Novel piperazine derivative or salt thereof

Abstract

The present invention addresses the problem of providing: a compound which has an activity of inhibiting a drug efflux pump of a drug-resistant bacterium and can restore the antibacterial activity of another drug when used in combination with said another drug; and a pharmaceutical composition. According to the present invention, there are provided: 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.

Description

Novel piperazine derivative or salt thereof

[0001] The present invention relates to novel piperazine derivatives or salts thereof which exhibit strong antibacterial activity against Gram-negative bacteria, particularly Pseudomonas aeruginosa, and pharmaceutical compositions containing them.

[0002] Drug-resistant bacteria are rapidly increasing worldwide, and it is predicted that in the near future, effective treatments will be unavailable, leading to an increase in deaths and significant economic losses due to drug-resistant bacteria. In particular, infections caused by multidrug-resistant Gram-negative bacteria, such as multidrug-resistant Pseudomonas aeruginosa, are ineffective against most antibacterial agents and represent a major global problem as intractable diseases. Gram-negative bacteria possess multiple drug resistance mechanisms, and the combination of these mechanisms leads to multidrug resistance. In particular, increased expression of drug efflux pumps, which transport and neutralize antibacterial agents outside the bacterial cell, is known as a mechanism for acquiring resistance to a wide variety of antibacterial agents. Bacteria possess many drug efflux pumps, which are involved in both innate and acquired resistance by excreting antibacterial agents from within the bacterial cell.

[0003] Pseudomonas aeruginosa is a type of Gram-negative bacterium and a major causative bacterial species of severe infections such as hospital-acquired pneumonia. Furthermore, P. aeruginosa tends to simultaneously exhibit resistance to multiple types of antibacterial agents. Currently, in Japan and overseas, treatment of multidrug-resistant P. aeruginosa infections involves the use of multiple antibacterial agents in combination, since a single antibacterial agent is not expected to be sufficiently effective. However, sufficient efficacy has not been achieved (Non-Patent Document 1). Compounds that inhibit these drug efflux pumps can restore the activity of antibacterial agents that have lost their effectiveness against multidrug-resistant P. aeruginosa by using them in combination.

[0004] Journal of Infection and Chemotherapy 2022, No. 5, pp. 595-601

[0005] There is a strong need to provide compounds and pharmaceutical compositions that have inhibitory activity against drug efflux pumps of enterobacteria or gram-negative bacteria and their drug-resistant bacteria, and that can restore the antibacterial activity of other drugs when used in combination with other drugs.

[0006] Under these circumstances, the present inventors have conducted intensive research and found that a compound represented by general formula [1] or a salt thereof strongly inhibits drug efflux pumps in Gram-negative bacteria such as Pseudomonas aeruginosa and drug-resistant Gram-negative bacteria including multidrug-resistant Pseudomonas aeruginosa, thereby completing the present invention.

[0007] The present invention provides the following: <1> A compound represented by general formula [1] “During the ceremony, Z. １ represents a nitrogen atom or a group represented by the formula CH; Z ２ is a nitrogen atom or a group of the general formula N ＋ -R ４ "During the ceremony, R ４ is an optionally substituted C １－６ represents an alkyl group; R １ represents a hydrogen atom or an optionally substituted amino group; X ３ is a compound of the general formula NR ３ "During the ceremony, R ３ represents a hydrogen atom or an optionally substituted C １－３ represents an alkyl group, an oxygen atom or a bond; X ４ represents a sulfonyl group, a carbonyl group, C １－３ an alkylene group or a bond; R ２ represents a hydrogen atom, an optionally substituted amino, an optionally substituted carbamoyl, an optionally substituted C １－６ Alkyl, optionally substituted C １－６ Alkoxy, optionally substituted C １－６ alkylthio, optionally substituted C ３－１０ cycloalkyl, optionally substituted cyclic amino, optionally substituted aryl and optionally substituted heterocyclic groups; １ is an optionally substituted C ２－６ an alkylene group; ２ represents a halogen atom or a hydroxyl group; Y １ represents an optionally substituted aryl group, or a salt thereof. <2> Z １ is a group represented by the formula CH; Z ２ is a nitrogen atom; R １is an optionally substituted amino group, or a salt thereof. １ But C ２－６ <4> The compound or salt thereof according to <1> or <2>, wherein X is an alkylene group. ２ <5> The compound or salt thereof according to <1> or <2>, wherein X is a halogen atom. ３ is represented by the general formula NR ３ａ "R ３ａ <6> The compound or salt thereof according to <1> or <2>, wherein X represents a hydrogen atom or an oxygen atom. ４ is a carbonyl group, C １－３ <7> The compound according to <1> or <2>, or a salt thereof, wherein R is an alkylene group or a bond. ２ is a hydrogen atom, an optionally substituted amino, an optionally substituted C １－６ Alkyl, optionally substituted C １－６ Alkoxy, optionally substituted C ３－１０ <8> The compound according to <1> or <2>, or a salt thereof, wherein R is a cycloalkyl group, an optionally substituted cyclic amino group, an optionally substituted aryl group, or an optionally substituted heterocyclic group. ２ is optionally substituted amino, optionally substituted C １－６ <9> The compound according to <1> or <2>, or a salt thereof, wherein R is an alkyl or an optionally substituted cyclic amino group. ２ <10> The compound or salt thereof according to <1> or <2>, wherein Y is an optionally substituted cyclic amino group. １is an optionally substituted phenyl group. <11> The compound or a salt thereof according to <1> or <2>, wherein the compound is (R)-2-amino-2-(1-(5-chloro-2-((((S)-pyrrolidin-3-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(2-((S)-3-aminopyrrolidin-1-yl)-5-chloro (R)-2-amino-2-(1-(5-chloro-2-(piperazin-1-yl)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-(piperazin-1-yl)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(2-((2-aminoethyl)(methyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-(((S)-pyrrolidin-3-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(2-((2-aminoethyl)amino)-5-chlorophenethyl)piperidine (R)-2-amino-2-(1-(2-((2-aminoethyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-((((S)-pyrrolidin-3-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(methylthio)benzyl)piperazin-1-yl)ethan-1-one;(R)-2-amino-2-(1-(5-chloro-2-((((S)-pyrrolidin-3-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-(((S)-pyrrolidin-3-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(methylthio)benzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-(((S)-pyrrolidin-3-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(methylthio)benzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-((((S)-pyrrolidin-2-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-(((S)-pyrrolidin-3-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-(((S)-pyrrolidin-3-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one; No-2-(1-(5-chloro-2-((((S)-pyrrolidin-2-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-5-hydroxybenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-(((S)-pyrrolidin-3-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-5-hydroxybenzyl)piperazin-1-yl)ethan-1-one; (S)-3,7 -diamino-N-(2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)heptanamide; (R)-N-(2-(2-(4-(1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)-2-((3-aminopropyl)amino)acetamide;(R)-2-amino-2-(1-(5-chloro-2-((((R)-piperazin-2-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-((((S)-piperazin-2-yl)methyl)amino (R)-2-amino-2-(1-(2-(bis(2-aminoethyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethane- 1-one; (R)-2-amino-2-(1-(5-chloro-2-((((S)-piperazin-2-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-((((R)-piperazin-2-yl)amino)phenethyl )piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-4-(1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)-1-(2-((2-aminoethyl)amino)-5-chlorophenethyl)-1-methylpiperidin-1-ium Bromide; (R)-2-amino-2-(1-(2-(2-aminoethoxy)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-((1,3-diaminopropan-2-yl)amino)phenethyl)piperi (R)-2-amino-2-(1-(5-chloro-2-(((S)-2,3-diaminopropyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-(((S)-2,3-diaminopropyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one;(R)-2-amino-2-(1-(2-((3-((3-aminopropyl)amino)propyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(2-((2-(2-aminoethoxy)ethyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one (R)-2-amino-2-(1-(5-chloro-2-(((R)-2,3-diaminopropyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-((3-(piperazin-1-yl)propyl)amino)phenethyl)piperidin-4-yl)-1-(4 -(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(2-((3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)propyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-1-(2-((2-(2-(4-(1- amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)ethyl)guanidine; (R)-2-amino-2-(1-(2-((2-((2-aminoethyl)amino)ethyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one;The compound according to <1>, which is a compound selected from (R)-2-amino-2-(1-(5-chloro-2-(((cis-4-hydroxypyrrolidin-3-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one and (R)-2-amino-2-(1-(5-chloro-2-(((trans-4-hydroxypyrrolidin-3-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one, or a salt thereof. <12> The compounds are (2S,4R)-4-((2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)-N-(2-aminoethyl)pyrrolidine-2-carboxamide; (S)-2,4-diamino-N-(2-((2-(2-(4- ((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)ethyl)butanamide; (2S,4R)-4-((2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)ethyl)butanamide (R)-2-amino-2-(1-(5-chloro-2-(((3R,5S)-5-(piperazine-1-carbonyl)pyrrolidin-3-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-methylphenyl)amino)-N-(2-aminoethyl)-N-methylpyrrolidine-2-carboxamide; ... -fluorobenzyl)piperazin-1-yl)ethan-1-one; (2S,4R)-4-((2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)-N-(2-(guanidinoethyl)pyrrolidine-2-carboxamide;(2R,4S)-4-((2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)-N-(2-aminoethyl)pyrrolidine-2-carboxamide; (2S,4S)-4-((2-(2-(4-((R)-1-amino-2-(4 -(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)-N-(2-aminoethyl)pyrrolidine-2-carboxamide; (2R,4R)-4-((2-(2-(4-((R)-1-amino-2-(4- ... (S)-2,5-diamino-N-(2-((2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)ethyl)pentanamide; and (S)-2,5-diamino-N-(2-(2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenoxy)ethyl)pentanamide or a salt thereof. <13> A pharmaceutical composition containing the compound or salt thereof according to any one of <1> to <12>.

[0008] <1a> General formula [1] “During the ceremony, Z. １ represents a nitrogen atom or a group represented by the formula CH; Z ２ is a nitrogen atom or a group of the general formula N ＋ -R ４ "During the ceremony, R ４ is an optionally substituted C １－６ represents an alkyl group; R １ represents a hydrogen atom or an optionally substituted amino group; X ３ is a compound of the general formula NR ３"During the ceremony, R ３ represents a hydrogen atom or an optionally substituted C １－３ represents an alkyl group, an oxygen atom or a bond; X ４ represents a sulfonyl group, a carbonyl group, C １－３ an alkylene group or a bond; R ２ represents a hydrogen atom, an optionally substituted amino, an optionally substituted carbamoyl, an optionally substituted C １－６ Alkyl, optionally substituted C １－６ Alkoxy, optionally substituted C １－６ alkylthio, optionally substituted C ３－１０ cycloalkyl, optionally substituted cyclic amino, optionally substituted aryl and optionally substituted heterocyclic groups; １ is an optionally substituted C ２－６ an alkylene group; ２ represents a halogen atom or a hydroxyl group; Y １ represents an optionally substituted aryl group, or a salt thereof. <2a> Z １ is a group represented by the formula CH; Z ２ is a nitrogen atom; R １ The compound according to <1a> or a salt thereof, wherein X is an optionally substituted amino group. １ But C ２－６ The compound according to <1a> or <2a> or a salt thereof, wherein X is an alkylene group. ２ <5a> The compound or salt thereof according to any one of <1a> to <3a>, wherein X is a halogen atom. ３ is represented by the general formula NR ３ａ "R ３ａ <6a> The compound or salt thereof according to any one of <1a> to <4a>, wherein X represents a hydrogen atom or an oxygen atom. ４ is a carbonyl group, C １－３ <7a> The compound or salt thereof according to any one of <1a> to <5a>, wherein R is an alkylene group or a bond. ２ is a hydrogen atom, an optionally substituted amino, an optionally substituted C １－６ Alkyl, optionally substituted C １－６Alkoxy, optionally substituted C ３－１０ <8a> The compound or salt thereof according to any one of <1a> to <6a>, wherein R is a cycloalkyl, an optionally substituted cyclic amino, an optionally substituted aryl, or an optionally substituted heterocyclic group. ２ is optionally substituted amino, optionally substituted C １－６ <9a> The compound or salt thereof according to any one of <1a> to <6a>, wherein R is an alkyl or an optionally substituted cyclic amino group. ２ <1a> The compound or salt thereof according to any one of <1a> to <6a>, wherein Y is an optionally substituted cyclic amino group. <10a> Y １is an optionally substituted phenyl group. <11a> The compound or salt thereof according to any one of <1a> to <9a>, wherein the compound is (R)-2-amino-2-(1-(5-chloro-2-((((S)-pyrrolidin-3-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(2-((S)-3-aminopyrrolidin-1-yl)-5-chloro (R)-2-amino-2-(1-(5-chloro-2-(piperazin-1-yl)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-(piperazin-1-yl)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(2-((2-aminoethyl)(methyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-(((S)-pyrrolidin-3-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(2-((2-aminoethyl)amino)-5-chlorophenethyl)piperidine (R)-2-amino-2-(1-(2-((2-aminoethyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-((((S)-pyrrolidin-3-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(methylthio)benzyl)piperazin-1-yl)ethan-1-one;(R)-2-amino-2-(1-(5-chloro-2-((((S)-pyrrolidin-3-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-(((S)-pyrrolidin-3-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(methylthio)benzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-(((S)-pyrrolidin-3-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(methylthio)benzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-((((S)-pyrrolidin-2-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-(((S)-pyrrolidin-3-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-(((S)-pyrrolidin-3-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one; No-2-(1-(5-chloro-2-((((S)-pyrrolidin-2-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-5-hydroxybenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-(((S)-pyrrolidin-3-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-5-hydroxybenzyl)piperazin-1-yl)ethan-1-one; (S)-3,7 -diamino-N-(2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)heptanamide; (R)-N-(2-(2-(4-(1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)-2-((3-aminopropyl)amino)acetamide;(R)-2-amino-2-(1-(5-chloro-2-((((R)-piperazin-2-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-((((S)-piperazin-2-yl)methyl)amino (R)-2-amino-2-(1-(2-(bis(2-aminoethyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethane- 1-one; (R)-2-amino-2-(1-(5-chloro-2-((((S)-piperazin-2-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-((((R)-piperazin-2-yl)amino)phenethyl )piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-4-(1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)-1-(2-((2-aminoethyl)amino)-5-chlorophenethyl)-1-methylpiperidin-1-ium Bromide; (R)-2-amino-2-(1-(2-(2-aminoethoxy)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-((1,3-diaminopropan-2-yl)amino)phenethyl)piperi (R)-2-amino-2-(1-(5-chloro-2-(((S)-2,3-diaminopropyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-(((S)-2,3-diaminopropyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one;(R)-2-amino-2-(1-(2-((3-((3-aminopropyl)amino)propyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(2-((2-(2-aminoethoxy)ethyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one (R)-2-amino-2-(1-(5-chloro-2-(((R)-2,3-diaminopropyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-((3-(piperazin-1-yl)propyl)amino)phenethyl)piperidin-4-yl)-1-(4 -(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(2-((3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)propyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-1-(2-((2-(2-(4-(1- amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)ethyl)guanidine; (R)-2-amino-2-(1-(2-((2-((2-aminoethyl)amino)ethyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one;The compound according to <1a> or a salt thereof, which is selected from (R)-2-amino-2-(1-(5-chloro-2-(((cis-4-hydroxypyrrolidin-3-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one and (R)-2-amino-2-(1-(5-chloro-2-(((trans-4-hydroxypyrrolidin-3-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one. <12a> The compounds are (2S,4R)-4-((2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)-N-(2-aminoethyl)pyrrolidine-2-carboxamide; (S)-2,4-diamino-N-(2-((2-(2-(4- ((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)ethyl)butanamide; (2S,4R)-4-((2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)ethyl)butanamide (R)-2-amino-2-(1-(5-chloro-2-(((3R,5S)-5-(piperazine-1-carbonyl)pyrrolidin-3-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-methylphenyl)amino)-N-(2-aminoethyl)-N-methylpyrrolidine-2-carboxamide; ... -fluorobenzyl)piperazin-1-yl)ethan-1-one; (2S,4R)-4-((2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)-N-(2-(guanidinoethyl)pyrrolidine-2-carboxamide;(2R,4S)-4-((2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)-N-(2-aminoethyl)pyrrolidine-2-carboxamide; (2S,4S)-4-((2-(2-(4-((R)-1-amino-2-(4 -(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)-N-(2-aminoethyl)pyrrolidine-2-carboxamide; (2R,4R)-4-((2-(2-(4-((R)-1-amino-2-(4- ... (S)-2,5-diamino-N-(2-((2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)-N-(2-aminoethyl)pyrrolidine-2-carboxamide; (S)-2,5-diamino-N-(2-((2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino the compound according to <1a> or a salt thereof, which is a compound selected from (S)-2,5-diamino-N-(2-(2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenoxy)ethyl)pentanamide; and (S)-2,5-diamino-N-(2-(2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenoxy)ethyl)pentanamide. <13a> A pharmaceutical composition comprising the compound according to any one of <1a> to <12a> or a salt thereof;

[0009] A method for treating an infection caused by gram-negative bacteria or drug-resistant bacteria thereof, comprising administering to a subject the compound according to any one of <1> to <13> or <1a> to <13a> or a salt thereof. The compound according to any one of <1> to <13> or <1a> to <13a> or a salt thereof for use in treating an infection caused by gram-negative bacteria or drug-resistant bacteria thereof. <C> Use of the compound according to any one of <1> to <13> or <1a> to <13a> or a salt thereof for the manufacture of a pharmaceutical composition. <D> Use of the compound according to any one of <1> to <13> or <1a> to <13a> or a salt thereof for the manufacture of a pharmaceutical composition for treating an infection caused by gram-negative bacteria or drug-resistant bacteria thereof.

[0010] The compound of the present invention or a salt thereof exhibits strong drug efflux pump inhibitory activity against bacteria that produce drug efflux pumps, such as enterobacteria or gram-negative bacteria that produce drug efflux pumps and drug-resistant bacteria thereof, and is useful as a medicine when used in combination with other antibacterial agents. The pharmaceutical composition of the present invention exhibits strong drug efflux pump inhibitory activity against bacteria that produce drug efflux pumps, such as enterobacteria or gram-negative bacteria that produce drug efflux pumps and drug-resistant bacteria thereof, and is useful as a medicine when used in combination with other antibacterial agents.

[0011] The present invention will be described in detail below. In this specification, unless otherwise specified, "%" means "mass %". In this specification, unless otherwise specified, the ratio of a compound means the weight ratio. In this specification, unless otherwise specified, each term has the following meaning.

[0012] A halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. １－６ The alkyl group refers to a straight or branched C alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, and hexyl groups. １－６ It means an alkyl group. １－３ An alkyl group means a methyl, ethyl, propyl or isopropyl group. ２－６The alkenyl group is a straight-chain or branched C alkyl group such as vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, 1,3-butadienyl, pentenyl, and hexenyl groups. ２－６ It means an alkenyl group. ２－６ The alkynyl group refers to a straight-chain or branched C alkyl group such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl groups. ２－６ It means an alkynyl group. ３－１０ The cycloalkyl group includes C 1 groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl groups. ３－１０ It means a cycloalkyl group. ３－８ The cycloalkenyl group includes C cycloalkenyl groups such as cyclopropenyl, cyclobutenyl, 2-cyclopenten-1-yl, 2-cyclohexen-1-yl, and 3-cyclohexen-1-yl groups. ３－８ The aryl group refers to a C cycloalkenyl group, such as phenyl, naphthyl, anthranyl, biphenyl, and phenanthryl groups. ６－１４ means an aryl group. Aryl C １－６ The alkyl group is, for example, an aryl C group such as benzyl, diphenylmethyl, trityl, phenethyl, and naphthylmethyl groups. １－６ It means an alkyl group.

[0013] C １－６ The alkylene group is a straight or branched C alkylene group such as methylene, ethylene, propylene, butylene, and hexylene groups. １－６ It means an alkylene group. １－３ The alkylene group means a methylene, ethylene, propylene or isopropylene group. ２－６ The alkylene group is a straight or branched C alkylene group such as ethylene, propylene, butylene, and hexylene groups. １－６ It means an alkylene group. ２－６ The alkenylene group is a straight-chain or branched C alkyl group such as vinylene, propenylene, butenylene, and pentenylene. ２－６ It means an alkenylene group. ２－６The alkynylene group is a straight-chain or branched C alkyl group such as ethynylene, propynylene, butynylene, and pentynylene. ２－６ It means an alkynylene group.

[0014] C １－６ The alkoxy group is a straight-chain or branched C alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy groups. １－６ It means an alkyloxy group. １－６ Alkoxy C １－６ The alkyl group is a C methyl group such as methoxymethyl and 1-ethoxyethyl groups. １－６ Alkyloxy C １－６ It means an alkyl group.

[0015] C ２－１２ The alkanoyl group refers to a straight-chain or branched C alkyl group such as acetyl, propionyl, valeryl, isovaleryl, and pivaloyl. ２－１２ The term "alkanoyl group" refers to, for example, aroyl group, such as benzoyl or naphthoyl group. The term "acyl group" refers to, for example, formyl group, succinyl group, glutaryl group, maleoyl group, phthaloyl group, C ２－１２ The acyloxy group refers to an alkanoyl group or an aroyl group. ２－１２ It means an alkanoyloxy group or an aroyloxy group such as a benzoyloxy or naphthoyloxy group.

[0016] C １－６ The alkoxycarbonyl group is a straight-chain or branched C alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, and 1,1-dimethylpropoxycarbonyl groups. １－６ It means an alkyloxycarbonyl group. Aryl C １－６ The alkoxycarbonyl group is an alkoxycarbonyl group such as a benzyloxycarbonyl group or a phenethyloxycarbonyl group. １－６ It means an alkyloxycarbonyl group. Aryl C １－６ Alkoxy C １－６The alkyl group is an alkyl group such as benzyloxymethyl, benzyloxyethyl, naphthylmethyloxymethyl, and phenethyloxymethyl. １－６ Alkyloxy C １－６ An aryloxycarbonyl group means, for example, a phenyloxycarbonyl or naphthyloxycarbonyl group.

[0017] C １－６ The alkylamino group is a straight-chain or branched C alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, tert-butylamino, pentylamino, and hexylamino groups. １－６ It means an alkylamino group. １－６ The term "(alkyl)amino group" refers to a linear or branched di(C)amino group such as dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, di(tert-butyl)amino, dipentylamino, dihexylamino, (ethyl)(methyl)amino, and (methyl)(propyl)amino groups. １－６ It means an amino group.

[0018] C １－６ The alkylthio group is a C alkylthio group such as methylthio, ethylthio, and propylthio groups. １－６ It means an alkylthio group. １－６ The alkylsulfonyl group includes C 11 groups such as methylsulfonyl, ethylsulfonyl, and propylsulfonyl groups. １－６ The term "arylsulfonyl group" refers to a benzenesulfonyl group, a p-toluenesulfonyl group, a naphthalenesulfonyl group, or the like. １－６ The alkylsulfonyloxy group is a C methylsulfonyloxy group, an ethylsulfonyloxy group, etc. １－６ An arylsulfonyloxy group means a benzenesulfonyloxy group or a p-toluenesulfonyloxy group.

[0019] The silyl group means a silyl group such as trimethylsilyl, triethylsilyl, tributylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and triisopropylsilyl groups.

[0020] The cyclic amino group refers to a cyclic amino group containing one or more nitrogen atoms and optionally further containing one or more oxygen atoms or sulfur atoms as ring-forming hetero atoms, such as aziridinyl, azetidinyl, pyrrolyl, dihydropyrrolyl, pyrrolidinyl, tetrahydropyridyl, piperidinyl, homopiperidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, thiazolinyl, thiazolidinyl, dihydrothiadiazolyl, piperazinyl, homopiperazinyl, morpholinyl, homomorpholinyl, and thiomorpholinyl groups.

[0021] The monocyclic nitrogen-containing heterocyclic group means a monocyclic nitrogen-containing heterocyclic group containing only a nitrogen atom as a ring-forming heteroatom, and examples thereof include an azetidinyl group; a 5-membered nitrogen-containing heterocyclic group such as a pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolidinyl, imidazolinyl, imidazolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, triazolyl, or tetrazolyl group; a 6-membered nitrogen-containing heterocyclic group such as a piperidyl, tetrahydropyridyl, pyridyl, piperazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, tetrahydropyrimidyl, or homopiperazinyl group; a 7-membered nitrogen-containing heterocyclic group such as a homopiperidinyl group; or an 8-membered nitrogen-containing heterocyclic group such as an octahydroazocinyl group. The monocyclic oxygen-containing heterocyclic group refers to a monocyclic oxygen-containing heterocyclic group containing only oxygen atoms as ring heteroatoms, such as a 5-membered ring oxygen-containing heterocyclic group such as tetrahydrofuranyl or furanyl group, or a 6-membered ring oxygen-containing heterocyclic group such as tetrahydropyranyl or pyranyl group. The monocyclic sulfur-containing heterocyclic group refers to a thienyl group, etc.

[0022] The monocyclic nitrogen- and oxygen-containing heterocyclic group refers to a monocyclic nitrogen- and oxygen-containing heterocyclic group containing only nitrogen and oxygen atoms as ring-forming heteroatoms, such as 5-membered nitrogen- and oxygen-containing heterocyclic groups such as oxazolyl, oxazolidinyl, isoxazolyl, and oxadiazolyl groups; or 6-membered nitrogen- and oxygen-containing heterocyclic groups such as morpholinyl groups. The monocyclic nitrogen- and sulfur-containing heterocyclic group refers to a monocyclic nitrogen- and sulfur-containing heterocyclic group containing only nitrogen and sulfur atoms as ring-forming heteroatoms, such as 5-membered nitrogen- and sulfur-containing heterocyclic groups such as thiazolyl, isothiazolyl, and thiadiazolyl groups; or 6-membered nitrogen- and sulfur-containing heterocyclic groups such as thiomorpholinyl, 1-oxidethiomorpholinyl, and 1,1-dioxidethiomorpholinyl groups. The monocyclic heterocyclic group refers to 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. The monocyclic saturated heterocyclic group refers to a monocyclic heterocyclic group that does not contain a multiple bond, such as aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, pyrazolidinyl, piperazinyl, oxazolidinyl, tetrahydropyrimidyl, tetrahydrofuranyl, tetrahydropyranyl, and morpholinyl.

[0023] The bicyclic nitrogen-containing heterocyclic group means a bicyclic nitrogen-containing heterocyclic group containing only nitrogen atoms as ring-forming heteroatoms, such as indolinyl, indolyl, isoindolinyl, isoindolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, quinolidinyl, cinnolinyl, phthalazinyl, quinazolinyl, dihydroquinoxalinyl, quinoxalinyl, naphthyridinyl, purinyl, pyrrolopyridinyl, dihydrocyclopentapyridinyl, pteridinyl, and quinuclidinyl groups. The bicyclic oxygen-containing heterocyclic group means a bicyclic oxygen-containing heterocyclic group containing only oxygen atoms as ring-forming heteroatoms, such as 2,3-dihydrobenzofuranyl, benzofuranyl, isobenzofuranyl, chromanyl, chromenyl, isochromanyl, 1,3-benzodioxolyl, 1,3-benzodioxanyl, and 1,4-benzodioxanyl groups.

[0024] The bicyclic sulfur-containing heterocyclic group refers to a bicyclic sulfur-containing heterocyclic group containing only sulfur atoms as ring-forming hetero atoms, such as 2,3-dihydrobenzothienyl and benzothienyl groups. The bicyclic nitrogen-containing oxygen-containing heterocyclic group refers to a bicyclic nitrogen-containing oxygen-containing heterocyclic group containing only nitrogen atoms and oxygen atoms as ring-forming hetero atoms, such as benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzomorpholinyl, dihydropyranopyridyl, dihydrodioxinopyridyl and dihydropyridoxazinyl groups. The bicyclic nitrogen-containing sulfur-containing heterocyclic group refers to a bicyclic nitrogen-containing sulfur-containing heterocyclic group containing only nitrogen atoms and sulfur atoms as ring-forming hetero atoms, such as benzothiazolyl, benzisothiazolyl and benzothiadiazolyl groups. A bicyclic heterocyclic group means 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.

[0025] The heterocyclic group means a monocyclic heterocyclic group or a bicyclic heterocyclic group.

[0026] The leaving group may be a halogen atom, C １－６Examples of the alkylsulfonyloxy group include an alkylsulfonyloxy group, an arylsulfonyloxy group, and an imidazole group. １－６ The alkylsulfonyloxy group, arylsulfonyloxy group or imidazole group may have a substituent.

[0027] The hydroxyl-protecting group includes all groups that can be used as a protecting group for a normal hydroxyl 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 group, C ２－６ Alkenyl group, aryl C １－６ Alkyl group, C １－６ Alkoxy C １－６ Alkyl group, acyl group, C １－６ Alkoxycarbonyl group, aryl C １－６ Alkoxycarbonyl group, C １－６ Examples of the alkylsulfonyl group include an alkylsulfonyl group, an arylsulfonyl group, a silyl group, a tetrahydrofuranyl group, and a tetrahydropyranyl group. These groups may be substituted with one or more groups selected from Substituent Group A1.

[0028] The amino-protecting group includes all groups that can be used as a protecting group for a normal amino group, and examples thereof include those 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 group, C １－６ Alkoxy C １－６ Alkyl group, acyl group, C １－６ Alkoxycarbonyl group, aryl C １－６Alkoxycarbonyl group, aryloxycarbonyl group, C １－６ Examples of the alkylsulfonyl group include an alkylsulfonyl group, an arylsulfonyl group, and a silyl group. These groups may be substituted with one or more groups selected from Substituent Group A1.

[0029] The imino-protecting group includes all groups that can be used as a protecting group for a normal imino group, and examples thereof include groups described in W. Greene et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 696-868, 2007, John Wiley & Sons, Inc. Specifically, aryl C １－６ Alkyl group, C １－６ Alkoxy C １－６ Alkyl group, acyl group, C １－６ Alkoxycarbonyl group, aryl C １－６ Alkoxycarbonyl group, aryloxycarbonyl group, C １－６ Examples of the alkylsulfonyl group include an alkylsulfonyl group, an arylsulfonyl group, and a silyl group. These groups may be substituted with one or more groups selected from Substituent Group A1.

[0030] The carboxyl-protecting group includes all groups that can be used as a conventional protecting group for a carboxyl 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 group, C ２－６ Alkenyl group, aryl C １－６ Alkyl group, C １－６ Alkoxy C １－６ Examples of the alkyl group include an alkyl group and a silyl group. These groups may be substituted with one or more groups selected from the substituent group A1.

[0031] Examples of halogenated hydrocarbons include methylene chloride, chloroform, and dichloroethane. Examples of alcohols include methanol, ethanol, propanol, 2-propanol, butanol, and 2-methyl-2-propanol. Examples of ethers include diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and diethylene glycol diethyl ether.

[0032] Examples of ketones include acetone, 2-butanone, and 4-methyl-2-pentanone. Examples of esters include methyl acetate, ethyl acetate, propyl acetate, and butyl acetate. Examples of amides include N,N-dimethylformamide, N,N-dimethylacetamide, and 1-methyl-2-pyrrolidone. Examples of nitriles include acetonitrile and propionitrile. Examples of aromatic hydrocarbons include benzene, toluene, and xylene.

[0033] In this specification, the substituent groups have the following meanings:

[0034] Substituent group A1: C optionally substituted with one or more groups selected from a hydrogen atom, a halogen atom, a cyano group, a nitro group, an oxo group, and Substituent group B2 １－６ an alkyl group, C optionally substituted with one or more groups selected from Substituent group B2; ２－６ an alkenyl group, C optionally substituted with one or more groups selected from Substituent group B2 ２－６ an alkynyl group, C optionally substituted with one or more groups selected from Substituent group B2 １－６ an alkoxy group, an aryloxy group which may be substituted with one or more groups selected from Substituent group B1, an acyl group which may be substituted with one or more groups selected from Substituent group B1, a C group which may be substituted with one or more groups selected from Substituent group B2, １－６an alkylamino group, a di(C) group optionally substituted with one or more groups selected from Substituent group B2; １－６ an imino group which may be protected or substituted with one or more groups selected from the substituent group B1; a C group which may be substituted with one or more groups selected from the substituent group B2; １－６ an alkylthio group, an arylthio group optionally substituted with one or more groups selected from Substituent group B1, a C group optionally substituted with one or more groups selected from Substituent group B2, １－６ an alkylsulfonyl group, an arylsulfonyl group optionally substituted with one or more groups selected from Substituent group B1, a C group optionally substituted with one or more groups selected from Substituent group B1 ３－１０ a cycloalkyl group, an aryl group optionally substituted with one or more groups selected from substituent group B1, a heterocyclic group optionally substituted with one or more groups selected from substituent group B1, a carbamoyl group optionally substituted with one or more groups selected from substituent group B1, a sulfamoyl group optionally substituted with one or more groups selected from substituent group B1, a hydroxyl group which may be protected, an amino group which may be protected, and a carboxyl group which may be protected.

[0035] Substituent group A2: a C optionally substituted with one or more groups selected from a hydrogen atom, a halogen atom, a cyano group, a nitro group, an oxo group, and Substituent group B2 １－６ an alkoxy group, an aryloxy group which may be substituted with one or more groups selected from Substituent group B1, an acyl group which may be substituted with one or more groups selected from Substituent group B1, a C group which may be substituted with one or more groups selected from Substituent group B2, １－６ an alkylamino group, a di(C) group optionally substituted with one or more groups selected from Substituent group B2; １－６ C optionally substituted with one or more groups selected from Substituent group B2 １－６ an alkylthio group, an arylthio group optionally substituted with one or more groups selected from Substituent group B1, a C group optionally substituted with one or more groups selected from Substituent group B2, １－６an alkylsulfonyl group, an arylsulfonyl group optionally substituted with one or more groups selected from Substituent group B1, a C group optionally substituted with one or more groups selected from Substituent group B1 ３－１０ a cycloalkyl group, an aryl group optionally substituted with one or more groups selected from substituent group B1, a heterocyclic group optionally substituted with one or more groups selected from substituent group B1, a carbamoyl group optionally substituted with one or more groups selected from substituent group B1, a sulfamoyl group optionally substituted with one or more groups selected from substituent group B1, a hydroxyl group which may be protected, an amino group which may be protected, and a carboxyl group which may be protected.

[0036] Substituent group B1: a hydrogen atom, a halogen atom, a cyano group, a nitro group, an oxo group, C optionally substituted with one or more groups selected from Substituent group C １－６ an alkyl group, a C optionally substituted with one or more groups selected from the substituent group C; ２－６ an alkenyl group, C optionally substituted with one or more groups selected from the substituent group C; ２－６ an alkynyl group, C optionally substituted with one or more groups selected from the substituent group C; １－６ an alkoxy group, an aryloxy group optionally substituted with one or more groups selected from substituent group C, an acyl group optionally substituted with one or more groups selected from substituent group C, an aryloxy ... １－６ an alkylamino group, a di(C) group optionally substituted with one or more groups selected from the substituent group C; １－６ C optionally substituted with one or more groups selected from the substituent group C １－６ an alkylthio group, an arylthio group optionally substituted with one or more groups selected from substituent group C, an arylthio group optionally substituted with one or more groups selected from substituent group C １－６ an alkylsulfonyl group, an arylsulfonyl group optionally substituted with one or more groups selected from Substituent Group C, an arylsulfonyl group optionally substituted with one or more groups selected from Substituent Group C, ３－１０a cycloalkyl group, an aryl group optionally substituted with one or more groups selected from substituent group C, a heterocyclic group optionally substituted with one or more groups selected from substituent group C, a carbamoyl group optionally substituted with one or more groups selected from substituent group C, a sulfamoyl group optionally substituted with one or more groups selected from substituent group C, an optionally protected hydroxyl group, an optionally protected amino group, and an optionally protected carboxyl group.

[0037] Substituent group B2: a hydrogen atom, a halogen atom, a cyano group, a nitro group, an oxo group, C optionally substituted with one or more groups selected from Substituent group C １－６ an alkoxy group, an aryloxy group optionally substituted with one or more groups selected from substituent group C, an acyl group optionally substituted with one or more groups selected from substituent group C, an aryloxy ... １－６ an alkylamino group, a di(C) group optionally substituted with one or more groups selected from the substituent group C; １－６ C optionally substituted with one or more groups selected from the substituent group C １－６ an alkylthio group, an arylthio group optionally substituted with one or more groups selected from substituent group C, an arylthio group optionally substituted with one or more groups selected from substituent group C １－６ an alkylsulfonyl group, an arylsulfonyl group optionally substituted with one or more groups selected from Substituent Group C, an arylsulfonyl group optionally substituted with one or more groups selected from Substituent Group C, ３－１０ a cycloalkyl group, an aryl group optionally substituted with one or more groups selected from substituent group C, a heterocyclic group optionally substituted with one or more groups selected from substituent group C, a carbamoyl group optionally substituted with one or more groups selected from substituent group C, a sulfamoyl group optionally substituted with one or more groups selected from substituent group C, a hydroxyl group which may be protected, an amino group which may be protected, and a carboxyl group which may be protected.

[0038] Substituent group C: a halogen atom, a cyano group, a carbamoyl group, C１－６ alkyl group, C １－６ an alkoxy group, an optionally protected amino group, an optionally protected imino group, an optionally protected hydroxyl group, an optionally protected carboxyl group.

[0039] R １ and R ２ The optionally substituted amino group may be substituted with one or more groups selected from Substituent Group A1. ２ Optionally substituted C ３－１０ The cycloalkyl group, the optionally substituted cyclic amino group, the optionally substituted aryl group, and the optionally substituted heterocyclic group may be substituted with one or more groups selected from the substituent group A1. ２ an optionally substituted carbamoyl group represented by the formula: １－６ alkyl group, optionally substituted C １－６ an alkoxy group, optionally substituted C １－６ The alkylthio group may be substituted with one or more groups selected from Substituent Group A2. １ Optionally substituted C ２－６ The alkylene group may be substituted with one or more groups selected from Substituent Group A2. ３ Optionally substituted C １－３ The alkyl group may be substituted with one or more groups selected from Substituent Group A2. ４ Optionally substituted C １－６ The alkyl group may be substituted with one or more groups selected from the substituent group A2. １ The optionally substituted aryl group may be substituted with one or more groups selected from the substituent group A1.

[0040] Among the compounds of the present invention, preferred compounds include the following compounds.

[0041] Z １ is preferably a compound in which Z is a group represented by the formula CH. ２ is preferably a nitrogen atom. １ is C ２－６An alkylene group is preferred, and an ethylene group is more preferred. ２ is preferably a halogen atom, more preferably a chlorine atom. ３ is a compound of the general formula NR ３ａ "R ３ａ represents a hydrogen atom or an oxygen atom, and ３ａ "R ３ａ represents a hydrogen atom is more preferred. ４ is a carbonyl group, C １－３ An alkylene group or a bond is preferred, and C １－３ An alkylene group is more preferred.

[0042] R １ is preferably an optionally substituted amino group, more preferably an amino group (a compound in which the conformation of the carbon atom to which the amino group is bonded is the R configuration). ２ represents a hydrogen atom, an optionally substituted amino, an optionally substituted C １－６ Alkyl, optionally substituted C １－６ Alkoxy, optionally substituted C ３－１０ Cycloalkyl, optionally substituted cyclic amino, optionally substituted aryl and optionally substituted heterocyclic groups are preferred, and optionally substituted amino, optionally substituted C １－６ Alkyl or an optionally substituted cyclic amino group is more preferred, and an optionally substituted cyclic amino group is even more preferred. ２ is preferably an optionally substituted pyrrolidinyl or piperidinyl group, and most preferably a pyrrolidinyl group. １ is preferably an optionally substituted phenyl group, and is preferably one or more hydroxy groups, C １－６ Alkoxy group or C １－６ A phenyl group substituted with an alkylthio group is more preferred.

