Novel compound having activity-enhancing effect on antifungal drugs, and method for producing the same

Abstract

To provide a novel compound having an effect of more effectively enhancing the antifungal activity of an antifungal drug than known pharmaceutical compounds.SOLUTION: The present invention provides a compound represented by the formula in the figure or a salt thereof, or a solvate of them. The present invention also provides: a method for producing the compound or a salt thereof, or a solvate of them; and an activity enhancer containing them as an active ingredient, for at least one antifungal drug selected from among a polyene macrolide-based drug, an azole-based drug, a candin-based drug and a fluoropyrimidine-based drug.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a novel compound having an activity enhancing effect on antifungal drugs and a method for producing the same, and in particular to a novel compound having an activity enhancing effect on at least one antifungal drug selected from the group consisting of polyene macrolide drugs, azole drugs, echinocandin drugs and fluoropyrimidine drugs, and a method for producing the same. [Background technology]

[0002] Since the 1950s, research and development of antibiotics has made rapid progress. As a result, antibiotics have become widely available, and various treatments for various infectious diseases have been developed. On the other hand, in recent years, phenomena such as an increase in and worsening of deep mycoses caused by fungi such as Candida, Aspergillus, and Cryptococcus have been observed. These phenomena are thought to be related to problems such as immunodeficiency caused by leukemia, malignant lymphoma, or HIV infection, reduced immune function due to the administration of anticancer drugs, or bacterial replacement due to the use of large amounts of antibiotics.

[0003] Antifungal drugs such as polyene macrolide drugs, azole drugs, echinocandin drugs, and fluoropyrimidine drugs are currently used to treat deep mycoses. For example, amphotericin B, a type of polyene macrolide drug, has strong antifungal activity and is therefore effective in treating serious diseases. However, this drug may cause side effects such as nephrotoxicity, and safety issues have been pointed out (Non-Patent Document 1). Flucytosine, a type of fluoropyrimidine drug, also has problems such as low safety and the presence of resistant bacteria.

[0004] Azole drugs are generally considered to have a wide safety margin and relatively few side effects. However, these drugs have a narrow antifungal spectrum and a bacteriostatic mechanism of action, so they are less effective against serious diseases. In addition, an increase in resistant bacteria to these drugs has been reported (Non-Patent Document 2).

[0005] In recent years, echinocandin drugs such as micafungin and caspofungin have been developed and are used to treat deep mycosis (Non-Patent Document 3). However, these drugs have a narrow antifungal spectrum, so the diseases to be treated are limited to candidiasis or aspergillosis. In addition, the number of reported cases of resistance to these drugs is gradually increasing.

[0006] Patent Document 1 and Non-Patent Document 4 describe novel cyclic or linear peptides and pharma- ceutical acceptable salts thereof that have activity of enhancing the activity of amphotericin B, a polyene macrolide antifungal agent. Non-Patent Document 4 describes the novel cyclic peptide as nectriatide. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Patent No. 7046344 [Non-patent literature]

[0008] [Non-Patent Document 1] Gallis et al., Rev. Infect. Dis., Vol. 12, pp. 309-329, 1990 [Non-Patent Document 2] Rex et al., Antimicrob. Agents Chemothe., Vol. 39, pp. 1-8, 1995 [Non-Patent Document 3] Denning, Lancet, Vol. 362, No. 9330, pp. 1142-1151, 2003 [Non-Patent Document 4] Fukuda et al., J. Nat. Prod., Vol. 82, pp. 2673-2681, 2019 Summary of the Invention [Problem to be solved by the invention]

[0009] In the case of blood diseases such as leukemia, or diseases accompanied by immunosuppression such as HIV infection, a state of susceptibility to infection is induced. Therefore, in patients with such diseases, the incidence of fungal infections as opportunistic infections may increase. In addition, these diseases accompanied by immunosuppression usually tend to become severe, so the treatment period is often long. As a result, chemotherapy for fungal infections is often long-term.

[0010] Antifungal drugs that are currently frequently used in the treatment of fungal infections such as deep mycosis have several problems. For example, amphotericin B, a type of polyene macrolide drug, may cause side effects such as severe nephrotoxicity. In addition, it is known that azole drugs are highly susceptible to the development of drug-resistant bacteria. Therefore, in order to obtain a therapeutic effect against fungal infections while avoiding these problems, a means is needed to reduce the dosage and shorten the administration period of the antifungal drug.

[0011] A compound having the effect of enhancing the antifungal activity of an antifungal drug can reduce the dose of the antifungal drug and / or shorten the administration period. Therefore, by using a compound having such an effect in combination with an antifungal drug, the dose of the antifungal drug can be reduced and / or the administration period can be shortened, thereby suppressing the occurrence of side effects such as nephrotoxicity and / or suppressing the occurrence of drug-resistant bacteria. As compounds having the above-mentioned effect, nectriatide, which is a cyclic peptide, and linear peptides, which are ring-opened derivatives thereof, as well as pharma-ceutical acceptable salts thereof, are known (Patent Document 1 and Non-Patent Document 4). However, in order to develop a highly effective pharmaceutical compound, a new compound having the effect of more effectively enhancing the antifungal activity of an antifungal drug has been required.

[0012] Therefore, an object of the present invention is to provide a novel compound that has the effect of more effectively enhancing the antifungal activity of an antifungal drug as compared with known pharmaceutical compounds. [Means for solving the problem]

[0013] The present inventors have investigated various means for solving the above problems. The present inventors have found that a novel cyclic or chain compound in which the constituent amino acids and 2-aminobenzoic acid (anthranilic acid) of nectriatide, a known pharmaceutical compound, are substituted with other amino acids or amino acid analogs has the effect of more effectively enhancing the antifungal activity of antifungal drugs than nectriatide. The present inventors have completed the present invention based on the above findings.

[0014] That is, the gist of the present invention is as follows. (Embodiment 1) Formula (I): [ka] [In the formula, R 1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, or substituted or unsubstituted heteroarylalkyloxycarbonyl; R 2is OH, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy; R 1 and R 2 together form a single bond, R 3 is a substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted cycloalkenylene, substituted or unsubstituted cycloalkynylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, with the proviso that the substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, and substituted or unsubstituted alkynylene are optionally interrupted by one or more substituted or unsubstituted cycloalkylene, substituted or unsubstituted cycloalkenylene, substituted or unsubstituted cycloalkynylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R 4is H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy; R 5 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, or substituted or unsubstituted heteroarylalkyloxycarbonyl; R 6is H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy; However, R 3 When R is 1,6-phenylene, 4 is not a substituted arylalkyl. or a salt thereof, or a solvate thereof. (Embodiment 2) R 1 is H, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C2-C5 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 cycloalkenyl, substituted or unsubstituted C4-C6 cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl-C1-C5 alkyl, substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 15Aryl-C1-C5 alkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxycarbonyl, substituted or unsubstituted C3-C6 cycloalkoxycarbonyl, substituted or unsubstituted 3-6 membered heterocycloalkoxycarbonyl, substituted or unsubstituted C6-C 15 Aryloxycarbonyl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyloxycarbonyl, substituted or unsubstituted C6-C 15 aryl-C2-C5 alkenyloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryloxycarbonyl, or substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyloxycarbonyl, and R 2 is OH, substituted or unsubstituted C1-C5 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, substituted or unsubstituted 3- to 6-membered heterocycloalkoxy, substituted or unsubstituted C6-C 15 Aryloxy, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyloxy, substituted or unsubstituted C6-C 15 aryl-C2-C5 alkenyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyloxy, or substituted or unsubstituted C1-C5 acyloxy; A compound according to embodiment 1, or a salt thereof, or a solvate thereof. (Embodiment 3) R 1 H, substituted or unsubstituted C6-C 15 Aryloxycarbonyl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyloxycarbonyl, substituted or unsubstituted C6-C 15aryl-C2-C5 alkenyloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryloxycarbonyl, or substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyloxycarbonyl, and R 2 is OH, or a substituted or unsubstituted C1-C5 alkoxy; The compound according to embodiment 2, or a salt thereof, or a solvate thereof. (Embodiment 4) R 3 is a substituted or unsubstituted C1-C5 alkylene or a substituted or unsubstituted C6-C 15 The compound according to any one of embodiments 1 to 3, which is an arylene, or a salt thereof, or a solvate thereof. (Embodiment 5) R 3 is 1,1-ethylene, 1,2-phenylene, 1,3-phenylene, or 1,4-phenylene, or a salt thereof, or a solvate thereof, according to embodiment 4. (Embodiment 6) R 4 is a substituted or unsubstituted C1-C5 alkyl, a substituted or unsubstituted C2-C5 alkenyl, a substituted or unsubstituted C2-C5 alkynyl, a substituted or unsubstituted C3-C6 cycloalkyl, a substituted or unsubstituted C4-C6 cycloalkenyl, a substituted or unsubstituted C4-C6 cycloalkynyl, a substituted or unsubstituted 3-6 membered heterocycloalkyl, a substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, a substituted or unsubstituted 3-6 membered heterocycloalkyl-C1-C5 alkyl, a substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 15 The compound according to any one of embodiments 1 to 5, which is aryl-C1-C5 alkyl, substituted or unsubstituted 5-15 membered heteroaryl, or substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyl, or a salt thereof, or a solvate thereof. (Embodiment 7) R 4is a substituted or unsubstituted C1-C5 alkyl, or a substituted or unsubstituted C6-C 15 The compound according to embodiment 6, which is aryl-C1-C5 alkyl, or a salt thereof, or a solvate thereof. (Embodiment 8) R 4 is a substituted or unsubstituted C2-C5 alkyl, or a substituted or unsubstituted C6-C 15 The compound according to embodiment 6, which is aryl-C1-C5 alkyl, or a salt thereof, or a solvate thereof. (Embodiment 9) R 4 The compound or salt thereof, or a solvate thereof according to any one of embodiments 6 to 8, wherein is 4-hydroxyphenylmethyl, 4-tert-butyloxyphenylmethyl, or phenylmethyl. (Embodiment 10) R 5 is H, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C2-C5 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 cycloalkenyl, substituted or unsubstituted C4-C6 cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl-C1-C5 alkyl, substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 15 The compound according to any one of embodiments 1 to 9, which is aryl-C1-C5 alkyl, substituted or unsubstituted 5-15 membered heteroaryl, or substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyl, or a salt thereof, or a solvate thereof. (Embodiment 11) R 5 The compound according to embodiment 10, or a salt thereof, or a solvate thereof, wherein is H, or substituted or unsubstituted C1-C5 alkyl. (Embodiment 12) R 6is a substituted or unsubstituted C1-C5 alkyl, a substituted or unsubstituted C2-C5 alkenyl, a substituted or unsubstituted C2-C5 alkynyl, a substituted or unsubstituted C3-C6 cycloalkyl, a substituted or unsubstituted C4-C6 cycloalkenyl, a substituted or unsubstituted C4-C6 cycloalkynyl, a substituted or unsubstituted 3-6 membered heterocycloalkyl, a substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, a substituted or unsubstituted 3-6 membered heterocycloalkyl-C1-C5 alkyl, a substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 15 The compound according to any one of embodiments 1 to 11, which is aryl-C1-C5 alkyl, substituted or unsubstituted 5-15 membered heteroaryl, or substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyl, or a salt thereof, or a solvate thereof. (Embodiment 13) R 6 is a substituted or unsubstituted C1-C5 alkyl, or a substituted or unsubstituted C6-C 15 The compound according to embodiment 12, or a salt thereof, or a solvate thereof, which is aryl-C1-C5 alkyl. (Embodiment 14) R 6 14. The compound according to embodiment 12 or 13, or a salt thereof, or a solvate thereof, wherein is methyl, propan-2-yl, 4-aminobutan-1-yl, or 4-(t-butoxycarbonylamino)butan-1-yl. (Embodiment 15) A method for producing the compound or a salt thereof, or a solvate thereof according to any one of embodiments 1 to 14, comprising the steps of: Formulae (VI), (VII), (VIII) and (IX): [ka] [In the formula, R 3 , R 4 , R 5 and R 6 has the meaning described in any one of embodiments 1 to 14.] or a protected derivative thereof, or a salt or solvate thereof, to form a main chain of the compound represented by formula (I) having a chain structure; The method comprising: (Embodiment 16) a cyclization step in which the compound represented by formula (I) having a chain structure obtained in the main chain formation step is subjected to intramolecular cyclization to obtain a compound represented by formula (I) having a cyclic structure; 16. The method of embodiment 15, further comprising: (Embodiment 17) An activity enhancer for at least one antifungal drug selected from the group consisting of polyene macrolide drugs, azole drugs, echinocandin drugs, and fluoropyrimidine drugs, comprising the compound according to any one of embodiments 1 to 14 or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable solvate thereof as an active ingredient. (Embodiment 18) A medicine comprising the compound according to any one of embodiments 1 to 14, or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable solvate thereof, as an active ingredient. (Embodiment 19) The medicament according to embodiment 18 for use in the prevention or treatment of one or more fungal infections. (Embodiment 20) The medicament according to embodiment 18 or 19, further comprising at least one antifungal agent selected from the group consisting of polyene macrolides, azoles, echinocandins and fluoropyrimidines. (Embodiment 21) A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 14, or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable solvate thereof, and one or more pharma- ceutically acceptable carriers. (Embodiment 22) 22. The pharmaceutical composition according to embodiment 21, for use in the prevention or treatment of one or more fungal infections. (Embodiment 23) The pharmaceutical composition according to embodiment 21 or 22, further comprising at least one antifungal agent selected from the group consisting of polyene macrolides, azoles, echinocandins and fluoropyrimidines. Effect of the Invention

[0015] According to the present invention, it is possible to provide a novel compound that has the effect of enhancing the antifungal activity of an antifungal drug more effectively than known medicinal compounds. Problems, configurations and effects other than those described above will become apparent from the following description of the embodiments. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Preferred embodiments of the present invention will now be described in detail. <1. New compound> As used herein, "alkyl" refers to a linear or branched saturated aliphatic hydrocarbon group containing the specified number of carbon atoms. For example, "C1-C5 alkyl" refers to a linear or branched saturated aliphatic hydrocarbon group containing at least 1 and at most 5 carbon atoms. Suitable alkyls include, but are not limited to, linear or branched C1-C5 alkyls such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl.

[0017] In the present specification, "alkenyl" refers to a group in which one or more C-C single bonds of the alkyl are replaced with double bonds. Suitable alkenyls include, but are not limited to, straight or branched C2-C5 alkenyls such as vinyl, 1-propenyl, allyl, 1-methylethenyl (isopropenyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, and 1-pentenyl.

[0018] In the present specification, "alkynyl" refers to a group in which one or more C-C single bonds of the alkyl are replaced with a triple bond. Suitable alkynyl includes, but is not limited to, linear or branched C2-C5 alkynyl such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, and 1-pentynyl.

[0019] As used herein, "cycloalkyl" refers to an alicyclic alkyl group containing a specific number of carbon atoms. For example, "C3-C6 cycloalkyl" refers to a cyclic hydrocarbon group containing at least 3 and at most 6 carbon atoms. Suitable cycloalkyls include, but are not limited to, C3-C6 cycloalkyls such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0020] In the present specification, "cycloalkenyl" refers to a group in which one or more C-C single bonds of the cycloalkyl are replaced with double bonds. Suitable cycloalkenyls include, but are not limited to, C4-C6 cycloalkenyls such as cyclobutenyl, cyclopentenyl, and cyclohexenyl.

[0021] In the present specification, "cycloalkynyl" refers to a group in which one or more C-C single bonds of the cycloalkyl are replaced with a triple bond. Suitable cycloalkynyl includes, but is not limited to, C4-C6 cycloalkynyl such as cyclobutynyl, cyclopentynyl, and cyclohexynyl.

[0022] In the present specification, "heterocycloalkyl" refers to a group in which one or more carbon atoms of the cycloalkyl, cycloalkenyl, or cycloalkynyl are each independently substituted with one or more heteroatoms selected from nitrogen (N), sulfur (S), and oxygen (O). In this case, substitution with N or S includes substitution with N-oxide or oxide or dioxide of S, respectively. Suitable heterocycloalkyls include, but are not limited to, 3- to 6-membered heterocycloalkyls such as pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl.

[0023] In the present specification, "cycloalkylalkyl" refers to a group in which one of the hydrogen atoms of the alkyl, alkenyl, or alkynyl is replaced by the cycloalkyl, cycloalkenyl, or cycloalkynyl. Suitable cycloalkylalkyl includes, but is not limited to, C3-C6 cycloalkyl-C1-C5 alkyl such as cyclohexylmethyl and cyclohexenylmethyl.

[0024] In the present specification, "heterocycloalkylalkyl" refers to a group in which one hydrogen atom of the alkyl, alkenyl, or alkynyl is substituted with the heterocycloalkyl. Suitable heterocycloalkylalkyl includes, but is not limited to, 3-6 membered heterocycloalkyl-C1-C5 alkyl.

[0025] In the present specification, "alkoxy" refers to a group in which the hydrogen atom of a hydroxyl is replaced by the above-mentioned alkyl, alkenyl, or alkynyl. Suitable alkoxy includes, but is not limited to, C1-C5 alkoxy such as methoxy, ethoxy, propoxy, butoxy, and pentoxy.

[0026] In the present specification, "cycloalkoxy" refers to a group in which a hydrogen atom of a hydroxyl is replaced by the above-mentioned cycloalkyl, cycloalkenyl, or cycloalkynyl. Suitable cycloalkoxy includes, but is not limited to, C3-C6 cycloalkoxy such as cyclopropoxy, cyclobutoxy, and cyclopentoxy.

[0027] In the present specification, "heterocycloalkoxy" refers to a group in which the hydrogen atom of a hydroxyl is replaced by the heterocycloalkyl. Suitable cycloalkoxy includes, but is not limited to, 3- to 6-membered heterocycloalkoxy.

[0028] As used herein, "aryl" refers to an aromatic ring group. Suitable aryls include, but are not limited to, C6-C aryls such as phenyl, biphenyl, terphenyl, naphthyl, and anthracenyl. 18 Mention may be made of aryl.

[0029] In the present specification, "arylalkyl" refers to a group in which one hydrogen atom of the alkyl, alkenyl, or alkynyl is replaced by the aryl. Suitable arylalkyls include, but are not limited to, C6-C arylalkyls such as benzyl, 1-phenethyl, 2-phenethyl, biphenylmethyl, terphenylmethyl, and styryl. 15 Examples include aryl-C1-C5 alkyl.

[0030] In the present specification, "heteroaryl" refers to a group in which one or more carbon atoms of the aryl are substituted with one or more heteroatoms each independently selected from N, S, and O. In this case, substitution with N or S includes substitution with N-oxide or oxide or dioxide of S, respectively. Suitable heteroaryls include, but are not limited to, 5-15 membered heteroaryls such as furanyl, thienyl (thiopheneyl), pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, and indolyl.

[0031] In the present specification, "heteroarylalkyl" refers to a group in which one hydrogen atom of the alkyl, alkenyl, or alkynyl is replaced by the heteroaryl. Suitable heteroarylalkyl includes, but is not limited to, 5-15 membered heteroaryl-C1-C5 alkyl such as pyridylmethyl.

[0032] In the present specification, "aryloxy" refers to a group in which the hydrogen atom of hydroxyl is replaced by the aryl. Suitable aryloxy includes, but is not limited to, C6-C aryloxy such as phenoxy, biphenyloxy, naphthyloxy, and anthryloxy (anthracenyloxy). 15 Mention may be made of aryloxy.

[0033] In the present specification, "arylalkyloxy" refers to a group in which the hydrogen atom of hydroxyl is replaced by the above-mentioned arylalkyl. Suitable arylalkyloxy includes, but is not limited to, C6-C arylalkyloxy such as benzyloxy, 1-phenethyloxy, 2-phenethyloxy, and styryloxy. 15 Examples include aryl-C1-C5 alkyloxy.

[0034] In the present specification, "heteroaryloxy" refers to a group in which a hydrogen atom of a hydroxyl is substituted with the heteroaryl. Suitable heteroaryloxy includes, but is not limited to, 5-15 membered heteroaryloxy such as furanyloxy, thienyloxy (thiophenyloxy), pyrrolyloxy, imidazolyloxy, pyrazolyloxy, triazolyloxy, tetrazolyloxy, thiazolyloxy, oxazolyloxy, isoxazolyloxy, oxadiazolyloxy, thiadiazolyloxy, isothiazolyloxy, pyridyloxy, pyridazinyloxy, pyrazinyloxy, pyrimidinyloxy, quinolinyloxy, isoquinolinyloxy, and indolyloxy.

[0035] In the present specification, "heteroarylalkyloxy" refers to a group in which the hydrogen atom of a hydroxyl is replaced by the heteroarylalkyl. Suitable heteroarylalkyloxy includes, but is not limited to, 5-15 membered heteroaryl-C1-C5 alkyloxy.

[0036] In the present specification, "acyl" refers to a group in which a monovalent group selected from the groups described above is linked to a carbonyl. Suitable acyl includes, but is not limited to, C1 to C5 aliphatic acyl such as formyl, acetyl, and propionyl, and C7 to C6 aliphatic acyl such as benzoyl. 20 C1-C including aromatic acylation 20 Acyl can be mentioned.

[0037] Each of the above-described groups can be independently unsubstituted or further substituted with one or more of the above-described monovalent groups.

[0038] As used herein, "halogen" or "halo" means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0039] One aspect of the present invention is a compound of formula (I): [ka] or a salt thereof, or a solvate thereof.

[0040] The present inventors have found that a novel cyclic or chain compound in which the constituent amino acids and 2-aminobenzoic acid (anthranilic acid) of nectriatide, a known pharmaceutical compound, are replaced with other amino acids or amino acid analogs has the effect of more effectively enhancing the antifungal activity of antifungal drugs compared to nectriatide. Although the novel cyclic or chain compound does not substantially exhibit antifungal activity when administered alone, it can significantly enhance the antifungal activity of amphotericin B when administered in combination with amphotericin B. The compound represented by formula (I) of this embodiment includes the novel cyclic or chain compound. Therefore, the compound represented by formula (I) of this embodiment can more effectively enhance the antifungal activity of antifungal drugs compared to known pharmaceutical compounds.

[0041] In formula (I), R 1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, or substituted or unsubstituted heteroarylalkyloxycarbonyl. R 1is H, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C2-C5 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 cycloalkenyl, substituted or unsubstituted C4-C6 cycloalkynyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C1-C5 alkyl, substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxycarbonyl, substituted or unsubstituted C3-C6 cycloalkoxycarbonyl, substituted or unsubstituted 3-6 membered heterocycloalkoxycarbonyl, substituted or unsubstituted C6-C 15 Aryloxycarbonyl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyloxycarbonyl, substituted or unsubstituted C6-C 15 It is preferably aryl-C2-C5 alkenyloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryloxycarbonyl, or substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyloxycarbonyl; H, substituted or unsubstituted C6-C 15 Aryloxycarbonyl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyloxycarbonyl, substituted or unsubstituted C6-C 15 more preferably aryl-C2-C5 alkenyloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryloxycarbonyl, or substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyloxycarbonyl; H or substituted or unsubstituted C6-C 15More preferably, it is aryl-C1-C5 alkyloxycarbonyl; H, or benzyloxycarbonyl. 1 is a group exemplified above, the compound represented by formula (I) of this embodiment can enhance the antifungal activity of an antifungal drug more effectively than known pharmaceutical compounds.

[0042] In formula (I), R 2 is OH, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy. R 2 is OH, substituted or unsubstituted C1-C5 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, substituted or unsubstituted 3- to 6-membered heterocycloalkoxy, substituted or unsubstituted C6-C 15 Aryloxy, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyloxy, substituted or unsubstituted C6-C 15 It is preferably aryl-C2-C5 alkenyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyloxy, or substituted or unsubstituted C1-C5 acyloxy; More preferably, it is OH, or a substituted or unsubstituted C1 to C5 alkoxy; More preferably, R is OH or methoxy. 2 is a group exemplified above, the compound represented by formula (I) of this embodiment can enhance the antifungal activity of an antifungal drug more effectively than known pharmaceutical compounds.

[0043] In one embodiment, R 1 and R2 may be taken together to form a single bond. In this embodiment, the compound represented by formula (I) has a cyclic structure. In another embodiment, R 1 and R 2 do not form a single bond together. In this embodiment, the compound represented by formula (I) has a chain structure, and R 1 and R 2 are each independently the groups exemplified above. 1 and R 2 are preferably not combined together to form a single bond and are each independently one of the groups exemplified above. In the case of an embodiment having a chain structure, the antifungal activity of the antifungal drug can be more effectively enhanced compared to an embodiment having a cyclic structure.

[0044] In formula (I), R 3 is a substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted cycloalkenylene, substituted or unsubstituted cycloalkynylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, with the proviso that the substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, and substituted or unsubstituted alkynylene are optionally interrupted by one or more substituted or unsubstituted cycloalkylene, substituted or unsubstituted cycloalkenylene, substituted or unsubstituted cycloalkynylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. R 3 is a substituted or unsubstituted C1-C5 alkylene, a substituted or unsubstituted C2-C5 alkenylene, a substituted or unsubstituted C2-C5 alkynylene, a substituted or unsubstituted C3-C6 cycloalkylene, a substituted or unsubstituted C4-C6 cycloalkenylene, a substituted or unsubstituted C4-C6 cycloalkynylene, a substituted or unsubstituted 3- to 6-membered heterocycloalkylene, a substituted or unsubstituted C6-C 15arylene, or a substituted or unsubstituted 5-15 membered heteroarylene, provided that the substituted or unsubstituted C1-C5 alkylene, the substituted or unsubstituted C2-C5 alkenylene, and the substituted or unsubstituted C2-C5 alkynylene are each independently one or more of a substituted or unsubstituted C3-C6 cycloalkylene, a substituted or unsubstituted C4-C6 cycloalkenylene, a substituted or unsubstituted C4-C6 cycloalkynylene, a substituted or unsubstituted 3-6 membered heterocycloalkylene, a substituted or unsubstituted C6-C 15 may be interrupted by arylene, or substituted or unsubstituted 5- to 15-membered heteroarylene; Substituted or unsubstituted C1-C5 alkylene, substituted or unsubstituted C2-C5 alkenylene, substituted or unsubstituted C2-C5 alkynylene, substituted or unsubstituted C3-C6 cycloalkylene, substituted or unsubstituted C4-C6 cycloalkenylene, substituted or unsubstituted C4-C6 cycloalkynylene, substituted or unsubstituted 3-6 membered heterocycloalkylene, substituted or unsubstituted C6-C 15 It is more preferably arylene, or substituted or unsubstituted 5- to 15-membered heteroarylene; Substituted or unsubstituted C1-C5 alkylene or substituted or unsubstituted C6-C 15 More preferably, it is arylene; Particularly preferred is 1,1-ethylene, 1,2-phenylene, 1,3-phenylene or 1,4-phenylene. 3 is a group exemplified above, the compound represented by formula (I) of this embodiment can enhance the antifungal activity of an antifungal drug more effectively than known pharmaceutical compounds.

[0045] In formula (I), R 4is H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy. R 4 is H, OH, substituted or unsubstituted C1-C5 alkyl or C2-C5 alkyl, substituted or unsubstituted C2-C5 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 cycloalkenyl, substituted or unsubstituted C4-C6 cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl-C1-C5 alkyl, substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkoxy, substituted or unsubstituted C6-C 15 Aryloxy, substituted or unsubstituted C6-C 15Aryl-C1-C5 alkyloxy, substituted or unsubstituted C6-C 15 It is preferably aryl-C2-C5 alkenyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyloxy, or substituted or unsubstituted C1-C5 acyloxy; Substituted or unsubstituted C1-C5 alkyl or C2-C5 alkyl, substituted or unsubstituted C2-C5 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 cycloalkenyl, substituted or unsubstituted C4-C6 cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl-C1-C5 alkyl, substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 15 More preferably, it is aryl-C1-C5 alkyl, a substituted or unsubstituted 5-15 membered heteroaryl, or a substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyl; Substituted or unsubstituted C1-C5 alkyl, or substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyl, or substituted or unsubstituted C2-C5 alkyl, or substituted or unsubstituted C6-C 15 More preferably, it is aryl-C1-C5 alkyl; Particularly preferred is methyl, 4-hydroxyphenylmethyl, 4-tert-butyloxyphenylmethyl or phenylmethyl, or 4-hydroxyphenylmethyl, 4-tert-butyloxyphenylmethyl or phenylmethyl. 4 is a group exemplified above, the compound represented by formula (I) of this embodiment can enhance the antifungal activity of an antifungal drug more effectively than known pharmaceutical compounds.

[0046] In formula (I), R 5is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, or substituted or unsubstituted heteroarylalkyloxycarbonyl. R 5 is H, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C2-C5 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 cycloalkenyl, substituted or unsubstituted C4-C6 cycloalkynyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C1-C5 alkyl, substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxycarbonyl, substituted or unsubstituted C3-C6 cycloalkoxycarbonyl, substituted or unsubstituted 3-6 membered heterocycloalkoxycarbonyl, substituted or unsubstituted C6-C 15 Aryloxycarbonyl, substituted or unsubstituted C6-C15 Aryl-C1-C5 alkyloxycarbonyl, substituted or unsubstituted C6-C 15 It is preferably aryl-C2-C5 alkenyloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryloxycarbonyl, or substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyloxycarbonyl; H, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C2-C5 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 cycloalkenyl, substituted or unsubstituted C4-C6 cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl-C1-C5 alkyl, substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 15 More preferably, it is aryl-C1-C5 alkyl, a substituted or unsubstituted 5-15 membered heteroaryl, or a substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyl; More preferably, it is H or a substituted or unsubstituted C1-C5 alkyl; H or methyl is particularly preferred. 5 is a group exemplified above, the compound represented by formula (I) of this embodiment can enhance the antifungal activity of an antifungal drug more effectively than known pharmaceutical compounds.

