WO2024043334A1 - 新規なピペラジン誘導体又はその塩及び医薬組成物 - Google Patents

新規なピペラジン誘導体又はその塩及び医薬組成物 Download PDF

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WO2024043334A1
WO2024043334A1 PCT/JP2023/030733 JP2023030733W WO2024043334A1 WO 2024043334 A1 WO2024043334 A1 WO 2024043334A1 JP 2023030733 W JP2023030733 W JP 2023030733W WO 2024043334 A1 WO2024043334 A1 WO 2024043334A1
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Prior art keywords
group
optionally substituted
amino
piperazin
ethyl
Prior art date
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Ceased
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PCT/JP2023/030733
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English (en)
French (fr)
Japanese (ja)
Inventor
一生 土井
将祐 藤原
賢太朗 古屋
朋史 仲江
啓太 田中
邦彦 西野
聖司 山▲崎▼
良介 中島
孝禎 鈴木
悠里 高田
敦史 中川
栄樹 山下
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Fujifilm Corp
University of Osaka NUC
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Osaka University NUC
Fujifilm Corp
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Application filed by Osaka University NUC, Fujifilm Corp filed Critical Osaka University NUC
Priority to AU2023331216A priority Critical patent/AU2023331216A1/en
Priority to JP2024542889A priority patent/JPWO2024043334A1/ja
Priority to EP23857442.0A priority patent/EP4578849A4/en
Priority to CN202380062202.6A priority patent/CN119816484A/zh
Publication of WO2024043334A1 publication Critical patent/WO2024043334A1/ja
Priority to US19/061,542 priority patent/US20250326744A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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Definitions

  • the present invention relates to novel piperazine derivatives or salts thereof that exhibit strong antibacterial activity against Gram-negative bacteria, particularly Pseudomonas aeruginosa, and pharmaceutical compositions containing them.
  • Drug-resistant bacteria are rapidly increasing in the world, and it is predicted that effective therapeutic drugs will run out in the near future, leading to an increase in deaths and large economic losses due to drug-resistant bacteria.
  • infections caused by multidrug-resistant Gram-negative bacteria such as multidrug-resistant Pseudomonas aeruginosa
  • Gram-negative bacteria have multiple drug resistance mechanisms, and the combination of these mechanisms results in multidrug resistance.
  • increased expression of drug efflux pumps that transport antibacterial agents to the outside of the bacterial cell and render them ineffective is known as a mechanism for acquiring resistance to a wide variety of antibacterial agents.
  • Bacteria have many drug efflux pumps, and drug efflux pumps are involved in both natural and acquired resistance of bacteria by expelling antimicrobial agents from the bacterial body.
  • Pseudomonas aeruginosa is a type of Gram-negative bacterium and is a major causative species of serious infections such as nosocomial pneumonia. Additionally, Pseudomonas aeruginosa tends to exhibit resistance to multiple types of antimicrobial agents simultaneously.
  • multiple antibacterial agents are used in combination because a single antibacterial agent cannot be expected to be sufficiently effective.
  • sufficient effects have not been obtained (Non-Patent Document 1). Compounds that inhibit these drug efflux pumps can restore the activity of antibacterial agents that are no longer effective against multidrug-resistant Pseudomonas aeruginosa.
  • the present inventors conducted extensive research and found that the compound represented by the general formula [1] or its salt inhibits Gram-negative bacteria such as Pseudomonas aeruginosa and multidrug-resistant Pseudomonas aeruginosa.
  • the present invention was completed based on the discovery that the drug strongly inhibits the drug efflux pump of drug-resistant Gram-negative bacteria, including the following:
  • Z 1 is a nitrogen atom or a group represented by the formula CH;
  • Z 2 is a nitrogen atom or the general formula CR 4 "wherein R 4 is a hydrogen atom, a hydroxyl group, a cyano group, an optionally substituted acyloxy group, an optionally substituted amino group, a substituted optionally substituted carbamoyl group, optionally substituted ureido group, optionally substituted C 1-6 alkyl group, optionally substituted C 1-6 alkoxyC 1-6 alkyl group, optionally substituted C 1-6 alkyl group, optionally substituted C 1-6 alkyl group, optionally substituted C 1-6 alkyl group a good aryl C 1-6 alkoxy C 1-6 alkyl group or an optionally substituted C 1-6 alkoxy group;
  • R 1 and R 2 are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group
  • Y 1 is an optionally substituted C 3-10 cycloalkyl group, an optionally substituted aryl group, an optionally substituted monocyclic heterocyclic group, or an optionally substituted bicyclic group a heterocyclic group
  • X 2 is a C 1-3 alkylene group or a bond
  • Y 2 is an optionally substituted C 3-10 cycloalkyl group, an optionally substituted aryl group, an optionally substituted monocyclic heterocyclic group, or an optionally substituted bicyclic group It shows a group represented by a heterocyclic group. ” or its salt.
  • Z 1 is a nitrogen atom or a group represented by the formula CH;
  • Z 2 is a nitrogen atom or the general formula CR 4a ⁇ wherein R 4a is a hydrogen atom, a hydroxyl group, a cyano group, an optionally substituted acyloxy group, an optionally substituted amino group, a substituted optionally substituted carbamoyl group, optionally substituted ureido group, optionally substituted C 1-6 alkyl group, optionally substituted C 1-6 alkoxyC 1-6 alkyl group, or optionally substituted C 1-6 alkyl group represents a good aryl C 1-6 alkoxy C 1-6 alkyl group (provided that at least one of Z 1 or Z 2 is a nitrogen atom);
  • R 1 and R 2 may be the same or different and may be substituted with a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted C 1-6 alkyl group, or both may be substituted.
  • R 3 is a hydrogen atom or an optionally substituted C 1-6 alkyl group;
  • X 1 is an optionally substituted C 2-6 alkylene group, an optionally substituted C 2-6 alkenylene group, an optionally substituted C 2-6 alkynylene group, the general formula -NR 5 -CO -, a group represented by the general formula -CO-NR 5 -, a group represented by the general formula -CR 5 -NR 5 -, a group represented by the general formula -CR 5 -O-,
  • R 5 represents a hydrogen atom or a C 1-6 alkyl group.
  • Y 1 is an optionally substituted C 3-10 cycloalkyl group, an optionally substituted aryl group, an optionally substituted monocyclic heterocyclic group, or an optionally substituted bicyclic group a heterocyclic group
  • X 2 is a C 1-3 alkylene group or a bond
  • Y 2 is an optionally substituted C 3-10 cycloalkyl group, an optionally substituted aryl group, an optionally substituted monocyclic heterocyclic group, or an optionally substituted bicyclic group
  • ⁇ 1> which is a heterocyclic group, or a salt thereof.
  • Z 1 is a group represented by the formula CH; The compound or salt thereof according to ⁇ 1> or ⁇ 2>, wherein Z 2 is a nitrogen atom.
  • Z 1 is a nitrogen atom
  • Z 2 is a general formula CR 4a "wherein R 4a is a hydrogen atom, a hydroxyl group, a cyano group, an optionally substituted acyloxy group, an optionally substituted amino group, An optionally substituted carbamoyl group, an optionally substituted ureido group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 1-6 alkoxyC 1-6 alkyl group, or a substituted arylC 1-6 alkoxyC 1-6 alkyl group which may be ⁇ 1> or ⁇ 2>
  • Y 1 is an optionally substituted C 3-10 cycloalkyl group, an optionally substituted aryl group, or an optionally substituted bicyclic heterocyclic group or a salt thereof.
  • ⁇ 5> The compound or salt thereof according to ⁇ 1> or ⁇ 2>, wherein R 3 is a hydrogen atom or an optionally substituted C 1-6 alkyl group.
  • R 1 and R 2 are the same or different and are a hydrogen atom, an optionally substituted amino group, or an optionally substituted C 1-6 alkyl group salt.
  • Y 1 is an optionally substituted aryl group.
  • ⁇ 8> The compound or salt thereof according to ⁇ 1> or ⁇ 2>, wherein Y 2 is an optionally substituted aryl group or an optionally substituted bicyclic heterocyclic group.
  • X 1 is an optionally substituted C 2-6 alkylene group or an optionally substituted C 2-6 alkenylene group.
  • X 2 is a methylene group.
  • the compound is (R)-2-amino-2-(1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4 -(2-(methylthio)benzyl)piperazin-1-yl)ethan-1-one, (R)-2-amino-2-(1-(2-(4-chloro-[1,1'-biphenyl]) -2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-6-fluorobenzyl)piperazin-1-yl)ethane-1-one, (R)-2-amino -2-(1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4- fluorobenzy
  • the compound is (R)-2-amino-2-(1-(2-(2',4-dichloro-3'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidine-4 -yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethane-1-one hydrochloride, (R)-2-amino-2-(1-(2- (3',4-dichloro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl) Piperazin-1-yl)ethane-1-one hydrochloride, (R)-2-amino-2-(1-(2-(4-chloro-2'-fluoro-5'-hydroxy-[1,1 '-biphenyl]-2-yl)ethyl)ethy
  • Z 1 is a nitrogen atom or a group represented by the formula CH;
  • Z 2 is a nitrogen atom or the general formula CR 4 "wherein R 4 is a hydrogen atom, a hydroxyl group, a cyano group, an optionally substituted acyloxy group, an optionally substituted amino group, a substituted optionally substituted carbamoyl group, optionally substituted ureido group, optionally substituted C 1-6 alkyl group, optionally substituted C 1-6 alkoxyC 1-6 alkyl group, optionally substituted C 1-6 alkyl group, optionally substituted C 1-6 alkyl group, optionally substituted C 1-6 alkyl group a good aryl C 1-6 alkoxy C 1-6 alkyl group or an optionally substituted C 1-6 alkoxy group;
  • R 1 and R 2 are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, an optionally substituted
  • Y 1 is an optionally substituted C 3-10 cycloalkyl group, an optionally substituted aryl group, an optionally substituted monocyclic heterocyclic group, or an optionally substituted bicyclic group a heterocyclic group
  • X 2 is a C 1-3 alkylene group or a bond
  • Y 2 is an optionally substituted C 3-10 cycloalkyl group, an optionally substituted aryl group, an optionally substituted monocyclic heterocyclic group, or an optionally substituted bicyclic group It shows a group represented by a heterocyclic group. ” or its salt.
  • Z 1 is a nitrogen atom or a group represented by the formula CH;
  • Z 2 is a nitrogen atom or the general formula CR 4a ⁇ wherein R 4a is a hydrogen atom, a hydroxyl group, a cyano group, an optionally substituted acyloxy group, an optionally substituted amino group, a substituted optionally substituted carbamoyl group, optionally substituted ureido group, optionally substituted C 1-6 alkyl group, optionally substituted C 1-6 alkoxyC 1-6 alkyl group, or optionally substituted C 1-6 alkyl group represents a good aryl C 1-6 alkoxy C 1-6 alkyl group (provided that at least one of Z 1 or Z 2 is a nitrogen atom);
  • R 1 and R 2 may be the same or different and may be substituted with a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted C 1-6 alkyl group, or both may be substituted.
  • R 3 is a hydrogen atom or an optionally substituted C 1-6 alkyl group;
  • X 1 is an optionally substituted C 2-6 alkylene group, an optionally substituted C 2-6 alkenylene group, an optionally substituted C 2-6 alkynylene group, general formula -NR 5 -CO -, a group represented by the general formula -CO-NR 5 -, a group represented by the general formula -CR 5 -NR 5 -, a group represented by the general formula -CR 5 -O-,
  • R 5 represents a hydrogen atom or a C 1-6 alkyl group.
  • Y 1 is an optionally substituted C 3-10 cycloalkyl group, an optionally substituted aryl group, an optionally substituted monocyclic heterocyclic group, or an optionally substituted bicyclic group a heterocyclic group
  • X 2 is a C 1-3 alkylene group or a bond
  • Y 2 is an optionally substituted C 3-10 cycloalkyl group, an optionally substituted aryl group, an optionally substituted monocyclic heterocyclic group, or an optionally substituted bicyclic group
  • Z 1 is a group represented by the formula CH; The compound or salt thereof according to ⁇ 1a> or ⁇ 2a>, wherein Z 2 is a nitrogen atom.
  • Z 1 is a nitrogen atom
  • Z 2 is a general formula CR 4a "wherein R 4a is a hydrogen atom, a hydroxyl group, a cyano group, an optionally substituted acyloxy group, an optionally substituted amino group, An optionally substituted carbamoyl group, an optionally substituted ureido group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 1-6 alkoxyC 1-6 alkyl group, or a substituted arylC 1-6 alkoxyC 1-6 alkyl group which may be ⁇ 1a> to ⁇ 2a> wherein Y 1 is an optionally substituted C 3-10 cycloalkyl group, an optionally substituted aryl group, or an optionally substituted bicyclic heterocyclic group A
  • ⁇ 5a> The compound or salt thereof according to any one of ⁇ 1a> to ⁇ 4a>, wherein R 3 is a hydrogen atom or an optionally substituted C 1-6 alkyl group.
  • R 3 is a hydrogen atom or an optionally substituted C 1-6 alkyl group.
  • ⁇ 6a> In any one of ⁇ 1a> to ⁇ 5a>, wherein R 1 and R 2 are the same or different and are a hydrogen atom, an optionally substituted amino group, or an optionally substituted C 1-6 alkyl group The described compound or its salt.
  • Y 1 is an optionally substituted aryl group.
  • ⁇ 8a> The compound or salt thereof according to any one of ⁇ 1a> to ⁇ 7a>, wherein Y 2 is an optionally substituted aryl group or an optionally substituted bicyclic heterocyclic group.
  • ⁇ 9a> The compound or salt thereof according to any one of ⁇ 1a> to ⁇ 8a>, wherein X 1 is an optionally substituted C 2-6 alkylene group or an optionally substituted C 2-6 alkenylene group .
  • ⁇ 10a> The compound or salt thereof according to any one of ⁇ 1a> to ⁇ 9a>, wherein X 2 is a methylene group.
  • the compound is (R)-2-amino-2-(1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4 -(2-(methylthio)benzyl)piperazin-1-yl)ethan-1-one, (R)-2-amino-2-(1-(2-(4-chloro-[1,1'-biphenyl]) -2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-6-fluorobenzyl)piperazin-1-yl)ethane-1-one, (R)-2-amino -2-(1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4- fluorobenz
  • the compound is (R)-2-amino-2-(1-(2-(2',4-dichloro-3'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidine-4 -yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethane-1-one hydrochloride, (R)-2-amino-2-(1-(2- (3',4-dichloro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl) Piperazin-1-yl)ethane-1-one hydrochloride, (R)-2-amino-2-(1-(2-(4-chloro-2'-fluoro-5'-hydroxy-[1,1 '-biphenyl]-2-yl)ethyl)ethy
  • ⁇ A> Treatment of infectious diseases caused by Gram-negative bacteria or drug-resistant bacteria thereof, comprising administering to a subject the compound or salt thereof according to any one of ⁇ 1> to ⁇ 12> or ⁇ 1a> to ⁇ 12a>.
  • ⁇ B> The compound according to any one of ⁇ 1> to ⁇ 12> or ⁇ 1a> to ⁇ 12a> or a salt thereof for use in the treatment of infections caused by Gram-negative bacteria or drug-resistant bacteria thereof.
  • ⁇ C> Use of the compound or a salt thereof according to any one of ⁇ 1> to ⁇ 12> or ⁇ 1a> to ⁇ 12a> for the manufacture of a pharmaceutical composition.
  • ⁇ D> The compound according to any one of ⁇ 1> to ⁇ 12> or ⁇ 1a> to ⁇ 12a> or a salt thereof for the production of a pharmaceutical composition for the treatment of infectious diseases caused by Gram-negative bacteria or their drug-resistant bacteria. Use of.
  • the compound of the present invention or a salt thereof exhibits strong drug efflux pump inhibitory activity against bacteria that produce drug efflux pumps, such as enterobacteria or Gram-negative bacteria that produce drug efflux pumps and their drug-resistant bacteria. It is useful as a medicine when used in combination with other antibacterial agents.
  • the pharmaceutical composition of the present invention exhibits strong drug efflux pump inhibitory activity against bacteria that produce drug efflux pumps, such as intestinal bacteria or Gram-negative bacteria that produce drug efflux pumps, and their drug-resistant bacteria; It is useful as a medicine when used in combination with other antibacterial agents.
  • a halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C 1-6 alkyl group refers to a straight or branched C 1-6 group such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, and hexyl group. means an alkyl group.
  • C 1-4 alkyl group means methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl or tert-butyl group.
  • C 1-3 alkyl group means methyl, ethyl, propyl or isopropyl group.
  • the C 2-6 alkenyl group refers to a straight or branched C 2-6 alkenyl group such as vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, 1,3-butadienyl, pentenyl, and hexenyl group. means.
  • the C 2-6 alkynyl group means a straight or branched C 2-6 alkynyl group such as ethynyl, propynyl, butynyl, pentynyl and hexynyl group.
  • a C 3-10 cycloalkyl group means a C 3-10 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl group.
  • C 3-8 cycloalkenyl group means C 3-8 cycloalkenyl groups such as cyclopropenyl, cyclobutenyl, 2-cyclopenten-1-yl, 2-cyclohexen-1-yl and 3-cyclohexen-1-yl group. do.
  • Aryl group means C 6-18 aryl groups such as phenyl and naphthyl groups.
  • Aryl C 1-6 alkyl group means, for example, aryl C 1-6 alkyl groups such as benzyl, diphenylmethyl, trityl, phenethyl and naphthylmethyl groups.
  • the C 1-6 alkylene group means a linear or branched C 1-6 alkylene group such as methylene, ethylene, propylene, butylene, pentylene, and hexylene group.
  • the C 1-5 alkylene group means a linear or branched C 1-5 alkylene group such as methylene, ethylene, propylene, butylene, and pentylene group.
  • C 1-3 alkylene group means methylene, ethylene, propylene or isopropylene group.
  • C 1-2 alkylene group means methylene or ethylene group.
  • the C 2-6 alkylene group means a linear or branched C 2-6 alkylene group such as ethylene, propylene, butylene, and hexylene group.
  • the C 2-6 alkenylene group means a linear or branched C 2-6 alkenylene group such as vinylene, propenylene, butenylene, and pentenylene group.
  • the C 2-6 alkynylene group means a straight or branched C 2-6 alkynylene group such as ethynylene, propynylene, butynylene and pentynylene groups.
  • a C 1-6 alkoxy group refers to a straight or branched C 1- such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy group.
  • 6 means alkyloxy group.
  • C 1-6 alkoxy C 1-6 alkyl group means C 1-6 alkyloxy C 1-6 alkyl group such as methoxymethyl and 1-ethoxyethyl group.
  • Benzyloxy C 1-6 alkyl group means benzyloxy C 1-6 alkyl group such as benzyloxymethyl and benzyloxyethylnaphthylmethyloxymethyl group.
  • the C 2-12 alkanoyl group means a straight or branched C 2-12 alkanoyl group such as acetyl, propionyl, valeryl, isovaleryl, and pivaloyl group.
  • Aroyl group means, for example, benzoyl or naphthoyl group.
  • Acyl group means, for example, formyl group, succinyl group, glutaryl group, maleoyl group, phthaloyl group, C 2-12 alkanoyl group or aroyl group.
  • the acyloxy group means a C 2-12 alkanoyloxy group such as acetyloxy and propionyloxy group, or an aroyloxy group such as benzoyloxy and naphthoyloxy group.
