Cyclic peptide derivative composition for improving brain function

Abstract

The present disclosure provides a cyclic peptide derivative composition for improving brain function.　The present disclosure relates to a composition containing a compound for improving brain function (particularly cognitivie function) or a pharmacologically acceptable salt, solvate, or prodrug thereof. More specifically, the composition of the present disclosure makes it possible to improve memory, particularly learning memory. The present disclosure also relates to a composition containing a compound for treating or preventing a disease associated with cognitive decline, or a pharmacologically acceptable salt, solvate, or prodrug thereof.

Description

Cyclic peptide derivative compositions for improving brain function

[0001] The present disclosure relates to cyclic peptide derivative compositions for improving brain function.

[0002] Brain functions are divided into primary and higher brain functions. Primary functions include perceptual and motor functions. Higher brain functions (cognitive functions) collectively refer to mental (psychological) functions, including cognitive processes such as perception, memory, learning, thinking, and judgment, as well as the emotional (affective) aspects of actions. Cognitive functions decline with age or are impaired (or damaged) by brain damage caused by illness (cerebrovascular disease, encephalopathy, encephalitis, etc.) or accidents (traumatic brain injury). Typical symptoms include memory loss (or impairment) and attention loss (or impairment). Improving these cognitive functions could be useful for treating or preventing diseases associated with cognitive decline.

[0003] The present disclosure provides cyclic peptide derivative compositions for improving brain function, particularly cognitive function.

[0004] As a result of intensive research, the present inventors have found that compounds represented by the following formula and related structural formulas, or pharmaceutically acceptable salts thereof (hereinafter sometimes referred to as "compounds of the present disclosure" or "compounds of the present disclosure") have a significant effect of improving brain function, and have completed the technical matters of the present disclosure. That is, the present disclosure is as follows. (Item 1) The following formula (1) or a pharmaceutically acceptable salt, solvate or prodrug thereof. １ , R ２ , R ５ , R ６ , R ７ , R ８ , R ９ and R １０ are each independently a hydrogen atom or an optionally substituted hydrocarbon group, or ７ and R ８ But, R ７ and R ８together with the carbon atom and nitrogen atom to which R is attached form an optionally substituted heterocycloalkyl group; ３ and R ４ are each independently a hydrogen atom, an optionally substituted hydrocarbon group, a carboxyl group, an optionally substituted alkoxycarbonyl group, or an optionally substituted alkoxycarbonyloxy group; R １１ , R １２ , R １３ , and R １４ are each independently a hydrogen atom, an optionally substituted hydrocarbon group, a hydroxy group, an optionally substituted alkoxy group, or an optionally substituted alkoxycarbonyloxy group, and X is CH ２ or CO, and A is O, NH, or S, where NH may be substituted as needed.] (Item 2) The following formula (1): or a pharmaceutically acceptable salt, solvate or prodrug thereof. １ , R ２ , R ５ , R ６ , R ７ , R ８ , R ９ and R １０ are each independently a hydrogen atom or an optionally substituted hydrocarbon group, or ７ and R ８ But, R ７ and R ８ together with the carbon atom and nitrogen atom to which R is attached form an optionally substituted heterocycloalkyl group; ３ and R ４ are each independently a hydrogen atom, an optionally substituted hydrocarbon group, a carboxyl group, an optionally substituted alkoxycarbonyl group, or an optionally substituted alkoxycarbonyloxy group; R １１ , R １２ , R １３ , and R １４are each independently a hydrogen atom, an optionally substituted hydrocarbon group, a hydroxy group, an optionally substituted alkoxy group, or an optionally substituted alkoxycarbonyloxy group, and X is CH ２ or CO, and A is O, NH, or S, where NH can be optionally substituted.] (Item 3) The composition according to any one of the preceding items, wherein the brain function is a cognitive function. (Item 4) The composition according to any one of the preceding items, wherein the cognitive function is memory. (Item 5) The composition according to any one of the preceding items, wherein the cognitive function is learning and memory. (Item 6) The composition according to any one of the preceding items, wherein the disease associated with cognitive decline is Alzheimer's disease, vascular dementia, dementia with Lewy bodies, or frontotemporal dementia. (Item 7) R １ and R ２ are each independently a hydrogen atom or C １－６ 8. The composition of any one of the preceding items, wherein R is an alkyl group. １ and R ２ 9. The composition of any one of the preceding items, wherein R is each independently a hydrogen atom, a methyl group, or an ethyl group. ３ and R ４ are each independently a hydrogen atom, a C substituted with a carboxyl group, １－６ 10. The composition of any one of the preceding items, wherein R is an alkyl group or a carboxyl group. ３ and R ４ 11. The composition of any one of the preceding items, wherein R is each independently a hydrogen atom, a carboxymethyl group, a carboxyethyl group, a carboxypropyl group, or a carboxyl group. ５ is a hydrogen atom, or C １－６ 12. The composition of any one of the preceding items, wherein R is an alkyl group. ５ 13. The composition of any one of the preceding claims, wherein R is a hydrogen atom. ６ is a hydrogen atom, or C １－６14. The composition of any one of the preceding items, wherein R is an alkyl group. ６ 15. The composition of any one of the preceding claims, wherein R is a hydrogen atom. ７ is a hydrogen atom, C １－６ Alkyl group, hydroxy C １－６ Alkyl group, carbamoyl C １－６ Alkyl group, C ６－１０ Aryl C １－６ Alkyl group, hydroxy C ６－１０ Aryl C １－６ Alkyl group, C ５－１０ Heteroaryl C １－６ Alkyl group, carboxy C １－６ Alkyl group, amino C １－６ Alkyl group, thio C １－６ Alkyl group, C １－６ Alkylthio C １－６ Alkyl group, or amidinoamino C １－６ 16. The composition of any one of the preceding claims, wherein R is an alkyl group. ７ 17. The composition of any one of the preceding items, wherein R is a hydrogen atom, a methyl group, an isopropyl group, an isobutyl group, a secbutyl group, a benzyl group, a hydroxymethyl group, a 1-hydroxyethyl group, a carboxymethyl group, a carboxyethyl group, a 4-hydroxybenzyl group, a 4-aminobutyl group, a thiomethyl group, a 2-methylthioethyl group, a carbamoylmethyl group, a carbamoylethyl group, an amidinoaminopropyl group, an indolylmethyl group, or a 4-imidazolemethyl group. ８ is a hydrogen atom, or C １－６ 18. The composition of any one of the preceding items, wherein R is an alkyl group. ８ 19. The composition of any one of the preceding claims, wherein R is a hydrogen atom. ７ and R ８ is R ７ and R ８ 20. The composition of any one of the preceding items, wherein R is taken together with the carbon atom and nitrogen atom to which it is attached to form an optionally substituted heterocycloalkyl group. ７ and R８ is R ７ and R ８ together with the carbon atom and nitrogen atom to which it is bonded, C ５－１０ 21. The composition of any one of the preceding claims, wherein R forms a heterocycloalkyl group. ９ and R １０ are each independently a hydrogen atom or C １－６ 22. The composition of any one of the preceding claims, wherein R is an alkyl group. ９ and R １０ 23. The composition of any one of the preceding items, wherein R is each independently a hydrogen atom or a methyl group. １１ , R １２ , R １３ , and R １４ 24. The composition of any one of the preceding claims, wherein R is each independently a hydrogen atom, an alkoxy group, or a hydroxy group. １２ 25. The composition of any one of the preceding claims, wherein R is a hydrogen atom, an alkoxy group, or a hydroxy group. １１ , R １２ , R １３ , and R １４ 26. The composition of any one of the preceding claims, wherein R is each independently a hydrogen atom, a methoxy group, or a hydroxy group. １２ 27. The composition of any one of the preceding claims, wherein X is a hydrogen atom, a methoxy group, or a hydroxy group. ２ 28. The composition of any one of the preceding items, wherein A is O, C １－６ The composition according to any one of the preceding items, wherein A is NH, NH, or S substituted with an alkyl group. (Item 29) The composition according to any one of the preceding items, wherein A is O, NH, or S. (Item A1) A compound represented by the following formula (A2): or a pharmaceutically acceptable salt, solvate or prodrug thereof. Ａ１ ~R Ａ４ , RＡ７ ~R Ａ１１ , R Ａ３１２ , and R Ａ１１２ are each independently a hydrogen atom or a hydrocarbon group, R Ａ１４ , and R Ａ２１２ are each independently a hydrogen atom, a carboxyl group or a salt thereof, or an alkoxycarbonyl group; R Ａ５ represents a hydrocarbon group, a hydroxyl group, an alkoxy group, or an alkylcarbonyloxy group, R Ａ５５ , and R Ａ６６ are each independently a hydrogen atom, a hydrocarbon group, or an alkylcarbonyloxy group. (Item A2) The composition according to any one of the preceding items, wherein the brain function is a cognitive function. (Item A3) The composition according to any one of the preceding items, wherein the cognitive function is memory. (Item A4) The composition according to any one of the preceding items, wherein the cognitive function is learning and memory. (Item A5) A compound represented by the following formula (A2): or a pharmaceutically acceptable salt, solvate or prodrug thereof. (wherein m is 0 to 3, n≧1, and R Ａ１ ~R Ａ４ , R Ａ７ ~R Ａ１１ , R Ａ３１２ , and R Ａ１１２ are each independently a hydrogen atom or a hydrocarbon group, R Ａ１４ , and R Ａ２１２ are each independently a hydrogen atom, a carboxyl group or a salt thereof, or an alkoxycarbonyl group; R Ａ５ represents a hydrocarbon group, a hydroxyl group, an alkoxy group, or an alkylcarbonyloxy group, R Ａ５５ , and R Ａ６６are each independently a hydrogen atom, a hydrocarbon group, or an alkylcarbonyloxy group. (Item A6) The composition according to any one of the preceding items, wherein the disease associated with cognitive decline is Alzheimer's disease, vascular dementia, dementia with Lewy bodies, or frontotemporal dementia. In the present disclosure, it is intended that one or more of the above features may be provided in further combinations in addition to the combinations explicitly stated. Still further embodiments and advantages of the present disclosure will be recognized by those skilled in the art upon reading and understanding the following detailed description, if necessary.

