Novel piperazine derivative or salt thereof, and pharmaceutical composition

Abstract

The present invention addresses the problem of providing a compound and a pharmaceutical composition which have inhibitory activity against a drug discharge pump for drug-resistant bacteria and which can restore the antibacterial activity of another drug when used in combination with the other drug. According to the present invention, provided are: a compound represented by general formula [1] (wherein each symbol is as defined in the description) or a salt thereof; and a pharmaceutical composition containing the compound or the salt. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a novel piperazine derivative or a salt thereof which exhibits strong antibacterial activity against Gram-negative bacteria, particularly Pseudomonas aeruginosa, and a pharmaceutical composition containing the same. Background Art

[0002] Drug-resistant bacteria are rapidly increasing worldwide, and effective treatments are expected to disappear in the near future. This will lead to an increase in deaths and significant economic losses. In particular, infectious diseases caused by multidrug-resistant Gram-negative bacteria, such as multidrug-resistant Pseudomonas aeruginosa, are ineffective against most antimicrobial agents, making them a major problem worldwide as they are difficult to treat.

[0003] Gram-negative bacteria possess multiple mechanisms of drug resistance, and a combination of these mechanisms can lead to multidrug resistance. In particular, increased expression of drug efflux pumps, which transport antimicrobial agents outside the bacteria and render them ineffective, is known to contribute to the acquisition of resistance to a wide range of antimicrobial agents. Bacteria possess a variety of drug efflux pumps, which contribute to both natural and acquired bacterial resistance by excreting antimicrobial agents from within the bacteria.

[0004] Pseudomonas aeruginosa, a Gram-negative bacterium, is a major pathogen causing severe infectious diseases such as hospital-acquired pneumonia. Furthermore, Pseudomonas aeruginosa tends to develop resistance to multiple antimicrobial agents. Currently, in the treatment of multidrug-resistant Pseudomonas aeruginosa infections both domestically and internationally, multiple antimicrobial agents are used in combination, as a single antimicrobial agent is insufficiently effective. However, this has not been sufficiently effective (Non-Patent Document 1).

[0005] These compounds that inhibit drug efflux pumps can be used to restore the activity of antimicrobial agents that are no longer effective against multidrug-resistant Pseudomonas aeruginosa.

[0006] Prior art literature

[0007] Non-patent literature

[0008] Non-patent document 1: Journal of Infection and Chemotherapy, 2022, No. 5, pp. 595-601 Summary of the Invention

[0009] Technical issues to be solved by the invention

[0010] There is an urgent need to provide a compound and a pharmaceutical composition that have an inhibitory activity against the efflux pumps of enteric bacteria or Gram-negative bacteria and their drug-resistant bacteria and that can restore the antibacterial activity of other drugs by combined use with other drugs.

[0011] Means for solving technical problems

[0012] Under such circumstances, the present inventors conducted intensive studies and found that the compound represented by the general formula [1] or a salt thereof strongly inhibits drug discharge pumps of resistant bacteria including Gram-negative bacteria such as Pseudomonas aeruginosa and multidrug-resistant Gram-negative bacteria such as Pseudomonas aeruginosa, thereby completing the present invention.

[0013] The present invention provides the following.

[0014] <1>

[0015] A compound or a salt thereof, wherein the compound or the salt thereof is represented by the general formula [1]:

[0016] [Chemical Formula 1]

[0017]

[0018] Where Z 1 represents a nitrogen atom or a group represented by the formula CH;

[0019] Z 2 Represents a nitrogen atom or the general formula CR 4 The group represented by the formula, wherein R 4 represents a hydrogen atom, a hydroxyl group, a cyano group, an acyloxy group which may be substituted, an amino group which may be substituted, a carbamoyl group which may be substituted, a urea group which may be substituted, a C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy C 1-6 Alkyl, aryl which may be substituted 1-6 Alkoxy C 1-6 Alkyl or optionally substituted C 1-6 alkoxy;

[0020] R 1 and R 2 The same or different ones represent a hydrogen atom, a halogen atom, a hydroxyl group, an amino group which may be substituted, a C 1-6 Alkyl, optionally substituted C 1-6 an alkoxy group, a guanidine group which may be substituted, an imino group which may be substituted together, or a divalent C 1-3 Alkylene-OC 1-3 a group represented by an alkylene group;

[0021] R 3 represents a hydrogen atom, a carboxyl group which may be protected, a carbamoyl group which may be substituted, a C 3-10 Cycloalkyl or optionally substituted C 1-6 alkyl;

[0022] X 1Indicates that C can be replaced 2-6 Alkylene, optionally substituted C 2-6 Alkenylene, optionally substituted C 2-6 Alkynylidene, general formula -NR 5 -CO- represented by the group, the general formula -CO-NR 5 - represented by the group, the general formula -CR 5 -NR 5 - represented by the group, the general formula -CR 5 -O-, in these formulas, R 5 Represents a hydrogen atom or C 1-6 Alkyl, wherein, in the formula, the connecting bond on the left side is connected to Y 1 Bonding, the connecting bond on the right is connected to Z 2 bonding;

[0023] Y 1 Indicates that C can be replaced 3-10 a cycloalkyl group, an aryl group which may be substituted, a monocyclic heterocyclic group which may be substituted, or a bicyclic heterocyclic group which may be substituted;

[0024] X 2 Indicates C 1-3 Alkylene or connecting bond;

[0025] Y 2 Indicates that C can be replaced 3-10 A group represented by a cycloalkyl group, an aryl group which may be substituted, a monocyclic heterocyclic group which may be substituted, or a bicyclic heterocyclic group which may be substituted.

[0026] <2>

[0027] The compound or salt thereof according to <1>, wherein

[0028] Z 1 represents a nitrogen atom or a group represented by the formula CH;

[0029] Z 2 Represents a nitrogen atom or the general formula CR 4a The group represented by the formula, wherein R 4a represents a hydrogen atom, a hydroxyl group, a cyano group, an acyloxy group which may be substituted, an amino group which may be substituted, a carbamoyl group which may be substituted, a urea group which may be substituted, a C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy C 1-6 Alkyl or aryl C 1-6 Alkoxy C 1-6 Alkyl, wherein Z 1 or Z 2 At least one of is a nitrogen atom;

[0030] R 1 and R 2 The same or different ones represent a hydrogen atom, a halogen atom, an amino group which may be substituted, a C 1-6 Alkyl, or imino which may be substituted together or divalent C which may be substituted 1-3 Alkylene-OC 1-3 a group represented by an alkylene group;

[0031] R 3 Represents a hydrogen atom or a C that can be substituted 1-6 alkyl;

[0032] X 1 Indicates that C can be replaced 2-6 Alkylene, optionally substituted C 2-6 Alkenylene, optionally substituted C 2-6 Alkynylidene, general formula -NR 5 -CO- represented by the group, the general formula -CO-NR 5 - represented by the group, the general formula -CR 5 -NR 5 - represented by the group, the general formula -CR 5 -O-, in these formulas, R 5 Represents a hydrogen atom or C 1-6 Alkyl, wherein, in the formula, the connecting bond on the left side is connected to Y 1 Bonding, the connecting bond on the right is connected to Z 2 bonding;

[0033] Y 1 Indicates that C can be replaced 3-10 a cycloalkyl group, an aryl group which may be substituted, a monocyclic heterocyclic group which may be substituted, or a bicyclic heterocyclic group which may be substituted;

[0034] X 2 Indicates C 1-3 Alkylene or connecting bond;

[0035] Y 2 Indicates that C can be replaced 3-10 a cycloalkyl group, an aryl group which may be substituted, a monocyclic heterocyclic group which may be substituted, or a bicyclic heterocyclic group which may be substituted.

[0036] <3>

[0037] The compound or salt thereof according to <1> or <2>, wherein

[0038] Z 1 represents a group represented by the formula CH;

[0039] Z 2 represents a nitrogen atom.

[0040] <4>

[0041] The compound or salt thereof according to <1> or <2>, wherein

[0042] Z 1 represents nitrogen atom, Z 2 Represents the general formula CR 4a The group represented by the formula, wherein R 4a represents a hydrogen atom, a hydroxyl group, a cyano group, an acyloxy group which may be substituted, an amino group which may be substituted, a carbamoyl group which may be substituted, a urea group which may be substituted, a C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy C 1-6 Alkyl or aryl C 1-6 Alkoxy C 1-6 alkyl;

[0043] Y 1 Indicates that C can be replaced 3-10 a cycloalkyl group, an aryl group which may be substituted, or a bicyclic heterocyclic group which may be substituted.

[0044] <5>

[0045] The compound or salt thereof according to <1> or <2>, wherein

[0046] R 3 A hydrogen atom or a substituted C 1-6 alkyl.

[0047] <6>

[0048] The compound or salt thereof according to <1> or <2>, wherein

[0049] R 1 and R 2 The same or different are hydrogen atoms, amino groups which may be substituted or C 1-6 alkyl.

[0050] <7>

[0051] The compound or salt thereof according to <1> or <2>, wherein

[0052] Y 1 is an aryl group which may be substituted.

[0053] <8>

[0054] The compound or salt thereof according to <1> or <2>, wherein

[0055] Y 2 It is an aryl group which may be substituted or a bicyclic heterocyclic group which may be substituted.

[0056] <9>

[0057] The compound or salt thereof according to <1> or <2>, wherein

[0058] X 1 C can be substituted 2-6 Alkylene or C 2-6 Alkenylene.

[0059] <10>

[0060] The compound or salt thereof according to <1> or <2>, wherein

[0061] X 2 For methylene.

[0062] <11>

[0063] The compound or salt thereof according to <1>, wherein

[0064] The compound is selected from (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)ethan-1-one, (R)-2-amino-2-(1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one, ethane-1-one, (R)-2-amino-1-(4-(benzo[b]thiophen-7-ylmethyl)piperazin-1-yl)-2-(1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)ethan-1-one, (R)-2-amino-2-(1-(2-(2',4-dichloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one, (R)-2-amino-2-(1-(5-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl) piperazin-1-yl)ethan-1-one, (R)-2-amino-2-(1-(2-(4-aminopyridin-3-yl)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one, (R)-2-amino-2-(1-(2-(2'-amino-4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one, (R)-2-amino-2-(1-(2-(4-chloro-3'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-ethoxy 1-yl)ethan-1-one, (R)-2-amino-2-(1-(2-(4-chloro-2'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)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-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one, and 2-(4-(3-chlorophenethyl)piperazin-1-yl)-1-(4-(2-methoxybenzyl)piperazin-1-yl)ethan-1-one.

[0065] <12>

[0066] The compound or salt thereof according to <1>, wherein

[0067] The compound is selected from the group consisting of (R)-2-amino-2-(1-(2-(2',4-dichloro-3'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-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)ethan-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)ethan-1-one hydrochloride, 1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrochloride, (R)-2-amino-2-(1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-5-hydroxybenzyl)piperazin-1-yl)ethan-1-one hydrochloride, (R)-2-amino-2-(1-(2-(4-chloro-3'-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrochloride, 3',4-dichloro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(methylthio)benzyl)piperazin-1-yl)ethan-1-one hydrochloride, (R)-2-amino-2-(1-(2-(4-chloro-2'-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(methylthio)benzyl)piperazin-1-yl)ethan-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-(ethylthio)-4-fluorobenzyl)piperidin-1-yl)ethan-1-one hydrochloride, oxazine-1-yl)ethan-1-one hydrochloride, (R)-2-amino-2-(1-(2-(4-chloro-2'-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazine-1-yl)ethan-1-one hydrochloride, (R)-2-amino-2-(1-(2-(2',4-dichloro-3'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazine-1-yl)ethan-1-one hydrochloride, (R)-2-amino-2-(1-(2-(4-chloro-3'-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazine-1-yl)ethan-1-one hydrochloride,1-(4-(2-(methylthio)benzyl)piperazin-1-yl)ethan-1-one hydrochloride, (R)-2-amino-2-(1-(2-(2',4-dichloro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-methylthio)benzyl)piperazin-1-yl)ethan-1-one hydrochloride, (R)-2-amino-2-(1-(2-(2',4-dichloro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(methylthio)benzyl)piperazin-1-yl)ethan-1-one hydrochloride, Compounds in the group consisting of (R)-2-amino-2-(1-(2-(4-chloro-3'-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-5-hydroxybenzyl)piperazin-1-yl)ethan-1-one hydrochloride and (R)-2-amino-2-(1-(2-(4-chloro-2'-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-5-hydroxybenzyl)piperazin-1-yl)ethan-1-one hydrochloride.

[0068] <13>

[0069] A pharmaceutical composition comprising the compound or a salt thereof according to any one of <1> to <12>.

[0070] <1a>

[0071] A compound or a salt thereof, wherein the compound or the salt thereof is represented by the general formula [1]:

[0072] [Chemical Formula 2]

[0073]

[0074] Where Z 1 represents a nitrogen atom or a group represented by the formula CH;

[0075] Z 2 Represents a nitrogen atom or the general formula CR 4 The group represented by the formula, wherein R 4 represents a hydrogen atom, a hydroxyl group, a cyano group, an acyloxy group which may be substituted, an amino group which may be substituted, a carbamoyl group which may be substituted, a urea group which may be substituted, a C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy C 1-6 Alkyl, aryl which may be substituted 1-6 Alkoxy C 1-6 Alkyl or optionally substituted C1-6 alkoxy;

[0076] R 1 and R 2 The same or different ones represent a hydrogen atom, a halogen atom, a hydroxyl group, an amino group which may be substituted, a C 1-6 Alkyl, optionally substituted C 1-6 an alkoxy group, a guanidine group which may be substituted, an imino group which may be substituted together, or a divalent C 1-3 Alkylene-OC 1-3 a group represented by an alkylene group;

[0077] R 3 represents a hydrogen atom, a carboxyl group which may be protected, a carbamoyl group which may be substituted, a C 3-10 Cycloalkyl or optionally substituted C 1-6 alkyl;

[0078] X 1 Indicates that C can be replaced 2-6 Alkylene, optionally substituted C 2-6 Alkenylene, optionally substituted C 2-6 Alkynylidene, general formula -NR 5 -CO- represented by the group, the general formula -CO-NR 5 - represented by the group, the general formula -CR 5 -NR 5 - represented by the group, the general formula -CR 5 -O-, in these formulas, R 5 Represents a hydrogen atom or C 1-6 Alkyl, wherein, in the formula, the connecting bond on the left side is connected to Y 1 Bonding, the connecting bond on the right is connected to Z 2 bonding;

[0079] Y 1 Indicates that C can be replaced 3-10 a cycloalkyl group, an aryl group which may be substituted, a monocyclic heterocyclic group which may be substituted, or a bicyclic heterocyclic group which may be substituted;

[0080] X 2 Indicates C 1-3 Alkylene or connecting bond;

[0081] Y 2 Indicates that C can be replaced 3-10 A group represented by a cycloalkyl group, an aryl group which may be substituted, a monocyclic heterocyclic group which may be substituted, or a bicyclic heterocyclic group which may be substituted.

[0082] <2a>

[0083] The compound or salt thereof according to <1a>, wherein

[0084] Z 1 represents a nitrogen atom or a group represented by the formula CH;

[0085] Z 2 Represents a nitrogen atom or the general formula CR 4a The group represented by the formula, wherein R 4a represents a hydrogen atom, a hydroxyl group, a cyano group, an acyloxy group which may be substituted, an amino group which may be substituted, a carbamoyl group which may be substituted, a urea group which may be substituted, a C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy C 1-6 Alkyl or aryl C 1-6 Alkoxy C 1-6 Alkyl, wherein Z 1 or Z 2 At least one of is a nitrogen atom;

[0086] R 1 and R 2 The same or different ones represent a hydrogen atom, a halogen atom, an amino group which may be substituted, a C 1-6 Alkyl, or imino which may be substituted together or divalent C which may be substituted 1-3 Alkylene-OC 1-3 a group represented by an alkylene group;

[0087] R 3 Represents a hydrogen atom or a C that can be substituted 1-6 alkyl;

[0088] X 1 Indicates that C can be replaced 2-6 Alkylene, optionally substituted C 2-6 Alkenylene, optionally substituted C 2-6 Alkynylidene, general formula -NR 5 -CO- represented by the group, the general formula -CO-NR 5 - represented by the group, the general formula -CR 5 -NR 5 - represented by the group, the general formula -CR 5 -O-, in these formulas, R 5 Represents a hydrogen atom or C 1-6 Alkyl, wherein, in the formula, the connecting bond on the left side is connected to Y 1 Bonding, the connecting bond on the right is connected to Z 2 bonding;

[0089] Y 1 Indicates that C can be replaced3-10 a cycloalkyl group, an aryl group which may be substituted, a monocyclic heterocyclic group which may be substituted, or a bicyclic heterocyclic group which may be substituted;

[0090] X 2 Indicates C 1-3 Alkylene or connecting bond;

[0091] Y 2 Indicates that C can be replaced 3-10 a cycloalkyl group, an aryl group which may be substituted, a monocyclic heterocyclic group which may be substituted, or a bicyclic heterocyclic group which may be substituted.

[0092] <3a>

[0093] The compound or salt thereof according to <1a> or <2a>, wherein

[0094] Z 1 represents a group represented by the formula CH;

[0095] Z 2 represents a nitrogen atom.

[0096] <4a>

[0097] The compound or salt thereof according to any one of <1a> to <2a>, wherein

[0098] Z 1 represents nitrogen atom, Z 2 Represents the general formula CR 4a The group represented by the formula, wherein R 4a represents a hydrogen atom, a hydroxyl group, a cyano group, an acyloxy group which may be substituted, an amino group which may be substituted, a carbamoyl group which may be substituted, a urea group which may be substituted, a C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy C 1-6 Alkyl or aryl C 1-6 Alkoxy C 1-6 alkyl;

[0099] Y 1 Indicates that C can be replaced 3-10 a cycloalkyl group, an aryl group which may be substituted, or a bicyclic heterocyclic group which may be substituted.

[0100] <5a>

[0101] The compound or salt thereof according to any one of <1a> to <4a>, wherein

[0102] R 3 A hydrogen atom or a substituted C 1-6 alkyl.

[0103] <6a>

[0104] The compound or salt thereof according to any one of <1a> to <5a>, wherein

[0105] R 1 and R 2 The same or different are hydrogen atoms, amino groups which may be substituted or C 1-6 alkyl.

[0106] <7a>

[0107] The compound or salt thereof according to any one of <1a> to <6a>, wherein

[0108] Y 1 is an aryl group which may be substituted.

[0109] <8a>

[0110] The compound or salt thereof according to any one of <1a> to <7a>, wherein

[0111] Y 2 It is an aryl group which may be substituted or a bicyclic heterocyclic group which may be substituted.

[0112] <9a>

[0113] The compound or salt thereof according to any one of <1a> to <8a>, wherein

[0114] X 1 C can be substituted 2-6 Alkylene or C 2-6 Alkenylene.

[0115] <10a>

[0116] The compound or salt thereof according to any one of <1a> to <9a>, wherein

[0117] X 2 For methylene.

[0118] <11a>

[0119] The compound or salt thereof according to <1a>, wherein

[0120] The compound is selected from (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)ethan-1-one, (R)-2-amino-2-(1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one, ethane-1-one, (R)-2-amino-1-(4-(benzo[b]thiophen-7-ylmethyl)piperazin-1-yl)-2-(1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)ethan-1-one, (R)-2-amino-2-(1-(2-(2',4-dichloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one, (R)-2-amino-2-(1-(5-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl) piperazin-1-yl)ethan-1-one, (R)-2-amino-2-(1-(2-(4-aminopyridin-3-yl)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one, (R)-2-amino-2-(1-(2-(2'-amino-4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one, (R)-2-amino-2-(1-(2-(4-chloro-3'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-ethoxy 1-yl)ethan-1-one, (R)-2-amino-2-(1-(2-(4-chloro-2'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)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-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one, and 2-(4-(3-chlorophenethyl)piperazin-1-yl)-1-(4-(2-methoxybenzyl)piperazin-1-yl)ethan-1-one.

[0121] <12a>

[0122] The compound or salt thereof according to <1>, wherein

[0123] The compound is selected from the group consisting of (R)-2-amino-2-(1-(2-(2',4-dichloro-3'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-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)ethan-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)ethan-1-one hydrochloride, 1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrochloride, (R)-2-amino-2-(1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-5-hydroxybenzyl)piperazin-1-yl)ethan-1-one hydrochloride, (R)-2-amino-2-(1-(2-(4-chloro-3'-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrochloride, 3',4-dichloro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(methylthio)benzyl)piperazin-1-yl)ethan-1-one hydrochloride, (R)-2-amino-2-(1-(2-(4-chloro-2'-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(methylthio)benzyl)piperazin-1-yl)ethan-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-(ethylthio)-4-fluorobenzyl)piperidin-1-yl)ethan-1-one hydrochloride, oxazine-1-yl)ethan-1-one hydrochloride, (R)-2-amino-2-(1-(2-(4-chloro-2'-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazine-1-yl)ethan-1-one hydrochloride, (R)-2-amino-2-(1-(2-(2',4-dichloro-3'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazine-1-yl)ethan-1-one hydrochloride, (R)-2-amino-2-(1-(2-(4-chloro-3'-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazine-1-yl)ethan-1-one hydrochloride,1-(4-(2-(methylthio)benzyl)piperazin-1-yl)ethan-1-one hydrochloride, (R)-2-amino-2-(1-(2-(2',4-dichloro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-methylthio)benzyl)piperazin-1-yl)ethan-1-one hydrochloride, (R)-2-amino-2-(1-(2-(2',4-dichloro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(methylthio)benzyl)piperazin-1-yl)ethan-1-one hydrochloride, Compounds in the group consisting of (R)-2-amino-2-(1-(2-(4-chloro-3'-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-5-hydroxybenzyl)piperazin-1-yl)ethan-1-one hydrochloride and (R)-2-amino-2-(1-(2-(4-chloro-2'-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-5-hydroxybenzyl)piperazin-1-yl)ethan-1-one hydrochloride.

[0124] <13a>

[0125] A pharmaceutical composition comprising the compound or a salt thereof according to any one of <1a> to <12a>.

[0126]

[0127] A method for treating an infectious disease caused by Gram-negative bacteria or drug-resistant bacteria thereof, comprising the step of administering the compound or salt thereof according to any one of <1> to <12> or <1a> to <12a> to a subject.

[0128]

[0129] The compound or salt thereof according to any one of <1> to <12> or <1a> to <12a>, which is for use in treating infectious diseases caused by Gram-negative bacteria or drug-resistant bacteria thereof.

[0130] <C>

[0131] Use of the compound or a salt thereof according to any one of <1> to <12> or <1a> to <12a> for producing a pharmaceutical composition.

[0132] <D>

[0133] Use of the compound or salt thereof according to any one of <1> to <12> or <1a> to <12a> for producing a pharmaceutical composition for treating an infectious disease caused by Gram-negative bacteria or drug-resistant bacteria thereof.

[0134] Effects of the Invention

[0135] The compound of the present invention or its salt exhibits strong drug efflux pump inhibitory activity against bacteria producing drug efflux pumps, such as enteric bacteria or Gram-negative bacteria producing drug efflux pumps and drug-resistant bacteria thereof, and is useful as a medicine when used in combination with other antimicrobial agents.

[0136] The pharmaceutical composition of the present invention exhibits strong drug excretion pump inhibitory activity against bacteria producing drug excretion pumps, such as enteric bacteria or Gram-negative bacteria producing drug excretion pumps and drug-resistant bacteria thereof, and is useful as a medicine when used in combination with other antimicrobial agents. DETAILED DESCRIPTION

[0137] Hereinafter, the present invention will be described in detail.

[0138] In this specification, "%" means "mass %" unless otherwise specified.

[0139] In this specification, unless otherwise specified, each term has the following meaning.

[0140] The halogen atom represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0141] C 1-6 Alkyl represents a linear or branched C group such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl and hexyl. 1-6 alkyl.

[0142] C 1-4 Alkyl represents methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl or tert-butyl.

[0143] C 1-3 The alkyl group represents a methyl group, an ethyl group, a propyl group or an isopropyl group.

[0144] C 2-6 Alkenyl represents a linear or branched C group such as vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, 1,3-butadienyl, pentenyl, and hexenyl. 2-6 Alkenyl.

[0145] C 2-6 Alkynyl represents a linear or branched C group such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl. 2-6 Alkynyl.

[0146] C3-10 Cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl. 3-10 Cycloalkyl.

[0147] C 3-8 Cycloalkenyl represents cyclopropenyl, cyclobutenyl, 2-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, and the like. 3-8 Cycloalkenyl.

[0148] Aryl represents phenyl and naphthyl etc. 6-18 Aryl.

[0149] Aryl C 1-6 The alkyl group represents, for example, an aryl group such as benzyl, diphenylmethyl, triphenylmethyl, phenethyl, and naphthylmethyl. 1-6 alkyl.

[0150] C 1-6 Alkylene represents a linear or branched C group such as methylene, ethylene, propylene, butylene, pentylene, and hexylene. 1-6 Alkylene.

[0151] C 1-5 Alkylene represents a linear or branched C group such as methylene, ethylene, propylene, butylene, and pentylene. 1-5 Alkylene.

[0152] C 1-3 The alkylene group represents a methylene group, an ethylene group, a propylene group or an isopropylene group.

[0153] C 1-2 Alkylene represents methylene or ethylene.

[0154] C 2-6 Alkylene represents a linear or branched C group such as ethylene, propylene, butylene, and hexylene. 2-6 Alkylene.

[0155] C 2-6 Alkenylene represents a linear or branched C group such as vinylene, propenylene, butenylene and pentenylene. 2-6 Alkenylene.

[0156] C 2-6 Alkyne represents a linear or branched C group such as ethynylene, propynylene, butynylene and pentynylene. 2-6 Alkynylidene.

[0157] C 1-6 Alkoxy represents a linear or branched C group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy. 1-6 Alkoxy.

[0158] C 1-6 Alkoxy C 1-6 Alkyl represents methoxymethyl and 1-ethoxyethyl etc. 1-6 Alkoxy C 1-6 alkyl.

[0159] Benzyloxy C 1-6 Alkyl represents benzyloxymethyl and benzyloxyethyl naphthylmethoxymethyl benzyloxy C 1-6 alkyl.

[0160] C 2-12 Alkanoyl represents a linear or branched C 2-12 Alkanoyl.

[0161] Aroyl represents, for example, benzoyl or naphthoyl.

[0162] Acyl groups include formyl, succinyl, glutaryl, maleyl, phthaloyl, C 2-12 Alkanoyl or aroyl.

[0163] Acyloxy represents C 2-12 Alkanoyloxy, benzoyloxy, naphthoyloxy and other aroyloxy groups.

[0164] C 1-6 Alkoxycarbonyl represents a linear or branched C alkyl group such as methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, and 1,1-dimethylpropyloxycarbonyl. 1-6 Alkoxycarbonyl.

[0165] Aryl C 1-6 Alkoxycarbonyl represents an aryl group such as benzyloxycarbonyl and phenethyloxycarbonyl. 1-6 Alkoxycarbonyl.

[0166] Aryl C 1-6 Alkoxy C 1-6 Alkyl represents an aromatic group such as benzyloxymethyl, benzyloxyethyl and phenethoxymethyl. 1-6 Alkoxy C 1-6 alkyl.

[0167] Aryloxycarbonyl represents, for example, phenoxycarbonyl or naphthoxycarbonyl.

[0168] C 1-6 Alkylamino represents a linear or branched C group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, tert-butylamino, pentylamino, and hexylamino. 1-6 Alkylamino.

[0169] 2 (C 1-6 The amino group is a linear or branched di(C)-2-amino group such as dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, di(tert-butyl)amino, dipentylamino, dihexylamino, (ethyl)(methyl)amino, and (methyl)(propyl)amino. 1-6 alkyl)amino.

[0170] C 1-6 Alkylthio represents C 1-6 Alkylthio.

[0171] C 1-6 Alkylsulfonyl represents C methylsulfonyl, ethylsulfonyl and propylsulfonyl. 1-6 Alkylsulfonyl.

[0172] The arylsulfonyl group represents a benzenesulfonyl group, a p-toluenesulfonyl group, a naphthylsulfonyl group, or the like.

[0173] C 1-6 Alkylsulfonyloxy represents C 1-6 Alkylsulfonyloxy.

[0174] The arylsulfonyloxy group represents a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, or the like.

[0175] The silyl group represents a silyl group such as a trimethylsilyl group, a triethylsilyl group, a tributylsilyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, and a triisopropylsilyl group.

[0176] The cyclic amino group refers to a cyclic amino group that contains one or more nitrogen atoms as heteroatoms forming a ring and may further contain one or more oxygen atoms or sulfur atoms, such as an aziridinyl group, an azetidinyl group, a pyrrolyl group, a dihydropyrrolyl group, a pyrrolidinyl group, a tetrahydropyridinyl group, a piperidinyl group, a homopiperidinyl group, a pyrazolyl group, a pyrazolinyl group, a pyrazolidinyl group, an imidazolyl group, an imidazolinyl group, an imidazolidinyl group, a thiazolinyl group, a thiazolidinyl group, a dihydrothiadiazolyl group, a piperazinyl group, a homopiperazinyl group, a morpholinyl group, a homomorpholinyl group, and a thiomorpholinyl group.

[0177] The monocyclic nitrogen-containing heterocyclic group means a monocyclic nitrogen-containing heterocyclic group containing only nitrogen atoms as heteroatoms forming the ring, and examples thereof include azetidinyl; 5-membered nitrogen-containing heterocyclic groups such as pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolidinyl, imidazolinyl, imidazolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, triazolyl or tetrazolyl; 6-membered nitrogen-containing heterocyclic groups such as piperidinyl, tetrahydropyridinyl, pyridinyl, piperazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, tetrahydropyrimidinyl or homopiperazinyl; 7-membered nitrogen-containing heterocyclic groups such as homopiperidinyl; or 8-membered nitrogen-containing heterocyclic groups such as octahydroazocinyl.

[0178] The monocyclic oxygen-containing heterocyclic group refers to a monocyclic oxygen-containing heterocyclic group containing only oxygen atoms as heteroatoms forming the ring, and examples thereof include 5-membered oxygen-containing heterocyclic groups such as tetrahydrofuranyl and furanyl; or 6-membered oxygen-containing heterocyclic groups such as tetrahydropyranyl and pyranyl.

[0179] The monocyclic sulfur-containing heterocyclic group represents a thienyl group or the like.

[0180] The monocyclic nitrogen / oxygen heterocyclic group refers to a monocyclic nitrogen / oxygen heterocyclic group containing only nitrogen atoms and oxygen atoms as heteroatoms forming the ring, and examples thereof include 5-membered nitrogen / oxygen heterocyclic groups such as oxazolyl, oxazolidinyl, isoxazolyl or oxadiazolyl; or 6-membered nitrogen / oxygen heterocyclic groups such as morpholinyl.

[0181] The monocyclic nitrogen / sulfur-containing heterocyclic group refers to a monocyclic nitrogen / sulfur-containing heterocyclic group containing only nitrogen atoms and sulfur atoms as heteroatoms forming the ring, and examples thereof include a 5-membered nitrogen / sulfur-containing heterocyclic group such as a thiazolyl group, an isothiazolyl group, or a thiadiazolyl group; or a 6-membered nitrogen / sulfur-containing heterocyclic group such as a thiomorpholinyl group, a thiomorpholinyl-1-oxide group, or a 1,1-dioxythiomorpholinyl group.

[0182] The monocyclic heterocyclic group represents a monocyclic nitrogen-containing heterocyclic group, a monocyclic oxygen-containing heterocyclic group, a monocyclic sulfur-containing heterocyclic group, a monocyclic nitrogen- and oxygen-containing heterocyclic group, or a monocyclic nitrogen- and sulfur-containing heterocyclic group.

[0183] The monocyclic saturated heterocyclic group refers to a monocyclic heterocyclic group not containing multiple bonds, and examples thereof include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, pyrazolidinyl, piperazinyl, oxazolidinyl, tetrahydropyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, and morpholinyl.

[0184] The bicyclic nitrogen-containing heterocyclic group refers to a bicyclic nitrogen-containing heterocyclic group containing only nitrogen atoms as heteroatoms forming a ring, such as indolinyl, indolyl, isoindolyl, isoindolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, tetrahydroquinolyl, quinolyl, tetrahydroisoquinolyl, isoquinolyl, quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, dihydroquinoxalinyl, quinoxalinyl, naphthyridinyl, purinyl, pyrrolopyridinyl, dihydrocyclopentapiperidinyl, pteridinyl, and quinuclidinyl.

[0185] The bicyclic oxygen-containing heterocyclic group refers to a bicyclic oxygen-containing heterocyclic group containing only oxygen atoms as hetero atoms forming a ring, such as 2,3-dihydrobenzofuranyl, benzofuranyl, isobenzofuranyl, chromanyl, chromenyl, isochromanyl, 1,3-benzodioxolyl, 1,3-benzodioxanyl, and 1,4-benzodioxanyl.

[0186] The bicyclic sulfur-containing heterocyclic group refers to a bicyclic sulfur-containing heterocyclic group containing only sulfur atoms as hetero atoms forming a ring, such as a 2,3-dihydrobenzothienyl group and a benzothienyl group.

[0187] The bicyclic nitrogen- and oxygen-containing heterocyclic group refers to a bicyclic nitrogen- and oxygen-containing heterocyclic group containing only nitrogen and oxygen atoms as heteroatoms forming a ring, such as benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzomorpholinyl, dihydropyranopyridinyl, dihydrodioxinopyridinyl, and dihydropyridoxazinyl.

[0188] The bicyclic nitrogen / sulfur-containing heterocyclic group refers to a bicyclic nitrogen / sulfur-containing heterocyclic group containing a nitrogen atom and a sulfur atom as hetero atoms forming a ring, such as a benzothiazolyl group, a benzisothiazolyl group, and a benzothiadiazolyl group.

[0189] The bicyclic heterocyclic group represents a bicyclic nitrogen-containing heterocyclic group, a bicyclic oxygen-containing heterocyclic group, a bicyclic sulfur-containing heterocyclic group, a bicyclic nitrogen- and oxygen-containing heterocyclic group, or a bicyclic nitrogen- and sulfur-containing heterocyclic group.

[0190] The heterocyclic group means a monocyclic heterocyclic group or a bicyclic heterocyclic group.

[0191] Examples of the leaving group include a halogen atom, a C 1-6 Alkylsulfonyloxy or arylsulfonyloxy, imidazolyl. 1-6 The alkylsulfonyloxy group, the arylsulfonyloxy group, or the imidazolyl group may have a substituent.

[0192] The hydroxyl protecting group includes all groups that can be used as a general hydroxyl protecting group, and examples thereof include those described in 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, C 2-6 Alkenyl, aryl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6Alkyl, acyl, C 1-6 Alkoxycarbonyl, aryl C 1-6 Alkoxycarbonyl, C 1-6 Alkylsulfonyl, arylsulfonyl, silyl, tetrahydrofuranyl or tetrahydropyranyl. These groups may be substituted with one or more groups selected from Substituent Group A1.

[0193] As the amino protecting group, all groups that can be used as a protecting group for an amino group are included, for example, the groups described in W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 696-926, 2007, John Wiley & Sons, Inc. Specifically, aryl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, acyl, C 1-6 Alkoxycarbonyl, aryl C 1-6 Alkoxycarbonyl, aryloxycarbonyl, C 1-6 Alkylsulfonyl, arylsulfonyl or silyl. These groups may be substituted with one or more groups selected from Substituent Group A1.

[0194] Examples of the imino-protecting group include all groups that can be used as a conventional imino-protecting group, and examples thereof include those described in W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 696-868, 2007, John Wiley & Sons, Inc. Specifically, examples thereof include aryl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, acyl, C 1-6 Alkoxycarbonyl, aryl C 1-6 Alkoxycarbonyl, aryloxycarbonyl, C 1-6 Alkylsulfonyl, arylsulfonyl or silyl. These groups may be substituted with one or more groups selected from Substituent Group A1.

[0195] The carboxyl protecting group includes all groups that can be used as a general carboxyl protecting group, and examples thereof include those described in W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 533-643, 2007, John Wiley & Sons, Inc. Specifically, C 1-6 Alkyl, C 2-6 Alkenyl, aryl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 These groups may be substituted with one or more groups selected from Substituent Group A1.

[0196] Examples of the halogenated hydrocarbons include dichloromethane, chloroform, and dichloroethane.

[0197] Examples of the alcohols include methanol, ethanol, propanol, 2-propanol, butanol, and 2-methyl-2-propanol.

[0198] Examples of the ethers include diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and diethylene glycol diethyl ether.

[0199] Examples of ketones include acetone, 2-butanone, and 4-methyl-2-pentanone.

[0200] Examples of the esters include methyl acetate, ethyl acetate, propyl acetate, and butyl acetate.

[0201] Examples of the amides include N,N-dimethylformamide, N,N-dimethylacetamide, and 1-methyl-2-pyrrolidone.

[0202] Examples of the nitriles include acetonitrile and propionitrile.

[0203] Examples of the aromatic hydrocarbons include benzene, toluene, and xylene.

[0204] In this specification, the substituent groups have the following meanings.

