Polypeptide with MMP2 inhibiting effect

Abstract

The present invention provides a substituted polypeptide represented by formula [I '] or a pharmaceutically acceptable salt thereof, said polypeptide having an MMP2-inhibiting activity. # imgabs0 #

Description

[0001] This application is a divisional application of a patent application with the original application date of November 6, 2020 (priority date of November 8, 2019), the original application number of 202080068221.6 (international application number of PCT / JP2020 / 042350), and the invention name of “Polypeptide with MMP2 inhibitory effect”. Technical Field

[0002] The present invention relates to a substituted polypeptide compound having an activity of inhibiting matrix metalloproteinase 2 (hereinafter, appropriately referred to as "MMP2"). Background Art

[0003] Matrix metalloproteinases are endopeptidases with zinc as their active center, and 24 genes are known. Since MMPs degrade extracellular matrices such as collagen and gelatin, they are involved not only in physiological phenomena such as bone remodeling and wound healing, but also in pathological processes such as inflammation and cancer progression (see Non-Patent Document 1).

[0004] Although a number of clinical trials of MMP inhibitors have been conducted, they have been abandoned due to side effects such as skeletal muscle pain and the possibility of promoting cancer metastasis, which are believed to be caused by relatively non-selective inhibition of various MMP subtypes (see Non-Patent Documents 2 and 3).

[0005] It is reported that the activation of MMP2 plays an important role in the infiltration and metastasis of cancer cells. The infiltration and metastasis of cancer cells are important factors affecting the prognosis of malignant tumors, and inhibiting the activity of MMP2 can become an effective therapeutic method in controlling cancer. It is reported that in animals with MMP2 gene defects, the proliferation of cancer is inhibited, and MMP2 plays an important role in the proliferation of cancer (refer to non-patent literature 4). Moreover, it is reported that MMP2 is associated with morbid progression in various cancer patients such as breast cancer, pancreatic cancer, bladder cancer, colorectal cancer, ovarian cancer, prostate cancer, brain tumors, gastric cancer, hepatocellular carcinoma, head and neck cancer, melanoma, uterine cancer, esophageal cancer, renal cell carcinoma, lung cancer, glioma, etc. (refer to non-patent literature 5 and 6). On the other hand, it is reported that MMP2 is also involved in their morbid formation in non-tumor diseases.

[0006] It is reported that in chronic kidney disease, MMP2 causes epithelial-mesenchymal transition of the renal tubules by changing the structure of the renal tubular basement membrane, thereby inducing tubular atrophy, fibrosis and decreased renal function (refer to non-patent literature 7). Moreover, in patients with chronic kidney disease, an increase in the concentration of MMP2 in the blood was observed (refer to non-patent literature 8 and 9). In addition, it is reported that renal fibrosis induced by unilateral ureteral ligation in MMP2 gene-deficient animals is inhibited (refer to non-patent literature 10 and 11). Therefore, inhibiting MMP2 activity to control the morbid progression of chronic kidney disease can become an effective treatment method.

[0007] In idiopathic pulmonary fibrosis, it is observed that the expression of MMP2 is hyperactive in lung epithelial cells, fibroblasts and macrophages, and in particular, in patients with rapidly progressive idiopathic pulmonary fibrosis, the expression of MMP2 in lung lavage fluid is hyperactive (see non-patent documents 12 and 13). In addition, it is reported that non-selective MMP inhibitors have the effect of reducing the collagen content in the lungs of mice with bleomycin-induced pulmonary fibrosis (see non-patent document 14) or have the effect of inhibiting the transformation of lung parenchymal fibroblasts induced by TGFβ (see non-patent document 15). Therefore, inhibiting MMP2 activity to control the pathological progression of idiopathic pulmonary fibrosis can be an effective therapeutic means.

[0008] Furthermore, MMP2 is suggested to be involved in non-tumor diseases such as multiple sclerosis, cerebral infarction, arteriosclerosis, abdominal aortic aneurysm, peritoneal sclerosis, myocardial infarction, acute renal dysfunction, diabetic nephropathy, nephrosclerosis, glomerulonephritis, multiple renal cysts, multiple liver cysts, alcoholic liver disease, non-alcoholic fatty liver disease, cholestatic liver injury, chronic obstructive pulmonary disease, interstitial pneumonia, diabetic retinopathy, age-related macular degeneration, Sjogren's syndrome, meningitis, muscular dystrophy, scleroderma, inflammatory bowel disease, and tuberculosis (see Non-Patent Document 16).

[0009] In view of these facts, finding a means to selectively inhibit MMP2 is a highly feasible approach to establish effective treatments for MMP2-related diseases.

[0010] As low molecular weight compounds having MMP2 inhibitory activity, there are reports of compounds in which hydroxamic acid or carboxylic acid is introduced as a zinc chelator, but it is not known that any of them exhibits a selective MMP2 inhibitory activity (for example, see Non-Patent Documents 17 and 18).

[0011] In addition, it is reported that the peptide compound "β-amyloid precursor protein (APP-IP, Ile-Ser-Tyr-Gly-Asn-Asp-Ala-Leu-Met-Pro)" composed of 10 natural amino acids shows a selective MMP2 inhibitory effect (see Non-Patent Document 19). However, it is generally known that since peptide compounds are rapidly metabolized and excreted in the body, even if the peptide compounds are administered, the expected pharmacological effects cannot be maintained.

[0012] Prior art literature

[0013] Non-patent literature

[0014] Non-patent document 1: HJ Ra and WC Parks Matrix Biol., 2007, 26(8), 587-596;

[0015] Non-patent document 2: AHDrummond et al. Ann NY Acad Sci., 1999, 878, 228-235;

[0016] Non-patent document 3: AD Baxter et al. Bioorg Med Chem Lett., 2001, 11, 1465-1468;

[0017] Non-patent document 4: T. Itoh et al. Cancer Res., 1998, 58, 1048-1051;

[0018] Non-patent document 5: R. Roy et al. J Clin Oncol., 2009, 27, 5287-5297;

[0019] Non-patent document 6: T. Turpeenniemi-Hujanen Biochimie., 2005, 87, 287-297;

[0020] Non-patent document 7: S. Cheng et al. FASEB J., 2006, 20, 1898-1900;

[0021] Non-patent document 8: K. Pawlak et al. Clin Biochem., 2011, 44, 838-843;

[0022] Non-patent document 9: H.R. Chang et al. Clin Chim Acta., 2006, 366, 243-248;

[0023] Non-patent document 10: X. Du et al. Lab Invest., 2012, 92, 1149-1160;

[0024] Non-patent literature 11: MKTveitaras et al. PLoS One., 2015, 10, e0143390;

[0025] Non-patent document 12: M. Selman et al. Am J Physiol Lung Cell Mol Physiol., 2000, 279, L562-L574;

[0026] Non-patent document 13: M. Suga et al. Am J Respir Crit Care Med., 2000, 162, 1949-1956;

[0027] Non-patent document 14: M. Corbel et al. J Pathol., 2001, 193, 538-545;

[0028] Non-patent document 15: J. Michael et al. Am J Respir Cell Mol Biol., 2009, 41, 731-741;

[0029] Non-patent document 16: A. Tokito et al. Int J Mol Sci., 2016, 17, E1178;

[0030] Non-patent document 17: DE Levy et al. J Med Chem., 1998, 41, 199-223;

[0031] Non-patent document 18: Y. Tamura et al. J Med Chem., 1998, 41, 640-649;

[0032] Non-patent document 19: S. Higashi et al. J Biol Chem., 2003, 278, 14020-14028. Summary of the invention

[0033] Problems to be solved by the invention

[0034] The object of the present invention is to provide a novel MMP2 inhibitor.

[0035] Means for solving problems

[0036] As a result of intensive studies to achieve the above-mentioned objects, the present inventors have found that a compound represented by the following formula [I'] (hereinafter, sometimes referred to as compound [I']) has an MMP2 inhibitory effect.

[0037] Hereinafter, the present invention will be described in detail.

[0038] That is, the aspects of the present invention are as follows.

[0039] (1) As one embodiment of the present invention, a substituted polypeptide represented by the following formula [I'] or a pharmaceutically acceptable salt thereof is provided:

[0040]

[0041] (In the above formula [I'],

[0042] AA 1 express:

[0043] Asp,

[0044] β-Asp, β-(d)-Asp, γ-Glu, or γ-(d)-Glu,

[0045] AA 2 represents one group selected from the following:

[0046] Ala,

[0047] By the following formulas [IV-7], [IV-8], [IV-9], [IV-11], [IV-12], [IV-13]

[0048]

[0049] The groups represented

[0050] From the following formula [IV-27]

[0051]

[0052] The groups represented

[0053] Pro, represented by the following formulas [II-1] and [II-2]

[0054]

[0055] The group represented by

[0056] Here, R AA2 represents a hydroxyl group or an amino group,

[0057] In addition, AA 1 and AA 2 Can be formed together with the following formula [IV-32]

[0058]

[0059] The structure represented by

[0060] AA3 represents one group selected from the following:

[0061] Val, Leu, Ile, are represented by the following formula [IV-2]

[0062]

[0063] The groups represented

[0064] Phe, Trp,

[0065] Tyr, Lys, represented by the following formulas [IV-3], [IV-4], [IV-5]

[0066]

[0067] The groups represented by

[0068] From the following formula [IV-9]

[0069]

[0070] The group represented by

[0071] AA 4 represents one group selected from the following:

[0072] single bond,

[0073] Gly, (d)-Ala, (N-Me)Ala, (N-Me)Val, (N-Me)Leu, (N-Me)Ile,

[0074] Pro, (d)-Pro,

[0075] (N-Me)Phe, (d)-Phe,

[0076] (N-Me)Tyr, (d)-Tyr,

[0077] (N-Me)Ser, (d)-Ser, homoSer, (d)-Thr,

[0078] Met, (N-Me)Met,

[0079] (N-Me)Asp, Glu, (N-Me)Glu, (d)-(N-Me)Glu, homoGlu,

[0080] (N-Me)Asn,

[0081] (N-Me)Arg, (d)-Arg,

[0082] From the following formulas [IV-7], [IV-9], [IV-13]

[0083]

[0084] The groups represented

[0085] Lys, and (N-Me)Lys,

[0086] Here, in AA 4 In the case of Lys,

[0087] The amino group of the Lys side chain may be substituted by a carboxyl group at the end. 2-16 Alkylcarbonyl substitution,

[0088] AA 5 represents one group selected from the following:

[0089] single bond,

[0090] Ala, represented by the following formula [IV-1]

[0091]

[0092] The groups represented

[0093] From the following formulas [IV-27], [IV-28], [IV-29]

[0094]

[0095] The groups represented

[0096] Pro, (d)-Pro, β-homoPro, homoPro, represented by the following formula [II-1']

[0097]

[0098] The group represented by

[0099] Phe, His,

[0100] Thr,

[0101] Arg, (d)-Arg,

[0102] From the following formulas [IV-7], [IV-9], [IV-13]

[0103]

[0104] The groups represented

[0105] Lys, (d)-Lys,

[0106] β-Ala, (N-Me)-β-Ala, GABA, Ape, Acp,

[0107] From the following formulas [III-6] to [III-13]

[0108]

[0109] The groups represented

[0110] From the following formulas [IV-25] and [IV-26]

[0111]

[0112] The group represented by

[0113] W 1 Indicates -L 1 -or-L 1 '-L 1 ”-,

[0114] L 1 represents a single bond,

[0115] L 1 ' represents a group selected from the following:

[0116] single bond,

[0117] β-Ala, GABA, (N-Me)GABA, Ape, Acp,

[0118] From the following formulas [III-6] to [III-13]

[0119]

[0120] The groups represented

[0121] From the following formulas [IV-23] and [IV-24]

[0122]

[0123] The group represented by

[0124] L 1 " represents one group selected from the following:

[0125] single bond,

[0126] Gly, (N-Me)Gly,

[0127] Ala, (N-Me)Ala, (d)-Ala, Val, (N-Me)Val, (N-Me)Leu, (N-Me)Ile,

[0128] From the following formula [IV-27]

[0129]

[0130] The groups represented

[0131] Pro, (d)-Pro, homoPro, Phe, (N-Me)Phe, (d)-Phe,

[0132] His, (d)-His, Trp, (N-Me)Trp, (d)-Trp,

[0133] Tyr, (N-Me)Tyr, (d)-Tyr,

[0134] (d)-Ser, homoSer, Thr, (N-Me)Thr, (d)-Thr,

[0135] Cys, (d)-Cys, Met, (N-Me)Met,

[0136] (N-Me)Asp, Glu, (N-Me)Glu, (d)-Glu,

[0137] Asn, (N-Me)Asn, (d)-Asn, Gln, (N-Me)Gln, (d)-Gln,

[0138] Arg, (N-Me)Arg, (d)-Arg, Cit, (d)-Cit,

[0139] By the following formulas [IV-7], [IV-9], [IV-10], [IV-13]

[0140]

[0141] The groups represented

[0142] Lys, (N-Me)Lys, (d)-Lys, are represented by the following formula [IV-14]

[0143]

[0144] The groups represented

[0145] β-Ala,

[0146] β-Asp, β-(d)-Asp,

[0147] From the following formulas [III-6] and [III-7]

[0148]

[0149] The group represented by

[0150] Here, in L 1 " represents Lys or (d)-Lys,

[0151] The amino group of the side chain of Lys and (d)-Lys may be substituted by a group represented by the following formula [VII-1]:

[0152] FA N -AA N5 -AA N4 -AA N3 -AA N2 -AA N1 -[VII-1]

[0153] In the formula [VII-1],

[0154] FA N Indicates that the terminal is substituted with a carboxyl group 2-16 Alkylcarbonyl,

[0155] AA N5 express:

[0156] single bond,

[0157] Arg, (d)-Arg,

[0158] Lys, (d)-Lys,

[0159] γ-Glu, or

[0160] From the following formula [IV-24]

[0161]

[0162] The group represented by

[0163] AA N4 express:

[0164] single bond,

[0165] Arg, (d)-Arg,

[0166] Lys, (d)-Lys, or

[0167] From the following formula [IV-24]

[0168]

[0169] The group represented by

[0170] AA N3 express:

[0171] single bond,

[0172] Arg, (d)-Arg,

[0173] Lys, (d)-Lys,

[0174] γ-Glu, or

[0175] From the following formula [IV-24]

[0176]

[0177] The group represented by

[0178] AA N2 represents a single bond, or (d)-Lys,

[0179] AA N1 represents a single bond, or (d)-Lys,

[0180] In addition, in L 1 "When represented by Glu, and AA 3 In the case represented by Lys,

[0181] As shown in the following formula [I'-α], the compound represented by the formula [I'] can be combined with L 3 Together they form a ring structure, the L 3 are respectively bonded to the functional groups of the side chains of the two amino acids,

[0182] At this time, the L 3 represents Gly, β-Ala, or GABA,

[0183]

[0184] L N1 represents the formula -C(=O)- or the formula -S(=O)2-,

[0185] L N2 Indicates: single key,

[0186] C 1-3 Alkanediyl,

[0187] C 2-3 Olefin diyl,

[0188] Ethylene diyl,

[0189] Formula -O-,

[0190] Formula -C(=O)-, formula -C(=O)-NH-, or

[0191] Triazolediyl,

[0192] L 2 represents a single bond,

[0193] Ring A represents an aromatic ring or a heteroaromatic ring,

[0194] R A1 , R A2 Independent representation: hydrogen atom,

[0195] Halogen atoms,

[0196] C 1-6 Alkyl, or

[0197] C 1-6 Alkoxy,

[0198] Ring B represents an aryl group or a heteroaryl group,

[0199] R B1 , R B2 , R B3 Independent representation:

[0200] Hydrogen atoms,

[0201] Carbamoyl,

[0202] Cyano,

[0203] Halogen atoms,

[0204] C 1-6 Alkyl (the C 1-6 The alkyl group may be substituted with one hydroxyl group), halogenated C 1-6 alkyl,

[0205] C 1-6 Alkoxy (the C 1-6 The alkoxy group may be substituted by one hydroxyl group), halogenated C 1-6 Alkoxy,

[0206] C 1-6 Alkylcarbonyl,

[0207] C 1-6 Alkylcarbonylamino,

[0208] Single C 1-6 Alkylaminocarbonyl, di-C 1-6 Alkylaminocarbonyl (the single C 1-6 Alkylaminocarbonyl and di-C 1-6 The alkyl group in the alkylaminocarbonyl group may be substituted by one group selected from the group consisting of a hydroxyl group, a carboxyl group, a carbamoyl group, and an amino group);

[0209] C 1-6 Alkylsulfonyl, or

[0210] Aryl,

[0211] WC is a single bond or a linker consisting of 1 to 3 amino acids,

[0212] Here, the 1 to 3 amino acids forming the linker are selected from the following groups, either identically or differently:

[0213] Gly,

[0214] Pro,

[0215] Arg, (d)-Arg,

[0216] Lys, (d)-Lys,

[0217] β-Ala, GABA, and Ape,

[0218] Here, in the C When the group represented by contains Lys or (d)-Lys,

[0219] The amino group of the side chain of Lys and (d)-Lys may be replaced by a C 2-16 Alkylcarbonyl, Lys (the amino group of the side chain of Lys may be C 2-16 substituted with an alkylcarbonyl group), or (d)-Lys (the amino group of the side chain of the (d)-Lys may be substituted with a C 2-16 substituted with alkylcarbonyl),

[0220] R C for:

[0221] Formula -OH, Formula -NH2,

[0222] C 1-6 Alkylamino (the C 1-6 Alkylamino C 1-6 The alkyl group may be substituted by one group selected from the following: hydroxyl, amino, C 1-6 alkoxy, and a 4- to 7-membered saturated heterocyclic group containing one nitrogen atom and optionally one heteroatom), or

[0223] A 4- to 7-membered saturated heterocyclic group containing one nitrogen atom and one heteroatom (the 4- to 7-membered saturated heterocyclic group containing one nitrogen atom and one heteroatom may be substituted by one group selected from the following: hydroxyl, amino, and C 1-6 Alkyl (the C 1-6 The alkyl group may be substituted with one carbamoyl group), and the two carbon atoms in the 4-7 membered saturated heterocyclic group containing one nitrogen atom and one heteroatom may be substituted with one carbamoyl group. 1-4 Alkanediyl crosslinking)).

[0224] (2) As another embodiment of the present invention, there is provided the substituted polypeptide or a pharmaceutically acceptable salt thereof as described in (1), wherein:

[0225] W C for:

[0226] single bond,

[0227] Pro,

[0228] Arg, (d)-Arg,

[0229] Lys, (d)-Lys,

[0230] β-Ala, GABA, Ape,

[0231] Gly-(d)-Lys, Gly-(d)-Lys-(d)-Lys, Gly-(d)-Lys-(d)-Arg, Gly-(d)-Arg-(d)-Lys,

[0232] Lys-Lys, (d)-Lys-(d)-Lys, (d)-Lys-(d)-Lys-(d)-Lys,

[0233] Arg-Arg, (d)-Arg-(d)-Arg, (d)-Arg-(d)-Lys,

[0234] Lys-(d)-Lys-(d)-Lys, (d)-Lys-Lys-(d)-Lys, (d)-Lys-(d)-Lys-Lys,

[0235] β-Ala-(d)-Lys, β-Ala-(d)-Lys-(d)-Arg, β-Ala-(d)-Arg-(d)-Lys, or β-Ala-(d)-Arg-(d)-Arg,

[0236] Here, in the C When the group represented by contains Lys,

[0237] The amino group of the Lys side chain may be substituted by a carboxyl group at the end. 2-16 Alkylcarbonyl or (d)-Lys (the amino group of the side chain of (d)-Lys may be C 2-16 substituted with alkylcarbonyl).

[0238] (3) As another embodiment of the present invention, there is provided a substituted polypeptide or a pharmaceutically acceptable salt thereof according to (1) or (2), wherein:

[0239] Ring A is a benzene ring, a thiophene ring, or a pyridine ring,

[0240] R A1 , R A2 are independently a hydrogen atom or a halogen atom,

[0241] Ring B is phenyl, oxazolyl, thiadiazolyl, pyridyl, or benzofuranyl,

[0242] R B1 , R B2 , R B3 Independent as:

[0243] Hydrogen atoms,

[0244] Carbamoyl,

[0245] Cyano,

[0246] Halogen atoms,

[0247] C 1-6 Alkyl (the C 1-6 The alkyl group may be substituted with one hydroxyl group), halogenated C 1-6 alkyl,

[0248] C 1-6 Alkoxy (the C 1-6 The alkoxy group may be substituted by one hydroxyl group), halogenated C 1-6 Alkoxy,

[0249] C 1-6 Alkylcarbonyl,

[0250] Single C 1-6 Alkylaminocarbonyl, di-C 1-6 Alkylaminocarbonyl (the single C 1-6 Alkylaminocarbonyl and di-C 1-6 The alkyl group in the alkylaminocarbonyl group may be substituted by one group selected from the group consisting of a hydroxyl group, a carboxyl group, a carbamoyl group, and an amino group), or

[0251] C 1-6 Alkylsulfonyl,

[0252] R C for:

[0253] Formula -OH, Formula -NH2,

[0254] C 1-6 Alkylamino (the C 1-6 Alkylamino C 1-6 The alkyl group may be selected from hydroxy, amino, C 1-6 alkoxy, and morpholinyl),

[0255] Azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl (the azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl groups may be selected from hydroxyl, amino, and C 1-6 Alkyl (the C 1-6 The alkyl group may be substituted with one carbamoyl group), and the two carbon atoms in the azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl groups may be substituted with one carbamoyl group. 1-4 Alkanediyl cross-linking).

[0256] (4) As another embodiment of the present invention, there is provided a substituted polypeptide or a pharmaceutically acceptable salt thereof according to any one of (1) to (3), wherein in the substituted polypeptide represented by the formula [I'],

[0257] Ring A is a benzene ring,

[0258] Ring B is phenyl,

[0259] L 1 " is a group selected from the following:

[0260] single bond,

[0261] Gly, (N-Me)Gly,

[0262] Ala, (N-Me)Ala, (d)-Ala, Val, (N-Me)Val, (N-Me)Leu, (N-Me)Ile,

[0263] From the following formula [IV-27]

[0264]

[0265] The groups represented

[0266] Pro, (d)-Pro, homoPro, Phe, (N-Me)Phe, (d)-Phe,

[0267] His, (d)-His, Trp, (N-Me)Trp, (d)-Trp,

[0268] Tyr, (N-Me)Tyr, (d)-Tyr,

[0269] (d)-Ser, homoSer, Thr, (N-Me)Thr, (d)-Thr,

[0270] Cys, (d)-Cys, Met, (N-Me)Met,

[0271] (N-Me)Asp, Glu, (N-Me)Glu, (d)-Glu,

[0272] Asn, (N-Me)Asn, (d)-Asn, Gln, (N-Me)Gln, (d)-Gln,

[0273] Arg, (N-Me)Arg, (d)-Arg, Cit, (d)-Cit,

[0274] By the following formulas [IV-7], [IV-9], [IV-10], [IV-13]

[0275]

[0276] The groups represented

[0277] Lys, (N-Me)Lys, (d)-Lys, are represented by the following formula [IV-14]

[0278]

[0279] The groups represented

[0280] β-Ala,

[0281] β-Asp, β-(d)-Asp,

[0282] From the following formulas [III-6] and [III-7]

[0283]

[0284] The group represented by

[0285] W C for:

[0286] single bond,

[0287] Pro,

[0288] Arg, (d)-Arg,

[0289] Lys, (d)-Lys,

[0290] β-Ala, GABA, Ape,

[0291] Gly-(d)-Lys, Gly-(d)-Lys-(d)-Lys, Gly-(d)-Lys-(d)-Arg, Gly-(d)-Arg-(d)-Lys,

[0292] Lys-Lys, (d)-Lys-(d)-Lys, (d)-Lys-(d)-Lys-(d)-Lys,

[0293] Arg-Arg, (d)-Arg-(d)-Arg, (d)-Arg-(d)-Lys,

[0294] Lys-(d)-Lys-(d)-Lys, (d)-Lys-Lys-(d)-Lys, (d)-Lys-(d)-Lys-Lys,

[0295] β-Ala-(d)-Lys, β-Ala-(d)-Lys-(d)-Arg, β-Ala-(d)-Arg-(d)-Lys, or β-Ala-(d)-Arg-(d)-Arg.