[0047] In formula (I), R 6is H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy. R 6 is H, OH, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C2-C5 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 cycloalkenyl, substituted or unsubstituted C4-C6 cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl-C1-C5 alkyl, substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkoxy, substituted or unsubstituted C6-C 15 Aryloxy, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyloxy, substituted or unsubstituted C6-C15 It is preferably aryl-C2-C5 alkenyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyloxy, or substituted or unsubstituted C1-C5 acyloxy; Substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C2-C5 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 cycloalkenyl, substituted or unsubstituted C4-C6 cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl-C1-C5 alkyl, substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 15 More preferably, it is aryl-C1-C5 alkyl, a substituted or unsubstituted 5-15 membered heteroaryl, or a substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyl; Substituted or unsubstituted C1-C5 alkyl, or substituted or unsubstituted C6-C 15 More preferably, it is aryl-C1-C5 alkyl; Even more preferably, it is a substituted or unsubstituted C1-C5 alkyl; Particularly preferred is methyl, propan-2-yl, 4-aminobutan-1-yl, or 4-(t-butoxycarbonylamino)butan-1-yl. 6 is a group exemplified above, the compound represented by formula (I) of this embodiment can enhance the antifungal activity of an antifungal drug more effectively than known pharmaceutical compounds.

[0048] In formula (I), R 3 When R is 1,6-phenylene, 4 is not a substituted arylalkyl.

[0049] In formula (I), when the group is substituted, the substituents are each independently selected from the group consisting of halogen (fluorine, chlorine, bromine, or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted heteroaryl. and at least one monovalent group selected from the group consisting of halogen (fluorine, chlorine, bromine, or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C2-C5 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 cycloalkenyl, substituted or unsubstituted C4-C6 cycloalkynyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C1-C5 alkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C1-C5 alkyl, substituted or unsubstituted C6- to C6 ... C6- to C6 cycloalkyl-C1-C5 alkyl, substituted or unsubstituted C6- to C6 cycloalkyl-C1-C5 alkyl, substituted or unsubstituted C6- to C6 cycloalkyl-C1-C5 alkyl, substituted or unsubstituted C6- to C6 cycloalkyl-C1-C 15 Aryl, substituted or unsubstituted C6-C 15Aryl-C1-C5 alkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkoxy, substituted or unsubstituted C6-C 15 Aryloxy, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyloxy, substituted or unsubstituted C1-C6 alkoxycarbonyl, substituted or unsubstituted C3-C6 cycloalkoxycarbonyl, substituted or unsubstituted C1-C 20 Acyl, substituted or unsubstituted C1-C 20 More preferably, it is at least one monovalent group selected from the group consisting of acyloxy and substituted or unsubstituted amino; hydroxyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, substituted or unsubstituted 3- to 6-membered heterocycloalkoxy, substituted or unsubstituted C6-C 15 Aryloxy, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyloxy, substituted or unsubstituted C1-C 20 More preferably, it is at least one monovalent group selected from the group consisting of acyloxy and substituted or unsubstituted amino. If the monovalent group is substituted, the substituent may be further selected from the monovalent groups mentioned above.

[0050] Preferably, the compound of formula (I) is R 1is H, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C2-C5 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 cycloalkenyl, substituted or unsubstituted C4-C6 cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl-C1-C5 alkyl, substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxycarbonyl, substituted or unsubstituted C3-C6 cycloalkoxycarbonyl, substituted or unsubstituted 3-6 membered heterocycloalkoxycarbonyl, substituted or unsubstituted C6-C 15 Aryloxycarbonyl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyloxycarbonyl, substituted or unsubstituted C6-C 15 aryl-C2-C5 alkenyloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryloxycarbonyl, or substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyloxycarbonyl; R 2 is OH, substituted or unsubstituted C1-C5 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, substituted or unsubstituted 3- to 6-membered heterocycloalkoxy, substituted or unsubstituted C6-C 15 Aryloxy, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyloxy, substituted or unsubstituted C6-C 15 aryl-C2-C5 alkenyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyloxy, or substituted or unsubstituted C1-C5 acyloxy; R 1 and R 2 together form a single bond, R 3 is a substituted or unsubstituted C1-C5 alkylene, a substituted or unsubstituted C2-C5 alkenylene, a substituted or unsubstituted C2-C5 alkynylene, a substituted or unsubstituted C3-C6 cycloalkylene, a substituted or unsubstituted C4-C6 cycloalkenylene, a substituted or unsubstituted C4-C6 cycloalkynylene, a substituted or unsubstituted 3- to 6-membered heterocycloalkylene, a substituted or unsubstituted C6-C 15 arylene, or substituted or unsubstituted 5-15 membered heteroarylene, provided that the substituted or unsubstituted C1-C5 alkylene, the substituted or unsubstituted C2-C5 alkenylene, and the substituted or unsubstituted C2-C5 alkynylene are each independently one or more of a substituted or unsubstituted C3-C6 cycloalkylene, a substituted or unsubstituted C4-C6 cycloalkenylene, a substituted or unsubstituted C4-C6 cycloalkynylene, a substituted or unsubstituted 3-6 membered heterocycloalkylene, a substituted or unsubstituted C6-C 15 may be interrupted by arylene, or substituted or unsubstituted 5- to 15-membered heteroarylene; R 4 is H, OH, substituted or unsubstituted C1-C5 alkyl or C2-C5 alkyl, substituted or unsubstituted C2-C5 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 cycloalkenyl, substituted or unsubstituted C4-C6 cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl-C1-C5 alkyl, substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 15Aryl-C1-C5 alkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkoxy, substituted or unsubstituted C6-C 15 Aryloxy, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyloxy, substituted or unsubstituted C6-C 15 aryl-C2-C5 alkenyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyloxy, or substituted or unsubstituted C1-C5 acyloxy; R 5 is H, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C2-C5 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 cycloalkenyl, substituted or unsubstituted C4-C6 cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl-C1-C5 alkyl, substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxycarbonyl, substituted or unsubstituted C3-C6 cycloalkoxycarbonyl, substituted or unsubstituted 3-6 membered heterocycloalkoxycarbonyl, substituted or unsubstituted C6-C 15 Aryloxycarbonyl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyloxycarbonyl, substituted or unsubstituted C6-C 15aryl-C2-C5 alkenyloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryloxycarbonyl, or substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyloxycarbonyl; R 6 is H, OH, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C2-C5 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 cycloalkenyl, substituted or unsubstituted C4-C6 cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl-C1-C5 alkyl, substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkoxy, substituted or unsubstituted C6-C 15 Aryloxy, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyloxy, substituted or unsubstituted C6-C 15 aryl-C2-C5 alkenyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyloxy, or substituted or unsubstituted C1-C5 acyloxy; However, R 3 When R is 1,6-phenylene, 4 is not a substituted arylalkyl, When the above groups are substituted, the substituents are each independently selected from the group consisting of halogen (fluorine, chlorine, bromine, or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C2-C5 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 cycloalkenyl, substituted or unsubstituted C4-C6 cycloalkynyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C1-C5 alkyl, substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkoxy, substituted or unsubstituted C6-C 15 Aryloxy, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyloxy, substituted or unsubstituted C1-C6 alkoxycarbonyl, substituted or unsubstituted C3-C6 cycloalkoxycarbonyl, substituted or unsubstituted C1-C 20 Acyl, substituted or unsubstituted C1-C 20 At least one monovalent group selected from the group consisting of acyloxy and substituted or unsubstituted amino.

[0051] More preferably, the compound of formula (I) is R 1is H, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C2-C5 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 cycloalkenyl, substituted or unsubstituted C4-C6 cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl-C1-C5 alkyl, substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxycarbonyl, substituted or unsubstituted C3-C6 cycloalkoxycarbonyl, substituted or unsubstituted 3-6 membered heterocycloalkoxycarbonyl, substituted or unsubstituted C6-C 15 Aryloxycarbonyl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyloxycarbonyl, substituted or unsubstituted C6-C 15 aryl-C2-C5 alkenyloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryloxycarbonyl, or substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyloxycarbonyl; R 2 is OH, substituted or unsubstituted C1-C5 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, substituted or unsubstituted 3- to 6-membered heterocycloalkoxy, substituted or unsubstituted C6-C 15 Aryloxy, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyloxy, substituted or unsubstituted C6-C 15 aryl-C2-C5 alkenyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyloxy, or substituted or unsubstituted C1-C5 acyloxy; R 3 is a substituted or unsubstituted C1-C5 alkylene, a substituted or unsubstituted C2-C5 alkenylene, a substituted or unsubstituted C2-C5 alkynylene, a substituted or unsubstituted C3-C6 cycloalkylene, a substituted or unsubstituted C4-C6 cycloalkenylene, a substituted or unsubstituted C4-C6 cycloalkynylene, a substituted or unsubstituted 3- to 6-membered heterocycloalkylene, a substituted or unsubstituted C6-C 15 arylene, or substituted or unsubstituted 5-15 membered heteroarylene, provided that the substituted or unsubstituted C1-C5 alkylene, the substituted or unsubstituted C2-C5 alkenylene, and the substituted or unsubstituted C2-C5 alkynylene are each independently one or more of a substituted or unsubstituted C3-C6 cycloalkylene, a substituted or unsubstituted C4-C6 cycloalkenylene, a substituted or unsubstituted C4-C6 cycloalkynylene, a substituted or unsubstituted 3-6 membered heterocycloalkylene, a substituted or unsubstituted C6-C 15 may be interrupted by arylene, or substituted or unsubstituted 5- to 15-membered heteroarylene; R 4 is H, OH, substituted or unsubstituted C1-C5 alkyl or C2-C5 alkyl, substituted or unsubstituted C2-C5 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 cycloalkenyl, substituted or unsubstituted C4-C6 cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl-C1-C5 alkyl, substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkoxy, substituted or unsubstituted C6-C15 Aryloxy, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyloxy, substituted or unsubstituted C6-C 15 aryl-C2-C5 alkenyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyloxy, or substituted or unsubstituted C1-C5 acyloxy; R 5 is H, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C2-C5 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 cycloalkenyl, substituted or unsubstituted C4-C6 cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl-C1-C5 alkyl, substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxycarbonyl, substituted or unsubstituted C3-C6 cycloalkoxycarbonyl, substituted or unsubstituted 3-6 membered heterocycloalkoxycarbonyl, substituted or unsubstituted C6-C 15 Aryloxycarbonyl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyloxycarbonyl, substituted or unsubstituted C6-C 15 aryl-C2-C5 alkenyloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryloxycarbonyl, or substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyloxycarbonyl; R 6is H, OH, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C2-C5 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 cycloalkenyl, substituted or unsubstituted C4-C6 cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl-C1-C5 alkyl, substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkoxy, substituted or unsubstituted C6-C 15 Aryloxy, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyloxy, substituted or unsubstituted C6-C 15 aryl-C2-C5 alkenyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyloxy, or substituted or unsubstituted C1-C5 acyloxy; However, R 3 When R is 1,6-phenylene, 4 is not a substituted arylalkyl, When the above groups are substituted, the substituents are each independently selected from the group consisting of halogen (fluorine, chlorine, bromine, or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C2-C5 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 cycloalkenyl, substituted or unsubstituted C4-C6 cycloalkynyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C1-C5 alkyl, substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkoxy, substituted or unsubstituted C6-C 15 Aryloxy, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyloxy, substituted or unsubstituted C1-C6 alkoxycarbonyl, substituted or unsubstituted C3-C6 cycloalkoxycarbonyl, substituted or unsubstituted C1-C 20 Acyl, substituted or unsubstituted C1-C 20 At least one monovalent group selected from the group consisting of acyloxy and substituted or unsubstituted amino.

[0052] More preferably, the compound of formula (I) is R 1is H, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C2-C5 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 cycloalkenyl, substituted or unsubstituted C4-C6 cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl-C1-C5 alkyl, substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxycarbonyl, substituted or unsubstituted C3-C6 cycloalkoxycarbonyl, substituted or unsubstituted 3-6 membered heterocycloalkoxycarbonyl, substituted or unsubstituted C6-C 15 Aryloxycarbonyl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyloxycarbonyl, substituted or unsubstituted C6-C 15 aryl-C2-C5 alkenyloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryloxycarbonyl, or substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyloxycarbonyl; R 2 is OH, substituted or unsubstituted C1-C5 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, substituted or unsubstituted 3- to 6-membered heterocycloalkoxy, substituted or unsubstituted C6-C 15 Aryloxy, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyloxy, substituted or unsubstituted C6-C 15 aryl-C2-C5 alkenyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyloxy, or substituted or unsubstituted C1-C5 acyloxy; R 3 is a substituted or unsubstituted C1-C5 alkylene, a substituted or unsubstituted C2-C5 alkenylene, a substituted or unsubstituted C2-C5 alkynylene, a substituted or unsubstituted C3-C6 cycloalkylene, a substituted or unsubstituted C4-C6 cycloalkenylene, a substituted or unsubstituted C4-C6 cycloalkynylene, a substituted or unsubstituted 3- to 6-membered heterocycloalkylene, a substituted or unsubstituted C6-C 15 arylene, or substituted or unsubstituted 5- to 15-membered heteroarylene; R 4 is a substituted or unsubstituted C1-C5 alkyl or C2-C5 alkyl, a substituted or unsubstituted C2-C5 alkenyl, a substituted or unsubstituted C2-C5 alkynyl, a substituted or unsubstituted C3-C6 cycloalkyl, a substituted or unsubstituted C4-C6 cycloalkenyl, a substituted or unsubstituted C4-C6 cycloalkynyl, a substituted or unsubstituted 3-6 membered heterocycloalkyl, a substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, a substituted or unsubstituted 3-6 membered heterocycloalkyl-C1-C5 alkyl, a substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 15 aryl-C1-C5 alkyl, substituted or unsubstituted 5-15 membered heteroaryl, or substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyl; R 5 is H, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C2-C5 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 cycloalkenyl, substituted or unsubstituted C4-C6 cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl-C1-C5 alkyl, substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 15aryl-C1-C5 alkyl, substituted or unsubstituted 5-15 membered heteroaryl, or substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyl; R 6 is a substituted or unsubstituted C1-C5 alkyl, a substituted or unsubstituted C2-C5 alkenyl, a substituted or unsubstituted C2-C5 alkynyl, a substituted or unsubstituted C3-C6 cycloalkyl, a substituted or unsubstituted C4-C6 cycloalkenyl, a substituted or unsubstituted C4-C6 cycloalkynyl, a substituted or unsubstituted 3-6 membered heterocycloalkyl, a substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, a substituted or unsubstituted 3-6 membered heterocycloalkyl-C1-C5 alkyl, a substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 15 aryl-C1-C5 alkyl, substituted or unsubstituted 5-15 membered heteroaryl, or substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyl; However, R 3 When R is 1,6-phenylene, 4 is not a substituted arylalkyl, When the above groups are substituted, the substituents are each independently selected from the group consisting of halogen (fluorine, chlorine, bromine, or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C2-C5 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 cycloalkenyl, substituted or unsubstituted C4-C6 cycloalkynyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C1-C5 alkyl, substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 15Aryl-C1-C5 alkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkoxy, substituted or unsubstituted C6-C 15 Aryloxy, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyloxy, substituted or unsubstituted C1-C6 alkoxycarbonyl, substituted or unsubstituted C3-C6 cycloalkoxycarbonyl, substituted or unsubstituted C1-C 20 Acyl, substituted or unsubstituted C1-C 20 At least one monovalent group selected from the group consisting of acyloxy and substituted or unsubstituted amino.

[0053] Even more preferably, the compound of formula (I) is R 1 H, substituted or unsubstituted C6-C 15 Aryloxycarbonyl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyloxycarbonyl, substituted or unsubstituted C6-C 15 aryl-C2-C5 alkenyloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryloxycarbonyl, or substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyloxycarbonyl; R 2 is OH or a substituted or unsubstituted C1-C5 alkoxy; R 3 is a substituted or unsubstituted C1-C5 alkylene or a substituted or unsubstituted C6-C 15 is an arylene, R 4 is a substituted or unsubstituted C1-C5 alkyl, or a substituted or unsubstituted C6-C 15Aryl-C1-C5 alkyl, or substituted or unsubstituted C2-C5 alkyl, or substituted or unsubstituted C6-C 15 aryl-C1-C5 alkyl; R 5 is H or a substituted or unsubstituted C1-C5 alkyl; R 6 is a substituted or unsubstituted C1-C5 alkyl, or a substituted or unsubstituted C6-C 15 aryl-C1-C5 alkyl; However, R 3 When R is 1,6-phenylene, 4 is not a substituted arylalkyl, When the above groups are substituted, the substituents are each independently selected from the group consisting of halogen (fluorine, chlorine, bromine, or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C2-C5 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 cycloalkenyl, substituted or unsubstituted C4-C6 cycloalkynyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C1-C5 alkyl, substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkoxy, substituted or unsubstituted C6-C 15 Aryloxy, substituted or unsubstituted C6-C 15Aryl-C1-C5 alkyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyloxy, substituted or unsubstituted C1-C6 alkoxycarbonyl, substituted or unsubstituted C3-C6 cycloalkoxycarbonyl, substituted or unsubstituted C1-C 20 Acyl, substituted or unsubstituted C1-C 20 At least one monovalent group selected from the group consisting of acyloxy and substituted or unsubstituted amino.

[0054] Particularly preferably, the compound of formula (I) is R 1 is H or benzyloxycarbonyl, R 2 is OH or methoxy; R 3 is 1,1-ethylene, 1,2-phenylene, 1,3-phenylene or 1,4-phenylene; R 4 is 4-hydroxyphenylmethyl, 4-tert-butyloxyphenylmethyl or phenylmethyl; R 5 is H or methyl; R 6 is methyl, propan-2-yl, 4-aminobutan-1-yl, or 4-(t-butoxycarbonylamino)butan-1-yl.

[0055] Particularly preferred compounds of formula (I) are N-benzyloxycarbonyl-L-valinyl-N-methyl-L-phenylalanyl-anthranyl-L-alanyl-O-methyl ester (3b, fp3-58) (Example 1-1); HL-Valinyl-N-methyl-L-phenylalanyl-anthranyl-L-alanine (2h, fp3-61) (Examples 1-2); Cyclo(L-valinyl-N-methyl-L-phenylalanyl-anthranyl-L-alanyl) (1b, fp3-90) (Examples 1-3); N-benzyloxycarbonyl-L-valinyl-N-methyl-L-alanyl-anthranyl-L-alanyl-O-methyl ester (3h, fp3-68) (Example 2-1); HL-Valinyl-N-methyl-L-alanyl-anthranyl-L-alanine (2h, fp3-72) (Example 2-2); Cyclo(L-valinyl-N-methyl-L-alanyl-anthranyl-L-alanyl) (1h, fp3-125) (Example 2-3); N-benzyloxycarbonyl-L-valinyl-N-methyl-O-tert-butyl-L-tyrosinyl-L-alanyl-L-alanyl-O-methyl ester (3g, fp3-78) (Example 3-1) (SEQ ID NO:1); HL-Valinyl-N-methyl-O-tert-butyl-L-tyrosinyl-L-alanyl-L-alanyl-O-methyl ester (2g, fp3-81) (Example 3-2) (SEQ ID NO:2); N-benzyloxycarbonyl-L-valinyl-N-methyl-O-tert-butyl-L-tyrosinyl-3-aminobenzoyl-L-alanyl-O-methyl ester (fp3-134) (Example 4-1); HL-Valinyl-N-methyl-O-tert-butyl-L-tyrosinyl-3-aminobenzoyl-L-alanyl-O-methyl ester (fp3-147) (Example 4-2); N-benzyloxycarbonyl-L-valinyl-N-methyl-O-tert-butyl-L-tyrosinyl-4-aminobenzoyl-L-alanyl-O-methyl ester (fp3-142) (Example 5-1); and HL-Valinyl-N-methyl-O-tert-butyl-L-tyrosinyl-3-aminobenzoyl-L-alanyl-O-methyl ester (fp3-149) (Example 5-2); The compound is selected from the group consisting of: The compound is a cyclic or chain compound or a protected form thereof. When the compound represented by formula (I) of this embodiment is the compound or a protected or deprotected form thereof, the compound can more effectively enhance the antifungal activity of an antifungal drug compared to known pharmaceutical compounds.

[0056] The compound represented by formula (I) according to one embodiment of the present invention, and the compounds represented by formulas (VI), (VII), (VIII) and (IX) described below, include not only the above or below compounds themselves but also salts thereof. As the salt of the above or below-mentioned compound, for example, a salt with a cation such as a sodium ion, a potassium ion, a calcium ion, a magnesium ion, or a substituted or unsubstituted ammonium ion, or a salt with an anion of an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid or phosphoric acid, or an anion of an organic acid such as formic acid, acetic acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, bismethylenesalicylic acid, methanesulfonic acid, ethanedisulfonic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, cyclohexylsulfamic acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, p-toluenesulfonic acid or naphthalenesulfonic acid, is preferred, but is not limited thereto. When the compound represented by formula (I) is in the form of the above-mentioned salt, it can enhance the antifungal activity of an antifungal drug more effectively than known pharmaceutical compounds.

[0057] The compound represented by formula (I) according to one embodiment of the present invention, and the compounds represented by formulas (VI), (VII), (VIII) and (IX) described below include not only the above or below compounds themselves, but also solvates of the compounds or their salts. The solvent capable of forming a solvate with the above or below compounds or their salts is not limited, but is preferably, for example, a lower alcohol (e.g., an alcohol having 1 to 6 carbon atoms such as methanol, ethanol or 2-propanol (isopropyl alcohol)), a higher alcohol (e.g., an alcohol having 7 or more carbon atoms such as 1-heptanol or 1-octanol), an organic solvent such as dimethyl sulfoxide (DMSO), acetic acid, ethanolamine or ethyl acetate, or water. When the compound represented by formula (I) or a salt thereof is in the form of a solvate with the above solvent, the antifungal activity of the antifungal drug can be more effectively enhanced compared to known pharmaceutical compounds.

[0058] The compound represented by formula (I) according to one embodiment of the present invention, and the compounds represented by formulas (VI), (VII), (VIII) and (IX) described below include not only the above or below compounds themselves, but also their protected or deprotected forms. In this specification, the term "protected form" refers to a form in which a protecting group is introduced into one or more functional groups (e.g., a hydroxyl group, a carboxylic acid group or an amino group), and the term "deprotected form" refers to a form in which a protecting group introduced into one or more functional groups (e.g., a hydroxyl group, a carboxylic acid group or an amino group) is removed. In this specification, the protected form of the compound represented by each formula may be described as a protected derivative of the compound represented by each formula, and the deprotected form of the compound represented by each formula may be described as a deprotected derivative of the compound represented by each formula. In addition, in this specification, the term "protecting group" refers to a group introduced into a specific functional group to prevent the progression of an undesired reaction, which is quantitatively removed under specific reaction conditions, and which is substantially stable, i.e., inactive, under other reaction conditions. Examples of the protecting group that can form the protected form of the compound include, but are not limited to, silyl (e.g., t-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS) or tert-butyldiphenylsilyl (TBDPS)) or alkoxy (e.g., tert-butyloxy (tBu), methoxymethoxy (MOM) or methoxy (Me)) for the protecting group of a hydroxyl group, alkyl ester (e.g., methyl, ethyl or isopropyl ester), arylalkyl ester (e.g., benzyl ester) or amide (e.g., amide with oxazolidinone) for the protecting group of a carboxylic acid group, and t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 2-bromobenzyloxycarbonyl (BrZ) or 9-fluorenylmethoxycarbonyl (Fmoc) for the protecting group of an amino group. Protection and deprotection with the protecting group can be appropriately performed by those skilled in the art based on known reaction conditions. Even when the compound represented by formula (I) according to one embodiment of the present invention is in a protected form with the above-mentioned protecting group, it may be possible to more effectively enhance the antifungal activity of an antifungal drug as compared with known pharmaceutical compounds.

[0059] When the compound represented by formula (I) according to one embodiment of the present invention and the compounds represented by formulae (VI), (VII), (VIII) and (IX) described below have one or more tautomers, the above-mentioned or below-mentioned compounds also include the individual tautomeric forms of the compounds.

[0060] Furthermore, when the compound represented by formula (I) according to one embodiment of the present invention and the compounds represented by formulae (VI), (VII), (VIII) and (IX) described below have one or more stereocenters (chiral centers), the above-mentioned or below-mentioned compounds also include the individual enantiomers and diastereomers of the compound, as well as mixtures thereof such as racemates.

[0061] By virtue of having the above-mentioned characteristics, the compound represented by formula (I) according to one embodiment of the present invention can enhance the antifungal activity of an antifungal drug more effectively than known pharmaceutical compounds.

[0062] <2. Method for producing new compounds> Another aspect of the present invention relates to a method for producing a compound represented by formula (I) of one aspect of the present invention. The method of this aspect includes a main chain formation step and, optionally, a cyclization step. Each step will be described in detail below.

[0063] [2-1. Main chain formation process] The method of this embodiment comprises reacting a compound represented by formulas (VI), (VII), (VIII) and (IX): [ka] or a protected derivative thereof, or a salt or solvate thereof, to form a main chain of the compound represented by formula (I) having a chain structure.

[0064] In formulae (VI), (VII), (VIII) and (IX), R 3 , R 4 , R 5and R 6 has the same meaning as above.

[0065] In this step, the conditions of the reaction for linking the amino group and the carboxyl group of the compounds represented by formulas (VI), (VII), (VIII) and (IX) or their protected derivatives, or their salts or solvates, can be appropriately set by a person skilled in the art based on known reaction conditions for liquid-phase or solid-phase synthesis of peptides. The reaction in this step can be carried out, for example, by liquid-phase synthesis. In this case, for example, the compound represented by formula (VI) and the compound represented by formula (VII) are condensed in a liquid phase system in the presence of a condensing agent to link the amino group of the compound represented by formula (VI) and the carboxyl group of the compound represented by formula (VII). Next, the condensation reaction product of the compound represented by formula (VI) and the compound represented by formula (VII) is condensed with the compound represented by formula (VIII) in the presence of a condensing agent in a liquid phase system to link the amino group of the compound represented by formula (VII) and the carboxyl group of the compound represented by formula (VIII). Next, the condensation reaction product of the compound represented by formula (VI), the compound represented by formula (VII) and the compound represented by formula (VIII) is condensed with the compound represented by formula (IX) in the presence of a condensing agent in a liquid phase system to link the amino group of the compound represented by formula (VIII) with the carboxyl group of the compound represented by formula (IX). This series of condensation reactions can form the main chain of the compound represented by formula (I) having a chain structure.

[0066] Alternatively, the reaction in this step can be carried out, for example, by solid-phase synthesis. In this case, for example, a resin (e.g., 2-chlorotrityl chloride resin) is introduced into the carboxylic acid group of any one compound selected from the compounds represented by formulas (VI), (VII), (VIII), and (IX), and then, based on the main chain structure of the compound represented by formula (I), the remaining compounds are sequentially subjected to a condensation reaction with any one compound selected from the compounds represented by formulas (VI), (VII), (VIII), and (IX) supported on the resin, thereby forming the main chain of the compound represented by formula (I) having a chain structure.

[0067] When this step is carried out by liquid phase synthesis or solid phase synthesis, various condensing agents commonly used in the art can be used. Examples of the condensing agent include 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), and 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol 7-aza-1-hydroxybenzotriazole 1-hydroxy-7-azabenzotriazole (HOAt), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl·HCl), hydroxybenzotriazole (HOBt), N,N'-diisopropylcarbodiimide (DIPCI), benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), and bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrop).

[0068] The compounds represented by formulae (VI), (VII), (VIII) and (IX) used in this step may be not only the compounds themselves but also precursors of the compounds. Examples of the precursors of the compounds represented by formulae (VI), (VII), (VIII) and (IX) include compounds having a structure in which the amino group of the compound is replaced with a nitro group. When using precursors of the compounds represented by formulae (VI), (VII), (VIII) and (IX), this step preferably further includes converting the precursors into the corresponding compounds represented by formulae (VI), (VII), (VIII) and (IX).

[0069] The compounds represented by formulae (VI), (VII), (VIII) and (IX) or their precursors or protected derivatives used in this step may be prepared by, for example, purchasing the compounds prepared in advance, or may be prepared by oneself based on reaction conditions known in the art as a method for protecting and / or deprotecting an amino acid.

[0070] By carrying out this step under the above conditions, it is possible to form the main chain of the compound represented by formula (I) having a chain structure.

[0071] [2-2. Cyclization process] The method of this embodiment includes a cyclization step in which the compound represented by formula (I) having a chain structure obtained in the main chain formation step is intramolecularly cyclized to obtain a compound represented by formula (I) having a cyclic structure.

[0072] In this step, the reaction conditions for intramolecular cyclization of the compound represented by formula (I) having a chain structure can be appropriately set by a person skilled in the art based on known reaction conditions for liquid phase or solid phase peptide synthesis.

