Method for producing cyclic peptide compound

Description

METHOD FOR PRODUCING CYCLIC PEPTIDE COMPOUND Technical Field

[001] The present invention relates to a method for producing a cyclic peptide compound, in particular, a method for producing a cyclic peptide compound with selective inhibitory action on KRAS with respect to HRAS and NRAS. Antecedent Technique

[002] RAS is a protein belonging to the small GTPase family, and KRAS, NRAS, and HRAS are known. RAS is defined as being in an activated or inactivated state depending on its GDP or GTP binding state. It is activated by the exchange reaction from GDP to GTP by GEFs (guanine nucleotide exchange factors) and inactivated by the GTP hydrolysis reaction by GAPs (GTPase activating proteins) (Non-Patent Literature 1). Activated RAS induces cell proliferation, survival, and differentiation by activating various downstream signals in the MAPK, PI3K / Akt, RAL, and other pathways, and constitutive RAS activation plays an important role in cancer development and progression. In cancer, the RAS-RAFMEK-ERK pathway is known to be activated by upstream RAS signaling, constitutive RAS activation, and / or RAS activating mutations (Non-Patent Literature 2). These RAS activating mutations have been found in several types of cancer.G12, G13, and Q61 are known as critical mutation points in RAS, and G12 is frequently found mutated in KRAS and Q61 in NRAS. These mutations are also known to be associated with patient prognosis (Non-Patent Literature 3).

[003] In this regard, a cyclic peptide compound represented by the following formula (1), which has selectivity in RAS, specifically selective inhibitory action in KRAS on HRAS and NRAS (hereinafter also referred to as cyclic peptide compound (1)), was Petition 870250088014, dated 09 / 29 / 2025, page 8 / 299 2 / 238 reported (Patent Literature 1). Formula 1 List of citations Patent Literature Patent Literature 1

[004] International Publication No. WO 2022 / 234853 Non-Patent Literature Non-Patent Literature 1

[005] Nat. Rev. Drug Discov. November 2014; 13(11): 828-851. Non-Patent Literature 2

[006] Nat. Rev. Drug Discov. December 2014; 13(12): 928-942. Non-Patent Literature 3

[007] Nat. Rev. Drug Discov. November 2016; 15(11): 771-785. Summary of the Invention Technical Problem

[008] To the best of the present inventors’ knowledge, there are no reported examples of which position of the precursor cyclization peptide compound is preferred for cyclization in the production of the cyclic peptide compound (1), which has a cross-linked double bond between amino acids. Patent Literature 1 describes a method for producing the cyclic peptide compound (1) by a cyclization reaction at the position Petition 870250088014, dated 09 / 29 / 2025, page 9 / 299 3 / 238 of cyclization A. However, as described in Examples 1-26 below, in the production method described in Patent Literature 1, a cyclic dimer is found as a byproduct, in addition to the target cyclic peptide compound (1), and the ratio between the cyclic peptide compound (1) and the cyclic dimer is 75:25, which is of low selectivity. Formula 2 Cyclization reaction at cyclization position A

[009] Furthermore, the production of the cyclization precursor peptide compound described in Patent Literature 1 is carried out by sequential linkage of amino acids or some tripeptides by the Fmoc method and solid-phase synthesis. As solid-phase synthesis requires excessive amounts of amino acids and reagents and a large amount of organic solvents for washing at each step, it is desirable to avoid solid-phase synthesis whenever possible for mass production. Furthermore, to the best of the present inventors’ knowledge, there are no reported examples of crystals of the cyclic peptide compound (1).

[0010] The present invention was made in view of such situations, and one objective thereof is to provide an efficient method for producing the cyclic peptide compound (1) having a cross-linked double bond between amino acids.

[0011] Another objective of the present invention is to provide a crystal with excellent stability of the cyclic peptide compound (1). Solution to the problem

[0012] In view of the above circumstances, the present inventors studied intensively and finally concluded the present invention. That is, in one aspect, the present invention provides, as a Petition 870250088014, dated 09 / 29 / 2025, p. 10 / 299 4 / 238 cyclization method in the production of the cyclic peptide compound (1) having a cross-linked double bond between amino acids, a cyclization method by means of a cyclization position that can reduce the amount of a cyclic dimer, which is a byproduct. In one aspect, the present invention also provides, as a method for producing the precursor cyclization peptide compound, an efficient production method in which three fragment peptides are each synthesized and liquid-phase fragment coupling is performed for the synthesis. In one aspect, the present invention further provides a crystal of the cyclic peptide compound (1) and a method for producing the crystal by crystallization.

[0013] In one specific, non-limiting aspect, the present invention encompasses the following.

[0014] [A1] A method for producing a cyclic peptide compound represented by formula (1), or a salt thereof, or a solvate thereof, the method comprising a reaction step of an N-terminal amino acid residue of a peptide compound represented by formula (2) or (3) with a C-terminal amino acid residue of the peptide compound in a solvent for cyclization (cyclization step): Formula 3 Petition 870250088014, dated 09 / 29 / 2025, page 11 / 299 5 / 238 (3) wherein Ri is a C1-C6 alkyl;

[0015] Pi is a C1-C6 alkyl;

[0016] R2 is a C1-C6 alkyl;

[0017] R3 is hydrogen, or R3 forms a saturated heterocyclic ring of 4 to 7 members together with P3, a carbon atom to which R3 is attached and a nitrogen atom to which P3 is attached;

[0018] P3 is a C1-C6 alkyl or a C3-C8 cycloalkyl, or P3 forms a saturated 4- to 7-membered heterocyclic ring together with R3, a carbon atom to which R3 is attached, and a nitrogen atom to which P3 is attached;

[0019] P4 is a C1-C6 alkyl;

[0020] R5 is benzyl optionally substituted with one or more Petition 870250088014, dated 09 / 29 / 2025, p. 12 / 299 6 / 238 groups selected from the group consisting of a C1-C6 alkyl, a C1-C6 haloalkyl, and a C3-C8 cycloalkyl;

[0021] P6 is a C1-C6 alkyl;

[0022] R7 is phenethyl optionally substituted with one or more groups selected from the group consisting of a halogen, a C1-C6 haloalkyl, and a C1-C6 alkoxy;

[0023] R8 forms a saturated 4- to 7-membered heterocyclic ring together with P8, a carbon atom to which R8 is attached, and a nitrogen atom to which P8 is attached, the saturated 4- to 7-membered heterocyclic ring optionally substituted with a C1-C6 alkoxy;

[0024] R9 forms a 3- to 8-membered alicyclic ring together with Q9 and a carbon atom to which R9 and Q9 are attached, the 3- to 8-membered alicyclic ring optionally substituted with one or more C1-C6 alkyls;

[0025] P9 is hydrogen or a C1-C6 alkyl;

[0026] R10 is a C1-C6 alkyl or a C3-C8 cycloalkyl;

[0027] P10 is a C1-C6 alkyl;

[0028] R11 is a di-C1-C6 alkylaminocarbonyl or a 4- to 8-membered cyclic aminocarbonyl;

[0029] P11 is a C1-C6 alkyl;

[0030] X1 and X5 are each independently either hydrogen or a protecting group for an amino group; and

[0031] X2 and X4 are each independently a halogen, a hydroxy group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy or a group represented by -OSiRxRyRz, wherein Rx, Ry, and Rz are each independently an alkyl or an aryl.

[0032] [A2] A method for producing a cyclic peptide compound represented by formula (1), or a salt thereof, or a solvate Petition 870250088014, dated 09 / 29 / 2025, p. 13 / 299 7 / 238 of the same, the method comprising: a step for supplying peptide compounds represented by formulas (4) to (6), or salts thereof, or solvates of the peptide compounds or salts; a reaction step of N-terminal amino acid residues of the peptide compounds represented by formulas (4) to (6) with C-terminal amino acid residues of the peptide compounds in a solvent for ligation (ligation step); and a reaction step of an N-terminal amino acid residue of a peptide compound obtained in step (b) with a C-terminal amino acid residue of the peptide compound in a solvent for cyclization (cyclization step): Formula 4 Petition 870250088014, dated 09 / 29 / 2025, page 14 / 299 8 / 238 (6) wherein Ri is a C1-C6 alkyl;

[0033] Pi is a C1-C6 alkyl;

[0034] R2 is a C1-C6 alkyl;

[0035] R3 is hydrogen, or R3 forms a saturated heterocyclic ring of 4 to 7 members together with P3, a carbon atom to which R3 is attached and a nitrogen atom to which P3 is attached;

[0036] P3 is a C1-C6 alkyl or a C3-C8 cycloalkyl, or P3 forms a saturated 4- to 7-membered heterocyclic ring together with R3, a carbon atom to which R3 is attached, and a nitrogen atom to which P3 is attached;

[0037] P4 is a C1-C6 alkyl;

[0038] R5 is benzyl optionally substituted with one or more groups selected from the group consisting of a C1-C6 alkyl, a C1-C6 haloalkyl, and a C3-C8 cycloalkyl;

[0039] P6 is a C1-C6 alkyl;

[0040] R7 is phenethyl optionally substituted with one or more groups selected from the group consisting of a halogen, a C1-C6 haloalkyl, and a C1-C6 alkoxy;

[0041] R8 forms a saturated 4- to 7-membered heterocyclic ring together with P8, a carbon atom to which R8 is attached, and a nitrogen atom to which P8 is attached, the saturated 4- to 7-membered heterocyclic ring optionally substituted with a C1-C6 alkoxy;

[0042] R9 forms a 3- to 8-membered alicyclic ring together with Q9 and a carbon atom to which R9 and Q9 are attached, the 3- to 8-membered alicyclic ring optionally substituted with one or more C1-C6 alkyls; Petition 870250088014, dated 09 / 29 / 2025, page 15 / 299 9 / 238

[0043] P9 is hydrogen or a C1-C6 alkyl;

[0044] R10 is a C1-C6 alkyl or a C3-C8 cycloalkyl;

[0045] P10 is a C1-C6 alkyl;

[0046] R11 is a di-C1-C6 alkylaminocarbonyl or a 4- to 8-membered cyclic aminocarbonyl;

[0047] P11 is a C1-C6 alkyl;

[0048] X1, X3 and X5 are each independently either hydrogen or a protecting group for an amino group; and

[0049] X2, X4 and X6 are each independently a halogen, a hydroxy group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy or a group represented by -OSiRxRyRz, wherein Rx, Ry, and Rz are each independently an alkyl or an aryl.

[0050] [A3] The method, according to [A2], comprising, in step (b),

[0051] (b-1) a reaction step of an N-terminal amino acid residue of the peptide compound represented by formula (5) with a C-terminal amino acid residue of the peptide compound represented by formula (6) in a solvent for binding, thus converting them into a peptide compound represented by formula (7) (binding step): Formula 5 (7) where R1, R2, R3, R7, R8, R9, R10, R11, Pi, P3, P8, P9, P10, P11, Q9, X4, and Petition 870250088014, dated 09 / 29 / 2025, p. 16 / 299 10 / 238 X5 are the same as in [A2].

[0052] [A4] The method, according to [A3], additionally comprising, in step (b),

[0053] (b-2) a reaction step of an N-terminal amino acid residue of the peptide compound represented by formula (4) with a C-terminal amino acid residue of the peptide compound represented by formula (7) in a solvent for binding, thus converting them into a peptide compound represented by formula (2) (binding step), and in step (c),

[0054] (c-1) a reaction step of an N-terminal amino acid residue of the peptide compound represented by formula (2) with a C-terminal amino acid residue of the peptide compound in a solvent for cyclization (cyclization step).

[0055] [A5] The method, according to [A3], additionally comprising, in step (b),

[0056] (b-3) a reaction step of an N-terminal amino acid residue of the peptide compound represented by formula (7) with a C-terminal amino acid residue of the peptide compound represented by formula (4) in a solvent for binding, thus converting them into a compound represented by formula (3) (binding step), and in step (c),

[0057] (c-2) a reaction step of an N-terminal amino acid residue of the peptide compound represented by formula (3) with a C-terminal amino acid residue of the peptide compound in a solvent for cyclization (cyclization step).

[0058] [A6] The method, according to any one of [A1] to [A5], in which the linkage of an N-terminal amino acid residue of a peptide compound with a C-terminal amino acid residue of a peptide compound is the linkage of an amino group of the N-terminal amino acid residue with a carboxyl group of the residue of Petition 870250088014, dated 09 / 29 / 2025, page 17 / 299 11 / 238 C-terminal amino acid.

[0059] [A7] The method, according to any one of [A1] to [A6], in which the linkage of an N-terminal amino acid residue of a peptide compound with a C-terminal amino acid residue of a peptide compound is the linkage by means of an amide bond of an amino group of the N-terminal amino acid residue with a carboxyl group of the C-terminal amino acid residue.

[0060] [A8] The method, according to any one of [A1] to [A7], in which the solvent in the cyclization step includes one or more selected from the group consisting of a nitrile-based solvent, a halogen-based solvent, an ether-based solvent, an amide-based solvent, an ester-based solvent and a carbonate-based solvent.

[0061] [A9] The method, according to [A8],

[0062] wherein the nitrile-based solvent is one or more selected from the group consisting of acetonitrile and propionitrile,

[0063] wherein the halogen-based solvent is one or more selected from the group consisting of dichloromethane, chloroform and 1,2-dichloroethane,

[0064] wherein the ether-based solvent is one or more selected from the group consisting of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentylmethyl ether, 4-methyltetrahydropyran, 1,3-dioxolane, 1,4-dioxane, 1,2-dimethoxyethane, diisopropyl ether, t-butylmethyl ether, diglylene, triglyceride, anisole and tetraglyceride,

[0065] wherein the amide-based solvent is one or more selected from the group consisting of DMF, NMP, DMA, NEP, NBP and formamide,

[0066] wherein the ester-based solvent is one or more selected from the group consisting of methyl acetate, ethyl acetate, methyl propionate, butyl acetate, propyl acetate, methyl acetate, Petition 870250088014, dated 09 / 29 / 2025, p. 18 / 299 12 / 238 isopropyl, isobutyl acetate, pentyl acetate and Π-valerolactone, and

[0067] wherein the carbonate-based solvent is one or more selected from the group consisting of dimethyl carbonate, diethyl carbonate and dibutyl carbonate.

[0068] [A10] The method, according to [A8], in which the solvent in the cyclization step is one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2-methyltetrahydropyran, 4-methyltetrahydropyran, tetrahydrofuran, ethyl acetate, isopropyl acetate, dichloromethane, DMF and anisole.

[0069] [A11] The method, according to [A8], in which the solvent in the cyclization step is one or more selected from the group consisting of acetonitrile, 2-methyltetrahydrofuran, ethyl acetate and dichloromethane.

[0070] [A12] The method, according to [A8], in which the solvent in the cyclization step is acetonitrile, 2-methyltetrahydrofuran or ethyl acetate.

[0071] [A13] The method, according to any one of [A1] to [A12], in which the cyclization step is carried out in the presence of a condensation reagent.

[0072] [A14] The method, according to [A13], in which the condensation reagent in the cyclization step is one or more selected from the group consisting of HATU, COMU, DMT-MM, PyOxim, PyBOP, HCTU, T3P, EDCI, BEP and PyClop.

[0073] [A15] The method, according to [A13], in which the condensation reagent in the cyclization step is one selected from the group consisting of HATU, COMU, PyOxim, PyBOP, HCTU and T3P.

[0074] [A16] The method, according to [A13], in which the condensation reagent in the cyclization step is HATU.

[0075] [A17] The method, according to [A13], in which the condensation reagent in the cyclization step is COMU. Petition 870250088014, dated 09 / 29 / 2025, page 19 / 299 13 / 238

[0076] [A18] The method, according to [A13], in which the condensation reagent in the cyclization step is HATU and the solvent in the cyclization step is acetonitrile.

[0077] [A19] The method, according to [A13], in which the condensation reagent in the cyclization step is HATU and the solvent in the cyclization step is 2-methyltetrahydrofuran.

[0078] [A20] The method, according to [A13], in which the condensation reagent in the cyclization step is COMU and the solvent in the cyclization step is acetonitrile.

[0079] [A21] The method, according to [A13], in which the condensation reagent in the cyclization step is COMU and the solvent in the cyclization step is 2-methyltetrahydrofuran.

[0080] [A22] The method, according to any one of [A1] to [A21], in which the cyclization step is performed in the presence of a base.

[0081] [A23] The method, according to [A22], in which the base in the cyclization step is an organic base.

[0082] [A24] The method, according to [A22], in which the base in the cyclization step is an organic base comprising a tertiary amine.

[0083] [A25] The method, according to [A22], wherein the base in the cyclization step is one or more selected from the group consisting of 2,2,6,6-tetramethylpiperidine, N-methylmorpholine, N,N-diisopropylethylamine (DIPEA), 2,4,6-colidine, 2,6-lutidine, pyridine, 1,8-diazabicyclo-7-undecene (DBU), 2,3,6,7-tetrahydro-1H,5H-9-azabenzo[ij]quinolidine, 1,4-diazabicyclooctane (DABCO), 1,5-diazabicyclo-5-nonene (DBN), 7-methyl-1,5,7-triazabicyclodec-5-ene, 1,1,3,3-tetramethylguanidine (TMG), 1,8-bis(tetramethylguanidino)naphthalene (TMGN), 2-tert-butyl1,1,3,3-tetramethylguanidine (BTMG), triethylamine (TEA), trimethylamine, 1methylpiperidine, N,N'-dimethylpiperazine, N-ethylmorpholine and p-dimethylaminopyridine (DMAP). Petition 870250088014, dated 09 / 29 / 2025, page 20 / 299 14 / 238

[0084] [A26] The method, according to [A22], wherein the base in the cyclization step is one or more selected from the group consisting of 2,2,6,6-tetramethylpiperidine, N-methylmorpholine, N,N-diisopropylethylamine (DIPEA), 2,4,6-colidine, 2,6-lutidine and pyridine.

[0085] [A27] The method, according to [A22], in which the condensation reagent in the cyclization step is HATU, the solvent in the cyclization step is acetonitrile and the base in the cyclization step is N,N-diisopropylethylamine (DIPEA).

[0086] [A28] The method, according to [A22], in which the condensation reagent in the cyclization step is HATU, the solvent in the cyclization step is 2-MeTHF and the base in the cyclization step is N,N-diisopropylethylamine (DIPEA).

[0087] [A29] The method, according to [A22], in which the condensation reagent in the cyclization step is COMU, the solvent in the cyclization step is acetonitrile and the base in the cyclization step is 2,6-lutidine.

[0088] [A30] The method, according to [A22], in which the condensation reagent in the cyclization step is COMU, the solvent in the cyclization step is 2-methyltetrahydrofuran and the base in the cyclization step is 2,6-lutidine.

[0089] [A31] The method, according to any one of [A1] to [A30], in which the cyclization step is carried out by a liquid phase method.

[0090] [A32] The method, according to any one of [A1] to [A31], in which in the cyclization step, the peptide compound and the base are mixed in a mixed solution obtained by mixing the solvent and the condensation reagent in the cyclization step.

[0091] [A33] The method, according to any one of [A1] to [A32], wherein the content of the total by-products generated in the cyclization step is less than 20%, less than 15%, less than 10%, less than 5% or less than 3%, as determined by the UV area value at 220 nm by HPLC analysis, based on the total quantity of products. Petition 870250088014, dated 09 / 29 / 2025, page 21 / 299 15 / 238

[0092] [A34] The method, according to any one of [A1] to [A33], wherein the content of each of the by-products generated in the cyclization step is less than 15%, less than 10%, less than 5%, less than 3%, less than 1% or an undetectable amount, as determined by the UV area value at 220 nm by HPLC analysis, based on the total amount of products.

[0093] [A35] The method, according to any one of [A1] to [A34], wherein the content of each of the by-products generated in the cyclization step is less than 15%, less than 10%, less than 5%, less than 3%, less than 1% or an undetectable amount, as determined by the UV area value at 220 nm by HPLC analysis, based on the total amount of products, and the by-products comprise an epimer and / or a cyclic dimer.

[0094] [A36] The method, according to any one of [A1] to [A35], wherein the by-products generated in the cyclization step comprise an epimer, and the epimer content is less than 10%, less than 7.5%, less than 5%, less than 2.5% or less than 1%, as determined by the UV area value at 220 nm by HPLC analysis, based on the total amount of products.

[0095] [A37] The method, according to any one of [A1] to [A36], wherein the by-products generated in the cyclization step comprise a cyclic dimer, and a cyclic dimer content is less than 15%, less than 10%, less than 5%, less than 2.5% or less than 1%, as determined by the UV area value at 220 nm by HPLC analysis, based on the total amount of products.

[0096] [A38] The method, according to any one of [A1] to [A37], in which the solvent in the linking step includes one or more selected from the group consisting of a nitrile-based solvent, a halogen-based solvent, an ether-based solvent, an amide-based solvent, an ester-based solvent and a solvent based on Petition 870250088014, dated 09 / 29 / 2025, p. 22 / 299 16 / 238 carbonate.

[0097] [A39] The method, according to [A38],

[0098] wherein the nitrile-based solvent is one or more selected from the group consisting of acetonitrile and propionitrile,

[0099] wherein the halogen-based solvent is one or more selected from the group consisting of dichloromethane, chloroform and 1,2-dichloroethane,

[00100] wherein the ether-based solvent is one or more selected from the group consisting of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentylmethyl ether, 4-methyltetrahydropyran, 1,3-dioxolane, 1,4-dioxane, 1,2-dimethoxyethane, diisopropyl ether, t-butylmethyl ether, diglylene, triglyceride, anisole and tetraglyceride,

[00101] wherein the amide-based solvent is one or more selected from the group consisting of DMF, NMP, DMA, NEP, NBP and formamide,

[00102] wherein the ester-based solvent is one or more selected from the group consisting of methyl acetate, ethyl acetate, methyl propionate, butyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, pentyl acetate and Π-valerolactone, and

[00103] wherein the carbonate-based solvent is one or more selected from the group consisting of dimethyl carbonate, diethyl carbonate and dibutyl carbonate.

[00104] [A40] The method, according to [A38], wherein the solvent in the linking step is one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, THF, ethyl acetate, isopropyl acetate, DMF and anisole.

[00105] [A41] The method, according to [A38], in which the solvent in the linking step is a mixed solvent of one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2 Petition 870250088014, dated 09 / 29 / 2025, page 23 / 299 17 / 238 methyltetrahydrofuran, 4-methyltetrahydropyran, THF, ethyl acetate, isopropyl acetate and anisole with DMF.

[00106] [A42] The method, according to [A38], in which the solvent in the linking step is a mixed solvent of acetonitrile, 2-methyltetrahydrofuran and DMF.

[00107] [A43] The method, according to [A38], in which the solvent in the linking step is a mixed solvent of 2-methyltetrahydrofuran and DMF.

[00108] [A44] The method, according to any one of [A1] to [A43], in which the linking step is carried out in the presence of a condensation reagent.

[00109] [A45] The method, according to [A44], in which the condensation reagent in the binding step is one or more selected from the group consisting of HATU, COMU, DMT-MM, PyOxim, PyBOP, HCTU, T3P, EDCI, BEP and PyClop.

[00110] [A46] The method, according to [A44], in which the condensation reagent in the binding step is one selected from the group consisting of HATU, COMU, PyOxim, PyBOP, HCTU and T3P.

[00111] [A47] The method, according to [A44], in which the condensation reagent in the binding step is one selected from the group consisting of HATU and COMU.

[00112] [A48] The method, according to [A44], in which the condensation reagent in the bonding step is HATU.

[00113] [A49] The method, according to [A44], in which the condensation reagent in the bonding step is COMU.

[00114] [A50] The method, according to [A44], wherein the condensation reagent in the linking step is HATU and the solvent in the linking step is acetonitrile or 2-MeTHF.

[00115] [A51] The method, according to [A44], wherein the condensation reagent in the linking step is HATU and the solvent in the linking step is a mixed solvent of acetonitrile, 2-MeTHF and DMF. Petition 870250088014, dated 09 / 29 / 2025, page 24 / 299 18 / 238

[00116] [A52] The method, according to [A44], wherein the condensation reagent in the linking step is COMU and the solvent in the linking step is acetonitrile or 2-MeTHF.

[00117] [A53] The method, according to [A44], wherein the condensation reagent in the linking step is COMU and the solvent in the linking step is a mixed solvent of acetonitrile, 2-MeTHF and DMF.

[00118] [A54] The method, according to any one of [A1] to [A53], in which the linking step is performed in the presence of a base.

[00119] [A55] The method, according to [A54], in which the base in the linking step is an organic base.

[00120] [A56] The method, according to [A54], in which the base in the linking step is an organic base comprising a tertiary amine.

[00121] [A57] The method, according to [A54], wherein the base in the linking step is one or more selected from the group consisting of 2,2,6,6-tetramethylpiperidine, N-methylmorpholine, N,N-diisopropylethylamine (DIPEA), 2,4,6-colidine, 2,6-lutidine, pyridine, 1,8-diazabicyclo7-undecene (DBU), 2,3,6,7-tetrahydro-1H,5H-9-azabenzo[ij]quinolidine, 1,4-diazabicyclooctane (DABCO), 1,5-diazabicyclo-5-nonene (DBN), 7-methyl-1,5,7-triazabicyclodec-5-ene, 1,1,3,3-tetramethylguanidine (TMG), 1,8-bis(tetramethylguanidino)naphthalene (TMGN), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), triethylamine (TEA), trimethylamine, 1-methylpiperidine, N,N'-dimethylpiperazine, N-ethylmorpholine and p-dimethylaminopyridine (DMAP).

[00122] [A58] The method, according to [A54], wherein the base in the linking step is one or more selected from the group consisting of 2,2,6,6-tetramethylpiperidine, N-methylmorpholine, N,N-diisopropylethylamine (DIPEA), 2,4,6-colidine, 2,6-lutidine and pyridine.

[00123] [A59] The method, according to [A54], in which the condensation reagent in the bonding step is HATU, the solvent in the step of Petition 870250088014, dated 09 / 29 / 2025, page 25 / 299 The 19 / 238 linkage is acetonitrile or 2-MeTHF, and the base in the linkage step is N,N-diisopropylethylamine (DIPEA).

[00124] [A60] The method, according to [A54], wherein the condensation reagent in the linking step is HATU, the solvent in the linking step is a mixed solvent of acetonitrile, 2-methyltetrahydrofuran and DMF, and the base in the linking step is N,N-diisopropylethylamine (DIPEA).

[00125] [A61] The method, according to [A54], in which the condensation reagent in the linking step is COMU, the solvent in the linking step is acetonitrile or 2-methyltetrahydrofuran, and the base in the linking step is N-methylmorpholine or 2,6-lutidine.

[00126] [A62] The method, according to [A54], wherein the condensation reagent in the linking step is COMU, the solvent in the linking step is a mixed solvent of acetonitrile, 2-methyltetrahydrofuran and DMF, and the base in the linking step is N-methylmorpholine or 2,6-lutidine.

[00127] The method, according to [A54], in which the condensation reagent in the linking step is HATU, the solvent in the linking step is a mixed solvent of acetonitrile and 2-methyltetrahydrofuran, and the base in the linking step is N-methylmorpholine.

[00128] The method, according to [A54], in which the condensation reagent in the linking step is HATU, the solvent in the linking step is acetonitrile and the base in the linking step is N-methylmorpholine.

[00129] [A63] The method, according to any one of [A1] to [A62], in which the bonding step is performed by a liquid phase method.

[00130] [A64] The method, according to any one of [A1] to [A63], in which column chromatography is used for isolation and / or purification of the cyclic peptide compound, or a salt thereof, or a solvate thereof.

[00131] [A65] The method, according to any one of [A1] to [A63], in which column chromatography is not used for isolation and / or purification of the cyclic peptide compound, or a salt thereof, or Petition 870250088014, dated 09 / 29 / 2025, page 26 / 299 20 / 238 a solvato of the same.

[00132] [A66] The method, according to any one of [A1] to [A65], further comprising a step of isolating and / or purifying the cyclic peptide compound, or a salt thereof, or a solvate thereof by crystallization to obtain a crystal of the cyclic peptide compound, or a salt thereof, or a solvate thereof.

[00133] [A67] The method, according to any one of [A1] to [A66], wherein Ri is a C3-C4 alkyl.

[00134] The method, according to any one of [A1] to [A66], where R1 is n-propyl.

[00135] The method, according to any one of [A1] to [A66], where R1 is 2-methylpropyl.

[00136] [A68] The method, according to any one of [A1] to [A67], wherein Pi is a C1-C4 alkyl.

[00137] The method, according to any of [A1] to [A67], where P1 is methyl.

[00138] [A69] The method, according to any one of [A1] to [A68], wherein R2 is a C3-C4 alkyl.

[00139] The method, according to any one of [A1] to [A68], wherein R2 is 1-methylpropyl.

[00140] [A70] The method, according to any one of [A1] to [A69], wherein R3 is hydrogen, or R3 forms a saturated 5-membered heterocyclic ring together with P3, a carbon atom to which R3 is attached, and a nitrogen atom to which P3 is attached.

[00141] The method, according to any one of [A1] to [A69], where R3 is hydrogen.

[00142] The method, according to any one of [A1] to [A69], in which R3 forms a saturated 5-membered heterocyclic ring together with P3, a carbon atom to which R3 is attached, and a nitrogen atom to which P3 is attached. Petition 870250088014, dated 09 / 29 / 2025, page 27 / 299 21 / 238

[00143] [A71] The method, according to any one of [A1] to [A70], wherein P3 is a C1-C4 alkyl, or P3 forms a saturated 5-membered heterocyclic ring together with R3, a carbon atom to which R3 is attached, and a nitrogen atom to which P3 is attached.

[00144] The method, according to any of [A1] to [A70], where P3 is methyl.

[00145] The method, according to any one of [A1] to [A70], in which P3 forms a saturated 5-membered heterocyclic ring together with R3, a carbon atom to which R3 is attached and a nitrogen atom to which P3 is attached.

[00146] [A72] The method, according to any one of [A1] to [A71], where P4 is a C1-C4 alkyl.

[00147] The method, according to any of [A1] to [A71], where P4 is methyl.

[00148] [A73] The method according to any one of [A1] to [A72], wherein R5 is benzyl optionally substituted with a C1-C4 alkyl.

[00149] The method according to any one of [A1] to [A72], wherein R5 is 4-trifluoromethylbenzyl.

[00150] [A74] The method, according to any one of [A1] to [A73], where P6 is a C1-C4 alkyl.

[00151] The method, according to any of [A1] to [A73], where P6 is methyl.

[00152] [A75] The method, according to any one of [A1] to [A74], wherein R7 is phenethyl optionally substituted with one or more groups selected from the group consisting of a halogen, trifluoromethyl and methoxy.

[00153] The method, according to any one of [A1] to [A74], where R7 is 3-methoxy-4-trifluoromethylphenethyl.

[00154] The method, according to any one of [A1] to [A74], wherein R7 is 3,5-difluoro-4-trifluoromethylphenethyl. Petition 870250088014, dated 09 / 29 / 2025, page 28 / 299 22 / 238

[00155] [A76] The method, according to any one of [A1] to [A75], wherein R8 forms a saturated 5-membered heterocyclic ring together with P8, a carbon atom to which R8 is attached, and a nitrogen atom to which P8 is attached, the saturated 5-membered heterocyclic ring substituted with a C1-C4 alkyl.

[00156] The method, according to any one of [A1] to [A75], in which R8 forms a saturated 5-membered heterocyclic ring together with P8, a carbon atom to which R8 is attached, and a nitrogen atom to which P8 is attached, the saturated 5-membered heterocyclic ring substituted with ethoxy.

[00157] [A77] The method, according to any one of [A1] to [A76], in which R9 forms a 4- to 6-membered alicyclic ring together with Q9 and a carbon atom to which R9 and Q9 are attached.

[00158] The method, according to any one of [A1] to [A76], in which R9 forms a 4-membered alicyclic ring together with Q9 and a carbon atom to which R9 and Q9 are attached.

[00159] The method, according to any one of [A1] to [A76], in which R9 forms a 5-membered alicyclic ring together with Q9 and a carbon atom to which R9 and Q9 are attached.

[00160] [A78] The method, according to any one of [A1] to [A77], wherein P9 is hydrogen or a C1-C4 alkyl.

[00161] The method, according to any of [A1] to [A77], where P9 is hydrogen.

[00162] The method, according to any of [A1] to [A77], where P9 is methyl.

[00163] [A79] The method, according to any one of [A1] to [A78], wherein R10 is a C4-C6 cycloalkyl.

[00164] The method, according to any one of [A1] to [A78], where R10 is cyclopentyl.

[00165] [A80] The method, according to any one from [A1] to [A79], Petition 870250088014, dated 09 / 29 / 2025, page 29 / 299 23 / 238 where P10 is a C1-C4 alkyl.

[00166] The method, according to any of [A1] to [A79], where P10 is methyl.

[00167] [A81] The method, according to any one of [A1] to [A80], wherein R11 is a di-C1-C4 alkylaminocarbonyl or a 5- to 6-membered cyclic aminocarbonyl.

[00168] The method, according to any one of [A1] to [A80], wherein R11 is dimethylaminocarbonyl.

[00169] [A82] The method, according to any one of [A1] to [A81], wherein P11 is a C1-C4 alkyl.

[00170] The method, according to any of [A1] to [A81], where P11 is methyl.

[00171] [A83] The method, according to any one of [A1] to [A82], wherein X1, X3 and X5 are each independently selected from the group consisting of hydrogen, a carbamate-based protecting group, an acyl-based protecting group, a sulfonamide-based protecting group and a silyl-based protecting group.

[00172] [A84] The method, according to [A83], wherein the carbamate-based protecting group is selected from the group consisting of an Fmoc group, a Cbz group, a Troc group, an Alloc group, a Teoc group, a TSoc group, a BIBSoc group, an IPCSoc group, a BBSoc group, a CHBSoc group, a CDBSoc group and a Boc group.

[00173] [A85] The method, according to [A83], wherein the acyl-based protecting group is selected from the group consisting of a trifluoroacetyl group, an acetyl group and a benzoyl group.

[00174] [A86] The method, according to [A83], wherein the sulfonamide-based protecting group is selected from the group consisting of a 2-nitrobenzenesulfonyl group, a 4-nitrobenzenesulfonyl group and a 2,4-dinitrobenzenesulfonyl group. Petition 870250088014, dated 09 / 29 / 2025, page 30 / 299 24 / 238

[00175] [A87] The method, according to [A83], wherein the silyl-based protective group is selected from the group consisting of a TMS group, a TBDMS group, a TES group, a TIPS group and a TBDPS group.

[00176] [A88] The method, according to any one of [A1] to [A87], wherein X1 is hydrogen or a carbamate-based protecting group.

[00177] The method, according to any of [A1] to [A87], where Xi is hydrogen.

[00178] The method, according to any of [A1] to [A87], where X1 is an Fmoc group.

[00179] [A89] The method, according to any one of [A1] to [A88], wherein X3 is hydrogen or a carbamate-based protecting group.

[00180] The method, according to any of [A1] to [A88], where X3 is hydrogen.

[00181] The method, according to any of [A1] to [A88], where X3 is a Cbz group.

[00182] [A90] The method, according to any one of [A1] to [A89], wherein X5 is hydrogen or a carbamate-based protecting group.

[00183] The method, according to any one of [A1] to [A89], where X5 is hydrogen.

[00184] The method, according to any of [A1] to [A89], where X5 is a Cbz group.

[00185] [A91] The method, according to any one of [A1] to [A90], wherein X2, X4 and X6 are each independently a halogen, a hydroxy group, an optionally substituted C1-C6 alkoxy, an optionally substituted C6-C10 aryloxy, an optionally substituted C7-C14 aralkoxy, an optionally substituted 4- to 8-membered cyclic aminooxy, or a group represented by -OSiRxRyRz, wherein Rx, Ry, and Rz are each independently a C1-C6 alkyl or a C6-C10 aryl. Petition 870250088014, dated 09 / 29 / 2025, p. 31 / 299 25 / 238

[00186] The method, according to any one of [A1] to [A90], in which the halogen is chlorine or bromine.

[00187] The method, according to any one of [A1] to [A90], in which the optionally substituted alkoxy is t-butoxy, methoxy, ethoxy or isopropoxy.

[00188] The method, according to any one of [A1] to [A90], in which the optionally substituted aryloxy is pentafluorophenyloxy or nitrophenyloxy.

[00189] The method, according to any one of [A1] to [A90], in which the optionally substituted aralkoxy is optionally substituted benzyloxy.

[00190] The method, according to any one of [A1] to [A90], in which the optionally substituted cyclic amino-oxy is N-hydroxysuccinimino-oxy.

[00191] The method, according to any one of [A1] to [A90], in which the group represented by -OSiRxRyRz is trimethylsilyloxy, triethylsilyloxy, tri-isopropylsilyloxy, triphenylsilyloxy, tri-t-butylsilyloxy, di-t-butylisobutylsilyloxy or tris(triethylsilyl)silyloxy.

[00192] [A92] The method, according to any one of [A1] to [A91], where X2 is a hydroxy, t-butoxy or benzyloxy group.

[00193] The method, according to any one of [A1] to [A91], where X2 is a hydroxyl group.

[00194] The method, according to any of [A1] to [A91], where X2 is t-butoxy.

[00195] [A93] The method, according to any one of [A1] to [A92], wherein X4 is a hydroxy, t-butoxy or benzyloxy group.

[00196] The method, according to any one of [A1] to [A92], wherein X4 is a hydroxyl group.

[00197] The method, according to any one of [A1] to [A92], wherein X4 is t-butoxy.

[00198] [A94] The method, according to any one of [A1] to [A93], Petition 870250088014, dated 09 / 29 / 2025, page 32 / 299 26 / 238 where X6 is a hydroxyl, t-butoxy, or benzyloxy group.

[00199] The method, according to any one of [A1] to [A93], wherein X6 is a hydroxyl group.

