Amino acid active ester and salt thereof

Abstract

The present invention provides a novel active ester of an amino acid to be used for amino acylation of tRNA, said ester being capable of reducing risks to safety and waste. The present invention provides a compound represented by formula (I) or a salt thereof, in particular, dichloropyridinyl methyl ester or 2,2,2-trifluoroethyl ester or a salt thereof.

Description

Amino acid activated esters and their salts

[0001] The present disclosure relates to an amino acid activated ester and a method for producing an aminoacylated tRNA using the ester.

[0002] In recent years, non-naturally occurring peptides containing unnatural amino acids have become important candidates for drug discovery. They are expected to not only exhibit high affinity and specificity for target molecules, but also excellent in vivo stability and membrane permeability. Among the previously reported methods for synthesizing non-natural peptides, there is a method for synthesizing non-natural peptides from various amino acids and amino acid derivatives, including unnatural amino acids, using flexizyme, which catalyzes the aminoacylation of tRNA (Patent Documents 1-6, Non-Patent Documents 4 and 5). In this method, dinitrobenzyl ester (DBE) or cyanomethyl ester (CME) has traditionally been used as the activated ester of the amino acid used in the aminoacylation of tRNA. Furthermore, the use of various esters, including picolyl esters, pyridoxy esters, and 2,2,2-trifluoroethyl esters, in amino acid ester synthesis and peptide synthesis has been disclosed (Patent Documents 7-13, Non-Patent Documents 1-3). Patent Document 14 discloses the use of 2,6-dichloro-4-pyridinemethanol derivatives as pesticides.

[0003] WO2007 / 066627 (A1) WO2008 / 059823 (A1) WO2011 / 049157 (A1) WO2015 / 030014 (A1) JP 2008-125396 A WO2020 / 040840 (A2) UK Patent No. 1212533 ​​EP Patent Publication No. 0450356 WO2010 / 057961 (A1) WO2013 / 100132 (A1) WO2016 / 118877 (A1) WO2018 / 174078 (A1) WO2018 / 225864 (A1) WO1999 / 012907 (A1)

[0004] J. A. Maclaren, Aust. J. Chem. 1972, 25, 1293-1299. J. A. Maclaren, Aust. J. Chem. 1978, 31, 1865-1868. Sklyarov et al. , Russian Journal of Bioorganic Chemistry 2000, 26, 245-256. Murakami et al. , 2003, Chemistry & Biology, 10, 655-662. Journal of the Japan Society of Biotechnology, 93(12), 744.

[0005] DBE and CME, which have traditionally been used as activated esters of amino acids for aminoacylation of tRNA, are explosive nitro compounds and highly toxic cyanide compounds, respectively. Therefore, to ensure safety during use, storage, and disposal, careful and complicated handling, as well as the associated costs, are required.

[0006] The present invention provides a novel active ester of an amino acid for use in aminoacylation of tRNA, which is easy to handle during use, storage, and disposal, and can reduce handling costs.

[0007] The inventors conducted extensive research to obtain activated esters that can replace DBE and CME, and as a result, discovered dichloropyridinylmethyl ester and 2,2,2-trifluoroethyl ester. It was confirmed that the use of these activated amino acid esters allows the aminoacylation of tRNA by Flexizyme to proceed, and the inventors also found that the use of these activated esters facilitates handling during use, storage, and disposal, and reduces handling costs.

[0008] The present specification includes the disclosure of the following inventions: [1-1] Formula (I):

[0009]

[0010] [Wherein X represents a pyridyl group substituted with two or more halogen atoms, or a C group substituted with three or more fluorine atoms. １−３ Q is alkyl;

[0011]

[0012] n is an integer of 0 to 3, preferably an integer of 0 to 2; R ７ and R ８ are each independently a hydrogen atom or C １−３ alkyl; R １ and R ２ are each independently a hydrogen atom, a halogen atom, cyano, Y １ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y １ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y １ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ２ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ２ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ２ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ３ C optionally substituted with one or more substituents selected from ６−１４ Aryl, Y ３ a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of —COOR １１ , and -CONR １２ R １３ or R １ and R ５ together with the carbon and nitrogen atoms to which they are attached, form Y ２ R １ and R ２ together with the carbon atoms to which they are attached, form Y ２ C optionally substituted with one or more substituents selected from ３−１０ Carbocyclic ring, or Y ２R ３ and R ４ are each independently a hydrogen atom, a halogen atom, cyano, Y １ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y １ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y １ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ２ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ２ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ２ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ３ C optionally substituted with one or more substituents selected from ６−１４ aryl, and Y ３ a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of —COOR １１ , and -CONR １２ R １３ or R ３ and R ４ together with the carbon atoms to which they are attached, form Y ２ C optionally substituted with one or more substituents selected from ３−１０ Carbocyclic ring, or Y ２ R １１ , R １２ , and R １３ are each independently Y １ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y １ C optionally substituted with one or more substituents selected from ２−１０Alkenyl, Y １ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ２ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ２ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ２ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ３ C optionally substituted with one or more substituents selected from ６−１４ aryl, and Y ３ Y is selected from 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from １ each independently represents a halogen atom, nitro, cyano, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ５ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ６ C optionally substituted with one or more substituents selected from ６−１４ Aryl, Y ６ a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of —SH, —COOR ２１ , -NR ２２ R ２３ , -S(O) ｐ R ２４ , -OR ２５ , -SO ２ NR ２６ R ２７ , and -CONR ２８ R ２９ and oxo; Y ２ each independently represents a halogen atom, nitro, cyano, Y ４ C optionally substituted with one or more substituents selected from１−１０ Alkyl, Y ４ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y ４ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ５ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ６ C optionally substituted with one or more substituents selected from ６−１４ Aryl, Y ６ a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of —SH, —COOR ２１ , -NR ２２ R ２３ , -S(O) ｐ R ２４ , -OR ２５ , -SO ２ NR ２６ R ２７ , and -CONR ２８ R ２９ and oxo; Y ３ each independently represents a halogen atom, nitro, cyano, Y ４ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y ４ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y ４ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ５a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ６ C optionally substituted with one or more substituents selected from ６−１４ Aryl, Y ６ a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of —SH, —COOR ２１ , -NR ２２ R ２３ , -S(O) ｐ R ２４ , -OR ２５ , -SO ２ NR ２６ R ２７ , and -CONR ２８ R ２９ is selected from R ２１ , R ２６ , R ２７ , R ２８ , and R ２９ are each independently a hydrogen atom, Y ４ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y ４ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y ４ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ５ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ６ C optionally substituted with one or more substituents selected from ６−１４ aryl, and Y ６ R is selected from 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from ２２ , and R ２５ are each independently a hydrogen atom, Y ４C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y ４ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y ４ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ５ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ６ C optionally substituted with one or more substituents selected from ６−１４ Aryl, Y ６ a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of: ａ１ , -CONR ａ２ R ａ３ , -COOR ａ４ , -C(=NR ａ５ ) NR ａ６ R ａ７ , and -SO ２ NR ａ８ R ａ９ is selected from R ２３ is a hydrogen atom, Y ４ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y ４ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y ４ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ５a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ６ C optionally substituted with one or more substituents selected from ６−１４ aryl, and Y ６ R is selected from 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from ２４ Is Y ４ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y ４ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y ４ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ５ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ６ C optionally substituted with one or more substituents selected from ６−１４ aryl, and Y ６ R is selected from 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from ａ１ , R ａ２ , R ａ３ , R ａ４ , R ａ５ , R ａ６ , R ａ７ , R ａ８ , and R ａ９ are each independently a hydrogen atom, Y ４ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y ４ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y ４ C optionally substituted with one or more substituents selected from２−１０ Alkynyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ５ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ６ C optionally substituted with one or more substituents selected from ６−１４ aryl, and Y ６ Y is selected from 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from ４ each independently represents a halogen atom, nitro, cyano, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ５ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ６ C optionally substituted with one or more substituents selected from ６−１４ Aryl, Y ６ a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of —SH, —COOR ３１ , -NR ３２ R ３３ , -S(O) ｐ R ３４ , -OR ３５ , -SO ２ NR ３６ R ３７ , and -CONR ３８ R ３９ and oxo; Y ５ each independently represents a halogen atom, nitro, cyano, Y ７ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y ７C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y ７ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ８ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ８ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ８ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ９ C optionally substituted with one or more substituents selected from ６−１４ Aryl, Y ９ a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of —SH, —COOR ３１ , -NR ３２ R ３３ , -S(O) ｐ R ３４ , -OR ３５ , -SO ２ NR ３６ R ３７ , -CONR ３８ R ３９ and oxo; Y ６ each independently represents a halogen atom, nitro, cyano, Y ７ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y ７ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y ７ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ８ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ８ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ８a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ９ C optionally substituted with one or more substituents selected from ６−１４ Aryl, Y ９ a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of —SH, —COOR ３１ , -NR ３２ R ３３ , -S(O) ｐ R ３４ , -OR ３５ , -SO ２ NR ３６ R ３７ , and -CONR ３８ R ３９ is selected from R ３１ , R ３６ , R ３７ , R ３８ , and R ３９ are each independently a hydrogen atom, Y ７ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y ７ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y ７ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ８ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ８ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ８ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ９ C optionally substituted with one or more substituents selected from ６−１４ aryl, and Y ９ R is selected from 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from ３２ , and R ３５ are each independently a hydrogen atom, Y ７C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y ７ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y ７ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ８ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ８ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ８ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ９ C optionally substituted with one or more substituents selected from ６−１４ Aryl, Y ９ a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of: ｂ１ , -CONR ｂ２ R ｂ３ , -CO ２ R ｂ４ , -C(=NR ｂ５ ) NR ｂ６ R ｂ７ , and -SO ２ NR ｂ８ R ｂ９ is selected from R ３３ is a hydrogen atom, Y ７ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y ７ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y ７ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ８ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ８ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ８a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ９ C optionally substituted with one or more substituents selected from ６−１４ aryl, and Y ９ R is selected from 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from ３４ Is Y ７ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y ７ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y ７ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ８ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ８ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ８ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ９ C optionally substituted with one or more substituents selected from ６−１４ aryl, and Y ９ R is selected from 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from ｂ１ , R ｂ２ , R ｂ３ , R ｂ４ , R ｂ５ , R ｂ６ , R ｂ７ , R ｂ８ , and R ｂ９ are each independently a hydrogen atom, Y ７ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y ７ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y ７ C optionally substituted with one or more substituents selected from２−１０ Alkynyl, Y ８ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ８ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ８ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ９ C optionally substituted with one or more substituents selected from ６−１４ aryl, and Y ９ Y is selected from 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from ７ each independently represents a halogen atom, nitro, cyano, Y １０ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y １１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y １１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y １１ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of １２ C optionally substituted with one or more substituents selected from ６−１４ Aryl, Y １２ a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of —SH, —COOR ４０ , -NR ４１ R ４２ , -S(O) ｐ R ４３ , -OR ４４ , -SO ２ NR ４５ R ４６, and -CONR ４７ R ４８ and oxo; Y ８ each independently represents a halogen atom, nitro, cyano, Y １０ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y １１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y １１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y １１ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of １２ C optionally substituted with one or more substituents selected from ６−１４ Aryl, Y １２ a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of —SH, —COOR ４０ , -NR ４１ R ４２ , -S(O) ｐ R ４３ , -OR ４４ , -SO ２ NR ４５ R ４６ , -CONR ４７ R ４８ and oxo; Y ９ each independently represents a halogen atom, nitro, cyano, Y １０ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y１１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y １１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y １１ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of １２ C optionally substituted with one or more substituents selected from ６−１４ Aryl, Y １２ a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of —SH, —COOR ４０ , -NR ４１ R ４２ , -S(O) ｐ R ４３ , -OR ４４ , -SO ２ NR ４５ R ４６ , and -CONR ４７ R ４８ is selected from R ４０ , R ４５ , R ４６ , R ４７ , and R ４８ are each independently a hydrogen atom, Y １０ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y １１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y １１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y １１ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of １２ C optionally substituted with one or more substituents selected from６−１４ aryl, and Y １２ R is selected from 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from ４１ , and R ４４ are each independently a hydrogen atom, Y １０ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y １１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y １１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y １１ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of １２ C optionally substituted with one or more substituents selected from ６−１４ Aryl, Y １２ a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of: ｃ１ , -CONR ｃ２ R ｃ３ , -COOR ｃ４ , -C(=NR ｃ５ ) NR ｃ６ R ｃ７ , and -SO ２ NR ｃ８ R ｃ９ is selected from R ４２ is a hydrogen atom, Y １０ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y １１C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y １１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y １１ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of １２ C optionally substituted with one or more substituents selected from ６−１４ aryl, and Y １２ R is selected from 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from ４３ Is Y １０ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y １１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y １１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y １１ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of １２ C optionally substituted with one or more substituents selected from ６−１４ aryl, and Y １２ R is selected from 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from ｃ１ , R ｃ２ , R ｃ３ , R ｃ４ , R ｃ５ , R ｃ６ , R ｃ７ , R ｃ８ , and R ｃ９ are each independently a hydrogen atom, Y １０ C optionally substituted with one or more substituents selected from１−１０ Alkyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y １１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y １１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y １１ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of １２ C optionally substituted with one or more substituents selected from ６−１４ aryl, and Y １２ Y is selected from 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from １０ are each independently selected from a halogen atom, nitro, cyano, a halogen atom, and an alkoxy １−１０ Alkoxy, halogen atoms and C １−６ C optionally substituted by one or more substituents selected from alkoxy ３−１０ Cycloalkyl, halogen atoms and C １−６ C optionally substituted by one or more substituents selected from alkoxy ３−１０ Cycloalkenyl, halogen atom and C １−６ 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from alkoxy, a halogen atom, and C １−６ C optionally substituted by one or more substituents selected from alkoxy ６−１４ Aryl, halogen atoms and C １−６ 5-14 membered heteroaryl optionally substituted by one or more substituents selected from alkoxy, a halogen atom, and C １−６ alkoxy (C １−１０ alkoxy)carbonyl, halogen atoms and C １−６Di(C) optionally substituted by one or more substituents selected from alkoxy １−６ alkyl)aminocarbonyl, a halogen atom and C １−６ C optionally substituted by one or more substituents selected from alkoxy １−６ Alkoxy, halogen atoms and C １−６ C optionally substituted by one or more substituents selected from alkoxy １−６ Alkylthio, halogen atoms and C １−６ C optionally substituted by one or more substituents selected from alkoxy １−６ Alkyl sulfanyl, a halogen atom and C １−６ C optionally substituted by one or more substituents selected from alkoxy １−６ Alkyl sulfinyl, a halogen atom and C １−６ C optionally substituted by one or more substituents selected from alkoxy １−６ alkylsulfonyl, and oxo; １１ each independently optionally substituted with one or more substituents selected from halogen atom, nitro, cyano, halogen atom and alkoxy １−１０ C optionally substituted by one or more substituents selected from alkyl, halogen atoms and alkoxy ２−１０ C optionally substituted by one or more substituents selected from alkenyl, halogen atoms and alkoxy ２−１０ C optionally substituted by one or more substituents selected from alkynyl, halogen atoms, and alkoxy １−１０ Alkoxy, halogen atoms and C １−６ C optionally substituted by one or more substituents selected from alkoxy ３−１０ Cycloalkyl, halogen atoms and C １−６ C optionally substituted by one or more substituents selected from alkoxy ３−１０ Cycloalkenyl, halogen atom and C １−６ 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from alkoxy, a halogen atom, and C １−６C optionally substituted by one or more substituents selected from alkoxy ６−１４ Aryl, halogen atoms and C １−６ 5-14 membered heteroaryl optionally substituted by one or more substituents selected from alkoxy, a halogen atom, and C １−６ alkoxy (C １−１０ alkoxy)carbonyl, halogen atoms and C １−６ Di(C) optionally substituted by one or more substituents selected from alkoxy １−６ alkyl)aminocarbonyl, a halogen atom and C １−６ C optionally substituted by one or more substituents selected from alkoxy １−６ Alkoxy, halogen atoms and C １−６ C optionally substituted by one or more substituents selected from alkoxy １−６ Alkylthio, halogen atoms and C １−６ C optionally substituted by one or more substituents selected from alkoxy １−６ Alkyl sulfanyl, a halogen atom and C １−６ C optionally substituted by one or more substituents selected from alkoxy １−６ Alkyl sulfinyl, a halogen atom and C １−６ C optionally substituted by one or more substituents selected from alkoxy １−６ alkylsulfonyl, and oxo; １２ each independently optionally substituted with one or more substituents selected from halogen atom, nitro, cyano, halogen atom and alkoxy １−１０ C optionally substituted by one or more substituents selected from alkyl, halogen atoms and alkoxy ２−１０ C optionally substituted by one or more substituents selected from alkenyl, halogen atoms and alkoxy ２−１０ C optionally substituted by one or more substituents selected from alkynyl, halogen atoms, and alkoxy １−１０ Alkoxy, halogen atoms and C １−６C optionally substituted by one or more substituents selected from alkoxy ３−１０ Cycloalkyl, halogen atoms and C １−６ C optionally substituted by one or more substituents selected from alkoxy ３−１０ Cycloalkenyl, halogen atom and C １−６ 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from alkoxy, a halogen atom, and C １−６ C optionally substituted by one or more substituents selected from alkoxy ６−１４ Aryl, halogen atoms and C １−６ 5-14 membered heteroaryl optionally substituted by one or more substituents selected from alkoxy, a halogen atom, and C １−６ alkoxy (C １−１０ alkoxy)carbonyl, halogen atoms and C １−６ Di(C) optionally substituted by one or more substituents selected from alkoxy １−６ alkyl)aminocarbonyl, a halogen atom and C １−６ C optionally substituted by one or more substituents selected from alkoxy １−６ Alkoxy, halogen atoms and C １−６ C optionally substituted by one or more substituents selected from alkoxy １−６ Alkylthio, halogen atoms and C １−６ C optionally substituted by one or more substituents selected from alkoxy １−６ Alkyl sulfanyl, a halogen atom and C １−６ C optionally substituted by one or more substituents selected from alkoxy １−６ Alkyl sulfinyl, and halogen atoms and C １−６ C optionally substituted by one or more substituents selected from alkoxy １−６ alkylsulfonyl, each p is independently an integer of 0 to 2, ５ is a hydrogen atom, and Y is on the benzene ring. １３benzyl optionally substituted with one or more substituents selected from the group consisting of １３ benzyloxycarbonyl optionally substituted by one or more substituents selected from １３ phenylcarbonyl optionally substituted by one or more substituents selected from (C １−１０ alkoxy)carbonyl, (C １−１０ alkyl)carbonyl, Y １ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y １ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y １ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ２ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ２ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ２ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ３ C optionally substituted with one or more substituents selected from ６−１４ aryl, and Y ３ R is selected from 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from ６ is a hydrogen atom, and Y is on the benzene ring. １３ benzyl optionally substituted with one or more substituents selected from the group consisting of １３ benzyloxycarbonyl optionally substituted by one or more substituents selected from １３ phenylcarbonyl optionally substituted by one or more substituents selected from (C １−１０ alkoxy)carbonyl, (C １−１０ alkyl)carbonyl, or R ５ and R ６form a 5- to 14-membered nitrogen-containing heterocycle having an imide structure together with the nitrogen atom to which they are bonded, and Y １３ are each independently a halogen atom, C １−１０ Alkoxy, and C １−１０ or a salt thereof.

[0013] [1-2] The compound according to [1-1], wherein n is 0 or 1, or a salt thereof. [1-3] R １ [1-4] The compound according to [1-1] or [1-2], or a salt thereof, wherein R is a hydrogen atom. ７ and R ８

[0023]

[0024] The compound or salt thereof according to any one of [1-1] to [1-3], wherein

[0014] [1-5] The compound according to any one of [1-1] to [1-4], wherein X is 2,6-dihalo-4-pyridyl, or a salt thereof. [1-6] The compound according to any one of [1-1] to [1-4], wherein X is 2,6-dichloro-4-pyridyl, or a salt thereof.

[0015] [1-7] X is perfluoro C １−３ [1-8] The compound according to any one of [1-1] to [1-4], or a salt thereof, wherein X is alkyl. [1-9] The compound according to any one of [1-1] to [1-4], or a salt thereof, wherein X is trifluoromethyl.

[0016] [1-9] A composition for use in acylation of tRNA, comprising the compound according to any one of [1-1] to [1-8] or a salt thereof. [1-10] The composition according to [1-9], for use in acylation of tRNA in the presence of flexizyme.

[0017] [1-11] Formula (I):

[0018]

[0019] [In the formula, R １ , R ２ , R ５ , R ６ , R ７ , R ８, Q and X are as defined in any one of [1-1] to [1-8]],

[0020]

[0021] with a compound represented by formula (III):

[0022]

[0023] [wherein L is a leaving group]. [1-12] The method according to [1-11], wherein the reaction is carried out in the presence of a base.

[0024] [1-13] The method according to [1-12], wherein the base is diisopropylethylamine. [1-14] A method for producing a tRNA having an acylated 3'-terminus, wherein the acyl group at the 3'-terminus is:

[0025]

[0026] [In the formula, R １ , R ２ , R ５ , R ６ and Q is as defined in any one of [1-1] to [1-8]], and

[0027]

[0028] [In the formula, R １ , R ２ , R ５ , R ６ , R ７ , R ８ , Q and X are as defined in any one of [1-1] to [1-8]], with tRNA in the presence of flexizyme.

[0029] [1-15] A method for preparing a peptide library, comprising: producing tRNA acylated at the 3' end by the method described in [1-14]; preparing an mRNA library; and synthesizing peptides corresponding to each mRNA from the mRNA library using a cell-free translation system to prepare a peptide library.

[0030] [1-16] A method for acylating the 3' end of tRNA, comprising:

[0031]

[0032] [In the formula, R １ , R ２ , R ５ , R ６ , R ７ , R ８ , Q and X are as defined in any one of [1-1] to [1-8]] to the 3' end of tRNA by reacting it with a compound represented by the following in the presence of flexizyme:

[0033]

[0034] [In the formula, R １ , R ２ , R ５ , R ６ and Q is as defined in any one of [1-1] to [1-8].

[0035] [2-1] Formula (Ia):

[0036]

[0037] [Wherein X represents a pyridyl group substituted with two or more halogen atoms, or a C group substituted with three or more fluorine atoms. １−３ alkyl; Z is —NR ５ R ６ or -OR ｄ and Q is

[0038]

