Method for preparing peptide compounds containing n-substited amino acid residue

Abstract

The subject of this invention is to provide an efficient method for producing high-purity peptide compounds in high yield. It has been found that this problem can be solved by loading the peptides onto a resin used in solid-phase synthesis prior to the initial extended reaction in the solid-phase process.

Description

technical field

[0001] The present invention relates to the preparation method of the peptide compound containing N-substitution-amino acid residue. prior art

[0002] Middle-molecular compounds (molecular weight 500-2000) have attracted attention as therapeutic tools (modalities), which can realize drug development for tough targets represented by protein-protein interaction inhibition ( Non-Patent Document 1).

[0003] Since peptides generally have low druglikeness (metabolic stability, membrane penetration, etc.), it is considered difficult to develop peptides themselves as pharmaceuticals. In recent years, it has been found that by cyclization of peptides, using unnatural amino acids such as N-methyl amino acids in peptides, metabolic stability, membrane permeability, etc. will be improved (non-patent literature 2, 3).

[0004] Among cyclic peptides containing unnatural amino acids, it is known that especially cyclic peptides containing N-substituted amino acids have drug-like properties (Patent Document 1).

[0005] It has also been suggested that display library compounds of cyclic peptides comprising non-natural amino acids are useful for creating inhibitors of protein-protein interactions (Non-Patent Document 4).

[0006] It is also known that cyclic peptides containing unnatural amino acids are required for druglike molecules with a degree of membrane penetration and metabolic stability that can be used as pharmaceuticals, as therapeutic agents. The attention of cyclic peptides as tools is further increasing (Patent Documents 2 and 3).

[0007] On the other hand, the problem of making peptides containing N-methyl amino acids in the sequence is the low reactivity of the condensation reaction due to the steric hindrance of the N-methyl group, and the α-position caused by the amino acid residues. Decrease in the yield of the target product due to racemization or the like. In addition, it has been reported that the amide bond at the N-methyl amino acid residue site is susceptible to a cleavage reaction under acidic conditions, and the detachment reaction of the two amino acid residues at the N-terminus due to the formation of diketopermazine has been reported. It is easy to cause many problems such as missing points, and it is well known that the synthesis of natural peptides is more difficult (Non-Patent Document 5).

[0008] The synthesis of peptides is achieved by extending the desired sequence through the formation of amide bonds. As a more specific method, a liquid-phase method and a solid-phase method are mentioned (Non-Patent Document 6).

[0009] Among them, the solid phase method includes: using an atomic group linked to a polymer resin (resin for solid phase synthesis) as a linker, and preparing a solid phase in which the C-terminus of an amino acid or peptide is supported on a resin for solid phase synthesis Step of resin for synthesis (loading step); Step of deprotection of amino acid or N-terminal amino group of peptide supported on resin for solid-phase synthesis; N-terminal protected amine by condensation reaction as the next sequence The condensation step of introducing amino acids; repeating these deprotection steps and condensation steps until the desired sequence is reached, whereby the amino acid residues are linked to the elongation step of the peptide chain with the target sequence; The peptide of the target sequence is cleaved with the resin used for synthesis (resin removal step). As the N-terminal protected amino acid used in the elongation step, amino acids whose N-terminal amine group is protected by Fmoc group or Boc group are widely used (Non-Patent Documents 7 and 8).

[0010] Resins for solid-phase synthesis are roughly classified according to the atomic groups that become linkers that are bonded to polymers used in the resins. The resins for solid-phase synthesis are widely used to contain trityl skeletons, benzyl groups, and A resin for solid-phase synthesis in which linker atomic groups such as skeletons are bonded. More specifically, it is represented by CTC resin, Wang resin, SASRIN resin, or Rink Amide resin, etc. (Non-Patent Document 8).

[0011] The deresinizing step is mainly carried out under acidic conditions, but the ease of deresinizing depends on the stability of the linker atomic group to the acid. For example, the deresinization of peptides derived from CTC resins that can be loaded with peptide residues using a trityl backbone as a linker can be performed even with weakly acidic reagents. On the other hand, strong acid conditions are applied to the deresinization reaction of peptides derived from Wang resin, which can bind peptides using a benzyl skeleton as a linker (Non-Patent Document 8).

[0012] If CTC resin is used, the deresinization reaction of the peptide can be carried out under milder acidic conditions. Therefore, in the manufacture of peptides using CTC resin, peptides with protective groups that are easily removed under acidic conditions can be used as Selective deresinization is carried out in such a way that the protecting group is not deprotected. Therefore, CTC resins are useful in the production of such peptides protected by protecting groups (Non-Patent Document 9). On the other hand, it has been reported that in the solid-phase synthesis of peptides using CTC resins, peptides can be deresinized from CTC resins under mild conditions, so under condensation reaction conditions, amino acids loaded on CTC resins or The covalent bond between the linker of the peptide and the resin is cleaved, and the yield of the target peptide is reduced (also known as premature cleavage, or premature peptide release, premature acidolytic cleavage (premature acidolytic cleavage) (Non-Patent Documents 10, 11). [Prior Art Literature] [Patent Document]

[0013] [Patent Document 1] International Publication No. 2013 / 100132 [Patent Document 2] International Publication No. 2018 / 115864 [Patent Document 3] International Publication No. 2020 / 122182 [Non-patent literature]

[0014] [Non-Patent Document 1] Future Med. Chem., 2009, 1, 1289-1310. [Non-Patent Document 2] Acc. Chem. Res., 2008, 41, 1331-1342. [Non-Patent Document 3]Angew. Chem. Int. Ed., 2013, 52, 254-269. [Non-Patent Document 4] Chem. Rev., 2019, 119, 10360-10391. [Non-Patent Document 5] J. Peptide Res., 2005, 65, 153-166. [Non-Patent Document 6] Amino Acids, Peptides and Proteins in Organic Chemistry: Building Blocks, Catalysis and Coupling Chemistry, Volume 3, 2011 [Non-Patent Document 7]Amino Acids, 2018, 50, 39-68. [Non-Patent Document 8] Solid phase peptide synthesis (issued by Bachem Corporation) [Retrieved on November 6, 2020], Internet <URL: https: / / www.bachem.com / fileadmin / user_upload / pdf / Catalogs_Brochures / Solid_Phase_Peptide_Synthesis .pdf> [Non-Patent Document 9] QSAR Comb. Sci., 2007, 26, 1027-1035. [Non-Patent Document 10]Biopolymers, 2012, 98, 89-97. [Non-Patent Document 11] ACS Comb. Sci., 2013, 15, 229-234. Contents of the invention

[0015] [Problem to be solved by the invention]

[0016] The problem of the present invention is to provide a method for efficiently producing high-purity peptide compounds with high yield.

[0017] Non-Patent Documents 10 and 11 describe the following gist: In the condensation reaction in which the carboxyl group of the natural amino acid protected by Fmoc is condensed with respect to the amine group of the natural amino acid supported on the CTC resin to form an amide bond, if oxyma , HOBt, HOAt and other acidic additives, there will be a decrease in yield accompanied by premature splitting. On the other hand, in the condensation reaction of HBTU and DIPEA using alkaline conditions, the yield can be increased. However, the inhibitory effect of premature splitting is limited, and the racemization of amino acids also occurs in alkaline conditions, so it cannot be called a better reaction condition. In particular, there are no reports so far addressing the problem of premature cleavage in the synthesis of peptides containing sterically hindered large unnatural amino acids such as N-methyl amino acids.

[0018] The inventors of the present invention attempted to identify amino acids that undergo premature cleavage in the solid-phase synthesis method using CTC resin. Furthermore, in the solid-phase synthesis method using CTC resin, the synthesis of peptides containing sterically hindered large amino acid residues such as N-substitution-amino acids was investigated. Amino acid (sometimes also called "first residue amino acid") and the amino acid of the second residue from the C-terminus (sometimes just called "second residue amino acid") ”) in the step of condensation, there are the following conditions: (i) the detachment reaction of the amino acid residue of the first residue from the CTC resin, i.e. a decrease in yield with premature cleavage; and (ii) the detached amine If the amino acid is excessively incorporated into the target amino acid sequence, the purity of the by-product of excess elongation will decrease.

[0019] As described above, the detachment of the amino acid residue or peptide residue loaded on the resin for solid phase synthesis from the linker of the resin for solid phase synthesis, more specifically, the first step of directly binding to the resin for solid phase synthesis The detachment of the amino acid residue from the resin linker for solid-phase synthesis can occur in various amino acid residues, but even so, it is still unknown to suppress the above-mentioned disadvantages and the formation of by-products. Efficient peptide synthesis. The problem of the present invention is to provide a method that uses a peptide supported on a resin for solid-phase synthesis as a starting material and utilizes a production method that is also applicable to the production of a peptide containing an unnatural amino acid residue, Produce high-purity peptide compounds at high yields. [means used to solve a problem]

[0020] As a result of studies conducted by the present inventors to solve the above-mentioned problems, they found a method of directly loading oligopeptides on a resin in the solid-phase synthesis of peptide compounds containing unnatural amino acids with large steric hindrance. In this way, the step of condensation of the amino acids of the first residue and the second residue in solid phase synthesis, which is prone to premature fragmentation, can be avoided. In addition, oligopeptides are less prone to detachment from the resin, and it was also confirmed that premature cleavage is suppressed in the case of an amino acid elongation step in which additional amino acids are added to the oligopeptide residues supported on the resin for solid-phase synthesis.

[0021] The present invention includes the following content in a non-limiting specific aspect. [1] A method for preparing a peptide compound containing at least one N-substituted amino acid residue, a salt thereof, or a solvate thereof by a solid-phase method, wherein the aforementioned method is characterized in that, Before the initial elongation reaction in the solid-phase method, the peptide is loaded on the resin for solid-phase synthesis. [2] A method for preparing a solvate of a peptide compound containing at least one N-substituted amino acid residue, a salt thereof, or a solvate thereof by a solid-phase method, the aforementioned method comprising loading the peptide Steps for resins used in solid-phase synthesis. [3] The method according to [1] or [2], wherein the peptide is an oligopeptide containing two or more amino acid residues. [4] The method described in any one of [1] to [3], wherein the peptide is a dipeptide or a tripeptide. [5] The method as described in any one of [1] to [4], wherein the amino acid residue at the C-terminal of the peptide and / or the amino group adjacent to the amino acid residue at the C-terminal Acid residues are unnatural amino acid residues. [6] The method according to any one of [1] to [5], wherein the amino acid residue at the C-terminal of the peptide is an unnatural amino acid residue. [7] The method according to [5] or [6], wherein the unnatural amino acid residue is an N-substituted amino acid residue. [8] The method as described in any one of [1] to [7], wherein the amino acid residue at the C-terminal of the peptide is bonded to the carbon atom at the β-position or the carbon atom at the γ-position of the amino group The combined carboxyl group is supported on the resin for solid phase synthesis. [9] The method as described in any one of [1] to [8], wherein the amino acid residue at the C-terminal of the peptide and / or the amino group adjacent to the amino acid residue at the C-terminal Acid residues have bulky side chains.

[10] The method described in [9], wherein the bulky side chain is a substitutable branched alkyl group.

[11] The method according to

[10] , wherein the alkanyl group is bonded to the carbon atom at the α-position of the carboxyl group.

[12] The method according to

[11] , wherein the branched chain alkyl group has a branch at the carbon atom at the β-position or the carbon atom at the γ-position of the carboxyl group.

[13] The method as described in any one of [1] to

[12] , wherein at least one N-substituted amino acid residue contained in the peptide compound is a non-natural N-substituted amino acid residue .

[14] The method according to any one of [1] to

[13] , wherein the peptide compound contains at least two N-substituted amino acid residues.

[15] The method according to any one of [1] to

[14] , wherein at least 30% of the total number of amino acid residues constituting the peptide compound are N-substituted amino acid residues.

[16] The method as described in any one of [1] to

[15] , wherein the amino acid residue at the C-terminal of the peptide is asparagine, 2-aminobutyric acid, glycine, Alanine, valine, proline, tyrosine, or 2-aminoisobutyric acid, or their N-substitution or derivatives, here, asparagine or its N-substitution Alternatively, the derivative is supported on the resin for solid-phase synthesis via the carboxyl group at the β-position of the amine group.

[17] The method according to any one of [1] to

[16] , wherein the amino acid residue at the C-terminal of the peptide is represented by the following formula (A). In the formula, L 1 is a single bond or -CHM 1-, -CH 2CHM 1-, -CHM 1CH 2-, -(CH 2) nS(CH 2) m-, -(CH 2) nS(O)(CH 2) m -, or-(CH 2 ) nS(O) 2(CH 2 ) m-, here, n and m are each independently and 1 or 2, R 1 is hydrogen, C 1-C 6 alkyl, C 2-C 6 alkenyl, C 2-C 6 alkynyl, C 1-C 6 alkoxy C 1-C 6 alkyl, C 7-C 14 Aralkyl (aralkyl), or aminocarbonyl (the amino group is -NH 2 , single C 1-C 6 alkylamine, di-C 1-C 6 alkylamine, or 4-8 membered cyclic amino group), each of which can be independently selected from halogen, side oxygen group, hydroxyl group, C 1-C 6 alkyl group, 4-7 membered heterocyclic group, aminocarbonyl group (the amino group is -NH 2 , single C 1 -C 6 alkylamino group, diC 1-C 6 alkylamino group, or 4~8 membered cyclic amino group), C 1-C 6 alkylsulfonyl group, and C 1-C 6 alkoxy group C 1-C 6 alkyl groups are replaced by one or more groups, or R 1 is a peptide chain containing 1 to 4 amino acid residues, or R 1 and P 1 form a 4-7 membered saturated heterocyclic ring together with the carbon atom bound by R 1 and the nitrogen atom bound by P 1 , or R 1 and Q 1 form a 3-8 membered alicyclic ring or a 4-7 membered saturated heterocyclic ring together with the carbon atoms bound to them, or R 1 and M 1 form a 3-8 membered alicyclic ring together with the carbon atom bound by R 1 and the carbon atom bound by M 1, Excluding the case where R 1 and P 1 form a 4-7 membered saturated heterocyclic ring, P 1 is hydrogen, or C 1-C 6 alkyl, and the C 1-C 6 alkyl can be independently selected from halogen, hydroxyl, C 1 -C 6 alkoxy group, amine group (the amine group is -NH 2 , mono C 1-C 6 alkyl amine group, di C 1-C 6 alkyl amine group, or 4-8 membered cyclic amine group, Each of them can also be replaced by a halogen), and an aminocarbonyl group (the amino group is -NH 2 , a single C 1-C 6 alkylamine group, a di-C 1-C 6 alkylamine group, or a 4-8 membered ring Substituted by one or more groups of the group consisting of amino groups), Excluding the case where R 1 and Q 1 form a 3-8 membered alicyclic ring or a 4-7 membered saturated heterocyclic ring, Q 1 is hydrogen or C 1-C 6 alkyl, Excluding the case where R 1 and M 1 form a 3-8-membered alicyclic ring, M 1 is hydrogen, *Indicates the bonding site with the resin for solid phase synthesis, The wavy line indicates the binding site with the adjacent amino acid residue.

[18] The method as described in

[17] , wherein L 1 is -CHM 1-, R 1 is hydrogen, C 1-C 6 alkyl, halogen C 1-C 6 alkyl, C 2-C 6 alkenyl, C 2-C 6 alkynyl, C 1-C 6 alkoxy C 1-C 6 alkyl (the C 1-C 6 alkoxy C 1-C 6 alkyl can be replaced by hydroxyl, or aminocarbonyl (the amine is -NH 2 , single C 1-C 6 alkylamino, di-C 1-C 6 alkylamino group, or 4-8 membered cyclic amino group) replaced), 1 or multiple halogen-substituted C 7-C 14 aralkyl groups, or aminocarbonyl group (the amino group is - NH 2 , single C 1-C 6 alkylamine group, diC 1-C 6 alkylamine group, or 4-8 membered cyclic amine group, the cyclic amine group can be replaced by one or more halogens, 1 One or multiple side oxygen groups, one or multiple C 1-C 6 alkyl groups, or 4-7 membered heterocyclic groups), or R1 and M1 form a 3-8 membered alicyclic ring together with the carbon atom bound by R1 and the carbon atom bound by M1, or R 1 and P 1 form a 4-7 membered saturated heterocyclic ring together with the nitrogen atom bound by P 1 and the carbon atom bound by R 1, Excluding the case where R 1 and M 1 form a 3-8-membered alicyclic ring, M 1 is hydrogen, Excluding the case where R 1 and P 1 form a 4-7 membered saturated heterocyclic ring, P 1 is hydrogen or C 1-C 6 alkyl, Q 1 is hydrogen.

[19] The method as described in

[17] , wherein the amino acid residue at the C-terminal of the peptide is bAla, bMeAla, 2-ACHxC, 2-ACPnC, 3-CF3-bAla, Asp-mor, Asp-mor (26-bicyc), Asp-mor(SO2), Asp-NMe2, Asp-oxz, Asp-pip, Asp-pip(345-F6), Asp-pip(4-Me), Asp-pip-tBu, Asp -piz(oxe), Asp-pyrro, Asp-pyrro(34-F4), Asp-pyrro(3-Me2), D-(Propargyl)Gly-(C#CH2), D-3-Abu, D-3 -MeAbu, D-Gly(Allyl)-(C#CH2), D-Hph-(C#CH2), D-Leu-(C#CH2), D-MeAsp-pyrro, D-MeLeu-(C#CH2 ), D-Pic(2)-(C#CH2), D-Pro-(C#CH2), D-Ser(iPen)-(C#CH2), D-Ser(NtBu-Aca)-(C#CH2 ), EtAsp-pip, MeAsp-aze, MeAsp-mor, MeAsp-mor(26-bicyc), MeAsp-mor(SO2), MeAsp-NMe2, MeAsp-oxz, MeAsp-pip, MeAsp-pip(345-F6) , MeAsp-pip(3-F2), MeAsp-pip(4-F2), MeAsp-pip(4-Me), MeAsp-piz(oxe), MeAsp-pyrro, MeAsp-pyrro(34-F4), MeAsp- pyrro(3-Me2), nPrAsp-pip, MeGly, MeVal, Pro, Aib, Ala, Gly, Tyr(tBu), Val, D-MeAsp-NMe2, Glu-mor, Glu-pip, MeGlu-pip, Glu- NMe2, MeGlu-NMe2, or MeCys(AcOH)-NMe2.

[20] The method as described in any one of [1] to

[19] , wherein the amino acid residue adjacent to the amino acid residue at the C-terminal of the peptide is represented by the following formula (B): express. In the formula, L 2 is a single bond or -CH 2-, R 2 is hydrogen, C 1-C 6 alkyl, C 2-C 6 alkynyl, C 1-C 6 alkoxy C 1-C 6 alkyl, C 3-C 8 cycloalkyl, C 3-C 8 cycloalkyl C 1-C 6 alkyl, C 3-C 8 cycloalkoxy C 1-C 6 alkyl, or C 7-C 14 aralkyl, each of which can be independently selected from halogen, hydroxy, Amino group (the amino group is -NH 2 , protected amino group, mono C 1-C 6 alkyl amino group, di C 1-C 6 alkyl amino group, or 4-8 membered cyclic amino group, each of which is also can be replaced by halogen), aminocarbonyl (the amino group is -NH 2 , protected amino group, mono C 1-C 6 alkyl amino group, di C 1-C 6 alkyl amino group, or 4-8 membered ring amine group), and one or more groups of C 1-C 6 alkyl sulfonyl group, or R 2 and P 2 form a 4-7 membered saturated heterocyclic ring together with the carbon atom bound by R 2 and the nitrogen atom bound by P 2 , or R 2 and Q 2 form a 3-8 membered alicyclic ring or a 4-7 membered saturated heterocyclic ring together with these bonded carbon atoms, or Excluding the case where R 2 and P 2 form a 4-7 membered saturated heterocyclic ring, P 2 is hydrogen or C 1-C 6 alkyl, and the C 1-C 6 alkyl can be independently selected from halogen, hydroxyl, C 1- C 6 alkoxy group, amine group (the amine group is -NH 2 , mono C 1-C 6 alkyl amine group, di C 1-C 6 alkyl amine group, or 4-8 membered cyclic amine group, its Each can also be replaced by halogen), and aminocarbonyl (the amino group is -NH 2 , mono-C 1-C 6 alkylamine, di-C 1-C 6 alkylamine, or 4-8 membered cyclic Amino group) replaced by one or more groups of the group, Excluding the case where R 2 and Q 2 form a 3-8 membered alicyclic ring or a 4-7 membered saturated heterocyclic ring, Q 2 is hydrogen or C 1-C 6 alkyl, *Indicates the binding site to the amino acid residue at the C-terminal, The wavy line indicates the binding site to the adjacent amino acid residue or the protecting group of the amine group.

[21] The method as described in

[20] , wherein R 2 is C 1-C 6 alkyl, halogen C 1-C 6 alkyl, hydroxy C 1-C 6 alkyl, C 1-C 6 alkyl Sulfonyl C 1-C 6 alkyl, C 2-C 6 alkynyl, C 1-C 6 alkoxy C 1-C 6 alkyl, C 3-C 8 which may be replaced by one or more halogens Cycloalkyl, C 3-C 8 cycloalkyl C 1-C 6 alkyl, C 3-C 8 cycloalkoxy C 1-C 6 alkyl, or C 7-C 14 aralkyl, or R 2 and P 2 form a 4-7 membered saturated heterocycle together with the nitrogen atom bound by P 2 and the carbon atom bound by R 2 , Excluding the case where R 2 and P 2 form a 4-7 membered saturated heterocyclic ring, P 2 is hydrogen or C 1-C 6 alkyl.

[22] The method as described in

[21] , wherein the amino acid residue adjacent to the amino acid residue at the C-terminal of the peptide is MeAla, MeLeu, MeCha, MeVal, MeAla(cPent), MeAla(cBu ), MeAla(cPr), MeChg, MeGly(cPent), MeGly(cBu), MeGly(cPr), MeAbu, MeNva, MeNle, Val, Leu, MeNva(5-F2), MeHle, MeIle, MeSer(nPr), MeSer(cPr), MeHnl, MeHnl(7-F2), MePRA, MeSer(Me), MeThr, MeSer(cBu), MeSer(Tfe), MeThr(Me), MeHse(Me), MeMet(O2), Ile, Nle, Chg, Ala(cBu), Gly(cPent), Hle, Nva, Phe, Hph, Gly, Aib, Lys(Boc), Ala, D-MeVal, Asn(Trt), Ser(tBu), or bAla( 2-Me2).

[23] The method according to any one of [1] to

[22] , wherein the peptide is a dipeptide represented by the following formula (1). In the formula, L 1 is a single bond or -CHM 1-, -CH 2CHM 1-, -CHM 1CH 2-, -(CH 2) nS(CH 2) m-, -(CH 2) nS(O)(CH 2) m -, or-(CH 2 ) nS(O) 2(CH 2 ) m, here, n and m are each independently and 1 or 2, R 1 is hydrogen, C 1-C 6 alkyl, C 2-C 6 alkenyl, C 2-C 6 alkynyl, C 1-C 6 alkoxy C 1-C 6 alkyl, C 7-C 14 Aralkyl group, or aminocarbonyl group (the amino group is -NH 2 , mono C 1-C 6 alkyl amino group, di C 1-C 6 alkyl amino group, or 4-8 membered cyclic amino group), Each of them can be independently selected from halogen, side oxygen group, hydroxyl group, C 1-C 6 alkyl group, 4-7 membered heterocyclic group, aminocarbonyl group (the amino group is -NH 2 , mono-C 1-C 6 alkane Substituted by one or more groups of the group consisting of amino group, di-C 1-C 6 alkyl amino group, or 4-8 membered cyclic amino group) and C 1-C 6 alkyl sulfonyl group , or R 1 is a peptide chain containing 1 to 4 amino acid residues, or R 1 and P 1 form a 4-7 membered saturated heterocyclic ring together with the carbon atom bound by R 1 and the nitrogen atom bound by P 1 , or R 1 and Q 1 form a 3-8 membered alicyclic ring or a 4-7 membered saturated heterocyclic ring together with the carbon atoms bound to them, or R 1 and M 1 form a 3-8 membered alicyclic ring together with the carbon atom bound by R 1 and the carbon atom bound by M 1, Excluding the case where R 1 and P 1 form a 4-7 membered saturated heterocyclic ring, P 1 is hydrogen, or C 1-C 6 alkyl, and the C 1-C 6 alkyl can be independently selected from halogen, hydroxyl, C 1 -C 6 alkoxy group, amine group (the amine group is -NH 2 , mono C 1-C 6 alkyl amine group, di C 1-C 6 alkyl amine group, or 4-8 membered cyclic amine group, Each of them can also be replaced by a halogen), and an aminocarbonyl group (the amino group is -NH 2 , a single C 1-C 6 alkylamine group, a di-C 1-C 6 alkylamine group, or a 4-8 membered ring Substituted by one or more groups of the group consisting of amino groups), Excluding the case where R 1 and Q 1 form a 3-8 membered alicyclic ring or a 4-7 membered saturated heterocyclic ring, Q 1 is hydrogen or C 1-C 6 alkyl, Excluding the case where R 1 and M 1 form a 3-8-membered alicyclic ring, M 1 is hydrogen, L 2 is a single bond or -CH 2-, R 2 is hydrogen, C 1-C 6 alkyl, C 2-C 6 alkynyl, C 1-C 6 alkoxy C 1-C 6 alkyl, C 3-C 8 cycloalkyl, C 3-C 8 cycloalkyl C 1-C 6 alkyl, C 3-C 8 cycloalkoxy C 1-C 6 alkyl, or C 7-C 14 aralkyl, each of which can be independently selected from halogen, hydroxy, Amino group (the amino group is -NH 2 , protected amino group, mono C 1-C 6 alkyl amino group, di C 1-C 6 alkyl amino group, or 4-8 membered cyclic amino group, each of which is also can be replaced by halogen), aminocarbonyl (the amino group is -NH 2 , protected amino group, mono C 1-C 6 alkyl amino group, di C 1-C 6 alkyl amino group, or 4-8 membered ring amine group), and one or more groups of C 1-C 6 alkyl sulfonyl group, or R 2 and P 2 form a 4-7 membered saturated heterocyclic ring together with the carbon atom bound by R 2 and the nitrogen atom bound by P 2 , or R 2 and Q 2 form a 3-8 membered alicyclic ring or a 4-7 membered saturated heterocyclic ring together with these bonded carbon atoms, or Excluding the case where R 2 and P 2 form a 4-7 membered saturated heterocyclic ring, P 2 is hydrogen or C 1-C 6 alkyl, and the C 1-C 6 alkyl can be independently selected from halogen, hydroxyl, C 1- C 6 alkoxy group, amine group (the amine group is -NH 2 , mono C 1-C 6 alkyl amine group, di C 1-C 6 alkyl amine group, or 4-8 membered cyclic amine group, its Each can also be replaced by halogen), and aminocarbonyl (the amino group is -NH 2 , mono-C 1-C 6 alkylamine, di-C 1-C 6 alkylamine, or 4-8 membered cyclic Amino group) replaced by one or more groups of the group, Excluding the case where R 2 and Q 2 form a 3-8 membered alicyclic ring or a 4-7 membered saturated heterocyclic ring, Q 2 is hydrogen or C 1-C 6 alkyl, *Indicates the bonding site with the resin for solid phase synthesis, PG is the protecting group of amine group, However, P 1 and P 2 are not both hydrogen.

[24] The method according to

[23] , wherein the peptide is a dipeptide represented by the following formula (2). In the formula, R 1 is hydrogen, C 1-C 6 alkyl, halogen C 1-C 6 alkyl, C 2-C 6 alkenyl, C 2-C 6 alkynyl, C 1-C 6 alkoxy C 1-C 6 alkyl (the C 1-C 6 alkoxy C 1-C 6 alkyl can be replaced by hydroxyl, or aminocarbonyl (the amine is -NH 2 , single C 1-C 6 alkylamino, di-C 1-C 6 alkylamino group, or 4-8 membered cyclic amino group) replacement), C 7-C 14 aralkyl group that can be replaced by one or more halogens, or aminocarbonyl group (the amino group is -NH 2 , single C 1-C 6 alkylamine group, diC 1-C 6 alkylamine group, or 4-8 membered cyclic amine group, the cyclic amine group can be replaced by one or more halogens, 1 or multiple side oxygen groups, 1 or multiple C 1-C 6 alkyl groups, or 4-7 membered heterocyclic groups for further replacement), or R1 and M1 form a 3-8 membered alicyclic ring together with the carbon atom bound by R1 and the carbon atom bound by M1, or R 1 and P 1 form a 4-7 membered saturated heterocyclic ring together with the nitrogen atom bound by P 1 and the carbon atom bound by R 1, Excluding the case where R 1 and M 1 form a 3-8-membered alicyclic ring, M 1 is hydrogen, Excluding the case where R 1 and P 1 form a 4-7 membered saturated heterocyclic ring, P 1 is hydrogen or C 1-C 6 alkyl, R 2 is C 1-C 6 alkyl, halogen C 1-C 6 alkyl, hydroxy C 1-C 6 alkyl, C 1-C 6 alkylsulfonyl C 1-C 6 alkyl, C 2- C 6 alkynyl, C 1-C 6 alkoxy C 1-C 6 alkyl, C 3-C 8 cycloalkyl, C 3-C 8 cycloalkyl C 1 -C 6 alkyl, C 3-C 8 cycloalkoxy C 1-C 6 alkyl, or C 7-C 14 aralkyl, or R 2 and P 2 form a 4-7 membered saturated heterocycle together with the nitrogen atom bound by P 2 and the carbon atom bound by R 2 , Excluding the case where R 2 and P 2 form a 4-7 membered saturated heterocyclic ring, P 2 is hydrogen or C 1-C 6 alkyl, Q 2 is hydrogen, *Indicates the bonding site with the resin for solid phase synthesis, PG is the protecting group of amine group, However, P 1 and P 2 are not both hydrogen.

[25] The method according to any one of [1] to

[24] , wherein the resin for solid-phase synthesis is a resin that can be removed under mild acidic conditions.

[26] The method described in

[25] , wherein the mild acidic condition does not remove the protecting group of one or more amino acid side chains contained in the peptide compound supported on the resin for solid phase synthesis. conditions.

[27] The method according to any one of

[25] or

[26] , wherein the mild acidic conditions include temperature conditions around room temperature.

[28] The method as described in any one of

[25] to

[27] , wherein the mild conditions include conditions of using a dilute acid solution, and the dilute acid solution is obtained by diluting the acid with a non-acidic solvent.

[29] The method as described in

[25] to

[28] , wherein the mild acidic conditions are acidic conditions of pH 2 or higher.

[30] The method described in

[28] or

[29] , wherein the pKa of the acid system in water is -1 or more, 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more acids.

[31] The method described in

[30] , wherein the acid is TFA, 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoroisopropanol, trichloroacetic acid, Acetic acid, formic acid, or oxalic acid, or mixtures thereof.

[32] The method described in any one of

[29] to

[31] , wherein the volume % of the acid in the dilute solution is 60% or less, 50% or less, 40% or less, 30% or less, 20% or less , 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less.

[33] The method described in any one of

[29] to

[32] , wherein the non-acidic solvent is DCM, dichloroethane, water, or 2-MeTHF, or a mixed solvent thereof.

[34] The method as described in any one of

[26] to

[33] , wherein the protecting group is selected from the group consisting of Boc, Trt, THP, and tBu.

[35] The method as described in any one of

[26] to

[34] , wherein the amino acid having a protecting group in the side chain is Tyr(tBu), Ser(tBu), Thr(tBu), Asp( tBu), Glu(tBu), Trp(Boc), Lys(Boc), His(Boc), Ser(Trt), Thr(Trt), Trp(Trt), Lys(Trt), His(Trt), Asn( Trt), Gln(Trt), Ser(THP), or Thr(THP), or N-alkyl forms thereof.

[36] The method according to any one of [1] to

[35] , wherein the resin for solid phase synthesis is CTC resin, Wang resin, SASRIN resin, Trt resin, Mtt resin, Mmt resin, or Sieber resin.

[37] The method described in

[36] , wherein the resin for solid phase synthesis is CTC resin or Sieber resin.

[38] The method according to any one of [1] and [3] to

[37] , comprising the step of loading the peptide on a resin for solid-phase synthesis.

[39] The method according to any one of [1] to

[38] , further comprising the step of extending the peptide by one or more amino acid residues.

[40] A method for preparing a cyclic peptide, a salt thereof, or a solvate thereof, comprising the following steps: Following the method described in any one of [1] to

[39] , the step of obtaining a solvate of a peptide compound containing at least one N-substituted amino acid residue, its salt, or the like; the step of removing the resin for solid phase synthesis; and A step of cyclizing the group on the C-terminal side and the group on the N-terminal side of the peptide compound, its salt, or a solvate thereof to form a ring.

[41] A method for improving the recovery rate of a peptide compound compared to the case of extending amino acid residues one by one, the method is characterized in that the method is carried out by a solid-phase method containing at least 1 In the manufacture of a peptide compound with N-substituted amino acid residues, a salt thereof, or a solvate thereof, the peptide is loaded on a resin for solid-phase synthesis before the initial elongation reaction.

[42] A method for suppressing the formation of impurities compared to the case of extending amino acid residue by residue, said method being characterized in that in the solid-phase method containing at least one N - In the production of peptide compounds, salts thereof, or solvates thereof in which amino acid residues are substituted, the peptide is loaded on a resin for solid-phase synthesis before the initial elongation reaction.

[43] A method for suppressing premature cleavage as compared with the case of extending amino acids residue by residue, said method being characterized in that at least one N-substitution In the production of peptide compounds of amino acid residues, their salts, or solvates thereof, the peptide is loaded on a resin for solid-phase synthesis before the initial elongation reaction. [Efficacy of the invention]

[0022] The present invention provides a useful method for producing peptide compounds with arbitrary sequences including arbitrary types and numbers of amino acid residues, and capable of producing high-yield and high-purity peptide compounds. The present invention can increase the yield by inhibiting premature splitting, and can increase the purity by avoiding the by-generation of excess extension bodies, thereby dramatically improving the purification efficiency of the target peptide compound and making the peptide solid The productivity of the phase synthesis method has been greatly improved. Brief description of the diagram

[0023] none. Implementation

[0024] [Mode for Carrying Out the Invention]

[0025] (abbreviation) The abbreviations used in this manual are described below. AA: Ammonium acetate Al: Allyl Alloc: Allyloxycarbonyl Boc:t-butoxycarbonyl Cbz: Benzyloxycarbonyl COMU: (1-cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino N-𠰌linylcarbenium hexafluorophosphate DBU:1,8-Diacridinebicyclo[5.4.0]-7-undecene DCM: dichloromethane DIC:N,N'-Diisopropylcarbodiimide DIPEA:N,N-Diisopropylethylamine DMF:N,N-Dimethylformamide DMSO: Dimethyroxide EDCI: 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride FA: formic acid Fmoc:9-Ferlenylmethyloxycarbonyl NMP: N-methyl-2-pyrrolidone HATU: O-(7-aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate HBTU: O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate HFIP:1,1,1,3,3,3-Hexafluoroisopropanol HOAt:1-Hydroxy-7-azabenzotriazole HOBt:1-Hydroxybenzotriazole oxyma: ethyl cyano(hydroxyimino)acetate TBME:t-Butyl methyl ether Teoc:2-(trimethylsilyl)ethoxycarbonyl TFA: Trifluoroacetic acid TFE:2,2,2-Trifluoroethanol THF: Tetrahydrofuran Trt: Trityl

[0026] The relationship between the abbreviations and structures of amino acids used in this specification is shown below. In addition, in the following tables, each amino acid is listed in the form of protecting the amino group with the Fmoc group, but the abbreviation of each amino acid or its residue and the structure of the amino acid having a free amino group after removing the Fmoc group The relationship can also be grasped by the following table. Specifically, for example, that MeAsp-pip is an amino acid having the following structure obtained by removing the Fmoc group from Fmoc-MeAsp-pip in the following table is understood by those skilled in the art to which the present invention pertains. The structure of the above-mentioned amino acid residues, ie MeAsp-pip, is also comprehensible to those skilled in the art to which the present invention belongs. [Form A]

[0027] (Definition of functional groups, etc.) As "halogen atom" in this specification, F, Cl, Br, or I are illustrated.

[0028] The so-called "alkyl group" in this specification refers to a valent group derived by removing any hydrogen atom from an aliphatic hydrocarbon, and does not contain heteroatoms (atoms other than carbon and hydrogen atoms) or unsaturated atoms in the skeleton. A carbon-carbon bond with a hydrocarbyl or a partial collection of hydrocarbyl structures containing hydrogen and carbon atoms. The alkyl group includes not only straight-chain ones but also branched-chain ones. Specifically, the alkyl group is an alkyl group having 1 to 20 carbon atoms (C 1-C 20 , hereinafter referred to as "C p -C q" means p to q carbon atoms), preferably C 1 -C 10 alkyl, more preferably C 1-C 6 alkyl. Specific examples of the alkyl group include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, isobutyl (2-methylpropyl base), n-pentyl, s-pentyl (1-methylbutyl), t-pentyl (1,1-dimethylpropyl), neopentyl (2,2-dimethylpropyl ), isopentyl (3-methylbutyl), 3-pentyl (1-ethylpropyl), 1,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 1, 1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1,2,2-tetramethylpropyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethyl Butyl, 2-ethylbutyl, etc.

[0029] The term "alkenyl" in this specification means a group having at least one double bond (two adjacent SP2 carbon atoms). Depending on the configuration of the double bond and the replacement moiety (where present), the geometry of the double bond can be entgegen (E) or zusammen (Z), cis or trans configuration. The alkenyl includes not only straight-chain ones but also branched-chain ones. The alkenyl group is preferably C 2-C 10 alkenyl, more preferably C 2-C 6 alkenyl, specifically vinyl, allyl, 1-propenyl, 2-propenyl, etc. 1-butenyl, 2-butenyl (including cis and trans), 3-butenyl, pentenyl, 3-methyl-2-butenyl, hexenyl, etc.

[0030] The term "alkynyl" in this specification refers to a group having a valency of at least one triple bond (two adjacent SP carbon atoms). The alkynyl group includes not only straight-chain ones but also branched-chain ones. The alkynyl group is preferably a C 2-C 10 alkynyl group, more preferably a C 2-C 6 alkynyl group, specifically, for example, ethynyl, 1-propynyl, propargyl, 3 -butynyl, pentynyl, hexynyl, 3-phenyl-2-propynyl, 3-(2'-fluorophenyl)-2-propynyl, 2-hydroxy-2-propynyl , 3-(3-fluorophenyl)-2-propynyl, 3-methyl-(5-phenyl)-4-pentynyl and the like.

[0031] The term "cycloalkyl" in this specification means a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group, including monocyclic, bicyclic, and spiro rings. As the cycloalkyl group, C 3-C 8 cycloalkyl group is preferably listed, specifically, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, spiro [3.3] heptyl, etc.