  • a C 1-6 alkoxycarbonyl group refers to a straight or branched C 1-6 alkyloxy group such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, and 1,1-dimethylpropoxycarbonyl group. means carbonyl group.
  • the aryl C 1-6 alkoxycarbonyl group means an aryl C 1-6 alkyloxycarbonyl group such as benzyloxycarbonyl and phenethyloxycarbonyl group.
  • Aryl C 1-6 alkoxy C 1-6 alkyl group means an aryl C 1-6 alkyloxy C 1-6 alkyl group such as benzyloxymethyl, benzyloxyethyl and phenethyloxymethyl group.
  • the aryloxycarbonyl group means, for example, phenyloxycarbonyl or naphthyloxycarbonyl group.
  • C 1-6 alkylamino group refers to a straight or branched chain such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, tert-butylamino, pentylamino, and hexylamino group. means a C 1-6 alkylamino group.
  • Di(C 1-6 alkyl)amino group means dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, di(tert-butyl)amino, dipentylamino, dihexylamino, (ethyl)(methyl)amino and It means a linear or branched di(C 1-6 alkyl)amino group such as a (methyl)(propyl)amino group.
  • the C 1-6 alkylthio group means a C 1-6 alkylthio group such as methylthio, ethylthio and propylthio group.
  • the C 1-6 alkylsulfonyl group means a C 1-6 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl and propylsulfonyl.
  • the arylsulfonyl group means benzenesulfonyl, p-toluenesulfonyl, naphthalenesulfonyl, or the like.
  • the C 1-6 alkylsulfonyloxy group means a C 1-6 alkylsulfonyloxy group such as methylsulfonyloxy and ethylsulfonyloxy.
  • the arylsulfonyloxy group means benzenesulfonyloxy or p-toluenesulfonyloxy group.
  • the silyl group means a silyl group such as trimethylsilyl, triethylsilyl, tributylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and triisopropylsilyl group.
  • Cyclic amino groups include aziridinyl, azetidinyl, pyrrolyl, dihydropyrrolyl, pyrrolidinyl, tetrahydropyridyl, piperidinyl, homopiperidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, thiazolinyl, thiazolidinyl, dihydrothiadiazolyl, piperazinyl, homopiperazinyl, It refers to a cyclic amino group that contains one or more nitrogen atoms as a heteroatom forming a ring, such as morpholinyl, homomorpholinyl, and thiomorpholinyl groups, and may further contain one or more oxygen or sulfur atoms.
  • a monocyclic nitrogen-containing heterocyclic group means a monocyclic nitrogen-containing heterocyclic group containing only a nitrogen atom as a ring-forming heteroatom; for example, azetidinyl group; pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolidinyl.
  • imidazolinyl imidazolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, triazolyl or tetrazolyl group
  • 5-membered nitrogen-containing heterocyclic group piperidyl, tetrahydropyridyl, pyridyl, piperazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, tetrahydropyrimidyl or homopiperazinyl group, etc.
  • a 6-membered nitrogen-containing heterocyclic group such as a homopiperidinyl group; a 7-membered nitrogen-containing heterocyclic group such as a homopiperidinyl group; or an 8-membered nitrogen-containing heterocyclic group such as an octahydroazosinyl group.
  • a monocyclic oxygen-containing heterocyclic group means a monocyclic oxygen-containing heterocyclic group containing only an oxygen atom as a ring-forming heteroatom, such as a 5-membered ring such as a tetrahydrofuranyl or furanyl group. Oxygen-containing heterocyclic groups; or 6-membered oxygen-containing heterocyclic groups such as tetrahydropyranyl or pyranyl groups.
  • the monocyclic sulfur-containing heterocyclic group means a thienyl group or the like.
  • a monocyclic nitrogen-containing/oxygen heterocyclic group means a monocyclic nitrogen-containing/oxygen heterocyclic group containing only nitrogen atoms and oxygen atoms as heteroatoms forming the ring, such as oxazolyl, oxazolidinyl, etc. , a 5-membered nitrogen-containing, oxygen-containing heterocyclic group such as an isoxazolyl or oxadiazolyl group; or a 6-membered, nitrogen-containing, oxygen-containing heterocyclic group such as a morpholinyl group.
  • a monocyclic nitrogen-containing/sulfur heterocyclic group means a monocyclic nitrogen-containing/sulfur heterocyclic group containing only nitrogen atoms and sulfur atoms as heteroatoms forming the ring, such as thiazolyl, isothiazolyl, etc. or a 5-membered nitrogen-containing sulfur heterocyclic group such as a thiadiazolyl group; or a 6-membered nitrogen-containing sulfur heterocyclic group such as a thiomorpholinyl, 1-oxidothiomorpholinyl, or 1,1-dioxidethiomorpholinyl group Examples include groups.
  • a monocyclic heterocyclic group means a monocyclic nitrogen-containing heterocyclic group, a monocyclic oxygen-containing heterocyclic group, a monocyclic sulfur-containing heterocyclic group, a monocyclic nitrogen-containing heterocyclic group, or a monocyclic nitrogen-containing heterocyclic group. group or a monocyclic nitrogen-containing/sulfur heterocyclic group.
  • a monocyclic saturated heterocyclic group means a monocyclic heterocyclic group that does not contain multiple bonds, such as aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, pyrazolidinyl, piperazinyl, oxazolidinyl, tetrahydropyrimidyl. , tetrahydrofuranyl, tetrahydropyranyl and morpholinyl groups.
  • Bicyclic nitrogen-containing heterocyclic groups include indolinyl, indolyl, isoindolinyl, isoindolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, tetrahydroquinolinyl, quinolyl, tetrahydroisoquinolinyl, isoquinolinyl, quinolidinyl, Bicyclics containing only a nitrogen atom as a heteroatom forming a ring such as cinnolinyl, phthalazinyl, quinazolinyl, dihydroquinoxalinyl, quinoxalinyl, naphthyridinyl, purinyl, pyrrolopyridinyl, dihydrocyclopentapyridinyl, pteridinyl and quinuclidinyl groups means a nitrogen-containing heterocyclic group.
  • Bicyclic oxygen-containing heterocyclic groups include 2,3-dihydrobenzofuranyl, benzofuranyl, isobenzofuranyl, chromanyl, chromenyl, isochromanyl, 1,3-benzodioxolyl, and 1,3-benzofuranyl. It means a bicyclic oxygen-containing heterocyclic group containing only an oxygen atom as a ring-forming heteroatom such as oxanyl and 1,4-benzodioxanyl groups.
  • a bicyclic sulfur-containing heterocyclic group refers to a bicyclic sulfur-containing heterocyclic group containing only a sulfur atom as a ring-forming heteroatom such as 2,3-dihydrobenzothienyl and benzothienyl groups.
  • Bicyclic nitrogen-oxygen heterocyclic groups include benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzomorpholinyl, dihydropyranopyridyl, dihydrodioxynopyridyl, and dihydropyridooxane.
  • a bicyclic nitrogen-oxygen heterocyclic group containing only nitrogen atoms and oxygen atoms as heteroatoms forming a ring, such as a dinyl group.
  • a bicyclic nitrogen-containing sulfur heterocyclic group is a bicyclic nitrogen-containing heterocyclic group containing a nitrogen atom and a sulfur atom as the heteroatoms forming the ring, such as benzothiazolyl, benzisothiazolyl, and benzothiadiazolyl groups. ⁇ Means a sulfur heterocyclic group.
  • Bicyclic heterocyclic group means bicyclic nitrogen-containing heterocyclic group, bicyclic oxygen-containing heterocyclic group, bicyclic sulfur-containing heterocyclic group, bicyclic nitrogen-containing heterocyclic group, ⁇ Means an oxygen heterocyclic group or a bicyclic nitrogen-containing/sulfur heterocyclic group.
  • Heterocyclic group means a monocyclic heterocyclic group or a bicyclic heterocyclic group.
  • Examples of the leaving group include a halogen atom, a C 1-6 alkylsulfonyloxy group or an arylsulfonyloxy group, and an imidazole group.
  • the C 1-6 alkylsulfonyloxy group, arylsulfonyloxy group or imidazole group may have a substituent.
  • Hydroxyl-protecting groups include all groups that can be used as conventional hydroxyl-protecting groups, such as those described by W. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 16-299, 2007, John Wiley & Sons. , INC.). Specifically, for example, C 1-6 alkyl group, C 2-6 alkenyl group, aryl C 1-6 alkyl group, C 1-6 alkoxyC 1-6 alkyl group, acyl group, C 1-6 alkoxycarbonyl group.
  • the amino-protecting group includes all groups that can be used as ordinary protecting groups for amino groups, such as W. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 696-926, 2007, John Wiley & Sons, Inc. Sons, INC.).
  • aryl C 1-6 alkyl group, C 1-6 alkoxy C 1-6 alkyl group, acyl group, C 1-6 alkoxycarbonyl group, aryl C 1-6 alkoxycarbonyl group, aryloxycarbonyl group, Examples include a C 1-6 alkylsulfonyl group, an arylsulfonyl group, and a silyl group. These groups may be substituted with one or more groups selected from substituent group A1.
  • Imino-protecting groups include all groups that can be used as conventional imino-protecting groups, such as W. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 696-868, 2007, John Wiley & Sons. Sons, INC.). Specifically, aryl C 1-6 alkyl group, C 1-6 alkoxy C 1-6 alkyl group, acyl group, C 1-6 alkoxycarbonyl group, aryl C 1-6 alkoxycarbonyl group, aryloxycarbonyl group, Examples include a C 1-6 alkylsulfonyl group, an arylsulfonyl group, and a silyl group. These groups may be substituted with one or more groups selected from substituent group A1.
  • Carboxyl-protecting groups include all groups that can be used as conventional carboxyl-protecting groups, such as those described by W. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 533-643, 2007, John Wiley & Sons. , INC.). Specific examples thereof include a C 1-6 alkyl group, a C 2-6 alkenyl group, an aryl C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, and a silyl group. These groups may be substituted with one or more groups selected from substituent group A1.
  • halogenated hydrocarbons include methylene chloride, chloroform or dichloroethane.
  • alcohols include methanol, ethanol, propanol, 2-propanol, butanol, and 2-methyl-2-propanol.
  • ethers include diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and diethylene glycol diethyl ether.
  • ketones include acetone, 2-butanone, and 4-methyl-2-pentanone.
  • esters include methyl acetate, ethyl acetate, propyl acetate, and butyl acetate.
  • amides include N,N-dimethylformamide, N,N-dimethylacetamide, and 1-methyl-2-pyrrolidone.
  • nitriles include acetonitrile and propionitrile.
  • aromatic hydrocarbons include benzene, toluene, and xylene.
  • Substituent group A1 hydrogen atom, halogen atom, cyano group, nitro group, oxo group, C 1-6 alkyl group optionally substituted with one or more groups selected from substituent group B2, C 2-6 alkenyl group optionally substituted with one or more groups selected from substituent group B2, a C 2-6 alkynyl group optionally substituted with one or more groups selected from substituent group B2, C 1-6 alkoxy group optionally substituted with one or more groups selected from substituent group B2, an aryloxy group optionally substituted with one or more groups selected from substituent group B1; an acyl group optionally substituted with one or more groups selected from substituent group B1; C 1-6 alkylamino group optionally substituted with one or more groups selected from substituent group B2, a di(C 1-6 alkyl)amino group which may be substituted with one or more groups selected from substituent group B2; An imino group that may be protected or substituted with one or more groups selected from substituent
  • Substituent group A2 hydrogen atom, halogen atom, cyano group, nitro group, oxo group, C 1-6 alkoxy group optionally substituted with one or more groups selected from substituent group B2, an aryloxy group optionally substituted with one or more groups selected from substituent group B1; an acyl group optionally substituted with one or more groups selected from substituent group B1; C 1-6 alkylamino group optionally substituted with one or more groups selected from substituent group B2, a di(C 1-6 alkyl)amino group which may be substituted with one or more groups selected from substituent group B2; C 1-6 alkylthio group optionally substituted with one or more groups selected from substituent group B2, an arylthio group optionally substituted with one or more groups selected from substituent group B1; C 1-6 alkylsulfonyl group optionally substituted with one or more groups selected from substituent group B2, an arylsulfonyl group optionally substituted with one
  • Substituent group B1 hydrogen atom, halogen atom, cyano group, nitro group, oxo group, a C 1-6 alkyl group optionally substituted with one or more groups selected from substituent group C; a C 2-6 alkenyl group optionally substituted with one or more groups selected from substituent group C; a C 2-6 alkynyl group optionally substituted with one or more groups selected from substituent group C; a C 1-6 alkoxy group optionally substituted with one or more groups selected from substituent group C; an aryloxy group optionally substituted with one or more groups selected from substituent group C; an acyl group optionally substituted with one or more groups selected from substituent group C; a C 1-6 alkylamino group optionally substituted with one or more groups selected from substituent group C; a di(C 1-6 alkyl)amino group which may be substituted with one or more groups selected from substituent group C; a C 1-6 alkylthio group optionally substituted with
  • Substituent group B2 hydrogen atom, halogen atom, cyano group, nitro group, oxo group, a C 1-6 alkoxy group optionally substituted with one or more groups selected from substituent group C; an aryloxy group optionally substituted with one or more groups selected from substituent group C; an acyl group optionally substituted with one or more groups selected from substituent group C; a C 1-6 alkylamino group optionally substituted with one or more groups selected from substituent group C; a di(C 1-6 alkyl)amino group which may be substituted with one or more groups selected from substituent group C; a C 1-6 alkylthio group optionally substituted with one or more groups selected from substituent group C; an arylthio group optionally substituted with one or more groups selected from substituent group C; C 1-6 alkylsulfonyl group optionally substituted with one or more groups selected from substituent group C, an arylsulfonyl group optionally substituted
  • Substituent group C halogen atom, cyano group, carbamoyl group, C 1-6 alkyl group, C 1-6 alkoxy group, an optionally protected amino group, an optionally protected imino group, an optionally protected hydroxyl group, A carboxyl group that may be protected.
  • the optionally substituted amino group, optionally substituted carbamoyl group, and optionally substituted ureido group of R4 may be substituted with one or more groups selected from substituent group A1.
  • R 4 optionally substituted acyloxy group, optionally substituted C 1-6 alkyl group, optionally substituted C 1-6 alkoxy C 1-6 alkyl group, optionally substituted aryl C
  • the 1-6 alkoxy C 1-6 alkyl group or the optionally substituted C 1-6 alkoxy group may be substituted with one or more groups selected from substituent group A2.
  • the amino group, which may be the same or differently substituted, the guanidino group, which may be substituted, or the imino group, which may be substituted together, of R 1 and R 2 are selected from substituent group A1.
  • substituent group A1 Optionally substituted with one or more groups.
  • the group represented by C 1-3 alkylene-O-C 1-3 alkylene may be substituted with one or more groups selected from substituent group A2.
  • the optionally substituted carbamoyl group or the optionally substituted C 3-10 cycloalkyl group of R 3 may be substituted with one or more groups selected from substituent group A1.
  • the optionally substituted C 1-6 alkyl group of R 3 may be substituted with one or more groups selected from substituent group A2.
  • the optionally substituted C 2-6 alkylene group, the optionally substituted C 2-6 alkenylene group, and the optionally substituted C 2-6 alkynylene group of X 1 are substituent groups excluding the oxo group. It may be substituted with one or more groups selected from A2.
  • Y 1 optionally substituted C 3-10 cycloalkyl group, optionally substituted aryl group, optionally substituted monocyclic heterocyclic group, or optionally substituted bicyclic group
  • the heterocyclic group may be substituted with one or more groups selected from substituent group A1.
  • Y 2 an optionally substituted C 3-10 cycloalkyl group, an optionally substituted aryl group, an optionally substituted monocyclic heterocyclic group, or an optionally substituted bicyclic group
  • the heterocyclic group may be substituted with one or more groups selected from substituent group A1.
  • the 6 -alkoxy C 1-6 alkyl group may be substituted with one or more groups selected from substituent group A1.
  • the optionally substituted C 1-6 alkyl group or the optionally substituted C 1-6 alkoxyC 1-6 alkyl group of R 4a is substituted with one or more groups selected from substituent group A2. You can leave it there.
  • preferred compounds include the following compounds.
  • Z 1 is a group represented by the formula CH
  • Z 2 is a nitrogen atom
  • Z 1 is a nitrogen atom
  • Z 2 is a compound of the general formula CR 4a "wherein R 4a is a hydrogen atom, a hydroxyl group, a cyano group, an optionally substituted acyloxy group, an optionally substituted amino group, optionally substituted carbamoyl group, optionally substituted ureido group, optionally substituted C 1-6 alkyl group, optionally substituted C 1-6 alkoxyC 1-6 alkyl group or an optionally substituted aryl C 1-6 alkoxy C 1-6 alkyl group.
  • R 4 in Z 2 is a hydrogen atom, a hydroxyl group, a cyano group, an optionally substituted acyloxy group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted ureido group group, optionally substituted C 1-6 alkyl group, optionally substituted C 1-6 alkoxyC 1-6 alkyl group, or optionally substituted arylC 1-6 alkoxyC 1-6 alkyl A group is preferred, and an optionally substituted C 1-6 alkyl group is more preferred.
  • R 3 is preferably a hydrogen atom or an optionally substituted C 1-6 alkyl group, and more preferably a hydrogen atom.
  • R 1 and R 2 are preferably the same or different and are a hydrogen atom, an optionally substituted amino group, or an optionally substituted C 1-6 alkyl group; More preferred is a hydrogen atom or an amino group (a compound in which the carbon atom to which the amino group is bonded has an R conformation).
  • X 1 is preferably an optionally substituted C 2-6 alkylene group or an optionally substituted C 2-6 alkenylene group, more preferably an optionally substituted C 2-6 alkylene group, and an ethylene group. is even more preferred.
  • X 2 is preferably a C 1-3 alkylene group, more preferably a methylene group.
  • Y 1 is an optionally substituted C 3-10 cycloalkyl group, an optionally substituted aryl group, an optionally substituted monocyclic heterocyclic group, or an optionally substituted bicyclic group A heterocyclic group is preferred, an optionally substituted aryl group is more preferred, and an optionally substituted phenyl group is even more preferred.
  • Y 2 is preferably an optionally substituted aryl group or an optionally substituted bicyclic heterocyclic group, more preferably an optionally substituted aryl group, and an optionally substituted phenyl group. is even more preferred.
  • Y 1 optionally substituted C 3-10 cycloalkyl group, optionally substituted aryl group, optionally substituted monocyclic heterocyclic group, or optionally substituted bicyclic group
  • the substituents of the heterocyclic group are: Halogen atom, optionally protected carboxyl group, optionally substituted carbamoyl group, hydroxyl group, optionally substituted amino group, optionally substituted C 1-6 alkyl group, substituted an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynylene group, an optionally substituted C 3-10 cycloalkyl group, an optionally substituted C 3-8 cycloalkenyl group, An optionally substituted C 1-6 alkoxy group, an optionally substituted acyl group, an optionally substituted aryl group, an optionally substituted monocyclic heterocyclic group, and an optionally substituted heterocyclic group
  • One or more groups selected from a good C 1-6 alkylthio group are preferred, including
  • Y 1 is an optionally substituted C 3-10 cycloalkyl group, an optionally substituted aryl group, an optionally substituted monocyclic heterocyclic group, or an optionally substituted bicyclic group.
