Polypeptide having MMP2 inhibitory effect

Abstract

To provide a novel MMP2 inhibitor.SOLUTION: Provided is a substituted polypeptide or a pharmaceutically acceptable salt thereof which has an effect of inhibiting MMP2 and is represented by the following formula [I'].SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a substituted polypeptide compound that has an inhibitory effect on matrix metalloproteinase 2 (hereinafter, appropriately abbreviated as "MMP2"). [Background technology]

[0002] Matrix metalloproteinases are endopeptidases that have zinc at the active center, and 24 different genes are known. MMPs degrade extracellular matrices such as collagen and gelatin, and are therefore 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).

[0003] To date, focusing on the anti-cancer effect of MMP inhibition, clinical trials of several MMP inhibitors have been conducted, but these have been abandoned due to side effects such as skeletal muscle pain, which are thought to be due to the relatively non-selective inhibitory effect on various MMP subtypes, and the possibility of promoting cancer metastasis (see Non-Patent Documents 2 and 3).

[0004] It has been reported that activation of MMP2 plays an important role in the invasion and metastasis of cancer cells. Invasion and metastasis of cancer cells are important factors related to the prognosis of malignant tumors, and suppression of MMP2 activity can be an effective therapeutic means for cancer control. It has been reported that cancer growth is suppressed in MMP2 gene-deficient animals, and that MMP2 plays an important role in cancer growth (see Non-Patent Document 4). Furthermore, it has been reported that MMP2 is related to the progression of pathology in patients with various cancers, such as breast cancer, pancreatic cancer, bladder cancer, colon 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, and glioma (see Non-Patent Documents 5 and 6). On the other hand, it has been reported that MMP2 is also involved in the formation of pathology in non-tumor diseases.

[0005] It has been reported that in chronic kidney disease, MMP2 induces epithelial-mesenchymal transition of the tubules by converting the structure of the tubular basement membrane, thereby inducing tubular atrophy, fibrosis, and impaired renal function (see Non-Patent Document 7). Furthermore, an increase in MMP2 concentration in the blood has been observed in patients with chronic kidney disease (see Non-Patent Documents 8 and 9). It has also been reported that renal fibrosis induced by unilateral ureteral ligation is suppressed in MMP2 gene-deficient animals (see Non-Patent Documents 10 and 11). For this reason, suppressing MMP2 activity to control the progression of the pathology of chronic kidney disease can be an effective therapeutic measure.

[0006] In idiopathic pulmonary fibrosis, increased expression of MMP2 has been observed in alveolar epithelial cells, fibroblasts, and macrophages, and in particular, increased expression of MMP2 in alveolar lavage fluid has been observed in patients with idiopathic pulmonary fibrosis accompanied by rapid progression (see Non-Patent Documents 12 and 13). In addition, it has been reported that non-selective MMP inhibitors have the effect of reducing collagen content in the lungs of mice with bleomycin-induced pulmonary fibrosis (see Non-Patent Document 14) and suppressing the transformation of pulmonary parenchymal fibroblasts induced by TGFβ (see Non-Patent Document 15). Therefore, suppressing MMP2 activity to control the progression of the pathology of idiopathic pulmonary fibrosis can be an effective therapeutic means.

[0007] Furthermore, a relationship with MMP2 has been suggested in non-tumor diseases such as multiple sclerosis, cerebral infarction, arteriosclerosis, abdominal aortic aneurysm, peritoneal sclerosis, myocardial infarction, acute kidney injury, diabetic nephropathy, nephrosclerosis, glomerulonephritis, polycystic kidney disease, polycystic liver, 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).

[0008] For these reasons, finding a means to selectively inhibit MMP2 is a highly feasible approach to establishing an effective treatment for diseases in which MMP2 is involved. There are reports of low molecular weight compounds that have a zinc chelator containing hydroxamic acid or carboxylic acid as an MMP2 inhibitor, but none of them show a selective MMP2 inhibitory effect (see, for example, Non-Patent Documents 17 and 18).

[0009] In addition, it has been reported that a peptide compound consisting of 10 natural amino acids, β-amyloid precursor protein (APP-IP, IIe-Ser-Tyr-Gly-Asn-Asp-Ala-Leu-Met-Pro), exhibits selective MMP2 inhibitory activity (see Non-Patent Document 19). However, it is generally known that peptide compounds are metabolized and excreted quickly in the body, and therefore the expected pharmacological action does not last even when administered. [Prior art documents] [Non-patent literature]

[0010] Non-patent document 1: HJ Ra and WC Parks Matrix Biol., 2007, 26(8), 587-596. Non-patent document 2: AH Drummond et al. Ann NY Acad Sci., 1999, 878, 228-235. Non-patent document 3: AD Baxter et al. Bioorg Med Chem Lett., 2001, 11, 1465-1468. Non-patent document 4: T. Itoh et al. Cancer Res., 1998, 58, 1048-1051. Non-patent document 5: R. Roy et al. J Clin Oncol., 2009, 27, 5287-5297. Non-patent document 6: T. Turpeenniemi-Hujanen Biochimie., 2005, 87, 287-297. Non-patent document 7: S. Cheng et al. FASEB J., 2006, 20, 1898-1900. Non-Patent Document 8: K. Pawlak et al., Clin Biochem., 2011, 44, 838 - 843. Non-Patent Document 9: H. R. Chang et al., Clin Chim Acta., 2006, 366, 243 - 248. Non-Patent Document 10: X. Du et al., Lab Invest., 2012, 92, 1149 - 1160. Non-Patent Document 11: M. K. Tveitaras et al., PLoS One., 2015, 10, e0143390. Non-Patent Document 12: M. Selman et al., Am J Physiol Lung Cell Mol Physiol., 2000, 279, L562 - L574. Non-Patent Document 13: M. Suga et al., Am J Respir Crit Care Med., 2000, 162, 1949 - 1956. Non-Patent Document 14: M. Corbel et al., J Pathol., 2001, 193, 538 - 545. Non-Patent Document 15: J. Michael et al., Am J Respir Cell Mol Biol., 2009, 41, 731 - 741. Non-Patent Document 16: A. Tokito et al., Int J Mol Sci., 2016, 17, E1178. Non-Patent Document 17: D. E. Levy et al., J Med Chem., 1998, 41, 199 - 223. Non-Patent Document 18: Y. Tamura et al., J Med Chem., 1998, 41, 640 - 649. Non-Patent Document 19: S. Higashi et al., J Biol Chem., 2003, 278, 14020 - 14028.

Summary of the Invention

Problems to be Solved by the Invention

[0011] An object of the present invention is to provide a novel MMP2 inhibitor. [Means for solving the problem]

[0012] As a result of extensive research aimed at achieving the above-mentioned object, the inventors have discovered that a compound represented by the following formula [I'] (hereinafter sometimes referred to as compound [I']) has the effect of inhibiting MMP2.

[0013] The present invention will be described in detail below. That is, the aspects of the present invention are as follows. (1) One aspect of the present invention is The following formula [I']

[0014] [ka]

[0015] (In the above formula [I'], AA 1 teeth, Asp, β-Asp, β-(d)-Asp, γ-Glu, or γ-(d)-Glu indicates, AA 2 teeth, Ala, The following formulas [IV-7], [IV-8], [IV-9], [IV-11], [IV-12], and [IV-13]

[0016] [ka]

[0017] A group represented by The following formula [IV-27]

[0018] [ka]

[0019] A group represented by Pro, the following formulas [II-1] and [II-2]

[0020] [ka]

[0021] represents one group selected from the group consisting of groups represented by Here, R AA2 represents hydroxy or amino, Also, A.A. 1 and A.A. 2 are taken together to give the following formula [IV-32]

[0022] [ka]

[0023] It may have a structure represented by AA 3 teeth, Val, Leu, Ile, the following formula [IV-2]

[0024] [ka]

[0025] A group represented by Phe, Trp, Tyr, Lys, following formula [IV-3], [IV-4], [IV-5]

[0026] [ka]

[0027] A group represented by the formula: The following formula [IV-9]

[0028] [ka]

[0029] A group selected from the group consisting of groups represented by indicates, AA 4 teeth, Single bond, Gly, (d)-Ala, (N-Me)Ala, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, Pro, (d)-Pro, (N-Me)Phe, (d)-Phe, (N-Me)Tyr, (d)-Tyr, (N-Me)Ser, (d)-Ser, homoSer, (d)-Thr, Met, (N-Me) Met, (N-Me)Asp, Glu, (N-Me)Glu, (d)-(N-Me)Glu, homoGlu, (N-Me)Asn, (N-Me)Arg, (d)-Arg, The following formulas [IV-7], [IV-9], and [IV-13]

[0030] [ka]

[0031] A group represented by one group selected from the group consisting of (N-Me)Lys, indicates, Here, A.A. 4 When represents Lys, The amino acid of the side chain of the Lys is substituted with a carboxyl group at the end. 2-16 may be substituted with alkylcarbonyl; AA 5 teeth, Single bond, Ala, the following formula [IV-1]

[0032] [ka]

[0033] A group represented by The following formulas [IV-27], [IV-28], and [IV-29]

[0034] [ka]

[0035] A group represented by Pro, (d)-Pro, β-homoPro, homoPro, the following formula [II-1']

[0036] [ka]

[0037] A group represented by Phe, His, Thr, Arg, (d)-Arg, The following formulas [IV-7], [IV-9], and [IV-13]

[0038] [ka]

[0039] A group represented by Lys, (d)-Lys, β-Ala, (N-Me)-β-Ala, GABA, Ape, Acp, The following formulas [III-6] to [III-13]

[0040] [ka]

[0041] A group represented by The following formulas [IV-25] and [IV-26]

[0042] [ka]

[0043] A group selected from the group consisting of groups represented by indicates, W 1 -L 1 -or-L 1 '-L 1 "-" and L 1 indicates a single bond, L 1 'teeth, Single bond, β-Ala, GABA, (N-Me)GABA, Ape, Acp, The following formulas [III-6] to [III-13]

[0044] [ka]

[0045] A group represented by The following formulas [IV-23] and [IV-24]

[0046] [ka]

[0047] A group selected from the group consisting of groups represented by indicates, L 1 "teeth, Single bond, Gly, (N-Me)Gly, Ala, (N-Me)Ala, (d)-Ala, Val, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, The following formula [IV-27]

[0048] [Chemistry]

[0049] a group represented by Pro, (d)-Pro, homoPro, Phe, (N-Me)Phe, (d)-Phe, His, (d)-His, Trp, (N-Me)Trp, (d)-Trp, Tyr, (N-Me)Tyr, (d)-Tyr, (d)-Ser, homoSer, Thr, (N-Me)Thr, (d)-Thr, Cys, (d)-Cys, Met, (N-Me)Met, (N-Me)Asp, Glu, (N-Me)Glu, (d)-Glu, Asn, (N-Me)Asn, (d)-Asn, Gln, (N-Me)Gln, (d)-Gln, Arg, (N-Me)Arg, (d)-Arg, Cit, (d)-Cit, the following formulas [IV-7], [IV-9], [IV-10], [IV-13]

[0050] [Chemistry]

[0051] a group represented by Lys, (N-Me)Lys, (d)-Lys, the following formula [IV-14]

[0052] [Chemistry]

[0053] a group represented by β-Ala, β-Asp, β-(d)-Asp, the following formulas [III-6] and [III-7]

[0054] [Chemistry]

[0055] A group selected from the group consisting of groups represented by indicates, Here, L 1 " represents Lys or (d)-Lys, The amino group in the side chain of the Lys and (d)-Lys may be substituted with a group represented by the following formula [VII-1]: FA N -AA N5 -AA N4 -AA N3 -AA N2 -AA N1 - [VII-1] In the formula [VII-1], FA N is a C 2-16 represents an alkylcarbonyl; AA N5 teeth, Single bond, Arg, (d)-Arg, Lys, (d)-Lys, γ-Glu, or The following formula [IV-24]

[0056] [ka]

[0057] A group represented by indicates, AA N4 teeth, Single bond, Arg, (d)-Arg, Lys, (d)-Lys, or The following formula [IV-24]

[0058] [ka]

[0059] A group represented by indicates, AA N3 teeth, Single bond, Arg, (d)-Arg, Lys, (d)-Lys, γ-Glu, or The following formula [IV-24]

[0060] [ka]

[0061] A group represented by indicates, AA N2 teeth, A single bond, or (d)-Lys indicates, AA N1 teeth, A single bond, or (d)-Lys indicates, Also, L 1 " is represented by Glu, and AA 3 When represented by Lys, The compound represented by the formula [I'] has L bonded to the functional groups of the side chains of the two amino acids, as represented by the following formula [I'-α]. 3 can form a cyclic structure together with At this time, the L 3 represents Gly, β-Ala, or GABA,

[0062] [ka]

[0063] L N1 represents the formula -C(=O)- or the formula -S(=O)2-, L N2 teeth, Single bond, C 1-3Alkanediyl, C 2-3 Alkene diyl, Ethyndiyl, Formula -O-, Formula -C(=O)-, Formula -C(=O)-NH-, or Triazolediyl indicates, L 2 indicates a single bond, Ring A represents an aromatic ring or a heteroaromatic ring; R A1 , R A2 is, independently, Hydrogen atoms, Halogen atoms, C 1-6 Alkyl, or C 1-6 Alkoxy indicates, Ring B is represents aryl or heteroaryl, R B1 , R B2 , R B3 is, independently, Hydrogen atoms, Carbamoyl, Cyano, Halogen atoms, C 1-6 Alkyl (C 1-6 The alkyl may be substituted with one hydroxyl. 1-6 Alkyl, C 1-6 Alkoxy (C 1-6 The alkoxy may be substituted with one hydroxyl. 1-6 Alkoxy, C 1-6 Alkyl carbonyl, C 1-6 Alkylcarbonylamino, Mono C 1-6 Alkylaminocarbonyl, diC 1-6 Alkylaminocarbonyl (The item C 1-6Alkylaminocarbonyl and diC 1-6 The alkyl in the alkylaminocarbonyl may be substituted with one group selected from the group consisting of hydroxy, carboxy, carbamoyl, and amino. C 1-6 Alkylsulfonyl, or Aryl indicates, W C is a linker consisting of a single bond or 1 to 3 amino acids, Here, the 1 to 3 amino acids forming the linker are Gly, Pro, Arg, (d)-Arg, Lys, (d)-Lys, β-Ala, GABA, and Ape each of which may be the same or different and is selected from the group consisting of Here, W C When the group represented by the formula (I) contains Lys or (d)-Lys, The amino acid in the side chain of the Lys and (d)-Lys is C 2-16 Alkylcarbonyl, Lys (the amino of the side chain of Lys is terminally substituted with carboxy) 2-16 Optionally substituted with alkylcarbonyl; or (d)-Lys (the amino acid in the side chain of the (d)-Lys is substituted with a carboxyl group at the end) 2-16 may be substituted with alkylcarbonyl. may be substituted, R C is represented by the formula -OH, -NH2, C 1-6 Alkylamino (C 1-6 Alkylamino C 1-6 Alkyl is hydroxy, amino, C 1-6 alkoxy, and 4- to 7-membered saturated heterocyclyl containing one nitrogen atom and optionally containing one further heteroatom; or 4- to 7-membered saturated heterocyclyl containing one nitrogen atom and optionally containing one further heteroatom (the 4- to 7-membered saturated heterocyclyl containing one nitrogen atom and optionally containing one further heteroatom is hydroxy, amino, and C 1-6 Alkyl (C 1-6 The alkyl may be substituted with one group selected from the group consisting of: And, two carbon atoms in the 4- to 7-membered saturated heterocyclyl containing one nitrogen atom and optionally containing one heteroatom are C 1-4 ) may be bridged with an alkanediyl. or a pharma- ceutically acceptable salt thereof.

[0064] (2) Another aspect of the present invention is W C but, Single bond, Pro, Arg, (d)-Arg, Lys, (d)-Lys, β-Ala, GABA, Ape, Gly-(d)-Lys, Gly-(d)-Lys-(d)-Lys, Gly-(d)-Lys-(d)-Arg, Gly-(d)-Arg-(d)-Lys, Lys-Lys, (d)-Lys-(d)-Lys, (d)-Lys-(d)-Lys-(d)-Lys, Arg-Arg, (d)-Arg-(d)-Arg, (d)-Arg-(d)-Lys, Lys-(d)-Lys-(d)-Lys, (d)-Lys-Lys-(d)-Lys, (d)-Lys-(d)-Lys-Lys, β-Ala-(d)-Lys, β-Ala-(d)-Lys-(d)-Arg, β-Ala-(d)-Arg-(d)-Lys, or β-Ala-(d)-Arg-(d)-Arg And, Here, W CWhen the group represented by the formula: contains Lys, The amino acid in the side chain of the Lys is C 2-16 Alkylcarbonyl or (d)-Lys (the amino acid in the side chain of the (d)-Lys is substituted with a carboxyl group at the end) 2-16 may be substituted with alkylcarbonyl. may be substituted, The present invention provides a substituted polypeptide according to (1) or a pharma- ceutically acceptable salt thereof.

[0065] (3) Another aspect of the present invention is Ring A is a benzene ring, a thiophene ring, or a pyridine ring; R A1 , R A2 But independently, A hydrogen atom, or Halogen atoms and Ring B is phenyl, oxazolyl, thiadiazolyl, pyridyl, or benzofuranyl; R B1 , R B2 , R B3 But independently, Hydrogen atoms, Carbamoyl, Cyano, Halogen atoms, C 1-6 Alkyl (C 1-6 The alkyl may be substituted with one hydroxyl. 1-6 Alkyl, C 1-6 Alkoxy (C 1-6 The alkoxy may be substituted with one hydroxyl. 1-6 Alkoxy, C 1-6 Alkyl carbonyl, Mono C 1-6 Alkylaminocarbonyl, diC 1-6Alkylaminocarbonyl (The item C 1-6 Alkylaminocarbonyl and diC 1-6 The alkyl in the alkylaminocarbonyl may be substituted with one group selected from the group consisting of hydroxy, carboxy, carbamoyl, and amino; or C 1-6 Alkyl sulfonyl and R C is represented by the formula -OH, -NH2, C 1-6 Alkylamino (C 1-6 Alkylamino C 1-6 Alkyl is hydroxy, amino, C 1-6 Optionally, substituted with one group selected from the group consisting of alkoxy and morpholinyl; Azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl, where the azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl are hydroxy, amino, and C 1-6 Alkyl (C 1-6 The alkyl may be substituted with one group selected from the group consisting of: and two carbon atoms in the azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl are C 1-4 Optionally, the alkylene group is bridged with an alkanediyl. The present invention provides a substituted polypeptide according to (1) or (2) or a pharma- ceutically acceptable salt thereof.

[0066] (4) Another aspect of the present invention is In the substituted polypeptide represented by the formula [I'], Ring A is a benzene ring; Ring B is phenyl; L 1 "but, Single bond, Gly, (N-Me)Gly, Ala, (N-Me)Ala, (d)-Ala, Val, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, the group represented by the following formula [IV-27]

[0067]

Chem.

[0068] and the group represented by Pro, (d)-Pro, homoPro, Phe, (N-Me)Phe, (d)-Phe, His, (d)-His, Trp, (N-Me)Trp, (d)-Trp, Tyr, (N-Me)Tyr, (d)-Tyr, (d)-Ser, homoSer, Thr, (N-Me)Thr, (d)-Thr, Cys, (d)-Cys, Met, (N-Me)Met, (N-Me)Asp, Glu, (N-Me)Glu, (d)-Glu, Asn, (N-Me)Asn, (d)-Asn, Gln, (N-Me)Gln, (d)-Gln, Arg, (N-Me)Arg, (d)-Arg, Cit, (d)-Cit, the following formula [IV-7], [IV-9], [IV-10], [IV-13]

[0069]

Chem.

[0070] and the group represented by Lys, (N-Me)Lys, (d)-Lys, the following formula [IV-14]

[0071]

Chem.

