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

Abstract

The present invention addresses the problem of providing a novel compound having an effect to more effectively enhance the antifungal activity of an antifungal drug compared with known pharmaceutical compounds. One aspect of the present invention relates to a compound represented by formula (I) [wherein R1, R2, R3, R4, R5, and R6 have meanings as set forth in the description and the claims], a salt of the compound, or a solvate of the compound or the salt. Another aspect of the present invention relates to: a method for producing a compound represented by formula (I), a salt of the compound, or a solvate of the compound or the salt; and an activity enhancer for at least one antifungal drug selected from the group consisting of a polyene macrolide-based drug, an azole-based drug, a candin-based drug, and a fluoropyrimidine-based drug, the activity enhancer containing, as an active ingredient, the compound, a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable solvate of the compound or the pharmaceutically acceptable salt.

Description

Novel compounds having activity enhancing effects on antifungal drugs and their production method

[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.

[0002] Since the 1950s, research and development of antibiotics has made rapid progress. Accordingly, antibiotics have become widely available, and various therapeutic drugs have been developed for various infectious diseases. Meanwhile, 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 issues such as immunodeficiency caused by leukemia, malignant lymphoma, or HIV infection, a decrease in immune function due to the administration of anticancer drugs, or bacterial replacement due to the excessive use of antibiotics.

[0003] Currently, antifungal drugs such as polyene macrolides, azoles, echinocandins, and fluoropyrimidines are used to treat deep fungal infections. For example, amphotericin B, a polyene macrolide drug, has strong antifungal activity and is effective in treating serious diseases. However, this drug may cause side effects such as nephrotoxicity, raising safety concerns (Non-Patent Document 1). Flucytosine, a fluoropyrimidine drug, also raises concerns about its 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, because these drugs have a narrow antifungal spectrum and a bacteriostatic mechanism of action, they are less effective against serious diseases. Furthermore, an increase in drug-resistant bacteria has also 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-seated mycoses (Non-Patent Document 3). However, because these drugs have a narrow antifungal spectrum, the diseases they treat are limited to candidiasis and aspergillosis. Furthermore, the number of reported cases of bacteria resistant to these drugs is gradually increasing.

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

[0007] Patent No. 7046344

[0008] Gallis et al., Rev. Infect. Dis., Vol. 12, pp. 309-329, 1990; Rex et al., Antimicrob. Agents Chemothe., Vol. 39, pp. 1-8, 1995; Denning, Lancet, Vol. 362, No. 9330, pp. 1142-1151, 2003; Fukuda et al., J. Nat. Prod., Vol. 82, pp. 2673-2681, 2019

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

[0010] Antifungal drugs currently frequently used in the treatment of fungal infections such as deep mycosis have several problems. For example, amphotericin B, a polyene macrolide drug, can cause side effects such as severe nephrotoxicity. Furthermore, azole drugs are known to be highly susceptible to the development of drug-resistant bacteria. Therefore, in order to obtain therapeutic effects for fungal infections while avoiding these problems, there is a need for a means to reduce the dosage and administration period of the antifungal drugs.

[0011] A compound that enhances the antifungal activity of an antifungal drug can reduce the dose and / or administration period of the antifungal drug. Therefore, by using a compound with such an effect in combination with an antifungal drug, the dose and / or administration period of the antifungal drug can be reduced, thereby suppressing the occurrence of side effects such as nephrotoxicity and / or the occurrence of drug-resistant bacteria. Known compounds with this effect include the cyclic peptide nectriatide and its ring-opened derivative, a linear peptide, as well as pharmaceutically acceptable salts thereof (Patent Document 1 and Non-Patent Document 4). However, in order to develop highly effective pharmaceutical compounds, novel compounds that can more effectively enhance the antifungal activity of antifungal drugs have been sought.

[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 compared to known pharmaceutical compounds.

[0013] The present inventors have investigated various means for solving the above problems. They have found that novel cyclic or chain compounds 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 have the effect of more effectively enhancing the antifungal activity of antifungal drugs than nectriatide. The present inventors have completed the present invention based on this finding.

[0014] That is, the gist of the present invention is as follows: (Embodiment 1) Formula (I): [In the formula, R 1is 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; or 1 and R 2 together form a single bond, R 3is 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, provided 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 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 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, with the proviso that R 3 is 1,6-phenylene, R 4is not a substituted arylalkyl.] or a salt thereof, or a solvate thereof. (Embodiment 2) R 1 is H, substituted or unsubstituted C1 to C5 alkyl, substituted or unsubstituted C2 to C5 alkenyl, substituted or unsubstituted C2 to C5 alkynyl, substituted or unsubstituted C3 to C6 cycloalkyl, substituted or unsubstituted C4 to C6 cycloalkenyl, substituted or unsubstituted C4 to C6 cycloalkynyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C3 to C6 cycloalkyl-C1 to C5 alkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl-C1 to C5 alkyl, substituted or unsubstituted C6 to C 15 Aryl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyl, substituted or unsubstituted 5- to 15-membered heteroaryl, substituted or unsubstituted 5- to 15-membered heteroaryl-C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxycarbonyl, substituted or unsubstituted C3-C6 cycloalkoxycarbonyl, substituted or unsubstituted 3- to 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(Embodiment 3) A compound according to embodiment 1, or a salt thereof, or a solvate thereof, wherein R is 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. 1 is H, substituted or unsubstituted C6 to 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 (Embodiment 4) The compound of embodiment 2, or a salt thereof, or a solvate thereof, wherein R is OH or substituted or unsubstituted C1-C5 alkoxy. 3 is a substituted or unsubstituted C1 to C5 alkylene, or a substituted or unsubstituted C6 to C 15 A compound according to any one of Embodiments 1 to 3, or a salt thereof, or a solvate thereof, wherein R is arylene. 3 (Embodiment 6) The compound according to embodiment 4, or a salt thereof, or a solvate thereof, wherein R is 1,1-ethylene, 1,2-phenylene, 1,3-phenylene, or 1,4-phenylene. 4 is substituted or unsubstituted C1 to C5 alkyl, substituted or unsubstituted C2 to C5 alkenyl, substituted or unsubstituted C2 to C5 alkynyl, substituted or unsubstituted C3 to C6 cycloalkyl, substituted or unsubstituted C4 to C6 cycloalkenyl, substituted or unsubstituted C4 to C6 cycloalkynyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C3 to C6 cycloalkyl-C1 to C5 alkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl-C1 to C5 alkyl, substituted or unsubstituted C6 to C 15 Aryl, substituted or unsubstituted C6-C15 Embodiment 7: A compound according to any one of Embodiments 1 to 5, wherein R is aryl-C1-C5 alkyl, substituted or unsubstituted 5- to 15-membered heteroaryl, or substituted or unsubstituted 5- to 15-membered heteroaryl-C1-C5 alkyl, or a salt thereof, or a solvate thereof. 4 is a substituted or unsubstituted C1 to C5 alkyl, or a substituted or unsubstituted C6 to C 15 Embodiment 8: The compound of embodiment 6, or a salt thereof, or a solvate thereof, wherein R is aryl-C1-C5 alkyl. 4 is a substituted or unsubstituted C2 to C5 alkyl, or a substituted or unsubstituted C6 to C 15 Embodiment 9: The compound of embodiment 6, or a salt thereof, or a solvate thereof, wherein R is aryl-C1-C5 alkyl. 4 (Embodiment 10) The compound or salt thereof, or solvate thereof, according to any one of Embodiments 6 to 8, wherein R is 4-hydroxyphenylmethyl, 4-tert-butyloxyphenylmethyl, or phenylmethyl. 5 is H, substituted or unsubstituted C1 to C5 alkyl, substituted or unsubstituted C2 to C5 alkenyl, substituted or unsubstituted C2 to C5 alkynyl, substituted or unsubstituted C3 to C6 cycloalkyl, substituted or unsubstituted C4 to C6 cycloalkenyl, substituted or unsubstituted C4 to C6 cycloalkynyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C3 to C6 cycloalkyl-C1 to C5 alkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl-C1 to C5 alkyl, substituted or unsubstituted C6 to C 15 Aryl, substituted or unsubstituted C6-C 15 (Embodiment 11) A compound according to any one of Embodiments 1 to 9, or a salt thereof, or a solvate thereof, wherein R is aryl-C1-C5 alkyl, substituted or unsubstituted 5- to 15-membered heteroaryl, or substituted or unsubstituted 5- to 15-membered heteroaryl-C1-C5 alkyl. 5Embodiment 12. The compound of embodiment 10, or a salt thereof, or a solvate thereof, wherein R is H or substituted or unsubstituted C1-C5 alkyl. 6 is substituted or unsubstituted C1 to C5 alkyl, substituted or unsubstituted C2 to C5 alkenyl, substituted or unsubstituted C2 to C5 alkynyl, substituted or unsubstituted C3 to C6 cycloalkyl, substituted or unsubstituted C4 to C6 cycloalkenyl, substituted or unsubstituted C4 to C6 cycloalkynyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C3 to C6 cycloalkyl-C1 to C5 alkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl-C1 to C5 alkyl, substituted or unsubstituted C6 to C 15 Aryl, substituted or unsubstituted C6-C 15 Embodiment 13: A compound according to any one of Embodiments 1 to 11, or a salt thereof, or a solvate thereof, wherein R is aryl-C1-C5 alkyl, substituted or unsubstituted 5- to 15-membered heteroaryl, or substituted or unsubstituted 5- to 15-membered heteroaryl-C1-C5 alkyl. 6 is a substituted or unsubstituted C1 to C5 alkyl, or a substituted or unsubstituted C6 to C 15 The compound of embodiment 12, or a salt thereof, or a solvate thereof, wherein R is aryl-C1-C5 alkyl. 6 (Embodiment 15) A method for producing a compound or a salt thereof, or a solvate thereof, according to any one of Embodiments 1 to 14, comprising: [In the formula, R 3 , R 4 , R 5 and R 6has the meaning as defined in any one of Embodiments 1 to 14. The method according to Embodiment 15, further comprising: a main chain formation step of linking the amino group and the carboxyl group of a compound represented by Formula (I) having a chain structure, or a protected derivative thereof, or a salt or solvate thereof, to form a main chain of a compound represented by Formula (I) having a chain structure. (Embodiment 16) The method according to Embodiment 15, further comprising: a cyclization step of intramolecularly cyclizing the compound represented by Formula (I) having a chain structure obtained in the main chain formation step, to obtain a compound represented by Formula (I) having a cyclic structure. (Embodiment 17) An activity enhancer for at least one antifungal agent selected from the group consisting of polyene macrolide agents, azole agents, echinocandin agents, and fluoropyrimidine agents, comprising, as an active ingredient, a compound according to any one of Embodiments 1 to 14, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. (Embodiment 18) A medicament comprising, as an active ingredient, a compound according to any one of Embodiments 1 to 14, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. (Embodiment 19) The medicament of Embodiment 18 for use in the prevention or treatment of one or more fungal infections. (Embodiment 20) The medicament of 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 of any of Embodiments 1 to 14, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and one or more pharmaceutically acceptable carriers. (Embodiment 22) The pharmaceutical composition of Embodiment 21 for use in the prevention or treatment of one or more fungal infections. (Embodiment 23) The pharmaceutical composition of Embodiment 21 or 22, further comprising at least one antifungal agent selected from the group consisting of polyene macrolides, azoles, echinocandins, and fluoropyrimidines.(Embodiment 24) A method for preventing or treating one or more symptoms, diseases, and / or disorders that are fungal infections, comprising administering to a subject in need thereof an effective amount of a compound of any one of Embodiments 1-14, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, in combination with at least one antifungal agent. (Embodiment 25) The method of Embodiment 24, wherein the at least one antifungal agent is selected from the group consisting of polyene macrolides, azoles, echinocandins, and fluoropyrimidines. (Embodiment 26) A compound of any one of Embodiments 1-14, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use in the prevention or treatment of one or more symptoms, diseases, and / or disorders that are fungal infections. (Embodiment 27) A compound of Embodiment 26, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, administered in combination with at least one antifungal agent in the prevention or treatment. (Embodiment 28) Use of a compound of any one of Embodiments 1-14, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for use in the prevention or treatment of one or more symptoms, diseases, and / or disorders that are fungal infections. (Embodiment 29) Use of a compound of any one of Embodiments 1-14, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for the prevention or treatment of one or more symptoms, diseases, and / or disorders that are fungal infections. (Embodiment 30) The use of Embodiment 28 or 29, wherein the compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, is administered together with at least one antifungal agent in the prevention or treatment.

[0015] The present invention provides a novel compound that has the effect of more effectively enhancing the antifungal activity of an antifungal drug than known pharmaceutical compounds. Other problems, configurations, and effects will become clear from the description of the following embodiments.

[0016] This specification includes part or all of the contents as disclosed in the specification and / or drawings of Japanese Patent Application No. 2023-141938, which is a priority document of the present application.

[0017] Preferred embodiments of the present invention are described in detail below. 1. Novel Compounds As used herein, "alkyl" refers to a linear or branched saturated aliphatic hydrocarbon group containing a specific number of carbon atoms. For example, "C1-C5 alkyl" refers to a linear or branched saturated aliphatic hydrocarbon group containing at least one and at most five 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.

[0018] As used herein, "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-chain 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.

[0019] As used herein, "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 groups include, but are not limited to, straight-chain or branched C2-C5 alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, and 1-pentynyl.