  • the substituents of the heterocyclic group in the formula are preferably two groups each selected from a halogen atom and a di-substituted phenyl group.
  • Y 2 optionally substituted C 3-10 cycloalkyl group, optionally substituted aryl group, optionally substituted monocyclic heterocyclic group, or optionally substituted bicyclic group
  • the substituents of the heterocyclic group are: Halogen atom, nitro group, cyano group, hydroxyl group, optionally protected carboxyl group, optionally substituted carbamoyl group, optionally substituted amino group, optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynylene group, an optionally substituted C 1-6 alkoxy group, and an optionally substituted C 1-
  • One or more groups selected from 6- alkylthio groups are preferred, and one or more groups selected from halogen atoms, optionally substituted C 1-6 alkoxy groups, and optionally substituted C 1-6 alkylthio groups. is more preferable.
  • Examples of the salt of the compound of general formula [1] include commonly known salts with a basic group such as an amino group or an acidic group such as a hydroxyl or carboxyl group.
  • Salts with basic groups include, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid. , salts with organic carboxylic acids such as tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid. can be mentioned.
  • mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid
  • formic acid acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid.
  • Salts at acidic groups include, for example, salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N,N- Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine and N,N'-dibenzylethylenediamine Examples include salt.
  • alkali metals such as sodium and potassium
  • salts with alkaline earth metals such as calcium and magnesium
  • ammonium salts and trimethylamine, triethylamine, tributylamine, pyridine, N,N- Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, dieth
  • preferable salts include pharmacologically acceptable salts.
  • the present invention includes those isomers, and It includes solvates, hydrates, and various forms of crystals.
  • the compound of the present invention or a salt thereof can be combined with one or more pharmaceutically acceptable carriers, excipients, or diluents to form a pharmaceutical composition (pharmaceutical formulation).
  • pharmaceutically acceptable carriers, excipients and diluents include water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, These include cellulose, water syrup, methylcellulose, polyvinylpyrrolidone, alkyl parahydroxybenzosorbates, talc, magnesium stearate, stearic acid, glycerin, and various oils such as sesame oil, olive oil, and soybean oil.
  • additives such as fillers, binders, disintegrants, pH adjusters, and solubilizers may be mixed with the above carriers, excipients, or diluents as necessary, and the formulation may be prepared using commonly used formulation techniques.
  • Oral or parenteral medicines such as tablets, pills, capsules, granules, powders, solutions, emulsions, suspensions, ointments, injections, or skin patches can be prepared according to the method.
  • the compound of the present invention can be used as a medicine against bacteria that produce drug efflux pumps, such as intestinal bacteria or gram-negative bacteria that produce drug efflux pumps, and their drug-resistant bacteria when used in combination with other antibacterial agents.
  • concomitant use may mean administering one or more of the compounds of the present invention and other antibacterial agents simultaneously or sequentially.
  • other antibacterial agents include penicillin-based antibacterial agents such as benzylpenicillin and piperacillin; piperacillin-tazobactam combination agents, but are not particularly limited as long as they are antibacterial agents that are excreted from the bacterial cell to the outside by a drug efflux pump.
  • ampicillin-sulbactam combinations ceftazidime-avibactam combinations, ceftolozane-tazobactam combinations, and ticarcillin-clavulanic acid combinations
  • ⁇ -lactam combinations such as cefazolin, cefmetazole, ceftriaxone, ceftazidime, cefepime, and cefiderocol
  • Antibacterial agents monobactam antibacterial agents such as aztreonam
  • carbapenem antibacterial agents such as doripenem, imipenem and meropenem
  • aminoglycoside antibacterial agents such as gentamicin, tobramycin, amikacin and netilmicin
  • gatifloxacin garenoxacin, moxifloxacin, sitafloxacin
  • Quinolone antibacterial agents such as ruscufloxacin, ciprofloxacin, levofloxacin, lomefloxacin, ofloxacin and pazuf
  • Compounds of the invention inhibit drug efflux pumps. For example, inhibiting MexB and/or MexY drug efflux pumps. Preferred compounds include those that inhibit both MexB and MexY drug efflux pumps.
  • Treatment with a compound of the invention or a salt thereof or a pharmaceutical composition includes therapy and prophylaxis.
  • the administration method, amount, and frequency of administration of the compound of the present invention, its salt, or pharmaceutical composition can be appropriately selected depending on the age, weight, and symptoms of the patient.
  • the compound of the present invention is administered orally or parenterally (e.g., injection, infusion, rectal administration, etc.) in an amount of 0.01 to 1000 mg/kg once to several times per day. It may be administered in divided doses.
  • the compound of the present invention or its salt or pharmaceutical composition is preferably administered as an injection.
  • the pharmaceutical composition containing the compound of the present invention or a salt thereof is preferably manufactured as a liquid, frozen solution, or lyophilized preparation, and a lyophilized preparation is more preferable.
  • the compound of the present invention can be manufactured by combining methods known per se, and for example, it can be manufactured according to the manufacturing method shown below.
  • R 1a is the same substituent as R 1 which may be protected;
  • R 2a is the same substituent as R 2 which may be protected;
  • R 4a is the same substituent as R 2 which may be protected;
  • R 4 may have the same substituent;
  • X 1a may have the same optionally protected substituent as X 1 ;
  • Y 1a may have the same optionally protected substituent as Y 1 ;
  • 2a is the same substituent as Y 2 which may be protected;
  • R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , Y 1 , Y 2 , Z 1 and Z 2 are It has the same meaning as above.
  • R 1a , R 2a , R 4a , X 1a , Y 1a or Y 2a is protected.
  • the compound represented by the general formula [1a] is, for example, W. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, 2007, John Wiley & Sons, INC. It can be produced by simultaneously or stepwise deprotection of the compound represented by the general formula [2a] using a known conventional method such as described above.
  • the compound represented by general formula [1a] is produced by deprotecting the amino-protecting group of the compound represented by general formula [2a] in the presence or absence of a solvent. can.
  • methods for deprotecting the amino protecting group include reduction by contact with a catalyst and reduction with an acid.
  • (1-a) Method of reducing by contact with a catalyst The compound represented by the general formula [1a] is produced by reducing the compound represented by the general formula [2a] in a hydrogen atmosphere and in the presence of a catalyst. can.
  • Catalysts used in this reaction include, for example, metal catalysts, such as metal palladium such as palladium-carbon and palladium black; palladium salts such as palladium oxide and palladium hydroxide; nickel metal such as Raney nickel and platinum oxide. Examples include platinum salts.
  • Preferred metal catalysts include, for example, palladium-carbon.
  • the amount of the catalyst used in this reaction is 0.001 to 20 times (W/W), preferably 0.01 to 5 times (W/W) relative to the compound represented by the general formula [2a]. Good to have.
  • the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but examples include alcohols, ethers, and esters, and these may be used in combination. good.
  • Preferred solvents include alcohols and esters, with methanol and ethanol being more preferred.
  • This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 0 to 50°C for 1 to 24 hours.
  • (1-b) Method using an acid The compound represented by the general formula [1a] can be produced by reacting the compound represented by the general formula [2a] with an acid in the presence or absence of a solvent.
  • acids used in this reaction include protonic acids such as hydrochloric acid and hydrobromic acid; Lewis acids such as aluminum chloride and iodotrimethylsilane; and the like.
  • the amount of acid used in this reaction may be 1 to 100 times, preferably 2 to 30 times, by mole relative to the compound represented by general formula [2a].
  • the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but examples include halogenated hydrocarbons, ethers, and nitrites, and these may not be used in combination. It's okay. Preferred solvents include halogenated hydrocarbons and nitriles, with dichloromethane and acetonitrile being more preferred.
  • the acid can also be used as a solvent if it is a liquid. This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 0 to 50°C for 1 to 24 hours.
  • (1-c) Method using a base The compound represented by the general formula [1a] can be produced by reacting the compound represented by the general formula [2a] with a base.
  • Examples of the base used in this reaction include inorganic bases such as sodium hydroxide and potassium carbonate; organic bases such as morpholine and triethylamine.
  • the amount of the base used in this reaction may be 1 to 100 times the molar amount, preferably 2 to 30 times the molar amount of the compound represented by the general formula [2a].
  • the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but examples include halogenated hydrocarbons, ethers, amides, alcohols, nitriles, and water. , these may be used in combination.
  • This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 0 to 50°C for 1 to 24 hours.
  • the same deprotection method as in production method (1-a) or production method (1-b) can be used.
  • the amino protecting group is a benzyl group
  • the same deprotection method as in production method (1-a) or production method (1-b) can be used.
  • the amino protecting group is a tert-butoxycarbonyl group
  • the same deprotection method as in production method (1-b) can be used.
  • the amino protecting group is a 9-fluorenylmethyloxycarbonyl group
  • the same deprotection method as in production method (1-c) can be used.
  • the compound represented by the general formula [1a] can be produced by deprotecting the compound represented by the general formula [2a].
  • Examples of the method for deprotecting the hydroxyl protecting group include a method of reducing by contact with a catalyst, a method of reducing with an acid, and a method using a fluoride ion.
  • (2-a) Method of reduction by contact with a catalyst The compound represented by the general formula [1a] is produced by reducing the compound represented by the general formula [2a] in a hydrogen atmosphere and in the presence of a catalyst. can.
  • Catalysts used in this reaction include metal catalysts, such as palladium metal such as palladium-carbon and palladium black; palladium salts such as palladium oxide and palladium hydroxide; nickel metal such as Raney nickel and platinum salts such as platinum oxide. Examples include. Preferred metal catalysts include palladium-carbon.
  • the amount of the catalyst used in this reaction is 0.001 to 20 times (W/W), preferably 0.01 to 5 times (W/W) relative to the compound represented by the general formula [2a]. Good to have.
  • the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but examples include alcohols, ethers, and esters, and these may be used in combination. good.
  • Preferred solvents include alcohols and esters, with methanol and ethanol being more preferred.
  • This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 0 to 50°C for 1 to 24 hours.
  • (2-b) Method using an acid The compound represented by the general formula [1a] can be produced by reacting the compound represented by the general formula [2a] with an acid in the presence or absence of a solvent.
  • Acids used in this reaction include protic acids such as hydrochloric acid and hydrobromic acid; and Lewis acids such as aluminum chloride and iodotrimethylsilane.
  • the amount of acid used in this reaction may be 2 to 100 times the molar amount, preferably 2 to 30 times the molar amount of the compound represented by the general formula [2a].
  • the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but examples include halogenated hydrocarbons, ethers, and nitrites, and these may not be used in combination. It's okay. Preferred solvents include halogenated hydrocarbons and nitriles, with dichloromethane and acetonitrile being more preferred.
  • the acid can also be used as a solvent if it is a liquid. This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 0 to 50°C for 1 to 24 hours. (2-c) Method using a base
  • the compound represented by the general formula [1a] can be produced by reacting the compound represented by the general formula [2a] with a base.
  • Examples of the base used in this reaction include inorganic bases such as sodium hydroxide and potassium carbonate; organic bases such as morpholine and triethylamine.
  • the amount of the base used in this reaction may be 1 to 100 times the molar amount, preferably 2 to 30 times the molar amount of the compound represented by the general formula [2a].
  • the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but examples include halogenated hydrocarbons, ethers, amides, alcohols, nitriles, and water. , these may be used in combination.
  • Preferred solvents include ethers, alcohols and water.
  • This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 0 to 50°C for 1 to 24 hours.
  • (2-d) Method using fluoride ions The compound represented by the general formula [1a] can be produced by reacting the compound represented by the general formula [2a] with a fluoride ion.
  • Fluoride ions can be generated from fluorine compounds, and examples of the fluorine compounds used in this reaction include tetrabutylammonium fluoride, potassium fluoride, and cesium fluoride.
  • Solvents used in this reaction include Although there are no particular limitations as long as they do not affect the reaction, examples include halogenated hydrocarbons, ethers, nitriles, amides, alcohols, and water, and these may be used in combination. Good too.
  • Preferred solvents include ethers and nitriles, with tetrahydrofuran and acetonitrile being more preferred.
  • the amount of the fluorine compound used in this reaction may be 1 to 100 times, preferably 2 to 30 times, the amount of the compound represented by the general formula [2a].
  • This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 0 to 50°C for 1 to 24 hours.
  • the hydroxyl protecting group is a benzyl group
  • the same deprotection method as in production method (2-a) or (2-b) can be used.
  • the hydroxyl protecting group is a 4-methoxybenzyl group
  • the same deprotection method as in production method (2-a) or (2-b) can be used.
  • the hydroxyl protecting group is a methoxymethyl group
  • the same deprotection method as in production method (2-b) can be used.
  • the hydroxyl protecting group is a tert-butyldimethylsilyl group
  • the same deprotection methods as in production method (2-b) and production method (2-d) can be used.
  • the hydroxyl protecting group is an acetyl group
  • the same deprotection methods as in production method (2-b) and production method (2-c) can be used.
  • the compound represented by the general formula [1a] can be produced by deprotecting the compound represented by the general formula [2a].
  • Examples of the method for deprotecting the carboxyl protecting group include a method of solvolysis with a base, a method of solvolysis with an acid, and a method of solvolysis with an enzyme.
  • (3-a) Method of solvolyzing with a base The compound represented by the general formula [1a] can be produced by solvolyzing the compound represented by the general formula [2a] in the presence of a base.
  • the base used in this reaction include alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, and barium hydroxide.
  • the amount of the base used in this reaction may be 1 to 100 times the molar amount, preferably 2 to 30 times the molar amount of the compound represented by the general formula [2a].
  • the solvent used in this reaction is not particularly limited, and examples thereof include alcohols, ethers, and water, and these may be used in combination. Preferred solvents include alcohols and water, and methanol and ethanol are more preferred as alcohols.
  • This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 0 to 50°C for 1 to 24 hours.
  • (3-b) Method of solvolyzing with an acid The compound represented by the general formula [1a] can be produced by solvolyzing the compound represented by the general formula [2a] in the presence of an acid.
  • acids used in this reaction include protonic acids such as hydrochloric acid and sulfuric acid; Lewis acids such as aluminum chloride and boron trichloride; and the like.
  • the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but examples include halogenated hydrocarbons, ethers, and nitrites, and these may be used in combination. good.
  • Preferred solvents include halogenated hydrocarbons and nitriles, with dichloromethane and acetonitrile being more preferred.
  • the acid can also be used as a solvent if it is a liquid.
  • the amount of acid used in this reaction may be 2 to 100 times the molar amount, preferably 2 to 30 times the molar amount of the compound represented by the general formula [2a]. This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 0 to 100°C for 1 to 24 hours.
  • (3-c) Method of solvolyzing with an enzyme The compound represented by the general formula [1a] can be produced by solvolyzing the compound represented by the general formula [2a] in the presence of an enzyme. Enzymes used in this reaction include esterases and carbonic anhydrases, such as those derived from pig liver and bovine red blood cells.
  • the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but water is more preferred.
  • This reaction may be carried out at 20 to 60°C for 30 minutes to 72 hours, preferably at 30 to 40°C for 1 to 24 hours.
  • the carboxyl protecting group is a methyl group
  • production method (3-a), production method (3-b), production method (3-c), etc. may be mentioned.
  • the amount of the compound represented by the general formula [2c] used in this reaction is not particularly limited, but is 0.9 to 10 times the mole of the compound represented by the general formula [2b], preferably 1.0 to It is sufficient if it is 2.0 times the molar amount.
  • Reducing agents used in this reaction include hydride reducing agents and boranes.
  • Preferred reducing agents include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, and 2-picoline borane, with sodium triacetoxyborohydride being more preferred.
  • the amount of the reducing agent used in this reaction may be 0.5 to 50 times, preferably 1 to 10 times, by mole relative to the compound represented by the general formula [2b].
  • a base may be added.
  • the base that may be used as desired include organic bases such as trimethylamine, triethylamine, and tributylamine, and a preferred base includes triethylamine.
  • the amount of the base optionally used in this reaction may be 1 to 10 times the mole, preferably 1 to 5 times the mole of the compound represented by the general formula [2b].
  • the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but examples include halogenated hydrocarbons, ethers, amides, and alcohols. May be used in combination. Preferred solvents include halogenated hydrocarbons and amides, with dichloromethane being more preferred.
  • the amount of the solvent used in this reaction is not particularly limited, but may be 1 to 500 times the amount (v/w) of the compound represented by general formula [2b].
  • This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 0 to 40°C for 1 to 24 hours.
  • Condensing agents used in this reaction are, for example, N,N'-diisopropylcarbodiimide (DIC), N,N'-di-(tert-butyl)carbodiimide, N,N'-dicyclohexylcarbodiimide (DCC) and 1- Carbodiimides such as ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC); 1,1'-carbonyldiimidazole (CDI) and 1,1'-carbonyldi(1,2,4-triazole) (CDT ); Acid azides such as diphenylphosphoryl azide; Acid cyanides such as diethylphosphoryl cyanide; (1-cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylaminomorpholinocarbenium hexafluorophos Uroniums such as phaate (COMU) and O-(7-(7-(
  • the amount of the condensing agent used in this reaction may be 1 to 50 times the mole, preferably 1 to 5 times the mole of the compound represented by the general formula [2d].
  • additional additives can be added.
  • optional additives include 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), and ethyl (hydroxyimino)cyanoacetate, with HOBt being preferred.
  • the amount of additives optionally used in this reaction may be 0.01 to 10 times, preferably 0.1 to 1 times, by mole relative to the compound represented by general formula [2d].
  • Examples of the base used in this reaction include organic bases such as triethylamine, N,N-diisopropylethylamine and N-methylmorpholine, with N,N-diisopropylethylamine being preferred.
  • the amount of the base used in this reaction may be 1 to 10 times the mole, preferably 1 to 5 times the mole of the compound represented by the general formula [2d].
  • the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but examples include halogenated hydrocarbons, ethers, esters, amides, nitriles, and aromatic hydrocarbons. and dimethyl sulfoxide, and these solvents may be used in combination.
  • Preferred solvents include halogenated hydrocarbons and amides, with dichloromethane and N,N-dimethylacetamide being more preferred.
  • the amount of the compound represented by the general formula [2e] to be used is not particularly limited, but it is 0.9 to 10 times the mole, preferably 1.0 to 2.0 times the mole of the compound represented by the general formula [2d]. good.
  • the amount of the solvent to be used is not particularly limited, but may be 1 to 500 times the amount (v/w) of the compound represented by the general formula [2d]. This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 0 to 40°C for 1 to 24 hours.
  • the compound represented by the general formula [2j] can be converted into a compound represented by the general formula [2h] or a salt thereof in the presence of a reducing agent, in the presence or absence of a base, or a salt thereof. It can be produced by reacting a compound represented by general formula [2i].
  • Reducing agents used in this reaction include hydride reducing agents and boranes.
  • Preferred reducing agents include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, and 2-picoline borane, with sodium triacetoxyborohydride being more preferred.
  • the amount of the reducing agent used in this reaction may be 0.5 to 50 times the mole, preferably 1 to 10 times the amount of the compound represented by the general formula [2h].
  • a base may be added.
  • the base that may be used as desired include organic bases such as trimethylamine, triethylamine, and tributylamine.
  • a preferred base is triethylamine.
  • the amount of the base optionally used in this reaction may be 1 to 10 times the mole, preferably 1 to 5 times the mole of the compound represented by the general formula [2h].