[0039] n is an integer of 0 to 3, preferably an integer of 0 to 2; R ７ and R ８ are each independently a hydrogen atom or C １−３ alkyl; R １ and R ２ are each independently a hydrogen atom, a halogen atom, cyano, Y １ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y １ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y １ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ２ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ２ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ２ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ３ C optionally substituted with one or more substituents selected from ６−１４ Aryl, Y ３ a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of —COOR １１ , and -CONR １２ R １３ or R １ and R ５ together with the carbon and nitrogen atoms to which they are attached, form Y ２ When n is an integer of 1 to 3, R １ and any one of R ３ together with the carbon atoms to which they are attached, form Y ２ C optionally substituted with one or more substituents selected from ３−１０ Carbocyclic ring, or Y ２R １ and R ２ together with the carbon atoms to which they are attached, form Y ２ C optionally substituted with one or more substituents selected from ３−１０ Carbocyclic ring, or Y ２ R ３ and R ４ are each independently a hydrogen atom, a halogen atom, cyano, Y １ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y １ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y １ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ２ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ２ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ２ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ３ C optionally substituted with one or more substituents selected from ６−１４ aryl, and Y ３ a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of —COOR １１ , and -CONR １２ R １３ or R ３ and R ４ together with the carbon atoms to which they are attached, form Y ２ C optionally substituted with one or more substituents selected from ３−１０ Carbocyclic ring, or Y ２When n is an integer of 1 to 3, R ５ and any one of R ３ together with the carbon atoms to which they are attached, form Y ２ R １１ , R １２ , and R １３ are each independently Y １ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y １ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y １ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ２ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ２ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ２ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ３ C optionally substituted with one or more substituents selected from ６−１４ aryl, and Y ３ Y is selected from 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from １ each independently represents a halogen atom, nitro, cyano, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ５ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ６ C optionally substituted with one or more substituents selected from６−１４ Aryl, Y ６ a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of —SH, —COOR ２１ , -NR ２２ R ２３ , −N ３ , -S(O) ｐ R ２４ , -OR ２５ , -SO ２ NR ２６ R ２７ , and -CONR ２８ R ２９ and oxo; Y ２ each independently represents a halogen atom, nitro, cyano, Y ４ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y ４ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y ４ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ５ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ６ C optionally substituted with one or more substituents selected from ６−１４ Aryl, Y ６ a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of —SH, —COOR ２１ , -NR ２２ R ２３ , -S(O) ｐ R ２４ , -OR ２５ , -SO ２ NR ２６ R ２７ , and -CONR ２８ R ２９and oxo; Y ３ each independently represents a halogen atom, nitro, cyano, Y ４ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y ４ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y ４ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ５ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ６ C optionally substituted with one or more substituents selected from ６−１４ Aryl, Y ６ a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of —SH, —COOR ２１ , -NR ２２ R ２３ , -S(O) ｐ R ２４ , -OR ２５ , -SO ２ NR ２６ R ２７ , and -CONR ２８ R ２９ is selected from R ２１ , R ２６ , R ２７ , R ２８ , and R ２９ are each independently a hydrogen atom, Y ４ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y ４ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y ４ C optionally substituted with one or more substituents selected from ２−１０Alkynyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ５ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ６ C optionally substituted with one or more substituents selected from ６−１４ aryl, and Y ６ R is selected from 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from ２２ , and R ２５ are each independently a hydrogen atom, Y ４ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y ４ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y ４ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ５ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ６ C optionally substituted with one or more substituents selected from ６−１４ Aryl, Y ６ a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of: ａ１ , -CONR ａ２ R ａ３ , -COOR ａ４ , -C(=NR ａ５ ) NR ａ６ R ａ７ , -S(O) ｐ R ２４, and -SO ２ NR ａ８ R ａ９ is selected from R ２３ is a hydrogen atom, Y ４ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y ４ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y ４ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ５ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ６ C optionally substituted with one or more substituents selected from ６−１４ aryl, and Y ６ R is selected from 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from ２４ Is Y ４ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y ４ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y ４ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ５ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ６ C optionally substituted with one or more substituents selected from６−１４ aryl, and Y ６ R is selected from 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from ａ１ , R ａ２ , R ａ３ , R ａ４ , R ａ５ , R ａ６ , R ａ７ , R ａ８ , and R ａ９ are each independently a hydrogen atom, Y ４ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y ４ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y ４ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ５ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ６ C optionally substituted with one or more substituents selected from ６−１４ aryl, and Y ６ Y is selected from 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from ４ each independently represents a halogen atom, nitro, cyano, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ５ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ５ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ６ C optionally substituted with one or more substituents selected from ６−１４Aryl, Y ６ a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of —SH, —COOR ３１ , -NR ３２ R ３３ , -S(O) ｐ R ３４ , -OR ３５ , -SO ２ NR ３６ R ３７ , and -CONR ３８ R ３９ and oxo; Y ５ each independently represents a halogen atom, nitro, cyano, Y ７ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y ７ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y ７ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ８ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ８ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ８ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ９ C optionally substituted with one or more substituents selected from ６−１４ Aryl, Y ９ a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of —SH, —COOR ３１ , -NR ３２ R ３３ , -S(O) ｐ R ３４ , -OR ３５ , -SO ２ NR ３６ R ３７ , -CONR ３８ R ３９ and oxo; Y ６each independently represents a halogen atom, nitro, cyano, Y ７ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y ７ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y ７ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ８ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ８ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ８ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ９ C optionally substituted with one or more substituents selected from ６−１４ Aryl, Y ９ a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of —SH, —COOR ３１ , -NR ３２ R ３３ , -S(O) ｐ R ３４ , -OR ３５ , -SO ２ NR ３６ R ３７ , and -CONR ３８ R ３９ is selected from R ３１ , R ３６ , R ３７ , R ３８ , and R ３９ are each independently a hydrogen atom, Y ７ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y ７ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y ７ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ８C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ８ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ８ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ９ C optionally substituted with one or more substituents selected from ６−１４ aryl, and Y ９ R is selected from 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from ３２ , and R ３５ are each independently a hydrogen atom, Y ７ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y ７ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y ７ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ８ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ８ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ８ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ９ C optionally substituted with one or more substituents selected from ６−１４ Aryl, Y ９ a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of: ｂ１ , -CONR ｂ２ R ｂ３ , -CO ２ R ｂ４ , -C(=NR ｂ５ ) NR ｂ６ R ｂ７ , and -SO ２ NR ｂ８ Rｂ９ is selected from R ３３ is a hydrogen atom, Y ７ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y ７ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y ７ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ８ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ８ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ８ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ９ C optionally substituted with one or more substituents selected from ６−１４ aryl, and Y ９ R is selected from 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from ３４ Is Y ７ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y ７ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y ７ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ８ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ８ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ８ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ９ C optionally substituted with one or more substituents selected from ６−１４ aryl, and Y ９R is selected from 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from ｂ１ , R ｂ２ , R ｂ３ , R ｂ４ , R ｂ５ , R ｂ６ , R ｂ７ , R ｂ８ , and R ｂ９ are each independently a hydrogen atom, Y ７ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y ７ C optionally substituted with one or more substituents selected from １２−１０ Alkenyl, Y ７ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ８ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ８ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ８ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ９ C optionally substituted with one or more substituents selected from ６−１４ aryl, and Y ９ Y is selected from 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from ７ each independently represents a halogen atom, nitro, cyano, Y １０ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y １１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y １１C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y １１ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of １２ C optionally substituted with one or more substituents selected from ６−１４ Aryl, Y １２ a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of —SH, —COOR ４０ , -NR ４１ R ４２ , -S(O) ｐ R ４３ , -OR ４４ , -SO ２ NR ４５ R ４６ , and -CONR ４７ R ４８ and oxo; Y ８ each independently represents a halogen atom, nitro, cyano, Y １０ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y １１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y １１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y １１ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of １２ C optionally substituted with one or more substituents selected from ６−１４ Aryl, Y １２ a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of —SH, —COOR ４０ , -NR ４１ R ４２ , -S(O)ｐ R ４３ , -OR ４４ , -SO ２ NR ４５ R ４６ , -CONR ４７ R ４８ and oxo; Y ９ each independently represents a halogen atom, nitro, cyano, Y １０ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y １１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y １１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y １１ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of １２ C optionally substituted with one or more substituents selected from ６−１４ Aryl, Y １２ a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of —SH, —COOR ４０ , -NR ４１ R ４２ , -S(O) ｐ R ４３ , -OR ４４ , -SO ２ NR ４５ R ４６ , and -CONR ４７ R ４８ is selected from R ４０ , R ４５ , R ４６ , R ４７ , and R ４８ are each independently a hydrogen atom, Y １０ C optionally substituted with one or more substituents selected from １−１０Alkyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y １１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y １１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y １１ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of １２ C optionally substituted with one or more substituents selected from ６−１４ aryl, and Y １２ R is selected from 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from ４１ , and R ４４ are each independently a hydrogen atom, Y １０ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y １１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y １１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y １１ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of １２ C optionally substituted with one or more substituents selected from ６−１４ Aryl, Y １２ a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of: ｃ１ , -CONR ｃ２R ｃ３ , -COOR ｃ４ , -C(=NR ｃ５ ) NR ｃ６ R ｃ７ , and -SO ２ NR ｃ８ R ｃ９ is selected from R ４２ is a hydrogen atom, Y １０ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y １１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y １１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y １１ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of １２ C optionally substituted with one or more substituents selected from ６−１４ aryl, and Y １２ R is selected from 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from ４３ Is Y １０ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y １１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y １１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y １１a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of １２ C optionally substituted with one or more substituents selected from ６−１４ aryl, and Y １２ R is selected from 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from ｃ１ , R ｃ２ , R ｃ３ , R ｃ４ , R ｃ５ , R ｃ６ , R ｃ７ , R ｃ８ , and R ｃ９ are each independently a hydrogen atom, Y １０ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y １０ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y １１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y １１ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y １１ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of １２ C optionally substituted with one or more substituents selected from ６−１４ aryl, and Y １２ Y is selected from 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from １０ are each independently selected from a halogen atom, nitro, cyano, a halogen atom, and an alkoxy １−１０ Alkoxy, halogen atoms and C １−６ C optionally substituted by one or more substituents selected from alkoxy ３−１０ Cycloalkyl, halogen atoms and C １−６C optionally substituted by one or more substituents selected from alkoxy ３−１０ Cycloalkenyl, halogen atom and C １−６ 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from alkoxy, a halogen atom, and C １−６ C optionally substituted by one or more substituents selected from alkoxy ６−１４ Aryl, halogen atoms and C １−６ 5-14 membered heteroaryl optionally substituted by one or more substituents selected from alkoxy, a halogen atom, and C １−６ alkoxy (C １−１０ alkoxy)carbonyl, halogen atoms and C １−６ Di(C) optionally substituted by one or more substituents selected from alkoxy １−６ alkyl)aminocarbonyl, a halogen atom and C １−６ C optionally substituted by one or more substituents selected from alkoxy １−６ Alkoxy, halogen atoms and C １−６ C optionally substituted by one or more substituents selected from alkoxy １−６ Alkylthio, halogen atoms and C １−６ C optionally substituted by one or more substituents selected from alkoxy １−６ Alkyl sulfanyl, a halogen atom and C １−６ C optionally substituted by one or more substituents selected from alkoxy １−６ Alkyl sulfinyl, a halogen atom and C １−６ C optionally substituted by one or more substituents selected from alkoxy １−６ alkylsulfonyl, and oxo; １１ each independently represents a C optionally substituted by one or more substituents selected from a halogen atom, nitro, cyano, a halogen atom, and an alkoxy; １−１０ C optionally substituted by one or more substituents selected from alkyl, halogen atoms and alkoxy ２−１０C optionally substituted by one or more substituents selected from alkenyl, halogen atoms and alkoxy ２−１０ C optionally substituted by one or more substituents selected from alkynyl, halogen atoms, and alkoxy １−１０ Alkoxy, halogen atoms and C １−６ C optionally substituted by one or more substituents selected from alkoxy ３−１０ Cycloalkyl, halogen atoms and C １−６ C optionally substituted by one or more substituents selected from alkoxy ３−１０ Cycloalkenyl, halogen atom and C １−６ 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from alkoxy, a halogen atom, and C １−６ C optionally substituted by one or more substituents selected from alkoxy ６−１４ Aryl, halogen atoms and C １−６ 5-14 membered heteroaryl optionally substituted by one or more substituents selected from alkoxy, a halogen atom, and C １−６ alkoxy (C １−１０ alkoxy)carbonyl, halogen atoms and C １−６ Di(C) optionally substituted by one or more substituents selected from alkoxy １−６ alkyl)aminocarbonyl, a halogen atom and C １−６ C optionally substituted by one or more substituents selected from alkoxy １−６ Alkoxy, halogen atoms and C １−６ C optionally substituted by one or more substituents selected from alkoxy １−６ Alkylthio, halogen atoms and C １−６ C optionally substituted by one or more substituents selected from alkoxy １−６ Alkyl sulfanyl, a halogen atom and C １−６ C optionally substituted by one or more substituents selected from alkoxy １−６ Alkyl sulfinyl, a halogen atom and C １−６C optionally substituted by one or more substituents selected from alkoxy １−６ alkylsulfonyl, and oxo; １２ each independently represents a C optionally substituted by one or more substituents selected from a halogen atom, nitro, cyano, a halogen atom, and an alkoxy; １−１０ C optionally substituted by one or more substituents selected from alkyl, halogen atoms and alkoxy ２−１０ C optionally substituted by one or more substituents selected from alkenyl, halogen atoms and alkoxy ２−１０ C optionally substituted by one or more substituents selected from alkynyl, halogen atoms, and alkoxy １−１０ Alkoxy, halogen atoms and C １−６ C optionally substituted by one or more substituents selected from alkoxy ３−１０ Cycloalkyl, halogen atoms and C １−６ C optionally substituted by one or more substituents selected from alkoxy ３−１０ Cycloalkenyl, halogen atom and C １−６ 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from alkoxy, a halogen atom, and C １−６ C optionally substituted by one or more substituents selected from alkoxy ６−１４ Aryl, halogen atoms and C １−６ 5-14 membered heteroaryl optionally substituted by one or more substituents selected from alkoxy, a halogen atom, and C １−６ alkoxy (C １−１０ alkoxy)carbonyl, halogen atoms and C １−６ Di(C) optionally substituted by one or more substituents selected from alkoxy １−６ alkyl)aminocarbonyl, a halogen atom and C １−６ C optionally substituted by one or more substituents selected from alkoxy １−６ Alkoxy, halogen atoms and C １−６C optionally substituted by one or more substituents selected from alkoxy １−６ Alkylthio, halogen atoms and C １−６ C optionally substituted by one or more substituents selected from alkoxy １−６ Alkyl sulfanyl, a halogen atom and C １−６ C optionally substituted by one or more substituents selected from alkoxy １−６ Alkyl sulfinyl, and halogen atoms and C １−６ C optionally substituted by one or more substituents selected from alkoxy １−６ alkylsulfonyl, each p is independently an integer of 0 to 2, ５ is a hydrogen atom, and Y is on the benzene ring. １３ benzyl optionally substituted with one or more substituents selected from the group consisting of １３ benzyloxycarbonyl optionally substituted by one or more substituents selected from １３ phenylcarbonyl optionally substituted by one or more substituents selected from (C １−１０ alkoxy)carbonyl, optionally substituted by a halogen atom (C １−１０ alkyl)carbonyl, Y １ C optionally substituted with one or more substituents selected from １−１０ Alkyl, Y １ C optionally substituted with one or more substituents selected from ２−１０ Alkenyl, Y １ C optionally substituted with one or more substituents selected from ２−１０ Alkynyl, Y ２ C optionally substituted with one or more substituents selected from ３−１０ cycloalkyl, Y ２ C optionally substituted with one or more substituents selected from ３−１０ cycloalkenyl, Y ２ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from the group consisting of ３ C optionally substituted with one or more substituents selected from６−１４ aryl, and Y ３ R is selected from 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from ６ is a hydrogen atom, and Y is on the benzene ring. １３ benzyl optionally substituted with one or more substituents selected from the group consisting of １３ benzyloxycarbonyl optionally substituted by one or more substituents selected from １３ phenylcarbonyl optionally substituted by one or more substituents selected from (C １−１０ alkoxy)carbonyl, (C １−１０ alkyl)carbonyl, or R ５ and R ６ are taken together with the nitrogen atom to which they are bonded to form a 5- to 14-membered nitrogen-containing heterocyclyl having an imido structure, or Y ２ R ｄ is a hydrogen atom, and Y is on the benzene ring. １３ benzyl optionally substituted with one or more substituents selected from the group consisting of １３ benzyloxycarbonyl optionally substituted by one or more substituents selected from １３ phenylcarbonyl optionally substituted by one or more substituents selected from (C １−１０ alkoxy)carbonyl, (C １−１０ alkyl)carbonyl; Y １３ are each independently a halogen atom, C １−１０ Alkoxy, and C １−１０ selected from alkyl, and when the 3- to 14-membered non-aromatic heterocyclyl is a monocyclic heterocyclyl, the heterocyclyl may be fused with a benzene ring; ６−１４ When aryl is phenyl, the phenyl may be fused with a 5- to 7-membered non-aromatic heterocycle] or a salt thereof (provided that in the formula, Z is hydroxy, n is 0, and R ７ and R８ is a hydrogen atom, X is 2,6-dichloropyridin-4-yl, R １ and R ２ is a hydrogen atom or R １ is a hydrogen atom, and R ２ is methyl, ethyl, isopropyl, n-butyl, tert-butyl, or isobutyl, or R １ is ethyl, and R ２ (Excluding compounds where is methyl or ethyl).

[0040] [2-2] The compound according to [2-1], wherein n is 0 or 1, or a salt thereof. [2-3] R １ [2-4] The compound according to [2-1] or [2-2], or a salt thereof, wherein R is a hydrogen atom. ７ and R ８ [2-1] - [2-3], wherein R is a hydrogen atom, or a salt thereof.

[0041] [2-5] The compound according to any one of [2-1] to [2-4], or a salt thereof, wherein X is 2,6-dihalo-4-pyridyl. [2-6] The compound according to any one of [2-1] to [2-4], or a salt thereof, wherein X is 2,6-dichloro-4-pyridyl.

[0042] [2-7] X is perfluoro C １−３ The compound according to any one of [2-1] to [2-4], or a salt thereof, which is alkyl. [2-8] The compound according to any one of [2-1] to [2-4], or a salt thereof, wherein X is trifluoromethyl.

[0043] [2-9] A composition for use in acylation of tRNA, comprising the compound or a salt thereof according to any one of [2-1] to [2-8]. [2-10] The composition according to [2-9] for use in acylating tRNA in the presence of flexizyme.

[0044] [2-11] Formula (Ia):

[0045]

[0046] [In the formula, R １, R ２ , R ７ , R ８ , Q, X, and Z are as defined in any one of [2-1] to [2-8]],

[0047]

[0048] with a compound represented by formula (III):

[0049]

[0050] [In the formula, L is a leaving group] The production method includes reacting with a compound represented by the following. [2-12] The method according to [2-11], wherein the reaction is performed in the presence of a base.

[0051] [2-13] The method according to [2-12], wherein the base is diisopropylethylamine. [2-14] A method for producing tRNA whose 3' end is acylated, wherein the acyl group at the 3' end is:

[0052]

[0053] [In the formula, R １ , R ２ , Q and Z are as defined in any one of [2-1] to [2-8]], and a group represented by formula (Ia):

[0054]

[0055] [In the formula, R １ , R ２ , R ７ , R ８ .

[0056] [2-15] A method for preparing a peptide library, comprising: producing tRNA acylated at the 3' end by the method described in [2-14]; preparing an mRNA library; and synthesizing peptides corresponding to each mRNA from the mRNA library using a cell-free translation system to prepare a peptide library.

[0057] [2-16] A method for acylating the 3' end of tRNA, comprising:

[0058]

[0059] [In the formula, R １ , R ２ , R ７ , R ８ , Q, X and Z are as defined in any of [2-1] to [2-8]] to the 3' end of tRNA by reacting it with a compound represented by:

[0060]

[0061] [In the formula, R １ , R ２ , R ５ , R ６ , and Q are as defined in any of [2-1] to [2-8]] A method for adding an acyl group represented by the following. [2-17] Z is -NR ５ R ６ The compound according to [2-1], or a salt thereof,

[0062] The amino acid activated esters of the present invention are useful as synthetic intermediates, for example, as reagents for acylation reactions. In one aspect of the present invention, the activated esters are used in the aminoacylation of tRNA by flexizyme, and are useful for synthesizing unique peptides composed of various amino acids and amino acid derivatives, including unnatural amino acids. Furthermore, the novel amino acid activated esters of the present invention are easy to handle during use, storage, and disposal, and can also reduce handling costs.

[0063] Figure 1-1 is a photograph, instead of a drawing, showing the results of confirming the acylation efficiency of (2,6-dichloropyridin-4-yl)methyl L-isoleucinate (Compound No. 21). Figure 1-2 is a photograph, instead of a drawing, showing the results of confirming the acylation efficiency of (2,6-dichloropyridin-4-yl)methyl glycinate (Compound No. 99). Figure 1-3 is a photograph, instead of a drawing, showing the results of confirming the acylation efficiency of 2,2,2-trifluoroethyl (S)-2-amino-4-phenylbutanoate (Compound No. 47). Figure 1-4 is a photograph, instead of a drawing, showing the results of confirming the acylation efficiency of 2,2,2-trifluoroethyl (S)-2-amino-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propanoate (Compound No. 81). FIG. 2 shows the Q ＤＳＣ and T ＤＳＣ This is a graph showing the results of confirming the presence or absence of danger of active esters of each amino acid, using a straight line connecting two points plotted with respective reference points as a danger determination line.

[0064] As used herein, the term "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, or the like. When a halogen atom is used as a substituent for an aryl, heteroaryl, or the like, preferred examples include a fluorine atom, a chlorine atom, and a bromine atom. When a halogen atom is used as a substituent for an alkyl or a group containing an alkyl as a part thereof (alkoxy, alkenyl, alkylthio, or the like) in this specification, preferred examples include a fluorine atom. Specific examples of groups having a halogen atom as a substituent include trifluoromethyl, pentafluoroethyl, trifluoromethoxy, pentafluoroethoxy, trifluoromethylthio, and pentafluoroethylthio.

[0065] As used herein, "C １−３ "Alkyl" means a monovalent group derived from a linear or branched saturated aliphatic hydrocarbon having 1 to 3 carbon atoms by removing one arbitrary hydrogen atom. Specific examples include methyl, ethyl, n-propyl, and isopropyl.

[0066] As used herein, "C １−１０ The term "alkyl" refers to a monovalent group derived by removing any one hydrogen atom from a linear or branched saturated aliphatic hydrocarbon having 1 to 10 carbon atoms. Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, 1-methylpropyl, n-pentyl, isopentyl, 2-methylbutyl, 1,1-dimethylpropyl, 1-ethylpropyl, hexyl, 4-methylpentyl, n-heptyl, 5-methylhexyl, 1-propylbutyl, 2-ethyl-2-methylbutyl, n-octyl, 5-methylheptyl, 2,3-dimethylhexyl, 1-methyl-1-propylbutyl, 2,2-diethylbutyl, 7-methyloctyl, 5-ethylheptyl, n-decyl, 8-methylnonyl, 5,5-dimethyloctyl, and 4-ethyl-6-methylheptyl.

[0067] As used herein, "C ２−１０ "Alkenyl" means a monovalent group derived by removing any one hydrogen atom from a straight-chain or branched-chain aliphatic hydrocarbon having 2 to 10 carbon atoms and at least one double bond (two adjacent SP2 carbon atoms). Specific examples include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-1-butenyl, 1,1-dimethyl-2-propenyl, 1-hexenyl, heptenyl, and octenyl.

[0068] As used herein, "optionally substituted C ２−１０ "Alkenyl" refers to an unsubstituted C ２−１０ Alkenyl or C in which one or more hydrogen atoms on the alkenyl are replaced by a given substituent ２−１０ means alkenyl. When having two or more substituents, each substituent may be the same or different. One carbon atom may be substituted with multiple substituents.

[0069] As used herein, "C ２−１０ "Alkynyl" means a monovalent group derived by removing any one hydrogen atom from a straight-chain or branched-chain aliphatic hydrocarbon having 2 to 10 carbon atoms and at least one triple bond (two adjacent SP carbon atoms). Specific examples include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-1-butynyl, 1,1-dimethyl-2-propynyl, 1-hexynyl, heptynyl, heptadiynyl, octynyl, and octadiynyl.

[0070] As used herein, "optionally substituted C ２−１０ "Alkynyl" refers to an unsubstituted C ２−１０ Alkynyl or C in which one or more hydrogen atoms on the alkynyl are replaced by a given substituent ２−１０ It means alkynyl. When it has two or more substituents, the substituents may be the same or different. One carbon atom may be substituted with multiple substituents.

[0071] As used herein, "C １−６ "Alkoxy" is C １−６ means an alkyl-O- group, where C １−６ Alkyl is as defined above. Specific examples include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, 1-pentyloxy, 1-hexyloxy, and the like.

[0072] As used herein, "C １−１０ "Alkoxy" is C １−１０ means an alkyl-O- group, where C １−１０The alkyl is as defined above. Specific examples include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, 1-pentyloxy, 1-hexyloxy, n-heptyloxy, 5-methylhexyloxy, 1-propylbutyloxy, 2-ethyl-2-methylbutyloxy, n-octyloxy, 5-methylheptyloxy, 2,3-dimethylhexyloxy, 1-methyl-1-propylbutyloxy, and 2,2-diethylbutyloxy, 7-methyloctyloxy, 5-ethylheptyloxy, n-decyloxy, 8-methylnonyloxy, 5,5-dimethyloctyloxy, and 4-ethyl-6-methylheptyloxy.

[0073] As used herein, "C １−６ "Alkylthio" means C １−６ means an alkyl-S- group, where C １−６ The alkyl is as defined above. Specific examples include methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio, t-butylthio, sec-butylthio, 1-methylpropylthio, n-pentylthio, isopentylthio, 2-methylbutylthio, 1,1-dimethylpropylthio, 1-ethylpropylthio, hexylthio, 4-methylpentylthio, and 2-ethylbutylthio.

[0074] In this specification, "(C １−１０ "Alkyl)carbonyl" is C １−１０ alkyl-C(O)— group, where C １−１０ The alkyl is as defined above. Specific examples include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, i-propylcarbonyl, n-butylcarbonyl, i-butylcarbonyl, sec-butylcarbonyl, t-butylcarbonyl, 1-methylpropylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, 2-methylbutylcarbonyl, 1,1-dimethylpropylcarbonyl, 1-ethylpropylcarbonyl, hexylcarbonyl, 4-methylpentylcarbonyl, and 2-ethylbutylcarbonyl.

[0075] As used herein, "(di(C １−６ alkyl)aminocarbonyl" is a di(C １−６ "Di(C alkyl)amino" means a carbonyl substituted with "di(C １−６ "Alkyl)amino" means two C １−６ It means an amino substituted with alkyl. Specific examples include dimethylaminocarbonyl, diethylaminocarbonyl, and the like.

[0076] As used herein, "C １−６ "Alkylsulfanyl" is C １−６ means an alkyl-S- group, where C １−６ The alkyl is as defined above. Specific examples include methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, etc., and preferred is methylsulfanyl.

[0077] As used herein, "C １−６ "Alkylsulfonyl" is C １−６ Alkyl-SO ２ - group, where C １−６ The alkyl is as defined above. Specific examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, etc., and preferred is methylsulfonyl.

[0078] As used herein, "C １−６ "Alkylsulfinyl" is C １−６ means an alkyl-S(=O)- group, where C １−６ The alkyl is as defined above. Specific examples include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, etc., and preferred is methylsulfinyl.

[0079] In this specification, "(C １−１０ "alkoxy)carbonyl" is C １−１０ means an alkyl-O—C(O)— group, where C １−１０The alkyl is as defined above. Specific examples include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, i-butoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl, 1-methylpropoxycarbonyl, n-pentyloxycarbonyl, isopentyloxycarbonyl, 2-methylbutoxycarbonyl, 1,1-dimethylpropoxycarbonyl, 1-ethylpropoxycarbonyl, hexyloxycarbonyl, 4-methylpentyloxycarbonyl, and 2-ethylbutoxycarbonyl.

[0080] As used herein, "C ６−１４ "Aryl" means a monovalent aromatic hydrocarbon ring group. ６−１４ Examples of aryl include phenyl, 1-naphthyl, and 2-naphthyl. ６−１４ When the aryl is phenyl, the phenyl may be fused with a 5- to 7-membered non-aromatic heterocycle, and the C ６−１４ An example of an aryl is 2,3-dihydrobenzo-1,4-dioxinyl.

[0081] As used herein, "5- to 14-membered heteroaryl" refers to an aromatic ring group containing one or more (e.g., 1 to 5, preferably 1 to 3) heteroatoms among 5 to 14 ring-constituting atoms. The ring may be a monocyclic or bicyclic ring. Specific examples of "5- to 14-membered heteroaryl" include thienyl, pyridazinyl, pyrazinyl, thiazolyl, oxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, quinolinyl, isoquinolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, pyridinyl, pyrimidinyl, indolyl, imidazolyl, furyl, thioxazolyl, pyrrolyl, tetrazolyl, oxopyrimidinyl, naphthyl, benzodioxinyl, benzisoxazolyl, benzisothiazolyl, indazolyl, benzothienyl, benzofuranyl, benzopyranyl, and triazolyl.

[0082] As used herein, "3- to 14-membered non-aromatic heterocyclyl" refers to a non-aromatic ring or ring system containing at least one heteroatom among 3 to 14 ring-constituting atoms. The heterocyclyl may have any degree of saturation, as long as at least one ring in the ring system is aromatic. The heteroatom may be present in a non-aromatic or aromatic ring in the ring system. In preferred 6-membered monocyclic heterocyclyls, the heteroatoms are selected from up to three O, N, or S atoms, and in preferred 5-membered monocyclic heterocyclyls, the heteroatoms are selected from up to two O, N, or S atoms. Examples of heterocyclyl include azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, pyridyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidinoyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thienyl, thiazolinyl, thiazolidinyl, etc. When the 3- to 14-membered non-aromatic heterocyclyl is a monocyclic heterocyclyl, the heterocyclyl may be fused with a benzene ring, and an example of a 3- to 14-membered non-aromatic heterocyclyl fused with a benzene ring includes at least 2,3-dihydrobenzo-1,4-dioxinyl.

[0083] As used herein, "C ３−１０ The "carbocycle" refers to a cycloalkane ring, cycloalkene ring, or cycloalkyne ring having 3 to 10 carbon atoms constituting the ring, and includes, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclononene, cyclodecene, cyclohexadiene, cyclooctadiene, and cyclooctyne.

[0084] In the present specification, the term "3- to 10-membered heterocycle" refers to a heterocyclic group containing one N atom as a heteroatom and consisting of 3 to 10 ring-constituting atoms. Specific examples include pyrrolidine, piperidine, azepane, azocane, etc., and particularly pyrrolidine and piperidine.

[0085] As used herein, "C ３−１０ "Cycloalkyl" means a cyclic saturated aliphatic hydrocarbon group having 3 to 10 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, etc.

[0086] As used herein, "C ３−６ "Cycloalkenyl" means a cyclic aliphatic hydrocarbon group having 3 to 6 carbon atoms and at least one double bond (two adjacent SP2 carbon atoms). Specific examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl.

[0087] As used herein, "C ３−１０ "Cycloalkenyl" means a cyclic aliphatic hydrocarbon group having 3 to 10 carbon atoms and at least one double bond (two adjacent SP2 carbon atoms). Specific examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodekenyl, etc.

[0088] In this specification, the term "5- to 14-membered nitrogen-containing heterocycle having an imide structure" refers to a heterocyclic group consisting of 5 to 14 ring-constituting atoms, which contains N as a ring-constituting atom and has an imide structure in which two carbonyl groups are bonded to the N. Specific examples include succinimide, glutarimide, and phthalimide.

