Cyclic compounds with selective KRAS inhibitory activity against HRAS and NRAS

Abstract

The present inventors found a cyclic compound that selectively inhibits KRAS. The present inventors also found that the cyclic compound interacts with a KRAS-specific amino acid residue.

Description

[Technical Field]

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

[0002] RAS is a protein belonging to the small GTPase family, and known proteins include KRAS, NRAS, and HRAS. RAS's activated or inactivated states are determined by their binding status to GDP or GTP. It is activated by the exchange of GDP for GTP by GEFs (guanine nucleotide exchange factors) and inactivated by the hydrolysis of GTP by GAPs (GTPase-activating proteins) (Non-Patent Document 1). Activated RAS induces cell proliferation, survival, and differentiation by activating various downstream signals, including the MAPK pathway, PI3K / Akt pathway, and RAL pathway. Constitutive activation of RAS plays an important role in the development and progression of cancer. It is known that the RAS-RAF-MEK-ERK pathway is activated in cancer due to activation of upstream RAS signals, constitutive activation of RAS, and / or activating mutations in RAS (Non-Patent Document 2). These activating RAS mutations have been observed in numerous types of cancer. G12, G13, and Q61 are known as hotspots for RAS mutations, with frequent mutations observed at G12 in KRAS and at Q61 in NRAS. These mutations are also known to be associated with poor patient prognosis (Non-Patent Document 3).

[0003] On the other hand, medium-molecular-weight compounds (molecular weight 500-2000 g / mol) may be superior to small-molecular-weight compounds in terms of access to tough targets, such as the inhibition of protein-protein interactions. Furthermore, medium-molecular-weight compounds may be superior to antibodies in terms of their ability to be transported into cells. Among physiologically active medium-molecular-weight compounds, peptide drugs are highly valuable molecular species, with over 40 types already on the market (Non-Patent Document 4). Representative examples of these peptide drugs include cyclosporin A and polymyxin B. These are peptides containing several unnatural amino acids. Unnatural amino acids are amino acids that are not naturally encoded by mRNA, and it is particularly interesting that naturally occurring cyclosporin A and polymyxin B contain unnatural amino acids.

[0004] Since it was discovered that naturally occurring peptides are useful as medicines, attention has been focused on peptides that have pharmacological activity and can be absorbed by the body, and peptides with molecular weights of approximately 500 to 2000 g / mol have been actively researched (Non-Patent Document 5).

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

[0006] Furthermore, the conditions necessary for a medium-sized peptide to satisfy the drug-likeness of a cyclic peptide have been clarified as conditions that can contribute to the improvement of pharmacokinetics (Patent Document 2).

[0007] Peptides that bind to RAS have been discovered, and the binding site between cyclic peptides and RAS has been analyzed by X-ray structural analysis (Non-Patent Document 6, Non-Patent Document 7, Non-Patent Document 8). In addition, cyclic peptides that suggest inhibition of binding between RAS and SOS have also been discovered (Patent Document 3). Furthermore, in a competitive assay of the binding of a specific compound to RAS, a cyclic peptide that suggests inhibition of binding to RAS has been discovered (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 document 1] Nat. Rev. Drug Discov. 2014 Nov;13(11):828-851. [Non-licensed document 2] Nat. Rev. Drug Discov. 2014 Dec;13(12):928-942. [Non-licensed document 3] Nat. Rev. Drug Discov. 2016 Nov;15(11):771-785.

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

[0010] The present invention relates to cyclic compounds that are effective against RAS-mutated cancers and unnatural amino acids and peptide compounds useful for their production. Patent Documents 1 and 2 describe drug-like peptides, but do not describe peptides that have antitumor effects against cancers, including RAS-mutated cancers. Patent Document 3 describes the inhibition of binding between RAS and SOS, and Patent Document 4 describes a peptide that competes with a compound that binds to RAS, but these cited documents do not disclose any pharmacological action, particularly an action on tumor cells, and do not describe any drug-like peptides.

[0011] The relationship between RAS and cancer is described in detail in Non-Patent Document 1. This document describes molecules that bind to RAS, and although their effectiveness has been demonstrated in preclinical trials, no compounds have been shown to be effective as pharmaceuticals specifically against RAS-mutated cancers, and no drug-like cyclic peptides have been disclosed. Non-Patent Document 2 provides a detailed description of RAS and the downstream RAF-MEK-ERK pathway of RAS. Although this document suggests the possibility of treating RAS-mutated cancers with inhibitors of RAF, MEK, and ERK, it does not disclose any compounds that directly inhibit RAS. Non-Patent Document 3 describes compounds that bind to the GTP / GDP binding site of RAS and inhibit RAS function, and the mechanism behind this. This document provides a detailed explanation of the interaction with the GTP / GDP binding site, but does not disclose pharmacological actions, particularly actions against tumor cells. Non-Patent Document 4 describes peptides used as medicines, but does not describe drug-like peptides or peptides useful for RAS-mutated cancers. Non-Patent Document 5 describes the molecular form of cyclic peptides and their pharmacokinetics, but does not describe compounds that are useful for RAS mutant cancers. Non-Patent Documents 6 to 8 describe peptides that bind to RAS, but their effects on tumor cells are limited, and there is no description of drug-like peptides.

[0012] Furthermore, to the best of the present inventors' knowledge, there have been no reports of compounds that have sufficiently selective KRAS inhibitory activity against HRAS and NRAS. [Means for solving the problem]

[0013] The present inventors have conducted extensive research to find cyclic compounds that have selective KRAS inhibitory activity against HRAS and NRAS, and have found a cyclic compound that interacts selectively with KRAS compared to HRAS and NRAS. In addition, they have found that the pharmacological effect of this cyclic compound is the growth inhibitory activity against tumor cells harboring RAS mutations.

[0014] In one non-limiting specific embodiment, the present invention includes the following. [1] Formula (1): [ka] or a salt thereof, or a solvate thereof, During the ceremony, L1 is a single bond; R1 is a C1 to C7 alkyl, or R1 forms a divalent group together with R5, and in this case, the partial structure *-CR1Q1-L1-CO-NP2-CR2Q2-CO-NP3-CR3Q3-CO-NP4-CR4Q4-CO-NP5-CR5Q5-* in the cyclic compound represented by formula (1) is the following formula: [ka] wherein: X2 is -L1-CO-NP2-CR2Q2-CO-NP3-CR3Q3-CO-NP4-CR4Q4-CO-NP5-, [ka] is a single or double bond, [ka] teeth, [ka] is a double bond, it means that it can be in either E or Z stereochemistry, n is 0, 1, or 2; m is 0, 1, 2, 3, or 4; * denotes a point of attachment to an adjacent atom; P1 is C1-C6 alkyl; Q1 is hydrogen; R2 is C1-C6 alkyl; P2 is hydrogen; Q2 is hydrogen; R3 is hydrogen or R3 together with P3, the carbon atom to which R3 is attached, and the nitrogen atom to which P3 is attached form a 4- to 7-membered saturated heterocyclic ring; P3 is C1-C6 alkyl or C3-C8 cycloalkyl, except when R3 and P3 form a 4-7 membered saturated heterocycle; Q3 is hydrogen; R4 forms a divalent group together with P5, and in this case, the partial structure *-CR4Q4-CO-NP5-* in the cyclic compound represented by formula (1) is represented by the following formula: [ka] Represented by; P4 is a C1-C6 alkyl; Q4 is hydrogen, R5 is benzyl optionally substituted by 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; Q6 is hydrogen, R7 is phenethyl optionally substituted by one or more groups independently selected from the group consisting of halogen, C1-C6 haloalkyl, and C1-C6 alkoxy; 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- to 7-membered saturated heterocycle, which may be substituted by C1-C6 alkoxy; Q8 is hydrogen, R9, together with Q9 and the carbon atom to which R9 and Q9 are attached, form a 3- to 8-membered alicyclic ring, which may be substituted by one or more C1-C6 alkyls; P9 is hydrogen or C1-C6 alkyl; R 10 is C1-C6 alkyl or C3-C8 cycloalkyl; P 10 is a C1-C6 alkyl, Q 10 is hydrogen, and L 11 is -CH2-, R 11 is diC1-C6 alkylaminocarbonyl or 4-8 membered cyclic aminocarbonyl; P 11 is a C1-C6 alkyl, Q 11 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-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 ]dotetracont-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 .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 ]dotetracont-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 ]dotetracont-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 ]pentatetracont-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 ]dotetracont-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-undecane, 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-undecane, 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-undecane, 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 ]dotetracont-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 ]dotetracont-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-undecane, 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-undecane, 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-undecane, 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-undecane, 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-undecane, 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-undecane, 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-undecane, 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-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, (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-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-undecane, (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-undecane, (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-undecane, (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-undecane, 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-undecane A cyclic compound, or a salt or solvate thereof, selected from the group consisting of: [2] The formula (1) is changed to the formula (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 is represented by (which is equivalent to [1]), The cyclic compound represented by the 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-undecane, 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-undecane, 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-undecane, 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-undecane, 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-undecane, 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-undecane, 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-undecane, 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-undecane, 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-undecane, 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-undecane, 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-undecane, (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-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-undecane, (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-undecane, (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-undecane, (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-undecane, 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-undecane The cyclic compound according to [1], or a salt thereof, or a solvate thereof, selected from the group consisting of: [3] The formula (1) is changed to the formula (3): [ka] (In the formula, R1 is C1-C7 alkyl; R5 is benzyl optionally substituted by 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 is represented by (which is equivalent to [1]), The cyclic compound represented by the 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 ]dotetracont-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 ]dotetracont-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]dotetracont-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 ]dotetracont-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 ]pentatetracont-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 ]dotetracont-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 ]dotetracont-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]dotetracont-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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane The cyclic compound according to [1], or a salt thereof, or a solvate thereof, selected from the group consisting of: [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 ]dotetracont-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 ]dotetracont-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 ]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 ]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 ]dotetracont-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 ]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 ]dotetracont-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 ]pentatetracont-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 ]dotetracont-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 ]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, 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 ]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, 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 ]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, 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 ]dotetracont-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 ]dotetracont-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 ]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, 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 ]pentapentaconta-37,43(54),44,46(53)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecane, 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 ]pentapentaconta-37,43(54),44,46(53)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecane, 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 ]tetrapentaconta-37,43(53),44,46(52)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, 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 ]tetrapentaconta-37,43(53),44,46(52)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, 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 ]pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecane, 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 ]tripentaconta-37,43(52),44,46(51)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,53-undecane, 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 ]tripentaconta-37,43(52),44,46(51)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,53-undecane, or a salt thereof, or a solvate thereof. [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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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[34.5.1.0]10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-undecazatetracyclo[37.5.1.0] 4,8 .0 26,30 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-(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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecane, or a salt thereof or a solvate thereof. [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-undecane, or a salt thereof or a solvate thereof. [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-undecane, or a salt thereof or a solvate thereof. [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-undecane, or a salt thereof or a solvate thereof. [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-undecane, or a salt thereof or a solvate thereof. [5] The cyclic compound or a salt thereof according to any one of [1] to [4-53]. [6] The cyclic compound according to any one of [1] to [4-53], or a solvate thereof. [7] A solvate of the cyclic compound or a salt thereof according to any one of [1] to [4-53]. [8] The cyclic compound according to any one of [1] to [4-53]. [9] The cyclic compound according to any one of [1] to [4-53], or a salt thereof, or a solvate thereof, which binds to KRAS.

[10] The cyclic compound according to any one of [1] to [4-53], or a salt thereof, or a solvate thereof, which inhibits KRAS.

[11] The cyclic compound according to any one of [1] to [4-53], or a salt thereof, or a solvate thereof, which has 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[3.0.0.0] 12,15 A cyclic compound according to any one of [1] to [4-53], or a salt thereof, or a solvate thereof, having higher KRAS selectivity (KRAS selectivity over NRAS and / or KRAS selectivity over HRAS) than ]nonatriacontane-33,1'-cyclobutane]-27-carboxamide.

[13] The cyclic compound according to any one of [1] to [4-53], or a salt thereof, or a solvate thereof, which selectively binds to KRAS.

[14] The cyclic compound according to any one of [1] to [4-53], or a salt thereof, or a solvate thereof, which selectively inhibits KRAS.

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

[16] The cyclic compound according to

[15] , or a salt thereof, or a solvate thereof, having KRAS binding activity that is 5 times, 7 times, 10 times, 15 times, or 20 times or more greater than NRAS binding activity and HRAS binding activity.

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

[18] The cyclic compound according to

[17] , or a salt thereof, or a solvate thereof, having a KRAS inhibitory activity that is 5 times, 7 times, 10 times, 15 times, or 20 times or more greater than the NRAS inhibitory activity and HRAS inhibitory activity.

[19] A pharmaceutical composition comprising the cyclic compound according to any one of [1] to [4-53], or a salt thereof, or a solvate thereof.

[20] A pharmaceutical composition for selectively inhibiting KRAS in a subject, comprising the cyclic compound according to any one of [1] to [4-53], or 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 greater 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 greater than the NRAS inhibitory activity and HRAS inhibitory activity of the compound.

[23] A pharmaceutical composition for treating or preventing cancer in a subject, comprising an effective amount of the cyclic compound according to any one of [1] to [4-53], or a salt thereof, or a solvate thereof.

[24] The pharmaceutical composition according to

[23] , wherein the cancer is lung cancer.

[25] The pharmaceutical composition according to any one of

[20] to

[24] , wherein the subject is a human.

[26] The cyclic compound according to any one of [1] to [4-53], or a salt thereof, or a solvate thereof, for use in treating or preventing cancer in a subject.

[27] The cyclic compound, or a salt thereof, or a solvate thereof according to

[26] , wherein the cancer is lung cancer.

[28] The cyclic compound according to any one of [1] to [4-53], or a salt thereof, or a solvate thereof, for use in selectively inhibiting KRAS in a subject.

[29] The cyclic compound according to any one of

[26] to

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

[30] Use of the cyclic compound according to any one of [1] to [4-53], or a salt thereof, or a solvate thereof, in the manufacture of a medicament for treating or preventing cancer in a subject.

[31] The use according to

[30] , wherein the cancer is lung cancer.

[32] Use of the cyclic compound according to any one of [1] to [4-53], or a salt thereof, or a solvate thereof, in the manufacture of a medicament for selectively inhibiting KRAS in a subject.

[33] The 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 an effective amount of the cyclic compound according to any one of [1] to [4-53], or a salt thereof, or a solvate thereof to a subject in need 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 an effective amount of the cyclic compound according to any one of [1] to [4-53], or a salt thereof, or a solvate thereof to a subject in need thereof.

[37] The method according to any one of

[34] to

[36] , wherein the subject is a human. [Effects of the Invention]

[0015] According to the present invention, it is possible to provide novel cyclic compounds having selective KRAS inhibitory activity. DETAILED DESCRIPTION OF THE INVENTION

[0016] (abbreviation) The abbreviations used in the present invention are listed 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-benzotriazin-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)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 carbonochloridate 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: Polyphosphoric acid

[0017] As used herein, the term "about" when used in conjunction with a numerical value means a range of values ​​of plus and minus 10% of that numerical value.

[0018] In this specification, the term "to" indicating a range includes both ends of the range. For example, "A to B" means a range that is equal to or greater than A and equal to or less than B.

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

[0020] The use of the articles "a," "an," and "the," both in this specification and in the claims, shall be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0021] (Definition of functional groups, etc.) As used herein, the term "halogen atom" includes, for example, F, Cl, Br, or I.

[0022] In this specification, "alkyl" refers to a monovalent group derived from an aliphatic hydrocarbon by removing any one hydrogen atom, and does not contain heteroatoms (atoms other than carbon and hydrogen atoms) or unsaturated carbon-carbon bonds in the skeleton, but has a subset of hydrocarbyl or hydrocarbon group structures containing hydrogen and carbon atoms. Alkyl includes not only linear but also branched chain alkyls. Specific examples of alkyl include alkyls having 1 to 20 carbon atoms (C1 to C2). 20 , hereinafter referred to as “C p ~C q " means that the number of carbon atoms is p to q), and preferably C1 to C 10 Alkyl is preferred, and C1 to C6 alkyl is more preferred. Specific 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, etc.

