WO2022270628A1 - Ｒｓウイルス感染症の処置および／または予防用医薬としてのヘテロシクロアルキル置換ポリヘテロアゾール誘導体 - Google Patents

Ｒｓウイルス感染症の処置および／または予防用医薬としてのヘテロシクロアルキル置換ポリヘテロアゾール誘導体 Download PDF

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WO2022270628A1
WO2022270628A1 PCT/JP2022/025361 JP2022025361W WO2022270628A1 WO 2022270628 A1 WO2022270628 A1 WO 2022270628A1 JP 2022025361 W JP2022025361 W JP 2022025361W WO 2022270628 A1 WO2022270628 A1 WO 2022270628A1
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optionally substituted
added
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solvent
aryl
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French (fr)
Japanese (ja)
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茂 松岡
博史 土川
健太郎 山田
明良 加藤
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NATIONAL UNIVERSITY Corp OITA UNIVERSITY
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NATIONAL UNIVERSITY Corp OITA UNIVERSITY
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Priority to CN202280044481.9A priority Critical patent/CN117730079A/zh
Priority to US18/573,760 priority patent/US20240327392A1/en
Priority to EP22828544.1A priority patent/EP4361148A4/en
Priority to AU2022296214A priority patent/AU2022296214A1/en
Priority to CA3223875A priority patent/CA3223875A1/en
Priority to JP2023530145A priority patent/JPWO2022270628A1/ja
Publication of WO2022270628A1 publication Critical patent/WO2022270628A1/ja
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems

Definitions

  • Respiratory Syncytial (RS) virus exists all over the world and is a respiratory infectious disease that universally repeats epidemics and subsides without regional or climatic bias. Nearly 100% of children are said to be infected by the age of 2, and due to the large number of opportunities for infection, it is thought to be an infectious disease with a higher mortality rate than influenza among newborns. In fact, there are no effective therapeutic agents for respiratory syncytial virus, causing approximately 30 million cases and approximately 100,000 deaths worldwide each year. In recent years, advances in diagnostic technology have made it possible to identify respiratory syncytial virus infections with high accuracy, and there is an urgent need to develop effective therapeutic agents (Non-Patent Document 1).
  • VIRAZOLE Rhibavirin for Inhalation Solution, USP
  • USP which is approved in the United States as a treatment for serious patients with respiratory syncytial virus infection
  • SYNAGIS registered trademark
  • Pivizumab a monoclonal antibody drug against the surface protein of RSV
  • Non-Patent Documents 4 and 5 Because it is necessary, it places a heavy burden on the patient, and since it is a biopharmaceutical, it is known as an expensive medicine, and insurance coverage is limited to high-risk children who are particularly prone to severe disease (Non-Patent Documents 4 and 5).
  • the present inventors selected low-molecular-weight compounds that were originally designed and synthesized by the present inventors and that exhibit growth inhibitory activity for respiratory syncytial virus at the level of cell experiments. I found The development of these compounds as therapeutic agents is expected to save the large number of newborns who die each year from respiratory syncytial virus.
  • the present invention includes the following aspects.
  • R 1 is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, or optionally substituted C6-10 heteroaryl;
  • R 2 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 C6-10 heteroaryl;
  • R 5 is optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C6-10 heteroaryl, un
  • substituents in "optionally substituted” are selected from: hydroxy, halogen, cyano, carbamoyl, amino, amidinoamino, carboxy, C6-10 aryl, C1-4 alkoxycarbonyl-substituted 5- to 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, 5-6 membered heterocycloalkyl, C3-6 cycloalkyl, 5-10 membered heteroaryl, (halogen-substituted C1-6 alkyl) substituted C6-10 aryl, and trialkylsilyloxy, alkylarylsilyloxy, triary
  • R 5 is not tert-butoxycarbonyl .
  • 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, optionally substituted C6-10 heteroaryl
  • 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, optionally substituted C6-10 heteroaryl
  • R 13 is represented by the formula: (Here, Z is hydrogen, amino, dimethylamino, halogen, hydroxy, cyano, carbamoyl, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy) is a group represented by; n is an integer from 1 to 5; R7 is the formula: (where X is hydrogen, amino, halogen, hydroxy, methoxy, or optionally substituted C1-4 alkyl) is a group represented by; R 11 is methyl or of the formula: (where each R 14 is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C6-10 heteroaryl, substituted optionally substituted carbonyl, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted acyl, or optionally substituted thioacyl; R 19 is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6
  • R 13 is represented by the formula: (Here, Z is hydrogen, amino, dimethylamino, halogen, hydroxy, cyano, carbamoyl, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy) is a group represented by; n is an integer from 1 to 5; R7 is the formula: (where X is hydrogen, amino, halogen, hydroxy, methoxy, or optionally substituted C1-4 alkyl) is a group represented by; R 11 is methyl or of the formula: (where each R 14 is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C6-10 heteroaryl, substituted optionally substituted carbonyl, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted acyl, or optionally substituted thioacyl; R 19 is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C
  • ⁇ Pharmaceutical composition > [12] A pharmaceutical composition containing the compound according to any one of [1] to [11], an enantiomer thereof, or a pharmaceutically acceptable salt thereof. [13] The pharmaceutical composition of [12] for treating or preventing respiratory syncytial virus infection.
  • low-molecular-weight compounds are provided that are expected to have good therapeutic effects on respiratory syncytial virus infections. Since this compound is an inexpensive and stable low-molecular-weight drug, it is expected to be widely used, including in developing countries, and have a large ripple effect on public health. Stay away from drugs.
  • group means a monovalent group.
  • non-univalent groups include alkylene groups (divalent) and the like.
  • group may be omitted.
  • substituents defined by “optionally substituted” or “substituted” is not particularly limited as long as it can be substituted, and 1 or more is. Also, unless otherwise indicated, the description of each substituent also applies when that substituent is part or a substituent of another substituent.
  • any portion of the group modified by "optionally substituted” or “substituted” in this specification may be substituted.
  • “optionally substituted arylalkyl” and “substituted arylalkyl” can be substituted on the aryl portion or substituted on the alkyl portion, and both the aryl and alkyl portions can be may be substituted.
  • substituent in the case of "optionally substituted” may be selected from the substituent group ⁇ consisting of the following, and substituted with 1 to 5 substituents that are the same or different may be: Substituent group ⁇ : hydroxy, halogen, cyano, carbamoyl, amino, amidinoamino, carboxy, C6-10 aryl, C1-4 alkoxycarbonyl-substituted 5- to 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, 5-6 membered heterocycloalkyl, C3-6 cycloalkyl, 5-10 membered heteroaryl, (
  • substituent groups ⁇ may be substituted with the same or different 1 to 5 substituents selected from the substituent group ⁇ : Substituent group ⁇ : halogen, hydroxy, carboxy, cyano, C3-10 alicyclic group, C1-6 alkoxy, C3-10 alicyclic oxy, C1-6 alkylthio, 5- or 6-membered heteroarylthio, C6- 10 aryl, 5- or 6-membered heteroaryl, 4-10 membered non-arylheterocycle, C1-6 alkylcarbonyl, C3-10 alicyclic carbonyl, C6-10 arylcarbonyl, 5- or 6-membered heteroarylcarbonyl, 4-10 membered non-arylheterocyclic carbonyl, protecting group.
  • substituent group ⁇ halogen, hydroxy, carboxy, cyano, C3-10 alicyclic group, C1-6 alkoxy, C3-10 alicyclic oxy, C1-6 alkylthio, 5- or 6-membered hetero
  • C1-6 as used herein means having 1 to 6 carbon atoms. 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. .
  • heteroatom refers to atoms other than carbon atoms and hydrogen atoms, such as oxygen atoms, nitrogen atoms, sulfur atoms, and the like.
  • Hydroxyloxy as used herein is a monovalent group of -OH. This group is sometimes called a "hydroxy group” or "hydroxy”.
  • Halogen as used herein means 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. More preferably, it is a fluorine atom.
  • Halogen may also be referred to as “halogen atom” or "halo”.
  • Carboxy as used herein is a monovalent group of -COOH. This group may also be referred to as a “carboxy group,” “carboxyl,” “carboxyl,” or “carboxylic acid group.”
  • Cyano as used herein is a monovalent group of -CN.
  • amino is the monovalent radical -NH2 . This group is sometimes called an “amino group”.
  • Alkyl as used herein means a linear or branched saturated aliphatic hydrocarbon group.
  • C1-6 alkyl is an alkyl group having 1 to 6 carbon atoms, and preferred examples include “C1-4 alkyl", more preferably “C1-3 alkyl”, still more preferably It is "C1-2 alkyl”.
  • Specific examples of "C1-4 alkyl” include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl and the like.
  • C1-6 alkyl include, but are not limited to, C1-4 alkyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1,2-dimethylpropyl, n-hexyl and the like.
  • alkenyl means a linear or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond.
  • C2-6 alkenyl is an alkenyl group having 2 to 6 carbon atoms, and preferred examples thereof include “C2-4 alkenyl”.
  • Specific examples of “C2-6 alkenyl” include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propylenyl, 2-methyl-2-propylenyl and the like. include, but are not limited to.
  • alkynyl means a linear or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond.
  • C2-6 alkynyl is an alkynyl group having 2 to 6 carbon atoms, and preferred examples thereof include “C2-4 alkynyl”. Specific examples of “C2-6 alkynyl” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 3-butynyl, 1-pentynyl, 1-hexynyl and the like. but not limited to these.
  • aryl means a monovalent group of a monocyclic or bicyclic aromatic hydrocarbon ring
  • C6-10 aryl means an aryl group having 6 to 10 carbon atoms.
  • Examples of “aryl” include, but are not limited to, C6 aryl, C10 aryl, and the like.
  • Specific examples of C6 aryl include, but are not limited to, phenyl and the like.
  • Specific examples of C10 aryl include, but are not limited to, 1-naphthyl, 2-naphthyl and the like.
  • arylalkyl means alkyl substituted with at least one aryl.
  • C6-10 arylC1-6 alkyl means C1-6 alkyl substituted with at least one C6-10 aryl.
  • Specific examples of C6-10arylC1-6alkyl include benzyl (phenyl - CH2-), phenethyl (phenyl - CH2CH2-), naphthalen-1-ylmethyl, naphthalen- 2 -ylmethyl, 2-(naphthalene -1-yl)ethyl, 2-(naphthalen-2-yl)ethyl, and the like, but are not limited thereto.
  • (optionally substituted amino)-arylalkyl means an arylalkyl substituted with an optionally substituted amino group, wherein an alkyl group or an aryl group or both is substituted with an amino group.
  • the amino group of said arylalkyl group may be unsubstituted or may have 1, 2 or 3 substituents such as optionally substituted alkyl (eg unsubstituted C1-6 alkyl, C3 -6 cycloalkyl-C1-6 alkyl, C3-6 cycloalkylcarbonyl, etc.).
  • Examples of (optionally substituted amino)-C6-10arylC1-6alkyl include 4-(dimethylamino)benzyl, 4-((cyclopentylmethyl)amino)benzyl, 4-((cyclopentylcarbonyl)amino ) benzyl, 4-((2-carbamoylethyl)carbonylamino)benzyl, and the like, but are not limited thereto.
  • C6-10 aryl portion of “C6-10 arylthio” is synonymous with the above C6-10 aryl.
  • C6-10 arylthio preferably includes “C6 or C10 arylthio”.
  • Specific examples of “C6-10 arylthio” include, but are not limited to, phenylthio, 1-naphthylthio, 2-naphthylthio and the like.
  • C6-10 arylsulfonyl means sulfonyl substituted with the above “C6-10 aryl”.
  • 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 and the like.
  • heteroaryl is a monocyclic or bicyclic aromatic heterocycle containing from 1 to 4 identical or different heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms. means a monovalent group of
  • 5- or 6-membered heteroaryl means from 5 to 6 atoms, including 1 to 4 identical or different heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms. means a monovalent group of a monocyclic aromatic heterocyclic ring.
  • 5- or 6-membered heteroaryl include pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and the like. include, but are not limited to.
  • 5- to 10-membered heteroaryl consists of 5 to 10 atoms containing 1 to 4 identical or different heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms. It means a monovalent radical of a monocyclic or bicyclic aromatic heterocycle.
  • 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, quinolon
  • heteroarylalkyl means alkyl substituted with at least one heteroaryl.
  • “5- to 10-membered heteroaryl C1-6 alkyl” means C1-6 alkyl substituted with at least one 5- to 10-membered heteroaryl.
  • Specific examples of 5- to 10-membered heteroaryl C1-6 alkyl include pyridin-2-ylmethyl, pyridin-4-ylmethyl, 2-(quinolin-8-yl)ethyl, 2-(quinolin-5-yl)ethyl, Examples include, but are not limited to, 2-(quinoxalin-5-yl)ethyl, 2-(1H-indol-3-yl)ethyl, and the like.
  • cycloalkyl means a non-aromatic saturated hydrocarbon ring group, including those having a partially crosslinked structure, those having a partially spiro structure, and those having 1 or 2 carbonyl structures.
  • C3-20 cycloalkyl means monocyclic or bicyclic cycloalkyl having 3 to 20 carbon atoms.
  • C3-6 cycloalkyl means monocyclic cycloalkyl having 3 to 6 carbon atoms. Specific examples of C3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • Cycloalkylalkyl as used herein means alkyl substituted with at least one cycloalkyl.
  • C3-6 cycloalkylC1-6 alkyl means C1-6 alkyl substituted with at least one C3-6 cycloalkyl.
  • C3-6 cycloalkylC1-6 alkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl , 3-cyclopropylpropyl, 3-cyclobutylpropyl, 3-cyclopentylpropyl, 3-cyclohexylpropyl, and the like, but are not limited thereto.
  • heterocycloalkyl means a non-aromatic saturated heterocyclic ring containing one or more heteroatoms which are the same or different and selected from the group consisting of oxygen, nitrogen and sulfur atoms. , including those with partially crosslinked structures and those that are partially spirolated.
  • the "4- to 20-membered non-aryl heterocyclic ring” includes 4 to 20 heteroatoms containing the same or different 1 or 2 or more heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom.
  • a non-arylheterocycle may form a fused ring with an aryl or heteroaryl.
  • heterocycles include those condensed with C6-10 aryl or 5- or 6-membered heteroaryl.
  • Non-aryl heterocycle e.g. lactams, thiolactams, lactones, thiolactones, cyclic imides, cyclic carbamates , cyclic thiocarbamates, etc.
  • carbonyl, sulfinyl and sulfonyl oxygen atoms and thiocarbonyl sulfur atoms are not included in the number of 4- to 20-membered members (ring size) and the number of ring-constituting heteroatoms.
  • the "4- to 10-membered non-aryl heterocycle” is the above-mentioned “4- to 20-membered non-aryl heterocycle", wherein the "4- to 10-membered non-aryl heterocycle” is a monovalent group. means a substituent with
  • the 4- to 10-membered non-aryl heterocyclic moiety of "4- to 10-membered non-aryl heterocyclic oxy" as used herein is synonymous with the above-mentioned "4- to 10-membered non-aryl heterocyclic ring".
  • the “4- to 10-membered non-arylheterocyclic oxy” is preferably “4- to 6-membered non-arylheterocyclic oxy”.
  • 4- to 10-membered non-arylheterocyclic oxy include, but are limited to, tetrahydrofuranyloxy, tetrahydropyranyloxy, azetidinyloxy, pyrrolidinyloxy, piperidinyloxy, and the like. not.
  • the 4- to 10-membered non-aryl heterocyclic moiety of "4- to 10-membered non-aryl heterocyclic thio" as used herein is synonymous with the above "4- to 10-membered non-aryl heterocyclic ring".
  • the "4- to 10-membered non-arylheterocyclic thio" is preferably "4- to 6-membered non-aryl-heterocyclic thio".
  • Specific examples of the "4- to 10-membered non-arylheterocyclic thio" include, but are not limited to, tetrahydropyranylthio, piperidinylthio and the like.
  • 4- to 10-membered non-aryl heterocyclic carbonyl means a carbonyl group substituted with the above "4- to 10-membered non-aryl heterocyclic ring".
  • the "4- to 10-membered non-aryl heterocyclic carbonyl” is preferably "4- to 6-membered non-aryl heterocyclic carbonyl”.
  • Specific examples of "4- to 10-membered non-arylheterocyclic carbonyl” include, but are not limited to, azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, morpholinylcarbonyl and the like.
  • 4- to 10-membered non-arylheterocyclic sulfonyl means a sulfonyl group substituted with the above "4- to 10-membered non-arylheterocyclic ring”.
  • the “4- to 10-membered non-arylheterocyclesulfonyl” is preferably “4- to 6-membered non-arylheterocyclesulfonyl”.
  • 4- to 10-membered non-arylheterocyclic sulfonyl include, but are not limited to, azetidinylsulfonyl, pyrrolidinylsulfonyl, piperidinylsulfonyl, morpholinylsulfonyl and the like.
  • 5- to 6-membered heterocycloalkyl means 5-6 ring atoms containing the same or different 1 or 2 or more heteroatoms selected from oxygen, nitrogen and sulfur atoms. means a heterocycloalkyl consisting of
  • Heterocycloalkylalkyl as used herein means alkyl substituted with at least one heterocycloalkyl.
  • Preferred examples of alkylcarbonyl include C1-6 alkylcarbonyl.
  • alkoxy is an -O-alkyl monovalent group.
  • Preferred examples of alkoxy include C1-6 alkoxy (ie C1-6 alkyl-O-), C1-4 alkoxy (ie C1-4 alkyl-O-) and the like.
  • C1-4 alkoxy examples include methoxy (CH 3 O-), ethoxy (CH 3 CH 2 O-), n-propoxy (CH 3 (CH 2 ) 2 O-), isopropoxy ((CH 3 ) 2 CHO-), n-butoxy (CH 3 (CH 2 ) 3 O-), isobutoxy ((CH 3 ) 2 CHCH 2 O-), tert-butoxy ((CH 3 ) 3 CO-), sec-butoxy ( CH3CH2CH ( CH3 )O-) and the like.
  • C1-6 alkoxy examples include C1-4 alkoxy, n-pentyloxy (CH 3 (CH 2 ) 4 O-), isopentyloxy ((CH 3 ) 2 CHCH 2 CH 2 O-), neopentyl oxy (( CH3 ) 3CCH2O- ), tert-pentyloxy ( CH3CH2C ( CH3 ) 2O- ), 1,2-dimethylpropoxy ( CH3CH ( CH3 )CH ( CH3 )O-) and the like, but are not limited thereto.
  • 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.
  • C1-6 alkoxycarbonyl examples include C1-4 alkoxycarbonyl, n-pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert-pentyloxycarbonyl, 1,2-dimethylpropyloxycarbonyl, n- Examples include, but are not limited to, hexyloxycarbonyl and the like.
  • 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, iso butoxycarbonylamino and the like.
  • C1-6 alkoxycarbonylamino examples include C1-4 alkoxycarbonylamino, n-pentyloxycarbonylamino, isopentyloxycarbonylamino, neopentyloxycarbonylamino, tert-pentyloxycarbonylamino, 1,2-dimethyl Examples include, but are not limited to, propyloxycarbonylamino, n-hexyloxycarbonylamino, and the like.
  • C1-6 alkylsulfonyl as used herein means a sulfonyl group substituted with the above “C1-6 alkyl”.
  • C1-6 alkylsulfonyl is preferably “C1-4 alkylsulfonyl”.
  • Specific examples of “C1-6 alkylsulfonyl” include, but are not limited to, methylsulfonyl, propylsulfonyl, butylsulfonyl and the like.
  • C1-6 alkyl portion of "C1-6 alkylthio” is synonymous with the above C1-6 alkyl.
  • C1-6 alkylthio include “C1-4 alkylthio", preferably “C1-3 alkylthio”.
  • Specific examples of “C1-6 alkylthio” include methylthio, ethylthio, propylthio, butylthio, isopropylthio, isobutylthio, tert-butylthio, sec-butylthio, isopentylthio, neopentylthio, tert-pentylthio, 1,2- Examples include, but are not limited to, dimethylpropylthio and the like.
  • Preferred examples of arylcarbonyl include C6-10 arylcarbonyl.
  • C6-10 aryl portion of “C6-10 aryloxy” is synonymous with the above C6-10 aryl.