[0032] The term "aryl" in this specification refers to a monovalent aromatic hydrocarbon ring, preferably C 6 -C 10 aryl. Specific examples of the aryl group include phenyl, naphthyl (for example, 1-naphthyl, 2-naphthyl) and the like.

[0033] The term "heterocyclic group" in this specification means a non-aromatic cyclic monovalent group containing 1 to 5 heteroatoms in addition to carbon atoms. The heterocyclic group may have a double bond and / or a triple bond in the ring, carbon atoms in the ring may be oxidized to form a carbonyl group, and may be a single ring or a condensed ring. The number of atoms constituting the ring is preferably 4-10 (4-10 membered heterocyclic group), more preferably 4-7 (4-7 membered heterocyclic group). Specific examples of the heterocyclic group include azetidinyl, oxiranyl, oxetanyl, azetidinyl, dihydrofuryl, tetrahydrofuryl, Dihydropyranyl, tetrahydropyranyl, tetrahydropyridyl, tetrahydropyrimidinyl, thiol, thiol, pyrrolidinyl, piperidinyl, piperyl, pyrazolidine base, imidazolinyl (imidazolinyl), imidazolidinyl, oxazolidinyl, isoxazolidinyl, tetrahydrothiazolyl, isotetrahydrothiazolyl, 1,2-thiazinyl, thiadiazolidinyl (thiadiazolidinyl ), acridyl, oxazolidone, benzodioxanyl, benzoxazolyl, dioxolanyl, dioxanyl, Tetrahydropyrrolo[1,2-c]imidazole (tetrahydropyrrolo[1,2-c]imidazole), thietanyl, 3,6-diacribicyclo[3.1.1]heptyl, 2,5- Diazinebicyclo[2.2.1]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl, sultam, 2-oxaspiro[3.3]heptyl (2- oxaspiro[3.3]heptyl) and so on.

[0034] The so-called "protected heterocyclic group" in this specification means one or more functional groups contained in the "heterocyclic group" defined above, for example, the group where the amine group is protected by any protective group. 4~7 membered heterocyclic group. The protecting group specifically includes Boc, Fmoc, Cbz, Troc, Alloc, etc., and the protecting heterocyclic group specifically includes, for example, Boc protecting azetidine and the like.

[0035] The term "heterocycloalkylene" in this specification means a divalence in which the free atomic valence generated by removing two hydrogen atoms from one carbon atom of the aforementioned "heterocyclic group" becomes part of a double bond. base. The heterocycloalkylene group is preferably a 4-7 membered heterocycloalkylene group, and specifically, for example, tetrahydropyran-4-ylidene group, azetidin-3-ylidene group, etc. can be mentioned.

[0036] The so-called "protected heterocycloalkylene" in this specification refers to one or more functional groups contained in the aforementioned "heterocycloalkylene", for example, a group where an amine group is protected by any protecting group. The best example is the protection of 4-7 membered heterocycloalkylene groups. The protecting group specifically includes Boc, Fmoc, Cbz, Troc, Alloc, etc., and the protecting heterocyclic group specifically includes, for example, Boc protecting azetidin-3-ylidene group and the like.

[0037] The term "heteroaryl" in this specification means an aromatic cyclic monovalent group containing 1 to 5 heteroatoms in addition to carbon atoms. A ring may be a single ring or a condensed ring with another ring, and may be partially saturated. The number of atoms constituting the ring is preferably 5-10 (5-10 membered heteroaryl), more preferably 5-7 (5-7 membered heteroaryl). Specific examples of the heteroaryl group include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl ( oxadiazolyl), thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridyl, pyridyl, trisyl, benzofuryl, benzothienyl, benzothio Adiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinoline octyl, cinnolinyl, quinazolinyl, quinazolyl, benzodioxolyl, indolizinyl, imidazopyridyl, etc.

[0038] The so-called "alkoxy" in this specification refers to the oxy group bound to the "alkyl" defined above, preferably C 1-C 6 alkoxy. Specific examples of the alkoxy group include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, s-butoxy , t-butoxy, pentyloxy, 3-methylbutoxy, etc.

[0039] The term "alkenyloxy" in this specification refers to the oxy group to which the above-mentioned "alkenyl" is bound, preferably C 2 -C 6 alkenyloxy. Specific examples of the alkenyloxy group include vinyloxy, allyloxy, 1-propenyloxy, 2-propenyloxy, 1-butenyloxy, 2-but Alkenyloxy (including cis and trans), 3-butenyloxy, pentenyloxy, hexenyloxy, etc.

[0040] The so-called "cycloalkoxy" in this specification refers to the oxy group to which the "cycloalkyl" defined above is combined, preferably C 3 -C 8 cycloalkoxy. Specific examples of the cycloalkoxy group include cyclopropoxy, cyclobutoxy, and cyclopentyloxy.

[0041] The term "aryloxy" in this specification refers to the oxy group to which the "aryl" defined above is bound, preferably C 6 -C 10 aryloxy. Specific examples of the aryloxy group include phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like.

[0042] The so-called "amino group" in this specification means -NH2 in a narrow sense, and -NRR' in a broad sense. Here, R and R' are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkane A group, a heterocyclyl group, an aryl group, or a heteroaryl group, or R and R' form a ring together with the nitrogen atom to which they are bound. As the amino group, -NH 2 , mono-C 1-C 6 alkylamine group, di-C 1-C 6 alkylamine group, 4-8 membered cyclic amino group, etc. are preferably cited.

[0043] The so-called "monoalkylamino group" in this specification means that among the "amino groups" defined above, R is hydrogen and R' is the "alkyl" group defined above, preferably a single C 1-C 6 alkylamine groups. As the monoalkylamino group, specifically, for example, methylamino group, ethylamino group, n-propylamino group, i-propylamino group, n-butylamino group, s-butylamino group, Amino group, t-butylamino group, etc.

[0044] The so-called "dialkylamino group" in this specification means that among the "amino groups" defined above, R and R' are independently defined as the "alkyl" group defined above, preferably two C 1- C 6 alkylamine group. Specific examples of the dialkylamino group include a dimethylamino group, a diethylamino group, and the like.

[0045] The so-called "cyclic amino group" in this specification means that among the "amino groups" defined above, R and R' form a ring together with the nitrogen atom to which they are bound, preferably 4-8 membered cyclic amines base. Specific examples of the cyclic amino group include 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 1-hexahydropyrrolidinyl, 4-alkonolinyl, 3- Oxazolidinyl, 1,1-dioxidethiol-4-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, etc.

[0046] The term "protected amino group" in this specification means an amino group protected by an arbitrary protecting group. Specific examples of the protected amine group include amine groups protected by protecting groups such as Boc, Fmoc, Cbz, Troc, Alloc, and Trt.

[0047] The so-called "aminocarbonyl" in this specification refers to the carbonyl to which the aforementioned "amino" is bound, preferably -CONH 2 , mono-C 1-C 6 alkylaminocarbonyl, di-C 1-C 6 Alkylaminocarbonyl, 4-8 membered cyclic aminocarbonyl. Specific examples of the aminocarbonyl group include -CONH 2 , dimethylaminocarbonyl, 1-azithenylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 1-piperidinylcarbonyl, and 1-piperidinylcarbonyl. Carbonyl, 4-oxazolinylcarbonyl, 3-oxazolidinylcarbonyl, 1,1-dioxidethiol-4-ylcarbonyl, 3-oxa-8-azabicyclo[3.2.1] Octane-8-ylcarbonyl, etc.

[0048] The term "alkenyloxycarbonyl" in this specification refers to the carbonyl to which the aforementioned "alkenyloxy" is bound, preferably C 2 -C 6 alkenyloxycarbonyl. Specific examples of the alkenyloxycarbonyl group include vinyloxycarbonyl, allyloxycarbonyl, 1-propenyloxycarbonyl, 2-propenyloxycarbonyl, 1-butenyloxy ylcarbonyl, 2-butenyloxycarbonyl (including cis and trans), 3-butenyloxycarbonyl, pentenyloxycarbonyl, hexenyloxycarbonyl, etc.

[0049] The term "alkylsulfonyl" in this specification refers to a sulfonyl group to which the aforementioned "alkyl" is bound, preferably a C 1-C 6 alkylsulfonyl group. Specific examples of the alkylsulfonyl group include a methylsulfonyl group and the like.

[0050] "Hydroxyalkyl" in this specification refers to a group in which one or more hydrogens of the "alkyl" defined above are replaced by hydroxy, preferably hydroxy C 1-C 6 alkyl. Specific examples of the hydroxyalkyl group include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, 5-hydroxypentyl and the like.

[0051] "Haloalkyl" in this specification means a group in which one or more hydrogens of the aforementioned "alkyl" are replaced by halogen, preferably halogen C 1-C 6 alkyl, more preferably C 1- C 6 fluoroalkyl. Specific examples of the haloalkyl group include difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3-difluoropropane 4,4-difluorobutyl, 5,5-difluoropentyl, etc.

[0052] The "cyanoalkyl" in this specification refers to a group in which one or more hydrogens of the "alkyl" defined above are replaced by cyano, preferably cyano C 1-C 6 alkyl. Specific examples of the cyanoalkyl group include cyanomethyl, 2-cyanoethyl and the like.

[0053] "Aminoalkyl" in this specification refers to a group in which one or more hydrogens of the aforementioned "alkyl" are replaced by the aforementioned "amino" group, preferably amino C 1-C 6 alkane base. Specific examples of the aminoalkyl group include 1-pyridylmethyl, 2-(1-piperidyl)ethyl, 3-(1-piperidyl)propyl, 4-aminobutyl Base etc.

[0054] "Carboxyalkyl" in this specification refers to a group in which one or more hydrogens of the aforementioned "alkyl" are replaced by carboxyl, preferably carboxy C 1-C 6 alkyl. Specific examples of the carboxyalkyl group include carboxymethyl and the like.

[0055] "Alkenyloxycarbonylalkyl" in this specification means a group in which one or more hydrogens of the aforementioned "alkyl" are replaced by the aforementioned "alkenyloxycarbonyl", preferably C2 -C 6 alkenyloxycarbonyl C 1-C 6 alkyl, more preferably C 2-C 6 alkenyloxycarbonyl C 1-C 2 alkyl. Specific examples of the alkenyloxycarbonylalkyl group include allyloxycarbonylmethyl, 2-(allyloxycarbonyl)ethyl and the like.

[0056] "Alkoxyalkyl" in this specification refers to a group in which one or more hydrogens of the "alkyl" defined above are replaced by the "alkoxy" defined above, preferably a C 1-C 6 alkane Oxygen C 1-C 6 alkyl, more preferably C 1-C 6 alkoxy C 1-C 2 alkyl. Specific examples of the alkoxyalkyl group include methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, n-butoxymethyl , i-butoxymethyl, s-butoxymethyl, t-butoxymethyl, pentyloxymethyl, 3-methylbutoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, etc.

[0057] "Cycloalkylalkyl" in this specification refers to a group in which one or more hydrogens of the "alkyl" defined above are replaced by the "cycloalkyl" defined above, preferably a C3-C8 ring Alkyl C 1-C 6 alkyl, more preferably C 3-C 6 cycloalkyl C 1-C 2 alkyl. Specific examples of the cycloalkylalkyl group include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.

[0058] "Cycloalkoxyalkyl" in this specification refers to a group in which one or more hydrogens of the "alkyl" defined above are replaced by the "cycloalkoxy" defined above, preferably C3-C 8 cycloalkoxy C 1-C 6 alkyl, more preferably C 3-C 6 cycloalkoxy C 1-C 2 alkyl. Specific examples of the cycloalkoxyalkyl group include cyclopropoxymethyl, cyclobutoxymethyl and the like.

[0059] "Heterocyclylalkyl" in this specification refers to a group in which one or more hydrogens of the "alkyl" defined above are replaced by the "heterocyclyl" defined above, preferably a 4-7 membered heterocyclic ring C 1-C 6 alkyl, more preferably 4-7 membered heterocyclyl C 1-C 2 alkyl. Specific examples of the heterocyclylalkyl group include 2-(tetrahydro-2H-pyran-4-yl)ethyl and 2-(azetidin-3-yl)ethyl.

[0060] "Alkylsulfonylalkyl" in the description refers to a group in which one or more hydrogens of the aforementioned "alkyl" are replaced by the aforementioned "alkylsulfonyl", preferably C 1- C 6 alkylsulfonyl C 1-C 6 alkyl, more preferably C 1-C 6 alkylsulfonyl C 1-C 2 alkyl. Specific examples of the alkylsulfonylalkyl group include methylsulfonylmethyl, 2-(methylsulfonyl)ethyl and the like.

[0061] "Aminocarbonylalkyl" in this specification refers to a group in which one or more hydrogens of the aforementioned "alkyl" are replaced by the aforementioned "aminocarbonyl", preferably aminocarbonyl C 1- C 6 alkyl, more preferably aminocarbonyl C 1-C 4 alkyl. As the aminocarbonylalkyl group, specifically, for example, methylaminocarbonylmethyl, dimethylaminocarbonylmethyl, t-butylaminocarbonylmethyl, 1-aziminocarbonylmethyl, , 1-pyrrolidinylcarbonylmethyl, 1-piperidinylcarbonylmethyl, 4-𠰌linylcarbonylmethyl, 2-(methylaminocarbonyl)ethyl, 2-(dimethylaminocarbonyl) Ethyl, 2-(1-azithenylcarbonyl)ethyl, 2-(1-pyrrolidinylcarbonyl)ethyl, 2-(4-alpinenylcarbonyl)ethyl, 3-(dimethylamino carbonyl)propyl, 4-(dimethylaminocarbonyl)butyl and the like.

[0062] "Aryloxyalkyl" in this specification refers to a group in which one or more hydrogens of the "alkyl" defined above are replaced by the "aryloxy" defined above, preferably C 6 -C 10 aryloxy C 1-C 6 alkyl, more preferably C 6-C 10 aryloxy C 1-C 2 alkyl. Specific examples of the aryloxyalkyl group include phenoxymethyl, 2-phenoxyethyl and the like.

[0063] "Aralkyl (arylalkyl)" in this specification means a group in which at least one hydrogen atom of the aforementioned "alkyl" is replaced by the aforementioned "aryl", preferably C 7-C 14 Aralkyl, more preferably C 7-C 10 aralkyl. Specific examples of the aralkyl group include benzyl, phenethyl, 3-phenylpropyl and the like.

[0064] "Aralkoxy" in this specification refers to the oxy group combined with the "aralkyl" defined above, preferably C 7-C 14 aralkoxy, more preferably C 7-C 10 aralkyloxy. Specific examples of the aralkoxy group include benzyloxy, phenethyloxy, 3-phenylpropoxy and the like.

[0065] "Aralkoxyalkyl" in this specification refers to a group in which one or more hydrogens of the "alkyl" defined above are replaced by the "aralkoxy" defined above, preferably C 7-C 14 aralkoxy C 1-C 6 alkyl, more preferably C 7-C 14 aralkoxy C 1-C 2 alkyl. Specific examples of the aralkoxyalkyl group include benzyloxymethyl, 1-(benzyloxy)ethyl and the like.

[0066] "Heteroarylalkyl" in this specification means a group in which at least one hydrogen atom of the aforementioned "alkyl" is replaced by the aforementioned "heteroaryl", preferably a 5-10 membered heteroaryl C 1-C 6 alkyl, more preferably 5-10 membered heteroaryl C 1-C 2 alkyl. Specific examples of the heteroarylalkyl group include 3-thienylmethyl, 4-thiazolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, 2-(4-pyridyl)ethyl, 2-(6-quinolyl)ethyl, 2-(7- Quinolinyl)ethyl, 2-(6-indolyl)ethyl, 2-(5-indolyl)ethyl, 2-(5-benzofuryl)ethyl and the like.

[0067] The "heteroarylalkoxy" in this specification refers to the oxy group bound to the "heteroarylalkyl" defined above, preferably 5-10 membered heteroaryl C 1-C 6 alkoxy, More preferably, it is a 5-10 membered heteroaryl C 1-C 2 alkoxy group. Specific examples of the heteroarylalkoxy group include 3-thienylmethoxy and 3-pyridylmethoxy.

[0068] "Heteroarylalkoxyalkyl" in this specification refers to a group in which one or more hydrogens of the "alkyl" defined above are replaced by "heteroarylalkoxy" defined above, preferably 5-10 membered heteroaryl C 1-C 6 alkoxy C 1-C 6 alkyl, more preferably 5-10 membered heteroaryl C 1-C 2 alkoxy C 1-C 2 alkyl. Specific examples of the heteroarylalkoxyalkyl group include 3-pyridylmethoxymethyl group and the like.

[0069] "Heterocycloalkylenealkyl" in this specification refers to a group in which one or more hydrogens of the "alkyl" defined above are replaced by the "heterocycloalkylene" defined above, preferably 4~ 7-membered heterocycloalkylene C 1-C 6 alkyl, more preferably 4-7 membered heterocycloalkylene C 1-C 2 alkyl. Specific examples of the heteroarylalkoxyalkyl group include tetrahydro-4H-pyran-4-ylidenemethyl, azetidin-3-ylidenemethyl, and the like.

[0070] "Alkoxyalkenyl" in this specification refers to a group in which one or more hydrogens of the "alkenyl" defined above are replaced by the "alkoxy" defined above, preferably C 1-C 6 alkane Oxy C 2-C 6 alkenyl. Specific examples of the alkoxyalkenyl group include (E)-4-methoxybut-2-en-1-yl ((E)-4-methylbut-2-en-1-yl) wait.

[0071] "Aminocarbonylalkenyl" in this specification means a group in which one or more hydrogens of the aforementioned "alkenyl" are replaced by the aforementioned "aminocarbonyl", preferably aminocarbonyl C 2- C 6 alkenyl. Specific examples of the aminocarbonylalkenyl group include (E)-3-(dimethylaminocarbonylcarbonyl)-prop-2-en-1-yl and the like.

[0072] The "haloalkoxy" in this specification refers to a group in which one or more hydrogens of the "alkoxy" defined above are replaced by halogen, preferably a halogen C 1-C 6 alkoxy. Specific examples of the haloalkoxy group include difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy and the like.

[0073] The "alkylene group" in this specification means a divalent group derived by further removing any one hydrogen atom from the aforementioned "alkyl group", preferably a C 4 -C 8 alkylene group. Specific examples of the alkylene group include -CH 2-, -(CH 2) 2-, -(CH 2) 3-, -CH(CH 3)CH 2-, -C(CH 3) 2- , -(CH 2) 4-, -CH(CH 3)CH 2CH 2-, -C(CH 3) 2CH 2-, -CH 2CH(CH 3)CH 2-, -CH 2C(CH 3) 2- , -CH 2CH 2CH(CH 3 )-, -(CH 2) 5-, -(CH 2) 6-, -(CH 2) 7-, -(CH 2) 8-, etc.

[0074] The "alicyclic ring" in this specification means a non-aromatic hydrocarbon ring. The alicyclic ring may have an unsaturated bond in the ring, or may be a polycyclic ring having two or more rings. Also, carbon atoms constituting the ring may be oxidized to form a carbonyl group. The alicyclic ring preferably includes a 3- to 8-membered alicyclic ring, specifically, a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, and a cycloheptane ring. , cyclooctane ring, bicyclo[2.2.1]heptane ring, etc.

[0075] The "saturated heterocyclic ring" in this specification means a non-aromatic heterocyclic ring that contains 1 to 5 heteroatoms in addition to carbon atoms and does not contain double bonds and / or triple bonds in the ring. A saturated heterocyclic ring can be a single ring, and can also form a condensed ring with other rings such as aromatic rings such as benzene rings. As the saturated heterocycle, preferably a 4-7 membered saturated heterocycle, specifically, an azetidine ring, an oxetane (oxetane) ring, a tetrahydrofuran ring, a tetrahydropyran ring, a thioline ring, etc. , Thio 𠰌line ring, pyrrolidine ring, 4-oxopyrrolidine ring, piperidine ring, 4-oxo-piperidine ring, piper 𠯤 ring, pyrazolidine ring, imidazolidine ring, oxazolidine ring , isoxazolidine ring, thiazolidine ring, isothiazolidine ring, thiazolidine ring, oxazolidine ring, dioxolane, dioxane ring, thietane ring, octahydroindole ring, indoline ring, etc.

[0076] The "peptide chain" in this specification refers to peptides with 1, 2, 3, 4, or more natural amino acids and / or unnatural amino acids linked by amide bonds and / or ester bonds. peptide chain. As the peptide chain, it is preferably a peptide chain comprising 1-4 amino acid residues, more preferably a peptide chain composed of 1-4 amino acid residues.

[0077] In the "protecting group of amine group" in this specification, urethane-type protecting group, amide-type protecting group, arylamide-type protecting group, alkylamine-type protecting group, amide-type protecting group, etc. Imine-type protecting groups, etc., specifically, Fmoc group, Boc group, Alloc group, Cbz group, Teoc group, trifluoroacetyl group, pentafluoropropionyl group, phthaloyl group, benzenesulfonyl group, p- Tosyl, 2-nitrobenzenesulfonyl (Nosyl), dinitro 2-nitrobenzenesulfonyl, t-Bu, trityl, group, benzylidene, 4-methoxybenzylidene, diphenylmethylene, etc.

[0078] The "protecting group of a carboxyl group" in the present specification includes an alkyl ester-type protecting group, a benzyl ester-type protecting group, a substituted alkyl ester-type protecting group, and the like. As a carboxyl protecting group, specifically, a methyl group, an ethyl group, a t-Bu group, a benzyl group, a trityl group, methoxytrityl, 2-(trimethylsilyl)ethyl, 2,2,2-trichloroethyl, allyl, etc.

[0079] The "protecting group of hydroxyl group" in this specification includes an alkyl ether type protecting group, an aralkyl ether type protecting group, a silyl ether type, a carbonate type protecting group, and the like. As the protecting group of hydroxyl group, specifically, methoxymethyl group, benzyloxymethyl group, tetrahydropyranyl group, tert-butyl group, allyl group, 2,2,2-trichloroethyl group, Benzyl, 4-methoxybenzyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, Methoxycarbonyl, 9-fenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl and the like.

[0080] The term "can be substituted" in this specification means that a group can be replaced by any substituting group.

[0081] The term "may be protected" in this specification means that a group can be protected by any protecting group.

[0082] The term "one or plural" in this specification means one or two or more numbers. "One or a plurality of" is used in the case of an article related to a substituting base of a base, and this term means the number from one to the maximum number of substituting bases allowed by the base. Specific examples of "one or more" include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and / or larger numbers.

[0083] The compounds of the present invention may be their salts, preferably their chemically or pharmaceutically acceptable salts. In addition, the compound of the present invention or its salt may be a solvate thereof, preferably a chemically or pharmaceutically acceptable solvate thereof. Among the salts of the compounds of the present invention, for example, include hydrochloride; hydrobromide; hydroiodide; phosphate; phosphonate; sulfate; Acetate, citrate, malate, tartrate, succinate, salicylate and other carboxylate salts; or, sodium salt, potassium salt and other alkali metal salts; magnesium salt, calcium salt and other alkaline earth metal salts ; Ammonium salts such as ammonium salts, alkyl ammonium salts, dialkyl ammonium salts, trialkyl ammonium salts, tetraalkyl ammonium salts, etc. Such salts are produced, for example, by contacting the compound with an acid or base which can be used in pharmaceutical production. In the present invention, the solvate of a compound refers to a compound that forms a molecular group with a solvent, and is not particularly limited as long as it is a solvate formed with a solvent that is allowed to be ingested with the administration of medicines. . As long as the solvent is water, it is called hydrate. The solvate of the compound of the present invention is preferably a hydrate, and as such a hydrate specifically includes 1 to 10 hydrates, preferably 1 to 5 hydrates, and more preferably 1 to 3 hydrates. The solvates of the compounds of the present invention include not only solvates with individual solvents such as water, alcohols (for example, methanol, ethanol, 1-propanol, 2-propanol, etc.), dimethylformamide, etc., but also Contains solvates with various vehicles.

[0084] The "amino acid" in this specification includes natural amino acid and unnatural amino acid. "Natural amino acid" in this specification means Gly, Ala, Ser, Thr, Val, Leu, Ile, Phe, Tyr, Trp, His, Glu, Asp, Gln, Asn, Cys, Met, Lys, Arg , Pro. The unnatural amino acid is not particularly limited, but examples include β-amino acid, γ-amino acid, D-amino acid, N-substituted amino acid, α,α-disubstituted amino acid, side chain and Naturally different amino acids, hydroxycarboxylic acids, etc. As the amino acid in this specification, any stereo configuration is allowed. The choice of the side chain of the amino acid is not particularly limited, but in addition to the hydrogen atom, for example also freely selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, cycloalkyl, One or two non-adjacent methylene groups among these groups may be replaced by an oxygen atom, a carbonyl group (-CO-), or a sulfonyl group (-SO 2-). Substituting groups can be given respectively, and these substituting groups are not limited. For example, they can be independently and freely selected from any substituting groups including halogen atoms, O atoms, S atoms, N atoms, B atoms, Si atoms, or P atoms. Choose 1 or more than 2. That is, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, cycloalkyl, etc. which may be substituted are exemplified. In a non-limiting aspect, the amino acid in this specification may be a compound having a carboxyl group and an amine group in the same molecule (even in this case, proline, imino acid such as hydroxyproline) are also included in amino acids).

[0085] The "side chain of an amino acid" in this specification means, in the case of an α-amino acid, an atomic group bonded to the carbon (α-carbon) to which an amino group and a carboxyl group are bonded. For example, the methyl group of Ala is the side chain of the amino acid. In the case of β-amino acid, the atomic group bonded to α-carbon and / or β-carbon becomes the side chain of the amino acid; in the case of γ-amino acid, bonded to α-carbon, β-carbon, and / or Or the atomic group of γ-carbon can become the side chain of amino acid.

[0086] The "main chain of amino acid" in this specification means that in the case of α-amino acid, it is a chain part composed of amine group, α-carbon, and carboxyl group, and in the case of β-amino acid, it is a chain part composed of amine group. In the case of γ-amino acid, it is a chain composed of amino group, γ-carbon, β-carbon, α-carbon, and carboxyl group. shaped part.

[0087] "The main chain of the peptide", "the main chain of the peptide compound" and "the main chain of the cyclic peptide compound" in this specification mean that the above-mentioned "main chains of amino acids" are pluralized by amide bonds. connections, and the structure formed by them.

[0088] The main chain amino group of the amino acid can be non-substituted (NH 2 group) or substituted (that is, -NHR group: R represents an alkyl, alkenyl, alkynyl, aryl, hetero Aryl, aralkyl, cycloalkyl, among these groups, one or two methylene groups that are not adjacent to each other can be replaced by oxygen atom, carbonyl (-CO-), or sulfonyl (-SO 2-) , Also, the carbon chain bonded to the N atom like proline and the carbon atom at the α position can form a ring). The substituents for the aforementioned R are selected in the same manner as the substituents in the side chains of the aforementioned amino acids. The aforementioned R in the case where the main chain amino group is substituted is included in the "side chain of amino acid" in this specification. In this specification, the amino acid whose main chain amino group is substituted is called "N-substituted amino acid". As the "N-substituted amino acid" in this specification, preferable examples are N-alkyl amino acid, N-C 1-C 6 alkyl amino acid, N-C 1-C 4 alkyl amino acid, N- Methyl amino acids, but not limited thereto. In addition, proline is excluded from non-natural N-substituted amino acid residues because it is a natural amino acid.

[0089] The "amino acid" constituting the peptide compound in this specification includes all isotopes corresponding to each. The isotope of an "amino acid" is one in which at least one atom is replaced by an atom with the same atomic number (number of protons) and a different mass number (the sum of the number of protons and neutrons) in a ratio different from that found in nature. Examples of isotopes contained in the "amino acids" constituting the peptide compound of the present invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, chlorine atoms, etc., respectively containing 2H , 3H, 13C, 14C, 15N, 17O, 18O, 31P, 32P, 35S, 18F, 36Cl, etc.

[0090] As a substituting group containing a halogen atom in this specification, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, etc. which have a halogen in a substituent group are illustrated, More specifically, a Fluoroalkyl, difluoroalkyl, trifluoroalkyl, etc.

[0091] Examples of substituents containing O atoms include hydroxyl (-OH), oxy (-OR), carbonyl (-C=O-R), carboxyl (-CO2H), oxycarbonyl (-C=O-OR), Carbonyloxy (-O-C=O-R), thiocarbonyl (-C=O-SR), carbonylthio (-S-C=O-R), aminocarbonyl (-C=O-NHR), carbonylamino (-NH -C=O-R), oxycarbonylamino group (-NH-C=O-OR), sulfonylamino group (-NH-SO 2-R), aminosulfonyl group (-SO 2-NHR), Aminosulfonylamino group (-NH-SO 2-NHR), thiocarboxy group (-C(=O)-SH), carboxyl carbonyl group (-C(=O)-CO 2H) and other groups.

[0092] Examples of the oxy group (—OR) include alkoxy, cycloalkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, aralkyloxy, and the like. The alkoxy group is preferably a C 1-C 4 alkoxy group and a C 1-C 2 alkoxy group, among which methoxy group or ethoxy group is preferable.

[0093] Examples of carbonyl (-C=O-R) include formyl (-C=O-H), alkylcarbonyl, cycloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aromatic Alkylcarbonyl, etc.

[0094] Examples of oxycarbonyl (-C=O-OR) include alkyloxycarbonyl, cycloalkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, oxycarbonyl, aralkyloxycarbonyl, etc.

[0095] Examples of carbonyloxy (-O-C=O-R) include alkylcarbonyloxy, cycloalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyl Oxygen, aralkylcarbonyloxy, etc.

[0096] Examples of thiocarbonyl (-C=O-SR) include alkylthiocarbonyl, cycloalkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, thiocarbonyl, aralkylthiocarbonyl, etc.

[0097] Examples of carbonylthio (-S-C=O-R) include alkylcarbonylthio, cycloalkylcarbonylthio, alkenylcarbonylthio, alkynylcarbonylthio, arylcarbonylthio, heteroarylcarbonyl Thio, aralkylcarbonylthio, etc.

[0098] Examples of aminocarbonyl (-C=O-NHR) include alkylaminocarbonyl (for example, C 1-C 6 or C 1-C 4 alkylaminocarbonyl, wherein ethylaminocarbonyl, ethylaminocarbonyl, methylaminocarbonyl, etc.), cycloalkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, etc. In addition to these, the H atom bonded to the N atom in -C=O-NHR can be further replaced by an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, or an aralkyl group. base.

[0099] Examples of carbonylamino groups (-NH-C=O-R) include alkylcarbonylamino groups, cycloalkylcarbonylamino groups, alkenylcarbonylamino groups, alkynylcarbonylamino groups, arylcarbonylamino groups, heteroarylcarbonylamino groups, Cylcarbonylamino, aralkylcarbonylamino, etc. In addition to these, the H atom bonded to the N atom in -NH-C=O-R is further replaced by an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, or an aralkyl group. base.

[0100] Examples of oxycarbonylamine (-NH-C=O-OR) include alkoxycarbonyl (alkoxycarbonyl) amine, cycloalkoxycarbonylamine, alkenyloxycarbonylamine, alkynyloxycarbonyl Amino group, aryloxycarbonylamine group, heteroaryloxycarbonylamine group, aralkyloxycarbonylamine group, etc. In addition to these, the H atom combined with the N atom in -NH-C=O-OR can be further replaced by an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, or an aralkyl group. The basis of substitution.

[0101] Examples of sulfonylamino groups (-NH-SO 2 -R) include alkylsulfonylamino groups, cycloalkylsulfonylamino groups, alkenylsulfonylamino groups, and alkynylsulfonylamino groups. Amino group, arylsulfonylamine group, heteroarylsulfonylamine group, aralkylsulfonylamine group, etc. In addition to these, the H atom bonded to the N atom in -NH-SO2-R is further replaced by an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, or an aralkyl group foundation.

[0102] Examples of the aminosulfonyl group (-SO2-NHR) include alkylaminosulfonyl, cycloalkylaminosulfonyl, alkenylaminosulfonyl, and alkynylaminosulfonyl groups. , arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, etc. In addition to these, groups in which the H atom bonded to the N atom in -SO2-NHR is further replaced by an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, or an aralkyl group .

[0103] Examples of the sulfamoylamine group (-NH-SO 2 -NHR) include alkylsulfamoylamine groups, cycloalkylsulfamoylamine groups, alkenylsulfamoylamine groups, alkyne Aminosulfamoylamine, arylsulfamoylamine, heteroarylsulfamoylamine, aralkylsulfamoylamine, etc. Furthermore, the two H atoms bonded to the N atom in -NH-SO2-NHR can be independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl The substituents of the formed group are substituted, and these two substituents can form a ring.

[0104] As a substituting group containing an S atom, thiol (-SH), thiol (-S-R), sulfinyl (-S=O-R), sulfonyl (-SO 2 -R), sulfonic acid ( -SO 3 H) and other bases.

[0105] As an example of thio group (-S-R), it is selected from alkylthio, cycloalkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, aralkylthio Waiting.

[0106] Examples of the sulfonyl group (-SO 2 -R) include alkylsulfonyl, cycloalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heteroaryl Sulfonyl, aralkylsulfonyl, etc.

[0107] As the substituting group including N atom, azide (-N 3 , also known as "azido group"), cyano group (-CN), primary amine group (-NH 2 ), secondary amine group (- NH -R; also known as single-replacement amino group), tertiary amino group (-NR(R'); also known as two-replacement amino group), formamidine group (-C(=NH)-NH 2), replacement Formamidino (-C(=NR)-NR'R"), Guanidino (-NH-C(=NH)-NH 2), Substituted Guanidino (-NR-C(=NR''')-NR 'R"), aminocarbonylamino (-NR-CO-NR'R"), pyridyl, piperidyl, N-alphalinyl, acridyl and other groups.

[0108] Examples of secondary amino groups (-NH-R; single-substituted amino groups) include alkylamine groups, cycloalkylamine groups, alkenylamine groups, alkynylamine groups, arylamine groups, heteroarylamino groups, and Amino groups, aralkylamino groups, etc.

[0109] Examples of tertiary amino groups (-NR(R'); disubstituted amino groups) include, for example, amino groups independently selected from alkyl (aralkyl) amino groups, alkyl groups, cycloalkyl groups, alkenyl groups, Amino group of any two substituents of alkynyl, aryl, heteroaryl, aralkyl, etc., and these arbitrary two substituents may form a ring. Specifically, among the dialkylamine groups, C 1-C 6 dialkylamine groups, C 1-C 4 dialkylamine groups, dimethylamine groups, diethylamine groups, and the like are exemplified. The so-called "C p-C q dialkylamine group" in this specification refers to the group that replaces two C p-C q alkyl groups in the amine group, and the two C p-C q alkyl groups may be the same or different.

[0110] As an example of substituting formamidine group (-C(=NR)-NR'R"), three substituting groups R, R', and R" on the N atom are independently selected from alkyl, cycloalkyl, etc. , alkenyl, alkynyl, aryl, heteroaryl, aralkyl, such as alkyl (aralkyl) (aryl) carboxamidinyl, etc.

[0111] As an example of a substituted guanidine group (-NR-C(=NR''')-NR'R"), R, R', R", and R''' are independently selected from alkyl, cycloalkane group, alkenyl group, alkynyl group, aryl group, heteroaryl group, aralkyl group, or such groups that form a ring, etc.

[0112] As an example of an aminocarbonylamino group (-NR-CO-NR'R"), R, R', and R" are independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, and an alkynyl group. , aryl, heteroaryl, aralkyl, or such groups that form a ring, etc.

[0113] In this specification, the "amino acid residue" constituting the peptide compound is sometimes simply referred to as "amino acid".

[0114] The so-called "linear peptide compound" in this specification refers to natural amino acids and / or unnatural amino acids linked by amide bonds or ester bonds, as long as they do not have a ring The compound of the shape part is not particularly limited. The total number of natural amino acids and unnatural amino acids constituting the linear peptide compound can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 , 15, 20, 25, 30, the preferred range is 6~20, 7~19, 7~18, 7~17, 7~16, 7~15, 8~14, 9~13.

[0115] The so-called "cyclic peptide compound" in this specification refers to natural amino acids and / or unnatural amino acids linked by amide bonds or ester bonds, as long as they have a ring part Compounds are not particularly limited. The total number of natural amino acids and non-natural amino acids constituting the cyclic peptide compound can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, the preferred range is 6~20, 7~19, 7~18, 7~17, 7~16, 7~15, 8~14, 9 ~13.

[0116] In this specification, the "cyclic portion" of a peptide compound means a cyclic portion formed by linking two or more amino acid residues. In addition, in this specification, the "linear part" used when referring to the partial structure of the cyclic peptide compound refers to a part not included in the main chain structure of the cyclic part, and has at least one amide in the chain of the part. bonds and / or ester bonds.

[0117] The number of amino acids constituting the cyclic portion of the cyclic peptide compound in this specification is not limited, but examples include 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 30 or less, 20 or less, 18 or less, 16 or less, 15 or less, 14 or less, 13 or less, 12 or less, 11 or less, 7, 8, 9, 10, 11, 12 , 13, 14, 15, and 16. If both membrane penetration and metabolic stability are taken into consideration, the number of amino acids forming the ring part is preferably 2-30, 2-15, or 5-15, more preferably 5-14, 7-14 , or 8~14, more preferably 8~13, 9~13, 8~12, 8~11, or 9~12, especially preferably 9~11.

[0118] In one aspect, the number of amino acids in the linear portion (the number of units) is preferably 0-8, more preferably 0-5, and even more preferably 0-3. In addition, in a non-limiting aspect, the "linear part" in this specification may include natural amino acids or unnatural amino acids (including amino acids that have undergone chemical modification, skeleton transformation, etc.) .

[0119] In one aspect, the molecular weight of the cyclic peptide compound in this specification may be 500-2000.

[0120] The "peptide compound" in this specification may include its pharmaceutically acceptable salts, or such solvates.

[0121] The term "side chain" in this specification refers to a side chain of an amino acid, or a side chain of a cyclic portion of a cyclic peptide compound, etc., which are used in articles and are not included in the respective main chain structures.

[0122] The so-called "number of amino acids" in this specification refers to the number of amino acid residues (amino acid units) constituting the peptide compound, which means the number of amide bonds, ester bonds, and the number of amino acid units produced when the cyclization part is combined.

[0123] The so-called "elongation reaction" in this specification refers to a reaction in which amino acids or peptides are extended on amino acids or peptides. The elongation can be performed by solid-phase synthesis of amino acids or peptides supported on a resin for solid-phase synthesis, and by liquid-phase synthesis without using a resin for solid-phase synthesis.

[0124] The term "supporting on a resin for solid-phase synthesis" in this specification means that an amino acid or a peptide is bound to a resin for solid-phase synthesis to which no amino acid or peptide is bound.

[0125] In this specification, the term "and / or" includes all appropriate combinations of "and" and "or". Specifically, for example, "A, B, and / or C" includes the following seven variations: (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C, (vii) A, B and C.