[0023] As used herein, "alkenyl" refers to an alkyl group having at least one double bond (two adjacent SP 2It is a monovalent group having 2 to 4 carbon atoms. Depending on the configuration of the double bond and the substituents (if any), the geometry of the double bond can be Entgegen (E) or Zusammen (Z), cis or trans. Alkenyl includes not only straight chain but also branched chain. Alkenyl is preferably C2 to C6 10 Alkenyl, more preferably C2 to C7 alkenyl, C2 to C6 alkenyl, is exemplified, and specific examples include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl (including cis and trans), 3-butenyl, pentenyl, 3-methyl-2-butenyl, hexenyl, 6-heptenyl, etc.

[0024] As used herein, "alkynyl" refers to a monovalent group having at least one triple bond (two adjacent SP carbon atoms). Alkynyl includes not only straight chain but also branched chain. Alkynyl is preferably C2 to C6. 10 Alkynyl, more preferably C2 to C6 alkynyl, is included, and specific examples include ethynyl, 1-propynyl, propargyl, 3-butynyl, pentynyl, hexynyl, 3-phenyl-2-propynyl, 3-(2'-fluorophenyl)-2-propynyl, 2-hydroxy-2-propynyl, 3-(3-fluorophenyl)-2-propynyl, 3-methyl-(5-phenyl)-4-pentynyl, etc.

[0025] As used herein, the term "cycloalkyl" refers to a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group, including monocyclic, bicyclic, and spirocyclic rings. Preferred examples of cycloalkyl include C3-C8 cycloalkyl, such as 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 to C 10Examples of aryl include phenyl and naphthyl (e.g., 1-naphthyl and 2-naphthyl). In this specification, aryl includes bicyclic aryl in which the aromatic hydrocarbon ring is fused with another saturated ring or unsaturated ring, and includes, for example, aryl having a fused ring structure in which the aromatic hydrocarbon ring is a benzene ring and the saturated ring is a 5-, 6-, or 7-membered saturated hydrocarbon ring or saturated heterocycle. Specific examples include indanyl, 1,2,3,4-tetrahydronaphthyl, and 2,3-dihydrobenzofuran.

[0027] As used herein, the term "heterocyclyl" refers to a non-aromatic cyclic monovalent group containing 1 to 5 heteroatoms in addition to carbon atoms. The heterocyclyl may have a double and / or triple bond in the ring, and a carbon atom in the ring may be oxidized to form a carbonyl, and may be a monocyclic or fused ring. 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), more preferably 3 to 7 (3- to 7-membered heterocyclyl) or 4 to 7 (4- to 7-membered heterocyclyl). Specific examples of heterocyclyl include azetidinyl, oxiranyl, oxetanyl, azetidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridyl, tetrahydropyrimidyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, and isothiazolidinyl. Examples include thiadiazolidinyl, 1,2-thiazinane, thiadiazolidinyl, azetidinyl, oxazolidone, benzodioxanyl, benzoxazolyl, dioxolanyl, dioxanyl, tetrahydropyrrolo[1,2-c]imidazole, thietanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, sultam, and 2-oxaspiro[3.3]heptyl.

[0028] As used herein, the term "protected heterocyclyl" refers to a group in which one or more functional groups included in the above-defined "heterocyclyl," such as an amino group, are protected with any protecting group, and preferably includes a protected 4- to 7-membered heterocyclyl. Specific examples of the protecting group include Boc, Fmoc, Cbz, Troc, and Alloc, and specific examples of the protected heterocyclyl include Boc-protected azetidine.

[0029] As used herein, "heterocycloalkylidene" refers to a divalent group resulting from the removal of two hydrogen atoms from one carbon atom of the above-defined "heterocyclyl," in which the free valence becomes part of a double bond. Preferred examples of heterocycloalkylidene include 4- to 7-membered heterocycloalkylidenes, and specific examples include tetrahydropyran-4-ylidene and azetidin-3-ylidene.

[0030] As used herein, the term "protected heterocycloalkylidene" refers to a group in which one or more functional groups included in the above-defined "heterocycloalkylidene," such as an amino group, are protected with any protecting group, and preferably includes a protected 4- to 7-membered heterocycloalkylidene. Specific examples of the protecting group include Boc, Fmoc, Cbz, Troc, and Alloc, and specific examples of the protected heterocycloalkylidene include Boc-protected azetidin-3-ylidene.

[0031] As used herein, "heteroaryl" refers to an aromatic cyclic monovalent group containing 1 to 5 heteroatoms in addition to carbon atoms. The ring may be a single ring or a condensed 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). Specific examples of heteroaryl include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, and imidazopyridyl.

[0032] As used herein, "alkoxy" refers to an oxy group bonded to an "alkyl" as defined above, and preferably includes C1 to C6 alkoxy. Specific examples of alkoxy include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentyloxy, and 3-methylbutoxy.

[0033] As used herein, "alkylthio" refers to a thiol group bonded to an "alkyl" as defined above, and preferably includes C1-C6 alkylthio. Specific examples of alkylthio include methylthio, ethylthio, 1-propylthio, 2-propylthio, n-butylthio, i-butylthio, s-butylthio, and t-butylthio.

[0034] As used herein, "alkenyloxy" refers to an oxy group bonded to the above-defined "alkenyl," and preferably includes C2-C6 alkenyloxy. Specific examples of alkenyloxy include vinyloxy, allyloxy, 1-propenyloxy, 2-propenyloxy, 1-butenyloxy, 2-butenyloxy (including cis and trans), 3-butenyloxy, pentenyloxy, and hexenyloxy.

[0035] As used herein, "cycloalkoxy" refers to an oxy group bonded to a "cycloalkyl" as defined above, and preferably includes C3 to C8 cycloalkoxy. Specific examples of cycloalkoxy include cyclopropoxy, cyclobutoxy, cyclopentyloxy, etc.

[0036] In the present specification, "aryloxy" means an oxy group to which the above-defined "aryl" is bonded, and preferably has a C6 to C 10 Specific examples of the aryloxy include phenoxy, 1-naphthyloxy, and 2-naphthyloxy.

[0037] As used herein, "amino" refers to -NH2 in a narrow sense and -NRR' in a broad sense, where R and R' are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or R and R' form a ring together with the nitrogen atom to which they are attached. Preferred examples of amino include -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, and 4- to 8-membered cyclic amino.

[0038] As used herein, "monoalkylamino" refers to a group in which R is hydrogen and R' is an "alkyl" as defined above, among the "amino" groups defined above, and preferably includes mono-C1-C6 alkylamino. Specific examples of monoalkylamino include methylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino, s-butylamino, and t-butylamino.

[0039] As used herein, "dialkylamino" refers to the above-defined "amino" group in which R and R' are independently the above-defined "alkyl", and preferably includes diC1-C6 alkylamino. Specific examples of dialkylamino include dimethylamino and diethylamino.

[0040] As used herein, "cyclic amino" refers to the above-defined "amino" in which R and R' form a ring together with the nitrogen atom to which they are attached, and preferably includes 4- to 8-membered cyclic amino. Specific examples of cyclic amino include 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] As used herein, the term "protected amino" refers to an amino group protected with any protecting group. Specific examples of the protected amino include amino protected with a protecting group such as Boc, Fmoc, Cbz, Troc, or Alloc.

[0042] As used herein, "alkylcarbonyl" refers to a carbonyl group bonded to the above-defined "alkyl," and preferably includes C1-C6 alkylcarbonyl. Specific examples of alkylcarbonyl include acetyl, propionyl, and butyryl. The number of carbon atoms in the above definition indicates the number of carbon atoms in the alkyl moiety. For example, "C1-C6" in "C1-C6 alkylcarbonyl" indicates that the alkyl moiety has 1 to 6 carbon atoms.

[0043] As used herein, "aminocarbonyl" refers to a carbonyl group bonded to the above-defined "amino," and preferred examples include -CONH2, mono-C1-C6 alkylaminocarbonyl, di-C1-C6 alkylaminocarbonyl, and 4- to 8-membered cyclic aminocarbonyl. Specific examples of aminocarbonyl include -CONH2, dimethylaminocarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 1-piperazinylcarbonyl, 4-morpholinylcarbonyl, 3-oxazolidinylcarbonyl, 1,1-dioxidethiomorpholinyl-4-ylcarbonyl, and 3-oxa-8-azabicyclo[3.2.1]octan-8-ylcarbonyl.

[0044] As used herein, "alkenyloxycarbonyl" refers to a carbonyl group bonded to an "alkenyloxy" as defined above, and preferably includes a C2-C6 alkenyloxycarbonyl. Specific examples of alkenyloxycarbonyl include vinyloxycarbonyl, allyloxycarbonyl, 1-propenyloxycarbonyl, 2-propenyloxycarbonyl, 1-butenyloxycarbonyl, 2-butenyloxycarbonyl (including cis and trans), 3-butenyloxycarbonyl, pentenyloxycarbonyl, and hexenyloxycarbonyl.

[0045] As used herein, "alkylsulfonyl" refers to a sulfonyl group having an "alkyl" bonded thereto, as defined above, and preferably includes C1-C6 alkylsulfonyl. Specific examples of alkylsulfonyl include methylsulfonyl.

[0046] As used herein, "hydroxyalkyl" refers to a group in which one or more hydrogen atoms of the "alkyl" defined above have been replaced with hydroxyl groups, and is preferably a C1-C6 hydroxyalkyl. Specific examples of hydroxyalkyl include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, and 5-hydroxypentyl.

[0047] As used herein, "haloalkyl" refers to a group in which one or more hydrogen atoms of the "alkyl" defined above have been substituted with halogen atoms, preferably C1-C6 haloalkyl, and more preferably C1-C6 fluoroalkyl. Specific examples of haloalkyl include difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3-difluoropropyl, 4,4-difluorobutyl, 5,5-difluoropentyl, and 1,1-difluoroethyl.

[0048] As used herein, "cyanoalkyl" refers to a group in which one or more hydrogen atoms of the "alkyl" defined above have been substituted with cyano, and C1-C6 cyanoalkyl is preferred. Specific examples of cyanoalkyl include cyanomethyl and 2-cyanoethyl.

[0049] As used herein, "aminoalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined above are substituted with an "amino" as defined above, and is preferably a C1-C6 aminoalkyl. Specific examples of aminoalkyl include 1-pyridylmethyl, 2-(1-piperidyl)ethyl, 3-(1-piperidyl)propyl, 4-aminobutyl, and 2-aminoethyl.

[0050] As used herein, "carboxyalkyl" refers to a group in which one or more hydrogen atoms of the "alkyl" defined above have been substituted with carboxy, with C1-C6 carboxyalkyl and C2-C6 carboxyalkyl being preferred. Specific examples of carboxyalkyl include carboxymethyl. The number of carbon atoms in the above definition indicates the number of carbon atoms in the alkyl moiety. For example, "C1-C6" in "C1-C6 carboxyalkyl" indicates that the alkyl moiety has 1 to 6 carbon atoms.

[0051] As used herein, "alkenyloxycarbonylalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined above are substituted with an "alkenyloxycarbonyl" as defined above, with C2-C6 alkenyloxycarbonylC1-C6 alkyl being preferred, and C2-C6 alkenyloxycarbonylC1-C2 alkyl being more preferred. Specific examples of alkenyloxycarbonylalkyl include allyloxycarbonylmethyl and 2-(allyloxycarbonyl)ethyl.

[0052] As used herein, "alkoxyalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined above are substituted with an "alkoxy" as defined above, with C1-C6 alkoxyC1-C6 alkyl being preferred, and C1-C6 alkoxyC1-C2 alkyl being more preferred. Specific examples of alkoxyalkyl include methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, n-butoxymethyl, i-butoxymethyl, s-butoxymethyl, t-butoxymethyl, pentyloxymethyl, 3-methylbutoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 1-ethoxyethyl, and 1-n-propyloxyethyl.

[0053] As used herein, "alkylthioalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined above are substituted with an "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] As used herein, "alkenyloxyalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined above are substituted with an "alkenyloxy" as defined above, preferably a C2-C6 alkenyloxyC1-C6 alkyl, and more preferably a C1-C6 alkenyloxyC1-C2 alkyl. Specific examples of alkenyloxyalkyl include vinyloxymethyl and allyloxymethyl.

[0055] As used herein, "cycloalkylalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined above are substituted with a "cycloalkyl" as defined above, preferably a C3-C8 cycloalkyl C1-C6 alkyl, and more preferably a C3-C6 cycloalkyl C1-C2 alkyl. Specific examples of cycloalkylalkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.

[0056] As used herein, "cycloalkoxyalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined above are substituted with a "cycloalkoxy" as defined above, and is preferably a C3-C8 cycloalkoxyC1-C6 alkyl, more preferably a C3-C6 cycloalkoxyC1-C2 alkyl. Specific examples of cycloalkoxyalkyl include cyclopropoxymethyl and cyclobutoxymethyl.

[0057] As used herein, "heterocyclylalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" defined above are substituted with a "heterocyclyl" defined above, and is preferably a 4- to 7-membered heterocyclylC1-C6 alkyl, more preferably a 4- to 7-membered heterocyclylC1-C2 alkyl. Specific examples of heterocyclylalkyl include 2-(tetrahydro-2H-pyran-4-yl)ethyl and 2-(azetidin-3-yl)ethyl.

[0058] As used herein, "alkylsulfonylalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined above are substituted with an "alkylsulfonyl" as defined above, with C1-C6 alkylsulfonylC1-C6 alkyl being preferred, and C1-C6 alkylsulfonylC1-C2 alkyl being more preferred. Specific examples of alkylsulfonylalkyl include methylsulfonylmethyl and 2-(methylsulfonyl)ethyl.

[0059] As used herein, "aminocarbonylalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined above are substituted with an "aminocarbonyl" as defined above, preferably an aminocarbonyl C1-C6 alkyl, and more preferably an aminocarbonyl C1-C4 alkyl. Specific examples of aminocarbonylalkyl 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] As used herein, "aryloxyalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" defined above are substituted with an "aryloxy" defined above, and is a C6 to C6 10 Aryloxy C1-C6 alkyl is preferred, and C6-C 10 Aryloxy C1-C2 alkyl is more preferred. Specific examples of aryloxy alkyl include phenoxymethyl and 2-phenoxyethyl.

[0061] As used herein, "aralkyl (arylalkyl)" refers to a group in which at least one hydrogen atom of an "alkyl" as defined above is substituted with an "aryl" as defined above, and is a C7 to C 14 Aralkyl is preferred, and C7 to C 10 Aralkyl is more preferred. Specific examples of aralkyl include benzyl, phenethyl, and 3-phenylpropyl.

[0062] As used herein, "aralkoxy" refers to an oxy group to which the above-defined "aralkyl" is bonded, and is a C7-C 14 Aralkoxy is preferred, C7-C 10 Aralkoxy is more preferred. Specific examples of aralkoxy include benzyloxy, phenethyloxy, and 3-phenylpropoxy.

[0063] As used herein, "aralkoxyalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" defined above are substituted with an "aralkoxy" defined above, and is a C7-C 14 Aralkoxy C1-C6 alkyl is preferred, and C7-C 14 Aralkoxy C1-C2 alkyl is more preferred. Specific examples of aralkoxy alkyl include benzyloxymethyl and 1-(benzyloxy)ethyl.

[0064] As used herein, the term "heteroarylalkyl" refers to a group in which at least one hydrogen atom of an "alkyl" as defined above is substituted with a "heteroaryl" as defined above, preferably a 5- to 10-membered heteroaryl C1-C6 alkyl, and more preferably a 5- to 10-membered heteroaryl C1-C2 alkyl. Specific examples of heteroarylalkyl include 3-thienylmethyl, 4-thiazolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, 2-(4-pyridyl)ethyl, 2-(6-quinolyl)ethyl, 2-(7-quinolyl)ethyl, 2-(6-indolyl)ethyl, 2-(5-indolyl)ethyl, and 2-(5-benzofuranyl)ethyl.

[0065] As used herein, "heteroarylalkoxy" refers to an oxy group bonded to the above-defined "heteroarylalkyl," and is preferably a 5- to 10-membered heteroaryl C1-C6 alkoxy, more preferably a 5- to 10-membered heteroaryl C1-C2 alkoxy. Specific examples of heteroarylalkoxy include 3-thienylmethoxy and 3-pyridylmethoxy.

[0066] As used herein, "heteroarylalkoxyalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined above are substituted with a "heteroarylalkoxy" as defined above, and is preferably a 5- to 10-membered heteroaryl C1-C6 alkoxy C1-C6 alkyl, more preferably a 5- to 10-membered heteroaryl C1-C2 alkoxy C1-C2 alkyl. Specific examples of heteroarylalkoxyalkyl include 3-pyridylmethoxymethyl.