[0020] As used herein, "cycloalkyl" refers to an alicyclic alkyl containing the specified number of carbon atoms. For example, a "C3-C6 cycloalkyl" refers to a cyclic hydrocarbon group containing at least three and at most six carbon atoms. Suitable cycloalkyls include, but are not limited to, C3-C6 cycloalkyls such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0021] As used herein, "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.

[0022] As used herein, "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 groups include, but are not limited to, C4-C6 cycloalkynyl groups such as cyclobutynyl, cyclopentynyl, and cyclohexynyl.

[0023] As used herein, "heterocycloalkyl" refers to a cycloalkyl, cycloalkenyl, or cycloalkynyl group in which one or more carbon atoms are each independently substituted with one or more heteroatoms selected from nitrogen (N), sulfur (S), and oxygen (O). In this case, substitution by N or S includes substitution by 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.

[0024] As used herein, "cycloalkylalkyl" refers to a group in which one of the hydrogen atoms of the alkyl, alkenyl, or alkynyl is substituted with the cycloalkyl, cycloalkenyl, or cycloalkynyl. Suitable cycloalkylalkyls include, but are not limited to, C3-C6 cycloalkyl-C1-C5 alkyl such as cyclohexylmethyl and cyclohexenylmethyl.

[0025] As used herein, "heterocycloalkylalkyl" refers to a group in which one hydrogen atom of the alkyl, alkenyl, or alkynyl is substituted with the heterocycloalkyl. Suitable heterocycloalkylalkyls include, but are not limited to, 3- to 6-membered heterocycloalkyl-C1-C5 alkyls.

[0026] As used herein, "alkoxy" refers to a group in which the hydrogen atom of a hydroxyl group is substituted with the alkyl, alkenyl, or alkynyl group described above. Suitable alkoxy groups include, but are not limited to, C1 to C5 alkoxy groups such as methoxy, ethoxy, propoxy, butoxy, and pentoxy.

[0027] As used herein, "cycloalkoxy" refers to a group in which the hydrogen atom of a hydroxyl is replaced by the above-mentioned cycloalkyl, cycloalkenyl, or cycloalkynyl. Suitable cycloalkoxy includes, but is not limited to, C3 to C6 cycloalkoxy such as cyclopropoxy, cyclobutoxy, and cyclopentoxy.

[0028] As used herein, "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.

[0029] As used herein, "aryl" refers to an aromatic ring group. Suitable aryls include, but are not limited to, C6 to C8 aryls, such as phenyl, biphenyl, terphenyl, naphthyl, and anthracenyl. 18 Mention may be made of aryl.

[0030] As used herein, "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, such as benzyl, 1-phenethyl, 2-phenethyl, biphenylmethyl, terphenylmethyl, and styryl. 15 Mention may be made of aryl-C1-C5 alkyl.

[0031] As used herein, "heteroaryl" refers to an aryl group in which one or more carbon atoms 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 heteroaryl groups include, but are not limited to, 5- to 15-membered heteroaryl groups such as furanyl, thienyl (thiophenyl), pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, and indolyl.

[0032] As used herein, "heteroarylalkyl" refers to a group in which one hydrogen atom of the alkyl, alkenyl, or alkynyl is substituted with the heteroaryl. Suitable heteroarylalkyl includes, but is not limited to, 5- to 15-membered heteroaryl-C1-C5 alkyl such as pyridylmethyl.

[0033] As used herein, "aryloxy" refers to a group in which the hydrogen atom of a 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.

[0034] As used herein, "arylalkyloxy" refers to a group in which the hydrogen atom of a hydroxyl is replaced by the arylalkyl. Suitable arylalkyloxy includes, but is not limited to, C6-C aryloxy, such as benzyloxy, 1-phenethyloxy, 2-phenethyloxy, and styryloxy. 15 Mention may be made of aryl-C1-C5 alkyloxy.

[0035] As used herein, "heteroaryloxy" refers to a group in which the hydrogen atom of a hydroxyl group is substituted with the heteroaryl group defined above. Suitable heteroaryloxy groups include, but are not limited to, 5- to 15-membered heteroaryloxy groups such as furanyloxy, thienyloxy (thiophenyloxy), pyrrolyloxy, imidazolyloxy, pyrazolyloxy, triazolyloxy, tetrazolyloxy, thiazolyloxy, oxazolyloxy, isoxazolyloxy, oxadiazolyloxy, thiadiazolyloxy, isothiazolyloxy, pyridyloxy, pyridazinyloxy, pyrazinyloxy, pyrimidinyloxy, quinolinyloxy, isoquinolinyloxy, and indolyloxy.

[0036] As used herein, "heteroarylalkyloxy" refers to a group in which the hydrogen atom of a hydroxyl group is substituted with the heteroarylalkyl group defined above. Suitable heteroarylalkyloxy groups include, but are not limited to, 5- to 15-membered heteroaryl-C1-C5 alkyloxy groups.

[0037] As used herein, "acyl" refers to a group in which a monovalent group selected from the groups described above is linked to a carbonyl. Suitable acyl groups include, but are not limited to, C1-C5 aliphatic acyl groups such as formyl, acetyl, and propionyl, and C7-C6 aliphatic acyl groups such as benzoyl. 20 C1-C including aromatic acyls 20 Acyl can be mentioned.

[0038] Each of the above-described groups can be independently unsubstituted or further substituted with one or more of the above-described monovalent groups.

[0039] As used herein, "halogen" or "halo" means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0040] One aspect of the present invention is a compound of formula (I): or a salt thereof, or a solvate thereof.

[0041] The present inventors have discovered that novel cyclic or chain compounds in which the constituent amino acids and 2-aminobenzoic acid (anthranilic acid) of the known pharmaceutical compound nectriatide are substituted with other amino acids or amino acid analogs have the effect of more effectively enhancing the antifungal activity of antifungal drugs than nectriatide. Although the novel cyclic or chain compounds exhibit substantially no antifungal activity when administered alone, they can significantly enhance the antifungal activity of amphotericin B when administered in combination with amphotericin B. The compounds represented by formula (I) of this embodiment encompass the novel cyclic or chain compounds. Therefore, the compounds represented by formula (I) of this embodiment can more effectively enhance the antifungal activity of antifungal drugs than known pharmaceutical compounds.

[0042] In formula (I), R 1is 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. 1 is H, substituted or unsubstituted C1 to C5 alkyl, substituted or unsubstituted C2 to C5 alkenyl, substituted or unsubstituted C2 to C5 alkynyl, substituted or unsubstituted C3 to C6 cycloalkyl, substituted or unsubstituted C4 to C6 cycloalkenyl, substituted or unsubstituted C4 to C6 cycloalkynyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C3 to C6 cycloalkyl-C1 to C5 alkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl-C1 to C5 alkyl, substituted or unsubstituted C6 to C 15 Aryl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyl, substituted or unsubstituted 5- to 15-membered heteroaryl, substituted or unsubstituted 5- to 15-membered heteroaryl-C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxycarbonyl, substituted or unsubstituted C3-C6 cycloalkoxycarbonyl, substituted or unsubstituted 3- to 6-membered heterocycloalkoxycarbonyl, substituted or unsubstituted C6-C 15 Aryloxycarbonyl, substituted or unsubstituted C6-C 15Aryl-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; 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, it is 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 15 More preferably, it is aryl-C1-C5 alkyloxycarbonyl; and particularly preferably, it is H or benzyloxycarbonyl. R 1 When is a group exemplified above, the compound represented by formula (I) of this embodiment can more effectively enhance the antifungal activity of an antifungal drug compared to known pharmaceutical compounds.

[0043] In formula (I), R 2 R 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. 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 15Aryl-C1-C5 alkyloxy, substituted or unsubstituted C6-C 15 R 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 OH or substituted or unsubstituted C1-C5 alkoxy; and even more preferably OH or methoxy. 2 When is a group exemplified above, the compound represented by formula (I) of this embodiment can more effectively enhance the antifungal activity of an antifungal drug compared to known pharmaceutical compounds.

[0044] In one embodiment, R 1 and R 2 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 and preferably do not combine 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.

[0045] In formula (I), R 3is 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, provided that the substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, and substituted or unsubstituted alkynylene may be 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. 3 is a substituted or unsubstituted C1 to C5 alkylene, a substituted or unsubstituted C2 to C5 alkenylene, a substituted or unsubstituted C2 to C5 alkynylene, a substituted or unsubstituted C3 to C6 cycloalkylene, a substituted or unsubstituted C4 to C6 cycloalkenylene, a substituted or unsubstituted C4 to C6 cycloalkynylene, a substituted or unsubstituted 3 to 6 membered heterocycloalkylene, a substituted or unsubstituted C6 to C 15 Arylene or substituted or unsubstituted 5- to 15-membered heteroarylene is preferred, provided that the substituted or unsubstituted C1-C5 alkylene, substituted or unsubstituted C2-C5 alkenylene, and substituted or unsubstituted C2-C5 alkynylene may be one or more of substituted or unsubstituted C3-C6 cycloalkylene, substituted or unsubstituted C4-C6 cycloalkenylene, substituted or unsubstituted C4-C6 cycloalkynylene, substituted or unsubstituted 3- to 6-membered heterocycloalkylene, substituted or unsubstituted C6-C 15substituted 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- to 6-membered heterocycloalkylene, substituted or unsubstituted C6-C 15 arylene, or substituted or unsubstituted 5- to 15-membered heteroarylene; substituted or unsubstituted C1-C5 alkylene, or substituted or unsubstituted C6-C 15 R is more preferably arylene; and 1,1-ethylene, 1,2-phenylene, 1,3-phenylene, or 1,4-phenylene is particularly preferred. 3 When is a group exemplified above, the compound represented by formula (I) of this embodiment can more effectively enhance the antifungal activity of an antifungal drug compared to known pharmaceutical compounds.

[0046] In formula (I), R 4 R 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.4 is H, OH, substituted or unsubstituted C1 to C5 alkyl or C2 to C5 alkyl, substituted or unsubstituted C2 to C5 alkenyl, substituted or unsubstituted C2 to C5 alkynyl, substituted or unsubstituted C3 to C6 cycloalkyl, substituted or unsubstituted C4 to C6 cycloalkenyl, substituted or unsubstituted C4 to C6 cycloalkynyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C3 to C6 cycloalkyl-C1 to C5 alkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl-C1 to C5 alkyl, substituted or unsubstituted C6 to C 15 Aryl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyl, substituted or unsubstituted 5- to 15-membered heteroaryl, substituted or unsubstituted 5- to 15-membered heteroaryl-C1-C5 alkyl, 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; 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 15More preferably, it is aryl-C1-C5 alkyl, substituted or unsubstituted 5-15 membered heteroaryl, or 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 Methyl, 4-hydroxyphenylmethyl, 4-tert-butyloxyphenylmethyl or phenylmethyl, or 4-hydroxyphenylmethyl, 4-tert-butyloxyphenylmethyl or phenylmethyl are particularly preferred. R 4 When is a group exemplified above, the compound represented by formula (I) of this embodiment can more effectively enhance the antifungal activity of an antifungal drug compared to known pharmaceutical compounds.

[0047] In formula (I), 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. 5is H, substituted or unsubstituted C1 to C5 alkyl, substituted or unsubstituted C2 to C5 alkenyl, substituted or unsubstituted C2 to C5 alkynyl, substituted or unsubstituted C3 to C6 cycloalkyl, substituted or unsubstituted C4 to C6 cycloalkenyl, substituted or unsubstituted C4 to C6 cycloalkynyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C3 to C6 cycloalkyl-C1 to C5 alkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl-C1 to C5 alkyl, substituted or unsubstituted C6 to C 15 Aryl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyl, substituted or unsubstituted 5- to 15-membered heteroaryl, substituted or unsubstituted 5- to 15-membered heteroaryl-C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxycarbonyl, substituted or unsubstituted C3-C6 cycloalkoxycarbonyl, substituted or unsubstituted 3- to 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 Preferred are 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 15More preferably, R is aryl-C1-C5 alkyl, substituted or unsubstituted 5-15 membered heteroaryl, or substituted or unsubstituted 5-15 membered heteroaryl-C1-C5 alkyl; even more preferably, R is H or substituted or unsubstituted C1-C5 alkyl; and especially preferably, R is H or methyl. 5 When is a group exemplified above, the compound represented by formula (I) of this embodiment can more effectively enhance the antifungal activity of an antifungal drug compared to known pharmaceutical compounds.

[0048] In formula (I), R 6 R 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. 6 is H, OH, substituted or unsubstituted C1 to C5 alkyl, substituted or unsubstituted C2 to C5 alkenyl, substituted or unsubstituted C2 to C5 alkynyl, substituted or unsubstituted C3 to C6 cycloalkyl, substituted or unsubstituted C4 to C6 cycloalkenyl, substituted or unsubstituted C4 to C6 cycloalkynyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C3 to C6 cycloalkyl-C1 to C5 alkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl-C1 to C5 alkyl, substituted or unsubstituted C6 to C 15Aryl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyl, substituted or unsubstituted 5- to 15-membered heteroaryl, substituted or unsubstituted 5- to 15-membered heteroaryl-C1-C5 alkyl, 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; 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, substituted or unsubstituted 5-15 membered heteroaryl, or 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 substituted or unsubstituted C1-C5 alkyl; and especially preferably, it is methyl, propan-2-yl, 4-aminobutan-1-yl, or 4-(t-butoxycarbonylamino)butan-1-yl. R 6When is a group exemplified above, the compound represented by formula (I) of this embodiment can more effectively enhance the antifungal activity of an antifungal drug compared to known pharmaceutical compounds.