[0072] and the group represented by β-Ala, β-Asp, β-(d)-Asp, The following formulas [III-6] and [III-7]

[0073] [ka]

[0074] A group selected from the group consisting of groups represented by and W C but, Single bond, Pro, Arg, (d)-Arg, Lys, (d)-Lys, β-Ala, GABA, Ape, Gly-(d)-Lys, Gly-(d)-Lys-(d)-Lys, Gly-(d)-Lys-(d)-Arg, Gly-(d)-Arg-(d)-Lys, Lys-Lys, (d)-Lys-(d)-Lys, (d)-Lys-(d)-Lys-(d)-Lys, Arg-Arg, (d)-Arg-(d)-Arg, (d)-Arg-(d)-Lys, Lys-(d)-Lys-(d)-Lys, (d)-Lys-Lys-(d)-Lys, (d)-Lys-(d)-Lys-Lys, β-Ala-(d)-Lys, β-Ala-(d)-Lys-(d)-Arg, β-Ala-(d)-Arg-(d)-Lys, or β-Ala-(d)-Arg-(d)-Arg The present invention also provides a substituted polypeptide according to any one of (1) to (3) or a pharma- ceutically acceptable salt thereof, wherein:

[0075] (5) Another aspect of the present invention is In the substituted polypeptide represented by the formula [I'], AA 2 is represented by the following formula [II-1]

[0076] [ka]

[0077] A group represented by The following formulas [IV-7], [IV-8], [IV-9], [IV-11], and [IV-12]

[0078] [ka]

[0079] is a group selected from the group consisting of groups represented by Here, R AA2 is amino, AA 3 is Val, Leu, Ile, Phe, or Trp; AA 4 is (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Asp, or (N-Me)Glu; AA 5 is β-Ala, GABA, Ape, Acp, Pro, (d)-Pro, or β-homoPro; W C is a single bond, Arg, (d)-Arg, Lys, or (d)-Lys; R C is represented by the formula -OH or the formula -NH2 The present invention also provides a substituted polypeptide according to any one of (1) to (4) or a pharma- ceutically acceptable salt thereof, wherein:

[0080] (6) Another aspect of the present invention is In the substituted polypeptide represented by the formula [I'], W 1 But -L 1'-L 1 "- and L 2 is a single bond, AA 1 is Asp, L 1 ' is β-Ala, GABA, Ape, Acp, the following formula [IV-23] and [IV-24]

[0081] [ka]

[0082] A group selected from the group consisting of groups represented by and L 1 " is a single bond, Asn, (d)-Ser, (d)-Thr, or Glu; L N1 is of the formula -C(=O)- or -S(=O)2-, L N2 is of the formula -O- or -C(=O)-NH-, R A1 , R A2 are hydrogen atoms, R B1 , R B2 , R B3 are independently a hydrogen atom, a carbamoyl, a halogen atom, or C 1-6 Alkoxy or haloC 1-6 Alkoxy The present invention also provides a substituted polypeptide according to any one of (1) to (5) or a pharma- ceutically acceptable salt thereof, wherein:

[0083] (7) Another aspect of the present invention is In the substituted polypeptide represented by the formula [I'], W 1 But -L 1 where L1 is a single bond, L 2 is a single bond, AA 1 is β-Asp, β-(d)-Asp, γ-Glu, or γ-(d)-Glu; AA 2 is represented by the following formula [II-1]

[0084] [ka]

[0085] A group represented by The following formulas [IV-7], [IV-8], [IV-9], [IV-11], and [IV-12]

[0086] [ka]

[0087] is a group selected from the group consisting of groups represented by Here, R AA2 is amino, AA 3 is Val, Leu, Ile, Phe, or Trp; AA 4 is (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Asp, or (N-Me)Glu; AA 5 is β-Ala, GABA, Ape, Acp, or β-homoPro; L N1 is of the formula -C(=O)- or -S(=O)2-, L N2 is a single bond, a group of the formula -O- or a group of the formula -C(=O)-NH-, R A1 , R A2are hydrogen atoms, R B1 , R B2 , R B3 are independently a hydrogen atom, a carbamoyl, a halogen atom, or C 1-6 Alkoxy or haloC 1-6 Alkoxy The present invention also provides a substituted polypeptide according to any one of (1) to (5) or a pharma- ceutically acceptable salt thereof, wherein:

[0088] (8) Another aspect of the present invention is The substituted polypeptide represented by the formula [I'] The following formula [I]

[0089] [ka]

[0090] A substituted polypeptide represented by In the above formula [I], AA 1 is β-Asp, γ-Glu, or γ-(d)-Glu, AA 2 is represented by the following formula [II-1] or formula [II-2]

[0091] [ka]

[0092] A group represented by and Here, R AA2 is hydroxy or amino, AA 3 is Val, Leu, Ile, Phe, or Trp, AA 4is 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; AA 5 is a single bond, Pro, (d)-Pro, β-homoPro, Arg, (d)-Arg, Lys, (d)-Lys, β-Ala, GABA, Ape, or Acp, L 1 is a single bond, L 2 is a single bond, L N1 is of the formula -C(=O)- or -S(=O)2-, L N2 is a single bond, C 1-3 alkanediyl, of the formula -O-, or of the formula -C(=O)-NH-; R A is a hydrogen atom, a halogen atom, C 1-6 Alkyl or C 1-6 is an alkoxy; R B is a hydrogen atom, carbamoyl, halogen atom, C 1-6 Alkyl or C 1-6 is an alkoxy; L C is a single bond, Pro, Arg, (d)-Arg, Lys, (d)-Lys, or (d)-Lys-(d)-Lys, R C is represented by the formula -OH or the formula -NH2 The substituted polypeptide according to any one of (1) to (4) or a pharma- ceutical acceptable salt thereof, The purpose of this project is to provide (9) Another aspect of the present invention is In the substituted polypeptide represented by the formula [I'], AA 1 is Asp, β-(d)-Asp, or γ-(d)-Glu; AA 2 is represented by the following formula [II-1]

[0093] [ka]

[0094] A group represented by The following formulas [IV-7] and [IV-9]

[0095] [ka]

[0096] A group selected from the group consisting of groups represented by and Here, R AA2 is amino, AA 3 is Val, Leu, or Ile; AA 4 is (N-Me)Ile or (N-Me)Glu, AA 5 is Ape or β-homoPro, W 1 But -L 1 -or-L 1 '-L 1 "- and Where: L 1 is a single bond, L 1 ' is GABA or Ape, L 1 " is Asn, (d)-Ser, (d)-Thr, or Glu, L N1 is of the formula -C(=O)- or -S(=O)2-, L N2 is of the formula -O- or -C(=O)-NH-, R A1 , R A2 are hydrogen atoms, R B1 , R B2 , RB3 are independently a hydrogen atom, a carbamoyl, a halogen atom, or C 1-6 Alkoxy or haloC 1-6 is an alkoxy; W C is a single bond or (d)-Lys; R C But the formula -NH2 The present invention also provides a substituted polypeptide according to any one of (1) to (5) or a pharma- ceutically acceptable salt thereof, wherein:

[0097] (10) Another aspect of the present invention is A substituted polypeptide or a pharma- ceutical acceptable salt thereof according to any one of (1) to (5) above, selected from the following compounds:

[0098] [ka]

[0099] [ka]

[0100] [ka]

[0101] The purpose of this project is to provide (11) Another aspect of the present invention is The present invention provides a pharmaceutical comprising, as an active ingredient, the substituted polypeptide according to any one of (1) to (10) or a pharma- ceutically acceptable salt thereof. (12) Another aspect of the present invention is The object of the present invention is to provide an MMP2 inhibitor comprising, as an active ingredient, the substituted polypeptide according to any one of (1) to (10) or a pharma- ceutically acceptable salt thereof. (13) Another aspect of the present invention is The object of the present invention is to provide an agent for suppressing the proliferation, invasion, or metastasis of cancer cells, comprising as an active ingredient a substituted polypeptide according to any one of (1) to (10) or a pharma- ceutically acceptable salt thereof. (14) Another aspect of the present invention is The object of the present invention is to provide a fibrosis inhibitor comprising, as an active ingredient, the substituted polypeptide according to any one of (1) to (10) or a pharma- ceutically acceptable salt thereof. (15) Another aspect of the present invention is The present invention provides a preventive or therapeutic agent for cancer disease or organ fibrosis, or a symptom associated with cancer disease or organ fibrosis, comprising as an active ingredient a substituted polypeptide according to any one of (1) to (10) or a pharma- ceutical acceptable salt thereof. Effect of the Invention

[0102] The compounds of the present invention (hereinafter sometimes referred to as "the compounds of the present invention") have an effect of inhibiting MMP2. In addition, some of the compounds of the present invention have an effect of selectively inhibiting MMP2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0103] The present invention provides a substituted polypeptide represented by the above formula [I'], or a pharma- ceutically acceptable salt thereof, which has an activity of inhibiting MMP2. The compounds of the present invention are described in more detail below, but the present invention is not limited to the exemplified compounds.

[0104] In this specification, the term "amino acid" refers in a broad sense to an organic compound having both amino and carboxy functional groups, while in a narrow sense (particularly in the field of biochemistry) to an "α-amino acid" that is a building block of proteins in living organisms (an α-amino acid is an amino acid in which an amino group is also bound to the carbon atom (α carbon) to which a carboxy group is bound).

[0105] As used herein, amino acids include, for example, natural proteinogenic L-amino acids, natural non-proteinogenic amino acids, and unnatural amino acids, including 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 that are characteristic of amino acids.

[0106] In the present specification, when the term "amino acid" is written by name without any abbreviation, such as three-letter code or one-letter code, it refers to an amino acid including L- or D-forms, or both.

[0107] In the present specification, when "amino acids" are abbreviated by three-letter code or one-letter code, they refer to L-amino acids. In some cases, "L" or "l" is added immediately before the "amino acid" to clarify that it is an L-amino acid.

[0108] In this specification, when "D" or "d" is placed immediately before an "amino acid", this refers to the D-amino acid. As used herein, a "natural proteinogenic L-amino acid" refers to a naturally occurring L-amino acid that constitutes a protein, such as Gly, Ala, Val, Leu, Ile, Pro, Phe, His, Trp, Tyr, Ser, Thr, Met, Cys, Asp, Glu, Asn, Gln, Lys, and Arg.

[0109] In this specification, "D-form of 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 distinguished into L-form and D-form according to the structures of L-form and D-form of glyceraldehyde.

[0110] In addition, D-amino acids can exist among amino acids other than the natural proteinogenic L-amino acids. As used herein, a "natural non-proteinogenic amino acid" refers to a naturally occurring amino acid that does not constitute protein, such as L-norleucine (hereinafter sometimes referred to as Nle; in the following description, "both in parentheses" indicate abbreviations), β-alanine (β-Ala), and L-ornithine (Orn).

[0111] When a natural non-proteinogenic amino acid has an asymmetric carbon, the amino acid exists in an L-form and a D-form. In addition, amino acids other than natural non-proteinogenic amino acids may also exist in an L-form and a D-form.

[0112] As used herein, the term "unnatural amino acid" refers to an amino acid that does not constitute a protein and is mainly artificially produced, and is an amino acid other than the aforementioned "natural proteinogenic L-amino acids and natural non-proteinogenic amino acids." Unnatural amino acids include, for example, D-forms of natural proteinogenic L-amino acids (D-Cys, D-Ser, etc.); α-methyl amino acids (such as 2-aminoisobutyric acid (Aib)); amino acids with an extra methylene in the side chain ("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), L-homoglutamic acid (homoGlu)); amino acids in which the carboxylic acid functional group in the side chain is replaced with a sulfonic acid group (such as L-cysteic acid); chemically modified amino acids such as amino acid variants and derivatives (hydroxyproline, L-2,3-diaminopropionic acid (Dap), L-2,4-diaminobutyric acid (Dab), N-methylglycine, etc.); and chemically synthesized compounds having properties known in the art to be characteristic of amino acids (such as 4-aminobenzoic acid).

[0113] When an unnatural amino acid has an asymmetric carbon, the amino acid exists in L- and D-forms. Specific examples of the "unnatural amino acid" herein include the following: ·(d)-Pro, (d)-Ser, (d)-Thr, (d)-Asp, (d)-Glu, (d)-Arg, (d)-Lys β-homoPro β-Ala, GABA, Ape, Acp ·(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 Formula [II-1] or formula [II-2]

[0114] [ka]

[0115] (wherein R AA2 is hydroxy or amino; Amino acids listed in Tables 1 and 2 below In this specification, the nitrogen atom involved in the peptide bond of the amino acid may be alkylated. In such a case, the amino acid is also called an "N-alkylamino acid." Here, the alkyl may be, for example, methyl or ethyl.

[0116] In this specification, the term "β-Asp" refers to aspartic acid that is involved in an amide bond in the main chain via a carboxyl side chain, as shown in the structure represented by the following formula [III-1]. Similarly, the terms "β-(d)-Asp", "γ-Glu", and "γ-(d)-Glu" refer to the structures represented by the following formulas [III-2] to [III-4], respectively.

[0117] [ka]

[0118] In addition, when it is written "(N-Me)Glu(OtBu)", it means the N-methyl form of the amino acid (Glu(OtBu)) as shown in the structure represented by the following formula [III-5].

[0119] [ka]

[0120] And, in this specification, AA 2When the structure corresponding to the above is described as "(2S,4S)-(4-amino)Pro", it means the structure represented by the following formula [II-3]. Similarly, when "(2S,4R)-(4-amino)Pro", "(2S,4S)-(4-hydroxy)Pro", or "(2S,4R)-(4-hydroxy)Pro" is described, it means the structures represented by the following formulas [II-4] to [II-6], respectively. Furthermore, when "(S)-piperazine" is described, it means the structure represented by the following formula [II-2].

[0121] [ka]

[0122] In this specification, "n" indicates normal, "i" indicates iso, "s" indicates secondary, "t" and "tert" indicate tertiary, "c" indicates cyclo, "o" indicates ortho, "m" indicates meta, and "p" indicates para.

[0123] The term "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. "C 1-6 The term "alkyl" refers to a straight-chain or branched alkyl having 1 to 6 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl.

[0124] "Haro C 1-6The term "alkyl" refers to a linear or branched alkyl having 1 to 6 carbon atoms and substituted with a halogen atom. The number of halogen atoms substituted is preferably 1 to 5, and the preferred halogen atom is a fluorine atom. Examples of the alkyl group 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-methylpropan-2-yl, 1,1-difluoro-2-methylpropan-2-yl, 1-fluoropentyl, 1-fluorohexyl, and 2,2,2-trifluoro-1-methylethyl.

[0125] The term "aryl" refers to a monocyclic aromatic hydrocarbon group or a condensed polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms, such as phenyl, naphthyl, and anthryl. The term "aromatic ring" refers to a monocyclic aromatic hydrocarbon ring or a condensed polycyclic aromatic hydrocarbon ring having 6 to 14 carbon atoms, such as a benzene ring, a naphthalene ring, or an anthracene ring.

[0126] Partially saturated aryl is also included in "aryl". The same applies to aromatic rings. "Partially saturated aryl" and the corresponding aromatic ring "partially saturated aromatic ring" refer to a group in which a monocyclic aromatic hydrocarbon group or a condensed polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms is partially saturated, and a ring having such a structure. Examples include dihydroindenyl and dihydroindene rings.

[0127] The term "heteroaryl" refers to a 5-7 membered monocyclic aromatic heterocyclic group consisting of 1 to 6 carbon atoms and one or more atoms selected the same or different from the group consisting of oxygen atoms, sulfur atoms, and nitrogen atoms, or a condensed polycyclic aromatic heterocyclic group consisting of 9 to 14 atoms consisting of 1 to 13 carbon atoms and one or more atoms selected the same or different from the group consisting of oxygen atoms, sulfur atoms, and nitrogen atoms. Examples of the heterocyclic group include imidazolyl, pyrazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, benzopyrazolyl, benzotriazolyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, quinoxalyl, etc.

[0128] The term "heteroaromatic ring" refers to a 5-7 membered monocyclic aromatic heterocycle consisting of 1 to 6 carbon atoms and one or more atoms selected the same or different from the group consisting of oxygen atoms, sulfur atoms, and nitrogen atoms, or a condensed polycyclic aromatic heterocycle consisting of 9 to 14 atoms consisting of 1 to 13 carbon atoms and one or more atoms selected the same or different from the group consisting of oxygen atoms, sulfur atoms, and nitrogen atoms. Examples of the heteroaromatic ring 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.

[0129] Also, partially saturated heteroaryl is included in "heteroaryl". The same applies to heteroaromatic rings. "Partially saturated heteroaryl" and the corresponding heteroaromatic ring "partially saturated heteroaromatic ring" refer to a 5-7 membered partially saturated monocyclic heterocyclic group consisting of one or more atoms selected the same or different from the group consisting of oxygen atoms, sulfur atoms, and nitrogen atoms and 1 to 6 carbon atoms, or a partially saturated condensed polycyclic heterocyclic group consisting of 9 to 14 atoms consisting of one or more atoms selected the same or different from the group consisting of oxygen atoms, sulfur atoms, and nitrogen atoms and 1 to 13 carbon atoms, and a ring having such a structure. Examples of such rings include oxazolidinyl, thiazolinyl, dihydropyridinyl, dihydrobenzofuranyl, chromanyl, dihydropyranopyridinyl, dihydrofuropyridinyl, tetrahydroquinolyl, dihydrobenzodioxinyl, tetrahydrotriazoloazepinyl, oxazolidine ring, thiazoline ring, dihydropyridine ring, dihydrobenzofuran ring, chroman ring, dihydropyranopyridine ring, dihydrofuropyridine ring, tetrahydroquinoline ring, tetrahydroquinoline ring, dihydrobenzodioxin ring, and tetrahydrotriazoloazepine ring.

[0130] The term "4- to 7-membered saturated heterocyclyl containing a nitrogen atom" refers to a 4- to 7-membered monocyclic saturated heterocyclic group consisting of one nitrogen atom and 3 to 6 carbon atoms, which may further contain one atom selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom in addition to the nitrogen atom. Examples include azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, thiomorpholinyl, and piperazinyl.

[0131] "4- to 7-membered saturated heterocyclyl containing one nitrogen atom and optionally containing one further heteroatom" refers to a 4- to 7-membered monocyclic saturated heterocyclic group consisting of one nitrogen atom and 3 to 6 carbon atoms, which may further contain one atom selected from the group consisting of oxygen atom, sulfur atom, and nitrogen atom in addition to the nitrogen atom. Examples include azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, thiomorpholinyl, and piperazinyl.

[0132] Also, "C 1-4 Examples of the "4- to 7-membered saturated heterocyclyl optionally bridged by alkanediyl, containing one nitrogen atom and optionally further containing one heteroatom" include 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]).

[0133] [ka]

[0134] "C 1-6 The term "alkoxy" refers to straight-chain or branched alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, and n-hexyloxy.

[0135] "Haro C 1-6The term "alkoxy" refers to a linear or branched alkoxy having 1 to 6 carbon atoms and substituted with a halogen atom. The number of halogen atoms substituted is preferably 1 to 5, and the preferred halogen atom is a fluorine atom. Examples of the alkoxy include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 1,1-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoropropoxy, 1,3-difluoropropan-2-yloxy, 2-fluoro-2-methylpropoxy, 2,2-difluoropropoxy, 1-fluoro-2-methylpropan-2-yloxy, 1,1-difluoro-2-methylpropan-2-yloxy, and 4,4,4-trifluorobutoxy.

[0136] "C 1-6 Alkylcarbonyl refers to the aforementioned "C 1-6 It refers to a group in which "alkyl" and a carbonyl are bonded. Examples include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, and n-hexylcarbonyl.

[0137] "C 1-6 Alkylcarbonylamino is the same as the above-mentioned "C 1-6 It refers to a group in which an "alkylcarbonyl" is bonded to an amino group. Examples include methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, n-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino, tert-butylcarbonylamino, n-pentylcarbonylamino, and n-hexylcarbonylamino.

[0138] "C 1-6 Alkylamino is the same as the above-mentioned "C 1-6It refers to amino having 1 or 2 identical or different "alkyl" substituents. Examples include 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.

[0139] "Mono C 1-6 Alkylamino is the same as the above-mentioned "C 1-6 It refers to an amino having one "alkyl" as a substituent. Examples thereof include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-pentylamino, and n-hexylamino.

[0140] "JiC 1-6 Alkylamino is the same as the above-mentioned "C 1-6 It refers to an amino group having two, the same or different, "alkyl" substituents. Examples thereof include dimethylamino, diethylamino, di(n-propyl)amino, di(isopropyl)amino, ethylmethylamino, and methyl(n-propyl)amino.

[0141] "Mono C 1-6 Alkylaminocarbonyl refers to the aforementioned "mono C 1-6 It refers to a group in which "alkylamino" is bonded to a carbonyl. Examples include methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, isobutylaminocarbonyl, n-pentylaminocarbonyl, and n-hexylaminocarbonyl.

[0142] "JiC 1-6 Alkylaminocarbonyl refers to the aforementioned "diC 1-6It refers to a group in which "alkylamino" is bonded to a carbonyl. Examples thereof include dimethylaminocarbonyl, diethylaminocarbonyl, di(n-propyl)aminocarbonyl, di(isopropyl)aminocarbonyl, ethylmethylaminocarbonyl, and methyl(n-propyl)aminocarbonyl.

[0143] "C 1-6 Alkylcarbonyl refers to the aforementioned "C 1-6 It refers to a group in which "alkyl" and a carbonyl are bonded. Examples include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, and n-hexylcarbonyl.

[0144] "C 2-16 The term "alkylcarbonyl" refers to a group in which a straight-chain or branched alkyl having 2 to 16 carbon atoms is bonded to a carbonyl. Examples include ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-decylcarbonyl (undecanoyl), n-dodecylcarbonyl (tridecanoyl), n-tetradecylcarbonyl (pentadecanoyl), and the like.

[0145] In addition, "terminally substituted with carboxyl group C 2-16 Alkylcarbonyl refers to the aforementioned "C 2-16 "C" in "Alkylcarbonyl" 2-16 This refers to a group in which a carboxy is substituted at the end of an alkyl group. Examples include 11-carboxyundecanoyl, 13-carboxytridecanoyl, and 15-carboxypentadecanoyl.

[0146] "C 1-6 Alkylsulfonyl refers to the above-mentioned "C 1-6It refers to a group in which "alkyl" and sulfonyl are bonded. Examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, and n-hexylsulfonyl.

[0147] "C 1-3 The term "alkanediyl" refers to a divalent hydrocarbon obtained by removing one hydrogen atom from an alkyl having 1 to 3 carbon atoms. Examples include methanediyl, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,1-diyl, propane-1,3-diyl, and propane-2,2-diyl.

[0148] "C 1-4 The term "alkanediyl" refers to a divalent hydrocarbon obtained by removing one hydrogen atom from an alkyl having 1 to 4 carbon atoms. Examples 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.

[0149] "C 2-3 The term "alkenediyl" refers to a divalent unsaturated hydrocarbon obtained by removing one hydrogen atom from an alkenyl having 2 to 3 carbon atoms. Examples include ethene-1,1-diyl, ethene-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.

[0150] The term "triazolediyl" refers to a divalent triazole formed by removing two hydrogen atoms from a triazole ring. Examples include structures represented by the following formulae [VIII-1] to [VIII-5].

[0151] [ka]

[0152] The abbreviations used in this specification refer to the structures shown in Tables 1 to 4 below.

[0153] [Table 1]

[0154] [Table 2-1]

[0155] [Table 2-2]

[0156] [Table 2-3]

[0157] [Table 2-4]

[0158] [Table 3]

[0159] [Table 4-1]

[0160] [Table 4-2]

[0161] Preferred embodiments of the substituted polypeptide or a pharma- ceutically acceptable salt thereof of the present invention represented by the above formula [I'] are as follows. Preferred AA 1is Asp, β-Asp, β-(d)-Asp, γ-Glu, or γ-(d)-Glu, One more preferred AA 1 is β-Asp, γ-Glu, or γ-(d)-Glu, In this case, the more preferable AA 1 is γ-(d)-Glu, Other more preferred AAs 1 is β-(d)-Asp or γ-(d)-Glu, In this case, the more preferable AA 1 is β-(d)-Asp, Other more preferred AAs 1 Asp It is.

[0162] Preferred AA 2 is represented by the following formula [II-1] or formula [II-2]

[0163] [ka]

[0164] A group represented by The following formula [IV-7], [IV-8], [IV-9], [IV-11] or [IV-12]

[0165] [ka]

[0166] A group represented by Ala, The following formula [IV-27]

[0167] [ka]

[0168] or Pro and Here, the preferred RAA2 is hydroxy or amino, More preferred AA 2 is represented by the following formula [II-1]

[0169] [ka]

[0170] A group represented by The following formula [IV-7], [IV-8], [IV-9], [IV-11], or [IV-12]

[0171] [ka]

[0172] A group represented by and Here, the preferred R AA2 is amino, More preferred AA 2 teeth, The following formula [IV-7] or [IV-9]

[0173] [ka]

[0174] or The following formula [II-1]

[0175] [ka]

[0176] A group represented by and Here, the preferred R AA2 is amino, One particularly preferred AA 2 teeth, The following formula [II-1]

[0177] [ka]

[0178] A group represented by and Here, the preferred R AA2 is amino, Other particularly preferred AAs 2 teeth, The following formula [IV-7] or [IV-9]

[0179] [ka]

[0180] A group represented by It is. Preferred AA 3 is Val, Leu, Ile, the following formula [IV-2]

[0181] [ka]

[0182] A group represented by Phe, the following formula [IV-3], [IV-4], or [IV-5]

[0183] [ka]

[0184] or Trp and More preferred AA 3 is Val, Leu, Ile, Phe, or Trp, More preferred AA 3 is Val, Leu, or Ile, One particularly preferred AA 3 is Val, Other particularly preferred AAs3 is Leu, Other particularly preferred AAs 3 is Ile.

