 35-1 was added while washing with butanol (0.82 ml). The mixture was heated under reflux for 14.5 hours under an argon atmosphere. After distilling off the solvent, the resulting residue was purified using a silica gel column Q-Pack SI30 size 10 (chloroform:methanol 100:0 to 95:5). After distilling off the solvent, 17 mg (0.048 mmol, 72%) of the desired compound 41 (oil) was obtained.

[0388] Example 58 tert-butyl (S)-2-(4-methyl-5-(3-phenylpropyl)-4H-1,2,4-triazol-3-yl)pyrrolidine-1-carboxylate 42-2 Example 58-1 tert-butyl (S)-2-(hydrazinecarbonyl)pyrrolidine-1-carboxylate 42-1

[0389] N-Boc-L-proline (500 mg, 2.32 mmol) was dissolved in dimethylformamide (2.50 ml) in a 10 ml eggplant-shaped flask. HATU (972 mg, 2.56 mmol) and diisopropylethylamine (0.8809 ml, 4.65 mmol) were then added and stirred at room temperature for 8 minutes under an argon atmosphere. This solution was then added to a 25 ml eggplant-shaped flask containing a solution of hydrazine-1-hydrate (0.576 ml, 11.6 mmol) in dimethylformamide (2.5 ml), washing with DMF (2.74 ml). The mixture was stirred at room temperature for 1 hour and 40 minutes. The mixture was made basic with saturated aqueous sodium bicarbonate (15 ml) and then extracted with ethyl acetate. The solvent was evaporated, and the resulting residue was purified on a silica gel column (Q-Pack SI30 size 60) (chloroform:methanol 95:5). After distilling off the solvent, 447 mg (1.95 mmol, 84%) of the desired compound 42-1 (amorphous solid) was obtained.

[0390] Example 58-2: Compound of Example 58 tert-butyl (S)-2-(4-methyl-5-(3-phenylpropyl)-4H-1,2,4-triazol-3-yl)pyrrolidine-1-carboxylate 42-2

[0391] Ethyl N-methyl-4-phenylbutanimidothioate (61 mg, 0.273 mmol) was added to a 10 ml eggplant-shaped flask, and compound 42-1 (25 mg, 0.109 mmol) prepared in Example 58-1 was added while washing with butanol (1.09 ml). The mixture was heated under reflux for 14.5 hours under an argon atmosphere, and after distillation of the solvent, the resulting residue was purified using a silica gel column Q-Pack SI30 size 10 (chloroform:methanol 100:0 to 95:5). After distillation of the solvent, 34.1 mg (0.092 mmol, 84%) of the desired product 42-2 (oil) was obtained.

[0392] Example 59 Naphthalene-2,6-diylbis(((2S,4R)-4-hydroxy-2-(4-methyl-5-(3-phenylpropyl)-4H-1,2,4-triazol-3-yl)pyrrolidin-1-yl)methanone) 43

[0393] Ethyl N-methyl-4-phenylbutanimidothioate (68 mg, 0.306 mmol) was added to a 10 ml eggplant-shaped flask, and compound 4-1 (50 mg, 0.204 mmol) prepared in Example 6-2 was added while washing with butanol (2.04 ml). The mixture was heated under reflux for 13 hours under an argon atmosphere, and the solvent was evaporated. The resulting residue was purified using a silica gel column Q-Pack SI30 size 20 (chloroform:methanol 100:0 to 90:10). After evaporation of the solvent, 58.7 mg (0.152 mmol, 74%) of the desired compound 43 (amorphous solid) was obtained.

[0394] The retention time (RT) and 1H-NMR data for the compounds of Examples 51 to 59 under the following LC / MS elution conditions are summarized in Table 7. Elution conditions: flow rate 0.9 mL / min, mobile phase A = 0.05% (v / v) formic acid aqueous solution, mobile phase B = acetonitrile containing 0.05% (v / v) formic acid; 0-0.9 min: linear gradient A:B (95:5) - A:B (10:90), 0.9-3 min: A:B (10:90).

[0395] Table 7-1

[0396] Table 7-2

[0397] Table 7-3

[0398] Example 60 Naphthalene-2,6-diylbis(((S)-2-(4-methyl-5-(3-phenylpropyl)-4H-1,2,4-triazol-3-yl)pyrrolidin-1-yl)methanone) 44-2 Example 60-1 (S)-3-(pyrrolidin-2-yl)-(4-methyl-5-(3-phenylpropyl)-4H-1,2,4-triazole hydrochloride 44-1

[0399] Compound 42-2 (15.4 mg, 0.042 mmol) prepared in Example 58-2 was added to a 10 ml recovery flask, and 4N hydrochloric acid / dioxane (0.277 ml), dioxane (0.277 ml), and water (0.028 ml) were added. The mixture was stirred at room temperature for 15 minutes. The solvent was then evaporated, and chloroform (1 ml) was added and the solvent was evaporated three times. The residue was then dried in vacuo to give 14.3 mg (0.042 mmol, 100%) of the desired compound 44-1 (amorphous solid).

[0400] Example 60-2: Compound of Example 60 naphthalene-2,6-diylbis(((S)-2-(4-methyl-5-(3-phenylpropyl)-4H-1,2,4-triazol-3-yl)pyrrolidin-1-yl)methanone) 44-2

[0401] 2,6-Naphthalenedicarboxylic acid (4.6 mg, 0.021 mmol) and DMF (0.339 ml) were added to a 10 ml eggplant-shaped flask, followed by HATU (20.6 mg, 0.054 mmol) and diisopropylethylamine (0.051 ml, 0.291 mmol). The mixture was stirred at room temperature for 5 minutes. Compound 44-1 (14.3 mg, 0.042 mmol), prepared in Example 60-1, was then added, washing with DMF (0.7 ml). The mixture was stirred at room temperature for 20 hours. The stir bar was then removed and the solvent was evaporated. The residue was purified using a silica gel column (Q-Pack SI30, size 10) (chloroform:methanol = 100:0 to 90:10). After evaporation, 13.2 mg (0.018 mmol, 86%) of the desired product 44-2 (white solid) was obtained.

[0402] Example 61 Spiro[3.3]heptane-2,6-diylbis(((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 45

[0403] Spiro[3.3]heptane-2,6-dicarboxylic acid (18.4 mg, 0.100 mmol) and dichloromethane (1.0 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (124.89 mg, 0.240 mmol) and diisopropylethylamine (0.139 ml, 0.800 mmol). The mixture was stirred at room temperature for 15 minutes. Compound 1-2 (53.8 mg, 0.209 mmol) was then added, washing in with dichloromethane (0.5 ml), and the mixture was stirred at room temperature for 16 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:methanol = 30:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to obtain the target compound 45 (oil) in an amount of 38.9 mg (0.059 mmol, 59%).

[0404] Example 62 Pyrazine-2,5-diylbis(((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)azetidin-1-yl)methanone) 46

[0405] Pyrazine-2,5-dicarboxylic acid (26.9 mg, 0.160 mmol) and dichloromethane (1.5 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (199.8 mg, 0.384 mmol) and diisopropylethylamine (0.223 ml, 1.280 mmol). The mixture was stirred at room temperature for 5 minutes. Compound 18-2 (82.0 mg, 0.337 mmol) was then added, washing in with dichloromethane (0.5 ml). The mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:methanol = 30:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to give the desired compound 46 (oil) in an amount of 74.8 mg (0.121 mmol, 75%).

[0406] Example 63 (Cyclohexane-1,4-diyl)bis(((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)azetidin-1-yl)methanone) 47

[0407] Cis-1,4-cyclohexanedicarboxylic acid (19.8 mg, 0.115 mmol) and dichloromethane (1.0 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (143.6 mg, 0.276 mmol) and diisopropylethylamine (0.160 ml, 0.920 mmol). The mixture was stirred at room temperature for 5 minutes. Compound 18-2 (58.8 mg, 0.242 mmol) was then added, washing in with dichloromethane (0.5 ml), and the mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:methanol = 30:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to give the desired compound 47 (oil) in an amount of 35.4 mg (0.057 mmol, 49%).

[0408] Example 64 Spiro[3.3]heptane-2,6-diylbis(((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)azetidin-1-yl)methanone) 48

[0409] Spiro[3.3]heptane-2,6-dicarboxylic acid (21.2 mg, 0.115 mmol) and dichloromethane (1.0 mL) were added to a 4 mL vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (143.6 mg, 0.276 mmol) and diisopropylethylamine (0.160 mL, 0.920 mmol). The mixture was stirred at room temperature for 5 minutes. Compound 18-2 (58.8 mg, 0.242 mmol) was then added, washing in with dichloromethane (0.5 mL). The mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 mL) and extracted with dichloromethane (1 mL x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by evaporation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:methanol = 30:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by evaporation under reduced pressure to give the desired compound 48 (oil) in an amount of 43.5 mg (0.068 mmol, 60%).

[0410] Example 65 Cubane-1,4-diylbis(((R)-3-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 49

[0411] 1,4-Cubanedicarboxylic acid (24.0 mg, 0.125 mmol) and dichloromethane (1.0 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (156.1 mg, 0.300 mmol) and diisopropylethylamine (0.174 ml, 1.000 mmol). The mixture was stirred at room temperature for 5 minutes. Compound 15-2 (67.4 mg, 0.262 mmol) was then added, washing in with dichloromethane (0.5 ml), and the mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by evaporation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:ethyl acetate = 2:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by evaporation under reduced pressure to give the desired compound 49 (oil) in an amount of 44.4 mg (0.066 mmol, 53%).

[0412] Example 66 Pyrazine-2,5-diylbis(((R)-3-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 50

[0413] Pyrazine-2,5-dicarboxylic acid (21.0 mg, 0.125 mmol) and dichloromethane (1.0 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (156.1 mg, 0.300 mmol) and diisopropylethylamine (0.174 ml, 1.000 mmol). The mixture was stirred at room temperature for 5 minutes. Compound 15-2 (67.4 mg, 0.262 mmol) was then added, washing in with dichloromethane (0.5 ml), and the mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: hexane:acetone = 2:1). The silica gel containing the target product was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to obtain 50.5 mg (0.078 mmol, 62%) of the desired compound 50 (oil).

[0414] Example 67)Cyclohexane-1,4-diyl)bis(((R)-3-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 51

[0415] Cis-1,4-cyclohexanedicarboxylic acid (12.9 mg, 0.075 mmol) and dichloromethane (0.5 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (93.7 mg, 0.180 mmol) and diisopropylethylamine (0.104 ml, 0.600 mmol). The mixture was stirred at room temperature for 5 minutes. Compound 15-2 (40.3 mg, 0.157 mmol) was then added, washing in with dichloromethane (0.5 ml), and the mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:methanol = 30:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to obtain 29.8 mg (0.046 mmol, 61%) of the desired compound 51 (oil).