[0043] R ２ C １－６ Examples of the substituent of the alkyl group include a halogen atom, a hydroxyl group, a guanidinium group, an optionally substituted amino group, an optionally substituted alkylthio group, an optionally substituted C ３－１０Examples of the aryl group include a cycloalkyl group, an optionally substituted aryl group, an optionally substituted cyclic amino group, and an optionally substituted heterocyclic group. ２ Examples of the substituent of the cyclic amino group include a halogen atom, a hydroxyl group, an amidino group, an oxo group, an optionally substituted amino group, an optionally substituted C １－６ Examples of such a carbonyl group include an alkyl group, an optionally substituted carbamoyl group, an optionally substituted acyl group, and a carbonyl group substituted with a cyclic amino group. A carbonyl group substituted with a hydroxyl group, an amino group, an optionally substituted carbamoyl group, and a cyclic amino group is preferred, and a carbamoyl group substituted with an alkyl group substituted with an amino group or a guanidinium group, and a carbonyl group substituted with a piperazinyl group are more preferred.

[0044] The following compounds are more preferred: (R)-2-amino-2-(1-(5-chloro-2-((((S)-pyrrolidin-3-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one or a salt thereof (compound of Example 1) (R)-2-amino-2-(1-(2-((S)-3-aminopyrrolidin-1-yl)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one or a salt thereof (compound of Example 4) (R)-2-amino-2-(1-(5-chloro-2-(piperazin-1-yl)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one or a salt thereof (compound of Example 8) (R)-2-amino-2-(1-(2-((2-aminoethyl)(methyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one or a salt thereof (compound of Example 12) (R)-2-amino-2-(1-(5-chloro-2-(((S)-pyrrolidin-3-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one or a salt thereof (compound of Example 17) (R)-2-amino-2-(1-(2-((2-aminoethyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one or a salt thereof (compound of Example 32) (R)-2-amino-2-(1-(2-((2-aminoethyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one or a salt thereof (compound of Example 63) (R)-2-amino-2-(1-(5-chloro-2-((((S)-pyrrolidin-3-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(methylthio)benzyl)piperazin-1-yl)ethan-1-one or a salt thereof (compound of Example 64)(R)-2-amino-2-(1-(5-chloro-2-((((S)-pyrrolidin-3-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one or a salt thereof (compound of Example 66) (R)-2-amino-2-(1-(5-chloro-2-(((S)-pyrrolidin-3-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(methylthio)benzyl)piperazin-1-yl)ethan-1-one or a salt thereof (compound of Example 68) (R)-2-amino-2-(1-(5-chloro-2-((((S)-pyrrolidin-2-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one or a salt thereof (compound of Example 69) (R)-2-amino-2-(1-(5-chloro-2-(((S)-pyrrolidin-3-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one or a salt thereof (compound of Example 70)

[0045] (R)-2-amino-2-(1-(5-chloro-2-((((S)-pyrrolidin-2-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-5-hydroxybenzyl)piperazin-1-yl)ethan-1-one or a salt thereof (compound of Example 74) (R)-2-amino-2-(1-(5-chloro-2-(((S)-pyrrolidin-3-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-5-hydroxybenzyl)piperazin-1-yl)ethan-1-one or a salt thereof (compound of Example 76) (S)-3,7-diamino-N-(2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)heptanamide or a salt thereof (Compound of Example 77) (R)-N-(2-(2-(4-(1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)-2-((3-aminopropyl)amino)acetamide or a salt thereof (Compound of Example 161) (R)-2-amino-2-(1-(5-chloro-2-((((R)-piperazin-2-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one or a salt thereof (compound of Example 177) (R)-2-amino-2-(1-(5-chloro-2-((((S)-piperazin-2-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one or a salt thereof (compound of Example 180) (R)-2-amino-2-(1-(2-(bis(2-aminoethyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one or a salt thereof (Compound of Example 182)(R)-2-amino-2-(1-(5-chloro-2-((((S)-piperazin-2-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one or a salt thereof (compound of Example 188) (R)-2-amino-2-(1-(5-chloro-2-((((R)-piperazin-2-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one or a salt thereof (compound of Example 189) (R)-4-(1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)-1-(2-((2-aminoethyl)amino)-5-chlorophenethyl)-1-methylpiperidin-1-ium bromide or a salt thereof (Compound of Example 202) (R)-2-amino-2-(1-(2-(2-aminoethoxy)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one or a salt thereof (Compound of Example 206) (R)-2-amino-2-(1-(5-chloro-2-((1,3-diaminopropan-2-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one or a salt thereof (Compound of Example 217)

[0046] (R)-2-amino-2-(1-(5-chloro-2-(((S)-2,3-diaminopropyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one or a salt thereof (Compound of Example 221) (R)-2-amino-2-(1-(2-((3-((3-aminopropyl)amino)propyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one or a salt thereof (Compound of Example 227) (R)-2-amino-2-(1-(2-((2-(2-aminoethoxy)ethyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one or a salt thereof (compound of Example 229) (R)-2-amino-2-(1-(5-chloro-2-(((R)-2,(R)-2-amino-2-(1-(5-chloro-2-((3-(piperazin-1-yl)propyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one or a salt thereof (compound of Example 231) (R)-2-amino-2-(1-(2-((3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)propyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one or a salt thereof (Compound of Example 233) (R)-1-(2-((2-(2-(4-(1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)ethyl)guanidine or a salt thereof (Compound of Example 235) (R)-2-amino-2-(1-(2-((2-((2-aminoethyl)amino)ethyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one or a salt thereof (Compound of Example 236) (R)-2-amino-2-(1-(5-chloro-2-(((cis-4-hydroxypyrrolidin-3-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one or a salt thereof (Compound of Example 237) (R)-2-amino-2-(1-(5-chloro-2-(((trans-4-hydroxypyrrolidin-3-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one or a salt thereof (compound of Example 238),

[0047] (2S,4R)-4-((2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)-N-(2-aminoethyl)pyrrolidine-2-carboxamide or a salt thereof (compound of Example 239) (S)-2,4-diamino-N-(2-((2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)ethyl)butanamide or a salt thereof (compound of Example 248) (2S,4R)-4-((2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)-N-(2-aminoethyl)-N-methylpyrrolidine-2-carboxamide or a salt thereof (Compound of Example 255) (R)-2-amino-2-(1-(5-chloro-2-(((3R,5S)-5-(piperazine-1-carbonyl)pyrrolidin-3-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one or a salt thereof (Compound of Example 256) (2S,4R)-4-((2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)-N-(2-(guanidinoethyl)pyrrolidine-2-carboxamide or a salt thereof (compound of Example 257) (2R,4S)-4-((2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)-N-(2-aminoethyl)pyrrolidine-2-carboxamide or a salt thereof (compound of Example 258) (2S,4S)-4-((2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)-N-(2-aminoethyl)pyrrolidine-2-carboxamide or a salt thereof (compound of Example 259) (2R,4R)-4-((2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)-N-(2-aminoethyl)pyrrolidine-2-carboxamide or a salt thereof (compound of Example 260) (S)-2,5-diamino-N-(2-((2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)ethyl)pentanamide or a salt thereof (compound of Example 261); (S)-2,5-diamino-N-(2-(2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenoxy)ethyl)pentanamide or a salt thereof (compound of Example 262);

[0048] Examples of salts of the compound of the general formula [1] include commonly known salts of a basic group such as an amino group or an acidic group such as a hydroxyl or carboxyl group.

[0049] Examples of salts of basic groups 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.

[0050] Salts of acidic groups include, for example, salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and 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-phenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine.

[0051] Of the above salts, preferred salts include pharmacologically acceptable salts.

[0052] When the compound of general formula [1] or a salt thereof has isomers (for example, optical isomers, geometric isomers, tautomers, etc.), the present invention encompasses these isomers as well as solvates, hydrates, and various forms of crystals.

[0053] The compound of the present invention or its salt can be combined with one or more pharmaceutically acceptable carriers, excipients, or diluents to form a pharmaceutical composition (pharmaceutical formulation). Examples of the carriers, excipients, and diluents include water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, water syrup, methylcellulose, polyvinylpyrrolidone, alkyl parahydroxybenzosorbate, talc, magnesium stearate, stearic acid, glycerin, and various oils such as sesame oil, olive oil, and soybean oil. In addition, the above-mentioned carriers, excipients or diluents can be mixed with commonly used additives such as fillers, binders, disintegrants, pH adjusters and solubilizers as needed, and oral or parenteral medicines such as tablets, pills, capsules, granules, powders, liquids, emulsions, suspensions, ointments, injections or skin patches can be prepared using conventional formulation techniques.

[0054] The compounds of the present invention are useful as pharmaceuticals in combination with other antibacterial agents against bacteria that produce drug efflux pumps, such as enterobacteria or gram-negative bacteria that produce drug efflux pumps, and drug-resistant bacteria thereof. In the present invention, "combination" refers to simultaneous or sequential administration of one or more of the compounds of the present invention and the other antibacterial agents. The other antibacterial agent is not particularly limited as long as it is an antibacterial agent that is excreted from inside to outside the bacterial cell by a drug efflux pump, and examples thereof include penicillin antibacterial agents such as benzylpenicillin and piperacillin; β-lactam combination agents such as piperacillin-tazobactam combination agents, ampicillin-sulbactam combination agents, ceftazidime-avibactam combination agents, ceftolozane-tazobactam combination agents, and ticarcillin-clavulanic acid combination agents; cephem antibacterial agents such as cefazolin, cefmetazole, ceftriaxone, ceftazidime, cefepime, and cefiderocol; monobactam antibacterial agents such as aztreonam; carbapenem antibacterial agents such as doripenem, imipenem, and meropenem; gentamicin, tobramycin, aminoglycoside antibacterial agents such as fluconazole, amikacin, and netilmicin; quinolone antibacterial agents such as gatifloxacin, garenoxacin, moxifloxacin, sitafloxacin, lascufloxacin, ciprofloxacin, levofloxacin, lomefloxacin, ofloxacin, and pazufloxacin; oxazolidinone antibacterial agents such as linezolid and tedizolid; macrolide antibacterial agents such as erythromycin, azithromycin, clarithromycin, and solithromycin; tetracycline antibacterial agents such as tetracycline, minocycline, and doxycycline; glycylcycline antibacterial agents such as tigecycline; and rifamycin antibacterial agents such as rifampicin.

[0055] The compounds of the present invention inhibit drug efflux pumps, for example, MexB and / or MexY drug efflux pumps. Preferred compounds include those that inhibit both MexB and MexY drug efflux pumps.

[0056] Treatment with the compound or salt thereof, or pharmaceutical composition of the present invention includes both therapeutic and prophylactic purposes. The administration method, dosage, and frequency of administration of the compound or salt thereof, or pharmaceutical composition of the present invention can be appropriately selected depending on the age, weight, and symptoms of the patient. Typically, for adults, the compound of the present invention may be administered orally or parenterally (for example, by injection, infusion, or rectal administration) at a dose of 0.01 to 1000 mg / kg per day, in one or several divided doses.

[0057] The compound or a salt thereof, or the pharmaceutical composition of the present invention is preferably administered as an injection. The pharmaceutical composition containing the compound or a salt thereof of the present invention is preferably produced as a liquid, a frozen liquid, or a lyophilized preparation, and more preferably a lyophilized preparation.

[0058] Next, a method for producing the compound of the present invention will be described. The compound of the present invention can be produced by combining known methods, for example, according to the following production method.

[0059] [Production method 1] Deprotection "During the ceremony, R １ａ is an optionally protected R １ The same substituents as those in ２ａ is an optionally protected R ２ The same substituents as those in ４ａ is an optionally protected R ４ The same substituents as those shown in １ａ is an optionally protected X １ The same substituents as those shown in ２ａ is an optionally protected X ２ The same substituents as those shown in ３ａ is an optionally protected X ３ The same substituents as those shown in ４ａ is an optionally protected X ４ The same substituents as those of １ａ is an optionally protected Y １ The same substituents as those in １ , R ２ , R ４ , X １ , X ２ , X ３ , X４ , Y １ , Z １ , and Z ２ has the same meaning as above. However, in the general formula [2a], R １ａ , R ２ａ , R ４ａ , X １ａ , X ２ａ , X ３ａ , X ４ａ or Y １ａ is protected." 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 known method such as that described in W. Greene et al., Protective Groups in Organic Synthesis, 4th Edition, 2007, John Wiley & Sons, INC.

[0060] (1) In the Case of Amino-Protecting Group: The compound represented by general formula [1a] can be produced by deprotecting the amino-protecting group of the compound represented by general formula [2a] in the presence or absence of a solvent. Methods for deprotecting the amino-protecting group include, for example, reduction by contact with a catalyst and reduction with an acid. (1-a) Reduction by Contact with a Catalyst: The compound represented by general formula [1a] can be produced by reducing the compound represented by general formula [2a] in the presence of a catalyst under a hydrogen atmosphere. Examples of catalysts used in this reaction include metal catalysts, such as metallic palladium such as palladium-carbon and palladium black; palladium salts such as palladium oxide and palladium hydroxide; nickel metals such as Raney nickel; and platinum salts such as platinum oxide. A preferred metal catalyst is palladium-carbon. The amount of catalyst used in this reaction may be 0.001 to 20 times, preferably 0.01 to 5 times, the amount of the compound represented by general formula [2a]. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but examples include alcohols, ethers, and esters, and these may be used in mixtures. Preferred solvents include alcohols and esters, with methanol and ethanol being more preferred. This reaction is carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 0 to 50°C for 1 to 24 hours. (1-b) Acid-Based Method: The compound represented by general formula [1a] can be produced by reacting the compound represented by general formula [2a] with an acid in the presence or absence of a solvent. Examples of acids used in this reaction include protonic acids such as hydrochloric acid and hydrobromic acid; and Lewis acids such as aluminum chloride and iodotrimethylsilane. The amount of acid used in this reaction is 1 to 100 times, preferably 2 to 30 times, the molar ratio of the compound represented by general formula [2a]. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but examples include halogenated hydrocarbons, ethers, and nitriles, and these may be used in mixtures.Preferred solvents include halogenated hydrocarbons and nitriles, with dichloromethane and acetonitrile being more preferred. In this reaction, if the acid is liquid, it can also be used as the solvent. This 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. (1-c) Base-Based Method: The compound represented by general formula [1a] can be produced by reacting the compound represented by general formula [2a] with a base. Examples of bases used in this reaction include inorganic bases such as sodium hydroxide and potassium carbonate; and organic bases such as morpholine and triethylamine. The amount of base used in this reaction is 1 to 100 times, preferably 2 to 30 times, the molar ratio of the compound represented by general formula [2a]. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction. Examples include halogenated hydrocarbons, ethers, amides, alcohols, nitriles, and water, and these may be used in combination. This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 0 to 50°C for 1 to 24 hours. For example, when the amino-protecting group is a benzyloxycarbonyl group, deprotection methods similar to those in Production Method (1-a) or Production Method (1-b) may be used. For example, when the amino-protecting group is a benzyl group, deprotection methods similar to those in Production Method (1-a) or Production Method (1-b) may be used. For example, when the amino-protecting group is a tert-butoxycarbonyl group, deprotection methods similar to those in Production Method (1-b) may be used. For example, when the amino-protecting group is a 9-fluorenylmethyloxycarbonyl group, deprotection methods similar to those in Production Method (1-c) may be used.

[0061] (2) Hydroxyl Protecting Group: Compounds represented by general formula [1a] can be produced by deprotecting compounds represented by general formula [2a]. Methods for deprotecting hydroxyl protecting groups include reduction by contact with a catalyst, reduction with an acid, and a method using fluoride ions. (2-a) Reduction by Contact with a Catalyst: Compounds represented by general formula [1a] can be produced by reducing compounds represented by general formula [2a] in the presence of a catalyst under a hydrogen atmosphere. Examples of catalysts used in this reaction include metal catalysts, such as metallic palladium (e.g., palladium-carbon and palladium black); palladium salts (e.g., palladium oxide and palladium hydroxide); nickel metals (e.g., Raney nickel); and platinum salts (e.g., platinum oxide). A preferred metal catalyst is palladium-carbon. The amount of catalyst used in this reaction may be 0.001 to 20 times, preferably 0.01 to 5 times, the amount of the compound represented by general formula [2a]. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction. Examples include alcohols, ethers, and esters, and these may be used in combination. Preferred solvents include alcohols and esters, with methanol and ethanol being more preferred. This reaction is carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 0 to 50°C for 1 to 24 hours. (2-b) Acid-Based Method: The compound represented by general formula [1a] can be produced by reacting the compound represented by general formula [2a] with an acid in the presence or absence of a solvent. Examples of acids used in this reaction include protic acids such as hydrochloric acid and hydrobromic acid, and Lewis acids such as aluminum chloride and iodotrimethylsilane. The amount of acid used in this reaction may be 2 to 100 times, preferably 2 to 30 times, the molar ratio of the compound represented by general formula [2a]. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction. Examples include halogenated hydrocarbons, ethers, and nitriles, and these may be used in combination.Preferred solvents include halogenated hydrocarbons and nitriles, with dichloromethane and acetonitrile being more preferred. In this reaction, if the acid is liquid, it can also be used as the solvent. This 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. (2-c) Base-Based Method: The compound represented by general formula [1a] can be produced by reacting the compound represented by general formula [2a] with a base. Examples of bases used in this reaction include inorganic bases such as sodium hydroxide and potassium carbonate; and organic bases such as morpholine and triethylamine. The amount of base used in this reaction is 1 to 100 times, preferably 2 to 30 times, the molar ratio of the compound represented by general formula [2a]. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction. Examples include halogenated hydrocarbons, ethers, amides, alcohols, nitriles, and water, and these may be used in combination. Preferred solvents include ethers, alcohols, and water. This 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. (2-d) Method Using Fluoride Ions: The compound represented by general formula [1a] can be produced by reacting the compound represented by general formula [2a] with fluoride ions. Fluoride ions can be generated from fluorine compounds, and examples of fluorine compounds used in this reaction include tetrabutylammonium fluoride, potassium fluoride, and cesium fluoride. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples include halogenated hydrocarbons, ethers, nitriles, amides, alcohols, and water, which may be used in combination. Preferred solvents include ethers and nitriles, with tetrahydrofuran and acetonitrile being more preferred. The amount of the fluorine compound used in this reaction can be 1 to 100 times, preferably 2 to 30 times, the molar ratio of the compound represented by general formula [2a].This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 0 to 50°C for 1 to 24 hours. For example, when the hydroxyl protecting group is a benzyl group, deprotection methods similar to those in Production Method (2-a) or (2-b) may be used. For example, when the hydroxyl protecting group is a 4-methoxybenzyl group, deprotection methods similar to those in Production Method (2-a) or (2-b) may be used. For example, when the hydroxyl protecting group is a methoxymethyl group, deprotection methods similar to those in Production Method (2-b) may be used. For example, when the hydroxyl protecting group is a tert-butyldimethylsilyl group, deprotection methods similar to those in Production Method (2-b) and Production Method (2-d) may be used. For example, when the hydroxyl protecting group is an acetyl group, deprotection methods similar to those in Production Method (2-b) and Production Method (2-c) may be used.

[0062] (3) In the Case of a Carboxyl-Protecting Group: A compound represented by general formula [1a] can be produced by deprotecting a compound represented by general formula [2a]. Methods for deprotecting a carboxyl-protecting group include base-assisted solvolysis, acid-assisted solvolysis, and enzymatic solvolysis. (3-a) Base-Assisted Solvolysis: A compound represented by general formula [1a] can be produced by solvolyzing a compound represented by general formula [2a] in the presence of a base. Examples of the base used in this reaction include alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, and barium hydroxide. The amount of base used in this reaction may be 1 to 100 times, preferably 2 to 30 times, the molar ratio of the compound represented by general formula [2a]. The solvent used in this reaction is not particularly limited, but examples include alcohols, ethers, and water, and these may be used in combination. Preferred solvents include alcohols and water, with methanol and ethanol being more preferred as alcohols. This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 0 to 50°C for 1 to 24 hours. (3-b) Acid-Based Solvolysis Method: The compound represented by general formula [1a] can be produced by solvolyzing the compound represented by general formula [2a] in the presence of an acid. Examples of the acid used in this reaction include protonic acids such as hydrochloric acid and sulfuric acid; and Lewis acids such as aluminum chloride and boron trichloride. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples include halogenated hydrocarbons, ethers, and nitriles, which may be used in mixtures. Preferred solvents include halogenated hydrocarbons and nitriles, with dichloromethane and acetonitrile being more preferred. In this reaction, if the acid is liquid, it can also be used as a solvent. The amount of acid used in this reaction may be 2 to 100 times, preferably 2 to 30 times, the molar ratio of the compound represented by general formula [2a]. This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 0 to 100°C for 1 to 24 hours.(3-c) Enzymatic Solvolysis Method The compound represented by general formula [1a] can be produced by solvolyzing the compound represented by general formula [2a] in the presence of an enzyme. Examples of the enzyme used in this reaction include esterase and carbonic anhydrase, such as enzymes derived from pig liver and bovine erythrocytes. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but water is preferred. The amount of enzyme used in this reaction may be 0.001 to 10 times the molar amount, preferably 0.01 to 0.5 times the molar amount, of the compound represented by general formula [2a]. This reaction may be carried out at 20 to 60°C for 30 minutes to 72 hours, preferably at 30 to 40°C for 1 to 24 hours. For example, when the carboxyl-protecting group is a methyl group, methods such as Production Method (3-a), Production Method (3-b), and Production Method (3-c) may be used.

[0063] [Production Method 2] Reductive amination "During the ceremony, R １ａ , R ２ａ , R ４ａ , X １ａ , X ２ａ , X ３ａ , X ４ａ , Y １ａ , Z １ , and Z ２has the same meaning as above." The compound represented by general formula [2a] can be produced by reacting a compound represented by general formula [2b] with a compound represented by general formula [2c] or a salt thereof in the presence of a reducing agent and in the presence or absence of a base. The amount of the compound represented by general formula [2c] used in this reaction is not particularly limited, but may be 0.9 to 10 times, preferably 1.0 to 2.0 times, the molar amount of the compound represented by general formula [2b]. Reducing agents used in this reaction include hydride reducing agents and boranes. Preferred reducing agents include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, and 2-picoline borane, with sodium triacetoxyborohydride being more preferred. The amount of the reducing agent used in this reaction may be 0.5 to 50 times, preferably 1 to 10 times, the molar amount of the compound represented by general formula [2b]. When the compound represented by general formula [2b] is an acid salt in this reaction, a base may be added. Optional bases include organic bases such as trimethylamine, triethylamine, and tributylamine, with triethylamine being preferred. The amount of the optional base used in this reaction may be 1 to 10 times, preferably 1 to 5 times, the molar ratio of the compound represented by general formula [2b]. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples include halogenated hydrocarbons, ethers, amides, and alcohols. These solvents may be used in combination. Preferred solvents include halogenated hydrocarbons and amides, with dichloromethane being more preferred. The amount of solvent used in this reaction is not particularly limited, and may be 1 to 500 times (v / w) the amount of the compound represented by general formula [2b]. This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 0 to 40°C for 1 to 24 hours.

[0064] [Production Method 3] Condensation "During the ceremony, R １ａ , R ２ａ , R ４ａ , X１ａ , X ２ａ , X ３ａ , X ４ａ , Y １ａ , Z １ , and Z ２has the same meaning as above." The compound represented by general formula [2a] can be produced by reacting a compound represented by general formula [2d] with a compound represented by general formula [2e] or a salt thereof in the presence of a condensing agent and a base. Condensing agents used in this reaction include, for example, 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); imidazoliums such as 1,1'-carbonyldiimidazole (CDI) and 1,1'-carbonyldi(1,2,4-triazole) (CDT); diphenylphosphine Examples of suitable condensing agents include acid azides such as phospholyl azide; acid cyanides such as diethylphosphoryl cyanide; and uroniums such as (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU). Preferred condensing agents include WSC hydrochloride and HATU. The amount of the condensing agent used in this reaction may be 1 to 50 times, and preferably 1 to 5 times, the molar amount of the compound represented by general formula [2d]. When a carbodiimide is used as the condensing agent in this reaction, an additive may be further added. Examples of optional additives include 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), and ethyl (hydroxyimino)cyanoacetate, with HOBt being preferred. The amount of optional additive used in this reaction may be 0.01 to 10 times, preferably 0.1 to 1 times, the molar amount of the compound represented by general formula [2d]. Examples of bases used in this reaction include organic bases such as triethylamine, N,N-diisopropylethylamine, and N-methylmorpholine, with N,N-diisopropylethylamine being preferred.The amount of base used in this reaction may be 1 to 10 times, preferably 1 to 5 times, the molar amount of the compound represented by general formula [2d]. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples include halogenated hydrocarbons, ethers, esters, amides, nitriles, aromatic hydrocarbons, and dimethyl sulfoxide. These solvents may be used in combination. Preferred solvents include halogenated hydrocarbons and amides, with dichloromethane and N,N-dimethylacetamide being more preferred. The amount of compound represented by general formula [2e] used is not particularly limited, but may be 0.9 to 10 times, preferably 1.0 to 2.0 times, the molar amount of the compound represented by general formula [2d]. The amount of solvent used is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound represented by general formula [2d]. This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 0 to 40°C for 1 to 24 hours.

[0065] [Production Method 4] Reductive amination "During the ceremony, R ６ represents an amino protecting group; X １ｂ is optionally substituted C １－５ An alkylene group; X １ｃ is optionally substituted C ２－６ The alkylene group is represented by R １ａ , R ２ａ , X ２ａ , X ３ａ , X ４ａ , Y １ａ and Z １ has the same meaning as above." The compound represented by the general formula [2j] can be produced by the following method.

[0066] (4-1) Condensation The compound represented by the general formula [2g] can be produced by reacting the compound represented by the general formula [2f] with the compound represented by the general formula [2e] in the same manner as in [Production Method 3]. (4-2) Deprotection The compound represented by the general formula [2h] or a salt thereof can be produced by reacting the compound represented by the general formula [2g] with R ６The compound represented by general formula [2j] can be produced by reacting the compound represented by general formula [2h] or a salt thereof with the compound represented by general formula [2i] in the presence of a reducing agent, with or without a base. Reducing agents used in this reaction include hydride reducing agents and boranes. Preferred reducing agents include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, and 2-picoline borane, with sodium triacetoxyborohydride being more preferred. The amount of reducing agent used in this reaction may be 0.5 to 50 times, preferably 1 to 10 times, the molar ratio of the compound represented by general formula [2h]. When the compound represented by general formula [2h] is an acid salt, a base may be added. Optional bases include organic bases such as trimethylamine, triethylamine, and tributylamine. A preferred base is triethylamine. The amount of base used in this reaction, if desired, may be 1 to 10 times, preferably 1 to 5 times, the molar ratio of the compound represented by general formula [2h]. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples include halogenated hydrocarbons, ethers, amides, and alcohols. These solvents may be used in combination. Preferred solvents include halogenated hydrocarbons and amides, with dichloromethane being more preferred. The amount of compound represented by general formula [2i] used in this reaction is not particularly limited, and may be 0.9 to 10 times, preferably 1.0 to 2.0 times, the molar ratio of the compound represented by general formula [2h]. The amount of solvent used in this reaction is not particularly limited, and may be 1 to 500 times (v / w) the amount of compound represented by general formula [2h]. This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 0 to 40°C for 1 to 24 hours.

[0067] [Production Method 5] Alkylation “During the ceremony, L. １ａ represents a leaving group; R １ａ , R ２ａ , X １ａ , X ２ａ , X ３ａ , X ４ａ , Y １ａ and Z １ has the same meaning as above. １ａ The leaving group represented by is a halogen atom, C １－６ Examples of the alkylsulfonyloxy group include an alkylsulfonyloxy group, an arylsulfonyloxy group, and an imidazole group. １－６ The alkylsulfonyloxy group, arylsulfonyloxy group, and imidazole group may have a substituent. The compound represented by general formula [2l] can be produced by reacting a compound represented by general formula [2h] or a salt thereof with a compound represented by general formula [2k] in the presence of a base. Examples of the base used in this reaction include inorganic bases such as sodium carbonate and potassium carbonate, and organic bases such as triethylamine and N,N-diisopropylethylamine. Preferred bases include inorganic bases, with potassium carbonate being more preferred. The amount of base used in this reaction may be 1 to 20 times, preferably 1 to 10 times, the molar ratio of the compound represented by general formula [2h]. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples include halogenated hydrocarbons, ethers, esters, ketones, amides, and nitriles. These solvents may be used in mixtures. Preferred solvents include amides and nitriles, with N,N-dimethylformamide and acetonitrile being more preferred. The amount of the compound represented by general formula [2k] used in this reaction is not particularly limited, but may be 0.9 to 10 times the molar amount, preferably 1.0 to 5.0 times the molar amount, of the compound represented by general formula [2h]. The amount of the solvent used in this reaction is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound represented by general formula [2h]. This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 20 to 80°C for 1 to 24 hours.

[0068] [Production Method 6] Alkylation “During the ceremony, L. １ｂ represents a leaving group; R ２ａ , R ４ａ , X １ａ , X ２ａ , X ３ａ , X ４ａ , Y １ａ and Z ２ has the same meaning as above. １ｂ The leaving group represented by is a halogen atom, C １－６ Examples of the alkylsulfonyloxy group include an alkylsulfonyloxy group, an arylsulfonyloxy group, and an imidazole group. １－６The alkylsulfonyloxy group, arylsulfonyloxy group, and imidazole group may have a substituent. The compound represented by general formula [2o] can be produced by reacting a compound represented by general formula [2m] with a compound represented by general formula [2n] or a salt thereof in the presence of a base. Examples of the base used in this reaction include inorganic bases such as sodium carbonate and potassium carbonate, and organic bases such as triethylamine and N,N-diisopropylethylamine. Preferred bases include inorganic bases, with potassium carbonate being more preferred. The amount of base used in this reaction may be 1 to 20 times, preferably 1 to 10 times, the molar ratio of the compound represented by general formula [2m]. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples include halogenated hydrocarbons, ethers, esters, amides, and nitriles. These solvents may be used in combination. Preferred solvents include amides and nitriles, with N,N-dimethylformamide and acetonitrile being more preferred. The amount of the compound represented by general formula [2n] used in this reaction is not particularly limited, but may be 0.9 to 10 times the molar amount, preferably 1.0 to 5.0 times the molar amount, of the compound represented by general formula [2m]. The amount of the solvent used in this reaction is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound represented by general formula [2m]. This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 20 to 80°C for 1 to 24 hours.

[0069] [Production Method 7] Coupling “During the ceremony, L. １ｃ represents a leaving group; R ３ｂ is an optionally protected R ３ The same substituents as those in １ａ , R ２ａ , R ４ａ , X １ａ , X ２ａ , X ４ａ , Y １ａ , Z １ and Z ２ has the same meaning as above.１ｃThe leaving group represented by is not particularly limited, but includes a halogen atom or a triflate such as trifluoromethanesulfonate, with a bromine atom being preferred. The compound represented by general formula [2r] can be produced by reacting a compound represented by general formula [2p] with a compound represented by general formula [2q] in the presence of a palladium catalyst, with or without a ligand, and with or without a base. The amount of the compound represented by general formula [2q] used in this reaction is not particularly limited, but may be 0.9 to 20 times the molar amount of the compound represented by general formula [2p], preferably 1.0 to 5.0 times the molar amount. Examples of palladium catalysts used in this reaction include palladium salts such as palladium chloride and palladium acetate, and palladium complexes such as dichloro(bistriphenylphosphine)palladium, tetrakis(triphenylphosphine)palladium, and tris(dibenzylideneacetone)dipalladium. Preferred palladium catalysts include palladium complexes, with tris(dibenzylideneacetone)dipalladium being more preferred. The amount of the palladium catalyst used in this reaction may be 0.001 to 10 times, preferably 0.01 to 0.5 times, the molar amount of the compound represented by general formula [2p]. Ligands optionally used in this reaction include tertiary phosphines such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl, and (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, and a preferred ligand is (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl. The amount of the ligand used in this reaction, if desired, may be 0.001 to 10 times by mole, preferably 0.01 to 0.5 times by mole, relative to the compound represented by the general formula [2p].Examples of bases that can be optionally used in this reaction include inorganic bases such as sodium tert-butoxide, lithium hexamethyldisilazide, potassium carbonate, cesium carbonate, potassium phosphate, and sodium phosphate. Preferred bases include cesium carbonate and potassium phosphate. The amount of base used in this reaction is 0.1 to 20 times the molar amount, preferably 1.0 to 5.0 times the molar amount, of the compound represented by general formula [2p]. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples include aromatic hydrocarbons, ethers, amides, alcohols, and water. These solvents may be used in mixtures. Preferred solvents include aromatic hydrocarbons or ethers and mixed solvents thereof, with 1,4-dioxane, toluene, and mixed solvents thereof being more preferred. The amount of solvent used in this reaction is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound represented by general formula [2p]. This reaction may be carried out at 0 to 150°C for 30 minutes to 72 hours, preferably at 70 to 120°C for 1 to 24 hours.

[0070] [Production Method 8] Condensation “During the ceremony, L. １ｄ represents a leaving group or a hydroxyl group; X ３ｂ is HN-R ３ｂ or a hydroxyl group; X ３ｃ is NR ３ｂ or an oxygen atom; R １ａ , R ２ａ , R ３ｂ , R ４ａ , X １ａ , X ２ａ , X ４ａ , Y １ａ , Z １ , and Z ２ has the same meaning as above. １ｄ The leaving group represented by is a halogen atom, C １－６ Examples of the alkylsulfonyloxy group include an alkylsulfonyloxy group, an arylsulfonyloxy group, and an imidazole group. １－６The alkylsulfonyloxy group, arylsulfonyloxy group, and imidazole group may have a substituent. The compound represented by general formula [2u] can be produced by reacting a compound represented by general formula [2s] or a salt thereof with a compound represented by general formula [2t] in the presence or absence of a condensing agent and in the presence of a base. Examples of the condensing agent optionally used in this 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); imidazoliums such as 1,1'-carbonyldiimidazole (CDI) and 1,1'-carbonyldi(1,2,4-triazole) (CDT); acid azides such as diphenylphosphoryl azide; and diethylphosphoryl cyanide. Examples of suitable condensing agents include acid cyanides; uronium compounds such as (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU); and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM). Preferred condensing agents include WSC hydrochloride, HATU, and DMT-MM. The amount of the condensing agent used in this reaction may be 1 to 50 times, and preferably 1 to 5 times, the molar amount of the compound represented by general formula [2s]. When a carbodiimide is used as the optional condensing agent in this reaction, an additive may be further added. Examples of optional additives include 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), and ethyl (hydroxyimino)cyanoacetate, with HOBt being preferred. The amount of optional additive used in this reaction may be 0.01 to 10 times, preferably 0.1 to 1 times, the molar amount of the compound represented by general formula [2s].Bases used in this reaction include inorganic bases such as sodium carbonate and potassium carbonate, and organic bases such as triethylamine, N,N-diisopropylethylamine, and N-methylmorpholine. Preferred bases include organic bases, with N,N-diisopropylethylamine and N-methylmorpholine being more preferred. The amount of base used in this reaction may be 1 to 10 times, and preferably 1 to 5 times, the molar amount of the compound represented by general formula [2s]. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples include halogenated hydrocarbons, ethers, esters, amides, nitriles, aromatic hydrocarbons, and dimethyl sulfoxide. These solvents may be used in combination. Preferred solvents include halogenated hydrocarbons and amides, with dichloromethane, THF, and N,N-dimethylformamide being more preferred. The amount of the compound represented by general formula [2t] used is not particularly limited, but may be 0.9 to 10 times the molar amount, preferably 1.0 to 2.0 times the molar amount, of the compound represented by general formula [2s]. The amount of the solvent used is not particularly limited, but may be 1 to 500 times (v / w) the molar amount of the compound represented by general formula [2s]. This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 0 to 70°C for 1 to 24 hours.

[0071] [Production Method 9] Reductive amination “During the ceremony, ３ｄ is HN-R ３ｂ ;X ３e is NR ３ｂ ;X ４ｂ is CH ２ ;R １ａ , R ２ａ , R ３ｂ , R ４ａ , X １ａ , X ２ａ , Y １ａ , Z １ , and Z ２has the same meaning as above." A compound represented by general formula [2x] can be produced by reacting a compound represented by general formula [2v] or a salt thereof with a compound represented by general formula [2w] in the presence of a reducing agent and in the presence or absence of a base. The amount of the compound represented by general formula [2w] used in this reaction is not particularly limited, but may be 0.9 to 10 times the molar amount, preferably 1.0 to 2.0 times the molar amount, of the compound represented by general formula [2v]. Reducing agents used in this reaction include hydride reducing agents and boranes. Preferred reducing agents include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, and 2-picoline borane, with sodium triacetoxyborohydride being more preferred. The amount of the reducing agent used in this reaction may be 0.5 to 50 times the molar amount, preferably 1 to 10 times the molar amount, of the compound represented by general formula [2v]. When the compound represented by general formula [2v] is an acid salt, a base may be added. Optional bases include organic bases such as trimethylamine, triethylamine, and tributylamine, with triethylamine being preferred. The amount of the optional base used in this reaction may be 1 to 10 times, preferably 1 to 5 times, the molar ratio of the compound represented by general formula [2v]. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples include halogenated hydrocarbons, ethers, amides, and alcohols. These solvents may be used in combination. Preferred solvents include halogenated hydrocarbons and amides, with dichloromethane being more preferred. The amount of solvent used in this reaction is not particularly limited, and may be 1 to 500 times (v / w) the amount of the compound represented by general formula [2v]. This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 0 to 40°C for 1 to 24 hours.

[0072] [Production Method 10] Alkylation "During the ceremony, R ４ｂ is an optionally substituted C １－３an alkyl group; １ａ , R １ａ , R ２ａ , X １ａ , X ２ａ , X ３ｅ , X ４ａ , Y １ａ and Z １ has the same meaning as above." The compound represented by general formula [2z] can be produced by reacting a compound represented by general formula [2l] or a salt thereof with a compound represented by general formula [2y]. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include halogenated hydrocarbons, ethers, esters, ketones, amides, and nitriles. These solvents may be used in combination. Preferred solvents include amides and nitriles, with N,N-dimethylformamide and acetonitrile being more preferred. The amount of the compound represented by general formula [2y] used in this reaction is not particularly limited, but may be 0.9 to 10 times, preferably 1.0 to 5.0 times, the molar amount of the compound represented by general formula [2l]. The amount of the solvent used in this reaction is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound represented by general formula [2l]. This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 20 to 80°C for 1 to 24 hours.

[0073] [Manufacturing method A] "During the ceremony, R ６ and Y １ａ has the same meaning as defined above." The compound represented by the general formula [2e] or a salt thereof can be produced by the following method.

[0074] (A-1) Reductive Amination The compound represented by general formula [3b] can be produced by reacting the compound represented by general formula [3a] with the compound represented by general formula [2c] in the presence of a reducing agent, using a method similar to that described in [Production Method 2]. The amount of the compound represented by general formula [2c] used in this reaction is not particularly limited, but may be 0.9 to 10 times the molar amount, preferably 1.0 to 2.0 times the molar amount, of the compound represented by general formula [3a]. Examples of reducing agents used in this reaction include hydride reducing agents and boranes. Preferred reducing agents include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, and 2-picoline borane, with sodium triacetoxyborohydride being more preferred. The amount of reducing agent used in this reaction may be 0.5 to 50 times the molar amount, preferably 1 to 10 times the molar amount, of the compound represented by general formula [3a]. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include halogenated hydrocarbons, ethers, amides, and alcohols, and these solvents may be used in combination. Preferred solvents include halogenated hydrocarbons, ethers, and amides, with dichloromethane or tetrahydrofuran being more preferred. The amount of solvent used in this reaction is not particularly limited, and may be 1 to 500 times (v / w) the amount of the compound represented by general formula [3a]. This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 0 to 40°C for 1 to 24 hours. (A-2) Deprotection The compound represented by general formula [2e] or a salt thereof can be prepared by deprotecting the compound represented by general formula [3b] with R ６ The compound can be produced by reacting the compound in the same manner as in [Production Method 1] (1-a), (1-b) or (1-c) appropriate for the type of compound.