[0185] Preferred AA 4 is a single bond, 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)Se r, (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, More preferred AA 4 are (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, One more preferred AA 4 is (N-Me)Glu or (N-Me)Asp, In this case, particularly preferred AA 4 is (N-Me)Glu, Other more preferred AAs 4 is (N-Me)Ile, (N-Me)Val, or (N-Me)Leu; In this case, particularly preferred AA 4 is (N-Me)Ile.

[0186] Preferred AA 5 is β-Ala, GABA, Ape, Acp, Pro, (d)-Pro, β-homoPro, single bond, Arg, (d)-Arg, The following formulas [IV-7], [IV-9], and [IV-13]

[0187] [ka]

[0188] A group represented by Lys, (d)-Lys, Ala, the following formula [IV-1]

[0189] [ka]

[0190] A group represented by The following formulas [IV-27], [IV-28], and [IV-29]

[0191] [ka]

[0192] A group represented by Phe, His, Thr, The following formulas [III-6] to [III-13]

[0193] [ka]

[0194] Any of the groups represented by and More preferred AA 5 is β-Ala, GABA, Ape, Acp, Pro, (d)-Pro, β-homoPro, single bond, Arg, (d)-Arg, The following formulas [IV-7], [IV-9], and [IV-13]

[0195] [ka]

[0196] A group represented by Lys, or (d)-Lys, More preferred AA5 is β-Ala, GABA, Ape, Acp, Pro, (d)-Pro, or β-homoPro, Particularly preferred AA 5 is β-Ala, GABA, Ape, Acp, or β-homoPro.

[0197] Preferred W 1 -L 1 -or-L 1 '-L 1 "- and Here, L 1 is a single bond, Also, L 1 ' is β-Ala, GABA, Ape, Acp, The following formulas [III-6] to [III-13]

[0198] [ka]

[0199] A group represented by The following formulas [IV-23] and [IV-24]

[0200] [ka]

[0201] and wherein the group consisting of the groups represented by L 1 " is a single bond, Asn, (d)-Ser, (d)-Thr, Lys, Arg, or Glu, One Better W 1 -L 1 -or-L 1 '-L 1 "- and Here, L 1 is a single bond, Also, L 1 ' is β-Ala, GABA, Ape, Acp, The following formulas [III-6] to [III-13]

[0202] [ka]

[0203] Any of the groups represented by and L 1 " is Asn, (d)-Ser, (d)-Thr, or Glu, In this case, the more preferable W 1 -L 1 -or-L 1 '-L 1 "- and Here, L 1 is a single bond, Also, L 1 ' is β-Ala, GABA, Ape, or Acp, L 1 " is Asn, (d)-Ser, (d)-Thr, or Glu, In this case, the particularly preferred W 1 -L 1 - and Here, L 1 is a single bond, Other preferred W 1 -L 1 '-L 1 "- and Here, L 1 ' is represented by the following formula [IV-23] or [IV-24]

[0204] [ka]

[0205] A group represented by and L 1 " is a single bond.

[0206] Preferred L 2 is a single bond. Preferred LN1 is of the formula -C(=O)- or -S(=O)2-, One more preferred L N1 is of the formula -C(=O)-, Other preferred L N1 has the formula -S(=O)2-.

[0207] Preferred L N2 is a single bond, a group of formula -O-, or a group of formula -C(=O)-NH-, More preferred L N2 is of the formula -O- or -C(=O)-NH-, One more preferred L N2 is of formula -O-, Other more preferred L N2 has the formula -C(=O)-NH-.

[0208] Preferred ring A is a benzene ring or a pyridine ring. More preferably, ring A is a benzene ring. Preferred R A1 , R A2 are independently a hydrogen atom or a halogen atom, More preferred R A1 , R A2 is a hydrogen atom.

[0209] Preferred ring B is phenyl or pyridyl. More preferably, ring B is phenyl. Preferred R B1 , R B2 , R B3 are independently a hydrogen atom, a carbamoyl, a halogen atom, or C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy or haloC 1-6 is an alkoxy; More preferred R B1 , R B2 , R B3 are independently a hydrogen atom, a carbamoyl, a halogen atom, or C1-6 Alkoxy or haloC 1-6 It is an alkoxy.

[0210] Preferred W C is a linker consisting of a single bond or 1 to 3 amino acids, Here, the 1 to 3 amino acids forming the linker are not particularly limited, but are preferably the same or different and selected from the group consisting of Gly, Pro, Arg, (d)-Arg, Lys, (d)-Lys, β-Ala, GABA, and Ape, Here, W C When the group represented by the formula (I) contains Lys or (d)-Lys, The amino acid in the side chain of the Lys and (d)-Lys is C 2-16 Alkylcarbonyl, Lys (the amino of the side chain of Lys is terminally substituted with carboxy) 2-16 Optionally substituted with alkylcarbonyl; or (d)-Lys (the amino acid in the side chain of the (d)-Lys is substituted with a carboxyl group at the end) 2-16 It may be substituted by alkylcarbonyl. More preferable W C is a single bond, Pro, Arg, (d)-Arg, Lys, (d)-Lys, or (d)-Lys-(d)-Lys, Even more desirable W C is a single bond, Arg, (d)-Arg, Lys, or (d)-Lys; One particularly favorable W C is a single bond, Other particularly preferred W C is (d)-Lys.

[0211] Preferred R C is a compound of formula -OH, formula -NH2, C 1-6 Alkylamino (C 1-6 Alkylamino C 1-6The alkyl may be substituted with one group selected from the group consisting of hydroxy, amino, and 4- to 7-membered saturated heterocyclyl containing a nitrogen atom.) or 4- to 7-membered saturated heterocyclyl containing one nitrogen atom and optionally containing one further heteroatom (the 4- to 7-membered saturated heterocyclyl containing one nitrogen atom and optionally containing one further heteroatom is selected from the group consisting of hydroxy, and C 1-6 Alkyl (C 1-6 The alkyl may be substituted with one group selected from the group consisting of: And, two carbon atoms in the 4- to 7-membered saturated heterocyclyl containing one nitrogen atom and optionally containing one heteroatom are C 1-4 may be bridged with an alkanediyl; More preferred R C is of formula -OH or formula -NH2, More preferred R C is the formula -NH2 It is.

[0212] Another preferred embodiment of the compound of the present invention is A substituted polypeptide represented by the formula [I'] or a pharma- ceutical acceptable salt thereof, AA 1 is β-Asp, γ-Glu, or γ-(d)-Glu, AA 2 is a group represented by the following formula [II-1] or formula [II-2]

[0213] [ka]

[0214] and Here, R AA2 is hydroxy or amino, AA 3 is Val, Leu, Ile, Phe, or Trp, AA 4is 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; AA 5 is a single bond, Pro, (d)-Pro, β-homoPro, Arg, (d)-Arg, Lys, (d)-Lys, β-Ala, GABA, Ape, or Acp, W 1 , L 1 And L 1 is a single bond, L 2 is a single bond, L N1 is of the formula -S(=O)2-, L N2 is a single bond, a group of formula -O-, or a group of formula -C(=O)-NH-, Ring A is a benzene ring; R A1 , R A2 is a hydrogen atom, Ring B is phenyl; R B1 , R B2 , R B3 are independently a hydrogen atom, a carbamoyl, a halogen atom, or C 1-6 is an alkoxy; W C is a single bond, Pro, Arg, (d)-Arg, Lys, (d)-Lys, or (d)-Lys-(d)-Lys, R C is the formula -NH2 It is.

[0215] Another preferred embodiment of the present invention is a substituted polypeptide represented by formula [I'] or a pharma- ceutical acceptable salt thereof, AA 1 is β-Asp, γ-Glu, or γ-(d)-Glu, In this case, the more preferable AA 1 is γ-(d)-Glu, AA 2 is a group represented by the following formula [II-1]

[0216] [ka]

[0217] and Here, R AA2 is amino, AA 3 is Val, Leu, or Ile, Where: One more preferred AA 3 is Val, Other more preferred AAs 3 is Leu, Other more preferred AAs 3 is Ile, AA 4 is (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Asp, or (N-Me)Glu; Where: One more preferred AA 4 is (N-Me)Val, (N-Me)Leu, or (N-Me)Ile; In this case, particularly preferred AA 4 is (N-Me)Ile, Other more preferred AAs 4 is (N-Me)Asp or (N-Me)Glu, In this case, particularly preferred AA 4 is (N-Me)Glu, AA 5 is Pro, (d)-Pro, β-homoPro, β-Ala, GABA, Ape, or Acp; Where: One more preferred AA 5 is Pro, (d)-Pro, or β-homoPro, In this case, particularly preferred AA5 is β-homoPro, Other more preferred AAs 5 is β-Ala, GABA, Ape, or Acp, In this case, particularly preferred AA 5 is β-Ala, GABA, or Ape, W 1 , L 1 and L 1 is a single bond, L 2 is a single bond, L N1 is of the formula -S(=O)2-, L N2 is a single bond, a group of formula -O-, or a group of formula -C(=O)-NH-, Where: One more preferred L N1 is of the formula -C(=O)-, Other more preferred L N1 is of the formula -S(=O)2-, Ring A is a benzene ring; R A1 , R A2 is a hydrogen atom, Ring B is phenyl; R B1 , R B2 , R B3 are independently a hydrogen atom, a carbamoyl, a halogen atom, or C 1-6 is an alkoxy; W C is a single bond or (d)-Lys, Where: One more desirable W C is a single bond, Other more preferred W C is (d)-Lys, R C is the formula -NH2 It is.

[0218] Another preferred embodiment of the compound of the present invention is W 1 But -L 1 '-L 1 "- and L 2 is a single bond, The following formula [I'-A]

[0219] [ka]

[0220] or a pharma- ceutically acceptable salt thereof, AA 2 , A.A. 3 , A.A. 4 , A.A. 5 , L 1 ', L 1 ", L N1 , L N2 , R B1 , R B2 , R B3 , W C , and R C The preferred embodiments are as described above.

[0221] More preferred embodiments of the polypeptide represented by the above formula [I'-A] or a pharma- ceutically acceptable salt thereof are as follows.

[0222] AA 2 is represented by the following formula [II-1]

[0223] [ka]

[0224] A group represented by The following formula [IV-7], [IV-8], [IV-9], [IV-11], or [IV-12]

[0225] [ka]

[0226] A group represented by and Here, R AA2 is amino, AA 3 is Val, Leu, Ile, Phe, or Trp, AA 4 is (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Asp, or (N-Me)Glu; AA 5 is β-Ala, GABA, Ape, Acp, Pro, (d)-Pro, or β-homoPro, L 1 ' is β-Ala, GABA, Ape, Acp, the following formula [IV-23] or [IV-24]

[0227] [ka]

[0228] A group represented by and L 1 " is a single bond, Asn, (d)-Ser, (d)-Thr, or Glu; L N1 is of the formula -C(=O)- or -S(=O)2-, L N2 is of the formula -O- or -C(=O)-NH-, R B1 , R B2 , R B3 are independently a hydrogen atom, a carbamoyl, a halogen atom, or C 1-6 Alkoxy or haloC 1-6is an alkoxy; W C is a single bond, Arg, (d)-Arg, Lys, or (d)-Lys; R C is of formula -OH or formula -NH2.

[0229] Further preferred embodiments of the polypeptide represented by the above formula [I'-A] or a pharma- ceutically acceptable salt thereof are as follows.

[0230] AA 2 is represented by the following formula [IV-7] or [IV-9]

[0231] [ka]

[0232] A group represented by and AA 3 is Val, Leu, or Ile, AA 4 is (N-Me)Ile or (N-Me)Glu, AA 5 is β-Ala, GABA, Ape, Acp, or β-homoPro, L 1 ' is GABA or Ape, L 1 " is Asn, Glu, (d)-Ser, or (d)-Thr, L N1 is of the formula -C(=O)- or -S(=O)2-, L N2 is of the formula -O- or -C(=O)-NH-, R B1 is a carbamoyl or a fluorine atom, R B2 is a hydrogen atom, R B3 is a hydrogen atom, W C is a single bond, R C is the formula -NH2 It is.

[0233] In this embodiment, one particularly preferred embodiment is as follows. In the above-mentioned polypeptide represented by formula [I'-A] or a pharma- ceutical acceptable salt thereof, AA 2 is represented by the following formula [IV-7] or [IV-9]

[0234] [ka]

[0235] A group represented by and AA 3 is Val, AA 3 may be Leu, AA 3 may be Ile, AA 4 is (N-Me)Ile, AA 4 may be (N-Me)Glu, AA 5 is β-Ala, GABA, Ape, or Acp, AA 5 may be β-homoPro, L 1 ' is GABA or Ape, L 1" is Asn, Glu, (d)-Ser, or (d)-Thr, L 1 ' and L 1 " is preferably GABA-Asn, Ape-Asn, Ape-Glu, Ape-(d)-Ser, or Ape-(d)-Thr, L N1 is of the formula -C(=O)-, L N1 may be of the formula -S(=O)2-, L N2 is of the formula -O-, L N2 may be of the formula -C(=O)-NH-, R B1 is a carbamoyl or a fluorine atom, R B2 is a hydrogen atom, R B3 is a hydrogen atom, W C is a single bond, R C is the formula -NH2 It is.

[0236] In addition, other particularly preferred aspects of this embodiment are as follows. The substituted polypeptide represented by the above formula [I'-A] is any of the following:

[0237] [ka]

[0238] Another preferred embodiment of the compound of the present invention is W 1 But -L 1 where L 1 is a single bond, L 2 is a single bond, The following formula [I'-B]

[0239] [ka]

[0240] or a pharma- ceutically acceptable salt thereof, AA 1 , A.A. 2 , A.A. 3 , A.A. 4 , A.A. 5 , L N1 , L N2 , R B1 , R B2 , R B3 , W C , and R C The preferred embodiments are as described above.

[0241] More preferred embodiments of the polypeptide represented by the above formula [I'-B] or a pharma- ceutically acceptable salt thereof are as follows.

[0242] AA 1 is β-Asp, β-(d)-Asp, γ-Glu, or γ-(d)-Glu, AA 2 is represented by the following formula [II-1]

[0243] [ka]

[0244] A group represented by The following formula [IV-7], [IV-8], [IV-9], [IV-11], or [IV-12]

[0245] [ka]

[0246] A group represented by and Here, R AA2 is amino, AA 3 is Val, Leu, Ile, Phe, or Trp, AA 4 is (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Asp, or (N-Me)Glu; AA 5 is β-Ala, GABA, Ape, Acp, or β-homoPro, L N1 is of the formula -C(=O)- or -S(=O)2-, L N2 is a single bond, a group of the formula -O- or a group of the formula -C(=O)-NH-, R B1 , R B2 , R B3 are independently a hydrogen atom, a carbamoyl, a halogen atom, or C 1-6 Alkoxy or haloC 1-6 is an alkoxy; W C is a single bond, Arg, (d)-Arg, Lys, or (d)-Lys; R C is of formula -OH or formula -NH2.

[0247] Further preferred embodiments of the polypeptide represented by the above formula [I'-B] or a pharma- ceutically acceptable salt thereof are as follows.

[0248] AA 1 is β-(d)-Asp or γ-(d)-Glu, AA 2 is represented by the following formula [II-1]

[0249] [ka]

[0250] A group represented by The following formula [IV-7] or [IV-9]

[0251] [ka]

[0252] A group represented by and Here, R AA2 is amino, AA 3 is Val, Leu, or Ile, AA 4 is (N-Me)Ile or (N-Me)Glu, AA 5 is β-Ala, GABA, Ape, Acp, or β-homoPro, L N1 is of the formula -C(=O)- or -S(=O)2-, L N2 is of the formula -O- or -C(=O)-NH-, R B1 is carbamoyl, chlorine atom, bromine atom, methoxy, or trifluoromethoxy; R B2 is a hydrogen atom, R B3 is a hydrogen atom, W C is a single bond or (d)-Lys, R C is the formula -NH2 It is.

[0253] In this embodiment, one particularly preferred embodiment is as follows. In the polypeptide represented by the above formula [I'-B] or a pharma- ceutical acceptable salt thereof, AA 1 is β-(d)-Asp, AA 1 may be γ-(d)-Glu; AA 2 is represented by the following formula [II-1]

[0254] [ka]

[0255] A group represented by and Here, R AA2 is amino, AA 2 is represented by the following formula [IV-7] or [IV-9]

[0256] [ka]

[0257] A group represented by may be AA 3 is Val, AA 3 may be Leu, AA 3 may be Ile, AA 4 is (N-Me)Ile, AA 4 may be (N-Me)Glu, AA 5 is β-Ala, GABA, Ape, or Acp, AA 5may be β-homoPro, L N1 is of the formula -C(=O)-, L N1 may be of the formula -S(=O)2-, L N2 is of formula -O-, L N2 may be of the formula -C(=O)-NH-, R B1 is carbamoyl, chlorine atom, bromine atom, methoxy, or trifluoromethoxy; R B2 is a hydrogen atom, R B3 is a hydrogen atom, W C is a single bond, W C may be (d)-Lys; R C has the formula -NH2.

[0258] In addition, other particularly preferred aspects of this embodiment are as follows. The substituted polypeptide represented by the above formula [I'-B] is any of the following:

[0259] [ka]

[0260] [ka]

[0261] Another preferred embodiment of the compound of the present invention is L 2 is a single bond, The following formula [I'-C]

[0262] [ka]

[0263] or a pharma- ceutically acceptable salt thereof, AA 1 , A.A. 2 , A.A. 3 , A.A. 4 , A.A. 5 , W 1 , L N1 , L N2 , R B1 , R B2 , R B3 , W C , and R C The preferred embodiments are as described above.

[0264] More preferred embodiments of the polypeptide represented by the above formula [I'-C] or a pharma- ceutically acceptable salt thereof are as follows.

[0265] AA 1 is Asp, β-(d)-Asp, or γ-(d)-Glu, AA 2 is represented by the following formula [IV-7] or [IV-9]

[0266] [ka]

[0267] or The following formula [II-1]

[0268] [ka]

[0269] A group represented by and Here, R AA2 is amino, AA 3 is Val, Leu, or Ile, AA 4 is (N-Me)Ile or (N-Me)Glu, AA 5 is Ape or β-homoPro, W 1 -L 1 -or-L 1 '-L 1 "- and Here, L 1 is a single bond, Also, L 1 ' is GABA or Ape, L 1 " is Asn, (d)-Ser, (d)-Thr, or Glu, L N1 is of the formula -C(=O)- or -S(=O)2-, L N2 is of the formula -O- or -C(=O)-NH-, R B1 , R B2 , R B3 are independently a hydrogen atom, a carbamoyl, a halogen atom, or C 1-6 Alkoxy or haloC 1-6 is an alkoxy; W C is a single bond or (d)-Lys, R C is the formula -NH2 It is.

[0270] Further preferred embodiments of the polypeptide represented by the above formula [I'-C] or a pharma- ceutically acceptable salt thereof are as follows.

[0271] AA 1 is Asp, AA 1may be β-(d)-Asp; AA 1 may be γ-(d)-Glu; AA 2 is represented by the following formula [IV-7] or [IV-9]

[0272] [ka]

[0273] A group represented by and AA 2 is represented by the following formula [II-1']

[0274] [ka]

[0275] may be a group represented by Here, R AA2 is amino, AA 3 is Val, AA 3 may be Leu, AA 3 may be Ile, AA 4 is (N-Me)Ile, AA 4 may be (N-Me)Glu, AA 5 is Ape, AA 5 may be β-homoPro, W 1 -L 1 -or-L 1 '-L 1 "- and L 1 is a single bond, L 1' and L 1 " for each combination (-L 1 '-L 1 "-) is GABA-Asn, Ape-Asn, Ape-Glu, Ape-(d)-Ser, or Ape-(d)-Thr, L N1 is of the formula -C(=O)-, L N1 may be of the formula -S(=O)2-, L N2 is of formula -O-, L N2 may be of the formula -C(=O)-NH-, R B1 is carbamoyl, chlorine atom, bromine atom, methoxy, or trifluoromethoxy; R B2 is a hydrogen atom, R B3 is a hydrogen atom, W C is a single bond, W C may be (d)-Lys; R C is the formula -NH2 It is.

[0276] In this embodiment, one particularly preferred embodiment is as follows. The substituted polypeptide represented by the above formula [I'-C] is any of the following:

[0277] [ka]

[0278] [ka]

[0279] [ka]

[0280] In addition, other particularly preferred aspects of this embodiment are as follows. The substituted polypeptide represented by the above formula [I'-C] is as follows:

[0281] [ka]

[0282] In addition, other particularly preferred aspects of this embodiment are as follows. The substituted polypeptide represented by the above formula [I'-C] is as follows:

[0283] [ka]

[0284] In addition, other particularly preferred aspects of this embodiment are as follows. The substituted polypeptide represented by the above formula [I'-C] is as follows:

[0285] [ka]

[0286] In addition, other particularly preferred aspects of this embodiment are as follows. The substituted polypeptide represented by the above formula [I'-C] is as follows:

[0287] [ka]

[0288] In addition, other particularly preferred aspects of this embodiment are as follows. The substituted polypeptide represented by the above formula [I'-C] is as follows:

[0289] [ka]

[0290] In addition, other particularly preferred aspects of this embodiment are as follows. The substituted polypeptide represented by the above formula [I'-C] is as follows:

[0291] [ka]

[0292] In addition, other particularly preferred aspects of this embodiment are as follows. The substituted polypeptide represented by the above formula [I'-C] is as follows:

[0293] [ka]

[0294] In addition, other particularly preferred aspects of this embodiment are as follows. The substituted polypeptide represented by the above formula [I'-C] is as follows:

[0295] [ka]

[0296] In addition, other particularly preferred aspects of this embodiment are as follows. The substituted polypeptide represented by the above formula [I'-C] is as follows:

[0297] [ka]

[0298] In addition, other particularly preferred aspects of this embodiment are as follows. The substituted polypeptide represented by the above formula [I'-C] is as follows:

[0299] [ka]

[0300] In addition, other particularly preferred aspects of this embodiment are as follows. The substituted polypeptide represented by the above formula [I'-C] is as follows:

[0301] [ka]

[0302] In addition, other particularly preferred aspects of this embodiment are as follows. The substituted polypeptide represented by the above formula [I'-C] is as follows:

[0303] [ka]

[0304] In addition, other particularly preferred aspects of this embodiment are as follows. The substituted polypeptide represented by the above formula [I'-C] is as follows:

[0305] [ka]

[0306] In addition, other particularly preferred aspects of this embodiment are as follows. The substituted polypeptide represented by the above formula [I'-C] is as follows:

[0307] [ka]

[0308] In addition, other particularly preferred aspects of this embodiment are as follows. The substituted polypeptide represented by the above formula [I'-C] is as follows:

[0309] [ka]

[0310] Another preferred embodiment of the compound of the present invention is A substituted polypeptide represented by the formula [I] or a pharma- ceutical acceptable salt thereof, AA 1 is β-Asp, γ-Glu, or γ-(d)-Glu, AA 2 is a group represented by the following formula [II-1] or formula [II-2]

[0311] [ka]

[0312] and Here, R AA2 is hydroxy or amino, AA 3 is Val, Leu, Ile, Phe, or Trp, 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; AA 5is a single bond, Pro, (d)-Pro, β-homoPro, Arg, (d)-Arg, Lys, (d)-Lys, β-Ala, GABA, Ape, or Acp, L 1 is a single bond, L 2 is a single bond, L N1 is of the formula -S(=O)2-, L N2 is a single bond, a group of formula -O-, or a group of formula -C(=O)-NH-, R A is a hydrogen atom, R B is a hydrogen atom, a carbamoyl, a halogen atom, or C 1-6 is an alkoxy; L C is a single bond, Pro, Arg, (d)-Arg, Lys, (d)-Lys, or (d)-Lys-(d)-Lys, R C is the formula -NH2 It is.