[0005] According to the present disclosure, novel cyclic peptide derivatives and compositions are provided that can improve brain function (particularly cognitive function) and thus may be useful for treating or preventing diseases associated with cognitive decline.

[0006] Figure 1 shows the Y-maze used in the Y-maze test. Figure 2 shows the results of the Y-maze test for the sham-operated group, vehicle control group, Compound 9-administered group (5 mg / kg), Compound 9-administered group (25 mg / kg), and donepezil-administered group (0.5 mg / kg). Figure 2-1 shows the total number of entries, Figure 2-2 shows the number of spontaneous alternations, and Figure 2-3 shows the spontaneous alternation rate. Figure 3 shows the results of the passive avoidance test for the sham-operated group, vehicle control group, Compound 9-administered group (5 mg / kg), Compound 9-administered group (25 mg / kg), and donepezil-administered group (0.5 mg / kg). Figure 3-1 shows the response latency of the acquisition trial, and Figure 3-2 shows the response latency of the retention trial.

[0007] The present disclosure will be described in more detail below. Throughout this specification, singular expressions should be understood to include the plural concept unless otherwise specified. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, it should be understood that the terms used in this specification are used in the sense commonly used in the relevant field unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In case of conflict, the present specification (including definitions) will prevail.

[0008] (Definitions) We first explain the terms and general techniques used in this disclosure.

[0009] The compounds of the present disclosure may exist in the form of hydrates and / or solvates, and therefore the hydrates and / or solvates of the compounds of the present disclosure or pharmaceutically acceptable salts thereof are also encompassed within the compounds of the present disclosure.

[0010] The compounds of the present disclosure may contain one or more asymmetric carbon atoms, which may result in geometric isomerism or axial chirality, and therefore may exist as several stereoisomers. The present disclosure encompasses these stereoisomers, mixtures thereof, and racemates. Thus, the compounds described herein may contain one or more asymmetric centers and therefore exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers (including racemic mixtures and mixtures enriched in one or more stereoisomers). The present disclosure also encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively as mixtures of various isomers.

[0011] Also, any one or more of the compounds of the present disclosure１ H ２ Deuterium conversion products converted to H(D) are also encompassed within the compounds of the present disclosure.

[0012] The compounds of the present disclosure and pharmaceutically acceptable salts thereof obtained as crystals may exist in the form of crystalline polymorphs, and the compounds of the present disclosure include all crystalline forms.

[0013] Next, the terms used in this specification will be explained below. In this specification, the term "group" means a monovalent group unless otherwise specified. Examples of non-monovalent groups include alkylene groups (divalent). In addition, in the following explanations of substituents, etc., the term "group" may be omitted in some cases, but may also be written in the explanations of terms.