[0075] [Manufacturing method B] “During the ceremony, L. １ａ , R ６ , and Y １ａhas the same meaning as above." The compound represented by general formula [3b] can be produced by reacting the compound represented by general formula [3a] with the compound represented by general formula [3c] in the presence of a base. Examples of the base used in this reaction include inorganic bases such as sodium carbonate and potassium carbonate, and organic bases such as triethylamine and N,N-diisopropylethylamine. Preferred bases include inorganic bases, with potassium carbonate being more preferred. The amount of the base used in this reaction may be 1 to 20 times, preferably 1 to 10 times, the molar amount of the compound represented by general formula [3a]. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples include halogenated hydrocarbons, ethers, esters, ketones, amides, and nitriles, and these solvents may be used in combination. Preferred solvents include ketones and amides, with N,N-dimethylformamide or acetone being more preferred. The amount of the compound represented by general formula [3c] used in this reaction is not particularly limited, but may be 0.9 to 10 times the molar amount, preferably 1.0 to 5.0 times the molar amount, of the compound represented by general formula [3a]. The amount of the solvent used in this reaction is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound represented by general formula [3a]. This reaction may be carried out at -30 to 150°C for 30 minutes to 72 hours, preferably at 20 to 90°C for 1 to 24 hours.

[0076] [Manufacturing method C] “During the ceremony, L. １ｂ , R ６ and Y １ａ has the same meaning as defined above." The compound represented by the general formula [3f] or a salt thereof can be produced by the following method.

[0077] (C-1) Condensation The compound represented by general formula [2m] can be produced by reacting a compound represented by general formula [2e] or a salt thereof with a compound represented by general formula [3d] in the presence of a base. Examples of the base used in this reaction include inorganic bases such as sodium carbonate and potassium carbonate, and organic bases such as triethylamine and N,N-diisopropylethylamine. Preferred bases include organic bases, with triethylamine being more preferred. The amount of base used in this reaction may be 1 to 20 times, and preferably 1 to 5 times, the molar amount of the compound represented by general formula [2e]. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples include halogenated hydrocarbons, ethers, esters, amides, and nitriles. These solvents may be used in combination. Preferred solvents include halogenated hydrocarbons, amides, and nitriles, with dichloromethane being more preferred. The amount of the compound represented by general formula [3d] used in this reaction is not particularly limited, but may be 0.9 to 10 times the molar amount, preferably 1.0 to 5.0 times the molar amount, of the compound represented by general formula [2e]. The amount of the solvent used is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound represented by general formula [2e]. This reaction may be carried out at -30 to 150°C for 30 minutes to 48 hours, preferably at 0 to 40°C for 1 to 5 hours. (C-2) Alkylation The compound represented by general formula [3e] can be produced by reacting a compound represented by general formula [2m] and a compound represented by general formula [3a] in the same manner as in [Production Method 6]. (C-3) Deprotection The compound represented by general formula [3f] or a salt thereof can be produced by converting the compound represented by general formula [3e] to R ６ The compound can be produced by reacting the compound in the same manner as in [Production Method 1] (1-a), (1-b) or (1-c) appropriate for the type of compound.

[0078] [Manufacturing method D] “During the ceremony, L. １ｂ , R ２ａ , R ４ａ , R ６ , X １ａ , X２ａ , X ３ａ , X ４ａ and Z ２ has the same meaning as defined above." The compound represented by the general formula [3i] or a salt thereof can be produced by the following method.

[0079] (D-1) Condensation A compound represented by general formula [3g] can be produced by reacting a compound represented by general formula [3a] with a compound represented by general formula [3d] or a salt thereof in the same manner as in (C-1) of [Production Method C]. (D-2) Alkylation A compound represented by general formula [3h] can be produced by reacting a compound represented by general formula [3g] with a compound represented by general formula [2n] or a salt thereof in the same manner as in [Production Method 6]. (D-3) Deprotection A compound represented by general formula [3i] or a salt thereof can be produced by reacting a compound represented by general formula [3h] with R ６ can be produced by reacting the compound of formula (1) with the compound of formula (1-a), (1-b) or (1-c) in the same manner as in [Production Method 1], which is suitable for the protecting group of formula (1).

[0080] [Manufacturing method E] "During the ceremony, R ７ represents a carboxyl protecting group; R １ａ , R ２ａ , X １ｂ , X １ｃ , X ２ａ , X ３ａ , X ４ａ and Z １ has the same meaning as above." The compound represented by the general formula [3l] can be produced by the following method.

[0081] (E-1) Reductive amination The compound represented by the general formula [3k] can be produced by reacting the compound represented by the general formula [3j] or a salt thereof with the compound represented by the general formula [2i] in the same manner as in [Production Method 4] (4-3). (E-2) Deprotection The compound represented by the general formula [3l] can be produced by reacting the compound represented by the general formula [3k] with R ７ can be produced by reacting the compound of formula (1) in the same manner as in (3-a), (3-b) or (3-c) of [Production Method 1], which is suitable for the protecting group of formula (1).

[0082] [Manufacturing method F] “During the ceremony, L. １ａ , R １ａ , R ２ａ , R ７ , X １ａ , X ２ａ , X ３ａ , X ４ａ and Z １ has the same meaning as above." The compound represented by the general formula [3n] can be produced by the following method.

[0083] (F-1) Alkylation The compound represented by the general formula [3m] can be produced by reacting the compound represented by the general formula [3j] or a salt thereof with the compound represented by the general formula [2k] in the same manner as in [Production Method 5]. (F-2) Deprotection The compound represented by the general formula [3n] can be produced by reacting the compound represented by the general formula [3m] with R ７ can be produced by reacting the compound of formula (1) in the same manner as in (3-a), (3-b) or (3-c) of [Production Method 1], which is suitable for the protecting group of formula (1).

[0084] [Manufacturing method G] "During the ceremony, R １ａ , R ２ａ , R ４ａ , R ６ , X １ａ , X ２ａ , X ３ａ , X ４ａ , Z １ and Z ２ has the same meaning as above." The compound represented by the general formula [2b] can be produced by the following method.

[0085] (G-1) Condensation The compound represented by the general formula [3o] can be produced by reacting the compound represented by the general formula [2d] with the compound represented by the general formula [3a] in the same manner as in [Production Method 3]. (G-2) Deprotection The compound represented by the general formula [2b] or a salt thereof can be produced by reacting the compound represented by the general formula [3o] with R ６ can be produced by reacting the compound of formula (1) with the compound of formula (1-a), (1-b) or (1-c) in the same manner as in [Production Method 1], which is suitable for the protecting group of formula (1).

[0086] Next, the present invention will be described with reference to Examples and Reference Examples, but the present invention is not limited to these.

[0087] Unless otherwise specified, silica gel column chromatography was performed using Selekt (Biotage Japan Co., Ltd.), and the carrier was Biotage Sfaer D or Biotage Sfaer HC D (Biotage Japan Co., Ltd.). NH silica gel column was used: Biotage Sfaer Amino D (Biotage Japan Co., Ltd.) or CHROMATOREX NH-DM1020 (Fuji Silysia Chemical Ltd.). The mixing ratio of the eluent is a volume ratio. NMR spectra were measured using an AVANCE III HD400 (Bruker Corporation). NMR spectra show proton NMR, and the internal standard is as follows, with δ values ​​expressed in ppm: Deuterated chloroform (CDCl3): tetramethylsilane (0.00 ppm) Deuterated methanol (CD3OD): methanol (CH3OH) (3.30 ppm) Deuterated dimethyl sulfoxide (CD3SOCD3): tetramethylsilane (0.00 ppm) Deuterated water (DO): sodium 3-(trimethylsilyl)propionate (0.00 ppm) Unless otherwise specified, NMR spectra were measured using CDCl3 in the Reference Examples and DO in the Examples.

[0088] MS spectra were measured by electrospray ionization (ESI) using an LCMS-2020 (Shimadzu Corporation).

[0089] In each Reference Example and Example, the abbreviations have the following meanings: Alloc: allyloxycarbonyl, Bn: benzyl, Boc: tert-butoxycarbonyl, Cbz: benzyloxycarbonyl, DIPEA: N,N-diisopropylethylamine, DMAC: N,N-dimethylacetamide, DMAP: 4-(dimethylamino)pyridine, DMF: N,N-dimethylformamide, DMSO: dimethyl sulfoxide, DMT-MM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorphonium chloride, ESI: electrospray ionization, Fmoc: 9-fluorenylmethyloxycarbonyl, HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, HO Bt: 1-hydroxybenzotriazole, HPLC: high performance liquid chromatography, IPE: diisopropyl ether, Ms: methanesulfonyl, MTBE: tert-butyl methyl ether, NMM: N-methylmorpholine, TBS: tert-butyldimethylsilyl, TEAA: triethylamine acetate, THF: tetrahydrofuran, WSC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, s: singlet, d: doublet, dd: double doublet, ddd: double double doublet, dt: double triplet, m: multiplet, q: quartet, quint: quintet, sep: septet, t: triplet, td: triple doublet, brs: broad singlet

[0090] Reference example 1 (1) To 2-ethoxy-6-fluorobenzaldehyde (2.70 g), dichloromethane (240 mL), tert-butyl piperazine-1-carboxylate (4.50 g), and sodium triacetoxyborohydride (7.68 g) were added and stirred at room temperature for 18 hours. Water (50 mL) was added to the reaction mixture, and then 10% aqueous sodium carbonate was added to adjust the pH to 9. The organic layer was separated. The resulting 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; ethyl acetate:hexane = 0:100 → 40:60] to obtain the target product (8.06 g) as a colorless oil. (2) To the compound obtained in (1) (8.06 g), dichloromethane (120 mL) and a 4 mol / L solution of hydrochloric acid in dioxane (30 mL) were added and stirred at room temperature for 20 hours and 30 minutes. The solvent was evaporated under reduced pressure, and ethyl acetate (200 mL) was added to the residue, followed by stirring at room temperature for 30 minutes. The solid was collected by filtration and dried under reduced pressure to give 1-(2-ethoxy-6-fluorobenzyl)piperazine hydrochloride (6.89 g) as a white solid.

[0091] In the same manner as in Reference Example 1, the compounds shown in Table 1 were obtained.

[0092] Reference example 3 (1) Dichloromethane (36 mL) and triethylamine (3.1 mL) were added to 1-(2-methoxybenzyl)piperazine hydrochloride (2.00 g) and stirred under ice cooling. A mixture of chloroacetyl chloride (0.60 mL) and dichloromethane (5 mL) was added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Water (30 mL) was added to the reaction mixture, and the organic layer was separated. The resulting 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; ethyl acetate:hexane = 20:80 → 100:0] to obtain the target product (1.94 g) as a pale yellow oil. (2) To the compound obtained in (1) (1.94 g), tert-butyl piperazine-1-carboxylate (1.28 g), DMF (27 mL), potassium carbonate (1.42 g), and sodium iodide (257 mg) were added and 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 resulting organic layer was washed successively with water and saturated aqueous sodium chloride, then 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 → 90:10] to obtain the target product (3.12 g) as a pale yellow solid. (3) To the compound obtained in (2) (2.97 g), dichloromethane (30 mL) and a 4 mol / L solution of hydrochloric acid in dioxane (17 mL) were added, and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure, followed by drying under reduced pressure to obtain the target product (2.87 g) as a pale yellow solid. (4) To the compound obtained in (3) (120 mg), dichloromethane (1.4 mL), 2-(2-bromo-5-chlorophenyl)acetaldehyde (83 mg), triethylamine (0.15 mL), and sodium triacetoxyborohydride (173 mg) were added, and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture, and then 10% aqueous sodium carbonate 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 evaporated under reduced pressure.The residue was purified by silica gel column chromatography [eluent; chloroform:methanol=100:0→93:7] to obtain 2-(4-(2-bromo-5-chlorophenethyl)piperazin-1-yl)-1-(4-(2-methoxybenzyl)piperazin-1-yl)ethan-1-one (118 mg) as a colorless oil.

[0093] Reference example 4 To 2-(4-(2-bromo-5-chlorophenethyl)piperazin-1-yl)-1-(4-(2-methoxybenzyl)piperazin-1-yl)ethan-1-one (30 mg), tert-butyl (S)-piperidin-3-ylcarbamate (22 mg), tris(dibenzylideneacetone)dipalladium(0) (5 mg), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (14 mg), cesium carbonate (44 mg), triethylamine (15 μL), toluene (0.3 mL), and 1,4-dioxane (0.3 mL) were added, and the mixture was stirred at 110°C for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added, and the organic layer was separated. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride and then 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→93:7] to give tert-butyl (S)-(1-(4-chloro-2-(2-(4-(2-(4-(2-methoxybenzyl)piperazin-1-yl)-2-oxoethyl)piperazin-1-yl)ethyl)phenyl)piperidin-3-yl)carbamate (5 mg) as a pale yellow oil.

[0094] Reference example 5 The tert-butyl (S)-piperidin-3-ylcarbamate of Reference Example 4 was replaced with tert-butyl (S)-pyrrolidin-3-ylcarbamate, and the reaction was carried out in the same manner as in Reference Example 4 to obtain tert-butyl (S)-(1-(4-chloro-2-(2-(4-(2-(4-(2-methoxybenzyl)piperazin-1-yl)-2-oxoethyl)piperazin-1-yl)ethyl)phenyl)pyrrolidin-3-yl)carbamate as a pale yellow oil.

[0095] Reference Example 6 (1) To 1-(2-ethoxy-6-fluorobenzyl)piperazine hydrochloride (3.81 g), (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) were added sequentially, 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 resulting 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; ethyl acetate:hexane = 0:100 → 80:20] to obtain the target product (6.34 g) as a white solid. (2) To the compound obtained in (1) (6.34 g) were added dichloromethane (63 mL) and a 4 mol / L solution of hydrochloric acid in dioxane (13 mL), and the mixture was stirred at room temperature for 20 hours and 30 minutes. The solvent was evaporated under reduced pressure, and ethyl acetate (60 mL) was added to the residue, followed by stirring at room temperature for 30 minutes. The solid matter was collected by filtration and dried under reduced pressure to obtain the target product (6.01 g) as a white solid. (3) To the compound obtained in (2) (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. Water (3 mL) was added to the reaction mixture, and then 10% aqueous sodium carbonate 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 evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane=10:90→100:0] to obtain the target product (363 mg) as a colorless oil. (4) To the compound obtained in (3) (179 mg), tert-butyl (S)-pyrrolidin-3-ylcarbamate (62 mg), tris(dibenzylideneacetone)dipalladium(0) (20 mg), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (56 mg), cesium carbonate (182 mg), and 1,4-dioxane (1.8 mL) were added, and the mixture was stirred at 100°C for 16 hours and 30 minutes under a nitrogen atmosphere.To the reaction mixture, tert-butyl (S)-pyrrolidin-3-ylcarbamate (62 mg), tris(dibenzylideneacetone)dipalladium(0) (20 mg), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (56 mg), and triethylamine (62 μL) were added and stirred at 100°C for 4 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 resulting 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 → 95:5] to obtain the target product (70 mg) as a pale yellow oil. (5) To the compound obtained in (4) (70 mg), dichloromethane (0.35 mL) and trifluoroacetic acid (0.14 mL) were added, and the mixture was stirred at room temperature for 3 hours. Chloroform was added to the reaction mixture, and then saturated aqueous sodium bicarbonate 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 evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol=100:0→50:50] to give benzyl ((R)-1-(1-(2-((S)-3-aminopyrrolidin-1-yl)-5-(benzyloxy)phenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (20 mg) as a pale yellow oil.

[0096] Reference example 7 (1) Dichloromethane (25 mL), 2-(2-bromo-5-chlorophenyl)acetaldehyde (1.51 g), triethylamine (0.69 mL), and sodium triacetoxyborohydride (1.58 g) were added to methyl (R)-2-(((benzyloxy)carbonyl)amino)-2-(piperidin-4-yl)acetate hydrochloride (1.70 g), and the mixture was stirred at room temperature for 25 hours and 30 minutes. Water (25 mL) was added to the reaction mixture, and then 10% aqueous sodium carbonate 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 evaporated 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. (2) To the compound (1.55 g) obtained in (1), THF (6.2 mL), methanol (1.6 mL), water (6.2 mL), and lithium hydroxide monohydrate (621 mg) were added, and the mixture was stirred at room temperature for 2 hours and 15 minutes. The solvent was concentrated under reduced pressure, and 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 was collected by filtration and dried at 60°C under reduced pressure to obtain the target product (1.26 g) as a white solid. (3) To the compound (1.26 g) obtained in (2), 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 sequentially, and the mixture was stirred at room temperature for 6 hours. To the reaction mixture were added WSC hydrochloride (142 mg), HOBt (100 mg), and DIPEA (0.22 mL), and the mixture was stirred at room temperature overnight. Water (10 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 evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 50:50 → 100:0] to give 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.

[0097] Reference example 8 tert-Butyl (R)-pyrrolidin-3-ylcarbamate (9 mg), palladium(II) acetate (1 mg), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (3 mg), cesium carbonate (30 mg), toluene (0.41 mL), and 1,4-dioxane (0.14 mL) were added to benzyl (R)-(1-(1-(2-bromo-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (30 mg), and the mixture was stirred under reflux under a nitrogen atmosphere for 15 hours and 30 minutes. To the reaction mixture, tert-butyl (R)-pyrrolidin-3-ylcarbamate (9 mg), palladium(II) acetate (1 mg), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (3 mg), and cesium carbonate (30 mg) were added, and the mixture was stirred under reflux for 5 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 organic layer was washed successively with water and a saturated aqueous solution of sodium chloride, then 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→90:10] to give tert-butyl ((R)-1-(2-(2-(4-((R)-1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)pyrrolidin-3-yl)carbamate (10 mg) as a pale yellow oil.

[0098] Reference example 9 The reaction was carried out in the same manner as in Reference Example 8, except that tert-butyl (R)-pyrrolidin-3-ylcarbamate in Reference Example 8 was replaced with (R)-fluoropyrrolidine hydrochloride, to give benzyl ((R)-1-(1-(5-chloro-2-((R)-3-fluoropyrrolidin-1-yl)phenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate as a pale yellow oil.

[0099] Reference example 10 To benzyl (R)-(1-(1-(2-bromo-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (30 mg), tert-butyl (S)-pyrrolidin-3-ylcarbamate (12 mg), tris(dibenzylideneacetone)dipalladium(0) (4 mg), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (10 mg), cesium carbonate (20 mg), and toluene (0.45 mL) were added, and the mixture was stirred under reflux under a nitrogen atmosphere for 15 hours and 30 minutes. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous sodium chloride solution and then 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→93:7] to give tert-butyl ((S)-1-(2-(2-(4-((R)-1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)pyrrolidin-3-yl)carbamate (19 mg) as a pale yellow oil.

[0100] Reference example 11 The reaction was carried out in the same manner as in Reference Example 10, except that tert-butyl (S)-pyrrolidin-3-ylcarbamate of Reference Example 10 was replaced with 4,4-difluoropiperidine hydrochloride, to give benzyl (R)-(1-(1-(5-chloro-2-(4,4-difluoropiperidin-1-yl)phenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate as a pale yellow oil.

[0101] Reference example 12 To benzyl (R)-(1-(1-(2-bromo-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (20 mg), tert-butyl (R)-3-(aminomethyl)pyrrolidine-1-carbamate (11 mg), tris(dibenzylideneacetone)dipalladium(0) (3 mg), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (7 mg), cesium carbonate (22 mg), triethylamine (8 μL), toluene (0.2 mL), and 1,4-dioxane (0.2 mL) were added, and the mixture was stirred at 110° C. for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and then ethyl acetate and saturated aqueous ammonium chloride solution were added, and the organic layer was separated. The organic layer was washed successively with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, 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→90:10] to give tert-butyl (R)-3-(((2-(2-(4-((R)-1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)methyl)pyrrolidine-1-carboxylate (20 mg) as a pale brown oil.

[0102] In the same manner as in Reference Example 12, the compounds shown in Table 2 were obtained.

[0103] Reference example 79 DMF (13.5 mL) was added to 5-(benzyloxy)-2-bromobenzaldehyde (300 mg) and the mixture was stirred under ice-cooling. Sodium ethanethiol (144 mg) was added to the reaction mixture at the same temperature, and the mixture was stirred at 70°C for 1 hour. Diethyl ether (13.5 mL) and water (13.5 mL) were added to the reaction mixture, and the organic layer was separated. The resulting organic layer was washed successively with water and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent was evaporated 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.

[0104] Reference example 80 (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 under a nitrogen atmosphere for 17 hours. 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 resulting organic layer was washed with a 5% aqueous sodium chloride solution and 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; ethyl acetate:hexane = 5:95 → 70:30] to obtain the target product (24.4 g) as a pale brown oil. (2) To the compound obtained in (1) (24.4 g), THF (50 mL), methanol (25 mL), water (100 mL), and lithium hydroxide monohydrate (9.77 g) were added, and the mixture was stirred at room temperature for 3 hours and 10 minutes. The solvent was concentrated under reduced pressure, and water (80 mL) was added to the residue. Concentrated hydrochloric acid was then added to adjust the pH to 5.6. The solid was collected by filtration and washed with water. MTBE was added to the resulting solid, and the mixture was stirred at room temperature for 16 hours. The solid was collected by filtration, washed with MTBE, and dried under reduced pressure to obtain the target product (22.5 g) as a white solid. (3) To the compound obtained in (2) (22.5 g), DMAC (200 mL) and tert-butyl piperazine-1-carboxylate (8.23 g) were added, and the mixture was stirred under ice cooling. To the reaction mixture, WSC hydrochloride (11.0 g), ethyl cyanohydroxyiminoacetate (7.53 g), and 4-methylmorpholine (19.4 mL) were added sequentially at the same temperature, 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 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 sequentially with water and 5% aqueous 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; ethyl acetate:hexane = 10:90 → 100:0] to obtain the target product (28.4 g) as a yellow oil.(4) To the compound obtained in (3) (28.4 g), 1,4-dioxane (56 mL), methanol (5.6 mL), and a 4 mol / L solution of hydrochloric acid in dioxane (52.3 mL) were added, and the mixture was stirred at room temperature for 17 hours and 50 minutes. After the solvent was removed 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. (5) To the compound obtained in (4) (5.00 g), dichloromethane (77 mL), 2-(ethylthio)-4-fluorobenzaldehyde (1.84 g), triethylamine (3.75 mL), and sodium triacetoxyborohydride (4.88 g) were added, and the mixture was stirred at room temperature for 16 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the pH was adjusted to 8, and the organic layer was separated. The aqueous layer was extracted three times with dichloromethane, and the organic layers were combined and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:heptane=67:33→100:0] to give benzyl (R)-(1-(1-(2-bromo-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (2.70 g) as a pale yellow oil.

[0105] The compounds shown in Table 3 were obtained in the same manner as in Reference Example 80.

[0106] Reference example 83 To benzyl (R)-(1-(1-(2-bromo-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (197 mg) were added tert-butyl (2-aminomethyl)carbamate (85 mg), tris(dibenzylideneacetone)dipalladium(0) (24 mg), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (66 mg), cesium carbonate (215 mg), triethylamine (53 μL), toluene (1.9 mL), and 1,4-dioxane (1.9 mL), the mixture was stirred at 110° C. for 21 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and then ethyl acetate and saturated aqueous ammonium chloride solution were added, and the organic layer was separated. The organic layer was washed successively with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography [eluent; ethyl acetate:hexane=25:75→100:0] to give tert-butyl (R)-(2-((2-(2-(4-(1-(((benzyloxy)carbonyl)amino)-2-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)ethyl)carbamate (83 mg).

[0107] The compounds shown in Table 4 were obtained in the same manner as in Reference Example 83.

[0108] Reference example 100 Acetonitrile (1 mL) and iodomethane (8.5 μL) were added to tert-butyl (R)-(2-((2-(2-(4-(1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)ethyl)carbamate (100 mg), and the mixture was stirred at room temperature for 19 hours and 30 minutes. The solvent was evaporated under reduced pressure, and the residue was then purified by silica gel column chromatography [eluent; chloroform:methanol=100:0→90:10] to give (R)-4-(1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)-1-(2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-5-chlorophenethyl)-1-methylpiperidin-1-ium iodide (44 mg) as a pale yellow solid.

[0109] The compounds shown in Table 5 were obtained in the same manner as in Reference Example 100.

[0110] Reference example 104 (1) Dichloromethane (5 mL) and imidazole (276 mg) were added to tert-butyl (4-chloro-2-(2-hydroxyethyl)phenyl)carbamate (500 mg) and stirred under ice-cooling. tert-Butyldimethylchlorosilane (311 mg) was added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 1 hour and 45 minutes. Imidazole (25 mg) and tert-butyldimethylchlorosilane (57 mg) were added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Water (5 mL) was added to the reaction mixture, and the organic layer was separated. The resulting organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 0:100 → 10:90] to obtain the target product (691 mg) as a colorless oil. (2) To the compound obtained in (1) (691 mg), dichloromethane (3.8 mL), DMAP (22 mg), triethylamine (0.27 mL), and di-tert-butyl dicarbonate (0.61 mL) were added and stirred at room temperature for 7 hours. DMAP (109 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour and 30 minutes. DMAP (175 mg) and di-tert-butyl dicarbonate (0.40 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 hours. Di-tert-butyl dicarbonate (0.40 mL) was added to the reaction mixture, and the mixture was stirred at 40°C for 30 minutes. A saturated aqueous ammonium chloride solution (4 mL) was added to the reaction mixture, and the organic layer was separated. The resulting organic layer was washed successively with a saturated aqueous ammonium chloride solution and a saturated aqueous 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: ethyl acetate:hexane = 0:100 → 10:90] to obtain the target product (848 mg) as a colorless oil. (3) THF (0.5 mL) was added to the compound obtained in (2) (50 mg) and stirred under ice cooling. At the same temperature, 1 mol / L tetrabutylammonium fluoride THF solution (0.11 mL) was added to the reaction mixture and stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride and dichloromethane were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 0:100 → 20:80] to obtain the desired product (30 mg) as a colorless oil. (4) Dichloromethane (2 mL) was added to the compound obtained in (3) (30 mg) and stirred under ice cooling. Dess-Martin periodinane (51 mg) was added to the reaction mixture at the same temperature and stirred at room temperature for 1 hour. 10% aqueous sodium thiosulfate (2 mL) and saturated aqueous sodium bicarbonate (2 mL) were added to the reaction mixture, and the organic layer was separated. The organic layer was washed sequentially with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 0:100 → 25:75] to obtain the desired product (26 mg) as a colorless oil. (5) To the compound obtained in (4) (26 mg), dichloromethane (0.38 mL), benzyl (R)-(2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxo-1-(piperidin-4-yl)ethyl)carbamate hydrochloride (38 mg), triethylamine (21 μL), and sodium triacetoxyborohydride (34 mg) were added, and the mixture was stirred at room temperature for 15 hours. Water and 10% aqueous sodium carbonate solution were added to the reaction mixture, and the pH was adjusted to 8, and the organic layer was separated. The organic layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous 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; ethyl acetate:hexane = 50:50 → 90:10] to obtain the target product (44 mg) as a colorless oil. (6) Dichloromethane (0.25 mL) and a 4 mol / L hydrochloric acid dioxane solution (64 μL) were added to the compound obtained in (5) (44 mg), and the mixture was stirred at room temperature for 3 hours. A 4 mol / L hydrochloric acid dioxane solution (32 μL) was added to the reaction mixture, and the mixture was stirred at room temperature for 14 hours. After the solvent was evaporated under reduced pressure, ethyl acetate (5 mL) and a saturated aqueous solution of sodium bicarbonate (5 mL) were added to the residue, and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium chloride and then 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→85:15] to obtain benzyl (R)-(1-(1-(2-amino-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (25 mg) as a colorless oil. (7) Dichloromethane (0.1 mL) was added to benzyl (R)-(1-(1-(2-amino-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (13 mg) and the mixture was stirred under ice-cooling. A 4 mol / L solution of hydrochloric acid in dioxane (20 μL) was added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 15 minutes. The solvent was evaporated under reduced pressure to give benzyl (R)-(1-(1-(2-amino-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate hydrochloride (15 mg) as a white solid.

[0111] Reference example 105 Benzyl (R)-(1-(1-(2-amino-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate hydrochloride (20 mg) ６ -((benzyloxy)carbonyl)-N ２-(tert-Butoxycarbonyl)-L-lysine (20 mg), HATU (20 mg), DMF (0.4 mL), and DIPEA (27 μL) were added, and the mixture was stirred at room temperature for one day. Ethyl acetate and saturated aqueous sodium bicarbonate solution were added to the reaction mixture, and the organic layer was separated. The organic layer was washed successively with saturated aqueous sodium bicarbonate solution and 5% aqueous sodium chloride solution, then 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→92:8] to give benzyl tert-butyl ((S)-6-((2-(2-(4-((R)-1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)-6-oxohexane-1,5-diyl)dicarbamate (26 mg) as a colorless oil.

[0112] The compounds shown in Table 6 were obtained in the same manner as in Reference Example 105.

[0113] Reference example 134 To benzyl (R)-(1-(1-(2-amino-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate hydrochloride (20 mg) were added (S)-7-(((benzyloxy)carbonyl)amino)-3-((tert-butoxycarbonyl)amino)heptanoic acid (41 mg), DMT-MM (30 mg), THF (0.4 mL), and NMM (20 μL), and the mixture was stirred at room temperature for one day. Ethyl acetate and water were added to the reaction mixture, and the organic layer was separated. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, then 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→92:8] to give benzyl tert-butyl ((S)-7-((2-(2-(4-((R)-1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)-7-oxoheptane-1,5-diyl)dicarbamate (27 mg) as a colorless oil.

[0114] The compounds shown in Table 7 were obtained in the same manner as in Reference Example 134.

[0115] Reference example 207 (1) Dichloromethane (2 mL), methanol (0.2 mL), and a 4 mol / L hydrochloric acid dioxane solution (0.62 mL) were added to tert-butyl (R)-(2-((2-(2-(4-(1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)ethyl)carbamate (200 mg), and the mixture was stirred at room temperature for 18 hours. Ethyl acetate (5 mL) and diethyl ether (5 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The solid was collected by filtration, washed with diethyl ether, and then dried under reduced pressure to give benzyl (R)-(1-(1-(2-((2-aminoethyl)amino)-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate hydrochloride (213 mg) as a pale yellow solid. (2) Acetonitrile (1 mL) and triethylamine (65 μL) were added to the compound obtained in (1) (100 mg), and the mixture was stirred under ice-cooling. Trimethylsilyl isocyanate (17 μL) was added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 17 hours and 45 minutes. Methanol was added to the reaction mixture, and the solvent was evaporated under reduced pressure. Chloroform and water were added to the residue, and the pH was adjusted to 8.5 with saturated aqueous sodium bicarbonate, and the organic layer was 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→85:15] to give benzyl (R)-(1-(1-(5-chloro-2-((2-ureidoethyl)amino)phenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (75 mg) as a white solid.

[0116] Reference example 208 To the hydrochloride salt (20 mg) of benzyl (R)-(1-(1-(2-amino-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate, tert-butyl (2-oxoethyl)carbamate (16.4 mg), dichloromethane (0.3 mL), and triethylamine (14.4 μL) were added, and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture, sodium triacetoxyborohydride (16.4 mg) was added, and the mixture was stirred at room temperature for 16 hours. To the reaction mixture, tert-butyl (2-oxoethyl)carbamate (24.6 mg) and sodium triacetoxyborohydride (32.8 mg) were added, and the mixture was stirred at room temperature for 22 hours. Water and 10% aqueous sodium carbonate were added to the reaction mixture, the pH was adjusted to 8, and the organic layer was separated. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, then 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→92:8] to give di-tert-butyl (((2-(2-(4-(1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)azanediyl)bis(ethane-2,1-diyl)) (R)-dicarbamate (5 mg) as a colorless oil.

[0117] Reference example 209 Imidazole-4-carboxaldehyde (3.2 mg), dichloromethane (0.3 mL), and triethylamine (14.4 μL) were added to benzyl (R)-(1-(1-(2-amino-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate hydrochloride (20 mg), and the mixture was stirred at room temperature for 10 minutes. Sodium triacetoxyborohydride (16.4 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 14 hours. Water and 10% aqueous sodium carbonate solution were added to the reaction mixture, and the pH was adjusted to 8, and the organic layer was separated. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous 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→92:8] to give benzyl (R)-(1-(1-(2-(((1H-imidazol-5-yl)methyl)amino)-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (5 mg) as a colorless oil.

[0118] The compounds shown in Table 8 were obtained in the same manner as in Reference Example 209.

[0119]

[0120] Reference example 214 (1) DMAC (100 mL) was added to (R)-2-(((benzyloxy)carbonyl)amino)-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (9.81 g), and the mixture was stirred under ice-cooling. Allyl piperazine-1-carboxylate hydrochloride (5.15 g), WSC hydrochloride (6.23 g), ethyl cyano(hydroxyimino)acetate (4.26 g), and 4-methylmorpholine (11 mL) were added sequentially to the reaction mixture at the same temperature, 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 sequentially with 5% aqueous sodium carbonate solution (300 mL), water (300 mL), and 5% aqueous sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated 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 (12.0 g) as a yellow oil. (2) To the compound obtained in (1) (12.0 g), 1,4-dioxane (25 mL), methanol (2.5 mL), and a 4 mol / L hydrochloric acid dioxane solution (16.4 mL) were added, and the mixture was stirred at room temperature for 17 hours and 15 minutes. The solvent was evaporated under reduced pressure, and then 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 dried under reduced pressure to obtain allyl (R)-4-(2-(((benzyloxy)carbonyl)amino)-2-(piperidin-4-yl)acetyl)piperazine-1-carboxylate hydrochloride (10.3 g) as a white solid.

[0121] Reference example 215 (1) Anhydrous THF (40 mL) was added to methyl 2-(2-(benzyloxy)-5-chlorophenyl)acetate (1.87 g) and the mixture was stirred under ice cooling. A 4 mol / L THF solution of lithium borohydride (6.43 mL) was added at the same temperature, and the mixture was stirred at room temperature for 4 hours. A 4 mol / L THF solution of lithium borohydride (10 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 48 hours. Water was added to the reaction mixture, and insoluble matter was removed by filtration through Celite. Ethyl acetate was added to the filtrate, and the organic layer was separated. The aqueous layer was extracted three times with ethyl acetate, and the organic layer was combined with the previously separated organic layer and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:heptane = 10:90 → 50:50] to obtain the target product (1.49 g). (2) Dichloromethane (20 mL) and triethylamine (1.24 mL) were added to the compound obtained in (1) (1.80 g) and stirred under ice cooling. Methanesulfonyl chloride was added at the same temperature and stirred for 1 hour and 30 minutes. Chloroform and water were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted three times with chloroform, and the organic layer was combined with the previously separated organic layer. This was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography [eluent; ethyl acetate:heptane = 15:85 → 40:60] to obtain the target product (2.19 g) as a colorless oil. (3) To the compound (1.28 g) obtained in (2), allyl (R)-4-(2-(((benzyloxy)carbonyl)amino)-2-(piperidin-4-yl)acetyl)piperazine-1-carboxylate hydrochloride (1.20 g), acetonitrile (13 mL), and potassium carbonate (1.72 g) were added, and the mixture was stirred at 75°C for 15 hours. 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 layer was combined with the previously separated organic layer and 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 = 10:90 → 50:50] to obtain the target product (1.60 g).(4) To the compound obtained in (3) (1.55 g), 1,3-dimethylbarbituric acid (0.53 g), dichloromethane (40 mL), and tetrakis(triphenylphosphine)palladium(0) (0.39 g) were added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated under reduced pressure, and the residue was purified by NH silica gel column chromatography [eluent; ethyl acetate:methanol = 100:0 → 90:10] to give benzyl (R)-(1-(1-(2-(benzyloxy)-5-chlorophenethyl)piperidin-4-yl)-2-oxo-2-(piperazin-1-yl)ethyl)carbamate (1.36 g) as a brown oil.

[0122] Reference example 216 (1) To methyl 2-(5-chloro-2-hydroxyphenyl)acetate (2.0 g), tert-butyl (2-hydroxyethyl)carbamate (1.85 g), triphenylphosphine (3.53 g), and THF (20 mL) were added and stirred under ice cooling. At the same temperature, a 1.9 mol / L solution of diisopropyl azodicarboxylate in toluene (7.1 mL) was added, and the mixture was stirred at room temperature for 18 hours and 40 minutes. Water and ethyl acetate 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 layer was combined with the previously separated organic layer. The mixture was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:heptane = 5:95 → 50:50] to obtain the target product (3.54 g). (2) To the compound obtained in (1) (3.54 g), anhydrous THF (50 mL) was added, and the mixture was stirred at -10°C. A 4 mol / L THF solution of lithium borohydride (10.3 mL) was added at the same temperature and stirred at room temperature for 3 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted three times with ethyl acetate, and the previously separated organic layer was combined and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: ethyl acetate:heptane = 5:95 → 50:50] to obtain the target product (2.90 g). (3) Dichloromethane (13.7 mL) and triethylamine (0.85 mL) were added to the compound obtained in (2) (1.48 g) and stirred under ice cooling. Methanesulfonyl chloride (0.40 mL) was added at the same temperature and stirred for 1 hour and 30 minutes. Chloroform and water were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted three times with chloroform, and the previously separated organic layer was combined and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography [eluent; ethyl acetate:heptane=15:85→40:60] to obtain the target product (1.67 g). (4) To the compound obtained in (3) (1.47 g), allyl (R)-4-(2-(((benzyloxy)carbonyl)amino)-2-(piperidin-4-yl)acetyl)piperazine-1-carboxylate hydrochloride (1.20 g), acetonitrile (13 mL), and potassium carbonate (1.72 g) were added, and the mixture was stirred at 80°C for 3 hours.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 previously separated organic layer was combined and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography [eluent; ethyl acetate:heptane = 10:90 → 80:20] to obtain the target product (1.59 g) as a pale orange oil. (5) To the compound (1.50 g) obtained in (4), 1,3-dimethylbarbituric acid (0.47 g), dichloromethane (40 mL), and tetrakis(triphenylphosphine)palladium(0) (0.35 g) were added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated under reduced pressure, and the residue was purified by NH silica gel column chromatography [eluent; ethyl acetate:methanol=100:0→90:10] to give tert-butyl (R)-(2-(2-(2-(4-(1-(((benzyloxy)carbonyl)amino)-2-oxo-2-(piperazin-1-yl)ethyl)piperidin-1-yl)ethyl)-4-chlorophenoxy)ethyl)carbamate (1.10 g).