[0416] Example 68 Spiro[3.3]heptane-2,6-diylbis(((R)-3-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 52

[0417] Spiro[3.3]heptane-2,6-dicarboxylic acid (13.8 mg, 0.075 mmol) and dichloromethane (0.5 mL) were added to a 4 mL vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (93.7 mg, 0.180 mmol) and diisopropylethylamine (0.104 mL, 0.600 mmol). The mixture was stirred at room temperature for 5 minutes. Compound 15-2 (40.3 mg, 0.157 mmol) was then added, washing in with dichloromethane (0.5 mL). The mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 mL) and extracted with dichloromethane (1 mL x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by evaporation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:methanol = 30:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by evaporation under reduced pressure to give the desired compound 52 (oil) in an amount of 20.6 mg (0.031 mmol, 41%).

[0418] Example 69 Naphthalene-2,6-diylbis(((S)-2-(3-phenethyl-1,2,4-oxadiazol-5-yl)azetidin-1-yl)methanone) 53

[0419] 2,6-Naphthalenedicarboxylic acid (16.5 mg, 0.076 mmol) and dichloromethane (0.5 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (95.2 mg, 0.183 mmol) and diisopropylethylamine (0.106 ml, 0.609 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 53 (36.6 mg, 0.160 mmol), synthesized by the same procedure as compound 18-2 in Example 24, was added while washing with dichloromethane (0.5 ml). The mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:methanol = 30:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to give the desired compound 54 (oil) in an amount of 33.0 mg (0.052 mmol, 68%).

[0420] Example 70 1,4-phenylenebis(((S)-2-(3-phenethyl-1,2,4-oxadiazol-5-yl)azetidin-1-yl)methanone) 55

[0421] 1,4-Benzenedicarboxylic acid (12.7 mg, 0.076 mmol) and dichloromethane (0.5 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (95.2 mg, 0.183 mmol) and diisopropylethylamine (0.106 ml, 0.609 mmol). The mixture was stirred at room temperature for 5 minutes. Compound 53 (36.6 mg, 0.160 mmol), synthesized in a similar manner to compound 18-2 in Example 24, was added while washing with dichloromethane (0.6 ml). The mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:methanol = 20:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to give the desired compound 55 (oil) in an amount of 31.1 mg (0.053 mmol, 69%).

[0422] Example 71 (Cis-cyclohexane-1,4-diyl)bis(((S)-2-(3-phenethyl-1,2,4-oxadiazol-5-yl)azetidin-1-yl)methanone) 56

[0423] Cis-1,4-cyclohexanedicarboxylic acid (14.5 mg, 0.084 mmol) and dichloromethane (0.5 mL) were added to a 4 mL vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (104.9 mg, 0.202 mmol) and diisopropylethylamine (0.117 mL, 0.672 mmol). The mixture was stirred at room temperature for 5 minutes. Compound 53 (40.5 mg, 0.177 mmol), synthesized in a similar manner to compound 18-2 in Example 24, was added while washing with dichloromethane (0.6 mL). The mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 mL) and extracted with dichloromethane (1 mL x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: hexane:ethyl acetate = 1:3). The silica gel containing the target product was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to give the desired compound 56 (oil) in an amount of 20.3 mg (0.034 mmol, 40%).

[0424] Example 72 Naphthalene-2,6-diylbis(((S)-2-(3-phenethyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 58

[0425] 2,6-Naphthalenedicarboxylic acid (20.1 mg, 0.093 mmol) and dichloromethane (0.5 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (116.2 mg, 0.223 mmol) and diisopropylethylamine (0.130 ml, 0.744 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 57 (47.8 mg, 0.196 mmol), synthesized by the same procedure as compound 1-2 in Example 1, was added while washing with dichloromethane (0.6 ml). The mixture was stirred at room temperature for 4 hours. The reaction was quenched by adding saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by evaporation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:methanol = 30:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by evaporation under reduced pressure to give the desired compound 58 (oil) in an amount of 35.7 mg (0.054 mmol, 58%).

[0426] Example 73 1,4-phenylenebis(((S)-2-(3-phenethyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 59

[0427] 1,4-Benzenedicarboxylic acid (15.5 mg, 0.093 mmol) and dichloromethane (0.5 mL) were added to a 4 mL vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (116.2 mg, 0.223 mmol) and diisopropylethylamine (0.130 mL, 0.744 mmol). The mixture was stirred at room temperature for 5 minutes. Compound 57 (47.8 mg, 0.196 mmol), synthesized by the same procedure as for compound 1-2 in Example 1, was then added while washing with dichloromethane (0.6 mL). The mixture was stirred at room temperature for 4 hours. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate (1.0 mL), and the mixture was extracted with dichloromethane (1 mL x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by evaporation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:methanol = 30:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by evaporation under reduced pressure to give 45.5 mg (0.074 mmol, 79%) of the desired compound 59 (oil).

[0428] Example 74 (Trans-cyclohexane-1,4-diyl)bis(((S)-2-(3-phenethyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 60

[0429] 1,4-Benzenedicarboxylic acid (16.0 mg, 0.093 mmol) and dichloromethane (0.5 mL) were added to a 4 mL vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (116.2 mg, 0.223 mmol) and diisopropylethylamine (0.130 mL, 0.744 mmol). The mixture was stirred at room temperature for 5 minutes. Compound 57 (47.8 mg, 0.196 mmol), synthesized using a procedure similar to that for Compound 1-2 in Example 1, was then added while washing with dichloromethane (0.6 mL). The mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 mL) and extracted with dichloromethane (1 mL x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:methanol = 30:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to obtain 16.6 mg (0.027 mmol, 29%) of the desired compound 60 (oil).

[0430] Example 75 Cubane-1,4-diylbis(((S)-2-(3-phenethyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 61

[0431] 1,4-cubanedicarboxylic acid (19.6 mg, 0.102 mmol) and dichloromethane (0.5 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (127.4 mg, 0.245 mmol) and diisopropylethylamine (0.142 ml, 0.816 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 57 (52.4 mg, 0.215 mmol), synthesized by the same procedure as for compound 1-2 in Example 1, was added while washing with dichloromethane (0.7 ml). The mixture was stirred at room temperature for 4 hours. The reaction was quenched by adding saturated aqueous sodium bicarbonate (1.0 ml), and the mixture was extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:methanol = 20:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to obtain 31.1 mg (0.048 mmol, 47%) of the desired compound 61 (oil).

[0432] Example 76 Pyrazine-2,5-diylbis(((S)-2-(3-phenethyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 62

[0433] 1,4-cubanedicarboxylic acid (17.2 mg, 0.102 mmol) and dichloromethane (0.5 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (127.4 mg, 0.245 mmol) and diisopropylethylamine (0.142 ml, 0.816 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 57 (52.4 mg, 0.215 mmol), synthesized by the same procedure as compound 1-2 in Example 1, was added while washing with dichloromethane (0.7 ml). The mixture was stirred at room temperature for 4 hours. The reaction was quenched by adding saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: hexane:acetone = 3:1). The silica gel containing the target product was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to obtain 43.2 mg (0.070 mmol, 68%) of the desired compound 62 (oil).

[0434] Example 77 (Cis-cyclohexane-1,4-diyl)bis(((S)-2-(3-phenethyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 63

[0435] Cis-1,4-cyclohexanedicarboxylic acid (17.6 mg, 0.102 mmol) and dichloromethane (0.5 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (127.4 mg, 0.245 mmol) and diisopropylethylamine (0.172 ml, 0.744 mmol). The mixture was stirred at room temperature for 5 minutes. Compound 57 (52.4 mg, 0.215 mmol), synthesized using a procedure similar to that for Compound 1-2 in Example 1, was then added while washing with dichloromethane (0.6 ml). The mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:methanol = 20:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to obtain 22.8 mg (0.037 mmol, 36%) of the desired compound 63 (oil).

[0436] Example 78 Naphthalene-2,6-diylbis(((S)-2-(3-phenethyl-1,2,4-oxadiazol-5-yl)-2,5-dihydro-1H-pyrrol-1-yl)methanone) 65

[0437] 2,6-Naphthalenedicarboxylic acid (19.2 mg, 0.089 mmol) and dichloromethane (0.5 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (116.2 mg, 0.214 mmol) and diisopropylethylamine (0.124 ml, 0.712 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 64 (45.2 mg, 0.187 mmol), synthesized in a similar manner to compound 23-2 in Example 29, was added while washing with dichloromethane (0.6 ml). The mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:methanol = 30:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to obtain 30.1 mg (0.045 mmol, 51%) of the desired compound 65 (oil).

[0438] Example 79 1,4-phenylenebis(((S)-2-(3-phenethyl-1,2,4-oxadiazol-5-yl)-2,5-dihydro-1H-pyrrol-1-yl)methanone) 66

[0439] 1,4-Benzenedicarboxylic acid (14.8 mg, 0.089 mmol) and dichloromethane (0.5 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (116.2 mg, 0.214 mmol) and diisopropylethylamine (0.124 ml, 0.712 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 64 (45.2 mg, 0.187 mmol), synthesized by a procedure similar to that for compound 23-2 in Example 29, was added while washing with dichloromethane (0.6 ml). The mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:methanol = 30:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to obtain 26.4 mg (0.043 mmol, 48%) of the desired compound 66 (oil).

[0440] Example 80 Cubane-1,4-diylbis(((S)-2-(3-phenethyl-1,2,4-oxadiazol-5-yl)-2,5-dihydro-1H-pyrrol-1-yl)methanone) 67

[0441] 1,4-Cubanedicarboxylic acid (19.1 mg, 0.099 mmol) and dichloromethane (0.5 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (124.3 mg, 0.239 mmol) and diisopropylethylamine (0.139 ml, 0.796 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 64 (50.5 mg, 0.209 mmol), synthesized in a similar manner to compound 23-2 in Example 29, was added while washing with dichloromethane (0.6 ml). The mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:methanol = 30:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to obtain 18.8 mg (0.029 mmol, 30%) of the desired compound 67 (oil).

[0442] The retention time (RT) and 1H-NMR data for the compounds of Examples 60 to 80 under the following LC / MS elution conditions are summarized in Table 8. Elution conditions: flow rate 0.9 mL / min, mobile phase A = 0.05% (v / v) formic acid aqueous solution, mobile phase B = 0.05% (v / v) formic acid in acetonitrile; 0-0.9 min: linear gradient A:B (95:5) - A:B (10:90), 0.9-3 min: A:B (10:90).