[00200] The method, according to any one of [A1] to [A93], where X6 is t-butoxy.

[00201] [A95] The method, according to any one of [A1] to [A94], wherein the cyclic peptide compound, or a salt thereof, or a solvate thereof, is a solvate of the cyclic peptide compound.

[00202] The method according to [A95], wherein the solvate of the cyclic peptide compound is a hydrate of the cyclic peptide compound.

[00203] [A96] The method according to any one of [A1] to [A95], wherein the cyclic peptide compound is represented by formula (1a): Formula 6 HN^O HN^O

[00204] [A97] The method, according to any one of [A1] to [A95], wherein the cyclic peptide compound is a crystal of a cyclic peptide compound represented by formula (1a): Formula 7 HN^O HN O (1a) .

[00205] The method, according to [A97], in which the crystal of a Petition 870250088014, dated 09 / 29 / 2025, page 33 / 299 27 / 238 cyclic peptide compound is a non-solvate crystal or a solvate crystal.

[00206] The method, according to [A97], in which the crystal of a cyclic peptide compound is a solvate crystal.

[00207] The method, according to , in which the solvate crystal of a cyclic peptide compound is a hydrate crystal.

[00208] [B1] A method for producing a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof, the method comprising a reaction step of an N-terminal amino acid residue of a peptide compound represented by formula (2a) or (3a) with a C-terminal amino acid residue of the peptide compound in a solvent for cyclization. (cyclization stage): Formula 8 F MeO^^ FaC^ F MeO^^ FaC^ \— / ω \— / ω x 9 9 .....v Ha a.....aoZHa • οΉ s «Jo H? θΑ a Πο θί° O ( O { / o G \ ' / ο Ό \ ' Petition 870250088014, dated 09 / 29 / 2025, page 34 / 299 28 / 238 HN^ / O HN O where Xi and X5 are each independently either hydrogen or a protecting group for an amino group; and

[00209] X2 and X4 are each independently a hydroxy group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy or a group represented by -OSiRxRyRz, wherein Rx, Ry and Rz are each independently an alkyl or an aryl.

[00210] [B2] A method for producing a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof, the method comprising:

[00211] a step for supplying peptide compounds represented by formulas (4a) to (6a), or salts thereof, or solvates of the peptide compounds or salts;

[00212] a reaction step of N-terminal amino acid residues of the peptide compounds represented by formulas (4a) to (6a) with C-terminal amino acid residues of the peptide compounds in a solvent for binding (binding step); and

[00213] a reaction step of an N-terminal amino acid residue of a peptide compound obtained in step (b) with a C-terminal amino acid residue of the peptide compound in a solvent for cyclization (cyclization step): Petition 870250088014, dated 09 / 29 / 2025, page 35 / 299 29 / 238 Formula 9 wherein Xi, X3, and X5 are each independently either hydrogen or a protecting group for an amino group; and

[00214] X2, X4 and X6 are each independently a hydroxy group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy or a group represented by -OSiRxRyRz, wherein Rx, Ry and Rz are each independently an alkyl or an aryl.

[00215] [B3] The method, according to [B2], comprising, in step (b),

[00216] (b-1) a reaction step of an N-terminal amino acid residue of the peptide compound represented by formula (5a) with a C-terminal amino acid residue of the peptide compound represented by formula (6a) in a solvent for binding, thereby converting them into a peptide compound represented by formula (7a) (binding step): Petition 870250088014, dated 09 / 29 / 2025, page 36 / 299 30 / 238 Formula 10 (7a) where X4 and X5 are the same as in [B2].

[00217] [B4] The method, according to [B3], further comprising, in step (b),

[00218] (b-2) a reaction step of an N-terminal amino acid residue of the peptide compound represented by formula (4a) with a C-terminal amino acid residue of the peptide compound represented by formula (7a) in a solvent for binding, thus converting them into a peptide compound represented by formula (2a) (binding step), and in step (c),

[00219] (c-1) a reaction step of an N-terminal amino acid residue of the peptide compound represented by formula (2a) with a C-terminal amino acid residue of the peptide compound in a solvent for cyclization (cyclization step).

[00220] [B5] The method, according to [B3], further comprising, in step (b),

[00221] (b-3) a reaction step of an N-terminal amino acid residue of the peptide compound represented by formula (7a) with a C-terminal amino acid residue of the peptide compound represented by formula (4a) in a solvent for binding, thus converting them into a peptide compound represented by formula (3a) (binding step), and in step (c), Petition 870250088014, dated 09 / 29 / 2025, page 37 / 299 31 / 238

[00222] (c-2) a reaction step of an N-terminal amino acid residue of the peptide compound represented by formula (3a) with a C-terminal amino acid residue of the peptide compound in a solvent for cyclization (cyclization step).

[00223] [B6] The method, according to any one of [B1] to [B5], wherein the solvent in the cyclization step is the solvent, according to any one of [A8] to [A12].

[00224] [B7] The method, according to any one of [B1] to [B6], in which the cyclization step is carried out in the presence of a condensation reagent.

[00225] [B8] The method, according to [B7], wherein the condensation reagent in the cyclization step is the condensation reagent, according to any one of [A14] to [A17].

[00226] [B9] The method, according to [B7], wherein the solvent and the condensation reagent in the cyclization step are the solvent and the condensation reagent, according to any one of [A18] to [A21].

[00227] [B10] The method, according to any one of [B1] to [B9], wherein the cyclization step is carried out in the presence of a base.

[00228] [B11] The method, according to [B10], wherein the basis in the cyclization step is the basis, according to any of [A24] to [A26].

[00229] [B12] The method, according to [B10], wherein the solvent, the condensation reagent and the base in the cyclization step are the solvent, the condensation reagent and the base, according to any one of [A27] to [A30].

[00230] [B13] The method, according to any one of [B1] to [B12], in which the cyclization step is carried out by a liquid phase method.

[00231] [B14] The method, according to any one of [B1] to [B13], in which in the cyclization step, the peptide compound and the base are mixed in a mixed solution obtained by mixing the solvent and the Petition 870250088014, dated 09 / 29 / 2025, page 38 / 299 32 / 238 condensation reagent in the cyclization step.

[00232] [B15] The method, according to any one of [B1] to [B14], wherein the content of the total by-products generated in the cyclization step is less than 20%, less than 15%, less than 10%, less than 5% or less than 3%, as determined by the UV area value at 220 nm by HPLC analysis, based on the total quantity of products.

[00233] [B16] The method, according to any one of [B1] to [B15], wherein the content of each of the by-products generated in the cyclization step is less than 15%, less than 10%, less than 5%, less than 3%, less than 1% or an undetectable amount, as determined by the UV area value at 220 nm by HPLC analysis, based on the total amount of products.

[00234] [B17] The method, according to any one of [B1] to [B16], wherein the content of each of the by-products generated in the cyclization step is less than 15%, less than 10%, less than 5%, less than 3%, less than 1% or an undetectable amount, as determined by the UV area value at 220 nm by HPLC analysis, based on the total amount of products, and the by-products comprise an epimer and / or a cyclic dimer.

[00235] [B18] The method, according to any one of [B1] to [B17], wherein the by-products generated in the cyclization step comprise an epimer, and the epimer content is less than 10%, less than 7.5%, less than 5%, less than 2.5% or less than 1%, as determined by the UV area value at 220 nm by HPLC analysis, based on the total amount of products.

[00236] [B19] The method, according to any one of [B1] to [B18], wherein the by-products generated in the cyclization step comprise a cyclic dimer, and the cyclic dimer content is less than 15%, less than 10%, less than 5%, less than 2.5% or less than 1%, as determined by the UV area value at 220 nm by HPLC analysis, with Petition 870250088014, dated 09 / 29 / 2025, page 39 / 299 33 / 238 based on the total quantity of products.

[00237] [B20] The method, according to any one of [B1] to [B19], wherein the solvent in the bonding step is the solvent, according to any one of [A38] to [A43].

[00238] [B21] The method, according to any one of [B1] to [B20], in which the bonding step is carried out in the presence of a condensation reagent.

[00239] [B22] The method, according to [B21], wherein the condensation reagent in the bonding step is the condensation reagent, according to any one of [A45] to [A49].

[00240] [B23] The method, according to [B21], wherein the solvent and the condensation reagent in the bonding step are the solvent and the condensation reagent, according to any one of [A50] to [A53].

[00241] [B24] The method, according to any one of [B1] to [B23], wherein the bonding step is carried out in the presence of a base.

[00242] [B25] The method according to [B24], wherein the base in the bonding step is the base according to any one of [A55] to [A59].

[00243] [B26] The method according to [B24], wherein the solvent, the condensation reagent and the base in the bonding step are the solvent, the condensation reagent and the base according to any one of [A60] to [A62].

[00244] [B27] The method, according to any one of [B1] to [B26], in which the bonding step is performed by a liquid phase method.

[00245] [B28] The method, according to any one of [B1] to [B27], in which column chromatography is used for isolation and / or purification of the cyclic peptide compound, or a salt thereof, or a solvate thereof.

[00246] [B29] The method, according to any one of [B1] to [B27], in which column chromatography is not used for isolation and / or purification of the cyclic peptide compound, or a salt thereof, or Petition 870250088014, dated 09 / 29 / 2025, page 40 / 299 34 / 238 a solvato of the same.

[00247] [B30] The method, according to any one of [B1] to [B29], further comprising a step of isolating and / or purifying the cyclic peptide compound, or a salt thereof, or a solvate thereof by crystallization to obtain a crystal of the cyclic peptide compound, or a salt thereof, or a solvate thereof.

[00248] [C1] A compound represented by formula (4a) or a salt thereof: Formula 11 (4a) wherein X1 is hydrogen or a protecting group for an amino group; and

[00249] X2 is a hydroxy group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic amino-oxy or a group represented by -OSiRxRyRz, wherein Rx, Ry, and Rz are each independently an alkyl or an aryl.

[00250] [C2] The compound or a salt thereof, according to [C1], wherein Xi is hydrogen.

[00251] [C3] The compound or a salt thereof, according to [C1], where X1 is an Fmoc group.

[00252] [C4] The compound or a salt thereof, according to any one of [C1] to [C3], where X2 is t-butoxy.

[00253] [C5] tert-butyl 2-[methyl-[(2S)-2-[(4Z,7S)-7-(methylamino)-8-oxo-2,3,6,7tetrahydroazocin-1-yl]-3-[4-(trifluoromethyl)phenyl]propanoyl]amino]acetate (compound 9).

[00254] [C6] A compound represented by formula (5a) or a salt thereof: Petition 870250088014, dated 09 / 29 / 2025, p. 41 / 299 35 / 238 Formula 12 (5a) where X3 is hydrogen or a protecting group for an amino group; and

[00255] X4 is a hydroxy group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy or a group represented by -OSiRxRyRz, where Rx, Ry and Rz are each independently an alkyl or an aryl.

[00256] [C7] The compound or a salt thereof, according to [C6], where X3 is hydrogen.

[00257] [C8] The compound or a salt thereof, according to [C6], where X3 is an Fmoc group or a Cbz group.

[00258] [C9] The compound or a salt thereof, according to any one of [C6] to [C8], where X4 is t-butoxy.

[00259] [C10] (2S)-1-[(2S,3S)-3-methyl-2-[[(2S)-2-(methylamino)pentanoyl]amino]pentanoyl]tert-butylpyrrolidine-2-acetate (compound 13).

[00260] [C11] A compound represented by formula (6a) or a salt thereof: Formula 13 (6a) where X5 is hydrogen or a protecting group for an amino group; and

[00261] X6 is a hydroxy group, an optionally substituted alkoxy, Petition 870250088014, dated 09 / 29 / 2025, p. 42 / 299 36 / 238 an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy or a group represented by -OSiRxRyRz, where Rx, Ry and Rz are each independently an alkyl or an aryl.

[00262] [C12] The compound or a salt thereof, according to [C11], where X5 is hydrogen.

[00263] [C13] The compound or a salt thereof, according to [C11], where X5 is a Cbz group.

[00264] [C14] The compound or a salt thereof, according to any one of [C11] to [C13], where X6 is a hydroxy or t-butoxy group.

[00265] [C15] Acid (3S)-3-[[(2S)-2-[[1-[[(2S,4R)-1-[(2S)-2-(Benzyloxycarbonylamino)-4-[3-methoxy-4-(trifluoromethyl)phenyl]butanoyl]-4-ethoxypyrrolid in-2-carbonyl]-methyl-amino]cyclobutanecarbonyl]-methyl-amino]-2cyclopentyl-acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butyric acid (compound 20).

[00266] [C16] A compound represented by formula (7a) or a salt thereof: Formula 14 wherein X5 is hydrogen or a protecting group for an amino group; and

[00267] X4 is a hydroxy group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy or a group represented by -OSiRxRyRz, where Rx, Ry and Rz are each independent Petition 870250088014, dated 09 / 29 / 2025, p. 43 / 299 37 / 238 depending on whether it is an alkyl or an aryl.

[00268] [C17] The compound or a salt thereof, according to [C16], where X5 is hydrogen.

[00269] [C18] The compound or a salt thereof, according to [C16], where X5 is a Cbz group.

[00270] [C19] The compound or a salt thereof, according to any one of [C16] to [C18], where X6 is a hydroxy or t-butoxy group.

[00271] [C20] Acid (2S)-1-[(2S,3S)-2-[[(2S)-2-[[(3S)-3-[[(2S)-2-[[1[[(2S,4R)-1-[(2S)-2-(Benzyloxycarbonylam ino)-4-[3-methoxy-4-(trifluoromethyl)phenyl]butanoyl]-4-ethoxy-pyrrolidine-2-carbonyl]-methyl- amino]cyclobutanecarbonyl]-methyl-amino]-2-cyclopentylacetyl]-methyl-amino]-4-(dimethylamino)4-oxo-butanoyl]-methyl-amino]pentanoyl]amino]-3-methyl-pentanoyl]pyrrolidine-2-carboxylic acid (compound 22).

[00272] (2S)-1-[(2S,3S)-2-[[(2S)-2-[[(3S)-3-[[(2S)-2-[[1-[[(2S,4R)-1[(2S)-2-amino-4-[3-methoxy-4-(trifluoromethyl)phenyl]butanoyl]-4-ethoxy-pyrrolidine tert-butyl -2-carbonyl]-methyl-amino]cyclobutanecarbonyl]-methyl-amino]-2-cyclopentyl-acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butanoyl]-methyl-amino]pentanoyl]amino]-3-methyl-pentanoyl]pyrrolidine-2-carboxylate (compound 37).

[00273] [C21] A compound represented by formula (2a) or a salt thereof: Formula 15 where X5 is hydrogen or a protecting group for an amino group; and

[00274] X2 is a hydroxy group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy Petition 870250088014, dated 09 / 29 / 2025, p. 44 / 299 38 / 238 tuído, an optionally substituted cyclic amino-oxy group or a group represented by -OSiRxRyRz, wherein Rx, Ry, and Rz are each independently an alkyl or an aryl group.

[00275] [C22] The compound or a salt thereof, according to [C21], where X5 is hydrogen.

[00276] [C23] The compound or a salt thereof, according to [C21], where X5 is a Cbz group.

[00277] [C24] The compound or a salt thereof, according to any one of [C21] to [C23], where X2 is a hydroxy or t-butoxy group.

[00278] [C25] acid 2-[[(2S)-2-[(4Z,7S)-7-[[(2S)-1-[(2S,3S)-2-[[(2S)2-[[(3S)-3-[[(2S)-2-[[1-[[(2S,4R)-1- [(2S)-2-Amino-4-[3-methoxy-4-(trifluoromethyl)phenyl]butanoyl]-4-ethoxy-pyrrolidine-2-ca rbonyl]-methyl-amino]cyclobutanecarbonyl]-methyl-amino]-2-cyclopentyl-acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butanoyl]-methyl-amino]pentanoyl]amino]-3-methyl-pentanoyl] pyrrolidine-2-carbonyl]-methyl-amino]-8-oxo-2,3,6,7-tetrahydroazocin-1-yl]3-[4-(trifluoromethyl)phenyl]propanoyl]-methyl-amino]acetic acid (compound 24).

[00279] [C26] A compound represented by formula (3a) or a salt thereof: Formula 16 HN^,O HN O1O (3a) where X1 is hydrogen or a protecting group for an amino group; and

[00280] X4 is a hydroxy group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic amino-oxy or a group represented by -OSiRxRyRz, where Rx, Ry and Rz are each, Petition 870250088014, dated 09 / 29 / 2025, p. 45 / 299 39 / 238 independently an alkyl or an aryl.

[00281] [C27] The compound or a salt thereof, according to [C26], where Xi is hydrogen.

[00282] [C28] The compound or a salt thereof, according to [C26], where X1 is an Fmoc group.

[00283] [C29] The compound or a salt thereof, according to any one of [C26] to [C28], where X4 is a hydroxy or t-butoxy group.

[00284] [C30] (S)-2-[(S)-3-[(S)-2-cyclopentyl-2-[1-[(2S,4R)-4-ethoxy-1 [(S)-4-[3-methoxy-4-(trifluoromethyl)phenyl]-2-[(2-[(S)-N-methyl-2-[(R,Z)-3-(methylamino)-2-oxo-3,4,7,8-tetrahydroazocin-1(2H)-yl]-3-[4-(trifluoromethyl)phenyl]propanamido]acetamido)butanoyl]-N-methylpyrrolidine-2-carboxiamido]-N-methylcyclobutane-1-carboxiamido]-N-methylacetamido]-4-(dimethylamino)N-methyl-4-oxobutanamido]pentanoyl]-L-isoleucyl-L-proline (compound 40).

[00285] [C31] A method for producing the compound, according to any one of [C1] to [C30], in which solid-phase synthesis is not used.

[00286] [C32] A method for producing a cyclic peptide compound represented by formula (1a), in which solid-phase synthesis is not used.

[00287] [D1] A crystal of a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof: Formula 17

[00288] [D2] The crystal, according to [D1], in which the crystal is Petition 870250088014, dated 09 / 29 / 2025, page 46 / 299 40 / 238 selected from the group consisting of a non-solvate crystal of a cyclic peptide compound, a solvate crystal of a cyclic peptide compound, a non-solvate crystal of a salt of a cyclic peptide compound, and a solvate crystal of a salt of a cyclic peptide compound.

[00289] [D3] The crystal, according to [D2], wherein the crystal is a solvate crystal of a cyclic peptide compound.

[00290] [D4] The crystal, according to [D3], wherein the solvate crystal is a hydrate crystal of a cyclic peptide compound.

[00291] [D5] The crystal, according to [D4], wherein the hydrate crystal is an A-form crystal including at least 7 peaks selected from the group consisting of 6.93°, 7.56°, 8.26°, 9.00°, 9.58°, 10.35°, 11.35°, 12.26°, 12.85°, 13.51°, 14.12°, 14.69°, 15.46°, 15.92°, 17.43°, and 17.73° (±0.2°) as diffraction angles (2θ values) by powder X-ray diffraction.

[00292] The crystal, according to [D4], wherein the hydrate crystal is an A-form crystal including at least 8 peaks selected from the group consisting of 6.93°, 7.56°, 8.26°, 9.00°, 9.58°, 10.35°, 11.35°, 12.26°, 12.85°, 13.51°, 14.12°, 14.69°, 15.46°, 15.92°, 17.43°, and 17.73° (±0.2°) as diffraction angles (2θ values) by powder X-ray diffraction.

[00293] The crystal, according to [D4], in which the hydrate crystal is an A-form crystal including peaks of 6.93°, 7.56°, 8.26°, 9.00°, 9.58°, 10.35°, 11.35°, 12.26°, 12.85°, 13.51°, 14.12°, 14.69°, 15.46°, 15.92°, 17.43°, and 17.73° (±0.2°) as diffraction angles (2θ values) by X-ray powder diffraction.

[00294] The crystal of form A, according to any of the [D5] a , wherein the diffraction angles (2θ values) are diffraction angles (2θ values) of a hydrate crystal stored at a relative humidity of 10% or more for 15 minutes or more. Petition 870250088014, dated 09 / 29 / 2025, p. 47 / 299 41 / 238

[00295] [D6] The crystal, according to [D4], wherein the hydrate crystal is a B-form crystal including at least 7 peaks selected from the group consisting of 4.99°, 8.65°, 9.85°, 10.84°, 11.32°, 12.35°, 13.20°, 14.44°, 15.20°, 16.03°, 16.69°, 17.21°, 18.82°, 19.49°, and 20.03° (±0.2°) as diffraction angles (2θ values) by powder X-ray diffraction.

[00296] The crystal, according to [D4], wherein the hydrate crystal is a B-form crystal including at least 8 peaks selected from the group consisting of 4.99°, 8.65°, 9.85°, 10.84°, 11.32°, 12.35°, 13.20°, 14.44°, 15.20°, 16.03°, 16.69°, 17.21°, 18.82°, 19.49°, and 20.03° (±0.2°) as diffraction angles (2θ values) by X-ray powder diffraction.

[00297] The crystal, according to [D4], wherein the hydrate crystal is a B-form crystal including peaks of 4.99°, 8.65°, 9.85°, 10.84°, 11.32°, 12.35°, 13.20°, 14.44°, 15.20°, 16.03°, 16.69°, 17.21°, 18.82°, 19.49°, and 20.03° (±0.2°) as diffraction angles (2θ values) by X-ray powder diffraction.

[00298] The crystal of form B, according to any of the [D6] a , wherein the diffraction angles (2θ values) are diffraction angles (2θ values) of a hydrate crystal stored at a relative humidity of 30% or more for 15 minutes or more.

[00299] [D7] The crystal, according to [D3], wherein the solvate crystal is an F-shaped crystal including at least 7 peaks selected from the group consisting of 6.99°, 8.49°, 9.49°, 9.88°, 10.21°, 11.81°, 12.32°, 12.75°, 13.17°, 13.94°, 14.92°, 15.20°, 15.64°, 16.78°, 17.01°, and 17.47° (±0.2°) as diffraction angles (2θ values) by powder X-ray diffraction.

[00300] The crystal, according to [D3], in which the solvate crystal is an F-shaped crystal including at least 8 peaks selected from the group consisting of 6.99°, 8.49°, 9.49°, 9.88°, 10.21°, 11.81°, 12.32°, Petition 870250088014, dated 09 / 29 / 2025, p. 48 / 299 42 / 238 12.75°, 13.17°, 13.94°, 14.92°, 15.20°, 15.64°, 16.78°, 17.01°, and 17.47° (±0.2°) as diffraction angles (2θ values) by X-ray diffraction in powder.

[00301] The crystal, according to [D3], in which the solvate crystal is an F-shaped crystal including peaks of 6.99°, 8.49°, 9.49°, 9.88°, 10.21°, 11.81°, 12.32°, 12.75°, 13.17°, 13.94°, 14.92°, 15.20°, 15.64°, 16.78°, 17.01°, and 17.47° (±0.2°) as diffraction angles (2θ values) by powder X-ray diffraction.

[00302] The crystal, according to any of [D7] to , where the solvate crystal is an acetone / heptane / water solvate.

[00303] [D8] The crystal, according to [D4], wherein the hydrate crystal is a J-shaped crystal including at least 7 peaks selected from the group consisting of 6.95°, 7.33°, 7.93°, 8.84°, 9.45°, 9.97°, 10.44°, 11.19°, 12.43°, 12.93°, 13.46°, 14.36°, 14.74°, 15.21°, 15.87°, 16.76°, 20.87°, and 22.97° (±0.2°) as diffraction angles (2θ values) by powder X-ray diffraction.

[00304] The crystal, according to [D4], wherein the hydrate crystal is a J-shaped crystal including at least 8 peaks selected from the group consisting of 6.95°, 7.33°, 7.93°, 8.84°, 9.45°, 9.97°, 10.44°, 11.19°, 12.43°, 12.93°, 13.46°, 14.36°, 14.74°, 15.21°, 15.87°, 16.76°, 20.87°, and 22.97° (±0.2°) as diffraction angles (2θ values) by powder X-ray diffraction.

[00305] The crystal, according to [D4], in which the hydrate crystal is a J-shaped crystal including peaks of 6.95°, 7.33°, 7.93°, 8.84°, 9.45°, 9.97°, 10.44°, 11.19°, 12.43°, 12.93°, 13.46°, 14.36°, 14.74°, 15.21°, 15.87°, 16.76°, 20.87°, and 22.97° (±0.2°) as diffraction angles (2θ values) by X-ray powder diffraction.

[00306] The J-shaped crystal, according to any of the [D8] a , where the diffraction angles (2θ values) are diffraction angles (2θ values) of a hydrate crystal stored at a relative humidity Petition 870250088014, dated 09 / 29 / 2025, p. 49 / 299 43 / 238 of less than 10% for 15 minutes or more.

[00307] [D9] The crystal, according to [D4], wherein the hydrate crystal is a Y-shaped crystal including at least 7 peaks selected from the group consisting of 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54°, and 21.24° (±0.2°) as diffraction angles (2θ values) by X-ray powder diffraction.

[00308] The crystal, according to [D4], wherein the hydrate crystal is a Y-shaped crystal including at least 8 peaks selected from the group consisting of 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54°, and 21.24° (±0.2°) as diffraction angles (2θ values) by X-ray powder diffraction.

[00309] The crystal, according to [D4], wherein the hydrate crystal is a Y-shaped crystal including peaks of 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54°, and 21.24° (±0.2°) as diffraction angles (2θ values) by X-ray powder diffraction.

[00310] The Y-shaped crystal, according to any of the [D9] a , wherein the diffraction angles (2θ values) are diffraction angles (2θ values) of a hydrate crystal stored at a relative humidity of less than 30% for 15 minutes or more.

[00311] [D10] The crystal, according to [D3], wherein the hydrate crystal is a K-shaped crystal including at least 7 peaks selected from the group consisting of 7.49°, 7.91°, 8.14°, 9.11°, 9.33°, 11.04°, 11.71°, 12.52°, 13.21°, 13.70°, 14.82°, 15.13°, 15.52°, 15.68°, 17.22°, and 17.51° (±0.2°) as diffraction angles (2θ values) by powder X-ray diffraction.

[00312] The crystal, according to [D3], wherein the hydrate crystal is a K-shaped crystal including at least 8 peaks selected from Petition 870250088014, dated 09 / 29 / 2025, page 50 / 299 44 / 238 of the group consisting of 7.49°, 7.91°, 8.14°, 9.11°, 9.33°, 11.04°, 11.71°, 12.52°, 13.21°, 13.70°, 14.82°, 15.13°, 15.52°, 15.68°, 17.22°, and 17.51° (±0.2°) as diffraction angles (2θ values) by X-ray powder diffraction.

[00313] The crystal, according to [D3], wherein the solvate crystal is a K-shaped crystal including peaks of 7.49°, 7.91°, 8.14°, 9.11°, 9.33°, 11.04°, 11.71°, 12.52°, 13.21°, 13.70°, 14.82°, 15.13°, 15.52°, 15.68°, 17.22°, and 17.51° (±0.2°) as diffraction angles (2θ values) by X-ray powder diffraction.

[00314] [D11] The crystal, according to [D3], wherein the solvate crystal is a dimethyl sulfoxide / heptane / water solvate crystal of G form with the single crystal X-ray analysis structure shown in Figure 1.

[00315] The crystal, according to [D3], wherein the solvate crystal is a 2-propanol / heptane / water solvate crystal of form E with the single crystal X-ray analysis structure shown in Figure 3.

[00316] The crystal, according to [D3], wherein the solvate crystal is an ethanol / water solvate crystal of H form with the single crystal X-ray analysis structure shown in Figure 8.

[00317] The crystal, according to [D3], wherein the solvate crystal is a D-shaped 1,4-dioxane / water solvate crystal with the single-crystal X-ray analysis structure shown in Figure 26.

[00318] The crystal, according to [D3], wherein the solvate crystal is an L-shaped dimethyl sulfoxide / water solvate crystal with the single-crystal X-ray analysis structure shown in Figure 28.

[00319] The crystal, according to [D3], wherein the solvate crystal is a propylene glycol / water solvate crystal of M form with the single crystal X-ray analysis structure shown in Figure 31.

[00320] The crystal, according to [D3], wherein the solvate crystal is a propylene glycol / water solvate crystal of M form with the powder X-ray diffraction angles shown in Figure 29. Petition 870250088014, dated 09 / 29 / 2025, page 51 / 299 45 / 238

[00321] The crystal, according to [D3], wherein the solvate crystal is a propylene glycol / water solvate crystal of M shape exhibiting the differential thermal analysis data by thermogravimetry shown in Figure 30(A).

[00322] The crystal, according to [D3], wherein the solvate crystal is an N-shaped propylene glycol solvate crystal with the powder X-ray diffraction angles shown in Figure 29.

[00323] The crystal, according to [D3], wherein the solvate crystal is an N-shaped propylene glycol solvate crystal exhibiting the thermogravimetric differential thermal analysis data shown in Figure 30(B).

[00324] [D12] A method for producing a crystal of a cyclic peptide compound, according to any one of [D1] to , the method comprising: a step of dissolving the cyclic peptide compound in a polar organic solvent in an amount that allows the cyclic peptide compound to dissolve therein to obtain a solution; and a step of adding a hydrocarbon-based solvent or water to the solution to obtain a crystal of the cyclic peptide compound.

[00325] The method, according to [D12], in which the cyclic peptide compound of the raw material has a purity of 85% or more.

[00326] [D13] A method for producing a crystal of a cyclic peptide compound, according to any one of [D1] to , the method comprising: a step of adding a mixed solution of a hydrocarbon-based solvent and a polar organic solvent or a mixed solution of water and a polar organic solvent to the cyclic peptide compound in an amorphous state to obtain a crystal of the cyclic peptide compound.

[00327] [D14] The method, according to any one of [D12] to , in which the polar organic solvent is one or more selected from the Petition 870250088014, dated 09 / 29 / 2025, page 52 / 299 46 / 238 group consisting of DMSO, acetone, 2-butanone, methanol, ethanol, 1-propanol, 2-propanol, propylene glycol, 1,4-dioxane and ethyl acetate.

[00328] [D15] The method, according to [D14], in which the polar organic solvent is acetone.

[00329] The method, according to [D14], in which the polar organic solvent is ethanol.

[00330] [D16] The method, according to any one of [D12] to , wherein the hydrocarbon-based solvent is one or more selected from the group consisting of heptane, hexane, pentane, toluene and xylene.

[00331] [D17] The method, according to [D16], in which the hydrocarbon-based solvent is heptane.

[00332] [D18] A method for producing a crystal of a cyclic peptide compound, according to any one of [D1] to , the method comprising: a step of dissolving the cyclic peptide compound in an amorphous state in DMSO to obtain a solution; a step of lyophilizing the solution to obtain a lyophilized product of the cyclic peptide compound; and a step of adding a mixed solution of water and a polar organic solvent to the lyophilized product to obtain a crystal of the cyclic peptide compound.

[00333] [D19] The method, according to [D18], in which the polar organic solvent is one or more selected from the group consisting of DMSO, acetone, 2-butanone, methanol, ethanol, 1-propanol, 2-propanol, 1,4-dioxane and propylene glycol.

[00334] [D20] The method, according to [D19], in which the polar organic solvent is acetone.

[00335] [D21] The method, according to any of [D12] to [D20], further comprising, after the step of obtaining a crystal of the cyclic peptide compound, a step of filtering the crystal. Petition 870250088014, dated 09 / 29 / 2025, page 53 / 299 47 / 238

[00336] [D22] The method, according to any of [D12] to [D21], further comprising, after the step of obtaining a crystal of the cyclic peptide compound, a step of drying the crystal.

[00337] [D23] The method, according to any of [D12] to [D22], in which the crystal of a cyclic peptide compound is a solvate crystal.

[00338] [D24] The method, according to [D23], in which the solvate crystal of a cyclic peptide compound is a hydrate crystal.

[00339] [D25] The method, according to [D21] or [D22], in which the crystal of a cyclic peptide compound is formed as a solvate crystal in a solvent and obtained as a hydrate crystal after the filtration and / or drying step.

[00340] [D26] A composition comprising a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof, wherein the compound contains a cyclic dimer of formula (1a), which is an impurity, in an amount of 1.5% w / w or less: Formula 18

[00341] [D27] A composition comprising a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof, wherein the compound contains a cyclic dimer of formula (1a), which is an impurity, in an amount of 0.001% in Petition 870250088014, dated 09 / 29 / 2025, page 54 / 299 48 / 238 p / p or more: Formula 19 Hhk / O

[00342] [D28] A composition comprising a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof, wherein the compound contains acetone in a proportion of 2.0% w / w or less: Formula 20 HN^ / O

[00343] [D29] A composition comprising a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof, wherein the compound contains acetone in a proportion of 0.001% w / w or more: Formula 21 Petition 870250088014, dated 09 / 29 / 2025, page 55 / 299 49 / 238 HN^O

[00344] In the above numbering, the number cited in the dependent item includes the branch number of the number, unless otherwise indicated. For example, the [A67] cited in the dependent item shows that not only [A67], but also its branch number are included. The same applies to other numbering. Advantageous effects of the invention

[00345] According to the present invention, a cyclic peptide compound, or a salt thereof, or a solvate thereof, can be efficiently produced while suppressing the production of a cyclic dimer, which is a byproduct. The production method of the present invention allows for reduced costs in the production of the peptide compound and also reduces environmental burdens, and therefore the production method of the present invention is particularly useful for large-scale peptide synthesis. Brief description of the figures

[00346] Figure 1 shows the crystal structure of the crystal (G-form) obtained in Example 3-1. Compound 1 is drawn using the Capped Stick model and the others are drawn using the Ball-and-Stick model.

[00347] Figure 2 shows the results of the X-ray diffraction measurement of the crystal powder (form A) obtained in Example 3-2. The vertical axis represents a diffraction intensity and the horizontal axis represents a diffraction angle 2Θ (°).

[00348] Figure 3 shows the crystal structure of the crystal obtained in Petition 870250088014, dated 09 / 29 / 2025, page 56 / 299 50 / 238 Example 3-3. Compound 1 is drawn using the Capped Stick model, and the others are drawn using the Ball-and-Stick model.

[00349] Figure 4 shows the results of the X-ray diffraction measurement of the crystal powder (E-form) obtained in Example 3-3. The vertical axis represents a diffraction intensity and the horizontal axis represents a diffraction angle 2Θ (°).

[00350] Figure 5 shows the results of the X-ray diffraction measurement of the crystal powder (form B) obtained in Example 3-4. The vertical axis represents a diffraction intensity and the horizontal axis represents a diffraction angle 2θ (°).

[00351] Figure 6 shows the results of the X-ray diffraction measurement of the crystal powder (form B) obtained in Example 3-5. The vertical axis represents a diffraction intensity and the horizontal axis represents a diffraction angle 2θ (°).

[00352] Figure 7 shows the crystal structure of the crystal (H-form) obtained in Example 3-6. Compound 1 is drawn using the Capped Stick model and the others are drawn using the Ball-and-Stick model.

[00353] Figure 8 shows the results of the X-ray diffraction measurement of the crystal powder (form B) obtained in Example 3-6. The vertical axis represents a diffraction intensity and the horizontal axis represents a diffraction angle 2θ (°).

[00354] Figure 9 shows the crystal structure of the crystal (C-form) obtained in Example 3-7. Compound 1 is drawn using the Capped Stick model, and the others are drawn using the Ball-and-Stick model.

[00355] Figure 10 shows the results of the X-ray diffraction measurement of the crystal powder (form B) obtained in Example 3-7. The vertical axis represents a diffraction intensity and the horizontal axis represents a diffraction angle 2θ (°).

[00356] Figure 11 shows the results of the X-ray diffraction measurement of the crystal powder (form A) obtained in Example 3-8. The vertical axis Petition 870250088014, dated 09 / 29 / 2025, page 57 / 299 51 / 238 represents a diffraction intensity and the horizontal axis represents a diffraction angle 2Θ (°).

[00357] Figure 12 shows the results of the differential thermogravimetric thermal analysis of the crystal (form A) obtained in Example 3-8. The horizontal axis represents a temperature (°C) and the right vertical axis represents a change in weight (%) of the sample in the thermogravimetric analysis. The left vertical axis represents a heat flux observed in the differential thermal analysis.

[00358] Figure 13 shows the results of the 1H-NMR measurement of the crystal (form A) obtained in Example 3-8. The vertical axis represents the signal intensity and the horizontal axis represents a chemical shift δ (ppm).

[00359] Figure 14 shows the results of the X-ray diffraction measurement of the crystal powder (form A) obtained in Example 3-9. The vertical axis represents a diffraction intensity and the horizontal axis represents a diffraction angle 2θ (°).

[00360] Figure 15 shows the results of the differential thermogravimetric thermal analysis of the crystal (form A) obtained in Example 3-9. The horizontal axis represents a temperature (°C) and the right vertical axis represents a change in weight (%) of the sample in the thermogravimetric analysis. The left vertical axis represents a heat flux observed in the differential thermal analysis.

[00361] Figure 16 shows the results of the 1H-NMR measurement of the crystal (form A) obtained in Example 3-9. The vertical axis represents the signal intensity and the horizontal axis represents a chemical shift δ (ppm).

[00362] Figure 17 shows the results of the X-ray diffraction measurement of the crystal powder (form F) obtained in Example 3-10. The vertical axis represents a diffraction intensity and the horizontal axis represents a diffraction angle 2θ (°). Petition 870250088014, dated 09 / 29 / 2025, page 58 / 299 52 / 238

[00363] Figure 18 shows the crystal structure of the crystal (form F) obtained in Example 3-11. Compound 1 is drawn using the Capped Stick model and the others are drawn using the Ball-and-Stick model.

[00364] Figure 19 shows the results of the powder X-ray diffraction measurement of the crystal (form A) obtained in Example 3-12. The vertical axis represents a diffraction intensity and the horizontal axis represents a diffraction angle 2Θ (°).