[0067] As used herein, "heterocycloalkylidenealkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" defined above are substituted with a "heterocycloalkylidene" defined above, and is preferably a 4- to 7-membered heterocycloalkylidene C1-C6 alkyl, more preferably a 4- to 7-membered heterocycloalkylidene C1-C2 alkyl. Specific examples of heterocycloalkylidenealkyl include tetrahydro-4H-pyran-4-ylidenemethyl and azetidin-3-ylidenemethyl.

[0068] As used herein, "alkoxyalkenyl" refers to a group in which one or more hydrogen atoms of an "alkenyl" as defined above are substituted with an "alkoxy" as defined above, and C1-C6 alkoxyC2-C6 alkenyl is preferred. Specific examples of alkoxyalkenyl include (E)-4-methoxybut-2-en-1-yl.

[0069] As used herein, "aminocarbonylalkenyl" refers to a group in which one or more hydrogen atoms of an "alkenyl" as defined above are substituted with an "aminocarbonyl" as defined above, and aminocarbonyl C2-C6 alkenyl is preferred. Specific examples of aminocarbonylalkenyl include (E)-3-(dimethylaminocarbonylcarbonyl)-prop-2-en-1-yl.

[0070] As used herein, "haloalkoxy" refers to a group in which one or more hydrogen atoms of the above-defined "alkoxy" have been substituted with halogen atoms, and C1-C6 haloalkoxy is preferred. Specific examples of haloalkoxy include difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, and 2,2,2-trifluoroethoxy.

[0071] As used herein, "alkylene" refers to a divalent group derived by further removing one optional hydrogen atom from the aforementioned "alkyl," and is preferably a C4 to C8 alkylene. Specific examples of alkylene include -CH2-, -(CH2)2-, -(CH2)3-, -CH(CH3)CH2-, -C(CH3)2-, -(CH2)4-, -CH(CH3)CH2CH2-, -C(CH3)2CH2-, -CH2CH(CH3)CH2-, -CH2C(CH3)2-, -CH2CH2CH(CH3)-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, and the like.

[0072] As used herein, "cycloalkylene" refers to a divalent group derived by further removing one optional hydrogen atom from the "cycloalkyl," and is preferably a C3-C8 cycloalkylene. Specific examples of cycloalkylene include cyclopropane-1,2-diyl, cyclobutane-1,2-diyl, cyclopentane-1,2-diyl, and cyclohexane-1,2-diyl.

[0073] As used herein, "heterocyclylene" refers to a divalent group derived from the "heterocyclyl" by further removing one optional hydrogen atom, and is preferably a 3- to 7-membered heterocyclylene. Specific examples of heterocyclylene include oxirane-2,3-diyl, oxetane-2,3-diyl, tetrahydrofuran-2,5-diyl, and tetrahydropyran-2,6-diyl.

[0074] As used herein, "alkenylene" refers to a divalent group derived from the above-mentioned "alkenyl" by further removing one optional hydrogen atom. Depending on the configuration of the double bond and substituents (if any), the geometry of the double bond can be entgegen (E) or zusammen (Z), cis or trans. Alkenylene includes linear and branched chains and includes C2 to C6 10 Alkenylene is preferred, and C2 to C6 alkenylene is more preferred.

[0075] In the present specification, "alkynylene" means a divalent group derived from the above-mentioned "alkynyl" by further removing one arbitrary hydrogen atom. Alkynylene includes linear and branched ones, and has C2 to C6 10 Alkynylene is preferred, and C2 to C6 alkynylene is more preferred.

[0076] As used herein, "arylene" refers to a divalent group derived from the aforementioned "aryl" by further removing any one hydrogen atom. The arylene may be a single ring or a condensed 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] As used herein, the term "spirocycloalkyl" refers to a group formed by sharing one carbon atom constituting a cycloalkane ring with a carbon atom in a group to which it is bound. Preferred examples of spirocycloalkyl include C3-C8 spirocycloalkyl, and specific examples include spirocyclopropyl, spirocyclobutyl, spirocyclopentyl, spirocyclohexyl, spirocycloheptyl, and spirocyclooctyl.

[0078] As used herein, "spiroheterocyclyl" refers to a group in which one or more carbon atoms in the above-mentioned "spirocycloalkyl" are replaced with heteroatoms. Preferred examples of heterospirocycloalkyl include 4- to 10-membered spiroheterocyclyl.

[0079] As used herein, "alicyclic ring" refers to a non-aromatic hydrocarbon ring. The alicyclic ring may have an unsaturated bond within the ring, or may be a polycyclic ring having two or more rings. Furthermore, the carbon atoms constituting the ring may be oxidized to form a carbonyl. Preferred examples of the alicyclic ring include 3- to 8-membered alicyclic rings, and specific examples include a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, and a bicyclo[2.2.1]heptane ring.

[0080] As used herein, the term "saturated heterocycle" refers to a non-aromatic heterocycle containing 1 to 5 heteroatoms in addition to carbon atoms and no double and / or triple bonds within the ring. The saturated heterocycle may be a monocycle or may form a condensed ring with another ring, for example, an aromatic ring such as a benzene ring. Preferred examples of the saturated heterocycle include 4- to 7-membered saturated heterocycles, such as an azetidine ring, an oxetane ring, a tetrahydrofuran ring, a tetrahydropyran ring, a morpholine ring, a thiomorpholine ring, a pyrrolidine ring, a 4-oxopyrrolidine ring, a piperidine ring, a 4-oxopiperidine ring, a piperazine ring, a pyrazolidine ring, an imidazolidine ring, an oxazolidine ring, an isoxazolidine ring, a thiazolidine ring, an isothiazolidine ring, a thiadiazolidine ring, an oxazolidone ring, a dioxolane ring, a dioxane ring, a thietane ring, an octahydroindole ring, an indoline ring, and an azepane ring.

[0081] As used herein, the term "peptide chain" refers to a peptide chain in which 1, 2, 3, 4, or more natural amino acids and / or unnatural amino acids are linked by amide bonds and / or ester bonds. The peptide chain preferably contains 1 to 4 amino acid residues, and more preferably consists of 1 to 4 amino acid residues.

[0082] As used herein, the term "optionally substituted" means that a group may be substituted with any substituent.

[0083] In this specification, the term "optionally protected" means that a certain group may be protected by any protecting group.

[0084] As used herein, "one or more" means one or more than one. When "one or more" is used in the context of substituents on a group, the term means from one to the maximum number of substituents permitted by that group. Specific examples of "one or more" include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and / or more.

[0085] The wavy lines in the structural formulae herein may mean that any stereochemistry is permitted. For example, if a wavy line is attached to an asymmetric center, the stereochemistry of the asymmetric center may be either S or R configuration. Also, if a wavy line is attached to a double bond, the stereochemistry of the double bond may be either E or Z configuration.

[0086] As used herein, "PPn 1 n 2 n 3 n 4 (where n 1 , n 2 , n 3 , and n 4 Each of the symbols (each independently represents an integer of 0 to 9) (for example, PP1574, PP1640, etc.) represents a compound number.

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

[0088] As used herein, "amino acid" includes natural amino acids and unnatural amino acids. As used herein, "natural amino acids" refers to Gly, Ala, Ser, Thr, Val, Leu, Ile, Phe, Tyr, Trp, His, Glu, Asp, Gln, Asn, Cys, Met, Lys, Arg, and Pro. Unnatural amino acids are not particularly limited, but examples include β-amino acids, γ-amino acids, D-amino acids, N-substituted amino acids, α,α-disubstituted amino acids, amino acids with side chains unrelated to natural amino acids, and hydroxycarboxylic acids. As used herein, amino acids may have any configuration. The side chain of an amino acid is not particularly limited, and may be freely selected from, in addition to a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, and a cycloalkyl group. In these groups, one or two non-adjacent methylene groups may be substituted with an oxygen atom, a carbonyl group (-CO-), or a sulfonyl group (-SO-). Each of these may have a substituent, and the substituents are not limited, and may be independently selected from any substituents containing, for example, a halogen atom, an O atom, an S atom, an N atom, a B atom, an Si atom, or a P atom. Examples of such substituents include optionally substituted alkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, aralkyl groups, and cycloalkyl groups. In a non-limiting embodiment, the amino acid herein may be a compound having a carboxy group and an amino group in the same molecule (even in this case, imino acids such as proline and hydroxyproline are also included in the definition of amino acids).

[0089] The main chain amino group of an amino acid may be unsubstituted (NH group) or substituted (i.e., -NHR group: R represents an alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or cycloalkyl group which may have a substituent, 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 for R is selected in the same manner as the substituent in the amino acid side chain described above. When the main chain amino group is substituted, R is included in the "amino acid side chain" herein. An amino acid having such a substituted main chain amino group is referred to herein as an "N-substituted amino acid." Preferred examples of the "N-substituted amino acid" herein include, but are not limited to, N-alkylamino acid, N-C1-C6 alkylamino acid, N-C1-C4 alkylamino acid, and N-methylamino acid.

[0090] The "amino acids" constituting the peptide compounds herein include all corresponding isotopes. An isotope of an "amino acid" is one in which at least one atom has been replaced with an atom having 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" constituting the peptide compounds of the present invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, and chlorine atoms, each of which is 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] In this specification, examples of the substituent containing a halogen atom include an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, and the like, each of which has a halogen atom as a substituent, and more specific examples thereof include a fluoroalkyl, a difluoroalkyl, a trifluoroalkyl, and the like.

[0092] Examples of the substituent containing an O atom include hydroxy (-OH), oxy (-OR), carbonyl (-C(=O)-R), carboxy (-COH), 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-SO-R), aminosulfonyl (-SO-NHR), sulfamoylamino (-NH-SO-NHR), thiocarboxy (-C(=O)-SH), and carboxycarbonyl (-C(=O)-COH).

[0093] Examples of oxy (-OR) include alkoxy, cycloalkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, aralkyloxy, etc. As the alkoxy, C1 to C4 alkoxy and C1 to C2 alkoxy are preferred, and among these, methoxy or ethoxy is preferred.

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

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

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

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

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

[0099] Examples of aminocarbonyl (-C(=O)-NHR) include alkylaminocarbonyl (e.g., C1-C6 or C1-C4 alkylaminocarbonyl, particularly ethylaminocarbonyl, methylaminocarbonyl, etc.), cycloalkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, etc. In addition to these, examples include compounds in which the H atom bonded to the N atom in -C(=O)-NHR is further substituted with an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl.

[0100] Examples of carbonylamino (-NH-C(=O)-R) include alkylcarbonylamino, cycloalkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylcarbonylamino, etc. 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 are also included.

[0101] Examples of oxycarbonylamino (-NH-C(=O)-OR) include alkoxycarbonylamino, cycloalkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, aralkyloxycarbonylamino, etc. 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 are also included.

[0102] Examples of sulfonylamino (-NH-SO2-R) include alkylsulfonylamino, cycloalkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, etc. 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 are also included.

[0103] Examples of aminosulfonyl (-SO2-NHR) include alkylaminosulfonyl, cycloalkylaminosulfonyl, alkenylaminosulfonyl, alkynylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, etc. 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 are also included.

[0104] Examples of sulfamoylamino (-NH-SO-NHR) include alkylsulfamoylamino, cycloalkylsulfamoylamino, alkenylsulfamoylamino, alkynylsulfamoylamino, arylsulfamoylamino, heteroarylsulfamoylamino, aralkylsulfamoylamino, etc. Furthermore, the two H atoms bonded to the N atom in -NH-SO-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] Examples of substituents containing an S atom include 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, aralkylthio, and the like.

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

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

[0109] Examples of secondary amino (-NH-R; monosubstituted amino) include alkylamino, cycloalkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino, aralkylamino, and the like.

[0110] Examples of tertiary amino (-NR(R'); disubstituted amino) include an amino group having any two substituents independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, etc., such as alkyl(aralkyl)amino, and these two substituents may form a ring. Specific examples include dialkylamino, particularly C1-C6 dialkylamino, C1-C4 dialkylamino, dimethylamino, diethylamino, etc. In the present specification, the term "C p -C q "Dialkylamino group" means an amino group with C p -C q A group substituted with two alkyl groups, both C p -C q The alkyl groups may be the same or different.

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

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

[0113] Examples of aminocarbonylamino (-NR-CO-NR'R") include groups in which R, R', and R" are each independently selected from a hydrogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, or groups in which these groups 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 the present invention, the meaning of the term "and / or" includes any combination of "and" and "or" as appropriate. 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, amino acid residues having P1, Q1, R1, and L1 in the formula are referred to as core 1, amino acid residues having P2, Q2, and R2 are referred to as core 2, amino acid residues having P3, Q3, and R3 are referred to as core 3, amino acid residues having P4, Q4, and R4 are referred to as core 4, amino acid residues having P5, Q5, and R5 are referred to as core 5, amino acid residues having P6, Q6, and R6 are referred to as core 6, amino acid residues having P7, Q7, and R7 are referred to as core 7, amino acid residues having P8, Q8, and R8 are referred to as core 8, amino acid residues having P9, Q9, and R9 are referred to as core 9, and amino acid residues having P10, Q11, and R12 are referred to as core 13. 10 , Q 10 , and R 10 The amino acid residues having the core 10, P 11 , Q 11 , R 11 , and L 11 The amino acid residues having the following structure are sometimes referred to as core 11 amino acid residues.

[0117] In certain embodiments, in formula (1), L 1 is a single bond.

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

[0119] In one embodiment, R1 together with R5 form a divalent group, and in this case, the partial structure *-CR1Q1-L1-CO-NP2-CR2Q2-CO-NP3-CR3Q3-CO-NP4-CR4Q4-CO-NP5-CR5Q5-* in the cyclic compound represented by formula (1) is represented by the following formula: [ka] Represented by: X2 is -L1-CO-NP2-CR2Q2-CO-NP3-CR3Q3-CO-NP4-CR4Q4-CO-NP5-, [ka] is a single or double bond, n is 0, 1, or 2; m is 0, 1, 2, 3, or 4; * denotes the point of attachment to the adjacent atom. In the formula [ka] teeth, [ka] is a double bond, this means that it can be in either E or Z stereochemistry.

[0120] The formula may be: [ka] is preferred.

[0121] In some embodiments, P1 is C1-C6 alkyl, preferably methyl.

[0122] In some embodiments, Q1 is hydrogen.

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

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

[0125] In some embodiments, P2 is hydrogen.

[0126] In some embodiments, Q2 is hydrogen.

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

[0128] In some embodiments, in formula (1), R3 is hydrogen.

[0129] In some embodiments, 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. Specific examples of 4- to 7-membered saturated heterocycles include a pyrrolidine ring.

[0130] In some embodiments, P3 is C1-C6 alkyl or C3-C8 cycloalkyl, preferably methyl or cyclopropyl.

[0131] In some embodiments, Q3 is hydrogen.

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

[0133] In some embodiments, R4 is taken together with P5 to form a divalent group, in which case the partial structure *-CR4Q4-CO-NP5-* in the cyclic compound represented by formula (1) is represented by the following formula: [ka] It is expressed as:

[0134] In some embodiments, P4 is C1-C6 alkyl, preferably methyl.

[0135] In some embodiments, Q4 is hydrogen.

[0136] Furthermore, when the side chain (R4) of Core 4 and the N-substituent (P5) of Core 5 are combined to form a divalent group, 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 Production Method" section below.

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

[0138] In one embodiment, in formula (1), R5 together with R1 form a divalent group, the details of which are as described above.

[0139] In some embodiments, P5 together with R4 form a divalent group, the details of which are set forth above.

[0140] In some embodiments, Q5 is hydrogen.

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

[0142] In some embodiments, in formula (1), R6 is hydrogen.

[0143] In some embodiments, P6 is C1-C6 alkyl, preferably methyl.

[0144] In some embodiments, Q6 is hydrogen.

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

[0146] In one embodiment, in formula (1), it is phenethyl optionally substituted by one or more groups independently selected from the group consisting of halogen, C1-C6 haloalkyl, and C1-C6 alkoxy, and is preferably 3,5-difluoro-4-(trifluoromethyl)phenethyl, 3,4-dichlorophenethyl, or 3-methoxy-4-(trifluoromethyl)phenethyl.

[0147] In some embodiments, P7 is hydrogen.