[0205] Substituent Group A1:

[0206] hydrogen atoms,

[0207] Halogen atoms,

[0208] cyano,

[0209] Nitro,

[0210] Oxo group,

[0211] C which may be substituted with one or more groups selected from Substituent Group B2 1-6 alkyl,

[0212] C which may be substituted with one or more groups selected from Substituent Group B2 2-6 Alkenyl,

[0213] C which may be substituted with one or more groups selected from Substituent Group B2 2-6 Alkynyl,

[0214] C which may be substituted with one or more groups selected from Substituent Group B2 1-6 Alkoxy,

[0215] an aryloxy group which may be substituted with one or more groups selected from Substituent Group B1,

[0216] an acyl group which may be substituted with one or more groups selected from Substituent Group B1,

[0217] C which may be substituted with one or more groups selected from Substituent Group B2 1-6 Alkylamino,

[0218] Di(C) which may be substituted with one or more groups selected from Substituent Group B2 1-6 alkyl)amino,

[0219] an imino group which may be protected or substituted with one or more groups selected from Substituent Group B1,

[0220] C which may be substituted with one or more groups selected from Substituent Group B2 1-6 Alkylthio,

[0221] an arylthio group which may be substituted with one or more groups selected from Substituent Group B1,

[0222] C which may be substituted with one or more groups selected from Substituent Group B2 1-6 Alkylsulfonyl,

[0223] an arylsulfonyl group which may be substituted with one or more groups selected from Substituent Group B1,

[0224] C which may be substituted with one or more groups selected from Substituent Group B1 3-10 Cycloalkyl,

[0225] an aryl group which may be substituted with one or more groups selected from Substituent Group B1,

[0226] a heterocyclic group which may be substituted with one or more groups selected from Substituent Group B1,

[0227] Carbamoyl group which may be substituted with one or more groups selected from Substituent Group B1,

[0228] a sulfamoyl group which may be substituted with one or more groups selected from Substituent Group B1,

[0229] The hydroxyl groups can be protected,

[0230] The amino group may be protected,

[0231] The carboxyl group may be protected.

[0232] Substituent Group A2:

[0233] hydrogen atoms,

[0234] Halogen atoms,

[0235] cyano,

[0236] Nitro,

[0237] Oxo group,

[0238] C which may be substituted with one or more groups selected from Substituent Group B2 1-6 Alkoxy,

[0239] an aryloxy group which may be substituted with one or more groups selected from Substituent Group B1,

[0240] an acyl group which may be substituted with one or more groups selected from Substituent Group B1,

[0241] C which may be substituted with one or more groups selected from Substituent Group B2 1-6 Alkylamino,

[0242] Di(C) which may be substituted with one or more groups selected from Substituent Group B2 1-6 alkyl)amino,

[0243] C which may be substituted with one or more groups selected from Substituent Group B2 1-6 Alkylthio,

[0244] an arylthio group which may be substituted with one or more groups selected from Substituent Group B1,

[0245] C which may be substituted with one or more groups selected from Substituent Group B2 1-6 Alkylsulfonyl,

[0246] an arylsulfonyl group which may be substituted with one or more groups selected from Substituent Group B1,

[0247] C which may be substituted with one or more groups selected from Substituent Group B1 3-10 Cycloalkyl,

[0248] an aryl group which may be substituted with one or more groups selected from Substituent Group B1,

[0249] a heterocyclic group which may be substituted with one or more groups selected from Substituent Group B1,

[0250] Carbamoyl group which may be substituted with one or more groups selected from Substituent Group B1,

[0251] a sulfamoyl group which may be substituted with one or more groups selected from Substituent Group B1,

[0252] The hydroxyl groups can be protected,

[0253] The amino group may be protected,

[0254] The carboxyl group may be protected.

[0255] Substituent group B1:

[0256] hydrogen atoms,

[0257] Halogen atoms,

[0258] cyano,

[0259] Nitro,

[0260] Oxo group,

[0261] C may be substituted with one or more groups selected from the substituent group C 1-6 alkyl,

[0262] C may be substituted with one or more groups selected from the substituent group C 2-6 Alkenyl,

[0263] C may be substituted with one or more groups selected from the substituent group C 2-6 Alkynyl,

[0264] C may be substituted with one or more groups selected from the substituent group C 1-6 Alkoxy,

[0265] an aryloxy group which may be substituted with one or more groups selected from Substituent Group C,

[0266] an acyl group which may be substituted with one or more groups selected from Substituent Group C,

[0267] C may be substituted with one or more groups selected from the substituent group C 1-6 Alkylamino,

[0268] Di(C 1-6 alkyl)amino,

[0269] C may be substituted with one or more groups selected from the substituent group C 1-6 Alkylthio,

[0270] an arylthio group which may be substituted with one or more groups selected from Substituent Group C,

[0271] C may be substituted with one or more groups selected from the substituent group C 1-6 Alkylsulfonyl,

[0272] an arylsulfonyl group which may be substituted with one or more groups selected from Substituent Group C,

[0273] C may be substituted with one or more groups selected from the substituent group C 3-10 Cycloalkyl,

[0274] an aryl group which may be substituted with one or more groups selected from Substituent Group C,

[0275] a heterocyclic group which may be substituted with one or more groups selected from Substituent Group C,

[0276] Carbamoyl group which may be substituted with one or more groups selected from Substituent Group C,

[0277] a sulfamoyl group which may be substituted with one or more groups selected from Substituent Group C,

[0278] The hydroxyl groups can be protected,

[0279] The amino group may be protected,

[0280] The carboxyl group may be protected.

[0281] Substituent group B2:

[0282] hydrogen atoms,

[0283] Halogen atoms,

[0284] cyano,

[0285] Nitro,

[0286] Oxo group,

[0287] C may be substituted with one or more groups selected from the substituent group C 1-6 Alkoxy,

[0288] an aryloxy group which may be substituted with one or more groups selected from Substituent Group C,

[0289] an acyl group which may be substituted with one or more groups selected from Substituent Group C,

[0290] C may be substituted with one or more groups selected from the substituent group C 1-6 Alkylamino,

[0291] Di(C 1-6 alkyl)amino,

[0292] C may be substituted with one or more groups selected from the substituent group C 1-6 Alkylthio,

[0293] an arylthio group which may be substituted with one or more groups selected from Substituent Group C,

[0294] C may be substituted with one or more groups selected from the substituent group C 1-6 Alkylsulfonyl,

[0295] an arylsulfonyl group which may be substituted with one or more groups selected from Substituent Group C,

[0296] C may be substituted with one or more groups selected from the substituent group C 3-10 Cycloalkyl,

[0297] an aryl group which may be substituted with one or more groups selected from Substituent Group C,

[0298] a heterocyclic group which may be substituted with one or more groups selected from Substituent Group C,

[0299] Carbamoyl group which may be substituted with one or more groups selected from Substituent Group C,

[0300] a sulfamoyl group which may be substituted with one or more groups selected from Substituent Group C,

[0301] The hydroxyl groups can be protected,

[0302] The amino group may be protected,

[0303] The carboxyl group may be protected.

[0304] Substituent Group C:

[0305] Halogen atoms,

[0306] cyano,

[0307] Carbamoyl,

[0308] C 1-6 alkyl,

[0309] C 1-6 Alkoxy,

[0310] The amino group may be protected,

[0311] The imino group may be protected,

[0312] The hydroxyl groups can be protected,

[0313] The carboxyl group may be protected.

[0314] R 4 The optionally substituted amino group, the optionally substituted carbamoyl group, and the optionally substituted urea group may be substituted with one or more groups selected from Substituent Group A1.

[0315] R 4 The acyloxy group which may be substituted, the C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy C 1-6 Alkyl, aryl which may be substituted 1-6 Alkoxy C 1-6 Alkyl or optionally substituted C 1-6 The alkoxy group may be substituted by one or more groups selected from Substituent Group A2.

[0316] R 1 and R 2 The same or different amino groups which may be substituted, the guanidino groups which may be substituted, or the imino groups which may be substituted together may be substituted with one or more groups selected from Substituent Group A1.

[0317] R 1 and R 2 The same or different C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy or divalent C which may be substituted together 1-3 Alkylene-OC 1-3 The group represented by the alkylene group may be substituted with one or more groups selected from the substituent group A2.

[0318] R 3 The carbamoyl group which may be substituted or the C 3-10 The cycloalkyl group may be substituted by one or more groups selected from Substituent Group A1.

[0319] R 3 C that can be replaced 1-6 The alkyl group may be substituted by one or more groups selected from the substituent group A2.

[0320] X 1 C that can be replaced 2-6 Alkylene, optionally substituted C 2-6 Alkenylene, optionally substituted C 2-6The alkynylene group may be substituted by one or more groups selected from the substituent group A2 excluding the oxo group.

[0321] Y 1 C that can be replaced 3-10 The cycloalkyl group, the aryl group which may be substituted, the monocyclic heterocyclic group which may be substituted, or the bicyclic heterocyclic group which may be substituted may be substituted with one or more groups selected from Substituent Group A1.

[0322] Y 2 C that can be replaced 3-10 The cycloalkyl group, the aryl group which may be substituted, the monocyclic heterocyclic group which may be substituted, or the bicyclic heterocyclic group which may be substituted may be substituted with one or more groups selected from Substituent Group A1.

[0323] R 4a an acyloxy group which may be substituted, an amino group which may be substituted, a carbamoyl group which may be substituted, a urea group which may be substituted, or an aryl group which may be substituted 1-6 Alkoxy C 1-6 The alkyl group may be substituted by one or more groups selected from Substituent Group A1.

[0324] R 4a C that can be replaced 1-6 Alkyl or optionally substituted C 1-6 Alkoxy C 1-6 The alkyl group may be substituted by one or more groups selected from the substituent group A2.

[0325] Among the compounds of the present invention, the following compounds can be mentioned as preferred compounds.

[0326] Z 1 or Z 2 At least one of them is preferably a compound containing a nitrogen atom.

[0327] Z 1 is a group represented by the formula CH, Z 2 Preferred are compounds containing nitrogen atoms.

[0328] Z 1 is a nitrogen atom, Z 2 Preferably, the general formula CR 4a The compound of the group represented by 4a represents a hydrogen atom, a hydroxyl group, a cyano group, an acyloxy group which may be substituted, an amino group which may be substituted, a carbamoyl group which may be substituted, a urea group which may be substituted, a C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy C 1-6 Alkyl or aryl C1-6 Alkoxy C 1-6 alkyl.

[0329] Z 2 R in 4 Preferred are hydrogen atom, hydroxyl group, cyano group, acyloxy group which may be substituted, amino group which may be substituted, carbamoyl group which may be substituted, urea group which may be substituted, C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy C 1-6 Alkyl or aryl C 1-6 Alkoxy C 1-6 Alkyl, more preferably C 1-6 alkyl.

[0330] R 3 Preferably, a hydrogen atom or a C 1-6 The alkyl group is more preferably a hydrogen atom.

[0331] R 1 and R 2 Preferably, the same or different atoms are hydrogen atoms, amino groups which may be substituted or C 1-6 The alkyl group is more preferably a hydrogen atom or an amino group which may be substituted, and even more preferably a hydrogen atom or an amino group (a compound in which the carbon atom to which the amino group is bonded is in the R-isomer configuration).

[0332] X 1 Preferably, C 2-6 Alkylene or C 2-6 Alkenylene, more preferably C 2-6 The alkylene group is more preferably an ethylene group.

[0333] X 2 Preferably C 1-3 The alkylene group is more preferably a methylene group.

[0334] Y 1 Preferably, C 3-10 The cycloalkyl group, the aryl group which may be substituted, the monocyclic heterocyclic group which may be substituted, or the bicyclic heterocyclic group which may be substituted, is more preferably the aryl group which may be substituted, and further preferably the phenyl group which may be substituted.

[0335] Y 2 An optionally substituted aryl group or an optionally substituted bicyclic heterocyclic group is preferred, an optionally substituted aryl group is more preferred, and an optionally substituted phenyl group is further preferred.

[0336] Y 1 C that can be replaced 3-10The substituent of the cycloalkyl group, the aryl group which may be substituted, the monocyclic heterocyclic group which may be substituted or the bicyclic heterocyclic group which may be substituted is preferably selected from a halogen atom, a protected carboxyl group, a substituted carbamoyl group, a hydroxyl group, a substituted amino group, a substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynylidene, optionally substituted C 3-10 Cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 1-6 Alkoxy, acyl which may be substituted, aryl which may be substituted, monocyclic heterocyclic group which may be substituted, and C 1-6 More preferably, one or more groups in the alkylthio group are selected from halogen atoms, optionally protected carboxyl groups, hydroxyl groups, optionally substituted amino groups, optionally substituted C 1-6 Alkyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 1-6 One or more groups selected from alkoxy, acyl which may be substituted, aryl which may be substituted, and monocyclic heterocyclic groups which may be substituted, more preferably selected from halogen atoms, C 3-10 The one or more groups selected from the group consisting of a cycloalkyl group, an aryl group which may be substituted, and a monocyclic heterocyclic group which may be substituted are most preferably one or more groups selected from the group consisting of a halogen atom and a phenyl group which may be substituted.

[0337] Moreover, Y 1 C that can be replaced 3-10 The substituents of the cycloalkyl group, the aryl group which may be substituted, the monocyclic heterocyclic group which may be substituted, or the bicyclic heterocyclic group which may be substituted are preferably two groups each selected from a halogen atom and a disubstituted phenyl group.

[0338] Y 2 C that can be replaced 3-10 The substituent of the cycloalkyl group, the aryl group which may be substituted, the monocyclic heterocyclic group which may be substituted or the bicyclic heterocyclic group which may be substituted is preferably selected from a halogen atom, a nitro group, a cyano group, a hydroxyl group, a protected carboxyl group, a substituted carbamoyl group, a substituted amino group, a substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynylidene, optionally substituted C 1-6 Alkoxy and C 1-6 More preferably, one or more groups in the alkylthio group are selected from halogen atoms, optionally substituted C1-6 Alkoxy and C 1-6 One or more alkylthio groups.

[0339] The following compounds are more preferred.

[0340] (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 hydrobromide (Compound of Example 1)

[0341] (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)ethan-1-one hydrobromide (Compound of Example 27)

[0342] (R)-2-amino-2-(1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrobromide (Compound of Example 30)

[0343] (R)-2-amino-1-(4-(benzo[b]thiophen-7-ylmethyl)piperazin-1-yl)-2-(1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)ethan-1-one hydrobromide (Compound of Example 31)

[0344] (R)-2-amino-2-(1-(2-(2',4-dichloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrobromide (Compound of Example 44)

[0345] (R)-2-amino-2-(1-(5-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrobromide (Compound of Example 71)

[0346] (R)-2-amino-2-(1-(2-(4-aminopyridin-3-yl)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrobromide (Compound of Example 93)

[0347] (R)-2-amino-2-(1-(2-(2'-amino-4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrobromide (Compound of Example 97)

[0348] (R)-2-amino-2-(1-(2-(4-chloro-3'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrobromide (Compound of Example 100)

[0349] (R)-2-amino-2-(1-(2-(4-chloro-2'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrochloride (Compound of Example 107)

[0350] (R)-2-amino-2-(1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrochloride (Compound of Example 137)

[0351] 2-(4-(3-chlorophenethyl)piperazin-1-yl)-1-(4-(2-methoxybenzyl)piperazin-1-yl)ethan-1-one hydrochloride (Compound of Example 272)

[0352] (R)-2-amino-2-(1-(2-(2',4-dichloro-3'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrochloride (Compound of Example 571)

[0353] (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)ethan-1-one hydrochloride (Compound of Example 584)

[0354] (R)-2-amino-2-(1-(2-(4-chloro-2'-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrochloride (Compound of Example 585)

[0355] (R)-2-amino-2-(1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-5-hydroxybenzyl)piperazin-1-yl)ethan-1-one hydrochloride (Compound of Example 589)

[0356] (R)-2-amino-2-(1-(2-(4-chloro-3'-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrochloride (Compound of Example 609)

[0357] (R)-2-amino-2-(1-(2-(3',4-dichloro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(methylthio)benzyl)piperazin-1-yl)ethan-1-one hydrochloride (Compound of Example 610)

[0358] (R)-2-amino-2-(1-(2-(4-chloro-2'-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(methylthio)benzyl)piperazin-1-yl)ethan-1-one hydrochloride (Compound of Example 612)

[0359] (R)-2-amino-2-(1-(2-(3',4-dichloro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrochloride (Compound of Example 614)

[0360] (R)-2-amino-2-(1-(2-(4-chloro-2'-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrochloride (Compound of Example 615)

[0361] (R)-2-amino-2-(1-(2-(2',4-dichloro-3'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrochloride (Compound of Example 616)

[0362] (R)-2-amino-2-(1-(2-(4-chloro-3'-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(methylthio)benzyl)piperazin-1-yl)ethan-1-one hydrochloride (Compound of Example 617)

[0363] (R)-2-amino-2-(1-(2-(2',4-dichloro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-methylthio)benzyl)piperazin-1-yl)ethan-1-one hydrochloride (Compound of Example 618)

[0364] (R)-2-amino-2-(1-(2-(2',4-dichloro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrochloride (Compound of Example 619)

[0365] (R)-2-amino-2-(1-(2-(4-chloro-3'-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-5-hydroxybenzyl)piperazin-1-yl)ethan-1-one hydrochloride (Compound of Example 620)

[0366] (R)-2-amino-2-(1-(2-(4-chloro-2'-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-5-hydroxybenzyl)piperazin-1-yl)ethan-1-one hydrochloride (Compound of Example 621)

[0367] Examples of the salt of the compound of the general formula [1] include salts of generally known basic groups such as amino groups or acidic groups such as hydroxyl groups and carboxyl groups.

[0368] Examples of the salt of the basic group include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; salts with organic carboxylic acids such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, 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.

[0369] Examples of the salt of the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and salts with nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenylethylamine, 1-phenylethylamine, and N,N'-dibenzylethylenediamine.

[0370] Among the above salts, pharmaceutically acceptable salts are preferred.

[0371] When the compound of the general formula [1] or a salt thereof has isomers (eg, optical isomers, geometric isomers, tautomers, etc.), the present invention includes these isomers, and also includes solvates, hydrates, and crystals of various shapes.

[0372] The compound of the present invention or a salt thereof can be combined with one or more pharmaceutically acceptable carriers, excipients or diluents to prepare a pharmaceutical composition (pharmaceutical preparation).

[0373] Examples of the carrier, excipient, and diluent include water, lactose, glucose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, glue, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, aqueous syrup, methylcellulose, polyvinyl pyrrolidone, alkyl parahydroxybenzoate, talc, magnesium stearate, stearic acid, glycerin, and various oils such as sesame oil, olive oil, and soybean oil.

[0374] Furthermore, the above-mentioned carriers, excipients or diluents may be mixed with commonly used additives such as extenders, binders, disintegrants, pH regulators and solubilizers as needed, and oral or parenteral pharmaceuticals such as tablets, pills, capsules, granules, powders, liquid preparations, emulsions, suspensions, ointments, injections or skin patches may be prepared by commonly used formulation techniques.

[0375] The compound of the present invention is useful as a medicine against bacteria that produce drug excretion pumps (for example, enteric bacteria or Gram-negative bacteria that produce drug excretion pumps, and drug-resistant bacteria thereof) when used in combination with other antimicrobial agents.

[0376] In the present invention, the term "combination use" refers to the simultaneous or sequential administration of one or more compounds of the present invention and other antibacterial agents.

[0377] Other antimicrobial agents are not particularly limited as long as they are excreted from the bacterial body to the outside of the bacterial body by the drug excretion pump. Examples thereof include: penicillin antimicrobial agents such as benzylpenicillin and piperacillin; β-lactam combination agents such as piperacillin-tazobactam combination, ampicillin-sulbactam combination, ceftazidime-avibactam combination, ceftolozane-tazobactam combination, and ampicillin-clavulanic acid combination; cephalosporin antimicrobial agents such as cefazolin, cefmetazole, ceftriaxone, ceftazidime, cefepime, and cefdrocor; monocyclic β-lactam antimicrobial agents such as azidothymidine; doripenem, imipenem, and imipenem. Carbapenem antibiotics such as gentamicin and meropenem; aminoglycoside antibiotics such as gentamicin, tobramycin, amikacin and netilmicin; quinolone antibiotics such as moxifloxacin, garnafin, moxifloxacin, strifloxacin, laskovacin, ciprofloxacin, levofloxacin, romycin, ofloxacin and pazifloxacin; oxazolidinone antibiotics such as linezolid and daptomycin; macrocyclic antibiotics such as erythromycin, azithromycin, clarithromycin and solithromycin; tetracycline antibiotics such as tetracycline, minocycline and doxycycline; glycylcycline antibiotics such as tigecycline; rifamycin antibiotics such as rifampicin.

[0378] The compounds of the present invention inhibit drug efflux pumps, for example, MexB and / or MexY drug efflux pumps.

[0379] Preferred compounds include compounds that inhibit both drug excretion pumps MexB and MexY.

[0380] Treatment based on the compound, salt or pharmaceutical composition of the present invention includes both treatment and prevention.

[0381] The method of administration, dosage, and frequency of administration of the compound of the present invention, its salt, or pharmaceutical composition can be appropriately selected according to the patient's age, weight, and symptoms. Generally, for adults, the compound of the present invention is administered orally or parenterally (e.g., by injection, intravenous drip, and rectal administration). 0.01 to 1000 mg / kg of the compound of the present invention is administered once or several times a day.

[0382] The compound of the present invention, its salt, or pharmaceutical composition is preferably administered as an injection.

[0383] The pharmaceutical composition containing the compound of the present invention or a salt thereof is preferably produced as a liquid preparation, a frozen liquid preparation, or a freeze-dried preparation, and more preferably a freeze-dried preparation.

[0384] Next, the method for producing the compound of the present invention will be described.

[0385] The compound of the present invention can be produced by combining known methods. For example, it can be produced according to the following production method.

[0386] [Production Method 1] Deprotection

[0387] [Chemical Formula 3]

[0388]

[0389] “Where, R 1a Indicates that R can be protected 1 The same substituents; R 2a Indicates that R can be protected 2 The same substituents; R 4a Indicates that R can be protected 4 The same substituent; X 1a Indicates that X can be protected 1 The same substituents; Y 1a Indicates that Y can be protected 1 The same substituents; Y 2a Indicates that Y can be protected 2 The same substituents; R 1 、R 2 、R 3 、R 4 、X 1 、X 2 、Y 1 、Y 2 , Z 1 and Z 2 Has the same meaning as above. 1a 、R 2a 、R 4a 、X 1a 、Y 1a or Y 2a At least one substituent in is protected."

[0390] The compound represented by the general formula [1a] can be produced by simultaneously or stepwise deprotecting the compound represented by the general formula [2a] by a conventional method known in the art as described in W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, 2007, John Wiley & Sons, Inc.

[0391] (1) In the case of amino protecting groups

[0392] The compound represented by the general formula [1a] can be produced by deprotecting the amino protecting group of the compound represented by the general formula [2a] in the presence or absence of a solvent. Examples of methods for deprotecting the amino protecting group include reduction by contact with a catalyst and reduction with an acid.

[0393] (1-a) Reduction method by contact with a catalyst

[0394] The compound represented by the general formula [1a] can be produced by reducing the compound represented by the general formula [2a] in a hydrogen atmosphere in the presence of a catalyst.

[0395] The catalyst used in this reaction may be, for example, a metal catalyst, for example, metal palladium such as palladium-carbon and palladium black; palladium salts such as palladium oxide and palladium hydroxide; nickel metal such as lanthanum nickel alloy; and platinum salts such as platinum oxide. A preferred metal catalyst is, for example, palladium-carbon.

[0396] The amount of the catalyst used in this reaction may be 0.001 to 20 times (W / W), preferably 0.01 to 5 times (W / W), the amount of the compound represented by the general formula [2a].

[0397] The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include alcohols, ethers, and esters, which may be used as a mixture.

[0398] Preferred solvents include alcohols and esters, with methanol and ethanol being more preferred.

[0399] The reaction can 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.

[0400] (1-b) Acid-based method

[0401] 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.

[0402] Examples of the acid used in the reaction include protonic acids such as hydrochloric acid and hydrobromic acid; and Lewis acids such as aluminum chloride and trimethylsilyl iodide.

[0403] The amount of the acid used in the reaction is 1 to 100 times the mole, preferably 2 to 30 times the mole, of the compound represented by the general formula [2a].

[0404] As the solvent used in this reaction, as long as it does not affect the reaction, then is not particularly limited, for example, halogenated hydrocarbons, ethers and nitriles etc. can be enumerated, and they can be used in combination. As preferred solvent, halogenated hydrocarbons and nitriles can be enumerated, more preferably methylene chloride and acetonitrile. In this reaction, when acid is a liquid, acid can also be used as a solvent.

[0405] The reaction can 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.

[0406] (1-c) Alkali-based method

[0407] The compound represented by the general formula [1a] can be produced by reacting the compound represented by the general formula [2a] with a base.

[0408] Examples of the base used in the reaction include inorganic bases such as sodium hydroxide and potassium carbonate; and organic bases such as morpholine and triethylamine.

[0409] The amount of the base used in the reaction may be 1 to 100 times the mole, preferably 2 to 30 times the mole, of the compound represented by the general formula [2a].

[0410] The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include halogenated hydrocarbons, ethers, amides, alcohols, nitriles, and water, and these can be used as a mixture.

[0411] The reaction can 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.

[0412] For example, when the amino-protecting group is a benzyloxycarbonyl group, the same deprotection method as in Production Method (1-a) or Production Method (1-b) can be used.

[0413] For example, when 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.

[0414] For example, when the amino-protecting group is a tert-butoxycarbonyl group, the same deprotection method as in Production Method (1-b) can be used.

[0415] For example, when the amino-protecting group is a 9-fluorenylmethoxycarbonyl group, the same deprotection method as in the production method (1-c) can be used.

[0416] (2) Hydroxyl protecting group

[0417] The compound represented by the general formula [1a] can be produced by deprotecting the compound represented by the general formula [2a]. Examples of methods for deprotecting the hydroxyl protecting group include reduction by contact with a catalyst, reduction with an acid, and use of fluoride ions.

[0418] (2-a) Reduction method by contact with a catalyst

[0419] The compound represented by the general formula [1a] can be produced by reducing the compound represented by the general formula [2a] in a hydrogen atmosphere in the presence of a catalyst.

[0420] The catalyst used in this reaction may be a metal catalyst, such as palladium on carbon and palladium black; palladium salts such as palladium oxide and palladium hydroxide; nickel metals such as lanthanum nickel alloys; and platinum salts such as platinum oxide. A preferred metal catalyst is palladium on carbon.

[0421] The amount of the catalyst used in this reaction may be 0.001 to 20 times (W / W), preferably 0.01 to 5 times (W / W), the amount of the compound represented by the general formula [2a].

[0422] The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include alcohols, ethers, and esters, which may be used as a mixture.

[0423] Preferred solvents include alcohols and esters, with methanol and ethanol being more preferred.

[0424] The reaction can 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.

[0425] (2-b) Acid-based method

[0426] 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.

[0427] Examples of the acid used in the reaction include protonic acids such as hydrochloric acid and hydrobromic acid; and Lewis acids such as aluminum chloride and trimethylsilyl iodide.

[0428] The amount of the acid used in the reaction may be 2 to 100 times the mole, preferably 2 to 30 times the mole, of the compound represented by the general formula [2a].

[0429] As the solvent used in this reaction, as long as it does not affect the reaction, then is not particularly limited, for example, halogenated hydrocarbons, ethers and nitriles etc. can be enumerated, and they can be used in combination. As preferred solvent, halogenated hydrocarbons and nitriles can be enumerated, more preferably methylene chloride and acetonitrile. In this reaction, when acid is a liquid, acid can also be used as a solvent.

[0430] The reaction can 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.

[0431] (2-c) Alkali-based method

[0432] The compound represented by the general formula [1a] can be produced by reacting the compound represented by the general formula [2a] with a base.

[0433] Examples of the base used in the reaction include inorganic bases such as sodium hydroxide and potassium carbonate; and organic bases such as morpholine and triethylamine.

[0434] The amount of the base used in the reaction may be 1 to 100 times the mole, preferably 2 to 30 times the mole, of the compound represented by the general formula [2a].

[0435] The solvent used in the reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include halogenated hydrocarbons, ethers, amides, alcohols, nitriles, and water, which can be mixed. Preferred solvents include ethers, alcohols, and water.

[0436] The reaction can 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.

[0437] (2-d) Method using fluoride ions

[0438] The compound represented by the general formula [1a] can be produced by reacting the compound represented by the general formula [2a] with fluoride ions.

[0439] Fluoride ions can be generated from a fluorine compound, and examples of the fluorine compound used in this reaction include tetrabutylammonium fluoride, potassium fluoride, and cesium fluoride.

[0440] The solvent used in the reaction is not particularly limited as long as it does not affect the reaction. For example, halogenated hydrocarbons, ethers, nitriles, amides, alcohols and water can be mentioned, and they can be mixed for use. Preferred solvents include ethers and nitriles, and more preferably tetrahydrofuran and acetonitrile.

[0441] The amount of the fluorine compound used in the reaction is 1 to 100 times the mole, preferably 2 to 30 times the mole, of the compound represented by the general formula [2a].

[0442] The reaction can 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.

[0443] For example, when the hydroxyl-protecting group is a benzyl group, the same deprotection method as in production method (2-a) or (2-b) can be used.

[0444] For example, when the hydroxyl-protecting group is 4-methoxybenzyl, the same deprotection method as in Production Method (2-a) or (2-b) can be used.

[0445] For example, when the hydroxyl-protecting group is a methoxymethyl group, the same deprotection method as in Production Method (2-b) can be used.

[0446] For example, when the hydroxyl-protecting group is a tert-butyldimethylsilyl group, the same deprotection methods as those in Production Method (2-b) and Production Method (2-d) can be used.

[0447] For example, when the hydroxyl-protecting group is an acetyl group, the same deprotection methods as those in Production Method (2-b) and Production Method (2-c) can be used.

[0448] (3) Carboxyl protecting group

[0449] The compound represented by the general formula [1a] can be produced by deprotecting the compound represented by the general formula [2a]. Examples of methods for deprotecting the carboxyl protecting group include solvolysis with a base, solvolysis with an acid, and solvolysis with an enzyme.

[0450] (3-a) Solvolysis with an alkali

[0451] The compound represented by the general formula [1a] can be produced by subjecting the compound represented by the general formula [2a] to solvolysis in the presence of a base.

[0452] Examples of the base used in the reaction include alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, and barium hydroxide.

[0453] The amount of the base used in the reaction may be 1 to 100 times the mole, preferably 2 to 30 times the mole, of the compound represented by the general formula [2a].

[0454] The solvent used in the reaction is not particularly limited, and examples thereof include alcohols, ethers, and water, which may be used as a mixture.

[0455] Preferred solvents include alcohols and water, and more preferred alcohols are methanol and ethanol.

[0456] The reaction can 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.

[0457] (3-b) Solvolysis by Acid

[0458] The compound represented by the general formula [1a] can be produced by subjecting the compound represented by the general formula [2a] to solvolysis in the presence of an acid.

[0459] Examples of the acid used in the reaction include protonic acids such as hydrochloric acid and sulfuric acid; and Lewis acids such as aluminum chloride and boron trichloride.

[0460] As the solvent used in this reaction, as long as it does not affect the reaction, then is not particularly limited, and halogenated hydrocarbons, ethers and nitriles etc. can be enumerated, and they can be used in combination. As preferred solvent, halogenated hydrocarbons and nitriles can be enumerated, more preferably methylene chloride and acetonitrile. In this reaction, when acid is a liquid, acid can also be used as solvent.

[0461] The amount of the acid used in the reaction may be 2 to 100 times the mole, preferably 2 to 30 times the mole, of the compound represented by the general formula [2a].

[0462] The reaction can 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.

[0463] (3-c) Enzymatic Solvolysis

[0464] 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.

[0465] Examples of the enzyme used in this reaction include esterase and carbonic anhydrase, and examples thereof include enzymes derived from pig liver or bovine erythrocytes.

[0466] The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction, but water is more preferable.

[0467] The reaction can 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.

[0468] For example, when the carboxyl protecting group is a methyl group, examples include Production Method (3-a), Production Method (3-b), and Production Method (3-c).

[0469] [Production Method 2] Reductive Amination

[0470] [Chemical Formula 4]

[0471]

[0472] “Where, X 2a Indicates C 1-2 Alkylene; R 1a 、R 2a 、R 3 、R 4a 、X 1a 、X 2 、Y 1a 、Y 2a 、Z 1 and Z 2 has the same meaning as above.”

[0473] The compound represented by the general formula [2a] can be produced by reacting a compound represented by the general formula [2b] with a compound represented by the general formula [2c] or a salt thereof in the presence of a reducing agent and in the presence or absence of a base.

[0474] The amount of the compound represented by the general formula [2c] used in the reaction is not particularly limited, but may be 0.9 to 10 times the mole, preferably 1.0 to 2.0 times the mole, of the compound represented by the general formula [2b].

[0475] The reducing agent used in this reaction includes 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.

[0476] The amount of the reducing agent used in the reaction is 0.5 to 50 times the mole, preferably 1 to 10 times the mole, of the compound represented by the general formula [2b].

[0477] In this reaction, when the compound represented by general formula [2b] is an acidic salt, a base may be added. Examples of the base used as needed include organic bases such as trimethylamine, triethylamine, and tributylamine, and triethylamine is a preferred base.

[0478] The amount of the base used in this reaction, if necessary, is 1 to 10 times the mole, preferably 1 to 5 times the mole, of the compound represented by the general formula [2b].

[0479] As the solvent used in this reaction, as long as it does not affect the reaction, then is not particularly limited, for example, halogenated hydrocarbons, ethers, amides and alcohols etc. can be enumerated, and these solvents can be used in combination. As preferred solvent, halogenated hydrocarbons and amides can be enumerated, more preferably methylene chloride.

[0480] The amount of the solvent used in the reaction is not particularly limited, and may be 1 to 500 times (v / w) the amount of the compound represented by the general formula [2b].

[0481] The reaction can 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.

[0482] [Manufacturing method 3] Condensation

[0483] [Chemical Formula 5]

[0484]

[0485] “Where, R 1a 、R 2a 、R 3 、R 4a 、X 1a 、X 2 、Y 1a 、Y 2a 、Z 1 and Z 2 has the same meaning as above.”

[0486] The compound represented by the general formula [2a] can be produced by reacting a compound represented by the general formula [2d] with a compound represented by the general formula [2e] or a salt thereof in the presence of a condensing agent and a base.

[0487] Examples of the condensing agent used in the reaction include carbodiimides such as N,N'-diisopropylcarbodiimide (DIC), N,N'-di-(tert-butyl)carbodiimide, N,N'-dicyclohexylcarbodiimide (DCC), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC); and imidazoliums such as 1,1'-carbonyldiimidazole (CDI) and 1,1'-carbonylbis(1,2,4-triazole) (CDT). Acid azides such as diphenylphosphoryl azide; acid cyanides such as diethylphosphoryl cyanide; ureas such as (1-cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylaminomorpholinium hexafluorophosphate (COMU) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU). Preferred condensing agents include the hydrochloride of WSC and HATU.

[0488] The amount of the condensing agent used in the 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].

[0489] When carbodiimides are used as the condensing agent in the reaction, additives may be further added. Examples of additives used as needed include 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), and ethyl (hydroxyimino)cyanoacetate, with HOBt being preferred.

[0490] The amount of the additive used as needed in the reaction may be 0.01 to 10 times the mole, preferably 0.1 to 1 times the mole, of the compound represented by the general formula [2d].

[0491] Examples of the base used in the reaction include organic bases such as triethylamine, N,N-diisopropylethylamine and N-methylmorpholine, and N,N-diisopropylethylamine is preferred.

[0492] The amount of the base used in the 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].

[0493] The solvent used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include halogenated hydrocarbons, ethers, esters, amides, nitriles, aromatic hydrocarbons, and dimethyl sulfoxide. These solvents may be mixed and used. Preferred solvents include halogenated hydrocarbons and amides, with dichloromethane and N,N-dimethylacetamide being more preferred.

[0494] The amount of the compound represented by the general formula [2e] used is not particularly limited, but may be 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].

[0495] The amount of the solvent used is not particularly limited, and may be 1 to 500 times (v / w) the amount of the compound represented by the general formula [2d].

[0496] The reaction can 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.

[0497] [Production Method 4] Reductive Amination

[0498] [Chemical Formula 6]

[0499]

[0500] “Where, R 5 represents an amino protecting group; X 1bIndicates that C can be replaced 1-5 Alkylene; X 1c Indicates that C can be replaced 2-6 Alkylene; R 1a 、R 2a 、R 3 、X 2 、Y 1a 、Y 2a and Z 1 has the same meaning as above.”

[0501] The compound represented by the general formula [2j] can be produced by the following method.

[0502] (4-1) Condensation

[0503] The compound represented by the general formula [2g] can be produced by reacting a compound represented by the general formula [2f] with a compound represented by the general formula [2e] in the same manner as in [Production Method 3].

[0504] (4-2) Deprotection

[0505] The compound represented by the general formula [2h] or a salt thereof can be prepared by reacting the compound represented by the general formula [2g] with a suitable 5 [Production Method 1] (1-a), (1-b) or (1-c) of the same type can be used to produce the same reaction.

[0506] (4-3) Reductive amination

[0507] The compound represented by the general formula [2j] can be produced by reacting a compound represented by the general formula [2h] or a salt thereof with a compound represented by the general formula [2i] in the presence of a reducing agent and in the presence or absence of a base.

[0508] The reducing agent used in this reaction includes 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.

[0509] The amount of the reducing agent used in the reaction may be 0.5 to 50 times the mole, preferably 1 to 10 times the mole, of the compound represented by the general formula [2h].