[00365] Figure 20 shows the results of the differential thermogravimetric thermal analysis of the crystal (form A) obtained in Example 3-12. The horizontal axis represents a temperature (°C) and the right vertical axis represents a change in weight (%) of the sample in the thermogravimetric analysis. The left vertical axis represents a heat flux observed in the differential thermal analysis.

[00366] Figure 21 shows the results of the X-ray diffraction measurement of the crystal powder obtained in Example 3-12 at a relative humidity of (A) 0% (form J), (B) 10% (form A), (C) 20% (form A), (D) 50% (form A), and (E) 90% (form A). The vertical axis represents a diffraction intensity and the horizontal axis represents a diffraction angle 2Θ (°). The peaks around 4.89° and 6.65° in the figure are the peaks originating from the measuring equipment.

[00367] Figure 22 shows the results of the X-ray diffraction measurement of the crystal powder (form B) obtained in Example 3-13. The vertical axis represents a diffraction intensity and the horizontal axis represents a diffraction angle 2θ (°).

[00368] Figure 23 shows the results of the differential thermogravimetric thermal analysis of the crystal (form B) obtained in Example 3-13. The horizontal axis represents a temperature (°C) and the right vertical axis represents a change in weight (%) of the sample in the thermogravimetric analysis. The left vertical axis represents a heat flux observed in the differential thermal analysis. Petition 870250088014, dated 09 / 29 / 2025, page 59 / 299 53 / 238

[00369] Figure 24 shows the results of the X-ray diffraction measurement of the crystal powder obtained in Example 3-13 at a relative humidity of (A) 0% (form Y), (B) 30% (form B), (C) 50% (form B), and (D) 90% (form B). The vertical axis represents a diffraction intensity and the horizontal axis represents a diffraction angle 2Θ (°). The peak around 6.63° in the figure is a peak originating from the measuring equipment.

[00370] Figure 25 shows the crystal structure of the crystal (form B) obtained in Example 3-14. Compound 1 is drawn using the Capped Stick model and the others are drawn using the Ball-and-Stick model.

[00371] Figure 26 shows the crystal structure of the crystal (form D) obtained in Example 3-15. Compound 1 is drawn using the Capped Stick model and the others are drawn using the Ball-and-Stick model.

[00372] Figure 27 shows the crystal structure of the crystal (form L) obtained in Example 3-16. Compound 1 is drawn using the Capped Stick model and the others are drawn using the Ball-and-Stick model.

[00373] Figure 28 shows the results of the X-ray diffraction measurement of the crystal powder (form L) obtained in Example 3-16 (A: wet powder, B: dry powder). The vertical axis represents a diffraction intensity and the horizontal axis represents a diffraction angle 2θ (°).

[00374] Figure 29 shows the results of the X-ray diffraction measurement of the crystal powder obtained in Example 3-17 (A: M form, B: N form). The vertical axis represents a diffraction intensity and the horizontal axis represents a diffraction angle 2Θ (°).

[00375] Figure 30 shows the results of the differential thermogravimetric thermal analysis of the crystal (N-form) obtained in Example 3-17. The horizontal axis represents a temperature (°C) and the right vertical axis represents a change in weight (%) of the sample in the thermogravimetric analysis. The left vertical axis represents a heat flux observed in the differential thermal analysis. Petition 870250088014, dated 09 / 29 / 2025, page 60 / 299 54 / 238

[00376] Figure 31 shows the crystal structure of the crystal (M-form) obtained in Example 3-18. Compound 1 is drawn using the Capped Stick model and the others are drawn using the Ball-and-Stick model.

[00377] Figure 32 shows the results of the powder X-ray diffraction measurement of the crystal (K-form) obtained in Example 3-19. The vertical axis represents a diffraction intensity and the horizontal axis represents a diffraction angle 2Θ (°).

[00378] Figure 33 shows the results of the differential thermogravimetric thermal analysis of the crystal (K-form) obtained in Example 3-19. The horizontal axis represents a temperature (°C) and the right vertical axis represents a change in weight (%) of the sample in the thermogravimetric analysis. The left vertical axis represents a heat flux observed in the differential thermal analysis.

[00379] Figure 34 shows the results of the 1H-NMR measurement of the crystal (K form) obtained in Example 3-19. The vertical axis represents the signal intensity and the horizontal axis represents a chemical shift δ (ppm).

[00380] Figure 35 shows the results of X-ray powder diffraction measurements of crystals obtained in (A) Example 5-1, (B) Example 5-2, (C) Example 5-3, (D) Example 5-4, (E) Example 5-5, (F) Example 5-6, (G) Example 5-7, (H) Example 5-8 and (I) Example 5-9. The vertical axis represents a diffraction intensity and the horizontal axis represents a diffraction angle 2θ (°).

[00381] Figure 36 shows the results of the X-ray diffraction measurement of the crystal powder (form B) obtained in Example 3-22. The vertical axis represents a diffraction intensity and the horizontal axis represents a diffraction angle 2θ (°). Description of the modalities Abbreviations

[00382] The abbreviations used in this document are Petition 870250088014, dated 09 / 29 / 2025, p. 61 / 299 55 / 238 listed below.

[00383] 2-MeTHF: 2-methyltetra-hydrofuran

[00384] 20% Pip / DMF: Solution of N,N-dimethylformamide containing 20% piperidine

[00385] EtOAc: ethyl acetate

[00386] Aloc: allyl oxycarbonyl

[00387] BEP: 2-bromo-1-ethyl pyridine tetrafluoroborate

[00388] BHT: 2,6-di-tert-butyl-4-methylphenol

[00389] Boc: t-butoxycarbonyl

[00390] Cbz: benzyloxycarbonyl

[00391] AS: (1-cyano-2-ethoxy-2-oxoethylidenoaminoxy)dimethylamino-morpholino-carbenium hexafluorophosphate

[00392] CPME: cyclopentyl methyl ether

[00393] CSA: 10-camforsulfonic acid

[00394] DCM: dichloromethane

[00395] DEPBT: diethyl phosphate 3,4-di-hydro-4-oxo-1,2,3-benzotriazine-3-yl

[00396] PATTERNS: N,N-di-isopropylethylamines

[00397] DMA: N,N-dimethylacetamide

[00398] DMAP: 4-dimethylaminopyridine

[00399] DMF: N,N-dimethylformamide

[00400] DMSO: dimethyl sulfoxide

[00401] DMT-MM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride

[00402] EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[00403] FDPP: pentafluorophenyl diphenyl phosphinate

[00404] Fmoc or FMOC: 9-fluorenylmethyloxycarbonyl

[00405] HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[00406] HMDS: 1,1,1,3,3,3-hexamethyldisilazane Petition 870250088014, dated 09 / 29 / 2025, page 62 / 299 56 / 238

[00407] HOAt: 1-hydroxy-7-azabenzotriazole

[00408] HOBt: 1-hydroxybenzotriazole

[00409] IPAc: isopropyl acetate

[00410] MeCN: acetonitrile

[00411] MTBE: methyl tert-butyl ether

[00412] MTHP: 4-methyltetrahydropyran

[00413] NMM: 4-methylmorpholine

[00414] NMP: N-methylpyrrolidone

[00415] PyBOP: 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate

[00416] PyClop: chlorotripyrrolidine phosphonium hexafluorophosphate

[00417] PyOxim: (ethylcyano(hydroxyimino)acetate-O2)-tri-(1-pyrrolidinyl)-phosphonium hexafluorophosphate

[00418] T3P: propylphosphonic anhydride

[00419] TBAF: tetrabutylammonium fluoride

[00420] Teoc: 2-(trimethylsilyl)ethoxycarbonyl

[00421] TFA: trifluoroacetic acid

[00422] THF: tetrahydrofuran

[00423] TMSOTf: trimethylsilyl trifluoromethanesulfonate

[00424] Troc: 2,2,2-trichloroethoxycarbonyl

[00425] PDA: photodiode array

[00426] FA: formic acid

[00427] qNMR: quantitative nuclear magnetic resonance

[00428] UPLC: Ultra-High Performance Liquid Chromatography (registered trademark of Waters Corporation)

[00429] HPLC: high-performance liquid chromatography

[00430] Et: ethyl

[00431] DBU: 1,8-diazabicycloundec-7-ene

[00432] ESI: electrospray ionization

[00433] Bu: butyl Petition 870250088014, dated 09 / 29 / 2025, page 63 / 299 57 / 238

[00434] Me: methyl

[00435] oxime: cyano(hydroxyimino)ethyl acetate

[00436] DIC: N,N'-diisopropylcarbodiimide

[00437] TFE: 2,2,2-trifluoroethanol

[00438] IPA: 2-propanol

[00439] NMI: 1-methylimidazole

[00440] TCFH: chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate

[00441] NMR: nuclear magnetic resonance

[00442] TMS: tetramethylsilane

[00443] Definition of functional and similar groups (All terms and phrases in this document are used as commonly understood in the art. Examples are provided below, but are not limited to them.)

[00444] The term halogen, as used in this document, refers to, for example, F, Cl, Br or I.

[00445] The term alkyl, as used in this document, is a monovalent group derived from an aliphatic hydrocarbon by the removal of any hydrogen atom, and has a subset of hydrocarbyl or hydrocarbon group structures that do not contain a heteroatom (that is, an atom other than carbon and hydrogen atoms) or an unsaturated carbon-carbon bond, and contain hydrogen and carbon atoms in the main chain. Alkyl includes not only a linear form but also a branched form. Alkyl is specifically an alkyl with 1 to 20 carbon atoms (C1 to C20; hereinafter, Cp to Cq means that the number of carbon atoms is paq), preferably a C1 to C10 alkyl and, more preferably, a C1 to C6 alkyl. Specific examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, isobutyl (2-methylpropyl), n-pentyl, s-pentyl (1-methylbutyl), t-pentyl (1,1-dimethylpropyl), neopentyl (2,2 Petition 870250088014, dated 09 / 29 / 2025, page 64 / 299 58 / 238 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-ethylbutyl and 2-ethylbutyl.

[00446] The term alkenyl, as used in this document, is a monovalent group with at least one double bond (two adjacent sp2 carbon atoms). Depending on the conformation of the double bond and a substituent (if present), the geometric morphology of the double bond can assume entgegen (E) or zusammen (Z) and cis or trans conformations. Alkenyl includes not only a linear form but also a branched form. Preferred examples of alkenyl include a C2-C10 alkenyl, and more preferred examples include a C2-C6 alkenyl. Specific examples of alkenyl include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl (which includes cis and trans), 3-butenyl, pentenyl, 3-methyl-2-butenyl, and hexenyl.

[00447] The term alkynyl, as used in this document, is a monovalent group with at least one triple bond (two adjacent sp-bonded carbon atoms). Alkynyl includes not only a linear form but also a branched form. Preferred examples of alkynyl include a C2-C10 alkynyl and, more preferably, a C2-C6 alkynyl. Specific examples of alkynyl include ethinyl, 1-propynyl, propargyl, 3-butynyl, pentinyl, and hexynyl.

[00448] The term cycloalkyl, as used in this document, means a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group and includes a monocyclic ring, a bicyclic ring, and a spiro ring. Cycloalkyl is preferably a C3-C8 cycloalkyl, more preferably a C3-C7 cycloalkyl, and even more preferably a C3-C6 cycloalkyl. Specific examples of Petition 870250088014, dated 09 / 29 / 2025, p. 65 / 299 59 / 238 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicycloheptyl and spiro[3.3]heptyl.

[00449] The term aryl, as used in this document, means a monovalent aromatic hydrocarbon ring, that is, an aromatic hydrocarbon ring group. Preferred examples of aryl include a C6-C10 aryl. Specific examples of aryl include phenyl and naphthyl (such as 1-naphthyl and 2-naphthyl).

[00450] The term heteroaryl, as used in this document, means a monovalent cyclic aromatic group containing a carbon atom as well as 1 to 5 heteroatoms, i.e., an aromatic heterocyclic group. The ring may be a monocyclic ring or a ring condensed with another ring and may be partially saturated. The number of atoms constituting the heteroaryl ring is preferably 5 to 10 (5-10 membered heteroaryl) and more preferably 5 to 7 (5-7 membered heteroaryl).Specific examples of heteroaryl include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, azaindolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl and imidazopyridyl, pyrazolopyridyl, imidazopyridyl, triazolopyrazinyl and flopyridyl.

[00451] An aralkyl (arylalkyl), as used herein, means a group in which one or more hydrogen atoms of the alkyl, as defined herein, are replaced by an aryl, as defined herein. As an aralkyl, a C7-C14 aralkyl is preferred, and a C7-C10 aralkyl is more preferred. Specific examples of aralkyl include benzyl, phenethyl, and 3-phenylpropyl. Petition 870250088014, dated 09 / 29 / 2025, p. 66 / 299 60 / 238

[00452] A heteroarylalkyl, as used herein, means a group in which one or more hydrogen atoms of the alkyl, as defined herein, are replaced by a heteroaryl, as defined herein. As a heteroarylalkyl, a 5- to 10-membered C1-C6 heteroaryl alkyl is preferred, and a 5- to 10-membered C1-C2 heteroaryl alkyl is more preferred. Specific examples of heteroarylalkyl 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-quinolyl)ethyl, 2(6-indolyl)ethyl, 2-(5-indolyl)ethyl and 2-(5-benzofuranyl)ethyl.

[00453] The term “alkoxy”, as used herein, means an oxy group to which the alkyl, as defined herein, is attached. As an alkoxy, a C1-C6 alkoxy is preferred, and a C1-C4 alkoxy is more preferred. Specific examples of alkoxy include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentyloxy, and 3-methylbutoxy.

[00454] The term alkoxyalkyl, as used herein, means a group in which one or more hydrogen atoms of the alkyl, as defined herein, are replaced by an alkoxy, as defined herein. As an alkoxyalkyl, a C1-C6 alkoxy-C1-C6 alkyl is preferred, and a C1-C6 alkoxy-C1-C2 alkyl is more preferred. Specific examples of alkoxyalkyl include methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, n-butoxymethyl, i-butoxymethyl, s-butoxymethyl, t-butoxymethyl, pentyloxymethyl, 3-methylbutoxymethyl, 1-methoxyethyl, 2-methoxyethyl, and 2-ethoxyethyl.

[00455] The term “aryloxy”, as used herein, means an oxy group to which the aryl group, as defined herein, is attached. A C6-C10 aryloxy group is preferred as an aryloxy group. Specific examples of aryloxy groups include phenoxy, 1-naphthyloxy, and 2-naphthyloxy.

[00456] The term “aralcóxi”, as used in this document, Petition 870250088014, dated 09 / 29 / 2025, p. 67 / 299 61 / 238 means an oxy group to which the aralkyl, as defined in this document, is attached. As for aralkoxy, a C7-C14 aralkoxy is preferred, and a C7-C10 aralkoxy is more preferred. Specific examples of aralkoxy include benzyloxy, phenethyloxy, and 3-phenylpropoxy.

[00457] The term amino, as used in this document, means -NH2 in the strict sense and -NRR' in the broad sense. In this context, R and R' are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, or R and R' signify a group in which they form a ring together with the nitrogen atom to which they are attached. Preferred examples of amino include -NH2, a mono-C1-C6 alkylamino, a di-C1-C6 alkylamino and a 4- to 8-membered cyclic amino.

[00458] The term monoalkylamino, as used herein, means a group in which R is hydrogen and R' is the alkyl group, as defined herein, within an amino group, as defined herein. Preferred examples of monoalkylamino include a mono-C1-C6 alkylamino. Specific examples of monoalkylamino include methylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino, s-butylamino, and t-butylamino.

[00459] The term dialkylamino, as used herein, means a group in which R and R' are independently alkyl, as defined herein, or amino, as defined herein. Preferred examples of dialkylamino include a di-C1-C6 alkylamino. Specific examples of dialkylamino include dimethylamino and diethylamino.

[00460] The term cyclic amino, as used herein, means a group in which R and R' form a ring together with the nitrogen atom to which they are attached, in the amino group, as defined herein. Preferred examples of cyclic amino groups Petition 870250088014, dated 09 / 29 / 2025, page 68 / 299 62 / 238 include a cyclic amino group with 4 to 8 members. Specific examples of cyclic amino groups include 1-azetidyl, 1-pyrrolidyl, 1-piperidyl, 1-piperazyl, 4-morpholinyl, 3-oxazolidyl, 1,1-dioxidothiomorpholinyl-4-yl, and 3-oxa-8-azabicyclooctan-8-yl.

[00461] The term cyclic amino-oxy, as used herein, means an oxy group to which the cyclic amino, as defined herein, is attached. Preferred examples of cyclic amino-oxy include a 4- to 8-membered cyclic amino-oxy. Specific examples of cyclic amino-oxy include 1-azetidylox, 1-pyrrolidyloxy, 1-piperidyloxy, 1-piperazyloxy, 4-morpholinyloxy, 3-oxazolidyloxy, 1,1-dioxidothiomorpholinyl-4-yloxy and 3-oxa-8-azabicyclooctan-8-yloxy.

[00462] The term aminocarbonyl, as used herein, means a carbonyl group to which amino, as defined herein, is attached. Preferred examples of aminocarbonyl include -CONH2, a mono-C1-C6 alkylaminocarbonyl, a mono-C3-C6 cycloalkylaminocarbonyl, a di-C1-C6 alkylaminocarbonyl, and a 4- to 8-membered cyclic aminocarbonyl. Specific examples of aminocarbonyl include -CONH2, dimethylaminocarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 1-piperazinylcarbonyl, 4-morpholinylcarbonyl, 3-oxazolidinylcarbonyl, 1,1-dioxidothiomorpholinyl-4-ylcarbonyl, and 3-oxa-8-azabicyclooctan-8-ylcarbonyl.

[00463] A haloalkyl, as used herein, means a group in which one or more hydrogen atoms of the alkyl, as defined herein, are replaced by halogen. As a haloalkyl, a halo-C1-C6 alkyl is preferred, and a fluoro-C1-C6 alkyl is more preferred. Specific examples of haloalkyl include difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3-difluoropropyl, 4,4-difluorobutyl, and 5,5-difluoropentyl.

[00464] The term alicyclic ring, as used herein, means a non-aromatic hydrocarbon ring. The ring Petition 870250088014, dated 09 / 29 / 2025, page 69 / 299 63 / 238 alicyclic rings can have an unsaturated bond in the ring. Furthermore, a carbon atom that constitutes the ring can be oxidized to form a carbonyl group. The alicyclic ring can be a monocycle (referred to herein as a monocyclic alicyclic ring) or it can form a fused ring with a saturated alicyclic ring, such as a cyclopentane ring and a cyclohexane ring, or an aromatic hydrocarbon ring, such as a benzene ring and a naphthalene ring. As an alicyclic ring, a 3- to 10-membered alicyclic ring is preferred, and a 3- to 8-membered alicyclic ring is more preferred. Specific examples of alicyclic rings include a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, and a bicycloheptane ring.

[00465] The term saturated heterocyclic ring, as used herein, means a non-aromatic heterocyclic ring preferably containing 1 to 5, more preferably 1 to 3, heteroatoms between the ring-constituting atoms and having no unsaturated bonds in the ring. The saturated heterocyclic ring has no double or triple bonds. The saturated heterocyclic ring may be a monocycle or may form a fused ring or spiro ring with a saturated alicyclic ring, such as a cyclopentane ring and a cyclohexane ring, or a saturated heterocyclic ring, such as a tetrahydropyrane ring, a dioxane ring and a pyrrolidine ring. As for saturated heterocyclic rings, a saturated heterocyclic ring with 4 to 10 members is preferred, a saturated heterocyclic ring with 4 to 7 members is more preferred, and a saturated heterocyclic ring with 5 members is even more preferred.Specific examples of saturated heterocyclic rings include an azetidine ring, an oxoazetidine ring, an oxetane ring, a tetrahydrofuran ring, a tetrahydropyran ring, a morpholine ring, a thiomorpholine ring, a pyrrolidine ring, a 2-oxopyrrolidine ring, a 4-oxopyrrolidine ring, a piperidine ring, and a 4-oxopiperidine ring. Petition 870250088014, dated 09 / 29 / 2025, page 70 / 299 64 / 238 a piperazine ring, a pyrazolidine ring, an imidazolidine ring, an oxazolidine ring, an isoxazolidine ring, a thiazolidine ring, an isothiazolidine ring, a thiadiazolidine ring, an oxazolidone ring, a dioxolane ring, a dioxane ring, a thiethane ring, an octahydroindole ring, an indoline ring, an azepane ring, a dioxepane ring and a 5,9-dioxaspiro[3.5]nonane ring.

[00466] Examples of the protecting group for an amino group, as used in this document, include a carbamate-based protecting group, an acyl-based protecting group, a sulfonamide-based protecting group, and a silyl-based protecting group. Specific examples of carbamate-based protecting groups include a 9-fluorenylmethyloxycarbonyl group (Fmoc group), a benzyloxycarbonyl group (Cbz group), a 2,2,2-trichloroethoxycarbonyl group (Troc group), an allyloxycarbonyl group (Alloc group), a 2-(trimethylsilyl)ethoxycarbonyl group (Teoc group), a tri-isopropylsilyloxycarbonyl group (TSoc group), a di-t-butylisobutylsilyloxycarbonyl group (BIBSoc group), a di-ipropyl-t-butylsilyloxycarbonyl group (IPCSoc group), a benzyl-di-t-butylsilyloxycarbonyl group (BBSoc group), a di-t-butylcyclohexylsilyloxycarbonyl group (CHBSoc group), a di-t-butyloctadecylsilyloxycarbonyl group (CDBSoc group), and a t-butoxycarbonyl group (Boc group).Specific examples of acyl-based protecting groups include a trifluoroacetyl group, an acetyl group, and a benzoyl group. Specific examples of sulfonamide-based protecting groups include a 2-nitrobenzenesulfonyl group, a 4-nitrobenzenesulfonyl group, and a 2,4-dinitrobenzenesulfonyl group. Specific examples of silyl-based protecting groups include a trimethylsilyl group (TMS group), a t-butyldimethylsilyl group (TBDMS group), a triethylsilyl group (TES group), a triisopropylsilyl group (TIPS group), and a t-butyldiphenylsilyl group (TDPS group).

[00467] The optionally replaced term, as used in Petition 870250088014, dated 09 / 29 / 2025, page 71 / 299 65 / 238 in this document means that a group can be replaced by any substitute.

[00468] The term optionally protected, as used in this document, means that a group can be protected by any protecting group.

[00469] The term one or more, as used in this document, means the number 1 or 2 or greater. When the term one or more is used in the context associated with a substituent of a group, the term means a number from 1 up to the maximum number of substituents acceptable by the group. Specific examples of the term one or more include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and / or greater numbers.

[00470] The term peptide compound, as used in this document, means one in which 2 or more amino acid residues are linked by an amide bond. Peptides possessing an ester linkage in part of the backbone, such as depsipeptides, are also included in the term peptide compound in this document. The number of amino acid residues contained in the peptide, according to this disclosure, is not particularly limited, but preferably from 5 to 30 residues, more preferably from 8 to 15 residues, and even more preferably from 9 to 13 residues. The peptide compound, according to this disclosure, preferably contains at least 3 N-substituted amino acids, more preferably at least 5, and even more preferably at least 6. These N-substituted amino acids may be present continuously or discontinuously in the peptide compound.The peptide compound, according to the present disclosure, can be linear or cyclic and is preferably a cyclic peptide compound.

[00471] The term cyclic peptide compound, as used in this document, refers to a peptide compound with a cyclic structure composed of 4 or more amino acid residues. A Petition 870250088014, dated 09 / 29 / 2025, page 72 / 299 66 / 238 The cyclic structure of the cyclic peptide compound may contain a linkage other than an amide linkage and may contain, for example, a linkage selected from the group consisting of a CO-C linkage, a C(O)-O linkage and a C(S)-O linkage through an oxygen atom, a C(O)-S linkage, a C(S)-S linkage, a CS-SC linkage, a CSC linkage, a CS(O)-C linkage and a CS(O2)-C linkage through a sulfur atom, a CNC linkage, a C=NC linkage, an NC(O)-N linkage, an NC(S)N linkage and a C(S)-N linkage through a nitrogen atom and a CC linkage. The cyclic peptide compound may have an amino acid or peptide chain structure that is not contained in the cyclic structure, in addition to the cyclic structure. It may also have a structure other than amino acids and peptide chain structures.

[00472] The term cyclization of a peptide compound means the formation of a cyclic structure from a cyclic portion containing 4 or more amino acid residues. The number of amino acids contained in the cyclic portion of the cyclic peptide compound is not particularly limited in this document, but examples include 4 to 20 residues, 5 to 15 residues, and 6 to 13 residues. The method for converting a linear peptide compound into a cyclic peptide compound can be performed by carrying out an intramolecular bond-formation reaction using the method described in Comprehensive Organic Transformations, A Guide to Functional Group Preparations, 3rd edition (by RC Larock), March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th edition (by MB Smith and J. March), or similar. It is also possible to additionally perform a functional group conversion reaction after the bond-formation reaction.Examples of bond-formation reactions include a C(O)-N bond formed from a carboxylic acid and an amine, a COC bond, a C(O)-O bond, and a C(S)-O bond. Petition 870250088014, dated 09 / 29 / 2025, p. 73 / 299 67 / 238 through an oxygen atom, a C(O)-S bond, a C(S)-S bond, a CSSC bond, a CSC bond, a CS(O)C bond, and a CS(O2)-C bond through a sulfur atom and a CNC bond, a C=NC bond, an NC(O)-N bond, an NC(S)N bond, and a C(S)-N bond through a nitrogen atom. Other examples of the same include a transition metal-catalyzed CC bond-formation reaction, such as the Suzuki reaction, the Heck reaction, and the Sonogashira reaction. Examples of functional group conversion reactions that are carried out in addition to bond-formation reactions include an oxidation reaction or a reduction reaction. Specific examples of the same include a reaction in which a sulfur atom is oxidized and converted into a sulfoxide group or a sulfone group.Other examples include a reduction reaction in which, between carbon-carbon bonds, a triple bond or a double bond is reduced and converted into a double bond or a single bond. Two amino acids can be linked in the amino acid back chain to form a closed ring structure by a peptide bond, or a covalent bond can be formed between two amino acids by means of, for example, a link between side chains or between a side chain and the back chain of the two amino acids.

[00473] The term amino acid, as used in this document, includes both a naturally occurring amino acid and a non-natural amino acid. The term amino acid, as used in this document, may mean an amino acid residue. The term naturally occurring amino acid, as used in this document, refers to Gly, Ala, Ser, Thr, Val, Leu, Ile, Phe, Tyr, Trp, His, Glu, Asp, Gln, Asn, Cys, Met, Lys, Arg, and Pro. Examples of non-natural amino acids include, but are not particularly limited to, a β-amino acid, a D-type amino acid, an N-substituted amino acid, an α-disubstituted amino acid, a Petition 870250088014, dated 09 / 29 / 2025, p. 74 / 299 68 / 238 amino acid that has a side chain different from that of natural amino acids, and a hydroxycarboxylic acid. As used in this document, the amino acid may have any configuration. The selection of an amino acid side chain is not particularly limited, and the side chain is freely selected from, in addition to a hydrogen atom, for example, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, a heteroarylalkyl group, a cycloalkyl group, a spiro-linked cycloalkyl group. Each of the side chains may have a substituent. The substituent is also not limited, and one or two or more substituents may be freely selected independently from any substituents, including, for example, a halogen atom, an oxygen atom, a nitrogen atom, a sulfur atom, a boron atom, a silicon atom, or a phosphorus atom.That is, examples of the side chain include an alkyl group, an alkoxy group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, and a cycloalkyl group that may be substituted, or oxo, aminocarbonyl, and a halogen atom. In a non-limiting embodiment, the amino acid as used herein may be a compound having a carboxyl group and an amino group in the same molecule (even in this case, proline, hydroxyproline, azetidine-2-carboxylic acid, and the like in which a nitrogen atom of the amino group and any atom of the side chain together form a ring are also included in the amino acid).

[00474] As used in this document, the amino acid residue that constitutes a peptide compound is sometimes simply called an amino acid.

[00475] The term N-terminal amino acid residue, as used in this document, means an amino acid residue Petition 870250088014, dated 09 / 29 / 2025, page 75 / 299 69 / 238 located at the N-terminus of a peptide. The term C-terminal amino acid residue, as used herein, means an amino acid residue located at the C-terminus of a peptide.

[00476] As used in this document, the term amino acid number (amino acid number) or amino acid residue number (amino acid residue number) refers to the number of amino acid residues (amino acid units) that constitute a peptide compound and means the number of amino acid units generated after the cleavage of amide bonds, ester bonds, and cyclized moieties that link the amino acids.

[00477] The amino acid, as used in this document, constituting a peptide compound includes all isotopes corresponding to each. An amino acid isotope is a form in which at least one atom is replaced by an atom that has the same atomic number (number of protons) and a different mass number (total number of protons and neutrons) in an abundance ratio different from the natural abundance ratio. Examples of isotopes included in the amino acid forming a peptide compound in this document include a hydrogen atom, a carbon atom, a nitrogen atom, an oxygen atom, a phosphorus atom, a sulfur atom, a fluorine atom, a chlorine atom, and the like, and they include 2H, 3H; 13C, 14C; 15N; 17O, 18O; 31P, 32P; 35S; 18F; 36Cl; and the like, respectively.For the compounds used in this document, all compounds containing any proportions of radioactive or non-radioactive isotopic elements are within the scope of the present invention.

[00478] Examples of substituents containing a halogen atom in this document include an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, and an aralkyl group having halogen as a substituent, and more Petition 870250088014, dated 09 / 29 / 2025, p. 76 / 299 70 / 238 specifically, includes a fluoroalkyl, a difluoroalkyl and a trifluoroalkyl.

[00479] Examples of substituents containing an O atom include hydroxy (-OH), oxy (-OR), carbonyl (-C=OR), carboxy (-CO2H), oxycarbonyl (-C=O-OR), carbonyloxy (-OC=OR), thiocarbonyl (-C=OSR), carbonylthio (-SC=OR), aminocarbonyl (-C=O-NHR), carbonylamino (-NH-C=OR), oxycarbonylamino (-NH-C=O-OR), sulfonylamino (NH-SO2-R), aminosulfonyl (-SO2-NHR), sulfamoylamino (-NH-SO2NHR), thiocarboxyl (-C(=O)-SH) and carboxylcarbonyl (-C(=O)-CO2H).

[00480] Examples of oxy (-OR) include an alkoxy, a cycloalkoxy, an alkenyloxy, an alkynyloxy, an aryloxy, a heteroaryloxy, and an aralkyloxy. The alkoxy is preferably a C1-C4 alkoxy oxy or a C1-C2 alkoxy, particularly preferably methoxy oxy or ethoxy.

[00481] Examples of carbonyl (-C=OR) include formyl (-C=OH), an alkylcarbonyl, a cycloalkylcarbonyl, an alkenylcarbonyl, an alkynylcarbonyl, an arylcarbonyl, a heteroarylcarbonyl, and an aralkylcarbonyl.

[00482] Examples of oxycarbonyl (-C=O-OR) include an alkyloxycarbonyl, a cycloalkyloxycarbonyl, an alkenyloxycarbonyl, an alkynyloxycarbonyl, an aryloxycarbonyl, a heteroaryloxycarbonyl, and an aralkyloxycarbonyl.

[00483] Examples of carbonyloxy (-OC=OR) include an alkylcarbonyloxy, a cycloalkylcarbonyloxy, an alkenylcarbonyloxy, an alkynylcarbonyloxy, an arylcarbonyloxy, a heteroarylcarbonyloxy, and an aralkylcarbonyloxy.

[00484] Examples of thiocarbonyl (-C=O-SR) include an alkylthiocarbonyl, a cycloalkylthiocarbonyl, an alkenylthiocarbonyl, an alkynylthiocarbonyl, an arylthiocarbonyl, a heteroarylthiocarbonyl, and an aralkylthiocarbonyl.

[00485] Examples of carbonylthion (-SC=OR) include an alkylcarbo Petition 870250088014, dated 09 / 29 / 2025, p. 77 / 299 71 / 238 nilthio, a cycloalkylcarbonylthio, an alkenylcarbonylthio, an alkynylcarbonylthio, an arylcarbonylthio, a heteroarylcarbonylthio and an aralkylcarbonylthio.

[00486] Examples of aminocarbonyl (-C=O-NHR) include an alkylaminocarbonyl (for example, a C1-C6 or C1-C4 alkylaminocarbonyl and, in particular, ethylaminocarbonyl and methylaminocarbonyl), a cycloalkylaminocarbonyl, an alkenylaminocarbonyl, an alkynylaminocarbonyl, an arylaminocarbonyl, a heteroarylaminocarbonyl and an aralkylaminocarbonyl. Examples of the same further include groups in which the H atom bonded to the N atom in -C=O-NHR is further replaced by an alkyl, a cycloalkyl, an alkenyl, an alkynyl, an aryl, a heteroaryl or an aralkyl.

[00487] Examples of carbonylamino (-NH-C=OR) include an alkylcarbonylamino, a cycloalkylcarbonylamino, an alkenylcarbonylamino, an alkynylcarbonylamino, an arylcarbonylamino, a heteroarylcarbonylamino, and an aralkylcarbonylamino. Examples of the same additionally include groups in which the H atom bonded to the N atom in -NH-C=OR is additionally replaced by an alkyl, a cycloalkyl, an alkenyl, an alkynyl, an aryl, a heteroaryl, or an aralkyl.

[00488] Examples of oxycarbonylamino (-NH-C=O-OR) include an alkoxycarbonylamino, a cycloalkoxycarbonylamino, an alkenyloxycarbonylamino, an alkynyloxycarbonylamino, an aryloxycarbonylamino, a heteroaryloxycarbonylamino, and an aralkyloxycarbonylamino. Examples of the same additionally include groups in which the H atom bonded to the N atom in -NH-C=O-OR is additionally replaced by an alkyl, a cycloalkyl, an alkenyl, an alkynyl, an aryl, a heteroaryl, or an aralkyl.

[00489] Examples of sulfonylamino (-NH-SO2-R) include an alkylsulfonylamino, a cycloalkylsulfonylamino, an alkenylsulfonylamino, an alkynylsulfonylamino, an arylsulfonylamino, a heteroarylsulfonylamino, and an aralkylsulfonylamino. Examples of the same additionally include Petition 870250088014, dated 09 / 29 / 2025, p. 78 / 299 72 / 238 groups in which the H atom bonded to the N atom in -NH-SO2-R is additionally replaced by an alkyl, a cycloalkyl, an alkenyl, an alkynyl, an aryl, a heteroaryl or an aralkyl.

[00490] Examples of aminosulfonyl (-SO2-NHR) include an alkylaminosulfonyl, a cycloalkylaminosulfonyl, an alkenylaminosulfonyl, an alkynylaminosulfonyl, an arylaminosulfonyl, a heteroarylaminosulfonyl, and an aralkylaminosulfonyl. Examples of the same additionally include groups in which the H atom bonded to the N atom in -SO2-NHR is additionally replaced by an alkyl, a cycloalkyl, an alkenyl, an alkynyl, an aryl, a heteroaryl, or an aralkyl.

[00491] Examples of sulfamoylamino (-NH-SO2-NHR) include an alkylsulfamoylamino, a cycloalkylsulfamoylamino, an alkenylsulfamoylamino, an alkynylsulfamoylamino, an arylsulfamoylamino, a heteroarylsulfamoylamino, and an aralkylsulfamoylamino. In addition, the two H atoms bonded to the N atoms in -NH-SO2-NHR can be replaced by substituents, each selected independently from the group consisting of an alkyl, a cycloalkyl, an alkenyl, an alkynyl, an aryl, a heteroaryl, and an aralkyl, and these two substituents can form a ring.

[00492] Examples of substituents containing an S atom include groups such as thiol (-SH), thio (-SR), sulfinyl (-S=OR), sulfonyl (-SO2-R) and sulfo (-SO3H).

[00493] Examples of thio (-SR) that can be selected include an alkylthio, a cycloalkylthio, an alkenylthio, an alkynylthio, an arylthio, a heteroarylthio and an aralkylthio.

[00494] Examples of sulfonyl (-SO2-R) include an alkylsulfonyl, a cycloalkylsulfonyl, an alkenylsulfonyl, an alkynylsulfonyl, an arylsulfonyl, a heteroarylsulfonyl, and an aralkylsulfonyl.

[00495] Examples of the substituent containing an N atom include Petition 870250088014, dated 09 / 29 / 2025, p. 79 / 299 73 / 238 groups such as azide (-N3; also known as azide group), cyano (-CN), primary amino (-NH2), secondary amino (-NH-R; also known as monosubstituted amino), tertiary amino (-NR(R'); also known as disubstituted amino), amidino (-C(=NH)-NH2), substituted amidino (-C(=NR)-NR'R), guanidino (-NH-C(=NH)-NH2), substituted guanidino (-NR-C(=NR''')-NR'R), aminocarbonylamino (-NR-CO-NR'R), pyridyl, piperidino, morpholino and azetidinyl.

[00496] Examples of secondary amino groups (-NH-R: monosubstituted amino) include an alkylamino, a cycloalkylamino, an alkenylamino, an alkynylamino, an arylamino, a heteroarylamino, and an aralkylamino.

[00497] Examples of tertiary amino groups (-NR(R'): disubstituted amino) include an amino group with any two substituents, each independently selected from an alkyl, a cycloalkyl, an alkenyl, an alkynyl, an aryl, a heteroaryl, and an aralkyl, for example, an alkyl(aralkyl)amino. These two substituents may form a ring. Specific examples thereof include a dialkylamino, particularly a C1-C6 dialkylamino, a C1-C4 dialkylamino, dimethylamino, and diethylamino. The term Cp-Cq dialkylamino group, as used herein, refers to a group in which an amino group is substituted by two Cp-Cq alkyl groups. The CpCq alkyl groups can be the same or different.