[0443] Table 8-1

[0444] Table 8-2

[0445] Table 8-3

[0446] Table 8-4

[0447] Table 8-5

[0448] Example 81 Naphthalene-2,6-diylbis(((R)-3-(3-phenethyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 69

[0449] 2,6-Naphthalenedicarboxylic acid (22.5 mg, 0.104 mmol) and dichloromethane (1.0 mL) were added to a 4 mL vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (129.9 mg, 0.249 mmol) and diisopropylethylamine (0.145 mL, 0.832 mmol). The mixture was stirred at room temperature for 5 minutes. Compound 68 (53.4 mg, 0.219 mmol), synthesized in a similar manner to compound 15-2 in Example 21, was added while washing with dichloromethane (0.5 mL). The mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 mL) and extracted with dichloromethane (1 mL x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by evaporation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:methanol = 30:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by evaporation under reduced pressure to give the desired compound 69 (oil) in an amount of 57.4 mg (0.086 mmol, 83%).

[0450] Example 82 1,4-phenylenebis(((R)-3-(3-phenethyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 70

[0451] 1,4-Benzenedicarboxylic acid (17.3 mg, 0.104 mmol) and dichloromethane (1.0 mL) were added to a 4 mL vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (129.9 mg, 0.249 mmol) and diisopropylethylamine (0.145 mL, 0.832 mmol). The mixture was stirred at room temperature for 5 minutes. Compound 68 (53.4 mg, 0.219 mmol), synthesized in a similar manner to compound 15-2 in Example 21, was added while washing with dichloromethane (0.5 mL). The mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 mL) and extracted with dichloromethane (1 mL x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:methanol = 30:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to obtain the target compound 70 (oil) in an amount of 60.0 mg (0.097 mmol, 94%).

[0452] Example 83 (Trans-cyclohexane-1,4-diyl)bis(((R)-3-(3-phenethyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 71

[0453] Trans-1,4-cyclohexanedicarboxylic acid (17.9 mg, 0.104 mmol) and dichloromethane (1.0 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (129.9 mg, 0.249 mmol) and diisopropylethylamine (0.145 ml, 0.832 mmol). The mixture was stirred at room temperature for 5 minutes. Compound 68 (53.4 mg, 0.219 mmol), synthesized in a similar manner to compound 15-2 in Example 21, was added while washing with dichloromethane (0.5 ml). The mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: toluene:ethyl acetate = 1:3). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to obtain 47.4 mg (0.076 mmol, 73%) of the desired compound 71 (oil).

[0454] Example 84 Cubane-1,4-diylbis(((R)-3-(3-phenethyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 72

[0455] 1,4-cubanedicarboxylic acid (25.6 mg, 0.128 mmol) and dichloromethane (1.0 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (159.9 mg, 0.307 mmol) and diisopropylethylamine (0.178 ml, 1.024 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 68 (65.2 mg, 0.268 mmol), synthesized by a procedure similar to that for compound 15-2 in Example 21, was added while washing with dichloromethane (0.6 ml). The mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: toluene:ethyl acetate = 1:3). The silica gel containing the target product was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to obtain 54.5 mg (0.085 mmol, 66%) of the desired compound 72 (oil).

[0456] Example 85 Pyrazine-2,5-diylbis(((R)-3-(3-phenethyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 73

[0457] Pyrazine-2,5-dicarboxylic acid (21.5 mg, 0.128 mmol) and dichloromethane (1.0 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (159.9 mg, 0.307 mmol) and diisopropylethylamine (0.178 ml, 1.024 mmol). The mixture was stirred at room temperature for 5 minutes. Compound 68 (65.2 mg, 0.268 mmol), synthesized in a similar manner to compound 15-2 in Example 21, was added while washing with dichloromethane (0.6 ml). The mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:methanol = 30:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to obtain the desired compound 73 (oil) in an amount of 33.6 mg (0.054 mmol, 42%).

[0458] Example 86 (Cis-cyclohexane-1,4-diyl)bis(((R)-3-(3-phenethyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 74

[0459] Cis-1,4-cyclohexanedicarboxylic acid (22.0 mg, 0.128 mmol) and dichloromethane (1.0 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (159.9 mg, 0.307 mmol) and diisopropylethylamine (0.178 ml, 1.024 mmol). The mixture was stirred at room temperature for 5 minutes. Compound 68 (65.2 mg, 0.268 mmol), synthesized in a similar manner to compound 15-2 in Example 21, was added while washing with dichloromethane (0.6 ml). The mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:acetone = 2:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to obtain 73.8 mg (0.118 mmol, 93%) of the desired compound 74 (oil).

[0460] The retention time (RT) and 1H-NMR data for the compounds of Examples 81 to 86 under the following LC / MS elution conditions are summarized in Table 9. Elution conditions: flow rate 0.9 mL / min, mobile phase A = 0.05% (v / v) formic acid aqueous solution, mobile phase B = 0.05% (v / v) formic acid in acetonitrile; 0-0.9 min: linear gradient A:B (95:5) - A:B (10:90), 0.9-3 min: A:B (10:90).

[0461] Table 9-1

[0462] Table 9-2

[0463] Example 87: N-benzyl-6-((2R,4S)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-N-methyl-2-naphthamide 75-6-LP Example 87-1: (9H-fluoren-9-yl)methyl (2S,4S)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate 75-1

[0464] Dichloromethane (2 ml), HATU (223 mg, 0.586 mmol), and N,N-diisopropylethylamine (0.332 ml, 1.95 mmol) were added to a 10 ml recovery flask containing (2S,4S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (200 mg, 0.488 mmol) and stirred at room temperature for 10 minutes. A solution of N'-hydroxy-3-phenylpropanimidamide (105 mg, 0.586 mmol) in dichloromethane (0.5 ml) was added to the reaction mixture and stirred at room temperature for 5 hours. After evaporation of the solvent, the mixture was made basic with saturated aqueous sodium bicarbonate (5 ml) and then extracted with ethyl acetate (20 ml). The organic layer was washed with water (5 ml) and then saturated brine (5 ml) and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified using a silica gel column, Q-Pack SI30, size 20 (hexane:ethyl acetate = 90:10 to 20:80) to obtain 197 mg (0.346 mmol, 71%) of the intermediate imidamide. The intermediate and toluene (7 ml) were placed in a 25 ml eggplant-shaped flask, attached to a Dean-Stark trap, and heated under reflux in an oil bath at 130 °C for 11 hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified using a silica gel column, Q-Pack SI30, size 20 (hexane:ethyl acetate = 90:10 to 40:60). After evaporation of the solvent, 151 mg (0.274 mmol, 81%) of the desired compound 75-1 (oil) was obtained.

[0465] Example 87-2: 5-((2S,4S)-4-(tert-butoxy)pyrrolidin-2-yl)-3-(3-phenylpropyl)-1,2,4-oxadiazole 75-2

[0466] Compound 75-1 (147 mg, 0.266 mmol) prepared in Example 87-1 was added to a 25 ml eggplant-shaped flask, followed by dichloromethane (2 ml) and piperidine (0.395 ml, 3.99 mmol). The mixture was stirred at room temperature for 1 hour. After evaporation of the solvent, the residue was purified using a silica gel column, Q-Pack SI30, size 20 (ethyl acetate:methanol = 100:0 or 85:15). After evaporation of the solvent, 71.3 mg (0.216 mmol, 81%) of the desired compound 75-2 (oil) was obtained.

[0467] Example 87-3: Methyl 6-((2S,4S)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-2-naphthoate 75-3

[0468] To a 25-ml eggplant-shaped flask containing 6-(methoxycarbonyl)-2-naphthoic acid (47.5 mg, 0.206 mmol), dichloromethane (2.3 ml), compound 75-2 (71.3 mg, 0.216 mmol) prepared in Example 87-2, HATU (94.1 mg, 0.247 mmol), and N,N-diisopropylethylamine (0.140 ml, 10.825 mmol) were added and stirred at room temperature for 2 hours. After removing the solvent under reduced pressure, ice chips and 5% aqueous sodium bicarbonate solution (5 mL) were added to the residue, followed by extraction with ethyl acetate (20 ml). The ethyl acetate layer was washed with water (5 ml) followed by saturated brine (5 ml) and then dried over anhydrous magnesium sulfate. After filtering off the magnesium sulfate, the ethyl acetate was evaporated under reduced pressure, and the resulting residue was purified on a silica gel column Q-pack SI30 size 20 (hexane:ethyl acetate = 100:0 to 40:60). After evaporation of the solvent, 90.5 mg (0.167 mmol, 81%) of the desired compound 75-3 was obtained.

[0469] Example 87-4: 6-((4S)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-2-naphthoic acid 75-4

[0470] To a 25 ml eggplant-shaped flask containing compound 75-3 (87.1 mg, 0.161 mmol) prepared in Example 87-3, a methanol:tetrahydrofuran:water (3:2:1) solution (4.5 ml) and lithium hydroxide monohydrate (20.2 mg, 0.481 mmol) were added and stirred at room temperature for 3 hours. Lithium hydroxide monohydrate (6.74 mg, 0.161 mmol) was then added and stirred at room temperature for 3 hours. After the solvent was removed under reduced pressure, ice chips and 1 M aqueous hydrochloric acid (5 mL) were added to the residue, followed by extraction with ethyl acetate (20 ml). The ethyl acetate layer was washed with water (5 ml) followed by saturated brine (5 ml) and then dried over anhydrous magnesium sulfate. After filtering off the magnesium sulfate, the ethyl acetate was removed under reduced pressure. The resulting residue was purified using a silica gel column Q-Pack SI30 size 20 (chloroform:methanol = 100:0 to 90:10). After distilling off the solvent, 73.7 mg (0.139 mmol, 87%) of the target compound 75-4 was obtained as a diastereomeric mixture.

[0471] Example 87-5: N-benzyl-6-((2R,4S)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-N-methyl-2-naphthamide 75-5-LP and N-benzyl-6-((2S,4S)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-N-methyl-2-naphthamide 75-5-P

[0472] To a 4 mL vial containing compound 75-4 (34.5 mg, 0.0653 mmol) prepared in Example 87-4, dichloromethane (0.5 mL), HATU (29.8 mg, 0.0784 mmol), and N,N-diisopropylethylamine (0.0444 mL, 0.261 mmol) were added and stirred at room temperature for 10 minutes. N-Methyl-1-phenylmethanamine (0.00884 mL, 0.0686 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. After distilling off the solvent under reduced pressure, ice chips and 5% aqueous sodium bicarbonate solution (2 mL) were added to the residue, followed by extraction with ethyl acetate (6 mL). The ethyl acetate layer was washed with water (2 mL) and then dried by passing through a Libra tube filled with anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; eluent: ethyl acetate). The target silica gel was scraped off and eluted with 10% MeOH in chloroform (20 ml). The solvent was removed under reduced pressure to obtain two diastereomers.