  • the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but examples include halogenated hydrocarbons, ethers, amides, and alcohols. May be used in combination. Preferred solvents include halogenated hydrocarbons and amides, with dichloromethane being more preferred.
  • the amount of the compound represented by the general formula [2i] used in this reaction is not particularly limited, but is 0.9 to 10 times the mole of the compound represented by the general formula [2h], preferably 1.0 to 1. It is sufficient if it is 2.0 times the molar amount.
  • the amount of the solvent used in this reaction is not particularly limited, but may be 1 to 500 times the amount (v/w) of the compound represented by the general formula [2h]. This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 0 to 40°C for 1 to 24 hours.
  • L 1a represents a leaving group; R 1a , R 2a , R 3 , X 1a , X 2 , Y 1a , Y 2a and Z 1 have the same meanings as above.”
  • the leaving group represented by L 1a includes a halogen atom, a C 1-6 alkylsulfonyloxy group, an arylsulfonyloxy group, and an imidazole group.
  • the C 1-6 alkylsulfonyloxy group, arylsulfonyloxy group and imidazole group may have a substituent.
  • the compound represented by the general formula [2l] can be produced by reacting the compound represented by the general formula [2h] or a salt thereof with the compound represented by the general formula [2k] in the presence of a base.
  • Bases used in this reaction include inorganic bases such as sodium carbonate and potassium carbonate and organic bases such as triethylamine and N,N-diisopropylethylamine.
  • Preferred bases include inorganic bases, with potassium carbonate being more preferred.
  • the amount of the base used in this reaction may be 1 to 20 times the mole, preferably 1 to 10 times the mole of the compound represented by the general formula [2h].
  • the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but examples include halogenated hydrocarbons, ethers, esters, ketones, amides, and nitriles. These solvents may be used in combination. Preferred solvents include amides and nitriles, with N,N-dimethylformamide and acetonitrile being more preferred.
  • the amount of the compound represented by the general formula [2k] used in this reaction is not particularly limited, but is 0.9 to 10 times the mole of the compound represented by the general formula [2h], preferably 1.0 to It is sufficient if it is 5.0 times the molar amount.
  • the amount of the solvent used in this reaction is not particularly limited, but may be 1 to 500 times the amount (v/w) of the compound represented by the general formula [2h].
  • This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 20 to 80°C for 1 to 24 hours.
  • Z 3a represents a protected hydroxyl group or amino group
  • Z 3 represents a hydroxyl group or an amino group
  • L 1a , R 3 , R 5 , X 1a , X 2 , Y 1a and Y 2a represent the above-mentioned has the same meaning.
  • the compound represented by the general formula [2t] can be produced by the following method.
  • the compound represented by the general formula [2 Mr] is prepared by combining the compound represented by the general formula [2m] with the compound represented by the general formula [2e] or its salt in the same manner as in [Production method 3]. It can be produced by reacting according to the following method.
  • (6-2) Deprotection The compound represented by the general formula [2p] or a salt thereof is prepared by converting the compound represented by the general formula [2schreib] into a compound represented by the general formula [2 Mr] according to [Production method 1] (1-a) suitable for the type of R5 . ), (1-b) or (1-c).
  • the compound represented by the general formula [2q] can be produced by reacting the compound represented by the general formula [2p] or its salt in the same manner as [Production method 5]. I can do it.
  • (6-4) Imination The compound represented by the general formula [2s] can be produced by reacting the compound represented by the general formula [2q] with the compound represented by the general formula [2r].
  • the amount of the compound represented by the general formula [2r] to be used is not particularly limited, but it is 1 to 20 times the molar amount, preferably 1 to 10 times the molar amount of the compound represented by the general formula [2q]. good.
  • the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but examples include halogenated hydrocarbons, ethers, esters, amides, alcohols, and nitriles. These solvents may be used in combination. Preferred solvents include ethers, amides and alcohols, with methanol being more preferred.
  • the amount of the solvent to be used is not particularly limited, but may be 1 to 500 times the amount (v/w) of the compound represented by the general formula [2q]. This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 20 to 100°C for 1 to 12 hours. (6-5) Deprotection
  • the compound represented by the general formula [2t] or its salt can be produced by reacting the compound represented by the general formula [2s] in the same manner as [Production method 1]. I can do it.
  • L 1b represents a leaving group; R 3 , R 4a , X 1a , X 2 , Y 1a , Y 2a and Z 2 have the same meanings as above.”
  • the leaving group represented by L 1b includes a halogen atom, a C 1-6 alkylsulfonyloxy group, an arylsulfonyloxy group, and an imidazole group.
  • the C 1-6 alkylsulfonyloxy group, arylsulfonyloxy group and imidazole group may have a substituent.
  • the compound represented by the general formula [2w] can be produced by reacting the compound represented by the general formula [2u] with the compound represented by the general formula [2v] or a salt thereof in the presence of a base.
  • Bases used in this reaction include inorganic bases such as sodium carbonate and potassium carbonate and organic bases such as triethylamine and N,N-diisopropylethylamine.
  • Preferred bases include inorganic bases, with potassium carbonate being more preferred.
  • the amount of the base used in this reaction may be 1 to 20 times the molar amount, preferably 1 to 10 times the molar amount of the compound represented by the general formula [2u].
  • the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but examples include halogenated hydrocarbons, ethers, esters, amides, and nitriles. These solvents may be used in combination. Preferred solvents include amides and nitriles, with N,N-dimethylformamide and acetonitrile being more preferred.
  • the amount of the compound represented by the general formula [2v] used in this reaction is not particularly limited, but is 0.9 to 10 times the mole of the compound represented by the general formula [2u], preferably 1.0 to 1. It is sufficient if it is 5.0 times the molar amount.
  • the amount of the solvent used in this reaction is not particularly limited, but may be 1 to 500 times the amount (v/w) of the compound represented by the general formula [2u].
  • This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 20 to 80°C for 1 to 24 hours.
  • the compound represented by the general formula [3b] is prepared by converting the compound represented by the general formula [3a] in the presence of a reducing agent, in the presence or absence of an acid, to the compound represented by the general formula [3a]. It can be produced by reacting the compound represented by [2c] with a method similar to [Production method 2].
  • the amount of the compound represented by the general formula [2c] used in this reaction is not particularly limited, but is 0.9 to 10 times the mole of the compound represented by the general formula [3a], preferably 1.0 to It is sufficient if it is 2.0 times the molar amount.
  • Reducing agents used in this reaction include hydride reducing agents and boranes.
  • Preferred reducing agents include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, and 2-picoline borane, with sodium triacetoxyborohydride being more preferred.
  • the amount of the reducing agent used in this reaction may be 0.5 to 50 times the mole, preferably 1 to 10 times the amount of the compound represented by the general formula [3a].
  • acids optionally used in this reaction include Lewis acids such as zinc chloride, tetraisopropyl orthotitanate, and acetic acid. Preferred acids include tetraisopropyl orthotitanate.
  • the amount of the acid optionally used in this reaction may be 0.1 to 10 times the mole, preferably 1 to 5 times the amount of the compound represented by the general formula [3a].
  • the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but examples include halogenated hydrocarbons, ethers, amides, and alcohols. May be used in combination. Preferred solvents include halogenated hydrocarbons, ethers and amides, with dichloromethane or tetrahydrofuran being more preferred.
  • the amount of the solvent used in this reaction is not particularly limited, but may be 1 to 500 times the amount (v/w) of the compound represented by the general formula [3a].
  • This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 0 to 40°C for 1 to 24 hours.
  • A-2 Deprotection
  • the compound represented by the general formula [2e] or a salt thereof is prepared by converting the compound represented by the general formula [3b] into a compound represented by the general formula [3b] according to [Production method 1] (1-a) suitable for the type of R5 . , (1-b) or (1-c).
  • the compound represented by the general formula [3b] can be produced by reacting the compound represented by the general formula [3a] with the compound represented by the general formula [3c] in the presence of a base.
  • Bases used in this reaction include inorganic bases such as sodium carbonate and potassium carbonate and organic bases such as triethylamine and N,N-diisopropylethylamine.
  • Preferred bases include inorganic bases, with potassium carbonate being more preferred.
  • the amount of the base used in this reaction may be 1 to 20 times the molar amount, preferably 1 to 10 times the molar amount of the compound represented by the general formula [3a].
  • the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but examples include halogenated hydrocarbons, ethers, esters, ketones, amides, and nitriles. These solvents may be used in combination. Preferred solvents include ketones and amides, with N,N-dimethylformamide or acetone being more preferred.
  • the amount of the compound represented by the general formula [3c] used in this reaction is not particularly limited, but is 0.9 to 10 times the mole of the compound represented by the general formula [3a], preferably 1.0 to It is sufficient if it is 5.0 times the molar amount.
  • the amount of the solvent used in this reaction is not particularly limited, but may be 1 to 500 times the amount (v/w) of the compound represented by the general formula [3a]. This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 20 to 90°C for 1 to 24 hours.
  • the compound represented by the general formula [2u] is prepared by reacting the compound represented by the general formula [2e] or a salt thereof with the compound represented by the general formula [3d] in the presence of a base.
  • Bases used in this reaction include inorganic bases such as sodium carbonate and potassium carbonate and organic bases such as triethylamine and N,N-diisopropylethylamine.
  • Preferred bases include organic bases, with triethylamine being more preferred.
  • the amount of the base used in this reaction may be 1 to 20 times the molar amount, preferably 1 to 5 times the molar amount of the compound represented by the general formula [2e].
  • the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but examples include halogenated hydrocarbons, ethers, esters, amides, and nitriles. These solvents may be used in combination. Preferred solvents include halogenated hydrocarbons, amides and nitriles, with dichloromethane being more preferred.
  • the amount of the compound represented by the general formula [3d] used in this reaction is not particularly limited, but is 0.9 to 10 times the mole of the compound represented by the general formula [2e], preferably 1.0 to It is sufficient if it is 5.0 times the molar amount.
  • the amount of the solvent to be used is not particularly limited, but may be 1 to 500 times the amount (v/w) of the compound represented by the general formula [2e].
  • This reaction may be carried out at -30 to 150°C for 30 minutes to 48 hours, preferably at 0 to 40°C for 1 to 5 hours.
  • C-2) Condensation The compound represented by the general formula [3e] is prepared by combining the compound represented by the general formula [2u] and the compound represented by the general formula [3a] in the same manner as in [Production method 7]. It can be produced by reaction.
  • (D-1) The compound represented by the condensed general formula [3h] is obtained by combining the compound represented by the general formula [3g] and the compound represented by the general formula [2v] or a salt thereof in the same manner as in [Production method 7]. It can be produced by reacting according to the following method.
  • (D-2) Deprotection
  • the compound represented by the general formula [3i] or a salt thereof is obtained by converting the compound represented by the general formula [3h] into a compound represented by the general formula [ 3h ] according to [Production method 1] (1-a ), (1-b) or (1-c).
  • R 6 represents a carboxyl protecting group
  • R 1a , R 2a , X 1b , X 1c , Y 1a and Z 1 have the same meanings as above.
  • the compound represented by the general formula [3l] can be produced by the following method.
  • (F-1) Alkylation The compound represented by the general formula [3m] is prepared by combining the compound represented by the general formula [3j] or a salt thereof with the compound represented by the general formula [2k] and [Production method 5]. It can be produced by reacting in a similar manner.
  • (F-2) Deprotection The compound represented by the general formula [3n] can be prepared by converting the compound represented by the general formula [ 3m ] to [Production method 1] (3-a), ( It can be produced by reacting in the same manner as 3-b) or (3-c).
  • (G-1) Condensation The compound represented by the general formula [3 Mr] is prepared by combining the compound represented by the general formula [3n] with the compound represented by the general formula [3a] in the same manner as in [Production method 3]. It can be produced by reaction.
  • (G-2) Deprotection The compound represented by the general formula [3p] or a salt thereof is obtained by converting the compound represented by the general formula [3o] into a compound represented by the general formula [ 3o ] according to [Production method 1] (1- It can be produced by reacting in the same manner as a), (1-b) or (1-c).
  • L 1c represents a leaving group
  • M 1 represents a substituent described below
  • Y 1b represents an optionally substituted aryl group, an optionally substituted monocyclic heterocyclic group, or a substituted Y 1c is an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted phenyl group, or an optionally substituted monocyclic group
  • R 1a , R 2a , R 3 , R 4a , X 1a , X 2 , Y 2a , Z 1 and Z 2 have the same meanings as above.
  • M 1 represents ZnR 7a , MgR 7b , Sn(R 7c ) 3 or B(OR 7d )(OR 7e ) “wherein R 7a and R 7b each independently represent a chlorine atom, a bromine atom or an iodine atom; represents an atom, R 7c represents a C 1-4 alkyl group or a phenyl group, R 7d is the same or different and represents a hydrogen atom, a C 1-4 alkyl group, or a phenyl group, R 7d and R 7e are the same may form a ring containing an oxygen atom and a boron atom.
  • the leaving group represented by L 1c is not particularly limited, but includes a halogen atom and a triflate such as phenyl trifluoromethanesulfonate, with a bromine atom being preferred.
  • the compound represented by the general formula [3s] can be converted into a compound represented by the general formula [3q] in the presence of a palladium catalyst, in the presence or absence of a ligand, in the presence or absence of a base. It can be produced by reacting a compound represented by formula [3r].
  • the amount of the compound represented by the general formula [3r] used in this reaction is not particularly limited, but is 0.9 to 20 times the mole of the compound represented by the general formula [3q], preferably 1.0 to It is sufficient if it is 5.0 times the molar amount.
  • Palladium catalysts used in this reaction include palladium salts such as palladium chloride and palladium acetate, dichloro(bistriphenylphosphine)palladium, tetrakis(triphenylphosphine)palladium and methanesulfonate (2-dicyclohexylphosphino-2', Examples include palladium complexes such as 4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium.
  • Preferred palladium catalysts include palladium complexes, with dichloro(bistriphenylphosphine)palladium being more preferred.
  • the amount of the palladium catalyst used in this reaction may be 0.001 to 10 times the mole, preferably 0.01 to 0.5 times the mole of the compound represented by the general formula [3q].
  • Ligands optionally used in this reaction include triphenylphosphine, tricyclohexylphosphine, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and ( ⁇ )-2,2'-bis Tertiary phosphines such as (diphenylphosphino)-1,1'-binaphthyl are mentioned, and preferred ligands include triphenylphosphine and 2-dicyclohexylphosphine-2',4',6'-triisopropyl.
  • Examples include biphenyl.
  • the amount of the ligand optionally used in this reaction may be 0.001 to 10 times the mole, preferably 0.01 to 0.5 times the mole of the compound represented by the general formula [3q].
  • Examples of the base optionally used in this reaction include inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, and cesium fluoride. Preferred bases include sodium carbonate and cesium fluoride. and potassium phosphate.
  • the amount of the base optionally used in this reaction may be 0.1 to 20 times, preferably 1.0 to 5.0 times, by mole relative to the compound represented by general formula [3q].
  • the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but examples include aromatic hydrocarbons, ethers, amides, alcohols, and water. You may use a mixture of solvents. Preferred solvents include mixed solvents of aromatic hydrocarbons or ethers and water, and more preferred are mixed solvents of 1,4-dioxane and water.
  • the amount of the solvent used in this reaction is not particularly limited, but may be 1 to 500 times the amount (v/w) of the compound represented by the general formula [3q]. This reaction may be carried out at 0 to 150°C for 30 minutes to 72 hours, preferably at 50 to 100°C for 1 to 24 hours.
  • silica gel column chromatography was carried out using Selekt manufactured by Biotage Japan Co., Ltd., and Biotage Sfaer D or Biotage Sfaer HC D manufactured by Biotage Japan Co., Ltd. was used as the carrier.
  • As the NH silica gel column CHROMATOREX NH-DM1020 manufactured by Fuji Silysia Chemical Co., Ltd. was used.
  • For medium pressure reverse phase silica gel column chromatography Biotage Japan Co., Ltd.'s Isolera SV was used, and the carrier was Biotage Japan Co., Ltd.'s Sfaer C18 D.
  • the mixing ratio in the eluent is a volume ratio.
  • NMR spectra were measured using AVANCE III HD400 (Bruker Co., Ltd.). The NMR spectrum shows proton NMR, the internal standards are as follows, and the ⁇ value is shown in ppm.
  • Heavy dimethyl sulfoxide (CD 3 SOCD 3 ) Tetramethylsilane (0.00ppm)
  • the description [1.45]1.46(3H,s) means that the peak derived from each diastereomer of a diastereomer mixture or the peak derived from each isomer of a geometric isomer mixture is a singlet at 1.45 and 1.46. observed, indicating a total number of protons of 3.
  • NMR spectra were measured using CDCl 3 in Reference Examples and D 2 O
  • MS spectrum was measured by electrospray ionization (ESI) using LCMS-2020 (Shimadzu Corporation).
  • each abbreviation has the following meaning.
  • Ac acetyl
  • Bn benzyl
  • Boc tert-butoxycarbonyl
  • Cbz benzyloxycarbonyl
  • COMU (1-cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylaminomorpholinocarbenium hexafluorophosphate
  • DIPEA N,N-diisopropylethylamine
  • DMAC N,N-dimethylacetamide
  • DMAP 4-(dimethylamino)pyridine
  • DMF N,N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • DPPA diphenylphosphoryl azide
  • ESI electro Spray ionization method
  • Fmoc 9-fluorenylmethyloxycarbonyl
  • HOAt 1-hydroxy-7-azabenzotriazole
  • HOBt 1-hydroxybenzotriazole
  • Reference example 4 The reaction was carried out in the same manner as in Reference Example 3 except that iodomethane in Reference Example 3 was replaced with benzyl bromide to obtain 4-((benzyloxy)methyl)-4-phenethylpiperidine hydrochloride.
  • Reference example 5 (1) 1-(tert-butoxycarbonyl)-4-phenethylpiperidine-4-carboxylic acid (700 mg), ammonium chloride (225 mg), WSC hydrochloride (443 mg), HOBt (312 mg), dichloromethane (7 mL) and DIPEA ( 1.2 mL) were added one after another, and the mixture was stirred at room temperature for 24 hours. Water (5 mL) was added to the reaction mixture, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Reference example 7 The 4 mol/L hydrochloric acid dioxane solution in Reference Example 6 was replaced with TFA, and the reaction was carried out in the same manner as in Reference Example 6 to obtain the TFA salt of ((4-phenethylpiperidin-4-yl)methyl)carbamate.
  • Reference example 8 (1) Toluene (30 mL), triethylamine (2.1 mL) and DPPA (1.9 mL) were added to 1-(tert-butoxycarbonyl)-4-phenethylpiperidine-4-carboxylic acid (2.00 g) and heated at 80°C for 30 minutes. Stirred. Benzyl alcohol (1.2 mL) was added to the reaction mixture, and the mixture was stirred under reflux for 6 hours. The reaction mixture was cooled to room temperature, water (30 mL) and ethyl acetate (60 mL) were added, and the organic layer was separated.
  • the reaction mixture was ice-cooled, water (50 mL) and ethyl acetate (100 mL) were added, and the organic layer was separated.