  • C6-10 aryloxy preferably includes “C6 or C10 aryloxy”.
  • Specific examples of the "C6-10 aryloxy group” include, but are not limited to, a phenoxy group, a 1-naphthyloxy group, a 2-naphthyloxy group and the like.
  • a "5- or 6-membered heteroarylcarbonyl group” means a carbonyl group substituted with the above "5- or 6-membered heteroaryl".
  • Specific examples of the "5- or 6-membered heteroarylcarbonyl group” include a pyrazoylcarbonyl group, a triazolylcarbonyl group, a thiazolylcarbonyl group, a thiadiazoylcarbonyl group, a pyridylcarbonyl group, a pyridazoylcarbonyl group, and the like. include but are not limited to:
  • the 5- or 6-membered heteroaryl portion of the "5- or 6-membered heteroaryloxy group” is synonymous with the above-mentioned "5-membered heteroaryl” or "6-membered heteroaryl".
  • Specific examples of the "5- or 6-membered heteroaryloxy group” include a pyrazoyloxy group, a triazolyloxy group, a thiazolyloxy group, a thiadiazoyloxy group, a pyridyloxy group, a pyridazoyloxy group, and the like. include but are not limited to:
  • the 5- or 6-membered heteroaryl portion of the "5- or 6-membered heteroarylthio group” is synonymous with 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 triazolylthio group, a thiazolylthio group, a thiadiazoylthio group, a pyridylthio group, a pyridazoylthio group, and the like.
  • a "5- or 6-membered heteroarylsulfonyl group” means a sulfonyl group substituted with the above "5- or 6-membered heteroaryl”.
  • Specific examples of the "5- or 6-membered heteroarylsulfonyl group” include a pyrazoylsulfonyl group, a triazolylsulfonyl group, a thiazolylsulfonyl group, a thiadiazoylsulfonyl group, a pyridylsulfonyl group, a pyridazoylsulfonyl group, and the like. include but are not limited to:
  • a group substituted with a certain substituent means that the group is substituted with at least one substituent.
  • hydroxy-substituted C1-6 alkyl means that the C1-6 alkyl is substituted with at least one hydroxy.
  • Examples of “carbamoyl-substituted C1-6 alkyl” include, but are not limited to, carbamoyl-substituted C1-4 alkyl.
  • 3-amino-3-oxo propyl i
  • nitrogen protecting group eg a tert-butoxycarbonyl group.
  • aminodinoamino-substituted C1-4 alkyl examples include (amidinoamino)methyl, 2-(amidinoamino)ethyl, 3-(amidinoamino)propyl, 4-(amidinoamino)butyl and the like. but not limited to these.
  • aminodinoamino-substituted C1-6 alkyl examples include amidinoamino-substituted C1-4 alkyl, 5-(amidinoamino)pentyl, 6-(amidinoamino)hexyl and the like, and these include Not limited.
  • Carboxy-substituted C1-6 alkyl as used herein is 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” and the like.
  • Specific examples of “carboxy-substituted C1-4 alkyl” include, but are not limited to, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl and the like.
  • Specific examples of “carboxy-substituted C1-6 alkyl” include, but are not limited to, carboxy-substituted C1-4 alkyl, 5-carboxypentyl, 6-carboxyhexyl and the like.
  • unsubstituted carbonyl in “unsubstituted or substituted carbonyl” means a carboxylic acid group, and “substituted carbonyl” is an ester of carboxy or an amide thereof, a hydroxyl group, an optionally substituted lower It means an alkylcarbonyl group, an optionally substituted arylcarbonyl group, and the like.
  • unsubstituted sulfonyl in “unsubstituted or substituted sulfonyl” means a sulfonic acid group
  • substituted sulfonyl refers to an ester of a sulfonic acid group or an amide thereof, a hydrosulfonyl group, a substituted It means a good lower alkylsulfonyl group, an optionally substituted arylsulfonyl group, and the like.
  • unsubstituted sulfinyl in “unsubstituted or substituted sulfinyl” means a sulfinic acid group
  • substituted sulfinyl means an ester of a sulfinic acid group or an amide thereof, a hydrosulfinyl group, a It means a lower alkylsulfinyl group, optionally substituted arylsulfinyl group, and the like.
  • unsubstituted acyl in “unsubstituted or substituted acyl” means an esterified acyl group such as carboxy, and "substituted acyl” means carbamoyl, optionally substituted lower alkylcarbamoyl, It means optionally substituted lower alkanoyl, aroyl, optionally substituted heteroarylcarbonyl and the like. Specific examples include trifluoroacetyl and the like.
  • unsubstituted thioacyl in “unsubstituted or substituted thioacyl” means thioacyl, and "substituted thioacyl"
  • Protecting group refers to a group of atoms that, when attached to a reactive functional group in a molecule, shields, reduces or prevents the reactivity of the functional group.
  • protecting groups can be selectively removed during synthetic processes, if desired. Examples of protecting groups include Peter G. M. 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.
  • a “protecting group” may fall under the substituent ⁇ definition.
  • Nitro-veratryloxycarbonyl examples include 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”), etc. Not limited.
  • hydroxyl protecting groups are 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 such as TMS, triethylsilyl, t-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS)), alkylarylsilyl ethers (e.g. t-butyldiphenylsilyl (TBDPS)), triarylsilyl ethers (e.g. triphenylsilyl), glycols Ethers (eg, ethylene glycol ether, propylene glycol ether, etc.), and allyl ethers include, but are not limited to.
  • substituents in "optionally substituted” are selected from: hydroxy, halogen, cyano, carbamoyl, amino, amidinoamino, carboxy, C6-10 aryl, C1-4 alkoxycarbonyl-substituted 5- to 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, 5-6 membered heterocycloalkyl, C3-6 cycloalkyl, 5-10 membered heteroaryl, (halogen-substituted C1-6 alkyl) substituted C6-10 aryl, and trialkylsilyloxy, alkylarylsilyloxy, triary
  • R 5 is not tert-butoxycarbonyl .
  • R 1 and R 2 are each independently optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, substituted optionally substituted C1-6 alkylthio, optionally substituted C1-6 alkylamino are preferred, and the substituents thereof are each independently optionally substituted C6-10 aryl or optionally substituted C6-10 More preferred is heteroaryl, ie R 1 and R 2 are each independently optionally substituted C6-10 arylalkyl or optionally substituted C6-10 heteroarylalkyl.
  • R 1 and R 2 are each independently represented by the formula: (Here, Z is hydrogen, amino, halogen, hydroxy, cyano, carbamoyl, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy.) is a group represented by; [wherein R is optionally substituted C1-6 alkyl or optionally substituted C1-5 alkylcarbonyl; X is N or C; m is an integer from 1 to 7. ] and compounds represented by formula (I).
  • R 1 and R 2 are each independently represented by the formula: (Here, Z is hydrogen, amino, halogen, hydroxy, cyano, carbamoyl, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy.) is a group represented by; [wherein A is unsubstituted carbonyl or unsubstituted amino; B is unsubstituted carbonyl or unsubstituted amino; wherein A and B are never the same group at the same time; The position of the substituent: -AB-methylene- is not limited. ] and compounds represented by the formula (I).
  • Another aspect of the present invention is a compound represented by formula (I): [wherein the group: is the formula: (Herein, R 15 is 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 C6-10 heteroaryl; R 16 is optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C6-10 heteroaryl. ) is a group represented by] There is provided a compound of the present invention represented by, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.
  • Another aspect of the present invention is a compound represented by formula (I): [wherein the group: is the formula: (wherein 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 C6-10 heteroaryl; R 17 is optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C6-10 heteroaryl. ) is a group represented by] There is provided a compound of the present invention represented by, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.
  • Another aspect of the present invention is a compound represented by formula (I): [wherein the group: is the formula: (wherein 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 C6-10 heteroaryl.) is a group represented by]
  • 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 C6-10 heteroaryl.
  • 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
  • Another aspect of the present invention is a compound represented by formula (I): [wherein the group: is the formula: (wherein 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 C6-10 heteroaryl.) is a group represented by]
  • 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 C6-10 heteroaryl.
  • 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
  • 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, optionally substituted C6-10 heteroaryl.
  • 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, optionally substituted C6-10 heteroaryl.
  • Another aspect of the present invention is a compound represented by formula (I): [wherein the group: is the formula: (where R is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-6 alkoxy, hydroxy, amino, cyano, carbamoyl or is halogen; R 5 is optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C6-10 heteroaryl, optionally substituted carbonyl, substituted optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted acyl, or optionally substituted thioacyl; n is an integer of 1 or 2. ) is a group represented by] There is provided a compound of the present invention represented by, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.
  • Another aspect of the present invention is a compound represented by formula (I): [wherein the group: is the formula: (where R is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-6 alkoxy, hydroxy, amino, cyano, carbamoyl or is halogen; R 5 is optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C6-10 heteroaryl, optionally substituted carbonyl, substituted optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted acyl, or optionally substituted thioacyl; q is an integer from 1 to 4.
  • a compound of the present invention represented by, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.
  • R is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-6 alkoxy, hydroxy, amino, cyano, carbamoyl or is halogen; R 5 is optionally substituted sulfonyl
  • Specific examples include the compounds of the present invention represented by, enantiomers thereof, or pharmaceutically acceptable salts thereof.
  • R 13 is represented by the formula: (Here, Z is hydrogen, amino, dimethylamino, halogen, hydroxy, cyano, carbamoyl, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy.) is a group represented by; n is an integer from 1 to 5; R7 is the formula: (where X is hydrogen, amino, halogen, hydroxy, methoxy, or optionally substituted C1-4 alkyl) is a group represented by; R 11 is methyl, or the formula: (where each R 14 is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C6-10 heteroaryl, substituted optionally substituted carbonyl, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted acyl, or optionally substituted thioacyl; R 19 is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optional
  • the compounds of the present invention are further described below.
  • the compounds of the present invention have stereoisomers such as tautomers, geometric isomers, and optical isomers depending on the type of substituents, and the present invention includes all of them and mixtures thereof. That is, when one or more asymmetric carbon atoms are present in the compound of the present invention, diastereomers and enantiomers exist, and mixtures of these diastereomers and enantiomers and isolated ones are also included in the present invention. contained in the compound of
  • the present invention includes various hydrates, solvates and crystal polymorphs.
  • the present invention also includes, as another embodiment, prodrugs corresponding to the compounds of the present invention.
  • a prodrug refers to a derivative that is hydrolyzed in vivo by acid hydrolysis or enzymatically to give a compound represented by formula (I).
  • the compound represented by formula (I) has a hydroxy, amino group, or carboxy group, these groups can be modified by conventional methods to produce prodrugs.
  • the technology of prodrugs is described, for example, in C. G. Wermuth, "The Practice of Medicinal Chemistry", 4th Ed., Academic Press, (2015), Chapter 28.
  • compounds having a carboxy group include compounds in which the carboxy is an alkoxycarbonyl group, an alkylthiocarbonyl group, or an alkylaminocarbonyl group.
  • a compound having an amino group a compound in which the amino group is substituted with an alkanoyl group to form an alkanoylamino group, a compound in which an alkoxycarbonyl group is substituted to form an alkoxycarbonylamino group, and an alkanoyloxymethylamino group. or hydroxylamine.
  • the hydroxy is substituted with the alkanoyl group to form an alkanoyloxy group, a phosphoric acid ester, or an alkanoyloxymethyloxy group.
  • the term "pharmaceutically acceptable salt” means acid addition salts and base addition salts that are pharmaceutically acceptable.
  • pharmaceutically acceptable salts include acetate, propionate, butyrate, formate, trifluoroacetate, maleate, fumarate, tartrate, citrate, stearate , succinate, ethyl succinate, malonate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, benzenesulfonic acid, paratoluenesulfonate (tosylate), lauryl Sulfate, Malate, Ascorbate, Mandelate, Saccharinate, Xinafoate, Pamoate, Cinnamate, Adipate, Cysteine, N-Acetylcysteine, Hydrochloride, Hydrogen Bromide acid addition salts such as acid salts, phosphates, sulfates, hydroiodes, nico
  • the compound of the present invention can be produced by the production method described below. These production methods can be appropriately improved based on the knowledge of those skilled in organic synthetic chemistry.
  • the compounds used as starting materials may be salts thereof as long as they do not interfere with the reaction.
  • the object compound can be obtained by protecting the site other than the reaction site as necessary and deprotecting after the reaction is completed or after a series of reactions.
  • Protective groups used in these processes include the literature (Peter G. M. Wuts, "Greene's Protective Groups in Organic Synthesis", 5th Ed., John Wiley & Sons, Inc., Hoboken, New Jersey (2014)), etc. The usual protecting groups described in can be used.
  • introduction and removal of a protecting group can be carried out by methods commonly used in organic synthetic chemistry (eg, methods described in the above literature) or methods based thereon.
  • the starting materials and intermediates in the production method below can be purchased as commercial products, or can be obtained by synthesizing from known compounds according to methods described in known literature or known methods. Moreover, these starting materials and intermediates may be salts thereof as long as they do not interfere with the reaction.
  • the intermediates and target compounds in the production method below can also be converted into other compounds included in the present invention by appropriately converting their functional groups.
  • the transformation of the functional group at that time is a method commonly used in organic synthetic chemistry (for example, R. C. Larock, "Comprehensive Organic Transformations", 2nd Ed., John Wiley and Sons, Inc., New York (1999) described method, etc.) or a method based thereon.
  • the inert solvent in the following production method means a solvent that does not react with raw materials, reagents, bases, acids, catalysts, ligands, etc. used in the reaction (hereinafter sometimes referred to as "raw materials used in the reaction, etc.”). means.
  • raw materials used in the reaction etc.
  • the solvent used in each step reacts with the raw materials used in the reaction, it can be used as an inert solvent as long as the desired reaction proceeds to obtain the desired compound.
  • the compounds of the present invention are represented by heterocycloalkyl-substituted polyheteroazole derivatives. Therefore, the preparation of the compounds of the present invention is based on heteroazole ring-forming reactions on heterocycloalkyl entities.
  • R 1 and R 1 ' are hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, or optionally substituted C6-10 heteroaryl;
  • R 2 and R 2 ' are 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 C6-10 heteroaryl;
  • R 5 is optionally substituted C1-6 alkyl, optionally substituted C6
  • substituents in "optionally substituted” are selected from: hydroxy, halogen, cyano, carbamoyl, amino, amidinoamino, carboxy, C6-10 aryl, C1-4 alkoxycarbonyl-substituted 5- to 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, 5-6 membered heterocycloalkyl, C3-6 cycloalkyl, 5-10 membered heteroaryl, (halogen-substituted C1-6 alkyl) substituted C6-10 aryl, and trialkylsilyloxy, alkylarylsilyloxy, triary
  • the present invention can include the following types as some embodiments of this form.
  • Step 1 of Scheme 1 and Step 3 of Scheme 2 Azole Formation
  • Some embodiments of this aspect can include the following reaction types. Table 2
  • Step 2 of Schemes 1 and 2 Deprotection Step 2 is a deprotection reaction to remove the protecting group P1. This deprotection reaction is well known to those skilled in the art. De-tert-butoxycarbonyl reaction and de-9-fluorenylmethyloxycarbonyl reaction are carried out.
  • Step 3 of Scheme 1 and Step 1 of Scheme 2 Substitution or Addition Step 3 of Scheme 1 and Step 1 of Scheme 2 are substitution ( or addition) reactions to introduce R5.
  • This reaction carries out sulfinylation, sulfonylation, carbonylation, thiocarbonylation, carbamate, acylation, carbonate, or alkylation reactions, which are well known to those skilled in the art.
  • the intermediates and target compounds in the above production method can be isolated by subjecting them to purification methods commonly used in synthetic organic chemistry (e.g., neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography, etc.). It can be isolated and purified. Further, each intermediate can be subjected to the next reaction without particular purification.
  • purification methods commonly used in synthetic organic chemistry e.g., neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography, etc.
  • the optically active form of the compound of the present invention can be produced by using an optically active starting material or intermediate, or by optically resolving the intermediate or final racemic form.
  • Examples of the optical resolution method include, but are not limited to, a separation method using an optically active column, a separation method such as a fractional crystallization method, and the like.
  • Diastereomers of the compounds of the present invention can be produced by, but not limited to, separation methods such as column chromatography and fractional crystallization.
  • compositions of compounds of formula (I) are represented by formula (1) in solvents such as, but not limited to, water, methanol, ethanol, 2-propanol, ethyl acetate, acetone and the like. It can be produced by mixing a compound represented by and a pharmaceutically acceptable acid or base.
  • the compounds of the invention are compounds that have antiviral activity against respiratory syncytial virus.
  • the compounds of the present invention have RS virus growth inhibitory activity and accordingly enable the treatment or prevention of respiratory syncytial virus infection.
  • the present invention provides a pharmaceutical composition, specifically for treating or preventing respiratory syncytial virus infection, containing a compound of the present invention, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition is provided.
  • Respiratory syncytial virus also known as respiratory syncytial virus
  • Respiratory syncytial virus exists all over the world and is a causative virus of respiratory infections that universally repeats epidemics and subsides without regional or climatic bias. Nearly 100% of children are said to be infected by the age of two, and because of the large number of opportunities for infection, it is thought that newborns have a higher mortality rate than influenza.
  • there are no effective therapeutic agents for respiratory syncytial virus causing approximately 30 million cases and approximately 100,000 deaths worldwide each year.
  • advances in diagnostic technology have made it possible to identify respiratory syncytial virus infections with high accuracy, and the development of effective therapeutic agents is an urgent need.
  • treatment means (1) delaying or preventing the onset of a disease or condition; (2) slowing or halting the progression, exacerbation, or deterioration of symptoms of a disease or condition; (3) a disease or condition. or (4) any method or process intended to cure a disease or condition. Treatment may be administered prior to the onset of the disease or condition as a prophylactic measure, or alternatively treatment may be administered after the onset of the disease.
  • prevention means preventing the onset of respiratory syncytial virus infection.
  • a pharmaceutical composition usually means an agent for treatment, treatment or prevention of a disease or pathological condition, or examination/diagnosis.
  • the compound of the present invention can be administered by oral or parenteral administration, either directly or by using an appropriate dosage form to prepare a formulation, medicament or pharmaceutical composition.
  • dosage forms include, but are not limited to, tablets, capsules, powders, granules, solutions, suspensions, injections, patches, poultices and the like.
  • these formulations can be produced by known methods using additives that are commonly used as pharmaceutical additives.
  • additives include excipients, disintegrants, binders, fluidizers, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, and stabilizers, depending on the purpose. , sweeteners, flavors and the like can be used.
  • additives include lactose, mannitol, crystalline cellulose, low-substituted hydroxypropylcellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl Alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc, and the like, but are not limited to these.
  • the dosage of the compound of the present invention is appropriately selected depending on the subject to be administered, administration route, disease, subject's age, body weight and symptoms.
  • the lower limit is 0.01 mg (preferably 100 mg) and the upper limit is 10000 mg (preferably 6000 mg) per day for adults, and this amount is divided once or several times a day.
  • Another aspect of the invention is a method for treating or preventing respiratory syncytial virus infection, comprising a compound of the invention, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, in need of such treatment or the like.
  • methods comprising administering to a subject, preferably comprising administering to such a subject an effective amount of a compound of the invention, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.
  • another aspect of the present invention relates to a compound of the present invention, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, for treating or preventing respiratory syncytial virus infection.
  • Yet another aspect of the present invention relates to the use of a compound of the present invention, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing respiratory syncytial virus infection.
  • Example 1 3-(3-Phenylpropyl)-5-[(2S)-1-tert-butoxycarbonylpyrrolidin-2-yl]-1,2,4-oxadiazole 1-1
  • Example 1-1 N'-hydroxy-4-phenylbutanimidamide 4-Phenylbutyronitrile (500 mg, 3.44 mmol) and 50% aqueous hydroxylamine solution (2.03 ml, 34.4 mmol) were added to an eggplant-shaped 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 a vacuum to obtain the title compound (oil, 614 mg, yield: 100%).