[0073] The above-described main chain formation step and cyclization step may include, if desired, a step of protecting and / or deprotecting the compound represented by formula (I) having a chain structure and the compound represented by formula (I) having a cyclic structure, and / or their precursors and intermediates. In this case, the reaction conditions for the protection and / or deprotection can be appropriately set by a person skilled in the art based on reaction conditions known in the art as a method for protecting and / or deprotecting amino acids.

[0074] The method of this embodiment makes it possible to provide a compound represented by formula (I) of one embodiment of the present invention, which can be an active ingredient of a medicine, or various compounds derived from said compound, in large quantities with high purity and at low cost.

[0075] <3. Medical Use> The compound represented by formula (I) according to one embodiment of the present invention has an activity of enhancing the antifungal activity of an antifungal drug. Therefore, another embodiment of the present invention relates to an activity enhancer for at least one antifungal drug, which comprises the compound represented by formula (I) according to one embodiment of the present invention or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable solvate thereof as an active ingredient. Another embodiment of the present invention relates to a medicine comprising the compound represented by formula (I) according to one embodiment of the present invention or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable solvate thereof as an active ingredient.

[0076] In each aspect of the present invention, the at least one antifungal drug is selected from the group consisting of polyene macrolide drugs, azole drugs, echinocandins and fluoropyrimidine drugs. The at least one antifungal drug is preferably a polyene macrolide drug. The polyene macrolide drug is preferably amphotericin B, pimaricin, nystatin or natamycin, more preferably amphotericin B. The azole drug is preferably an imidazole compound such as miconazole, or a triazole compound such as fluconazole, itraconazole, phosphofluconazole or voriconazole. The echinocandin drug is preferably micafungin or caspofungin. The fluoropyrimidine drug is preferably flucytosine. Amphotericin B, a polyene macrolide drug, has high antifungal activity and is useful for treating severe fungal infections, but may exhibit side effects such as nephrotoxicity. The compound represented by formula (I) according to one embodiment of the present invention has an activity of enhancing the antifungal activity of antifungal drugs such as polyene macrolide drugs, azole drugs, echinoid drugs, and fluoropyrimidine drugs. Therefore, by administering the compound represented by formula (I) according to one embodiment of the present invention together with at least one antifungal drug selected from the group consisting of polyene macrolide drugs, azole drugs, echinoid drugs, and fluoropyrimidine drugs, it is possible to reduce the dosage of the antifungal drug that may cause side effects and / or shorten the administration period. This makes it possible to substantially reduce the occurrence of side effects caused by at least one antifungal drug.

[0077] In each embodiment of the present invention, "administered together" means that the drugs are administered simultaneously or separately (e.g., consecutively at a fixed interval). In the present specification, such an administration form may be described as "concomitant administration". By administering the compound represented by formula (I) of one embodiment of the present invention and at least one antifungal drug in combination, the dosage of the antifungal drug that may cause side effects can be reduced and / or the administration period can be shortened. This can substantially reduce the occurrence of side effects caused by the at least one antifungal drug.

[0078] The compound represented by formula (I) in one embodiment of the present invention has an activity of enhancing the antifungal activity of at least one antifungal drug. On the other hand, the compound represented by formula (I) in one embodiment of the present invention may or may not have antifungal activity by itself. The compound represented by formula (I) in one embodiment of the present invention usually does not have substantially antifungal activity by itself. Even if the compound represented by formula (I) in one embodiment of the present invention does not have substantially antifungal activity by itself, it has an activity of enhancing the antifungal activity of at least one antifungal drug, so that the dose of the antifungal drug that may cause side effects can be reduced and / or the administration period can be shortened by coadministration with at least one antifungal drug. This can substantially reduce the occurrence of side effects caused by at least one antifungal drug.

[0079] The antifungal activity of the compound represented by formula (I) and at least one antifungal agent according to one embodiment of the present invention can be determined, for example, but not limited to, by the following means. The compound represented by formula (I) or at least one antifungal agent is administered to any test fungus (e.g., yeast fungi, filamentous fungi, and zygomycetes) by the broth microdilution method according to the Clinical Laboratory Standards Institute (CLSI) M27-A3 and M38-A2 methods. After culturing under predetermined conditions, the turbidity (e.g., OD 550The growth of the fungus is measured using the colony diameter or the like as an index, and the inhibition rate (%) is calculated by comparing it with the value at the start of the culture. The minimum concentration of the compound at which the calculated inhibition rate is a predetermined value (e.g., 90%) or more is defined as the minimum inhibitory concentration (MIC value) of the compound. Based on the inhibition rate and MIC value thus determined, the antifungal activity of the compound represented by formula (I) according to one embodiment of the present invention and at least one antifungal drug can be evaluated.

[0080] The activity of the compound represented by formula (I) of one embodiment of the present invention to enhance the antifungal activity of at least one antifungal drug can be determined, for example, by the following means, but is not limited to these. Based on the above means, the MIC value when the at least one antifungal drug is administered alone is determined. Then, under the same test conditions, the compound represented by formula (I) and the at least one antifungal drug are administered together (for example, simultaneously) to determine the MIC value when the compound represented by formula (I) and the at least one antifungal drug are administered in combination. Based on the following formula (M-1), the enhancement rate of the antifungal activity of at least one antifungal drug of the compound represented by formula (I) of one embodiment of the present invention is calculated. For example, when the enhancement rate is 2 times, the MIC value of the at least one antifungal drug when the compound represented by formula (I) of one embodiment of the present invention is administered in combination is 1 / 2 of the MIC value when the antifungal drug is administered alone. Based on the enhancement rate determined in this way, the activity of the compound represented by formula (I) of one embodiment of the present invention to enhance the antifungal activity of at least one antifungal drug can be evaluated.

[0081]

number

[0082] In this embodiment, the at least one antifungal drug administered in combination with the compound represented by formula (I) of one embodiment of the present invention has an MIC value, determined by the above procedure, of usually 0.5 μg / mL or more, for example 1.0 μg / mL or more, and particularly 2.0 μg / mL or more against yeast fungi (e.g., Candida albicans and Cryptococcus neoformans) and Zygomycetes (Rhizopus oryzae). In this case, the compound represented by formula (I) of one embodiment of the present invention is administered in combination with at least one antifungal drug at a concentration of usually 0.5 μg / mL or more, for example, in the range of 1 to 32 μg / mL, and particularly in the range of 2 to 32 μg / mL, and can enhance the antifungal activity of at least one antifungal drug at an enhancement rate of usually 2-fold or more, for example, in the range of 2 to 32-fold, and particularly in the range of 4 to 32-fold. In contrast, in the case of nectriatide, a known pharmaceutical compound, co-administration with at least one antifungal drug at a concentration of 2 μg / mL or more can enhance the antifungal activity of at least one antifungal drug, usually at an enhancement rate of 2-fold or more, for example, in the range of 2-8-fold, particularly in the range of 2-4-fold. Therefore, the compound represented by formula (I) of this embodiment can enhance the antifungal activity of an antifungal drug more effectively than known pharmaceutical compounds. In addition, when the compound represented by formula (I) of one embodiment of the present invention has an enhancement rate in the above range, co-administration with at least one antifungal drug can reduce the dosage of the antifungal drug that may cause side effects and / or shorten the administration period. This can substantially reduce the occurrence of side effects caused by at least one antifungal drug.

[0083] When the compound represented by formula (I) of one embodiment of the present invention is applied to a medical use, the compound represented by formula (I) includes not only the compound itself but also a pharma- ceutically acceptable salt of the compound and a pharma-ceutically acceptable solvate thereof. The pharma-ceutically acceptable salt of the compound represented by formula (I) of one embodiment of the present invention and a pharma-ceutically acceptable solvate thereof are not limited, but are preferably, for example, the salts or solvates exemplified above. When the compound represented by formula (I) is in the form of the salt or solvate, the compound can be applied to a desired medical use without substantially decreasing the activity of enhancing the antifungal activity of at least one antifungal drug.

[0084] When the compound represented by formula (I) of one embodiment of the present invention is applied to medical use, the compound represented by formula (I) includes not only the compound itself but also the prodrug form of the compound. In this specification, "prodrug" means a compound that is converted to a parent drug in vivo. The prodrug form of the compound includes, but is not limited to, for example, when a hydroxyl group is present, an ester of the hydroxyl group with any carboxylic acid, and an amide of the hydroxyl group with any amine. When the compound represented by formula (I) of one embodiment of the present invention is in the prodrug form, the pharmacokinetics of the prodrug form administered to a subject can be improved without substantially decreasing the activity of the parent drug compound represented by formula (I) to enhance the antifungal activity of at least one antifungal drug.

[0085] When the compound represented by formula (I) of one aspect of the present invention is applied to a pharmaceutical use, the compound may be used alone or in combination with one or more pharma- ceutical acceptable ingredients. The pharmaceutical of this aspect can be formulated into various dosage forms commonly used in the art, depending on the desired administration method. Therefore, the pharmaceutical of this aspect can also be provided in the form of a pharmaceutical composition containing the compound represented by formula (I) of one aspect of the present invention or a salt thereof, or a solvate thereof, and one or more pharma- ceutical acceptable carriers. In this case, the pharmaceutical composition of this aspect may or may not contain at least one antifungal agent. The pharmaceutical composition of this aspect may contain, in addition to the above-mentioned ingredients, one or more pharma- ceutical acceptable vehicles (e.g., a solvent such as sterilized water or a solution such as physiological saline), excipients, binders, vehicles, solubilizing agents, preservatives, stabilizers, swelling agents, lubricants, surfactants, emulsifiers, oily liquids (e.g., vegetable oils), suspending agents, buffers, soothing agents, antioxidants, sweeteners, flavoring agents, and the like.

[0086] The dosage form of the pharmaceutical containing the compound represented by formula (I) of one embodiment of the present invention or a pharma- ceutically acceptable salt thereof, or a pharma-ceutically acceptable solvate thereof as an active ingredient is not particularly limited, and may be a preparation for use in parenteral administration or a preparation for use in oral administration. The dosage form of the pharmaceutical of this embodiment may be a preparation in a unit dose form or a preparation in a multiple dose form. Examples of the preparation for use in parenteral administration include injections such as sterile solutions or suspensions with water or other pharma-ceutically acceptable media. Examples of ingredients that can be mixed into the injection include, but are not limited to, vehicles such as isotonic solutions containing physiological saline, glucose, or other auxiliary agents (e.g., D-sorbitol, D-mannitol, D-mannose, or sodium chloride), dissolution aids such as alcohol (e.g., ethanol or benzyl alcohol), polyalcohols (e.g., propylene glycol or polyethylene glycol), or esters (e.g., benzyl benzoate), nonionic surfactants such as polysorbate 80 (trademark) or polyoxyethylene hydrogenated castor oil, oily liquids such as sesame oil or soybean oil, buffers such as phosphate buffer or sodium acetate buffer, pain relievers such as benzalkonium chloride or procaine hydrochloride, stabilizers such as human serum albumin or polyethylene glycol, preservatives, and antioxidants. The prepared injection is usually filled into a suitable vial (e.g., ampule) and stored under an appropriate environment until use.

[0087] Examples of preparations for oral administration include tablets, pills, powders, capsules, microcapsules, elixirs, liquids, syrups, slurries, and suspensions. Tablets may be prepared as sugar-coated tablets or sugar-coated tablets with a soluble coating, gelatin-coated tablets, enteric-coated tablets, or film-coated tablets, or as double- or multi-layered tablets, if desired.

[0088] Ingredients that can be mixed into tablets or capsules include, but are not limited to, binders such as water, ethanol, propanol, simple syrup, glucose solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, gelatin, corn starch, tragacanth gum, or gum arabic; excipients such as crystalline cellulose, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, or silicic acid; dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, and the like. Examples of the disintegrating agent include ester, sodium lauryl sulfate, monoglyceride stearic acid, starch, or lactose; disintegration inhibitors such as white sugar, stearic cocoa butter, or hydrogenated oil; absorption promoters such as quaternary ammonium salts or sodium lauryl sulfate; moisturizing agents such as glycerin or starch; adsorbents such as starch, lactose, kaolin, bentonite, or colloidal silicic acid; lubricants such as purified talc, stearates (e.g., magnesium stearate), boric acid powder, or polyethylene glycol; sweeteners such as sucrose, lactose, or saccharin; and flavoring agents such as peppermint, saffron oil, or cherry. When the preparation is a capsule, it may further contain a liquid carrier such as oil or fat.

[0089] A medicament containing the compound represented by formula (I) of one embodiment of the present invention or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable solvate thereof as an active ingredient can also be formulated as a depot preparation. In this case, the medicament of this embodiment in the form of a depot preparation can be administered, for example, by subcutaneous or intramuscular implantation, or by intramuscular injection. By applying the medicament of this embodiment to a depot preparation, the activity of the compound represented by formula (I) of one embodiment of the present invention to enhance the antifungal activity of at least one antifungal drug can be sustained for a long period of time.

[0090] When the compound represented by formula (I) of one aspect of the present invention is applied to a pharmaceutical use, the compound may be provided together with at least one antifungal drug, or may be provided separately. Either case is included in the embodiment of this aspect. In the case of an embodiment further comprising at least one antifungal drug in addition to the compound represented by formula (I) of one aspect of the present invention, that is, in the case of an embodiment in which the compound represented by formula (I) of one aspect of the present invention and at least one antifungal drug are provided together, the medicine of this aspect can be in the form of a pharmaceutical composition comprising a combination of the compound represented by formula (I) of one aspect of the present invention or a salt thereof, or a solvate thereof, and at least one antifungal drug. In this embodiment, the medicine of this aspect can be provided in the form of a single formulation containing, for example, the compound represented by formula (I) of one aspect of the present invention or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable solvate thereof, and at least one antifungal drug. In the case of an embodiment in which the compound represented by formula (I) of one aspect of the present invention is provided separately from at least one antifungal drug, the pharmaceutical of this aspect can be in the form of a pharmaceutical composition containing at least the compound represented by formula (I) of one aspect of the present invention or a salt thereof, or a solvate thereof, which is used in combination with at least one antifungal drug. In the case of this embodiment, the pharmaceutical of this aspect can be provided in the form of a pharmaceutical combination or kit containing multiple preparations in which the compound represented by formula (I) of one aspect of the present invention or a salt thereof, or a solvate thereof and at least one antifungal drug are separately formulated. In the case of the pharmaceutical combination or kit form, each preparation can be administered simultaneously or separately (e.g., consecutively). Alternatively, the pharmaceutical of this aspect can be provided in the form of a preparation containing only the compound represented by formula (I) of one aspect of the present invention or a salt thereof, or a solvate thereof (i.e., not containing at least one antifungal drug). In any embodiment, the compound represented by formula (I) of one aspect of the present invention and at least one antifungal drug can be administered in combination.

[0091] A pharmaceutical comprising the compound represented by formula (I) of one aspect of the present invention or a pharma- ceutical acceptable salt thereof, or a pharma- ceutical acceptable solvate thereof as an active ingredient can also be used in combination with one or more other drugs useful as pharmaceuticals other than at least one antifungal drug. In this case, the pharmaceutical of this aspect is in the form of a combination pharmaceutical comprising the compound represented by formula (I) of one aspect of the present invention or a pharma- ceutical acceptable salt thereof, or a pharma- ceutical acceptable solvate thereof, and one or more of the other drugs. The combination pharmaceutical may be in the form of a pharmaceutical composition comprising a compound represented by formula (I) of one aspect of the present invention or a pharma- ceutical acceptable salt thereof, or a pharma- ceutical acceptable solvate thereof, and one or more of the other drugs, or may be in the form of a pharmaceutical composition comprising the compound represented by formula (I) of one aspect of the present invention or a pharma- ceutical acceptable salt thereof, or a pharma- ceutical acceptable solvate thereof, and used in combination with one or more of the other drugs. When the pharmaceutical of this embodiment is in the form of a combined pharmaceutical as described above, it may be provided in the form of a single preparation containing the compound represented by formula (I) of one embodiment of the present invention or a pharma- ceutical acceptable salt thereof, or a pharma- ceutical acceptable solvate thereof and one or more other drugs, or it may be provided in the form of a pharmaceutical combination or kit containing multiple preparations in which one or more other drugs are separately formulated. In the case of the pharmaceutical combination or kit form, each preparation can be administered simultaneously or separately (for example, consecutively).

[0092] A medicine comprising, as an active ingredient, the compound represented by formula (I) according to one embodiment of the present invention or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable solvate thereof, can similarly prevent or treat one or more fungal infections. The fungi causing the one or more fungal infections include, but are not limited to, yeast fungi such as Candida albicans, Candida parapsilosis, Candida glabrata, and Cryptococcus neoformans; filamentous fungi such as Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, and Aspergillus terreus; Zygomycetes such as Rhizopus oryzae, Rhizomucor pusillus, Rhizopus microspores, and Absidia corymbifera. corymbifera). The one or more fungal infections can include, but are not limited to, deep mycosis, superficial mycosis, and dermatomycosis. The one or more fungal infections are preferably one or more diseases, symptoms, or disorders selected from the group consisting of deep mycosis, superficial mycosis, and dermatomycosis. The one or more fungal infections can be prevented or treated by administering the pharmaceutical agent of this embodiment to a subject in need of prevention or treatment of the one or more fungal infections.

[0093] A medicament comprising the compound represented by formula (I) or a pharma- ceutically acceptable salt thereof, or a pharma- ceutical acceptable solvate thereof as an active ingredient according to one embodiment of the present invention, can be applied to various subjects requiring prevention or treatment of one or more symptoms, diseases, and / or disorders caused by fungal infection. The subject is preferably a subject or patient such as a human or non-human mammal (e.g., a warm-blooded animal such as a pig, a dog, a cow, a rat, a mouse, a guinea pig, a rabbit, a chicken, a sheep, a cat, a monkey, a hamadryas baboon, or a chimpanzee), or a reptile (e.g., a cold-blooded animal such as a frog, a snake, or a lizard). By administering the medicament according to this embodiment to the subject, various diseases, symptoms, and / or disorders caused by one or more fungal infections that the subject has can be prevented or treated.

[0094] As used herein, "prevention" means substantially preventing or partially reducing the occurrence (onset or manifestation) of a symptom, disease, and / or disorder in a subject who may have the symptom, disease, and / or disorder in the future, e.g., a healthy subject. Also, as used herein, "treatment" means suppressing (e.g., suppressing the progression of), alleviating, repairing, and / or curing the symptom, disease, and / or disorder that has occurred (onset or manifested) in a subject having the symptom, disease, and / or disorder.

[0095] The compound represented by formula (I) according to one embodiment of the present invention can be used for the prevention or treatment of one or more symptoms, diseases, and / or disorders (e.g., deep mycosis, superficial mycosis, or dermatomycosis) of the fungal infection described above in a subject having the symptoms, diseases, and / or disorders. Therefore, the medicament according to this embodiment is preferably a medicament for use in the prevention or treatment of one or more symptoms, diseases, and / or disorders of the fungal infection described above, and more preferably a medicament for use in the prevention or treatment of one or more fungal infections selected from the group consisting of deep mycosis, superficial mycosis, and dermatomycosis. By using the medicament according to this embodiment for the prevention or treatment of one or more symptoms, diseases, and / or disorders of the fungal infection described above, the symptoms, diseases, and / or disorders can be prevented or treated through the activity of the compound represented by formula (I) according to one embodiment of the present invention in enhancing the antifungal activity of at least one antifungal agent.

[0096] The compound represented by formula (I) according to one embodiment of the present invention can be used in the prevention or treatment of one or more of the above-described symptoms, diseases and / or disorders (e.g., deep mycosis, superficial mycosis or dermatomycosis) in a subject having the symptoms, diseases and / or disorders which are one or more of the above-described fungal infections. Therefore, another embodiment of the present invention is a method for preventing or treating one or more of the above-described symptoms, diseases and / or disorders which are one or more of the above-described fungal infections, comprising administering an effective amount of the compound represented by formula (I) of the present invention or a pharma- ceutical acceptable salt thereof, or a pharma-ceutical acceptable solvate thereof, together with at least one antifungal agent, to a subject in need of such prevention or treatment. The one or more of the above-described symptoms, diseases and / or disorders which are fungal infections are preferably one or more of the diseases or symptoms selected from the group consisting of deep mycosis, superficial mycosis and dermatomycosis. By administering a compound represented by formula (I) according to one aspect of the present invention together with at least one antifungal agent to a subject in need of prevention or treatment of one or more of the symptoms, diseases and / or disorders resulting from fungal infection, the symptoms, diseases and / or disorders can be prevented or treated via the activity of the compound represented by formula (I) according to one aspect of the present invention in enhancing the antifungal activity of the at least one antifungal agent.

[0097] Another aspect of the present invention is a compound represented by formula (I) according to one aspect of the present invention, or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable solvate thereof, for use in the prophylaxis or treatment of one or more symptoms, diseases, and / or disorders caused by fungal infections as described above. Another aspect of the present invention is the use of a compound represented by formula (I) according to one aspect of the present invention, or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable solvate thereof, for the manufacture of a medicament for use in the prophylaxis or treatment of one or more symptoms, diseases, and / or disorders caused by fungal infections as described above. Yet another aspect of the present invention is the use of a compound represented by formula (I) according to one aspect of the present invention, or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable solvate thereof, for the prophylaxis or treatment of one or more symptoms, diseases, and / or disorders caused by fungal infections as described above. The one or more symptoms, diseases, and / or disorders caused by fungal infections as described above are preferably one or more diseases or symptoms selected from the group consisting of deep mycoses, superficial mycoses, and dermatomycoses. By using a compound or medicine represented by formula (I) according to one aspect of the present invention for the prevention or treatment of one or more symptoms, diseases and / or disorders that are fungal infections, the symptoms, diseases and / or disorders can be prevented or treated via the activity of the compound represented by formula (I) according to one aspect of the present invention to enhance the antifungal activity of at least one antifungal agent.

[0098] When administering a medicament containing, as an active ingredient, a compound represented by formula (I) according to one aspect of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, to a subject, particularly a human patient, the exact dosage and usage (e.g., dosage amount, frequency of administration and / or route of administration) should be finally determined by the attending physician in consideration of many factors such as the age, sex of the subject, the exact condition (e.g., severity) of the symptom, disease and / or disorder to be prevented or treated, and the route of administration, etc., taking into account a therapeutically effective dosage amount, frequency of administration, route of administration, etc. Therefore, in the medicament of this aspect, the compound represented by formula (I) as the active ingredient is administered to the subject in a therapeutically effective amount and frequency. For example, when administering the medicament of this aspect to a human patient, the dosage amount of the compound represented by formula (I) as the active ingredient is usually in the range of 0.001 to 100 mg / kg body weight per administration, typically in the range of 0.01 to 10 mg / kg body weight per administration, and particularly in the range of 0.1 to 10 mg / kg body weight per administration. Also, the frequency of administration of the medicament of this aspect can be, for example, once or multiple times a day, or once every few days. Further, the route of administration of the medicament of this aspect is not particularly limited and may be administered orally, or parenterally (e.g., rectally, transmucosally, enterally, intramuscularly, subcutaneously, intramedullary, intrathecally, directly into the ventricle, intravenously, intravitreally, intraperitoneally, intranasally or intraocularly) in a single or multiple administrations. By using the medicament of this aspect in the above-mentioned dosage and usage, through the activity of enhancing the antifungal activity of at least one antifungal agent of the compound represented by formula (I) according to one aspect of the present invention, the symptoms, diseases and / or disorders of the above-mentioned one or more fungal infections can be prevented or treated.

Example

[0099] Hereinafter, the present invention will be described more specifically with reference to examples. However, the technical scope of the present invention is not limited to these examples.

[0100] <I. Production of Compounds> [I-1. Equipment and Conditions Used] Unless otherwise stated, all reagents were purchased of the highest commercial quality and used without further purification. Reactions were monitored by thin layer chromatography (TLC) using Silica Gel 70 PF254 plates - Wako. The plates were visualized by UV light and stained with ethanolic phosphomolybdic acid. NMR spectra were 1 400 MHz for H, 13 C were recorded on an Agilent MR-400 spectrometer operating at 100 MHz. Proton chemical shifts are reported in ppm and referenced to residual solvent (δ 7.26 for CDCl3, δ 3.31 for CD3OD, δ 2.48 for DMSO-d6). Carbon chemical shifts are reported in ppm and referenced to residual solvent (δ 77.0 for CDCl3, δ 49.0 for CD3OD, δ 39.5 for DMSO-d6). 1 H NMR data are reported as chemical shifts, integrals, multiplicities (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), and coupling constants (Hz). 13C NMR data are reported in terms of chemical shifts. IR spectra were recorded as KBr pellets on a JASCO FT / IR-460 plus spectrometer. Optical rotations were obtained using a JASCO P-2200 polarimeter. High-resolution mass spectra were measured using a JEOL AccuTOF LC-plus T100LP mass spectrometer equipped with an ESI interface. Analytical high-performance liquid chromatography (HPLC) was performed on an Agilent 1200 system using a SHISEIDO CAPCELL CORE C18 (2.1 × 50 mm). A linear gradient of 5–100% CH3CN containing 0.1% HCO2H in H2O was used for 8 min at a flow rate of 0.4 mL / min. UV absorption was detected at 210 nm. Purification was performed on a Yamazen YFLC-AI-580 equipped with a packed silica gel column. Preparative HPLC was performed on a Senshu Scientific system equipped with a SSC-3462 pump, SSC-3462 UV detector, and DG-3210 degasser using a Nacalai Tesque COSMOSIL π NAP (20×250 mm). A single condition of 90% CH3OH was used at a flow rate of 15 mL / min. UV absorption was detected at 210 nm. Purification was performed using a Universal column (Yamazen) on a Yamazen YFLC-AI-580. Melting points were determined using a Yanaco MP-S3 and were uncorrected.

[0101] [I-2. Abbreviations] Ant = anthranilic acid, DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene, DIPEA = N-diisopropylethylamine, DMF = N,N-dimethylformamide, HATU = O-(7-aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, HFIP = 1,1,1,3,3,3-hexafluoro-2-propanol, TFA = trifluoroacetic acid, PyBop = benzotriazol-1-yloxytriopyrrolidinophosphonium hexafluorophosphite, PyBrop = bromotri(pyrrolidino)phosphonium hexafluorophosphate, TIPS = triisopropylsilane.

[0102] [I-3. Synthesis of nectriatide] (S)-2-(2-nitrobenzamido)propionic acid methyl ester (4) [ka] To a solution of 2-nitrobenzoic acid (501 mg, 3.00 mmol) and HCl·H-Ala-OMe (418 mg, 3.00 mmol) in CHCl (30 mL) was added EDCI·HCl (575 mg, 3.00 mmol) and HOBt (446 mg, 3.30 mmol). Then, DIPEA (522 μL, 3.00 mmol) was added. The mixture was stirred at room temperature for 18 h. After the reaction was completed, the solvent was evaporated. The resulting mixture was diluted with ethyl acetate and washed with H2O, 1N hydrochloric acid, saturated aqueous NaHCO3, and saturated brine. The organic phase was dried over Na2SO4, filtered, and evaporated. The residue was purified by silica gel column chromatography (CHCl3 / MeOH = 99 / 1) to give compound 4 (680 mg, 90%) as a colorless solid.

[0103] [α] D 26 -20 (c = 1.0, CHCl3). IR (KBr) max3294, 3067, 3000, 2953, 1746, 1644, 1532, 1451, 1349, 1270, 1214, 1170, 792, 741, 703 cm -1 . HRMS (ESI-TOF) C 11 H 12 Calculated value for N2NaO5: 275.0644, Found value m / z: 275.0632 [M+Na] + . 1 H NMR (400 MHz, CDCl3) δ 8.09 (1H, dd, J = 8.0, 1.5 Hz), 7.69 (1H, dt, J = 7.5, 1.5 Hz), 7.60 (1H, ddd, J = 8.0, 7.5, 1.5 Hz), 7.56 (1H, dd, J = 7.5, 1.5 Hz), 6.43 (1H, brd, J = 7.5 Hz), 4.82 (1H, dq, J = 7.0, 7.0 Hz), 3.80 (3H, s), 1.56 (3H, d, J = 7.0 Hz). 13 C NMR (100 MHz, CDCl3) δ 173.1, 165.7, 146.4, 133.7, 132.4, 130.6, 128.7, 124.5, 52.6, 48.6, 18.1.

[0104] (S)-2-(2-aminobenzamido)propionic acid ethyl ester (5) [ka] To a suspension of 10% Pd / C (55 mg) in MeOH (20 mL) was added compound 4 (550 mg, 2.18 mmol). The resulting mixture was purged with H2 and stirred at room temperature for 5 h. The mixture was filtered through a pad of Celite and the filtrate was evaporated. The residue was purified by silica gel column chromatography (CHCl3 / MeOH = 99 / 1) to give compound 5 (480 mg, 99%) as a colorless solid.

[0105] [α]D 24 +2.0 (c = 1.0, CHCl3). IR (KBr) ν max 3464, 3357, 2993, 2949, 1735, 1637, 1617, 1585, 1523, 1450, 1259, 1214, 1161, 1047, 750 cm -1 . HRMS (ESI-TOF) C 11 H 15 Calculated value of N2O3 is 223.1083, measured value m / z 223.1073 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.39 (1H, dd, J = 8.5, 1.0 Hz), 7.20 (1H, ddd, J = 7.5, 7.0, 1.0 Hz), 6.66 (1H, dd, J = 7.5, 1.0 Hz), 6.65 (1H, ddd, J = 8.5, 7.0, 1.0 Hz), 6.63 (1H, brd, J = 7.0 Hz), 5.51 (H, brs), 4.74 (1H, dq, J = 7.0, 7.0 Hz), 3.78 (3H, s), 1.50 (3H, d, J = 7.0 Hz). 13 C NMR (100 MHz, CDCl3) δ 173.7, 168.7, 148.8, 132.5, 127.4, 117.3, 116.6, 115.2, 52.5, 48.1, 18.1.