[0089] In this specification, "optionally substituted by" and "substituted by" mean "optionally substituted by one substituent" and "substituted by one substituent", respectively, unless the number of substituents is specified (e.g., "one or more," "1 to 3," "1 or 2," "2," or "1"). For example, "B optionally substituted by A" and "B substituted by A" mean "B optionally substituted by one A" and "B substituted by one A," respectively.

[0090] In one aspect of the present invention, the compound of formula (I) or a salt thereof preferably comprises R ７ and R ８ is a hydrogen atom and X is 2,6-dichloro-4-pyridyl. Dichloropyridinylmethyl ester represented by the following formula may be referred to as "DCPE" hereinafter in this specification. In one aspect of the present invention, the compound represented by formula (I) or a salt thereof is ７ and R ８ is a hydrogen atom and X is trifluoromethyl. The 2,2,2-trifluoroethyl ester represented by the following formula may be referred to as "TEE" in this specification.

[0091]

[0092]

[0093] In one aspect of the present invention, a compound of formula (I) can be converted to a compound of formula (V):

[0094]

[0095] [In the formula, R １ is a hydrogen atom, and R ｘ is 2-methylpropyl or octyl, or R １ is 2-methylpropyl, and R ｘ is methyl] are excluded.

[0096] In addition, in this specification, the main chain amino group of the compound represented by formula (I) may be protected with a general protecting group such as an Fmoc group or a Boc group.

[0097]

[0098] [In the formula, R １ , R ２ , R ７ , R ８ and X is as defined herein; ７ and R ８ is a hydrogen atom, X is 2,6-dichloropyridin-4-yl, R１ and R ２ is a hydrogen atom or R １ is a hydrogen atom, and R ２ is methyl, ethyl, isopropyl, n-butyl, tert-butyl, or isobutyl, or R １ is ethyl, and R ２ is methyl or ethyl). As used herein, salts of the compound represented by formula (I) include acid addition salts and base addition salts. Examples of acid addition salts include hydrochloride, hydrobromide, hydroiodide, phosphate, phosphonate, sulfate, etc.; sulfonate salts such as methanesulfonate, ethanesulfonate, benzenesulfonate, and p-toluenesulfonate; and carboxylate salts such as acetate, citrate, malate, tartrate, succinate, salicylate, maleate, fumarate, benzoate, malonate, glycolate, oxalate, glucuronate, adipate, glutarate, ketoglutarate, and hippurate. Examples of base addition salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, ammonium salts such as ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt, and tetraalkylammonium salt, and amino acid salts such as lysine salt, arginine salt, glycine salt, valine salt, threonine salt, serine salt, proline salt, and alanine salt, etc. These salts are produced by contacting the compound with an acid or base that can be used in the production of pharmaceuticals.

[0099] In this specification, the compound represented by formula (I) or a salt thereof may be an anhydrate or may form a solvate such as a hydrate. As used herein, the term "solvate" refers to a solid in which the compound molecule and the solvent molecule form a complex, for example, when the solvent is water, it is called a hydrate. Solvates other than hydrates include solids containing alcohols (e.g., methanol, ethanol, n-propanol), dimethylformamide, etc.

[0100] The compounds of formula (I) and their salts can exist in several tautomeric forms, such as keto and enol forms, imine and enamine forms, and mixtures thereof. Tautomers exist as a mixture of tautomers in solution. In solid form, one tautomer usually predominates. Although one tautomer may be described, the present invention includes all tautomers of the compounds of the present invention.

[0101] The present invention includes all stereoisomers of the compounds of formula (I), such as enantiomers, diastereomers (including cis and trans geometric isomers), racemates, and other mixtures of such isomers. For example, the compounds of the present invention may have one or more asymmetric centers, and the compounds of the present invention include racemic mixtures, diastereomeric mixtures, and enantiomers of such compounds.

[0102] When the compound represented by formula (I) is obtained in a free form, it can be converted into a salt which the compound may form, or a hydrate or solvate thereof, in a conventional manner.

[0103] Furthermore, when the compound represented by formula (I) is obtained as a salt, hydrate, or solvate of the compound, it can be converted into the free form of the compound by a conventional method. The elements constituting the compound represented by formula (I) may be any isotope, and the present invention encompasses compounds of formula (I) containing isotopes. An isotope of the compound is one in which at least one atom has been replaced with an atom having the same atomic number (number of protons) but a different mass number (sum of the number of protons and neutrons). Examples of isotopes contained in the compound of the present invention include a hydrogen atom, a carbon atom, a nitrogen atom, an oxygen atom, a phosphorus atom, a sulfur atom, a fluorine atom, and a chlorine atom, each of which is ２ H. ３ H. １３ C. １４ C. １５ N, １７ O. １８ O. ３１ P, ３２ P, ３５ S. １８ F. ３６ Cl, etc. In particular,３ H and １４ Radioisotopes that decay by emitting radioactivity, such as C, are useful in testing the tissue distribution of pharmaceuticals or compounds in the body. Stable isotopes do not decay, their abundance remains almost constant, and they are not radioactive, so they can be used safely. The isotopes of the compounds of the present invention can be converted in accordance with conventional methods by replacing the reagents used in the synthesis with reagents containing the corresponding isotope.

[0104] In one aspect of the present invention, the compound represented by formula (I) can be used as a reagent in an acylation reaction. Examples of the acylation reaction include acylation of a hydroxyl or an amino group which may have a substituent. In one aspect of the present invention, the compound represented by formula (I) can be used as an activated ester for use in a peptide synthesis reaction. Peptide synthesis can be carried out by well-known techniques.

[0105] In another aspect of the present invention, the compound of formula (I) can be used as an activated ester for modifying groups, such as hydroxy or optionally substituted amino groups, contained in peptides or proteins by acylation.

[0106] In one aspect of the present invention, a compound represented by formula (I) can be used as a reagent for the aminoacylation reaction of tRNA. The compound represented by formula (I) is an ester obtained by reacting an amino acid represented by formula (II) with a compound represented by formula (III), and the amino acid represented by formula (II) includes not only natural amino acids but also unnatural amino acids. The inventors have discovered that by reacting the above ester with tRNA, an amino acid represented by formula II can be attached to the 3' end of the tRNA (aminoacylation reaction). This reaction can be carried out by known methods. In one embodiment, the aminoacylation reaction of tRNA can be carried out in the presence of a catalyst or enzyme, preferably in the presence of Flexizyme. Flexizyme is an artificial aminoacylation RNA catalyst that recognizes and activates only the A (adenosine residue) of the CCA at the 3' end of all tRNAs. In other words, because Flexizyme does not have strict substrate specificity, it is possible to bind a variety of amino acids, including unnatural amino acids, and amino acid derivatives to any tRNA (aminoacylation of tRNA), thereby synthesizing unique peptides incorporating unnatural amino acids, etc. Examples of such Flexizymes include: original Flexizyme Fx [5'-GGAUCGAAAGAUUUCCGCAGGCCCGAAAGGGUAUUGGCGUUAGGU-3', 45nt] (SEQ ID NO: 1), enhanced Flexizyme eFx [5'-GGAUCGAAAGAUUUCCGCGGCCCCGAAAGGGGAUUAGCGUUAGGU-3', 45nt] (SEQ ID NO: 2), dinitrobenzyl Flexizyme dFx [5'-GGAUCGAAAGAUUUCCGCAUCCCCGAAAGGGUACAUGGCGUUAGGU-3', 46nt] (SEQ ID NO: 3), Aminoflexizyme aFx [5'-GGAUCGAAAGAUUUCCGCACCCCCCGAAAGGGGUAAGUGGCGUUAGGU-3', 47 nt] (SEQ ID NO: 4) and the like are known (WO 2011 / 049157), but the present invention is not limited to these, and any substance having flexizyme activity can be suitably used.Although not limited thereto, dFx can be preferably used for DCPE, and eFx can be preferably used for TEE.

[0107] In one aspect of the present invention, a peptide synthesis method is provided, comprising synthesizing corresponding peptides from mRNA using an aminoacylated tRNA synthesized by the aminoacylation reaction described above in a cell-free translation system. Furthermore, in another aspect of the present invention, a peptide library preparation method is provided, comprising preparing an mRNA library and synthesizing peptides corresponding to each mRNA from the mRNA library using an cell-free translation system using the aminoacylated tRNA synthesized by the aminoacylation reaction described above, thereby preparing a peptide library. Here, the mRNA library may be prepared by purchasing it from a commercial source or by preparation by hand. For example, when preparing an mRNA library, a DNA library may be obtained according to the method described in Chemistry & Biology 18, 1562-1570 (2011) and / or Chemistry & Biology 21, 766-774 (2014), and the mRNA library may be prepared by transcribing the DNA library in a test tube.

[0108] As used herein, the cell-free translation system is not particularly limited as long as it does not contain cells. In one aspect of the present invention, a system that synthesizes a target peptide or protein in a test tube using protein synthesis function extracted from cells can be used as the cell-free translation system. Examples of cell-free translation systems that can be used include Escherichia coli extract, wheat germ extract, rabbit erythrocyte extract, and insect cell extract. In one aspect of the present invention, a reconstituted cell-free translation system can be used as the cell-free translation system, constructed by reconstituting purified ribosomal proteins, aminoacyl-tRNA synthetases (aaRSs), ribosomal RNAs, amino acids, rRNAs, GTP, ATP, translation initiation factors (IFs), elongation factors (EFs), release factors (RFs), and ribosome recycling factors (RRFs), as well as other factors necessary for translation.

[0109] In this specification, the cell-free translation system may be a system containing RNA polymerase for simultaneous transcription from DNA. In one aspect of the present invention, the cell-free translation system used may be a commercially available system, and examples of the system derived from Escherichia coli include RTS-100 (registered trademark) from Roche Diagnostics, examples of the reconstituted translation system include PURESYSTEM (registered trademark) from PGI and PURExpressR InVitroProtein Synthesis Kit from New England BioLabs, and examples of the system using wheat germ extract include those from Zoigene and Cell Free Sciences.

[0110] Furthermore, as a system using Escherichia coli ribosomes, the techniques described in the following documents are known, for example: H. F. Kung et al., 1977, The Journal of Biological Chemistry, Vol. 252, No. 19, 6889-6894; M. C. Gonza et al., 1985, Proceedings of the National Academy of Sciences of the United States of America, Vol. 82, 1648-1652; M. Y. Pavlovand M. Ehrenberg, 1996, Archives of Biochemistry and Biophysics, Vol. 328, No. 1, 9-16; Y. Shimizu et al., 2001, Nature Biotechnology, Vol. 19, No. 8, 751-755; H. Ohashi et al., 2007, Biochemical and Biophysical Research Communications, Vol. 352, No. 1, 270-276. Cell-free translation systems allow expression products to be obtained in a highly pure form without purification. Expression of a peptide using a cell-free translation system can be carried out using a Flexible In Vitro Translation System (FIT system) in accordance with the method described in, for example, Goto, Y., Katoh, T. & Suga, H. Flexizymes for genetic code reprogramming. Nat Protoc 6, 779-790, (2011).

[0111] In one aspect of the present invention, a compound of formula (II):

[0112]

[0113] with a compound represented by formula (III):

[0114]

[0115] wherein L is a leaving group. In one embodiment of the present invention, the leaving group is a halogen atom, and R Ｄ-SO ２ The group represented by O- is selected from, for example, a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy, trifluoromethanesulfonyloxy, pentafluoroethanesulfonyloxy, etc. The method can be carried out by methods known to those skilled in the art.

[0116] In one embodiment of the present invention, the method is carried out in a solvent, such as DMF. In one embodiment of the present invention, the method is carried out in the presence of a base, such as diisopropylethylamine.

[0117] In one embodiment of the present invention, the compound represented by formula (III) can be used in an amount of 0.45 to 1.45 equivalents, 0.65 to 1.25 equivalents, preferably 0.85 to 1.05 equivalents, relative to the compound represented by formula (II).

[0118] In one embodiment of the present invention, the reaction temperature is set in the range of 0 to 40° C., 0 to 30° C., and preferably 0 to 25° C. In one embodiment of the present invention, the reaction time is set in the range of 30 minutes to 24 hours, 30 minutes to 12 hours, 30 minutes to 6 hours, and preferably 30 minutes to 2 hours.

[0119] In one aspect of the present invention, an activated amino acid ester is provided that is highly safe in terms of dangers when used as a reagent, such as ignition and explosion. The activated ester of the present invention is not a nitro compound or a cyanide compound, and is therefore considered to be safer than DBE and CME, which have been used as activated amino acid esters for the aminoacylation of tRNA. Evaluation tests were conducted to support this. Differential scanning calorimetry (DSC) can be used as a method for determining the danger of an activated amino acid ester (Akiyoshi et al., Netsu Sokutei 2018, 45(4), 161-167; Sakira Kaneko, Netsu Sokutei 1995, 22(1), 36-43). DSC is a method for determining the reaction onset temperature (TＤＳＣ ) and the heat of reaction (Q ＤＳＣ Since DSC can measure the heat release rate (exothermic decomposition energy) with a small sample, it is an effective means for assessing the hazards of self-reactive substances. A correlation has been recognized between the calorific value (exothermic decomposition energy) obtained by DSC and the fire and explosive properties of chemical substances, and DSC has traditionally been used as a hazard assessment test. In Japan, DSC is used as a test to determine whether a chemical substance falls under the category of Class 5 hazardous materials (self-reactive substances) under the Fire Service Act. Internationally, the UN Recommendation on the Transport of Dangerous Goods (TDG) first uses the exothermic decomposition energy obtained by DSC to determine whether a chemical substance falls under the category of explosives. If, as a result of such testing, the chemical substance in question is determined to be a Class 5 hazardous material, careful and complicated measures will be required when storing and handling the substance, such as avoiding heat, impact, and friction, keeping it away from flammable materials, not allowing it to come into contact with other chemicals, storing it in a cool, dark place, and taking care not to damage the container, which will increase the costs of storage and transportation.

[0120] As a test method for determining whether a substance is classified as a Class 5 hazardous material (self-reactive substance) under the Fire Service Act, 2,4-dinitrotoluene and benzoyl peroxide are used as standard compounds. ＤＳＣ and T ＤＳＣ One method is to plot the reference points of each of the above and use a straight line connecting the two points as the risk assessment line. If the substance is on or above the assessment line, it is deemed "risky" (corresponding to Class 5 hazardous materials), and if it is below the assessment line, it is deemed "not risky" (not corresponding to Class 5 hazardous materials). The present inventors performed the above method on DBE, which has previously been used as an activated ester of an amino acid for aminoacylation of tRNA, and the DCPE and TEE of the present invention. As a result, DBE was determined to be a Class 5 hazardous material, while DCPE and TEE were determined not to be Class 5 hazardous materials (Test Example). This demonstrates that the activated ester of the present invention reduces safety and waste risks, is easy to handle, and can reduce disposal costs compared to conventional activated esters.

[0121] Example 1: Synthesis of activated ester of amino acid The present invention will be explained in more detail below by showing synthesis examples as examples, but the present invention is not limited to these examples.

[0122] In the present specification, when amino acids and the like are represented by abbreviations, each representation is based on the abbreviations according to the IUPAC-IUB Commission on Biochemical Nomenclature or on the abbreviations commonly used in the art.

[0123] The abbreviations used in the synthesis examples are as follows: Fmoc for 9-fluorenylmethyloxycarbonyl or 9-fluorenylmethoxycarbonyl; Boc for tertiary butoxycarbonyl; tBu for tertiary butyl; DMF for N,N-dimethylformamide; DIPEA for diisopropylethylamine; EtOAc for ethyl acetate; Na for sodium sulfate. ２ SO ４ DCM as dichloromethane; MTHP as 4-methyltetrahydropyran; MTBE as methyl tertiary butyl ether; CPME as cyclopentyl methyl ether; Fx as Flexizyme; THF as tetrahydrofuran; HCl as hydrochloric acid; mL as milliliters; M as molar (mol / L); mM as millimolar; mm as millimeters; nm as nanometers; μm as micrometers; Å as angstroms; min as minutes; MS as mass spectrometry; mmol as millimole; mg as milligrams; LC-MS or LC / MS as liquid chromatography-mass spectrometry; and tR as retention time.

[0124] Unless otherwise specified, proton nuclear magnetic resonance (H NMR) in the following synthesis examples was measured in a deuterated chloroform or deuterated dimethyl sulfoxide solvent using a JEOL JNM-ECP300 or a JEOL JNM-ECX300, or a Bruker Ascend™500, and chemical shifts are shown as δ values ​​(ppm) using tetramethylsilane as an internal standard (0.0 ppm).

[0125] In describing NMR spectra, "s" means singlet, "d" means doublet, "t" means triplet, "q" means quartet, "dd" means doublet of doublets, "dt" means doublet of triplets, "sept" means septet, "m" means multiplet, "br" means broad, "J" means coupling constant, "Hz" means Hertz, "CDCl3" means deuterated chloroform, and "DMSO-d6" means deuterated dimethyl sulfoxide.

[0126] Unless otherwise specified, high performance liquid chromatography / mass spectrometry was measured using either an ACQUITY UPLC H-Class / QDa manufactured by Waters, an ACQUITY UPLC H-Class / SQD2 manufactured by Waters, or an LC-20AD / Triple Tof5600 manufactured by Shimadzu.

[0127] In the description of high performance liquid chromatography / mass spectrometry, ESI+ means electrospray ionization in positive mode, M+H means proton adduct, and M+Na means sodium adduct.

[0128] In the descriptions of high-performance liquid chromatography / mass spectrometry, ESI- stands for negative mode of electrospray ionization, and M-H stands for proton-deficient. The purity of the activated esters of amino acids synthesized according to the following synthesis examples was calculated from the area ratio of the LC / MS chromatograms under the following analytical conditions A to D, and mass spectrometry was performed using a single quadrupole mass spectrometer and an ESI-MS(+) ion source.

[0129] Analysis Condition A Column: Kinetex (registered trademark) EVO C18, 2.6 μm, 2.1 × 150 mm, 100 Å Mobile phase A: 0.025% TFA in H ２ O Mobile phase B: 0.025% TFA in CH ３ CN Column temperature: 60°C Gradient (% B): 0-40% over 7.15 minutes, then 40% from 7.16 minutes to 9.00 minutes, then 95-95% over 1.55 minutes Flow rate: 0.5 mL / min Detection: UV 220 nm Analysis condition B Column: Kinetex® EVO C18, 2.6 μm, 2.1 × 150 mm, 100 Å Mobile phase A: 0.025% TFA in H ２ O Mobile phase B: 0.025% TFA in CH ３ CN Column temperature: 60°C Gradient (% B): 5-95% over 7.15 minutes, then 95% from 7.16 minutes to 10.55 minutes Flow rate: 0.5 mL / min Detection: UV 220 nm. Analysis condition C Column: Waters XBridge BEH C18 2.5 μm 2.1 × 150 mm 130 Å Mobile phase A: 0.025% TFA in H ２ O Mobile phase B: 0.025% TFA in CH ３ CN Column temperature: 60°C Gradient (% B): 0-40% over 7.15 minutes, then 40% from 7.16 minutes to 9.00 minutes, then 95-95% over 1.55 minutes Flow rate: 0.5 mL / min Detection: UV 220 nm. Analysis condition D Column: Waters ACQUITY UPLC BEH C18 1.7 μm 2.1 x 50 mm, 130 Å Mobile phase A: 0.025% TFA in H ２ O Mobile phase B: 0.025% TFA in CH ３ CN Column temperature: 60°C Gradient (% B): 5-95% over 2.78 minutes, then 95% from 2.78 minutes to 3.61 minutes Flow rate: 0.4 mL / min Detection: UV 220 nm The structures of the activated esters of amino acids synthesized according to the following synthesis examples and the results of LC / MS analysis are shown in Table 1.

[0130] Example 1-1: (2,2,2-trifluoroethyl L-phenylalaninate hydrochloride (Compound No. 39)

[0131]

[0132] To a flask equipped with a nitrogen balloon, (tert-butoxycarbonyl)-L-phenylalanine (7.96 g, 30.0 mmol), DMF (60.0 mL), 2,2,2-trifluoroethyl trifluoromethanesulfonate (6.61 g, 28.5 mmol), and DIPEA (6.29 mL, 36.0 mmol) were added in that order. After stirring at room temperature, the reaction was quenched by adding 1M aqueous HCl. The mixture was extracted with EtOAc, and the organic layer was washed with saturated brine and diluted with anhydrous NaCl. ２ SO ４ The mixture was dried by filtration, filtered through a glass filter, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; EtOAc / hexane = 0 / 100 → 100 / 0). DCM (30.0 mL) and 4N-HCl / MTHP (30.0 mL) were added sequentially to the obtained compound. After stirring at room temperature, the mixture was concentrated under reduced pressure. MTBE was added to the residue, filtered, washed with MTBE, and dried in vacuo to obtain 2,2,2-trifluoroethyl L-phenylalaninate hydrochloride (7.28 g, 25.7 mmol, 86% yield) as a colorless solid.

[0133] Example 1-2: 2,2,2-trifluoroethyl(2-chloroacetyl)-L-phenylalaninate (Compound No. 90)

[0134]

[0135] To a flask equipped with a nitrogen balloon, 2,2,2-trifluoroethyl-L-phenylalanine hydrochloride (2.84 g, 10.0 mmol), THF (25.0 mL), N-methylmorpholine (2.42 mL, 22.0 mmol), and chloroacetyl chloride (0.881 mL, 11.0 mmol) were added in order while maintaining the temperature below -15°C. After stirring at -15°C, the reaction was quenched by adding 1M HCl. The mixture was extracted with EtOAc, and the organic layer was washed with saturated brine and added with anhydrous NaCl.２ SO ４ The residue was purified by flash column chromatography (silica gel; EtOAc / hexane = 0 / 100 → 100 / 0) to give 2,2,2-trifluoroethyl(2-chloroacetyl)-L-phenylalaninate (3.00 g, 9.27 mmol, yield 93%) as a colorless solid.

[0136] Example 1-3: (2,6-dichloropyridin-4-yl)methylacetyl-L-alaninate (Compound No. 87)

[0137]

[0138] Acetyl-L-alanine (2.62 g, 20.0 mmol), DMF (40.0 mL), 4-(bromomethyl)-2,6-dichloropyridine (4.58 g, 19.0 mmol), and DIPEA (4.19 mL, 24.0 mmol) were added sequentially to a flask equipped with a nitrogen balloon. After stirring at room temperature, the reaction was quenched by adding 2M aqueous HCl. The mixture was extracted with EtOAc, and the organic layer was washed with saturated brine and diluted with anhydrous NaCl. ２ SO ４ The mixture was dried over 1000 ml of ethyl acetate, filtered through a glass filter, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; EtOAc / hexane = 0 / 100 → 100 / 0) to give (2,6-dichloropyridin-4-yl)methylacetyl-L-alaninate (2.93 g, 10.1 mmol, yield 50%) as a colorless solid.

[0139] Example 1-4: (2,6-dichloropyridin-4-yl)methyl(2-([1,1′-biphenyl]-4-yl)ethyl)glycinate hydrochloride (Compound No. 35)

[0140]

[0141] In a flask equipped with a nitrogen balloon, (2-([1,1′-biphenyl]-4-yl)ethyl)glycine (1.55 g, 6.07 mmol, CAS Registry Number: 1906593-76-7), 1,4-dioxane (14.0 mL), H ２0 (7.00 mL), sodium bicarbonate (1.53 g, 18.2 mmol), and di-tert-butyl dicarbonate (1.32 g, 6.07 mmol, CAS registration number: 24424-99-5) were added in this order under ice-cooling. After stirring at room temperature, the reaction was quenched by adding aqueous citric acid. The mixture was extracted with EtOAc, and the organic layer was washed with saturated brine and diluted with anhydrous Na ２ SO ４ The mixture was dried over 1000 kJ / min, filtered through a glass filter, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; 0.1% formic acid aqueous solution / acetonitrile = 50 / 50 → 20 / 80). DMF (5.6 mL), 4-(bromomethyl)-2,6-dichloropyridine (0.644 g, 2.67 mmol), and DIPEA (0.590 mL, 3.38 mmol) were added to the obtained compound (1.00 g) in this order. After stirring at room temperature, the reaction was quenched by adding 1M aqueous HCl solution. The mixture was extracted with EtOAc, and the organic layer was washed successively with aqueous sodium bicarbonate and saturated brine, and then with anhydrous NaCl. ２ SO ４ The mixture was dried over 1000 kJ / min, filtered through a glass filter, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; EtOAc / hexane = 20 / 80 → 40 / 60). DCM (8.0 mL) and 4N-HCl / MTHP (8.0 mL) were added sequentially to the obtained compound. After stirring at room temperature, the mixture was concentrated under reduced pressure. Diisopropyl ether was added to the residue, filtered, washed with diisopropyl ether, and dried in vacuo to obtain 2,6-dichloropyridin-4-yl)methyl(2-([1,1'-biphenyl]-4-yl)ethyl)glycinate hydrochloride (941 mg, 2.08 mmol) as a colorless solid.

[0142] Example 1-5: (2,6-Dichloropyridin-4-yl)methyl (S)-2-amino-3-(3-guanidinophenyl)propanoate dihydrochloride (Compound No. 74)

[0143]

[0144] To a flask equipped with a nitrogen balloon, (S)-3-(3-aminophenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (1.03 g, 3.67 mmol), absolute ethanol (15 mL), and N,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (1.14 g, 3.67 mmol, CAS Registry Number: 152120-54-2) were added in that order. After stirring at room temperature, the reaction was quenched by adding 1M aqueous HCl. The mixture was extracted with EtOAc, and the organic layer was washed with saturated brine and diluted with anhydrous NaCl. ２ SO ４ The mixture was dried over 1000 kJ / min, filtered through a glass filter, and concentrated under reduced pressure. DMF (60.0 mL), 4-(bromomethyl)-2,6-dichloropyridine (0.841 g, 3.49 mmol), and DIPEA (0.770 mL, 4.41 mmol) were added to the resulting residue in that order. After stirring at room temperature, the reaction was quenched by adding 1M aqueous HCl. The mixture was extracted with EtOAc, and the organic layer was washed successively with aqueous sodium bicarbonate and saturated brine, and then with anhydrous NaCl. ２ SO ４ The mixture was dried over 100°C, filtered through a glass filter, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; EtOAc / hexane = 10 / 90 → 30 / 70). DCM (26.0 mL) and 4N-HCl / MTHP (26.0 mL) were added sequentially to the obtained compound. After stirring at room temperature, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue, filtered, washed with diethyl ether, and dried in vacuo to obtain (2,6-dichloropyridin-4-yl)methyl (S)-2-amino-3-(3-guanidinophenyl)propanoate dihydrochloride (962 mg, 2.11 mmol) as a colorless solid.