[0049] In formula (I), R 3 is 1,6-phenylene, R 4 is not a substituted arylalkyl.

[0050] In formula (I), when the group is substituted, the substituents are each independently 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 aryloxy, substituted or unsubstituted heteroarylalkyloxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, and substituted or unsubstituted amino; 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 to C5 alkyl, substituted or unsubstituted 5 to 15 membered heteroaryl, substituted or unsubstituted 5 to 15 membered heteroaryl-C1 to C5 alkyl, substituted or unsubstituted C1 to C6 alkoxy, substituted or unsubstituted C3 to C6 cycloalkoxy, substituted or unsubstituted 3 to 6 membered heterocycloalkoxy, substituted or unsubstituted C6 to C 15 Aryloxy, substituted or unsubstituted C6-C 15 Aryl-C1 to C5 alkyloxy, substituted or unsubstituted 5 to 15-membered heteroaryloxy, substituted or unsubstituted 5 to 15-membered heteroaryl-C1 to C5 alkyloxy, substituted or unsubstituted C1 to C6 alkoxycarbonyl, substituted or unsubstituted C3 to C6 cycloalkoxycarbonyl, substituted or unsubstituted C1 to 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- to 15-membered heteroaryloxy, substituted or unsubstituted 5- to 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. When the monovalent group is substituted, the substituent can be further selected from the monovalent groups described above.

[0051] Preferably, the compound of formula (I) is R 1is H, substituted or unsubstituted C1 to C5 alkyl, substituted or unsubstituted C2 to C5 alkenyl, substituted or unsubstituted C2 to C5 alkynyl, substituted or unsubstituted C3 to C6 cycloalkyl, substituted or unsubstituted C4 to C6 cycloalkenyl, substituted or unsubstituted C4 to C6 cycloalkynyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C3 to C6 cycloalkyl-C1 to C5 alkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl-C1 to C5 alkyl, substituted or unsubstituted C6 to C 15 Aryl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyl, substituted or unsubstituted 5- to 15-membered heteroaryl, substituted or unsubstituted 5- to 15-membered heteroaryl-C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxycarbonyl, substituted or unsubstituted C3-C6 cycloalkoxycarbonyl, substituted or unsubstituted 3- to 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, 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; or 1and R 2 together form a single bond, R 3 is a substituted or unsubstituted C1 to C5 alkylene, a substituted or unsubstituted C2 to C5 alkenylene, a substituted or unsubstituted C2 to C5 alkynylene, a substituted or unsubstituted C3 to C6 cycloalkylene, a substituted or unsubstituted C4 to C6 cycloalkenylene, a substituted or unsubstituted C4 to C6 cycloalkynylene, a substituted or unsubstituted 3 to 6 membered heterocycloalkylene, a substituted or unsubstituted C6 to C 15 arylene, or substituted or unsubstituted 5- to 15-membered heteroarylene, provided that the substituted or unsubstituted C1-C5 alkylene, substituted or unsubstituted C2-C5 alkenylene, and substituted or unsubstituted C2-C5 alkynylene may be one or more of substituted or unsubstituted C3-C6 cycloalkylene, substituted or unsubstituted C4-C6 cycloalkenylene, substituted or unsubstituted C4-C6 cycloalkynylene, substituted or unsubstituted 3- to 6-membered heterocycloalkylene, substituted or unsubstituted C6-C 15 R may be interrupted by arylene or substituted or unsubstituted 5- to 15-membered heteroarylene; 4 is H, OH, substituted or unsubstituted C1 to C5 alkyl or C2 to C5 alkyl, substituted or unsubstituted C2 to C5 alkenyl, substituted or unsubstituted C2 to C5 alkynyl, substituted or unsubstituted C3 to C6 cycloalkyl, substituted or unsubstituted C4 to C6 cycloalkenyl, substituted or unsubstituted C4 to C6 cycloalkynyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C3 to C6 cycloalkyl-C1 to C5 alkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl-C1 to C5 alkyl, substituted or unsubstituted C6 to C 15 Aryl, substituted or unsubstituted C6-C 15Aryl-C1-C5 alkyl, substituted or unsubstituted 5- to 15-membered heteroaryl, substituted or unsubstituted 5- to 15-membered heteroaryl-C1-C5 alkyl, 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; 5 is H, substituted or unsubstituted C1 to C5 alkyl, substituted or unsubstituted C2 to C5 alkenyl, substituted or unsubstituted C2 to C5 alkynyl, substituted or unsubstituted C3 to C6 cycloalkyl, substituted or unsubstituted C4 to C6 cycloalkenyl, substituted or unsubstituted C4 to C6 cycloalkynyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C3 to C6 cycloalkyl-C1 to C5 alkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl-C1 to C5 alkyl, substituted or unsubstituted C6 to C 15 Aryl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyl, substituted or unsubstituted 5- to 15-membered heteroaryl, substituted or unsubstituted 5- to 15-membered heteroaryl-C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxycarbonyl, substituted or unsubstituted C3-C6 cycloalkoxycarbonyl, substituted or unsubstituted 3- to 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, 6 is H, OH, substituted or unsubstituted C1 to C5 alkyl, substituted or unsubstituted C2 to C5 alkenyl, substituted or unsubstituted C2 to C5 alkynyl, substituted or unsubstituted C3 to C6 cycloalkyl, substituted or unsubstituted C4 to C6 cycloalkenyl, substituted or unsubstituted C4 to C6 cycloalkynyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C3 to C6 cycloalkyl-C1 to C5 alkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl-C1 to C5 alkyl, substituted or unsubstituted C6 to C 15 Aryl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyl, substituted or unsubstituted 5- to 15-membered heteroaryl, substituted or unsubstituted 5- to 15-membered heteroaryl-C1-C5 alkyl, 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- to 15-membered heteroaryloxy, substituted or unsubstituted 5- to 15-membered heteroaryl-C1-C5 alkyloxy, or substituted or unsubstituted C1-C5 acyloxy, with the proviso that R 3 is 1,6-phenylene, R 4is not a substituted arylalkyl, and when the group is substituted, the substituents are each independently selected from 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 to C5 alkyl, substituted or unsubstituted 5 to 15 membered heteroaryl, substituted or unsubstituted 5 to 15 membered heteroaryl-C1 to C5 alkyl, substituted or unsubstituted C1 to C6 alkoxy, substituted or unsubstituted C3 to C6 cycloalkoxy, substituted or unsubstituted 3 to 6 membered heterocycloalkoxy, substituted or unsubstituted C6 to C 15 Aryloxy, substituted or unsubstituted C6-C 15 Aryl-C1 to C5 alkyloxy, substituted or unsubstituted 5 to 15-membered heteroaryloxy, substituted or unsubstituted 5 to 15-membered heteroaryl-C1 to C5 alkyloxy, substituted or unsubstituted C1 to C6 alkoxycarbonyl, substituted or unsubstituted C3 to C6 cycloalkoxycarbonyl, substituted or unsubstituted C1 to 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 to C5 alkyl, substituted or unsubstituted C2 to C5 alkenyl, substituted or unsubstituted C2 to C5 alkynyl, substituted or unsubstituted C3 to C6 cycloalkyl, substituted or unsubstituted C4 to C6 cycloalkenyl, substituted or unsubstituted C4 to C6 cycloalkynyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C3 to C6 cycloalkyl-C1 to C5 alkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl-C1 to C5 alkyl, substituted or unsubstituted C6 to C 15 Aryl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyl, substituted or unsubstituted 5- to 15-membered heteroaryl, substituted or unsubstituted 5- to 15-membered heteroaryl-C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxycarbonyl, substituted or unsubstituted C3-C6 cycloalkoxycarbonyl, substituted or unsubstituted 3- to 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, 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; 3is a substituted or unsubstituted C1 to C5 alkylene, a substituted or unsubstituted C2 to C5 alkenylene, a substituted or unsubstituted C2 to C5 alkynylene, a substituted or unsubstituted C3 to C6 cycloalkylene, a substituted or unsubstituted C4 to C6 cycloalkenylene, a substituted or unsubstituted C4 to C6 cycloalkynylene, a substituted or unsubstituted 3 to 6 membered heterocycloalkylene, a substituted or unsubstituted C6 to C 15 arylene, or substituted or unsubstituted 5- to 15-membered heteroarylene, provided that the substituted or unsubstituted C1-C5 alkylene, substituted or unsubstituted C2-C5 alkenylene, and substituted or unsubstituted C2-C5 alkynylene may be one or more of substituted or unsubstituted C3-C6 cycloalkylene, substituted or unsubstituted C4-C6 cycloalkenylene, substituted or unsubstituted C4-C6 cycloalkynylene, substituted or unsubstituted 3- to 6-membered heterocycloalkylene, substituted or unsubstituted C6-C 15 R may be interrupted by arylene or substituted or unsubstituted 5- to 15-membered heteroarylene; 4 is H, OH, substituted or unsubstituted C1 to C5 alkyl or C2 to C5 alkyl, substituted or unsubstituted C2 to C5 alkenyl, substituted or unsubstituted C2 to C5 alkynyl, substituted or unsubstituted C3 to C6 cycloalkyl, substituted or unsubstituted C4 to C6 cycloalkenyl, substituted or unsubstituted C4 to C6 cycloalkynyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C3 to C6 cycloalkyl-C1 to C5 alkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl-C1 to C5 alkyl, substituted or unsubstituted C6 to C 15 Aryl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyl, substituted or unsubstituted 5- to 15-membered heteroaryl, substituted or unsubstituted 5- to 15-membered heteroaryl-C1-C5 alkyl, 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-C15 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; 5 is H, substituted or unsubstituted C1 to C5 alkyl, substituted or unsubstituted C2 to C5 alkenyl, substituted or unsubstituted C2 to C5 alkynyl, substituted or unsubstituted C3 to C6 cycloalkyl, substituted or unsubstituted C4 to C6 cycloalkenyl, substituted or unsubstituted C4 to C6 cycloalkynyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C3 to C6 cycloalkyl-C1 to C5 alkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl-C1 to C5 alkyl, substituted or unsubstituted C6 to C 15 Aryl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyl, substituted or unsubstituted 5- to 15-membered heteroaryl, substituted or unsubstituted 5- to 15-membered heteroaryl-C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxycarbonyl, substituted or unsubstituted C3-C6 cycloalkoxycarbonyl, substituted or unsubstituted 3- to 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, 6is H, OH, substituted or unsubstituted C1 to C5 alkyl, substituted or unsubstituted C2 to C5 alkenyl, substituted or unsubstituted C2 to C5 alkynyl, substituted or unsubstituted C3 to C6 cycloalkyl, substituted or unsubstituted C4 to C6 cycloalkenyl, substituted or unsubstituted C4 to C6 cycloalkynyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C3 to C6 cycloalkyl-C1 to C5 alkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl-C1 to C5 alkyl, substituted or unsubstituted C6 to C 15 Aryl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyl, substituted or unsubstituted 5- to 15-membered heteroaryl, substituted or unsubstituted 5- to 15-membered heteroaryl-C1-C5 alkyl, 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- to 15-membered heteroaryloxy, substituted or unsubstituted 5- to 15-membered heteroaryl-C1-C5 alkyloxy, or substituted or unsubstituted C1-C5 acyloxy, with the proviso that R 3 is 1,6-phenylene, R 4is not a substituted arylalkyl, and when the group is substituted, the substituents are each independently selected from 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 to C5 alkyl, substituted or unsubstituted 5 to 15 membered heteroaryl, substituted or unsubstituted 5 to 15 membered heteroaryl-C1 to C5 alkyl, substituted or unsubstituted C1 to C6 alkoxy, substituted or unsubstituted C3 to C6 cycloalkoxy, substituted or unsubstituted 3 to 6 membered heterocycloalkoxy, substituted or unsubstituted C6 to C 15 Aryloxy, substituted or unsubstituted C6-C 15 Aryl-C1 to C5 alkyloxy, substituted or unsubstituted 5 to 15-membered heteroaryloxy, substituted or unsubstituted 5 to 15-membered heteroaryl-C1 to C5 alkyloxy, substituted or unsubstituted C1 to C6 alkoxycarbonyl, substituted or unsubstituted C3 to C6 cycloalkoxycarbonyl, substituted or unsubstituted C1 to 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] More preferably, the compound of formula (I) is R 1is H, substituted or unsubstituted C1 to C5 alkyl, substituted or unsubstituted C2 to C5 alkenyl, substituted or unsubstituted C2 to C5 alkynyl, substituted or unsubstituted C3 to C6 cycloalkyl, substituted or unsubstituted C4 to C6 cycloalkenyl, substituted or unsubstituted C4 to C6 cycloalkynyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C3 to C6 cycloalkyl-C1 to C5 alkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl-C1 to C5 alkyl, substituted or unsubstituted C6 to C 15 Aryl, substituted or unsubstituted C6-C 15 Aryl-C1-C5 alkyl, substituted or unsubstituted 5- to 15-membered heteroaryl, substituted or unsubstituted 5- to 15-membered heteroaryl-C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxycarbonyl, substituted or unsubstituted C3-C6 cycloalkoxycarbonyl, substituted or unsubstituted 3- to 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, 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; 3is a substituted or unsubstituted C1 to C5 alkylene, a substituted or unsubstituted C2 to C5 alkenylene, a substituted or unsubstituted C2 to C5 alkynylene, a substituted or unsubstituted C3 to C6 cycloalkylene, a substituted or unsubstituted C4 to C6 cycloalkenylene, a substituted or unsubstituted C4 to C6 cycloalkynylene, a substituted or unsubstituted 3 to 6 membered heterocycloalkylene, a substituted or unsubstituted C6 to 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- to 6-membered heterocycloalkyl, a substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, a substituted or unsubstituted 3- to 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- to 15-membered heteroaryl, or substituted or unsubstituted 5- to 15-membered heteroaryl-C1-C5 alkyl; R 5 is H, substituted or unsubstituted C1 to C5 alkyl, substituted or unsubstituted C2 to C5 alkenyl, substituted or unsubstituted C2 to C5 alkynyl, substituted or unsubstituted C3 to C6 cycloalkyl, substituted or unsubstituted C4 to C6 cycloalkenyl, substituted or unsubstituted C4 to C6 cycloalkynyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C3 to C6 cycloalkyl-C1 to C5 alkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl-C1 to C5 alkyl, substituted or unsubstituted C6 to C 15 Aryl, substituted or unsubstituted C6-C 15aryl-C1-C5 alkyl, substituted or unsubstituted 5- to 15-membered heteroaryl, or substituted or unsubstituted 5- to 15-membered heteroaryl-C1-C5 alkyl; R 6 is substituted or unsubstituted C1 to C5 alkyl, substituted or unsubstituted C2 to C5 alkenyl, substituted or unsubstituted C2 to C5 alkynyl, substituted or unsubstituted C3 to C6 cycloalkyl, substituted or unsubstituted C4 to C6 cycloalkenyl, substituted or unsubstituted C4 to C6 cycloalkynyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C3 to C6 cycloalkyl-C1 to C5 alkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl-C1 to C5 alkyl, substituted or unsubstituted C6 to C 15 Aryl, substituted or unsubstituted C6-C 15 aryl-C1-C5 alkyl, substituted or unsubstituted 5- to 15-membered heteroaryl, or substituted or unsubstituted 5- to 15-membered heteroaryl-C1-C5 alkyl, where R 3 is 1,6-phenylene, R 4 is not a substituted arylalkyl, and when the group is substituted, the substituents are each independently selected from 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 to C5 alkyl, substituted or unsubstituted 5 to 15 membered heteroaryl, substituted or unsubstituted 5 to 15 membered heteroaryl-C1 to C5 alkyl, substituted or unsubstituted C1 to C6 alkoxy, substituted or unsubstituted C3 to C6 cycloalkoxy, substituted or unsubstituted 3 to 6 membered heterocycloalkoxy, substituted or unsubstituted C6 to C 15 Aryloxy, substituted or unsubstituted C6-C 15 Aryl-C1 to C5 alkyloxy, substituted or unsubstituted 5 to 15-membered heteroaryloxy, substituted or unsubstituted 5 to 15-membered heteroaryl-C1 to C5 alkyloxy, substituted or unsubstituted C1 to C6 alkoxycarbonyl, substituted or unsubstituted C3 to C6 cycloalkoxycarbonyl, substituted or unsubstituted C1 to 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] Even more preferably, the compound of formula (I) is R 1 is H, substituted or unsubstituted C6 to 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, 2 is OH or substituted or unsubstituted C1-C5 alkoxy, R 3 is a substituted or unsubstituted C1 to C5 alkylene, or a substituted or unsubstituted C6 to C 15 is arylene, and R 4 is a substituted or unsubstituted C1 to C5 alkyl, or a substituted or unsubstituted C6 to C 15 Aryl-C1-C5 alkyl, or substituted or unsubstituted C2-C5 alkyl, or substituted or unsubstituted C6-C 15aryl-C1-C5 alkyl, R 5 is H or substituted or unsubstituted C1-C5 alkyl, and R 6 is a substituted or unsubstituted C1 to C5 alkyl, or a substituted or unsubstituted C6 to C 15 aryl-C1-C5 alkyl, where R 3 is 1,6-phenylene, R 4 is not a substituted arylalkyl, and when the group is substituted, the substituents are each independently selected from 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 to C5 alkyl, substituted or unsubstituted 5 to 15 membered heteroaryl, substituted or unsubstituted 5 to 15 membered heteroaryl-C1 to C5 alkyl, substituted or unsubstituted C1 to C6 alkoxy, substituted or unsubstituted C3 to C6 cycloalkoxy, substituted or unsubstituted 3 to 6 membered heterocycloalkoxy, substituted or unsubstituted C6 to C 15 Aryloxy, substituted or unsubstituted C6-C 15 Aryl-C1 to C5 alkyloxy, substituted or unsubstituted 5 to 15-membered heteroaryloxy, substituted or unsubstituted 5 to 15-membered heteroaryl-C1 to C5 alkyloxy, substituted or unsubstituted C1 to C6 alkoxycarbonyl, substituted or unsubstituted C3 to C6 cycloalkoxycarbonyl, substituted or unsubstituted C1 to C 20 Acyl, substituted or unsubstituted C1-C 20At least one monovalent group selected from the group consisting of acyloxy and substituted or unsubstituted amino.

