Cyclic compounds exhibiting selective KRAS inhibitory activity against HRAS and NRAS.

Abstract

This invention provides cyclic compounds effective against RAS-mutated cancers, as well as non-natural amino acids and peptide compounds useful for their production, particularly peptide compounds that exhibit sufficiently selective KRAS inhibitory activity against HRAS and NRAS. [Solution] The present invention provides a cyclic compound having a specific amino acid sequence that interacts with and selectively inhibits amino acid residues specific to KRAS, or a salt thereof, or a solvate thereof. The pharmacological effect of the cyclic compound is to inhibit the proliferation of tumor cells having RAS mutations.

Description

[Technical Field]

[0001] In one aspect, the present invention relates to a cyclic compound having selective KRAS inhibitory activity against HRAS and NRAS. [Background technology]

[0002] RAS is a protein belonging to the small GTPase family, with KRAS, NRAS, and HRAS being known. The activation or inactivation state of RAS is determined by its binding state to GDP or GTP. It is activated by the exchange reaction of GDP to GTP by GEF (guanine nucleotide exchange factor) and inactivated by the hydrolysis reaction of GTP by GAP (GTPase-activating proteins) (Non-Patent Literature 1). Activated RAS induces cell proliferation, survival, and differentiation by activating various downstream signals such as the MAPK pathway, PI3K / Akt pathway, and RAL pathway, and constitutive activation of RAS plays an important role in the development and progression of cancer. In cancer, the RAS-RAF-MEK-ERK pathway is known to be activated by the activation of upstream signals of RAS, constitutive activation of RAS, and / or activating mutations of RAS (Non-Patent Literature 2). These activating mutations of RAS have been found in numerous cancer types. G12, G13, and Q61 are known as hotspots for RAS mutations, with G12 frequently occurring in KRAS and Q61 frequently occurring in NRAS. These mutations are also known to be associated with patient prognosis (Non-Patent Literature 3).

[0003] On the other hand, access to tough targets, such as inhibition of protein-protein interactions, may be superior for medium-sized molecules (molecular weight 500-2000 g / mol) compared to small molecules. Furthermore, medium-sized molecules may be superior to antibodies in that they can be transported into cells. Among physiologically active medium-sized molecules, peptide drugs are highly valuable molecular species, with more than 40 types already on the market (Non-Patent Literature 4). Representative examples of these peptide drugs include cyclosporine A and polymyxin B. These are peptides that contain several non-natural amino acids. Non-natural amino acids are amino acids that are not naturally encoded on mRNA, and it is very interesting that naturally derived cyclosporine A and polymyxin B contain non-natural amino acids.

[0004] Since the discovery of the usefulness of naturally derived peptides as medicines, attention has been focused on peptides that possess pharmacological activity and can be absorbed by living organisms, and those with molecular weights of around 500 to 2000 g / mol have been actively researched (Non-Patent Literature 5).

[0005] Conditions for improving membrane permeability and metabolic stability (conditions necessary to satisfy drug-likeness) that can contribute to the improvement of the pharmacokinetics of medium-sized peptides have been reported (Patent Document 1).

[0006] Furthermore, the conditions necessary to satisfy the drug-like characteristics of cyclic peptides have been identified as conditions under which medium-sized peptides can contribute to improved pharmacokinetics (Patent Document 2).

[0007] Peptides that bind to RAS have been identified, and the binding sites of cyclic peptides to RAS have been analyzed by X-ray crystallography (Non-Patent Documents 6, 7, and 8). In addition, cyclic peptides suggesting inhibition of binding between RAS and SOS have been found (Patent Document 3). Furthermore, in competitive assays for the binding of specific compounds to RAS, cyclic peptides suggesting inhibition of binding to RAS have been identified (Patent Document 4). [Prior art documents] [Chartered documents]

[0008]

Patent Document 1

Patent document 2

Patent document 3

Patent document 4

Non-licensed literature

[0009]

Non-licensed literature 1

Non-licensed Document 2

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

[0010] This invention relates to cyclic compounds effective against RAS-mutated cancers and to unnatural amino acids and peptide compounds useful for their production. While Patent Documents 1 and 2 describe drug-like peptides, they do not describe peptides that have antitumor effects against cancers, including RAS-mutated cancers. Patent document 3 describes the inhibition of RAS-SOS binding, and patent document 4 describes peptides that compete with compounds that bind to RAS. However, these cited documents do not show pharmacological effects, particularly effects on tumor cells. Furthermore, these cited documents do not describe drug-like peptides.

[0011] Non-patent document 1 details the relationship between RAS and cancer. This document describes molecules that bind to RAS and have shown efficacy in preclinical studies, but no compounds have been shown to have specific efficacy against RAS-mutated cancers as pharmaceuticals, nor have any drug-like cyclic peptides been disclosed. Non-patent document 2 provides a detailed description of the RAS and the downstream RAF-MEK-ERK pathway. While this document suggests the possibility of treating RAS-mutated cancers with inhibitors of RAF, MEK, and ERK, it does not identify any compounds that directly inhibit the RAS. Non-patent document 3 describes a compound that binds to the GTP / GDP binding site of RAS and inhibits RAS function, as well as its mechanism of action. While this document details the interaction with the GTP / GDP binding site, it does not describe the pharmacological effects, particularly those on tumor cells. Non-patent document 4 describes peptides used as pharmaceuticals, but it does not describe drug-like peptides or peptides useful for RAS-mutated cancers. Non-patent document 5 describes the molecular form and pharmacokinetics of cyclic peptides, but does not describe any compounds useful for RAS-mutated cancers. Non-patent documents 6-8 describe peptides that bind to RAS, but their effects on tumor cells are limited, and there is no mention of drug-like peptides.

[0012] Furthermore, to the best of our knowledge, there are no reported examples of compounds that exhibit sufficiently selective KRAS inhibitory activity against HRAS and NRAS. [Means for solving the problem]

[0013] The inventors diligently searched for cyclic compounds that selectively inhibit KRAS against HRAS and NRAS, and as a result, found a cyclic compound that selectively interacts with KRAS compared to HRAS and NRAS. In addition, they found that this cyclic compound has a pharmacological effect of inhibiting the proliferation of tumor cells with RAS mutations.

[0014] In a non-limiting specific embodiment, the present invention includes the following: [1] Formula (1): [ka] A cyclic compound represented by, or a salt thereof, or a solvate thereof, During the ceremony, L1 is a single bond; R1 is either a C1-C7 alkyl group, or R1 together with R5 forms a divalent group, in which case the substructure in the cyclic compound represented by formula (1): *-CR1Q1-L1-CO-NP2-CR2Q2-CO-NP3-CR3Q3-CO-NP4-CR4Q4-CO-NP5-CR5Q5-* is represented by the following formula: [ka] It is expressed as follows, in the formula: X2 is -L1-CO-NP2-CR2Q2-CO-NP3-CR3Q3-CO-NP4-CR4Q4-CO-NP5-, [ka] These are single or double bonds, [ka] teeth, [ka] This means that if it is a double bond, it can have either E or Z stereochemistry. n is 0, 1, or 2. m is 0, 1, 2, 3, or 4. * indicates a bond point with an adjacent atom; P1 is a C1-C6 alkyl group; Q1 is hydrogen; R2 is a C1-C6 alkyl group; P2 is hydrogen; Q2 is hydrogen; R3 is either hydrogen, or R3, together with P3, the carbon atom to which R3 is bonded, and the nitrogen atom to which P3 is bonded, forms a 4- to 7-membered saturated heterocycle; Unless R3 and P3 form a 4- to 7-membered saturated heterocycle, P3 is a C1- to C6 alkyl or a C3- to C8 cycloalkyl; Q3 is hydrogen; R4, together with P5, forms a divalent group, in which case the substructure *-CR4Q4-CO-NP5-* in the cyclic compound represented by formula (1) is given by the following formula: [ka] It is represented by; P4 is a C1-C6 alkyl group; Q4 is hydrogen, R5 is a benzyl that may be substituted with one or more groups selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, and C3-C8 cycloalkyl, except when R1 and R5 form a divalent group; Q5 is hydrogen, R6 is hydrogen; P6 is a C1-C6 alkyl group. Q6 is hydrogen, R7 is a phenethyl that may be substituted with one or more groups independently selected from the group consisting of halogens, C1-C6 haloalkyls, and C1-C6 alkoxys; P7 is hydrogen, Q7 is hydrogen, R8, together with P8, the carbon atom to which R8 is bonded, and the nitrogen atom to which P8 is bonded, forms a 4-7 membered saturated heterocycle, which may be substituted with C1-C6 alkoxy groups; Q8 is hydrogen, R9, together with Q9 and the carbon atoms to which R9 and Q9 are bonded, forms a 3- to 8-membered alicyclic ring, which may be substituted with one or more C1-C6 alkyl groups; P9 is hydrogen or a C1-C6 alkyl group. R 10 These are C1-C6 alkyl or C3-C8 cycloalkyl groups; P 10 These are C1-C6 alkyl groups, Q 10 is hydrogen, and L 11 It is -CH2-, R 11 These are diC1-C6 alkylaminocarbonyl or 4-8 membered cyclic aminocarbonyl; P 11 These are C1-C6 alkyl groups, Q 11 It is hydrogen, The cyclic compound represented by formula (1) is PP1574: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-Cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-N-ethyl-27-isobutyl-N,4,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 dotetracont-38-en-17,1'-cyclopentane]-23-carboxamide, PP1650: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-Cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-27-isobutyl-N,N,3',3',4,19,22,26,32,35-decamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 dotetracont-38-en-17,1'-cyclobutane]-23-carboxamide, PP1827: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-Cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-N-ethyl-N,3,18,21,25,31,34-heptamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13]Pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-22-carboxamide, PP1830: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3',3',18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]Pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-22-carboxamide, PP2093: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-N,N,3',3',4,19,22,26,35-nonamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-23-carboxamide, PP2260: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3',3',18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]Pentapentaconta-37,43(54),44,46(53)-tetraene-16,1'-cyclobutane]-22-carboxamide, PP2316: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,16,19,22,26,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-23-carboxamide, PP2320: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaoxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 Pentatetraconta-42-ene-23,1'-cyclobutane]-17-carboxamide, PP2328: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,16,19,22,26,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-23-carboxamide, PP2574: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13]Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, PP2576: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, PP2583: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3',3',18,21,25,34-heptamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, PP2687: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-2-[(4-ethylphenyl)methyl]-27-isobutyl-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,3',3',4,19,22,26,32,35-decamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-23-carboxamide, PP2691: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-2-[(4-cyclopropylphenyl)methyl]-12-ethoxy-27-isobutyl-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,3',3',4,19,22,26,32,35-decamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-23-carboxamide, PP2957: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,34-pentamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13]Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, PP3033: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]Pentapentaconta-37,43(54),44,46(53)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecaone, PP3034: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]Pentapentaconta-37,43(54),44,46(53)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecaone, PP3036: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]Tetrapentaconta-37,43(53),44,46(52)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, PP3037: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]Tetrapentaconta-37,43(53),44,46(52)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, PP3047: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-7-[2-(3,4-dichlorophenyl)ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13]Pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undaone, PP3093: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.9.2 43,46 .1 35,41 .0 9,13 ]tripentaconta-37,43(52),44,46(51)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,53-undaone, PP3094: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-11-propoxy-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.9.2 43,46 .1 35,41 .0 9,13 ]tripentaconta-37,43(52),44,46(51)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,53-undaone, PP3095: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3096: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3097: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3098: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3099: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 ]Pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undaone, PP3100: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-13-propyl-38-(p-tolylmethyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 ]Pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undaone, PP3101: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-17-(pyrrolidine-1-carbonyl)-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 ]Pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undaone, PP3102: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-38-(p-tolylmethyl)-17-(pyrrolidine-1-carbonyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30]Pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undaone, PP3103: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3104: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3105: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrroridine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3106: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3110: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazaltricyclo[34.5.1.0 10,14]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3111: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3112: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3113: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3114: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 ]Pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undaone, PP3115: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-13-propyl-38-(p-tolylmethyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30]Pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undaone, PP3116: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-17-(pyrrolidine-1-carbonyl)-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 ]Pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undaone, PP3117: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-38-(p-tolylmethyl)-17-(pyrrolidine-1-carbonyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 ]Pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undaone, PP3118: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3119: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3120: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14Dotetracont-38-en-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecone, PP3121: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 Dotetracont-38-en-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecone, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-N-ethyl-N,3,18,21,25,31,34-heptamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 Pentapentacont-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-22-carboxamide, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-Cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3',3',18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-22-carboxamide, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-Cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41.0 9,13 ]Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3',3',18,21,25,34-heptamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-31-Cyclopropyl-7-[2-[3,5-Difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-Ethoxy-19-(1-ethylpropyl)-3,18,21,25,34-Pentamethyl-29-[(1S)-1-methylpropyl]-22-(Pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-Undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undekaone, and (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-7-[2-(3,4-dichlorophenyl)ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undaone A cyclic compound, or a salt thereof, or a solvate thereof, selected from the group consisting of the following. [2] The above equation (1) is, equation (2): [ka] (In the formula, [ka] n, m, P1, R2, R3, P3, P4, P6, R7, R8, P8, R9, P9, Q9, R 10 , P 10 , R 11 , and P 11 This is represented by (which has the same meaning as [1]), The cyclic compound represented by formula (2) is PP1827: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-N-ethyl-N,3,18,21,25,31,34-heptamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46.1 35,41 .0 9,13 ]Pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-22-carboxamide, PP1830: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3',3',18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]Pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-22-carboxamide, PP2260: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3',3',18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]Pentapentaconta-37,43(54),44,46(53)-tetraene-16,1'-cyclobutane]-22-carboxamide, PP2574: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, PP2576: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, PP2583: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3',3',18,21,25,34-heptamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, PP2957: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,34-pentamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, PP3033: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.243,46 .1 35,41 .0 9,13 ]Pentapentaconta-37,43(54),44,46(53)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecaone, PP3034: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]Pentapentaconta-37,43(54),44,46(53)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecaone, PP3036: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]Tetrapentaconta-37,43(53),44,46(52)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, PP3037: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]Tetrapentaconta-37,43(53),44,46(52)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, PP3047: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-7-[2-(3,4-dichlorophenyl)ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]Pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undaone, PP3093: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.9.2 43,46 .1 35,41 .09,13 ]tripentaconta-37,43(52),44,46(51)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,53-undaone, PP3094: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-11-propoxy-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.9.2 43,46 .1 35,41 .0 9,13 ]tripentaconta-37,43(52),44,46(51)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,53-undaone, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-N-ethyl-N,3,18,21,25,31,34-heptamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]Pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-22-carboxamide, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3',3',18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxospiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]Pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-22-carboxamide, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41.0 9,13 ]Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3',3',18,21,25,34-heptamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-31-Cyclopropyl-7-[2-[3,5-Difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-Ethoxy-19-(1-ethylpropyl)-3,18,21,25,34-Pentamethyl-29-[(1S)-1-methylpropyl]-22-(Pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-Undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undekaone, and (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-7-[2-(3,4-dichlorophenyl)ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undaone A cyclic compound as described in [1], or a salt thereof, or a solvate thereof, selected from the group consisting of the above. [3] Equation (1) above is Equation (3): [ka] (In the formula, R1 is a C1-C7 alkyl group; R5 is a benzyl which may be substituted with one or more groups selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, and C3-C8 cycloalkyl; [ka] n, m, P1, R2, R3, P3, P4, P6, R7, R8, P8, R9, P9, Q9, R 10 , P 10 , R 11 , and P 11 This is represented by (which has the same meaning as [1]), The cyclic compound represented by formula (3) is PP1574: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-N-ethyl-27-isobutyl-N,4,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclopentane]-23-carboxamide, PP1650: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-27-isobutyl-N,N,3',3',4,19,22,26,32,35-decamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-23-carboxamide, PP2093: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-N,N,3',3',4,19,22,26,35-nonamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14]dotetraconta-38-ene-17,1'-cyclobutane]-23-carboxamide, PP2316: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,16,19,22,26,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-23-carboxamide, PP2320: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaoxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 Pentatetraconta-42-ene-23,1'-cyclobutane]-17-carboxamide, PP2328: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,16,19,22,26,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-23-carboxamide, PP2687: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-2-[(4-ethylphenyl)methyl]-27-isobutyl-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,3',3',4,19,22,26,32,35-decamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-23-carboxamide, PP2691: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-2-[(4-cyclopropylphenyl)methyl]-12-ethoxy-27-isobutyl-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,3',3',4,19,22,26,32,35-decamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14]dotetraconta-38-ene-17,1'-cyclobutane]-23-carboxamide, PP3095: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3096: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3097: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3098: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3099: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30]Pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undaone, PP3100: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-13-propyl-38-(p-tolylmethyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 ]Pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undaone, PP3101: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-17-(pyrrolidine-1-carbonyl)-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 ]Pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undaone, PP3102: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-38-(p-tolylmethyl)-17-(pyrrolidine-1-carbonyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 ]Pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undaone, PP3103: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3104: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3105: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrroridine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3106: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3110: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazaltricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3111: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3112: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3113: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3114: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 ]Pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undaone, PP3115: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-13-propyl-38-(p-tolylmethyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 ]Pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undaone, PP3116: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-17-(pyrrolidine-1-carbonyl)-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 ]Pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undaone, PP3117: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-38-(p-tolylmethyl)-17-(pyrrolidine-1-carbonyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .026,30 ]Pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undaone, PP3118: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3119: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3120: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undekaone, and PP3121: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undekaone A cyclic compound as described in [1], or a salt thereof, or a solvate thereof, selected from the group consisting of the above. [4-1] PP1574: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-N-ethyl-27-isobutyl-N,4,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 A cyclic compound that is ]dotetraconta-38-ene-17,1'-cyclopentane]-23-carboxamide, or a salt thereof or a solvate thereof. [4-2] PP1650: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-27-isobutyl-N,N,3',3',4,19,22,26,32,35-decamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 A cyclic compound that is ]dotetraconta-38-ene-17,1'-cyclobutane]-23-carboxamide, or a salt thereof or a solvate thereof. [4-3] PP1827: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-N-ethyl-N,3,18,21,25,31,34-heptamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 A cyclic compound that is pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-22-carboxamide, or a salt thereof or a solvate thereof. [4-4] PP1830: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3',3',18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 A cyclic compound that is pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-22-carboxamide, or a salt thereof or a solvate thereof. [4-5] PP2093: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-N,N,3',3',4,19,22,26,35-nonamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 A cyclic compound that is ]dotetraconta-38-ene-17,1'-cyclobutane]-23-carboxamide, or a salt thereof or a solvate thereof. [4-6] PP2260: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3',3',18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 A cyclic compound that is pentapentaconta-37,43(54),44,46(53)-tetraene-16,1'-cyclobutane]-22-carboxamide, or a salt thereof or a solvate thereof. [4-7] PP2316: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,16,19,22,26,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 A cyclic compound that is ]dotetraconta-38-ene-17,1'-cyclobutane]-23-carboxamide, or a salt thereof or a solvate thereof. [4-8] PP2320: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaoxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 A cyclic compound that is pentatetraconta-42-ene-23,1'-cyclobutane]-17-carboxamide, or a salt thereof or a solvate thereof. [4-9] PP2328: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,16,19,22,26,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 A cyclic compound that is ]dotetraconta-38-ene-17,1'-cyclobutane]-23-carboxamide, or a salt thereof or a solvate thereof. [4-10] PP2574: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 A cyclic compound that is tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, or a salt thereof or a solvate thereof. [4-11] PP2576: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 A cyclic compound that is tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, or a salt thereof or a solvate thereof. [4-12] PP2583: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3',3',18,21,25,34-heptamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 A cyclic compound that is tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, or a salt thereof or a solvate thereof. [4-13] PP2687: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-2-[(4-ethylphenyl)methyl]-27-isobutyl-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,3',3',4,19,22,26,32,35-decamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 A cyclic compound that is ]dotetraconta-38-ene-17,1'-cyclobutane]-23-carboxamide, or a salt thereof or a solvate thereof. [4-14] PP2691: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-2-[(4-cyclopropylphenyl)methyl]-12-ethoxy-27-isobutyl-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,3',3',4,19,22,26,32,35-decamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 A cyclic compound that is ]dotetraconta-38-ene-17,1'-cyclobutane]-23-carboxamide, or a salt thereof or a solvate thereof. [4-15] PP2957: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,34-pentamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.243,46 .1 35,41 .0 9,13 A cyclic compound that is tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, or a salt thereof or a solvate thereof. [4-16] PP3033: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 A cyclic compound that is pentapentaconta-37,43(54),44,46(53)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undekaone, or a salt thereof or a solvate thereof. [4-17] PP3034: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 A cyclic compound that is pentapentaconta-37,43(54),44,46(53)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undekaone, or a salt thereof or a solvate thereof. [4-18] PP3036: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 A cyclic compound that is tetrapentaconta-37,43(53),44,46(52)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undekaone, or a salt thereof or a solvate thereof. [4-19] PP3037: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 A cyclic compound that is tetrapentaconta-37,43(53),44,46(52)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undekaone, or a salt thereof or a solvate thereof. [4-20] PP3047: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-7-[2-(3,4-dichlorophenyl)ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 A cyclic compound that is ]pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecaone, or a salt thereof or a solvate thereof. [4-21] PP3093: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.9.2 43,46 .1 35,41 .0 9,13 A cyclic compound that is tripentaconta-37,43(52),44,46(51)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,53-undecaone, or a salt thereof or a solvate thereof. 〔4-22〕PP3094: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-Cyclopentyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-11-propoxy-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.9.2 43,46 .1 35,41 .0 9,13 tricyclo[3.3.1.0 〔4-23〕PP3095: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-Cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 tetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecaone, or a salt thereof or a solvate thereof. [4-24] PP3096: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 A cyclic compound that is ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecaone, or a salt thereof or a solvate thereof. [4-25] PP3097: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 A cyclic compound that is ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecaone, or a salt thereof or a solvate thereof. [4-26] PP3098: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 A cyclic compound that is ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecaone, or a salt thereof or a solvate thereof. [4-27] PP3099: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 A cyclic compound that is pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecaone, or a salt thereof or a solvate thereof. [4-28] PP3100: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-Cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-13-propyl-38-(p-tolylmethyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 pentatetracont-42-en-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecaone cyclic compound, or a salt thereof or a solvate thereof. [4-29] PP3101: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-Cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-17-(pyrrolidine-1-carbonyl)-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 pentatetracont-42-en-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecaone cyclic compound, or a salt thereof or a solvate thereof. [4-30] PP3102: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-38-(p-tolylmethyl)-17-(pyrrolidine-1-carbonyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 A cyclic compound that is pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecaone, or a salt thereof or a solvate thereof. [4-31] PP3103: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 A cyclic compound that is ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecaone, or a salt thereof or a solvate thereof. [4-32] PP3104: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 A cyclic compound that is ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecaone, or a salt thereof or a solvate thereof. [4-33] PP3105: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 A cyclic compound that is ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecaone, or a salt thereof or a solvate thereof. [4-34] PP3106: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.010,14 A cyclic compound that is ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecaone, or a salt thereof or a solvate thereof. [4-35] PP3110: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 A cyclic compound that is ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecaone, or a salt thereof or a solvate thereof. [4-36] PP3111: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 A cyclic compound that is ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecaone, or a salt thereof or a solvate thereof. [4-37] PP3112: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 A cyclic compound that is ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecaone, or a salt thereof or a solvate thereof. [4-38] PP3113: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 A cyclic compound that is ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecaone, or a salt thereof or a solvate thereof. [4-39] PP3114: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 A cyclic compound that is pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecaone, or a salt thereof or a solvate thereof. [4-40] PP3115: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-13-propyl-38-(p-tolylmethyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 A cyclic compound that is pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecaone, or a salt thereof or a solvate thereof. [4-41] PP3116: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-17-(pyrrolidine-1-carbonyl)-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 A cyclic compound that is pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecaone, or a salt thereof or a solvate thereof. [4-42] PP3117: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-38-(p-tolylmethyl)-17-(pyrrolidine-1-carbonyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetetracyclo[37.5.1.0 4,8 .0 26,30 A cyclic compound that is pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecaone, or a salt thereof or a solvate thereof. [4-43] PP3118: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 A cyclic compound that is ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecaone, or a salt thereof or a solvate thereof. [4-44] PP3119: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 A cyclic compound that is ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecaone, or a salt thereof or a solvate thereof. [4-45] PP3120: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrroridine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 A cyclic compound that is ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecaone, or a salt thereof or a solvate thereof. [4-46] PP3121: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 A cyclic compound that is ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecaone, or a salt thereof or a solvate thereof. [4-47] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-N-ethyl-N,3,18,21,25,31,34-heptamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 Pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-22-carboxamide, or a salt thereof or a solvate thereof. [4-48] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3',3',18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 Pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-22-carboxamide, or a salt thereof or a solvate thereof. [4-49] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undeaone, or its salts or solvates. [4-50] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undeaone, or its salts or solvates. [4-51] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3',3',18,21,25,34-heptamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undeaone, or its salts or solvates. [4-52] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-31-Cyclopropyl-7-[2-[3,5-Difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-Ethoxy-19-(1-ethylpropyl)-3,18,21,25,34-Pentamethyl-29-[(1S)-1-methylpropyl]-22-(Pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-Undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undeaone, or its salts or solvates. [4-53] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-7-[2-(3,4-dichlorophenyl)ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 Pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undaone, or its salts or solvates. A cyclic compound or salt thereof as described in any of [5], [1], to [4-53]. A cyclic compound or solvate thereof, as described in any of [6], [1], to [4-53]. A cyclic compound or a solvate of a salt thereof, as described in any of [7], [1], to [4-53]. A cyclic compound as described in any of [8], [1], to [4-53]. [9] A cyclic compound described in any of [1] to [4-53], or a salt thereof, or a solvate thereof, that is bonded to KRAS.