[0123] Reference example 217 (1) THF (15 mL) and 1,1'-carbonyldiimidazole (1.36 g) were added to 2-(5-chloro-2-phenoxyphenyl)acetic acid (2.0 g) and stirred at room temperature for 1 hour. The reaction mixture was added to a mixture of sodium borohydride (0.72 g) and water (5 mL) and stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:heptane = 5:95 → 30:70] to obtain the target product (1.80 g) as a colorless oil. (2) Dichloromethane (13.2 mL) and triethylamine (1.2 mL) were added to the compound obtained in (1) (1.64 g) and stirred at -10°C. A solution of methanesulfonyl chloride (0.57 mL) in dichloromethane (3 mL) was added at the same temperature, and the mixture was stirred for 2 hours. Chloroform and water 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 layer was combined. The mixture was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:heptane = 5:95 → 25:75] to obtain the target product (2.00 g) as a colorless oil. (3) Acetonitrile (13 mL), potassium carbonate (1.44 g), and the compound obtained in (2) (1.02 g) were added sequentially to allyl (R)-4-(2-(((benzyloxy)carbonyl)amino)-2-(piperidin-4-yl)acetyl)piperazine-1-carboxylate hydrochloride (1.0 g), and the mixture was stirred at 80°C for 3 hours. 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 previously separated organic layer was combined and dried over anhydrous sodium sulfate. The solvent was evaporated 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 (955 mg) as a white solid. (4) To the compound obtained in (3) (955 mg), 1,3-dimethylbarbituric acid (331 mg), dichloromethane (40 mL), and tetrakis(triphenylphosphine)palladium(0) (327 mg) were added, and the mixture was stirred at room temperature for 19 hours.The reaction mixture was evaporated under reduced pressure, and the residue was purified by NH silica gel column chromatography [eluent; ethyl acetate:methanol=100:0→90:10] to give benzene (R)-(1-(1-(5-chloro-2-phenoxyphenethyl)piperidin-4-yl)-2-oxo-2-(piperazin-1-yl)ethyl)carbamate (698 mg) as an orange oil.

[0124] Reference example 218 Dichloromethane (2.3 mL), 2-(ethylthio)-4-fluorobenzaldehyde (118 mg), and sodium triacetoxyborohydride (451 mg) were added to tert-butyl (R)-(2-(2-(2-(4-(1-(((benzyloxy)carbonyl)amino)-2-oxo-2-(piperazin-1-yl)ethyl)piperidin-1-yl)ethyl)-4-chlorophenoxy)ethyl)carbamate (280 mg), and the mixture was stirred at room temperature for 16 hours and 20 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 organic layers separated earlier were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:methanol=100:0→88:12] to give tert-butyl (R)-(2-(2-(2-(4-(1-(((benzyloxy)carbonyl)amino)-2-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenoxy)ethyl)carbamate (320 mg).

[0125] The compounds shown in Table 9 were obtained in the same manner as in Reference Example 218.

[0126] Reference example 227 To benzyl (R)-(1-(1-(2-bromo-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (112 mg), tert-butyl (2-aminoethyl)(2-((tert-butoxycarbonyl)amino)ethyl)carbamate (93 mg), tris(dibenzylideneacetone)dipalladium(0) (7 mg), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (19 mg), cesium carbonate (63 mg), triethylamine (21 μL), toluene (1.2 mL), and 1,4-dioxane (1.2 mL) were added, and the mixture was stirred at 110° C. for 3 hours under a nitrogen atmosphere. Tris(dibenzylideneacetone)dipalladium(0) (7 mg) and (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (19 mg) were added to the reaction mixture, and the mixture was stirred at 110°C for 2 hours. After the reaction mixture was cooled to room temperature, ethyl acetate (5 mL) and saturated aqueous ammonium chloride solution (5 mL) were added, and the organic layer was separated. The organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated aqueous 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→90:10] to give tert-butyl (R)-(2-((2-(2-(4-(1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)ethyl)(2-((tert-butoxycarbonyl)amino)ethyl)carbamate (87 mg) as a yellow oil.

[0127] Reference example 228 Benzyl (R)-(1-(1-(2-bromo-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (33 mg) was added with benzyl tert-butyl (4-aminobutane-1,3-diyl)(S)-dicarbamate (31 mg), tris(dibenzylideneacetone)dipalladium(0) (4 mg), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (12 mg), cesium carbonate (37 mg), triethylamine (13 μL), toluene (0.4 mL), and 1,4-dioxane (0.4 mL) and stirred at 110° C. for 3 hours under a nitrogen atmosphere. Tris(dibenzylideneacetone)dipalladium(0) (4 mg) and (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (12 mg) were added to the reaction mixture, and the mixture was stirred at 110°C for 2 hours and 50 minutes. After the reaction mixture was cooled to room temperature, ethyl acetate (5 mL) and saturated aqueous ammonium chloride solution (5 mL) were added, and the organic layer was separated. The organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated aqueous 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; ethyl acetate:methanol=100:0→80:20] to give benzyl tert-butyl ((S)-4-((2-(2-(4-((R)-1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)butane-1,3-diyl)dicarbamate (32 mg) as a yellow solid.

[0128] Reference example 229 To tert-butyl (R)-(1-(1-(2-bromo-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (100 mg), tert-butyl (R)-(1-amino-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)carbamate (88 mg), tris(dibenzylideneacetone)dipalladium(0) (13 mg), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (36 mg), cesium carbonate (118 mg), triethylamine (40 μL), toluene (1 mL), and 1,4-dioxane (1 mL) were added, and the mixture was stirred at 110° C. for 3 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, ethyl acetate (20 mL) and saturated aqueous ammonium chloride solution (20 mL) were added, and the organic layer was separated. The organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 50:50 → 80:20] to give tert-butyl ((R)-1-(1-(2-(((R)-2-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)propyl)amino)-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (49 mg) as an orange solid.

[0129] Reference example 230 Di-tert-butyl (2-aminopropane-1,3-diyl)dicarbamate (20 mg), tris(dibenzylideneacetone)dipalladium(0) (7.5 mg), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (20.5 mg), cesium carbonate (38 mg), triethylamine (9.5 μL), toluene (0.2 mL), and 1,4-dioxane (0.2 mL) were added to benzyl (R)-(1-(1-(2-bromo-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (20 mg), and the mixture was stirred at 110° C. for 3 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, ethyl acetate (5 mL) and saturated aqueous ammonium chloride solution (5 mL) were added, and the organic layer was separated. The organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, then 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→90:10] to give di-tert-butyl (2-((2-(2-(4-(1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)propane-1,3-diyl)(R)-dicarbamate (14.5 mg) as a colorless oil.

[0130] Reference example 231 To tert-butyl (R)-(1-(1-(2-bromo-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (40 mg), tert-butyl (S)-(1-amino-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)carbamate (35 mg), tris(dibenzylideneacetone)dipalladium(0) (11 mg), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (29 mg), cesium carbonate (66 mg), triethylamine (16 μL), toluene (0.4 mL), and 1,4-dioxane (0.4 mL) were added, and the mixture was stirred at 100° C. for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and then ethyl acetate (5 mL) and saturated aqueous ammonium chloride (5 mL) were added to separate the organic layer, which was washed successively with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:heptane=10:90→0:100] and then by preparative HPLC [eluent; water:acetonitrile:methanol=20:80:0→0:100:0→0:0:100] to give tert-butyl ((R)-1-(1-(2-(((S)-2-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)propyl)amino)-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (12 mg) as a yellow oil.

[0131] Reference example 232 To tert-butyl (R)-(1-(1-(2-bromo-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (55 mg), tert-butyl (2S,4R)-4-amino-2-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine-1-carboxylate (58 mg), tris(dibenzylideneacetone)dipalladium(0) (22 mg), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (59 mg), cesium carbonate (103 mg), triethylamine (22 μL), toluene (0.55 mL), and 1,4-dioxane (0.55 mL) were added, and the mixture was stirred at 100° C. for 3 hours and 10 minutes under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and then ethyl acetate (5 mL) and saturated aqueous ammonium chloride (5 mL) were added to separate the organic layer, which was washed successively with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:heptane=10:90→0:100] and then by preparative HPLC [eluent; water:acetonitrile:methanol=20:80:0→0:100:0→0:0:100] to give tert-butyl (2S,4R)-4-((2-(2-(4-((R)-1-((tert-butoxycarbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)-2-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine-1-carboxylate (20 mg) as a yellow oil.

[0132] Reference example 233 To tert-butyl (R)-(1-(1-(2-bromo-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (70 mg), tert-butyl (3S,4S)-3-amino-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate (70 mg), tris(dibenzylideneacetone)dipalladium(0) (28 mg), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (75 mg), cesium carbonate (131 mg), triethylamine (28 μL), toluene (0.7 mL), and 1,4-dioxane (0.7 mL) were added, and the mixture was stirred at 100° C. for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and then ethyl acetate (5 mL) and saturated aqueous ammonium chloride (5 mL) were added to separate the organic layer, which was washed successively with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:heptane=5:95→50:50] and then by preparative HPLC [eluent; water:acetonitrile:methanol=20:80:0→0:100:0→0:20:80] to give tert-butyl (3S,4S)-3-((2-(2-(4-((R)-1-((tert-butoxycarbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)-2-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate (46 mg) as a yellow oil.

[0133] Reference example 234 To benzyl (R)-(1-(1-(2-bromo-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (30 mg), tert-butyl 4-aminopiperidine-1-carboxylate (17 mg), tris(dibenzylideneacetone)dipalladium(0) (6 mg), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (15 mg), cesium carbonate (34 mg), triethylamine (12 μL), toluene (0.3 mL), and 1,4-dioxane (0.3 mL) were added, and the mixture was stirred at 120° C. for 3 hours and 30 minutes under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and then ethyl acetate and saturated aqueous ammonium chloride solution were added, and the organic layer was separated. The organic layer was washed successively with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, 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→90:10] to give tert-butyl (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)amino)piperidine-1-carboxylate (16 mg) as a colorless oil.

[0134] The compounds shown in Table 10 were obtained in the same manner as in Reference Example 234.

[0135] Reference example 239 To tris(dibenzylideneacetone)dipalladium(0) (5.6 mg), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (15 mg) and 1,4-dioxane (0.3 mL) were added, and the mixture was stirred at 120°C for 5 minutes under a nitrogen atmosphere. To the reaction mixture were added benzyl (R)-(1-(1-(2-bromo-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (30 mg), di-tert-butyl (3-aminopropane-1,2-diyl)(R)-dicarbamate (24 mg), cesium carbonate (35 mg), triethylamine (12 μL), and toluene (0.3 mL), and the mixture was stirred at 120° C. for 1 hour under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and then ethyl acetate and a saturated aqueous solution of ammonium chloride were added, and the organic layer was separated. The organic layer was washed successively with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=90:10→0:100] to give di-tert-butyl ((R)-3-((2-(2-(4-((R)-1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)propane-1,2-diyl)dicarbamate (18 mg) as a yellow solid.

[0136] Reference example 240 Di-tert-butyl (3-aminopropane-1,2-diyl)(R)-dicarbamate of Reference Example 239 was replaced with di-tert-butyl (3-aminopropane-1,2-diyl)(S)-dicarbamate, and the reaction was carried out in a similar manner to Reference Example 239 to obtain di-tert-butyl ((S)-3-((2-(2-(4-((R)-1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)propane-1,2-diyl)dicarbamate as a pale yellow solid.

[0137] Reference example 241 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), tert-butyl (3-aminopropyl)(3-((tert-butoxycarbonyl)amino)propyl)carbamate (97 mg), tris(dibenzylideneacetone)dipalladium(0) (13 mg), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (34 mg), cesium carbonate (112 mg), triethylamine (38 μL), toluene (1 mL), and 1,4-dioxane (1 mL) were added, and the mixture was stirred at 120° C. for 3 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, ethyl acetate and saturated aqueous ammonium chloride were added, and the organic layer was separated. The organic layer was washed successively with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=90:10→5:95] to give tert-butyl (R)-(3-((2-(2-(4-(1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)propyl)(3-((tert-butoxycarbonyl)amino)propyl)carbamate (58 mg) as a yellow solid.

[0138] The compounds shown in Table 11 were obtained in the same manner as in Reference Example 241.

[0139] Reference example 246 To tert-butyl (R)-(1-(1-(2-bromo-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (100 mg), tert-butyl ((3R,4S)-4-aminotetrahydrofuran-3-yl)carbamate (58 mg), tris(dibenzylideneacetone)dipalladium(0) (13 mg), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (36 mg), cesium carbonate (117 mg), triethylamine (40 μL), toluene (1 mL), and 1,4-dioxane (1 mL) were added, and the mixture was stirred at 120° C. for 3 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, ethyl acetate (20 mL) and saturated aqueous ammonium chloride solution (20 mL) were added, and the organic layer was separated. The organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 10:90 → 0:100] to give tert-butyl ((3R,4S)-4-((2-(2-(4-((R)-1-((tert-butoxycarbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)tetrahydrofuran-3-yl)carbamate (81 mg) as a pale yellow solid.

[0140] Reference example 247 Dichloromethane (0.43 mL) and DIPEA (27 μL) were added to benzyl (R)-(1-(1-(2-amino-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate hydrochloride (50 mg), and the mixture was stirred under ice-cooling. At the same temperature, a dichloromethane solution (0.22 mL) of benzyl (2-(chlorosulfonyl)ethyl)carbamate (20 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Benzyl (2-(chlorosulfonyl)ethyl)carbamate (20 mg) and DMAP (8 mg) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour 35 minutes. Benzyl (2-(chlorosulfonyl)ethyl)carbamate (39 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours 15 minutes. Dichloromethane (10 mL) and saturated aqueous sodium bicarbonate solution (10 mL) were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 10:90 → 100:0] to give benzyl (R)-(2-(N-(2-(2-(4-(1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)sulfamoyl)ethyl)carbamate (28 mg) as a white solid.

[0141] Reference example 248 To tris(dibenzylideneacetone)dipalladium(0) (19 mg), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (51 mg) and 1,4-dioxane (1 mL) were added, and the mixture was stirred for 5 minutes at 120°C under a nitrogen atmosphere. To the reaction mixture, 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), tert-butyl cis-3-(aminomethyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate (91 mg), triethylamine (38 μL), and toluene (1 mL) were added, and the mixture was stirred for 2 hours and 30 minutes at 120°C under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, ethyl acetate (20 mL) and saturated aqueous ammonium chloride solution (20 mL) were added, and the organic layer was separated. The organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 10:90 → 90:10] to give tert-butyl cis-3-(((2-(2-(4-((R)-1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)methyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate (86 mg) as a pale yellow solid.

[0142] Reference example 249

[0111] Except for replacing tert-butyl cis-3-(aminomethyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate in Reference Example 248 with tert-butyl trans-3-(aminomethyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate, the reaction was carried out in a similar manner to Reference Example 248 to give tert-butyl trans-3-(((2-(2-(4-((R)-1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)methyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate as a pale orange solid.

[0143] Reference example 250 THF (8 mL) was added to lithium aluminum hydride (189 mg) and the mixture was stirred under ice-cooling. Then, a solution of tert-butyl (2S,4S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-cyanopyrrolidine-1-carboxylate (1.00 g) in THF (2 mL) was added, and the mixture was stirred at the same temperature for 30 minutes. A saturated aqueous solution of potassium tartrate (10 mL) was added to the reaction mixture, and ethyl acetate was added, and the organic layer was separated. The resulting organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 0:100 → 25:75] to give tert-butyl (2S,4R)-4-(aminomethyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine-1-carboxylate (382 mg) as a colorless oil.

[0144] Reference example 251 To tert-butyl (R)-(1-(1-(2-bromo-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (100 mg), tert-butyl (2S,4R)-4-(aminomethyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine-1-carboxylate (100 mg), tris(dibenzylideneacetone)dipalladium(0) (13 mg), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (36 mg), cesium carbonate (120 mg), triethylamine (40 μL), toluene (1 mL), and 1,4-dioxane (1 mL) were added, and the mixture was stirred under reflux for 3 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, ethyl acetate (20 mL) and saturated aqueous ammonium chloride solution (20 mL) were added, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 10:90 → 70:30] to give tert-butyl (2S,4R)-4-(((2-(2-(4-((R)-1-((tert-butoxycarbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)methyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine-1-carboxylate (90 mg) as a yellow oil.

[0145] Reference example 252

[0111] The reaction was carried out in the same manner as in Reference Example 251, except that tert-butyl (2S,4R)-4-(aminomethyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine-1-carboxylate of Reference Example 251 was replaced with (R)-3-((tert-butyldimethylsilyl)oxy)piperidine, to give tert-butyl ((R)-1-(1-(2-((R)-3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate as a pale yellow solid.

[0146] Reference example 253 To benzyl (R)-(1-(1-(2-bromo-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (30 mg), tert-butyl (S)-3-amino-2-((tert-butoxycarbonyl)amino)propanoate (22 mg), tris(dibenzylideneacetone)dipalladium(0) (4 mg), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (10 mg), cesium carbonate (36 mg), triethylamine (12 μL), toluene (0.3 mL), and 1,4-dioxane (0.3 mL) were added, and the mixture was stirred under reflux for 3 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, ethyl acetate (6 mL) and saturated aqueous ammonium chloride solution (6 mL) were added, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane = 10:90 → 90:10] to give tert-butyl (S)-3-((2-(2-(4-((R)-1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)-2-((tert-butoxycarbonyl)amino)propanoate (27 mg) as a yellow solid.

[0147] The compounds shown in Table 12 were obtained in the same manner as in Reference Example 253.

[0148] Reference example 257 2-(2-chloro-3,4-bis((4-methoxybenzyl)oxy)phenyl)-2-oxoacetic acid (14 mg), HATU (12 mg), DMF (0.2 mL), and DIPEA (19 μL) were added to benzyl (R)-(1-(1-(2-amino-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate hydrochloride (20 mg), and the mixture was stirred at room temperature for 3 hours and 30 minutes. Ethyl acetate (5 mL) and water (5 mL) were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride and then 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 give benzyl (R)-(1-(1-(5-chloro-2-(2-(2-chloro-3,4-bis((4-methoxybenzyl)oxy)phenyl)-2-oxoacetamido)phenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (20 mg) as a pale yellow oil.

[0149] Reference example 258 (1) Dichloromethane (2.4 mL), methanol (0.24 mL), and a 4 mol / L hydrochloric acid dioxane solution (71 μL) were added to tert-butyl (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)piperazine-1-carbamate (237 mg), and the mixture was stirred at room temperature for 17 hours. A 4 mol / L hydrochloric acid dioxane solution (0.64 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (6 mL) and diethyl ether (6 mL) were added to the reaction mixture, and the solid was collected by filtration. The obtained solid was dried under reduced pressure to obtain the target product (216 mg) as a white solid. (2) To the compound obtained in (1) (50 mg), (S)-2-(((benzyloxy)carbonyl)amino)-4-((tert-butoxycarbonyl)amino)butyric acid (25 mg), HATU (28 mg), DMF (0.5 mL), and DIPEA (43 μL) were added, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate (5 mL) and water (5 mL) were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol=100:0→90:10] to give benzyl tert-butyl ((S)-4-(4-(2-(2-(4-((R)-1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)piperazin-1-yl)-4-oxobutane-1,3-diyl)dicarbamate (51 mg) as a pale yellow oil.

[0150] Reference example 259 (S)-2-(((benzyloxy)carbonyl)amino)-4-((tert-butoxycarbonyl)amino)butyric acid of Reference Example 258 was replaced with 3-((tert-butoxycarbonyl)amino)propionic acid, and the reaction was carried out in a similar manner to Reference Example 258(2) to give tert-butyl (R)-(3-(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)piperazin-1-yl)-3-oxopropyl)carbamate as a pale yellow oil.

[0151] Reference 260 DMF (0.5 mL) and DIPEA (43 μL) were added to benzyl (R)-(1-(1-(5-chloro-2-(piperazin-1-yl)phenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate hydrochloride (50 mg), and the mixture was stirred under ice-cooling. Benzyl (2-(chlorosulfonyl)ethyl)carbamate (20 mg) was added at the same temperature, and the mixture was stirred at room temperature for 2 hours and 30 minutes. Ethyl acetate (5 mL) and water (5 mL) were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride and then 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→90:10] to give benzyl (R)-(2-((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)piperazin-1-yl)sulfonyl)ethyl)carbamate (37 mg) as a pale yellow oil.

[0152] Reference example 261 DMF (1.4 mL) and (S)-2,5-bis((tert-butoxycarbonyl)amino)valeric acid (66 mg) were added to benzyl (R)-(1-(1-(2-((2-aminoethyl)amino)-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate hydrochloride (141 mg), and the mixture was stirred under ice-cooling. HATU (76 mg) and DIPEA (0.15 mL) were added at the same temperature, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride and then 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→90:10] to give di-tert-butyl ((S)-5-((2-((2-(2-(4-((R)-1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)ethyl)amino)-5-oxopentane-1,4-diyl)dicarbamate (114 mg) as a white solid.

[0153] The compounds shown in Table 13 were obtained in the same manner as in Reference Example 261.

[0154] Reference example 264 (1) To benzyl (R)-(1-(1-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (208 mg) were added chloroform (2 mL), methanol (0.21 mL), and a 4 mol / L hydrochloric acid dioxane solution (0.64 mL), and the mixture was stirred at room temperature for 1 hour and 25 minutes. To the reaction mixture were added ethyl acetate (6 mL) and diethyl ether (6 mL), and the solid was collected by filtration. The obtained solid was dried under reduced pressure to obtain the target product (187 mg) as a white solid. (2) To the compound obtained in (1) (83 mg), DMF (0.83 mL) and (S)-2,5-bis((tert-butoxycarbonyl)amino)valeric acid (41 mg) were added and stirred under ice-cooling. HATU (49 mg) and DIPEA (74 μL) were added at the same temperature, and the mixture was stirred at room temperature for 2 hours and 15 minutes. Ethyl acetate (5 mL) and water (5 mL) were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride solution and then 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→90:10] to give di-tert-butyl ((S)-5-((2-(2-(2-(4-((R)-1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenoxy)ethyl)amino)-5-oxopentane-1,4-diyl)dicarbamate (66 mg) as a pale yellow oil.

[0155] The compounds shown in Table 14 were obtained in the same manner as in Reference Example 264.

[0156]

[0157] Reference example 267 (1) To tert-butyl (R)-3-(((2-(2-(4-((R)-1-((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)methyl)pyrrolidine-1-carboxylate (269 mg) were added chloroform (2.7 mL), methanol (0.27 mL), and a 4 mol / L hydrochloric acid dioxane solution (0.79 mL), followed by stirring at room temperature for 2 hours. To the reaction mixture were added ethyl acetate (4 mL) and diethyl ether (4 mL), and the solid was collected by filtration. To the obtained solid was added methanol (20 mL), and the solvent was evaporated under reduced pressure. To the residue was added ethyl acetate (10 mL), and the solvent was evaporated under reduced pressure, followed by drying under reduced pressure to obtain the target product (289 mg) as a pale yellow solid. (2) To the compound obtained in (1) (155 mg), DMF (1.6 mL) and (S)-2,5-bis((tert-butoxycarbonyl)amino)valeric acid (69 mg) were added and stirred under ice-cooling. HATU (79 mg) and DIPEA (0.16 mL) were added at the same temperature, and the mixture was stirred at room temperature for 2 hours and 10 minutes. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction mixture, and the organic layer was separated. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, then 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→94:6] to give benzyl tert-butyl ((S)-4-((R)-3-(((2-(2-(4-((R)-1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)methyl)pyrrolidin-1-yl)-4-oxobutane-1,3-diyl)dicarbamate (154 mg) as a yellow solid.

[0158] Reference example 268 (S)-2,5-bis((tert-butoxycarbonyl)amino)valeric acid of Reference Example 267 was replaced with (S)-2-(((benzyloxy)carbonyl)amino)-4-((tert-butoxycarbonyl)amino)butyric acid, and the reaction was carried out in a similar manner to Reference Example 267(2) to give benzyl tert-butyl ((S)-4-(4-(2-(2-(4-((R)-1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)piperazin-1-yl)-4-oxobutane-1,3-diyl)dicarbamate as a white solid.

[0159] Reference example 269 (1) The reaction was carried out in the same manner as in Reference Example 216(1), except that tert-butyl (2-hydroxyethyl)carbamate in Reference Example 216 was replaced with tert-butyl (S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate, to obtain the target product as a colorless oil. (2) The compound obtained in (1) was reacted in the same manner as in Reference Example 216(2), to obtain the target product as a colorless oil. (3) Dichloromethane (13 mL) was added to the compound obtained in (2) (486 mg), and the mixture was stirred under ice cooling. Dess-Martin periodinane (1.16 g) was added at the same temperature, and the mixture was stirred at room temperature for 2 hours and 30 minutes. 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. Water (5 mL), 10% aqueous sodium thiosulfate solution (5 mL), and saturated aqueous sodium bicarbonate solution (5 mL) were added to the organic layer, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the target product (520 mg). (4) To the compound obtained in (3) (520 mg), dichloromethane (7.2 mL), benzyl (R)-(2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxo-1-(piperidin-4-yl)ethyl)carbamate hydrochloride (717 mg), triethylamine (0.34 mL), and sodium triacetoxyborohydride (649 mg) were added, and the mixture was stirred at room temperature for 3 hours and 15 minutes. Water (14 mL) was added to the reaction mixture, and then 10% aqueous sodium carbonate solution (3.9 mL) 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 evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:methanol=100:0→95:5] to give tert-butyl (S)-3-((2-(2-(4-((R)-1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenoxy)methyl)pyrrolidine-1-carboxylate (821 mg) as a white solid.

[0160] Reference example 270 (1) To tert-butyl (S)-3-((2-(2-(4-((R)-1-((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenoxy)methyl)pyrrolidine-1-carboxylate (240 mg) were added chloroform (2.4 mL), methanol (0.24 mL), and a 4 mol / L hydrochloric acid dioxane solution (0.71 mL), and the mixture was stirred at room temperature for 1 hour and 45 minutes. Ethyl acetate (6 mL) and diethyl ether (6 mL) were added to the reaction mixture, and the solvent was evaporated under reduced pressure. Methanol (20 mL) was added to the residue, and the solvent was evaporated under reduced pressure. Diethyl ether was added to the residue, and the solvent was evaporated under reduced pressure. The residue was dried under reduced pressure to obtain the target product (212 mg) as a pale yellow solid. (2) To the compound obtained in (1) (100 mg), DMF (1 mL) and (S)-2,5-bis((tert-butoxycarbonyl)amino)valeric acid (50 mg) were added and stirred under ice-cooling. HATU (58 mg) and DIPEA (85 μL) were added at the same temperature, and the mixture was stirred at room temperature for 3 hours. Ethyl acetate (5 mL) and water (5 mL) were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography [eluent; ethyl acetate:hexane=0:100→100:0] to give di-tert-butyl ((S)-5-((S)-3-((2-(2-(2-(4-((R)-1-((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenoxy)methyl)pyrrolidin-1-yl)-5-oxopentane-1,4-diyl)dicarbamate (65 mg) as a pale yellow oil.

[0161] Reference example 271 (S)-2,5-bis((tert-butoxycarbonyl)amino)valeric acid of Reference Example 270 was replaced with (S)-2-(((benzyloxy)carbonyl)amino)-4-((tert-butoxycarbonyl)amino)butyric acid, and the reaction was carried out in a similar manner to Reference Example 270(2) to give benzyl tert-butyl((S)-4-((S)-3-((2-(2-(2-(4-((R)-1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenoxy)methyl)pyrrolidin-1-yl)-4-oxobutane-1,3-diyl)dicarbamate as a pale yellow oil.

[0162] Reference example 272 (1) To benzyl ((R)-1-(1-(2-((R)-3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (183 mg) were added chloroform (1.8 mL), methanol (0.18 mL), and a 4 mol / L hydrochloric acid dioxane solution (0.53 mL), and the mixture was stirred at room temperature for 2 hours. Ethyl acetate (10 mL) was added to the reaction mixture, and the solid was collected by filtration. Methanol (10 mL) was added to the obtained solid, and the solvent was evaporated under reduced pressure. Water (10 mL), methanol (2 mL), a 1 mol / L aqueous sodium hydroxide solution (0.6 mL), and chloroform (10 mL) were added to the residue, and the organic layer was separated. The aqueous layer was extracted with chloroform (10 mL). This was combined with the organic layer obtained earlier, and the solvent was evaporated under reduced pressure. The mixture was then dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dried under reduced pressure to obtain the target product (148 mg) as a yellow solid. (2) THF (1.3 mL) was added to the compound obtained in (1) (50 mg) and the mixture was stirred under ice cooling. Trichloroacetyl isocyanate (16 μL) was added at the same temperature, and the mixture was stirred for 1 hour and 50 minutes. Trichloroacetyl isocyanate (16 μL) was added to the reaction mixture, and the mixture was stirred for 1 hour. The solvent was evaporated under reduced pressure, and the residue was mixed with methanol (0.89 mL), water (0.44 mL), and sodium formate (46 mg) and stirred at room temperature for 10 minutes. The solvent was evaporated under reduced pressure, and the residue was added with chloroform (10 mL) and water (10 mL), and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride and then 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→90:10] to give benzyl ((R)-1-(1-(2-((R)-3-(carbamoyloxy)piperidin-1-yl)-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (48 mg) as a pale yellow solid.

[0163] Reference example 273 Chloroform (0.5 mL) and 1,1'-carbonyldiimidazole (22 mg) were added to benzyl ((R)-1-(1-(5-chloro-2-((R)-3-hydroxypiperidin-1-yl)phenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (50 mg), and the mixture was stirred at room temperature for 2 hours. 1,1'-Carbonyldiimidazole (11 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. tert-Butyl (2-aminoethyl)carbamate (53 μL) was added to the reaction mixture, and the mixture was stirred at room temperature for 20 hours and 15 minutes. Chloroform (5 mL) and water (5 mL) were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:ethyl acetate=100:0→0:100] to give (R)-1-(2-(2-(4-((R)-1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)piperidin-3-yl tert-butyl ethane-1,2-diyldicarbamate (47 mg) as a pale red solid.

[0164] Reference example 274 The tert-butyl (2-aminoethyl)carbamate of Reference Example 273 was replaced with N,N-dimethylethylenediamine, and the reaction was carried out in a similar manner to Reference Example 273 to give (R)-1-(2-(2-(4-((R)-1-(((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)piperidin-3-yl (2-(dimethylamino)ethyl)carbamate as a pale yellow solid.

[0165] Reference example 275 (1) 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), 1-(tert-butyl) 2-methyl(2S,4R)-4-aminopyrrolidine-1,2-dicarboxylate (63 mg), tris(dibenzylideneacetone)dipalladium(0) (13 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (34 mg), cesium carbonate (121 mg), triethylamine (38 μL), toluene (1 mL), and 1,4-dioxane (1 mL) were added, and the mixture was stirred under reflux for 3 hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, ethyl acetate (20 mL) and saturated aqueous ammonium chloride (20 mL) were added, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:ethyl acetate = 100:0 → 40:60] to obtain the target product (95 mg) as a pale yellow solid. (2) THF (0.21 mL), methanol (0.14 mL), and 1 mol / L aqueous sodium hydroxide (0.28 mL) were added to the compound obtained in (1) (71 mg), and the mixture was stirred at room temperature for 3 hours and 20 minutes. Ethyl acetate (10 mL), water (10 mL), and saturated aqueous ammonium chloride (10 mL) were added to the reaction mixture, and the organic layer was separated. The organic layer was washed sequentially with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dried under reduced pressure to obtain the target product (70 mg) as a yellow solid. (3) DMF (0.64 mL) and tert-butyl (2-aminoethyl)carbamate (14 μL) were added to the compound obtained in (2) (64 mg) and stirred under ice-cooling. HATU (33 mg) and DIPEA (16 μL) were added at the same temperature and stirred at room temperature for 1 hour. Ethyl acetate (10 mL) and water (10 mL) were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride and then 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→92:8] to give tert-butyl (2S,4R)-4-((2-(2-(4-((R)-1-((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)-2-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)pyrrolidine-1-carboxylate (63 mg) as a yellow solid.

[0166] The compounds shown in Table 15 were obtained in the same manner as in Reference Example 275.

[0167] Example 1 Anisole (0.04 mL) and a 5.1 mol / L hydrobromic acid / acetic acid solution (0.2 mL) were added to tert-butyl (R)-3-(((2-(2-(4-((R)-1-((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)methyl)pyrrolidine-1-carboxylate (20 mg), and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (1 mL) and diethyl ether (1 mL) were added sequentially to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was centrifuged, and the supernatant was removed. Ethyl acetate (1 mL) and diethyl ether (1 mL) were added to the residue, and the mixture was centrifuged, and the supernatant was removed. Ethyl acetate (1 mL) and diethyl ether (1 mL) were added to the residue, followed by centrifugation. The supernatant was removed and the residue was dried under reduced pressure to give (R)-2-amino-2-(1-(5-chloro-2-((((S)-pyrrolidin-3-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrobromide (23.3 mg) as a white solid. NMR: 1.42(3H,t,J=7.0Hz), 1.64-1.94(3H,m), 1.98-2.16(2H,m), 2.16-2.44(2H,m), 2.68-2.86(1H,m), 2.90-3.19(5H,m), 3.19-3.49(9H,m), 3.49-3.57(2H,m), 3.57-3.97(5H,m), 4.11-4.33(3H,m), 4.52(2H,s), 4.60(1H,d,J=7.2Hz), 6.84(1H,d,J=8.8Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.19(1H,d,J=2.4Hz), 7.26(1H,dd,J=8.8,2.4Hz), 7.46-7.58(1H,m) MS: 615.30[M+H] +

[0168] In the same manner as in Example 1, the compounds shown in Table 16 were obtained.

[0169] The NMR and MS measurement values ​​of the compounds in the table are shown. Example 2 NMR: 1.42 (3H, t, J = 7.0 Hz), 1.61-1.87 (2H, m), 1.94-2.17 (3H, m), 2.22-2.38 (1H, m), 2.38-2.59 (1H, m), 2.95-3.23 (7H, m), 3.23-3.67 (9H, m), 3.67-3.93 (3H, m), 3.97-4.12 (1H, m), 4.12-4.31 (3H, m), 4.51 (2H, s), 4.59 (1H, d, J = 5.6 Hz), 6.88 (1H, dd, J = 8.8, 8.8 Hz), 6.97 (1H, d, J = 8.4 Hz), 7.15-7.25(1H,m), 7.28-7.42(2H,m), 7.47-7.61(1H,m) MS:601.30[M+H] + Example 3 NMR: 1.42 (3H, t, J = 7.0 Hz), 1.63-1.84 (2H, m), 1.95-2.12 (2H, m), 2.13-2.51 (3H, m), 2.90-3.26 (6H, m), 3.26-3.66 (10H, m), 3.66-3.84 (3H, m), 4.15-4.26 (3H, m), 4.51 (2H, s), 4.57 (1H, d, J = 5.6 Hz), 5.34-5.58 (1H, m), 6.89 (1H, dd, J = 8.8, 8.8 Hz), 6.97 (1H, d, J = 8.4 Hz), 7.15-7.27 (1H, m), 7.27-7.42(2H,m), 7.47-7.59(1H,m) MS:604.30[M+H] +Example 4 NMR: 1.41 (3H, t, J = 7.0 Hz), 1.62-1.84 (2H, m), 1.97-2.15 (3H, m), 2.22-2.39 (1H, m), 2.39-2.59 (1H, m), 2.97-3.21 (6H, m), 3.21-3.47 (5H, m), 3.47-3.68 (4H, m), 3.68-3.88 (3H, m), 3.88-4.12 (2H, m), 4.12-4.30 (3H, m), 4.51 (2H, s), 4.58 (1H, d, J = 6.0 Hz), 6.88 (1H, dd, J = 8.8, 8.8 Hz), 6.96(1H,d,J=8.4Hz), 7.14-7.25(1H,m), 7.25-7.39(2H,m), 7.44-7.59(1H,m) MS:601.25[M+H] + Example 5 NMR: 1.42 (3H, t, J = 7.0 Hz), 1.63-1.83 (2H, m), 1.98-2.12 (2H, m), 2.11-2.24 (2H, m), 2.24-2.38 (1H, m), 2.89-3.04 (2H, m), 3.04-3.31 (5H, m), 3.31-3.71 (6H, m), 3.71-3.90 (3H, m), 4.08-4.31 (3H, m), 4.51 (2H, s), 4.55-4.64 (1H, m), 6.88 (1H, dd, J = 8.8, 8.8 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.22-7.68(4H,m) MS:636.25[M+H] +Example 6 NMR: 1.42(3H,t,J=7.0Hz), 1.50-1.68(1H,m), 1.68-1.86(3H,m), 1.86-2.00(1H,m), 2.00-2.22(3H,m), 2.22-2.44(1H,m), 2.63-2.73(1H,m), 2.73-2.87(1H,m), 2.87-2.99(1H,m), 2.99-3.18(4H,m), 3.18-3.30(2H,m), 3.30-3.61(6H,m), 3.61-3.83(4H,m), 3.83-3.98(1H,m), 4.07-4.32(3H,m), 4.52(2H,s), 4.60(1H,d,J=5.6Hz), 6.89(1H,dd,J=9.0,9.0Hz), 6.97(1H,d,J=8.4Hz), 7.23-7.31(1H,m), 7.31-7.41(2H,m), 7.46-7.59(1H,m) MS: 615.30[M+H] + Example 7 NMR: 1.42(3H,t,J=7.0Hz), 1.50-1.67(1H,m), 1.67-1.86(3H,m), 1.86-2.00(1H,m), 2.00-2.24(3H,m), 2.24-2.41(1H,m), 2.65-2.77(1H,m), 2.77-2.86(1H,m), 2.86-2.98(1H,m), 2.98-3.19(4H,m), 3.19-3.31(2H,m), 3.31-3.49(4H,m), 3.49-3.69(3H,m), 3.69-3.83(3H,m), 3.83-3.99(1H,m), 4.06-4.33(3H,m), 4.52(2H,s), 4.60(1H,d,J=6.0Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.21-7.32(1H,m), 7.32-7.42(2H,m), 7.45-7.62(1H,m) MS: 615.30[M+H] +Example 8 NMR: 1.42 (3H, t, J = 7.0 Hz), 1.67-1.86 (2H, m), 1.98-2.17 (2H, m), 2.25-2.48 (1H, m), 2.99-3.24 (8H, m), 3.24-3.52 (9H, m), 3.52-3.83 (5H, m), 3.83-4.01 (1H, m), 4.01-4.27 (3H, m), 4.52 (2H, s), 4.60 (1H, d, J = 5.6 Hz), 6.89 (1H, dd, J = 8.8, 8.8 Hz), 6.97 (1H, d, J = 8.4 Hz), 7.25-7.34 (1H, m), 7.34-7.43(2H,m), 7.46-7.59(1H,m) MS:601.30[M+H] + Example 9 NMR: 1.42 (3H, t, J = 7.0 Hz), 1.63-1.85 (2H, m), 1.96-2.17 (3H, m), 2.17-2.41 (1H, m), 2.81-3.00 (4H, m), 3.00-3.18 (4H, m), 3.18-3.48 (5H, m), 3.48-3.84 (6H, m), 3.84-3.97 (4H, m), 4.06-4.33 (3H, m), 4.51 (2H, s), 4.59 (1H, d, J = 5.2 Hz), 6.89 (1H, dd, J = 9.0, 9.0 Hz), 6.97 (1H, d, J = 8.4 Hz), 7.28(1H,d,J=9.2Hz), 7.33-7.46(2H,m), 7.46-7.62(1H,m) MS:602.25[M+H] +Example 10 NMR: 1.42(3H,t,J=7.0Hz), 1.64-1.83(2H,m), 1.83-1.98(2H,m), 1.98-2.14(2H,m), 2.14-2.25(2H,m), 2.25-2.40(1H,m), 2.83(2H,t,J=11.6Hz), 2.91(6H,s), 3.00-3.25(7H,m), 3.25-3.47(5H,m), 3.47-3.71(3H,m), 3.71-3.92(3H,m), 4.11-4.31(3H,m), 4.52(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), 7.27(1H,d,J=8.4Hz), 7.31-7.40(2H,m), 7.46-7.58 (1H,m) MS: 643.35[M+H] + Example 11 NMR: 1.42(3H,t,J=7.0Hz), 1.67-1.87(2H,m), 1.98-2.18(2H,m), 2.24-2.43(1H,m), 2.87-3.04(2H,m), 3.04-3.32(10H,m), 3.32-3.50(4H,m), 3.50-3.70(5H,m), 3.70-3.85(3H,m), 3.85-3.99(1H,m), 4.12-4.34(3H,m), 4.52(2H,s), 4.60(1H,d,J=5.6Hz), 6.89(1H,dd,J=9.0,9.0Hz), 6.97(1H,d,J=8.4Hz), 7.25(1H,d,J=9.2Hz), 7.30-7.42(2H,m), 7.46-7.58(1H,m) MS: 627.35[M+H] +