  • the obtained organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Reference example 10 (1) Dichloromethane (2.4 mL), benzylamine (0.11 mL) and sodium triacetoxyborohydride (204 mg) were added to tert-butyl 4-(2-phenylacetyl)piperidine-1-carboxylate (146 mg), and the mixture was heated to room temperature. The mixture was stirred for 6 days. After adding water and ethyl acetate to the reaction mixture, 1 mol/L hydrochloric acid was added to adjust the pH to 2, and the organic layer was separated. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Reference example 14 The iodoethane in Reference Example 13 was replaced with iodomethane and the reaction was carried out in the same manner as in (1) and (2) of Reference Example 13 to obtain 2-fluoro-6-methoxy-3-(methoxymethoxy)benzaldehyde as a pale yellow oil. .
  • Reference example 15 (1) Add dichloromethane (13 mL), benzyl piperazine-1-carboxylate (290 mg) and sodium triacetoxyborohydride (418 mg) to 6-ethoxy-2-fluoro-3-(methoxymethoxy)benzaldehyde (300 mg), The mixture was stirred at room temperature for 19 hours and 30 minutes. Sodium triacetoxyborohydride (418 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. After adding water (5 mL) to the reaction mixture, 10% aqueous sodium carbonate solution was added to adjust the pH to 8, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Reference example 16 6-Ethoxy-2-fluoro-3-(methoxymethoxy)benzaldehyde in Reference Example 15 was replaced with 2-fluoro-6-methoxy-3-(methoxymethoxy)benzaldehyde, the reaction was carried out in the same manner as in Reference Example 15, and 1-( 2-Fluoro-6-methoxy-3-(methoxymethoxy)benzyl)piperazine was obtained as a colorless oil.
  • Reference example 17 (1) After adding THF (0.56 mL) to tert-butyl piperazine-1-carboxylate (186 mg), 1-(2-fluoro-6-methoxyphenyl)ethane-1-one (252 mg) was added under nitrogen atmosphere. and tetraisopropyl orthotitanate (0.89 mL) were added, and the mixture was stirred at 75°C for 18 hours. After the reaction mixture was cooled to -48°C, sodium triacetoxyborohydride (636 mg) was added, and the mixture was heated to room temperature over 2 hours. After the reaction mixture was cooled to 0°C, a 5 mol/L aqueous sodium hydroxide solution was added, and insoluble matter was filtered off.
  • Reference example 20 (1) Dichloromethane (240 mL), tert-butyl piperazine-1-carboxylate (4.50 g) and sodium triacetoxyborohydride (7.68 g) were added to 2-ethoxy-6-fluorobenzaldehyde (2.70 g), and the mixture was heated to room temperature. Stirred for 18 hours. After adding water (50 mL) to the reaction mixture, 10% aqueous sodium carbonate solution was added to adjust the pH to 9, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Reference example 29 (1) Dichloromethane (36 mL) and triethylamine (3.1 mL) were added to 1-(2-methoxybenzyl)piperazine hydrochloride (2.00 g), and the mixture was stirred under ice cooling. A mixture of chloroacetyl chloride (0.60 mL) and dichloromethane (5 mL) was added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Water (30 mL) was added to the reaction mixture, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Reference example 30 The hydrochloride of 1-(2-methoxybenzyl)piperazine in Reference Example 29 was replaced with the hydrochloride of 1-(2-ethoxy-6-fluorobenzyl)piperazine, and the reaction was carried out in the same manner as in (1) of Reference Example 29. -chloro-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one was obtained as a pale yellow oil.
  • Reference example 32 (1) Tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate (8.70g), 1-phenethylpiperazine hydrochloride (8.72g), DMF (132mL), potassium carbonate (16.0g) and iodine.
  • Sodium chloride (1.24 g) was added, and the mixture was stirred at 70°C for 6 hours.
  • Ethyl acetate (260 mL) and water (130 mL) were added to the reaction mixture, and the organic layer was separated. The obtained organic layer was washed successively with water and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Reference example 33 (1) Dichloromethane (176 mL) was added to 2-(4-chloro-[1,1'-biphenyl]-2-yl)ethan-1-ol (2.70 g), and the mixture was stirred under ice cooling. Dessmartin periodinane (7.38 g) was added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 2 hours and 20 minutes. Dessmartin periodinane (2.95 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour.
  • Reference example 72 (R)-2-(((benzyloxy)carbonyl)amino)-2-(1-(2-(4- Chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)acetic acid (70 mg), WSC hydrochloride (34 mg), HOBt (24 mg), dichloromethane (1.4 mL) and DIPEA (80 ⁇ L) were added one after another, and the mixture was stirred at room temperature for 22 hours. Water (2 mL) was added to the reaction mixture, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Reference example 74 Benzyl (R)-(2-oxo-1-(1-phenethylpiperidin-4-yl)-2-(piperazin-1-yl)ethyl)carbamate hydrochloride (150 mg), dichloromethane (2.8 mL), Ethoxy-6-fluorobenzaldehyde (52 mg), triethylamine (97 ⁇ L) and sodium triacetoxyborohydride (177 mg) were added, and the mixture was stirred at room temperature for 21 hours and 30 minutes. After adding water (2 mL) to the reaction mixture, 10% aqueous sodium carbonate solution was added to adjust the pH to 8, and the organic layer was separated.
  • Reference example 78 (1) 60% oily sodium hydride (1.02 g) was added to THF (12 mL), and the mixture was stirred under ice cooling under a nitrogen atmosphere. A mixture of diethyl cyanomethylphosphonate (3.85 mL) and THF (12 mL) was added dropwise to the reaction mixture at the same temperature, and the mixture was stirred at 0°C for 15 minutes. A mixture of 3-ethoxy-2-methylbenzaldehyde (3.00 g) and THF (23 mL) was added dropwise to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 1 hour and 30 minutes.
  • the reaction mixture was cooled to 0° C., diethyl ether (50 mL) and water were added, and then 1 mol/L hydrochloric acid was added to adjust the pH to 7, and the organic layer was separated.
  • the obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • the reaction mixture was cooled to room temperature, ammonium chloride (864 mg) and sodium azide (1.05 g) were added, and the mixture was stirred at 150°C for 2 hours.
  • the reaction mixture was cooled to room temperature, water (10 mL) and ethyl acetate (10 mL) were added, and then a saturated aqueous sodium bicarbonate solution was added to adjust the pH to 6.4, and the organic layer was separated.
  • the aqueous layer was extracted five times with ethyl acetate (5 mL), the organic layers separated earlier were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Reference example 84 1-(6-ethoxy-2-fluoro-3-(methoxymethoxy)benzyl)piperazine (250 mg) to (R)-2-(((benzyloxy)carbonyl)amino)-2-(1-phenethylpiperidine-4 -yl)acetic acid (333 mg), WSC hydrochloride (177 mg), HOBt (125 mg), dichloromethane (5 mL) and DIPEA (0.18 mL) were added sequentially, and the mixture was stirred at room temperature for 24 hours. Water (5 mL) was added to the reaction mixture, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Reference example 91 (1) Add (R)-2-(((benzyloxy)carbonyl)amino)-2-(1-(tert-butoxy) to 1-(2-ethoxy-6-fluorobenzyl)piperazine hydrochloride (3.81 g). Carbonyl)piperidin-4-yl)acetic acid (4.80 g), WSC hydrochloride (2.58 g), HOBt (1.82 g), dichloromethane (48 mL) and DIPEA (6.8 mL) were sequentially added, and the mixture was stirred at room temperature for 20 hours and 30 minutes. . Water (50 mL) was added to the reaction mixture, and the organic layer was separated.
  • Reference example 93 (1) Ethyl 2-(2-bromo-5-chlorophenyl)acetate (1.00g), 2-chlorophenylboronic acid (1.13g), sodium carbonate (955mg), 1,4-dioxane (20mL) and water (3.6mL). ) and stirred. Dichloro(bistriphenylphosphine)palladium(II) (416 mg) was added to the reaction mixture under nitrogen atmosphere, and the mixture was stirred under reflux for 17 hours and 30 minutes. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the organic layer was separated.
  • Reference example 100 (1) Ethyl 2-(2-bromo-5-chlorophenyl)acetate (500mg), cyclopropylboronic acid (156mg), palladium(II) acetate (20mg), tricyclohexylphosphine (51mg), tripotassium phosphate (1.34mg) g), toluene (7.2 mL) and water (0.36 mL) were sequentially added, and the mixture was stirred at 100° C. for 4 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the organic layer was separated.
  • Reference example 132 Benzyl (R)-(1-(1-(2-(1H-indol-3-yl)ethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazine-1 -yl)-2-oxoethyl) carbamate (47 mg), DMSO (1.0 mL), copper(I) iodide (33 mg), 1H-benzotriazole (44 mg), iodobenzene (9 ⁇ L), and tripotassium phosphate (97 mg). was added and stirred at 110°C for 18 hours and 30 minutes. After the reaction mixture was cooled to room temperature, water was added and the solid matter was collected by filtration.
  • Reference example 133 Benzyl (R)-(1-(1-(2-(1H-indol-3-yl)ethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazine-1 -yl)-2-oxoethyl)carbamate (57 mg), DMF (1.0 mL), 1,2-difluorobenzene (45 ⁇ L) and tripotassium phosphate (116 mg) were added, and the mixture was stirred at 150° C. for 17 hours and 10 minutes. After the reaction mixture was cooled to 0° C., water was added and the solid matter was collected by filtration.
  • Ethyl carbamate hydrochloride (2.00 g) was obtained as a pale yellow solid.
  • Dichloromethane (35 mL), 2-phenylacetaldehyde (0.45 mL), triethylamine (1.2 mL) and sodium triacetoxyborohydride (2.24 g) were added to the compound (1.95 g) obtained in (2), and the mixture was heated to room temperature. The mixture was stirred for 22 hours and 30 minutes. After adding water (10 mL) to the reaction mixture, 10% aqueous sodium carbonate solution was added to adjust the pH to 8, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Reference example 147 1-(2-bromoethyl)-2-fluorobenzene in Reference Example 146 was replaced with 3-(2-bromoethyl)thiophene, the reaction was carried out in the same manner as in Reference Example 146, and benzyl (R)-(2-(4-(2) -methoxybenzyl)piperazin-1-yl)-2-oxo-1-(1-(2-(thiophen-3-yl)ethyl)piperidin-4-yl)ethyl)carbamate.
  • Reference example 148 Potassium carbonate ( 258 mg), sodium iodide (124 mg) and DMF (4 mL) were added, and the mixture was stirred under ice cooling under an argon atmosphere. 1-(2-bromoethyl)-2-chlorobenzene (76 ⁇ L) was added to the reaction mixture at the same temperature, and the mixture was stirred at 70° C. for 16 hours and 20 minutes. After the reaction mixture was cooled to 0°C, water and ethyl acetate were added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, the organic layers separated earlier were combined, washed twice with water, and the solvent was distilled off under reduced pressure.
  • Reference example 149 Reference Example 148 1-(2-Bromoethyl)-2-chlorobenzene was replaced with 1-(2-bromoethyl)-3-chlorobenzene and the reaction was carried out in the same manner as Reference Example 148 to produce benzyl (R)-(1-(1-(3- Chlorophenethyl)piperidin-4-yl)-2-(4-(2-methoxybenzyl)piperazin-1-yl)-2-oxoethyl)carbamate was obtained.
  • Reference example 150 Dichloromethane (2 mL) and triethylamine (0.39 mL) were added to 2-(5-chlorothiophen-2-yl)ethan-1-ol (181 mg), and the mixture was stirred at -10°C under an argon atmosphere. Methanesulfonyl chloride (0.10 mL) was added to the reaction mixture at the same temperature and stirred for 1 hour to obtain a dichloromethane mixture of 2-(5-chlorothiophen-2-yl)ethyl methanesulfonate.
  • Reference example 152 (1) Methyl (R)-2-(((benzyloxy)carbonyl)amino)-2-(piperidin-4-yl)acetate hydrochloride (1.70 g), dichloromethane (25 mL), 2-(2-bromo -5-chlorophenyl)acetaldehyde (1.51 g), triethylamine (0.69 mL) and sodium triacetoxyborohydride (1.58 g) were added, and the mixture was stirred at room temperature for 25 hours and 30 minutes. After adding water (25 mL) to the reaction mixture, a 10% aqueous sodium carbonate solution was added to adjust the pH to 8, and the organic layer was separated.
  • Reference example 154 Benzyl (R)-(1-(1-(2-bromo-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)- 2-oxoethyl) carbamate (200 mg), 4-(4,4,5,5-tetramethyl-1,2,3-dioxaborolan-2-yl)phenol (78 mg), tripotassium phosphate (147 mg) and 2- Methyl-2-butanol (2 mL) was added.
  • XPhos Pd G4 (12 mg) was added to the reaction mixture under nitrogen atmosphere, and the mixture was stirred under reflux for 17 hours.
  • Reference example 155 The 4-(4,4,5,5-tetramethyl-1,2,3-dioxaborolan-2-yl)phenol of Reference Example 154 was Substituting 3-dioxaborolan-2-yl)phenol, the reaction was carried out in the same manner as in Reference Example 154, and benzyl (R)-(1-(1-(2-(4-chloro-3'-hydroxy-[1,1' -biphenyl]-2-yl)ethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate was obtained.
  • Reference example 168 Benzyl (R)-(1-(1-(2-bromo-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)- 2-oxoethyl) carbamate (75 mg), 2-fluorophenylboronic acid (22 mg), dichloro(bistriphenylphosphine)palladium(II) (7 mg), sodium carbonate (22 mg), 1,4-dioxane (0.75 mL) and water. (0.1 mL) was added, and the mixture was stirred at 80° C. overnight under a nitrogen atmosphere.
  • Reference example 180 Benzyl (R)-(1-(1-(2-bromo-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)- tert-butyl (3-(4,4,5,5-tetramethyl-1,2,3-dioxaborolan-2-yl)pyridin-4-yl)carboxylate (35mg) in 2-oxoethyl)carbamate (50mg) , dichloro(bistriphenylphosphine)palladium(II) (5 mg), sodium carbonate (15 mg), 1,4-dioxane (0.5 mL) and water (68 ⁇ L) were added, and the mixture was stirred under reflux under a nitrogen atmosphere overnight.
  • Reference example 300 DMF (13.5 mL) was added to 5-(benzyloxy)-2-bromobenzaldehyde (300 mg), and the mixture was stirred under ice cooling. Ethanethiol sodium (144 mg) was added to the reaction mixture at the same temperature, and the mixture was stirred at 70°C for 1 hour. Diethyl ether (13.5 mL) and water (13.5 mL) were added to the reaction mixture, and the organic layer was separated. The obtained organic layer was washed successively with water and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Reference example 301 The reaction was carried out in the same manner as in Reference Example 300 except that sodium ethanethiol in Reference Example 300 was replaced with sodium methanethiol to obtain 5-(benzyloxy)-2-(methylthio)benzaldehyde as a light brown oil.
  • Reference example 303 The reaction was carried out in the same manner as in Reference Example 302 except that sodium ethanethiol in Reference Example 302 was replaced with sodium methanethiol to obtain 2-(benzyloxy)-6-(methylthio)benzaldehyde as a white solid.
  • Reference example 376 (1) Methyl (R)-2-(((benzyloxy)carbonyl)amino)-2-(piperidin-4-yl)acetate hydrochloride (20.0g), acetonitrile (400mL), 2-bromo-5- Chlorophenethyl methanesulfonate (27.4 g) and potassium carbonate (40.3 g) were added, and the mixture was stirred at 75° C. for 17 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and insoluble matter was filtered off.
  • Reference example 419 (1) Benzyl (R)-(2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxo-1-(piperidin-4-yl)ethyl)carbamate hydrochloride (300 mg), dichloromethane (3 mL), 2-(5-(benzyloxy)-2-bromophenyl)acetaldehyde (172 mg), triethylamine (0.14 mL) and sodium triacetoxyborohydride (272 mg) were added, and the mixture was heated to room temperature for 20 minutes. Stir for hours.
  • Reference example 421 The iodomethane in Reference Example 420 was replaced with tert-butyl bromoacetate, the reaction was carried out in the same manner as in Reference Example 420, and (R)-4-(1-(((benzyloxy)carbonyl)amino)-2-(4-(2 -ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)-1-(2-(tert-butoxy)-2-oxoethyl)-1-(2-(4-chloro-[1,1 '-Biphenyl]-2-yl)ethyl)piperidin-1-ium bromide was obtained as a pale red solid.
  • Reference example 421 (1) Benzyl 2-(4-(benzyloxy)-2-bromophenyl) acetate (100 mg), phenylboronic acid (39 mg), sodium carbonate (41 mg), [1,1-bis(diphenylphosphino)ferrocene] Dichloropalladium (II) (27 mg), 1,2-dimethoxyethane (1 mL) and water (0.5 mL) were added, and the mixture was stirred at 80°C for 16 hours and 30 minutes. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the organic layer was separated.
  • Reference example 422 (1) Add DMAC (100 mL) to (R)-2-(((benzyloxy)carbonyl)amino)-2-(1-(tert-butoxycarbonyl)piperidin-4-yl) (9.81 g) and add ice The mixture was stirred under cooling. Allyl piperazine-1-carboxylate hydrochloride (5.15 g), WSC hydrochloride (6.23 g), ethyl cyano(hydroxyimino)acetate (4.26 g) and 4-methylmorpholine (11 mL) were added to the reaction mixture at the same temperature. The mixtures were added one after another and stirred at room temperature for 17 hours.
  • Reference example 423 (1) Dichloromethane (26.5 mL) and triethylamine (2.5 mL) were added to 2-(4-phenylthiophen-3-yl)ethan-1-ol (2.80 g), and the mixture was stirred at -15°C. A dichloromethane solution (6.2 mL) of methanesulfonyl chloride (1.2 mL) was added at the same temperature, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were added to the reaction mixture, and the organic layer was separated.
  • the aqueous layer was extracted three times with ethyl acetate, the organic layers separated earlier were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Reference example 435 (1) 1-(2- Ethoxy-6-fluorobenzyl)piperazine hydrochloride (1.99 g), WSC hydrochloride (1.35 g), HOBt (0.95 g), dichloromethane (22 mL) and DIPEA (3.6 mL) were added sequentially, and the mixture was stirred at room temperature for 20 hours. . Water (20 mL) was added to the reaction mixture, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 1 Benzyl (R)-(1-(1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-2-(4-(2-( Anisole (0.14 mL) and 5.1 mol/L hydrobromide-acetic acid solution (0.7 mL) were added to methylthio)benzyl)piperazin-1-yl)-2-oxoethyl)carbamate (70 mg), and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (5 mL) and diethyl ether (5 mL) were sequentially added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes.
  • Example 31 Benzyl (R)-(2-(4-(benzo[b]thiophen-7-ylmethyl)piperazin-1-yl)-1-(1-(2-(4-chloro-[1,1'-biphenyl] -2-yl)ethyl)piperidin-4-yl)-2-oxoethyl)carbamate (80mg) was added with anisole (0.16mL) and 5.1mol/L hydrobromide and acetic acid solution (0.8mL), and the mixture was heated at room temperature for 1 hour. Stirred. Ethyl acetate (10 mL) was added to the reaction mixture, stirred at room temperature for 30 minutes, and the solid matter was collected by filtration.
  • Example 44 Benzyl (R)-(1-(1-(2-(2',4-dichloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-2-(4-( To 2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl) carbamate (240 mg) were added anisole (0.48 mL) and 5.1 mol/L hydrobromide and acetic acid solution (2.4 mL), and the mixture was heated at room temperature. Stirred for 1 hour.