[0313] The compound of the present invention is a compound having a polypeptide skeleton consisting of 3 to 7 amino acids and further having a substituted benzoyl or substituted phenylsulfonyl, and may be a pharma- ceutically acceptable salt thereof.

[0314] Examples of pharma- ceutically acceptable salts include mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, and nitrate, sulfonate salts 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 salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate, inorganic salts such as lithium salt, sodium salt, potassium salt, calcium salt, and magnesium salt, and salts with organic bases such as ammonium salt, triethylamine salt, diisopropylamine salt, and cyclohexylamine salt. The salts include hydrated salts.

[0315] The compounds of the present invention may have asymmetric centers, and in such cases, various optical isomers exist. Thus, the compounds of the present invention may exist as separate optically active forms, i.e., (R) and (S), and as racemic or (RS) mixtures. In addition, in the case of compounds having two or more asymmetric centers, diastereomers due to the respective optical isomers also exist. The compounds of the present invention also include mixtures containing all of these forms in any ratio. For example, diastereomers can be separated by methods well known to those skilled in the art, such as fractional crystallization, and optically active forms can be obtained by organic chemistry techniques well known for this purpose. In addition, the compounds of the present invention may exist in geometric isomers, such as cis and trans isomers. Furthermore, the compounds of the present invention have tautomerism, and various tautomers exist. The compounds of the present invention also include these isomers and mixtures containing these isomers in any ratio.

[0316] Furthermore, when the compound of the present invention or a salt thereof forms a hydrate or solvate, these are also included within the scope of the compound of the present invention or a salt thereof. "Matrix metalloproteinase 2 (MMP2)" is a type of endopeptidase that has zinc at its active center.

[0317] As mentioned above, MMP2 degrades extracellular matrices such as collagen and gelatin, and is therefore involved in cell invasion, migration, metastasis, and the like, and is involved in the pathology of cancer diseases, organ fibrosis, and the like.

[0318] 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. The compound of the present invention has an effect of inhibiting MMP 2. Therefore, the compound of the present invention can be used as an MMP 2 inhibitor, or an active ingredient of a preventive or therapeutic drug for cancer diseases and organ fibrosis.

[0319] The compounds of the present invention can also be used as active ingredients of preventive or therapeutic drugs for symptoms associated with cancer diseases and organ fibrosis. Here, examples of "cancer disease" include breast cancer, pancreatic cancer, bladder cancer, colon 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. Examples of "symptoms related to cancer disease" include pain, weight loss, tumor-associated syndrome, etc. associated with an increase in neoplastic cells or tumor growth.

[0320] Here, "organ fibrosis" includes chronic kidney disease, interstitial pneumonia, idiopathic pulmonary fibrosis, etc. Furthermore, "symptoms related to organ fibrosis" include proteinuria and abnormal renal function in chronic kidney disease, and exertional dyspnea and dry cough in interstitial pneumonia and idiopathic pulmonary fibrosis.

[0321] The MMP2 inhibitory effect of the compound of the present invention can be evaluated according to known techniques, such as the methods described in the Test Examples section of this specification below. The pharmaceutical composition of the present invention contains the compound of the present invention having the effect of inhibiting MMP2 or a pharma- ceutically acceptable salt thereof, which can be administered alone or together with a pharma- ceutical or pharmaceutical acceptable additive.

[0322] The additives may be conventional excipients or diluents, and if necessary, commonly used binders, disintegrants, lubricants, coating agents, sugar coating agents, pH adjusters, solubilizers, or aqueous or non-aqueous solvents.Specific examples include water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, corn starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, water syrup, methylcellulose, polyvinylpyrrolidone, alkyl parahydroxybenzoate, talc, stearic acid, magnesium stearate, agar, pectin, gum arabic, glycerin, sesame oil, olive oil, soybean oil, cocoa butter, ethylene glycol, low viscosity hydroxypropylcellulose (HPC-L), microcrystalline cellulose, carboxymethylcellulose (CMC), sodium carboxymethylcellulose (CMC-Na), and other commonly used ones.

[0323] The medicament according to the present invention may be in any form of a solid composition, a liquid composition, or other composition, and the most suitable one will be selected according to the needs. The medicine of the present invention can be prepared into tablets, pills, capsules, granules, powders, liquids, emulsions, suspensions, injections, etc. by adding the above-mentioned additives to the compound of the present invention and using conventional formulation techniques.

[0324] Furthermore, the pharmaceutical agent according to the present invention can be formulated by forming an inclusion compound between the compound of the present invention and α-, β- or γ-cyclodextrin, methylated cyclodextrin, or the like.

[0325] The pharmaceutical agent according to the present invention may be a single preparation (combined preparation) or two or more preparations (combined preparation) obtained by separately formulating the compound of the present invention and a compound that can be used in combination with each other. When these compounds are formulated separately to form two or more types of preparations, the individual preparations can be administered simultaneously or at a certain time interval. In this case, it does not matter which one is administered first. The two or more preparations can be administered at different times a day. The two or more preparations can also be administered by different routes.

[0326] When these compounds are formulated separately to form two different preparations, they may be administered simultaneously or at a very short interval. For example, it is preferable to state in documents such as package inserts or sales pamphlets of commercially available pharmaceuticals that they are to be used in combination.

[0327] It is also preferable to formulate these active ingredients separately and provide a kit consisting of two types of formulations. When the compound of the present invention is used as an MMP2 inhibitor, the administration form is not particularly limited, and the compound of the present invention can be administered orally or parenterally as it is. The compound of the present invention may also be administered orally or parenterally as a preparation containing the compound of the present invention as an active ingredient.

[0328] In addition, when the compound of the present invention is used as an agent for preventing or improving cancer disease and organ fibrosis, and symptoms associated with cancer disease and organ fibrosis, the compound of the present invention can be administered orally or parenterally as it is. In addition, the compound of the present invention may be administered orally or parenterally as a drug containing the compound of the present invention as an active ingredient.

[0329] Here, parenteral administration is preferably intravenous administration, subcutaneous administration, or transdermal administration. In addition, dosage forms for parenteral administration include injections, drip infusions, implants, transdermal absorption agents, transmucosal absorption agents, patches, etc., and may also be microsphere preparations.

[0330] The dosage of the compound of the present invention varies depending on the subject, administration route, target disease, symptoms, etc., but for example, when administered orally or parenterally to an adult patient, the single dose is usually 0.1 mg to 1000 mg, preferably 1 mg to 200 mg, and this amount is desirably administered once to three times a day, or once every 2 to 3 days.

[0331] Examples of preparations of the compounds of the present invention are given below. Formulation Example 1 Granules containing the following ingredients are prepared:

[0332] Ingredients: Compound represented by general formula [I'], lactose, corn starch, HPC-L. The compound represented by the general formula [I'] and lactose are passed through a sieve. Cornstarch is passed through a sieve. These are mixed in a mixer. An aqueous solution of HPC-L is added to the mixed powder, kneaded, granulated (extrusion granulation), and then dried. The resulting dried granules are passed through a vibrating sieve to obtain a granule.

[0333] Formulation Example 2 A capsule filling powder is prepared containing the following ingredients:

[0334] Ingredients: Compound represented by general formula [I'], lactose, corn starch, magnesium stearate. The compound represented by the general formula [I'] and lactose are passed through a sieve. Cornstarch is passed through a sieve. These and magnesium stearate are mixed in a mixer to obtain a powder. The obtained powder can be filled into capsules.

[0335] Formulation Example 3 Granules for filling capsules are prepared containing the following ingredients:

[0336] Ingredients: Compound represented by general formula [I'], lactose, corn starch, HPC-L. The compound represented by the general formula [I'] and lactose are passed through a sieve. Cornstarch is passed through a sieve. These are mixed in a mixer. An aqueous solution of HPC-L is added to the mixed powder, which is kneaded, granulated, and then dried. The resulting dried granules are passed through a vibrating sieve and sized to obtain granules. The resulting granules can be filled into capsules.

[0337] Formulation Example 4 A tablet containing the following ingredients is prepared:

[0338] Ingredients: Compound represented by general formula [I'], lactose, microcrystalline cellulose, magnesium stearate, CMC-Na. 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. This mixed powder is directly compressed to obtain tablets.

[0339] Formulation Example 5 An injection containing the following ingredients is prepared:

[0340] Ingredients: Compound represented by general formula [I'], purified egg yolk lecithin, oleic acid, refined soybean oil, glycerin, water for injection. 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 glycerin is added and emulsified using an emulsifier. Water for injection is added to this, and the mixture is dispensed into ampoules, sealed, and sterilized to prepare an injection.

[0341] The method for producing the compound [I'] according to the present invention will be described in detail below, but the method is not particularly limited to the exemplified one. 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.

[0342] In the production of compound [I'], the order of the steps in the production can be appropriately changed. In this production, the raw material compounds may be used in the form of a salt, and examples of the salt include the above-mentioned "pharmaceutical acceptable salts."

[0343] Compound [I'] can be produced by solid phase synthesis, liquid phase synthesis, or a combination of these. In the following production method, a production example by solid phase synthesis is shown. The compound [I'] can be produced by the methods described in Schemes 1 to 9 or a combination of these methods.

[0344] In addition, the amino acid forming the polypeptide portion of compound [I'] may have a functional group on its side chain, and the functional group may be protected with a protecting group. Here, examples of the protecting group include tBu for carboxy, Trt for carbamoyl, tBu for hydroxy, tBu for phenolic hydroxy, tBu for thiol (sulfanyl), Boc for amino, Trt for imidazolyl, Boc for indolyl, and Pbf for guanidino. In addition, all of these protecting groups can be deprotected by treating with acid.

[0345] Moreover, the amino acids can be used in the preparation even if the functional groups of the side chains are not protected. A method for producing compound [1-f] in which the amino of the N-terminal amino acid of the polypeptide portion is sulfonylated and the carboxy of the C-terminal amino acid is amidated (-CONH2) (Method A). The compound [1-f] can be prepared, for example, by solid phase synthesis as outlined below (Scheme 1).

[0346] [ka]

[0347] (In Scheme 1, R A1, R A2 , R B1 , R B2 , R B3 , L N2 , ring A, and ring B are the same as defined above. HZ x -OH indicates an amino acid, x represents an integer from 1 to m; m represents an integer from 2 to 15; Here, Z x is AA in the compound represented by formula [I'] x , L 2 , W 1 , or W c and can also represent a single bond, PG x is an amino acid (HZ x This shows a fat-soluble protecting group that protects the amino of the --OH. (1) [Step 1-1] The resin having an Fmoc-protected amino group (compound [1-a]) is subjected to Fmoc removal using a base. (2)[Step 1-2] The resin obtained in (1) above is provided with a fat-soluble protecting group (PG x ) is reacted with an amino-protected amino acid (compound [1-b]) to cause an amidation reaction between the free amino in the resin and the carboxy in the compound [1-b]. (3) [Step 1-3] The lipophilic protecting group of the amino acid of the N-terminal amino acid of the polypeptide portion of the compound obtained in (2) above is deprotected. (4) By repeating the above steps (2) and (3) two or more times, it is possible to produce compound [1-c] in which the carboxyl of the C-terminal amino acid of the polypeptide portion is bound to the resin and the amino of the N-terminal amino acid is free. (5)[Step 1-4] Compound [1-c] obtained in the above (4) is reacted with compound [1-d] to sulfonylate the free amino in compound [1-c], thereby producing compound [1-e]. (6)[Step 1-5] The compound [1-e] obtained in the above (5) is subjected to cleavage of the bond with the resin using an acid to produce the compound of the present invention represented by compound [1-f]. An example of the acid that can be used in this step is TFA.

[0348] At this time, when the amino acid forming the polypeptide portion has a protected functional group in its side chain, the protecting group of the functional group can be simultaneously deprotected. 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.

[0349] In the method described in the above scheme 1, the resin [1-a], the compound [1-b], and the compound [1-d] used as raw materials can be produced by a method known per se or can be obtained by purchasing a commercially available product.

[0350] A method for producing a compound [2-c] in which the amino of the N-terminal amino acid of the polypeptide portion is acylated and the carboxy of the C-terminal amino acid is amidated (-CONH2) (Method B). The compound [2-c] can be produced, for example, by solid phase synthesis using the compound [1-c] as a starting material as outlined below (Scheme 2).

[0351] [ka]

[0352] (In Scheme 2, R A1 , R A2 , R B1 , R B2 , R B3 , L N2 , ring A, ring B, HZ x -OH, x, m, and Z xis the same as defined above. Y 1 represents a hydroxy or chlorine atom. (1) [Step 2-1] Compound [2-b] can be produced by reacting compound [1-c] with compound [2-a] to carry out an amidation reaction. (2)[Step 2-2] The compound [2-b] obtained in the above (1) is subjected to cleavage of the bond with the resin using an acid to produce the compound of the present invention represented by compound [2-c]. An example of the acid that can be used in this step is TFA.

[0353] At this time, when the amino acid forming the polypeptide portion has a protected functional group in its side chain, the protecting group of the functional group can be simultaneously deprotected. 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.

[0354] In the method described in the above scheme 2, the compound [2-a] used as a starting compound can be produced by a method known per se or can be obtained by purchasing a commercial product. Compound [1-c] can be produced by the method described in the above scheme 1.

[0355] A method for producing a compound [3-h] in which the amino of the N-terminal amino acid of the polypeptide portion is sulfonylated or acylated and the carboxy of the C-terminal amino acid is secondary or tertiary amidated (Method C-1) The compound [3-h] can be prepared, for example, by solid phase synthesis as outlined below (Scheme 3).

[0356] Examples of the resin (resin [3-a]) that can be used in this production method include chlorotrityl chloride resin and Wang resin.

[0357] [ka]

[0358] (In Scheme 3, 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 , P.G. x , and Y 1 is the same as defined above. R r represents a hydroxy or chlorine atom, R c’ , R c” are the same or different, a hydrogen atom or C 1-6 alkyl, wherein the C 1-6 Alkyl is hydroxy, amino, and C 1-6 may be substituted with one group selected from the group consisting of alkoxy; Also, R c’ , R c” may combine with the adjacent nitrogen atom to form a 4- to 7-membered saturated heterocycle containing a nitrogen atom, And R c’ and R c” The nitrogen atom-containing 4- to 7-membered saturated heterocycle formed by combining with the adjacent nitrogen atom is hydroxy, amino, C 1-6 Alkyl, and C 1-6 may be substituted with one group selected from the group consisting of alkoxy; In addition, R c’ and R c” The two carbon atoms in the 4- to 7-membered saturated heterocycle containing a nitrogen atom formed together with the adjacent nitrogen atom are C 1-4It may be bridged with an alkanediyl. (1) [Step 3-1] The resin (compound [3-a]) is provided with a fat-soluble protecting group (PG 1 Compound [3-c] can be produced by reacting an amino-protected amino acid (compound [3-b]) with the above-mentioned aryl group. (2)[Step 3-2] The lipophilic protecting group (PG 1 ) is deprotected. (3)[Step 3-3] The compound obtained in (2) above is provided with a fat-soluble protecting group (PG x ) is reacted with an amino-protected amino acid (compound [1-b]), and the free amino in the compound obtained in (1) above and the carboxy in compound [1-b] are subjected to an amidation reaction. (4)[Step 3-4] The lipophilic protecting group of the amino acid of the N-terminal amino acid of the polypeptide portion of the compound obtained in (3) above is deprotected. (5) By repeating the above steps (3) and (4) two or more times, it is possible to produce compound [3-d] in which the carboxyl of the C-terminal amino acid of the polypeptide portion is bound to the resin and the amino of the N-terminal amino acid is free. (6)[Step 3-5] Compound [3-d] obtained in the above (5) can be reacted with compound [1-d] or compound [2-a] to produce compound [3-e] by sulfonylation or acylation of the free amino in compound [3-d]. (7)[Step 3-6] Compound [3-e] obtained in the above (6) is subjected to cleavage of the bond with the resin using an acid to produce compound [3-f] in which the carboxyl group of the C-terminal amino acid of the polypeptide portion is free. An example of the acid that can be used in this step is TFA.

[0359] At this time, when the amino acid forming the polypeptide portion has a protected functional group in its side chain, the protecting group of the functional group can be simultaneously deprotected. (8)[Step 3-7] The compound [3-f] obtained in the above (7) can be reacted with compound [3-g] to carry out an amidation reaction, thereby producing the compound of the present invention represented by compound [3-h].

[0360] 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.

[0361] In the method described in the above scheme 3, the compounds [3-a], [3-b], [1-b], [1-d], [2-a], and [3-g] used as starting compounds can be produced by methods known per se or obtained by purchasing commercially available products.

[0362] A method for producing a compound [4-e] in which the amino of the N-terminal amino acid of the polypeptide portion is sulfonylated or acylated and the carboxy of the C-terminal amino acid is secondary or tertiary amidated (Method C-2) The compound [4-e] can also be prepared by solid phase synthesis as outlined below (Scheme 4).

[0363] In addition, scheme 4 illustrates a method for producing a compound [4-e] in which a functional group exists in the side chain of the m'th amino acid from the C-terminal amino acid in the polypeptide portion. Resins that can be used in this production method include, as in Scheme 3, chlorotrityl chloride resin and Wang resin.

[0364] [ka]

[0365] (In Scheme 4, 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” is the same as defined above. m' represents an integer of 1 to 15, provided that the relationship of "m'≦m" is satisfied; L sc is C 1-4 Represents an alkanediyl, FG sc represents a functional group present in the side chain of the m'th amino acid from the C-terminal amino acid of the aforementioned polypeptide portion, 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), and -NHC(=NH)NH- (-NHC(=NH)NH2). PG sc represents a protecting group for the functional group, As mentioned above, examples of the functional group include tBu, Trt, Boc, and Pbf. (1) [Step 4-1] Compound [4-b] in which the carboxyl group of the C-terminal amino acid of the polypeptide portion is free can be produced by cleaving the bond between compound [4-a] and the resin using an acid.

[0366] In this case, by using a weak acid as the acid, the protecting group (PG sc The weak acid can prevent deprotection of the aryl group. Examples of the weak acid include HFIP, acetic acid, and diluted TFA. (2)[Step 4-2] Compound [4-b] obtained in the above (1) is reacted with compound [4-c] to cause an amidation reaction between the free carboxy in compound [4-b] and the amino in compound [4-c], thereby producing compound [4-d]. (3) [Step 4-3] Using an acid, the protecting group (PG sc The compound of the present invention represented by compound [4-e] can be produced by deprotecting the above-mentioned aryl group. An example of an acid that can be used in this step is TFA.

[0367] 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.

[0368] In the method described in the above scheme 4, the compound [4-c] used as a starting compound can be produced by a method known per se or purchased commercially. Compound [4-a] can be produced by the method described in the above scheme 3.

[0369] In the case where a functional group is present in the side chain of an amino acid forming a polypeptide portion, the functional group is replaced with a polypeptide linker, and further, the amino acid of the N-terminal amino acid of the polypeptide linker is replaced with "carboxy". 1-20 Method for preparing the compound [5-f] substituted with "alkylcarbonyl" (Method D) The compound [5-f] can be prepared by solid phase synthesis as outlined below (Scheme 5).

[0370] Here, the polypeptide linker consists of 1 to 5 amino acids. In Scheme 5, in compound [5-f], a functional group is present in the side chain of the m'th amino acid from the C-terminal amino acid of the polypeptide portion, and the functional group is substituted with a polypeptide linker. Furthermore, the amino acid of the N-terminal amino acid of the polypeptide linker is "substituted with carboxy." 1-20 The following describes an example of a method for producing a compound substituted with "alkylcarbonyl".

[0371] [ka]

[0372] (In Scheme 5, 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 is the same as defined above. PG s’ is the functional group (FG) present in the side chain of the aforementioned amino acid. sc’ ) represents a protecting group for the amino group, and examples of the protecting group include Dde, ivDde, Alloc, and Mtt for amino; HZ sc y -OH is a functional group (FG sc’ ) represents the amino acids forming the polypeptide linker in which they are substituted, y represents an integer from 1 to p; p represents an integer of 0 to 5; PG sc y is an amino acid (HZ sc y This shows a fat-soluble protecting group that protects the amino of the --OH. FG sc’ represents a functional group present in the side chain of an amino acid. Examples of the functional group include -NH- (-NH2) and -COO- (-COOH). In the above scheme 5, FG sc’is represented by the formula -NH- (formula -NH2). n represents an integer of 1 to 20. (1) [Step 5-1] The protecting group (PG) of the functional group present in the side chain of the m'th amino acid from the C-terminal amino acid of the polypeptide portion of compound [5-a] is S’ ) is selectively deprotected. (2)[Step 5-2] The compound obtained in (1) above is provided with a fat-soluble protecting group (PG sc y ) to react with an amino-protected amino acid (compound [5-b]), and the free functional group (FG sc’ ) is subjected to an amidation reaction with the carboxy in the compound [5-b]. (3)[Step 5-3] Lipid-soluble protecting group (PG sc y ) is deprotected. (4) By repeating the above steps (2) and (3) one or more times, a compound [5-c] can be produced in which the carboxy of the C-terminal amino acid of the polypeptide portion is bound to the resin, the functional group present in the side chain of the m'th amino acid from the C-terminal amino acid is substituted with a polypeptide linker, and further, the amino of the N-terminal amino acid of the polypeptide linker is free. (5)[Step 5-4] Compound [5-c] obtained in the above (4) is reacted with compound [5-d], which is an alkanedicarboxylic acid, to produce compound [5-e] by amidation of the free amino in compound [5-c] with one carboxy in compound [5-d]. (6)[Step 5-5] The compound [5-e] obtained in the above (5) is subjected to cleavage of the bond with the resin using an acid to produce the compound of the present invention represented by compound [5-f]. An example of the acid that can be used in this step is TFA.

[0373] At this time, when the amino acid forming the polypeptide portion has a protected functional group in its side chain, the protecting group of the functional group can be simultaneously deprotected. 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.