[0106] H-NMeTyr(tBu)-Ant-Ala-OMe(6)

Chem.

[0107] [α] D 24 -54 (c = 2.2, CHCl3). IR (KBr) max 3290, 2976, 2927, 1744, 1648, 1600, 1581, 1508, 1443, 1365, 1258, 1236, 1210, 1163, 897, 758 cm -1 . HRMS (ESI-TOF) C 25 H 34 Calculated value for N3O5: 456.2499, Found value: m / z: 456.2489 [M+H] + . 11H NMR (400 MHz, CDCl3) δ 11.62 (1H, s), 8.63 (1H, dd, J = 8.0, 1.0 Hz), 7.53 (1H, dd, J = 8.0, 1.0 Hz), 7.47 (1H, dt, J = 8.0, 1.0 Hz), 7.13 (2H, d, J = 8.5 Hz), 7.08 (1H, dt, J = 7.5, 1.0 Hz), 6.90 (2H, d, J = 8.5 Hz), 6.80 (1H, d, J = 7.0 Hz), 4.78 (1H, dq, J = 7.0, 7.0 Hz), 3.78 (3H, s), 3.27 (1H, dd, J = 10.0, 4.0 Hz), 3.20 (1H, dd, J = 14.0, 4.0 Hz), 2.71 (1H, dd, J = 14.0, 10.0 Hz), 2.32 (3H, s), 1.50 (3H, d, J = 7.0 Hz), 1.30 (9H, s). 13 13C NMR (100 MHz, CDCl3) δ 173.3 (× 2), 167.9, 154.2, 138.7, 132.5, 132.4, 129.4 (× 2), 126.8, 124.3 (× 2), 122.9, 121.6, 121.4, 78.3, 67.7, 52.6, 48.4, 39.0, 35.5, 28.7 (× 3), 18.5.

[0108] Cbz-Val-NMeTyr(tBu)-Ant-Ala-OMe(3a)

Chem.

[0109] [α] D 25 -76 (c = 1.1, CHCl3). IR (KBr) max 3350, 2973, 2930, 1738, 1718, 1646, 1597, 1586, 1508, 1447, 1402, 1364, 1297, 1255, 1234, 1216, 1163, 1087, 1025, 897, 756cm -1 . HRMS (ESI-TOF) C 38 H 48 Calculated value for N4NaO8: 711.3370, Found value m / z: 711.3353 [M+Na] + . A 2.5:1 rotamer ratio was observed by NMR. Major rotamers: 1H NMR (400 MHz, CDCl3) δ 11.36 (1H, s), 8.60 (1H, dd, J = 8.0, 0.5 Hz), 7.51 (1H, dd, J = 8.0, 1.0 Hz), 7.47 (1H, dt, J = 8.0, 1.0 Hz), 7.36-7.28 (4H, m), 7.11 (2H, d, J = 8.5 Hz), 7.07 (1H, dt, J = 8.0, 1.0 Hz), 6.93-6.89 (1H, m), 6.86 (2H, d, J = 8.5 Hz), 6.80 (1H, d, J = 7.0 Hz), 5.39 (1H, dd, J = 9.0, 6.0 Hz), 5.28 (1H, d, J = 9.5 Hz), 5.11 (1H, d, J = 12.0 Hz), 5.03 (1H, d, J = 12.0 Hz), 4.70 (1H, dq, J = 7.0, 7.0 Hz), 4.44 (1H, dd, J = 9.5, 5.0 Hz), 3.77 (3H, s), 3.47 (1H, dd, J = 14.0, 6.0 Hz), 3.01 (3H, s), 2.97 (1H, dd, J = 14.0, 9.0 Hz), 2.09 (1H, m), 1.47 (3H, d, J = 7.0 Hz), 1.27 (9H, s), 0.97 (3H, d, J = 6.5 Hz), 0.86 (3H, d, J = 6.5 Hz). 13 C NMR (100 MHz, CDCl3) δ 173.3, 172.5, 168.7, 167.9, 156.2, 154.0, 139.4, 136.5, 132.8, 132.0, 129.4 (× 2), 128.4 (× 2), 128.1, 127.9 (× 2), 126.7, 124.1 (× 2), 123.0, 121.4, 119.7, 78.3, 66.7, 60.7, 55.8, 52.6, 48.3, 33.4, 32.6, 30.6, 28.8 (× 3), 19.9, 18.3, 16.9. A small amount of the opposite sex: 1H NMR (400 MHz, CDCl3) δ 11.27 (1H, s), 8.66 (1H, dd, J = 8.0, 0.5 Hz), 7.52 (1H, dt, J = 8.0, 1.0 Hz), 7.43 (1H, dd, J = 8.0, 1.0 Hz), 7.36-7.28 (4H, m), 7.17 (2H, d, J = 8.5 Hz), 7.12 (1H, dt, J = 8.0, 1.0 Hz), 6.93-6.89 (1H, m), 6.91 (2H, d, J = 8.5 Hz), 6.51 (1H, d, J = 7.0 Hz), 5.78 (1H, d, J = 10.0 Hz), 4.95 (1H, dd, J = 11.0, 3.5 Hz), 4.83 (1H, d, J = 12.0 Hz), 4.78 (1H, d, J = 12.0 Hz), 4.58 (1H, dq, J = 7.0, 7.0 Hz), 3.93 (1H, dd, J = 10.0, 7.5 Hz), 3.77 (3H, s), 3.58 (1H, dd, J = 13.5, 3.5 Hz), 2.92 (3H, s), 2.91 (1H, dd, J = 13.5, 11.0 Hz), 1.87 (1H, m), 1.32 (9H, s), 1.29 (3H, d, J = 7.0 Hz), 0.79 (3H, d, J = 6.5 Hz), 0.49 (3H, d, J = 6.5 Hz). 13 C NMR (100 MHz, CDCl3) δ 173.4, 171.7, 168.4, 168.2, 156.3, 154.4, 139.0, 135.8, 132.9, 131.9, 129.8 (× 2), 128.2 (× 2), 128.0 (× 2), 127.9, 127.1, 124.2 (× 2), 123.2, 121.0, 120.1, 78.2, 67.2, 63.5, 55.8, 52.7, 48.3, 33.5, 30.3, 30.1, 28.7 (× 3), 19.6, 17.8, 17.5.

[0110] Cbz-Val-NMeTyr(tBu)-Ant-Ala-OH(12) [ka] To a solution of compound 3a (482 mg, 700 μmol) in THF (5.6 mL) was added 1N LiOH (1.4 mL, 1.40 mmol) at 5° C. After stirring for 1 h, the solvent was evaporated. The crude product was diluted with EtOAc and washed with 1N HCl and saturated brine. The organic phase was dried over Na2SO4, filtered and evaporated. Compound 12 was obtained as a pale yellow foamy solid and was used in the next reaction without further purification.

[0111] [α] D 23 -74 (c = 1.0, CHCl3). IR (KBr) max 3315, 2974, 2937, 2869, 1702, 1646, 1600, 1509, 1446, 1296, 1258, 1235, 1162, 1087, 1027, 926, 897, 756 cm -1 . HRMS (ESI-TOF) C 37 H 47 Calculated value for N4O8: 675.3393, Found value m / z: 675.3396 [M+H] + . Major rotamers: 1H NMR (400 MHz, CDCl3) δ 11.39 (1H, s), 8.57 (1H, dd, J = 8.0, 1.0 Hz), 7.50 (1H, dd, J = 8.0, 1.0 Hz), 7.46 (1H, dt, J = 8.0, 1.0 Hz), 7.36-7.28 (4H, m), 7.10 (2H, d, J = 8.5 Hz), 7.07 (1H, t, J = 7.5 Hz), 6.97-6.95 (1H, m), 6.86 (2H, d, J = 8.5 Hz), 6.76 (1H, d, J = 7.0 Hz), 5.86 (1H, d, J = 9.5 Hz), 5.32 (1H, dd, J = 8.5, 6.5 Hz), 5.12 (1H, d, J = 12.0 Hz), 5.07 (1H, d, J = 12.0 Hz), 4.72 (1H, dq, J = 7.0, 7.0 Hz), 4.43 (1H, dd, J = 9.5, 6.5 Hz), 3.46 (1H, dd, J = 14.0, 6.5 Hz), 3.03 (3H, s), 2.96 (1H, dd, J = 14.0, 9.0 Hz), 1.96 (1H, m), 1.53 (3H, d, J = 7.0 Hz), 1.27 (9H, s), 0.89 (3H, d, J = 6.5 Hz), 0.84 (3H, d, J = 6.5 Hz). 13 C NMR (100 MHz, CDCl3) δ 175.0, 173.0, 168.5, 168.4, 156.8, 154.0, 139.2, 136.4, 132.9, 131.8, 129.5 (× 2), 128.5 (× 2), 128.1, 127.9 (× 2), 126.8, 124.2 (× 2), 123.0, 121.3, 119.7, 78.3, 67.0, 60.8, 56.3, 48.5, 33.3, 32.8, 30.7, 28.8 (× 3), 19.6, 17.8, 17.4. A small amount of the opposite sex: 1H NMR (400 MHz, CDCl3) δ 11.44 (1H, s), 8.65 (1H, dd, J = 8.0, 1.0 Hz), 7.51 (1H, dt, J = 8.0, 1.0 Hz), 7.43 (1H, dd, J = 8.0, 1.0 Hz), 7.36-7.28 (4H, m), 7.17 (2H, d, J = 8.5 Hz), 7.06 (1H, t, J = 7.5 Hz), 6.97-6.95 (1H, m), 6.94 (2H, d, J = 8.5 Hz), 6.51 (1H, d, J = 7.0 Hz), 6.01 (1H, d, J = 10.0 Hz), 5.13 (1H, dd, J = 11.0, 3.5 Hz), 4.87 (1H, d, J = 12.0 Hz), 4.84 (1H, d, J = 12.0 Hz), 4.56 (1H, dq, J = 7.0, 7.0 Hz), 3.97 (1H, dd, J = 10.0, 8.5 Hz), 3.60 (1H, dd, J = 14.5, 3.5 Hz), 2.89 (3H, s), 2.88 (1H, dd, J = 14.5, 11.0 Hz), 1.85 (1H, m), 1.34 (3H, d, J = 7.0 Hz), 1.31 (9H, s), 0.79 (3H, d, J = 6.5 Hz), 0.39 (3H, d, J = 6.5 Hz). 13 C NMR (100 MHz, CDCl3) δ 174.7, 173.1, 168.3, 167.8, 156.4, 154.5, 139.2, 135.9, 133.0, 131.7, 129.9 (× 2), 128.2 (× 2), 127.9 (× 2), 127.9, 127.0, 124.3 (× 2), 123.2, 121.1, 119.7, 78.4, 67.2, 63.8, 56.1, 48.4, 33.5, 30.5, 30.2, 28.7 (× 3), 19.3, 17.8, 17.7.

[0112] H-Val-NMeTyr(tBu)-Ant-Ala-OH(2a) [ka] To a suspension of 10% Pd / C (150 mg) in MeOH (7 mL) was added compound 12 (459 mg, 680 mmol). The resulting mixture was purged with H2 and stirred at room temperature for 3 h. The mixture was filtered through a pad of Celite, and the filtrate was then evaporated. The residue was triturated with diethyl ether to give compound 2a (328 mg, 92%) as an off-white foamy solid.

[0113] [α] D 23 -28 (c = 1.0, CH3OH) IR (KBr) max 2976, 2933, 1639, 1590, 1508, 1446, 1236, 1223, 1162 cm -1 . HRMS (ESI-TOF) C 29 H 41 Calculated value for N4O6: 541.3037, Found value m / z: 541.3026 [M+H] + . 11H NMR (400 MHz, CD3OD) δ 8.59 (1H, dd, J = 8.0, 1.0 Hz), 7.81 (1H, dd, J = 8.0, 1.5 Hz), 7.48 (1H, ddd, J = 8.0, 7.5, 1.5 Hz), 7.18 (2H, d, J = 8.5 Hz), 7.13 (1H, dt, J = 7.5, 1.0 Hz), 6.95 (2H, d, J = 8.5 Hz), 4.45 (1H, dd, J = 11.0, 5.0 Hz), 4.20 (1H, d, J = 2.5 Hz), 4.17 (1H, q, J = 7.5 Hz), 3.50 (1H, dd, J = 14.5, 4.5 Hz), 3.33 (1H, dd, J = 14.5, 11.0 Hz), 3.01 (3H, s), 1.82 (1H, dqq, J = 7.0, 7.0, 2.5 Hz), 1.44 (3H, d, J = 7.5 Hz), 1.32 (9H, s), 1.05 (3H, d, J = 7.0 Hz), 0.91 (3H, d, J = 7.0 Hz) 13 13C NMR (100 MHz, CD3OD) δ 181.7, 171.4, 170.3, 169.9, 155.3, 140.5, 134.6, 133.3, 130.7 (× 2), 129.1, 125.5 (× 2), 123.9, 121.1, 121.0, 79.5, 69.3, 56.8, 53.7, 39.9, 33.7, 29.7, 29.2 (× 3), 19.9, 17.1, 16.3.

[0114] Cyclo(Val-NMeTyr(tBu)-Ant-Ala)(7)

Chem.

[0115] [α] D 26 -91(c = 1.3, CHCl3) IR (KBr) max 3327, 2974, 2930, 1643, 1567, 1445, 1299, 1236, 1162 cm -1 HRMS (ESI-TOF) C 29 H 39 Calculated value for N4O5: 523.2920, Found value m / z: 523.2918 [M+H] + . 1H NMR (DMSO-d6, 400 MHz)δ 9.66 (1H, s), 8.30 (1H, dd, J = 7.5, 1.0 Hz), 8.29 (1H, d, J = 5.0 Hz), 7.57 (1H, dd, J = 7.5, 1.0 Hz), 7.56 (1H, d, J = 9.5 Hz), 7.47 (1H, dt, J = 7.5, 1.0 Hz), 7.13 (1H, dt, J = 7.5, 1.0 Hz), 7.11 (2H, d, J = 8.0 Hz), 6.86 (2H, d, J = 8.0 Hz), 4.28 (1H, dd, J = 10.5, 4.0 Hz), 4.26 (1H, dd, J = 10.0, 9.5 Hz), 3.93 (1H, dq, J = 7.0, 5.0 Hz), 3.24 (1H, dd, J = 13.5, 4.0 Hz), 3.11 (1H, dd, J = 13.5, 10.5 Hz), 2.77 (3H, s), 1.92 (1H, dqq, J = 10.0, 6.5, 6.5 Hz), 1.32 (3H, d, J = 7.0 Hz), 1.24 (9H, s), 0.78 (3H, d, J = 6.5 Hz), 0.75 (3H, d, J = 6.5 Hz) 13 C NMR (DMSO-d6, 100 MHz)δ 172.5, 170.9, 169.7, 167.9, 153.3, 136.7, 133.4, 131.1, 129.7 (× 2), 126.9, 124.4, 123.8 (× 2), 122.4, 119.9, 77.6, 67.6, 53.9, 53.2, 39.3, 32.4, 29.2, 28.5 (× 3), 19.2, 18.1, 15.5.

[0116] シクロ(Val-NMeTyr-Ant-Ala), ネクトリアタイド(1a) (Comparative Example 1)

change

[0117] [α] D 24 -97 (c 0.50, CH3OH) IR (KBr) max 3324, 2965, 1643, 1514, 1444, 1304, 1232, 1170cm -1 HRMS (ESI-TOF) C 25 H 31 Calculated value for N4O5: 467.2294, Found value: m / z: 467.2288 [M+H] + . 1H NMR (DMSO-d6, 400 MHz) δ9.63 (1H, s), 9.20 (1H, s), 8.30 (1H, d, J = 5.0 Hz), 8.29 (1H, d, J = 8.0 Hz), 7.56 (1H, dd, J = 7.5, 1.0 Hz), 7.51 (1H, d, J = 9.5 Hz), 7.47 (1H, ddd, J = 8.0, 7.0, 1.0 Hz), 7.12 (1H, t, J = 7.5 Hz), 6.98 (2H, d, J = 7.5 Hz), 6.65 (2H, d, J = 7.5 Hz), 4.31 (1H, dd, J = 10.0, 9.5 Hz), 4.17 (1H, dd, J = 10.5, 3.5 Hz), 3.93 (1H, dq, J = 7.0, 5.0 Hz), 3.17 (1H, dd, J = 13.5, 3.5 Hz), 3.00 (1H, dd, J = 13.5, 10.5 Hz), 2.79 (3H, s), 1.95 (1H, dqq, J = 10.0, 6.5, 6.5 Hz), 1.32 (3H, d, J = 7.0 Hz), 0.81 (3H, d, J = 6.5 Hz), 0.77 (3H, d, J = 6.5 Hz); 13 C NMR (DMSO-d6, 100 MHz) δ172.5, 170.9, 169.8, 168.0, 155.7, 136.8, 131.1, 130.1 (× 2), 128.6, 126.9, 124.4, 122.4, 119.9, 115.1 (× 2), 67.9, 53.9, 53.2, 39.4, 32.1, 29.3, 19.2, 18.2, 15.5.

[0118] [I-4. Synthesis of DN-メチルチロシン replacement body] HD-NMeTyr(tBu)-Ant-Ala-OMe(6e)

change

[0119] [α] D 24 +68 (c = 1.0, CHCl3). IR (KBr) max 3276, 3059, 2978, 2950, ​​2803, 1746, 1678, 1650, 1600, 1581, 1509, 1445, 1389, 1365, 1294, 1260, 1236, 1211, 1165, 897, 757cm -1 . HRMS (ESI-TOF) C 25 H 34 Calculated value for N3O5: 456.2499, Found value: m / z: 456.2508 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 11.66 (1H, s), 8.65 (1H, dd, J = 8.0, 1.0 Hz), 7.53 (1H, dd, J = 8.0, 1.0 Hz), 7.50 (1H, ddd, J = 8.0, 7.5, 1.0 Hz), 7.13 (2H, d, J = 8.5 Hz), 7.09 (1H, dt, J = 8.0, 1.0 Hz), 6.91 (2H, d, J = 8.5 Hz), 6.74 (1H, d, J = 7.0 Hz), 4.77 (1H, dq, J = 7.0, 7.0 Hz), 3.76 (3H, s), 3.28 (1H, dd, J = 10.0, 4.0 Hz), 3.21 (1H, dd, J = 13.5, 4.0 Hz), 2.71 (1H, dd, J = 13.5, 10.0 Hz), 2.32 (3H, s), 1.52 (3H, d, J = 7.0 Hz), 1.31 (9H, s). 13 C NMR (100 MHz, CDCl3) δ 173.3 (× 2), 167.9, 154.2, 138.8, 132.5, 132.3, 129.4 (× 2), 126.9, 124.3 (× 2), 122.9, 121.6, 121.3, 78.3, 67.6, 52.6, 48.3, 39.0, 35.5, 28.8 (× 3), 18.5.

[0120] Cbz-Val-D-NMeTyr(tBu)-Ant-Ala-OMe(3e, fp4-40) (Reference example 1-1) [ka] The reaction was carried out according to the procedure for the synthesis of compound 3a using compound 6e (560 mg, 1.22 mmol) and Cbz-Val-OH (360 mg, 1.22 mmol), affording compound 3e as a colorless foamy solid (726 mg, 1.05 mmol, 86%).

[0121] [α] D 24 +63 (c = 1.0, CHCl3). IR (KBr) max 3336, 2974, 2933, 2875, 1720, 1697, 1646, 1598, 1509, 1447, 1405, 1366, 1300, 1234, 1214, 1163, 1086, 1027, 897, 755 cm -1 . HRMS (ESI-TOF) C 38 H 49 Calculated value for N4O8: 689.3550, Found value m / z: 689.3535 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 11.57 (1H, s), 8.65 (1H, dd, J = 8.0, 1.0 Hz), 7.53 (1H, dd, J = 8.0, 1.0 Hz), 7.49 (1H, dt, J = 8.0, 1.0 Hz), 7.28-7.23 (5H, m), 7.11 (2H, d, J = 8.5 Hz), 7.10 (1H, dt, J = 8.0, 1.0 Hz), 6.88 (2H, d, J = 8.5 Hz), 6.85 (1H, d, J = 7.0 Hz), 5.81 (1H, d, J = 8.5 Hz), 5.69 (1H, dd, J = 11.5, 4.5 Hz), 5.11 (1H, d, J = 12.5 Hz), 5.04 (1H, d, J = 12.5 Hz), 4.70 (1H, dq, J = 7.0, 7.0 Hz), 4.58 (1H, dd, J = 8.5, 4.5 Hz), 3.70 (3H, s), 3.54 (1H, dd, J = 15.0, 4.5 Hz), 3.00 (3H, s), 2.98 (1H, dd, J = 15.0, 11.5 Hz), 1.63 (1H, m), 1.42 (3H, d, J = 7.0 Hz), 1.30 (9H, s), 0.74 (3H, d, J = 6.5 Hz), 0.64 (3H, d, J = 6.5 Hz). 13 C NMR (100 MHz, CDCl3) δ 173.4, 172.9, 168.7, 167.8, 156.3, 154.1, 139.5, 136.7, 132.9, 131.7, 129.0 (× 2), 128.3 (× 2), 127.8, 127.4 (× 2), 126.7, 124.2 (× 2), 123.0, 121.2, 119.5, 78.2, 66.4, 59.0, 56.0, 52.6, 48.3, 33.0, 31.4, 31.0, 28.7 (× 3), 19.6, 18.7, 16.4.

[0122] H-Val-D-NMeTyr(tBu)-Ant-Ala-OH(2e, fp4-51) (Reference example 1-2) [ka] The reaction was carried out according to the procedure for the synthesis of compound 2a with compound 3e (570 mg, 827 μmol). Compound 2e was obtained as a colorless foamy solid (409 mg, 756 μmol, 91%).

[0123] [α] D 24 +95 (c = 1.0, CH3OH). IR (KBr) max 3247, 2975, 2935, 2879, 1655, 1638, 1596, 1524, 1509, 1448, 1396, 1365, 1310, 1278, 1237, 1163, 1105, 897, 758 cm -1 . HRMS (ESI-TOF) C 29 H 41 Calculated value for N4O6: 541.3026, Found value m / z: 541.3028 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 8.57 (1H, dd, J = 8.0, 1.0 Hz), 7.79 (1H, dd, J = 8.0, 1.5 Hz), 7.49 (1H, dt, J = 8.0, 1.5 Hz), 7.20 (2H, d, J = 8.5 Hz), 7.17 (1H, dt, J = 8.0, 1.0 Hz), 6.91 (2H, d, J = 8.5 Hz), 5.74 (1H, dd, J = 12.5, 4.5 Hz), 4.33 (1H, d, J = 3.5 Hz), 4.09 (1H, q, J = 7.0 Hz), 3.61 (1H, dd, J = 15.0, 4.5 Hz), 3.10 (3H, s), 3.00 (1H, dd, J = 15.0, 12.5 Hz), 1.77 (1H, m), 1.44 (3H, d, J = 7.0 Hz), 1.32 (9H, s), 0.86 (3H, d, J = 7.0 Hz), 0.56 (3H, d, J = 7.0 Hz). 13 C NMR (100 MHz, CDCl3) δ 181.0, 171.8, 170.9, 169.8, 155.5, 139.6, 133.5, 133.3, 130.3 (× 2), 129.4, 125.4 (× 2), 124.6, 122.4, 121.4, 79.5, 61.2, 56.9, 53.8, 33.8, 32.1, 30.1, 29.2 (× 3), 19.1, 17.3, 16.5.

[0124] Cyclo(Val-D-NMeTyr(tBu)-Ant-Ala)(7e) [ka] The reaction was carried out using compound 2e (54.0 mg, 100 μmol) according to the procedure for the synthesis of compound 7. Compound 7e was obtained as a colorless foamy solid (28.0 mg, 53.4 μmol, 53%).

[0125] [α] D23 -5.0 (c = 1.0, CHCl3). IR (KBr) ν max 3305, 2975, 2933, 2873, 1684, 1645, 1614, 1583, 1527, 1508, 1447, 1405, 1389, 1365, 1304, 1258, 1237, 1163, 1097, 897,756cm -1 . HRMS (ESI-TOF) C 29 H 39 Calculated value of N4O5 523.2920, measured value m / z 523.2917 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.74 (1H, s), 8.46 (1H, d, J = 5.0 Hz), 8.18 (1H, dd, J = 8.0, 1.0 Hz), 8.01 (1H, d, J = 9.5 Hz), 7.46 (1H, dd, J = 8.0, 1.0 Hz), 7.45 (1H, dt, J = 8.0, 1.0 Hz), 7.16 (1H, dt, J = 8.0, 1.0 Hz), 7.14 (2H, d, J = 8.5 Hz), 6.85 (2H, d, J = 8.5 Hz), 5.36 (1H, dd, J = 12.0, 4.5 Hz), 4.26 (1H, t, J = 10.0 Hz), 3.99 (1H, dq, J = 7.0, 5.0 Hz), 3.31 (1H, dd, J = 15.0, 4.5 Hz), 3.09 (1H, dd, J = 15.0, 12.0 Hz), 2.90 (3H, s), 1.97 (1H, m), 1.34 (3H, d, J = 7.0 Hz), 1.22 (9H, s), 0.74 (3H, d, J = 6.5 Hz), 0.54 (3H, d, J = 6.5 Hz). 13C NMR (100 MHz, DMSO-d6) δ 173.0, 171.8, 168.7, 168.6, 153.3, 135.4, 132.3, 130.5, 128.8 (× 2), 127.1, 126.8, 123.7 (× 2), 123.4, 120.4, 77.6, 59.1, 54.0, 53.4, 31.9, 30.3, 29.3, 28.5 (× 3), 19.2, 18.0, 15.8.

[0126] Cyclo(Val-D-NMeTyr-Ant-Ala) (1e, fp4-56) (Reference Example 1-3) [ka] The reaction was carried out using compound 7e (54.5 mg, 104 μmol) according to the procedure for the synthesis of compound 1a. Compound 1e was obtained as a colorless foamy solid (46.6 mg, 99.9 μmol, 94%).

[0127] [α] D 23 +35.0 (c = 1.0, CH3OH). IR (KBr) max 3466, 2965, 2924, 1672, 1658, 1638, 1582, 1554, 1518, 1447, 1309, 1261, 1246, 1159, 1095, 1063, 829, 766 cm -1 . HRMS (ESI-TOF) C 25 H 31 Calculated value for N4O5: 467.2294, Found value: m / z: 467.2278 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.18 (1H, s), 8.81 (1H, s), 8.45 (1H, d, J = 5.0 Hz), 8.20 (1H, dd, J = 8.0, 1.0 Hz), 7.98 (1H, d, J = 9.5 Hz), 7.46 (1H, dd, J = 8.0, 1.0 Hz), 7.45 (1H, dt, J = 8.0, 1.0 Hz), 7.16 (1H, dt, J = 8.0, 1.0 Hz), 7.01 (2H, d, J = 8.5 Hz), 6.64 (2H, d, J = 8.5 Hz), 5.23 (1H, dd, J = 11.5, 4.5 Hz), 4.29 (1H, t, J = 10.0 Hz), 3.98 (1H, dq, J = 7.0, 5.0 Hz), 3.22 (1H, dd, J = 15.0, 4.5 Hz), 3.03 (1H, dd, J = 15.0, 11.5 Hz), 2.91 (3H, s), 1.99 (1H, m), 1.34 (3H, d, J = 7.0 Hz), 0.76 (3H, d, J = 6.5 Hz), 0.61 (3H, d, J = 6.5 Hz). 13 C NMR (100 MHz, DMSO-d6) δ 172.9, 171.9, 169.0, 168.8, 155.7, 135.5, 130.6, 129.0 (× 2), 127.5, 126.7 (× 2), 123.3, 120.3, 115.1 (× 2), 59.4, 54.0, 53.4, 31.9, 30.3, 29.3, 19.3, 18.0, 15.8.

[0128] [I-5. Synthesis of L-チロシン replacement body] H-Tyr(tBu)-Ant-Ala-OMe(6c)

change

[0129] [α] D 24 -40 (c = 1.0, CHCl3). IR (KBr) max 3294, 2978, 2950, ​​2933, 1743, 1648, 1600, 1582, 1508, 1446, 1365, 1295, 1260, 1235, 1213, 1164, 1109, 1053, 897, 839, 757cm -1 . HRMS (ESI-TOF) C 24 H 32 Calculated value for N3O5: 442.2342, Found value m / z: 442.2342 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 11.71 (1H, s), 8.66 (1H, dd, J = 8.5, 1.0 Hz), 7.55 (1H, dd, J = 8.0, 1.0 Hz), 7.45 (1H, ddd, J = 8.5, 8.0, 1.0 Hz), 7.14 (2H, d, J = 8.0 Hz), 7.10 (1H, dt, J = 8.5, 1.0 Hz), 6.92 (2H, d, J = 8.0 Hz), 6.78 (1H, d, J = 7.0 Hz), 4.79 (1H, dq, J = 7.0, 7.0 Hz), 3.79 (3H, s), 3.70 (1H, dd, J = 9.5, 4.0 Hz), 3.28 (1H, dd, J = 13.5, 4.0 Hz), 2.76 (1H, dd, J = 13.5, 9.5 Hz), 1.51 (3H, d, J = 7.0 Hz), 1.31 (9H, s). 13C NMR (100 MHz, CDCl3) δ 173.8, 173.3, 167.9, 154.2, 138.8, 132.6 (× 2), 129.7 (× 2), 126.9, 124.3 (× 2), 123.0, 121.5, 121.1, 78.3, 57.9, 52.6, 48.4, 40.5, 28.8 (× 3), 18.5.