[0510] In this reaction, when the compound represented by the general formula [2h] is an acidic salt, a base may be added. Examples of the base used as needed include organic bases such as trimethylamine, triethylamine, and tributylamine. Preferred bases include triethylamine.

[0511] The amount of the base used in this reaction, if necessary, is 1 to 10 times the mole, preferably 1 to 5 times the mole, of the compound represented by the general formula [2h].

[0512] As the solvent used in this reaction, as long as it does not affect the reaction, then is not particularly limited, for example, halogenated hydrocarbons, ethers, amides and alcohols etc. can be enumerated, and these solvents can be used in combination. As preferred solvent, halogenated hydrocarbons and amides can be enumerated, more preferably methylene chloride.

[0513] The amount of the compound represented by the general formula [2i] used in the reaction is not particularly limited, but may be 0.9 to 10 times the mole, preferably 1.0 to 2.0 times the mole, of the compound represented by the general formula [2h].

[0514] The amount of the solvent used in the reaction is not particularly limited, and may be 1 to 500 times (v / w) the amount of the compound represented by the general formula [2h].

[0515] The reaction can 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.

[0516] [Production Method 5] Alkylation

[0517] [Chemical Formula 7]

[0518]

[0519] “Where, L 1a Represents a leaving group; R 1a 、R 2a 、R 3 、X 1a 、X 2 、Y 1a 、Y 2a and Z 1 has the same meaning as above.”

[0520] As L 1a Examples of the leaving group represented by include halogen atoms, C 1-6 Alkylsulfonyloxy, arylsulfonyloxy and imidazolyl. 1-6 The alkylsulfonyloxy group, the arylsulfonyloxy group, and the imidazolyl group may have a substituent.

[0521] The compound represented by the general formula [2l] can be produced by reacting a compound represented by the general formula [2h] or a salt thereof with a compound represented by the general formula [2k] in the presence of a base.

[0522] Examples of the base used in the 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, and potassium carbonate is more preferred.

[0523] The amount of the base used in the 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].

[0524] The solvent used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include halogenated hydrocarbons, ethers, esters, ketones, amides, and nitriles, and these solvents may be mixed. Preferred solvents include amides and nitriles, with N,N-dimethylformamide and acetonitrile being more preferred.

[0525] The amount of the compound represented by the general formula [2k] used in the reaction is not particularly limited, but may be 0.9 to 10 times the mole, preferably 1.0 to 5.0 times the mole, of the compound represented by the general formula [2h].

[0526] The amount of the solvent used in the reaction is not particularly limited, and may be 1 to 500 times (v / w) the amount of the compound represented by the general formula [2h].

[0527] The reaction can 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.

[0528] [Manufacturing method 6]

[0529] [Chemical Formula 8]

[0530]

[0531] “Where Z 3a represents a protected hydroxyl or amino group; Z 3 Represents hydroxyl or amino; L 1a 、R 3 、R 5 、X 1a 、X 2 、Y 1a and Y 2a has the same meaning as above.”

[0532] The compound represented by the general formula [2t] can be produced by the following method.

[0533] (6-1) Condensation

[0534] The compound represented by the general formula [2o] can be produced by reacting a compound represented by the general formula [2m] with a compound represented by the general formula [2e] or a salt thereof in the same manner as in [Production Method 3].

[0535] (6-2) Deprotection

[0536] The compound represented by the general formula [2p] or a salt thereof can be prepared by reacting the compound represented by the general formula [2o] with a suitable 5 [Production Method 1] (1-a), (1-b) or (1-c) of the same type can be used to produce the same reaction.

[0537] (6-3) Alkylation

[0538] The compound represented by the general formula [2q] can be produced by reacting a compound represented by the general formula [2p] or a salt thereof in the same manner as in [Production Method 5].

[0539] (6-4) Imidylation

[0540] The compound represented by the general formula [2s] can be produced by reacting a compound represented by the general formula [2q] with a compound represented by the general formula [2r].

[0541] The amount of the compound represented by the general formula [2r] used is not particularly limited, but may be 1 to 20 times the mole, preferably 1 to 10 times the mole, of the compound represented by the general formula [2q].

[0542] The solvent used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include halogenated hydrocarbons, ethers, esters, amides, alcohols, and nitriles, and these solvents may be mixed. Preferred solvents include ethers, amides, and alcohols, with methanol being more preferred.

[0543] The amount of the solvent used is not particularly limited, and may be 1 to 500 times (v / w) the amount of the compound represented by the general formula [2q].

[0544] The reaction can 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.

[0545] (6-5) Deprotection

[0546] The compound represented by the general formula [2t] or a salt thereof can be produced by reacting the compound represented by the general formula [2s] in the same manner as in [Production Method 1].

[0547] [Manufacturing Method 7] Condensation

[0548] [Chemical Formula 9]

[0549]

[0550] “Where, L 1b Represents a leaving group; R 3 、R 4a 、X 1a 、X 2 、Y 1a 、Y 2a and Z 2 has the same meaning as above.”

[0551] As L 1b Examples of the leaving group represented by include halogen atoms, C 1-6 Alkylsulfonyloxy, arylsulfonyloxy and imidazolyl. 1-6 The alkylsulfonyloxy group, the arylsulfonyloxy group, and the imidazolyl group may have a substituent.

[0552] The compound represented by the general formula [2w] can be produced by reacting a compound represented by the general formula [2u] with a compound represented by the general formula [2v] or a salt thereof in the presence of a base.

[0553] Examples of the base used in the 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, and potassium carbonate is more preferred.

[0554] The amount of the base used in the reaction may be 1 to 20 times the mole, preferably 1 to 10 times the mole, of the compound represented by the general formula [2u].

[0555] The solvent used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include halogenated hydrocarbons, ethers, esters, amides, and nitriles, and these solvents may be mixed. Preferred solvents include amides and nitriles, with N,N-dimethylformamide and acetonitrile being more preferred.

[0556] The amount of the compound represented by the general formula [2v] used in the reaction is not particularly limited, but may be 0.9 to 10 times the mole, preferably 1.0 to 5.0 times the mole, of the compound represented by the general formula [2u].

[0557] The amount of the solvent used in the reaction is not particularly limited, and may be 1 to 500 times (v / w) the amount of the compound represented by the general formula [2u].

[0558] The reaction can 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.

[0559] [Manufacturing method A]

[0560] [Chemical Formula 10]

[0561]

[0562] “Where, R 3 、R 5 、X 2 、X 2a and Y 2a has the same meaning as above.”

[0563] The compound represented by the general formula [2e] or a salt thereof can be produced by the following method.

[0564] (A-1) Reductive amination

[0565] 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 [2c] in the presence of a reducing agent and in the presence or absence of an acid in the same manner as in [Production Method 2].

[0566] The amount of the compound represented by the general formula [2c] used in the reaction is not particularly limited, but may be 0.9 to 10 times the mole, preferably 1.0 to 2.0 times the mole, of the compound represented by the general formula [3a].

[0567] The reducing agent used in this reaction includes 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.

[0568] The amount of the reducing agent used in the reaction is 0.5 to 50 times the mole, preferably 1 to 10 times the mole, of the compound represented by the general formula [3a].

[0569] Examples of the acid used in this reaction as needed include Lewis acids such as zinc chloride, tetraisopropyl orthotitanate, and acetic acid. A preferred acid is tetraisopropyl orthotitanate.

[0570] The amount of the acid used in this reaction, if necessary, is 0.1 to 10 times the mole, preferably 1 to 5 times the mole, of the compound represented by the general formula [3a].

[0571] The solvent used in the reaction is not particularly limited as long as it does not affect the reaction. For example, halogenated hydrocarbons, ethers, amides and alcohols can be enumerated, and these solvents can be used in combination. Preferred solvents include halogenated hydrocarbons, ethers and amides, and more preferably dichloromethane or tetrahydrofuran.

[0572] The amount of the solvent used in the reaction is not particularly limited, and may be 1 to 500 times (v / w) the amount of the compound represented by the general formula [3a].

[0573] The reaction can 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.

[0574] (A-2) Deprotection

[0575] The compound represented by the general formula [2e] or a salt thereof can be prepared by reacting the compound represented by the general formula [3b] with a suitable 5 [Production Method 1] (1-a), (1-b) or (1-c) of the same type can be used to produce the same reaction.

[0576] [Manufacturing method B]

[0577] [Chemical Formula 11]

[0578]

[0579] “Where, L 1a 、R 3 、R 5 、X 2 、X 2a and Y 2a has the same meaning as above.”

[0580] The compound represented by the general formula [3b] can be produced by reacting a compound represented by the general formula [3c] with a compound represented by the general formula [3a] in the presence of a base.

[0581] Examples of the base used in the 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, and potassium carbonate is more preferred.

[0582] The amount of the base used in the reaction may be 1 to 20 times the mole, preferably 1 to 10 times the mole, of the compound represented by the general formula [3a].

[0583] The solvent used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include halogenated hydrocarbons, ethers, esters, ketones, amides, and nitriles, and these solvents may be mixed. Preferred solvents include ketones and amides, and more preferably N,N-dimethylformamide or acetone.

[0584] The amount of the compound represented by the general formula [3c] used in the reaction is not particularly limited, but may be 0.9 to 10 times the mole, preferably 1.0 to 5.0 times the mole, of the compound represented by the general formula [3a].

[0585] The amount of the solvent used in the reaction is not particularly limited, and may be 1 to 500 times (v / w) the amount of the compound represented by the general formula [3a].

[0586] The reaction can 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.

[0587] [Manufacturing method C]

[0588] [Chemical Formula 12]

[0589]

[0590] “Where, L 1b 、R 3 、R 5 、X 2 and Y 2a has the same meaning as above.”

[0591] The compound represented by the general formula [3f] or a salt thereof can be produced by the following method.

[0592] (C-1) Condensation

[0593] The compound represented by the general formula [2u] can be produced by reacting a compound represented by the general formula [2e] or a salt thereof with a compound represented by the general formula [3d] in the presence of a base.

[0594] Examples of the base used in the 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, and triethylamine is more preferred.

[0595] The amount of the base used in the reaction may be 1 to 20 times the mole, preferably 1 to 5 times the mole, of the compound represented by the general formula [2e].

[0596] The solvent used in the reaction is not particularly limited as long as it does not affect the reaction. For example, halogenated hydrocarbons, ethers, esters, amides and nitriles can be enumerated, and these solvents can be used in combination. Preferred solvents include halogenated hydrocarbons, amides and nitriles, and more preferably dichloromethane.

[0597] The amount of the compound represented by the general formula [3d] used in the reaction is not particularly limited, but may be 0.9 to 10 times the mole, preferably 1.0 to 5.0 times the mole, of the compound represented by the general formula [2e].

[0598] The amount of the solvent used is not particularly limited, and may be 1 to 500 times (v / w) the amount of the compound represented by the general formula [2e].

[0599] The reaction can 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.

[0600] (C-2) condensation

[0601] The compound represented by the general formula [3e] can be produced by reacting 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].

[0602] (C-3) Deprotection

[0603] The compound represented by the general formula [3f] or a salt thereof can be prepared by reacting the compound represented by the general formula [3e] with a suitable 5 [Production Method 1] (1-a), (1-b) or (1-c) of the same type can be used to produce the same reaction.

[0604] [Manufacturing method D]

[0605] [Chemical Formula 13]

[0606]

[0607] “Where, L 1b 、R 4a 、R 5 、X 1a 、Y 1a and Z 2 has the same meaning as above.”

[0608] The compound represented by the general formula [3i] or a salt thereof can be produced by the following method.

[0609] (D-1) Condensation

[0610] The compound represented by the general formula [3h] can be produced by reacting a compound represented by the general formula [3g] with a compound represented by the general formula [2v] or a salt thereof in the same manner as in [Production Method 7].

[0611] (D-2) Deprotection

[0612] The compound represented by the general formula [3i] or a salt thereof can be prepared by reacting the compound represented by the general formula [3h] with a suitable 5 [Production Method 1] The protective group of is prepared by reacting in the same manner as (1-a), (1-b) or (1-c).

[0613] [Manufacturing Method E]

[0614] [Chemical Formula 14]

[0615]

[0616] “Where, R 6 Represents a carboxyl protecting group; R 1a 、R 2a 、X 1b 、X 1c 、Y 1a and Z 1 has the same meaning as above.”

[0617] The compound represented by the general formula

[31] can be produced by the following method.

[0618] (E-1) Reductive amination

[0619] The compound represented by the general formula [3k] can be produced by reacting a compound represented by the general formula [3j] or a salt thereof with a compound represented by the general formula [2i] in the same manner as in [Production Method 4] (4-3).

[0620] (E-2) Deprotection

[0621] The compound represented by the general formula [3l] can be prepared by reacting the compound represented by the general formula [3k] with a suitable 6 [Production Method 1] The protective group of is prepared by reacting in the same manner as (3-a), (3-b) or (3-c).

[0622] [Manufacturing Method F]

[0623] [Chemical Formula 15]

[0624]

[0625] “Where, L 1a 、R 1a 、R 2a 、R 6 、X 1a 、Y 1a and Z 1 has the same meaning as above.”

[0626] The compound represented by the general formula [3n] can be produced by the following method.

[0627] (F-1) Alkylation

[0628] The compound represented by the general formula [3m] can be produced by reacting a compound represented by the general formula [3j] or a salt thereof with a compound represented by the general formula [2k] in the same manner as in [Production Method 5].

[0629] (F-2) Deprotection

[0630] The compound represented by the general formula [3n] can be prepared by reacting the compound represented by the general formula [3m] with a suitable 6 [Production Method 1] The protective group of is prepared by reacting in the same manner as (3-a), (3-b) or (3-c).

[0631] [Manufacturing method G]

[0632] [Chemical Formula 16]

[0633]

[0634] “Where, R 1a 、R 2a 、R 5 、X 1a 、Y 1a and Z 1 has the same meaning as above.”

[0635] The compound represented by the general formula [3o] can be produced by the following method.

[0636] (G-1) condensation

[0637] The compound represented by the general formula [3o] can be produced by reacting a compound represented by the general formula [3n] with a compound represented by the general formula [3a] in the same manner as in [Production Method 3].

[0638] (G-2) Deprotection

[0639] The compound represented by the general formula [3p] or a salt thereof can be prepared by reacting the compound represented by the general formula [3o] with a suitable 5 [Production Method 1] The protective group of is prepared by reacting in the same manner as (1-a), (1-b) or (1-c).

[0640] [Manufacturing Method H] Coupling

[0641] [Chemical Formula 17]

[0642]

[0643] “Where, L 1cIndicates the detached group; M 1 represents a substituent described below; Y 1b represents an aryl group which may be substituted, a monocyclic heterocyclic group which may be substituted, or a bicyclic heterocyclic group which may be substituted; Y 1c represents an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted phenyl group or an optionally substituted monocyclic heterocyclic group; R 1a 、R 2a 、R 3 、R 4a 、X 1a 、X 2 、Y 2a , Z 1 and Z 2 has the same meaning as above.”

[0644] M 1 ZnR 7a MgR 7b 、Sn(R 7c )3 or B(OR 7d )(OR 7e )“Where R 7a and R 7b Each independently represents a chlorine atom, a bromine atom or an iodine atom, R 7c Indicates C 1-4 Alkyl or phenyl, R 7d The same or different hydrogen atoms, C 1-4 Alkyl or phenyl, R 7d and R 7e Together they can form a ring containing oxygen and boron atoms."

[0645] As L 1c The leaving group represented is not particularly limited, and examples thereof include a halogen atom and a triflate such as phenyl triflate, and a bromine atom is preferred.

[0646] The compound represented by the general formula [3s] can be produced by reacting a compound represented by the general formula [3q] with a compound represented by the general formula [3r] in the presence of a palladium catalyst, in the presence or absence of a ligand, and in the presence or absence of a base.

[0647] The amount of the compound represented by the general formula [3r] used in the reaction is not particularly limited, but may be 0.9 to 20 times the mole, preferably 1.0 to 5.0 times the mole, of the compound represented by the general formula [3q].

[0648] Examples of the palladium catalyst used in this reaction include palladium salts such as palladium chloride and palladium acetate, palladium complexes such as dichloro(bistriphenylphosphine)palladium, tetrakistriphenylphosphine palladium, and palladium methanesulfonate (2-dicyclohexylphosphine-2',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.

[0649] The amount of the palladium catalyst used in the reaction is 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].

[0650] Examples of the ligand used as needed in the reaction include tertiary phosphine groups such as triphenylphosphine, tricyclohexylphosphine, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, and (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl. Preferred ligands include triphenylphosphine and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0651] The amount of the ligand used as needed in this reaction is 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].

[0652] Examples of the base used as necessary in the 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 potassium phosphate.

[0653] The amount of the base used in this reaction, if necessary, is 0.1 to 20 times the mole, preferably 1.0 to 5.0 times the mole, of the compound represented by the general formula [3q].

[0654] The solvent used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include aromatic hydrocarbons, ethers, amides, alcohols, and water, and these solvents may be mixed. Preferred solvents include mixed solvents of aromatic hydrocarbons or ethers and water, and more preferably, mixed solvents of 1,4-dioxane and water.

[0655] The amount of the solvent used in the reaction is not particularly limited, and may be 1 to 500 times (v / w) the amount of the compound represented by the general formula [3q].

[0656] The reaction can 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.

[0657] Example

[0658] Next, the present invention will be described with reference to Examples and Reference Examples, but the present invention is not limited thereto.

[0659] Unless otherwise specified, Selekt manufactured by Biotage Japan KK was used for silica gel column chromatography, and Biotage Sfaer D or Biotage Sfaer HC D manufactured by Biotage Japan KK was used as the carrier.

[0660] As the NH silica gel column, CHROMATOREX NH-DM1020 manufactured by FUJI SILYSIA CHEMICAL LTD. was used.

[0661] For medium-pressure reverse-phase silica gel column chromatography, IsoleraSV manufactured by Biotage Japan KK was used, and Sfaer C18 D manufactured by Biotage Japan KK was used as the carrier.

[0662] The mixing ratio in the eluent is a volume ratio.

[0663] NMR spectra were measured using AVANCE III HD400 (Bruker Corporation).

[0664] NMR spectra represent proton NMR, the internal standards are as follows, and δ values ​​are expressed in ppm.

[0665] Deuterated chloroform (CDCl3): Tetramethylsilane (0.00ppm)

[0666] Deuterated methanol (CD3OD): methanol (CH3OH) (3.30ppm)

[0667] Deuterated dimethyl sulfoxide (CD3SOCD3): Tetramethylsilane (0.00ppm)

[0668] Heavy water (D2O): water (4.65ppm)

[0669] In an NMR spectrum, for example, [1.45]1.46 (3H, s) means that peaks derived from each secondary isomer of a secondary isomer mixture or peaks derived from each isomer of a geometric isomer mixture are observed as single peaks at 1.45 and 1.46, and the total number of protons is 3.

[0670] Unless otherwise specified, NMR spectra were measured using CDCl 3 in Reference Examples and using D 2 O in Examples.

[0671] The MS spectrum was measured by electrospray ionization (ESI) using LCMS-2020 (Shimadzu Corporation).

[0672] In each reference example and example, each abbreviation has the following meaning.

[0673] Ac: acetyl, Bn: benzyl, Boc: tert-butoxycarbonyl, Cbz: benzyloxycarbonyl, COMU: (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinium hexafluorophosphate, DIPEA: N,N-diisopropylethylamine, DMAC: N,N-dimethylacetamide, DMAP: 4-(dimethylamino)pyridine, DMF: N,N-dimethylformamide, DMSO: dimethyl sulfoxide, DPPA: diphenylphosphoryl azide, ESI: electrospray ionization, Fmoc: 9-fluorenylmethoxycarbonyl, HOAt: 1-hydroxy-7-nitropropane -azabenzotriazole, HOBt: 1-hydroxybenzotriazole, HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, LAH: lithium aluminum hydride, LDA: lithium diisopropylamide, MOM: methoxymethyl, Ms: methanesulfonyl, MTBE: tert-butyl methyl ether, NBS: N-bromosuccinimide, PMB: 4-methoxybenzyl, TBS: tert-butyldimethylsilyl, TFA: trifluoroacetic acid, THF: tetrahydrofuran, WSC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, XPhos Pd G4: (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl) palladium(II) mesylate, s: singlet, brs: broad singlet, d: doublet, dd: double doublet, ddd: double double doublet, dt: double triplet, m: multiplet, t: triplet, Alloc: allyloxycarbonyl, IPE: diisopropyl ether, TMS: trimethylsilyl, HPLC: high performance liquid chromatography, TEAA: triethylamine acetate

[0674] Reference Example 1

[0675] [Chemical Formula 18]

[0676]

[0677] To tert-butyl (E)-4-phenylvinylpiperidine-1-carboxylate (400 mg) were added dichloromethane (7 mL) and a 4 mol / L hydrochloric acid solution in dioxane (1.4 mL), followed by stirring at room temperature for 18 hours and 30 minutes. The solvent was distilled off under reduced pressure, followed by drying under reduced pressure to obtain (E)-4-phenylvinylpiperidine hydrochloride (305 mg) as a pale yellow solid.

[0678] Reference Example 2

[0679] [Chemical Formula 19]

[0680]

[0681] The hydrochloride of (Z)-4-phenylvinylpiperidine was obtained by reacting in the same manner as in Reference Example 1 except that tert-butyl (E)-4-phenylvinylpiperidine-1-carboxylate was used instead of tert-butyl (Z)-4-phenylvinylpiperidine-1-carboxylate.

[0682] Reference Example 3

[0683] [Chemical Formula 20]

[0684]

[0685] (1) DMF (8.4 mL) was added to tert-butyl 4-(hydroxymethyl)-4-phenylethylpiperidine-1-carboxylate (400 mg), and the mixture was stirred under ice-cooling. 60% oily sodium hydride (101 mg) was added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 30 minutes. Iodomethane (0.21 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours and 30 minutes. Ice and ethyl acetate (20 mL) were added to the reaction mixture, and the organic layer was separated. The obtained organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 0:100→15:85] to obtain the target compound (322 mg) as a colorless oil.

[0686] (2) To the compound obtained in (1) (320 mg) were added dichloromethane (4.8 mL) and a 4 mol / L hydrochloric acid dioxane solution (0.96 mL), and the mixture was stirred at room temperature for 20 hours and 30 minutes. The solvent was distilled off under reduced pressure, and the mixture was dried under reduced pressure to obtain 4-(methoxymethyl)-4-phenethylpiperidine hydrochloride (258 mg) as a white solid.

[0687] Reference Example 4

[0688] [Chemical Formula 21]

[0689]

[0690] The hydrochloride of 4-((benzyloxy)methyl)-4-phenethylpiperidine was obtained by reacting in the same manner as in Reference Example 3 except that benzyl bromide was used in place of iodomethane in Reference Example 3.

[0691] Reference Example 5

[0692] [Chemical Formula 22]

[0693]

[0694] (1) To 1-(tert-butoxycarbonyl)-4-phenethylpiperidine-4-carboxylic acid (700 mg) were added ammonium chloride (225 mg), WSC hydrochloride (443 mg), HOBt (312 mg), dichloromethane (7 mL), and DIPEA (1.2 mL) in this order, 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. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 10:90 → 65:35] to obtain the target compound (530 mg) as a white solid.

[0695] (2) To the compound obtained in (1) (530 mg) were added dichloromethane (8 mL) and a 4 mol / L hydrochloric acid solution in dioxane (1.6 mL), and the mixture was stirred at room temperature for 17 hours. The solvent was distilled off under reduced pressure, and the mixture was dried under reduced pressure to obtain 4-phenethylpiperidine-4-carboxamide hydrochloride (399 mg) as a white solid.

[0696] Reference Example 6

[0697] [Chemical Formula 23]

[0698]

[0699] (1) Dichloromethane (7.6 mL) and triethylamine (0.4 mL) were added to tert-butyl 4-(aminomethyl)-4-phenethylpiperidine-1-carboxylate (760 mg), and the mixture was stirred under ice-cooling. Benzyl chloroformate (0.39 mL) was added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction mixture, and 1 mol / L hydrochloric acid was added to adjust the pH to 2, 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. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane=0:100→15:85] to obtain the target compound (525 mg) as a colorless oil.

[0700] (2) To the compound obtained in (1) (520 mg) were added dichloromethane (5.7 mL) and a 4 mol / L hydrochloric acid dioxane solution (1.1 mL), and the mixture was stirred at room temperature for 24 hours and 30 minutes. After the solvent was distilled off under reduced pressure, the mixture was dried under reduced pressure to obtain benzyl ((4-phenethylpiperidin-4-yl)methyl)carbamate hydrochloride (411 mg) as a white solid.

[0701] Reference Example 7

[0702] [Chemical Formula 24]

[0703]

[0704] The 4 mol / L hydrochloric acid in 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 a TFA salt of ((4-phenethylpiperidin-4-yl)methyl)carbamate.

[0705] Reference Example 8

[0706] [Chemical Formula 25]

[0707]

[0708] (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 the mixture was stirred at 80°C for 30 minutes. 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, and water (30 mL) and ethyl acetate (60 mL) were added, and the organic layer was separated. The obtained organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 0:100→20:80] to obtain the target compound (2.63 g) as a light yellow oil.

[0709] (2) To the compound obtained in (1) (2.60 g) were added dichloromethane (30 mL) and a 4 mol / L hydrochloric acid dioxane solution (5.9 mL), and the mixture was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, and the mixture was dried under reduced pressure to obtain benzyl (4-phenethylpiperidin-4-yl)carbamate hydrochloride (2.96 g) as a light brown oil.

[0710] Reference Example 9

[0711] [Chemical Formula 26]

[0712]

[0713] (1) THF (4.6 mL), DIPEA (0.48 mL), acetic anhydride (0.13 mL) and DMAP (22 mg) were added to 1-benzyl-4-phenethylpiperidin-4-ol (271 mg), and the mixture was stirred at room temperature overnight. DMAP (112 mg) was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour and 30 minutes. 1,4-Dioxane (4.6 mL), DIPEA (1.6 mL) and acetic anhydride (0.43 mL) were added to the reaction mixture, and the mixture was stirred at 100°C for 7 hours. The reaction mixture was ice-cooled, and water (50 mL) and ethyl acetate (100 mL) were added to separate the organic layer. The obtained organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane=0:100→40:60] to obtain the target compound (300 mg) as a colorless oil.

[0714] (2) To the compound obtained in (1) (300 mg) were added ethanol (8.9 mL) and 10% palladium carbon (90 mg) in this order, and the mixture was stirred at room temperature for 17 hours under a hydrogen atmosphere. Impurities were removed by filtration through celite, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol = 100:0 → 90:10] to obtain 4-phenethylpiperidin-4-yl acetate (113 mg) as a light yellow oil.

[0715] Reference Example 10

[0716] [Chemical Formula 27]

[0717]

[0718] (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 stirred at room temperature 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 sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 0:100→50:50] to obtain the target compound (133 mg) as a colorless oil.

[0719] (2) Dichloromethane (3.3 mL) and DIPEA (0.14 mL) were added to the compound (130 mg) obtained in (1), and the mixture was stirred under ice-cooling. Benzyl chloroformate (0.11 mL) was added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution (50 mL), 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 with water and saturated aqueous sodium chloride solution in sequence, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate: hexane = 0:100 → 20:80] to obtain the target compound (143 mg) as a colorless oil.

[0720] (3) To the compound obtained in (2) (130 mg) were added dichloromethane (1.2 mL) and TFA (28 μL), and the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off under reduced pressure, the mixture was dried under reduced pressure to obtain the TFA salt of benzylbenzyl (2-phenyl-1-(piperidin-4-yl)ethyl)carbamate (140 mg) as a colorless oil.

[0721] Reference Example 11

[0722] [Chemical Formula 28]

[0723]

[0724] (1) DMF (4 mL), potassium carbonate (735 mg) and tert-butyl 2-bromo-2-methylpropionate (0.34 mL) were added to 1-phenethylpiperidine hydrochloride (200 mg), 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 obtained organic layer was washed with water and a saturated sodium chloride aqueous solution in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol = 100:0 → 95:5] to obtain the target compound (183 mg) as a light yellow oil.

[0725] (2) Dichloromethane (3 mL) was added to the compound (180 mg) obtained in (1), and the mixture was stirred under ice-cooling. TFA (0.41 mL) was added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 22 hours and 30 minutes. TFA (0.20 mL) was added to the reaction mixture, and the mixture was stirred for 3 hours and 30 minutes. The solvent was distilled off under reduced pressure, and a 1 mol / L hydrochloric acid diethyl ether solution (3 mL) was added to the residue, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and chloroform was added to the residue. The solid matter was filtered and dried under reduced pressure to obtain the hydrochloride salt (45 mg) of 2-methyl-2-(4-phenylethylpiperazin-1-yl)propionic acid as a white solid.

[0726] Reference Example 12

[0727] [Chemical Formula 29]

[0728]

[0729] To 2-hydroxy-6-methoxybenzaldehyde (200 mg) were added DMF (2.6 mL), potassium carbonate (218 mg), and tert-butyl (2-bromoethyl) carbamate (353 mg), and the mixture was stirred at 80°C for 1 hour and 30 minutes. Ethyl acetate (10 mL) and water (5 mL) were added to the reaction mixture, and the organic layer was separated. The resulting organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent: ethyl acetate:hexane = 0:100 → 35:65] to obtain tert-butyl (2-(2-formyl-3-methoxyphenoxy)ethyl) carbamate (237 mg) as a yellow oil.

[0730] Reference Example 13

[0731] [Chemical formula 30]

[0732]

[0733] (1) DMF (47 mL), potassium carbonate (2.93 g) and iodoethane (1.7 mL) were added to 3-fluoro-4-(methoxymethoxy)phenol (2.37 g), and the mixture was stirred at room temperature for 2 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 with 0.1 mol / L hydrochloric acid and saturated sodium chloride aqueous solution in sequence, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate: hexane = 0:100 → 8:92] to obtain the target compound (1.76 g) as a light yellow oil.

[0734] (2) THF (18 mL) was added to the compound (1.76 g) obtained in (1), and the mixture was stirred at -70°C. 2 mol / L LDA solution (6.6 mL) was added to the reaction mixture at the same temperature, and the mixture was stirred at -70°C for 1 hour. DMF (1.3 mL) was added to the reaction mixture at the same temperature, and the mixture was stirred at -70°C for 1 hour. Saturated aqueous ammonium chloride solution (20 mL) was added to the reaction mixture, and the mixture was heated to room temperature. Ethyl acetate (50 mL) was added to the reaction mixture, and the organic layer was separated. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 0:100→13:87] to obtain 6-ethoxy-2-fluoro-3-(methoxymethoxy)benzaldehyde (1.22 g) as a yellow oil.

[0735] (3) Methanol (1.5 mL) was added to the compound (200 mg) obtained in (2), and the mixture was stirred under ice-cooling. At the same temperature, 6 mol / L hydrochloric acid (0.73 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 5 hours. The solvent was concentrated under reduced pressure, ethyl acetate (2 mL) was added to the residue, and the organic layer was separated. The obtained organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution in sequence, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 6-ethoxy-2-fluoro-3-hydroxybenzaldehyde (147 mg) as a yellow oil.

[0736] Reference Example 14

[0737] [Chemical Formula 31]

[0738]

[0739] The ethyl iodide in Reference Example 13 was replaced with methyl iodide, and the reaction was carried out in the same manner as in Reference Example 13 (1) and (2) to obtain 2-fluoro-6-methoxy-3-(methoxymethoxy)benzaldehyde as a pale yellow oil.

[0740] Reference Example 15

[0741] [Chemical Formula 32]

[0742]

[0743] (1) Dichloromethane (13 mL), benzylpiperazine-1-carboxylate (290 mg) and sodium triacetoxyborohydride (418 mg) were added to 6-ethoxy-2-fluoro-3-(methoxymethoxy)benzaldehyde (300 mg), and 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), a 10% aqueous sodium carbonate solution was added to the reaction mixture 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. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 0:100→30:70] to obtain the target compound (557 mg) as a light yellow oil.

[0744] (2) Methanol (5.6 mL) and 10% palladium on carbon (111 mg) were added to the compound obtained in (1) (557 mg) in this order, and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. Impurities were removed by filtration through celite, and the solvent was distilled off under reduced pressure. The mixture was then dried under reduced pressure to obtain 1-(6-ethoxy-2-fluoro-3-(methoxymethoxy)benzyl)piperazine (387 mg) as a yellow oil.

[0745] Reference Example 16

[0746] [Chemical Formula 33]

[0747]

[0748] 6-Ethoxy-2-fluoro-3-(methoxymethoxy)benzaldehyde in Reference Example 15 was replaced with 2-fluoro-6-methoxy-3-(methoxymethoxy)benzaldehyde, and the reaction was carried out in the same manner as in Reference Example 15 to obtain 1-(2-fluoro-6-methoxy-3-(methoxymethoxy)benzyl)piperazine as a colorless oil.

[0749] Reference Example 17

[0750] [Chemical Formula 34]

[0751]

[0752] (1) After adding THF (0.56 mL) to tert-butylpiperazine-1-carboxylate (186 mg), 1-(2-fluoro-6-methoxyphenyl)ethane-1-one (252 mg) and tetraisopropyl titanate (0.89 mL) were added under a nitrogen atmosphere and stirred at 75°C for 18 hours. After cooling the reaction mixture to -48°C, sodium triacetoxyborohydride (636 mg) was added and the temperature was raised to room temperature over 2 hours. After cooling the reaction mixture to 0°C, a 5 mol / L sodium hydroxide aqueous solution was added and the insoluble matter was filtered off. Ethyl acetate was added to the filtrate and the organic layer was separated. The obtained organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol = 100:0 → 90:10] to obtain the target compound (279 mg) as a pale yellow solid.

[0753] (2) To the compound obtained in (1) (273 mg) were added dichloromethane (1.5 mL) and a 4 mol / L hydrochloric acid dioxane solution (3.0 mL), and the mixture was stirred at room temperature for 1 hour and 30 minutes. The solvent was distilled off under reduced pressure, MTBE was added to the residue, and the solid matter was filtered out. The obtained solid matter was dried under reduced pressure to obtain 1-(1-(2-fluoro-6-methoxyphenyl)ethyl)piperazine hydrochloride (245 mg) as a light yellow solid.

[0754] In the same manner as in Reference Example 17, the compounds shown in Table 1 were obtained.

[0755] [Table 1]

[0756]

[0757] Reference Example 20

[0758] [Chemical Formula 35]

[0759]

[0760] (1) Dichloromethane (240 mL), tert-butylpiperazine-1-carboxylate (4.50 g) and sodium triacetoxyborohydride (7.68 g) were added to 2-ethoxy-6-fluorobenzaldehyde (2.70 g) and stirred at room temperature for 18 hours. After adding water (50 mL) to the reaction mixture, a 10% sodium carbonate aqueous 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. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 0:100→40:60] to obtain the target product (8.06 g) as a colorless oil.

[0761] (2) To the compound obtained in (1) (8.06 g) were added dichloromethane (120 mL) and a 4 mol / L hydrochloric acid dioxane solution (30 mL), and the mixture was stirred at room temperature for 20 hours and 30 minutes. The solvent was distilled off under reduced pressure, and ethyl acetate (200 mL) was added to the residue, and the mixture was stirred at room temperature for 30 minutes. The solid was filtered and dried under reduced pressure to obtain 1-(2-ethoxy-6-fluorobenzyl)piperazine hydrochloride (6.89 g) as a white solid.

[0762] In the same manner as in Reference Example 20, the compounds shown in Table 2 were obtained.

[0763] [Table 2]

[0764]

[0765] Reference Example 29

[0766] [Chemical Formula 36]

[0767]

[0768] (1) Dichloromethane (36 mL) and triethylamine (3.1 mL) were added to the hydrochloride of 1-(2-methoxybenzyl)piperazine (2.00 g), and the mixture was stirred under ice-cooling. A mixed solution 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. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane=20:80→100:0] to obtain 2-chloro-1-(4-(2-methoxybenzyl)piperazin-1-yl)ethan-1-one (1.94 g) as a light yellow oil.

[0769] (2) To the compound (1.94 g) obtained in (1) were added tert-butylpiperazine-1-carboxylate (1.28 g), DMF (27 mL), potassium carbonate (1.42 g) and sodium iodide (257 mg), and the mixture was stirred at 70°C for 2 hours. Ethyl acetate (60 mL) and water (30 mL) were added to the reaction mixture, and the organic layer was separated. The obtained organic layer was washed with water and a saturated sodium chloride aqueous solution in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol = 100:0 → 90:10] to obtain the target compound (3.12 g) as a light yellow solid.

[0770] (3) To the compound obtained in (2) (2.97 g) were added dichloromethane (30 mL) and a 4 mol / L hydrochloric acid dioxane solution (17 mL), and the mixture was stirred at room temperature for 24 hours. After the solvent was distilled off under reduced pressure, the mixture was dried under reduced pressure to obtain the hydrochloride salt of 1-(4-(2-methoxybenzyl)piperazin-1-yl)-2-(piperazin-1-yl)ethan-1-one (2.87 g) as a pale yellow solid.

[0771] Reference Example 30

[0772] [Chemical Formula 37]

[0773]

[0774] 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 to obtain 2-chloro-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one in the form of a pale yellow oil.