[0374] In the method described in the above scheme 5, the compounds [5-b] and [5-d] used as starting compounds can be produced by known methods or purchased commercially. Compound [5-a] can be produced by the method described in the above scheme 1 or scheme 2, or a method similar thereto.

[0375] In two of the amino acids forming the polypeptide portion, functional groups are present in the side chains of the respective amino acids, and each functional group is the same as the polypeptide linker (-Z sc 1 -Z sc 2 -…-Z sc y’ -) to form a ring (Method E) The compound [6-c] can be prepared, for example, by solid phase synthesis as outlined below (Scheme 6).

[0376] Here, the polypeptide linker consists of 1 to 4 amino acids. Scheme 6 illustrates an example of a method for producing a compound [6-a] in which functional groups are present in the side chains of the m'-th and m"-th amino acids from the C-terminal amino acid of the polypeptide moiety, and the functional groups are substituted with the same polypeptide linker to form a ring.

[0377] [ka]

[0378] (In Scheme 6, 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 is the same as the above definition. m” represents an integer from 2 to 15, provided that the relationship “m’ < m” ≤ m” holds. The polypeptide linker (-Z sc 1 -Z sc 2 -…-Z sc y’ -) in compound [6-c] corresponds to L 3 (where the L 3 represents Gly, β-Ala, or GABA.) y’ represents an integer from 1 to p’, p’ represents an integer from 1 to 4. L sc’ and L sc” represent C 1-4 alkanediyl. FG sc’ and FG sc” represent the functional groups present in the side chains of amino acids. The functional groups are, for example, represented by the formula -O- (formula -OH), formula -S- (formula -SH), formula -NH- (formula -NH2), formula -C(=O)O- (formula -C(=O)OH), formula -C(=O)NH- (formula -C(=O)NH2). PG sc’ and PG sc” represent the protecting groups for the functional groups present in the side chains of amino acids. The functional groups are, for example, Dde, ivDde, Alloc, allyl. (1) [Step 6-1] Selectively deprotect the protecting group (PG sc’ ) of the functional group present in the side chain of the m’-th amino acid from the C-terminal amino acid of the polypeptide portion in compound [6-a]. (2) [Step 6-2] To the compound obtained in (1) above, a lipophilic protecting group (PGsc y’ ) to react with an amino-protected amino acid (compound [6-d]) to obtain the free functional group (FG sc’ ) is subjected to an amidation reaction with the carboxy in the compound [6-d] in which the amino group is protected with a fat-soluble protecting group. (3) [Step 6-3] The lipophilic protecting group is removed. (4) By repeating the above steps (2) and (3) one or more times, the functional group present in the side chain of the m'th amino acid from the C-terminal amino acid of the polypeptide portion is substituted with a polypeptide linker, the amino acid of the N-terminal amino acid of the polypeptide linker is free, and the functional group (FG sc” ) is a protecting group (PG sc” ) protected compound [6-b] can be prepared. (5) [Step 6-4] The protecting group (PG) present in the side chain of the m”th amino acid from the C-terminal amino acid of the polypeptide portion of compound [6-b] sc” ) is selectively deprotected. (6)[Step 6-5] The "free functional group (FG sc” )" and "Z scp’ This is reacted with a free amino group in the compound to undergo an intramolecular cyclization reaction. (7)[Step 6-6] The compound of the present invention represented by compound [6-c] can be produced by cleaving the bond between the resin and the compound obtained in the above (6) using an acid. An example of the acid that can be used in this step is TFA.

[0379] At this time, when the amino acid forming the polypeptide portion has a protected functional group in its side chain, the protecting group of the functional group can be simultaneously deprotected. 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.

[0380] In the method described in the above scheme 6, the compound [6-d] used as a starting compound can be produced by a method known per se or can be obtained by purchasing a commercial product. Compound [6-a] can be produced by the method described in the above scheme 1 or scheme 2, or a method equivalent thereto.

[0381] Method for preparing compound [7-f] having a substituent "alkylaminocarbonyl substituted with a functional group" on ring B (Method F) The compound [7-f] can be prepared, for example, by solid phase synthesis as outlined below (Scheme 7).

[0382] [ka]

[0383] (In Scheme 7, 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 1 is the same as defined above. L R is C 1-4 Represents an alkanediyl, FG R is a substituent "alkylaminocarbonyl (L)" present on ring B. R -NHC(=O)-)" alkyl(L R)" represents a functional group substituted therewith, and examples thereof include -O-(-OH), -S-(-SH), -NH-(-NH2), -C(=O)O-(-C(=O)OH), and -C(=O)NH-(-C(=O)NH2). PG R is the above functional group (FG R ) protecting group, and examples of the protecting group include tBu for carboxy, Trt for carbamoyl, tBu for hydroxy, tBu for thiol (sulfanyl), and Boc for amino. Note that all of these protecting groups can be deprotected by treatment with acid. (1) [Step 7-1] By reacting compound [1-c] with compound [7-a] or compound [7-b], the free amino acid of the N-terminal amino acid of the polypeptide portion in compound [1-c] is sulfonylated or acylated to produce compound [7-c] having a carboxy on ring B. (2) [Step 7-2] Compound [7-c] can be reacted with compound [7-d] to produce compound [7-e] by amidation reaction of the carboxy in compound [7-c] with the amino in compound [7-d]. (3) [Step 7-3] By using an acid on the compound [7-e] obtained in (2) above, the bond with the resin is cut and at the same time, the functional group (FG R The protecting group (PG R ) is deprotected to produce the compound of the present invention represented by compound [7-f]. An example of an acid that can be used in this step is TFA. At this time, if the amino acid forming the polypeptide portion has a protected functional group in its side chain, the protecting group of the functional group can be deprotected at the same time.

[0384] 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.

[0385] In the method described in the above scheme 7, the compounds [7-a], [7-b], and [7-d] used as starting compounds can be produced by known methods or purchased commercially. Compound [1-c] can be produced by the method described in the above scheme 1 or a method similar thereto.

[0386] Method for preparing compound [8-f] in which ring A is directly substituted with ring B (Method G) The compound [8-f] can be prepared, for example, by solid phase synthesis as outlined below (Scheme 8).

[0387] [ka]

[0388] (In Scheme 8, 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 is the same as defined above.

[0389] LG A represents a leaving group, and examples of the leaving group include a chlorine atom, a bromine atom, an iodine atom, and a haloC 1-6 alkylsulfonyloxy; M B represents a boronic acid, a boronic acid ester, an alkyltin, an alkylsilane, or an alkoxysilane. (1) [Step 8-1] Compound [8-c] can be produced by reacting compound [1-c] with compound [8-a] or compound [8-b] to sulfonylate or acylate the free amino acid of the N-terminal amino acid of the polypeptide portion in compound [1-c]. (2) [Step 8-2] 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. (3) [Step 8-3] The compound [8-e] obtained in the above (2) is subjected to cleavage of the bond with the resin using an acid to produce the compound of the present invention represented by compound [8-f]. An example of the acid that can be used in this step is TFA.

[0390] At this time, when the amino acid forming the polypeptide portion has a protected functional group in its side chain, the protecting group of the functional group can be simultaneously deprotected. 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.

[0391] In the method described in the above scheme 8, the compounds [8-a], [8-b], and [8-d] used as starting compounds can be produced by known methods or purchased commercially. Compound [1-c] can be produced by the method described in the above scheme 1 or a method equivalent thereto.

[0392] Method for preparing compound [9-f] having a substituent "arylcarbonylamino (formula ring BC(=O)NH-)" on ring A (Method H) The compound [9-f] can be prepared, for example, by solid phase synthesis as outlined below (Scheme 9).

[0393] [ka]

[0394] (In Scheme 9, 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 is the same as defined above. Y 2 represents a hydroxy or chlorine atom, PG A represents a fat-soluble protecting group that protects the amino group present on ring A, Here, an example of the lipophilic protecting group is Fmoc. (1) [Step 9-1] As in 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 acid of the N-terminal amino acid of the polypeptide portion in compound [1-c], thereby producing compound [9-c]. (2) [Step 9-2] The lipophilic protecting group (PG A ) is deprotected. (3) [Step 9-3] The compound obtained in (2) above is reacted with compound [9-d] to produce compound [9-e] by amidation (acylation) reaction of the free amino in the compound obtained in (2) above with the carboxy in compound [9-d]. (4) [Step 9-4] The compound [9-e] obtained in the above (3) is subjected to cleavage of the bond with the resin using an acid to produce the compound of the present invention represented by compound [9-f]. An example of the acid that can be used in this step is TFA.

[0395] At this time, when the amino acid forming the polypeptide portion has a protected functional group in its side chain, the protecting group of the functional group can be simultaneously deprotected. 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.

[0396] In the method described in the above scheme 9, the compounds [9-a], [9-b], and [9-d] used as starting compounds can be produced by known methods or purchased commercially. Compound [1-c] can be produced by the method described in the above scheme 1 or a method similar thereto.

[0397] In the production method of compound [I'] according to the present invention shown in the above-mentioned schemes 1 to 9, any amino acid can be used as the amino acid, and examples thereof include the natural proteinogenic L-amino acids Gly, Ala, Val, Leu, Ile, Pro, Phe, His, Trp, Tyr, Ser, Thr, Met, Cys, Asp, Glu, Asn, Gln, Lys, and Arg.

[0398] In addition, in the present production method, unnatural amino acids, including natural non-proteinogenic amino acids and D-forms of the above-mentioned natural proteinogenic L-amino acids, can also be used. Examples of unnatural amino acids that can be used in the present production method include the following: ·(d)-Pro, (d)-Ser, (d)-Thr, (d)-Asp, (d)-Glu, (d)-Arg, (d)-Lys β-homoPro β-Ala, GABA, Ape, Acp ·(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 Formula [II-1] or formula [II-2]

[0399] [ka]

[0400] (wherein R AA2 is hydroxy or amino) Amino acids listed in Tables 1 and 2 above Examples of the lipophilic protecting group include carbonate, amide, or alkyl protecting groups such as 9-fluorenylmethoxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), benzyl (Bn), allyl, allyloxycarbonyl (Alloc), and acetyl (Ac). To introduce a lipophilic protecting group into an amino acid, for example, Fmoc can be introduced by adding 9-fluorenylmethyl-N-succinidyl carbonate and sodium hydrogen carbonate and carrying out a reaction. The reaction is carried out at 0 to 50°C, preferably at room temperature, for about 1 to 5 hours.

[0401] The amino acid protected with a lipophilic protecting group may be a commercially available one, 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.

[0402] Furthermore, examples of amino acids protected with a lipophilic protecting group, in which a protecting group has been 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.

[0403] The resin may be any resin that is typically used in solid-phase synthesis, such as 2-chlorotrityl chloride resin functionalized with chlorine atoms, Wang resin, HMPA-PEGA resin, or Amino-PEGA resin functionalized with amino.

[0404] A method for obtaining an amide at the C-terminus of a peptide is preferably a solid-phase synthesis using a resin for amide synthesis. For example, Rink-Amide-AM resin, SAL-PEG resin, SAL-MBHA resin, and Rink-Amide-PEGA resin can be used. An amide at the C-terminus of the peptide can be obtained by cleaving these resins and the peptide with an acid.

[0405] The bond between an amino acid whose amino group is protected with a fat-soluble protecting group and a resin can be achieved, for example, by esterifying the carboxy of the amino acid to the resin when a resin having a hydroxyl group or a resin functionalized with a chlorine atom is used. Also, when an amino-functionalized resin is used, the carboxy of the amino acid can be attached to the resin via an amide bond.

[0406] 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-collidine. When a resin having hydroxyl groups is used, a known dehydration condensation agent such as 1-(mesitylene-2-sulfonyl)-3-nitro-1,2,4-triazole (MSNT), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), etc. can be used as an esterification catalyst. The ratio of the amino acid and the dehydration condensation agent used is usually 1 to 10 equivalents, preferably 2 to 5 equivalents, of the latter relative to 1 equivalent of the former.

[0407] The esterification reaction is preferably carried out, for example, by placing the resin in a solid-phase column, washing the resin with a solvent, and then adding a solution of the amino acid. Examples of the washing solvent include chloroform, dimethylformamide (DMF), 2-propanol, and dichloromethane. Examples of the solvent for dissolving the amino acid include chloroform, dimethylsulfoxide (DMSO), DMF, and dichloromethane. The esterification reaction is 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.

[0408] At this time, it is also preferable to cap unreacted hydroxyl groups on the solid phase by acetylation with acetic anhydride or the like. The removal of the lipophilic protecting group can be carried out, for example, by treatment with a base. Examples of the base include piperidine and morpholine. In this case, it is preferable to carry out the treatment in the presence of a solvent. Examples of the solvent include DMF, DMSO, and methanol.

[0409] The amidation reaction between the free amino and the carboxy of any amino acid whose amino group is protected with a fat-soluble protecting group is preferably carried out in the presence of an activating agent and a solvent. Examples of the activating agent include dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (WSC / HCl), diphenylphosphoryl azide (DPPA), carbonyldiimidazole (CDI), diethylcyanophosphonate (DEPC), benzotriazol-1-yloxy-trispyrrolidinophosphonium (DIPCI), and benzotriazol-1-yloxy-trispyrrolidinophosphonium (DIPCI). Pyrrolidinophosphonium hexafluorophosphate (PyBOP), 1-hydroxybenzotriazole (HOBt), hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP), 1-hydroxy-7-azabenzotriazole (HOAt), hydroxyphthalimide (HOPht), pentafluorophenol (Pfp-OH), 2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate (HBTU), 1-[bis(dimethylamino)methylene]-5-chloro-1H-benzotriazolium 3-oxide Examples of such compounds include 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-hydrodi-4-oxa-1,2,3-benzotriazine (Dhbt), N-[1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino(morpholino)]uronium hexafluorophosphate (COMU), and cyano(hydroxyimino)ethyl acetate (Oxyma).

[0410] The amount of the activator used is preferably 1 to 20 equivalents, more preferably 1 to 10 equivalents, and even more preferably 1 to 5 equivalents, relative to any amino acid whose amino group is protected with a fat-soluble protecting group.

[0411] Examples of the solvent include DMF, DMSO, dichloromethane, etc. The reaction is carried out at 0 to 50° C., preferably at room temperature, for about 10 minutes to 30 hours, preferably about 15 minutes to 2 hours.

[0412] When the peptide chain is cut off from the resin, it can be carried out by treatment with an acid. Examples of the acid include trifluoroacetic acid (TFA) and hydrogen fluoride (HF). The resin removal reaction is 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.

[0413] The present invention will be explained in more detail by the following examples, reference examples, and test examples, but these do not limit the present invention and may be modified without departing from the scope of the present invention.

[0414] The abbreviations used in this specification are as follows. APCI: Atmospheric Pressure Chemical Ionization Arg(Pbf):N ω -2,2,4,6,7-Pentamethyldihydrobenzofuransulfonylarginine Bu: butyl BuOH: butanol Dde: 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-ethyl DMSO-d6: 6 deuterated dimethyl sulfoxide ELSD: Evaporative Light Scattering Detector ESI: Electrospray ionization HPLC: High-performance liquid chromatography ivDde: 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl LCMS: Liquid Chromatography Mass Spectrometry NMP: 1-methyl-2-pyrrolidone Trt: Trityl UV: Ultraviolet light In this specification, "room temperature" refers to 20 to 30°C unless otherwise specified. "Under ice-cooling" means 0 to 5°C unless otherwise specified.

[0415] In the present specification, the "silica gel cartridge" used in purification by column chromatography was Biotage (registered trademark) SNAP Ultra manufactured by Biotage or REVELERIS (registered trademark) Silica 40 μm manufactured by Buchi.

[0416] Purification using reverse phase column chromatography (hereinafter sometimes referred to as preparative LCMS) was performed under the following two conditions appropriately selected. Fractionation apparatus: Agilent Agilent 1260 Infinity and Agilent 6130 (ionization method: Electron Spray Ionization: ESI), and when an ELSD detector was attached, Agilent 385-ELSD was used. Solvent: Solution A: Water containing 0.1% formic acid, Solution B: Acetonitrile containing 0.1% formic acid Flow rate: 50mL / min The columns used were either of the following: Waters XBridge Prep C18, 5μm, 30×50mm Waters XSelect CSH C18, 5μm, 30×50mm (Preparative separation condition A) 0.0-0.5 minutes (A liquid / B liquid = 90 / 10) 0.5-7.5 minutes (A liquid / B liquid = 90 / 10~20 / 80) 7.5-7.95 minutes (A liquid / B liquid = 20 / 80) 7.95-8.0 minutes (A liquid / B liquid = 20 / 80~5 / 95) 8.0-9.0 minutes (A liquid / B liquid = 5 / 95) (Preparative separation condition B) 0.0-0.5 minutes (A liquid / B liquid = 95 / 5) 0.5-7.5 minutes (A liquid / B liquid = 95 / 5~50 / 50) 7.5-7.95 minutes (A liquid / B liquid = 50 / 50) 7.95-8.0 minutes (A liquid / B liquid = 50 / 50~5 / 95) 8.0-9.0 minutes (A liquid / B liquid = 5 / 95) The instrumental data described in this specification were measured using the following instruments. Microwave reactor: Initiator (Biotage AB) NMR spectrum: [1H-NMR] 600MHz: JNM-ECA600 (JEOL), 400MHz: AVANCE III HD 400 (BRUKER) In this specification, high performance liquid chromatography mass spectrum (LCMS) and retention time (RT) were measured under the conditions shown below. Measuring equipment: Shimadzu LCMS-2010EV Column: Shimadzu XR-ODS, 2.2 μm, 2.0 × 30 mm Ionization method: ESI / APCI dual source Solvent: Solution A: Water containing 0.1% formic acid, Solution B: Acetonitrile containing 0.1% formic acid Flow rate: 0.6mL / min, Detection method: UV210nm, 254nm (Analysis conditions A) 0.0-1.0 minutes (A liquid / B liquid = 90 / 10~60 / 40) 1.0-2.0 minutes (A liquid / B liquid = 60 / 40~1 / 99) 2.0-2.6 minutes (A liquid / B liquid = 1 / 99) (Analysis conditions B) 0.0-0.5 minutes (A liquid / B liquid = 90 / 10) 0.5-1.5 minutes (A liquid / B liquid = 90 / 10~70 / 30) 1.5-2.5 minutes (A liquid / B liquid = 70 / 30~1 / 99) 2.5-5.0 minutes (A liquid / B liquid = 1 / 99) The names of compounds in the Production Examples, Reference Examples, and Examples were named according to "ACD / Name 2019.1.2 (ACDLabs 2019.1.2, Advanced Chemistry Development Inc.)".

[0417] Reference Example 1 4-(4-carbamoylbenzamido)benzenesulfonyl chloride

[0418] [ka]

[0419] To a solution of 4-carbamoylbenzoic acid (150 g) in DMF (180 mL), WSC monohydrochloride (209 g), HOBt monohydrate (167 g) and DIPEA (380 mL) were added. 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 collected by filtration to obtain N-phenylterephthalamide (147 g) as a yellow amorphous substance. 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 cooled on ice and then added to ice water. The precipitated solid was collected by filtration, washed with water, and dried to obtain the title compound (198 g) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.54 (bs, 1 H), 7.62 (d, J=8.2 Hz, 2 H), 7.79 (d, J=8.2 Hz, 2 H), 7.96-8.09 (m, 4 H), 8.14 (bs, 1 H), 10.46 (s, 1 H) Reference Example 2 4-(4-(trifluoromethoxy)benzamido)benzenesulfonyl chloride

[0420] [ka]

[0421] The title compound was obtained as a yellow solid from the corresponding starting materials by a method similar to that of Reference Example 1. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.52 (d, J=8.3 Hz, 2 H), 7.58 (d, J=8.3 Hz, 2 H), 7.72 (d, J=8.3 Hz, 2 H), 8.08 (d, J=8.3 Hz, 2 H), 10.42 (s, 1 H) Reference Example 3 4-(4-(methylcarbamoyl)benzamido)benzenesulfonyl chloride

[0422] [ka]

[0423] The title compound was obtained as a gray solid from the corresponding starting materials by a method similar to that of Reference Example 1. 1 H NMR (600 MHz, DMSO-d6) δ ppm 2.81 (d, J=4.1 Hz, 3 H), 7.57-7.61 (m, 2 H), 7.72-7.78 (m, 2 H), 7.96 (d, J=8.7 Hz, 2 H), 8.03 (d, J=8.7 Hz, 2 H), 8.62 (q, J=4.1, 1 H), 10.42 (s, 1 H) Reference Example 4 4-(4-(dimethylcarbamoyl)benzamido)benzenesulfonyl chloride

[0424] [ka]

[0425] The title compound was obtained as a brown solid from the corresponding starting materials by a method similar to that of Reference Example 1. 1H NMR (600 MHz, DMSO-d6) δ ppm 2.91 (s, 3 H), 3.01 (s, 3 H), 7.54 (d, J=8.3 Hz, 2 H), 7.58 (d, J=8.3 Hz, 2 H), 7.74 (d, J=8.3 Hz, 2 H), 8.01 (d, J=8.3 Hz, 2 H), 10.41 (s, 1 H) Reference Example 5 4-(4-(trifluoromethyl)benzamido)benzenesulfonyl chloride

[0426] [ka]

[0427] The title compound was obtained as a white solid from the corresponding starting materials by a method similar to that of Reference Example 1. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.81 (d, J=8.2 Hz, 2 H), 7.93 (d, J=8.1 Hz, 2 H), 8.01 (d, J=8.2 Hz, 2 H), 8.08 (d, J=8.1 Hz, 3 H) Reference Example 6 4-(4-cyanobenzamido)benzenesulfonyl chloride

[0428] [ka]

[0429] The title compound was obtained as a light brown solid from the corresponding starting materials by a method similar to that of Reference Example 1. 1 H NMR (600 MHz, DMSO-d6) δ ppm 7.58 (d, J=8.3 Hz, 2 H), 7.74 (d, J=8.3 Hz, 2 H), 7.99 (d, J=8.3 Hz, 2 H), 8.01 (d, J=8.3 Hz, 2 H), 10.42 (s, 1 H) Reference Example 7 4-(4-(1,1,2,2-tetrafluoroethoxy)benzamido)benzenesulfonyl chloride

[0430] [ka]

[0431] The title compound was obtained as a yellow solid from the corresponding starting materials by a method similar to that of Reference Example 1. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.95 (tt, J=53.2 Hz, 2.8 Hz, 1 H), 7.37 (d, J=8,6 Hz, 2 H), 7.92 (d, J=7.2 Hz, 2 H), 7.94 (d, J=7.2 Hz, 2 H), 8.05 (d, J=8.6 Hz, 2 H), 8.12 (s, 1 H) Reference Example 8 4-(2-fluorobenzamido)benzenesulfonyl chloride

[0432] [ka]

[0433] The title compound was obtained as a white solid from the corresponding starting materials by a method similar to that of Reference Example 1. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.20-7.27 (m, 1 H), 7.37 (dd, J=7.6 Hz, 7.6 Hz, 1 H), 7.56-7.63 (m, 1 H), 7.95 (d, J=9.1 Hz, 2 H), 8.06 (d, J=9.1 Hz, 2 H), 8.20 (td, J=8.0 Hz, 1.8 Hz, 1 H), 8.75 (d, J=16.9 Hz, 1 H) Reference Example 9 2-Fluoro-4-phenoxybenzoic acid

[0434] [ka]

[0435] Potassium carbonate (535 mg) was added to a solution of 2,4-difluorobenzaldehyde (250 mg) and phenol (199 mg) in DMF (10 mL), 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.