[0014] In this specification, when defined as "optionally substituted," "optionally substituted," or "substituted," the number of substituents is not particularly limited and is one or more, provided that substitution is possible. Furthermore, unless otherwise specified, the description of each substituent also applies to the case where the substituent is a part of or a substituent for another substituent. Examples of substituents in the present disclosure include a hydrogen atom, a hydroxyl group, a carboxyl group, a sulfinic acid group, a sulfonic acid group, a phosphate group, a guanidine group, a cyano group, a halogen atom (fluorine atom, chlorine atom, etc.), an alkyl group, an alkylthio group, a cycloalkylthio group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkylcarbonyl group, an alkylcarbonyloxy group, an alkylsulfinyl group, a cycloalkylsulfinyl group, an alkoxy group, a cycloalkoxy group, an alkoxycarbonyl group, a cycloalkyloxycarbonyl group, an alkyl Examples of the substituent include a carbonyl group, an aryl group, an arylcarbonyl group, an arylthio group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclic group, an amino group, a cyclic amino group, an aminocarbonyl group, an aminosulfinyl group, an aminosulfonyl group, a heterocyclicoxycarbonyl group, a heterocyclicsulfinyl group, a heterocyclicsulfonyl group, a heterocycliccarbonyl group, an alkylsulfonyl group, a cycloalkylsulfonyl group, an arylsulfonyl group, an arylsulfonyl group, a heteroarylsulfonyl group, a heteroarylsulfonyl group, and a triphenylphosphonium cation group. The above substituents may be further substituted with the above-mentioned substituents.

[0015] As used herein, the "maximum number of possible substitutions" refers to the maximum number of substituents that a group can have, and may vary for each group. For example, the maximum number of possible substitutions is 3 for a methyl group, 5 for an ethyl group, 7 for a benzyl group, and 11 for a naphthalenylethyl group.

[0016] In the present specification, in groups modified by "optionally substituted," "optionally substituted," or "substituted," any part of the group may be substituted. For example, in "optionally substituted arylalkyl" and "substituted arylalkyl," the aryl moiety may be substituted, the alkyl moiety may be substituted, or both the aryl and alkyl moieties may be substituted.

[0017] In the present specification, examples of substituents in the cases where "may be substituted" or "substituted as needed" are substituent group α and substituent group β. In the cases where "may be substituted" or "substituted as needed", the substituent may be selected from substituent group α, and may be substituted with 1 to 5 substituents which may be the same or different. The type of atom in the substituent participating in the bond is not particularly limited depending on the type of substituent, but when the atom to which the substituent is bonded is an oxygen atom, nitrogen atom or sulfur atom, it is limited to those of the following substituents in which the atom to which the substituent is bonded is a carbon atom. Substituent group α includes: 1) halogen atoms 2) hydroxyl groups 3) carboxyl groups 4) cyano groups 5) C １－６ Alkyl 6) C ２－６ Alkenyl 7) C ２－６ Alkynyl 8) C １－６ Alkoxy 9) C １－６ Alkylthio 10) C １－６ Alkylcarbonyl 11) C １－６ Alkylsulfonyl (wherein each of the substituents 5) to 11) may be substituted with 1 to 5 identical or different substituents selected from Substituent Group β). 12) C ３－１０ Cycloalkyl group 13) C ３－１０ Cycloalkyloxy 14) C ６－１０ Aryloxy 15) C ５－１０ Heteroaryloxy 16) C ４－１０ Non-aryl heterocyclic oxy 17) C ３－１０ Cycloalkylthio 18) C ６－１０ Arylthio 19) C ５－１０ Heteroarylthio 20) C ４－１０ Non-aryl heterocyclic thio 21) C６－１０ Aryl 22) C ５－１０ Heteroaryl 23) C ４－１０ Non-aryl heterocycle 24) C ３－１０ Cycloalkylcarbonyl 25) C ６－１０ Arylcarbonyl 26) C ５－１０ Heteroarylcarbonyl 27) C ４－１０ Non-aryl heterocyclic carbonyl 28) C ３－１０ Cycloalkylsulfonyl 29) C ６－１０ Arylsulfonyl 30) C ５－１０ Heteroarylsulfonyl 31) C ４－１０ Non-aryl heterocyclic sulfonyl (provided that each of the substituents in 12) to 31) is 1 to 5 of the substituent group β or the above-mentioned 5) C １－６ 32) -NR, optionally substituted with alkyl １０ａ R １１ａ 33) -SO ２ -NR １０ｂ R １１ｂ 34)-NR １０ｃ -C(=O)R １１ｃ 35)-NR １０ｄ -C(=O)OR １１ｄ 36)-NR １２ａ -C(=O)NR １０ｅ R １１ｅ 37) -NR １０ｉ -SO ２ -R １１ｉ 38)-NR １２ｃ -SO ２ -NR １０ｊ R １１ｊ 39)-C(=O)OR １０ｋ 40)-C(=O)NR １０ｌ R １１ｋ 41)-C(=O)NR １０ｍ OR １１ｌ 42)-C(=O)NR １２ｄ -NR １０ｎ R １１ｍ 43)-C(=NR １３ａ ) R １０ｓ 44)-C(=NR １３ｃ ) NR １０ｔ R １１ｑ 45)-C(=NR １３ｄ ) NR １２ｆ-NR １０ｕ R １１ｒ 46)-NR １７ｃ -C(=NR １３ｋ ) R １７ｄ 47)-NR １２ｇ -C(=NR １３ｅ )-NR １０ｖ R １１ｓ 48)-NR １４ -C(=NR １３ｆ )-NR １２ｈ -NR １０ｗ R １１ｔ 49)-OC(=O)R １０ｘ 50)-OC(=O)OR １０ｙ 51)-OC(=O)NR １０ｚ１ R １１ｕ 52)-NR １２ｉ -NR １０ｚ２ R １１ｖ 53)-NR １０ｚ３ OR １１ｗ 54) Protecting group, and the substituent group β includes 1) a halogen atom, 2) a hydroxyl group, 3) a carboxyl group, 4) a cyano group, 5) C ３－１０ 6) a cycloalkyl group, １－６ Alkoxy, 7) C ３－１０ cycloalkyloxy, 8) C １－６ Alkylthio, 9) C ５－１０ heteroarylthio, 10) C ６－１０ aryl, 11) C ５－１０ Heteroaryl, 12) C ４－１０ Non-aryl heterocycle, 13) C １－６ Alkylcarbonyl, 14) C ３－１０ cycloalkylcarbonyl, 15) C ６－１０ arylcarbonyl, 16) C ５－１０ Heteroarylcarbonyl, 17) C ４－１０ Non-aryl heterocyclic carbonyl, 18)-NR １５ａ R １６ａ , 19)-SO ２ -NR １５ｂ R １６ｂ , 20)-NR １５ｃ -C(=O)R １６ｃ 21) -NR １７ａ -C(=O)NR １５ｄ R１６ｄ , 22)-C(=O)NR １５ｅ R １６ｅ , 23)-C(=NR １３ｇ ) R １５ｆ , 24)-C(=NR １３ｈ ) NR １５ｇ R １６ｆ 25)-NR １６ｇ -C(=NR １３ｉ ) R １５ｈ 26) -NR １７ｂ -C(=NR １３ｊ )-NR １５ｉ R １６ｈ 27) Protecting group (provided that, among the substituent group β, each of the substituents 5) to 17) is a halogen atom, a hydroxyl group, a cyano group, a carboxyl group, —NR １８ａ R １８ｂ and R １３ａ , R １３ａ２ , R １３ｃ , R １３ｃ２ , R １３ｄ , R １３ｄ２ , R １３ｅ , R １３ｆ , R １３ｇ , R １３ｇ２ , R １３ｈ , R １３ｈ２ , R １３ｉ , R １３ｊ , R １３ｋ are each independently the same or different and represent a hydrogen atom, a hydroxyl group, or C １－６ Alkyl, C １－６ Alkoxy, or C １－６ alkoxycarbonyl, R １０ａ , R １０ｂ , R １０ｃ , R １０ｄ , R １０ｅ , R １０ｉ , R １０ｊ , R １０ｋ , R １０ｌ , R １０ｍ , R １０ｎ , R １０ｓ , R １０ｓ２ , R １０ｔ , R １０ｔ２ , R １０ｕ , R １０ｕ２ , R １０ｖ , R１０ｗ , R １０ｘ , R １０ｙ , R １０ｚ１ , R １０ｚ２ , R １０ｚ３ , R １１ａ , R １１ｂ , R １１ｃ , R １１ｄ , R １１ｅ , R １１ｉ , R １１ｊ , R １１ｋ , R １１ｌ , R １１ｍ , R １１ｑ , R １１ｑ２ , R １１ｒ , R １１ｒ２ , R １１ｓ , R １１ｔ , R １１ｕ , R １１ｖ , R １１ｗ , R １２ａ , R １２ｃ , R １２ｄ , R １２ｆ , R １２ｆ２ , R １２ｇ , R １２ｈ , R １２ｉ , R １４ , R １５ａ , R １５ｂ , R １５ｃ , R １５ｄ , R １５ｅ , R １５ｆ , R １５ｆ２ , R １５ｇ , R １５ｇ２ , R １５ｈ , R １５ｉ , R １６ａ , R １６ｂ , R １６ｃ , R １６ｄ , R １６ｅ , R １６ｆ , R １６ｆ２ , R １６ｇ , R １６ｈ , R １７ａ , R １７ｂ , R １７ｃ , R １７ｄ are each independently the same or different and represent a hydrogen atom, C １－６ Alkyl (the C １－６ Alkyl is a hydroxyl group, a cyano group, C １－６ Alkoxy, —NR １８ａ R １８ｂand optionally substituted with 1 to 3 identical or different substituents selected from the following, or C １－６ alkoxycarbonyl, R １８ａ and R １８ｂ are each independently the same or different and represent a hydrogen atom or C １－６ In an exemplary embodiment, any hydrogen atom of the hydroxyl group and amino group in the substituent groups α and β may be substituted with a protecting group.