[0170] Example 12 NMR: 1.42 (3H, t, J = 7.0 Hz), 1.62-1.88 (2H, m), 1.98-2.23 (2H, m), 2.23-2.46 (1H, m), 2.65 (3H, s), 3.00-3.27 (7H, m), 3.27-3.47 (4H, m), 3.47-3.67 (3H, m), 3.67-3.97 (4H, m), 3.97-4.09 (1H, m), 4.09-4.29 (3H, m), 4.52 (2H, s), 4.60 (1H, d, J = 6.4 Hz), 6.89 (1H, dd, J = 8.8, 8.8 Hz), 6.97(1H,d,J=8.4Hz), 7.28-7.43(3H,m), 7.47-7.60(1H,m) MS:589.35[M+H] + Example 13 NMR: 1.42 (3H, t, J = 7.0 Hz), 1.64-1.87 (3H, m), 1.87-2.18 (4H, m), 2.22-2.43 (2H, m), 2.76-2.97 (2H, m), 2.97-3.22 (5H, m), 3.22-3.44 (4H, m), 3.44-3.55 (2H, m), 3.55-3.71 (2H, m), 3.71-3.83 (3H, m), 3.83-4.00 (2H, m), 4.09-4.31 (3H, m), 4.52 (2H, s), 4.60 (1H, d, J = 6.0 Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.20-7.43(3H,m), 7.45-7.60(1H,m) MS:615.35[M+H] +Example 14 NMR: 1.42 (3H, t, J = 7.0 Hz), 1.64-1.89 (2H, m), 1.94-2.19 (6H, m), 2.24-2.42 (1H, m), 2.42-2.61 (1H, m), 2.98-3.25 (5H, m), 3.25-3.54 (7H, m), 3.54-3.72 (4H, m), 3.72-3.90 (3H, m), 4.12-4.28 (3H, m), 4.36-4.46 (1H, m), 4.52 (2H, s), 4.60 (1H, d, J = 6.0 Hz), 6.89 (1H, dd, J = 8.8, 8.8 Hz), 6.97(1H,d,J=8.8Hz), 7.29-7.46(3H,m), 7.46-7.59(1H,m) MS:643.35[M+H] + Example 15 NMR: 1.42 (3H, t, J = 7.0 Hz), 1.64-1.87 (2H, m), 1.97-2.13 (2H, m), 2.13-2.43 (5H, m), 2.92-3.07 (2H, m), 3.07-3.29 (7H, m), 3.29-3.47 (4H, m), 3.47-3.70 (3H, m), 3.70-3.95 (3H, m), 4.10-4.29 (5H, m), 4.52 (2H, s), 4.61 (1H, d, J = 5.2 Hz), 6.89 (1H, dd, J = 8.8, 8.8 Hz), 6.97 (1H, d, J = 8.8 Hz), 7.30-7.47(3H,m), 7.47-7.62(1H,m) MS:627.30[M+H] + Example 16 NMR: 1.42 (3H, t, J = 6.8 Hz), 1.64-1.94 (4H, m), 1.98-2.23 (4H, m), 2.23-2.40 (1H, m), 2.74-2.94 (2H, m), 2.94-3.21 (6H, m), 3.21-3.51 (6H, m), 3.51-3.70 (3H, m), 3.70-3.95 (3H, m), 4.12-4.32 (3H, m), 4.52 (2H, s), 4.59 (1H, d, J = 5.6 Hz), 6.89 (1H, dd, J = 9.0, 9.0 Hz), 6.97 (1H, d, J = 8.4 Hz), 7.27(1H,d,J=8.8Hz), 7.31-7.41(2H,m), 7.46-7.60(1H,m) MS:615.30[M+H] +Example 17 NMR: 1.42(3H,t,J=7.0Hz), 1.65-1.86(2H,m), 1.98-2.20(3H,m), 2.24-2.39(1H,m), 2.39-2.54(1H,m), 2.89-3.19(4H,m), 3.19-3.50(7H,m), 3.50-3.91(8H,m), 4.09-4.27(3H,m), 4.27-4.39(1H,m), 4.52(2H,s), 4.60(1H,d,J=5.6Hz), 6.80(1H,d,J=8.8Hz), 6.89(1H,dd,J=9.0,9.0Hz), 6.96(1H,d,J=8.4Hz), 7.21(1H,d,J=2.4Hz), 7.28(1H,dd,J=8.8,2.4Hz), 7.45-7.58(1H,m) MS: 601.25[M+H] + Example 18 NMR: 1.42(3H,t,J=7.0Hz), 1.48-1.67(2H,m), 1.67-1.85(2H,m), 1.85-2.19(5H,m), 2.23-2.41(1H,m), 2.78-2.97(2H,m), 3.01(2H,d,J=6.4Hz), 3.05-3.24(6H,m), 3.24-3.40(2H,m), 3.40-3.71(6H,m), 3.71-3.94(3H,m), 4.12-4.35(3H,m), 4.52(2H,s), 4.59(1H,d,J=6.0Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.8Hz), 7.27-7.43(3H,m), 7.47-7.61(1H,m) MS: 629.30[M+H] +Example 19 NMR: 1.42(3H,t,J=7.0Hz), 1.64-1.85(2H,m), 1.97-2.20(3H,m), 2.25-2.39(1H,m), 2.39-2.56(1H,m), 2.90-3.06(2H,m), 3.06-3.19(2H,m), 3.19-3.51(7H,m), 3.51-3.61(2H,m), 3.61-3.94(6H,m), 4.12-4.28(3H,m), 4.28-4.38(1H,m), 4.52(2H,s), 4.60(1H,d,J=5.6Hz), 6.80(1H,d,J=8.8Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.21(1H,d,J=2.4Hz), 7.28(1H,dd,J=8.8,2.4Hz), 7.46-7.60(1H,m) MS: 601.25[M+H] + Example 20 NMR: 1.41(3H,t,J=7.0Hz), 1.62-1.84(2H,m), 1.93-2.12(2H,m), 2.20-2.41(1H,m), 2.93-3.17(4H,m), 3.17-3.35(3H,m), 3.35-3.60(4H,m), 3.60-3.75(3H,m), 3.75-3.95(1H,m), 3.95-4,15(1H,m), 4.20(2H,q,J=6.9Hz), 4.50(2H,s), 4.57(1H,d,J=6.0Hz), 6.77-7.06(4H,m), 7.35(1H,d,J=8.4Hz), 7.42-7.64(3H,m), 8.12(2H,d,J=7.6Hz) MS: 609.25[M+H] +Example 21 NMR: 1.41 (3H, t, J = 7.0 Hz), 1.57-1.77 (2H, m), 1.90-2.05 (2H, m), 2.17-2.31 (1H, m), 2.84-3.23 (4H, m), 3.23-3.41 (3H, m), 3.41-3.69 (5H, m), 3.69-3.90 (3H, m), 3.90-4.14 (2H, m), 4.20 (2H, q, J = 6.9 Hz), 4.50 (2H, s), 4.55 (1H, d, J = 6.0 Hz), 6.82-6.93 (2H, m), 6.96 (1H, d, J = 8.4 Hz), 7.33(1H,d,J=8.4Hz), 7.37-7.60(3H,m), 8.35(2H,d,J=4.8Hz) MS:610.25[M+H] + , 608.30[MH] -

[0171] Example 22 NMR: 1.42 (3H, t, J = 7.0 Hz), 1.64-1.91 (3H, m), 1.98-2.15 (2H, m), 2.22-2.43 (2H, m), 2.67-2.83 (1H, m), 2.97-3.26 (8H, m), 3.26-3.55 (8H, m), 3.55-3.69 (2H, m), 3.69-3.91 (3H, m), 4.04-4.35 (3H, m), 4.52 (2H, s), 4.60 (1H, d, J = 5.6 Hz), 6.89 (1H, dd, J = 8.8, 8.8 Hz), 6.97 (1H, d, J = 8.8 Hz), 7.26(1H,d,J=8.8Hz), 7.31-7.43(2H,m), 7.46-7.61(2H,d,J=4.8Hz) MS:615.30[M+H] +Example 23 NMR: 1.42 (3H, t, J = 7.0 Hz), 1.67-1.97 (3H, m), 1.97-2.20 (2H, m), 2.26-2.48 (2H, m), 2.69-2.89 (1H, m), 3.01-3.32 (8H, m), 3.32-3.53 (6H, m), 3.53-3.70 (3H, m), 3.70-3.96 (4H, m), 4.09-4.35 (3H, m), 4.52 (2H, s), 4.60 (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=8.8Hz), 7.33-7.42(2H,m), 7.47-7.57(1H,m) MS:615.30[M+H] + Example 24 NMR: 1.42 (3H, t, J = 7.0 Hz), 1.63-1.86 (2H, m), 1.98-2.16 (2H, m), 2.23-2.42 (1H, m), 2.64-2.79 (1H, m), 2.84-3.05 (3H, m), 3.05-3.35 (7H, m), 3.35-3.51 (3H, m), 3.51-3.83 (5H, m), 3.83-3.99 (2H, m), 3.99-4.13 (3H, m), 4.13-4.36 (3H, m), 4.52 (2H, s), 4.60 (1H, d, J = 5.6 Hz), 6.89(1H,dd,J=9.0,9.0Hz), 6.97(1H,d,J=8.4Hz), 7.21-7.32(1H,m), 7.32-7.41(2H,m), 7.46-7.58(1H,m) MS: 631.25[M+H] +Example 25 NMR: 1.42(3H,t,J=7.0Hz), 1.67-1.85(2H,m), 1.97-2.15(2H,m), 2.24-2.45(1H,m), 2.62-2.78(1H,m), 2.78-3.02(3H,m), 3.02-3.25(7H,m), 3.25-3.49(4H,m), 3.49-3.81(5H,m), 3.81-3.97(2H,m), 3.97-4.14(2H,m), 4,14-4.30(3H,m), 4.52(2H,s), 4.59(1H,d,J=5.6Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.23-7.32(1H,m), 7.35-7.47(2H,m), 7.47-7.60(1H,m) MS: 631.30[M+H] + Example 26 NMR: 1.42(3H,t,J=7.0Hz), 1.66-1.89(3H,m), 1.97-2.19(4H,m), 2.19-2.45(2H,m), 2.92-3.07(2H,m), 3.07-3.28(3H,m), 3.28-3.44(6H,m), 3.44-3.58(3H,m), 3.58-3.71(1H,m), 3.71-3.84(3H,m), 3.84-4.02(2H,m), 4,09-4.35(3H,m), 4.52(2H,s), 4.60(1H,d,J=6.4Hz), 6.80(1H,d,J=8.8Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.20(1H,d,J=2.4Hz), 7.27(1H,dd,J=8.8,2.4Hz), 7.46-7.61(1H,m) MS: 615.30[M+H] +Example 27 NMR: 1.41(3H,t,J=7.2Hz), 1.62-1.82(2H,m), 1.94-2.12(2H,m), 2.20-2.38(1H,m), 2.91-3.16(4H,m), 3.16-3.62(7H,m), 3.62-3.74(3H,m), 3.74-4.09(2H,m), 4.20(2H,q,J=7.2Hz), 4.51(2H,s), 4.57(1H,d,J=5.6Hz), 6.88(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.34(1H,d,J=8.4Hz), 7.45(1H,dd,J=8.8,2.4Hz), 7.48-7.59(2H,m), 7.70(1H,dd,J=8.8,5.6Hz), 7.83(1H,m), 8.04(1H,d,J=2.4Hz), 8.09(1H,d,J=5.2Hz) MS: 609.25[M+H] + , 607.15[M-H] - Example 28 NMR: 1.41(3H,t,J=7.2Hz), 1.63-1.89(2H,m), 1.93-2.18(2H,m), 2.22-2.44(1H,m), 2.94-3.19(4H,m), 3.19-3.41(4H,m), 3.41-3.62(3H,m), 3.62-3.76(3H,m), 3.76-3.94(1H,m), 4.09-4.28(3H,m), 4.51(2H,s), 4.58(1H,d,J=6.0Hz), 6.88(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.08(1H,dd,J=6.4,6.4Hz), 7.15(1H,d,J=8.8Hz), 7.41(2H,d,J=8.8Hz), 7.46-7.67(3H,m), 7.84(1H,d,J=6.4Hz), 8.05(1H,ddd,J=9.2,7.2,1.6Hz) MS: 609.25[M+H] + , 607.10[M-H] -Example 29 NMR: 1.42(3H,t,J=7.0Hz), 1.67-1.86(3H,m), 1.86-2.21(4H,m), 2.21-2.43(2H,m), 2.78-2.96(2H,m), 2.96-3.06(1H,m), 3.06-3.21(4H,m), 3.21-3.44(4H,m), 3.44-3.67(4H,m), 3.67-4.04(5H,m), 4.12-4.30(3H,m), 4.52(2H,s), 4.60(1H,d,J=6.4Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.22-7.42(3H,m), 7.46-7.58(1H,m) MS: 615.30[M+H] + Example 30 NMR: 1.42(3H,t,J=6.8Hz), 1.64-1.89(3H,m), 1.97-2.19(4H,m), 2.19-2.47(2H,m), 2.85-3.06(2H,m), 3.06-3.22(2H,m), 3.22-3.59(10H,m), 3.59-3.84(4H,m), 3.84-4.02(2H,m), 4.06-4.36(3H,m), 4.52(2H,s), 4.56-4.65(1H,m), 6.80(1H,d,J=8.8Hz), 6.89(1H,dd,J=9.0,9.0Hz), 6.97(1H,d,J=8.4Hz), 7.14-7.24(1H,m), 7.26(1H,dd,J=8.8,2.6Hz), 7.43-7.63(1H,m) MS: 615.30[M+H] +Example 31 NMR: 1.41(3H,t,J=7.0Hz), 1.58-1.82(2H,m), 1.92-2.11(2H,m), 2.18-2.40(1H,m), 2.85-3.15(4H,m), 3.15-3.53(6H,m), 3.53-3.93(5H,m), 4.04-4.33(3H,m), 4.51(2H,s), 4.56(1H,d,J=5.6Hz), 6.88(1H,dd,J=9.0,9.0Hz), 6.96(1H,d,J=8.8Hz), 7.34(1H,d,J=8.4Hz), 7.43(1H,dd,J=8.8,2.4Hz), 7.46-7.61(2H,m), 7.92(1H,d,J=3.2Hz), 8.01(1H,dd,J=2.8,1.2Hz), 8.20(1H,d,J=1.2Hz) MS: 610.25[M+H] + , 608.15[M-H] -

[0172] Example 32 NMR: 1.42(3H,t,J=7.0Hz), 1.65-1.86(2H,m), 1.97-2.18(2H,m), 2.24-2.41(1H,m), 2.92-3.06(2H,m), 3.06-3.20(2H,m), 3.20-3.30(3H,m), 3.30-3.47(4H,m), 3.47-3.59(3H,m), 3.59-3.72(2H,m), 3.72-3.93(3H,m), 4.09-4.32(3H,m), 4.52(2H,s), 4.60(1H,d,J=6.4Hz), 6.79(1H,d,J=8.8Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.8Hz), 7.19(1H,d,J=2.4Hz), 7.27(1H,dd,J=8.6,2.6Hz), 7.45-7.59(1H,m) MS: 575.35[M+H] +Example 33 NMR: 1.41 (3H, t, J = 7.0 Hz), 1.61 - 1.81 (2H, m), 1.92 - 2.07 (2H, m), 2.16 - 2.36 (1H, m), 2.86 - 3.14 (4H, m), 3.14 - 3.43 (4H, m), 3.43 - 3.57 (2H, m), 3.57 - 3.72 (3H, m), 3.72 - 3.92 (2H, m), 4.08 - 4.28 (3H, m), 4.51 (2H, s), 4.56 (1H, d, J = 6.0 Hz), 6.67 - 6.76 (1H, m), 6.77 - 6.84 (1H, m), 6.84 - 6.93 (2H, m), 6.96 (1H, d, J = 8.8 Hz), 7.27 (1H, d, J = 8.4 Hz), 7.31 - 7.41 (2H, m), 7.41 - 7.47 (1H, m), 7.47 - 7.58 (1H, m) MS: 623.35 [M + H] + , 621.00 [M - H] - Example 34 NMR: 1.42 (3H, t, J = 7.0 Hz), 1.66 - 1.96 (4H, m), 1.98 - 2.24 (4H, m), 2.24 - 2.44 (3H, m), 2.95 - 3.22 (4H, m), 3.22 - 3.53 (5H, m), 3.53 - 3.84 (5H, m), 3.53 - 3.84 (5H, m), 3.84 - 3.97 (1H, m), 4.02 (1H, quin, J = 8.0 Hz), 4.11 - 4.34 (3H, m), 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 = 8.4 Hz), 7.07 - 7.22 (1H, m), 7.32 - 7.45 (2H, m), 7.45 - 7.60 (1H, m) MS: 586.35 [M + H] +Example 35 NMR: 0.38 - 0.63(2H, m), 0.71 - 0.94(2H, m), 1.42(3H, t, J = 7.0Hz), 1.61 - 1.84(1H, m), 1.84 - 2.00(1H, m), 2.00 - 2.23(1H, m), 2.23 - 2.41(1H, m), 2.41 - 2.57(1H, m), 2.87 - 3.01(2H, m), 3.01 - 3.18(2H, m), 3.18 - 3.50(5H, m), 3.50 - 3.80(5H, m), 3.80 - 4.02(2H, m), 4.08 - 4.39(3H, m), 4.51(2H, s), 4.59(1H, d, J = 5.2Hz), 6.88(1H, dd, J = 8.8, 8.8Hz), 6.97(1H, d, J = 8.8Hz), 7.12 - 7.23(1H, m), 7.23 - 7.38(2H, m), 7.44 - 7.62(1H, m) MS: 572.30[M + H] + Example 36 NMR: 1.42(3H, t, J = 7.0Hz), 1.62 - 1.86(2H, m), 1.86 - 2.01(1H, m), 2.01 - 2.25(2H, m), 2.25 - 2.40(1H, m), 2.40 - 2.58(2H, m), 2.58 - 2.74(2H, m), 2.93 - 3.07(2H, m), 3.07 - 3.32(4H, m), 3.32 - 3.48(3H, m), 3.48 - 3.59(1H, m), 3.59 - 3.71(2H, m), 3.71 - 3.83(2H, m), 3.83 - 4.10(2H, m), 4.10 - 4.35(3H, m), 4.52(2H, s), 4.56 - 4.69(1H, m), 6.60(1H, d, J = 8.8Hz), 6.88(1H, dd, J = 8.8, 8.8Hz), 6.96(1H, d, J = 8.4Hz), 7.22(1H, dd, J = 11.2, 2.4Hz), 7.26(1H, d, J = 2.4Hz), 7.43 - 7.63(1H, m) MS: 601.30[M + H] +Example 37 NMR: 1.07 - 1.38 (5H, m), 1.42 (3H, t, J = 7.0 Hz), 1.56 - 1.69 (1H, m), 1.69 - 1.90 (4H, m), 1.93 - 2.19 (4H, m), 2.19 - 2.44 (1H, m), 2.93 - 3.08 (2H, m), 3.08 - 3.25 (2H, m), 3.25 - 3.47 (5H, m), 3.47 - 3.64 (3H, m), 3.64 - 3.81 (2H, m), 3.81 - 3.89 (1H, m), 3.89 - 4.12 (1H, m), 4.12 - 4.31 (3H, m), 4.51 (2H, s), 4.59 (1H, d, J = 6.0 Hz), 6.88 (1H, dd, J = 9.0, 9.0 Hz), 6.97 (1H, d, J = 8.4 Hz), 7.02 (1H, d, J = 8.8 Hz) 7.27 (1H, d, J = 2.4 Hz), 7.30 (1H, dd, J = 8.8, 2.4 Hz), 7.52 (1H, dd, J = 15.4, 8.6 Hz) MS: 614.35 [M + H] + Example 38 NMR: 1.26 - 1.53 (5H, m), 1.64 - 1.88 (4H, m), 1.88 - 2.16 (3H, m), 2.22 - 2.45 (1H, m), 2.91 - 3.04 (2H, m), 3.04 - 3.20 (4H, m), 3.21 - 3.40 (3H, m), 3.40 - 3.50 (3H, m), 3.50 - 3.67 (3H, m), 3.67 - 3.83 (3H, m), 3.83 - 4.05 (3H, m), 4.12 - 4.32 (3H, m), 4.51 (2H, s), 4.59 (1H, d, J = 6.0 Hz), 6.80 - 6.93 (2H, m), 6.97 (1H, d, J = 8.8 Hz), 7.19 (1H, d, J = 2.0 Hz) 7.26 (1H, dd, J = 8.8, 2.4 Hz), 7.52 (1H, ddd, J = 8.5, 8.5, 7.1 Hz) MS: 630.35 [M + H] +Example 39 NMR: 1.42 (3H, t, J = 7.0 Hz), 1.64-1.87 (2H, m), 1.94-2.11 (2H, m), 2.24-2.40 (1H, m), 2.44-2.62 (1H, m), 2.84-3.02 (6H, m), 3.02-3.34 (7H, m), 3.34-3.63 (7H, m), 3.63-3.82 (3H, m), 3.82-3.97 (1H, m), 3.97-4.12 (2H, m), 4.12-4.33 (3H, m), 4.49 (2H, s), 4.58 (1H, d, J = 6.0 Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.17-7.28(1H,m) 7.28-7.40(2H,m), 7.52(1H,ddd,J=8.5,8.5,6.9Hz) MS: 629.35[M+H] + Example 40 NMR: 1.42 (3H, t, J = 7.0 Hz), 1.63-1.87 (2H, m), 1.97-2.17 (2H, m), 2.22-2.42 (1H, m), 2.91-3.06 (3H, m), 3.06-3.30 (4H, m), 3.30-3.42 (5H, m), 3.42-3.48 (2H, m), 3.48-3.67 (3H, m), 3.67-3.79 (2H, m), 3.79-3.92 (2H, m), 3.92-4.15 (3H, m), 4.15-4.29 (3H, m), 4.51 (2H, s), 4.60(1H,d,J=6.0Hz), 6.82(1H,d,J=8.4Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.19(1H,d,J=2.4Hz), 7.26(1H,dd,J=8.8,2.4Hz), 7.52(1H,ddd,J=8.4,8.4,7.2Hz) MS:631.35[M+H] +Example 41 NMR: 1.42(3H,t,J=7.0Hz), 1.66-1.90(2H,m), 1.94-2.17(2H,m), 2.22-2.41(1H,m), 2.99-3.28(5H,m), 3.28-3.62(7H,m), 3.62-3.85(3H,m), 3.85-3.99(1H,m), 3.99-4.14(1H,m), 4.14-4.33(3H,m), 4.51(2H,s), 4.60(1H,d,J=6.0Hz), 6.46(1H,d,J=8.8Hz), 6.89(1H,d,J=8.8,8.8Hz), 6.97(1H,d,J=8.8Hz), 7.11(1H,dd,J=8.8,2.4Hz), 7.22(1H,d,J=2.4Hz), 7.43-7.58(1H,m), 7.79(1H,dd,J=6.8,6.8Hz), 7.87(1H,d,J=8.0Hz), 8.35(1H,ddd,J=7.9,7.9,1.5Hz), 8.62(1H,dd,J=5.6,0.8Hz) MS: 623.30[M+H] +

[0173] Example 42 NMR: 1.42(3H,t,J=7.0Hz), 1.65-1.87(2H,m), 1.97-2.16(2H,m), 2.21-2.40(1H,m), 2.77-2.97(4H,m), 2.97-3.22(4H,m), 3.22-3.44(4H,m), 3.44-3.80(6H,m), 3.83(4H,t,J=4.6Hz), 3.87-3.98(1H,m), 3.98-4.15(1H,m), 4.20(2H,q,J=7.1Hz), 4.51(2H,s), 4.59(1H,d,J=6.0Hz), 6.88(1H,dd,J=8.6,8.6Hz), 6.97(1H,d,J=8.8Hz), 7.13-7.33(3H,m), 7.52(1H,ddd,J=8.4,8.4,7.2Hz) MS: 617.35[M+H] +Example 43 NMR: 1.42(3H,t,J=7.0Hz), 1.61-1.87(2H,m), 1.87-2.18(6H,m), 2.18-2.35(1H,m), 2.93-3.03(2H,m), 3.03-3.21(3H,m), 3.21-3.32(2H,m), 3.32-3.44(5H,m), 3.47(2H,t,J=6.4Hz), 3.60(2H,t,J=6.2Hz), 3.63-3.92(6H,m), 3.92-4.03(1H,m), 4.03-4.15(1H,m), 4.20(2H,q,J=7.1Hz), 4.37(2H,s), 4.49(1H,d,J=6.4Hz), 6.79(1H,d,J=8.8Hz), 6.88(1H,dd,J=8.8,8.8Hz), 6.96(1H,d,J=8.4Hz), 7.20(1H,d,J=2.4Hz), 7.28(1H,dd,J=8.8,2.4Hz), 7.43-7.57(1H,m) MS: 629.35[M+H] + Example 44 NMR: 1.42(3H,t,J=7.0Hz), 1.65-1.91(2H,m), 1.93-2.17(2H,m), 2.22-2.41(1H,m), 2.96-3.24(4H,m), 3.24-3.45(4H,m), 3.45-3.62(4H,m), 3.62-3.81(4H,m), 3.81-3.99(3H,m), 3.99-4.14(1H,m), 4.21(2H,q,J=6.9Hz), 4.40-4.57(3H,m), 4.69(1H,d,J=6.0Hz), 5.33-5.57(1H,m), 6.83-6.94(2H,m), 6.97(1H,d,J=8.4Hz), 7.24(1H,d,J=2.4Hz), 7.29(1H,dd,J=8.8,2.4Hz), 7.46-7.59(1H,m) MS: 619.30[M+H] +Example 45 NMR: 1.42(3H,t,J=7.0Hz), 1.65-1.92(2H,m), 1.97-2.16(2H,m), 2.21-2.42(1H,m), 2.76(3H,s), 2.92-3.06(2H,m), 3.06-3.23(2H,m), 3.23-3.34(2H,m), 3.34-3.45(3H,m), 3.45-3.71(6H,m), 3.71-3.84(3H,m), 3.84-3.99(1H,m), 3.99-4.16(1H,m), 4.21(2H,q,J=7.1Hz), 4.51(2H,s), 4.60(1H,d,J=6.0Hz), 6.78(1H,d,J=8.8Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.8Hz), 7.19(1H,d,J=2.4Hz), 7.26(1H,dd,J=8.6,2.6Hz), 7.52(1H,ddd,J=8.4,8.4,7.2Hz) MS: 589.35[M+H] + Example 46 NMR: 1.42(3H,t,J=7.0Hz), 1.65-1.90(2H,m), 1.95-2.15(2H,m), 2.22-2.45(1H,m), 2.91-3.06(3H,m), 3.06-3.17(2H,m), 3.17-3.42(7H,m), 3.42-3.64(5H,m), 3.64-3.89(4H,m), 3.89-3.99(1H,m), 3.99-4.11(2H,m), 4.11-4.24(3H,m), 4.51(2H,s), 4.59(1H,d,J=6.0Hz), 6.82(1H,d,J=8.8Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.19(1H,d,J=2.4Hz), 7.26(1H,dd,J=8.8,2.4Hz), 7.52(1H,ddd,J=8.4,8.4,8.4Hz) MS: 631.30[M+H] +Example 47 NMR: 1.42(3H,t,J=7.0Hz), 1.65-1.90(2H,m), 1.96-2.20(2H,m), 2.23-2.42(1H,m), 2.94-3.06(2H,m), 3.06-3.22(2H,m), 3.22-3.43(5H,m), 3.43-3.50(4H,m), 3.50-3.68(6H,m), 3.68-3.82(3H,m), 3.82-4.14(5H,m), 4.14-4.30(3H,m), 4.51(2H,s), 4.60(1H,d,J=6.0Hz), 6.79(1H,d,J=8.8Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.8Hz), 7.20(1H,d,J=2.8Hz), 7.27(1H,dd,J=8.8,2.4Hz), 7.52(1H,ddd,J=8.4,8.4,6.8Hz) MS: 645.35[M+H] + Example 48 NMR: 1.42(3H,t,J=7.0Hz), 1.67-1.88(2H,m), 1.99-2.17(2H,m), 2.25-2.43(1H,m), 3.00-3.25(4H,m), 3.25-3.49(4H,m), 3.49-3.70(3H,m), 3.70-3.86(3H,m), 3.86-4.01(1H,m), 4.01-4.17(1H,m), 4.20(2H,q,J=7.0Hz), 4.52(2H,s), 4.61(1H,d,J=6.0Hz), 4.70(2H,s), 6.49(1H,d,J=8.8Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), \7.11(1H,dd,J=8.4,2.4Hz), 7.21(1H,d,J=2.4Hz), 7.52(1H,ddd,J=8.4,8.4,7.2Hz), 8.00(1H,dd,J=8.8,6.6Hz), 8.54(1H,d,J=8.4Hz), 8.67(1H,d,J=6.0Hz), 8.70(1H,d,J=0.8Hz) MS: 623.30[M+H] +Example 49 NMR: 1.42(3H,t,J=7.0Hz), 1.68-1.92(2H,m), 1.99-2.18(2H,m), 2.24-2.45(1H,m), 3.04-3.28(4H,m), 3.28-3.72(7H,m), 3.72-3.86(2H,m), 3.86-3.99(1H,m), 3.99-4.12(1H,m), 4.12-4.30(3H,m), 4.50(2H,s), 4.60(1H,d,J=6.0Hz), 4.76-4.79(2H,m), 6.38(1H,d,J=8.8Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.8Hz), 7.09(1H,dd,J=8.8,2.4Hz), 7.23(1H,d,J=2.8Hz), 7.48-7.57(1H,m), 7.94(2H,d,J=6.4Hz),8.64(2H,d,J=6.8Hz) MS: 623.30[M+H] + Example 50 NMR: 1.42(3H,t,J=7.0Hz), 1.65-1.87(2H,m), 1.96-2.14(2H,m), 2.19-2.36(1H,m), 2.36-2.60(1H,m), 2.74-2.92(1H,m), 2.92-3.06(2H,m), 3.06-3.21(2H,m), 3.23-3.48(5H,m), 3.48-3.67(3H,m), 3.67-3.80(4H,m,), 3.80-3.95(2H,m), 3.95-4.06(1H,m), 4.06-4.16(1H,m), 4.16-4.30(3H,m), 4.42(2H,s), 4.52(1H,d,J=6.0Hz), 6.80(1H,d,J=8.8Hz), 6.96(1H,d,J=8.8Hz), 7.21(1H,d,J=2.4Hz), 7.27(1H,dd,J=8.8,2.4Hz), 7.44-7.56(1H,m) MS: 651.30[M+H] +Example 51 NMR: 1.42(3H,t,J=7.0Hz), 1.65-1.90(2H,m), 1.98-2.18(2H,m), 2.24-2.46(1H,m), 2.95-3.06(2H,m), 3.06-3.20(2H,m), 3.20-3.48(6H,m), 3.48-3.56(3H,m), 3.56-3.81(6H,m), 3.81-4.03(3H,m), 4.03-4.10(1H,m), 4.10-4.31(4H,m), 4.52(2H,s), 4.61(1H,d,J=6.0Hz), 6.77(1H,d,J=8.8Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.19(1H,d,J=2.4Hz), 7.26(1H,dd,J=8.8,2.6Hz), 7.52(1H,ddd,J=8.4,8.4,7.2Hz) MS: 631.35[M+H] +

[0174] Example 52 NMR: 1.42(3H,t,J=7.0Hz), 1.47(3H,s), 1.66-1.87(2H,m), 1.90-2.00(1H,m), 2.00-2.04(5H,m), 2.04-2.37(1H,m), 3.00-3.08(2H,m), 3.08-3.23(2H,m), 3.03-3.59(10H,m), 3.59-3.82(3H,m), 3.82-3.97(1H,m,), 3.97-4.10(1H,m), 4.10-4.29(3H,m), 4.47(2H,s), 4.57(1H,d,J=6.0Hz), 6.83-6.93(2H,m), 6.97(1H,d,J=8.4Hz), 7.20(1H,d,J=2.4Hz), 7.26(1H,dd,J=8.8,2.4Hz), 7.45-7.58(1H,m) MS: 629.35[M+H] +Example 53 NMR: 1.42(3H,t,J=7.0Hz), 1.66 - 1.89(2H,m), 1.98 - 2.18(3H,m), 2.23 - 2.37(1H,m), 2.55 - 2.70(1H,m), 2.96 - 3.07(2H,m), 3.07 - 3.22(2H,m), 3.30 - 3.43(3H,m), 3.43 - 3.54(3H,m), 3.54 - 3.67(3H,m), 3.67 - 3.82(4H,m), 3.82 - 3.97(1H,m), 3.97 - 4.11(1H,m), 4.11 - 4.32(4H,m), 4.48(2H,s), 4.57(1H,d,J=6.0Hz), 5.44 - 5.62(1H,m), 6.82(1H,d,J=8.8Hz), 6.89(1H,dd,J=9.0,9.0Hz), 6.97(1H,d,J=8.4Hz), 7.21(1H,d,J=2.4Hz), 7.27(1H,dd,J=8.4,2.6Hz), 7.52(1H,ddd,J=8.4,8.4,7.2Hz) MS: 633.35[M+H]<XXX>Example 54 NMR: 1.42(3H,t,J=7.0Hz), 1.67 - 1.88(2H,m), 1.98 - 2.16(2H,m), 2.18 - 2.40(2H,m), 2.53 - 2.74(1H,m), 2.93 - 3.07(2H,m), 3.07 - 3.21(2H,m), 3.28 - 3.66(10H,m), 3.66 - 3.85(4H,m), 3.85 - 3.97(1H,m), 3.97 - 4.10(1H,m,), 4.10 - 4.26(4H,m), 4.47(2H,s), 4.57(1H,d,J=6.0Hz), 5.43 - 5.65(1H,m), 6.82(1H,d,J=8.8Hz), 6.89(1H,dd,J=9.0,9.0Hz), 6.97(1H,d,J=8.4Hz), 7.21(1H,d,J=2.8Hz), 7.27(IN,dd,J=8.8,2.4Hz), 7.46 - 7.57(1H,m) MS: 633.XX[M+H]<XXX> Note: The "<XXX>" in the translation is because the original " + " and " + " seem to be some kind of specific identifiers without clear indication of what they should be exactly translated to. If there is more context available, a more accurate translation could be provided for those parts.Example 55 NMR: 1.42 (3H, t, J = 7.0 Hz), 1.65-1.89 (2H, m), 1.95-2.18 (3H, m), 2.23-2.39 (1H, m), 2.41-2.57 (1H, m), 2.77 (3H, s), 3.01-3.33 (7H, m), 3.33-3.66 (8H, m), 3.66-3.99 (5H, m), 3.99-4.14 (1H, m), 4.20 (2H, q, J = 7.0 Hz), 4.51 (2H, s), 4.59 (1H, d, J = 6.0 Hz), 6.88 (1H, d, J = 9.0 Hz), 6.97(1H,d,J=8.4Hz), 7.16-7.26(1H,m), 7.26-7.39(2H,m), 7.52(1H,ddd,J=8.4,8.4,7.2Hz) MS: 615.35[M+H] + Example 56 NMR: 1.42 (3H, t, J = 7.0 Hz), 1.67-1.86 (2H, m), 1.99-2.14 (2H, m), 2.22-2.39 (1H, m), 2.93-3.05 (2H, m), 3.05-3.20 (2H, m), 3.26-3.44 (6H, m), 3.44-3.57 (5H, m), 3.57-3.81 (5H, m), 3.81-3.96 (2H, m), 3.96-4.11 (2H, m), 4.11-4.25 (3H, m), 4.46 (2H, s), 4.56 (1H, d, J = 6.0 Hz), 6.77(1H,d,J=8.8Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.20(1H,d,J=2.8Hz), 7.27(1H,dd,J=8.8,2.6Hz), 7.47-7.56(1H,m) MS:631.30[M+H] +Example 57 NMR: 1.32 - 1.50 (9H, m), 1.66 - 1.90 (2H, m), 1.98 - 2.17 (2H, m), 2.24 - 2.42 (1H, m), 2.95 - 3.08 (2H, m), 3.08 - 3.27 (2H, m), 3.27 - 3.59 (8H, m), 3.59 - 3.84 (3H, m), 3.84 - 3.98 (1H, m), 3.98 - 4.12 (1H, m), 4.12 - 4.34 (3H, m), 4.49 (2H, s), 4.58 (1H, d, J = 6.0Hz), 6.81 - 6.93 (2H, m), 6.97 (1H, d, J = 8.8Hz), 7.19 (1H, d, J = 2.8Hz), 7.25 (1H, dd, J = 8.8, 2.8Hz), 7.46 - 7.58 (1H, m) MS: 603.30 [M + H] + Example 58 NMR: 1.42 (3H, t, J = 7.0Hz), 1.66 - 1.90 (2H, m), 1.95 - 2.13 (2H, m), 2.18 - 2.43 (3H, m), 2.93 - 3.07 (2H, m), 3.07 - 3.25 (2H, m), 3.25 - 3.42 (4H, m), 3.43 (3H, s), 3.45 - 3.58 (3H, m), 3.58 - 3.83 (6H, m), 3.83 - 3.97 (1H, m), 3.97 - 4.11 (1H, m), 4.11 - 4.28 (4H, m), 4.30 - 4.43 (1H, m), 4.48 (2H, s), 4.58 (1H, d, J = 6.0Hz), 6.77 (1H, d, J = 8.8Hz), 6.89 (1H, dd, J = 8.8, 8.8Hz), 6.97 (1H, d, J = 8.8Hz), 7.17 - 7.24 (1H, m), 7.28 (1H, dd, J = 8.8, 2.4Hz), 7.44 - 7.58 (1H, m) MS: 645.35 [M + H] +Example 59 NMR: 1.42(3H,t,J=7.0Hz), 1.64-1.88(2H,m), 1.91-2.18(4H,m), 2.21-2.42(1H,m), 2.90-3.05(2H,m), 3.05-3.22(4H,m), 3.27(2H,t,7.2Hz), 3.31-3.42(3H,m), 3.42-3.58(3H,m), 3.58-3.82(3H,m), 3.82-3.97(1H,m), 3.97-4.10(1H,m), 4.10-4.29(3H,m), 4.47(2H,s), 4.57(1H,d,J=6.0Hz), 6.82(1H,d,J=8.8Hz), 6.89(1H,dd,J=8.8,8.8Hz) 6.97(1H,d,J=8.4Hz), 7.19(1H,d,J=2.4Hz), 7.27(1H,dd,J=8.8,2.4Hz), 7.44-7.59(1H,m) MS: 589.30[M+H] + Example 60 NMR: 1.42(3H,t,J=7.0Hz), 1.61-1.90(6H,m), 1.96-2.16(2H,m), 2.21-2.41(1H,m), 2.90-3.06(4H,m), 3.06-3.17(2H,m), 3.20(2H,t,J=7.0Hz), 3.26-3.42(3H,m), 3.42-3.64(4H,m), 3.64-3.83(2H,m), 3.83-3.97(1H,m), 3.97-4.11(1H,m), 4.11-4.31(3H,m), 4.49(2H,s), 4.58(1H,d,J=6.4Hz), 6.84(1H,d,J=8.8Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.19(1H,d,J=2.4Hz),7.26(1H,dd,J=8.8,2.4Hz), 7.45-7.59(1H,m) MS: 603.30[M+H] +Example 61 NMR: 1.41 (3H, t, J = 7.0 Hz), 1.58-1.79 (2H, m), 1.90-2.06 (2H, m), 2.12-2.32 (1H, m), 2.89-3.21 (4H, m), 3.21-3.34 (3H, m), 3.34-3.50 (3H, m), 3.50-3.65 (2H, m), 3.65-3.76 (1H, m), 3.76-3.90 (1H, m), 3.90-4.03 (1H, m), 4.03-4.15 (1H, m), 4.19 (2H, q, J = 7.1 Hz), 4.40 (2H, s), 4.48(1H,d,J=6.0Hz), 6.77-6.84(1H,m) 6.88(1H,dd,J=8.8,8.8Hz), 6.96(1H,d,J=8.8Hz), 7.34(1H,d,J=8.4Hz), 7.46(1H,dd,J=8.6,2.2Hz), 7.48-7.54(2H,m), 8.17-8.29(1H,m), 8.48(1H,s) MS:610.25[M+H] + , 608.15[MH] -

[0175] Example 62 NMR: 1.41 (3H, t, J = 7.0 Hz), 1.59-1.80 (2H, m), 1.91-2.13 (2H, m), 2.18-2.37 (1H, m), 2.85-3.14 (4H, m), 3.14-3.44 (4H, m), 3.44-3.58 (3H, m), 3.58-3.78 (2H, m), 3.78-3.93 (1H, m), 3.93-4.09 (1H, m), 4.09-4.31 (3H, m), 4.49 (2H, s), 4.54 (1H, d, J = 6.0 Hz), 6.71 (1H, d, J = 8.8 Hz), 6.83-7.00(4H,m), 7.00-7.13(2H,m), 7.23(1H,dd,J=8.4,2.4Hz), 7.32(1H,d,J=2.4Hz), 7.47-7.58(1H,m) MS:623.30[M+H] +

[0176] Example 63 Anisole (0.17 mL) and a 5.1 mol / L hydrobromic acid / acetic acid solution (0.84 mL) were added to tert-butyl (R)-(2-((2-(2-(4-(1-(((benzyloxy)carbonyl)amino)-2-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)ethyl)carbamate (83 mg), and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (3.1 mL) and diethyl ether (3.1 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The solid was collected by filtration. The solid was washed with diethyl ether, then water was added and the mixture was lyophilized to give (R)-2-amino-2-(1-(2-((2-aminoethyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrobromide (85 mg) as a pale yellow solid. NMR: 1.29(3H,t,J=7.4Hz), 1.67-1.89(2H,m), 1.96-2.15(2H,m), 2.21-2.41(1H,m), 2.90-3.21(6H,m), 3.25(2H,t,J=6.2Hz), 3.29-3.43(3H,m), 3.43-3.59(5H,m), 3.60-3.82(3H,m), 3.82-3.95(1H,m), 3.95-4.08(1H,m), 4.08-4.29(1H,m), 4.51(2H,s), 4.59(1H,d,J=6.0Hz), 6.79(1H,d,J=8.8Hz), 7.11(1H,ddd,J=8.4,8.4,2.8Hz), 7.20(1H,d,J=2.4Hz), 7.27(1H,dd,J=8.6,2.6Hz), 7.36(1H,dd,J=9.6,2.4Hz), 7.54(1H,dd,J=8.6,5.8Hz) MS:591.30[M+H] +

[0177] The compounds shown in Table 17 were obtained in the same manner as in Example 63.