[0296] (5) As another embodiment of the present invention, there is provided a substituted polypeptide or a pharmaceutically acceptable salt thereof according to any one of (1) to (4), wherein in the substituted polypeptide represented by the formula [I'],

[0297] AA 2 is a group selected from the following:

[0298] From the following formula [II-1]

[0299]

[0300] The group represented by

[0301] The following formulas [IV-7], [IV-8], [IV-9], [IV-11], and [IV-12]

[0302]

[0303] The group represented by

[0304] Here, R AA2 For amino,

[0305] AA 3 is Val, Leu, Ile, Phe, or Trp,

[0306] AA 4 is (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Asp, or (N-Me)Glu,

[0307] AA 5 is β-Ala, GABA, Ape, Acp, Pro, (d)-Pro, or β-homoPro,

[0308] W C is a single bond, Arg, (d)-Arg, Lys, or (d)-Lys,

[0309] R C It is of the formula -OH or -NH2.

[0310] (6) As another embodiment of the present invention, there is provided a substituted polypeptide or a pharmaceutically acceptable salt thereof according to any one of (1) to (5), wherein in the substituted polypeptide represented by the formula [I'],

[0311] W 1 For -L 1 '-L 1 ”-,

[0312] L 2 is a single bond,

[0313] AA 1 For Asp,

[0314] L 1 ' is a group selected from the following:

[0315] β-Ala, GABA, Ape, Acp, represented by the following formulas [IV-23] and [IV-24]

[0316]

[0317] The group represented by

[0318] L 1 " is a single bond, Asn, (d)-Ser, (d)-Thr, or Glu,

[0319] L N1 is of the formula -C(=O)- or the formula -S(=O)2-,

[0320] L N2 is of the formula -O- or -C(=O)-NH-,

[0321] R A1 , R A2 are hydrogen atoms,

[0322] R B1 , R B2 , R B3 is independently a hydrogen atom, a carbamoyl group, a halogen atom, a C 1-6 Alkoxy or halogenated C 1-6 Alkoxy.

[0323] (7) As another embodiment of the present invention, there is provided a substituted polypeptide or a pharmaceutically acceptable salt thereof according to any one of (1) to (5), wherein in the substituted polypeptide represented by the formula [I'],

[0324] W 1For -L 1 -, here, L 1 is a single bond,

[0325] L 2 is a single bond,

[0326] AA 1 is β-Asp, β-(d)-Asp, γ-Glu, or γ-(d)-Glu,

[0327] AA 2 is a group selected from the following:

[0328] From the following formula [II-1]

[0329]

[0330] The groups represented

[0331] The following formulas [IV-7], [IV-8], [IV-9], [IV-11], and [IV-12]

[0332]

[0333] The group represented by

[0334] Here, R AA2 For amino,

[0335] AA 3 is Val, Leu, Ile, Phe, or Trp,

[0336] AA 4 is (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Asp, or (N-Me)Glu,

[0337] AA 5 is β-Ala, GABA, Ape, Acp, or β-homoPro,

[0338] L N1 is of the formula -C(=O)-, or -S(=O)2-,

[0339] L N2 is a single bond, a compound of the formula -O-, or a compound of the formula -C(=O)-NH-,

[0340] R A1 , R A2 are hydrogen atoms,

[0341] R B1 , R B2 , R B3is independently a hydrogen atom, a carbamoyl group, a halogen atom, a C 1-6 Alkoxy or halogenated C 1-6 Alkoxy.

[0342] (8) As another embodiment of the present invention, there is provided a substituted polypeptide or a pharmaceutically acceptable salt thereof according to any one of (1) to (4), wherein the substituted polypeptide represented by the formula [I'] is a substituted polypeptide represented by the following formula [I]:

[0343]

[0344] In the above formula [I],

[0345] AA 1 is β-Asp, γ-Glu, or γ-(d)-Glu,

[0346] AA 2 The following formula [II-1] or formula [II-2]

[0347]

[0348] The group represented by

[0349] Here, R AA2 is a hydroxyl group or an amino group,

[0350] AA 3 is Val, Leu, Ile, Phe, or Trp,

[0351] AA 4 is a single bond, Pro, (N-Me)Ala, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Phe, (N-Me)Tyr, (N-Me)Ser, (N-Me)Asp, or (N-Me)Glu,

[0352] AA 5 is a single bond, Pro, (d)-Pro, β-homoPro, Arg, (d)-Arg, Lys, (d)-Lys, β-Ala, GABA, Ape, or Acp,

[0353] L 1 is a single bond,

[0354] L 2 is a single bond,

[0355] L N1 is of the formula -C(=O)-, or -S(=O)2-,

[0356] L N2 For a single bond, C1-3 Alkanediyl, formula -O-, or formula -C(=O)-NH-,

[0357] R A For hydrogen atoms, halogen atoms, C 1-6 Alkyl, or C 1-6 Alkoxy,

[0358] R B is a hydrogen atom, a carbamoyl group, a halogen atom, a C 1-6 Alkyl, or C 1-6 Alkoxy,

[0359] L C is a single bond, Pro, Arg, (d)-Arg, Lys, (d)-Lys, or (d)-Lys-(d)-Lys,

[0360] R C It is of the formula -OH or -NH2.

[0361] (9) As another embodiment of the present invention, there is provided a substituted polypeptide or a pharmaceutically acceptable salt thereof according to any one of (1) to (5), wherein in the substituted polypeptide represented by the formula [I'],

[0362] AA 1 is Asp, β-(d)-Asp, or γ-(d)-Glu,

[0363] AA 2 is a group selected from the following:

[0364] From the following formula [II-1]

[0365]

[0366] The groups represented

[0367] From the following formulas [IV-7] and [IV-9]

[0368]

[0369] The group represented by

[0370] Here, R AA2 For amino,

[0371] AA 3 is Val, Leu, or Ile,

[0372] AA 4 is (N-Me)Ile, or (N-Me)Glu,

[0373] AA 5Ape, or β-homoPro,

[0374] W 1 For -L 1 -, or -L 1 '-L 1 ”-,

[0375] Here, L 1 is a single bond,

[0376] L 1 ' is GABA, or Ape,

[0377] L 1 ” is Asn, (d)-Ser, (d)-Thr, or Glu,

[0378] L N1 is of the formula -C(=O)-, or -S(=O)2-,

[0379] L N2 is of the formula -O-, or of the formula -C(=O)-NH-,

[0380] R A1 , R A2 are hydrogen atoms,

[0381] R B1 , R B2 , R B3 is independently a hydrogen atom, a carbamoyl group, a halogen atom, a C 1-6 Alkoxy or halogenated C 1-6 Alkoxy,

[0382] W C is a single bond, or (d)-Lys,

[0383] R C The formula is -NH2.

[0384] (10) As another embodiment of the present invention, there is provided a substituted polypeptide or a pharmaceutically acceptable salt thereof according to any one of (1) to (5), which is selected from the following compounds:

[0385]

[0386]

[0387]

[0388] (11) As another aspect of the present invention, there is provided a drug comprising the substituted polypeptide or a pharmaceutically acceptable salt thereof according to any one of (1) to (10) as an active ingredient.

[0389] (12) As another aspect of the present invention, there is provided an MMP2 inhibitor comprising the substituted polypeptide or a pharmaceutically acceptable salt thereof according to any one of (1) to (10) as an active ingredient.

[0390] (13) As another embodiment of the present invention, there is provided an inhibitor of cancer cell proliferation, invasion, or metastasis comprising the substituted polypeptide or a pharmaceutically acceptable salt thereof according to any one of (1) to (10) as an active ingredient.

[0391] (14) As another aspect of the present invention, there is provided a fibrosis inhibitor comprising the substituted polypeptide or a pharmaceutically acceptable salt thereof according to any one of (1) to (10) as an active ingredient.

[0392] (15) As another embodiment of the present invention, there is provided a preventive or therapeutic drug for cancer disease or organ fibrosis, or symptoms associated with cancer disease or organ fibrosis, comprising a substituted polypeptide or a pharmaceutically acceptable salt thereof as an active ingredient.

[0393] Effects of the Invention

[0394] The compound of the present invention (hereinafter also referred to as "the compound of the present invention") has an activity of inhibiting MMP2. The compound of the present invention also includes a compound having an activity of selectively inhibiting MMP2. DETAILED DESCRIPTION

[0395] The present invention provides a substituted polypeptide represented by the formula [I'] or a pharmaceutically acceptable salt thereof having an MMP2 inhibitory effect.

[0396] Hereinafter, the compound of the present invention will be described in further detail, but the present invention is not limited to the exemplified compounds.

[0397] In this specification, "amino acid" refers to an organic compound having both an amino group and a carboxyl group in a broad sense. On the other hand, in a narrow sense (especially in the field of biochemistry), it refers to an "α-amino acid" that is a structural unit of protein in an organism (the α-amino acid refers to an amino acid in which the amino group is also bonded to the carbon (α carbon) to which the carboxyl group is bonded).

[0398] As amino acids in this specification, for example, natural proteinogenic L-amino acids, natural non-proteinogenic amino acids, and unnatural amino acids can be mentioned. Here, as unnatural amino acids, there can be mentioned: D-forms of natural proteinogenic L-amino acids, chemically modified amino acids such as amino acid variants and derivatives, and chemically synthesized compounds having properties known in the art as characteristics of amino acids.

[0399] In the present specification, when the name of an "amino acid" is described without abbreviating it into, for example, a three-letter representation or a one-letter representation, it means an amino acid of L-form or D-form, or a combination of both.

[0400] In this specification, when "amino acid" is described by abbreviations such as three-letter representation or one-letter representation, it means L-type amino acid. In some cases, "L" or "1" is added before "amino acid" to clarify that it is L-type amino acid.

[0401] In the present specification, when "D" or "d" is added before "amino acid", it means D-type amino acid.

[0402] In the present specification, "natural proteinogenic L-amino acid" refers to naturally occurring L-amino acids constituting proteins, and examples thereof include Gly or Ala, Val, Leu, Ile, Pro, Phe, His, Trp, Tyr, Ser, Thr, Met, Cys, Asp, Glu, Asn, Gln, Lys, Arg, etc.

[0403] In the present specification, "D-form of a natural proteinogenic L-amino acid" refers to the enantiomer of the natural proteinogenic L-amino acid. Natural proteinogenic L-amino acids other than glycine have at least one asymmetric carbon and are optically active. The structures of these amino acids are different from the L-form and the D-form according to the structures of the L-form and the D-form of glyceraldehyde.

[0404] It should be noted that D-amino acids may also exist among the amino acids other than the naturally proteinogenic L-amino acids.

[0405] In the present specification, "natural non-proteinogenic amino acids" refer to naturally occurring amino acids that do not constitute proteins, and examples thereof include: L-norleucine (hereinafter, also recorded as Nle; it should be noted that, hereinafter, in the present specification, "collectively recorded in parentheses" represents an abbreviation) or β-alanine (β-Ala), L-ornithine (Orn).

[0406] In addition, when a natural non-proteinogenic amino acid has an asymmetric carbon, the amino acid exists in L-form and D-form. In addition, amino acids other than natural non-proteinogenic amino acids may also exist in L-form and D-form.

[0407] In the present specification, "non-natural amino acids" refer to amino acids that do not constitute proteins and are mainly artificially produced, and refer to amino acids other than the above-mentioned "natural proteinogenic L-amino acids and natural non-proteinogenic amino acids". Examples of non-natural amino acids include: D-types of natural proteinogenic L-amino acids (D-Cys, D-Ser, etc.); α-methyl amino acids (2-aminoisobutyric acid (Aib), etc.); amino acids having an excess of methylene groups in the side chains (“homo” amino acids such as L-β-homoproline (β-Hep or β-homoPro), L-homoserine (Hes or homoSer), L-homocysteine ​​(Hec or homoCys), L-homoproline (homoPro), and L-homoglutamic acid (homoGlu); amino acids in which the carboxylic acid functional group in the side chain is substituted with a sulfonic acid group (L-cysteine, etc.); chemically modified amino acids such as amino acid variants and derivatives (hydroxyproline, L-2,3-diaminopropionic acid (Dap), L-2,4-diaminobutyric acid (Dab), and N-methylglycine); and chemically synthesized compounds having properties known in the art that are characteristic of amino acids (4-aminobenzoic acid, etc.).

[0408] When the non-natural amino acid has an asymmetric carbon, the amino acid exists in an L-form and a D-form.

[0409] Specific examples of the "unnatural amino acid" in the present specification include the following.

[0410] ·(d)-Pro, (d)-Ser, (d)-Thr, (d)-Asp, (d)-Glu, (d)-Arg, (d)-Lys;

[0411] β-homoPro;

[0412] ·β-Ala, GABA, Ape, Acp;

[0413] ·(N-Me)Ala, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Phe, (N-Me)Tyr, (N-Me)Ser, (N-Me)Asp, (N-Me)Glu;

[0414] · The following formula [II-1] or formula [II-2]

[0415]

[0416] The group represented by (here, R AA2 is hydroxyl or amino);

[0417] Amino acids listed in Table 1 and Table 2 described below.

[0418] It should be noted that the nitrogen atom involved in the peptide bond of the amino acid in this specification may be alkylated. In this case, the amino acid is also referred to as an "N-alkyl amino acid". Here, examples of the alkyl group include a methyl group and an ethyl group.

[0419] In this specification, when "β-Asp" is described, it refers to aspartic acid participating in the amide bond of the main chain via the carboxyl group of the side chain, as shown in the structure represented by the following formula [III-1]. Similarly, when "β-(d)-Asp", "γ-Glu", and "γ-(d)-Glu" are described, they refer to the structures represented by the following formulas [III-2] to [III-4], respectively.

[0420]

[0421] In addition, when described as "(N-Me)Glu(OtBu)", as shown in the structure represented by the following formula [III-5], it means the N-methyl form of the amino acid (Glu(OtBu)).

[0422]

[0423] Moreover, in this specification, when AA 2 When the corresponding structure is recorded as "(2S,4S)-(4-amino)Pro", it refers to the structure represented by the following formula [II-3]. Similarly, when it is recorded as "(2S,4R)-(4-amino)Pro", "(2S,4S)-(4-hydroxy)Pro", "(2S,4R)-(4-hydroxy)Pro", it refers to the structures represented by the following formulas [II-4] to [II-6] respectively. Moreover, when it is recorded as "(S)-piperazine", it refers to the structure represented by the following formula [II-2].

[0424]

[0425] In the present specification, "n" means "normal", "i" means "iso", "s" means "secondary", "t" and "tert" mean "tertiary", "c" means "cyclo", "o" means "ortho", "m" means "meta", and "p" means "para".

[0426] The "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0427] “C 1-6The term "alkyl" refers to a linear or branched alkyl group having 1 to 6 carbon atoms. Examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl.

[0428] "Halogenated C 1-6 The term "alkyl" refers to a linear or branched alkyl group having 1 to 6 carbon atoms substituted by a halogen atom. The preferred number of substitutions for the halogen atom is 1 to 5, and the preferred halogen atom is a fluorine atom. Examples thereof include monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1,1,2,2-tetrafluoroethyl, 1,1,2,2,2-pentafluoroethyl, 2-fluoroethyl, 2-fluoro-2-methylpropyl, 2,2-difluoropropyl, 1-fluoro-2-methylpropane-2-yl, 1,1-difluoro-2-methylpropane-2-yl, 1-fluoropentyl, 1-fluorohexyl, and 2,2,2-trifluoro-1-methylethyl.

[0429] The "aryl group" refers to a monocyclic aromatic hydrocarbon group or a condensed polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms, and examples thereof include phenyl, naphthyl, anthracenyl, and the like.

[0430] The "aromatic ring" refers to a monocyclic aromatic hydrocarbon ring or a condensed polycyclic aromatic hydrocarbon ring having 6 to 14 carbon atoms, and examples thereof include a benzene ring, a naphthalene ring, and an anthracene ring.

[0431] In addition, partially saturated aryl groups are also included in "aryl groups". The same applies to aromatic rings. "Partially saturated aryl groups" and "partially saturated aromatic rings" as the corresponding aromatic rings mean: a monocyclic aromatic hydrocarbon group or a condensed polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms that is partially saturated, and a ring having such a structure. Examples include: dihydroindenyl, dihydroindenyl ring, etc.

[0432] The "heteroaryl group" refers to a 5- to 7-membered monocyclic aromatic heterocyclic group consisting of one or more atoms selected from oxygen atoms, sulfur atoms and nitrogen atoms and 1 to 6 carbon atoms, or a condensed polycyclic aromatic heterocyclic group consisting of 9 to 14 atoms consisting of one or more atoms selected from oxygen atoms, sulfur atoms and nitrogen atoms and 1 to 13 carbon atoms. Examples thereof include imidazolyl, pyrazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, benzopyrazolyl, benzotriazolyl, benzofuranyl, benzothienyl, quinolyl, isoquinolyl, quinoxalinyl and the like.

[0433] The "heteroaromatic ring" refers to a 5- to 7-membered monocyclic aromatic heterocyclic ring composed of one or more atoms selected from oxygen atoms, sulfur atoms and nitrogen atoms and 1 to 6 carbon atoms, or a condensed polycyclic aromatic heterocyclic ring composed of 9 to 14 atoms composed of one or more atoms selected from oxygen atoms, sulfur atoms and nitrogen atoms and 1 to 13 carbon atoms. Examples thereof include an imidazole ring, a pyrazole ring, a thiophene ring, a thiazole ring, an isothiazole ring, a thiadiazole ring, an oxazole ring, an isoxazole ring, an oxadiazole ring, a pyrrole ring, a triazole ring, a tetrazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a triazine ring, an indole ring, a benzopyrazole ring, a benzotriazole ring, a benzofuran ring, a benzothiophene ring, a quinoline ring, an isoquinoline ring, and a quinoxaline ring.

[0434] In addition, partially saturated heteroaryl groups are also included in the “heteroaryl group”. The same applies to heteroaromatic rings. “Partially saturated heteroaryl groups” and “partially saturated heteroaromatic rings” as the corresponding heteroaromatic rings mean: a 5- to 7-membered partially saturated monocyclic heterocyclic group consisting of one or more atoms selected from the same or different oxygen atoms, sulfur atoms and nitrogen atoms and 1 to 6 carbon atoms, or a partially saturated fused polycyclic heterocyclic group consisting of 9 to 14 atoms consisting of one or more atoms selected from the same or different oxygen atoms, sulfur atoms and nitrogen atoms and 1 to 13 carbon atoms, and a ring having such a structure. For example, oxazolidinyl, thiazolinyl, dihydropyridyl, dihydrobenzofuranyl, chromanyl, dihydropyranopyridyl, dihydrofuranopyridyl, tetrahydroquinolinyl, dihydrobenzodioxinyl (dihydrobenzodioxynyl), tetrahydrotriazoloazepinyl, oxazolidine ring, thiazoline ring, dihydropyridine ring, dihydrobenzofuran ring, chroman ring, dihydropyranopyridine ring, dihydrofuranopyridine ring, tetrahydroquinoline ring, tetrahydroquinoline ring, dihydrobenzodioxinyl ring, tetrahydrotriazoloazepinyl ring and the like can be mentioned.

[0435] "A 4- to 7-membered saturated heterocyclic group containing a nitrogen atom" means a 4- to 7-membered monocyclic saturated heterocyclic group consisting of one nitrogen atom and 3 to 6 carbon atoms, and in addition to the nitrogen atom, it may contain one atom selected from an oxygen atom, a sulfur atom and a nitrogen atom. Examples thereof include azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, thiomorpholinyl and piperazinyl.

[0436] "A 4- to 7-membered saturated heterocyclic group containing one nitrogen atom and optionally containing one heteroatom" means a 4- to 7-membered monocyclic saturated heterocyclic group consisting of one nitrogen atom and 3 to 6 carbon atoms, and in addition to the nitrogen atom, it may contain one atom selected from an oxygen atom, a sulfur atom and a nitrogen atom. Examples thereof include azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, thiomorpholinyl and piperazinyl.

[0437] In addition, as "can be 1-4 The term "4- to 7-membered saturated heterocyclic group" is a group cross-linked with an alkanediyl group and containing one nitrogen atom and one heteroatom, for example, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl (a group represented by the following formula [VI-16]) and 3,8-diazabicyclo[3.2.1]octan-3-yl (a group represented by the following formula [VI-18]).

[0438]

[0439] “C 1-6 The term "alkoxy" refers to a straight-chain or branched alkoxy group having 1 to 6 carbon atoms. Examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy and n-hexyloxy.

[0440] "Halogenated C 1-6 The term "alkoxy" refers to a linear or branched alkoxy group having 1 to 6 carbon atoms which is substituted by a halogen atom. The preferred number of substitutions for the halogen atom is 1 to 5, and the preferred halogen atom is a fluorine atom. Examples thereof include a monofluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a 1-fluoroethoxy group, a 1,1-difluoroethoxy group, a 1,1,2,2-tetrafluoroethoxy group, a 2-fluoroethoxy group, a 2,2,2-trifluoroethoxy group, a 3,3,3-trifluoropropoxy group, a 1,3-difluoropropane-2-yloxy group, a 2-fluoro-2-methylpropoxy group, a 2,2-difluoropropoxy group, a 1-fluoro-2-methylpropane-2-yloxy group, a 1,1-difluoro-2-methylpropane-2-yloxy group, and a 4,4,4-trifluorobutoxy group.

[0441] “C 1-6 "Alkylcarbonyl" means the "C 1-6 "Alkyl" is a group bonded to a carbonyl group. Examples thereof include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl and n-hexylcarbonyl.

[0442] “C 1-6 "Alkylcarbonylamino" means the "C 1-6 "Alkylcarbonyl" is a group bonded to an amino group. Examples thereof include methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, n-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino, tert-butylcarbonylamino, n-pentylcarbonylamino and n-hexylcarbonylamino.

[0443] “C 1-6 "Alkylamino" means having 1 to 2 identical or different "C 1-6The amino group having an "alkyl" group as a substituent. For example, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-pentylamino, n-hexylamino, dimethylamino, diethylamino, di(n-propyl)amino, di(isopropyl)amino, ethylmethylamino, and methyl(n-propyl)amino.

[0444] "Single C 1-6 "Alkylamino" means having one of the "C 1-6 An amino group having an "alkyl" group as a substituent. Examples thereof include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-pentylamino and n-hexylamino.

[0445] "Two C 1-6 "Alkylamino" means having two identical or different "C 1-6 An amino group having an "alkyl" group as a substituent. Examples thereof include dimethylamino, diethylamino, di(n-propyl)amino, di(isopropyl)amino, ethylmethylamino and methyl(n-propyl)amino.

[0446] "Single C 1-6 "Alkylaminocarbonyl" means the "mono-C 1-6 "Alkylamino" is a group bonded to a carbonyl group. Examples thereof include methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, isobutylaminocarbonyl, n-pentylaminocarbonyl and n-hexylaminocarbonyl.

[0447] "Two C 1-6 "Alkylaminocarbonyl" means the "diC 1-6 "Alkylamino" is a group bonded to a carbonyl group. Examples thereof include dimethylaminocarbonyl, diethylaminocarbonyl, di(n-propyl)aminocarbonyl, di(isopropyl)aminocarbonyl, ethylmethylaminocarbonyl, methyl(n-propyl)aminocarbonyl, and the like.

[0448] “C 1-6 "Alkylcarbonyl" means the "C 1-6 "Alkyl" is a group bonded to a carbonyl group. Examples thereof include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl and n-hexylcarbonyl.

[0449] “C 2-16The term "alkylcarbonyl" refers to a group in which a linear or branched alkyl group having 2 to 16 carbon atoms is bonded to a carbonyl group. Examples thereof include ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-decylcarbonyl (undecanoyl), n-dodecylcarbonyl (tridecanoyl), and n-tetradecylcarbonyl (pentadecanoyl).

[0450] In addition, "the C 2-16 "Alkylcarbonyl" means the "C 2-16 The "C" in "alkylcarbonyl" 2-16 A group in which the terminal of an "alkyl group" is substituted with a carboxyl group. Examples thereof include 11-carboxoundecanoyl, 13-carboxytridecanoyl, and 15-carboxypentadecanoyl.

[0451] “C 1-6 "Alkylsulfonyl" means the "C 1-6 A group in which an "alkyl" group is bonded to a sulfonyl group. Examples thereof include a methylsulfonyl group, an ethylsulfonyl group, an n-propylsulfonyl group, an isopropylsulfonyl group, an n-butylsulfonyl group, an isobutylsulfonyl group, a sec-butylsulfonyl group, a tert-butylsulfonyl group, an n-pentylsulfonyl group, and an n-hexylsulfonyl group.

[0452] “C 1-3 The term "alkanediyl" refers to a divalent hydrocarbon obtained by removing one hydrogen atom from an alkyl group having 1 to 3 carbon atoms. Examples thereof include methanediyl, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,1-diyl, propane-1,3-diyl, and propane-2,2-diyl.

[0453] “C 1-4 The term "alkanediyl" refers to a divalent hydrocarbon obtained by removing one hydrogen atom from an alkyl group having 1 to 4 carbon atoms. Examples thereof include methanediyl, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,1-diyl, propane-1,3-diyl, propane-2,2-diyl, and butane-1,4-diyl.