[0126] (preparation method) In one aspect, the present invention relates to a method for preparing a peptide compound containing at least one N-substituted amino acid residue, a salt thereof, or a solvate thereof by a solid-phase method, The method is characterized in that the peptide is loaded on the resin for solid phase synthesis before the initial elongation reaction in the solid phase method. Also, in one aspect, the present invention relates to the preparation of a solvate of a peptide compound containing at least one N-substituted amino acid residue, its salt, or the like by a solid-phase method The method, the aforementioned method includes the step of loading the peptide on the resin for solid-phase synthesis.

[0127] That is, in the present invention, a peptide such as an oligopeptide prepared in advance by a liquid phase method is loaded on a resin for solid phase synthesis, and the peptide chain is extended in a solid phase method for the peptide, whereby Synthesis of peptide compounds with desired amino acid sequences. In this specification, the peptide supported on the resin for solid-phase synthesis prior to the initial elongation reaction in the solid-phase method may be referred to as "starting peptide".

[0128] The initial elongation reaction in this specification is preferably an amino acid elongation on the starting peptide.

[0129] Conventionally, the production of peptide compounds using the solid-phase method was carried out by sequentially elongating the amino acids after loading the amino acids on a resin for solid-phase synthesis. However, in this method, for making the next amino acid (the amino acid residue of the second residue) on the amino acid (the amino acid residue of the first residue) supported on the resin for solid phase synthesis In the condensation step of the elongation of the acid residue), there is a case where the amino acid residue of the first residue is detached from the resin for solid phase synthesis (premature cleavage). This detachment is evident when a resin for solid-phase synthesis capable of cleaving a peptide compound under mild conditions is used. In addition, before the extension of the amino acid residue of the second residue, there is a case where an excess elongation body is by-product formed on the amino acid residue of the first residue by prematurely The amino acid residue of the first residue separated from the split is extended, followed by the extension of the amino acid residue of the second residue. Furthermore, among the unnatural amino acid residues, there are elongation reactions by solid-phase methods, e.g., the extension of the amino acid residue of the first residue to the amino acid residue of the second residue In the case where the reaction is not sufficiently carried out, the amino acid residue of the second residue is not linked, and the next amino acid remains missing. This is evident where the amino acid residue of the second residue is an N-substituted amino acid residue with a bulky side chain. By using the method of the present invention, these disadvantages can be avoided, and the desired peptide compound can be produced with high yield and high purity.

[0130] In the present invention, the starting peptide can be a peptide containing any number and any kind of amino acid residues. Specific examples of such peptides include oligopeptides containing two or more amino acid residues, preferably dipeptides or tripeptides. Also, the amine group of the N-terminal amino acid residue of the starting peptide is preferably protected by a protecting group. Such starting peptides can be produced using methods known in the art such as liquid phase methods. The preparation method of the starting peptide whose N-terminus is protected is not limited, but, for example, specifically, it can be produced by the following steps: For an amino acid residue whose carboxyl group is protected, an amino acid whose amino group is protected Residue and condensing agent, carry out the extension reaction of the amino acid residue, then for the generated peptide, carry out the deprotection reaction of the N-terminal protecting group and the extension reaction of the amino acid whose amino group is protected, and repeat this process Until the desired number of residues is obtained, the deprotection reaction of the C-terminal protecting group is carried out in the final step. The amino acid residues used as raw materials for the production of the starting peptide can be obtained from commercial co-owners, or produced by known methods such as the method described in WO2018 / 225864.

[0131] In one aspect, the starting peptide can include those whose C-terminal amino acid residue (the amino acid residue of the first residue) is an unnatural amino acid residue, as an unnatural amino acid residue N-substituted amino acid residues such as N-alkyl amino acids are preferred. As N-alkyl amino acid, preferably N-C 1-C 6 alkyl amino acid, more preferably N-methyl amino acid. While not being bound by a particular theory, the amino acid residue of the first residue is an N-substituting amino acid residue compared to an N-non-substituting amino acid residue. There is a tendency to be prone to premature splitting, and this tendency is more obvious in the case of side chains with bulky groups. Therefore, the present invention is particularly useful in the manufacture of peptide compounds with such amino acid residues as C-terminal amino acid residues.

[0132] In one aspect, the amino acid residue at the C-terminus of the starting peptide (the amino acid residue of the first residue) is bonded to the carbon atom at the alpha position of the amino group, the carbon atom at the beta position, Or a carboxyl group bonded to a carbon atom at the γ position is supported on a resin for solid-phase synthesis. Asparagine acid or its derivatives are mentioned as an example of the amino acid residue supported on the resin for solid phase synthesis by the carboxyl group bonded to the carbon atom of the β position of an amino group. Specifically, the case where the carboxyl group present in the side chain of asparagine acid is supported on the resin for solid phase synthesis corresponds to the case where the carboxyl group bonded to the carbon atom at the β position of the amine group is supported on the resin for solid phase synthesis. The case of using resin. Also, examples of the amino acid residue supported on the resin for solid-phase synthesis through the carboxyl group bonded to the carbon atom at the γ-position of the amino group include glutamic acid or its derivatives. Specifically, the case where the carboxyl group present in the side chain of glutamic acid is supported on the resin for solid phase synthesis corresponds to the case where the carboxyl group bonded to the carbon atom at the γ position of the amino group is supported on the resin for solid phase synthesis. The case of resin. Other natural amino acid residues or their N-substituted amino acid residues are usually supported on the resin for solid-phase synthesis through the carboxyl group bonded to the carbon atom at the α position.

[0133] In one aspect, the amino acid residue at the C-terminus of the starting peptide (the amino acid residue of the first residue) can be asparagine, 2-aminobutyric acid, glycine, Alanine, valine, proline, tyrosine, or 2-aminoisobutyric acid, or their N-substitutions and / or derivatives. In cases where the amino acid residue of the first residue is such an amino acid residue, premature cleavage is prone to occur. As the N-substituted form of such amino acid residues, preferably an N-alkyl form, more preferably an N-methyl form. Examples of derivatives of these amino acid residues include any functional group (for example, amino group, carboxyl group, hydroxyl group, etc. ) protected by any substituent (eg, protecting group). In particular, as a derivative of asparagine, specifically, a resin for solid-phase synthesis and a free carboxyl group bonded to an amino acid residue of the second residue are exemplified by amino carbonylation. Specific examples of asparagine that undergoes aminocarbonylation include asparagine that undergoes dialkylaminocarbonylation such as dimethylaminocarbonyl, and saturated heterocyclic rings containing N atoms ( For example, asparagine acid carbonylated with an amino group between the N atoms of the azetidine ring, thioline ring, pyrrolidine ring, piperidine ring, nitrogen thiol ring, etc., such asparagine acid can also be It is an N-substitution body such as an N-alkyl body. When the amino acid residue of the first residue is asparagine or its N-substitution and / or derivatives, the amino acid residue is preferably separated by the carboxyl group at the β position of the amino group. Loaded on resin for solid phase synthesis. In addition, as an amino acid residue in which an arbitrary functional group (for example, an amino group, a carboxyl group, a hydroxyl group, etc.) is protected by an arbitrary protecting group, the amino group of the side chain of the amino acid residue is exemplified by a Boc group or a Cbz group. An isocarbamate-type protecting group protector, specifically, for example, one in which the amine group of the side chain of Lys is protected by a Boc group. In addition, the amide group of the side chain of the amino acid residue is protected by an alkylamine-type protecting group such as t-Bu group or Trt group, specifically, for example, the amide group of the side chain of Asn, Gln, etc. Group protected by Trt group, amino acid residue side chain hydroxyl group protected by alkyl ether type protection group such as t-Bu group, etc., specifically, for example, Ser side chain hydroxyl group, Thr side chain The hydroxyl group of the chain, the hydroxyl group of the side chain of Tyr, etc. are protected by the t-Bu group, etc.

[0134] In one aspect, the starting peptide can be exemplified as one in which the amino acid residue adjacent to its C-terminal amino acid residue (the amino acid of the second residue) is a non-natural amino acid residue. As the unnatural amino acid residue, it is preferably an N-substituted amino acid residue such as N-alkyl amino acid and / or an amino acid derivative, and as an N-substituted amino acid residue, it is preferably N-methyl body. As derivatives of amino acid residues, any functional group (for example, amine group, carboxyl group, hydroxyl group, etc.) irrespective of the combination with the adjacent amino acid residue can be replaced by any substituting group (for example, protecting group). )protector. Specifically, the amine group of the side chain of an exemplary amino acid residue is protected by a carbamate-type protecting group such as Boc group or Cbz group. More specifically, for example, the amine group of the side chain of Lys is protected by Boc base protector. In addition, the amide group of the side chain of the amino acid residue is protected by an alkylamine-type protecting group such as a t-Bu group or a Trt group. Specifically, for example, an amide group of a side chain such as Asn or Gln The amino group is protected by a Trt group, and the hydroxyl group of the side chain of an amino acid residue is protected by an alkyl ether-type protecting group such as a t-Bu group. Specifically, for example, the hydroxyl group of the side chain of Ser, the hydroxyl group of Thr The hydroxyl group of the side chain, the hydroxyl group of the side chain of Tyr, etc. are protected by the t-Bu group, etc. While not being bound by a particular theory, where the amino acid of the second residue is an N-substituted amino acid residue, compared to an N-non-substituted amino acid residue, There is a tendency for premature cleavage to occur, especially where the side chains have bulky groups. Therefore, the present invention is particularly useful in the manufacture of peptide compounds in which the amino acid residue is accompanied by the second residue.

[0135] In one aspect, the amino acid residue at the C-terminus of the starting peptide (the amino acid residue of the first residue) and the amino acid residue adjacent to the amino acid residue at the C-terminus (the amino acid residue of the first residue) The amino acids of the two residues) can both be natural amino acid residues, but preferably one or both of them are non-natural amino acid residues.

[0136] In one aspect, the C-terminal amino acid residue of the starting peptide (the amino acid residue of the first residue), and / or the amino acid adjacent to the C-terminal amino acid residue residue (the amino acid residue of the second residue) has a bulky side chain. For example, as a natural amino acid having a bulky side chain, amino acids having a side chain having 2 or more carbon atoms are exemplified, such as Met, Phe, Tyr, Val, Leu, Ile, Trp, Arg, His, Glu, Lys, Gln, Asp, Asn, Cys, Thr, etc. Also, when the side chain has a bulky protecting group, it can also be an amino acid residue having a bulky side chain. For example, although Ser itself does not have a bulky side chain, Ser (tBu) whose side chain is protected by tBu corresponds to an amino acid residue with a bulky side chain. Also, whether natural or unnatural, an amino acid residue having a branched chain alkyl group that can be replaced in the side chain of the amino acid residue can be an amino acid residue having a bulky side chain. Such a branched chain alkyl group is preferably bonded to the carbon atom at the α position of the carboxyl group of the amino acid residue, and the branching position of the branched chain alkyl group is preferably the carbon atom at the β position or the carbon atom at the γ position of the carboxyl group. For example, Val is an example of an amino acid residue in which the carbon atom at the α-position of the carboxyl group of an amino acid residue has a branched chain alkyl group, and the carbon atom at its β-position has a branched amino acid residue. Val-like amino acids The residue can be an amino acid residue with a bulky side chain. Also, Leu is an example of an amino acid residue with a branched chain alkyl group at the carbon atom at the α-position of the carboxyl group of an amino acid, and a branched amino acid residue at the carbon atom at its γ-position. The Leu-like amino acid can be Amino acid residues with bulky side chains. The number and types of substituting groups that the branched chain alkyl group can have are not particularly limited, but the branched chain alkyl group can have a group independently selected from alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, Alkoxy, alkenyloxy, cycloalkoxy, aryloxy, amino, aminocarbonyl, alkenyloxycarbonyl, alkylsulfonyl, hydroxyl, halogen, cyano, carboxyl, alkenyloxy 1 to 5 substituents of the group consisting of ylcarbonyl, aralkoxy, heteroarylalkoxy, alkoxyalkenyl, aminocarbonylalkenyl, and haloalkoxy. While not being bound by a particular theory, in the case where the amino acid residue of the first residue and / or the amino acid residue of the second residue has a bulky side chain, due to the tendency for excessive Early cleavage, so the present invention is particularly useful for the manufacture of peptide compounds containing such amino acids.

[0137] In one aspect, the amino acid residue at the C-terminal of the starting peptide (the amino acid residue of the first residue) can be represented by the following formula (A).

[0138] In formula (A), L 1 is a single bond or -CHM 1-, -CH 2CHM 1-, -CHM 1CH 2-, -(CH 2) nS(CH 2) m-, -(CH 2) nS(O )(CH 2) m-, or -(CH 2) nS(O) 2(CH 2) m-, here, n and m are 1 or 2 independently.

[0139] When L 1 is -(CH 2 ) nS(CH 2 ) m-, as -(CH 2 ) nS(CH 2 ) m-, specific examples include -CH 2 SCH 2-, -CH 2CH 2SCH 2-, -CH 2SCH 2CH 2-, -CH 2CH 2SCH 2CH 2-, etc.

[0140] When L1 is -(CH2)nS(O)(CH2)m-, as -(CH2)nS(O)(CH2)m-, specifically, -CH2S( O)CH 2-, -CH 2CH 2S(O)CH 2-, -CH 2S(O)CH 2CH 2-, -CH 2CH 2S(O)CH 2CH 2-, etc.

[0141] When L 1 is -(CH 2 ) nS(O) 2(CH 2 ) m-, as -(CH 2 ) nS(O) 2(CH 2 ) m-, specific examples include -CH 2S(O) 2CH 2-, -CH 2CH 2S(O) 2CH 2-, -CH 2S(O) 2CH 2CH 2-, -CH 2CH 2S(O) 2CH 2CH 2-, etc.

[0142] In formula (A), R 1 is hydrogen, C 1-C 6 alkyl, C 2-C 6 alkenyl, C 2-C 6 alkynyl, C 1-C 6 alkoxy C 1-C 6 alkyl , C 7-C 14 aralkyl, or aminocarbonyl (the amino group is -NH 2 , mono-C 1-C 6 alkylamino, di-C 1-C 6 alkylamino, or 4-8 members Cyclic amino group), each of which can be independently selected from halogen, side oxygen group, hydroxyl group, C 1-C 6 alkyl group, 4-7 membered heterocyclic group, aminocarbonyl group (the amino group is -NH 2 , mono C 1-C 6 alkylamine group, diC 1-C 6 alkylamine group, or 4~8 membered cyclic amino group), C 1-C 6 alkylsulfonyl group, and C 1-C 6 alkane One or more radicals of the group consisting of oxy C 1-C 6 alkyl groups are substituted, or R 1 is a peptide chain containing 1 to 4 amino acid residues. R1 is the case of a peptide chain comprising 1 to 4 amino acid residues, the 1 to 4 amino acid residues constituting the peptide chain can be natural amino acid residues or unnatural amines amino acid residues, and may be the same or different.

[0143] When L is a single bond, R is preferably hydrogen, C 1-C 6 alkyl, C 1-C 6 alkoxy C 1-C 6 alkyl that can be substituted by hydroxyl, or can be replaced by 1 or C 7-C 14 aralkyl substituted by multiple halogens or C 1-C 6 alkoxy C 1-C 6 alkyl.

[0144] When L 1 is a single bond, R 1 is more preferably hydrogen, methyl, isopropyl, C 1-C 6 alkoxy C 1-C 2 alkyl that may be substituted by hydroxy, or C 1-C 2 alkyl that may be substituted by fluorine or t - benzyl substituted with butoxy, specifically, hydrogen, (2-hydroxy-2-methyl-propyloxy)methyl, benzyl, 3-fluorobenzyl, 4-fluorobenzyl base.

[0145] When L 1 is -CHM 1-, -CH 2CHM 1-, or -CHM 1CH 2-, R 1 is preferably hydrogen, C 1-C 6 alkyl, halogen C 1-C 6 alkyl, C 2- C 6 alkenyl, C 2-C 6 alkynyl, C 1-C 6 alkoxy C 1-C 6 alkyl (the C 1-C 6 alkoxy C 1-C 6 alkyl can be hydroxy, or Aminocarbonyl (the amino group is -NH 2 , single C 1-C 6 alkylamine, di-C 1-C 6 alkylamine, or 4-8 membered cyclic amino) replacement), can be replaced by 1 C 7-C 14 aralkyl, or aminocarbonyl (the amino group is -NH 2 , mono-C 1-C 6 alkylamino, di-C 1-C 6 alkylamino) replaced by one or more halogens , or a 4-8 membered cyclic amine group, the cyclic amine group can be replaced by 1 or multiple halogens, 1 or multiple side oxygen groups, 1 or multiple C 1-C 6 alkyl groups, or 4~ 7-membered heterocyclyl for further substitution).

[0146] When L 1 is -CHM 1-, -CH 2CHM 1-, or -CHM 1CH 2-, R 1 is more preferably hydrogen, C 1-C 6 alkyl, C 1-C 6 fluoroalkyl, C 2-C 3 alkenyl, C 2-C 3 alkynyl, C 1-C 6 alkoxy C 1-C 2 alkyl that can be replaced by a single C 1-C 4 alkylaminocarbonyl, dimethylamino Carbonyl; one or more fluorine, C 1-C 4 alkyl, or a 4-8 membered cyclic aminocarbonyl group that can be replaced by a 4-7 membered heterocyclic group; benzyl, phenethyl.

[0147] When L 1 is -CHM 1-, -CH 2CHM 1-, or -CHM 1CH 2-, specific examples of R 1 include hydrogen, methyl, isobutyl, trifluoromethyl, and allyl , prop-2-iso-1-yl, (isoamyloxy)methyl, {2-(t-butylamino)-2-oxoethoxy}methyl, dimethylamino Carbonyl, acridylcarbonyl, pyrrolidinylcarbonyl, 3,3-dimethylpyrrolidinylcarbonyl, 3,3,4,4-tetrafluoropyrrolidinylcarbonyl, 4-methylpiperidinylcarbonyl, 4- (t-Butyl)-piperidinylcarbonyl, 3,3,4,4,5,5-hexafluoropiperidinylcarbonyl, 3,3-difluoropiperidinylcarbonyl, 4,4-difluoropiperidinylcarbonyl ylcarbonyl, piperidinylcarbonyl, N-𠰌linylcarbonyl, oxazolidin-3-ylcarbonyl, 3-oxa-8-azabicyclo[3.2.1]octane-8-ylcarbonyl, 1,1 -dioxide thiol-olinylcarbonyl, 1-(oxetan-3-yl)-piperyl-4-ylcarbonyl, phenethyl and the like.

[0148] When L 1 is -(CH 2) nS(CH 2) m-, -(CH 2) nS(O)(CH 2) m or -(CH 2) nS(O) 2(CH 2) m, R 1 is preferably an aminocarbonyl group (the amino group is -NH 2 , a single C 1-C 6 alkylamine group, a di-C 1-C 6 alkylamine group, or a 4-8 membered cyclic amino group).

[0149] In formula (A), R 1 and P 1 can form a 4-7 membered saturated heterocyclic ring together with the carbon atom bound by R 1 and the nitrogen atom bound by P 1 .

[0150] When R 1 and P 1 form a 4-7 membered saturated heterocyclic ring, the 4-7 membered saturated heterocyclic ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperidine ring, or a phenoline ring.

[0151] In the formula (A), R 1 and Q 1 can form a 3-8 membered alicyclic ring or a 4-7 membered saturated heterocyclic ring together with these bonded carbon atoms.

[0152] When R1 and Q1 are 3-8 membered alicyclic rings or 4-7 membered saturated heterocyclic rings, the 3-8 membered alicyclic rings are preferably cyclopropane rings, cyclobutane rings, and cyclopentane rings. Ring, cyclohexane ring, as 4-7 membered saturated heterocycle, preferably tetrahydrofuran ring, tetrahydropyran ring.

[0153] In the formula (A), when L 1 is -CHM 1-, -CH 2CHM 1-, or -CHM 1CH 2-, R 1 and M 1 can be bound to the carbon atom of R 1 and the carbon to which M 1 is bound The atoms together form a 3-8 membered alicyclic ring.

[0154] When R 1 and M 1 form a 3-8 membered alicyclic ring, the 3-8 membered alicyclic ring is preferably a cyclopentane ring or a cyclohexane ring.

[0155] In formula (A), when L 1 is -CHM 1-, -CH 2CHM 1-, or -CHM 1CH 2-, excluding the case where R 1 and M 1 form a 3-8-membered alicyclic ring, M 1 is hydrogen.

[0156] In formula (A), excluding the case where R 1 and P 1 form a 4-7 membered saturated heterocyclic ring, P 1 is hydrogen or C 1-C 6 alkyl, and the C 1-C 6 alkyl can be independently selected from Halogen, hydroxyl, C 1-C 6 alkoxy, amine (the amine is -NH 2 , mono C 1-C 6 alkyl amine, di C 1-C 6 alkyl amine, or 4~8 cyclic amine groups, each of which can also be replaced by halogen), and aminocarbonyl (the amine group is -NH 2 , mono-C 1-C 6 alkylamine, di-C 1-C 6 alkylamine, or 4-8 membered cyclic amino groups) to be substituted by one or more groups.

[0157] As P 1 , preferably hydrogen, C 1-C 6 alkyl. Specific examples of such P1 include hydrogen, methyl, ethyl, n-propyl and the like.

[0158] Excluding the case where R 1 and Q 1 form a 3-8 membered alicyclic ring or a 4-7 membered saturated heterocyclic ring, Q 1 is hydrogen or C 1-C 6 alkyl, preferably hydrogen or methyl.

[0159] Preferably R 1 is -CONR 1AR 1B, where R 1A and R 1B are independently hydrogen or C 1-C 6 alkyl (preferably methyl), or R 1A and R 1B are the same The combined nitrogen atoms together form a 4-8 membered saturated heterocyclic ring. The 4-8 membered saturated heterocyclic ring can be independently selected from 1 or multiple halogens (preferably fluorine), 1 or multiple side oxygen groups, 1 or multiple C 1-C 6 alkyl groups (preferably C 1-C 4 alkyl), and 4 to 7 membered heterocyclyl (preferably oxetan-3-yl) group consisting of one or more substitutions.

[0160] In the formula (A), * represents the binding site with the resin for solid-phase synthesis, and the wavy line indicates the binding site with the adjacent amino acid residue.

[0161] When L is a single bond, the amino acid residue represented by the formula (A) specifically includes, for example, MeSer(tBuOH), MeGly, MePhe, MePhe(3-F), MePhe(4 -F), D-MePhe, MeVal, Pro, Aib, Ala, Gly, Tyr(tBu), Val.

[0162] When L 1 is -CHM 1-, the amino acid residue represented by the formula (A) specifically includes, for example, bAla, bMeAla, 2-ACHxC, 2-ACPnC, 3-CF3-bAla , Asp-mor, Asp-mor(26-bicyc), Asp-mor(SO2), Asp-NMe2, Asp-oxz, Asp-pip, Asp-pip(345-F6), Asp-pip(4-Me) , Asp-pip-tBu, Asp-piz(oxe), Asp-pyrro, Asp-pyrro(34-F4), Asp-pyrro(3-Me2), D-(Propargyl)Gly-(C#CH2), D -3-Abu, D-3-MeAbu, D-Gly(Allyl)-(C#CH2), D-Hph-(C#CH2), D-Leu-(C#CH2), D-MeAsp-pyrro, D-MeLeu-(C#CH2), D-Pic(2)-(C#CH2), D-Pro-(C#CH2), D-Ser(iPen)-(C#CH2), D-Ser( NtBu-Aca)-(C#CH2), EtAsp-pip, MeAsp-aze, MeAsp-mor, MeAsp-mor(26-bicyc), MeAsp-mor(SO2), MeAsp-NMe2, MeAsp-oxz, MeAsp-pip , MeAsp-pip(345-F6), MeAsp-pip(3-F2), MeAsp-pip(4-F2), MeAsp-pip(4-Me), MeAsp-piz(oxe), MeAsp-pyrro, MeAsp- pyrro(34-F4), MeAsp-pyrro(3-Me2), nPrAsp-pip, D-MeAsp-NMe2.

[0163] When L 1 is -CH 2CHM 1- or -CHM 1CH 2-, the amino acid residue represented by the formula (A) specifically includes, for example, Glu-mor, Glu-pip, MeGlu - pip, Glu-NMe2, or MeGlu-NMe2.

[0164] When L 1 is -(CH 2) nS(CH 2) m-, -(CH 2) nS(O)(CH 2) m or -(CH 2) nS(O) 2(CH 2) m- , As the amino acid residue represented by the formula (A), specifically, for example, MeCys(AcOH)-NMe2 can be mentioned.

[0165] In one aspect, the amino acid residue of the starting peptide adjacent to its C-terminal amino acid residue (the amino acid residue of the second residue) can be represented by the following formula (B) .

[0166] In formula (B), L 2 is a single bond or -CH 2-.

[0167] In formula (B), R 2 is hydrogen, C 1-C 6 alkyl, C 2-C 6 alkynyl, C 1-C 6 alkoxy C 1-C 6 alkyl, C 3-C 8 cycloalkane C 3-C 8 cycloalkyl C 1-C 6 alkyl, C 3-C 8 cycloalkoxy C 1-C 6 alkyl, or C 7-C 14 aralkyl, each of which can be independently Selected from halogen, hydroxyl, amino group (the amino group is -NH 2 , protected amino group, mono C 1-C 6 alkyl amino group, di C 1-C 6 alkyl amino group, or 4-8 membered cyclic Amino groups, each of which may also be replaced by halogen), aminocarbonyl (the amino group is -NH 2 , protected amino groups, mono-C 1-C 6 alkylamino groups, di-C 1-C 6 alkylamino groups, or 4-8 membered cyclic amino groups), and C 1-C 6 alkylsulfonyl groups are replaced by one or more groups.

[0168] When L 2 is a single bond, R 2 is preferably hydrogen, C 1-C 6 alkyl, halogen C 1-C 6 alkyl, hydroxy C 1-C 6 alkyl, amino C 1-C 6 Alkyl group (the amine group is -NH 2 , protected amine group, mono C 1-C 6 alkyl amine group, di C 1-C 6 alkyl amine group, or 4-8 membered cyclic amine group, each of which can be replaced by one or more halogens), aminocarbonyl C 1-C 6 alkyl (the amino group is -NH 2 , protected amino, mono C 1-C 6 alkylamino, di-C 1-C 6 Alkylamino, or 4-8 membered cyclic amino, each of which can be replaced by one or more halogens), C 1-C 6 alkylsulfonyl C 1-C 6 alkyl, C 2-C 6 alkynyl, C 1-C 6 alkoxy C 1-C 6 alkyl, C 3-C 8 cycloalkyl, C 3-C 8 cycloalkyl C 1- C 6 alkyl, C 3-C 8 cycloalkoxy, C 1-C 6 alkyl, or C 7-C 14 aralkyl.

[0169] When L 2 is a single bond, R 2 is more preferably C 1-C 6 alkyl, fluoro C 1-C 6 alkyl, hydroxy C 1-C 4 alkyl, protected amino C 1-C 4 alkane group, protected aminocarbonyl C 1-C 4 alkyl, methylsulfonyl C 1-C 2 alkyl, C 2-C 3 alkynyl, C 1-C 4 which may be replaced by one or more fluorine Alkoxy C 1-C 2 alkyl, C 3-C 6 cycloalkyl, C 3-C 6 cycloalkyl C 1-C 2 alkyl, C 3-C 6 cycloalkoxy C 1-C 2 Alkyl, benzyl, phenethyl.

[0170] When L2 is a single bond, as R2, more specifically, methyl, ethyl, n-propyl, i-propyl, 2-methylpropyl, 1-methylpropyl, n -Butyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, propargyl, 3,3-difluorobutyl, 5,5-difluoropentyl, methoxymethyl , 1-methoxyethyl, 2-methoxyethyl, n-propoxymethyl, 1-hydroxyethyl, cyclopropoxymethyl, cyclobutoxymethyl, (2,2, 2-trifluoroethoxy)methyl, 2-methylsulfonylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl group, cyclohexylmethyl group, benzyl group, phenethyl group, 4-(t-butoxycarbonylamino)butyl group, tritylaminocarbonylmethyl group, t-butoxymethyl group, etc.

[0171] When L 2 is -CH 2-, R 2 is preferably C 1-C 6 alkyl, more preferably methyl.

[0172] In formula (B), R 2 and P 2 can form a 4-7 membered saturated heterocyclic ring together with the carbon atom bound by R 2 and the nitrogen atom bound by P 2 .

[0173] When R 2 and P 2 form a 4-7 membered saturated heterocyclic ring, the 4-7 membered saturated heterocyclic ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperidine ring, or a phenoline ring.

[0174] In the formula (B), R 2 and Q 2 can form a 3-8 membered alicyclic ring or a 4-7 membered saturated heterocyclic ring together with these bonded carbon atoms.

[0175] When R 2 and Q 2 form a 3-8 membered alicyclic ring or a 4-7 membered saturated heterocyclic ring, the 3-8 membered alicyclic ring is preferably cyclopropane ring, cyclobutane ring, or cyclopentane Ring, cyclohexane ring, as 4-7 membered saturated heterocycle, preferably tetrahydrofuran ring, tetrahydropyran ring.

[0176] In formula (B), excluding the case where R 2 and P 2 form a 4-7 membered saturated heterocycle, P 2 is hydrogen or C 1-C 6 alkyl, and the C 1-C 6 alkyl can be independently selected from halogen , hydroxyl, C 1-C 6 alkoxy, amine group (the amine group is -NH 2 , single C 1-C 6 alkylamine group, di-C 1-C 6 alkylamine group, or 4~8 members Cyclic amino groups, each of which may also be replaced by halogen), and aminocarbonyl (the amino group is -NH 2 , mono-C 1-C 6 alkylamino, di-C 1-C 6 alkylamino, or 4 to 8 membered cyclic amino groups) are replaced by one or more groups of the group. P 2 is preferably hydrogen or a C 1-C 2 alkyl group, and specifically, hydrogen and methyl are exemplified.

[0177] Excluding the case where R 2 and Q 2 form a 3-8 membered alicyclic ring or a 4-7 membered saturated heterocyclic ring, Q 2 is hydrogen or C 1-C 6 alkyl, preferably hydrogen or methyl.

[0178] *Indicates the binding site to the amino acid residue at the C-terminal, The wavy line indicates the binding site to the adjacent amino acid residue or the protecting group of the amine group.

[0179] As the amino acid residue represented by the formula (B), specifically, for example, MeAla, MeLeu, MeCha, MeVal, MeAla(cPent), MeAla(cBu), MeAla(cPr), MeChg, MeGly( cPent), MeGly(cBu), MeGly(cPr), MeAbu, MeNva, MeNle, Val, Leu, MeNva(5-F2), MeHle, MeIle, MeSer(nPr), MeSer(cPr), MeHnl, MeHnl(7- F2), MePRA, MeSer(Me), MeThr, MeSer(cBu), MeSer(Tfe), MeThr(Me), MeHse(Me), MeMet(O2), Ile, Nle, Chg, Ala(cBu), Gly( cPent), Hle, Nva, Phe, Hph, Gly, Aib, Lys(Boc), Ala, D-MeVal, Asn(Trt), Ser(tBu), bAla(2-Me2).

[0180] In one aspect, the peptide supported on the resin for solid phase synthesis before the initial elongation reaction in the solid phase method can be a dipeptide represented by the following formula (1). (where, L 1 is a single bond or -CHM 1-, -CH 2CHM 1-, -CHM 1CH 2-, -(CH 2) nS(CH 2) m-, -(CH 2) nS(O)(CH 2) m -, or-(CH 2 ) nS(O) 2(CH 2 ) m-, here, n and m are each independently and 1 or 2, R 1 is hydrogen, C 1-C 6 alkyl, C 2-C 6 alkenyl, C 2-C 6 alkynyl, C 1-C 6 alkoxy C 1-C 6 alkyl, C 7-C 14 Aralkyl group, or aminocarbonyl group (the amino group is -NH 2 , mono C 1-C 6 alkyl amino group, di C 1-C 6 alkyl amino group, or 4-8 membered cyclic amino group), Each of them can be independently selected from halogen, side oxygen group, hydroxyl group, C 1-C 6 alkyl group, 4-7 membered heterocyclic group, aminocarbonyl group (the amino group is -NH 2 , mono-C 1-C 6 alkane Substituted by one or more of the group consisting of amino group, diC 1-C 6 alkyl amino group, or 4-8 membered cyclic amino group) and C 1-C 6 alkyl sulfonyl group , or R 1 is a peptide chain containing 1 to 4 amino acid residues, or R 1 and P 1 form a 4-7 membered saturated heterocyclic ring together with the carbon atom bound by R 1 and the nitrogen atom bound by P 1 , or R 1 and Q 1 form a 3-8 membered alicyclic ring or a 4-7 membered saturated heterocyclic ring together with the carbon atoms bound to them, or R 1 and M 1 form a 3-8 membered alicyclic ring together with the carbon atom bound by R 1 and the carbon atom bound by M 1, Excluding the case where R 1 and P 1 form a 4-7 membered saturated heterocyclic ring, P 1 is hydrogen or C 1-C 6 alkyl, and the C 1-C 6 alkyl can be independently selected from halogen, hydroxyl, C 1- C 6 alkoxy group, amine group (the amine group is -NH 2 , mono C 1-C 6 alkyl amine group, di C 1-C 6 alkyl amine group, or 4-8 membered cyclic amine group, its Each can also be replaced by halogen), and aminocarbonyl (the amino group is -NH 2 , mono-C 1-C 6 alkylamine, di-C 1-C 6 alkylamine, or 4-8 membered cyclic Amino group) replaced by one or more groups of the group, Excluding the case where R 1 and Q 1 form a 3-8 membered alicyclic ring or a 4-7 membered saturated heterocyclic ring, Q 1 is hydrogen or C 1-C 6 alkyl, Excluding the case where R 1 and M 1 form a 3-8-membered alicyclic ring, M 1 is hydrogen, L 2 is a single bond or -CH 2-, R 2 is hydrogen, C 1-C 6 alkyl, C 2-C 6 alkynyl, C 1-C 6 alkoxy C 1-C 6 alkyl, C 3-C 8 cycloalkyl, C 3-C 8 cycloalkyl C 1-C 6 alkyl, C 3-C 8 cycloalkoxy C 1-C 6 alkyl, or C 7-C 14 aralkyl, each of which can be independently selected from halogen, hydroxy, Amino group (the amino group is -NH 2 , protected amino group, mono C 1-C 6 alkyl amino group, di C 1-C 6 alkyl amino group, or 4-8 membered cyclic amino group, each of which is also can be replaced by halogen), aminocarbonyl (the amino group is -NH 2 , protected amino group, mono C 1-C 6 alkyl amino group, di C 1-C 6 alkyl amino group, or 4-8 membered ring amine group), and one or more groups of C 1-C 6 alkyl sulfonyl group, or R 2 and P 2 form a 4-7 membered saturated heterocyclic ring together with the carbon atom bound by R 2 and the nitrogen atom bound by P 2 , or R 2 and Q 2 form a 3-8 membered alicyclic ring or a 4-7 membered saturated heterocyclic ring together with these bonded carbon atoms, or Excluding the case where R 2 and P 2 form a 4-7 membered saturated heterocyclic ring, P 2 is hydrogen or C 1-C 6 alkyl, and the C 1-C 6 alkyl can be independently selected from halogen, hydroxyl, C 1- C 6 alkoxy group, amine group (the amine group is -NH 2 , mono C 1-C 6 alkyl amine group, di C 1-C 6 alkyl amine group, or 4-8 membered cyclic amine group, its Each can also be replaced by halogen), and aminocarbonyl (the amino group is -NH 2 , mono-C 1-C 6 alkylamine, di-C 1-C 6 alkylamine, or 4-8 membered cyclic Amino group) replaced by one or more groups of the group, Excluding the case where R 2 and Q 2 form a 3-8 membered alicyclic ring or a 4-7 membered saturated heterocyclic ring, Q 2 is hydrogen or C 1-C 6 alkyl, *Indicates the bonding site with the resin for solid phase synthesis, PG is the protecting group of amine group, However, P 1 and P 2 are not both hydrogen. )

[0181] As the dipeptide represented by the following formula (1), a dipeptide represented by the following formula (2) is preferable. (where, R 1 is hydrogen, C 1-C 6 alkyl, halogen C 1-C 6 alkyl, C 2-C 6 alkenyl, C 2-C 6 alkynyl, C 1-C 6 alkoxy C 1-C 6 alkyl (the C 1-C 6 alkoxy C 1-C 6 alkyl can be replaced by hydroxyl, or aminocarbonyl (the amine is -NH 2 , single C 1-C 6 alkylamino, di-C 1-C 6 alkylamino group, or 4-8 membered cyclic amino group) replacement), C 7-C 14 aralkyl group that can be replaced by one or more halogens, or aminocarbonyl group (the amino group is -NH 2 , single C 1-C 6 alkylamine group, diC 1-C 6 alkylamine group, or 4-8 membered cyclic amine group, the cyclic amine group can be replaced by one or more halogens, 1 or multiple side oxygen groups, 1 or multiple C 1-C 6 alkyl groups, or 4-7 membered heterocyclic groups for further replacement), or R 1 and M 1 form a 3-8 membered alicyclic ring together with the carbon atom bound by R 1 and the carbon atom bound by M 1, or R 1 and P 1 form a 4-7 membered saturated heterocyclic ring together with the nitrogen atom bound by P 1 and the carbon atom bound by R 1, Excluding the case where R 1 and M 1 form a 3-8-membered alicyclic ring, M 1 is hydrogen, Excluding the case where R 1 and P 1 form a 4-7 membered saturated heterocyclic ring, P 1 is hydrogen or C 1-C 6 alkyl, R 2 is C 1-C 6 alkyl, halogen C 1-C 6 alkyl, hydroxy C 1-C 6 alkyl, C 1-C 6 alkylsulfonyl C 1-C 6 alkyl, C 2- C 6 alkynyl, C 1-C 6 alkoxy C 1-C 6 alkyl, C 3-C 8 cycloalkyl, C 3-C 8 cycloalkyl C 1 -C 6 alkyl, C 3-C 8 cycloalkoxy C 1-C 6 alkyl, or C 7-C 14 aralkyl, or R 2 and P 2 form a 4-7 membered saturated heterocycle together with the nitrogen atom bound by P 2 and the carbon atom bound by R 2 , Excluding the case where R 2 and P 2 form a 4-7 membered saturated heterocyclic ring, P 2 is hydrogen or C 1-C 6 alkyl, Q 2 is hydrogen, *Indicates the bonding site with the resin for solid phase synthesis, PG is the protecting group of amine group, However, P 1 and P 2 are not both hydrogen. )

[0182] In one aspect, L 1 , P 1 , Q 1 , and R 1 in formula (1) or formula (2) can be combined with L 1 , P 1 , Q 1 , and R 1 in formula (A) respectively. are the same groups, and L 2 , P 2 , Q 2 , and R 2 may be the same groups as L 2 , P 2 , Q 2 , and R 2 in the aforementioned formula (B), respectively. However, in formula (1) or formula (2), it is preferable that neither P 1 nor P 2 is hydrogen.