[0148] In some embodiments, 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 C1-C6 alkoxy, preferably ethoxy, or n-propoxy. Specific examples of the 4- to 7-membered saturated heterocycle include a pyrrolidine ring.

[0151] In some embodiments, 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, form a 3- to 8-membered alicyclic ring. The 3- to 8-membered alicyclic ring may be substituted with one or more C1-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 some embodiments, P9 is hydrogen or C1-C6 alkyl, 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 formula (1), R 10 is C1-C6 alkyl or C3-C8 cycloalkyl, preferably pentan-3-yl or cyclopentyl.

[0157] In one embodiment, P 10 is C1 to C6 alkyl, preferably methyl.

[0158] In one embodiment, Q 10 is hydrogen.

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

[0160] In some embodiments, in formula (1), L 11 is -CH2-.

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

[0162] In one embodiment, P 11 is C1 to C6 alkyl, preferably methyl.

[0163] In one embodiment, Q 11 is hydrogen.

[0164] In some embodiments, the compounds of the present invention are: 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-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 ]dotetracont-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 ]dotetracont-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 ]dotetracont-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 ]pentatetracont-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 ]dotetracont-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-undecane, 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-undecane, 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-undecane, 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 ]dotetracont-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 ]dotetracont-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-undecane, 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-undecane, 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-undecane, 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-undecane, 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-undecane, 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-undecane, 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-undecane, 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-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, (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-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-undecane, (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-undecane, (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-undecane, (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-undecane, 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-undecane or a salt or solvate thereof. These compounds may be included in the formula (1) above.

[0165] In some embodiments, the compounds of the present invention have the formula (2): [ka] Preferred are compounds represented by 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 has the same meaning as in the formula (1). 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 encompassed by 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-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-undecane, (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-undecane, (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-undecane, (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-undecane, 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-undecane

[0166] In some embodiments, the compounds of the present invention have the formula (3): [ka] A compound represented by the following formula is preferred. In formula (3), R1 is a C1-C7 alkyl; R5 is benzyl optionally substituted by 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 has the same meaning as formula (1). For example, the compounds of 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 may be encompassed by formula (3).

[0167] In some embodiments, the cyclic compounds of the present invention have high selectivity for KRAS. In some embodiments, the cyclic compounds of the present invention selectively inhibit KRAS. Without being bound by any particular theory, the divalent group formed by R4 and P5 interacts with His95 of KRAS, thereby achieving high selectivity for KRAS. RAS proteins are known to have three isotypes: HRAS, KRAS, and NRAS, and His95 is present only in KRAS. Therefore, compounds that specifically interact with His95 of KRAS can inhibit KRAS with high selectivity for 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, cows, horses, pigs, goats, lemurs, cynomolgus monkeys, chimpanzees, and chickens, but human-derived HRAS, KRAS, and NRAS are preferred. The amino acid sequences of human-derived NRAS, human-derived HRAS, and human-derived KRAS are shown in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3.

[0169] In some embodiments, the cyclic compounds of the present invention have KRAS inhibitory activity that is three times or more greater than that of NRAS and / or HRAS inhibitory activity, and in some embodiments, the cyclic compounds of the present invention have KRAS binding activity that is three times or more greater than that of NRAS and / or HRAS binding activity.

[0170] In certain embodiments, the cyclic compounds of the invention have KRAS inhibitory activity that is 5-fold, 7-fold, 10-fold, 15-fold, or 20-fold or more greater than NRAS and / or HRAS inhibitory activity. In certain embodiments, the cyclic compounds of the invention have KRAS binding activity that is 5-fold, 7-fold, 10-fold, 15-fold, or 20-fold or more greater than NRAS and / or HRAS binding activity.

[0171] In the present invention, the KRAS inhibitory activity relative to the 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. As an example, this ratio can be expressed as the IC of the cyclic compound of the present invention against NRAS and / or HRAS. 50 value] is calculated by dividing the IC value of the cyclic compound of the present invention by the IC value of the KRAS 50 When the KRAS inhibitory activity is defined as a value obtained by dividing the KRAS inhibitory activity by the NRAS inhibitory activity and / or HRAS inhibitory activity, a larger value means that the KRAS inhibitory activity relative to the NRAS inhibitory activity and / or HRAS inhibitory activity is large, i.e., the selective inhibitory activity of the cyclic compound of the present invention on KRAS is large; conversely, a smaller value means that the KRAS inhibitory activity relative to the NRAS inhibitory activity and / or HRAS inhibitory activity is small, i.e., the selective inhibitory activity of the cyclic compound of the present invention on KRAS 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, when this ratio is defined as the value obtained by dividing [KD values ​​for NRAS and HRAS] by [KD for KRAS], a larger value indicates a larger binding activity to KRAS relative to the binding activity to NRAS and / or HRAS, i.e., a larger binding selectivity for KRAS over NRAS and / or HRAS. Conversely, a smaller value indicates a smaller binding activity to KRAS relative to the binding activity to NRAS and / or HRAS, i.e., a smaller binding selectivity for KRAS over NRAS and / or HRAS.

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

[0174] In the present invention, whether or not a cyclic compound interacts with histidine (referred to as His95 or H95), the 95th amino acid residue in the wild-type human KRAS protein, can be determined by the interatomic distance between the two non-hydrogen atoms (in the case of a bond via other molecules such as water molecules, the interatomic distance between the two non-hydrogen atoms is determined ignoring the other molecules). When the interatomic distance is 5.1 angstroms (Å) or less, it can be determined that the two non-hydrogen atoms interact. In some embodiments, the interatomic distance between the 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. Alternatively, it can be 2.0 Å or more, 2.1 Å or more, or 2.5 Å or more.

[0175] In the present invention, interatomic distances can be measured, for example, by analyzing the three-dimensional structure of a complex between a wild-type human KRAS protein and a cyclic compound of the present invention. Specifically, crystals of the complex between a wild-type human KRAS protein and a cyclic compound of the present invention are prepared. X-ray diffraction of the crystals is performed to obtain X-ray diffraction intensity data such as the space group and unit cell. The obtained X-ray diffraction intensity data can be applied to a program for determining initial or refined structures known to those skilled in the art, 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), to determine the three-dimensional structure of the complex between human KRAS wild-type protein and the cyclic compound of the present invention.

[0176] Once the three-dimensional structure of the complex between the human KRAS wild-type protein and the cyclic compound of the present invention can be determined, it is possible to measure interatomic distances by methods well known to those skilled in the art. For example, structural information about the complex between the cyclic compound of the present invention and the human KRAS wild-type protein can be loaded into a software program used for molecular modeling or molecular simulation, such as Discovery studio 2020 Client, MOE (Molecular Operating Environment), or Maestro, and interatomic distances can be measured using a function built into the software program (e.g., the Distance Monitor function in the case of Discovery studio 2020 Client). In addition, details about the conditions and criteria used by the software to determine whether or not an interaction exists can be found in the instructions or specifications that came 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 find details about the conditions and criteria used to determine whether or not an interaction exists).

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

[0178] Wild-type human KRAS protein can also be obtained by methods known to those skilled in the art. For example, wild-type human KRAS protein can be prepared using, but is not limited to, recombinant polypeptide expression methods using cells. In one embodiment, a nucleic acid encoding the wild-type human KRAS protein of the present invention is inserted into an appropriate expression vector, the vector is introduced into appropriate cells, the transformed cells are cultured, and the expressed protein is isolated and purified. Such proteins can also be expressed as fusion proteins with other proteins for purposes such as facilitating purification. For example, a method using Escherichia coli as a host to prepare a fusion protein with maltose-binding protein (vector pMAL series available from New England BioLabs, USA), a method using glutathione S-transferase (GST) (vector pGEX series available from Amersham Pharmacia Biotech), a method using a histidine tag (pET series available from Novagen), or a method using a HAT tag can be used. Host cells are not particularly limited as long as they are suitable for expressing recombinant proteins. In addition to the aforementioned Escherichia coli, for example, yeast, various animal and plant cells, and insect cells can be used. Various methods known to those skilled in the art can be used to introduce vectors into host cells. For example, introduction into Escherichia coli can be achieved using a calcium ion-based introduction method (Mandel, M., Higa, A. (1970) Journal of Molecular Biology, 53, 158-162; Hanahan, D. (1983) Journal of Molecular Biology, 166, 557-580). Proteins expressed in host cells can be purified and recovered from the host cells, their cell cultures, or culture supernatants by methods known to those skilled in the art. When proteins are expressed as fusion proteins with the aforementioned maltose-binding protein or HAT tag, for example, they can be easily purified by affinity purification or gel filtration chromatography (size exclusion chromatography, SEC).Affinity chromatography and SEC purification can be performed using an AKTAxpress™ instrument (GE Healthcare) or an NGC™ chromatography system (Bio-Rad) or a BioLogic DuoFlow™ chromatography system (Bio-Rad), or the like.

[0179] Interatomic energy can also be measured by methods well known to those skilled in the art. For example, the three-dimensional structure of the substance to be measured can be read 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 calculations can be easily performed by selecting the force field (e.g., Amber, CHARM, etc.) to be used in the calculation and the atoms to be subjected to the energy calculation according to the instructions of the program. For example, in the case of Discovery studio 2020 Client, interatomic energy can be calculated using the Calculate Interaction Energy function.

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

[0181] Without being bound by any particular theory, it is believed that the formation of a complex between the cyclic compound of the present invention and the human KRAS wild-type protein in this manner is related to the contribution of the cyclic compound of the present invention to the high binding activity of the cyclic compound of the present invention to the human KRAS wild-type protein, as well as to the binding selectivity to HRAS and NRAS.

[0182] The present invention also relates to unnatural amino acids used in the production of cyclic compounds of the present invention. In one embodiment, the unnatural amino acids of the present invention are N-protected unnatural amino acids used in the production of peptide compounds using solid-phase synthesis. In another embodiment, the unnatural amino acids of the present invention are unnatural amino acids 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, Boc, Cbz, Alloc, nosyl, dinitronosyl, t-Bu, trityl, and cumyl groups. Of these, Fmoc, Boc, Cbz, and Alloc are preferred, with Fmoc being more preferred.

[0183] In one embodiment, N-protected unnatural amino acids having an Fmoc group as a protecting group in the present invention include, for example, the following amino acids listed in Table 4, or salts thereof, 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-difluoro-butanoic 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-methyl-azetidine-2-carboxylic acid, aa099: (2S,3R)-1-(9H-fluoren-9-ylmethoxycarbonyl)-3-methyl-azetidine-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)amino]acetic acid, aa220: (2S)-4-(4-chloro-3,5-difluoro-phenyl)-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-difluoro-pentanoic acid, aa246: (2S,4R)-1-(9H-fluoren-9-ylmethoxycarbonyl)-4-propoxy-pyrrolidine-2-carboxylic acid, aa250: (2R)-2-[9H-fluoren-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-fluoren-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-methyl-pentanoic 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-indol-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-methylindol-6-yl)butanoic acid, aa403: (2S)-4-(1,3-dimethylindol-6-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, aa404: (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(1,2,3-trimethylindol-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-dimethyl-phenyl]butanoic acid, aa408: (2S)-4-(4-chloro-3-methoxy-phenyl)-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-difluoro-phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, aa411: (2S)-4-(4-chloro-3,5-dimethyl-phenyl)-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-methyl-pentanoic acid, aa426: (3S)-3-cyclohexyl-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid, and aa443: (2S)-2-[but-3-enyl(9H-fluoren-9-ylmethoxycarbonyl)amino]-3-(p-tolyl)propanoic acid.

[0184] (General manufacturing method) General methods for producing the cyclic compounds of the present invention, as well as oligopeptide compounds and unnatural amino acids used to produce these compounds, are described below. Note that, herein, cyclic compounds are sometimes referred to as "cyclic peptide compounds." As used herein, the "cyclic portion" of a peptide compound refers to a cyclic portion formed by linking two or more amino acid residues.

[0185] Chemical synthesis method of peptide compounds Examples of chemical synthesis methods for peptide compounds or cyclic compounds herein include liquid-phase synthesis, solid-phase synthesis using Fmoc synthesis or Boc synthesis, and combinations thereof. In Fmoc synthesis, the base unit is an amino acid in which the main chain amino group is protected with an Fmoc group, and the side chain functional groups are protected as needed with a protecting group that is not cleaved by a base such as piperidine, such as a t-Bu group, a THP group, or a Trt group, and the main chain carboxylic acid is not protected. The base unit is not particularly limited as long as it has an Fmoc-protected amino group and a carboxyl group. For example, a dipeptide or tripeptide may be used as the base 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 base unit located at the N-terminus may be other than an Fmoc amino acid. For example, it may be a Boc amino acid, a Tfa group, an Ns group, or a carboxylic acid analog without an amino group. The main chain carboxyl group or the side chain carboxyl group of an amino acid with a side chain carboxyl group protected by an appropriate protecting group is supported on the solid support by chemical reaction with the functional group of the solid support. The Fmoc group is then deprotected with a base such as piperidine or DBU, and the newly generated amino group is condensed with the subsequently added carboxyl-containing amino acid of the base unit to form a peptide bond. Various combinations of carboxyl group activators are available for the condensation reaction, including DIC and HOBt, DIC and HOAt, and HATU and DIPEA. The desired peptide sequence can be generated by repeated Fmoc group removal and subsequent peptide bond formation. After the desired sequence is obtained, the peptide is cleaved from the solid support and, if necessary, the protective groups on the introduced side chain functional groups are deprotected. Furthermore, structural transformations and cyclization of the peptide can be performed before cleavage from the solid support. Cleavage from the solid phase and deprotection may be carried out under the same conditions, for example, 90:10 TFA / H2O, or may be carried out under different conditions as necessary.Some cleavage from the solid phase can be achieved with a weak acid such as 1% TFA, while others utilize protecting groups that can be deprotected using a Pd-containing catalyst, taking advantage of the orthogonality of the two chemical reactions. Cyclization and other steps can also be performed between or after these steps. For example, a side-chain carboxylic acid can be condensed with an amino group on the N-terminal main chain, or a side-chain amino group can be condensed with a carboxylic acid on the C-terminal main chain. Alternatively, olefins can be introduced into two or more positions on the side chain and / or nitrogen atom substituents, followed by cyclization via metathesis. Furthermore, the double bond formed by cyclization can be reduced to a single bond. The double bond formed by cyclization can also be converted to a cyclopropane ring using conditions such as diiodomethane-diethylzinc. These cyclization, reduction, and conversion to a cyclopropane ring steps can also be performed during the synthesis of basic units such as dipeptides and tripeptides. Note that 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 or hydroxy group and the side-chain amino group to be cyclized, or between the olefin in the side-chain and / or nitrogen atom substituent and the olefin to be cyclized. As mentioned above, protecting groups are selected with consideration for their orthogonality. Furthermore, by positioning a chloroacetyl group at the N-terminus, cyclization with the thiol group in the side chain of a cysteine ​​residue is also possible. The resulting reaction product can be purified using a reverse-phase column or molecular sieve column. Details of these procedures are described, for example, in the Solid-Phase Synthesis Handbook published by Merck Ltd. on May 1, 2002. Commercially available resins for solid-phase synthesis can be used, such as CTC resin, Wang resin, or SASRIN resin.

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

[0187] The Fmoc amino acid can be supported on the resin 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 reaction vessel equipped with a filter, and the resin is allowed to swell. The solvent and resin are then separated, and a mixture of the resin, a C-terminal-free Fmoc amino acid dissolved in a 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 support the Fmoc amino acid on the resin. After separating the resin from the reaction solution, the resin is mixed with a mixture of one or more solvents and a base (e.g., a mixture of dehydrated dichloromethane, dehydrated methanol, and diisopropylethylamine) and washed. The resin is washed with a solvent (e.g., dichloromethane) multiple times as necessary, and then the resin is separated from the reaction solution. The resulting resin is dried overnight under reduced pressure to give a resin carrying an Fmoc amino acid. [ka] (In the formula, n represents an integer of 1 to 11, and P1 to P 11 , Q1~Q 11 , R1~R 11 are defined in this specification. 11 , Q1~Q 11 , R1~R 11 and L1 and L 11 are L1 and L2 as described herein. 11 and L2 to L 10 indicates a single bond, and ○ indicates a resin site.) The above structure shows that in the Fmoc-amino acid, the 2-chlorotrityl group on the resin is bound to the carboxylic acid of the Fmoc amino acid via an ester bond.