  • Example 1-2 3-(3-phenylpropyl)-5-[(2S)-1-tert-butoxycarbonylpyrrolidin-2-yl]-1,2,4-oxadiazole 1-1
  • N-Boc-L-proline 100 mg, 0.465 mmol
  • dichloromethane 3.15 ml
  • HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate
  • diisopropyl Ethylamine 0.162 ml, 0.929 mmol
  • N'-hydroxy-4-phenylbutanimidamide 99 mg, 0.557 mmol
  • dichloromethane 1.5 ml
  • Example 2 3-(3-Phenylpropyl)-5-[(2S)-1-isobutylsulfonylpyrrolidin-2-yl]-1,2,4-oxadiazole 1A
  • Example 2-1 3-(3-phenylpropyl)-5-[(2S)-pyrrolidin-2-yl]-1,2,4-oxadiazole TFA salt 1-2
  • Compound 1-1 (115 mg, 0.324 mmol) prepared in Example 1 was added to a 10 ml eggplant-shaped flask, dichloromethane (0.85 ml) and TFA (0.15 ml) were added, and the mixture was stirred at room temperature for 1 hour.
  • Example 2-2 3-(3-phenylpropyl)-5-[(2S)-pyrrolidin-2-yl]-1,2,4-oxadiazole 1-2
  • Compound 1-1 (323 mg, 0.903 mmol) prepared in Example 1 was added to a 25 ml eggplant-shaped flask, dichloromethane (2.37 ml) and TFA (0.418 ml) were added, and the mixture was stirred at room temperature for 1 hour. Then, after removing the stirrer bar and distilling off the solvent, the reaction mixture was made basic by adding saturated aqueous sodium hydrogencarbonate solution (5 ml), and then extracted with ethyl acetate.
  • Example 2-3 3-(3-phenylpropyl)-5-[(2S)-1-isobutylsulfonylpyrrolidin-2-yl]-1,2,4-oxadiazole 1A
  • TFA salt of compound 1-2 22 mg, 0.059 mmol
  • Example 2-1 was added to a 10 ml eggplant-shaped flask, super-dehydrated THF (0.916 ml), triethylamine (0.051 ml, 0.366 mmol), DMAP (2.2 mg, 0.018 mmol) was sequentially added, and after cooling to 0°C, isobutylsulfonyl chloride (0.0185 ml, 0.137 mmol) was added and stirred at 0°C for 1 hour.
  • Example 3 3-(3-phenylpropyl)-5-[(2S)-1-cyclohexylsulfonylpyrrolidin-2-yl]-1,2,4-oxadiazole 1B
  • Compound 1-2 (16.5 mg, 0.064 mmol) prepared in Example 2-2 was added to a 10 ml eggplant-shaped flask, and CH 2 Cl 2 (0.916 ml), pyridine (20.7 ⁇ l, 0.256 mmol), cyclohexanesulfonyl Chloride (20.7 ⁇ l, 0.128 mmol) and DMAP (2.4 mg, 19 ⁇ mol) were sequentially added, and the mixture was stirred at 50°C for 4.5 hours.
  • Example 6 3-(3-phenylpropyl)-5-[(2S)-1-benzenesulfonylpyrrolidin-2-yl]-1,2,4-oxadiazole 1D
  • Compound 1-2 (18.3 mg, 0.071 mmol) prepared in Example 2-2 was added to a 10 ml eggplant-shaped flask, and CH 2 Cl 2 (1.42 ml), pyridine (23 ⁇ l, 0.284 mmol), benzenesulfonyl Chloride (18.4 ⁇ l, 0.142 mmol) and DMAP (2.6 mg, 21 ⁇ mol) were sequentially added, and the mixture was stirred at room temperature for 1 hour.
  • Example 7 3-(3-Phenylpropyl)-5-[(2S)-1-benzylsulfonylpyrrolidin-2-yl]-1,2,4-oxadiazole 1E
  • TFA salt of compound 1-2 (20 mg, 0.055 mmol) prepared in Example 2-1 was added to a 4 ml vial bottle, and superdehydrated THF (1.1 ml), triethylamine (68.9 ⁇ l, 0.497 mmol) and DMAP were added. (2.7 mg, 22 ⁇ mol) were sequentially added, and finally benzylsulfonyl chloride (32.5 mg, 0.166 mmol) was added and stirred at room temperature for 1.5 hours.
  • the compounds prepared in Examples 1-7 are shown in Table 3 together with their physical data.
  • Example 8 3-(3-Phenylpropyl)-5-[(2S)-1-tert-butoxycarbonylpiperidin-2-yl]-1,2,4-oxadiazole 2-1
  • N-Boc-L-pipecolic acid 100 mg, 0.436 mmol
  • HATU 199 mg, 0.523 mmol
  • diisopropylethylamine (0.113 ml, 0.872 mmol) were added, and the mixture was stirred at room temperature for 10 minutes under nitrogen atmosphere.
  • N'-hydroxy-4-phenylbutanimidamide 93.3 mg, 0.523 mmol was added while washing with dichloromethane (1.0 ml) and stirred at room temperature for 3 hours.
  • Example 9 3-(3-Phenylpropyl)-5-[(2S)-1-isobutylsulfonylpiperidin-2-yl]-1,2,4-oxadiazole 2A
  • Example 9-1 3-(3-phenylpropyl)-5-[(2S)-piperidin-2-yl]-1,2,4-oxadiazole TFA salt 2-2
  • Compound 2-1 (20.4 mg, 0.057 mmol) prepared in Example 8 was added to a 10 ml eggplant-shaped flask, dichloromethane (0.48 ml) and TFA (0.080 ml) were added, and the mixture was stirred at room temperature for 1 hour.
  • Example 9-2 3-(3-phenylpropyl)-5-[(2S)-piperidin-2-yl]-1,2,4-oxadiazole 2-2
  • Compound 2-1 224.8 mg, 0.605 mmol
  • dichloromethane (1.59 ml)
  • TFA 0.280 ml
  • the mixture was stirred at room temperature for 1 hour.
  • the mixture was made basic by adding a saturated aqueous sodium hydrogencarbonate solution (5 ml), and then extracted with ethyl acetate.
  • Example 9-3 3-(3-phenylpropyl)-5-[(2S)-1-isobutylsulfonylpiperidin-2-yl]-1,2,4-oxadiazole 2A
  • TFA salt of compound 2-2 22 mg, 0.057 mmol
  • Example 9-1 was added to a 10 ml eggplant-shaped flask, super-dehydrated THF (0.732 ml), triethylamine (45.7 ⁇ l, 0.329 mmol), DMAP (1.3 mg, 0.011 mmol) was sequentially added, and after cooling to 0°C, isobutylsulfonyl chloride (14.8 ⁇ l, 0.110 mmol) was added, and the mixture was stirred at 0°C for 30 minutes and then at room temperature for 1 hour.
  • Example 10 3-(3-phenylpropyl)-5-[(2S)-1-cyclohexylsulfonylpiperidin-2-yl]-1,2,4-oxadiazole 2B
  • Compound 2-2 25 mg, 0.092 mmol
  • CH 2 Cl 2 0.3 ml
  • pyridine 29.7 ⁇ l, 0.369 mmol
  • the mixture was ice-cooled to 20°C, washed with CH 2 Cl 2 (0.6 ml), added with cyclohexanesulfonyl chloride (35.4 mg, 0.184 mmol), and stirred at room temperature for 65.5 hours.
  • Example 11 3-(3-Phenylpropyl)-5-[(2S)-1-methanesulfonylpiperidin-2-yl]-1,2,4-oxadiazole 2C TFA salt of compound 2-2 (21 mg, 0.055 mmol) prepared in Example 9-1 was added to a 4 ml vial bottle, super-dehydrated THF (1.09 ml), triethylamine (68.0 ⁇ l, 0.490 mmol), and DMAP. (2.7 mg, 22 ⁇ mol) were sequentially added, and finally methanesulfonyl chloride (12.8 ⁇ l, 0.163 mmol) was added and stirred at room temperature for 1 hour.
  • Example 12 3-(3-phenylpropyl)-5-[(2S)-1-benzenesulfonylpiperidin-2-yl]-1,2,4-oxadiazole 2D
  • Compound 2-2 (20.3 mg, 0.075 mmol) prepared in Example 9-2 was added to a 4 ml vial bottle, and super-dehydrated THF (0.997 ml), triethylamine (0.187 ml, 1.347 mmol), DMAP (4.6 mg , 37 ⁇ mol) were added sequentially, and finally benzenesulfonyl chloride (29 ⁇ l, 0.224 mmol) was added and stirred at 40° C. for 3.5 hours.
  • Example 13 3-(3-Phenylpropyl)-5-[(2S)-1-benzylsulfonylpiperidin-2-yl]-1,2,4-oxadiazole 2E TFA salt of compound 2-2 (21 mg, 0.055 mmol) prepared in Example 9-1 was added to a 4 ml vial bottle, super-dehydrated THF (1.09 ml), triethylamine (68.0 ⁇ l, 0.490 mmol), DMAP (2.7 mg, 22 ⁇ mol) were sequentially added, and finally benzylsulfonyl chloride (32.1 mg, 0.163 mmol) was added and stirred at room temperature for 1 hour.
  • the compounds prepared in Examples 8-13 are shown in Table 4 along with their physical data.
  • Example 14 3-(3-Phenylpropyl)-5-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxypyrrolidin-2-yl]-1,2,4-oxadiazole 3-1 N-Boc-(2S,4R)-4-hydroxyproline (500 mg, 2.163 mmol) and N'-hydroxy-4-phenylbutanimidamide (463 mg, 2.595 mmol) were added to a 50 ml eggplant-shaped flask in dichloromethane ( 10.8 ml) was added while washing.
  • Example 15 3-(3-phenylpropyl)-5-[(2S,4R)-4-hydroxy-1-isobutylsulfonylpyrrolidin-2-yl]-1,2,4-oxadiazole 3A
  • Example 15-1 3-(3-phenylpropyl)-5-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-1,2,4-oxadiazole 3-2
  • Compound 3-1 (270 mg, 0.723 mmol) prepared in Example 14 was added to a 25 ml eggplant-shaped flask, dichloromethane (1.90 ml), TFA (0.670 ml) and water (33.5 ⁇ l) were added, and the mixture was stirred at room temperature for 5.5 Stirred for hours.
  • Example 15-2 3-(3-phenylpropyl)-5-[(2S,4R)-4-hydroxy-1-isobutylsulfonylpyrrolidin-2-yl]-1,2,4-oxadiazole 3A
  • Compound 3-2 (15.2 mg, 0.056 mmol) prepared in Example 15-1 was added to a 10 ml eggplant-shaped flask, dichloromethane (0.556 ml) and triethylamine (18.5 ⁇ l, 0.133 mmol) were added, and the mixture was heated to 0°C. After cooling, isobutylsulfonyl chloride (8.8 ⁇ l, 0.067 mmol) was added and stirred at room temperature for 5.5 hours.
  • Example 16 3-(3-phenylpropyl)-5-[(2S,4R)-1-cyclohexylsulfonyl-4-hydroxypyrrolidin-2-yl]-1,2,4-oxadiazole 3B
  • Compound 3-2 (18.2 mg, 0.067 mmol) prepared in Example 15-1 was added to a 10 ml eggplant-shaped flask, CH 2 Cl 2 (0.666 ml) and pyridine (12.9 ⁇ l, 0.160 mmol) were added, After cooling to 0° C., cyclohexanesulfonyl chloride (15.4 mg, 0.080 mmol) was added and stirred at room temperature for 22.5 hours.
  • Example 17 3-(3-phenylpropyl)-5-[(2S,4R)-4-hydroxy-1-methanesulfonylpyrrolidin-2-yl]-1,2,4-oxadiazole 3C
  • Compound 3-2 (15.6 mg, 0.057 mmol) prepared in Example 15-1 was added to a 10 ml eggplant-shaped flask, CH 2 Cl 2 (0.571 ml) and pyridine (11.1 ⁇ l, 0.137 mmol) were added, After cooling to 0° C., methanesulfonyl chloride (5.35 ⁇ l, 0.068 mmol) was added and stirred at room temperature for 2.5 hours.
  • Example 18 3-(3-phenylpropyl)-5-[(2S,4R)-1-benzenesulfonyl-4-hydroxypyrrolidin-2-yl]-1,2,4-oxadiazole 3D
  • Compound 3-2 (16.5 mg, 0.060 mmol) prepared in Example 15-1 was added to a 10 ml eggplant-shaped flask, CH 2 Cl 2 (0.604 ml) and triethylamine (18.4 ⁇ l, 0.133 mmol) were added, After cooling to 0° C., benzenesulfonyl chloride (8.58 ⁇ l, 0.066 mmol) was added and stirred at room temperature for 1.5 hours.
  • Example 19 3-(3-phenylpropyl)-5-[(2S,4R)-1-benzylsulfonyl-4-hydroxypyrrolidin-2-yl]-1,2,4-oxadiazole 3E
  • Compound 3-2 (15.3 mg, 0.056 mmol) prepared in Example 15-1 was added to a 10 ml eggplant-shaped flask, CH 2 Cl 2 (0.560 ml) and triethylamine (17.1 ⁇ l, 0.123 mmol) were added, After cooling to 0° C., benzylsulfonyl chloride (12.1 mg, 0.062 mmol) was added and stirred at room temperature for 3.5 hours.
  • the compounds prepared in Examples 14-19 are shown in Table 5 along with their physical data.
  • Example 20 3-(3-Phenylpropyl)-5-[(2S,4R)-4-tert-butoxy-1-cyclohexylsulfonyl-pyrrolidin-2-yl]-1,2,4-oxadiazole 4B
  • Example 20-1 3-(3-phenylpropyl)-5-[(2S,4R)-1-[(9H-fluoren-9-yl)methoxycarbonyl]-4-tert-butoxypyrrolidin-2-yl ]-1,2,4-oxadiazole 4-1
  • N-Fmoc-4-trans-1-butoxy-L-proline (1000 mg, 2.442 mmol) and N'-hydroxy-4-phenylbutanimidamide (479 mg, 2.686 mmol) were added to a 50 ml eggplant-shaped flask in dichloromethane ( 12.2 ml) was added while washing.
  • pre-dried MS4 ⁇ (5.16 g) was added and dissolved in ultra-dehydrated toluene (10.66 ml).
  • a Dimroth condenser was attached, and the mixture was stirred at 110°C for 15.5 hours.
  • Example 20-2 3-(3-phenylpropyl)-5-[(2S,4R)-4-tert-butoxypyrrolidin-2-yl]-1,2,4-oxadiazole 4-2
  • Compound 4-1 (852 mg, 1.544 mmol) prepared in Example 20-1 was added to a 25 ml eggplant-shaped flask, and dichloromethane (7.72 ml) and piperidine (0.787 ml, 7.72 mmol) were added. Stirred for hours.
  • Example 20-3 3-(3-phenylpropyl)-5-[(2S,4R)-4-tert-butoxy-1-cyclohexylsulfonyl-pyrrolidin-2-yl]-1,2,4-oxazide Azole 4B
  • Compound 4-2 (38.5 mg, 0.141 mmol), CH 2 Cl 2 (1.41 ml), and pyridine (45.5 ⁇ l, 0.563 mmol) prepared in Example 20-2 were added to a 10 ml eggplant-shaped flask, and the mixture was heated to 0°C.
  • Examples 21 and 22 3-(3-Phenylpropyl)-5-[(2S,4R)-4-tert-butoxy-1-(6-carbamoyl-2-naphthyl)-pyrrolidin-2-yl]-1,2,4-oxa diazole 4-3, and naphthalene-2,6-diylbis(((2S,4R)-4-(tert-butoxy)-2-(3-(3-phenylpropyl)-1,2,4-oxazide
  • Azoll-5-yl)pyrrolidin-1-yl)methanone) 4-4 Naphthoyl dichloride prepared from 2,6-naphthalene dicarboxylic acid and oxalyl chloride was separately added to a 10 ml eggplant-shaped flask to which Compound 4-2 (10 mg, 0.030 mmol) prepared in Example 20-2 was added.
  • Example 23 3-(3-phenylpropyl)-5-[(2S,4R)-4-hydroxy-1-(6-carbamoyl-2-naphthyl)-pyrrolidin-2-yl]-1,2,4-oxadiazole 4-5
  • Compound 4-3 (3.7 mg, 7.0 ⁇ mol) prepared in Example 21 was added to a 4 ml vial bottle, dichloromethane (0.14 ml), TFA (70 ⁇ l) and water (3.5 ⁇ l) were added, and the mixture was stirred at room temperature for 2.5 ⁇ l. Stirred for hours. After distilling off the solvent, the procedure of dissolving in chloroform (1 ml) and distilling off was repeated three times to remove TFA. After that, it was vacuum-dried for 20 hours to obtain 3.4 mg (7.0 ⁇ mol, 100%) of the target compound 4-5 (amorphous solid).
  • Example 24 Naphthalene-2,6-diylbis(((2S,4R)-4-hydroxy-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl) ) methane) 4-6
  • Compound 4-4 (4.7 mg, 5.6 ⁇ mol) prepared in Example 22 was added to a 4 ml vial bottle, dichloromethane (0.14 ml), TFA (70 ⁇ l) and water (3.5 ⁇ l) were added, and the mixture was stirred at room temperature for 2.5 ⁇ l. Stirred for hours. After distilling off the solvent, the procedure of dissolving in chloroform (1 ml) and distilling off was repeated three times to remove TFA. After that, it was vacuum-dried for 20 hours to obtain 4.2 mg (5.6 ⁇ mol, 100%) of the target compound 4-6 (amorphous solid).
  • the compounds prepared in Examples 20-24 are shown in Table 6 along with their physical data.
  • Example 25 3-(3-Phenylpropyl)-5- ⁇ (6S)-5-isobutylsulfonyl-5-azaspiro[2.4]hept-6-yl ⁇ -1,2,4-oxadiazole 5A
  • Example 25-1 3-(3-phenylpropyl)-5- ⁇ (6S)-5-tert-butoxycarbonyl-5-azaspiro[2.4]hept-6-yl ⁇ -1,2,4-oxazi Azole 5-1
  • (6S)-5-(tert-Butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid 241.3 mg, 1.0 mmol
  • dichloromethane 7.0 ml
  • HATU 456.3 mg, 1.2 mmol
  • diisopropylethylamine (0.34 ml, 2.0 mmol) were added, and the mixture was stirred at room temperature for 10 minutes under nitrogen atmosphere.
  • N'-hydroxy-4-phenylbutanimidamide 213.9 mg, 1.2 mmol was added while washing with dichloromethane (3.0 ml), and the mixture was stirred at room temperature for 3.5 hours.
  • the stirrer bar was removed and dichloromethane (20.0 ml) and 5% aqueous sodium bicarbonate solution (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 distilled off to obtain a mixture of imidamide and urea compound (686.0 mg) as an intermediate.
  • the mixture (686.0 mg) was dissolved in toluene (18.0 ml) in a 25 ml eggplant-shaped flask.
  • the 25-ml eggplant-shaped flask was set in a Dean-Stark trap and heated under reflux at an oil bath temperature of 130°C for 16 hours. did.
  • Example 25-2 3-(3-phenylpropyl)-5- ⁇ (6S)-5-azaspiro[2.4]hept-6-yl ⁇ -1,2,4-oxadiazole TFA salt 5-2
  • Compound 5-1 (40.0 mg, 0.104 mmol) prepared in Example 25-1 was added to a 4.0 ml screw tube vial, dichloromethane (1.0 ml) and TFA (0.16 ml) were added, and the mixture was stirred at room temperature for 1 hour. . Thereafter, the stirrer bar was removed, and after distilling off the solvent, the mixture was dissolved in chloroform (2 ml) and distilled under reduced pressure. The operation was repeated three times to remove TFA. After that, it was vacuum-dried for 3 hours to obtain 41.5 mg (0.104 mmol, 100%) of the target compound 5-2 (amorphous solid) as a TFA salt.