  • Example 93 (1) Benzyl (R)-(1-(1-(2-(4-((tert-butoxycarbonyl)amino)pyridin-3-yl)-5-chlorophenethyl)piperidin-4-yl)-2- Dichloromethane (0.42 mL) and 4 mol/L hydrochloric acid dioxane solution (0.1 mL) were added to (4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl) carbamate (240 mg), and the mixture was heated at room temperature. Stir overnight.
  • Example 94 Benzyl (R)-(2-(4-(6-ethoxy-2-fluoro-3-(methoxymethoxy)benzyl)piperazin-1-yl)-2-oxo-1-(1-phenethylpiperidin-4-yl ) Ethyl) carbamate (429 mg) was added with anisole (0.43 mL) and a 5.1 mol/L hydrobromic acid acetic acid solution (4.3 mL), and the mixture was stirred at room temperature for 6 hours. Ethyl acetate (20 mL) was added to the reaction mixture, stirred at room temperature for 30 minutes, and the solid matter was collected by filtration. The solid was dried under reduced pressure to obtain a light brown solid.
  • Example 97 Benzyl (R)-(1-(1-(2-(2'-((tert-butoxycarbonyl)amino)-4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidine-4 -yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (66 mg) with anisole (0.13 mL) and 5.1 mol/L hydrobromide and acetic acid. A solution (0.66 mL) was added and stirred at room temperature for 1 hour.
  • Example 104 Acetonitrile (0.81 mL) was added to sodium iodide (140 mg), and the mixture was stirred under ice cooling. Chlorotrimethylsilane (0.12 mL) was added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 10 minutes.
  • the solvent was distilled off under reduced pressure, and ethyl acetate (2 mL), diethyl ether (2 mL), and water (4 mL) were added to the residue, then 1 mol/L hydrochloric acid was added to adjust the pH to 1.0, and the aqueous layer was separated. did.
  • Example 106 NMR: 1.41(3H,t,J 7.0Hz), 1.51-1.72(2H,m),1.85-2.00(2H,m), 2.07-2.23(1H,m), 2.70-2.89(2H,m), 3.02-3.17(4H,m),3.19-3.61
  • Example 107 Acetonitrile (0.32 mL) and chlorotrimethylsilane (28 ⁇ L) were sequentially added to sodium iodide (33 mg), and the mixture was stirred at room temperature for 15 minutes. The resulting reaction mixture was dissolved in benzyl (R)-(1-(1-(2-(2'-(benzyloxy)-4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidine- 4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (46 mg) in acetonitrile solution (0.32 mL) and heated at 50°C for 2 hours.
  • the solvent was distilled off under reduced pressure, diethyl ether and water were added to the residue, and then 1 mol/L hydrochloric acid was added to adjust the pH to 1, and the aqueous layer was separated. After washing the aqueous layer with diethyl ether (10 mL), ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to adjust the pH to 8, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a pale yellow oil (5 mg).
  • Example 108 In the same manner as in Example 107, (R)-2-amino-2-(1-(2-(4-chloro-4'-fluoro-2'-hydroxy-[1,1'-biphenyl]-2-yl) ) Ethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethane-1-one hydrochloride was obtained.
  • Example 109 Benzyl (R)-(1-(1-(2-([1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluoro Methanol (2.5 mL) and 10% palladium on carbon (125 mg) were sequentially added to benzyl)piperazin-1-yl)-2-oxoethyl)carbamate (250 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. Unwanted substances were removed by filtration through Celite, and the solvent was distilled off under reduced pressure.
  • Example 131 (R)-2-Amino-1-(4-(2-methoxybenzyl)piperazin-1-yl)-2-(1-phenethylpiperidin-4-yl)ethane-1-one (100 mg) and dichloromethane (1 mL) ), 13.31 mol/L formaldehyde aqueous solution (17 ⁇ L), 5 drops of methanol (total 25 ⁇ L) using a Pasteur pipette, and sodium triacetoxyborohydride (71 mg) were added sequentially, and the mixture was stirred at room temperature for 22 hours and 20 minutes.
  • Example 132 Benzyl (R)-(2-(4-(2-fluoro-6-(2-methoxyethoxy)benzyl)piperazin-1-yl)-2-oxo-1-(1-phenethylpiperidin-4-yl)ethyl )
  • Anisole (0.47 mL) and 5.1 mol/L hydrobromide-acetic acid solution (4.7 mL) were added to carbamate (470 mg), and the mixture was stirred at room temperature for 3 hours.
  • Ethyl acetate (20 mL) and diethyl ether (20 mL) were added to the reaction mixture, stirred at room temperature for 30 minutes, and the solid matter was collected by filtration.
  • Example 133 Benzyl (R)-(2-(4-(2-methoxybenzyl)piperazin-1-yl)-2-oxo-1-(1-(2-(thiophen-3-yl)ethyl)piperidin-4-yl ) Ethyl) carbamate (90 mg) were added with acetic acid (1 mL) and a 5.1 mol/L hydrobromic acid acetic acid solution (0.5 mL), and the mixture was stirred at room temperature for 3 hours and 30 minutes. The reaction mixture was added to a saturated aqueous sodium hydrogen carbonate solution (10 mL) under ice cooling.
  • Example 136 (1) Benzyl ((1R)-1-(1-(3-((tert-butoxycarbonyl)amino)-2-phenylpropyl)piperidin-4-yl)-2-(4-(2-methoxybenzyl) Methanol (1.2 mL) and 10% palladium on carbon (47 mg) were sequentially added to piperazin-1-yl)-2-oxoethyl) carbamate (124 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. 10% palladium on carbon (47 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere.
  • Example 137 Benzyl (R)-(1-(1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-2-(4-(2-ethoxy -6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (225 mg) was added with anisole (0.23 mL) and 5.1 mol/L hydrobromic acid acetic acid solution (2.3 mL), and the mixture was stirred at room temperature for 5 hours. Stir for 1 minute. After adding the reaction mixture to ice water, ethyl acetate (10 mL) was added and the aqueous layer was extracted.
  • Example 138 Methyl (R)-2'-(2-(4-(1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl )-[1,1'-biphenyl]-3-carboxylate hydrochloride (65 mg), THF (0.65 mL), methanol (65 ⁇ L), water (0.65 mL) and lithium hydroxide monohydrate (23 mg) ) and stirred at room temperature for 1 hour. After adding 1 mol/L hydrochloric acid to the reaction mixture and adjusting the pH to 1.0, ethyl acetate was added and the aqueous layer was separated.
  • the obtained solution containing the target product was distilled off under reduced pressure, dried, and (R)-2'-(2-(4-(1-amino-2-(4-(2-ethoxy-6-fluoro) Hydrochloride (7 mg) of benzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-[1,1'-biphenyl]-3-carboxylic acid was obtained as a white solid.
  • Example 139 Benzyl (R)-(1-(1-(2-(4-chloro-2'-fluoro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-2-(4 -(2-Ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (73 mg) was added with anisole (0.15 mL) and 5.1 mol/L hydrobromide and acetic acid solution (0.73 mL), The mixture was stirred at room temperature for 1 hour and 30 minutes.
  • Example 140 Potassium carbonate ( 261 mg), sodium iodide (123 mg) and DMF (4 mL) were added, and the mixture was stirred under ice cooling under an argon atmosphere. 1-(2-bromoethyl)-3-chlorobenzene (80 ⁇ L) was added at the same temperature, and the mixture was stirred at 70° C. for 18 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, combined with the obtained organic layer, washed twice with water, and then the solvent was distilled off under reduced pressure.
  • Example 141 Dichloromethane (2 mL) and triethylamine (0.38 mL) were added to 2-methylphenethyl alcohol (145 ⁇ L), and the mixture was stirred at ⁇ 10° C. under an argon atmosphere. Methanesulfonyl chloride (92 ⁇ L) was added to the reaction mixture and stirred at the same temperature for 1 hour to obtain a dichloromethane mixture of 2-methylphenethyl methanesulfonate. Potassium carbonate ( 430 mg), sodium iodide (167 mg) and DMF (4 mL) were added, and the mixture was stirred under ice cooling under an argon atmosphere.
  • Example 142 Benzyl (R)-(1-(1-(3-chlorophenethyl)piperidin-4-yl)-2-(4-(2-methoxybenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (108mg) Acetic acid (1 mL) and 5.1 mol/L hydrobromide-acetic acid solution (0.5 mL) were added to the mixture, and the mixture was stirred at room temperature for 2 hours and 30 minutes. The reaction mixture was added to a saturated aqueous sodium hydrogen carbonate solution (30 mL) under ice cooling, stirred at the same temperature for 10 minutes, and then stirred at room temperature for 15 minutes.
  • Example 143 (1) (9H-fluoren-9-yl)methyl (R)-(2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxo-1-(piperidine-4 DMF (6 mL), 1-(2-bromoethyl)-2-chlorobenzene (0.5 mL), potassium carbonate (935 mg) and sodium iodide (204 mg) were added to hydrochloride (584 mg) of ethyl)) carbamate under ice cooling. ) and stirred at 70° C. for 4 hours under an argon atmosphere. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated.
  • Example 144 Benzyl (R)-(1-(1-(2-(5-chlorothiophen-2-yl)ethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazine- Anisole (0.1 mL) and 5.1 mol/L hydrobromide-acetic acid solution (1 mL) were added to 1-yl)-2-oxoethyl) carbamate (33 mg), and the mixture was stirred at room temperature for 1 hour and 55 minutes. Ethyl acetate (15 mL) was added to the reaction mixture, and after stirring at room temperature for 5 minutes, the solid matter was precipitated and the supernatant liquid was removed.
  • Example 146 NMR: 1.41(3H,t,J 7.0Hz), 1.68-1.91(2H,m), 1.98-2.42(2H,m),2.64-2.87(1H,m), 3.08-3.92(
  • Example 148 Benzyl (R)-(1-(1-(2-(1H-indol-3-yl)ethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazine-1
  • Anisole (0.15 mL) and 5.1 mol/L hydrobromide-acetic acid solution (1.5 mL) were added to (46 mg) of (2-oxoethyl)-yl) carbamate, and the mixture was stirred at room temperature for 1 hour and 20 minutes.
  • Ethyl acetate (25 mL) was added to the reaction mixture, and after stirring at room temperature for 15 minutes, the solid matter was collected by filtration.
  • Example 150 NMR: 1.38(3H,t,J 7.0Hz), 1.65-1.91(2H,m),
  • Example 200 2-(4-Phenethylpiperazin-1-yl)-1-(piperazin-1-yl)ethane-1-one hydrochloride (750 mg), dichloromethane (15 mL), 2-(difluoromethoxy)benzaldehyde (455 mg), Triethylamine (1.2 mL) and sodium triacetoxyborohydride (560 mg) were sequentially added, and the mixture was stirred at room temperature for 6 hours. Sodium triacetoxyborohydride (300 mg) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. Chloroform and water were added to the reaction mixture, and the organic layer was separated.
  • the aqueous layer was extracted twice with chloroform, the organic layers separated earlier were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Diethyl ether (20 mL) and 1 mol/L hydrochloric acid diethyl ether solution (5 mL) were added to the obtained oil, stirred for 30 minutes under ice cooling, and the solid substance was collected by filtration.
  • Example 201 The compound of Example 201 was obtained by replacing 2-(difluoromethoxy)benzaldehyde in Example 200 with benzaldehyde. NMR: 2.80-3.33(9H,m), 3.34-3.66(9H,m), 3.66-3.88(2H,m),3.88-4.23(1H,m), 4.40(2H,s), 4.46-4.64(1H ,m), 7.25-7.39(3H,m), 7.39-7.46(2H,m),7.47-7.62(5H,m) MS: 407.25[M+H] +
  • Example 202 The compound of Example 202 was obtained by replacing 2-(difluoromethoxy)benzaldehyde in Example 200 with 2-methylbenzaldehyde.
  • Example 203 The compound of Example 203 was obtained by replacing 2-(difluoromethoxy)benzaldehyde in Example 200 with 3-methoxybenzaldehyde.
  • Example 204 The compound of Example 204 was obtained by replacing 2-(difluoromethoxy)benzaldehyde in Example 200 with 4-methoxybenzaldehyde.
  • Example 205 The compound of Example 205 was obtained by replacing 2-(difluoromethoxy)benzaldehyde in Example 200 with 3,4-dimethoxybenzaldehyde.
  • Example 206 The compound of Example 206 was obtained by replacing 2-(difluoromethoxy)benzaldehyde in Example 200 with 2-fluoro-4,5-dimethoxybenzaldehyde.
  • Example 207 The compound of Example 207 was obtained by replacing 2-(difluoromethoxy)benzaldehyde in Example 200 with 1,4-benzodioxane-6-carboxaldehyde.
  • Example 208 A compound of Example 208 was obtained by replacing 2-(difluoromethoxy)benzaldehyde in Example 200 with 2-bromo-4,5-dimethoxybenzaldehyde.
  • Example 209 The compound of Example 209 was obtained by replacing 2-(difluoromethoxy)benzaldehyde in Example 200 with 4-methoxy-2-methylbenzaldehyde.
  • Example 210 The compound of Example 210 was obtained by replacing 2-(difluoromethoxy)benzaldehyde in Example 200 with cyclohexanecarboxaldehyde.
  • Example 211 The compound of Example 211 was obtained by replacing 2-(difluoromethoxy)benzaldehyde in Example 200 with cyclopentanecarboxaldehyde.
  • Example 212 The compound of Example 212 was obtained by replacing 2-(difluoromethoxy)benzaldehyde in Example 200 with cycloheptanecarboxaldehyde.
  • Example 213 The compound of Example 213 was obtained by replacing 2-(difluoromethoxy)benzaldehyde in Example 200 with methyl 2-formylbenzoate.
  • Example 214 The compound of Example 214 was obtained by replacing 2-(difluoromethoxy)benzaldehyde in Example 200 with 2,6-dimethoxybenzaldehyde.
  • Example 215 2-(4-Phenethylpiperazin-1-yl)-1-(piperazin-1-yl)ethane-1-one hydrochloride (300 mg), dichloromethane (7 mL), 2-fluoro-6-methoxybenzaldehyde (120 mg) , triethylamine (0.34 mL) and sodium triacetoxyborohydride (448 mg) were sequentially added, and the mixture was stirred at room temperature for 23 hours. After adding water to the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution was added to adjust the pH to 8, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 218 The compound of Example 218 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde in Example 215 with 2-isopropylbenzaldehyde.
  • Example 219 The compound of Example 219 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde in Example 215 with 2-bromobenzaldehyde.
  • Example 220 The compound of Example 220 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde in Example 215 with 2-ethoxybenzaldehyde.
  • Example 221 The compound of Example 221 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde of Example 215 with 2-(trifluoromethoxy)benzaldehyde.
  • Example 222 The compound of Example 222 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde in Example 215 with 2-isopropoxybenzaldehyde.
  • Example 223 The compound of Example 223 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde in Example 215 with 2-methoxy-6-methylbenzaldehyde.
  • Example 224 The compound of Example 224 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde of Example 215 with 2-(dimethylamino)benzaldehyde.
  • Example 225 The compound of Example 225 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde in Example 215 with 2-propoxybenzaldehyde.
  • Example 226 The compound of Example 226 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde in Example 215 with 2-(isopentyloxy)benzaldehyde.
  • Example 227 The compound of Example 227 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde in Example 215 with 2-chloro-4-hydroxybenzaldehyde.
  • Example 228 The compound of Example 228 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde in Example 215 with 2-chloro-5-hydroxybenzaldehyde.
  • Example 229 The compound of Example 229 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde in Example 215 with 2-chloro-6-hydroxybenzaldehyde.
  • Example 230 The compound of Example 230 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde in Example 215 with 2-(methylthio)benzaldehyde.
  • Example 231 The compound of Example 231 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde in Example 215 with 4-hydroxy-2-methoxybenzaldehyde.
  • Example 232 The compound of Example 232 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde in Example 215 with 5-hydroxy-2-methoxybenzaldehyde.
  • Example 233 The compound of Example 233 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde in Example 215 with 2-chloro-5-nitrobenzaldehyde.
  • Example 234 The compound of Example 234 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde in Example 215 with 2-formylbenzonitrile.
  • Example 235 The compound of Example 235 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde in Example 215 with 2-nitrobenzaldehyde.
  • Example 236 The compound of Example 236 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde in Example 215 with 2-hydroxy-6-methoxybenzaldehyde.
  • Example 237 The compound of Example 237 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde in Example 215 with 2-fluoro-4,5-dihydroxybenzaldehyde.
  • Example 238 The compound of Example 238 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde in Example 215 with 1-naphthaldehyde.
  • Example 239 The compound of Example 239 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde in Example 215 with 5-fluoro-2-methoxybenzaldehyde.
  • Example 240 The compound of Example 240 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde of Example 215 with 4-fluoro-2-methoxybenzaldehyde.
  • Example 241 The compound of Example 241 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde in Example 215 with 3-fluoro-2-methoxybenzaldehyde.
  • Example 242 The compound of Example 242 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde in Example 215 with 2-chloro-6-methoxybenzaldehyde.
  • Example 243 The compound of Example 243 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde of Example 215 with 2-bromo-6-methoxybenzaldehyde.
  • Example 244 The compound of Example 244 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde in Example 215 with 2-ethoxy-6-fluorobenzaldehyde.
  • Example 245 The compound of Example 245 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde in Example 215 with 2-methoxy-6-(trifluoromethyl)benzaldeh
  • Example 246 The compound of Example 246 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde of Example 215 with 2-fluoro-6-(trifluoromethyl)benzaldehyde.
  • Example 247 The compound of Example 247 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde of Example 215 with 4,5-difluoro-2-methoxybenzaldehyde.
  • Example 248 The compound of Example 248 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde in Example 215 with 2-fluoro-6-methylbenzaldehyde.
  • Example 249 The compound of Example 249 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde of Example 215 with 3-methoxythiophene-2-carbaldehyde.
  • Example 250 The compound of Example 250 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde in Example 215 with 3-methylthiophene-2-carbaldehyde.
  • Example 251 The compound of Example 251 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde of Example 215 with 3-chlorothiophene-2-carbaldehyde.
  • Example 252 The compound of Example 252 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde of Example 215 with 2-methoxythiophene-3-carbaldehyde.
  • Example 253 The compound of Example 253 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde of Example 215 with 2-chlorothiophene-3-carbaldehyde.
  • Example 254 The compound of Example 254 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde in Example 215 with 4-methylthiophene-3-carbaldehyde.
  • Example 255 The compound of Example 255 was obtained by replacing 2-fluoro-6-methoxybenzaldehyde of Example 215 with 4-chlorothiophene-3-carbaldehyde.
  • Example 257 (1) 2-(4-phenethylpiperazin-1-yl)-1-(piperazin-1-yl)ethane-1-one hydrochloride (100 mg), dichloromethane (2.3 mL), methyl 3-formylbenzoate (40 mg) ), triethylamine (0.16 mL) and sodium triacetoxyborohydride (75 mg) were added sequentially, and the mixture was stirred at room temperature for 15 hours. Dichloromethane and water were added to the reaction mixture, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 257 3-formylbenzoate in Example 257 was replaced with 4-formylbenzoate, the reaction was carried out in the same manner as in Example 257, and 4-((4-(2-(4-phenethylpiperazin-1-yl)acetyl)piperazine-1- The sodium salt of yl)methyl)benzenecarboxylic acid was obtained.