[0145] Example 1-6: (2,6-dichloropyridin-4-yl)methyl (S)-3-cyclopentyl-2-(methylamino)propanoate hydrochloride (Compound No. 75)

[0146]

[0147] To a flask equipped with a nitrogen balloon, (S)-2-((tert-butoxycarbonyl)amino)-3-cyclopentylpropanoic acid (10.0 g, 38.9 mmol, CAS Registry Number: 143415-31-0), THF (300 mL), and 60% sodium hydride (2.80 g, 117 mmol, CAS Registry Number: 7646-69-7) were added in this order under ice-cooling. The mixture was stirred at room temperature for 30 minutes, and then iodomethane (11.0 g, 77.7 mmol, CAS Registry Number: 74-88-4) was added to the mixture. The mixture was stirred at room temperature overnight, and then aqueous citric acid was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; acetonitrile / 0.1% formic acid aqueous solution = 10 / 90 → 80 / 20) to give (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-cyclopentylpropanoic acid (5.00 g). To the resulting compound, DMF (25 mL), 4-(bromomethyl)-2,6-dichloropyridine (4.30 g, 17.9 mmol, CAS registration number: 175204-45-2), and DIPEA (3.92 mL, 22.6 mmol) were added in that order. The mixture was stirred at room temperature for 3 hours, and then ethyl acetate was added to the mixture. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; acetonitrile / 0.1% formic acid aqueous solution = 10 / 90 → 100 / 0) to give (2,6-dichloropyridin-4-yl)methyl (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-cyclopentylpropanoate (6.67 g). To the obtained compound (3.00 g), dichloromethane (26 mL) and 4 M hydrochloric acid / MTHP (26 mL) were added in that order under ice-cooling. The mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure.The residue was washed with diethyl ether and dried in vacuo to give (2,6-dichloropyridin-4-yl)methyl (S)-3-cyclopentyl-2-(methylamino)propanoate hydrochloride (2.62 g, 7.13 mmol) as a colorless solid.

[0148] Example 1-7: 2,2,2-trifluoroethyl (S)-2-amino-3-(6-phenylpyridin-3-yl)propanoate dihydrochloride (Compound No. 76)

[0149]

[0150] To a flask equipped with a nitrogen balloon, zinc (9.22 g, 141 mmol, CAS Registry Number: 7440-66-6), DMF (150 mL), and iodine (1.79 g, 7.05 mmol, CAS Registry Number: 7553-56-2) were added in that order. After stirring the mixture at room temperature for 10 minutes, (S)-methyl 2-(tert-butoxycarbonylamino)-3-iodopropanoate (15.5 g, 47.0 mmol, CAS Registry Number: 93267-04-0) and iodine (1.79 g, 7.05 mmol, CAS Registry Number: 7553-56-2) were added in that order. After stirring the mixture at room temperature for 30 minutes, 5-bromo-2-phenylpyridine (13.2 g, 56.4 mmol, CAS Registry Number: 27012-25-5), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.96 g, 2.3 mmol, CAS Registry Number: 657408-07-6), and tris(dibenzylideneacetone)dipalladium-chloroform (1.46 g, 1.41 mmol, CAS Registry Number: 52522-40-4) were sequentially added to the mixture. After stirring at 50°C for 3 hours, the mixture was filtered and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether = 1 / 10 → 1 / 3) to give methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(6-phenylpyridin-3-yl)propanoate (16.0 g). To the resulting compound, isopropanol (180 mL), water (60 mL), calcium chloride (79.7 g, 718 mmol, CAS Registry Number: 10043-52-4), and lithium hydroxide monohydrate (7.55 g, 180 mmol, CAS Registry Number: 1310-66-3) were added in this order under ice cooling. The mixture was stirred at room temperature for 24 hours, and then sodium dihydrogen phosphate was added to quench the reaction. The mixture was filtered and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by flash column chromatography (silica gel; methanol / dichloromethane = 1 / 50 → 1 / 10) to give (S)-2-((tert-butoxycarbonyl)amino)-3-(6-phenylpyridin-3-yl)propanoic acid (14.1 g). To the resulting compound, DMF (140 mL), 2,2,2-trifluoroethyl trifluoromethanesulfonate (9.08 g, 39.1 mmol, CAS registration number: 6226-25-1), and DIPEA (6.39 g, 49.4 mmol) were added in that order. The mixture was stirred at room temperature for 3 hours, and then water and sodium dihydrogen phosphate were added in that order to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether = 1 / 10 → 1 / 1) to give 2,2,2-trifluoroethyl (S)-2-((tert-butoxycarbonyl)amino)-3-(6-phenylpyridin-3-yl)propanoate (15.1 g). To the obtained compound (1.87 g), dichloromethane (30 mL) and 4 M hydrochloric acid / MTHP (30 mL) were added in sequence. The mixture was stirred at room temperature for 3 hours, and then concentrated under reduced pressure. The residue was suspended and washed with diethyl ether and dried in vacuo to give 2,2,2-trifluoroethyl (S)-2-amino-3-(6-phenylpyridin-3-yl)propanoate dihydrochloride (1.56 g, 4.32 mmol) as a colorless solid.

[0151] Example 1-8: (2,6-Dichloropyridin-4-yl)methyl (S)-2-amino-4-(quinolin-5-yl)butanoate dihydrochloride (Compound No. 77)

[0152]

[0153] To a flask equipped with a nitrogen balloon, zinc (47.2 g, 721 mmol, CAS Registry Number: 7440-66-6), DMF (500 mL), and iodine (36.6 g, 144 mmol, CAS Registry Number: 7553-56-2) were added in that order. After stirring the mixture at room temperature for 5 minutes, methyl (S)-2-((tert-butoxycarbonyl)amino)-4-iodobutanoate (99.0 g, 288 mmol, CAS Registry Number: 101650-14-0) was added. After stirring the mixture at room temperature for 1 hour, 5-bromoquinoline (50.0 g, 240 mmol, CAS Registry Number: 4964-7-10), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (9.85 g, 24.0 mmol, CAS Registry Number: 657408-07-6), and tris(dibenzylideneacetone)dipalladium-chloroform (11.0 g, 12.0 mmol, CAS Registry Number: 52522-40-4) were sequentially added to the mixture. After stirring at 50°C for 3 hours, the mixture was filtered and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether = 1 / 1) to give methyl (S)-2-((tert-butoxycarbonyl)amino)-4-(quinolin-5-yl)butanoate (40.0 g). To the resulting compound, THF (200 mL) and lithium hydroxide monohydrate (5.85 g, 139 mmol, CAS Registry Number: 1310-66-3) dissolved in water (200 mL) were added sequentially under ice cooling. The mixture was stirred at room temperature for 2 hours, and then aqueous sodium dihydrogen phosphate was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S)-2-((tert-butoxycarbonyl)amino)-4-(quinolin-5-yl)butanoic acid (20.0 g). To the obtained compound (5.00 g) were added DMF (50 mL), 4-(bromomethyl)-2,6-dichloropyridine (3.46 g, 14.4 mmol, CAS registration number: 175204-45-2) and DIPEA (3.17 mL, 18.2 mmol) in that order.The mixture was stirred at room temperature for 30 minutes, and then aqueous sodium dihydrogen phosphate was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether = 1 / 5) to give (2,6-dichloropyridin-4-yl)methyl (S)-2-((tert-butoxycarbonyl)amino)-4-(quinolin-5-yl)butanoate (6.31 g). Dichloromethane (25 mL) and 4 M hydrochloric acid / MTHP (25 mL) were added sequentially to the obtained compound (3.30 g). The mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. The residue was suspended and washed with diethyl ether and dried in vacuo to give (2,6-dichloropyridin-4-yl)methyl (S)-2-amino-4-(quinolin-5-yl)butanoate dihydrochloride (2.92 g, 6.84 mmol) as a colorless solid.

[0154] Example 1-9: (2,6-dichloropyridin-4-yl)methyl (S)-2-amino-3-(6-aminopyridin-3-yl)propanoate dihydrochloride (Compound No. 78)

[0155]

[0156] Zinc (22.7 g, 347 mmol, CAS Registry Number: 7440-66-6), DMF (400 mL), and iodine (8.80 g, 34.7 mmol, CAS Registry Number: 7553-56-2) were sequentially added to a flask equipped with a nitrogen balloon. After stirring the mixture at room temperature, (S)-methyl 2-(tert-butoxycarbonylamino)-3-iodopropanoate (41.9 g, 127 mmol, CAS Registry Number: 93267-04-0) and iodine (8.80 g, 34.7 mmol, CAS Registry Number: 7553-56-2) were sequentially added to the mixture. After stirring the mixture at room temperature for 30 minutes, 2-amino-5-bromopyridine (20.0 g, 116 mmol, CAS Registry Number: 1072-97-5), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (9.49 g, 23.1 mmol, CAS Registry Number: 657408-07-6), and tris(dibenzylideneacetone)dipalladium-chloroform (5.29 g, 5.78 mmol, CAS Registry Number: 52522-40-4) were sequentially added to the mixture. After stirring at 50°C for 3 hours, ethyl acetate was added to the mixture, which was then filtered and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether = 1 / 1) to give methyl (S)-3-(6-aminopyridin-3-yl)-2-((tert-butoxycarbonyl)amino)propanoate (30.0 g). To the resulting compound (40.0 g), dichloromethane (200 mL), tert-butanol (800 mL), di-tert-butyl dicarbonate (35.5 g, 163 mmol, CAS Registry Number: 24424-99-5), and sodium iodide (24.4 g, 163 mmol, CAS Registry Number: 7681-82-5) were added in that order. The mixture was stirred at room temperature overnight, then concentrated under reduced pressure, ethyl acetate was added, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether = 1 / 1) to give methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(6-((tert-butoxycarbonyl)amino)pyridin-3-yl)propanoate (50.0 g). To the resulting compound (30.0 g), THF (100 mL), isopropanol (600 mL), water (200 mL), calcium chloride (135 g, 1210 mmol, CAS Registry Number: 10043-52-4), and lithium hydroxide monohydrate (12.8 g, 304 mmol, CAS Registry Number: 1310-66-3) were added in this order under ice cooling. The mixture was stirred at room temperature, and then sodium dihydrogen phosphate was added to quench the reaction. The mixture was filtered and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / dichloromethane = 1 / 1) to give (S)-2-((tert-butoxycarbonyl)amino)-3-(6-phenylpyridin-3-yl)propanoic acid (15.0 g). To the resulting compound (9.00 g), DMF (50 mL), 4-(bromomethyl)-2,6-dichloropyridine (5.40 g, 22.4 mmol, CAS registration number: 175204-45-2), and DIPEA (4.93 mL, 28.3 mmol) were added in this order. The mixture was stirred at room temperature for 2 hours, and then ethyl acetate was added to the mixture. The organic layer was washed successively with aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether=1 / 5) to give (2,6-dichloropyridin-4-yl)methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(6-((tert-butoxycarbonyl)amino)pyridin-3-yl)propanoate (11.2 g). To the obtained compound (3.00 g), dichloromethane (25 mL) and 4 M hydrochloric acid / MTHP (25 mL) were added in that order. The mixture was stirred at room temperature, and then concentrated under reduced pressure.The residue was suspended and washed with methyl tert-butyl ether and dried in vacuo to give (2,6-dichloropyridin-4-yl)methyl (S)-2-amino-3-(6-aminopyridin-3-yl)propanoate dihydrochloride (2.32 g, 5.60 mmol) as a colorless solid.

[0157] Example 1-10: (2,6-dichloropyridin-4-yl)methyl (S)-2-amino-4-(2-aminopyridin-4-yl)butanoate dihydrochloride (Compound No. 79)

[0158]

[0159] Zinc (8.57 g, 131 mmol, CAS Registry Number: 7440-66-6), DMF (200 mL), and iodine (6.66 g, 26.2 mmol, CAS Registry Number: 7553-56-2) were sequentially added to a flask equipped with a nitrogen balloon. After stirring the mixture at room temperature for 5 minutes, methyl (S)-2-((tert-butoxycarbonyl)amino)-4-iodobutanoate (15.0 g, 43.7 mmol, CAS Registry Number: 101650-14-0) was added to the mixture. After stirring the mixture at room temperature for 1 hour, 2-amino-4-bromopyridine (8.32 g, 48.1 mmol, CAS Registry Number: 84249-14-9), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (3.59 g, 8.75 mmol, CAS Registry Number: 657408-07-6), and tris(dibenzylideneacetone)dipalladium-chloroform (2.00 g, 2.18 mmol, CAS Registry Number: 52522-40-4) were sequentially added to the mixture. After stirring at 60°C for 3 hours, the mixture was filtered and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether = 1 / 2) to give methyl (S)-4-(2-aminopyridin-4-yl)-2-((tert-butoxycarbonyl)amino)butanoate (9.00 g). To the resulting compound, tert-butanol (90 mL), sodium iodide (5.23 g, 34.9 mmol, CAS Registry Number: 7681-82-5), and di-tert-butyl dicarbonate (7.62 g, 34.9 mmol, CAS Registry Number: 24424-99-5) were added, in that order. The mixture was stirred at room temperature for 16 hours, and then ethyl acetate was added to the mixture. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether=1 / 2) to give methyl (S)-2-((tert-butoxycarbonyl)amino)-4-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)butanoate (8.80 g).To the resulting compound, isopropanol (120 mL), calcium chloride (38.2 g, 344 mmol, CAS Registry Number: 10043-52-4), and lithium hydroxide monohydrate (3.61 g, 86.0 mmol, CAS Registry Number: 1310-66-3) dissolved in water (40 mL) were added sequentially under ice cooling. The mixture was stirred at room temperature for 16 hours, then filtered, and the reaction was quenched by the addition of aqueous sodium dihydrogen phosphate solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether = 1 / 1) to give (S)-2-((tert-butoxycarbonyl)amino)-4-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)butanoic acid (8.00 g). To the resulting compound, DMF (80 mL), 4-(bromomethyl)-2,6-dichloropyridine (4.63 g, 19.2 mmol, CAS Registry Number: 175204-45-2), and DIPEA (4.23 mL, 24.3 mmol) were added in that order. The mixture was stirred at room temperature for 30 minutes, and then aqueous sodium dihydrogen phosphate was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; acetonitrile / 10 mM aqueous ammonium bicarbonate = 10 / 90 → 100 / 0) to give (2,6-dichloropyridin-4-yl)methyl (S)-2-((tert-butoxycarbonyl)amino)-4-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)butanoate (5.62 g). To the resulting compound (3.00 g), dichloromethane (18 mL), triisopropylsilane (2.14 g, 13.5 mmol, CAS registration number: 6485-79-6), and 2,2,2-trifluoroacetic acid (12.5 mL) were added in that order. The mixture was stirred at room temperature for 18 hours, then concentrated under reduced pressure, and 4 M hydrochloric acid / CPME (25 mL) was added.After the mixture was stirred at room temperature for 1 hour, it was filtered, washed with diethyl ether, and dried in vacuo to give (2,6-dichloropyridin-4-yl)methyl (S)-2-amino-4-(2-aminopyridin-4-yl)butanoate dihydrochloride (1.52 g, 3.55 mmol) as a colorless solid.

[0160] Example 1-11: (S)-2-(4-(4-amino-5-((2,6-dichloropyridin-4-yl)methoxy)-5-oxopentanoyl)piperazin-1-yl)acetic acid dihydrochloride (Compound No. 60)

[0161]

[0162] To a flask equipped with a nitrogen balloon, (S)-5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoic acid (15.0 g, 44.5 mmol, CAS Registry Number: 30924-93-7), tert-butyl 2-(piperazin-1-yl)acetate (8.90 g, 44.5 mmol, CAS Registry Number: 112257-22-4), and THF (300 mL) were added in this order under ice cooling. After stirring the mixture at room temperature, ethyl 2-cyano-2-(hydroxyimino)acetate (6.94 g, 48.9 mmol, CAS Registry Number: 3849-21-6) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (9.38 g, 48.9 mmol, CAS Registry Number: 25952-53-8) were sequentially added to the mixture under ice-cooling. After stirring the mixture at room temperature overnight, ethyl acetate was added to the mixture, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether=1 / 1) to give benzyl (S)-5-(4-(2-(tert-butoxy)-2-oxoethyl)piperazin-1-yl)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoate (13.0 g). Methanol (260 mL) and palladium on carbon (2.60 g, CAS registration number: 7440-05-3) were added sequentially to the obtained compound. After stirring under a hydrogen atmosphere at room temperature for 2 hours, the mixture was filtered, extracted with ethyl acetate, and concentrated under reduced pressure to give (S)-5-(4-(2-(tert-butoxy)-2-oxoethyl)piperazin-1-yl)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoic acid (12.0 g). To the resulting compound, DMF (100 mL), 4-(bromomethyl)-2,6-dichloropyridine (6.39 g, 26.5 mmol, CAS registration number: 175204-45-2), and DIPEA (5.60 mL, 32.1 mmol) were added in this order. After stirring the mixture at room temperature for 2 hours, ethyl acetate was added to the mixture, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether=1 / 1) to give (2,6-dichloropyridin-4-yl)methyl (S)-5-(4-(2-(tert-butoxy)-2-oxoethyl)piperazin-1-yl)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoate (9.07 g). To the obtained compound (3.00 g), dichloromethane (25 mL) and 4 M hydrochloric acid / CPME (25 mL) were added in that order. The mixture was stirred at room temperature for 3 hours, and then concentrated under reduced pressure. The residue was suspended and washed with methyl tert-butyl ether and dried in vacuo to give (S)-2-(4-(4-amino-5-((2,6-dichloropyridin-4-yl)methoxy)-5-oxopentanoyl)piperazin-1-yl)acetic acid dihydrochloride (2.39 g, 4.72 mmol) as a colorless solid.

[0163] Example 1-12: (2,6-dichloropyridin-4-yl)methyl(3-methoxypropyl)glycinate hydrochloride (Compound No. 61)

[0164]

[0165] To a flask equipped with a nitrogen balloon, 3-methoxypropylamine (10.0 g, 112 mmol, CAS Registry Number: 5332-73-0), ethyl glyoxylate (23.0 mL, 225 mmol, CAS Registry Number: 924-44-7), and dichloromethane (200 mL) were added sequentially. After the mixture was stirred at room temperature for 3 minutes, sodium cyanoborohydride (14.0 g, 223 mmol, CAS Registry Number: 25895-60-7) and acetic acid (9.5 mL) were added sequentially. After the mixture was stirred at room temperature for 30 minutes, triethylamine (31.3 mL, 224 mmol) and di-tert-butyl dicarbonate (37.0 g, 170 mmol, CAS Registry Number: 24424-99-5) were added sequentially. After the mixture was stirred at room temperature, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether = 1 / 1) to give ethyl N-(tert-butoxycarbonyl)-N-(3-methoxypropyl)glycinate (11.0 g). To the obtained compound (9.50 g), 1,4-dioxane (10 mL), water (10 mL), and lithium hydroxide monohydrate (2.30 g, 54.8 mmol) were added sequentially at room temperature. The mixture was stirred at room temperature, and then aqueous sodium dihydrogen phosphate solution was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give N-(tert-butoxycarbonyl)-N-(3-methoxypropyl)glycine (8.30 g). To the resulting compound (7.30 g), DMF (50 mL), 4-(bromomethyl)-2,6-dichloropyridine (5.70 g, 1.91 mmol, CAS registration number: 175204-45-2), and DIPEA (6.0 mL, 2.30 mmol) were added in that order. After stirring the mixture at room temperature, the mixture was purified by flash column chromatography (silica gel; water / methanol = 95 / 5 → 0 / 100) to give (2,6-dichloropyridin-4-yl)methyl N-(tert-butoxycarbonyl)-N-(3-methoxypropyl)glycinate (6.18 g).To the resulting compound (1.90 g), dichloromethane (18 mL) and 4 M hydrochloric acid / CPME (18 mL) were added in that order. The mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. The residue was suspended and washed with diethyl ether and dried in vacuo to give (2,6-dichloropyridin-4-yl)methyl(3-methoxypropyl)glycinate (1.31 g, 3.81 mmol) as a colorless solid.

[0166] Example 1-13: 2,2,2-trifluoroethyl (S)-2-amino-3-(4-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)phenyl)propanoate hydrochloride (Compound No. 62)

[0167]

[0168] To a flask equipped with a nitrogen balloon, (S)-3-(4-aminophenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (7.01 g, 25 mmol, CAS Registry Number: 55533-24-9), DMF (50 mL), allyl (2,5-dioxopyrrolidin-1-yl)carbonate (4.88 g, 24.5 mmol, CAS Registry Number: 135544-68-2), and DIPEA (4.80 mL, 27.5 mmol) were added in this order under ice cooling. The mixture was stirred at room temperature, and then hydrochloric acid was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S)-3-(4-((allyloxy)carbonyl)amino)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid. DMF (50 mL), 2,2,2-trifluoroethyl trifluoromethanesulfonate (5.80 g, 25.0 mmol, CAS Registry Number: 6226-25-1), and DIPEA (5.24 mL, 30 mmol) were added to the resulting compound in that order. The mixture was stirred at room temperature, and then hydrochloric acid was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / heptane = 0 / 100 → 100 / 0) to give 2,2,2-trifluoroethyl (S)-3-(4-(((aroxy)carbonyl)amino)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (3.70 g). To the obtained compound (3.57 g), dichloromethane (20 mL), tetrakis(triphenylphosphine)palladium (0.185 g, 0.160 mmol, CAS Registry Number: 14221-01-3), and phenylsilane (2.95 mL, 24.0 mmol, CAS Registry Number: 694-53-1) were added in this order under a nitrogen atmosphere and ice cooling.After stirring under ice-cooling under a nitrogen atmosphere, the mixture was purified by flash column chromatography (silica gel; ethyl acetate / heptane = 0 / 100 → 100 / 0) to give 2,2,2-trifluoroethyl (S)-3-(4-aminophenyl)-2-((tert-butoxycarbonyl)amino)propanoate (2.26 g). To the resulting compound (0.725 g), DMF (8.0 mL), biotin (0.537 g, 2.20 mmol, CAS Registry Number: 58-85-5), ethyl 2-cyano-2-(hydroxyimino)acetate (0.313 g, 2.20 mmol, CAS Registry Number: 3849-21-6), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.422 g, 2.20 mmol, CAS Registry Number: 25952-53-8) were added in that order. The mixture was stirred at room temperature, and then water was added to quench the reaction. The resulting residue was collected by filtration, washed with water, and purified by flash column chromatography (silica gel; methanol / dichloromethane = 3 / 97 → 20 / 80) to give 2,2,2-trifluoroethyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)phenyl)propanoate (0.965 g). Dichloromethane (8.2 mL) and 4 M hydrochloric acid / MTHP (8.2 mL) were added sequentially to the resulting compound. The mixture was stirred at room temperature, and then concentrated under reduced pressure. The residue was washed with methyl tert-butyl ether and dried in vacuo to give 2,2,2-trifluoroethyl (S)-2-amino-3-(4-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)phenyl)propanoate (0.501 g, 0.954 mmol) as a colorless solid.

[0169] Example 1-14: (2,6-dichloropyridin-4-yl)methyl (S)-2-(methylamino)-5-ureidopentanoate hydrochloride (Compound No. 63)

[0170]

[0171] N-(tert-butoxycarbonyl)-L-glutamine (30.0 g, 122 mmol, CAS Registry Number: 13726-85-7), pyridine (210 mL), and dicyclohexylcarbodiimide (22.6 g, 110 mmol, CAS Registry Number: 538-75-0) were added sequentially to a flask equipped with a nitrogen balloon under ice-cooling. After stirring the mixture at room temperature for 3 hours, the mixture was filtered and extracted with dichloromethane. The organic layer was washed sequentially with hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether = 1 / 1) to give (S)-2-((tert-butoxycarbonyl)amino)-4-cyanobutanoic acid (23.0 g). To the resulting compound, THF (150 mL) and 60% sodium hydride (8.00 g, 200 mmol, CAS Registry Number: 7646-69-7) were added at 10° C. After stirring the mixture for 30 minutes, iodomethane (110 g, 775 mmol, CAS Registry Number: 74-88-4) was added to the mixture. The mixture was stirred at room temperature overnight, and then water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed successively with citric acid and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S)-2-((tert-butoxycarbonyl)(methyl)amino)-4-cyanobutanoic acid (13.0 g). To the resulting compound, isopropanol (100 mL), concentrated hydrochloric acid (3 mL), and platinum dioxide (1.00 g, 4.48 mmol, CAS Registry Number: 1314-15-4) were added in that order. After stirring at room temperature under a hydrogen atmosphere for 6 hours, the mixture was filtered and concentrated under reduced pressure to give (S)-5-amino-2-((tert-butoxycarbonyl)(methyl)amino)pentanoic acid hydrochloride (13.0 g). To the resulting compound, THF (200 mL), water (130 mL), and potassium cyanate (12.9 g, 159 mmol, CAS Registry Number: 590-28-3) were added in that order. The mixture was stirred at room temperature overnight, and then hydrochloric acid was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by flash column chromatography (silica gel; acetonitrile / 0.1% formic acid aqueous solution = 10 / 90 → 50 / 50) to give (S)-2-((tert-butoxycarbonyl)(methyl)amino)-5-ureidopentanoic acid (5.03 g). To the obtained compound (3.50 g), DMF (50 mL), 4-(bromomethyl)-2,6-dichloropyridine (2.77 g, 11.5 mmol, CAS registration number: 175204-45-2), and DIPEA (2.54 mL, 14.5 mmol) were added in that order. After stirring the mixture at room temperature for 16 hours, the mixture was purified by flash column chromatography (silica gel; methanol / dichloromethane = 1 / 99 → 20 / 80) to give (2,6-dichloropyridin-4-yl)methyl (S)-2-((tert-butoxycarbonyl)(methyl)amino)-5-ureidopentanate (4.00 g). To the obtained compound (3.00 g), dichloromethane (25 mL) and 4 M hydrochloric acid / CPME (25 mL) were added, successively. The mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. The residue was suspended and washed with diethyl ether to give (2,6-dichloropyridin-4-yl)methyl (S)-2-(methylamino)-5-ureidopentanoate (2.17 g, 5.63 mmol) as a colorless solid.