[0473] 75-5-LP: Rf value = 0.71 (developing solvent: acetic acid acetyl) 12.7 mg (0.0201 mmol, 31%) 1H-NMR (CDCl3) δ: 8.12-8.06 (1H, br s), 7.98-7.76 (3H, m), 7.75-7.52 (2H, m), 7.45-7.19 (10H, m), 5.63 (1H, t, J = 6.8 Hz), 4.86-4.76 (1H, br s), 4.62-4.50 (1H, br s), 4.44-4.35 (1H, br s), 4.00-3.90 (1H, br s), 3.53-3.42 (1H, br s), 3.09 (1.5 H, br s) and 2.92 (1.5H, br s), 2.76 (2H, t, J=7.6 Hz), 2.72 (2H, t, J=7.6 Hz), 2.46-2.35 (81H, m), 2.33-2.18 (1H, m), 2.11 (2H, quint, J=7.6 Hz), 1.12 (9H, s). 75-5-P: Rf value = 0.59 (developing solvent: acetic acid acetyl) 17.1 mg (0.0271 mmol, 42%) 1H-NMR (CDCl3) δ: 8.13 (1H, br s), 8.02-7.80 (3H, m), 7.78-7.56 (2H, m), 7.45-7.10 (10H, m), 5.55 (1H, t J=7.5 Hz), 4.82 (1H, br s), 4.56 (1H, br s), 4.26 (1H, br s), 3.80-3.62 (2H, br s), 3.09 (1.5H, br s) and 2.92 (1.5H, br s), 2.72 (2H, t, J=7.6 Hz), 2.68 (2H, t J=7.6 Hz), 2.67-2.58 (1H, m), 2.28-2.16 (1H, m), 2.09 (2H, quint, J=7.6 Hz), 1.1. (9H, s).

[0474] Example 87-6: Compound of Example 87 N-benzyl-6-((2R,4S)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-N-methyl-2-naphthamide 75-6-LP

[0475] Compound 75-5-LP (12.7 mg, 0.0201 mmol) prepared in Example 87-5 was placed in a 4 mL vial, and water (0.008 mL) and trifluoroacetic acid (0.160 mL) were added and stirred at room temperature for 1 hour. The reaction mixture was transferred to a 10 mL recovery flask, acetonitrile (1 mL) was added, and the mixture was concentrated under reduced pressure. This procedure was repeated once more. Next, chloroform (1.5 mL) was added, and the mixture was concentrated under reduced pressure. This procedure was also repeated once more. Finally, the mixture was dried under reduced pressure using a vacuum pump for one week, yielding 11.6 mg (0.0201 mmol, 100%) of the desired compound 75-6-LP.

[0476] Example 88 N-benzyl-6-((2S,4S)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-N-methyl-2-naphthamide 75-6-P

[0477] Compound 75-5-P (17.1 mg, 0.0271 mmol) prepared in Example 87-5 was placed in a 4 mL vial, and water (0.0105 mL) and trifluoroacetic acid (0.210 mL) were added and stirred at room temperature for 1 hour. The reaction mixture was transferred to a 10 mL recovery flask, and acetonitrile (1 mL) was added and concentrated under reduced pressure. This procedure was repeated. Next, chloroform (1.5 mL) was added and concentrated under reduced pressure. This procedure was also repeated. Finally, the mixture was dried under reduced pressure using a vacuum pump for one week to obtain 15.6 mg (0.0271 mmol, 100%) of the desired compound 75-6-P.

[0478] Example 89 ((2R,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(6-((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)naphthalen-2-yl)methanone 76-2 Example 89-1: ((2R,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(6-((2S,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)naphthalen-2-yl)methanone 76-1

[0479] To a 4 mL vial containing compound 6-4 (25.8 mg, 0.0489 mmol) prepared in Example 11-4, dichloromethane (0.3 mL), HATU (22.3 mg, 0.0587 mmol), and N,N-diisopropylethylamine (0.0333 mL, 0.196 mmol) were added and stirred at room temperature for 10 minutes. A solution of compound 6-2 (16.9 mg, 0.0514 mmol) prepared in Example 11-2 in dichloromethane (0.1 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. After distilling off the solvent under reduced pressure, ice chips and 5% aqueous sodium bicarbonate solution (2 mL) were added to the residue, followed by extraction with ethyl acetate (6 mL). The ethyl acetate layer was washed with water (2 mL) and then dried by passing through a Libra tube filled with anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; eluent: ethyl acetate). The silica gel containing the target compound was scraped off, and the mixture was eluted with 10% MeOH in chloroform (20 ml). The solvent was removed under reduced pressure, yielding 10.3 mg (0.0123 mmol, 25%) of the target compound 76-1.

[0480] Example 89-2: Compound of Example 89 ((2R,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(6-((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)naphthalen-2-yl)methanone 76-2

[0481] To a 4 mL vial containing compound 76-1 (10.3 mg, 0.0122 mmol) prepared in Example 89-1, water (0.01 mL) and trifluoroacetic acid (0.2 mL) were added and stirred at room temperature for 1 hour. The reaction mixture was transferred to a 10 mL recovery flask, acetonitrile (1 mL) was added, and the mixture was concentrated under reduced pressure. This procedure was repeated. Next, chloroform (1.5 mL) was added and the mixture was concentrated under reduced pressure. This procedure was also repeated. Finally, the mixture was dried under reduced pressure using a vacuum pump for one week to obtain 8.51 mg (0.0117 mmol, 95.5%) of the desired compound 76-2.

[0482] Example 90 Naphthalene-2,6-diylbis(((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanethione) 77 ((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(6-((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonothioyl)naphthalen-2-yl)methanone 78

[0483] Compound 1-3 (300 mg, 0.432 mmol) prepared in Example 1-4 and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiadiphosphetane 2,4-disulfide (Lawson's reagent) (183 mg, 0.453 mmol) were dissolved in tetrahydrofuran (20 ml) and heated at 55°C under an argon atmosphere for 1.5 hours. The solvent was removed under reduced pressure, and the residue was purified using a silica gel column, Q-pack SI30, size 60 (hexane:ethyl acetate = 90:10 to 25:75). The solvent was removed under reduced pressure to give compound 77 (236 mg, 0.325 mmol, 75%) and compound 78 (55.6 mg, 0.0782 mmol, 18%).

[0484] Example 91 ((1S,4S)-Cyclohexane-1,4-diyl)bis(((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)azetidin-1-yl)methanone) 79 ((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)azetidin-1-yl)((1S,4S)-4-((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carbonothioyl)cyclohexyl)methanone 80

[0485] Compound 20 (41.4 mg, 0.0664 mmol) prepared in Example 26 and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiadiphosphetane 2,4-disulfide (Lawson's reagent) (28.2 mg, 0.0697 mmol) were dissolved in tetrahydrofuran (1.5 ml) and heated at 55 °C under an argon atmosphere for 20 hours. The solvent was evaporated under reduced pressure, and the residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: ethyl acetate). The silica gel containing the target compound was scraped off and eluted with 10% MeOH in chloroform (20 ml). The solvent was evaporated under reduced pressure to give compound 79 (20.7 mg, 0.0316 mmol, 47.5%) and compound 80 (10.7 mg, 0.0167 mmol, 25%).

[0486] Example 92 ((1S,4S)-Cyclohexane-1,4-diyl)bis(((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanethione) 81 ((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)((1S,4S)-4-((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonothioyl)cyclohexyl)methanone 82

[0487] Compound 14 (181 mg, 0.278 mmol) prepared in Example 20 and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiadiphosphetane 2,4-disulfide (Lawson's reagent) (118 mg, 0.297 mmol) were dissolved in toluene (12 ml) and heated to reflux under an argon atmosphere for 12 hours. The solvent was removed under reduced pressure, and the residue was purified using a silica gel column, Q-pack SI30, size 20 (ethyl acetate:methanol = 100:0 to 95:5). The solvent was removed under reduced pressure to give compound 81 (112 mg, 0.164 mmol, 59%) and compound 82 (31.8 mg, 0.0477 mmol, 17%).

[0488] Example 93 1,4-phenylenebis(((S)-2-(3-phenethyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)methanone) 84

[0489] 1,4-Benzenedicarboxylic acid (14.5 mg, 0.087 mmol) and dichloromethane (0.5 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (108.7 mg, 0.209 mmol) and diisopropylethylamine (0.122 ml, 0.696 mmol). The mixture was stirred at room temperature for 5 minutes. Compound 83 (46.8 mg, 0.182 mmol), synthesized by the same procedure as for compound 2-2 in Example 3, was then added while washing with dichloromethane (0.8 ml). The mixture was stirred at room temperature for 4 hours. The reaction was quenched by adding saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: hexane:acetone = 3:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to obtain 19.5 mg (0.030 mmol, 35%) of the desired compound 84 (oil).

[0490] Example 94 Pyrazine-2,5-diylbis(((S)-2-(3-phenethyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)methanone) 85

[0491] Pyrazine-2,5-dicarboxylic acid (14.6 mg, 0.087 mmol) and dichloromethane (0.5 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (108.7 mg, 0.209 mmol) and diisopropylethylamine (0.122 ml, 0.696 mmol). The mixture was stirred at room temperature for 5 minutes. Compound 83 (46.8 mg, 0.182 mmol), synthesized in a similar manner to compound 2-2 in Example 3, was added while washing with dichloromethane (0.8 ml). The mixture was stirred at room temperature for 4 hours. The reaction was quenched by adding saturated aqueous sodium bicarbonate (1.0 ml), and the mixture was extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: hexane:acetone = 3:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to obtain 10.5 mg (0.016 mmol, 19%) of the desired compound 85 (oil).

[0492] Example 95 Cubane-1,4-diylbis(((S)-2-(3-phenethyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)methanone) 86

[0493] 1,4-cubanedicarboxylic acid (19.2 mg, 0.100 mmol) and dichloromethane (1.0 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (124.9 mg, 0.240 mmol) and diisopropylethylamine (0.140 ml, 0.800 mmol). The mixture was stirred at room temperature for 10 minutes. Compound 83 (54.2 mg, 0.211 mmol), synthesized by a procedure similar to that for compound 2-2 in Example 3, was then added while washing with dichloromethane (0.5 ml). The mixture was stirred at room temperature for 16 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: hexane:ethyl acetate = 2:1). The silica gel containing the target product was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to obtain 27.0 mg (0.040 mmol, 40%) of the desired compound 86 (oil).

[0494] Example 96 Naphthalene-2,6-diylbis(((2S,4R)-4-fluoro-2-(3-phenethyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 88

[0495] 2,6-Naphthalenedicarboxylic acid (23.4 mg, 0.108 mmol) and dichloromethane (1.0 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (134.9 mg, 0.259 mmol) and diisopropylethylamine (0.151 ml, 0.864 mmol). The mixture was stirred at room temperature for 10 minutes. Compound 87 (59.0 mg, 0.226 mmol), synthesized in a similar manner to compound 26-2 in Example 32, was added while washing with dichloromethane (0.5 ml). The mixture was stirred at room temperature for 16 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:ethyl acetate = 2:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to give the desired compound 88 (oil) in an amount of 25.9 mg (0.036 mmol, 34%).