[0454] “C 2-3 The term "olefin diyl" refers to a divalent unsaturated hydrocarbon obtained by removing one hydrogen atom from an alkenyl group having 2 to 3 carbon atoms. Examples thereof include ethylene-1,1-diyl, ethylene-1,2-diyl, prop-1-ene-1,1-diyl, prop-2-ene-1,1-diyl, prop-1-ene-1,3-diyl, prop-2-ene-1,3-diyl, and prop-1-ene-2,2-diyl.

[0455] The "triazolediyl group" refers to a divalent triazole obtained by removing two hydrogen atoms from a triazole ring. Examples thereof include structures represented by the following formulae [VIII-1] to [VIII-5].

[0456]

[0457] The abbreviations used in this specification refer to the structures shown in Tables 1 to 4 below.

[0458] [Table 1-1]

[0459]

[0460] [Table 2-1]

[0461]

[0462] [Table 2-2]

[0463]

[0464]

[0465] [Table 2-3]

[0466]

[0467]

[0468] [Table 2-4]

[0469]

[0470]

[0471] [Table 3-1]

[0472]

[0473] [Table 4-1]

[0474]

[0475]

[0476] [Table 4-2]

[0477]

[0478]

[0479] Preferred embodiments of the substituted polypeptide represented by the formula [I'] or a pharmaceutically acceptable salt thereof of the present invention are shown below.

[0480] Preferred AA 1 is Asp, β-Asp, β-(d)-Asp, γ-Glu, or γ-(d)-Glu,

[0481] A more preferred AA 1 is β-Asp, γ-Glu, or γ-(d)-Glu,

[0482] At this time, the further preferred AA 1 is γ-(d)-Glu,

[0483] Other more preferred AA 1 is β-(d)-Asp or γ-(d)-Glu,

[0484] At this time, the further preferred AA 1 is β-(d)-Asp,

[0485] Other more preferred AA 1 For Asp.

[0486] Preferred AA 2 The following formula [II-1] or formula [II-2]

[0487]

[0488] The groups represented

[0489] The following formula [IV-7], [IV-8], [IV-9], [IV-11] or [IV-12]

[0490]

[0491] The groups represented

[0492] Ala,

[0493] From the following formula [IV-27]

[0494]

[0495] The group represented by

[0496] Pro,

[0497] Here, the preferred R AA2 is a hydroxyl group or an amino group,

[0498] More preferred AA 2 The following formula [II-1]

[0499]

[0500] The groups represented

[0501] The following formula [IV-7], [IV-8], [IV-9], [IV-11], or [IV-12]

[0502]

[0503] The group represented by

[0504] Here, the preferred R AA2 For amino,

[0505] Further preferred AA 2 The following formula [IV-7] or [IV-9]

[0506]

[0507] A group represented by or represented by the following formula [II-1]

[0508]

[0509] The group represented by

[0510] Here, the preferred R AA2 For amino,

[0511] A particularly preferred AA 2 The following formula [II-1]

[0512]

[0513] The group represented by

[0514] Here, the preferred R AA2 For amino,

[0515] Other particularly preferred AA 2 The following formula [IV-7] or [IV-9]

[0516]

[0517] Represents the group.

[0518] Preferred AA 3 Val, Leu, Ile, represented by the following formula [IV-2]

[0519]

[0520] The groups represented

[0521] Phe, represented by the following formula [IV-3], [IV-4], or [IV-5]

[0522]

[0523] The group represented by

[0524] Trp,

[0525] More preferred AA 3 is Val, Leu, Ile, Phe, or Trp,

[0526] Further preferred AA 3 is Val, Leu, or Ile,

[0527] A particularly preferred AA 3 For Val,

[0528] Other particularly preferred AA 3 For Leu,

[0529] Other particularly preferred AA 3 For Ile.

[0530] Preferred AA 4 For single bonds, Pro, Gly, homoSer, Met, Glu, (N-Me)Ala, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Phe, (N-Me)Tyr, (N-Me)S er, (N-Me)Met, (N-Me)Asp, (N-Me)Glu, (d)-Pro, (d)-Ala, (d)-Phe, (d)-Tyr, (d)-Ser, (d)-Thr, or (d)-(N-Me)Glu,

[0531] More preferred AA 4 (N-Me)Ala, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Phe, (N-Me)Tyr, (N-Me)Ser, (N-Me)Met, ( N-Me)Asp, (N-Me)Glu), (d)-Pro, (d)-Ala, (d)-Phe, (d)-Tyr, (d)-Ser, (d)-Thr, or (d)-(N-Me)Glu,

[0532] A further preferred AA 4 is (N-Me)Glu or (N-Me)Asp,

[0533] In this case, AA is particularly preferred 4 is (N-Me)Glu,

[0534] Other further preferred AA 4 is (N-Me)Ile, (N-Me)Val, or (N-Me)Leu,

[0535] In this case, AA is particularly preferred 4 It is (N-Me)Ile.

[0536] Preferred AA 5 Any of the following groups:

[0537] β-Ala, GABA, Ape, Acp, Pro, (d)-Pro, β-homoPro, single bond, Arg, (d)-Arg,

[0538] From the following formulas [IV-7], [IV-9], [IV-13]

[0539]

[0540] The groups represented

[0541] Lys, (d)-Lys,

[0542] Ala, represented by the following formula [IV-1]

[0543]

[0544] The groups represented

[0545] From the following formulas [IV-27], [IV-28], [IV-29]

[0546]

[0547] The groups represented

[0548] Phe, His, Thr,

[0549] From the following formulas [III-6] to [III-13]

[0550]

[0551] The group represented by

[0552] More preferred AA 5 β-Ala, GABA, Ape, Acp, Pro, (d)-Pro, β-homoPro, single bond, Arg, (d)-Arg,

[0553] From the following formulas [IV-7], [IV-9], [IV-13]

[0554]

[0555] The groups represented

[0556] Lys, or (d)-Lys,

[0557] Further preferred AA 5is β-Ala, GABA, Ape, Acp, Pro, (d)-Pro, or β-homoPro,

[0558] Particularly preferred AA 5 It is β-Ala, GABA, Ape, Acp, or β-homoPro.

[0559] Preferred W 1 For -L 1 -or-L 1 '-L 1 ”-,

[0560] Here, L 1 is a single bond,

[0561] In addition, L 1 ' is a group selected from the following:

[0562] β-Ala, GABA, Ape, Acp,

[0563] From the following formulas [III-6] to [III-13]

[0564]

[0565] The groups represented

[0566] From the following formulas [IV-23] and [IV-24]

[0567]

[0568] The group represented by

[0569] L 1 " is a single bond, Asn, (d)-Ser, (d)-Thr, Lys, Arg, or Glu,

[0570] A more preferred W 1 For -L 1 -or-L 1 '-L 1 ”-,

[0571] Here, L 1 is a single bond,

[0572] In addition, L 1 ' is any one of the following groups:

[0573] β-Ala, GABA, Ape, Acp,

[0574] From the following formulas [III-6] to [III-13]

[0575]

[0576]

[0577] The group represented by

[0578] L 1 ” is Asn, (d)-Ser, (d)-Thr, or Glu,

[0579] At this time, it is further preferred that W 1 For -L 1 -or-L 1 '-L 1 ”-,

[0580] Here, L 1 is a single bond,

[0581] In addition, L 1 ' is β-Ala, GABA, Ape, or Acp,

[0582] L 1 ” is Asn, (d)-Ser, (d)-Thr, or Glu,

[0583] In this case, W is particularly preferred 1 For -L 1 -,

[0584] Here, L 1 is a single bond,

[0585] Other more preferred W 1 For -L 1 '-L 1 ”-,

[0586] Here, L 1 ' is the following formula [IV-23] or [IV-24]

[0587]

[0588] The group represented by

[0589] L 1 " is a single key.

[0590] Preferred L 2 For a single key.

[0591] Preferred L N1 is of the formula -C(=O)- or the formula -S(=O)2-,

[0592] A more preferred L N1 The formula is -C(=O)-,

[0593] Other more preferred L N1The formula is -S(=O)2-.

[0594] Preferred L N2 is a single bond, a compound of the formula -O-, or a compound of the formula -C(=O)-NH-,

[0595] More preferably, L N2 is of the formula -O- or -C(=O)-NH-,

[0596] A further preferred L N2 The formula is -O-,

[0597] Other further preferred L N2 The formula is -C(=O)-NH-.

[0598] The preferred ring A is a benzene ring or a pyridine ring,

[0599] More preferably, ring A is a benzene ring,

[0600] Preferred R A1 , R A2 are independently a hydrogen atom or a halogen atom,

[0601] More preferably R A1 , R A2 A hydrogen atom.

[0602] Preferred ring B is phenyl or pyridyl,

[0603] More preferably, ring B is phenyl,

[0604] Preferred R B1 , R B2 , R B3 is independently a hydrogen atom, a carbamoyl group, a halogen atom, a C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkoxy,

[0605] More preferably R B1 , R B2 , R B3 is independently a hydrogen atom, a carbamoyl group, a halogen atom, a C 1-6 Alkoxy or halogenated C 1-6 Alkoxy.

[0606] Preferred W C is a single bond or a linker consisting of 1 to 3 amino acids,

[0607] Here, the 1 to 3 amino acids forming the linker are not particularly limited, but are preferably selected from Gly, Pro, Arg, (d)-Arg, Lys, (d)-Lys, β-Ala, GABA, and Ape, respectively, which are the same or different.

[0608] Here, in the C When the group represented by contains Lys or (d)-Lys,

[0609] The amino group of the side chain of Lys and (d)-Lys may be replaced by a C 2-16 Alkylcarbonyl, Lys (the amino group of the side chain of Lys may be C 2-16 substituted with an alkylcarbonyl group), or (d)-Lys (the amino group of the side chain of the (d)-Lys may be substituted with a C 2-16 substituted with alkylcarbonyl),

[0610] More preferably W C is a single bond, Pro, Arg, (d)-Arg, Lys, (d)-Lys, or (d)-Lys-(d)-Lys,

[0611] Further preferred W C is a single bond, Arg, (d)-Arg, Lys, or (d)-Lys,

[0612] A particularly preferred W C is a single bond,

[0613] Other particularly preferred W C is (d)-Lys.

[0614] Preferred R C Formula: -OH, -NH2, C 1-6 Alkylamino (the C 1-6 Alkylamino C 1-6 The alkyl group may be substituted by one group selected from hydroxyl, amino, and a 4-7-membered saturated heterocyclic group containing a nitrogen atom), or a 4-7-membered saturated heterocyclic group containing one nitrogen atom and further containing one heteroatom (the 4-7-membered saturated heterocyclic group containing one nitrogen atom and further containing one heteroatom may be selected from hydroxyl, and C 1-6 Alkyl (the C 1-6 The alkyl group may be substituted with a carbamoyl group), and the two carbon atoms in the 4-7 membered saturated heterocyclic group containing a nitrogen atom and a heteroatom may be substituted with a C 1-4 Alkanediyl crosslinking),

[0615] More preferably R C Is of formula -OH or formula -NH2,

[0616] More preferably, R C The formula is -NH2.

[0617] Another preferred embodiment of the compound of the present invention is a substituted polypeptide represented by the formula [I'] or a pharmaceutically acceptable salt thereof, wherein:

[0618] AA 1 is β-Asp, γ-Glu, or γ-(d)-Glu,

[0619] AA 2 The following formula [II-1] or formula [II-2]

[0620]

[0621] The group represented by

[0622] Here, R AA2 is a hydroxyl group or an amino group,

[0623] AA 3 is Val, Leu, Ile, Phe, or Trp,

[0624] AA 4 is a single bond, Pro, (N-Me)Ala, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Phe, (N-Me)Tyr, (N-Me)Ser, (N-Me)Asp, or (N-Me)Glu,

[0625] AA 5 is a single bond, Pro, (d)-Pro, β-homoPro, Arg, (d)-Arg, Lys, (d)-Lys, β-Ala, GABA, Ape, or Acp,

[0626] W 1 For L 1 , L 1 is a single bond,

[0627] L 2 is a single bond,

[0628] L N1 The formula is -S(=O)2-,

[0629] L N2 is a single bond, a compound of the formula -O-, or a compound of the formula -C(=O)-NH-,

[0630] Ring A is a benzene ring,

[0631] R A1 , R A2is a hydrogen atom,

[0632] Ring B is phenyl,

[0633] R B1 , R B2 , R B3 are independently a hydrogen atom, a carbamoyl group, a halogen atom, or C 1-6 Alkoxy,

[0634] W C is a single bond, Pro, Arg, (d)-Arg, Lys, (d)-Lys, or (d)-Lys-(d)-Lys,

[0635] R C The formula is -NH2.

[0636] Another preferred embodiment of the present invention is a substituted polypeptide represented by formula [I'] or a pharmaceutically acceptable salt thereof, wherein:

[0637] AA 1 is β-Asp, γ-Glu, or γ-(d)-Glu,

[0638] At this time, the further preferred AA 1 is γ-(d)-Glu,

[0639] AA 2 The following formula [II-1]

[0640]

[0641] The group represented by

[0642] Here, R AA2 For amino,

[0643] AA 3 is Val, Leu, or Ile,

[0644] Here,

[0645] A further preferred AA 3 For Val,

[0646] Other further preferred AA 3 For Leu,

[0647] Other further preferred AA 3 For Ile,

[0648] AA 4 is (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Asp, or (N-Me)Glu,

[0649] Here,

[0650] A further preferred AA 4 is (N-Me)Val, (N-Me)Leu, or (N-Me)Ile,

[0651] In this case, AA is particularly preferred 4 is (N-Me)Ile,

[0652] Other further preferred AA 4 is (N-Me)Asp or (N-Me)Glu,

[0653] In this case, AA is particularly preferred 4 is (N-Me)Glu,

[0654] AA 5 is Pro, (d)-Pro, β-homoPro, β-Ala, GABA, Ape, or Acp,

[0655] Here,

[0656] A further preferred AA 5 is Pro, (d)-Pro, or β-homoPro,

[0657] In this case, AA is particularly preferred 5 For β-homoPro,

[0658] Other further preferred AA 5 is β-Ala, GABA, Ape, or Acp,

[0659] In this case, AA is particularly preferred 5 is β-Ala, GABA, or Ape,

[0660] W 1 For L 1 ,

[0661] L 1 is a single bond,

[0662] L 2 is a single bond,

[0663] L N1 The formula is -S(=O)2-,

[0664] L N2 is a single bond, a compound of the formula -O-, or a compound of the formula -C(=O)-NH-,

[0665] Here,

[0666] A further preferred L N1The formula is -C(=O)-,

[0667] Other further preferred L N1 The formula is -S(=O)2-,

[0668] Ring A is a benzene ring,

[0669] R A1 , R A2 is a hydrogen atom,

[0670] Ring B is phenyl,

[0671] R B1 , R B2 , R B3 are independently a hydrogen atom, a carbamoyl group, a halogen atom, or C 1-6 Alkoxy,

[0672] W C is a single bond or (d)-Lys,

[0673] Here,

[0674] A further preferred W C is a single bond,

[0675] Other further preferred W C is (d)-Lys,

[0676] R C The formula is -NH2.

[0677] Another preferred embodiment of the compound of the present invention is W 1 For -L 1 '-L 1 ”-、L 2 is a single bond, a substituted polypeptide represented by the following formula [I'-A] or a pharmaceutically acceptable salt thereof,

[0678]

[0679] Among them, AA 2 AA 3 AA 4 AA 5 , L 1 ', L 1 ”, L N1 , L N2 , R B1 , R B2 , R B3 , W C , and R C The preferred embodiment is as described above.

[0680] Among the polypeptide represented by the above formula [I'-A] or a pharmaceutically acceptable salt thereof, more preferred embodiments are shown below.

[0681] AA 2 The following formula [II-1]

[0682]

[0683] The groups represented

[0684] The following formula [IV-7], [IV-8], [IV-9], [IV-11], or [IV-12]

[0685]

[0686] The group represented by

[0687] Here, R AA2 For amino,

[0688] AA 3 is Val, Leu, Ile, Phe, or Trp,

[0689] AA 4 is (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Asp, or (N-Me)Glu,

[0690] AA 5 is β-Ala, GABA, Ape, Acp, Pro, (d)-Pro, or β-homoPro,

[0691] L 1 ' is β-Ala, GABA, Ape, Acp, represented by the following formula [IV-23] or [IV-24]

[0692]

[0693] The group represented by

[0694] L 1 " is a single bond, Asn, (d)-Ser, (d)-Thr, or Glu,

[0695] L N1 is of the formula -C(=O)- or the formula -S(=O)2-,

[0696] L N2 is of the formula -O- or -C(=O)-NH-,

[0697] R B1 , R B2 , R B3is independently a hydrogen atom, a carbamoyl group, a halogen atom, a C 1-6 Alkoxy or halogenated C 1-6 Alkoxy,

[0698] W C is a single bond, Arg, (d)-Arg, Lys, or (d)-Lys,

[0699] R C It is of the formula -OH or -NH2.

[0700] Among the polypeptide represented by the above formula [I'-A] or a pharmaceutically acceptable salt thereof, further preferred embodiments are shown below.

[0701] AA 2 The following formula [IV-7] or [IV-9]

[0702]

[0703] The group represented by

[0704] AA 3 is Val, Leu, or Ile,

[0705] AA 4 is (N-Me)Ile or (N-Me)Glu,

[0706] AA 5 is β-Ala, GABA, Ape, Acp, or β-homoPro,

[0707] L 1 ' is GABA or Ape,

[0708] L 1 ” is Asn, Glu, (d)-Ser, or (d)-Thr,

[0709] L N1 is of the formula -C(=O)- or the formula -S(=O)2-,

[0710] L N2 is of the formula -O- or -C(=O)-NH-,

[0711] R B1 is a carbamoyl group or a fluorine atom,

[0712] R B2 is a hydrogen atom,

[0713] R B3 is a hydrogen atom,

[0714] W C is a single bond,

[0715] R C The formula is -NH2.

[0716] Furthermore, in this embodiment, a particularly preferred embodiment is shown below.

[0717] In the polypeptide represented by the above formula [I'-A] or a pharmaceutically acceptable salt thereof,

[0718] AA 2 The following formula [IV-7] or [IV-9]

[0719]

[0720] The group represented by

[0721] AA 3 For Val,

[0722] AA 3 Can be Leu,

[0723] AA 3 Can be Ile,

[0724] AA 4 is (N-Me)Ile,

[0725] AA 4 It can be (N-Me)Glu,

[0726] AA 5 is β-Ala, GABA, Ape, or Acp,

[0727] AA 5 Can be β-homoPro,

[0728] L 1 ' is GABA or Ape,

[0729] L 1 ” is Asn, Glu, (d)-Ser, or (d)-Thr,

[0730] L 1 ' and L 1 " is preferably a combination of GABA-Asn, Ape-Asn, Ape-Glu, Ape-(d)-Ser, or Ape-(d)-Thr,

[0731] L N1 The formula is -C(=O)-,

[0732] L N1 It can be of the formula -S(=O)2-,

[0733] L N2Formula -O-, L N2 It may be of the formula -C(=O)-NH-,

[0734] R B1 is a carbamoyl group or a fluorine atom,

[0735] R B2 is a hydrogen atom,

[0736] R B3 is a hydrogen atom,

[0737] W C is a single bond,

[0738] R C The formula is -NH2.

[0739] In addition, in this embodiment, other particularly preferred embodiments are as follows.

[0740] The substituted polypeptide represented by formula [I'-A] is any of the following:

[0741]

[0742] Another preferred embodiment of the compound of the present invention is W 1 For -L 1 -, and here L 1 For a single bond, L 2 is a single bond, a substituted polypeptide represented by the following formula [I'-B] or a pharmaceutically acceptable salt thereof,

[0743]

[0744] Among them, AA 1 AA 2 AA 3 AA 4 AA 5 , L N1 , L N2 , R B1 , R B2 , R B3 , W C , and R C The preferred embodiment is as described above.

[0745] Among the polypeptides represented by the above formula [I'-B] or pharmaceutically acceptable salts thereof, more preferred embodiments are shown below.

[0746] AA 1 is β-Asp, β-(d)-Asp, γ-Glu, or γ-(d)-Glu,

[0747] AA 2The following formula [II-1]

[0748]

[0749] The groups represented

[0750] The following formula [IV-7], [IV-8], [IV-9], [IV-11], or [IV-12]

[0751]

[0752] The group represented by

[0753] Here, R AA2 For amino,

[0754] AA 3 is Val, Leu, Ile, Phe, or Trp,

[0755] AA 4 is (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Asp, or (N-Me)Glu,

[0756] AA 5 is β-Ala, GABA, Ape, Acp, or β-homoPro,

[0757] L N1 is of the formula -C(=O)- or the formula -S(=O)2-,

[0758] L N2 is a single bond, a formula -O- or a formula -C(=O)-NH-,

[0759] R B1 , R B2 , R B3 is independently a hydrogen atom, a carbamoyl group, a halogen atom, a C 1-6 Alkoxy or halogenated C 1-6 Alkoxy,

[0760] W C is a single bond, Arg, (d)-Arg, Lys, or (d)-Lys,

[0761] R C It is of the formula -OH or -NH2.

[0762] Among the polypeptide represented by the above formula [I'-B] or a pharmaceutically acceptable salt thereof, further preferred embodiments are shown below.

[0763] AA 1 is β-(d)-Asp or γ-(d)-Glu,

[0764] AA 2 The following formula [II-1]

[0765]

[0766] The groups represented

[0767] By the following formula [IV-7] or [IV-9]

[0768]

[0769] The group represented by

[0770] Here, R AA2 For amino,

[0771] AA 3 is Val, Leu, or Ile,

[0772] AA 4 is (N-Me)Ile or (N-Me)Glu,

[0773] AA 5 is β-Ala, GABA, Ape, Acp, or β-homoPro,

[0774] L N1 is of the formula -C(=O)- or the formula -S(=O)2-,

[0775] L N2 is of the formula -O- or -C(=O)-NH-,

[0776] R B1 is a carbamoyl group, a chlorine atom, a bromine atom, a methoxy group, or a trifluoromethoxy group,

[0777] R B2 is a hydrogen atom,

[0778] R B3 is a hydrogen atom,

[0779] W C is a single bond or (d)-Lys,

[0780] R C The formula is -NH2.

[0781] Furthermore, in this embodiment, a particularly preferred embodiment is shown below.

[0782] In the polypeptide represented by the above formula [I'-B] or a pharmaceutically acceptable salt thereof,

[0783] AA 1 is β-(d)-Asp,

[0784] AA 1 It can be γ-(d)-Glu,

[0785] AA 2 The following formula [II-1]

[0786]

[0787] The group represented by

[0788] Here, R AA2 For amino,

[0789] AA 2 It can be represented by the following formula [IV-7] or [IV-9]

[0790]

[0791] The group represented by

[0792] AA 3 For Val,

[0793] AA 3 Can be Leu,

[0794] AA 3 Can be Ile,

[0795] AA 4 is (N-Me)Ile,

[0796] AA 4 It can be (N-Me)Glu,

[0797] AA 5 is β-Ala, GABA, Ape, or Acp,

[0798] AA 5 Can be β-homoPro,

[0799] L N1 The formula is -C(=O)-,

[0800] L N1 It can be of the formula -S(=O)2-,

[0801] L N2 The formula is -O-,

[0802] L N2 It may be of the formula -C(=O)-NH-,

[0803] R B1 is a carbamoyl group, a chlorine atom, a bromine atom, a methoxy group, or a trifluoromethoxy group,

[0804] R B2 is a hydrogen atom,

[0805] R B3 is a hydrogen atom,

[0806] W C is a single bond,

[0807] W C can be (d)-Lys,

[0808] R C The formula is -NH2.

[0809] In addition, in this embodiment, other particularly preferred embodiments are as follows.

[0810] The substituted polypeptide represented by the formula [I'-B] is any of the following:

[0811]

[0812]

[0813]

[0814] Another preferred embodiment of the compound of the present invention is L 2 is a single bond, a substituted polypeptide represented by the following formula [I'-C] or a pharmaceutically acceptable salt thereof,

[0815]

[0816] Among them, AA 1 AA 2 AA 3 AA 4 AA 5 , W 1 , L N1 , L N2 , R B1 , R B2 , R B3 , W C , and R C The preferred embodiment is as described above.

[0817] Among the polypeptides represented by the above formula [I'-C] or pharmaceutically acceptable salts thereof, more preferred embodiments are shown below.