[0172] Example 1-15: (S)-2-(4-(2-amino-3-((2,6-dichloropyridin-4-yl)methoxy)-3-oxopropyl)piperidin-1-yl)acetic acid dihydrochloride (Compound No. 64)

[0173]

[0174] To a flask were sequentially added (S)-2-((tert-butoxycarbonyl)amino)-3-(pyridin-4-yl)propanoic acid (45.0 g, 169 mmol, CAS Registry Number: 37535-57-2), isopropanol (675 mL), 1 M aqueous hydrochloric acid (169 mL), and platinum dioxide (6.52 g, 28.7 mmol, CAS Registry Number: 1314-15-4). After stirring for 16 hours under a hydrogen atmosphere at room temperature, the mixture was filtered and concentrated under reduced pressure to give (S)-2-((tert-butoxycarbonyl)amino)-3-(piperidin-4-yl)propanoic acid hydrochloride (50.0 g). To the resulting compound, THF (1000 mL) and bis(trimethylsilyl)acetamide (115 g, 567 mmol, CAS Registry Number: 10416-59-8) were added in sequence under ice cooling. After stirring for 1 hour under ice cooling, DIPEA (62.8 mL, 243 mmol) and tert-butyl bromoacetate (47.4 g, 243 mmol, CAS Registry Number: 5292-43-3) were added in sequence under ice cooling. After stirring for 1 hour under ice cooling and at room temperature for another 1 hour, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; methanol / dichloromethane = 1 / 100 → 1 / 1) to give (S)-3-(1-(2-(tert-butoxy)-2-oxoethyl)piperidin-4-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid (55.0 g). To the resulting compound (8.20 g), DMF (80 mL), 4-(bromomethyl)-2,6-dichloropyridine (4.86 g, 20.2 mmol, CAS registration number: 175204-45-2), and DIPEA (4.43 mL, 25.5 mmol) were added in this order. The mixture was stirred at room temperature for 2 hours, and then aqueous sodium dihydrogen phosphate solution was added to quench the reaction. The mixture was extracted with isopropyl acetate, and the organic layer was washed successively with aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether=1 / 1) to give (2,6-dichloropyridin-4-yl)methyl (S)-3-(1-(2-(tert-butoxy)-2-oxoethyl)piperidin-4-yl)-2-((tert-butoxycarbonyl)amino)propanoate (7.06 g). To the obtained compound (1.60 g), dichloromethane (15 mL) and 4 M hydrochloric acid / MTHP (15 mL) were added in that order. The mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. The residue was suspended and washed with diethyl ether and dried in vacuo to give (S)-2-(4-(2-amino-3-((2,6-dichloropyridin-4-yl)methoxy)-3-oxopropyl)piperidin-1-yl)acetic acid dihydrochloride (1.49 g, 3.22 mmol) as a colorless solid.

[0175] Example 1-16: (2,6-dichloropyridin-4-yl)methyl (S)-2-amino-3-(1-carbamoylpiperidin-4-yl)propanoate hydrochloride (Compound No. 65)

[0176]

[0177] To (S)-2-((tert-butoxycarbonyl)amino)-3-(piperidin-4-yl)propanoic acid hydrochloride (80.0 g, 259 mmol) obtained in Example 1-15, THF (600 mL), water (400 mL), and potassium cyanate (36.0 g, 444 mmol, CAS Registry Number: 590-28-3) were added in that order. The mixture was stirred at room temperature for 16 hours, and then aqueous sodium dihydrogen phosphate was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S)-2-((tert-butoxycarbonyl)amino)-3-(1-carbamoylpiperidin-4-yl)propanoic acid (80.0 g). To the resulting compound (15.0 g), DMF (150 mL), 4-(bromomethyl)-2,6-dichloropyridine (10.9 g, 45.2 mmol, CAS registration number: 175204-45-2), and DIPEA (9.94 mL, 57.1 mmol) were added in that order. The mixture was stirred at room temperature for 1 hour, and then water was added to quench the reaction. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; methanol / dichloromethane = 1 / 10) to give (2,6-dichloropyridin-4-yl)methyl (S)-2-((tert-butoxycarbonyl)amino)-3-1-carbamoylpiperidin-4-yl)propanoate (10.7 g). To the resulting compound (3.00 g), dichloromethane (25 mL) and 4 M hydrochloric acid / MTHP (25 mL) were added in sequence. The mixture was stirred at room temperature for 30 minutes, and then concentrated under reduced pressure. The residue was suspended and washed with diethyl ether and dried in vacuo to give (2,6-dichloropyridin-4-yl)methyl (S)-2-amino-3-(1-carbamoylpiperidin-4-yl)propanoate hydrochloride (2.90 g, 6.48 mmol) as a colorless solid.

[0178] Example 1-17: (S)-2-(4-((5-amino-6-((2,6-dichloropyridin-4-yl)methoxy)-6-oxohexyl)carbamoyl)piperazin-1-yl)acetic acid dihydrochloride (Compound No. 66)

[0179]

[0180] To a flask, (tert-butoxycarbonyl)-L-lysine (10.0 g, 40.6 mmol, CAS Registry Number: 13734-28-6), THF (66 mL), and bis(trimethylsilyl)acetamide (18.2 g, 89.3 mmol, CAS Registry Number: 10416-59-8) were added in this order under ice cooling. The mixture was stirred at room temperature for 30 minutes, and then DIPEA (8.49 mL, 48.7 mmol) and 4-nitrophenyl chloroformate (7.77 g, 38.6 mmol, CAS Registry Number: 7693-46-1) dissolved in THF (17 mL) were added in this order under ice cooling. After stirring at 10°C or below for 1.5 hours, the reaction was quenched by the addition of hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether=1 / 1) to give N ２ -(tert-butoxycarbonyl)-N ６ 1,1-dimethylethyl 1-piperazine acetate (5.32 g, 26.5 mmol) dissolved in THF (90 mL), DMF (10 mL), and DIPEA (4.84 mL, 27.8 mmol) were added to the resulting compound (10.4 g) in turn under ice-cooling. The mixture was stirred at room temperature for 4 hours, and then an aqueous solution of sodium dihydrogen phosphate was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; methanol / dichloromethane = 8 / 92) to give N ６-(4-(2-(tert-butoxy)-2-oxoethyl)piperazine-1-carbonyl)-N ２ 1-(tert-butoxycarbonyl)-L-lysine (8.00 g) was obtained. To the obtained compound, DMF (80 mL), 4-(bromomethyl)-2,6-dichloropyridine (3.87 g, 16.1 mmol, CAS registration number: 175204-45-2), and DIPEA (2.63 g, 20.3 mmol) were added in this order. The mixture was stirred at room temperature for 1 hour, and then water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; methanol / dichloromethane = 4 / 96) to give (2,6-dichloropyridin-4-yl)methyl N-( ... ６ -(4-(2-(tert-butoxy)-2-oxoethyl)piperazine-1-carbonyl)-N ２ To the resulting compound (5.07 g), dichloromethane (10 mL) and 2,2,2-trifluoroacetic acid (12.5 mL) were added in that order. After the mixture was stirred at room temperature for 20 hours, the mixture was concentrated under reduced pressure, and acetonitrile and 4 M hydrochloric acid / MTHP (25 mL) were added in that order. The mixture was filtered, washed with THF, and dried in vacuo to give (S)-2-(4-((5-amino-6-((2,6-dichloropyridin-4-yl)methoxy)-6-oxohexyl)carbamoyl)piperazin-1-yl)acetic acid dihydrochloride (4.10 g, 8.01 mmol) as a colorless solid.

[0181] Example 1-18: (2,6-dichloropyridin-4-yl)methyl (S)-2-amino-4-(benzylsulfonyl)butanoate hydrochloride (Compound No. 67)

[0182]

[0183] S-benzyl-N-(tert-butoxycarbonyl)-L-homocysteine ​​(0.325 g, 1.00 mmol, CAS Registry Number: 16947-99-2), methanol (2.0 mL), and magnesium bis(monoperoxyphthalate) hexahydrate (0.594 g, 1.20 mmol, CAS Registry Number: 84665-66-7) were added to a flask in this order under ice cooling. The mixture was stirred at room temperature, and then hydrochloric acid was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S)-4-(benzylsulfonyl)-2-((tert-butoxycarbonyl)amino)butanoic acid (0.357 g). To the resulting compound, DMF (2.0 mL), 4-(bromomethyl)-2,6-dichloropyridine (0.229 g, 0.95 mmol, CAS Registry Number: 175204-45-2), and DIPEA (0.210 mL, 1.20 mmol) were added in that order. The mixture was stirred at room temperature, and then hydrochloric acid was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / hexane = 0 / 100 → 100 / 0) to give (2,6-dichloropyridin-4-yl)methyl (S)-4-(benzylsulfonyl)-2-((tert-butoxycarbonyl)amino)butanoate (0.474 g). To the resulting compound, dichloromethane (4.6 mL) and 4 M hydrochloric acid / MTHP (4.6 mL) were added in sequence. After stirring the mixture at room temperature, the mixture was concentrated under reduced pressure. The residue was suspended and washed with methyl tert-butyl ether and dried in vacuo to give (2,6-dichloropyridin-4-yl)methyl (S)-2-amino-4-(benzylsulfonyl)butanoate hydrochloride (0.384 g, 0.845 mmol) as a colorless solid.

[0184] Example 1-19: (2,6-Dichloropyridin-4-yl)methyl (S)-2-amino-3-(2-carbamoyl-1H-imidazol-4-yl)propanoate dihydrochloride (Compound No. 68)

[0185]

[0186] To a flask equipped with a nitrogen balloon, 4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (80.0 g, 247 mmol, CAS Registry Number: 518329-44-7) and THF (1400 mL) were added sequentially. After the mixture was stirred at room temperature for 30 minutes, 2M LDA / THF (148 mL, 296 mmol, CAS Registry Number: 4111-54-0) was added to the mixture at −78° C. After stirring at −78° C. for 30 minutes, the mixture was added to a mixture of ethyl chloroformate (93.7 g, 864 mmol, CAS Registry Number: 541-41-3) and THF (500 mL) at −78° C. After stirring at −78° C. for 30 minutes, water was added to quench the reaction. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether = 20 / 80 → 50 / 50) to give ethyl 4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate (80.0 g). The obtained compound (80.0 g) was added with 4M-NH ３To the resulting mixture was added MeOH (1600 mL, CAS Registry Number: 7664-41-7). After stirring at 60° C. for 2.5 hours, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether = 20 / 80 → 50 / 50) to give 4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxamide (52.0 g). To a flask equipped with a nitrogen balloon were added zinc (23.5 g, 359 mmol, CAS Registry Number: 7440-66-6), DMF (880 mL), and iodine (9.12 g, 35.9 mmol, CAS Registry Number: 7553-56-2), in that order. After stirring at 60°C for 30 minutes, (S)-methyl 2-(tert-butoxycarbonylamino)-3-iodopropanoate (78.9 g, 240 mmol, CAS Registry Number: 93267-04-0) was added to the mixture, and the mixture was stirred at room temperature for 1.5 hours to prepare an organozinc reagent. To a flask equipped with a nitrogen balloon, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (4.92 g, 12.0 mmol, CAS Registry Number: 657408-07-6), tris(dibenzylideneacetone)dipalladium-chloroform (2.74 g, 3.00 mmol, CAS Registry Number: 52522-40-4), and DMF (40 mL) were added in that order, and the mixture was stirred at 60°C for 30 minutes to prepare a palladium complex solution.

[0187] The prepared palladium complex solution and 4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxamide (44.0 g) dissolved in DMF (160 mL) were added sequentially to the prepared organozinc reagent at room temperature. After stirring at 60° C. for 1 hour, the mixture was filtered and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether = 20 / 80 → 40 / 60) to give methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(2-carbamoyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)propanoate (30.0 g). To the resulting compound, isopropanol (900 mL), water (300 mL), calcium chloride (120 g, 1080 mmol, CAS Registry Number: 10043-52-4), and lithium hydroxide monohydrate (11.4 g, 271 mmol, CAS Registry Number: 1310-66-3) were added in this order under ice-cooling. The mixture was stirred at room temperature for 2 hours, and then sodium dihydrogen phosphate was added to quench the reaction. The mixture was filtered and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether = 40 / 60 → 60 / 40) to give (S)-2-((tert-butoxycarbonyl)amino)-3-(2-carbamoyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)propanoic acid (20.0 g). To the obtained compound (20.0 g), DMF (400 mL), 4-(bromomethyl)-2,6-dichloropyridine (10.7 g, 44.3 mmol, CAS registration number: 175204-45-2), and DIPEA (7.24 g, 56.0 mmol) were added in this order. The mixture was stirred at room temperature for 2 hours, and then water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by flash column chromatography (silica gel; acetonitrile / 0.1% formic acid aqueous solution = 40 / 60 → 60 / 40) to give (2,6-dichloropyridin-4-yl)methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(2-carbamoyl-1-((2-(trimethylsilyl)methoxy))-1H-imidazol-4-yl)propanoate (10.7 g). Dichloromethane (32 mL) and 4 M hydrochloric acid / MTHP (32 mL) were added sequentially to the obtained compound (5.01 g). The mixture was stirred at room temperature for 3 days, and then concentrated under reduced pressure. The residue was suspended and washed with diethyl ether and dried in vacuo. The residue was purified by flash column chromatography (silica gel; acetonitrile / water = 2 / 98 → 15 / 85), and water and acetonitrile were added and the mixture was lyophilized to give (2,6-dichloropyridin-4-yl)methyl (S)-2-amino-3-(6-aminopyridin-3-yl)propanoate dihydrochloride (0.368 g, 0.854 mmol) as a colorless solid.

[0188] Example 1-20: (2,6-dichloropyridin-4-yl)methyl N ５ -(4-aminobutyl)-L-glutamate dihydrochloride (Compound No. 69)

[0189]

[0190] In the flask, ２ -(((9H-fluoren-9-yl)methoxy)carbonyl)-N ５ -(4-((tert-butoxycarbonyl)amino)butyl)-L-glutamine (2.70 g, 5.00 mmol, purchased from Amatek Chemical Co. (AS02649)), acetonitrile (10 mL), and triethylamine (2.53 g, 25.0 mmol) were added in that order at room temperature. After stirring at 60° C. for 1 hour, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue, which was then filtered, washed with diethyl ether, dried in vacuo, and purified by N ５To the resulting compound, 1,4-dioxane (15 mL), water (10 mL), sodium carbonate (1.59 g, 15.0 mmol), and di-tert-butyl dicarbonate (1.31 g, 6.00 mmol, CAS registration number: 24424-99-5) were added in this order at room temperature. The mixture was stirred at room temperature, and then concentrated under reduced pressure. ２ -(tert-butoxycarbonyl)-N ５ -(4-((tert-butoxycarbonyl)amino)butyl)-L-glutamine was obtained. DMF (10 mL), DIPEA (0.775 g, 6.00 mmol), and 4-(bromomethyl)-2,6-dichloropyridine (1.14 g, 4.75 mmol, CAS registration number: 175204-45-2) were added to the obtained compound in this order to give a mixture. After stirring at room temperature, water was added to the mixture to quench the reaction. The mixture was extracted with isopropyl acetate, and the organic layer was washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / heptane=0 / 100→75 / 25) to give (2,6-dichloropyridin-4-yl)methyl N-(4-((tert-butoxycarbonyl)amino)butyl)-L-glutamine. ２ -(tert-butoxycarbonyl)-N ５ To the resulting compound, dichloromethane (25 mL) and 4M hydrochloric acid / MTHP (25 mL) were added in that order. The mixture was stirred at room temperature and then concentrated under reduced pressure. The residue was suspended and washed with diethyl ether to give (2,6-dichloropyridin-4-yl)methyl N-(4-((tert-butoxycarbonyl)amino)butyl)-L-glutamate. ５ As a result, 4-(4-aminobutyl)-L-glutamate dihydrochloride (1.12 g, 2.49 mmol) was obtained as a colorless solid.

[0191] Example 1-21: (2,6-dichloropyridin-4-yl)methyl O-isobutyl-L-homoserinate hydrochloride (Compound No. 70)

[0192]

[0193] To a flask were added (S)-4-(tert-butoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid (50.0 g, 173 mmol, CAS Registry Number: 34582-32-6), THF (500 mL), 4-methylmorpholine (22.7 g, 224 mmol, CAS Registry Number: 109-02-4), and isopropyl chloroformate (23.1 g, 188 mmol, CAS Registry Number: 108-23-6) in that order at −10° C. After stirring at −10° C. for 30 minutes, sodium borohydride (13.1 g, 346 mmol, CAS Registry Number: 16940-66-2) was added to the mixture at −10° C. After stirring at -10°C for 30 minutes, sodium borohydride (13.1 g, 346 mmol) dissolved in water (150 mL) was added at -10°C. After stirring at -10°C for 2 hours, aqueous ammonium chloride solution was added to the mixture to quench the reaction. The mixture was extracted with ethyl acetate, washed with aqueous ammonium chloride and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain tert-butyl(tert-butoxycarbonyl)-L-homoserinate (45.0 g). To thionyl chloride (56.2 g, 472 mmol, CAS Registry Number: 7719-09-7) dissolved in acetonitrile (850 mL), tert-butyl(tert-butoxycarbonyl)-L-homoserinate (50.0 g) dissolved in acetonitrile (150 mL) was added at -40°C. After stirring at −40° C. for 15 minutes, pyridine (86.2 g, 1090 mmol) was added to the mixture at −40° C. After stirring at 0° C. for 20 minutes, water was added to the mixture to quench the reaction. The mixture was extracted with dichloromethane, washed with 1 M aqueous hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether=1 / 10) to give di-tert-butyl (4S)-1,2,3-oxathiazinane-3,4-dicarboxylate 2-oxide (30.0 g).To the resulting compound, dimethyl carbonate (300 mL) and ruthenium trichloride hydrate (0.21 g, 0.933 mmol, CAS No.: 14898-67-0) dissolved in water and sodium periodate (59.9 g, 280 mmol, CAS No.: 14898-67-0) were added in sequence under ice cooling. After stirring the mixture at room temperature for 3 hours, the mixture was filtered, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether = 1 / 10) to give di-tert-butyl (S)-1,2,3-oxathiazinane-3,4-dicarboxylate 2,2-dioxide (25.0 g). To the resulting compound (14.5 g), sodium dihydrogen phosphate (20.6 g, 172 mmol, CAS registration: 7558-79-4) and 2-methylpropan-1-ol (79.6 g, 1070 mmol, CAS registration: 78-83-1) were added at room temperature. After stirring at 55 °C for 3 hours, the mixture was concentrated under reduced pressure. The mixture was dissolved in ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain tert-butyl N-(tert-butoxycarbonyl)-O-isobutyl-L-homoserinate (13.6 g). To the resulting compound, 1,4-dioxane (35 mL) and 4 M aqueous hydrochloric acid solution (105 mL) were added sequentially at room temperature. After stirring at 85 °C for 3 hours, the mixture was concentrated under reduced pressure to obtain O-isobutyl-L-homoserine hydrochloride (8.60 g). To the resulting compound, 1,4-dioxane (90 mL), water (60 mL), sodium bicarbonate (13.6 g, 162 mmol, CAS Registry Number: 497-19-8), and di-tert-butyl dicarbonate (10.6 g, 48.6 mmol, CAS Registry Number: 24424-99-5) were added in this order under ice-cooling. The mixture was stirred at room temperature for 5 hours, and then quenched with 1 M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by flash column chromatography (silica gel; methanol / dichloromethane = 1 / 10) to give N-(tert-butoxycarbonyl)-O-isobutyl-L-homoserine (10.4 g). To the resulting compound, DMF (100 mL), DIPEA (5.86 g, 45.3 mmol), and 4-(bromomethyl)-2,6-dichloropyridine (8.64 g, 35.9 mmol, CAS registration number: 175204-45-2) were added in sequence. The mixture was stirred at room temperature for 1 hour, and then aqueous sodium dihydrogen phosphate was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed successively with aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether = 1 / 5) to give (2,6-dichloropyridin-4-yl)methyl N-(tert-butoxycarbonyl)-O-isobutyl-L-homoserinate (9.95 g). To the resulting compound (4.98 g), dichloromethane (42 mL) and 4 M hydrochloric acid / MTHP (43 mL) were added, successively. The mixture was stirred at room temperature for 17 hours, and then concentrated under reduced pressure. The residue was suspended and washed with diethyl ether to give (2,6-dichloropyridin-4-yl)methyl O-isobutyl-L-homoserinate hydrochloride (3.11 g, 8.37 mmol) as a colorless solid.

[0194] Example 1-22: (2,6-dichloropyridin-4-yl)methyl N ２ , N ５ , N ５ -Trimethyl-L-glutamate hydrochloride (Compound No. 71)

[0195]

[0196] To a flask, ((benzyloxy)carbonyl)-L-glutamic acid (50.0 g, 178 mmol, CAS Registry Number: 1155-62-0), paraformaldehyde (16.0 g, 533 mmol, CAS Registry Number: 30525-89-4), 10-camphorsulfonic acid (8.25 g, 35.6 mmol, CAS Registry Number: 3144-16-9), and toluene (800 mL) were added in this order. After stirring at 80°C overnight, ethyl acetate was added to the mixture, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; methanol / dichloromethane = 1 / 10) to give (S)-3-(3-((benzyloxy)carbonyl)-5-oxooxazolidin-4-yl)propanoic acid (50.0 g). To the resulting compound (20.0 g), DMF (300 mL), dimethylamine hydrochloride (8.34 g, 102 mmol, CAS Registry Number: 506-59-2), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (51.9 g, 136 mmol, CAS Registry Number: 148893-10-1), and DIPEA (35.3 g, 273 mmol) were added in this order at room temperature. The mixture was stirred overnight at room temperature, and then ethyl acetate was added to the mixture. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether=1 / 1) to give benzyl (S)-4-(3-(dimethylamino)-3-oxopropyl)-5-oxooxazolidine-3-carboxylate (20.0 g). To the obtained compound (6.50 g), dichloromethane (30 mL), triisopropylsilane (10.5 g, 66.5 mmol, CAS registration number: 6485-79-6), and 2,2,2-trifluoroacetic acid (30.0 mL) were added in this order at room temperature. The mixture was stirred overnight at room temperature, and then concentrated under reduced pressure. ２ -((benzyloxy)carbonyl)-N ２ , N ５ , N ５To the resulting compound, methanol (170 mL) and palladium on carbon (1.77 g, CAS Registry Number: 7440-05-3) were added in that order. After stirring overnight at room temperature under a hydrogen atmosphere, the mixture was filtered, extracted with methanol, and concentrated under reduced pressure. ２ , N ５ , N ５ 1,4-Dioxane (100 mL) and water (100 mL) were added to the resulting compound. After stirring the mixture at room temperature, sodium carbonate (21.4 g, 202 mmol, CAS Registry Number: 497-19-8) and di-tert-butyl dicarbonate (33.1 g, 151 mmol, CAS Registry Number: 24424-99-5) were added in sequence under ice-cooling. The mixture was stirred overnight at room temperature, and then hydrochloric acid was added to quench the reaction. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then diluted with N ２ -(tert-butoxycarbonyl)-N ２ , N ５ , N ５ To the resulting compound, DMF (100 mL), 4-(bromomethyl)-2,6-dichloropyridine (7.62 g, 31.6 mmol, CAS registration number: 175204-45-2), and DIPEA (5.16 g, 40.0 mmol) were added in this order. The mixture was stirred at room temperature for 1 hour, and then water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether = 1 / 1) to give (2,6-dichloropyridin-4-yl)methyl N-( ... ２ -(tert-butoxycarbonyl)-N ２ , N ５ , N ５To the resulting compound (4.48 g), dichloromethane (25 mL) and 4M hydrochloric acid / MTHP (25 mL) were added in that order. The mixture was stirred at room temperature for 17 hours, and then concentrated under reduced pressure. The residue was suspended and washed with methyl tert-butyl ether, dried in vacuo, and (2,6-dichloropyridin-4-yl)methyl N-glutamate was obtained. ２ , N ５ , N ５ -trimethyl-L-glutamate hydrochloride (3.54 g, 9.21 mmol) was obtained as a colorless solid.

[0197] Example 1-23: (2,6-dichloropyridin-4-yl)methyl (S)-3-(5-hydroxypyridin-3-yl)-2-(methylamino)propanoate dihydrochloride (Compound No. 72)

[0198]

[0199] N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-serine (150 g, 439 mmol, CAS Registry Number: 291311-48-3), methanol (1500 mL), and concentrated sulfuric acid (50 mL) were added sequentially to a flask equipped with a nitrogen balloon. The mixture was stirred at 60°C and then concentrated under reduced pressure. Ethyl acetate was added to the mixture, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain methyl N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-L-serinate (120 g). To the resulting compound (71.0 g), dichloromethane (500 mL), triphenylphosphine (78.6 g, 300 mmol, CAS Registry Number: 603-35-0), imidazole (20.4 g, 300 mmol, CAS Registry Number: 288-32-4), and iodine (76.1 g, 300 mmol, CAS Registry Number: 7553-56-2) were added in this order under ice cooling. After stirring the mixture at room temperature for 30 minutes, dichloromethane was added to the mixture, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether = 1 / 1) to give methyl (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-iodopropanoate (70.0 g). Zinc (19.0 g, 290 mmol, CAS Registry Number: 7440-66-6), DMF (400 mL), and iodine (14.7 g, 58.0 mmol, CAS Registry Number: 7553-56-2) were sequentially added to a flask equipped with a nitrogen balloon. After stirring the mixture at room temperature for 2 minutes, methyl (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-iodopropanoate (45.0 g) was added to the mixture.After stirring the mixture at room temperature for 30 minutes, 5-bromopyridin-3-ol (20.2 g, 116 mmol, CAS Registry Number: 74115-13-2), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (1.98 g, 4.83 mmol, CAS Registry Number: 657408-07-6), and tris(dibenzylideneacetone)dipalladium-chloroform (2.21 g, 2.42 mmol, CAS Registry Number: 52522-40-4) were added to the mixture in this order at room temperature. After stirring at 50°C for 3 hours, water was added to the mixture, which was then filtered and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether=1 / 3) to give methyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(5-hydroxypyridin-3-yl)propanoate (18.0 g).

[0200] To the resulting compound (10.0 g), isopropanol (120 mL), water (40 mL), calcium chloride (41.1 g, 370 mmol, CAS Registry Number: 10043-52-4), and lithium hydroxide monohydrate (3.88 g, 92.5 mmol, CAS Registry Number: 1310-66-3) were added in this order under ice cooling. The mixture was stirred overnight at room temperature, and then sodium dihydrogen phosphate was added to quench the reaction. The mixture was filtered and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether = 1 / 5) to give (S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(5-hydroxypyridin-3-yl)propanoic acid (8.00 g). To the resulting compound (6.7 g), THF (20 mL) and diethylamine (3.51 g, 48.0 mmol, CAS Registry Number: 109-89-7) were added in that order. After stirring the mixture at room temperature for 1 hour, the mixture was concentrated under reduced pressure to give (S)-3-(5-hydroxypyridin-3-yl)-2-(methylamino)propanoic acid (3.14 g). To the resulting compound, THF (30 mL), di-tert-butyl dicarbonate (7.68 g, 35.2 mmol, CAS Registry Number: 24424-99-5), and DIPEA (4.13 g, 31.2 mmol) were added in that order under ice cooling. The mixture was stirred overnight at room temperature, and then concentrated under reduced pressure to give (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(5-((tert-butoxycarbonyl)oxy)pyridin-3-yl)propanoic acid (6.00 g). To the resulting compound were added DMF (30 mL), 4-(bromomethyl)-2,6-dichloropyridine (3.45 g, 14.3 mmol, CAS registration number: 175204-45-2), and DIPEA (2.35 g, 18.2 mmol), in that order. The mixture was stirred at room temperature for 1 hour, and then aqueous sodium dihydrogen phosphate solution was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed successively with aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether=1 / 4) to give (2,6-dichloropyridin-4-yl)methyl (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(5-((tert-butoxycarbonyl)oxy)pyridin-3-yl)propanoic acid (4.95 g). To the obtained compound (2.62 g), dichloromethane (21.3 mL) and 4 M hydrochloric acid / MTHP (21.3 mL) were added in that order. The mixture was stirred at room temperature for 4 hours, and then concentrated under reduced pressure. The residue was suspended and washed with diethyl ether and dried in vacuo to give (2,6-dichloropyridin-4-yl)methyl (S)-3-(5-hydroxypyridin-3-yl)-2-(methylamino)propanoate dihydrochloride (1.99 g, 4.64 mmol) as a light brown solid.