[0188] In the preparation of the compounds described herein, if a defined group undergoes undesired chemical transformation under the conditions of the method, the compound can be prepared by, for example, protecting and deprotecting the functional group. The selection and deprotection of protecting groups can be performed using methods such as those described in Greene's "Protective Groups in Organic Synthesis" (5th ed., John Wiley & Sons 2014), which can be used appropriately depending on the reaction conditions. The order of reaction steps, such as introducing substituents, can also be changed as necessary. Examples of protecting groups for amino groups include Fmoc, Boc, Cbz, and Alloc groups. These carbamate groups can be introduced by reacting the amino group with a carbamating agent in the presence of a base catalyst. Examples of carbamating agents include BocO, 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, N,N-dimethylaminopyridine, etc. A carbamate group, which is a protecting group for an amino group, can be removed under basic conditions, acidic conditions, or hydrogenolysis conditions.

[0189] ( Method for synthesizing cyclic compounds by cyclization of peptide compounds Linear peptide compounds can be converted into cyclic compounds by intramolecular bond formation reactions using methods such as those described in "Comprehensive Organic Transformations, A Guide to Functional Group Preparations, 3rd Edition, by R.C. Larock" or "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition, by M.B. March." Functional group transformation reactions can also be performed after the bond formation reaction. Examples of bond formation reactions include the C(O)-N bond formed between a carboxylic acid and an amine; the C-O-C bond, C(O)-O bond, C(S)-O bond using an oxygen atom; the C(O)-S bond, C(S)-S bond, C-S-C bond, C-S-C bond, C-S-C bond, C-S(O)-C bond, and C-N-C bond using a nitrogen atom; and the C-N-C bond, C=N-C bond, N-C(O)-N bond, N-C(S)-N bond, and C(S)-N bond using a nitrogen atom. Further examples include transition metal-catalyzed C-C bond formation reactions such as the Suzuki reaction, the Heck reaction, the Sonogashira reaction, and metathesis. Examples of functional group conversion reactions that can be performed after a bond formation reaction include oxidation and reduction reactions. Specifically, a reaction in which a sulfur atom is oxidized to convert it to a sulfoxide group or a sulfone group is exemplified. Another example is a reduction reaction in which a triple bond or a double bond among carbon-carbon bonds is reduced to convert it to a double bond or a single bond. When two amino acids are bonded to each other in the main chain of an amino acid, a closed ring structure is formed by a peptide bond. However, a covalent bond between the two amino acids may also be formed by bonding the side chains of the two amino acids together, or by bonding the side chains to the main chain. Below, black circles or black squares represent amino acid residues, and linked black circles or black squares represent peptide chains linked by amide bonds. There is no particular limitation on the number of amino acid residues that make up a peptide chain, and the number of amino acid residues is not limited to the number of black circles or black squares exemplified below.

[0190] ( General method for preparing cyclic compounds 1 ) [ka] The cyclic portion of a cyclic compound with a linear portion can be cyclized by activating the N-terminal amino group and the C-terminal side chain 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 agent or by converting them into activated esters, followed by an intramolecular condensation reaction to form a C(O)-N bond.

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

[0192] In the case of cyclic compounds in which the linear portion has become C-Terminus, as described in General Method 1 for Producing Cyclic Compounds, the amino group at the N-terminus and the carboxyl group at the side chain on the C-terminus (for example, in the case of aspartic acid and its derivatives, L = -CH2-, and in the case of glutamic acid and its derivatives, L = -CH2CH2-) can be activated with an activating agent or converted into an activated ester, followed by an intramolecular condensation reaction to form a C(O)-N bond and cyclization.

[0193] ( General method for preparing cyclic compounds 3 ) (Method of cyclization with haloalkyl group and SH group) [ka] The cyclic portion of a cyclic compound with a linear portion can be cyclized by intramolecularly reacting the haloalkyl group of an amino acid residue with the thiol group of the amino acid residue to form a C-SC bond. Similarly, in the case of cyclic compounds with a C-Terminus linear portion described in General Cyclic Compound Preparation Method 1, the haloalkyl group of an amino acid residue can be cyclized intramolecularly with the thiol group of the amino acid residue to form a C-SC bond. Furthermore, the sulfur atom can be oxidized to a sulfoxide or sulfone to form a C-S(O)-C or C-S(O2)-C bond.

[0194] (Cyclization method using vinyl and SH groups) [ka] The cyclic portion of a cyclic compound with a linear portion can be cyclized by intramolecularly reacting the vinyl group of an amino acid residue with the thiol group of the amino acid residue to form a C-SC bond. Similarly, the cyclic compound with a C-Terminus linear portion, as described in General Cyclic Compound Preparation Method 1, can be cyclized by intramolecularly reacting the vinyl group of an amino acid residue with the thiol group of the amino acid residue to form a C-SC bond. Furthermore, the sulfur atom can be oxidized to sulfoxide or sulfone, forming a C-S(O)-C bond or a C-S(O2)-C bond.

[0195] (Cyclization method using ethynyl group and SH group) [ka] The cyclic portion of a cyclic compound with a linear portion can be cyclized by forming a C-SC bond by reacting the ethynyl group of an amino acid residue with the thiol group of an amino acid residue intramolecularly. Similarly, the cyclic compound with a C-Terminus linear portion, as described in General Cyclic Compound Preparation Method 1, can be cyclized by forming a C-SC bond by reacting the ethynyl group of an amino acid residue with the thiol group of an amino acid residue intramolecularly. Furthermore, the sulfur atom can be oxidized to a sulfoxide or sulfone, forming a C-S(O)-C bond or a C-S(O2)-C bond. The double bond can also be reduced to a single bond.

[0196] (Vinyl group-vinyl group cyclization method) [ka] The cyclic portion of a cyclic compound with a linear portion can be cyclized by forming a CC bond by reacting vinyl groups with different amino acid residues intramolecularly. Similarly, in the cyclic compound in which the linear portion is C-Terminus, as described in General Method 1 for Cyclic Compounds, the vinyl groups with different amino acid residues can be cyclized by forming a CC bond by reacting them intramolecularly.

[0197] (A method of forming a triazole ring between an azide group and an ethynyl group to cyclize the compound) [ka] The cyclic portion of a cyclic compound having a straight-chain portion can be cyclized by intramolecularly reacting the azide group of an amino acid residue with the ethynyl group of the amino acid residue to form a triazole ring. Similarly, the cyclic compound in which the straight-chain portion is C-Terminus described in General Preparation Method 1 of Cyclic Compounds can be cyclized by intramolecularly reacting the azide group of an amino acid residue with the ethynyl group of the amino acid residue to form a triazole ring.

[0198] A general method for producing a peptide compound by peptide modification is shown below. In the following scheme, P n represents a substituent on a nitrogen atom, and R n and Q n represents an amino acid side chain, a black circle represents an amino acid residue, linked black circles represent peptide chains linked by amide bonds, and m represents the number of amino acid residues and can be any integer value greater than or equal to 1.

[0199] (Method for producing peptides containing N-alkylamino acids) Peptides containing N-alkylamino acids can be synthesized using Fmoc-protected N-alkylamino acids as starting materials according to the general peptide synthesis method described in this example, or by alkylation of the N-terminal nitrogen on a resin, as shown in the following method. 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, followed by treatment with a reducing agent, as described in Organic Letters, 2008, 10, 4815-4818, etc., to produce the desired peptide having an N-alkylamino 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 at the N-terminal nitrogen n As an alternative method for introducing P, the method described below in Nature Protocols, 2012, 7, 432-444 can also be used. Specifically, the N-terminal amine of the peptide supported on the resin is converted to an Ns-substituted compound, and then P is introduced by the Mitsunobu reaction. n Then, the Ns group is deprotected to give the desired P n Furthermore, a cyclic compound can be produced by carrying out peptide elongation, cleavage from the resin, cyclization, deprotection, and purification according to the general peptide synthesis method described in this example. [ka]

[0201] P on nitrogen atom n As a method for synthesizing peptides containing glycine with P introduced at the Fmoc-protected nitrogen atom, nIn addition to the synthesis method described in this example using glycine containing P as a starting material according to the general peptide synthesis method, it can also be produced by the substitution reaction of the N-terminal halocarbon with an amine as shown below. Specifically, the N-terminal amine is reacted with iodoacetic acid, and then reacted with any primary amine, with reference to Organic Letters, 2010, 12, 4928-4931, etc., to form a P on the target nitrogen atom. n Furthermore, a cyclic compound can be produced by carrying out peptide elongation, cleavage from the resin, cyclization, deprotection, and purification according to the general peptide synthesis method described in this example. [ka]

[0202] (Method for producing peptides containing aryloxy or heteroaryloxy groups in the side chain) Peptides containing an aryloxy group or heteroaryloxy group in the side chain can be produced by the general peptide synthesis method described in this example using an Fmoc amino acid having the desired aryloxy group or heteroaryloxy group in the side chain as a starting material. In addition, peptides having an alcohol in the side chain shown below can be used as precursors, with reference to Organic Letters, 2014, 16, 4944-4947 or Tetrahedron Letters, 2003, 44, 3863-3865, etc. Specifically, a peptide having an aryloxy group or heteroaryloxy group in the side chain can be produced by reacting a peptide having an alcohol in the 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 the side chain can be produced by a general peptide synthesis method described in this example using an Fmoc amino acid having the desired ether group in the side chain as a starting material. In addition, peptides having an alcohol in the side chain shown below as a precursor can be produced by referring to the method described in Journal of Medicinal Chemistry, 2011, 54, 4815-4830 or the method described in Journal of Medicinal Chemistry, 2014, 57, 159-170. Specifically, a peptide having an ether group in the 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 alcohol-containing peptide with an alkyl halide in the presence of a phase-transfer catalyst such as a tetraalkylammonium salt using aqueous sodium hydroxide as a base. [ka]

[0204] (Method for producing peptides containing aryl or heteroaryl groups in the side chain) Peptides having an aryl or heteroaryl group in the side chain can be produced by a general peptide synthesis method described in the present Examples using an Fmoc amino acid having the desired aryl or heteroaryl group in the side chain as a starting material, or by using a peptide having a carboxylic acid in the side chain as a precursor, as shown below, with reference to the method described in J. Am. Chem. Soc., 2016, 138, 5016-5019. Specifically, a peptide having a carboxylic acid in the side chain can be activated with N-hydroxyphthalimide and reacted with any aryl halide or heteroaryl halide to produce a peptide having the desired aryl or heteroaryl group in the side chain. [ka]

[0205] Furthermore, peptides having a carboxylic acid at the nitrogen atom substituent and / or side chain and an aryl halide or heteroaryl halide at the nitrogen atom substituent and / or side chain can be used to produce peptide compounds with crosslinked peptide backbones. Specifically, a peptide having a carboxylic acid is activated with N-hydroxyphthalimide and crosslinked by reaction with the aryl halide or heteroaryl halide in the molecule, producing a crosslinked compound. [ka]

[0206] As an alternative method for producing peptides having an aryl 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 is synthesized using an Fmoc amino acid having a boronic acid in the side chain as a starting material, and then reacted with any aryl halide in the presence of a palladium catalyst to produce the desired peptide having an aromatic ring in the side chain. [ka]

[0207] Furthermore, peptides having boronic acid at the nitrogen atom substituent and / or side chain and aryl halide at the nitrogen atom substituent and / or side chain of another nitrogen atom in the molecule can be used to produce peptide compounds with crosslinked peptide backbones. Specifically, a crosslinked compound can be produced by crosslinking a peptide having boronic acid with an aryl halide in the molecule in the presence of a palladium catalyst. [ka]

[0208] Furthermore, peptide compounds having an olefin in the substituent and / or side chain of a nitrogen atom and an aryl halide in the substituent and / or side chain of another nitrogen atom in the molecule can be used to produce peptide compounds bridged with alkylenes, including arylenes. Specifically, a bridged compound can be produced by converting the olefin into a boron compound by hydroboration, and then reacting it with an aryl halide in the molecule in the presence of a palladium catalyst to form a crosslink. [ka]

[0209] (Method for producing peptides containing amide groups in the side chains) Peptides having an amide group in the side chain can be synthesized by a method using an Fmoc amino acid having the desired amide group in the side chain as a starting material, or by amidation using a peptide having a carboxylic acid in the side chain as a precursor, as shown in the following method. Specifically, a peptide having a protected carboxylic acid in the side chain is deprotected to synthesize a precursor peptide having a carboxylic acid in the side chain, and this precursor peptide can be condensed with any amine using HATU or a similar condensing agent to obtain the desired peptide having an amide group in the side chain. [ka]

[0210] Furthermore, peptide compounds with crosslinked peptide backbones can be produced using peptides with carboxylic acid at the nitrogen atom substituent and / or side chain and amino group at another nitrogen atom substituent and / or side chain in the molecule. Specifically, a precursor peptide with carboxylic acid and amino group is synthesized by deprotection, and then crosslinked by intramolecular amidation reaction by condensation with a condensing agent such as HATU, thereby producing a crosslinked compound. [ka]

[0211] Synthesis of peptides containing highly substituted structures that may contain double bonds in the side chains Peptides with highly substituted structures that may contain double bonds in the side chain can be synthesized by using an Fmoc amino acid having a double bond in the desired side chain as a starting material, or by functionalizing a terminal olefin. Specifically, a peptide having a terminal olefin in the side chain can be synthesized according to the general peptide synthesis method described in this example, and then converted to a side chain having a highly substituted olefin by coupling with a substrate having any terminal olefin via an olefin metathesis reaction. The olefin can also be converted to the corresponding side chain by reducing it via a hydrogenation reaction. [ka]

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

[0213] Furthermore, as the above-mentioned crosslinked compound, a peptide compound crosslinked by an arylene and a divalent group containing a double bond can be produced using a peptide containing an aryl having an olefin-containing substituent in the nitrogen atom substituent and / or side chain. Specifically, a peptide having an olefin-containing aryl and an olefin in the nitrogen atom substituent and / or side chain can be synthesized according to the general peptide synthesis method described in this example, and two olefins can be crosslinked by an olefin metathesis reaction to produce a crosslinked compound. Furthermore, a compound crosslinked by an arylene-containing alkylene 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 the side chain can be produced by a click reaction with an azide group. Specifically, a peptide having an azide group in the side chain can be synthesized according to the general peptide synthesis method described in this example, and then coupled with any acetylene in the presence of copper(I) iodide, with reference to Bioorganic & Medicinal Chemistry Letters, 2009, 19, 4130-4133, etc., to produce a peptide compound having an azide group in the side chain. [ka]

[0215] Furthermore, peptides having an azide group at the nitrogen atom substituent and / or side chain and an acetylene at the nitrogen atom substituent and / or side chain in another nitrogen atom in the molecule can be used to produce peptide compounds with crosslinked peptide backbones. Specifically, a crosslinked compound can be produced by crosslinking a peptide having an azide group with an acetylene in the molecule 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 an aryl group substituted with an alkynyl group in the side chain can be synthesized by Sonogashira coupling reaction with an aryl halide group. Specifically, a peptide having an aryl iodide group in the side chain can be synthesized according to the general peptide synthesis method described in this example, and then converted into a peptide compound having an aryl group substituted with an alkynyl group in the side chain by coupling with any acetylene in the presence of copper(I) iodide. [ka]

[0217] Furthermore, peptides having an aryl halide group at the nitrogen atom substituent and / or side chain and an acetylene at the nitrogen atom substituent and / or side chain can be used to produce peptide compounds with crosslinked peptide backbones. Specifically, a peptide having an aryl iodide group can be crosslinked by coupling with an acetylene in the molecule in the presence of copper(I) iodide to produce a crosslinked compound. [ka]

[0218] (General method for producing oligopeptide compounds) The following shows a general method for producing an oligopeptide in which a cyclic structure is formed between the nitrogen atom substituent and the 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 is the side chain of an amino acid, P n-1 , P n , P n+1represents a nitrogen atom substituent, and Y1 and Y2 represent hydrogen, halogen, or alkyl. In the amino acid production methods described below, functional groups other than the intended one may undergo chemical reactions. In such cases, introducing protecting groups to the unintended functional groups allows only the desired reaction to proceed. Examples of methods for removing such protecting groups include those described in Greene's "Protective Groups in Organic Synthesis" (5th ed., John Wiley & Sons, 2014). For functional group transformation reactions in compounds, see Larock's Comprehensive Organic Transformations: A Guide to Functional Group Preparations (5th ed.) and Smith's March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (8th ed.).