[0055] Particularly preferably, the compound of formula (I) is 1 is H or benzyloxycarbonyl, R 2 is OH or methoxy, and R 3 is 1,1-ethylene, 1,2-phenylene, 1,3-phenylene or 1,4-phenylene, and R 4 is 4-hydroxyphenylmethyl, 4-tert-butyloxyphenylmethyl or phenylmethyl, R 5 is H or methyl, and R 6 is methyl, propan-2-yl, 4-aminobutan-1-yl, or 4-(t-butoxycarbonylamino)butan-1-yl.

[0056] Particularly preferred compounds of formula (I) are as follows: 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) (Example 1-2); cyclo(L-valinyl-N-methyl-L-phenylalanyl-anthranyl-L-alanyl) (1b, fp3-90) (Example 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 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.

[0057] The compound represented by formula (I) according to one aspect of the present invention, and the compounds represented by formulas (VI), (VII), (VIII), and (IX) described below, include not only the above-mentioned or below-mentioned compounds themselves, but also salts thereof. Preferred salts of the above-mentioned or below-mentioned compounds include, but are not limited to, salts with cations such as sodium ion, potassium ion, calcium ion, magnesium ion, or substituted or unsubstituted ammonium ion, or salts with anions of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, or phosphoric acid, or organic acids 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. When the compound represented by formula (I) is in the form of the salt, it can more effectively enhance the antifungal activity of antifungal drugs compared to known pharmaceutical compounds.

[0058] The compound represented by formula (I) according to one embodiment of the present invention, as well as the compounds represented by formulae (VI), (VII), (VIII), and (IX) described below, encompass not only the compounds themselves but also solvates of the compounds or salts thereof. Solvents that can form solvates with the compounds or salts thereof include, but are not limited to, lower alcohols (e.g., alcohols having 1 to 6 carbon atoms such as methanol, ethanol, or 2-propanol (isopropyl alcohol)), higher alcohols (e.g., alcohols having 7 or more carbon atoms such as 1-heptanol or 1-octanol), organic solvents 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 solvent, the antifungal activity of an antifungal drug can be more effectively enhanced than known pharmaceutical compounds.

[0059] The compound represented by formula (I) according to one embodiment of the present invention, as well as the compounds represented by formulas (VI), (VII), (VIII), and (IX) described below, encompass not only the compounds themselves but also their protected or deprotected forms. As used herein, the term "protected form" refers to a form in which a protecting group has been 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 previously introduced into one or more functional groups (e.g., a hydroxyl group, a carboxylic acid group, or an amino group) has been removed. In this specification, the protected form of a compound represented by each formula may be referred to as a protected derivative of the compound represented by each formula, and the deprotected form of a compound represented by each formula may be referred to as a deprotected derivative of the compound represented by each formula. Furthermore, as used herein, the term "protecting group" refers to a group introduced into a specific functional group to prevent an undesired reaction from proceeding, which is quantitatively removed under specific reaction conditions and is substantially stable, i.e., inert, under other reaction conditions. Protecting groups 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 protecting hydroxyl groups; alkyl esters (e.g., methyl, ethyl, or isopropyl esters), arylalkyl esters (e.g., benzyl esters), or amides (e.g., amides with oxazolidinones) for protecting carboxylic acid groups; and t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 2-bromobenzyloxycarbonyl (BrZ), or 9-fluorenylmethoxycarbonyl (Fmoc) for protecting amino groups. Protection and deprotection using the above protecting groups can be carried out appropriately 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 protected by the above-mentioned protecting group, it may be possible to more effectively enhance the antifungal activity of an antifungal drug compared to known pharmaceutical compounds.

[0060] When the compound represented by formula (I) according to one aspect 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 encompass the individual tautomeric forms of the compounds.

[0061] 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 compounds described above or below also encompass the individual enantiomers and diastereomers of the compound, as well as mixtures thereof such as racemates.

[0062] By virtue of having the above-described characteristics, the compound represented by formula (I) according to one aspect of the present invention can more effectively enhance the antifungal activity of antifungal drugs compared to known pharmaceutical compounds.

[0063] 2. Method for Producing Novel Compounds Another aspect of the present invention relates to a method for producing a compound represented by formula (I) according to 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.

[0064] [2-1. Main Chain Formation Step] The method of this embodiment is a step of forming a main chain of a compound represented by formulas (VI), (VII), (VIII) and (IX): 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.

[0065] In formulas (VI), (VII), (VIII) and (IX), R 3 , R 4 , R 5 and R 6 has the same meaning as above.

[0066] In this step, the conditions for the reaction to link 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 determined by those skilled in the art based on known reaction conditions for liquid-phase or solid-phase peptide synthesis. The reaction in this step can be carried out, for example, by liquid-phase synthesis. In this case, for example, a compound represented by formula (VI) and a compound represented by formula (VII) are condensed in a liquid phase in the presence of a condensing agent to link the amino group of the compound represented by formula (VI) with 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 a compound represented by formula (VIII) in the presence of a condensing agent to link the amino group of the compound represented by formula (VII) with 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 a liquid phase in the presence of a condensing agent 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.

[0067] 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 formulae (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 formulae (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.

[0068] 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, such as 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).

[0069] The compounds represented by formulas (VI), (VII), (VIII), and (IX) used in this step may be not only the compounds themselves, but also precursors of the compounds. Examples of precursors of the compounds represented by formulas (VI), (VII), (VIII), and (IX) include compounds having a structure in which the amino group of the compound is substituted with a nitro group. When precursors of the compounds represented by formulas (VI), (VII), (VIII), and (IX) are used, this step preferably further comprises converting the precursors into the corresponding compounds represented by formulas (VI), (VII), (VIII), and (IX).

[0070] The compounds represented by formulae (VI), (VII), (VIII), and (IX), or precursors or protected derivatives thereof used in this step may be prepared by purchasing the pre-prepared compounds, or may be prepared by oneself based on reaction conditions known in the art as a method for protecting and / or deprotecting amino acids.

[0071] 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.

[0072] [2-2. Cyclization Step] 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.

[0073] In this step, the reaction conditions for intramolecularly cyclizing 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.

[0074] The main chain formation step and cyclization step described above may optionally include a step of protecting and / or deprotecting the compound represented by formula (I) having a linear structure and the compound represented by formula (I) having a cyclic structure, and / or their precursors and intermediates. In this case, the conditions for the protection and / or deprotection reactions can be appropriately set by a person skilled in the art based on reaction conditions known in the art for methods of protecting and / or deprotecting amino acids.

[0075] 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 pharmaceutical, or a variety of compounds derived from said compound, in large quantities with high purity and at low cost.

[0076] 3. Pharmaceutical Uses The compound represented by formula (I) of one embodiment of the present invention has the 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, comprising, as an active ingredient, the compound represented by formula (I) of one embodiment of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. Furthermore, another embodiment of the present invention relates to a pharmaceutical comprising, as an active ingredient, the compound represented by formula (I) of one embodiment of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

[0077] 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. Preferably, the at least one antifungal drug is a polyene macrolide drug. The polyene macrolide drug is preferably amphotericin B, pimaricin, nystatin, or natamycin, and 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) of one embodiment of the present invention has the activity of enhancing the antifungal activity of antifungal drugs such as polyene macrolide drugs, azole drugs, echinocandins, and fluoropyrimidine drugs. Therefore, by administering the compound represented by formula (I) of one embodiment of the present invention together with at least one antifungal drug selected from the group consisting of polyene macrolide drugs, azole drugs, echinocandins, and fluoropyrimidine drugs, it is possible to reduce the dosage and / or administration period of the antifungal drug, which may cause side effects. This allows the occurrence of side effects caused by the at least one antifungal drug to be substantially reduced.

[0078] In each aspect of the present invention, "administered together" means that the multiple agents are administered simultaneously or separately (e.g., consecutively at a regular interval). In this specification, such an administration form may be referred to as "combined administration." By administering the compound represented by formula (I) of one aspect of the present invention and at least one antifungal agent in combination, the dosage of the antifungal agent, which 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 agent.

[0079] A compound represented by formula (I) in one embodiment of the present invention has the activity of enhancing the antifungal activity of at least one antifungal drug. On the other hand, a compound represented by formula (I) in one embodiment of the present invention may or may not have antifungal activity itself. A compound represented by formula (I) in one embodiment of the present invention usually has substantially no antifungal activity itself. Even if a compound represented by formula (I) in one embodiment of the present invention does not have substantially antifungal activity itself, it has the activity of enhancing the antifungal activity of at least one antifungal drug. Therefore, when administered in combination with at least one antifungal drug, the dosage and / or administration period of the antifungal drug, which may cause side effects, can be reduced. This can substantially reduce the occurrence of side effects caused by at least one antifungal drug.