[0201] Example 1-24: (2,6-dichloropyridin-4-yl)methyl (S)-3-(6-aminopyridin-3-yl)-2-(methylamino)propanoate dihydrochloride (Compound No. 73)

[0202]

[0203] Zinc (22.4 g, 343 mmol, CAS Registry Number: 7440-66-6), DMF (450 mL), and iodine (17.4 g, 68.6 mmol, CAS Registry Number: 7553-56-2) were sequentially added to a flask equipped with a nitrogen balloon. After stirring the mixture at room temperature for 10 minutes, methyl (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-iodopropanoate (53.2 g) obtained from Example 1-23 was added to the mixture. After stirring the mixture at room temperature for 1 hour, 5-bromopyridin-2-amine (20.0 g, 116 mmol, CAS Registry Number: 1072-97-5), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (9.40 g, 22.9 mmol, CAS Registry Number: 657408-07-6), and tris(dibenzylideneacetone)dipalladium-chloroform (5.80 g, 5.72 mmol, CAS Registry Number: 52522-40-4) were added to the mixture at room temperature in that order. After stirring at 50°C for 16 hours, water was added to the mixture, which was then filtered and extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether=2 / 1) to give methyl ((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(6-aminopyridin-3-yl)propanoate (30.0 g). The obtained compound was dissolved in tert-butanol (600 mL), di-tert-butyl dicarbonate (18.2 g, 83.4 mmol, CAS registration number: 24424-99-5) and sodium iodide. (12.5 g, 83.4 mmol, CAS Registry Number: 7681-82-5) was added in sequence. The mixture was stirred at room temperature for 16 hours, and then concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether = 1 / 4) to give methyl (S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(6-((tert-butoxycarbonyl)amino)pyridin-3-yl)propanoate (20.0 g).To the resulting compound, isopropanol (360 mL), calcium chloride (66.8 g, 602 mmol, CAS Registry Number: 10043-52-4), water (120 mL), and lithium hydroxide monohydrate (3.61 g, 151 mmol, CAS Registry Number: 1310-66-3) were added in this order under ice cooling. The mixture was stirred at room temperature for 16 hours, and then hydrochloric acid was added to quench the reaction. The mixture was filtered and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(6-((tert-butoxycarbonyl)amino)pyridin-3-yl)propanoic acid. To the resulting compound, THF (50 mL) and diethylamine (5.50 g, 75.2 mmol, CAS Registry Number: 109-89-7) were added in that order. After stirring the mixture at room temperature for 5 hours, the mixture was concentrated under reduced pressure to give (S)-3-(6-((tert-butoxycarbonyl)amino)pyridin-3-yl)-2-(methylamino)propanoic acid.

[0204] To the resulting compound, THF, TEA (11.4 g, 75.2 mmol), and di-tert-butyl dicarbonate (9.86 g, 45.2 mmol, CAS Registry Number: 24424-99-5) were added in that order. The mixture was stirred at room temperature for 16 hours, and then concentrated under reduced pressure to give (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(6-((tert-butoxycarbonyl)amino)pyridin-3-yl)propanoic acid. To the resulting compound, DMF (200 mL), 4-(bromomethyl)-2,6-dichloropyridine (10.8 g, 44.9 mmol, CAS Registry Number: 175204-45-2), and DIPEA (7.33 g, 56.7 mmol) were added in that order. The mixture was stirred at room temperature for 1 hour, and then aqueous sodium dihydrogen phosphate solution was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed successively with aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether=1 / 5) to give (2,6-dichloropyridin-4-yl)methyl (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(6-((tert-butoxycarbonyl)amino)pyridin-3-yl)propanoate (11.3 g). Dichloromethane (20 mL) and 4 M hydrochloric acid / MTHP (20 mL) were added sequentially to the obtained compound (4.44 g). The mixture was stirred at room temperature, and then concentrated under reduced pressure. The residue was suspended and washed with heptane, dried in vacuo, dissolved in water and acetonitrile, and then freeze-dried to give (2,6-dichloropyridin-4-yl)methyl (S)-3-(6-aminopyridin-3-yl)-2-(methylamino)propanoate dihydrochloride (3.33 g, 7.77 mmol) as a colorless solid.

[0205] Example 1-25: (S)-2-(4-((6-((2,6-dichloropyridin-4-yl)methyl)-5-(methylamino)-6-oxohexyl)carbamoyl)piperazin-1-yl)acetic acid dihydrochloride (Compound No. 74)

[0206]

[0207] A flask equipped with a nitrogen balloon was charged with N ２ -(tert-butoxycarbonyl)-N ６ To the mixture were added 18.4 g, 459 mmol, CAS Registry Number: 7646-69-7) and 10.0 g of diazo-L-lysine (50.0 g, 183 mmol, CAS Registry Number: 846549-33-5), THF (500 mL), and 60% sodium hydride (18.4 g, 459 mmol, CAS Registry Number: 7646-69-7) in this order under ice-cooling. After stirring for 1 hour under ice-cooling, iodomethane (78.2 g, 551 mmol, CAS Registry Number: 74-88-4) was added under ice-cooling. The mixture was stirred overnight at room temperature, and then water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed with aqueous sodium dihydrogen phosphate and saturated brine in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then diluted with N ２ -(tert-butoxycarbonyl)-N ６ -Diazo-N ２ To the resulting compound, methanol (400 mL) and palladium on carbon (4.00 g, CAS Registry Number: 7440-05-3) were added in that order. After stirring overnight at room temperature under a hydrogen atmosphere, the mixture was filtered, extracted with methanol, concentrated under reduced pressure, and then diluted with N ２ -(tert-butoxycarbonyl)-N ２To the resulting compound (30.0 g), methanol (300 mL), bis(trimethylsilyl)acetamide (46.9 g, 230 mmol, CAS Registry Number: 10416-59-8), 1-bromo-2-(2-bromoethoxy)ethane (28.1 g, 121 mmol, CAS Registry Number: 5414-19-7), and DIPEA (44.7 g, 346 mmol) were added in this order at room temperature. After stirring at 60° C. for 24 hours, the mixture was concentrated under reduced pressure to give (S)-2-((tert-butoxycarbonyl)(methyl)amino)-6-morpholinohexanoic acid (30.0 g). To the resulting compound, DMF (300 mL), 4-(bromomethyl)-2,6-dichloropyridine (26.3 g, 109 mmol, CAS Registry Number: 175204-45-2), and DIPEA (17.6 g, 136 mmol) were added in that order. The mixture was stirred at room temperature for 2 hours, and then aqueous sodium dihydrogen phosphate was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; acetonitrile / 10 mM aqueous ammonium bicarbonate = 20 / 80 → 60 / 40) to give (2,6-dichloropyridin-4-yl)methyl (S)-2-((tert-butoxycarbonyl)(methyl)amino)-6-morpholinohexanoate (9.80 g). To the resulting compound (4.90 g), dichloromethane (25 mL) and 4 M hydrochloric acid / MTHP (25 mL) were added in sequence. The mixture was stirred at room temperature and then concentrated under reduced pressure. Methyl tert-butyl ether was added to the residue, which was then filtered, washed with methyl tert-butyl ether, and dried in vacuo to give (2,6-dichloropyridin-4-yl)methyl (S)-2-(methylamino)-6-morpholinohexanoate dihydrochloride (39.1 g, 8.45 mmol) as a colorless solid.

[0208] Example 1-26: (2,6-dichloropyridin-4-yl)methyl (S)-2-(methylamino)-6-morpholinohexanoate dihydrochloride (Compound No. 75)

[0209]

[0210] In a flask, add N ２ -(tert-butoxycarbonyl)-N ２ To the mixture were added 35.0 g of methyl-L-lysine, 500 mL of THF, 60.2 g of bis(trimethylsilyl)acetamide (60.2 g, 296 mmol, CAS Registry Number: 10416-59-8), 20.9 g of DIPEA (161 mmol), and 25.2 g of 4-nitrophenyl chloroformate (25.2 g, 128 mmol, CAS Registry Number: 7693-46-1) in this order under ice-cooling. The mixture was stirred at room temperature for 2 hours, and then hydrochloric acid was added under ice-cooling to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether = 1 / 1) to give N-methyl-L-lysine. ２ -(tert-butoxycarbonyl)-N ２ -methyl-N ６ To the resulting compound, THF (108 mL), DMF (12 mL), and 1,1-dimethylethyl 1-piperazine acetate (5.99 g, 29.6 mmol) were added in this order under ice-cooling. The mixture was stirred overnight at 30°C, and then aqueous sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. ６ -(4-(2-(tert-butoxy)-2-oxoethyl)piperazine-1-carbonyl)-N ２ -(tert-butoxycarbonyl)-N ２To the resulting compound, DMF (60 mL), 4-(bromomethyl)-2,6-dichloropyridine (6.11 g, 25.4 mmol, CAS registration number: 175204-45-2), and DIPEA (4.14 g, 32.1 mmol) were added in that order. The mixture was stirred at room temperature for 1 hour, and then aqueous sodium dihydrogen phosphate was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed successively with aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; acetonitrile / 0.1% aqueous ammonium bicarbonate = 30 / 70 → 50 / 50) to give (2,6-dichloropyridin-4-yl)methyl N-lysine. ６ -(4-(2-(tert-butoxy)-2-oxoethyl)piperazine-1-carbonyl)-N ２ -(tert-butoxycarbonyl)-N ２ To the resulting compound (3.02 g), dichloromethane (14 mL) and 2,2,2-trifluoroacetic acid (14 mL) were added in that order. After the mixture was stirred at room temperature for 23 hours, it was concentrated under reduced pressure, and acetonitrile and 4 M hydrochloric acid / MTHP were added in that order. The mixture was filtered, washed with diethyl ether, and dried in vacuo to give (S)-2-(4-((6-((2,6-dichloropyridin-4-yl)methoxy)-5-(methylamino)-6-oxohexyl)carbamoyl)piperazin-1-yl)acetic acid dihydrochloride (2.18 g, 4.67 mmol) as a pale yellow solid.

[0211] Example 1-27: (2,6-dichloropyridin-4-yl)methyl (S)-2-amino-3-(2-oxo-1,2-dihydropyridin-4-yl)propanoate hydrochloride (Compound No. 76)

[0212]

[0213] Zinc (20.9 g, 319 mmol, CAS Registry Number: 7440-66-6), DMF (600 mL), and iodine (16.2 g, 63.8 mmol, CAS Registry Number: 7553-56-2) were sequentially added to a flask equipped with a nitrogen balloon. After stirring the mixture at room temperature, (S)-methyl 2-(tert-butoxycarbonylamino)-3-iodopropanoate (42.0 g, 128 mmol, CAS Registry Number: 93267-04-0) was added to the mixture. After stirring the mixture at room temperature for 60 minutes, 4-bromo-2-methoxypyridine (20.0 g, 106 mmol, CAS Registry Number: 100367-39-3), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (8.73 g, 21.3 mmol, CAS Registry Number: 657408-07-6), and tris(dibenzylideneacetone)dipalladium-chloroform (5.44 g, 5.32 mmol, CAS Registry Number: 52522-40-4) were sequentially added to the mixture. After stirring at 50°C for 16 hours, water was added to the mixture, which was then filtered and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether=1 / 5) to give methyl (S)-2-(((tert-butoxycarbonyl)amino)-3-(2-methoxypyridin-4-yl)propanoate (25.0 g). 1,4-Dioxane (250 mL) and 48% aqueous hydrogen bromide solution (250 mL) were added to the obtained compound in that order. After stirring at 100° C. overnight, the mixture was concentrated under reduced pressure to give (S)-2-amino-3- (2-Oxo-1,2-dihydropyridin-4-yl)propanoic acid hydrobromide was obtained. 1,4-Dioxane (300 mL), water (300 mL), DIPEA (49.4 g, 380 mmol), and di-tert-butyl dicarbonate (24.9 g, 114 mmol, CAS registration number: 24424-99-5) were added to the obtained compound in this order under ice cooling. The mixture was stirred at room temperature for 4 hours, and then aqueous hydrochloric acid was added to quench the reaction. The mixture was then concentrated under reduced pressure.The residue was purified by flash column chromatography (silica gel; acetonitrile / 10 mM aqueous ammonium bicarbonate = 10 / 90 → 50 / 50) to give (S)-2-((tert-butoxycarbonyl)amino)-3-(2-oxo-1,2-dihydropyridin-4-yl)propanoic acid (20.0 g). To the resulting compound, DMF (150 mL), DIPEA (11.1 g, 63.8 mmol), and 4-(bromomethyl)-2,6-dichloropyridine (12.2 g, 50.5 mmol, CAS registration number: 175204-45-2) were added, in that order. The mixture was stirred at room temperature for 2 hours, and then quenched by the addition of 1 M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed successively with aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; methanol / dichloromethane = 1 / 10) to give (2,6-dichloropyridin-4-yl)methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(2-oxo-1,2-dihydropyridin-4-yl)propanoate (10.8 g). Dichloromethane (42 mL) and 4 M hydrochloric acid / MTHP (42 mL) were added sequentially to the obtained compound (5.00 g). The mixture was stirred at room temperature for 5 hours and then concentrated under reduced pressure. The residue was suspended and washed with diethyl ether and dried in vacuo to give (2,6-dichloropyridin-4-yl)methyl (S)-2-amino-3-(2-oxo-1,2-dihydropyridin-4-yl)propanoate hydrochloride (4.85 g, 12.81 mmol) as a colorless solid.

[0214] Example 1-28: (2,6-dichloropyridin-4-yl)methyl (S)-2-amino-4-(2-oxo-1,2-dihydroquinolin-6-yl)butanoate hydrochloride (Compound No. 77)

[0215]

[0216] Zinc (16.5 g, 252 mmol, CAS Registry Number: 7440-66-6), DMF (500 mL), and iodine (6.40 g, 25.2 mmol, CAS Registry Number: 7553-56-2) were sequentially added to a flask equipped with a nitrogen balloon. After stirring the mixture at room temperature, (S)-2-((tert-butoxycarbonyl)amino)-4-iodobutanoate (34.6 g, 101 mmol, CAS Registry Number: 101650-14-0) was added to the mixture. After stirring the mixture at room temperature for 60 minutes, 6-bromo-2-methoxyquinoline (20.0 g, 84.0 mmol, CAS Registry Number: 99455-05-7), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (6.90 g, 16.8 mmol, CAS Registry Number: 657408-07-6), and tris(dibenzylideneacetone)dipalladium-chloroform (4.35 g, 4.20 mmol, CAS Registry Number: 52522-40-4) were sequentially added to the mixture. After stirring at 50°C for 3 hours, water was added to the mixture, which was then filtered and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether=1 / 5) to give methyl (S)-2-(((tert-butoxycarbonyl)amino)-4-(2-methoxyquinolin-6-yl)butanoate (25.0 g). 1,4-Dioxane (300 mL) and 48% aqueous hydrogen bromide solution (300 mL) were added to the obtained compound in that order. After stirring at 100° C. overnight, the mixture was concentrated under reduced pressure to give (S)-2-amino- 4-(2-oxo-1,2-dihydroquinolin-6-yl)butanoic acid hydrobromide was obtained. 1,4-Dioxane (200 mL), water (200 mL), DIPEA (34.8 g, 269 mmol), and di-tert-butyl dicarbonate (17.6 g, 80.7 mmol, CAS registration number: 24424-99-5) were added to the obtained compound under ice-cooling. The mixture was stirred at room temperature overnight, and then aqueous hydrochloric acid was added to quench the reaction. The mixture was then concentrated under reduced pressure.The residue was purified by flash column chromatography (silica gel; methanol / dichloromethane = 1 / 5) to give (S)-2-((tert-butoxycarbonyl)amino)-4-(2-oxo-1,2-dihydroquinolin-6-yl)butanoic acid (20.0 g). To the resulting compound (12.0 g), DMF (120 mL), DIPEA (5.37 g, 41.6 mmol), and 4-(bromomethyl)-2,6-dichloropyridine (7.93 g, 32.9 mmol, CAS registration number: 175204-45-2) were added in this order. The mixture was stirred at room temperature for 2 hours, and then quenched by the addition of 1 M aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was washed successively with aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / dichloromethane=1 / 1) to give (2,6-dichloropyridin-4-yl)methyl (S)-2-((tert-butoxycarbonyl)amino)-4-(2-oxo-1,2-dihydroquinolin-6-yl)butanoate (10.1 g). To the obtained compound (3.66 g), dichloromethane (27 mL) and 4 M hydrochloric acid / MTHP (27 mL) were added in that order. The mixture was stirred at room temperature for 16 hours, and then concentrated under reduced pressure. Diethyl ether was added to the residue, filtered, washed with diethyl ether, and dried in vacuo to give (2,6-dichloropyridin-4-yl)methyl (S)-2-amino-4-(2-oxo-1,2-dihydroquinolin-6-yl)butanoate hydrochloride (3.14 g, 7.09 mmol) as a colorless solid.

[0217] Example 1-29: 2,2,2-trifluoroethyl (S)-2-amino-3-(4-(2-aminopyridin-3-yl)phenyl)propanoate dihydrochloride (Compound No. 78)

[0218]

[0219] A flask was charged with (S)-3-(4-bromophenyl)-2-(((tert-butoxycarbonyl)amino)propanoic acid (20.0 g, 58.1 mmol, CAS Registry Number: 62129-39-9), 1,4-dioxane (160 mL), water (40 mL), (2-((tert-butoxycarbonyl)amino)pyridin-3-yl)boronic acid (16.6 g, 69.7 mmol, CAS Registry Number: 863753-35-9), potassium carbonate (24.1 g, 174 mmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloro To the mixture, palladium (3.03 g, 4.65 mmol, CAS Registry Number: 95408-45-0) was added at room temperature. After stirring at 50° C. for 6 hours under a nitrogen atmosphere, the reaction was quenched by adding 1 M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; methanol / dichloroethane=1 / 5) to give (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(2-((tert- (butoxycarbonyl)amino)pyridin-3-yl)phenyl)propanoic acid (14.5 g) was obtained. To the obtained compound, DMF (150 mL), 2,2,2-trifluoroethyl trifluoromethanesulfonate (6.99 g, 30.1 mmol, CAS registration number: 6226-25-1), and DIPEA (4.92 g, 38.0 mmol) were added in that order. The mixture was stirred at room temperature for 3 hours, and then an aqueous solution of sodium dihydrogen phosphate was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed with an aqueous solution of sodium bicarbonate and saturated brine. The mixture was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether = 1 / 1) to give 2,2,2-trifluoroethyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(2-((tert-butoxycarbonyl)amino)pyridin-3-yl)phenyl)propanoate (10.3 g). To the resulting compound (4.32 g), dichloromethane (20 mL) and 4 M hydrochloric acid / MTHP (20 mL) were added, in that order.After stirring at room temperature, the mixture was concentrated under reduced pressure, and the residue was triturated with methyl tert-butyl ether and dried in vacuo to give 2,2,2-trifluoroethyl (S)-2-amino-3-(4-(2-aminopyridin-3-yl)phenyl)propanoate dihydrochloride (3.33 g, 8.10 mmol) as a light beige solid.

[0220] Example 1-30: (2,6-Dichloropyridin-4-yl)methyl (S)-2-amino-3-(2-carbamoyl-1H-imidazol-4-yl)propanoate dihydrochloride (Compound No. 79)

[0221]

[0222] 2-(1-trityl-1H-imidazol-4-yl)ethan-1-amine (11.7 g, 33.1 mmol, CAS Registry Number: 195053-92-0), acetonitrile (300 mL), DIPEA (8.56 g, 66.2 mmol), and 2-bromobenzyl acetate (8.34 g, 36.4 mmol, CAS Registry Number: 5437-45-6) were added to a flask under ice cooling in this order. The mixture was stirred at room temperature for 5 hours, and then water was added to quench the reaction. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; methanol / dichloroethane = 0 / 100 → 7 / 93) to give benzyl (2-(1-trityl-1H-imidazol-4-yl)ethyl)glycinate (13.6 g). To the resulting compound, methanol (120 mL) and palladium on carbon (4.08 g, CAS Registry Number: 7440-05-3) were added in that order. After stirring for 4 hours under a hydrogen atmosphere at room temperature, the mixture was filtered, extracted with methanol, and concentrated under reduced pressure to give (2-(1-trityl-1H-imidazol-4-yl)ethyl)glycine (11.5 g). To the resulting compound (5.70 g), 1,4-dioxane (30 mL), water (10 mL), sodium bicarbonate (2.33 g, 27.7 mmol), and di-tert-butyl dicarbonate (3.63 g, 16.6 mmol, CAS Registry Number: 24424-99-5) were added in that order under ice cooling. The mixture was stirred at room temperature for 2 hours, and then aqueous citric acid was added to quench the reaction. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; methanol / dichloroethane = 1 / 100 → 1 / 10) to give N-(tert-butoxycarbonyl)-N-(2-(1-trityl-1H-imidazol-4-yl)ethyl)glycine (4.50 g). DMF (20 mL), 4-(bromomethyl)-2,6-dichloropyridine (2.01 g, 8.36 mmol, CAS registration number: 175204-45-2), and DIPEA (1.36 g, 4.69 mmol) were added to the resulting compound in that order.The mixture was stirred at room temperature for 2 hours, and then water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether = 1 / 100 → 1 / 1) to give (2,6-dichloropyridin-4-yl)methyl N-(tert-butoxycarbonyl)-N-(2-(1-trityl-1H-imidazol-4-yl)ethyl)glycinate (2.69 g). To the obtained compound (1.50 g), dichloromethane (3.5 mL), triisopropylsilane (1.0 mL), and 2,2,2-trifluoroacetic acid (3.4 mL) were added in that order. The mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. acetonitrile and 4 M hydrochloric acid / MTHP were added in that order. After the mixture was stirred at room temperature for 30 minutes, the mixture was filtered, washed with diethyl ether, and dried in vacuo to give (2,6-dichloropyridin-4-yl)methyl (S)-2-amino-3-(2-carbamoyl-1H-imidazol-4-yl)propanoate dihydrochloride (0.487 g, 1.21 mmol) as a gray solid.

[0223] Example 1-31: (2,6-Dichloropyridin-4-yl)methyl (S)-2-amino-3-(3-((3-aminopropyl)carbamoyl)phenyl)propanoate dihydrochloride (Compound No. 80)

[0224]

[0225] 3-Bromobenzoic acid (10.0 g, 49.7 mmol, CAS Registry Number: 585-76-2), DMF (200 mL), tert-butyl (3-aminopropyl)carbamate (10.4 g, 59.7 mmol, CAS Registry Number: 75178-96-0), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (10.5 g, 54.7 mmol, CAS Registry Number: 25952-53-8), and ethyl 2-cyano-2-(hydroxyimino)acetate (7.78 g, 54.7 mmol, CAS Registry Number: 3849-21-6) were added to a flask at room temperature in this order. The mixture was stirred at room temperature for 2 hours, and then water was added to quench the reaction. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether = 1 / 1) to give tert-butyl (3-(3-bromobenzamido)propyl)carbamate (15.0 g). Zinc (8.24 g, 126 mmol, CAS Registry Number: 7440-66-6), DMF (300 mL), and iodine (3.20 g, 12.6 mmol, CAS Registry Number: 7553-56-2) were added sequentially to a flask equipped with a nitrogen balloon. After the mixture was stirred at room temperature, methyl (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodopropanoate (20.8 g, 46.2 mmol, CAS Registry Number: 156017-42-4) and iodine (3.20 g, 12.6 mmol, CAS Registry Number: 7553-56-2) were added sequentially to the mixture. The mixture was stirred at room temperature for 30 minutes, and then the obtained tert-butyl(3-(3-bromobenzamido)propyl)carbamate (15.0 g), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (3.45 g, 8.40 mmol, CAS Registry Number: 657408-07-6), and tris(dibenzylideneacetone)dipalladium-chloroform (1.92 g, 2.10 mmol, CAS Registry Number: 52522-40-4) were added to the mixture in that order at room temperature.After stirring at 50°C for 3 hours, the mixture was filtered, ethyl acetate was added, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was suspended and washed with diethyl ether and dried in vacuo to give methyl (S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(((tert-butoxycarbonyl)amino)propyl)carbamoyl)phenyl)propanoate (20.0 g).

[0226] To the resulting compound (23.0 g), isopropyl alcohol (300 mL), water (100 mL), THF (50 mL), calcium chloride (67.9 g, 612 mmol, CAS Registry Number: 10043-52-4), and lithium hydroxide monohydrate (6.42 g, 153 mmol, CAS Registry Number: 1310-66-3) were added in this order under ice-cooling. The mixture was stirred at room temperature, and then an aqueous solution of sodium dihydrogen phosphate was added to quench the reaction. The mixture was filtered, extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / petroleum ether = 1 / 1) to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(((tert-butoxycarbonyl)amino)propyl)carbamoyl)phenyl)propanoic acid (19.5 g). To the obtained compound (1.20 g), acetonitrile (10 mL) and triethylamine (1.01 g, 10.0 mmol) were added in that order at room temperature. The mixture was stirred at 60°C for 1 hour and then concentrated under reduced pressure. The residue was suspended and washed with diethyl ether and dried in vacuo to give (S)-2-amino-3-(3-(((tert-butoxycarbonyl)amino)propyl)carbamoyl)phenyl)propanoic acid. To the resulting compound were added 1,4-dioxane (6.0 mL), water (4.0 mL), sodium carbonate (0.636 g, 6.00 mmol), and di-tert-butyl dicarbonate (0.524 g, 2.4 mmol, CAS registration number: 24424-99-5) in that order at room temperature.