[0436] 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. 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.75-6.92 (m, 2 H), 7.17 (d, J=7.5 Hz, 2 H), 7.24-7.33 (m, 1 H), 7.43-7.55 (m, 2 H), 7.83-7.97 (m, 1 H), 13.0 (brs, 1H) Reference Example 10 4-(4-carbamoyl-2-fluorophenoxy)benzoic acid

[0437] [ka]

[0438] The title compound was obtained as a white solid from the corresponding starting materials by a method similar to that of Reference Example 9. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.12 (d, J=8.4 Hz, 1 H), 7.19 (d, J=8.4 Hz, 2 H), 7.40 (t, J=8.3 Hz, 1 H), 7.53 (br s, 1 H), 7.82 (t, J=8.3 Hz, 1 H), 7.90-8.00 (m, 2 H), 8.07 (br s, 1 H), 9.95 (s, 1 H) Reference Example 11 3-Fluoro-4-(2-fluorophenoxy)benzoic acid

[0439] [ka]

[0440] The title compound was obtained as a white solid from the corresponding starting materials by a method similar to that of Reference Example 9. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.89 (t, J=8.1 Hz, 1 H), 7.10-7.25 (m, 4H), 7.80 (d, J=8.4 Hz, 1 H), 7.89 (d, J=11.3 Hz, 1 H) Reference Example 12 5-((4-(4-carbamoylphenoxy)phenyl)sulfonamido)pentanoic acid

[0441] [ka]

[0442] (1)

[0443] [ka]

[0444] To a solution of benzyl 5-aminopentanoate tosylate (1.48 g) in chloroform (20 mL), triethylamine (2.3 mL) and 4-fluorobenzenesulfonyl chloride (800 mg) were added under ice cooling, and the mixture was stirred for 1 hour under ice cooling. After the reaction was completed, a saturated aqueous solution of sodium bicarbonate 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 benzyl 5-((4-fluorophenyl)sulfonamido)pentanoate (1.24 g) as a colorless oily substance. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.46-1.56 (m, 2 H), 1.58-1.68 (m, 2 H), 2.33 (t, J=7.0 Hz, 2 H), 2.96 (q, J=6.5 Hz, 2 H), 4.40-4.47 (m, 1 H), 5.09 (s, 2 H), 7.18 (t, J=8.2 Hz, 2 H), 7.31-7.39 (m, 5 H), 7.86 (dd, J=7.6 Hz, 5.3 Hz, 2 H) (2)

[0445] [ka]

[0446] 4-Hydroxybenzonitrile (179 mg) and potassium carbonate (567 mg) were added to a DMF (13 mL) solution of benzyl 5-((4-fluorophenyl)sulfonamido)pentanoate (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 allowed to cool, ethyl acetate and water were added to the reaction mixture to separate the layers. The aqueous layer was washed with ethyl acetate, adjusted to pH 1 with 1M aqueous hydrochloric acid, 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)sulfonamido)pentanoic acid (285 mg) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.32-1.49 (m, 4 H), 2.10-2.17 (m, 2 H), 2.69-2.78 (m, 2 H), 7.23-7.31 (m, 2 H), 7.43 (t, J=8.7 Hz, 2 H), 7.59-7.66 (m, 1 H), 7.81-7.87 (m, 3 H), 7.91 (d, J=8.3 Hz, 1 H) (3) To a solution of 5-((4-(4-cyanophenoxy)phenyl)sulfonamido)pentanoic acid (100 mg) obtained in (2) above in DMSO (2 mL), potassium carbonate (81 mg) and 30% hydrogen peroxide solution (0.15 mL) were added and stirred at room temperature for 2 hours. After completion of the reaction, an aqueous solution of sodium thiosulfate and an aqueous solution of 1M hydrochloric acid 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. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32-1.50 (m, 4 H), 2.10-2.18 (m, 2 H), 2.69-2.78 (m, 2 H), 7.16 (d, J= 8.2 Hz, 1 H), 7.19 (d, J= 8.6 Hz, 1 H), 7.34 (br s, 1 H), 7.43 (t, J= 8.6 Hz, 2 H), 7.52-7.58 (m, 1 H), 7.59-7.66 (m, 1 H), 7.86- 7.79 (m 3 H), 7.96 (d, J=7.7 Hz, 1 H), 12.0 (br s, 1 H) Example 1 Compound No. 1: Compound (N-[4-(4-carbamoylbenzamido)benzene-1-sulfonyl]-D-γ-glutamyl-(4S)-4-amino-L-prolyl-L-leucyl-N-(5-amino-5-oxopentyl)-N 2 -Synthesis of -methyl-L-α-glutamine)

[0447]

change

[0448] (1) Fmoc-Rink Amide AM resin (0.10 mmol) was treated with piperidine in DMF (40%, 1.6 mL) for 3 min, followed by treatment with piperidine in DMF (20%, 1.6 mL) for 12 min to deprotect the Fmoc of the resin. Then, Fmoc-Ape-OH (0.40 mmol) in DMF (0.8 mL), COMU (0.40 mmol) and Oxyma (0.40 mmol) in DMF (0.8 mL), and DIPEA (0.80 mmol) in NMP (0.4 mL) were added and shaken at room temperature for 40 min to introduce the Ape residue. In the same manner, Fmoc deprotection and condensation were repeated. Specifically, Fmoc-(N-Me)Glu(OtBu)-OH, Fmoc-Leu-OH, Fmoc-(2S,4S)-(4-NHBoc)Pro-OH, and Fmoc-(d)-Glu-OtBu were successively condensed, and the N-terminal Fmoc of the resulting resin was deprotected by piperidine / DMF treatment in the same manner as above, to synthesize the peptide-bound resin H-γ-(d)-Glu(OtBu)-(2S,4S)-(4-NHBoc)Pro-Leu-(N-Me)Glu(OtBu)-Ape-Rink Amide AM resin. (2) To the resin obtained in (1) above, a solution of 4-(4-carbamoylbenzamido)benzenesulfonyl chloride (0.30 mmol) and DIPEA (0.60 mmol) in DMF (3 mL) obtained in Reference Example 1 was added, and the mixture was shaken at room temperature for 1 hour. After completion of the reaction, the resin obtained was washed with DMF (3 mL x 3 times) and chloroform (3 mL x 3 times). (3) To the resin obtained in (2) above, TFA:water:triisopropylsilane (92.5:2.5:5, 4 mL) was added, 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 diethyl ether was removed by decantation. This procedure was repeated three times to obtain a crude peptide. The obtained crude was purified by preparative LCMS (preparative condition B). The eluate was fractionated in a test tube, and the eluted fraction containing the target product was collected and lyophilized to obtain the title compound (46 mg) as a white powder.

[0449] Example 2 Compound No. 106 (N 2 -[4-(4-phenoxybenzamido)butanoyl]-L-asparaginyl-N-[(2S)-4-amino-1-({(2S)-1-[{(2S,3S)-1-[(2S)-2-(2-amino-2-oxoethyl)pyrro Synthesis of lidin-1-yl]-3-methyl-1-oxopentan-2-yl}(methyl)amino]-4-methyl-1-oxopentan-2-yl}amino)-1-oxobutan-2-yl]-L-α-asparagine)

[0450] [ka]

[0451] (1) Fmoc-NH-SAL-PEG resin (0.12 mmol) was treated with piperidine in DMF (40%, 1.9 mL) for 3 min, followed by treatment with piperidine in DMF (20%, 1.9 mL) for 12 min to deprotect the Fmoc of the resin. Then, Fmoc-β-homoPro-OH (0.48 mmol) in DMF (1.0 mL), COMU (0.48 mmol) and Oxyma (0.48 mmol) in DMF (1.0 mL), and DIPEA (0.96 mmol) in NMP (0.48 mL) were added and shaken at room temperature for 40 min to introduce the β-homoPro residue. In the same manner, Fmoc deprotection and condensation 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 the resin Ph-O-Ph-CO-GABA-Asn(Trt)-Asp(OtBu)-Dab(Boc)-Leu-(N-Me)Ile-β-homoPro-NH-SAL-PEG resin with the peptide bound thereto. After the reaction was completed, the resin obtained was washed with DMF (3 mL x 3 times) and chloroform (3 mL x 3 times). (2) To the resin obtained in (1) above, TFA:water:triisopropylsilane:dithiothreitol (90:2.5:5:2.5, 4 mL) was added, 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 diethyl ether was removed by decantation. This procedure was repeated three times to obtain a crude peptide. The obtained crude was purified by preparative LCMS (preparative condition A). The eluate was fractionated in a test tube, and the eluted fraction containing the target product was collected and lyophilized to obtain the title compound (14 mg) as a white powder.

[0452] Example 3 Compound No. 177 (N 2Synthesis of -(4-{4-[4-(methylcarbamoyl)phenoxy]benzamido}butanoyl)-L-asparaginyl-L-α-aspartyl-L-alanyl-L-leucyl-L-methionyl-L-prolinamide)

[0453] [ka]

[0454] (1) Fmoc-NH-SAL-PEG resin (0.10 mmol) was treated with piperidine in DMF (40%, 1.6 mL) for 3 min, followed by treatment with piperidine in DMF (20%, 1.6 mL) for 12 min to deprotect the Fmoc of the resin. Then, Fmoc-Pro-OH (0.40 mmol) in DMF (0.8 mL), COMU (0.40 mmol) and Oxyma (0.40 mmol) in DMF (0.8 mL), and DIPEA (0.80 mmol) in NMP (0.4 mL) were added and shaken at room temperature for 40 min to introduce the Pro residue. In the same manner, Fmoc deprotection and condensation 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 successively condensed. The N-terminal Fmoc of the resulting resin was deprotected by piperidine / DMF treatment in the same manner as above, to synthesize the peptide-bound resin, H-GABA-Asn(Trt)-Asp(OtBu)-Ala-Leu-Met-Pro-NH-SAL-PEG resin. (2) A solution of 4,4'-oxybisbenzoic acid (0.75 mmol), HATU (0.15 mmol), and DIPEA (2.0 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 resin obtained was washed with DMF (3 mL x 3 times). (3) To the resin obtained in (2) above, HATU (0.30 mmol), DIPEA (0.60 mmol), and a DMF (3 mL) solution of methylamine in methanol (concentration: 9.8 mol / L, 0.30 mmol) were added and stirred at room temperature for 4 hours. After the reaction was completed, the resin obtained was washed with DMF (3 mL x 3 times) and chloroform (3 mL x 3 times). (4) To the resin obtained in (3) above, TFA:water:triisopropylsilane:dithiothreitol (90:2.5:5:2.5, 4 mL) was added, 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 diethyl ether was removed by decantation. This procedure was repeated three times to obtain a crude peptide. The obtained crude product was purified by preparative LCMS (preparative condition A). The eluate was fractionated in a test tube, and the eluted fraction containing the target product was collected and lyophilized to obtain the title compound (30 mg) as a white powder.

[0455] Example 4 Synthesis of Compound No. 587 (N-{5-[(4-methylphenyl)ethynyl]thiophene-2-sulfonyl}-β-alanyl-L-asparaginyl-L-α-aspartyl-L-alanyl-L-leucyl-N-methyl-L-methionyl-L-prolinamide)

[0456] [ka]

[0457] (1) Fmoc-NH-SAL-PEG resin (0.10 mmol) was treated with piperidine in DMF (40%, 1.6 mL) for 3 min, followed by treatment with piperidine in DMF (20%, 1.6 mL) for 12 min to deprotect the Fmoc of the resin. Then, Fmoc-Pro-OH (0.40 mmol) in DMF (0.8 mL), COMU (0.40 mmol) and Oxyma (0.40 mmol) in DMF (0.8 mL), and DIPEA (0.80 mmol) in NMP (0.4 mL) were added and shaken at room temperature for 40 min to introduce the Pro residue. In the same manner, Fmoc deprotection and condensation were repeated. 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 successively condensed. The N-terminal Fmoc of the resulting resin was deprotected by piperidine / DMF treatment in the same manner as above, to synthesize the peptide-bound resin, H-β-Ala-Asn(Trt)-Asp(OtBu)-Ala-Leu-(N-Me)Met-Pro-NH-SAL-PEG resin. (2) To the resin obtained in (1) above, a solution of 5-bromothiophene-2-sulfonyl chloride (0.20 mmol) and DIPEA (0.40 mmol) in DMF (3 mL) was added and the mixture was shaken at room temperature for 2 hours. After the reaction was completed, the resin obtained was washed with DMF (3 mL x 3 times) and chloroform (3 mL x 3 times). (3) To the resin obtained in (2) above, TFA:water:triisopropylsilane:dithiothreitol (90:2.5:5:2.5, 4 mL) was added, 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 diethyl ether was removed by decantation. This procedure was repeated three times to obtain a crude peptide. The crude peptide obtained was purified by preparative LCMS (preparative condition B). The eluate was fractionated in a test tube, and the eluted fraction containing the target substance was collected and freeze-dried to obtain 5-Br-thiophene-2-SO2-β-Ala-Asn-Asp-Ala-Leu-(N-Me)Met-Pro-NH2 (27 mg) as a white powder. (4) The compound obtained in (3) above was dissolved in DMF (0.5 mL), and 4-ethynyltoluene (0.30 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.01 mmol), triethylamine (0.18 mmol), and copper iodide (0.01 mmol) were added, followed by heating and stirring at 50°C for 5 hours under a nitrogen gas atmosphere. After cooling to room temperature, the reaction solution was diluted with DMSO and filtered, and then purified by preparative LCMS (preparative condition A). The eluate was fractionated in a test tube, and the eluted fraction containing the target product was collected and freeze-dried to obtain the title compound (4 mg) as a white powder.

[0458] 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 Synthesis of -[4-(1-phenyl-1H-1,2,3-triazol-4-yl)benzene-1-sulfonyl]-D-glutamine)

[0459] [ka]

[0460] (1) Fmoc-Rink Amide AM resin (0.10 mmol) was treated with piperidine in DMF (40%, 1.6 mL) for 3 min, followed by treatment with piperidine in DMF (20%, 1.6 mL) for 12 min to deprotect the Fmoc of the resin. Then, Fmoc-β-homoPro-OH (0.40 mmol) in DMF (0.8 mL), COMU (0.40 mmol) and Oxyma (0.40 mmol) in DMF (0.8 mL), and DIPEA (0.80 mmol) in NMP (0.4 mL) were added and shaken at room temperature for 40 min to introduce the β-homoPro residue. In the same manner, Fmoc deprotection and condensation were repeated, specifically, Fmoc-(N-Me)Ile-OH, Fmoc-Leu-OH, Fmoc-Dab(Boc)-OH, and Fmoc-(d)-Glu-OtBu were successively condensed, and the N-terminal Fmoc of the resulting resin was deprotected by piperidine / DMF treatment in the same manner as above to synthesize the peptide-bound resin H-γ-(d)-Glu(OtBu)-Dab(Boc)-Leu-(N-Me)Ile-β-homoPro-Rink Amide AM resin. (2) A solution of 4-bromobenzenesulfonyl chloride (0.30 mmol) and DIPEA (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 was completed, the resin obtained was washed with DMF (2 mL x 3 times). (3) To the resin obtained in (2) above, a solution of trimethylsilylacetylene (0.30 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.03 mmol), and copper iodide (0.03 mmol) in DMF (2 mL) was added, and the mixture was heated and stirred at 80° C. for 30 minutes under microwave irradiation. After the reaction was completed, the resin obtained was washed with DMF (2 mL x 3 times) and chloroform (2 mL x 3 times). A solution of tetrabutylammonium fluoride in tetrahydrofuran (concentration: 0.33 mol / L, 0.50 mmol) was added to the obtained resin, and the mixture was shaken at room temperature for 1 hour. After the reaction was completed, the obtained resin was washed with DMF (2 mL x 3 times) and chloroform (2 mL x 3 times). (4) A solution of azidobenzene (0.20 mmol), copper(II) sulfate pentahydrate (0.40 mmol), and ascorbic acid (0.40 mmol) in water (2 mL) and tBuOH (1 mL) was added to the resin obtained in (3) above, and the mixture was heated and stirred at 60°C for 1 hour under microwave irradiation. After the reaction was completed, the resin obtained was washed with DMF (2 mL x 3 times) and chloroform (2 mL x 3 times). (5) To the resin obtained in (4) above, TFA:water:triisopropylsilane (92.5:2.5:5, 4 mL) was added, 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 diethyl ether was removed by decantation. This procedure was repeated three times to obtain a crude peptide. The obtained crude product was purified by preparative LCMS (preparative condition A). The eluate was fractionated in a test tube, and the eluted fraction containing the target product was collected and lyophilized to obtain the title compound (12 mg) as a white powder.

[0461] Example 6 Compound No. 634 (N 2 -(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)

[0462] [ka]

[0463] (1) Fmoc-NH-SAL-PEG resin (0.10 mmol) was treated with piperidine in DMF (40%, 1.6 mL) for 3 min, followed by treatment with piperidine in DMF (20%, 1.6 mL) for 12 min to deprotect the Fmoc of the resin. Then, Fmoc-β-homoPro-OH (0.40 mmol) in DMF (0.8 mL), COMU (0.40 mmol) and Oxyma (0.40 mmol) in DMF (0.8 mL), and DIPEA (0.80 mmol) in NMP (0.4 mL) were added and shaken at room temperature for 40 min to introduce the β-homoPro residue. In the same manner, Fmoc deprotection and condensation were repeated, specifically, Fmoc-(N-Me)Ile-OH, Fmoc-Leu-OH, Fmoc-Ala-OH, and Fmoc-(d)-Asp-OtBu were successively condensed, and the N-terminal Fmoc of the resulting resin was deprotected by piperidine / DMF treatment in the same manner as above to synthesize the peptide-bound resin H-β-(d)-Asp(OtBu)-Ala-Leu-(N-Me)Ile-β-homoPro-NH-SAL-PEG resin. (2) To the resin obtained in (1) above, a solution of 4-iodobenzenesulfonyl chloride (0.30 mmol) and DIPEA (0.60 mmol) in DMF (2 mL) was added and the mixture was shaken at room temperature for 2 hours. After the reaction was completed, the resin obtained was washed with DMF (2 mL x 3 times) and chloroform (2 mL x 3 times). (3) To the resin obtained in (2) above, 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) was added, and the mixture was heated and stirred at 100° C. for 30 minutes under microwave irradiation. After the reaction was completed, the resin obtained was washed with DMF (2 mL×3 times) and chloroform (2 mL×3 times). (4) To the resin obtained in (3) above, TFA:water:triisopropylsilane (92.5:2.5:5, 4 mL) was added and 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 diethyl ether was removed by decantation. This procedure was repeated three times to obtain a crude peptide. The obtained crude product was purified by preparative LCMS (preparative condition A). The eluate was fractionated in a test tube, and the eluted fraction containing the target product was collected and lyophilized to obtain the title compound (8 mg) as a white powder.

[0464] 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

[0465] [ka]

[0466] (1) Fmoc-Rink Amide AM resin (0.10 mmol) was treated with piperidine in DMF (40%, 1.6 mL) for 3 min, followed by treatment with piperidine in DMF (20%, 1.6 mL) for 12 min to deprotect the Fmoc of the resin. Then, Fmoc-β-homoPro-OH (0.40 mmol) in DMF (0.8 mL), COMU (0.40 mmol) and Oxyma (0.40 mmol) in DMF (0.8 mL), and DIPEA (0.80 mmol) in NMP (0.4 mL) were added and shaken at room temperature for 40 min to introduce the β-homoPro residue. In the same manner, Fmoc deprotection and condensation were repeated. Specifically, Fmoc-(N-Me)Ile-OH, Fmoc-Leu-OH, Fmoc-Dap(Boc)-OH, and Fmoc-(d)-Asp-OtBu were successively condensed, and the N-terminal Fmoc of the resulting resin was deprotected by piperidine / DMF treatment in the same manner as above to synthesize the peptide-bound resin, H-γ-(d)-Asp(OtBu)-Dap(Boc)-Leu-(N-Me)Ile-β-homoPro-Rink Amide AM resin. (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 resin obtained was washed with DMF (3 mL x 3 times). Then, a solution of piperidine in DMF (concentration: 20%, 3 mL) and Oxyma (0.01 mmol) were added, and the mixture was shaken at room temperature for 10 minutes. (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 was completed, the resin obtained was washed with chloroform (3 mL x 3 times). (4) To the resin obtained in (3) above, TFA:water:triisopropylsilane:dithiothreitol (90:2.5:5:2.5, 4 mL) was added, 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 diethyl ether was removed by decantation. This procedure was repeated three times to obtain a crude peptide. The obtained crude product was purified by preparative LCMS (preparative condition A). The eluate was fractionated in a test tube, and the eluted fraction containing the target product was collected and lyophilized to obtain the title compound (12 mg) as a white powder.

[0467] 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]butanamido}-1,4,7,13,16-pentaazacyclohenicosan-2-yl]acetic acid)

[0468] [ka]

[0469] (1) Fmoc-NH-SAL-PEG resin (0.12 mmol) was treated with piperidine in DMF (40%, 1.9 mL) for 3 min, followed by treatment with piperidine in DMF (20%, 1.9 mL) for 12 min to deprotect the Fmoc of the resin. Then, Fmoc-β-homoPro-OH (0.48 mmol) in DMF (1.0 mL), COMU (0.48 mmol) and Oxyma (0.48 mmol) in DMF (1.0 mL), and DIPEA (0.96 mmol) in NMP (0.48 mL) were added and shaken at room temperature for 40 min to introduce the β-homoPro residue. In the same manner, Fmoc deprotection and condensation were repeated. 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 successively condensed, and the N-terminal Fmoc of the resulting resin was deprotected by piperidine / DMF treatment in the same manner as above, to synthesize the peptide-bound resin, H-GABA-Glu(OAllyl)-Asp(OtBu)-Ala-Lys(Dde)-(N-Me)Ile-β-homoPro-SAL-PEG resin. (2) To the resin obtained in (1) above, a solution of 4-phenoxybenzenesulfonyl chloride (0.36 mmol) and DIPEA (0.72 mmol) in DMF (3 mL) was added, and the mixture was shaken at room temperature for 1.5 hours. After the reaction was completed, the resin obtained was washed with DMF (3 mL x 3 times). (3) To the resin obtained in (2) above, a DMF solution of hydrazine monohydrate (concentration: 5%, 3 mL) and allyl alcohol (3.1 mmol) were added, and the mixture was shaken at room temperature for 30 minutes to deprotect the Dde on 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 the Gly residue. After the reaction was completed, the resin obtained was washed with DMF (3 mL x 3 times) and chloroform (3 mL x 3 times). (4) To the resin obtained in (3) above, a solution of tetrakis(triphenylphosphine)palladium(0) (0.12 mmol) and phenylsilane (0.60 mmol) in chloroform (4 mL) was added and shaken at room temperature for 1.5 hours to deprotect the Allyl on the Glu side chain. Next, a DMF solution of piperidine (concentration: 20%, 3 mL) was added and shaken at room temperature for 30 minutes to deprotect Fmoc. After the reaction was completed, the resin obtained was washed with DMF (3 mL x 5 times). (5) To the resin obtained in (4) above, a solution of PyBOP (0.36 mmol) and DIPEA (0.12 mmol) in DMF (4 mL) was added and shaken at room temperature for 2 hours. After the reaction was completed, the resin obtained was washed with DMF (3 mL x 3 times) and chloroform (3 mL x 3 times). (6) To the resin obtained in (5) above, TFA:water:triisopropylsilane:dithiothreitol (90:2.5:5:2.5, 4 mL) was added, 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 diethyl ether was removed by decantation. This procedure was repeated three times to obtain a crude peptide. The obtained crude product was purified by preparative LCMS (preparative condition A). The eluate was fractionated in a test tube, and the eluted fraction containing the target product was collected and lyophilized to obtain the title compound (10 mg) as a white powder.