  • Example 25-3 3-(3-Phenylpropyl)-5- ⁇ (6S)-5-isobutylsulfonyl-5-azaspiro[2.4]hept-6-yl ⁇ -1,2,4-oxadiazole 5A
  • Superdehydrated THF 1.5 ml
  • triethylamine 0.073 ml, 0.522 mmol
  • DMAP 3.8 mg, 0.031 mmol
  • a solution of isobutylsulfonyl chloride 0.027 ml, 0.137 mmol
  • superdehydrated THF 0.5 ml
  • Example 27 3-(3-Phenylpropyl)-5- ⁇ (6S)-5-methanesulfonyl-5-azaspiro[2.4]hept-6-yl ⁇ -1,2,4-oxadiazole 5C
  • Superdehydrated THF 1.5 ml
  • triethylamine 0.073 ml, 0.522 mmol
  • DMAP 3.8 mg, 0.031 mmol
  • a solution of methanesulfonyl chloride 0.016 ml, 0.209 mmol
  • superdehydrated THF 0.5 ml
  • Example 30 3-(3-phenylpropyl)-5- ⁇ (6S)-5-benzylsulfonyl-5-azaspiro[2.4]hept-6-yl ⁇ -1,2,4-oxadiazole 5E
  • Superdehydrated THF 1.5 ml
  • triethylamine 0.073 ml, 0.522 mmol
  • DMAP 3.8 mg, 0.031 mmol
  • a solution of benzylsulfonyl chloride 39.8 mg, 0.209 mmol
  • superdehydrated THF 0.5 ml
  • the compounds prepared in Examples 25-30 are shown in Table 7-1 along with their physical data.
  • Example 31 3-(3-Phenylpropyl)-5-(1-isobutylsulfonyl-4-cyclobutylmethylpyrrolidin-2-yl)-1,2,4-oxadiazole 6A
  • Example 31-1 3-(3-phenylpropyl)-5-(1-tert-butoxycarbonyl-4-cyclobutylmethylpyrrolidin-2-yl)-1,2,4-oxadiazole 6-1 (rac-(2S,4S)-1-[(tert-butoxy)carbonyl]-4-(cyclobutylmethyl)pyrrolidine-2-carboxylic acid (283.4 mg, 1.0 mmol) was added to a 25 ml eggplant-shaped flask, and dichloromethane was added.
  • the stirrer bar was removed and dichloromethane (20.0 ml) and 5% aqueous sodium bicarbonate solution (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 distilled off to obtain a mixture of imidamide and urea compound (740.0 mg) as an intermediate.
  • the mixture (740.0 mg) was dissolved in toluene (18.0 ml) in a 25 ml eggplant-shaped flask.
  • the 25-ml eggplant-shaped flask was set in a Dean-Stark trap and heated under reflux at an oil bath temperature of 130°C for 16 hours.
  • Example 31-2 3-(3-phenylpropyl)-5-(4-cyclobutylmethylpyrrolidin-2-yl)-1,2,4-oxadiazole 6-2
  • Compound 6-1 241.7 mg, 0.568 mmol
  • dichloromethane 6.0 ml
  • TFA 0.70 ml
  • Example 31-3 3-(3-Phenylpropyl)-5-(1-isobutylsulfonyl-4-cyclobutylmethylpyrrolidin-2-yl)-1,2,4-oxadiazole 6A
  • Superdehydrated THF 1.5 ml
  • triethylamine 0.032 ml, 0.227 mmol
  • DMAP 2.8 mg , 0.023 mmol
  • a solution of isobutylsulfonyl chloride 0.020 ml, 0.151 mmol
  • was added was stirred at 0° C. for 1 hour and at room temperature for 1 hour.
  • the compounds prepared in Examples 31-35 are shown in Table 8-1 along with their physical data.
  • Example 36 3-(3-Phenylpropyl)-5-[(2S,4S)-1-isobutylsulfonyl-4-phenylpyrrolidin-2-yl]-1,2,4-oxadiazole 7A
  • Example 36-1 3-(3-phenylpropyl)-5-[(2S,4S)-1-tert-butoxycarbonyl-4-phenylpyrrolidin-2-yl]-1,2,4-oxadiazole 7-1 (2S,4S)-1-(tert-butoxycarbonyl)-4-phenylpyrrolidine-2-carboxylic acid (291.3 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
  • diisopropylethylamine (0.34 ml, 2.0 mmol) were added, and the mixture was stirred at room temperature for 10 minutes under nitrogen atmosphere.
  • N'-hydroxy-4-phenylbutanimidamide 213.9 mg, 1.2 mmol was added while washing with dichloromethane (3.0 ml), and the mixture was stirred at room temperature for 3.5 hours.
  • the stirrer bar was removed and dichloromethane (20.0 ml) and 5% aqueous sodium bicarbonate solution (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 distilled off to obtain a mixture of imidamide and urea compound (740.0 mg) as an intermediate.
  • the mixture (740.0 mg) was dissolved in toluene (18.0 ml) in a 25 ml eggplant-shaped flask.
  • the 25-ml eggplant-shaped flask was set in a Dean-Stark trap and heated under reflux at an oil bath temperature of 130°C for 16 hours.
  • Example 36-2 3-(3-Phenylpropyl)-5-[(2S,4S)-4-phenylpyrrolidin-2-yl]-1,2,4-oxadiazole 7-2
  • Compound 7-1 (370.1 mg, 0.854 mmol) prepared in Example 36-1 was added to a 25 ml eggplant-shaped flask, dichloromethane (8.7 ml) and TFA (1.306 ml) were added, and the mixture was stirred at room temperature for 1 hour. . After removing the stir bar and evaporating the solvent, the mixture was dissolved in chloroform (10 ml) and evaporated under reduced pressure three times to remove TFA.
  • Example 36-3 3-(3-Phenylpropyl)-5-[(2S,4S)-1-isobutylsulfonyl-4-phenylpyrrolidin-2-yl]-1,2,4-oxadiazole 7A
  • THF 1.75 ml
  • triethylamine 0.042 ml, 0.30 mmol
  • DMAP 3.7 mg , 0.030 mmol
  • a solution of isobutylsulfonyl chloride 0.027 ml, 0.20 mmol
  • superdehydrated THF (0.25 ml) was added, and the mixture was stirred at 0° C.
  • Example 38 3-(3-Phenylpropyl)-5-[(2S,4S)-1-methanesulfonyl-4-phenylpyrrolidin-2-yl]-1,2,4-oxadiazole 7C
  • THF 1.75 ml
  • triethylamine 0.042 ml, 0.30 mmol
  • DMAP 3.7 mg , 0.030 mmol
  • a solution of methanesulfonyl chloride 0.016 ml, 0.20 mmol
  • superdehydrated THF (0.25 ml) was added, and the mixture was stirred at 0° C. for 1 hour and at room temperature for 1 hour.
  • the compounds prepared in Examples 36-40 are shown in Table 9-1 along with their physical data.
  • Example 41 3-(3-Phenylpropyl)-5-[(2S,4R)-1-isobutylsulfonyl-4-fluoropyrrolidin-2-yl]-1,2,4-oxadiazole 8A
  • Example 41-1 3-(3-phenylpropyl)-5-[(2S,4R)-1-tert-butoxycarbonyl-4-fluoropyrrolidin-2-yl]-1,2,4-oxadiazole 8-1 (2S,4R)-1-(tert-Butoxycarbonyl)-4-fluoro-2-pyrrolidinecarboxylic acid (233.2 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
  • diisopropylethylamine (0.34 ml, 2.0 mmol) were added, and the mixture was stirred at room temperature for 10 minutes under nitrogen atmosphere.
  • N'-hydroxy-4-phenylbutanimidamide 213.9 mg, 1.2 mmol was added while washing with dichloromethane (3.0 ml), and the mixture was stirred at room temperature for 3.5 hours.
  • the stirrer bar was removed and dichloromethane (20.0 ml) and 5% aqueous sodium bicarbonate solution (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 distilled off to obtain a mixture of imidamide and urea compound (740.0 mg) as an intermediate.
  • the mixture (740.0 mg) was dissolved in toluene (18.0 ml) in a 25 ml eggplant-shaped flask.
  • the 25-ml eggplant-shaped flask was set in a Dean-Stark trap and heated under reflux at an oil bath temperature of 130°C for 16 hours.
  • Example 41-2 3-(3-phenylpropyl)-5-[(2S,4R)-4-fluoropyrrolidin-2-yl]-1,2,4-oxadiazole 8-2
  • Compound 8-1 (304.3 mg, 0.81 mmol) prepared in Example 41-1 was added to a 25 ml eggplant-shaped flask, dichloromethane (8.3 ml) and TFA (1.24 ml, 16.2 mmol) were added, and the mixture was stirred at room temperature for 1 Stirred for hours. After removing the stir bar and evaporating the solvent, the mixture was dissolved in chloroform (10 ml) and evaporated under reduced pressure three times to remove TFA.
  • Example 41-3 3-(3-Phenylpropyl)-5-[(2S,4R)-1-isobutylsulfonyl-4-fluoropyrrolidin-2-yl]-1,2,4-oxadiazole 8A
  • Superdehydrated THF (1.75 ml) triethylamine (0.042 ml, 0.30 mmol), DMAP (3.7 mg , 0.030 mmol) were sequentially added, and after cooling to 0° C., a solution of isobutylsulfonyl chloride (0.027 ml, 0.20 mmol) in superdehydrated THF (0.25 ml) was added, and the mixture was stirred at 0° C.
  • Example 42 3-(3-Phenylpropyl)-5-[(2S,4R)-1-methanesulfonyl-4-fluoropyrrolidin-2-yl]-1,2,4-oxadiazole 8C
  • THF 1.75 ml
  • triethylamine 0.042 ml, 0.30 mmol
  • DMAP 3.7 mg , 0.030 mmol
  • a solution of methanesulfonyl chloride 0.016 ml, 0.20 mmol
  • superdehydrated THF (0.25 ml) was added, and the mixture was stirred at 0° C. for 1 hour and at room temperature for 1 hour.
  • Example 44 3-(3-Phenylpropyl)-5-[(2S,4R)-1-benzylsulfonyl-4-fluoropyrrolidin-2-yl]-1,2,4-oxadiazole 8E
  • Superdehydrated THF (1.75 ml) triethylamine (0.042 ml, 0.30 mmol), DMAP (3.7 mg , 0.030 mmol) were sequentially added, and after cooling to 0°C, a solution of benzylsulfonyl chloride (38.2 mg, 0.20 mmol) in superdehydrated THF (0.25 ml) was added, and the mixture was stirred at 0°C for 1 hour and at room temperature for 1 hour.
  • the compounds prepared in Examples 41-44 are shown in Table 10-1 together with their physical data.
  • Example 45 3-(2-Phenylethyl)-5-[(2S)-1-tert-butoxycarbonylpyrrolidin-2-yl]-1,2,4-oxadiazole 9-1
  • Example 45-1 N'-Hydroxy-3-phenylpropaneimidamide 3-Phenylpropionitrile (526 mg, 4.01 mmol) and 50% aqueous hydroxylamine solution (2.36 ml, 40.1 mmol) were added to an eggplant-shaped 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 a vacuum to obtain the title compound (oil, 657 mg, yield: 100%).
  • Example 45-2 3-(2-phenylethyl)-5-[(2S)-1-tert-butoxycarbonylpyrrolidin-2-yl]-1,2,4-oxadiazole 9-1
  • N-Boc-L-proline 100 mg, 0.465 mmol
  • HATU 212 mg, 0.558 mmol
  • diisopropylethylamine 0.162 ml, 0.929 mmol
  • Example 46 3-(2-Phenylethyl)-5-[(2S)-1-isobutylsulfonylpyrrolidin-2-yl]-1,2,4-oxadiazole 9A
  • Example 46-1 3-(2-phenylethyl)-5-[(2S)-pyrrolidin-2-yl]-1,2,4-oxadiazole TFA salt 9-2
  • Compound 9-1 (20.6 mg, 0.060 mmol) prepared in Example 45 was added to a 10 ml eggplant-shaped flask, dichloromethane (0.480 ml) and TFA (0.080 ml) were added, and the mixture was stirred at room temperature for 1 hour.
  • Example 46-2 3-(2-Phenylethyl)-5-[(2S)-1-isobutylsulfonylpyrrolidin-2-yl]-1,2,4-oxadiazole 9A TFA salt of 9-2 (21 mg, 0.060 mmol) was added to a 10 ml eggplant-shaped flask, and super-dehydrated THF (0.60 ml), triethylamine (0.048 ml, 0.349 mmol), and DMAP (1.4 mg, 1.2 ⁇ mol) were added sequentially. After cooling to 0° C., isobutylsulfonyl chloride (9.4 ⁇ l, 0.070 mmol) was added, and the mixture was stirred at 0° C.
  • the compounds prepared in Examples 45-46 are shown in Table 11 along with their physical data.
  • Example 48 3-(2-Phenylethyl)-5-[(2S)-1-isobutylsulfonylpiperidin-2-yl]-1,2,4-oxadiazole 10A
  • Example 48-1 3-(2-phenylethyl)-5-[(2S)-piperidin-2-yl]-1,2,4-oxadiazole TFA salt 10-2
  • Compound 10-1 (20.4 mg, 0.057 mmol) prepared in Example 47 was added to a 10 ml eggplant-shaped flask, dichloromethane (0.480 ml) and TFA (0.080 ml) were added, and the mixture was stirred at room temperature for 1 hour.
  • the mixture was dissolved in chloroform (1 ml) and evaporated to remove TFA three times. After that, it was vacuum-dried for 2 hours to obtain 21 mg (0.057 mmol, 100%) of the target compound 10-2 (amorphous solid) as a TFA salt.
  • Example 48-2 3-(2-phenylethyl)-5-[(2S)-1-isobutylsulfonylpiperidin-2-yl]-1,2,4-oxadiazole 10A
  • TFA salt of 10-2 (21 mg, 0.057 mmol) prepared in Example 48-1 was added to a 10 ml eggplant-shaped flask, and super-dehydrated THF (0.885 ml), triethylamine (0.049 ml, 0.354 mmol) and DMAP were added.
  • the compounds prepared in Examples 47-48 are shown in Table 12 along with their physical data.
  • Example 49 3-[(1-naphthoylamino)methyl]-5-[(2S)-1-isobutylsulfonylpyrrolidin-2-yl]-1,2,4-oxadiazole 11A
  • Example 49-1 3-[(tert-butoxycarbonylamino)methyl]-5- ⁇ (2S)-1-[(9H-fluoren-9-yl)methoxycarbonyl]pyrrolidin-2-yl ⁇ -1, 2,4-Oxadiazole 11-1
  • N-Fmoc-L-proline 200 mg, 0.593 mmol
  • HATU (271 mg, 0.711 mmol) and diisopropylethylamine (0.207 ml, 1.19 mmol) were added, and the mixture was stirred at room temperature for 10 minutes under nitrogen atmosphere.
  • tert-butyl(N-hydroxycarbamimidoylmethyl)carbamate (129 mg, 0.652 mmol) was added while washing with dichloromethane (1 ml), and the mixture was stirred at room temperature for 1.5 hours.
  • molecular sieves 4 ⁇ 1.5 g
  • ultra-dehydrated toluene (5.93 ml) were added, and the mixture was stirred at 110°C for 16 hours.
  • Example 49-2 3-[(1-naphthoylamino)methyl]-5- ⁇ (2S)-1-[(9H-fluoren-9-yl)methoxycarbonyl]pyrrolidin-2-yl ⁇ -1, 2,4-Oxadiazole 11-2
  • Compound 11-1 39.7 mg, 0.081 mmol
  • Example 49-1 was added to a 10 ml eggplant-shaped flask, dichloromethane (0.81 ml) and TFA (0.12 ml) were added, and the mixture was stirred at room temperature for 1 hour and 10 minutes. Stirred.
  • Example 49-3 3-[(1-naphthoylamino)methyl]-5-[(2S)-1-(pyrrolidin-2-yl)]-1,2,4-oxadiazole 11-3
  • Compound 11-2 (23.7 mg, 0.044 mmol) prepared in Example 49-2 was added to a 10 ml eggplant-shaped flask, dichloromethane (0.58 ml) and piperidine (35.5 ⁇ l, 0.348 mmol) were added, and the mixture was stirred at room temperature for 8 hours. Stirred for hours.
  • Example 49-4 3-[(1-naphthoylamino)methyl]-5-[(2S)-1-isobutylsulfonylpyrrolidin-2-yl]-1,2,4-oxadiazole 11A
  • Compound 11-3 (6.2 mg, 0.019 mmol) prepared in Example 49-3 was added to a 10 ml eggplant-shaped flask, and superdehydrated THF (0.641 ml), triethylamine (26.7 ⁇ l, 0.192 mmol), DMAP (0.94 mg, 0.008 mmol) were added sequentially, and finally isobutylsulfonyl chloride (12.9 ⁇ l, 0.096 mmol) was added and stirred at room temperature for 1 hour.
  • Example 50 3-[(1-naphthoylamino)methyl]-5-[(2S)-1-cyclohexylsulfonylpyrrolidin-2-yl]-1,2,4-oxadiazole 11B
  • Compound 11-3 (5.7 mg, 0.018 mmol) prepared in Example 49-3 was added to a 10 ml eggplant-shaped flask, and superdehydrated THF (0.589 ml), triethylamine (36.8 ⁇ l, 0.265 mmol), DMAP (0.87 mg, 0.007 mmol) were sequentially added, and finally cyclohexanesulfonyl chloride (14.3 ⁇ l, 0.088 mmol) was added and stirred at room temperature for 2 hours.
  • Example 51 (S)-N-benzyl-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxamide 1F
  • Compound 1-2 (5.3 mg, 21 ⁇ mol) prepared in Example 2-1 was added to a 4 ml vial, followed by THF (0.275 ml) and benzyl isocyanate (3.1 ⁇ l, 25 ⁇ mol). Stirred for 3 hours. Water was added to stop the reaction, and the mixture was extracted with ethyl acetate. After drying with magnesium sulfate, the residue was separated by filtration, and the solvent was distilled off. 7.4 mg (19 ⁇ mol, 93% ) of the desired compound 1F (amorphous solid) was obtained.
  • Example 52 (S)-N-isopropyl-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxamide 1G
  • Example 52-1 4-Nitrophenyl (S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate 1-3
  • Compound 1-2 (32.8 mg, 0.127 mmol) prepared in Example 2-1 was added to a dried 10 ml eggplant-shaped flask while washing with dichloromethane (1.28 ml), and triethylamine (35.3 ⁇ l, 0.255 mmol) was added. was added.
  • Example 52-2 (S)-N-isopropyl-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxamide 1G
  • Compound 1-3 (7.6 mg, 18 ⁇ mol) prepared in Example 52-1 was added to a 4 ml vial, and dichloromethane (0.486 ml), triethylamine (7.5 ⁇ l, 54 ⁇ mol), isopropylamine (0.344 ml, 3.94 mmol) was sequentially added, and the mixture was stirred at 50° C. for 67 hours.
  • Example 53 (S)-N-isopropyl-2-(3-phenethyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxamide 10G
  • Example 53-1 (S)-3-phenethyl-5-(piperidin-2-yl)-1,2,4-oxadiazole 10-2
  • Compound 10-1 (92.4 mg, 0.258 mmol) prepared in Example 47 was added to a 4 ml vial, dichloromethane (1.0 ml), TFA (0.333 ml) and water (16.7 ⁇ l) were added, and the mixture was stirred at room temperature for 1 hour. Stirred for 40 minutes.
  • the mixture was made basic by adding a saturated aqueous sodium hydrogencarbonate solution (5 ml), and then extracted with ethyl acetate.
  • Example 53-2 4-Nitrophenyl (S)-2-(3-phenethyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate 10-3
  • Compound 10-2 (31.5 mg, 0.122 mmol) prepared in Example 53-1 was added to a 10 ml eggplant-shaped flask while washing with dichloromethane (1.22 ml), triethylamine (33.9 ⁇ l, 0.245 mmol), p- Nitrophenyl chloroformate (30.2 mg, 0.147 mmol) was sequentially added and stirred at room temperature for 1 hour. After removing the stirrer bar and evaporating the solvent, water was added and the mixture was extracted with ethyl acetate.
  • Example 53-3 (S)-N-isopropyl-2-(3-phenethyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxamide 10G
  • Compound 10-3 (21.5 mg, 51 ⁇ mol) prepared in Example 53-2 was added to a 10 ml eggplant-shaped flask, and dichloromethane (1.454 ml), triethylamine (21.2 ⁇ l, 0.153 mmol), isopropylamine (0.890 ml , 10.17 mmol) was sequentially added, and the mixture was stirred at 50°C for 18 hours.