[0818] AA 1 is Asp, β-(d)-Asp, or γ-(d)-Glu,

[0819] AA 2 The following formula [IV-7] or [IV-9]

[0820]

[0821] The group represented by

[0822] From the following formula [II-1]

[0823]

[0824] The group represented by

[0825] Here, R AA2 For amino,

[0826] AA 3 is Val, Leu, or Ile,

[0827] AA 4 is (N-Me)Ile or (N-Me)Glu,

[0828] AA 5 Ape or β-homoPro,

[0829] W 1 For -L 1 -or-L 1 '-L 1 ”-,

[0830] Here, L 1 is a single bond,

[0831] In addition, L 1 ' is GABA or Ape,

[0832] L 1 ” is Asn, (d)-Ser, (d)-Thr, or Glu,

[0833] L N1 is of the formula -C(=O)- or the formula -S(=O)2-,

[0834] L N2 is of the formula -O- or -C(=O)-NH-,

[0835] R B1 , R B2 , R B3 is independently a hydrogen atom, a carbamoyl group, a halogen atom, a C 1-6 Alkoxy or halogenated C 1-6 Alkoxy,

[0836] W C is a single bond or (d)-Lys,

[0837] R C The formula is -NH2.

[0838] Among the polypeptide represented by the above formula [I'-C] or a pharmaceutically acceptable salt thereof, further preferred embodiments are shown below.

[0839] AA 1 For Asp,

[0840] AA 1 It can be β-(d)-Asp,

[0841] AA 1 It can be γ-(d)-Glu,

[0842] AA 2 The following formula [IV-7] or [IV-9]

[0843]

[0844] The group represented by

[0845] AA 2 It can be represented by the following formula [II-1']

[0846]

[0847] The group represented by

[0848] Here, R AA2 For amino,

[0849] AA 3 For Val,

[0850] AA 3 Can be Leu,

[0851] AA 3 Can be Ile,

[0852] AA 4 is (N-Me)Ile,

[0853] AA 4 It can be (N-Me)Glu,

[0854] AA 5 For Ape,

[0855] AA 5 Can be β-homoPro,

[0856] W 1 For -L 1 -or-L 1 '-L 1 ”-,

[0857] L 1 is a single bond,

[0858] L 1 ' and L 1 "Combination (-L 1 '-L 1 ”-) is GABA-Asn, Ape-Asn, Ape-Glu, Ape-(d)-Ser, or Ape-(d)-Thr,

[0859] L N1 The formula is -C(=O)-,

[0860] L N1 It can be of the formula -S(=O)2-,

[0861] L N2 The formula is -O-,

[0862] L N2 It may be of the formula -C(=O)-NH-,

[0863] R B1 is a carbamoyl group, a chlorine atom, a bromine atom, a methoxy group, or a trifluoromethoxy group,

[0864] R B2 is a hydrogen atom,

[0865] R B3 is a hydrogen atom,

[0866] W C is a single bond,

[0867] W C can be (d)-Lys,

[0868] R C The formula is -NH2.

[0869] In this embodiment, a particularly preferred embodiment is shown below.

[0870] The substituted polypeptide represented by the formula [I'-C] is any of the following:

[0871]

[0872]

[0873]

[0874]

[0875] In addition, in this embodiment, other particularly preferred embodiments are as follows.

[0876] The substituted polypeptide represented by the formula [I'-C] is as follows:

[0877]

[0878] In addition, in this embodiment, other particularly preferred embodiments are as follows.

[0879] The substituted polypeptide represented by the formula [I'-C] is as follows:

[0880]

[0881] In addition, in this embodiment, other particularly preferred embodiments are as follows.

[0882] The substituted polypeptide represented by the formula [I'-C] is as follows:

[0883]

[0884] In addition, in this embodiment, other particularly preferred embodiments are as follows.

[0885] The substituted polypeptide represented by the formula [I'-C] is as follows:

[0886]

[0887] In addition, in this embodiment, other particularly preferred embodiments are as follows.

[0888] The substituted polypeptide represented by the formula [I'-C] is as follows:

[0889]

[0890] In addition, in this embodiment, other particularly preferred embodiments are as follows.

[0891] The substituted polypeptide represented by the formula [I'-C] is as follows:

[0892]

[0893] In addition, in this embodiment, other particularly preferred embodiments are as follows.

[0894] The substituted polypeptide represented by the formula [I'-C] is as follows:

[0895]

[0896] In addition, in this embodiment, other particularly preferred embodiments are as follows.

[0897] The substituted polypeptide represented by the formula [I'-C] is as follows:

[0898]

[0899] In addition, in this embodiment, other particularly preferred embodiments are as follows.

[0900] The substituted polypeptide represented by the formula [I'-C] is as follows:

[0901]

[0902] In addition, in this embodiment, other particularly preferred embodiments are as follows.

[0903] The substituted polypeptide represented by the formula [I'-C] is as follows:

[0904]

[0905] In addition, in this embodiment, other particularly preferred embodiments are as follows.

[0906] The substituted polypeptide represented by the formula [I'-C] is as follows:

[0907]

[0908] In addition, in this embodiment, other particularly preferred embodiments are as follows.

[0909] The substituted polypeptide represented by the formula [I'-C] is as follows:

[0910]

[0911] In addition, in this embodiment, other particularly preferred embodiments are as follows.

[0912] The substituted polypeptide represented by the formula [I'-C] is as follows:

[0913]

[0914] In addition, in this embodiment, other particularly preferred embodiments are as follows.

[0915] The substituted polypeptide represented by the formula [I'-C] is as follows:

[0916]

[0917] In addition, in this embodiment, other particularly preferred embodiments are as follows.

[0918] The substituted polypeptide represented by the formula [I'-C] is as follows:

[0919]

[0920] Another preferred embodiment of the compound of the present invention is a substituted polypeptide represented by the formula [I] or a pharmaceutically acceptable salt thereof, wherein:

[0921] AA 1 is β-Asp, γ-Glu, or γ-(d)-Glu,

[0922] AA 2 The following formula [II-1] or formula [II-2]

[0923]

[0924] The group represented by

[0925] Here, R AA2 is a hydroxyl group or an amino group,

[0926] AA 3 is Val, Leu, Ile, Phe, or Trp,

[0927] AA 4 is a single bond, Pro, (N-Me)Ala, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Phe, (N-Me)Tyr, (N-Me)Ser, (N-Me)Asp, or (N-Me)Glu,

[0928] AA 5 is a single bond, Pro, (d)-Pro, β-homoPro, Arg, (d)-Arg, Lys, (d)-Lys, β-Ala, GABA, Ape, or Acp,

[0929] L 1 is a single bond,

[0930] L 2 is a single bond,

[0931] L N1 The formula is -S(=O)2-,

[0932] L N2 is a single bond, a compound of the formula -O-, or a compound of the formula -C(=O)-NH-,

[0933] R A is a hydrogen atom,

[0934] R B is a hydrogen atom, a carbamoyl group, a halogen atom, or C 1-6 Alkoxy,

[0935] L Cis a single bond, Pro, Arg, (d)-Arg, Lys, (d)-Lys, or (d)-Lys-(d)-Lys,

[0936] R C The formula is -NH2.

[0937] The compound of the present invention is a compound having a polypeptide composed of 3 to 7 amino acids as a basic skeleton and having a substituted benzoyl group or a substituted phenylsulfonyl group, and may be a pharmaceutically acceptable salt thereof.

[0938] As pharmaceutically acceptable salts, for example, inorganic salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, and nitrate can be cited; sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and trifluoromethanesulfonate; acid addition salts such as organic acid salts such as oxalate, tartrate, citrate, maleate, succinate, acetate, trifluoroacetate, benzoate, mandelate, ascorbate, lactate, gluconate, and malate; amino acid salts such as glycine, lysine, arginine, ornithine, glutamate, and aspartate; or inorganic salts such as lithium, sodium, potassium, calcium, and magnesium salts, or salts with organic bases such as ammonium, triethylamine, diisopropylamine, and cyclohexylamine. It should be noted that the salts include aqueous salts.

[0939] The compounds of the present invention may have an asymmetric center, in which case there are various optical isomers. Therefore, the compounds of the present invention may exist as separate optically active bodies of (R) and (S) and as racemates or (RS) mixtures. In addition, in the case of compounds with more than two asymmetric centers, there are also diastereomers based on their respective optical isomers. The compounds of the present invention also include mixtures containing all these types in any proportion. For example, diastereomers can be separated by methods well known to those skilled in the art, such as fractional crystallization, and optically active bodies can be obtained by methods of organic chemistry well known for this purpose. In addition, geometric isomers such as cis and trans may exist in the compounds of the present invention. Moreover, the compounds of the present invention have tautomerism and there are various tautomers. The compounds of the present invention also include their isomers and mixtures containing these isomers in any proportion.

[0940] Furthermore, when the compound of the present invention or a salt thereof forms a hydrate or a solvate, these are also included in the scope of the compound of the present invention or a salt thereof.

[0941] "Matrix metalloproteinase 2 (MMP2)" is an endopeptidase with zinc as its active center.

[0942] As described above, since MMP2 degrades extracellular matrices such as collagen and gelatin, it is involved in cell invasion / migration, metastasis, etc., and is involved in pathological conditions such as cancer diseases and organ fibrosis.

[0943] Therefore, by inhibiting MMP2, cancer diseases and organ fibrosis, as well as symptoms associated with cancer diseases and organ fibrosis, can be prevented or treated.

[0944] The compound of the present invention has an effect of inhibiting MMP2. Therefore, the compound of the present invention can be used as an MMP2 inhibitor, or an active ingredient of a preventive or therapeutic drug for cancer diseases and organ fibrosis.

[0945] Furthermore, the compound of the present invention can be used as an active ingredient of a preventive or therapeutic drug for symptoms associated with cancer diseases and organ fibrosis.

[0946] Here, "cancer disease" includes: breast cancer, pancreatic cancer, bladder cancer, colorectal cancer, ovarian cancer, prostate cancer, brain tumor, gastric cancer, hepatocellular carcinoma, head and neck cancer, melanoma, uterine cancer, esophageal cancer, renal cell carcinoma, lung cancer, glioma, etc. In addition, as "symptoms associated with cancer disease", there are: pain, weight loss, tumor-associated syndrome, etc. associated with the increase of new cells or tumor growth.

[0947] Here, "organ fibrosis" includes chronic kidney disease, interstitial pneumonia, idiopathic pulmonary fibrosis, etc. In addition, "symptoms associated with organ fibrosis" include proteinuria or abnormal renal function in chronic kidney disease, and exertional dyspnea or dry cough in interstitial pneumonia and idiopathic pulmonary fibrosis.

[0948] In addition, in order to evaluate the MMP2-inhibiting action of the compound of the present invention, it can be carried out according to a known method such as the method described in the Test Examples described later in the present specification.

[0949] The drug of the present invention may contain the compound having MMP2 inhibitory activity or a pharmaceutically acceptable salt thereof as the compound of the present invention, and may be administered alone or together with a pharmaceutically or pharmacologically acceptable additive.

[0950] As additives, commonly used excipients or diluents can be used, and commonly used adhesives, disintegrating agents, lubricants, coating agents, sugar coating agents, pH adjusting agents, dissolving agents or aqueous or non-aqueous solvents can be used as required. Specifically, water, lactose, glucose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, corn starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, water syrup, methylcellulose, polyvinyl pyrrolidone, alkyl parabens, talc, stearic acid, magnesium stearate, agar, pectin, gum arabic, glycerine, sesame oil, olive oil, soybean oil cocoa butter, ethylene glycol, low viscosity hydroxypropyl cellulose (HPC-L), microcrystalline cellulose, carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose (CMC-Na) etc. or other commonly used additives can be mentioned.

[0951] The medicine involved in the present invention can be in any form of solid composition, liquid composition or other composition, and the best composition can be selected according to needs.

[0952] The drugs involved in the present invention can be prepared into tablets, pills, capsules, granules, powders, granules, liquids, emulsions, suspensions, injections, etc. by adding the additives mentioned above to the compounds of the present invention through common formulation techniques.

[0953] In addition, the drug of the present invention can be formulated by forming an inclusion compound with the compound of the present invention and α, β or γ-cyclodextrin or methylated cyclodextrin.

[0954] The drug involved in the present invention may be prepared as a single preparation (formulated preparation) or as two or more preparations (combination preparation) obtained by separately formulating the compound that can be used in combination with the compound of the present invention.

[0955] When these compounds are separated and prepared into two or more preparations, each preparation can be administered simultaneously or at a certain time interval. In this case, whichever one is given first. The two or more preparations can also be administered with different times in 1 day. In addition, the two or more preparations can also be administered by different routes.

[0956] When these compounds are formulated separately to form two preparations, they may be administered simultaneously or at very short intervals. For example, the purpose of combining the two preparations is preferably described in the instructions attached to the commercially available drugs or in the sales brochure.

[0957] Furthermore, it is also preferable that these active ingredients are separately formulated into a kit containing two formulations.

[0958] When the compound of the present invention is used as an MMP2 inhibitor, etc., there is no particular limitation on the form of administration, and the compound of the present invention can be directly administered orally or parenterally. In addition, it can also be administered orally or parenterally as a preparation containing the compound of the present invention as an active ingredient.

[0959] In addition, when the compound of the present invention is used as a preventive or ameliorative agent for cancerous diseases and organ fibrosis and symptoms associated with cancerous diseases and organ fibrosis, the compound of the present invention may be directly administered orally or parenterally. In addition, the compound of the present invention may be used as a preparation containing an active ingredient, and may be administered orally or parenterally.

[0960] Here, as parenteral administration, intravenous administration, subcutaneous administration, or transdermal administration is preferred.

[0961] In addition, as the dosage form in the case of parenteral administration, injections, infusions, implants, percutaneous absorption preparations, transmucosal absorption preparations, patches, etc. are mentioned, and microsphere preparations may also be used.

[0962] The dosage of the compound of the present invention varies depending on the subject of administration, route of administration, target disease, symptoms, etc. For example, in the case of oral administration or parenteral administration to adult patients, the single dose is usually 0.1 mg to 1000 mg, preferably 1 mg to 200 mg. It is ideal to administer this amount once to three times a day, or once every two to three days.

[0963] The following are examples of preparations of the compounds of the present invention.

[0964] Preparation Example 1

[0965] Granules containing the following ingredients were prepared.

[0966] Ingredients: a compound represented by the general formula [I'], lactose, corn starch, HPC-L.

[0967] The compound represented by the general formula [I'] and lactose are sieved. Corn starch is sieved. They are mixed in a mixer. The HPC-L aqueous solution is added to the mixed powder, kneaded, granulated (extrusion granulation), and then dried. The obtained dry granules are sieved using a vibrating sieve to obtain granules.

[0968] Preparation Example 2

[0969] A powder for capsule filling containing the following ingredients is manufactured.

[0970] Ingredients: a compound represented by the general formula [I'], lactose, corn starch, magnesium stearate.

[0971] The compound represented by the general formula [I'] and lactose are sieved. Corn starch is sieved. They are mixed with magnesium stearate in a mixer to obtain a powder. The obtained powder can be filled into capsules.

[0972] Preparation Example 3

[0973] Granules for capsule filling containing the following ingredients were prepared.

[0974] Ingredients: a compound represented by the general formula [I'], lactose, corn starch, HPC-L.

[0975] The compound represented by the general formula [I'] and lactose are sieved. Corn starch is sieved. They are mixed in a mixer. The HPC-L aqueous solution is added to the mixed powder, kneaded, granulated, and then dried. The obtained dry granules are sieved and sized using a vibrating sieve to obtain granules. The obtained granules can be filled into capsules.

[0976] Preparation Example 4

[0977] Tablets containing the following ingredients were manufactured.

[0978] Ingredients: a compound represented by the general formula [I'], lactose, microcrystalline cellulose, magnesium stearate, CMC-Na.

[0979] The compound represented by the general formula [I'], lactose, microcrystalline cellulose and CMC-Na are sieved and mixed. Magnesium stearate is added to the mixed powder to obtain a mixed powder for preparation. The mixed powder is directly compressed to obtain tablets.

[0980] Preparation Example 5

[0981] An injection containing the following ingredients is manufactured.

[0982] Ingredients: a compound represented by the general formula [I'], purified egg yolk lecithin, oleic acid, purified soybean oil, glycerol, and water for injection.

[0983] The compound represented by the general formula [I'], purified egg yolk lecithin and oleic acid are added to purified soybean oil, dissolved, and then water for injection mixed with glycerol is added and emulsified using an emulsifier. Water for injection is added thereto, and the mixture is dispensed into ampoules, which are sealed and sterilized to prepare injections.

[0984] The following is a detailed description of the method for producing the compound [I'] of the present invention, which is not particularly limited to the method exemplified. In addition, the solvent used in the production may be any solvent that does not inhibit each reaction, and is not particularly limited to the following description.

[0985] In the production of compound [I'], the order of the steps in the production may be appropriately changed.

[0986] In addition, in this production, the raw material compound may be used as a salt. Examples of the salt include the above-mentioned "pharmaceutically acceptable salt".

[0987] Compound [I'] can be produced by solid phase synthesis or liquid phase synthesis or a combination thereof. In addition, in the following production method, a production example based on solid phase synthesis is shown.

[0988] Compound [I'] can be produced by the methods described in Schemes 1 to 9 or a combination of these methods.

[0989] It should be noted that the amino acids forming the polypeptide part of compound [I'] may have a functional group on the side chain, and the functional group may be protected by a protecting group. Here, examples of the protecting group include tBu for carboxyl, Trt for carbamoyl, tBu for hydroxyl, tBu for phenolic hydroxyl, tBu for thiol (sulfanyl), Boc for amino, Trt for imidazole, Boc for indolyl, and Pbf for guanidino. It should be noted that these protecting groups can be deprotected by treating with an acid.

[0990] Furthermore, the amino acid can be used in production even if the functional group of the side chain is not protected.

[0991] Method for producing a compound in which the amino group of the N-terminal amino acid of the polypeptide part is sulfonylated and the carboxyl group of the C-terminal amino acid is amidated (-CONH2) [1-f] (Method A)

[0992] The compound [1-f] can be produced, for example, by solid phase synthesis as outlined below (Scheme 1).

[0993] Diagram 1

[0994]

[0995] (In Figure 1,

[0996] R A1 , R A2 , R B1 , R B2 , R B3 , L N2 , Ring A, and Ring B are the same as defined above.

[0997] HZ x -OH represents amino acid,

[0998] x represents an integer from 1 to m,

[0999] m represents an integer from 2 to 15,

[1000] Here, Z x Equivalent to AA in the compound represented by formula [I'] x , L 2 , W 1 , or W C , in addition, it also represents a single bond,

[1001] PG x Denotes protected amino acid (HZ x -OH) amino group.

[1002] (1) [Step 1-1]

[1003] In the resin having an amino group protected by Fmoc (compound [1-a]), Fmoc removal is carried out using a base.

[1004] (2) [Step 1-2]

[1005] The amino group is protected by a lipid-soluble protective group (PG x ) protected amino acid (compound [1-b]) is reacted with the resin obtained in the above (1), so that the free amino group in the resin and the carboxyl group in the compound [1-b] undergo an amidation reaction.

[1006] (3) [Steps 1-3]

[1007] The lipid-soluble protecting group of the amino group of the N-terminal amino acid of the polypeptide portion of the compound obtained in (2) above is deprotected.

[1008] (4) By repeating the above steps (2) and (3) two or more times, a compound [1-c] can be produced in which the carboxyl group of the C-terminal amino acid of the polypeptide portion is bonded to the resin and the amino group of the N-terminal amino acid is free.

[1009] (5) [Steps 1-4]

[1010] Compound [1-d] is reacted with compound [1-c] obtained in the above (4) to sulfonylate the free amino group in compound [1-c], thereby producing compound [1-e].

[1011] (6) [Steps 1-5]

[1012] The compound [1-e] obtained in the above (5) can be subjected to cleavage of the bond with the resin using an acid to produce the compound of the present invention represented by the compound [1-f]. Examples of the acid that can be used in this step include TFA.

[1013] In addition, at this time, when there is a protected functional group on the side chain of the amino acid constituting the polypeptide portion, the protecting group of the functional group can be deprotected at the same time.

[1014] The compound [1-f] thus obtained can be isolated and purified by known separation and purification means, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.

[1015] In the method described in Scheme 1 above, the resin [1-a], compound [1-b] and compound [1-d] used as raw material compounds can be produced by a known method or can be obtained by purchasing commercial products.

[1016] Method for producing a compound [2-c] in which the amino group of the N-terminal amino acid of the polypeptide part is acylated and the carboxyl group of the C-terminal amino acid is amidated (-CONH2) (Method B)

[1017] The compound [2-c] can be produced, for example, by solid phase synthesis as outlined below using the compound [1-c] as a starting material (Scheme 2).

[1018] Diagram 2

[1019]

[1020] (In Figure 2,

[1021] R A1 , R A2 , R B1 , R B2 , R B3 , L N2 , Ring A, Ring B, HZ x -OH, x, m, and Z x Same definition as described above.

[1022] Y 1 represents a hydroxyl group or a chlorine atom. )

[1023] (1) [Step 2-1]

[1024] Compound [2-a] can be reacted with compound [1-c] to undergo an amidation reaction to produce compound [2-b].

[1025] (2) [Step 2-2]

[1026] The compound [2-b] obtained in the above (1) can be subjected to cleavage of the bond with the resin using an acid to produce the compound of the present invention represented by the compound [2-c]. Examples of the acid that can be used in this step include TFA.

[1027] In addition, at this time, when there is a protected functional group on the side chain of the amino acid constituting the polypeptide portion, the protecting group of the functional group can be deprotected at the same time.

[1028] The compound [2-c] thus obtained can be isolated and purified by known separation and purification means, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.

[1029] It should be noted that in the method described in Scheme 2, the compound [2-a] used as the raw material compound can be produced by a known method or can be obtained by purchasing a commercial product. In addition, the compound [1-c] can be produced by the method described in Scheme 1.

[1030] Method for producing a compound in which the amino group of the N-terminal amino acid of a polypeptide part is sulfonylated or acylated, and the carboxyl group of the C-terminal amino acid is secondary amidated or tertiary amidated [3-h] (method C-1)

[1031] The compound [3-h] can be produced, for example, by solid phase synthesis as outlined below (Scheme 3).

[1032] In addition, as a resin (resin [3-a]) which can be used in this manufacturing method, a chlorotrityl chloride resin and a Wang resin are mentioned, for example.

[1033] Diagram 3

[1034]

[1035] (In Figure 3,

[1036] R A1 , R A2 , R B1 , R B2 , R B3 , L N1 , L N2 , Ring A, Ring B, HZ x -OH, x, m, Z x PG x , and Y 1 Same definition as described above.

[1037] R r represents a hydroxyl group or a chlorine atom,

[1038] R C’ , R C” Identically or differently represent hydrogen atoms or C 1-6 Alkyl, here, the C 1-6 The alkyl group may be selected from hydroxy, amino, and C 1-6 One alkoxy group is substituted,

[1039] In addition, R C’ , R C”Together with the adjacent nitrogen atom, it can form a 4- to 7-membered saturated heterocyclic ring containing the nitrogen atom.

[1040] Moreover, R C’ and R C” The 4- to 7-membered saturated heterocyclic ring containing the nitrogen atom formed together with the adjacent nitrogen atom may be selected from hydroxyl, amino, C 1-6 Alkyl, and C 1-6 One alkoxy group is substituted,

[1041] Moreover, R C’ and R C” Two carbon atoms in a 4- to 7-membered saturated heterocyclic ring including a nitrogen atom formed together with an adjacent nitrogen atom can be bonded to the carbon atom. 1-4 Alkanediyl crosslinking.

[1042] (1) [Step 3-1]

[1043] The amino group is protected by a lipid-soluble protective group (PG 1 )-protected amino acid (compound [3-b]) is reacted with a resin (compound [3-a]) to produce compound [3-c].

[1044] (2) [Step 3-2]

[1045] The fat-soluble protective group (PG 1 ) for deprotection.

[1046] (3) [Step 3-3]

[1047] The amino group is protected by a lipid-soluble protective group (PG x ) is reacted with the compound obtained in the above (2) to cause the free amino group in the compound obtained in the above (1) and the carboxyl group in the compound [1-b] to undergo an amidation reaction.

[1048] (4) [Step 3-4]

[1049] The lipid-soluble protecting group of the amino group of the N-terminal amino acid of the polypeptide portion of the compound obtained in (3) above is deprotected.

[1050] (5) By repeating the above steps (3) and (4) two or more times, a compound [3-d] can be produced in which the carboxyl group of the C-terminal amino acid of the polypeptide portion is bonded to the resin and the amino group of the N-terminal amino acid is free.

[1051] (6) [Steps 3-5]

[1052] Compound [1-d] or compound [2-a] is reacted with compound [3-d] obtained in the above (5) to sulfonylate or acylate the free amino group in compound [3-d], thereby producing compound [3-e].

[1053] (7) [Steps 3-6]

[1054] By using an acid to cleave the bond between the compound [3-e] obtained in (6) above and the resin, a compound [3-f] in which the carboxyl group of the C-terminal amino acid of the polypeptide part is free can be produced. Examples of the acid that can be used in this step include TFA.