[0080] 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 method. 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 550 The 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 equal to or greater than a predetermined value (e.g., 90%) is defined as the minimum inhibitory concentration (MIC value) of the compound. The antifungal activity of the compound represented by formula (I) according to one embodiment of the present invention and at least one antifungal agent can be evaluated based on the inhibition rate and MIC value determined in this manner.

[0081] The activity of a compound represented by formula (I) of one embodiment of the present invention to enhance the antifungal activity of at least one antifungal agent can be determined, for example, by the following method, but is not limited to this. Based on this method, the MIC value when the at least one antifungal agent is administered alone is determined. Then, under the same test conditions, the compound represented by formula (I) and the at least one antifungal agent are administered together (e.g., simultaneously) to determine the MIC value when the compound represented by formula (I) and the at least one antifungal agent are administered in combination. The enhancement rate of the antifungal activity of at least one antifungal agent by the compound represented by formula (I) of one embodiment of the present invention is calculated based on the following formula (M-1). For example, if the enhancement rate is 2-fold, the MIC value of the at least one antifungal agent when administered in combination with the compound represented by formula (I) of one embodiment of the present invention will be half the MIC value when the antifungal agent is administered alone. Based on the enhancement rate determined in this manner, the activity of a compound represented by formula (I) of one embodiment of the present invention to enhance the antifungal activity of at least one antifungal agent can be evaluated.

[0082]

[0083] In this embodiment, the at least one antifungal agent administered in combination with the compound represented by formula (I) of one embodiment of the present invention has an MIC value, as determined by the above procedure, against yeast fungi (e.g., Candida albicans and Cryptococcus neoformans) and Zygomycetes (Rhizopus oryzae), of typically 0.5 μg / mL or higher, for example, 1.0 μg / mL or higher, and particularly 2.0 μg / mL or higher. In this case, the compound represented by formula (I) of one embodiment of the present invention, when administered in combination with the at least one antifungal agent at a concentration of typically 0.5 μg / mL or higher, for example, in the range of 1 to 32 μg / mL, particularly in the range of 2 to 32 μg / mL, can enhance the antifungal activity of the at least one antifungal agent by an enhancement rate typically of 2-fold or higher, for example, in the range of 2 to 32-fold, particularly in the range of 4 to 32-fold. In contrast, when the known pharmaceutical compound nectriatide is administered in combination with at least one antifungal agent at a concentration of 2 μg / mL or higher, it can enhance the antifungal activity of the at least one antifungal agent, typically by an enhancement rate of 2-fold or more, for example, in the range of 2- to 8-fold, and particularly in the range of 2- to 4-fold. Therefore, the compound represented by formula (I) of this embodiment can enhance the antifungal activity of an antifungal agent more effectively than known pharmaceutical compounds. Furthermore, when the compound represented by formula (I) of one embodiment of the present invention has an enhancement rate within the above range, when administered in combination with at least one antifungal agent, it can reduce the dosage and / or administration period of the antifungal agent, which may cause side effects. This can substantially reduce the occurrence of side effects caused by the at least one antifungal agent.

[0084] When the compound represented by formula (I) according to one embodiment of the present invention is used for medicinal purposes, the compound represented by formula (I) encompasses not only the compound itself but also pharmaceutically acceptable salts of the compound and pharmaceutically acceptable solvates thereof. The pharmaceutically acceptable salts of the compound represented by formula (I) according to one embodiment of the present invention and pharmaceutically acceptable solvates thereof are, but are not limited to, preferably the salts or solvates exemplified above. When the compound represented by formula (I) is in the form of such a salt or solvate, the compound can be used for the desired medicinal purposes without substantially reducing its activity of enhancing the antifungal activity of at least one antifungal agent.

[0085] When the compound represented by formula (I) of one embodiment of the present invention is applied to pharmaceutical purposes, the compound represented by formula (I) encompasses not only the compound itself but also prodrug forms of the compound. As used herein, "prodrug" refers to a compound that is converted into a parent drug in vivo. Examples of prodrug forms of the compound include, but are not limited to, esters of a hydroxyl group, when present, between the hydroxyl group and any carboxylic acid, and amides of the hydroxyl group and 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 upon administration to a subject can be improved without substantially reducing the activity of the parent drug, the compound represented by formula (I), in enhancing the antifungal activity of at least one antifungal agent.

[0086] When the compound represented by formula (I) of one embodiment of the present invention is applied to pharmaceutical use, the compound may be used alone or in combination with one or more pharmaceutically acceptable ingredients. The pharmaceutical of this embodiment can be formulated into various dosage forms commonly used in the art depending on the desired administration method. Therefore, the pharmaceutical of this embodiment can also be provided in the form of a pharmaceutical composition containing the compound represented by formula (I) of one embodiment of the present invention, or a salt thereof, or a solvate thereof, and one or more pharmaceutically acceptable carriers. In this case, the pharmaceutical composition of this embodiment may or may not contain at least one antifungal agent. In addition to the above ingredients, the pharmaceutical composition of this embodiment may also contain one or more pharmaceutically acceptable vehicles (e.g., a solvent such as sterile water or a solution such as physiological saline), excipients, binders, vehicles, solubilizers, preservatives, stabilizers, bulking agents, lubricants, surfactants, emulsifiers, oily liquids (e.g., vegetable oils), suspending agents, buffers, soothing agents, antioxidants, sweeteners, flavoring agents, etc.

[0087] The dosage form of a pharmaceutical comprising, as an active ingredient, the compound represented by formula (I) of one embodiment of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, is not particularly limited, and may be a formulation for parenteral administration or a formulation for oral administration. Furthermore, the dosage form of the pharmaceutical of this embodiment may be a unit-dose formulation or a multiple-dose formulation. Examples of formulations for parenteral administration include injections such as sterile solutions or suspensions with water or other pharmaceutically acceptable media. Ingredients that can be mixed into an 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), solubilizers such as alcohols (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™ or polyoxyethylene hydrogenated castor oil, oily solutions such as sesame oil or soybean oil, buffers such as phosphate buffer or sodium acetate buffer, soothing agents 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 an appropriate vial (e.g., ampule) and stored under an appropriate environment until use.

[0088] Examples of formulations for oral administration include tablets, pills, powders, capsules, microcapsules, elixirs, liquids, syrups, slurries, suspensions, etc. Tablets may be formulated as sugar-coated tablets or sugar-soluble coated tablets, gelatin-coated tablets, enteric-coated tablets, or film-coated tablets, or as double- or multi-layer tablets, as desired.

[0089] 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 suitable carriers include disintegrants such as esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, or lactose; disintegration inhibitors such as sucrose, stearic cocoa butter, or hydrogenated oils; 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, sucrose oil, or cherry. When the formulation is a capsule, it may further contain a liquid carrier such as an oil or fat.

[0090] A pharmaceutical comprising, as an active ingredient, the compound represented by formula (I) of one embodiment of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, can also be formulated as a depot preparation. In this case, the pharmaceutical of this embodiment in the form of a depot preparation can be administered, for example, by implantation subcutaneously or intramuscularly, or by intramuscular injection. By applying the pharmaceutical of this embodiment to a depot preparation, the activity of the compound represented by formula (I) of one embodiment of the present invention in enhancing the antifungal activity of at least one antifungal agent can be sustained over a long period of time.

[0091] When the compound represented by formula (I) according to one aspect of the present invention is used for pharmaceutical purposes, the compound may be provided together with at least one antifungal agent, or may be provided separately. Both cases are encompassed within the present embodiment. In the case of an embodiment further comprising at least one antifungal agent in addition to the compound represented by formula (I) according to one aspect of the present invention, i.e., in the case of an embodiment in which the compound represented by formula (I) according to one aspect of the present invention and at least one antifungal agent are provided together, the medicament according to this aspect can be in the form of a pharmaceutical composition comprising a combination of the compound represented by formula (I) according to one aspect of the present invention, or a salt thereof, or a solvate thereof, and at least one antifungal agent. In this embodiment, the medicament according to this aspect can be provided, for example, in the form of a single formulation comprising the compound represented by formula (I) according to one aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and at least one antifungal agent. In an embodiment in which the compound represented by formula (I) according to one aspect of the present invention is provided separately from at least one antifungal agent, the medicament according to this aspect can be in the form of a pharmaceutical composition containing at least the compound represented by formula (I) according to one aspect of the present invention, or a salt thereof, or a solvate thereof, to be used in combination with at least one antifungal agent. In this embodiment, the medicament according to this aspect can be provided in the form of a pharmaceutical combination or kit containing multiple formulations in which the compound represented by formula (I) according to one aspect of the present invention, or a salt thereof, or a solvate thereof, and at least one antifungal agent are separately formulated. In the case of a pharmaceutical combination or kit, the respective formulations can be administered simultaneously or separately (e.g., sequentially). Alternatively, the medicament according to this aspect can be provided in the form of a formulation containing only the compound represented by formula (I) according to one aspect of the present invention, or a salt thereof, or a solvate thereof (i.e., not including at least one antifungal agent). In either embodiment, the compound represented by formula (I) according to one aspect of the present invention and at least one antifungal agent can be administered in combination.

[0092] A pharmaceutical comprising, 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 can also be used in combination with one or more other pharmaceutical agents useful as pharmaceuticals other than at least one antifungal agent. In this case, the pharmaceutical of this aspect is in the form of a combination pharmaceutical comprising 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, and one or more of the other pharmaceutical agents. The combination pharmaceutical may be in the form of a pharmaceutical composition comprising 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, in combination with one or more of the other pharmaceutical agents, or it may be in the form of a pharmaceutical composition comprising 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, used in combination with one or more of the other pharmaceutical agents. 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 formulation containing the compound represented by formula (I) of one embodiment of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutically 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 formulations in which the one or more other drugs are separately formulated. When in the form of a pharmaceutical combination or kit, the respective formulations can be administered simultaneously or separately (for example, sequentially).

[0093] A medicament comprising, as an active ingredient, the compound represented by formula (I) according to one aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, can similarly prevent or treat one or more types of fungal infections. Examples of 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; and zygomycetes such as Rhizopus oryzae, Rhizomucor pusillus, Rhizopus microspores, and Absidia corymbifera. The one or more fungal infections include, but are not limited to, deep mycoses, superficial mycoses, and dermatomycoses. Preferably, the one or more fungal infections are one or more diseases, symptoms, or disorders selected from the group consisting of deep mycoses, superficial mycoses, and dermatomycoses. By administering the medicament of this aspect to a subject in need of prevention or treatment of the one or more fungal infections, the disease, symptom, or disorder can be prevented or treated.

[0094] A pharmaceutical comprising, as an active ingredient, a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, according to one embodiment of the present invention, can be used in various subjects requiring prevention or treatment of one or more fungal infection symptoms, diseases, and / or disorders. The subject is preferably a human or non-human mammal (e.g., a warm-blooded animal such as a pig, dog, cow, rat, mouse, guinea pig, rabbit, chicken, sheep, cat, monkey, hamadryas baboon, or chimpanzee), or a reptile (e.g., a cold-blooded animal such as a frog, snake, or lizard). By administering the pharmaceutical of this embodiment to the subject, various fungal infection diseases, symptoms, and / or disorders present in the subject can be prevented or treated.

[0095] As used herein, "prevention" means substantially preventing or partially reducing the occurrence (development 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 progression), alleviating, repairing, and / or curing a symptom, disease, and / or disorder that has developed (developed or manifested) in a subject with the symptom, disease, and / or disorder.

[0096] The compound represented by formula (I) in one aspect of the present invention can be used to prevent or treat one or more of the symptoms, diseases, and / or disorders caused by fungal infections described above (e.g., deep mycoses, superficial mycoses, or dermatomycoses) in a subject with the symptoms, diseases, and / or disorders. Therefore, the medicament of this aspect is preferably a medicament for use in the prevention or treatment of one or more of the symptoms, diseases, and / or disorders caused by fungal infections described above, and more preferably a medicament for use in the prevention or treatment of one or more of the fungal infections selected from the group consisting of deep mycoses, superficial mycoses, and dermatomycoses. Use of the medicament of this aspect for the prevention or treatment of one or more of the symptoms, diseases, and / or disorders caused by fungal infections can prevent or treat the symptoms, diseases, and / or disorders via the activity of the compound represented by formula (I) in one aspect of the present invention to enhance the antifungal activity of at least one antifungal agent.

[0097] The compound represented by formula (I) in one aspect of the present invention can be used for the prevention or treatment of one or more of the above-described symptoms, diseases, and / or disorders caused by fungal infection (e.g., deep mycosis, superficial mycosis, or dermatomycosis) in a subject with the symptoms, diseases, and / or disorders. Therefore, another aspect of the present invention is a method for the prevention or treatment of one or more of the above-described symptoms, diseases, and / or disorders caused by fungal infection, comprising administering an effective amount of the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, together with at least one antifungal agent, to a subject in need of such prevention or treatment. The one or more fungal symptoms, diseases, and / or disorders are preferably one or more 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.

[0098] Another aspect of the present invention is a compound represented by formula (I) according to one aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use in the prevention or treatment of one or more of the symptoms, diseases, and / or disorders caused by fungal infections described above. Another aspect of the present invention is use of a compound represented by formula (I) according to one aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for use in the prevention or treatment of one or more of the symptoms, diseases, and / or disorders caused by fungal infections described above. Yet another aspect of the present invention is use of a compound represented by formula (I) according to one aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for the prevention or treatment of one or more of the symptoms, diseases, and / or disorders caused by fungal infections described above. The one or more symptoms, diseases, and / or disorders caused by fungal infections 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 medicament represented by formula (I) according to one aspect of the present invention for the prevention or treatment of one or more of the 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.