[0178] The NMR and MS measurement values ​​of the compounds in the table are shown. Example 64 NMR: 1.67-1.89 (3H, m), 2.00-2.17 (2H, m), 2.17-2.42 (2H, m), 2.55 (3H, s), 2.79 (1H, sep, J = 7.8 Hz), 2.93-3.23 (5H, m), 3.23-3.34 (3H, m), 3.34-3.49 (5H, m), 3.49-3.70 (4H, m), 3.70-3.88 (3H, m), 3.88-4.39 (2H, m), 4.60 (2H, s), 4.62 (1H, d, J = 6.0 Hz), 6.87 (1H, d, J = 8.8 Hz), 7.21(1H,d,J=2.4Hz), 7.27(1H,dd,J=8.8,2.4Hz), 7.31-7.42(1H,m), 7.47-7.63(3H,m) MS:599.25[M+H] + Example 65 NMR: 1.67-1.88 (2H, m), 1.89-2.15 (2H, m), 2.20-2.44 (1H, m), 2.55 (3H, s), 2.92-3.06 (2H, m), 2.92-3.06 (2H, m), 3.06-3.21 (2H, m), 3.25 (2H, t, J = 6.2 Hz), 3.30-3.47 (3H, m), 3.47-3.68 (6H, m), 3.68-3.83 (3H, m), 3.83-4.28 (2H, m), 4.59 (2H, s), 4.61 (1H, d, J = 6.0 Hz), 6.79 (1H, d, J = 8.4 Hz), 7.19(1H,d,J=2.4Hz), 7.26(1H,dd,J=8.8,2.4Hz) 7.31-7.41(1H,m), 7.47-7.61(3H,m) MS:559.25[M+H] +Example 66 NMR: 1.29 (3H, t, J = 7.4 Hz), 1.65 - 1.89 (3H, m), 1.99 - 2.14 (2H, m), 2.16 - 2.43 (2H, m), 2.77 (1H, sep, J = 7.7 Hz), 2.91 - 3.20 (7H, m), 3.20 - 3.40 (6H, m), 3.40 - 3.68 (6H, m), 3.68 - 3.82 (3H, m), 3.82 - 4.34 (2H, m), 4.58 (2H, s), 4.61 (1H, d, J = 6.0 Hz), 6.84 (1H, d, J = 8.8 Hz), 7.12 (1H, ddd, J = 8.4, 8.4, 2.8 Hz), 7.20 (1H, d, J = 2.4 Hz), 7.26 (1H, dd, J = 8.6, 2.6 Hz), 7.37 (1H, dd, J = 9.8, 2.6 Hz), 7.56 (1H, dd, J = 8.6, 5.8 Hz) MS: 631.30 [M + H] + Example 67 NMR: 1.64 - 1.92 (3H, m), 1.96 - 2.19 (4H, m), 2.19 - 2.41 (2H, m), 2.55 (3H, s) 2.92 - 3.06 (2H, m), 3.06 - 3.25 (2H, m), 3.25 - 3.63 (10H, m), 3.63 - 3.83 (3H, m), 3.83 - 4.28 (4H, m), 4.56 (2H, s), 4.60 (1H, d, J = 6.0 Hz), 6.80 (1H, d, J = 8.8 Hz), 7.20 (1H, d, J = 2.4 Hz), 7.26 (1H, dd, J = 8.8, 2.4 Hz), 7.31 - 7.40 (1H, m), 7.51 (1H, d, J = 7.6 Hz), 7.53 - 7.60 (2H, m) MS: 599.30 [M + H] +Example 68 NMR: 1.66 - 1.88 (2H, m), 1.97 - 2.18 (3H, m), 2.23 - 2.38 (1H, m), 2.40 - 2.51 (1H, m) 2.55 (3H, s), 2.97 - 3.06 (2H, m), 3.06 - 3.25 (2H, m), 3.30 (1H, dd, J = 12.4, 4.4 Hz), 3.33 - 3.42 (3H, m), 3.42 - 3.51 (4H, m), 3.51 - 3.60 (1H, m), 3.60 - 3.81 (4H, m), 3.81 - 3.94 (1H, m), 3.94 - 4.06 (1H, m), 4.06 - 4.28 (1H, m), 4.28 - 4.37 (1H, m), 4.51 (2H, s), 4.58 (1H, d, J = 6.0 Hz), 6.80 (1H, d, J = 8.8 Hz), 7.21 (1H, d, J = 2.4 Hz), 7.28 (1H, dd, J = 8.6, 2.6 Hz), 7.31 - 7.39 (1H, m), 7.50 (1H, d, J = 7.6 Hz), 7.52 - 7.59 (2H, m) MS: 585.30 [M + H] + Example 69 NMR: 1.29 (3H, t, J = 7.4 Hz), 1.66 - 1.90 (3H, m), 1.99 - 2.18 (4H, m), 2.18 - 2.44 (2H, m), 2.94 - 3.28 (6H, m), 3.28 - 3.44 (5H, m), 3.44 - 3.64 (6H, m), 3.64 - 3.82 (2H, m), 3.82 - 4.20 (4H, m), 4.56 (2H, s), 4.60 (1H, d, J = 6.0 Hz), 6.80 (1H, d, J = 8.8 Hz), 7.11 (1H, ddd, J = 8.5, 8.5, 2.7 Hz), 7.20 (1H, d, J = 2.4 Hz), 7.26 (1H, dd, J = 8.6, 2.4 Hz), 7.37 (1H, dd, J = 9.6, 2.8 Hz), 7.55 (1H, dd, J = 8.6, 2.2 Hz) MS: 631.30 [M + H] +Example 70 NMR: 1.29 (3H, t, J = 7.4 Hz), 1.65-1.90 (2H, m), 1.96-2.19 (3H, m), 2.23-2.38 (1H, m), 2.38-2.54 (1H, m), 2.93-3.23 (6H, m), 3.23-3.34 (1H, m), 3.34-3.42 (3H, m), 3.42-3.61 (5H, m), 3.61-3.82 (4H, m), 3.82-3.94 (1H, m), 3.94-4.07 (1H, m), 4.07-4.26 (1H, m), 4.28-4.38 (1H, m), 4.50(2H,s), 4.59(1H,d,J=6.0Hz), 6.80(1H,d,J=8.8Hz), 7.11(1H,ddd,J=8.4,8.4,2.4Hz), 7.21(1H,d,J=2.4Hz), 7.28(1H,dd,J=8.8,2.4Hz), 7.36(1H,dd,J=9.6,2.4Hz), 7.54(1H,dd,J=8.4,2.0Hz) MS:617.30[M+H] +

[0179] Implementation Example 71 Anisole (24 μL) and a 5.1 mol / L hydrobromic acid / acetic acid solution (0.12 mL) were added to benzyl (R)-(1-(1-(2-amino-5-chlorophenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (12 mg), and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (1 mL) and diethyl ether (1 mL) were added sequentially to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was centrifuged, and the supernatant was removed. Ethyl acetate (1 mL) and diethyl ether (1 mL) were added to the residue, and the mixture was centrifuged, and the supernatant was removed. Ethyl acetate (1 mL) and diethyl ether (1 mL) were added to the residue, followed by centrifugation. The supernatant was removed and the residue was dried under reduced pressure to give (R)-2-amino-2-(1-(2-amino-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrobromide (14.8 mg) as a white solid. NMR: 1.42(3H,t,J=7.0Hz), 1.64-1.89(2H,m), 1.94-2.16(2H,m), 2.24-2.41(1H,m), 2.91-3.04(2H,m), 3.04-3.23(2H,m), 3.23-3.67(7H,m), 3.67-3.82(2H,m), 3.82-3.97(1H,m), 3.97-4.13(1H,m), 4.13-4.29(3H,m), 4.51(2H,s), 4.59(1H,d,J=6.4Hz), 6.82-6.94(2H,m), 6.97(1H,d,J=8.4Hz), 7.13-7.23(2H,m), 7.45-7.58(1H,m) MS: 532.25[M+H] +

[0180] Example 72 Anisole (0.55 mL) and a 5.1 mol / L hydrobromic acid / acetic acid solution (2.7 mL) were added to benzyl (R)-(1-(1-(5-chloro-2-(pyrimidin-2-ylamino)phenethyl)piperidin-4-yl)-2-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (249 mg), and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate (10 mL) and diethyl ether (10 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The solid was collected by filtration. Water was added to the resulting solid, and the mixture was lyophilized. The residue was purified by preparative HPLC [eluent; 0.1% TEAA water:0.1% TEAA acetonitrile = 77:23 → 27:73]. The solvent was evaporated under reduced pressure, and then ethyl acetate and saturated aqueous sodium bicarbonate were added to the residue, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Dichloromethane (3 mL) and a 1 mol / L hydrochloric acid diethyl ether solution (1 mL) were added to the residue, and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and then water was added to the residue, and the mixture was lyophilized to give (R)-2-amino-2-(1-(5-chloro-2-(pyrimidin-2-ylamino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrochloride (44 mg) as a white solid. NMR: 1.29(3H,t,J=7.2Hz), 1.57-1.78(2H,m), 1.85-2.07(2H,m), 2.11-2.32(1H,m), 2.87-3.13(6H,m), 3.13-3.51(6H,m), 3.51-3.74(3H,m), 3.74-3.89(1H,m), 3.89-4.00(1H,m), 4.00-4.20(1H,m), 4.41(2H,s), 4.52(1H,d,J=6.0Hz), 6.89(1H,t,J=5.0Hz), 7.09(1H,ddd,J=8.5,8.5,2.7Hz), 7.34(1H,d,J=8.8Hz), 7.35(1H,dd,J=9.2,2.4Hz), 7.42(1H,dd,J=8.4,2.4Hz), 7.47(1H,d,J=2.4Hz), 7.51(1H,dd,J=8.4,2.0Hz), 8.35(2H,d,J=4.8Hz) MS:626.25[M+H]+ , 624.15[MH] -

[0181] Example 73 In the same manner as in Example 72, (R)-2-amino-2-(1-(5-chloro-2-(pyrimidin-2-ylamino)phenethyl)piperidin-4-yl)-1-(4-(2-(methylthio)benzyl)piperazin-1-yl)ethan-1-one hydrochloride was obtained as a white solid. NMR: 1.58-1.79(2H,m), 1.90-2.07(2H,m), 2.17-2.31(1H,m), 2.54(3H,s), 2.88-3.12(4H,m), 3.24-3.42(3H,m), 3.42-3.52(3H,m), 3.52-3.78(3H,m), 3.78-3.91(1H,m), 3.91-4.04(1H,m), 4.04-4.27(1H,m), 4.50(2H,s), 4.53(1H,d,J=6.0Hz), 6.88(1H,t,J=5.0Hz), 7.30-7.39(2H,m), 7.39-7.44(1H,m), 7.44-7.51(2H,m), 7.51-7.58(2H,m), 8.35(2H,d,J=5.2Hz) MS: 594.25[M+H] + , 592.15[MH] -

[0182] Example 74 Toluene (3.6 mL) and titanium tetrachloride (0.15 mL) were added to tert-butyl (S)-2-(((2-(2-(4-((R)-2-(4-(5-(benzyloxy)-2-(ethylthio)benzyl)piperazin-1-yl)-1-(((benzyloxy)carbonyl)amino)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)methyl)pyrrolidine-1-carboxylate (211 mg), and the mixture was stirred at room temperature for 20 minutes. Ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Anisole (0.37 mL) and a 5.1 mol / L hydrobromic acid / acetic acid solution (1.8 mL) were added to the residue, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate (6.7 mL) and diethyl ether (6.7 mL) were added to the reaction mixture, which was stirred at room temperature for 30 minutes. The solid was collected by filtration. Water (20 mL), potassium carbonate (306 mg), and methanol (20 mL) were added to the resulting solid, which was stirred at room temperature for 30 minutes. Ethyl acetate and water were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC [eluent; 0.1% TEAA water:0.1% TEAA acetonitrile = 96:4 → 46:54]. The solvent was evaporated under reduced pressure, and then ethyl acetate and saturated aqueous sodium bicarbonate were added to the residue, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Dichloromethane (3 mL) and a 1 mol / L hydrochloric acid diethyl ether solution (1 mL) were added to the residue, and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and then water was added to the residue, followed by lyophilization to give (R)-2-amino-2-(1-(5-chloro-2-((((S)-pyrrolidin-2-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-5-hydroxybenzyl)piperazin-1-yl)ethan-1-one hydrochloride (61 mg) as a white solid.NMR: 1.16(3H,t,J=7.4Hz), 1.66-1.88(3H,m), 1.91-2.18(4H,m), 2.18-2.41(2H,m), 2.85(2H,q,J=7.3Hz), 2.91-3.05(2H,m), 3.05-3.20(2H,m), 3.20-3.43(6H,m), 3.43-3.68(6H,m), 3.68-3.82(2H,m), 3.82-4.00(2H,m), 4.00-4.30(1H,m), 4.59(1H,d,J=6.0Hz), 4.61(2H,s), 6.80(1H,d,J=8.8Hz), 7.05(1H,dd,J=8.8,2.8Hz), 7.08(1H,d,J=2.8Hz), 7.19(1H,d,J=2.4Hz), 7.26(1H,dd,J=8.8,2.4Hz), 7.60(1H,d,J=8.4Hz) MS: 629.35[M+H]. + , 627.45[MH] -

[0183] The compounds shown in Table 18 were obtained in the same manner as in Example 74.

[0184] The NMR and MS measurements of the compounds in the table are shown below. Example 75 NMR: 1.16 (3H, t, J = 7.4 Hz), 1.66-1.87 (2H, m), 1.95-2.16 (2H, m), 2.22-2.43 (1H, m), 2.85 (2H, q, J = 7.3 Hz), 2.91-3.04 (2H, m), 3.04-3.19 (2H, m), 3.24 (2H, t, J = 6.2 Hz), 3.29-3.43 (3H, m), 3.43-3.70 (6H, m), 3.70-3.82 (2H, m), 3.82-4.26 (4H, m), 4.59 (1H, d, J = 6.0 Hz), 4.61 (2H, s), 6.79(1H,d,J=8.8Hz), 7.05(1H,dd,J=8.8,2.8Hz), 7.08(1H,d,J=2.8Hz), 7.19(1H,d,J=2.4Hz), 7.26(1H,dd,J=8.8,2.4Hz), 7.60(1H,d,J=8.8Hz) MS:589.40[M+H] + , 587.40[MH] -Example 76 NMR: 1.16 (3H, t, J = 7.4 Hz), 1.71-1.97 (2H, m), 1.97-2.20 (3H, m), 2.20-2.36 (1H, m), 2.36-2.51 (1H, m), 2.85 (2H, q, J = 7.3 Hz), 2.92-3.16 (4H, m), 3.16-3.37 (3H, m), 3.37-3.48 (3H, m), 3.48-3.57 (3H, m), 3.57-3.68 (2H, m), 3.68-3.85 (3H, m), 3.85-3.99 (1H, m), 3.99-4.23 (1H, m), 4.28-4.39(1H,m), 4.59(1H,d,J=6.0Hz), 4.61(2H,s), 6.80(1H,d,J=8.8Hz), 7.05(1H,dd,J=8.6,2.6Hz), 7.09(1H,d,J=2.4Hz), 7.20(1H,d,J=2.4Hz), 7.27(1H,dd,J=8.4,2.4Hz), 7.60(1H,d,J=8.8Hz) MS:615.30[M+H] + , 613.40[MH] -

[0185] Implementation Example 77 Anisole (56 μL) and a 5.1 mol / L hydrobromic acid / acetic acid solution (0.28 mL) were added to benzyl tert-butyl ((S)-7-((2-(2-(4-((R)-1-((benzyloxy)carbonyl)amino)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)-7-oxoheptane-1,5-diyl) dicarbamate (28 mg), and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (1 mL) and diethyl ether (1 mL) were added sequentially to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was centrifuged, and the supernatant was removed. Ethyl acetate (1 mL) and diethyl ether (1 mL) were added to the residue, and the mixture was centrifuged, and the supernatant was removed. Ethyl acetate (1 mL) and diethyl ether (1 mL) were added to the residue, followed by centrifugation. The supernatant was removed and the residue was dried under reduced pressure to give (S)-3,7-diamino-N-(2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)heptanamide hydrobromide (29.7 mg) as a white solid.NMR: 1.42(3H,t,J=7.0Hz), 1.45-1.61(2H,m), 1.65-1.88(5H,m), 2.00-2.16(3H,m), 2.26-2.41(1H,m), 2.65(1H,dd,J=17.6,8.0Hz), 2.79(1H,dd,J=17.4,4.6Hz), 2.91(1H,dd,J=16.6,7.8Hz), 2.97-3.10(6H,m), 3.10-3.22(1H,m), 3.22-3.40(3H,m), 3.40-3.56(2H,m), 3.56-3.82(4H,m), 3.82-4.02(1H,m), 4.02-4.17(1H,m), 4.21(2H,q,J=7.1Hz), 4.52(2H,s), 4.61(1H,d,J=6.0Hz), 6.89(1H,dd,J=8.8,8,8Hz), 6.97(1H,d,J=8.8Hz), 7.26(1H,d,J=8.4Hz), 7.41(1H,dd,J=8.4,2.4Hz), 7.44-7.48(1H,m), 7.48-7.58(1H,m) MS: 674.30[M+H]. + , 672.60[MH] -

[0186] The compounds shown in Table 19 were obtained in the same manner as in Example 77.

[0187] The NMR and MS measurement values ​​of the compounds in the table are shown. Example 78 NMR: 1.42 (3H, t, J = 7.0 Hz), 1.65-1.84 (2H, m), 1.97-2.12 (2H, m), 2.17-2.33 (1H, m), 2.96-3.16 (4H, m), 3.16-3.28 (1H, m), 3.28-3.45 (5H, m), 3.55-3.78 (3H, m), 3.78-3.91 (1H, m), 3.91-4.01 (1H, m), 4.01-4.14 (3H, m), 4.20 (2H, q, J = 7.1 Hz), 4.35 (2H, s), 4.47 (1H, d, J = 6.0 Hz), 6.88(1H,t,J=8.8Hz), 6.96(1H,d,J=8.4Hz), 7.31(1H,d,J=8.4Hz), 7.43(1H,dd,J=8.8,2.4Hz), 7.45-7.54(2H,m) MS:589.30[M+H] + , 587.15[MH] - Example 79 NMR: 1.42 (3H, t, J = 7.0 Hz), 1.61-1.82 (2H, m), 1.92-2.07 (2H, m), 2.12-2.29 (1H, m), 2.73-2.95 (2H, m), 2.95-3.09 (2H, m), 3.13-3.32 (6H, m), 3.32-3.42 (2H, m), 3.52-3.65 (2H, m), 3.65-3.77 (1H, m), 3.77-3.89 (1H, m), 3.89-3.99 (1H, m), 3.99-4.15 (1H, m), 4.19 (2H, q, J = 6.9 Hz), 4.31(2H,s), 4.44(1H,d,J=6.0Hz), 4.82(1H,t,J=7.4Hz), 6.87(1H,dd,J=8.8Hz), 6.95(1H,d,J=8.8Hz), 7.01(1H,d,J=8.4Hz), 7.33-7.41(3H,m), 7.41-7.55(5H,m) MS:679.30[M+H] + , 677.55[MH] -Example 80 NMR: 1.14(3H, d, J = 6.8Hz), 1.17(3H, d, J = 6.8Hz), 1.42(3H, t, J = 7.0Hz), 1.63 - 1.87(2H, m), 1.95 - 2.12(2H, m), 2.16 - 2.33(1H, m), 2.33 - 2.53(1H, m), 2.92 - 3.16(4H, m), 3.16 - 3.29(1H, m), 3.29 - 3.50(5H, m), 3.59 - 3.78(3H, m), 3.78 - 3.91(1H, m), 3.91 - 4.02(1H, m), 4.02 - 4.10(1H, m), 4.18(1H, d, J = 5.6Hz), 4.20(2H, q, J = 7.1Hz), 4.35(2H, s), 4.47(1H, d, J = 6.0Hz), 6.88(1H, dd, J = 8.6Hz), 6.96(1H, d, J = 8.4Hz), 7.29(1H, d, J = 8.8Hz), 7.44(1H, dd, J = 8.4, 2.4Hz), 7.46 - 7.55(2H, m) MS: 631.35[M + H] + , 629.45[M - H] - Example 81 NMR: 1.42(3H, t, J = 7.0Hz), 1.63 - 1.85(2H, m), 1.94 - 2.11(2H, m), 2.15 - 2.32(1H, m), 2.85(3H, s), 2.94 - 3.14(4H, m), 3.14 - 3.24(1H, m), 3.24 - 3.44(5H, m), 3.60 - 3.77(3H, m), 3.77 - 3.89(1H, m), 3.89 - 4.00(1H, m), 4.00 - 4.12(1H, m), 4.14 - 4.26(4H, m), 4.31(2H, s), 4.44(1H, d, J = 6.0Hz), 6.88(1H, dd, J = 9.0Hz), 6.96(1H, d, J = 8.4Hz), 7.31(1H, d, J = 8.4Hz), 7.43(1H, dd, J = 8.4, 2.4Hz), 7.45 - 7.55(2H, m) MS: 603.30[M + H] + , 601.40[M - H] -Example 82 NMR: 1.42 (3H, t, J = 7.0 Hz), 1.65 - 1.87 (2H, m), 1.96 - 2.13 (2H, m), 2.19 - 2.45 (3H, m), 2.51 - 2.67 (2H, m), 2.94 - 3.18 (4H, m), 3.22 - 3.53 (6H, m), 3.61 - 3.80 (3H, m), 3.80 - 3.94 (1H, m), 3.94 - 4.06 (1H, m), 4.06 - 4.16 (1H, m), 4.20 (2H, q, J = 6.9 Hz), 4.34 (1H, dd, J = 7.2, 1.6 Hz), 4.42 (2H, s), 4.53 (1H, d, J = 6.0 Hz), 6.88 (1H, dd, J = 8.8 Hz), 6.96 (1H, d, J = 8.8 Hz), 7.31 (1H, d, J = 8.4 Hz), 7.43 (1H, dd, J = 8.4, 2.4 Hz), 7.46 - 7.56 (2H, m) MS: 660.30 [M + H] + , 658.40 [M - H] - Example 83 NMR: 1.41 (3H, t, J = 7.0 Hz), 1.64 - 1.86 (2H, m), 1.92 - 2.16 (2H, m), 2.20 - 2.40 (1H, m), 2.75 - 2.96 (2H, m), 2.96 - 3.19 (2H, m), 3.19 - 3.41 (6H, m), 3.41 - 3.76 (6H, m), 3.76 - 3.99 (1H, m), 3.99 - 4.17 (1H, m), 4.20 (2H, q, J = 6.9 Hz), 4.46 - 4.56 (3H, m), 4.59 (1H, d, J = 6.0 Hz), 6.88 (1H, dd, J = 8.8 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.02 (1H, d, J = 8.8 Hz), 7.35 - 7.41 (3H, m), 7.41 - 7.58 (5H, m) MS: 679.35 [M + H] + , 677.50 [M - H] -Example 84 NMR: 1.42(3H,t,J=7.0Hz), 1.64-1.88(2H,m), 1.96-2.16(2H,m), 2.23-2.42(1H,m), 2.97(2H,t,J=6.6Hz), 3.00-3.20(4H,m), 3.20-3.28(1H,m), 3.28-3.42(5H,m), 3.42-3.79(6H,m), 3.79-3.97(1H,m), 3.97-4.10(1H,m), 4.21(2H,q,J=7.1Hz), 4.51(2H,s), 4.59(1H,d,J=6.0Hz), 6.89(1H,dd,J=9.0Hz), 6.97(1H,d,J=8.4Hz), 7.27(1H,d,J=8.4Hz), 7.41(1H,dd,J=8.4,2.4Hz), 7.46(1H,d,J=2.4Hz), 7.48-7.58(1H,m) MS: 603.30[M+H] + , 601.50[M-H] - Example 85 NMR: 1.42(3H,t,J=7.0Hz), 1.59(2H,quin,J=8.0Hz), 1.68-1.88(4H,m), 1.98-2.22(4H,m), 2.25-2.40(1H,m), 2.96- 3.27(7H,m), 3.27-3.45(3H,m), 3.45-3.65(3H,m), 3.65-3.80(3H,m), 3.80-3.99(1H,m), 3.99-4.17(1H,m), 4.21(2H,q,J=7.1Hz), 4.34(1H,t,J=6.4Hz), 4.52(2H,s), 4.60(1H,d,J=6.0Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.8Hz),7.25(1H,d,J=8.4Hz), 7.43(1H,dd,J=8.4,2.4Hz), 7.46-7.60(2H,m) MS: 660.35[M+H] + , 658.50[M-H] -Example 86 NMR: 1.42(3H,t,J=7.0Hz), 1.69-1.91(2H,m), 1.96-2.20(2H,m), 2.26-2.44(1H,m), 2.96-3.23(5H,m), 3.23-3.42(3H,m), 3.42-3.82(8H,m), 3.82-4.00(1H,m), 4.00-4.17(1H,m), 4.21(2H,q,J=7.1Hz), 4.52(2H,s), 4.56-4.64(2H,m), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.35(1H,d,J=8.4Hz), 7.43(1H,dd,J=8.4,2.4Hz), 7.46-7.58(2H,m) MS: 618.30[M+H] + , 616.50[M-H] - Example 87 NMR: 1.42(3H,t,J=7.0Hz), 1.68-1.87(2H,m), 1.95-2.10(2H,m), 2.10-2.39(4H,m), 2.57-2.72(1H,m), 2.96-3.06(2H,m), 3.06-3.21(2H,m), 3.21-3.42(3H,m), 3.42-3.62(5H,m), 3.62-3.79(3H,m), 3.79-3.98(1H,m), 3.98-4.17(1H,m), 4.21(2H,q,J=7.1Hz), 4.51(2H,s), 4.59(1H,d,J=6.0Hz), 4.62-4.69(2H,m), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.8Hz), 7.28(1H,d,J=8.4Hz), 7.43(1H,dd,J=8.4,2.4Hz), 7.47(1H,d,J=2.0Hz), 7.49-7.58(1H,m) MS: 629.35[M+H] + , 627.50[M-H] -

[0188] Example 88 NMR: 1.42(3H,t,J=7.0Hz), 1.64-1.84(2H,m), 1.84-1.98(2H,m), 1.98-2.13(3H,m), 2.15-2.40(2H,m), 2.89-3.05(2H,m), 3.05-3.21(4H,m), 3.21-3.40(5H,m), 3.40-3.66(5H,m), 3.66-3.77(3H,m), 3.77-3.98(1H,m), 3.98-4.17(1H,m), 4.21(2H,q,J=6.9Hz), 4.51(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), 7.23(1H,d,J=8.4Hz), 7.42(1H,dd,J=8.8,2.4Hz), 7.44-7.48(1H,m), 7.48-7.58(1H,m) MS: 643.35[M+H] + , 641.50[M-H] - Example 89 NMR: 1.42(3H,t,J=7.0Hz), 1.62-1.84(4H,m), 1.84-1.99(2H,m), 1.99-2.16(3H,m), 2.23-2.37(1H,m), 2.37-2.49(1H,m), 2.86-3.05(2H,m), 3.05-3.22(3H,m), 3.22-3.47(4H,m), 3.47-3.65(4H,m), 3.65-3.84(3H,m), 3.84-3.99(1H,m), 3.99-4.16(1H,m), 4.16-4.28(3H,m), 4.52(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), 7.26(1H,d,J=8.4Hz), 7.43(1H,dd,J=8.4,2.4Hz), 7.45-7.49(1H,m), 7.49-7.57(1H,m) MS: 643.30[M+H] + , 641.40[M-H] -Example 90 NMR: 1.42(3H,t,J=7.0Hz), 1.53-1.76(2H,m), 1.84-2.06(2H,m), 2.10-2.27(1H,m), 2.42-2.73(3H,m), 2.73-2.86(1H,m), 2.86-3.10(2H,m), 3.10-3.71(7H,m), 3.71-3.99(2H,m), 3.99-4.15(1H,m), 4.21(2H,q,J=6.9Hz), 4.52(2H,s), 4.54-4.62(1H,m), 5.32-5.43(1H,m), 6.90(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.22-7.31(1H,m), 7.37-7.45(2H,m), 7.45-7.57(1H,m), 7.57-7.73(5H,m) MS: 665.35[M+H] + , 663.50[M-H]<了 - Example 91 NMR: 1.42(3H,t,J=7.0Hz), 1.63-1.87(2H,m), 1.93-2.13(2H,m), 2.22-2.40(1H,m), 2.89-3.19(4H,m), 3.19-3.40(5H,m), 3.40-3.65(4H,m), 3.65-3.77(3H,m), 3.77-4.09(3H,m), 4.09-4.27(3H,m), 4.27-4.39(1H,m), 4.51(2H,s), 4.59(1H,d,J=6.0Hz), 4.66-4.72(2H,m), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.25(1H,d,J=8.4Hz), 7.43(1H,dd,J=8.8,2.4Hz), 7.46-7.49(1H,m), 7.49-7.57(1H,m) MS: 645.35[M+H] + , 643.40[M-H] - It should be noted that there is an incorrect character "了" in the tag in the original text. It is assumed that this is a typo and has been left as is in the translation for the purpose of maintaining the integrity of the original content.Example 92 NMR: 1.01(3H,t,J=7.4Hz), 1.14(3H,t,J=7.2Hz), 1.30-1.39(1H,m), 1.42(3H,t,J=7.0Hz), 1.55-1.69(1H,m), 1.69-1.90(2H,m), 1.96-2.11(2H,m), 2.11-2.24(1H,m), 2.24-2.42(1H,m), 2.81-3.27(5H,m), 3.27-3.66(7H,m), 3.66-3.82(2H,m), 3.82-3.97(1H,m), 3.97-4.14(1H,m), 4.14-4.26(3H,m), 4.51(2H,s), 4.59(1H,d,J=5.6Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.27(1H,d,J=8.8Hz), 7.43(1H,dd,J=8.4,2.4Hz), 7.45-7.49(1H,m), 7.49-7.59(1H,m) MS: 645.35[M+H] + , 643.45[M-H] - Example 93 NMR: 1.42(3H,t,J=7.0Hz), 1.64-1.88(2H,m), 1.95-2.15(2H,m), 2.15-2.38(2H,m), 2.42-2.61(2H,m), 2.61-2.79(1H,m), 2.90-3.03(2H,m), 3.03-3.16(2H,m), 3.16-3.42(4H,m), 3.42-3.60(2H,m), 3.60-4.00(5H,m), 4.11-4.34(3H,m), 4.51(2H,s), 4.53-4.63(2H,m), 6.89(1H,dd,J=8.8,8.8Hz), 6.96(1H,d,J=8.4Hz), 7.23(1H,d,J=8.4Hz), 7.42(1H,dd,J=8.6,2.2Hz), 7.45-7.49(1H,m), 7.49-7.57(1H,m) MS: 643.30[M+H] + , 641.40[M-H] -Example 94 NMR: 0.59 - 0.73(1H,m), 0.77 - 1.00(3H,m), 1.39 - 1.49(4H,m), 1.65 - 1.88(2H,m), 1.95 - 2.16(2H,m), 2.22 - 2.39(1H,m), 2.95 - 3.21(4H,m), 3.21 - 3.45(4H,m), 3.45 - 3.64(4H,m), 3.64 - 3.79(2H,m), 3.79 - 3.95(1H,m), 3.95 - 4.10(1H,m), 4.10 - 4.30(3H,m), 4.51(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), 7.27(1H,d,J = 8.4Hz), 7.44(1H,dd,J = 8.4,2.4Hz), 7.47 - 7.58(2H,m) MS: 629.35[M + H] + , 627.45[M - H] - Example 95 NMR: 1.42(3H,t,J = 7.0Hz), 1.59 - 1.82(2H,m), 1.83 - 2.01(2H,m), 2.14 - 2.30(1H,m), 2.30 - 2.51(2H,m), 2.88(2H,t,J = 8.2Hz), 2.92 - 3.11(4H,m), 3.19 - 3.40(3H,m), 3.40 - 3.57(3H,m), 3.57 - 3.72(3H,m), 3.76 - 3.95(1H,m), 3.95 - 4.09(1H,m), 4.09 - 4.28(3H,m), 4.38(1H,t,J = 6.4Hz), 4.51(2H,s), 4.55(1H,d,J = 6.0Hz), 6.89(1H,dd,J = 9.0,9.0Hz), 6.97(1H,d,J = 8.8Hz), 7.16(1H,d,J = 8.4Hz), 7.27 - 7.44(6H,m), 7.46(1H,d,J = 2.4Hz), 7.48 - 7.58(1H,m) MS: 693.40[M + H] + , 691.55[M - H] -Example 96 NMR: 1.42(3H,t,J=7.0Hz), 1.65-1.90(2H,m), 1.96-2.12(2H,m), 2.17(3H,s), 2.22-2.47(3H,m), 2.75(2H,t,J=7.4Hz), 2.89-3.07(3H,m), 3.07-3.23(2H,m), 3.23-3.46(4H,m), 3.46-3.65(3H,m), 3.65-3.80(2H,m), 3.80-3.98(1H,m), 3.98-4.11(1H,m), 4.21(2H,q,J=6.9Hz), 4.37-4.48(1H,m), 4.51(2H,s), 4.59(1H,d,J=6.4Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J-8.8Hz), 7.30(1H,d,J=8.8Hz), 7.37-7.59(3H,m) MS: 663.35[M+H] + , 661.55[M-H] - Example 97 NMR: 1.40(3H,t,J=7.0Hz), 1.57-1.80(2H,m), 1.87-2.06(2H,m), 2.16-2.35(1H,m), 2.90-3.16(4H,m), 3.16-3.58(6H,m), 3.58-3.76(3H,m), 3.76-3.92(1H,m), 3.92-4.07(1H,m), 4.07-4.25(3H,m), 4.49(2H,s), 4.54(1H,d,J=5.6Hz), 6.87(1H,dd,J=9.0,9.0Hz), 6.95(1H,d,J=8.8Hz), 7.33(1H,d,J=8.4Hz), 7.41-7.57(3H,m), 7.61(2H,dd,J=7.8,7.8Hz), 7.71(1H,dd,J=7.4,7.4Hz), 7.89-7.99(2H,m) MS: 636.30[M+H] + , 634.45[M-H] -