[0219] Oligopeptide compounds in which the nitrogen atom substituent of an amino acid and the side chain of another amino acid form a cyclic structure can be synthesized using the following method. An olefin-containing alkyl group can be introduced into a protected amino acid by treating it with an olefin-containing alkylating agent in the presence of a base. Subsequently, any amino acid with a protected C-terminus can be condensed to extend the C-terminus. The condensation reaction can be performed using various combinations of carboxyl group activators, such as DIC and HOBt, DIC and HOAt, or HATU and DIPEA. After deprotection of the nitrogen atom protecting group, the protected amino acid with an olefin in the side chain can be extended. The olefin in the molecule can then be cyclized by metathesis. The C-terminal protecting group can then be deprotected to produce a C-terminus-free oligopeptide compound in which a double bond is formed between the nitrogen atom substituent and the side chain. [ka]

[0220] Furthermore, an oligopeptide compound having a cyclic structure in which the double bond is converted to a single bond can be produced using an oligopeptide compound having a cyclic structure in which the double bond is converted to a single bond. Specifically, a C-terminal protected compound having a cyclic structure in which a double bond is converted to a single bond can be reduced by a hydrogenation reaction, and then the protecting group at the C-terminus can be deprotected to produce an oligopeptide compound having a C-terminus free in which a cyclic structure is formed by alkylene between the nitrogen atom substituent and the side chain. [ka]

[0221] Furthermore, an oligopeptide compound having a cyclic structure containing a double bond can be used to produce an oligopeptide compound having a bridged structure in which the double bond has been converted into a cyclopropane ring. Specifically, the double bond of a C-terminal protected compound having a cyclic structure containing a double bond can be converted into a cyclopropane ring under conditions such as diiodomethane-diethylzinc. The protecting group at the C-terminus is then removed to produce an oligopeptide compound having a bridged structure in which the double bond has been converted into a cyclopropane ring. [ka]

[0222] Oligopeptide compounds in which the nitrogen atom substituent of an amino acid and the side chain of another amino acid form a cyclic structure can also be synthesized using the following method. An oxazolidinone compound with a cyclic protecting group can be obtained by treating a protected amino acid with an aldehyde according to the method of Freidinger et al. (J. Org. Chem., 1983, 48(1), 77-81). Next, an alkyl group bearing an olefin can be introduced onto the nitrogen atom by a ring-opening reaction using a silicon compound bearing an olefin according to the method of Nguyen et al. (Synthesis, 2009, 12, 1991). Subsequently, any amino acid with a protected C-terminus can be condensed to extend the C-terminus. After deprotecting the nitrogen atom protecting group, a protected amino acid bearing an olefin in the side chain can be extended. The olefin within the molecule can then be cyclized by a metathesis reaction. The protecting group at the C-terminus is then deprotected to produce an oligopeptide compound with a free C-terminus that forms a cyclic structure containing a double bond between the nitrogen atom substituent and the side chain. [ka]

[0223] Oligopeptides containing an aryl group substituted with an alkenyl group (y = 0 to 2) in the side chain can be synthesized by Suzuki coupling reaction between an aryl halide and a boron compound having an alkenyl group. Specifically, a peptide having an aryl iodide group in the 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 to 2) in the side chain by coupling with a boron compound having an alkenyl group in the presence of a palladium catalyst. [ka]

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

[0225] (Method for cyclization of peptide compounds on resin) In addition to being cyclized according to the method described in this example, cyclic compounds and oligopeptide compounds having a cyclic structure can also be cyclized by a metathesis reaction on a resin as shown below. Specifically, a peptide supported on a resin having olefins at two positions in the nitrogen atom substituent and / or side chain is synthesized according to the general peptide synthesis method described in this example, and the two olefins are cyclized by a metathesis reaction to produce a compound having a cyclic structure. Furthermore, cyclic compounds and oligopeptide compounds having a cyclic structure can be produced by carrying out peptide elongation, cleavage from the resin, cyclization, deprotection, and purification according to the general peptide synthesis method described in this example. [ka]

[0226] (General method for producing unnatural amino acids) The general method for producing a C-terminal free unnatural amino acid in which the nitrogen atom of the amino acid is protected is shown below. In the following scheme, PG1 and PG1' are protecting groups for the nitrogen atom, PG2 and PG2' are protecting groups for the oxygen atom, PG3 and PG4 are protecting groups for the side chain of the amino acid, R n and Q n is the side chain of an amino acid, P n represents a nitrogen atom substituent, P' represents a C1-C5 alkyl, and R, R', R'', and R''' represent hydrogen or amino group substituents. In the amino acid production methods shown below, functional groups other than the intended one may undergo chemical reactions. In such cases, introducing protecting groups to the unintended functional groups allows only the desired reaction to proceed. Examples of such protecting group removal reactions include those described in Greene's "Protective Groups in Organic Synthesis" (5th ed., John Wiley & Sons 2014). For functional group transformation reactions in compounds, see Larock's Comprehensive Organic Transformations: A Guide to Functional Group Preparations (5th ed.) and Smith's March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (8th ed.).

[0227] The following method can be used to produce an unnatural amino acid in which a protecting group (PG1) has been introduced at the nitrogen atom of the amino acid. The desired unnatural amino acid with a free C-terminus can be produced by introducing a protecting group and, if necessary, deprotecting the N-terminus-free amino acid available from a commercial supplier according to standard methods. [ka]

[0228] The following method can be used to produce an unnatural amino acid having a protecting group (PG1') introduced at the nitrogen atom of the amino acid. The desired unnatural amino acid with a free C-terminus can be produced by conventional deprotection and protecting group introduction reactions of an amino acid having a protecting group (PG1) introduced at the N-terminus, which is available from a commercial supplier. [ka]

[0229] Substituents of nitrogen atoms of amino acids (P n The following method can be used to produce unnatural amino acids with an aminoalkyl group introduced at the C-terminus. Bromoacetate derivatives available from commercial suppliers are reacted with an amino alcohol according to the method of King et al. (Tetrahedron Letters, 2002, 43(11), 1987-1990), followed by introduction of a protecting group (PG1) at the nitrogen atom. The hydroxyl group is then oxidized according to the method of Dess et al. (J. Org. Chem., 1983, 48(22), 4155-4156), followed by reductive amination of the aldehyde group to introduce an amino group according to the method of Borch et al. (J. Org. Chem. 1972, 37(10), 1673-1674). The protecting group at the oxygen atom is then removed to produce the desired C-terminus-free unnatural amino acid. [ka]

[0230] N-substituted amino acids are amino acids with a substituent (P n The bromoacetate derivative, available from a commercial supplier, can be converted to an amine (P n The desired C-terminal free unnatural amino acid can be produced by reacting the unnatural amino acid with NH2, followed by introducing a protecting group (PG1) to the nitrogen atom. The protecting group on the oxygen atom can then be removed. [ka]

[0231] Unnatural amino acids having a -CH2-P' group introduced at the nitrogen atom of the amino acid can be produced by the following scheme. An oxazolidinone derivative having a cyclic protecting group introduced therein can be obtained by reacting an aldehyde with a C-terminal free amino acid available from a commercial supplier according to the method of Freidinger et al. (J. Org. Chem., 1983, 48(1), 77-81). The desired C-terminal free unnatural amino acid can then be produced by a ring-opening reaction. [ka]

[0232] P on the nitrogen atom of amino acids n The unnatural amino acid having the introduced group can be produced by the following scheme: A commercially available C-terminal free amino acid is reacted with an alkylating agent (P n -X) to form P n Then, a deprotection reaction and a protecting group introduction reaction are carried out by a standard method to produce an unnatural amino acid with a free C-terminus. [ka]

[0233] Unnatural amino acids with an amide group introduced into the side chain of the amino acid can be produced by the following scheme. A commercially available protected amino acid (n = 1 or 2) is deprotected, and the resulting carboxylic acid is reacted with an amine (R"R"'NH) to introduce an amide group into the side chain. The C-terminal protecting group is then deprotected to produce an unnatural amino acid with no C-terminus. [ka]

[0234] Unnatural amino acids with an amide group introduced into the side chain and a -CH2-P' group 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) is reacted with an aldehyde according to the method of Freidinger et al. (J. Org. Chem., 1983, 48(1), 77-81) to obtain an oxazolidinone derivative with a cyclic protecting group. Next, the protecting group in the side chain is deprotected, and then an amine (R''R'''NH) is reacted to obtain an amide derivative. A ring-opening reaction is then performed to produce the desired unnatural amino acid with a free C-terminus. [ka]

[0235] Unnatural amino acids with an amino group introduced into the side chain 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 commercially available protected amino acid (n = 1 or 2). Subsequently, 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, thereby producing an unnatural amino acid with a free C-terminus. [ka]

[0236] Unnatural amino acids with an amino group introduced into the side chain and a -CH2-P' group 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 an amino acid (n = 1 or 2) protected with a cyclic protecting group. Subsequently, 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 unnatural amino acid with a free C-terminus. [ka]

[0237] An unnatural amino acid having a fluoroalkyl group introduced into the side chain of the amino acid can be produced by the following scheme. The carboxyl group of a commercially available protected amino acid (n = 1 or 2) is converted to an aldehyde group by a standard method through reduction, and then a fluorine atom is introduced by a standard method, thereby converting the aldehyde group into a difluoromethyl group. The protecting group at the C-terminus is then deprotected to produce an unnatural amino acid with a free C-terminus. [ka]

[0238] An unnatural amino acid having a halogenated alkyl group introduced into the side chain of the amino acid and a -CH-P' group introduced into the nitrogen atom of the amino acid can be produced according to the following scheme. The carboxyl group of an amino acid (n = 1 or 2) protected with a cyclic protecting group is converted into an aldehyde group by a standard method through reduction, and then a halogen atom is introduced by a standard method to convert the aldehyde group into a dihalogenated methyl group. The cyclic protecting group at the C-terminus is then opened to produce an unnatural amino acid with a free C-terminus. [ka]

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

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

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

[0242] Unnatural amino acids having an aryl or heteroaryl group (these groups are referred to as "Ar" in the scheme) introduced into the side chain of the 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 or heteroaryl group is introduced by the reaction with an aryl halide or heteroaryl halide according to the method of He et al. (Org. Lett. 2014, 16(24), 6488-6491). This allows the production of unnatural amino acids having an aralkyl or heteroaralkyl group in the side chain. Subsequent deprotection and protecting group introduction reactions allow the production of the desired C-terminal-free unnatural amino acid. [ka]

[0243] [ka]

[0244] An unnatural amino acid having a halogen atom introduced into the aralkyl group in the side chain of the amino acid can be produced by the following scheme. a A boronate ester can be introduced into the aralkyl group, which may have a C-terminus, according to the method of Ishiyama et al. (J. Am. Chem. Soc. 2002, 124(3), 390-391). A halogen atom can be introduced into the introduced boryl group using an N-halogenated succinimide according to the method of Lindner et al. (Chem. Eur. J., 2016, 22, 13218-13235). The desired C-terminus-free unnatural amino acid can be produced by removing the protecting group from the resulting unnatural amino acid as needed. [ka]

[0245] An unnatural amino acid having a halogen atom introduced into the aralkyl group in the side chain of the amino acid and a -CH2-P' group introduced into the nitrogen atom of the amino acid can be produced by the following scheme. a A boronate ester can be introduced into the aryl group of an amino acid bearing an aralkyl group optionally containing a C-terminus, according to the method of Ishiyama et al. (J. Am. Chem. Soc. 2002, 124(3), 390-391). A halogen atom can be introduced into the introduced boryl group using an N-halogenated succinimide according to the method of Lindner et al. (Chem. Eur.J., 2016, 22, 13218-13235). The desired C-terminus-free unnatural amino acid can be produced by removing the protecting group from the resulting unnatural amino acid as needed. [ka]

[0246] The amino acid side chain may be substituted with an alkoxy group or an aralkoxy group (R b The synthesis of unnatural amino acids bearing a nosyl (Ns) group can be carried out according to the following scheme. After introducing a nosyl (Ns) group into commercially available serine derivatives (n = 1 or 2) by standard methods, a cyclized product can be obtained according to the method of Mitsunobu et al. (Synthesis, 1981, 1,1-28). The cyclized product can be reacted with an appropriate alcohol (R b The resulting unnatural amino acid can be subjected to ring-opening with hydroxyl group (OH) to obtain a serine ether. The desired unnatural amino acid with a free C-terminus can be produced by removing the protecting group from the unnatural amino acid obtained here, as needed. [ka]

[0247] The amino acid side chain may be substituted with an alkoxy group or an aralkoxy group (R b The synthesis of unnatural amino acids having n=1 or 2 can be carried out according to the following scheme. A commercially available cyclic compound (n=1 or 2) is reacted with an appropriate alcohol (R b The resulting unnatural amino acid can be subjected to ring-opening with hydroxyl group (OH) to obtain a serine ether. The desired unnatural amino acid with a free C-terminus can be produced by removing the protecting group from the unnatural amino acid obtained here, as needed. [ka]

[0248] The amino acid side chain may be substituted with an alkoxy group or an aralkoxy group (R bUnnatural amino acids having n=1 or 2 can be prepared by the following scheme: A commercially available serine derivative (n=1 or 2) is reacted with an alkylating agent (R b By reacting with α-X), serine ether can be obtained. b If has further convertible functional groups, additional functional group conversion can be performed to obtain R b can be converted to the desired functional group. Additional functional group conversions include, for example, reduction of multiple bonds. The unnatural amino acid obtained here can then be deprotected to produce the desired unnatural amino acid with a free C-terminus. [ka]

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

[0250] Unnatural amino acids having a protected hydroxy group on the side chain of the amino acid can be produced according to the following scheme: A commercially available serine derivative or a serine derivative (n = 1 or 2) produced by the method described above can be subjected to an appropriate deprotection reaction to remove the protecting group, thereby producing the desired unnatural amino acid with a free C-terminus. [ka]

[0251] Unnatural amino acids bearing a protecting hydroxy group in the side chain and a -CH2-P' group introduced at the nitrogen atom of the amino acid can be produced 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 reacted with an aldehyde according to the method of Freidinger et al. (J. Org. Chem., 1983, 48(1), 77-81) to obtain an oxazolidinone derivative with a cyclic protecting group. Subsequently, a ring-opening reaction and a protecting group introduction reaction are carried out to produce the desired unnatural amino acid with a free C-terminus. [ka]

[0252] The hydroxyl group of the cyclic amino acid is substituted with a substituent (R c A cyclic unnatural amino acid having the desired -OR group introduced therein can be produced by the following scheme. A commercially available cyclic amino acid can be subjected to an appropriate functional group introduction reaction to produce the desired -OR group. c As a conversion reaction of a functional group, according to the method of Williamson (Liebigs Ann. Chem. 1851, 77, 37-49), an alkylating agent (R c By reacting R with -X, an ether bond can be formed. c If has further convertible functional groups, additional functional group conversion can be performed to obtain R cThe desired C-terminal free unnatural amino acid can then be produced by deprotection. [ka]

[0253] A cyclic unnatural amino acid can be produced by introducing a protecting group (PG3) into the hydroxyl group of a cyclic amino acid according to the following scheme: A commercially available cyclic amino acid can be subjected to an appropriate deprotection reaction to remove the protecting group, thereby producing the desired C-terminal-free unnatural amino acid. [ka]

[0254] Unnatural amino acids with a boronic acid introduced into the side chain of the amino acid can be produced by the following scheme. A commercially available glycine derivative can be reacted with an aldehyde according to the method of Lee et al. (Bioorg. Med. Chem. Lett., 2009, 19(17), 4887-5274) to obtain an unnatural amino acid with a boronic acid ester introduced. The desired unnatural amino acid with a free C-terminus can then be produced by appropriately removing the protecting group. [ka]

[0255] (Synthesis of Fmoc-linked unnatural amino acids with carboxyl groups in the side chains 1) Fmoc unnatural amino acids bearing a carboxyl group in the side chain can be prepared according to the following scheme. The main chain carboxyl group of a starting material (n = 1 or 2) whose side chain carboxyl group is protected with PG3, which is available from a commercial supplier, can be converted to an amide group by condensing with an amine (R''R''NH) in the presence of a condensing agent such as DIC. Subsequently, a deprotection reaction of PG3 can be performed to prepare the desired Fmoc unnatural amino acid bearing a carboxyl group in the side chain. [ka]

[0256] (Synthesis of Fmoc-linked unnatural amino acids with carboxyl groups in the side chains 2) Fmoc unnatural amino acids bearing a carboxyl group in the side chain and further incorporating a -CH2-P' group at the nitrogen atom of the amino acid can be prepared according to the following scheme. The main chain carboxyl group of a starting material (n = 1 or 2) whose side chain carboxyl group is protected with PG3, available from a commercial supplier, can be converted to an amide group by condensing with an amine (R''R'''NH) in the presence of a condensing agent such as DIC. Subsequently, a deprotection reaction of PG3 can be performed to prepare the desired Fmoc unnatural amino acid bearing a carboxyl group in the side chain. [ka]

[0257] (Synthesis of Fmoc-linked unnatural amino acids with vinyl halide side chains) Fmoc unnatural amino acids bearing a vinyl halide in the side chain can be synthesized according to the method of Shendage et al. (Eur. J. Org. Chem., 2005, 719-727) using the following scheme: Boc-2-t-butyl-3-methylimidazolidin-4-one, available from a commercial supplier, is reacted with an alkylating agent bearing a vinyl halide in the side chain in the presence of a base, and the desired Fmoc unnatural amino acid bearing a vinyl halide in the 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: An amino acid with a protected side chain thiol group is subjected to carboxylic acid amidation, and after deprotection of the thiol group, the amino acid is reacted with a halogenated acetic acid with a protected carboxylic acid to form a thioether bond. The carboxylic acid in the side chain is then deprotected to produce an amino acid with a thioether group in the side chain. [ka]

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

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

[0261] When the compound according to the present invention is obtained as a free form, the compound can be converted into a salt which the compound may form, or a hydrate or solvate thereof, in a conventional manner.