[10] A cyclic compound described in any of [1] to [4-53] that inhibits KRAS, or a salt thereof or a solvate thereof.

[11] A cyclic compound described in any of [1] to [4-53], or a salt thereof, or a solvate thereof, having high selectivity for KRAS.

[12] PP1820: (3S,9S,12S,17S,20S,23S,27S,30S,36S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-30-cyclopentyl-23-isobutyl-9-(isopentyloxymethyl)-N,N,7,17,18,24,28,31-octamethyl-20-[(1S)-1-methylpropyl]-2,5,8,11,16,19,22,25,29,32,35-undecaoxo-10-propyl-spiro[1,4,7,10,15,18,21,24,28,31,34-undecazatricyclo[34.3.0.0 12,15 A cyclic compound described in any of [1] to [4-53], or a salt thereof or a solvate thereof, having higher KRAS selectivity (KRAS selectivity for NRAS and / or KRAS selectivity for HRAS) than ]nonatriacontane-33,1'-cyclobutane]-27-carboxamide.

[13] A cyclic compound described in any of [1] to [4-53], or a salt thereof, or a solvate thereof, that selectively binds to KRAS.

[14] A cyclic compound described in any of [1] to [4-53], or a salt thereof, or a solvate thereof, that selectively inhibits KRAS.

[15] A cyclic compound according to any of [1] to [4-53], or a salt thereof or a solvate thereof, wherein the KRAS binding activity is three times or more than the NRAS binding activity and HRAS binding activity.

[16] A cyclic compound as described in

[15] , or a salt thereof or a solvate thereof, wherein the KRAS binding activity is 5 times, 7 times, 10 times, 15 times, or 20 times or more compared to the NRAS binding activity and HRAS binding activity.

[17] A cyclic compound according to any of [1] to [4-53], or a salt thereof or a solvate thereof, wherein the KRAS inhibitory activity is three times or more than the NRAS inhibitory activity and HRAS inhibitory activity.

[18] A cyclic compound as described in

[17] , or a salt thereof or a solvate thereof, wherein the KRAS inhibitory activity is 5 times, 7 times, 10 times, 15 times, or 20 times or more compared to the NRAS inhibitory activity and HRAS inhibitory activity. A pharmaceutical composition comprising a cyclic compound described in any of

[19] , [1] to [4-53], or a salt thereof, or a solvate thereof. A pharmaceutical composition for selectively inhibiting KRAS in a target, comprising a cyclic compound described in any of

[20] , [1] to [4-53], a salt thereof, or a solvate thereof.

[21] The pharmaceutical composition according to

[20] , wherein the KRAS inhibitory activity of the compound is three times or more than the NRAS inhibitory activity and HRAS inhibitory activity of the compound.

[22] The pharmaceutical composition according to

[21] , wherein the KRAS inhibitory activity of the compound is 5 times, 7 times, 10 times, 15 times, or 20 times or more compared to the NRAS inhibitory activity and HRAS inhibitory activity of the compound. A pharmaceutical composition for treating or preventing cancer in a subject, comprising an effective amount of a cyclic compound, a salt thereof, or a solvate thereof, as described in any of

[23] [1] to [4-53].

[24] The pharmaceutical composition according to

[23] , wherein the cancer is lung cancer.

[25] A pharmaceutical composition according to any of

[20] to

[24] , wherein the subject is a human.

[26] A cyclic compound, a salt thereof, or a solvate thereof, as described in any of [1] to [4-53], for use in the treatment or prevention of cancer in a subject.

[27] The cyclic compound described in

[26] , or a salt thereof, or a solvate thereof, wherein the cancer is lung cancer.

[28] A cyclic compound, a salt thereof, or a solvate thereof, as described in any of [1] to [4-53], for use in selective inhibition of KRAS in a subject.

[29] A cyclic compound as described in any of

[26] to

[28] , or a salt thereof, or a solvate thereof, whose subject is human.

[30] Use of any of the cyclic compounds described in [1] to [4-53], or salts thereof or solvates thereof, in the manufacture of a medicament for treating or preventing cancer in a subject.

[31] The use described in

[30] , where the cancer is lung cancer. Use of a cyclic compound according to any one of [1] to [4-53], or a salt or solvate thereof, in the manufacture of a medicament for selectively inhibiting KRAS in a subject. 〔33〕Use according to any one of

[30] to

[32] , wherein the subject is a human. 〔34〕A method for treating or preventing cancer in a subject, comprising administering to the subject an effective amount of a cyclic compound according to any one of [1] to [4-53], or a salt or solvate thereof. 〔35〕The method according to

[34] , wherein the cancer is lung cancer. 〔36〕A method for selectively inhibiting KRAS in a subject, comprising administering to the subject an effective amount of a cyclic compound according to any one of [1] to [4-53], or a salt or solvate thereof. 〔37〕The method according to any one of

[34] to

[36] , wherein the subject is a human.

Effect of the Invention

[0015] According to the present invention, a novel cyclic compound having a selective KRAS inhibitory action can be provided.

Modes for Carrying Out the Invention

[0016] (Abbreviations) The abbreviations used in the present invention are described below. AA: Ammonium acetate Boc: tert-Butoxycarbonyl CSA: (+)-10-Camphorsulfonic acid CPME: Cyclopentyl methyl ether DAST: (Diethylamino)sulfur trifluoride DBU: 1,8-Diazabicyclo[5.4.0]-7-undecene DCM: Dichloromethane DCE: 1,2-Dichloroethane DEAD: Diethyl azodicarboxylate DEPBT:3-(diethoxyphosphoryloxy)-1,2,3-benzotriazine-4(3H)-one DIAD: Diisopropyl azodicarboxylate DIC: N,N'-Diisopropylcarbodiimide DIPEA: N,N-diisopropylethylamine DHP:3,4-dihydro-2H-pyran DMA: N,N-dimethylacetamide DMAP: N,N-dimethyl-4-aminopyridine DMF: N,N-dimethylformamide dtbbpy: 4,4'-di-tert-butyl-2,2'-bipyridine EDTA: Ethylenediaminetetraacetic acid FA: Formic acid Fmoc:9-Fluorenylmethyloxycarbonyl NMP:N-methyl-2-pyrrolidone TBME: t-butyl methyl ether TES: Triethylsilane TFA: Trifluoroacetic acid TFE: 2,2,2-trifluoroethanol THF: Tetrahydrofuran THP: Tetrahydropyranyl TMSCl:Chlorotrimethylsilane HFIP: 1,1,1,3,3,3-Hexafluoroisopropyl alcohol HOAt: 1-Hydroxy-7-Azabenzotriazole HOBt: 1-hydroxybenzotriazole HOOBt:3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine IPAC: Isopropyl acetate oxyma: ethyl cyano(hydroxyimino)ethyl acetate PPTS: Pyridinium p-toluenesulfonate Pis:2-phenylisopropyl WSCI·HCl, WSCDI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride TIPS: Triisopropylsilane TfOH: Trifluoromethanesulfonic acid HATU:O-(7-aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate DMSO: Dimethyl sulfoxide Fmoc-Cl:(9H-fluoren-9-yl)methyl carbochloride acid Fmoc-OSu: N-succinimidyl carbonate, 9-fluorenylmethyl Ns:o-nitrobenzenesulfonyl Trt: Triphenylmethyl 9-BBN:9-Borabicyclo[3.3.1]nonane HMDS: 1,1,1,3,3,3-Hexamethyldisilazane LDA: Lithium diisopropylamide TMSOTf: Trimethylsilyl trifluoromethanesulfonate PPA: Polyphosphate

[0017] In this specification, the term "approximately" when used in combination with a number means a range of +10% and -10% of that number.

[0018] In this specification, the range symbol "~" includes the values ​​at both ends of the range; for example, "A~B" means a range where A is greater than or equal to B and B is less than or equal to B.

[0019] In this specification, the unit of molecular weight is "g / mol" (hereinafter, the unit of molecular weight may be omitted in this specification).

[0020] The use of the articles “a,” “an,” and “the” in both this specification and the claims shall be interpreted as encompassing both singular and plural forms unless otherwise specifically indicated herein or explicitly refuted by the context.

[0021] (Definition of functional groups, etc.) Examples of "halogen atoms" as used herein include F, Cl, Br, or I.

[0022] In this specification, "alkyl" refers to a monovalent group derived from an aliphatic hydrocarbon by removing one arbitrary hydrogen atom, and does not contain heteroatoms (atoms other than carbon and hydrogen atoms) or unsaturated carbon-carbon bonds in its skeleton, but has a subset of a hydrocarbyl or hydrocarbon group structure containing hydrogen and carbon atoms. Alkyls include not only linear but also branched chains. Specifically, alkyls include groups with 1 to 20 carbon atoms (C1 to C20). 20 , hereinafter referred to as “C p ~C q " means an alkyl group with p to q carbon atoms, preferably C1 to C 10 Alkyl, more preferably C1-C6 alkyl, is a possible example. Specifically, examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, isobutyl(2-methylpropyl), n-pentyl, s-pentyl(1-methylbutyl), t-pentyl(1,1-dimethylpropyl), neopentyl(2,2-dimethylpropyl), isopentyl(3-methylbutyl), 3-pentyl(1-ethylpropyl), 1,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1,2,2-tetramethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, and the like.

[0023] In this specification, "alkenyl" means at least one double bond (two adjacent SPs) 2It is a monovalent group having carbon atoms. Depending on the arrangement of the double bond and substitutions (if present), the geometric form of the double bond can be entgegen (E) or thusanmen (Z), cis or trans configuration. Alkenyls include not only linear but also branched chains. Preferably, the alkenyl is C2-C 10 Examples include alkenyls, more preferably C2-C7 alkenyls and C2-C6 alkenyls, specifically vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl (including cis and trans), 3-butenyl, pentenyl, 3-methyl-2-butenyl, hexenyl, and 6-heptenyl.

[0024] In this specification, "alkynyl" refers to a monovalent group having at least one triple bond (two adjacent SP carbon atoms). Alkynnyls include not only linear but also branched chains. Preferably, alkynyls are C2-C 10 Examples include alkynyls, more preferably C2-C6 alkynyls, specifically ethinyl, 1-propynyl, propargyl, 3-butynyl, pentynyl, hexynyl, 3-phenyl-2-propynyl, 3-(2'-fluorophenyl)-2-propynyl, 2-hydroxy-2-propynyl, 3-(3-fluorophenyl)-2-propynyl, and 3-methyl-(5-phenyl)-4-pentynyl.

[0025] In this specification, "cycloalkyl" means a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group, including monocyclic, bicyclocyclic, and spirocyclic groups. Preferred cycloalkyls include C3-C8 cycloalkyls, specifically, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, and spiro[3.3]heptyl.

[0026] In this specification, "aryl" means a monovalent aromatic hydrocarbon ring, preferably C6-C6. 10Examples of aryls include phenyl and naphthyl (e.g., 1-naphthyl, 2-naphthyl). In this specification, aryls include bicyclic aryls in which the aromatic hydrocarbon ring is fused with other saturated or unsaturated rings, for example, fused aryls in which the aromatic hydrocarbon ring is a benzene ring and the saturated ring is a 5-membered, 6-membered, or 7-membered saturated hydrocarbon ring or saturated heterocycle. Examples include indanyl, 1,2,3,4-tetrahydronaphthyl, and 2,3-dihydrobenzofuran.

[0027] In this specification, "heterocyclyl" means a non-aromatic, cyclic, monovalent group containing 1 to 5 heteroatoms in addition to carbon atoms. Heterocyclyls may have double and / or triple bonds in the ring, the carbon atoms in the ring may be oxidized to form carbonyls, and they may be monocyclic or fused rings. The number of atoms constituting the ring is preferably 3 to 10 (3 to 10-membered heterocyclyl) or 4 to 10 (4 to 10-membered heterocyclyl), and more preferably 3 to 7 (3 to 7-membered heterocyclyl) or 4 to 7 (4 to 7-membered heterocyclyl). Examples of heterocyclyls include, for example, azetidinil, oxyranil, oxetanil, azetidinil, dihydrofuryl, tetrahydrofuryl, dihydropyranil, tetrahydropyranil, tetrahydropyridyl, tetrahydropyrimidyl, morpholinil, thiomorpholinil, pyrrolidinil, piperidinil, piperazinil, pyrazolidinil, imidazolinil, imidazolidinil, oxazolidinil, isoxazolidinil, thiazolidinil, isothiazolidinil Examples include yl, 1,2-thiadinane, thiadiazolidinyl, azetidinyl, oxazolidone, benzodioxanil, benzoxazolyl, dioxolanil, dioxanil, tetrahydropyrrolo[1,2-c]imidazole, thietanil, 3,6-diazabicyclo[3.1.1]heptanil, 2,5-diazabicyclo[2.2.1]heptanil, 3-oxa-8-azabicyclo[3.2.1]octanil, sultam, and 2-oxaspiro[3.3]heptyl.

[0028] In this specification, "protected heterocyclyl" means a group in which one or more functional groups, such as an amino group, contained in the "heterocyclyl" as defined above are protected by any protecting group, preferably a protected 4- to 7-membered heterocyclyl. Specific examples of protecting groups include Boc, Fmoc, Cbz, Troc, and Alloc, and specific examples of protected heterocyclyls include Boc-protected azetidine.

[0029] In this specification, "heterocycloalkylidene" means a divalent group whose free valence is part of a double bond, obtained by removing two hydrogen atoms from one carbon atom of the "heterocyclyl" as defined above. Preferred heterocycloalkylides are 4 to 7-membered heterocycloalkylides, specifically, for example, tetrahydropyran-4-ylidene and azetidine-3-ylidene.

[0030] In this specification, "protected heterocycloalkylidene" means a group in which one or more functional groups, for example, an amino group, contained in the "heterocycloalkylidene" as defined above is protected with any protecting group, preferably a protected 4- to 7-membered heterocycloalkylidene. Specific examples of protecting groups include Boc, Fmoc, Cbz, Troc, and Alloc, and specific examples of protected heterocycloalkylenes include Boc-protected azetidine-3-ylidene.

[0031] In this specification, "heteroaryl" means an aromatic, cyclic, monovalent group containing one to five heteroatoms in addition to a carbon atom. The ring may be a monoring or a fused ring with other rings, and may be partially saturated. The number of atoms constituting the ring is preferably 5 to 10 (5 to 10-membered heteroaryl), and more preferably 5 to 7 (5 to 7-membered heteroaryl). Examples of heteroaryl compounds include, for instance, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolidinyl, and imidazopyridyl.

[0032] In this specification, "alkoxy" means an oxy group to which the "alkyl" defined above is bonded, and preferably C1-C6 alkoxys are mentioned. Specific examples of alkoxys include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentyloxy, and 3-methylbutoxy.

[0033] In this specification, "alkylthio" means a thiol group to which the "alkyl" defined above is bonded, and preferably C1-C6 alkylthios are included. Specifically, examples of alkylthios include methylthio, ethylthio, 1-propylthio, 2-propylthio, n-butylthio, i-butylthio, s-butylthio, and t-butylthio.

[0034] In this specification, "alkenyloxy" means an oxy group to which the "alkenyl" defined above is bonded, and preferably C2-C6 alkenyloxys are mentioned. Specific examples of alkenyloxys include vinyloxy, allyloxy, 1-propenyloxy, 2-propenyloxy, 1-butenyloxy, 2-butenyloxy (including cis and trans), 3-butenyloxy, pentenyloxy, hexenyloxy, and the like.

[0035] In this specification, "cycloalkoxy" means an oxy group to which the "cycloalkyl" defined above is bonded, and preferably C3-C8 cycloalkoxys are included. Specific examples of cycloalkoxys include cyclopropoxy, cyclobutoxy, and cyclopentyloxy.

[0036] In this specification, "aryloxy" means an oxy group to which the "aryl" defined above is attached, preferably C6-C6. 10 Examples of aryloxys include phenoxy, 1-naphthyloxy, and 2-naphthyloxy.

[0037] In this specification, "amino" means -NH2 in the narrow sense and -NRR' in the broad sense, where R and R' are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or R and R' together with the nitrogen atom to which they are bonded to form a ring. Preferred aminos include -NH2, monoC1-C6 alkylaminos, diC1-C6 alkylaminos, and 4-8 membered cyclic aminos.

[0038] In this specification, "monoalkylamino" means a group of "amino" as defined above, in which R is hydrogen and R' is "alkyl" as defined above, and preferably monoC1-C6 alkylaminos. Specifically, examples of monoalkylaminos include methylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino, s-butylamino, and t-butylamino.

[0039] In this specification, "dialkylamino" means a group of "amino" as defined above, in which R and R' are independently "alkyl" as defined above, and preferably includes diC1-C6 alkylaminos. Specific examples of dialkylaminos include dimethylamino and diethylamino.

[0040] In this specification, "cyclic amino" means, among the "amino" as defined above, groups R and R' that, together with the nitrogen atom to which they are bonded, form a ring, and preferably, 4- to 8-membered cyclic aminos. Specific examples of cyclic aminos include, for example, 1-azetidyl, 1-pyrrolidyl, 1-piperidyl, 1-piperazyl, 4-morpholinyl, 3-oxazolidyl, 1,1-dioxidethiomorpholinyl-4-yl, and 3-oxa-8-azabicyclo[3.2.1]octan-8-yl.

[0041] In this specification, "protected amino" means an amino group protected with any protecting group. Specific examples of protected aminos include aminos protected with protecting groups such as Boc, Fmoc, Cbz, Troc, and Alloc.

[0042] In this specification, "alkylcarbonyl" means a carbonyl group to which the "alkyl" defined above is bonded, and preferably refers to C1-C6 alkylcarbonyls. Specific examples of alkylcarbonyls include acetyl, propionyl, and butyryl. The number of carbon atoms indicated in the above definition refers to the number of carbon atoms in the alkyl portion. For example, "C1-C6" in "C1-C6 alkylcarbonyl" indicates that the alkyl portion has 1 to 6 carbon atoms.

[0043] In this specification, "aminocarbonyl" means a carbonyl group to which "amino" as defined above is attached, and preferably includes -CONH2, monoC1-C6 alkylaminocarbonyl, diC1-C6 alkylaminocarbonyl, and 4-8 membered cyclic aminocarbonyl. Specifically, examples of aminocarbonyls include -CONH2, dimethylaminocarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 1-piperazinylcarbonyl, 4-morpholinylcarbonyl, 3-oxazolidinylcarbonyl, 1,1-dioxidethiomorpholinyl-4-ylcarbonyl, and 3-oxa-8-azabicyclo[3.2.1]octane-8-ylcarbonyl.

[0044] In this specification, "alkenyloxycarbonyl" means a carbonyl group to which the "alkenyloxy" defined above is attached, and preferably includes C2-C6 alkenyloxycarbonyl. Specific examples of alkenyloxycarbonyl include vinyloxycarbonyl, allyloxycarbonyl, 1-propenyloxycarbonyl, 2-propenyloxycarbonyl, 1-butenyloxycarbonyl, 2-butenyloxycarbonyl (including cis and trans forms), 3-butenyloxycarbonyl, pentenyloxycarbonyl, and hexenyloxycarbonyl.

[0045] In this specification, "alkylsulfonyl" means a sulfonyl group to which the "alkyl" defined above is attached, and preferably C1-C6 alkylsulfonyls are included. Specifically, examples of alkylsulfonyls include methylsulfonyl.

[0046] In this specification, "hydroxyalkyl" means a group in which one or more hydrogen atoms of the "alkyl" defined above are substituted with hydroxyl groups, and C1-C6 hydroxyalkyls are preferred. Specific examples of hydroxyalkyls include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, and 5-hydroxypentyl.

[0047] In this specification, "haloalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are substituted with halogens, and C1-C6 haloalkyls are preferred, and C1-C6 fluoroalkyls are more preferred. Specific examples of haloalkyls include difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3-difluoropropyl, 4,4-difluorobutyl, 5,5-difluoropentyl, and 1,1-difluoroethyl.

[0048] In this specification, "cyanoalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are substituted with cyano, and C1-C6 cyanoalkyls are preferred. Specific examples of cyanoalkyls include cyanomethyl and 2-cyanoethyl.

[0049] In this specification, "aminoalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are substituted with the "amino" as defined above, and C1-C6 aminoalkyls are preferred. Specific examples of aminoalkyls include 1-pyridylmethyl, 2-(1-piperidyl)ethyl, 3-(1-piperidyl)propyl, 4-aminobutyl, and 2-aminoethyl.

[0050] In this specification, "carboxyalkyl" means a group in which one or more hydrogen atoms of the "alkyl" as defined above are substituted with carboxyl atoms, and C1-C6 carboxyalkyl and C2-C6 carboxyalkyl are preferred. Specifically, examples of carboxyalkyl include carboxymethyl. The number of carbon atoms shown in the above definition indicates the number of carbon atoms in the alkyl portion. For example, "C1-C6" in "C1-C6 carboxyalkyl" indicates that the alkyl portion has 1 to 6 carbon atoms.

[0051] In this specification, "alkenyloxycarbonylalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are substituted with the "alkenyloxycarbonyl" as defined above, and C2-C6 alkenyloxycarbonyl C1-C6 alkyl is preferred, and C2-C6 alkenyloxycarbonyl C1-C2 alkyl is more preferred. Specific examples of alkenyloxycarbonylalkyl include allyloxycarbonylmethyl and 2-(allyloxycarbonyl)ethyl.

[0052] In this specification, "alkoxyalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are substituted with the "alkoxy" as defined above, with C1-C6 alkoxyC1-C6 alkyl being preferred and C1-C6 alkoxyC1-C2 alkyl being more preferred. Specific examples of alkoxyalkyls include methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, n-butoxymethyl, i-butoxymethyl, s-butoxymethyl, t-butoxymethyl, pentyloxymethyl, 3-methylbutoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 1-ethoxyethyl, and 1-n-propyloxyethyl.

[0053] In this specification, "alkylthioalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are substituted with "alkylthio" as defined above, with C1-C6 alkylthioC1-C6 alkyl being preferred and C1-C6 alkylthioC1-C2 alkyl being more preferred. Specific examples of alkylthioalkyl include methylthiomethyl, ethylthiomethyl, 1-propylthiomethyl, 2-propylthiomethyl, n-butylthiomethyl, i-butylthiomethyl, s-butylthiomethyl, and t-butylthiomethyl.

[0054] In this specification, "alkenyloxyalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are substituted with the "alkenyloxy" as defined above, and C2-C6 alkenyloxy C1-C6 alkyl is preferred, and C1-C6 alkenyloxy C1-C2 alkyl is more preferred. Specific examples of alkenyloxyalkyls include vinyloxymethyl and allyloxymethyl.

[0055] In this specification, "cycloalkylalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are substituted with the "cycloalkyl" as defined above, with C3-C8 cycloalkyl and C1-C6 alkyl being preferred, and C3-C6 cycloalkyl and C1-C2 alkyl being more preferred. Specific examples of cycloalkylalkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.

[0056] In this specification, "cycloalkoxyalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are substituted with the "cycloalkoxy" as defined above, with C3-C8 cycloalkoxy C1-C6 alkyl being preferred, and C3-C6 cycloalkoxy C1-C2 alkyl being more preferred. Specific examples of cycloalkoxyalkyls include cyclopropoxymethyl and cyclobutoxymethyl.

[0057] In this specification, "heterocyclylalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are substituted with the "heterocyclyl" as defined above, and 4- to 7-membered heterocyclyl C1-C6 alkyl is preferred, and 4- to 7-membered heterocyclyl C1-C2 alkyl is more preferred. Specific examples of heterocyclylalkyls include 2-(tetrahydro-2H-pyran-4-yl)ethyl and 2-(azetidine-3-yl)ethyl.

[0058] In this specification, "alkylsulfonylalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are substituted with "alkylsulfonyl" as defined above, with C1-C6 alkylsulfonyl C1-C6 alkyl being preferred, and C1-C6 alkylsulfonyl C1-C2 alkyl being more preferred. Specific examples of alkylsulfonylalkyl include methylsulfonylmethyl and 2-(methylsulfonyl)ethyl.

[0059] In this specification, "aminocarbonylalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are substituted with the "aminocarbonyl" as defined above, with aminocarbonyl C1-C6 alkyl being preferred and aminocarbonyl C1-C4 alkyl being more preferred. Specific examples of aminocarbonylalkyls include methylaminocarbonylmethyl, dimethylaminocarbonylmethyl, t-butylaminocarbonylmethyl, 1-azetidinylcarbonylmethyl, 1-pyrrolidinylcarbonylmethyl, 1-piperidinylcarbonylmethyl, 4-morpholinylcarbonylmethyl, 2-(methylaminocarbonyl)ethyl, 2-(dimethylaminocarbonyl)ethyl, 2-(1-azetidinylcarbonyl)ethyl, 2-(1-pyrrolidinylcarbonyl)ethyl, 2-(4-morpholinylcarbonyl)ethyl, 3-(dimethylaminocarbonyl)propyl, and 4-(dimethylaminocarbonyl)butyl.

[0060] In this specification, "aryloxyalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are substituted with the "aryloxy" as defined above, C6~C 10 Aryloxy C1-C6 alkyl is preferred, C6-C 10 Aryloxy C1-C2 alkyl groups are more preferred. Specific examples of aryloxy alkyl groups include phenoxymethyl and 2-phenoxyethyl.

[0061] In this specification, "aralkyl (arylalkyl)" means a group in which at least one hydrogen atom of the "alkyl" as defined above is substituted with the "aryl" as defined above, C7~C 14 Aralkyl is preferred, C7~C 10 Aralkyl is more preferable. Specific examples of aralkyl include benzyl, phenethyl, and 3-phenylpropyl.