[0775] Reference Example 31

[0776] [Chemical Formula 38]

[0777]

[0778] The tert-butylpiperazine-1-carboxylate in Reference Example 29 was replaced with tert-butylpiperidin-4-ylcarbamate, and the reaction was carried out in the same manner as in Reference Example 29 to obtain 2-(4-aminopiperidin-1-yl)-1-(4-(2-methoxybenzyl)piperazin-1-yl)ethane-1-one as a yellow solid.

[0779] Reference Example 32

[0780] [Chemical Formula 39]

[0781]

[0782] (1) 1-Phenethylpiperazine hydrochloride (8.72 g), DMF (132 mL), potassium carbonate (16.0 g) and sodium iodide (1.24 g) were added to tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate (8.70 g), 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 with water and a saturated sodium chloride aqueous solution in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol = 100:0 → 95:5] to obtain the target compound (13.8 g) as a light yellow solid.

[0783] (2) To the compound obtained in (1) (13.8 g) were added dichloromethane (166 mL) and a 4 mol / L hydrochloric acid dioxane solution (58 mL), and the mixture was stirred at room temperature for 24 hours and 30 minutes. After the solvent was distilled off under reduced pressure, the mixture was dried under reduced pressure to obtain 2-(4-phenethylpiperazin-1-yl)-1-(piperazin-1-yl)ethan-1-one hydrochloride (10.3 g) as a white solid.

[0784] Reference Example 33

[0785] [Chemical Formula 40]

[0786]

[0787] (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. Dess-Martin 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. Dess-Martin periodinane (2.95 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. 10% aqueous sodium thiosulfate solution (170 mL) and saturated aqueous sodium bicarbonate solution (100 mL) were added to the reaction mixture, and the organic layer was separated. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 0:100→20:80] to obtain the target compound (2.57 g) as a colorless oil.

[0788] (2) To the compound obtained in (1) (2.54 g) were added dichloromethane (42 mL), methyl (R)-2-(((benzyloxy)carbonyl)amino)-2-(piperidin-4-yl)acetate hydrochloride (2.90 g), triethylamine (1.2 mL) and sodium triacetoxyborohydride (2.69 g), and the mixture was stirred at room temperature for 23 hours. After adding water (40 mL) to the reaction mixture, a 10% sodium carbonate aqueous 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. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 0:100→35:65] to obtain the target product (3.92 g) as a colorless oil.

[0789] (3) THF (16 mL), methanol (7.8 mL), water (16 mL) and lithium hydroxide monohydrate (1.58 g) were added to the compound obtained in (2) (3.92 g), and the mixture was stirred at room temperature for 2 hours. The solvent was concentrated under reduced pressure, and concentrated hydrochloric acid was added to the residue to adjust the pH to 6.5. Ethyl acetate (50 mL) was added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted four times with ethyl acetate (50 mL), and the previously separated organic layers were combined and dried over anhydrous sodium sulfate. After concentrating the solvent under reduced pressure, the solid matter was filtered to obtain (R)-2-(((benzyloxy)carbonyl)amino)-2-(1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)acetic acid (3.92 g) as a white solid.

[0790] (4) To the compound (2.40 g) obtained in (3) were added tert-butylpiperazine-1-carboxylate (0.97 g), WSC hydrochloride (1.09 g), HOBt (768 mg), dichloromethane (47 mL) and DIPEA (0.99 mL) in this order, and the mixture was stirred at room temperature overnight. To the reaction mixture were added tert-butylpiperazine-1-carboxylate (264 mg), WSC hydrochloride (272 mg), HOBt (192 mg) and DIPEA (0.25 mL), and the mixture was stirred at room temperature for 3 hours. Water (40 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. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 40:60 → 80:20] to obtain the target compound (3.13 g) as a colorless oil.

[0791] (5) Dichloromethane (21 mL) and a 4 mol / L hydrochloric acid dioxane solution (5.2 mL) were added to the compound obtained in (4) (2.80 g), and the mixture was stirred at room temperature for 3 hours. After the solvent was distilled off under reduced pressure, the mixture was dried under reduced pressure to obtain benzyl (R)-(1-(1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-2-oxo-2-(piperazin-1-yl)ethyl)carbamate hydrochloride (2.73 g) as a white solid.

[0792] Reference Example 34

[0793] [Chemical Formula 41]

[0794]

[0795] To the hydrochloride salt (60 mg) of benzyl (R)-(1-(1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-2-oxo-2-(piperazin-1-yl)ethyl)carbamate were added dichloromethane (0.93 mL), triethylamine (45 μL), and 2-(methylthio)benzaldehyde (18 mg), followed by stirring at room temperature for 10 minutes. Sodium triacetoxyborohydride (59 mg) was added to the reaction mixture, followed by stirring at room temperature for 15 hours and 20 minutes. After adding water (2 mL), a saturated aqueous sodium bicarbonate solution was added to adjust the pH to 8, and the organic layer was separated. The resulting organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol=100:0→90:10] to obtain benzyl (R)-(1-(1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-2-(4-(2-(methylthio)benzyl)piperazin-1-yl)-2-oxoethyl)carbamate (70 mg) as a colorless oil.

[0796] In the same manner as in Reference Example 34, the compounds shown in Table 3 were obtained.

[0797] [Table 3]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804] Reference Example 72

[0805] [Chemical Formula 42]

[0806]

[0807] To the hydrochloride salt of 1-(6-ethoxy-2,3-difluorobenzyl)piperazine (59 mg) were added (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 μL) in this order, followed by stirring at room temperature for 22 hours. Water (2 mL) was added to the reaction mixture, and the organic layer was separated. The resulting organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol=100:0→93:7] to obtain benzyl (R)-(1-(1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-2-(4-(6-ethoxy-2,3-difluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (100 mg) as a colorless oil.

[0808] Reference Example 73

[0809] [Chemical Formula 43]

[0810]

[0811] (1) DMAC (58 mL), (2-bromoethyl)benzene (4.69 g) and potassium carbonate (7.00 g) were added to methyl (R)-2-(((benzyloxy)carbonyl)amino)-2-(piperidin-4-yl)acetate hydrochloride (5.8 g), and stirred at 85°C for 23 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and ethyl acetate (150 mL) and ethanol (150 mL) were added. Then, concentrated hydrochloric acid was added to adjust the pH to 8.8, and the organic layer was separated. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 10:90 → 70:30] to obtain the target product as a light brown oil.

[0812] (2) THF (14 mL), methanol (7 mL), water (28 mL) and lithium hydroxide monohydrate (3.55 g) were added to the compound obtained in (1), and the mixture was stirred at room temperature for 4 hours and 40 minutes. The solvent was concentrated under reduced pressure, MTBE (30 mL) was added to the residue, and the aqueous layer was separated. Concentrated hydrochloric acid was added to the aqueous layer to adjust the pH to 5.6. The solid was filtered, washed with water, and then dried to obtain (R)-2-(((benzyloxy)carbonyl)amino)-2-(1-phenethylpiperidin-4-yl)acetic acid (4.44 g) as a white solid.

[0813] (3) To the compound obtained in (2) (1.30 g) were added tert-butylpiperazine-1-carboxylate (672 mg), WSC hydrochloride (754 mg), HOBt (532 mg), dichloromethane (33 mL), and DIPEA (0.69 mL) in this order, and the mixture was stirred at room temperature overnight. Water (30 mL) was added to the reaction mixture, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol = 100:0 → 85:15] to obtain the target compound (1.85 g) as a colorless oil.

[0814] (4) To the compound obtained in (3) (1.85 g) were added dichloromethane (16 mL) and a 4 mol / L hydrochloric acid solution in dioxane (4.1 mL), and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the mixture was dried under reduced pressure to obtain benzyl (R)-(2-oxo-1-(1-phenethylpiperidin-4-yl)-2-(piperazin-1-yl)ethyl)carbamate hydrochloride (1.76 g) as a white solid.

[0815] Reference Example 74

[0816] [Chemical Formula 44]

[0817]

[0818] To benzyl (R)-(2-oxo-1-(1-phenethylpiperidin-4-yl)-2-(piperazin-1-yl)ethyl)carbamate hydrochloride (150 mg) were added dichloromethane (2.8 mL), 2-ethoxy-6-fluorobenzaldehyde (52 mg), triethylamine (97 μL), and sodium triacetoxyborohydride (177 mg), followed by stirring at room temperature for 21 hours and 30 minutes. Water (2 mL) was added to the reaction mixture, followed by a 10% aqueous sodium carbonate solution to adjust the pH to 8, and the organic layer was separated. The resulting organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol=100:0→90:10] to obtain benzyl (R)-(2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxo-1-(1-phenethylpiperidin-4-yl)ethyl)carbamate (112 mg) as a colorless oil.

[0819] The compounds shown in Table 4 were obtained in the same manner as in Reference Example 74.

[0820] [Table 4]

[0821]

[0822] Reference Example 78

[0823] [Chemical Formula 45]

[0824]

[0825] (1) 60% oily sodium hydride (1.02 g) was added to THF (12 mL), and the mixture was stirred under a nitrogen atmosphere and ice-cooling. A mixed solution of diethylcyanomethylphosphonic acid (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, and diethyl ether (50 mL) and water were added. 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 sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane=0:100→15:85] to obtain the target compound (3.10 g) as a pale yellow oil.

[0826] (2) Chloroform (116 mL), NBS (4.13 g) and benzoyl peroxide (500 mg) were added to the compound (2.90 g) obtained in (1), and the mixture was stirred under reflux for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, water (100 mL) was added, and the organic layer was separated. The obtained organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, dichloromethane (10 mL) was added to the residue, and the solid matter was filtered out to obtain (E)-3-(2-bromomethyl)-3-ethoxyphenyl)acrylonitrile (705 mg) as a white solid. After distilling off the filtrate under reduced pressure, IPE (10 mL) was added, and the solid matter was filtered out to obtain (E)-3-(2-bromomethyl)-3-ethoxyphenyl)acrylonitrile (1.74 g) as a white solid.

[0827] Reference Example 79

[0828] [Chemical Formula 46]

[0829]

[0830] (1) To (E)-3-(2-bromomethyl)-3-ethoxyphenyl)acrylonitrile (2.44 g) were added tert-butylpiperazine-1-carboxylate (1.88 g), potassium carbonate (6.35 g), and acetone (203 mL), and the mixture was stirred under reflux for 30 minutes under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, the solid matter was filtered out, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 15:85 → 20:80] to obtain tert-butyl (E)-4-(2-(2-cyanovinyl)-6-ethoxybenzyl)piperazine-1-carboxylate (3.57 g) as a colorless oil.

[0831] (2) DMF (12 mL), ammonium chloride (1.30 g) and sodium azide (1.58 g) were added to the compound obtained in (1) (600 mg), and the mixture was stirred at 150°C for 2 hours. The reaction mixture was cooled to room temperature, and 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, and water (10 mL) and ethyl acetate (10 mL) were added. 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 were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol=100:0→91:9] to obtain tert-butyl (E)-4-(2-(2-(1H-tetrazol-5-yl)vinyl)-6-ethoxybenzyl)piperazine-1-carboxylate (610 mg) as a light brown solid.

[0832] Reference Example 80

[0833] [Chemical Formula 47]

[0834]

[0835] The (E)-3-(2-bromomethyl)-3-ethoxyphenyl)acrylonitrile in Reference Example 79 was replaced with (E)-3-(2-bromomethyl)phenyl)acrylonitrile, and the reaction was carried out in the same manner as in Reference Example 79 to obtain tert-butyl (E)-4-(2-(2-(1H-tetrazol-5-yl)vinyl)benzyl)piperazine-1-carboxylate.

[0836] Reference Example 81

[0837] [Chemical Formula 48]

[0838]

[0839] (1) 1,4-Dioxane (4 mL) and a 4 mol / L hydrochloric acid solution in dioxane (4.4 mL) were added to tert-butyl (E)-4-(2-(2-(1H-tetrazol-5-yl)vinyl)-6-ethoxybenzyl)piperazine-1-carboxylate (610 mg), and the mixture was stirred at room temperature for 30 minutes. Dichloromethane (4 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The solid was collected by filtration and dried under reduced pressure to obtain the target compound (366 mg) as a light brown solid.

[0840] (2) To the compound obtained in (1) (117 mg) were added (R)-2-(((benzyloxy)carbonyl)amino)-2-(1-phenethylpiperidin-4-yl)acetic acid (100 mg), HATU (196 mg) and DMF (2 mL), and the mixture was stirred at room temperature for 10 minutes. DIPEA (0.22 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour and 30 minutes. After adding water (5 mL) and ethyl acetate (5 mL), 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 (15 mL), and the organic layers separated were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol=100:0→100:25] to obtain benzyl (R,E)-(2-(4-(2-(2-(1H-tetrazol-5-yl)vinyl)-6-ethoxybenzyl)piperazin-1-yl)-2-oxo-1-(1-phenethylpiperidin-4-yl)ethyl)carbamate (112 mg) as a brown solid.

[0841] The compounds shown in Table 5 were obtained in the same manner as in Reference Example 81.

[0842] [Table 5]

[0843]

[0844] Reference Example 84

[0845] [Chemical Formula 49]

[0846]

[0847] To 1-(6-ethoxy-2-fluoro-3-(methoxymethoxy)benzyl)piperazine (250 mg) were added (R)-2-(((benzyloxy)carbonyl)amino)-2-(1-phenethylpiperidin-4-yl)acetic acid (333 mg), WSC hydrochloride (177 mg), HOBt (125 mg), dichloromethane (5 mL), and DIPEA (0.18 mL) in this order, followed by stirring 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. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol=100:0→92:8] to obtain 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) as a pale yellow oil.

[0848] The compounds shown in Table 6 were obtained in the same manner as in Reference Example 84.

[0849] [Table 6]

[0850]

[0851] Reference Example 91

[0852] [Chemical Formula 50]

[0853]

[0854] (1) To the hydrochloride of 1-(2-ethoxy-6-fluorobenzyl)piperazine (3.81 g) were added (R)-2-(((benzyloxy)carbonyl)amino)-2-(1-(tert-butoxycarbonyl)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) in this order, 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. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 0:100→80:20] to obtain the target compound (6.34 g) as a white solid.

[0855] (2) Dichloromethane (63 mL) and a 4 mol / L hydrochloric acid dioxane solution (13 mL) were added to the compound obtained in (1) (6.34 g), and the mixture was stirred at room temperature for 20 hours and 30 minutes. The solvent was distilled off under reduced pressure, and ethyl acetate (60 mL) was added to the residue, and the mixture was stirred at room temperature for 30 minutes. The solid matter was filtered and dried under reduced pressure to obtain benzyl (R)-(2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxo-1-(piperidin-4-yl)ethyl)carbamate hydrochloride (6.01 g) as a white solid.

[0856] Reference Example 92

[0857] [Chemical Formula 51]

[0858]

[0859] The hydrochloride of 1-(2-ethoxy-6-fluorobenzyl)piperazine in Reference Example 91 was replaced with the hydrochloride of 1-(2-methoxybenzyl)piperazine, and the reaction was carried out in the same manner as in Reference Example 91 to obtain the hydrochloride of benzyl (R)-(2-(4-(2-methoxybenzyl)piperazin-1-yl)-2-oxo-1-(piperidin-4-yl)ethyl)carbamate in the form of a white solid.

[0860] Reference Example 93

[0861] [Chemical Formula 52]

[0862]

[0863] (1) 2-Chlorophenylboronic acid (1.13 g), sodium carbonate (955 mg), 1,4-dioxane (20 mL) and water (3.6 mL) were added to ethyl 2-(2-bromo-5-chlorophenyl) acetate (1.00 g) and stirred. Dichloro(bistriphenylphosphine)palladium(II) (416 mg) was added to the reaction mixture under a 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. The obtained organic layer was washed with water and a saturated sodium chloride aqueous solution in sequence, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 0:100→8:92] to obtain the target compound (817 mg) as a colorless oil.

[0864] (2) THF (13 mL) was added to the compound (817 mg) obtained in (1), and the mixture was stirred under ice-cooling. LAH (150 mg) was added to the reaction mixture at the same temperature, and the mixture was stirred for 2 hours. Ice water and a saturated sodium potassium tartrate aqueous solution (15 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (20 mL) was added to the reaction mixture, and the organic layer was separated. The obtained organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate: hexane = 0:100→24:76] to obtain the target compound (576 mg) as a colorless oil.

[0865] (3) Dichloromethane (21 mL) was added to the compound (570 mg) obtained in (2), and the mixture was stirred under ice-cooling. Dess-Martin periodinane (1.81 g) was added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 2 hours. 10% aqueous sodium thiosulfate solution (25 mL) and saturated aqueous sodium bicarbonate solution (25 mL) were added to the reaction mixture, and the organic layer was separated. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 0:100→8:92] to obtain 2-(2',4-dichloro-[1,1'-biphenyl]-2-yl)acetaldehyde (475 mg) as a yellow oil.

[0866] The compounds shown in Table 7 were obtained in the same manner as in Reference Example 93.

[0867] [Table 7]

[0868]

[0869] Reference Example 96

[0870] [Chemical Formula 53]

[0871]

[0872] (1) Phenylboronic acid (329 mg), sodium carbonate (382 mg), 1,2-dimethoxyethane (10 mL) and water (1 mL) were added to ethyl 2-(2-bromo-6-chlorophenyl) acetate (500 mg) and stirred. Dichloro(bistriphenylphosphine)palladium(II) (126 mg) was added to the reaction mixture under a nitrogen atmosphere, and stirred at 120°C for 2 hours using a microwave synthesis apparatus (Initiator+ manufactured by Biotage, 0.5-2 mL vial, absorption level = Very High). Ethyl acetate and water were added to the reaction mixture, and the organic layer was separated. The obtained organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 0:100→10:90] to obtain the target compound (448 mg) as a colorless oil.

[0873] (2) The compound obtained in (1) (448 mg) was reacted in the same manner as in Reference Example 93 (2) to obtain the target compound (264 mg) as a white solid.

[0874] (3) The compound obtained in (2) (264 mg) was reacted in the same manner as in Reference Example 93 (3) to obtain 2-(3-chloro-[1,1'-biphenyl]-2-yl)acetaldehyde (103 mg) as a colorless oil.

[0875] The compounds shown in Table 8 were obtained in the same manner as in Reference Example 96.

[0876] [Table 8]

[0877]

[0878] Reference Example 100

[0879] [Chemical Formula 54]

[0880]

[0881] (1) Cyclopropylboronic acid (156 mg), palladium (II) acetate (20 mg), tricyclohexylphosphine (51 mg), tripotassium phosphate (1.34 g), toluene (7.2 mL) and water (0.36 mL) were added to ethyl 2-(2-bromo-5-chlorophenyl) acetate (500 mg) in this order, and 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. The obtained organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 0:100→9:91] to obtain the target compound (366 mg) as a yellow oil.

[0882] (2) The compound obtained in (1) (366 mg) was reacted in the same manner as in Reference Example 93 (2) to obtain the target compound (267 mg) as a yellow oil.

[0883] (3) The compound obtained in (2) (260 mg) was reacted in the same manner as in Reference Example 93 (3) to obtain 2-(5-chloro-2-cyclopropylphenyl)acetaldehyde (160 mg) as a colorless oil.

[0884] Reference Example 101

[0885] [Chemical Formula 55]

[0886]

[0887] To benzyl (R)-(2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxo-1-(piperidin-4-yl)ethyl)carbamate hydrochloride (250 mg) were added dichloromethane (2.5 mL), 2-(2',4-dichloro-[1,1'-biphenyl]-2-yl)acetaldehyde (136 mg), triethylamine (0.12 mL), and sodium triacetoxyborohydride (226 mg), and the mixture was stirred at room temperature for 20 hours. Water (5 mL) was added to the reaction mixture, followed by the addition of a 10% aqueous sodium carbonate solution to adjust the pH to 8. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol=100:0→95:5] to obtain benzyl (R)-(1-(1-(2-(2',4-dichloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (245 mg) as a colorless oil.

[0888] In the same manner as in Reference Example 101, the compounds shown in Table 9 were obtained.

[0889] [Table 9]

[0890]

[0891]

[0892]

[0893] Reference Example 118

[0894] [Chemical Formula 56]

[0895]

[0896] To benzyl (R)-(2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxo-1-(piperidin-4-yl)ethyl)carbamate hydrochloride (300 mg) were added DMF (3 mL), potassium carbonate (248 mg), and 2-(2-bromoethyl)-4-chloro-[1,1']-biphenyl (182 mg), followed by stirring at 70°C for 17 hours. Ethyl acetate and water were added to the reaction mixture, and the organic layer was separated. The resulting organic layer was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol=100:0→95:5] to obtain 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 (229 mg) as a yellow solid.

[0897] The compounds shown in Table 10 were obtained in the same manner as in Reference Example 118.

[0898] [Table 10]

[0899]

[0900]

[0901] Reference Example 129

[0902] [Chemical Formula 57]

[0903]

[0904] To benzyl (R)-(2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxo-1-(piperidin-4-yl)ethyl)carbamate hydrochloride (127 mg) were added potassium carbonate (194 mg), sodium iodide (135 mg), and DMF (3 mL), and the mixture was stirred under an argon atmosphere and ice-cooling. 3-(2-bromoethyl)indole (156 mg) was added to the reaction mixture at the same temperature, and the mixture was stirred at 70°C for 24 hours. After cooling the reaction mixture to 0°C, water was added, and the solid was collected by filtration. The obtained solid material was dissolved in ethyl acetate and dichloromethane and purified by silica gel column chromatography [eluent; chloroform:methanol=100:0→90:10] to obtain benzyl (R)-(1-(1-(2-(1H-indol-3-yl)ethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (87 mg) as a pale yellow solid.

[0905] The compounds shown in Table 11 were obtained in the same manner as in Reference Example 129.

[0906] [Table 11]

[0907]

[0908] Reference Example 132

[0909] [Chemical Formula 58]

[0910]

[0911] To benzyl (R)-(1-(1-(2-(1H-indol-3-yl)ethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (47 mg) were added DMSO (1.0 mL), copper (I) iodide (33 mg), 1H-benzotriazole (44 mg), iodobenzene (9 μL), and tripotassium phosphate (97 mg), followed by stirring at 110°C for 18 hours and 30 minutes. After cooling the reaction mixture to room temperature, water was added, and the solid was collected by filtration. The obtained solid material was washed with water and hexane in that order, then dissolved in dichloromethane and purified by silica gel column chromatography [eluent; chloroform:methanol=100:0→95:5] to obtain benzyl (R)-(2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxo-1-(1-(2-(1-phenyl-1H-indol-3-yl)ethyl)piperidin-4-yl)ethyl)carbamate (3 mg) as a yellow oily substance.

[0912] Reference Example 133

[0913] [Chemical Formula 59]

[0914]

[0915] To benzyl (R)-(1-(1-(2-(1H-indol-3-yl)ethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (57 mg) were added DMF (1.0 mL), 1,2-difluorobenzene (45 μL), and tripotassium phosphate (116 mg), followed by stirring at 150°C for 17 hours and 10 minutes. The reaction mixture was cooled to 0°C, water was added, and the solid was collected by filtration. The obtained solid material was washed with water, dissolved in ethyl acetate, and purified by silica gel column chromatography [eluent; chloroform:methanol = 100:0→97:3] to obtain benzyl (R)-(2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-1-(1-(2-(1-(2-fluorophenyl)-1H-indol-3-yl)ethyl)piperidin-4-yl)-2-oxoethyl)carbamate (10 mg) as a yellow oily substance.

[0916] Reference Example 134

[0917] [Chemical Formula 60]

[0918]

[0919] To 2-(5-chlorothien-2-yl)ethane-1-ol (216 mg) were added dichloromethane (2 mL) and triethylamine (0.46 mL), and the mixture was stirred at -15°C under an argon atmosphere. Methanesulfonyl chloride (0.12 mL) was added to the reaction mixture at the same temperature, and the mixture was stirred for 1 hour to obtain a dichloromethane mixture of 2-(5-chlorothien-2-yl)ethyl methanesulfonate.

[0920] To benzyl (R)-(2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxo-1-(piperidin-4-yl)ethyl)carbamate hydrochloride (270 mg) were added potassium carbonate (205 mg), sodium iodide (85 mg), and DMF (4 mL), and the mixture was stirred under an argon atmosphere with ice cooling. A dichloromethane mixture of 2-(5-chlorothien-2-yl)ethyl methanesulfonate prepared at the same temperature was added, and the mixture was stirred at 70°C for 15 hours and 15 minutes. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. After extracting the aqueous layer with ethyl acetate, the previously separated organic layers were combined, washed twice with water, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:methanol=100:0→70:30] to obtain benzyl (R)-(1-(1-(2-(5-chlorothien-2-yl)ethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (33 mg) as a colorless oil.

[0921] The compounds shown in Table 12 were obtained in the same manner as in Reference Example 134.

[0922] [Table 12]

[0923]

[0924]

[0925] Reference Example 142

[0926] [Chemical Formula 61]

[0927]

[0928] To benzyl (R)-(2-(4-(2-methoxybenzyl)piperazin-1-yl)-2-oxo-1-(piperidin-4-yl)ethyl)carbamate hydrochloride (2.20 g) were added dichloromethane (40 mL), 2-phenylacetaldehyde (0.51 mL), triethylamine (1.4 mL), and sodium triacetoxyborohydride (2.53 g), followed by stirring at room temperature for 22 hours and 30 minutes. Water (20 mL) was added to the reaction mixture, followed by the addition of a 10% aqueous sodium carbonate solution to adjust the pH to 8, and the organic layer was separated. The resulting organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol=100:0→90:10] to obtain benzyl (R)-(2-(4-(2-methoxybenzyl)piperazin-1-yl)-2-oxo-1-(1-phenethylpiperidin-4-yl)ethyl)carbamate (1.80 g) as a colorless oil.

[0929] In the same manner as in Reference Example 142, the compounds shown in Table 13 were obtained.

[0930] [Table 13]

[0931]

[0932] Reference Example 145

[0933] [Chemical Formula 62]

[0934]

[0935] (1) To 1-(2-methoxybenzyl)piperazine hydrochloride (1.90 g) were added (S)-2-(((benzyloxy)carbonyl)amino)-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (2.43 g), WSC hydrochloride (1.42 g), HOBt (1.00 g), dichloromethane (62 mL) and DIPEA (3.5 mL) in this order, and the mixture was stirred at room temperature for 2 hours. 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. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 50:50 → 100:0] to obtain the target compound (2.31 g) as a light yellow oil.

[0936] (2) To the compound obtained in (1) (2.05 g) were added dichloromethane (18 mL) and a 4 mol / L hydrochloric acid dioxane solution (4.4 mL), and the mixture was stirred at room temperature for 12 hours and 30 minutes. After the solvent was distilled off under reduced pressure, the mixture was dried under reduced pressure to obtain benzyl (S)-(2-(4-(2-methoxybenzyl)piperazin-1-yl)-2-oxo-1-(piperidin-4-yl)ethyl)carbamate hydrochloride (2.00 g) as a pale yellow solid.

[0937] (3) To the compound obtained in (2) (1.95 g) were added dichloromethane (35 mL), 2-phenylacetaldehyde (0.45 mL), triethylamine (1.2 mL) and sodium triacetoxyborohydride (2.24 g), and the mixture was stirred at room temperature for 22 hours and 30 minutes. After adding water (10 mL) to the reaction mixture, a 10% sodium carbonate aqueous 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. The residue was purified using [eluent; ethyl acetate:hexane = 50:50→100:0] to obtain benzyl (S)-(2-(4-(2-methoxybenzyl)piperazin-1-yl)-2-oxo-1-(1-phenethylpiperidin-4-yl)ethyl)carbamate (1.83 g) as a colorless oil.

[0938] Reference Example 146

[0939] [Chemical Formula 63]

[0940]

[0941] To benzyl (R)-(2-(4-(2-methoxybenzyl)piperazin-1-yl)-2-oxo-1-(piperidin-4-yl)ethyl)carbamate hydrochloride (200 mg) were added DMF (2 mL), potassium carbonate (175 mg), and 1-(2-bromoethyl)-2-fluorobenzene (88 mg), followed by stirring at 70°C for 4 hours. A solution of 1-(2-bromoethyl)-2-fluorobenzene (44 mg) in DMF (0.2 mL) was added to the reaction mixture, followed by stirring at 70°C for 2 hours and 30 minutes. Ethyl acetate and water were added to the reaction mixture, and the organic layer was separated. The obtained organic layer was washed with water and a saturated sodium chloride aqueous solution in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol=100:0→90:10] to obtain benzyl (R)-(1-(1-(2-fluorophenethyl)piperidin-4-yl)-2-(4-(2-methoxybenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (177 mg) as a colorless oil.

[0942] Reference Example 147

[0943] [Chemical Formula 64]

[0944]

[0945] 1-(2-bromoethyl)-2-fluorobenzene in Reference Example 146 was replaced with 3-(2-bromoethyl)thiophene, and the reaction was carried out in the same manner as in Reference Example 146 to obtain benzyl (R)-(2-(4-(2-methoxybenzyl)piperazin-1-yl)-2-oxo-1-(1-(2-(thiophen-3-yl)ethyl)piperidin-4-yl)ethyl)carbamate.

[0946] Reference Example 148

[0947] [Chemical Formula 65]

[0948]

[0949] To benzyl (R)-(2-(4-(2-methoxybenzyl)piperazin-1-yl)-2-oxo-1-(piperidin-4-yl)ethyl)carbamate hydrochloride (204 mg) were added potassium carbonate (258 mg), sodium iodide (124 mg), and DMF (4 mL), and the mixture was stirred under an argon atmosphere and ice-cooled. At the same temperature, 1-(2-bromoethyl)-2-chlorobenzene (76 μL) was added to the reaction mixture, and the mixture was stirred at 70°C for 16 hours and 20 minutes. After cooling the reaction mixture to 0°C, water and ethyl acetate were added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, and the previously separated organic layers were combined, washed twice with water, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane=0:100→43:57] to obtain benzyl (R)-(1-(1-(2-chlorophenethyl)piperidin-4-yl)-2-(4-(2-methoxybenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (119 mg) as a colorless oil.

[0950] Reference Example 149

[0951] [Chemical Formula 66]

[0952]

[0953] 1-(2-bromoethyl)-2-chlorobenzene in Reference Example 148 was replaced with 1-(2-bromoethyl)-3-chlorobenzene, and the reaction was carried out in the same manner as in Reference Example 148 to obtain benzyl (R)-(1-(1-(3-chlorophenethyl)piperidin-4-yl)-2-(4-(2-methoxybenzyl)piperazin-1-yl)-2-oxoethyl)carbamate.

[0954] Reference Example 150

[0955] [Chemical Formula 67]

[0956]

[0957] To 2-(5-chlorothien-2-yl)ethane-1-ol (181 mg) were added dichloromethane (2 mL) and triethylamine (0.39 mL), 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 the mixture was stirred for 1 hour to obtain a dichloromethane mixture of 2-(5-chlorothien-2-yl)ethyl methanesulfonate.

[0958] To benzyl (R)-(2-(4-(2-methoxybenzyl)piperazin-1-yl)-2-oxo-1-(piperidin-4-yl)ethyl)carbamate hydrochloride (214 mg) were added potassium carbonate (217 mg), sodium iodide (134 mg), and DMF (4 mL), and the mixture was stirred under an argon atmosphere and ice-cooled. A dichloromethane mixture of 2-(5-chlorothien-2-yl)ethyl methanesulfonate prepared at the same temperature was added, and the mixture was stirred overnight at 70°C. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. After extracting the aqueous layer with ethyl acetate, the previously separated organic layers were combined, washed twice with water, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane=50:50→0:100] to obtain benzyl (R)-(1-(1-(2-(5-chlorothien-2-yl)ethyl)piperidin-4-yl)-2-(4-(2-methoxybenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (81 mg) as a colorless oil.

[0959] Reference Example 151

[0960] [Chemical Formula 68]

[0961]

[0962] (1) THF (30 mL), water (30 mL), sodium carbonate (3.82 g), and 9-fluorenylmethyl chloroformate (2.38 g) were added to (R)-2-amino-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (1.52 g) in this order, and the mixture was stirred at room temperature for 25 hours. Diethyl ether was added to the reaction mixture, and the organic layer was separated. After the aqueous layer was extracted with diethyl ether, the organic layers obtained above were combined, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:methanol = 80:20 → 50:50] to obtain the target compound (1.57 g) as a light yellow solid.

[0963] (2) The compound obtained in (1) (1.08 g) was added to a reaction mixture of 1-(2-ethoxy-6-fluorobenzyl)piperazine hydrochloride (840 mg), DMF (2 mL), DIPEA (2.3 mL) and HOAt (184 mg) that was being stirred under ice cooling. HATU (1.17 g) was added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 3 hours. Water and dichloromethane were added to the reaction mixture, and the organic layer was separated. After the aqueous layer was extracted with dichloromethane, the previously separated organic layers were combined, washed with a saturated aqueous sodium carbonate solution and a saturated aqueous sodium chloride solution in that order, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 29:71 → 100:0] to obtain the target compound (580 mg) as a light orange oil.

[0964] (3) Dichloromethane (3 mL) was added to the compound (580 mg) obtained in (2), and the mixture was stirred under ice-cooling. 4 mol / L hydrochloric acid in dioxane solution (3 mL) was added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the mixture was dried under reduced pressure to obtain (9H-fluoren-9-yl)methyl (R)-(2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxo-1-(piperidin-4-yl)ethyl)carbamate hydrochloride (584 mg) as a pale orange solid.

[0965] Reference Example 152

[0966] [Chemical Formula 69]

[0967]

[0968] (1) Methyl (R)-2-(((benzyloxy)carbonyl)amino)-2-(piperidin-4-yl)acetate hydrochloride (1.70 g) was added with dichloromethane (25 mL), 2-(2-bromo-5-chlorophenyl)acetaldehyde (1.51 g), triethylamine (0.69 mL) and sodium triacetoxyborohydride (1.58 g), 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. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 0:100→35:65] to obtain the target product (1.55 g) as a colorless oil.

[0969] (2) THF (6.2 mL), methanol (1.6 mL), water (6.2 mL) and lithium hydroxide monohydrate (621 mg) were added to the compound obtained in (1) (1.55 g), and the mixture was stirred at room temperature for 2 hours and 15 minutes. The solvent was concentrated under reduced pressure, diethyl ether (15 mL) was added to the residue, and the aqueous layer was separated. Concentrated hydrochloric acid was added to the aqueous layer to adjust the pH to 6, and the mixture was stirred at room temperature for 30 minutes. The solid matter was filtered and dried under reduced pressure at 60°C to obtain the target product (1.26 g) as a white solid.

[0970] (3) To the compound obtained in (2) (1.26 g), 1-(2-ethoxy-6-fluorobenzyl)piperazine hydrochloride (0.77 g), WSC hydrochloride (521 mg), HOBt (367 mg), dichloromethane (13 mL), and DIPEA (1.4 mL) were added in this order, and the mixture was stirred at room temperature for 6 hours. WSC hydrochloride (142 mg), HOBt (100 mg), and DIPEA (0.22 mL) were added to the reaction mixture, and the mixture was stirred overnight at room temperature. Water (10 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. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane=50:50→100:0] to obtain benzyl (R)-(1-(1-(2-bromo-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (1.80 g) as a white solid.

[0971] Reference Example 153

[0972] [Chemical Formula 70]

[0973]

[0974] 2-(2-Bromo-5-chlorophenyl)acetaldehyde in Reference Example 152 was replaced with (2-bromophenyl)acetaldehyde, and the reaction was carried out in the same manner as in Reference Example 152 to obtain benzyl (R)-(1-(1-(2-bromophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate as a colorless oil.

[0975] Reference Example 154

[0976] [Chemical Formula 71]

[0977]

[0978] To 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) were added 4-(4,4,5,5-tetramethyl-1,2,3-dioxafluoren-2-yl)phenol (78 mg), tripotassium phosphate (147 mg), and 2-methyl-2-butanol (2 mL). Under a nitrogen atmosphere, XPhos Pd G4 (12 mg) was added to the reaction mixture, and the mixture was stirred at reflux for 17 hours. 4-(4,4,5,5-tetramethyl-1,2,3-dioxaindan-2-yl)phenol (78 mg), tripotassium phosphate (147 mg), and XPhos Pd G4 (12 mg) were added to the reaction mixture, and the mixture was stirred at reflux for 6 hours. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added, and the organic layer was separated. The resulting organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent: chloroform:methanol = 100:0 → 93:7] to obtain benzyl (R)-(1-(1-(2-(4-chloro-4'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (136 mg) as a light brown oil.

[0979] Reference Example 155

[0980] [Chemical Formula 72]

[0981]

[0982] 4-(4,4,5,5-tetramethyl-1,2,3-dioxolan-2-yl)phenol in Reference Example 154 was replaced with 3-(4,4,5,5-tetramethyl-1,2,3-dioxolan-2-yl)phenol, and the reaction was carried out in the same manner as in Reference Example 154 to obtain 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.

[0983] Reference Example 156

[0984] [Chemical Formula 73]

[0985]

[0986] To 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) were added 2,5-dichlorophenylboronic acid (78 mg), sodium carbonate (58 mg), 1,2-dimethoxyethane (2.7 mL), and water (0.3 mL). Under a nitrogen atmosphere, XPhos Pd G4 (12 mg) was added to the reaction mixture, and the mixture was stirred at reflux for 17 hours. Dichloro(bistriphenylphosphine)palladium(II) (25 mg), 2,5-dichlorophenylboronic acid (78 mg), and sodium carbonate (58 mg) were added to the reaction mixture, and the mixture was stirred at reflux for 6 hours. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added, and the organic layer was separated. The obtained organic layer was washed with water and saturated sodium chloride solution in that order, then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent: chloroform:methanol = 100:0 → 95:5] to obtain benzyl (R)-(2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxo-1-(1-(2-(2',4,5'-trichloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)ethyl)carbamate (57 mg) as a light brown oil.