[0189] Example 98 NMR: 1.40 (3H, t, J = 7.0 Hz), 1.61 - 1.83 (2H, m), 1.93 - 2.12 (2H, m), 2.20 - 2.38 (1H, m), 2.92 - 3.16 (4H, m), 3.16 - 3.63 (6H, m), 3.63 - 3.78 (3H, m), 3.78 - 3.93 (1H, m), 3.93 - 4.13 (1H, m), 4.13 - 4.33 (3H, m), 4.50 (2H, s), 4.57 (1H, d, J = 6.0 Hz), 6.88 (1H, dd, J = 8.8, 8.8 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.36 (1H, d, J = 8.4 Hz), 7.43 - 7.63 (3H, m), 8.28 (2H, dd, J = 5.2, 1.6 Hz), 8.94 (2H, dd, J = 5.2, 1.6 Hz) MS: 637.30 [M + H] + , 635.40 [M - H] - Example 99 NMR: 1.41 (3H, t, J = 7.0 Hz), 1.61 - 1.84 (2H, m), 1.92 - 2.13 (2H, m), 2.19 - 2.36 (1H, m), 2.93 - 3.14 (4H, m), 3.14 - 3.42 (4H, m), 3.42 - 3.61 (2H, m), 3.61 - 3.77 (3H, m), 3.77 - 3.94 (1H, m), 3.94 - 4.09 (1H, m), 4.09 - 4.30 (3H, m), 4.50 (2H, s), 4.56 (1H, d, J = 6.0 Hz), 6.88 (1H, dd, J = 8.8, 8.8 Hz), 6.96 (1H, d, J = 8.8 Hz), 7.14 (1H, d, J = 8.4 Hz), 7.46 (1H, dd, J = 8.4, 2.4 Hz), 7.48 - 7.58 (2H, m), 8.06 (1H, s), 8.45 (1H, s) MS: 626.30 [M + H] + , 624.40 [M - H] -Example 100 NMR: 1.41(3H,t,J=7.0Hz), 1.60-1.82(2H,m), 1.91-2.11(2H,m), 2.19-2.36(1H,m), 2.93-3.13(4H,m), 3.13-3.39(4H,m), 3.39-3.58(2H,m), 3.58-3.81(4H,m), 3.81-4.10(1H,m), 4.10-4.31(3H,m), 4.51(2H,s), 4.56(1H,dd,J=5.6Hz), 6.88(1H,dd,J=8.8,8.8Hz), 6.96(1H,d,J=8.4Hz), 7.31(1H,d,J=8.4Hz), 7.45(1H,dd,J=8.4,2.4Hz), 7.47-7.56(2H,m), 7.58(1H,s) MS: 658.25[M+H] + , 656.40[M-H] - Example 101 NMR: 1.42(3H,t,J=7.0Hz), 1.66-1.87(2H,m), 1.95-2.17(2H,m), 2.23-2.42(1H,m), 2.87-3.24(5H,m), 3.24-3.46(6H,m), 3.46-3.67(6H,m), 3.67-3.87(3H,m), 3.92(2H,dd,J=13.4,3.8Hz), 4.21(2H,q,J=7.1Hz), 4.46(1H,dd,J=10.8,3.6Hz), 4.52(2H,s), 4.60(1H,d,J=5.6Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.8Hz), 7.28(1H,d,J=8.4Hz), 7.43(1H,dd,J=8.6,2.2Hz), 7.45-7.58(2H,m) MS: 644.30[M+H] + , 642.55[M-H] -Example 102 NMR: 1.42(3H,t,J=7.0Hz), 1.67-1.90(2H,m), 1.97-2.16(2H,m), 2.24-2.42(1H,m), 2.91-3.20(5H,m), 3.20-3.47(6H,m), 3.47-3.67(6H,m), 3.67-3.87(3H,m), 3.93(2H,dd,J=13.4,3.8Hz), 4.21(2H,q,J=6.9Hz), 4.48(1H,dd,J=10.8,3.2Hz), 4.52(2H,s), 4.60(1H,d,J=6.0Hz), 6.88(1H,dd,J=9.0,9.0Hz), 6.97(1H,d,J=8.4Hz), 7.28(1H,d,J=8.8Hz), 7.43(1H,dd,J=8.4,2.4Hz), 7.45-7.58(2H,m) MS: 644.30[M+H] + , 642.55[M-H] - Example 103 NMR: 1.42(3H,t,J=7.0Hz), 1.70(3H,d,J=7.2Hz), 1.73-1.87(2H,m), 1.97-2.15(2H,m), 2.23-2.40(1H,m), 2.95-3.06(2H,m), 3.06-3.19(2H,m), 3.19-3.44(4H,m), 3.44-3.63(3H,m), 3.63-3.80(3H,m), 3.80-3.97(1H,m), 3.97-4.13(1H,m), 4.20(2H,q,J=6.9Hz), 4.36(1H,q,J=7.2Hz), 4.50(2H,s), 4.59(1H,d,J=6.0Hz), 6.88(1H,dd,J=9.0,9.0Hz), 6.96(1H,d,J=8.4Hz), 7.27(1H,d,J=8.4Hz), 7.43(1H,dd,J=8.4,2.4Hz), 7.45-7.49(1H,m), 7.49-7.58(1H,m) MS: 603.30[M+H] + , 601.45[M-H] -Example 104 NMR: 1.42(3H,t,J=7.0Hz), 1.70(3H,d,J=5.8Hz), 1.72 - 1.88(2H,m), 1.94 - 2.15(2H,m), 2.22 - 2.39(1H,m), 2.95 - 3.06(2H,m), 3.06 - 3.19(2H,m), 3.19 - 3.44(4H,m), 3.44 - 3.61(3H,m), 3.61 - 3.80(3H,m), 3.80 - 3.97(1H,m), 3.97 - 4.12(1H,m), 4.20(2H,q,J=7.1Hz), 4.36(1H,q,J=7.1Hz), 4.50(2H,s), 4.58(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=8.8Hz), 7.43(1H,dd,J=8.4,2.4Hz), 7.45 - 7.48(1H,m), 7.48 - 7.58(1H,m) MS: 603.30[M + H] + , 601.45[M - H] - Example 105 NMR: 1.41(3H,t,J=7.0Hz), 1.62 - 1.85(2H,m), 1.93 - 2.15(2H,m), 2.20 - 2.38(1H,m), 2.62 - 2.72(2H,m), 2.72 - 2.84(2H,m), 2.96 - 3.12(4H,m), 3.12 - 3.37(3H,m), 3.37 - 3.64(3H,m), 3.64 - 3.76(4H,m), 3.76 - 4.05(2H,m), 4.20(2H,q,J=7.1Hz), 4.51(2H,s), 4.58(1H,d,J=6.0Hz), 6.88(1H,dd,J=8.8,8.8Hz), 6.96(1H,d,J=8.8Hz), 7.21(1H,d,J=8.4Hz), 7.40(1H,dd,J=8.4,2.4Hz), 7.42 - 7.48(1H,m), 7.48 - 7.57(1H,m) MS: 631.30[M + H] + , 629.65[M - H] -Example 106 NMR: 1.42(3H,t,J=7.0Hz), 1.66 - 1.88(2H,m), 1.97 - 2.16(2H,m), 2.20 - 2.39(2H,m), 2.46 - 2.61(1H,m), 2.94 - 3.06(2H,m), 3.06 - 3.18(2H,m), 3.18 - 3.39(3H,m), 3.39 - 3.65(9H,m), 3.65 - 3.83(3H,m), 3.83 - 3.97(1H,m), 3.97 - 4.13(1H,m), 4.21(2H,q,J=6.9Hz), 4.51(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), 7.25(1H,d,J=8.4Hz), 7.42(1H,dd,J=8.6,2.2Hz), 7.44 - 7.48(1H,m), 7.48 - 7.57(1H,m) MS: 629.30[M + H] + , 627.55[M - H] - Example 107 NMR: 1.42(3H,t,J=7.0Hz), 1.65 - 1.87(2H,m), 1.94 - 2.13(2H,m), 2.21 - 2.40(1H,m), 2.93 - 3.18(4H,m), 3.18 - 3.39(5H,m), 3.39 - 3.64(5H,m), 3.64 - 3.82(3H,m), 3.83 - 3.96(1H,m), 3.97 - 4.17(2H,m), 4.21(2H,q,J=6.9Hz), 4.28 - 4.38(1H,m), 4.51(2H,s), 4.59(1H,d,J=6.0Hz), 4.67 - 4.72(2H,m), 6.89(1H,dd,J=9.0,9.0Hz), 6.97(1H,d,J=8.8Hz), 7.25(1H,d,J=8.4Hz), 7.43(1H,dd,J=8.4,2.4Hz), 7.46 - 7.58(2H,m) MS: 645.30[M + H] + , 643.45[M - H] -

[0190] Example 108 NMR: 0.94 - 1.13 (3H, m), 1.13 - 1.35 (4H, m), 1.42 (3H, t, J = 7.0 Hz), 1.44 - 1.55 (1H, m), 1.58 - 1.87 (7H, m), 1.87 - 1.98 (2H, m), 1.98 - 2.12 (2H, m), 2.23 - 2.38 (1H, m), 2.94 - 3.06 (2H, m), 3.06 - 3.19 (2H, m), 3.19 - 3.43 (3H, m), 3.43 - 3.62 (3H, m), 3.62 - 3.80 (2H, m), 3.80 - 3.97 (1H, m), 3.97 - 4.12 (1H, m), 4.20 (2H, q, J = 6.9 Hz), 4.34 (1H, dd, J = 8.0, 6.4 Hz), 4.50 (2H, m), 4.58 (1H, d, J = 6.0 Hz), 6.89 (1H, dd, J = 9.0, 9.0 Hz), 6.97 (1H, d, J = 8.4 Hz), 7.25 (1H, d, J = 8.8 Hz), 7.43 (1H, dd, J = 8.4, 2.4 Hz), 7.46 - 7.61 (2H, m) MS: 685.40 [M + H] + , 683.90 [M - H] - Example 109 NMR: 1.40 (3H, t, J = 7.0 Hz), 1.60 - 1.82 (2H, m), 1.93 - 2.12 (2H, m), 2.18 - 2.37 (1H, m), 2.94 - 3.16 (4H, m), 3.16 - 3.50 (5H, m), 3.50 - 3.74 (4H, m), 3.74 - 4.09 (2H, m), 4.09 - 4.34 (3H, m), 4.50 (2H, s), 4.56 (1H, d, J = 6.0 Hz), 6.88 (1H, dd, J = 8.8, 8.8 Hz), 6.96 (1H, d, J = 8.8 Hz), 7.35 (1H, d, J = 8.4 Hz), 7.43 - 7.58 (3H, m), 7.98 (1H, dd, J = 8.2, 5.4 Hz), 8.76 (1H, ddd, J = 8.0, 1.8, 1.8 Hz), 8.91 (1H, dd, J = 5.4, 1.4 Hz), 9.22 (1H, d, J = 1.6 Hz) MS: 637.30 [M + H] + , 635.45 [M - H] -Example 110 NMR: 1.42 (3H, t, J = 7.0 Hz), 1.65 - 1.86 (2H, m), 1.96 - 2.15 (2H, m), 2.20 - 2.29 (1H, m), 2.77 - 2.95 (2H, m), 2.95 - 3.16 (4H, m), 3.16 - 3.43 (3H, m), 3.43 - 3.61 (3H, m), 3.61 - 3.77 (4H, m), 3.77 - 4.02 (3H, m), 4.02 - 4.16 (1H, m), 4.20 (2H, q, J = 6.9 Hz), 4.51 (2H, s), 4.58 (1H, d, J = 6.0 Hz), 4.98 (1H, dd, J = 8.8, 4.0 Hz), 5.51 - 5.75 (1H, m), 6.88 (1H, dd, J = 8.8, 8.8 Hz), 6.97 (1H, d, J = 8.4 Hz), 7.25 (1H, d, J = 8.8 Hz), 7.43 (1H, dd, J = 8.8, 2.4 Hz), 7.45 - 7.57 (2H, m) MS: 647.30 [M + H] + , 645.45 [M - H] - Example 111 NMR: 1.42 (3H, t, J = 7.0 Hz), 1.67 - 1.88 (2H, m), 1.97 - 2.15 (2H, m), 2.23 - 2.38 (1H, m), 2.40 - 2.62 (1H, m), 2.90 - 3.31 (5H, m), 3.31 - 3.44 (3H, m), 3.44 - 3.63 (3H, m), 3.63 - 3.82 (4H, m), 3.82 - 3.99 (2H, m), 3.99 - 4.17 (1H, m), 4.20 (2H, q, J = 6.9 Hz), 4.51 (2H, s), 4.59 (1H, d, J = 6.0 Hz), 4.87 - 5.00 (2H, m), 5.52 - 5.74 (1H, m), 6.88 (1H, dd, J = 8.6, 8.6 Hz), 6.97 (1H, d, J = 8.8 Hz), 7.30 (1H, d, J = 8.4 Hz), 7.43 (1H, dd, J = 8.4, 2.4 Hz), 7.47 (1H, d, J = 2.4 Hz), 7.48 - 7.57 (1H, m) MS: 647.30 [M + H] + , 645.40 [M - H] -Example 112 NMR: 1.12(3H,t,J=7.4Hz), 1.42(3H,t,J=7.0Hz), 1.67-1.86(2H,m), 1.98-2.19(4H,m), 2.24-2.37(1H,m), 2.94-3.06(2H,m), 3.06-3.20(2H,m), 3.20-3.45(4H,m), 3.45-3.64(3H,m), 3.64-3.85(3H,m), 3.85-4.00(1H,m), 4.00-4.13(1H,m), 4.15-4.29(3H,m), 4.50(2H,m), 4.58(1H,d,J=6.0Hz), 6.88(1H,dd,J=8.8,8.8Hz), 6.96(1H,d,J=8.4Hz), 7.27(1H,d,J=8.4Hz), 7.43(1H,dd,J=8.4,2.4Hz), 7.46-7.57(2H,m) MS: 617.30[M+H] + , 615.65[M-H] - Example 113 NMR: 1.42(3H,t,J=7.0Hz), 1.65-1.97(5H,m), 1.97-2.16(2H,m), 2.16-2.40(2H,m), 2.94-3.28(6H,m), 3.28-3.30(2H,m), 3.30-3.47(5H,m), 3.47-3.64(3H,m), 3.64-3.79(3H,m), 3.79-3.9(1H,m), 3.95-4.10(1H,m), 4.20(2H,q,J=7.2Hz), 4.51(2H,s), 4.59(1H,d,J=5.6Hz), 6.88(1H,dd,J=8.8,8.8Hz), 6.96(1H,d,J=8.8Hz), 7.23(1H,d,J=8.4Hz), 7.41(1H,dd,J=8.4,2.4Hz), 7.46(1H,d,J=2.0Hz), 7.52(1H,ddd,J=8.4,8.4,6.8Hz) MS: 643.30[M+H] + , 641.45[M-H] -Example 114 NMR: 1.07-1.37 (6H, m), 1.42 (3H, t, J = 7.0 Hz), 1.65-1.92 (8H, m), 1.97-2.15 (2H, m), 2.24-2.39 (1H, m), 2.93-3.23 (4H, m), 3.23-3.45 (3H, m), 3.45-3.62 (3H, m), 3.62-3.81 (3H, m), 3.81-3.98 (1H, m), 3.98-4.17 (2H, m), 4.21 (2H, q, J = 6.8 Hz), 4.51 (2H, s), 4.59 (1H, d, J = 6.4 Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.28(1H,d,J=8.8Hz), 7.43(1H,dd,J=8.4,2.4Hz), 7.48(1H,d,J=2.4Hz), 7.49-7.57(1H,m) MS:671.40[M+H] + , 669.55[MH] - Example 115 NMR: 1.42 (3H, t, J = 7.0 Hz), 1.50-1.69 (5H, m), 1.81-1.97 (2H, m), 2.06-2.22 (1H, m), 2.36-2.68 (2H, m), 2.68-2.87 (2H, m), 2.87-3.11 (2H, m), 3.11-3.73 (7H, m), 3.73-3.93 (1H, m), 3.93-4.10 (2H, m), 4.15-4.27 (3H, m), 4.47-4.60 (3H, m), 6.89 (1H, dd, J = 8.8, 8.8 Hz), 6.97 (1H, d, J = 8.8 Hz), 7.18-7.25(1H,m), 7.33-7.43(3H,m), 7.43-7.58(5H,m) MS:664.35[M+H] + , 662.50[MH] -Example 116 NMR: 1.42(3H,t,J=7.0Hz), 1.52-1.84(5H,m), 1.84-2.15(5H,m), 2.19-2.38(1H,m), 2.38-2.46(1H,m), 2.90-3.06(2H,m), 3.06-3.20(3H,m), 3.20-3.46(4H,m), 3.46-3.63(3H,m), 3.63-3.78(3H,m), 3.78-4.10(2H,m), 4.16-4.26(3H,m), 4.52(2H,s), 4.60(1H,d,J=6.0Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.26(1H,d,J=8.4Hz), 7.43(1H,dd,J=8.4,2.4Hz), 7.48(1H,d,J=2.0Hz), 7.52(1H,ddd,J=8.4,8.4,7.2Hz) MS: 643.30[M+H] + , 641.45[M-H] - Example 117 NMR: 1.42(3H,t,J=7.0Hz), 1.53-1.74(2H,m), 1.82-2.03(2H,m), 2.10-2.28(1H,m), 2.40-2.73(3H,m), 2.73-2.86(1H,m), 2.86-3.08(2H,m), 3.08-3.38(3H,m), 3.38-3.75(4H,m), 3.75-3.96(1H,m), 3.96-4.10(1H,m), 4.17-4.26(3H,m), 4.53(2H,s), 4.57(1H,t,J=5.6Hz), 5.37(1H,d,J=1.2Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.24-7.31(1H,m), 7.39-7.45(2H,m), 7.48-7.56(1H,m), 7.56-7.71(5H,m) MS: 665.35[M+H] + , 663.50[M-H] -

[0191] Example 118 NMR: 1.42(3H,t,J=7.0Hz), 1.72(3H,d,J=7.2Hz), 1.73 - 1.86(2H,m), 1.98 - 2.15(2H,m), 2.24 - 2.38(1H,m), 2.79(3H,s), 2.98 - 3.06(2H,m), 3.06 - 3.21(2H,m), 3.21 - 3.47(4H,m), 3.47 - 3.67(3H,m), 3.67 - 3.84(3H,m), 3.84 - 4.00(1H,m), 4.00 - 4.10(1H,m), 4.17 - 4.28(3H,m), 4.52(2H,s), 4.59(1H,d,J=6.0Hz), 6.89(1H,dd,J=9.0Hz), 6.97(1H,d,J=8.4Hz), 7.28(1H,d,J=8.4Hz), 7.43(1H,dd,J=8.4,2.4Hz), 7.46 - 7.57(2H,m) MS: 617.30[M+H] + , 615.45[M - H] - Example 119 NMR: 1.42(3H,t,J=7.0Hz), 1.66 - 1.83(2H,m), 1.97 - 2.15(5H,m), 2.23 - 2.36(1H,m), 2.36 - 2.50(1H,m), 2.9,1 - 3.16(4H,m), 3.16 - 3.43(4H,m), 3.43 - 3.64(3H,m), 3.64 - 3.75(3H,m), <3.75 - 3.95(1H,m), 3.95 - 4.05(1H,m), 4.05 - 4.14(1H,m), 4.16 - 4.25(3H,m), 4.51(2H,s), 4.55 - 4.64(2H,m), 6.89(1H,dd,J=9.0,9.0Hz), 6.97(1H,d,J=8.4Hz), 7.19 - 7.26(1H,m), 7.42(1H,dd,J=8.4,2.4Hz), 7.45 - 7.58(2H,m) MS: 630.30[M+H] + , 628.40[M - H] - It should be noted that there seems to be a formatting issue in the "3.75 - 3.95(1H,m)" part in Example 119 in the original text. It is presented as "<3.75 - 3.95(1H,m)" which might be a misprint. The translation is done based on the best understanding of the provided text.Example 120 NMR: 1.42(3H,t,J=7.0Hz), 1.66-1.86(2H,m), 1.95(1H,quin,J=7.5Hz), 2.00-2.15(4H,m), 2.23-2.38(1H,m), 2.51(1H,t,J=7.2Hz), 2.64(2H,t,J=7.4Hz), 2.93-3.16(6H,m), 3.16-3.38(3H,m), 3.38-3.61(3H,m), 3.61-3.77(2H,m), 3.77-3.97(1H,m), 3.97-4.17(1H,m), 4.21(2H,q,J=7.1Hz), 4.52(2H,s), 4.59(1H,d,J=6.0Hz), 6.89(1H,dd,J=9.0,9.0Hz), 6.97(1H,d,J=8.4Hz), 7.23(1H,d,J=8.4Hz), 7.41(1H,dd,J=8.4,2.4Hz), 7.44-7.48(1H,m), 7.48-7.58(1H,m) MS: 617.30[M+H] + , 615.60[M-H] - Example 121 NMR: 1.42(3H,t,J=7.0Hz), 1.67-2.12(6H,m), 2.12-2.27(4H,m), 2.27-2.41(1H,m), 2.74(1H,ddt,J=11.0,11.0,3.8Hz), 2.93(1H,ddt,J=11.6,11.6,3.7Hz), 2.97-3.21(5H,m), 3.21-3.39(2H,m), 3.39-3.49(2H,m), 3.49-3.62(3H,m), 3.62-3.76(2H,m), 3.76-3.93(1H,m), 3.93-4.10(1H,m), 4.10-4.28(3H,m), 4.52(2H,s), 4.60(1H,d,J=5.6Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.8Hz), 7.22(1H,d,J=8.8Hz), 7.41(1H,dd,J=8.4,2.4Hz), 7.44-7.48(1H,m), 7.48-7.58(1H,m) MS: 643.30[M+H] + , 641.50[M-H] -Example 122 NMR: 1.42(3H,t,J=7.0Hz), 1.67-1.88(2H,m), 1.98-2.14(2H,m), 2.24-2.39(1H,m), 2.95-3.05(2H,m), 3.05-3.23(2H,m), 3.23-3.50(5H,m), 3.50-3.63(3H,m), 3.63-3.82(3H,m), 3.82-3.98(2H,m), 3.98-4.17(3H,m), 4.17-4.26(3H,m), 4.44(1H,dd,J=12.4,4.0Hz), 4.47-4.57(3H,m), 4.60(1H,d,J=6.0Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.27(1H,d,J=8.4Hz), 7.43(1H,dd,J=8.4,2.4Hz), 7.48(1H,d,J=2.4Hz), 7.52(1H,ddd,J=8.4,8.4,7.2Hz) MS: 645.30[M+H] + , 643.50[M-H] - Example 123 NMR: 1.42(3H,t,J=7.0Hz), 1.67-1.87(2H,m), 1.98-2.14(2H,m), 2.23-2.40(1H,m), 2.96-3.06(2H,m), 3.06-3.21(2H,m), 3.21-3.47(5H,m), 3.47-3.65(4H,m), 3.65-3.86(3H,m), 3.86-3.99(2H,m), 3.99-4.16(3H,m), 4.21(2H,q,J=7.2Hz), 4.44(1H,dd,J=12.8,4.0Hz), 4.48-4.57(3H,m), 4.60(1H,d,J=6.0Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.27(1H,d,J=8.8Hz), 7.43(1H,dd,J=8.4,2.4Hz), 7.48(1H,d,J=2.0Hz), 7.52(1H,ddd,J=8.4,8.4,7.2Hz) MS: 645.30[M+H] + , 643.40[M-H] -Example 124 NMR: 1.42(3H,t,J=7.0Hz), 1.68-1.86(2H,m), 1.96-2.15(2H,m), 2.23-2.39(1H,m), 2.84-2.98(1H,m), 2.98-3.06(2H,m), 3.06-3.26(4H,m), 3.26-3.43(3H,m), 3.43-3.63(3H,m), 3.63-3.81(3H,m), 3.81-3.99(3H,m), 3.99-4.16(1H,m), 4.21(2H,q,J=7.2Hz), 4.51(2H,s), 4.60(1H,d,J=6.0Hz), 4.98-5.00(1H,m), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.29(1H,d,J=8.4Hz), 7.43(1H,dd,J=8.8,2.4Hz), 7.48(1H,d,J=2.0Hz), 7.52(1H,ddd,J=8.4,8.4,7.2Hz) MS: 665.35[M+H] + , 663.50[M-H] - Example 125 NMR: 1.42(3H,t,J=7.0Hz), 1.65-1.87(2H,m), 1.99-2.13(2H,m), 2.10-2.40(2H,m), 2.45-2.70(1H,m), 2.95-3.06(2H,m), 3.06-3.19(2H,m), 3.19-3.39(3H,m), 3.39-3.50(3H,m), 3.50-3.65(6H,m), 3.65-3.82(3H,m), 3.82-3.94(1H,m), 3.94-4.09(1H,m), 4.21(2H,q,J=7.0Hz), 4.51(2H,s), 4.59(1H,d,J=5.6Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.25(1H,d,J=8.4Hz), 7.41(1H,dd,J=8.4,2,4Hz), 7.46(1H,d,J=2.0Hz), 7.52(1H,ddd,J=8.4,8.4,6,8Hz) MS: 629.30[M+H] + , 627.50[M-H] -Example 126 NMR: 1.41 (3H, t, J = 7.0 Hz), 1.66 - 1.84 (2H, m), 1.96 - 2.12 (2H, m), 2.22 - 2.38 (1H, m), 2.77 - 2.97 (2H, m), 2.97 - 3.13 (2H, m), 3.22 - 3.39 (5H, m), 3.39 - 5.57 (3H, m), 3.57 - 3.71 (3H, m), 3.71 - 4.10 (2H, m), 4.15 - 4.26 (3H, m), 4.44 - 4.54 (3H, m), 4.59 (1H, d, J = 5.6 Hz), 6.88 (1H, dd, J = 8.8, 8.8 Hz), 6.95 (1H, d, J = 8.4 Hz), 7.06 (1H, d, J = 8.8 Hz), 7.13 - 7.26 (2H, m), 7.35 - 7.42 (3H, m), 7.44 (1H, d, J = 2.4 Hz), 7.46 - 7.55 (1H, m) MS: 697.30 [M + H] + , 695.50 [M - H] - Example 127 NMR: 1.13 (3H, d, J = 7.0 Hz), 1.16 (3H, d, J = 7.0 Hz), 1.42 (3H, t, J = 7.0 Hz), 1.68 - 1.81 (2H, m), 1.98 - 2.14 (2H, m), 2.25 - 2.37 (1H, m), 2.42 (1H, ddd, J = 12.4, 6.8, 5.6 Hz), 2.97 - 3.08 (2H, m), 3.08 - 3.24 (2H, m), 3.24 - 3.47 (4H, m), 3.47 - 3.61 (2H, m), 3.61 - 3.80 (3H, m), 3.80 - 3.97 (1H, m), 3.97 - 4.10 (1H, m), 4.13 (1H, d, J = 5.6 Hz), 4.20 (1H, q, J = 6.8 Hz), 4.51 (2H, s), 4.59 (1H, d, J = 6.0 Hz), 6.89 (1H, dd, J = 8.8, 8.8 Hz), 6.97 (1H, d, J = 8.4 Hz), 7.28 (1H, d, J = 8.4 Hz), 7.42 (1H, dd, J = 8.4, 2.4 Hz), 7.46 - 7.57 (2H, m) MS: 631.40 [M + H] + , 629.45 [M - H]​​​Example 128 NMR: 1.41(3H,t,J=7.0Hz), 1.67-1.86(2H,m), 1.95-2.13(2H,m), 2.23-2.37(1H,m), 2.96-3.16(4H,m), 3.26-3.39(3H,m), 3.39-3.49(3H,m), 3.49-3.59(2H,m), 3.59-3.76(4H,m), 3.76-3.95(1H,m), 3.95-4.10(1H,m), 4.15-4.24(3H,m), 4.51(2H,s), 4.55(2H,d,J=6.0Hz), 4.59(1H,d,J=6.0Hz), 6.88(1H,dd,J=9.0,9.0Hz), 6.97(1H,d,J=8.4Hz), 7.25-7.34(2H,m), 7.34-7.42(3H,m), 7.44(1H,dd,J=8.4,2.4Hz), 7.47-7.56(2H,m) MS: 691.30[M+H] + , 689.45[M-H] - Example 129 NMR: 1.03(3H,d,J=6.8Hz), 1.05(3H,d,J=6.4Hz), 1.42(3H,t,J=7.0Hz)1.69-1.85(3H,m), 1.85-2.00(2H,m), 2.00-2.14(2H,m), 2.24-2.39(1H,m), 2.79(3H,s), 2.98-3.06(2H,m), 3.06-3.21(2H,m), 3.21-... + , 657.50[M-H] -Example 130 NMR: 1.42(3H,t,J=7.0Hz), 1.70-1.88(2H,m), 2.00-2.14(3H,m), 2.17(3H,s), 2.25-2.46(3H,m), 2.75(2H,t,J=7.6Hz), 2.90-3.08(3H,m), 3.08-3.24(2H,m), 3.24-3.46(4H,m), 3.46-3.64(3H,m), 3.64-3.90(3H,m), 3.90-4.10(1H,m), 4.17-4.25(3H,m), 4.39-4.45(1H,m), 4.52(2H,s), 4.60(1H,d,J=6.0Hz), 6.89(1H,d,d,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.30(1H,d,J=8.4Hz), 7.39-7.57(3H,m) MS: 663.30[M+H] + , 661.70[M-H] - Example 131 NMR: 1.40(3H,t,J=7.0Hz), 1.57-1.78(2H,m), 1.90-2.07(2H,m), 2.16-2.36(1H,m), 2.92-3.07(2H,m), 3.07-3.16(2H,m), 3.16-3.48(5H,m), 3,48-3.92(6H,m), 4.00-4.34(3H,m), 4.50(2H,s), 4.57(1H,d,J=5.2Hz), 6.88(1H,d,J=8.8,8.8Hz), 6.95(1H,d,J=8.4Hz), 7.39(1H,d,J=8.4Hz), 7.44-7.58(3H,m), 7.68-7.79(1H,m), 8.05-8.22(2H,m), 8.73(1H,d,J=4.8Hz) MS: 637.30[M+H] + , 635.45[M-H] -Example 132 NMR: 1.42 (3H, t, J = 7.0 Hz), 1.44 - 1.66 (3H, m), 1.66 - 1.87 (2H, m), 1.87 - 2.11 (4H, m), 2.11 - 2.24 (1H, m), 2.24 - 2.37 (1H, m), 2.39 (1H, d, J = 6.8 Hz), 2.51 (2H, d, J = 7.2 Hz), 2.91 - 3.17 (5H, m), 3.17 - 3.38 (3H, m), 3.38 - 3.52 (4H, m), 3.52 - 3.60 (1H, m), 3.60 - 3.76 (3H, m), 3.76 - 3.95 (1H, m), 3.95 - 4.17 (1H, m), 4.21 (2H, g, J = 6.9 Hz), 4.51 (2H, s), 4.59 (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 = 8.4 Hz), 7.41 (1H, dd, J = 8.6, 2.2 Hz), 7.46 (1H, d, J = 2.0 Hz), 7.48 - 7.60 (1H, m) MS: 657.35 [M + H] + , 655.45 [M - H] - Example 133 NMR: 1.42 (3H, t, J = 7.0 Hz), 1.66 - 1.94 (8H, m), 1.98 - 2.13 (2H, m), 2.21 - 2.41 (1H, m), 2.93 - 3.05 (2H, m), 3.05 - 3.23 (2H, m), 3.23 - 3.44 (4H, m), 3.44 - 3.61 (3H, m), 3.61 - 3.82 (3H, m), 3.82 - 3.98 (1H, m), 3.98 - 4.16 (1H, m), 4.20 (2H, q, J = 7.1 Hz), 4.51 (2H, s), 4.59 (1H, d, J = 6.0 Hz), 6.89 (1H, dd, J = 8.8, 8.8 Hz), 6.97 (1H, d, J = 8.8 Hz), 7.23 (1H, d, J = 8.4 Hz), 7.44 (1H, dd, J = 8.6, 2.2 Hz), 7.46 - 7.59 (2H, m) MS: 617.30 [M + H] + , 615.65 [M - H] -Example 134 NMR: 1.42(3H,t,J=7.0Hz), 1.66-1.87(2H,m), 1.94-2.16(2H,m), 2.19-2.45(3H,m), 2.51-2.72(2H,m), 2.81-2.94(2H,m), 2.95-3.07(2H,m), 3.07-3.21(2H,m), 3.21-3.43(4H,m), 3.43-3.63(3H,m), 3.63-3.83(3H,m), 3.83-3.97(1H,m), 3.97-4.17(1H,m), 4.20(2H,q,J=7.1Hz), 4.51(2H,s), 4.59(1H,d,J=6.0Hz), 6.88(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.26(1H,d,J=8.4Hz), 7.45(1H,dd,J=8.4,2.4 Hz), 7.47-7.58(2H,m) MS: 629.30[M+H] + , 627.35[M-H] - Example 135 NMR: 1.41(3H,t,J=7.0Hz), 1.62-1.83(2H,m), 1.95-2.11(2H,m), 2.18-2.37(1H,m), 2.93-3.14(5H,m), 3.14-3.42(4H,m), 3.42-3.60(2H,m), 3.60-3.72(3H,m), 3.72-3.95(1H,m), 3.95-4.16(1H,m), 4.19(2H,q,J=7.1Hz), 4.51(2H,s), 4.57(1H,d,J=6.0Hz), 6.88(1H,dd,J=8.8,8.8Hz), 6.96(1H,d,J=8.4Hz), 7.28(1H,d,J=8.4Hz), 7.44(1H,dd,J=8.4,2.4Hz), 7.47-7.58(2H,m), 7.90(1H,s) MS: 658.25[M+H] + , 656.40[M-H] -Example 136 NMR: 1.41(3H,t,J=7.0Hz), 1.65-1.86(2H,m), 1.95-2.14(2H,m), 2.23-2.41(1H,m), 2.93-3.18(4H,m), 3.18-3.45(4H,m), 3.45-3.63(3H,m), 3.63-3.82(2H,m), 3.82-3.96(1H,m), 3.96-4.10(1H,m), 4.10-4.26(5H,m), 4.51(2H,s), 4.59(1H,d,J=6.0Hz), 6.88(1H,dd,J=9.0,9.0Hz), 6.96(1H,d,J=8.8Hz), 7.24(1H,d,J=8.4Hz), 7.40(1H,dd,J=8.4,2.4Hz), 7.46(1H,d,J=2.0Hz), 7.48-7.58(1H,m), 8.04(1H,dd,J=8.0,6.0Hz), 8.52-8.61(1H,m), 8.74(1H,d,J=5.6Hz), 8.78-8.84(1H,m) MS: 651.30[M+H] + , 649.55[M-H] - Example 137 NMR: 1.19(9H,s), 1.42(3H,t,J=7.0Hz), 1.67-1.88(2H,m), 1.97-2.13(2H,m), 2.23-2.39(1H,m), 2.99-3.19(4H,m), 3.19-3.45(4H,m), 3.45-3.62(3H,m), 3.62-3.83(3H,m), 3.83-3.97(1H,m), 3.99(1H,s), 4.01-4.16(1H,m), 4.20(2H,q,J=6.9Hz), 4.50(2H,s), 4.58(1H,d,J=6.0Hz), 6.88(1H,dd,J=8.8,8.8Hz), 6.96(1H,d,J=8.4Hz), 7.29(1H,d,J=8.4Hz), 7.42(1H,dd,J=8.8,2.4Hz), 7.45-7.57(2H,m) MS: 645.30[M+H] + , 643.50[M-H] -

[0193] Example 138 NMR: 1.42(3H,t,J=7.0Hz), 1.58-1.80(2H,m), 1.86-2.03(2H,m), 2.15-2.32(1H,m), 2.75-2.98(4H,m), 3.09-3.26(2H,m), 3.26-3.50(5H,m), 3.50-3.79(3H,m), 3.79-3.97(1H,m), 4.00(2H,s), 4.03-4.17(1H,m), 4.21(2H,q,J=7.1Hz), 4.34(2H,s), 4.52(2H,s), 4.58(1H,d,J=6.0Hz), 6.89(1H,dd,J=9.0,9.0Hz), 6.97(1H,d,J=8.4Hz), 7.23(1H,d,J=8.4Hz), 7.37-7.60(7H,m) MS: 679.30[M+H] + , 677.50[M-H] - Example 139 NMR: 1.42(3H,t,J=7.0Hz), 1.66-1.88(3H,m), 1.93-2.19(5H,m), 2.21-2.40(2H,m), 2.73-2.96(1H,m), 2.96-3.19(5H,m), 3.19-3.41(5H,m), 3.41-3.62(3H,m), 3.62-3.81(3H,m), 3.81-4.17(3H,m), 4.21(2H,q,J=6.9Hz), 4.52(2H,s), 4.60(1H,d,J=6.0Hz), 6.89(1H,dd,J=9.0,9.0Hz), 6.97(1H,d,J=8.4Hz), 7.26(1H,d,J=8.4Hz), 7.41(1H,dd,J=8.4,2.4Hz), 7.44-7.48(1H,m), 7.48-7.58(1H,m) MS: 643.30[M+H] + , 641.65[M-H] -Example 140 NMR: 1.42(3H,t,J=7.0Hz), 1.60-1.80(2H,m), 1.86-1.98(2H,m), 2.14-2.29(1H,m), 2.29-2.49(2H,m), 2.87(2H,t,J=8.2Hz), 2.92-3.10(4H,m), 3.22-3.40(3H,m), 3.40-3.58(3H,m), 3.58-3.76(3H,m), 3.76-3.96(1H,m), 3.96-4.14(1H,m), 4.17-4.25(3H,m), 4.37(1H,t,J=6.4Hz), 4.51(2H,s), 4.55(1H,d,J=6.0Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.17(1H,d,J=8.4Hz), 7.28-7.44(6H,m), 7.46(1H,d,J=2.0Hz), 7.52(1H,ddd,J=8.8,8.8,6.8Hz) MS: 693.35[M+H] + , 691.55[M-H] - Example 141 NMR: 1.41(3H,t,J=7.0Hz), 1.66-1.84(2H,m), 1.97-2.13(2H,m), 2.22-2.38(1H,m), 2.73-2.94(2H,m), 2.94-3.15(2H,m), 3.15-3.40(5H,m), 3.40-3.57(3H,m), 3.57-3.74(3H,m), 3.74-3.98(1H,m), 3.98-4.12(1H,m), 4.16-4.25(3H,m), 4.44-4.55(3H,m), 4.58(1H,d,J=5.6Hz), 6.88(1H,dd,J=8.8,8.8Hz), 6.96(1H,d,J=8.4Hz), 7.06(1H,d,J=8.4Hz), 7.32-7.42(3H,m), 7.42-7.56(4H,m) MS: 713.30[M+H] + , 711.50[M-H] -Example 142 NMR: 1.41(3H,t,J=7.0Hz), 1.66 - 1.85(2H,m), 1.97 - 2.14(2H,m), 2.23 - 2.38(1H,m), 2.72 - 2.95(2H,m), 2.95 - 3.14(2H,m), 3.14 - 3.38(5H,m), 3.38 - 3.57(3H,m), 3.57 - 3.75(3H,m), 3.75 - 3.98(1H,m), 3.98 - 4.10(1H,m), 4.16 - 4.25(3H,m), 4.44 - 4.55(3H,m), 4.58(1H,d,J=5.6Hz), 6.88(1H,dd,J=8.8,8.8Hz), 6.96(1H,d,J=8.4Hz), 7.56(1H,d,J=8.4Hz), 7.32 - 7.42(3H,m), 7.42 - 7.56(4H,m) MS: 713.30[M+H] + , 711.55[M - H] - Example 143 NMR: 1.11 - 1.38(5H,m), 1.41(3H,t,J=7.0Hz), 1.64 - 1.92(7H,m), 1.94 - 2.14(3H,m), 2.19 - 2.35(1H,m), 2.97 - 3.17(4H,m), 3.17 - 3.56(6H,m), 3.62 - 3.79(3H,m), 3.79 - 3.94(1H,m), 3.94 - 4.06(1H,m), 4.08(1H,d,J=5.6Hz), 4.15 - 4.25(3H,m), 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=8.8Hz), 7.27(1H,d,J=8.4Hz), 7.42(1H,dd,J=8.4,2.4Hz), 7.45 - 7.55(2H,m) MS: 671.40[M+H] + , 669.55[M - H] -Example 144 NMR: 1.41 (3H, t, J = 7.0 Hz), 1.66-1.85 (2H, m), 1.96-2.12 (2H, m), 2.22-2.37 (1H, m), 2.78-2.98 (2H, m), 2.98-3.15 (2H, m), 3.25-3.42 (5H, m), 3.42-3.58 (3H, m), 3.58-3.65 (2H, m), 3.65-3.80 (1H, m), 3.80-3.99 (1H, m), 3.99-4.09 (1H, m), 4.15-4.25 (3H, m), 4.45-4.55 (3H, m), 4.58(1H,d,J=6.0Hz), 6.88(1H,dd,J=8.8,8.8Hz), 6.96(1H,d,J=8.8Hz), 7.05(1H,d,J=8.4Hz), 7.15-7.24(2H,m), 7.34-7.42(3H,m), 7.44(1H,d,J=2.4Hz), 7.51(1H,ddd,J=8.4,8.4,6.8Hz) MS:697.35[M+H] + , 695.50[MH] - Example 145 NMR: 1.27-1.46 (3H, m), 1.60-1.83 (2H, m), 1.90-2.06 (2H, m), 2.18-2.34 (1H, m), 2.85-3.14 (5H, m), 3.14-3.50 (7H, m), 3.50-3.90 (5H, m), 4.08-4.27 (2H, m), 4.48 (2H, s), 4.56 (1H, d, J=6.0 Hz), 4.90-5.00 (2H, m), 6.70-7.00 (3H, m), 7.30-7.60 (8H, m), 8.75-8.83 (2H, m), 9.03-9.13(1H,m) MS:785.40[M+H] + , 783.75[MH] -Example 146 NMR: 1.41 (3H, t, J = 7.0 Hz), 1.65 - 1.84 (2H, m), 1.94 - 2.06 (2H, m), 2.21 - 2.36 (1H, m), 2.90 - 3.20 (4H, m), 3.20 - 3.40 (3H, m), 3.40 - 3.60 (3H, m), 3.60 - 3.80 (3H, m), 3.90 - 4.10 (2H, m), 4.16 - 4.25 (3H, m), 4.51 (2H, s), 4.58 (1H, d, J = 6.0 Hz), 6.89 (1H, dd, J = 8.8, 8.8 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.11 (1H, dd, J = 8.8, 1.6 Hz), 7.25 (1H, d, J = 8.4 Hz), 7.36 - 7.58 (4H, m), 8.16 - 8.20 (1H, m) MS: 638.30 [M + H] + , 636.45 [M - H] - Example 147 NMR: 1.36 - 1.46 (3H, m), 1.54 - 1.76 (2H, m), 1.85 - 2.05 (2H, m), 2.14 - 2.30 (1H, m), 2.55 - 2.84 (4H, m), 2.84 - 3.10 (2H, m), 3.10 - 3.41 (3H, m), 3.41 - 3.74 (4H, m), 3.90 - 4.10 (2H, m), 4.14 - 4.24 (3H, m), 4.52 (2H, s), 4.56 (1H, d, J = 6.0 Hz), 6.80 - 7.00 (2H, m), 7.04 - 7.15 (2H, m), 7.34 - 7.56 (4H, m), 8.21 - 8.26 (1H, m) MS: 636.70 [M - H] -