  • Example 259 Dichloromethane (15 mL), 2-fluorobenzaldehyde (328 mg), triethylamine (1.2 mL) and sodium triacetoxyborohydride (560 mg) were added sequentially, and the mixture was stirred at room temperature for 5 hours. Sodium triacetoxyborohydride (300 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. Ethyl acetate and water were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate, the organic layers separated earlier were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 259 2-fluorobenzaldehyde in Example 259 was replaced with 2-chlorobenzaldehyde, the reaction was carried out in the same manner as in Example 259, and 1-(4-(2-chlorobenzyl)piperazin-1-yl)-2-(4-phenethylpiperazine) -1-yl)ethane-1-one hydrochloride was obtained.
  • Example 261 1-(2-methoxybenzyl)piperazine hydrochloride (250mg), 2-(4-phenethylpiperazin-1-yl)propanoic acid (266mg), WSC hydrochloride (201mg), HOBt (142mg), dichloromethane (9.5mL) ) and DIPEA (0.53 mL) were added sequentially, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 262 Example 261 1-(2-methoxybenzyl)piperazine hydrochloride and 2-(4-phenethylpiperazin-1-yl)propanoic acid were converted to (2-(piperazin-1-ylmethyl)phenyl)methanol hydrochloride and 2-(4-phenethylpiperazin-1-yl)propanoic acid. By substituting (4-phenethylpiperazin-1-yl)acetic acid, the compound of Example 262 was obtained.
  • Example 263 The hydrochloride of 1-(2-methoxybenzyl)piperazine and 2-(4-phenethylpiperazin-1-yl)propanoic acid of Example 261 were converted to the hydrochloride of 1-(2-(methoxymethyl)benzyl)piperazine and 2- By substituting (4-phenethylpiperazin-1-yl)acetic acid, the compound of Example 263 was obtained.
  • Example 264 The compound of Example 264 was obtained by replacing 2-(4-phenethylpiperazin-1-yl)propanoic acid in Example 261 with 2-methyl-2-(4-phenethylpiperazin-1-yl)propanoic acid.
  • Example 265 1-(4-(2-chloro-5-nitrobenzyl)piperazin-1-yl)-2-(4-phenethylpiperazin-1-yl)ethane-1-one hydrochloride (200 mg) and methanol (2 mL) and 10% palladium on carbon (40 mg) were added, and the mixture was stirred at room temperature for 1 hour and 30 minutes under a hydrogen atmosphere. Unwanted substances were removed by filtration through Celite, and the solvent was distilled off under reduced pressure. Diethyl ether (6 mL) and 1 mol/L hydrochloric acid diethyl ether solution (0.4 mL) were added to the residue, and the mixture was stirred at room temperature for 30 minutes.
  • Example 266 (1) 2-(4-phenethylpiperazin-1-yl)-1-(piperazin-1-yl)ethane-1-one hydrochloride (300 mg), dichloromethane (7 mL), tert-butyl (2-(2 -formyl-3-methoxyphenoxy)ethyl)carbamate (229 mg), triethylamine (0.34 mL) and sodium triacetoxyborohydride (448 mg) were added sequentially, and the mixture was stirred at room temperature for 18 hours and 30 minutes. After adding water (5 mL) to the reaction mixture, 10% aqueous sodium hydrogen carbonate solution was added to adjust the pH to 8, and the organic layer was separated.
  • the obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 269 2-(4-Phenethylpiperazin-1-yl)acetic acid (80 mg), dichloromethane (1.6 mL), 1-(1-(2-fluoro-6-methoxyphenyl)ethyl)piperazindi hydrochloride (100 mg), COMU( 276 mg) and DIPEA (0.23 mL) were added sequentially, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 270 by replacing the hydrochloride of 1-(1-(2-fluoro-6-methoxyphenyl)ethyl)piperazinedi in Example 269 with the hydrochloride of 1-(1-(2-methoxyphenyl)ethyl)piperazinedi The compound was obtained.
  • Example 271 by replacing the hydrochloride of 1-(1-(2-fluoro-6-methoxyphenyl)ethyl)piperazinedi in Example 269 with the hydrochloride of 1-(1-(2-ethoxyphenyl)ethyl)piperazinedi The compound was obtained.
  • Example 272 1-(4-(2-methoxybenzyl)piperazin-1-yl)-2-(piperazin-1-yl)ethane-1-one hydrochloride (187 mg), DMF (3 mL), potassium carbonate (224 mg), and sodium iodide (134 mg) were added one after another, and the mixture was stirred under ice-cooling under an argon atmosphere. 1-(2-bromoethyl)-3-chlorobenzene (90 ⁇ L) was added to the reaction mixture at the same temperature, and the mixture was stirred at 70° C. for 18 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated.
  • Example 273 The compound of Example 273 was obtained by replacing 1-(2-bromoethyl)-3-chlorobenzene of Example 272 with 1-(2-bromoethyl)-2-methoxybenzene.
  • Example 274 The compound of Example 274 was obtained by replacing 1-(2-bromoethyl)-3-chlorobenzene of Example 272 with 1-(2-bromoethyl)-2-fluorosibenzene.
  • Example 275 The compound of Example 275 was obtained by replacing 1-(2-bromoethyl)-3-chlorobenzene of Example 272 with (2-bromoethyl)cyclohexane.
  • Example 276 The compound of Example 276 was obtained by replacing 1-(2-bromoethyl)-3-chlorobenzene of Example 272 with 1-(2-bromoethyl)-3-fluorosybenzene.
  • Example 277 The compound of Example 277 was obtained by replacing 1-(2-bromoethyl)-3-chlorobenzene of Example 272 with 1-(2-bromoethyl)-4-fluorosibenzene.
  • Example 278 The compound of Example 278 was obtained by replacing 1-(2-bromoethyl)-3-chlorobenzene of Example 272 with 1-(2-bromoethyl)-4-methoxybenzene.
  • Example 279 The compound of Example 279 was obtained by replacing 1-(2-bromoethyl)-3-chlorobenzene of Example 272 with 1-(2-bromoethyl)-3-methoxybenzene.
  • Example 280 The compound of Example 280 was obtained by replacing 1-(2-bromoethyl)-3-chlorobenzene of Example 272 with 1-(2-bromoethyl)-2-chlorobenzene.
  • Example 281 The compound of Example 281 was obtained by replacing 1-(2-bromoethyl)-3-chlorobenzene of Example 272 with 1-(2-bromoethyl)-4-chlorobenzene.
  • Example 282 The compound of Example 282 was obtained by replacing 1-(2-bromoethyl)-3-chlorobenzene of Example 272 with 4-(2-bromoethyl)tetrahydro-2H-pyran.
  • Example 283 The compound of Example 283 was obtained by replacing 1-(2-bromoethyl)-3-chlorobenzene of Example 272 with 4-(2-chloroethyl)thiazole.
  • Example 284 The compound of Example 284 was obtained by replacing 1-(2-bromoethyl)-3-chlorobenzene of Example 272 with 1-(4-(2-chloroethyl)ethane-1-one).
  • Example 285 Dichloromethane (1 mL) was added to methanesulfonyl chloride (0.13 mL), stirred under ice cooling under an argon atmosphere, and 2-(5-chlorothiophen-2-yl)ethane-1-ol (261 mg) and A solution of triethylamine (0.48 m ⁇ L) in dichloromethane (2 mL) was added and stirred for 1 hour and 30 minutes to obtain a dichloromethane mixture of 2-(5-chlorothiophen-2-yl)ethyl methanesulfonate.
  • Example 286 The compound of Example 286 was obtained by replacing 2-(5-chlorothiophen-2-yl)ethan-1-ol in Example 285 with 2-(thiophen-2-yl)ethan-1-ol.
  • Example 287 The compound of Example 287 was obtained by replacing 2-(5-chlorothiophen-2-yl)ethan-1-ol in Example 285 with 2-(thiophen-3-yl)ethan-1-ol.
  • Example 288 The compound of Example 288 was obtained by replacing 2-(5-chlorothiophen-2-yl)ethan-1-ol in Example 285 with 2-(pyridin-2-yl)ethan-1-ol.
  • Example 289 The compound of Example 289 was obtained by replacing 2-(5-chlorothiophen
  • Example 290 The compound of Example 290 was obtained by replacing 2-(5-chlorothiophen-2-yl)ethan-1-ol in Example 285 with 2-(furan-2-yl)ethan-1-ol.
  • Example 291 The compound of Example 291 was obtained by replacing 2-(5-chlorothiophen-2-yl)ethan-1-ol in Example 285 with 2-(furan-3-yl)ethan-1-ol.
  • Example 292 The compound of Example 292 was obtained by replacing 2-(5-chlorothiophen-2-yl)ethan-1-ol in Example 285 with 2-(pyridin-3-yl)ethan-1-ol.
  • Example 293 The compound of Example 292 was obtained by replacing 2-(5-chlorothiophen-2-yl)ethan-1-ol in Example 285 with 2-(thiazol-2-yl)ethan-1-ol.
  • Example 294 The compound of Example 293 was obtained by replacing 2-(5-chlorothiophen-2-yl)ethan-1-ol in Example 285 with 2-(thiazol-5-yl)ethan-1-ol.
  • Example 295 (1) Dichloromethane (6.8 mL), tert-butyl (3-oxo -2-phenylpropyl) carbamate (186 mg), triethylamine (0.33 mL) and sodium triacetoxyborohydride (432 mg) were added sequentially, and the mixture was stirred at room temperature for 16 hours and 30 minutes. After adding dichloromethane (5 mL) and water (5 mL) to the reaction mixture, a 10% aqueous sodium carbonate solution was added to adjust the pH to 8, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 296 1-(4-(4,5-dimethoxy-2-methylbenzyl)piperazin-1-yl)-2-(piperazin-1-yl)ethane-1-one hydrochloride (200 mg) in dichloromethane (4.1 mL) , 2-(ortho-tolyl)acetylaldehyde (58 mg), triethylamine (0.29 mL) and sodium triacetoxyborohydride (131 mg) were added sequentially, and the mixture was stirred at room temperature for 18 hours and 30 minutes. Dichloromethane and water were added to the reaction mixture, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 299 (1) 1-(2-methoxybenzyl)piperazine hydrochloride (200mg), 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2,2-difluoroacetic acid (200mg), WSC hydrochloride (151 mg), HOBt (107 mg), dichloromethane (4 mL) and DIPEA (0.40 mL) were added sequentially, and the mixture was stirred at room temperature for 21 hours. Water (5 mL) was added to the reaction mixture, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 301 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2,2-difluoroacetic acid of Example 299 was converted to 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)- The reaction was carried out in the same manner as in step (1) of Example 299 except that 2-oxoacetic acid was used to obtain the desired product as a colorless oil.
  • the compound (667 mg) obtained in (1) was reacted in the same manner as in step (2) of Example 299 to obtain the desired product (623 mg) as a white solid.
  • the compound (145 mg) obtained in (2) was reacted in the same manner as in step (3) of Example 299 to obtain the desired product (106 mg) as a pale yellow solid.
  • Example 301 The reaction was carried out in the same manner as in Example 301 except that tert-butoxycarbonylhydrazine in Example 301 was replaced with O-(tetrahydro-2H-pyran-2-yl)hydroxylamine, resulting in 2-(hydroxyimino)-1-(4-( Hydrochloride of 2-methoxybenzyl)piperazin-1-yl)-2-(1-phenethylpiperidin-4-yl)ethane-1-one was obtained.
  • Example 303 (1) 1-(2-methoxybenzyl)piperazine hydrochloride (70mg), 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)oxetane-3-carboxylic acid (72mg), HATU (112mg) , DMAC (0.7 mL) and DIPEA (0.15 mL) were sequentially added thereto, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Ethyl acetate (5 mL) and water (5 mL) were added to the reaction mixture, and the organic layer was separated.
  • the obtained organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Dichloromethane (1.2 mL) and 4 mol/L hydrochloric acid dioxane solution (0.43 mL) were added to the compound obtained in (1) (116 mg), and the mixture was stirred at room temperature overnight. After the solvent was distilled off under reduced pressure, the residue was dried under reduced pressure to obtain the desired product (103 mg) as a white solid.
  • Example 304 (1) 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)oxetane-3-carboxylic acid of Example 303 to 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid Instead, the reaction was carried out in the same manner as in step (1) of Example 303 to obtain the desired product as a colorless oil.
  • (2) Dichloromethane (7 mL) and 4 mol/L hydrochloric acid dioxane solution (4.4 mL) were added to the compound (1.9 g) obtained in (1), and the mixture was stirred at room temperature for 5 hours.
  • the solvent was distilled off under reduced pressure, ethyl acetate and water were added to the residue, and the aqueous layer was separated.
  • the solvent was distilled off under reduced pressure to obtain the desired product (874 mg) as a light brown oil.
  • Example 400 2-chloro-1-(4-(2-methoxybenzyl)piperazin-1-yl)ethan-1-one (300 mg), (E)-4-styrylpiperidine hydrochloride (237 mg), DMF (4.2 mL) , potassium carbonate (367 mg) and sodium iodide (40 mg) were successively added thereto, and the mixture was stirred at 70°C for 3 hours. Ethyl acetate (10 mL) and water (10 mL) were added to the reaction mixture, and the organic layer was separated. The obtained organic layer was washed successively with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 401 The compound of Example 401 was obtained by replacing (E)-4-styrylpiperidine hydrochloride in Example 400 with 4-phenethylpiperidine-4-carbonitrile hydrochloride.
  • Example 402 The compound of Example 402 was obtained by replacing (E)-4-styrylpiperidine hydrochloride in Example 400 with 4-(methoxymethyl)-4-phenethylpiperidine hydrochloride.
  • Example 403 The compound of Example 403 was obtained by replacing (E)-4-styrylpiperidine hydrochloride in Example 400 with 4-((benzyloxy)methyl)-4-phenethylpipe
  • Example 404 The compound of Example 404 was obtained by replacing the hydrochloride of (E)-4-styrylpiperidine in Example 400 with the hydrochloride of 4-phenethylpiperidine-4-carboxamide.
  • Example 405 The compound of Example 405 was obtained by replacing (E)-4-styrylpiperidine hydrochloride in Example 400 with 4-(phenylethynyl)piperidine hydrochloride.
  • Example 406 The compound of Example 406 was obtained by replacing the hydrochloride of (E)-4-styrylpiperidine in Example 400 with the hydrochloride of (Z)-4-styrylpiperidine.
  • Example 407 The compound of Example 407 was obtained by replacing (E)-4-styrylpiperidine hydrochloride in Example 400 with 4-phenethylpiperidine hydrochloride
  • Example 408 The compound of Example 408 was obtained by replacing the hydrochloride of (E)-4-styrylpiperidine in Example 400 with the hydroch
  • Example 409 The compound of Example 409 was prepared by replacing the hydrochloride of (E)-4-styrylpiperidine in Example 400 with the hydrochloride of N-(4-(tert-butyl)thiazol-2-yl)piperidine-4-carboxamide.
  • Example 410 The compound of Example 410 was obtained by replacing (E)-4-styrylpiperidine hydrochloride in Example 400 with 4-(benzyloxy)piperidine hydrochloride.
  • Example 411 The compound of Example 411 was obtained by replacing the hydrochloride of (E)-4-styrylpiperidine in Example 400 with the hydrochloride of N-methyl-N-phenylpiperidine-4-carboxamide.
  • Example 412 The hydrochloride of 2-chloro-1-(4-(2-methoxybenzyl)piperazin-1-yl)ethan-1-one and (E)-4-styrylpiperidine of Example 400 was mixed with 2-chloro-1-( The compound of Example 412 was obtained by substituting the hydrochloride of 4-(2-ethoxy-6-fluor
  • Example 413 Hydrochloric acid of benzyl ((4-phenethylpiperidin-4-yl)methyl)carbamate in 2-chloro-1-(4-(2-methoxybenzyl)piperazin-1-yl)ethan-1-one (290mg) Salt (399 mg), DMF (4.1 mL), potassium carbonate (354 mg) and sodium iodide (38 mg) were successively added, and the mixture was stirred at 70°C for 3 hours and 30 minutes. Ethyl acetate (10 mL) and water (10 mL) were added to the reaction mixture, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous sodium chloride solution.
  • Example 413 The hydrochloride of ((4-phenethylpiperidin-4-yl)methyl)carbamate in Example 413 was replaced with the hydrochloride of benzyl (4-phenethylpiperidin-4-yl)carbamate, the reaction was carried out in the same manner as in Example 413, and 2 -(4-Amino-4-phenethylpiperidin-1-yl)-1-(4-(2-methoxybenzyl)piperazin-1-yl)ethane-1-one hydrochloride was obtained.
  • Example 416 2-(4-amino-4-phenethylpiperidin-1-yl)-1-(4-(2-methoxybenzyl)piperazin-1-yl)ethane-1-one (200 mg) in THF (4.4 mL) and isocyanogen. Trimethylsilyl acid (0.30 mL) was added and stirred at 50°C overnight. After the solvent was distilled off under reduced pressure, dichloromethane (2 mL), methanol (2 mL) and 1 mol/L hydrochloric acid diethyl ether solution (1 mL) were added to the residue, stirred at room temperature for 30 minutes, and the solvent was distilled off under reduced pressure.
  • Example 417 2-(4-aminopiperidin-1-yl)-1-(4-(2-methoxybenzyl)piperazin-1-yl)ethane-1-one hydrochloride (300 mg), benzoic acid (80 mg), WSC hydrochloric acid Salt (139 mg), HOBt (98 mg), dichloromethane (6 mL) and DIPEA (0.48 mL) were added sequentially, and the mixture was stirred at room temperature for 4 hours. Water (5 mL) was added to the reaction mixture, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 418 (1) 2-chloro-3 to 2-(4-aminopiperidin-1-yl)-1-(4-(2-methoxybenzyl)piperazin-1-yl)ethane-1-one hydrochloride (300 mg) ,4-bis((4-methoxybenzyl)oxy)benzoic acid (282 mg), WSC hydrochloride (139 mg), HOBt (98 mg), dichloromethane (6 mL) and DIPEA (0.48 mL) were added sequentially and stirred at room temperature for 4 hours. did. Water (5 mL) was added to the reaction mixture, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 420 Dichloromethane (2.3 mL) to 2-(4-(benzylamino)piperidin-1-yl)-1-(4-(2-methoxybenzyl)piperazin-1-yl)ethane-1-one hydrochloride (125 mg) , triethylamine (0.11 mL), formaldehyde aqueous solution (19 ⁇ L), and sodium triacetoxyborohydride (146 mg) were added sequentially, and the mixture was stirred at room temperature for 16 hours. After adding water (2 mL) to the reaction mixture, 10% aqueous sodium hydrogen carbonate solution was added to adjust the pH to 8, and the organic layer was separated.
  • the obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Diethyl ether (2.7 mL) and 1 mol/L hydrochloric acid diethyl ether solution (0.7 mL) were added to the obtained oil, and the mixture was stirred at room temperature for 30 minutes.
  • Example 421 4-Phenethylpiperidin-4-yl acetate (101 mg), acetonitrile (4.1 mL), potassium carbonate (282 mg) and 2-chloro-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl) Ethan-1-one (129 mg) was added one after another, and the mixture was stirred at room temperature for 17 hours. Ethyl acetate (100 mL) and water (50 mL) were added to the reaction mixture, and the organic layer was separated. The obtained organic layer was washed successively with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 422 1-(2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)-4-phenethylpiperidin-4-yl acetate (95 mg), THF (0.45 mL), methanol (0.45 mL) and a 1 mol/L aqueous sodium hydroxide solution (0.90 mg) were added sequentially, and the mixture was stirred at room temperature for 3 hours, and then at 50°C for 1 hour. THF (0.45 mL), methanol (0.45 mL) and 1 mol/L aqueous sodium hydroxide solution (0.90 mg) were added to the reaction mixture, and the mixture was stirred at 50°C for 2 hours.