[0062] In this specification, "aralkoxy" means an oxy group to which the "aralkyl" defined above is bonded, C7-C 14 Allalcoxy is preferred, C7~C 10 Aralcoxy is more preferred. Specific examples of aralcoxy include benzyloxy, phenethyloxy, and 3-phenylpropoxy.

[0063] In this specification, "aralcoxyalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are substituted with the "aralcoxy" as defined above, C7~C 14 Aralcoxyl C1-C6 alkyl is preferred, C7-C 14 Aralkoxy C1-C2 alkyl groups are more preferred. Specific examples of aralkoxyalkyl groups include benzyloxymethyl and 1-(benzyloxy)ethyl.

[0064] In this specification, "heteroarylalkyl" means a group in which at least one hydrogen atom of the "alkyl" as defined above is substituted with the "heteroaryl" as defined above, and 5-10 membered heteroaryl C1-C6 alkyls are preferred, and 5-10 membered heteroaryl C1-C2 alkyls are more preferred. Specific examples of heteroarylalkyls include 3-thienylmethyl, 4-thiazolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, 2-(4-pyridyl)ethyl, 2-(6-quinolyl)ethyl, 2-(7-quinolyl)ethyl, 2-(6-indolyl)ethyl, 2-(5-indolyl)ethyl, and 2-(5-benzofuranyl)ethyl.

[0065] In this specification, "heteroarylalkoxy" means an oxy group to which a "heteroarylalkyl" as defined above is bonded, and 5-10 membered heteroaryl C1-C6 alkoxys are preferred, and 5-10 membered heteroaryl C1-C2 alkoxys are more preferred. Specific examples of heteroarylalkoxys include 3-thienylmethoxy and 3-pyridylmethoxy.

[0066] In this specification, "heteroarylalkoxyalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are substituted with the "heteroarylalkoxy" as defined above, and 5-10 membered heteroaryl C1-C6 alkoxy C1-C6 alkyl is preferred, and 5-10 membered heteroaryl C1-C2 alkoxy C1-C2 alkyl is more preferred. Specific examples of heteroarylalkoxyalkyls include, for example, 3-pyridylmethoxymethyl.

[0067] In this specification, "heterocycloalkylidene alkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are substituted with the "heterocycloalkylidene" as defined above, and 4- to 7-membered heterocycloalkylidene C1-C6 alkyl is preferred, and 4- to 7-membered heterocycloalkylidene C1-C2 alkyl is more preferred. Specific examples of heterocycloalkylides include tetrahydro-4H-pyran-4-ylidenemethyl and azetidine-3-ylidenemethyl.

[0068] In this specification, "alkoxyalkenyl" means a group in which one or more hydrogens of the "alkenyl" as defined above are substituted with the "alkoxy" as defined above, and C1-C6 alkoxy and C2-C6 alkenyls are preferred. Specific examples of alkoxyalkenyls include (E)-4-methoxybuto-2-en-1-yl.

[0069] In this specification, "aminocarbonyl alkenyl" means a group in which one or more hydrogens of the "alkenyl" as defined above are substituted with the "aminocarbonyl" as defined above, and aminocarbonyl C2-C6 alkenyls are preferred. Specific examples of aminocarbonyl alkenyls include (E)-3-(dimethylaminocarbonylcarbonyl)-propa-2-en-1-yl.

[0070] In this specification, "haloalkoxy" means a group in which one or more hydrogens of the "alkoxy" as defined above are substituted with a halogen, and C1-C6 haloalkoxys are preferred. Specific examples of haloalkoxys include difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, and 2,2,2-trifluoroethoxy.

[0071] In this specification, "alkylene" means a divalent group derived by removing one arbitrary hydrogen atom from the aforementioned "alkyl," and C4-C8 alkylenes are preferred. Specific examples of alkylenes include -CH2-, -(CH2)2-, -(CH2)3-, -CH(CH3)CH2-, -C(CH3)2CH2-, -CH2CH(CH3)CH2-, -CH2C(CH3)2-, -CH2CH2CH(CH3)-, -(CH2)5-, -(CH2)6-, -(CH2)7-, and -(CH2)8-.

[0072] In this specification, "cycloalkylene" means a divalent group derived by removing one arbitrary hydrogen atom from the "cycloalkyl" group, and C3-C8 cycloalkylenes are preferred. Specific examples of cycloalkylenes include cyclopropane-1,2-diyl, cyclobutane-1,2-diyl, cyclopentane-1,2-diyl, and cyclohexane-1,2-diyl.

[0073] In this specification, "heterocyclylene" means a divalent group derived by removing one arbitrary hydrogen atom from the "heterocyclyl," and 3- to 7-membered heterocyclylenes are preferred. Specific examples of heterocyclylenes include oxirane-2,3-diyl, oxetane-2,3-diyl, tetrahydrofuran-2,5-diyl, and tetrahydropyran-2,6-diyl.

[0074] In this specification, "alkenylene" means a divalent group derived from the "alkenyl" by removing one additional hydrogen atom of any choice. Depending on the arrangement of the double bond and substitutions (if present), the geometric configuration of the double bond can be entgegen (E) or thusanmen (Z), cis or trans configuration. Alkenylenes include linear or branched chains, C2-C 10 Alkenylenes are preferred, and C2-C6 alkenylenes are more preferred.

[0075] In this specification, "alkynylene" means a divalent group derived by removing one more arbitrary hydrogen atom from "alkynyl". Alkynylenes include linear or branched chains, C2-C 10 Alkynylenes are preferred, and C2-C6 alkynylenes are more preferred.

[0076] In this specification, "arylene" means a divalent group derived by removing one arbitrary hydrogen atom from the "aryl" group. Arylene may be a monocyclic or fused ring. The number of atoms constituting the ring is not particularly limited, but is preferably 6 to 10 (C6-10 arylene). Specific examples of arylene include 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene, 1,3-naphthylene, and 1,4-naphthylene.

[0077] In this specification, "spirocycloalkyl" means a group formed by sharing one carbon atom in a cycloalkane ring with a carbon atom in a bonded group. Preferred spirocycloalkyls include C3-C8 spirocycloalkyls, specifically spirocyclopropyl, spirocyclobutyl, spirocyclopentyl, spirocyclohexyl, spirocycloheptyl, and spirocyclooctyl.

[0078] In this specification, "spiroheterocyclyl" means a group in which one or more carbon atoms in the "spirocycloalkyl" are replaced by heteroatoms. Preferred heterospirocycloalkyls include 4- to 10-membered spiroheterocyclyls.

[0079] In this specification, "alicyclic ring" means a non-aromatic hydrocarbon ring. An alicyclic ring may have unsaturated bonds within the ring, or it may be a polycyclic ring having two or more rings. The carbon atoms constituting the ring may also be oxidized to form carbonyls. Preferred alicyclic rings are 3 to 8-membered alicyclic rings, specifically, for example, cyclopropane rings, cyclobutane rings, cyclopentane rings, cyclohexane rings, cycloheptane rings, cyclooctane rings, and bicyclo[2.2.1]heptane rings.

[0080] In this specification, "saturated heterocycle" means a non-aromatic heterocycle that contains 1 to 5 heteroatoms in addition to carbon atoms and does not contain double and / or triple bonds in the ring. A saturated heterocycle may be a monocycle or may form a fused ring with another ring, such as an aromatic ring such as a benzene ring. Preferably saturated heterocycles are 4 to 7 membered saturated heterocycles, specifically including, for example, azetidine rings, oxetane rings, tetrahydrofuran rings, tetrahydropyran rings, morpholine rings, thiomorpholine rings, pyrrolidine rings, 4-oxopyrrolidine rings, piperidine rings, 4-oxopiperidine rings, piperazine rings, pyrazolidine rings, imidazolidine rings, oxazolidine rings, isoxazolidine rings, thiazolidine rings, isothiazolidine rings, thiadiazolidine rings, oxazolidone rings, dioxolane rings, dioxane rings, thiethane rings, octahydroindole rings, indoline rings, azepane rings, and the like.

[0081] In this specification, "peptide chain" means a peptide chain in which one, two, three, four, or more natural amino acids and / or non-natural amino acids are linked by amide bonds and / or ester bonds. Preferably, the peptide chain is a peptide chain containing one to four amino acid residues, and more preferably a peptide chain consisting of one to four amino acid residues.

[0082] In this specification, “may be substituted” means that a group may be substituted with any substituent.

[0083] In this specification, “may be protected” means that a group may be protected by any protecting group.

[0084] In this specification, “one or more” means one or more numbers. When “one or more” is used in a context relating to substituents of a group, the term means a number from one up to the maximum number of substituents permitted by that group. Specifically, “one or more” could be, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and / or greater numbers.

[0085] In this specification, wavy lines in structural formulas may indicate the possibility of any stereochemistry. For example, if a wavy line is attached to a chiral center, the stereochemistry of that chiral center may be either an S configuration or an R configuration. Similarly, if a wavy line is attached to a double bond, the stereochemistry of that double bond may be either an E configuration or a Z configuration.

[0086] In this specification, "PPn 1 n 2 n 3 n 4 (Here, n 1 , n 2 , n 3 , and n 4 The symbols represented by (where each represents an integer from 0 to 9 independently) (for example, PP1574, PP1640, etc.) represent the compound number.

[0087] The compounds of the present invention may be salts thereof, preferably chemically or pharmaceutically acceptable salts thereof. Furthermore, the compounds of the present invention or their salts may be solvates thereof, preferably chemically or pharmaceutically acceptable solvates thereof. Examples of salts of the compounds of the present invention include hydrochloride salts; hydrobromide salts; hydroiodide salts; phosphate salts; phosphonate salts; sulfate salts; sulfonates such as methanesulfonate and p-toluenesulfonate; carboxylate salts such as acetate, citrate, malate, tartrate, succinate, and salicylate salts; or alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; and ammonium salts such as ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts, and tetraalkylammonium salts. These salts are produced, for example, by contacting the compound with an acid or base that can be used in the manufacture of pharmaceuticals. In the present invention, a solvate of a compound refers to a compound that, together with a solvent, forms a molecular group; if the solvent is water, it is called a hydrate. The solvates of the compounds of the present invention are preferably hydrates, and specifically, such hydrates include 1-10 hydrates, preferably 1-5 hydrates, and more preferably 1-3 hydrates. The solvates of the compounds of the present invention include not only solvates with a single solvent such as water, alcohol (e.g., methanol, ethanol, 1-propanol, 2-propanol, etc.), and dimethylformamide, but also solvates with multiple solvents.

[0088] In this specification, "amino acids" include natural amino acids and non-natural amino acids. In this specification, "natural amino acids" refer to Gly, Ala, Ser, Thr, Val, Leu, Ile, Phe, Tyr, Trp, His, Glu, Asp, Gln, Asn, Cys, Met, Lys, Arg, and Pro. Non-natural amino acids are not particularly limited, but examples include β-amino acids, γ-amino acids, D-type amino acids, N-substituted amino acids, α,α-disubstituted amino acids, amino acids with side chains different from those of natural amino acids, and hydroxycarboxylic acids. Any stereochemistry is permitted for amino acids in this specification. There are no particular restrictions on the selection of amino acid side chains, but in addition to hydrogen atoms, they can be freely selected from, for example, alkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, aralkyl groups, and cycloalkyl groups, and one or two non-adjacent methylene groups among these groups may be substituted with oxygen atoms, carbonyl groups (-CO-), or sulfonyl groups (-SO2-). Each of these groups may be substituted, and these substituents are not limited; for example, one or more substituents may be freely selected independently from any group containing halogen atoms, oxygen atoms, sulfur atoms, nitrogen atoms, boron atoms, silicon atoms, or phosphorus atoms. Examples include substituted alkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, aralkyl groups, and cycloalkyl groups. In one non-limiting embodiment, the amino acids in this specification may be compounds having both a carboxyl group and an amino group within the same molecule (even in this case, imino acids such as proline and hydroxyproline are also included as amino acids).

[0089] The amino group in the main chain of an amino acid may be unsubstituted (NH2 group) or substituted (i.e., an -NHR group: R represents an alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or cycloalkyl group which may have substituents, and one or two non-adjacent methylene groups in these groups may be substituted with an oxygen atom, a carbonyl group (-CO-), or a sulfonyl group (-SO2-), and the carbon chain bonded to the N atom and the carbon atom at the α position may form a ring, as in proline). The substituent of R is selected in the same way as the substituents in the amino acid side chain described above. When the main chain amino group is substituted, R is included in the "side chain of an amino acid" as used herein. Amino acids in which such a main chain amino group is substituted are referred to as "N-substituted amino acids" as used herein. Examples of "N-substituted amino acids" as used herein are preferably N-alkyl amino acids, N-C1~C6 alkyl amino acids, N-C1~C4 alkyl amino acids, and N-methyl amino acids, but are not limited to these.

[0090] The "amino acids" that constitute the peptide compounds in this specification include all of their corresponding isotopes. An isotope of an "amino acid" is one in which at least one atom is substituted with an atom that has the same atomic number (number of protons) but a different mass number (sum of the number of protons and neutrons). Examples of isotopes contained in the "amino acids" that constitute the peptide compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine atoms, respectively. 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Includes Cl, etc.

[0091] Examples of substituents containing halogen atoms in this specification include alkyl groups, cycloalkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, and aralkyl groups having halogens as substituents, and more specifically, examples include fluoroalkyl groups, difluoroalkyl groups, and trifluoroalkyl groups.

[0092] Substituents containing an oxygen atom include groups such as hydroxy(-OH), oxy(-OR), carbonyl(-C(=O)-R), carboxy(-CO2H), oxycarbonyl(-C(=O)-OR), carbonyloxy(-OC(=O)-R), thiocarbonyl(-C(=O)-SR), carbonylthio(-SC(=O)-R), aminocarbonyl(-C(=O)-NHR), carbonylamino(-NH-C(=O)-R), oxycarbonylamino(-NH-C(=O)-OR), sulfonylamino(-NH-SO2-R), aminosulfonyl(-SO2-NHR), sulfamoylamino(-NH-SO2-NHR), thiocarboxy(-C(=O)-SH), and carboxycarbonyl(-C(=O)-CO2H).

[0093] Examples of oxy (-OR) compounds include alkoxy, cycloalkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, and aralkyloxy compounds. C1-C4 alkoxys and C1-C2 alkoxys are preferred, with methoxy or ethoxy compounds being particularly preferred.

[0094] Examples of carbonyl (-C(=O)-R) include formyl (-C(=O)-H), alkylcarbonyl, cycloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, and aralkylcarbonyl.

[0095] Examples of oxycarbonyl (-C(=O)-OR) include alkyloxycarbonyl, cycloalkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, and aralkyloxycarbonyl.

[0096] Examples of carbonyloxy (-OC(=O)-R) include alkylcarbonyloxy, cycloalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, and aralkylcarbonyloxy.

[0097] Examples of thiocarbonyl (-C(=O)-SR) include alkylthiocarbonyl, cycloalkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, and aralkylthiocarbonyl.

[0098] Examples of carbonylthio (-SC(=O)-R) include alkylcarbonylthio, cycloalkylcarbonylthio, alkenylcarbonylthio, alkynylcarbonylthio, arylcarbonylthio, heteroarylcarbonylthio, and aralkylcarbonylthio.

[0099] Examples of aminocarbonyl (-C(=O)-NHR) include alkylaminocarbonyls (e.g., C1-C6 or C1-C4 alkylaminocarbonyls, particularly ethylaminocarbonyl and methylaminocarbonyl), cycloalkylaminocarbonyls, alkenylaminocarbonyls, alkynylaminocarbonyls, arylaminocarbonyls, heteroarylaminocarbonyls, and aralkylaminocarbonyls. In addition to these, compounds in which the H atom bonded to the N atom in -C(=O)-NHR is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl compounds are also included.

[0100] Examples of carbonylamino (-NH-C(=O)-R) include alkylcarbonylamino, cycloalkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, and aralkylcarbonylamino. In addition to these, compounds in which the H atom bonded to the N atom in -NH-C(=O)-R is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl compounds are also included.

[0101] Examples of oxycarbonylamino (-NH-C(=O)-OR) include alkoxycarbonylamino, cycloalkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, and aralkyloxycarbonylamino. In addition to these, compounds in which the H atom bonded to the N atom in -NH-C(=O)-OR is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl groups are also included.

[0102] Examples of sulfonylaminos (-NH-SO2-R) include alkylsulfonylaminos, cycloalkylsulfonylaminos, alkenylsulfonylaminos, alkynylsulfonylaminos, arylsulfonylaminos, heteroarylsulfonylaminos, and aralkylsulfonylaminos. In addition to these, compounds in which the H atom bonded to the N atom in -NH-SO2-R is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl compounds are also included.

[0103] Examples of aminosulfonyl (-SO2-NHR) include alkylaminosulfonyl, cycloalkylaminosulfonyl, alkenylaminosulfonyl, alkynylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, and aralkylaminosulfonyl. In addition to these, compounds in which the H atom bonded to the N atom in -SO2-NHR is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl compounds are also included.

[0104] Examples of sulfamoylamino (-NH-SO2-NHR) include alkyl sulfamoylamino, cycloalkyl sulfamoylamino, alkenyl sulfamoylamino, alkynyl sulfamoylamino, aryl sulfamoylamino, heteroaryl sulfamoylamino, and aralkyl sulfamoylamino. Furthermore, the two H atoms bonded to the N atom in -NH-SO2-NHR may be substituted with substituents independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, and these two substituents may form a ring.

[0105] Substituents containing a sulfur atom include groups such as thiol (-SH), thio (-SR), sulfinyl (-S(=O)-R), sulfonyl (-SO2-R), and sulfo (-SO3H).

[0106] Examples of thio(-SR) are selected from alkylthio, cycloalkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, and aralkylthio.

[0107] Examples of sulfonyl (-SO2-R) compounds include alkylsulfonyl, cycloalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heteroarylsulfonyl, and aralkylsulfonyl compounds.

[0108] Substituents containing an N atom include azide (-N3, also called "azide group"), cyano (-CN), primary amino (-NH2), secondary amino (-NH-R; also called monosubstituted amino), tertiary amino (-NR(R'); also called disubstituted amino), amidino (-C(=NH)-NH2), substituted amidino (-C(=NR)-NR'R"), guanidino (-NH-C(=NH)-NH2), substituted guanidino (-NR-C(=NR''')-NR'R"), aminocarbonylamino (-NR-CO-NR'R"), pyridyl, piperidino, morpholino, and azetidinyl groups.

[0109] Examples of secondary amino acids (-NH-R; monosubstituted amino acids) include alkylaminos, cycloalkylaminos, alkenylaminos, alkynylaminos, arylaminos, heteroarylaminos, and aralkylaminos.

[0110] Examples of tertiary aminos (-NR(R'); disubstituted aminos) include, for example, alkyl (aralkyl)aminos, and amino groups having any two substituents independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl groups, where any two substituents may form a ring. Specifically, dialkylaminos, particularly C1-C6 dialkylaminos, C1-C4 dialkylaminos, dimethylaminos, and diethylaminos are examples. In this specification, "C p -C q A "dialkylamino group" is an amino group with a carbon atom. p -C q This refers to a group in which two alkyl groups are substituted, and both C p -C q The alkyl groups may be the same or different.

[0111] Examples of substituted amidinos (-C(=NR)-NR'R") include groups in which the three substituents R, R', and R'' on the N atom are independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl groups, such as alkyl(aralkyl)(aryl)amidinos.

[0112] Examples of substituted guanidinos (-NR-C(=NR''')-NR'R") include groups where R, R', R'', and R''' are independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl groups, or groups in which these groups form a ring.

[0113] Examples of aminocarbonylamino (-NR-CO-NR'R") include groups where R, R', and R'' are independently selected from a hydrogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl groups, or groups that form a ring.

[0114] In this specification, the "peptide residues" and "amino acid residues" that constitute a peptide compound may be simply referred to as "peptides" and "amino acids," respectively.

[0115] In this invention, the meaning of the terms "and / or" includes any combination in which "and" and "or" are appropriately combined. Specifically, for example, "A, B, and / or C" includes the following seven variations: (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C, (vii) A, B, and C.

[0116] In one embodiment, the present invention relates to a cyclic compound represented by the following formula (1), or a salt thereof, or a solvate thereof. [ka] The cyclic compound of formula (1) has a ring composed of 11 amino acid residues. In this specification, the amino acid residue having P1, Q1, R1, and L1 in the formula is referred to as core 1, the amino acid residue having P2, Q2, and R2 as core 2, the amino acid residue having P3, Q3, and R3 as core 3, the amino acid residue having P4, Q4, and R4 as core 4, the amino acid residue having P5, Q5, and R5 as core 5, the amino acid residue having P6, Q6, and R6 as core 6, the amino acid residue having P7, Q7, and R7 as core 7, the amino acid residue having P8, Q8, and R8 as core 8, the amino acid residue having P9, Q9, and R9 as core 9, P 10 Q 10 , and R 10 The amino acid residue having core 10, P 11 Q 11 , R 11 , and L 11 Amino acid residues containing this are sometimes referred to as core 11 amino acid residues.

[0117] In one embodiment, in equation (1), L1 is a single bond.

[0118] In one embodiment, in formula (1), R1 is a C1-C7 alkyl group, preferably 2-methylpropyl or n-propyl.

[0119] In one embodiment, R1 together with R5 forms a divalent group, in which case the substructure in the cyclic compound represented by formula (1): *-CR1Q1-L1-CO-NP2-CR2Q2-CO-NP3-CR3Q3-CO-NP4-CR4Q4-CO-NP5-CR5Q5-* is represented by the following formula: [ka] It is expressed as follows: X2 is -L1-CO-NP2-CR2Q2-CO-NP3-CR3Q3-CO-NP4-CR4Q4-CO-NP5-, [ka] These are single or double bonds, n is 0, 1, or 2. m is 0, 1, 2, 3, or 4. * indicates a bond point with an adjacent atom. In the formula [ka] teeth, [ka] This means that if it is a double bond, it can have either E or Z stereochemistry.

[0120] The aforementioned formula is: [ka] It is preferable.

[0121] In one embodiment, P1 is a C1-C6 alkyl group, preferably methyl.

[0122] In one aspect, Q1 is hydrogen.

[0123] Except for the case where the side chain of core 1 (R1) and the side chain of core 5 (R5) combine to form a divalent group, specific examples of amino acid residues of core 1 include, for example, MeLeu and MeNva. Furthermore, when the side chain of core 1 (R1) and the side chain of core 5 (R5) combine to form a divalent group, the group at the position corresponding to R1 in MeAhpe(2), MeAocte(2), and MeAhxe(2) and the group at the position corresponding to the side chain of core 5 (R5) can be linked, for example, using the method described later in the "General Manufacturing Method" section.

[0124] In one embodiment, in formula (1), R2 is a C1-C6 alkyl group, preferably It is 1-methylpropyl.

[0125] In one embodiment, P2 is hydrogen.

[0126] In one aspect, Q2 is hydrogen.

[0127] A specific example of a core 2 amino acid residue is Ile.

[0128] In one embodiment, R3 in equation (1) is hydrogen.

[0129] In one embodiment, R3, together with P3, the carbon atom to which R3 is bonded, and the nitrogen atom to which P3 is bonded, forms a 4- to 7-membered saturated heterocycle. Specifically, a pyrrolidine ring is an example of a 4- to 7-membered saturated heterocycle.

[0130] In one embodiment, P3 is a C1-C6 alkyl or C3-C8 cycloalkyl, preferably methyl or cyclopropyl.

[0131] In one aspect, Q3 is hydrogen.

[0132] Specific examples of core 3 amino acid residues include MeGly, Pro, and cPrGly.

[0133] In one embodiment, R4, together with P5, forms a divalent group, in which case the substructure *-CR4Q4-CO-NP5-* in the cyclic compound represented by formula (1) is given by the following formula: [ka] It is represented as follows.

[0134] In one embodiment, P4 is a C1-C6 alkyl group, preferably methyl.

[0135] In one aspect, Q4 is hydrogen.

[0136] Furthermore, when the side chain (R4) of core 4 and the N substituent (P5) of core 5 combine to form a divalent group, preferably, the group at the position corresponding to R4 of MeAlgly and the group at the position corresponding to the N substituent (P5) of core 5 can be linked, for example, using the method described in the "General Manufacturing Method" section later.

[0137] In one embodiment, in formula (1), R5 may be a benzyl substituted with one or more groups independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, and C3-C8 cycloalkyl, preferably 4-cyclopropylbenzyl, 4-(trifluoromethyl)benzyl, 4-methylbenzyl, or 4-ethylbenzyl.

[0138] In one embodiment, in formula (1), R5 combines with R1 to form a divalent group. The details of this group are as described above.

[0139] In one embodiment, P5 combines with R4 to form a divalent group. Details of this group are as described above.

[0140] In one aspect, Q5 is hydrogen.

[0141] When the side chain (R5) of core 5 and the side chain (R1) of core 1 combine to form a divalent group, and the N substituent (P5) of core 5 and the side chain (R4) of core 4 combine to form a divalent group, for example, the groups at the positions corresponding to R5 and P5 of ButenylPhe(4-CH=CH2) and the groups at the positions corresponding to the side chain (R1) of core 1 and the side chain (R4) of core 4 can be linked, for example, using the method described in the "General Manufacturing Method" section later. Furthermore, if the side chain of core 5 (R5) and the side chain of core 1 (R1) do not form a divalent group, and the N substituent of core 5 (P5) and the side chain of core 4 (R4) form a divalent group, then, for example, the group at the position corresponding to P5 in ButenylPhe(4-Et), ButenylPhe(4-cPr), or AllylPhe(4-CF3) and the group at the position corresponding to the side chain of core 4 (R4) can be linked, for example, using the method described in the "General Manufacturing Method" section later.