[0183] PG in formula (1) or formula (2) is a protecting group for an amine group.

[0184] In one aspect, when the starting peptide is a dipeptide, non-limiting specific examples of the dipeptide include, for example, Fmoc-MeVal-MeAsp-pip, Fmoc-MeIle-MeAsp-pip, Fmoc -MeGly(cPent)-MeAsp-pip, Fmoc-MeChg-MeAsp-pip, Fmoc-MeLeu-MeAsp-pip, Fmoc-MeGly(cPent)-MeAsp-NMe2, Fmoc-MeLeu-MeAsp-NMe2, Fmoc-MeVal-D -3-MeAbu-OH, Fmoc-MeChg-D-3-MeAbu-OH, Fmoc-MeVal-MeGly-OH, Fmoc-MeVal-Asp-NMe2, Fmoc-Gly-MeAsp-NMe2, Fmoc-Aib-MeAsp-NMe2 , Fmoc-D-MeVal-MeAsp-NMe2, Fmoc-MeVal-D-MeAsp-NMe2, Fmoc-bAla(2-Me2)-MeAsp-NMe2, Fmoc-bAla(2-Me2)-D-3-MeAbu-OH , Fmoc-MeLeu-MeVal-OH, Fmoc-MeVal-Pro-OH, Fmoc-Phe-Pro-OH, Fmoc-Lys(Boc)-Pro-OH, Fmoc-MeLeu-Aib-OH, Fmoc-MeVal-Gly- OH, Fmoc-Ala-Ala-OH, Fmoc-Gly-Tyr(tBu)-OH, Fmoc-Phe-Gly-OH, Fmoc-Asn(Trt)-Gly-OH, Fmoc-MeGly(cPent)-MeAsp-mor , Fmoc-Gly-Val-OH, Fmoc-Ser(tBu)-Gly-OH, etc.

[0185] In one aspect, when the starting peptide is a tripeptide, non-limiting specific examples of the tripeptide include, for example, Ala-Ala-Pro, Gly-Gly-Gly, Ala-Gly-Asp Or its N-substitute or derivatives, etc. Each amino acid residue constituting the tripeptide can be N-substituted or derivatized. In this way, premature splitting can be suppressed by using a tripeptide-loaded resin for solid-phase synthesis. In the case of extending the continuous sequence of amino acids of the same kind, the peptide can be used for one extension instead of performing multiple amino acid extension reactions, and the reaction steps can be shortened.

[0186] The "peptide compound" of the present invention produced by the aforementioned method carried out by the solid-phase method is a straight-chain peptide compound, except for the total number of natural amino acid residues and unnatural amino acid residues mentioned above In addition to the conditions, at least 1, preferably at least 2 (specifically 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, preferably 5, 6 or 7, the preferred range is 2~30, 3~30, 6~20, 7~19, 7~18, 7~17, 7-16, 7-15, 8-14, 9-13) N-substituted amino acid residues, and include at least one amino acid residue that is not N-substituted. Examples of the ratio of the number of N-substituted amino acid residues contained in the peptide compound include 30% or more, 40% or more, 50% or more, and 60% or more of the total number of amino acid residues constituting the peptide compound. More than 70%, more than 80%. The N-substituted amino acid residues in the present invention may be non-natural N-substituted amino acid residues other than proline. The peptide compound of the present invention may comprise a repeating sequence, for example, a repeating sequence of 2 amino acid residues, 3 amino acid residues, 4 amino acid residues, or 5 amino acid residues, but the number of repetitions is relatively small. Preferably, it is less than 2 times or less than 3 times. In addition, the peptide compound of the present invention preferably does not contain such repetitive sequences.

[0187] In one aspect, the "resin for solid-phase synthesis" used in the present invention is not particularly limited as long as it can be used for the synthesis of peptide compounds by the solid-phase method. Specific examples of such resins for solid-phase synthesis include CTC resin, Sieber resin, Wang resin, SASRIN resin, trityl chlorinated resin (Trt resin), 4-methyltrityl chloride Chemical resin (Mtt resin), 4-methoxytrityl chlorinated resin (Mmt), etc. can be removed under acidic conditions. The resin can be appropriately selected according to the functional group on the side of the amino acid to be used. For example, when using a carboxylic acid (main chain carboxylic acid, or a side chain carboxylic acid represented by Asp, Glu, etc.), or a hydroxyl group on an aromatic ring (a phenolic group represented by Tyr) as the amino acid side In the case of the functional group, it is preferable to use trityl chlorinated resin (Trt resin) or 2-chlorotrityl chlorinated resin (CTC resin) as the resin. In the case of using an aliphatic hydroxyl group (aliphatic alcohol group represented by Ser, Thr, etc.) as the functional group on the side of the amino acid, as the resin, it is preferable to use trityl chloride resin (Trt resin), 2-chlorotrityl chlorinated resin (CTC resin) or 4-methyltrityl chlorinated resin (Mtt resin). In addition, in this specification, resin may be described as resin. The resin for solid-phase synthesis can be linked to an amino acid at any position not limited to the C-terminal amino acid in the peptide. Preferably, the carboxyl group of the amino acid at the C-terminal is connected to the resin for solid-phase synthesis, and the carboxyl group can be a carboxyl group of the main chain or a carboxyl group of a side chain. When using a resin having a trityl skeleton at the linker site, specifically, when using CTC resin, Trt resin, Mtt resin, or Mmt resin as the resin for solid-phase synthesis, premature cleavage is likely to occur, so the present invention method is particularly beneficial.

[0188] The kind of polymer constituting the resin is not particularly limited. In the case of a resin composed of polystyrene, either 100-200 mesh or 200-400 mesh may be used. Also, the cross-linking rate is not particularly limited, but is preferably 1% DVB (divinylbenzene) cross-linked. Moreover, as a kind of polymer which comprises a resin, Tentagel and Chemmatrix are mentioned.

[0189] In one aspect, the present invention can comprise the step of loading the peptide on a resin for solid phase synthesis. In the reaction conditions of this step, any reaction conditions known in the art can be used, and are not particularly limited, but preferably the reaction conditions described in WO2013 / 100132 or WO2018 / 225864, Merck Co., Ltd. Reaction conditions, etc. recorded in the Solid Phase Synthesis Handbook issued on May 1, 2014.

[0190] As the step of loading the peptide on the resin for solid phase synthesis, the following are specifically exemplified, but not limited thereto. The resin is swelled with an appropriate solvent, and the peptide solution whose amine group is protected by a protecting group (protected peptide) reacts with the resin for solid-phase synthesis in the presence of a base, so that the resin can be loaded with the protected peptide. Examples of solvents used for swelling and preparation of peptide solutions include halogen-based solvents such as DCM (dichloromethane), chloroform, and DCE (1,2-dichloroethane), THF (tetrahydrofuran), 2-Methyltetrahydrofuran, 4-methyltetrahydropyran, dioxane, DME (1,2-dimethoxyethane), TBME (t-butyl methyl ether), CPME (cyclopentyl methyl ether), iso Ether-based solvents such as sorbitol dimethyl ether, acetone, MEK (methyl ethyl ketone), 4-methyl-2-pentanone, cyclopentanone and other ketone-based solvents, TMU (N,N,N',N' -tetramethylurea), DMI (1,3-dimethyl-2-imidazolinone), DMPU (N,N'-dimethylpropylene urea) and other urea solvents, DMF (N,N-dimethyl dimethylformamide), DMA (N,N-dimethylacetamide), NFM (N-formyl-2-pyrroline), NMP (N-methyl-2-pyrrolidone), NBP (N-butyl amide-based solvents such as base-2-pyrrolidone), propylene-based solvents such as DMSO (dimethyl sulfide), ethylene-based solvents such as cyclobutylene, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate Esters, isobutyl acetate, GVL (γ-valerolactone) and other ester-based solvents, methyl phenyl ether, toluene, α,α,α-trifluorotoluene, 1,2-dichlorobenzene, benzene and other aromatics Carbonate-based solvents such as dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, etc. In addition to these, acetonitrile, methanol, ethylene glycol, water, silene (silene) can also be used , limonene and other solvents. In addition, as these solvents, a mixture of a plurality of solvents in an arbitrary ratio can also be used. As the protecting group for the amine group, carbamate-type protecting groups such as Fmoc group, Boc group, Alloc group, Cbz group, and Teoc group, amide-type protecting groups such as trifluoroacetyl group, benzenesulfonamide group, etc., can be used. aryl amide-type protecting groups such as p-toluenesulfonyl, 2-nitrobenzenesulfonyl, dinitro 2-nitrobenzenesulfonyl, t-Bu, trityl, An alkylamine-type protecting group such as a benzylidene group, a 4-methoxybenzylidene group, an imide-type protecting group such as a diphenylmethylene group, or the like. Among the bases, triethylamine, DIPEA (N,N-diisopropylethylamine), NMM (N-methylmethanol), DABCO (1,4-diacribicyclo[2.2.2]- tertiary amine bases such as octane), pyridine bases such as pyridine, lutidine, colin base, DMAP (4-dimethylaminopyridine), etc.

[0191] In one aspect, the present invention further comprises the step of extending the peptide loaded on the resin for solid-phase synthesis by one or more amino acids. Through this step, a peptide compound having a desired amino acid sequence can be obtained. In this step, methods known in the art can be used, such as methods described in WO2013 / 100132, WO2018 / 225851, WO2018 / 225864, published by Merck Co., Ltd. on May 1, 2014 The methods recorded in the Solid Phase Synthesis Handbook etc.

[0192] As the step of extending the peptide supported on the resin for solid-phase synthesis by one or more amino acid residues, specifically, the following are exemplified, but not limited thereto. A step of deprotecting the N-terminal protecting group of the peptide supported on the resin for solid-phase synthesis is carried out, and the amino acid residue (protected amino acid residue) whose amine group is protected by the protecting group is separated from the base by the condensation reagent. The step of reacting with the aforementioned peptide in the solvent under the presence or absence of presence, repeating these two steps, thereby extending multiple amino acid residues. As the N-terminal protecting group, carbamate-type protecting groups such as Fmoc group, Boc group, Alloc group, Cbz group, and Teoc group, amide-type protecting groups such as trifluoroacetyl group, and benzenesulfonyl group can be used. , p-toluenesulfonyl, 2-nitrobenzenesulfonyl, dinitro 2-nitrobenzenesulfonyl and other aryl amide-type protecting groups, t-Bu, trityl, An alkylamine-type protecting group such as a benzylidene group, a benzylidene group, a 4-methoxybenzylidene group, an imide-type protecting group such as a diphenylmethylene group, etc., and the Fmoc group is preferably used. In the case of using the Fmoc group as a protecting group, in its deprotection, piperidine or DBU (1,8-diacribicyclo[5.4.0]-7-undecene), DBN (1,5-diacri Bicyclo[4.3.0]-5-nonene), etc. Among the condensation reagents, DCC (N,N'-dicyclohexylcarbodiimide), DIC (N,N'-diisopropylcarbodiimide), EDCI (1-ethyl-3-( 3-dimethylaminopropyl) carbodiimide hydrochloride) and other carbodiimide condensing agents and HOAt (1-hydroxy-7-azabenzotriazole), HOBt (1-hydroxybenzo Triazole), HOOBt (3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazole), oxyma (cyano (hydroxyimino) ethyl acetate), etc. A combination of activators; HATU (O-(7-aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), HBTU(O -(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate), HCTU(O-(6-chloro-1H-benzotriazole- 1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), COMU((1-cyano-2-ethoxy-2-oxoethyleneaminooxy base) uronium salt-based condensing agent such as dimethylamino N-𠰌linyl carbonium hexafluorophosphate); PyAOP ((7-azabenzotriazol-1-yloxy) ginseng Phosphate), PyBOP (1H-benzotriazol-1-yloxy-tris(pyrrolidinyl)phosphonium hexafluorophosphate), PyOxim ([ethylcyano(hydroxyimino)acetate-O 2 ] Tris-1-pyrrolidinylphosphonium hexafluorophosphate) and other phosphonium salt-based condensing agents; 1-chloro-N,N-2-trimethyl-1-propenylamine (Ghosez reagent), TCFH (chloro-N , N,N',N'-tetramethylformamidine hexafluorophosphate), PyCIU (N,N,N',N'-bis(tetramethylene)chloroformamidine hexafluorophosphate), BTFFH (fluorine - N,N,N',N'-bis(tetramethylene)formamidine hexafluorophosphate), TFFH (fluoro-N,N,N',N'-tetramethylamidine hexafluorophosphate), etc. Formamidine salt-based condensing agent, etc. Among the bases, triethylamine, DIPEA (N,N-diisopropylethylamine), NMM (N-methylmethanol), DABCO (1,4-diacribicyclo[2.2.2]- tertiary amine bases such as octane), pyridine bases such as pyridine, lutidine, colin base, DMAP (4-dimethylaminopyridine), etc. Examples of the solvent include halogen-based solvents such as DCM (dichloromethane), chloroform, and DCE (1,2-dichloroethane), THF (tetrahydrofuran), 4-methyltetrahydrofuran, 4-methyltetrahydropyran, Dioxane, DME (1,2-dimethoxyethane), TBME (t-butyl methyl ether), CPME (cyclopentyl methyl ether), isosorbide dimethyl ether and other ether solvents, acetone, MEK (methyl ether) ethyl ketone), 4-methyl-2-pentanone, cyclopentanone and other ketone solvents, TMU (N,N,N′,N′-tetramethylurea), DMI (1,3-dimethyl base-2-imidazolinone), urea solvents such as DMPU (N,N'-dimethylpropylene urea), DMF (N,N-dimethylformamide), DMA (N,N-dimethyl Acetamide), NFM (N-formyl phenoline), NMP (N-methyl-2-pyrrolidone), NBP (N-butyl-2-pyrrolidone) and other amide-based solvents, DMSO Athylene-based solvents such as (dimethylene oxymethylene), cyclobutylene-based solvents, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, GVL (γ-valerolactone) Ester solvents, methyl phenyl ether, toluene, α,α,α-trifluorotoluene, 1,2-dichlorobenzene, benzene and other aromatic solvents, dimethyl carbonate, diethyl carbonate, ethylene carbonate Carbonate-based solvents such as propylene carbonate, etc. In addition to these, solvents such as acetonitrile, methanol, ethylene glycol, water, silicene, and limonene can also be used. In addition, as these solvents, a mixture of a plurality of solvents in an arbitrary ratio can also be used.

[0193] In one aspect, the present invention relates to a method for preparing a cyclic peptide compound, which further comprises: obtaining the linear peptide compound, its salt, or the like produced by the above-mentioned method of the present invention The step of solvate; the step of removing the resin for solid phase synthesis; and the step of cyclizing the group on the C-terminal side and the group on the N-terminal side to form a cyclic part.

[0194] In the step of removing the peptide compound from the resin for solid-phase synthesis, and in the step of cyclizing the C-terminal group and the N-terminal group of the peptide compound to form a cyclic part, all methods in the art can be used. Known methods can be applied, for example, the methods described in WO2013 / 100132, WO2018 / 225851, WO2018 / 225864, the methods described in the solid phase synthesis manual issued by Merck Co., Ltd. on May 1, 2014, etc.

[0195] As the step of removing the peptide compound from the resin for solid-phase synthesis, specifically, the following are exemplified, but not limited thereto. After the peptide chain is extended until it becomes the desired amino acid sequence, the resin for solid-phase synthesis is swollen with an appropriate solvent, and then an acidic solution is applied to remove the peptide compound from the resin. Examples of solvents used for swelling include halogen-based solvents such as DCM (dichloromethane), chloroform, DCE (1,2-dichloroethane), THF (tetrahydrofuran), 4-methyltetrahydrofuran, 4-methyl Tetrahydropyran, dioxane, DME (1,2-dimethoxyethane), TBME (t-butyl methyl ether), CPME (cyclopentyl methyl ether), isosorbide dimethyl ether and other ether solvents, Acetone, MEK (methyl ethyl ketone), ketone solvents such as 4-methyl-2-pentanone, cyclopentanone, TMU (N,N,N',N'-tetramethylurea), DMI (1 , 3-dimethyl-2-imidazolinone), DMPU (N,N'-dimethylpropylene urea) and other urea solvents, DMF (N,N-dimethylformamide), DMA (N, N-dimethylacetamide), NFM (N-formyl 𠰌line), NMP (N-methyl-2-pyrrolidone), NBP (N-butyl-2-pyrrolidone) and other acyl Amine-based solvents, propylene-based solvents such as DMSO (dimethylsulfoxide), ethylene-based solvents such as cyclobutanol, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, GVL (γ -Valerolactone) and other ester solvents, methyl phenyl ether, toluene, α,α,α-trifluorotoluene, 1,2-dichlorobenzene, benzene and other aromatic solvents, dimethyl carbonate, dicarbonate In addition to carbonate-based solvents such as ethyl ester, ethylene carbonate, and propylene carbonate, solvents such as acetonitrile, methanol, ethylene glycol, water, silicene, and limonene can also be used. In addition, as these solvents, a mixture of a plurality of solvents in an arbitrary ratio can also be used. In acidic solution, TFE (2,2,2-trifluoroethanol), HFIP (1,1,1,3,3,3-hexafluoroisopropanol) and other fluoroalcohols, TFA (trifluoroacetic acid) can be used Such as carboxylic acid, hydrochloric acid, etc.

[0196] In one aspect, the "resin for solid-phase synthesis" used in the present invention is preferably a peptide compound having a target amino acid sequence synthesized by a solid-phase method, for example, if the constituents are not removed The amino acid side chain protecting group of the peptide compound is cleaved under mild acidic conditions. Specific examples of the protecting group for the side chain of the amino acid include Boc, Trt, THP, tBu and the like. As the amino acid having a protecting group in the side chain, for example, Tyr (tBu), Ser (tBu), Thr (tBu), Asp (tBu), Glu (tBu), Trp (Boc), Lys (Boc) , His(Boc), Ser(Trt), Thr(Trt), Trp(Trt), Lys(Trt), His(Trt), Asn(Trt), Gln(Trt), Ser(THP), or Thr(THP ), such N-alkyl bodies such as N methyl bodies, etc.

[0197] In one aspect, the "resin for solid-phase synthesis" used in the present invention is preferably one that can cut out the loaded peptide compound under mild acidic conditions. For example, it is preferably a resin having a trityl skeleton at the linker site, specifically CTC resin, Trt resin, Mtt resin or Mmt resin, a resin having a diphenylmethyl skeleton at the linker site, etc., specifically For Sieber resin. As such a resin for solid-phase synthesis, more preferably, CTC resin or Sieber resin is mentioned, and most preferably, CTC resin is mentioned.

[0198] In one aspect, temperature conditions can be included in mildly acidic conditions. The "resin for solid-phase synthesis" used in the present invention is preferably one that can be removed under mild acidic conditions at a temperature near room temperature, for example, room temperature ± 10°C.

[0199] In one aspect, mildly acidic conditions are acidic conditions above pH 2. Also, in one aspect, mild acidic conditions can include the use of dilute acid solutions. In this specification, the dilute solution of an acid means one obtained by diluting an acid with a non-acidic solvent, and can be prepared by mixing an acid with a non-acidic solvent. As the acid used for the dilute solution, pKa in water is -1 or more, 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more acids, specifically, for example, TFA, 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoroisopropanol, trichloroacetic acid , acetic acid, formic acid, or oxalic acid, or a mixture of these, etc. As such an acid, preferably TFA, 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoroisopropanol, acetic acid, or a mixture thereof, more preferably for TFA. The volume % of the acid in the dilute solution can be less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%, preferably less than 20%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%, more preferably less than 10%, less than 5%, or less than 4% Less than, 3% or less, 2% or less, or 1% or less. The non-acidic solvent used as the acid dilute solution is preferably DCM, dichloroethane, water, or 2-MeTHF, or a mixed solvent of these, more preferably DCM. As such a dilute solution of an acid, specifically, for example, a DCM solution containing TFA at a volume % of 20% or less, a DCM solution containing TFA at a volume % of 10% or less, and a DCM solution containing TFA at a volume % of 5% or less, for example. DCM solution of TFA, DCM solution of TFA containing less than 1% volume %, DCM solution containing less than 20% of acetic acid and less than 20% of 2,2,2-trifluoroethanol, containing less than 20% of 1,1 , DCM solution of 1,3,3,3-hexafluoroisopropanol, etc.

[0200] As the step of cyclizing the group on the C-terminal side and the group on the N-terminal side of the peptide compound to form a ring-shaped part, specifically, the following are exemplified, but not limited thereto. The linear peptide compound dissolved in an appropriate solvent and the condensation reagent are reacted in the presence or absence of a base, whereby the group on the C-terminal side and the N-terminal side of the peptide compound can be cyclized And form the annular part. Examples of the solvent include halogen-based solvents such as DCM (dichloromethane), chloroform, and DCE (1,2-dichloroethane), THF (tetrahydrofuran), 4-methyltetrahydrofuran, 4-methyltetrahydropyran, Dioxane, DME (1,2-dimethoxyethane), TBME (t-butyl methyl ether), CPME (cyclopentyl methyl ether), isosorbide dimethyl ether and other ether solvents, acetone, MEK (methyl ether) ethyl ketone), 4-methyl-2-pentanone, cyclopentanone and other ketone solvents, TMU (N,N,N′,N′-tetramethylurea), DMI (1,3-dimethyl base-2-imidazolinone), urea solvents such as DMPU (N,N'-dimethylpropylene urea), DMF (N,N-dimethylformamide), DMA (N,N-dimethyl Acetamide), NFM (N-formyl phenoline), NMP (N-methyl-2-pyrrolidone), NBP (N-butyl-2-pyrrolidone) and other amide-based solvents, DMSO Athylene-based solvents such as (dimethylene oxymethylene), cyclobutylene-based solvents, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, GVL (γ-valerolactone) Ester solvents, methyl phenyl ether, toluene, α,α,α-trifluorotoluene, 1,2-dichlorobenzene, benzene and other aromatic solvents, dimethyl carbonate, diethyl carbonate, ethylene carbonate Carbonate-based solvents such as propylene carbonate, etc. In addition to these, solvents such as acetonitrile, silicene, and limonene can also be used. In addition, as these solvents, a mixture of a plurality of solvents in an arbitrary ratio can also be used. Among the condensation reagents, DCC (N,N'-dicyclohexylcarbodiimide), DIC (N,N'-diisopropylcarbodiimide), EDCI (1-ethyl-3-( 3-dimethylaminopropyl) carbodiimide hydrochloride) and other carbodiimide condensing agents and HOAt (1-hydroxy-7-azabenzotriazole), HOBt (1-hydroxybenzo Triazole), HOOBt (3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazole), oxyma (cyano (hydroxyimino) ethyl acetate) etc. A combination of activators; HATU (O-(7-aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), HBTU(O -(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate), HCTU(O-(6-chloro-1H-benzotriazole- 1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), COMU((1-cyano-2-ethoxy-2-oxoethyleneaminooxy base) uronium salt-based condensing agent such as dimethylamino N-𠰌linyl carbonium hexafluorophosphate); PyAOP ((7-azabenzotriazol-1-yloxy) ginseng Phosphate), PyBOP (1H-benzotriazol-1-yloxy-tris(pyrrolidinyl)phosphonium hexafluorophosphate), PyOxim ([ethylcyano(hydroxyimino)acetate-O 2 ] Tris-1-pyrrolidinylphosphonium hexafluorophosphate) and other phosphonium salt-based condensing agents; 1-chloro-N,N-2-trimethyl-1-propenylamine (Ghosez reagent), TCFH (chloro-N , N,N',N'-tetramethylformamidine hexafluorophosphate), PyCIU (N,N,N',N'-bis(tetramethylene)chloroformamidine hexafluorophosphate), BTFFH (fluorine - N,N,N',N'-bis(tetramethylene)formamidine hexafluorophosphate), TFFH (fluoro-N,N,N',N'-tetramethylamidine hexafluorophosphate), etc. Formamidine salt-based condensing agent, etc. Among the bases, triethylamine, DIPEA (N,N-diisopropylethylamine), NMM (N-methylmethanol), DABCO (1,4-diacribicyclo[2.2.2]- tertiary amine bases such as octane), pyridine bases such as pyridine, lutidine, colin base, DMAP (4-dimethylaminopyridine), etc.

[0201] In one aspect, the number of N-substituted amino acids contained in the peptide portion of the cyclic peptide compound is preferably 2 or more or 3 or more, more preferably 4 or more, 5 or more, or 6 or more, and even more preferably It is 7 or more, particularly preferably 8 or more, and more preferably 20 or less, 15 or less, 14 or less, 13 or less, 12 or less, 10 or less, and 9 or less. As the number of N-substituted amino acids contained in the cyclic peptide compound in this specification, 30% or more, 40% or more, 50% or more, 60% or more, and More than 70%, more than 80%.

[0202] In one aspect, the present invention relates to a method for improving the recovery rate of a peptide compound compared to the case of extending amino acid residue by residue, and is characterized in that, in the solid phase method In the production of a peptide compound containing at least one N-substituted amino acid residue, a salt thereof, or a solvate thereof, the peptide is loaded on a resin for solid-phase synthesis before the initial elongation reaction . That is to say, the present invention relates to using a peptide (preferably a dipeptide or a tripeptide) as a starting material to extend the peptide chain by a solid-phase method to obtain a peptide with a target amino acid sequence As a result, the recovery rate of the target peptide compound can be increased by, for example, 5% or more compared to the case of using amino acids as the starting material and producing peptide compounds with the same amino acid sequence by the solid-phase method , More than 10%, more than 20%, more than 30%, more than 40%, more than 50%.

[0203] In one aspect, the present invention relates to a method which suppresses the generation of impurities compared to the case of extending amino acid residue by residue, and is characterized in that, when carried out by the solid phase method In the production of a peptide compound containing at least one N-substituted amino acid residue, a salt thereof, or a solvate thereof, the peptide is loaded on a resin for solid-phase synthesis before the initial elongation reaction. That is to say, the present invention relates to using a peptide (preferably a dipeptide or a tripeptide) as a starting material to extend the peptide chain by a solid-phase method to obtain a peptide with a target amino acid sequence As a result, compared with the case of using amino acids as starting materials and producing peptide compounds with the same amino acid sequence by solid-phase method, impurities (such as epimers, Production inhibition of excess extension form, amino acid deletion form, for example, 0.5% or more, 1% or more, 5% or more, 10% or more, 20% or more, 30% or more, 40% or more.

[0204] In one aspect, the invention relates to a method which inhibits premature cleavage compared to the case of elongation of amino acids residue by residue, and is characterized in that, in the case of solid-phase methods involving In the manufacture of a peptide compound having at least one N-substituted amino acid residue, a salt thereof, or a solvate thereof, the peptide is loaded on a resin for solid-phase synthesis before the initial elongation reaction. That is to say, the present invention relates to using a peptide (preferably a dipeptide or a tripeptide) as a starting material to extend the peptide chain by a solid-phase method to obtain a peptide with a target amino acid sequence As a result, compared with the case of using amino acid as the starting material and producing a peptide compound with the same amino acid sequence by a solid-phase method, premature cleavage can be greatly suppressed, for example, by more than 5%, 10% More than %, more than 20%, more than 30%, more than 40%, more than 50%.

[0205] In the compounds of the present invention, their salts, or solvates thereof, all stereoisomers (for example, enantiomers, diastereomers (including cis and trans geometric isomers) ), racemates of the aforementioned isomers, and other mixtures. For example, the compounds of the present invention may have one or more asymmetric points, and the present invention includes racemic mixtures, diastereomeric mixtures, and mirror isomers of such compounds.

[0206] When the compound of the present invention can be a free body, the compound can be converted in accordance with ordinary methods in the state of a salt that the compound can form or a hydrate or solvate thereof.

[0207] In addition, the compound of the present invention may be a salt, a hydrate, or a solvate of the compound, and the compound may be converted into its free form according to a usual method.

[0208] In addition, all the prior art documents cited in this specification are incorporated in this specification as a reference. [Example]

[0209] Utilize the following examples to further illustrate the content of the present invention, but the present invention is not limited to its content. All starting materials and reagents were obtained from commercial suppliers or synthesized using known methods.

[0210] The analysis conditions of LCMS are described in the table below [Table 1] Analysis conditions device String (I.D. x Length)(mm) mobile phase Gradient (A / B) flow rate (mL / min) String temperature(℃) wavelength SQDFA05 Acquity UPLC / SQD2 Ascentis Express C18 (2.1x50) A) 0.1% FA, water B) 0.1% FA, acetonitrile 95 / 5 (start) 0 / 100 (1.0 minutes) => 0 / 100 (0.4 minutes) 1.0 35 210-400nm Total PDA SQDFA05_55deg Acquity UPLC / SQD2 Ascentis Express C18 (2.1x50) A) 0.1% FA, water B) 0.1% FA, acetonitrile 95 / 5 (start) 0 / 100 (1.0 minutes) => 0 / 100 (0.4 minutes) 1.0 35 210-400nm Total PDA SQDFA05long Acquity UPLC / SQD2 Ascentis Express C18 (2.1x50) A) 0.1% FA, water B) 0.1% FA, acetonitrile 95 / 5 (start) 0 / 100 (4.5 minutes) => 0 / 100 (0.5 minutes) 1.0 35 210-400nm Total PDA SQDAA50 Acquity UPLC / SQD2 Ascentis Express C18 (2.1x50) A) 10mM AA, water B) Methanol 50 / 50 (starting) 0 / 100 (0.7 minutes) => 0 / 100 (0.7 minutes) 1.0 35 210-400nm Total PDA SQDAA50long Acquity UPLC / SQD2 Ascentis Express C18 (2.1x50) A) 10mM AA, water B) Methanol 50 / 50 (starting) 0 / 100 (4.5 minutes) => 0 / 100 (0.5 minutes) 1.0 35 210-400nm Total PDA SMDmethod_1 Shimadzu / 2020 Ascentis Express C18 (2.1x50) A) 0.1% FA, water B) 0.1% FA, acetonitrile 95 / 5 (start) 5 / 95 (2.5 minutes) 5 / 95 (1.2 minutes) => 95 / 5 (0.1 minutes) 1.0 40 190-400nm Total PDA SMDmethod_2 Shimadzu / 2020 Ascentis Express C18 (2.1x50) A) 0.1% FA, water B) 0.1% FA, acetonitrile 95 / 5 (start) 5 / 95 (2.0 minutes) 5 / 95 (0.7 minutes) => 95 / 5 (0.1 minutes) 1.0 40 190-400nm Total PDA SMDmethod_3 Shimadzu / 2020 Ascentis Express C18 (3.0x50) A) 0.05% TFA, water B) 0.05% TFA, Acetonitrile 70 / 30 (starting) 30 / 70 (3.2 minutes) 5 / 95 (0.5 minutes) 5 / 95 (1.0 minutes) => 95 / 5 (0.1 minutes) 1.0 40 190-400nm Total PDA SMDmethod_4 Shimadzu / 2020 HALO C18 (3.0x30) A) 0.05% TFA, water B) 0.05% TFA, Acetonitrile 95 / 5 (start) 0 / 100 (0.7 minutes) 0 / 100 (0.4 minutes) => 95 / 5 (0.02 minutes) 1.5 40 190-400nm Total PDA SMDmethod_5 Shimadzu / 2020 HALO C18 (3.0x30) A) 0.05% TFA, water B) 0.05% TFA, Acetonitrile 95 / 5 (start) 0 / 100 (1.1 minutes) 0 / 100 (0.6 minutes) => 95 / 5 (0.05 minutes) 1.5 40 190-400nm Total PDA SMDmethod_6 Shimadzu / 2020 HALO C18 (3.0x30) A) 0.05% TFA, water B) 0.05% TFA, Acetonitrile 95 / 5 (start) 0 / 100 (1.1 minutes) 0 / 100 (0.6 minutes) => 95 / 5 (0.05 minutes) 1.3 40 190-400nm Total PDA SMDmethod_7 Shimadzu / 2020 Shim-pack XR-ODS (3.0x50) A) 0.05% TFA, water B) 0.05% TFA, Acetonitrile 60 / 40 (starting) 5 / 95 (3.0 minutes) 5 / 95 (0.7 minutes) => 95 / 5 (0.05 minutes) 1.2 40 190-400nm Total PDA

[0211] Example 1 Synthesis of compounds such as amino acids used in peptide synthesis by a peptide synthesis machine In the synthesis of the peptides described in this specification, the amino acids or peptides described in Table 2, Table 3, Table 4, and Table 5, and resins loaded therewith are used.

[0212] Example 1-1. Direct use of purchased Fmoc-amino acids and peptides The Fmoc-amino acids and peptides described in Table 2 were purchased from commercial suppliers.

[0213] [Table 2]

[0214] Example 1-2. Synthesis of Fmoc-dipeptide The Fmoc-peptides described in Table 3 were synthesized according to the flow chart shown below.

[0215] [table 3]

[0216] Synthesis of compound aa2-001, Fmoc-MeVal-MeAsp-pip

[0217] Compound aa2-001-a, (3S)-3-[[(2S)-2-[9H-fen-9-ylmethoxycarbonyl(methyl)amino]-3-methylbutyryl]-methylamine Synthesis of prop-2-enyl]-4-oxo-4-piperidin-1-ylbutanoate (Fmoc-MeVal-MeAsp(OAl)-pip) The starting material Fmoc-MeAsp(OAl)-pip was synthesized following the method described in WO2018 / 225864. Under nitrogen flow, Fmoc-MeVal-OH (4.25 g, 12.0 mmol), EDCI (3.23 g, 16.8 mmol), oxyma (2.05 g, 14.4 mmol) and DMF (40 mL) were added to the reaction vessel. The reaction solution was stirred for 30 minutes to obtain the active ester solution of Fmoc-MeVal-OH. Under nitrogen flow, Fmoc-MeAsp(OAl)-pip (5.00 g, 10.5 mmol) and DMF (40 mL) were added to the reaction vessel, followed by DBU (1.60 g, 10.5 mmol) at room temperature. After stirring the reaction solution for 5 minutes, pyridine hydrochloride (1.33 g, 11.5 mmol) was added at room temperature under nitrogen flow. After the reaction solution was stirred for 10 minutes, the active ester solution of Fmoc-MeVal-OH prepared above and DIPEA (1.49 g, 11.5 mmol) were added under nitrogen flow at room temperature, and the reaction solution was stirred for 5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase silica gel column chromatography (water / acetonitrile=95 / 5→20 / 80) to obtain 3.03 g of a peach-colored solid (yield 48%) Compound aa2-001-a. LCMS(ESI) m / z=590.6 (M+H) + Hold time: 1.06 minutes (analysis condition SQDFA05)

[0218] Compound aa2-001, (3S)-3-[[(2S)-2-[9H-fen-9-ylmethoxycarbonyl(methyl)amino]-3-methylbutyryl]-methylamino] -Synthesis of 4-oxo-4-piperidin-1-ylbutanoic acid (Fmoc-MeVal-MeAsp-pip) Under nitrogen flow, compound aa2-001-a (1.18 g, 2.00 mmol) and tetrakistriphenylphosphine palladium (23.1 mg, 0.020 mmol) were added in a reaction vessel, followed by DCM (4.0 mL). After dropping phenylsilane (0.152 g, 1.40 mmol) into the reaction solution, the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was diluted with TBME (11.8 mL), extracted with saturated aqueous sodium bicarbonate / water (1 / 1, 11.8 mL), and then extracted with water (5.9 mL). 85% phosphoric acid aqueous solution (0.700 mL, 10.2 mmol) was added to the combined aqueous layers to make it acidic around pH 2, and the aqueous layer was extracted twice with DCM (11.8 mL). The combined organic layers were washed with saturated aqueous sodium chloride / water (1 / 1, 11.8 mL), and then dried over sodium sulfate. After filtering off the dried material, the filtrate was concentrated under reduced pressure to obtain 1.06 g (97% yield) of compound aa2-001 as light brown amorphous crystals. LCMS(ESI) m / z=550.5 (M+H) + Hold time: 0.93 minutes (analysis condition SQDFA05)

[0219] Synthesis of compound aa2-002, Fmoc-MeIle-MeAsp-pip

[0220] Compound aa2-002-a, (3S)-3-[[(2S,3S)-2-[9H-fen-9-ylmethoxycarbonyl(methyl)amino]-3-methylpentyl] Synthesis of -methylamino]-4-oxo-4-piperidin-1-ylbutanoic acid prop-2-enyl (Fmoc-MeIle-MeAsp(OAl)-pip) Using compound Fmoc-MeAsp(OAl)-pip (10.0 g, 21.0 mmol) and Fmoc-MeIle-OH (6.80 g, 18.5 mmol) as starting materials, using the same method as the synthesis of compound aa2-001-a, Compound aa2-002-a was obtained as 3.64 g (29% yield) of orange solid. LCMS(ESI) m / z=604.6 (M+H) + Hold time: 1.10 minutes (analysis condition SQDFA05)

[0221] Compound aa2-002, (3S)-3-[[(2S,3S)-2-[9H-Oxime-9-ylmethoxycarbonyl (methyl)amino]-3-methylpentyl]-methanol Synthesis of Fmoc-MeIle-MeAsp-pip Using compound aa2-002-a (1.21 g, 2.00 mmol) as the starting material, the compound aa2 was obtained as light brown amorphous 1.05 g (yield 93%) by the same method as the synthesis of compound aa2-001 -002. LCMS(ESI) m / z=564.7 (M+H) + Hold time: 0.99 minutes (analysis condition SQDFA05)

[0222] Synthesis of compound aa2-003, Fmoc-MeGly(cPent)-MeAsp-pip

[0223] Compound aa2-003-a, (3S)-3-[[(2S)-2-cyclopentyl-2-[9H-fen-9-ylmethoxycarbonyl(methyl)amino]acetyl]- Synthesis of Methylamino]-4-oxo-4-piperidin-1-ylbutanoic acid prop-2-enyl (Fmoc-MeGly(cPent)-MeAsp(OAl)-pip) Using the compound Fmoc-MeAsp(OAl)-pip (10.0 g, 21.0 mmol) and Fmoc-MeGly(cPent)-OH (8.75 g, 23.1 mmol) as starting materials, using the same compound as the compound aa2-001-a , obtained 3.49 g (27% yield) of compound aa2-003-a as an orange solid. LCMS(ESI) m / z=616.6 (M+H) + Hold time: 1.11 minutes (analysis condition SQDFA05)

[0224] Compound aa2-003, (3S)-3-[[(2S)-2-cyclopentyl-2-[9H-fen-9-ylmethoxycarbonyl(methyl)amino]acetyl]-methyl Synthesis of Amino]-4-oxo-4-piperidin-1-ylbutyric acid (Fmoc-MeGly(cPent)-MeAsp-pip) Using compound aa2-003-a (1.23 g, 2.00 mmol) as the starting material, the compound aa2 was obtained as 1.12 g (yield 97%) of light brown amorphous crystal by the same method as the synthesis of compound aa2-001 -003. LCMS(ESI) m / z=576.8 (M+H) + Hold time: 0.95 minutes (analysis condition SQDFA05)