[0130] Cbz-Val-Tyr(tBu)-Ant-Ala-OMe(3c, fp3-47) (Reference example 2-1) [ka] Following the procedure for the synthesis of compound 3a, the reaction was carried out using compound 6c (211 mg, 477 μmol) and Cbz-Val-OH (132 mg, 525 μmol). Compound 3c was obtained as a colorless foamy solid (317 mg, 469 μmol, 98%).

[0131] [α] D 24 -12 (c = 1.0, CHCl3). IR (KBr) max 3315, 2975, 2930, 1726, 1702, 1650, 1602, 1588, 1508, 1447, 1389, 1365, 1345, 1293, 1235, 1214, 1163, 1101, 898, 757 cm -1 . HRMS (ESI-TOF) C 37 H 47 Calculated value for N4O8: 675.3393, Found value m / z: 675.3378 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 11.17 (1H, s), 8.48 (1H, dd, J = 8.0, 1.0 Hz), 7.52 (1H, dd, J = 8.0, 1.5 Hz), 7.46 (1H, dt, J = 8.0, 1.5 Hz), 7.38-7.28 (5H, m), 7.10 (1H, dt, J = 8.0, 1.0 Hz), 7.06 (2H, d, J = 8.5 Hz), 6.83 (2H, d, J = 8.5 Hz), 6.81 (1H, d, J = 7.0 Hz), 6.60 (1H, d, J = 7.5 Hz), 5.29 (1H, d, J = 8.0 Hz), 5.13 (1H, d, J = 12.5 Hz), 5.08 (1H, d, J = 12.5 Hz), 4.80 (1H, dt, J = 7.5, 6.5 Hz), 4.71 (1H, dq, J = 7.0, 7.0 Hz), 4.07 (1H, dt, J = 8.0, 6.5 Hz), 3.79 (3H, s), 3.16 (1H, dd, J = 13.5, 6.5 Hz), 3.09 (1H, dd, J = 13.5, 6.5 Hz), 2.15 (1H, m), 1.50 (3H, d, J = 7.0 Hz), 1.25 (9H, s), 0.92 (3H, d, J = 6.5 Hz), 0.84 (3H, d, J = 6.5 Hz). 13 C NMR (100 MHz, CDCl3) δ 173.4, 170.9, 169.3, 167.9, 156.3, 154.3, 138.8, 136.3, 132.8, 130.8, 129.7 (× 2), 128.5 (× 2), 128.1, 128.0 (× 2), 126.8, 124.3 (× 2), 123.3, 121.6, 120.1, 78.3, 67.1, 60.3, 55.6, 52.7, 48.5, 38.1, 30.8, 28.7 (× 3), 19.3, 18.2, 17.5.

[0132] H-Val-Tyr(tBu)-Ant-Ala-OH(2c, fp3-49) (Reference Example 2-2) [ka] Following the synthesis procedure of compound 2a, the reaction was carried out with compound 3c (258 mg, 381 μmol). Compound 2c was obtained as a colorless foamy solid (172 mg, 326 μmol, 86%).

[0133] [α] D 23 -23 (c = 1.0, CH3OH). IR (KBr) max 3434, 2971, 2920, 1639, 1596, 1509, 1447, 1402, 1364, 1239, 1161, 1063, 897, 759 cm -1 . HRMS (ESI-TOF) C 28 H 39 Calculated value for N4O6: 527.2869, Found value m / z: 527.2858 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 8.49 (1H, dd, J = 8.0, 1.0 Hz), 7.75 (1H, dd, J = 8.0, 1.5 Hz), 7.46 (1H, ddd, J = 8.0, 7.5, 1.5 Hz), 7.19 (2H, d, J = 8.5 Hz), 7.15 (1H, dt, J = 7.5, 1.0 Hz), 6.91 (2H, d, J = 8.5 Hz), 4.45 (1H, dd, J = 10.5, 5.0 Hz), 4.27 (1H, q, J = 7.0 Hz), 3.64 (1H, d, J = 4.5 Hz), 3.38 (1H, dd, J = 14.5, 5.0 Hz), 3.18 (1H, dd, J = 14.5, 10.5 Hz), 2.01 (1H, dqq, J = 7.0, 7.0, 4.5 Hz), 1.45 (3H, d, J = 7.0 Hz), 1.29 (9H, s), 0.90 (3H, d, J = 7.0 Hz), 0.78 (3H, d, J = 7.0 Hz). 13 C NMR (100 MHz, CD3OD) δ 180.4, 172.3, 171.4, 170.3, 155.3, 139.6, 134.1, 133.0, 130.7 (× 2), 129.1, 125.4 (× 2), 124.5, 122.9, 121.6, 79.5, 60.4, 58.3, 53.0, 36.2, 31.7, 29.1 (× 3), 19.3, 18.1, 17.4.

[0134] Cyclo(Val-Tyr(tBu)-Ant-Ala)(7c) [ka] The reaction was carried out using compound 2c (45.0 mg, 85.4 μmol) according to the procedure for the synthesis of compound 7. Compound 7c was obtained as a colorless foamy solid (29.5 mg, 58.0 μmol, 70%).

[0135] [α] D23 -72 (c = 1.0, CH3OH). IR (KBr) ν max 3303, 2973, 2930, 1646, 1584, 1534, 1508, 1445, 1364, 1296, 1236, 1163, 899, 755 cm -1 . HRMS (ESI-TOF) C 28 H 37 Calculated for C 28 H 37 N4O5 509.2763, found m / z 509.2748 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.57 (1H, s), 8.94 (1H, d, J = 7.0 Hz), 8.57 (1H, d, J = 5.0 Hz), 8.26 (1H, brd, J = 8.0 Hz), 7.51 (1H, dd, J = 7.5, 1.5 Hz), 7.46 (1H, dt, J = 7.5, 1.5 Hz), 7.19 (1H, d, J = 9.0 Hz), 7.13 (1H, dt, J = 7.5, 1.0 Hz), 7.08 (2H, d, J = 8.0 Hz), 6.81 (2H, d, J = 8.0 Hz), 4.20 (1H, ddd, J = 10.5, 7.0, 4.5 Hz), 3.91 (1H, dq, J = 7.0, 5.0 Hz), 3.83 (1H, dd, J = 10.0, 9.0 Hz), 3.27 (1H, dd, J = 14.5, 4.5 Hz), 2.93 (1H, dd, J = 14.5, 10.5 Hz), 1.72 (1H, dqq, J = 10.0, 6.5, 6.5 Hz), 1.33 (3H, d, J = 7.0 Hz), 1.24 (9H, s), 0.73 (3H, d, J = 6.5 Hz), 0.61 (3H, d, J = 6.5 Hz). 13C NMR (100 MHz, DMSO-d6) δ 172.7, 171.0, 169.3, 169.2, 153.1, 136.5, 133.3, 130.8, 129.6 (× 2), 127.0, 125.3, 123.5 (× 2), 122.6, 120.5, 77.5, 59.1, 55.5, 53.3, 33.6, 29.8, 28.5 (× 3), 18.9, 18.6, 15.7.

[0136] Cyclo(Val-Tyr-Ant-Ala) (1c, fp3-99) (Reference Example 2-3) [ka] The reaction was carried out according to the procedure for the synthesis of compound 1a with compound 7c (27.5 mg, 54.0 μmol). Compound 1c was obtained as a colorless foamy solid (21.6 mg, 47.7 μmol, 89%).

[0137] [α] D 25 -105 (c = 0.50, DMSO). IR (KBr) max 3292, 3069, 2966, 2933, 1658, 1642, 1600, 1585, 1534, 1517, 1446, 1384, 1371, 1342, 1308, 1267, 1230, 1172, 1103, 902, 756 cm -1 . HRMS (ESI-TOF) C 24 H 29 Calculated value for N4O5: 453.2137, Found value m / z: 453.2134 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.55 (1H, s), 9.10 (1H, s), 8.89 (1H, d, J = 7.0 Hz), 8.55 (1H, d, J = 5.0 Hz), 8.25 (1H, dd, J = 8.0, 1.0 Hz), 7.51 (1H, dd, J = 8.0, 1.5 Hz), 7.45 (1H, dt, J = 8.0, 1.5 Hz), 7.17 (1H, d, J = 9.0 Hz), 7.13 (1H, dt, J = 8.0, 1.0 Hz), 6.96 (2H, d, J = 8.0 Hz), 6.62 (2H, d, J = 8.0 Hz), 4.07 (1H, ddd, J = 10.0, 7.0, 4.0 Hz), 3.88 (1H, dq, J = 7.0, 5.0 Hz), 3.87 (1H, dd, J = 10.0, 9.0 Hz), 3.21 (1H, dd, J = 14.0, 4.0 Hz), 2.82 (1H, dd, J = 14.0, 10.0 Hz), 1.75 (1H, m), 1.32 (3H, d, J = 7.0 Hz), 0.75 (3H, d, J = 6.5 Hz), 0.70 (3H, d, J = 6.5 Hz). 13 C NMR (100 MHz, DMSO-d6) δ 172.7, 171.0, 169.4, 169.1, 155.5, 136.6, 130.9, 130.0 (× 2), 128.8, 127.0, 125.2, 122.6, 120.6, 114.9 (× 2), 59.1, 56.1, 53.3, 33.4, 29.9, 19.0, 18.6, 15.7.

[0138] [I-6. LN-メチルフェニルアラニン replacement body synthesis] H-NMePhe-Ant-Ala-OMe(6b)

change

[0139] [α] D 23 -53 (c = 1.0, CHCl3). IR (KBr) ν max 3290, 2935, 2850, 1744, 1648, 1597, 1582, 1512, 1444, 1354, 1294, 1265, 1211, 1168,1139 758, 701 cm -1 . HRMS (ESI-TOF) C 21 H 26 Calculated value of N3O4 is 384.1923, measured value m / z 384.1917 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 11.64 (1H, s), 8.64 (1H, dd, J = 8.0, 1.0 Hz), 7.54 (1H, dd, J = 8.5, 1.0 Hz), 7.48 (1H, ddd, J = 8.5, 8.0, 1.0 Hz), 7.31-7.19 (5H, m), 7.09 (1H, dt, J = 8.0, 1.0 Hz), 6.83 (1H, d, J = 7.0 Hz), 4.78 (1H, dq, J = 7.0, 7.0 Hz), 3.79 (3H, s), 3.32 (1H, dd, J = 10.0, 4.0 Hz), 3.25 (1H, dd, J = 13.5, 4.0 Hz), 2.76 (1H, dd, J = 13.5, 10.0 Hz), 2.33 (3H, s), 1.50 (3H, d, J = 7.0 Hz). 13C NMR (100 MHz, CDCl3) δ 173.2, 173.1, 167.8, 138.6, 137.6, 132.4, 129.0 (× 2), 128.6 (× 2), 126.8, 126.7, 123.0, 121.7, 121.5, 67.6, 52.6, 48.3, 39.7, 35.5, 18.5.

[0140] Cbz-Val-NMePhe-Ant-Ala-OMe (3b, fp3-58) (Example 1-1) [ka] Following the procedure for the synthesis of compound 3a, the reaction was carried out using compound 6b (237 mg, 618 μmol) and Cbz-Val-OH (155 mg, 618 μmol). Compound 3b was obtained as a colorless foamy solid (228 mg, 369 μmol, 60%).

[0141] [α] D 23 -94 (c = 1.0, CHCl3). IR (KBr) max 3323, 2960, 2933, 1742, 1717, 1703, 1646, 1600, 1586, 1518, 1447, 1405, 1351, 1297, 1265, 1218, 1170, 1087, 1027, 754, 699cm -1 . HRMS (ESI-TOF) C 34 H 41 Calculated value for N4O7: 617.2975, Found value m / z: 617.2968 [M+H] + . A 2.7:1 rotamer ratio was observed by NMR. Major rotamers: 1H NMR (400 MHz, CDCl3) δ 11.39 (1H, s), 8.61 (1H, dd, J = 8.0, 1.0 Hz), 7.52 (1H, dd, J = 8.0, 1.0 Hz), 7.48 (1H, dt, J = 8.0, 1.0 Hz), 7.40-7.25 (5H, m), 7.24-7.16 (4H, m), 7.14-7.04 (2H, m), 6.89 (1H, d, J = 7.0 Hz), 5.52 (1H, dd, J = 9.5, 6.0 Hz), 5.21 (1H, d, J = 9.5 Hz), 5.07 (2H, s), 4.69 (1H, dq, J = 7.0, 7.0 Hz), 4.41 (1H, dd, J = 9.5, 5.0 Hz), 3.78 (3H, s), 3.53 (1H, dd, J = 14.0, 6.0 Hz), 3.01 (3H, s), 2.98 (1H, dd, J = 14.0, 9.5 Hz), 2.13 (1H, m), 1.47 (3H, d, J = 7.0 Hz), 0.98 (3H, d, J = 6.5 Hz), 0.87 (3H, d, J = 6.5 Hz). 13 C NMR (100 MHz, CDCl3) δ 173.3, 172.7, 168.7, 167.9, 156.1, 139.4, 137.1, 136.5, 132.9, 129.0 (× 2), 128.5 (× 2), 128.3 (× 2), 128.1, 127.9 (× 2), 126.7, 126.5, 123.1, 121.5, 119.7, 66.7, 60.2, 55.7, 52.7, 48.3, 34.1, 32.3, 30.6, 19.9, 18.3, 16.9. A small amount of the opposite sex: 11H NMR (400 MHz, CDCl3) δ 11.32 (1H, s), 8.68 (1H, dd, J = 8.0, 1.0 Hz), 7.53 (1H, dt, J = 8.0, 1.0 Hz), 7.43 (1H, dd, J = 8.0, 1.0 Hz), 7.40 - 7.25 (3H, m), 7.24 - 7.16 (4H, m), 7.14 - 7.04 (2H, m), 6.91 (2H, d, J = 7.5 Hz), 6.45 (1H, d, J = 7.0 Hz), 5.74 (1H, d, J = 10.0 Hz), 4.95 (1H, dd, J = 11.0, 3.0 Hz), 4.81 (2H, s), 4.57 (1H, dq, J = 7.0, 7.0 Hz), 3.79 (1H, dd, J = 10.0, 6.0 Hz), 3.77 (3H, s), 3.63 (1H, dd, J = 14.0, 3.0 Hz), 2.94 (1H, dd, J = 14.0, 11.0 Hz), 2.91 (3H, s), 1.82 (1H, m), 1.29 (3H, d, J = 7.0 Hz), 0.75 (3H, d, J = 6.5 Hz), 0.38 (3H, d, J = 6.5 Hz). 13 13C NMR (100 MHz, CDCl3) δ 173.3, 171.6, 168.3, 168.2, 156.2, 139.1, 137.4, 135.8, 133.0, 129.3 (× 2), 128.8 (× 2), 128.2 (× 2), 128.1 (× 2), 127.9, 127.1, 126.9, 123.2, 121.0, 119.9, 67.2, 63.5, 55.7, 52.7, 48.3, 34.1, 30.3, 30.0, 19.3, 17.9, 17.5.

[0142] H-Val-NMePhe-Ant-Ala-OH (2h, fp3 - 61) (Example 1 - 2)

Chem.

[0143] [α] D 23 -16 (c = 1.0, CH3OH). IR (KBr) max 3380, 2971, 2940, 1634, 1597, 1522, 1447, 1399, 1361, 1310, 1173, 1080, 756, 701 cm -1 . HRMS (ESI-TOF) C 25 H 33 Calculated value for N4O5: 469.2450, Found value: m / z: 469.2448 [M+H] + . A 7.3:1 rotamer ratio was observed by NMR. Major rotamers: 1 H NMR (400 MHz, CD3OD) δ 8.59 (1H, dd, J = 8.0, 1.0 Hz), 7.81 (1H, dd, J = 8.0, 1.0 Hz), 7.48 (1H, dt, J = 8.0, 1.0 Hz), 7.35-7.24 (5H, m), 7.13 (1H, dt, J = 8.0, 1.0 Hz), 4.45 (1H, dd, J = 11.0, 4.5 Hz), 4.20 (1H, d, J = 2.5 Hz), 4.15 (1H, q, J = 7.5 Hz), 3.55 (1H, dd, J = 14.5, 4.5 Hz), 3.34 (1H, dd, J = 14.5, 11.0 Hz), 2.99 (3H, s), 1.84 (1H, m), 1.46 (3H, d, J = 7.5 Hz), 1.08 (3H, d, J = 7.5 Hz), 0.91 (3H, d, J = 7.5 Hz). 13C NMR (100 MHz, CD3OD) δ 181.6, 171.5, 170.3, 169.9, 140.5, 139.6, 133.3, 130.2 (× 2), 129.6 (× 2), 129.1, 127.8, 123.9, 121.1, 121.0, 69.4, 56.9, 53.7, 39.9, 34.4, 29.6, 19.9, 17.1, 16.2. A small amount of the opposite sex: 1 H NMR (400 MHz, CD3OD) δ 8.33 (1H, dd, J = 8.0, 1.0 Hz), 7.76 (1H, dd, J = 8.0, 1.0 Hz), 7.50 (1H, dt, J = 8.0, 1.0 Hz), 7.35-7.24 (5H, m), 7.20 (1H, dt, J = 8.0, 1.0 Hz), 4.71 (1H, dd, J = 9.0, 4.5 Hz), 4.35 (1H, d, J = 3.0 Hz), 4.16 (1H, q, J = 7.5 Hz), 3.48 (1H, dd, J = 14.0, 4.5 Hz), 3.16 (1H, dd, J = 14.0, 9.0 Hz), 3.07 (3H, s), 1.84 (1H, m), 1.46 (3H, d, J = 7.5 Hz), 1.08 (3H, d, J = 7.5 Hz), 1.01 (1H, m), 0.54 (3H, d, J = 7.5 Hz). 13 C NMR (100 MHz, CD3OD) δ 180.0, 170.8, 170.7, 168.8, 139.2, 138.7, 133.1, 130.6 (× 2), 130.0 (× 2), 129.3, 128.3, 125.1, 122.5, 121.0, 64.8, 56.8, 53.2, 35.4, 30.7, 29.7, 19.6, 17.7, 15.6.

[0144] シクロ(Val-NMePhe-Ant-Ala) (1b, fp3-90) (Example 1-3)

change

[0145] [α] D 26 -101 (c = 1.0, CHCl3). IR (KBr) max 3322, 2963, 2872, 1694, 1644, 1599, 1584, 1521, 1444, 1412, 1387, 1341, 1299, 1169, 1099, 753, 701 cm -1 . HRMS (ESI-TOF) C 25 H 31 Calculated value for N4O4: 451.2345, Found value: m / z: 451.2338 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 9.51 (1H, s), 8.17 (1H, dd, J = 8.0, 1.0 Hz), 7.28 (1H, dd, J = 8.0, 1.5 Hz), 7.24 (1H, dt, J = 8.0, 1.5 Hz), 7.16-7.03 (5H, m), 6.96 (1H, d, J = 3.5 Hz), 6.91 (1H, dt, J = 8.0, 1.0 Hz), 6.02 (1H, d, J = 9.5 Hz), 4.31 (1H, t, J = 9.5 Hz), 3.86 (1H, dq, J = 7.0, 3.5 Hz), 3.65 (1H, dd, J = 10.5, 3.5 Hz), 3.45 (1H, dd, J = 14.0, 3.5 Hz), 3.04 (1H, dd, J = 14.0, 10.5 Hz), 2.69 (3H, s), 1.74 (1H, m), 1.14 (3H, d, J = 7.0 Hz), 0.71 (3H, d, J = 6.5 Hz), 0.68 (3H, d, J = 6.5 Hz). 13 C NMR (100 MHz, CDCl3) δ 172.9, 171.8, 170.2, 167.5, 138.7, 136.8, 131.9, 129.2 (× 2), 128.6 (× 2), 126.7, 126.0, 123.8, 123.0, 122.2, 69.5, 54.9, 53.6, 40.0, 33.8, 30.6, 19.3, 18.2, 16.0.

[0146] [I-7. LN-メチルアラニン replacement body synthesis] H-NMeAla-Ant-Ala-OMe(6h)

change

[0147] [α] D 23 -27 (c = 1.0, CHCl3). IR (KBr) max 758 cm -1 . HRMS (ESI-TOF) C 15 H 22 Calculated value for N3O4: 308.1610, Found value m / z: 308.1610 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 11.59 (1H, s), 8.62 (1H, dd, J = 8.0, 1.0 Hz), 7.53 (1H, dd, J = 8.0, 1.0 Hz), 7.47 (1H, dt, J = 8.0, 1.0 Hz), 7.08 (1H, dt, J = 8.0, 1.0 Hz), 6.82 (1H, d, J = 7.0 Hz), 4.79 (1H, dq, J = 7.0, 7.0 Hz), 3.78 (3H, s), 3.18 (1H, q, J = 7.0 Hz), 2.44 (3H, s), 1.51 (3H, d, J = 7.0 Hz), 1.36 (3H, d, J = 7.0 Hz). 13 C NMR (100 MHz, CDCl3) δ 174.4, 173.3, 168.0, 138.9, 132.5, 126.8, 122.9, 121.6, 121.2, 61.5, 52.6, 48.4, 35.2, 19.8, 18.5.

[0148] Cbz-Val-NMeAla-Ant-Ala-OMe(3h,fp3-68) (Example 2-1) [ka] Following the procedure for the synthesis of compound 3a, the reaction was carried out using compound 6h (120 mg, 390 μmol) and Cbz-Val-OH (163 mg, 429 μmol). Compound 3h was obtained as a colorless foamy solid (161 mg, 298 μmol, 76%).

[0149] [α] D 24 -37 (c = 1.0, CHCl3). IR (KBr) max 3314, 2961, 2875, 1742, 1701, 1645, 1600, 1586, 1518, 1447, 1407, 1351, 1293, 1262, 1217, 1170, 1087, 1026, 980, 755, 698cm -1 . HRMS (ESI-TOF) C 28 H 37 Calculated value for N4O7: 541.2662, Found value: m / z: 541.2658 [M+H] + . 11H NMR (400 MHz, CDCl3) δ 11.29 (1H, s), 8.58 (1H, dd, J = 8.0, 1.0 Hz), 7.54 (1H, dd, J = 8.0, 1.0 Hz), 7.47 (1H, dt, J = 8.0, 1.0 Hz), 7.36 - 7.34 (4H, m), 7.32 (1H, m), 7.10 (1H, dt, J = 8.0, 1.0 Hz), 6.83 (1H, d, J = 7.0 Hz), 5.60 (1H, d, J = 9.0 Hz), 5.35 (1H, q, J = 7.0 Hz), 5.12 (1H, d, J = 12.0 Hz), 5.07 (1H, d, J = 12.0 Hz), 4.71 (1H, dq, J = 7.0, 7.0 Hz), 4.60 (1H, dd, J = 9.0, 5.0 Hz), 3.79 (3H, s), 3.06 (3H, s), 2.26 (1H, m), 1.50 (3H, d, J = 7.0 Hz), 1.46 (3H, d, J = 7.0 Hz), 1.04 (3H, d, J = 7.0 Hz), 0.92 (3H, d, J = 7.0 Hz). 13 13C NMR (100 MHz, CDCl3) δ 173.2, 172.8, 169.7, 168.0, 156.5, 139.4, 136.4, 132.9, 128.5 (× 2), 128.0, 127.9 (× 2), 126.7, 123.0, 121.5, 119.7, 66.8, 55.9, 54.3, 52.7, 48.4, 31.3, 30.7, 19.9, 18.3, 16.8, 13.8.

[0150] H-Val-NMeAla-Ant-Ala-OH (2h, fp3 - 72) (Example 2 - 2)

Chem.

[0151] [α] D 25 -66 (c = 1.0, CH3OH). IR (KBr) max 3391, 2974, 2937, 1642, 1597, 1521, 1402, 1363, 1312, 1278, 1242, 1172, 1092, 930, 893, 759 cm -1 . HRMS (ESI-TOF) C 19 H 29 Calculated value for N4O5: 393.2127, Measured value m / z: 393.2133 [M+H] + . A 5.6:1 rotamer ratio was observed by NMR. Major rotamers: 1 H NMR (400 MHz, CD3OD) δ 8.51 (1H, dd, J = 8.0, 1.0 Hz), 7.78 (1H, dd, J = 8.0, 1.0 Hz), 7.46 (1H, dt, J = 8.0, 1.0 Hz), 7.13 (1H, dt, J = 8.0, 1.0 Hz), 4.32 (1H, d, J = 3.5 Hz), 4.22 (1H, q, J = 7.0 Hz), 4.20 (1H, q, J = 7.0 Hz), 3.33 (3H, s), 2.33 (1H, m), 1.50 (3H, d, J = 7.0 Hz), 1.45 (3H, d, J = 7.0 Hz), 1.17 (3H, d, J = 7.0 Hz), 0.97 (3H, d, J = 7.0 Hz). 13C NMR (100 MHz, CDCl3) δ 181.3, 171.2, 170.9, 170.3, 140.2, 133.1, 129.0, 123.9, 121.8, 121.1, 62.2, 56.8, 53.5, 37.4, 30.0, 19.5, 17.4, 16.3, 12.9. Minor rotamers: 1 H NMR (400 MHz, CD3OD) δ 8.30 (1H, dd, J = 8.0, 1.0 Hz), 7.67 (1H, dd, J = 8.0, 1.0 Hz), 7.47 (1H, dt, J = 8.0, 1.0 Hz), 7.19 (1H, dt, J = 8.0, 1.0 Hz), 4.46 (1H, d, J = 4.0 Hz), 4.41 (1H, q, J = 7.0 Hz), 3.97 (1H, q, J = 7.0 Hz), 2.90 (3H, s), 2.20 (1H, m), 1.52 (3H, d, J = 7.0 Hz), 1.45 (3H, d, J = 7.0 Hz), 1.15 (3H, d, J = 7.0 Hz), 1.03 (3H, d, J = 7.0 Hz). 13 C NMR (100 MHz, CD3OD) δ 179.7, 170.9 (× 2), 170.0, 138.8, 132.6, 128.9, 125.0 (× 2), 122.7, 57.8, 56.9, 53.0, 37.4, 31.3, 19.5, 17.7, 16.9, 15.3.

[0152] Cyclo(Val-NMeAla-Ant-Ala) (1h, fp3-125) (Example 2-3) [ka] The reaction was carried out using compound 2h (78.5 mg, 200 μmol) according to the synthesis procedure of compound 7. Compound 1h was obtained as a colorless foamy solid (18.1 mg, 48.3 μmol, 24%).

[0153] [α] D 25 -1.4 (c = 0.5, CH3OH). IR (KBr) ν max 3317, 2940, 2914, 1697, 1664, 1639, 1601, 1581, 1540, 1509, 1442, 1384, 1309, 1292, 1236, 1217, 1156, 679, 657 cm -1 . HRMS (ESI-TOF) C 19 H 27 Calculated value of N4O4 is 375.2032, measured value m / z 375.2025 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.69 (1H, s), 8.36 (1H, d, J = 5.0 Hz), 8.23 ​​(1H, dd, J = 8.0, 1.0 Hz), 7.56 (1H, dd, J = 8.0, 1.5 Hz), 7.45 (1H, dt, J = 8.0, 1.5 Hz), 7.35 (1H, d, J = 10.0 Hz), 7.11 (1H, dt, J = 8.0, 1.5 Hz), 4.45 (1H, t, J = 10.0 Hz), 3.97 (1H, q, J = 6.5 Hz), 3.94 (1H, dq, J = 7.0, 5.0 Hz), 3.26 (3H, s), 1.88 (1H, m), 1.34 (3H, d, J = 7.0 Hz), 1.30 (3H, d, J = 6.5 Hz), 0.80 (3H, d, J = 6.5 Hz), 0.76 (3H, d, J = 6.5 Hz). 13 C NMR (100 MHz, DMSO-d6) δ 172.8, 171.0, 169.7, 168.7, 137.0, 131.1, 127.0, 124.3, 122.3, 120.1, 60.9, 53.8, 53.3, 37.8, 29.8, 18.8, 18.2, 15.5, 12.6.

[0154] [I-8. Synthesis of L-alanine substitutes] Boc-Ala-Ala-OMe(4g) [ka] The reaction was carried out according to the synthesis method of compound 4 using Boc-Ala-OH (378 mg, 2.00 mmol) and HCl·H-Ala-OMe (279 mg, 2.00 mmol), to obtain compound 4g as a colorless foamy solid (433 mg, 1.58 mmol, 79%).

[0155] [α] D 25 -30 (c = 1.0, CHCl3). IR (KBr) max 3311, 3078, 2979, 2937, 1745, 1663, 1526, 1454, 1366, 1309, 1249, 1212, 1165, 1070, 1053, 1021, 985, 781, 756 cm -1 . HRMS (ESI-TOF) C 12 H 23 Calculated value for N2O5: 275.1607, Measured value m / z: 275.1599 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 6.67 (1H, brd, J = 7.0 Hz), 5.04 (1H, brs), 4.56 (1H, dq, J = 7.0, 7.0 Hz), 4.17 (1H, brs), 3.74 (3H, s), 1.44 (9H, s), 1.39 (3H, d, J = 7.0 Hz), 1.35 (3H, d, J = 7.0 Hz). 13 C NMR (100 MHz, CDCl3) δ 173.2, 172.2, 155.4, 80.1, 52.4, 50.0, 48.0, 28.3 (× 3), 18.3, 18.2.