[00498] Examples of substituted amidyne (-C(=NR)-NR'R) include groups in which three substituents R, R' and R on the N atoms are each independently selected from an alkyl, a cycloalkyl, an alkenyl, an alkynyl, an aryl, a heteroaryl and an aralkyl, for example, an alkyl(aralkyl)(aryl)amidyne.

[00499] Examples of substituted guanidino (-NR-C(=NR''')-NR'R) include groups in which R, R', R and R''' are each independently selected from an alkyl, a cycloalkyl, an alkenyl, an alkynyl, an aryl, a heteroaryl and an aralkyl, and Petition 870250088014, dated 09 / 29 / 2025, p. 80 / 299 74 / 238 groups in which these substituents form a ring.

[00500] Examples of aminocarbonylamino (-NR-CO-NR'R) include groups in which R, R', and R are each independently selected from a hydrogen atom, an alkyl, a cycloalkyl, an alkenyl, an alkynyl, an aryl, a heteroaryl, and an aralkyl, and groups in which these substituents form a ring.

[00501] The compound according to the present invention may be a salt thereof, preferably a chemically acceptable salt thereof. The compound according to the present invention, or a salt thereof, may be a solvate thereof, preferably a chemically acceptable solvate thereof. Examples of the salt of the compound according to the present invention include: hydrochloride; hydrobromide; iodide; phosphate; phosphonate; sulfate; sulfonate, such as methanesulfonate and ptoluenesulfonate; carboxylate, such as acetate, citrate, malate, tartrate, succinate and salicylate; alkali metal salts, such as sodium salt and potassium salt; alkaline earth metal salts, such as magnesium salt and calcium salt; and ammonium salts, such as ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt and tetraalkylammonium salt. These salts are produced, for example, by placing the compound in contact with an acid or base that can be used in the production of a medicine.In the present invention, the solvate of the compound is one in which the compound and a solvent together form a molecular aggregate, and is not particularly limited, provided it is a solvate formed by a solvent. When the solvent is water, the solvate is called a hydrate. The solvate of the compound, according to the present invention, is preferably a hydrate, and specific examples of such a hydrate include a mono- to deca-hydrate, preferably a mono- to penta-hydrate, and even more preferably a mono- to tri-hydrate. The solvate of the compound, according to the present invention, includes not only solvates with a single solvent, such as water, alcohol (such as meta- Petition 870250088014, dated 09 / 29 / 2025, p. 81 / 299 75 / 238 nol, ethanol, 1-propanol and 2-propanol) or dimethylformamide, but also solvates with a plurality of solvents.

[00502] When the compound according to the present invention is obtained as a free form, the compound can be conventionally transformed into the state of a hydrate or solvate thereof. When the compound according to the present invention is obtained as a free form, the compound can be conventionally transformed into the state of a salt that can be formed from the compound, or a hydrate or solvate thereof. Examples thereof include a hydrate and an ethanolate of the cyclic peptide compound represented by formula (1a) or a salt thereof.Specific examples thereof include, but are not limited to, a hemihydrate, a monohydrate, a dihydrate, a trihydrate, a tetrahydrate, a pentahydrate, a hexahydrate, a heptahydrate, an octahydrate, a nonahydrate, a decahydrate or a monoethanolate of the cyclic peptide compound represented by formula (1a); a hemihydrate, a monohydrate, a dihydrate, a trihydrate, a tetrahydrate, a pentahydrate, a hexahydrate, a heptahydrate, an octahydrate, a nonahydrate, a decahydrate or a monoethanolate of a sodium salt of the compound represented by formula (1a); or a hydrate or an ethanolate of a hydrochloride of the cyclic peptide compound represented by formula (1a). The hydrate or solvate can be produced in crystalline or non-crystalline form. In the case of the crystalline form, the hydrate or solvate may have crystalline polymorphs.As for the method for producing the hydrate or solvate, the hydrate or solvate can be obtained by a conventional method, for example, by adding a solvent such as ethanol and / or water to the cyclic peptide compound represented by formula (1a) or to the peptide compound described in this document, followed by agitation, cooling, concentration and / or drying. Petition 870250088014, dated 09 / 29 / 2025, page 82 / 299 76 / 238 Formula 22

[00503] When the compound according to the present invention is obtained as a salt, a hydrate or a solvate of the compound, the compound can be conventionally transformed into a free form thereof.

[00504] The term solvent A / water solvate crystal, as used herein, refers to a crystal in which solvent A molecules and water molecules are contained in the crystalline structure of the compound. The term solvent A / solvent B / water solvate crystal, as used herein, refers to a crystal in which solvent A molecules, solvent B molecules and water molecules are contained in the crystalline structure of the compound. Specifically, for example, the term acetone / heptane / water solvate crystal refers to a crystal in which acetone, heptane and water are contained in the crystalline structure of the compound.

[00505] The meaning of the term and / or, as used in this document, includes any combination in which and or are appropriately combined. Specifically, for example, the term A, B and / or C includes the following seven variations:

[00506] A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C, and (vii) A, B and C.

[00507] The term epimer, as used in this document, means a compound in which the configuration of a side chain attached to the α-carbon of an amino acid residue that constitutes a cyclic peptide compound is sterically inverted (epimer). The “epimer” includes a cyclic peptide compound in which the α-carbon of Petition 870250088014, dated 09 / 29 / 2025, p. 83 / 299 The C-terminal amino acid residue of a linear peptide compound is sterically inverted when the linear peptide compound is cyclized to produce the cyclic peptide compound. The epimer in the total products, including the cyclic peptide compound produced by the method of the present invention, can be determined, for example, by the UV area value at 210 nm or 220 nm by HPLC analysis.

[00508] The term cyclic dimer, as used in this document, means a compound in which peptide compounds, which are the raw material of the cyclic peptide compound, are linearly linked together and then further cyclized. The cyclic dimer in the total products, including the cyclic peptide compound produced by the method of the present invention, can be determined, for example, by the UV area value at 210 nm or 220 nm by HPLC analysis. Method for producing cyclic peptide compound

[00509] In one aspect, the present invention relates to a method for producing a cyclic peptide compound represented by formula (1), or a salt thereof, or a solvate thereof. The method includes a reaction step of an N-terminal amino acid residue of a peptide compound represented by formula (2) or (3) with a C-terminal amino acid residue of the peptide compound in a solvent for cyclization (cyclization step) (hereinafter also referred to as aspect 1). Formula 23 Petition 870250088014, dated 09 / 29 / 2025, p. 84 / 299 78 / 238 (3)

[00510] In one aspect, the present invention relates to a method for producing a cyclic peptide compound represented by formula (1), or a salt thereof, or a solvate thereof. The method includes a step of providing peptide compounds represented by formulas (4) to (6), or salts thereof, or solvates of the peptide compounds or salts, a step of reacting N-terminal amino acid residues of the peptide compounds represented by formulas (4) to (6) with C-terminal amino acid residues of the peptide compounds in a solvent for binding (binding step), and a step of reacting an N-terminal amino acid residue of a peptide compound obtained in step (b) with a residue of Petition 870250088014, dated 09 / 29 / 2025, page 85 / 299 79 / 238 C-terminal amino acid of the peptide compound in a solvent for cyclization (cyclization step) (hereinafter also referred to as aspect 2). Formula 24

[00511] In aspect 2, step (b) may include (b-1) a reaction step of an N-terminal amino acid residue of the peptide compound represented by formula (5) with a C-terminal amino acid residue of the peptide compound represented by formula (6) in a solvent for binding, thereby converting them into a peptide compound represented by formula (7) (binding step). Petition 870250088014, dated 09 / 29 / 2025, page 86 / 299 80 / 238

[00512] In aspect 2, step (b) may include, in addition to step (b-1),

[00513] (b-2) a reaction step of an N-terminal amino acid residue of the peptide compound represented by formula (4) with a C-terminal amino acid residue of the peptide compound represented by formula (7) in a solvent for binding, thereby converting them into a peptide compound represented by formula (2) (binding step), and step (c) may include

[00514] (c-1) a reaction step of an N-terminal amino acid residue of the peptide compound represented by formula (2) with a C-terminal amino acid residue of the peptide compound in a solvent for cyclization (cyclization step).

[00515] In aspect 2, step (b) may include, in addition to step (b-1),

[00516] (b-3) a reaction step of an N-terminal amino acid residue of the peptide compound represented by formula (7) with a C-terminal amino acid residue of the peptide compound represented by formula (4) in a solvent for binding, thereby converting them into a compound represented by formula (3) (binding step), and step (c) may include

[00517] (c-2) a reaction step of an N-terminal amino acid residue of the peptide compound represented by formula (3) with Petition 870250088014, dated 09 / 29 / 2025, page 87 / 299 81 / 238 a C-terminal amino acid residue of the peptide compound in a solvent for cyclization (cyclization step).

[00518] In aspects 1 and 2, the linkage of an N-terminal amino acid residue of a peptide compound with a C-terminal amino acid residue of a peptide compound is preferably the linkage of an amino group of the N-terminal amino acid residue with a carboxyl group of the C-terminal amino acid residue, and the linkage of an N-terminal amino acid residue of a peptide compound with a C-terminal amino acid residue of a peptide compound is more preferably the linkage via an amide bond of an amino group of the N-terminal amino acid residue with a carboxyl group of the C-terminal amino acid residue.

[00519] In one aspect, the solvent in the cyclization step preferably includes one or more selected from the group consisting of a nitrile-based solvent, a halogen-based solvent, an ether-based solvent, an amide-based solvent, an ester-based solvent, and a carbonate-based solvent. Specific examples of nitrile-based solvents include acetonitrile and propionitrile. Specific examples of halogen-based solvents include dichloromethane, chloroform, and 1,2-dichloroethane. Specific examples of ether-based solvents include diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, 4-methyltetrahydropyran, 1,3-dioxolane, 1,4-dioxane, 1,2-dimethoxyethane, diisopropyl ether, tert-butyl methyl ether, diglylene, triglyceride, anisole, and tetraglyceride. Specific examples of amide-based solvents include DMF, NMP, DMA, NEP, NBP, and formamide.Specific examples of ester-based solvents include methyl acetate, ethyl acetate, methyl propionate, butyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, pentyl acetate, and Π-valerolactone. Specific examples of carbonate-based solvents include dimethyl carbonate, diethyl carbonate, and carbonate. Petition 870250088014, dated 09 / 29 / 2025, page 88 / 299 82 / 238 dibutyl. The solvent in the cyclization step is preferably one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, tetrahydrofuran, ethyl acetate, isopropyl acetate, dichloromethane, DMF and anisole, more preferably one or more selected from the group consisting of acetonitrile, 2-methyltetrahydrofuran, ethyl acetate and dichloromethane, and even more preferably acetonitrile, 2-methyltetrahydrofuran or ethyl acetate.

[00520] In one aspect, the cyclization step can be carried out by stirring the reaction mixture in a solvent in the presence or absence of a condensation reagent, in the presence or absence of a base, at a temperature between -20 °C and near the boiling point of the solvent, preferably between -20 °C and 100 °C, preferably between 5 °C and 60 °C, for 10 minutes to 48 hours.

[00521] The condensing reagent and base used in the cyclization step, as well as the amounts to be used, are not particularly limited, but a condensing reagent and base commonly used in peptide synthesis, as well as the amount to be used, are preferred (see, for example, Peptide Coupling Reagents, More than a Letter Soup (Chem. Rev. 2011, 111, 6557-6602)). When a condensing reagent is not used in the cyclization step, the carboxyl group can be converted into an active ester beforehand.

[00522] Specific examples of the condensation reagent in the cyclization step include N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI HCl), 1-hydroxy-1H-benzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), 2-cyano-2-(hydroxyimino)ethyl acetate (oxime), 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (HOOBt or HODhbt), N-hydroxy-5-norbornene-2,3-dicarboximide Petition 870250088014, dated 09 / 29 / 2025, page 89 / 299 83 / 238 (HONB), 2,3,4,5,6-pentafluorophenol (HOPfp), N-hydroxysuccinimide (HOSu), 6-chloro-1-hydroxy-1H-benzotriazole (Cl-HOBt), O-(Nxa-benzotriazol,Nlu,1-spha'-yl) of tetramethylluronium (HBTU), O(7-aza-1H-benzotriazol-1-yl)-N,N,N',N'-hexafluorophosphate of tetramethylluronium (HATU), N-[1-(cyano-2-ethoxy-2-oxoethylidenoamino-diphomorphomino)oxy uranium (COMU), O-[(etoxiccarbonyl)cyanomethylenoamino]-N,N,N',N'-hexafluorophosphate of tetramethylluronium (HOTU), O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluoroborate (TBFluoroborode) O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TATU), [ethylcyano(hydroxy-imino)acetate-O2]tri-1-pyrrolidinylphosphonium hexafluorophosphate-1 (ethyl-Py-ObO tetrafluoroborate (BEP), 1H-benzotriazol-1-yloxy-tri(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), 1H-benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexatofluorophos (Borophos bromotri(pyrrolidino)phosphonium hexafluorophosphate (PyBroP),chlorotri(pyrrolidino)phosphonium hexafluorophosphate (PyCloP), (7azabenzotriazol-1-yloxy)tripyrrolidine phosphonium hexafluorophosphate (PyAOP), hexafluorophosphate de bromotris (Bsdimethylamine), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazine-4(3H)-one (DEPBT), tetrafluoroborate of N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium (TSTU), hexafluorophosphate of N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium (HSTU), tetrafluoroborate of O-(3,4-di-hydro-4-oxo-1,2,3-benzotriazine-3-yl)-N,N,N',N'-tetramethyluronium (TDBTU S-(1-oxide-2-pyridyl)-N,N,N',N'-tetramethylthiuronium tetrafluoroborate (TOTT), O-(2-oxo-1(2H)pyridyl)N,N,N',N'-tetramethyluronium (CDI-carbon), N,N' 1,1'carbonyl-di-(1,2,4-triazol) (CDT), 4-(4,6-dimethoxy-1,3,5-triazine2-yl)-4-methylmorpholinium chloride (DMT-MM) and propylphosphonic anhydride (T3P). Among them, from the point of view of the suppression of by-products,The condensation reagent in the cyclization step is preferably one or more selected from the group consisting of HATU, COMU, DMTMM, PyOxim, PyBOP, HCTU, T3P, EDCI, BEP and PyClop, plus, Petition 870250088014, dated 09 / 29 / 2025, pp. 90-299 84 / 238 preferably one selected from the group consisting of HATU, COMU, PyOxim, PyBOP, HCTU and T3P, and even more preferably HATU or COMU. Furthermore, the combination of solvent and condensation reagent is preferably HATU and acetonitrile or 2-methyltetrahydrofuran; or COMU and acetonitrile or 2-methyltetrahydrofuran, since by-products can be further suppressed.

[00523] As a basis in the cyclization step, organic bases are suitablely used and, in particular, organic bases containing tertiary amines are preferred. Specific examples of such a base include 2,2,6,6-tetramethylpiperidine, N-methylmorpholine, N,N-diisopropylethylamine (DIPEA), 2,4,6-collidine, 2,6-lutidine, pyridine, 1,8-diazabicyclo-7undecene (DBU), 2,3,6,7-tetrahydro-1H,5H-9-azabenzo[ij]quinolidine, 1,4-diazabicyclooctane (DABCO), 1,5-diazabicyclo-5-nonene (DBN), 7methyl-1,5,7-triazabicyclodec-5-ene, 1,1,3,3-tetramethylguanidine (TMG), 1,8-bis(tetramethylguanidino)naphthalene (TMGN), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), triethylamine (TEA), trimethylamine, 1-methylpiperidine, N,N'-dimethylpiperazine, N-ethylmorpholine and p-dimethylaminopyridine (DMAP).Among these, from the point of view of byproduct suppression, the base in the cyclization step is preferably one or more selected from the group consisting of 2,2,6,6-tetramethylpiperidine, N-methylmorpholine, N,N-diisopropylethylamine (DIPEA), 2,4,6-colidine, 2,6-lutidine and pyridine, and preferably N,N-diisopropylethylamine (DIPEA) or 2,6-lutidine. Furthermore, the combination of solvent, condensation reagent and base is preferably HATU, acetonitrile and N,N-diisopropylethylamine (DIPEA); HATU, 2-methyltetrahydrofuran and N,N-diisopropylethylamine (DIPEA); COMU, acetonitrile and 2,6-lutidine; or COMU, 2-methyltetrahydrofuran and 2,6-lutidine, since the byproducts can be further suppressed.

[00524] In one aspect, the cycling stage is performed by a Petition 870250088014, dated 09 / 29 / 2025, pp. 91 / 299 85 / 238 liquid phase method.

[00525] In one aspect, the cyclization step is carried out by mixing the peptide compound and, optionally, the base in a mixed solution obtained by mixing the solvent and the condensation reagent. This operation may be referred to in this document as reverse drop-by-drop addition. Reverse drop-by-drop addition of the peptide compound and the base over a long period of time, such as from several hours to several days, preferably from 1 to 24 hours and, more preferably, from 1 to 10 hours, can suppress the generation of by-products without using a large amount of solvent for dilution.

[00526] The cyclic peptide compounds produced by the method of the present invention are of high purity with low by-product content (such as epimer and cyclic dimer), as described below.

[00527] In one aspect, the content of total by-products generated in the cyclization step is less than 20%, less than 15%, less than 10%, less than 5% or less than 3%, as determined by the UV area value at 220 nm by HPLC analysis, based on the total quantity of products.

[00528] In one aspect, the content of each of the byproducts generated in the cyclization step is less than 15%, less than 10%, less than 5%, less than 3%, less than 1%, or an undetectable amount, as determined by the UV area value at 220 nm by HPLC analysis, based on the total amount of products.

[00529] In one aspect, the content of each of the byproducts generated in the cyclization step is less than 15%, less than 10%, less than 5%, less than 3%, less than 1%, or an undetectable amount, as determined by the UV area value at 220 nm by HPLC analysis, based on the total amount of products, and the byproducts comprise an epimer and / or a cyclic dimer.

[00530] In one aspect, the by-products generated in the step of Petition 870250088014, dated 09 / 29 / 2025, page 92 / 299 86 / 238 cyclization comprises an epimer, and the epimer content is less than 10%, less than 7.5%, less than 5%, less than 2.5%, or less than 1%, as determined by the UV area value at 220 nm by HPLC analysis, based on the total quantity of products.

[00531] In one aspect, the byproducts generated in the cyclization step comprise a cyclic dimer, and the cyclic dimer content is less than 15%, less than 10%, less than 5%, less than 2.5%, or less than 1%, as determined by the UV area value at 220 nm by HPLC analysis, based on the total quantity of products.

[00532] In one aspect, the solvent in the linking step preferably includes one or more selected from the group consisting of a nitrile-based solvent, a halogen-based solvent, an ether-based solvent, an amide-based solvent, an ester-based solvent, and a carbonate-based solvent. Examples of nitrile-based solvent, halogen-based solvent, ether-based solvent, amide-based solvent, ester-based solvent, and carbonate-based solvent include those exemplified as the solvent in the cyclization step described above.The solvent in the linking step is preferably one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, tetrahydrofuran, ethyl acetate, isopropyl acetate, DMF and anisole, more preferably a mixed solvent of one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, tetrahydrofuran, ethyl acetate, isopropyl acetate and anisole with DMF, even more preferably a mixed solvent of acetonitrile, 2-methyltetrahydrofuran and DMF, and particularly preferably a mixed solvent of 2-methyltetrahydrofuran and DMF.

[00533] In one aspect, the linking step can be carried out by stirring the reaction composition in a solvent in the presence of or Petition 870250088014, dated 09 / 29 / 2025, page 93 / 299 87 / 238 absence of a condensation reagent, in the presence or absence of a base, at a temperature between -20 °C and near the boiling point of the solvent, preferably between -20 °C and 100 °C, preferably between -5 °C and 60 °C, for 10 minutes to 48 hours.

[00534] The condensing reagent and base used in the linking step, as well as the amounts to be used, are not particularly limited, but a condensing reagent and base commonly used in peptide synthesis, as well as the amount to be used, are preferred (see, for example, Peptide Coupling Reagents, More than a Letter Soup (Chem. Rev. 2011, 111, 6557-6602)). When a condensing reagent is not used in the linking step, the carboxyl group can be converted into an active ester beforehand.

[00535] Examples of the condensation reagent in the linking step include those exemplified as the condensation reagent in the cyclization step described above. Among them, from the point of view of byproduct suppression, the condensation reagent in the linking step is preferably one or more selected from the group consisting of HATU, COMU, DMT-MM, PyOxim, PyBOP, HCTU, T3P, EDCI, BEP and PyClop, more preferably one selected from the group consisting of HATU, COMU, PyOxim, PyBOP, HCTU and T3P, and even more preferably HATU or COMU. Furthermore, the combination of solvent and condensation reagent is preferably HATU and acetonitrile or 2-methyltetrahydrofuran; HATU and a mixed solvent of acetonitrile, 2-methyltetrahydrofuran and DMF; COMU and acetonitrile or 2-methyltetrahydrofuran; or COMU and a mixed solvent of acetonitrile, 2-methyltetrahydrofuran and DMF, since by-products can be further suppressed.

[00536] Examples of the base in the linkage step include those exemplified as the base in the cyclization step described above. Petition 870250088014, dated 09 / 29 / 2025, pp. 94 / 299 88 / 238 Among them, from the point of view of byproduct suppression, the base in the linking step is preferably one or more selected from the group consisting of 2,2,6,6-tetramethylpiperidine, N-methylmorpholine, N,N-diisopropylethylamine (DIPEA), 2,4,6-colidine, 2,6-lutidine, pyridine, 1,8-diazabicyclo-7-undecene (DBU), 2,3,6,7-tetrahydro-1H,5H9-azabenzo[ij]quinolidine, 1,4-diazabicyclooctane (DABCO), 1,5-diazabicyclo-5-nonene (DBN), 7-methyl-1,5,7-triazabicyclodec-5-ene, 1,1,3,3-tetramethylguanidine (TMG), 1,8-bis(tetramethylguanidino)naphthalene (TMGN), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), triethylamine (TEA), trimethylamine, 1-methylpiperidine, N,N'-dimethylpiperazine, N-ethylmorpholine and p-dimethylaminopyridine (DMAP) and, preferably, one or more selected from the group consisting of 2,2,6,6-tetramethylpiperidine, N-methylmorpholine, N,N-diisopropylethylamine (DIPEA), 2,4,6-colidine, 2,6-lutidine and pyridine.Furthermore, the combination of solvent, condensation reagent, and base is preferably HATU, acetonitrile or 2-methyltetrahydrofuran and N,N-diisopropylethylamine (DIPEA); HATU, a mixed solvent of acetonitrile, 2-methyltetrahydrofuran and DMF, and N,N-diisopropylethylamine (DIPEA); COMU, acetonitrile or 2-methyltetrahydrofuran and N-methylmorpholine or 2,6-lutidine; or COMU, a mixed solvent of acetonitrile, 2-methyltetrahydrofuran and DMF and N-methylmorpholine or 2,6-lutidine, since byproducts can be further suppressed.

[00537] In one aspect, the binding step is performed by a liquid phase method.

[00538] In one aspect, the method of the present invention further includes a step for supplying peptide compounds represented by formulas (4) to (6), or salts thereof, or solvates thereof. The peptide compounds represented by formulas (4) to (6) can be produced, for example, by the following general production methods. Petition 870250088014, dated 09 / 29 / 2025, pp. 95 / 299 89 / 238 General production method for peptide compound represented by formula (4) (peptide compound (4))

[00539] A general production method for the peptide compound (4) will be shown below. In the following scheme, Pg4 and Pgs represent protecting groups for an amino group, Xge represents an oxygen atom and a protecting group attached to it, Rs represents a side chain of an amino acid and P4 and ε represent substituents of a nitrogen atom.

[00540] The peptide compound (4) can be produced using the following method. Formula 26

[00541] By allowing an aldehyde to act on a protected amino acid, according to the method of Freidinger et al. (J. Org. Chem., 1983, 48(1), 77-81), an oxazolidinone form with an introduced cyclic protecting group can be obtained. Then, by performing a ring-opening reaction using a silicon compound with an olefin, according to the method of Nguyen et al. (Synthesis, 2009, 12, 1991), an alkyl group with an olefin can be introduced at the nitrogen atom. Then, by condensing an amino acid whose C-terminal has been protected, the amino acid can be elongated on the C-terminal side. For the condensation reaction, the condensation reagent and base used in the bonding step described above can be used. For example, several methods are possible as activator of the carboxyl group, such as Petition 870250088014, dated 09 / 29 / 2025, pp. 96 / 299 90 / 238 the combination of DIC and Oxyma, the combination of DIC and HOAt, the combination of HATU and DIPEA, or by means of a mixed acid anhydride or an acid halide. Then, after deprotecting the protecting group from the amino group, the protected amino acid that has an olefin as a side chain can be elongated. Then, by means of a metathesis reaction, the intramolecular olefins can be cyclized. In the metathesis reaction, dichloro(2-isopropoxybenzylidene)(tricyclohexylphosphine)ruthenium(II): CAS No. 203714-71-0, dichloro(3-phenyl-1H-inden-1-ylidene)bis(tricyclohexylphosphine)ruthenium(II): CAS No. 250220-36-1, dichloro(benzylidene) [...] [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidynylidene]dichloro(benzylidene)(tricyclohexylphosphine)ruthenium(II): CAS No.246047-72-3, [1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(2-isopropoxybenzylidene)ruthenium(II): CAS No. 30122440-8, [1,3-bis-(2-tolyl)-2-imidazolidinylidene]dichloro(2-isopropoxybenzylidene)ruthenium(II): CAS No. 927429-61-6, [1,3-bis(2,4,6-trimethylphenyl)-2imidazolidynylidene]dichloro[(2-isopropoxy)(5-trifluoroacetamido)benzylidene]ruthenium(II): CAS No. 1025728-56-6, [1,3-bis(2,6-di-isopropylphenyl)-2-imidazolidinylidene]dichloro[5-(isobutoxycarbonylamido)-2-isopropoxybenzylidene]ruthenium(II): CAS No. 1212009-05-6, or similar, can be used as a catalyst. Then, the C-terminal protecting group can be deprotected to produce the peptide compound (4) with the C-terminal unprotected, or the N-terminal protecting group can be deprotected to produce the peptide compound (4) with the N-terminal unprotected.

[00542] The peptide compound (4) can also be produced using the following method. Petition 870250088014, dated 09 / 29 / 2025, pp. 97 / 299 91 / 238 Formula 27 X , = HsX2= Xg6ou Xi = Pg4'X2=OH

[00543] By allowing an alkylating agent with an olefin to act on an amino acid in the presence of a base, an alkyl group with an olefin can be introduced onto the nitrogen atom. Then, by condensing an amino acid whose C-terminal has been protected, the amino acid can be elongated on the C-terminal side. For the condensation reaction, the condensation reagent and the base used in the linking step described above can be used. For example, several methods are possible as activators of the carboxyl group, such as the combination of DIC and Oxyma, the combination of DIC and HOAt, the combination of HATU and DIPEA, or by means of a mixed acid anhydride or an acid halide. Subsequently, after deprotection of the amino group's protecting group, the protected amino acid that has an olefin as a side chain can be elongated. Then, by means of a metathesis reaction, the intramolecular olefins can be cyclized. The catalyst used in the metathesis reaction is the same as described above.Next, the C-terminal protecting group can be deprotected to produce the peptide compound (4) with the C-terminal unprotected, or the N-terminal protecting group can be deprotected to produce the peptide compound (4) with the N-terminal unprotected. General production method for peptide compound represented by formula (5) (peptide compound (5))

[00544] A general production method for the peptide compound Petition 870250088014, dated 09 / 29 / 2025, pp. 98 / 299 92 / 238 (5) will be shown below. In the following scheme, Pgi and Pg2 represent protecting groups for an amino group, Xgs represents an oxygen atom and a protecting group attached to it, Ri, R2 and R3 represent side chains of an amino acid and Pi and P3 represent substituents of a nitrogen atom.

[00545] The peptide compound (5) can be produced using the following method. Formula 28 X3=H.X4 = Xg3 or x3=Pgi.X4=OH

[00546] By condensing a protected amino acid into an amino acid whose C-terminal has been protected, the amino acid can be elongated on the N-terminal side. For the condensation reaction, the condensation reagent and base used in the above linking step can be used. For example, several methods are possible as activators of the carboxyl group, such as the combination of DIC and Oxyma, the combination of DIC and HOAt, the combination of HATU and DIPEA, or by means of a mixed acid anhydride or an acid halide. Then, after deprotecting the protecting group from the amino group, a protected amino acid can be condensed, thus synthesizing a fragment composed of 3 amino acids. Next, the C-terminal protecting group can be deprotected to produce the peptide compound (5) with the C-terminal unprotected, or the N-terminal protecting group can be deprotected to produce the peptide compound (5) with the N-terminal unprotected.

[00547] The peptide compound (5) can also be produced by solid-phase synthesis. In this case, Xgs in the formula above is an amino acid linked to the solid-phase carrier via an oxygen atom. Petition 870250088014, dated 09 / 29 / 2025, pp. 99 / 299 93 / 238 and a ligand attached to it, to which a protected amino acid can be condensed, thus elongating the amino acid on the N-terminal side. For the condensation reaction, the condensation reagent and base used in the above linking step can be used. For example, several methods are possible as activator of the carboxyl group, such as the combination of DIC and Oxyma, the combination of DIC and HOAt, the combination of HATU and DIPEA, or by means of a mixed acid anhydride or an acid halide. Then, sequentially performing the deprotection of the protecting group to the amino group and the condensation of a protected amino acid, a fragment composed of 3 amino acids can be synthesized. Then, by cutting the solid phase, the peptide compound (5) with the C-terminal unprotected can be produced. General production method for peptide compound represented by formula (6) (peptide compound (6))

[00548] A general production method for the peptide compound (6) will be shown below. In the following scheme, Pg?, Pgs, Pgg and Pgw represent protecting groups for an amino group, Xgn represents an oxygen atom and a protecting group attached to it, R?, Rs, Rg, Qg, Rw, and Ri 1 represent side chains of an amino acid and Ps, Pg, Pw and Pi 1 represent substituents of a nitrogen atom.

[00549] The peptide compound (6) can be produced using the following method. Formula 29 ^011 o P / NOH Lack of protection Condensation Lack of protection ÕH Condensation Petition 870250088014, dated 09 / 29 / 2025, pp. 100 / 299 94 / 238 Lack of protection RaPsO R10 Pt (51 ' Xj-H,X6= Xg11 OR λ5=X& = OH

[00550] By condensing a protected amino acid into an amino acid with a β-amino acid backbone with the carboxy group protected, the amino acid can be elongated at the N-terminal side. For the condensation reaction, the condensation reagent and the base used in the linking step described above can be used. For example, a variety of methods are possible as activators of the carboxyl group, such as the combination of DIC and Oxyma, the combination of DIC and HOAt, the combination of HATU and DIPEA, or by means of a mixed acid anhydride or an acid halide. Then, by sequentially performing the deprotection of the protecting group to the amino group and the condensation of a protected amino acid, a fragment composed of 5 amino acids can be synthesized. Next, the C-terminal protecting group can be deprotected to produce the peptide compound (6) with the C-terminal unprotected, or the N-terminal protecting group can be deprotected to produce the peptide compound (6) with the N-terminal unprotected.

[00551] The peptide compound (6) can also be produced by solid-phase synthesis. In this case, Xgn in the formula above is an amino acid with a β-amino acid backbone linked to the solid-phase carrier via an oxygen atom and a ligand attached to it, to which a protected amino acid can be condensed, thus elongating the amino acid on the N-terminal side. For the condensation reaction, the condensation reagent and base used in the linking step described above can be used. For example, a variety of methods are possible as activators of the carboxyl group, such as the combination of DIC and Oxyma, the combination of DIC and HOAt, the combination of HATU and DIPEA, or via a mixed acid anhydride or an acid halide. Petition 870250088014, dated 09 / 29 / 2025, pp. 101 / 299 95 / 238 Subsequently, by sequentially deprotecting the protecting group to the amino group and condensing a protected amino acid, a fragment composed of 5 amino acids can be synthesized. Then, by cutting the solid phase, the peptide compound (6) with the C-terminal deprotected can be produced.

[00552] In the production methods of the peptide compounds represented by formulas (4) to (6) shown above, chemical reactions may occur with functional groups different from the target functional group. In these cases, only the desired reaction can proceed by introducing a protecting group to the non-target functional group. For such a desorption reaction of the protecting group, the method described in, for example, Greene's, 'Protective Groups in Organic Synthesis' (5th ed., John Wiley & Sons 2014) can be used. For functional group conversion reactions of the compounds, Comprehensive Organic Transformations: A Guide to Functional Group Preparations (5th ed.) by Larock and March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (8th ed.) by Smith can be referenced.

[00553] In one aspect, it is possible to use column chromatography in the isolation and / or purification of the cyclic peptide compound, or a salt thereof, or a solvate thereof produced by the method of the present invention, or it is also possible not to use column chromatography.

[00554] The cyclic peptide compound, or a salt thereof, or a solvate thereof produced by the method of the present invention can be isolated and / or purified by crystallization. Specifically, for example, the reaction solution after the condensation reaction can be subjected to a separate operation, the organic layer can be concentrated and / or filtered as needed, then a suitable solvent for crystallization can be added to the residue obtained, optionally a seed crystal is added and Petition 870250088014, dated 09 / 29 / 2025, page 102 / 299 96 / 238 stirred as necessary to obtain a crystal of the cyclic peptide compound, or a salt thereof, or a solvate thereof. The solvent added during crystallization is not particularly limited, provided it is a solvent with which the cyclic peptide compound can be crystallized, but preferably a solvent with which an operation to reduce the solubility of the cyclic peptide compound can be performed to a solution in which the cyclic peptide compound is dissolved. For example, when a cyclic peptide compound can be crystallized by reducing the solubility of the cyclic peptide compound by adding a weak solvent or by cooling a solution, a solvent capable of such an operation may be used.Furthermore, when a crystal of the cyclic peptide compound can be obtained by maintaining a crude crystal of the cyclic peptide compound in a suspension state for any period of time, a solvent capable of such manipulation can be used for crystallization. Specific examples of solvents added during crystallization include acetone, water, DMSO, acetonitrile, ethanol, and a mixture of these solvents.

[00555] The following is a description of each symbol used in the structural formula of the cyclic peptide compound represented by formula (1) and the structural formulas of the peptide compounds represented by formulas (2) to (7).

[00556] Ri is a C1-C6 alkyl. Ri is preferably a C3-C4 alkyl, and more preferably n-propyl or 2-methylpropyl.

[00557] Pi is a C1-C6 alkyl. Pi is preferably a C1-C4 alkyl, and more preferably methyl.

[00558] R2 is a C1-C6 alkyl. R2 is preferably a C3-C4 alkyl and more preferably 1-methylpropyl.

[00559] R3 is hydrogen, or R3 forms a saturated heterocyclic ring of 4 to 7 members together with P3, a carbon atom to which R3 is attached. Petition 870250088014, dated 09 / 29 / 2025, page 103 / 299 97 / 238 is bonded and a nitrogen atom to which P3 is bonded. Preferably, R3 is hydrogen, or R3 forms a saturated 5-membered heterocyclic ring together with P3, a carbon atom to which R3 is bonded, and a nitrogen atom to which P3 is bonded. In one aspect, R3 is preferably hydrogen. In one aspect, R3 preferably forms a saturated 5-membered heterocyclic ring together with P3, a carbon atom to which R3 is bonded, and a nitrogen atom to which P3 is bonded.

[00560] P3 is a C1-C6 alkyl or a C3-C8 cycloalkyl, or P3 forms a saturated 4- to 7-membered heterocyclic ring together with R3, a carbon atom to which R3 is attached, and a nitrogen atom to which P3 is attached. Preferably, P3 is a C1-C4 alkyl, or P3 forms a saturated 5-membered heterocyclic ring together with R3, a carbon atom to which R3 is attached, and a nitrogen atom to which P3 is attached. In one aspect, P3 is preferably methyl. In one aspect, P3 preferably forms a saturated 5-membered heterocyclic ring together with R3, a carbon atom to which R3 is attached, and a nitrogen atom to which P3 is attached.

[00561] P4 is a C1-C6 alkyl. P4 is preferably a C1-C4 alkyl, and more preferably a methyl.

[00562] R5 is benzyl optionally substituted with one or more groups selected from the group consisting of a C1-C6 alkyl, a C1-C6 haloalkyl and a C3-C8 cycloalkyl. R5 is preferably benzyl optionally substituted with a C1-C4 haloalkyl, and more preferably 4-trifluoromethylbenzyl.

[00563] P6 is a C1-C6 alkyl. P6 is preferably a C1-C4 alkyl, and more preferably a methyl.

[00564] R7 is phenethyl optionally substituted with one or more groups selected from the group consisting of a halogen, a C1-C6 haloalkyl and a C1-C6 alkoxy. R7 is preferably phenethyl Petition 870250088014, dated 09 / 29 / 2025, p. 104 / 299 98 / 238 optionally replaced with one or more groups selected from the group consisting of a halogen, trifluoromethyl and methoxy, and more preferably 3-methoxy-4-trifluoromethylphenethyl or 3,5-difluoro-4-trifluoromethylphenethyl.

[00565] R8 forms a saturated 4- to 7-membered heterocyclic ring together with P8, a carbon atom to which R8 is attached, and a nitrogen atom to which P8 is attached, the saturated 4- to 7-membered heterocyclic ring optionally substituted with a C1-C6 alkoxy. R8 preferably forms a saturated 5-membered heterocyclic ring together with P8, a carbon atom to which R8 is attached, and a nitrogen atom to which P8 is attached, the saturated 5-membered heterocyclic ring substituted with a C1-C4 alkyl and more preferably forms a saturated 5-membered heterocyclic ring together with P8, a carbon atom to which R8 is attached, and a nitrogen atom to which P8 is attached, the saturated 5-membered heterocyclic ring substituted with an ethoxy.