[0142] In one embodiment, in equation (1), R6 is hydrogen.

[0143] In one embodiment, P6 is a C1-C6 alkyl group, preferably methyl.

[0144] In one aspect, Q6 is hydrogen.

[0145] A specific example of a core 6 amino acid residue is MeGly.

[0146] In one embodiment, the phenethyl in formula (1) may be substituted with one or more groups independently selected from the group consisting of halogens, C1-C6 haloalkyls, and C1-C6 alkoxys, preferably 3,5-difluoro-4-(trifluoromethyl)phenethyl, 3,4-dichlorophenethyl, or 3-methoxy-4-(trifluoromethyl)phenethyl.

[0147] In one aspect, P7 is hydrogen.

[0148] In one aspect, Q7 is hydrogen.

[0149] Specific examples of core 7 amino acid residues include Hph(4-CF3-35-F2), Hph(34-Cl2), and Hph(4-CF3-3-OMe).

[0150] In one embodiment, in formula (1), R8 can form a 4- to 7-membered saturated heterocycle together with P8, the carbon atom to which R8 is bonded, and the nitrogen atom to which P8 is bonded. The 4- to 7-membered saturated heterocycle may be substituted with a C1- to C6 alkoxy, preferably an ethoxy, or an n-propoxy. A pyrrolidine ring is a specific example of the 4- to 7-membered saturated heterocycle.

[0151] In one aspect, Q8 is hydrogen.

[0152] Specific examples of core 8 amino acid residues include Hyp(Et) and Hyp(nPr).

[0153] In one embodiment, in formula (1), R9 together with Q9 and the carbon atom to which R9 and Q9 are bonded forms a 3- to 8-membered alicyclic ring. The 3- to 8-membered alicyclic ring may be substituted with one or more C1- to C6 alkyl groups, for example, two methyl groups. Specific examples of the 3- to 8-membered alicyclic ring include a cyclobutane ring and a cyclopentane ring.

[0154] In one embodiment, P9 is hydrogen or a C1-C6 alkyl group, preferably hydrogen or methyl.

[0155] Specific examples of core 9 amino acid residues include cLeu, cVal, cVal(3-Me2), and MecVal.

[0156] In one embodiment, in equation (1), R 10 The group is a C1-C6 alkyl or C3-C8 cycloalkyl group, preferably pentan-3-yl or cyclopentyl.

[0157] In one aspect, P 10 The alkyl group is C1-C6 alkyl, preferably methyl.

[0158] In one aspect, Q 10 It is hydrogen.

[0159] Specific examples of core 10 amino acid residues include MeGly(cPent) and MeNva(3-Et).

[0160] In one form, in equation (1), L 11 It is -CH2-.

[0161] In one embodiment, in equation (1), R 11 The compound is a diC1-C6 alkylaminocarbonyl or a 4-8 membered cyclic aminocarbonyl, preferably dimethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, pyrrolidinylcarbonyl, or piperidinylcarbonyl.

[0162] In one aspect, P 11 The alkyl group is C1-C6 alkyl, preferably methyl.

[0163] In one aspect, Q 11 It is hydrogen.

[0164] In one embodiment, the compounds of the present invention are as follows: PP1574: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-N-ethyl-27-isobutyl-N,4,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclopentane]-23-carboxamide, PP1650: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-27-isobutyl-N,N,3',3',4,19,22,26,32,35-decamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-23-carboxamide, PP1827: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-N-ethyl-N,3,18,21,25,31,34-heptamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]Pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-22-carboxamide, PP1830: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3',3',18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .135,41 .0 9,13 ]Pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-22-carboxamide, PP2093: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-N,N,3',3',4,19,22,26,35-nonamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-23-carboxamide, PP2260: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3',3',18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]Pentapentaconta-37,43(54),44,46(53)-tetraene-16,1'-cyclobutane]-22-carboxamide, PP2316: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,16,19,22,26,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-23-carboxamide, PP2320: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaoxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 Pentatetraconta-42-ene-23,1'-cyclobutane]-17-carboxamide, PP2328: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,16,19,22,26,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.010,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-23-carboxamide, PP2574: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, PP2576: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, PP2583: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3',3',18,21,25,34-heptamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, PP2687: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-2-[(4-ethylphenyl)methyl]-27-isobutyl-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,3',3',4,19,22,26,32,35-decamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-23-carboxamide, PP2691: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-2-[(4-cyclopropylphenyl)methyl]-12-ethoxy-27-isobutyl-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,3',3',4,19,22,26,32,35-decamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-23-carboxamide, PP2957: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,34-pentamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, PP3033: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13]Pentapentaconta-37,43(54),44,46(53)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecaone, PP3034: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]Pentapentaconta-37,43(54),44,46(53)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecaone, PP3036: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]Tetrapentaconta-37,43(53),44,46(52)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, PP3037: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]Tetrapentaconta-37,43(53),44,46(52)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, PP3047: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-7-[2-(3,4-dichlorophenyl)ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]Pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undaone, PP3093: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.9.2 43,46 .1 35,41 .09,13 ]tripentaconta-37,43(52),44,46(51)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,53-undaone, PP3094: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-11-propoxy-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.9.2 43,46 .1 35,41 .0 9,13 ]tripentaconta-37,43(52),44,46(51)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,53-undaone, PP3095: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3096: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3097: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3098: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3099: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 ]Pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undaone, PP3100: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-13-propyl-38-(p-tolylmethyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 ]Pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undaone, PP3101: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-17-(pyrrolidine-1-carbonyl)-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 ]Pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undaone, PP3102: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-38-(p-tolylmethyl)-17-(pyrrolidine-1-carbonyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 ]Pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undaone, PP3103: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3104: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3105: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrroridine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3106: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3110: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazaltricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3111: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3112: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3113: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3114: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 ]Pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undaone, PP3115: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-13-propyl-38-(p-tolylmethyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 ]Pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undaone, PP3116: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-17-(pyrrolidine-1-carbonyl)-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.04,8 .0 26,30 ]Pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undaone, PP3117: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-38-(p-tolylmethyl)-17-(pyrrolidine-1-carbonyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 ]Pentatetraconta-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undaone, PP3118: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3119: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3120: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 ]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, PP3121: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14]dotetraconta-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undaone, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-N-ethyl-N,3,18,21,25,31,34-heptamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]Pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-22-carboxamide, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3',3',18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxospiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]Pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-22-carboxamide, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3',3',18,21,25,34-heptamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .135,41 .0 9,13 ]Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-31-Cyclopropyl-7-[2-[3,5-Difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-Ethoxy-19-(1-ethylpropyl)-3,18,21,25,34-Pentamethyl-29-[(1S)-1-methylpropyl]-22-(Pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-Undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undekaone, and (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-7-[2-(3,4-dichlorophenyl)ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undaone It may be one or more selected from the group consisting of, or a salt thereof, or a solvate thereof. These compounds may be included in the formula represented by formula (1) above.

[0165] In one embodiment, the compound of the present invention is of formula (2): [ka] Compounds represented by the formula are preferred, and the compound in the formula [ka] n, m, P1, R2, R3, P3, P4, P6, R7, R8, P8, R9, P9, Q9, R 10 , P 10 , R 11 , and P 11 This has the same meaning as equation (1) above. For example, the compounds PP1827, PP1830, PP2260, PP2574, PP2576, PP2583, PP2957, PP3033, PP3034, PP3036, PP3037, PP3047, PP3093, and PP3094, as well as the following compounds, may be included in formula (2). (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-N-ethyl-N,3,18,21,25,31,34-heptamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]Pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-22-carboxamide, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3',3',18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxospiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]Pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-22-carboxamide, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,3',3',18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41.0 9,13 ]Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3',3',18,21,25,34-heptamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecaone, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-31-Cyclopropyl-7-[2-[3,5-Difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-Ethoxy-19-(1-ethylpropyl)-3,18,21,25,34-Pentamethyl-29-[(1S)-1-methylpropyl]-22-(Pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-Undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]Tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undekaone, and (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-7-[2-(3,4-dichlorophenyl)ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undaone

[0166] In one embodiment, the compound of the present invention is of formula (3): [ka] Compounds represented by are preferred. In formula (3), R1 is a C1-C7 alkyl group; R5 is a benzyl which may be substituted with one or more groups selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, and C3-C8 cycloalkyl; [ka] n, m, P1, R2, R3, P3, P4, P6, R7, R8, P8, R9, P9, Q9, R 10 , P 10 , R 11 , and P 11 This is equivalent to equation (1). For example, the compounds PP1574, PP1650, PP2093, PP2316, PP2320, PP2328, PP2687, PP2691, PP3095, PP3096, PP3097, PP3098, PP3099, PP3100, PP3101, PP3102, PP3103, PP3104, PP3105, PP3106, PP3110, PP3111, PP3112, PP3113, PP3114, PP3115, PP3116, PP3117, PP3118, PP3119, PP3120, and PP3121 can be included in formula (3).

[0167] In one embodiment, the cyclic compound of the present invention exhibits high selectivity for KRAS. Furthermore, in another embodiment, the cyclic compound of the present invention selectively inhibits KRAS. While not constrained by any particular theory, high selectivity for KRAS can be achieved through the interaction of the divalent group formed by the combined R4 and P5 with His95 of KRAS. Three isotypes of RAS proteins are known to exist: HRAS, KRAS, and NRAS. His95 is present only in KRAS. Therefore, a compound that specifically interacts with His95 of KRAS can inhibit KRAS with high selectivity compared to NRAS and / or HRAS.

[0168] In the present invention, the origin of NRAS, HRAS, and KRAS is not particularly limited and may include those derived from various animals such as humans, mice, rats, rabbits, dogs, cats, cattle, horses, pigs, goats, rhesus monkeys, crab-eating macaques, chimpanzees, and chickens, but human-derived HRAS, KRAS, and NRAS are preferred. The amino acid sequence of human-derived NRAS is shown in SEQ ID NO: 1, the amino acid sequence of human-derived HRAS is shown in SEQ ID NO: 2, and the amino acid sequence of human-derived KRAS is shown in SEQ ID NO: 3.

[0169] In one embodiment, the cyclic compound of the present invention exhibits KRAS inhibitory activity at least three times greater than NRAS inhibitory activity and / or HRAS inhibitory activity. In another embodiment, the cyclic compound of the present invention exhibits KRAS binding activity at least three times greater than NRAS binding activity and / or HRAS binding activity.

[0170] In one embodiment, the cyclic compound of the present invention exhibits KRAS inhibitory activity that is 5 times, 7 times, 10 times, 15 times, or 20 times or more compared to NRAS inhibitory activity and / or HRAS inhibitory activity. In one embodiment, the cyclic compound of the present invention exhibits KRAS binding activity that is 5 times, 7 times, 10 times, 15 times, or 20 times or more compared to NRAS binding activity and / or HRAS binding activity.

[0171] In the present invention, the KRAS inhibitory activity relative to NRAS inhibitory activity and / or HRAS inhibitory activity can be determined from the ratio of the NRAS inhibitory activity and / or HRAS inhibitory activity of the cyclic compound of the present invention to the KRAS inhibitory activity of the cyclic compound of the present invention. For example, the ratio can be expressed as follows: [IC of the cyclic compound of the present invention relative to NRAS and / or HRAS] 50 [Value] to [IC value for the cyclic compound of the present invention relative to KRAS] 50 When defined as the value obtained by dividing by [value], a larger value means that the KRAS inhibitory activity against NRAS inhibitory activity and / or HRAS inhibitory activity is large, that is, the selective inhibitory activity of KRAS by the cyclic compound of the present invention is large, and conversely, a smaller value means that the KRAS inhibitory activity against NRAS inhibitory activity and / or HRAS inhibitory activity is small, that is, the selective inhibitory activity of KRAS by the cyclic compound of the present invention is small.

[0172] Furthermore, in the present invention, the binding activity to KRAS relative to the binding activity to NRAS and / or HRAS can be determined from the ratio of the binding activity to NRAS and / or HRAS of the cyclic compound of the present invention to the binding activity to KRAS of the cyclic compound of the present invention. For example, if this ratio is defined as the value obtained by dividing the [KD value for NRAS and HRAS] by the [KD value for KRAS], then a larger value means that the binding activity to KRAS is greater than the binding activity to NRAS and / or HRAS, i.e., the binding selectivity to KRAS relative to NRAS and / or HRAS is greater. Conversely, a smaller value means that the binding activity to KRAS is less than the binding activity to NRAS and / or HRAS, i.e., the binding selectivity to KRAS relative to NRAS and / or HRAS is less.

[0173] In the present invention, "interaction" means non-covalent interactions, such as electrostatic interactions (including ionic bonds, hydrogen bonds, and dipole interactions) and van der Waals interactions (including hydrophobic interactions). For example, it means CH-π interactions, NH-π interactions, S-π interactions, cation-π interactions, or halogen-π interactions. The interactions in the present invention may be mediated by other molecules such as water molecules, or they may not be mediated by other molecules such as water molecules, but it is preferable that the interactions are not mediated by other molecules such as water molecules.

[0174] In this invention, whether or not histidine (represented as His95 or H95), the 95th amino acid residue in the human KRAS wild-type protein, interacts with a cyclic compound can be determined by the interatomic distance between the two non-hydrogen atoms (or, in the case of bonding via other molecules such as water molecules, the interatomic distance between the two non-hydrogen atoms ignoring those other molecules). If the interatomic distance is 5.1 angstroms (Å) or less, it can be determined that the two non-hydrogen atoms are interacting. In some embodiments, the interatomic distance between two interacting non-hydrogen atoms can be, for example, 5.1 Å or less, 4.8 Å or less, 4.5 Å or less, 4.3 Å or less, 4.2 Å or less, 4.1 Å or less, 4.0 Å or less, 3.9 Å or less, or 3.7 Å or less. It can also be 2.0 Å or more, 2.1 Å or more, or 2.5 Å or more.

[0175] In this invention, the interatomic distance can be measured, for example, by analyzing the three-dimensional structure of the complex of human KRAS wild-type protein and the cyclic compound in this invention. Specifically, a crystal of the complex of human KRAS wild-type protein and the cyclic compound in this invention is prepared. X-ray diffraction is performed on the crystal to obtain X-ray diffraction intensity data such as space group and unit cell. By applying the acquired X-ray diffraction intensity data to programs well known to those skilled in the art for determining initial or precise structures, such as Coot (Emsley, P. et al., 2010), Phenix (Adams, PD et al., 2010), Phaser (J. Appl. Cryst. 40: 658-674 (2007)), Refmac5 (Acta Cryst. D67: 355-467 (2011)), and ARP / wARP (Cohen, SX et al., 2008), the three-dimensional structure of the complex of human KRAS wild-type protein and the cyclic compound in the present invention can be determined.

[0176] If the three-dimensional structure of the complex of the human KRAS wild-type protein and the cyclic compound in the present invention can be determined, the interatomic distance can be measured by methods well known to those skilled in the art. For example, by loading the structural information of the complex of the cyclic compound in the present invention and the human KRAS wild-type protein into a software program used for molecular modeling or molecular simulation, such as Discovery Studio 2020 Client, MOE (Molecular Operating Environment), or Maestro, and using a function built into the software program (for example, the Distance Monitor function in the case of Discovery Studio 2020 Client), the interatomic distance can be measured. Furthermore, details on the conditions and criteria used by the software to determine whether or not an interaction exists can be found in the instruction manual and specifications included with the software (for example, in the case of Discovery Studio 2020 Client, you can open the specifications web page from the Help button, select "Receptor-Ligand Interactions tools", then select "Theory-Receptor-Ligand Interactions", and then select "Non-bond Interactions" to see details on the conditions and criteria used to determine whether or not an interaction exists).

[0177] Crystals of the complex of human KRAS wild-type protein and the cyclic compound of the present invention can also be obtained by methods well known to those skilled in the art. For example, a solution containing the cyclic compound of the present invention can be mixed with a solution containing human KRAS wild-type protein to obtain a complex of human KRAS wild-type protein and the cyclic compound of the present invention. The resulting complex can then be subjected to crystallization methods well known to those skilled in the art, such as vapor diffusion, batch methods (bulk batch, microbatch), dialysis, and counterdiffusion, to prepare crystals of the complex of human KRAS wild-type protein and the cyclic compound of the present invention. Known vapor diffusion methods include the sitting drop method, the hanging drop method, and the sandwich drop method.

[0178] Human KRAS wild-type protein can also be obtained by methods known to those skilled in the art. For example, human KRAS wild-type protein can be prepared using recombinant polypeptide expression methods using cells, but is not limited to this. In one embodiment, the nucleic acid encoding the human KRAS wild-type protein of the present invention is inserted into a suitable expression vector, the vector is introduced into suitable cells, the transformed cells are cultured, and the expressed protein is isolated and purified. Such a protein can also be expressed as a fusion protein with other proteins for purposes such as facilitating purification. For example, it is possible to use methods such as preparing it as a fusion protein with maltose-binding protein using Escherichia coli as the host (vector pMAL series sold by New England BioLabs, USA), preparing it as a fusion protein with glutathione-S-transferase (GST) (vector pGEX series sold by Amersham Pharmacia Biotech), preparing it by adding a histidine tag (pET series from Novagen), or preparing it by adding a HAT tag. There are no particular restrictions on the host cell, as long as it is suitable for the expression of recombinant protein. In addition to E. coli mentioned above, yeast, various animal and plant cells, insect cells, etc., can be used. Various methods known to those skilled in the art can be used to introduce the vector into the host cell. For example, a method using calcium ions can be used to introduce the vector into E. coli (Mandel, M., Higa, A. (1970) Journal of Molecular Biology, 53, 158-162, Hanahan, D. (1983) Journal of Molecular Biology, 166, 557-580). The protein expressed in the host cell can be purified and recovered from the host cell, its cell culture, or culture supernatant by methods known to those skilled in the art. When the protein is expressed as a fusion protein with the above-mentioned maltose-binding protein or HAT tag, affinity purification or gel filtration chromatography (size exclusion chromatography, SEC) purification can be easily performed.For affinity chromatography purification and SEC purification, an AKTAxpress™ instrument (GE Healthcare), an NGC™ chromatography system (Bio-Rad), or a BioLogic DuoFlow™ chromatography system (Bio-Rad) can be used.

[0179] Interatomic energy can also be measured by methods well known to those skilled in the art. For example, by loading the 3D structure of the substance to be measured into a molecular simulation program well known to those skilled in the art, such as Discovery Studio 2020 Client, MOE (Molecular Operating Environment), or Maestro, and following the program's instructions to select the force field to be used for the calculation (e.g., Amber, CHARM, etc.) and the atoms to be included in the energy calculation, the calculation can be easily performed. For example, in Discovery Studio 2020 Client, interatomic energy can be calculated using the Calculate Interaction Energy function.

[0180] In one non-limiting embodiment, in a complex of the cyclic compound of the present invention with human KRAS wild-type protein, the cyclic compound of the present invention interacts with His95 in the human KRAS wild-type protein.

[0181] While not bound by any particular theory, it is believed that the formation of a complex between the cyclic compound in this invention and the human KRAS wild-type protein in this manner is related to the high binding activity of the cyclic compound in this invention to the human KRAS wild-type protein, and furthermore, to its binding selectivity to HRAS and NRAS.

[0182] The present invention also relates to unnatural amino acids used in the production of the cyclic compounds of the present invention. In one embodiment, the unnatural amino acid of the present invention is an N-protected unnatural amino acid used in the production of peptide compounds by solid-phase synthesis, and in another embodiment, the unnatural amino acid of the present invention is an unnatural amino acid having a free amino group obtained by removing the protecting group from an N-protected unnatural amino acid. Examples of protecting groups for N-protected unnatural amino acids include Fmoc group, Boc group, Cbz group, Alloc group, nosyl group, dinitronosyl group, t-Bu group, trityl group, cumyl group, etc., of which Fmoc group, Boc group, Cbz group, and Alloc group are preferred, and Fmoc group is more preferred.

[0183] In one aspect, the N-protected unnatural amino acids having an Fmoc group as a protecting group in the present invention include, for example, the following amino acids or salts thereof listed in Table 4, or solvates thereof. aa004: (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]octanoic acid, aa013: (2R)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-methylsulfanyl-propanoic acid, aa019: (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4,4-difluorobutanoic acid, aa023: (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-(3-thienyl)propanoic acid, aa028: (2S)-3-(3,4-dichlorophenyl)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid, aa043: (2S)-5,5-dichloro-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]pentanoic acid, aa056: (2R)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-2-methyl-propanoic acid, aa098: (2S,3S)-1-(9H-fluoren-9-ylmethoxycarbonyl)-3-methylazetidine-2-carboxylic acid, aa099: (2S,3R)-1-(9H-fluoren-9-ylmethoxycarbonyl)-3-methylazetidine-2-carboxylic acid, aa100: (2S)-1-(9H-fluoren-9-ylmethoxycarbonyl)-3,3-dimethyl-azetidine-2-carboxylic acid, aa111: (2R)-3-allyloxy-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid, aa136: (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(propyl)amino]-3-[4-(trifluoromethyl)phenyl]propanoic acid, aa174: (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(propyl)amino]-3-(p-tolyl)propanoic acid, aa210: (2S)-2-cyclopentyl-2-[ethyl(9H-fluoren-9-ylmethoxycarbonyl)aminoacetic acid, aa220: (2S)-4-(4-chloro-3,5-difluorophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, aa229: (2S)-4-(benzothiophen-5-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, aa233: (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-[3-methyl-4-(trifluoromethyl)phenyl]butanoic acid, aa235: (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-[3-methoxy-4-(trifluoromethyl)phenyl]butanoic acid, aa239: (2S,4S)-1-(9H-fluoren-9-ylmethoxycarbonyl)-4-methyl-pyrrolidine-2-carboxylic acid, aa244: (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-5,5-difluoropentanoic acid, aa246: (2S,4R)-1-(9H-fluoren-9-ylmethoxycarbonyl)-4-propoxy-pyrrolidine-2-carboxylic acid, aa250: (2R)-2-[9H-fluorene-9-ylmethoxycarbonyl(methyl)amino]-3-propoxy-propanoic acid, aa264: (2S,3R)-1-(9H-fluoren-9-ylmethoxycarbonyl)-3-hydroxy-pyrrolidine-2-carboxylic acid, aa265: (2S,3S)-1-(9H-fluoren-9-ylmethoxycarbonyl)-3-hydroxy-pyrrolidine-2-carboxylic acid, aa268: (1S,2S,5R)-3-(9H-fluorene-9-ylmethoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid, aa279: (2S,4R)-1-(9H-fluoren-9-ylmethoxycarbonyl)-4-tetrahydropyran-2-yloxy-pyrrolidine-2-carboxylic acid, aa281: (2S,4R)-1-(9H-fluoren-9-ylmethoxycarbonyl)-4-methoxy-pyrrolidine-2-carboxylic acid, aa331: (2S)-3-ethyl-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]pentanoic acid. aa389: (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(propyl)amino]-4-methylpentanoic acid, aa391: (2S,3R)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-propoxy-butanoic acid, aa397: (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(propyl)amino]-3-isopentyloxy-propanoic acid, aa398: (2S)-3-(cyclobutoxy)-2-[9H-fluoren-9-ylmethoxycarbonyl(propyl)amino]propanoic acid, aa399: (2S)-4-(7-chloro-1-methyl-indole-5-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, aa400: (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(2-fluoro-3-methyl-benzothiophen-5-yl)butanoic acid, aa401: (2S)-4-(7-chlorobenzothiophen-5-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, aa402: (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(1-methylindole-6-yl)butanoic acid, aa403: (2S)-4-(1,3-dimethylindole-6-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, aa404: (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(1,2,3-trimethylindole-6-yl)butanoic acid, aa405: (2S)-4-(2,3-dimethylbenzothiophen-5-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, aa406: (2S)-4-(3-chloro-4-ethyl-phenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, aa407: (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-[4-(methoxymethyl)-3,5-dimethylphenyl]butanoic acid, aa408: (2S)-4-(4-chloro-3-methoxyphenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, aa409: (2S)-4-[4-chloro-3-(trifluoromethyl)phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, aa410: (2S)-4-[4-(difluoromethyl)-3,5-difluorophenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, aa411: (2S)-4-(4-chloro-3,5-dimethylphenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, aa414: (2S,4R)-4-(cyclopentoxy)-1-(9H-fluoren-9-ylmethoxycarbonyl)pyrrolidine-2-carboxylic acid, aa415: (2S,4R)-4-(cyclobutoxy)-1-(9H-fluoren-9-ylmethoxycarbonyl)pyrrolidine-2-carboxylic acid, aa423: (3S)-3-cyclobutyl-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid, aa424: (3R)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]pentanoic acid, aa425: (3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-methylpentanoic acid, aa426: (3S)-3-cyclohexyl-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid, and aa443: (2S)-2-[buta-3-enyl(9H-fluoren-9-ylmethoxycarbonyl)amino]-3-(p-tolyl)propanoic acid.

[0184] (General manufacturing method) This document describes the cyclic compounds of the present invention, as well as general methods for producing oligopeptide compounds and unnatural amino acids used in the production of these compounds. In this specification, cyclic compounds may sometimes be referred to as "cyclic peptide compounds." In this specification, the "cyclic portion" of a peptide compound refers to the ring portion formed by the linkage of two or more amino acid residues.