[1055] In addition, at this time, when there is a protected functional group on the side chain of the amino acid constituting the polypeptide portion, the protecting group of the functional group can be deprotected at the same time.

[1056] (8) [Steps 3-7]

[1057] The compound [3-g] is reacted with the compound [3-f] obtained in the above (7) to carry out an amidation reaction, thereby producing the compound of the present invention represented by the compound [3-h].

[1058] The compound [3-h] thus obtained can be isolated and purified by known separation and purification means, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.

[1059] It should be noted that in the method described in Scheme 3 above, compounds [3-a], [3-b], [1-b], [1-d], [2-a], and [3-g] used as raw material compounds can be produced by methods known per se, or can be obtained by purchasing commercial products.

[1060] Method for producing a compound in which the amino group of the N-terminal amino acid of a polypeptide part is sulfonylated or acylated, and the carboxyl group of the C-terminal amino acid is secondary amidated or tertiary amidated [4-e] (method C-2)

[1061] The compound [4-e] can also be produced by solid phase synthesis as outlined below (Scheme 4).

[1062] In addition, Scheme 4 illustrates a method for producing a compound [4-e] having a functional group on the side chain of the amino acid at the m'-th position from the C-terminal amino acid of the polypeptide part.

[1063] As the resin that can be used in the present production method, similarly to FIG3 , for example, chlorotrityl chloride resin and Wang resin can be mentioned.

[1064] Diagram 4

[1065]

[1066] (In Figure 4,

[1067] R A1 , R A2 , R B1 , R B2 , R B3 , L N1 , L N2 , Ring A, Ring B, HZ x -OH, x, m, Z x , R C ', and R C ” has the same definition as stated above.

[1068] m' represents an integer from 1 to 15, wherein the relationship is "m'≤m".

[1069] L sc Represents C 1-4 Alkanediyl,

[1070] FG sc represents the functional group present on the amino acid side chain at the m'th position from the C-terminal amino acid of the polypeptide portion,

[1071] Here, examples of the functional group include: -O-(-OH), -S-(-SH), -NH-(-NH2), -C(=O)O-(-C(=O)OH), -C(=O)NH-(-C(=O)NH2), -NHC(=NH)NH-(-NHC(=NH)NH2),

[1072] PG sc represents a protecting group for the functional group,

[1073] Here, as the functional group, for example, as described above, tBu, Trt, Boc, and Pbf can be cited.)

[1074] (1) [Step 4-1]

[1075] By cleaving the bond to the resin with an acid, compound [4-a] can be produced in which the carboxyl group of the C-terminal amino acid of the polypeptide portion is free.

[1076] In this case, by using a weak acid as the acid, the protective group (PG sc ) is deprotected. Examples of the weak acid include HFIP, acetic acid, and diluted TFA.

[1077] (2) [Step 4-2]

[1078] Compound [4-d] can be produced by reacting compound [4-c] with compound [4-b] obtained in the above (1) to cause an amidation reaction between the free carboxyl group in compound [4-b] and the amino group in compound [4-c].

[1079] (3) [Step 4-3]

[1080] The protecting group (PG) present on the amino acid side chain at the m'th position from the C-terminal amino acid is removed by using an acid. sc ) is subjected to deprotection to produce the compound of the present invention represented by compound [4-e]. Examples of the acid that can be used in this step include TFA.

[1081] The compound [4-e] thus obtained can be isolated and purified by known separation and purification means, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.

[1082] In the method described in Scheme 4, compound [4-c] used as a raw material compound can be produced by a known method or can be obtained by purchasing a commercial product. In addition, compound [4-a] can be produced by the method described in Scheme 3.

[1083] When there is a functional group on the side chain of the amino acid forming the polypeptide part, the functional group is replaced by a polypeptide linker, and the amino group of the N-terminal amino acid of the polypeptide linker is replaced by a "C-substituted with a carboxyl group". 1-20 Method for preparing compounds [5-f] substituted with "alkylcarbonyl" (Method D)

[1084] The compound [5-f] can be produced by solid phase synthesis as outlined below (Scheme 5).

[1085] Here, the polypeptide linker consists of 1 to 5 amino acids.

[1086] It should be noted that Scheme 5 illustrates a method for producing a compound [5-f], wherein a functional group exists on the side chain of the amino acid at the m'th position from the C-terminal amino acid of the polypeptide part, the functional group is substituted by a polypeptide linker, and the amino group of the N-terminal amino acid of the polypeptide linker is replaced by a "C-terminal amino acid substituted by a carboxyl group". 1-20 Alkylcarbonyl" substitution.

[1087] Diagram 5

[1088]

[1089] (In Figure 5,

[1090] R A1 , R A2 , R B1 , R B2 , R B3 , L N1 , L N2 , Ring A, Ring B, HZ x -OH, x, m, m', Z x , and L sc Same definition as described above.

[1091] PG s ' represents the functional group (FG sc Here, as the protecting group, for example, Dde, ivDde, Alloc, Mtt for amino group can be mentioned,

[1092] HZ scy -OH represents a functional group (FG sc ') is substituted amino acid forming a polypeptide linker,

[1093] y represents an integer from 1 to p,

[1094] p represents an integer from 0 to 5,

[1095] PG scy Denotes protected amino acid (HZ scy -OH) amino group.

[1096] FG sc’ represents a functional group present on the amino acid side chain. Examples of such functional groups include: -NH- (formula -NH2) and -COO- (formula -COOH). It should be noted that in the above-mentioned diagram 5, FG sc’ In the case of being represented by the formula -NH- (formula -NH2).

[1097] n represents an integer from 1 to 20. )

[1098] (1) [Step 5-1]

[1099] The protective group (PG) of the functional group present on the amino acid side chain at the m'th position from the C-terminal amino acid of the polypeptide part in compound [5-a] is S’ ) is selectively deprotected.

[1100] (2) [Step 5-2]

[1101] The amino group is protected by a lipid-soluble protective group (PG scy) protected amino acid (compound [5-b]) and the compound obtained in the above (1) to react, thereby free functional groups (FG sc’ ) undergoes an amidation reaction with the carboxyl group in the compound [5-b].

[1102] (3) [Step 5-3]

[1103] The lipid-soluble protective group (PG scy ) for deprotection.

[1104] (4) By repeating the above steps (2) and (3) more than once, a compound [5-c] can be produced in which the carboxyl group of the C-terminal amino acid of the polypeptide portion is bonded to the resin, the functional group existing on the amino acid side chain at the m'-th position from the C-terminal amino acid is replaced by a polypeptide linker, and the amino group of the N-terminal amino acid of the polypeptide linker is free.

[1105] (5) [Step 5-4]

[1106] Compound [5-e] can be produced by reacting compound [5-d] which is an alkanedicarboxylic acid with compound [5-c] obtained in the above (4) to subject the free amino group in compound [5-c] to an amidation reaction with one carboxyl group in compound [5-d].

[1107] (6) [Step 5-5]

[1108] The compound [5-e] obtained in the above (5) can be subjected to cleavage of the bond with the resin using an acid to produce the compound of the present invention represented by the compound [5-f]. Examples of the acid that can be used in this step include TFA.

[1109] In addition, at this time, when there is a protected functional group on the side chain of the amino acid constituting the polypeptide portion, the protecting group of the functional group can be deprotected at the same time.

[1110] The compound [5-f] thus obtained can be isolated and purified by known separation and purification means, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.

[1111] In the method described in Scheme 5, the compounds [5-b] and [5-d] used as raw materials can be produced by known methods or can be obtained by purchasing commercial products. In addition, compound [5-a] can be produced by the method described in Scheme 1 or Scheme 2 or by a method similar thereto.

[1112] Method (Method E) for manufacturing compound [6-c], wherein, among the 2 amino acids forming the polypeptide moiety, functional groups are present on the respective side chains of these amino acids, and the respective functional groups are each replaced by the same polypeptide linker (-Z sc1 -Z sc2 -…-Z scy '-) to form a ring

[1113] Compound [6-c] can be manufactured, for example, by solid-phase synthesis outlined below (Scheme 6).

[1114] Here, the polypeptide linker consists of 1 to 4 amino acids.

[1115] It should be noted that in Scheme 6, a method for manufacturing compound [6-a] is exemplified, in which functional groups are present on the amino acid side chains at the m'-th and m''-th positions starting from the C-terminal amino acid of the polypeptide moiety, and the functional groups are each replaced by the same polypeptide linker to form a ring.

[1116] Scheme 6

[1117]

[1118] (In Scheme 6,

[1119] R A1 、R A2 、R B1 、R B2 、R B3 、L N1 、L N2 、ring A, ring B, H-Z x -OH, x, m, m’, Z x 、and L sc have the same definitions as described above.

[1120] m'' represents an integer from 2 to 15, where the relationship is "m' < m'' ≤ m",

[1121] The polypeptide linker (-Z sc1 -Z sc2 -…-Z scy’ -) in compound [6-c] corresponds to L in the compound represented by formula [I'] 3 (Here, this L 3 represents Gly, β-Ala, or GABA),

[1122] y' represents an integer from 1 to p',

[1123] p' represents an integer from 1 to 4.

[1124] L sc’ and L sc” represent C1-4 Alkanediyl.

[1125] FG sc’ and FG sc” It represents a functional group present on the side chain of an amino acid. It should be noted that the functional group is, for example, represented by the formula -O- (formula -OH), the formula -S- (formula -SH), the formula -NH- (formula -NH2), the formula -C(=O)O- (formula -C(=O)OH), and the formula -C(=O)NH- (formula -C(=O)NH2).

[1126] PG sc’ and PG sc” It represents a protecting group for a functional group present on the amino acid side chain. Such functional groups are, for example, Dde, ivDde, Alloc, and allyl.

[1127] (1) [Step 6-1]

[1128] The protective group (PG) of the functional group present on the amino acid side chain at the m'th position from the C-terminal amino acid of the polypeptide part in compound [6-a] is sc’ ) is selectively deprotected.

[1129] (2) [Step 6-2]

[1130] The amino group is protected by a lipid-soluble protective group (PG scy’ ) protected amino acid (compound [6-d]) is reacted with the compound obtained in the above (1) to make the free functional group (FG sc’ ) undergoes an amidation reaction with the carboxyl group of the compound [6-d] in which the amino group is protected by a fat-soluble protective group.

[1131] (3) [Step 6-3]

[1132] The lipid-soluble protecting group is deprotected.

[1133] (4) By repeating the steps (2) and (3) above one or more times, a functional group (FG) existing on the side chain of the amino acid at the m'th position from the C-terminal amino acid of the polypeptide portion can be produced, wherein the functional group existing on the side chain of the amino acid at the m'th position from the C-terminal amino acid is replaced by a polypeptide linker, the amino group of the N-terminal amino acid of the polypeptide linker is free, and the functional group (FG) existing on the side chain of the amino acid at the m"th position from the C-terminal amino acid is replaced by a polypeptide linker. sc” ) Protected group (PG sc” ) protected compound [6-b].

[1134] (5) [Step 6-4]

[1135] The protecting group (PG) present on the amino acid side chain at the m"th position from the C-terminal amino acid of the polypeptide part in compound [6-b] issc” ) is selectively deprotected.

[1136] (6) [Step 6-5]

[1137] The "free functional group (FG sc” )" and "Z scp’ The free amino group in the molecule "reacts" and undergoes an intramolecular cyclization reaction.

[1138] (7) [Step 6-6]

[1139] The compound obtained in the above (6) can be subjected to cleavage of the bond with the resin using an acid to produce the compound of the present invention represented by compound [6-c]. Examples of the acid that can be used in this step include TFA.

[1140] In addition, at this time, when there is a protected functional group on the side chain of the amino acid constituting the polypeptide portion, the protecting group of the functional group can be deprotected at the same time.

[1141] The compound [6-c] thus obtained can be isolated and purified by known separation and purification means, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.

[1142] It should be noted that in the method described in Scheme 6 above, the compound [6-d] used as a raw material compound can be produced by a known method or can be obtained by purchasing a commercial product. In addition, compound [6-a] can be produced by the method described in Scheme 1 or Scheme 2 above or by a method analogous thereto.

[1143] Method for producing compound [7-f] having a substituent "alkylaminocarbonyl substituted with a functional group" on ring B (Method F)

[1144] The compound [7-f] can be produced, for example, by solid phase synthesis as outlined below (Scheme 7).

[1145] Diagram 7

[1146]

[1147] (In Figure 7,

[1148] R A1 , R A2 , R B1 , R B2 , L N1 , L N2 , Ring A, Ring B, HZ x -OH, x, m, Z x , and Y 1Same definition as described above.

[1149] L R Represents C 1-4 Alkanediyl,

[1150] FG R represents the substituent "alkylaminocarbonyl (L R -NHC(=O)-)" R )" substituted functional groups include, for example, formula -O-(formula -OH), formula -S-(formula -SH), formula -NH-(formula -NH2), formula -C(=O)O-(formula -C(=O)OH), and formula -C(=O)NH-(formula -C(=O)NH2).

[1151] PG R The above functional group (FG R ) as a protecting group, for example, tBu for carboxyl, Trt for carbamoyl, tBu for hydroxyl, tBu for thiol (sulfanyl), Boc for amino. It should be noted that these protecting groups can be deprotected by treating with an acid. )

[1152] (1) [Step 7-1]

[1153] By reacting compound [7-a] or compound [7-b] with compound [1-c], the free amino group of the N-terminal amino acid in the polypeptide portion of compound [1-c] is sulfonylated or acylated, thereby producing compound [7-c] having a carboxyl group on ring B.

[1154] (2) [Step 7-2]

[1155] Compound [7-d] can be reacted with compound [7-c] to cause an amidation reaction between the carboxyl group in compound [7-c] and the amino group in compound [7-d], thereby producing compound [7-e].

[1156] (3) [Step 7-3]

[1157] Compound [7-e] obtained in (2) above is cleaved from the resin using an acid, and the "functional group (FG R The protective group (PG R ) is subjected to deprotection to produce the compound of the present invention represented by compound [7-f]. Examples of the acid that can be used in this step include TFA.

[1158] In addition, at this time, when there is a protected functional group on the side chain of the amino acid constituting the polypeptide portion, the protecting group of the functional group can be deprotected at the same time.

[1159] The compound [7-f] thus obtained can be isolated and purified by known separation and purification means, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.

[1160] It should be noted that in the method described in Scheme 7, the compounds [7-a], [7-b] and [7-d] used as raw materials can be produced by known methods or can be obtained by purchasing commercial products. In addition, compound [1-c] can be produced by the method described in Scheme 1 or by a method similar thereto.

[1161] Method for producing compound [8-f] in which ring A is directly substituted by ring B (Method G)

[1162] The compound [8-f] can be produced, for example, by solid phase synthesis as outlined below (Scheme 8).

[1163] Diagram 8

[1164]

[1165] (In Figure 8,

[1166] R A1 , R A2 , R B1 , R B2 , R B3 , L N1 , Ring A, Ring B, HZ x -OH, x, m, Z x , and Y 1 Same definition as described above.

[1167] LG A represents a leaving group, and examples of the leaving group include a chlorine atom, a bromine atom, an iodine atom, a halogenated C 1-6 Alkylsulfonyloxy,

[1168] M B represents boric acid, boric acid ester, alkyltin, alkylsilane, or alkoxysilane. )

[1169] (1) [Step 8-1]

[1170] Compound [8-c] can be produced by reacting compound [8-a] or compound [8-b] with compound [1-c] to sulfonylate or acylate the free amino group of the N-terminal amino acid in the polypeptide portion of compound [1-c].

[1171] (2) [Step 8-2]

[1172] Compound [8-c] can be subjected to a coupling reaction with compound [8-d] in the presence of a metal catalyst and a base to produce compound [8-e] in which ring A is directly substituted with ring B. Examples of the metal catalyst include tetrakis(triphenylphosphine)palladium, palladium acetate, and tris(dibenzylideneacetone)dipalladium. Examples of the base include metal carbonates such as cesium carbonate, potassium carbonate, and sodium carbonate, potassium phosphate, cesium fluoride, potassium fluoride, and tetrabutylammonium fluoride.

[1173] (3) [Step 8-3]

[1174] The compound [8-e] obtained in the above (2) can be subjected to cleavage of the bond with the resin using an acid to produce the compound of the present invention represented by the compound [8-f]. Examples of the acid that can be used in this step include TFA.

[1175] In addition, at this time, when there is a protected functional group on the side chain of the amino acid constituting the polypeptide portion, the protecting group of the functional group can be deprotected at the same time.

[1176] The compound [8-f] thus obtained can be isolated and purified by known separation and purification means, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.

[1177] It should be noted that in the method described in Scheme 8, the compounds [8-a], [8-b] and [8-d] used as raw materials can be produced by known methods or can be obtained by purchasing commercial products. In addition, compound [1-c] can be produced by the method described in Scheme 1 or by a method similar thereto.

[1178] Method for producing compound [9-f] having a substituent "arylcarbonylamino group (formula ring BC (=O) NH-)" on ring A (H method)

[1179] The compound [9-f] can be produced, for example, by solid phase synthesis as outlined below (Scheme 9).

[1180] Diagram 9

[1181]

[1182] (In Figure 9,

[1183] R A1 , R A2 , R B1 , R B2 , R B3 , LN1 , Ring A, Ring B, HZ x -OH, x, m, Z x , and Y 1 Same definition as described above.

[1184] Y 2 represents a hydroxyl group or a chlorine atom,

[1185] PG A represents a fat-soluble protecting group for protecting the amino group present on ring A,

[1186] Here, as the fat-soluble protecting group, for example, Fmoc can be mentioned.)

[1187] (1) [Step 9-1]

[1188] In the same manner as step 8-1 of Scheme 8, compound [9-a] or compound [9-b] is reacted with compound [1-c] to sulfonylate or acylate the free amino group of the N-terminal amino acid in the polypeptide portion of compound [1-c], thereby producing compound [9-c].

[1189] (2) [Step 9-2]

[1190] The fat-soluble protective group (PG A ) for deprotection.

[1191] (3) [Step 9-3]

[1192] Compound [9-d] is reacted with the compound obtained in the above (2) to subject the free amino group in the compound obtained in the above (2) to an amidation (acylation) reaction with the carboxyl group in the compound [9-d], thereby producing compound [9-e].

[1193] (4) [Step 9-4]

[1194] The compound [9-e] obtained in the above (3) can be subjected to cleavage of the bond with the resin using an acid to produce the compound of the present invention represented by the compound [9-f]. Examples of the acid that can be used in this step include TFA.

[1195] In addition, at this time, when there is a protected functional group on the side chain of the amino acid constituting the polypeptide portion, the protecting group of the functional group can be deprotected at the same time.

[1196] The compound [9-f] thus obtained can be isolated and purified by known separation and purification means, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.

[1197] It should be noted that in the method described in Scheme 9, the compounds [9-a], [9-b] and [9-d] used as raw materials can be produced by known methods or can be obtained by purchasing commercial products. In addition, compound [1-c] can be produced by the method described in Scheme 1 or by a method similar thereto.

[1198] In the method for producing the compound [I'] involved in the present invention shown in the above-mentioned Schemes 1 to 9, all amino acids can be used as amino acids, for example, Gly or Ala, Val, Leu, Ile, Pro, Phe, His, Trp, Tyr, Ser, Thr, Met, Cys, Asp, Glu, Asn, Gln, Lys, Arg which are natural proteinogenic L-amino acids.

[1199] In addition, in the present production method, natural non-proteinogenic amino acids or non-natural amino acids represented by the D-form of the above-mentioned natural proteinogenic L-amino acids can also be used.

[1200] Here, examples of non-natural amino acids that can be used in the present production method include the following.

[1201] ·(d)-Pro, (d)-Ser, (d)-Thr, (d)-Asp, (d)-Glu, (d)-Arg, (d)-Lys;

[1202] β-homoPro;

[1203] ·β-Ala, GABA, Ape, Acp;

[1204] ·(N-Me)Ala, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Phe, (N-Me)Tyr, (N-Me)Ser, (N-Me)Asp, (N-Me)Glu;

[1205] · The following formula [II-1] or formula [II-2]

[1206]

[1207] The group represented by (here, R AA2 is hydroxyl or amino);

[1208] The amino acids listed in Table 1 and Table 2.

[1209] As fat-soluble protecting groups, for example, carbonate-based, amide-based, or alkyl-based protecting groups such as 9-fluorenylmethoxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), benzyl (Bn), allyl (Allyl), allyloxycarbonyl (Alloc), and acetyl (Ac) can be cited. In order to introduce a fat-soluble protecting group into an amino acid, for example, in the case of introducing Fmoc, it can be introduced by adding 9-fluorenylmethyl-N-succinimidyl carbonate (9-fluorenylmethyl-N-succinimidyl carbonate) and sodium bicarbonate for reaction. The reaction can be carried out at 0 to 50° C., preferably at room temperature for about 1 to 5 hours.

[1210] As amino acids protected by fat-soluble protecting groups, commercially available products can be used, for example, Fmoc-Ser-OH, Fmoc-Asn-OH, Fmoc-Val-OH, Fmoc-Leu-OH, Fmoc-Ile-OH, Fmoc-Ala-OH, Fmoc-Tyr-OH, Fmoc-Gly-OH, Fmoc-Lys-OH, Fmoc-Arg-OH, Fmoc-His-OH, Fmoc-Asp-OH, Fmoc-Glu-OH, Fmoc-Gln-OH, Fmoc-Thr-OH, Fmoc-Cys-OH, Fmoc-Met-OH, Fmoc-Phe-OH, Fmoc-Trp-OH, and Fmoc-Pro-OH.

[1211] In addition, examples of amino acids protected with a lipophilic protecting group and having a protecting group introduced into the side chain include Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Cys(tBu)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Gln(Trt)-OH, Fmoc-His(Trt)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Trp(Boc)-OH, and Fmoc-Tyr(tBu)-OH.

[1212] The resin may be any resin used in solid phase synthesis, and for example, 2-chlorotrityl chloride resin functionalized with chlorine atoms, Wang resin, HMPA-PEGA resin, and amino-PEGA resin functionalized with amino groups can be used.

[1213] As a method for obtaining an amide body (amide compound) at the C-terminus of a peptide, a solid phase synthesis can be performed using a resin for synthesizing an amide body. For example, Rink-Amide-AM resin, SAL-PEG resin, SAL-MBHA resin, and Rink-Amide-PEGA resin can be used. The amide body at the C-terminus of a peptide can be obtained by cleaving these resins and the peptide with an acid.

[1214] Regarding the bonding of an amino acid whose amino group is protected by a fat-soluble protective group to a resin, for example, when a resin having a hydroxyl group or a resin functionalized with a chlorine atom is used, the bonding can be performed by ester bonding the carboxyl group of the amino acid to the resin.

[1215] When an amino-functionalized resin is used, the bond can be achieved by amide bonding the carboxyl group of the amino acid to the resin.

[1216] When 2-chlorotrityl chloride resin is used, esterification can be carried out using a base such as diisopropylethylamine (DIPEA), triethylamine, pyridine, or 2,4,6-trimethylpyridine.

[1217] When a resin having a hydroxyl group is used, as an esterification catalyst, for example, a known dehydrating and fusing agent (dehydrating and condensing agent) such as 1-(mesitylene-2-sulfonyl)-3-nitro-1,2,4-triazole (MSNT), dicyclohexylcarbodiimide (DCC), and diisopropylcarbodiimide (DIC) can be used. The ratio of the amino acid to the dehydrating and fusing agent is generally 1 to 10 equivalents, preferably 2 to 5 equivalents, relative to 1 equivalent of the former.

[1218] The esterification reaction is preferably carried out, for example, by loading the resin into a solid phase column, washing the resin with a solvent, and then adding a solution of an amino acid. Examples of washing solvents include chloroform, dimethylformamide (DMF), 2-propanol, and dichloromethane. Examples of solvents for dissolving amino acids include chloroform, dimethyl sulfoxide (DMSO), DMF, and dichloromethane. The esterification reaction can be carried out at 0 to 50° C., preferably at room temperature, for about 10 minutes to 30 hours, preferably about 15 minutes to 24 hours.

[1219] At this time, it is also preferred to acetylate and cap the unreacted hydroxyl groups on the solid phase using acetic anhydride or the like.

[1220] The removal of the fat-soluble protecting group can be carried out, for example, by treating with a base. Examples of the base include piperidine and morpholine. In this case, it is preferably carried out in the presence of a solvent. Examples of the solvent include DMF, DMSO, and ethanol.

[1221] The amidation reaction of a free amino group and a carboxyl group of any amino acid whose amino group is protected by a fat-soluble protecting group is preferably carried out in the presence of an activating agent and a solvent.