[0194] Example 148 NMR: 1.42 (3H, t, J = 7.0 Hz), 1.56-1.74 (2H, m), 1.90-2.02 (2H, m), 2.12-2.30 (1H, m), 2.67-2.81 (2H, m), 2.81-2.91 (2H, m), 3.10-3.34 (3H, m), 3.34-3.45 (3H, m), 3.45-3.70 (3H, m), 3.70-3.87 (3H, m), 3.87-4.10 (1H, m), 4.17-4.25 (3H, m), 4.52 (2H, s), 4.56 (1H, d, J = 5.6 Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.8Hz), 7.20-7.27(2H,m), 7.38-7.45(3H,m), 7.48-7.57(2H,m) MS: 656.25[M+H] + , 654.65[MH] - Example 149 NMR: 1.40 (3H, t, J = 7.0 Hz), 1.61-1.79 (2H, m), 1.94-2.06 (2H, m), 2.19-2.33 (1H, m), 2.95-3.14 (4H, m), 3.14-3.43 (5H, m), 3.43-3.72 (5H, m), 3.72-4.08 (1H, m), 4.15-4.24 (3H, m), 4.50 (2H, s), 4.56 (1H, d, J = 6.0 Hz), 6.88 (1H, dd, J = 8.8, 8.8 Hz), 6.96 (1H, d, J = 8.8 Hz), 7.33 (1H, d, J = 8.4 Hz), 7.42-7.59(3H,m), 8.58(1H,s), 9.24(1H,s) MS:643.25[M+H] + , 641.35[MH] -Example 150 NMR: 1.40(3H,t,J=7.0Hz), 1.63-1.80(2H,m), 1.94-2.06(2H,m), 2.20-2.34(1H,m), 2.97-3.16(4H,m), 3.16-3.43(4H,m), 3.43-3.61(3H,m), 3.61-3.82(3H,m), 3.82-3.98(1H,m), 3.98-4.10(1H,m), 4.19(2H,q,J=7.2Hz), 4.30(2H,s), 4.49(2H,s), 4.56(1H,d,J=6.0Hz), 6.88(1H,dd,J=8.8,8.8Hz), 6.95(1H,d,J=8.4Hz), 7.33(1H,d,J=8.4Hz), 7.44-7.56(3H,m), 7.64(2H,d,J=8.4Hz), 8.00(2H,d,J=8.4Hz) MS: 665.55[M+H] + , 663.75[M-H] - Example 151 NMR: 1.42(3H,t,J=7.0Hz), 1.68-1.86(3H,m), 1.95-2.18(4H,m), 2.21-2.38(2H,m), 2.74-2.94(1H,m), 2.93-3.20(6H,m), 3.20-3.42(6H,m), 3.42-3.62(3H,m), 3.62-3.82(3H,m), 3.82-3.93(1H,m), 3.93-4.04(1H,m), 4.21(2H,q,J=6.8Hz), 4.52(2H,s), 4.59(1H,d,J=6.0Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.8Hz), 7.26(1H,d,J=8.4Hz), 7.41(1H,dd,J=8.4,2.4Hz), 7.46(1H,d,J=6.0Hz), 7.52(1H,ddd,J=8.4,8.4,7.2Hz) MS: 643.30[M+H] + , 641.50[M-H] -Example 152 NMR: 1.40(3H,t,J=7.0Hz), 1.58 - 1.78(2H,m), 1.90 - 2.05(2H,m), 2.18 - 2.32(1H,m), 2.93 - 3.14(4H,m), 3.14 - 3.46(5H,m), 3.46 - 3.78(5H,m), 3.78 - 4.09(1H,m), 4.15 - 4.24(3H,m), 4.50(2H,s), 4.55(1H,d,J=5.6Hz), 6.88(1H,d,J=8.8,8.8Hz), 6.96(1H,d,J=8.8Hz), 7.37(1H,d,J=8.8Hz), 7.47 - 7.57(3H,m), 8.44(1H,d,J=2.0Hz), 9.11(1H,d,J=2.0Hz) MS: 643.25[M+H] + , 641.35[M - H] - Example 153 NMR: 1.42(3H,t,J=7.0Hz), 1.68 - 1.87(2H,m), 1.97 - 2.10(2H,m), 2.10 - 2.40(4H,m), 2.58 - 2.70(1H,m), 2.96 - 3.07(2H,m), 3.07 - 3.19(2H,m), 3.19 - 3.52(7H,m), 3.52 - 3.65(2H,m), 3.65 - 3.83(3H,m), 3.83 - 3.99(1H,m), 3.99 - 4.10(1H,m), 4.21(2H,q,J=6.8Hz), 4.51(2H,s), 4.60(1H,d,J=5.6Hz), 4.63 - 4.69(1H,m), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.28(1H,d,J=8.4Hz), 7.43(1H,dd,J=8.4,2.4Hz), 7.48(1H,d,J=2.0Hz), 7.52(1H,ddd,J=8.4,8.4,7.2Hz) MS: 629.35[M+H] + , 627.75[M - H] -Example 154 NMR: 1.42(3H,t,J=7.0Hz), 1.65-1.91(2H,m), 1.96-2.17(2H,m), 2.24-2.41(1H,m), 2.97-3.21(4H,m), 3.21-3.46(4H,m), 3.46-3.67(4H,m), 3.67-3.83(3H,m), 3.83-4.01(1H,m), 4.01-4.17(1H,m), 4.21(2H,q,J=6.9Hz), 4.52(2H,s), 4.56-4.66(3H,m), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.36(1H,d,J=8.4Hz), 7.43(1H,dd,J=8.4,2.4Hz), 7.46-7.49(1H,m), 7.49-7.57(1H,m) MS: 618.30[M+H] + , 616.45[M-H] - Example 155 NMR: 1.42(3H,t,J=7.0Hz), 1.65-1.98(7H,m), 1.98-2.12(2H,m), 2.12-2.46(3H,m), 2.92-3.20(6H,m), 3.20-3.43(3H,m), 3.43-3.62(3H,m), 3.63-3.87(3H,m), 3.87-4.13(2H,m), 4.21(2H,q,J=7.0Hz), 4.51(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), 7.26(1H,d,J=8.4Hz), 7.41(1H,dd,J=8.4,2.4Hz), 7.47(1H,d,J=2.4Hz), 7.52(1H,ddd,J=8.4,8.4,8.4Hz) MS: 643.30[M+H] + , 641.45[M-H] -Example 156 NMR: 1.42(3H,t,J=7.0Hz), 1.50(6H,s), 1.68 - 1.86(2H,m), 2.00 - 2.14(2H,m), 2.24 - 2.40(1H,m), 2.87(2H,s), 2.97 - 3.21(4H,m), 3.21 - 3.46(4H,m), 3.46 - 3.65(3H,m), 3.65 - 3.83(3H,m), 3.83 - 3.99(1H,m), 3.99 - 4.00(1H,m), 4.21(2H,q,J=7.0Hz), 4.52(2H,s), 4.60(1H,d,J=6.0Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.27(1H,d,J=8.4Hz), 7.42(1H,dd,J=8.4,2.4Hz), 7.47(1H,d,J=2.0Hz), 7.48 - 7.58(1H,m) MS: 631.35[M + H] + , 629.55[M - H] - Example 157 NMR: 1.05(6H,d,J=6.8Hz), 1.42(3H,t,J=7.0Hz), 1.66 - 1.87(2H,m), 1.94 - 2.14(3H,m), 2.24 - 2.39(1H,m), 2.79 - 2.90(1H,m), 2.92 - 2.99(1H,m), 2.99 - 3.18(4H,m), 3.18 - 3.41(3H,m), 3.41 - 3.57(3H,m), 3.57 - 3.66(2H,m), 3.66 - 3.80(2H,m), 3.80 - 3.99(1H,m), 3.99 - 4.10(1H,m), 4.17 - 4.33(3H,m), 4.51(2H,s),4.60(1H,d,J=5.6Hz), 6.88(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.8Hz), 7.26(1H,d,J=8.4Hz), 7.41(1H,dd,J=8.4,2.4Hz), 7.46(1H,d,J=2.0Hz), 7.52(1H,ddd,J=8.4,8.4,6.8Hz) MS: 645.35[M + H] + , 643.40[M - H] -

[0195] Example 158 NMR: 1.27 - 1.45(6H, m), 1.45 - 1.68(3H, m), 1.68 - 1.85(2H, m), 1.89 - 2.14(5H, m), 2.20 - 2.38(2H, m), 2.64 - 2.76(1H, m), 2.92 - 3.04(2H, m), 3.04 - 3.17(2H, m), 3.17 - 3.43(5H, m), 3.43 - 3.64(3H, m), 3.64 - 4.10(3H, m), 4.28(2H, q, J = 7.0Hz), 4.51(2H, s), 4.59(1H, d, J = 6.0Hz), 6.88(1H, dd, J = 8.8, 8.8Hz), 6.96(1H, d, J = 8.4Hz), 7.21(1H, d, J = 8.4Hz), 7.41(1H, dd, J = 8.4, 2.4Hz), 7.46(1H, d, J = 2.4Hz), 7.52(1H, ddd, J = 8.4, 8.4, 7.2Hz) MS: 657.35[M + H] + , 655.55[M - H] - Example 159 NMR: 1.27 - 1.46(5H, m), 1.46 - 1.68(3H, m), 1.68 - 1.86(2H, m), 1.96 - 2.22(6H, m), 2.22 - 2.40(2H, m), 2.65 - 2.78(1H, m), 2.92 - 3.16(3H, m), 3.16 - 3.39(3H, m), 3.39 - 3.64(3H, m), 3.64 - 3.79(3H, m), 3.79 - 4.10(3H, m), 4.20(2H, q, J = 7.0Hz), 4.51(2H, s), 4.59(1H, d, J = 6.0Hz), 6.88(1H, dd, J = 8.8, 8.8Hz), 6.96(1H, d, J = 8.4Hz), 7.20(1H, d, J = 8.4Hz), 7.41(1H, dd, J = 8.4, 2.4Hz), 7.46(1H, d, J = 2.0Hz), 7.48 - 7.56(1H, m) MS: 657.35[M + H] + , 655.40[M - H] -Example 160 NMR: 1.41(3H,t,J=7.0Hz), 1.65-1.84(2H,m), 1.95-2.09(2H,m), 2.22-2.35(1H,m), 2.84-3.01(5H,m), 3.01-3.17(4H,m), 3.17-3.41(3H,m), 3.41-3.59(3H,m), 3.59-3.79(3H,m), 3.79-3.96(1H,m), 3.96-4.16(2H,m), 4.20(2H,q,J=7.0Hz), 4.50(2H,s), 4.57(1H,d,J=5.6Hz), 6.88(1H,dd,J=8.8,8.8Hz), 6.96(1H,d,J=8.4Hz), 7.12(1H,d,J=8.4Hz), 7.29-7.48(7H,m), 7.52(1H,ddd,J=8.4,8.4,6.8Hz) MS: 693.25[M+H] + , 691.75[M-H] - Example 161 NMR: 1.42(3H,t,J=7.0Hz), 1.69-1.88(2H,m), 1.98-2.12(2H,m), 2.12-2.23(2H,m), 2.23-2.40(1H,m), 2.98-3.08(2H,m), 3.08-3.19(4H,m), 3.19-3.39(5H,m), 3.39-3.66(4H,m), 3.66-3.86(3H,m), 3.86-4.00(1H,m), 4.00-4.17(1H,m), 4.20(2H,q,J=7.0Hz), 4.25(2H,s), 4.51(2H,s), 4.59(1H,d,J=6.0Hz), 6.88(1H,dd,J=8.8,8.8Hz), 6.96(1H,d,J=8.4Hz), 7.31(1H,d,J=8.4Hz), 7.42(1H,dd,J=8.4,2.4Hz), 7.47(1H,d,J=2.4Hz), 7.52(1H,ddd,J=8.4,8.4,7.2Hz) MS: 646.25[M+H] + , 644.40[M-H] -Example 162 NMR: 1.42(3H,t,J=7.0Hz), 1.67-1.81(2H,m), 1.99-2.13(2H,m), 2.24-2.39(1H,m), 2.97-3.07(2H,m), 3.07-3.19(2H,m), 3.19-3.41(4H,m), 3.41-3.62(7H,m), 3.62-3.80(3H,m), 3.80-3.95(1H,m), 3.95-4.17(5H,m), 4.20(2H,q,J=6.8Hz), 4.31(2H,s), 4.51(2H,s), 4.59(1H,d,J=5.6Hz), 6.88(1H,dd,J=8.8,8.8Hz), 6.96(1H,d,J=8.4Hz), 7.30(1H,d,J=8.4Hz), 7.42(1H,dd,J=8.4,2.4Hz), 7.46(1H,d,J=2.4Hz), 7.52(1H,ddd, J=8.4,8.4,7.2Hz) MS: 659.20[M+H] + , 657.65[M-H] - Example 163 NMR: 1.42(3H,t,J=7.0Hz), 1.64-1.86(3H,m), 1.98-2.14(2H,m), 2.21-2.38(2H,m), 2.54-2.60(1H,m), 2.61-2.82(3H,m), 2.90-3.23(5H,m), 3.23-3.38(4H,m), 3.38-3.65(6H,m), 3.65-3.75(2H,m), 3.75-3.97(1H,m), 3.97-4.16(1H,m), 4.20(2H,q,J=7.0Hz), 4.51(2H,s), 4.59(1H,d,J=6.0Hz), 6.88(1H,dd,J=8.8,8.8Hz), 6.96(1H,d,J=8.4Hz), 7.22(1H,d,J=8.8Hz), 7.41(1H,dd,J=8.4,2.4Hz), 7.46(1H,d,J=2.0Hz), 7.52(1H,ddd, J=8.4,8.4,7.2Hz) MS: 643.25[M+H] + , 641.40[M-H] -Example 164 NMR: 1.42(3H,t,J=7.0Hz), 1.64-1.86(3H,m), 1.98-2.12(2H,m), 2.22-2.38(2H,m), 2.54-2.60(1H,m), 2.60-2.85(3H,m), 2.90-3.21(5H,m), 3.21-3.38(4H,m), 3.38-3.65(6H,m), 3.65-3.75(2H,m), 3.75-3.95(1H,m), 3.95-4.16(1H,m), 4.20(2H,q,J=7.0Hz), 4.51(2H,s), 4.59(1H,d,J=6.0Hz), 6.88(1H,dd,J=8.8,8.8Hz), 6.96(1H,d,J=8.4Hz), 7.22(1H,d,J=8.4Hz), 7.41(1H,dd,J=8.4,2.4Hz), 7.46(1H,d,J=2.0Hz), 7.52(1H,ddd, J=8.4,8.4,7.2Hz) MS: 643.20[M+H] + , 641.40[M-H] - Example 165 NMR: 1.38-1.46(6H,m), 1.67-1.87(2H,m), 1.97-2.16(2H,m), 2.23-2.40(1H,m), 2.62-2.75(1H,m), 2.90(2H,d,J=6.8Hz), 2.97-3.18(4H,m), 3.18-3.40(3H,m), 3.40-3.65(4H,m), 3.65-3.90(4H,m), 3.90-4.16(1H,m), 4.21(2H,q,J=7.0Hz), 4.52(2H,s), 4.60(1H,d,J=6.0Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.27(1H,d,J=8.8Hz), 7.42(1H,dd,J=8.8,2.4Hz), 7.46(1H,d,J=2.0Hz), 7.52(1H,ddd,J=8.4,8.4,7.2Hz) MS: 617.25[M+H] + , 615.40[M-H] -Example 166 NMR: 1.42(3H,t,J=7.0Hz), 1.54 - 1.66(2H,m), 1.73 - 1.86(4H,m), 1.99 - 2.21(4H,m), 2.25 - 2.40(1H,m), 2.90 - 3.21(7H,m), 3.21 - 3.46(4H,m), 3.46 - 3.62(2H,m), 3.62 - 3.81(3H,m), 3.81 - 4.00(1H,m), 4.00 - 4.17(1H,m), 4.21(2H,q,J=7.2Hz), 4.30 - 4.40(1H,m), 4.52(2H,s), 4.58 - 4.63(1H,m), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.26(1H,d,J=8.4Hz), 7.43(1H,dd,J=8.4,2.4Hz), 7.46 - 7.57(2H,m) MS: 660.30[M + H] + , 658.70[M - H] - Example 167 NMR: 1.42(3H,t,J=7.0Hz), 1.67 - 1.96(6H,m), 1.96 - 2.27(4H,m), 2.27 - 2.47(2H,m), 2.94 - 3.20(5H,m), 3.20 - 3.42(4H,m), 3.42 - 3.63(3H,m), 3.63 - 3.79(2H,m), 3.79 - 3.93(1H,m), 3.93 - 4.16(2H,m), 4.21(2H,q,J=6.8Hz), 4.52(2H,s), 4.60(1H,d,J=6.4Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.4Hz), 7.27(1H,dd,J=8.4,3.6Hz), 7.42(1H,dd,J=8.8,2.4Hz), 7.50(1H,d,J=2.0Hz), 7.52(1H,ddd,J=8.4,8.4,7.2Hz) MS: 643.25[M + H] + , 641.75[M - H] -

[0196] Example 168 NMR: 1.42(3H,t,J=7.0Hz), 1.65-1.98(7H,m), 1.98-2.13(2H,m), 2.13-2.48(4H,m), 2.94-3.21(5H,m), 3.21-3.42(3H,m), 3.42-3.65(3H,m), 3.65-3.80(2H,m), 3.80-3.94(1H,m), 3.94-4.16(2H,m), 4.21(2H,q,J=7.0Hz), 4.51(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), 7.26(1H,d,J=8.8Hz), 7.41(1H,dd,J=8.4,8.4Hz), 7.47(1H,d,J=2.4Hz), 7.52(1H,ddd,J=8.4,8.4,7.2Hz) MS: 643.30[M+H] + , 641.40[M-H]<o000706>Example 169 NMR: 1.42(3H,t,J=7.0Hz), 1.66-1.89(2H,m), 1.97-2.17(2H,m), 2.24-2.40(1H,m), 2.66-2.74(1H,m), 2.90-2.99(2H,m), 2.99-3.06(2H,m), 3.06-3.18(2H,m), 3.18-3.42(4H,m), 3.42-3.49(2H,m), 3.49-3.63(2H,m), 3.63-3.81(4H,m), 3.81-3.97(3H,m), 3.97-4.17(3H,m), 4.21(2H,q,J=7.1Hz), 4.52(2H,s), 4.60(1H,d,J=5.6Hz), 6.89(1H,dd,J=9.0,zoHz), 6.97(1H,d,J=8.4Hz), 7.27(1H,d,J=8.8Hz), 7.41(1H,dd,J=8.4,2.4Hz), 7.46(1H,d,J=2.0Hz), 7.48-7.57(1H,m) MS: 659.25[M+H] + , 657.45[M-H] - It should be noted that there seems to be a typo in the original text where "<o000706>" should probably be " - ". Also, the "zoHz" in the NMR data of Example 169 might be a typo and should perhaps be "8.8Hz" as per the pattern. The translation has been done as accurately as possible based on the provided text.Example 170 NMR: 1.38 - 1.49 (6H, m), 1.65 - 1.88 (2H, m), 1.99 - 2.16 (2H, m), 2.24 - 2.41 (1H, m), 2.66 - 2.73 (1H, m), 2.91 (2H, d, J = 6.4Hz), 2.98 - 3.07 (2H, m), 3.07 - 3.21 (2H, m), 3.21 - 3.42 (3H, m), 3.42 - 3.63 (3H, m), 3.63 - 3.72 (3H, m), 3.78 - 3.99 (2H, m), 3.99 - 4.17 (1H, m), 4.21 (2H, q, J = 7.1Hz), 4.52 (2H, s), 4.60 (1H, d, J = 5.6Hz), 6.89 (1H, dd, J = 8.8, 8.8Hz), 6.97 (1H, d, J = 8.4Hz), 7.27 (1H, d, J = 8.8Hz), 7.41 (1H, dd, J = 8.4, 2.4Hz), 7.44 - 7.49 (1H, m), 7.49 - 7.58 (1H, m) MS: 617.25[M + H] + , 615.55[M - H] - Example 171 NMR: 1.42 (3H, t, J = 7.0Hz), 1.66 - 1.82 (2H, m), 1.82 - 2.00 (3H, m), 2.00 - 2.00 - 2.13 (3H, m), 2.13 - 2.25 (2H, m), 2.25 - 2.52 (2H, m), 2.93 - 3.15 (4H, m), 3.15 - 3.25 (1H, m), 3.25 - 3.40 (3H, m), 3.40 - 3.63 (3H, m), 3.63 - 3.78 (3H, m), 3.78 - 3.99 (2H, m), 3.99 - 4.17 (1H, m), 4.21 (2H, q, J = 6.9Hz), 4.51 (2H, s), 4.59 (1H, d, J = 6.0Hz), 6.89 (1H, dd, J = 8.6, 8.6Hz), 6.97 (1H, d, J = 8.4Hz), 7.24 (1H, d, J = 8.4Hz), 7.41 (1H, dd, J = 8.6, 2.2Hz), 7.46 (1H, d, J = 2.4Hz), 7.48 - 7.57 (1H, m) MS: 643.30[M + H] + , 641.85[M - H] -Example 172 NMR: 1.40 (3H, t, J = 7.0 Hz), 1.59 - 1.80 (2H, m), 1.86 - 2.08 (4H, m), 2.08 - 2.32 (4H, m), 2.72 - 2.93 (4H, m), 2.93 - 3.05 (3H, m), 3.05 - 3.25 (5H, m), 3.25 - 3.39 (3H, m), 3.39 - 3.73 (6H, m), 3.73 - 3.95 (2H, m), 4.07 - 4.27 (4H, m), 4.30 - 4.42 (1H, m), 6.86 (1H, dd, J = 9.0, 9.0 Hz), 6.94 (1H, d, J = 9.2 Hz), 7.21 (1H, d, J = 8.4 Hz), 7.37 - 7.55 (3H, m) MS: 657.35 [M + H] + , 655.60 [M - H] - Example 173 NMR: 1.40 (3H, t, J = 7.0 Hz), 1.59 - 1.77 (2H, m), 1.91 - 2.06 (2H, m), 2.15 - 2.32 (1H, m), 2.93 - 3.07 (2H, m), 3.07 - 3.15 (2H, m), 3.15 - 3.41 (4H, m), 3.41 - 3.60 (2H, m), 3.60 - 3.80 (4H, m), 3.80 - 4.05 (1H, m), 4.05 - 4.25 (3H, m), 4.50 (2H, s), 4.54 (1H, d, J = 5.6 Hz), 6.88 (1H, dd, J = 8.8, 8.8 Hz), 6.95 (1H, d, J = 8.4 Hz), 7.33 - 7.58 (6H, m), 8.05 (1H, dd, J = 4.2, 1.4 Hz) MS: 652.25 [M + H] + , 650.50 [M - H] -Example 174 NMR: 1.41 (3H, t, J = 7.0 Hz), 1.60 - 1.82 (2H, m), 1.94 - 2.11 (2H, m), 2.20 - 2.38 (1H, m), 2.93 - 3.18 (4H, m), 3.18 - 3.45 (4H, m), 3.45 - 3.64 (3H, m), 3.64 - 3.84 (3H, m), 3.84 - 4.07 (2H, m), 4.20 (2H, q, J = 7.1 Hz), 4.50 (2H, s), 4.57 (1H, d, J = 6.0 Hz), 6.88 (1H, dd, J = 8.8, 8.8 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.05 (1H, d, J = 7.2 Hz), 7.32 (1H, d, J = 8.4 Hz), 7.43 - 7.58 (3H, m), 8.08 (1H, dd, J = 7.2, 1.2 Hz), 8.71 - 8.78 (1H, m) MS: 652.30 [M + H] + , 650.50 [M - H] - Example 175 NMR: 1.42 (3H, t, J = 7.0 Hz), 1.69 - 1.87 (2H, m), 1.99 - 2.15 (2H, m), 2.24 - 2.44 (1H, m), 2.65 - 2.73 (1H, m), 2.91 - 2.99 (2H, m), 2.99 - 3.06 (2H, m), 3.06 - 3.20 (2H, m), 3.20 - 3.42 (4H, m), 3.42 - 3.49 (2H, m), 3.49 - 3.63 (2H, m), 3.63 - 3.81 (4H, m), 3.81 - 3.98 (3H, m), 4.02 - 4.17 (3H, m), 4.21 (2H, q, J = 7.1 Hz), 4.52 (2H, s), 4.60 (1H, d, J = 6.4 Hz), 6.89 (1H, dd, J = 8.8, 8.8 Hz), 6.97 (1H, d, J = 8.4 Hz), 7.27 (1H, d, J = 8.4 Hz), 7.41 (1H, dd, J = 8.4, 2.4 Hz), 7.46 (1H, d, J = 2.4 Hz), 7.48 - 7.57 (1H, m) MS: 659.30 [M + H] + , 657.40 [M - H] -Example 176 NMR: 1.42 (3H, t, 7.0 Hz), 1.67-1.89 (2H, m), 1.98-2.15 (2H, m), 2.25-2.41 (1H, m), 2.68-2.92 (1H, m), 2.99-3.25 (6H, m), 3.25-3.42 (3H, m), 3.42-3.51 (3H, m), 3.51-3.66 (2H, m), 3.66-3.85 (3H, m), 3.85-3.98 (1H, m), 3.98-4.18 (2H, m), 4.21 (2H, q, J = 7.1 Hz), 4.52 (2H, s), 4.60(1H,d,J=6.0Hz), 6.89(1H,dd,J=8.8,8.8Hz), 6.97(1H,d,J=8.8Hz), 7.30(1H,d,J=8.4Hz), 7.42(1H,dd,J=8.4,2.4Hz), 7.46(1H,d,J=2.0Hz), 7.48-7.57(1H,m) MS:632.30[M+H] + , 630.15[MH] -

[0197] Example 177 Anisole (0.47 mL) and a 5.1 mol / L hydrobromic acid / acetic acid solution (2.2 mL) were added to di-tert-butyl (S)-2-(((2-(2-(4-((R)-1-(((benzyloxy)carbonyl)amino)-2-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)methyl)piperazine-1,4-dicarboxylate (254 mg), and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (7.9 mL) and diethyl ether (7.9 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The solid was collected by filtration. The solid was washed with diethyl ether, then water was added and the mixture was freeze-dried to give (R)-2-amino-2-(1-(5-chloro-2-((((R)-piperazin-2-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one hydrobromide (209 mg) as a pale yellow solid. NMR: 1.29(3H,t,J=7.4Hz), 1.67-1.86(2H,m), 1.98-2.12(2H,m), 2.21-2.38(1H,m), 2.93-3.23(9H,m), 3.23-3.57(11H,m), 3.57-3.64(1H,m), 3.64-3.81(3H,m), 3.81-3.92(1H,m), 3.92-4.03(1H,m), 4.03-4.17(1H,m), 4.42(2H,s), 4.57(1H,d,J=6.0Hz), 6.77(1H,d,J=8.8Hz), 7.09(1H,dt,J=8.4,2.8Hz), 7.19(1H,d,J=2.8Hz), 7.26(1H,dd,J=8.4,2.8Hz), 7.35(1H,dd,J=10.0,2.8Hz), 7.52(1H,dd,J=8.4,5.6Hz) MS:646.25[M+H] +

[0198] The compounds shown in Table 20 were obtained in the same manner as in Example 177.

[0199] The NMR and MS measurement values ​​of the compounds in the table are shown. Example 178 NMR: 1.68-1.85 (2H, m), 1.98-2.13 (2H, m), 2.21-2.36 (1H, m), 2.54 (3H, s), 2.90-3.06 (3H, m), 3.06-3.21 (5H, m), 3.21-3.52 (11H, m), 3.52-3.62 (1H, m), 3.62-3.80 (3H, m), 3.80-3.91 (1H, m), 3.91-4.01 (1H, m), 4.01-4.16 (1H, m), 4.40 (2H, s), 4.55 (1H, d, J = 6.0 Hz), 6.77 (1H, d, J = 8.8 Hz), 7.19(1H,d,J=2.4Hz), 7.26(1H,dd,J=8.4,2.4Hz), 7.30-7.39(1H,m), 7.48(1H,d,J=7.6Hz), 7.52(1H,d,J=4.0Hz) MS: 614.25[M+H] + Example 179 NMR: 1.69-1.85 (2H, m), 1.98-2.13 (2H, m), 2.22-2.36 (1H, m), 2.54 (3H, s), 2.90-3.05 (3H, s), 3.05-3.22 (5H, m), 3.22-3.53 (11H, m), 3.53-3.62 (1H, m), 3.62-3.80 (3H, m), 3.80-3.92 (1H, m), 3.92-4.02 (1H, m) 4.02-4.14 (1H, m), 4.41 (2H, s), 4.55 (1H, d, J = 6.0 Hz), 6.77 (1H, d, J = 8.8 Hz), 7.19(1H,d,J=2.4Hz), 7.26(1H,dd,J=8.4,2.4Hz), 7.30-7.39(1H,m), 7.48(1H,d,J=7.2Hz), 7.53(1H,d,J=3.6Hz) MS: 614.25[M+H] +Example 180 NMR: 1.29 (3H, t, J = 7.4 Hz), 1.70-1.86 (2H, m), 2.00-2.13 (2H, m), 2.24-2.38 (1H, m), 2.92-3.29 (10H, m), 3.29-3.58 (10H, m), 3.58-3.82 (4H, m), 3.82-3.95 (1H, m), 3.95-4.07 (1H, m), 4.07-4.22 (1H, m), 4.48 (2H, s), 4.58 (1H, d, J = 6.0 Hz), 6.76 (1H, d, J = 8.8 Hz), 7.10 (1H, dt, J = 8.0, 2.8 Hz), 7.19(1H,d,J=2.4Hz), 7.26(1H,dd,J=8.8,2.4Hz), 7.36(1H,dd,J=10.0,2.8Hz), 7.53(1H,dd,J=8.4,5.6Hz) MS: 646.25[M+H] +

[0200] Example 181 Anisole (0.15 mL) and a 5.1 mol / L hydrobromic acid / acetic acid solution (0.75 mL) were added to benzyl (R)-(1-(1-(5-chloro-2-((2-ureidoethyl)amino)phenethyl)piperidin-4-yl)-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)carbamate (75 mg), and the mixture was stirred at room temperature for 1 hour and 30 minutes. Ethyl acetate (5 mL) and diethyl ether (5 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes, and the solid was collected by filtration. The solid was washed with diethyl ether and then dried under reduced pressure to give (R)-1-(2-((2-(2-(4-(1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)ethyl)urea hydrobromide (78 mg) as a pale yellow solid. NMR: 1.42(3H,t,J=7.0Hz), 1.65-1.88(2H,m), 1.99-2.20(2H,m), 2.23-2.46(1H,m), 2.91-3.08(2H,m), 3.08-3.20(2H,m), 3.20-3.49(9H,m), 3.50-3.88(6H,m), 4.08-4.36(3H,m), 4.52(2H,s), 4.57-4.67(1H,m), 6.89(1H,dd,J=8.8,8.8Hz), 6.99(2H,dd,J=16.2,8.6Hz), 7.28(1H,s), 7.33(1H,dd,J=8.4,2.4Hz), 7.52(1H,dd,J=15.4,8.6Hz) MS:618.35[M+H] +

[0201] Example 182 Anisole (10 μL) and a 5.1 mol / L hydrobromic acid / acetic acid solution (50 μL) were added to di-tert-butyl (((2-(2-(4-(1-(((benzyloxy)carbonyl)amino)-2-(4-(2-e...

Claims

1. General formula [1] “During the ceremony, Z. １ represents a nitrogen atom or a group represented by the formula CH; ２ is a nitrogen atom or a group of the general formula N ＋ -R ４ "During the ceremony, R ４ is an optionally substituted C １－６ represents an alkyl group; R １ represents a hydrogen atom or an optionally substituted amino group; X ３ is a compound of the general formula NR ３ "During the ceremony, R ３ represents a hydrogen atom or an optionally substituted C １－３ represents an alkyl group, an oxygen atom or a bond; X ４ represents a sulfonyl group, a carbonyl group, C １－３ an alkylene group or a bond; R ２ represents a hydrogen atom, an optionally substituted amino, an optionally substituted carbamoyl, an optionally substituted C １－６ Alkyl, optionally substituted C １－６ Alkoxy, optionally substituted C １－６ alkylthio, optionally substituted C ３－１０ cycloalkyl, optionally substituted cyclic amino, optionally substituted aryl and optionally substituted heterocyclic groups; １ is an optionally substituted C ２－６ an alkylene group; ２ represents a halogen atom or a hydroxyl group; Y １ represents an optionally substituted aryl group, or a salt thereof.

2. Z １ is a group represented by the formula CH; Z ２ is a nitrogen atom; R １ is an optionally substituted amino group or a salt thereof according to claim 1.

3. X １ But C ２－６ The compound or salt thereof according to claim 1 or 2, wherein the compound or salt is an alkylene group.

4. X ２ The compound or salt thereof according to claim 1 or 2, wherein is a halogen atom.

5. X ３ is represented by the general formula NR ３ａ "R ３ａ The compound or salt thereof according to claim 1 or 2, wherein represents a hydrogen atom or an oxygen atom.

6. X ４ is a carbonyl group, C １－３ The compound or salt thereof according to claim 1 or 2, wherein the alkylene group or bond is an alkylene group or a bond.

7. R ２ is a hydrogen atom, an optionally substituted amino, an optionally substituted C １－６ Alkyl, optionally substituted C １－６ Alkoxy, optionally substituted C ３－１０ 3. The compound or salt thereof according to claim 1 or 2, which is a cycloalkyl, an optionally substituted cyclic amino, an optionally substituted aryl, or an optionally substituted heterocyclic group.

8. R ２ is optionally substituted amino, optionally substituted C １－６ 3. The compound or salt thereof according to claim 1 or 2, wherein the cyclic amino group may be alkyl or optionally substituted.

9. R ２ 3. The compound or salt thereof according to claim 1 or 2, wherein is an optionally substituted cyclic amino group.

10. Y １ 3. The compound or salt thereof according to claim 1 or 2, wherein is an optionally substituted phenyl group.

11. The compound is (R)-2-amino-2-(1-(5-chloro-2-((((S)-pyrrolidin-3-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(2-((S)-3-aminopyrrolidin-1-yl)-5-chloro (R)-2-amino-2-(1-(5-chloro-2-(piperazin-1-yl)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-(piperazin-1-yl)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(2-((2-aminoethyl)(methyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-(((S)-pyrrolidin-3-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(2-((2-aminoethyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(2-((2-aminoethyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2- amino-2-(1-(2-((2-aminoethyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-((((S)-pyrrolidin-3-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(methylthio)benzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-((((S)-pyrrolidin-3-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one;(R)-2-amino-2-(1-(5-chloro-2-(((S)-pyrrolidin-3-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(methylthio)benzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-((((S)-pyrrolidin-2-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-((((S)-pyrrolidin-2-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-(((S)-pyrrolidin-3-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-((((S)-pyrrolidin-2-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-5-hydroxy ... (S)-3,7-diamino-N-(2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)heptanamide; (R)-N-(2 -(2-(4-(1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)-2-((3-aminopropyl)amino)acetamide; (R)-2-amino-2-(1-(5-chloro-2-((((R)-piperazin-2-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one;(R)-2-amino-2-(1-(5-chloro-2-((((S)-piperazin-2-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(2-(bis(2-aminoethyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-((((S)-piperazin-2-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one (R)-2-amino-2-(1-(5-chloro-2-((((R)-piperazin-2-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-4-(1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)-1-(2-((2-aminoethyl)amino)-5-chlorophenethyl)-1-methylpiperidin-1-ium Bromide; (R)-2-amino-2-(1-(2-(2-aminoethoxy)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-(ethylthio)-4-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-((1,3-diaminopropan-2-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)- 2-amino-2-(1-(5-chloro-2-(((S)-2,3-diaminopropyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(2-((3-((3-aminopropyl)amino)propyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one;(R)-2-amino-2-(1-(2-((2-(2-aminoethoxy)ethyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-(((R)-2,3-diaminopropyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro- 2-((3-(piperazin-1-yl)propyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(2-((3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)propyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-1-(2-((2 -(2-(4-(1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)ethyl)guanidine; (R)-2-amino-2-(1-(2-((2-((2-aminoethyl)amino)ethyl)amino)-5-chlorophenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (R)-2-amino-2-(1-(5-chloro-2-(((c The compound or salt thereof according to claim 1, which is a compound selected from (R)-2-amino-2-(1-(5-chloro-2-(((trans-4-hydroxypyrrolidin-3-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one and (R)-2-amino-2-(1-(5-chloro-2-(((trans-4-hydroxypyrrolidin-3-yl)methyl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one.

12. The compound is (2S,4R)-4-((2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)-N-(2-aminoethyl)pyrrolidine-2-carboxamide; (S)-2,4-diamino-N-(2-((2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)ethyl)butanamide; (2S,4R)-4-((2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)-N-(2-aminoethyl)-N-methylpyrrolidine-2-carboxamide; (R)-2-amino-2-(1-(5-chloro-2-(((3R,5S)-5-(piperazine-1-carbonyl)pyrrolidin-3-yl)amino)phenethyl)piperidin-4-yl)-1-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)ethan-1-one; (2S,4R)-4-((2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)-N-(2-(guanidinoethyl)pyrrolidine-2-carboxamide; (2R,4S)-4-((2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)-N-(2-aminoethyl)pyrrolidine-2-carboxamide; (2S,4S)-4-((2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)-N-(2-aminoethyl)pyrrolidine-2-carboxamide; (2R,4R)-4-((2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)-N-(2-aminoethyl)pyrrolidine-2-carboxamide; (S)-2,5-diamino-N-(2-((2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazine-1- 2. The compound or salt thereof according to claim 1, which is a compound selected from the group consisting of (S)-2,5-diamino-N-(2-(2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenyl)amino)ethyl)pentanamide; and (S)-2,5-diamino-N-(2-(2-(2-(4-((R)-1-amino-2-(4-(2-ethoxy-6-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)ethyl)-4-chlorophenoxy)ethyl)pentanamide.

13. A pharmaceutical composition containing the compound or salt thereof according to any one of claims 1 to 12.

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