[0099] When a pharmaceutical comprising, as an active ingredient, a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, according to one embodiment of the present invention, is administered to a subject, particularly a human patient, the exact dosage and administration method (e.g., dosage amount, frequency of administration, and / or route of administration) should be ultimately determined by the attending physician, taking into account many factors, such as the subject's age, sex, the symptoms to be prevented or treated, the exact state (e.g., severity) of the disease and / or disorder, and the route of administration, and taking into account a therapeutically effective dosage amount, frequency of administration, and route of administration. Therefore, in the pharmaceutical of this embodiment, the compound represented by formula (I), which is the active ingredient, is administered to the subject in a therapeutically effective amount and frequency. For example, when the pharmaceutical of this embodiment is administered to a human patient, the dosage of the compound represented by formula (I), which is the active ingredient, is usually administered 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. The medicament of this embodiment may be administered once or multiple times a day, or once every few days, for example. The route of administration of the medicament of this embodiment is not particularly limited, and the medicament may be administered orally or parenterally (e.g., intrarectally, intramucosally, intestinal, intramuscularly, subcutaneously, intramedullary, intrathecally, directly into the ventricle, intravenously, intravitreally, intraperitoneally, intranasally, or intraocularly) in a single or multiple doses. By using the medicament of this embodiment in the dosage and administration method described above, the one or more symptoms, diseases, and / or disorders resulting from fungal infection can be prevented or treated via 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 agent.

[0100] The present invention will be described in more detail below using examples, although the technical scope of the present invention is not limited to these examples.

[0101] <I. Preparation of Compounds> [I-1. Equipment and Conditions Used] Unless otherwise specified, 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 phosphomolybdic acid ethanol solution. 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 are referenced to the residual solvent (δ 7.26 for CDCl3, δ 3.31 for CD3OD, and δ 2.48 for DMSO-d6). Carbon chemical shifts are reported in ppm and are referenced to the residual solvent (δ 77.0 for CDCl3, δ 49.0 for CD3OD, and δ 39.5 for DMSO-d6). 1 H NMR data are reported as chemical shift, integral, multiplicity (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 to 100% CH3CN containing 0.1% HCOH in H2O was used over 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 packed silica gel column. Preparative HPLC was performed on a Senshu Scientific system equipped with a Nacalai Tesque COSMOSIL π NAP (20 × 250 mm), an SSC-3462 pump, an SSC-3462 UV detector, and a DG-3210 degasser. 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 Yamazen Universal column (Yamazen) on a Yamazen YFLC-AI-580 column. Melting points were determined using a Yanaco MP-S3 and are uncorrected.

[0102] [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.

[0103] [I-3. Synthesis of nectriatide] (S)-2-(2-nitrobenzamido)propionic acid methyl ester (4) 2-Nitrobenzoic acid (501 mg, 3.00 mmol) and HCl·H-Ala-OMe (418 mg, 3.00 mmol) in CHCl 2 To a solution of EDCI·HCl (30 mL) was added 575 mg (3.00 mmol) and HOBt (446 mg, 3.30 mmol). Subsequently, DIPEA (522 μL, 3.00 mmol) was added. The mixture was stirred at room temperature for 18 hours. 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.

[0104] [α] D 26 -20 (c = 1.0, CHCl3). IR (KBr) ν max 3294, 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 m / z: 275.0632 [M+Na] + . 1H 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.

[0105] (S)-2-(2-aminobenzamido)propionic acid ethyl ester (5) 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.

[0106] [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 for N2O3: 223.1083, Found m / z: 223.1073 [M+H] + . 1H 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.

[0107] H-NMeTyr(tBu)-Ant-Ala-OMe (6) To a solution of compound 5 (1.26 g, 5.66 mmol) and Fmoc-NMeTyr(tBu)-OH (2.43 g, 5.74 mmol) in THF (30 mL) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) (1.88 g, 6.79 mmol). The mixture was stirred at room temperature for 22 hours. 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 used in the next reaction without further purification. The residue was dissolved in CHCl2 (49 mL), and DBU (1 mL) was added. The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the solvent was evaporated. The residue was purified by silica gel column chromatography (CHCl3 / MeOH = 95 / 5) to give compound 6 (2.20 g, 94%) as a colorless foamy solid.

[0108] [α] D 24 -54 (c = 2.2, CHCl3). IR (KBr) ν max3290, 2976, 2927, 1744, 1648, 1600, 1581, 1508, 1443, 1365, 1258, 1236, 1210, 1163, 897, 758 cm -1 . . . . HRMS (ESI-TOF) c 25 H 34 Solubility of N3O5 is 456.2499, absorbance m / z 456.2489 [M+H] + . . . . 1 H 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 C 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, 78.3, 67.7, 52.6, 48.4, 39.0, 35.5, 28.7 (×3), 18.5.

[0109] Cbz-Val-NMeTyr(tBu)-Ant-Ala-OMe(3a) To a solution of compound 6 (111 mg, 244 μmol) and Cbz-Val-OH (61.0 mg, 244 μmol) in DMF (2.5 mL), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (102 mg, 268 μmol) and 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol 7-aza-1-hydroxybenzotriazole (HOAt) (50.0 mg, 366 μmol) were added. Subsequently, DIPEA (85 μL, 480 μmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, the mixture was diluted with EtOAc and washed with HO, 1N HCl, saturated aqueous NaHCO, and saturated brine. The organic phase was dried over NaSO, filtered, and evaporated. The residue was purified by silica gel column chromatography (CHCl / MeOH = 95 / 5) to give compound 3a (137 mg, 82%) as a colorless foamy solid.

[0110] [α] D 25 -76 (c = 1.1, CHCl3). IR (KBr) ν 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 m / z: 711.3353 [M+Na] + A 2.5:1 rotamer ratio was observed by NMR. Major rotamer: 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 heterosexuality: 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.

[0111] Cbz-Val-NMeTyr(tBu)-Ant-Ala-OH (12) 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.

[0112] [α] D 23 -74 (c = 1.0, CHCl3). IR (KBr) ν 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 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.

[0113] H-Val-NMeTyr(tBu)-Ant-Ala-OH(2a) 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 evaporated. The residue was triturated with diethyl ether to give compound 2a (328 mg, 92%) as an off-white foamy solid.

[0114] [α] D 23 -28 (c = 1.0, CH3OH) IR (KBr) ν 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 m / z: 541.3026 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.59 (1H, dd, J = 8.0, 1.0 Hz), 7.81 (1H, dd, J = 8.0, 1.5 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) 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.

[0115] Cyclo(Val-NMeTyr(tBu)-Ant-Ala) (7) To a solution of compound 2a (54.0 mg, 100 μmol) in DMF (4.0 mL) were added HATU (41.8 mg, 110 μmol) and TMP (29.6 μL, 210 μmol). The mixture was stirred at room temperature for 22 h. The resulting mixture was diluted with ethyl acetate and washed with H2O, 10% citric acid, saturated aqueous NaHCO3, and saturated brine. The organic phase was dried over Na2SO4, filtered, and evaporated. The residue was purified by preparative HPLC (20 × 250 mm; COSMOSIL πNAP, Nacalai Tesque Inc.) using 90% aqueous methanol as the mobile phase at a flow rate of 15.0 mL / min with UV detection at 215 nm. The peak at 8.0 min was collected and concentrated to give compound 7 (36.5 mg, 70%) as a colorless foamy solid.

[0116] [α] D 26 -91 (c = 1.3, CHCl3) IR (KBr) ν 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 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.

[0117] シクロ(Val-NMeTyr-Ant-Ala), ネクトリアタイド (1a) (Comparative Example 1) Compound 7 (37.1 mg, 49.3 μmol) was treated with TFA / TIPS / CHCl (60:5:35, v / v / v, 1.0 mL) for 1 h at 0° C. After removal of the solvent, the residue was triturated with diethyl ether to give nectriatide 1a (29.2 mg, 86%) as a colorless foamy solid.

[0118] [α] D 24 -97 (c 0.50, CH3OH) IR (KBr) ν max 3324, 2965, 1643, 1514, 1444, 1304, 1232, 1170cm -1 HRMS (ESI-TOF) C 25 H 31 Calculated value for N4O5: 467.2294, Found m / z: 467.2288 [M+H] + . 1 H 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); 13C 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.

[0119] [I-4. Synthesis of DN-methyltyrosine substitution] HD-NMeTyr(tBu)-Ant-Ala-OMe (6e) The reaction was carried out according to the procedure for the synthesis of compound 6 using compound 5 (444 mg, 2.00 mmol) and Fmoc-D-NMeTyr(tBu)-OH (946 mg, 2.00 mmol), affording compound 6e as a colorless foamy solid (628 mg, 1.38 mmol, 69%).

[0120] [α] D 24 +68 (c = 1.0, CHCl3). IR (KBr) ν 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 m / z: 456.2508 [M+H] + . 1H 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.

[0121] Cbz-Val-D-NMeTyr(tBu)-Ant-Ala-OMe (3e, fp4-40) (Reference example 1-1) Following the procedure for the synthesis of 3a, the reaction was carried out using 6e (560 mg, 1.22 mmol) and Cbz-Val-OH (360 mg, 1.22 mmol), affording 3e as a colorless foamy solid (726 mg, 1.05 mmol, 86%).

[0122] [α] D 24 +63 (c = 1.0, CHCl3). IR (KBr) ν max3336, 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 of N4O8 is 689.3550, measured value m / z 689.3535 [M+H] + . 1 H 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). 13C 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.

[0123] H-Val-D-NMeTyr(tBu)-Ant-Ala-OH (2e, fp4-51) (Reference example 1-2) The reaction was carried out according to the procedure for the synthesis of compound 2a using compound 3e (570 mg, 827 μmol), to give compound 2e as a colorless foamy solid (409 mg, 756 μmol, 91%).

[0124] [α] D 24 +95 (c = 1.0, CH3OH). IR (KBr) ν 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 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.

[0125] Cyclo(Val-D-NMeTyr(tBu)-Ant-Ala) (7e) 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%).

[0126] [α] D 23 -5.0 (c = 1.0, CHCl3). IR (KBr) ν max3305, 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 is 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.

[0127] Cyclo(Val-D-NMeTyr-Ant-Ala) (1e, fp4-56) (Reference Example 1-3) The reaction was carried out according to the procedure for the synthesis of compound 1a using compound 7e (54.5 mg, 104 μmol), to give compound 1e as a colorless foamy solid (46.6 mg, 99.9 μmol, 94%).

[0128] [α] D 23 +35.0 (c = 1.0, CH3OH). IR (KBr) ν 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 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.

[0129] [I-5. Synthesis of L-tyrosine substitution] H-Tyr(tBu)-Ant-Ala-OMe (6c) The reaction was carried out according to the procedure for the synthesis of compound 6 using compound 5 (226 mg, 1.02 mmol) and Fmoc-Tyr(tBu)-OH (459 mg, 1.02 mmol), affording compound 6c as a colorless foamy solid (367 mg, 81.5 μmol, 82%).

[0130] [α]D 24 -40 (c = 1.0, CHCl3). IR (KBr) ν max 3294 , 2978 , 2950 , 2933 , 1743 , 1648 , 1600 , 1582 , 1508 , 1446 , 1365 , 1295 , 1260 , 1235 , 1213 , 1164 , 1109 , 1053 , 897 . 839, 757 cm -1 . . . . HRMS (ESI-TOF) c 24 H 32 Solubility of N3O5 is 442.2342, absorbance 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), (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). 13 C 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, 78.3, 57.9, 52.6, 48.4, 40.5, 28.8 (×3), 18.5.

[0131] Cbz-Val-Tyr(tBu)-Ant-Ala-OMe (3c, fp3-47) (Reference example 2-1) Following the synthesis procedure for compound 3a, compound 6c (211 mg, 477 μmol) and Cbz-Val-OH (132 mg, 525 μmol) were used to prepare compound 3c as a colorless foamy solid (317 mg, 469 μmol, 98%).

[0132] [α] D 24 -12 (c = 1.0, CHCl3). IR (KBr) ν 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 m / z: 675.3378 [M+H] + . 11H 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 13C 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.

[0133] H-Val-Tyr(tBu)-Ant-Ala-OH (2c, fp3 - 49) (Reference Example 2 - 2) The synthesis of compound 2a is easy and the compound 3c (258 mg, 381 μmol) is easy to synthesize. Compound 2c was obtained as a colorless vesicular solid (172 mg, 326 μmol, 86%).

[0134] [α] D 23 -23 (c = 1.0, CH3OH). IR (KBr) ν 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 of N4O6 is 527.2869, measured value m / z 527.2858 [M+H] + . 1 H 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). 13C 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.

[0135] Cyclo(Val-Tyr(tBu)-Ant-Ala) (7c) 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%).

[0136] [α] D 23 -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 value for N4O5: 509.2763, Found m / z: 509.2748 [M+H] + . 1H 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, dd, 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). 13 C 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.

[0137] Cyclo(Val-Tyr-Ant-Ala) (1c, fp3-99) (Reference Example 2-3) The reaction was carried out according to the procedure for the synthesis of compound 1a using compound 7c (27.5 mg, 54.0 μmol), to give compound 1c as a colorless foamy solid (21.6 mg, 47.7 μmol, 89%).

[0138] [α] D 25 -105 (c = 0.50, DMSO). IR (KBr) ν 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 for C 24 H 29 N4O5 453.2137, found m / z 453.2134 [M+H] + . 1 H 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). 13C 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.