[0156] HCl·H-Ala-Ala-OMe(5g) [ka] Compound 4g (400 mg, 1.45 mmol) was treated with 4N hydrochloric acid in dioxane for 1 h at 0° C. After removal of the solvent, the residue was triturated with diethyl ether to give compound 5g (287 mg, 1.45 mmol, 93%) as a colorless foamy solid.

[0157] [α] D 25 -33 (c = 1.0, CH3OH). IR (KBr) max 3435, 3222, 3068, 2996, 2956, 1736, 1677, 1560, 1459, 1293, 1222, 1162, 1126, 1055 cm -1 . HRMS (ESI-TOF) C7H 15 Calculated value for N2O3: 175.1082, Measured value m / z: 175.1081 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 4.46 (1H, q, J = 7.0 Hz), 3.97 (1H, q, J = 7.0 Hz), 3.72 (3H, s), 1.53 (3H, d, J = 7.0 Hz), 1.42 (3H, d, J = 7.0 Hz). 13 C NMR (100 MHz, CD3OD) δ 174.2, 170.9, 52.8, 50.1, 49.5, 17.5, 17.3.

[0158] H-NMeTyr(tBu)-Ala-Ala-OMe (6g) [ka] Following the procedure for the synthesis of compound 6, the reaction was carried out using compound 5g (280 mg, 1.32 mmol) and Fmoc-NMeTyr(tBu)-OH (550 mg, 1.16 mmol). Compound 6g was obtained as a colorless foamy solid (383 mg, 940 μmol, 88%).

[0159] [α] D 25 -68 (c = 1.0, CHCl3). IR (KBr) max 3303, 2978, 2934, 1746, 1648, 1507, 1452, 1365, 1236, 1209, 1164, 897 cm -1 . HRMS (ESI-TOF) C 21 H 34 Calculated value for N3O5: 408.2498, Found value m / z: 408.2492 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.64 (1H, d, J = 8.0 Hz), 7.07 (2H, d, J = 8.5 Hz), 6.91 (2H, d, J = 8.5 Hz), 6.86 (1H, d, J = 7.0 Hz), 4.53 (1H, dq, J = 7.0, 7.0 Hz), 4.50 (1H, dq, J = 8.0, 7.0 Hz), 3.73 (3H, s), 3.19 (1H, dd, J = 9.0, 4.0 Hz), 3.11 (1H, dd, J = 14.0, 4.0 Hz), 2.67 (1H, dd, J = 14.0, 9.0 Hz), 2.28 (3H, s), 1.39 (3H, d, J = 7.0 Hz), 1.36 (3H, d, J = 7.0 Hz), 1.32 (9H, s). 13C NMR (100 MHz, CDCl3) δ 173.8, 173.1, 171.7, 154.3, 131.9, 129.4 (× 2), 124.3 (× 2), 78.4, 65.9, 52.4, 48.1 (× 2), 38.3, 35.5, 28.8 (× 3), 18.2, 17.7.

[0160] Cbz-Val-NMeTyr(tBu)-Ala-Ala-OMe (3g, fp3-78) (Example 3-1) (SEQ ID NO: 1) [ka] Following the synthesis procedure of compound 3a, the reaction was carried out using compound 6g (350 mg, 858 μmol) and Cbz-Val-OH (216 mg, 858 μmol), to obtain compound 3g as a colorless foamy solid (402 mg, 627 μmol, 73%).

[0161] [α] D 25 -97 (c = 1.0, CHCl3). IR (KBr) max 3303, 2976, 2933, 2872, 1739, 1719, 1658, 1632, 1527, 1508, 1454, 1366, 1297, 1252, 1236, 1214, 1163, 1026, 897, 698 cm -1 . HRMS (ESI-TOF) C 34 H 48 Calculated value for N4O8: 641.3550, Found value m / z: 641.3541 [M+H] + . A 1.6:1 rotamer ratio was observed by NMR. Major rotamers: 1H NMR (400 MHz, CDCl3) δ 7.36-7.27 (5H, m), 7.07 (2H, d, J = 8.5 Hz), 6.86 (2H, d, J = 8.5 Hz), 6.68 (1H, d, J = 7.5 Hz), 6.60 (1H, d, J = 7.5 Hz), 5.50 (1H, d, J = 9.0 Hz), 5.11 (1H, d, J = 12.0 Hz), 5.08 (1H, dd, J = 8.0, 7.5 Hz), 5.02 (1H, d, J = 12.0 Hz), 4.50 (1H, dq, J = 7.0, 7.0 Hz), 4.40 (1H, dd, J = 9.0, 6.5 Hz), 4.37 (1H, dq, J = 7.0, 7.0 Hz), 3.71 (3H, s), 3.29 (1H, dd, J = 14.0, 7.5 Hz), 3.02 (3H, s), 2.95 (1H, dd, J = 14.0, 8.0 Hz), 1.93 (1H, m), 1.34 (3H, d, J = 7.0 Hz), 1.29 (3H, d, J = 7.0 Hz), 1.28 (9H, s), 0.93 (3H, d, J = 6.5 Hz), 0.90 (3H, d, J = 7.0 Hz). 13 C NMR (100 MHz, CDCl3) δ 173.1, 172.8, 171.1, 169.5, 156.4, 154.1, 136.3, 131.5, 129.3 (× 2), 128.5 (× 2), 128.1, 128.0 (× 2), 124.2 (× 2), 78.3, 66.9, 59.3, 55.9, 52.4, 48.9, 48.0, 33.2, 32.6, 30.9, 28.8 (× 3), 19.5, 18.1, 17.6, 17.3. A small amount of the opposite sex: 1H NMR (400 MHz, CDCl3) δ 7.72 (1H, d, J = 7.0 Hz), 7.36-7.27 (5H, m), 7.08 (2H, d, J = 8.5 Hz), 6.89 (2H, d, J = 8.5 Hz), 6.84 (1H, d, J = 7.0 Hz), 5.40 (1H, d, J = 8.5 Hz), 5.12 (1H, d, J = 12.0 Hz), 4.99 (1H, d, J = 12.0 Hz), 4.78 (1H, dd, J = 8.0, 6.0 Hz), 4.51 (1H, dq, J = 7.0, 7.0 Hz), 4.41 (1H, dq, J = 7.0, 7.0 Hz), 4.27 (1H, dd, J = 8.5, 6.0 Hz), 3.72 (3H, s), 3.45 (1H, dd, J = 14.0, 6.0 Hz), 2.94 (3H, s), 2.86 (1H, dd, J = 14.0, 8.0 Hz), 1.33 (3H, d, J = 7.0 Hz), 1.32 (9H, s), 1.29 (3H, d, J = 7.0 Hz), 1.26 (1H, m), 0.80 (3H, d, J = 6.5 Hz), 0.70 (3H, d, J = 7.0 Hz). 13 C NMR (100 MHz, CDCl3) δ 173.3, 172.6, 171.5, 168.9, 157.6, 154.5, 135.6, 131.9, 129.7 (× 2), 128.6 (× 2), 128.3, 127.9 (× 2), 124.2 (× 2), 78.3, 67.5, 62.4, 55.4, 52.4, 49.8, 47.9, 33.9, 29.6, 29.3, 28.7 (× 3), 19.9, 18.2, 17.3, 17.0.

[0162] H-Val-NMeTyr(tBu)-Ala-Ala-OMe(2g, fp3-81) (Example 3-2) (Allocation No. 2)

change

[0163] [α] D 24 -39 (c = 1.0, CH3OH). IR (KBr) max 3348, 2976, 2937, 2879, 1647, 1607, 1524, 1508, 1451, 1403, 1365, 1319, 1258, 1237, 1162, 1105, 897 cm -1 . HRMS (ESI-TOF) C 25 H 41 Calculated value for N4O6: 493.3026, Found value: m / z: 493.3012 [M+H] + . A 2.0:1 rotamer ratio was observed by NMR. Major rotamers: 1 H NMR (400 MHz, CD3OD) δ 7.20 (2H, d, J = 8.5 Hz), 6.92 (2H, d, J = 8.5 Hz), 4.95 (1H, dd, J = 10.5, 5.5 Hz), 4.34 (1H, q, J = 7.0 Hz), 4.20 (1H, q, J = 7.0 Hz), 4.02 (1H, d, J = 3.5 Hz), 3.35 (1H, dd, J = 14.0, 5.5 Hz), 3.21 (1H, dd, J = 14.0, 10.5 Hz), 2.95 (3H, s), 2.05 (1H, m), 1.38 (3H, d, J = 7.0 Hz), 1.36 (3H, d, J = 7.0 Hz), 1.32 (9H, s), 1.03 (3H, d, J = 7.0 Hz), 0.96 (3H, d, J = 7.0 Hz). 13C NMR (100 MHz, CD3OD) δ 178.9, 170.9, 169.0, 168.1, 155.1, 132.1, 131.8 (× 2), 125.4 (× 2), 79.5, 64.6, 61.7, 51.9, 50.3, 37.2, 34.4, 33.6, 29.1 (× 3), 19.8, 18.8, 18.7, 17.7. Minor rotamers: 1 H NMR (400 MHz, CD3OD) δ 7.18 (2H, d, J = 8.5 Hz), 6.93 (2H, d, J = 8.5 Hz), 4.79 (1H, dd, J = 11.0, 3.5 Hz), 4.40 (1H, q, J = 7.0 Hz), 4.17 (1H, q, J = 7.0 Hz), 3.62 (1H, d, J = 5.5 Hz), 3.26 (1H, dd, J = 14.0, 3.5 Hz), 3.09 (1H, dd, J = 14.0, 11.0 Hz), 2.97 (3H, s), 2.05 (1H, m), 1.39 (3H, d, J = 7.0 Hz), 1.36 (3H, d, J = 7.0 Hz), 1.32 (9H, s), 0.68 (3H, d, J = 6.5 Hz), 0.64 (3H, d, J = 6.5 Hz). 13 C NMR (100 MHz, CD3OD) δ 178.9, 170.9, 169.0, 168.1, 155.1, 132.1, 131.8 (× 2), 125.4 (× 2), 79.5, 64.6, 61.7, 51.9, 50.3, 37.2, 34.4, 33.6, 29.1 (× 3), 19.8, 18.8, 18.7, 17.7.

[0164] [I-9. Synthesis of substituted 3-aminobenzoic acids] (3-Nitrobenzoyl)-L-alanine methyl ester, (S)-2-(3-nitrobenzamido)propionic acid methyl ester (fp3-130) [ka] The procedure for the synthesis of compound 4 was followed using 3-nitrobenzoic acid (835 mg, 5.00 mmol) and HCl·H-Ala-OMe (698 mg, 5.00 mmol). Compound fp3-130 was obtained as a colorless foamy solid (1.17 g, 4.63 mmol, 92%).

[0165] [α] D 26 +44 (c = 1.0, CHCl3). IR (KBr) max 3324, 3084, 2996, 2954, 1744, 1648, 1529, 1454, 1351, 1272, 1217, 1173, 719 cm -1 . ESI-MS C 11 H 13 Calculated value for N2O5: 253.0824, measured value m / z: 253.0817 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.61 (1H, dd, J = 1.5, 1.0 Hz), 8.35 (1H, dt, J = 8.0, 1.0 Hz), 8.13 (1H, ddd, J = 8.0, 1.5, 1.0 Hz), 7.62 (1H, t, J = 8.0 Hz), 7.03 (1H, d, J = 7.0 Hz), 4.81 (1H, dq, J = 7.0, 7.0 Hz), 3.81 (3H, s), 1.55 (3H, d, J = 7.0 Hz). 13 C NMR (100 MHz, CDCl3) δ 173.5, 164.4, 148.2, 135.4, 133.1, 129.8, 126.2, 122.0, 52.8, 48.7, 18.4.

[0166] (3-Aminobenzoyl)-L-alanine methyl ester, H-3-ABz-Ala-OMe (fp3-131) [ka] The reaction was carried out using compound fp3-130 (1.07 g, 4.26 mmol) according to the procedure for the synthesis of compound 5. Compound fp3-131 was obtained as a colorless foamy solid (887 mg, 3.99 mmol, 94%).

[0167] [α] D 26 +32 (c = 1.0, CHCl3). IR (KBr) max 3350, 3055, 2992, 2952, 1737, 1639, 1603, 1585, 1531, 1489, 1455, 1380, 1345, 1323, 1284, 1258, 1217, 1164, 752, 687 cm -1 . ESI-MS C 11 H 15 Calculated value for N2O3: 223.1082, Measured value: m / z: 223.1081 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.18 (1H, t, J = 8.0 Hz), 7.13 (1H, dd, J = 1.5, 1.0 Hz), 7.10 (1H, ddd, J = 8.0, 1.5, 1.0 Hz), 6.79 (1H, dt, J = 8.0, 1.0 Hz), 6.74 (1H, brd, J = 7.0 Hz), 4.77 (1H, dq, J = 7.0, 7.0 Hz), 3.73 (3H, s), 3.58 (2H, brs), 1.49 (3H, d, J = 7.0 Hz). 13 C NMR (100 MHz, CDCl3) δ 173.7, 167.0, 146.8, 135.0, 129.4, 118.1, 116.5, 113.7, 52.5, 48.4, 18.6.

[0168] H-NMe-Tyr(tBu)-3-ABz-Ala-OMe(fp3-133) [ka] The reaction was carried out according to the procedure for the synthesis of compound 6 using compound fp3-131 (222 mg, 1.00 mmol) and Fmoc-NMeTyr(tBu)-OH (473 mg, 1.00 mmol). Compound fp3-133 was obtained as a colorless foamy solid (455 mg, 1.00 mmol, 100%).

[0169] [α] D 26 -70 (c = 1.0, CHCl3). IR (KBr) max 3292, 2977, 2947, 2799, 1742, 1648, 1607, 1588, 1534, 1507, 1485, 1454, 1434, 1365, 1341, 1304, 1236, 1210, 1161, 897, 755cm -1 . ESI-MS C 25 H 34 Calculated value of N3O5 456.2498, measured m / z 456.2487 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 9.43 (1H, brs), 7.91 (1H, t, J = 1.0 Hz), 7.90 (1H, dd, J = 8.0, 1.0 Hz), 7.53 (1H, dd, J = 8.0, 1.0 Hz), 7.40 (1H, t, J = 8.0 Hz), 7.12 (2H, d, J = 8.5 Hz), 6.94 (2H, d, J = 8.5 Hz), 6.81 (1H, d, J = 7.0 Hz), 4.80 (1H, dq, J = 7.0, 7.0 Hz), 3.79 (3H, s), 3.28 (1H, dd, J = 9.0, 4.0 Hz), 3.24 (1H, dd, J = 13.5, 4.0 Hz), 2.70 (1H, dd, J = 13.5, 9.0 Hz), 2.33 (3H, s), 1.52 (3H, d, J = 7.0 Hz), 1.32 (9H, s). 13 C NMR (100 MHz, CDCl3) δ 173.5, 172.1, 166.4, 154.4, 138.2, 134.7, 131.7, 129.41 (× 2), 129.35, 124.4 (× 2), 122.5, 122.4, 117.9, 78.5, 66.6, 52.5, 48.5, 38.4, 35.7, 28.8 (× 3), 18.5.

[0170] Cbz-Val-NMe-Tyr(tBu)-3-ABz-Ala-OMe (fp3-134) (Example 4-1) [ka] Following the procedure for the synthesis of compound 3a, the reaction was carried out using compound fp3-133 (421 mg, 925 μmol) and Cbz-Val-OH (232 mg, 925 μmol) to give compound fp3-134 as a colorless foamy solid (552 mg, 801 μmol, 86%).

[0171] [α] D 26-54 (c = 1.0, CHCl3). IR (KBr) max 3304, 3064, 3033, 2975, 2933, 2872, 1735, 1697, 1639, 1591, 1550, 1534, 1508, 1485, 1455, 1412, 1365, 1348, 1304, 1258, 1236, 1218, 1162, 1025, 897, 753, 697 cm -1 . ESI-MS C 38 H 49 Calculated value of N4O8 689.3550, measured m / z 689.3544 [M+H] + . A 1:1 rotamer ratio was observed by NMR. Major rotamers: 1H NMR (400 MHz, CDCl3) δ 9.51 (1H, s), 8.11 (1H, brs), 7.91 (1H, d, J = 8.0 Hz), 7.51 (1H, d, J = 8.0 Hz), 7.36 (1H, t, J = 8.0 Hz), 7.36-7.28 (5H, m), 7.12 (2H, d, J = 8.0 Hz), 6.92 (2H, d, J = 8.0 Hz), 6.78 (1H, d, J = 7.0 Hz), 5.61 (1H, d, J = 8.0 Hz), 5.25 (1H, d, J = 8.0 Hz) = 12.0 Hz), 5.05 (1H, d, J = 12.0 Hz), 4.92 (1H, dd, J = 7.5, 6.5 Hz), 4.74 (1H, dq, J = 7.0, 7.0 Hz), 4.30 (1H, dd, J = 8.0, 7.0 Hz), 3.71 (3H, s), 3.52 (1H, dd, J = 14.0, 6.5 Hz), 3.00 (3H, s), 2.91 (1H, dd, J = 14.0, 7.5 Hz), 1.45 (3H, d, J = 7.0 Hz), 1.34 (1H, m), 1.33 (9H, s), 0.87 (3H, d, J = 6.5 Hz), 0.76 (3H, d, J = 6.5 Hz). 13 C NMR (100 MHz, CDCl3) δ 173.5, 172.5, 166.9, 166.4, 157.8, 154.5, 138.7, 135.6, 134.6, 131.8, 129.8 (× 2), 129.1, 128.5 (× 2), 128.3 (or 128.1), 128.0 (× 2), 124.3 (× 2), 122.8, 122.6, 118.4, 78.4, 67.8, 63.3, 55.4, 52.5, 48.5, 34.2, 29.8, 29.3, 28.8 (× 3), 20.1, 18.4, 17.6. A small amount of the opposite sex: 11H NMR (400 MHz, CDCl3) δ 8.42 (1H, s), 7.80 (1H, brs), 7.61 (1H, d, J = 8.0 Hz), 7.45 (1H, d, J = 8.0 Hz), 7.36 - 7.28 (5H, m), 7.27 (1H, t, J = 8.0 Hz), 7.10 (2H, d, J = 8.0 Hz), 6.87 (2H, d, J = 8.0 Hz), 6.87 (1H, d, J = 7.0 Hz), 5.52 (1H, d, J = 9.0 Hz), 5.29 (1H, t, J = 7.5 Hz), 5.10 (1H, d, J = 12.0 Hz), 4.99 (1H, d, J = 12.0 Hz), 4.75 (1H, dq, J = 7.0, 7.0 Hz), 4.45 (1H, dd, J = 8.5, 7.0 Hz), 3.76 (3H, s), 3.35 (1H, dd, J = 14.0, 7.5 Hz), 3.13 (3H, s), 3.02 (1H, dd, J = 14.0, 7.5 Hz), 1.95 (1H, m), 1.50 (3H, d, J = 7.0 Hz), 1.28 (9H, s), 0.90 (3H, d, J = 6.5 Hz), 0.87 (3H, d, J = 6.5 Hz). 13 13C NMR (100 MHz, CDCl3) δ 173.6, 173.5, 168.2, 166.3, 156.3, 154.2, 137.9, 136.2, 134.6, 131.3, 129.3 (× 2), 129.1, 128.5 (× 2), 128.1 (or 128.3), 128.0 (× 2), 124.3 (× 2), 122.9, 122.8, 118.4, 78.3, 67.0, 59.7, 56.1, 52.5, 48.5, 33.2, 32.2, 30.9, 28.8 (× 3), 19.4, 18.3, 17.3.

[0172] H-Val-NMe-Tyr(tBu)-3-ABz-Ala-OMe (fp3 - 147) (Example 4 - 2) [ka] The reaction was carried out according to the procedure for the synthesis of compound 2a using compound fp3-134 (172 mg, 250 μmol). Compound fp3-147 was obtained as a colorless foamy solid (114 mg, 210 μmol, 84%).

[0173] ESI-MS C 29 H 41 Calculated value for N4O6: 541.3026, Measured value: m / z: 541.3007 [M+H] + .

[0174] [I-10. Synthesis of substituted 4-aminobenzoic acids] (4-Nitrobenzoyl)-L-alanine methyl ester (fp3-136) [ka] Following the procedure for the synthesis of compound 4, the reaction was carried out using 4-nitrobenzoic acid (835 mg, 5.00 mmol) and HCl·H-Ala-OMe (698 mg, 5.00 mmol), affording compound fp3-136 as a colorless foamy solid (1.15 g, 4.55 mmol, 91%).

[0175] [α] D 24 +41 (c = 1.0, CHCl3). IR (KBr) max 3294, 3075, 3007, 2988, 2957, 1741, 1640, 1603, 1546, 1525, 1453, 1352, 1318, 1297, 1226, 1170, 1123, 867, 722 cm -1 . ESI-MS C 11 H 13 Calculated value for N2O5: 253.0824, measured value m / z: 253.0827 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.28 (2H, dd, J = 8.5, 2.0 Hz), 7.96 (2H, dd, J = 8.5, 1.0 Hz), 6.91 (1H, brd, J = 7.0 Hz), 4.79 (1H, dq, J = 7.0, 7.0 Hz), 3.81 (3H, s), 1.54 (3H, d, J = 7.0 Hz). 13 C NMR (100 MHz, CDCl3) δ 173.3, 164.7, 149.7, 139.4, 128.3 (× 2), 123.8 (× 2), 52.8, 48.7, 18.4.

[0176] H-4-ABz-Ala-OMe (fp3-137) [ka] The reaction was carried out using compound fp3-136 (958 mg, 3.79 mmol) according to the procedure for the synthesis of compound 5. Compound fp3-137 was obtained as a colorless foamy solid (729 mg, 3.28 mmol, 86%).

[0177] [α] D 24 +47 (c = 1.0, CHCl3). IR (KBr) max 3349, 3055, 2991, 2952, 1735, 1627, 1604, 1569, 1540, 1506, 1453, 1380, 1348, 1323, 1302, 1270, 1219, 1185, 845, 771 cm -1 . ESI-MS C 11 H 15 Calculated value for N2O3: 223.1082, measured value m / z: 223.1079 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 7.62 (2H, d, J = 8.5 Hz), 6.64 (2H, d, J = 8.5 Hz), 6.59 (1H, brd, J = 7.0 Hz), 4.77 (1H, dq, J = 7.0, 7.0 Hz), 4.22 (2H, brs), 3.76 (3H, s), 1.48 (3H, d, J = 7.0 Hz). 13 C NMR (100 MHz, CDCl3) δ 174.0, 166.5, 149.8, 128.8 (× 2), 123.3, 114.0 (× 2), 52.4, 48.3, 18.7.

[0178] H-NMe-Tyr(tBu)-4-ABz-Ala-OMe(fp3-139) [ka] Following the procedure for the synthesis of compound 6, the reaction was carried out using compound fp3-137 (222 mg, 1.00 mmol) and Fmoc-NMeTyr(tBu)-OH (473 mg, 1.00 mmol) to give compound fp3-139 as a colorless foamy solid (454 mg, 1.00 mmol, 99%).

[0179] [α] D 26 -85 (c = 1.0, CHCl3). IR (KBr) max 3304, 2978, 2951, 2875, 2804, 1743, 1678, 1642, 1607, 1506, 1454, 1406, 1365, 1348, 1312, 1237, 1215, 1164, 1126, 897, 854, 756cm -1 . ESI-MS C 25 H 34 Calculated value for N3O5: 456.2498, measured value m / z: 456.2490 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 9.44 (1H, s), 7.79 (2H, d, J = 8.5 Hz), 7.66 (2H, d, J = 8.5 Hz), 7.11 (2H, d, J = 8.5 Hz), 6.93 (2H, d, J = 8.5 Hz), 6.74 (1H, d, J = 7.0 Hz), 4.79 (1H, dq, J = 7.0, 7.0 Hz), 3.79 (3H, s), 3.29 (1H, dd, J = 9.0, 4.0 Hz), 3.23 (1H, dd, J = 13.5, 4.0 Hz), 2.75 (1H, dd, J = 13.5, 9.0 Hz), 2.36 (3H, s), 1.52 (3H, d, J = 7.0 Hz), 1.32 (9H, s). 13 C NMR (100 MHz, CDCl3) δ 173.7, 172.1, 166.1, 154.5, 140.9, 131.6, 129.4 (× 2), 129.0, 128.1 (× 2), 124.4 (× 2), 118.9 (× 2), 78.5, 66.6, 52.5, 48.4, 38.3, 35.7, 28.8 (× 3), 18.6.

[0180] Cbz-Val-NMe-Tyr(tBu)-4-ABz-Ala-OMe (fp3-142) (Example 5-1) [ka] Following the procedure for the synthesis of compound 3a, the reaction was carried out using compound fp3-139 (381 mg, 836 μmol) and Cbz-Val-OH (10 mg, 836 μmol) to give compound fp3-142 as a colorless foamy solid (420 mg, 609 μmol, 73%).

[0181] [α] D 26 -48 (c = 1.0, CHCl3). IR (KBr) max3304, 3059, 3030, 296, 2933, 2872, 1736, 1698, 1639, 1607, 1530, 1506, 1454, 1407, 1365, 1345, 1313, 1237, 1220, 1163, 1026, 897, 852, 754, 698cm -1 . ESI-MS C 38 H 49 Calculated value for N4O8: 689.3550, measured value m / z: 689.3541 [M+H] + . A 1:1 rotamer ratio was observed by NMR. 1H NMR (400 MHz, CDCl3) δ 9.50 (1H, s), 8.38 (1H, s), 7.75-7.70 (4H, m), 7.67 (2H, d, J = 8.0 Hz), 7.45 (2H, d, J = 8.0 Hz), 7.39-7.28 (10H, m), 7.12 (2H, d, J = 8.0 Hz), 7.11 (2H, d, J = 8.0 Hz), 6.92 (2H, d, J = 8.0 Hz), 6.89 (2H, d, J = 8.0 Hz), 6.79 (1H, d, J = 7.0 Hz), 6.77 (1H, d, J = 7.0 Hz), 5.68 (1H, d, J = 8.0 Hz), 5.42 (1H, d, J = 9.0 Hz), 5.25 (1H, t, J = 7.5 Hz), 5.17 (1H, d, J = 12.0 Hz), 5.11 (1H, d, J = 12.0 Hz), 5.02 (1H, d, J = 12.0 Hz), 4.95 (1H, d, J = 12.0 Hz), 4.91 (1H, t, J = 7.0 Hz), 4.79 (1H, dq, J = 7.0, 7.0 Hz), 4.78 (1H, dq, J = 7.0, 7.0 Hz), 4.47 (1H, dd, J = 8.0, 6.5 Hz), 4.29 (1H, t, J = 7.5 Hz), 3.78 (3H, s), 3.77 (3H, s), 3.52 (1H, dd, J = 14.0, 7.5 Hz), 3.37 (1H, dd, J = 14.0, 7.5 Hz), 3.12 (3H, s), 3.03 (1H, dd, J = 14.0, 7.5 Hz), 2.99 (3H, s), 2.91 (1H, dd, J = 14.0, 7.5 Hz), 1.95 (1H, m), 1.51 (3H, d, J = 7.0 Hz), 1.49 (3H, d, J = 7.0 Hz), 1.35 (1H, m), 1.32 (9H, s), 1.29 (9H, s), 0.91 (3H, d, J = 6.5 Hz), 0.87 (6H, d, J = 6.5 Hz) , 0.77 (3H, d, J = 6.5 Hz). 13 C NMR (100 MHz, CDCl3) δ 173.9, 173.8, 173.6, 172.5, 168.2, 166.9, 166.1, 166.0, 157.8, 156.3, 154.5, 154.3, 141.4, 140.7, 136.2, 135.4, 131.7, 131.2, 129.8 (× 2), 129.3 (× 2), 129.2 (× 2), 128.6 (× 2), 128.5 (× 2), 128.4, 128.2, 128.0 (× 4), 127.9 (× 2), 127.8 (× 2), 124.3 (× 4), 119.3, 119.1, 78.4 (× 2), 67.7, 67.0, 63.4, 59.9, 56.0, 55.5, 52.5 (× 2), 48.4 (× 2), 34.2, 33.2, 32.1, 30.9, 29.7, 29.3, 28.8 (× 6), 20.1, 19.4, 18.6, 18.5, 17.6, 17.2.

[0182] H-Val-NMe-Tyr(tBu)-3-ABz-Ala-OMe (fp3-149) (Example 5-2) [ka] The reaction was carried out according to the procedure for the synthesis of compound 2a using compound fp3-142 (172 mg, 250 μmol). Compound fp3-149 was obtained as a colorless foamy solid (103 mg, 190 μmol, 76%).

[0183] ESI-MS C 29 H 41 Calculated value for N4O6: 541.3026, Measured value: m / z: 541.3008 [M+H] + .

[0184] [I-11. Synthesis of D-alanine substitutes] (R)-2-(2-nitrobenzamido)propionic acid methyl ester (ent-4) [ka] Following the procedure for the synthesis of compound 4, the reaction was carried out using 2-nitrobenzoic acid (835 mg, 5.00 mmol) and HCl·HD-Ala-OMe (698 mg, 5.00 mmol), affording compound ent-4 as a colorless foamy solid (1.02 g, 4.04 mmol, 80%).