[0018] As used herein, "C １－６ " means that the number of carbon atoms is 1 to 6. The same applies to other numbers, for example, "C １－４ " means that the number of carbon atoms is 1 to 4, and "C １－３ " means that the number of carbon atoms is 1 to 3. In this specification, descriptions limiting the number of carbon atoms are merely preferred numerical ranges, and it is intended that groups having substituents with carbon atoms other than the specified number of carbon atoms also fall within the scope of the present disclosure.

[0019] As used herein, the term "hydrocarbon group" is also referred to as a "hydrocarbyl group" and refers to a group formed by removing at least one hydrogen from a "hydrocarbon" containing at least one carbon and at least one hydrogen.

[0020] In this specification, the term "functional group" refers to any group that imparts some functionality, and includes a carboxyl group, a nitrile group, a carbonyl group, a hydroxy group, an amino group, an imino group, a nitro group, a halogen group, as well as an alkyl group, and in a broad sense also includes groups formed by bonds such as acid anhydrides, ester bonds, amide bonds, and ether bonds.

[0021] As used herein, the term "heteroatom" refers to an atom other than carbon or hydrogen atoms, such as an oxygen atom, nitrogen atom, or sulfur atom. A group containing a heteroatom may be referred to as a hetero... group (for example, a heteroaryl group (meaning that an aryl group contains at least a heteroatom)) or a hetero... group (for example, a heterocyclic group (meaning that a ring group (carbocyclic group) contains at least one heteroatom)).

[0022] As used herein, a "halogen atom" refers to an atom belonging to the halogen group, such as a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. A fluorine atom or a chlorine atom is preferred. A fluorine atom is more preferred. A "halogen atom" may also be referred to as "halogen" or "halo".

[0023] As used herein, a "hydroxyl group" refers to a monovalent group of -OH. This group may also be called a "hydroxy group" or "hydroxy."

[0024] As used herein, a "carboxyl group" refers to a monovalent group of -COOH. This group may also be called a "carboxy group," "carboxy," or "carboxyl."

[0025] As used herein, an "amino group" refers to -NH ２ This group is sometimes called "amino".

[0026] As used herein, a "thio group" is a monovalent group of -SH. This group may also be referred to as "thio".

[0027] As used herein, a "cyano group" is a monovalent radical of -CN. This group is also sometimes called "cyano."

[0028] As used herein, an "alkyl" group refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group. １－１２ "Alkyl" refers to an alkyl group having 1 to 12 carbon atoms, examples of which include C １－６ Examples of alkyl include, but are not limited to, alkyl, heptyl, isoheptyl, octyl, isooctyl, nonyl, isononyl, decyl, isodecyl, undecyl, isoundecyl, dodecyl, and isododecyl. １－６ "Alkyl" is an alkyl group having 1 to 6 carbon atoms, and preferred examples include "C １－４ alkyl", and more preferably "C １－３ alkyl," and more preferably "C １－２ "C alkyl". １－４Specific examples of "alkyl" include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, etc. １－６ Specific examples of "alkyl" include C １－４ Examples include, but are not limited to, alkyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1,2-dimethylpropyl, n-hexyl, and the like.

[0029] As used herein, an "alkenyl" group refers to a straight- or branched-chain unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond. ２－１２ "Alkenyl" refers to an alkenyl group having 2 to 12 carbon atoms, and examples include, but are not limited to, heptenyl, isoheptenyl, octenyl, isooctenyl, nonenyl, isononenyl, decenyl, isodecenyl, undecenyl, isoundecenyl, dodecenyl, isododecenyl, and the like. ２－６ "Alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms, and preferred examples include "C ２－４ "C alkenyl" is an example. ２－６ Specific examples of "alkenyl" include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, and the like.