[0227] The mixture was stirred at room temperature and then concentrated under reduced pressure to give (S)-2-((tert-butoxycarbonyl)amino)-3-(3-((tert-butoxycarbonyl)amino)propyl)phenyl)propanoic acid. To the obtained compound were added DMF (4.0 mL) and 4-(bromomethyl)-2,6-dichloropyridine (0.458 g, 1.90 mmol, CAS registration number: 175204-45-2), in that order. The mixture was stirred at room temperature, and then water was added to quench the reaction. The mixture was extracted with isopropyl acetate, and the organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; ethyl acetate / heptane = 0 / 100 → 80 / 20) to give (2,6-dichloropyridin-4-yl)methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-((tert-butoxycarbonyl)amino)carbamoyl)phenyl)propanoate. Dichloromethane (25 mL) and 4 M hydrochloric acid / MTHP (25 mL) were added sequentially to the obtained compound. The mixture was stirred at room temperature, and then concentrated under reduced pressure. The residue was suspended and washed with diethyl ether and dried in vacuo to give (2,6-dichloropyridin-4-yl)methyl (S)-2-amino-3-(3-((3-aminopropyl)carbamoyl)phenyl)propanoate dihydrochloride (0.262 g, 0.525 mmol) as a colorless solid.

[0228] Example 1-32: (2,6-dichloropyridin-4-yl)methyl (S)-2-amino-4-(3,3-difluoropiperidin-1-yl)butanoate dihydrochloride (Compound No. 81)

[0229]

[0230] To a flask, (S)-4-(tert-butoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid (40.0 g, 138 mmol, CAS Registry Number: 34582-32-6), DMF (800 mL), 3,3-difluoropiperidine hydrochloride (24.0 g, 152 mmol, CAS Registry Number: 496807-97-7), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (29.2 g, 152 mmol, CAS Registry Number: 25952-53-8), ethyl 2-cyano-2-(hydroxyimino)acetate (21.6 g, 152 mmol, CAS Registry Number: 3849-21-6), and DIPEA (26.8 g, 207 mmol) were added in this order under ice-cooling. The mixture was stirred overnight at room temperature, and then aqueous sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; methanol / dichloromethane=1 / 20) to give tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-4-(3,3-difluoropiperidin-1-yl)-4-oxobutanoate (44.0 g). To 1,1,3,3-tetramethyldisiloxane (120 g, 897 mmol, CAS Registry Number: 3277-26-7) and dodecacarbonyltriruthenium (3.58 g, 5.61 mmol, CAS Registry Number: 15243-33-1) dissolved in THF was added tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-4-(3,3-difluoropiperidin-1-yl)-4-oxobutanoate (44.0 g) dissolved in THF (800 mL). After stirring overnight at 40° C. under an atmospheric atmosphere, the mixture was concentrated under reduced pressure to give tert-butyl (S)-2-(((tert-butoxycarbonyl)amino)-4-(3,3-difluoropiperidin-1-yl)butanoate. 1,4-Dioxane (300 mL) and 4 M aqueous hydrochloric acid solution (300 mL) were added to the obtained compound in that order at room temperature.After stirring overnight at 100 ° C, the mixture was concentrated under reduced pressure to give (S)-2-amino-4-(3,3-difluoropiperidin-1-yl)butanoic acid dihydrochloride. 1,4-Dioxane (300 mL), water (300 mL), sodium carbonate (57.5 g, 542 mmol, CAS Registry Number: 497-19-8), and di-tert-butyl dicarbonate (35.5 g, 163 mmol, CAS Registry Number: 24424-99-5) were added to the resulting compound in this order under ice cooling. The mixture was stirred overnight at room temperature, and then an aqueous solution of sodium dihydrogen phosphate was added to quench the reaction.

[0231] The mixture was extracted with ethyl acetate, and the organic layer was washed successively with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S)-2-((tert-butoxycarbonyl)amino)-4-(3,3-difluoropiperidin-1-yl)butanoic acid (14.0 g). To the resulting compound were added DMF (150 mL), DIPEA (6.74 g, 52.1 mmol), and 4-(bromomethyl)-2,6-dichloropyridine (9.94 g, 41.3 mmol, CAS registration number: 175204-45-2), successively. The mixture was stirred at room temperature for 1 hour, and then quenched by adding 1 M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed successively with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; acetonitrile / 0.1% formic acid aqueous solution = 5 / 95 → 100 / 0) to give (2,6-dichloropyridin-4-yl)methyl (S)-2-((tert-butoxycarbonyl)amino)-4-(3,3-difluoropiperidin-1-yl)butanoate (7.30 g). Dichloromethane (20 mL) and 4 M hydrochloric acid / MTHP (20 mL) were added sequentially to the obtained compound (3.22 g). The mixture was stirred at room temperature for 4 hours and then concentrated under reduced pressure. The residue was suspended and washed with diethyl ether and dried in vacuo to give (2,6-dichloropyridin-4-yl)methyl (S)-2-amino-4-(3,3-difluoropiperidin-1-yl)butanoate dihydrochloride (2.68 g, 5.89 mmol) as a colorless solid.

[0232] The compounds shown below were synthesized according to the procedure of Example 1-1 using the corresponding starting amino acids, esterification reagents, and deprotection conditions in the table.

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

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[0245]

[0246]

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[0269]

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[0277]

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[0279]

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[0283]

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[0286]

[0287]

[0288]

[0289]

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[0309]

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[0316]

[0317]

[0318]

[0319]

[0320]

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[0322]

[0323]

[0324]

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[0329]

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[0347]

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[0352]

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[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

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[0363]

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[0375]

[0376]

[0377]

[0378]

[0379]

[0380] The compounds shown below were synthesized according to the procedures in Examples 1-2 using the corresponding starting amino acids in the table.

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389] The compounds shown below were synthesized according to the procedures of Examples 1-3 using the corresponding starting amino acids and esterification reagents in the table.

[0390]

[0391]

[0392]

[0393] The compounds shown below were synthesized according to the procedures of Examples 1-4 using the corresponding starting amino acids and esterification reagents in the table.

[0394]

[0395]

[0396] The compounds shown below were synthesized according to the procedures of Examples 1-5 using the corresponding starting amino acids and esterification reagents in the table.

[0397]

[0398]

[0399]

[0400] The compounds shown below were synthesized according to the procedures in Examples 1-6 using the corresponding starting materials in the table.

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407] The compounds shown below were synthesized according to the procedures in Examples 1-7 using the corresponding starting compounds in the table.

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417] The compounds shown below were synthesized according to the procedures in Examples 1-8 using the corresponding starting compounds in the table.

[0418]

[0419] The compounds shown below were synthesized according to the procedures of Examples 1-9 using the corresponding starting compounds in the table.

[0420]

[0421]

[0422] The compounds shown below were synthesized according to the procedures of Examples 1-10 using the corresponding starting compounds in the table.

[0423]

[0424] The compounds shown below were synthesized according to the procedures of Examples 1-11 using the corresponding starting compounds in the table.

[0425]

[0426]

[0427] Following the procedures of Examples 1-12, the compounds shown below were synthesized.

[0428]

[0429] Following the procedures of Examples 1-13, the compounds shown below were synthesized.

[0430]

[0431] Following the procedures of Examples 1-14, the compounds shown below were synthesized.

[0432]

[0433] Following the procedures of Examples 1-15, the compounds shown below were synthesized.

[0434]

[0435] Following the procedures of Examples 1-16, the compounds shown below were synthesized.

[0436] Following the procedures of Examples 1-17, the compounds shown below were synthesized.

[0437] Following the procedures of Examples 1-18, the compounds shown below were synthesized.

[0438]

[0439] Following the procedures of Examples 1-19, the compounds shown below were synthesized.

[0440]

[0441] The compounds shown below were synthesized according to the procedures of Examples 1-20 using the corresponding starting amino acids in the table.

[0442]

[0443]

[0444] Following the procedures of Examples 1-21, the compounds shown below were synthesized.

[0445]

[0446] The compounds shown below were synthesized according to the procedures of Examples 1-22 using the corresponding starting compounds in the table.

[0447]

[0448]

[0449] The compounds shown below were synthesized according to the procedures of Examples 1-23 using the corresponding starting compounds in the table.

[0450]

[0451]

[0452] Following the procedures of Examples 1-24, the compounds shown below were synthesized.

[0453]

[0454] Following the procedures of Examples 1-25, the compounds shown below were synthesized.

[0455]

[0456] Following the procedures of Examples 1-26, the compounds shown below were synthesized.

[0457]

[0458] The compounds shown below were synthesized according to the procedures of Examples 1-27 using the corresponding starting compounds in the table.

[0459]

[0460]

[0461]

[0462] Following the procedures of Examples 1-28, the compounds shown below were synthesized.

[0463]

[0464] Following the procedures of Examples 1-29, the compounds shown below were synthesized.

[0465] Following the procedures of Examples 1-30, the compounds shown below were synthesized.

[0466]

[0467] The compounds shown below were synthesized according to the procedures of Examples 1-31 using the corresponding starting amino acids in the table.

[0468]

[0469] Following the procedures of Examples 1-32, the compounds shown below were synthesized.

[0470]

[0471] Example 2: Confirmation of tRNA aminoacylation and measurement of aminoacylation efficiency In this embodiment, Flexizyme was used to perform aminoacylation of tRNA using the activated ester synthesized in Example 1 as a substrate. In order to simply confirm acylation with various amino acids, the starting tRNA (tRNA Ｍｅｔ Instead of α-aminohelix, the acylation reaction was carried out using its short-chain analog, microhelix. The reaction solution was then subjected to polyacrylamide gel electrophoresis under acidic conditions to confirm the efficiency of aminoacylation. The mobility of the microhelix-derived band slowed when aminoacylated. The efficiency of aminoacylation could be determined by comparing the intensity of the microhelix band and the acylated microhelix band.

[0472] Example 2-1: Measurement of tRNA aminoacylation efficiency of (2,6-dichloropyridin-4-yl)methyl-L-isoleucinate (Compound No. 21) and (2,6-dichloropyridin-4-yl)methyl glycinate (Compound No. 99) The acylation reaction was carried out in 50 mM Hepes-K buffer (pH 7.5), 50 mM MgCl ２ 25 M flexizyme (dFx), 25 μM tRNA analog (microhelix), and 5 mM substrate were added to 20% DMSO in a flask, and the mixture was reacted overnight on ice. The base sequence of dFx is shown in SEQ ID NO:3.

[0473] The detailed procedure was as follows: 1 μL of 500 mM Hepes-K buffer (pH 7.5), 1 μL of 250 μM Flexizyme (dFx), and 1 μL of 250 μM tRNA analog were added to 3 μL of ultrapure water, heated at 95°C for 2 minutes, and cooled at room temperature for 5 minutes. ２The solution was added with 2 μL of DMSO and incubated on ice for 1 minute. The acylation reaction of the tRNA analog was initiated by adding 1.5 μL of DMSO and 0.5 μL of 100 mM substrate, and incubated on ice overnight. The reaction was stopped by adding 1 μL of 3 M sodium acetate, pH 5.2. This solution was analyzed by 20% denaturing PAGE (50 mM sodium acetate, 6 M urea) under acidic conditions.

[0474] The results of acylation using (2,6-dichloropyridin-4-yl)methyl L-isoleucinate (Compound No. 21) or (2,6-dichloropyridin-4-yl)methyl glycinate (Compound No. 99) as the substrate are shown in Figures 1-1 and 1-2. These results confirmed that amino acid derivatives were efficiently acylated by Flexizyme.

[0475] Example 2-2: Measurement of tRNA aminoacylation efficiency of 2,2,2-trifluoroethyl (S)-2-amino-4-phenylbutanoate (Compound No. 47) and 2,2,2-trifluoroethyl (S)-2-amino-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propanoate (Compound No. 81) The acylation reaction was carried out in 50 mM Hepes-K buffer (pH 7.5), 600 mM MgCl ２ 25 μM flexizyme (eFx), 25 μM tRNA analog (microhelix), and 5 mM substrate were added to 20% DMSO in a flask and reacted overnight on ice. The nucleic acid sequence of eFx is shown in SEQ ID NO:2.

[0476] The detailed procedure was as follows: 4 μL of 500 mM Hepes-K buffer (pH 7.5), 4 μL of 250 μM Flexizyme (eFx), and 4 μL of 250 μM tRNA analog were added to 12 μL of ultrapure water, heated at 95°C for 3 minutes, and cooled at room temperature for 5 minutes. ２8 μL of tRNA analog was added, and the mixture was left at room temperature for 5 minutes, followed by another 5 minutes on ice. The acylation reaction of the tRNA analog was initiated by adding 6 μL of DMSO and 2 μL of 100 mM substrate, and the mixture was left on ice overnight. The reaction was stopped by adding 4 μL of 3 M sodium acetate, pH 5.2. This solution was analyzed by 20% denaturing PAGE (50 mM sodium acetate, 6 M urea) under acidic conditions.

[0477] The results of acylation using 2,2,2-trifluoroethyl (S)-2-amino-4-phenylbutanoate (Compound Number 47) and 2,2,2-trifluoroethyl (S)-2-amino-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propanoate (Compound Number 81) as substrates are shown in Figures 1-3 and 1-4. These results confirmed that amino acid derivatives were efficiently acylated by Flexizyme.

[0478] Test Example: Differential scanning calorimetry (DSC) was performed on Compounds 21, 47, 81, and 99 prepared in Example 1-1 to determine the reaction initiation temperature (T ＤＳＣ ) and reaction heat (Q ＤＳＣ The Q values ​​of 2,4-dinitrotoluene (compound number 115) and benzoyl peroxide (compound number 116) were calculated. ＤＳＣ and T ＤＳＣ The values ​​used were those described in the following document: DSC Data Collection of Reactive Substances (2) (RIIS-SD-89), https: / / www.jniosh.johas.go.jp / publication / houkoku / houkoku_2007_03_list.html The detailed procedure for differential scanning calorimetry (DSC) is as follows.

[0479] An activated amino acid ester (approximately 2 mg) was sealed in a stainless steel pressure-resistant cell and set in a heat flux type differential scanning calorimeter. The cell was heated to 500°C at 10°C / min in a nitrogen atmosphere of 50 mL / min. The cell was filled in the atmosphere, and an empty cell was used as the reference material. The indium (In) value measured under the same conditions was used as the standard for correction.

[0480] The results are shown in Figure 2. Figure 2 shows the Q values ​​of 2,4-dinitrotoluene (compound number 115) and benzoyl peroxide (compound number 116) as reference compounds. ＤＳＣ and T ＤＳＣ The line connecting the two plotted reference points is used as the risk assessment line, and the results show the results of confirming whether or not each activated ester of amino acid is dangerous. In the figure, the dotted line indicates the risk assessment line. If it is on or above the assessment line, it is judged as "risky" (corresponding to hazardous material type 5), and if it is below the assessment line, it is judged as "not risky" (not corresponding to hazardous material type 5). The horizontal axis is log(T ＤＳＣ -25) and the vertical axis is log Q ＤＳＣ In the figure, -L-Hph-DBE_HCl represents the hydrochloride of 3,5-dinitrobenzyl (S)-2-amino-4-phenylbutanoate (compound number 114), Gly-DBE_HCl represents the hydrochloride of 3,5-dinitrobenzyl glycinate (compound number 112), -L-Ile-DBE_HCl represents the hydrochloride of 3,5-dinitrobenzyl L-isoleucinate (compound number 111), and -L-W7N-DBE_HCl represents the hydrochloride of 3,5-dinitrobenzyl (S)-2-amino-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propanoate (compound number 112). -L-Ile-DCPE_HCl indicates the hydrochloride salt of (2,6-dichloropyridin-4-yl)methyl L-isoleucinate (Compound No. 21), -L-W7N-TEE_HCl indicates 2,2,2-trifluoroethyl (S)-2-amino-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propanoate (Compound No. 81), and Gly-DCPE_HCl indicates (2,6-dichloropyridin-4-yl)methyl glycinate (Compound No. 99). L-Hph-DBE_HCl, Gly-DBE_HCl, L-Ile-DBE_HCl, and L-W7N-DBE_HCl were plotted above the danger judgment line, while L-Ile-DCPE_HCl, L-W7N-TEE_HCl, and Gly-DCPE_HCl were plotted below the danger judgment line (Figure 2). From the above, it was shown that DCPE and TEE are not considered to be classified as Class 5 dangerous goods.