[0496] Example 97 1,4-phenylenebis(((2S,4R)-4-fluoro-2-(3-phenethyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 89

[0497] 1,4-Benzenedicarboxylic acid (17.9 mg, 0.108 mmol) and dichloromethane (1.0 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (134.9 mg, 0.259 mmol) and diisopropylethylamine (0.151 ml, 0.864 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 87 (59.0 mg, 0.226 mmol), synthesized by the same procedure as compound 26-2 in Example 32, was added while washing with dichloromethane (0.5 ml). The mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: hexane:ethyl acetate = 1:1). The silica gel containing the target product was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to obtain 53.3 mg (0.082 mmol, 76%) of the desired compound 89 (oil).

[0498] Example 98 Pyrazine-2,5-diylbis(((2S,4R)-4-fluoro-2-(3-phenethyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 90

[0499] Pyrazine-2,5-dicarboxylic acid (18.2 mg, 0.108 mmol) and dichloromethane (1.0 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (134.9 mg, 0.259 mmol) and diisopropylethylamine (0.151 ml, 0.864 mmol). The mixture was stirred at room temperature for 5 minutes. Compound 87 (59.0 mg, 0.226 mmol), synthesized in a similar manner to compound 26-2 in Example 32, was added while washing with dichloromethane (0.5 ml). The mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: hexane:acetone = 3:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to obtain 13.1 mg (0.020 mmol, 19%) of the desired compound 90 (oil).

[0500] Example 99 Cubane-1,4-diylbis(((2S,4R)-4-fluoro-2-(3-phenethyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) 91

[0501] 1,4-Cubanedicarboxylic acid (26.9 mg, 0.140 mmol) and dichloromethane (1.0 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (174.9 mg, 0.336 mmol) and diisopropylethylamine (0.196 ml, 1.120 mmol). The mixture was stirred at room temperature for 15 minutes. Compound 87 (77.0 mg, 0.295 mmol), synthesized in a similar manner to compound 26-2 in Example 32, was added while washing with dichloromethane (1.0 ml). The mixture was stirred at room temperature for 16 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: hexane:ethyl acetate = 1:1). The silica gel containing the target product was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to obtain the desired compound 91 (oil) in an amount of 32.9 mg (0.048 mmol, 35%).

[0502] Example 100 Naphthalene-2,6-diylbis(((S)-6-(3-phenethyl-1,2,4-oxadiazol-5-yl)-5-azaspiro[2.4]heptan-5-yl)methanone) 93

[0503] 2,6-Naphthalenedicarboxylic acid (16.9 mg, 0.078 mmol) and dichloromethane (0.6 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (97.4 mg, 0.187 mmol) and diisopropylethylamine (0.109 ml, 0.624 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 92 (44.1 mg, 0.164 mmol), synthesized in a similar manner to compound 10-2 in Example 16, was added while washing with dichloromethane (0.6 ml). The mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:ethyl acetate = 1:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to obtain 54.4 mg (0.076 mmol, 97%) of the desired compound 93 (oil).

[0504] Example 101 1,4-phenylenebis(((S)-6-(3-phenethyl-1,2,4-oxadiazol-5-yl)-5-azaspiro[2.4]heptan-5-yl)methanone) 94

[0505] 1,4-Benzenedicarboxylic acid (13.0 mg, 0.078 mmol) and dichloromethane (0.6 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (97.4 mg, 0.187 mmol) and diisopropylethylamine (0.109 ml, 0.624 mmol). The mixture was stirred at room temperature for 5 minutes. Compound 92 (44.1 mg, 0.164 mmol), synthesized in a similar manner to compound 10-2 in Example 16, was added while washing with dichloromethane (0.6 ml). The mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:ethyl acetate = 1:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to obtain 46.4 mg (0.069 mmol, 89%) of the desired compound 94 (oil).

[0506] Example 102 Pyrazine-2,5-diylbis(((S)-6-(3-phenethyl-1,2,4-oxadiazol-5-yl)-5-azaspiro[2.4]heptan-5-yl)methanone) 95

[0507] Pyrazine-2,5-dicarboxylic acid (13.1 mg, 0.078 mmol) and dichloromethane (0.6 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (97.4 mg, 0.187 mmol) and diisopropylethylamine (0.109 ml, 0.624 mmol). The mixture was stirred at room temperature for 5 minutes. Compound 92 (44.1 mg, 0.164 mmol), synthesized in a similar manner to compound 10-2 in Example 16, was added while washing with dichloromethane (0.6 ml). The mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: dichloromethane:methanol = 30:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to obtain 15.7 mg (0.023 mmol, 30%) of the desired compound 95 (oil).

[0508] Example 103 (Trans-cyclohexane-1,4-diyl)bis(((S)-6-(3-phenethyl-1,2,4-oxadiazol-5-yl)-5-azaspiro[2.4]heptan-5-yl)methanone) 96

[0509] Trans-1,4-cyclohexanedicarboxylic acid (14.6 mg, 0.085 mmol) and dichloromethane (1.0 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (106.2 mg, 0.204 mmol) and diisopropylethylamine (0.118 ml, 0.680 mmol). The mixture was stirred at room temperature for 5 minutes. Compound 92 (47.9 mg, 0.178 mmol), synthesized in a similar manner to compound 10-2 in Example 16, was added while washing with dichloromethane (0.5 ml). The mixture was stirred at room temperature for 17 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: hexane:acetone = 3:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to obtain 45.5 mg (0.067 mmol, 79%) of the desired compound 96 (oil).

[0510] Example 104 (Cis-cyclohexane-1,4-diyl)bis(((S)-6-(3-phenethyl-1,2,4-oxadiazol-5-yl)-5-azaspiro[2.4]heptan-5-yl)methanone) 97

[0511] Cis-1,4-cyclohexanedicarboxylic acid (16.3 mg, 0.085 mmol) and dichloromethane (1.0 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (106.2 mg, 0.204 mmol) and diisopropylethylamine (0.118 ml, 0.680 mmol). The mixture was stirred at room temperature for 10 minutes. Compound 92 (47.9 mg, 0.178 mmol), synthesized in a similar manner to compound 10-2 in Example 16, was added while washing with dichloromethane (0.5 ml). The mixture was stirred at room temperature for 17 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: hexane:acetone = 3:1). The silica gel containing the target compound was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to obtain the desired compound 97 (oil) in an amount of 34.5 mg (0.051 mmol, 60%).

[0512] Example 105 Cubane-1,4-diylbis(((S)-6-(3-phenethyl-1,2,4-oxadiazol-5-yl)-5-azaspiro[2.4]heptan-5-yl)methanone) 98

[0513] 1,4-cubanedicarboxylic acid (14.6 mg, 0.085 mmol) and dichloromethane (1.0 ml) were added to a 4 ml vial, followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (106.2 mg, 0.204 mmol) and diisopropylethylamine (0.118 ml, 0.680 mmol). The mixture was stirred at room temperature for 5 minutes. Next, compound 92 (47.9 mg, 0.178 mmol), synthesized in a similar manner to compound 10-2 in Example 16, was added while washing with dichloromethane (0.5 ml). The mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (1.0 ml) and extracted with dichloromethane (1 ml x 2). After drying over sodium sulfate, the mixture was filtered and the solvent was removed by distillation. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: hexane:acetone = 3:1). The target silica gel was scraped off and eluted with acetone (20 ml). The solvent was removed by distillation under reduced pressure to obtain the desired compound 98 (oil) in an amount of 32.6 mg (0.051 mmol, 60%). The LC-MS and 1H-NMR data for the obtained compound are summarized in Table X below.

[0514] The retention time (RT) and 1H-NMR data for the compounds of Examples 87 to 105 under the following LC / MS elution conditions are summarized in Table 10. Elution conditions: flow rate 0.9 mL / min, mobile phase A = 0.05% (v / v) formic acid aqueous solution, mobile phase B = 0.05% (v / v) formic acid in acetonitrile; 0-0.9 min: linear gradient A:B (95:5) - A:B (10:90), 0.9-3 min: A:B (10:90).

[0515] Table 10-1

[0516] Table 10-2

[0517] Table 10-3

[0518] Table 10-4

[0519] Table 10-5

[0520] Table 10-6

[0521] Example 106 Naphthalene-2,6-diylbis(((R)-3-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanethione) 99

[0522] Compound 15-3 (10 mg, 0.0144 mmol) prepared in Example 21-3 and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiadiphosphetane 2,4-disulfide (Lawson's reagent) (6.11 mg, 0.0151 mmol) were dissolved in toluene (0.8 ml) and heated under reflux for 3 hours under an argon atmosphere. The solvent was evaporated under reduced pressure, and the residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: ethyl acetate:hexane = 3:2). The silica gel containing the target compound was scraped off, and the mixture was eluted with 10% MeOH in chloroform (20 ml). The solvent was evaporated under reduced pressure to give target compound 99 (6.73 mg, 0.00926 mmol, 64%).

[0523] Example 107 ((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)-2,5-dihydro-1H-pyrrol-1-yl)(6-((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)-2,5-dihydro-1H-pyrrole-1-carbonothioyl)naphthalen-2-yl)methanone 100

[0524] Compound 23-3 (18.5 mg, 0.0268 mmol) prepared in Example 29-3 and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiadiphosphetane 2,4-disulfide (Lawson's reagent) (11.4 mg, 0.0281 mmol) were dissolved in toluene (1.5 ml) and heated to reflux under an argon atmosphere for 1 hour. The solvent was evaporated under reduced pressure, and the residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: ethyl acetate:hexane = 3:1). The silica gel containing the target compound was scraped off and eluted with 10% MeOH in chloroform (20 ml). The solvent was evaporated under reduced pressure to give compound 100 (1.90 mg, 0.00269 mmol, 10%).

[0525] Example 108 Methyl (S)-6-(2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-2-naphthoate 101

[0526] 6-Methoxycarbonyl-2-naphthoic acid (110 mg, 0.469 mmol) and dichloromethane (2.38 ml) were added to a 25 ml eggplant-shaped flask. Subsequently, HATU (178 mg, 0.469 mmol), diisopropylethylamine (0.233 ml, 1.34 mmol), and compound 1-2 (115 mg, 0.446 mmol) prepared in Example 1-3 were added while washing with dichloromethane (0.60 ml). The mixture was stirred at room temperature for 1 hour. The stir bar was then removed and the solvent was evaporated. The residue was purified using a silica gel column (Q-Pack SI30, size 20) (hexane:ethyl acetate = 50:50). After evaporation of the solvent, 169 mg (0.360 mmol, 81%) of the desired product 101 (white solid) was obtained.