[00566] R9 forms a 3- to 8-membered alicyclic ring together with Q9 and a carbon atom to which R9 and Q9 are attached, the 3- to 8-membered alicyclic ring optionally substituted with one or more C1-C6 alkyls. R9 preferably forms a 4- to 6-membered alicyclic ring together with Q9 and a carbon atom to which R9 and Q9 are attached. In one aspect, R9 preferably forms a 4-membered alicyclic ring together with Q9 and a carbon atom to which R9 and Q9 are attached. In one aspect, R9 preferably forms a 5-membered alicyclic ring together with Q9 and a carbon atom to which R9 and Q9 are attached.

[00567] P9 is hydrogen or a C1-C6 alkyl. P9 is preferably hydrogen or a C1-C4 alkyl. In one aspect, P9 is preferably hydrogen. In one aspect, P9 is preferably methyl.

[00568] R10 is a C1-C6 alkyl or a C3-C8 cycloalkyl. R10 is Petition 870250088014, dated 09 / 29 / 2025, p. 105 / 299 99 / 238 preferably a C4-C6 cycloalkyl and more preferably a cyclopentyl.

[00569] P10 is a C1-C6 alkyl. P10 is preferably a C1-C4 alkyl and more preferably a methyl.

[00570] R11 is a di-C1-C6 alkylaminocarbonyl or a 4- to 8-membered cyclic aminocarbonyl. R11 is preferably a di-C1-C4 alkylaminocarbonyl or a 5- to 6-membered cyclic aminocarbonyl, and more preferably a dimethylaminocarbonyl.

[00571] P11 is a C1-C6 alkyl. P11 is preferably a C1-C4 alkyl and more preferably a methyl.

[00572] X1, X3 and X5 are each independently either hydrogen or a protecting group for an amino group. X1, X3 and X5 are preferably each independently selected from the group consisting of hydrogen, a carbamate-based protecting group, an acyl-based protecting group, a sulfonamide-based protecting group and a silyl-based protecting group. In one aspect, the carbamate-based protecting group is selected from the group consisting of an Fmoc group, a Cbz group, a Troc group, an Alloc group, a Teoc group, a TSoc group, a BIBSoc group, an IPCSoc group, a BBSoc group, a CHBSoc group, a CDBSoc group and a Boc group. In one aspect, the acyl-based protecting group is selected from the group consisting of a trifluoroacetyl group, an acetyl group and a benzoyl group.In one aspect, the sulfonamide-based protecting group is selected from the group consisting of a 2-nitrobenzenesulfonyl group, a 4-nitrobenzenesulfonyl group, and a 2,4-dinitrobenzenesulfonyl group. In another aspect, the silyl-based protecting group is selected from the group consisting of a TMS group, a TBDMS group, a TES group, a TIPS group, and a TBDPS group.

[00573] In one aspect, X1 is hydrogen or a protecting group. Petition 870250088014, dated 09 / 29 / 2025, page 106 / 299 100 / 238 based on carbamate. In one aspect, Xi is preferably hydrogen. In one aspect, Xi is preferably an Fmoc group.

[00574] In one aspect, X3 is hydrogen or a carbamate-based protecting group. In one aspect, X3 is preferably hydrogen. In one aspect, X3 is preferably a Cbz group.

[00575] In one aspect, X5 is hydrogen or a carbamate-based protecting group. In one aspect, X5 is preferably hydrogen. In one aspect, X5 is preferably a Cbz group.

[00576] X2, X4 and X6 are each independently a halogen, a hydroxy group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy or a group represented by -OSiRxRyRz, wherein Rx, Ry, and Rz are each independently an alkyl or an aryl. X2, X4, and X6 are preferably each independently a halogen, a hydroxy group, an optionally substituted C1-C6 alkoxy, an optionally substituted C6-C10 aryloxy, an optionally substituted C7-C14 aralkoxy, an optionally substituted 4- to 8-membered cyclic aminooxy, or a group represented by OSiRxRyRz, wherein Rx, Ry, and Rz are each independently a C1-C6 alkyl or a C6-C10 aryl. In one aspect, the halogen is chlorine or bromine. In one aspect, the optionally substituted alkoxy is t-butoxy, methoxy, ethoxy, or isopropoxy.In one aspect, the optionally substituted aryloxy is pentafluorophenyloxy or nitrophenyloxy. In one aspect, the optionally substituted aralkoxy is optionally substituted benzyloxy. In one aspect, the optionally substituted cyclic aminooxy is N-hydroxysucciniminooxy. In one aspect, the group represented by OSiRxRyRz is trimethylsilyloxy, triethylsilyloxy, tri-isopropylsilyloxy, triphenylsilyloxy, tri-t-butylsilyloxy, di-t-butylisobutylsilyloxy or tris(triethylsilyl)silyloxy.

[00577] In one aspect, X2 is a hydroxy, t-butoxyoxy, or benzyloxy group. In one aspect, X2 is preferably a hydroxy group. Petition 870250088014, dated 09 / 29 / 2025, p. 107 / 299 101 / 238 aspect, X2 is preferably t-butoxy.

[00578] In one aspect, X4 is a hydroxy, t-butoxy, or benzyloxy group. In one aspect, X4 is preferably a hydroxy group. In one aspect, X4 is preferably t-butoxy.

[00579] In one aspect, X6 is a hydroxy, t-butoxy, or benzyloxy group. In one aspect, X6 is preferably a hydroxy group. In one aspect, X6 is preferably t-butoxy.

[00580] In one aspect of the structural formula of the cyclic peptide compound represented by formula (1) and of the structural formulas of the peptide compounds represented by formulas (2) and (3),

[00581] Ri is a C1-C6 alkyl;

[00582] Pi is a C1-C6 alkyl;

[00583] R2 is a C1-C6 alkyl;

[00584] R3 is hydrogen, or R3 forms a saturated heterocyclic ring of 4 to 7 members together with P3, a carbon atom to which R3 is attached and a nitrogen atom to which P3 is attached;

[00585] P3 is a C1-C6 alkyl or a C3-C8 cycloalkyl, or P3 forms a saturated 4- to 7-membered heterocyclic ring together with R3, a carbon atom to which R3 is attached, and a nitrogen atom to which P3 is attached;

[00586] P4 is a C1-C6 alkyl;

[00587] R5 is benzyl optionally substituted with one or more groups selected from the group consisting of a C1-C6 alkyl, a C1-C6 haloalkyl, and a C3-C8 cycloalkyl;

[00588] P6 is a C1-C6 alkyl;

[00589] R7 is phenethyl optionally substituted with one or more groups selected from the group consisting of a halogen, a C1-C6 haloalkyl, and a C1-C6 alkoxy;

[00590] R8 forms a saturated 4- to 7-membered heterocyclic ring together with P8, a carbon atom to which R8 is attached, and a Petition 870250088014, dated 09 / 29 / 2025, pp. 108 / 299 102 / 238 nitrogen atom to which P8 is attached, the saturated 4- to 7-membered heterocyclic ring optionally substituted with a C1-C6 alkoxy;

[00591] R9 forms a 3- to 8-membered alicyclic ring together with Q9 and a carbon atom to which R9 and Q9 are attached, the 3- to 8-membered alicyclic ring optionally substituted with one or more C1-C6 alkyls;

[00592] P9 is hydrogen or a C1-C6 alkyl;

[00593] R10 is a C1-C6 alkyl or a C3-C8 cycloalkyl;

[00594] P10 is a C1-C6 alkyl;

[00595] R11 is a di-C1-C6 alkylaminocarbonyl or a 4- to 8-membered cyclic aminocarbonyl;

[00596] P11 is a C1-C6 alkyl;

[00597] X1 and X5 are each independently either hydrogen or a protecting group for an amino group; and

[00598] X2 and X4 are each independently a halogen, a hydroxy group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy, or a group represented by -OSiRxRyRz, wherein Rx, Ry, and Rz are each independently an alkyl or an aryl.

[00599] In one aspect of the structural formula of the cyclic peptide compound represented by formula (1) and of the structural formulas of the peptide compounds represented by formulas (2) and (3), preferably,

[00600] R1 is a C3-C4 alkyl;

[00601] Pi is a C1-C4 alkyl;

[00602] R2 is a C3-C4 alkyl;

[00603] R3 is hydrogen, or R3 forms a saturated 5-membered heterocyclic ring together with P3, a carbon atom to which R3 is attached, and a nitrogen atom to which P3 is attached; Petition 870250088014, dated 09 / 29 / 2025, pp. 109 / 299 103 / 238

[00604] P3 is a C1-C4 alkyl, or P3 forms a saturated 5-membered heterocyclic ring together with R3, a carbon atom to which R3 is attached and a nitrogen atom to which P3 is attached;

[00605] P4 is a C1-C4 alkyl;

[00606] R5 is benzyl optionally substituted with a C1-C4 haloalkyl;

[00607] P6 is a C1-C4 alkyl;

[00608] R7 is phenethyl optionally substituted with one or more groups selected from the group consisting of a halogen, trifluoromethyl and methoxy;

[00609] R8 forms a saturated 5-membered heterocyclic ring together with P8, a carbon atom to which R8 is attached, and a nitrogen atom to which P8 is attached, the saturated 5-membered heterocyclic ring being substituted with a C1-C4 alkyl group;

[00610] R9 forms a 4- to 6-membered alicyclic ring together with Q9 and a carbon atom to which R9 and Q9 are attached;

[00611] P9 is hydrogen or a C1-C4 alkyl;

[00612] R10 is a C4-C6 cycloalkyl;

[00613] P10 is a C1-C4 alkyl;

[00614] R11 is a di-C1-C4 alkylaminocarbonyl or a 5- to 6-membered cyclic aminocarbonyl;

[00615] P11 is a C1-C4 alkyl;

[00616] X1 and X5 are each independently selected from the group consisting of hydrogen, a carbamate-based protecting group, an acyl-based protecting group, a sulfonamide-based protecting group and a silyl-based protecting group; and

[00617] X2 and X4 are each independently a halogen, a hydroxy group, an optionally substituted C1-C6 alkoxy, an optionally substituted C6-C10 aryloxy, an optionally substituted C7-C14 aralkoxy, an optionally substituted 4- to 8-membered cyclic amino-oxy Petition 870250088014, dated 09 / 29 / 2025, page 110 / 299 104 / 238 substituted, or a group represented by -OSiRxRyRz, wherein Rx, Ry and Rz are each independently a C1-C6 alkyl or a C6C10 aryl.

[00618] In one aspect of the structural formula of the cyclic peptide compound represented by formula (1) and of the structural formulas of the peptide compounds represented by formulas (2) and (3), more preferably,

[00619] Ri is n-propyl or 2-methylpropyl;

[00620] P1 is methyl;

[00621] R2 is 1-methylpropyl;

[00622] R3 is hydrogen, or R3 forms a saturated 5-membered heterocyclic ring together with P3, a carbon atom to which R3 is attached, and a nitrogen atom to which P3 is attached;

[00623] P3 is methyl, or P3 forms a saturated 5-membered heterocyclic ring together with R3, a carbon atom to which R3 is attached, and a nitrogen atom to which P3 is attached;

[00624] P4 is methyl;

[00625] R5 is 4-trifluoromethylbenzyl;

[00626] P6 is methyl;

[00627] R7 is 3-methoxy-4-trifluoromethylphenethyl or 3,5-difluoro-4-trifluoromethylphenethyl;

[00628] R8 forms a saturated 5-membered heterocyclic ring together with P8, a carbon atom to which R8 is attached, and a nitrogen atom to which P8 is attached, the saturated 5-membered heterocyclic ring optionally substituted with ethoxy;

[00629] R9 forms a 4-membered alicyclic ring or a 5-membered alicyclic ring together with Q9 and a carbon atom to which R9 and Q9 are attached;

[00630] P9 is hydrogen or methyl;

[00631] R10 is cyclopentyl; Petition 870250088014, dated 09 / 29 / 2025, page 111 / 299 105 / 238

[00632] Pio is methyl;

[00633] Rii is dimethylaminocarbonyl;

[00634] Pii is methyl;

[00635] Xi is hydrogen or a carbamate-based protecting group;

[00636] X5 is hydrogen or a carbamate-based protecting group;

[00637] X2 is a hydroxy, t-butoxyoxy or benzyloxy group; and

[00638] X4 is a hydroxy, t-butoxy oxy or benzyloxy group.

[00639] In one aspect of the structural formulas of the peptide compounds represented by formulas (4) to (6),

[00640] Ri is a C1-C1 alkyl; [0064i] Pi is a Ci-C6 alkyl;

[00642] R2 is a C1-C6 alkyl;

[00643] R3 is hydrogen, or R3 forms a saturated heterocyclic ring of 4 to 7 members together with P3, a carbon atom to which R3 is attached and a nitrogen atom to which P3 is attached;

[00644] P3 is a C1-C6 alkyl or a C3-C8 cycloalkyl, or P3 forms a saturated 4- to 7-membered heterocyclic ring together with R3, a carbon atom to which R3 is attached, and a nitrogen atom to which P3 is attached;

[00645] P4 is a C1-C6 alkyl;

[00646] R5 is benzyl optionally substituted with one or more groups selected from the group consisting of a C1-C6 alkyl, a C1-C6 haloalkyl, and a C3-C8 cycloalkyl;

[00647] P6 is a C1-C6 alkyl;

[00648] R7 is phenethyl optionally substituted with one or more groups selected from the group consisting of a halogen, a C1-C6 haloalkyl, and a C1-C6 alkoxy;

[00649] R8 forms a saturated heterocyclic ring with 4 to 7 members Petition 870250088014, dated 09 / 29 / 2025, p. 112 / 299 106 / 238 together with P8, a carbon atom to which R8 is attached, and a nitrogen atom to which P8 is attached, the saturated 4- to 7-membered heterocyclic ring optionally substituted with a C1-C6 alkoxy;

[00650] R9 forms a 3- to 8-membered alicyclic ring together with Q9 and a carbon atom to which R9 and Q9 are attached, the 3- to 8-membered alicyclic ring optionally substituted with one or more C1-C6 alkyls;

[00651] P9 is hydrogen or a C1-C6 alkyl;

[00652] R10 is a C1-C6 alkyl or a C3-C8 cycloalkyl;

[00653] P10 is a C1-C6 alkyl;

[00654] R11 is a di-C1-C6 alkylaminocarbonyl or a 4- to 8-membered cyclic aminocarbonyl;

[00655] P11 is a C1-C6 alkyl;

[00656] X1, X3 and X5 are each independently either hydrogen or a protecting group for an amino group; and

[00657] X2, X4 and X6 are each independently a halogen, a hydroxy group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy or a group represented by -OSiRxRyRz, wherein Rx, Ry, and Rz are each independently an alkyl or an aryl.

[00658] In one aspect of the structural formulas of the peptide compounds represented by formulas (4) to (6), preferably,

[00659] Ri is a C3-C4 alkyl;

[00660] Pi is a C1-C4 alkyl;

[00661] R2 is a C3-C4 alkyl;

[00662] R3 is hydrogen, or R3 forms a saturated 5-membered heterocyclic ring together with P3, a carbon atom to which R3 is attached, and a nitrogen atom to which P3 is attached;

[00663] P3 is a C1-C4 alkyl, or P3 forms a heterocyclic ring Petition 870250088014, dated 09 / 29 / 2025, p. 113 / 299 107 / 238 saturated 5-membered group together with R3, a carbon atom to which R3 is bonded and a nitrogen atom to which P3 is bonded;

[00664] P4 is a C1-C4 alkyl;

[00665] R5 is benzyl optionally substituted with a C1-C4 haloalkyl;

[00666] P6 is a C1-C4 alkyl;

[00667] R7 is phenethyl optionally substituted with one or more groups selected from the group consisting of a halogen, trifluoromethyl and methoxy;

[00668] R8 forms a saturated 5-membered heterocyclic ring together with P8, a carbon atom to which R8 is attached, and a nitrogen atom to which P8 is attached, the saturated 5-membered heterocyclic ring being substituted with a C1-C4 alkyl group;

[00669] R9 forms a 4- to 6-membered alicyclic ring together with Q9 and a carbon atom to which R9 and Q9 are attached;

[00670] P9 is hydrogen or a C1-C4 alkyl;

[00671] R10 is a C4-C6 cycloalkyl;

[00672] P10 is a C1-C4 alkyl;

[00673] R11 is a di-C1-C4 alkylaminocarbonyl or a 5- to 6-membered cyclic aminocarbonyl;

[00674] P11 is a C1-C4 alkyl;

[00675] X1, X3 and X5 are each independently selected from the group consisting of hydrogen, a carbamate-based protecting group, an acyl-based protecting group, a sulfonamide-based protecting group and a silyl-based protecting group; and

[00676] X2, X4 and X6 are each independently a halogen, a hydroxy group, an optionally substituted C1-C6 alkoxy, an optionally substituted C6-C10 aryloxy, an optionally substituted C7-C14 aralkoxy, an optionally substituted 4- to 8-membered cyclic aminooxy, or a group represented by -OSiRxRyRz, wherein Rx, Ry and Rz Petition 870250088014, dated 09 / 29 / 2025, page 114 / 299 108 / 238 are each independently either a C1-C6 alkyl or a C6-C10 aryl.

[00677] In one aspect of the structural formulas of the peptide compounds represented by formulas (4) to (6), more preferably,

[00678] R1 is n-propyl or 2-methylpropyl;

[00679] Pi is methyl;

[00680] R2 is 1-methylpropyl;

[00681] R3 is hydrogen, or R3 forms a saturated 5-membered heterocyclic ring together with P3, a carbon atom to which R3 is attached, and a nitrogen atom to which P3 is attached;

[00682] P3 is methyl, or P3 forms a saturated 5-membered heterocyclic ring together with R3, a carbon atom to which R3 is attached, and a nitrogen atom to which P3 is attached;

[00683] P4 is methyl;

[00684] R5 is 4-trifluoromethylbenzyl;

[00685] P6 is methyl;

[00686] R7 is 3-methoxy-4-trifluoromethylphenethyl or 3,5-difluoro-4-trifluoromethylphenethyl;

[00687] R8 forms a saturated 5-membered heterocyclic ring together with P8, a carbon atom to which R8 is attached, and a nitrogen atom to which P8 is attached, the saturated 5-membered heterocyclic ring optionally substituted with ethoxy;

[00688] R9 forms a 4-membered alicyclic ring or a 5-membered alicyclic ring together with Q9 and a carbon atom to which R9 and Q9 are attached;

[00689] P9 is hydrogen or methyl;

[00690] R10 is cyclopentyl;

[00691] P10 is methyl;

[00692] R11 is dimethylaminocarbonyl;

[00693] P11 is methyl; Petition 870250088014, dated 09 / 29 / 2025, page 115 / 299 109 / 238

[00694] Xi is hydrogen or a carbamate-based protecting group;

[00695] X3 is hydrogen or a carbamate-based protecting group;

[00696] X5 is hydrogen or a carbamate-based protecting group;

[00697] X2 is a hydroxy, t-butoxy oxy, or benzyl oxy group;

[00698] X4 is a hydroxy, t-butoxy oxy, or benzyl oxy group; and

[00699] X6 is a hydroxy, t-butoxy oxy, or benzyl oxy group.

[00700] In one aspect, the cyclic peptide compound, or a salt thereof, or a solvate thereof produced by the method of the present invention is preferably a solvate, and more preferably a hydrate.

[00701] In one aspect, the cyclic peptide compound produced by the method of the present invention is a cyclic peptide compound represented by the following formula (1a): Formula 30 or a salt of the same, or a solvate of the same.

[00702] In one aspect, the present invention relates to a method for producing a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof. The method includes a reaction step of an N-terminal amino acid residue of a peptide compound represented by formula (2a) or (3a) with Petition 870250088014, dated 09 / 29 / 2025, p. 116 / 299 110 / 238 a C-terminal amino acid residue of the peptide compound in a solvent for cyclization (cyclization step) (hereinafter also referred to as aspect 1). Formula 31

[00703] In one aspect, the present invention relates to a method for producing a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof. The method Petition 870250088014, dated 09 / 29 / 2025, p. 117 / 299 111 / 238 includes

[00704] a step for supplying peptide compounds represented by formulas (4a) to (6a), or salts thereof, or solvates of the peptide compounds or salts;

[00705] a reaction step of N-terminal amino acid residues of the peptide compounds represented by formulas (4a) to (6a) with C-terminal amino acid residues of the peptide compounds for linkage (linkage step); and

[00706] a reaction step of an N-terminal amino acid residue of a peptide compound obtained in step (b) with a C-terminal amino acid residue of the peptide compound for cyclization (cyclization step) (hereinafter also referred to as aspect 2). Formula 32 O o

[00707] In aspect 2', step (b) may include (b-1) a linkage step of an N-terminal amino acid residue of the peptide compound represented by formula (5a) with a C-terminal amino acid residue of the peptide compound represented by formula (6a), Petition 870250088014, dated 09 / 29 / 2025, pp. 118 / 299 112 / 238 thus converting them into a peptide compound represented by formula (7a). Formula 33

[00708] In aspect 2', step (b) may include, in addition to step (b-1),

[00709] (b-2) a step of linking an N-terminal amino acid residue of the peptide compound represented by formula (4a) with a C-terminal amino acid residue of the peptide compound represented by formula (7a), thereby converting them into a peptide compound represented by formula (2a) (linking step), and step (c) may include

[00710] (c-1) a step of reacting an N-terminal amino acid residue of the peptide compound represented by formula (2a) with a C-terminal amino acid residue of the peptide compound in a solvent for cyclization (cyclization step).

[00711] In aspect 2', step (b) may include, in addition to step (b-1),

[00712] (b-3) a step of linking an N-terminal amino acid residue of the peptide compound represented by formula (7a) with a C-terminal amino acid residue of the peptide compound represented by formula (4a), thereby converting them into a peptide compound represented by formula (3a) (linking step), and step (c) may include

[00713] (c-2) a step of reacting an N-terminal amino acid residue of the peptide compound represented by formula (3a) with a C-terminal amino acid residue of the peptide compound in a solvent for cyclization (cyclization step). Petition 870250088014, dated 09 / 29 / 2025, page 119 / 299 113 / 238

[00714] In aspects 1' and 2', the linkage of an N-terminal amino acid residue of a peptide compound with a C-terminal amino acid residue of a peptide compound is preferably the linkage of an amino group of the N-terminal amino acid residue with a carboxyl group of the C-terminal amino acid residue, and the linkage of an N-terminal amino acid residue of a peptide compound with a C-terminal amino acid residue of a peptide compound is more preferably the linkage via an amide bond of an amino group of the N-terminal amino acid residue with a carboxyl group of the C-terminal amino acid residue.

[00715] The solvent in the cyclization step, the condensation reagent in the cyclization step, the base in the cyclization step, the byproducts generated in the cyclization step, the solvent in the linking step, the condensation reagent in the linking step, the base in the linking step and similar in aspects 1' and 2' are the same as described in aspects 1 and 2 above.

[00716] Each symbol used in the structural formula of the cyclic peptide compound represented by formula (1a) and in the structural formulas of the peptide compounds represented by formulas (2a) to (7a) in aspects 1' and 2' is the same as those described in aspects 1 and 2 above. Peptide compound

[00717] In one aspect, the present invention relates to a compound represented by formula (4a). Formula 34 (4a)

[00718] In formula (4a), X1 is hydrogen or a protecting group for Petition 870250088014, dated 09 / 29 / 2025, pp. 120 / 299 114 / 238 an amino group. Here, the protecting group on Xi is the same as described in aspects 1 and 2 above. In one aspect, Xi is preferably hydrogen. In one aspect, Xi is preferably an Fmoc group.

[00719] In formula (4a), X2 is a hydroxy group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy or a group represented by -OSiRxRyRz, where Rx, Rye and Rz are each independently an alkyl or an aryl. Herein, the optionally substituted alkoxy, the optionally substituted aryloxy, the optionally substituted aralkoxy, the optionally substituted cyclic aminooxy and -OSiRxRyRz in X2 are the same as described in aspects 1 and 2 above. In one aspect, X2 is preferably t-butoxy.

[00720] In one aspect, the compound represented by formula (4a) is preferably 2-[methyl-[(2S)-2-[(4Z,7S)-7-(methylamino)-8-oxo-2,3,6,7-tetrahydroazocin-1-yl]-3-[4-(trifluoromethyl)phenyl]propanoyl]amino] tert-butyl acetate (compound 9).

[00721] In one aspect, the compound represented by formula (4a) (peptide compound (4a)) can be produced using the following method. Formula 35 X = H. Xz = XgB OR Xi = PgdxX2=OH

[00722] By allowing an aldehyde to act on a protected amino acid (4a-1), according to the method of Freidinger et al. (J. Org. Chem., Petition 870250088014, dated 09 / 29 / 2025, pp. 121 / 299 115 / 238 (1983, 48(1), 77-81), an oxazolidinone form with an introduced cyclic protecting group (4a-2) can be obtained. Then, by performing a ring-opening reaction using a silicon compound with an olefin, according to the method of Nguyen et al. (Synthesis, 2009, 12, 1991), a compound with an alkyl group with an olefin introduced at the nitrogen atom (4a-3) can be obtained. Then, by condensing an amino acid whose C-terminal has been protected (4a-4), the amino acid can be elongated on the C-terminal side. For the condensation reaction, the condensation reagent and base used in the above bonding step can be used. For example, a variety of methods are possible as an activator of the carboxyl group, such as the combination of DIC and Oxyma, the combination of DIC and HOAt, the combination of HATU and DIPEA, or by means of a mixed acid anhydride or an acid halide.Next, after the amino group's protecting group is deprotected, the protected amino acid having an olefin as a side chain (4a-6) can then be elongated. Then, through a metathesis reaction, the intramolecular olefins can be cyclized. In the metathesis reaction, dichloro(2-isopropoxybenzylidene)(tricyclohexylphosphine)ruthenium(II): CAS No. 203714-71-0, dichloro(3-phenyl-1H-inden-1-ylidene)bis(tricyclohexylphosphine)ruthenium(II): CAS No. 250220-36-1, dichloro(benzylidene)bis(tricyclohexylphosphine)ruthenium(II): CAS No. 172222-30-9, [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(3-phenyl-1H-inden-1-ylidene)(tricyclohexylphosphine)ruthenium(II): CAS No. 536724-67-1, [1,3-bis(2,4,6-trimethylphenyl)2-imidazolidinylidene]dichloro(benzylidene)(tricyclohexylphosphine)ruthenium(II): CAS No. 246047-72-3, [1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene] dichloro(2-isopropoxybenzylidene)ruthenium(II): CAS No.301224-40-8, [1,3bis-(2-tolyl)-2-imidazolidinylidene]dichloro(2-isopropoxybenzylidene)ruthenium (II): CAS No. 927429-61-6, [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro[(2-isopropoxy)(5-trifluoroacetamido)benzylidene]ruthenium(II): CAS No. 1025728-56-6, [1,3-bis(2,6-diisopropylphenyl)-2-imidazolidinyl. Petition 870250088014, dated 09 / 29 / 2025, pp. 122 / 299 116 / 238 deno]dichloro[5-(isobutoxycarbonylamido)-2-isopropoxybenzylidene]ruthenium(II): CAS No. 1212009-05-6, or similar, can be used as a catalyst. Then, the C-terminal protecting group can be deprotected to produce the peptide compound (4a) with the C-terminal unprotected, or the N-terminal protecting group can be deprotected to produce the peptide compound (4a) with the N-terminal unprotected.

[00723] The peptide compound (4a) can also be produced using the following method. Formula 36 OR X1 = Pg4, X2 = OH

[00724] By allowing an alkylating agent with an olefin to act on an amino acid (4a-9) in the presence of a base, an amino acid with an alkyl group with an olefin introduced at the N-atom (4a-10) can be obtained. Then, by condensing an amino acid whose C-terminal has been protected (4a-4), the amino acid can be elongated on the C-terminal side. For the condensation reaction, the condensation reagent and base used in the above linking step can be used. For example, a variety of methods are possible as an activator of the carboxyl group, such as the combination of DIC and Oxyma, the combination of DIC and HOAt, the combination of HATU and DIPEA, or by means of an anhydride. Petition 870250088014, dated 09 / 29 / 2025, pp. 123 / 299 117 / 238 mixed acid or an acid halide. Then, after deprotecting the protecting group from the amino group, the protected amino acid that has an olefin as a side chain can then be elongated. Then, through a metathesis reaction, the intramolecular olefins can be cyclized. The catalyst used in the metathesis reaction is the same as described above. Then, the C-terminal protecting group can be deprotected to produce the peptide compound (4a) with the C-terminal unprotected, or the N-terminal protecting group can be deprotected to produce the peptide compound (4a) with the N-terminal unprotected.

[00725] In one aspect, the present invention relates to a compound represented by formula (5a). Formula 37 (5a)

[00726] In formula (5a), X3 is hydrogen or a protecting group for an amino group. Here, the protecting group for an amino group in X3 is the same as described in aspects 1 and 2 above. In one aspect, X3 is preferably hydrogen. In one aspect, X3 is preferably an Fmoc group or a Cbz group.

[00727] In formula (5a), X4 is a hydroxy group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy or a group represented by -OSiRxRyRz, where Rx, Ry and Rz are each independently an alkyl or an aryl. Here, the optionally substituted alkoxy, the optionally substituted aryloxy, the optionally substituted aralkoxy, the optionally substituted cyclic aminooxy Petition 870250088014, dated 09 / 29 / 2025, pp. 124 / 299 118 / 238 replaced and -OSiRxRyRzem X2 are the same as described in aspects 1 and 2 above. In one aspect, X4 is preferably t-butoxy.

[00728] In one aspect, the compound represented by formula (5a) is preferably (2S)-1-[(2S,3S)-3-methyl-2-[[(2S)-2-(methylamino)pentanoyl]amino]pentanoyl]pyrrolidine-2-tert-butyl acetate (compound 13).

[00729] In one aspect, the compound represented by formula (5a) (peptide compound (5a)) can be produced using the following method. Formula 38 OR X3=Pgi.X4=OH

[00730] By condensing a protected amino acid (5a-2) to proline whose C-terminal has been protected (5a-1), a compound (5a-3) can be obtained. For the condensation reaction, the condensation reagent and base used in the linking step described above can be used and, for example, a variety of methods are possible as the activator of the carboxyl group, such as the combination of DIC and Oxyma, the combination of DIC and HOAt, the combination of HATU and DIPEA, or by means of a mixed acid anhydride or an acid halide. Subsequently, after deprotection of the nitrogen atom's protecting group, a protected amino acid (5a-4) can be condensed, thus synthesizing a fragment composed of 3 amino acids (5a-5). Next, the C-terminal protecting group can be deprotected to produce the peptide compound (5a) with the C-terminal deprotected, or the N-terminal protecting group can be deprotected to produce the peptide compound (5a) with the N-terminal deprotected.

[00731] In one aspect, the present invention relates to a Petition 870250088014, dated 09 / 29 / 2025, pp. 125 / 299 119 / 238 compound represented by formula (6a). Formula 39 (6a)

[00732] In formula (6a), X5 is hydrogen or a protecting group for an amino group. Here, the protecting group for an amino group in X5 is the same as described in aspects 1 and 2 above. In one aspect, X5 is preferably hydrogen. In one aspect, X5 is preferably a Cbz group.

[00733] ​​In formula (6a), X6 is a hydroxy group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy, or a group represented by -OSiRxRyRz, where Rx, Ry and Rz are each independently an alkyl or an aryl. Herein, the optionally substituted alkoxy, the optionally substituted aryloxy, the optionally substituted aralkoxy, the optionally substituted cyclic aminooxy and -OSiRxRyRz in X6 are the same as described in aspects 1 and 2 above. In one aspect, X6 is preferably t-butoxy.

[00734] In one aspect, the compound represented by formula (6a) is preferably (3S)-3-[[(2S)-2-[[1-[[(2S,4R)-1-[(2S)-2-(benzyloxycarbonylamino)-4-[3-methoxy-4-(trifluoromethyl)phenyl]butanoyl]-4-ethoxypyrrolidine-2-carbonyl]-methylamino]cyclobutanecarbonyl]-methylamino]-2-cyclopentylacetyl]-methylamino]-4-(dimethylamino)-4-oxobutyric acid (compound 20).

[00735] In one aspect, the compound represented by formula (6a) (peptide compound (6a)) can be produced using the following method. Petition 870250088014, dated 09 / 29 / 2025, pp. 126 / 299 120 / 238 Formula 40 or X5 = Pg7. X6 = OH

[00736] By condensing a protected amino acid (6a-2) into an amino acid with a β-amino acid backbone with the carboxy group protected (6a-1), a compound (6a-3) can be obtained. For the condensation reaction, the condensation reagent and base used in the linking step described above can be used, and, for example, a variety of methods are possible as the carboxyl group activator, such as the combination of DIC and Oxyma, the combination of DIC and HOAt, the combination of HATU and DIPEA, or by means of a mixed acid anhydride or an acid halide. Subsequently, by sequentially performing the deprotection of the protecting group to the amino group and the condensation of a protected amino acid, a fragment composed of 5 amino acids (6a9) can be synthesized.Next, the C-terminal protecting group can be deprotected to produce the C-terminal unprotected peptide compound (6a), or the N-terminal protecting group can be deprotected to produce the N-terminal unprotected peptide compound (6a).

[00737] In one aspect, the present invention relates to a compound represented by formula (7a). Petition 870250088014, dated 09 / 29 / 2025, pp. 127 / 299 121 / 238 Formula 41 (7a)

[00738] In formula (7a), X5 is hydrogen or a protecting group for an amino group. Here, the protecting group for an amino group in X5 is the same as described in aspects 1 and 2 above. In one aspect, X5 is preferably hydrogen. In one aspect, X5 is preferably a Cbz group.

[00739] In formula (7a), X4 is a hydroxy group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy or a group represented by -OSiRxRyRz, where Rx, Ry and Rz are each independently an alkyl or an aryl. Herein, the optionally substituted alkoxy, the optionally substituted aryloxy, the optionally substituted aralkoxy, the optionally substituted cyclic aminooxy and -OSiRxRyRz in X4 are the same as described in aspects 1 and 2 above. In one aspect, X4 is preferably a hydroxyoxy or t-butoxy group.

[00740] In one aspect, the compound represented by formula (7a) is preferably (2S)-1-[(2S,3S)-2-[[(2S)-2-[[(3S)-3-[[(2S)-2-[[1[[(2S,4R)-1-[(2S)-2-(benzyloxycarbonylamino)-4-[3-methoxy-4-(trifluoromethyl)phenyl]butanoyl]-4-ethoxypyrrolidine-2-carbonyl]-methylamino]cyclobutanecarbonyl]-methylamino]-2-cyclopentylacetyl]-methylamino]-4-(dimethylamino)4-oxo-butanoyl]-methylamino]pentanoyl]amino]-3-methylPetition 870250088014, dated 29 / 09 / 2025, page 128 / 299 122 / 238 pentanoyl]pyrrolidine-2-carboxylic acid (compound 22). Furthermore, in one aspect, the compound represented by formula (7a) is preferably (2S)-1-[(2S,3S)-2-[[(2S)-2-[[(3S)-3-[[(2S)-2-[[1-[[(2S,4R)-1-[(2S)-2amino-4-[3-methoxy-4-(trifluoromethyl)phenyl]butanoyl]-4-ethoxy-pyrrolidine-2-carbonyl]-methyl-amino]cyclobutanecarbonyl]-methyl-amino]-2-cyclopentylacetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butanoyl]-methyl-amino]pentanoyl]amino]-3-methyl-pentanoyl]pyrrolidine-2-carboxylate tert-butyl (compound 37).

[00741] In one aspect, the compound represented by formula (7a) can be produced by the reaction of an N-terminal amino acid residue of the peptide compound represented by formula (5a) with a C-terminal amino acid residue of the peptide compound represented by formula (6a) in a solvent for binding (binding step). The solvent in the binding step, the condensation reagent in the binding step, the base in the binding step and the like are the same as described in aspects 1 and 2 above.

[00742] In one aspect, the present invention relates to a compound represented by formula (2a). Formula 42

[00743] In formula (2a), X5 is hydrogen or a protecting group for an amino group. Here, the protecting group for an amino group in X5 is the same as described in aspects 1 and 2 above. In one aspect, X5 is preferably hydrogen. In one aspect, X5 is preferably a group Petition 870250088014, dated 09 / 29 / 2025, pp. 129 / 299 123 / 238 Cbz.

[00744] In formula (2a), X2 is a hydroxy group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy or a group represented by -OSiRxRyRz, where Rx, Ry and Rz are each independently an alkyl or an aryl. Herein, the optionally substituted alkoxy, the optionally substituted aryloxy, the optionally substituted aralkoxy, the optionally substituted cyclic aminooxy and -OSiRxRyRz in X2 are the same as described in aspects 1 and 2 above. In one aspect, X2 is preferably a hydroxyoxy or t-butoxy group.

[00745] In one aspect, the compound represented by formula (2a) is preferably 2-[[(2S)-2-[(4Z,7S)-7-[[(2S)-1-[(2S,3S)-2-[[(2S)2-[[(3S)-3-[[(2S)-2-[[1-[[(2S,4R)-1-[(2S)-2-amino-4-[3-methoxy-4-(trifluoromethyl)phenyl]butanoyl]-4-ethoxy-pyrrolidine-2-carbonyl]-methyl-amino]cyclobutanecarbonyl]-methyl-amino]-2-cyclopentyl-acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butanoyl]-methyl-amino]pentanoyl]amino]-3-methyl-pentanoyl] pyrrolidine-2-carbonyl]-methyl-amino]-8-oxo-2,3,6,7-tetrahydroazocin-1-yl]3-[4-(trifluoromethyl)phenyl]propanoyl]-methyl-amino]acetic acid (compound 24).

[00746] In one aspect, the compound represented by formula (2a) can be produced by the reaction of an N-terminal amino acid residue of the peptide compound represented by formula (4a) with a C-terminal amino acid residue of the peptide compound represented by formula (7a) in a solvent for binding (binding step). The solvent in the binding step, the condensation reagent in the binding step, the base in the binding step and the like are the same as described in aspects 1 and 2 above.