  • Example 54 (S)-N-(tert-butyl)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxamide 1H
  • Compound 1-2 (6.3 mg, 24 ⁇ mol) prepared in Example 2-1 was added to a 4-ml vial, and THF (0.326 ml) and t-butyl isocyanate (14.7 ⁇ l, 0.122 mmol) were sequentially added. The mixture was stirred at room temperature for 1 hour and 30 minutes. After distilling off the solvent and excess reagent, water was added and the mixture was extracted with ethyl acetate.
  • Example 55 tert-Butyl (S)-2-(3-(2-(pyridin-4-yl)ethyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate 12-1
  • Example 55-1 N'-Hydroxy-3-(pyridin-4-yl)propaneimidamide 3-Pyrid-4-yl-propiononitrile (497 mg, 3.76 mmol) and 50% aqueous hydroxylamine solution (2.22 ml, 37.6 mmol) were added to an eggplant-shaped flask and dissolved in absolute ethanol (12.5 ml). It was heated to reflux for 4 hours. After distilling off the solvent, the residue was dried in a vacuum to obtain the title compound (oil, 621 mg, yield: 100%).
  • Example 55-2 tert-butyl (S)-2-(3-(2-(pyridin-4-yl)ethyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxy Rate 12-1
  • N-Boc-L-pipecolic acid 300 mg, 1.31 mmol
  • dichloromethane 3.54 ml
  • HATU 547 mg, 1.44 mmol
  • diisopropylethylamine 0.456 ml, 2.62 mmol
  • N'-hydroxy-3-pyrid-4-yl-propaneimidamide (238 mg, 1.44 mmol) prepared in Example 55-1 was added while washing with dichloromethane (3.0 ml), and the mixture was stirred at room temperature for 1 hour. Stirred.
  • Example 56 (S)-N-(tert-butyl)-2-(3-(2-(pyridin-4-yl)ethyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxamide 12H
  • Example 56-1 (S)-5-(piperidin-2-yl)-3-(2-(pyridin-4-yl)ethyl)-1,2,4-oxadiazole 120-2
  • Compound 12-1 (226 mg, 0.631 mmol) was added to a 25 ml eggplant flask, dichloromethane (1.58 ml) and TFA (0.525 ml) were added, and the mixture was stirred at room temperature for 14 hours.
  • the mixture was made basic by adding a saturated aqueous sodium hydrogencarbonate solution (5 ml), and then extracted with ethyl acetate. After drying with magnesium sulfate, the residue was separated by filtration, and the solvent was distilled off to obtain 131 mg (0.509 mmol, 81%) of the desired compound 12-2 (an oily substance).
  • Example 56-2 (S)-N-(tert-butyl)-2-(3-(2-(pyridin-4-yl)ethyl)-1,2,4-oxadiazol-5-yl) Piperidine-1-carboxamide 12H
  • Compound 12-2 (11.5 mg, 45 ⁇ mol) prepared in Example 56-1 was added to a 4 ml vial, THF (0.594 ml) and t-butyl isocyanate (26.8 ⁇ l, 0.223 mmol) were added in that order, Stirred at room temperature for 3 hours. Water was added and the mixture was extracted with ethyl acetate.
  • Example 57 (S)-5-(1-(isobutylsulfonyl)piperidin-2-yl)-3-(2-(pyridin-4-yl)ethyl)-1,2,4-oxadiazole 12A 12-2 (22.3 mg, 86 ⁇ mol) prepared in Example 56-1 was added to a 10 ml eggplant-shaped flask, and THF (0.863 ml), triethylamine (108 ⁇ l, 0.777 mmol), DMAP (2.1 mg, 17 ⁇ mol) was sequentially added, followed by addition of isobutylsulfonyl chloride (34.9 ⁇ l, 0.259 mmol), followed by stirring at room temperature for 1 hour.
  • Table 14 Physical property data for the compounds prepared in Examples 51-57 are shown in Table 14.
  • Example 58 (1s,4s)-N-(tert-butyl)-1-(3-(2-(pyridin-4-yl)ethyl)-1,2,4-oxadiazol-5-yl)-2-azabicyclo [2.2.2] Octane-2-carboxamide 13H
  • Example 58-1 5-((1s,4s)-2-azabicyclo[2.2.2]octan-1-yl)-3-(2-(pyridin-4-yl)ethyl)-1,2,4 -oxadiazole 13-2
  • N-Boc-2-azabicyclo[2.2.2]octane-1-carboxylic acid (24.5 mg, 96 ⁇ mol) was added to a 10 ml eggplant-shaped flask and dissolved in dichloromethane (0.480 ml) and pyridine (0.480 ml).
  • Oxalyl chloride (25.2 ⁇ l, 0.288 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere.
  • Example 58-2 (1s,4s)-N-(tert-butyl)-1-(3-(2-(pyridin-4-yl)ethyl)-1,2,4-oxadiazole-5- yl)-2-azabicyclo[2.2.2]octane-2-carboxamide 13H
  • Compound 13-2 (2.7 mg, 9 ⁇ mol) prepared in Example 58-1 was added to a 10 ml round-bottomed flask, and THF (0.317 ml) and t-butyl isocyanate (11.4 ⁇ l, 95 ⁇ mol) were added sequentially. , and stirred at room temperature for 4 hours. After distilling off the solvent, 3.6 mg (9 ⁇ mol, 100%) of the target compound 13H (oil) was obtained.
  • Example 59 tert-Butyl (1s,4s)-1-(3-(2-(pyridin-4-yl)ethyl)-1,2,4-oxadiazol-5-yl)-2-azabicyclo[2.2.2] Octane-2-carboxylate 13-1
  • Compound 13-2 (3.0 mg, 11 ⁇ mol) prepared in Example 58-1 was added to a 10 ml round-bottomed flask, and THF (0.422 ml), di-t-butyl dicarbonate (6.1 mg, 27 ⁇ mol), A 2M aqueous sodium hydroxide solution (11.6 ⁇ l, 23 ⁇ mol) was added in sequence, and the mixture was stirred at 50° C. for 2 hours.
  • Table 15 Physical property data for the compounds prepared in Examples 58-59 are shown in Table 15.
  • Example 60 Isobutyl (S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate 1I
  • Compound 1-2 (6.4 mg, 25 ⁇ mol) prepared in Example 2-2 was added to a 4 ml vial, and dichloromethane (0.332 ml), triethylamine (10.3 ⁇ l, 75 ⁇ mol), isobutyl chloroformate (5.0 ⁇ l, 37 ⁇ mol) was sequentially added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Water was added to stop the reaction, and the mixture was extracted with ethyl acetate.
  • Example 61 Benzyl (S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate 1J
  • Compound 1-2 (5.7 mg, 25 ⁇ mol) prepared in Example 2-2 was added to a 4 ml vial, and dichloromethane (0.295 ml), triethylamine (132 ⁇ l, 0.952 mmol), benzyl chloroformate (37.4 ⁇ l, 0.255 mmol) was sequentially added, and the mixture was stirred at room temperature for 3 hours and 30 minutes. Water was added to stop the reaction, and the mixture was extracted with ethyl acetate.
  • Example 62 Methyl (S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate 1K
  • Compound 1-2 (5.9 mg, 23 ⁇ mol) prepared in Example 2-2 was added to a 4 ml vial, and dichloromethane (0.306 ml), triethylamine (12.7 ⁇ l, 92 ⁇ mol), methyl chloroformate (3.7 ⁇ l, 46 ⁇ mol) was sequentially added, and the mixture was stirred at room temperature for 1 hour. Water was added to stop the reaction, and the mixture was extracted with ethyl acetate.
  • Example 63 Isopropyl (S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate 1L
  • Compound 1-2 (6.5 mg, 25 ⁇ mol) prepared in Example 2-2 was added to a 4 ml vial, and dichloromethane (0.337 ml), triethylamine (10.5 ⁇ l, 76 ⁇ mol), isopropyl chloroformate (4.5 ⁇ l, 38 ⁇ mol) was sequentially added, and the mixture was stirred at room temperature for 1 hour. Water was added to stop the reaction, and the mixture was extracted with ethyl acetate.
  • Example 64 Phenyl (S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate 1M
  • Compound 1-2 (6.5 mg, 25 ⁇ mol) prepared in Example 2-2 was added to a 4 ml vial, and dichloromethane (0.337 ml), triethylamine (10.5 ⁇ l, 76 ⁇ mol), phenyl chloroformate (4.9 ⁇ l, 38 ⁇ mol) was sequentially added, and the mixture was stirred at room temperature for 2 hours. Water was added to stop the reaction, and the mixture was extracted with ethyl acetate.
  • Example 65 (-)-Menthyl (S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate 1N
  • Compound 1-2 (6.7 mg, 26 ⁇ mol) prepared in Example 2-2 was added to a 4 ml vial, and dichloromethane (0.347 ml), triethylamine (10.8 ⁇ l, 78 ⁇ mol), menthyl chloroformate (8.5 ⁇ l, 39 ⁇ mol) was sequentially added, and the mixture was stirred at room temperature for 2 hours. Water was added to stop the reaction, and the mixture was extracted with ethyl acetate.
  • Example 66 Cyclopentyl (S)-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate 1O
  • Compound 1-2 (6.9 mg, 27 ⁇ mol) prepared in Example 2-2 was added to a 4 ml vial, and dichloromethane (0.358 ml), triethylamine (123 ⁇ l, 0.885 mmol), cyclopentyl chloroformate (48.5 ⁇ l, 37 ⁇ mol) were sequentially added, and the mixture was stirred at room temperature for 1 hour and 50 minutes. Water was added to stop the reaction, and the mixture was extracted with ethyl acetate.
  • Table 16 Physical property data for the compounds prepared in Examples 60-66 are shown in Table 16.
  • HATU 378 mg, 0.995 mmol
  • diisopropylethylamine 0.289 ml, 1.658 mmol
  • N'-hydroxy-3-phenylpropaneimidamide 163 mg, 0.995 mmol
  • dichloromethane 1.5 ml
  • Example 68 5-((1R,3S,4S)-2-(isobutylsulfonyl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-phenethyl-1,2,4-oxadiazole 14A
  • Example 68-1 5-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-yl)-3-phenethyl-1,2,4-oxadiazole 14-2
  • Compound 14-1 (252 mg, 0.681 mmol) prepared in Example 67 was added to a 10 ml eggplant flask, dichloromethane (1.70 ml) and TFA (0.567 ml) were added, and the mixture was stirred at room temperature for 1 hour.
  • the mixture was made basic by adding a saturated aqueous sodium hydrogencarbonate solution (5 ml), and then extracted with ethyl acetate. After drying with magnesium sulfate, the residue was separated by filtration, and the solvent was distilled off to obtain 171 mg (0.636 mmol, 93%) of the desired compound 14-2 (oil).
  • Example 68-2 5-((1R,3S,4S)-2-(isobutylsulfonyl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-phenethyl-1,2,4-oxa Diazole 14A 14-2 (12 mg, 45 ⁇ mol) prepared in Example 68-1 was added to a 10 ml eggplant-shaped flask, and THF (0.446 ml), triethylamine (55.6 ⁇ l, 0.401 mmol), DMAP (1.1 mg, 9 ⁇ mol) were sequentially added, followed by addition of isobutylsulfonyl chloride (18.0 ⁇ l, 0.134 mmol), followed by stirring at room temperature for 2 hours.
  • THF 0.446 ml
  • triethylamine 55.6 ⁇ l, 0.401 mmol
  • DMAP 1.1 mg, 9 ⁇ mol
  • Table 17 Physical property data for the compounds prepared in Examples 67-68 are shown in Table 17.
  • Example 69 (S)-2-Phenyl-1-(2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)ethan-1-one 1P
  • Compound 1-2 (8.5 mg, 33 ⁇ mol) prepared in Example 2-2 was added to a 4 ml vial, and dichloromethane (0.330 ml), triethylamine (54.9 ⁇ l, 0.396 mmol), phenylacetyl chloride (13.8 ⁇ l, 99 ⁇ mol) was sequentially added, and the mixture was stirred at room temperature for 1 hour and 30 minutes.
  • Example 70 (S)-3-methyl-1-(2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)butan-1-one 1Q
  • Compound 1-2 (8.8 mg, 34 ⁇ mol) prepared in Example 2-2 was added to a 4 ml vial, and dichloromethane (0.342 ml), triethylamine (56.9 ⁇ l, 0.410 mmol), isovaleryl chloride (12.6 ⁇ l , 0.103 mmol) was sequentially added, and the mixture was stirred at room temperature for 1 hour and 30 minutes.
  • Example 71 (S)-1-(2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)ethan-1-one 1R
  • Compound 1-2 (11.4 mg, 44 ⁇ mol) prepared in Example 2-2 was added to a 4 ml vial, and dichloromethane (0.443 ml), triethylamine (49.1 ⁇ l, 0.354 mmol), acetyl chloride (6.4 ⁇ l, 88.6 ⁇ mol) was sequentially added, and the mixture was stirred at room temperature for 1 hour and 30 minutes.
  • Example 72 (S)-Phenyl(2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methanone 1S
  • Compound 1-2 (18.8 mg, 34 ⁇ mol) prepared in Example 2-2 was added to a 4 ml vial, and dichloromethane (0.342 ml), triethylamine (37.9 ⁇ l, 0.274 mmol), benzoyl chloride (8.1 ⁇ l, 68 ⁇ mol) was sequentially added, and the mixture was stirred at room temperature for 1 hour and 30 minutes.
  • Example 73 (S)-5-(1-Isopentylpyrrolidin-2-yl)-3-(3-phenylpropyl)-1,2,4-oxadiazole 1T
  • Isovaleraldehyde (16.4 ⁇ l, 0.150 mmol) was added to compound 1-2 (7.7 mg, 30 ⁇ mol) prepared in Example 2-2 in a 4 ml vial while washing with THF (0.4 ml). .
  • triacetoxyphorohydride (19 mg, 90 ⁇ mol) was added and the mixture was stirred at room temperature for 15 hours.
  • a saturated aqueous sodium hydrogencarbonate solution was added to stop the reaction, and the mixture was extracted with ethyl acetate.
  • Example 75 (S)-5-(1-(4-fluorobenzyl)pyrrolidin-2-yl)-3-(3-phenylpropyl)-1,2,4-oxadiazole 1V
  • 4-fluorobenzaldehyde (14.8 ⁇ l, 0.138 mmol) was added while washing with THF (0.37 ml).
  • triacetoxyholohydride (17.5 mg, 83 ⁇ mol) was added and the mixture was stirred at room temperature for 1 hour and 30 minutes.
  • Table 18 Physical property data for the compounds prepared in Examples 69-75 are shown in Table 18.
  • Example 76 tert-Butyl (1s,4s)-1-(3-phenethyl-1,2,4-oxadiazol-5-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate 15-1
  • Example 76-1 5-((1s,4s)-2-azabicyclo[2.2.2]octan-1-yl)-3-(2-(pyridin-4-yl)ethyl)-1,2,4 -oxadiazole 15-2
  • N-Boc-2-azabicyclo[2.2.2]octane-1-carboxylic acid (24.5 mg, 96 ⁇ mol) was added to a 10 ml eggplant-shaped flask and dissolved in dichloromethane (0.480 ml) and pyridine (0.480 ml).
  • Oxalyl chloride (25.2 ⁇ l, 0.288 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 2 hours under nitrogen atmosphere. After evaporating the solvent and excess reagents, azeotroping toluene once, dichloromethane (0.360 ml) and pyridine (387 ⁇ l, 4.80 mmol) were added, and N'-hydroxy-3-phenylpropanimidamide ( 17.3 mg, 0.106 mmol) was added while washing with dichloromethane (0.6 ml), and the mixture was stirred at room temperature for 12 hours and 30 minutes.
  • Example 76-2 tert-butyl (1s,4s)-1-(3-phenethyl-1,2,4-oxadiazol-5-yl)-2-azabicyclo[2.2.2]octane-2-carboxy Rate 15-1
  • Compound 15-2 (3.2 mg, 11 ⁇ mol) prepared in Example 76-1 was added to a 10 ml round-bottomed flask, and THF (0.452 ml), di-t-butyl dicarbonate (6.5 mg, 29 ⁇ mol), A 2M aqueous sodium hydroxide solution (12.4 ⁇ l, 25 ⁇ mol) was added in sequence, and the mixture was stirred at 50° C. for 2 hours. Water was added and the mixture was extracted with ethyl acetate.
  • Example 77 5-((1s,4s)-2-(methylsulfonyl)-2-azabicyclo[2.2.2]octan-1-yl)-3-phenethyl-1,2,4-oxadiazole 15C 15-1 (3.8 mg, 13 ⁇ mol) prepared in Example 76-2 was added to a 10 ml round-bottomed flask, and super-dehydrated THF (0.67 ml), triethylamine (66.9 ⁇ l, 0.483 mmol), DMAP (0.7 mg, 5 ⁇ mol) were sequentially added, and finally methanesulfonyl chloride (11.9 ⁇ l, 0.121 mmol) was added, and the mixture was stirred at room temperature for 10 hours and 30 minutes.
  • Example 78 tert-Butyl (S)-2-(5-phenethyl-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate C2-16-1
  • Example 78-1 tert-butyl (S)-2-(N'-hydroxycarbamimidoyl)piperidine-1-carboxylate 16-0
  • S -1-N-Boc-cyanopiperidine (300 mg, 1.43 mmol) and 50% aqueous hydroxylamine solution (0.252 ml, 4.28 mmol) were added to a 10 ml eggplant-shaped flask and dissolved in absolute ethanol (1.9 ml). The mixture was heated to reflux at 95° C. for 5 hours. After distilling off the solvent, it was dried in vacuum to obtain the target compound 16-0 (white solid, 347 mg, yield: 100%).
  • Example 78-2 tert-butyl (S)-2-(5-phenethyl-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate C2-16-1 3-Phenylpropionic acid (38.8 mg, 0.253 mmol) was added to a 10 ml eggplant-shaped flask and dissolved in dichloromethane (0.545 ml). Subsequently, HATU (96.3 mg, 0.253 mmol) and diisopropylethylamine (80.2 ⁇ l, 0.460 mmol) were added, and the mixture was stirred at room temperature for 5 minutes under nitrogen atmosphere.
  • Example 82 tert-Butyl (2S,4S)-4-phenyl-2-(3-(4-phenylbutyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate C4-7-1
  • Example 82-1 N'-Hydroxy-5-phenylpentanimidamide 5-Phenylpentanenitrile (269 mg, 1.69 mmol) and 50% hydroxylamine aqueous 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 at 95°C for 7 hours and 30 minutes. Heated to reflux. After distilling off the solvent, the residue was dried in vacuo to obtain the target compound N'-hydroxy-5-phenylpentanimidamide (pale blackish white solid, 318 mg, yield: 98%).
  • Example 82-2 tert-Butyl (2S,4S)-4-phenyl-2-(3-(4-phenylbutyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate C4-7-1 (2S,4S)-1-(tert-butoxycarbonyl)-4-phenylpyrrolidine-2-carboxylic acid (50 mg, 0.172 mmol) was added to a 10 ml eggplant-shaped flask and dissolved in dichloromethane (0.716 ml).
  • Example 83 tert-Butyl (2S,4S)-4-phenyl-2-(3-(5-phenylpentyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate C5-7-1
  • Example 83-1 N'-Hydroxy-6-phenylhexanimidamide Add 6-phenylhexanenitrile (783 mg, 4.52 mmol) and 50% aqueous hydroxylamine solution (1.20 ml, 20.3 mmol) to a 10 ml eggplant-shaped flask, dissolve in absolute ethanol (5.65 ml), and heat at 95°C for 7 hours and 30 minutes. Heated to reflux. After distilling off the solvent, the residue was dried in vacuo to obtain the target compound N'-hydroxy-6-phenylhexaneimidamide (pale black white solid, 918 mg, yield: 98%).
  • Example 83-2 tert-butyl (2S,4S)-4-phenyl-2-(3-(5-phenylpentyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxy Rate C5-7-1 (2S,4S)-1-(tert-butoxycarbonyl)-4-phenylpyrrolidine-2-carboxylic acid (50 mg, 0.172 mmol) was added to a 10 ml eggplant-shaped flask and dissolved in dichloromethane (0.716 ml).