[0030] As used herein, an "alkynyl" group refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond. ２－１２ "Alkynyl" refers to an alkynyl group having 2 to 12 carbon atoms, and examples include, but are not limited to, heptynyl, isoheptynyl, octynyl, isooctynyl, nonynyl, isononynyl, decynyl, isodecynyl, undecynyl, isoundecynyl, dodecynyl, isododecynyl, and the like. ２－６ "Alkynyl" refers to an alkynyl group having 2 to 6 carbon atoms, and preferred examples include "C ２－４ "C alkynyl" is an example. ２－６Examples of "alkynyl" include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 3-butynyl, 1-pentynyl, 1-hexynyl, and the like.

[0031] As used herein, an "aryl" group refers to a monovalent radical of a monocyclic or bicyclic aromatic hydrocarbon ring, and ６－１０ "Aryl" means an aryl group having 6 to 10 carbon atoms. Examples of "aryl" include C ６ Aryl, C １０ Examples include, but are not limited to, aryl and the like. ６ Specific examples of aryl include, but are not limited to, phenyl. １０ Specific examples of aryl include, but are not limited to, 1-naphthyl, 2-naphthyl, and the like.

[0032] An aryl group as a substituent or part thereof may be fused with an alicyclic group. For example, a phenyl group may be fused with a cyclohexane ring to form a 1,2,3,4-tetrahydronaphthalenyl group, in which case any available carbon atom on the benzene ring is bonded to the parent skeleton or to a group or atom thereof close to the parent skeleton. Aryl groups include 5,6,7,8-tetrahydronaphthalen-1-yl and 5,6,7,8-tetrahydronaphthalen-2-yl.

[0033] As used herein, an "arylalkyl" group refers to an alkyl substituted with at least one aryl. ６－１０ Aryl C １－６ "Alkyl" means a group having at least one C ６－１０ Aryl-substituted C １－６ It means alkyl. ６－１０ Aryl C １－６ Specific examples of alkyl include benzyl (phenyl-CH ２ -), phenethyl (phenyl-CH ２ CH ２-), naphthalen-1-ylmethyl, naphthalen-2-ylmethyl, 2-(naphthalen-1-yl)ethyl, 2-(naphthalen-2-yl)ethyl and the like.

[0034] As used herein, the term "(optionally substituted amino)-arylalkyl" refers to an arylalkyl substituted with an optionally substituted amino group, where the alkyl group, the aryl group, or both are substituted with an amino group. The amino group of the arylalkyl group may be unsubstituted or may have one, two, or three substituents, such as an optionally substituted alkyl (e.g., an unsubstituted C １－６ Alkyl, C ３－６ Cycloalkyl-C １－６ Alkyl, C ３－６ (Optionally substituted amino)-C ６－１０ Aryl C １－６ Examples of alkyl include, but are not limited to, (di(alkyl)amino)benzyl, ((cycloalkylalkyl)amino)benzyl, ((cycloalkylcarbonyl)amino)benzyl, ((carbamoylalkyl)carbonylamino)benzyl, ((carboxyalkyl)carbonyl)aminobenzyl, (di(alkyl)amino)naphthalenylmethyl, ((cycloalkylalkyl)amino)naphthalenylmethyl, ((cycloalkylcarbonyl)amino)naphthalenylmethyl, ((carbamoylalkyl)carbonylamino)naphthalenylmethyl, or ((carboxyalkyl)carbonyl)aminonaphthalenylmethyl, and the like.

[0035] As used herein, a "hydroxyaryl" group refers to an aryl substituted with at least one hydroxy. ６－１０ "Aryl" refers to a C substituted with at least one hydroxyl group. ６－１０ aryl. Hydroxy C ６－１０ Specific examples of aryl include, but are not limited to, 2-hydroxyphenyl, 3-hydroxynaphthalene, and the like.

[0036] As used herein, a "hydroxyarylalkyl" group refers to an alkyl substituted with at least one hydroxyaryl. ６－１０ Aryl C １－６ "Alkyl" means a group having at least one hydroxy C ６－１０ Aryl-substituted C １－６ alkyl. Hydroxy C ６－１０ Aryl C １－６ Specific examples of alkyl include 2-hydroxybenzyl (2-hydroxyphenyl-CH ２ -), 2-hydroxyphenethyl (2-hydroxyphenyl-CH ２ CH ２ -), 3-hydroxynaphthalen-1-ylmethyl, 3-hydroxynaphthalen-2-ylmethyl, 2-(3-hydroxynaphthalen-1-yl)ethyl, 2-(3-hydroxynaphthalen-2-yl)ethyl and the like.

[0037] As used herein, the aryl moiety of the "arylthio" group has the same meaning as the aryl defined above. ６－１０ As "arylthio", preferably "C ６ Or C １０ "C" is an example of an arylthio group. ６－１０ Specific examples of "arylthio" include, but are not limited to, phenylthio, 1-naphthylthio, 2-naphthylthio, and the like.

[0038] As used herein, the term "arylsulfonyl" refers to a sulfonyl group substituted with the above-mentioned "aryl". ６－１０ As "arylsulfonyl", preferably "C ６ or C １０ "C is an arylsulfonyl group. ６－１０ Specific examples of "arylsulfonyl" include, but are not limited to, phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, and the like.

[0039] As used herein, the term "heteroaryl" refers to a monovalent monocyclic or bicyclic aromatic heterocyclic group containing the same or different heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms. The number of heteroatoms may be any number up to the number of carbon atoms in the aryl, typically 1 to 4, and may be 1, 2, 3, etc.

[0040] As used herein, "C ５－１０ A "heteroaryl" group means a monovalent monocyclic or bicyclic aromatic heterocycle of 5 to 10 atoms containing the same or different, typically 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms. ５－１０ Specific examples of "heteroaryl" include quinolyl, isoquinolyl, naphthyridinyl, quinoxalinyl, cinnolinyl, quinazolinyl, phthalazinyl, imidazopyridyl, imidazothiazolyl, imidazooxazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, pyrrolopyridyl, thienopyridyl, furopyridyl, benzothiadiazolyl, benzoxadiazolyl, pyridopyrimidinyl, benzofuryl, benzothienyl, benzo[1,3]dioxole, thienofuryl, chromenyl, chromanyl, coumarinyl, quinolonyl, and the like, but are not limited to these.