[0527] Example 109 (S)-6-(2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-2-naphthoic acid 102

[0528] Compound 101 (12 mg, 0.026 mmol) prepared in Example 108 was added to a 10 ml eggplant-shaped flask, followed by lithium iodide (52.9 mg, 0.383 mmol), pyridine (0.207 ml, 2.56 mmol), and toluene (0.62 ml). The mixture was stirred at 115°C for 15.5 hours. 1 M hydrochloric acid (2 ml) and saturated brine (3 ml) were added, followed by extraction with ethyl acetate. After evaporation of the solvent, the residue was purified using a silica gel column Q-Pack SI30 size 10 (chloroform:methanol = 100:0 to 90:10). After evaporation of the solvent, 9.3 mg (0.020 mmol, 80%) of the desired compound 102 (light brown solid) was obtained.

[0529] Example 110 t-butyl (4-(3-(5-((S)-1-(6-((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-2-naphthoyl)pyrrolidin-2-yl)-1,2,4-oxadiazol-3-yl)propyl)phenyl)carbamate 103-3 Example 110-1 t-butyl (4-(3-cyanopropyl)phenyl)carbamate

[0530] t-Butyl(4-bromophenyl)carbamate (1.50 g, 5.51 mmol) was placed in a 100 ml eggplant-shaped flask, and bis(triphenylphosphine)palladium(II) dichloride (118 mg, 0.165 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (161 mg, 0.331 mmol), and potassium phosphate hydrate (4.78 g, 22.05 mmol) were added in that order, followed by the addition of THF (7.33 ml) to form a suspension. To this solution, a separately prepared alkylborane solution (prepared by adding a 0.5 M THF solution of 9-borabicyclo[3.3.1]nonane (33.07 ml, 16.54 mmol) to a THF solution (1.80 ml) of allyl cyanide (0.726 ml, 8.27 mmol) and stirring at 50°C for 2.5 hours) was added all at once using a funnel, and the mixture was stirred at 50°C for 2 hours. The reaction was quenched by adding saturated aqueous ammonium chloride (30 ml) and extracted with ethyl acetate. After evaporation of the solvent, the residue was purified using an NH column DNH-30 size 60 (hexane:ethyl acetate = 95:5 to 83:17). After evaporation of the solvent, 909 mg (3.492 mmol, 63%) of the desired compound (white solid) was obtained.

[0531] Example 110-2 t-butyl (4-(4-amino-4-(hydroxyimino)butyl)phenyl)carbamate

[0532] t-Butyl (4-(3-cyanopropyl)phenyl)carbamate (153 mg, 0.587 mmol) and 50% aqueous hydroxylamine solution (0.277 ml, 4.692 mmol) were added to a 25 ml eggplant-shaped flask, dissolved in absolute ethanol (2.93 ml), and heated to reflux at 95°C for 5 hours. After distilling off the solvent, the residue was dried in vacuo to obtain the title compound (oil, 172 mg, yield: 100%).

[0533] Example 110-3 (9H-Fluoren-9-yl)methyl (S)-2-(3-(3-(4-((t-butoxycarbonyl)amino)phenyl)propyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate 103-1

[0534] N-Fmoc-L-proline (180 mg, 0.534 mmol) was added to a 20 ml eggplant-shaped flask and dissolved in dichloromethane (1.07 ml). Subsequently, HATU (223 mg, 0.587 mmol) and diisopropylethylamine (0.204 ml, 1.17 mmol) were added, and the mixture was stirred at room temperature for 5 minutes. The carbamate derivative (172 mg, 0.587 mmol) prepared in Example 41-2 was then added, and the mixture was stirred at room temperature for 1 hour. The stir bar was then removed, and the solvent was evaporated. The residue was then purified using a silica gel column (Q-Pack SI30, size 20) (hexane:ethyl acetate = 30:70). The resulting intermediate (288 mg, 0.469 mmol) was transferred to a 30 ml eggplant-shaped flask, pre-dried MS4Å (1.44 g) was added, and the mixture was dissolved in toluene (3.13 ml). A Dimroth condenser was attached and the mixture was stirred at 110°C for 16 hours. After removing MS4Å by filtration through Celite, the solvent was evaporated, and the resulting residue was purified on a silica gel column, Q-Pack SI30, size 20 (hexane:ethyl acetate = 50:50). After evaporation of the solvent, 211 mg (0.354 mmol, 66% (after two steps)) of the desired 103-1 (white solid) was obtained.

[0535] Example 110-4 t-butyl (S)-(4-(3-(5-(pyrrolidin-2-yl)-1,2,4-oxadiazol-3-yl)propyl)phenyl)carbamate 103-2

[0536] Compound 103-1 (183 mg, 0.307 mmol) prepared in Example 110-3 was added to a 20 ml eggplant-shaped flask, followed by dichloromethane (1.53 ml) and piperidine (0.188 ml, 1.84 mmol). The mixture was stirred at room temperature for 2 hours. The stir bar was then removed and the solvent was evaporated. The residue was purified using a silica gel column (Q-Pack SI30, size 20) (hexane:ethyl acetate = 66:34 and chloroform:methanol 100:0 to 95:5). After evaporation of the solvent, 109 mg (0.293 mmol, 95%) of the desired compound 103-2 (oil) was obtained.

[0537] Example 110-5: Compound of Example 110 t-butyl (4-(3-(5-((S)-1-(6-((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-2-naphthoyl)pyrrolidin-2-yl)-1,2,4-oxadiazol-3-yl)propyl)phenyl)carbamate 103-3

[0538] Compound 102 (25.2 mg, 0.055 mmol) prepared in Example 109 and dichloromethane (0.506 ml) were added to a 10 ml recovery flask. This was followed by HATU (22 mg, 0.058 mmol), diisopropylethylamine (0.029 ml, 0.166 mmol), and compound 103-2 (20.6 mg, 0.055 mmol) prepared in Example 110-4, washed with dichloromethane (0.6 ml). The mixture was stirred at room temperature for 1 hour. The stir bar was then removed and the solvent was evaporated. The residue was purified using an NH column (DNH-30, size 10) (hexane:ethyl acetate = 66:34 to 20:80). After evaporation, 40.3 mg (0.050 mmol, 90%) of the desired product 103-3 (amorphous solid) was obtained.

[0539] Example 111 ((S)-2-(3-(3-(4-aminophenyl)propyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(6-((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)naphthalen-2-yl)methanone 103-4

[0540] Compound 103-3 (33.3 mg, 0.041 mmol) prepared in Example 110-5 was added to a 4 ml vial, followed by the addition of dichloromethane (0.411 ml) and trifluoroacetic acid (0.082 ml) and stirring at room temperature for 1 hour. After distilling off the solvent, the mixture was made basic by adding saturated aqueous sodium bicarbonate (2 ml) and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated to obtain 28.5 mg (0.040 mmol, 98%) of the desired compound 103-4 (white solid).

[0541] Example 112 t-butyl (4-(3-(5-((S)-1-(6-((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-2-naphthoyl)pyrrolidin-2-yl)-1,2,4-oxadiazol-3-yl)propyl)benzyl)carbamate 104-3 Example 112-1 t-butyl (4-(3-cyanopropyl)benzyl)carbamate

[0542] t-Butyl(4-bromobenzyl)carbamate (0.50 g, 1.75 mmol) was placed in a 100 ml eggplant-shaped flask, and bis(triphenylphosphine)palladium(II) dichloride (62.6 mg, 0.087 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (85 mg, 0.175 mmol), and potassium phosphate hydrate (1.89 g, 8.74 mmol) were added in that order, followed by the addition of THF (2.43 ml) to form a suspension. To this solution, a separately prepared alkylborane solution (prepared by adding a 0.5 M THF solution of 9-borabicyclo[3.3.1]nonane (13.98 ml, 6.99 mmol) to a THF solution (3.00 ml) of allyl cyanide (0.307 ml, 3.49 mmol) and stirring at 50°C for 2.5 hours) was added all at once using a funnel, and the mixture was stirred at 50°C for 2.5 hours. The reaction was quenched by adding saturated aqueous ammonium chloride (15 ml) and extracted with ethyl acetate. After evaporation of the solvent, the residue was purified using an NH column DNH-30 size 60 (hexane:ethyl acetate = 75:25). After evaporation of the solvent, 311 mg (1.13 mmol, 65%) of the desired compound (oil) was obtained.

[0543] Example 112-2 t-butyl (4-(4-amino-4-(hydroxyimino)butyl)benzyl)carbamate

[0544] t-Butyl (4-(3-cyanopropyl)benzyl)carbamate (152 mg, 0.554 mmol) and 50% aqueous hydroxylamine solution (0.261 ml, 4.432 mmol) were added to a 25 ml eggplant-shaped flask, dissolved in absolute ethanol (2.77 ml), and heated to reflux at 95°C for 5 hours. After distilling off the solvent, the residue was dried in vacuo to obtain the title compound (amorphous solid, 168 mg, yield: 99%).

[0545] Example 112-3 (9H-Fluoren-9-yl)methyl (S)-2-(3-(3-(4-((t-butoxycarbonyl)amino)methyl)phenyl)propyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate 104-1

[0546] N-Fmoc-L-proline (168 mg, 0.498 mmol) was added to a 20 ml eggplant-shaped flask and dissolved in dichloromethane (0.929 ml). Subsequently, HATU (208 mg, 0.548 mmol) and diisopropylethylamine (0.191 ml, 1.10 mmol) were added, and the mixture was stirred at room temperature for 3 minutes. The carbamate derivative (168 mg, 0.548 mmol) prepared in Example 112-2 was then added, washing with dichloromethane (2.0 ml), and the mixture was stirred at room temperature for 1 hour. The stir bar was then removed, and the solvent was evaporated. The residue was purified using a silica gel column (Q-Pack SI30, size 20) (hexane:ethyl acetate = 28:72). The resulting intermediate (269 mg, 0.428 mmol) was transferred to a 30 ml eggplant-shaped flask, pre-dried MS4Å (1.34 g) was added, and the mixture was dissolved in toluene (2.86 ml). A Dimroth condenser was attached and the mixture was stirred at 110 °C for 16 hours. After removing MS4Å by filtration through Celite, the solvent was evaporated, and the resulting residue was purified using a silica gel column, Q-Pack SI30, size 20 (hexane:ethyl acetate = 60:40). After evaporation of the solvent, 209 mg (0.343 mmol, 69% (after two steps)) of the desired 104-1 (amorphous solid) was obtained.