[0185] Chemical synthesis methods for peptide compounds Examples of chemical synthesis methods for peptide compounds or cyclic compounds as described herein include liquid-phase synthesis, solid-phase synthesis using Fmoc synthesis or Boc synthesis, and combinations thereof. In Fmoc synthesis, the main chain amino group is protected by an Fmoc group, and the side chain functional group is protected as needed by a protecting group that is not cleaved by basics such as piperidine, such as a t-Bu group, THP group, or Trt group, and the main chain carboxylic acid is not protected. The basic unit is an amino acid. The basic unit is not particularly limited as long as it is a combination of an Fmoc-protected amino group and a carboxyl group. For example, dipeptides and tripeptides may be used as the basic unit, and a cyclic structure may be formed between the substituent and / or side chain of the nitrogen atom contained in the dipeptide or tripeptide. The basic unit to be placed at the N-terminus may be something other than an Fmoc amino acid. For example, it may be a Boc amino acid, a Tfa group or an Ns group, or a carboxylic acid analog that does not have an amino group. The carboxyl group of an amino acid having a carboxyl group in its main chain or a side chain protected by an appropriate protecting group is supported on a solid phase by a chemical reaction with the functional group of the solid phase support. Subsequently, the Fmoc group is deprotected with a base such as piperidine or DBU, and the newly formed amino group is condensed with the subsequently added protected amino acid having a carboxyl group to generate a peptide bond. In the condensation reaction, various combinations of carboxyl group activators are possible, such as a combination of DIC and HOBt, a combination of DIC and HOAt, and a combination of HATU and DIPEA. By repeating the de-Fmoc group removal and subsequent peptide bond formation reaction, the desired peptide sequence can be generated. After the desired sequence is obtained, it is cleaved from the solid phase and, if necessary, the protecting group of the introduced side chain functional group is deprotected. It is also possible to perform structural transformation or cyclization of the peptide before cleaving from the solid phase. The extraction from the solid phase and deprotection can be carried out under the same conditions, for example, 90:10 TFA / H2O, or deprotection can be carried out under different conditions as needed.For solid-phase cleavage, some compounds can be cleaved using a weak acid such as 1% TFA, while others can utilize the orthogonality of the chemical reactions by using protecting groups that can be deprotected with Pd-containing catalysts. Cyclization and other steps can be performed during or at the end of these processes. For example, the side-chain carboxylic acid can be condensed with the amino group of the N-terminal main chain, or the side-chain amino group can be condensed with the carboxylic acid of the C-terminal main chain. Furthermore, olefins can be introduced at two or more substituents on the side chain and / or nitrogen atom, and cyclization can be performed by metathesis. In addition, the double bond resulting from cyclization can be reduced to a single bond. It is also possible to convert the double bond resulting from cyclization into a cyclopropane ring under conditions such as diiodomethane-diethylzinc. Note that these steps of cyclization, reduction, and conversion to a cyclopropane ring may be performed within the process of synthesizing basic units such as dipeptides and tripeptides. Furthermore, reaction orthogonality is required between the C-terminal carboxylic acid and the side-chain carboxylic acid to be cyclized, between the N-terminal main-chain amino group or hydroxyl group and the side-chain amino group to be cyclized, or between the olefin substituent on the side chain and / or nitrogen atom and the olefin to be cyclized. As mentioned above, the selection of protecting groups is made considering the orthogonality of the protecting groups. It is also possible to cyclize with the thiol group on the side chain of the cysteine ​​residue by positioning a chloroacetyl group at the N-terminus. The reaction products obtained in this way can be purified using reversed-phase columns or molecular sieve columns. Details of these processes are described, for example, in the Solid-Phase Synthesis Handbook published by Merck KGaA on May 1, 2002. Commercially available resins can be used for solid-phase synthesis, with CTC resin, Wang resin, or SASRIN resin being examples.

[0186] The following describes a general method for synthesizing amino acid-supported resins used in peptide synthesis using a peptide synthesizer.

[0187] The loading of Fmoc amino acids onto resin can be carried out according to the method described in WO2013 / 100132 or WO2018 / 225864. Specifically, for example, 2-chlorotrityl chloride resin and a solvent (e.g., dehydrated dichloromethane) are placed in a filtered reaction vessel and the resin is allowed to swell. The solvent and resin are then separated, and a mixture of the resin, C-terminus-free Fmoc amino acids dissolved in the solvent (e.g., dehydrated dichloromethane), a solvent (e.g., dehydrated methanol), and a base (e.g., diisopropylethylamine) is added to the reaction vessel and mixed to load the Fmoc amino acids onto the resin. After separating the resin from the reaction mixture, the resin is washed by mixing it with a mixture of one or more solvents and bases (e.g., a mixture of dehydrated dichloromethane, dehydrated methanol, and diisopropylethylamine). After washing the resin with a solvent (e.g., dichloromethane) multiple times as needed, the resin and reaction mixture are separated. By drying the resulting resin under reduced pressure overnight, a resin supporting Fmoc amino acids can be obtained. [ka] (In the formula, n represents an integer from 1 to 11, and P1 to P 11 Q1~Q 11 R1~R 11 P1 to P as defined herein 11 Q1~Q 11 R1~R 11 These mean L1 and L respectively. 11 L1 and L as described in this specification 11 These mean L2~L 10 (This represents a single bond, and ○ indicates a resin portion.) In the structure shown above, the 2-chlorotrityl group on the resin in the Fmoc amino acid is bonded to the carboxylic acid of the Fmoc amino acid via an ester bond.

[0188] In the production of the compounds described herein, if the defined group undergoes an undesirable chemical transformation under the conditions of the method, the compound can be produced by means such as functional group protection or deprotection. Examples of methods for selecting and deprotecting protecting groups include those described in "Greene's, 'Protective Groups in Organic Synthesis' (5th edition, John Wiley & Sons 2014)," which may be used as appropriate depending on the reaction conditions. Furthermore, the order of reaction steps, such as substituent introduction, can be changed as needed. For example, examples of amino group protecting groups include Fmoc, Boc, Cbz, or Alloc groups. These carbamate groups can be introduced by reacting the amino group with a carbamate agent in the presence of a base catalyst. Examples of carbamate agents include Boc2O, BocOPh, FmocOSu, FmocCl, CbzCl, and AllocCl. Examples of base catalysts include lithium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium phosphate, potassium phosphate, N-methylmorpholine, triethylamine, diisopropylethylamine, and N,N-dimethylaminopyridine. The carbamate group, which is the protecting group for the amino group, can be removed under basic conditions, acidic conditions, or conditions of hydrolysis.

[0189] ( (Method for synthesizing cyclic compounds by cyclization of peptide compounds) Methods for converting linear peptide compounds into cyclic compounds can be carried out by intramolecular bond formation reactions, as described in "Comprehensive Organic Transformations, A Guide to Functional Group Preparations, 3rd Edition, by RC Larock" or "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition, by MB March." Further functional group transformation reactions can also be performed after the bond formation reaction. Examples of bond formation reactions include C(O)-N bonds formed from carboxylic acids and amines, COC bonds, C(O)-O bonds, C(S)-O bonds utilizing oxygen atoms, C(O)-S bonds, C(S)-S bonds, CSSC bonds, CSC bonds, CS(O)-C bonds, CS(O2)-C bonds utilizing sulfur atoms, and CNC bonds, C=NC bonds, NC(O)-N bonds, NC(S)N bonds, and C(S)-N bonds utilizing nitrogen atoms. Furthermore, examples include transition metal-catalyzed CC bond formation reactions such as the Suzuki reaction, Heck reaction, Sonogashira reaction, and metathesis reaction. Following bond formation reactions, further functional group transformation reactions include oxidation or reduction reactions. Specifically, examples include reactions that oxidize sulfur atoms to convert them into sulfoxide or sulfone groups. Also, examples include reduction reactions that reduce triple or double carbon-carbon bonds to convert them into double or single bonds. When two amino acids are bonded in the main chain of an amino acid, a ring-closed structure is formed by a peptide bond; however, covalent bonds between two amino acids may also be formed by bonding of the side chains of the two amino acids, or between the side chains and the main chain. In the following, black circles or black squares represent amino acid residues, and linked black circles or black squares represent peptide chains linked by amide bonds. There are no particular restrictions on the number of amino acid residues constituting a peptide chain; the number of amino acid residues is not limited to the number of black circles or black squares exemplified below.

[0190] ( General method for producing cyclic compounds 1 ) [ka] The cyclic portion of a cyclic compound with a linear chain can be cyclized by activating the N-terminal amino group and the C-terminal carboxyl group (for example, L=-CH2- in the case of aspartic acid and its derivatives, and L=-CH2CH2- in the case of glutamic acid and its derivatives) with an activating reagent or by converting them to an activated ester, followed by an intramolecular condensation reaction to form a C(O)-N bond.

[0191] ( General method for producing cyclic compounds 2 ) [ka]

[0192] In cyclic compounds where the linear portion is a C-terminus, as described in General Method 1 for the Preparation of Cyclic Compounds, the N-terminal amino group and the carboxyl group of the C-terminal side chain (for example, L=-CH2- in the case of aspartic acid and its derivatives, and L=-CH2CH2- in the case of glutamic acid and its derivatives) can be activated with an activating reagent or converted to an activated ester, and then cyclized by an intramolecular condensation reaction to form a C(O)-N bond.

[0193] ( General method for producing cyclic compounds 3 ) (Method of cyclization using a haloalkyl group and an SH group) [ka] The cyclic portion of a cyclic compound having a linear portion can be cyclized by forming a CSC bond through intramolecular reaction between the haloalkyl group of an amino acid residue and the thiol group of an amino acid residue. Similarly, in cyclic compounds where the linear portion is a C-term, as described in General Synthesis Method 1 for Cyclic Compounds, cyclization can be achieved by forming a CSC bond through intramolecular reaction between the haloalkyl group of an amino acid residue and the thiol group of an amino acid residue. Furthermore, the sulfur atom can be oxidized to a sulfoxide or sulfone to form a CS(O)-C bond or a CS(O2)-C bond.

[0194] (Method of cyclization using vinyl and SH groups) [ka] The cyclic portion of a cyclic compound having a linear portion can be cyclized by forming a CSC bond through intramolecular reaction between the vinyl group of an amino acid residue and the thiol group of an amino acid residue. Similarly, in cyclic compounds where the linear portion is a C-term, as described in General Synthesis Method 1 for Cyclic Compounds, cyclization can be achieved by forming a CSC bond through intramolecular reaction between the vinyl group of an amino acid residue and the thiol group of an amino acid residue. Furthermore, the sulfur atom can be oxidized to a sulfoxide or sulfone to form a CS(O)-C bond or a CS(O2)-C bond.

[0195] (Method of cyclization using an ethynyl group and an SH group) [ka] The cyclic portion of a cyclic compound with a linear chain can be cyclized by forming a CSC bond through intramolecular reaction between the ethynyl group of an amino acid residue and the thiol group of an amino acid residue. Similarly, in cyclic compounds where the linear portion is a C-term, as described in General Synthesis Method 1 for Cyclic Compounds, cyclization can be achieved by forming a CSC bond through intramolecular reaction between the ethynyl group of an amino acid residue and the thiol group of an amino acid residue. Furthermore, the sulfur atom can be oxidized to a sulfoxide or sulfone, forming a CS(O)-C bond or a CS(O2)-C bond. The double bond site can also be reduced to a single bond.

[0196] (Method of cyclization using vinyl groups) [ka] The cyclic portion of a cyclic compound having a linear portion can be cyclized by forming a CC bond through intramolecular reaction between vinyl groups with different amino acid residues. Similarly, in cyclic compounds where the linear portion is a C-term, as described in General Synthesis Method 1 for Cyclic Compounds, cyclization can be achieved by forming a CC bond through intramolecular reaction between vinyl groups with different amino acid residues.

[0197] (A method of cyclization by forming a triazole ring with an azide group and an ethynyl group) [ka] The cyclic portion of a linear compound can be cyclized by reacting the azide group of an amino acid residue with the ethynyl group of an amino acid residue intramolecularly to form a triazole ring. Similarly, in cyclic compounds where the linear portion is a C-term, as described in General Manufacturing Method 1 for Cyclic Compounds, the azide group of an amino acid residue with the ethynyl group of an amino acid residue can be reacted intramolecularly to form a triazole ring.

[0198] The following shows a general method for producing peptide compounds by peptide modification. In the following scheme, P n R represents a substituent on the nitrogen atom. n and Q n The '' represents the side chain of an amino acid, the black circle indicates an amino acid residue, the linked black circles represent a peptide chain linked by an amide bond, and 'm' indicates the number of amino acid residues and can take any integer value greater than or equal to 1.

[0199] (Method for producing peptides containing N-alkyl amino acids) Peptides containing N-alkyl amino acids can be produced not only by the general peptide synthesis method described in this example using Fmoc-protected N-alkyl amino acids as raw materials, but also by alkylation of the N-terminal nitrogen on a resin as shown below. Specifically, the nitrogen of the Tfa amide (trifluoroacetamide) at the N-terminus of a peptide supported on a resin is reacted with an alkyl halide under basic conditions, and then treated with a reducing agent, referring to Organic Letters, 2008, 10, 4815-4818, etc., to produce a peptide having the desired N-alkyl amino acid at the N-terminus. Furthermore, cyclic compounds can be produced by peptide elongation, cleavage from the resin, cyclization, deprotection, and purification according to the general peptide synthesis method described in this example. [ka]

[0200] P is attached to the nitrogen at the N-terminus. n Alternatively, the method described in Nature Protocols, 2012, 7, 432-444 below can also be used to introduce P. Specifically, the N-terminal amine of the peptide supported on the resin is converted to an Ns-substituted compound, and then P is introduced via the Mitsunobu reaction. n By introducing and then deprotecting the Ns group, the target P is achieved. n A peptide having the N-terminus can be obtained. Furthermore, a cyclic compound can be produced by peptide elongation, cleavage from resin, cyclization, deprotection, and purification according to the general peptide synthesis method described in this example. [ka]

[0201] P on the nitrogen atom n As a method for synthesizing peptides containing glycine into which P is introduced, nIn addition to the method of synthesis using glycine with introduced P as a raw material according to the general peptide synthesis method described in this example, it can also be produced by the substitution reaction of the N-terminal halogenated carbon with an amine as shown in the following method. Specifically, by reacting the N-terminal amine with iodoacetic acid and then reacting it with any primary amine, referring to Organic Letters, 2010, 12, 4928-4931, the desired nitrogen atom can be subjected to P n A peptide having a glycine molecule with the addition of the compound introduced into it at its N-terminus can be obtained. Furthermore, a cyclic compound can be produced by peptide elongation, cleavage from resin, cyclization, deprotection, and purification according to the general peptide synthesis method described in this example. [ka]

[0202] (Method for producing peptides containing an aryloxy group or heteroaryloxy group in the side chain) Peptides containing an aryloxy group or heteroaryloxy group in their side chain can be produced in addition to the general peptide synthesis method described in this example, using an Fmoc amino acid having the desired aryloxy group or heteroaryloxy group in its side chain as a raw material. Alternatively, they can be produced using a peptide containing an alcohol in its side chain as a precursor, as described below, with reference to Organic Letters, 2014, 16, 4944-4947 or Tetrahedron Letters, 2003, 44, 3863-3865, etc. Specifically, peptides containing an aryloxy group or heteroaryloxy group in their side chain can be produced by reacting a peptide containing an alcohol in its side chain with a triarylboroxane-pyridine complex in the presence of copper(II) acetate. [ka]

[0203] Peptides having an ether group other than an aryloxy group or heteroaryloxy group in their side chain can be produced not only by the general peptide synthesis method described in this example using an Fmoc amino acid having the desired ether group in its side chain as a raw material, but also by using a peptide having an alcohol in its side chain as a precursor, as described in the following methods, with reference to the methods described in Journal of Medicinal Chemistry, 2011, 54, 4815-4830 or Journal of Medicinal Chemistry, 2014, 57, 159-170. Specifically, peptides having the desired ether group in their side chain can be produced by reacting an alcohol-containing peptide with an alkyl halide in the presence of silver(I) oxide, or by reacting an alkyl halide with a phase-transfer catalyst such as a tetraalkylammonium salt using an aqueous sodium hydroxide solution as a base. [ka]

[0204] (Method for producing peptides containing aryl or heteroaryl groups in their side chains) Peptides having an aryl group or heteroaryl group in their side chain can be produced not only by the general peptide synthesis method described in this example, using an Fmoc amino acid having the desired aryl group or heteroaryl group in its side chain as a raw material, but also by using a peptide having a carboxylic acid in its side chain as a precursor, as shown in the following method, and referring to the method described in J.Am.Chem.Soc.,2016,138,5016-5019. Specifically, a peptide having a carboxylic acid in its side chain can be activated with N-hydroxyphthalimide and reacted with an arbitrary aryl halide or heteroaryl halide to produce a peptide having the desired aryl group or heteroaryl group in its side chain. [ka]

[0205] Furthermore, it is possible to produce peptide compounds with cross-linked peptide backlines using peptides that have a carboxylic acid substituent on a nitrogen atom and / or a carboxylic acid in their side chain, and an aryl halide or heteroaryl halide substituent on another nitrogen atom within the molecule and / or a side chain. Specifically, cross-linked compounds can be produced by activating a peptide with a carboxylic acid with N-hydroxyphthalimide and cross-linking it through a reaction with an aryl halide or heteroaryl halide within the molecule. [ka]

[0206] As an alternative method for producing peptides having an aryl group or heteroaryl group in the side chain, they can also be synthesized by Suzuki coupling using a peptide having a boronic acid in the side chain as a precursor, as shown in the following method. Specifically, a precursor peptide can be synthesized using an Fmoc amino acid having a boronic acid in the side chain as a starting material, and then reacted with an arbitrary aryl halide in the presence of a palladium catalyst to produce a peptide having an aromatic ring in the side chain. [ka]

[0207] Furthermore, it is possible to produce peptide compounds with cross-linked peptide main chains using peptides that have a boronic acid substituent on a nitrogen atom and / or a side chain, and an aryl halide substituent on another nitrogen atom within the molecule and / or a side chain. Specifically, cross-linked compounds can be produced by cross-linking a peptide containing a boronic acid with an aryl halide within the molecule in the presence of a palladium catalyst. [ka]

[0208] Furthermore, peptides having an olefin substituent on a nitrogen atom and / or a side chain, and an aryl halide substituent on another nitrogen atom within the molecule and / or a side chain, can be used to produce peptide compounds crosslinked with alkylenes containing arylene. Specifically, crosslinked compounds can be produced by converting the olefin to a boron compound through a hydroboration reaction, and then crosslinking it by reacting it with the intramolecular aryl halide in the presence of a palladium catalyst. [ka]

[0209] (Method for producing peptides containing amide groups in the side chain) Peptides having an amide group in their side chain can be synthesized not only by using an Fmoc amino acid having the desired amide group in its side chain as a starting material, but also by amidation using a peptide having a carboxylic acid in its side chain as a precursor, as shown in the following method. Specifically, a precursor peptide having a carboxylic acid in its side chain can be synthesized by deprotecting a peptide having a protected carboxylic acid in its side chain, and then condensing it with an arbitrary amine using HATU or the like as a coupling agent to obtain the peptide having an amide group in its side chain. [ka]

[0210] Furthermore, it is possible to produce peptide compounds with cross-linked peptide backlines using peptides that have a carboxylic acid substituent on a nitrogen atom and / or a carboxylic acid on a side chain, and an amino group substituent on another nitrogen atom within the molecule and / or a side chain. Specifically, cross-linked compounds can be produced by synthesizing a precursor peptide having a carboxylic acid and an amino group through deprotection, and then cross-linking it via an intramolecular amidation reaction by condensation using a coupling agent such as HATU. [ka]

[0211] (Synthesis of peptides containing highly substituted structures that may include double bonds in their side chains) The synthesis of peptides having highly substituted structures that may contain double bonds in their side chains can be carried out not only by using Fmoc amino acids having double bonds in the target side chains as raw materials, but also by functionalization of terminal olefins. Specifically, peptides having terminal olefins in their side chains can be synthesized according to the general peptide synthesis method described in this example, and then converted to side chains with highly substituted olefins by coupling with a substrate having an arbitrary terminal olefin via an olefin metathesis reaction. Furthermore, the olefins can be converted to the corresponding side chains by reduction via a hydrogenation reaction. [ka]

[0212] Furthermore, peptide compounds with a crosslinked peptide main chain can be produced using peptides that have multiple double bonds in the nitrogen atom substituent and / or side chain. Specifically, a peptide having olefins at two locations in the nitrogen atom substituent and / or side chain can be synthesized according to the general peptide synthesis method described in this example, and then, referring to Nature Protocols, 2011, 6, 761-771, the two olefins can be crosslinked by an olefin metathesis reaction to produce a crosslinked compound. Furthermore, a compound crosslinked with saturated alkylene can be produced by reducing the olefin by a hydrogenation reaction. [ka]

[0213] Furthermore, as the above-mentioned crosslinked compounds, peptides containing an aryl group having an olefin-containing substituent on the nitrogen atom and / or in the side chain can be used to produce peptide compounds crosslinked with arylene and a divalent group containing a double bond. Specifically, a peptide having an aryl group containing an olefin and an olefin on the nitrogen atom substituent and / or in the side chain can be synthesized according to the general peptide synthesis method described in this example, and a crosslinked compound can be produced by crosslinking the two olefins by an olefin metathesis reaction. Furthermore, a compound crosslinked with alkylene containing arylene can be produced by reducing the olefin by a hydrogenation reaction. [ka]

[0214] (Synthesis of peptides containing triazole in the side chain) Peptides having a triazole group in their side chain can be produced by a click reaction with an azide group. Specifically, peptides having an azide group in their side chain can be synthesized according to the general peptide synthesis method described in this example, and then, referring to Bioorganic & Medicinal Chemistry Letters, 2009, 19, 4130-4133, etc., peptide compounds having an azide group in their side chain can be produced by coupling them with any acetylene in the presence of copper(I) iodide. [ka]

[0215] Furthermore, it is possible to produce peptide compounds with crosslinked peptide main chains using peptides that have an azide group as a substituent on a nitrogen atom and / or a side chain, and an acetylene group as a substituent on another nitrogen atom and / or a side chain within the molecule. Specifically, crosslinked compounds can be produced by crosslinking a peptide having an azide group with intramolecular acetylene in the presence of a palladium catalyst. [ka]

[0216] (Synthesis of peptides containing aryl groups substituted with alkynyl groups in the side chain) Peptides containing aryl groups substituted with alkynyl groups in their side chains can be synthesized by Sonogashira coupling reactions with aryl halides. Specifically, peptides having aryl iodide groups in their side chains can be synthesized according to the general peptide synthesis method described in this example, and then converted into peptide compounds having aryl groups substituted with alkynyl groups in their side chains by coupling them with any acetylene in the presence of copper(I) iodide. [ka]

[0217] Furthermore, it is possible to produce peptide compounds with crosslinked peptide main chains using peptides that have an aryl halide group as a substituent on a nitrogen atom and / or a side chain, and an acetylene group as a substituent on another nitrogen atom and / or a side chain within the molecule. Specifically, crosslinked compounds can be produced by crosslinking a peptide having an aryl iodide group with an acetylene group within the molecule in the presence of copper(I) iodide. [ka]

[0218] (General method for producing oligopeptide compounds) The following shows a general method for producing oligopeptides that form a cyclic structure with a substituent on the nitrogen atom and a side chain. In the following scheme, PG1 and PG1' are protecting groups for the nitrogen atom, PG2 and PG2' are protecting groups for the oxygen atom, and R n-1 , R n , R n+1 Q n P is the side chain of an amino acid. n-1 , P n , P n+1is a substituent on the nitrogen atom, and Y1 and Y2 represent hydrogen, halogen, or alkyl, respectively. In the amino acid production methods shown below, chemical reactions may occur in functional groups other than the target functional group. In such cases, the desired reaction can be controlled by introducing a protecting group to the unintended functional group. Examples of such protecting group desorption reactions include the method described in "Greene's, "Protective Groups in Organic Synthesis" (5th edition, John Wiley & Sons 2014)". For functional group transformation reactions of compounds, refer to Larock's "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" (5th edition) and Smith's "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" (8th edition).