[1222] Examples of the activating agent include dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (WSC / HCl), diphenylphosphoryl azide (DPPA), carbonyldiimidazole (CDI), diethyl cyanophosphonate (DEPC), benzotriazol-1-yloxy-tripyrrolidinophosphonium (DIPCI), benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (PyBOP), 1-hydroxybenzotriazole (HOBt), hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP), 1-hydroxy-7-azabenzotriazole (HOAt), hydroxyphthalimide (HOPht), pentafluorophenol (Pfp-OH), 2-(1H-benzotriazole)- ...1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1 -1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate (HBTU), 1-[bis(dimethylamino)methylene]-5-chloro-1H-benzotriazolium 3-oxide hexafluorophosphate (HCTU), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphonate (HATU), O-benzotriazol-1-yl-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 3,4-dihydro-3-hydroxy-4-oxa-1,2,3-benzotriazine (Dhht), N-[1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino(morpholino)]uronium hexafluorophosphate (COMU), ethyl cyano(hydroxyimino)acetate (Oxyma), etc.

[1223] The amount of the activating agent used is preferably 1 to 20 equivalents, more preferably 1 to 10 equivalents, and more preferably 1 to 5 equivalents, relative to any amino acid whose amino group is protected by a fat-soluble protecting group.

[1224] Examples of the solvent include DMF, DMSO, and dichloromethane. The reaction can be performed at 0 to 50°C, preferably at room temperature, for about 10 minutes to 30 hours, preferably about 15 minutes to 2 hours.

[1225] When the peptide chain is cut from the resin, it can be carried out by acid treatment. Examples of the acid include trifluoroacetic acid (TFA) and hydrogen fluoride (HF). The de-resin reaction can be carried out at 0 to 50°C, preferably at room temperature, for about 10 minutes to 10 hours, preferably about 30 minutes to 4 hours.

[1226] The present invention is described in more detail by the following Examples, Reference Examples, and Test Examples, but the present invention is not limited thereto and may be modified within the scope not departing from the scope of the present invention.

[1227] The abbreviations used in this manual are as follows.

[1228] APCI: atmospheric pressure chemical ionization;

[1229] Arg(Pbf):N ω -2,2,4,6,7-pentamethyldihydrobenzofuransulfonylarginine;

[1230] Bu: butyl;

[1231] BuOH: butanol;

[1232] Dde: 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-ethyl;

[1233] DMSO-d6: hexadeuterated dimethyl sulfoxide;

[1234] ELSD: Evaporative Light Scattering Detector;

[1235] ESI: electrospray ionization;

[1236] HPLC: high performance liquid chromatography;

[1237] ivDde: 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl;

[1238] LCMS: liquid chromatography mass spectrometry;

[1239] NMP: 1-methyl-2-pyrrolidone;

[1240] Trt: trityl;

[1241] UV: Ultraviolet light.

[1242] In this specification, "room temperature" means 20 to 30°C unless otherwise specified.

[1243] Unless otherwise specified, "under ice cooling" means 0 to 5°C.

[1244] In the present specification, Biotage (registered trademark) SNAP Ultra manufactured by Biotage or REVELERIS (registered trademark) Silica 40 μm manufactured by Buchi is used as a “Silica gel cartridge” when purification is performed using column chromatography.

[1245] Purification using reverse phase column chromatography (hereinafter sometimes referred to as preparative LCMS) was performed by appropriately selecting from the following two conditions.

[1246] Preparation apparatus: Agilent 1260 Infinity and Agilent 6130 (ionization method: Electron Spray Ionization: ESI) from Agilent, and Agilent 385-ELSD connected to an ELSD detector were used.

[1247] Solvent: Solution A: water containing 0.1% formic acid, Solution B: acetonitrile containing 0.1% formic acid;

[1248] Flow rate: 50 mL / min.

[1249] The column uses any of the following:

[1250] Waters XBridge Prep C18, 5μm, 30×50mm;

[1251] Waters XSelect CSH C18, 5μm, 30×50mm.

[1252] (Preparation Condition A)

[1253] 0.0-0.5 minutes (liquid A / liquid B = 90 / 10);

[1254] 0.5-7.5 minutes (liquid A / liquid B = 90 / 10 to 20 / 80);

[1255] 7.5-7.95 minutes (liquid A / liquid B = 20 / 80);

[1256] 7.95-8.0 minutes (liquid A / liquid B = 20 / 80 to 5 / 95);

[1257] 8.0-9.0 minutes (liquid A / liquid B=5 / 95).

[1258] (Preparation Condition B)

[1259] 0.0-0.5 minutes (liquid A / liquid B = 95 / 5);

[1260] 0.5-7.5 minutes (liquid A / liquid B = 95 / 5 to 50 / 50);

[1261] 7.5-7.95 minutes (liquid A / liquid B = 50 / 50);

[1262] 7.95-8.0 minutes (liquid A / liquid B = 50 / 50 to 5 / 95);

[1263] 8.0-9.0 minutes (liquid A / liquid B=5 / 95).

[1264] Each instrument data described in this specification was measured using the following instruments.

[1265] Microwave reaction apparatus: Initiator (Biotage AB);

[1266] NMR spectrum: [1H-NMR] 600 MHz: JNM-ECA600 (JEOL), 400 MHz: AVANCE III HD 400 (BRUKER).

[1267] The high performance liquid chromatography mass spectrometry (LCMS) and retention time (RT) in this specification were measured under the conditions shown below.

[1268] Measurement instrument: Shimadzu LCMS-2010EV;

[1269] Column: Shimadzu XR-ODS, 2.2 μm, 2.0 × 30 mm;

[1270] Ionization method: ESI / APCI dual source;

[1271] Solvent: Solution A: water containing 0.1% formic acid, Solution B: acetonitrile containing 0.1% formic acid;

[1272] Flow rate: 0.6 mL / min, detection method: UV 210 nm, 254 nm.

[1273] (Analysis Condition A)

[1274] 0.0-1.0 minutes (liquid A / liquid B = 90 / 10 to 60 / 40);

[1275] 1.0-2.0 minutes (liquid A / liquid B = 60 / 40 to 1 / 99);

[1276] 2.0-2.6 minutes (liquid A / liquid B=1 / 99).

[1277] (Analysis Condition B)

[1278] 0.0-0.5 minutes (liquid A / liquid B = 90 / 10);

[1279] 0.5-1.5 minutes (liquid A / liquid B = 90 / 10 to 70 / 30);

[1280] 1.5-2.5 minutes (liquid A / liquid B = 70 / 30 to 1 / 99);

[1281] 2.5-5.0 minutes (liquid A / liquid B=1 / 99).

[1282] The compound names in Preparation Examples, Reference Examples, and Examples are named according to "ACD / Name 2019.1.2 (ACD Labs 2019.1.2, Advanced Chemistry Development Inc.)".

[1283] Reference Example 1 4-(4-Carbamoylbenzamide)benzenesulfonyl chloride

[1284]

[1285] To a DMF (180 mL) solution of 4-carbamoylbenzoic acid (150 g) was added WSC-hydrochloride (209 g), HOBt monohydrate (167 g) and DIPEA (380 mL). After stirring at room temperature for 5 minutes, aniline (99 mL) was added and stirred at room temperature for 72 hours. Water was added to the reaction solution and the precipitated solid was filtered to obtain N-phenylterephthalamide (147 g) as a yellow amorphous substance.

[1286] Chlorosulfonic acid (407 mL) was added to the obtained N-phenylterephthalamide, and the mixture was heated and stirred at 60°C for 1 hour. The reaction mixture was ice-cooled and then added to ice water. The precipitated solid was filtered, washed with water, and dried to obtain the title compound (198 g) as a light yellow solid.

[1287] 1 H NMR (400MHz, DMSO-d6) δppm 7.54 (bs, 1H), 7.62 (d, J=8.2Hz, 2H), 7.79 (d, J=8.2Hz, 2H), 7.96-8.09 (m, 4H), 8.14 (bs, 1H), 10.46 (s.1H)

[1288] Reference Example 2 4-(4-(trifluoromethoxy)benzamide)benzenesulfonyl chloride

[1289]

[1290] In the same manner as in Reference Example 1, the title compound was obtained as a yellow solid from the corresponding starting materials.

[1291] 1 H NMR (400MHz, DMS0-d6) δppm 7.52 (d, J=8.3Hz, 2H), 7.58 (d, J=8.3Hz, 2H), 7.72 (d, J=8.3Hz, 2H), 8.08 (d, J=8.3Hz, 2H), 10.42 (s, 1H)

[1292] Reference Example 3 4-(4-(Methylcarbamoyl)benzamide)benzenesulfonyl chloride

[1293]

[1294] In the same manner as in Reference Example 1, the title compound was obtained as a gray solid from the corresponding starting materials.

[1295] 1 H NMR (600MHz, DMS0-d6) δppm 2.81 (d, J=4.1Hz, 3H), 7.57-7.61 (m, 2H), 7.72-7.78 (m, 2H), 7.96 (d, J=8.7Hz, 2H), 8.03 (d, J=8.7Hz, 2H), 8.62 (q, J=4.1, 1H), 10.42 (s, 1H)

[1296] Reference Example 4 4-(4-(Dimethylcarbamoyl)benzamide)benzenesulfonyl chloride

[1297] In the same manner as in Reference Example 1, the title compound was obtained as a brown solid from the corresponding starting materials.

[1298] 1 H NMR (600MHz, DMS0-d6) δppm 2.91 (s, 3H), 3.01 (s, 3H), 7.54 (d, J = 8.3Hz, 2H), 7.58 (d, J = 8.3Hz, 2H), 7.74 (d, J = 8.3Hz, 2H), 8.01 (d, J = 8.3Hz, 2H), 10.41 (s, 1H)

[1299] Reference Example 5 4-(4-(Trifluoromethyl)benzamide)benzenesulfonyl chloride

[1300]

[1301] In the same manner as in Reference Example 1, the title compound was obtained as a white solid from the corresponding starting materials.

[1302] 1 H NMR (400MHz, CHL0R0F0RM-d) δppm 7.81 (d, J=8.2Hz, 2H), 7.93 (d, J=8.1Hz, 2H), 8.01 (d, J=8.2Hz, 2H), 8.08 (d, J=8.1Hz, 3H)

[1303] Reference Example 6 4-(4-Cyanobenzamide)benzenesulfonyl chloride

[1304]

[1305] In the same manner as in Reference Example 1, the title compound was obtained as a light brown solid from the corresponding starting materials.

[1306] 1 H NMR (600MHz, DMS0-d6) δppm 7.58 (d, J=8.3Hz, 2H), 7.74 (d, J=8.3Hz, 2H), 7.99 (d, J=8.3Hz, 2H), 8.01 (d, J=8.3Hz, 2H), 10.42 (s, 1H)

[1307] Reference Example 7 4-(4-(1,1,2,2-tetrafluoroethoxy)benzamide)benzenesulfonyl chloride

[1308] In the same manner as in Reference Example 1, the title compound was obtained as a yellow solid from the corresponding starting materials.

[1309] 1 H NMR (400MHz, CHL0R0F0RM-d) δppm 5.95 (tt, J=53.2Hz, 2.8Hz, 1H), 7.37 (d, J=8, 6Hz, 2H), 7.92 (d, J=7.2Hz, 2H), 7.94 (d, J=7.2Hz, 2H), 8.05 (d, J=8.6Hz, 2H), 8.12 (s, 1H)

[1310] Reference Example 8 4-(2-Fluorobenzamide)benzenesulfonyl chloride

[1311]

[1312] In the same manner as in Reference Example 1, the title compound was obtained as a white solid from the corresponding starting materials.

[1313] 1 H NMR (400MHz, CHL0R0F0RM-d) δppm 7.20-7.27 (m, 1H), 7.37 (dd, J=7.6Hz, 7.6Hz, 1H), 7.56-7.63 (m, 1H), 7.95 (d, J=9.1 HZ, 2H), 8.06 (d, J=9.1Hz, 2H), 8.20 (td, J=8.0Hz, 1.8Hz, 1H), 8.75 (d, J=16.9Hz.1H)

[1314] Reference Example 9 2-Fluoro-4-phenoxybenzoic acid

[1315]

[1316] Potassium carbonate (535 mg) was added to a DMF (10 mL) solution of 2,4-difluorobenzaldehyde (250 mg) and phenol (199 mg), and the mixture was heated and stirred at 120°C for 4 hours. After cooling to room temperature, the reaction solution was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 2-fluoro-4-phenoxybenzaldehyde.

[1317] The obtained 2-fluoro-4-phenoxybenzaldehyde was dissolved in tetrahydrofuran (5 mL) and water (5 mL), and sodium dihydrogen phosphate (844 mg), 2-methyl-2-butene (1.49 mL) and sodium chlorite (636 mg) were added, and stirred at room temperature for 3 hours. Chloroform was added to the reaction solution, and washed with water. The organic layer was passed through a phase separator and concentrated under reduced pressure to obtain the title compound (182 mg) as a white solid.

[1318] 1 H NMR (400MHz, DMSO-d6) δppm 6.75-6.92 (m, 2H), 7.17 (d, J=7.5Hz, 2H), 7.24-7.33 (m, 1H), 7.43-7.55 (m, 2H), 7.83-7.97 (m, 1H), 13.0 (br s, 1H)

[1319] Reference Example 10 4-(4-Carbamoyl-2-fluorophenoxy)benzoic acid

[1320]

[1321] In the same manner as in Reference Example 9, the title compound was obtained as a white solid from the corresponding starting materials.

[1322] 1 H NMR (400MHz, DMS0-d6) δppm 7.12 (d, J=8.4Hz, 1H), 7.19 (d, J=8.4Hz, 2H), 7.40 (t, J=8.3Hz, 1H), 7.53 (br s, 1H), 7.82 (t, J=8.3Hz, 1H), 7.90-8.00 (m, 2H), 8.07 (brs, 1H), 9.95 (s, 1H)

[1323] Reference Example 11 3-Fluoro-4-(2-fluorophenoxy)benzoic acid

[1324]

[1325] In the same manner as in Reference Example 9, the title compound was obtained as a white solid from the corresponding starting materials.

[1326] 1 H NMR (400MHz, CHL0R0F0RM-d) δppm 6.89 (t, J=8.1Hz, 1H), 7.10-7.25 (m, 4H), 7.80 (d, J=8.4Hz, 1H), 7.89 (d, J=11.3Hz, 1H)

[1327] Reference Example 12 5-((4-(4-Carbamoylphenoxy)phenyl)sulfonamide)pentanoic acid

[1328] Triethylamine (2.3 mL) and 4-fluorobenzenesulfonyl chloride (800 mg) were added to a solution of 5-aminopentanoic acid benzyl ester / toluenesulfonate (1.48 g) in chloroform (20 mL) under ice-cooling, and the mixture was stirred for 1 hour under ice-cooling. After the reaction was completed, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was passed through a phase separator and concentrated under reduced pressure. The residue was purified by column chromatography (Silica gel cartridge, hexane: ethyl acetate = 80:20 to 50:50) to obtain 5-((4-fluorophenyl)sulfonamide) benzyl pentanoate (1.24 g) as a colorless oily substance.

[1329] 1 H NMR (400MHz, CHL0R0F0RM-d) δppm 1.46-1.56 (m, 2H), 1.58-1.68 (m, 2H), 2.33 (t, J=7.0Hz, 2H), 2.96 (q, J=6.5Hz, 2H), 4.40-4.4 7 (m, 1H), 5.09 (s, 2H), 7.18 (t, J = 8.2Hz, 2H), 7.31-7.39 (m, 5H), 7.86 (dd, J = 7.6Hz, 5.3Hz, 2H) (2)

[1331]

[1332] 4-Hydroxybenzonitrile (179 mg) and potassium carbonate (567 mg) were added to a DMF (13 mL) solution of 5-((4-fluorophenyl)sulfonamide)pentanoic acid benzyl ester (500 mg) obtained in (1) above, and the mixture was stirred at 180° C. for 1 hour under microwave irradiation. After the reaction solution was cooled, ethyl acetate and water were added to the reaction mixture for separation. The aqueous layer was washed with ethyl acetate, adjusted to pH 1 with a 1M aqueous hydrochloric acid solution, and extracted with a mixed solvent of ethyl acetate / toluene. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 5-((4-(4-cyanophenoxy)phenyl)sulfonamide)pentanoic acid (285 mg) as a white solid.

[1333] 1 H NMR (400MHz, DMS0-d6) δppm 1.32-1.49(m, 4H), 2.10-2.17(m, 2H), 2.69-2.78(m, 2H), 7.23-7.31(m, 2H), 7. 43(t, J=8.7Hz, 2H), 7.59-7.66(m, 1H), 7.81-7.87(m, 3H), 7.91(d, J=8.3Hz, 1H)

[1334] (3) Potassium carbonate (81 mg) and 30% aqueous hydrogen peroxide solution (0.15 mL) were added to a DMSO (2 mL) solution of 5-((4-(4-cyanophenoxy)phenyl)sulfonamide)pentanoic acid (100 mg) obtained in (2) above, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, aqueous sodium thiosulfate solution and 1 M aqueous hydrochloric acid solution were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (89 mg) as a white solid.

[1335] 1 H NMR (400MHz, DMS0-d6) δppm 1.32-1.50 (m, 4H), 2.10-2.18 (m, 2

[1336] H), 2.69-2.78 (m, 2H), 7.16 (d, J = 8.2Hz, 1H), 7.19 (d, J = 8.6Hz,

[1337] 1H), 7.34 (br s, 1H), 7.43 (t, J=8.6Hz, 2H), 7.52-7.58 (m, 1H), 7.59-7.66 (m, 1H), 7.86-7.79 (m3H), 7.96 (d, J=7.7Hz, 1H), 12.0 (br s, 1H)

[1338] Example 1 Compound No. 1 (N-[4-(4-carbamoylbenzamido)benzene-1-sulfonyl]-D-γ-glutamyl-(4S)-4-amino-L-prolyl-L-leucyl-N-(5-amino-5-oxopentanyl)-N 2 -Methyl-L-α-glutamine)

[1339]

[1340] (1) Fmoc-Rink Amide AM resin (0.10 mmol) was treated with a DMF solution of piperidine (concentration: 40%, 1.6 mL) for 3 minutes, and then treated with a DMF solution of piperidine (concentration: 20%, 1.6 mL) for 12 minutes to deprotect the Fmoc residue of the resin. Next, a DMF (0.8 mL) solution of Fmoc-Ape-OH (0.40 mmol), a DMF (0.8 mL) solution of COMU (0.40 mmol) and Oxyma (0.40 mmol), and a NMP (0.4 mL) solution of DIPEA (0.80 mmol) were added, and the mixture was shaken at room temperature for 40 minutes to introduce an Ape residue. The deprotection and fusion of Fmoc were repeated in the same manner. Specifically, Fmoc-(N-Me)Glu(OtBu)-OH, Fmoc-Leu-OH, Fmoc-(2S,4S)-(4-NHBoc)Pro-OH, and Fmoc-(d)-Glu-OtBu were fused in sequence, and the N-terminal Fmoc of the obtained resin was deprotected by treatment with piperidine / DMF using the same method as above, thereby synthesizing a resin H-γ-(d)-Glu(OtBu)-(2S,4S)-(4-NHBoc)Pro-Leu-(N-Me)Glu(OtBu)-Ape-Rink Amide AM resin in a state in which a peptide was bonded.

[1341] (2) A DMF (3 mL) solution of 4-(4-carbamoylbenzamide)benzenesulfonyl chloride (0.30 mmol) and DIPEA (0.60 mmol) obtained in Reference Example 1 was added to the resin obtained in (1) above, and the mixture was shaken at room temperature for 1 hour. After the reaction was completed, the obtained resin was washed with DMF (3 mL × 3 times) and chloroform (3 mL × 3 times).

[1342] (3) TFA: water: triisopropylsilane (92.5: 2.5: 5, 4 mL) was added to the resin obtained in (2) above, and the mixture was shaken at room temperature for 1.5 hours, and the resin was removed by filtration. Cooled diethyl ether was added to the filtrate, and the precipitated white powder was precipitated by centrifugation. The operation of removing diethyl ether by decantation was repeated 3 times to obtain a crude peptide. The crude product was purified by preparative LCMS (preparative condition B). The eluate was fractionated in a test tube, and the eluted fractions containing the target substance were collected and lyophilized to obtain the title compound (46 mg) as a white powder.

[1343] Example 2 Compound No. 106 (N 2Synthesis of -[4-(4-phenoxybenzamido)butyryl]-L-asparagine-N-[(2S)-4-amino-1-({(2S)-1-[{(2S,3S)-1-[(2S)-2-(2-amino-2-oxoethyl)pyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}(methyl)amino]-4-methyl-1-oxopentan-2-yl}amino)-1-oxobutan-2-yl]-L-α-asparagine)

[1344]

[1345] (1) Fmoc-NH-SAL-PEG resin (0.12 mmol) was treated with a DMF solution of piperidine (concentration: 40%, 1.9 mL) for 3 minutes, and then treated with a DMF solution of piperidine (concentration: 20%, 1.9 mL) for 12 minutes to deprotect the Fmoc residue of the resin. Next, a DMF (1.0 mL) solution of Fmoc-β-homoPro-OH (0.48 mmol), a DMF (1.0 mL) solution of COMU (0.48 mmol) and Oxyma (0.48 mmol), and a NMP (0.48 mL) solution of DIPEA (0.96 mmol) were added, and the mixture was shaken at room temperature for 40 minutes to introduce a β-homoPro residue. In the same manner, the deprotection and condensation of Fmoc were repeated. Specifically, Fmoc-(N-Me)Ile-OH, Fmoc-Leu-OH, Fmoc-Dab(Boc)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Asn(Trt)-OH, Fmoc-GABA-OH, and 4-phenoxybenzoic acid were condensed in sequence to synthesize a resin Ph-O-Ph-CO-GABA-Asn(Trt)-As p(OtBu)-Dab(Boc)-Leu-(N-Me)Ile-β-homoPro-NH-SAL-PEG resin in a state where a peptide was bonded. After the reaction was completed, the obtained resin was washed with DMF (3 mL × 3 times) and chloroform (3 mL × 3 times).

[1346] (2) TFA: water: triisopropylsilane: dithiothreitol (90: 2.5: 5: 2.5, 4 mL) was added to the resin obtained in (1) above, and the mixture was shaken at room temperature for 2 hours. The resin was removed by filtration. Cooled diethyl ether was added to the filtrate, and the precipitated white powder was precipitated by centrifugation. The operation of removing diethyl ether by decantation was repeated 3 times to obtain a crude peptide. The crude product was purified by preparative LCMS (preparative condition A). The eluate was fractionated in a test tube, and the eluted fractions containing the target substance were collected and lyophilized to obtain the title compound (14 mg) as a white powder.

[1347] Example 3 Compound No. 177 (N 2 Synthesis of -(4-{4-[4-(methylcarbamoyl)phenoxy]benzamido}butyryl)-L-asparagine-L-α-aspartyl-L-alanyl-L-leucyl-L-methionyl-L-prolinamide)

[1348]

[1349] (1) Fmoc-NH-SAL-PEG resin (0.10 mmol) was treated with a DMF solution of piperidine (concentration: 40%, 1.6 mL) for 3 minutes, and then treated with a DMF solution of piperidine (concentration: 20%, 1.6 mL) for 12 minutes to deprotect the Fmoc residue of the resin. Next, a DMF (0.8 mL) solution of Fmoc-Pro-OH (0.40 mmol), a DMF (0.8 mL) solution of COMU (0.40 mmol) and Oxyma (0.40 mmol), and a NMP (0.4 mL) solution of DIPEA (0.80 mmol) were added, and the mixture was shaken at room temperature for 40 minutes to introduce a Pro residue. In the same manner, the deprotection and fusion of Fmoc were repeated. Specifically, Fmoc-Met-OH, Fmoc-Leu-OH, Fmoc-Ala-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Asn(Trt)-OH, and Fmoc-GABA-OH were fused in sequence, and the N-terminal Fmoc of the obtained resin was deprotected by treatment with piperidine / DMF in the same manner as above, thereby synthesizing a resin H-GABA-Asn(Trt)-Asp(OtBu)-Ala-Leu-Met-Pro-NH-SAL-PEG resin in a state of being bonded with a peptide.

[1350] (2) A DMF (3 mL) solution of 4,4'-oxybisbenzoic acid (0.75 mmol), HATU (0.15 mmol), and DIPEA (2.0 mmol) was added to the resin obtained in (1) above, and the mixture was shaken at room temperature for 2 hours. After the reaction, the obtained resin was washed with DMF (3 mL x 3 times).

[1351] (3) A solution of HATU (0.30 mmol), DIPEA (0.60 mmol) and an ethanol solution of methylamine (concentration: 9.8 mol / L, 0.30 mmol) in DMF (3 mL) was added to the resin obtained in (2) above, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the obtained resin was washed with DMF (3 mL × 3 times) and chloroform (3 mL × 3 times).