[0041] As used herein, a "heteroarylalkyl" group refers to an alkyl substituted with at least one heteroaryl. ５－１０ Heteroaryl C １－６ "Alkyl" means a group having at least one C ５－１０ Heteroaryl-substituted C １－６ It means alkyl. ５－１０ Heteroaryl C １－６ Specific examples of alkyl include, but are not limited to, pyridin-2-ylmethyl, pyridin-4-ylmethyl, 2-(quinolin-8-yl)ethyl, 2-(quinolin-5-yl)ethyl, 2-(quinoxalin-5-yl)ethyl, 2-(1H-indol-3-yl)ethyl, and the like.

[0042] As used herein, the term "cycloalkyl" refers to a non-aromatic saturated hydrocarbon ring group, including those having a partially bridged structure, those having a partially spiro structure, and those having one, two, or more carbonyl structures. ３－２０ "Cycloalkyl" means a monocyclic or bicyclic cycloalkyl having 3 to 20 carbon atoms. ３－６ "Cycloalkyl" means a monocyclic cycloalkyl having 3 to 6 carbon atoms. ３－６ Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0043] A cycloalkyl group as a substituent or part thereof may be fused with an aryl and / or heteroaryl ring. For example, a cyclohexyl group may be fused with a benzene ring to form a 1,2,3,4-tetrahydronaphthalenyl group, in which case any available carbon atom on the cyclohexane ring is bonded to the parent skeleton or to a group or atom thereof close to the parent skeleton. Cycloalkyl groups include 1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3,4-tetrahydronaphthalen-2-yl, indan-1-yl, indan-2-yl, 5,6,7,8-tetrahydroquinolin-5-yl, and 5,6,7,8-tetrahydroquinolin-6-yl.

[0044] As used herein, a "cycloalkylalkyl" group refers to an alkyl substituted with at least one cycloalkyl. ３－６ Cycloalkyl C １－６ "Alkyl" means a group having at least one C ３－６ Cycloalkyl-substituted C １－６ It means alkyl. ３－６ Cycloalkyl C １－６Specific examples of alkyl include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, 3-cyclopropylpropyl, 3-cyclobutylpropyl, 3-cyclopentylpropyl, 3-cyclohexylpropyl, and the like.

[0045] As used herein, the term "heterocycloalkyl" refers to a non-aromatic saturated or partially unsaturated heterocycle composed of three or more atoms, including one, two, or more identical or different heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms, and includes those having a partially bridged structure and those having a partially spiro-type structure. "Heterocycloalkyl" encompasses "non-aryl heterocycles." Heterocycloalkyls can have a structure in which a non-aromatic heterocycle is fused with an aryl ring and / or a heteroaryl ring.

[0046] As used herein, the term "non-aryl heterocycle" refers to a monocyclic or bicyclic non-aromatic heterocycle consisting of three or more atoms, including one or two or more identical or different heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms, and includes saturated non-aryl heterocycles, those having a partially unsaturated bond, those having a partially bridged structure, and those having a partially spiro-bonded structure. The non-aryl heterocycle may form a fused ring with an aryl or heteroaryl. For example, C ６－１０ Aryl or C ５－１０A heterocycle also includes a group fused with a heteroaryl. The non-aryl heterocycle may contain one, two, or more carbonyls, thiocarbonyls, sulfinyls, or sulfonyls, and cyclic groups such as lactams, thiolactams, lactones, thiolactones, cyclic imides, cyclic carbamates, and cyclic thiocarbamates are also included in the non-aryl heterocycle. Here, the oxygen atom of the carbonyl, sulfinyl, and sulfonyl and the sulfur atom of the thiocarbonyl are not included in the number of ring members (ring size) and the number of heteroatoms constituting the ring.

[0047] As used herein, "C ４－１０ The "non-aryl heterocycle" is a "C" among the above "non-aryl heterocycles". ４－１０ "Non-aryl heterocycle" refers to a substituent in which the "non-aryl heterocycle" is a monovalent group.

[0048] As used herein, the non-aryl heterocyclic moiety of the "non-aryl heterocyclic oxy" group has the same meaning as the above-mentioned "non-aryl heterocyclic ring". For example, "C ４－１０ "Non-aryl heterocyclic oxy" and "C ４－１０ As the "non-aryl heterocycle oxy", preferably, "C ４－１０ "Non-aryl heterocyclic oxy." ４－１０ Specific examples of "non-aryl heterocycleoxy" include, but are not limited to, tetrahydrofuranyloxy, tetrahydropyranyloxy, azetidinyloxy, pyrrolidinyloxy, piperidinyloxy, and the like.

[0049] As used herein, the non-aryl heterocyclic moiety of the "non-aryl heterocyclic thio" group has the same meaning as the above-mentioned "non-aryl heterocyclic ring". For example, "C ４－１０ "Non-aryl heterocyclic thio" and "C ４－１０ As the non-aryl heterocyclic thio, preferably, "C ４－６ "Non-aryl heterocyclic thio" ４－１０ Specific examples of "non-aryl heterocyclethio" include, but are not limited to, tetrahydropyranylthio, piperidinylthio, and the like.

[0050] As used herein, the term "non-aryl heterocycle carbonyl" refers to a carbonyl group substituted with the above-mentioned "non-aryl heterocycle". For example, "C ４－１０ "Non-aryl heterocyclic carbonyl" and "C ４－１０ As the "non-aryl heterocyclic carbonyl", preferably, "C ４－６ "Non-aryl heterocyclic carbonyl." ４－１０ Specific examples of "non-aryl heterocycle carbonyl" include, but are not limited to, azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, morpholinylcarbonyl, and the like.

[0051] As used herein, the term "non-aryl heterocyclic sulfonyl" refers to a sulfonyl group substituted with the above-mentioned "non-aryl heterocyclic". For example, "C ４－１０ "Non-aryl heterocyclic sulfonyl" and "C ４－１０ As the "non-aryl heterocycle sulfonyl", preferably, "C ４－６ "Non-aryl heterocycle sulfonyl." ４－１０ Specific examples of "non-aryl heterocycle sulfonyl" include, but are not limited to, azetidinylsulfonyl, pyrrolidinylsulfonyl, piperidinylsulfonyl, morpholinylsulfonyl, and the like.

[0052] As used herein, "C ５－１０ A "heterocycloalkyl" group means a heterocycloalkyl consisting of 5 to 10 ring atoms, including one or two or more heteroatoms that may be the same or different and selected from oxygen, nitrogen, and sulfur atoms.

[0053] As used herein, a "heterocycloalkylalkyl" group refers to an alkyl substituted with at least one heterocycloalkyl.