[0185] Compound ent-4 1 H NMR and 13 The C NMR data was consistent with that of compound 4. [α] D 26 +21 (c = 1.0, CHCl3). HRMS (ESI-TOF) C 11 H 13 Calculated value for N2O5: 253.0824, Measured value m / z: 253.0817 [M+H] + .

[0186] (S)-2-(2-nitrobenzamido)propionic acid methyl ester (ent-5) [ka] The reaction was carried out using compound ent-4 (969 mg, 3.84 mmol) according to the procedure for the synthesis of compound 5. Compound ent-5 was obtained as a colorless foamy solid (853 mg, 3.84 mmol, quantitative).

[0187] Compound ent-5 1 H NMR and 13 The C NMR data was consistent with that of compound 5. [α] D 26 -1.6 (c = 1.0, CHCl3). HRMS (ESI-TOF) C 11 H 15 Calculated value for N2O3: 223.1083, Measured value m / z: 223.1074 [M+H] + .

[0188] H-NMeTyr(tBu)-Ant-Ala-OMe (6d) [ka] The reaction was carried out according to the procedure for the synthesis of compound 6 using compound ent-5 (222 mg, 1.00 mmol) and Fmoc-NMeTyr(tBu)-OH (425 mg, 1.00 mmol), affording compound 6d as a colorless foamy solid (337 mg, 740 μmol, 74%).

[0189] [α] D 26 -69 (c = 1.0, CHCl3). IR (KBr) max 3268, 2978, 2956, 2803, 1746, 1678, 1650, 1600, 1581, 1509, 1444, 1365, 1294, 1260, 1236, 1211, 1163, 897, 757 cm -1 . HRMS (ESI-TOF) C 25 H 34 Calculated value for N3O5: 456.2499, Found value: m / z: 456.2491 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 11.65 (1H, s), 8.65 (1H, dd, J = 8.0, 1.0 Hz), 7.54 (1H, dd, J = 8.0, 1.0 Hz), 7.49 (1H, dt, J = 8.0, 1.0 Hz), 7.14 (2H, d, J = 8.5 Hz), 7.10 (1H, dt, J = 8.0, 1.0 Hz), 6.91 (2H, d, J = 8.5 Hz), 6.72 (1H, d, J = 7.0 Hz), 4.77 (1H, dq, J = 7.0, 7.0 Hz), 3.77 (3H, s), 3.29 (1H, dd, J = 10.0, 3.5 Hz), 3.22 (1H, dd, J = 13.5, 3.5 Hz), 2.72 (1H, dd, J = 13.5, 10.0 Hz), 2.32 (3H, s), 1.52 (3H, d, J = 7.0 Hz), 1.31 (9H, s). 13 C NMR (100 MHz, CDCl3) δ 173.3, 173.2, 167.9, 154.2, 138.8, 132.6, 132.4, 129.5 (× 2), 126.8, 124.3 (× 2), 123.0, 121.7, 121.3, 78.3, 67.6, 52.6, 48.3, 39.0, 35.5, 28.8 (× 3), 18.5.

[0190] Cbz-Val-NMeTyr(tBu)-Ant-D-Ala-OMe (3d, fp4-5) (Reference example 3-1) [ka] The reaction was carried out according to the procedure for the synthesis of compound 3a using compound 6d (309 mg, 681 μmol) and Cbz-Val-OH (171 mg, 681 μmol), affording compound 3d as a colorless foamy solid (389 mg, 564 μmol, 82%).

[0191] [α] D 26-97 (c = 1.0, CHCl3). IR (KBr) max 3339, 3064, 3030, 2975, 2933, 2872, 1739, 1717, 1645, 1600, 1586, 1509, 1446, 1407, 1365, 1298, 1258, 1234, 1217, 1164, 1087, 1026, 897, 756cm -1 . HRMS (ESI-TOF) C 38 H 49 Calculated value for N4O8: 689.3550, Found value m / z: 689.3537 [M+H] + . A 2.5:1 rotamer ratio was observed by NMR. Major rotamers: 1H NMR (400 MHz, CDCl3) δ 11.37 (1H, s), 8.61 (1H, dd, J = 8.0, 1.0 Hz), 7.52 (1H, dd, J = 8.0, 1.5 Hz), 7.47 (1H, dt, J = 8.0, 1.0 Hz), 7.36-7.28 (5H, m), 7.11 (2H, d, J = 8.5 Hz), 7.09-7.04 (1H, m), 6.86 (2H, d, J = 8.5 Hz), 6.83 (1H, d, J = 7.0 Hz), 5.38 (1H, dd, J = 9.5, 6.5 Hz), 5.34 (1H, d, J = 9.0 Hz), 5.12 (1H, d, J = 12.0 Hz), 5.04 (1H, d, J = 12.0 Hz), 4.70 (1H, dq, J = 7.0, 7.0 Hz), 4.45 (1H, dd, J = 9.5, 6.0 Hz), 3.76 (3H, s), 3.46 (1H, dd, J = 14.0, 6.5 Hz), 3.02 (3H, s), 2.98 (1H, dd, J = 14.0, 9.5 Hz), 2.10 (1H, m), 1.47 (3H, d, J = 7.0 Hz), 1.27 (9H, s), 0.97 (3H, d, J = 6.5 Hz), 0.87 (3H, d, J = 6.5 Hz). 13 C NMR (100 MHz, CDCl3) δ 173.2, 172.5, 168.7, 167.9, 156.2, 154.0, 139.4, 136.5, 132.9, 131.9, 129.4 (× 2), 128.4 (× 2), 128.1, 127.9 (× 2), 126.7, 124.1 (× 2), 123.0, 121.4, 119.6, 78.2, 66.8, 60.7, 55.8, 52.6, 48.3, 33.5, 32.6, 30.7, 28.8 (× 3), 19.9, 18.4, 16.9. A small amount of the opposite sex: 1H NMR (400 MHz, CDCl3) δ 11.24 (1H, s), 8.64 (1H, dd, J = 8.0, 1.0 Hz), 7.47 (1H, dt, J = 8.0, 1.0 Hz), 7.38 (1H, dd, J = 8.0, 1.0 Hz), 7.16 (2H, d, J = 8.5 Hz), 7.09-7.04 (4H, m), 6.97-6.95 (2H, m), 6.94 (2H, d, J = 8.5 Hz), 6.58 (1H, d, J = 7.0 Hz), 5.91 (1H, d, J = 10.0 Hz), 4.97 (1H, dd, J = 11.0, 3.5 Hz), 4.83 (1H, d, J = 12.0 Hz), 4.74 (1H, d, J = 12.0 Hz), 4.57 (1H, dq, J = 7.0, 7.0 Hz), 3.91 (1H, dd, J = 10.0, 8.5 Hz), 3.76 (3H, s), 3.60 (1H, dd, J = 14.0, 3.5 Hz), 2.92 (3H, s), 2.89 (1H, dd, J = 14.0, 11.0 Hz), 1.90 (1H, m), 1.45 (3H, d, J = 7.0 Hz), 1.32 (9H, s), 0.79 (3H, d, J = 6.5 Hz), 0.46 (3H, d, J = 6.5 Hz). 13 C NMR (100 MHz, CDCl3) δ 173.3, 171.7, 168.3, 168.1, 156.3, 154.4, 139.0, 136.0, 132.9, 132.0, 129.7 (× 2), 128.0 (× 2), 127.8, 127.6 (× 2), 126.9, 124.3 (× 2), 123.1, 121.0, 120.0, 78.3, 66.8, 63.6, 55.9, 52.7, 48.6, 33.4, 30.2, 30.0, 28.7 (× 3), 19.7, 18.2, 17.6.

[0192] H-Val-NMeTyr(tBu)-Ant-D-Ala-OH(2d, fp4-7) (Reference Example 3-2) [ka] The reaction was carried out according to the procedure for the synthesis of compound 2a with compound 3d (275 mg, 400 μmol), to obtain compound 2d as a colorless foamy solid (205 mg, 379 μmol, 95%).

[0193] [α] D 26 -32 (c = 1.0, CH3OH). IR (KBr) max 3376, 2975, 2927, 2879, 1656, 1638, 1597, 1508, 1446, 1400, 1365, 1296, 1258, 1237, 1162, 897, 759 cm -1 . HRMS (ESI-TOF) C 29 H 41 Calculated value for N4O6: 541.3026, Found value m / z: 541.3038 [M+H] + . A 1.4:1 rotamer ratio was observed by NMR. Major rotamers: 1H NMR (400 MHz, CD3OD) δ 8.52 (1H, dd, J = 8.0, 1.0 Hz), 7.73 (1H, dd, J = 8.0, 1.0 Hz), 7.48 (1H, dt, J = 7.5, 1.5 Hz), 7.20 (2H, d, J = 8.0 Hz), 7.15 (1H, dt, J = 7.5, 1.5 Hz), 6.94 (2H, d, J = 8.0 Hz), 4.51 (1H, dd, J = 10.5, 5.0 Hz), 4.26 (1H, d, J = 4.5 Hz), 4.08 (1H, q, J = 7.0 Hz), 3.51 (1H, dd, J = 14.0, 5.0 Hz), 3.41 (1H, dd, J = 14.0, 10.5 Hz), 3.00 (3H, s), 1.94 (1H, m), 1.47 (3H, d, J = 7.0 Hz), 1.32 (9H, s), 0.98 (3H, d, J = 7.0 Hz), 0.94 (3H, d, J = 7.0 Hz). 13 C NMR (100 MHz, CDCl3) δ 179.9, 170.9 (× 2), 169.7, 155.4, 139.8, 134.5, 133.1, 130.7 (× 2), 129.2, 125.5 (× 2), 124.3, 122.6, 121.5, 79.5, 68.9, 57.2, 53.5, 39.6, 34.2, 30.2, 29.2 (× 3), 19.6, 17.8, 17.0. A small amount of the opposite sex: 1H NMR (400 MHz, CD3OD) δ 8.38 (1H, dd, J = 8.0, 1.0 Hz), 7.73 (1H, dd, J = 8.0, 1.0 Hz), 7.50 (1H, dt, J = 7.5, 1.5 Hz), 7.21 (2H, d, J = 8.0 Hz), 7.15 (1H, dt, J = 7.5, 1.5 Hz), 6.96 (2H, d, J = 8.0 Hz), 4.79 (1H, dd, J = 9.5, 4.5 Hz), 4.43 (1H, d, J = 3.0 Hz), 4.15 (1H, q, J = 7.0 Hz), 3.54 (1H, dd, J = 14.0, 4.5 Hz), 3.08 (1H, dd, J = 14.0, 9.5 Hz), 3.07 (3H, s), 1.44 (3H, d, J = 7.0 Hz), 1.34 (9H, s), 1.15 (1H, m), 0.91 (3H, d, J = 7.0 Hz), 0.60 (3H, d, J = 7.0 Hz). 13 C NMR (100 MHz, CDCl3) δ 180.5, 171.1, 170.9, 168.9, 155.9, 139.1, 133.6, 133.0, 131.2 (× 2), 129.2, 125.4 (× 2), 124.9, 123.9, 122.1, 79.6, 64.9, 56.6, 53.6, 34.6, 30.9, 29.8, 29.2 (× 3), 19.5, 17.5, 15.7.

[0194] Cyclo(Val-NMeTyr(tBu)-Ant-D-Ala)(7d) [ka] The reaction was carried out using compound 2d (54.0 mg, 100 μmol) according to the procedure for the synthesis of compound 7. Compound 7d was obtained as a colorless foamy solid (19.5 mg, 37.3 μmol, 37%).

[0195] [α] D26 -60 (c = 1.0, CHCl3). IR (KBr) ν max 3315, 2976, 2935, 2872, 1686, 1640, 1601, 1584, 1508, 1444, 1413, 1389, 1366, 1319, 1297, 1236, 1162, 897, 756 cm -1 . HRMS (ESI-TOF) C 29 H 39 Calculated value of N4O5 is 523.2920, measured value m / z 523.2917 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.05 (1H, s), 8.87 (1H, d, J = 7.5 Hz), 8.21 (1H, dd, J = 8.0, 1.0 Hz), 7.50 (1H, d, J = 9.5 Hz), 7.48 (1H, dd, J = 8.0, 1.5 Hz), 7.45 (1H, dt, J = 8.0, 1.5 Hz), 7.13 (2H, d, J = 8.5 Hz), 7.10 (1H, dt, J = 8.0, 1.0 Hz), 6.80 (2H, d, J = 8.5 Hz), 4.37 (1H, t, J = 9.5 Hz), 4.29 (1H, dd, J = 10.5, 4.5 Hz), 3.72 (1H, dq, J = 7.5, 7.0 Hz), 3.28 (1H, dd, J = 14.0, 4.5 Hz), 3.07 (1H, dd, J = 14.0, 10.5 Hz), 2.83 (3H, s), 1.87 (1H, m), 1.32 (3H, d, J = 7.0 Hz), 1.25 (9H, s), 0.79 (3H, d, J = 6.5 Hz), 0.76 (3H, d, J = 6.5 Hz). 13C NMR (100 MHz, DMSO-d6) δ 171.4, 170.4, 168.7, 168.0, 153.3, 136.8, 133.5, 131.0, 129.7 (× 2), 126.6, 124.6, 123.8 (× 2), 122.4, 120.4, 77.7, 67.5, 54.3, 49.9, 39.5, 32.5, 29.7, 28.5 (× 3), 19.2, 18.5, 15.2.

[0196] Cyclo(Val-NMeTyr-Ant-D-Ala) (1d, fp4-25) (Reference Example 3-3) [ka] The reaction was carried out according to the procedure for the synthesis of compound 1a with compound 7d (34.7 mg, 66.3 μmol), to obtain compound 1d as a colorless foamy solid (21.3 mg, 45.6 μmol, 69%).

[0197] [α] D 24 -57 (c 1.0, CH3OH) IR (KBr) max 3311, 2964, 1685, 1677, 1638, 1516, 1444, 1320, 1230, 1171 cm -1 . HRMS (ESI-TOF) C 25 H 31 Calculated value for N4O5: 467.2294, Found value: m / z: 467.2298 [M+H] + . 1H NMR (DMSO-d6, 400 MHz) δ 10.01 (1H, s), 9.20 (1H, s), 8.85 (1H, d, J = 6.5 Hz), 8.20 (1H, dd, J = 8.5, 1.0 Hz), 7.48 (1H, dd, J = 8.0, 1.0 Hz), 7.47 (1H, d, J = 10.0 Hz), 7.44 (1H, dt, J = 8.5, 1.0 Hz), 7.10 (1H, dt, J = 8.5, 1.0 Hz), 7.00 (2H, d, J = 8.0 Hz), 6.65 (2H, d, J = 8.0 Hz), 4.41 (1H, t, J = 10.0 Hz), 4.17 (1H, dd, J = 10.5, 3.5 Hz), 3.70 (1H, dq, J = 7.0, 7.0 Hz), 3.22 (1H, dd, J = 14.0, 3.5 Hz), 2.96 (1H, dd, J = 14.0, 10.5 Hz), 2.85 (3H, s), 1.88 (1H, m), 1.32 (3H, d, J = 7.0 Hz), 0.81 (6H, d, J = 7.0 Hz). 13 C NMR (DMSO-d6, 100 MHz) δ 171.3, 170.4, 168.7, 168.0, 155.7, 136.8, 130.9, 130.0 (× 2), 128.7, 126.6, 124.6, 122.4, 120.4, 115.0 (× 2), 67.8, 54.3, 49.9, 39.6, 32.2, 29.8, 19.2, 18.5, 15.2.

[0198] [I-12. Synthesis of L-アラニンsubstituted body] Cbz-Ala-NMeTyr(tBu)-Ant-Ala-OMe(3i, fp3-64) (Reference Example 4-1)

change

[0199] [α] D 24 -93 (c = 1.0, CHCl3). IR (KBr) max 3321, 2978, 2933, 1745, 1718, 1699, 1645, 1599, 1586, 1508, 1447, 1409, 1365, 1301, 1234, 1214, 1162, 1082, 1063, 897, 756, 698cm -1 . HRMS (ESI-TOF) C 36 H 45 Calculated value for N4O8: 661.3237, Found value m / z: 661.3223 [M+H] + . A 3.2:1 rotamer ratio was observed by NMR. Major rotamers: 1H NMR (400 MHz, CDCl3) δ 11.45 (1H, s), 8.63 (1H, dd, J = 8.0, 1.0 Hz), 7.52 (1H, dd, J = 8.0, 1.0 Hz), 7.48 (1H, dt, J = 8.0, 1.0 Hz), 7.38-7.28 (4H, m), 7.17-7.15 (1H, m), 7.10 (2H, d, J = 8.5 Hz), 7.09 (1H, dt, J = 8.0, 1.0 Hz), 6.95 (2H, d, J = 8.5 Hz), 6.81 (1H, d, J = 7.0 Hz), 5.53 (1H, d, J = 8.5 Hz), 5.26 (1H, dd, J = 10.0, 5.5 Hz), 5.10 (1H, d, J = 12.0 Hz), 5.02 (1H, d, J = 12.0 Hz), 4.65 (1H, dq, J = 7.0, 7.0 Hz), 4.59 (1H, dq, J = 8.5, 7.0 Hz), 3.77 (3H, s), 3.51 (1H, dd, J = 14.0, 5.5 Hz), 3.04 (1H, dd, J = 14.0, 10.0 Hz), 2.95 (3H, s), 1.46 (3H, d, J = 7.0 Hz), 1.36 (3H, d, J = 7.0 Hz), 1.27 (9H, s). 13 C NMR (100 MHz, CDCl3) δ 173.2 (× 2), 168.6, 168.0, 155.3, 154.0, 139.5, 136.5, 133.0, 132.1, 129.4 (× 2), 128.4 (× 2), 128.0, 127.9 (× 2), 126.7, 124.2 (× 2), 123.0, 121.3, 119.4, 78.2, 66.6, 61.6, 52.6, 48.4, 47.2, 33.1 (× 2), 28.8 (× 3), 18.4, 18.2. A small amount of the opposite sex: 11H NMR (400 MHz, CDCl3) δ 11.46 (1H, s), 8.62 (1H, dd, J = 8.0, 1.0 Hz), 7.53 (1H, dt, J = 8.0, 1.0 Hz), 7.47 (1H, dd, J = 8.0, 1.0 Hz), 7.38 - 7.28 (4H, m), 7.11 (1H, dt, J = 8.0, 1.0 Hz), 7.10 (2H, d, J = 8.5 Hz), 7.02 - 7.01 (1H, m), 6.85 (2H, d, J = 8.5 Hz), 6.56 (1H, d, J = 7.0 Hz), 5.80 (1H, d, J = 8.5 Hz), 4.93 (1H, d, J = 12.0 Hz), 4.85 (1H, d, J = 12.0 Hz), 4.82 (1H, dd, J = 11.0, 3.0 Hz), 4.61 (1H, dq, J = 7.0, 7.0 Hz), 4.18 (1H, dq, J = 8.5, 7.0 Hz), 3.78 (3H, s), 3.53 (1H, dd, J = 14.0, 3.0 Hz), 2.92 (1H, dd, J = 14.0, 11.0 Hz), 2.91 (3H, s), 1.31 (9H, s), 1.29 (3H, d, J = 7.0 Hz), 0.86 (3H, d, J = 7.0 Hz). 13 13C NMR (100 MHz, CDCl3) δ 173.3, 172.6, 168.1 (× 2), 155.5, 154.3, 139.1, 136.0, 133.0, 132.2, 129.7 (× 2), 128.2 (× 2), 128.0, 127.9 (× 2), 127.0, 124.6 (× 2), 123.3, 121.2, 119.9, 78.4, 66.9, 63.9, 52.7, 48.3, 46.2, 33.2, 30.4, 28.7 (× 3), 18.1, 17.9.

[0200] H-Ala-NMeTyr(tBu)-Ant-Ala-OH(2i, fp3 - 71) (Reference Example 4 - 2) [ka] The reaction was carried out according to the procedure for the synthesis of compound 2a with compound 3i (226 mg, 342 μmol), to give compound 2i as a colorless foamy solid (143 mg, 279 μmol, 81%).

[0201] [α] D 25 -39 (c = 1.0, CH3OH). IR (KBr) max 3369, 2978, 2934, 1662, 1632, 1596, 1524, 1508, 1448, 1399, 1365, 1301, 1259, 1237, 1162, 1092, 897, 756 cm -1 . HRMS (ESI-TOF) C 27 H 37 Calculated value for N4O6: 513.2713, Found value m / z: 513.2705 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.58 (1H, dd, J = 8.0, 1.0 Hz), 7.81 (1H, dd, J = 7.5, 1.0 Hz), 7.47 (1H, ddd, J = 8.0, 7.5, 1.0 Hz), 7.16 (2H, d, J = 8.5 Hz), 7.13 (1H, dt, J = 7.5, 1.0 Hz), 6.95 (2H, d, J = 8.5 Hz), 4.34 (1H, dd, J = 10.5, 5.5 Hz), 4.28 (1H, q, J = 7.0 Hz), 4.12 (1H, q, J = 7.0 Hz), 3.43 (1H, dd, J = 14.0, 5.5 Hz), 3.37 (1H, dd, J = 14.0, 10.5 Hz), 2.91 (3H, s), 1.45 (3H, d, J = 7.0 Hz), 1.33 (9H, s), 1.18 (3H, d, J = 7.0 Hz). 13C NMR (100 MHz, CD3OD) δ 181.6, 171.3, 171.2, 170.0, 155.4, 140.4, 134.5, 133.3, 131.1 (× 2), 129.2, 125.4 (× 2), 123.9, 121.2, 121.0, 79.5, 69.3, 53.7, 48.3, 39.6, 33.3, 29.2 (× 3), 17.1, 16.6.

[0202] Cyclo(Ala-NMeTyr(tBu)-Ant-Ala) (7i) [ka] The reaction was carried out using compound 2i (110 mg, 214 μmol) according to the procedure for the synthesis of compound 7. Compound 7i was obtained as a colorless foamy solid (71.0 mg, 143 μmol, 73%).

[0203] [α] D 25 -84 (c = 1.0, CHCl3). IR (KBr) max 3315, 3218, 2977, 2933, 2872, 1690, 1645, 1600, 1583, 1530, 1506, 1444, 1414, 1389, 1365, 1345, 1296, 1258, 1235, 1161, 896, 755cm -1 . HRMS (ESI-TOF) C 27 H 35 Calculated value for N4O5: 495.2607, Measured value m / z: 495.2600 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.79 (1H, s), 8.32 (1H, d, J = 5.0 Hz), 8.27 (1H, dd, J = 8.0, 1.0 Hz), 7.58 (1H, dd, J = 8.5, 1.0 Hz), 7.58 (1H, d, J = 8.5 Hz), 7.47 (1H, dt, J = 8.0, 1.5 Hz), 7.13 (1H, dt, J = 8.0, 1.0 Hz), 7.03 (2H, d, J = 8.5 Hz), 6.89 (2H, d, J = 8.5 Hz), 4.83 (1H, dq, J = 8.5, 6.5 Hz), 4.15 (1H, dd, J = 9.5, 5.5 Hz), 3.92 (1H, dq, J = 7.0, 5.0 Hz), 3.17 (1H, dd, J = 14.0, 5.5 Hz), 3.12 (1H, dd, J = 14.0, 9.5 Hz), 2.71 (3H, s), 1.29 (3H, d, J = 7.0 Hz), 1.25 (9H, s), 1.10 (3H, d, J = 6.5 Hz). 13 C NMR (100 MHz, DMSO-d6) δ 172.0, 171.5, 169.7, 168.0, 153.4, 136.9, 133.5, 131.2, 129.7 (× 2), 127.0, 124.2, 123.8 (× 2), 122.4, 119.9, 77.6, 67.4, 53.2, 42.8, 39.1, 31.9, 28.6 (× 3), 17.4, 15.5.

[0204] Cyclo(Ala-NMeTyr-Ant-Ala) (1i, fp3-123) (Reference Example 4-3) [ka] The reaction was carried out according to the procedure for the synthesis of compound 1a with compound 7i (70.0 mg, 141 μmol). Compound 1i was obtained as a colorless foamy solid (46.5 mg, 106 μmol, 75%).

[0205] [α] D 26 -120 (c = 1.0, CH3OH). IR (KBr) ν max 3303, 2974, 2937, 1637, 1598, 1584, 1537, 1516, 1445, 1418, 1380, 1345, 1299, 1258, 1234, 1171, 828, 809, 760 cm -1 . HRMS (ESI-TOF) C 23 H 27 Calculated value of N4O5 439.1981, measured value m / z 439.1972 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.75 (1H, s), 9.20, (1H, s), 8.31 (1H, d, J = 5.0 Hz), 8.27 (1H, dd, J = 8.0, 1.0 Hz), 7.55 (1H, dd, J = 8.0, 1.0 Hz), 7.53 (1H, d, J = 9.0 Hz), 7.47 (1H, dt, J = 8.0, 1.5 Hz), 7.12 (1H, dt, J = 8.0, 1.0 Hz), 6.92 (2H, d, J = 8.5 Hz), 6.67 (2H, d, J = 8.5 Hz), 4.85 (1H, dq, J = 9.0, 6.5 Hz), 4.07 (1H, dd, J = 10.0, 5.0 Hz), 3.92 (1H, dq, J = 7.0, 5.0 Hz), 3.10 (1H, dd, J = 13.5, 5.0 Hz), 3.05 (1H, dd, J = 13.5, 10.0 Hz), 2.74 (3H, s), 1.30 (3H, d, J = 7.0 Hz), 1.10 (3H, d, J = 6.5 Hz). 13C NMR (100 MHz, DMSO-d6) δ 172.0, 171.4, 169.7, 168.1, 155.7, 136.9, 131.2, 130.0 (× 2), 128.7, 127.0, 124.3, 122.4, 119.9, 115.2 (× 2), 67.6, 53.2, 42.8, 39.2, 31.7, 17.4, 15.5.

[0206] [I-13. Synthesis of D-valine substitutes] Cbz-D-Val-NMeTyr(tBu)-Ant-Ala-OMe(3f, fp4-43) (Reference Example 5-1) [ka] Following the procedure for the synthesis of compound 3a, the reaction was carried out with compound 6 (300 mg, 658 μmol) and Cbz-D-Val-OH (165 mg, 658 μmol), affording compound 3f as a colorless foamy solid (395 mg, 573 μmol, 87%).

[0207] [α] D 23 -50 (c = 1.0, CHCl3). IR (KBr) max 3335, 3061, 3027, 2973, 2933, 2875, 1735, 1720, 1647, 1601, 1587, 1509, 1448, 1405, 1365, 1301, 1234, 1217, 1164, 1085, 1027, 897, 756, 698cm -1 . HRMS (ESI-TOF) C 38 H 49 Calculated value for N4O8: 689.3550, Found value m / z: 689.3539 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 11.46 (1H, s), 8.63 (1H, dd, J = 8.5, 1.0 Hz), 7.52 (1H, dd, J = 8.5, 1.0 Hz), 7.49 (1H, dt, J = 8.5, 1.0 Hz), 7.29-7.25 (5H, m), 7.11 (2H, d, J = 8.5 Hz), 7.10 (1H, dt, J = 8.0, 1.0 Hz), 6.88 (2H, d, J = 8.5 Hz), 6.79 (1H, d, J = 7.0 Hz), 5.86 (1H, d, J = 9.0 Hz), 5.69 (1H, dd, J = 11.5, 5.0 Hz), 5.14 (1H, d, J = 12.5 Hz), 5.03 (1H, d, J = 12.5 Hz), 4.75 (1H, dq, J = 7.0, 7.0 Hz), 4.55 (1H, dd, J = 8.5, 5.0 Hz), 3.75 (3H, s), 3.55 (1H, dd, J = 15.0, 5.0 Hz), 2.98 (3H, s), 2.97 (1H, dd, J = 15.0, 11.5 Hz), 1.65 (1H, m), 1.47 (3H, d, J = 7.0 Hz), 1.31 (9H, s), 0.73 (3H, d, J = 6.5 Hz), 0.54 (3H, d, J = 6.5 Hz). 13 C NMR (100 MHz, CDCl3) δ 173.4, 172.8, 168.7, 167.8, 156.3, 154.1, 139.3, 136.7, 132.9, 131.8, 129.1 (× 2), 128.3 (× 2), 127.8, 127.5 (× 2), 126.7, 124.2 (× 2), 123.1, 121.2, 119.9, 78.2, 66.4, 59.1, 56.0, 52.6, 48.3, 32.9, 31.5, 31.0, 28.7 (× 3), 19.6, 18.4, 16.4.

[0208] HD-Val-NMeTyr(tBu)-Ant-Ala-OH(2f, fp4-45) (Reference example 5-2) [ka] The reaction was carried out according to the procedure for the synthesis of compound 2a with compound 3f (308 mg, 447 μmol). Compound 2f was obtained as a colorless foamy solid (201 mg, 372 μmol, 83%).