[0225] Synthesis of compound aa2-004, Fmoc-MeChg-MeAsp-pip

[0226] Compound aa2-004-a, (3S)-3-[[(2S)-2-cyclohexyl-2-[9H-fen-9-ylmethoxycarbonyl(methyl)amino]acetyl]-methanol Synthesis of 4-oxo-4-piperidin-1-ylbutanoic acid prop-2-enyl (Fmoc-MeChg-MeAsp(OAl)-pip) Using compound Fmoc-MeAsp(OAl)-pip (10.0 g, 21.0 mmol) and Fmoc-MeChg-OH (9.10 g, 23.1 mmol) as starting materials, using the same method as the synthesis of compound aa2-001-a, 5.52 g (42% yield) of compound aa2-004-a were obtained as a yellow solid. LCMS(ESI) m / z=630.6 (M+H) + Hold time: 1.13 minutes (analysis condition SQDFA05)

[0227] Compound aa2-004, (3S)-3-[[(2S)-2-cyclohexyl-2-[9H-fluorene-9-ylmethoxycarbonyl(methyl)amino]acetyl]-methylamine Synthesis of ]-4-oxo-4-piperidin-1-ylbutanoic acid (Fmoc-MeChg-MeAsp-pip) Using compound aa2-004-a (1.26 g, 2.00 mmol) as the starting material, the compound aa2 was obtained in the form of 0.953 g (yield: 81%) of light brown amorphous crystal by the same method as the synthesis of compound aa2-001 -004. LCMS(ESI) m / z=590.6 (M+H) + Hold time: 0.97 minutes (analysis condition SQDFA05)

[0228] Synthesis of compound aa2-005, Fmoc-MeLeu-MeAsp-pip

[0229] Compound aa2-005-a, (3S)-3-[[(2S)-2-[9H-fen-9-ylmethoxycarbonyl (methyl)amino]-4-methylpentyl]-methanol Synthesis of Prop-2-enyl (Fmoc-MeLeu-MeAsp(OAl)-pip) Using compound Fmoc-MeAsp(OAl)-pip (8.00 g, 16.79 mmol) and Fmoc-MeLeu-OH (6.48 g, 17.63 mmol) as starting materials, using the same method as the synthesis of compound aa2-001-a, 5.00 g (yield 49%) of compound aa2-005-a were obtained as yellow amorphous crystals. LCMS(ESI) m / z=604.6 (M+H) + Hold time: 1.10 minutes (analysis condition SQDFA05)

[0230] Compound aa2-005, (3S)-3-[[(2S)-2-[9H-fen-9-ylmethoxycarbonyl(methyl)amino]-4-methylpentyl]-methylamine Synthesis of ]-4-oxo-4-piperidin-1-ylbutanoic acid (Fmoc-MeLeu-MeAsp-pip) Compound aa2-005-a (1.21 g, 2.00 mmol) was used as the starting material, and compound aa2 was obtained as light brown amorphous 1.09 g (yield 96%) by the same method as the synthesis of compound aa2-001 -005. LCMS(ESI) m / z=564.5 (M+H) + Hold time: 0.94 minutes (analysis condition SQDFA05)

[0231] Synthesis of compound aa2-006, Fmoc-MeGly(cPent)-MeAsp-NMe2

[0232] Compound aa2-006-a, (3S)-4-(dimethylamino)-3-[9H-fen-9-ylmethoxycarbonyl(methyl)amino]-4-oxobutanoic acid propane Synthesis of -2-alkenyl (Fmoc-MeAsp(OAl)-NMe2) The starting material Fmoc-MeAsp(OAl)-OH was synthesized following the method described in WO2018 / 225864. Under nitrogen flow, EDCI (16.9 g, 88.0 mmol) and DMF (144 mL) were added to the reaction vessel, and cooled to 0°C. Add HOBt (10.9 g, 80.6 mmol) and a solution of Fmoc-MeAsp(OAl)-OH (30.0 g, 73.3 mmol) in DCM / DMF (60 mL / 60 mL) sequentially at 0°C. °C and stirred for 30 minutes. Dimethylamine (2 mol / L THF solution, 40.5 mL, 80.6 mmol) was added dropwise at 0°C, and stirred at 0°C for 30 minutes. Ethyl acetate (300 mL) was added to the reaction solution, and the organic layer was washed with 1 mol / L hydrochloric acid aqueous solution (240 mL) twice, water (300 mL) twice, and saturated sodium bicarbonate aqueous solution / After washing with water (1 / 1,300 mL) twice, and with saturated aqueous sodium chloride / water (1 / 1,300 mL), the organic layer was dried over sodium sulfate. After filtering off the dried material, the filtrate was concentrated under reduced pressure to obtain 32.7 g (102% yield) of compound aa2-006-a as light brown amorphous crystals. LCMS(ESI) m / z=437.2 (M+H) + Hold time: 0.86 minutes (analysis condition SQDFA05)

[0233] Compound aa2-006-b, (3S)-3-[[(2S)-2-cyclopentyl-2-[9H-fen-9-ylmethoxycarbonyl(methyl)amino]acetyl]- Synthesis of methylamino]-4-(dimethylamino)-4-oxobutanoic acid prop-2-enyl (Fmoc-MeGly(cPent)-MeAsp(OAl)-NMe2) Using compound aa2-006-a (8.50 g, 19.5 mmol) and Fmoc-MeGly(cPent)-OH (7.76 g, 20.5 mmol) as starting materials, using the same method as the synthesis of compound aa2-001-a, 5.02 g (43% yield) of compound aa2-006-b were obtained as yellow amorphous crystals. LCMS(ESI) m / z=576.5 (M+H) + Hold time: 1.02 minutes (analysis condition SQDFA05)

[0234] Compound aa2-006, (3S)-3-[[(2S)-2-cyclopentyl-2-[9H-fen-9-ylmethoxycarbonyl(methyl)amino]acetyl]-methyl Synthesis of Amino]-4-(Dimethylamino)-4-oxobutyric Acid (Fmoc-MeGly(cPent)-MeAsp-NMe2) Using compound aa2-006-b (0.921 g, 1.60 mmol) as the starting material, the compound aa2 was obtained in the form of 0.786 g (yield 92%) of light brown amorphous crystal by the same method as the synthesis of compound aa2-001 -006. LCMS(ESI) m / z=536.5 (M+H) + Hold time: 0.85 minutes (analysis condition SQDFA05)

[0235] Synthesis of compound aa2-007, Fmoc-MeLeu-MeAsp-NMe2

[0236] Compound aa2-007-b, (3S)-4-(dimethylamino)-3-[[(2S)-2-[9H-oxa-9-ylmethoxycarbonyl(methyl)amino]- Synthesis of 4-methylpentyl]-methylamino]-4-oxobutanoic acid prop-2-enyl (Fmoc-MeLeu-MeAsp(OAl)-NMe2) Using compound aa2-006-a (8.50 g, 19.5 mmol) and Fmoc-MeLeu-OH (7.76 g, 20.5 mmol) as starting materials, using the same method as the synthesis of compound aa2-001-a, a yellow 5.00 g (48% yield) of compound aa2-007-b as amorphous crystals. LCMS(ESI) m / z=564.5 (M+H) + Hold time: 1.02 minutes (analysis condition SQDFA05)

[0237] Compound aa2-007, (3S)-4-(dimethylamino)-3-[[(2S)-2-[9H-oxa-9-ylmethoxycarbonyl(methyl)amino]-4- Synthesis of Methylpentyl]-Methylamino]-4-oxobutyric Acid (Fmoc-MeLeu-MeAsp-NMe2) Using compound aa2-007-b (1.13 g, 2.00 mmol) as the starting material, the compound aa2 was obtained in the form of 0.995 g (yield 95%) of light brown amorphous crystal by the same method as the synthesis of compound aa2-001 -007. LCMS(ESI) m / z=524.5 (M+H) + Hold time: 0.86 minutes (analysis condition SQDFA05)

[0238] Synthesis of compound aa2-008, Fmoc-MeVal-D-3-MeAbu-OH

[0239] Compound aa2-008-a, (3R)-3-[9H-fluorene-9-ylmethoxycarbonyl(methyl)amino]butyric acid prop-2-enyl (Fmoc-D-3-MeAbu-OAl) Synthesis Under nitrogen flow, at 0°C, Fmoc-D-3-MeAbu-OH (20.0 g, 59.0 mmol), EDCI (17.0 g, 88.5 mmol), HOBt (13.6 g, 88.5 mmol), HOBt (13.6 g, 88.5 mmol), Allyl alcohol (8.1 mL, 118 mmol), DMF (140 mL), and DCM (40 mL), stirred at 0°C for 30 minutes. Next, DIPEA (15.4 mL, 88.5 mmol) was added, stirred at 0° C. for 30 minutes, and then stirred at room temperature for 15 minutes. Ethyl acetate (200 mL) was added to the reaction solution, and the organic layer was washed with saturated aqueous sodium bicarbonate (200 mL), and then dried over sodium sulfate. After filtering off the dried material, the filtrate was concentrated under reduced pressure to obtain 22.1 g (99% yield) of the crude product of compound aa2-008-a as a yellow oily substance. LCMS(ESI) m / z=380.1 (M+H) + Hold time: 2.12 minutes (analysis condition SMDmethod_1)

[0240] Compound aa2-008-b, (3R)-3-[[(2S)-2-[9H-fen-9-ylmethoxycarbonyl(methyl)amino]-3-methylbutyryl]-methylamine Synthesis of prop-2-enyl butyric acid (Fmoc-MeVal-D-3-MeAbu-OAl) Using compound aa2-008-a (6.00 g, 15.8 mmol) and Fmoc-MeVal-OH (5.82 g, 16.62 mmol) as starting materials, using the same method as the synthesis of compound aa2-001-a, brown 3.79 g (49% yield) of compound aa2-008-b as amorphous crystals. LCMS(ESI) m / z=493.5 (M+H) + Hold time: 1.03 minutes (analysis condition SQDFA05)

[0241] Compound aa2-008, (3R)-3-[[(2S)-2-[9H-fen-9-ylmethoxycarbonyl(methyl)amino]-3-methylbutyryl]-methylamino] Synthesis of Butyric Acid (Fmoc-MeVal-D-3-MeAbu-OH) Using compound aa2-008-b (0.788 g, 1.60 mmol) as the starting material, the compound aa2 was obtained in the form of 0.607 g (yield 84%) of light brown amorphous crystal by the same method as the synthesis of compound aa2-001 -008. LCMS(ESI) m / z=453.4 (M+H) + Hold time: 0.85 minutes (analysis condition SQDFA05)

[0242] Synthesis of compound aa2-009, Fmoc-MeChg-D-3-MeAbu-OH

[0243] Compound aa2-009-b, (3R)-3-[[(2S)-2-cyclohexyl-2-[9H-fen-9-ylmethoxycarbonyl(methyl)amino]acetyl]-methanol Synthesis of Amino]prop-2-enyl Butyrate (Fmoc-MeChg-D-3-MeAbu-OAl) Using compound aa2-008-a (4.70 g, 12.4 mmol) and Fmoc-MeChg-OH (5.10 g, 13.0 mmol) as starting materials, using the same method as the synthesis of compound aa2-001-a, a yellow 3.70 g (56% yield) of compound aa2-009-b in oily substance. LCMS(ESI) m / z=533.6 (M+H) + Hold time: 1.11 minutes (analysis condition SQDFA05)

[0244] Compound aa2-009, (3R)-3-[[(2S)-2-cyclohexyl-2-[9H-fluorene-9-ylmethoxycarbonyl(methyl)amino]acetyl]-methylamine Synthesis of butyric acid (Fmoc-MeChg-D-3-MeAbu-OH) Using compound aa2-009-b (0.799 g, 1.50 mmol) as the starting material, the compound aa2 was obtained in the form of 0.501 g (yield: 68%) of light brown amorphous crystal by the same method as the synthesis of compound aa2-001 -009. LCMS(ESI) m / z=493.5 (M+H) + Hold time: 0.95 minutes (analysis condition SQDFA05)

[0245] Synthesis of compound aa2-010, Fmoc-MeVal-MeGly-OH

[0246] Synthesis of Compound aa2-010-a, 2-[9H-Oxyl-9-ylmethoxycarbonyl(methyl)amino]prop-2-enyl Acetate (Fmoc-MeGly-OAl) Under nitrogen flow, Fmoc-MeGly-OH (6.00 g, 19.3 mmol), EDCI (4.43 g, 23.1 mmol), HOBt (3.12 g, 23.1 mmol), allyl alcohol (1.23 g, 21.2 mmol), DMF (40 mL), and DCM (12 mL), stirred at room temperature for 30 minutes. Ethyl acetate (60 mL) was added to the reaction solution, and the organic layer was washed sequentially with 1 mol / L aqueous hydrochloric acid (60 mL), saturated aqueous sodium bicarbonate (60 mL), and saturated aqueous sodium chloride (60 mL) Then, the organic layer was concentrated under reduced pressure to obtain 6.00 g (yield 89%) of a crude product of compound aa2-010-a as a yellow oily substance. LCMS(ESI) m / z=352.1 (M+H) + Hold time: 1.75 minutes (analysis condition SMDmethod_2)

[0247] Compound aa2-010-b, 2-[[(2S)-2-[9H-Oxime-9-ylmethoxycarbonyl(methyl)amino]-3-methylbutyryl]-methylamino]acetic acid propyl Synthesis of -2-alkenyl (Fmoc-MeVal-MeGly-OAl) Using compound aa2-010-a (6.00 g, 17.07 mmol) and Fmoc-MeVal-OH (6.63 g, 18.76 mmol) as starting materials, using the same method as the synthesis of compound aa2-001-a, a peach-colored 3.37 g (43% yield) of compound aa2-010-b as amorphous crystals. LCMS(ESI) m / z=465.5 (M+H) + Hold time: 1.00 minutes (analysis condition SQDFA05)

[0248] Compound aa2-010, 2-[[(2S)-2-[9H-fluorene-9-ylmethoxycarbonyl (methyl)amino]-3-methylbutyryl]-methylamino]acetic acid (Fmoc- Synthesis of MeVal-MeGly-OH) Using compound aa2-010-b (0.929 g, 2.00 mmol) as the starting material, the compound aa2 was obtained in the form of 0.841 g (yield 99%) of light brown amorphous crystal by the same method as the synthesis of compound aa2-001 -010. LCMS(ESI) m / z=425.4 (M+H) + Hold time: 0.83 minutes (analysis condition SQDFA05)

[0249] Synthesis of compound aa2-011, Fmoc-MeGly(cPent)-MeAsp-mor

[0250] Compound aa2-011-a, (3S)-3-[9H-Oxyl-9-ylmethoxycarbonyl(methyl)amino]-4-N-𠰌linyl-4-oxo-butyric acid allyl Synthesis of the base (Fmoc-MeAsp(OAl)-mor) The starting material Fmoc-MeAsp(OAl)-OH was synthesized following the method described in WO2018 / 225864. The condensation reaction between the carboxyl group and thioline was synthesized by using thioline to replace the dimethylamine used in the synthesis of compound aa2-006-a.

[0251] Compound aa2-011-b, (3S)-3-[[(2S)-2-cyclopentyl-2-[9H-fen-9-ylmethoxycarbonyl(methyl)amino]acetyl]- Synthesis of Methyl-amino]-4-N-𠰌linyl-4-oxo-butyric acid allyl (Fmoc-MeGly(cPent)-MeAsp(OAl)-mor) In a solution of compound aa2-011-a (10 g, 20.90 mmol) in dehydrated DMF (50 mL) under nitrogen atmosphere, DBU (3.15 mL, 20.90 mmol) was added dropwise at room temperature and stirred for 10 min. In the reaction mixture, pyridine hydrochloride (2.66 g, 22.99 mmol) was added at room temperature and stirred for 10 minutes. To this reaction mixture, a separately prepared active ester solution (described later) was added at room temperature, followed by dropwise addition of DIPEA (4.01 mL, 22.99 mmol). After the resulting reaction mixture was stirred at room temperature for 4 hours and 15 minutes, ethyl acetate (100 mL), hexane (20 mL) and 1 mol / L hydrochloric acid aqueous solution (100 mL) were added. The resulting mixture was extracted with ethyl acetate-hexane (5:1) (the total amount of the organic phase was about 300 mL), and the organic phase was mixed with 1 mol / L hydrochloric acid aqueous solution (100 mL), water (100 mL), carbonic acid Wash with aqueous sodium hydrogen solution (100 mL x 2) and saturated aqueous sodium chloride solution (100 mL), dry over sodium sulfate, and distill off the solvent under reduced pressure. The obtained crude product was purified by sequential silica gel chromatography (hexane-ethyl acetate) to obtain 9.98 g of compound aa2-011-b (yield 81%). The preparation of the active ester solution was carried out as follows. Under nitrogen atmosphere, in (2S)-2-cyclopentyl-2-[9H-fluorene-9-ylmethoxycarbonyl(methyl)amino]acetic acid (7.53 g, 19.85 mmol), WSCI·HCl (5.21 g, 27.2 mmol) and Oxyma (3.56 g, 25.08 mmol), add dehydrated DMF (55 mL) at room temperature, stir for 40 minutes, and use the resulting reaction mixture as an active ester solution. LCMS(ESI) m / z=618 (M+H) + Hold time: 0.96 minutes (analysis condition SQDFA05)

[0252] Compound aa2-011, (3S)-3-[[(2S)-2-cyclopentyl-2-[9H-fen-9-ylmethoxycarbonyl(methyl)amino]acetyl]-methyl Synthesis of -amino]-4-N-𠰌linyl-4-oxo-butyric acid (Fmoc-MeGly(cPent)-MeAsp-mor) Under nitrogen atmosphere, add dehydrated DCM (15 ml) to the mixture of compound aa2-011-b (9.90 g, 16.03 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.185 g, 0.16 mmol), in Stir at room temperature. In the resulting solution, phenylsilane (1.38 mL, 11.22 mmol) was dropped. After the resulting reaction mixture was stirred for 30 minutes, MTBE (100 mL) was added, followed by slowly dropping aqueous sodium bicarbonate solution (diluted 2-fold with saturated aqueous solution) (100 mL) to stop the reaction. The resulting mixture was extracted twice with water (the total amount of the aqueous phase was about 150 mL), and DCM (100 mL) and phosphoric acid (5.6 mL) were added to the aqueous phase. The resulting mixture was extracted twice with DCM (the total amount of the organic phase was about 200ml), the organic phase was washed with a saturated aqueous sodium chloride solution (80 mL x 2), dried over sodium sulfate, and the solvent was distilled off under reduced pressure , The resulting 9.57 g of compound aa2-011 (yield: 100%) was used in the next reaction. LCMS(ESI) m / z=578 (M+H) + Hold time: 0.79 minutes (analysis condition SQDFA05)

[0253] Synthesis of compound aa2-012, Fmoc-MeVal-Asp-NMe2

[0254] Compound aa2-012-a, (3S)-4-(dimethylamino)-3-(9H-fen-9-ylmethoxycarbonylamino)-4-oxobutanoic acid prop-2-ene Synthesis of base (Fmoc-Asp(OAl)-NMe2) Using Fmoc-Asp(OAl)-OH (100.0 g, 252.9 mmol) purchased from a commercial supplier as a starting material, the compound aa2-006-a was synthesized in the same way as a yellow oily substance. 89 g (82% yield) of compound aa2-012-a. LCMS(ESI) m / z=423.2 (M+H) + Hold time: 2.24 minutes (analysis condition SMDmethod_3)

[0255] Compound aa2-012-b, (3S)-4-(dimethylamino)-3-[[(2S)-2-[9H-oxa-9-ylmethoxycarbonyl(methyl)amino]- Synthesis of 3-methylbutyryl]amino]-4-oxobutanoic acid prop-2-enyl (Fmoc-MeVal-Asp(OAl)-NMe2) Using compound aa2-012-a (5.0 g, 11.8 mmol) and Fmoc-MeVal-OH (4.39 g, 12.4 mmol) as starting materials, using the same method as the synthesis of compound aa2-001-a, the obtained off-white 3.4 g (53% yield) of compound aa2-012-b as a solid. LCMS(ESI) m / z=536.5 (M+H) + Hold time: 0.94 minutes (analysis condition SQDFA05)

[0256] Compound aa2-012, (3S)-4-(dimethylamino)-3-[[(2S)-2-[9H-oxa-9-ylmethoxycarbonyl(methyl)amino]-3- Synthesis of methylbutyryl]amino]-4-oxobutanoic acid (Fmoc-MeVal-Asp-NMe2) Using compound aa2-012-b (1.16 g, 2.17 mmol) as the starting material, the compound aa2- 012. LCMS(ESI) m / z=496.5 (M+H) + Hold time: 0.78 minutes (analysis condition SQDFA05)

[0257] Synthesis of compound aa2-013, Fmoc-Gly-MeAsp-NMe2

[0258] Compound aa2-013-b, (3S)-4-(dimethylamino)-3-[[2-(9H-fen-9-ylmethoxycarbonylamino)acetyl]-methylamino Synthesis of ]-4-oxobutanoic acid prop-2-enyl (Fmoc-Gly-MeAsp(OAl)-NMe2) Using compound aa2-006-a (5.0 g, 11.5 mmol) and Fmoc-Gly-OH (7.15 g, 24.1 mmol) as starting materials, using the same method as the synthesis of compound aa2-001-a, a yellow 3.9 g (68% yield) of compound aa2-013-b as amorphous crystals. LCMS(ESI) m / z=494.5 (M+H) + Hold time: 0.81 minutes (analysis condition SQDFA05)

[0259] Compound aa2-013, (3S)-4-(dimethylamino)-3-[[2-(9H-fen-9-ylmethoxycarbonylamino)acetyl]-methylamino]- Synthesis of 4-oxobutanoic acid (Fmoc-Gly-MeAsp-NMe2) Using compound aa2-013-b (1.07 g, 2.17 mmol) as the starting material, the compound aa2 was obtained as 1.01 g (yield 103%) of light brown amorphous crystal by the same method as the synthesis of compound aa2-001 -013. LCMS(ESI) m / z=454.4 (M+H) + Hold time: 0.67 minutes (analysis condition SQDFA05)

[0260] Synthesis of compound aa2-014, Fmoc-Aib-MeAsp-NMe2

[0261] Compound aa2-014-a, (3S)-4-(dimethylamino)-3-(methylamino)-4-oxobutanoic acid prop-2-enyl (H-MeAsp(OAl) -Synthesis of NMe2) Compound aa2-006-a (18.0 g, 41.2 mmol) and DCM (180 mL) were added to a reaction vessel, followed by DBU (6.28 g, 41.2 mmol) at room temperature. After the reaction solution was stirred for 5 minutes, the reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to sequential silica gel column chromatography (petroleum ether / ethyl acetate=100 / 0→0 / 100, followed by DCM / methanol =100 / 0→85 / 15) to obtain 8.1 g (yield 87%) of compound aa2-014-a as a yellow oily substance. LCMS(ESI) m / z=215.2 (M+H) + Hold time: 0.41 minutes (analysis condition SMDmethod_4)

[0262] Compound aa2-014-b, (3S)-4-(dimethylamino)-3-[[2-(9H-fen-9-ylmethoxycarbonylamino)-2-methylpropionyl] Synthesis of -methylamino]-4-oxobutanoic acid prop-2-enyl (Fmoc-Aib-MeAsp(OAl)-NMe2) Under nitrogen flow, compound aa2-014-a (4.35 g, 20.3 mmol), Fmoc-Aib-OH (6.0 g, 18.4 mmol), COMU (11.8 g, 27.7 mmol), and DMF (60 mL ), followed by dropwise addition of DIPEA (2.38 g, 18.4 mmol) at 0 °C. After the reaction solution was stirred at 40 °C for 16 hours, ethyl acetate (120 mL) was added to the reaction solution, and the organic layer was washed twice with 1 mol / L hydrochloric acid aqueous solution (60 mL) and washed with water (60 mL). After washing once, washing twice with saturated aqueous sodium bicarbonate (60 mL), and washing with saturated aqueous sodium chloride (60 mL), the organic layer was dried over sodium sulfate. After filtering off the dried material, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to normal-phase silica gel column chromatography (petroleum ether / ethyl acetate=100 / 0→50 / 50), followed by reverse-phase silica gel column chromatography. Purification by chromatography (water / acetonitrile=95 / 5→50 / 50) obtained 3.31 g (yield 37%) of compound aa2-014-b as a yellow solid. LCMS(ESI) m / z=522.5 (M+H) + Hold time: 0.85 minutes (analysis condition SQDFA05)

[0263] Compound aa2-014, (3S)-4-(dimethylamino)-3-[[2-(9H-fen-9-ylmethoxycarbonylamino)-2-methylpropionyl]-methanol Synthesis of Amino]-4-oxobutanoic Acid (Fmoc-Aib-MeAsp-NMe2) Compound aa2-014-b (1.14 g, 2.19 mmol) was used as the starting material, and compound aa2 was obtained as light brown amorphous 1.04 g (yield 99%) by the same method as the synthesis of compound aa2-001 -014. LCMS(ESI) m / z=482.4 (M+H) + Hold time: 0.70 minutes (analysis condition SQDFA05)

[0264] Synthesis of Compound aa2-015, Fmoc-bAla(2-Me2)-D-3-MeAbu-OH

[0265] Compound aa2-015-b, (3R)-3-[[3-(9H-Oxime-9-ylmethoxycarbonylamino)-2,2-dimethylpropionyl]-methylamino]butyl Synthesis of Acid Prop-2-enyl (Fmoc-bAla(2-Me2)-D-3-MeAbu-OAl) Using compound aa2-008-a (8.0 g, 21.1 mmol) and Fmoc-bAla(2-Me2)-OH (7.5 g, 22.2 mmol) as starting materials, using the same synthesis method as compound aa2-001-a 1.28 g (yield 13%) of compound aa2-015-b was obtained as a light yellow oily substance. LCMS(ESI) m / z=479.5 (M+H) + Hold time: 1.00 minutes (analysis condition SQDFA05)

[0266] Compound aa2-015, (3R)-3-[[3-(9H-fluorene-9-ylmethoxycarbonylamino)-2,2-dimethylpropionyl]-methylamino]butanoic acid ( Synthesis of Fmoc-bAla(2-Me2)-D-3-MeAbu-OH) Under nitrogen flow, compound aa2-015-b (602 mg, 1.26 mmol) and tetrakistriphenylphosphine palladium (14.5 mg, 0.013 mmol) were added in a reaction vessel, followed by DCM (2.5 mL). In the reaction liquid, after dropping phenylsilane (95 mg, 0.88 mmol), the reaction liquid was stirred at room temperature for 30 minutes. Then tetraphenyltriphenylphosphine palladium (14.5 mg, 0.013 mmol) and phenylsilane (95 mg, 0.88 mmol) were added to the reaction solution, and stirred at room temperature for 30 minutes. The reaction solution was diluted with TBME (6.0 mL), extracted with saturated aqueous sodium bicarbonate / water (1 / 1, 6.0 mL), and then extracted with water (3.0 mL). An 85% phosphoric acid aqueous solution (0.516 mL, 7.55 mmol) was added to the combined aqueous layers to make it acidic around pH 2, and the aqueous layer was extracted twice with DCM (6.0 mL). After the combined organic layers were washed with saturated aqueous sodium chloride / water (1 / 1, 6.0 mL), the organic layer was dried over sodium sulfate. After filtering off the dried material, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by reverse phase silica gel column chromatography (water / acetonitrile=90 / 10→30 / 70) to obtain 285 mg of white solid ( Yield 52%) of compound aa2-015. LCMS(ESI) m / z=439.5 (M+H) + Hold time: 0.80 minutes (analysis condition SQDFA05)

[0267] Synthesis of compound aa2-016, Fmoc-MeLeu-MeVal-OH

[0268] Compound aa2-016-a, (2S)-2-[9H-fluorene-9-ylmethoxycarbonyl (methyl)amino]-3-methylbutyric acid prop-2-enyl (Fmoc-MeVal-OAl )Synthesis Under nitrogen flow, Fmoc-MeVal-OH (2.00 g, 5.66 mmol), allyl bromide (0.75 g, 6.20 mmol), potassium carbonate (1.17 g, 8.47 mmol) and DMF (20 mL) were added to the reaction vessel, The reaction was stirred at room temperature for 4 hours. After filtration, the filtrate was neutralized with 1 mol / L hydrochloric acid aqueous solution at 0 °C, and extracted three times with ethyl acetate. After the combined organic layers were washed once with water and twice with saturated aqueous sodium chloride, the organic layer was dried over sodium sulfate. After filtering off the dried material, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by parallel-phase silica gel column chromatography (petroleum ether / ethyl acetate=100 / 0→90 / 10) to obtain a colorless oil Material 1.9 g (85% yield) of compound aa2-016-a. LCMS(ESI) m / z=394.2 (M+H) + Hold time: 1.21 minutes (analysis condition SMDmethod_5)

[0269] Compound aa2-016-b, (2S)-2-[[(2S)-2-[9H-fen-9-ylmethoxycarbonyl (methyl)amino]-4-methylpentyl]-methanol Synthesis of 2-amino]-3-methylbutanoic acid prop-2-enyl (Fmoc-MeLeu-MeVal-OAl) Using compound aa2-016-a (1.0 g, 2.64 mmol) and Fmoc-MeLeu-OH (1.02 g, 2.77 mmol) as starting materials, using the same method as the synthesis of compound aa2-001-a, obtained as 0.90 g (64% yield) of compound aa2-016-b as a colored oily substance. LCMS(ESI) m / z=521.6 (M+H) + Hold time: 1.16 minutes (analysis condition SQDFA05)

[0270] Compound aa2-016, (2S)-2-[[(2S)-2-[9H-fen-9-ylmethoxycarbonyl(methyl)amino]-4-methylpentyl]-methylamine Synthesis of ]-3-methylbutanoic acid (Fmoc-MeLeu-MeVal-OH) Using compound aa2-016-b (417 mg, 0.80 mmol) as the starting material, the compound aa2 was obtained as 185 mg (yield 48%) of light brown amorphous crystal by the same method as the synthesis of compound aa2-001 -016. LCMS(ESI) m / z=481.5 (M+H) + Hold time: 0.97 minutes (analysis condition SQDFA05)

[0271] Synthesis of compound aa2-017, Fmoc-MeVal-Pro-OH

[0272] Compound aa2-017-a, (2S)-pyrrolidine-1,2-dicarboxylic acid 2-O-prop-2-enyl 1-O-(9H-fluorene-9-ylmethyl)(Fmoc-Pro -OAl) synthesis Using Fmoc-Pro-OH (5.00 g, 14.8 mmol) as the starting material, compound aa2 was obtained in the form of 5.3 g (yield 94%) of a colorless oily substance by the same method as the synthesis of compound aa2-016-a -017-a. LCMS(ESI) m / z=378.2 (M+H) + Hold time: 1.10 minutes (analysis condition SMDmethod_5)

[0273] Compound aa2-017-b, (2S)-1-[(2S)-2-[9H-Oxyl-9-ylmethoxycarbonyl(methyl)amino]-3-methylbutyryl]pyrrolidine-2- Synthesis of Prop-2-enyl Carboxylate (Fmoc-MeVal-Pro-OAl) Using compound aa2-017-a (5.3 g, 14.0 mmol) and Fmoc-MeVal-OH (5.21 g, 14.7 mmol) as starting materials, using the same method as the synthesis of compound aa2-001-a, obtained as 5.2 g (74% yield) of compound aa2-017-b as a colored oily substance. LCMS(ESI) m / z=491.5 (M+H) + Hold time: 1.00 minutes (analysis condition SQDFA05)

[0274] Compound aa2-017, (2S)-1-[(2S)-2-[9H-Oxime-9-ylmethoxycarbonyl(methyl)amino]-3-methylbutyryl]pyrrolidine-2-carboxylic acid Synthesis of (Fmoc-MeVal-Pro-OH) Using compound aa2-017-b (1.57 g, 3.20 mmol) as the starting material, the compound aa2 was obtained as 1.35 g (yield 94%) of light brown amorphous crystal by the same method as the synthesis of compound aa2-001 -017. LCMS(ESI) m / z=451.5 (M+H) + Hold time: 0.81 minutes (analysis condition SQDFA05)

[0275] Synthesis of compound aa2-018, Fmoc-MeLeu-Aib-OH

[0276] Synthesis of compound aa2-018-a, 2-(9H-fluorene-9-ylmethoxycarbonylamino)-2-methylpropanoic acid prop-2-enyl (Fmoc-Aib-OAl) Using Fmoc-Aib-OH (7.00 g, 21.5 mmol) as a starting material, 7.5 g (yield 94%) of compound aa2 was obtained as a colorless oily substance by the same method as the synthesis of compound aa2-016-a -018-a. LCMS(ESI) m / z=366.1 (M+H) + Hold time: 1.08 minutes (analysis condition SMDmethod_5)

[0277] Compound aa2-018-b, 2-[[(2S)-2-[9H-oxa-9-ylmethoxycarbonyl(methyl)amino]-4-methylpentyl]amino]-2- Synthesis of prop-2-enyl methylpropanoate (Fmoc-MeLeu-Aib-OAl) Using compound aa2-018-a (7.00 g, 19.2 mmol) and Fmoc-MeLeu-OH (7.39 g, 20.1 mmol) as starting materials, using the same method as the synthesis of compound aa2-001-a, a yellow 6.2 g (65% yield) of compound aa2-018-b in oily substance. LCMS(ESI) m / z=493.5 (M+H) + Hold time: 1.07 minutes (analysis condition SQDFA05)

[0278] Compound aa2-018, 2-[[(2S)-2-[9H-fluorene-9-ylmethoxycarbonyl(methyl)amino]-4-methylpentyl]amino]-2-methyl Synthesis of Propanic Acid (Fmoc-MeLeu-Aib-OH) Using compound aa2-018-b (985 mg, 2.00 mmol) as the starting material, the compound aa2 was obtained as 608 mg (yield 67%) of light brown amorphous crystal by the same method as the synthesis of compound aa2-001 -018. LCMS(ESI) m / z=453.5 (M+H) + Hold time: 0.91 minutes (analysis condition SQDFA05)

[0279] Synthesis of compound aa2-019, Fmoc-MeVal-Gly-OH

[0280] Synthesis of compound aa2-019-a, 2-(9H-fluorene-9-ylmethoxycarbonylamino)acetate prop-2-enyl (Fmoc-Gly-OAl) Using Fmoc-Gly-OH (7.00 g, 23.5 mmol) as a starting material, 7.5 g (yield 91%) of compound aa2 was obtained as a colorless oily substance by the same method as the synthesis of compound aa2-016-a -019-a. LCMS(ESI) m / z=338.2 (M+H) + Hold time: 1.16 minutes (analysis condition SMDmethod_6)

[0281] Compound aa2-019-b, 2-[[(2S)-2-[9H-oxa-9-ylmethoxycarbonyl(methyl)amino]-3-methylbutyryl]amino]acetate prop-2- Synthesis of Alkenyl (Fmoc-MeVal-Gly-OAl) Using compound aa2-019-a (5.0 g, 14.8 mmol) and Fmoc-MeVal-OH (5.5 g, 15.6 mmol) as starting materials, using the same method as the synthesis of compound aa2-001-a, obtained as 4.3 g (64% yield) of compound aa2-019-b as a colored oily substance. LCMS(ESI) m / z=451.5 (M+H) + Hold time: 0.96 minutes (analysis condition SQDFA05)

[0282] Compound aa2-019, 2-[[(2S)-2-[9H-fluorene-9-ylmethoxycarbonyl (methyl)amino]-3-methylbutyryl]amino]acetic acid (Fmoc-MeVal-Gly -OH) synthesis Using compound aa2-019-b (1.47 g, 3.27 mmol) as the starting material, the compound aa2 was obtained as 1.31 g (yield 98%) of light brown amorphous crystal by the same method as the synthesis of compound aa2-001 -019. LCMS(ESI) m / z=411.4 (M+H) + Hold time: 0.79 minutes (analysis condition SQDFA05)

[0283] Synthesis of compound aa2-020, Fmoc-D-MeVal-MeAsp-NMe2

[0284] Compound aa2-020-b, (3S)-4-(dimethylamino)-3-[[(2R)-2-[9H-oxa-9-ylmethoxycarbonyl(methyl)amino]- Synthesis of 3-methylbutyryl]-methylamino]-4-oxobutanoic acid prop-2-enyl (Fmoc-D-MeVal-MeAsp(OAl)-NMe2) Using compound aa2-006-a (5.00 g, 11.5 mmol) and Fmoc-D-MeVal-OH (4.08 g, 11.5 mmol) as starting materials, using the same method as the synthesis of compound aa2-001-a, to obtain 3.1 g (49% yield) of compound aa2-020-b as a white solid. LCMS(ESI) m / z=550.5 (M+H) + Hold time: 0.98 minutes (analysis condition SQDFA05)

[0285] Compound aa2-020, (3S)-4-(dimethylamino)-3-[[(2R)-2-[9H-oxa-9-ylmethoxycarbonyl(methyl)amino]-3- Synthesis of methylbutyryl]-methylamino]-4-oxobutanoic acid (Fmoc-D-MeVal-MeAsp-NMe2) Using compound aa2-020-b (1.37 g, 2.50 mmol) as a starting material, the compound aa2-b was obtained as 1.20 g (yield 94%) of white amorphous crystals by the same method as that of compound aa2-001. 020. LCMS(ESI) m / z=510.5 (M+H) + Hold time: 0.79 minutes (analysis condition SQDFA05)

[0286] Synthesis of Compound aa2-021, Fmoc-bAla(2-Me2)-MeAsp-NMe2

[0287] Compound aa2-021-b, (3S)-4-(dimethylamino)-3-[[3-(9H- fen-9-ylmethoxycarbonylamino)-2,2-dimethylpropane Synthesis of Acyl]-Methylamino]-4-oxobutyric acid prop-2-enyl (Fmoc-bAla(2-Me2)-MeAsp(OAl)-NMe2) Using compound aa2-014-a (5.92 g, 27.6 mmol) and Fmoc-bAla (2-Me2)-OH) (8.6 g, 25.3 mmol) as starting materials, using the same synthesis method as compound aa2-014-b , obtained 3.63 g (26% yield) of compound aa2-021-b as a yellow solid. LCMS(ESI) m / z=536.6 (M+H) + Hold time: 0.90 minutes (analysis condition SQDFA05)

[0288] Compound aa2-021, (3S)-4-(dimethylamino)-3-[[3-(9H-fen-9-ylmethoxycarbonylamino)-2,2-dimethylpropionyl Synthesis of ]-methylamino]-4-oxobutanoic acid (Fmoc-bAla(2-Me2)-MeAsp-NMe2) Compound aa2-021-b (1.07 g, 2.00 mmol) was used as the starting material, and 874 mg (yield: 88%) of compound aa2 was obtained as light brown amorphous crystals by the same method as the synthesis of compound aa2-001 -021. LCMS(ESI) m / z=496.5 (M+H) + Hold time: 0.74 minutes (analysis condition SQDFA05)