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

[0263] <Pharmaceutical Composition> The present invention provides a pharmaceutical composition containing the cyclic compound of the present invention. The pharmaceutical composition of the present invention can be formulated by a known method by incorporating a pharmaceutically acceptable carrier in addition to the compound of the present invention, its salt, or a solvate thereof. 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 composition can be formulated by a conventional method by blending ingredients generally used as raw materials for pharmaceutical preparations. For example, to produce an oral preparation, the compound of the present invention or a salt thereof and an excipient are added, and if necessary, a binder, a disintegrant, a lubricant, a colorant, a flavoring agent, etc., and then the compound is processed into powders, fine granules, granules, tablets, coated tablets, capsules, etc. by conventional methods.

[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 hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymers, 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 silicic anhydride, 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, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl methylcellulose, hydroxypropyl cellulose, 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] Coloring agents that are permitted to be added to pharmaceuticals are used, and flavoring agents include cocoa powder, peppermint, aromatic powder, peppermint oil, borneol, cinnamon powder, etc.

[0270] These tablets and granules may be coated with sugar or other suitable coatings as necessary. When preparing liquid preparations such as syrups and injection preparations, the compounds of the present invention or their pharmacologically acceptable salts are formulated in a conventional manner by adding a pH adjuster, a solubilizer, an isotonicity adjuster, and, if necessary, a solubilizer, a stabilizer, etc.

[0271] For example, they can be administered parenterally in the form of a sterile solution or suspension in water or other pharmaceutically acceptable liquid for injection. For example, they can be formulated by appropriately combining them with pharmacologically acceptable carriers or vehicles, specifically, sterile water, physiological saline, vegetable oils, emulsifiers, suspending agents, surfactants, stabilizers, flavoring agents, excipients, vehicles, preservatives, binders, etc., and blending them in a unit dosage form required for generally accepted pharmaceutical practice. Specific 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 fatty acid triglycerides, polyoxyethylene hydrogenated castor oil 60, sucrose, carboxymethylcellulose, cornstarch, inorganic salts, etc. The amount of active ingredient in these formulations is such that an appropriate dose within the indicated range can be obtained. Sterile compositions for injection can be formulated according to conventional pharmaceutical practice using a vehicle such as distilled water for injection.

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

[0273] Examples of oily liquids include sesame oil and soybean oil, and they may be used in combination with solubilizing agents such as benzyl benzoate and benzyl alcohol. They may also contain buffers such as phosphate buffer and sodium acetate buffer, soothing agents such as procaine hydrochloride, stabilizers such as benzyl alcohol, phenol, and antioxidants. The prepared injection solution is usually filled into suitable ampoules.

[0274] The administration is preferably oral administration, but the administration method is not limited to oral administration. Specific examples of parenteral administration include injections, intranasal administrations, pulmonary administrations, transdermal administrations, etc. Examples of injections include intravenous injections, intramuscular injections, intraperitoneal injections, subcutaneous injections, etc., which can be used for systemic or local administration.

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

[0276] In certain embodiments, the cyclic compounds of the present invention, or salts thereof, or solvates thereof, or pharmaceutical compositions comprising the cyclic compounds of the present invention, or salts thereof, or solvates thereof, can bind to or selectively bind to KRAS in a subject and can be used to selectively inhibit KRAS.

[0277] In certain embodiments, the cyclic compounds of the present invention, or salts thereof, or solvates thereof, can bind to or selectively bind to KRAS in a subject and can be used in the manufacture of a medicament for selectively inhibiting KRAS.

[0278] In certain aspects, the present invention relates to a method for binding or selectively binding a cyclic compound of the present invention to KRAS in a subject, or for selectively inhibiting KRAS in a subject, comprising administering to a subject in need thereof an effective amount of a cyclic compound of the present invention, or a salt thereof, or a solvate thereof.

[0279] Such a cyclic compound of the present invention, or a salt thereof, or a solvate thereof has high selectivity for KRAS in a subject. For example, a cyclic compound of the present invention may be 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[3.0.0.0.0] 12,15 ]nonatriacontane-33,1'-cyclobutane]-27-carboxamide has higher KRAS selectivity (KRAS selectivity over NRAS and / or KRAS selectivity over HRAS).

[0280] In one embodiment, the pharmaceutical composition of the present invention has KRAS inhibitory activity that is three-fold or more greater than NRAS inhibitory activity and HRAS inhibitory activity.

[0281] In certain embodiments, the pharmaceutical composition of the present invention has KRAS inhibitory activity that is 5-fold, 7-fold, 10-fold, 15-fold, or 20-fold or more relative to NRAS inhibitory activity and HRAS inhibitory activity.

[0282] In certain embodiments, the cyclic compounds of the present invention, or salts thereof, or solvates thereof, or pharmaceutical compositions comprising the cyclic compounds of the present invention, or salts thereof, or solvates thereof, can be used to treat and / or prevent cancer in a subject.

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

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

[0285] A specific example of cancer is lung cancer.

[0286] As used herein, the term "subject" includes mammals, preferably humans.

[0287] All prior art documents cited in this specification are hereby incorporated by reference. [Example]

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

[0289] [Table 1] TIFF0007823181000089.tif211149TIFF0007823181000090.tif212149TIFF0007823181000091.tif212149TIFF0007823181000092.tif214149

[0290] Example 1 Solid Phase Synthesis of Peptide Compounds According to the peptide synthesis method using the Fmoc method described in WO2013 / 100132 or WO2018 / 225864, peptide elongation was carried out using the following basic route (sometimes referred to as the basic peptide synthesis method): 1) The carboxylic acid of the Asp side chain or the carboxylic acid of the peptide main chain is supported on 2-chlorotrityl resin, and the peptide is elongated from the N-terminus of the amino acid by the Fmoc method. 2) Peptide cleavage process from 2-chlorotrityl resin, 3) Amide cyclization by condensation of the carboxylic acid of the Asp side chain or the carboxylic acid of the peptide main chain generated by the cleavage process from the 2-chlorotrityl resin with the amino group of the N-terminus (triangle unit) of the peptide chain. 4) Deprotection of the protecting groups of the side chain functional groups contained in the peptide chain, if necessary; 5) Purification of the compound by preparative HPLC. In this example, unless otherwise specified, the peptide compound was 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 in the synthesis using a peptide synthesizer. The Fmoc-amino acids listed in Table 2 were synthesized according to the method 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] TIFF0007823181000096.tif203149TIFF0007823181000097.tif202149TIFF00078231810 00098.tif198149TIFF0007823181000099.tif208149TIFF0007823181000100.tif206149 TIFF0007823181000101.tif203149TIFF0007823181000102.tif203149TIFF00078231810 00103.tif173149TIFF0007823181000104.tif132149TIFF0007823181000105.tif118149

[0294] [Table 4] TIFF0007823181000107.tif201149TIFF0007823181000108.tif209149TIFF0007823181000109.tif205149TIFF0007823181 000110.tif77149TIFF0007823181000111.tif146149TIFF0007823181000112.tif146149TIFF0007823181000113.tif39149

[0295] Synthesis of Fmoc-amino acids Synthesis of compound aa004 [ka]

[0296] Compound aa004-a (3.00 g, 7.86 mmol) was dissolved in toluene (79 mL), and paraformaldehyde (708 mg, 23.6 mmol) and CSA (91 mg, 0.393 mmol) were added. 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 an additional 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 aqueous sodium bicarbonate (50 mL) and then with 50% brine (50 mL). The mixture was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain compound aa004-b as a 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 stirred at room temperature for 1 hour. The reaction mixture was washed with saturated ammonium chloride solution (40 mL), 50% brine (40 mL), dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in acetonitrile (40 mL) and washed twice with n-hexane (40 mL). The solvent was evaporated under reduced pressure to give 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 a starting material, aa028-b was obtained as a crude product (9.61 g, 94%) in a similar manner to the synthesis of compound aa004-b.

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

[0301] Synthesis of compound aa018 [ka]

[0302] Compound aa018-b (2.71 g, 87%) was obtained using compound aa018-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]pent-4-ynoic acid, Fmoc-PRA-OH) (3 g, 8.95 mmol) as the starting material in a similar manner to the synthesis of compound aa004-b. 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 (986 mg, 99%) was obtained by the same method as in 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-b (4.2 g, 82%) was obtained using compound aa049-a ((2S)-3-(2-chlorophenyl)-2-[9H-fluoren-9-ylmethoxycarbonylamino]propanoic acid, Fmoc-Phe(2-Cl)-OH) (5 g, 11.85 mmol) as a starting material in a manner similar to that used for the synthesis of compound aa004-b. LCMS(ESI)m / z=434(M+H)+ Retention time: 1.01 minutes (Analysis conditions SQDFA05)

[0306] Using the obtained compound aa049-b (4.2 g), compound aa049 (3.32 g, 79%) was obtained by a method similar to that used for 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] Using compound aa199-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]-3-[4-(trifluoromethyl)phenyl]propanoic acid, Fmoc-Phe(4-CF3)-OH) (200 g, 439 mmol) as a starting material, compound aa199-b (206.8 g) was obtained as a crude product in the same manner as in 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 (205 g), compound aa199 was obtained (195 g, 95% yield over two steps) in the same manner as in the synthesis of compound aa004. 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 a starting material, aa013-b was obtained as a crude product (5.29 g, 102%) in a similar manner to 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, and the mixture was dissolved in TBME (100 mL) and washed with 1 M aqueous potassium hydrogen phosphate (50 mL). The aqueous layer was extracted three times with TBME, and the combined organic layers were removed under reduced pressure. Acetonitrile / n-hexane (1 / 2, 100 mL) was added, and the mixture was extracted with 5% aqueous potassium bicarbonate (100 mL). The aqueous layer was acidified with 6 M hydrochloric acid and extracted twice with TBME (30 mL). The organic layer was dried over sodium sulfate and filtered, and the solvent was removed under reduced pressure. Acetonitrile (100 mL) was added, and the mixture was washed with n-hexane (50 mL), and the solvent was evaporated 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 aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, and then filtered. The resulting solution was concentrated under reduced pressure to give the crude product, compound aa030-b (859 mg). This was used in the next reaction without further purification.

[0315] Under a nitrogen atmosphere, TES (2.75 mL, 17.22 mmol) and TFA (3.98 mL, 51.7 mmol) were added to a solution of compound aa030-b (853 mg) in DCE (10 mL) at room temperature, and the mixture was stirred at 60 °C for 5 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to obtain a crude product. t-Butyl methyl ether / n-hexane (1 / 1) was added to the crude product, which was then extracted five times with saturated aqueous sodium bicarbonate. The pH of the resulting aqueous layer was adjusted to acidic with concentrated hydrochloric acid, and then extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure to obtain compound aa030 (811 mg, 99% yield for two steps). The resulting compound aa060 was used for 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] Using compound aa029-a ((2S)-3-(4-cyanophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid, Fmoc-Phe(4-CN)-OH) (1 g, 2.425 mmol) as the starting material, compound aa029 was obtained as a crude product (1.14 g, 108% over two steps) in a manner similar to 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) (1 g, 2.425 mmol) was used as a starting material, and the crude product was obtained in the same manner as in the synthesis of compound aa030-b. The crude product obtained using the obtained compound aa031-b in the same manner as in 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, 51% for two steps). 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 a starting material, and compound aa050-b was obtained as a crude product in the same manner as in the synthesis of compound aa004-b. Furthermore, compound aa050-b was obtained in the same manner as in the synthesis of compound aa030, using compound aa050-b (74.4 mg, 69% in two steps). 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. TES (1.10 mL, 6.92 mmol) was added and the mixture was stirred at room temperature for 40 minutes. BF3·OEt2 (0.877 mL, 6.92 mmol) was added and the mixture was stirred at room temperature. The reaction solution was washed with saturated aqueous sodium chloride (25 mL) and saturated brine (50 mL). The organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated 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 a starting material, aa331 (9.09 g, 86%) was obtained by a method similar to that used for the synthesis of compound aa019. LCMS(ESI)m / z=382(M+H)+ Retention time: 0.94 minutes (Analysis conditions SQDFA05)

[0326] Synthesis of compound aa020 [ka]

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

[0328] 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) under a nitrogen atmosphere, and cyclopropanol (1.665 mL, 26.3 mmol) was added. Then, boron trifluoride diethyl ether complex (BF3·OEt2) (0.291 mL, 2.319 mmol) was added under ice cooling. After 2 hours of reaction under ice cooling, the reaction mixture was quenched by adding water and saturated aqueous sodium bicarbonate. The aqueous layer was removed using a phase separator, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4 / 1) to give 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 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. The mixture was stirred at room temperature for 5 hours. 1N hydrochloric acid (72 mL) was then added to the reaction mixture, and the isopropanol and THF were removed by concentration under reduced pressure. 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 reduced pressure. The resulting residue was washed with ethyl acetate / n-hexane (1 / 2, 20 v / w) to give 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 stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the organic and aqueous layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with saturated brine, dried over sodium sulfate, and evaporated under reduced pressure to give compound aa020-e (3.1 g, quant.) as a crude product. 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) was added 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) under ice cooling and nitrogen atmosphere, and the mixture was stirred for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated aqueous ammonium chloride solution, then 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. The acetonitrile layer was then 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 in the same manner as in 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 (10.5 g) was reacted in the same manner as in the synthesis of compound aa020, and the obtained 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 (10.11 g, 96% over two steps). LCMS(ESI)m / z=394(M+H)+ Retention time: 0.98 minutes (Analysis conditions SQDFA05)

[0335] Synthesis of compound aa010 [ka]

[0336] Using compound aa010-a ((2S)-3-cyclobutyl-2-[9H-fluoren-9-ylmethoxycarbonylamino]propanoic acid, Fmoc-Ala(cBu)-OH) (3.36 g, 9.19 mmol) as a starting material, compound aa010-b was obtained as a crude product (3.63 g) in the same manner as in 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 (3.63 g) was reacted using a method similar to that used to synthesize 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 (3.18 g, 91% over two steps). 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) (2 g, 4.98 mmol) was used as the starting material, and the reaction mixture obtained in the same manner as in the synthesis of compound aa020-e was added with saturated aqueous sodium bicarbonate, charged onto a silica gel column (2 v / w), and eluted with DCM to obtain compound aa047-b as a crude product (1.45 g). Using the obtained compound aa047-b, compound aa047 was obtained (1.21 g, 58% for two steps) in the same manner as in the synthesis of compound aa020. LCMS(ESI)m / z=416(M+H)+ Retention time: 0.94 minutes (Analysis conditions SQDFA05)

[0340] Compound aa060 synthesis [ka]