[0470] 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-pentaazaoctatetracontane-1,32,48-tricarboxylic acid)

[0471] [ka]

[0472] (1) Fmoc-Rink Amide AM resin (0.12 mmol) was treated with piperidine in DMF (40%, 1.9 mL) for 3 min, followed by treatment with piperidine in DMF (20%, 1.9 mL) for 12 min to deprotect the Fmoc of the resin. Then, Fmoc-β-homoPro-OH (0.48 mmol) in DMF (1.0 mL), COMU (0.48 mmol) and Oxyma (0.48 mmol) in DMF (1.0 mL), and DIPEA (0.96 mmol) in NMP (0.48 mL) were added and shaken at room temperature for 40 min to introduce the β-homoPro residue. In the same manner, Fmoc deprotection and condensation were repeated. 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 sequentially condensed, and the N-terminal Fmoc of the resulting resin was deprotected by piperidine / DMF treatment in the same manner as above to synthesize the peptide-bound resin, H-GABA-Lys(Dde)-Asp(OtBu)-Ala-Leu-(N-Me)Ile-β-homoPro-Rink Amide AM resin. (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 2 hours. After the reaction was completed, the resin obtained was washed with DMF (3 mL x 3 times). (3) A DMF solution of hydrazine monohydrate (concentration: 5%, 3 mL) was added to the resin obtained in (2) above, and the operation of shaking at room temperature for 30 minutes was repeated four times to deprotect the Dde on the Lys side chain. Condensation and de-Fmoc were repeated on the obtained resin, specifically, Fmoc-Adox-OH, Fmoc-Adox-OH, and Fmoc-Glu-OtBu were condensed in sequence to elongate the peptide on the Lys side chain. The N-terminal Fmoc on the Lys side chain was deprotected by piperidine / DMF treatment. (4) To the resin obtained in (3) above, a solution of hexadecanedioic acid (0.96 mmol), COMU (0.18 mmol), Oxyma (0.18 mmol), and DIPEA (0.96 mmol) in DMF (3 mL) was added and shaken at room temperature for 1 hour. After the reaction was completed, the resin obtained was washed with DMF (3 mL x 4 times) and chloroform (3 mL x 3 times). (5) To the resin obtained in (4) above, TFA:water:triisopropylsilane:dithiothreitol (90:2.5:5:2.5, 4 mL) was added, 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 diethyl ether was removed by decantation. This procedure was repeated three times to obtain a crude peptide. The obtained crude product was purified by preparative LCMS (preparative condition A). The eluate was fractionated in a test tube, and the eluted fraction containing the target product was collected and lyophilized to obtain the title compound (29 mg) as a white powder.

[0473] The structures of the compounds represented by formula [I'-1] in Example 1 or those synthesized in a similar manner to Example 1 are shown in the following table.

[0474] [ka]

[0475] [Table 5-1]

[0476] [Table 5-2]

[0477] The structure of the compound represented by formula [I'-2], which was synthesized in the same manner as in Example 1, is shown in the following table.

[0478] [ka]

[0479] [Table 6]

[0480] The structure of the compound represented by formula [I'-3], which was synthesized in the same manner as in Example 1, is shown in the following table.

[0481] [ka]

[0482] [Table 7]

[0483] The structure of the compound represented by formula [I'-4], which was synthesized in the same manner as in Example 1, is shown in the following table.

[0484] [ka]

[0485] [Table 8]

[0486] The structure of the compound represented by formula [I'-5], which was synthesized in the same manner as in Example 1, is shown in the following table.

[0487] [ka]

[0488] [Table 9]

[0489] The structure of the compound represented by formula [I'-6], which was synthesized in the same manner as in Example 1, is shown in the following table.

[0490] [ka]

[0491] [Table 10]

[0492] The structure of the compound represented by formula [I'-7], which was synthesized in the same manner as in Example 1, is shown in the following table.

[0493] [ka]

[0494] [Table 11]

[0495] The structure of the compound represented by formula [I'-8], which was synthesized in the same manner as in Example 1, is shown in the following table.

[0496] [ka]

[0497] [Table 12-1]

[0498] [Table 12-2]

[0499] [Table 12-3]

[0500] The structures of the compounds represented by formula [I'-9] and synthesized in Example 2 or in a similar manner to Example 2 are shown in the following table.

[0501] [ka]

[0502] [Table 13-1]

[0503] [Table 13-2]

[0504] [Table 13-3]

[0505] [Table 13-4]

[0506] The structure of the compound represented by formula [I'-10], which was synthesized in the same manner as in Example 9, is shown in the following table.

[0507] [ka]

[0508] [Table 14]

[0509] The structures of the compounds represented by formula [I'-9] and synthesized in Example 2 or in a similar manner to Example 2 are shown in the following table.

[0510] [ka]

[0511] [Table 15]

[0512] The structures of the compounds represented by formula [I'-9] in Example 3 or synthesized in a similar manner to Example 3 are shown in the following table.

[0513] [ka]

[0514] [Table 16-1]

[0515] [Table 16-2]

[0516] The structure of the compound represented by formula [I'-11], which was synthesized in the same manner as in Example 2, is shown in the following table.

[0517] [ka]

[0518] [Table 17]

[0519] The structure of the compound represented by formula [I'-12], which was synthesized in the same manner as in Example 2, is shown in the following table.

[0520] [ka]

[0521] [Table 18]

[0522] The structure of the compound represented by formula [I'-13], which was synthesized in the same manner as in Example 2, is shown in the following table.

[0523] [ka]

[0524] [Table 19]

[0525] The structure of the compound represented by formula [I'-14], which was synthesized in the same manner as in Example 2, is shown in the following table.

[0526] [ka]

[0527] [Table 20-1]

[0528] [Table 20-2]

[0529] [Table 20-3]

[0530] [Table 20-4]

[0531] [Table 20-5]

[0532] The structure of the compound represented by formula [I'-15], which was synthesized in the same manner as in Example 2, is shown in the following table.

[0533] [ka]

[0534] [Table 21]

[0535] The structure of the compound represented by formula [I'-14], which was synthesized in the same manner as in Example 2, is shown in the following table.

[0536] [ka]

[0537] [Table 22-1]

[0538] [Table 22-2]

[0539] [Table 22-3]

[0540] [Table 22-4]

[0541] [Table 22-5]

[0542] [Table 22-6]

[0543] [Table 22-7]

[0544] [Table 22-8]

[0545] [Table 22-9]

[0546] [Table 22-10]

[0547] [Table 22-11]

[0548] [Table 22-12]

[0549] [Table 22-13]

[0550] The structures of the compounds represented by formula [I'-16] and synthesized in Example 4 or in a similar manner to Example 4 are shown in the following table.

[0551] [ka]

[0552] [Table 23]

[0553] The structure of the compound represented by formula [I'-17], which was synthesized in the same manner as in Example 2, is shown in the following table.

[0554] [ka]

[0555] [Table 24]

[0556] The structure of the compound represented by formula [I'-18], which was synthesized in the same manner as in Example 2, is shown in the following table.

[0557] [ka]

[0558] [Table 25]

[0559] The structure of the compound represented by formula [I'-19], which was synthesized in the same manner as in Example 2, is shown in the following table.

[0560] [ka]

[0561] [Table 26]

[0562] The structure of the compound represented by formula [I'-20], which was synthesized in the same manner as in Example 1, is shown in the following table.

[0563] [ka]

[0564] [Table 27]

[0565] The structure of the compound represented by formula [I'-21], which was synthesized in the same manner as in Example 1, is shown in the following table.

[0566] [ka]

[0567] [Table 28]

[0568] The structure of the compound represented by formula [I'-22], which was synthesized in the same manner as in Example 2, is shown in the following table.

[0569] [ka]

[0570] [Table 29]

[0571] The structure of the compound represented by formula [I'-23], which was synthesized in the same manner as in Example 2, is shown in the following table.

[0572] [ka]

[0573] [Table 30]

[0574] The structure of the compound represented by formula [I'-24], which was synthesized in the same manner as in Example 2, is shown in the following table.

[0575] [ka]

[0576] [Table 31]

[0577] The structure of the compound represented by formula [I'-25], which was synthesized in the same manner as in Example 2, is shown in the following table.

[0578] [ka]

[0579] [Table 32]

[0580] The structure of the compound represented by formula [I'-26], which was synthesized in the same manner as in Example 2, is shown in the following table.

[0581] [ka]

[0582] [Table 33]

[0583] The structure of the compound represented by formula [I'-27], which was synthesized in the same manner as in Example 1, is shown in the following table.

[0584] [ka]

[0585] [Table 34]

[0586] The structure of the compound represented by formula [I'-28], which was synthesized in the same manner as in Example 1, is shown in the following table.

[0587] [ka]

[0588] [Table 35]

[0589] The structure of the compound represented by formula [I'-29], which was synthesized in the same manner as in Example 1, is shown in the following table.

[0590] [ka]

[0591] [Table 36]

[0592] The structure of the compound represented by formula [I'-30], which was synthesized by the method described in Example 5, is shown in the following table.

[0593] [ka]

[0594] [Table 37]

[0595] The structure of the compound represented by formula [I'-31], which was synthesized in the same manner as in Example 5, is shown in the following table.

[0596] [ka]

[0597] [Table 38]

[0598] The structure of the compound represented by formula [I'-32], which was synthesized in the same manner as in Example 1, is shown in the following table.

[0599] [ka]

[0600] [Table 39-1]

[0601] [Table 39-2]

[0602] [Table 39-3]

[0603] The structures of the compounds represented by formula [I'-32] and synthesized in Example 6 or in a similar manner to Example 6 are shown in the following table.

[0604] [ka]

[0605] [Table 40-1]

[0606] [Table 40-2]

[0607] The structure of the compound represented by formula [I'-33], which was synthesized in the same manner as in Example 1, is shown in the following table.

[0608] [ka]

[0609] [Table 41]

[0610] The structure of the compound represented by formula [I'-34], which was synthesized in the same manner as in Example 1, is shown in the following table.

[0611] [ka]

[0612] [Table 42-1]

[0613] [Table 42-2]

[0614] [Table 42-3]

[0615] [Table 42-4]

[0616] The structures of the compounds represented by formula [I'-34] in Example 7 or synthesized in a similar manner to Example 7 are shown in the following table.

[0617] [ka]

[0618] [Table 43]

[0619] The structure of the compound represented by formula [I'-35], which was synthesized in the same manner as in Example 1, is shown in the following table.

[0620] [ka]

[0621] [Table 44-1]

[0622] [Table 44-2]

[0623] [Table 44-3]

[0624] [Table 44-4]

[0625] [Table 44-5]

[0626] [Table 44-6]

[0627] The structure of the compound represented by formula [I'-36], which was synthesized in the same manner as in Example 1, is shown in the following table.

[0628] [ka]

[0629] [Table 45-1]

[0630] [Table 45-2]

[0631] [Table 45-3]

[0632] [Table 45-4]

[0633] [Table 45-5]

[0634] [Table 45-6]

[0635] [Table 45-7]

[0636] [Table 45-8]

[0637] The structure of the compound represented by formula [I'-37], which was synthesized in Example 8 or in a similar manner to Example 8, is shown in the following table.

[0638] [ka]

[0639] [Table 46]

[0640] The structures of the compounds represented by formula [I'-38] and synthesized in Example 9 or in a similar manner to Example 9 are shown in the following table.

[0641] [ka]

[0642] [Table 47]

[0643] The structure of the compound represented by formula [I'-39], which was synthesized in the same manner as in Example 9, is shown in the following table.

[0644] [ka]

[0645] [Table 48-1]

[0646] [Table 48-2]

[0647] [Table 48-3]

[0648] [Table 48-4]

[0649] The structure of the compound represented by formula [I'-40], which was synthesized in the same manner as in Example 9, is shown in the following table.

[0650] [ka]

[0651] (In the above formula [I'-40], The following formula [VII-2] -AA WC1 -AA WC2 -AA WC3 -AA WC4 -AA WC5 - [VII-2] The structure represented by In the compound represented by the formula [I'], W which is a "linker consisting of 1 to 3 amino acids" C is equivalent to Where: AA WC1 , A.A. WC2 , A.A. WC4 , and A.A. WC5 are each the same or differently selected from the group consisting of a single bond and (d)-Lys; AA WC3is Lys or (d)-Lys, AA WCS is a single bond or (d)-Lys.

[0652] [Table 49]

[0653] The high performance liquid chromatography mass spectrum (LCMS), retention time (RT), and analytical conditions of the compound of the present invention are shown in the following table.

[0654] [Table 50-1]

[0655] [Table 50-2]

[0656] [Table 50-3]

[0657] [Table 50-4]

[0658] [Table 50-5]

[0659] [Table 50-6]

[0660] [Table 50-7]

[0661]

Table 50-8

[0662]

Table 50-9

[0663]

Table 50-10

[0664]

Table 50-11

[0665]

Table 50-12

[0666]

Table 50-13

[0667]

Table 50-14

[0668]

Table 50-15

[0669]

Table 50-16

[0670]

Table 50-17

[0671] [Table 50-18]

[0672] [Table 50-19]

[0673] [Table 50-20]

[0674] [Table 50-21]

[0675] [Table 50-22]

[0676] [Table 50-23]

[0677] [Table 50-24]

[0678] [Table 50-25]

[0679] [Table 50-26]

[0680] 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 and 1-2. Test Example 1-1: Test to evaluate the inhibitory effect of each compound of the present invention on human MMP2 (Method 1) The human MMP2 inhibitory activity of each compound was measured 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 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. The human MMP2 activated by the reaction was poured into a 96-well microplate to a final concentration of 0.7 or 7 ng / mL. Each compound of the present invention diluted to various concentrations was then added and allowed to stand at room temperature for 15 minutes. Next, MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 was added to a final concentration of 5 or 16 μmol / L to initiate the enzyme reaction. After reacting at room temperature for 2 hours, the fluorescence intensity (Ex 320 nm / Em 400 nm) 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% inhibitory concentration (IC 50 The values ​​were calculated.

[0681] Enzyme inhibition rate (%) = [1-(AB) / (CB)]*100 A: Fluorescence value when compound was added B: Fluorescence value without addition of compound or enzyme C: Fluorescence value without compound addition Test Example 1-2: Evaluation test of the inhibitory effect of each compound of the present invention on human MMP2 (Method 2) The human MMP2 inhibitory activity of each compound was measured by 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 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. The human MMP2 activated by the reaction was poured into a 384-well microplate to a final concentration of 7 or 2.8 ng / mL. Each compound of the present invention diluted to various concentrations was then added and allowed to stand at room temperature for 10 minutes. Next, MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 was added to a final concentration of 16 or 5 μmol / L to initiate the enzyme reaction. After reacting at room temperature for 1 to 2 hours, the fluorescence intensity (Ex 320 nm / Em 405 nm) 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% inhibitory concentration (IC 50 The values ​​were calculated.

[0682] Enzyme inhibition rate (%) = [1-(AB) / (CB)]*100 A: Fluorescence value when compound was added B: Fluorescence value without addition of compound or enzyme C: Fluorescence value without compound addition The results of the inhibitory effect of the compounds of the present invention on human MMP2 enzyme activity are shown in the following table.

[0683] [Table 51-1]

[0684] [Table 51-2]

[0685]

Table 51-3

[0686]

Table 51-4

[0687]

Table 51-5

[0688]

Table 51-6

[0689]

Table 51-7

[0690]

Table 51-8

[0691]

Table 51-9

[0692]

Table 51-10

[0693]

Table 51-11

[0694]

Table 51-12

[0695]

Table 51-13

[0696] [Table 51-14]

[0697] [Table 51-15]

[0698] [Table 51-16]

[0699] [Table 51-17]

[0700] Moreover, the inhibitory effect of the compound of the present invention on each MMP can be measured by the methods described in Test Examples 2-9. Test Example 2: Test to evaluate the inhibitory effect of each compound of the present invention on human MMP1 The human MMP1 inhibitory activity of each compound is measured 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 4-Aminophenylmercuric acetate are 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 120 minutes. The human MMP1 activated by the reaction is poured into a 96-well microplate to a final concentration of 8 ng / mL. Each compound of the present invention diluted to various concentrations is then added and allowed to stand at room temperature for 15 minutes. Next, MOCAc-Lys-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 is added to a final concentration of 11 μmol / L to initiate the enzyme reaction. After reacting at room temperature for 1 hour, the fluorescence intensity (Ex 320 nm / Em 400 nm) is measured using a microplate reader. The enzyme inhibition rate (%) is calculated using the measured fluorescence value according to the following formula, and the 50% inhibitory concentration (IC 50 Calculate the value.

[0701] Enzyme inhibition rate (%) = [1-(AB) / (CB)]*100 A: Fluorescence value when compound was added B: Fluorescence value without addition of compound or enzyme C: Fluorescence value without compound addition Test Example 3: Test to evaluate the inhibitory effect of each compound of the present invention on human MMP3 The human MMP3 inhibitory activity of each compound is measured 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 chymotrypsin are 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 is added to 2 mmol / L to stop the reaction. The human MMP3 activated by the reaction is poured into a 96-well microplate to a final concentration of 52 ng / mL. Each compound of the present invention diluted to various concentrations is then added and allowed to stand at room temperature for 15 minutes. Next, MOCAc-Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg-Lys(Dnp)-NH2 is added to a final concentration of 26 μmol / L to initiate the enzyme reaction. After reacting at room temperature for 1 hour, the fluorescence intensity (Ex 320 nm / Em 400 nm) is measured using a microplate reader. The enzyme inhibition rate (%) is calculated using the measured fluorescence value according to the following formula, and the 50% inhibitory concentration (IC 50 Calculate the value.

[0702] Enzyme inhibition rate (%) = [1-(AB) / (CB)]*100 A: Fluorescence value when compound was added B: Fluorescence value without addition of compound or enzyme C: Fluorescence value without compound addition Test Example 4: Test to evaluate the inhibitory effect of each compound of the present invention on human MMP7 The human MMP7 inhibitory activity of each compound is measured 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 4-Aminophenylmercuric acetate are 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. The human MMP7 activated by the reaction is poured into a 96-well microplate to a final concentration of 18 ng / mL. Each compound of the present invention diluted to various concentrations is then added and allowed to stand at room temperature for 15 minutes. Next, MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 is added to a final concentration of 22 μmol / L to initiate the enzyme reaction. After reacting at room temperature for 1 hour, the fluorescence intensity (Ex 320 nm / Em 400 nm) is measured using a microplate reader. The enzyme inhibition rate (%) is calculated using the measured fluorescence value according to the following formula, and the 50% inhibitory concentration (IC 50 Calculate the value.

[0703] Enzyme inhibition rate (%) = [1-(AB) / (CB)]*100 A: Fluorescence value when compound was added B: Fluorescence value without addition of compound or enzyme C: Fluorescence value without compound addition Test Example 5: Test to evaluate the inhibitory effect of each compound of the present invention on human MMP8 The human MMP8 inhibitory activity of each compound is measured 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 4-Aminophenylmercuric acetate are 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. The human MMP8 activated by the reaction is poured into a 96-well microplate to a final concentration of 149 ng / mL. Each compound of the present invention diluted to various concentrations is then added and allowed to stand at room temperature for 15 minutes. Next, MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 is added to a final concentration of 25 μmol / L to initiate the enzyme reaction. After reacting at room temperature for 1 hour, the fluorescence intensity (Ex 320 nm / Em 400 nm) is measured using a microplate reader. The measured fluorescence value is used to calculate the enzyme inhibition rate (%) according to the following formula, and the 50% inhibitory concentration (IC 50 Calculate the value.

[0704] Enzyme inhibition rate (%) = [1-(AB) / (CB)]*100 A: Fluorescence value when compound was added B: Fluorescence value without addition of compound or enzyme C: Fluorescence value without compound addition Test Example 6: Test to evaluate the inhibitory effect of each compound of the present invention on human MMP9 The human MMP9 inhibitory activity of each compound is measured 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 4-Aminophenylmercuric acetate are 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. The human MMP9 activated by the reaction is poured into a 96-well microplate to a final concentration of 58 ng / mL. Each compound of the present invention diluted to various concentrations is then added and allowed to stand at room temperature for 15 minutes. Next, MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 is added to a final concentration of 3 μmol / L to initiate the enzyme reaction. After reacting at room temperature for 1 hour, the fluorescence intensity (Ex 320 nm / Em 400 nm) is measured using a microplate reader. The enzyme inhibition rate (%) is calculated using the measured fluorescence value according to the following formula, and the 50% inhibitory concentration (IC 50 Calculate the value.

[0705] Enzyme inhibition rate (%) = [1-(AB) / (CB)]*100 A: Fluorescence value when compound was added B: Fluorescence value without addition of compound or enzyme C: Fluorescence value without compound addition Test Example 7: Test to evaluate the inhibitory effect of each compound of the present invention on human MMP12 The human MMP12 inhibitory activity of each compound was measured 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 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 4 or 24 hours. The human MMP12 activated by the reaction was poured into a 96-well microplate to a final concentration of 17 or 5.2 ng / mL. Each compound of the present invention diluted to various concentrations was then added and allowed to stand at room temperature for 15 minutes. Next, MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 was added to a final concentration of 5 or 14 μmol / L to initiate the enzyme reaction. After reacting at room temperature for 1 hour, the fluorescence intensity (Ex 320 nm / Em 400 nm) 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% inhibitory concentration (IC 50 The values ​​were calculated.