[0289] Synthesis of compound aa2-022, Fmoc-MeVal-D-MeAsp-NMe2

[0290] Compound aa2-022-a, (4R)-5-oxo-4-(2-oxo-2-prop-2-oxiranyl)-1,3-oxazolidine-3-carboxylic acid Synthesis of 9H-Oxen-9-ylmethyl Under nitrogen flow, add Fmoc-D-Asp(OAl)-OH (20.0 g, 50.6 mmol), paraformaldehyde (4.56 g, 152 mmol), p-toluenesulfonic acid (0.09 g, 0.506 mmol) into the reaction vessel and toluene (500 mL), and the reaction solution was stirred at 90 °C for 16 hours. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in TBME, washed with an aqueous sodium carbonate solution, and the organic phase was dried with sodium sulfate. After filtering off the dried material, the filtrate was concentrated under reduced pressure to obtain 20 g (90% yield) of compound aa2-022-a as a yellow oily substance. LCMS(ESI) m / z=408.2 (M+H) + Hold time: 1.05 minutes (analysis condition SMDmethod_5)

[0291] Compound aa2-022-b, (2R)-2-[9H-fluorene-9-ylmethoxycarbonyl (methyl)amino]-4-oxo-4-prop-2-epoxybutanoic acid (Fmoc Synthesis of -D-MeAsp(OAl)-OH) Under nitrogen flow, compound aa2-022-a (20 g, 49.1 mmol), triethylsilane (11.4 g, 98.2 mmol), DCM (200 mL) and zinc bromide (11.1 g, 49.1 mmol) were added to the reaction vessel ), the reaction solution was stirred at room temperature for 48 hours, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in an aqueous potassium carbonate solution, and washed twice with hexane. The aqueous phase was adjusted to pH 2 with hydrochloric acid, extracted three times with ethyl acetate, and the organic phase was dried over sodium sulfate. After filtering off the dried material, the filtrate was concentrated under reduced pressure to obtain 15 g (93% yield) of compound aa2-022-b as a white solid. LCMS(ESI) m / z=410.2 (M+H) + Hold time: 0.98 minutes (analysis condition SMDmethod_5)

[0292] Compound aa2-022-c, (3R)-4-(dimethylamino)-3-[9H-fen-9-ylmethoxycarbonyl(methyl)amino]-4-oxobutyric acid propane Synthesis of -2-alkenyl (Fmoc-D-MeAsp(OAl)-NMe2) Compound aa2-022-b (15.7 g, 38.3 mmol) was used as a starting material, and 13 g (yield 78%) of compound aa2 was obtained as a yellow oily substance by the same method as the synthesis of compound aa2-006-a -022-c. LCMS(ESI) m / z=437.2 (M+H) + Hold time: 1.86 minutes (analysis condition SMDmethod_7)

[0293] Compound aa2-022-d, (3R)-4-(dimethylamino)-3-[[(2S)-2-[9H-oxa-9-ylmethoxycarbonyl(methyl)amino]- Synthesis of 3-methylbutyryl]-methylamino]-4-oxobutanoic acid prop-2-enyl (Fmoc-MeVal-D-MeAsp(OAl)-NMe2) Using compound aa2-022-c (7.00 g, 16.0 mmol) and Fmoc-MeVal-OH (6.23 g, 17.6 mmol) as starting materials, the white 3.34 g (35% yield) of compound aa2-022-d as a solid. LCMS(ESI) m / z=550.6 (M+H) + Hold time: 0.97 minutes (analysis condition SQDFA05)

[0294] Compound aa2-022, (3R)-4-(dimethylamino)-3-[[(2S)-2-[9H-fennel-9-ylmethoxycarbonyl(methyl)amino]-3- Synthesis of methylbutyryl]-methylamino]-4-oxobutanoic acid (Fmoc-MeVal-D-MeAsp-NMe2) Using compound aa2-022-d (1.37 g, 2.50 mmol) as a starting material, the compound aa2- 022. LCMS(ESI) m / z=510.5 (M+H) + Hold time: 0.79 minutes (analysis condition SQDFA05)

[0295] Synthesis of compound aa2-023, Fmoc-Ala-MeGly(cPent)-MeAsp-NMe2

[0296] Compound aa2-023-b, (3S)-3-[[(2S)-2-cyclopentyl-2-[[(2S)-2-(9H-fen-9-ylmethoxycarbonylamino)propane Acyl]-methylamino]acetyl]-methylamino]-4-(dimethylamino)-4-oxobutanoic acid prop-2-enyl (Fmoc-Ala-MeGly( Synthesis of cPent)-MeAsp(OAl)-NMe2) Using compound aa2-006-b (1.17 g, 2.03 mmol) and Fmoc-Ala-OH (601 mg, 1.93 mmol) as starting materials, using the same method as the synthesis of compound aa2-001-a, a yellow 575 mg (44% yield) of compound aa2-023-b as amorphous crystals. LCMS(ESI) m / z=647.7 (M+H) + Hold time: 0.98 minutes (analysis condition SQDFA05)

[0297] Compound aa2-023, (3S)-3-[[(2S)-2-cyclopentyl-2-[[(2S)-2-(9H-fen-9-ylmethoxycarbonylamino)propionyl ]-methylamino]acetyl]-methylamino]-4-(dimethylamino)-4-oxobutanoic acid (Fmoc-Ala-MeGly(cPent)-MeAsp-NMe2) synthesis Using compound aa2-023-b (575 mg, 0.889 mmol) as a starting material, compound aa2-023 was obtained as a crude product by the same method as that of compound aa2-001. The resulting crude product was dissolved in DMSO and purified by reverse-phase silica gel column chromatography (water / acetonitrile=85 / 15→20 / 80) to obtain 476 mg (yield 88%) of the compound as a white solid aa2-023. LCMS(ESI) m / z=607.6 (M+H) + Hold time: 0.83 minutes (analysis condition SQDFA05)

[0298] Example 1-3. Synthesis of Fmoc-amino acids The Fmoc-amino acids described in Table 4 were synthesized according to the scheme shown below.

[0299] [Table 4]

[0300] Compound aa3-001, (3S)-3-[9H-fluorene-9-ylmethoxycarbonyl (methyl)amino]-4-oxo-4-piperidin-1-ylbutanoic acid (Fmoc-MeAsp -pip) synthesis Compound aa3-001 was synthesized following the method described in WO2018 / 225864.

[0301] Compound aa3-002, (3S)-4-(dimethylamino)-3-[9H-fluorene-9-ylmethoxycarbonyl (methyl)amino]-4-side oxybutanoic acid (Fmoc- Synthesis of MeAsp-NMe2) Using compound aa2-006-a (32.0 g, 73.3 mmol) as the starting material, the compound aa3 was obtained as 25.1 g (yield 86%) of light brown amorphous crystal by the same method as the synthesis of compound aa2-001 -002. LCMS(ESI) m / z=397.2 (M+H) + Hold time: 0.68 minutes (analysis condition SQDFA05)

[0302] Synthesis of compound aa3-003, Fmoc-Asp-NMe2

[0303] Compound aa3-003-a, (3S)-4-(dimethylamino)-3-(9H-fluorene-9-ylmethoxycarbonylamino)-4-oxobutanoic acid-2-methyl Synthesis of Propan-2-yl (Fmoc-Asp(OtBu)-NMe2) Using Fmoc-Asp(OtBu)-OH (25.0 g, 60.8 mmol) purchased from a commercial supplier as a starting material, the crude product was obtained by the same method as the synthesis of compound aa2-006-a. 29.8 g of compound aa3-003-a. LCMS(ESI) m / z=461.3 (M+Na) + Hold time: 0.88 minutes (analysis condition SQDFA05)

[0304] Compound aa3-003, (3S)-4-(dimethylamino)-3-(9H-fluorene-9-ylmethoxycarbonylamino)-4-oxobutanoic acid (Fmoc-Asp-NMe2) Synthesis The crude product of compound aa3-003-a (29.8 g), TFE (270 mL) was added to the reaction vessel, and then 4 mol / L dioxane hydrochloride solution (15.2 mL, 60.8 mmol) was added dropwise. Stir at room temperature for 1 hour. After diluting the reaction solution with TBME (500 mL), it was extracted with 5% aqueous sodium carbonate (600 mL). An 85% phosphoric acid aqueous solution (40-50 mL) was added to the obtained aqueous layer to make it acidic around pH 2-3, and the aqueous layer was extracted with TBME (400 mL). The obtained organic layer was washed with 10% sodium chloride aqueous solution (400 mL) and water (400 mL), and the organic layer was dried over sodium sulfate. After filtering off the dried material, the filtrate was concentrated under reduced pressure to obtain 21.4 g of compound aa3-003 (92% yield). LCMS(ESI) m / z=383.2 (M+H) + Hold time: 0.66 minutes (analysis condition SQDFA05)

[0305] Example 1-4. Synthesis of amino acids and peptide-loaded resins In this specification, when a polymer or resin is combined with a compound, there are cases where the polymer or resin part is marked with ○. In addition, for the purpose of clarifying the reaction point of the resin part, there are cases where the chemical structure of the reaction part is marked by linking with ○. For example, in the above-mentioned structure Fmoc-MeAsp(O-Trt(2-Cl)resin)-pip, the 2-chlorotrityl group of the resin is combined through the side chain carboxylic acid and ester bond of MeAsp, and in Fmoc - MeAsp(NH-Sieber resin)-pip, 9H-𠮿 of the resin The -9-amino group is combined through the side chain carboxylic acid and amide bond of MeAsp. In addition, the so-called pip means piperidine, and in the above structure, the carboxylic acid group at the C-terminal forms a bond between piperidine and amide. 2-Chlorotrityl chloride resin (1.25-1.69 mmol / g, 100-200 mesh, 1%DVB) was purchased from Watanabe Chemical Industry Co., Ltd. and SUNRESIN Company, Fmoc-NH-Sieber resin (0.69 mmol / g , 100-200 mesh, 1%DVB) were purchased from Novabiochem.

[0306] The Fmoc-amino acid or peptide-loaded resins described in Table 5 were synthesized according to the flow chart shown below.

[0307] [table 5]

[0308] Compound aa2-001-resin, (3S)-3-[[(2S)-2-[9H-fen-9-ylmethoxycarbonyl(methyl)amino]-3-methylbutyryl]-methylamine Synthesis of -4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin (Fmoc-MeVal-MeAsp(O-Trt(2-Cl)resin)-pip) 2-Chlorotrityl chloride resin (1.25 mmol / g, 3.10 g, 3.87 mmol) and DCM (21.7 mL) were placed in a reaction vessel with a filter, and shaken at room temperature for 45 minutes. After removing DCM by applying nitrogen pressure, DCM was added to compound aa2-001 (1.06 g, 1.94 mmol), methanol (0.627 mL, 15.5 mmol) and DIPEA (1.62 mL, 9.29 mmol), and a total of 21.7 mL of the prepared The mixture was added to the reaction vessel and shaken at room temperature for 60 minutes. After applying nitrogen pressure and removing the reaction solution, DCM was added to methanol (4.39 mL, 108 mmol) and DIPEA (1.62 mL, 9.29 mmol), and a total of 21.7 mL of the prepared mixture was added to the reaction vessel, shaken at room temperature for 90 minute. After applying nitrogen pressure and removing the reaction solution, put DCM (21.7 mL), shake for 5 minutes, apply nitrogen pressure and remove the reaction solution. This washing operation of the resin using DCM was repeated 5 times, and the obtained resin was dried under reduced pressure overnight to obtain 3.58 g of aa2-001-resin.

[0309] Fmoc quantitative method In order to confirm the loading capacity, the obtained aa2-001-resin (11.94 mg) was put into a reaction vessel, DMF (4.0 mL) was added, and shaken at room temperature for 30 minutes. Afterwards, DBU (40 μL) was added and shaken at 30 °C for 15 min. Thereafter, DMF was added so that the reaction mixture became 10.0 mL, and 80 μL of the solution was diluted with DMF (920 μL). The resulting diluted solution was analyzed by LC / MS (injection volume: 5 μL), and the loading amount of aa2-001-resin was calculated to be 0.363 from the UVarea value of dibenzofulvene (294 nm: 4211.62, 304 nm: 3791.08). mmol / g. (A mixed solution of Fmoc-Gly-OH (purchased from a commercial supplier) and DBU with a known concentration was used as a standard substance, and the UVarea values ​​of dibenzofulvene at wavelengths 294 nm and 304 nm were used for each measurement day For the calibration curve made as a reference, the average value of the loads calculated at each wavelength is taken as the load of the resin).

[0310] Compound aa2-002-resin, (3S)-3-[[(2S,3S)-2-[9H-fen-9-ylmethoxycarbonyl(methyl)amino]-3-methylpentyl] -Methylamino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin (Fmoc-MeIle-MeAsp(O-Trt(2-Cl)resin)- Synthesis of pip) Using 2-chlorotrityl chloride resin (1.25 mmol / g, 2.98 g, 3.72 mmol) and compound aa2-002 (1.05 g, 1.86 mmol) as starting materials, using the same synthesis method as compound aa2-001-resin 3.54 g of compound aa2-002-resin were obtained by the method. If the dry resin (10.47 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.326 mmol / g. (UVarea value at 294 nm: 3648.96, UVarea value at 304 nm: 3280.91)

[0311] Compound aa2-003-resin, (3S)-3-[[(2S)-2-cyclopentyl-2-[9H-oxa-9-ylmethoxycarbonyl(methyl)amino]acetyl]- Methylamino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin (Fmoc-MeGly(cPent)-MeAsp(O-Trt(2-Cl)resin )-pip) synthesis Using 2-chlorotrityl chloride resin (1.25 mmol / g, 3.11 g, 3.88 mmol) and compound aa2-003 (1.12 g, 1.94 mmol) as starting materials, using the same synthesis method as compound aa2-001-resin 3.73 g of compound aa2-003-resin were obtained by the method. If the dry resin (11.34 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.362 mmol / g. (UVarea value at 294 nm: 3979.93, UVarea value at 304 nm: 3588.46)

[0312] Compound aa2-004-resin, (3S)-3-[[(2S)-2-cyclohexyl-2-[9H-oxa-9-ylmethoxycarbonyl(methyl)amino]acetyl]-methanol Amino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin (Fmoc-MeChg-MeAsp(O-Trt(2-Cl)resin)-pip) Synthesis Using 2-chlorotrityl chloride resin (1.25 mmol / g, 2.57 g, 3.22 mmol) and compound aa2-004 (0.949 g, 1.61 mmol) as starting materials, using the same synthesis method as compound aa2-001-resin 3.07 g of compound aa2-004-resin was obtained by the method. If the dry resin (10.09 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.347 mmol / g. (UVarea value at 294 nm: 3412.72, UVarea value at 304 nm: 3069.21)

[0313] Compound aa2-005-resin, (3S)-3-[[(2S)-2-[9H-oxa-9-ylmethoxycarbonyl(methyl)amino]-4-methylpentyl]-methanol Amino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin (Fmoc-MeLeu-MeAsp(O-Trt(2-Cl)resin)-pip) Synthesis Using 2-chlorotrityl chloride resin (1.25 mmol / g, 3.09 g, 3.86 mmol) and compound aa2-005 (1.09 g, 1.93 mmol) as starting materials, using the same synthesis method as compound aa2-001-resin 3.57 g of compound aa2-005-resin was obtained by the method. If the dry resin (10.42 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.355 mmol / g. (UVarea value at 294 nm: 3592.54, UVarea value at 304 nm: 3232.59)

[0314] Compound aa2-006-resin, (3S)-3-[[(2S)-2-cyclopentyl-2-[9H-oxa-9-ylmethoxycarbonyl(methyl)amino]acetyl]- Methylamino]-4-(dimethylamino)-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-MeGly(cPent)-MeAsp(O-Trt(2-Cl) resin)-NMe2) synthesis Using 2-chlorotrityl chloride resin (1.25 mmol / g, 2.35 g, 2.94 mmol) and compound aa2-006 (0.786 g, 1.47 mmol) as starting materials, using the same synthesis method as compound aa2-001-resin 2,72 g of compound aa2-006-resin were obtained by the method. If the dry resin (11.77 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.345 mmol / g. (UVarea value at 294 nm: 3965.86, UVarea value at 304 nm: 3566.11)

[0315] Compound aa2-007-resin, (3S)-4-(dimethylamino)-3-[[(2S)-2-[9H-oxa-9-ylmethoxycarbonyl(methyl)amino]- 4-Methylpentyl]-methylamino]-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-MeLeu-MeAsp(O-Trt(2-Cl)resin)-NMe2 )Synthesis Using 2-chlorotrityl chloride resin (1.25 mmol / g, 3.04 g, 3.80 mmol) and compound aa2-007 (0.995 g, 1.90 mmol) as starting materials, using the same synthesis method as compound aa2-001-resin 3.51 g of compound aa2-007-resin were obtained by the method. If the dry resin (10.88 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.384 mmol / g. (UVarea value at 294 nm: 4057.77, UVarea value at 304 nm: 3645.68)

[0316] Compound aa2-008-resin, (3R)-3-[[(2S)-2-[9H-fen-9-ylmethoxycarbonyl(methyl)amino]-3-methylbutyryl]-methylamine Synthesis of butyric acid-2-chlorotrityl resin (Fmoc-MeVal-D-3-MeAbu-O-Trt(2-Cl) resin) Using 2-chlorotrityl chloride resin (1.25 mmol / g, 2.15 g, 2.68 mmol) and compound aa2-008 (0.607 g, 1.34 mmol) as starting materials, using the same synthesis method as compound aa2-001-resin 2.47 g of compound aa2-008-resin were obtained by the method. If the dry resin (11.13 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.415 mmol / g. (UVarea value at 294 nm: 4513.80, UVarea value at 304 nm: 4054.24)

[0317] Compound aa2-009-resin, (3R)-3-[[(2S)-2-cyclohexyl-2-[9H-oxa-9-ylmethoxycarbonyl(methyl)amino]acetyl]-methanol Synthesis of Amino]butyric acid-2-chlorotrityl resin (Fmoc-MeChg-D-3-MeAbu-O-Trt(2-Cl) resin) Using 2-chlorotrityl chloride resin (1.25 mmol / g, 1.62 g, 2.03 mmol) and compound aa2-009 (0.500 g, 1.02 mmol) as starting materials, using the same synthesis method as compound aa2-001-resin 1.91 g of compound aa2-009-resin was obtained by the method. If the dry resin (12.74 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.397 mmol / g. (UVarea value at 294 nm: 4946.37, UVarea value at 304 nm: 4444.88)

[0318] Compound aa2-010-resin, 2-[[(2S)-2-[9H-oxa-9-ylmethoxycarbonyl(methyl)amino]-3-methylbutyryl]-methylamino]acetic acid- Synthesis of 2-chlorotrityl resin (Fmoc-MeVal-MeGly-O-Trt(2-Cl) resin) Using 2-chlorotrityl chloride resin (1.25 mmol / g, 3.17 g, 3.96 mmol) and compound aa2-010 (0.841 g, 1.98 mmol) as starting materials, using the same synthesis method as compound aa2-001-resin 3.49 g of compound aa2-010-resin were obtained by the method. If the dry resin (11.25 mg) was used and the loading was calculated by the Fmoc quantification method, it was 0.374 mmol / g. (UVarea value at 294 nm: 4080.46, UVarea value at 304 nm: 3686.94)

[0319] Compound aa2-011-resin, (3S)-3-[[(2S)-2-cyclopentyl-2-[9H-oxa-9-ylmethoxycarbonyl(methyl)amino]acetyl]- Methyl-amino]-4-N-𠰌linyl-4-oxo-butyric acid-2-chlorotrityl resin (Fmoc-MeGly(cPent)-MeAsp-(O-Trt(2-Cl )resin)-mor) synthesis Put 2-chlorotrityl chloride resin (1.36 mmol / g, 20.5 g, 15.07 mmol) and DCM (140 mL) into a reaction vessel (400 mL) with a filter, and let it stand at room temperature for 1 hour. After removal of DCM by applying nitrogen pressure, a solution of compound aa2-011 (9.50 g, 16.45 mmol), methanol (5.32 mL, 132 mmol) and DIPEA (13.8 mL, 79 mmol) in DCM (140 mL) was added to the reaction vessel, Shake at 60 rpm for 60 minutes at 25°C. After nitrogen pressure was applied and the reaction liquid was removed, methanol (20 ml, 493 mmol) and DIPEA (13.8 mL, 79 mmol) in DCM (140 mL) were added to the reaction vessel and shaken at 60 rpm at 25°C for 60 min. After nitrogen pressure was applied and the reaction solution was removed, DCM (140 mL) was placed and mixed, and nitrogen pressure was applied to discharge. This washing operation of the resin using DCM was repeated 5 times in total, and the obtained resin was dried under reduced pressure for one day to obtain 26.89 g of compound aa2-011-resin. The calculation of the supported amount of the amino acid on the resin was carried out as follows. The obtained compound compound aa2-011-resin (10 mg) was put into a reaction container, DMF (2 mL) was added, and it was left to stand at room temperature for 1 hour. Afterwards, add DBU (40 μL) and shake at 25 °C for 30 min. Thereafter, DMF (8 mL) was added to the reaction mixture, and 1 ml of the solution was diluted with DMF (11.5 mL). The absorbance (294 nm) of the resulting diluted solution was measured (measured using Shimadzu, UV-1600PC (quartz colorimetric tube length 1.0 cm)), and the loading capacity of compound aa2-011-resin was calculated to be 0.415 mmol / g.

[0320] Compound aa2-012-resin, (3S)-4-(dimethylamino)-3-[[(2S)-2-[9H-oxa-9-ylmethoxycarbonyl(methyl)amino]- Synthesis of 3-methylbutyryl]amino]-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-MeVal-Asp(O-Trt(2-Cl)resin)-NMe2) Using 2-chlorotrityl chloride resin (1.25 mmol / g, 3.28 g, 4.10 mmol) and compound aa2-012 (1.02 g, 2.05 mmol) as starting materials, using the same synthesis method as compound aa2-001-resin 3.73 g of compound aa2-012-resin were obtained by the method. If the dry resin (12.55 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.373 mmol / g. (UVarea value at 294 nm: 5042.25, UVarea value at 304 nm: 4531.21)

[0321] Compound aa2-013-resin, (3S)-4-(dimethylamino)-3-[[2-(9H-fen-9-ylmethoxycarbonylamino)acetyl]-methylamino Synthesis of ]-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-Gly-MeAsp(O-Trt(2-Cl)resin)-NMe2) Using 2-chlorotrityl chloride resin (1.25 mmol / g, 3.57 g, 4.46 mmol) and compound aa2-013 (1.01 g, 2.23 mmol) as starting materials, using the same synthesis method as compound aa2-001-resin 3.98 g of compound aa2-013-resin were obtained by the method. If the dry resin (12.33 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.386 mmol / g. (UVarea value at 294 nm: 5134.21, UVarea value at 304 nm: 4593.14)

[0322] Compound aa2-014-resin, (3S)-4-(dimethylamino)-3-[[2-(9H-fen-9-ylmethoxycarbonylamino)-2-methylpropionyl] Synthesis of -methylamino]-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-Aib-MeAsp(O-Trt(2-Cl)resin)-NMe2) Using 2-chlorotrityl chloride resin (1.25 mmol / g, 3.46 g, 4.32 mmol) and compound aa2-014 (1.04 g, 2.16 mmol) as starting materials, using the same synthesis method as compound aa2-001-resin 3.96 g of compound aa2-014-resin were obtained by the method. If the dry resin (10.22 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.413 mmol / g. (UVarea value at 294 nm: 4205.24, UVarea value at 304 nm: 3774.43)

[0323] Compound aa2-015-resin, (3R)-3-[[3-(9H-fluorene-9-ylmethoxycarbonylamino)-2,2-dimethylpropionyl]-methylamino]butyl Synthesis of Acid-2-Chlorotrityl Resin (Fmoc-bAla(2-Me2)-D-3-MeAbu-O-Trt(2-Cl)resin) Using 2-chlorotrityl chloride resin (1.25 mmol / g, 1.02 g, 1.28 mmol) and compound aa2-015 (281 mg, 0.640 mmol) as starting materials, using the same synthesis method as compound aa2-001-resin 1.14 g of compound aa2-015-resin was obtained by the method. If the dry resin (10.46 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.443 mmol / g. (UVarea value at 294 nm: 4615.90, UVarea value at 304 nm: 4143.20)

[0324] Compound aa2-016-resin, (2S)-2-[[(2S)-2-[9H-fen-9-ylmethoxycarbonyl (methyl)amino]-4-methylpentyl]-methanol Synthesis of Fmoc-MeLeu-MeVal-O-Trt(2-Cl)resin Using 2-chlorotrityl chloride resin (1.25 mmol / g, 617 mg, 0.771 mmol) and compound aa2-016 (185 mg, 0.386 mmol) as starting materials, using the same synthesis method as compound aa2-001-resin By the method, 663 mg of compound aa2-016-resin was obtained. If the dry resin (12.18 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.348 mmol / g. (UVarea value at 294 nm: 4325.21, UVarea value at 304 nm: 3876.60)

[0325] Compound aa2-017-resin, (2S)-1-[(2S)-2-[9H-fen-9-ylmethoxycarbonyl(methyl)amino]-3-methylbutyryl]pyrrolidine-2- Synthesis of Carboxylic Acid-2-Chlorotrityl Resin (Fmoc-MeVal-Pro-O-Trt(2-Cl)resin) Using 2-chlorotrityl chloride resin (1.25 mmol / g, 4.79 g, 5.99 mmol) and compound aa2-017 (1.35 g, 3.00 mmol) as starting materials, using the same synthesis method as compound aa2-001-resin 5.40 g of compound aa2-017-resin was obtained by the method. If the dry resin (10.38 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.364 mmol / g. (UVarea value at 294 nm: 3850.10, UVarea value at 304 nm: 3472.31)

[0326] Compound aa2-018-resin, 2-[[(2S)-2-[9H-oxa-9-ylmethoxycarbonyl(methyl)amino]-4-methylpentyl]amino]-2- Synthesis of Methylpropanoic Acid-2-Chlorotrityl Resin (Fmoc-MeLeu-Aib-O-Trt(2-Cl)resin) Using 2-chlorotrityl chloride resin (1.25 mmol / g, 2.15 g, 2.69 mmol) and compound aa2-018 (608 mg, 1.34 mmol) as starting materials, using the same synthesis method as compound aa2-001-resin 2.29 g of compound aa2-018-resin were obtained by the method. If the dry resin (9.61 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.300 mmol / g. (UVarea value at 294 nm: 2934.11, UVarea value at 304 nm: 2651.64)

[0327] Compound aa2-019-resin, 2-[[(2S)-2-[9H-oxa-9-ylmethoxycarbonyl(methyl)amino]-3-methylbutyryl]amino]acetic acid-2-chloro Synthesis of Trityl Resin (Fmoc-MeVal-Gly-O-Trt(2-Cl) resin) Using 2-chlorotrityl chloride resin (1.25 mmol / g, 5.11 g, 6.38 mmol) and compound aa2-019 (1.31 g, 3.19 mmol) as starting materials, using the same synthesis method as compound aa2-001-resin 5.46 g of compound aa2-019-resin was obtained by the method. If the dry resin (10.73 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.303 mmol / g. (UVarea value at 294 nm: 3312.44, UVarea value at 304 nm: 2987.09)

[0328] Compound aa2-020-resin, (3S)-4-(dimethylamino)-3-[[(2R)-2-[9H-oxa-9-ylmethoxycarbonyl(methyl)amino]- 3-methylbutyryl]-methylamino]-4-oxobutyric acid-2-chlorotrityl resin (Fmoc-D-MeVal-MeAsp(O-Trt(2-Cl)resin)-NMe2 )Synthesis Using 2-chlorotrityl chloride resin (1.25 mmol / g, 3.77 g, 4.71 mmol) and compound aa2-020 (1.20 g, 2.36 mmol) as starting materials, using the same synthesis method as compound aa2-001-resin 4.47 g of compound aa2-020-resin was obtained by the method. If the dry resin (11.75 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.396 mmol / g. (UVarea value at 294 nm: 4635.95, UVarea value at 304 nm: 4167.33)

[0329] Compound aa2-021-resin, (3S)-4-(dimethylamino)-3-[[3-(9H- fen-9-ylmethoxycarbonylamino)-2,2-dimethylpropane Acyl]-methylamino]-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-bAla(2-Me2)-MeAsp(O-Trt(2-Cl)resin)-NMe2 )Synthesis Using 2-chlorotrityl chloride resin (1.25 mmol / g, 2.82 g, 3.53 mmol) and compound aa2-021 (874 mg, 1.76 mmol) as starting materials, using the same synthesis method as compound aa2-001-resin 3.24 g of compound aa2-021-resin were obtained by the method. If the dry resin (9.82 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.407 mmol / g. (UVarea value at 294 nm: 3979.96, UVarea value at 304 nm: 3574.96)

[0330] Compound aa2-022-resin, (3R)-4-(dimethylamino)-3-[[(2S)-2-[9H-oxa-9-ylmethoxycarbonyl(methyl)amino]- 3-Methylbutyryl]-methylamino]-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-MeVal-D-MeAsp(O-Trt(2-Cl)resin)-NMe2 )Synthesis Using 2-chlorotrityl chloride resin (1.25 mmol / g, 3.97 g, 4.96 mmol) and compound aa2-022 (1.26 g, 2.48 mmol) as starting materials, using the same synthesis method as compound aa2-001-resin 4.75 g of compound aa2-022-resin was obtained by the method. If the dry resin (10.79 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.396 mmol / g. (UVarea value at 294 nm: 4264.54, UVarea value at 304 nm: 3819.26)

[0331] Compound aa2-023-resin, (3S)-3-[[(2S)-2-cyclopentyl-2-[[(2S)-2-(9H-fen-9-ylmethoxycarbonylamino)propane Acyl]-methylamino]acetyl]-methylamino]-4-(dimethylamino)-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-Ala -Synthesis of MeGly(cPent)-MeAsp(O-Trt(2-Cl)resin)-NMe2) Using 2-chlorotrityl chloride resin (1.25 mmol / g, 700 mg, 0.875 mmol) and compound aa2-023 (265 mg, 0.437 mmol) as starting materials, using the same synthesis method as compound aa2-001-resin 801 mg of compound aa2-023-resin were obtained by the method. If the dry resin (9.35 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.378 mmol / g. (UVarea value at 294 nm: 3477.62, UVarea value at 304 nm: 3130.63)

[0332] Compound aa2-024-resin, (2S)-1-[(2S)-2-(9H-fen-9-ylmethoxycarbonylamino)-3-phenylpropionyl]pyrrolidine-2-carboxylic acid Synthesis of -2-chlorotrityl resin (Fmoc-Phe-Pro-O-Trt(2-Cl) resin) Using 2-chlorotrityl chloride resin (1.25 mmol / g, 1.12 g, 1.40 mmol) and Fmoc-Phe-Pro-OH (339 mg, 0.700 mmol) as starting materials, using the compound aa2-001-resin Synthesis of the same method, to obtain 1.23 g of the compound aa2-024-resin. If the dry resin (9.62 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.383 mmol / g. (UVarea value at 294 nm: 3782.71, UVarea value at 304 nm: 3403.88)

[0333] Compound aa2-025-resin, (2S)-1-[(2S)-2-(9H-fen-9-ylmethoxycarbonylamino)-6-[(2-methylpropan-2-yl)oxy Synthesis of Fmoc-Lys(Boc)-Pro-O-Trt(2-Cl)resin) Using 2-chlorotrityl chloride resin (1.25 mmol / g, 1.12 g, 1.40 mmol) and Fmoc-Lys(Boc)-Pro-OH (396 mg, 0.700 mmol) as starting materials, using compound aa2- 001-resin was synthesized by the same method, and 1.24 g of compound aa2-025-resin was obtained. If the dry resin (11.50 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.339 mmol / g. (UVarea value at 294 nm: 4200.46, UVarea value at 304 nm: 3772.96)

[0334] Compound aa2-026-resin, (2S)-2-[[2-(9H-oxa-9-ylmethoxycarbonylamino)acetyl]amino]-3-[4-[(2-methyl Synthesis of propan-2-yl)oxy]phenyl]propanoic acid-2-chlorotrityl resin (Fmoc-Gly-Tyr(tBu)-O-Trt(2-Cl)resin) Using 2-chlorotrityl chloride resin (1.25 mmol / g, 1.12 g, 1.40 mmol) and Fmoc-Gly-Tyr(tBu)-OH (362 mg, 0.700 mmol) as starting materials, using compound aa2- 001-resin was synthesized by the same method, and 1.15 g of compound aa2-026-resin was obtained. If the dry resin (9.88 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.244 mmol / g. (UVarea value at 294 nm: 2478.91, UVarea value at 304 nm: 2222.03)

[0335] Compound aa2-027-resin, (2S)-2-[[(2S)-2-(9H-fen-9-ylmethoxycarbonylamino)propionyl]amino]propanoic acid-2-chlorotriphenyl Synthesis of Methyl Resin (Fmoc-Ala-Ala-O-Trt(2-Cl)resin) Using 2-chlorotrityl chloride resin (1.25 mmol / g, 1.28 g, 1.60 mmol) and Fmoc-Ala-Ala-OH (306 mg, 0.800 mmol) as starting materials, using the compound aa2-001-resin Synthesis of the same method, to obtain 1.39 g of the compound aa2-027-resin. If the dry resin (9.69 mg) was used and the loading was calculated by the Fmoc quantification method, it was 0.334 mmol / g. (UVarea value at 294 nm: 3496.53, UVarea value at 304 nm: 3128.64)

[0336] Compound aa2-028-resin, 2-[[(2S)-2-(9H-oxa-9-ylmethoxycarbonylamino)-3-phenylpropionyl]amino]acetic acid-2-chlorotriphenyl Synthesis of methyl resin (Fmoc-Phe-Gly-O-Trt(2-Cl) resin) Using 2-chlorotrityl chloride resin (1.25 mmol / g, 1.28 g, 1.60 mmol) and Fmoc-Phe-Gly-OH (356 mg, 0.800 mmol) as starting materials, using the compound aa2-001-resin Synthesis of the same method, to obtain 1.36 g of the compound aa2-028-resin. If the dry resin (10.12 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.248 mmol / g. (UVarea value at 294 nm: 2703.55, UVarea value at 304 nm: 2442.89)

[0337] Compound aa2-029-resin, 2-[[(2S)-2-(9H-fluorene-9-ylmethoxycarbonylamino)-4-oxo-4-(tritylamino)butyryl] Synthesis of amino]acetic acid-2-chlorotrityl resin (Fmoc-Asn(Trt)-Gly-O-Trt(2-Cl) resin) Using 2-chlorotrityl chloride resin (1.25 mmol / g, 1.12 g, 1.40 mmol) and Fmoc-Asn(Trt)-Gly-OH (458 mg, 0.700 mmol) as starting materials, using compound aa2- 001-resin was synthesized by the same method, and 1.15 g of compound aa2-029-resin was obtained. If the dry resin (9.67 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.259 mmol / g. (UVarea value at 294 nm: 2698.79, UVarea value at 304 nm: 2427.13)

[0338] Compound aa2-030-resin, (2S)-2-[[2-(9H-oxa-9-ylmethoxycarbonylamino)acetyl]amino]-3-methylbutyric acid-2-chlorotris Synthesis of Benzyl Resin (Fmoc-Gly-Val-O-Trt(2-Cl) resin) Using 2-chlorotrityl chloride resin (1.25 mmol / g, 1.28 g, 1.60 mmol) and Fmoc-Gly-Val-OH (317 mg, 0.800 mmol) as starting materials, using the compound aa2-001-resin Synthesis of the same method, to obtain 1.38 g of the compound aa2-030-resin. If the dry resin (10.06 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.278 mmol / g. (UVarea value at 294 nm: 3013.51, UVarea value at 304 nm: 2712.54)

[0339] Compound aa2-031-resin, 2-[[(2S)-2-(9H-fluorene-9-ylmethoxycarbonylamino)-3-[(2-methylpropan-2-yl)oxy]propane Synthesis of Acyl]amino]acetic acid-2-chlorotrityl resin (Fmoc-Ser(tBu)-Gly-O-Trt(2-Cl)resin) Using 2-chlorotrityl chloride resin (1.25 mmol / g, 1.12 g, 1.40 mmol) and Fmoc-Ser(tBu)-Gly-OH (308 mg, 0.700 mmol) as starting materials, using compound aa2- 001-resin was synthesized by the same method, and 1.10 g of compound aa2-031-resin was obtained. If the dry resin (10.35 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.258 mmol / g. (UVarea value at 294 nm: 2884.14, UVarea value at 304 nm: 2584.43)

[0340] Compound aa2-032-resin, (2S)-1-[(2S)-2-[[(2S)-2-(9H-fen-9-ylmethoxycarbonylamino)propionyl]amino]propane Synthesis of Acyl]pyrrolidine-2-carboxylic acid-2-chlorotrityl resin (Fmoc-Ala-Ala-Pro-O-Trt(2-Cl)resin) Using 2-chlorotrityl chloride resin (1.25 mmol / g, 1.12 g, 1.40 mmol) and Fmoc-Ala-Ala-Pro-OH (336 mg, 0.700 mmol) as starting materials, using compound aa2-001 Synthesis of -resin In the same way, 1.24 g of compound aa2-032-resin was obtained. If the dry resin (11.15 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.393 mmol / g. (UVarea value at 294 nm: 4495.05, UVarea value at 304 nm: 4047.48)

[0341] Compound aa3-001-resin, (3S)-3-[9H-fluorene-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-piperidin-1-ylbutanoic acid-2 -Synthesis of chlorotrityl resin (Fmoc-MeAsp(O-Trt(2-Cl)resin)-pip) Using 2-chlorotrityl chloride resin (1.44 mmol / g, 44.5 g, 64.1 mmol) and compound aa3-001 (14.0 g, 32.1 mmol) as starting materials, using the same synthesis method as compound aa2-001-resin 52.7 g of compound aa3-001-resin was obtained by the method. If the dry resin (11.29 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.455 mmol / g. (UVarea value at 294 nm: 5277.47, UVarea value at 304 nm: 4746.13)

[0342] Compound aa3-002-resin, (3S)-4-(dimethylamino)-3-[9H-fen-9-ylmethoxycarbonyl(methyl)amino]-4-oxobutanoic acid- Synthesis of 2-Chlorotrityl Resin (Fmoc-MeAsp(O-Trt(2-Cl)resin)-NMe2) Using 2-chlorotrityl chloride resin (1.60 mmol / g, 8.83 g, 14.1 mmol) and compound aa3-002 (2.80 g, 7.06 mmol) as starting materials, using the same synthesis method as compound aa2-001-resin 10.4 g of compound aa3-002-resin was obtained by the method. If the dry resin (11.04 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.442 mmol / g. (UVarea value at 294 nm: 4990.63, UVarea value at 304 nm: 4516.89)