  • Table 20 Physical property data for the compounds prepared in Examples 78-83 are shown in Table 20.
  • Example 84 tert-Butyl (S)-2-(5-phenethyl-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate 17-1
  • Example 84-1 tert-butyl (S)-2-(hydrazinecarbonyl)piperidine-1-carboxylate 17-0 N-Boc-L-pipecolic acid (100 mg, 0.436 mmol) was added to a 10 ml eggplant-shaped flask and dissolved in DMF (0.5 ml).
  • HATU 182 mg, 0.480 mmol
  • diisopropylethylamine (0.152 ml, 0.872 mmol) were added, and the mixture was stirred at room temperature for 10 minutes under nitrogen atmosphere.
  • This solution was then added dropwise to a 10 ml eggplant-shaped flask in which hydrazine-1-hydrate (108 ⁇ l, 2.18 mmol) was dissolved in DMF (0.5 ml) while washing with DMF (0.744 ml). Stirred for 40 minutes. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate.
  • Example 84-2 tert-butyl (S)-2-(5-phenethyl-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate 17-1
  • Compound 17-0 (18.7 mg, 77 ⁇ mol) prepared in Example 84-1 and 3-phenylpropanoic acid (13 mg, 85 ⁇ mol) were added to a 10 ml eggplant-shaped flask and dissolved in dichloromethane (0.77 ml). rice field.
  • HATU 38 mg, 0.100 mmol
  • diisopropylethylamine (40.2 ⁇ l, 0.231 mmol) were added, and the mixture was stirred at room temperature for 1 hour and 30 minutes under nitrogen atmosphere.
  • triphenylphosphine (21.7 mg, 79 ⁇ mol) and iodine (20.3 mg, 79 ⁇ mol) were added to a pre-dried 10 ml eggplant flask and dissolved in dichloromethane (0.448 ml). After slowly adding triethylamine (21.8 ⁇ l, 0.157 mmol) dropwise, the condensate (11.8 mg, 31 ⁇ mol) was added slowly while washing with dichloromethane (0.60 ml), and the mixture was stirred at room temperature for 1 hour and 45 minutes.
  • Example 85 tert-Butyl (S)-2-(5-(3-phenylpropyl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate 18-1
  • Compound 17-0 (26 mg, 0.107 mmol) prepared in Example 84-1 and 4-phenylbutanoic acid (19.7 mg, 0.118 mmol) were added to a 10 ml eggplant-shaped flask and dissolved in dichloromethane (1.07 ml). rice field.
  • HATU 52.8 mg, 0.139 mmol
  • diisopropylethylamine 55.8 ⁇ l, 0.321 mmol
  • a saturated aqueous solution of sodium hydrogencarbonate was added and the mixture was extracted with ethyl acetate.
  • Example 86 tert-Butyl (2S,4S)-4-phenyl-2-(5-(3-phenylpropyl)-4H-1,2,4-triazol-3-yl)pyrrolidine-1-carboxylate 19-1
  • Example 86-1 tert-butyl (2S,4S)-2-(hydrazinecarbonyl)-4-phenylpyrrolidine-1-carboxylate 19-0
  • (2S,4S)-1-(tert-butoxycarbonyl)-4-phenylpyrrolidine-2-carboxylic acid 50 mg, 0.172 mmol
  • dichloromethane (1.216 ml).
  • HATU 78.3 mg, 0.206 mmol
  • diisopropylethylamine 89.7 ⁇ l, 0.515 mmol
  • a solution of hydrazine-1-hydrate (10.2 ⁇ l, 0.206 mmol) in dichloromethane 0.5 ml was added, and the mixture was stirred at room temperature for 1 hour and 20 minutes.
  • the reaction was quenched with a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate.
  • Example 86-2 Ethyl 4-phenylbutaneimidate 4-Phenylbutyronitrile (0.740 ml, 5.0 mmol) was added to an eggplant-shaped flask and dissolved in absolute ethanol (3.47 ml), and acetyl chloride (2.82 ml, 40 mmol) was slowly added dropwise while cooling with cold water.
  • Example 86-3 tert-butyl (2S,4S)-4-phenyl-2-(5-(3-phenylpropyl)-4H-1,2,4-triazol-3-yl)pyrrolidine-1-carboxy rate 19-1
  • Compound 19-0 (6.6 mg, 22 ⁇ mol) prepared in Example 86-1 and ethyl-4-phenylbutanimidate (21.1 mg, 0.108 ⁇ mol) prepared in Example 86-2 were added to a 10 ml eggplant-shaped flask.
  • Example 87 tert-Butyl (S)-2-(5-(3-phenylpropyl)-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate 20-1
  • mmol) and triethylamine (21.6 ⁇ l, 0.156 mmol) were added, dissolved in ultra-dehydrated ethanol (1.30 ml), and stirred at 95° C. for 18 hours and at 110° C.
  • Example 88 5-((2S)-1-(tert-butylsulfinyl)piperidin-2-yl)-3-(3-phenylpropyl)-1,2,4-oxadiazole 2W
  • Compound 2-2 (19.6 mg, 72 ⁇ mol) prepared in Example 9-2, CH 2 Cl 2 (0.722 ml), and triethylamine (45.1 ⁇ l, 0.325 mmol) were sequentially added to a 10 ml eggplant-shaped flask.
  • t-Butylsulfinyl chloride (18.8 ⁇ l, 0.108 mmol) was slowly added to the mixture and stirred at room temperature for 2 hours.
  • Example 89 (S)-5-(1-(tert-butylsulfonyl)piperidin-2-yl)-3-(3-phenylpropyl)-1,2,4-oxadiazole 2X
  • Compound 2W (11.8 mg, 31 ⁇ mol) prepared in Example 88 was added to a 10 ml eggplant-shaped flask and dissolved in CH 2 Cl 2 (1.05 ml). ⁇ mol) was added slowly and stirred at room temperature for 40 minutes. A saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium sulfite solution were added to stop the reaction, and the mixture was extracted with ethyl acetate.
  • Example 90 (S)-N-((5-(1-(Cyclohexylsulfonyl)piperidin-2-yl)-1,2,4-oxadiazol-3-yl)methyl)benzo[d][1,3]dioxole -5-Carboxamide 21B
  • Example 90-1 tert-butyl (S)-((5-(piperidin-2-yl)-1,2,4-oxadiazol-3-yl)methyl)carbamate 21-2 N-Fmoc-L-piperidinecarboxylic acid (200 mg, 0.569 mmol) was added to a 25 ml eggplant-shaped flask and dissolved in dichloromethane (2.29 ml).
  • HATU 260 mg, 0.683 mmol
  • diisopropylethylamine 0.198 ml, 1.14 mmol
  • tert-butyl(N-hydroxycarbamimidoylmethyl)carbamate 123 mg, 0.626 mmol
  • dichloromethane 1.5 ml
  • Example 90-2 tert-butyl (S)-((5-(1-(cyclohexylsulfonyl)piperidin-2-yl)-1,2,4-oxadiazol-3-yl)methyl)carbamate 21- 3
  • Compound 21-2 (40.3 mg, 0.143 mmol) prepared in Example 90-1, CH 2 Cl 2 (0.827 ml) and pyridine (57.6 ⁇ l, 0.714 mmol) were sequentially added to a 10 ml eggplant-shaped flask.
  • Example 90-3 (S)-N-((5-(1-(cyclohexylsulfonyl)piperidin-2-yl)-1,2,4-oxadiazol-3-yl)methyl)benzo[d] [1,3]dioxol-5-carboxamide 21B
  • Compound 21-3 (9.0 mg, 21 ⁇ mol) prepared in Example 90-2 was added to a 10 ml eggplant-shaped flask, dichloromethane (0.42 ml) and TFA (84 ⁇ l) were added, and the mixture was stirred at room temperature for 1 hour. .
  • Example 91 (S)-3-Methyl-1-(2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)butan-1-one 2Q
  • Compound 2-2 (5.4 mg, 19.9 ⁇ mol) prepared in Example 9-2, CH 2 Cl 2 (0.398 ml) and triethylamine (33.1 ⁇ l, 0.239 mmol) were sequentially added to a 4 ml vial, and finally iso Valeryl chloride (7.34 ⁇ l, 59.7 ⁇ mol) was added and the mixture was stirred at room temperature for 1 hour and 30 minutes.
  • Example 92 (S)-1-(2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethan-1-one 2R
  • Compound 2-2 (5.2 mg, 19 ⁇ mol) prepared in Example 9-2 was added to a 4 ml vial, and dichloromethane (0.383 ml), triethylamine (31.9 ⁇ l, 0.230 mmol), acetyl chloride (4.15 ⁇ l, 57.5 ⁇ l), and ⁇ mol) was sequentially added, and the mixture was stirred at room temperature for 1 hour and 30 minutes.
  • Example 93 (S)-Phenyl(2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)methanone 2S Compound 2-2 (5.2 mg, 19 ⁇ mol) prepared in Example 9-2 was added to a 4 ml vial, and dichloromethane (0.383 ml), triethylamine (31.9 ⁇ l, 0.230 mmol), benzoyl chloride (6.8 ⁇ l, 57.5 ⁇ l), and ⁇ mol) was sequentially added, and the mixture was stirred at room temperature for 1 hour and 30 minutes.
  • Example 94 (S)-2-Phenyl-1-(2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethan-1-one 2P
  • Compound 2-2 (5.0 mg, 18.4 ⁇ mol) prepared in Example 9-2 was added to a 4 ml vial, and dichloromethane (0.369 ml), triethylamine (30.6 ⁇ l, 0.221 mmol), phenylacetyl chloride (7.7 ⁇ l, 55 ⁇ mol) was sequentially added, and the mixture was stirred at room temperature for 1 hour and 30 minutes.
  • Example 95 (S)-Cyclohexyl(2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)methanone 2Y
  • Compound 2-2 (7.0 mg, 25.8 ⁇ mol) prepared in Example 9-2 was added to a 4 ml vial, and dichloromethane (0.516 ml), triethylamine (42.9 ⁇ l, 0.310 mmol), cyclohexanecarbonyl chloride (10.7 ⁇ l, 77.4 ⁇ mol) was sequentially added, and the mixture was stirred at room temperature for 1 hour and 30 minutes.
  • Example 96 (S)-5-(1-Isopentylpiperidin-2-yl)-3-(3-phenylpropyl)-1,2,4-oxadiazole 2T
  • Isovaleraldehyde (13.8 ⁇ l, 0.125 mmol) was added to compound 2-2 (6.8 mg, 25 ⁇ mol) prepared in Example 9-2 in a 4 ml vial while washing with THF (0.33 ml). .
  • triacetoxyphorohydride (15.9 mg, 75 ⁇ mol) was added and the mixture was stirred at room temperature for 15 hours.
  • a saturated aqueous sodium hydrogencarbonate solution was added to stop the reaction, and the mixture was extracted with ethyl acetate.
  • Example 97 (S)-5-(1-ethylpiperidin-2-yl)-3-(3-phenylpropyl)-1,2,4-oxadiazole 2Z
  • Acetaldehyde (28 ⁇ l, 0.494 mmol) and THF (0.33 ml) were added to Compound 2-2 (6.7 mg, 25 ⁇ mol) prepared in Example 9-2 in a 4 ml vial, and the mixture was stirred at room temperature for 10 minutes.
  • triacetoxy holohydride (26.2 mg, 0.123 mmol) was added and stirred at room temperature for 16 hours.
  • a saturated aqueous sodium hydrogencarbonate solution was added to stop the reaction, and the mixture was extracted with ethyl acetate.
  • Example 98 (S)-5-(1-benzylpiperidin-2-yl)-3-(3-phenylpropyl)-1,2,4-oxadiazole 2AA
  • Benzaldehyde (12.9 ⁇ l, 0.125 mmol) and THF (0.33 ml) were added to compound 2-2 (6.8 mg, 25 ⁇ mol) prepared in Example 9-2 in a 4 ml vial, and the mixture was stirred at room temperature for 10 minutes.
  • triacetoxy holohydride (15.9 mg, 75 ⁇ mol) was added, and the mixture was stirred at room temperature for 15 hours and 30 minutes.
  • Example 99 (S)-5-(1-phenethylpiperidin-2-yl)-3-(3-phenylpropyl)-1,2,4-oxadiazole 2AB Phenylacetaldehyde (26.5 ⁇ l, 0.118 mmol) and THF (0.31 ml) were added to compound 2-2 (6.4 mg, 24 ⁇ mol) prepared in Example 9-2 in a 4 ml vial, and the mixture was stirred at room temperature for 10 minutes. After stirring, triacetoxy holohydride (15 mg, 71 ⁇ mol) was added, and the mixture was stirred at room temperature for 14 hours and 30 minutes.
  • Example 100 (S)-5-(1-(Cyclohexylmethyl)piperidin-2-yl)-3-(3-phenylpropyl)-1,2,4-oxadiazole 2U Cyclohexanecarboxaldehyde (15.4 ⁇ l, 0.125 mmol) was added to compound 2-2 (6.8 mg, 25 ⁇ mol) prepared in Example 9-2 in a 4 ml vial while washing with THF (0.33 ml). After stirring at room temperature for 10 minutes, triacetoxyholohydride (15.9 mg, 75 ⁇ mol) was added and the mixture was stirred at room temperature for 4 hours.
  • Example 101 Ethyl (S)-1-((2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)sulfonyl)piperidine-4-carboxylate 2AC
  • Compound 2-2 (37.3 mg, 0.138 mmol) prepared in Example 9-2, CH 2 Cl 2 (0.775 ml) and pyridine (55.5 ⁇ l, 0.687 mmol) were sequentially added to a 10 ml eggplant-shaped flask.
  • Example 102 (S)-3-(3-Phenylpropyl)-5-(1-(piperidin-1-ylsulfonyl)piperidin-2-yl)-1,2,4-oxadiazole 2AD
  • Compound 2-2 (31.2 mg, 0.115 mmol) prepared in Example 9-2, CH 2 Cl 2 (0.70 ml), and pyridine (46.4 ⁇ l, 0.575 mmol) were sequentially added to a 10 ml eggplant-shaped flask.
  • Example 103 (S)-4-((2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)sulfonyl)morpholine 2AE
  • Compound 2-2 (33.7 mg, 0.124 mmol) prepared in Example 9-2, CH 2 Cl 2 (0.792 ml), and pyridine (50.1 ⁇ l, 0.621 mmol) were sequentially added to a 10 ml eggplant-shaped flask. The mixture was ice-cooled to 20°C, washed with CH 2 Cl 2 (0.45 ml), added with morpholine-4-sulfonyl chloride (61.6 mg, 0.315 mmol), and stirred at room temperature for 112 hours and 30 minutes.
  • Example 104 tert-Butyl (S)-2-(3-(3-(3,4-dimethoxyphenyl)propyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate 22-1
  • Example 104-1 4-(3,4-dimethoxyphenyl-N'-hydroxybutanimidamide 4-(3,4-dimethoxyphenylbutanenitrile (603 mg, 2.94 mmol) and 50% hydroxylamine aqueous solution (0.780 ml, 13.22 mmol) were added to an eggplant-shaped flask, dissolved in absolute ethanol (3.67 ml), and heated at 95°C. After heating under reflux for 7 hours and 30 minutes, the solvent was distilled off and dried in vacuum to obtain the title compound (white solid, 625 mg, yield: 89%).
  • Example 104-2 tert-Butyl (S)-2-(3-(3-(3,4-dimethoxyphenyl)propyl)-1,2,4-oxadiazol-5-yl)piperidine-1- Carboxylate 22-1 N-Boc-L-pipecolic acid (200 mg, 0.872 mmol) was added to a 25 ml eggplant-shaped flask and dissolved in dichloromethane (2.36 ml). Subsequently, HATU (365 mg, 0.960 mmol) and diisopropylethylamine (0.304 ml, 1.745 mmol) were added, and the mixture was stirred at room temperature for 10 minutes under nitrogen atmosphere.
  • HATU 365 mg, 0.960 mmol
  • diisopropylethylamine (0.304 ml, 1.745 mmol
  • Example 105 (S)-5-(1-(Cyclohexylsulfonyl)piperidin-2-yl)-3-(3-(3,4-dimethoxyphenyl)propyl)-1,2,4-oxadiazole 22B and by-products 22B'
  • Example 105-1 (S)-3-(3-(3,4-dimethoxyphenyl)propyl)-5-(piperidin-2-yl)-1,2,4-oxadiazole 22-2
  • Compound 22-1 (304 mg, 0.704 mmol) prepared in Example 104-2 was added to a 10 ml eggplant-shaped flask, dichloromethane (1.76 ml) and TFA (0.587 ml) were added, and the mixture was stirred at room temperature for 1 hour.
  • Example 105-2 (S)-5-(1-(Cyclohexylsulfonyl)piperidin-2-yl)-3-(3-(3,4-dimethoxyphenyl)propyl)-1,2,4-oxadi Azole 22B, and by-product 22B' Compound 22-2 (39.4 mg, 0.119 mmol) prepared in Example 104-2, CH 2 Cl 2 (0.589 ml) and pyridine (48 ⁇ l, 0.594 mmol) were sequentially added to a 10 ml eggplant-shaped flask.
  • Example 106 tert-Butyl (S)-2-(3-(2-oxo-2-(phenylamino)ethyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate 23-1
  • Example 106-1 tert-Butyl (S)-2-(3-(2-ethoxy-2-oxoethyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate 23- 0 N-Boc-L-pipecolic acid (150 mg, 0.654 mmol) was added to a 25 ml eggplant-shaped flask and dissolved in dichloromethane (3.27 ml).
  • Example 106-2 tert-Butyl (S)-2-(3-(2-oxo-2-(phenylamino)ethyl)-1,2,4-oxadiazol-5-yl)piperidine-1- Carboxylate 23-1
  • Compound 23-0 (59.4 mg, 0.175 mmol) prepared in Example 106-1 was added to a 10 ml eggplant-shaped flask, dissolved in tetrahydrofuran (0.467 ml), methanol (0.70 ml) and water (0.233 ml), Lithium hydroxide monohydrate (22 mg, 0.530 mmol) was added, and the mixture was stirred at room temperature for 1 hour and 30 minutes.
  • Example 107 5-((2S)-1-(tert-butylsulfinyl)piperidin-2-yl)-3-(3-phenylpropyl)-1,2,4-oxadiazole 2W' Compound 2-2 (23.4 mg, 86 ⁇ mol) prepared in Example 9-2, CH 2 Cl 2 (0.862 ml), and triethylamine (53.8 ⁇ l, 0.388 mmol) were sequentially added to a 10 ml eggplant-shaped flask. t-Butylsulfinyl chloride (17.9 ⁇ l, 0.103 mmol) was slowly added to the mixture, and the mixture was stirred at room temperature for 1 hour.
  • Table 21 Physical property data for the compounds prepared in Examples 84-107 are shown in Table 21.
  • heptane-2-carboxylate 24-1 Example 108-1: tert-butyl (1R,3S,4S)-3-(hydrazinecarbonyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate 24-0 2-Boc-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (606 mg, 2.512 mmol) was added to a 10 ml eggplant-shaped flask and dissolved in DMF (3.0 ml).
  • HATU (1.05 g, 2.76 mmol) and diisopropylethylamine (0.875 ml, 5.02 mmol) were added, and the mixture was stirred at room temperature for 10 minutes under nitrogen atmosphere. After that, this solution was added dropwise to a 10 ml eggplant-shaped flask in which hydrazine-1-hydrate (623 ⁇ l, 12.56 mmol) was dissolved in DMF (1.5 ml) while washing with DMF (1.779 ml). minutes. After distilling off the solvent, the reaction was quenched with a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate.
  • Example 108-2 Ethyl 2-(1H-indol-3-yl)acetimidate 3-Indoleacetonitrile (200 mg, 1.28 mmol) was added to an eggplant-shaped flask and dissolved in absolute ethanol (0.89 ml), and acetyl chloride (0.724 ml, 10.2 mmol) was slowly added dropwise while cooling with cold water. After that, the mixture was stirred at room temperature for 3 hours, and vacuum-dried for 15 minutes after distilling off the solvent. The residue was dissolved in ethyl acetate, saturated aqueous sodium hydrogencarbonate solution was slowly added, and the mixture was extracted with ethyl acetate. After evaporating the solvent and vacuum drying, the title compound (pale brown solid, 258 mg, yield: 100%) was obtained.