[0547] Example 112-4 t-butyl (S)-(4-(3-(5-(pyrrolidin-2-yl)-1,2,4-oxadiazol-3-yl)propyl)benzyl)carbamate 35-2

[0548] Compound 104-1 (201 mg, 0.33 mmol) prepared in Example 112-3 was added to a 20 ml eggplant-shaped flask, followed by dichloromethane (1.65 ml) and piperidine (0.202 ml, 1.98 mmol). The mixture was stirred at room temperature for 1.5 hours. The stir bar was then removed and the solvent was evaporated. The residue was purified using a silica gel column (Q-Pack SI30, size 20) (hexane:ethyl acetate = 66:34 and chloroform:methanol 100:0 to 95:5). After evaporation of the solvent, 122 mg (0.316 mmol, 96%) of the desired compound 104-2 (oil) was obtained.

[0549] Example 112-5: Compound of Example 112 t-butyl (4-(3-(5-((S)-1-(6-((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-2-naphthoyl)pyrrolidin-2-yl)-1,2,4-oxadiazol-3-yl)propyl)benzyl)carbamate 104-3

[0550] Compound 102 (25.5 mg, 0.056 mmol) prepared in Example 109 and dichloromethane (0.520 ml) were added to a 10 ml recovery flask. This was followed by HATU (22.4 mg, 0.059 mmol), diisopropylethylamine (0.029 ml, 0.168 mmol), and compound 104-2 (21.6 mg, 0.056 mmol) prepared in Example 112-4, washing with dichloromethane (0.6 ml). The mixture was stirred at room temperature for 1 hour. The stir bar was then removed and the solvent was evaporated. The residue was purified using an NH column (DNH-30, size 10) (hexane:ethyl acetate = 66:34 to 20:80). After evaporation, 44.6 mg (0.054 mmol, 97%) of the desired 104-3 (amorphous solid) was obtained.

[0551] Example 113 ((S)-2-(3-(3-(4-(aminomethyl)phenyl)propyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(6-((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)naphthalen-2-yl)methanone 104-4

[0552] Compound 104-3 (37.5 mg, 0.046 mmol) prepared in Example 112-5 was added to a 4 ml vial, followed by the addition of dichloromethane (0.455 ml) and trifluoroacetic acid (0.091 ml) and stirring at room temperature for 1 hour. After distilling off the solvent, the mixture was made basic by adding saturated aqueous sodium bicarbonate (2 ml) and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated to obtain 30.4 mg (0.042 mmol, 92%) of the desired compound 104-4 (amorphous solid).

[0553] Example 114 (Cyclohexane-1,4-diyl)bis(((S)-2-(4-methyl-5-(3-phenylpropyl)-4H-1,2,4-triazol-3-yl)pyrrolidin-1-yl)methanone) 105-2 Example 114-1 (S)-3-(pyrrolidin-2-yl)-(4-methyl-5-(3-phenylpropyl)-4H-1,2,4-triazole hydrochloride 105-1

[0554] Compound 42-2 (15.4 mg, 0.042 mmol) prepared in Example 58-2 was added to a 10 ml recovery flask, and 4N hydrochloric acid / dioxane (0.277 ml), dioxane (0.277 ml), and water (0.028 ml) were added. The mixture was stirred at room temperature for 15 minutes. The solvent was then evaporated, and chloroform (1 ml) was added and the solvent was evaporated three times. The residue was then dried in vacuo to obtain 14.3 mg (0.042 mmol, 100%) of the desired compound 105-1 (amorphous solid).

[0555] Example 114-2: Compound of Example 114 (cyclohexane-1,4-diyl)bis(((S)-2-(4-methyl-5-(3-phenylpropyl)-4H-1,2,4-triazol-3-yl)pyrrolidin-1-yl)methanone) 105-2

[0556] To a 10 ml eggplant-shaped flask, trans-1,4-cyclohexanedicarboxylic acid (3.6 mg, 0.021 mmol) and DMF (0.326 ml) were added, followed by HATU (20.3 mg, 0.053 mmol) and diisopropylethylamine (0.050 ml, 0.287 mmol). The mixture was stirred at room temperature for 3 minutes. Compound 105-1 (14.1 mg, 0.041 mmol), prepared in Example 114-1, was then added, washing with DMF (0.7 ml). The mixture was stirred at room temperature for 18 hours. The stir bar was then removed and the solvent was evaporated. The residue was purified using a silica gel column (Q-Pack SI30, size 10) (chloroform:methanol = 100:0 to 80:20). After evaporation, 4.7 mg (0.007 mmol, 34%) of the desired compound 105-2 (white solid) was obtained.

[0557] Example 115 ((1R,4R)-cyclohexane-1,4-diyl)bis(((R)-3-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanethione) 106

[0558] Compound 17 (51.6 mg, 0.0793 mmol) prepared in Example 23 and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiadiphosphetane 2,4-disulfide (Lawson's reagent) (33.7 mg, 0.0833 mmol) were dissolved in toluene (4.5 ml) and heated to reflux under an argon atmosphere for 21 hours. The solvent was evaporated under reduced pressure, and the residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: ethyl acetate:hexane = 1:1). The silica gel containing the target compound was scraped off, and the mixture was eluted with 10% MeOH in chloroform (20 ml). The solvent was evaporated under reduced pressure to give target compound 106 (48.6 mg, 0.0712 mmol, 90%).

[0559] Example 116 Pyrazine-2,5-diylbis(((S)-2-(3-phenethyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)methanethione) 107

[0560] Compound 85 (51.4 mg, 0.0795 mmol) prepared in Example 94 and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiadiphosphetane 2,4-disulfide (Lawson's reagent) (33.8 mg, 0.0835 mmol) were dissolved in toluene (4.5 ml) and heated at 80°C under an argon atmosphere for 2 hours. The solvent was evaporated under reduced pressure, and the residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; developing solvent: ethyl acetate:hexane = 2:3). The silica gel containing the target compound was scraped off, and the mixture was eluted with 10% MeOH in chloroform (20 ml). The solvent was evaporated under reduced pressure to give target compound 107 (45.9 mg, 0.0676 mmol, 85%).

[0561] Example 117 ((R)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)-2,5-dihydro-1H-pyrrol-1-yl)((1S,4R)-4-((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)-2,5-dihydro-1H-pyrrole-1-carbonyl)cyclohexyl)methanone 108-2 Example 117-1 5-(2,5-dihydro-1H-pyrrol-2-yl)-3-(3-phenylpropyl)-1,2,4-oxadiazole 108-1

[0562] Compound 23-1 (134.1 mg, 0.377 mmol) prepared in Example 29-1 was added to a 50 ml recovery flask, followed by the addition of dichloromethane (3.3 ml) and TFA (0.577 ml), and the mixture was stirred at room temperature for 1 hour. The mixture was then made basic by the addition of saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The mixture was dried over sodium sulfate, filtered, and the solvent was evaporated to give compound 108-1 (oil) as a mixture of optical isomers.

[0563] Example 117-2: Compound of Example 117 ((R)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)-2,5-dihydro-1H-pyrrol-1-yl)((1S,4R)-4-((S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)-2,5-dihydro-1H-pyrrole-1-carbonyl)cyclohexyl)methanone 108-2

[0564] Trans-1,4-cyclohexanedicarboxylic acid (32.2 mg, 0.187 mmol) and dichloromethane (1.5 ml) were added to a 20 ml vial, followed by HATU (171 mg, 0.449 mmol) and diisopropylethylamine (0.255 ml, 1.49 mmol). The mixture was stirred at room temperature for 10 min. Next, 108-1 (150 mg, 0.392 mmol) prepared in Example 117-1 was added, washing with dichloromethane (1.0 ml). The mixture was stirred at room temperature for 22 h. The stir bar was then removed and the solvent was evaporated. The residue was purified by SiO2-PTLC (PLC Silica Gel 60 F254, 0.5 mm layer thickness, 20 x 20 cm; eluent: ethyl acetate:methanol = 95:5). The target silica gel was scraped off and eluted with 10% methanol in chloroform (20 ml). The solvent was evaporated under reduced pressure to give 49.3 mg (0.0762 mmol, 41%) of the desired compound 108-2 (oil). The LC-MS and 1H-NMR data of the obtained compound are summarized in Table X below.

[0565] The retention time (RT) and 1H-NMR data for the compounds of Examples 106 to 117 under the following LC / MS elution conditions are summarized in Table 11. Elution conditions: flow rate 0.9 mL / min, mobile phase A = 0.05% (v / v) formic acid aqueous solution, mobile phase B = 0.05% (v / v) formic acid in acetonitrile; 0-0.9 min: linear gradient A:B (95:5) - A:B (10:90), 0.9-3 min: A:B (10:90).

[0566] Table 11-1

[0567] Table 11-2

[0568] Table 11-3

[0569] Test Example 1: Evaluation of in vitro activity of naphthalene-2,6-diylbis(((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) The compound naphthalene-2,6-diylbis(((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone) is a compound described as Compounds 4-6 in PCT / JP2022 / 025361 (WO 2022 / 270628) filed by the same applicant as the present application. The in vitro activity of compounds 4-6 was evaluated by inducing fibrosis in MRC5 cells derived from human fetal lung by stimulating them with TGF-β. Type 1 collagen (Col1) and smooth muscle actin (SMA) were used as fibrosis markers, and β-tubulin was used as an internal standard for correcting protein amount. The expression of fibrosis markers under TGF-β stimulation was compared with that of cells treated with solvent alone (DMSO).

[0570] Specifically, human fetal lung-derived MRC5 cells (normal embryonic lung fibroblasts with accurate PDL, RIKEN) were cultured in DMEM (Nakarai) supplemented with 10% FCS (Nichirei) at 37°C under 5% CO. The resulting MRC5 cells were plated at 1 x 10 in a 12-well dish (Thermo Fisher Scientific, JP). 5Cells were seeded at 1000p per dish and cultured for 1 day. To serum-starve the cells, the medium was replaced with DMEM supplemented with 0.5% FCS and cultured for an additional day. Compounds (10 mM in DMSO) were diluted in DMEM supplemented with 0.5% FCS, and the compound-containing dilutions were added to the cells (final compound concentrations: 5 μM and 10 μM). Two hours after compound addition, TGF-β1 (R&D Systems) was added to a final concentration of 2 ng / ml. Forty-eight hours after addition, cells were harvested in 75 μl of Laemmli sample buffer (277.8 mM Tris, 4.4% LDS, 44.4% glycerol, 0.02% bromophenol blue, pH 6.8). The harvested cell suspension was separated by SDS-PAGE and transferred to a PVDF membrane (Millipore). The protein levels were assessed by Western blotting using anti-αSMA antibody (Abcam 1A4) and anti-type 1 collagen antibody (self-made). Anti-β-tubulin antibody (ProteinTec) was used to normalize the protein levels between samples.