[0343] Compound aa3-003-resin, (3S)-4-(dimethylamino)-3-(9H-fen-9-ylmethoxycarbonylamino)-4-oxobutanoic acid-2-chlorotri Synthesis of Benzyl Resin (Fmoc-Asp(O-Trt(2-Cl)resin)-NMe2) Using 2-chlorotrityl chloride resin (1.44 mmol / g, 39.0 g, 56.2 mmol) and compound aa3-003 (10.7 g, 28.0 mmol) as starting materials, using the same synthesis method as compound aa2-001-resin 45.0 g of compound aa3-003-resin was obtained by the method. If the dry resin (10.48 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.469 mmol / g. (UVarea value at 294 nm: 4929.82, UVarea value at 304 nm: 4428.76)

[0344] Compound aa4-001-resin, (3R)-3-[9H-fluorene-9-ylmethoxycarbonyl (methyl) amino]butyric acid-2-chlorotrityl resin (Fmoc-D-3-MeAbu Synthesis of -O-Trt(2-Cl)resin) Put 2-chlorotrityl chloride resin (1.60 mmol / g, 25.0 g, 40.0 mmol) and DCM (125 mL) into a reaction vessel with a filter, and shake at room temperature for 20 minutes. After removing DCM by applying nitrogen pressure, DCM was added to Fmoc-D-3-MeAbu-OH (3.60 g, 10.6 mmol), methanol (0.859 mL, 21.2 mmol) and DIPEA (12.3 mL, 70.7 mmol), and the prepared A total of 145 mL of the mixture was added to the reaction vessel and shaken at room temperature for 30 minutes. After applying nitrogen pressure and removing the reaction solution, DCM was added to methanol (12.5 mL, 143 mmol) and DIPEA (12.5 mL, 71.8 mmol), and a total of 250 mL of the prepared mixture was added to the reaction vessel, and shaken at room temperature for 90 minute. After applying nitrogen pressure and removing the reaction solution, put DCM (180 mL), shake for 5 minutes, apply nitrogen pressure and remove the reaction solution. This washing operation of the resin using DCM was repeated three times, and the resulting resin was dried overnight under reduced pressure to obtain 28.3 g of aa4-001-resin. If the dry resin (10.36 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.369 mmol / g. (UVarea value at 294 nm: 3920.38, UVarea value at 304 nm: 3530.84)

[0345] Compound aa4-002-resin, 2-[9H- fluorene-9-ylmethoxycarbonyl (methyl) amino] acetic acid-2-chlorotrityl resin (Fmoc-MeGly-O-Trt(2-Cl) resin) synthesis Put 2-chlorotrityl chloride resin (1.60 mmol / g, 12.3 g, 19.7 mmol) and DCM (125 mL) into a reaction vessel with a filter, and shake at room temperature for 20 minutes. After removing DCM by applying nitrogen pressure, a mixture of Fmoc-MeGly-OH (3.07 g, 9.87 mmol), DIPEA (8.25 mL, 47.4 mmol), and DCM (110 mL) was added to the reaction vessel and shaken at room temperature for 60 minutes . After nitrogen pressure was applied and the reaction solution was removed, a mixture of methanol (12.8 mL, 316 mmol), DIPEA (8.25 mL, 47.4 mmol), and DCM (110 mL) was added to the reaction vessel and shaken at room temperature for 90 minutes. After applying nitrogen pressure and removing the reaction solution, put DCM (180 mL), shake for 5 minutes, apply nitrogen pressure and remove the reaction solution. This washing operation of the resin using DCM was repeated twice, and the obtained resin was dried under reduced pressure overnight to obtain 22.2 g of compound aa4-002-resin. If the dry resin (10.00 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.573 mmol / g. (UVarea value at 294 nm: 5879.66, UVarea value at 304 nm: 5289.40)

[0346] Compound aa4-003-resin, (2S)-2-[9H-fluorene-9-ylmethoxycarbonyl (methyl)amino]-3-methylbutanoic acid-2-chlorotrityl resin (Fmoc- Synthesis of MeVal-O-Trt(2-Cl) resin) Using 2-chlorotrityl chloride resin (1.25 mmol / g, 3.03 g, 3.79 mmol) and Fmoc-MeVal-OH (669 mg, 1.89 mmol) as starting materials, the compound aa2-001-resin was synthesized In the same way, 3.37 g of compound aa4-003-resin was obtained. If the dry resin (10.21 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.436 mmol / g. (UVarea value at 294 nm: 4751.39, UVarea value at 304 nm: 4274.97)

[0347] Compound aa4-004-resin, (2S)-pyrrolidine-1,2-dicarboxylic acid 1-O-(9H-fen-9-ylmethyl) 2-O-2-chlorotrityl resin (Fmoc -Synthesis of Pro-O-Trt(2-Cl)resin) Using 2-chlorotrityl chloride resin (1.69 mmol / g, 25.0 g, 42.3 mmol) and Fmoc-Pro-OH (7.13 mg, 21.1 mmol) as starting materials, the compound aa2-001-resin was synthesized In the same way, 28.8 g of compound aa4-004-resin was obtained. If the dry resin (10.87 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.432 mmol / g. (UVarea value at 294 nm: 4714.30, UVarea value at 304 nm: 4225.61)

[0348] Compound aa4-005-resin, 2-(9H- fen-9-ylmethoxycarbonylamino)-2-methylpropanoic acid-2-chlorotrityl resin (Fmoc-Aib-O-Trt(2- Cl)resin)synthesis Using 2-chlorotrityl chloride resin (1.25 mmol / g, 3.15 g, 3.93 mmol) and Fmoc-Aib-OH (640 mg, 1.97 mmol) as starting materials, the compound aa2-001-resin was synthesized In the same way, 3.41 g of compound aa4-005-resin was obtained. If the dry resin (10.43 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.390 mmol / g. (UVarea value at 294 nm: 4336.95, UVarea value at 304 nm: 3918.58)

[0349] Synthesis of compound aa4-006-resin, 2-(9H-fluorene-9-ylmethoxycarbonylamino)acetic acid-2-chlorotrityl resin (Fmoc-Gly-O-Trt(2-Cl)resin) Using 2-chlorotrityl chloride resin (1.25 mmol / g, 2.40 g, 3.00 mmol) and Fmoc-Gly-OH (446 mg, 1.50 mmol) as starting materials, the compound aa2-001-resin was synthesized In the same way, 2.39 g of compound aa4-006-resin was obtained. If the dry resin (10.06 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.250 mmol / g. (UVarea value at 294 nm: 2563.25, UVarea value at 304 nm: 2311.09)

[0350] Compound aa5-001-resin, N-[(2S)-1-[[(2S)-4-[(Sieber resin) amino]-1,4-dioxo-1-piperidin-1-yl Butane-2-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]-N-methylamine formic acid 9H-fluorene-9-ylmethyl (Fmoc- Synthesis of MeVal-MeAsp(NH-Sieber resin)-pip) Put Fmoc-NH-Sieber resin (0.69 mmol / g, 600 mg, 0.414 mmol) into a solid-phase reaction vessel with a filter (glass frit), add DCM (7.2 mL), and let it stand for 30 minutes to proceed the resin After swelling, the solution is drained from the frit. A solution of DBU in DMF (2% v / v, 4.2 mL) was added to the solid-phase reaction vessel containing the resin, and allowed to react at room temperature for 4.5 minutes. After the removal reaction of the Fmoc group was carried out, the solution was drained from the frit. DMF (4.2 mL) was added here, and after standing for 5 minutes, the solution was drained from the frit. This resin washing step was further repeated 3 times. Then, compound aa2-001 (594 mg, 1.08 mmol) and HOAt (92 mg, 0.676 mmol) in NMP (1.80 mL), and DIC (192 mg, 1.52 mmol) in DMF (2.16 mL) were mixed After that, it was added to the resin, and the solid-phase reaction container was heated to 40° C. and reacted for 2.5 hours to perform condensation reaction, and the solution was discharged from the glass frit. Then, the resin was washed 4 times with DMF (4.2 mL) and then 5 times with DCM (4.2 mL), and the obtained resin was dried overnight under reduced pressure to obtain 688 mg of compound aa5-001-resin. If the dry resin (11.46 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.538 mmol / g. (UVarea value at 294 nm: 6072.34, UVarea value at 304 nm: 5457.70)

[0351] Example 2. In the peptide synthesis under solid phase, the comparison experiment of the recovery rate and purity of the peptide in the case of loaded dipeptide and the case of loaded amino acid monomer In this example, a comparison of the recovery rate and purity when the tripeptide represented by Fmoc-AA3-AA2-AA1-resin was synthesized under the following 3 conditions by solid phase reaction using a peptide synthesizer is described.

[0352] [Table 6]

[0353] [Table 7]

[0354] The peptide synthesis by solid-phase reaction described in this example was carried out by the Fmoc method using a peptide synthesizer (Multipep RS; manufactured by Intavis Corporation). The detailed procedure on operation follows the manual attached to the synthesizer.

[0355] The detailed synthesis conditions in Example 2 are disclosed in Synthesis Method 1 below.

[0356] Synthesis 1 Solution 1 was prepared by dissolving HOAt or oxyma (0.375 mol / L) in NMP as an activator of Fmoc-protected amino acids (0.6 mol / L) and carboxylic acids constituting the target peptide. When the Fmoc-protected amino acid is insoluble, solution 1 was prepared by adding DMSO to 20-30% (v / v). Moreover, it mixed with DMF so that DIC might become 10% (v / v), and the solution 2 was prepared. Put the resin (100 mg) loaded with the Fmoc amino acid or peptide prepared in Examples 1-4 into a solid-phase reaction vessel with a filter (glass frit), and install it in a peptide synthesis machine. DCM (1.2 mL) was added and allowed to stand for 30 min to allow swelling of the resin, and the solution was drained from the frit. Install solution 1 and solution 2 into the peptide synthesis machine, and start the automatic synthesis by the peptide synthesis machine.

[0357] A DBU solution (2% v / v, 0.7 mL) was added to a solid-phase reaction vessel containing the resin, and the Fmoc group removal reaction was carried out at room temperature. In the deprotection of the first residue, allow to react for 4.5 min and in the deprotection of the second residue after that, allow to react for 10 min. After that, the solution is drained from the frit. DMF (0.7 mL) was added here, and after standing for 5 minutes, the solution was drained from the frit. This resin washing step was further repeated 3 times. Next, mix solution 1 (0.3 mL) and solution 2 (0.36 mL) with the mixing vial of the synthesis machine, add to the resin, heat the solid-phase reaction vessel to 40°C or 50°C, and react for 2.5 hours or 10 After hours, the amine groups on the resin and the Fmoc-protected amino acids undergo condensation reactions, and the solution is discharged from the glass frit. The resin was then washed 3 times with DMF (0.7 mL). After the removal reaction of the Fmoc group, the condensation reaction of the Fmoc amino acid is set as one cycle, and by repeating this cycle, the peptide is extended on the resin surface.

[0358] After peptide extension, the obtained resin was washed 4 times with DMF (0.7 mL) and 4 times with DCM (0.7 mL), and then dried naturally at room temperature for 48 hours. A part of the obtained resin (about 10 mg) was put into a reaction vessel, and the loading amount of the peptide on the resin was calculated following the Fmoc quantitative method described in Examples 1-4. Also, put a part of the obtained resin (about 20 mg) into a reaction vessel, add DIPEA containing 0.75% (v / v) or TFE / DCM solution (1 / 1, 1 mL) not containing, shake at room temperature for 2 Hours, the cutting-out reaction of the peptide was carried out. After the reaction, the excised solution was analyzed by LCMS to confirm the product on the resin.

[0359] The definition and calculation method of the recovery rate in Example 2 are disclosed in the recovery rate calculation method below.

[0360] Calculation method of recovery rate In Example 2, the recovery rate was defined as follows, and the detachment rate of amino acids and peptides from the resin in the solid-phase reaction was evaluated, in other words, the inhibition rate of premature cleavage. Recovery = Loading amount of resin loaded with reaction product (mmol / g) ÷ Loading amount of resin (mmol / g) when the target product is 100% produced (Formula 1)

[0361] The supported amount (mmol / g) of the resin when 100% of the target substance was produced was calculated as follows. Loading amount of resin (mmol / g) in the case of 100% formation of the target object = loading amount of starting material resin (mmol / g) × weight (g) of raw material resin ÷ case of 100% formation of the target object The weight of the resin (g) (Equation 2)

[0362] The weight (g) of the resin in the case where 100% of the target object was formed was calculated as follows. The weight of the resin (g) in the case where the target substance is 100% produced = the weight (g) of the starting material resin - the weight (g) of the amino acid or peptide component on the starting material resin + the target substance has been 100 The weight (g) of the peptide component on the resin in the case of % formation (Formula 3)

[0363] The weight (g) of the amino acid or peptide component on the starting material resin is calculated as follows. The weight (g) of the amino acid or peptide component on the starting material resin = the weight (g) of the starting material resin × the loading amount of the starting material resin (mmol / g) × the amine on the starting material resin Molecular weight (g / mol)×0.001(mol / mmol) of amino acid or peptide component (Formula 4)

[0364] The weight (g) of the peptide component on the resin when the target object is 100% produced is calculated as follows. The weight (g) of the peptide component on the resin when the target substance is 100% produced = the weight (g) of the starting material resin x the loading amount of the starting material resin (mmol / g) x the peptide component of the target substance Molecular weight (g / mol) × 0.001 (mol / mmol) (formula 5)

[0365] If formula 3, formula 4, and formula 5 are substituted into formula 2, then Loading amount of the resin (mmol / g) in the case where the target substance is 100% produced = loading amount of the starting material resin (mmol / g) ÷ (1 - loading amount of the starting material resin (mmol / g) × starting Molecular weight (g / mol) of the amino acid or peptide component on the raw material resin x 0.001 (mol / mmol) + loading amount of the starting material resin (mmol / g) x molecular weight of the target peptide component (g / mol)×0.001(mol / mmol)) = 1÷(1÷loading capacity of starting material resin (mmol / g) - molecular weight of amino acid or peptide component on starting material resin (g / mol )×0.001(mol / mmol) + molecular weight of the target peptide component (g / mol)×0.001(mol / mmol))(Formula 6)

[0366] When formula 6 is substituted into formula 1, the recovery rate is calculated by the following formula. Recovery rate = loading amount of reaction product loading resin (mmol / g) × (1÷ loading amount of starting material resin (mmol / g) - amino acid on the starting material resin, or molecular weight of peptide component ( g / mol)×0.001(mol / mmol) + molecular weight of the target peptide component (g / mol)×0.001(mol / mmol))

[0367] Compound pd2-001-resin, (3S)-3-[[(2S)-2-[[(2S,3S)-2-(9H-fennel-9-ylmethoxycarbonylamino)-3-methyl Pentyl]-methylamino]-3-methylbutyryl]-methylamino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl resin ( Synthesis of Fmoc-Ile-MeVal-MeAsp(O-Trt(2-Cl)resin)-pip) Synthesis of pd2-001-resin by condition 1

[0368] The two peptide-loaded resin aa2-001-resin (Fmoc-MeVal-MeAsp(O-Trt(2-Cl) resin)-pip) (100 mg, 0.363 mmol / g) prepared in Examples 1-4 was used as As the starting material, following Synthesis 1, the extension of Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours) was carried out to synthesize pd2-001-resin. If the dry resin (11.36 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.344 mmol / g. (UVarea value at 294 nm: 3907.18, UVarea value at 304 nm: 3521.50)

[0369] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.344 × (1 ÷ 0.363 - 549.67 × 0.001 + 662.83 × 0.001)=98.7% Furthermore, as a result of analyzing the excised reaction solution by LCMS, the purity of the target pd2-001 was 98.2 area %, and the epimer pd2-001-a was observed at 1.8 area %. Furthermore, this epimer is an impurity already seen in the preparation stage of compound aa2-001, not an impurity originating from this step of elongating AA3 (here Ile).

[0370] Analysis conditions: SQDAA50long [Table 8] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area% pd2-001 Target 662.83 663.7(M+H)+ 1.78 98.2 pd2-001-a Epimer 662.83 663.7(M+H)+ 2.01 1.8

[0371] Synthesis of pd2-001-resin by condition 2 The amino acid-loaded resin aa3-001-resin (Fmoc-MeAsp(O-Trt(2-Cl) resin)-pip) (100 mg, 0.455 mmol / g) prepared in Examples 1-4 was used as a starting point Raw materials, following the synthesis method 1, the extension of Fmoc-MeVal-OH (HOAt, 40°C, 2.5 hours), followed by the extension of Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours) to synthesize pd2-001-resin . If the dry resin (10.45 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.292 mmol / g. (UVarea value at 294 nm: 3046.82, UVarea value at 304 nm: 2746.87)

[0372] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.292 × (1 ÷ 0.455 - 436.51 × 0.001 + 662.83 × 0.001)=70.8% In addition, the results of the cut-out reaction solution were analyzed by LCMS. The purity of the target pd2-001 was 61.6 area%, the epimer pd2-001-a was 6.5 area%, and the excess extension pd2-001-b was 2.4 area%. %, AA2 deletion pd2-001-c was observed in 29.5 area%. Here, the so-called excess extension body pd2-001-b means the following compound: when AA2 (here MeVal) is elongated, AA1 (here MeAsp-pip) is detached from the resin, and the detached AA1 will be supported on AA1 on the resin is extended, that is, a compound that combines two AA1s, and then AA2 and AA3 are extended. Unless otherwise specified, in the following examples, the so-called excess extension body also refers to a compound in which two AA1s are combined.

[0373] Analysis conditions: SQDAA50long [Table 9] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area% pd2-001 Target 662.83 663.7(M+H)+ 1.78 61.6 pd2-001-a Epimer 662.83 663.7(M+H)+ 2.00 6.5 pd2-001-b excess extension 859.08 859.8(M+H)+ 2.18 2.4 pd2-001-c AA2 deletion 549.67 550.5(M+H)+ 1.63 29.5

[0374] Synthesis of pd2-001-resin by condition 3 The amino acid-loaded resin aa3-001-resin (Fmoc-MeAsp(O-Trt(2-Cl) resin)-pip) (100 mg, 0.455 mmol / g) prepared in Examples 1-4 was used as a starting point Raw materials, following Synthesis 1, carried out the extension of Fmoc-MeVal-OH (oxyma, 50°C, 10 hours), followed by the extension of Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours) to synthesize pd2-001-resin . If the dry resin (10.89 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.332 mmol / g. (UVarea value at 294 nm: 3612.81, UVarea value at 304 nm: 3267.35)

[0375] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.332 × (1 ÷ 0.455 - 436.51 × 0.001 + 662.83 × 0.001)=80.5% Furthermore, as a result of LCMS analysis of the excised reaction solution, the purity of the target pd2-001 was 93.7 area %, the epimer pd2-001-a was 2.6 area %, and the excess extension pd2-001-b was observed is 3.7 area%.

[0376] Analysis conditions: SQDAA50long [Table 10] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area% pd2-001 Target 662.83 663.6(M+H)+ 1.79 93.7 pd2-001-a Epimer 662.83 663.7(M+H)+ 2.02 2.6 pd2-001-b excess extension 859.08 859.8(M+H)+ 2.20 3.7

[0377] The above results are summarized in the table below. [Table 11] Recovery rate(%) Target pd2-001 (area%) Epimer pd2-001-a (area%) excess extension pd2-001-b (area%) AA2 deletion pd2-001-c (area%) Condition 1 98.7 98.2 1.8 - - Condition 2 70.8 61.6 6.5 2.4 29.5 Condition 3 80.5 93.7 2.6 3.7 -

[0378] In condition 1 of loading dipeptide, the target substance can be obtained with high recovery rate and high purity. In the case of loaded amino acid monomers, in the usual condition 2, in addition to the decrease in the recovery rate due to premature cleavage, the formation of excess elongators and poor elongation from the difficult-to-extend site, that is, AA2, were also observed. The resulting generation of AA2 deletions. In condition 3 corresponding to the difficult-to-extend sequence, a decrease in the recovery rate due to premature division was also observed, and although no AA2 deletion was observed, an increase in the generation of excess elongation was confirmed.

[0379] In addition, in condition 1, similarly to condition 2 and condition 3, the epimer (pd2-001-a) which is an impurity was also confirmed. This is also an impurity that has been seen during the preparation stage of compound aa2-001 as previously described. That is, it is an impurity that can be avoided by strict purification of the compound aa2-001 prepared by the liquid phase method. On the other hand, in conditions 2 and 3, which are general peptide synthesis methods, there is a decrease in purity due to progress of epimerization on a solid phase. In the case where AA2 is difficult to elongate amino acids and easily causes epimerization upon elongation, in the point of avoiding the possibility of reducing the purity of the peptide due to epimerization, it has also been shown that two Advantages of peptide elongation method.

[0380] Compound pd2-002-resin, (3S)-3-[[(2S,3S)-2-[[(2S,3S)-2-(9H-Oxyl-9-ylmethoxycarbonylamino)-3- Methylpentyl]-methylamino]-3-methylpentyl]-methylamino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotriphenyl Synthesis of Methyl Resin (Fmoc-Ile-MeIle-MeAsp(O-Trt(2-Cl)resin)-pip)

[0381] Synthesis of pd2-002-resin by condition 1 The two peptide-loaded resin aa2-002-resin (Fmoc-MeIle-MeAsp(O-Trt(2-Cl) resin)-pip) (100 mg, 0.326 mmol / g) prepared in Examples 1-4 was used as As the starting material, following Synthesis Method 1, the extension of Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours) was carried out to synthesize pd2-002-resin. If the dry resin (10.24 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.336 mmol / g. (UVarea value at 294 nm: 3446.83, UVarea value at 304 nm: 3102.30)

[0382] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.336 × (1 ÷ 0.326 - 563.70 × 0.001 + 676.86 × 0.001)=106.9% Furthermore, as a result of analyzing the excised reaction liquid by LCMS, the purity of the target pd2-002 was 99.4 area %, and the epimer pd2-002-a was observed at 0.6 area %.

[0383] Analysis conditions: SQDAA50long [Table 12] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area% pd2-002 Target 676.86 677.6(M+H)+ 2.00 99.4 pd2-002-a Epimer 676.86 677.7(M+H)+ 2.20 0.6

[0384] Synthesis of pd2-002-resin by condition 2 The amino acid-loaded resin aa3-001-resin (Fmoc-MeAsp(O-Trt(2-Cl) resin)-pip) (100 mg, 0.455 mmol / g) prepared in Examples 1-4 was used as a starting point Raw materials, following the synthesis method 1, carried out the extension of Fmoc-MeIle-OH (HOAt, 40°C, 2.5 hours), followed by the extension of Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours) to synthesize pd2-002-resin . When using dry resin (10.81 mg) and calculating the loading by Fmoc quantitative method, it was 0.326 mmol / g. (UVarea value at 294 nm: 3524.40, UVarea value at 304 nm: 3171.55)

[0385] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.326 × (1 ÷ 0.455 - 436.51 × 0.001 + 676.86 × 0.001)=79.5% In addition, the results of the cut-out reaction solution were analyzed by LCMS. The purity of the target pd2-002 was 58.0 area%, the epimer pd2-002-a was 1.4 area%, and the excess extension pd2-002-b was 1.8 area%. %, AA2 deletion pd2-002-c was observed in 38.8 area%.

[0386] Analysis conditions: SQDAA50long [Table 13] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area % pd2-002 Target 676.86 677.6(M+H)+ 2.00 58.0 pd2-002-a Epimer 676.86 677.7(M+H)+ 2.00 1.4 pd2-002-b excess extension 873.11 873.8(M+H)+ 2.37 1.8 pd2-002-c AA2 deletion 549.67 550.5(M+H)+ 1.62 38.8

[0387] Synthesis of pd2-002-resin by condition 3 The amino acid-loaded resin aa3-001-resin (Fmoc-MeAsp(O-Trt(2-Cl) resin)-pip) (100 mg, 0.455 mmol / g) prepared in Examples 1-4 was used as a starting point Raw materials, following the synthesis method 1, carried out the extension of Fmoc-MeIle-OH (oxyma, 50°C, 10 hours), followed by the extension of Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours) to synthesize pd2-002-resin . If the dry resin (10.41 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.330 mmol / g. (UVarea value at 294 nm: 3437.60, UVarea value at 304 nm: 3100.91)

[0388] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.330 × (1 ÷ 0.455 - 436.51 × 0.001 + 676.86 × 0.001)=80.5% Furthermore, as a result of LCMS analysis of the excised reaction solution, the purity of the target pd2-002 was 95.2 area %, the epimer pd2-002-a was 1.4 area %, and the excess extension pd2-002-b was observed is 3.4 area%.

[0389] Analysis conditions: SQDAA50long [Table 14] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area % pd2-002 Target 676.86 677.7(M+H)+ 2.01 95.2 pd2-002-a Epimer 676.86 677.6(M+H)+ 2.22 1.4 pd2-002-b excess extension 873.11 873.9(M+H)+ 2.39 3.4

[0390] The above results are summarized in the table below. [Table 15] Recovery rate(%) Target pd2-002 (area%) Epimer pd2-002-a (area%) excess extension pd2-002-b (area%) AA2 deletion pd2-002-c (area%) Condition 1 106.9 99.4 0.6 - - Condition 2 79.5 58.0 1.4 1.8 38.8 Condition 3 80.5 95.2 1.4 3.4 -

[0391] In condition 1 where the dipeptide has been loaded, the target substance can be obtained with high recovery rate and high purity. In the case of loaded amino acid monomers, in the usual condition 2, in addition to the decrease in the recovery rate due to premature cleavage, the formation of excess elongators and poor elongation from the difficult-to-extend site, that is, AA2, were also observed. The resulting generation of AA2 deletions. In condition 3 corresponding to the difficult-to-extend sequence, a decrease in the recovery rate due to premature division was also observed, and although no AA2 deletion was observed, an increase in the generation of excess elongation was confirmed.

[0392] Compound pd2-003-resin, (3S)-3-[[(2S)-2-cyclopentyl-2-[[(2S,3S)-2-(9H-fen-9-ylmethoxycarbonylamino )-3-Methylpentyl]-methylamino]acetyl]-methylamino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl Synthesis of Base Resin (Fmoc-Ile-MeGly(cPent)-MeAsp(O-Trt(2-Cl)resin)-pip)

[0393] Synthesis of pd2-003-resin by condition 1 The two peptide-loaded resin aa2-003-resin (Fmoc-MeGly(cPent)-MeAsp(O-Trt(2-Cl) resin)-pip) (100 mg, 0.362 mmol / g) As a starting material, following the synthesis method 1, the extension of Fmoc-Ile-OH was carried out (HOAt, 40°C, 2.5 hours) to synthesize pd2-003-resin. If the dry resin (10.14 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.348 mmol / g. (UVarea value at 294 nm: 3532.70, UVarea value at 304 nm: 3179.43)

[0394] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.348 × (1 ÷ 0.362 - 575.71 × 0.001 + 688.87 × 0.001)=100.1% In addition, as a result of analyzing the excised reaction solution by LCMS, the purity of the target pd2-003 was 99.8 area %, and the epimer pd2-003-a was observed at 0.2 area %.

[0395] Analysis conditions: SQDAA50long [Table 16] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area% pd2-003 Target 688.87 689.7(M+H)+ 2.06 99.8 pd2-003-a Epimer 688.87 689.6(M+H)+ 2.27 0.2

[0396] Synthesis of pd2-003-resin by condition 2 The amino acid-loaded resin aa3-001-resin (Fmoc-MeAsp(O-Trt(2-Cl) resin)-pip) (100 mg, 0.455 mmol / g) prepared in Examples 1-4 was used as a starting point Starting materials, following the synthesis method 1, the extension of Fmoc-MeGly(cPent)-OH (HOAt, 40°C, 2.5 hours), followed by the extension of Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours), synthesized pd2- 003-resin. If the dry resin (10.05 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.320 mmol / g. (UVarea value at 294 nm: 3216.77, UVarea value at 304 nm: 2905.18)

[0397] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.320 × (1 ÷ 0.455 - 436.51 × 0.001 + 688.87 × 0.001)=78.4% In addition, the results of the cut-out reaction solution were analyzed by LCMS. The purity of the target pd2-003 was 83.9 area%, the epimer pd2-003-a was 1.2 area%, and the excess extension pd2-003-b was 3.9 area%. %, AA2 deletion pd2-003-c was observed in 11.0 area%.

[0398] Analysis conditions: SQDAA50long [Table 17] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area% pd2-003 Target 688.87 689.6(M+H)+ 2.06 83.9 pd2-003-a Epimer 688.87 689.7(M+H)+ 2.27 1.2 pd2-003-b excess extension 885.12 885.8(M+H)+ 2.43 3.9 pd2-003-c AA2 deletion 549.67 550.5(M+H)+ 1.63 11.0

[0399] Synthesis of pd2-003-resin by condition 3 The amino acid-loaded resin aa3-001-resin (Fmoc-MeAsp(O-Trt(2-Cl) resin)-pip) (100 mg, 0.455 mmol / g) prepared in Examples 1-4 was used as a starting point The raw material was followed by the synthesis method 1, the extension of Fmoc-MeGly(cPent)-OH (oxyma, 50°C, 10 hours), followed by the extension of Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours), and the synthesis of pd2- 003-resin. If the dry resin (9.45 mg) was used and the loading was calculated by the Fmoc quantification method, it was 0.232 mmol / g. (UVarea value at 294 nm: 2194.45, UVarea value at 304 nm: 1975.12)

[0400] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.232 × (1 ÷ 0.455 - 436.51 × 0.001 + 688.87 × 0.001)=56.8% Furthermore, as a result of LCMS analysis of the excised reaction solution, the purity of the target pd2-003 was 91.4 area %, the epimer pd2-003-a was 0.1 area %, and the excess extension pd2-003-b was observed is 8.5 area%.

[0401] Analysis conditions: SQDAA50long [Table 18] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area% pd2-003 Target 688.87 689.7(M+H)+ 2.09 91.4 pd2-003-a Epimer 688.87 689.5(M+H)+ 2.29 0.1 pd2-003-b excess extension 885.12 885.8(M+H)+ 2.45 8.5

[0402] The above results are summarized in the table below. [Table 19] Recovery rate(%) Target pd2-003 (area%) Epimer pd2-003-a (area%) excess extension pd2-003-b (area%) AA2 deletion pd2-003-c (area%) Condition 1 100.1 99.8 0.2 - - Condition 2 78.4 83.9 1.2 3.9 11.0 Condition 3 56.8 91.4 0.1 8.5 -

[0403] In condition 1 where the dipeptide has been loaded, the target substance can be obtained with high recovery rate and high purity. In the case of loaded amino acid monomers, in the usual condition 2, in addition to the decrease in the recovery rate due to premature cleavage, the formation of excess elongators and poor elongation from the difficult-to-extend site, that is, AA2, were also observed. The resulting generation of AA2 deletions. In condition 3 corresponding to the difficult-to-extend sequence, a decrease in the recovery rate due to premature division was also observed, and although no AA2 deletion was observed, an increase in the generation of excess elongation was confirmed.

[0404] Compound pd2-004-resin, (3S)-3-[[(2S)-2-cyclohexyl-2-[[(2S,3S)-2-(9H-fennel-9-ylmethoxycarbonylamino) -3-Methylpentyl]-methylamino]acetyl]-methylamino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl Synthesis of Resin (Fmoc-Ile-MeChg-MeAsp(O-Trt(2-Cl)resin)-pip)

[0405] Synthesis of pd2-004-resin by condition 1 The two peptide-loaded resin aa2-004-resin (Fmoc-MeChg-MeAsp(O-Trt(2-Cl) resin)-pip) (100 mg, 0.347 mmol / g) prepared in Example 1-4 was used as As the starting material, following Synthesis Method 1, the extension of Fmoc-Ile-OH was carried out (HOAt, 40°C, 2.5 hours) to synthesize pd2-004-resin. If the dry resin (10.66 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.328 mmol / g. (UVarea value at 294 nm: 3502.36, UVarea value at 304 nm: 3152.54)

[0406] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.328 × (1 ÷ 0.347 - 589.73 × 0.001 + 702.89 × 0.001)=98.2% Furthermore, as a result of analyzing the excised reaction solution by LCMS, the purity of the target pd2-004 was 99.2 area %, and the epimer pd2-004-a was observed at 0.8 area %.

[0407] Analysis conditions: SQDAA50long [Table 20] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area% pd2-004 Target 702.89 703.6(M+H)+ 2.23 99.2 pd2-004-a Epimer 702.89 703.6(M+H)+ 2.43 0.8

[0408] Synthesis of pd2-004-resin by condition 2 The amino acid-loaded resin aa3-001-resin (Fmoc-MeAsp(O-Trt(2-Cl) resin)-pip) (100 mg, 0.455 mmol / g) prepared in Examples 1-4 was used as a starting point Raw materials, following the synthesis method 1, carried out the extension of Fmoc-MeChg-OH (HOAt, 40°C, 2.5 hours), followed by the extension of Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours) to synthesize pd2-004-resin . If the dry resin (9.68 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.314 mmol / g. (UVarea value at 294 nm: 3037.14, UVarea value at 304 nm: 2743.09)

[0409] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.314 × (1 ÷ 0.455 - 436.51 × 0.001 + 702.89 × 0.001)=77.4% In addition, the results of the cut-out reaction solution were analyzed by LCMS. The purity of the target pd2-004 was 74.1 area%, the epimer pd2-004-a was 2.3 area%, and the excess extension pd2-004-b was 4.0 area%. %, AA2 deletion pd2-004-c was observed in 19.5 area%.

[0410] Analysis conditions: SQDAA50long [Table 21] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area% pd2-004 Target 702.89 703.6(M+H)+ 2.24 74.1 pd2-004-a Epimer 702.89 703.6(M+H)+ 2.43 2.3 pd2-004-b excess extension 899.14 899.8(M+H)+ 2.58 4.0 pd2-004-c AA2 deletion 549.67 550.5(M+H)+ 1.63 19.5

[0411] Synthesis of pd2-004-resin by condition 3 The amino acid-loaded resin aa3-001-resin (Fmoc-MeAsp(O-Trt(2-Cl) resin)-pip) (100 mg, 0.455 mmol / g) prepared in Examples 1-4 was used as a starting point Raw materials, following the synthesis method 1, carried out the extension of Fmoc-MeChg-OH (oxyma, 50°C, 10 hours), followed by the extension of Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours) to synthesize pd2-004-resin . If the dry resin (9.91 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.226 mmol / g. (UVarea value at 294 nm: 2235.50, UVarea value at 304 nm: 2016.81)

[0412] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.226 × (1 ÷ 0.455 - 436.51 × 0.001 + 702.89 × 0.001)=55.7% Furthermore, as a result of LCMS analysis of the excised reaction solution, the purity of the target pd2-004 was 91.7 area %, the epimer pd2-004-a was 0.6 area %, and the excess extension pd2-004-b was observed is 7.7 area%.

[0413] Analysis conditions: SQDAA50long [Table 22] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area% pd2-004 Target 702.89 703.6(M+H)+ 2.26 91.7 pd2-004-a Epimer 702.89 703.7(M+H)+ 2.44 0.6 pd2-004-b excess extension 899.14 899.8(M+H)+ 2.60 7.7

[0414] The above results are summarized in the table below. [Table 23] Recovery rate(%) Target pd2-004 (area%) Epimer pd2-004-a (area%) excess extension pd2-004-b (area%) AA2 deletion pd2-004-c (area%) Condition 1 98.2 99.2 0.8 - - Condition 2 77.4 74.1 2.3 4.0 19.5 Condition 3 55.7 91.7 0.6 7.7 -

[0415] In condition 1 where the dipeptide has been loaded, the target substance can be obtained with high recovery rate and high purity. In the case of loaded amino acid monomers, in the usual condition 2, in addition to the decrease in the recovery rate due to premature cleavage, the formation of excess elongators and poor elongation from the difficult-to-extend site, that is, AA2, were also observed. The resulting generation of AA2 deletions. In condition 3 corresponding to the difficult-to-extend sequence, a decrease in the recovery rate due to premature division was also observed, and although no AA2 deletion was observed, an increase in the generation of excess elongation was confirmed.

[0416] Compound pd2-005-resin, (3S)-3-[[(2S)-2-[[(2S,3S)-2-(9H-fennel-9-ylmethoxycarbonylamino)-3-methyl Pentyl]-methylamino]-4-methylpentyl]-methylamino]-4-oxo-4-piperidin-1-ylbutanoic acid-2-chlorotrityl Synthesis of Resin (Fmoc-Ile-MeLeu-MeAsp(O-Trt(2-Cl)resin)-pip)

[0417] Synthesis of pd2-005-resin by condition 1 The two peptide-loaded resin aa2-005-resin (Fmoc-MeLeu-MeAsp(O-Trt(2-Cl) resin)-pip) (100 mg, 0.355 mmol / g) prepared in Example 1-4 was used as As the starting material, following Synthesis Method 1, the extension of Fmoc-Ile-OH was carried out (HOAt, 40°C, 2.5 hours) to synthesize pd2-005-resin. If the dry resin (10.81 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.342 mmol / g. (UVarea value at 294 nm: 3697.14, UVarea value at 304 nm: 3330.28)

[0418] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.342 × (1 ÷ 0.355 - 563.70 × 0.001 + 676.86 × 0.001)=100.2% Furthermore, as a result of analyzing the excised reaction solution by LCMS, the purity of the target pd2-005 was 99.9 area %, and the epimer pd2-005-a was observed at 0.1 area %.

[0419] Analysis conditions: SQDAA50long [Table 24] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area% pd2-005 Target 676.86 677.7(M+H)+ 2.03 99.9 pd2-005-a Epimer 676.86 677.6(M+H)+ 2.23 0.1

[0420] Synthesis of pd2-005-resin by condition 2 The amino acid-loaded resin aa3-001-resin (Fmoc-MeAsp(O-Trt(2-Cl) resin)-pip) (100 mg, 0.455 mmol / g) prepared in Examples 1-4 was used as a starting point Raw materials, following Synthesis 1, carried out the extension of Fmoc-MeLeu-OH (HOAt, 40°C, 2.5 hours), followed by the extension of Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours) to synthesize pd2-005-resin . If the dry resin (10.74 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.369 mmol / g. (UVarea value at 294 nm: 3953.19, UVarea value at 304 nm: 3570.96)

[0421] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.369 × (1 ÷ 0.455 - 436.51 × 0.001 + 676.86 × 0.001)=90.0% Furthermore, as a result of LCMS analysis of the excised reaction solution, the purity of the target pd2-005 was 98.3 area %, the epimer pd2-005-a was 0.1 area %, and the excess extension pd2-005-b was observed is 1.6 area%. In this matrix, the AA2 deletion pd2-005-c was also observed in condition 2.