[0706] Enzyme inhibition rate (%) = [1-(AB) / (CB)]*100 A: Fluorescence value when compound was added B: Fluorescence value without addition of compound or enzyme C: Fluorescence value without compound addition The results of the inhibitory effect of each of the compounds of the present invention on human MMP12 enzyme activity are shown in the table below.

[0707] [Table 52]

[0708] Test Example 8: Test to evaluate the inhibitory effect of each compound of the present invention on human MMP13 The human MMP13 inhibitory activity of each compound was measured 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 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 2 hours. The human MMP13 activated by the reaction was poured into a 96-well microplate to a final concentration of 5 ng / mL. Each compound of the present invention diluted to various concentrations was then added and allowed to stand at room temperature for 15 minutes. Next, MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 was added to a final concentration of 6 μmol / L to initiate the enzyme reaction. After reacting at room temperature for 1 hour, the fluorescence intensity (Ex 320 nm / Em 400 nm) was measured using a microplate reader. The measured fluorescence value was used to calculate the enzyme inhibition rate (%) according to the following formula, and the 50% inhibitory concentration (IC 50 The values ​​were calculated.

[0709] Enzyme inhibition rate (%) = [1-(AB) / (CB)]*100 A: Fluorescence value when compound was added B: Fluorescence value without addition of compound or enzyme C: Fluorescence value without compound addition The results of the inhibitory effect of each of the compounds of the present invention on human MMP13 enzyme activity are shown in the table below.

[0710] [Table 53]

[0711] Test Example 9: Test to evaluate the inhibitory effect of each compound of the present invention on human MMP14 The human MMP14 inhibitory activity of each compound is measured 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 trypsin are 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 for 25 minutes at room temperature, trypsin inhibitor is added to 25 μg / mL to stop the reaction. The human MMP14 activated by the reaction is poured into a 96-well microplate to a final concentration of 6 ng / mL. Furthermore, each compound of the present invention diluted to various concentrations is added and left to stand at room temperature for 15 minutes. Next, MOCAc-Lys-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 is added to a final concentration of 5 μmol / L to initiate the enzyme reaction. After reacting at room temperature for 1 hour, the fluorescence intensity (Ex 320 nm / Em 400 nm) is measured using a microplate reader. The enzyme inhibition rate (%) is calculated using the measured fluorescence value according to the following formula, and the 50% inhibitory concentration (IC 50 Calculate the value.

[0712] Enzyme inhibition rate (%) = [1-(AB) / (CB)]*100 A: Fluorescence value when compound was added B: Fluorescence value without addition of compound or enzyme C: Fluorescence value without compound addition [Industrial Applicability]

[0713] The compound of the present invention has an excellent effect of inhibiting MMP2, and the present invention makes it possible to provide pharmaceuticals that are effective in the prevention or treatment of cancer diseases, organ fibrosis, and symptoms associated with cancer diseases and organ fibrosis, which are expected to reduce the burden on patients and contribute to the development of the pharmaceutical industry.

Claims

1. The following formula [I'] 【Chemistry 1】 (In the above formula [I'], A.A. １ teeth, Asp, β-Asp, β-(d)-Asp, γ-Glu, or γ-(d)-Glu indicates, A.A. ２ teeth, Ala, The following formulas [IV-7], [IV-8], [IV-9], [IV-11], [IV-12] and [IV-13] 【Chemistry 2】 A group represented by The following formula [IV-27] 【Chemistry 3】 A group represented by Pro, a compound represented by the following formulas [II-1] and [II-2] 【Chemistry 4】 represents one group selected from the group consisting of groups represented by Here, R ＡＡ２ represents hydroxy or amino, Also, A.A. １ and A.A. ２ are taken together to form the following formula [IV-32] 【Chemistry 5】 It may have a structure represented by A.A. ３ teeth, Val, Leu, Ile, the following formula [IV-2] 【Chemistry 6】 A group represented by Phe, Trp, Tyr, Lys, the following formula [IV-3], [IV-4], [IV-5] 【Chemistry 7】 A group represented by the formula: The following formula [IV-9] 【Chemistry 8】 A group selected from the group consisting of groups represented by indicates, A.A. ４ teeth, Single bond, Gly, (d)-Ala, (N-Me)Ala, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, Pro, (d)-Pro, (N-Me)Phe, (d)-Phe, (N-Me)Tyr, (d)-Tyr, (N-Me)Ser, (d)-Ser, homoSer, (d)-Thr, Met, (N-Me)Met, (N-Me)Asp, Glu, (N-Me)Glu, (d)-(N-Me)Glu, homoGlu, (N-Me)Asn, (N-Me)Arg, (d)-Arg, The following formulas [IV-7], [IV-9] and [IV-13] 【Chemistry 9】 A group represented by Lys, and (N-Me)Lys indicates, Here, A.A. ４ When represents Lys, The amino acid of the side chain of the Lys is C, which is substituted with carboxy at the end. ２－１６ may be substituted with alkylcarbonyl; A.A. ５ teeth, Single bond, Ala, the following formula [IV-1] 【Chemistry 10】 A group represented by The following formulas [IV-27], [IV-28] and [IV-29] 【Chemistry 11】 A group represented by Pro, (d)-Pro, β-homoPro, homoPro, the following formula [II-1'] 【Chemistry 12】 A group represented by Phe, His, Thr, Arg, (d)-Arg, The following formulas [IV-7], [IV-9] and [IV-13] 【Chemistry 13】 A group represented by Lys, (d)-Lys, β-Ala, (N-Me)-β-Ala, GABA, Ape, Acp, The following formulas [III-6] to [III-13] 【Chemistry 14】 A group represented by The following formulas [IV-25] and [IV-26] 【Chemistry 15】 A group selected from the group consisting of groups represented by indicates, W １ Is, -L １ -or-L １ '-L １ "-" L １ indicates a single bond, L １ 'teeth, Single bond, β-Ala, GABA, (N-Me)GABA, Ape, Acp, The following formulas [III-6] to [III-13] 【Chemistry 16】 A group represented by The following formulas [IV-23] and [IV-24] 【Chemistry 17】 A group selected from the group consisting of groups represented by indicates, L １ "teeth, Single bond, Gly, (N-Me)Gly, Ala, (N-Me)Ala, (d)-Ala, Val, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, The following formula [IV-27] 【Chemistry 18】 A group represented by Pro, (d)-Pro, homoPro, Phe, (N-Me)Phe, (d)-Phe, His, (d)-His, Trp, (N-Me)Trp, (d)-Trp, Tyr, (N-Me)Tyr, (d)-Tyr, (d)-Ser, homoSer, Thr, (N-Me)Thr, (d)-Thr, Cys, (d)-Cys, Met, (N-Me)Met, (N-Me)Asp, Glu, (N-Me)Glu, (d)-Glu, Asn, (N-Me)Asn, (d)-Asn, Gln, (N-Me)Gln, (d)-Gln, Arg, (N-Me)Arg, (d)-Arg, Cit, (d)-Cit, The following formulas [IV-7], [IV-9], [IV-10] and [IV-13] 【Chemistry 19】 A group represented by Lys, (N-Me)Lys, (d)-Lys, the following formula [IV-14] 【Chemistry 20】 A group represented by β-Ala, β-Asp, β-(d)-Asp, The following formulas [III-6] and [III-7] 【Chemistry 21】 A group selected from the group consisting of groups represented by indicates, Here, L １ " represents Lys or (d)-Lys, The amino group in the side chain of the Lys and (d)-Lys may be substituted with a group represented by the following formula [VII-1]: FA Ｎ -AA Ｎ５ -AA Ｎ４ -AA Ｎ３ -AA Ｎ２ -AA Ｎ１ -[VII-1] In the formula [VII-1], F.A. Ｎ is a C terminally substituted with carboxy ２－１６ represents an alkylcarbonyl; A.A. Ｎ５ teeth, Single bond, Arg, (d)-Arg, Lys, (d)-Lys, γ-Glu, or The following formula [IV-24] 【Chemical 22】 A group represented by indicates, A.A. Ｎ４ teeth, Single bond, Arg, (d)-Arg, Lys, (d)-Lys, or The following formula [IV-24] 【Chemistry 23】 A group represented by indicates, A.A. Ｎ３ teeth, Single bond, Arg, (d)-Arg, Lys, (d)-Lys, γ-Glu, or The following formula [IV-24] 【Chemistry 24】 A group represented by indicates, A.A. Ｎ２ teeth, A single bond, or (d) -Lys indicates, A.A. Ｎ１ teeth, A single bond, or (d) -Lys indicates, Also, L １ " is represented by Glu, and AA ３ When represented by Lys, The compound represented by the formula [I'] has L bonded to the functional groups of the side chains of the two amino acids, as represented by the following formula [I'-α]. ３ can form a cyclic structure together with At this time, the L ３ represents Gly, β-Ala, or GABA, 【Chemistry 25】 L Ｎ１ is represented by the formula -C(=O)- or the formula -S(=O) ２ - indicates L Ｎ２ teeth, Single bond, C １－３ Alkanediyl, C ２－３ Alkene diyl, Ethyndiyl, Formula -O-, Formula -C(=O)-, Formula -C(=O)-NH-, or Triazolediyl indicates, L ２ indicates a single bond, Ring A represents an aromatic ring or a heteroaromatic ring; R Ａ１ , R Ａ２ is, independently, Hydrogen atoms, Halogen atoms, C １－６ Alkyl, or C １－６ Alkoxy indicates, Ring B is represents aryl or heteroaryl, R Ｂ１ , R Ｂ２ , R Ｂ３ is, independently, Hydrogen atoms, Carbamoyl, Cyano, Halogen atoms, C １－６ Alkyl (C １－６ The alkyl may be substituted with one hydroxyl.), haloC １－６ Alkyl, C １－６ Alkoxy (C １－６ The alkoxy may be substituted with one hydroxyl.), haloC １－６ Alkoxy, C １－６ Alkyl carbonyl, C １－６ Alkylcarbonylamino, Mono C １－６ Alkylaminocarbonyl, diC １－６ Alkylaminocarbonyl (The Mono C １－６ Alkylaminocarbonyl and diC １－６ The alkyl in the alkylaminocarbonyl may be substituted with one group selected from the group consisting of hydroxy, carboxy, carbamoyl, and amino. C １－６ Alkylsulfonyl, or Aryl indicates, W Ｃ is a linker consisting of a single bond or 1 to 3 amino acids, wherein the 1 to 3 amino acids forming the linker are Gly, Pro, Arg, (d)-Arg, Lys, (d)-Lys, β-Ala, GABA, and Ape each of which may be the same or different and is selected from the group consisting of Here, W Ｃ When the group represented by the formula (I) contains Lys or (d)-Lys, The amino acid in the side chain of the Lys and (d)-Lys is a C ２－１６ Alkylcarbonyl, Lys (the amino on the side chain of Lys is substituted with carboxy at the end) ２－１６ may be substituted with alkylcarbonyl; or (d)-Lys (the amino acid in the side chain of the (d)-Lys is a C ２－１６ may be substituted with alkylcarbonyl. may be substituted, R Ｃ is represented by the formula -OH, the formula -NH ２ , C １－６ Alkylamino (the C １－６ Alkylamino C １－６ Alkyl is hydroxy, amino, C １-６ alkoxy, and 4- to 7-membered saturated heterocyclyl containing one nitrogen atom and optionally containing one further heteroatom; or 4- to 7-membered saturated heterocyclyl containing one nitrogen atom and optionally containing one further heteroatom (the 4- to 7-membered saturated heterocyclyl containing one nitrogen atom and optionally containing one further heteroatom is hydroxy, amino, and C １－６ Alkyl (C １－６ The alkyl may be substituted with one group selected from the group consisting of: And, two carbon atoms in the 4- to 7-membered saturated heterocyclyl containing one nitrogen atom and optionally containing one heteroatom are C １－４ ) may be bridged with an alkanediyl. or a pharma- ceutically acceptable salt thereof.

2. W Ｃ but, Single bond, Pro, Arg, (d)-Arg, Lys, (d)-Lys, β-Ala, GABA, Ape, Gly-(d)-Lys, Gly-(d)-Lys-(d)-Lys, Gly-(d)-Lys-(d)-Arg, Gly-(d)-Arg-(d)-Lys, Lys-Lys, (d)-Lys-(d)-Lys, (d)-Lys-(d)-Lys-(d)-Lys, Arg-Arg, (d)-Arg-(d)-Arg, (d)-Arg-(d)-Lys, Lys-(d)-Lys-(d)-Lys, (d)-Lys-Lys-(d)-Lys, (d)-Lys-(d)-Lys-Lys, β-Ala-(d)-Lys, β-Ala-(d)-Lys-(d)-Arg, β-Ala-(d)-Arg-(d)-Lys, or β-Ala-(d)-Arg-(d)-Arg And, Here, W Ｃ When the group represented by the formula: contains Lys, The amino acid in the side chain of the Lys is a C ２－１６ Alkylcarbonyl or (d)-Lys (the amino acid in the side chain of the (d)-Lys is a C ２－１６ may be substituted with alkylcarbonyl. may be substituted, 2. The substituted polypeptide of claim 1 or a pharma- ceutically acceptable salt thereof.

3. Ring A is a benzene ring, a thiophene ring, or a pyridine ring; R Ａ１ , R Ａ２ But independently, A hydrogen atom, or Halogen atoms and Ring B is phenyl, oxazolyl, thiadiazolyl, pyridyl, or benzofuranyl; R Ｂ１ , R Ｂ２ , R Ｂ３ But independently, Hydrogen atoms, Carbamoyl, Cyano, Halogen atoms, C １－６ Alkyl (C １－６ The alkyl may be substituted with one hydroxyl.), haloC １－６ Alkyl, C １－６ Alkoxy (C １－６ The alkoxy may be substituted with one hydroxyl.), haloC １－６ Alkoxy, C １－６ Alkyl carbonyl, Mono C １－６ Alkylaminocarbonyl, diC １－６ Alkylaminocarbonyl (The Mono C １－６ Alkylaminocarbonyl and diC １－６ The alkyl in the alkylaminocarbonyl may be substituted with one group selected from the group consisting of hydroxy, carboxy, carbamoyl, and amino; or C １－６ Alkyl sulfonyl and R Ｃ is represented by the formula -OH, -NH ２ , C １－６ Alkylamino (the C １－６ Alkylamino C １－６ Alkyl is hydroxy, amino, C １-６ may be substituted with one group selected from the group consisting of alkoxy and morpholinyl; Azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl, where the azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl are selected from the group consisting of hydroxy, amino, and C １－６ Alkyl (C １－６ The alkyl may be substituted with one group selected from the group consisting of: and two carbon atoms in the azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl are C １－４ and optionally bridged with an alkanediyl.

3. A substituted polypeptide according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof.

4. In the substituted polypeptide represented by the formula [I'], Ring A is a benzene ring; Ring B is phenyl; L １ "but, Single bond, Gly, (N-Me)Gly, Ala, (N-Me)Ala, (d)-Ala, Val, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, The following formula [IV-27] 【Chemistry 26】 A group represented by Pro, (d)-Pro, homoPro, Phe, (N-Me)Phe, (d)-Phe, His, (d)-His, Trp, (N-Me)Trp, (d)-Trp, Tyr, (N-Me)Tyr, (d)-Tyr, (d)-Ser, homoSer, Thr, (N-Me)Thr, (d)-Thr, Cys, (d)-Cys, Met, (N-Me)Met, (N-Me)Asp, Glu, (N-Me)Glu, (d)-Glu, Asn, (N-Me)Asn, (d)-Asn, Gln, (N-Me)Gln, (d)-Gln, Arg, (N-Me)Arg, (d)-Arg, Cit, (d)-Cit, The following formulas [IV-7], [IV-9], [IV-10] and [IV-13] 【Chemical 27】 A group represented by Lys, (N-Me)Lys, (d)-Lys, the following formula [IV-14] 【Chemistry 28】 A group represented by β-Ala, β-Asp, β-(d)-Asp, The following formulas [III-6] and [III-7] 【Chemical 29】 A group selected from the group consisting of groups represented by and W Ｃ but, Single bond, Pro, Arg, (d)-Arg, Lys, (d)-Lys, β-Ala, GABA, Ape, Gly-(d)-Lys, Gly-(d)-Lys-(d)-Lys, Gly-(d)-Lys-(d)-Arg, Gly-(d)-Arg-(d)-Lys, Lys-Lys, (d)-Lys-(d)-Lys, (d)-Lys-(d)-Lys-(d)-Lys, Arg-Arg, (d)-Arg-(d)-Arg, (d)-Arg-(d)-Lys, Lys-(d)-Lys-(d)-Lys, (d)-Lys-Lys-(d)-Lys, (d)-Lys-(d)-Lys-Lys, β-Ala-(d)-Lys, β-Ala-(d)-Lys-(d)-Arg, β-Ala-(d)-Arg-(d)-Lys, or β-Ala-(d)-Arg-(d)-Arg The substituted polypeptide according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof.

5. In the substituted polypeptide represented by the formula [I'], A.A. ２ is represented by the following formula [II-1] 【Chemistry 30】 A group represented by The following formulas [IV-7], [IV-8], [IV-9], [IV-11], and [IV-12] 【Chemistry 31】 is a group selected from the group consisting of groups represented by Here, R ＡＡ２ is amino, A.A. ３ is Val, Leu, Ile, Phe, or Trp; A.A. ４ is (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Asp, or (N-Me)Glu; A.A. ５ is β-Ala, GABA, Ape, Acp, Pro, (d)-Pro, or β-homoPro; W Ｃ is a single bond, Arg, (d)-Arg, Lys, or (d)-Lys; R Ｃ is represented by the formula -OH or the formula -NH ２ The substituted polypeptide according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof,

6. In the substituted polypeptide represented by the formula [I'], W １ But, -L １ '-L １ "- and L ２ is a single bond, A.A. １ is Asp, L １ ' is β-Ala, GABA, Ape, Acp, the following formula [IV-23] and [IV-24] 【Chemistry 32】 A group selected from the group consisting of groups represented by and L １ " is a single bond, Asn, (d)-Ser, (d)-Thr, or Glu; L Ｎ１ Formula -C(=O)- or Formula -S(=O) ２ - and L Ｎ２ is of the formula -O- or -C(=O)-NH-, R Ａ１ , R Ａ２ are hydrogen atoms, R Ｂ１ , R Ｂ２ , R Ｂ３ are independently a hydrogen atom, a carbamoyl group, a halogen atom, or １－６ Alkoxy or haloC １－６ Alkoxy The substituted polypeptide according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein:

7. In the substituted polypeptide represented by the formula [I'], W １ But, -L １ -, where L １ is a single bond, L ２ is a single bond, A.A. １ is β-Asp, β-(d)-Asp, γ-Glu, or γ-(d)-Glu, A.A. ２ is represented by the following formula [II-1] 【Chemical 33】 A group represented by The following formulas [IV-7], [IV-8], [IV-9], [IV-11], and [IV-12] 【Chemical 34】 is a group selected from the group consisting of groups represented by Here, R ＡＡ２ is amino, A.A. ３ is Val, Leu, Ile, Phe, or Trp; A.A. ４ is (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Asp, or (N-Me)Glu; A.A. ５ is β-Ala, GABA, Ape, Acp, or β-homoPro; L Ｎ１ Formula -C(=O)- or Formula -S(=O) ２ - and L Ｎ２ is a single bond, a group of the formula -O- or a group of the formula -C(=O)-NH-; R Ａ１ , R Ａ２ are hydrogen atoms, R Ｂ１ , R Ｂ２ , R Ｂ３ are independently a hydrogen atom, a carbamoyl group, a halogen atom, or １－６ Alkoxy or haloC １－６ Alkoxy The substituted polypeptide according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein:

8. The substituted polypeptide represented by the formula [I'] The following formula [I] 【Chemistry 35】 A substituted polypeptide represented by In the above formula [I], A.A. １ is β-Asp, γ-Glu, or γ-(d)-Glu, A.A. ２ is represented by the following formula [II-1] or formula [II-2] 【Chemical 36】 A group represented by and Here, R ＡＡ２ is hydroxy or amino, A.A. ３ is Val, Leu, Ile, Phe, or Trp; 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, AA ５ is a single bond, Pro, (d)-Pro, β-homoPro, Arg, (d)-Arg, Lys, (d)-Lys, β-Ala, GABA, Ape, or Acp, L １ is a single bond, L ２ is a single bond, L Ｎ１ is represented by the formula -C(=O)- or the formula -S(=O) ２ - and L Ｎ２ is a single bond, C １－３ alkanediyl, of the formula -O-, or of the formula -C(=O)-NH-; R Ａ is a hydrogen atom, a halogen atom, C １－６ Alkyl, or C １－６ is an alkoxy; R Ｂ is a hydrogen atom, a carbamoyl, a halogen atom, １－６ Alkyl, or C １－６ is an alkoxy; L Ｃ is a single bond, Pro, Arg, (d)-Arg, Lys, (d)-Lys, or (d)-Lys-(d)-Lys; R Ｃ is represented by the formula -OH or the formula -NH ２ The substituted polypeptide according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof,

9. In the substituted polypeptide represented by the formula [I'], A.A. １ is Asp, β-(d)-Asp, or γ-(d)-Glu; A.A. ２ is represented by the following formula [II-1] 【Chemical 37】 A group represented by The following formulas [IV-7] and [IV-9] 【Chemical Formula 38】 A group selected from the group consisting of groups represented by and Here, R ＡＡ２ is amino, A.A. ３ is Val, Leu, or Ile; A.A. ４ is (N-Me)Ile or (N-Me)Glu, A.A. ５ is Ape or β-homoPro, W １ But, -L １ -or-L １ '-L １ "- and Where: L １ is a single bond, L １ ' is GABA or Ape, L １ " is Asn, (d)-Ser, (d)-Thr, or Glu, L Ｎ１ Formula -C(=O)- or Formula -S(=O) ２ - and L Ｎ２ is of the formula -O- or -C(=O)-NH-, R Ａ１ , R Ａ２ are hydrogen atoms, R Ｂ１ , R Ｂ２ , R Ｂ３ are independently a hydrogen atom, a carbamoyl group, a halogen atom, or １－６ Alkoxy or haloC １－６ is an alkoxy; W Ｃ is a single bond or (d)-Lys; R Ｃ is represented by the formula -NH ２ The substituted polypeptide according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein:

10. A substituted polypeptide or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 5, selected from the following compounds: 【Chemistry 39-1】 【Chemistry 39-2】 【Chemistry 39-3】

11. A pharmaceutical comprising the substituted polypeptide or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 10 as an active ingredient.

12. 11. An MMP2 inhibitor comprising, as an active ingredient, the substituted polypeptide according to any one of claims 1 to 10 or a pharma- ceutically acceptable salt thereof.

13. A preventive or therapeutic agent for cancer disease or organ fibrosis, or a symptom associated with cancer disease or organ fibrosis, comprising as an active ingredient the substituted polypeptide according to any one of claims 1 to 10 or a pharma- ceutically acceptable salt thereof.

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