[0139] [I-6. Synthesis of N-methylphenylalanine substitution] H-NMePhe-Ant-Ala-OMe (6b) Following the synthesis procedure for compound 6, the reaction was carried out using compound 5 (186 mg, 836 μmol) and Fmoc-NMePhe-OH (349 mg, 836 μmol) to give compound 6b as a colorless foamy solid (300 mg, 782 μmol, 93%).

[0140] [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 for N3O4: 384.1923, Found m / z: 384.1917 [M+H] + . 1H 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). 13 C 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.

[0141] Cbz-Val-NMePhe-Ant-Ala-OMe (3b, fp3-58) (Example 1-1) Compound 3a was synthesized with ease, compound 6b (237 mg, 618 μmol) and Cbz-Val-OH (155 mg, 618 μmol) were synthesized using the same method. Compound 3b was obtained as a colorless vesicular solid (228 mg, 369 μmol, 60%).

[0142] [α] D 23 -94 (c = 1.0, CHCl3). IR (KBr) ν max3323, 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 of N4O7 is 617.2975, measured value m / z 617.2968 [M+H] + . 2.7:1 Return to the opposite sex body ratio and NMR test. Main characters of the opposite sex: 1 H 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). 13C 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 heterosexuality: 1 H 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). 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.

[0143] H-Val-NMePhe-Ant-Ala-OH (2h, fp3-61) (Example 1-2) Following the synthesis procedure for compound 2a, compound 3b (190 mg, 309 μmol) was reacted to afford compound 2b as a colorless foamy solid (105 mg, 224 μmol, 73%).

[0144] [α] D 23 -16 (c = 1.0, CH3OH). IR (KBr) ν 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 m / z: 469.2448 [M+H] + A 7.3:1 rotamer ratio was observed by NMR. Major rotamer: 1H 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). 13 C 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 opposite sex: 1H 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.

[0145] Cyclo(Val-NMePhe-Ant-Ala) (1b, fp3-90) (Examples 1-3) The reaction was carried out using compound 2b (50.0 mg, 106 μmol) according to the procedure for the synthesis of compound 7. Compound 1b was obtained as a colorless foamy solid (26.0 mg, 57.7 μmol, 54%).

[0146] [α] D 26 -101 (c = 1.0, CHCl3). IR (KBr) ν max3322, 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 of N4O4 is 451.2345, measured value m / z 451.2338 [M+H] + . 1 H 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.

[0147] [I-7. Synthesis of N-methylalanine substituted derivatives] H-NMeAla-Ant-Ala-OMe (6h) The reaction was carried out according to the procedure for the synthesis of compound 6 using compound 5 (393 mg, 1.75 mmol) and Fmoc-NMeAla-OH (570 mg, 1.75 mmol), affording compound 6h as a colorless foamy solid (457 mg, 1.48 mmol, 85%).

[0148] [α] D 23 -27 (c = 1.0, CHCl3). IR (KBr) ν max 758 cm -1 HRMS (ESI-TOF) C 15 H 22 Calculated value for N3O4: 308.1610, Found 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.

[0149] Cbz-Val-NMeAla-Ant-Ala-OMe(3h, fp3-68) (Example 2-1) Following the synthesis procedure for compound 3a, compound 6h (120 mg, 390 μmol) and Cbz-Val-OH (163 mg, 429 μmol) were used to prepare compound 3h as a colorless foamy solid (161 mg, 298 μmol, 76%).

[0150] [α] D 24 -37 (c = 1.0, CHCl3). IR (KBr) ν 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 m / z: 541.2658 [M+H] + . 1H 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 C 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.

[0151] H-Val-NMeAla-Ant-Ala-OH (2h, fp3-72) (Example 2-2) The synthesis of compound 2a is easy and the reaction of compound 3h (111 mg, 205 μmol) is easy. Compound 2h was obtained as a colorless vesicular solid (56.1 mg, 143 μmol, 70%).

[0152] [α] D 25-66 (c = 1.0, CH3OH). IR (KBr) ν 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, Found m / z: 393.2133 [M+H] + A 5.6:1 rotamer ratio was observed by NMR. Major rotamer: 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). 13 C 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: 1H 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.

[0153] シクロ(Val-NMeAla-Ant-Ala) (1h, fp3-125) (Example 2-3) Compound 7 was synthesized with ease, and compound 2h (78.5 mg, 200 μmol) was synthesized using the same method. Compound 1h was obtained as a colorless vesicular solid (18.1 mg, 48.3 μmol, 24%).

[0154] [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 27Calculated value for N4O4: 375.2032, Found 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.

[0155] [I-8. Synthesis of L-alanine substituted derivatives] Boc-Ala-Ala-OMe (4g) Following the synthesis of compound 4, the reaction was carried out using Boc-Ala-OH (378 mg, 2.00 mmol) and HCl·H-Ala-OMe (279 mg, 2.00 mmol), affording compound 4g (433 mg, 1.58 mmol, 79%) as a colorless foamy solid.

[0156] [α] D 25 -30 (c = 1.0, CHCl3). IR (KBr) ν max3311, 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, Found 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.

[0157] HCl·H-Ala-Ala-OMe (5g) Compound 4g (400 mg, 1.45 mmol) was treated with 4N hydrochloric acid in dioxane for 1 hour 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.

[0158] [α] D 25 -33 (c = 1.0, CH3OH). IR (KBr) ν 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, Found 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.

[0159] H-NMeTyr(tBu)-Ala-Ala-OMe (6g) 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), affording compound 6g as a colorless foamy solid (383 mg, 940 μmol, 88%).

[0160] [α] D 25 -68 (c = 1.0, CHCl3). IR (KBr) ν 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 m / z: 408.2492 [M+H] + . 1H 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). 13 C 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.

[0161] Cbz-Val-NMeTyr(tBu)-Ala-Ala-OMe (3g, fp3-78) (Example 3-1) (Allocation No. 1) Compound 3a was synthesized in a convenient way, compound 6g (350 mg, 858 μmol) and Cbz-Val-OH (216 mg, 858 μmol) were synthesized using the same method. A colorless vesicular solid (402 mg, 627 μmol, 73%) and 3g of the compound were obtained.

[0162] [α] D 25 -97 (c = 1.0, CHCl3). IR (KBr) ν 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 of N4O8 is 641.3550, measured value m / z 641.3541 [M+H] + . 1.6:1 Return to the ratio of the opposite sex by NMR. Main characters of the opposite sex: 1 H 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.

[0163] H-Val-NMeTyr(tBu)-Ala-Ala-OMe (2g, fp3-81) (Example 3-2) (Allocation No. 2) The reaction was carried out with compound 3g (344 mg, 536 μmol) according to the procedure for the synthesis of compound 2a, to give compound 2g as a colorless foamy solid (212 mg, 430 μmol, 86%).

[0164] [α] D 24 -39 (c = 1.0, CH3OH). IR (KBr) ν 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 m / z: 493.3012 [M+H] + A 2.0:1 rotamer ratio was observed by NMR. Major rotamer: 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.

[0165] [I-9. Synthesis of substituted 3-aminobenzoic acids] (3-nitrobenzoyl)-L-alanine methyl ester, (S)-2-(3-nitrobenzamido)propionic acid methyl ester (fp3-130) 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%).

[0166] [α] D 26 +44 (c = 1.0, CHCl3). IR (KBr) ν 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.

[0167] (3-Aminobenzoyl)-L-alanine methyl ester, H-3-ABz-Ala-OMe (fp3-131) 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%).

[0168] [α] D 26 +32 (c = 1.0, CHCl3). IR (KBr) ν 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.

[0169] H-NMe-Tyr(tBu)-3-ABz-Ala-OMe (fp3-133) 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%).

[0170] [α] D26 -70 (c = 1.0, CHCl3). IR (KBr) ν max 3292 , 2977 , 2947 , 2799 , 1742 , 1648 , 1607 , 1588 , 1534 , 1507 , 1485 , 1454 , 1434 , 1365 , 1341 , 1304 , 1236 , 1210 , 1161 . 897, 755 cm -1 . . . . ESI-MS C 25 H 34 Determination of N3O5 456.2498. Mean m / z 456.2487 [M+H] + . . . . 1 H 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, 1.0 Hz). 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, 117.9, 78.5, 66.6, 52.5, 48.5, 38.4, 35.7, 28.8 (×3), 18.5.

[0171] Cbz-Val-NMe-Tyr(tBu)-3-ABz-Ala-OMe (fp3-134) (Example 4-1) 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%).

[0172] [α] D 26 -54 (c = 1.0, CHCl3). IR (KBr) ν 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 rotamer: 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 = 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 number of heterosexuals: 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.

[0173] H-Val-NMe-Tyr(tBu)-3-ABz-Ala-OMe (fp3-147) (Example 4-2) 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%).

[0174] ESI-MS C 29 H 41 N4O 6 Calculated value 541.3026, observed value m / z 541.3007 [M+H] + .

[0175] [I-10. Synthesis of substituted 4-aminobenzoic acids] (4-nitrobenzoyl)-L-alanine methyl ester (fp3-136) 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%).

[0176] [α] D 24 +41 (c = 1.0, CHCl3). IR (KBr) ν 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] + . 1 H 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.

[0177] H-4-ABz-Ala-OMe (fp3-137) 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%).

[0178] [α] D 24 +47 (c = 1.0, CHCl3). IR (KBr) ν 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 of N2O3: 223.1082, measured value m / z: 223.1079 [M+H] + . 1 H 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.

[0179] H-NMe-Tyr(tBu)-4-ABz-Ala-OMe (fp3-139) 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%).

[0180] [α] D 26 -85 (c = 1.0, CHCl3). IR (KBr) ν 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). 13C 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.

[0181] Cbz-Val-NMe-Tyr(tBu)-4-ABz-Ala-OMe (fp3-142) (Example 5-1) 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%).

[0182] [α] D 26 -48 (c = 1.0, CHCl3). IR (KBr) ν max 3304, 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.

[0183] H-Val-NMe-Tyr(tBu)-3-ABz-Ala-OMe (fp3-149) (Example 5-2) 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%).

[0184] ESI-MS C 29 H 41 Calculated value for N4O6: 541.3026, Found m / z: 541.3008 [M+H] + .

[0185] [I-11. Synthesis of D-alanine substitutions] (R)-2-(2-nitrobenzamido)propionic acid methyl ester (ent-4) The procedure for the synthesis of compound 4 was followed 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%).

[0186] 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, Found m / z: 253.0817 [M+H] + .

[0187] (S)-2-(2-nitrobenzamido)propionic acid methyl ester (ent-5) 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).

[0188] 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, Found m / z: 223.1074 [M+H] + .

[0189] H-NMeTyr(tBu)-Ant-Ala-OMe (6d) Following the procedure for the synthesis of compound 6, the reaction was carried out 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%).

[0190] [α] D 26 -69 (c = 1.0, CHCl3). IR (KBr) ν 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 m / z: 456.2491 [M+H] + . 1 H 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). 13C 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.

[0191] Cbz-Val-NMeTyr(tBu)-Ant-D-Ala-OMe (3d, fp4-5) (Reference example 3-1) Following the procedure for the synthesis of compound 3a, the reaction was carried out 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%).

[0192] [α] D 26 -97 (c = 1.0, CHCl3). IR (KBr) ν 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 m / z: 689.3537 [M+H] + A 2.5:1 rotamer ratio was observed by NMR. Major rotamer: 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 heterosexuality: 11H 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 13C 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.

[0193] H-Val-NMeTyr(tBu)-Ant-D-Ala-OH (2d, fp4 - 7) (Reference Example 3 - 2) The reaction was carried out using compound 3d (275 mg, 400 μmol) according to the procedure for the synthesis of compound 2a, to obtain compound 2d as a colorless foamy solid (205 mg, 379 μmol, 95%).

[0194] [α] D 26 -32 (c = 1.0, CH3OH). IR (KBr) ν 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 m / z: 541.3038 [M+H] + A 1.4:1 rotamer ratio was observed by NMR. Major rotamer: 1 H 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). 13C 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 heterosexuals: 1 H 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.

[0195] シクロ(Val-NMeTyr(tBu)-Ant-D-Ala)(7d) 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%).

[0196] [α] D 26 -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 for N4O5: 523.2920, Found 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.

[0197] Cyclo(Val-NMeTyr-Ant-D-Ala) (1d, fp4-25) (Reference Example 3-3) The reaction was carried out according to the procedure for the synthesis of compound 1a using compound 7d (34.7 mg, 66.3 μmol), to obtain compound 1d as a colorless foamy solid (21.3 mg, 45.6 μmol, 69%).

[0198] [α] D 24 -57 (c 1.0, CH3OH) IR (KBr) ν 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 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.

[0199] [I-12. Synthesis of L-alanine substituted derivatives] Cbz-Ala-NMeTyr(tBu)-Ant-Ala-OMe (3i, fp3-64) (Reference Example 4-1) Following the procedure for the synthesis of compound 3a, the reaction was carried out using compound 6 (228 mg, 500 μmol) and Cbz-Val-OH (112 mg, 500 μmol), affording compound 3i as a colorless foamy solid (276 mg, 417 μmol, 83%).

[0200] [α]D 24 -93 (c = 1.0, CHCl3). IR (KBr) ν 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 of N4O8 is 661.3237, measured value m / z 661.3223 [M+H] + . 3.2:1 Return to heterosexual body ratio and NMR inspection. Main characters of the opposite sex: 1 H 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). 13C 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 heterosexuality: 1 H 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). 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.