[0422] Analysis conditions: SQDAA50long [Table 25] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area% pd2-005 Target 676.86 677.6(M+H)+ 2.03 98.3 pd2-005-a Epimer 676.86 677.6(M+H)+ 2.23 0.1 pd2-005-b excess extension 873.11 873.8(M+H)+ 2.41 1.6 pd2-005-c AA2 deletion 549.67 not detected

[0423] Synthesis of pd2-005-resin by condition 3 The amino acid-loaded resin aa3-001-resin (Fmoc-MeAsp(O-Trt(2-Cl) resin)-pip) (100 mg, 0.455 mmol / g) prepared in Examples 1-4 was used as a starting point Raw materials, following the synthesis method 1, carried out the extension of Fmoc-MeLeu-OH (oxyma, 50°C, 10 hours), followed by the extension of Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours) to synthesize pd2-005-resin . If the dry resin (10.73 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.337 mmol / g. (UVarea value at 294 nm: 3610.72, UVarea value at 304 nm: 3254.78)

[0424] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.337 × (1 ÷ 0.455 - 436.51 × 0.001 + 676.86 × 0.001)=82.2% Furthermore, as a result of LCMS analysis of the excised reaction solution, the purity of the target pd2-005 was 97.7 area %, the epimer pd2-005-a was 0.1 area %, and the excess extension pd2-005-b was observed is 2.2 area%.

[0425] Analysis conditions: SQDAA50long [Table 26] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area% pd2-005 Target 676.86 677.6(M+H)+ 2.05 97.7 pd2-005-a Epimer 676.86 677.6(M+H)+ 2.25 0.1 pd2-005-b excess extension 873.11 873.9(M+H)+ 2.42 2.2

[0426] The above results are summarized in the table below. [Table 27] Recovery rate(%) Target pd2-005 (area%) Epimer pd2-005-a (area%) excess extension pd2-005-b (area%) AA2 deletion pd2-005-c (area%) Condition 1 100.2 99.9 0.1 - - Condition 2 90.0 98.3 0.1 1.6 - Condition 3 82.2 97.7 0.1 2.2 - In condition 1 where the dipeptide has been loaded, the target substance can be obtained with high recovery rate and high purity. In condition 2 and condition 3 where the amino acid monomer has been loaded, in addition to the decrease in the recovery rate due to premature cleavage, the formation of excess elongation was also observed.

[0427] Compound pd2-006-resin, (3S)-3-[[(2S)-2-cyclopentyl-2-[[(2S,3S)-2-(9H-fen-9-ylmethoxycarbonylamino )-3-methylpentyl]-methylamino]acetyl]-methylamino]-4-(dimethylamino)-4-oxobutanoic acid-2-chlorotriphenyl Synthesis of Methyl Resin (Fmoc-Ile-MeGly(cPent)-MeAsp(O-Trt(2-Cl)resin)-NMe2)

[0428] Synthesis of pd2-006-resin by condition 1 The two peptide-loaded resin aa2-006-resin (Fmoc-MeGly(cPent)-MeAsp(O-Trt(2-Cl) resin)-NMe2) prepared in Example 1-4 (100 mg, 0.345 mmol / g ) will be used as the starting material to synthesize pd2-006-resin by prolonging Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours) following Synthesis Method 1. If the dry resin (10.23 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.349 mmol / g. (UVarea value at 294 nm: 3565.79, UVarea value at 304 nm: 3223.59)

[0429] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.349 × (1 ÷ 0.345 - 535.64 × 0.001 + 648.80 × 0.001)=105.1% Furthermore, as a result of analyzing the excised reaction solution by LCMS, the purity of the target pd2-006 was 100 area %.

[0430] Analysis conditions: SQDFA05 [Table 28] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area% pd2-006 Target 648.80 649.6(M+H)+ 0.96 100 pd2-006-a Epimer 648.80 not detected

[0431] Synthesis of pd2-006-resin by condition 2 The amino acid-loaded resin aa3-002-resin (Fmoc-MeAsp(O-Trt(2-Cl) resin)-NMe2) (100 mg, 0.442 mmol / g) prepared in Examples 1-4 was used as a starting point Starting materials, following the synthesis method 1, the extension of Fmoc-MeGly(cPent)-OH (HOAt, 40°C, 2.5 hours), followed by the extension of Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours), synthesized pd2- 006-resin. If the dry resin (10.73 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.304 mmol / g. (UVarea value at 294 nm: 3263.10, UVarea value at 304 nm: 2945.28)

[0432] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.304 × (1 ÷ 0.442 - 396.44 × 0.001 + 648.80 × 0.001)=76.5% In addition, the results of the cut-out reaction solution were analyzed by LCMS. The purity of the target pd2-006 was 76.3 area%, the epimer pd2-006-a was 1.2 area%, and the excess extension pd2-006-b was 5.6 area%. %, AA2 deletion pd2-006-c was observed in 16.9 area%.

[0433] Analysis conditions: SQDFA05 [Table 29] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area% pd2-006 Target 648.80 649.7(M+H)+ 0.97 76.3 pd2-006-a Epimer 648.80 649.6(M+H)+ 1.03 1.2 pd2-006-b excess extension 804.98 805.7(M+H)+ 0.93 5.6 pd2-006-c AA2 deletion 509.60 510.5(M+H)+ 0.88 16.9

[0434] Synthesis of pd2-006-resin by condition 3 The amino acid-loaded resin aa3-002-resin (Fmoc-MeAsp(O-Trt(2-Cl) resin)-NMe2) (100 mg, 0.442 mmol / g) prepared in Examples 1-4 was used as a starting point The raw material was followed by the synthesis method 1, the extension of Fmoc-MeGly(cPent)-OH (oxyma, 50°C, 10 hours), followed by the extension of Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours), and the synthesis of pd2- 006-resin. If the dry resin (10.60 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.211 mmol / g. (UVarea value at 294 nm: 2239.56, UVarea value at 304 nm: 2018.13).

[0435] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.211 × (1 ÷ 0.442 - 396.44 × 0.001 + 648.80 × 0.001)=53.1% Furthermore, as a result of LCMS analysis of the excised reaction solution, the purity of the target substance pd2-006 was 85.9 area %, and the excess extension body pd2-006-b was observed to be 14.1 area %.

[0436] Analysis conditions: SQDFA05 [Table 30] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area% pd2-006 Target 648.80 649.6(M+H)+ 0.96 85.9 pd2-006-a Epimer 648.80 not detected pd2-006-b excess extension 804.98 805.7(M+H)+ 0.92 14.1

[0437] The above results are summarized in the table below. [Table 31] Recovery rate(%) Target pd2-006 (area%) Epimer pd2-006-a (area%) excess extension pd2-006-b (area%) AA2 deletion pd2-006-c (area%) Condition 1 105.1 100 - - - Condition 2 76.5 76.3 1.2 5.6 16.9 Condition 3 53.1 85.9 - 14.1 -

[0438] In condition 1 where the dipeptide has been loaded, the target substance can be obtained with high recovery rate and high purity. In the case of loaded amino acid monomers, in the usual condition 2, in addition to the decrease in the recovery rate due to premature cleavage, the formation of excess elongators and poor elongation from the difficult-to-extend site, that is, AA2, were also observed. The resulting generation of AA2 deletions. In condition 3 corresponding to the difficult-to-extend sequence, a decrease in the recovery rate due to premature division was also observed, and although no AA2 deletion was observed, an increase in the generation of excess elongation was confirmed.

[0439] Compound pd2-007-resin, (3S)-4-(dimethylamino)-3-[[(2S)-2-[[(2S,3S)-2-(9H-fennel-9-ylmethyl Oxycarbonylamino)-3-methylpentyl]-methylamino]-4-methylpentyl]-methylamino]-4-oxobutanoic acid-2-chlorotrityl Synthesis of Base Resin (Fmoc-Ile-MeLeu-MeAsp(O-Trt(2-Cl)resin)-NMe2)

[0440] Synthesis of pd2-007-resin by condition 1 The two peptide-loaded resin aa2-007-resin (Fmoc-MeLeu-MeAsp(O-Trt(2-Cl) resin)-NMe2) (100 mg, 0.384 mmol / g) prepared in Example 1-4 was used as As the starting material, following Synthesis Method 1, the extension of Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours) was carried out to synthesize pd2-007-resin. If the dry resin (9.96 mg) was used and the loading was calculated by the Fmoc quantification method, it was 0.367 mmol / g. (UVarea value at 294 nm: 3654.86, UVarea value at 304 nm: 3298.78)

[0441] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.367 × (1 ÷ 0.384 - 523.63 × 0.001 + 636.79 × 0.001)=99.7% Furthermore, as a result of analyzing the cut-out reaction solution by LCMS, the purity of the target pd2-007 was 100 area %.

[0442] Analysis conditions: SQDFA05 [Table 32] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area% pd2-007 Target 636.79 637.6(M+H)+ 0.96 100 pd2-007-a Epimer 636.79 not detected

[0443] Synthesis of pd2-007-resin by condition 2 The amino acid-loaded resin aa3-002-resin (Fmoc-MeAsp(O-Trt(2-Cl) resin)-NMe2) (100 mg, 0.442 mmol / g) prepared in Examples 1-4 was used as a starting point Raw materials, following the synthesis method 1, carried out the extension of Fmoc-MeLeu-OH (HOAt, 40°C, 2.5 hours), followed by the extension of Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours) to synthesize pd2-007-resin . If the dry resin (10.15 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.371 mmol / g. (UVarea value at 294 nm: 3770.57, UVarea value at 304 nm: 3391.62)

[0444] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.371 × (1 ÷ 0.442 - 396.44 × 0.001 + 636.79 × 0.001)=92.9% In addition, as a result of analyzing the excised reaction solution by LCMS, the purity of the target pd2-007 was 97.9 area %, and the excess extension body pd2-007-b was observed at 2.1 area %. In this matrix, the AA2 deletion pd2-007-c was not observed in condition 2 either.

[0445] Analysis conditions: SQDFA05 [Table 33] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area% pd2-007 Target 636.79 637.7(M+H)+ 0.97 97.9 pd2-007-a Epimer 636.79 not detected pd2-007-b excess extension 792.97 793.7(M+H)+ 0.92 2.1 pd2-007-c AA2 deletion 509.60 not detected

[0446] Synthesis of pd2-007-resin by condition 3 The amino acid-loaded resin aa3-002-resin (Fmoc-MeAsp(O-Trt(2-Cl) resin)-NMe2) (100 mg, 0.442 mmol / g) prepared in Examples 1-4 was used as a starting point Raw materials, following the synthesis method 1, carried out the extension of Fmoc-MeLeu-OH (oxyma, 50°C, 10 hours), followed by the extension of Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours) to synthesize pd2-007-resin . If the dry resin (10.73 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.334 mmol / g. (UVarea value at 294 nm: 3587.19, UVarea value at 304 nm: 3234.07)

[0447] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.334 × (1 ÷ 0.442 - 396.44 × 0.001 + 636.79 × 0.001)=83.6% Furthermore, as a result of LCMS analysis of the excised reaction solution, the purity of the target pd2-007 was 96.6 area %, and the excess extension body pd2-007-b was observed to be 3.4 area %.

[0448] Analysis conditions: SQDFA05 [Table 34] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area% pd2-007 Target 636.79 637.6(M+H)+ 0.96 96.6 pd2-007-a Epimer 636.79 not detected pd2-007-b excess extension 792.97 793.7(M+H)+ 0.92 3.4

[0449] The above results are summarized in the table below. [Table 35] Recovery rate(%) Target pd2-007 (area%) Epimer pd2-007-a (area%) excess extension pd2-007-b (area%) AA2 deletion pd2-007-c (area%) Condition 1 99.7 100 - - - Condition 2 92.9 97.9 - 2.1 - Condition 3 83.6 96.6 - 3.4 -

[0450] In condition 1 where the dipeptide has been loaded, the target substance can be obtained with high recovery rate and high purity. In condition 2 and condition 3 where the amino acid monomer has been loaded, in addition to the decrease in the recovery rate due to premature cleavage, the formation of excess elongation was also observed.

[0451] Compound pd2-008-resin, (3R)-3-[[(2S)-2-[[(2S,3S)-2-(9H-Fil-9-ylmethoxycarbonylamino)-3-methyl Pentyl]-methylamino]-3-methylbutyryl]-methylamino]butyric acid-2-chlorotrityl resin (Fmoc-Ile-MeVal-D-3-MeAbu-O-Trt Synthesis of (2-Cl)resin

[0452] Synthesis of pd2-008-resin by condition 1 The two peptide-loaded resin aa2-008-resin (Fmoc-MeVal-D-3-MeAbu-O-Trt(2-Cl) resin) (100 mg, 0.415 mmol / g) prepared in Example 1-4 As a starting material, following Synthesis Method 1, the extension of Fmoc-Ile-OH was performed (HOAt, 40°C, 2.5 hours) to synthesize pd2-008-resin. If the dry resin (10.74 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.378 mmol / g. (UVarea value at 294 nm: 4060.03, UVarea value at 304 nm: 3652.89)

[0453] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.378 × (1 ÷ 0.415 - 452.44 × 0.001 + 565.71 × 0.001)=95.4% Furthermore, as a result of analyzing the cut-out reaction solution by LCMS, the purity of the target pd2-008 was 100 area %.

[0454] Analysis conditions: SQDAA50long [Table 36] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area % pd2-008 Target 565.71 566.5(M+H)+ 1.49 100 pd2-008-a Epimer 565.71 not detected

[0455] Synthesis of pd2-008-resin by condition 2 The amino acid loaded resin aa4-001-resin (Fmoc-D-3-MeAbu-O-Trt(2-Cl) resin) (100 mg, 0.369 mmol / g) prepared in Examples 1-4 was used as starting material The starting materials were followed by the synthesis method 1, the extension of Fmoc-MeVal-OH (HOAt, 40°C, 2.5 hours), followed by the extension of Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours), and the synthesis of pd2-008- resin. If the dry resin (10.62 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.295 mmol / g. (UVarea value at 294 nm: 3138.26, UVarea value at 304 nm: 2821.05)

[0456] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.295 × (1 ÷ 0.369 - 339.39 × 0.001 + 565.71 × 0.001)=86.6% In addition, as a result of analyzing the excised reaction solution by LCMS, the purity of the target substance pd2-008 was 99.1 area %, and the excess extension body pd2-008-b was observed at 1.0 area %. In this matrix, the AA2 deletion pd2-008-c was not observed in condition 2 either.

[0457] Analysis conditions: SQDAA50long [Table 37] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area % pd2-008 Target 565.71 566.5(M+H)+ 1.50 99.1 pd2-008-a Epimer 565.71 not detected pd2-008-b excess extension 664.84 665.6(M+H)+ 1.58 1.0 pd2-008-c AA2 deletion 452.55 not detected

[0458] Synthesis of pd2-008-resin by condition 3 The amino acid loaded resin aa4-001-resin (Fmoc-D-3-MeAbu-O-Trt(2-Cl) resin) (100 mg, 0.369 mmol / g) prepared in Examples 1-4 was used as starting material The starting material was followed by the synthesis method 1, and the extension of Fmoc-MeVal-OH (oxyma, 50°C, 10 hours), followed by the extension of Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours), synthesized pd2-008- resin. If the dry resin (10.44 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.284 mmol / g. (UVarea value at 294 nm: 2964.86, UVarea value at 304 nm: 2667.78)

[0459] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.284 × (1 ÷ 0.369 - 339.39 × 0.001 + 565.71 × 0.001)=83.4% Furthermore, as a result of LCMS analysis of the excised reaction solution, the purity of the target pd2-008 was 98.1 area %, and the excess extension body pd2-008-b was observed at 1.9 area %.

[0460] Analysis conditions: SQDAA50long [Table 38] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area% pd2-008 Target 565.71 566.5(M+H)+ 1.51 98.1 pd2-008-a Epimer 565.71 not detected pd2-008-b excess extension 664.84 665.6(M+H)+ 1.59 1.9

[0461] The above results are summarized in the table below. [Table 39] Recovery rate(%) Target pd2-008 (area%) Epimer pd2-008-a (area%) excess extension pd2-008-b (area%) AA2 deletion pd2-008-c (area%) Condition 1 95.4 100 - - - Condition 2 86.6 99.1 - 1.0 - Condition 3 83.4 98.1 - 1.9 -

[0462] In condition 1 where the dipeptide has been loaded, the target substance can be obtained with high recovery rate and high purity. In condition 2 and condition 3 where the amino acid monomer has been loaded, in addition to the decrease in the recovery rate due to premature cleavage, the formation of excess elongation was also observed.

[0463] Compound pd2-009-resin, (3R)-3-[[(2S)-2-cyclohexyl-2-[[(2S,3S)-2-(9H-fen-9-ylmethoxycarbonylamino) -3-Methylpentyl]-methylamino]acetyl]-methylamino]butanoic acid-2-chlorotrityl resin (Fmoc-Ile-MeChg-D-3-MeAbu-O -Synthesis of Trt(2-Cl)resin)

[0464] Synthesis of pd2-009-resin by condition 1 The two peptide-loaded resin aa2-009-resin (Fmoc-MeChg-D-3-MeAbu-O-Trt(2-Cl) resin) (100 mg, 0.397 mmol / g) prepared in Example 1-4 As a starting material, following Synthesis Method 1, the extension of Fmoc-Ile-OH was carried out (HOAt, 40°C, 2.5 hours) to synthesize pd2-009-resin. If the dry resin (11.10 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.362 mmol / g. (UVarea value at 294 nm: 4014.43, UVarea value at 304 nm: 3627.15)

[0465] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.362 × (1 ÷ 0.397 - 492.62 × 0.001 + 605.78 × 0.001)=95.3% Furthermore, as a result of analyzing the cut-out reaction solution by LCMS, the purity of the target pd2-009 was 100 area %.

[0466] Analysis conditions: SQDFA05long [Table 40] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area% pd2-009 Target 605.78 606.5(M+H)+ 3.04 100 pd2-009-a Epimer 605.78 not detected In addition, although the retention time of pd2-009 in this experiment (condition 1) is not completely consistent with the retention time of pd2-009 in condition 3, this is caused by the error between measurements.

[0467] Synthesis of pd2-009-resin by condition 2 The amino acid loaded resin aa4-001-resin (Fmoc-D-3-MeAbu-O-Trt(2-Cl) resin) (100 mg, 0.369 mmol / g) prepared in Examples 1-4 was used as starting material According to the synthesis method 1, the extension of Fmoc-MeChg-OH (HOAt, 40°C, 2.5 hours), followed by the extension of Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours), synthesized pd2-009- resin. If the dry resin (10.20 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.293 mmol / g. (UVarea value at 294 nm: 2987.04, UVarea value at 304 nm: 2692.68)

[0468] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.293 × (1 ÷ 0.369 - 339.39 × 0.001 + 605.78 × 0.001)=87.2% In addition, as a result of LCMS analysis of the excised reaction solution, the purity of the target pd2-009 was 92.8 area %, the excess extension body pd2-009-b was 3.4 area %, and the AA2 deletion body pd2-009-c was observed to be 3.8 area %. area%.

[0469] Analysis conditions: SQDFA05long [Table 41] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area% pd2-009 Target 605.78 606.5(M+H)+ 3.03 92.8 pd2-009-a Epimer 605.78 not detected pd2-009-b excess extension 704.91 705.6(M+H)+ 2.96 3.4 pd2-009-c AA2 deletion 452.56 453.5(M+H)+ 2.52 3.8 In addition, although the retention time of pd2-009 and pd2-009-b in this experiment (condition 2) is not completely consistent with the retention time of pd2-009 and pd2-009-b in condition 3, this is due to the caused by the error.

[0470] Synthesis of pd2-009-resin by condition 3 The amino acid loaded resin aa4-001-resin (Fmoc-D-3-MeAbu-O-Trt(2-Cl) resin) (100 mg, 0.369 mmol / g) prepared in Examples 1-4 was used as starting material According to the synthesis method 1, the extension of Fmoc-MeChg-OH (oxyma, 50°C, 10 hours), followed by the extension of Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours), synthesized pd2-009- resin. If the dry resin (9.56 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.217 mmol / g. (UVarea value at 294 nm: 2072.81, UVarea value at 304 nm: 1864.82)

[0471] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.217 × (1 ÷ 0.369 - 339.39 × 0.001 + 605.78 × 0.001)=64.6% Furthermore, as a result of LCMS analysis of the excised reaction solution, the purity of the target pd2-009 was 94.5 area%, and the excess extension pd2-009-b was observed at 5.5 area%.

[0472] Analysis conditions: SQDFA05long [Table 42] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area% pd2-009 Target 605.78 606.6(M+H)+ 2.97 94.5 pd2-009-a Epimer 605.78 not detected pd2-009-b excess extension 704.91 705.7(M+H)+ 2.92 5.5

[0473] The above results are summarized in the table below. [Table 43] Recovery rate(%) Target pd2-009 (area%) Epimer pd2-009-a (area%) excess extension pd2-009-b (area%) AA2 deletion pd2-009-c (area%) Condition 1 95.3 100 - - - Condition 2 87.2 92.8 - 3.4 3.8 Condition 3 64.6 94.5 - 5.5 -

[0474] In condition 1 where the dipeptide has been loaded, the target substance can be obtained with high recovery rate and high purity. In the case of loaded amino acid monomers, in the usual condition 2, in addition to the decrease in the recovery rate due to premature cleavage, the formation of excess elongators and poor elongation from the difficult-to-extend site, that is, AA2, were also observed. The resulting generation of AA2 deletions. In condition 3 corresponding to the difficult-to-extend sequence, a decrease in the recovery rate due to premature division was also observed, and although no AA2 deletion was observed, an increase in the generation of excess elongation was confirmed.

[0475] Compound pd2-010-resin, 2-[[(2S)-2-[[(2S,3S)-2-(9H-Oxime-9-ylmethoxycarbonylamino)-3-methylpentyl] Synthesis of -Methylamino]-3-methylbutyryl]-methylamino]acetic acid-2-chlorotrityl resin (Fmoc-Ile-MeVal-MeGly-O-Trt(2-Cl) resin)

[0476] Synthesis of pd2-010-resin by condition 1 The two peptide-loaded resin aa2-010-resin (Fmoc-MeVal-MeGly-O-Trt(2-Cl) resin) (100 mg, 0.374 mmol / g) prepared in Examples 1-4 was used as a starting material , follow the synthetic method 1, carry out the extension of Fmoc-Ile-OH (HOAt, 40 ℃, 2.5 hours), synthesize pd2-010-resin. If the dry resin (10.86 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.325 mmol / g. (UVarea value at 294 nm: 3525.31, UVarea value at 304 nm: 3180.92)

[0477] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.325 × (1 ÷ 0.374 - 424.50 × 0.001 + 537.66 × 0.001)=90.6% Furthermore, as a result of analyzing the cut-out reaction solution by LCMS, the purity of the target pd2-010 was 100 area %.

[0478] Analysis conditions: SQDFA05 [Table 44] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area % pd2-010 Target 537.66 538.5(M+H)+ 0.94 100 pd2-010-a Epimer 537.66 not detected

[0479] Synthesis of pd2-010-resin by condition 2 With the amino acid loaded resin aa4-002-resin (Fmoc-MeGly-O-Trt (2-Cl) resin) (100 mg, 0.573 mmol / g) prepared in embodiment 1-4 as starting material, follow Synthesis method 1, the extension of Fmoc-MeVal-OH (HOAt, 40°C, 2.5 hours), followed by the extension of Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours), synthesized pd2-010-resin. If the dry resin (10.20 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.326 mmol / g. (UVarea value at 294 nm: 3322.12, UVarea value at 304 nm: 3002.34)

[0480] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.326 × (1 ÷ 0.573 - 311.34 × 0.001 + 537.66 × 0.001)=64.3% Furthermore, as a result of LCMS analysis of the excised reaction solution, the purity of the target pd2-010 was 95.6 area%, and the excess extension pd2-010-b was observed to be 4.4 area%. In this matrix, the AA2 deletion pd2-010-c was not observed in condition 2 either.

[0481] Analysis conditions: SQDFA05 [Table 45] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area% pd2-010 Target 537.66 538.5(M+H)+ 0.94 95.6 pd2-010-a Epimer 537.66 not detected pd2-010-b excess extension 608.74 607.4(M+H)+ 0.90 4.4 pd2-010-c AA2 deletion 424.50 not detected

[0482] Synthesis of pd2-010-resin by condition 3 The amino acid-loaded resin aa4-002-resin (Fmoc-MeGly-(O-Trt(2-Cl) resin)) (100 mg, 0.573 mmol / g) prepared in Examples 1-4 was used as a starting material , followed the synthesis method 1, carried out the extension of Fmoc-MeVal-OH (oxyma, 50 ℃, 10 hours), followed by the extension of Fmoc-Ile-OH (HOAt, 40 ℃, 2.5 hours), synthesized pd2-010-resin. If the dry resin (10.69 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.331 mmol / g. (UVarea value at 294 nm: 3542.66, UVarea value at 304 nm: 3189.92)

[0483] The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.331 × (1 ÷ 0.573 - 311.34 × 0.001 + 537.66 × 0.001)=65.3% Furthermore, as a result of analyzing the excised reaction solution by LCMS, the purity of the target substance pd2-010 was 93.9 area %, and the excess extension body pd2-010-b was observed to be 6.1 area %.

[0484] Analysis conditions: SQDFA05 [Table 46] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area % pd2-010 Target 537.66 538.5(M+H)+ 0.93 93.9 pd2-010-a Epimer 537.66 not detected pd2-010-b excess extension 608.74 607.6(M+H)+ 0.89 6.1

[0485] The above results are summarized in the table below. [Table 47] Recovery rate(%) Target pd2-010 (area%) Epimer pd2-010-a (area%) excess extension pd2-010-b (area%) AA2 deletion pd2-010-c (area%) Condition 1 90.6 100 - - - Condition 2 64.3 95.6 - 4.4 - Condition 3 65.3 93.9 - 6.1 -

[0486] In condition 1 where the dipeptide has been loaded, the target substance can be obtained with high recovery rate and high purity. In condition 2 and condition 3 where the amino acid monomer has been loaded, in addition to the decrease in the recovery rate due to premature cleavage, the formation of excess elongation was also observed.

[0487] Compound pd2-011-resin, (3S)-4-(Dimethylamino)-3-[[(2S)-2-[[(2S,3S)-2-(9H-Oxime-9-ylmethyl Oxycarbonylamino)-3-methylpentyl]-methylamino]-3-methylbutyryl]amino]-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc- Synthesis of Ile-MeVal-Asp(O-Trt(2-Cl)resin)-NMe2)

[0488] Synthesis of pd2-011-resin by condition 1 The two peptide-loaded resin aa2-012-resin (Fmoc-MeVal-Asp(O-Trt(2-Cl) resin)-NMe2) (100 mg, 0.373 mmol / g) prepared in Examples 1-4 was used as As raw materials, following Synthesis Method 1, prolongation of Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours) was carried out to synthesize pd2-011-resin. If the dry resin (9.87 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.343 mmol / g. (UVarea value at 294 nm: 3397.67, UVarea value at 304 nm: 3086.76) The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.343 × (1 ÷ 0.373 - 495.57 × 0.001 + 608.73 × 0.001)=95.8% Furthermore, as a result of analyzing the cut-out reaction solution by LCMS, the purity of the target pd2-011 was 100 area %.

[0489] Analysis conditions: SQDFA05long [Table 48] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area% pd2-011 Target 608.73 609.6(M+H)+ 2.41 100 pd2-011-a Epimer 608.73 not detected

[0490] Synthesis of pd2-011-resin by condition 2 The amino acid-loaded resin aa3-003-resin (Fmoc-Asp(O-Trt(2-Cl) resin)-NMe2) (100 mg, 0.469 mmol / g) prepared in Example 1-4 was used as a raw material, Following the synthesis method 1, the extension of Fmoc-MeVal-OH (HOAt, 40°C, 2.5 hours), followed by the extension of Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours), synthesized pd2-011-resin. If the dry resin (10.54 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.292 mmol / g. (UVarea value at 294 nm: 3084.36, UVarea value at 304 nm: 2800.28) The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.292 × (1 ÷ 0.469 - 382.41 × 0.001 + 608.73 × 0.001)=68.9% Furthermore, as a result of analyzing the cut-out reaction solution by LCMS, the purity of the target pd2-011 was 100 area %.

[0491] Analysis conditions: SQDFA05long [Table 49] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area % pd2-011 Target 608.73 609.6(M+H)+ 2.42 100 pd2-011-a Epimer 608.73 not detected pd2-011-b excess extension 750.88 not detected pd2-011-c AA2 deletion 495.57 not detected

[0492] Synthesis of pd2-011-resin by condition 3 The amino acid-loaded resin aa3-003-resin (Fmoc-Asp(O-Trt(2-Cl) resin)-NMe2) (100 mg, 0.469 mmol / g) prepared in Example 1-4 was used as a raw material, Following the synthesis method 1, the extension of Fmoc-MeVal-OH (oxyma, 50°C, 10 hours), followed by the extension of Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours), synthesized pd2-011-resin. If the dry resin (10.13 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.320 mmol / g. (UVarea value at 294 nm: 3260.97, UVarea value at 304 nm: 2943.08) The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.320 × (1 ÷ 0.469 - 382.41 × 0.001 + 608.73 × 0.001)=75.5% Furthermore, as a result of analyzing the cut-out reaction solution by LCMS, the purity of the target pd2-011 was 100 area %.

[0493] Analysis conditions: SQDFA05long [Table 50] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area % pd2-011 Target 608.73 609.6(M+H)+ 2.41 100 pd2-011-a Epimer 608.73 not detected pd2-011-b excess extension 750.88 not detected

[0494] The above results are summarized in the table below. [Table 51] Recovery rate(%) Target pd2-011 (area%) Epimer pd2-011-a (area%) excess extension pd2-011-b (area%) AA2 deletion pd2-011-c (area%) Condition 1 95.8 100 - - - Condition 2 68.9 100 - - - Condition 3 75.5 100 - - -

[0495] In condition 1 where the dipeptide has been loaded, the target substance can be obtained with high recovery rate and high purity. In Conditions 2 and 3 where the amino acid monomers were loaded, it was confirmed that the target product was obtained with high purity, and that the recovery rate decreased due to premature fragmentation.

[0496] Compound pd2-012-resin, (3S)-4-(dimethylamino)-3-[[2-[[(2S,3S)-2-(9H-fen-9-ylmethoxycarbonylamino )-3-methylpentyl]amino]acetyl]-methylamino]-4-oxobutanoic acid-2-chlorotrityl resin (Fmoc-Ile-Gly-MeAsp(O -Synthesis of Trt(2-Cl)resin)-NMe2)

[0497] Synthesis of pd2-012-resin by condition 1 The two peptide-loaded resin aa2-013-resin (Fmoc-Gly-MeAsp(O-Trt(2-Cl) resin)-NMe2) (100 mg, 0.386 mmol / g) prepared in Examples 1-4 was used as As raw materials, following Synthesis Method 1, the extension of Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours) was carried out to synthesize pd2-012-resin. If the dry resin (12.05 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.364 mmol / g. (UVarea value at 294 nm: 4412.01, UVarea value at 304 nm: 3987.67) The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.364 × (1 ÷ 0.386 - 453.49 × 0.001 + 566.65 × 0.001)=98.4% Furthermore, as a result of analyzing the cut-out reaction solution by LCMS, the purity of the target pd2-012 was 100 area %.

[0498] Analysis conditions: SQDFA05long [Table 52] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area % pd2-012 Target 566.65 567.5(M+H)+ 2.14 100

[0499] Synthesis of pd2-012-resin by condition 2 The amino acid-loaded resin aa3-002-resin (Fmoc-MeAsp(O-Trt(2-Cl) resin)-NMe2) (100 mg, 0.442 mmol / g) prepared in Examples 1-4 was used as a raw material, Following Synthesis 1, the extension of Fmoc-Gly-OH (HOAt, 40°C, 2.5 hours), followed by the extension of Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours), synthesized pd2-012-resin. If the dry resin (10.16 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.375 mmol / g. (UVarea value at 294 nm: 3841.95, UVarea value at 304 nm: 3448.96) The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.375 × (1 ÷ 0.442 - 396.44 × 0.001 + 566.65 × 0.001)=91.2% Furthermore, as a result of analyzing the cut-out reaction solution by LCMS, the purity of the target pd2-012 was 100 area %.

[0500] Analysis conditions: SQDFA05long [Table 53] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area % pd2-012 Target 566.65 567.5(M+H)+ 2.14 100 pd2-012-b excess extension 722.83 not detected pd2-012-c AA2 deletion 509.59 not detected

[0501] Synthesis of pd2-012-resin by condition 3 The amino acid-loaded resin aa3-002-resin (Fmoc-MeAsp(O-Trt(2-Cl) resin)-NMe2) (100 mg, 0.442 mmol / g) prepared in Examples 1-4 was used as a raw material, Following Synthesis Method 1, the extension of Fmoc-Gly-OH (oxyma, 50°C, 10 hours), followed by the extension of Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours), synthesized pd2-012-resin. If the dry resin (10.23 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.346 mmol / g. (UVarea value at 294 nm: 3565.67, UVarea value at 304 nm: 3211.93) The recovery rate is calculated according to the recovery rate calculation method and using the following formula. Recovery rate=0.346 × (1 ÷ 0.442 - 396.44 × 0.001 + 566.65 × 0.001)=84.2% Furthermore, as a result of analyzing the cut-out reaction solution by LCMS, the purity of the target pd2-011 was 100 area %.

[0502] Analysis conditions: SQDFA05long [Table 54] molecular weight LCMS(ESI) m / z Hold time (minutes) LC Area % pd2-012 Target 566.65 567.5(M+H)+ 2.14 100 pd2-012-b excess extension 722.83 not detected

[0503] The above results are summarized in the table below. [Table 55] Recovery rate(%) Target pd2-012 (area%) excess extension pd2-012-b (area%) AA2 deletion pd2-012-c (area%) Condition 1 98.4 100 - - Condition 2 91.2 100 - - Condition 3 84.2 100 - -

[0504] In condition 1 where the dipeptide has been loaded, the target substance can be obtained with high recovery rate and high purity. In Conditions 2 and 3 where the amino acid monomers were loaded, it was confirmed that the target product was obtained with high purity, and that the recovery rate decreased due to premature fragmentation.

[0505] Compound pd2-013-resin, (3S)-4-(dimethylamino)-3-[[2-[[(2S,3S)-2-(9H-fen-9-ylmethoxycarbonylamino )-3-methylpentyl]amino]-2-methylpropionyl]-methylamino]-4-oxobutyric acid-2-chlorotrityl resin (Fmoc-Ile- Synthesis of Aib-MeAsp(O-Trt(2-Cl)resin)-NMe2)

[0506] Synthesis of pd2-013-resin by condition 1 The two peptide-loaded resin aa2-014-resin (Fmoc-Aib-MeAsp(O-Trt(2-Cl) resin)-NMe2) (100 mg, 0.413 mmol / g) prepared in Examples 1-4 was used as As raw materials, following Synthesis Method 1, the extension of Fmoc-Ile-OH (HOAt, 40°C, 2.5 hours) was carried out to synthesize pd2-013-resin. If the dry resin (10.37 mg) was used and the loading was calculated by the Fmoc quantitative method, it was 0.305 mmol / g. (UVarea value at 294 nm: 3188.07, UVarea value at 304 nm: 2860.10) The recovery rate is calculated according to the recovery rate calculation method and usi...

Claims

1. A method for preparing a peptide compound containing at least one N-substituted amino acid residue, its salt, or a solvate thereof by a solid-phase method, characterized in that the peptide is loaded onto a resin for solid-phase synthesis prior to the initial elongation reaction in the solid-phase method.

2. A method for preparing a peptide compound containing at least one N-substituted amino acid residue, its salt, or a solvate thereof by a solid-phase method, the method comprising the step of loading the peptide onto a resin for solid-phase synthesis.

3. As in request item 1 or 2, wherein, Peptides are oligopeptides containing two or more amino acid residues.

4. The method described in any of requests 1 to 3, wherein, The amino acid residue at the C-terminus of the peptide, and / or the amino acid residue adjacent to the C-terminal amino acid residue, are non-natural amino acid residues.

5. The method described in any of requests 1 to 4, wherein, The amino acid residues at the C-terminus of the peptide are non-natural amino acid residues.

6. As in request item 5 or 6, wherein, Non-natural amino acid residues are N-substituted amino acid residues.

7. The method described in any of requests 1 to 6, wherein, The amino acid residues at the C-terminus of the peptide are loaded onto a resin for solid-phase synthesis via a carboxyl group that has been bonded to the carbon atom at the β- or γ-position of the amino group.

8. The method described in any of requests 1 to 7, wherein, The amino acid residue at the C-terminus of the peptide, and / or the amino acid residue adjacent to the C-terminal amino acid residue, has a large side chain.

9. As in request item 8, wherein, The bulky side chains are branched alkyl groups that can be replaced.

10. As in request item 9, wherein, Branched alkyl groups are bonded to the carbon atom at the α-position of the carboxyl group.

11. As in request item 10, wherein, The branched alkyl group has a branched carbon atom at the β-position or γ-position of the carboxyl group.

12. The method of any one of requests 1 to 11, wherein, The resins used for solid-phase synthesis are CTC resin, Wang resin, SASRIN resin, TRT resin, Mtt resin, or Mmt resin.

13. As in request item 12, wherein, The resin used for solid-phase synthesis is CTC resin.

14. The method of any one of claims 1 and 3 through 13, wherein, It includes the step of loading peptides onto a resin for solid-phase synthesis.

15. The method of any one of requests 1 to 14, wherein, It further includes the step of extending the peptide by one or more amino acids.

16. A method for preparing a cyclic peptide, its salt, or a solvate thereof, comprising the following steps: obtaining a peptide compound, its salt, or a solvate thereof containing at least one N-substituted amino acid residue by following the method of any one of claims 1 to 15; removing a resin used for solid-phase synthesis; and cyclizing the C-terminal group and the N-terminal group of the peptide compound, its salt, or the solvate thereof to form a cyclic portion.

17. A method for improving the recovery rate of peptide compounds compared to the case of extending amino acids residue by residue, characterized in that, in the manufacture of peptide compounds, salts thereof, or solvates thereof containing at least one N-substituted amino acid residue by solid-phase method, the peptide is loaded onto a resin for solid-phase synthesis prior to the initial extension reaction.

18. A method for suppressing the formation of impurities compared to the case of elongating an amino acid residue one residue at a time, characterized in that, in the manufacture of a peptide compound, its salt, or a solvate thereof containing at least one N-substituted amino acid residue by a solid-phase method, the peptide is loaded onto a resin for solid-phase synthesis prior to the initial elongation reaction.

19. A method for suppressing premature cleavage compared to the case of elongating amino acids residue by residue, characterized in that, in the manufacture of a peptide compound, its salt, or a solvate thereof containing at least one N-substituted amino acid residue by a solid-phase method, the peptide is loaded onto a resin for solid-phase synthesis prior to the initial elongation reaction.