Claims

1. Formula (Ia): 【Chemical 1】 [wherein, X is pyridyl substituted with two or more halogen atoms, or C １－３ alkyl substituted with three or more fluorine atoms; Z is -NR ５ R ６ or -OR ｄ and is Q is [Chemical Formula 2] a group represented by n is an integer from 0 to 3, preferably n is an integer from 0 to 2, R ７ and R ８ are each independently selected from a hydrogen atom or C １－３ alkyl; R １ and R ２ are each independently a hydrogen atom, a halogen atom, cyano, Y １ optionally substituted with one or more substituents selected from C １－１０ alkyl, Y １ optionally substituted with one or more substituents selected from C ２－１０ alkenyl, Y １ optionally substituted with one or more substituents selected from C ２－１０ alkynyl, Y ２ optionally substituted with one or more substituents selected from C ３－１０ cycloalkyl, Y ２ optionally substituted with one or more substituents selected from C ３－１０ cycloalkenyl, Y ２ optionally substituted with one or more substituents selected from 3- to 14-membered non-aromatic heterocyclyl, Y ３ optionally substituted with one or more substituents selected from C ６－１４ aryl, Y ３ optionally substituted with one or more substituents selected from 5- to 14-membered heteroaryl, -COOR １１ , and -CONR １２ R １３ selected from, or R １ and R ５ together with the carbon and nitrogen atoms to which they are attached form a 3- to 10-membered non-aromatic heterocycle optionally substituted by one or more substituents selected from Y ２ and When n is an integer from 1 to 3, R １ and any one of R ３ together with the carbon atom to which they are attached form a C ２ carbocyclic ring optionally substituted with one or more substituents selected from Y ３－１０ or a 3- to 10-membered non-aromatic heterocyclic ring optionally substituted with one or more substituents selected from Y ２ and form, R １ and R ２ together with the carbon atom to which they are attached, may be substituted by one or more substituents selected from Y ２ optionally substituted C ３－１０ carbocyclic ring, or 3- to 10-membered non-aromatic heterocyclic ring optionally substituted by one or more substituents selected from Y ２ to form, R ３ and R ４ are each independently a hydrogen atom, a halogen atom, cyano, Y １ optionally substituted with one or more substituents selected from C １－１０ alkyl, Y １ optionally substituted with one or more substituents selected from C ２－１０ alkenyl, Y １ optionally substituted with one or more substituents selected from C ２－１０ alkynyl, Y ２ optionally substituted with one or more substituents selected from C ３－１０ cycloalkyl, Y ２ optionally substituted with one or more substituents selected from C ３－１０ cycloalkenyl, Y ２ optionally substituted with one or more substituents selected from a 3- to 14-membered non-aromatic heterocyclyl, Y ３ optionally substituted with one or more substituents selected from C ６－１４ aryl, and Y ３ optionally substituted with one or more substituents selected from a 5- to 14-membered heteroaryl, -COOR １１ , and -CONR １２ R １３ selected from, or R ３ and R ４ together with the carbon atom to which they are attached may be substituted with one or more substituents selected from Y ２ a C ３－１０ carbocyclic ring which may be substituted with one or more substituents selected from Y ２ or form a 3- to 10-membered non-aromatic heterocyclic ring which may be substituted with one or more substituents selected from Y When n is an integer from 1 to 3, R ５ and any one of R ３ together with the nitrogen atom and carbon atom to which they are attached form a 3- to 10-membered nitrogen-containing non-aromatic heterocycle which may be substituted with one or more substituents selected from Y ２ and form a 3- to 10-membered nitrogen-containing non-aromatic heterocycle which may be substituted with one or more substituents selected from Y R １１ 、R １２ 、and R １３ are each independently C １ alkyl optionally substituted with one or more substituents selected from Y １－１０ ; C １ alkenyl optionally substituted with one or more substituents selected from Y ２－１０ ; C １ alkynyl optionally substituted with one or more substituents selected from Y ２－１０ ; C ２ cycloalkyl optionally substituted with one or more substituents selected from Y ３－１０ ; C ２ cycloalkenyl optionally substituted with one or more substituents selected from Y ３－１０ ; a 3- to 14-membered non-aromatic heterocyclyl optionally substituted with one or more substituents selected from Y ２ ; C ３ aryl optionally substituted with one or more substituents selected from Y ６－１４ ; and a 5- to 14-membered heteroaryl optionally substituted with one or more substituents selected from Y ３ and are selected from Y １ is, independently of one another, a halogen atom, nitro, cyano, Y ５ optionally substituted by one or more substituents selected from C ３－１０ cycloalkyl, Y ５ optionally substituted by one or more substituents selected from C ３－１０ cycloalkenyl, Y ５ a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from Y ６ optionally substituted by one or more substituents selected from C ６－１４ aryl, Y ６ a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from Y, -SH, -COOR ２１ , -NR ２２ R ２３ , -N ３ , -S(O) ｐ R ２４ , -OR ２５ , -SO ２ NR ２６ R ２７ , and -CONR ２８ R ２９ , and is selected from oxo, Y ２ is, independently of each other, a halogen atom, nitro, cyano, Y ４ optionally substituted with one or more substituents selected from C １－１０ alkyl, Y ４ optionally substituted with one or more substituents selected from C ２－１０ alkenyl, Y ４ optionally substituted with one or more substituents selected from C ２－１０ alkynyl, Y ５ optionally substituted with one or more substituents selected from C ３－１０ cycloalkyl, Y ５ optionally substituted with one or more substituents selected from C ３－１０ cycloalkenyl, Y ５ optionally substituted with one or more substituents selected from a 3- to 14-membered non-aromatic heterocyclyl, Y ６ optionally substituted with one or more substituents selected from C ６－１４ aryl, Y ６ optionally substituted with one or more substituents selected from a 5- to 14-membered heteroaryl, -SH, -COOR ２１ , -NR ２２ R ２３ , -S(O) ｐ R ２４ , -OR ２５ , -SO ２ NR ２６ R ２７ , and -CONR ２８ R ２９ , and is selected from oxo, Y ３ is, independently of each other, a halogen atom, nitro, cyano, Y ４ optionally substituted by one or more substituents selected from C １－１０ alkyl, Y ４ optionally substituted by one or more substituents selected from C ２－１０ alkenyl, Y ４ optionally substituted by one or more substituents selected from C ２－１０ alkynyl, Y ５ optionally substituted by one or more substituents selected from C ３－１０ cycloalkyl, Y ５ optionally substituted by one or more substituents selected from C ３－１０ cycloalkenyl, Y ５ optionally substituted by one or more substituents selected from 3- to 14-membered non-aromatic heterocyclyl, Y ６ optionally substituted by one or more substituents selected from C ６－１４ aryl, Y ６ optionally substituted by one or more substituents selected from 5- to 14-membered heteroaryl, -SH, -COOR ２１ , -NR ２２ R ２３ , -S(O) ｐ R ２４ , -OR ２５ , -SO ２ NR ２６ R ２７ , and -CONR ２８ R ２９ selected from and R ２１ 、R ２６ 、R ２７ 、R ２８ 、and R ２９ are each independently C ４ alkyl optionally substituted with one or more substituents selected from Y １－１０ 、C ４ alkenyl optionally substituted with one or more substituents selected from Y ２－１０ 、C ４ alkynyl optionally substituted with one or more substituents selected from Y ２－１０ 、C ５ cycloalkyl optionally substituted with one or more substituents selected from Y ３－１０ 、C ５ cycloalkenyl optionally substituted with one or more substituents selected from Y ３－１０ 、a 3- to 14-membered non-aromatic heterocyclyl optionally substituted with one or more substituents selected from Y ５ 、C ６ aryl optionally substituted with one or more substituents selected from Y ６－１４ 、and a 5- to 14-membered heteroaryl optionally substituted with one or more substituents selected from Y ６ and are selected from R ２２ and R ２５ are each independently a hydrogen atom, a C ４ alkyl optionally substituted by one or more substituents selected from Y １－１０ , a C ４ alkenyl optionally substituted by one or more substituents selected from Y ２－１０ , a C ４ alkynyl optionally substituted by one or more substituents selected from Y ２－１０ , a C ５ cycloalkyl optionally substituted by one or more substituents selected from Y ３－１０ , a C ５ cycloalkenyl optionally substituted by one or more substituents selected from Y ３－１０ , a 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from Y ５ , a C ６ aryl optionally substituted by one or more substituents selected from Y ６－１４ , a 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from Y, -COR ６ , -CONR ａ１ R ａ２ , -COOR ａ３ , -C(=NR ａ４ ))NR ａ５ R ａ６ R ａ７ , -S(O) ｐ R ２４ , and -SO ２ NR ａ８ R ａ９ selected from, R ２３ is C optionally substituted with one or more substituents selected from a hydrogen atom, Y ４ alkyl, C optionally substituted with one or more substituents selected from Y １－１０ alkenyl, C optionally substituted with one or more substituents selected from Y ４ alkynyl, C optionally substituted with one or more substituents selected from Y ２－１０ cycloalkyl, C optionally substituted with one or more substituents selected from Y ４ cycloalkenyl, 3- to 14-membered non-aromatic heterocyclyl optionally substituted with one or more substituents selected from Y ２－１０ C optionally substituted with one or more substituents selected from Y ５ aryl, and 5- to 14-membered heteroaryl optionally substituted with one or more substituents selected from Y ３－１０ and is selected from ５ C optionally substituted with one or more substituents selected from Y ３－１０ aryl, and 5- to 14-membered heteroaryl optionally substituted with one or more substituents selected from Y ５ and is optionally substituted with one or more substituents selected from 3- to 14-membered non-aromatic heterocyclyl optionally substituted with one or more substituents selected from Y ６ C optionally substituted with one or more substituents selected from Y ６－１４ aryl, and 5- to 14-membered heteroaryl optionally substituted with one or more substituents selected from Y ６ and is selected from R ２４ is C optionally substituted by one or more substituents selected from Y ４ alkyl, C optionally substituted by one or more substituents selected from Y １－１０ alkenyl, C optionally substituted by one or more substituents selected from Y ４ alkynyl, C optionally substituted by one or more substituents selected from Y ２－１０ cycloalkyl, C optionally substituted by one or more substituents selected from Y ４ cycloalkenyl, 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from Y ２－１０ C optionally substituted by one or more substituents selected from Y ５ aryl, and 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from Y ３－１０ and is selected from ５ C optionally substituted by one or more substituents selected from Y ３－１０ cycloalkenyl, 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from Y ５ C optionally substituted by one or more substituents selected from Y ６ aryl, and 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from Y ６－１４ and is selected from ６ 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from Y R ａ１ 、R ａ２ 、R ａ３ 、R ａ４ 、R ａ５ 、R ａ６ 、R ａ７ 、R ａ８ 、and R ａ９ are each independently C optionally substituted with one or more substituents selected from a hydrogen atom, Y ４ alkyl, C optionally substituted with one or more substituents selected from Y １－１０ alkenyl, C optionally substituted with one or more substituents selected from Y ４ alkynyl, C optionally substituted with one or more substituents selected from Y ２－１０ cycloalkyl, C optionally substituted with one or more substituents selected from Y ４ cycloalkenyl, 3- to 14-membered non-aromatic heterocyclyl optionally substituted with one or more substituents selected from Y ２－１０ C optionally substituted with one or more substituents selected from Y ５ aryl, and 5- to 14-membered heteroaryl optionally substituted with one or more substituents selected from Y ３－１０ and are selected from ５ C optionally substituted with one or more substituents selected from Y ３－１０ cycloalkenyl, 3- to 14-membered non-aromatic heterocyclyl optionally substituted with one or more substituents selected from Y ５ C optionally substituted with one or more substituents selected from Y ６ aryl, and 5- to 14-membered heteroaryl optionally substituted with one or more substituents selected from Y ６－１４ and are selected from ６ 5- to 14-membered heteroaryl optionally substituted with one or more substituents selected from Y Y ４ is, independently of one another, a halogen atom, nitro, cyano, Y ５ optionally substituted with one or more substituents selected from C ３－１０ cycloalkyl, Y ５ optionally substituted with one or more substituents selected from C ３－１０ cycloalkenyl, Y ５ optionally substituted with one or more substituents selected from 3- to 14-membered non-aromatic heterocyclyl, Y ６ optionally substituted with one or more substituents selected from C ６－１４ aryl, Y ６ optionally substituted with one or more substituents selected from 5- to 14-membered heteroaryl, -SH, -COOR ３１ , -NR ３２ R ３３ , -S(O) ｐ R ３４ , -OR ３５ , -SO ２ NR ３６ R ３７ , and -CONR ３８ R ３９ , and is selected from oxo, Y ５ is, independently of each other, C which may be substituted by one or more substituents selected from halogen atom, nitro, cyano, Y ７ alkyl, C which may be substituted by one or more substituents selected from Y １－１０ alkenyl, C which may be substituted by one or more substituents selected from Y ７ alkynyl, C which may be substituted by one or more substituents selected from Y ２－１０ cycloalkyl, C which may be substituted by one or more substituents selected from Y ７ cycloalkenyl, 3- to 14-membered non-aromatic heterocyclyl which may be substituted by one or more substituents selected from Y ２－１０ aryl, 5- to 14-membered heteroaryl which may be substituted by one or more substituents selected from Y, -SH, -COOR ８ -NR ３－１０ R ８ -S(O) ３－１０ R ８ -OR, -SO ９ NR ６－１４ R, -CONR ９ R, and oxo, and is selected from ３１ -NR ３２ R ３３ -S(O) ｐ R ３４ -OR ３５ -SO ２ NR ３６ R ３７ -CONR ３８ R ３９ and oxo, and is selected from Y ６ is, independently of each other, C which may be substituted with one or more substituents selected from a halogen atom, nitro, cyano, Y ７ alkyl, C which may be substituted with one or more substituents selected from Y １－１０ alkenyl, C which may be substituted with one or more substituents selected from Y ７ alkynyl, C which may be substituted with one or more substituents selected from Y ２－１０ cycloalkyl, C which may be substituted with one or more substituents selected from Y ７ cycloalkenyl, C which may be substituted with one or more substituents selected from Y ２－１０ 3- to 14-membered non-aromatic heterocyclyl which may be substituted with one or more substituents selected from Y ８ C which may be substituted with one or more substituents selected from Y ３－１０ aryl, C which may be substituted with one or more substituents selected from Y ８ 5- to 14-membered heteroaryl which may be substituted with one or more substituents selected from Y, -SH, -COOR ３－１０ -NR ８ R ９ -S(O) ６－１４ R ９ -OR, -SO ３１ NR ３２ R ３３ -CONR ｐ R ３４ and is selected from -COOR ３５ -OR, -SH, -S(O) ２ R, -SO ３６ NR ３７ R, -CONR ３８ R ３９ and R ３１ 、R ３６ 、R ３７ 、R ３８ 、and R ３９ are each independently C alkyl optionally substituted with one or more substituents selected from hydrogen atom, Y ７ ; C alkenyl optionally substituted with one or more substituents selected from Y １－１０ ; C alkynyl optionally substituted with one or more substituents selected from Y ７ ; C cycloalkyl optionally substituted with one or more substituents selected from Y ２－１０ ; C cycloalkenyl optionally substituted with one or more substituents selected from Y ７ ; 3- to 14-membered non-aromatic heterocyclyl optionally substituted with one or more substituents selected from Y ２－１０ ; C aryl optionally substituted with one or more substituents selected from Y ８ ; and 5- to 14-membered heteroaryl optionally substituted with one or more substituents selected from Y ３－１０ and are selected from ８ ; ３－１０ ; ８ ; 3- to 14-membered non-aromatic heterocyclyl optionally substituted with one or more substituents selected from Y ９ ; C aryl optionally substituted with one or more substituents selected from Y ６－１４ ; and ９ 5- to 14-membered heteroaryl optionally substituted with one or more substituents selected from Y R ３２ and R ３５ are each independently a hydrogen atom, C ７ alkyl optionally substituted with one or more substituents selected from Y １－１０ , C ７ alkenyl optionally substituted with one or more substituents selected from Y ２－１０ , C ７ alkynyl optionally substituted with one or more substituents selected from Y ２－１０ , C ８ cycloalkyl optionally substituted with one or more substituents selected from Y ３－１０ , C ８ cycloalkenyl optionally substituted with one or more substituents selected from Y ３－１０ , a 3- to 14-membered non-aromatic heterocyclyl optionally substituted with one or more substituents selected from Y ８ , C ９ aryl optionally substituted with one or more substituents selected from Y ６－１４ , a 5- to 14-membered heteroaryl optionally substituted with one or more substituents selected from Y, -COR ９ , -CONR ｂ１ R ｂ２ , -CO ｂ３ R ２ , -C(=NR ｂ４ )NR ｂ５ R ｂ６ , and -SO ｂ７ NR ２ R ｂ８ selected from ｂ９ and R ３３ is C optionally substituted with one or more substituents selected from a hydrogen atom, Y ７ alkyl, C optionally substituted with one or more substituents selected from Y １－１０ alkenyl, C optionally substituted with one or more substituents selected from Y ７ alkynyl, C optionally substituted with one or more substituents selected from Y ２－１０ cycloalkyl, C optionally substituted with one or more substituents selected from Y ７ cycloalkenyl, 3- to 14-membered non-aromatic heterocyclyl optionally substituted with one or more substituents selected from Y ２－１０ aryl, and 5- to 14-membered heteroaryl optionally substituted with one or more substituents selected from Y ８ is selected from C optionally substituted with one or more substituents selected from Y ３－１０ cycloalkyl, 3- to 14-membered non-aromatic heterocyclyl optionally substituted with one or more substituents selected from Y ８ aryl, and 5- to 14-membered heteroaryl optionally substituted with one or more substituents selected from Y ３－１０ cycloalkenyl, 3- to 14-membered non-aromatic heterocyclyl optionally substituted with one or more substituents selected from Y ８ is selected from 3- to 14-membered non-aromatic heterocyclyl optionally substituted with one or more substituents selected from Y ９ aryl, and 5- to 14-membered heteroaryl optionally substituted with one or more substituents selected from Y ６－１４ and is selected from 5- to 14-membered heteroaryl optionally substituted with one or more substituents selected from Y ９ ​ R ３４ is C optionally substituted by one or more substituents selected from Y ７ alkyl, C optionally substituted by one or more substituents selected from Y １－１０ alkenyl, C optionally substituted by one or more substituents selected from Y ７ alkynyl, C optionally substituted by one or more substituents selected from Y ２－１０ cycloalkyl, C optionally substituted by one or more substituents selected from Y ７ cycloalkenyl, 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from Y ２－１０ C optionally substituted by one or more substituents selected from Y ８ aryl, and 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from Y ３－１０ and is selected from ８ C optionally substituted by one or more substituents selected from Y ３－１０ cycloalkenyl, 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from Y ８ C optionally substituted by one or more substituents selected from Y ９ aryl, and 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from Y ６－１４ and is selected from C optionally substituted by one or more substituents selected from Y ９ aryl, and 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from Y R ｂ１ , R ｂ２ , R ｂ３ , R ｂ４ , R ｂ５ , R ｂ６ , R ｂ７ , R ｂ８ , and R ｂ９ each independently represents a hydrogen atom, Y ７ C which may be substituted by one or more substituents selected from １－１０ Alkyl, Y ７ C 2-10 alkenyl, optionally substituted by one or more substituents selected from ７ C which may be substituted by one or more substituents selected from ２－１０ Alkynyl, Y ８ C which may be substituted by one or more substituents selected from ３－１０ Cycloalkyl, Y ８ C which may be substituted by one or more substituents selected from ３－１０ Cycloalkenyl, Y ８ 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from ９ C which may be substituted by one or more substituents selected from ６－１４ Aryl, and Y ９ 5-14 membered heteroaryl, optionally substituted by one or more substituents selected from Y ７ is, independently of each other, a halogen atom, nitro, cyano, Y １０ optionally substituted by one or more substituents selected from C １－１０ alkyl, Y １０ optionally substituted by one or more substituents selected from C ２－１０ alkenyl, Y １０ optionally substituted by one or more substituents selected from C ２－１０ alkynyl, Y １１ optionally substituted by one or more substituents selected from C ３－１０ cycloalkyl, Y １１ optionally substituted by one or more substituents selected from C ３－１０ cycloalkenyl, Y １１ optionally substituted by one or more substituents selected from 3- to 14-membered non-aromatic heterocyclyl, Y １２ optionally substituted by one or more substituents selected from C ６－１４ aryl, Y １２ optionally substituted by one or more substituents selected from 5- to 14-membered heteroaryl, -SH, -COOR ４０ , -NR ４１ R ４２ , -S(O) ｐ R ４３ , -OR ４４ , -SO ２ NR ４５ R ４６ , and -CONR ４７ R ４８ , and is selected from oxo, Y ８ each independently represents a halogen atom, nitro, cyano, Y １０ C which may be substituted by one or more substituents selected from １－１０ Alkyl, Y １０ C which may be substituted by one or more substituents selected from ２－１０ Alkenyl, Y １０ C which may be substituted by one or more substituents selected from ２－１０ Alkynyl, Y １１ C which may be substituted by one or more substituents selected from ３－１０ Cycloalkyl, Y １１ C which may be substituted by one or more substituents selected from ３－１０ Cycloalkenyl, Y １１ 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from １２ C which may be substituted by one or more substituents selected from ６－１４ Aryl, Y １２ 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of -SH, -COOR ４０ , -NR ４１ R ４２ , -S(O) ｐ R ４３ , -OR ４４ , -SO ２ N.R. ４５ R ４６ , -CONR ４７ R ４８ and oxo; Y ９ is, independently of each other, a halogen atom, nitro, cyano, Y １０ optionally substituted by one or more substituents selected from １－１０ C alkyl, Y １０ optionally substituted by one or more substituents selected from ２－１０ C alkenyl, Y １０ optionally substituted by one or more substituents selected from ２－１０ C alkynyl, Y １１ optionally substituted by one or more substituents selected from ３－１０ C cycloalkyl, Y １１ optionally substituted by one or more substituents selected from ３－１０ C cycloalkenyl, Y １１ optionally substituted by one or more substituents selected from 3- to 14-membered non-aromatic heterocyclyl, Y １２ optionally substituted by one or more substituents selected from ６－１４ C aryl, Y １２ optionally substituted by one or more substituents selected from 5- to 14-membered heteroaryl, -SH, -COOR ４０ , -NR ４１ R ４２ , -S(O) ｐ R ４３ , -OR ４４ , -SO ２ NR ４５ R ４６ , and -CONR ４７ R ４８ selected from, R ４０ 、R ４５ 、R ４６ 、R ４７ 、and R ４８ are each independently C １０ alkyl optionally substituted with one or more substituents selected from Y １－１０ 、C １０ alkenyl optionally substituted with one or more substituents selected from Y ２－１０ 、C １０ alkynyl optionally substituted with one or more substituents selected from Y ２－１０ 、C １１ cycloalkyl optionally substituted with one or more substituents selected from Y ３－１０ 、C １１ cycloalkenyl optionally substituted with one or more substituents selected from Y ３－１０ 、a 3- to 14-membered non-aromatic heterocyclyl optionally substituted with one or more substituents selected from Y １１ 、C １２ aryl optionally substituted with one or more substituents selected from Y ６－１４ 、and a 5- to 14-membered heteroaryl optionally substituted with one or more substituents selected from Y １２ and are selected from R ４１ and R ４４ are each independently a hydrogen atom, a C １０ alkyl optionally substituted with one or more substituents selected from Y １－１０ , a C １０ alkenyl optionally substituted with one or more substituents selected from Y ２－１０ , a C １０ alkynyl optionally substituted with one or more substituents selected from Y ２－１０ , a C １１ cycloalkyl optionally substituted with one or more substituents selected from Y ３－１０ , a C １１ cycloalkenyl optionally substituted with one or more substituents selected from Y ３－１０ , a 3- to 14-membered non-aromatic heterocyclyl optionally substituted with one or more substituents selected from Y １１ , a C １２ aryl optionally substituted with one or more substituents selected from Y ６－１４ , a 5- to 14-membered heteroaryl optionally substituted with one or more substituents selected from Y, -COR １２ , -CONR ｃ１ R ｃ２ , -COOR ｃ３ , -C(=NR ｃ４ )NR ｃ５ R ｃ６ , and -SO ｃ７ NR ２ R ｃ８ selected from ｃ９ and R ４２ is C optionally substituted with one or more substituents selected from a hydrogen atom, Y １０ alkyl, C optionally substituted with one or more substituents selected from Y １－１０ alkenyl, C optionally substituted with one or more substituents selected from Y １０ alkynyl, C optionally substituted with one or more substituents selected from Y ２－１０ cycloalkyl, C optionally substituted with one or more substituents selected from Y １０ cycloalkenyl, 3- to 14-membered non-aromatic heterocyclyl optionally substituted with one or more substituents selected from Y ２－１０ C optionally substituted with one or more substituents selected from Y １１ aryl, and 5- to 14-membered heteroaryl optionally substituted with one or more substituents selected from Y ３－１０ is selected from １１ and ３－１０ is selected from １１ and １２ is selected from ６－１４ and １２ is selected from 5- to 14-membered heteroaryl optionally substituted with one or more substituents selected from R ４３ is C optionally substituted with one or more substituents selected from Y １０ alkyl, C optionally substituted with one or more substituents selected from Y １－１０ alkenyl, C optionally substituted with one or more substituents selected from Y １０ alkynyl, C optionally substituted with one or more substituents selected from Y ２－１０ cycloalkyl, C optionally substituted with one or more substituents selected from Y １０ cycloalkenyl, 3- to 14-membered non-aromatic heterocyclyl optionally substituted with one or more substituents selected from Y ２－１０ aryl, and 5- to 14-membered heteroaryl optionally substituted with one or more substituents selected from Y １１ and is selected from ３－１０ C optionally substituted with one or more substituents selected from Y １１ alkyl, C optionally substituted with one or more substituents selected from Y ３－１０ alkenyl, C optionally substituted with one or more substituents selected from Y １１ alkynyl, C optionally substituted with one or more substituents selected from Y １２ cycloalkyl, C optionally substituted with one or more substituents selected from Y ６－１４ cycloalkenyl, 3- to 14-membered non-aromatic heterocyclyl optionally substituted with one or more substituents selected from Y １２ aryl, and 5- to 14-membered heteroaryl optionally substituted with one or more substituents selected from Y R ｃ１ , R ｃ２ , R ｃ３ , R ｃ４ , R ｃ５ , R ｃ６ , R ｃ７ , R ｃ８ , and R ｃ９ each independently represents a hydrogen atom, Y １０ C which may be substituted by one or more substituents selected from １－１０ Alkyl, Y １０ C which may be substituted by one or more substituents selected from ２－１０ Alkenyl, Y １０ C which may be substituted by one or more substituents selected from ２－１０ Alkynyl, Y １１ C which may be substituted by one or more substituents selected from ３－１０ Cycloalkyl, Y １１ C which may be substituted by one or more substituents selected from ３－１０ Cycloalkenyl, Y １１ 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from １２ C which may be substituted by one or more substituents selected from ６－１４ Aryl, and Y １２ 5-14 membered heteroaryl, optionally substituted by one or more substituents selected from Y １０ is independently C optionally substituted with one or more substituents selected from a halogen atom, nitro, cyano, a halogen atom, and alkoxy １－１０ alkoxy, a halogen atom, and C １－６ cycloalkyl optionally substituted with one or more substituents selected from a halogen atom, and alkoxy ３－１０ cycloalkenyl, a halogen atom, and C １－６ 3- to 14-membered non-aromatic heterocyclyl optionally substituted with one or more substituents selected from a halogen atom, and alkoxy ３－１０ aryl, a halogen atom, and C １－６ 5- to 14-membered heteroaryl optionally substituted with one or more substituents selected from a halogen atom, and alkoxy １－６ C optionally substituted with one or more substituents selected from a halogen atom, and alkoxy ６－１４ aryl, a halogen atom, and C １－６ 5- to 14-membered heteroaryl optionally substituted with one or more substituents selected from a halogen atom, and alkoxy １－６ (C １－１０ alkoxy)carbonyl, a halogen atom, and C １－６ di(C １－６ alkyl)aminocarbonyl, a halogen atom, and C １－６ C optionally substituted with one or more substituents selected from a halogen atom, and alkoxy １－６ alkoxy, a halogen atom, and C １－６ C optionally substituted with one or more substituents selected from a halogen atom, and alkoxy １－６ alkylthio, a halogen atom, and C １－６ C optionally substituted with one or more substituents selected from a halogen atom, and alkoxy １－６ alkylsulfanyl, a halogen atom, and C １－６ C optionally substituted with one or more substituents selected from a halogen atom, and alkoxy １－６ alkylsulfinyl, a halogen atom, and C １－６ C which may be substituted by one or more substituents selected from alkoxy １－６ selected from alkylsulfonyl and oxo, and Y １１ is each independently C optionally substituted by one or more substituents selected from a halogen atom, nitro, cyano, a halogen atom, and alkoxy １－１０ alkyl, C optionally substituted by one or more substituents selected from a halogen atom and alkoxy ２－１０ alkenyl, C optionally substituted by one or more substituents selected from a halogen atom and alkoxy ２－１０ alkynyl, C optionally substituted by one or more substituents selected from a halogen atom and alkoxy １－１０ alkoxy, C optionally substituted by one or more substituents selected from a halogen atom and C １－６ alkoxy ３－１０ cycloalkyl, C optionally substituted by one or more substituents selected from a halogen atom and C １－６ alkoxy ３－１０ cycloalkenyl, C optionally substituted by one or more substituents selected from a halogen atom and C １－６ 3- to 14-membered non-aromatic heterocyclyl optionally substituted by one or more substituents selected from a halogen atom and C １－６ alkoxy ６－１４ aryl, C optionally substituted by one or more substituents selected from a halogen atom and C １－６ 5- to 14-membered heteroaryl optionally substituted by one or more substituents selected from a halogen atom and C １－６ alkoxy １－１０ (C １－６ alkoxy)carbonyl, C optionally substituted by one or more substituents selected from a halogen atom and C １－６ di(C １－６ alkyl)aminocarbonyl, C optionally substituted by one or more substituents selected from a halogen atom and C １－６ alkoxy, C optionally substituted by one or more substituents selected from a halogen atom and C １－６ alkoxy １－６ alkylthio, C optionally substituted by one or more substituents selected from a halogen atom and C １－６ C optionally substituted by one or more substituents selected from alkoxy １－６ alkylsulfanyl, a halogen atom, and C １－６ C optionally substituted by one or more substituents selected from alkoxy １－６ alkylsulfinyl, a halogen atom, and C １－６ C optionally substituted by one or more substituents selected from alkoxy １－６ alkylsulfonyl, and oxo, and is selected from Y １２ is each independently C optionally substituted with one or more substituents selected from a halogen atom, nitro, cyano, a halogen atom, and alkoxy １－１０ alkyl, C optionally substituted with one or more substituents selected from a halogen atom and alkoxy ２－１０ alkenyl, C optionally substituted with one or more substituents selected from a halogen atom and alkoxy ２－１０ alkynyl, C optionally substituted with one or more substituents selected from a halogen atom and alkoxy １－１０ alkoxy, C optionally substituted with one or more substituents selected from a halogen atom and C １－６ alkoxy ３－１０ cycloalkyl, C optionally substituted with one or more substituents selected from a halogen atom and C １－６ alkoxy ３－１０ cycloalkenyl, C optionally substituted with one or more substituents selected from a halogen atom and C １－６ alkoxy, 3- to 14-membered non-aromatic heterocyclyl optionally substituted with one or more substituents selected from a halogen atom and C １－６ alkoxy ６－１４ aryl, C optionally substituted with one or more substituents selected from a halogen atom and C １－６ alkoxy, 5- to 14-membered heteroaryl optionally substituted with one or more substituents selected from a halogen atom and C １－６ alkoxy １－１０ (C １－６ alkoxy)carbonyl, C optionally substituted with one or more substituents selected from a halogen atom and C １－６ alkoxy １－６ di(C １－６ alkyl)aminocarbonyl, C optionally substituted with one or more substituents selected from a halogen atom and C １－６ alkoxy １－６ alkylthio, C optionally substituted with one or more substituents selected from a halogen atom and C １－６ C optionally substituted with one or more substituents selected from alkoxy １－６ alkylsulfanyl, a halogen atom, and C １－６ C optionally substituted with one or more substituents selected from alkoxy １－６ alkylsulfinyl, and a halogen atom and C １－６ C optionally substituted with one or more substituents selected from alkoxy １－６ selected from alkylsulfonyl, p is, independently of each other, an integer from 0 to 2, R ５ is benzyl which may be substituted by one or more substituents selected from a hydrogen atom and Y １３ on the benzene ring, benzyloxycarbonyl which may be substituted by one or more substituents selected from Y １３ on the benzene ring, phenylcarbonyl which may be substituted by one or more substituents selected from Y １３ on the benzene ring, (C １－１０ alkoxy)carbonyl, (C １－１０ alkyl)carbonyl which may be substituted by a halogen atom, Y １ C １－１０ alkyl which may be substituted by one or more substituents selected from Y １ C ２－１０ alkenyl which may be substituted by one or more substituents selected from Y １ C ２－１０ alkynyl which may be substituted by one or more substituents selected from Y ２ C ３－１０ cycloalkyl which may be substituted by one or more substituents selected from Y ２ C ３－１０ cycloalkenyl which may be substituted by one or more substituents selected from Y ２ 3- to 14-membered non-aromatic heterocyclyl which may be substituted by one or more substituents selected from Y ３ C ６－１４ aryl, and 5- to 14-membered heteroaryl which may be substituted by one or more substituents selected from Y ３ and is selected from R ６ is benzyl which may be substituted by one or more substituents selected from hydrogen atoms and Y １３ on the benzene ring, benzyloxycarbonyl which may be substituted by one or more substituents selected from Y １３ on the benzene ring, phenylcarbonyl which may be substituted by one or more substituents selected from Y １３ on the benzene ring, (C １－１０ alkoxy)carbonyl, (C １－１０ alkyl)carbonyl, or R ５ and R ６ together with the nitrogen atom to which they are attached form a 5- to 14-membered nitrogen-containing heterocyclyl having an imide structure, or a 3- to 14-membered non-aromatic heterocyclyl containing two or more nitrogen atoms as ring atoms, which may be substituted by one or more substituents selected from Y ２ and form, R ｄ is benzyl optionally substituted with one or more substituents selected from a hydrogen atom and Y on the benzene ring, benzyloxycarbonyl optionally substituted with one or more substituents selected from Y on the benzene ring, １３ phenylcarbonyl optionally substituted with one or more substituents selected from Y, (C １３ alkoxy)carbonyl, (C １３ alkyl)carbonyl, and is selected from １－１０ ; １－１０ ​ Y １３ is, independently of one another, selected from a halogen atom, C １－１０ alkoxy, and C １－１０ alkyl, when the 3- to 14-membered non-aromatic heterocyclyl is a monocyclic heterocyclyl, the heterocyclyl may be condensed with a benzene ring, Said C ６－１４ When the aryl is phenyl, the phenyl may be condensed with a 5- to 7-membered non-aromatic heterocyclic ring. The compound represented by, or a salt thereof (wherein Z is hydroxy, n is 0, R ７ and R ８ are hydrogen atoms, and X is 2,6-dichloropyridin-4-yl), R １ and R ２ is a hydrogen atom, or R １ is a hydrogen atom, and R ２ is methyl, ethyl, isopropyl, n-butyl, tert-butyl, or isobutyl, or R １ is ethyl, and excluding compounds where R ２ is methyl or ethyl).

2. Z is -NR ５ R ６ The compound according to claim 1, or a salt thereof, wherein Z is -NR ５ R ６ .

3. The compound according to claim 1, or a salt thereof, wherein n is 0 or 1.

4. R １ The compound according to claim 1, or a salt thereof, wherein R is a hydrogen atom.

5. R ７ and R ８ is a hydrogen atom, the compound according to claim 1, or a salt thereof.

6. The compound according to claim 1, or a salt thereof, wherein X is 2,6-dihalo-4-pyridyl.

7. The compound according to claim 1, or a salt thereof, wherein X is 2,6-dichloro-4-pyridyl.

8. X is perfluoro C １－３ alkyl, the compound according to claim 1, or a salt thereof.

9. The compound according to claim 1, or a salt thereof, wherein X is trifluoromethyl.

10. A composition for use in acylating tRNA, comprising the compound according to any one of claims 1 to 9, or a salt thereof.

11. The composition according to claim 10, for use in acylating tRNA in the presence of a flexizyme.

12. Formula (Ia): 【Chemical 3】 [wherein R １ , R ２ , R ７ , R ８ , Q, X and Z are as defined in any one of claims 1 to 9] A process for producing a compound represented by, comprising reacting a compound represented by formula (IIa): 【Chemical Formula 4】 with a compound represented by formula (III): 【Chemical Formula 5】 [wherein L is a leaving group] The said production method, which comprises reacting with the compound represented by.

13. The method according to claim 12, wherein the reaction is carried out in the presence of a base.

14. The method according to claim 13, wherein the base is diisopropylethylamine.

15. A process for producing tRNA acylated at the 3'-end, wherein the acyl group at the 3'-end is: 【Chemical Formula 6】 [wherein, R １ , R ２ , R ５ , R ６ , Q and Z are as defined in any one of claims 1 to 9] a group represented by Formula (Ia): 【Chemical Formula 7】 [wherein, R １ , R ２ , R ５ , R ６ , R ７ , R ８ , Q, X and Z are as defined in any one of claims 1 to 9] The said production method, which comprises reacting the compound represented by with tRNA in the presence of a flexizyme.

16. A method for preparing a peptide library, comprising producing tRNA acylated at the 3'-end by the method according to claim 15, preparing a library of mRNAs, and synthesizing peptides corresponding to each mRNA from the mRNA library using a cell-free translation system to prepare a peptide library The said method, which comprises.

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