[0219] Oligopeptide compounds in which a cyclic structure is formed between a substituent on the nitrogen atom of an amino acid and the side chain of another amino acid can be synthesized using the following method. An alkyl group containing an olefin can be introduced into a protected amino acid by reacting it with an alkylating agent containing an olefin in the presence of a base. Then, any amino acid can be extended to the C-terminus by condensation with any C-terminus protected amino acid. Various combinations of carboxyl group activators are possible in the condensation reaction, such as a combination of DIC and HOBt, a combination of DIC and HOAt, or a combination of HATU and DIPEA. Subsequently, after deprotecting the protecting group on the nitrogen atom, a protected amino acid with an olefin in the side chain can be extended. Then, the intramolecular olefin can be cyclized by a metathesis reaction. Finally, by deprotecting the protecting group at the C-terminus, a C-terminus-free oligopeptide compound can be produced that forms a cyclic structure containing a double bond between the substituent on the nitrogen atom and the side chain. [ka]

[0220] Furthermore, using oligopeptide compounds that form a cyclic structure containing a double bond, it is possible to produce oligopeptide compounds having a cyclic structure in which the double bond is converted to a single bond. Specifically, by reducing a C-terminally protected compound that forms a cyclic structure containing a double bond by hydrogenation, and then deprotecting the C-terminal protecting group, a C-terminally free oligopeptide compound that forms an alkylene cyclic structure between the nitrogen atom substituent and the side chain can be produced. [ka]

[0221] Furthermore, using an oligopeptide compound that forms a cyclic structure containing a double bond, an oligopeptide compound having a cross-linked structure can be produced in which the double bond is converted to a cyclopropane ring. Specifically, the double bond can be converted to a cyclopropane ring under conditions such as diiodomethane-diethylzinc for a C-terminal protected compound that forms a cyclic structure containing a double bond. Then, by deprotecting the C-terminal protecting group, an oligopeptide compound having a cross-linked structure in which the double bond is converted to a cyclopropane ring can be produced. [ka]

[0222] Oligopeptide compounds in which a substituent on the nitrogen atom of an amino acid and the side chain of another amino acid form a cyclic structure can also be synthesized using the following method. By reacting a protected amino acid with an aldehyde according to the method of Freidinger et al. (J. Org. Chem., 1983, 48(1), 77-81), an oxazolidinone compound with a cyclic protecting group can be obtained. Next, by performing a ring-opening reaction using a silicon compound containing an olefin according to the method of Nguyen et al. (Synthesis, 2009, 12, 1991), an alkyl group containing an olefin can be introduced on the nitrogen atom. Then, by condensing any amino acid with a protected C-terminus, any amino acid can be extended to the C-terminus. Subsequently, after deprotecting the protecting group on the nitrogen atom, a protected amino acid with an olefin in its side chain can be extended. Finally, the intramolecular olefin can be cyclized by a metathesis reaction. Subsequently, by deprotecting the C-terminal protecting group, a C-terminus-free oligopeptide compound can be produced that forms a cyclic structure containing a double bond between the nitrogen atom substituent and the side chain. [ka]

[0223] The synthesis of oligopeptides containing aryl groups substituted with alkenyl groups (y=0-2) in their side chains can be carried out by a Suzuki coupling reaction between an aryl halide group and a boron compound having an alkenyl group. Specifically, a peptide having an aryl iodide group in its side chain can be synthesized according to the general oligopeptide synthesis method described in this example, and then converted into an oligopeptide compound having an aryl group substituted with an alkenyl group (y=0-2) in its side chain by coupling it with a boron compound having any alkenyl group in the presence of a palladium catalyst. [ka]

[0224] Oligopeptide compounds in which a cyclic structure is formed by an amide bond between a substituent on the nitrogen atom of an amino acid and the side chain of another amino acid can be synthesized using the following method. Specifically, a C-terminus protected peptide can be synthesized according to the general synthesis method described in this example, the N-terminus can be deprotected, and then an amino group with a protecting group can be introduced to the N substituent by a reductive amination reaction with an aldehyde compound containing an amino group with a protecting group. Subsequently, after condensation with a protected amino acid containing a carboxyl group with a protecting group on its side chain, the protecting groups on the carboxyl group and the amino group are removed, and then intramolecular condensation is performed, followed by deprotection of the C-terminus, thereby converting it into an oligopeptide compound in which a cyclic structure is formed by an amide bond between a substituent on the nitrogen atom of an amino acid and the side chain of another amino acid. [ka]

[0225] (Cyclization method of peptide compounds on resin) Cyclic compounds and oligopeptide compounds having a cyclic structure can be cyclized according to the method described in this example, as well as by a metathesis reaction on a resin as shown in the following method. Specifically, a peptide having olefins at two positions on the nitrogen atom substituent and / or the side chain can be synthesized as a peptide supported on a resin according to the general peptide synthesis method described in this example, and a compound having a cyclic structure can be produced by cyclizing the two olefin positions by a metathesis reaction. Furthermore, cyclic compounds and oligopeptide compounds having a cyclic structure can be produced by peptide elongation, cleavage from the resin, cyclization, deprotection, and purification according to the general peptide synthesis method described in this example. [ka]

[0226] (General manufacturing methods for non-natural amino acids) The following shows a general method for producing C-terminus-free, unnatural amino acids with protected nitrogen atoms. In the following scheme, PG1 and PG1' are nitrogen atom protecting groups, PG2 and PG2' are oxygen atom protecting groups, PG3 and PG4 are amino acid side chain protecting groups, and R n and Q n P is the side chain of an amino acid. n ' is a substituent on a nitrogen atom, P' is a C1-C5 alkyl group, and R, R', R'', and R''' are substituents on a hydrogen or amino group. In the amino acid production methods shown below, chemical reactions may occur in functional groups other than the target group. In such cases, the desired reaction can be controlled by introducing a protecting group to the unintended functional group. Examples of such protecting group desorption reactions can be found in the method described in Greene's "Protective Groups in Organic Synthesis" (5th edition, John Wiley & Sons 2014). For functional group transformation reactions of compounds, refer to Larock's "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" (5th edition) and Smith's "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" (8th edition).

[0227] The following method can be used to produce non-natural amino acids in which a protecting group (PG1) is introduced to the nitrogen atom of the amino acid. By performing a protecting group introduction reaction and, if necessary, a deprotection reaction on an N-terminus-free amino acid available from a commercial supplier according to a standard procedure, the desired C-terminus-free non-natural amino acid can be produced. [ka]

[0228] The following method can be used to produce unnatural amino acids in which a protecting group (PG1') is introduced to the nitrogen atom of the amino acid. By performing a deprotection reaction and a protecting group introduction reaction using standard methods on an amino acid with a protecting group (PG1) introduced at the N-terminus, which is available from a commercial supplier, the desired C-terminus-free unnatural amino acid can be produced. [ka]

[0229] Substituents of the nitrogen atom of an amino acid (P n The following method can be used to produce non-natural amino acids in which an aminoalkyl group has been introduced: A bromoacetate derivative available from a commercial supplier is reacted with an amino alcohol according to the method of King et al. (Tetrahedron Letters, 2002, 43(11), 1987-1990), and then a protecting group (PG1) is introduced to the nitrogen atom. Next, the hydroxyl group is oxidized according to the method of Dess et al. (J. Org. Chem., 1983, 48(22), 4155-4156), and then the aldehyde group is subjected to a reductive amination reaction according to the method of Borch et al. (J. Org. Chem. 1972, 37(10), 1673-1674) to introduce an amino group. Finally, the protecting group of the oxygen atom is deprotected to produce the desired C-terminus-free non-natural amino acid. [ka]

[0230] N-substituted amino acids are amino acids in which the substituent (P) of the nitrogen atom of the amino acid is replaced. n It can also be manufactured by the following scheme, which involves introducing ) into a bromoacetate derivative available from a commercial supplier, in the presence of a base, an amine (P n By reacting NH2) and then introducing a protecting group (PG1) to the nitrogen atom, and then deprotecting the oxygen atom, the desired C-terminus-free non-natural amino acid can be produced. [ka]

[0231] Unnatural amino acids, in which a -CH2-P' group is introduced to the nitrogen atom of an amino acid, can be produced by the following scheme. By reacting a C-terminus-free amino acid available from commercial suppliers with an aldehyde according to the method of Freidinger et al. (J. Org. Chem., 1983, 48(1), 77-81), an oxazolidinone compound with a cyclic protecting group can be obtained. Subsequently, a ring-opening reaction can be performed to produce the desired C-terminus-free unnatural amino acid. [ka]

[0232] P is present on the nitrogen atom of the amino acid. n Non-natural amino acids into which a group has been introduced can be produced by the following scheme: Commercially available C-terminus-free amino acids are subjected to alkylating agents (P) in the presence of a base. n By applying -X), P n A protective group can be introduced. Subsequently, by performing a deprotection reaction and a protecting group introduction reaction according to a standard method, a C-terminus-free non-natural amino acid can be produced. [ka]

[0233] Unnatural amino acids, in which an amide group is introduced into the side chain of an amino acid, can be produced by the following scheme: An amide group can be introduced into the side chain by reacting a carboxylic acid obtained by deprotecting a commercially available protected amino acid (n=1 or 2) with an amine (R''R'''NH). Then, by deprotecting the C-terminal protecting group, a C-terminus-free unnatural amino acid can be produced. [ka]

[0234] Unnatural amino acids, in which an amide group is introduced into the side chain of an amino acid and a -CH2-P' group is introduced into the nitrogen atom of the amino acid, can be produced by the following scheme. A commercially available protected amino acid (n=1 or 2) can be treated with an aldehyde according to the method of Freidinger et al. (J. Org. Chem., 1983, 48(1), 77-81) to obtain an oxazolidinone with a cyclic protecting group. Then, after deprotecting the protecting group of the side chain, the amide can be obtained by treating it with an amine (R''R'''NH). Finally, a ring-opening reaction can be performed to produce the desired C-terminus-free unnatural amino acid. [ka]

[0235] Unnatural amino acids, in which an amino group is introduced into the side chain of an amino acid, can be produced by the following scheme: An amide group can be introduced into the side chain by reacting the carboxyl group of a commercially available protected amino acid (n=1 or 2) with an amine (R''R'''NH). Then, a reduction reaction is carried out according to the method of Reeves et al. (Advanced Synthesis & Catalysis, 2013, 355(1), 47-52), followed by deprotection of the C-terminal protecting group to produce a C-terminus-free unnatural amino acid. [ka]

[0236] Unnatural amino acids, in which an amino group is introduced into the side chain of an amino acid and a -CH2-P' group is introduced into the nitrogen atom of the amino acid, can be produced by the following scheme. An amide group can be introduced into the side chain by reacting an amine (R''R'''NH) with the carboxyl group of a cyclic protecting amino acid (n=1 or 2). Then, a reduction reaction is carried out according to the method of Reeves et al. (Advanced Synthesis & Catalysis, 2013, 355(1), 47-52), followed by a ring-opening reaction to produce the desired C-terminus-free unnatural amino acid. [ka]

[0237] Unnatural amino acids, in which a fluoroalkyl group is introduced into the side chain of an amino acid, can be produced by the following scheme: The carboxyl group of a commercially available protected amino acid (n=1 or 2) can be converted to an aldehyde group by conventional reduction, and then the aldehyde group can be converted to a difluoromethyl group by conventional introduction of a fluorine atom. The C-terminal protecting group can then be deprotected to produce a C-terminus-free unnatural amino acid. [ka]

[0238] A method for producing unnatural amino acids in which a halogenated alkyl group is introduced into the side chain of an amino acid and a -CH2-P' group is introduced into the nitrogen atom of the amino acid can be carried out by the following scheme. The carboxyl group of the cyclic protecting amino acid (n=1 or 2) can be converted to an aldehyde group by conventional reduction, and then the aldehyde group can be converted to a dihalogenated methyl group by introducing a halogen atom by conventional method. Then, by opening the ring of the cyclic protecting group at the C-terminus, a C-terminus-free unnatural amino acid can be produced. [ka]

[0239] Furthermore, by the method described below, a halogenated alkyl group can be introduced into the side chain of the amino acid, and a C-terminus-free non-natural amino acid in which a -CH2-P' group is introduced into the nitrogen atom of the amino acid can also be produced. [ka]

[0240] Unnatural amino acids, in which an aryl group or heteroaryl group (referred to as "Ar" in the scheme) is introduced into the side chain of an amino acid, can be produced by the following scheme. An NHPI group can be introduced into the side chain by reacting the carboxyl group of a protected amino acid (n=1 or 2) with N-hydroxyphthalimide (NHPI). An aryl group or heteroaryl group can be introduced by reacting with an aryl halide or heteroaryl halide according to the method of Huihui et al. (J. Am. Chem. Soc., 2016, 138(15), 5016-5019), thereby producing an unnatural amino acid having an aralkyl group or heteroaralkyl group in the side chain. Subsequently, a C-terminus-free unnatural amino acid can be produced by deprotecting the C-terminal protecting group. [ka]

[0241] Unnatural amino acids, in which an aryl group or heteroaryl group (referred to as "Ar" in the scheme) is introduced into the side chain of an amino acid, and a -CH2-P' group is further introduced into the nitrogen atom of the amino acid, can be produced by the following scheme. An NHPI group can be introduced into the side chain by reacting the carboxyl group of a cyclic protecting amino acid (n=1 or 2) with N-hydroxyphthalimide (NHPI). Following the method of Huihui et al. (J. Am. Chem. Soc., 2016, 138(15), 5016-5019), an aryl group or heteroaryl group can be introduced by reacting with an aryl halide or heteroaryl halide, and an unnatural amino acid protected by a cyclic protecting group having an aralkyl group or heteroarylalkyl group in the side chain can be produced. Subsequently, a ring-opening reaction can be performed to produce the desired C-terminus-free unnatural amino acid. [ka]

[0242] Unnatural amino acids, in which an aryl group or heteroaryl group (referred to as "Ar" in the scheme) is introduced into the side chain of an amino acid, can be produced by the following scheme. After introducing a protecting group into a commercially available protected amino acid (n=0 or 1), an aryl halide or heteroaryl halide can be reacted with it according to the method of He et al. (Org. Lett. 2014, 16(24), 6488-6491) to introduce an aryl group or heteroaryl group, thereby producing an unnatural amino acid having an aralkyl group or heteroaralkyl group in the side chain. Subsequently, a deprotection reaction and a protecting group introduction reaction can be carried out to produce the desired C-terminus-free unnatural amino acid. [ka]

[0243] [ka]

[0244] Unnatural amino acids, in which a halogen atom is introduced to the aralkyl group of the amino acid side chain, can be produced by the following scheme: (R) a Aralkyl groups that may have a boryl group can be given a boronic acid ester by a method similar to that of Ishiyama et al. (J. Am. Chem. Soc. 2002, 124(3), 390-391). The introduced boryl group can then have a halogen atom introduced using N-halogenated succinimide, according to the method of Lindner et al. (Chem. Eur.J., 2016, 22, 13218-13235). By appropriately removing protecting groups from the resulting non-natural amino acids as needed, the desired C-terminus-free non-natural amino acids can be produced. [ka]

[0245] Unnatural amino acids, in which a halogen atom is introduced to the aralkyl group of the amino acid side chain and a -CH2-P' group is introduced to the nitrogen atom of the amino acid, can be produced by the following scheme: (R) a The aryl group of an amino acid having an aralkyl group (which may also have a boryl group) can be modified by introducing a boronic acid ester according to the method of Ishiyama et al. (J. Am. Chem. Soc. 2002, 124(3), 390-391). The introduced boryl group can then have a halogen atom introduced using N-halogenated succinimide according to the method of Lindner et al. (Chem. Eur.J., 2016, 22, 13218-13235). The resulting non-natural amino acid can then be modified by appropriately removing protecting groups as needed to produce the desired C-terminus-free non-natural amino acid. [ka]

[0246] An alkoxy group or aralkoxy group (R) which may be substituted on the side chain of an amino acid. b A method for producing unnatural amino acids having O) can be carried out by the following scheme. After introducing a nosyl (Ns) group to a commercially available serine derivative (n=1 or 2) by a standard method, a cyclized product can be obtained according to the method of Mitsunobu et al. (Synthesis, 1981, 1,1-28). The cyclized product is then subjected to a suitable alcohol (R) in the presence of a Lewis acid such as BF3·OEt2. b By opening the ring with OH), a serine ether can be obtained. The resulting non-natural amino acid can then be used to produce the desired C-terminus-free non-natural amino acid by appropriately removing protecting groups as needed. [ka]

[0247] An alkoxy group or aralkoxy group (R) which may be substituted on the side chain of an amino acid. b A method for producing unnatural amino acids having O) can be carried out by the following scheme: A commercially available cyclic compound (n=1 or 2) is subjected to a suitable alcohol (R) in the presence of a Lewis acid such as BF3·OEt2 according to a standard method. b By opening the ring with OH), a serine ether can be obtained. The resulting non-natural amino acid can then be used to produce the desired C-terminus-free non-natural amino acid by appropriately removing protecting groups as needed. [ka]

[0248] An alkoxy group or aralkoxy group (R) which may be substituted on the side chain of an amino acid. bNon-natural amino acids having O) can be produced by the following scheme: A commercially available serine derivative (n=1 or 2) is subjected to an alkylating agent (R) in the presence of a suitable base, according to Williamson's method (Liebigs Ann. Chem. 1851, 77, 37-49). b By applying -X), the serine ether can be obtained. b If it has further convertible functional groups, R can be further converted by performing additional functional group transformations. b These can be converted into the desired functional group. Examples of additional functional group conversions include reduction reactions of multiple bonds. The non-natural amino acids obtained here can then be subjected to a deprotection reaction to produce the desired C-terminus-free non-natural amino acids. [ka]

[0249] An alkoxy group or aralkoxy group (R) which may be substituted on the side chain of an amino acid. b A method for producing a non-natural amino acid having O) and further having a -CH2-P' group introduced to the nitrogen atom of the amino acid can be carried out by the following scheme. A commercially available serine derivative, or a serine derivative (n=1 or 2) produced by the method described above, can be treated with an aldehyde according to the method of Freidinger et al. (J. Org. Chem., 1983, 48(1), 77-81) to obtain an oxazolidinone compound with a cyclic protecting group introduced. Subsequently, a ring-opening reaction can be performed to produce the desired C-terminus-free non-natural amino acid. [ka]

[0250] Unnatural amino acids having a protected hydroxyl group in the side chain can be produced by the following scheme. By appropriately desorbing a protecting group from a commercially available serine derivative or a serine derivative (n=1 or 2) produced by the method described above, the desired C-terminus-free unnatural amino acid can be produced. [ka]

[0251] Unnatural amino acids having a protected hydroxyl group in the side chain of the amino acid and an additional -CH2-P' group introduced to the nitrogen atom of the amino acid can be produced by the following scheme. Commercially available serine derivatives, or serine derivatives (n=1 or 2) produced by the method described above, can be treated with an aldehyde according to the method of Freidinger et al. (J. Org. Chem., 1983, 48(1), 77-81) to obtain oxazolidinone compounds with introduced cyclic protecting groups. Subsequently, ring-opening and protecting group introduction reactions can be carried out to produce the desired C-terminus-free unnatural amino acids. [ka]

[0252] A substituent (R) is attached to the hydroxyl group of a cyclic amino acid. c Cyclic non-natural amino acids into which the desired -OR can be introduced can be produced by the following scheme: Commercially available cyclic amino acids can be subjected to appropriate functional group introduction reactions to produce the desired -OR. c It is possible to convert to a functional group. As a functional group conversion reaction, following Williamson's method (Liebigs Ann. Chem. 1851, 77, 37-49), an alkylating agent (R) is used in the presence of a suitable base. c By applying -X), an ether bond can be generated. c If it has further convertible functional groups, R can be further converted by performing additional functional group transformations. cThis allows for the conversion to the desired functional group. Subsequently, a deprotection reaction can be carried out to produce the desired C-terminus-free non-natural amino acid. [ka]

[0253] Cyclic non-natural amino acids can be produced by introducing a protecting group (PG3) to the hydroxyl group of a cyclic amino acid using the following scheme. The desired C-terminus-free non-natural amino acid can be produced by appropriately performing protecting group desorption reactions on commercially available cyclic amino acids. [ka]

[0254] Unnatural amino acids, in which boronic acid is introduced into the side chain of the amino acid, can be produced by the following scheme. By treating a commercially available glycine derivative with an aldehyde according to the method of Lee et al. (Bioorg. Med. Chem. Lett., 2009, 19(17), 4887-5274), unnatural amino acids with introduced boronic acid esters can be obtained. Subsequently, by performing appropriate protecting group desorption reactions, the desired C-terminus-free unnatural amino acid can be produced. [ka]

[0255] (Synthesis of Fmoc unnatural amino acids with carboxyl groups in the side chain 1) Fmoc unnatural amino acids having a carboxyl group in the side chain can be produced by the following scheme. The main chain carboxyl group of a starting material (n=1 or 2) with a PG3-protected side chain carboxyl group, available from commercial suppliers, can be converted to an amide group by condensation with an amine (R''R'''NH) in the presence of a coupling agent such as DIC. Subsequently, by deprotecting the PG3, the desired Fmoc unnatural amino acid having a carboxyl group in the side chain can be produced. [ka]

[0256] (Synthesis of Fmoc unnatural amino acids with carboxyl groups in the side chain 2) Fmoc unnatural amino acids, which have a carboxyl group in their side chain and an additional -CH2-P' group on the nitrogen atom of the amino acid, can be produced by the following scheme. The main chain carboxyl group of a starting material (n=1 or 2), which is available from commercial suppliers and has a side-chain carboxyl group protected with PG3, can be converted to an amide group by condensation with an amine (R''R'''NH) in the presence of a coupling agent such as DIC. Subsequently, by deprotecting the PG3, the desired Fmoc unnatural amino acid with a carboxyl group in its side chain can be produced. [ka]

[0257] (Synthesis of Fmoc unnatural amino acids with vinyl halides in their side chains) Fmoc unnatural amino acids with vinyl halides in their side chains can be synthesized according to the method of Shendage et al. (Eur. J. Org. Chem., 2005, 719-727) using the following scheme. By reacting a Boc-2-t butyl-3-methylimidazolidinion-4-one, which is available from commercial suppliers, with an alkylating agent having vinyl halides in its side chain in the presence of a base, the desired Fmoc unnatural amino acid with vinyl halides in its side chain can be produced by the method described in the literature. [ka]

[0258] Unnatural amino acids (n=1 or 2) containing a thioether group in the side chain can be produced by the following scheme: Amidation of a carboxylic acid is performed on an amino acid with a protected side-chain thiol group, followed by deprotection of the thiol group and then reaction with a halogenated acetic acid with a protected carboxylic acid to form a thioether bond. Subsequently, deprotection of the side-chain carboxylic acid is performed to produce an amino acid having a thioether group in the side chain. [ka]

[0259] Peptides containing a thioether group in the peptide backbone can be produced using amino acids having a thioether group in the side chain as a starting material. Alternatively, they can be produced by Roberts et al.'s method (Tetrahedron Letters, 1998, 39, 8357-8360), which involves reacting the N-terminal bromoacetamide with the cysteine ​​side chain, or by Robey et al.'s method (Journal of Peptide Research, 2000, 56, 115-120), which involves reacting the N-terminal chloroacetamide with the cysteine ​​side chain.

[0260] Furthermore, the compounds of the present invention, their salts, or solvates thereof include all stereoisomers of the target compound obtained through the above-described reaction steps (e.g., enantiomers, diastereomers (including cis and trans geometric isomers)), racemates of the isomers, and other mixtures. For example, the compounds of the present invention may have one or more chiral centers, and the present invention includes racemic mixtures, diastereomer mixtures, and enantiomers of such compounds.

[0261] When the compound according to the present invention is obtained as a free compound, it can be converted to a salt or a hydrate or solvate thereof, which may be formed by the compound, according to conventional methods.

[0262] Furthermore, if the compound according to the present invention is obtained as a salt, hydrate, or solvate of the compound, the compound can be converted to its free form according to conventional methods.

[0263] <Pharmaceutical composition> The present invention provides a pharmaceutical composition containing the cyclic compound of the present invention. The pharmaceutical compositions of the present invention can be formulated by introducing a pharmaceutically acceptable carrier in addition to the compound of the present invention, its salt, or solvates thereof, using known methods. For formulation, commonly used excipients, binders, lubricants, colorants, flavoring agents, and, if necessary, stabilizers, emulsifiers, absorption enhancers, surfactants, pH adjusters, preservatives, antioxidants, etc., can be used, and the formulation is carried out by conventional methods using components generally used as raw materials for pharmaceutical formulations. For example, to manufacture an oral preparation, the compound of the present invention or a salt thereof, an excipient, and optionally a binder, disintegrant, lubricant, coloring agent, flavoring agent, etc. are added, and then the preparation is carried out by conventional methods to form a powder, fine granules, granules, tablet, coated tablet, capsule, etc.

[0264] Examples of these components include animal and vegetable oils such as soybean oil, beef tallow, and synthetic glycerides; hydrocarbons such as liquid paraffin, squalane, and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols such as cetostearyl alcohol and behenyl alcohol; silicone resins; silicone oils; surfactants such as polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, and polyoxyethylene polyoxypropylene block copolymers; water-soluble polymers such as hydroxyethylcellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone, and methylcellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol, and sorbitol; sugars such as glucose and sucrose; inorganic powders such as anhydrous silicic acid, aluminum magnesium silicate, and aluminum silicate, and purified water.

[0265] Examples of excipients include lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, and silicon dioxide.

[0266] Examples of binders include polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polypropylene glycol / polyoxyethylene block polymer, and meglumine.

[0267] Examples of disintegrants include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, and carboxymethylcellulose calcium.

[0268] Examples of lubricants include magnesium stearate, talc, polyethylene glycol, silica, and hydrogenated vegetable oil.

[0269] As coloring agents, those permitted for addition to pharmaceuticals are used, while as flavoring and deodorizing agents, cocoa powder, peppermint, aromatic powders, peppermint oil, borneol, cinnamon powder, etc., are used.

[0270] These tablets and granules may, of course, be coated with sugar or other coatings as needed. Furthermore, when manufacturing liquid preparations such as syrups and injectable preparations, the compound according to the present invention or a pharmaceutically acceptable salt thereof may be compounded by conventional methods by adding pH adjusters, solvents, isotonic agents, and, if necessary, solubilizers and stabilizers.

[0271] For example, it can be used parenterally in the form of an injectable sterile solution or suspension with water or other pharmaceutically acceptable liquid. For example, it can be formulated by mixing it with a pharmacologically acceptable carrier or medium, specifically sterile water, physiological saline, vegetable oil, emulsifier, suspension agent, surfactant, stabilizer, flavoring agent, excipient, vehicle, preservative, binder, etc., in a unit dose form generally accepted for pharmaceutical practice. Specifically, examples of carriers include light anhydrous silicic acid, lactose, crystalline cellulose, mannitol, starch, carmellose calcium, carmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl acetal diethylaminoacetate, polyvinylpyrrolidone, gelatin, medium-chain triglycerides, polyoxyethylene hydrogenated castor oil 60, sucrose, carboxymethylcellulose, corn starch, and inorganic salts. The amount of active ingredient in these formulations should be such that an appropriate volume within the indicated range is obtained. Sterile compositions for injection can be formulated using a vehicle such as distilled water for injection, following standard formulation procedures.