[00747] In one aspect, the present invention relates to a compound represented by formula (3a). Petition 870250088014, dated 09 / 29 / 2025, pp. 130 / 299 124 / 238 Formula 43

[00748] In formula (3a), Xi is hydrogen or a protecting group for an amino group. Here, the protecting group for an amino group in Xi is the same as described in aspects 1 and 2 above. In one aspect, X1 is preferably hydrogen. In one aspect, Xi is preferably an Fmoc group.

[00749] In formula (3a), X4 is a hydroxy group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy or a group represented by -OSiRxRyRz, where Rx, Ry and Rz are each independently an alkyl or an aryl. Herein, the optionally substituted alkoxy, the optionally substituted aryloxy, the optionally substituted aralkoxy, the optionally substituted cyclic aminooxy and -OSiRxRyRz in X4 are the same as described in aspects 1 and 2 above. In one aspect, X4 is preferably a hydroxyoxy or t-butoxy group.

[00750] In one aspect, the compound represented by formula (3a) is preferably (S)-2-[(S)-3-[(S)-2-cyclopentyl-2-[1-[(2S,4R)-4-ethoxy-1 [(S)-4-[3-methoxy-4-(trifluoromethyl)phenyl]-2-[(2-[(S)-N-methyl-2-[(R,Z)-3-(methylamino)-2-oxo-3,4,7,8-tetrahydroazocin-1(2H)-yl]-3-[4-(trifluoromethyl)phenyl]propanamido]acetamido)butanoyl]-N-methylpyrrolidine-2-carboxamide] -N-methylcyclobutane-1-carboxyamido]-N-methylacetamido]-4-(dimethylamino)-N-methyl-4-oxobutanamido]pentanoyl]-L-isoleucyl-L-proline (compound Petition 870250088014, dated 09 / 29 / 2025, pp. 131 / 299 125 / 238 40).

[00751] In one aspect, the compound represented by formula (3a) can be produced by the reaction of an N-terminal amino acid residue of the peptide compound represented by formula (7a) with a C-terminal amino acid residue of the peptide compound represented by formula (4a) in a solvent for binding (binding step). The solvent in the binding step, the condensation reagent in the binding step, the base in the binding step and the like are the same as described in aspects 1 and 2 above.

[00752] In the production methods of the compounds represented by formulas (2a) to (7a), it is preferable not to use solid-phase synthesis.

[00753] In the production method of the cyclic peptide compound represented by formula (1a), it is preferable not to use solid-phase synthesis. Cyclic peptide compound crystal

[00754] In one aspect, the present invention relates to a crystal of a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof. Specific examples of the crystal of this compound include a non-solvate crystal or a solvate crystal of this compound, or a non-solvate crystal or a solvate crystal of a salt of this compound. Among these, a solvate crystal of the cyclic peptide compound represented by formula (1a) is preferred. Preferred examples of the solvate crystal include a hydrate crystal.

[00755] The diffraction angle 2Θ in powder X-ray diffraction is a diffraction peak measured using CuKa or CuKa1 radiation. A crystal that is additionally identified with diffraction angles 2θ in powder X-ray diffraction, from these solvate crystals, can be called an A-form crystal of a hydrate, as shown below, for example, or simply called A-form.

[00756] In one aspect, when the crystal of the peptide compound Petition 870250088014, dated 09 / 29 / 2025, pp. 132 / 299 126 / 238 cyclic of formula (1a) is a hydrate crystal, the crystal is an A-form crystal with a powder X-ray diffraction pattern including at least 7 peaks of the following as diffraction angles 2Θ in the powder X-ray diffraction. Note that the diffraction angles (2θ values) described below are preferably diffraction angles (2θ values) of a hydrate crystal stored at a relative humidity of 10% or more for 15 minutes or more and, more preferably, diffraction angles (2θ values) of a hydrate crystal stored at a relative humidity of 10% for 15 minutes.

[00757] 6.93°, 7.56°, 8.26°, 9.00°, 9.58°, 10.35°, 11.35°, 12.26°, 12.85°, 13.51°, 14.12°, 14.69°, 15.46°, 15.92°, 17.43°, and 17.73° (±0.2°)

[00758] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal is an A-form crystal with a powder X-ray diffraction pattern including at least 8 peaks of the following 2θ diffraction angles in the powder X-ray diffraction. Note that the diffraction angles (2θ values) described below are preferably diffraction angles (2θ values) of a hydrate crystal stored at a relative humidity of 10% or more for 15 minutes or more, and more preferably diffraction angles (2θ values) of a hydrate crystal stored at a relative humidity of 10% for 15 minutes.

[00759] 6.93°, 7.56°, 8.26°, 9.00°, 9.58°, 10.35°, 11.35°, 12.26°, 12.85°, 13.51°, 14.12°, 14.69°, 15.46°, 15.92°, 17.43°, and 17.73° (±0.2°)

[00760] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal is an A-form crystal with a powder X-ray diffraction pattern including the following peaks as 2θ diffraction angles in the powder X-ray diffraction. Note that the diffraction angles (2θ values) described below are preferably diffraction angles (2θ values) of a hydrate crystal stored at a relative humidity of 30% or more for 15 Petition 870250088014, dated 09 / 29 / 2025, pp. 133 / 299 127 / 238 minutes or more and, more preferably, diffraction angles (2θ values) of a hydrate crystal stored at 30% relative humidity for 15 minutes.

[00761] 6.93°, 7.56°, 8.26°, 9.00°, 9.58°, 10.35°, 11.35°, 12.26°, 12.85°, 13.51°, 14.12°, 14.69°, 15.46°, 15.92°, 17.43°, and 17.73° (±0.2°)

[00762] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal is a B-form crystal with a powder X-ray diffraction pattern including at least 7 peaks of the following as 2θ diffraction angles in powder X-ray diffraction. Note that the diffraction angles (2θ values) described below are preferably diffraction angles (2θ values) of a hydrate crystal stored at a relative humidity of 30% or more for 15 minutes or more, and more preferably diffraction angles (2θ values) of a hydrate crystal stored at a relative humidity of 30% for 15 minutes.

[00763] 4.99°, 8.65°, 9.85°, 10.84°, 11.32°, 12.35°, 13.20°, 14.44°, 15.20°, 16.03°, 16.69°, 17.21°, 18.82°, 19.49°, and 20.03° (±0.2°)

[00764] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal is a B-form crystal with a powder X-ray diffraction pattern including at least 8 peaks of the following as 2θ diffraction angles in the powder X-ray diffraction. Note that the diffraction angles (2θ values) described below are preferably diffraction angles (2θ values) of a hydrate crystal stored at a relative humidity of 30% or more for 15 minutes or more and, more preferably, diffraction angles (2θ values) of a hydrate crystal stored at a relative humidity of 30% for 15 minutes.

[00765] 4.99°, 8.65°, 9.85°, 10.84°, 11.32°, 12.35°, 13.20°, 14.44°, 15.20°, 16.03°, 16.69°, 17.21°, 18.82°, 19.49°, and 20.03° (±0.2°)

[00766] In one aspect, when the crystal of the peptide compound Petition 870250088014, dated 09 / 29 / 2025, page 134 / 299 128 / 238 cyclic of formula (1a) is a hydrate crystal, the crystal is a B-form crystal with a powder X-ray diffraction pattern including the following peaks as 2Θ diffraction angles in the powder X-ray diffraction. Note that the diffraction angles (2θ values) described below are preferably diffraction angles (2θ values) of a hydrate crystal stored at a relative humidity of 30% or more for 15 minutes or more and, more preferably, diffraction angles (2θ values) of a hydrate crystal stored at a relative humidity of 30% for 15 minutes.

[00767] 4.99°, 8.65°, 9.85°, 10.84°, 11.32°, 12.35°, 13.20°, 14.44°, 15.20°, 16.03°, 16.69°, 17.21°, 18.82°, 19.49°, and 20.03° (±0.2°)

[00768] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a solvate crystal, the crystal is an F-shaped crystal with a powder X-ray diffraction pattern including at least 7 peaks of the following as diffraction angles 2θ in the powder X-ray diffraction pattern.

[00769] 6.99°, 8.49°, 9.49°, 9.88°, 10.21°, 11.81°, 12.32°, 12.75°, 13.17°, 13.94°, 14.92°, 15.20°, 15.64°, 16.78°, 17.01°, and 17.47° (±0.2°)

[00770] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a solvate crystal, the crystal is an F-form crystal with a powder X-ray diffraction pattern including at least 8 peaks of the following 2θ diffraction angles in the powder X-ray diffraction.

[00771] 6.99°, 8.49°, 9.49°, 9.88°, 10.21°, 11.81°, 12.32°, 12.75°, 13.17°, 13.94°, 14.92°, 15.20°, 15.64°, 16.78°, 17.01°, and 17.47° (±0.2°)

[00772] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a solvate crystal, the crystal is an F-form crystal with a powder X-ray diffraction pattern including the following peaks as 2θ diffraction angles in the powder X-ray diffraction pattern. Petition 870250088014, dated 09 / 29 / 2025, pp. 135 / 299 129 / 238

[00773] 6.99°, 8.49°, 9.49°, 9.88°, 10.21°, 11.81°, 12.32°, 12.75°, 13.17°, 13.94°, 14.92°, 15.20°, 15.64°, 16.78°, 17.01°, and 17.47° (±0.2°)

[00774] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a solvate crystal, the crystal is a J-shaped crystal with a powder X-ray diffraction pattern including at least 7 peaks of the following as 2Θ diffraction angles in the powder X-ray diffraction. Note that the diffraction angles (2θ values) described below are preferably diffraction angles (2θ values) of a solvate crystal stored at a relative humidity of less than 10% for 15 minutes or more and, more preferably, diffraction angles (2θ values) of a solvate crystal stored at a relative humidity of less than 10% for 15 minutes.

[00775] 6.95°, 7.33°, 7.93°, 8.84°, 9.45°, 9.97°, 10.44°, 11.19°, 12.43°, 12.93°, 13.46°, 14.36°, 14.74°, 15.21°, 15.87°, 16.76°, 20.87°, and 22.97° (±0.2°)

[00776] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a solvate crystal, the crystal is a J-shaped crystal with a powder X-ray diffraction pattern including at least 8 peaks of the following as diffraction angles 2θ in the powder X-ray diffraction. Note that the diffraction angles (2θ values) described below are preferably diffraction angles (2θ values) of a solvate crystal stored at a relative humidity of less than 10% for 15 minutes or more and, more preferably, diffraction angles (2θ values) of a solvate crystal stored at a relative humidity less than 10% for 15 minutes.

[00777] 6.95°, 7.33°, 7.93°, 8.84°, 9.45°, 9.97°, 10.44°, 11.19°, 12.43°, 12.93°, 13.46°, 14.36°, 14.74°, 15.21°, 15.87°, 16.76°, 20.87°, and 22.97° (±0.2°)

[00778] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a solvate crystal, the crystal is a crystal of form Petition 870250088014, dated 09 / 29 / 2025, pp. 136 / 299 130 / 238 J with a powdered X-ray diffraction pattern including the following peaks as 2Θ diffraction angles in the powdered X-ray diffraction pattern. Note that the diffraction angles (2θ values) described below are preferably diffraction angles (2θ values) of a solvate crystal stored at a relative humidity of less than 10% for 15 minutes or more and, more preferably, diffraction angles (2θ values) of a solvate crystal stored at a relative humidity of less than 10% for 15 minutes.

[00779] 6.95°, 7.33°, 7.93°, 8.84°, 9.45°, 9.97°, 10.44°, 11.19°, 12.43°, 12.93°, 13.46°, 14.36°, 14.74°, 15.21°, 15.87°, 16.76°, 20.87°, and 22.97° (±0.2°)

[00780] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal is a J-shaped crystal with a powder X-ray diffraction pattern including at least 7 peaks of the following as diffraction angles 2θ in the powder X-ray diffraction. Note that the diffraction angles (2θ values) described below are preferably diffraction angles (2θ values) of a hydrate crystal stored at a relative humidity of less than 10% for 15 minutes or more and, more preferably, diffraction angles (2θ values) of a hydrate crystal stored at a relative humidity of less than 10% for 15 minutes.

[00781] 6.95°, 7.33°, 7.93°, 8.84°, 9.45°, 9.97°, 10.44°, 11.19°, 12.43°, 12.93°, 13.46°, 14.36°, 14.74°, 15.21°, 15.87°, 16.76°, 20.87°, and 22.97° (±0.2°)

[00782] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal is a J-shaped crystal with a powder X-ray diffraction pattern including at least 8 peaks of the following 2θ diffraction angles in the powder X-ray diffraction. Note that the diffraction angles (2θ values) described below are preferably diffraction angles (2θ values) of a Petition 870250088014, dated 09 / 29 / 2025, pp. 137 / 299 131 / 238 hydrate crystal stored in a relative humidity of less than 10% for 15 minutes or more and, more preferably, diffraction angles (2θ values) of a hydrate crystal stored in a relative humidity of less than 10% for 15 minutes.

[00783] 6.95°, 7.33°, 7.93°, 8.84°, 9.45°, 9.97°, 10.44°, 11.19°, 12.43°, 12.93°, 13.46°, 14.36°, 14.74°, 15.21°, 15.87°, 16.76°, 20.87°, and 22.97° (±0.2°)

[00784] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal is a J-shaped crystal with a powder X-ray diffraction pattern including the following peaks as 2θ diffraction angles in the powder X-ray diffraction. Note that the diffraction angles (2θ values) described below are preferably diffraction angles (2θ values) of a hydrate crystal stored at a relative humidity of less than 10% for 15 minutes or more and, more preferably, diffraction angles (2θ values) of a hydrate crystal stored at a relative humidity of less than 10% for 15 minutes.

[00785] 6.95°, 7.33°, 7.93°, 8.84°, 9.45°, 9.97°, 10.44°, 11.19°, 12.43°, 12.93°, 13.46°, 14.36°, 14.74°, 15.21°, 15.87°, 16.76°, 20.87°, and 22.97° (±0.2°)

[00786] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal includes a J-shaped crystal with a powder X-ray diffraction pattern including at least 7 peaks of the following: 6.95°, 7.33°, 7.93°, 8.84°, 9.45°, 9.97°, 10.44°, 11.19°, 12.43°, 12.93°, 13.46°, 14.36°, 14.74°, 15.21°, 15.87°, 16.76°, 20.87°, and 22.97° (±0.2°) as 2θ diffraction angles in powder X-ray diffraction pattern at a relative humidity less than 10%, and includes an A-shaped crystal with a powder X-ray diffraction pattern including at least 7 peaks from the following: 6.93°, 7.56°, 8.26°, 9.00°, 9.58°, 10.35°, 11.35°, 12.26°, 12.85°, 13.51°, 14.12°, 14.69°, Petition 870250088014, dated 09 / 29 / 2025, pp. 138 / 299 132 / 238 15.46°, 15.92°, 17.43°, and 17.73° (±0.2°) at a relative humidity of 10% or more.

[00787] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal includes a J-shaped crystal with a powder X-ray diffraction pattern including at least 8 peaks of the following: 6.95°, 7.33°, 7.93°, 8.84°, 9.45°, 9.97°, 10.44°, 11.19°, 12.43°, 12.93°, 13.46°, 14.36°, 14.74°, 15.21°, 15.87°, 16.76°, 20.87°, and 22.97° (±0.2°) as 2Θ diffraction angles in powder X-ray diffraction pattern at a relative humidity less than 10%, and includes an A-shaped crystal with a powder X-ray diffraction pattern including at least 8 peaks from the following: 6.93°, 7.56°, 8.26°, 9.00°, 9.58°, 10.35°, 11.35°, 12.26°, 12.85°, 13.51°, 14.12°, 14.69°, 15.46°, 15.92°, 17.43°, and 17.73° (±0.2°) at a relative humidity of 10% or more.

[00788] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal includes a J-shaped crystal with a powder X-ray diffraction pattern including peaks at 6.95°, 7.33°, 7.93°, 8.84°, 9.45°, 9.97°, 10.44°, 11.19°, 12.43°, 12.93°, 13.46°, 14.36°, 14.74°, 15.21°, 15.87°, 16.76°, 20.87°, and 22.97° (±0.2°) as 2θ diffraction angles in X-ray powder diffraction at a relative humidity below 10% and includes an A-shaped crystal with an X-ray powder diffraction pattern including peaks of 6.93°, 7.56°, 8.26°, 9.00°, 9.58°, 10.35°, 11.35°, 12.26°, 12.85°, 13.51°, 14.12°, 14.69°, 15.46°, 15.92°, 17.43°, and 17.73° (±0.2°) at a relative humidity of 10% or more.

[00789] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a solvate crystal, the crystal is a Y-shaped crystal with a powder X-ray diffraction pattern including at least 7 peaks of the following as diffraction angles 2θ in the powder X-ray diffraction. Note that the diffraction angles (2θ values) described Petition 870250088014, dated 09 / 29 / 2025, pp. 139 / 299 133 / 238 below are preferably diffraction angles (2θ values) of a solvate crystal stored at a relative humidity of less than 30% for 15 minutes or more and, more preferably, diffraction angles (2θ values) of a solvate crystal stored at a relative humidity of less than 30% for 15 minutes.

[00790] 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54°, and 21.24° (±0.2°)

[00791] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a solvate crystal, the crystal is a Y-shaped crystal with a powder X-ray diffraction pattern including at least 8 peaks of the following as 2θ diffraction angles in the powder X-ray diffraction pattern. Note that the diffraction angles (2θ values) described below are preferably diffraction angles (2θ values) of a solvate crystal stored at a relative humidity of less than 30% for 15 minutes or more and, more preferably, diffraction angles (2θ values) of a solvate crystal stored at a relative humidity of less than 30% for 15 minutes.

[00792] 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54°, and 21.24° (±0.2°)

[00793] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a solvate crystal, the crystal is a Y-shaped crystal with a powder X-ray diffraction pattern including the following peaks as 2θ diffraction angles in the powder X-ray diffraction. Note that the diffraction angles (2θ values) described below are preferably diffraction angles (2θ values) of a solvate crystal stored at a relative humidity of less than 30% for 15 minutes or more and, more preferably, diffraction angles (2θ values) of a solvate crystal stored at a relative humidity of less than 30% for 15 minutes.

[00794] 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, Petition 870250088014, dated 09 / 29 / 2025, pp. 140 / 299 134 / 238 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54°, and 21.24° (±0.2°)

[00795] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal is a Y-shaped crystal with a powder X-ray diffraction pattern including at least 7 peaks of the following as 2Θ diffraction angles in powder X-ray diffraction. Note that the diffraction angles (2θ values) described below are preferably diffraction angles (2θ values) of a solvate crystal stored at a relative humidity of less than 30% for 15 minutes or more and, more preferably, diffraction angles (2θ values) of a hydrate crystal stored at a relative humidity of less than 30% for 15 minutes.

[00796] 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54°, and 21.24° (±0.2°)

[00797] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal is a Y-shaped crystal with a powder X-ray diffraction pattern including at least 8 peaks of the following as 2θ diffraction angles in powder X-ray diffraction. Note that the diffraction angles (2θ values) described below are preferably diffraction angles (2θ values) of a solvate crystal stored at a relative humidity of less than 30% for 15 minutes or more and, more preferably, diffraction angles (2θ values) of a hydrate crystal stored at a relative humidity of less than 30% for 15 minutes.

[00798] 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54°, and 21.24° (±0.2°)

[00799] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal is a Y-shaped crystal with a powder X-ray diffraction pattern including the following peaks as 2θ diffraction angles in the powder X-ray diffraction pattern. Note that the diffraction angles (2θ values) Petition 870250088014, dated 09 / 29 / 2025, pp. 141 / 299 135 / 238 described below are preferably diffraction angles (2θ values) of a hydrate crystal stored at a relative humidity of less than 30% for 15 minutes or more, and more preferably diffraction angles (2θ values) of a hydrate crystal stored at a relative humidity of less than 30% for 15 minutes.

[00800] 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54°, and 21.24° (±0.2°)

[00801] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal includes a Y-shaped crystal with a powder X-ray diffraction pattern including at least 7 peaks of the following: 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54°, and 21.24° (±0.2°) as 2θ diffraction angles in a powder X-ray diffraction pattern at a relative humidity of less than 30%, and includes a B-shaped crystal with a powder X-ray diffraction pattern including at least 7 peaks from the following: 4.99°, 8.65°, 9.85°, 10.84°, 11.32°, 12.35°, 13.20°, 14.44°, 15.20°, 16.03°, 16.69°, 17.21°, 18.82°, 19.49°, and 20.03° (±0.2°) at a relative humidity of 30% or more.

[00802] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal includes a Y-shaped crystal with a powder X-ray diffraction pattern including at least 8 peaks of the following: 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54°, and 21.24° (±0.2°) as 2θ diffraction angles in powder X-ray diffraction pattern at a relative humidity less than 30%, and includes a B-shaped crystal with a diffraction pattern of Powder X-rays including at least 8 peaks of the following: 4.99°, 8.65°, 9.85°, 10.84°, 11.32°, 12.35°, 13.20°, 14.44°, 15.20°, 16.03°, 16.69°, 17.21°, 18.82°, 19.49°, and 20.03° (±0.2°) at a relative humidity of 30% or more.

[00803] In one aspect, when the crystal of the peptide compound Petition 870250088014, dated 09 / 29 / 2025, pp. 142 / 299 136 / 238 cyclic of formula (1a) is a hydrate crystal, the crystal includes a Y-shaped crystal with a powder X-ray diffraction pattern including peaks of 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54°, and 21.24° (±0.2°) as 2Θ diffraction angles in powder X-ray diffraction at a relative humidity less than 30% and includes a B-shaped crystal with a powder X-ray diffraction pattern including peaks of 4.99°, 8.65°, 9.85°, 10.84°, 11.32°, 12.35°, 13.20°, 14.44°, 15.20°, 16.03°, 16.69°, 17.21°, 18.82°, 19.49°, and 20.03° (±0.2°) at a relative humidity of 30% or more.

[00804] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal is a K-shaped crystal with a powder X-ray diffraction pattern including at least 7 peaks of the following as diffraction angles 2θ in the powder X-ray diffraction.

[00805] 7.49°, 7.91°, 8.14°, 9.11°, 9.33°, 11.04°, 11.71°, 12.52°, 13.21°, 13.70°, 14.82°, 15.13°, 15.52°, 15.68°, 17.22°, and 17.51° (±0.2°)

[00806] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal is a K-form crystal with a powder X-ray diffraction pattern including at least 8 peaks of the following 2 θ diffraction angles in the powder X-ray diffraction.

[00807] 7.49°, 7.91°, 8.14°, 9.11°, 9.33°, 11.04°, 11.71°, 12.52°, 13.21°, 13.70°, 14.82°, 15.13°, 15.52°, 15.68°, 17.22°, and 17.51° (±0.2°)

[00808] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal is a K-form crystal with a powder X-ray diffraction pattern including the following peaks as 2θ diffraction angles in the powder X-ray diffraction.

[00809] 7.49°, 7.91°, 8.14°, 9.11°, 9.33°, 11.04°, 11.71°, 12.52°, 13.21°, 13.70°, 14.82°, 15.13°, 15.52°, 15.68°, 17.22°, and 17.51° (±0.2°) Petition 870250088014, dated 09 / 29 / 2025, pp. 143 / 299 137 / 238

[00810] In one aspect, the present invention relates to a method for producing a crystal of a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof. The method comprises: a step of dissolving the cyclic peptide compound in a polar organic solvent in an amount that allows the cyclic peptide compound to dissolve therein to obtain a solution; and a step of adding a hydrocarbon-based solvent or water to the solution to obtain a crystal of the cyclic peptide compound (hereinafter also referred to as aspect 3). In aspect 3, the properties of the cyclic peptide compound to be dissolved are not restricted and, for example, the cyclic peptide compound in solid state, amorphous state or crystalline state may be used.

[00811] In one aspect, the present invention relates to a method for producing a crystal of a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof. The method comprises: a step of adding a mixed solution of a hydrocarbon-based solvent and a polar organic solvent or a mixed solution of water and a polar organic solvent to the cyclic peptide compound in an amorphous or crystalline state to obtain a crystal of the cyclic peptide compound (hereinafter, also referred to as aspect 4).

[00812] As a polar organic solvent used in aspects 3 and 4, specifically, DMSO, acetone, 2-butanone, methanol, ethanol, 1-propanol, 2-propanol, ethyl acetate, propylene glycol and a mixed solvent thereof are preferably exemplified, and acetone is most preferably exemplified. As the amount that enables the cyclic peptide compound to dissolve in it in aspect 3, the polar organic solvent may be used in the range of 3 to 10 v / w, preferably in the range of 3 to 7 v / w, relative to the cyclic peptide compound of formula (1a). Petition 870250088014, dated 09 / 29 / 2025, pp. 144 / 299 138 / 238

[00813] As hydrocarbon-based solvents used in aspects 3 and 4, specifically, heptane, hexane, pentane, toluene, xylene and a mixed solvent thereof are preferably exemplified, and heptane is most preferably exemplified.

[00814] In aspect 4, as a mixing ratio between the hydrocarbon-based solvent and the polar organic solvent in the mixed solution of the hydrocarbon-based solvent and the polar organic solvent, 0.5 to 10 parts by weight of the hydrocarbon-based solvent may be used in relation to 1 part by weight of the polar organic solvent, and it is preferable to use preferably 1 to 7 parts by weight of the hydrocarbon-based solvent, and even more preferably 1 to 5 parts by weight of the hydrocarbon-based solvent. Furthermore, in aspect 4, as a mixing ratio between water and the polar organic solvent in the mixed solution of water and polar organic solvent, 0.5 to 10 parts by weight of water may be used in relation to 1 part by weight of the polar organic solvent, and it is preferable to use preferably 1 to 7 parts by weight of water, and even more preferably 1 to 5 parts by weight of water.

[00815] Furthermore, in a certain aspect of aspect 4, in the operation of adding a mixed solution of a hydrocarbon-based solvent and a polar organic solvent or a mixed solution of water and a polar organic solvent to the cyclic peptide compound in an amorphous or crystalline state, glass beads (e.g., 1 to 5 grains) can be added to the crystal and stirred.

[00816] In one aspect, the present invention relates to a method for producing a crystal of a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof. The method comprises: a step of dissolving the cyclic peptide compound in an amorphous state in DMSO to obtain a solution; a step of lyophilizing the solution to obtain a lyophilized product of the cyclic peptide compound; and a step of adding a solution Petition 870250088014, dated 09 / 29 / 2025, pp. 145 / 299 139 / 238 mixing water and a polar organic solvent with the lyophilized product to obtain a crystal of the cyclic peptide compound (hereinafter also referred to as aspect 5).

[00817] As polar organic solvents used in aspect 5, specifically, DMSO, acetone, 2-butanone, methanol, ethanol, 1-propanol, 2-propanol, propylene glycol and a mixed solvent thereof are preferably exemplified, and acetone is most preferably exemplified.

[00818] In aspect 5, as a mixing ratio between water and polar organic solvent in the mixed solution of water and polar organic solvent, 0.5 to 10 parts by weight of water may be used in relation to 1 part by weight of polar organic solvent, and it is preferable to use preferably 1 to 7 parts by weight of water, and even more preferably 1 to 5 parts by weight of water.

[00819] In one aspect, the present invention relates to a method for producing a crystal of a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof. The method comprises a step of heating the crystal of the cyclic peptide compound to obtain another crystalline polymorph of the cyclic peptide compound (hereinafter also referred to as aspect 6). The heating temperature is, for example, 30 to 350 °C, preferably 30 to 120 °C.

[00820] In aspects 3 to 6, the methods may additionally comprise, after the step of obtaining a crystal of the cyclic peptide compound, a step of filtering the crystal.

[00821] In aspects 3 to 6, the methods may additionally comprise, after the step of obtaining a crystal of the cyclic peptide compound, a step of drying the crystal.

[00822] In one aspect, the crystal of the cyclic peptide compound produced by the method of the present invention is preferably a Petition 870250088014, dated 09 / 29 / 2025, pp. 146 / 299 140 / 238 solvate crystal and, more preferably, a hydrate crystal.

[00823] In one aspect, the cyclic peptide compound crystal produced by the method of the present invention is formed as a solvate crystal in a solvent and obtained as a hydrate crystal after the filtration and / or drying step. Furthermore, in one aspect, the cyclic peptide compound crystal produced by the method of the present invention is obtained as a hydrate crystal by incorporating atmospheric moisture after the filtration and / or drying step. Composition containing a cyclic peptide compound

[00824] In one aspect, the present invention relates to a composition comprising a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof. The compound contains a cyclic dimer of formula (1a), which is an impurity, in an amount of 1.5% w / w or less.

[00825] In one aspect, the present invention relates to a composition comprising a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof. The compound contains a cyclic dimer of formula (1a), which is an impurity, in an amount of 0.001% w / w or more.

[00826] In one aspect, the present invention relates to a composition comprising a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof. The compound contains acetone in a proportion of 2.0% w / w or less.

[00827] In one aspect, the present invention relates to a composition comprising a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof. The compound contains acetone in a proportion of 0.001% w / w or more. Examples

[00828] The content of the present invention will be described further. Petition 870250088014, dated 09 / 29 / 2025, pp. 147 / 299 141 / 238 described by the following Examples, but the present invention is not limited to its content. Except those specifically described, the starting crude substances, starting raw materials, solvents and reagents were obtained from commercial suppliers or synthesized using known methods. Compound 25 used in Example 126 described below was synthesized by the method described in International Publication No. WO 2022 / 234853.

[00829] The LCMS analysis conditions are shown below. LCMS Analysis Conditions Method 1

[00830] Device: Shimadzu LCMS 2020

[00831] Column: CORTECS C18 column, 3.0 mm ID χ 50 mm, 2.7 pm

[00832] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[00833] Elution method: B) 5% (0 min) ^ 95% (2.0 min) ^ 95% (2.8 min) ^ 5% (2.81 min) ^ 5% (3 min)

[00834] Flow rate: 1.5 ml / min

[00835] Column temperature: 40 °C

[00836] Wavelength detection: 190 to 800 nm (PDA) LCMS Analysis Conditions Method 2

[00837] Appliance: UPLC / SQD Water

[00838] Column: Ascentis Express RP 90A amide, 2.1 mm ID χ 50 mm, 2.7 pm (PDA) m

[00839] Mobile phase: 0.1% FA / water (A), 0.1% FA / MeCN (B)

[00840] Elution method: B) 5% (0 min) ^ 100% (4.5 min) ^ 100% (5.0 min) ^ 5% (5.01 min) ^ 5% (7 min)

[00841] Flow rate: 0.5 ml / min

[00842] Column temperature: 40 °C

[00843] Wavelength detection: 210 to 400 nm (PDA) LCMS Analysis Conditions Method 3

[00844] Appliance: UPLC / SQD Water

[00845] Column: Ascentis Express 90A C18, 2.1 mm ID χ 50 mm, 2.7 Petition 870250088014, dated 09 / 29 / 2025, pp. 148 / 299 142 / 238 pm

[00846] Mobile phase: 0.1% FA / water (A), 0.1% FA / MeCN (B)

[00847] Elution method: B) 5% (0 min) ^ 100% (5 min) ^ 5% (5.01 min) ^ 5% (7 min)

[00848] Flow rate: 0.5 ml / min

[00849] Column temperature: Off

[00850] Wavelength detection: 210 to 400 nm (PDA) LCMS Analysis Conditions Method 4

[00851] Appliance: UPLC / SQD Water

[00852] Column: ACQUITY UPLC BEH C18 Column, 2.1 mm ID χ 50 mm, 1.7 pm

[00853] Mobile phase: 0.1% FA / water (A), 0.1% FA / MeCN (B)

[00854] Elution method: B) 5% (0 min) ^ 98% (8 min) ^ 98% (10 min) ^ 5% (10.01 min) ^ 5% (12 min)

[00855] Flow rate: 0.5 ml / min

[00856] Column temperature: 60 °C

[00857] Wavelength detection: 210 to 400 nm (PDA) LCMS Analysis Conditions Method 5

[00858] Appliance: UPLC / SQD Water

[00859] Column: Ascentis Express C18 2.1 χ 50 mm, 5 pm

[00860] Mobile phase: 10 mM ammonium acetate in water (A), MeOH (B)

[00861] Elution method: B) 50% (0 min) ^ 100% (1 min) ^ 100% (1.99 min) ^ 50% (2.01 min) ^ 50% (2.5 min)

[00862] Flow rate: 1.0 ml / min

[00863] Column temperature: 35 °C

[00864] Wavelength detection: 210 to 400 nm (PDA) LCMS M-method analysis conditions

[00865] Device: Waters Acquity UPLC / QDa

[00866] Column: Ascentis Express 90A C18, 2.1 mm ID χ 50 mm, 2.7 Petition 870250088014, dated 09 / 29 / 2025, pp. 149 / 299 143 / 238 pm

[00867] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[00868] Elution method: B) 5% (0 min) ^ 100% (5 min) ^ 5% (5.01 min) ^ 5% (7 min)

[00869] Flow rate: 0.5 ml / min

[00870] Column temperature: 35 °C

[00871] Wavelength detection: 210 nm (PDA) LCMS K-1 method of analysis conditions

[00872] Device: Waters Acquity UPLC / QDa

[00873] Column: CAPCELL CORE ADME, 2.1 mm χ 50 mm, 2.7 pm (Osaka Soda)

[00874] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[00875] Elution method: B) 5% (0 min) ^ 100% (10 min) ^ 5% (10.1 min) ^ 5% (12 min)

[00876] Flow rate: 0.5 ml / min

[00877] Column temperature: 35 °C

[00878] Wavelength detection: 210 nm (PDA) LCMS K-2 method of analytical conditions

[00879] Device: Waters Acquity UPLC / QDa

[00880] Column: CAPCELL CORE ADME, 2.1 mm χ 50 mm, 2.7 pm (Osaka Soda)

[00881] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[00882] Elution method: B) 5% (0 min) ^ 100% (5 min) ^ 5% (5.1 min) ^ 5% (7 min)

[00883] Flow rate: 0.5 ml / min

[00884] Column temperature: 35 °C

[00885] Wavelength detection: 210 nm (PDA) LCMS analysis conditions method P3-4

[00886] Device: Waters Acquity UPLC / QDa

[00887] Column: Ascentis Express 90A C18, 2.1 mm ID χ 50 mm, 2.7 Petition 870250088014, dated 09 / 29 / 2025, pp. 150 / 299 144 / 238 pm

[00888] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[00889] Elution method: B) 5% (0 min) ^ 100% (5 min) ^ 5% (5.01 min) ^ 5% (7 min)

[00890] Flow rate: 0.5 ml / min

[00891] Column temperature: 35 °C

[00892] Wavelength detection: 210 nm (PDA) FC 2 method of analysis conditions for LCMS

[00893] Device: UPLC Water

[00894] Column: ACQUITY UPLC CSH C18, 2.1 mm ID χ 100 mm, 1.7 pm

[00895] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[00896] Elution method: B) 20% (0 min) ^ 100% (10 min) ^ 100% (13.5 min) ^ 20% (13.6 min) ^ 20% (15.5 min)

[00897] Flow rate: 0.3 ml / min

[00898] Column temperature: 50 °C

[00899] Wavelength detection: 210 nm (PDA) LC analysis conditions cyc method

[00900] Device: UPLC Water

[00901] Column: ACQUITY UPLC CSH Phenyl-Hexyl, 2.1 mm ID χ 150 mm, 1.7 pm

[00902] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[00903] Elution method: B) 20% (0 min) ^ 100% (24 min) ^ 100% (29 min) ^ 20% (29.1 min) ^ 20% (34 min)

[00904] Flow rate: 0.3 ml / min

[00905] Column temperature: 50 °C

[00906] Wavelength detection: 220 nm (PDA) LC analysis conditions method H

[00907] Device: UPLC Water

[00908] Column: Ascentis Express RP-Amide, 3.0 mm ID χ 50 mm χ, Petition 870250088014, dated 09 / 29 / 2025, pp. 151 / 299 145 / 238 2.7 pm

[00909] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[00910] Elution method: B) 5% (0 min) ^ 95% (10.0 min) ^ 95% (12.0 min) ^ 5% (12.1 min) ^ 5% (15.0 min)

[00911] Flow rate: 0.7 ml / min

[00912] Column temperature: 30 °C

[00913] Wavelength detection: 210 nm (PDA)

[00914] The HPLC analysis conditions are shown below. Method 1 of HPLC analysis conditions

[00915] Device: Waters Class H

[00916] Column: ACQUITY UPLC BEH C18 Column, 2.1 mm ID χ 50 mm, 1.7 pm

[00917] Mobile phase: 0.1% FA / water (A), 0.1% FA / MeCN (B)

[00918] Elution method: B) 5% (0 min) ^ 98% (4.0 min) ^ 98% (6.0 min) ^ 5% (6.01 min) ^ 5% (8 min)

[00919] Flow rate: 0.5 ml / min

[00920] Column temperature: 60 °C

[00921] Wavelength detection: 210 nm (PDA)

[00922] The qNMR measurement method was performed by dissolving a residue containing a target compound and an internal standard substance in CDCl3 or DMSO-d6 and subjecting it to the following analysis conditions. The yield was calculated using the following expression, using the target compound content value in the residue calculated by qNMR or HPLC. Expression 1

[00923] yield (%) = weight of residue (g) x theoretical yield (%) x 100

[00924] Measuring device: Bruker Avance III 400

[00925] Internal standard substance: 3,5-bis(trifluoromethyl)benzoic acid

[00926] Measurement conditions (19F-NMR): CDCl3 or DMSO-d6, 24.8 °C, pulse angle 90°, digital resolution of 0.24 Hz, relay time Petition 870250088014, dated 09 / 29 / 2025, pp. 152 / 299 146 / 238 15-second locking, without rotation, cumulative number of 64 times

[00927] Measuring device: JEOL JNM-ECZ500R / S1

[00928] Measurement conditions (1H-NMR): methanol-d4, 25.3 °C, pulse angle 45°, digital resolution 0.76 Hz, relaxation time 5 seconds, with rotation, cumulative number 8 times

[00929] The LCMS, LC and HPLC measurement methods were performed by preparing a mixed solution containing a target compound as a sample, according to any of the following methods and subjecting it to the analysis conditions described above.