[1352] (4) TFA: water: triisopropylsilane: dithiothreitol (90: 2.5: 5: 2.5, 4 mL) was added to the resin obtained in (3) above, and the mixture was shaken at room temperature for 2 hours, and the resin was removed by filtration. Cooled diethyl ether was added to the filtrate, and the precipitated white powder was precipitated by centrifugation. The operation of removing diethyl ether by decantation was repeated 3 times to obtain a crude peptide. The crude product was purified by preparative LCMS (preparative condition A). The eluate was fractionated in a test tube, and the eluted fractions containing the target substance were collected and lyophilized to obtain the title compound (30 mg) as a white powder.

[1353] Example 4 Synthesis of Compound No. 587 (N-{5-[(4-methylphenyl)ethynyl]thiophene-2-sulfonyl}-β-alanyl-L-asparagine-L-α-aspartyl-L-alanyl-L-leucyl-N-methyl-L-methionyl-L-prolinamide)

[1354]

[1355] (1) Fmoc-NH-SAL-PEG resin (0.10 mmol) was treated with a DMF solution of piperidine (concentration: 40%, 1.6 mL) for 3 minutes, and then treated with a DMF solution of piperidine (concentration: 20%, 1.6 mL) for 12 minutes to deprotect the Fmoc residue of the resin. Next, a DMF (0.8 mL) solution of Fmoc-Pro-OH (0.40 mmol), a DMF (0.8 mL) solution of COMU (0.40 mmol) and Oxyma (0.40 mmol), and a NMP (0.4 mL) solution of DIPEA (0.80 mmol) were added, and the mixture was shaken at room temperature for 40 minutes to introduce a Pro residue. The deprotection and fusion of Fmoc were repeated in the same manner. Specifically, Fmoc-(N-Me)Met-OH, Fmoc-Leu-OH, Fmoc-Ala-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Asn(Trt)-OH, and Fmoc-β-Ala-OH were fused in sequence, and the N-terminal Fmoc of the obtained resin was deprotected by treatment with piperidine / DMF using the same method as above, thereby synthesizing a resin H-β-Ala-Asn(Trt)-Asp(OtBu)-Ala-Leu-(N-Me)Met-Pro-NH-SAL-PEG resin in a state of being bonded with a peptide.

[1356] (2) A solution of 5-bromothiophene-2-sulfonyl chloride (0.20 mmol) and DIPEA (0.40 mmol) in DMF (3 mL) was added to the resin obtained in (1) above, and the mixture was shaken at room temperature for 2 hours. After the reaction was completed, the obtained resin was washed with DMF (3 mL × 3 times) and chloroform (3 mL × 3 times).

[1357] (3) TFA: water: triisopropylsilane: dithiothreitol (90: 2.5: 5: 2.5, 4 mL) was added to the resin obtained in (2) above, and the mixture was shaken at room temperature for 2 hours, and the resin was removed by filtration. Cooled diethyl ether was added to the filtrate, and the precipitated white powder was precipitated by centrifugation. The operation of removing diethyl ether by decantation was repeated 3 times to obtain a crude peptide. The crude product was purified by preparative LCMS (preparative condition B). The eluate was fractionated in a test tube, and the eluted fractions containing the target product were collected and lyophilized to obtain 5-bromo-thiophene-2-SO2-β-Ala-Asn-Asp-Ala-Leu-(N-Me)Met-Pro-NH2 (27 mg) as a white powder.

[1358] (4) The compound obtained in (3) above was dissolved in DMF (0.5 mL), 4-ethynyltoluene (0.30 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.01 mmol), triethylamine (0.18 mmol), copper iodide (0.01 mmol) were added, and heated and stirred at 50° C. for 5 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction solution was diluted with DMSO and filtered, and then purified by preparative LCMS (preparative conditions A). The eluate was fractionated in a test tube, and the eluted fractions containing the target product were collected and lyophilized to obtain the title compound (4 mg) as a white powder.

[1359] Example 5 Compound No. 608 (N-[(2S)-4-amino-1-({(2S)-1-[{(2S,3S)-1-[(2S)-2-(2-amino-2-oxoethyl)pyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}(methyl)amino]-4-methyl-1-oxopentan-2-yl}amino)-1-oxobutan-2-yl]-N 2 -[4-(1-phenyl-1H-1,2,3-triazol-4-yl)benzene-1-sulfonyl]-D-glutamine)

[1360]

[1361] (1) Fmoc-Rink Amide AM resin (0.10 mmol) was treated with a DMF solution of piperidine (concentration: 40%, 1.6 mL) for 3 minutes, and then treated with a DMF solution of piperidine (concentration: 20%, 1.6 mL) for 12 minutes to deprotect the Fmoc residue of the resin. Next, a DMF (0.8 mL) solution of Fmoc-β-homoPro-OH (0.40 mmol), a DMF (0.8 mL) solution of COMU (0.40 mmol) and Oxyma (0.40 mmol), and a NMP (0.4 mL) solution of DIPEA (0.80 mmol) were added, and the mixture was shaken at room temperature for 40 minutes to introduce a β-homoPro residue. The deprotection and fusion of Fmoc were repeated in the same manner. Specifically, Fmoc-(N-Me)Ile-OH, Fmoc-Leu-OH, Fmoc-Dab(Boc)-OH, and Fmoc-(d)-Glu-OtBu were fused in sequence, and the N-terminal Fmoc of the obtained resin was deprotected by treating with piperidine / DMF in the same manner as above, thereby synthesizing a resin H-γ-(d)-Glu(OtBu)-Dab(Boc)-Leu-(N-Me)Ile-β-homoPro-Rink Amide AM resin in a state where a peptide was bonded.

[1362] (2) A solution of 4-bromobenzenesulfonyl chloride (0.30 mmol) and DI PEA (0.60 mmol) in DMF (2 mL) was added to the resin obtained in (1) above, and the mixture was shaken at room temperature for 2 hours. After the reaction, the obtained resin was washed with DMF (2 mL x 3 times).

[1363] (3) A DMF (2 mL) solution of trimethylsilylacetylene (0.30 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.03 mmol), and copper iodide (0.03 mmol) was added to the resin obtained in the above (2), and heated and stirred at 80° C. for 30 minutes under microwave irradiation. After the reaction was completed, the obtained resin was washed with DMF (2 mL×3 times) and chloroform (2 mL×3 times).

[1364] To the obtained resin, a tetrabutylammonium fluoride tetrahydrofuran solution (concentration: 0.33 mol / L, 0.50 mmol) was added and shaken at room temperature for 1 hour. After the reaction was completed, the obtained resin was washed with DMF (2 mL × 3 times) and chloroform (2 mL × 3 times).

[1365] (4) To the resin obtained in the above (3) were added phenylazide (0.20 mmol), copper (II) sulfate pentahydrate (0.40 mmol), ascorbic acid (0.40 mmol) in water (2 mL) and tBuOH (1 mL) solution, and heated and stirred at 60°C for 1 hour under microwave irradiation. After the reaction was completed, the obtained resin was washed with DMF (2 mL × 3 times) and chloroform (2 mL × 3 times).

[1366] (5) TFA: water: triisopropylsilane (92.5: 2.5: 5, 4 mL) was added to the resin obtained in (4) above, shaken at room temperature for 2 hours, and the resin was removed by filtration. Cooled diethyl ether was added to the filtrate, and the precipitated white powder was precipitated by centrifugation. The operation of removing diethyl ether by decantation was repeated 3 times to obtain a crude peptide. The crude obtained was purified by preparative LCMS (preparative condition A). The eluate was fractionated in a test tube, and the eluted fractions containing the target substance were collected and lyophilized to obtain the title compound (12 mg) as a white powder.

[1367] Example 6 Compound No. 634 (N 2 Synthesis of -(4'-acetyl[1,1'-biphenyl]-4-sulfonyl)-N-[(2S)-1-({(2S)-1-[{(2S,3S)-1-[(2S)-2-(2-amino-2-oxoethyl)pyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}(methyl)amino]-4-methyl-1-oxopentan-2-yl}amino)-1-oxopropan-2-yl]-D-asparagine)

[1368]

[1369] (1) Fmoc-NH-SAL-PEG resin (0.10 mmol) was treated with a DMF solution of piperidine (concentration: 40%, 1.6 mL) for 3 minutes, and then treated with a DMF solution of piperidine (concentration: 20%, 1.6 mL) for 12 minutes to deprotect the Fmoc residue of the resin. Next, a DMF (0.8 mL) solution of Fmoc-β-homoPro-OH (0.40 mmol), a DMF (0.8 mL) solution of COMU (0.40 mmol) and Oxyma (0.40 mmol), and a NMP (0.4 mL) solution of DIPEA (0.80 mmol) were added, and the mixture was shaken at room temperature for 40 minutes to introduce a β-homoPro residue. The deprotection and fusion of Fmoc were repeated in the same manner. Specifically, Fmoc-(N-Me)Ile-OH, Fmoc-Leu-OH, Fmoc-Ala-OH, and Fmoc-(d)-Asp-OtBu were fused in sequence, and the N-terminal Fmoc of the obtained resin was deprotected by treating it with piperidine / DMF using the same method as above, thereby synthesizing a resin H-β-(d)-Asp(OtBu)-Ala-Leu-(N-Me)Ile-β-homoPro-NH-SAL-PEG resin in a state in which a peptide was bonded.

[1370] (2) A solution of 4-iodobenzenesulfonyl chloride (0.30 mmol) and DI PEA (0.60 mmol) in DMF (2 mL) was added to the resin obtained in (1) above, and the mixture was shaken at room temperature for 2 hours. After the reaction, the obtained resin was washed with DMF (2 mL × 3 times) and chloroform (2 mL × 3 times).

[1371] (3) To the resin obtained in the above (2) was added a solution of 4-acetylphenylboronic acid (0.40 mmol), tetrakis(triphenylphosphine)palladium(0) (0.03 mmol), potassium phosphate (0.50 mmol) in 1,4-dioxane (1.5 mL) and water (1.5 mL), and heated and stirred at 100° C. for 30 minutes under microwave irradiation. After completion of the reaction, the obtained resin was washed with DMF (2 mL×3 times) and chloroform (2 mL×3 times).

[1372] (4) TFA: water: triisopropylsilane (92.5: 2.5: 5, 4 mL) was added to the resin obtained in (3) above, and the mixture was shaken at room temperature for 2 hours, and the resin was removed by filtration. Cooled diethyl ether was added to the filtrate, and the precipitated white powder was precipitated by centrifugation. The operation of removing diethyl ether by decantation was repeated 3 times to obtain a crude peptide. The crude product was purified by preparative LCMS (preparative condition A). The eluate was fractionated in a test tube, and the eluted fractions containing the target substance were collected and lyophilized to obtain the title compound (8 mg) as a white powder.

[1373] Example 7 Compound No. 692 (N-[(2S)-3-amino-1-({(2S)-1-[{(2S,3S)-1-[(2S)-2-(2-amino-2-oxoethyl)pyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}(methyl)amino]-4-methyl-1-oxopentan-2-yl}amino)-1-oxopropan-2-yl]-N 2 Synthesis of -[4-(4-methoxybenzamido)benzene-1-sulfonyl]-D-asparagine)

[1374]

[1375] (1) Fmoc-Rink Amide AM resin (0.10 mmol) was treated with a DMF solution of piperidine (concentration: 40%, 1.6 mL) for 3 minutes, and then treated with a DMF solution of piperidine (concentration: 20%, 1.6 mL) for 12 minutes to deprotect the Fmoc residue of the resin. Next, a DMF (0.8 mL) solution of Fmoc-β-homoPro-OH (0.40 mmol), a DMF (0.8 mL) solution of COMU (0.40 mmol) and Oxyma (0.40 mmol), and a NMP (0.4 mL) solution of DIPEA (0.80 mmol) were added, and the mixture was shaken at room temperature for 40 minutes to introduce a β-homoPro residue. The deprotection and fusion of Fmoc were repeated in the same manner. Specifically, Fmoc-(N-Me)Ile-OH, Fmoc-Leu-OH, Fmoc-Dap(Boc)-OH, and Fmoc-(d)-Asp-OtBu were fused in sequence, and the N-terminal Fmoc of the obtained resin was deprotected by treatment with piperidine / DMF using the same method as above, thereby synthesizing a resin H-γ-(d)-Asp(OtBu)-Dap(Boc)-Leu-(N-Me)Ile-β-homoPro-Rink Amide AM resin in a state where a peptide was bonded.

[1376] (2) To the resin obtained in (1) above, a solution of (9H-fluoren-9-yl)methyl(4-(chlorosulfonyl)phenyl)carbamate (0.30 mmol) and DIPEA (0.60 mmol) in 1,4-dioxane (3 mL) was added, and the mixture was shaken at room temperature for 1 hour. After the reaction was completed, the obtained resin was washed with DMF (3 mL × 3 times). Next, a DMF solution of piperidine (concentration: 20%, 3 mL) and Oxyma (0.01 mmol) were added, and the mixture was shaken at room temperature for 10 minutes.

[1377] (3) A solution of 4-methoxybenzoyl chloride (0.30 mmol) and DIPEA (0.60 mmol) in 1,4-dioxane (2 mL) was added to the resin obtained in (2) above, and the mixture was shaken at room temperature for 3 hours. After the reaction, the obtained resin was washed with chloroform (3 mL x 3 times).

[1378] (4) TFA: water: triisopropylsilane: dithiothreitol (90: 2.5: 5: 2.5, 4 mL) was added to the resin obtained in (3) above, and the mixture was shaken at room temperature for 2 hours, and the resin was removed by filtration. Cooled diethyl ether was added to the filtrate, and the precipitated white powder was precipitated by centrifugation. The operation of removing diethyl ether by decantation was repeated 3 times to obtain a crude peptide. The crude product was purified by preparative LCMS (preparative condition A). The eluate was fractionated in a test tube, and the eluted fractions containing the target substance were collected and lyophilized to obtain the title compound (12 mg) as a white powder.

[1379] Example 8 Synthesis of Compound No. 892 ([(2S,5S,8S,20S)-8-[{(2S,3S)-1-[(2S)-2-(2-amino-2-oxoethyl)pyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}(methyl)carbamoyl]-5-methyl-3,6,14,17,21-pentaoxo-20-{4-[(4-phenoxybenzene-1-sulfonyl)amino]butyramido}-1,4,7,13,16-pentaazacyclohexane-2-yl]acetic acid)

[1380]

[1381] (1) Fmoc-NH-SAL-PEG resin (0.12 mmol) was treated with a DMF solution of piperidine (concentration: 40%, 1.9 mL) for 3 minutes, and then treated with a DMF solution of piperidine (concentration: 20%, 1.9 mL) for 12 minutes to deprotect the Fmoc residue of the resin. Next, a DMF (1.0 mL) solution of Fmoc-β-homoPro-OH (0.48 mmol), a DMF (1.0 mL) solution of COMU (0.48 mmol) and Oxyma (0.48 mmol), and a NMP (0.48 mL) solution of DIPEA (0.96 mmol) were added, and the mixture was shaken at room temperature for 40 minutes to introduce a β-homoPro residue. The deprotection and fusion of Fmoc were repeated in the same manner. Specifically, Fmoc-(N-Me)Ile-OH, Fmoc-Lys(Dde)-OH, Fmoc-Ala-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Glu(OAllyl)-OH, and Fmoc-GABA-OH were fused in sequence, and the N-terminal Fmoc of the obtained resin was deprotected by treatment with piperidine / DMF using the same method as above, thereby synthesizing a resin H-GABA-Glu(OAllyl)-Asp(OtBu)-Ala-Lys(Dde)-(N-Me)Ile-β-homoPro-SAL-PEG resin in a state of being bonded with a peptide.

[1382] (2) A solution of 4-phenoxybenzenesulfonyl chloride (0.36 mmol) and DIPEA (0.72 mmol) in DMF (3 mL) was added to the resin obtained in (1) above, and the mixture was shaken at room temperature for 1.5 hours. After the reaction, the obtained resin was washed with DMF (3 mL x 3 times).

[1383] (3) A DMF solution of hydrazine monohydrate (concentration: 5%, 3 mL) and allyl alcohol (3.1 mmol) were added to the resin obtained in (2) above, and the mixture was shaken at room temperature for 30 minutes to deprotect the Dde of the Lys side chain. Next, a DMF (3 mL) solution of Fmoc-Gly-OH (0.48 mmol), COMU (0.48 mmol), Oxyma (0.48 mmol), and DIPEA (0.96 mmol) was added, and the mixture was shaken at room temperature for 30 minutes to introduce a Gly residue. After the reaction was completed, the obtained resin was washed with DMF (3 mL × 3 times) and chloroform (3 mL × 3 times).

[1384] (4) A chloroform (4 mL) solution of tetrakis(triphenylphosphine)palladium(0) (0.12 mmol) and phenylsilane (0.60 mmol) was added to the resin obtained in (3) above, and the mixture was shaken at room temperature for 1.5 hours to deprotect the Allyl group of the Glu side chain. Next, a DMF solution of piperidine (concentration: 20%, 3 mL) was added, and the mixture was shaken at room temperature for 30 minutes to deprotect the Fmoc group. After the reaction was completed, the obtained resin was washed with DMF (3 mL × 5 times).

[1385] (5) A DMF (4 mL) solution of PyBOP (0.36 mmol) and DIPEA (0.12 mmol) was added to the resin obtained in (4) above, and the mixture was shaken at room temperature for 2 hours. After the reaction, the obtained resin was washed with DMF (3 mL × 3 times) and chloroform (3 mL × 3 times).

[1386] (6) TFA: water: triisopropylsilane: dithiothreitol (90: 2.5: 5: 2.5, 4 mL) was added to the resin obtained in (5) above, and the mixture was shaken at room temperature for 2 hours, and the resin was removed by filtration. Cooled diethyl ether was added to the filtrate, and the precipitated white powder was precipitated by centrifugation. The operation of removing diethyl ether by decantation was repeated 3 times to obtain a crude peptide. The crude product was purified by preparative LCMS (preparative condition A). The eluate was fractionated in a test tube, and the eluted fractions containing the target substance were collected and lyophilized to obtain the title compound (10 mg) as a white powder.

[1387] Example 9 Synthesis of Compound No. 903 ((2S,5S,32R)-2-{[(2S)-1-({(2S)-1-[{(2S,3S)-1-[(2S)-2-(2-amino-2-oxoethyl)pyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}(methyl)amino]-4-methyl-1-oxopentan-2-yl}amino)-1-oxopropan-2-yl]carbamoyl}-4,11,20,29,34-pentaoxo-5-{4-[(4-phenoxybenzene-1-sulfonyl)amino]butanamido}-13,16,22,25-tetraoxa-3,10,19,28,33-pentaazatetraoctadecane-1,32,48-tricarboxylic acid)

[1388]

[1389] (1) Fmoc-Rink Amide AM resin (0.12 mmol) was treated with a DMF solution of piperidine (concentration: 40%, 1.9 mL) for 3 minutes, and then treated with a DMF solution of piperidine (concentration: 20%, 1.9 mL) for 12 minutes to deprotect the Fmoc residue of the resin. Next, a DMF (1.0 mL) solution of Fmoc-β-homoPro-OH (0.48 mmol), a DMF (1.0 mL) solution of COMU (0.48 mmol) and Oxyma (0.48 mmol), and a NMP (0.48 mL) solution of DIPEA (0.96 mmol) were added, and the mixture was shaken at room temperature for 40 minutes to introduce a β-homoPro residue. The deprotection and fusion of Fmoc were repeated in the same manner. Specifically, Fmoc-(N-Me)Ile-OH, Fmoc-Leu-OH, Fmoc-Ala-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Lys(Dde)-OH, and Fmoc-GABA-OH were fused in sequence, and the N-terminal Fmoc of the obtained resin was deprotected by treatment with piperidine / DMF using the same method as above, thereby synthesizing a resin H-GABA-Lys(Dde)-Asp(OtBu)-Ala-Leu-(N-Me)Ile-β-homoPro-Rink Amide AM resin in a state of being bonded with a peptide.

[1390] (2) A DMF (3 mL) solution of 4-phenoxybenzenesulfonyl chloride (0.36 mmol) and DIPEA (0.72 mmol) was added to the resin obtained in (1) above, and the mixture was shaken at room temperature for 2 hours. After the reaction, the obtained resin was washed with DMF (3 mL x 3 times).

[1391] (3) A DMF solution of hydrazine monohydrate (concentration: 5%, 3 mL) was added to the resin obtained in the above (2), and the operation of shaking at room temperature for 30 minutes was repeated 4 times to deprotect the Dde of the Lys side chain. The obtained resin was repeatedly fused and de-Fmoc was removed. Specifically, Fmoc-Adox-OH, Fmoc-Adox-OH, and Fmoc-Glu-OtBu were fused in sequence to extend the peptide on the Lys side chain. The N-terminal Fmoc of the Lys side chain was deprotected by piperidine / DMF treatment.

[1392] (4) A DMF (3 mL) solution of hexadecanedioic acid (0.96 mmol), COMU (0.18 mmol), Oxyma (0.18 mmol), and DIPEA (0.96 mmol) was added to the resin obtained in the above (3), and the mixture was shaken at room temperature for 1 hour. After the reaction, the obtained resin was washed with DMF (3 mL × 4 times) and chloroform (3 mL × 3 times).

[1393] (5) TFA: water: triisopropylsilane: dithiothreitol (90: 2.5: 5: 2.5, 4 mL) was added to the resin obtained in (4) above, and the mixture was shaken at room temperature for 2 hours, and the resin was removed by filtration. Cooled diethyl ether was added to the filtrate, and the precipitated white powder was precipitated by centrifugation. The operation of removing diethyl ether by decantation was repeated 3 times to obtain a crude peptide. The crude product was purified by preparative LCMS (preparative condition A). The eluate was fractionated in a test tube, and the eluted fractions containing the target substance were collected and lyophilized to obtain the title compound (29 mg) as a white powder.

[1394] The structures of the compounds represented by the formula [I′-1] and synthesized in Example 1 or by the same method as Example 1 are shown in the following table.

[1395]

[1396] [Table 5]

[1397]

[1398]

[1399] The structures of the compounds represented by the formula [I′-2] and synthesized by the same method as in Example 1 are shown in the following table.

[1400]

[1401] [Table 6]

[1402]

[1403] The structures of the compounds represented by the formula [I′-3] and synthesized by the same method as in Example 1 are shown in the following table.

[1404]

[1405] [Table 7]

[1406]

[1407] The structures of the compounds represented by the formula [I′-4] and synthesized by the same method as in Example 1 are shown in the following table.

[1408]

[1409] [Table 8]

[1410]

[1411] The structures of the compounds represented by the formula [I′-5] and synthesized by the same method as in Example 1 are shown in the following table.

[1412]

[1413] [Table 9]

[1414]

[1415] The structures of the compounds represented by the formula [I′-6] and synthesized by the same method as in Example 1 are shown in the following table.

[1416]

[1417] [Table 10]

[1418]

[1419] The structures of the compounds represented by the formula [I′-7] and synthesized by the same method as in Example 1 are shown in the following table.

[1420]

[1421] [Table 11]

[1422]

[1423] The structures of the compounds represented by the formula [I′-8] and synthesized by the same method as in Example 1 are shown in the following table.

[1424]

[1425] [Table 12]

[1426]

[1427]

[1428]

[1429] The structures of the compounds represented by formula [I′-9] and synthesized in Example 2 or by the same method as Example 2 are shown in the following table.

[1430]

[1431] [Table 13]

[1432]

[1433]

[1434]

[1435]

[1436] The structures of the compounds represented by the formula [I′-10] and synthesized by the same method as in Example 9 are shown in the following table.

[1437]

[1438] [Table 14]

[1439]

[1440] The structures of the compounds represented by formula [I′-9] and synthesized in Example 2 or by the same method as Example 2 are shown in the following table.

[1441]

[1442] [Table 15]

[1443]

[1444] The structures of the compounds represented by the formula [I′-9] and synthesized in Example 3 or by the same method as Example 3 are shown in the following table.

[1445]

[1446] [Table 16]

[1447]

[1448]

[1449] The structures of the compounds represented by the formula [I′-11] and synthesized by the same method as in Example 2 are shown in the following table.

[1450]

[1451] [Table 17]

[1452]

[1453] The structures of the compounds represented by the formula [I′-12] and synthesized by the same method as in Example 2 are shown in the following table.

[1454]

[1455] [Table 18]

[1456]

[1457] The structures of the compounds represented by the formula [I′-13] and synthesized by the same method as in Example 2 are shown in the following table.

[1458]

[1459] [Table 19]

[1460]

[1461] The structures of the compounds represented by the formula [I′-14] and synthesized by the same method as in Example 2 are shown in the following table.