[0272] Examples of aqueous solutions for injection include physiological saline, isotonic solutions containing glucose or other adjuvants such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride. These may be used in combination with appropriate solubilizers, such as alcohol, specifically ethanol, polyalcohols such as propylene glycol and polyethylene glycol, and nonionic surfactants such as polysorbate 80 (registered trademark) and HCO-50.

[0273] Examples of oily liquids include sesame oil and soybean oil, and may be used in combination with benzyl benzoate or benzyl alcohol as solubilizers. It may also be combined with buffers such as phosphate buffer or sodium acetate buffer, analgesics such as procaine hydrochloride, stabilizers such as benzyl alcohol or phenol, and antioxidants. The prepared injection solution is usually filled into appropriate ampoules.

[0274] Administration is preferably by oral administration, but the method of administration is not limited to oral administration. Parenteral administration methods include, specifically, injectable, nasal, pulmonary, and transdermal formulations. Examples of injectable formulations include systemic or local administration by intravenous, intramuscular, intraperitoneal, or subcutaneous injection.

[0275] Furthermore, the administration method can be appropriately selected depending on the patient's age and symptoms. For example, the dosage of the pharmaceutical composition containing the peptide compound produced by the method of the present invention can be selected within the range of 0.0001 mg to 1000 mg per kg of body weight per dose. Alternatively, the dosage can be selected within the range of 0.001 to 100,000 mg / body per patient, but is not necessarily limited to these values. The dosage and administration method will vary depending on the patient's weight, age, symptoms, etc., but a person skilled in the art can appropriately select them.

[0276] In one embodiment, a cyclic compound of the present invention, or a salt thereof or a solvate thereof, or a pharmaceutical composition comprising a cyclic compound of the present invention, or a salt thereof or a solvate thereof, can bind to or selectively bind to KRAS in a target, and can further be used to selectively inhibit KRAS.

[0277] In one embodiment, the cyclic compounds of the present invention, or salts thereof, or solvates thereof, can bind to or selectively bind to KRAS in a target, and can be used in the manufacture of pharmaceuticals for selectively inhibiting KRAS.

[0278] In one embodiment, the present invention relates to a method for conjugating or selectively conjugating a cyclic compound of the present invention to KRAS in a subject, or a method for selectively inhibiting KRAS in a subject, comprising the step of administering an effective amount of the cyclic compound of the present invention, or a salt thereof, or a solvate thereof, to a subject requiring such conjugation.

[0279] Such cyclic compounds of the present invention, or salts thereof, or solvates thereof, have high selectivity for KRAS in the target. For example, the cyclic compound of the present invention is PP1820: (3S,9S,12S,17S,20S,23S,27S,30S,36S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-30-cyclopentyl-23-isobutyl-9-(isopentyloxymethyl)-N,N,7,17,18,24,28,31-octamethyl-20-[(1S)-1-methylpropyl]-2,5,8,11,16,19,22,25,29,32,35-undecaoxo-10-propyl-spiro[1,4,7,10,15,18,21,24,28,31,34-undecazatricyclo[34.3.0.0 12,15 It has higher KRAS selectivity (KRAS selectivity for NRAS and / or KRAS selectivity for HRAS) than nonatriacontane-33,1'-cyclobutane]-27-carboxamide.

[0280] In one embodiment, the pharmaceutical composition of the present invention exhibits KRAS inhibitory activity at least three times greater than NRAS inhibitory activity and HRAS inhibitory activity.

[0281] In one embodiment, the pharmaceutical composition of the present invention exhibits KRAS inhibitory activity that is 5 times, 7 times, 10 times, 15 times, or 20 times or more compared to NRAS inhibitory activity and HRAS inhibitory activity.

[0282] In one embodiment, a cyclic compound of the present invention, or a salt thereof or a solvate thereof, or a pharmaceutical composition comprising a cyclic compound of the present invention, or a salt thereof or a solvate thereof, can be used to treat and / or prevent cancer in a subject.

[0283] In one embodiment, the cyclic compounds of the present invention, or salts thereof, or solvates thereof, can be used in the manufacture of pharmaceuticals for treating and / or preventing cancer in a subject.

[0284] In one embodiment, the present invention relates to a method for treating and / or preventing cancer in a subject, comprising the step of administering an effective amount of the cyclic compound of the present invention, or a salt thereof, or a solvate thereof, to a subject in need.

[0285] Specifically, lung cancer is one example of cancer.

[0286] In this specification, "subjects" include mammals, and among mammals, humans are preferred.

[0287] Furthermore, all prior art documents cited herein are incorporated herein by reference. [Examples]

[0288] The present invention will be further illustrated by the following examples and reference examples, but the present invention is not limited thereto. Unless otherwise stated, the starting materials and reagents were obtained from commercial suppliers or synthesized using known methods. The LC / MS analytical conditions are shown in Table 1.

[0289] [Table 1] TIFF2026086799000089.tif211149TIFF2026086799000090.tif212149TIFF2026086799000091.tif212149TIFF2026086799000092.tif214149

[0290] Example 1: Solid-phase synthesis of peptide compounds Peptide elongation was performed using the following basic route (sometimes called the basic peptide synthesis method) according to the Fmoc method described in WO2013 / 100132 or WO2018 / 225864. That is, 1) A peptide elongation reaction by the Fmoc method from the N-terminus of an amino acid, in which the carboxylic acid of the Asp side chain or the carboxylic acid of the peptide main chain is supported on 2-chlorotritylc resin. 2) Process of cleaving peptides from 2-chlorotrityllesin, 3) Amidocyclization by condensation of the carboxylic acid of the Asp side chain or the carboxylic acid of the peptide main chain, which is detached from 2-chlorotrityl resin during the cleavage process, with the amino group of the N-terminus (triangular unit) of the peptide chain. 4) Deprotection of protecting groups of side chain functional groups contained in peptide chains as needed. The process consists of five steps: 5) purification of the compound by preparative HPLC. In this example, unless otherwise specified, the peptide compounds were synthesized based on this basic route. [ka]

[0291] 1-1. Fmoc-amino acids used in peptide synthesis using a peptide synthesizer In the peptide synthesis described herein, the Fmoc-amino acids listed in Tables 2 to 4 were used for synthesis using a peptide synthesizer. The Fmoc-amino acids listed in Table 2 were synthesized according to the methods described in WO2018 / 225851 or WO2018 / 225864. The Fmoc amino acids listed in Table 3 were purchased from commercial suppliers. The Fmoc-amino acids listed in Table 4 were synthesized according to the scheme shown below.

[0292] [Table 2]

[0293] [Table 3] TIFF2026086799000096.tif203149TIFF2026086799000097.tif202149TIFF20260867990 00098.tif198149TIFF2026086799000099.tif208149TIFF2026086799000100.tif206149 TIFF2026086799000101.tif203149TIFF2026086799000102.tif203149TIFF20260867990 00103.tif173149TIFF2026086799000104.tif132149TIFF2026086799000105.tif118149

[0294] [Table 4] TIFF2026086799000107.tif201149TIFF2026086799000108.tif209149TIFF2026086799000109.tif205149TIFF2026086799 000110.tif77149TIFF2026086799000111.tif146149TIFF2026086799000112.tif146149TIFF2026086799000113.tif39149

[0295] Fmoc-amino acid synthesis Synthesis of compound aa004 [ka]

[0296] Compound aa004-a (3.00 g, 7.86 mmol) was dissolved in toluene (79 mL), paraformaldehyde (708 mg, 23.6 mmol) and CSA (91 mg, 0.393 mmol) were added, and the mixture was stirred at 90°C for 5 hours. After cooling to room temperature, paraformaldehyde (236 mg, 7.86 mmol) and CSA (46 mg, 0.197 mmol) were added, and the mixture was stirred at 90°C for a further 30 minutes. After cooling to room temperature, the mixture was filtered through Celite, and the residue was washed with ethyl acetate (50 mL). The filtrate was washed twice with saturated sodium bicarbonate aqueous solution (50 mL) and then with 50% saline solution (50 mL). This was dried over sodium sulfate and filtered off, and the solvent was removed under reduced pressure to obtain compound aa004-b as the crude product. LCMS(ESI)m / z=394(M+H)+ Retention time: 1.08 minutes (Analysis conditions SQDFA05)

[0297] The crude product of compound aa004-b (7.86 mmol) was dissolved in DCM (39 mL), and boron trifluoride diethyl ether complex (BF3·OEt2) (2.96 mL, 23.6 mmol), TES (1.95 mL, 23.6 mmol), and water (0.142 mL, 7.86 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with saturated ammonium chloride solution (40 mL), washed with 50% saline solution (40 mL), dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting residue was dissolved in acetonitrile (40 mL) and washed twice with n-hexane (40 mL). The solvent was removed under reduced pressure to obtain compound aa004 (3.04 g, 98%). LCMS(ESI)m / z=396(M+H)+ Retention time: 1.00 minutes (Analysis conditions SQDFA05)

[0298] Synthesis of compound aa028 [ka]

[0299] Using aa028-a as the starting material, aa028-b was obtained as a crude product (9.61 g, 94%) by the same method as the synthesis of compound aa004-b.

[0300] Using aa028-b as the starting material, aa028 was obtained using the same method as the synthesis of compound aa004 (8.10 g, 84%). LCMS(ESI)m / z=470(M+H)+ Retention time: 0.99 minutes (Analysis conditions SQDFA05)

[0301] Synthesis of compound aa018 [ka]

[0302] Compound aa018-a, ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]pento-4-ic acid, Fmoc-PRA-OH) (3g, 8.95 mmol) was used as a starting material, and compound aa018-b was obtained using the same method as the synthesis of compound aa004-b (2.71g, 87%). LCMS(ESI)m / z=348(M+H)+ Retention time: 0.87 minutes (Analysis conditions SQDFA05)

[0303] Using the obtained compound aa018-b (989 mg, 2.85 mmol), compound aa018 was obtained (986 mg, 99%) using the same method as the synthesis of compound aa004. LCMS(ESI)m / z=350(M+H)+ Retention time: 0.79 minutes (Analysis conditions SQDFA05)

[0304] Synthesis of compound aa049 [ka]

[0305] Compound aa049-a, ((2S)-3-(2-chlorophenyl)-2-[9H-fluoren-9-ylmethoxycarbonylamino]propanoic acid, Fmoc-Phe(2-Cl)-OH) (5g, 11.85 mmol) was used as the starting material, and compound aa049-b was obtained using the same method as the synthesis of compound aa004-b (4.2g, 82%). LCMS(ESI)m / z=434(M+H)+ Retention time: 1.01 minutes (Analysis conditions SQDFA05)

[0306] Using the obtained compound aa049-b (4.2g), compound aa049 was obtained (3.32g, 79%) using the same method as the synthesis of compound aa004. LCMS(ESI)m / z=436(M+H)+ Retention time: 0.94 minutes (Analysis conditions SQDFA05)

[0307] Synthesis of compound aa199 [ka]

[0308] Compound aa199-a, ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]-3-[4-(trifluoromethyl)phenyl]propanoic acid, Fmoc-Phe(4-CF3)-OH) (200g, 439mmol) was used as the starting material, and compound aa199-b was obtained as the crude product (206.8g) by the same method as the synthesis of compound aa004-b. LCMS(ESI)m / z=469(M+H)+ Retention time: 3.30 minutes (Analysis conditions SMDmethod_03)

[0309] Using the obtained compound aa199-b (205g), compound aa199 was obtained using the same method as the synthesis of compound aa004 (195g, 2 steps, 95%). LCMS(ESI)m / z=470(M+H)+ Retention time: 2.96 minutes (Analysis conditions SMDMethod_03)

[0310] Synthesis of compound aa013 [ka]

[0311] Using aa013-a as the starting material, aa013-b was obtained as the crude product (5.29 g, 102%) by the same method as the synthesis of compound aa004-b. LCMS(ESI)m / z=370(M+H)+ Retention time: 0.89 minutes (Analysis conditions SQDFA05)

[0312] Compound aa013-b (5.29 g, 14.3 mmol) was dissolved in DCM (125 mL), and TES (22.9 mL, 143 mmol) and TFA (36.4 mL, 473 mmol) were added. The mixture was stirred at 38°C for 8 hours. The solvent was removed under reduced pressure, the mixture was dissolved in TBME (100 mL), and washed with 1 M dipotassium hydrogen phosphate aqueous solution (50 mL). The aqueous layer was extracted three times with TBME, and the organic layers were combined and the solvent was removed under reduced pressure. Acetonitrile / n-hexane = 1 / 2 (100 mL) was added, and the mixture was extracted with 5% potassium bicarbonate aqueous solution (100 mL). 6 M hydrochloric acid was added to the aqueous layer to make it acidic, and it was extracted twice with TBME (30 mL). The organic layer was dried over sodium sulfate and filtered off, and the solvent was removed under reduced pressure. Acetonitrile (100 mL) was added, and the mixture was washed with n-hexane (50 mL). The solvent was then removed under reduced pressure to obtain compound aa013 (4.06 g, 76%). LCMS(ESI)m / z=372(M+H)+ Retention time: 0.83 minutes (Analysis conditions SQDFA05)

[0313] Synthesis of compound aa030 [ka]

[0314] Under a nitrogen atmosphere, paraformaldehyde (172 mg, 5.74 mmol) and TFA (1.326 mL, 17.22 mmol) were added to a toluene solution (5.7 mL) of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-cyanophenyl)propanoic acid (aa030-a, Fmoc-Phe(3-CN)-OH) (789 mg, 1.913 mmol), and the mixture was stirred at room temperature for 5 hours and 30 minutes. The reaction mixture was concentrated under reduced pressure, diluted with DCM, washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous magnesium sulfate, and filtered. The resulting solution was concentrated under reduced pressure to obtain the crude product, compound aa030-b (859 mg). This compound was used in the next reaction without further purification.

[0315] Under a nitrogen atmosphere, compound aa030-b (853 mg) was dissolved in DCE (10 mL) and TES (2.75 mL, 17.22 mmol) and TFA (3.98 mL, 51.7 mmol) were added at room temperature. The mixture was stirred at 60°C for 5 hours. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure to obtain the crude product. t-butyl methyl ether / n-hexane = 1 / 1 was added to the crude product, and it was extracted five times with saturated sodium bicarbonate aqueous solution. The pH of the resulting aqueous layer was made acidic using concentrated hydrochloric acid, and then extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to obtain compound aa030 (811 mg, 2-step 99%). The obtained compound aa060 was used in peptide synthesis without further purification. LCMS(ESI)m / z=427(M+H)+ Retention time: 0.83 minutes (Analysis conditions SQDFA05)

[0316] Synthesis of compound aa029 [ka]

[0317] Compound aa029-a, ((2S)-3-(4-cyanophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid, Fmoc-Phe(4-CN)-OH) (1g, 2.425 mmol) was used as the starting material, and compound aa029 was obtained as the crude product (1.14g, 2 steps, 108%) using the same method as the synthesis of compound aa030. The obtained compound aa029 was used in peptide synthesis without further purification. LCMS(ESI)m / z=427(M+H)+ Retention time: 0.82 minutes (Analysis conditions SQDFA05)

[0318] Synthesis of compound aa031 [ka]

[0319] Compound aa031-a, ((2S)-3-(2-cyanophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid, Fmoc-Phe(2-CN)-OH) (1g, 2.425 mmol) was used as a starting material, and compound aa031-b was obtained as a crude product by the same method as the synthesis of compound aa030-b. Using the obtained compound aa031-b, the crude product obtained by the same method as the synthesis of compound aa030 was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to obtain compound aa031 (529 mg, 2 steps, 51%). LCMS(ESI)m / z=427(M+H)+ Retention time: 0.85 minutes (Analysis conditions SQDFA05)

[0320] Synthesis of compound aa050 [ka]

[0321] Compound aa050-a, ((2S)-3-(3,4-difluorophenyl)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid, Fmoc-Phe(34-F2)-OH) (105 mg, 0.247 mmol) was used as the starting material, and compound aa050-b was obtained as the crude product by the same method as the synthesis of compound aa004-b. Furthermore, compound aa050 was obtained using aa050-b by the same method as the synthesis of compound aa030 (74.4 mg, 2 steps, 69%). LCMS(ESI)m / z=438(M+H)+ Retention time: 0.88 minutes (Analysis conditions SQDFA05)

[0322] Synthesis of compound aa019 [ka]

[0323] Compound aa019-a (5.00 g, 13.8 mmol) was suspended in DCM (46 mL), and paraformaldehyde (2.08 g, 69 mmol) and magnesium sulfate (4.16 g, 34.6 mmol) were added. Boron trifluoride diethyl ether complex (BF3·OEt2) (2.10 mL, 16.6 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The solid was filtered off, and TES (5.51 mL, 34.6 mmol) and water (0.249 mL, 13.8 mmol) were added. BF3·OEt2 (2.63 mL, 20.8 mmol) was added dropwise at 0°C, and the mixture was stirred at room temperature for 1 hour. Add TES (1.10 mL, 6.92 mmol) and stir at room temperature for 40 minutes. Add BF3·OEt2 (0.877 mL, 6.92 mmol) and stir at room temperature. Wash the reaction solution with saturated sodium chloride aqueous solution (25 mL) and then with saturated brine (50 mL). Dry the organic layer over sodium sulfate and filter off, then remove the solvent under reduced pressure. The resulting solid was crushed and washed three times with n-hexane (50 mL) to obtain compound aa019 (4.93 g, 95%). LCMS(ESI)m / z=376(M+H)+ Retention time: 0.80 minutes (Analysis conditions SQDFA05)

[0324] Synthesis of compound aa331 [ka]

[0325] Using aa331-a as the starting material, aa331 was obtained using the same method as the synthesis of compound aa019 (9.09 g, 86%). LCMS(ESI)m / z=382(M+H)+ Retention time: 0.94 minutes (Analysis conditions SQDFA05)

[0326] Synthesis of compound aa020 [ka]

[0327] (S)-N-tritylaziridine-2-carboxylate methyl (aa020-a, CAS number 75154-68-6) (50 g, 146 mmol) was added to a mixed solution of chloroform (145 mL) and methanol (145 mL). Under a nitrogen atmosphere at 0°C, TFA (33 mL, 3 equivalents) was added dropwise, and the mixture was stirred for 7 hours. DIPEA (127 mL, 5 equivalents) was added to this reaction mixture at 0°C, and then a solution of Fmoc-Cl (36 g, 139 mmol) in 1,4-dioxane (145 mL) was added dropwise, and the mixture was stirred under a nitrogen atmosphere at 0°C for 90 minutes. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, and then washed sequentially with water, aqueous ammonium chloride, aqueous sodium bicarbonate, and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 0 / 100~10 / 90) to obtain compound aa020-b, (1-O-(9H-fluoren-9-ylmethyl) 2-O-methyl (2S)-aziridine-1,2-dicarboxylate) (40g, 85%). LCMS(ESI)m / z=324(M+H)+ Retention time: 2.631 minutes (Analysis conditions SMDmethod_10)

[0328] Under a nitrogen atmosphere, compound aa020-b, (1-O-(9H-fluoren-9-ylmethyl) 2-O-methyl (2S)-aziridine-1,2-dicarboxylate) (5 g, 15.46 mmol) was dissolved in DCM (30.9 mL), cyclopropanol (1.665 mL, 26.3 mmol) was added, and then boron trifluoride diethyl ether complex (BF3·OEt2) (0.291 mL, 2.319 mmol) was added under ice cooling. After reacting under ice cooling for 2 hours, water and saturated sodium bicarbonate aqueous solution were added to the reaction mixture to stop the reaction, and the aqueous layer was removed using a phase separator. The organic layer was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4 / 1) to obtain compound aa020-c (4.6 g, 78%). LCMS(ESI)m / z=382(M+H)+ Retention time: 0.89 minutes (Analysis conditions SQDFA05)

[0329] Calcium chloride (20.08 g, 181 mmol) was dissolved in water (50.2 mL), and lithium hydroxide monohydrate (2.024 g, 48.2 mmol) was added and the mixture was stirred at room temperature for 5 minutes to prepare aqueous solution A. Compound aa020-c (4.6 g, 12.06 mmol) was dissolved in isopropanol (201 mL) and THF (50.2 mL), and the previously prepared aqueous solution A was added and the mixture was stirred at room temperature for 5 hours. After that, 1N hydrochloric acid (72 mL) was added to the reaction mixture, and the isopropanol and THF were removed by vacuum concentration. The resulting aqueous layer was diluted with water (50.2 mL) and extracted three times with ethyl acetate (total volume 100 mL). The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The resulting residue was washed with ethyl acetate / n-hexane (1 / 2, 20 v / w) to obtain aa020-d, ((2S)-3-cyclopropyloxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid, Fmoc-Ser(cPr)-OH) (3.5 g, 79%). LCMS(ESI)m / z=368(M+H)+ Retention time: 0.78 minutes (Analysis conditions SQDFA05)

[0330] To a solution of compound aa020-d, ((2S)-3-cyclopropyloxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid, Fmoc-Ser(cPr)-OH) (2.89 g, 7.85 mmol) in DCM (87 mL), paraformaldehyde (1.815 g, 60.5 mmol), magnesium sulfate (2.36 g, 19.63 mmol), and boron trifluoride diethyl ether complex (BF3·OEt2) (1.184 mL, 9.42 mmol) were added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and the organic layer and aqueous layer were separated. The aqueous layer was extracted twice with DCM, and the combined organic layers were washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure to obtain compound aa020-e as the crude product (3.1 g, quant.). LCMS(ESI)m / z=380(M+H)+ Retention time: 0.93 minutes (Analysis conditions SQDFA05)

[0331] To a solution of the obtained compound aa020-e (2.98 g, 7.85 mmol) in DCM (26.2 mL), triethylsilane (3.13 mL, 19.64 mmol), water (0.141 mL, 7.85 mmol), and boron trifluoride diethyl ether complex (BF3·OEt2) (2.49 mL, 19.6 mmol) were added and the mixture was stirred for 2 hours under ice cooling and a nitrogen atmosphere. Saturated ammonium chloride aqueous solution was added to the reaction mixture, and the organic layer was separated. The organic layer was washed with saturated ammonium chloride aqueous solution, then washed with saturated brine, and concentrated under reduced pressure to obtain the crude product. The obtained crude product was dissolved in acetonitrile and washed with n-hexane, and the acetonitrile layer was concentrated under reduced pressure to obtain compound aa020 (2.71 g, 90%). LCMS(ESI)m / z=382(M+H)+ Retention time: 0.83 minutes (Analysis conditions SQDFA05)

[0332] Synthesis of compound aa006 [ka]

[0333] Compound aa006-a, ((2S)-3-cyclopentyl-2-[9H-fluoren-9-ylmethoxycarbonylamino]propanoic acid, Fmoc-Ala(cPent)-OH) (10 g, 26.4 mmol) was used as a starting material, and compound aa006-b (10.5 g) was obtained as a crude product by the same method as the synthesis of compound aa020-e. LCMS(ESI)m / z=392(M+H)+ Retention time: 1.05 minutes (Analysis conditions SQDFA05)

[0334] The obtained compound aa006-b (10.5g) was reacted using the same method as for the synthesis of compound aa020, and the resulting crude product was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to obtain compound aa006 (10.11g, 2 steps, 96%). LCMS(ESI)m / z=394(M+H)+ Retention time: 0.98 minutes (Analysis conditions SQDFA05)

[0335] Synthesis of compound aa010 [ka]

[0336] Compound aa010-a, ((2S)-3-cyclobutyl-2-[9H-fluoren-9-ylmethoxycarbonylamino]propanoic acid, Fmoc-Ala(cBu)-OH) (3.36 g, 9.19 mmol) was used as a starting material, and compound aa010-b was obtained as a crude product (3.63 g) by the same method as the synthesis of compound aa020-e. LCMS(ESI)m / z=378(M+H)+ Retention time: 1.01 minutes (Analysis conditions SQDFA05)

[0337] The obtained compound aa010-b (3.63g) was reacted using the same method as for the synthesis of compound aa020, and the resulting crude product was purified by reverse-phase column chromatography (0.1% formic acid-water / 0.1% formic acid-acetonitrile) to obtain compound aa010 (3.18g, 2 steps, 91%). LCMS(ESI)m / z=380(M+H)+ Retention time: 0.94 minutes (Analysis conditions SQDFA05)

[0338] Synthesis of compound aa047 [ka]

[0339] Compound aa047-a, ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]-3-(2-methylphenyl)propanoic acid, Fmoc-Phe(2-Me)-OH) (2g, 4.98 mmol) was used as the starting material. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture obtained by the same method as the synthesis of compound aa020-e, and the mixture was charged onto a silica gel column (2v / w) and eluted by DCM to obtain compound aa047-b as the crude product (1.45g). Compound aa047 was obtained using the obtained compound aa047-b by the same method as the synthesis of compound aa020 (1.21g, 2 steps, 58%). LCMS(ESI)m / z=416(M+H)+ Retention time: 0.94 minutes (Analysis conditions SQDFA05)

[0340] Compound aa060 synthesis [ka]

[0341] Compound aa060-a, (2S)-2-cyclobutyl-2-[9H-fluoren-9-ylmethoxycarbonylamino]acetic acid, Fmoc-Gly(cBu)-OH) (2.5g, 7.11 mmol) was used as a starting material, and compound aa075-b was obtained as a crude product by the same method as the synthesis of compound aa020-e. LCMS(ESI)m / z=364(M+H)+ Retention time: 0.97 minutes (Analysis conditions SQDFA05)