[00930] Sample preparation method 1: a mixed solution containing a target compound was diluted with acetonitrile.

[00931] Sample preparation method 2: a mixed solution containing a target compound was diluted with a mixed solution of acetonitrile and water in a 9:1 ratio.

[00932] Sample preparation method K: a mixed solution containing a target compound was diluted with a mixed solution of acetonitrile and n-propylamine in a ratio of 100:1.

[00933] The reaction conversion rate was calculated by any of the following expressions using the area value of the raw material and the area value of the target material, or the area value of the raw material, the area value of the raw material and the area value of the target material, or the area value of the raw material before the reaction and the area value of the raw material after the reaction calculated by HPLC analysis.

[00934] Expression 1: reaction conversion rate (%) = target material area value / (raw material area value + target material area value) χ 100

[00935] Expression 2: reaction conversion rate (%) = 100 - (value of the area of ​​the raw material after the reaction / value of the area of ​​the raw material before the reaction χ 100)

[00936] The cyclization selectivity (compound 1 / cyclic dimer) was Petition 870250088014, dated 09 / 29 / 2025, pp. 153 / 299 147 / 238 calculated using the following expressions, employing the target material area value and the cyclic dimer area value calculated by HPLC analysis.

[00937] Expression 1: ratio of compound 1 (%) = area value of compound 1 / (area value of compound 1 + area value of cyclic dimer) x 100

[00938] Expression 2: cyclic dimer ratio (%) = cyclic dimer area value / (area value of compound 1 + cyclic dimer area value) x 100 Example 1-1 Synthesis of compound 2: 9H-fluoren-9-ylmethyl (4S)-5-oxo-4-[[4-(trifluoromethyl)phenyl]methyl]oxazolidine-3-carboxylate Formula 44

[00939] To a reaction vessel after nitrogen replacement, DCM (45 L) and (2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-[4(trifluoromethyl)phenyl]propionic acid (3.05 kg) was added at room temperature and the mixture was stirred. Subsequently, paraformaldehyde (0.90 kg) and MgSO4 (2.02 kg) were added, and the mixture was stirred at 20 °C for 10 minutes. The external temperature of the reaction vessel was cooled to 15 °C, and BF3Et2 (0.95 kg) was added slowly dropwise at an internal temperature of 15 to 20 °C. The reaction mixture was stirred at 20–25 °C for 12 hours, then filtered through a silica gel-lined filter (3.05 kg) and washed with DCM (15.3 L x 2). The filtrate was concentrated under reduced pressure at an external temperature of 30 °C, and the crude product containing compound 2 was purified in a column (petroleum ether / ethyl acetate = 4 / 1) and concentrated under reduced pressure to obtain compound 2 (2.76 kg). Petition 870250088014, dated 09 / 29 / 2025, pp. 154 / 299 148 / 238 Example 1-2 Synthesis of compound 3: (2S)-2-[but-3-enyl(9H-fluoren-9-ylmethoxycarbonyl)amino]-3-[4-(trifluoromethyl)phenyl]propionic acid Formula 45

[00940] To a reaction vessel after nitrogen replacement, toluene (22.4 L) and compound 2 (2.80 kg) were added at room temperature, and the mixture was stirred. Subsequently, allyltrimethylsilane (1.37 kg) and ZnBr2 (1.35 kg) were added, and the mixture was stirred at 20 °C for 10 minutes. The internal temperature of the reaction vessel was heated to 40–45 °C, and the reaction mixture was stirred for 10 hours. The reaction mixture was added to ice water (28.0 L) at an internal temperature of 10 ± 5 °C and stirred. The aqueous layer was discharged, and the organic layer was washed with 5% saline solution (28.0 L). The resulting organic layer was concentrated under reduced pressure at an external temperature of 45–50 °C to obtain compound 3 (2.44 kg). Example 1-3 Synthesis of compound 4: tert-butyl 2-[[[(2S)-2-[but-3-enyl(9H-fluoren-9-ylmethoxycarbonyl)amino]-3-[4-(trifluoromethyl)phenyl]propanoyl]-methyl-amino]acetate Formula 46

[00941] To a reaction vessel after the nitrogen was replaced, N-methyl-2-pyrrolidone (17.0 L) and compound 3 (2.44 kg) were added at room temperature, and the mixture was stirred. Subsequently, Petition 870250088014, dated 09 / 29 / 2025, pp. 155 / 299 149 / 238 sarcosine tert-butyl ester hydrochloride (0.87 kg) and HATU (2.18 kg) were added at 20 °C, and the mixture was stirred for 30 minutes. DIPEA (1.85 kg) was added dropwise over 60 minutes at an internal temperature of 15 to 20 °C. The reaction mixture was stirred at 20 to 25 °C for 3 hours and then diluted with methyl tert-butyl ether (48.8 L). The organic layer was washed with water (48.8 L χ 2) and 5% saline solution (24.4 L), and then concentrated under reduced pressure to obtain a crude product containing compound 4. The resulting crude product was subjected to column purification (petroleum ether / ethyl acetate = 4 / 1) and concentrated under reduced pressure at 35 °C to obtain compound 4 (2.79 kg) as a dark yellow oil. Example 1-4 Synthesis of compound 5: 2-[[(2S)-2-(but-3-enylamino)-3-[4-(trifluoromethyl)phenyl]propanoyl]-methylamino] tert-butyl acetate Formula 47

[00942] To a reaction vessel after nitrogen replacement, toluene (28.0 L) and compound 4 (2.79 kg) were added at room temperature, and the mixture was stirred. Subsequently, DBU (0.67 kg) was added at an internal temperature of 20 °C, and the mixture was stirred for 2 hours. The reaction mixture was added to ice water (27.9 L) at an internal temperature of 20 ± 5 °C and stirred. After stirring with the addition of ethyl acetate (14.0 L), the aqueous layer was discharged. The organic layer was washed with 5% saline solution (28.0 L) and concentrated under reduced pressure at 45 ± 5 °C. The crude product containing compound 5 was subjected to column purification (petroleum ether / ethyl acetate = 4 / 1) and then concentrated Petition 870250088014, dated 09 / 29 / 2025, pp. 156 / 299 150 / 238 auger under reduced pressure to obtain compound 5 (1.49 kg) as a light yellow oil. Example 1-5 Synthesis of compound 6: N-[(1S)-1-chlorocarbonylbut-3-enyl]-N-methyl-carbamate 9H-fluoren-9-ylmethyl Formula 48 Fmoc' (COCI)2

[00943] To a reaction vessel after nitrogen replacement, DCM (10 L), (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]pent-4-enoic acid (1.7 kg) and DMF (0.02 kg) were added at an internal temperature of 20 °C, and the mixture was stirred. Oxalyl chloride (1.84 kg) was added at an internal temperature of 10 °C for 2 hours, and the mixture was stirred for 2 hours maintaining the internal temperature at 10 °C. The resulting solution was concentrated under reduced pressure from 30 to 35 °C. The addition of DCM (3.4 L) to the concentrated product and concentration under reduced pressure were carried out twice to obtain compound 6 (1.65 kg) as a yellow oil. Example 1-6 Synthesis of compound 7: tert-butyl 2-[[[(2S)-2-[but-3-enyl-[(2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]pent-4-enoyl]amino]-3-[4-(trifluoromethyl)phenyl]propanoyl]-methyl-amino]acetate Formula 49

[00944] To a reaction vessel after the replacement of nitrogen, DCM (15.0 L) and compound 5 (1.49 kg) were added at temperature Petition 870250088014, dated 09 / 29 / 2025, pp. 157 / 299 151 / 238 ambient temperature, and the mixture was stirred. Subsequently, compound 6 (1.72 kg) dissolved in DCM (2.96 L) was added dropwise over 1 hour at an internal temperature of 0 to 10 °C. The mixture was stirred at an internal temperature of 10 °C for 30 minutes, followed by the dropwise addition of DIPEA (0.926 kg) at an internal temperature of 0 to 10 °C for 1 hour. After stirring at 20 °C for 2 hours, the reaction solution was added to ice-cold water (14.8 L) at an internal temperature of 20 °C and stirred. An organic layer 1 was separated by liquid-liquid separation. The aqueous layer was extracted with DCM (7.4 L), which was combined with the organic layer 1 that had been separated. The combined organic layer was washed with 5% saline solution (14.9 L x 2) and the organic layer was concentrated under reduced pressure at 30 ± 5 °C.The concentrated product containing compound 7 was purified by column filtration (petroleum ether / ethyl acetate = 5 / 1) and concentrated under reduced pressure to obtain compound 7 (1.97 kg) as a colorless powder. Example 1-7 Synthesis of compound 8: tert-butyl 2-[[[(2S)-2-[(4Z,7S)-7-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-8-oxo-2,3,6,7-tetrahydroazocin-1-yl]-3-[4-(trifluoromethyl)phenyl]propanoyl]-methyl-amino]acetate Formula 50

[00945] To a reaction vessel after the nitrogen was replaced, toluene (59.0 L) and compound 7 (0.655 kg) were added at room temperature, and the mixture was stirred. Subsequently, p-benzoquinone (28.4 g) was added and the internal temperature was increased to 100 °C. For the mixed solution that was heated to a temperature Petition 870250088014, dated 09 / 29 / 2025, pp. 158 / 299 152 / 238 internal temperature of 100 °C, a solution of first-generation HOVEYDA-GRUBBS catalyst (42.0 g) in toluene (100 ml) was added dropwise over 20 minutes. The reaction described above was repeated in three batches. The resulting solutions from the three batches were mixed and concentrated under reduced pressure at 45 °C, and the crude product containing compound 8 was purified by column filtration (petroleum ether / ethyl acetate = 4 / 1) and concentrated under reduced pressure to obtain compound 8 (1.05 kg) as a yellow oil. Example 1-8 Synthesis of compound 9: tert-butyl 2-[methyl-[(2S)-2-[(4Z,7S)-7-(methylamino)-8-oxo2,3,6,7-tetrahydroazocin-1-yl]-3-[4-(trifluoromethyl)phenyl]propanoyl]amino]acetate Formula 51

[00946] To a reaction vessel after nitrogen replacement, toluene (11.0 L) and compound 8 (1.05 kg) were added at room temperature, and the mixture was stirred. Subsequently, DBU (223 g) was added to the mixed solution at 10 °C, and the mixture was stirred at an internal temperature of 20 °C for 2 hours. The resulting solution was added to ice water (11.0 L) at 10 ± 5 °C and stirred. The mixture was extracted with ethyl acetate (5.25 L). The organic layer was washed with 5% saline solution (5.25 L), and the organic layer was concentrated under reduced pressure at 40 °C to approximately 1.1 L. Toluene (9.5 L) and a 1 M aqueous solution of potassium dihydrogen phosphate (6.3 L) were added to the concentrated solution, and the mixture was stirred at 20 °C for 3 hours. The resulting solution was filtered and the filtered product was washed with Petition 870250088014, dated 09 / 29 / 2025, pp. 159 / 299 153 / 238 toluene / n-heptane = 1 / 1 (11.0 L). Ethanol (31.5 L) was added to the resulting filtered product and heated to 40 °C to dissolve it. D(-)tartaric acid (215 g) was added and the mixture was stirred at 20 °C for 3 hours to obtain a precipitate. The resulting precipitate was filtered and washed with n-heptane (3.15 L χ2). The washed precipitate was transferred to a reaction vessel, to which a 1M aqueous solution of tripotassium phosphate was added, and the pH was adjusted to 7-8. The mixture was extracted with DCM (10.5 L). The organic layer was washed with 5% saline solution (5.25 L) and the resulting solution was concentrated under reduced pressure at 40 °C to approximately 0.5 L. n-Heptane (10.5 L) was added to the concentrated solution to obtain a precipitate. The resulting precipitate was filtered and washed with n-heptane (3.15 L). The resulting residue was dried under reduced pressure to obtain compound 9 (449 g), which is a colorless solid.

[00947] LCMS (ESI) of compound 9: retention time: 1.24 minutes, m / z = 498 [M+H]+(LCMS analysis conditions method 1) Example 1-9 Synthesis of compound 10: (2S)-1-[(2S,3S)-2-(benzyloxycarbonylamino)-3-methylpentanoyl]pyrrolidine-2-carboxylate tert-butyl Formula 52 n CH3

[00948] To a reaction vessel after the replacement of the nitrogen, (2S)-pyrrolidine-2-carboxylate tert-butyl (18.8 g), (2S,3S)-2-(benzyloxycarbonylamino)-3-methylpentanoic acid (20.0 g) and DMF (140 ml) were added at room temperature, and the mixture was stirred. The resulting solution was cooled to 0 °C and DIPEA (52.7 ml) was added. Petition 870250088014, dated 09 / 29 / 2025, pp. 160 / 299 154 / 238 dos. A propylphosphonic anhydride solution, 50% by weight in ethyl acetate (58.3 ml) was added to the mixed solution at 0 °C for 20 minutes, and the mixture was stirred at 0 °C for 1.5 hours. Water (100 ml) and ethyl acetate (200 ml) were added to the mixture, in that order. An aqueous layer 1 and an organic layer 2 were separated by liquid-liquid separation, and the aqueous layer 1 was disassembled. The organic layer 1 was washed with a 5% aqueous solution of potassium sulfate (100 ml), a 5% aqueous solution of sodium carbonate (100 ml), and a 10% saline solution (100 ml). To the disassembled aqueous layer 1, water (100 ml) and ethyl acetate (200 ml) were added, and after stirring, the organic layer 2 was obtained by liquid-liquid separation. Organic layer 1 and organic layer 2 were combined and concentrated under reduced pressure to obtain compound 10 (33.8 g).

[00949] LCMS (ESI) of compound 10: retention time: 2.75 minutes, m / z = 419 [M+H]+(LCMS analysis conditions method 2) Example 1-10. Synthesis of compound 11: (2S)-1-[(2S,3S)-2-amino-3-methyl-pentanoyl]pyrrolidine-2-carboxylate tert-butyl Formula 53 ch3ch3

[00950] For a reaction vessel after nitrogen substitution, a solution of compound 10 (31.6 g) obtained in Example 1-9 in 2-MeTHF (221 ml) was cooled to 10 °C. To this solution, 5% Pd / C (6.32 g, 50% aqueous content) was added, followed by triethylsilane (60.3 ml) over 20 minutes. The resulting mixture was stirred at an internal temperature of 15 °C for 6 hours and then further stirred at room temperature for 17 hours. The mixed solution Petition 870250088014, dated 09 / 29 / 2025, pp. 161 / 299 155 / 238 was filtered and the filtrate was concentrated under reduced pressure to obtain compound 11. Compound 11 was used in Example 1-11 without further purification.

[00951] LCMS (ESI) of compound 11: retention time: 1.14 minutes, m / z = 285 [M+H]+(LCMS analysis conditions method 2) Example 1-11 Synthesis of compound 12: (2S)-1-[(2S,3S)-2-[[(2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]pentanoyl]amino]-3-methyl-pentanoyl]pyrrolidine2-carboxylate tert-butyl Formula 54

[00952] To a solution of compound 11 obtained in Example 1-10 in acetonitrile (221 ml) was added (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]pentanoic acid (28.0 g) and DIPEA (39.6 ml) in that order at 5 °C. HATU (34.5 g) was slowly added to the mixture at 2.5 °C, and the resulting solution was stirred at 2.5 °C for 1 hour and then stirred at room temperature for 2.5 hours. A 5% aqueous sodium carbonate solution (189 ml) and water (150 ml) were added to the mixture in that order. The resulting solution was extracted with toluene (80 ml) and 2-MeTHF (140 ml). The organic layer was washed with a 5% aqueous solution of potassium sulfate (190 ml x 2) and a 10% saline solution (190 ml x 2). The resulting organic layer was concentrated under reduced pressure to obtain compound 12. Compound 12 was used in Example 1-12 without further purification.

[00953] LCMS (ESI) of compound 12: retention time: 3.43 min Petition 870250088014, dated 09 / 29 / 2025, pp. 162 / 299 156 / 238 tos, m / z = 620 [M+H]+(LCMS analysis conditions method 2) Example 1-12 Synthesis of compound 13: (2S)-1-[(2S,3S)-3-methyl-2-[[(2S)-2-(methylamino)pentanoyl]amino]pentanoyl]pyrrolidine-2-tert-butyl acetate Formula 55

[00954] After the nitrogen was replaced, compound 12 (296 mg) synthesized by the same method as in Example 1-11 and toluene (2.07 ml) were added to the reaction vessel, and the mixture was stirred. DBU (0.072 ml) was added to the mixed solution and the mixture was stirred for 30 minutes. Acetonitrile (1.00 ml) was added to the mixed solution and the mixture was then stirred for 30 minutes. DBU (0.072 ml) was added and the mixture was further stirred for 30 minutes. After the addition of 1N hydrochloric acid (2.00 ml) and n-heptane (1.00 ml), an aqueous layer 1 and an organic layer 1 were separated. Organic layer 1 was extracted with 1N hydrochloric acid (1.00 ml) to obtain an aqueous layer 2 containing compound 13. Aqueous layer 1 and aqueous layer 2 were combined, extracted with a 5% aqueous solution of potassium carbonate (2.00 ml) and toluene (4.00 ml), and the organic layer containing compound 13 was separated.The resulting organic layer was washed with 10% saline solution (2.00 ml) and then concentrated under reduced pressure to obtain compound 13 (166 mg).

[00955] LCMS (ESI) of compound 13: retention time: 1.36 minutes, m / z = 398 [M+H]+(LCMS analysis conditions method 2) Petition 870250088014, dated 09 / 29 / 2025, pp. 163 / 299 157 / 238 Example 1-13 Synthesis of the 14-resin compound Compound 14: (3S)-4-(dimethylamino)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxobutyric acid Formula 56

[00956] A reaction vessel with a filter (1 L) was loaded with 2-chlorotritile chloride resin (1.12 mmol / g, 70 g, 78.4 mmol) and DCM (560 ml), and the mixture was left at room temperature for 30 minutes. After filtration of the DCM under reduced pressure, a solution of (3S)-4-(dimethylamino)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxybutanoic acid (23.4 g, 56.0 mmol) in DCM (140 ml) was added, and another DCM (140 ml) was used for washing. DIPEA (27.4 ml) was added to the reaction vessel and, after stirring for 45 minutes, DCM (140 ml) was added and the mixture was stirred at room temperature for 105 minutes. The reaction solution was filtered under reduced pressure and then washed with DCM (280 ml χ 2). A solution of methanol (28.0 ml) and DIPEA (14.0 ml) in DMF (238 ml) was added to the reaction vessel and the mixture was stirred at room temperature for 120 minutes.After filtering the reaction solution under reduced pressure, IPA (280 ml) was added and the mixture was stirred. After 15 minutes, the reaction solution was filtered under reduced pressure, DMF (280 ml) was added, and the mixture was stirred for 15 minutes. After filtering the reaction solution under reduced pressure, the entire quantity of 14-resin compound, excluding the portion for measuring the amount of support, was used to proceed to Example 1-14. Petition 870250088014, dated 09 / 29 / 2025, pp. 164 / 299 158 / 238

[00957] The amount of amino acid support in the resin was calculated as follows. The obtained 14-resin compound (4.76 mg) was placed in a reaction vessel, a 20% Pip / DMF solution (50 ml) was added, and the mixture was stirred at room temperature for 1 hour. The absorbance of the solution (301 nm) was measured (using Shimadzu, UV-1600 PC (cell length: 1.0 cm)), and the amount of support in the 14-resin compound was calculated to be 0.632 mmol / g. Example 1-14 Synthesis of the 15-resin compound Compound 15: (3S)-3-[[(2S)-2-cyclopentyl-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butyric acid Formula 57 Me O NA FMOC Resin OH Resin fmoc^.AN Me Me %e

[00958] A reaction vessel with a filter (1 L) was loaded with 14-resin compound (0.632 mmol / g), to which a 20% Pip / DMF solution (280 ml) was added, and the mixture was stirred at room temperature for 10 minutes to carry out the de-Fmoc reaction. The reaction solution was filtered under reduced pressure, a 20% Pip / DMF solution (280 ml) was added again, and the mixture was stirred at room temperature for 10 minutes to carry out the de-Fmoc reaction. The reaction mixture was filtered under reduced pressure, and the resin was washed 10 times with DMF (280 ml). The condensation reaction of Fmoc-MeGly(cPent)-OH (Cas No. 187475-29-2) was carried out on the resulting resin. The condensation reaction was carried out by adding a solution of Fmoc-MeGly(cPent)-OH (Cas No. 187475-29-2, 42.5 g), oxime (7.96 g) and DIC (34.9 ml) in DMF (280 ml) to the resin, stirring the mixture for 5 Petition 870250088014, dated 09 / 29 / 2025, pp. 165 / 299 159 / 238 minutes and left to stand at room temperature for 16 hours. The condensation reaction solution was filtered under reduced pressure, IPA (280 ml) was added, and the mixture was stirred. After 10 minutes, the reaction solution was filtered under reduced pressure, DMF (280 ml) was added, and the mixture was stirred for 10 minutes. After filtering the reaction solution under reduced pressure, the entire quantity of compound 15-resin, excluding the portion for measuring the amount of support, was used to proceed to Example 1-15.

[00959] The amount of amino acid support in the resin was calculated as follows. The obtained 15-resin compound (4.91 mg) was placed in a reaction vessel, a 20% Pip / DMF solution (50 ml) was added, and the mixture was stirred at room temperature for 1 hour. The absorbance of the solution (301 nm) was measured (using Shimadzu, UV-1600 PC (cell length: 1.0 cm)), and the amount of support in the 15-resin compound was calculated to be 0.635 mmol / g.

[00960] Using a small amount of compound 15 supported on the resin, the compound was cut from the resin with TFE / DCM (1 / 1), and the structure was confirmed by LC / MS.

[00961] LCMS (ESI) of compound 15: retention time: 2.53 minutes, m / z = 536 [M+H]+(LCMS analysis conditions method 2) Example 1-15 Synthesis of the 16-resin compound Compound 16: (3S)-3-[[(2S)-2-cyclopentyl-2-[[1-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]cyclobutanecarbonyl]-methylamino]acetyl]-methylamino]-4-(dimethylamino)-4-oxo-butyric acid Formula 58 Q, Resin Petition 870250088014, dated 09 / 29 / 2025, pp. 166 / 299 160 / 238

[00962] A reaction vessel with a filter (1 L) was loaded with 15-resin compound (0.635 mmol / g), to which a 20% Pip / DMF solution (280 ml) was added, and the mixture was stirred at room temperature for 5 minutes to carry out the de-Fmoc reaction. After filtering the reaction solution under reduced pressure, a 20% Pip / DMF solution (280 ml) was added again, and the mixture was stirred at room temperature for 5 minutes to carry out the deFmoc reaction. The reaction solution was filtered under reduced pressure and the resin was then washed 10 times with DMF (280 ml). The Fmoc-MecVal-OH condensation reaction (Cas No. 1700368-07-5) was carried out on the resulting resin. The condensation reaction was carried out by adding a solution of Fmoc-MecVal-OH (Cas No. 1700368-07-5, 39.4 g) and oxime (7.96 g) to DMF (280 ml), then adding DIC (34.9 ml), stirring the mixture for 5 minutes and letting it stand for 94 hours.After filtration of the condensation reaction solution under reduced pressure, the resin was washed with each of the following: DMF (280 ml), IPA (280 ml), and DMF (280 ml). After filtration of the washing solution under reduced pressure, the entire quantity of the resulting 16-resin compound, excluding the portion for measuring the amount of support, was used to proceed to Example 1-17.

[00963] The amount of amino acid support in the resin was calculated as follows. The obtained 16-resin compound (5.24 mg) was placed in a reaction vessel, a 20% Pip / DMF solution (50 ml) was added, and the mixture was stirred at room temperature for 1 hour. The absorbance of the solution (301 nm) was measured (using Shimadzu, UV-1600 PC (cell length: 1.0 cm)), and the amount of support in the 16-resin compound was calculated to be 0.513 mmol / g.

[00964] Using a small amount of compound 16 supported on the resin, the compound was cut from the resin with TFE / DCM. Petition 870250088014, dated 09 / 29 / 2025, pp. 167 / 299 161 / 238 (1 / 1), and the structure was confirmed by LC / MS.

[00965] LCMS (ESI) of compound 16: retention time: 2.75 minutes, m / z = 647 [M+H]+ (LCMS analytical conditions method 2) Example 1-16 Synthesis of compound 17: (2S,4R)-2-chlorocarbonyl-4-ethoxypyrrolidine-1-carboxylate of 9H-fluoren-9-ylmethyl Formula 59 EtO SOCI2

[00966] To a reaction vessel after nitrogen substitution, (2S,4R)-4-ethoxy-1-(9H-fluoren-9-ylmethoxycarbonyl)pyrrolidine-2-carboxylic acid (Cas No. 1446478-31-4, 42.7 g), toluene (128 ml) and thionyl chloride (12.3 ml) were added sequentially at room temperature. After stirring at an external temperature of 60 °C for 0.5 hours, the mixture was stirred at an external temperature of 55 °C for 3 hours. Part of the reaction mixture was collected and diluted in MeOH, left to stand for 5 minutes to be converted to the corresponding compound 18, and the conversion rate of the reaction to compound 17 was then confirmed to be 99.9% by HPLC analysis (calculation expression 1 for the reaction conversion rate). The external temperature of the reaction vessel was adjusted to 40 °C, and the reaction solution was concentrated under reduced pressure.After concentration under reduced pressure, the DCM addition (214 ml) and reduced pressure concentration operation was repeated twice. The resulting concentrated solution was dried under reduced pressure overnight to obtain a crude product containing compound 17 (45.5 g, 95% yield). Petition 870250088014, dated 09 / 29 / 2025, pp. 168 / 299 162 / 238 Compound 18: O2-methyl (2S,4R)-4-ethoxypyrrolidine-1,2-dicarboxylate of O1-(9H-fluoren-9-ylmethyl) Formula 60 Eto MeOH

[00967] LCMS (ESI) of compound 18: retention time: 2.68 minutes, m / z = 396 [M+H]+ (LCMS analytical conditions method 2) Example 1-17 Synthesis of compound 19-resin Compound 19: (3S)-3-[[(2S)-2-cyclopentyl-2-[[1-[[(2S,4R)-4-ethoxy-1(9H-fluoren-9-ylmethoxycarbonyl)pyrrolidine-2-carbonyl]-methyl-amino]cyclobutanecarbonyl]-methyl-amino]acetyl]-methyl-amino]-4-(dimethylamino)-4oxo-butyric acid Formula 61 O' Resin Resin

[00968] A reaction vessel with a filter (1 L) was loaded with 16-resin compound (0.513 mmol / g), and swelling with DMF (280 ml) for 15 minutes and discharge of the solution was performed twice. To the swollen resin, a 20% Pip / DMF solution (280 ml) was added, and the mixture was stirred at room temperature for 15 minutes to carry out the de-Fmoc reaction. After filtering the reaction solution under reduced pressure, a 20% Pip / DMF solution (280 ml) was added again, and the mixture was stirred at room temperature for 15 minutes to carry out the de-Fmoc reaction. The reaction solution was Petition 870250088014, dated 09 / 29 / 2025, pp. 169 / 299 163 / 238 filtered under reduced pressure and the resin was then washed 13 times with DCM (280 ml). The condensation reaction of compound 17 was carried out on the resulting resin. The condensation reaction was carried out by sequentially adding a DCM solution (280 ml) of compound 17 (46.0 g) obtained in Example 1-16 and colidine (74.0 ml), stirring the mixture for 5 minutes and letting it stand at room temperature for 4 hours. After filtering the condensation reaction solution under reduced pressure, the resin was washed with DCM (280 ml), and the entire quantity of the resulting compound 19-resin, excluding the portion for measuring the amount of support, was used to proceed to Example 1-18.

[00969] The amount of amino acid support in the resin was calculated as follows. The obtained 17-resin compound (7.27 mg) was placed in a reaction vessel, a 20% Pip / DMF solution (50 ml) was added, and the mixture was stirred at room temperature for 1 hour. The absorbance of the solution (301 nm) was measured (using Shimadzu, UV-1600 PC (cell length: 1.0 cm)), and the amount of support in the 19-resin compound was calculated to be 0.473 mmol / g.

[00970] Using a small amount of compound 19 supported on the resin, the compound was cut from the resin with TFE / DCM (1 / 1), and the structure was confirmed by LC / MS.

[00971] LCMS (ESI) of compound 17: retention time: 2.68 minutes, m / z = 788 [M+H]+(LCMS analysis conditions method 2) Example 1-18 Synthesis of the 20-resin compound Compound 20: (3S)-3-[[(2S)-2-[[1-[[(2S,4R)-1-[(2S)-2-(benzyloxycarbonylamino)-4-[3-methoxy-4-(trifluoromethyl)phenyl]butanoyl]-4-ethoxy-pyrrolide acid ina-2-carbonyl]-methyl-amino]cyclobutanecarbonyl]-methyl-amino]-2-cyclopentyl-acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butyric acid Petition 870250088014, dated 09 / 29 / 2025, pp. 170 / 299 164 / 238 Formula 62 Resin OMe Resin

[00972] A reaction vessel with a filter (1 L) was loaded with 19-resin compound (0.473 mmol / g), and swelling with DMF (280 ml) for 15 minutes and discharge of the solution was performed twice. To the swollen resin, a 20% Pip / DMF solution (280 ml) was added, and the mixture was stirred at room temperature for 15 minutes to carry out the de-Fmoc reaction. After filtering the reaction solution under reduced pressure, a 20% Pip / DMF solution (280 ml) was added again, and the mixture was stirred at room temperature for 15 minutes to carry out the de-Fmoc reaction. The reaction solution was filtered under reduced pressure and the resin was then washed 13 times with DMF (280 ml). The Cbz-Hph(4-CF3-3OMe)-OH condensation reaction was carried out on the resulting resin.The condensation reaction was carried out by adding a solution of Cbz-Hph(4-CF3-3-OMe)-OH (46.1 g) and oxime (7.96 g) in DMF (280 ml) and DIC (34.9 ml) to the resin, stirring the mixture for 5 minutes and then letting it stand for 3.5 hours. The condensation reaction solution was filtered under reduced pressure and the resin was then washed twice with DMF (280 ml). IPA (280 ml) was added and then the mixture was stirred for 15 minutes. After the solution was discharged, DCM (280 ml) was added and the mixture was stirred for 15 minutes. Washing with IPA (280 ml) and DCM (280 ml) and the solution was discharged again. After washing with IPA (280 ml χ 3), the resin was dried under reduced pressure. After drying under reduced pressure, the resulting compound... Petition 870250088014, dated 09 / 29 / 2025, pp. 171 / 299 165 / 238 tant 20-resin was 122 g.

[00973] Using a small amount of compound 20 supported on the resin, the compound was cut from the resin with TFE / DCM (1 / 1), and the structure was confirmed by LC / MS.

[00974] LCMS (ESI) of compound 20: retention time: 2.91 minutes, m / z = 960 [M+H]+(LCMS analysis conditions method 2) Example 1-19 Synthesis of compound 20 Formula 63 Resin Cbz^H °' Cbz~NH°H\ ^P λ zs. .. λ ___\ o — o Z\ Me OSO Me qi Me,eN, Me Me Mealy Me / X Me Me

[00975] To a reaction vessel after nitrogen replacement, compound 20-resin (60.0 g) obtained by the same method as compound 20-resin (122 g) obtained in Example 1-18 and 2-MeTHF (1.10 L) were added sequentially at room temperature. The external temperature of the reaction vessel was adjusted to 0 °C, and hexamethyldisilazane (77.3 mL) was added. After stirring for 20 minutes, trimethylsilyl trifluoromethanesulfonate (50.0 mL) was added so that the internal temperature did not exceed 7 °C. 20 minutes after the addition was complete, the reaction mixture was filtered under reduced pressure and the residue was washed with 2-MeTHF (364 mL χ 3). The filtrate was washed with a 5% aqueous solution of disodium hydrogen phosphate (1.10 L), a 5% aqueous solution of potassium bicarbonate (1.10 L), and a 5% aqueous solution of sodium chloride (1.10 L). The resulting organic layer was concentrated under reduced pressure to obtain 77.6 g of crude product.Part of the crude product obtained and 3,5-bis(trifluoromethyl)benzoic acid were dissolved in CDCh and subjected to qNMR analysis. After correction of the content, it was calculated that... Petition 870250088014, dated 09 / 29 / 2025, pp. 172 / 299 166 / 238 compound 20 was contained in 69.0 g.

[00976] LCMS (ESI) of compound 20: retention time: 3.90 minutes, m / z = 960 [M+H]+ (LCMS analytical conditions method 3) Example 1-20 Synthesis of compound 21: (2S)-1-[(2S,3S)-2-[[(2S)-2-[[(3S)-3-[[(2S)-2-[[1[[(2S,4R)-1-[(2S)-2-benzyloxycarbonylamino)-4-[3-methoxy-4-(trifluoromethyl)phenyl]butan tert-butyl oil]-4-ethoxy-pyrrolidine-2-carbonyl]-methyl-amino]cyclobutanecarbonyl]-methyl-amino]-2-cyclopentyl-acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butanoyl]-methyl-amino]pentanoyl]amino]-3-methyl-pentanoyl]pyrrolidine-2-carboxylate Formula 64

[00977] The crude product containing compound 20 (80.7 g) and compound 13 (45.8 g) was added to a reaction vessel. After nitrogen replacement, 2-MeTHF (484 ml), DIPEA (64.5 ml), and DMF (121 ml) were added at room temperature, and the mixture was stirred. HATU (48.0 g) was added to the resulting solution at room temperature. After 1 hour, the reaction mixture was collected for sample preparation (sample preparation method 2), and the reaction conversion rate was confirmed to be 98% or more by HPLC analysis (calculation expression 1 for the reaction conversion rate). The external temperature of the reaction vessel was adjusted to 5 °C, and a 2.5% aqueous ammonia solution (484 ml) was added to the reaction mixture. After discharge of the aqueous layer by a liquid separation operation, the organic layer was washed with a Petition 870250088014, dated 09 / 29 / 2025, pp. 173 / 299 167 / 238 a 10% aqueous solution of sodium bicarbonate (484 ml), a 5% aqueous solution of sodium carbonate (484 ml), and a 5% saline solution (484 ml) were used. The resulting organic layer was concentrated under reduced pressure with the external temperature set to 40 °C. To the resulting concentrated mixture, 2-MeTHF (161 ml χ2) was added, and concentration under reduced pressure was repeated to obtain 134 g of crude product. The yield of crude product was not calculated and was used in Example 1-21.

[00978] LCMS (ESI) of compound 21: retention time: 5.02 minutes, m / z = 1340 [M+H]+(LCMS analysis conditions method 3) Example 1-21 Synthesis of compound 22: Acid (2S)-1-[(2S,3S)-2-[[(2S)-2-[[(3S)-3-[[(2S) -2-[[1 -[[(2S,4R)-1-[(2S)-2-(benzyloxycarbonylamino)-4-[3-methoxy-4-(trifluoromethyl)phenyl]butanoyl]-4-ethoxy-pyrrolidine-2-carbonyl]-methyl-amino]cyclob utanocarbonyl]-methyl-amino]-2-cyclopentylacetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butanoyl]-methyl-amino]pentanoyl]amino]-3-methyl-pentanoyl] pyrrolidine-2-carboxylic acid Formula 65

[00979] To a reaction vessel after the replacement of nitrogen, a solution of the crude product containing compound 19 from Example 120 (111 g) in 2-MeTHF (666 ml) was added hexamethyldisilazane (69.5 ml) and then trimethylsilyl trifluoromethanesulfonate (44.9 ml) in this order, so that the internal temperature did not exceed 15 °C. After the addition was complete, the external temperature was raised to 10 °C and the mixture was stirred for 1 hour and 20 minutes. The mixture of Petition 870250088014, dated 09 / 29 / 2025, pp. 174 / 299 A sample of reaction 168 / 238 was collected for sample preparation (sample preparation method 2), and the reaction conversion rate to compound 22 was confirmed to be 99% by HPLC analysis (calculation expression 1 for the reaction conversion rate). At an external temperature of 0 °C, a mixed solution of 5% aqueous sodium carbonate solution (555 ml) and 5% saline solution (333 ml) was added so that the internal temperature did not exceed 25 °C. After the addition was complete, the aqueous layer was discharged by a liquid separation operation. The resulting organic layer was washed with a 10% aqueous sodium bicarbonate solution (555 ml), a 5% aqueous sodium carbonate solution (555 ml), and a 5% saline solution (555 ml). The resulting organic layer was concentrated under reduced pressure at an external temperature of 40 °C.To the resulting concentrated product, 2-MeTHF (222 ml χ 2) was added and the concentration under reduced pressure was repeated to obtain 128 g of crude product. The crude product obtained and 3,5-bis(trifluoromethyl)benzoic acid were dissolved in CDCl3 and subjected to qNMR analysis, and as a result, compound 22 was calculated to be contained in 96.1 g.