[0201] H-Ala-NMeTyr(tBu)-Ant-Ala-OH (2i, fp3-71) (Reference Example 4-2) The reaction was carried out according to the procedure for the synthesis of compound 2a using compound 3i (226 mg, 342 μmol), to give compound 2i as a colorless foamy solid (143 mg, 279 μmol, 81%).

[0202] [α] D 25 -39 (c = 1.0, CH3OH). IR (KBr) ν 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 m / z: 513.2705 [M+H] + . 1H 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). 13 C 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.

[0203] Cyclo(Ala-NMeTyr(tBu)-Ant-Ala) (7i) 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%).

[0204] [α] D 25 -84 (c = 1.0, CHCl3). IR (KBr) ν max3315, 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 of N4O5 is 495.2607, measured value m / z 495.2600 [M+H] + . 1 H 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.

[0205] Cyclo(Ala-NMeTyr-Ant-Ala) (1i, fp3-123) (Reference Example 4-3) The reaction was carried out according to the procedure for the synthesis of compound 1a using compound 7i (70.0 mg, 141 μmol), to give compound 1i as a colorless foamy solid (46.5 mg, 106 μmol, 75%).

[0206] [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 for N4O5: 439.1981, Found m / z: 439.1972 [M+H] + . 1H 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). 13 C 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.

[0207] [I-13. Synthesis of D-valine substitution product] Cbz-D-Val-NMeTyr(tBu)-Ant-Ala-OMe (3f, fp4-43) (Reference Example 5-1) Following the procedure for the synthesis of compound 3a, compound 6 (300 mg, 658 μmol) and Cbz-D-Val-OH (165 mg, 658 μmol) were reacted to afford compound 3f as a colorless foamy solid (395 mg, 573 μmol, 87%).

[0208] [α] D 23-50 (c = 1.0, CHCl3). IR (KBr) ν max 3335, 3061, 3027, 2973, 2933, 2875, 1735, 1720, 1647, 1601, 1587, 1509, 1448, 1405, 1365, 1301, 1234, 1217, 1164, 1085, 1027, 897, 756, 698 cm -1 .HRMS (ESI-TOF) C 38 H 49 Calculated value of C + . 1 H 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). 13C 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.

[0209] HD-Val-NMeTyr(tBu)-Ant-Ala-OH (2f, fp4-45) (Reference Example 5-2) The reaction was carried out using compound 3f (308 mg, 447 μmol) according to the procedure for the synthesis of compound 2a, to give compound 2f as a colorless foamy solid (201 mg, 372 μmol, 83%).

[0210] [α] D 23 -109 (c = 0.50, CH3OH). IR (KBr) ν 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 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.

[0211] Cyclo(D-Val-NMeTyr(tBu)-Ant-Ala) (7f) 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%).

[0212] [α] D 23 -49 (c = 1.0, CHCl3). IR (KBr) ν max3290, 2974, 2937, 1639, 1508, 1447, 1235, 1161 cm -1 . HRMS (ESI-TOF) C 29 H 39 Calculated value of N4O5 is 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). 13 C 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.

[0213] Cyclo(D-Val-NMeTyr-Ant-Ala) (1f, fp4-49) (Reference Example 5-3) The reaction was carried out using compound 7f (99.6 mg, 190 μmol) according to the procedure for the synthesis of compound 1a, to give compound 1f as a colorless foamy solid (76.7 mg, 164 μmol, 86%).

[0214] [α] D 22 -40 (c = 0.37, CH3OH). IR (KBr) ν 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 m / z: 467.2284 [M+H] + . 1 H 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). 13C 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.

[0215] [I-14. Synthesis of L-lysine substitution product] Cbz-Lys(Boc)-NMe-Tyr(tBu)-Ant-Ala-OMe (fp4-63) (Reference Example 6-1) Following the procedure for the synthesis of compound 3a, the reaction was carried out with compound 6 (376 mg, 825 μmol) and Cbz-Lys(Boc)-OH (313 mg, 825 μmol), affording compound fp4-63 as a colorless foamy solid (478 mg, 584 μmol, 70%).

[0216] [α] D 23 -79 (c = 1.0, CHCl3). IR (KBr) ν 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] + .

[0217] Cbz-Lys-NMe-Tyr(tBu)-Ant-Ala-OMe (fp4-64) (Reference Example 6-2) Compound fp4-63 (32.7 mg, 40.0 μmol) in CHCl 2 To the (400 μL) solution, TMSOTf (29 μL, 160 μmol) and 2,6-lutidine (37 μL, 320 μmol) were added. The mixture was stirred at room temperature for 2 hours. 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.

[0218] [α] D 24 -66 (c = 0.80, CHCl3). IR (KBr) ν max 3318, 2977, 2952, 1702, 1640, 1600, 1509, 1448, 1410, 1366, 1241, 1162, 1031, 896, 757 cm -1 ESI-MS C 39 H 52 Calculated value for N5O8: 718.3815, Measured value m / z: 718.3815 [M+H] + .

[0219] <II. Pharmacological Testing of New 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., Ltd. DMSO was purchased from Nacalai Tesque.

[0220] [Equipment, Instruments, and Materials] A YAZAWA automatic mixer was used as a vortex mixer. A Bio-Rad iMark Microplate was used to measure absorbance. An AS ONE NS-4P plate mixer was used. An N-Biotek NB-203 incubator for 96-well plates (AS ONE) was used. An Olympus CK2 microscope was used. 150 mm bottle-top filters (pore size 0.22 mm), 15 mL centrifuge tubes, and 50 mL centrifuge tubes were purchased from Corning.

[0221] [Test strains] The following fungi owned by the laboratory were used as test strains: Candida albicans ATCC 90029, Cryptococcus neoformans ATCC 90113, and Rhizopus oryzae NBRC 4705.

[0222] [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.

[0223] [Preparation of RPMI 1640 Medium] 10.4 g of RPMI 1640 powder medium and 34.5 g of MOPS 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 then diluted to 1 L with sterile distilled water. The diluted solution was sterilized by filtration using a 150 mm bottle-top filter (Corning). The resulting sterile solution was designated RPMI 1640 medium and stored at 4°C.

[0224] [Test II-1: Activity Evaluation Test of Antifungal 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 collected 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 Sterile saline was used to measure the concentration of 0.5 McFarland (OD 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.

[0225] The method for preparing an inoculum of Zygomycete (Rhizopus oryzae) is as follows. 2 mL of sterile saline was measured and placed in 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 resulting suspension was diluted 50-fold with RPMI 1640 medium. The resulting diluted solution was used as the inoculum.

[0226] [Evaluation of Antifungal Spectrum by Broth Microdilution Method] Antifungal spectrum was measured by broth microdilution according to the Clinical and Laboratory Standards Institute (CLSI) methods M27-A4 and M38-A3 (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)). To each well of a sterile 96-well plate, 1.0 μL of a dilution of the test compound prepared in DMSO was added to give final concentrations of 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. Each test group and control group was prepared in eight wells. Next, the yeast fungus was added to each well in a ratio of 19 μL of RPMI 1640 medium and 180 μL of inoculum. 550The OD of each well was measured (this was taken as the initial turbidity). Using an NB-203 (N-Biotek) incubator, 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 higher was defined as the minimum inhibitory concentration (MIC value) of that compound.

[0227] Using the same procedure as above, compounds and DMSO (control) were dispensed into designated wells of a 96-well plate. The zygomycetes were added to designated wells at a ratio of 99 μL of RPMI 1640 medium and 100 μL of inoculum. After addition, the yeast fungi inoculated into the wells of the 96-well plate were cultured at 35°C using an NB-203 incubator, with the zygomycetes cultured for 24 hours. Each well was observed under a microscope (CK2: Olympus). Based on the observations, the minimum concentration of each compound at which the growth of the filamentous fungus was completely inhibited was determined. This concentration was designated the MIC value of the compound.

[0228] The results of this test showed that amphotericin B did not exhibit 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.Furthermore, none of the test compounds exhibited growth inhibitory activity against Candida albicans, Cryptococcus neoformans, or Rhizopus oryzae at concentrations of 64 μg / mL or less.

[0229] [Test II-2: Evaluation of the potentiating activity against the antifungal agent amphotericin B] [Preparation of bacterial suspension] A loopful of Candida albicans ATCC90029 strain was applied to PDA medium and cultured at 27°C for 2-3 days. This culture was subcultured twice and grown until colonies reached a diameter of 1 mm or more. Five mL of sterile saline was measured into a sterilized 15 mL centrifuge tube (Corning). Five colonies (approximately 1 mm in diameter) were picked using a sterilized bamboo skewer and suspended in the measured sterile saline. The suspension 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 Sterile saline was used to measure the concentration of 0.5 McFarland (OD 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.

[0230] Inoculation solutions of the yeast fungus (Cryptococcus neoformans) and the zygomycete (Rhizopus oryzae) were prepared in the same manner as in Test II-1.

[0231] [Evaluation of fungal inhibition rate by 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 a dilution of the test compound prepared in DMSO was added to each well of a sterile 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 at a ratio of 19 μL of RPMI 1640 medium and 180 μL of inoculum solution. After addition, the OD of each well was measured. 550 The OD of each well was measured (this was taken 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 higher was defined as the MIC value of the compound.

[0232] Using the same procedure as above, compounds and a control DMSO were dispensed into designated wells of a 96-well plate. Zygomycetes (Rhizopus oryzae) were added to designated wells at a ratio of 99 μL of RPMI 1640 medium and 100 μL of inoculum. 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). Based on the observations, the minimum concentration at which growth was completely inhibited for each compound was determined. This concentration was designated as the MIC value of the compound.

[0233] [Evaluation of the Amphotericin B Activity Enhancement Effect of Test Compounds by Broth Microdilution Method] To each well of a sterilized 96-well plate, 1.0 μL of a test compound and amphotericin B diluted 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, and 0.00313 μg / mL. As a control, 2.0 μL of DMSO alone was added. One well was prepared for each test group, and eight control wells were prepared. Next, the fungus was added to each well in a ratio of 18 μL of RPMI 1640 medium to 180 μL of inoculum, and the zygomycete was added to each well in a ratio of 98 μL of RPMI 1640 medium to 100 μL of inoculum. After addition, the OD of each well was 550 The OD of each well was measured (this was taken 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 higher was defined as the MIC value of amphotericin B in the combined administration of each test compound and amphotericin B. Furthermore, the amphotericin B activity enhancement rate of each test compound was calculated based on the following formula (M-3). The amphotericin B activity enhancement rate of each compound was calculated by repeating the test three times.

[0234] The following table shows the MIC values ​​of amphotericin B when the test compound and amphotericin B were co-administered. In the table, the column "Test compound concentration" shows the concentration of the test compound when the test compound and amphotericin B were co-administered, and the column "Amphotericin B concentration" shows the MIC value of amphotericin B and the activity enhancement rate when the test compound and amphotericin B were co-administered.

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247] 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. These results demonstrate that any of the test compounds can more effectively enhance the antifungal activity of antifungal drugs than the known compound nectriatide (Comparative Example 1, Table 1).

[0248] The present invention is not limited to the above-described embodiments, but includes various modifications. 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 described configurations. Furthermore, it is possible to add, delete, and / or replace part of the configuration of each embodiment with other configurations.

[0249] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

Claims

1. Formula (I): [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; or 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, provided 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; 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, with the proviso that 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 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 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 The compound according to claim 1, which is 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, or a salt thereof, or a solvate thereof.

3. R 1 H, substituted or unsubstituted C6 to 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 The compound according to claim 2, or a salt thereof, or a solvate thereof, wherein:

4. R 3 is a substituted or unsubstituted C1-C5 alkylene or a substituted or unsubstituted C6-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 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- to 6-membered heterocycloalkyl, a substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, a substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C1-C5 alkyl, a substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 15 The compound according to claim 1, which 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, or a salt thereof, or a solvate thereof.

7. R 4 is a substituted or unsubstituted C1-C5 alkyl or a substituted or unsubstituted C6-C 15 The compound according to claim 6, which is aryl-C1 to C5 alkyl, or a salt thereof, or a solvate thereof.

8. R 4 is a substituted or unsubstituted C2-C5 alkyl or a substituted or unsubstituted C6-C 15 The compound according to claim 6, which is aryl-C1 to C5 alkyl, or a salt thereof, or a solvate thereof.

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 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 The compound according to claim 1, which 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, or a salt thereof, or a solvate thereof.

11. R 5 The compound according to claim 10, or a salt thereof, or a solvate thereof, wherein is H, or a substituted or unsubstituted C1 to C5 alkyl.

12. 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- to 6-membered heterocycloalkyl, a substituted or unsubstituted C3-C6 cycloalkyl-C1-C5 alkyl, a substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C1-C5 alkyl, a substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 15 The compound according to claim 1, which 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, or a salt thereof, or a solvate thereof.

13. R 6 is a substituted or unsubstituted C1-C5 alkyl or a substituted or unsubstituted C6-C 15 The compound according to claim 12, which is aryl-C1 to C5 alkyl, or a salt thereof, or a solvate thereof.

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: [In the formula, R 3 , R 4 , R 5 and R 6 has the meaning as defined 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.

16. The method according to claim 15, further comprising a cyclization step of intramolecularly cyclizing the compound represented by formula (I) having a chain structure obtained in the main chain formation step to obtain a compound represented by formula (I) having a cyclic structure.

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. A medicine 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. A medicament as claimed in claim 18 for use in the prevention or treatment of one or more fungal infections.

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

23. 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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