[0054] As used herein, an "alkylcarbonyl" group is a monovalent radical of -C(=O)-alkyl. Preferred examples of alkylcarbonyl include C １－６ Examples include alkylcarbonyl. １－６ Specific examples of alkylcarbonyl include acetyl (CH３ C(=O)-), n-propanoyl (CH ３ CH ２ C(=O)-), n-butanoyl (CH ３ CH ２ CH ２ C(=O)-), n-pentanoyl (CH ３ (CH ２ ) ３ C(=O)-), n-hexanoyl (CH ３ (CH ２ ) ４ C(=O)-), n-heptanoyl (CH ３ (CH ２ ) ５ Examples include, but are not limited to, C(═O)—.

[0055] As used herein, an "alkoxy" group is a monovalent group of -O-alkyl. Preferred examples of alkoxy include C １－６ Alkoxy (i.e., C １－６ alkyl-O-), C １－４ Alkoxy (i.e., C １－４ alkyl-O-) and the like. １－４ Specific examples of alkoxy include methoxy (CH ３ O-), ethoxy (CH ３ CH ２ O-), n-propoxy (CH ３ (CH ２ ) ２ O-), isopropoxy ((CH ３ ) ２ CHO-), n-butoxy (CH ３ (CH ２ ) ３ O-), isobutoxy ((CH ３ ) ２ CHCH ２ O-), tert-butoxy ((CH ３ ) ３ CO-), sec-butoxy (CH ３ CH ２ CH (CH ３ ) O-) and the like. １－６ Specific examples of alkoxy include C １－４ Alkoxy, n-pentyloxy (CH ３(CH ２ ) ４ O-), isopentyloxy ((CH ３ ) ２ CHCH ２ CH ２ O-), neopentyloxy ((CH ３ ) ３ CCH ２ O-), tert-pentyloxy (CH ３ CH ２ C(CH ３ ) ２ O-), 1,2-dimethylpropoxy (CH ３ CH (CH ３ ) CH(CH ３ )O-) and the like, but are not limited to these.

[0056] As used herein, an "alkoxycarbonyl" group is a monovalent radical -C(=O)-O-alkyl. Examples of alkoxycarbonyl include C １－６ Alkoxycarbonyl, preferably C １－４ Examples include, but are not limited to, alkoxycarbonyl. １－４ Specific examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, and isobutoxycarbonyl. １－６ Specific examples of the alkoxycarbonyl include C １－４ Examples include, but are not limited to, alkoxycarbonyl, n-pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert-pentyloxycarbonyl, 1,2-dimethylpropyloxycarbonyl, n-hexyloxycarbonyl, and the like.

[0057] As used herein, an "alkoxycarbonyloxy" group is a monovalent radical of -O-C(=O)-O-alkyl. Examples of alkoxycarbonyloxy include C １－６ Alkoxycarbonyloxy, preferably C １－４ Examples include, but are not limited to, alkoxycarbonyloxy.１－４ Specific examples of alkoxycarbonyloxy include methoxycarbonyloxy, ethoxycarbonyloxy, n-propoxycarbonyloxy, isopropoxycarbonyloxy, n-butoxycarbonyloxy, sec-butoxycarbonyloxy, tert-butoxycarbonyloxy, and isobutoxycarbonyloxy. １－６ Specific examples of the alkoxycarbonyloxy include C １－４ Examples of such alkoxycarbonyloxy include, but are not limited to, alkoxycarbonyloxy, n-pentyloxycarbonyloxy, isopentyloxycarbonyloxy, neopentyloxycarbonyloxy, tert-pentyloxycarbonyloxy, 1,2-dimethylpropyloxycarbonyloxy, n-hexyloxycarbonyloxy, and the like.

[0058] As used herein, an "alkoxycarbonylamino" group is a monovalent radical -NH-C(=O)-O-alkyl. Examples of alkoxycarbonylamino include C １－６ Alkoxycarbonylamino, preferably C １－４ Examples include, but are not limited to, alkoxycarbonylamino. １－４ Specific examples of alkoxycarbonylamino include methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, n-butoxycarbonylamino, sec-butoxycarbonylamino, tert-butoxycarbonylamino, and isobutoxycarbonylamino. １－６ Specific examples of alkoxycarbonylamino include C １－４ Examples include, but are not limited to, alkoxycarbonylamino, n-pentyloxycarbonylamino, isopentyloxycarbonylamino, neopentyloxycarbonylamino, tert-pentyloxycarbonylamino, 1,2-dimethylpropyloxycarbonylamino, n-hexyloxycarbonylamino, and the like.

[0059] As used herein, a "haloalkyl" group is a monovalent halogenated alkyl group in which one or more hydrogens on the alkyl group are replaced with halogen. Also, the term "perhaloalkyl" refers to a haloalkyl in which all hydrogens on the alkyl group are replaced with halogens. For example, perfluoroethyl is -CF ２ CF ３ and perchloro-n-propyl is —CCl ２ CCl ２ CCl ３ Examples of haloalkyl include C １－６ Haloalkyl, C １－４ Haloalkyl, C １－３ haloalkyl and the like. １－３ Specific examples of haloalkyl include, but are not limited to, fluoromethyl, chloromethyl, bromomethyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, fluorochloromethyl, difluorochloromethyl, fluorodichloromethyl, fluoroethyl, chloroethyl, bromoethyl, trifluoroethyl, trichloroethyl, tribromoethyl, perfluoroethyl, perchloroethyl, perbromoethyl, perfluoropropyl, perchloropropyl, perbromopropyl, perfluoroisopropyl, perchloroisopropyl, perbromoisopropyl, and the like. １－４ Specific examples of haloalkyl include C １－３ Examples include, but are not limited to, haloalkyl, perfluorobutyl, perchlorobutyl, perbromobutyl, perfluoroisobutyl, perfluoro-t-butyl, and the like. １－６ Specific examples of haloalkyl include C １－４ These include, but are not limited to, haloalkyl, perfluoro-n-pentyl, perfluoroisopentyl, perfluoroneopentyl, perfluorotert-pentyl, perfluoro-1,2-dimethylpropyl, and the like.