[00980] LCMS (ESI) of compound 22: retention time: 4.24 minutes, m / z = 1283 [M+H]+(LCMS analysis conditions method 3) Example 1-22 Compound 23: 2-[[(2S)-2-[(4Z,7S)-7-[[(2S)-1-[(2S,3S)-2-[[(2S)-2-[[(3S)3-[[(2S)-2-[[1-[[(2S,4R)-1-[(2S)-2-(benzyloxycarbonylamino)-4-[3-methoxy4-(trifluoromethyl)phenyl]butanoyl]-4-ethoxypyrrolidine-2-carbonyl]methylamino] cyclobutanecarbonyl]-methyl-amino]-2-cyclopentyl-acetyl]-methyl-amino]-4(dimethylamino)-4-oxo-butanoyl]-methyl-amino]pentanoyl]amino]-3-methylpe ntanoyl]pyrrolidine-2-carbonyl]-methyl-amino]-8-oxo-2,3,6,7-tetra-hydroazocin-1-yl]-3-[4-(trifluoromethyl)phenyl]propanoyl]-methyl-amino]acetate tert z-butyl Petition 870250088014, dated 09 / 29 / 2025, page. 175 / 299 169 / 238 Formula 66

[00981] To a reaction vessel, the crude product containing compound 22 (94.0 g) from Example 1-21 and compound 9 (40.1 g) were added, and after nitrogen substitution, 2-MeTHF (564 ml) and DMF (141 ml) were added and the mixture was stirred at room temperature. DIPEA (56.2 ml) was added and the mixture was stirred at an outside temperature of 43 °C for 1 hour. After cooling to an outside temperature of 33 °C, HATU (41.8 g) was added to the resulting solution. After 1 hour, the mixture was cooled to room temperature and stirred for 6 hours. The reaction mixture was collected for sample preparation (sample preparation method 2), and the reaction conversion rate was confirmed to be 98% or more by HPLC analysis (calculation expression 1 for the reaction conversion rate). The solution was washed with a 2.8% aqueous ammonia solution (564 ml) at room temperature.The organic layer was washed with a 10% aqueous solution of sodium bicarbonate (564 ml), a 5% aqueous solution of sodium carbonate (564 ml), and a 5% saline solution (564 ml). The resulting solution was concentrated under reduced pressure at an external temperature of 40 °C to obtain 157 g of crude product. The crude product obtained, containing compound 23 and 3,5-bis(trifluoromethyl)benzoic acid, was dissolved in CDCl3 and subjected to qNMR analysis, and as a result, it was calculated that compound 23 was contained in 127.8 g (98.9% yield).

[00982] LCMS (ESI) of compound 23: retention time: 5.34 Petition 870250088014, dated 09 / 29 / 2025, pp. 176 / 299 170 / 238 minutes, m / z = 1763 [M+H]+(LCMS analysis conditions method 3) Example 1-23 Synthesis of compound 24: Acid 2-[[(2S)-2-[(4Z,7S)-7-[[(2S)-1-[(2S,3S)2-[[(2S)-2-[[(3S)-3-[[(2S)-2-[[1-[[(2S,4R)-1-[(2S)-2-amino-4-[3-methoxy-4(trifluoromethyl)phenyl]butanoyl]-4-ethoxy-pyrrolidine-2-carbonyl]-methyl-amino] cyclobutanecarbonyl]-methyl-amino]-2-cyclopentyl-acetyl]-methyl-amino]-4(dimethylamino)-4-oxo-butanoyl]-methyl-amino]pentanoyl]amino]-3-methylpe ntanoyl]pyrrolidine-2-carbonyl]-methyl-amino]-8-oxo-2,3,6,7-tetra-hydroazocin-1-yl]-3-[4-(trifluoromethyl)phenyl]propanoyl]-methyl-amino]acetic Formula 67

[00983] To a reaction vessel, the crude product containing compound 23 (90.8 g), L-cysteine ​​(6.3 g), and 2-MeTHF (363 ml) were added sequentially. After replenishing the nitrogen in the reaction vessel, the external temperature was adjusted to 20 °C. Hexamethyldisilazane (119 ml) was added with stirring. Subsequently, trimethylsilyl trifluoromethanesulfonate (93.5 ml) was added over 20 minutes. After 25 minutes, the mixture was heated to an internal temperature of 50 °C. After stirring for 8 hours at this temperature, the reaction mixture was cooled to room temperature and stored overnight. The mixture was heated to an internal temperature of 50 °C again, and the reaction solution was stirred at 50 °C for 4 hours. After cooling to an external temperature of 0 °C, a 5% aqueous solution of sodium carbonate (272 ml) was added slowly dropwise so that the internal temperature did not exceed 40 °C. Petition 870250088014, dated 09 / 29 / 2025, pp. 177 / 299 Subsequently, the aqueous layer containing compound 24 was separated by a liquid separation operation. To the separated aqueous layer, 2-MeTHF (727 ml), MeCN (182 ml), and 10% sodium sulfate (545 ml) were added, and a liquid separation operation was performed. After discharge of the aqueous layer, the organic layer was washed with a 5% aqueous solution of disodium hydrogen phosphate (545 ml χ2) and a 10% aqueous solution of sodium chloride (273 ml χ2). The resulting organic layer was concentrated under reduced pressure with the external temperature adjusted to 40 °C. To the resulting concentrated product, 2-MeTHF (182 ml χ2) was added, and concentration under reduced pressure was repeated to obtain 115 g of crude product. The crude product containing compound 24 and 3,5-bis(trifluoromethyl)benzoic acid was dissolved in DMSO-d6 and subjected to qNMR analysis, and as a result, it was calculated that compound 24 was contained in 68.2 g (yield of 83.9%).

[00984] LCMS (ESI) of compound 24: retention time: 4.37 minutes, m / z = 1572 [M+H]+(LCMS analysis conditions method 4)

[00985] The deprotection reaction of a Cbz group is generally carried out under catalytic hydrogen reduction conditions in the presence of a metallic catalyst, exemplified by palladium / carbon. However, when applying the conditions of the conventional catalytic hydrogen reduction method to the deprotection reaction of the Cbz group in compound 23, which has an olefin in the molecule, there is a problem that the olefin in the molecule is reduced. To solve this problem, the present inventors have found a method by which the deprotection of the Cbz group can be achieved without reducing the intramolecular olefin under the conditions described in Example 1-23, i.e., TMSOTf / HMDS conditions. Example 1-24-1 Synthesis of compound 1: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S, Petition 870250088014, dated 09 / 29 / 2025, pp. 178 / 299 172 / 238 42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaoxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.04,8.026,30]pentatetracont-42-ene-23,1'-cyclobutane]-17-carboxamide (cyclization position B) Formula 68

[00986] In a reaction vessel after nitrogen replacement, a solution of COMU (65.0 g) in acetonitrile (1.9 L) was cooled to 0 °C. To the resulting solution, a solution of compound 24 (62.7 g) and lutidine (21.3 mL) in acetonitrile (0.941 L) was slowly added dropwise (4.4 mL / min). Immediately after the addition was complete, the reaction mixture was collected for sample preparation (sample preparation method 2), and it was confirmed that the reaction conversion rate was 99% (calculation expression 1 for the reaction conversion rate) and compound 1 / cyclic dimer = 98 / 2 (calculation expressions 1 and 2 for cyclization selectivity) by HPLC analysis. The external temperature of the reaction vessel was heated to 40 °C and the reaction solution was concentrated.The external temperature of the reaction vessel was cooled to 25 °C, and to the resulting concentrated product, isopropyl acetate (627 ml) and a 2.5% aqueous ammonia solution (627 ml) were added, and the mixture was stirred. After discharge of the aqueous layer by liquid-liquid separation, the resulting organic layer was washed with a 10% aqueous sodium bicarbonate solution. Petition 870250088014, dated 09 / 29 / 2025, pp. 179 / 299 173 / 238 (627 ml), a 5% aqueous solution of disodium hydrogen phosphate (627 ml x 2), and a 5% aqueous solution of sodium chloride (627 ml) were added. The resulting organic layer was washed with a 0.5% aqueous solution of sodium chloride (627 ml x 2). The external temperature was adjusted to 40 °C, and the resulting organic layer was concentrated under reduced pressure to obtain 92.23 g of a crude product containing compound 1. The crude product obtained containing compound 1 was used in Example 1-25. Cyclic dimer: Formula 69

[00987] LCMS (ESI) of compound 1: retention time: 6.07 minutes, m / z = 1555 [M+H]+ (LCMS analysis conditions method 4)

[00988] LCMS (ESI) of cyclic dimer: retention time: 7.63 minutes, m / z = 1555 [M+H]2+ (LCMS analysis conditions method 4)

[00989] HPLC of compound 1: retention time: 4.09 minutes (HPLC analysis conditions method 1)

[00990] Cyclic dimer HPLC: retention time: 4.91 minutes (HPLC analysis conditions method 1) Example 1-24-2 Synthesis of compound 1: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22, Petition 870250088014, dated 09 / 29 / 2025, pp. 180 / 299 174 / 238 25,31,34,37,45-undecaoxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.04'8.026'30]pentatetracont-42-ene-23,1'-cyclobutane]-17-carboxamide (cyclization position B) Formula 70

[00991] HATU (72.6 mg) and acetonitrile (1.80 ml) were added to a reaction vessel. A solution of the crude product containing compound 24 (100 mg) from Example 1-23 and DIPEA (40 pl) in acetonitrile (5.5 ml) was added dropwise over 5 hours and 42 minutes. Immediately after completion of the addition, the reaction mixture was collected for sample preparation (sample preparation method 2), and it was confirmed that the reaction conversion rate was 99% (calculation expression 1 for the reaction conversion rate) and compound 1 / cyclic dimer = 98 / 2 (calculation expressions 1 and 2 for cyclization selectivity) by HPLC analysis.

[00992] HPLC of compound 1: retention time: 3.99 minutes (method 1 of HPLC analysis conditions)

[00993] Cyclic dimer HPLC: retention time: 4.80 minutes (HPLC analysis conditions method 1) Example 1-25 Crystallization of compound 1: synthesis of the hydrate crystal (form A) of (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaxo Petition 870250088014, dated 09 / 29 / 2025, pp. 181 / 299 175 / 238 -13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30, 33,36,39-undecazatetracyclo[37.5.1.04'8.026'30]pentatetracont-42-ene23,1'-cyclobutane]-17-carboxamide

[00994] 24 g of the concentrated dry product containing compound 1 obtained in Example 1-24-1 were loaded into the Biotage Sfar C18 Duo 100 Â 30 pm 240 g, developed with 0.1% formic acid-water / 0.1% formic acid-acetonitrile = 90 / 10 ^ 18 / 82) and purified. To the resulting compound 1 (9.70 g), acetone (29.0 ml) and heptane (29.0 ml) were added at an external temperature of 35 °C. After confirmation of dissolution, a crystal of acetone / heptane / water solvate of compound 1 (form F) (about 1.00 mg), obtained by the same operation as in Example 3-8, was added to the reaction vessel and the mixture was stirred at 35 °C for 23 hours. The mixture was cooled to 25 °C and further stirred for 6 hours. Heptane (4.90 ml) was added over 1 hour and the mixture was stirred at 25 °C for 14 hours. Heptane (4.90 ml) was further added over 1 hour and the mixture was stirred for 3 hours. Finally, heptane (4.90 ml) was added over 2 hours and the mixture was stirred for 3 hours.The reaction mixture was filtered under reduced pressure and the resulting crystal was washed with a mixed solution of acetone (7.76 ml) and heptane (11.6 ml). The resulting crystal was dried for 16 hours with the external temperature set to 40 °C. The dried powder was collected to obtain a white powder (6.8 g, form A). Example 1-26 Synthesis of compound 1: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaoxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro [2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.04,8.026,30]pentatetracont-42-ene-23,1'-cyclobutane]-17-carboxamide (cyclization position A) Petition 870250088014, dated 09 / 29 / 2025, pp. 182 / 299 176 / 238 Formula 71

[00995] To a reaction vessel after nitrogen replacement, HATU (6.94 g) and acetonitrile (180 ml) were added. After confirmation of HATU dissolution, a solution containing compound 25 (9.56 g) and DIPEA (3.82 ml) in acetonitrile (540 ml) was added dropwise over 6 hours. Immediately after completion of the addition, 10 pl of the reaction mixture was collected and diluted in 0.1 ml of acetonitrile containing 2 pl of ethanolamine. LCMS analysis confirmed that compound 1 / cyclic dimer = 75 / 25 (calculation expressions 1 and 2 for cyclization selectivity).

[00996] LCMS (ESI) of compound 1: retention time: 0.78 minutes, m / z = 1553 [MH]-(LCMS analytical conditions method 5)

[00997] LCMS (ESI) of cyclic dimer: retention time: 0.94 minutes, m / z = 1553 [MH]2-(LCMS analytical conditions method 5)

[00998] Chemical name and structural formula of compound 25:

[00999] (3S)-3-[[(2S)-2-cyclopentyl-2[[1-[[(2S,4R)-4-ethoxy-1[(2S)-4-[3-methoxy-4-(trifluoromethyl)phenyl]-2-[ [2-[methyl-[(2S)-2-[(4Z,7S)-7[methyl-[(2S)-1-[(2S,3S)-3-methyl-2-[[(2S)-2-(methylamino)pentanoyl]amino] pentanoyl]pyrrolidine-2-carbonyl]amino]-8-oxo-2,3,6,7-tetrahydroazocin1-yl]-3-[4-(trifluoromethyl)phenyl]propanoyl]amino]acetyl]amin o]butanoyl]pyrrolidine-2-carbonyl]-methyl-amino]cyclobutanecarbonyl]-methyl-amino]acetyl]methyl-amino]-4-(dimethylamino)-4-oxo-butyric acid Petition 870250088014, dated 09 / 29 / 2025, pp. 183 / 299 177 / 238 Formula 72 Example 2-1 Compound 26: (S)-2-(but-3-en-1-ylamino)-3-(4-(trifluoromethyl)phenyl) propionic acid Formula 73 [001000] To a reaction vessel after nitrogen replacement, acetonitrile (822 ml), 4-bromo-1-butene (235.07 g), and triethylamine (17.66 g) were added at an external temperature of 25 °C, and the mixture was stirred for 1 hour. Subsequently, (S)-2-amino-3-(4-(trifluoromethyl)phenyl)propionic acid (135.46 g), water (676 ml), and triethylamine (158.19 g) were added, the external temperature was raised to 70 °C, and the mixture was stirred for 3.5 hours. Cooled to 25 °C, the precipitated solid was filtered through a Kiriyama funnel and washed with a mixture of acetonitrile and water (1:1.676 ml). Subsequently, the solid was further washed with acetonitrile (676 ml). The resulting wet powder was dried with the outside temperature set to 40 °C. The dry powder was collected to obtain a white solid (124.73 g). [001001] LCMS (ESI) of compound 26: retention time: 2.34 mi Petition 870250088014, dated 09 / 29 / 2025, pp. 184 / 299 178 / 238 nuts, m / z = 288 [M+H]+(LCMS P3-4 analysis conditions method) Example 2-2 Compound 27: (S)-N-(2-(but-3-en-1-ylamino)-3-(4-(trifluoromethyl)phenyl)propanoyl)-N-methylglycinate tert-butyl hydrochloride Formula 74 HCI [001002] To a reaction vessel after nitrogen replacement, (S)-2-(but-3-en-1-ylamino)-3-(4-(trifluoromethyl)phenyl)propionic acid (107.26 g), sarcosine tert-butyl ester hydrochloride (102.00 g), acetonitrile (751 ml) and diazabicycloundecene (233.03 g) were added at an outside temperature of 25 °C, and the mixture was stirred for 10 minutes. After confirming the homogeneity of the solution, the outside temperature was adjusted to 2 °C and a 50% solution of propanephosphonic acid anhydride in 2-methyltetrahydrofuran (309.03 g) was added dropwise over 2 hours and 14 minutes. After confirmation of the reaction's completion, toluene (751 ml) and a 1 N aqueous NaOH solution (536 ml) were added to the reaction mixture, which was stirred for 30 minutes, and the aqueous layer was discharged by liquid-liquid separation. The organic layer was stored at room temperature overnight.After storage, a 5% aqueous solution of sodium carbonate (536 ml) was added to the organic layer, which was stirred for 10 minutes, and the aqueous layer was then discharged by liquid-liquid separation. Subsequently, a 5% aqueous solution of sodium dihydrogen phosphate (751 ml) was added to the organic layer, which was stirred for 10 minutes, and the aqueous layer was then discharged by liquid-liquid separation. Furthermore, a 5% aqueous solution of sodium dihydrogen phosphate (751 ml) was added to the organic layer once more. Petition 870250088014, dated 09 / 29 / 2025, pages 185 / 299 The 179 / 238 mixture was stirred for 10 minutes, and the aqueous layer was then discharged by liquid-liquid separation. Subsequently, 5% saline solution (751 ml) was added to the organic layer, which was stirred for 10 minutes, and the aqueous layer was then discharged by liquid-liquid separation. The organic layer was stored at an external temperature of 5 °C overnight. After storage, the organic layer was concentrated under reduced pressure at 40 °C to approximately 215 ml. Toluene (215 ml) was added to the concentrated solution, the mixture was concentrated under reduced pressure at 40 °C to approximately 215 ml, and this operation was repeated two more times. The precipitated inorganic salt was filtered, the target material and the toluene in the resulting filtrate were quantified, and toluene was added until a total of 296 ml was reached.In another reaction vessel, pyridine hydrochloride (43.28 g) and acetonitrile (148 ml) were added, and the prepared solution was added dropwise over 45 minutes to the target material solution in toluene at an outside temperature of 25 °C. The precipitation of a crystal was confirmed during the dropwise addition. Furthermore, washing with acetonitrile (74 ml) was performed, and the mixture was stirred for 1 hour. Then, toluene (1.7 L) was added, the mixture was stirred for 1 hour, and then the outside temperature was reduced to 0 °C and the mixture was further stirred for 2 hours. The resulting crystal was filtered through a Kiriyama funnel and washed twice with toluene (296 ml), which was cooled to 0 °C. The resulting wet powder was stored at an outside temperature of 5 °C for a weekend. After storage, the wet powder was dried with the outside temperature adjusted to 40 °C. The dry powder was collected to obtain a white solid (98.66 g). [001003] LCMS (ESI) of compound 27: retention time: 3.03 minutes, m / z = 415 [M+H]+(LCMS P3-4 analytical conditions method) Petition 870250088014, dated 09 / 29 / 2025, pp. 186 / 299 180 / 238 Example 2-3 Compound 28: 2-[[[(2S)-2-[(4Z,7S)-7-[9H-fluoren-9-ylmethoxycarbonyl (methyl)amino]-8-oxo-2,3,6,7-tetrahydroazocin-1-yl]-3-[4-(trifluoromethyl)phenyl]propanyl]-methyl-amino]acetic acid [001004] To a reaction vessel, 2-MeTHF (1.35 ml), compound 8 (145 mg), and HMDS (98 pl) were added at room temperature and the mixture was stirred. Subsequently, TMSOTf (51 pl) was added to the mixed solution at room temperature and the mixture was stirred for 4 hours. After HPLC measurement and confirmation that the reaction conversion rate was 99% or more, the external temperature was cooled to 5 °C, a 5% aqueous solution of dipotassium phosphate (1.35 ml) was slowly added at an internal temperature of 15 °C or lower, and the mixture was stirred at room temperature. The aqueous layer was discharged by liquid-liquid separation. The organic layer was washed with a 5% aqueous solution of dihydrogenated sodium phosphate (1.35 ml x 2) and 5% saline solution (1.35 ml), and the organic layer was concentrated under reduced pressure at an external temperature of 40 °C to obtain compound 28 (133 mg). [001005] LCMS (ESI) of compound 28: retention time: 4.34 minutes, m / z = 664 [M+H]+(LCMS analysis conditions method P3-4) [001006] To a reaction vessel, a solution of compound 8 (3.89 kg) in 2-MeTHF (20.5 kg) was added at room temperature and then cooled to an external temperature of 15 °C. HMDS (2.19 kg) was added and the mixture was stirred. Subsequently, TMSOTf (1.80 kg) was slowly added to the mixed solvent at an internal temperature of 15 °C. Petition 870250088014, dated 09 / 29 / 2025, pp. 187 / 299 181 / 238 at 25 °C or less, and the mixture was stirred at an internal temperature of 25 °C for 2 hours. 2-MeTHF (16.6 kg) and acetonitrile (4.60 kg) were added and, after cooling to an internal temperature of 15 °C or less, a 5% aqueous solution of sodium bicarbonate (27.3 kg) was slowly added at an internal temperature of 30 °C, the mixture was stirred at room temperature and the aqueous layer was discharged by liquid-liquid separation. The organic layer was washed with a 5% aqueous solution of sodium bicarbonate (27.2 kg) and 5% saline solution (27.2 kg χ 3) and concentrated at an outside temperature of 40 °C to 10 L. Toluene (56.0 kg) was added to the concentrated solution, which was concentrated to 55 L at an outside temperature of 40 °C, and then the addition of toluene (15.6 kg) and concentration at an outside temperature of 40 °C to 54 L was repeated twice.After confirming the precipitation of a crystal, cyclohexane (14.0 kg) was added and the mixture was stirred overnight, filtered, and the crystal was washed with a mixed solution of toluene / cyclohexane = 3:1 (15.2 kg). The resulting wet crystal was dried under reduced pressure at an external temperature of 50 °C to obtain the compound 28-toluene monosolvate (3.21 kg) as a white solid. Example 2-4 Synthesis of compound 10: tert-butyl N-[(benzyloxy)carbonyl]-L-isoleucyl-L-prolinate Formula 76 [001007] For N-cyclohexylcyclohexanaminium (2S,3S)-2-{[(benzyloxy)carbonyl]amino}-3-methylpentanoate (135 g), toluene (583 g) and 5% of Petition 870250088014, dated 09 / 29 / 2025, pp. 188 / 299 182 / 238 aqueous sodium sulfate (2066 g) was added and, after stirring at room temperature for 10 minutes, the organic layer was separated. The resulting organic layer was washed with 5% aqueous hydrogenated sodium sulfate solution (2066 g), followed by 5% saline solution (1397 g), and the solvent was distilled under reduced pressure. To the resulting residue, toluene (55 ml), 1,3-dimethyl-2-imidazolidinone (270 ml), (2S)-2-(tert-butoxycarbonyl)pyrrolidin-1-io chloride (75.3 g), 2-methyltetrahydrofuran (540 ml) and 4-methylmorpholine (133 ml) were added, and the mixture was stirred at an external temperature of 15 °C. To this mixture, a 50% solution of propylphosphonic anhydride in 2-methyltetrahydrofuran (370 ml) was added dropwise over approximately 1 hour, and the resulting reaction mixture was stirred at an external temperature of 20 °C for 1 hour.To this reaction mixture, 5% aqueous sodium bicarbonate (993 g) and 1-methylimidazole (24 ml) were added at an internal temperature of 20 °C or lower, and after stirring at an external temperature of 20 °C for about 30 minutes, the organic layer was separated. The resulting organic layer was washed with 10% aqueous sodium bicarbonate solution (709 g), 10% aqueous sodium bicarbonate solution (639 g), and 10% aqueous sodium bicarbonate solution (710 g) in that order, and the solvent was distilled under reduced pressure to obtain a solution (137 g) containing the title compound. [001008] LCMS (ESI) of compound 10: retention time: 4.21 minutes, m / z = 419 [M+H]+(LCMS M analytical conditions method) Example 2-5 Synthesis of compound 11: tert-butyl L-isoleucyl-L-prolinate Formula 77 Petition 870250088014, dated 09 / 29 / 2025, pages 189 / 299 183 / 238 [001009] Pd / C (50% wet, 36.7 g) and 2-methyltetrahydrofuran (253 ml) were stirred at an external temperature of 25 °C under hydrogen pressure (0.4 MPa) for 2 hours. To the resulting mixture, the solution (137 g) containing compound 10 obtained in Example 2-4 and 2-methyltetrahydrofuran (495 ml) were added, and the mixture was stirred at an external temperature of 25 °C under hydrogen pressure (0.2 MPaG) for 2 hours. The reaction mixture was filtered, the solid was washed three times with 2-methyltetrahydrofuran (127 ml), all filtrates were combined, and the solvent was distilled under reduced pressure to obtain a solution (160 g) containing the title compound. [001010] LCMS (ESI) of compound 11: retention time: 2.40 minutes, m / z = 285 [M+H]+(LCMS M analytical conditions method) Example 2-6 Synthesis of compound 29: tert-butyl N-[(benzyloxy)carbonyl]-N-methyl-L-norvalyl-L-isoleucyl-L-prolinate Formula 78 [001011] A mixture of the solution (120 g) containing compound 11 obtained in Example 2-5, N-[(benzyloxy)carbonyl]-N-methyl-L-norvaline (72.12 g), 2-methyltetrahydrofuran (257 ml), and 4-methylmorpholine (100 ml) was stirred at an outside temperature of 15 °C. To this mixture, a 50% solution of propylphosphonic anhydride in 2-methyltetrahydrofuran (277 ml) was added dropwise over approximately 40 minutes, and the resulting reaction mixture was stirred at an outside temperature of 20 °C for 1 hour. To this reaction mixture, 5% aqueous sodium bicarbonate (472 g) and 1-methylimidazole (18 ml) were added at an inside temperature of 30 °C or lower, and after stirring at an outside temperature Petition 870250088014, dated 09 / 29 / 2025, pp. 190 / 299 184 / 238 at 15 °C for about 30 minutes, the organic layer was separated. The organic layer obtained was washed with 10% aqueous sodium hydrogen sulfate (338 g), 10% aqueous sodium hydrogen sulfate (338 g) and 10% aqueous sodium bicarbonate (340 g) in this order at an outside temperature of 20 °C, and the solvent was distilled under reduced pressure to obtain a solution (219 g) containing the title compound. [001012] LCMS (ESI) of compound 29: retention time: 4.58 minutes, m / z = 532 [M+H]+(LCMS M analytical conditions method) Example 2-7 Synthesis of compound 13: tert-butyl N-methyl-L-norvalyl-L-isoleucyl-L-prolinate Formula 79 [001013] Pd / C (50% wet, 22.9 g) and 2-methyltetrahydrofuran (400 ml) were stirred at an external temperature of 25 °C under hydrogen pressure (0.4 MPaG) for 2 hours. To the resulting mixture, the solution (182 g) containing compound 29 obtained in Example 2-6 and 2-methyltetrahydrofuran (50 ml) was added, and the mixture was stirred at an external temperature of 25 °C under hydrogen pressure (0.4 MPaG) for 2 hours. The reaction mixture was filtered, the solid was washed three times with 2-methyltetrahydrofuran (100 ml), and all filtrates were combined and concentrated under reduced pressure to obtain a solution (109 g) containing the title compound. For 9.5346 g of this solution, the solvent was distilled under reduced pressure and heptane (100 ml) was added to the resulting residue. The mixture was dissolved at an external temperature of 50 °C, and the seed crystal (11.0 mg) obtained in Example 2-7-1 was added at an internal temperature of 40 °C.After stirring the mixture at an external temperature of 42 °C for 15 minutes, at a temperature. Petition 870250088014, dated 09 / 29 / 2025, pp. 191 / 299 185 / 238 external temperature of 43 °C for 13 minutes and at an external temperature of 44 °C for 17 minutes, the external temperature was cooled to 0 °C at a rate of 12 °C per hour, and the mixture was further stirred at an external temperature of 0 °C for 1.5 hours. The resulting solid was filtered, washed with cold heptane (25 ml) and dried under reduced pressure at an external temperature of 30 °C to 40 °C to obtain the title compound (4.8474 g). [001014] LCMS (ESI) of compound 13: retention time: 2.56 minutes, m / z = 398 [M+H]+ (LCMS analytical conditions method M) Example 2-7-1 Synthesis of the seed crystal of compound 13: tert-butyl N-methyl-L-norvalyl-L-isoleucyl-L-prolinate [001015] Part of the solution containing the title compound obtained in the reaction of Example 2-7 was concentrated under reduced pressure, and to the resulting residue (0.3811 g), heptane (7622 pl) was added. After dissolving the solid produced at an outside temperature of 50 °C, it was cooled to room temperature under stirring, and to the resulting fluid paste, heptane (3811 pl) was added and stirring continued. The solid was filtered and washed with heptane (1906 pl) and dried under...

Claims

1. Method for producing a cyclic peptide compound represented by formula (1), or a salt thereof, or a solvate thereof, characterized in that it comprises a reaction step of an N-terminal amino acid residue of a peptide compound represented by formula (2) or (3) with a C-terminal amino acid residue of the peptide compound in a solvent for cyclization (cyclization step): Formula 1 Petition 870250088014, dated 29 / 09 / 2025, page 246 / 299 2 / 9 (3) wherein Ri is a C1-C6 alkyl; Pi is a C1-C6 alkyl; R2 is a C1-C6 alkyl; R3 is hydrogen, or R3 forms a saturated 4- to 7-membered heterocyclic ring together with P3, a carbon atom to which R3 is attached and a nitrogen atom to which P3 is attached; P3 is a C1-C6 alkyl or a C3-C8 cycloalkyl, or P3 forms a saturated 4- to 7-membered heterocyclic ring together with R3, a carbon atom to which R3 is attached, and a nitrogen atom to which P3 is attached; P4 is a C1-C6 alkyl;R5 is benzyl optionally substituted with one or more groups selected from the group consisting of a C1-C6 alkyl, a C1-C6 haloalkyl, and a C3-C8 cycloalkyl; P6 is a C1-C6 alkyl; R7 is phenethyl optionally substituted with one or more groups selected from the group consisting of a halogen, a C1-C6 haloalkyl, and a C1-C6 alkoxy; R8 forms a saturated heterocyclic ring of 4 to 7 members together with P8, a carbon atom to which R8 is attached, and a nitrogen atom to which P8 is attached, the saturated heterocyclic ring Petition 870250088014, dated 09 / 29 / 2025, p. 247 / 299 3 / 9 of 4 to 7 members optionally substituted with a C1-C6 alkoxy; R9 forms a 3- to 8-membered alicyclic ring together with Q9 and a carbon atom to which R9 and Q9 are attached, the 3- to 8-membered alicyclic ring optionally substituted with one or more C1-C6 alkyls; P9 is hydrogen or a C1-C6 alkyl; R10 is a C1-C6 alkyl or a C3-C8 cycloalkyl;P10 is a C1-C6 alkyl; R11 is a di-C1-C6 alkylaminocarbonyl or a 4- to 8-membered cyclic aminocarbonyl; P11 is a C1-C6 alkyl; Xi and X5 are each independently hydrogen or a protecting group for an amino group; and X2 and X4 are each independently a halogen, a hydroxy group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy, or a group represented by -OSiRxRyRz, wherein Rx, Ry, and Rz are each independently an alkyl or an aryl.

2. Method for producing a cyclic peptide compound represented by formula (1), or a salt thereof, or a solvate thereof, characterized in that it comprises: a step for supplying peptide compounds represented by formulas (4) to (6), or salts thereof, or solvates of the peptide compounds or salts; a step for reacting N-terminal amino acid residues of the peptide compounds represented by formulas (4) to (6) with C-terminal amino acid residues of the peptide compounds in a solvent for binding (binding step); and a step for reacting an N-terminal amino acid residue Petition 870250088014, dated 09 / 29 / 2025, page. 248 / 299 4 / 9 terminal of a peptide compound obtained in step (b) with a C-terminal amino acid residue of the peptide compound in a solvent for cyclization (cyclization step): Formula 2 wherein Ri is a C1-C6 alkyl; Pi is a C1-C6 alkyl; R2 is a C1-C6 alkyl;R3 is hydrogen, or R3 forms a saturated 4- to 7-membered heterocyclic ring together with P3, a carbon atom to which R3 is attached, and a nitrogen atom to which P3 is attached; Petition 870250088014, dated 09 / 29 / 2025, p. 249 / 299 5 / 9 P3 is a C1-C6 alkyl or a C3-C8 cycloalkyl, or P3 forms a saturated 4- to 7-membered heterocyclic ring together with R3, a carbon atom to which R3 is attached, and a nitrogen atom to which P3 is attached; P4 is a C1-C6 alkyl; R5 is benzyl optionally substituted with one or more groups selected from the group consisting of a C1-C6 alkyl, a C1-C6 haloalkyl, and a C3-C8 cycloalkyl; P6 is a C1-C6 alkyl; R7 is phenethyl optionally substituted with one or more groups selected from the group consisting of a halogen, a C1-C6 haloalkyl, and a C1-C6 alkoxy;R8 forms a saturated 4- to 7-membered heterocyclic ring together with P8, a carbon atom to which R8 is attached, and a nitrogen atom to which P8 is attached, the saturated 4- to 7-membered heterocyclic ring optionally substituted with a C1-C6 alkoxy; R9 forms a 3- to 8-membered alicyclic ring together with Q9 and a carbon atom to which R9 and Q9 are attached, the 3- to 8-membered alicyclic ring optionally substituted with one or more C1-C6 alkyls; P9 is hydrogen or a C1-C6 alkyl; R10 is a C1-C6 alkyl or a C3-C8 cycloalkyl; P10 is a C1-C6 alkyl; R11 is a di-C1-C6 alkylaminocarbonyl or a 4- to 8-membered cyclic aminocarbonyl; P11 is a C1-C6 alkyl; X1, X3, and X5 are each independently either hydrogen or a protecting group for an amino group;and X2, X4 and X6 are each independently a halogen, a hydroxy group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy or a group represented by -OSiRxRyRz, wherein Rx, Ry, and Rz are each independently an alkyl or an aryl.

3. Method according to claim 2, characterized in that it comprises, in step (b), (b-1) a reaction step of an N-terminal amino acid residue of the peptide compound represented by formula (5) with a C-terminal amino acid residue of the peptide compound represented by formula (6) in a solvent for binding, thereby converting them into a peptide compound represented by formula (7) (binding step): Formula 3 wherein Ri, R2, R3, R7, R8, R9, R10, R11, Pi, P3, P8, P9, P10, P11, Q9, X4, and X5 are the same as defined in claim 2.

4. Method according to claim 3, characterized in that it further comprises, in step (b), (b-2) a reaction step of an N-terminal amino acid residue of the peptide compound represented by formula (4) with a C-terminal amino acid residue of the peptide compound represented by formula (7) in a solvent for binding, converting them thus into a peptide compound represented by formula (2) (binding step), and in step (c), (c-1) a reaction step of an N-terminal amino acid residue of the peptide compound represented by formula (2) with a C-terminal amino acid residue of the peptide compound in a solvent for cyclization (cyclization step).

5. Method according to claim 3, characterized in that it further comprises, in step (b), (b-3) a reaction step of an N-terminal amino acid residue of the peptide compound represented by formula (7) with a C-terminal amino acid residue of the peptide compound represented by formula (4) in a solvent for binding, thereby converting them into a compound represented by formula (3) (binding step), and in step (c), (c-2) a reaction step of an N-terminal amino acid residue of the peptide compound represented by formula (3) with a C-terminal amino acid residue of the peptide compound in a solvent for cyclization (cyclization step).

6. A method according to any one of claims 1 to 5, characterized in that the linkage of an N-terminal amino acid residue of a peptide compound with a C-terminal amino acid residue of a peptide compound is the linkage of an amino group of the N-terminal amino acid residue with a carboxyl group of the C-terminal amino acid residue.

7. A method according to any one of claims 1 to 6, characterized in that the solvent in the cyclization step includes one or more solvents selected from the group consisting of a nitrile-based solvent, a halogen-based solvent, an ether-based solvent, an amide-based solvent, an ester-based solvent, and a carbonate-based solvent. Petition 870250088014, dated 09 / 29 / 2025, p. 252 / 299 8 / 9 8. A method according to any one of claims 1 to 7, characterized in that the cyclization step is carried out in the presence of a condensation reagent.

9. A method, according to any one of claims 1 to 8, characterized in that the cycling step is carried out in the presence of a base.

10. A method according to any one of claims 1 to 9, characterized in that the cyclization step is carried out by a liquid-phase method.

11. A method according to any one of claims 1 to 10, characterized in that the solvent in the linking step includes one or more solvents selected from the group consisting of a nitrile-based solvent, a halogen-based solvent, an ether-based solvent, an amide-based solvent, an ester-based solvent, and a carbonate-based solvent.

12. Crystal of a cyclic peptide compound, characterized in that it is represented by formula (1a), or a salt thereof, or a solvate thereof: Formula 4 13. Crystal, according to claim 12, characterized in that the crystal is a solvate crystal, wherein the solvate crystal is a hydrate crystal, wherein the hydrate crystal is a crystal. Petition 870250088014, dated 09 / 29 / 2025, page. 253 / 299 9 / 9 of form A including at least 7 peaks selected from the group consisting of 6.93°, 7.56°, 8.26°, 9.00°, 9.58°, 10.35°, 11.35°, 12.26°, 12.85°, 13.51°, 14.12°, 14.69°, 15.46°, 15.92°, 17.43°, and 17.73° (±0.2°) as diffraction angles (2θ values) by X-ray diffraction on powder, and wherein the diffraction angles (2θ values) are diffraction angles (2θ values) of a hydrate crystal stored at a relative humidity of 10% or more for 15 minutes or more.

14. Crystal according to claim 12, characterized in that the crystal is a solvate crystal, wherein the solvate crystal is a hydrate crystal, wherein the hydrate crystal is a B-form crystal including at least 7 peaks selected from the group consisting of 4.99°, 8.65°, 9.85°, 10.84°, 11.32°, 12.35°, 13.20°, 14.44°, 15.20°, 16.03°, 16.69°, 17.21°, 18.82°, 19.49°, and 20.03° (±0.2°) as diffraction angles (2θ values) by X-ray powder diffraction, and wherein the diffraction angles (2θ values) are diffraction angles (2θ values) of a hydrate crystal stored at a relative humidity of 30% or more for 15 minutes or more.

15. Method for producing the crystal of a cyclic peptide compound, as defined in any one of claims 12 to 14, characterized in that it comprises: a step of dissolving the cyclic peptide compound in a polar organic solvent in an amount that allows the cyclic peptide compound to dissolve therein to obtain a solution; and a step of adding a hydrocarbon-based solvent or water to the solution to obtain a crystal of the cyclic peptide compound.

16. Method according to claim 15, characterized in that it further comprises, after the step of obtaining a crystal of the cyclic peptide compound, a step of filtering the crystal.

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