[0987] Reference Example 157

[0988] [Chemical Formula 74]

[0989]

[0990] To 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) were added (3-((tert-butoxycarbonyl)amino)phenyl)boronic acid (97 mg), XPhos Pd G4 (12 mg), tripotassium phosphate (116 mg), 1,4-dioxane (2 mL), and water (0.3 mL). The mixture was stirred at 120°C for 1 hour under a nitrogen atmosphere using a microwave synthesis apparatus (Initiator+ manufactured by Biotage, 0.5-2 mL vial, absorption level = Very High). Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The obtained organic layer was washed with water and a saturated sodium chloride aqueous solution in that order, then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol=100:0→95:5] to obtain benzyl (R)-(1-(1-(2-(3'-((tert-butoxycarbonyl)amino)-4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (216 mg) as a pale yellow oil.

[0991] The compounds shown in Table 14 were obtained in the same manner as in Reference Example 157.

[0992] [Table 14]

[0993]

[0994] Reference Example 161

[0995] [Chemical Formula 75]

[0996]

[0997] To benzyl (R)-(1-(1-(2-bromo-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (50 mg) were added benzyl 4-(4,4,5,5-tetramethyl-1,2,3-dioxafluoren-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (35 mg), dichloro(bistriphenylphosphine)palladium(II) (5 mg), sodium carbonate (15 mg), 1,2-dimethoxyethane (0.5 mL), and water (68 μL), and the mixture was stirred under reflux overnight under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added, and the organic layer was separated. The obtained organic layer was washed with water and a saturated sodium chloride aqueous solution in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol=100:0→95:5] to obtain benzyl (R)-4-(2-(2-(4-(1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (58 mg) as a pale yellow oil.

[0998] The compounds shown in Table 15 were obtained in the same manner as in Reference Example 161.

[0999] [Table 15]

[1000]

[1001]

[1002] Reference Example 168

[1003] [Chemical Formula 76]

[1004]

[1005] To 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) were added 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), and the mixture was stirred overnight at 80°C under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added, and the organic layer was separated. The obtained organic layer was washed with water and a saturated sodium chloride aqueous solution in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol=100:0→95:5] to obtain 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) as a pale yellow oil.

[1006] The compounds shown in Table 16 were obtained in the same manner as in Reference Example 168.

[1007] [Table 16]

[1008]

[1009]

[1010] Reference Example 180

[1011] [Chemical Formula 77]

[1012]

[1013] To benzyl (R)-(1-(1-(2-bromo-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (50 mg) were added tert-butyl (3-(4,4,5,5-tetramethyl-1,2,3-dioxafluoren-2-yl)pyridin-4-yl)carboxylate (35 mg), dichloro(bistriphenylphosphine)palladium(II) (5 mg), sodium carbonate (15 mg), 1,4-dioxane (0.5 mL), and water (68 μL), and the mixture was stirred under reflux overnight under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added, and the organic layer was separated. The obtained organic layer was washed with water and a saturated sodium chloride aqueous solution in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol=100:0→95:5] to obtain benzyl (R)-(1-(1-(2-(4-((tert-butoxycarbonyl)amino)pyridin-3-yl)-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (35 mg) as a pale yellow oil.

[1014] The compounds shown in Table 17 were obtained in the same manner as in Reference Example 180.

[1015] [Table 17]

[1016]

[1017]

[1018] Reference Example 192

[1019] [Chemical Formula 78]

[1020]

[1021] To benzyl (R)-(1-(1-(2-bromophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (250 mg) were added phenylboronic acid (66 mg), sodium carbonate (72 mg), 1,2-dimethoxyethane (3.6 mL), and water (0.36 mL). Under a nitrogen atmosphere, dichloro(bistriphenylphosphine)palladium(II) (25 mg) was added to the reaction mixture, and the mixture was stirred under reflux for 15 hours. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added, and the organic layer was separated. The resulting organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol=100:0→93:7] to obtain benzyl (R)-(1-(1-(2-([1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (250 mg) as a brown oil.

[1022] The compounds shown in Table 18 were obtained in the same manner as in Reference Example 192.

[1023] [Table 18]

[1024]

[1025] Reference Example 196

[1026] [Chemical Formula 79]

[1027]

[1028] (1) THF (16 mL) was added to methyl 2-(2-bromo-5-trifluoromethoxy)phenyl acetate (1.03 g), and the mixture was stirred under ice-cooling. 4 mol / L lithium borohydride THF solution (16.4 mL) was added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 19 hours. The reaction mixture was cooled to 0°C and ice water was added. 6 mol / L hydrochloric acid was added to adjust the pH to 6, and ethyl acetate (20 mL) was added to separate the organic layer. The obtained organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 0:100→25:75] to obtain the target compound (886 mg) as a colorless oil.

[1029] (2) Dichloromethane (11 mL) was added to the compound (300 mg) obtained in (1), and the mixture was stirred under ice-cooling. Dess-Martin periodinane (893 mg) was added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 2 hours. 10% sodium thiosulfate aqueous solution (10 mL) and saturated sodium bicarbonate aqueous solution (10 mL) were added to the reaction mixture, and the organic layer was separated. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane=0:100→13:87] to obtain the target compound (216 mg) as a colorless oil.

[1030] (3) To the compound obtained in (2) (145 mg), benzyl (R)-(2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxo-1-(piperidin-4-yl)ethyl)carbamate hydrochloride (250 mg), dichloromethane (2.5 mL), triethylamine (0.12 mL) and sodium triacetoxyborohydride (226 mg) were added, and the mixture was stirred at room temperature for 18 hours. After adding water (5 mL), a 10% sodium carbonate aqueous 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. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol = 100:0→95:5] to obtain the target compound (315 mg) as a colorless oil.

[1031] (4) Phenylboronic acid (36 mg), dichloro(bistriphenylphosphine)palladium(II) (14 mg), sodium carbonate (42 mg), 1,4-dioxane (1.6 mL), and water (0.2 mL) were added to the compound obtained in (3) (155 mg), and stirred overnight at 100°C under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added, and the organic layer was separated. The obtained organic layer was washed with water and a saturated sodium chloride aqueous solution in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol=100:0→95:5] to obtain benzyl (R)-(2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxo-1-(1-(2-(4-(trifluoromethoxy)-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)ethyl)carbamate (117 mg) as a pale yellow oil.

[1032] The compounds shown in Table 19 were obtained in the same manner as in Reference Example 196.

[1033] [Table 19]

[1034]

[1035]

[1036] Reference Example 300

[1037] [Chemical formula 80]

[1038]

[1039] DMF (13.5 mL) was added to 5-(benzyloxy)-2-bromobenzaldehyde (300 mg) and stirred under ice cooling. At the same temperature, sodium ethanethiolate (144 mg) was added to the reaction mixture, 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 with water and saturated sodium chloride aqueous solution in sequence, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate: hexane = 0:100→20:80] to obtain 5-(benzyloxy)-2-(ethylthio)benzaldehyde (230 mg) as a white solid.

[1040] Reference Example 301

[1041] [Chemical Formula 81]

[1042]

[1043] The reaction was carried out in the same manner as in Reference Example 300 except that sodium methylthiolate was used in place of sodium ethylthiolate to obtain 5-(benzyloxy)-2-(methylthio)benzaldehyde as a light brown oil.

[1044] Reference Example 302

[1045] [Chemical Formula 82]

[1046]

[1047] DMF (0.65 mL) was added to sodium ethanethiolate (244 mg) and stirred under ice-cooling. At the same temperature, a solution of 2-(benzyloxy)-6-fluorobenzaldehyde (200 mg) in DMF (0.65 mL) was added to the reaction mixture and stirred at room temperature for 1 hour. Diethyl ether (3 mL) and water (3 mL) were added to the reaction mixture, and the organic layer was separated. The obtained organic layer was washed with water and a saturated sodium chloride aqueous solution in sequence, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate: hexane = 0: 100 → 20: 80] to obtain 2-(benzyloxy)-6-(ethylthio)benzaldehyde (172 mg) as a white solid.

[1048] Reference Example 303

[1049] [Chemical Formula 83]

[1050]

[1051] The reaction was carried out in the same manner as in Reference Example 302 except that sodium methylthiolate was used in place of sodium ethylthiolate to obtain 2-(benzyloxy)-6-(methylthio)benzaldehyde as a white solid.

[1052] The compounds shown in Table 20 were obtained in the same manner as in Reference Example 34.

[1053] [Table 20]

[1054]

[1055]

[1056]

[1057]

[1058]

[1059]

[1060]

[1061] The compounds shown in Table 21 were obtained in the same manner as in Reference Example 180.

[1062] [Table 21]

[1063]

[1064]

[1065]

[1066]

[1067]

[1068] Reference Example 376

[1069] [Chemical Formula 84]

[1070]

[1071] (1) Acetonitrile (400 mL), 2-bromo-5-chlorophenethyl methanesulfonate (27.4 g) and potassium carbonate (40.3 g) were added to methyl (R)-2-(((benzyloxy)carbonyl)amino)-2-(piperidin-4-yl)acetate hydrochloride (20.0 g), and the mixture was stirred at 75°C for 17 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and the insoluble matter was filtered off. Ethyl acetate (300 mL) and water (300 mL) were added to the filtrate, and then concentrated hydrochloric acid was added to adjust the pH to 8.3, and the organic layer was separated. The obtained organic layer was washed with a 5% sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane=5:95→70:30] to obtain the target product (24.4 g) as a light brown oil.

[1072] (2) THF (50 mL), methanol (25 mL), water (100 mL) and lithium hydroxide monohydrate (9.77 g) were added to the compound (24.4 g) obtained in (1), and the mixture was stirred at room temperature for 3 hours and 10 minutes. The solvent was concentrated under reduced pressure, water (80 mL) was added to the residue, and concentrated hydrochloric acid was added to adjust the pH to 5.6. The solid matter was filtered and washed with water. MTBE was added to the obtained solid matter, and the mixture was stirred at room temperature for 16 hours. The solid matter was filtered, washed with MTBE, and then dried under reduced pressure to obtain the target product (22.5 g) as a white solid.

[1073] (3) DMAC (200 mL) and tert-butylpiperazine-1-carboxylate (8.23 g) were added to the compound (22.5 g) obtained in (2), and the mixture was stirred under ice-cooling. At the same temperature, WSC hydrochloride (11.0 g), ethyl cyano(hydroxyimino)acetate (7.53 g), and 4-methylmorpholine (19.4 mL) were added to the reaction mixture in this order, and the mixture was stirred at room temperature for 19 hours and 15 minutes. Ethyl acetate (400 mL) and water (400 mL) were added to the reaction mixture, and then a 5% aqueous sodium carbonate solution was added to adjust the pH to 9.0, and the organic layer was separated. The organic layer was washed with water and a 5% aqueous sodium chloride solution in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 10:90 → 100:0] to obtain the target compound (28.4 g) as a yellow oil.

[1074] (4) To the compound obtained in (3) (28.4 g) were added 1,4-dioxane (56 mL), methanol (5.6 mL), and a 4 mol / L hydrochloric acid solution in dioxane (52.3 mL), and the mixture was stirred at room temperature for 17 hours and 50 minutes. After the solvent was distilled off under reduced pressure, IPE (360 mL) was added to the residue, and the mixture was stirred at room temperature for 2 hours and 50 minutes. The solid was collected by filtration, washed with IPE, and then dried under reduced pressure to obtain the target product (27.1 g) as a white solid.

[1075] (5) To the compound obtained in (4) (200 mg) were added dichloromethane (2 mL), 2-(methylthio)benzaldehyde (51 mg), triethylamine (0.11 mL) and sodium triacetoxyborohydride (130 mg), and the mixture was stirred at room temperature for 16 hours and 30 minutes. After adding water to the reaction mixture, a 10% sodium carbonate aqueous solution was added to adjust the pH to 8.2, 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. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 50:50→100:0] to obtain benzyl (R)-(1-(1-(2-bromo-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-(methylthio)benzyl)piperazin-1-yl)-2-oxoethyl)carbamate (173 mg) as a light yellow oil.

[1076] The compounds shown in Table 22 were obtained in the same manner as in Reference Example 376.

[1077] [Table 22]

[1078]

[1079] Reference Example 379

[1080] [Chemical Formula 85]

[1081]

[1082] To benzyl (R)-(1-(1-(2-bromo-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-(methylthio)benzyl)piperazin-1-yl)-2-oxoethyl)carbamate (200 mg) were added (3-(benzyloxy)-5-chlorophenyl)boronic acid (108 mg), dichloro(bistriphenylphosphine)palladium(II) (20 mg), sodium carbonate (61 mg), 1,4-dioxane (2 mL), and water (0.27 mL). The mixture was stirred at 100°C under an argon atmosphere for 15 hours and 10 minutes. After cooling the reaction mixture to room temperature, water and ethyl acetate were added, and the organic layer was separated. The obtained organic layer was washed with water and a saturated sodium chloride aqueous solution in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane=50:50→100:0] to obtain 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).

[1083] The compounds shown in Table 23 were obtained in the same manner as in Reference Example 379.

[1084] [Table 23]

[1085]

[1086]

[1087]

[1088] Reference Example 396

[1089] [Chemical Formula 86]

[1090]

[1091] To benzyl (R)-(1-(1-(2-bromo-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (250 mg) were added (3-(benzyloxy)-5-fluorophenyl)boronic acid (121 mg), dichloro(bistriphenylphosphine)palladium(II) (24 mg), sodium carbonate (73 mg), 1,4-dioxane (2.4 mL), and water (0.33 mL). The mixture was stirred at 100°C under an argon atmosphere for 15 hours and 10 minutes. After cooling the reaction mixture to room temperature, water and ethyl acetate were added, and the organic layer was separated. The obtained organic layer was washed with water and a saturated sodium chloride aqueous solution in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane=50:50→100:0] to obtain benzyl (R)-(1-(1-(2-(3'-(benzyloxy)-4-chloro-5'-fluoro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-2-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (239 mg).

[1092] The compounds shown in Table 24 were obtained in the same manner as in Reference Example 396.

[1093] [Table 24]

[1094]

[1095]

[1096]

[1097] Reference Example 413

[1098] [Chemical Formula 87]

[1099]

[1100] To benzyl (R)-(1-(1-(2-bromo-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (200 mg) were added (5-(benzyloxy)-2-fluorophenyl)boronic acid (87 mg), dichloro(bistriphenylphosphine)palladium(II) (17 mg), sodium carbonate (52 mg), 1,4-dioxane (1.7 mL), and water (0.23 mL). The mixture was stirred at 100°C under an argon atmosphere for 15 hours and 40 minutes. After cooling the reaction mixture to room temperature, water and ethyl acetate were added, and the organic layer was separated. The obtained organic layer was washed with water and a saturated sodium chloride aqueous solution in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane=50:50→100:0] to obtain benzyl (R)-(2-(4-(5-(benzyloxy)-2-(ethylthio)benzyl)piperazin-1-yl)-1-(1-(2-(5'-(benzyloxy)-4-chloro-2'-fluoro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-2-oxoethyl)carbamate (212 mg).

[1101] The compounds shown in Table 25 were obtained in the same manner as in Reference Example 413.

[1102] [Table 25]

[1103]

[1104] Reference Example 416

[1105] [Chemical Formula 88]

[1106]

[1107] (1) THF (8 mL) was added to methyl 2-(4-chloro-[1,1'-biphenyl]-3-yl)acetate (417 mg), and the mixture was stirred under ice-cooling. 4 mol / L lithium borohydride THF solution (2 mL) was added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 2 hours and then at 50°C for 3 hours. After adding ice water under ice-cooling, 6 mol / L hydrochloric acid was added to adjust the pH to 5, and ethyl acetate (10 mL) was added to separate the organic layer. The obtained organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 0:100→25:75] to obtain the target compound (367 mg) as a colorless oil.

[1108] (2) Dichloromethane (16 mL) was added to the compound (367 mg) obtained in (1), and the mixture was stirred under ice-cooling. Dess-Martin periodinane (1.34 g) was added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 2 hours. 10% aqueous sodium thiosulfate solution (10 mL) and saturated aqueous sodium bicarbonate solution (10 mL) were added to the reaction mixture, and the organic layer was separated. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane=0:100→10:90] to obtain the target compound (253 mg) as a colorless oil.

[1109] (3) To the compound obtained in (2) (43 mg), benzyl (R)-(2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxo-1-(piperidin-4-yl)ethyl)carbamate hydrochloride (100 mg), dichloromethane (1 mL), triethylamine (48 μL), and sodium triacetoxyborohydride (91 mg) were added, and the mixture was stirred at room temperature for 20 hours. After adding water (1 mL), 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. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol=100:0→90:10] to obtain benzyl (R)-(1-(1-(2-(4-chloro-[1,1'-biphenyl]-3-yl)ethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (124 mg) as a colorless oil.

[1110] Reference Example 417

[1111] [Chemical Formula 89]

[1112]

[1113] To benzyl (R)-(1-(1-(2-bromo-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (100 mg) were added triethylamine (1 mL), trimethylsilylacetylene (29 μL), copper (I) iodide (1.3 mg), and tetrakis(triphenylphosphine)palladium(0) (8 mg), followed by stirring at 70°C for 17 hours and 30 minutes. After cooling the reaction mixture to room temperature, ethyl acetate (7 mL) was added, the insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane=50:50→80:20] to obtain benzyl (R)-(1-(1-(5-chloro-2-((trimethylsilyl)ethynyl)phenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (61 mg) as a pale yellow oil.

[1114] Reference Example 418

[1115] [Chemical formula 90]

[1116]

[1117] The trimethylsilyl acetylene in Reference Example 417 was replaced with phenyl acetylene, and the reaction was carried out in the same manner as in Reference Example 417 to obtain benzyl (R)-(1-(1-(5-chloro-2-(phenylethynyl)phenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate as a pale yellow oil.

[1118] Reference Example 419

[1119] [Chemical Formula 91]

[1120]

[1121] (1) To benzyl (R)-(2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxo-1-(piperidin-4-yl)ethyl)carbamate hydrochloride (300 mg) were added dichloromethane (3 mL), 2-(5-(benzyloxy)-2-bromophenyl)acetaldehyde (172 mg), triethylamine (0.14 mL) and sodium triacetoxyborohydride (272 mg), and the mixture was stirred at room temperature for 20 hours. After adding water (3 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. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 10:90 → 100:0] to obtain the target compound (363 mg) as a colorless oil.

[1122] (2) Phenylboronic acid (41 mg), dichloro(bistriphenylphosphine)palladium(II) (16 mg), sodium carbonate (47 mg), 1,4-dioxane (1.8 mL), and water (0.22 mL) were added to the compound obtained in (1) (179 mg), and stirred at 100°C for 16 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added, 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. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol=100:0→95:5] to obtain benzyl (R)-(1-(1-(2-(4-(benzyloxy)-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (163 mg) as a pale yellow oil.

[1123] Reference Example 420

[1124] [Chemical Formula 92]

[1125]

[1126] Acetonitrile (1 mL) and iodomethane (9.4 μL) were added to 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 (100 mg), and the mixture was stirred at room temperature for 19 hours and 30 minutes. Ethyl acetate and water were added to the reaction mixture, and the organic layer was separated. The resulting organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol = 100:0 → 85:15] to obtain (R)-4-(1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)-1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)-1-methylpiperidin-1-ium iodide (35 mg) as a pale red solid.

[1127] Reference Example 421

[1128] [Chemical Formula 93]

[1129]

[1130] The iodomethane in Reference Example 420 was replaced with tert-butyl bromoacetate, and the reaction was carried out in the same manner as in Reference Example 420 to obtain (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 as a light red solid.

[1131] Reference Example 421

[1132] [Chemical Formula 94]

[1133]

[1134] (1) To benzyl 2-(4-(benzyloxy)-2-bromophenyl)acetate (100 mg) were added 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), 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. The aqueous layer was extracted three times with ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:heptane = 5:95 → 40:60] to obtain the target compound (85 mg) as a colorless oil.

[1135] (2) THF (40 mL) was added to LAH (234 mg) and stirred under ice-cooling. A THF solution (60 mL) of the compound obtained in (1) (1.26 g) was added at the same temperature and stirred at room temperature for 2 hours. Water and ethyl acetate were added to the reaction mixture, insoluble matter was filtered off, and the organic layer was separated. The aqueous layer was extracted three times with ethyl acetate, and the previously separated organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:heptane = 10:90 → 50:50] to obtain 2-(5-(benzyloxy)-[1,1'-biphenyl]-2-yl)ethan-1-ol (1.30 g) as a mixture with benzyl alcohol.

[1136] Reference Example 422

[1137] [Chemical Formula 95]

[1138]

[1139] (1) DMAC (100 mL) was added to (R)-2-(((benzyloxy)carbonyl)amino)-2-(1-(tert-butoxycarbonyl)piperidin-4-yl) (9.81 g), and the mixture was stirred under ice-cooling. At the same temperature, allylpiperazine-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 in this order, and the mixture was stirred at room temperature for 17 hours. Ethyl acetate (300 mL) and water (300 mL) were added to the reaction mixture, and then concentrated hydrochloric acid was added to adjust the pH to 2.3, and the organic layer was separated. The organic layer was washed with a 5% aqueous sodium carbonate solution (300 mL), water (300 mL), and a 5% aqueous sodium chloride solution (300 mL) in this order, and then dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane=5:95→70:30] to obtain the target compound (12.0 g) as a yellow oil.

[1140] (2) To the compound obtained in (1) (12.0 g) were added 1,4-dioxane (25 mL), methanol (2.5 mL), and a 4 mol / L hydrochloric acid dioxane solution (16.4 mL), and the mixture was stirred at room temperature for 17 hours and 15 minutes. After the solvent was distilled off under reduced pressure, IPE was added to the residue, and the mixture was stirred at room temperature for 20 minutes. The solid was collected by filtration, washed with IPE, and then dried under reduced pressure to obtain allyl (R)-4-(2-(((benzyloxy)carbonyl)amino)-2-(piperidin-4-yl)acetyl)piperazine-1-carboxylate (10.3 g) as a white solid.

[1141] Reference Example 423

[1142] [Chemical Formula 96]

[1143]

[1144] (1) Dichloromethane (26.5 mL) and triethylamine (2.5 mL) were added to 2-(4-phenylthiophen-3-yl)ethane-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, and the organic layers separated were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography [eluent; ethyl acetate:heptane = 5:95 → 33:67] to obtain the target product (3.34 g).

[1145] (2) Acetonitrile (13 mL), potassium carbonate (1.44 g), and the compound obtained in (1) (0.88 g) were added to the hydrochloride salt (1.0 g) of allyl (R)-4-(2-(((benzyloxy)carbonyl)amino)-2-(piperidin-4-yl)acetyl)piperazine-1-carboxylate, and the mixture was stirred at 80°C for 3 hours. 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, and the organic layers separated were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography [eluent; ethyl acetate:heptane = 15:85 → 45:55] to obtain the target product (0.90 g) as a white solid.

[1146] (3) 1,3-Dimethylbarbituric acid (335 mg) and dichloromethane (40 mL) were added to the compound obtained in (2) (902 mg), and then tetrakis(triphenylphosphine)palladium(0) (330 mg) was added under an argon atmosphere, and the mixture was stirred at room temperature for 19 hours. The reaction mixture was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography [eluent; ethyl acetate:methanol = 100:0 → 90:10] to obtain benzyl (R)-(2-oxo-1-(1-(2-(4-phenylthiophen-3-yl)ethyl)piperidin-4-yl)-2-(piperazin-1-yl)ethyl)carbamate (566 mg) as a light yellow oil.

[1147] The compounds shown in Table 26 were obtained in the same manner as in Reference Example 423.

[1148] [Table 26]

[1149]

[1150] Reference Example 426

[1151] [Chemical Formula 97]

[1152]

[1153] To benzyl (R)-(2-oxo-1-(1-(2-(4-phenylthiophen-3-yl)ethyl)piperidin-4-yl)-2-(piperazin-1-yl)ethyl)carbamate (230 mg) were added dichloromethane (3 mL), 2-(ethylthio)-4-fluorobenzaldehyde (116 mg), and sodium triacetoxyborohydride (178 mg), followed by stirring at room temperature for 17 hours and 30 minutes. Water and chloroform were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted twice with chloroform, and the previously separated organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:methanol=100:0→92:8] to obtain benzyl (R)-(2-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)-2-oxo-1-(1-(2-(4-phenylthiophen-3-yl)ethyl)piperidin-4-yl)ethyl)carbamate (314 mg).

[1154] The compounds shown in Table 27 were obtained in the same manner as in Reference Example 426.

[1155] [Table 27]

[1156]

[1157]

[1158] Reference Example 435

[1159] [Chemical Formula 98]

[1160]

[1161] (1) To (R)-2-(((benzyloxy)carbonyl)amino)-2-(1,4-dioxaspiro[4.5]decane-8-yl)acetic acid (2.23 g) were added 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) in this order, 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. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 0:100→80:20] to obtain the target compound (3.22 g) as a white solid.

[1162] (2) Acetic acid (21 mL), THF (3.2 mL), water (8.1 mL) and dichloroacetic acid (1.4 mL) were added to the compound (3.22 g) obtained in (1), and the mixture was stirred at room temperature for 23 hours. Water (4 mL) and dichloroacetic acid (0.7 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 17 hours. Sodium carbonate was added to the reaction mixture to adjust the pH to 6.0, and then chloroform (70 mL) and water (30 mL) were added. 10% sodium carbonate aqueous solution was added to the reaction mixture to adjust the pH to 8.6, and the organic layer was separated. After the solvent was distilled off under reduced pressure, the mixture was dried under reduced pressure to obtain the target product (3.03 g) as a white solid.

[1163] (3) To the compound obtained in (2) (300 mg) were added dichloromethane (3 mL), benzylamine (86 mg) and sodium triacetoxyborohydride (302 mg), and the mixture was stirred at room temperature for 21 hours. After adding water to the reaction mixture, a 10% sodium carbonate aqueous solution was added to adjust the pH to 8.3, 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. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol = 100:0 → 95:5] to obtain benzyl (R)-(1-(4-(benzylamino)cyclohexyl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (236 mg) as a colorless oil.

[1164] (4) To the compound obtained in (3) (131 mg) were added dichloromethane (2.1 mL), 38% formaldehyde aqueous solution (18 μL), and sodium triacetoxyborohydride (90 mg), and the mixture was stirred at room temperature for 16 hours and 30 minutes. After adding water to the reaction mixture, a 10% sodium carbonate aqueous solution was added to adjust the pH to 8.3, 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. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol = 100:0 → 95:5] to obtain benzyl (R)-(1-(4-(benzyl(methyl)amino)cyclohexyl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (116 mg) as a colorless oil.

[1165] Example 1

[1166] [Chemical Formula 99]

[1167]

[1168] To benzyl (R)-(1-(1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-2-(4-(2-(methylthio)benzyl)piperazin-1-yl)-2-oxoethyl)carbamate (70 mg) were added anisole (0.14 mL) and a 5.1 mol / L hydrobromic acid / acetic acid solution (0.7 mL), followed by stirring at room temperature for 1 hour. Ethyl acetate (5 mL) and diethyl ether (5 mL) were added sequentially to the reaction mixture, followed by stirring at room temperature for 30 minutes. The reaction mixture was centrifuged, and the supernatant was removed. Ethyl acetate (5 mL) and diethyl ether (5 mL) were added to the residue, followed by centrifugation, and the supernatant was removed. To the residue were added ethyl acetate (2.5 mL) and diethyl ether (2.5 mL), the mixture was centrifuged, the supernatant was removed, and the residue was dried under reduced pressure to obtain (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 hydrobromide (64 mg) as a white solid.

[1169] NMR: 1.57-1.73(2H,m),1.90-2.02(2H,m),2.15-2.29(1H,m),2.59(3H,s),2.75-2.90(2H,m),3.04-3.28(4H,m),3 .30-3.73(7H,m),3.76-4.21(3H,m),4.57(1H,d,J=6.0Hz),4.61(2H,s),7.34(1H,d,J=8.0Hz),7.37-7.67(11H,m)

[1170] MS:577.30[M+H] +

[1171] In the same manner as in Example 1, the compounds shown in Table 28 were obtained.

[1172] [Table 28]

[1173]

[1174]

[1175]

[1176]

[1177]

[1178] The measured values ​​of NMR and MS of the compounds in the table are shown.

[1179] Example 2

[1180] NMR: 1.55-1.71(2H,m),1.89-2.02(2H,m),2.13-2.27(1H,m),2.74-2.89(2H,m),3.04-3.26(5H,m),3.28-3.75(7H,m),3.77-4 .27(2H,m),4.52(2H,s),4.54(1H,d,J=6.4Hz),4.71-4.90(2H,m),7.20-7.27(2H,m),7.34(1H,d,J=8.0Hz),7.42-7.64(9H,m)

[1181] MS:629.30[M+H] +

[1182] Example 3

[1183] NMR: 1.50-1.70(2H,m),1.86-1.99(2H,m),2.08-2.24(1H,m),2.73-2.86(2H,m),3.03-3.24(5H,m),3.26-3.56(6H,m),3.62-4.22(3H,m),4 .51(1H,d,J=6.0Hz),4.66(2H,s),7.10-7.14(1H,m),7.34(1H,d,J=8.0Hz),7.42-7.62(9H,m),7.77(1H,d,J=8.0Hz),7.95(1H,d,J=2.4Hz)

[1184] MS:571.30[M+H] +

[1185] Example 4

[1186] NMR: 1.51-1.70(2H,m),1.86-1.98(2H,m),2.09-2.22(1H,m),2.71-2. 86(2H,m),3.03-3.16(5H,m),3.25-3.55(7H,m),3.70-4.08(2H,m),4.5 0(1H,d,J=6.0Hz),4.73(2H,s),7.34(1H,d,J=8.0Hz),7.41-7.62(10H,m),7.69(1H,d,J=5.6Hz),7.85(1H,d,J=5.6Hz),8.18(1H,d,J=8.0Hz)

[1187] MS:587.30[M+H]+

[1188] Example 5

[1189] NMR: 1.56-1.73(2H,m),1.84-2.03(2H,m),2.14-2.28(1H,m),2.73-2.94(2H,m),2.98-3.21(6H,m ),3.30-3.73(6H,m),3.79-4.08(2H,m),4.36-4.63(3H,m),7.17-7.66(12H,m),7.69-7.76(1H,m)

[1190] MS:570.40[M+H] +

[1191] Example 6

[1192] NMR: 1.51-1.70(2H,m),1.84-2.00(2H,m),2.08-2.23(1H,m),2.68-2.87(2H,m),3.00-3.16(4H,m),3.28-3.60(6H,m),3.62-4.29(4H, m),4.52(1H,d,J=6.0Hz),4.62(2H,s),7.34(1H,d,J=8.0Hz),7.41-7.62(9H,m),7.70(1H,d,J=7.6Hz),7.79-7.84(1H,m),8.10(1H,s)

[1193] MS:571.30[M+H] +

[1194] Example 7

[1195] NMR: 1.51-1.67(2H,m),1.84-1.98(2H,m),2.08-2.22(1H,m),2.69-2.83(2H,m),3.04-3.19(5H,m),3.22-3.47(6H,m),3.51-4.37(3H,m ),4.48(1H,d,J=5.2Hz),4.61(2H,s),7.34(1H,d,J=8.0Hz),7.42-7.63(9H,m),7.95(1H,s),8.01(1H,d,J=8.0Hz),8.09(1H,d,J=8.4Hz)

[1196] MS:587.30[M+H] +

[1197] Example 8

[1198] NMR: 1.49 - 1.68 (2H, m), 1.80 - 1.94 (2H, m), 2.05 - 2.22 (1H, m), 2.62 - 2.85 (2H, m), 3.00 - 3.14 (4H, m), 3.15 - 4.27 (10H, m), 4.49 (1H, d, J = 6.0 Hz), 4.69 (2H, s), 7.28 - 7.39 (3H, m), 7.40 - 7.65 (8H, m), 7.67 (1H, s), 7.76 - 7.82 (1H, m)

[1199] MS: 570.35 [M + H] +

[1200] Example 9

[1201] NMR: 1.47 (3H, t, J = 7.0 Hz), 1.55 - 1.72 (2H, m), 1.87 - 2.01 (2H, m), 2.13 - 2.26 (1H, m), 2.73 - 2.88 (2H, m), 3.00 - 3.29 (5H, m), 3.30 - 3.60 (6H, m), 3.63 - 3.79 (1H, m), 3.80 - 3.92 (1H, m), 3.97 - 4.11 (1H, m), 4.25 (2H, q, J = 7.0 Hz), 4.52 (2H, s), 4.55 (1H, d, J = 6.0 Hz), 7.16 (1H, dd, J = 9.0, 9.0 Hz), 7.34 (1H, d, J = 8.0 Hz), 7.41 - 7.62 (7H, m), 7.70 (1H, dd, J = 9.0, 6.2 Hz)

[1202] MS: 627.30 [M + H] +

[1203] Example 10

[1204] NMR: 1.54 - 1.72 (2H, m), 1.89 - 2.00 (2H, m), 2.01 - 2.09 (2H, m), 2.14 - 2.27 (1H, m), 2.74 - 2.90 (4H, m), 3.04 - 3.16 (4H, m), 3.18 - 4.25 (10H, m), 4.32 (2H, t, J = 5.0 Hz), 4.42 (2H, s), 4.55 (H, d, J = 5.6 Hz), 7.00 (1H, dd, J = 7.6, 7.6 Hz), 7.25 (1H, d, J = 6.8 Hz), 7.30 - 7.36 (2H, m), 7.41 - 7.62 (7H, m)

[1205] MS: 587.35 [M + H]+

[1206] Example 11

[1207] NMR: 1.52-1.72(2H,m),1.87-2.01(2H,m),2.14-2.28(1H,m),2.74-2.90(2H,m),2.97-3.27(5H,m),3.29-3.62(6H,m),3.6 6-4.20(3H,m),4.27-4.40(4H,m),4.49(2H,s),4.56(1H,d,J=6.0Hz),6.74(1H,s),7.33(1H,d,J=8.4Hz),7.41-7.62(7H,m)

[1208] MS: 595.25[M+H] +

[1209] Example 12

[1210] NMR: 1.55-1.72(2H,m),1.88-2.01(2H,m),2.14-2.27(1H,m),2.73-2.89(2H,m),3.03-3.26(5H,m),3.31-3.63(6H,m),3.79-4 .19(3H,m),3.94(6H,s),4.52(2H,s),4.55(1H,d,J=6.0Hz),7.10(1H,dd,J=9.2,9.2Hz),7.26-7.36(2H,m),7.41-7.61(7H,m)

[1211] MS:609.30[M+H] +

[1212] Example 13

[1213] NMR: 1.53-1.72(2H,m),1.88-2.00(2H,m),2.15-2.28(1H,m),2.73-2.91(2H,m),3.00-3.28(5H,m),3.30-3.67(6H,m),3.74-4.38 (3H,m),4.56(1H,d,J=6.0Hz),4.64(2H,s),7.33(1H,d,J=8.0Hz),7.41-7.61(7H,m),7.96(1H,d,J=2.0Hz),9.14(1H,d,J=2.0Hz)

[1214] MS: 538.25[M+H] +

[1215] Example 14

[1216] NMR: 1.45(3H,t,J=7.0Hz),1.71-1.94(2H,m),2.02-2.24(2H,m),2.31-2.45(1H, m),3.03-3.48(5H,m),3.51-3.88(6H,m),3.90-4.09(2H,m),4.13-4.40(3H,m),4. 54(2H,s),4.61-4.84(3H,m),6.92(1H,dd,J=8.8,8.8Hz),6.97-7.06(2H,m),7.51 -7.59(1H,m),7.98(1H,d,J=10.0Hz),8.13(1H,d,J=9.6Hz),8.60(1H,d,J=2.4Hz)

[1217] MS:569.30[M+H] +

[1218] Example 15

[1219] NMR: 1.54-1.73(2H,m),1.88-2.03(2H,m),2.16-2.28(1H,m),2.75-2.90(2H,m),2.99-3.29(4H,m),3.34-3.66(6H ,m),3.68-4.39(4H,m),4.57(1H,d,J=6.0Hz),4.61(2H,s),7.31-7.38(2H,m),7.40-7.62(8H,m),7.68-7.77(1H,m)

[1220] MS:633.30[M+H] +

[1221] Example 16

[1222] NMR: 1.56-1.73(2H,m),1.89-2.02(2H,m),2.15-2.29(1H,m),2.75-2.89(2H,m),3.01-3.28(4H,m),3.30-3.65(6H,m),3.68-4.39 (4H,m),4.53-4.61(3H,m),7.06(1H,t,J=72.4Hz),7.19-7.27(2H,m),7.34(1H,d,J=8.0Hz),7.41-7.62(7H,m),7.62-7.72(1H,m)

[1223] MS:615.30[M+H] +

[1224] Example 17

[1225] NMR: 1.55-1.73(2H,m),1.90-2.02(2H,m),2.13-2.27(1H,m),2.35(3H,s),2.75-2.90(2H,m),3.00-3.29(5H,m),3.31-3.65(6H,m),3. 76-4.24(3H,m),3.88(3H,s),4.52(2H,s),4.55(1H,d,J=6.0Hz),7.06(1H,dd,J=9.0,9.0Hz),7.34(1H,d,J=8.0Hz),7.42-7.65(8H,m)