[0342] Using the entire amount of compound aa060-b obtained above, the reaction was carried out in the same manner as the synthesis of compound aa020. The resulting crude product was then purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to obtain compound aa060 (2.32 g, 2 steps, 89%). LCMS(ESI)m / z=366(M+H)+ Retention time: 0.88 minutes (Analysis conditions SQDFA05)

[0343] Synthesis of compound aa021 [ka]

[0344] 2-Nitrobenzenesulfonyl chloride (NsCl) (32.37 g, 146 mmol) and L-serine methyl ester hydrochloride (aa021-a, 25 g, 161 mmol, CAS number 5680-80-8) were dissolved in DCM (874 mL), and DIPEA (51 mL, 292 mmol) was added at 5°C. After stirring at room temperature for 1 hour, the mixture was washed twice with water (440 mL), then once with saturated saline / water (1 / 1, 440 mL), and finally dried over magnesium sulfate. After removing the magnesium sulfate by filtration, the mixture was concentrated under reduced pressure to obtain compound aa021-b as the crude product (39.4 g, 89%). LCMS(ESI)m / z=302.9(MH)- Retention time: 0.729 minutes (Analysis conditions SMDmethod_06)

[0345] Compound aa021-b (23g, 75.6 mmol) was dissolved in DCM (598 mL), and triphenylphosphine (31.7 g, 121 mmol) was added at room temperature. After cooling to -14°C, DEAD (55.0 mL, 121 mmol) was added over 10 minutes, and the mixture was stirred at -5°C for 50 minutes. n-hexane (300 mL) was added, and the precipitate was filtered off. The filtrate was purified by silica gel column chromatography (n-hexane / DCM = 50:50 to 0:100) to obtain compound aa021-c (13.3 g, 62%). LCMS(ESI)m / z=287(M+H)+ Retention time: 0.872 minutes (Analysis conditions SMDmethod_06)

[0346] Compound aa021-c (10.7 g, 37.3 mmol) was dissolved in TFE (75 mL), and boron trifluoride diethyl ether complex (BF3·OEt2) (0.469 mL, 3.73 mmol) was added, followed by stirring at 70°C for 30 minutes. The TFE was removed under reduced pressure, and the resulting crude product was purified by reverse-phase column chromatography (acetonitrile with 0.1% formic acid / distilled water with 0.1% formic acid) to obtain compound aa021-d (12.3 g, 85%). LCMS(ESI)m / z=387(M+H)+ Retention time: 0.72 minutes (Analysis conditions SQDFA05)

[0347] Compound aa021-d (12 g, 31.1 mmol) was dissolved in methanol (47 mL), and an aqueous solution of lithium hydroxide monohydrate (5.21 g, 124 mmol) (31 mL) was added. After stirring at room temperature for 90 minutes, formic acid (11.7 mL, 311 mmol) was added, and the mixture was diluted with water (30 mL). The mixture was then purified by reverse-phase column chromatography (0.1% formic acid in acetonitrile / 0.1% formic acid in distilled water) to obtain compound aa021-e (7.90 g, 68%). LCMS(ESI)m / z=373(M+H)+ Retention time: 0.63 minutes (Analysis conditions SQDFA05)

[0348] Compound aa021-e (7.72 g, 20.7 mmol) was dissolved in acetonitrile (104 mL), potassium carbonate (7.17 g, 51.8 mmol) and dodecanethiol (7.44 mL, 31.1 mmol) were added, and the mixture was stirred at room temperature for 74 hours. This was diluted with water (100 mL) and washed twice with TBME (200 mL). To the resulting aqueous solution, a solution of Fmoc-OSu (3.5 g) in 1,4-dioxane (150 mL) was added and the mixture was stirred for 25 minutes. A solution of Fmoc-OSu (700 mg) in 1,4-dioxane (10 mL) was then added and the mixture was stirred for 5 minutes. A solution of Fmoc-OSu (350 mg) in 1,4-dioxane (5 mL) was then added and the mixture was stirred for 5 minutes. Furthermore, a solution of Fmoc-OSu (350 mg) in 1,4-dioxane (5 mL) was added and the mixture was stirred for 5 minutes, after which formic acid (3.9 mL) was added and the solvent was removed under reduced pressure. The resulting crude product was purified by reverse-phase column chromatography (acetonitrile with 0.1% formic acid / distilled water with 0.1% formic acid) to obtain compound aa021-f, ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(2,2,2-trifluoroethoxy)propanoic acid, Fmoc-Ser(Tfe)-OH) (5.67 g, 67%). LCMS(ESI)m / z=410(M+H)+ Retention time: 2.35 minutes (Analysis conditions SQDFA05long)

[0349] Starting with compound aa021-f (2.00g, 4.89 mmol), compound aa021-g was obtained as a crude product using the same method as the synthesis of compound aa020-e. Furthermore, compound aa021 was obtained using the same method as the synthesis of compound aa020 (1.80g, 2 steps, 87%). LCMS(ESI)m / z=424(M+H)+ Retention time: 0.84 minutes (Analysis conditions SQDFA05)

[0350] Synthesis of compound aa022 [ka]

[0351] Under a nitrogen atmosphere, compound aa020-b (1 g, 3.09 mmol) was dissolved in toluene (6.2 mL), ethanol (0.542 mL, 9.28 mmol) was added, and then BF3·OEt2 (0.059 mL, 0.464 mmol) was added dropwise over 5 minutes under ice cooling. The mixture was stirred for 2.5 hours while returning to room temperature. The reaction was stopped by adding saturated NaHCO3 aqueous solution, and the aqueous layer was removed using a phase separator. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Ethyl acetate / hexane (3 / 1, 24 mL) was added to the resulting residue, and the solvent was removed under reduced pressure. Hexane / TBME (85 / 15, 24 mL) was added to the obtained solid, and after stirring for 30 minutes, the solvent was filtered off to obtain compound aa022-b (787 mg, 69%). LCMS(ESI)m / z=370(M+H)+ Retention time: 0.86 minutes (Analysis conditions SQDFA05)

[0352] Aqueous solution A was prepared by dissolving calcium chloride (2.25 g, 20.3 mmol) in H2O (5.7 mL), adding lithium hydroxide monohydrate (227 mg, 5.41 mmol), and stirring at room temperature for 5 minutes.

[0353] Compound aa022-b was dissolved in isopropanol (22.6 mL) and THF (57 mL), and the previously prepared aqueous solution A was added. The mixture was stirred at room temperature for 7 hours. Then, 1N hydrochloric acid (8.1 mL) was added to the reaction mixture, and the isopropanol and THF were removed by vacuum concentration. The resulting aqueous layer was diluted with H2O and extracted three times with ethyl acetate. The organic layer was washed with H2O and saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under vacuum. Compound aa022-c was obtained by trituration with ethyl acetate / n-hexane (1 / 5, 20 v / w) (3.5 g, 79%). LCMS(ESI)m / z=356(M+H)+ Retention time: 0.78 minutes (Analysis conditions SQDFA05)

[0354] Using aa022-c as a starting material, aa022-d was obtained as a crude product (871 mg, 84%) by the same method as the synthesis of compound aa004-b. LCMS(ESI)m / z=368(M+H)+ Retention time: 0.84 minutes (Analysis conditions SQDFA05)

[0355] Using aa022-d as a starting material, aa022 was obtained using the same method as the synthesis of compound aa004 (254 mg, 90%). LCMS(ESI)m / z=370(M+H)+ Retention time: 0.80 minutes (Analysis conditions SQDFA05)

[0356] Synthesis of compound aa210 [ka]

[0357] Compound aa210-a (5.00 g, 13.7 mmol) was dissolved in toluene (17 mL), and TFA (9.49 mL, 123 mmol) and paraaldehyde (5.42 mL, 41.0 mmol) were added. The mixture was stirred at 45°C for 24 hours. The mixture was cooled to 0°C, and toluene (17 mL), TFA (19.0 mL, 246 mmol), and TES (19.6 mL, 123 mmol) were added. The mixture was stirred overnight at 50°C. The solvent was removed under reduced pressure, and the mixture was washed with saturated sodium bicarbonate aqueous solution and saturated brine. The organic layer was dried over sodium sulfate and filtered off. The solvent was removed under reduced pressure. The mixture was purified by reverse-phase chromatography (acetonitrile with 0.1% formic acid / distilled water with 0.1% formic acid) to obtain aa210 (2.17 g, 40%). LCMS(ESI)m / z=394(M+H)+ Retention time: 0.94 minutes (Analysis conditions SQDFA05)

[0358] Synthesis of compound aa201 [ka]

[0359] Under a nitrogen atmosphere, compound aa201-a, ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(4-methylphenyl)propanoic acid, Fmoc-Phe(4-Me)-OH) (5.62 g, 14.0 mmol, CAS number 199006-54-7) was suspended in DCE (17.5 mL), paraaldehyde (5.61 mL, 42.0 mmol) and TFA (9.65 mL, 126 mmol) were added, and the mixture was stirred at 60°C for 6 hours. The resulting reaction solution containing compound aa201-b was used directly in the next step. LCMS(ESI)m / z=428(M+H)+ Retention time: 1.03 minutes (Analysis conditions SQDFA05)

[0360] To the reaction solution of the obtained compound aa201-b, DCE (17.5 mL), TFA (19.3 mL, 252 mmol), and TES (20.1 mL, 126 mmol) were added, and the mixture was stirred at 60°C for 17 hours. After cooling to room temperature and concentrating under reduced pressure, the resulting residue was dissolved in ethyl acetate (40 mL). The organic layer was washed with saturated sodium bicarbonate aqueous solution (40 mL) and saturated brine (40 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was dissolved in acetonitrile (30 mL), washed twice with hexane (15 mL), and the solvent was removed under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (acetonitrile with 0.1% formic acid / distilled water with 0.1% formic acid) to obtain compound aa201, ((2S)-2-[ethyl(9H-fluoren-9-ylmethoxycarbonyl)amino]-3-(4-methylphenyl)propanoic acid, Fmoc-EtPhe(4-Me)-OH) (4.4g, 73% in 2 steps). LCMS(ESI)m / z=430(M+H)+ Retention time: 0.95 minutes (Analysis conditions SQDFA05)

[0361] Synthesis of compound aa164 [ka]

[0362] Under a nitrogen atmosphere, compound aa164-a, ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-[4-(trifluoromethyl)phenyl]propanoic acid, Fmoc-Phe(4-CF3)-OH) (4.04 g, 8.87 mmol, CAS number 247113-86-6) was suspended in DCE (11.1 mL), and anhydrous magnesium sulfate (4.27 g, 35.4 mmol), paraaldehyde (3.55 mL, 26.6 mmol), and TFA (6.11 mL, 80 mmol) were added, and the mixture was stirred at 60°C for 3 hours. Further anhydrous magnesium sulfate (2.14 g, 17.7 mmol) was added, and the mixture was stirred at 60°C for 1 hour. The resulting reaction solution containing compound aa164-b was used directly in the next reaction. LCMS(ESI)m / z=482(M+H)+ Retention time: 1.04 minutes (Analysis conditions SQDFA05)

[0363] To the reaction solution containing the obtained compound aa164-b, DCE (11.1 mL), TFA (12.2 mL, 159 mmol), and triethylsilane (12.7 mL, 80 mmol) were added, and the mixture was stirred at 60°C for 10 hours. After cooling to room temperature and filtering off the magnesium sulfate, the mixture was concentrated under reduced pressure. Since the desired reaction was not completed, the resulting residue was dissolved in DCE (22.2 mL), TFA (18.3 mL, 239 mmol), and triethylsilane (12.7 mL, 80 mmol) were added, and the mixture was stirred at 60°C for 8 hours. After cooling to room temperature and concentrating under reduced pressure, the resulting residue was dissolved in ethyl acetate (40 mL). The organic layer was washed with saturated sodium bicarbonate aqueous solution (40 mL) and saturated brine (40 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was dissolved in acetonitrile (30 mL), washed twice with hexane (15 mL), and the solvent was removed under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (containing 0.1% formic acid, water-acetonitrile) to obtain compound aa164 (1.90 g, 44% in 2 steps). LCMS(ESI)m / z=484(M+H)+ Retention time: 0.97 minutes (Analysis conditions SQDFA05)

[0364] Synthesis of compound aa136 [ka]

[0365] Compound aa136-a (10.1 g, 22.1 mmol) was dissolved in toluene (28 mL), propionaldehyde (14.3 mL, 199 mmol), TFA (15.3 mL, 199 mmol), and magnesium sulfate (7.99 g, 66.4 mmol) were added, and the mixture was stirred at 60°C for 3 hours. The solid was filtered off using a silica gel pad, and the filtrate was washed twice with water (100 mL). Acetonitrile (20 mL) was added, and the mixture was washed with 1 M dipotassium hydrogen phosphate aqueous solution (30 mL), washed three times with 3.5% potassium bicarbonate aqueous solution (40 mL), and washed with saturated brine (100 mL). The mixture was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to obtain compound aa136-b as the crude product. The crude product of compound aa136-b was dissolved in toluene (28 mL), and TES (7.07 mL, 44.3 mmol) was added. The mixture was cooled to 0°C, TiCl4 (4.88 mL, 44.3 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. Water (50 mL) was added dropwise, and the organic layer was washed with water (100 mL) and then with 1 M dipotassium hydrogen phosphate aqueous solution (50 mL). n-hexane (90 mL) was added, and the mixture was extracted three times with a mixed solvent of acetonitrile (15 mL) and 1% potassium bicarbonate aqueous solution (30 mL). Further extraction was performed twice with a mixed solvent of acetonitrile (20 mL) and 1% potassium bicarbonate aqueous solution (30 mL). n-hexane (90 mL) was added to the organic layer, and the mixture was extracted twice with a mixed solvent of acetonitrile (20 mL) and 1% potassium bicarbonate aqueous solution (30 mL). The aqueous layers were combined, n-hexane (80 mL) was added, and phosphoric acid was added to adjust the pH to 3. The mixture was then extracted three times with TBME (150 mL). The organic layer was washed with saturated saline solution (50 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to obtain compound aa136 (5.03 g, 46%). LCMS(ESI)m / z=498(M+H)+ Retention time: 1.02 minutes (Analysis conditions SQDFA05)

[0366] Synthesis of compound aa174 [ka]

[0367] Using aa174-a as the starting material, aa174 was obtained using the same method as the synthesis of compound aa136 (18.6g, 84%). LCMS(ESI)m / z=460(M+NH4)+ Retention time: 1.41 minutes (Analysis conditions SMD method_04)

[0368] Synthesis of compound aa264 [ka]

[0369] Compound aa264-a (H-cisHyp(3)-OH, 950 mg, 7.24 mmol) was dissolved in water (22 mL), and DIPEA (3.47 mL, 19.9 mmol) was added. A 1,4-dioxane solution of Fmoc-OSu (2.44 g, 7.24 mmol) (14.5 mL) was added to this. The resulting solid was crushed with a spatula and further ground by ultrasonic irradiation. 1,4-dioxane (15 mL) was added to dissolve it, and the mixture was stirred at room temperature for 40 minutes. The mixture was washed twice with n-hexane / CPME (3 / 1, 10 mL), and potassium bisulfate (3.70 g, 27.2 mmol) was added. The compound aa264-b was obtained by extracting three times with isopropyl acetate (30 mL), washing the organic layer with 50% saline solution (30 mL), drying over anhydrous sodium sulfate, filtering, and removing the solvent under reduced pressure (2.39 g, 93%). LCMS(ESI)m / z=355(M+H)+ Retention time: 0.64 minutes (Analysis conditions SQDFA05)

[0370] Compound 264-b (2.39 g, 6.76 mmol) and PPTS (0.170 g, 0.676 mmol) were suspended in DCM (23 mL), and DHP (1.39 mL, 15.2 mmol) was added and the mixture was stirred at room temperature for 19 hours. PPTS (0.085 g, 0.338 mmol) and DHP (0.741 mL, 8.11 mmol) were added and the mixture was stirred at room temperature for 3 hours. The mixture was washed with water and then with saturated brine. The mixture was dried over anhydrous sodium sulfate and filtered, and the solvent was removed under reduced pressure. This was dissolved in THF (25 mL), and phosphate buffer (pH=8.2, 25 mL) was added and the mixture was stirred at 50°C for 11 hours. Ethyl acetate (25 mL) was added to remove the aqueous layer, and the aqueous layer was extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was removed under reduced pressure. This was dissolved in DCM (30 mL) and n-hexane (30 mL) was added. Only the DCM was removed under reduced pressure, and then the n-hexane was removed under further reduced pressure. The resulting solid was mixed with n-hexane and irradiated with sonication to remove the n-hexane by decantation, and then dried under reduced pressure to obtain compound aa264 as a sodium salt. This was dissolved in isopropyl acetate (50 mL), and 0.05 M aqueous phosphoric acid solution (pH=2, 90 mL) was added and stirred at room temperature for 10 minutes, after which the aqueous layer was removed. The aqueous layer was extracted with isopropyl acetate, the organic layer was dried over anhydrous sodium sulfate and filtered off, and the solvent was removed under reduced pressure. The resulting crude product was purified by reverse-phase chromatography (acetonitrile with 0.1% formic acid / distilled water with 0.1% formic acid) to obtain compound aa264 (2.33 g, 79%). LCMS(ESI)m / z=456(M+NH3)+ Retention time: 0.81 minutes (Analysis conditions SQDFA05)

[0371] Synthesis of compound aa265 [ka]

[0372] Using aa265-a as the starting material, aa265 was obtained using the same method as the synthesis of compound aa264 (1.38 g, 78%). LCMS(ESI)m / z=439(M+H)+ Retention time: 0.85 minutes (Analysis conditions SQDFA05)

[0373] Synthesis of compound aa267 [ka]

[0374] Using aa267-a as the starting material, aa267 was obtained using the same method as the synthesis of compound aa264 (9.04 g, quant.). LCMS(ESI)m / z=460(M+Na)+ Retention time: 0.81 minutes (Analysis conditions SQDFA05)

[0375] Synthesis of compound aa279 [ka]

[0376] Using aa279-a as the starting material, aa279 was obtained using the same method as the synthesis of compound aa264 (5.15 g, 83%). LCMS(ESI)m / z=460(M+Na)+ Retention time: 0.85 minutes (Analysis conditions SQDFA05)

[0377] Synthesis of compound aa244 [ka]

[0378] Compound aa244-a, ((2S)-2-(phenylmethoxycarbonylamino)pentanedioic acid) (50 g, 177.8 mmol), paraformaldehyde (11.87 g), and p-toluenesulfonic acid (1.84 g, 10.69 mmol) were mixed in toluene (500 mL) and stirred at 120 °C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain compound aa244-b as the crude product (52 g, 96%). This crude product was used in the next reaction without purification.

[0379] A solution of compound aa244-b (4 g, 13.64 mmol) in thionyl chloride (50 mL) was stirred at 85°C for 1 hour, and the solvent was removed under reduced pressure. The residue was dissolved in THF (20 mL) and cooled to -78°C under a nitrogen atmosphere. A solution of lithium tri-tert-butoxyaluminum hydride (2.76 g, 10.87 mmol) in THF (20 mL) was added dropwise over 2.5 hours. After stirring at -78°C for 3 hours, water was added to the reaction mixture, and the precipitate was removed by filtration. The filtrate was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain compound aa244-c (2 g). 1 H-NMR(400MHz,CDCl3)δ7.41-7.32(m,5H),5.49(br.s,1H),5.27-5.11(m,3H),4.38-4.33(m,1H),2.58-2.19(m,4H)

[0380] Under a nitrogen atmosphere at 0°C, a solution of compound aa244-c (450 mg, 1.62 mmol) in DCM (20 mL) was mixed with (diethylamino) sulfur trifluoride (DAST) (780 mg, 4.84 mmol) and stirred at room temperature for 16 hours. After adding water to the reaction mixture, it was diluted with DCM and washed sequentially with aqueous sodium bicarbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain compound aa244-d (0.35 g, 72%). This was mixed with another batch synthesized in the same manner and the following reaction was carried out. 1 H-NMR(400MHz,CDCl3)δ7.42-7.35(m,5H),5.97-5.58(m,2H),5.25-5.16(m,3H),4.50-4.35(m,1H),2.14-1.68(m,4H) 19 F-NMR (400 MHz, CDCl3) δ-116.562

[0381] Compound aa244-d (1 g, 3.34 mmol) and TES (12.63 g, 109 mmol) were dissolved in TFA / DCM (10 / 10 mL), stirred at room temperature for 4 days, and then the solvent was removed under reduced pressure. The residue was diluted with aqueous sodium bicarbonate solution, washed with ether, and then adjusted to pH 3 with 2N hydrochloric acid. After extraction with DCM, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain compound aa244-e (0.6 g) as the crude product. This crude product was used in the next reaction without purification.

[0382] A mixture of compound aa244-e (0.6 g) and palladium carbon (10%, 60 mg) in methanol (10 mL) was stirred for 16 hours under a hydrogen atmosphere of approximately 3 atm. Palladium carbon was removed by filtration, and the solvent was removed from the filtrate under reduced pressure to obtain compound aa244-f (0.23 g) as the crude product. Without purification, this crude product was mixed with another batch synthesized in the same manner, and the following reaction was carried out.

[0383] Compound aa244-f (0.3 g, 1.79 mmol) and potassium carbonate (745 mg, 5.4 mmol) were mixed in 1,4-dioxane / water (5 / 5 mL) and Fmoc-OSu (0.9 g, 1.5 equivalents) was added and the mixture was stirred for 2 hours. The reaction mixture was diluted with water, washed with diethyl ether, and then adjusted to pH 3 with 2N hydrochloric acid. The mixture was extracted three times with ethyl acetate, and the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (acetonitrile with 0.05% TFA / distilled water with 0.05% TFA) to obtain compound aa244 (0.2 g, 29%). Another lot synthesized in the same manner was also used for peptide synthesis in this example. Retention time: 3.153 minutes (Analysis conditions SMDmethod_19) 1 H-NMR(300MHz,DMSO-d6)δ12.94(br.s,1H),7.92-7.88(d,J=7.2Hz,2H),7.66-7.61(m,2H ),7.44-7.31(m,4H),6.35-5.75(m,1H),4.49-4.26(m,4H),2.72(s,3H),1.78-1.65(m,4H) 19 F-NMR(300MHz,DMSO-d6)δ-115.730

[0384] Synthesis of compound aa043 [ka]

[0385] Under a nitrogen atmosphere, aa244-c (18 g, 64.98 mmol) was dissolved in dichloromethane (50 mL), and a solution of phosphorus pentachloride (27 g, 130 mmol) in carbon tetrachloride (550 mL) was slowly added dropwise at 0°C. The reaction solution was stirred at room temperature for 16 hours, then diluted with dichloromethane. The resulting solution was washed with water, the aqueous phase was extracted twice with dichloromethane, and the organic phase was mixed and washed with an aqueous sodium bicarbonate solution. The resulting solution was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by normal-phase column chromatography (hexane-ethyl acetate) to obtain aa043-a (7.2 g, 33%).

[0386] aa043-a (7.2 g, 21.75 mmol) was dissolved in dichloromethane (150 mL), triethylsilane (83.2 g, 718 mmol) and trifluoroacetic acid (24.8 g, 218 mmol) were added, and the mixture was stirred at room temperature for 4 days. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in aqueous sodium bicarbonate. The aqueous phase was then washed with diethyl ether. The resulting solution was then adjusted to pH 3 with 2N hydrochloric acid. The mixed solution was extracted twice with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting crude product aa043-b (5.5 g) was used directly in the next step.

[0387] To the crude product aa043-b (1.1 g), a solution of 33% hydrobromide in acetic acid (10 mL) diluted with acetic acid (10 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water. The resulting solution was washed with diethyl ether, and the solvent was removed under reduced pressure to obtain the crude product aa043-c (1.0 g). The crude product aa043-b was used directly in the next reaction. LCMS(ESI)m / z=200(M+H)+ Retention time: 0.88 minutes (Analysis conditions SMD method_12)

[0388] Crude product aa043-c (1.00 g) and potassium carbonate (1.48 g, 10.7 mmol) were dissolved in water (10 mL), and a 1,4-dioxane solution of Fmoc-OSu (1.8 g, 5.36 mmol) (10 mL) was added. After stirring at room temperature for 2 hours, the reaction solution was diluted with water. The resulting solution was washed with diethyl ether (30 mL), and 2N hydrochloric acid was added to adjust the pH to 3. Subsequently, the mixed solution was extracted three times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting concentrate was purified by reverse-phase column chromatography (water-acetonitrile) to obtain aa043 (0.5 g, 27%, 3 steps). LCMS(ESI)m / z=422(M+H)+ Retention time: 2.3 minutes (Analysis conditions SMD method_13)

[0389] Synthesis of compound aa056 [ka]

[0390] Under a nitrogen atmosphere, aa056-a (90 g, 443 mmol) and methyl iodide (314 g, 2.21 mol) were dissolved in tetrahydrofuran (3.15 L). The mixed solution was cooled to 0°C, and sodium hydride (60%, 77.56 g, 2.21 mol) was added while stirring. The reaction solution was stirred at 25°C for 3 hours, then added to ice water. The resulting solution was washed three times with t-butyl methyl ether / n-hexane (1 / 3). 1N hydrochloric acid was added to the aqueous phase to adjust the pH to 2-3, and the solution was extracted three times with ethyl acetate. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain aa056-b (94 g) as the crude product. The obtained crude product was used directly in the next reaction. LCMS(ESI)m / z=240(M+Na)+ Retention time: 1.1 minutes (Analysis conditions SMD method_14)

[0391] The crude product of aa056-b (94 g) was dissolved in dichloromethane (600 mL). This solution was cooled to 0°C, and 4NHC...

Claims

[Claim 1] The invention described in the specification.

Images