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

[0342] The entire amount of compound aa060-b obtained above was reacted in the same manner as in 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 aa060 (2.32 g, 89% for two steps). 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), once with saturated brine / water (1 / 1, 440 mL), and then dried over magnesium sulfate. After filtering off the magnesium sulfate, the mixture was concentrated under reduced pressure to give compound aa021-b as a 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 (23 g, 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, followed by stirring at -5 °C for 50 minutes. n-Hexane (300 mL) was added, and the precipitate was removed by filtration. 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 etherate (BF3·OEt2) (0.469 mL, 3.73 mmol) was added, followed by stirring at 70 °C for 30 min. TFE was removed under reduced pressure, and the resulting crude product was purified by reverse-phase column chromatography (0.1% formic acid in acetonitrile / 0.1% formic acid in distilled water) to give 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 a solution of lithium hydroxide monohydrate (5.21 g, 124 mmol) in water (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 purified by reverse-phase column chromatography (0.1% formic acid in acetonitrile / 0.1% formic acid in distilled water) to give 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. The mixture was diluted with water (100 mL) and washed twice with TBME (200 mL). A solution of Fmoc-OSu (3.5 g) in 1,4-dioxane (150 mL) was added to the resulting solution and stirred for 25 minutes. A solution of Fmoc-OSu (700 mg) in 1,4-dioxane (10 mL) was then added and stirred for 5 minutes. A solution of Fmoc-OSu (350 mg) in 1,4-dioxane (5 mL) was then added and stirred for 5 minutes. A solution of Fmoc-OSu (350 mg) in 1,4-dioxane (5 mL) was added and stirred for 5 minutes. After adding formic acid (3.9 mL), the solvent was evaporated under reduced pressure. The resulting crude product was purified by reverse-phase column chromatography (0.1% formic acid in acetonitrile / 0.1% formic acid in distilled water) to give 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] Compound aa021-f (2.00 g, 4.89 mmol) was used as a starting material, and compound aa021-g was obtained as a crude product by a method similar to that for compound aa020-e. Compound aa021 (1.80 g, 87% yield over two steps) was obtained by a method similar to that for compound aa020. 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 allowed to return to room temperature and stirred for 2.5 hours. The reaction was quenched by adding saturated aqueous NaHCO3, and the aqueous layer was removed using a phase separator. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Ethyl acetate / hexane (3 / 1, 24 mL) was added to the resulting residue, and the solvent was evaporated under reduced pressure. Hexane / TBME (85 / 15, 24 mL) was added to the resulting solid, and the mixture was stirred for 30 minutes. The solvent was then removed by filtration to give compound aa022-b (787 mg, 69%). LCMS(ESI)m / z=370(M+H)+ Retention time: 0.86 minutes (Analysis conditions SQDFA05)

[0352] Calcium chloride (2.25 g, 20.3 mmol) was dissolved in H2O (5.7 mL), and lithium hydroxide monohydrate (227 mg, 5.41 mmol) was added thereto and stirred at room temperature for 5 minutes to prepare aqueous solution A.

[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. 1N hydrochloric acid (8.1 mL) was then added to the reaction mixture, and the isopropanol and THF were removed by concentration under reduced pressure. The resulting aqueous layer was diluted with HO and extracted three times with ethyl acetate. The organic layer was washed with HO and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was triturated with ethyl acetate / n-hexane (1 / 5, 20 v / w) to give compound aa022-c (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%) in a similar manner to 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 (254 mg, 90%) was obtained in the same manner as in the synthesis of compound aa004. 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), TFA (9.49 mL, 123 mmol), and paraldehyde (5.42 mL, 41.0 mmol) were added, and 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, followed by stirring at 50 °C overnight. The solvent was evaporated under reduced pressure, and ethyl acetate was added. The mixture was washed with saturated aqueous sodium bicarbonate and then with saturated brine. The organic layer was dried over sodium sulfate and filtered, and the solvent was evaporated under reduced pressure. Purification by reverse-phase chromatography (0.1% formic acid in acetonitrile / 0.1% formic acid in distilled water) gave 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), paraldehyde (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 stirred at 60 °C for 17 hours. After cooling to room temperature and concentrating under reduced pressure, the obtained residue was dissolved in ethyl acetate (40 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (40 mL) and saturated brine (40 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in acetonitrile (30 mL), washed twice with hexane (15 mL), and the solvent was evaporated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (0.1% formic acid in acetonitrile / 0.1% formic acid in distilled water) to give compound aa201, ((2S)-2-[ethyl(9H-fluoren-9-ylmethoxycarbonyl)amino]-3-(4-methylphenyl)propanoic acid, Fmoc-EtPhe(4-Me)-OH) (4.4 g, 73% yield over two 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), paraldehyde (3.55 mL, 26.6 mmol), and TFA (6.11 mL, 80 mmol) were added, followed by stirring at 60 °C for 3 hours. Anhydrous magnesium sulfate (2.14 g, 17.7 mmol) was then added, followed by stirring 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 mixture 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 stirred at 60 °C for 10 hours. The mixture was cooled to room temperature, the magnesium sulfate was removed by filtration, and the mixture was concentrated under reduced pressure. Since the desired reaction was not completed, the resulting residue was dissolved in DCE (22.2 mL), and TFA (18.3 mL, 239 mmol) and triethylsilane (12.7 mL, 80 mmol) were added. The mixture was stirred at 60 °C for 8 hours. After cooling to room temperature and concentration under reduced pressure, the resulting residue was dissolved in ethyl acetate (40 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (40 mL) and saturated brine (40 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in acetonitrile (30 mL), washed twice with hexane (15 mL), and the solvent was evaporated under reduced pressure. The resulting residue was purified by reverse phase column chromatography (water-acetonitrile containing 0.1% formic acid) to give compound aa164 (1.90 g, 44% over two 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), and propionaldehyde (14.3 mL, 199 mmol), TFA (15.3 mL, 199 mmol), and magnesium sulfate (7.99 g, 66.4 mmol) were added. The mixture was stirred at 60 °C for 3 hours. The solid was removed by filtration through 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 aqueous potassium hydrogen phosphate (30 mL), 3.5% aqueous potassium bicarbonate (40 mL) three times, and saturated brine (100 mL). The mixture was dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure to obtain compound aa136-b as a 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, TiCl (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 aqueous potassium hydrogen phosphate (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% aqueous potassium bicarbonate (30 mL). This was further extracted twice with a mixed solvent of acetonitrile (20 mL) and 1% aqueous potassium bicarbonate (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% aqueous potassium bicarbonate (30 mL). The aqueous layers were combined, and n-hexane (80 mL) was added. After adding phosphoric acid to adjust the pH to 3, the mixture was extracted three times with TBME (150 mL). The organic layer was washed with saturated brine (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 a starting material, aa174 (18.6 g, 84%) was obtained by the same method as in the synthesis of compound aa136. 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 solution of Fmoc-OSu (2.44 g, 7.24 mmol) in 1,4-dioxane (14.5 mL) was added. The resulting solid was crushed with a spatula and further pulverized by ultrasonic irradiation. 1,4-dioxane (15 mL) was added to dissolve the solid, 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 hydrogen sulfate (3.70 g, 27.2 mmol) was added. The mixture was extracted three times with isopropyl acetate (30 mL), and the organic layer was washed with 50% brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give compound aa264-b (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), 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 saturated brine. The mixture was dried over anhydrous sodium sulfate and filtered, and the solvent was evaporated under reduced pressure. The mixture was dissolved in THF (25 mL), 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, and the aqueous layer was removed. The aqueous layer was extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was evaporated under reduced pressure. This was dissolved in DCM (30 mL), and n-hexane (30 mL) was added. DCM was removed by distillation under reduced pressure, followed by n-hexane. The resulting solid was added with n-hexane and sonicated. The n-hexane was removed by decantation, and the mixture was dried under reduced pressure to obtain compound aa264 as a sodium salt. This was dissolved in isopropyl acetate (50 mL), 0.05 M aqueous phosphoric acid (pH = 2, 90 mL) was added, and the mixture was stirred at room temperature for 10 minutes. The aqueous layer was then removed. The aqueous layer was extracted with isopropyl acetate, and the organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed by distillation under reduced pressure. The resulting crude product was purified by reverse-phase chromatography (0.1% formic acid in acetonitrile / 0.1% formic acid in distilled water) 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 a starting material, aa265 (1.38 g, 78%) was obtained by a method similar to that used for the synthesis of compound aa264. 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 a starting material, aa267 (9.04 g, quant.) was obtained in the same manner as in the synthesis of compound aa264. 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 a starting material, aa279 (5.15 g, 83%) was obtained by a method similar to that used for the synthesis of compound aa264. LCMS (ESI) m / z = 460 (M + Na) + Retention time: 0.85 minutes (Analysis conditions SQDFA05)

[0377] Synthesis of compound aa244 [ka]

[0378] A mixture of 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) in toluene (500 mL) was 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 evaporated under reduced pressure to give compound aa244-b (52 g, 96%) as a crude product. This crude product was used in the next reaction without further 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 then the solvent was evaporated 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, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give 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, (diethylamino)sulfur trifluoride (DAST) (780 mg, 4.84 mmol) was added to a solution of compound aa244-c (450 mg, 1.62 mmol) in DCM (20 mL) at 0°C, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, which was then diluted with DCM and washed sequentially with aqueous sodium bicarbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give compound aa244-d (0.35 g, 72%). This was mixed with another lot synthesized in the same way and subjected to the next reaction. 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 (400MHz, 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 mL / 10 mL) and stirred at room temperature for 4 days. The solvent was then evaporated under reduced pressure. The residue was diluted with aqueous sodium bicarbonate, washed with ether, and adjusted to pH 3 with 2N hydrochloric acid. Extraction with DCM followed by washing the organic layer with saturated brine, drying over anhydrous sodium sulfate, and evaporation of the solvent under reduced pressure afforded compound aa244-e (0.6 g) as a crude product. This crude product was used in the next reaction without further purification.

[0382] A mixture of compound aa244-e (0.6 g) and palladium-carbon (10%, 60 mg) in methanol (10 mL) was stirred under a hydrogen atmosphere of approximately 3 atm for 16 hours. The palladium-carbon was removed by filtration, and the filtrate was evaporated under reduced pressure to give compound aa244-f (0.23 g) as a crude product. This crude product was mixed with another batch synthesized in the same way without purification and used for the next reaction.

[0383] Fmoc-OSu (0.9 g, 1.5 equivalents) was added to a 1,4-dioxane / water (5 mL / 5 mL) mixture of compound aa244-f (0.3 g, 1.79 mmol) and potassium carbonate (745 mg, 5.4 mmol), and the mixture was stirred for 2 hours. The reaction mixture was diluted with water, washed with diethyl ether, and 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 evaporated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (acetonitrile containing 0.05% TFA / distilled water containing 0.05% TFA) to yield compound aa244 (0.2 g, 29%). A separate lot synthesized in the same manner was also used for the 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, and the aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with aqueous sodium bicarbonate. The resulting solution was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting 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), and triethylsilane (83.2 g, 718 mmol) and trifluoroacetic acid (24.8 g, 218 mmol) were added. 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, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting crude product aa043-b (5.5 g) was used directly in the next step.

[0387] A solution of 33% hydrogen bromide in acetic acid (10 mL) diluted with acetic acid (10 mL) was added to the crude product aa043-b (1.1 g) and 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 evaporated under reduced pressure to give 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] The 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 (10 mL) of Fmoc-OSu (1.8 g, 5.36 mmol) 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 the pH was adjusted to 3 with 2N hydrochloric acid. The mixture was then extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting concentrate was purified by reverse-phase column chromatography (water-acetonitrile) to give 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 mixture was cooled to 0 °C, and sodium hydride (60%, 77.56 g, 2.21 mol) was added with stirring. The reaction solution was stirred at 25 °C for 3 hours and then poured into 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 mixture 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 a crude product. The resulting 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 4N HCl / 1,4-dioxane (660 mL) was added. The reaction solution was stirred at 25 °C for 3 hours and concentrated under reduced pressure to give the crude product of aa056-c (90 g). LCMS(ESI)m / z=118(M+H)+ Retention time: 0.25 minutes (Analysis conditions SMD method_14)

[0392] The crude product of aa056-c (90 g) was dissolved in water (560 mL), and potassium carbonate was added to adjust the pH to 7. Subsequently, potassium carbonate (149 g, 1.08 mol), Fmoc-OSu (131 g, 389 mmol), and 1,4-dioxane (560 mL) were added to the reaction solution, and the mixture was stirred at 25°C for 3 hours. The reaction solution was then washed with t-butyl methyl ether / n-hexane (1 / 3), and the pH was adjusted to 2-3 with 1N hydrochloric acid. The solid was collected by filtration. The resulting solid was washed with water and dried under reduced pressure at 50°C for 16 hours to obtain aa056 (130 g, 86% yield (3 steps)). LCMS(ESI)m / z=362(M+Na)+ Retention time: 2.0 minutes (Analysis conditions SMD method_15)

[0393] Synthesis of compound aa246 [ka]

[0394] Under a nitrogen atmosphere, aa246-a (30 g, 113 mmol) was dissolved in tetrahydrofuran (300 mL), and sodium hydride (oily, 60%, 5.97 g, 249 mmol) was added at 0°C. The reaction solution was stirred at room temperature for 4 hours, then cooled to 0°C, and 3-bromo-1-propene (15.73 g, 130 mmol) was added dropwise. The reaction solution was then stirred at room temperature for 2 hours, and ice water was added to quench the reaction. The resulting mixture was adjusted to pH 2 with concentrated hydrochloric acid and extracted twice with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain crude aa246-b (27.3 g). LCMS(ESI)m / z=306(M+H)+ Retention time: 2.0 minutes (Analysis conditions SMD method_16)

[0395] The crude product of aa246-b (26 g) was dissolved in methanol (260 mL), and 2 M ammonia-methanol solution (63.9 mL) and 10% palladium-carbon (3.3 g) were added. The reaction solution was stirred under a hydrogen atmosphere at room temperature for 16 hours and then filtered. The resulting filtrate was concentrated under reduced pressure to give the crude product of aa246-c (14.2 g). LCMS(ESI)m / z=174(M+H)+ Retention time: 0.84 minutes (Analysis conditions SMD method_16)

[0396] The crude product of aa246-c (10 g) was dissolved in 1,4-dioxane (100 mL) and water (100 mL), and potassium carbonate (23.9 g, 172 mmol) was added. Fmoc-OSu (17.4 g, 51.7 mmol) was added to the reaction solution, which was stirred at room tem...

Claims

1. (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaoxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37,38,39,42Z]] ]pentatetracont-42-ene-23,1'-cyclobutane]-17-carboxamide.

2. A pharmaceutical composition comprising the compound described in claim 1.

3. A pharmaceutical composition for selectively inhibiting KRAS in a subject, comprising the compound of claim 1.

4. A pharmaceutical composition for treating or preventing cancer in a subject, comprising an effective amount of a compound described in claim 1.

5. The pharmaceutical composition described in claim 4, wherein the cancer is lung cancer.

6. The pharmaceutical composition described in claim 4, wherein the subject is a human.

7. (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[37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,91,92,94,95,98,91,92,93,94,95,96,97 ... ]pentatetracont-42-ene-23,1'-cyclobutane]-17-carboxamide solvate.

8. The solvate described in claim 7, which is a hydrate.

9. A pharmaceutical composition comprising the solvate described in claim 7 or 8.

10. A pharmaceutical composition for selectively inhibiting KRAS in a subject, comprising the solvate of claim 7 or 8.

11. A pharmaceutical composition for treating or preventing cancer in a subject, comprising an effective amount of the solvate described in claim 7 or 8.

12. The pharmaceutical composition described in claim 11, wherein the cancer is lung cancer.

13. The pharmaceutical composition described in claim 11, wherein the subject is a human.

14. (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[37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,91,92,94,95,98,91,92,93,94,95,96,97 ...8,91 ]pentatetracont-42-ene-23,1'-cyclobutane]-17-carboxamide or a solvate thereof.

15. A pharmaceutical composition comprising the salt or solvate thereof described in claim 14.

16. A pharmaceutical composition for selectively inhibiting KRAS in a subject, comprising the salt or solvate thereof described in claim 14.

17. A pharmaceutical composition for treating or preventing cancer in a subject, comprising an effective amount of the salt or solvate thereof described in claim 14.

18. The pharmaceutical composition described in claim 17, wherein the cancer is lung cancer.

19. The pharmaceutical composition described in claim 17, wherein the subject is a human.

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