[1226] MS: 593.35[M+H] +

[1227] Example 18

[1228] NMR: 1.55-1.73(2H,m),1.88-2.03(2H,m),2.14-2.27(1H,m),2.74-2.90(2H,m),3.02-3.28(5H,m),3.29-3.73(6H,m),3.7 4-4.25(3H,m),4.44-4.61(5H,m),6.37(1H,tt,J=54.0,3.0Hz),6.97-7.06(2H,m),7.34(1H,d,J=8.4Hz),7.41-7.65(8H,m)

[1229] MS:629.30[M+H] +

[1230] Example 19

[1231] NMR: 1.55-1.73(2H,m),1.89-2.04(2H,m),2.14-2.28(1H,m),2.74-2.90(2H m),3.04-3.16(4H,m),3.17-4.28(10H,m),4.43-4.60(5H,m),6.37(1H,tt, J=54.2,3.1Hz),7.17-7.24(2H,m),7.34(1H,d,J=8.0Hz),7.41-7.64(9H,m)

[1232] MS:611.30[M+H] +

[1233] Example 20

[1234] NMR: 1.56 - 1.73 (2H, m), 1.89 - 2.01 (2H, m), 2.14 - 2.27 (1H, m), 2.76 - 2.89 (2H, m), 3.06 - 3.29 (4H, m), 3.30 - 3.72 (7H, m), 3.80 - 3.96 (1H, m), 3.98 - 4.36 (5H, m), 4.53 (2H, s), , 4.56 (1H, d, J = 6.0 Hz), 7.04 (1H, ddd, J = 9.0, 9.0, 3.6 Hz), 7.34 (1H, d, J = 8.0 Hz), 7.37 - 7.62 (8H, m)

[1235] MS: m / z 597.30 [M + H]+ +

[1236] Example 21

[1237] NMR: 1.45 (3H, t, J = 7.0 Hz), 1.55 - 1.73 (2H, m), 1.88 - 2.02 (2H, m), 2.15 - 2.28 (1H, m), 2.74 - 2.91 (2H, m), 3.03 - 3.16 (4H, m), 3.17 - 3.98 (9H, m), 4.10 - 4.30 (​​​​​​​​​​​​​​

[1242] Example 23

[1243] NMR: 1.44(3H,t,J=7.0Hz),1.56-1.72(2H,m),1.88-2.01(2H,m),2.15-2.27(1H,m),2.76-2.90(2H,m),3.05-3.16(5H,m),3.17-4.1 4(9H,m),4.20(2H,q,J=6.9Hz),4.47(2H,s),4.57(1H,d,J=6.0Hz),7.16(1H,dd,J=9.0,4.5Hz),7.24-7.37(3H,m),7.40-7.62(7H,m)

[1244] MS: 593.30[M+H] +

[1245] Example 24

[1246] NMR: 1.55-1.74(2H,m),1.88-2.02(2H,m),2.16-2.30(1H,m),2.76-2.91(2H,m),3.04-3.29(4H,m),3.31-3.66 (6H,m),3.68-4.41(4H,m),4.51-4.62(3H,m),7.28-7.36(3H,m),7.39(1H,dd,J=6.8,2.8Hz),7.41-7.62(7H,m)

[1247] MS:611.30[M+H] +

[1248] Example 25

[1249] NMR: 1.44(3H,t,J=7.0Hz),1.57-1.72(2H,m),1.89-2.02(2H,m),2.15-2.24(1H,m),2.25(3H,d,J=1.2Hz),2.75-2.90(2H,m),3.02-3. 29(5H,m),3.30-4.15(9H,m),4.21(2H,q,J=7.1Hz),4.49-4.59(3H,m),6.91(1H,d,J=8.4Hz),7.34(1H,d,J=8.4Hz),7.38-7.62(8H,m)

[1250] MS: 607.35[M+H] +

[1251] Example 26

[1252] NMR: 1.29 (3H, t, J = 7.4 Hz), 1.55 - 1.72 (2H, m), 1.90 - 2.02 (2H, m), 2.14 - 2.28 (1H, m), 2.75 - 2.90 (2H, m), 3.02 - 3.29 (5H, m), 3.07 (2H, q, J = 7.3 Hz), 3.34 - 3.64 (6H, m), 3.77 - 4.23 (3H, m), 4.56 (1H, d, J = 6.0 Hz), 4.65 (2H, s), 7.34 (1H, d, J = 8.0 Hz), 7.41 - 7.63 (10H, m), 7.67 - 7.72 (1H, m)

[1253] MS: 591.35 [M + H] +

[1254] Example 27

[1255] NMR: 1.31 (3H, t, J = 7.4 Hz), 1.57 - 1.73 (2H, m), 1.91 - 2.02 (2H, m), 2.16 - 2.28 (1H, m), 2.77 - 2.89 (2H, m), 3.02 - 3.30 (7H, m), 3.36 - 3.70 (6H, m), 3.80 - 4.38 (3H, m), 4.57 (1H, d, J = 6.0 Hz), 4.70 (2H, s), 7.21 (1H, dd, J = 8.6, 8.6 Hz), 7.34 (1H, d, J = 8.0 Hz), 7.41 - 7.52 (5H, m), 7.52 - 7.64 (4H, m)

[1256] MS: 609.25 [M + H] +

[1257] Example 28

[1258] NMR: 1.57 - 1.73 (2H, m), 1.90 - 2.02 (2H, m), 2.16 - 2.28 (1H, m), 2.62 (3H, s), 2.75 - 2.90 (2H, m), 3.04 - 3.29 (4H, m), 3.33 - 3.75 (7H, m), 3.79 - 4.37 (3H, m), 4.57 (1H, d, J = 6.0 Hz), 4.66 (2H, s), 7.17 (1H, dd, J = 9.0, 9.0 Hz), 7.34 (1H, d, J = 8.4 Hz), 7.38 (1H, d, J = 8.0 Hz), 7.42 - 7.52 (4H, m), 7.52 - 7.64 (4H, m)

[1259] MS: 595.25[M+H] +

[1260] Example 29

[1261] NMR: 1.56-1.73(2H,m),1.89-2.03(2H,m),2.16-2.27(1H,m),2.61(3H,s),2.76-2.90(2H,m),3.05-3.30(4H,m),3.31-3.71(7H ,m),3.73-4.30(3H,m),4.52-4.60(1H,m),4.56(2H,s),7.11(1H,ddd,J=8.4,8.4,2.4Hz),7.28-7.37(2H,m),7.41-7.62(8H,m)

[1262] MS: 595.25[M+H] +

[1263] Example 30

[1264] NMR: 1.33(3H,t,J=7.2Hz),1.56-1.71(2H,m),1.89-2.01(2H,m),2.15-2.27(1H,m),2.76-2.89(2H,m),3.05-3.30(7H,m),3.32-3.64(6 H,m),3.73-4.32(3H,m),4.56(1H,d,J=6.0Hz),4.58(2H,s),7.15(1H,ddd,J=8.4,8.4,2.8Hz),7.34(1H,d,J=8.4Hz),7.38-7.62(9H,m)

[1265] MS:609.30[M+H] +

[1266] Example 31

[1267] [Chemical Formula 100]

[1268]

[1269] To 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 (80 mg) were added anisole (0.16 mL) and a 5.1 mol / L hydrobromic acid / acetic acid solution (0.8 mL), followed by stirring at room temperature for 1 hour. Ethyl acetate (10 mL) was added to the reaction mixture, stirred at room temperature for 30 minutes, and the solid was collected by filtration. The solid substance was dried under reduced pressure to obtain (R)-2-amino-1-(4-(benzo[b]thiophen-7-ylmethyl)piperazin-1-yl)-2-(1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)ethan-1-one hydrobromide (60 mg) as a white solid.

[1270] NMR: 1.52-1.70(2H,m),1.86-2.00(2H,m),2.09-2.24(1H,m),2.73-2.86(2H,m),3.03-3.19(4H,m),3.31-3.54(6H,m),3.58-4.33(4H ,m),4.52(1H,d,J=6.0Hz),4.68(2H,s),7.34(1H,d,J=8.4Hz),7.41-7.63(10H,m),7.75(1H,d,J=5.6Hz),8.09(1H,dd,J=5.2,3.6Hz)

[1271] MS: 587.25[M+H] +

[1272] In the same manner as in Example 31, the compounds shown in Table 29 were obtained.

[1273] [Table 29]

[1274]

[1275]

[1276] The measured values ​​of NMR and MS of the compounds in the table are shown.

[1277] Example 32

[1278] NMR: 1.66-1.85(2H,m),2.02-2.14(2H,m),2.24-2.41(1H,m),3.02-3.21(5H,m),3.40-3.63(6H,m),3.70-3.83(3H,m),3.87-4.10(2H,m), 4.59(1H,d,J=6.0Hz),4.71(2H,s),7.30-7.42(4H,m),7.43-7.50(2H,m),7.58-7.73(3H,m),7.99(1H,d,J=7.6Hz),8.13(1H,d,J=16.0Hz)

[1279] MS: 515.35[M+H] + ,513.25[MH] -

[1280] Example 33

[1281] NMR: 1.49(3H,t,J=7.0Hz),1.67-1.84(2H,m),2.02-2.15(2H,m),2.24-2.39(1H,m ),3.00-3.24(5H,m),3.26-4.09(11H,m),4.27(2H,q,J=7.1Hz),4.60(1H,d,J=5.2H z),4.74(2H,s),7.26(1H,d,J=8.4Hz),7.32(1H,d,J=16.0Hz),7.36-7.42(3H,m), 7.43-7.49(2H,m),7.54(1H,d,J=8.0Hz),7.61-7.68(1H,m),8.09(1H,d,J=16.4Hz)

[1282] MS: 559.35[M+H] + ,557.25[MH] -

[1283] Example 34

[1284] NMR: 1.47(3H,t,J=7.0Hz),1.70-1.87(2H,m),2.05-2.16(2H,m),2.28-2.4 2(1H,m),3.08-3.20(4H,m),3.40-3.71(8H,m),3.74-3.99(4H,m),4.21-4.3 4(2H,m),4.59-4.72(3H,m),6.26(1H,d,J=16.4Hz),7.21-7.31(1H,m),7.3 5-7.43(3H,m),7.43-7.50(3H,m),7.58-7.71(1H,m),7.99(1H,d,J=16.4Hz)

[1285] MS: 516.35[M+H] +

[1286] Example 35

[1287] NMR: 1.44(3H,t,J=7.0Hz),1.53-1.70(2H,m),1.89-2.00(2H,m),2.13-2.24(1H,m),2.74-2.88(2H,m),3.00-3.27(5H,m),3.29-3.57(6H,m) ),3.59-4.11(3H,m),4.20(2H,q,J=7.1Hz),4.49(2H,s),4.53(1H,d,J=6.0Hz),6.90-6.97(1H,m),7.34(1H,d,J=8.0Hz),7.41-7.62(8H,m)

[1288] MS:611.30[M+H] +

[1289] Example 36

[1290] NMR: 1.54-1.70(2H,m),1.86-2.00(2H,m),2.12-2.24(1H,m),2.74-2.87(2H,m),2.99-3.21(4H,m),3.23-3.52(6H,m),3.5 5-4.25(4H,m),4.35(2H,s),4.52(1H,d,J=6.0Hz),6.08(2H,s),6.94-7.08(3H,m),7.34(1H,d,J=8.4Hz),7.41-7.61(7H,m)

[1291] MS: 575.25[M+H] +

[1292] Example 37

[1293] NMR: 1.54 - 1.71 (2H, m), 1.86 - 2.00 (2H, m), 2.14 - 2.26 (1H, m), 2.72 - 2.90 (2H, m), 3.01 - 3.26 (5H, m), 3.27 - 3.68 (6H, m), 3.69 - 4.19 (3H, m), 4.33 - 4.48 (6H, m), 4.54 (1H, d, J = 5.6 Hz), 6.98 - 7.07 (2H, m), 7.11 (1H, dd, J = 7.6, 2.0 Hz), 7.34 (1H, d, J = 8.4 Hz), 7.42 - 7.61 (7H, m)

[1294] MS: 589.30 [M + H] +

[1295] Example 38

[1296] NMR: 1.53 - 1.71 (2H, m), 1.88 - 2.00 (2H, m), 2.13 - 2.25 (1H, m), 2.73 - 2.88 (2H, m), 2.97 - 3.23 (5H, m), 3.24 - 3.62 (8H, m), 3.65 - 4.22 (3H, m), 4.38 (2H, s), 4.53 (1H, d, J = 5.6 Hz), 4.69 (2H, t, J = 8.8 Hz), 7.02 (1H, dd, J = 7.4, 7.4 Hz), 7.23 (1H, d, J = 7.2 Hz), 7.34 (1H, d, J = 8.4 Hz), 7.42 - 7.62 (8H, m)

[1297] MS: 573.30 [M + H] +

[1298] Example 39

[1299] NMR: 1.50 - 1.67 (2H, m), 1.82 - 1.98 (2H, m), 2.07 - 2.19 (1H, m), 2.69 - 2.85 (2H, m), 3.07 - 3.14 (4H, m), 3.16 - 3.42 (6H, m), 3.58 - 4.08 (4H, m), 4.46 (1H, d, J = 5.6 Hz), 4.5 (2H, s), 7.03 (1H, d, J = 2.0 Hz), 7.34 (1H, d, J = 8.0 Hz), 7.38 - 7.61 (9H, m), 7.84 (1H, d, J = 7.2 Hz), 7.88 (1H, d, J = 2.4 Hz)

[1300] MS: 571.30 [M + H] +

[1301] Example 40

[1302] NMR: 1.50-1.72(2H,m),1.80-2.00(2H,m),2.09-2.26(1H,m),2.70-2.89(2H,m),2.99-3.15(4H,m),3.24- 3.60(7H,m),3.72-4.06(3H,m),4.41(2H,s),4.53(1H,d,J=5.6Hz),6.95-7.07(1H,m),7.14-7.77(12H,m)

[1303] MS: 570.75[M+H] +

[1304] Example 41

[1305] NMR: 1.03-1.21(1H,m),1.27-1.47(2H,m),1.42(3H,t,J=7.0Hz),1.47-1.95(9H,m), 1.96-2.27(2H,m),2.28-2.42(1H,m),2.65-2.94(1H,m),2.94-3.52(6H,m),3.52-3. 96(5H,m),3.97-4.37(2H,m),4.20(2H,q,J=6.9Hz),4.41-4.68(2H,m),4.51(2H,s), 6.88(1H,dd,J=9.0,9.0Hz),6.96(1H,d,J=8.4Hz),7.52(1H,ddd,J=8.5,8.5,7.1Hz)

[1306] MS: 475.30[M+H] +

[1307] Example 42

[1308] NMR: 1.44(3H,t,J=7.0Hz),1.70-1.98(2H,m),2.01-2.24(2H,m),2.26-2.46(1H,m),2.99-3. 22(2H,m),3.22-3.62(8H,m),3.62-3.94(5H,m),4.21(2H,q,J=7.1Hz),4.24-4.39(1H,m),4. 51(2H,s),4.59-4.70(1H,m),6.89(1H,dd,J=9.0,9.0Hz),6.96(1H,d,J=8.8Hz),7.42-7.58( 3H,m),7.58-7.75(2H,m),7.92(1H,d,J=7.6Hz),8.01(1H,d,J=8.4Hz),8.07(1H,d,J=8.4Hz)

[1309] MS: 533.30[M+H] +

[1310] Example 43

[1311] NMR: 1.43(3H,t,J=7.0Hz),1.67-1.92(2H,m),1.99-2.19(2H,m),2.24-2.39(1H,m),3 .02-3.29(4H,m),3.31-3.60(7H,m),3.61-4.12(5H,m),4.21(2H,q,J=7.1Hz),4.50(2H ,s),4.59(1H,d,J=6.0Hz),6.89(1H,dd,J=8.8,8.8Hz),6.97(1H,d,J=8.4Hz),7.21-7 .31(1H,m),7.34-7.44(2H,m),7.52(1H,ddd,J=8.5,8.5,6.9Hz),7.68(1H,d,J=8.0Hz)

[1312] MS: 563.20[M+H] + ,561.20[MH] -

[1313] Example 44

[1314] [Chemical Formula 101]

[1315]

[1316] To benzyl (R)-(1-(1-(2-(2',4-dichloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (240 mg) were added anisole (0.48 mL) and a 5.1 mol / L hydrobromic acid / acetic acid solution (2.4 mL), followed by stirring at room temperature for 1 hour. Ethyl acetate (10 mL) and diethyl ether (20 mL) were added to the reaction mixture, stirred at room temperature for 30 minutes, and the solid was collected by filtration. The solid substance was dried under reduced pressure to obtain (R)-2-amino-2-(1-(2-(2',4-dichloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrobromide (237 mg) as a light yellow solid.

[1317] NMR: 1.41(3H,t,J=7.0Hz),1.49-1.70(2H,m),1.82-2.01(2H,m),2.06-2.26(1H,m),2.69-3 .03(4H,m),3.03-3.24(2H,m),3.24-3.53(6H,m),3.59-3.90(2H,m),3.90-4.14(2H,m),4.2 0(2H,q,J=6.9Hz),4.43(2H,s),4.48(1H,d,J=6.0Hz),6.88(1H,dd,J=8.8,8.8Hz),6.96(1H ,d,J=8.8Hz),7.27(1H,d,J=8.4Hz),7.34-7.42(1H,m),7.42-7.59(5H,m),7.59-7.68(1H,m)

[1318] MS:627.30[M+H] +

[1319] In the same manner as in Example 44, the compounds shown in Table 30 were obtained.

[1320] [Table 30]

[1321]

[1322]

[1323]

[1324]

[1325]

[1326]

[1327]

[1328]

[1329] The measured values ​​of NMR and MS of the compounds in the table are shown.

[1330] Example 45

[1331] NMR: 1.63-1.86(2H,m),1.97-2.19(2H,m),2.20-2.41(1H,m),2.92-3.20(4H,m),3.20-3.50(5H,m),3.62-3.92(5H,m),4.06-4.39(1H,m) ,4.40-4.69(4H,m),4.69-4.82(2H,m),7.01(1H,d,J=8.8Hz),7.03(1H,d,J=8.4Hz),7.26-7.51(5H,m),7.59(1H,ddd,J=8.5,8.5,6.9Hz)

[1332] MS: 537.25[M+H] +

[1333] Example 46

[1334] NMR: 1.41(3H,t,J=7.0Hz),1.65-1.87(2H,m),1.95-2.16(2H,m),2.21-2.39( 1H,m),2.97-3.22(4H,m),3.22-3.62(7H,m),3.62-3.83(3H,m),3.84-3.98(1 H,m),3.98-4.12(1H,m),4.17(2H,q,J=7.1Hz),4.49(2H,s),4.59(1H,d,J=6. 0Hz),6.90(1H,ddd,J=9.6,3.2,1.6Hz),7.31-7.38(3H,m),7.38-7.49(3H,m)

[1335] MS:501.30[M+H] +

[1336] Example 47

[1337] NMR: 0.88-1.05(2H,m),1.07-1.38(4H,m),1.42(3H,t,J=7.0Hz),1.52-1.93(9H,m ),1.93-2.16(2H,m),2.16-2.39(1H,m),3.00(2H,t,J=12.8Hz),3.09-3.22(2H,m), 3.22-3.79(7H,m),3.80-4.15(3H,m),4.20(2H,q,J=6.9Hz),4.49(2H,s),4.57(1H ,d,J=6.0Hz),6.89(1H,dd,J=8.8,8.8Hz),6.97(1H,d,J=8.4Hz),7.43-7.59(1H,m)

[1338] MS:489.30[M+H] +

[1339] Example 48

[1340] NMR: 1.41(3H,t,J=7.0Hz),1.54-1.74(2H,m),1.88-2.04(2H,m),2.12-2.29(1H, m),2.75-2.97(2H,m),2.97-3.20(4H,m),3.20-3.72(7H,m),3.72-4.15(3H,m),4. 20(2H,q,J=7.1Hz),4.51(2H,s),4.59(1H,d,J=6.4Hz),6.88(1H,dd,J=8.8,8.8H z),6.96(1H,d,J=8.4Hz),6.99-7.11(3H,m),7.28-7.38(1H,m),7.39-7.60(4H,m)

[1341] MS:595.30[M+H] +

[1342] Example 49

[1343] NMR: 1.41 (3H, t, J = 7.0 Hz), 1.51 - 1.75 (2H, m), 1.85 - 2.10 (2H, m), 2.12 - 2.32 (1H, m), 2.70 - 3.04 (4H, m), 3.04 - 3.68 (9H, m), 3.68 - 4.15 (3H, m), 4.20 (2H, q, J = 7.1 Hz), 4.50 (2H, s), 4.54 (1H, d, J = 6.0 Hz), 6.88 (1H, dd, J = 9.0, 9.0 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.24 - 7.33 (1H, m), 7.41 - 7.56 (6H, m), 7.59 (1H, d, J = 8.8 Hz)

[1344] MS: 627.25 [M + H] +

[1345] Example 50

[1346] NMR: 1.42 (3H, t, J = 7.0 Hz), 1.51 - 1.69 (2H, m), 1.82 - 2.01 (2H, m), 2.10 - 2.27 (1H, m), 2.67 - 2.91 (2H, m), 2.96 - 3.16 (4H, m), 3.16 - 4.02 (9H, m), 4.04 - 4.29 (1H, m), 4.20 (2H, q, J = 7.1 Hz), 4.51 (2H, s), 4.53 (1H, d, J = 6.4 Hz), 6.88 (1H, dd, J = 8.8, 8.8 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.10 - 7.25 (2H, m), 7.32 (1H, dd, J = 8.4, 6.0 Hz), 7.36 - 7.45 (2H, m), 7.45 - 7.63 (4H, m)

[1347] MS: 577.30 [M + H] +

[1348] Example 51

[1349] NMR: 1.42 (3H, t, J = 7.0 Hz), 1.50 - 1.70 (2H, m), 1.84 - 2.01 (2H, m), 2.09 - 2.25 (lH, m), 2.69 - 2.90 (2H, m), 2.96 - 3.13 (4H, m), 3.13 - 3.73 (8H, m), 3.7? - 4.13 (ZH, m), Z.88 (3H, s), Z.ZO (ZH, q, J = 6.9 Hz), 4.51 (ZH, s), 4.53 (lH, d, J = 6.OHz), 6.88 (lH, dd, J = 8.8, 8.8 Hz), Z.96 (lH, d, J = 8.4 Hz), Z.99 - 7.08 (ZH, m), 7.29 (lH, d, J = 8.0 Hz), Z.33 - 7.43 (ZH,m), 7.43 - 7.60 (4H, m)

[1350] MS: 589.35 [M+H] +

[1351] Example 52

[1352] NMR: 1.42 (3H, t, J = 7.0 Hz), 1.51 - 1.72 (2H, m), 1.86 - 2.02 (2H, m), 2.09 - 2.28 (lH, m), 2.74 - 2.94 (2H, m), 3.00 - 3.18 (4H, m), 3.18 - 3.95 (10H, m), 4.20 (ZH, q, J = 6.9 Hz), 4.51 (ZH, s), 4.54 (lH, d, J = 6.OHz), 6.88 (lH, dd, J = 9.0, 9.0 Hz), Z.96 (lH, d, J = 8.8 Hz), 7.16 (lH, d, J = 7.6 Hz), 7.21 (lH, dd, J = 9.2, 9.2 Hz), Z.35 - 7.46 (3H, m), 7.47 - 7.62 (4H, m)

[1353] MS: 577.30 [M+H] +

[1354] Example 53

[1355] NMR: 1.42(3H,t,J=7.0Hz),1.51-1.72(2H,m),1.85-2.03(2H,m),2.10-2.27(1 H,m),2.70-2.95(2H,m),2.96-3.25(5H,m),3.25-3.90(9H,m),4.20(2H,q,J=6. 9Hz),4.51(2H,s),4.53(1H,d,J=6.0Hz),6.88(1H,dd,J=8.8,8.8Hz),6.94(1H ,d,J=8.4Hz),7.25(1H,dd,J=7.6,0.8Hz),7.32-7.44(3H,m),7.46-7.63(5H,m)

[1356] MS: 593.30[M+H] +

[1357] Example 54

[1358] NMR(CD3OD): 1.51(3H,t,J=7.0Hz),1.83-2.23(4H,m),2.23-2.47

[1359] (1H,m),3.26-3.55(6H,m),3.55-3.98(5H,m),3.99-4.19(2H,m),4.24(2H,q,J=7.1Hz),4.40-4.6 3(3H,m),4.64-4.78(1H,m),6.89(1H,dd,J=8.6,8.6Hz),6.99(1H,d,J=8.4Hz),7.42-7.77(6H,m)

[1360] MS:519.30[M+H] +

[1361] Example 55

[1362] NMR: 1.42 (3H, t, J = 7.0 Hz), 1.55 - 1.76 (2H, m), 1.86 - 2.05 (2H, m), 2.14 - 2.34 (1H, m), 2.72 - 3.04 (4H, m), 3.04 - 3.26 (2H, m), 3.26 - 3.69 (7H, m), 3.74 - 4.14 (3H, m), 4.20 (2H, q, J = 6.9 Hz), 4.50 (2H, s), 4.54 (1H, d, J = 6.0 Hz), 6.89 (1H, dd, J = 8.8, 8.8 Hz), 6.96 (1H, d, J = 8.8 Hz), 7.25 (1H, d, J = 8.0 Hz), 7.39 - 7.56 (5H, m), 7.59 (1H, d, J = 8.4 Hz)

[1363] MS: 661.20 [M + H] +

[1364] Example 56

[1365] NMR: 1.43 (3H, t, J = 7.0 Hz), 1.53 - 1.89 (6H, m), 1.89 - 2.24 (6H, m), 2.24 - 2.43 (1H, m), 2.87 - 3.18 (4H, m), 3.18 - 3.62 (7H, m), 3.62 - 4.16 (5H, m), 4.21 (2H, q, J = 6.9 Hz), 4.50 (2H, s), 4.59 (1H, d, J = 6.0 Hz), 5.57 - 5.74 (1H, m), 6.89 (1H, dd, J = 8.8, 8.8 Hz), 6.97 (1H, d, J = 8.4 Hz), 7.17 (1H, d, J = 8.0 Hz), 7.26 - 7.42 (2H, m), 7.48 - 7.59 (1H, m)

[1366] MS: 597.30 [M + H] +

[1367] Example 57

[1368] NMR: 1.42 (3H, t, J = 7.0 Hz), 1.53 - 1.73 (2H, m), 1.85 - 2.03 (2H, m), 2.11 - 2.28 (1H, m), 2.65 - 2.94 (2H, m), 2.94 - 3.26 (4H, m), 3.26 - 3.58 (6H, m), 3.58 - 4.15 (4H, m), 4.21 (2H, q, J = 6.8 Hz), 4.45 (2H, s), 4.50 (1H, d, J = 5.6 Hz), 6.89 (1H, dd, J = 8.8, 8.8 Hz), 6.97 (1H, d, J = 8.8 Hz), 7.33 (1H, d, J = 8.0 Hz), 7.39 - 7.57 (3H, m), 7.57 - 7.67 (1H, m), 7.71 (1H, dd, J = 7.8, 7.8 Hz), 7.95 (1H, s), 7.98 (1H, d, J = 8.4 Hz)

[1369] MS: 719.25 [M + H] +

[1370] Example 58

[1371] [[ID=IO]]NMR: 1.41 (3H, t, J = 7.0 Hz), 1.50 - 1.73 (2H, m), 1.81 - 1.99 (2H, m), 1.87 (3H, s), 1.90 (3H, s), 2.12 - 2.28 (1H, m), 2.71 - 2.97 (2H, m), 2.97 - 3.22 (4H, m), 3.22 - 3.65 (7H, m), 3.68 - 4.29 (3H, m), 4.20 (2H, q, J = 6.9 Hz), 4.49 (2H, s), 4.52 (1H, d, J = 6.0 Hz), 6.88 (1H, dd, J = 8.8, 8.8 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.31 (1H, d, J = 8.4 Hz), 7.41 - 7.57 (3H, m), 7.65 (1H, dd, J = 7.6, 1.2 Hz), 7.69 - 7.79 (2H, m), 7.80 - 7.89 (1H, m)

[1372] MS: 669.30 [M + H] +

[1373] Example 59

[1374] NMR: 1.42(3H,t,J=7.0Hz),1.71-1.92(2H,m),2.01-2.19(2H,m),2.21-2.40 (1H,m),3.07-3.27(2H,m),3.27-3.62(5H,m),3.62-4.16(7H,m),4.21(2H,q ,J=7.1Hz),4.45(2H,s),4.56(1H,d,J=6.0Hz),6.04[6.16](1H,dd,J=10.4, 2.0Hz),6.89(1H,dd,J=8.8,8.8Hz),6.97(1H,d,J=8.4Hz),7.42-7.59(6H,m)

[1375] MS:501.30[M+H] +

[1376] Example 60

[1377] NMR: 1.42(3H,t,J=7.0Hz),1.50-1.74(2H,m),1.81-2.05(2H,m),2.07-2.28(1H,m ),2.66-2.96(2H,m),2.96-3.21(4H,m),3.21-3.53(6H,m),3.61-4.16(4H,m),4.2 0(2H,q,J=7.1Hz),4.44(2H,s),4.49(1H,d,J=6.0Hz),6.88(1H,dd,J=8.8,8.8Hz) ,6.96(1H,d,J=8.4Hz),7.13-7.28(3H,m),7.31(1H,d,J=8.4Hz),7.39-7.61(4H,m)

[1378] MS: 611.25[M+H] +

[1379] Example 61

[1380] NMR: 1.42 (3H, t, J = 7.0 Hz), 1.49 - 1.71 (2H, m), 1.79 - 2.04 (2H, m), 2.04 - 2.24 (1H, m), 2.66 - 2.94 (2H, m), 2.94 - 3.20 (4H, m), 3.20 - 3.53 (6H, m), 3.60 - 4.15 (4H, m), 4.20 (2H, q, J = 6.9 Hz), 4.44 (2H, s), 4.49 (1H, d, J = 5.6 Hz), 6.88 (1H, dd, J = 8.8, 8.8 Hz), 6.96 (1H, d, J = 8.8 Hz), 7.20 - 7.35 (3H, m), 7.35 - 7.57 (5H, m)

[1381] MS: 611.30 [M + H] +

[1382] Example 62

[1383] NMR: 1.42 (3H, t, J = 7.0 Hz), 1.50 - 1.74 (2H, m), 1.80 - 2.06 (2H, m), 2.06 - 2.33 (1H, m), 2.69 - 2.96 (2H, m), 2.96 - 3.22 (4H, m), 3.22 - 3.57 (6H, m), 3.58 - 4.15 (4H, m), 4.20 (2H, q, J = 6.9 Hz), 4.46 (2H, s), 4.49 (1H, d, J = 6.4 Hz), 6.88 (1H, dd, J = 8.8, 8.8 Hz), 6.96 (1H, d, J = 8.8 Hz), 7.21 - 7.39 (2H, m), 7.39 - 7.59 (6H, m)

[1384] MS: 627.25 [M + H] +

[1385] Example 63

[1386] NMR: 1.41 (3H, t, J = 7.0 Hz), 1.51 - 1.72 (2H, m), 1.84 - 2.02 (2H, m), 2.11 - 2.29 (1H, m), 2.67 - 2.93 (2H, m), 2.93 - 3.15 (4H, m), 3.15 - 3.69 (7H, m), 3.69 - 4.14 (3H, m), 4.20 (2H, q, J = 6.9 Hz), 4.51 (2H, s), 4.52 (1H, d, J = 5.6 Hz), 6.88 (1H, dd, J = 9.0, 9.0 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.28 (1H, d, J = 8.0 Hz), 7.37 (2H, d, J = 8.0 Hz), 7.40 - 7.48 (2H, m), 7.48 - 7.62 (3H, m)

[1387] MS: 627.25 [M + H] +

[1388] Example 64

[1389] NMR: 1.41 (3H, t, J = 7.0 Hz), 1.50 - 1.73 (2H, m), 1.83 - 2.04 (2H, m), 2.08 - 2.27 (1H, m), 2.67 - 3.07 (4H, m), 3.07 - 3.25 (2H, m), 3.25 - 3.53 (6H, m), 3.59 - 4.15 (4H, m), 4.20 (2H, q, J = 6.9 Hz), 4.43 (2H, s), 4.48 (1H, d, J = 6.0 Hz), 6.88 (1H, dd, J = 8.8, 8.8 Hz), 6.96 (1H, d, J = 8.8 Hz), 7.36 (1H, d, J = 8.0 Hz), 7.45 - 7.59 (4H, m), 7.65 (1H, ddd, J = 7.8, 7.8, 1.0 Hz), 7.83 (1H, ddd, J = 7.6, 7.6, 1.2 Hz), 7.95 (1H, d, J = 8.0 Hz)

[1390] MS: 618.30 [M + H] +

[1391] Example 65

[1392] NMR: 1.42 (3H, t, J = 7.0 Hz), 1.53 - 1.72 (2H, m), 1.83 - 2.02 (2H, m), 2.11 - 2.29 (1H, m), 2.67 - 2.95 (2H, m), 2.95 - 3.22 (4H, m), 3.22 - 3.58 (6H, m), 3.58 - 4.11 (4H, m), 4.20 (2H, q, J = 7.1 Hz), 4.47 (2H, s), 4.51 (1H, d, J = 6.0 Hz), 6.88 (1H, dd, J = 8.8, 8.8 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.30 (1H, d, J = 8.4 Hz), 7.40 - 7.57 (3H, m), 7.57 - 7.76 (2H, m), 7.81 (1H, s), 7.83 - 7.92 (1H, m)

[1393] MS: 618.30 [M + H] +

[1394] Example 66

[1395] NMR: 1.42 (3H, t, J = 7.0 Hz), 1.52 - 1.75 (2H, m), 1.84 - 2.06 (2H, m), 2.12 - 2.29 1H, m), 2.68 - 2.94 (2H, m), 2.94 - 3.21 (4H, m), 3.21 - 3.60 (6H, m), 3.60 - 4.15 (4H, m), 4.20 (2H, q, J = 7.1 Hz), 4.47 (2H, s), 4.51 (1H, d, J = 6.0 Hz), 6.89 (1H, dd, J = 8.8, 8.8 Hz), 6.96 (1H, d, J = 8.8 Hz), 7.31 (1H, d, J = 8.4 Hz), 7.41 - 7.66 (5H, m), 7.91 (2H, d, J = 8.4 Hz)

[1396] MS: 618.30 [M + H] +

[1397] Example 67

[1398] NMR: 1.41 (3H, t, J = 7.0 Hz), 1.49 - 1.70 (2H, m), 1.80 - 1.98 (2H, m), 2.05 (3H, s), 2.11 - 2.28 (1H, m), 2.59 - 2.87 (2H, m), 2.87 - 3.24 (4H, m), 3.24 - 3.70 (7H, m), 3.70 - 4.14 (3H, m), 4.20 (2H, q, J = 6.9 Hz), 4.44 - 4.58 (1H, m), 4.50 (2H, s), 6.88 (1H, dd, J = 8.8, 8.8 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.21 (1H, dd, J = 8.4, 8.4 Hz), 7.31 - 7.60 (6H, m)

[1399] MS: 607.30 [M + H] +

[1400] Example 68

[1401] NMR: 1.42 (3H, t, J = 7.0 Hz), 1.50 - 1.72 (2H, m), 1.72 - 2.04 (2H, m), 2.04 - 2.27 (1H, m), 2.40 (3H, s), 2.64 - 2.94 (2H, m), 2.94 - 3.20 (4H, m), 3.20 - 3.58 (6H, m), 3.59 - 4.14 (4H, m), 4.20 (2H, q, J = 6.8 Hz), 4.47 (2H, s), 4.50 (1H, d, J = 5.6 Hz), 6.88 (1H, dd, J = 8.8, 8.8 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.20 (1H, d, J = 7.2 Hz), 7.25 (1H, s), 7.27 (1H, d, J = 8.0 Hz), 7.34 (1H, d, J = 7.6 Hz), 7.39 - 7.58 (4H, m)

[1402] MS: 607.30 [M + H] +

[1403] Example 69

[1404] NMR: 1.42 (3H, t, J = 7.0 Hz), 1.51 - 1.72 (2H, m), 1.81 - 2.07 (2H, m), 2.07 - 2.30 (1H, m), 2.41 (3H, s), 2.66 - 2.95 (2H, m), 2.95 - 3.21 (4H, m), 3.21 - 3.60 (6H, m), 3.60 - 4.15 (4H, m), 4.20 (2H, q, J = 6.9 Hz), 4.48 (2H, s), 4.51 (1H, d, J = 6.0 Hz), 6.88 (1H, dd, J = 8.8, 8.8 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.18 - 7.34 (3H, m), 7.34 - 7.47 (4H, m), 7.47 - 7.60 (1H, m)