[1462]

[1463] [Table 20]

[1464]

[1465]

[1466]

[1467]

[1468]

[1469] The structures of the compounds represented by the formula [I′-15] and synthesized by the same method as in Example 2 are shown in the following table.

[1470]

[1471] [Table 21]

[1472]

[1473] The structures of the compounds represented by the formula [I′-14] and synthesized by the same method as in Example 2 are shown in the following table.

[1474]

[1475] [Table 22]

[1476]

[1477]

[1478]

[1479]

[1480]

[1481]

[1482]

[1483]

[1484]

[1485]

[1486]

[1487]

[1488]

[1489] The structures of the compounds represented by the formula [I′-16] and synthesized in Example 4 or by the same method as Example 4 are shown in the following table.

[1490]

[1491] [Table 23]

[1492]

[1493] The structures of the compounds represented by the formula [I′-17] and synthesized by the same method as in Example 2 are shown in the following table.

[1494]

[1495] [Table 24]

[1496]

[1497] The structures of the compounds represented by the formula [I′-18] and synthesized by the same method as in Example 2 are shown in the following table.

[1498]

[1499] [Table 25]

[1500]

[1501] The structures of the compounds represented by the formula [I′-19] and synthesized by the same method as in Example 2 are shown in the following table.

[1502]

[1503] [Table 26]

[1504]

[1505] The structures of the compounds represented by the formula [I′-20] and synthesized by the same method as in Example 1 are shown in the following table.

[1506]

[1507] [Table 27]

[1508]

[1509] The structures of the compounds represented by the formula [I′-21] and synthesized by the same method as in Example 1 are shown in the following table.

[1510]

[1511] [Table 28]

[1512]

[1513] The structures of the compounds represented by the formula [I′-22] and synthesized by the same method as in Example 2 are shown in the following table.

[1514]

[1515] [Table 29]

[1516]

[1517] The structures of the compounds represented by the formula [I'-23] and synthesized by the same method as in Example 2 are shown in the following table.

[1518]

[1519] [Table 30]

[1520]

[1521] The structures of the compounds represented by the formula [I'-24] and synthesized by the same method as in Example 2 are shown in the table below.

[1522]

[1523] [Table 31]

[1524]

[1525] The structures of the compounds represented by the formula [I′-25] and synthesized by the same method as in Example 2 are shown in the following table.

[1526]

[1527] [Table 32]

[1528]

[1529] The structures of the compounds represented by the formula [I'-26] and synthesized by the same method as in Example 2 are shown in the following table.

[1530]

[1531] [Table 33]

[1532]

[1533] The structures of the compounds represented by the formula [I'-27] and synthesized by the same method as in Example 1 are shown in the following table.

[1534]

[1535] [Table 34]

[1536]

[1537] The structures of the compounds represented by the formula [I'-28] and synthesized by the same method as in Example 1 are shown in the following table.

[1538]

[1539] [Table 35]

[1540]

[1541] The structures of the compounds represented by the formula [I'-29] and synthesized by the same method as in Example 1 are shown in the following table.

[1542]

[1543] [Table 36]

[1544]

[1545] The structures of the compounds represented by the formula [I'-30] and synthesized by the method described in Example 5 are shown in the following table.

[1546]

[1547] [Table 37]

[1548]

[1549] The structures of the compounds represented by the formula [I′-31] and synthesized by the same method as in Example 5 are shown in the following table.

[1550]

[1551] [Table 38]

[1552]

[1553] The structures of the compounds represented by the formula [I′-32] and synthesized by the same method as in Example 1 are shown in the following table.

[1554]

[1555] [Table 39]

[1556]

[1557]

[1558]

[1559] The structures of the compounds represented by formula [I′-32] and synthesized in Example 6 or by the same method as Example 6 are shown in the following table.

[1560]

[1561] [Table 40]

[1562]

[1563]

[1564] The structures of the compounds represented by the formula [I′-33] and synthesized by the same method as in Example 1 are shown in the following table.

[1565]

[1566] [Table 41]

[1567]

[1568] The structures of the compounds represented by the formula [I′-34] and synthesized by the same method as in Example 1 are shown in the following table.

[1569]

[1570] [Table 42]

[1571]

[1572]

[1573]

[1574]

[1575] The structures of the compounds represented by formula [I′-34] and synthesized in Example 7 or by the same method as Example 7 are shown in the following table.

[1576]

[1577] [Table 43]

[1578]

[1579] The structures of the compounds represented by the formula [I′-35] and synthesized by the same method as in Example 1 are shown in the following table.

[1580]

[1581] [Table 44]

[1582]

[1583]

[1584]

[1585]

[1586]

[1587]

[1588] The structures of the compounds represented by the formula [I'-36] and synthesized by the same method as in Example 1 are shown in the table below.

[1589]

[1590] [Table 45]

[1591]

[1592]

[1593]

[1594]

[1595]

[1596]

[1597]

[1598]

[1599] The structures of the compounds represented by formula [I′-37] and synthesized in Example 8 or by the same method as Example 8 are shown in the following table.

[1600]

[1601] [Table 46]

[1602]

[1603] The structures of the compounds represented by formula [I′-38] and synthesized in Example 9 or by the same method as Example 9 are shown in the following table.

[1604]

[1605] [Table 47]

[1606]

[1607] The structures of the compounds represented by the formula [I'-39] and synthesized by the same method as in Example 9 are shown in the following table.

[1608]

[1609] [Table 48]

[1610]

[1611]

[1612]

[1613]

[1614] The structures of the compounds represented by the formula [I′-40] and synthesized by the same method as in Example 9 are shown in the table below.

[1615]

[1616] (In the above formula [I'-40],

[1617] From the following formula [VII-2]

[1618] -AA WC1 -AA WC2 -AA WC3 -AA WC4 -AA WC5 -[VII-2]

[1619] The structure represented by the formula [I'] is equivalent to W C , which is a "linker composed of 1 to 3 amino acids",

[1620] Here,

[1621] AA WC1 AA WC2 AA WC4 , and AA WC5 are each identically or differently selected from a single bond and (d)-Lys,

[1622] AA WC3 is Lys or (d)-Lys,

[1623] AA WCS is a single bond or (d)-Lys. )

[1624] [Table 49]

[1625]

[1626] The high performance liquid chromatography mass spectra (LCMS), retention times (RT) and analysis conditions of the compounds of the present invention are shown in the following table.

[1627] [Table 50]

[1628]

[1629]

[1630]

[1631]

[1632]

[1633]

[1634]

[1635]

[1636]

[1637]

[1638]

[1639]

[1640]

[1641]

[1642]

[1643]

[1644]

[1645]

[1646]

[1647]

[1648]

[1649]

[1650]

[1651]

[1652]

[1653]

[1654] The inhibitory effect of the compound of the present invention on MMP2 was measured by the methods described in the following Test Examples 1-1 to 1-2.

[1655] Test Example 1-1: Evaluation test of the inhibitory effect of each compound of the present invention on human MMP2 (Method 1)

[1656] The human MMP2 inhibitory effect of each compound was determined by an enzyme assay using MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 as a substrate. 100 μg / mL of human recombinant MMP2 enzyme and 1 mmol / L of 4-aminophenylmercuric acetate were mixed in a reaction solution [50 mmol / L Tris-HCl (pH 7.5), 150 mmol / L NaCl, 10 mmol / L CaCl2, 0.05% Brij L23] and reacted at 37°C for 60 minutes. Human MMP2 activated by the reaction was injected into a 96-well microplate to a final concentration of 0.7 ng / mL or 7 ng / mL. Further, each compound of the present invention diluted to various concentrations was added and allowed to stand at room temperature for 15 minutes. Then, MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 was added to a final concentration of 5 μmol / L or 16 μmol / L to start the enzyme reaction. After reacting for 2 hours at room temperature, the fluorescence intensity (Ex320nm / Em400nm) was measured using a microplate reader. The enzyme inhibition rate (%) was calculated using the measured fluorescence value according to the following formula, and the 50% inhibition concentration (IC) of each invention compound was calculated. 50 value).

[1657] Enzyme inhibition rate (%) = [1-(AB) / (CB)] × 100

[1658] A: fluorescence value when the compound was added;

[1659] B: fluorescence value when no compound and enzyme were added;

[1660] C: Fluorescence value when no compound was added.

[1661] Test Example 1-2: Evaluation test of the inhibitory effect of each compound of the present invention on human MMP2 (Method 2)

[1662] The human MMP2 inhibitory effect of each compound was determined by an enzyme assay using MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 as a substrate. 12.5 μg / mL of human recombinant MMP2 enzyme and 1 mmol / L of acetic acid-4-aminophenylmercuric were mixed in a reaction solution [50 mmol / L Tris-HCl (pH 7.5), 150 mmol / L NaCl, 10 mmol / L CaCl2, 0.05% BrijL23] and reacted at 37°C for 60 minutes. Human MMP2 activated by the reaction was injected into a 384-well microplate to a final concentration of 7 ng / mL or 2.8 ng / mL. Further, each compound of the present invention diluted to various concentrations was added and allowed to stand at room temperature for 10 minutes. Then, MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 was added to a final concentration of 16 μmol / L or 5 μmol / L to start the enzyme reaction. After reacting at room temperature for 1 to 2 hours, the fluorescence intensity (Ex 320nm / Em 405nm) was measured using an enzyme reader. The measured fluorescence value was used to calculate the enzyme inhibition rate (%) according to the following formula, and the 50% inhibition concentration (IC) of each invention compound was calculated. 50 value).

[1663] Enzyme inhibition rate (%) = [1-(AB) / (CB)] × 100

[1664] A: fluorescence value when the compound was added;

[1665] B: fluorescence value when no compound and enzyme were added;

[1666] C: Fluorescence value when no compound was added.

[1667] The results of the inhibitory effects of the compounds of the present invention on human MMP2 enzyme activity are shown in the following table.

[1668] [Table 51-1]

[1669]

[1670]

[1671] [Table 51-2]

[1672]

[1673]

[1674] [Table 51-3]

[1675]

[1676]

[1677] [Table 51-4]

[1678]

[1679]

[1680] [Table 51-5]

[1681]

[1682] [Table 51-6]

[1683]

[1684] [Table 51-7]

[1685]

[1686]

[1687] [Table 51-8]

[1688]

[1689]

[1690] [Table 51-9]

[1691]

[1692]

[1693] [Table 51-10]

[1694]

[1695]

[1696] [Table 51-11]

[1697]

[1698]

[1699] [Table 51-12]

[1700]

[1701] [Table 51-13]

[1702]

[1703] [Table 51-14]

[1704]

[1705]

[1706] [Table 51-15]

[1707]

[1708]

[1709] [Table 51-16]

[1710]

[1711]

[1712] [Table 51-17]

[1713]

[1714] In addition, the inhibitory action of the compounds of the present invention on each MMP can be measured by the methods described in Test Examples 2 to 9.

[1715] Test Example 2: Evaluation test of the inhibitory effect of each compound of the present invention on human MMP1

[1716] The human MMP1 inhibitory effect of each compound was determined by an enzyme assay using MOCAc-Lys-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 as a substrate. 50 μg / mL of human recombinant MMP1 enzyme and 1 mmol / L of acetic acid-4-aminophenylmercuric were mixed in a reaction solution [50 mmol / L Tris-HCl (pH 7.5), 150 mmol / L NaCl, 10 mmol / L CaCl2, 0.05% BrijL23] and reacted at 37°C for 120 minutes. Human MMP1 activated by the reaction was injected into a 96-well microplate to a final concentration of 8 ng / mL. Further, each compound of the present invention diluted to various concentrations was added and allowed to stand at room temperature for 15 minutes. Then, MOCAc-Lys-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 was added to a final concentration of 11 μmol / L to start the enzyme reaction. After reacting at room temperature for 1 hour, the fluorescence intensity (Ex 320nm / Em 400nm) was measured using a microplate reader. The enzyme inhibition rate (%) was calculated using the measured fluorescence value according to the following formula, and the 50% inhibition concentration (IC 50 value).

[1717] Enzyme inhibition rate (%) = [1-(AB) / (CB)] × 100

[1718] A: fluorescence value when the compound was added;

[1719] B: fluorescence value when no compound and enzyme were added;

[1720] C: Fluorescence value when no compound was added.

[1721] Test Example 3: Evaluation test of the inhibitory effect of each compound of the present invention on human MMP3

[1722] The human MMP3 inhibitory effect of each compound was determined by an enzyme assay using MOCAc-Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg-Lys(Dnp)-NH2 as a substrate. 3 μg / mL of human recombinant MMP3 enzyme and 5 μg / mL of chymosin were mixed in a reaction solution [50 mmol / L Tris-HCl (pH 7.5), 150 mmol / L NaCl, 10 mmol / L CaCl2, 0.05% Brij L23]. After reacting at 37°C for 30 minutes, PMSF was added to 2 mmol / L to stop the reaction. Human MMP3 activated by the reaction was injected into a 96-well microplate to a final concentration of 52 ng / mL. Further, each compound of the present invention diluted to various concentrations was added and allowed to stand at room temperature for 15 minutes. Then, MOCAc-Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg-Lys(Dnp)-NH2 was added to a final concentration of 26 μmol / L to start the enzyme reaction. After reacting at room temperature for 1 hour, the fluorescence intensity (Ex 320nm / Em 400nm) was measured using an ELISA reader. The enzyme inhibition rate (%) was calculated using the measured fluorescence value according to the following formula to calculate the 50% inhibition concentration (IC) of each invention compound. 50 value).

[1723] Enzyme inhibition rate (%) = [1-(AB) / (CB)] × 100

[1724] A: fluorescence value when the compound was added;

[1725] B: fluorescence value when no compound and enzyme were added;

[1726] C: Fluorescence value when no compound was added.

[1727] Test Example 4: Evaluation test of the inhibitory effect of each compound of the present invention on human MMP7

[1728] The human MMP7 inhibitory effect of each compound was determined by an enzyme assay using MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 as a substrate. 50 μg / mL of human recombinant MMP7 enzyme and 1 mmol / L of 4-aminophenylmercuric acetate were mixed in a reaction solution [50 mmol / L Tris-HCl (pH 7.5), 150 mmol / L NaCl, 10 mmol / L CaCl2, 0.05% Brij L23] and reacted at 37°C for 60 minutes. Human MMP7 activated by the reaction was injected into a 96-well microplate to a final concentration of 18 ng / mL. Further, each compound of the present invention diluted to various concentrations was added and allowed to stand at room temperature for 15 minutes. Then, MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 was added to a final concentration of 22 μmol / L to start the enzyme reaction. After reacting at room temperature for 1 hour, the fluorescence intensity (Ex 320nm / Em 400nm) was measured using a microplate reader. The enzyme inhibition rate (%) was calculated using the measured fluorescence value according to the following formula, and the 50% inhibition concentration (IC 50 value).

[1729] Enzyme inhibition rate (%) = [1-(AB) / (CB)] × 100

[1730] A: fluorescence value when the compound was added;

[1731] B: fluorescence value when no compound and enzyme were added;

[1732] C: Fluorescence value when no compound was added.

[1733] Test Example 5: Evaluation test of the inhibitory effect of each compound of the present invention on human MMP8

[1734] The human MMP8 inhibitory effect of each compound was determined by an enzyme assay using MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 as a substrate. 100 μg / mL of human recombinant MMP8 enzyme and 1 mmol / L of 4-aminophenylmercuric acetate were mixed in a reaction solution [50 mmol / L Tris-HCl (pH 7.5), 150 mmol / L NaCl, 10 mmol / L CaCl2, 0.05% Brij L23] and reacted at 37°C for 60 minutes. Human MMP8 activated by the reaction was injected into a 96-well microplate to a final concentration of 149 ng / mL. Further, each compound of the present invention diluted to various concentrations was added and allowed to stand at room temperature for 15 minutes. Then, MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 was added to a final concentration of 25 μmol / L to start the enzyme reaction. After reacting at room temperature for 1 hour, the fluorescence intensity (Ex 320nm / Em 400nm) was measured using a microplate reader. The enzyme inhibition rate (%) was calculated using the measured fluorescence value according to the following formula, and the 50% inhibition concentration (IC 50 value).

[1735] Enzyme inhibition rate (%) = [1-(AB) / (CB)] × 100

[1736] A: fluorescence value when the compound was added;

[1737] B: fluorescence value when no compound and enzyme were added;

[1738] C: Fluorescence value when no compound was added.

[1739] Test Example 6: Evaluation test of the inhibitory effect of each compound of the present invention on human MMP9

[1740] The human MMP9 inhibitory effect of each compound was determined by an enzyme assay using MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 as a substrate. 50 μg / mL of human recombinant MMP9 enzyme and 1 mmol / L of 4-aminophenylmercuric acetate were mixed in a reaction solution [50 mmol / L Tris-HCl (pH 7.5), 150 mmol / L NaCl, 10 mmol / L CaCl2, 0.05% Brij L23] and reacted at 37°C for 24 hours. Human MMP9 activated by the reaction was injected into a 96-well microplate to a final concentration of 58 ng / mL. Further, each compound of the present invention diluted to various concentrations was added and allowed to stand at room temperature for 15 minutes. Then, MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 was added to a final concentration of 3 μmol / L to start the enzyme reaction. After reacting at room temperature for 1 hour, the fluorescence intensity (Ex 320nm / Em 400nm) was measured using a microplate reader. The enzyme inhibition rate (%) was calculated using the measured fluorescence value according to the following formula, and the 50% inhibition concentration (IC 50 value).

[1741] Enzyme inhibition rate (%) = [1-(AB) / (CB)] × 100

[1742] A: fluorescence value when the compound was added;

[1743] B: fluorescence value when no compound and enzyme were added;

[1744] C: Fluorescence value when no compound was added.

[1745] Test Example 7: Evaluation test of the inhibitory effect of each compound of the present invention on human MMP12

[1746] The human MMP12 inhibitory effect of each compound was determined by an enzyme assay using MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 as a substrate. 50 μg / mL of human recombinant MMP12 enzyme and 1 mmol / L of acetic acid-4-aminophenylmercuric were mixed in a reaction solution [50 mmol / L Tris-HCl (pH 7.5), 150 mmol / L NaCl, 10 mmol / L CaCl2, 0.05% BrijL23] and reacted at 37°C for 4 hours or 24 hours. Human MMP12 activated by the reaction was injected into a 96-well microplate to a final concentration of 17 ng / mL or 5.2 ng / mL. Further, each compound of the present invention diluted to various concentrations was added and allowed to stand at room temperature for 15 minutes. Then, MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 was added to a final concentration of 5 μmol / L or 14 μmol / L to start the enzyme reaction. After reacting at room temperature for 1 hour, the fluorescence intensity (Ex 320nm / Em 400nm) was measured using an enzyme reader. The measured fluorescence value was used to calculate the enzyme inhibition rate (%) according to the following formula to calculate the 50% inhibition concentration (IC) of each invention compound. 50 value).

[1747] Enzyme inhibition rate (%) = [1-(AB) / (CB)] × 100

[1748] A: fluorescence value when the compound was added;

[1749] B: fluorescence value when no compound and enzyme were added;

[1750] C: Fluorescence value when no compound was added.

[1751] The results of the inhibitory effects of the compounds of the present invention on the enzymatic activity of human MMP12 are shown in the following table.

[1752] [Table 52]

[1753]

[1754] Test Example 8: Evaluation test of the inhibitory effect of each compound of the present invention on human MMP13

[1755] The human MMP13 inhibitory effect of each compound was determined by an enzyme assay using MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 as a substrate. 50 μg / mL of human recombinant MMP13 enzyme and 1 mmol / L of acetic acid-4-aminophenylmercuric were mixed in a reaction solution [50 mmol / L Tris-HCl (pH 7.5), 150 mmol / L NaCl, 10 mmol / L CaCl2, 0.05% BrijL23] and reacted at 37°C for 2 hours. Human MMP13 activated by the reaction was injected into a 96-well microplate to a final concentration of 5 ng / mL. Further, each compound of the present invention diluted to various concentrations was added and allowed to stand at room temperature for 15 minutes. Then, MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 was added to a final concentration of 6 μmol / L to start the enzyme reaction. After reacting at room temperature for 1 hour, the fluorescence intensity (Ex 320nm / Em 400nm) was measured using a microplate reader. The enzyme inhibition rate (%) was calculated using the measured fluorescence value according to the following formula, and the 50% inhibition concentration (IC 50 value).

[1756] Enzyme inhibition rate (%) = [1-(AB) / (CB)] × 100

[1757] A: fluorescence value when the compound was added;

[1758] B: fluorescence value when no compound and enzyme were added;

[1759] C: Fluorescence value when no compound was added.

[1760] The results of the inhibitory effects of the compounds of the present invention on the human MMP13 enzyme activity are shown in the following table.

[1761] [Table 53]

[1762]

[1763] Test Example 9: Evaluation test of the inhibitory effect of each compound of the present invention on human MMP14

[1764] The human MMP14 inhibitory effect of each compound was determined by an enzyme assay using MOCAc-Lys-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 as a substrate. 100 μg / mL of human recombinant MMP14 enzyme and 5 μg / mL of trypsin were mixed in a reaction solution [50 mmol / L Tris-HCl (pH 7.5), 200 mmol / L NaCl, 5 mmol / L CaCl2, 20 μmol / L ZnSO4, 0.05% Brij L23]. After reacting at room temperature for 25 minutes, trypsin inhibitor was added to reach 25 μg / mL to stop the reaction. Human MMP14 activated by the reaction was injected into a 96-well microplate to a final concentration of 6 ng / mL. Further, each compound of the present invention diluted to various concentrations was added and allowed to stand at room temperature for 15 minutes. Then, MOCAc-Lys-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 was added to a final concentration of 5 μmol / L to start the enzyme reaction. After reacting at room temperature for 1 hour, the fluorescence intensity (Ex 320nm / Em 400nm) was measured using an enzyme reader. The enzyme inhibition rate (%) was calculated using the measured fluorescence value according to the following formula, and the 50% inhibition concentration (IC) of each invention compound was calculated. 50 value).

[1765] Enzyme inhibition rate (%) = [1-(AB) / (CB)] × 100

[1766] A: fluorescence value when the compound was added;

[1767] B: fluorescence value when no compound and enzyme were added;

[1768] C: Fluorescence value when no compound was added.

[1769] Industrial Applicability

[1770] The compounds of the present invention have an excellent effect of inhibiting MMP2. The present invention can provide medicines effective for preventing or treating cancer diseases and organ fibrosis, as well as symptoms associated with cancer diseases and organ fibrosis, and is expected to reduce the burden on patients and contribute to the development of the pharmaceutical industry.

Claims

1. A substituted polypeptide represented by the following formula [I'-B] or a pharmaceutically acceptable salt thereof: In the above formula [I'-B], AA 1 β-(d)-Asp or γ-(d)-Glu, AA 2 The following formula [II-1] The groups represented By the following formula [IV-7] or [IV-9] The group represented by Here, R AA2 For amino, AA 3 is Val, Leu or Ile, AA 4 is (N-Me)Ile or (N-Me)Glu, AA 5 For β-Ala、GABA、Ape、Acp or β-homoPro、 L N1 is of the formula -C(=O)- or the formula -S(=O)2-, L N2 is of the formula -O- or -C(=O)-NH-, R B1 is a carbamoyl group, a chlorine atom, a bromine atom, a methoxy group or a trifluoromethoxy group, R B2 is a hydrogen atom, R B3 is a hydrogen atom, W C is a single bond or (d)-Lys, R C The formula is -NH2.

2. The substituted polypeptide or pharmaceutically acceptable salt thereof according to claim 1, which is selected from the following compounds:

3. A medicine comprising the substituted polypeptide according to claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient.

4. A MMP2 inhibitor comprising the substituted polypeptide or a pharmaceutically acceptable salt thereof according to claim 1 or 2 as an active ingredient.

5. Use of the substituted polypeptide or a pharmaceutically acceptable salt thereof according to claim 1 or 2 in the manufacture of an MMP2 inhibitor.

6. Use of the substituted polypeptide according to claim 1 or 2 or a pharmaceutically acceptable salt thereof in the manufacture of a preventive or therapeutic agent for breast cancer, pancreatic cancer, bladder cancer, colorectal cancer, ovarian cancer, prostate cancer, brain tumor, gastric cancer, hepatocellular carcinoma, head and neck cancer, melanoma, uterine cancer, esophageal cancer, renal cell carcinoma, lung cancer, glioma, chronic kidney disease, interstitial pneumonia or idiopathic pulmonary fibrosis in which MMP2 is involved, or for symptoms associated with breast cancer, pancreatic cancer, bladder cancer, colorectal cancer, ovarian cancer, prostate cancer, brain tumor, gastric cancer, hepatocellular carcinoma, head and neck cancer, melanoma, uterine cancer, esophageal cancer, renal cell carcinoma, lung cancer, glioma, chronic kidney disease, interstitial pneumonia or idiopathic pulmonary fibrosis in which MMP2 is involved.

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