[0571] The results are shown in Figure 1. The band intensities of type 1 collagen and β-tubulin, used as an internal standard for correction, in Figure 1 were quantified using ImageJ software (National Institutes of Health, USA). As shown in Equation 1, the band intensity of type 1 collagen (C) was divided by the band intensity of β-tubulin (T) to correct for the loading amount, thereby obtaining a comparable type 1 collagen expression level (C) between samples. N ) was standardized as

[0572] This normalization allowed for comparative analysis of changes in type 1 collagen expression before and after the addition of the compound, minimizing the influence of internal variability. The decrease in type 1 collagen expression due to the compound upon addition of TGF-β1 (ΔC) was quantitatively evaluated using Equation 2. ΔC （Cmpd.） is 1 if the expression of type 1 collagen is completely inhibited, and 0 if there is no activity at all. （Cmpd.）The ΔC value was 0.32 at 5 μM and 0.43 at 10 μM. （TGF-β1－） The mean β-amyloid ...

[0573] Test Example 2: Evaluation of in vitro activity of the compounds of the present invention In the same manner as in Test Example 1, the inhibitory activity of the compounds of the present invention on type 1 collagen expression was measured by ΔC （Cmpd.） The results are shown in Tables 12 and 13. The compound had a larger ΔC than the compound used in Test Example 1. （Cmpd.） Compounds that showed a value of A were designated as compounds with a ΔC below that value but larger than that of the negative control (DMSO). （Cmpd.） Compounds that showed a value of B were identified as compounds with a ΔC value lower than that of DMSO. （Cmpd.） Compounds that showed this value were rated C.

[0574] Table 12-1

[0575] Table 12-2

[0576] Table 13-1

[0577] Table 13-2

[0578] Table 13-3

[0579] Table 13-4

[0580] Table 13-5

[0581] Table 13-6

[0582] The present invention is useful in treating or preventing fibrosis, particularly pulmonary fibrosis, and more particularly idiopathic pulmonary fibrosis.

Claims

1. Formula (I): [In the formula, are the same or different and each independently: A and C are each independently a bond, or optionally substituted methylene, carbonyl, thiocarbonyl, sulfinyl, sulfonyl, phosphoryl, optionally substituted amido, or thioamido; B is a bond, or straight-chain C1-6 alkylene, C3-11 cycloalkylene, or C3-11 heterocycloalkylene, straight-chain C2-6 alkenylene, C3-8 cycloalkenylene, or C3-8 heterocycloalkenyne, straight-chain C1-6 alkynylene, optionally substituted by 1 to 3 groups selected from the group consisting of C1-6 alkyl, C3-8 cycloalkyl, trifluoromethyl, hydroxyl, amino, amido, halogen, and C1-6 alkoxy, or an arylene or heteroarylene group optionally substituted by 1 or 2 groups selected from the group consisting of C1-6 alkyl, trifluoromethyl, hydroxyl, amino, amido, halogen, and C1-6 alkoxy; Y 1 , Y 2 , Y 3 and X 4 are each independently -O-, -N=, -S-, or -NR 1 - or -CR 2 = ; where Y 1 , Y 2 , Y 3 and X 4 At least one of these is -N= or -NR 1 - and R 1 is hydrogen, optionally substituted C alkyl, optionally substituted C aryl, or optionally substituted 5-10 membered heteroaryl; R 2 is hydrogen, optionally substituted C alkyl, optionally substituted C carbonyl, optionally substituted C alkoxy, optionally substituted C alkylthio, optionally substituted C alkylamino, optionally substituted C aryl, or optionally substituted 5-10 membered heteroaryl; R 6 , R 7 , R 10 , R 11 and R 12 are each independently hydrogen, optionally substituted C alkyl, optionally substituted C aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C alkoxy, hydroxy, amino, cyano, carbamoyl or halogen; n is 1, 2 or 3; where, when n is 2, one carbon atom is not substituted with R 6 and R 7 are bonded together, and the other carbon atom has R 8 and R 9 when n is 3, the two carbon atoms each independently have R 6 and R 7 are bonded together independently, and the remaining carbon atoms are 8 and R 9 are bonded together; R 8 and R 9 are each independently hydrogen, optionally substituted C alkyl, optionally substituted C aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C alkoxy, hydroxy, amino, cyano, carbamoyl or halogen; or R 6 and R 7 , R 8 and R 9 , and R 10 and R 11 each independently bridges together with the carbon to which it is bonded to form a C3-6 spiro ring, and R 6 or R 7 and R 8 or R 9 forms a double bond with the adjacent carbon atom, and R 8 or R 9 and R 10 or R 11 forms a double bond with the adjacent carbon atom, and R 8 or R 9 and R 12 forms a double bond with the adjacent carbon atom, and R 10 or R 11 and R 12 forms a double bond together with the adjacent carbon atom, and the adjacent R 6 or R 7 and R 6 or R 7 are bridged together to form -CH2- or -CH2-CH2-, and adjacent R 6 or R 7 and R 8 or R 9 are bridged together to form -CH2-, -CH2-CH2-, -CH2-CH2-CH2- or -CH2-CH2-CH2-CH2-, and adjacent R 7 and R 8 and R 10 or R 11 are bridged together to form -CH2-, -CH2-CH2-, -CH2-CH2-CH2- or -CH2-CH2-CH2-CH2-, R 12 and R 6 or R 7 are bridged together to form -CH2- or -CH2-CH2-, and R 12 and R 8 or R 9 are bridged together to form -CH2- or -CH2-CH2-, or R 12 and R 10 or R 11 are joined together to bridge and form -CH2- or -CH2-CH2-. Here, the substituents in "optionally substituted" are selected from the following: hydroxy, halogen, cyano, carbamoyl, amino, amidinoamino, carboxy, C6-10 aryl, 5- to 10-membered heteroaryl substituted with C1-4 alkoxycarbonyl, C6-10 aryl substituted with C1-4 alkyl, C6-10 aryl substituted with hydroxy, C6-10 aryl substituted with halogen, C6-10 aryl substituted with C1-4 alkoxy, (optionally substituted amino)-C6-10 aryl, C1-4 alkoxycarbonyl, C1-4 alkoxycarbonylamino, 5- to 6-membered heterocycloalkyl, C3-6 cycloalkyl, 5- to 10-membered heteroaryl, C6-10 aryl substituted with (C1-6 alkyl substituted with halogen), and trialkylsilyloxy, alkylarylsilyloxy, triarylsilyloxy, or a protecting group. However, the formula: excluding compounds represented by the following formula: ] a compound represented by the following formula: or an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

2. In formula (I), is a group represented by the formula:

2. The compound according to claim 1, its enantiomer, or a pharmaceutically acceptable salt thereof, wherein R is a group represented by the formula:

3. In formula (I), is a group represented by the formula: (wherein R is hydrogen, optionally substituted C alkyl, optionally substituted C aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C alkoxy, hydroxy, optionally substituted C amino, optionally substituted C amido, cyano, carbamoyl or halogen; R is hydrogen or optionally substituted C alkyl; Z is optionally substituted C alkyl, hydroxy or halogen; and the wavy line in the above group has the formula:

3. The compound according to claim 2, its enantiomer, or a pharmaceutically acceptable salt thereof, wherein the compound is a group represented by the formula:

4. In formula (I), is a group represented by the formula: (wherein R is hydrogen, optionally substituted C alkyl, optionally substituted C aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C alkoxy, hydroxy, optionally substituted C amino, optionally substituted C amido, cyano, carbamoyl or halogen; R is hydrogen or optionally substituted C alkyl; Z is optionally substituted C alkyl, hydroxy or halogen; and the wavy line in the above group has the formula:

4. The compound according to claim 3, its enantiomer, or a pharmaceutically acceptable salt thereof, wherein the compound is a group represented by the formula:

5. In formula (I), is a group represented by the formula: (Here, at the end of the wavy line, there is the formula: and R is hydrogen, hydroxy, t-butyloxy, phenyl, fluorine, cyano, or carbamoyl).

6. In formula (I), the formula: is an azole ring represented by the formula: (Here, R 15 is optionally substituted C alkyl, optionally substituted C alkoxy, optionally substituted C alkylthio, optionally substituted C alkylamino, optionally substituted C aryl, optionally substituted 5-10 membered heteroaryl; R 16 is an optionally substituted C1-6 alkyl, an optionally substituted C6-10 aryl, or an optionally substituted 5- to 10-membered heteroaryl), or a compound according to claim 1, its enantiomer, or a pharmaceutically acceptable salt thereof.

7. In formula (I), the formula: The azole ring represented by the formula: (Here, R 12 and R 13 are each independently hydrogen, optionally substituted C alkyl, optionally substituted C alkoxy, optionally substituted C alkylthio, optionally substituted C alkylamino, optionally substituted C aryl, or optionally substituted 5-10 membered heteroaryl; R 17 wherein R is an optionally substituted C1-6 alkyl, an optionally substituted C6-10 aryl, or an optionally substituted 5- to 10-membered heteroaryl; and R is a group represented by the formula (I), or an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

8. In formula (I), the formula: is an azole ring represented by the formula: (Here, R 12 and R 13 are each independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C1-6 alkylthio, optionally substituted C1-6 alkylamino, optionally substituted C6-10 aryl, or optionally substituted 5-10 membered heteroaryl).

9. In formula (I), the formula: is an azole ring represented by the formula: (wherein R is hydrogen, optionally substituted C1-6 alkyl, R 13 is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C1-6 alkylthio, optionally substituted C1-6 alkylamino, optionally substituted C6-10 aryl, or optionally substituted 5- to 10-membered heteroaryl), or an enantiomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 8.

10. In formula (I), R, which is a side chain of the azole ring, 2 but, (wherein X is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C5-10 membered heteroaryl, optionally substituted C1-6 alkoxy, hydroxy, amino, cyano, carbamoyl or halogen; Z is O, NH, S; and n is an integer from 1 to 5), a compound according to claim 1, its enantiomer, or a pharmaceutically acceptable salt thereof, 11. In formula (I), R, which is a side chain of the azole ring, 2 but, 11. The compound of claim 10, its enantiomer, or a pharmaceutically acceptable salt thereof, wherein:

12. In formula (I), A and C each independently represent the formula: wherein Z is C, S, SO, SO2 or P; Y is O or S; R 3 2. The compound according to claim 1, its enantiomer, or a pharmaceutically acceptable salt thereof, wherein:

13. In formula (I), A and C each independently represent the formula:

13. The compound of claim 12, its enantiomer, or a pharmaceutically acceptable salt thereof, wherein:

14. In formula (I), B is a group represented by the formula:

14. The compound of claim 13, its enantiomer, or a pharmaceutically acceptable salt thereof, wherein:

15. In formula (I), B is a group represented by the formula:

15. The compound of claim 14, its enantiomer, or a pharmaceutically acceptable salt thereof, wherein:

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, its enantiomer, or a pharmaceutically acceptable salt thereof.

17. The pharmaceutical composition according to claim 16 for treating or preventing fibrosis.

18. The pharmaceutical composition according to claim 17, wherein the fibrosis is pulmonary fibrosis.

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