[1405] MS: 607.30 [M + H] +

[1406] Example 70

[1407] NMR: 1.41 (3H, t, J = 7.0 Hz), 1.50 - 1.74 (2H, m), 1.85 - 2.03 (2H, m), 2.11 - 2.30 (1H, m), 2.74 - 2.95 (2H, m), 2.95 - 3.20 (4H, m), 3.26 - 3.68 (7H, m), 3.69 - 4.16 (3H, m), 4.20 (2H, q, J = 7.1 Hz), 4.50 (2H, s), 4.54 (1H, d, J = 6.0 Hz), 6.88 (1H, dd, J = 9.0, 9.0 Hz), 6.96 (1H, d, J = 8.8 Hz), 7.24 - 7.34 (3H, m), 7.36 - 7.47 (4H, m), 7.52 (1H, ddd, J = 8.5, 8.5, 6.9 Hz)

[1408] MS: 608.25 [M + H] +

[1409] Example 71

[1410] NMR: 1.43 (3H, t, J = 7.0 Hz), 1.63 - 1.91 (2H, m), 1.97 - 2.17 (2H, m), 2.21 - 2.42 (1H, m), 2.51 - 2.71 (2H, m), 2.98 - 3.24 (4H, m), 3.24 - 3.62 (8H, m), 3.62 - 3.82 (3H, m), 3.82 - 4.16 (5H, m), 4.21 (2H, q, J = 7.1 Hz), 4.49 (2H, s), 4.58 (1H, d, J = 5.6 Hz), 5.69 - 5.84 (1H, m), 6.89 (1H, dd, J = 8.8, 8.8 Hz), 6.97 (1H, d, J = 8.4 Hz), 7.21 (1H, d, J = 8.4 Hz), 7.37 (1H, dd, J = 8.4, 2.0 Hz), 7.40 (1H, d, J = 2.0 Hz), 7.52 (1H, ddd, J = 8.4, 8.4, 7.2 Hz)

[1411] MS: 598.30 [M + H] +

[1412] Example 72

[1413] NMR: 1.42 (3H, t, J = 7.0 Hz), 1.53 - 1.73 (2H, m), 1.85 - 2.03 (2H, m), 2.10 - 2.27 (1H, m), 2.71 - 3.05 (2H, m), 3.05 - 3.25 (4H, m), 3.25 - 3.57 (6H, m), 3.60 - 3.89 (2H, m), 3.89 - 4.13 (2H, m), 4.20 (2H, q, J = 6.9 Hz), 4.38 (2H, s), 4.46 (1H, d, J = 6.0 Hz), 6.88 (1H, dd, J = 8.8, 8.8 Hz), 6.96 (1H, d, J = 8.8 Hz), 7.19 (1H, dd, J = 7.6, 1.2 Hz), 7.22 (1H, dd, J = 5.2, 3.6 Hz), 7.38 - 7.55 (4H, m), 7.58 (1H, dd, J = 9.0, 1.0 Hz)

[1414] MS: 599.25 [M + H] +

[1415] Example 73

[1416] NMR: 1.41 (3H, t, J = 7.0 Hz), 1.53 - 1.77 (2H, m), 1.85 - 2.03 (2H, m), 2.12 - 2.30 (1H, m), 2.75 - 2.98 (2H, m), 2.98 - 3.10 (2H, m), 3.10 - 3.25 (2H, m), 3.25 - 3.60 (6H, m), 3.61 - 3.77 (1H, m), 3.78 - 4.14 (3H, m), 4.20 (2H, q, J = 7.1 Hz), 4.48 (2H, s), 4.52 (1H, d, J = 6.0 Hz), 6.88 (1H, dd, J = 9.0, 9.0 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.30 (1H, d, J = 8.0 Hz), 7.43 - 7.56 (3H, m), 7.75 (1H, ddd, J = 7.6, 5.2, 0.8 Hz), 8.09 (1H, ddd, J = 8.2, 1.8, 1.8 Hz), 8.63 (1H, dd, J = 2.0, 0.8 Hz), 8.67 (1H, dd, J = 5.2, 1.6 Hz)

[1417] MS: 594.25 [M + H] + [[ID=⑥]]

[1418] Example 74

[1419] NMR: 1.41 (3H, t, J = 7.0 Hz), 1.57 - 1.74 (2H, m), 1.82 - 2.04 (2H, m), 2.12 - 2.30 (1H, m), 2.72 - 3.01 (2H, m), 3.01 - 3.13 (2H, m), 3.13 - 3.25 (2H, m), 3.28 - 3.60 (6H, m), 3.60 - 4.15 (4H, m), 4.20 (2H, q, J = 7.1 Hz), 4.47 (2H, s), 4.52 (1H, d, J = 6.4 Hz), 6.88 (1H, dd, J = 8.6, 8.6 Hz), 6.96 (1H, d, J = 8.8 Hz), 7.�5 (1H, d, J = 8.0 Hz), 7.46 - 7.58 (3H, m), 7.71 (2H, dd, J = 4.8, 1.6 Hz), 8.䜷2 (2H, dd, J = 4.8, 1.6 Hz)

[1420] MS: 594.25 [M + H] +

[1421] Example 75

[1422] It should be noted that in the original text, there is a hexadecimal "⑥" which may be an error. I have translated it as "6" as a regular number in the English translation. If this is not what you intended, please correct the original text for a more accurate translation.NMR: 1.35 (9H, s), 1.43 (3H, t, J = 7.0 Hz), 1.51 - 1.75 (2H, m), 1.77 - 2.02 (2H, m), 2.05 - 2.27 (1H, m), 2.58 - 2.90 (2H, m), 2.95 - 3.19 (4H, m), 3.19 - 3.56 (6H, m), 3.59 - 4.16 (4H, m), 4.16 - 4.31 (2H, m), 4.36 - 4.59 (1H, m), 4.46 (2H, s), 6.89 (1H, dd, J = 8.8, 8.8 Hz), 6.97 (1H, d, J = 8.4 Hz), 7.23 (1H, d, J = 6.8 Hz), 7.29 (1H, d, J = 8.0 Hz), 7.38 - 7.70 (6H, m)

[1423] MS: 649.35 [M + H] +

[1424] Example 76

[1425] NMR: 1.42 (3H, t, J = 7.0 Hz), 1.51 - 1.71 (2H, m), 1.82 - 1.99 (2H, m), 2.10 - 2.28 (1H, m), 2.62 - 3.00 (4H, m), 3.00 - 3.21 (2H, m), 3.21 - 3.53 (6H, m), 3.58 - 4.16 (4H, m), 3.80 (3H, s), 4.20 (2H, q, J = 7.1 Hz), 4.43 (2H, s), 4.48 (1H, d, J = 6.0 Hz), 6.88 (1H, dd, J = 9.0, 9.0 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.10 - 7.31 (4H, m), 7.40 - 7.60 (4H, m)

[1426] MS: 623.35 [M + H] +

[1427] Example 77

[1428] NMR: 1.23 (3H, t, J = 7.0 Hz), 1.42 (3H, t, J = 7.0 Hz), 1.48 - 1.70 (2H, m), 1.81 - 1.99 (2H, m), 2.08 - 2.26 (1H, m), 2.57 - 3.21 (6H, m), 3.21 - 3.54 (6H, m), 3.59 - 4.08 (4H, m), 4.12 (2H, q, J = 7.1 Hz), 4.20 (2H, q, J = 7.1 Hz), 4.44 (2H, s), 4.48 (1H, d, J = 6.0 Hz), 6.88 (1H, dd, J = 8.8, 8.8 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.11 - 7.32 (4H, m), 7.40 - 7.60 (4H, m)

[1429] MS: 637.35 [M + H] +

[1430] Example 78

[1431] NMR: 0.60 - 0.75 (2H, m), 0.95 - 1.08 (2H, m), 1.42 (3H, t, J = 7.0 Hz), 1.66 - 1.87 (2H, m), 1.87 - 1.98 (1H, m), 1.98 - 2.17 (2H, m), 2.17 - 2.43 (1H, m), 3.00 - 3.21 (3H, m), 3.21 - 3.49 (6H, m), 3.59 - 3.95 (6H, m), 4.10 - 4.32 (1H, m), 4.20 (2H, q, J = 6.9 Hz), 4.52 (2H, s), 4.61 (1H, d, J = 5.6 Hz), 6.89 (1H, dd, J = 8.8, 8.8 Hz), 6.97 (1H, d, J = 8.8 Hz), 7.08 (1H, d, J = 8.0 Hz), 7.23 - 7.36 (2H, m), 7.48 - 7.59 (1H, m)

[1432] MS: 557.30 [M + H] +

[1433] Example 79

[1434] NMR: 1.42 (3H, t, J = 7.0 Hz), 1.49 - 1.73 (2H, m), 1.77 - 2.04 (2H, m), 2.04 - 2.28 (1H, m), 2.66 - 2.96 (2H, m), 2.96 - 3.22 (4H, m), 3.22 - 3.53 (6H, m), 3.59 - 4.15 (4H, m), 4.20 (2H, q, J = 6.9 Hz), 4.45 (2H, s), 4.49 (1H, d, J = 6.0 Hz), 6.88 (1H, dd, J = 9.0, 9.0 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.14 (1H, d, J = 8.0 Hz), 7.35 - 7.46 (2H, m), 7.46 - 7.62 (5H, m)

[1435] MS: 611.30 [M + H] +

[1436] Example 80

[1437] NMR: 1.42 (3H, t, J = 7.0 Hz), 1.51 - 1.79 (2H, m), 1.82 - 2.04 (2H, m), 2.07 - 2.29 (1H, m), 2.62 - 2.97 (3H, m), 2.97 - 3.25 (3H, m), 3.25 - 3.62 (6H, m), 3.62 - 4.13 (4H, m), 4.20 (2H, q, J = 6.8 Hz), 4.49 (2H, s), 4.52 (1H, d, J = 6.0 Hz), 6.89 (1H, dd, J = 9.0, 9.0 Hz), 6.97 (1H, d, J = 8.8 Hz), 7.10 (1H, d, J = 8.0 Hz), 7.32 - 7.44 (1H, m), 7.44 - 7.70 (5H, m)

[1438] MS: 645.30 [M + H] +

[1439] Example 81

[1440] NMR: 1.42 (3H, t, J = 7.0 Hz), 1.48 - 1.68 (2H, m), 1.79 - 1.99 (2H, m), 2.04 - 2.25 (1H, m), 2.38 (3H, s), 2.66 - 2.88 (2H, m), 2.90 - 3.14 (4H, m), 3.23 - 3.62 (6H, m), 3.62 - 4.16 (4H, m), 4.20 (2H, q, J = 7.1 Hz), 4.49 (2H, s), 4.51 (1H, d, J = 6.0 Hz), 6.89 (1H, dd, J = 8.8, 8.8 Hz), 6.97 (1H, d, J = 8.8 Hz), 7.20 - 7.33 (3H, m), 7.33 - 7.44 (2H, m), 7.44 - 7.62 (4H, m)

[1441] MS: 573.40 [M + H] +

[1442] Example 82

[1443] NMR: 1.42 (3H, t, J = 7.0 Hz), 1.51 - 1.72 (2H, m), 1.80 - 2.01 (2H, m), 2.10 - 2.26 (1H, m), 2.40 (3H, s), 2.66 - 3.01 (4H, m), 3.01 - 3.25 (2H, m), 3.25 - 3.61 (6H, m), 3.62 - 4.15 (4H, m), 4.21 (2H, q, J = 6.9 Hz), 4.49 (2H, s), 4.52 (1H, d, J = 6.0 Hz), 6.89 (1H, dd, J = 8.8, 8.8 Hz), 6.97 (1H, d, J = 8.4 Hz), 7.20 (1H, d, J = 8.0 Hz), 7.24 - 7.33 (2H, m), 7.36 (1H, dd, J = 5.8, 3.4 Hz), 7.42 - 7.58 (3H, m), 7.63 (1H, dd, J = 5.6, 3.2 Hz)

[1444] MS: 607.35 [M + H] +

[1445] Example 83

[1446] NMR: 1.42 (3H, t, J = 7.0 Hz), 1.50 - 1.73 (2H, m), 1.73 - 2.04 (2H, m), 2.04 - 2.29 (1H, m), 2.64 - 2.93 (2H, m), 2.99 - 3.23 (4H, m), 3.23 - 3.59 (6H, m), 3.61 - 4.16 (4H, m), 4.20 (2H, q, J = 6.9 Hz), 4.47 (2H, s), 4.50 (1H, d, J = 6.0 Hz), 6.89 (1H, dd, J = 8.8, 8.8 Hz), 6.97 (1H, d, J = 8.8 Hz), 7.38 - 7.47 (2H, m), 7.47 - 7.64 (5H, m), 7.68 - 7.81 (2H, m)

[1447] MS: 627.35 [M+H] +

[1448] Example 84

[1449] NMR: 1.42 (3H, t, J = 7.0 Hz), 1.50 - 1.73 (2H, m), 1.82 - 2.07 (2H, m), 2.07 - 2.30 (1H, m), 2.64 - 3.00 (3H, m), 3.00 - 3.27 (3H, m), 3.27 - 3.60 (6H, m), 3.61 - 4.15 (4H, m), 4.20 (2H, q, J = 6.9 Hz), 4.47 (2H, s), 4.51 (1H, d, J = 6.0 Hz), 6.89 (1H, dd, J = 8.8, 8.8 Hz), 6.97 (1H, d, J = 8.4 Hz), 7.35 - 7.44 (1H, m), 7.44 - 7.60 (4H, m), 7.60 - 7.71 (1H, m), 7.77 (1H, d, J = 8.4 Hz), 7.79 (1H, s)

[1450] MS: 661.30 [M+H] +

[1451] Example 85

[1452] NMR: 1.42(3H, t, J = 7.0 Hz), 1.49 - 1.71(2H, m), 1.77 - 2.03(2H, m), 2.03 - 2.29(1H, m), 2.65 - 2.94(2H, m), 2.96 - 3.21(4H, m), 3.22 - 3.55(6H, m), 3.58 - 4.15(4H, m), 4.20(2H, q, J = 6.9 Hz), 4.48(2H, s), 4.50(1H, d, J = 6.4 Hz), 6.89(1H, dd, J = 8.8, 8.8 Hz), 6.97(1H, d, J = 8.8 Hz), 7.30 - 7.46(5H, m), 7.46 - 7.65(4H, m)

[1453] MS: 643.30[M + H] +

[1454] Example 86

[1455] NMR: 1.42(3H, t, J = 6.8 Hz), 1.51 - 1.73(2H, m), 1.82 - 2.06(2H, m), 2.06 - 2.29(1H, m), 2.67 - 3.06(4H, m), 3.06 - 3.26(2H, m), 3.26 - 3.60(6H, m), 3.61 - 4.15(4H, m), 4.20(2H, q, J = 6.9 Hz), 4.47(2H, s), 4.51(1H, d, J = 6.0 Hz), 6.89(1H, dd, J = 9.0, 9.0 Hz), 6.96(1H, d, J = 8.8 Hz), 7.27 - 7.44(4H, m), 7.44 - 7.58(3H, m), 7.58 - 7.70(1H, m)

[1456] MS: 677.30[M + H] +

[1457] Example 87

[1458] NMR: 1.42 (3H, t, J = 7.0 Hz), 1.69 - 1.93 (4H, m), 1.93 - 2.22 (4H, m), 2.22 - 2.45 (1H, m), 3.09 - 3.29 (6H, m), 3.29 - 3.66 (7H, m), 3.69 - 4.16 (5H, m), 4.21 (2H, q, J = 6.9 Hz), 4.52 (2H, s), 4.61 (1H, d, J = 6.4 Hz), 5.01 (1H, s), 6.89 (1H, dd, J = 8.8, 8.8 Hz), 6.97 (1H, d, J = 8.8 Hz), 7.32 - 7.47 (3H, m), 7.52 (1H, ddd, J = 8.5, 8.5, 7.1 Hz)

[1459] MS: 598.30 [M+H] +

[1460] Example 88

[1461] NMR: 1.42 (3H, t, J = 7.0 Hz), 1.66 - 1.90 (2H, m), 1.97 - 2.20 (2H, m), 2.20 - 2.40 (1H, m), 2.50 - 2.68 (2H, m), 2.96 - 3.23 (4H, m), 3.23 - 3.60 (8H, m), 3.60 - 3.80 (3H, m), 3.80 - 4.15 (5H, m), 4.21 (2H, q, J = 7.1 Hz), 4.49 (2H, s), 4.58 (1H, d, J = 6.0 Hz), 5.91 - 6.04 (1H, m), 6.89 (1H, dd, J = 8.8, 8.8 Hz), 6.97 (1H, d, J = 8.4 Hz), 7.22 (1H, d, J = 8.0 Hz), 7.38 (1H, dd, J = 8.4, 2.0 Hz), 7.41 (1H, d, J = 2.0 Hz), 7.52 (1H, ddd, J = 8.4, 8.4, 7.2 Hz)

[1462] MS: 598.30 [M+H] +

[1463] Example 89

[1464] NMR: 1.41 (3H, t, J = 7.0 Hz), 1.56 - 1.80 (2H, m), 1.89 - 2.13 (2H, m), 2.16 - 2.38 (1H, m), 2.73 - 2.90 (1H, m), 2.90 - 3.12 (3H, m), 3.12 - 3.31 (2H, m), 3.31 - 3.70 (7H, m), 3.70 - 4.15 (3H, m), 4.20 (2H, q, J = 6.9 Hz), 4.49 (2H, s), 4.55 (1H, d, J = 6.0 Hz), 6.88 (1H, dd, J = 8.8, 8.8 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.08 (1H, dd, J = 7.2, 2.4 Hz), 7.31 (1H, d, J = 8.0 Hz), 7.46 - 7.59 (3H, m), 7.89 (1H, dd, J = 7.2, 1.6 Hz), 7.95 (1H, dd, J = 6.4, 1.6 Hz)

[1465] MS: 609.30 [M + H] +

[1466] Example 90

[1467] NMR: 1.41 (3H, t, J = 7.0 Hz), 1.51 - 1.74 (2H, m), 1.82 - 2.09 (2H, m), 2.09 - 2.30 (1H, m), 2.71 - 3.03 (4H, m), 3.03 - 3.24 (2H, m), 3.24 - 3.67 (6H, m), 3.74 - 4.14 (4H, m), 4.20 (2H, q, J = 6.9 Hz), 4.49 (2H, s), 4.52 (1H, d, J = 6.0 Hz), 6.88 (1H, dd, J = 8.8, 8.8 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.18 - 7.32 (2H, m), 7.38 (1H, dd, J = 8.6, 6.2 Hz), 7.42 - 7.57 (4H, m)

[1468] MS: 645.25 [M + H] +

[1469] Example 91

[1470] NMR: 1.41(3H,t,J=7.0Hz),1.57-1.79(2H,m),1.88-2.07(2H,m),2.17-2.35(1H,m),2.74-2.89( 1H,m),2.89-3.06(3H,m),3.06-3.45(5H,m),3.45-3.94(5H,m),3.94-4.29(2H,m),4.20(2H,q,J= 6.9Hz),4.50(2H,s),4.55(1H,d,J=5.6Hz),6.88(1H,dd,J=8.8,8.8Hz),6.96(1H,d,J=8.8Hz),7 .30(1H,d,J=8.4Hz),7.44-7.63(3H,m),8.06(1H,d,J=6.0Hz),8.70(1H,s),8.71(1H,d,J=7.6Hz)

[1471] MS:628.30[M+H] +

[1472] Example 92

[1473] NMR: 1.41(3H,t,J=7.0Hz),1.54-1.77(2H,m),1.87-2.06(2H,m),2.14-2.34(1H,m),2.69-3 .04(4H,m),3.04-3.39(5H,m),3.39-3.96(5H,m),3.96-4.35(2H,m),4.20(2H,q,J=7.1Hz), 4.50(2H,s),4.54(1H,d,J=5.2Hz),6.88(1H,dd,J=9.0,9.0Hz),6.96(1H,d,J=8.8Hz),7.29 (1H,d,J=8.0Hz),7.42-7.64(4H,m),7.88(1H,dd,J=7.6,1.6Hz),8.46(1H,dd,J=8.6,1.4Hz)

[1474] MS: 628.25[M+H] +

[1475] Example 93

[1476] [Chemical Formula 102]

[1477]

[1478] (1) To benzyl (R)-(1-(1-(2-(4-((tert-butoxycarbonyl)amino)pyridin-3-yl)-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (240 mg) were added dichloromethane (0.42 mL) and a 4 mol / L hydrochloric acid dioxane solution (0.1 mL), and the mixture was stirred at room temperature overnight. Chloroform was added to the reaction mixture, followed by addition of a saturated sodium bicarbonate aqueous solution 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. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol=100:0→95:5→85:15] to obtain the target compound (12 mg) as a colorless oil.

[1479] (2) In the same manner as in Example 44, (R)-2-amino-2-(1-(2-(4-aminopyridin-3-yl)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrobromide (13 mg) was obtained as a pale yellow solid.

[1480] NMR: 1.42(3H,t,J=7.0Hz),1.59-1.80(2H,m),1.90-2.07(2H,m),2.16-2.34(1H,m),2.75-2.92(1H,m),2.92- 3.12(3H,m),3.12-3.28(2H,m),3.28-3.51(4H,m),3.51-3.63(2H,m),3.63-3.76(1H,m),3.79-4.16(3H,m),4. 20(2H,q,J=6.9Hz),4.44(2H,s),4.51(1H,d,J=6.0Hz),6.88(1H,dd,J=9.0,9.0Hz),6.96(1H,d,J=8.4Hz),7.0 4(1H,d,J=6.8Hz),7.32(1H,d,J=8.4Hz),7.41-7.63(3H,m),8.06(1H,d,J=0.8Hz),8.12(1H,dd,J=7.2,1.2Hz)

[1481] MS:609.30[M+H] +

[1482] Example 94

[1483] [Chemical Formula 103]

[1484]

[1485] To 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) were added anisole (0.43 mL) and a 5.1 mol / L hydrobromic acid / acetic acid solution (4.3 mL), followed by stirring 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 material was filtered out. The solid material was dried under reduced pressure to obtain a light brown solid. The obtained solid was dissolved in water and purified by medium-pressure reverse-phase silica gel column chromatography [eluent; water:acetonitrile = 100:0 → 70:30]. After distilling off the solution containing the obtained target product under reduced pressure, diethyl ether was added to the residue. After the solvent was distilled off under reduced pressure, the mixture was dried under reduced pressure to obtain (R)-2-amino-1-(4-(6-ethoxy-2-fluoro-3-hydroxybenzyl)piperazin-1-yl)-2-(1-phenethylpiperidin-4-yl)ethan-1-one hydrobromide (195 mg) as a white solid.

[1486] NMR: 1.40(3H,t,J=7.0Hz),1.62-1.88(2H,m),1.98-2.15(2H,m),2.22-2.37( 1H,m),2.93-3.23(4H,m),3.23-3.58(6H,m),3.58-3.97(4H,m),3.98-4.26(2H ,m),4.13(2H,q,J=7.1Hz),4.46(2H,s),4.59(1H,d,J=6.0Hz),6.84(1H,dd,J= 9.2,1.2Hz),7.14(1H,dd,J=9.6,9.6Hz),7.28-7.40(3H,m),7.40-7.50(2H,m)

[1487] MS:499.30[M+H] + ,497.20[MH] -

[1488] The compounds shown in Table 31 were obtained in the same manner as in Example 94.

[1489] [Table 31]

[1490]

[1491] The measured values ​​of NMR and MS of the compounds in the table are shown.

[1492] Example 95

[1493] NMR: 1.64-1.87(2H,m),1.95-2.14(2H,m),2.22-2.41(1H,m),2.99-3.23(4 H,m),3.23-3.57(6H,m),3.58-3.82(3H,m),3.82-3.97(1H,m),3.87(3H,s) ,3.97-4.28(2H,m),4.45(2H,s),4.58(1H,d,J=6.0Hz),6.85(1H,dd,J=9.2 ,1.2Hz),7.16(1H,dd,J=9.6,9.6Hz),7.30-7.40(3H,m),7.40-7.49(2H,m)

[1494] MS: 485.25[M+H] + ,483.05[MH] -

[1495] Example 96

[1496] NMR(CD3OD): 1.40(3H,t,J=6.8Hz),1.58-1.94(4H,m),2.01-2.25

[1497] (1H,m),2.65-2.92(4H,m),2.92-3.10(2H,m),3.10-3.35(7H,m),3.35-3.58(3H,m), 3.64(6H,s),4.13(2H,q,J=6.8Hz),4.39(2H,s),4.44(1H,d,J=6.4Hz),6.68(2H,d,J= 8.4Hz),6.79(1H,dd,J=9.0,9.0Hz),6.89(1H,d,J=8.4Hz),6.93(1H,d,J=8.0Hz),7.1 9(1H,dd,J=8.0,2.0Hz),7.29(1H,dd,J=8.4,8.4Hz),7.33(1H,s),7.37-7.49(1H,m))

[1498] MS:653.30[M+H] +

[1499] Example 97

[1500] [Chemical Formula 104]

[1501]

[1502] To benzyl (R)-(1-(1-(2-(2'-((tert-butoxycarbonyl)amino)-4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (66 mg) were added anisole (0.13 mL) and a 5.1 mol / L hydrobromic acid / acetic acid solution (0.66 mL), followed by stirring at room temperature for 1 hour. Ethyl acetate (3 mL) and diethyl ether (6 mL) were added to the reaction mixture, followed by stirring at room temperature for 30 minutes, and the solid was collected by filtration. The resulting pale yellow solid was dissolved in water and purified by medium-pressure reverse-phase silica gel column chromatography (eluent: water:acetonitrile = 100:0 → 70:30). After the solution containing the obtained target product was distilled off under reduced pressure, diethyl ether was added to the residue, and the solid was collected by filtration. The solid substance was dried under reduced pressure to obtain (R)-2-amino-2-(1-(2-(2'-amino-4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrobromide (13 mg) as a light yellow solid.

[1503] NMR: 1.41(3H,t,J=7.0Hz),1.51-1.73(2H,m),1.84-2.01(2H,m),2.12-2.29(1H,m),2.64-2.91(3H,m) ,2.91-3.15(1H,m),3.15-3.25(3H,m),3.25-3.69(6H,m),3.69-4.15(3H,m),4.20(2H,q,J=7.1Hz),4.5 0(2H,s),4.52(1H,d,J=6.4Hz),6.88(1H,dd,J=9.0,9.0Hz),6.96(1H,d,J=8.4Hz),7.08-7.19(2H,m), 7.23(1H,dd,J=8.2,1.2Hz),7.26(1H,d,J=8.0Hz),7.41(1H,ddd,J=7.6,7.6,1.6Hz),7.44-7.59(3H,m)

[1504] MS:608.30[M+H] +

[1505] The compounds shown in Table 32 were obtained in the same manner as in Example 97.

[1506] [Table 32]

[1507]

[1508] The measured values ​​of NMR and MS of the compounds in the table are shown.

[1509] Example 98

[1510] NMR: 1.41(3H,t,J=7.0Hz),1.47-1.67(2H,m),1.79-1.97(2H,m),1.97-2.16(1H,m), 2.66-2.92(2H,m),2.95-3.13(4H,m),3.13-3.48(6H,m),3.58-4.06(4H,m),4.19(2H ,q,J=6.9Hz),4.28(2H,s),4.36(1H,d,J=5.6Hz),6.87(1H,dd,J=8.8,8.8Hz),6.94( 1H,d,J=8.4Hz),7.02(2H,d,J=8.8Hz),7.29(2H,dd,J=8.2,2.6Hz),7.34-7.55(4H,m)

[1511] MS: 609.25[M+H] + ,607.20[MH] -

[1512] Example 99

[1513] NMR: 1.42(3H,t,J=7.0Hz),1.51-1.72(2H,m),1.83-2.02(2H,m),2.10-2.27(1H,m),2.69-2.97(2H,m),2.97-3.24(4H,m),3.24-3.56(6H,m) ),3.60-4.16(4H,m),4.20(2H,q,J=6.9Hz),4.44(2H,s),4.49(1H,d,J=6.0Hz),6.79-7.03(5H,m),7.28(1H,d,J=8.0Hz),7.32-7.58(4H,m)

[1514] MS:608.30[M+H] +

[1515] Example 100

[1516] NMR: 1.42 (3H, t, J = 7.0 Hz), 1.50 - 1.82 (2H, m), 1.82 - 2.09 (2H, m), 2.09 - 2.35 (1H, m), 2.66 - 2.97 (2H, m), 2.97 - 3.18 (4H, m), 3.18 - 3.52 (6H, m), 3.52 - 4.15 (4H, m), 4.20 (2H, q, J = 6.9 Hz), 4.38 (2H, s), 4.43 (1H, d, J = 6.0 Hz), 6.76 - 7.04 (4H, m), 7.19 - 7.58 (6H, m)

[1517] MS: 609.25 [M + H] + , 607.15 [M + H] -

[1518] Example 101

[1519] NMR: 1.42 (3H, t, J = 7.0 Hz), 1.53 - 1.71 (2H, m), 1.85 - 2.02 (2H, m), 2.11 - 2.24 (1H, m), 2.71 - 2.99 (2H, m), 2.99 - 3.26 (4H, m), 3.26 - 3.57 (6H, m), 3.57 - 4.16 (4H, m), 4.20 (2H, q, J = 6.9 Hz), 4.44 (2H, s), 4.48 (1H, d, J = 5.6 Hz), 6.89 (1H, dd, J = 8.8, 8.8 Hz), 6.97 (1H, d, J = 8.4 Hz), 7.18 - 7.57 (6H, m), 7.57 - 7.70 (1H, m)

[1520] MS: 599.25 [M + H] +

[1521] Example 102

[1522] NMR: 1.41(3H,t,J=7.0Hz),1.51-1.83(2H,m),1.85-2.12(2H,m),2.14-2.40(1H,m),2.68 -3.02(4H,m),3.03-3.50(8H,m),3.50-3.86(4H,m),3.91(3H,s),4.20(2H,q,J=6.9Hz),4 .50(2H,s),4.54(1H,d,J=5.2Hz),6.88(1H,dd,J=8.8,8.8Hz),6.96(1H,d,J=8.8Hz),7.1 5-7.31(2H,m),7.40-7.60(3H,m),7.74(1H,dd,J=7.2,1.6Hz),8.22(1H,dd,J=5.2,1.6Hz)

[1523] MS:624.30[M+H] +

[1524] Example 103

[1525] NMR: 1.41(3H,t,J=7.0Hz),1.51-1.73(2H,m),1.84-2.03(2H,m),2.09-2.30(1H,m),2.22(3H,s),2.59-2.77(1H,m),2. 77-3.03(3H,m),3.03-3.23(2H,m),3.23-3.54(6H,m),3.54-3.75(1H,m),3.75-3.91(1H,m),3.75-3.91(1H,m),3.91-4 .06(1H,m),4.06-4.16(1H,m),4.20(2H,q,J=6.9Hz),4.44(2H,s),4.48(1H,d,J=6.0Hz),6.88(1H,dd,J=8.8,8.8Hz),6 .96(1H,d,J=8.8Hz),7.26(1H,d,J=8.0Hz),7.41-7.60(3H,m),7.68(1H,d,J=5.6Hz),8.44(1H,s),8.55(1H,d,J=5.6Hz)

[1526] MS:608.30[M+H] +

[1527] Example 104

[1528] [Chemical Formula 105]

[1529]

[1530] Acetonitrile (0.81 mL) was added to sodium iodide (140 mg), followed by stirring under ice-cooling. Chlorotrimethylsilane (0.12 mL) was added to the reaction mixture at the same temperature, followed by stirring at room temperature for 10 minutes. A dichloromethane solution (0.41 mL) of benzyl (R)-(1-(1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-2-(4-(6-ethoxy-2-fluoro-3-hydroxybenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (58 mg) was added to the reaction mixture, followed by stirring at room temperature for 2 hours. The reaction mixture was cooled on ice, and methanol (1.7 mL) was added, followed by stirring at room temperature for 5 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. The organic layer was extracted twice with hydrochloric acid (5 mL) adjusted to pH = 1, and the combined aqueous layer was washed with diethyl ether (10 mL). Ethyl acetate (5 mL) was added to the aqueous layer, and saturated sodium bicarbonate aqueous solution was added under ice cooling to adjust the pH to 8.2, and the organic layer was separated. After the aqueous layer was extracted three times with ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a colorless oil (48 mg). Dichloromethane (1.4 mL) and 1 mol / L hydrochloric acid diethyl ether solution (0.27 mL) were added to the obtained oil, and stirred at room temperature for 30 minutes. After the solvent was distilled off under reduced pressure, the mixture was dried under reduced pressure to obtain (R)-2-amino-2-(1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(6-ethoxy-2-fluoro-3-hydroxybenzyl)piperazin-1-yl)ethan-1-one hydrochloride (35 mg) as a white solid.

[1531] NMR: 1.41(3H,t,J=7.0Hz),1.51-1.68(2H,m),1.84-1.99(2H,m),2.06-2.20( 1H,m),2.69-2.89(2H,m),3.01-3.15(4H,m),3.16-3.45(6H,m),3.54-4.08(4 H,m),4.15(2H,q,J=6.9Hz),4.34(2H,s),4.45(1H,d,J=5.6Hz),6.86(1H,d,J =8.8Hz),7.14(1H,dd,J=9.4,9.4Hz),7.34(1H,d,J=8.0Hz),7.41-7.62(7H,m)

[1532] MS: 609.25[M+H] +,607.05[MH] -

[1533] In the same manner as in Example 104, the compounds shown in Table 33 were obtained.

[1534] [Table 33]

[1535]

[1536] The measured values ​​of NMR and MS of the compounds in the table are shown.

[1537] Example 105

[1538] NMR: 1.56-1.73(2H,m),1.89-2.02(2H,m),2.14-2.28(1H,m),2.74-2.90(2H,m),3.01-3.19(4H,m),3.30-3.76(7H,m ),3.79-4.33(3H,m),4.57(1H,d,J=6.0Hz),4.63(2H,s),7.00-7.08(2H,m),7.33(1H,d,J=8.0Hz),7.41-7.62(7H,m)

[1539] MS: 597.20[M+H] + ,595.10[MH] -

[1540] Example 106

[1541] NMR: 1.41(3H,t,J=7.0Hz),1.51-1.72(2H,m),1.85-2.00(2H,m),2.07-2.2 3(1H,m),2.70-2.89(2H,m),3.02-3.17(4H,m),3.19-3.61(7H,m),3.64-4. 10(3H,m),4.15(2H,q,J=6.9Hz),4.36(2H,s),4.49(1H,d,J=5.6Hz),6.97( 1H,d,J=2.8Hz),7.00-7.11(2H,m),7.34(1H,d,J=8.0Hz),7.41-7.62(7H,m)

[1542] MS:591.30[M+H] + ,589.20[MH] -

[1543] Example 107

[1544] [Chemical Formula 106]

[1545]

[1546] Acetonitrile (0.32 mL) and chlorotrimethylsilane (28 μL) were added sequentially to sodium iodide (33 mg), and the mixture was stirred at room temperature for 15 minutes. The resulting reaction mixture was added to an acetonitrile solution (0.32 mL) of benzyl (R)-(1-(1-(2-(2'-(benzyloxy)-4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (46 mg) and stirred at 50°C for 2 hours. Sodium iodide (33 mg), acetonitrile (0.32 mL), and chlorotrimethylsilane (28 μL) were stirred at room temperature for 15 minutes before addition of the resulting mixture, which was stirred at 50°C for 4 hours. To the reaction mixture was added a reactant obtained by stirring sodium iodide (33 mg), acetonitrile (0.32 mL) and chlorotrimethylsilane (28 μL) at room temperature for 15 minutes, and stirred at 50°C for 5 hours. The reaction mixture was ice-cooled and methanol (1 mL) was added. The solvent was distilled off under reduced pressure, diethyl ether and water were added to the residue, 1 mol / L hydrochloric acid was added, the pH was adjusted 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, the pH was adjusted to 8, and the organic layer was separated. After washing the organic layer with a saturated aqueous sodium chloride solution, it was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a light yellow oil (5 mg). Dichloromethane (0.15 mL) and a 1 mol / L hydrochloric acid diethyl ether solution (29 μL) were added to the obtained oil and stirred at room temperature for 30 minutes. The solid substance was collected by filtration and then dried under reduced pressure to obtain (R)-2-amino-2-(1-(2-(4-chloro-2'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrochloride (4 mg) as a light yellow solid.

[1547] NMR: 1.41(3H,t,J=7.0Hz),1.47-1.68(2H,m),1.74-1.98(2H,m),1.98-2.16(1H,m),2.76-2.86(2H,m),2.8 6-3.02(2H,m),3.02-3.25(6H,m),3.25-3.48(2H,m),3.60-4.06(4H,m),4.18(2H,q,J=7.1Hz),4.23(2H,s), 4.33(1H,d,J=5.6Hz),6.87(1H,dd,J=8.8,8.8Hz),6.94(1H,d,J=8.8Hz),7.06(1H,d,J=8.0Hz),7.10(1H,dd ,J=7.2,7.2Hz),7.23(1H,d,J=7.2Hz),7.27(1H,d,J=8.0Hz),7.40(1H,dd,J=8.0,8.0Hz),7.42-7.55(3H,m)

[1548] MS:609.30[M+H] + ,607.15[MH] -

[1549] Example 108

[1550] [Chemical Formula 107]

[1551]

[1552] In the same manner as in Example 107, the hydrochloride salt of (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)ethan-1-one was obtained.