  • Example 423 (1) Same procedure as in Example 421 except that 4-phenethylpiperidin-4-yl acetate in Example 421 was replaced with trifluoroacetate of benzyl (2-phenyl-1-(piperidin-4-yl)ethyl) carbamate. The reaction was performed to obtain the desired product as a pale yellow solid. (2) Ethanol (0.6 mL) and 10% palladium on carbon (13 mg) were sequentially added to the compound (42 mg) obtained in (1), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. Unwanted substances were removed by filtration through Celite, and the solvent was distilled off under reduced pressure.
  • Example 424 Anisole (66 ⁇ L) and a 5.1 mol/L hydrobromic acid acetic acid solution (0.72 mL) were added to the compound (43 mg) obtained in Example 423 (1), and the mixture was stirred at room temperature for 3 hours. After adding ethyl acetate (10 mL) to the reaction mixture, the solid matter was collected by filtration. The obtained solid was dried under reduced pressure to give 2-(4-(1-(benzylamino)-2-phenylethyl)piperidin-1-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)). The hydrobromide salt of piperazin-1-yl)ethane-1-one (45 mg) was obtained as a white solid.
  • Example 425 (1) 4-Phenethylpiperidin-4-yl acetate in Example 421 was replaced with trifluoroacetate of benzyl ((4-phenethylpiperidin-4-yl)methyl)carbamate, the reaction was carried out in the same manner as in Example 421, and the desired The product was obtained as a pale yellow solid. (2) The compound (33 mg) obtained in (1) was reacted in the same manner as in Example 424, and 2-(4-(aminomethyl)-4-phenethylpiperidin-1-yl)-1-(4-( The hydrobromide salt of 2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one (30 mg) was obtained as a white solid.
  • Example 426 The compound (42 mg) obtained in Example 425 (1) was reacted in the same manner as in Example 423 (2) to obtain the target compound (27 mg) as a pale yellow oil.
  • (2) Dichloromethane, tert-butyl (2-oxoethyl) carbamate (9 mg) and sodium triacetoxyborohydride (28 mg) were sequentially added to the compound (27 mg) obtained in (1), and the mixture was stirred at room temperature for 74 hours.
  • Tert-butyl (2-oxoethyl) carbamate (9 mg) and sodium triacetoxyborohydride (28 mg) were added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours.
  • Example 427 (1) The reaction was carried out in the same manner as in Example 426 (2) except that tert-butyl (2-oxoethyl) carbamate in Example 426 was replaced with 2-((tert-butyldimethylsilyl)oxy)acetaldehyde.
  • Example 511 NMR: 1.41(3H,t,J 7.0Hz), 1.49-1.72(2H,m),1.82-2.02(2H,m), 2.09-2.29(1H,m), 2.69-2.89(2H,m), 2.95-3.24(5H,m),3.24-3.70(
  • Example 520 NMR: 1.49-1.72(2H,m), 1.85-2.01(2H,m), 2.09-2.28(1H,m),2.70-2.89(2H,m), 2.97-3.13(5H,m), 3.13-3.29 (3H,m), 3.29-3.47(2H,m),3.59-3.73(1H,m), 3.73-3.84(1H,m), 3.84-3.95(1H,m), 3.95-4.08(1H,m) , 4.31(2H,s),4.45-4.55(3H,m), 4.55-4.64(2H,m), 7.26-7.35(2H,m), 7.37-7.61(7H,m),8.16(1H,d, J 6.0Hz) MS: 590.30[M+H] +
  • Example 544 Benzyl (R)-(1-(1-(2-(3'-((tert-butoxycarbonyl)amino)-4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidine-4 -yl)-2-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (195 mg), anisole (0.39 mL) and 5.1 mol/L hydrogen bromide Acid-acetic acid solution (2.0 mL) was added, and the mixture was stirred at room temperature for 1 hour.
  • Example 566 NMR: 1.42(3H,t,J 7.0Hz), 1.65-1.93(2H,m),1.93-2.19(2H,m), 2.23-2.42(1H,m), 3.02-3.23(2H,m), 3.23-3.35(2H,m
  • Example 571 Acetonitrile (1.2 mL) and chlorotrimethylsilane (0.35 mL) were sequentially added to sodium iodide (415 mg), and the mixture was stirred at room temperature for 15 minutes. The resulting reaction mixture was dissolved in benzyl (R)-(1-(1-(2-(3'-(benzyloxy)-2',4-dichloro-[1,1'-biphenyl]-2-yl)ethyl ) piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl) carbamate (80 mg) in acetonitrile solution (0.56 mL), and added to the acetonitrile solution (0.56 mL) at 80°C.
  • the mixture was stirred for 3 hours.
  • the reaction mixture was cooled to room temperature and methanol (3 mL) was added.
  • the solvent was distilled off under reduced pressure, diethyl ether (10 mL) and water (5 mL) were added to the residue, and then the aqueous layer was separated. After washing the aqueous layer with diethyl ether (10 mL), ethyl acetate (10 mL), a 20% aqueous sodium thiosulfate solution and a 10% aqueous sodium carbonate solution were added to adjust the pH to 8.5, and the organic layer was separated.
  • the aqueous layer was extracted with ethyl acetate (10 mL), and the organic layers separated earlier were combined, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate.
  • the solvent was distilled off under reduced pressure to obtain a pale yellow oil (43 mg).
  • Dichloromethane (1.3 mL) and 1 mol/L hydrochloric acid diethyl ether solution (0.23 mL) were added to the obtained oil, and the mixture was stirred at room temperature for 30 minutes.
  • Example 596 In the same manner as in Example 107, (R)-2-amino-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-(1-(2-(4-hydroxy- The hydrochloride of [1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)ethane-1-one was obtained.
  • Example 609 Benzyl (R)-(1-(1-(2-(3'-(benzyloxy)-4-chloro-5'-fluoro-[1,1'-biphenyl]-2-yl)ethyl)piperidine-4 -yl)-2-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (239 mg), toluene (4.5 mL) and titanium tetrachloride (0.18 mL) was added and stirred at room temperature for 20 minutes. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the organic layer was separated.
  • Example 610 Benzyl (R)-(1-(1-(2-(3'-(benzyloxy)-4,5'-dichloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl )-2-(4-(2-(methylthio)benzyl)piperazin-1-yl)-2-oxoethyl)carbamate (193 mg) was added with toluene (3.7 mL) and titanium tetrachloride (0.15 mL), and the mixture was heated at room temperature for 20 minutes. The mixture was stirred for a minute.
  • Example 612 NMR: 1.50-1.73(2H,m), 1.81-2.02(2H,m), 2.06-2.
  • Test Example 1 Evaluation of efflux capacity inhibition effect on drug efflux pump The efflux capacity inhibition effect of the test compound on drug efflux pump was evaluated using bacterial growth ability in the presence of EM or LVFX as an index.
  • EM is a macrolide antibacterial agent, which is excreted outside the bacteria by MexB and MexY.
  • LVFX is a quinolone antibacterial agent, which is excreted outside the bacteria by MexB and MexY.
  • the test compound has the ability to inhibit the efflux ability of drug efflux pumps, the combined use of EM or LVFX and the test compound suppresses bacterial growth compared to when EM or LVFX is used alone.
  • a mutant strain transfected with the gene of MexAB-OprM as a plasmid (hereinafter referred to as "mexB (EC) strain") and a gene transfer strain of MexXY-OprM, another main multidrug efflux system of Pseudomonas aeruginosa (hereinafter referred to as " mexY (EC) strain) was used for the evaluation of the test compound.
  • mexB (EC) strain has an increased expression level of MexB, a drug efflux pump
  • the mexY (EC) strain has an increased expression level of MexY, a drug efflux pump.
  • a 96-well plate medium volume per hole: 100 ⁇ L
  • LB medium Lia-Bertani broth
  • mexB (EC) and mexY (EC) strains were cultured for 16 to 20 hours in a medium supplemented with EM or LVFX and various concentrations (0 to 800 ⁇ M) of the test compound, and the growth of the strains was measured by optical turbidity at 595 nm ( OD595 ).
  • the concentration of the antibacterial agents (EM and LVFX) in the medium was set to 1/4 (hereinafter referred to as 1/4 MIC) of the MIC (minimum inhibitory concentration) of the antibacterial agent alone.
  • Bacterial growth was measured when the antibacterial agent was added at a concentration of 1/4 MIC when the test compound was not added, and compared with the bacterial growth when the test compound was added.
  • the concentration was defined as the ability of the test compound to inhibit the drug efflux pump, and was defined as EC 75 (75% inhibitory effect concentration).
  • the test compound showed high ability to inhibit drug efflux pumps against mexB (EC) strain and mexY (EC) strain.
  • the compound of the present invention significantly increases the sensitivity of both strains to EM and/or LVFX by inhibiting the efflux ability of MexB and/or MexY, which are drug efflux pumps. That is, the compounds of the present invention are useful as drug efflux pump inhibitors.
  • Test Example 2 Evaluation of the effect of combined use with an antibacterial agent against Pseudomonas aeruginosa
  • mexB (PA) strain a mutant strain of Pseudomonas aeruginosa that expresses MexAB-OprM as a main drug efflux pump was used.
  • LVFX, TC, or AZT was used as the antibacterial agent used in combination.
  • the mexB (PA) strain is a mexCD- This is a strain created by deleting OprJ, MexEF-OprN and MexXY genes. In addition, in the mexB(PA) strain, the expression level of MexB as a drug efflux pump is increased.
  • TC is a tetracycline antibacterial agent, which is excreted outside the bacteria by MexB.
  • AZT is a monobactam antibacterial agent, which is excreted outside the bacteria by MexB.
  • Strain S-3769 was used to evaluate the inhibitory ability against MexXY-OprM. AMK or GM was used as the antibacterial agent used in combination.
  • Strain S-3769 is a clinical isolate collected from a domestic medical institution, and is a strain in which the expression level of MexY is increased.
  • AMK and GM are aminoglycoside antibacterial agents, which are not excreted outside the bacteria by MexB but are excreted outside the bacteria by MexY.
  • a 96-well plate (medium volume per hole: 100 ⁇ L) was used, and CAMHB (cation-adjusted Mueller Hintonbroth) was used. The amount of inoculated bacteria was 10 4 to 5 CFU/well.
  • the mexB (PA) strain and the S-3769 strain were cultured for 16 to 20 hours in a medium supplemented with each antibacterial agent and the test compound at various concentrations (0 to 800 ⁇ M), and the growth of the strains was measured by optical turbidity (OD) at 595 nm. 595 ).
  • the antibacterial agent concentration in the medium was 1/4 MIC.
  • Bacterial growth was measured without the addition of the test compound and antibacterial agent, and the test compound with the lowest inhibition of 99% or more was compared to the bacterial growth with the test compound added when the antibacterial agent was added at a concentration of 1/4 MIC.
  • the concentration was defined as the ability of the test compound to inhibit the drug efflux pump, and was defined as EC 99 (99% inhibitory effect concentration).
  • Table 52 shows the combined effects of each antibacterial agent on each drug efflux pump using Pseudomonas aeruginosa strains of each test compound.
  • N.T means not tested.
  • test compound had a high growth-inhibiting effect on the Pseudomonas aeruginosa strain under the combined administration of each antibacterial agent.
  • Test Example 3 Evaluation of efflux capacity inhibition effect on drug efflux pumps In the same manner as in Test Example 1, the efflux capacity inhibitory effect of the test compound on drug efflux pumps was evaluated using bacterial growth ability in the presence of EM or LVFX as an index.
  • the test compound showed high ability to inhibit drug efflux pumps against mexB (EC) strain and mexY (EC) strain.
  • the compound of the present invention significantly increases the sensitivity of both strains to EM and/or LVFX by inhibiting the efflux ability of MexB and/or MexY, which are drug efflux pumps. That is, the compounds of the present invention are useful as drug efflux pump inhibitors.
  • Test Example 4 Evaluation of the effect of combined use with an antibacterial agent against Pseudomonas aeruginosa The effect of the test compound in combination with an antibacterial agent against Pseudomonas aeruginosa was evaluated in the same manner as in Test Example 2.
  • Table 54 shows the combined effects of each antibacterial agent on each drug efflux pump using Pseudomonas aeruginosa strains of each test compound.
  • test compound had a high growth-inhibiting effect on the Pseudomonas aeruginosa strain under the combined administration of each antibacterial agent.
  • the compound of the present invention significantly increases the susceptibility of both strains to each antibacterial agent by inhibiting the efflux ability of MexB and/or MexY, which are drug efflux pumps of Pseudomonas aeruginosa strains. That is, the compounds of the present invention are useful as drug efflux pump inhibitors.
  • the compound of the present invention or a salt thereof exhibits strong drug efflux pump inhibitory activity against bacteria that produce drug efflux pumps, such as enterobacteria or Gram-negative bacteria that produce drug efflux pumps and their drug-resistant bacteria. It is useful as a medicine when used in combination with other antibacterial agents.

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025178125A1 (ja) * 2024-02-22 2025-08-28 富士フイルム株式会社 新規なピペラジン誘導体又はその塩

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09241241A (ja) * 1996-03-08 1997-09-16 Roussel Morishita Kk Ｎ−（１−置換−４−ピペリジル）ベンズアミド誘導体
CN1342649A (zh) * 2001-09-26 2002-04-03 上海众普生物科技有限公司 具有钙离子拮抗作用的双哌嗪类衍生物
WO2002087589A1 (en) * 2001-04-26 2002-11-07 Daiichi Pharmaceutical Co., Ltd. Medicine for inhibiting drug elimination pump
US20030229097A1 (en) * 2001-07-16 2003-12-11 Watkins Will J. Fungal efflux pump inhibitors
JP2005162726A (ja) * 2003-01-24 2005-06-23 Tanabe Seiyaku Co Ltd ピラゾロピリミジン化合物およびその製法
CN101070308A (zh) * 2007-06-19 2007-11-14 天津药物研究院 异噁唑啉衍生物及其用途
JP2009506987A (ja) * 2005-08-02 2009-02-19 ニューロゲン コーポレイション ジピペラジニルケトンおよび関連する類似体
WO2020081450A1 (en) * 2018-10-15 2020-04-23 Nurix Therapeutics, Inc. Bifunctional compounds for degrading btk via ubiquitin proteosome pathway
CN113527227A (zh) * 2020-04-15 2021-10-22 成都弘达药业有限公司 一种卡利拉嗪的制备方法
WO2022047008A1 (en) * 2020-08-26 2022-03-03 Tarveda Therapeutics, Inc. Hsp90-binding conjugates and formulations thereof
WO2023055952A1 (en) * 2021-09-29 2023-04-06 C4 Therapeutics, Inc. Neurotrophic tyrosine receptor kinase (ntrk) degrading compounds

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20080061613A (ko) * 2006-12-28 2008-07-03 (주) 비엔씨바이오팜 2-(메틸티오)피리미딘 유도체, 그 제조방법 및 이를포함하는 항바이러스용 약학적 조성물
CN101361741B (zh) * 2008-09-22 2011-07-27 天津药物研究院 异噁唑啉类衍生物抗肿瘤新用途
CN104610160A (zh) * 2013-11-04 2015-05-13 南京大学 含哌嗪环的5-硝基咪唑类衍生物及其制备与在抗菌药物中的应用
US11820781B2 (en) * 2019-12-04 2023-11-21 Nurix Therapeutics, Inc. Bifunctional compounds for degrading BTK via ubiquitin proteosome pathway
CN112358466B (zh) * 2020-10-10 2021-10-26 广东省微生物研究所（广东省微生物分析检测中心） 1,2,4-三唑-诺氟沙星杂合体及其制备方法和应用
CN112592339B (zh) * 2020-12-22 2022-06-07 广东省微生物研究所（广东省微生物分析检测中心） 1,3,4-恶二唑-2(3h)-硫酮-诺氟沙星杂合体及其制备方法和应用

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09241241A (ja) * 1996-03-08 1997-09-16 Roussel Morishita Kk Ｎ−（１−置換−４−ピペリジル）ベンズアミド誘導体
WO2002087589A1 (en) * 2001-04-26 2002-11-07 Daiichi Pharmaceutical Co., Ltd. Medicine for inhibiting drug elimination pump
US20030229097A1 (en) * 2001-07-16 2003-12-11 Watkins Will J. Fungal efflux pump inhibitors
CN1342649A (zh) * 2001-09-26 2002-04-03 上海众普生物科技有限公司 具有钙离子拮抗作用的双哌嗪类衍生物
JP2005162726A (ja) * 2003-01-24 2005-06-23 Tanabe Seiyaku Co Ltd ピラゾロピリミジン化合物およびその製法
JP2009506987A (ja) * 2005-08-02 2009-02-19 ニューロゲン コーポレイション ジピペラジニルケトンおよび関連する類似体
CN101070308A (zh) * 2007-06-19 2007-11-14 天津药物研究院 异噁唑啉衍生物及其用途
WO2020081450A1 (en) * 2018-10-15 2020-04-23 Nurix Therapeutics, Inc. Bifunctional compounds for degrading btk via ubiquitin proteosome pathway
CN113527227A (zh) * 2020-04-15 2021-10-22 成都弘达药业有限公司 一种卡利拉嗪的制备方法
WO2022047008A1 (en) * 2020-08-26 2022-03-03 Tarveda Therapeutics, Inc. Hsp90-binding conjugates and formulations thereof
WO2023055952A1 (en) * 2021-09-29 2023-04-06 C4 Therapeutics, Inc. Neurotrophic tyrosine receptor kinase (ntrk) degrading compounds

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY 13 July 2022 (2022-07-13), ANONYMOUS : "INDEX NAME NOT YET A SSIGNED ", XP093143300, retrieved from STN Database accession no. 2790230-40-7 *
DATABASE REGISTRY 27 April 2012 (2012-04-27), ANONYMOUS : "Benzamide, 2-methyl-N- [1-[2-[4-[(2-methylp henyl)methyl]-1-pip erazinyl]-2- oxoethyl]-4-piperidi nyl]- (CA INDEX NAME) ", XP093143302, retrieved from STN Database accession no. 1370788-27-4 *
JOURNAL OF INFECTION AND CHEMOTHERAPY, vol. 5, 2022, pages 595 - 601
See also references of EP4578849A4
W. GREENE ET AL.: "Protective Groups in Organic Synthesis", 2007, JOHN WILEY & SONS, INC, pages: 533 - 643
YAMASAKI SEIJI, NAKASHIMA RYOSUKE, SAKURAI KEISUKE, YAMAGUCHI AKIHITO, NISHINO KUNIHIKO: "Structural Analysis and New Drug Development against Multidrug Efflux Pumps", YAKUGAKU ZASSHI. THE PHARMACEUTICAL SOCIETY OF JAPAN, vol. 137, no. 4, 21 March 2017 (2017-03-21), pages 377 - 382, XP093143293 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025178125A1 (ja) * 2024-02-22 2025-08-28 富士フイルム株式会社 新規なピペラジン誘導体又はその塩

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