  • Example 108-3 tert-butyl (1R,3S,4S)-3-(5-((1H-indol-3-yl)methyl)-4H-1,2,4-triazol-3-yl)- 2-Azabicyclo[2.2.1]heptane-2-carboxylate 24-1
  • Ethyl 2-(1H-indol-3-yl)acetimidate (99.4 mg, 0.481 mmol) prepared in Example 108-3 was added to a 25 ml eggplant-shaped flask, and Compound 24-0 (108.5 mg, 0.425 mmol) prepared above was dissolved in ultra-dehydrated toluene (8.50 ml), and the mixture was stirred at 60° C.
  • Example 109 (1R,3S,4S)-3-(5-((1H-indol-3-yl)methyl)-4H-1,2,4-triazol-3-yl)-N-benzyl-2-azabicyclo[2.2 .1]heptane-2-carboxamide 24F and 24F'
  • Compound 24-1 (46.5 mg, 0.118 mmol) prepared in Example 108-3 was added to a 10 ml eggplant-shaped flask, and 4N hydrochloric acid/dioxane (1.18 ml) and water (0.118 ml) were added, The mixture was stirred at room temperature for 1 hour and 15 minutes.
  • Trihydrochloride 24-2 Hydrochloride 8.0 mg (20 ⁇ mol) was dissolved in superdehydrated tetrahydrofuran (0.397 ml), triethylamine (33 ⁇ l, 0.238 mmol) and benzyl isocyanate (3.0 ⁇ l, 24 ⁇ mol) were added, and the mixture was stirred at room temperature for 1 Stirred for 15 minutes. Water was added to stop the reaction, and the mixture was extracted with ethyl acetate.
  • Example 110 (1R,3S,4S)-3-(5-((1H-indol-3-yl)methyl)-4H-1,2,4-triazol-3-yl)-N-(tert-butyl)-2 -azabicyclo[2.2.1]heptane-2-carboxamide 24H 24-2 Hydrochloride (7.6 mg, 18.9 ⁇ mol) as the trihydrochloride prepared in Example 109 was added to the test tube, basified with a saturated aqueous sodium hydrogencarbonate solution, and extracted with chloroform. After the organic layer was separated by filtration with a phase separator, the solvent was distilled off to obtain 4.4 mg (15.0 ⁇ mol, 80%) of Compound 24-2.
  • Example 111 tert-butyl (1R,3S,4S)-3-(5-(2-(pyridin-4-yl)ethyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2. 1] heptane-2-carboxylate 25-1
  • Example 111-1 Ethyl 3-(pyridin-4-yl)propaneimidate hydrochloride 3-Pyridin-4-yl-propiononitrile (200 mg, 1.513 mmol) was added to an eggplant-shaped flask and dissolved in absolute ethanol (1.05 ml). Dripped. After that, the mixture was stirred at room temperature for 3 hours, the solvent was distilled off, and the mixture was vacuum-dried for 15 minutes to obtain the title compound (white solid, 250 mg, yield: 99%). .
  • Example 111-2 tert-butyl (1R,3S,4S)-3-(5-(2-(pyridin-4-yl)ethyl)-4H-1,2,4-triazol-3-yl)- 2-Azabicyclo[2.2.1]heptane-2-carboxylate 25-1
  • Compound 24-0 (19 mg, 74 ⁇ mol) prepared in Example 108-1 and ethyl 3-(pyridin-4-yl)propaneimidate hydrochloride (21 mg, 83 ⁇ mol) were added to a 10 ml eggplant-shaped flask.
  • Example 112 Compound 25AD' Compound 25-1 (22 mg, 60 ⁇ mol) prepared in Example 111-2 was added to a 10 ml eggplant-shaped flask, 4N hydrochloric acid/dioxane (0.595 ml) and water (60 ⁇ l) were added, The mixture was stirred at room temperature for 2 hours and 30 minutes. The stirrer bar was removed, the solvent was distilled off, and the residue was vacuum dried to obtain 22.5 mg (60 ⁇ mol, 100%) of the trihydrochloride.
  • Example 113 (1R,3S,4S)-2-(isobutylsulfonyl)-3-(5-(2-(pyridin-4-yl)ethyl)-4H-1,2,4-triazol-3-yl)-2- Azabicyclo[2.2.1]heptane 25A
  • Example 113-1 (1R,3S,4S)-3-(5-(2-(pyridin-4-yl)ethyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo [2.2.1]
  • Trihydrochloride 25-2 hydrochloride (28 mg, 74 ⁇ mol) prepared in Example 112 was added to the test tube, water was added, and after washing with chloroform, a saturated aqueous sodium hydrogen carbonate solution was added to make basic.
  • Example 113-2 (1R,3S,4S)-2-(isobutylsulfonyl)-3-(5-(2-(pyridin-4-yl)ethyl)-4H-1,2,4-triazole-3 -yl)-2-azabicyclo[2.2.1]heptane 25A
  • Compound 25-2 (5.7 mg, 21 ⁇ mol) prepared in Example 111-2 was added to a 10 ml eggplant-shaped flask, and superdehydrated THF (0.423 ml), triethylamine (7.6 ⁇ l, 55 ⁇ mol), DMAP (0.78 mg, 6 ⁇ mol) were added sequentially, isobutylsulfonyl chloride (3.7 ⁇ l, 28 ⁇ mol) was added, and the mixture was stirred at room temperature for 1 hour and 45 minutes.
  • Example 114 (1R,3S,4S)-2-(piperidin-1-ylsulfonyl)-3-(5-(2-(pyridin-4-yl)ethyl)-4H-1,2,4-triazol-3-yl )-2-azabicyclo[2.2.1]heptane 25AD and 25AD'' Compound 25-2 (15 mg, 55.7 ⁇ mol) prepared in Example 111-2 was added to a 10 ml eggplant-shaped flask, dissolved in dichloromethane (0.496 ml), pyridine (13.5 ⁇ l, 0.167 mmol) was added, and finally The mixture was ice-cooled to 20°C, piperidine-1-sulfonyl chloride (13.3 mg, 72 ⁇ mol) was washed with CH 2 Cl 2 (0.30 ml), added, and the mixture was stirred at room temperature for 25 hours.
  • Example 115 5-((2S)-1-((adamantan-1-yl)sulfinyl)piperidin-2-yl)-3-(3-phenylpropyl)-1,2,4-oxadiazole 2AF and 2AF' Compound 2-2 (41 mg, 0.151 mmol) prepared in Example 9-2, dichloromethane (1 ml), and triethylamine (94.2 ⁇ l, 0.680 mmol) were sequentially added to a 10 ml eggplant-shaped flask, and finally adamantane- 1-Sulfinyl chloride (44.5 mg, 0.193 mmol) was slowly added while washing with dichloromethane (0.51 ml), and stirred at room temperature for 4 hours.
  • Example 116 5-((S)-1-((adamantan-1-yl)sulfonyl)piperidin-2-yl)-3-(3-phenylpropyl)-1,2,4-oxadiazole 2AG
  • Compound 2AF (13.5 mg, 30 ⁇ mol) prepared in Example 115 was added to a 10 ml eggplant-shaped flask and dissolved in CH 2 Cl 2 (0.992 ml). ⁇ mol) was added slowly and stirred at room temperature for 1 hour and 30 minutes. A saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium sulfite solution were added to stop the reaction, and the mixture was extracted with ethyl acetate.
  • Example 117 (S)-N-((5-(1-(cyclohexylsulfonyl)piperidin-2-yl)-1,2,4-oxadiazol-3-yl)methyl)-1-naphthamide 26B
  • Compound 21-3 (9.4 mg, 21.9 ⁇ mol) prepared in Example 90-2 was added to a 10 ml eggplant-shaped flask, dichloromethane (0.439 ml) and TFA (88 ⁇ l) were added, and the mixture was stirred at room temperature for 1 hour. . After removing the stirrer bar and distilling off the solvent, a saturated aqueous solution of sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate.
  • Example 118 (S)-N-((5-(1-(cyclohexylsulfonyl)piperidin-2-yl)-1,2,4-oxadiazol-3-yl)methyl)-3,4-dimethoxybenzamide 27B
  • Compound 21-3 (9.4 mg, 21.9 ⁇ mol) prepared in Example 90-2 was added to a 10 ml eggplant-shaped flask, dichloromethane (0.439 ml) and TFA (88 ⁇ l) were added, and the mixture was stirred at room temperature for 1 hour. . After removing the stir bar and evaporating the solvent, a saturated aqueous solution of sodium hydrogencarbonate was added and the mixture was extracted with ethyl acetate.
  • Example 119 tert-butyl (1R,3S,4S)-3-(5-((1H-indol-2-yl)methyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2. 1] heptane-2-carboxylate 28-1
  • Example 119-1 Ethyl 2-(1H-indol-2-yl)acetimidate 2-Indoleacetonitrile (50 mg, 0.32 mmol) was added to an eggplant-shaped flask and dissolved in absolute ethanol (0.796 ml), and acetyl chloride (0.181 ml, 2.56 mmol) was slowly added dropwise thereto while cooling with cold water.
  • Example 119-2 tert-butyl (1R,3S,4S)-3-(5-((1H-indol-2-yl)methyl)-4H-1,2,4-triazol-3-yl)- 2-Azabicyclo[2.2.1]heptane-2-carboxylate 28-1
  • Ethyl 2-(1H-indol-2-yl)acetimidate (59.4 mg, 0.294 mmol) prepared in Example 119-1 was added to a 25 ml eggplant-shaped flask, and The obtained compound 24-0 (57.7 mg, 0.226 mmol) was dissolved in ultra-dehydrated toluene (4.52 ml), and the mixture was stirred at 60°C for 2 hours under nitrogen atmosphere.
  • Table 22 Physical property data for the compounds prepared in Examples 108-119 are shown in Table 22.
  • Example 120 (1R,3S,4S)-2-(Cyclohexylsulfonyl)-3-(5-(2-(pyridin-4-yl)ethyl)-4H-1,2,4-triazol-3-yl)-2- Azabicyclo[2.2.1]heptane 29B
  • Example 120-1 (1R,3S,4S)-2-(Cyclohexylsulfonyl)-2-azabicyclo[2.2.1]heptane-3-carbohydrazide 29-0
  • 2-Cyclohexylsulfonyl-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (18.5 mg, 64 ⁇ mol) was added to a 10 ml eggplant-shaped flask and dissolved in DMF (0.3 ml).
  • HATU 26.9 mg, 71 ⁇ mol
  • diisopropylethylamine 22.4 ⁇ l, 0.129 mmol
  • this solution was added dropwise to a 10 ml eggplant-shaped flask in which hydrazine-1-hydrate (22.3 ⁇ l, 0.451 mmol) was dissolved in DMF (0.205 ml) while washing with DMF (0.3 ml). Stirred for 15 minutes. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate.
  • Example 120-2 (1R,3S,4S)-2-(cyclohexylsulfonyl)-3-(5-(2-(pyridin-4-yl)ethyl)-4H-1,2,4-triazole-3 -yl)-2-azabicyclo[2.2.1]heptane 29B
  • Compound 29-0 (19.2 mg, 64 ⁇ mol) prepared in Example 120-1 and ethyl 3-(pyridin-4-yl)propaneimidate (19.5 mg, 0.108 mmol) were added to a 10 ml eggplant-shaped flask. , was dissolved in ultra-dehydrated toluene (1.5 ml) and stirred at 60°C for 2 hours under an argon atmosphere.
  • Example 121 tert-butyl (S)-(4-(3-(5-(1-(cyclohexylsulfonyl)piperidin-2-yl)-1,2,4-oxadiazol-3-yl)propyl)benzyl)carbamate 30B
  • Example 121-1 tert-butyl-(4-(4-amino-4-(hydroxyimino)butyl)benzyl)carbamate
  • t-Butyl-4-(3-cyanopropyl)benzylcarbamate 38.4 mg, 0.140 mmol
  • 50% aqueous hydroxylamine solution 83 ⁇ l, 1.4 mmol
  • the mixture was heated to reflux at 95° C. for 4 hours. After distilling off the solvent, it was dried in vacuum to obtain the title compound (amorphous solid, 42.6 mg, yield: 99%).
  • Example 121-2 tert-butyl (S)-(4-(3-(5-(1-(cyclohexylsulfonyl)piperidin-2-yl)-1,2,4-oxadiazol-3-yl) Propyl)benzyl)carbamate 30B (S)-1-(Cyclohexylsulfonyl)piperidine-2-carboxylic acid (35 mg, 0.127 mmol) was added to a 10 ml eggplant-shaped flask and dissolved in dichloromethane (0.471 ml).
  • HATU 53.2 mg, 0.140 mmol
  • diisopropylethylamine 44.3 ⁇ l, 0.254 mmol
  • tert-butyl-(4-(4-amino-4-(hydroxyimino)butyl)benzyl)carbamate 43 mg, 0.140 mmol
  • dichloromethane 0.8 ml
  • Example 122 (1R,3S,4S)-3-(5-((1H-indol-3-yl)methyl)-4H-1,2,4-triazol-3-yl)-N-(quinolin-3-ylmethyl) -2-Azabicyclo[2.2.1]heptane-2-carboxamide 24AH
  • Example 122-1 (1R,3S,4S)-3-(hydrazinecarbonyl)-N-(quinolin-3-ylmethyl)-2-azabicyclo[2.2.1]heptane-2-carboxamide 31-0 2-((Quinolin-3-ylmethyl)carbamoyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (22 mg, 68 ⁇ mol) was added to a 10 ml eggplant-shaped flask and dissolved in DMF (0.345 ml).
  • Example 122-2 (1R,3S,4S)-3-(5-((1H-indol-3-yl)methyl)-4H-1,2,4-triazol-3-yl)-N-( Quinolin-3-ylmethyl)-2-azabicyclo[2.2.1]heptane-2-carboxamide 24AH
  • Ethyl 2-(1H-indol-3-yl)acetimidate (8.4 mg, 41 ⁇ mol) was added to a 10 ml eggplant-shaped flask, and compound 31-0 (5.5 mg , 16 ⁇ mol), ultra-dehydrated toluene (0.81 ml) and ultra-dehydrated THF (0.405 ml) were added, and the mixture was stirred at 60° C.
  • Example 123 (1R,3S,4S)-3-(5-((1H-indol-2-yl)methyl)-4H-1,2,4-triazol-3-yl)-N-(quinolin-3-ylmethyl) -2-Azabicyclo[2.2.1]heptane-2-carboxamide 28AH
  • Ethyl 2-(1H-indol-3-yl)acetimidate (15.6 mg, 77 ⁇ mol) was added to a 10 ml eggplant-shaped flask, and compound 31-0 (6.4 mg, 19 ⁇ mol) and superdehydrated toluene (0.943 ⁇ mol) were added thereto.
  • Example 124 Methyl (S)-2-(1-(cyclohexylsulfonyl)piperidin-2-yl)-5-methyloxazole-4-carboxylate 32B
  • Example 124-1 Methyl (S)-2-((S)-1-(cyclohexylsulfonyl)piperidine-2-carboxamido)-3-oxobutanoate 32-1
  • S)-1-(Cyclohexylsulfonyl)piperidine-2-carboxylic acid (50 mg, 0.182 mmol) and threonine methyl ester hydrochloride (34.9 mg, 0.200 mmol) were added to a 10 ml eggplant-shaped flask, and dichloromethane (0.471 ml) was added.
  • Example 124-2 Methyl (S)-2-(1-(cyclohexylsulfonyl)piperidin-2-yl)-5-methyloxazole-4-carboxylate 32B Triphenylphosphine (16.4 mg, 60 ⁇ mol) and iodine (15.4 mg, 60 ⁇ mol) were added to a 10 ml eggplant-shaped flask and dissolved in dichloromethane (0.567 ml). Next, triethylamine (16.5 ⁇ l, 0.119 mmol) was slowly added, followed by slow addition of amide 32-1 (13.6 mg, 0.35 mmol) prepared in Example 124-1 while washing with dichloromethane (0.60 ml).
  • Example 125 (S)-2-(1-(Cyclohexylsulfonyl)piperidin-2-yl)-5-methyloxazole-4-carboxylic acid 33B
  • Compound 32B (8.5 mg, 23 ⁇ mol) prepared in Example 124 was added to a 10 ml eggplant-shaped flask and dissolved in tetrahydrofuran (0.671 ml) and water (63 ⁇ l).
  • Lithium hydroxide monohydrate 17.4 mg, 0.414 mmol
  • methanol (0.189 ml) was added and the mixture was further stirred for 3 hours.
  • Example 126 (S)-N-benzyl-2-(1-(cyclohexylsulfonyl)piperidin-2-yl)-5-methyloxazole-4-carboxamide 34B
  • Compound 33B (6.4 mg, 18 ⁇ mol) prepared in Example 125 was added to a 10 ml eggplant-shaped flask and dissolved in dichloromethane (0.718 ml). Subsequently, diisopropylethylamine (9.4 ⁇ l, 54 ⁇ mol) and HATU (8.9 mg, 23.3 ⁇ mol) were added, and the mixture was stirred at room temperature for 1 hour and 30 minutes under an argon atmosphere.
  • Example 127 Methyl (S)-2-(1-(cyclohexylsulfonyl)piperidin-2-yl)-5-methylthiazole-4-carboxylate 35B
  • Compound 32-1 14 mg, 36 ⁇ mol
  • Lawesson's reagent 27.6 mg, 68 ⁇ mol
  • tetrahydrofuran 1.2 ml
  • Example 128 (S)-2-(1-(Cyclohexylsulfonyl)piperidin-2-yl)-5-methylthiazole-4-carboxylic acid 36B
  • Compound 35B (11.1 mg, 29 ⁇ mol) prepared in Example 127 was added to a 10 ml eggplant-shaped flask and dissolved in tetrahydrofuran (0.84 ml), methanol (0.235 ml) and water (78 ⁇ l).
  • Lithium hydroxide monohydrate (21.7 mg, 0.517 mmol) was added and stirred at room temperature for 17 hours.
  • a 1 M aqueous solution of hydrochloric acid was added to make the mixture acidic (about pH 4), and the mixture was extracted with chloroform. After filtering the organic layer with a phase separator (3 ml), the solvent was distilled off to obtain 7.7 mg (23.5 ⁇ mol, 72%) of the target compound 36B (amorphous solid).
  • Example 129 (S)-N-benzyl-2-(1-(cyclohexylsulfonyl)piperidin-2-yl)-5-methylthiazole-4-carboxamide 37B
  • Compound 36B (5.5 mg, 15 ⁇ mol) prepared in Example 128 was added to a 10 ml eggplant-shaped flask and dissolved in dichloromethane (0.591 ml). Subsequently, diisopropylethylamine (7.7 ⁇ l, 44 ⁇ mol) and HATU (7.9 mg, 20.7 ⁇ mol) were added, and the mixture was stirred at room temperature for 1 hour under an argon atmosphere.
  • Table 23 Physical property data for the compounds prepared in Examples 120-129 are shown in Table 23.
  • Example 130 Methyl (S)-2-(1-(cyclohexylsulfonyl)piperidin-2-yl)-5-methyl-1H- Imidazole-4-carboxylate 38B
  • Compound 32-1 (22.1 mg, 57 ⁇ mol) was added to a 10 ml eggplant-shaped flask, and toluene (0.25 ml) was added to perform azeotropic operation once.
  • toluene (0.948 ml), trifluoroacetic acid (8.7 ⁇ l, 0.114 mmol), and 2M ethanol solution of ammonia (57 ⁇ l, 0.114 mmol) were added, and the mixture was stirred at 110° C. for 18 hours under an argon atmosphere.
  • Example 131 (S)-1-Benzyl-4-(1-((4-fluorophenyl)sulfonyl)pyrrolidin-2-yl)-1H-1,2,3-triazole 39AJ
  • Example 131-1 (S)-1-benzyl-4-(pyrrolidin-2-yl)-1H-1,2,3-triazole 39-2
  • Compound 39-1 38.6 mg, 0.118 mmol
  • 4 N HCl / Dioxane (1.18 ml) and water (0.118 ml) were added, and the mixture was stirred at room temperature for 1 hour.