[0209] [α] D 23 -109 (c = 0.50, CH3OH). IR (KBr) max 2974, 2927, 1633, 1597, 1509, 1447, 1398, 1365, 1308, 1239, 1162 cm -1 . HRMS (ESI-TOF) C 29 H 41 Calculated value for N4O6: 541.3018, Found value m / z: 541.3026 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 8.50 (1H, dd, J = 8.0, 1.0 Hz), 7.78 (1H, dd, J = 8.0, 1.0 Hz), 7.51 (1H, dt, J = 8.0, 1.0 Hz), 7.19 (2H, d, J = 8.5 Hz), 7.17 (1H, dt, J = 8.0, 1.0 Hz), 6.90 (2H, d, J = 8.5 Hz), 5.84 (1H, dd, J = 12.0, 4.5 Hz), 4.35 (1H, d, J = 5.0 Hz), 4.07 (1H, q, J = 7.0 Hz), 3.52 (1H, dd, J = 16.0, 4.5 Hz), 3.00 (3H, s), 2.97 (1H, dd, J = 16.0, 12.0 Hz), 1.82 (1H, m), 1.45 (3H, d, J = 7.0 Hz), 1.32 (9H, s), 0.74 (3H, d, J = 7.0 Hz), 0.65 (3H, d, J = 7.0 Hz). 13 C NMR (100 MHz, CD3OD) δ 180.4, 172.0, 171.1, 169.5, 155.4, 139.6, 133.4 (× 2), 130.5 (× 2), 129.4, 125.4 (× 2), 124.5, 122.0, 121.6, 79.5, 60.5, 57.0, 54.0, 33.3, 32.0, 30.8, 29.2 (× 3), 18.7, 17.4, 17.2.

[0210] Cyclo(D-Val-NMeTyr(tBu)-Ant-Ala)(7f) [ka] The reaction was carried out using compound 2f (54.0 mg, 100 μmol) according to the procedure for the synthesis of compound 7. Compound 7f was obtained as a colorless foamy solid (48.3 mg, 92.2 mmol, 92%).

[0211] [α] D23 -49 (c = 1.0, CHCl3). IR (KBr) ν max 3290, 2974, 2937, 1639, 1508, 1447, 1235, 1161 cm -1 . HRMS (ESI-TOF) C 29 H 39 Calculated value of N4O5 523.2920, measured value m / z 523.2914 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (1H, d, J = 7.0 Hz), 9.02 (1H, s), 8.05 (1H, dd, J = 8.0, 1.0 Hz), 7.95 (1H, d, J = 10.0 Hz), 7.46 (1H, dt, J = 8.0, 1.5 Hz), 7.30 (1H, dd, J = 7.5, 1.5 Hz), 7.15 (1H, dt, J = 8.0, 1.0 Hz), 7.14 (2H, d, J = 8.5 Hz), 6.81 (2H, d, J = 8.5 Hz), 5.68 (1H, dd, J = 11.5, 4.5 Hz), 4.44 (1H, dq, J = 7.0, 7.0 Hz), 4.25 (1H, t, J = 10.0 Hz), 3.09 (1H, dd, J = 14.5, 4.5 Hz), 2.91 (1H, dd, J = 14.5, 11.5 Hz), 2.83 (3H, s), 1.87 (1H, m), 1.22 (3H, d, J = 7.0 Hz), 1.21 (9H, s), 0.78 (3H, d, J = 6.5 Hz), 0.28 (3H, d, J = 6.5 Hz). 13C NMR (100 MHz, DMSO-d6) δ 172.0, 171.4, 169.4, 168.3, 153.3, 135.0, 131.9, 130.4, 129.5 (× 2), 127.0, 126.8, 123.5 (× 2), 123.3, 121.6, 77.5, 56.9, 54.5, 49.3, 31.2, 29.9, 29.1, 28.4 (× 3), 18.5, 18.3, 14.5.

[0212] Cyclo(D-Val-NMeTyr-Ant-Ala) (1f, fp4-49) (Reference Example 5-3) [ka] The reaction was carried out using compound 7f (99.6 mg, 190 μmol) according to the procedure for the synthesis of compound 1a. Compound 1f was obtained as a colorless foamy solid (76.7 mg, 164 μmol, 86%).

[0213] [α] D 22 -40 (c = 0.37, CH3OH). IR (KBr) max 3303, 2961, 1638, 1515, 1447, 1335, 125,0 1175 cm -1 . HRMS (ESI-TOF) C 25 H 31 Calculated value for N4O5: 467.2294, Found value: m / z: 467.2284 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.08 (1H, d, J = 7.0 Hz), 9.07 (1H, s), 9.02 (1H, s), 8.03 (1H, d, J = 8.0 Hz), 7.93 (1H, d, J = 9.5 Hz), 7.45 (1H, dt, J = 8.0, 1.5 Hz), 7.36 (1H, dd, J = 8.0, 1.5 Hz), 7.14 (1H, dt, J = 8.0, 1.0 Hz), 7.00 (2H, d, J = 8.5 Hz), 6.60 (2H, d, J = 8.5 Hz), 5.57 (1H, dd, J = 11.5, 4.5 Hz), 4.43 (1H, dq, J = 7.5, 7.0 Hz), 4.26 (1H, t, J = 10.0 Hz), 3.03 (1H, dd, J = 14.5, 4.5 Hz), 2.82 (3H, s), 2.80 (1H, dd, J = 14.5, 11.5 Hz), 1.89 (1H, m), 1.23 (3H, d, J = 7.0 Hz), 0.79 (3H, d, J = 7.0 Hz), 0.35 (3H, d, J = 7.0 Hz). 13 C NMR (100 MHz, DMSO-d6) δ 171.9, 171.3, 169.4, 168.3, 155.7, 135.0, 130.4, 129.8 (× 2), 127.1, 126.9, 126.8, 123.3, 121.5, 114.9 (× 2), 57.2, 54.6, 49.2, 31.1, 29.9, 29.1, 18.5, 18.2, 14.5.

[0214] [I-14. Synthesis of L-リジンsubstituted body] Cbz-Lys(Boc)-NMe-Tyr(tBu)-Ant-Ala-OMe(fp4-63) (Reference Example 6-1)

change

[0215] [α] D 23 -79 (c = 1.0, CHCl3). IR (KBr) max 3336, 2977, 2930, 2867, 1699, 1645, 1520, 1449, 1407, 1365, 1238, 1217, 756 cm -1 . ESI-MS C 44 H 60 N5O 10 Calculated value 818.4340, measured value m / z 818.4323 [M+H] + .

[0216] Cbz-Lys-NMe-Tyr(tBu)-Ant-Ala-OMe(fp4-64) (Reference Example 6-2) [ka] To a solution of compound fp4-63 (32.7 mg, 40.0 μmol) in CHCl (400 μL), TMSOTf (29 μL, 160 μmol) and 2,6-lutidine (37 μL, 320 μmol) were added. The mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with CHCl and washed with saturated brine. The organic phase was dried over NaSO, filtered and evaporated. The residue was purified by silica gel column chromatography (CHCl / MeOH = 99 / 1) to give compound fp4-64 (8.0 mg, 27%) as a colorless solid.

[0217] [α] D 24 -66 (c = 0.80, CHCl3). IR (KBr) max3318, 2977, 2952, 1702, 1640, 1600, 1509, 1448, 1410, 1366, 1241, 1162, 1031, 896, 757 cm -1 . ESI-MS C 39 H 52 Calculated value of C5H8N5O8 is 718.3815, measured value m / z 718.3815 [M+H]+ + .

[0218] <II. Pharmacological Tests of Novel Compounds> [Reagents] RPMI 1640 powder medium was purchased from GIBCO. 3-Morpholinopropanesulfonic acid (MOPS) was purchased from DOJINDO. Sodium chloride was purchased from Kanto Chemical Co., Inc. DMSO was purchased from Nacalai Tesque, Inc.

[0219] [Instruments, Apparatus and Materials] An automatic mixer from YAZAWA was used as the vortex mixer. An iMark Microplate from Bio-Rad was used for absorbance measurement. An NS-4P from AS ONE was used as the plate mixer. An NB-203 from N-Biotek was used for the incubator of 96-well plates (from AS ONE). A CK2 from Olympus was used as the microscope. 150 mm bottle top filters (pore size 0.22 mm), 15 mL centrifuge tubes and 50 mL centrifuge tubes were purchased from Corning.

[0220] [Test Bacteria] The following fungi kept in the laboratory were used as test bacteria: Candida albicans ATCC 90029, Cryptococcus neoformans ATCC 90113, Rhizopus oryzae NBRC 4705.

[0221] [Preparation of Reagents] Amphotericin B was prepared as a 0.8 mg / mL DMSO solution. Each test compound was prepared as a 1.6 mg / mL DMSO solution. All solutions were stored at -20°C after preparation. Physiological saline (0.85% sodium chloride aqueous solution) and bamboo skewers were sterilized by high-pressure steam (121°C, 15 minutes) and then stored at room temperature.

[0222] [Preparation of RPMI 1640 medium] RPMI 1640 powder medium and MOPS (10.4 and 34.5 g, respectively) were added to 900 mL of sterile distilled water and stirred until the added components were dissolved. The solution was then adjusted to pH 7.0 with 2 M NaOH. The solution was made up to 1 L with sterile distilled water. The solution was sterilized by filtration using a 150 mm bottle top filter (Corning). The resulting sterile solution was used as RPMI 1640 medium and stored at 4°C.

[0223] [Test II-1: Activity evaluation test of antifungal active substances] [Preparation of bacterial solution] The method for preparing an inoculum of yeast fungi (Candida albicans and Cryptococcus neoformans) is as follows. 5 mL of sterile saline was measured and placed in a sterilized 15 mL centrifuge tube (Corning). Five colonies (approximately 1 mm in diameter) of each test fungus were picked using a sterilized bamboo skewer and suspended in the measured amount of sterile saline. This was vortexed for 15 seconds using an automatic mixer (YAZAWA). 100 μL of this suspension was dispensed into a sterilized 96-well plate (AS ONE), and the OD 550 The OD was measured using sterile saline at 0.5 McFarland concentration. 550 = 0.0548). The resulting suspension was diluted 100-fold with RPMI 1640 medium. This 100-fold diluted solution was further diluted 20-fold with RPMI 1640 medium. The resulting diluted solution was used as the inoculum.

[0224] The method for preparing an inoculum of Zygomycete (Rhizopus oryzae) is as follows. 2 mL of sterile saline was measured into a sterilized 15 mL centrifuge tube. Spores of each test fungus were scraped with a platinum loop and suspended in the measured amount of sterile saline. This was left to stand for 5 minutes. 100 μL of this suspension was dispensed into a sterilized 96-well plate, and the OD 550 The OD of the filamentous fungus was measured using sterile saline. 550 = 0.0621, and zygomycetes have OD 550 = 0.0765. The obtained suspension was diluted 50-fold with RPMI 1640 medium. The obtained diluted solution was used as the inoculum.

[0225] [Evaluation of antifungal spectrum by broth microdilution method] The antifungal spectrum was measured by broth microdilution according to the Clinical Laboratory Standards Institute (CLSI) M27-A4 and M38-A3 methods (Reference Method for Broth Dilution Antifungal Succeptibity Testing of Years; Approved Standard - Fourth Edition, Wayne, PA, 28, M27-A4 (2017), Filamentous Fungi; Approved Standard-Third Edition Wayne, PA, 28, M38-A3 (2017)). 1.0 μL of a dilution of the test compound prepared with DMSO was added to each well of a sterilized 96-well plate so that the final concentrations of the test compound were 32, 16, 8.0, 4.0, 2.0, 1.0, and 0.5 μg / mL. As a control, 1.0 μL of DMSO alone was added. Eight wells were prepared for each test group and control group. Next, yeast fungi were added to each well in a ratio of 19 μL of RPMI 1640 medium and 180 μL of inoculum. After addition, the OD 550The OD of each well was measured (this was defined as the initial turbidity). Using an NB-203 (N-Biotek) incubator, the yeast fungi inoculated into the wells of a 96-well plate were cultured at 35°C for 24 hours for Candida albicans and 72 hours for Cryptococcus neoformans. The 96-well plate was then shaken and agitated for 30 minutes using an NS-4P (As One). After agitation, the OD of each well was measured. 550 was measured (this was defined as the terminal turbidity). The inhibition rate of each compound was calculated based on the following formula (M-2). The minimum concentration of the compound at which the calculated inhibition rate was 90% or more was defined as the minimum inhibitory concentration (MIC value) of the compound.

number

[0226] In the same manner as above, the compounds and DMSO as a control were dispensed into the designated wells of a 96-well plate. The zygomycetes were added to the designated wells at a ratio of 99 μL of RPMI 1640 medium and 100 μL of inoculum solution. After addition, the yeast fungi inoculated into the wells of the 96-well plate were cultured at 35° C. using an NB-203 incubator, and the zygomycetes were cultured for 24 hours. Each well was observed under a microscope (CK2: Olympus). As a result of the observation, the minimum concentration at which the growth of the filamentous fungus was completely inhibited for each compound was determined. This concentration was taken as the MIC value of the compound.

[0227] As a result of this test, amphotericin B showed no growth inhibitory activity against Candida albicans and Rhizopus oryzae at concentrations of 1.0 μg / mL or less, and against Cryptococcus neoformans at concentrations of 2.0 μg / mL or less, and none of the test compounds showed growth inhibitory activity against Candida albicans, Cryptococcus neoformans, or Rhizopus oryzae at concentrations of 64 μg / mL or less.

[0228] [Test II-2: Evaluation of potentiation activity against the antifungal agent amphotericin B] [Preparation of bacterial solution] A loopful of Candida albicans ATCC90029 strain was applied to PDA medium and cultured at 27°C for 2-3 days. This culture was passaged twice and grown until the colonies reached a diameter of 1 mm or more. 5 mL of sterile saline was measured into a sterilized 15 mL centrifuge tube (Corning). Five colonies of the grown bacteria (approximately 1 mm in diameter) were picked using a sterilized bamboo skewer and suspended in the measured amount of sterile saline. This was vortexed for 15 seconds using an automatic mixer (YAZAWA). 100 μL of this suspension was dispensed into a sterilized 96-well plate (AS ONE), and the OD 550 The OD was measured using sterile saline at 0.5 McFarland concentration. 550 = 0.0548). The resulting suspension was diluted 100-fold with RPMI 1640 medium. This 100-fold diluted solution was further diluted 20-fold with RPMI 1640 medium. The resulting diluted solution was used as the inoculum.

[0229] Inoculation solutions of the yeast fungus (Cryptococcus neoformans) and the zygomycete (Rhizopus oryzae) were prepared in the same manner as in Test II-1.

[0230] [Evaluation of fungal inhibition rate using broth microdilution method] The inhibition rate against the fungus Candida albicans ATCC90029 strain was measured by broth microdilution method according to CLSI M27-A4 and M38-A3 methods (Reference Method for Broth Dilution Antifungal Succeptibity Testing of Years; Approved Standard - Fourth Edition, Wayne, PA, 28, M27-A4 (2017), Filamentous Fungi; Approved Standard-Third Edition Wayne, PA, 28, M38-A3 (2017)). 1.0 μL of the dilution solution of the test compound prepared with DMSO was added to each well of a sterilized 96-well plate so that the final concentrations of the test compound were 32, 16, 8.0, 4.0, 2.0, 1.0 and 0.5 μg / mL. As a control, 1.0 μL of DMSO alone was added. Eight wells were prepared for each test group and control group. Next, the fungus was added to each well in a ratio of 19 μL of RPMI 1640 medium and 180 μL of inoculum. After addition, the OD 550 The OD of each well was measured (this was defined as the initial turbidity). Using an NB-203 (N-Biotek) incubator, the fungi inoculated into the wells of a 96-well plate were cultured at 35°C for 24 hours for Candida albicans and 72 hours for Cryptococcus neoformans. The 96-well plate was then shaken and agitated for 30 minutes using an NS-4P (As One). After agitation, the OD of each well was measured. 550 was measured (this was defined as the terminal turbidity). The inhibition rate of each compound was calculated based on the above formula (M-1). The minimum concentration of the compound at which the calculated inhibition rate was 90% or more was defined as the MIC value of the compound.

[0231] Using the same procedure as above, compounds and DMSO as a control were dispensed into the designated wells of a 96-well plate. Zygomycetes (Rhizopus oryzae) were added to the designated wells at a ratio of 99 μL of RPMI 1640 medium and 100 μL of inoculum solution. After addition, the zygomycetes inoculated into the wells of the 96-well plate were cultured at 35°C for 24 hours using an NB-203 incubator. Each well was observed under a microscope (CK2: Olympus). As a result of the observation, the minimum concentration at which growth was completely inhibited for each compound was determined. This concentration was taken as the MIC value of the compound.

[0232] [Evaluation of the amphotericin B activity enhancing effect of test compounds using broth microdilution method] To each well of a sterilized 96-well plate, 1.0 μL of each of the diluted solutions of the test compound and amphotericin B prepared in DMSO was added so that the final concentrations of the test compound were 32, 16, 8.0, 4.0, 2.0, 1.0 and 0.5 μg / mL, and the final concentrations of amphotericin B were 1.0, 0.5, 0.25, 0.125, 0.0625 or 0.00313 μg / mL. As a control, 2.0 μL of DMSO alone was added. One well for each test group and eight wells for the control group were prepared. Next, the fungus was added to each well in a ratio of 18 μL of RPMI 1640 medium and 180 μL of inoculum, and the zygomycete was added to each well in a ratio of 98 μL of RPMI 1640 medium and 100 μL of inoculum. After addition, the OD of each well was measured. 550 The OD of each well was measured (this was defined as the initial turbidity). Using an NB-203 (N-Biotek) incubator, the fungi and zygomycetes inoculated into the wells of a 96-well plate were cultured at 35°C for 24 hours for Candida albicans and Rhizopus oryzae, and for 72 hours for Cryptococcus neoformans. The 96-well plate was then shaken and agitated for 30 minutes using an NS-4P (As One). After agitation, the OD of each well was measured. 550was measured (this was defined as the terminal turbidity). The inhibition rate due to the combined administration of each test compound and amphotericin B was calculated based on the above formula (M-2). The minimum concentration of amphotericin B at which the calculated inhibition rate was 90% or more was defined as the MIC value of amphotericin B in the combined administration of each test compound and amphotericin B. In addition, the amphotericin B activity enhancement rate of each test compound was calculated based on the following formula (M-3). The calculation of the amphotericin B activity enhancement rate of each compound was performed by repeating the test three times.

number

[0233] The following table shows the MIC values ​​of amphotericin B when a test compound and amphotericin B were co-administered. In the table, the column "Test compound concentration" shows the concentration of the test compound when a test compound and amphotericin B were co-administered, and the column "Amphotericin B concentration" shows the MIC value and activity enhancement rate of amphotericin B when a test compound and amphotericin B were co-administered.

[0234] [Table 1] TIFF2025035113000067.tif67141TIFF2025035113000068.tif67141

[0235] [Table 2] TIFF2025035113000070.tif66141TIFF2025035113000071.tif66141

[0236] [Table 3] TIFF2025035113000073.tif65141TIFF2025035113000074.tif65141

[0237]

Table 4

[0238]

Table 5

[0239]

Table 6

[0240]

Table 7

[0241]

Table 8

[0242]

Table 9

[0243]

Table 10

[0244] [Table 11] TIFF2025035113000097.tif65141TIFF2025035113000098.tif65141

[0245] [Table 12]

[0246] As shown in Tables 2 to 12, when any of the test compounds was administered in combination with amphotericin B at a concentration of 0.5 μg / mL or more, for example, in the range of 1 to 32 μg / mL, particularly in the range of 2 to 32 μg / mL, the antifungal activity of amphotericin B against at least one of Candida albicans, Cryptococcus neoformans, and Rhizopus oryzae, particularly against Candida albicans, was enhanced by 2-fold or more, for example, in the range of 2 to 32-fold, particularly 4 to 32-fold. From these results, it was revealed that any of the test compounds can more effectively enhance the antifungal activity of antifungal drugs compared to the known compound nectriatide (Comparative Example 1, Table 1).

[0247] The present invention is not limited to the above-described embodiments, but includes various modified examples. For example, the above-described embodiments have been described in detail to clearly explain the present invention, and the present invention is not necessarily limited to those including all of the configurations described. In addition, it is possible to add, delete, and / or replace part of the configuration of each embodiment with other configurations.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, R 1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, or substituted or unsubstituted heteroarylalkyloxycarbonyl; R 2 is OH, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy; R 1 and R 2 together form a single bond, R 3 is a substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted cycloalkenylene, substituted or unsubstituted cycloalkynylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, with the proviso that the substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, and substituted or unsubstituted alkynylene are optionally interrupted by one or more substituted or unsubstituted cycloalkylene, substituted or unsubstituted cycloalkenylene, substituted or unsubstituted cycloalkynylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R 4 is H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy; R 5 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, or substituted or unsubstituted heteroarylalkyloxycarbonyl; R 6 is H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy; However, R 3 When R is 1,6-phenylene, 4 is not a substituted arylalkyl. or a salt thereof, or a solvate thereof.

2. R 1 is H, substituted or unsubstituted C 1 ~C 5 Alkyl, substituted or unsubstituted C 2 ~C 5 Alkenyl, substituted or unsubstituted C 2 ~C 5 Alkynyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 4 ~C 6 Cycloalkenyl, substituted or unsubstituted C 4 ~C 6 Cycloalkynyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl-C 1 ~C 5 Alkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C 1 ~C 5 Alkyl, substituted or unsubstituted C 6 ~C 15 Aryl, substituted or unsubstituted C 6 ~C 15 Aryl-C 1 ~C 5 Alkyl, substituted or unsubstituted 5- to 15-membered heteroaryl, substituted or unsubstituted 5- to 15-membered heteroaryl-C 1 ~C 5 Alkyl, substituted or unsubstituted C 1 ~C 5 Alkoxycarbonyl, substituted or unsubstituted C 3 ~C 6 Cycloalkoxycarbonyl, substituted or unsubstituted 3- to 6-membered heterocycloalkoxycarbonyl, substituted or unsubstituted C 6 ~C 15 Aryloxycarbonyl, substituted or unsubstituted C 6 ~C 15 Aryl-C 1 ~C 5 Alkyloxycarbonyl, substituted or unsubstituted C 6 ~C 15 Aryl-C 2 ~C 5 alkenyloxycarbonyl, substituted or unsubstituted 5- to 15-membered heteroaryloxycarbonyl, or substituted or unsubstituted 5- to 15-membered heteroaryl-C 1 ~C 5 alkyloxycarbonyl, and R 2 is OH, substituted or unsubstituted C 1 ~C 5 Alkoxy, substituted or unsubstituted C 3 ~C 6 Cycloalkoxy, substituted or unsubstituted 3- to 6-membered heterocycloalkoxy, substituted or unsubstituted C 6 ~C 15 Aryloxy, substituted or unsubstituted C 6 ~C 15 Aryl-C 1 ~C 5 Alkyloxy, substituted or unsubstituted C 6 ~C 15 Aryl-C 2 ~C 5 alkenyloxy, substituted or unsubstituted 5- to 15-membered heteroaryloxy, substituted or unsubstituted 5- to 15-membered heteroaryl-C 1 ~C 5 Alkyloxy or substituted or unsubstituted C 1 ~C 5 is acyloxy, 2. The compound according to claim 1, or a salt thereof, or a solvate thereof.

3. R 1 is H, substituted or unsubstituted C 6 ~C 15 Aryloxycarbonyl, substituted or unsubstituted C 6 ~C 15 Aryl-C 1 ~C 5 Alkyloxycarbonyl, substituted or unsubstituted C 6 ~C 15 Aryl-C 2 ~C 5 alkenyloxycarbonyl, substituted or unsubstituted 5- to 15-membered heteroaryloxycarbonyl, or substituted or unsubstituted 5- to 15-membered heteroaryl-C 1 ~C 5 alkyloxycarbonyl, and R 2 is OH or substituted or unsubstituted C 1 ~C 5 is an alkoxy; 3. The compound according to claim 2, or a salt thereof, or a solvate thereof.

4. R 3 is substituted or unsubstituted C 1 ~C 5 Alkylene, or substituted or unsubstituted C 6 ~C 15 The compound according to claim 1, which is an arylene, or a salt thereof, or a solvate thereof.

5. R 3 The compound according to claim 4, wherein is 1,1-ethylene, 1,2-phenylene, 1,3-phenylene or 1,4-phenylene, or a salt thereof, or a solvate thereof.

6. R 4 is substituted or unsubstituted C 1 ~C 5 Alkyl, substituted or unsubstituted C 2 ~C 5 Alkenyl, substituted or unsubstituted C 2 ~C 5 Alkynyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 4 ~C 6 Cycloalkenyl, substituted or unsubstituted C 4 ~C 6 Cycloalkynyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl-C 1 ~C 5 Alkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C 1 ~C 5 Alkyl, substituted or unsubstituted C 6 ~C 15 Aryl, substituted or unsubstituted C 6 ~C 15 Aryl-C 1 ~C 5 Alkyl, substituted or unsubstituted 5- to 15-membered heteroaryl, or substituted or unsubstituted 5- to 15-membered heteroaryl-C 1 ~C 5 The compound according to claim 1, or a salt thereof, or a solvate thereof, wherein R is an alkyl group.

7. R 4 is substituted or unsubstituted C 1 ~C 5 Alkyl, or substituted or unsubstituted C 6 ~C 15 Aryl-C 1 ~C 5 The compound according to claim 6, or a salt thereof, or a solvate thereof, wherein R is an alkyl group.

8. R 4 is substituted or unsubstituted C 2 ~C 5 Alkyl, or substituted or unsubstituted C 6 ~C 15 Aryl-C 1 ~C 5 The compound according to claim 6, or a salt thereof, or a solvate thereof, wherein R is an alkyl group.

9. R 4 The compound according to claim 6, wherein is 4-hydroxyphenylmethyl, 4-tert-butyloxyphenylmethyl, or phenylmethyl, or a salt thereof, or a solvate thereof.

10. R 5 is H, substituted or unsubstituted C 1 ~C 5 Alkyl, substituted or unsubstituted C 2 ~C 5 Alkenyl, substituted or unsubstituted C 2 ~C 5 Alkynyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 4 ~C 6 Cycloalkenyl, substituted or unsubstituted C 4 ~C 6 Cycloalkynyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl-C 1 ~C 5 Alkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C 1 ~C 5 Alkyl, substituted or unsubstituted C 6 ~C 15 Aryl, substituted or unsubstituted C 6 ~C 15 Aryl-C 1 ~C 5 Alkyl, substituted or unsubstituted 5- to 15-membered heteroaryl, or substituted or unsubstituted 5- to 15-membered heteroaryl-C 1 ~C 5 The compound according to claim 1, or a salt thereof, or a solvate thereof, wherein R is an alkyl group.

11. R 5 is H or substituted or unsubstituted C 1 ~C 5 The compound according to claim 10, or a salt thereof, or a solvate thereof, wherein R is an alkyl group.

12. R 6 is substituted or unsubstituted C 1 ~C 5 Alkyl, substituted or unsubstituted C 2 ~C 5 Alkenyl, substituted or unsubstituted C 2 ~C 5 Alkynyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 4 ~C 6 Cycloalkenyl, substituted or unsubstituted C 4 ~C 6 Cycloalkynyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl-C 1 ~C 5 Alkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C 1 ~C 5 Alkyl, substituted or unsubstituted C 6 ~C 15 Aryl, substituted or unsubstituted C 6 ~C 15 Aryl-C 1 ~C 5 Alkyl, substituted or unsubstituted 5- to 15-membered heteroaryl, or substituted or unsubstituted 5- to 15-membered heteroaryl-C 1 ~C 5 The compound according to claim 1, or a salt thereof, or a solvate thereof, wherein R is an alkyl group.

13. R 6 is substituted or unsubstituted C 1 ~C 5 Alkyl, or substituted or unsubstituted C 6 ~C 15 Aryl-C 1 ~C 5 The compound according to claim 12, or a salt thereof, or a solvate thereof, wherein R is an alkyl group.

14. R 6 The compound according to claim 12, or a salt thereof, or a solvate thereof, wherein is methyl, propan-2-yl, 4-aminobutan-1-yl, or 4-(t-butoxycarbonylamino)butan-1-yl.

15. A method for producing the compound according to claim 1 or a salt thereof, or a solvate thereof, comprising the steps of: Formulae (VI), (VII), (VIII) and (IX): 【Chemistry 2】 [In the formula, R 3 , R 4 , R 5 and R 6 has the meaning given in claim 1. or a protected derivative thereof, or a salt or solvate thereof, to form a main chain of the compound represented by formula (I) having a chain structure; The method comprising:

16. a cyclization step in which the compound represented by formula (I) having a chain structure obtained in the main chain formation step is subjected to intramolecular cyclization to obtain a compound represented by formula (I) having a cyclic structure; 16. The method of claim 15, further comprising:

17. An activity enhancer for at least one antifungal drug selected from the group consisting of polyene macrolide drugs, azole drugs, echinocandin drugs and fluoropyrimidine drugs, comprising the compound according to claim 1 or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable solvate thereof as an active ingredient.

18. 13. A pharmaceutical comprising the compound according to claim 1 or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable solvate thereof, as an active ingredient.

19. 19. A medicament according to claim 18 for use in the prevention or treatment of one or more fungal infections.

20. 19. The pharmaceutical composition of claim 18, further comprising at least one antifungal agent selected from the group consisting of polyene macrolide agents, azole agents, echinocandin agents, and fluoropyrimidine agents.

21. A pharmaceutical composition comprising the compound according to claim 1 or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable solvate thereof, and one or more pharma- ceutically acceptable carriers.

22. 22. A pharmaceutical composition according to claim 21 for use in the prevention or treatment of one or more fungal infections.

23. 22. The pharmaceutical composition of claim 21, further comprising at least one antifungal agent selected from the group consisting of polyene macrolide agents, azole agents, echinocandin agents, and fluoropyrimidine agents.

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