[1553] NMR: 1.41(3H,t,J=7.0Hz),1.48-1.71(2H,m),1.80-2.01(2H,m),2.01-2.21( 1H,m),2.68-3.01(4H,m),3.01-3.53(8H,m),3.60-4.13(4H,m),4.19(2H,q,J =6.9Hz),4.35(2H,s),4.42(1H,d,J=6.0Hz),6.76-6.92(3H,m),6.95(1H,d,J =8.4Hz),7.21(1H,dd,J=7.4,7.4Hz),7.26(1H,d,J=8.0Hz),7.41-7.59(3H,m)

[1554] MS:627.30[M+H] + ,625.15[MH] -

[1555] Example 109

[1556] [Chemical Formula 108]

[1557]

[1558] To benzyl (R)-(1-(1-(2-([1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (250 mg) were added methanol (2.5 mL) and 10% palladium on carbon (125 mg) in this order, and the mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. Impurities were removed by filtration through celite, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol = 100:0 → 70:30] to obtain a light yellow oil (147 mg). To the obtained oil, dichloromethane (4.4 mL), 1 mol / L hydrochloric acid in diethyl ether solution (0.92 mL), and diethyl ether (4.4 mL) were added in this order, and the mixture was stirred at room temperature for 30 minutes. After the solvent was distilled off under reduced pressure, the mixture was dried under reduced pressure to obtain (R)-2-(1-(2-([1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-2-amino-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrochloride (128 mg) as a pale yellow solid.

[1559] NMR: 1.42(3H,t,J=7.0Hz),1.49-1.69(2H,m),1.81-2.01(2H,m),2.06-2.21 (1H,m),2.67-2.91(2H,m),3.00-3.18(4H,m),3.21-3.53(6H,m),3.54-4.15( 4H,m),4.20(2H,q,J=7.1Hz),4.42(2H,s),4.46(1H,d,J=6.4Hz),6.88(1H,d d,J=8.8,8.8Hz),6.96(1H,d,J=8.4Hz),7.31-7.39(1H,m),7.39-7.61(9H,m)

[1560] MS:559.30[M+H] +

[1561] The compounds shown in Table 34 were obtained in the same manner as in Example 109.

[1562] [Table 34]

[1563]

[1564]

[1565]

[1566] The measured values ​​of NMR and MS of the compounds in the table are shown.

[1567] Example 110

[1568] NMR: 1.69-1.87(2H,m),2.00-2.17(2H,m),2.28-2.40(1H,m),3.05-3.20(4H,m),3.40-3.64(7H,m),3.67- 3.86(3H,m),3.89-4.14(2H,m),4.55-4.67(3H,m),7.00-7.07(2H,m),7.33-7.42(3H,m),7.43-7.50(2H,m)

[1569] MS: 487.25[M+H] + ,485.15[MH] -

[1570] Example 111

[1571] NMR: 1.63-1.84(2H,m),1.97-2.12(2H,m),2.20-2.37(1H,m),2.94-3.17(4 H,m),3.23-3.62(7H,m),3.62-3.81(3H,m),3.81-4.15(2H,m),3.92(3H,s) ,4.44(2H,s),4.57(1H,d,J=6.4Hz),7.10(1H,ddd,J=7.6,7.6,0.8Hz),7.1 7(1H,d,J=8.0Hz),7.29-7.39(3H,m),7.39-7.48(3H,m),7.52-7.60(1H,m)

[1572] MS:451.30[M+H] +

[1573] Example 112

[1574] NMR: 1.63-1.83(2H,m),1.95-2.16(2H,m),2.22-2.40(1H,m),2.96-3.16 (4H,m),3.16-3.48(6H,m),3.48-3.86(5H,m),3.91(3H,s),4.07-4.33(1H ,m),4.44(2H,s),4.58(1H,d,J=4.2Hz),7.09(1H,dd,J=7.6,7.6Hz),7.16 (1H,d,J=8.4Hz),7.29-7.39(3H,m),7.39-7.48(3H,m),7.51-7.61(1H,m)

[1575] MS: 451.25[M+H] +

[1576] Example 113

[1577] NMR: 1.42(3H,t,J=7.0Hz),1.63-1.85(2H,m),1.93-2.16(2H,m),2.21-2.39(1H, m),2.95-3.23(4H,m),3.23-3.61(6H,m),3.62-3.81(3H,m),3.83-4.16(3H,m),4. 20(2H,q,J=6.9Hz),4.44(2H,s),4.56(1H,d,J=6.0Hz),7.09(1H,dd,J=7.4,7.4H z),7.16(1H,d,J=8.4Hz),7.29-7.40(3H,m),7.40-7.49(3H,m),7.49-7.60(1H,m)

[1578] MS: 465.30[M+H] +

[1579] Example 114

[1580] NMR: 1.42 (3H, t, J = 7.0 Hz), 1.63 - 1.85 (2H, m), 1.92 - 2.15 (2H, m), 2.18 - 2.39 (1H, m), 2.93 - 3.21 (4H, m), 3.22 - 3.53 (6H, m), 3.60 - 3.81 (3H, m), 3.81 - 4.16 (3H, m), 4.21 (2H, q, J = 7.1 Hz), 4.45 (2H, s), 4.55 (1H, d, J = 6.4 Hz), 6.89 (1H, dd, J = 9.0, 9.0 Hz), 6.97 (1H, d, J = 8.4 Hz), 7.27 - 7.40 (3H, m), 7.40 - 7.47 (2H, m), 7.47 - 7.57 (1H, m)

[1581] MS: 483.30 [M + H] +

[1582] Example 115

[1583] NMR: 1.58 - 1.85 (2H, m), 1.95 - 2.16 (2H, m), 2.17 - 2.40 (1H, m), 2.97 - 3.19 (4H, m), 3.19 - 3.53 (6H, m), 3.59 - 3.80 (3H, m), 3.80 - 3.94 (1H, m), 3.90 (3H, s), 3.94 - 4.25 (2H, m), 4.40 (2H, s), 4.56 (1H, d, J = 6.0 Hz), 6.85 - 6.96 (1H, m), 7.29 - 7.39 (3H, m), 7.39 - 7.52 (3H, m)

[1584] MS: 487.30 [M + H] +

[1585] Example 116

[1586] NMR: 1.60 - 1.85 (2H, m), 1.92 - 2.13 (2H, m), 2.13 - 2.33 (1H, m), 2.98 - 3.17 (5H, m), 3.17 - 3.32 (3H, m), 3.35 - 3.45 (2H, m), 3.46 (3H, s), 3.61 - 3.85 (4H, m), 3.85 - 4.10 (4H, m), 4.25 (2H, s), 4.27 - 4.37 (2H, m), 4.43 (1H, d, J = 6.0 Hz), 6.91 (1H, dd, J = 8.8, 8.8 Hz), 6.96 (1H, d, J = 8.8 Hz), 7.30 - 7.40 (3H, m), 7.40 - 7.55 (3H, m)

[1587] MS:513.30[M+H] +

[1588] Example 117

[1589] NMR: 0.27-0.47(2H,m),0.52-0.74(2H,m),1.26-1.40(1H,m),1.59-1.82(2 H,m),1.90-2.10(2H,m),2.10-2.33(1H,m),2.96-3.32(8H,m),3.32-3.52(2 H,m),3.62-4.08(8H,m),4.09-4.28(2H,m),4.28-4.47(1H,m),6.88(1H,dd ,J=8.8,8.8Hz),6.93(1H,d,J=8.4Hz),7.29-7.40(3H,m),7.40-7.54(3H,m)

[1590] MS:509.30[M+H] +

[1591] Example 118

[1592] NMR: 1.37(6H,d,J=6.0Hz),1.63-1.84(2H,m),1.94-2.14(2H,m),2.18-2.37(1H,m), 2.96-3.20(4H,m),3.20-3.57(6H,m),3.57-3.81(3H,m),3.81-4.28(3H,m),4.43(2H ,s),4.54(1H,d,J=6.0Hz),4.70-4.85(1H,m),6.87(1H,dd,J=8.8,8.8Hz),7.00(1H, d,J=8.4Hz),7.31-7.40(3H,m),7.40-7.47(2H,m),7.51(1H,ddd,J=8.4,8.4,7.6Hz)

[1593] MS:497.30[M+H] +

[1594] Example 119

[1595] NMR: 1.65-1.84(2H,m),1.95-2.15(2H,m),2.21-2.38(1H,m),2.95-3.18(4H,m),3.24-3.54(6H,m), 3.67-3.83(4H,m),3.88(3H,s),3.92(3H,s),3.97-4.20(2H,m),4.43(2H,s),4.56(1H,d,J=6.0Hz), 7.02(1H,ddd,J=7.4,7.4,1.0Hz),7.06-7.14(2H,m),7.14(1H,d,J=8.0Hz),7.28(1H,dd,J=7.2,1.2 Hz),7.35(1H,ddd,J=7.8,7.8,1.0Hz),7.43(1H,dd,J=7.6,1.2Hz),7.56(1H,ddd,J=8.4,7.8,1.2Hz)

[1596] MS: 481.30[M+H] +

[1597] Example 120

[1598] NMR: 1.59-1.89(2H,m),1.93-2.16(2H,m),2.17-2.38(1H,m),2.94-3.23(4H ,m),3.24-3.53(6H,m),3.66-3.83(4H,m),3.92(3H,s),3.96-4.16(2H,m),4 .43(2H,s),4.56(1H,d,J=6.0Hz),7.10(1H,ddd,J=7.6,7.6,0.8Hz),7.14-7 .26(3H,m),7.31-7.41(2H,m),7.43(1H,dd,J=7.6,1.6Hz),7.52-7.60(1H,m)

[1599] MS: 469.20[M+H] +

[1600] Example 121

[1601] NMR: 1.42 (3H, t, J = 7.0 Hz), 1.64 - 1.87 (2H, m), 1.95 - 2.15 (2H, m), 2.19 - 2.35 (1H, m), 2.99 - 3.22 (4H, m), 3.23 - 3.53 (6H, m), 3.58 - 3.81 (3H, m), 3.81 - 4.16 (3H, m), 4.20 (2H, q, J = 6.9 Hz), 4.42 (2H, s), 4.53 (1H, d, J = 6.4 Hz), 6.89 (1H, dd, J = 8.8, 8.8 Hz), 6.97 (1H, d, J = 8.4 Hz), 7.13 - 7.27 (2H, m), 7. – 7.43 (2H, m), 7.51 (1H, ddd, J = 8.4, 8.4, 7.2 Hz)

[1602] MS: 501.30 [M+H] +

[1603] Example 122

[1604] NMR: 1.42 (3H, t, J = 7.0 Hz), 1.63 - 1.86 (2H, m), 1.95 - 2.14 (2H, m), 2.19 - 2.35 (1H, m), 2.96 - 3.18 (4H, m), 3.25 - 3.55 (6H, m), 3.58 - 3.81 (3H, m), 3.82 - 3.95 (1H, m), 3.88 (3H, s), 3.95 - 4.17 (2H, m), 4.20 (2H, q, J = 6.9 Hz), 4.43 (2H, s), 4.53 (1H, d, J = 6.0 Hz), 6.89 (1H, dd, J = 8.8, 8.8 Hz), 6.97 (1H, d, J = 8.8 Hz), 7.02 (1H, ddd, J = 7.5, 7.5, 0.9 Hz), 7.09 (1H, d, J = 8.0 Hz), 7.28 (1H, dd, J = 7.6, 1.6 Hz), 7.38 (1H, ddd, J = 7.9, 7.9, 1.3 Hz), 7.51 (1H, ddd, J = 8.4, 8.4, 7.0 Hz)

[1605] MS: 513.30 [M+H] +

[1606] Example 123

[1607] NMR: 1.21-1.38(1H,m),1.42(3H,t,J=7.0Hz),1.47-1.60(3H,m),1.60-1.95(6H,m),1.95 -2.13(2H,m),2.17-2.33(1H,m),2.91-3.10(2H,m),3.12-3.57(8H,m),3.57-3.78(3H,m), 3.79-3.91(1H,m),3.91-4.16(3H,m),4.20(2H,q,J=7.1Hz),4.42(2H,s),4.52(1H,d,J=6. 0Hz),6.88(1H,dd,J=8.8,8.8Hz),6.96(1H,d,J=8.4Hz),7.51(1H,ddd,J=8.4,8.4,7.2Hz)

[1608] MS: 491.35[M+H] +

[1609] Example 124

[1610] NMR: 1.19-1.35(1H,m),1.42(3H,t,J=7.0Hz),1.48-1.80(7H,m),1.80-1.93(1H,m),1.94 -2.14(2H,m),2.17-2.33(1H,m),2.90-3.08(2H,m),3.08-3.54(8H,m),3.56-3.78(3H,m), 3.78-3.94(3H,m),3.94-4.16(2H,m),4.20(2H,q,J=7.1Hz),4.42(2H,s),4.51(1H,d,J=6. 4Hz),6.88(1H,dd,J=9.0,9.0Hz),6.96(1H,d,J=8.4Hz),7.51(1H,ddd,J=8.4,8.4,6.8Hz)

[1611] MS: 491.35[M+H] +

[1612] Example 125

[1613] NMR: 1.38-1.56(8H,m),1.42(3H,t,J=7.0Hz),1.57-1.80(8H,m),1.81-1.98(3H,m),1.9 8-2.13(2H,m),2.18-2.35(1H,m),2.98(2H,dd,J=12.4,10.8Hz),3.09-3.23(2H,m),3.2 3-3.58(4H,m),3.58-4.16(6H,m),4.20(2H,q,J=7.1Hz),4.47(2H,s),4.54(1H,d,J=6.0 Hz),6.89(1H,dd,J=8.8,8.8Hz),6.97(1H,d,J=8.4Hz),7.52(1H,ddd,J=8.4,8.4,7.2Hz)

[1614] MS: 541.35[M+H] +

[1615] Example 126

[1616] NMR: 0.89(3H,s),1.21-1.53(10H,m),1.42(3H,t,J=7.0Hz),1.59-1.81(4H,m),1.98 -2.11(2H,m),2.21-2.39(1H,m),3.00(2H,t,J=12.8Hz),3.08-3.20(2H,m),3.21-3.6 1(5H,m),3.62-4.14(5H,m),4.20(2H,q,J=6.9Hz),4.50(2H,s),4.57(1H,d,J=6.4Hz) ,6.89(1H,dd,J=8.8,8.8Hz),6.97(1H,d,J=8.4Hz),7.52(1H,ddd,J=8.6,8.6,6.9Hz)

[1617] MS: 503.35[M+H] +

[1618] Example 127

[1619] NMR: 1.42 (3H, t, J = 7.0 Hz), 1.61 - 1.80 (3H, m), 1.80 - 1.94 (1H, m), 1.94 - 2.14 (2H, m), 2.17 - 2.40 (3H, m), 2.80 - 3.13 (4H, m), 3.13 - 3.55 (7H, m), 3.55 - 4.16 (6H, m), 4.20 (2H, q, J = 6.9 Hz), 4.43 (2H, s), 4.53 (1H, d, J = 6.0 Hz), 6.88 (1H, dd, J = 8.8, 8.8 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.22 - 7.41 (4H, m), 7.44 - 7.57 (1H, m)

[1620] MS: 523.35 [M + H] +

[1621] Example 128

[1622] NMR: 1.41 (3H, t, J = 7.0 Hz), 1.50 - 1.71 (2H, m), 1.79 - 2.02 (2H, m), 2.05 - 2.24 (1H, m), 2.67 - 2.93 (2H, m), 2.97 - 3.18 (4H, m), 3.21 - 3.52 (6H, m), 3.59 - 3.89 (2H, m), 3.90 - 4.01 (1H, m), 3.96 (3H, s), 4.01 - 4.14 (1H, m), 4.20 (2H, q, J = 7.1 Hz), 4.41 (2H, s), 4.45 (1H, d, J = 6.0 Hz), 6.88 (1H, dd, J = 8.8, 8.8 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.31 - 7.40 (1H, m), 7.41 - 7.58 (4H, m), 7.62 - 7.76 (2H, m), 8.03 (1H, s), 8.07 - 8.16 (1H, m)

[1623] MS: 617.35 [M + H] +

[1624] Example 129

[1625] NMR: 1.43(3H,t,J=7.0Hz),1.67-1.92(2H,m),1.97-2.17(2H,m),2.20-2.38(1H,m),3.02-3.25(2H ,m),3.29-3.54(5H,m),3.38(3H,s),3.60-3.84(3H,m),3.84-3.98(1H,m),3.94(3H,s),3.97-4.16 (2H,m),4.21(2H,q,J=6.9Hz),4.46(2H,s),4.56(1H,d,J=6.0Hz),6.89(1H,dd,J=8.8,8.8Hz),6.9 7(1H,d,J=8.8Hz),7.39-7.56(3H,m),7.62(1H,ddd,J=7.6,7.6,1.6Hz),8.01(1H,dd,J=7.8,1.4Hz)

[1626] MS:541.30[M+H] + ,

[1627] Example 130

[1628] NMR: 1.40(3H,t,J=7.0Hz),1.63-1.83(2H,m),1.96-2.17(2H,m),2.17-2.42(1H,m),2.92-4.00(16H,m),4.19(2H,q,J=7.1Hz),4.4 9(2H,s),4.58(1H,d,J=6.0Hz),6.75-6.91(4H,m),6.95(1H,d,J=8.0Hz),7.27(1H,dd,J=8.0,8.0Hz),7.50(1H,dd,J=15.6,8.0Hz)

[1629] MS: 499.31[M+H] + ,

[1630] Example 131

[1631] [Chemical Formula 109]

[1632]

[1633] To (R)-2-amino-1-(4-(2-methoxybenzyl)piperazin-1-yl)-2-(1-phenethylpiperidin-4-yl)ethan-1-one (100 mg) was added dichloromethane (1 mL), 13.31 mol / L aqueous formaldehyde solution (17 μL), 5 drops of methanol (25 μL total), and sodium triacetoxyborohydride (71 mg) in this order using a Pasteur pipette, and the mixture was stirred at room temperature for 22 hours and 20 minutes. Chloroform (5 mL) and water (5 mL) were added to the reaction mixture, and the pH was adjusted to 8 with 10% aqueous sodium carbonate solution. The organic layer was then separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: chloroform:methanol = 100:0 → 80:20] to obtain a colorless oil (6 mg). To the resulting oil were added diethyl ether (0.2 mL) and a 1 mol / L hydrochloric acid solution in diethyl ether (45 μL), followed by stirring at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the mixture was dried under reduced pressure to obtain the hydrochloride salt (6 mg) of (R)-1-(4-(2-methoxybenzyl)piperazin-1-yl)-2-(methylamino)-2-(1-phenethylpiperidin-4-yl)ethan-1-one as a white solid.

[1634] NMR: 1.54-1.82(2H,m),1.94-2.06(1H,m),2.06-2.21(1H,m),2.21-2.37(1H,m),2.65( 3H,m),2.98-3.18(4H,m),3.18-3.51(6H,m),3.60-3.81(3H,m),3.81-3.96(1H,m),3.91 (3H,s),3.96-4.20(2H,m),4.33(2H,s),4.44(1H,d,J=5.6Hz),7.09(1H,ddd,J=7.4,7.4 ,0.8Hz),7.17(1H,d,J=8.0Hz),7.31-7.40(3H,m),7.40-7.47(3H,m),7.51-7.61(1H,m)

[1635] MS: 465.30[M+H] +

[1636] Example 132

[1637] [Chemical Formula 110]

[1638]

[1639] To benzyl (R)-(2-(4-(2-fluoro-6-(2-methoxyethoxy)benzyl)piperazin-1-yl)-2-oxo-1-(1-phenethylpiperidin-4-yl)ethyl)carbamate (470 mg) were added anisole (0.47 mL) and a 5.1 mol / L hydrobromic acid / acetic acid solution (4.7 mL), and 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 material was filtered out. Diethyl ether (10 mL) was added to the obtained solid material, stirred at room temperature for 30 minutes, and the solid material was filtered out. Dichloromethane (2 mL) and triethylamine (0.31 mL) were added to the obtained solid material and dissolved, and purified by fractional thin-layer chromatography [developing solution; chloroform:methanol = 10:1]. To the obtained fraction, dichloromethane (2 mL), a 1 mol / L hydrochloric acid solution in diethyl ether (0.4 mL), and diethyl ether (2 mL) were added in sequence, and the mixture was stirred at room temperature for 30 minutes. After the solvent was distilled off under reduced pressure, the mixture was dried under reduced pressure to obtain (R)-2-(2-((4-(2-amino-2-(1-phenethylpiperidin-4-yl)acetyl)piperazin-1-yl)methyl)-3-fluorophenoxy)ethyl acetate hydrochloride (70 mg) as a pale yellow solid.

[1640] NMR: 1.62-1.88(2H,m),1.96-2.09(2H,m),2.13(3H,s),2.21-2.37(1H,m),2.92-3 .21(4H,m),3.28-3.60(6H,m),3.61-3.83(3H,m),3.83-3.96(1H,m),3.96-4.28(2 H,m),4.34-4.41(2H,m),4.44(2H,s),4.52-4.62(3H,m),6.93(1H,dd,J=9.0,9.0H z),6.98(1H,d,J=8.4Hz),7.28-7.39(3H,m),7.39-7.48(2H,m),7.48-7.61(1H,m)

[1641] MS:541.30[M+H] +

[1642] Example 133

[1643] [Chemical Formula 111]

[1644]

[1645] Acetic acid (1 mL) and a 5.1 mol / L hydrobromic acid / acetic acid solution (0.5 mL) were added to 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), and the mixture was stirred at room temperature for 3 hours and 30 minutes. The reaction mixture was added to a saturated sodium bicarbonate aqueous solution (10 mL) under ice cooling. After adding ethyl acetate (10 mL) to the reaction mixture, a 10% sodium carbonate aqueous solution was added to adjust the pH to 8, and the organic layer was separated. The aqueous layer was extracted three times with ethyl acetate (10 mL), and the previously separated organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol = 100:0→70:30] to obtain a colorless oil (21 mg). To the resulting oil were added dichloromethane (0.63 mL) and a 1 mol / L hydrochloric acid solution in diethyl ether (0.16 mL), followed by stirring at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the mixture was dried under reduced pressure to obtain the hydrochloride salt (21 mg) of (R)-2-amino-1-(4-(2-methoxybenzyl)piperazin-1-yl)-2-(1-(2-(thiophen-3-yl)ethyl)piperidin-4-yl)ethan-1-one as a white solid.

[1646] NMR: 1.61-1.83(2H,m),1.93-2.13(2H,m),2.14-2.36(1H,m),2.93-3.22( 4H,m),3.23-3.53(6H,m),3.60-3.81(4H,m),3.92(3H,s),3.95-4.25(2H,m ),4.39(2H,s),4.51(1H,d,J=6.4Hz),7.05-7.15(2H,m),7.17(1H,d,J=8. 0Hz),7.29(1H,d,J=1.6Hz),7.42(1H,dd,J=7.6,1.6Hz),7.46-7.62(2H,m)

[1647] MS: 457.20[M+H] +

[1648] In the same manner as in Example 133, the compounds shown in Table 35 were obtained.

[1649] [Table 35]

[1650]

[1651] The measured values ​​of NMR and MS of the compounds in the table are shown.

[1652] Example 134

[1653] NMR: 1.67-2.28(4H,m),2.28-2.51(1H,m),3.02-3.92(15H,m),4.00(3H,s),4.14-4.45(1H,m),4.54(2H,s),4.62-4.82(1H,m),6.92 (1H,d,J=3.2Hz),6.99(1H,d,J=3.6Hz),7.18(1H,dd,J=7.4,7.4Hz),7.25(1H,d,J=8.4Hz),7.52(1H,d,J=6.8Hz),7.56-7.72(1H,m)

[1654] MS: 491.22[M+H] +

[1655] Example 135

[1656] NMR: 1.57-1.86(2H,m),1.93-2.15(2H,m),2.15-2.41(1H,m),2.95-3.66(14H,m),3.66-3.82(2H,m),3.88(3H,s),4.41(2H,s),4.56(1H,d ,J=6.0Hz),7.06(1H,dd,J=7.4,7.4Hz),7.13(1H,d,J=8.4Hz),7.23-7.33(2H,m),7.33-7.43(2H,m),7.43-7.49(1H,m),7.49-7.57(1H,m)

[1657] MS: 485.26[M+H] +

[1658] Example 136

[1659] [Chemical Formula 112]

[1660]

[1661] To (1) benzyl ((1R)-1-(1-(3-((tert-butoxycarbonyl)amino)-2-phenylpropyl)piperidin-4-yl)-2-(4-(2-methoxybenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (124 mg) were added methanol (1.2 mL) and 10% palladium on carbon (47 mg) in this order, 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 under a hydrogen atmosphere for 2 hours. Impurities were removed by filtration through celite, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol = 100:0 → 70:30] to obtain the target compound (66 mg) as a white solid.

[1662] (2) To the compound obtained in (1) (66 mg) were added dichloromethane (1.1 mL) and a 4 mol / L hydrochloric acid dioxane solution (1.1 mL), and the mixture was stirred at room temperature for 23 hours and 30 minutes. After the solvent was distilled off under reduced pressure, the mixture was dried under reduced pressure to obtain (2R)-2-amino-2-(1-(3-amino-2-phenylpropyl)piperidin-4-yl)-1-(4-(2-methoxybenzyl)piperazin-1-yl)ethan-1-one hydrochloride (55 mg) as a white solid.

[1663] NMR: 1.51-1.76(2H,m),1.80-2.04(2H,m),2.10-2.27(1H,m),2.91-3.11(2H, m),3.18-3.61(9H,m),3.61-3.75(3H,m),3.78-3.88(1H,m),3.91(3H,s),3.9 3-4.18(2H,m),4.38(2H,s),4.45[4.56](1H,d,J=6.2Hz),7.09(1H,dd,J=7.6 ,7.6Hz),7.16(1H,d,J=8.4Hz),7.41(1H,dd,J=7.6,1.2Hz),7.45-7.60(6H,m)

[1664] MS: 480.30[M+H] +

[1665] Example 137

[1666] [Chemical Formula 113]

[1667]

[1668] To 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) were added anisole (0.23 mL) and a 5.1 mol / L hydrobromic acid / acetic acid solution (2.3 mL), followed by stirring at room temperature for 5 hours and 30 minutes. The reaction mixture was added to ice water, followed by ethyl acetate (10 mL), and the aqueous layer was extracted. Ethyl acetate (10 mL) was added to the aqueous layer, followed by addition of saturated sodium bicarbonate aqueous solution to adjust the pH to 8.5, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a light yellow oil (114 mg). To the resulting oil were added diethyl ether (3.4 mL) and a 1 mol / L hydrochloric acid solution in diethyl ether (0.67 mL), followed by stirring at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the mixture was dried under reduced pressure to obtain the hydrochloride salt (115 mg) of (R)-2-amino-2-(1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one as a pale yellow solid.

[1669] NMR: 1.42(3H,t,J=7.0Hz),1.50-1.76(2H,m),1.77-2.07(2H,m),2.08-2.33( 1H,m),2.66-2.90(2H,m),2.96-3.16(4H,m),3.22-3.75(7H,m),3.76-4.10(3 H,m),4.20(2H,q,J=6.9Hz),4.47(2H,s),4.49(1H,d,J=6.0Hz),6.89(1H,dd, J=8.8,8.8Hz),6.96(1H,d,J=8.4Hz),7.30(1H,d,J=8.4Hz),7.36-7.62(8H,m)

[1670] MS: 593.25[M+H] +

[1671] Example 138

[1672] [Chemical Formula 114]

[1673]

[1674] To methyl (R)-2'-(2-(4-(1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-[1,1'-biphenyl]-3-carboxylate hydrochloride (65 mg) were added THF (0.65 mL), methanol (65 μL), water (0.65 mL), and lithium hydroxide monohydrate (23 mg), and the mixture was stirred at room temperature for 1 hour. 1 mol / L hydrochloric acid was added to the reaction mixture to adjust the pH to 1.0, followed by addition of ethyl acetate and separation of the aqueous layer. The aqueous layer was purified by medium-pressure reverse-phase silica gel column chromatography [eluent: water:acetonitrile = 100:0 → 75:25]. The solution containing the obtained target product was distilled off under reduced pressure and then dried to obtain (R)-2'-(2-(4-(1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-[1,1'-biphenyl]-3-carboxylic acid hydrochloride (7 mg) as a white solid.

[1675] NMR (CD3OD): 1.49 (3H, t, J = 7.0Hz), 1.69-2.01 (4H, m), 2.10-2.29

[1676] (1H,m),2.85-3.01(2H,m),3.05-3.22(4H,m),3.22-3.40(3H,m),3.40-3.94 (7H,m),4.23(2H,q,J=6.9Hz),4.49(2H,s),4.52-4.62(1H,m),6.88(1H,dd,J =8.8,8.8Hz),6.98(1H,d,J=8.8Hz),7.22-7.32(1H,m),7.34-7.48(3H,m),7 .52(1H,dd,J=8.4,8.4Hz),7.58-7.67(2H,m),7.96(1H,s),8.02-8.13(1H,m)

[1677] MS:603.30[M+H] + ,601.20[M+H] -

[1678] Example 139

[1679] [Chemical Formula 115]

[1680]

[1681] To 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) were added anisole (0.15 mL) and a 5.1 mol / L hydrobromic acid / acetic acid solution (0.73 mL), followed by stirring at room temperature for 1 hour and 30 minutes. Ethyl acetate (3 mL) and diethyl ether (6 mL) were added to the reaction mixture, followed by stirring at ...

Claims

1. A compound or a salt thereof, wherein the compound or the salt thereof is represented by the general formula [1]: [Chemical formula 1] In the formula, Z 1 represents a nitrogen atom or a group represented by the formula CH; Z 2 Represents nitrogen atom or general formula CR 4 The group represented by 4 represents a hydrogen atom, a hydroxyl group, a cyano group, an acyloxy group which may be substituted, an amino group which may be substituted, a carbamoyl group which may be substituted, an ureido group which may be substituted, a C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy C 1-6 Alkyl, aryl which may be substituted 1-6 Alkoxy C 1-6 Alkyl or substituted C 1-6 Alkoxy; R 1 and R 2 The same or different ones represent a hydrogen atom, a halogen atom, a hydroxyl group, an amino group which may be substituted, a C 1-6 Alkyl, optionally substituted C 1-6 an alkoxy group, an optionally substituted guanidine group, or an optionally substituted imino group or an optionally substituted divalent C 1-3 Alkylene-OC 1-3 A group represented by an alkylene group; R 3 represents a hydrogen atom, a carboxyl group which may be protected, a carbamoyl group which may be substituted, a C 3-10 Cycloalkyl or optionally substituted C 1-6 alkyl; X 1 Indicates that C can be replaced 2-6 Alkylene, optionally substituted C 2-6 Alkenylene, optionally substituted C 2-6 Alkynylidene, general formula -NR 5 -CO- represented by the group, the general formula -CO-NR 5 - represented by the group, the general formula -CR 5 -NR 5 - represented by the group, the general formula -CR 5 -O-, in these formulas, R 5 Represents a hydrogen atom or C 1-6 Alkyl, wherein In the formula, the connecting bond on the left side is 1 Bonding, the connecting bond on the right side is connected to Z 2 Bonding; Y 1 Indicates that C can be replaced 3-10 a cycloalkyl group, an aryl group which may be substituted, a monocyclic heterocyclic group which may be substituted, or a bicyclic heterocyclic group which may be substituted; X 2 Represents C 1-3 Alkylene or linking bond; Y 2 Indicates that C can be replaced 3-10 A group represented by a cycloalkyl group, an aryl group which may be substituted, a monocyclic heterocyclic group which may be substituted, or a bicyclic heterocyclic group which may be substituted.

2. The compound or salt thereof according to claim 1, wherein Z 1 represents a nitrogen atom or a group represented by the formula CH; Z 2 Represents nitrogen atom or general formula CR 4a The group represented by 4a represents a hydrogen atom, a hydroxyl group, a cyano group, an acyloxy group which may be substituted, an amino group which may be substituted, a carbamoyl group which may be substituted, an ureido group which may be substituted, a C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy C 1-6 Alkyl or substituted aryl C 1-6 Alkoxy C 1-6 Alkyl, wherein Z 1 or Z 2 At least one of is a nitrogen atom; R 1 and R 2 The same or different ones represent a hydrogen atom, a halogen atom, an amino group which may be substituted, a C 1-6 an alkyl group, or an imino group which may be substituted together, or a divalent C 1-3 Alkylene-OC 1-3 A group represented by an alkylene group; R 3 Represents a hydrogen atom or a C that can be substituted 1-6 alkyl; X 1 Indicates that C can be replaced 2-6 Alkylene, optionally substituted C 2-6 Alkenylene, optionally substituted C 2-6 Alkynylidene, general formula -NR 5 -CO- represented by the group, the general formula -CO-NR 5 - represented by the group, the general formula -CR 5 -NR 5 - represented by the group, the general formula -CR 5 -O-, in these formulas, R 5 Represents a hydrogen atom or C 1-6 Alkyl, wherein, in the formula, the connecting bond on the left side is 1 Bonding, the connecting bond on the right side is connected to Z 2 Bonding; Y 1 Indicates that C can be replaced 3-10 a cycloalkyl group, an aryl group which may be substituted, a monocyclic heterocyclic group which may be substituted, or a bicyclic heterocyclic group which may be substituted; X 2 Represents C 1-3 Alkylene or linking bond; Y 2 Indicates that C can be replaced 3-10 a cycloalkyl group, an aryl group which may be substituted, a monocyclic heterocyclic group which may be substituted, or a bicyclic heterocyclic group which may be substituted.

3. The compound or salt thereof according to claim 1 or 2, wherein Z 1 A group represented by the formula CH; Z 2 represents a nitrogen atom.

4. The compound or salt thereof according to claim 1 or 2, wherein Z 1 Represents nitrogen atom, Z 2 Represents the general formula CR 4a The group represented by 4a represents a hydrogen atom, a hydroxyl group, a cyano group, an acyloxy group which may be substituted, an amino group which may be substituted, a carbamoyl group which may be substituted, an ureido group which may be substituted, a C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy C 1-6 Alkyl or substituted aryl C 1-6 Alkoxy C 1-6 alkyl; Y 1 Indicates that C can be replaced 3-10 a cycloalkyl group, an aryl group which may be substituted, or a bicyclic heterocyclic group which may be substituted.

5. The compound or salt thereof according to claim 1 or 2, wherein R 3 A hydrogen atom or a substituted C 1-6 alkyl.

6. The compound or salt thereof according to claim 1 or 2, wherein R 1 and R 2 The same or different ones are hydrogen atoms, amino groups which may be substituted or C 1-6 alkyl.

7. The compound or salt thereof according to claim 1 or 2, wherein Y 1 is an aryl group which may be substituted.

8. The compound or salt thereof according to claim 1 or 2, wherein Y 2 It is an aryl group which may be substituted or a bicyclic heterocyclic group which may be substituted.

9. The compound or salt thereof according to claim 1 or 2, wherein X 1 C can be replaced 2-6 Alkylene or optionally substituted C 2-6 Alkenylene.

10. The compound or salt thereof according to claim 1 or 2, wherein X 2 For methylene.

11. The compound or salt thereof according to claim 1, wherein The compound is selected from (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)ethan-1-one, (R)-2-amino-2-(1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one, (R)-2-amino-1-(4-(benzo[b]thien-7-ylmethyl)piperazin-1-yl)-2-(1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)ethan-1-one, (R)-2-amino-2-(1-(2-(2',4-dichloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one, (R)-2-amino-2-(1-(5-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one, (R)-2-amino-2-(1-(2-(4-aminopyridin-3-yl)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one, (R)-2-amino-2-(1-(2-(2'-amino-4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one, (R)-2-amino-2-(1-(2-(4-chloro-3'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one, (R)-2-amino-2-(1-(2-(4-chloro-2'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)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-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one and Compounds in the group consisting of 2-(4-(3-chlorophenethyl)piperazin-1-yl)-1-(4-(2-methoxybenzyl)piperazin-1-yl)ethan-1-one.

12. The compound or salt thereof according to claim 1, wherein The compound is selected from the hydrochloride salt of (R)-2-amino-2-(1-(2-(2',4-dichloro-3'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one, (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)ethan-1-one hydrochloride, (R)-2-amino-2-(1-(2-(4-chloro-2'-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrochloride, (R)-2-amino-2-(1-(2-(4-chloro-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-5-hydroxybenzyl)piperazin-1-yl)ethan-1-one hydrochloride, (R)-2-amino-2-(1-(2-(4-chloro-3'-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-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-(methylthio)benzyl)piperazin-1-yl)ethan-1-one hydrochloride, (R)-2-amino-2-(1-(2-(4-chloro-2'-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(methylthio)benzyl)piperazin-1-yl)ethan-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-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrochloride, (R)-2-amino-2-(1-(2-(4-chloro-2'-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrochloride, (R)-2-amino-2-(1-(2-(2',4-dichloro-3'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrochloride, (R)-2-amino-2-(1-(2-(4-chloro-3'-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(methylthio)benzyl)piperazin-1-yl)ethan-1-one hydrochloride, (R)-2-amino-2-(1-(2-(2',4-dichloro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-methylthio)benzyl)piperazin-1-yl)ethan-1-one hydrochloride, (R)-2-amino-2-(1-(2-(2',4-dichloro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrochloride, Compounds among the hydrochloride salt of (R)-2-amino-2-(1-(2-(4-chloro-3'-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-5-hydroxybenzyl)piperazin-1-yl)ethan-1-one and the hydrochloride salt of (R)-2-amino-2-(1-(2-(4-chloro-2'-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-5-hydroxybenzyl)piperazin-1-yl)ethan-1-one. 13 . A pharmaceutical composition comprising the compound or a salt thereof according to claim 1 .

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