  • the mixture was made basic by adding a saturated aqueous solution of sodium hydrogencarbonate, and then extracted with chloroform. After drying with magnesium sulfate, the residue was separated by filtration, and the solvent was distilled off to obtain 27.3 mg (0.118 mmol, 100%) of the target compound 39-2 (white solid).
  • Example 131-2 (S)-1-benzyl-4-(1-((4-fluorophenyl)sulfonyl)pyrrolidin-2-yl)-1H-1,2,3-triazole 39AJ
  • Compound 39-2 (8.5 mg, 37.2 ⁇ mol) was added to a 10 ml eggplant-shaped flask while washing with dichloromethane (0.745 ml), pyridine (12 ⁇ l, 0149 mmol) and DMAP (1.4 mg, 11 ⁇ mol) were sequentially added, and finally 4-Fluorobenzenesulfonyl chloride (14.6 mg, 74 ⁇ mol) was added to and stirred at room temperature for 1 hour and 20 minutes.
  • Example 132 S)-1-(Cyclohexylsulfonyl)-2-(5-phenyl-1H-imidazol-2-yl)piperidine 40B
  • Example 132-1 (S)-1-(Cyclohexylsulfonyl)-N-(2-oxo-2-phenylethyl)piperidine-2-carboxamide
  • 40-1 (S)-1-(Cyclohexylsulfonyl)piperidine-2-carboxylic acid (50 mg, 0.182 mmol) and 2-amino-1-(phenyl)ethanone hydrochloride (36.1 mg, 0.200 mmol) were placed in a 10 ml eggplant-shaped flask.
  • Example 132-2 S)-1-(Cyclohexylsulfonyl)-2-(5-phenyl-1H-imidazol-2-yl)piperidine 40B
  • Compound 40-1 (8.4 mg, 21 ⁇ mol) was added to a 10 ml eggplant-shaped flask, and toluene (0.2 ml) was added to perform azeotropic operation once.
  • toluene (1.07 ml) and separately prepared ammonium trifluoroacetate (70.1 mg, 0.535 mmol) were added, and the mixture was heated under reflux at 130° C. for 16 hours under an argon atmosphere.
  • Example 134 (3S,5S)-1-((4-fluorophenyl)sulfonyl)-5-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-3-carbonitrile 41AJ
  • Example 135 (3S,5S)-1-((4-fluorophenyl)sulfonyl)-5-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-3-carboxamide 42AJ
  • Example 135-1: (3S,5S)-5-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-3-carboxamide 42-2 Compound 41-1 (38.9 mg, 0.102
  • Example 134-2 (3S,5S)-1-((4-fluorophenyl)sulfonyl)-5-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl) Pyrrolidine-3-carbonitrile 41AJ
  • Example 135-2 (3S,5S)-1-((4-fluorophenyl)sulfonyl)-5-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl) Pyrrolidine-3-carboxamide 42AJ
  • a mixture of compounds 41-2 and 42-2 (11.5 mg, 40.7 ⁇ mol) was added to a 10 ml eggplant flask while washing with dichloromethane (0.718 ml), and pyridine (26.2 ⁇ l, 0.326 mmol) and DMAP (1.5 mg, 12 ⁇ mol) were added.
  • Example 136 (2S,4S)-N,4-diphenyl-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbothioamide 7AQ
  • Compound 7-2 (8.5 mg, 25 ⁇ mol) was added to a 4 ml vial, THF (0.34 ml) and phenylisothiocyanate (4.6 ⁇ l, 38 ⁇ mol) were added in that order, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Water was added and the mixture was extracted with ethyl acetate.
  • Example 137 (2S,4S)-N-benzyl-4-phenyl-2-(3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbothioamide 7AR
  • Compound 7-2 (8.3 mg, 25 ⁇ mol) was added to a 4 ml vial, THF (0.33 ml) and benzylisothiocyanate (4.0 ⁇ l, 30 ⁇ mol) were added in that order, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Water was added and the mixture was extracted with ethyl acetate.
  • Example 138 tert-butyl ((5-((2S,4S)-1-((4-fluorophenyl)sulfonyl)-4-phenylpyrrolidin-2-yl)-1,2,4-oxadiazol-3-yl) Methyl) carbamate 43AJ
  • Example 138-1 (9H-fluoren-9-yl)methyl (2S,4S)-2-(3-(((tert-butoxycarbonyl)amino)methyl)-1,2,4-oxadiazole- 5-yl)-4-phenylpyrrolidine-1-carboxylate 43-1
  • 1-Fmoc-4-phenylpyrrolidine-2-carboxylic acid 131 mg, 0.317 mmol was added to a 25 ml eggplant-shaped flask and dissolved in dichloromethane (1.97 ml).
  • HATU 144.6 mg, 0.380 mmol
  • diisopropylethylamine (0.110 ml, 0.634 mmol) were added, and the mixture was stirred at room temperature for 5 minutes under an argon atmosphere.
  • tert-butyl(N-hydroxycarbamimidoylmethyl)carbamate (68.7 mg, 0.349 mmol) was added while washing with dichloromethane (1.2 ml), and the mixture was stirred at room temperature for 1.5 hours.
  • Example 138-2 tert-butyl ((5-((2S,4S)-1-((4-fluorophenyl)sulfonyl)-4-phenylpyrrolidin-2-yl)-1,2,4-oxadi Azoll-3-yl)methyl)carbamate 43AJ
  • Compound 43-1 (17.4 mg, 31 ⁇ mol) was added to a 10 ml eggplant-shaped flask, dichloromethane (0.61 ml) and piperidine (47 ⁇ l, 0.461 mmol) were added, and the mixture was stirred at room temperature for 1 hour and 30 minutes.
  • Example 139 N-((5-((2S,4S)-1-((4-fluorophenyl)sulfonyl)-4-phenylpyrrolidin-2-yl)-1,2,4-oxadiazol-3-yl)methyl ) quinoline-2-carboxamide 45AJ
  • Example 139-1 (5-((2S,4S)-1-((4-fluorophenyl)sulfonyl)-4-phenylpyrrolidin-2-yl)-1,2,4-oxadiazole-3- yl)methanamine 44AJ
  • Compound 44AJ (11.0 mg, 21.9 ⁇ mol) was added to a 10 ml eggplant-shaped flask, 4N hydrochloric acid/dioxane (0.292 ml) and water (29 ⁇ l) were added, and the mixture was stirred at room temperature for 1 hour.
  • Example 139-2 N-((5-((2S,4S)-1-((4-fluorophenyl)sulfonyl)-4-phenylpyrrolidin-2-yl)-1,2,4-oxadiazole -3-yl)methyl)quinoline-2-carboxamide 45AJ
  • Compound 44AJ (4.0 mg, 9.9 ⁇ mol) was added to a 4 ml vial bottle, followed by dichloromethane (0.398 ml), HATU (6.1 mg, 15.9 ⁇ mol) and 2-quinolinecarboxylic acid (2.6 mg, 14.9 ⁇ mol).
  • Diisopropylethylamine (17.3 ⁇ l, 99 ⁇ mol) was added, and the mixture was stirred at room temperature for 1 hour.
  • Example 140 N-((5-((2S,4S)-1-((4-fluorophenyl)sulfonyl)-4-phenylpyrrolidin-2-yl)-1,2,4-oxadiazol-3-yl)methyl ) quinoline-3-carboxamide 46AJ
  • Compound 44AJ (4.7 mg, 11.7 ⁇ mol) was added to a 4 ml vial bottle, followed by dichloromethane (0.467 ml), HATU (7.1 mg, 18.7 ⁇ mol) and 3-quinolinecarboxylic acid (3.1 mg, 17.5 ⁇ mol).
  • Diisopropylethylamine (20.3 ⁇ l, 0.117 mmol) was added and stirred at room temperature for 1 hour.
  • Test example 1 In vitro anti-respiratory syncytial virus growth inhibitory activity test Vero cells (3.4 x 10 5 cells/mL) and human respiratory syncytial virus A2 strain (1.7 x 10 4 TCID50/mL) mixed solution (10% FCS-added EMEM medium) at 50 ⁇ L/ After addition to a 96-well flat plate in wells, 10% FCS-added EMEM medium adjusted to the desired final concentration of the test compound was added at 50 ⁇ L/well, 37° C., in the presence of 5% CO 2 cultured in After culturing for 3 days, remove the supernatant, wash the cells with PBS(-), and drop 50 ⁇ L/well of the cell lysis buffer attached to the SingleShot (registered trademark) Cell Lysis Kit (Bio-Rad). The cells were lysed with a lysate to obtain a cell lysate.
  • Vero cells 3.4 x 10 5 cells/mL
  • Human RS virus RNA copy numbers in cell lysates were determined by quantitative RT-PCR using the iTaq Universal SYBR Green One-Step Kit (Bio-Rad). That is, a primer targeting the human respiratory syncytial virus N gene (Rameix-Welti et al, Nat Commun. 5: 5104, 2014. doi: 10.1038/ncomms6104) was used, and the reaction solution was prepared according to the instructions attached to the kit. PCR reactions and signal detection were performed using the 96-well PikoReal Real-Time PCR System (TCR0096, Thermo Fisher Scientific).
  • the copy number was calculated by a relative method using a comparative Ct method using virus-infected cells to which no compound was added as a control.
  • the results are shown in Tables 25-29.
  • the results demonstrate antiviral activity in the following IC50 ranges: A: IC50 ⁇ 10 ⁇ M, B: IC50 10 ⁇ M ⁇ 50 ⁇ M, C: IC50 >50 ⁇ M
  • Table 30 similarly shows the antiviral activity of the compounds prepared in Tables 7-3 and 8-3.
  • the present invention is useful in treating or preventing respiratory syncytial virus infection.

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002516904A (ja) * 1998-06-03 2002-06-11 ジーピーアイ ニル ホールディングス インコーポレイテッド Ｎ−複素環式カルボン酸またはカルボン酸等配電子体のｎ−結合スルホンアミド
JP2004500355A (ja) * 1999-12-01 2004-01-08 アゴウロン・ファーマスーティカルス・インコーポレーテッド ニューロンの生長及び伸長を刺激する化合物、組成物及び方法
JP2004502688A (ja) * 2000-06-30 2004-01-29 エフ．ホフマン−ラ　ロシュ　アーゲー スルホニル−ピロリジン誘導体
JP2004123556A (ja) * 2002-09-30 2004-04-22 Taisho Pharmaceut Co Ltd オキサジアゾール誘導体
JP2004123557A (ja) * 2002-09-30 2004-04-22 Taisho Pharmaceut Co Ltd アリールオキシメチルオキサジアゾール誘導体
JP2006523669A (ja) * 2003-03-10 2006-10-19 ファイザー・インク Ｎｉｍａ調節タンパク質（ｐｉｎ１）を阻害するための、リン酸／硫酸エステル化合物および医薬組成物
JP2008501752A (ja) * 2004-06-08 2008-01-24 サンセラ ファーマシューティカルズ （シュバイツ） アーゲー Ｄｐｐ−ｉｖ阻害剤
JP2009526065A (ja) * 2006-02-08 2009-07-16 ワイス Ｃ型肝炎ウイルスによる感染を治療するためのスルホンアミド誘導体
JP2013515746A (ja) * 2009-12-24 2013-05-09 ヴァーテックス ファーマシューティカルズ、 インコーポレイテッド フラビウイルス感染症の治療又は予防のための類似体
JP2013522375A (ja) * 2010-03-24 2013-06-13 バーテックス ファーマシューティカルズ インコーポレイテッド フラビウイルス感染を処置または予防するためのアナログ
WO2014105926A1 (en) * 2012-12-31 2014-07-03 Hetero Research Foundation Novel betulinic acid proline derivatives as hiv inhibitors
JP2015506348A (ja) * 2011-12-22 2015-03-02 ギリアード サイエンシーズ， インコーポレイテッド 抗ウイルス剤としてのピラゾロ［１，５−ａ］ピリミジン
WO2015198263A2 (en) * 2014-06-26 2015-12-30 Hetero Research Foundation Novel betulinic proline substituted derivatives as hiv inhibitors
WO2016001820A1 (en) * 2014-06-30 2016-01-07 Hetero Research Foundation Novel betulinic proline imidazole derivatives as hiv inhibitors
JP2016504284A (ja) * 2012-11-16 2016-02-12 バイオクリスト ファーマスーティカルズ，インコーポレイテッドＢｉｏｃｒｙｓｔ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． 抗ウイルス性アザ糖を含有するヌクレオシド
JP2017537118A (ja) * 2014-12-08 2017-12-14 ヤンセン・サイエンシズ・アイルランド・ユーシー Ｒｓウイルス（ｒｓｖ）複製の阻害活性を有するピペリジン置換ピラゾロ［１，５−ａ］ピリミジン誘導体
WO2018051255A1 (en) * 2016-09-14 2018-03-22 Aurigene Discovery Technologies Limited Cyclic substituted-1,3,4-oxadiazole and thiadiazole compounds as immunomodulators
WO2018051254A1 (en) * 2016-09-14 2018-03-22 Aurigene Discovery Technologies Limited Cyclic substituted-1,2,4-oxadiazole compounds as immunomodulators
WO2020067930A1 (ru) * 2018-09-28 2020-04-02 Общество с ограниченной ответственностью "Необиотек" Соединения для лечения сахарного диабета 2-го типа
JP2021106034A (ja) 2017-07-13 2021-07-26 株式会社マキタ 衣服及び報知システム
WO2021201036A1 (ja) * 2020-03-31 2021-10-07 田辺三菱製薬株式会社 ヒドロキシピロリジン誘導体およびその医薬用途

Patent Citations (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002516904A (ja) * 1998-06-03 2002-06-11 ジーピーアイ ニル ホールディングス インコーポレイテッド Ｎ−複素環式カルボン酸またはカルボン酸等配電子体のｎ−結合スルホンアミド
JP2004500355A (ja) * 1999-12-01 2004-01-08 アゴウロン・ファーマスーティカルス・インコーポレーテッド ニューロンの生長及び伸長を刺激する化合物、組成物及び方法
JP2004502688A (ja) * 2000-06-30 2004-01-29 エフ．ホフマン−ラ　ロシュ　アーゲー スルホニル−ピロリジン誘導体
JP2004123556A (ja) * 2002-09-30 2004-04-22 Taisho Pharmaceut Co Ltd オキサジアゾール誘導体
JP2004123557A (ja) * 2002-09-30 2004-04-22 Taisho Pharmaceut Co Ltd アリールオキシメチルオキサジアゾール誘導体
JP2006523669A (ja) * 2003-03-10 2006-10-19 ファイザー・インク Ｎｉｍａ調節タンパク質（ｐｉｎ１）を阻害するための、リン酸／硫酸エステル化合物および医薬組成物
JP2008501752A (ja) * 2004-06-08 2008-01-24 サンセラ ファーマシューティカルズ （シュバイツ） アーゲー Ｄｐｐ−ｉｖ阻害剤
JP2009526065A (ja) * 2006-02-08 2009-07-16 ワイス Ｃ型肝炎ウイルスによる感染を治療するためのスルホンアミド誘導体
JP2013515746A (ja) * 2009-12-24 2013-05-09 ヴァーテックス ファーマシューティカルズ、 インコーポレイテッド フラビウイルス感染症の治療又は予防のための類似体
JP2013522375A (ja) * 2010-03-24 2013-06-13 バーテックス ファーマシューティカルズ インコーポレイテッド フラビウイルス感染を処置または予防するためのアナログ
JP2015506348A (ja) * 2011-12-22 2015-03-02 ギリアード サイエンシーズ， インコーポレイテッド 抗ウイルス剤としてのピラゾロ［１，５−ａ］ピリミジン
JP2016504284A (ja) * 2012-11-16 2016-02-12 バイオクリスト ファーマスーティカルズ，インコーポレイテッドＢｉｏｃｒｙｓｔ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． 抗ウイルス性アザ糖を含有するヌクレオシド
WO2014105926A1 (en) * 2012-12-31 2014-07-03 Hetero Research Foundation Novel betulinic acid proline derivatives as hiv inhibitors
WO2015198263A2 (en) * 2014-06-26 2015-12-30 Hetero Research Foundation Novel betulinic proline substituted derivatives as hiv inhibitors
WO2016001820A1 (en) * 2014-06-30 2016-01-07 Hetero Research Foundation Novel betulinic proline imidazole derivatives as hiv inhibitors
JP2017537118A (ja) * 2014-12-08 2017-12-14 ヤンセン・サイエンシズ・アイルランド・ユーシー Ｒｓウイルス（ｒｓｖ）複製の阻害活性を有するピペリジン置換ピラゾロ［１，５−ａ］ピリミジン誘導体
WO2018051255A1 (en) * 2016-09-14 2018-03-22 Aurigene Discovery Technologies Limited Cyclic substituted-1,3,4-oxadiazole and thiadiazole compounds as immunomodulators
WO2018051254A1 (en) * 2016-09-14 2018-03-22 Aurigene Discovery Technologies Limited Cyclic substituted-1,2,4-oxadiazole compounds as immunomodulators
JP2021106034A (ja) 2017-07-13 2021-07-26 株式会社マキタ 衣服及び報知システム
WO2020067930A1 (ru) * 2018-09-28 2020-04-02 Общество с ограниченной ответственностью "Необиотек" Соединения для лечения сахарного диабета 2-го типа
WO2021201036A1 (ja) * 2020-03-31 2021-10-07 田辺三菱製薬株式会社 ヒドロキシピロリジン誘導体およびその医薬用途

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
ALJABR, W.TOUZELET, 0.POLLAKIS, G.WU, W.MUNDAY, D. C.HUGHES, M.HERTZ-FOWLER, C.KENNY, J.FEARNS, R.BARR, J. N.: "Investigating the Influence of Ribavirin on Human Respiratory Syncytial Virus RNA Synthesis by Using a High-Resolution Transcriptome Sequencing Approach", J. VIROL., vol. 90, 2015, pages 4876 - 4888
BARR, R.GREEN, C. A.SANDE, C. J.DRYSDALE, S. B., THER. ADV. INFECTIOUS DIS., vol. 6, 2019, pages 1 - 9
DOMACHOWSKE, J. B.ANDERSON, E. J.GOLDSTEIN, M.: "The Future of Respiratory Syncytial Virus Disease Prevention and Treatment", INFECT. DIS. THER., vol. 10, 2021
HARRISON ET AL.: "Compendium of Synthetic Organic Methods", vol. 1-8, 2015, JOHN WILEY & SONS
HIROYUKI TSUTSUMI, CLINICAL SIGNIFICANCE OF PALIVIZUMAB ADMINISTRATION, INFECTIOUS AGENTS SURVEILLANCE REPORT (IASR, vol. 39, 2018, pages 219 - 220
K. OKADAM. MIZUNOH. MORIUCHI, SKUSUDA, IMORIOKA, Y.MORI, K.OKAMOTO, K.OKADA, S.YOSHIHARA, T.YAMAGISHI, U.: "Japanese Journal of Pediatrics", vol. 123, 2019, JAPANESE SOCIETY OF PAEDIATRICS COMMITTEE, article "Consensus Guidelines for the Use of Palivizumab in Japan", pages: 807 - 813
KANG IOU-JIUN, HSU SHENG-JU, YANG HUI-YUN, YEH TENG-KUANG, LEE CHUNG-CHI, LEE YEN-CHUN, TIAN YA-WEN, SONG JEN-SHIN, HSU TSU-AN, CH: "A Potent, Selective, and Orally Bioavailable HCV NS5A Inhibitor for Treatment of Hepatitis C Virus: ( S )-1-(( R )-2-(Cyclopropanecarboxamido)-2-phenylacetyl)- N -(4-phenylthiazol-2-yl)pyrrolidine-2-carboxamide", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 60, no. 1, 12 January 2017 (2017-01-12), US , pages 228 - 247, XP093016829, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.6b00962 *
PETER G. M. WUTS: "Greene's Protecting groups in Organic Synthesis", 2014, JOHN WILEY & SONS, INC.
RC. LAROCK: "Comprehensive Organic Transformations", 1999, JOHN WILEY AND SONS, INC.
See also references of EP4361148A4

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025206404A1 (ja) * 2024-03-29 2025-10-02 国立大学法人 大分大学 線維症治療のための抗線維化化合物

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