[0060] As used herein, "haloalkoxy" and "haloalkyloxy" groups are monovalent groups of -O-haloalkyl in which one or more hydrogens on the alkyl group are replaced with halogen. Also, the term "perhaloalkoxy" refers to a haloalkoxy in which all hydrogens on the alkyl group are replaced with halogen. For example, perfluoroethoxy is -OCF ２ CF ３ and perchloro-n-propoxy is —OCCl ２ CCl ２ CCl ３ Preferred examples of haloalkoxy include C １－６ Haloalkoxy, C １－４ Haloalkoxy, C １－３ haloalkoxy and the like. １－３ Specific examples of haloalkoxy include fluoromethoxy, chloromethoxy, bromomethoxy, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, fluorochloromethoxy, difluorochloromethoxy, fluorodichloromethoxy, fluoroethoxy, chloroethoxy, bromoethoxy, trifluoroethoxy, trichloroethoxy, tribromoethoxy, perfluoroethoxy, perchloroethoxy, perbromoethoxy, perfluoropropoxy, perchloropropoxy, perbromopropoxy, perfluoroisopropoxy, perchloroisopropoxy, perbromoisopropoxy, and the like, but are not limited to these. １－４ Specific examples of haloalkoxy include C １－３ Examples include, but are not limited to, haloalkoxy, perfluorobutoxy, perchlorobutoxy, perbromobutoxy, perfluoroisobutoxy, perfluoro-t-butoxy, and the like. １－６ Specific examples of haloalkoxy include C １－４ These include, but are not limited to, haloalkoxy, perfluoro-n-pentyloxy, perfluoroisopentyloxy, perfluoroneopentyloxy, perfluorotert-pentyloxy, perfluoro-1,2-dimethylpropoxy, and the like.

[0061] As used herein, the term "alkylsulfonyl" refers to a sulfonyl group substituted with the above-mentioned "alkyl". １－６ As "alkylsulfonyl", preferably "C １－４ "C alkylsulfonyl". １－６ Specific examples of "alkylsulfonyl" include, but are not limited to, methylsulfonyl, propylsulfonyl, butylsulfonyl, and the like.

[0062] As used herein, the alkyl moiety of the "alkylthio" group has the same meaning as the alkyl defined above. １－６ An example of "alkylthio" is "C １－４ alkylthio", preferably "C １－３ "Alkylthio" is an example. １－６ Specific examples of "alkylthio" include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, isopropylthio, isobutylthio, tert-butylthio, sec-butylthio, isopentylthio, neopentylthio, tert-pentylthio, 1,2-dimethylpropylthio, and the like.

[0063] As used herein, an "arylcarbonyl" group is a monovalent radical of -C(=O)-aryl. Preferred examples of arylcarbonyl include C ６－１０ Examples of the arylcarbonyl include C. ６－１０ Illustrative examples of arylcarbonyl include, but are not limited to, benzoyl (ie, phenyl-C(=O)-), 1-naphthylcarbonyl, 2-naphthylcarbonyl, and the like.

[0064] As used herein, the aryl moiety of the "aryloxy" group has the same meaning as the aryl defined above. ６－１０ As the "aryloxy", preferably "C ６ Or C １０ "C aryloxy" is an example. ６－１０ Specific examples of the "aryloxy group" include, but are not limited to, a phenoxy group, a 1-naphthyloxy group, and a 2-naphthyloxy group.

[0065] As used herein, a "heteroarylcarbonyl" group is a monovalent group of -C(=O)-heteroaryl, and refers to a carbonyl group substituted by the above-mentioned "heteroaryl". ５－１０ Specific examples of the "heteroarylcarbonyl group" include, but are not limited to, a pyrazoylcarbonyl group, a triazoylcarbonyl group, a thiazoylcarbonyl group, a thiadiazoylcarbonyl group, a pyridylcarbonyl group, and a pyridazoylcarbonyl group.

[0066] As used herein, the heteroaryl portion of the "heteroaryloxy" group has the same meaning as the above-mentioned "heteroaryl". ５－１０ Specific examples of the "heteroaryloxy group" include, but are not limited to, a pyrazolyloxy group, a triazolyloxy group, a thiazoyloxy group, a thiadiazoyloxy group, a pyridyloxy group, and a pyridazoyloxy group.

[0067] As used herein, the heteroaryl moiety of the "heteroarylthio" group has the same meaning as the above-mentioned "heteroaryl". ５－１０ Specific examples of the "heteroarylthio group" include, but are not limited to, a pyrazoylthio group, a triazoylthio group, a thiazoylthio group, a thiadiazoylthio group, a pyridylthio group, and a pyridazoylthio group.

[0068] As used herein, an "optionally substituted carbonyl" group refers to a monovalent group of -C(=O)- (hydrogen or any group selected from the substituent group described herein). Examples of "optionally substituted carbonyl" groups include, but are not limited to, formyl, optionally substituted carbamoyl, alkylcarbonyl, alkoxycarbonyl, alkenylcarbonyl, alkenyloxycarbonyl, alkynylcarbonyl, alkynyloxycarbonyl, arylcarbonyl, aryloxycarbonyl, cycloalkylcarbonyl, cycloalkyloxycarbonyl, heteroarylcarbonyl, heteroaryloxycarbonyl, heterocycloalkylcarbonyl, heterocycloalkyloxycarbonyl, and the like. A carbonyl group substituted with hydrogen is a formyl group. A carbonyl group substituted with amino is a carbamoyl group.

[0069] As used herein, an "optionally substituted oxy" group refers to a monovalent group of -O- (hydrogen or any group selected from the substituent group described herein). Examples of "optionally substituted oxy" groups include, but are not limited to, hydroxy, optionally substituted alkyloxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, heterocycloalkyloxy, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, heterocycloalkylcarbonyloxy, and the like. An oxy group substituted with hydrogen is a hydroxy group.

[0070] As used herein, a "carbamoyl" group is defined as -C(=O)-NH ２ is a monovalent group.

[0071] As used herein, an "amidinoamino" group is defined as -NH-C(=NH)-NH ２ is a monovalent group.

[0072] In this specification, the expression "a group substituted with a certain substituent" means that the group is substituted with at least one substituent. For example, "hydroxy-substituted C １－６"Alkyl" is C １－６ It means that the alkyl is substituted with at least one hydroxy.

[0073] As used herein, "carbamoyl C １－６ An "alkyl" group is one that has at least one -C(=O)-NH ２ C substituted with a group １－６ It is an alkyl. "Carbamoyl C １－４ A specific example of an "alkyl" group is 2-amino-2-oxoethyl (i.e., H ２ NC(=O)-CH ２ -, or carbamoylmethyl), 3-amino-3-oxopropyl (i.e., H ２ NC(=O)-CH ２ CH ２ -, or carbamoylethyl), 4-amino-4-oxobutyl (i.e., H ２ NC(=O)-(CH ２ ) ３ -, or carbamoylpropyl), 5-amino-5-oxopentyl (i.e., H ２ NC(=O)-(CH ２ ) ４ -, or carbamoylbutyl), etc. １－６ Specific examples of "alkyl" include carbamoyl-substituted C １－４ alkyl, 6-amino-6-oxohexyl (i.e., H ２ NC(=O)-(CH ２ ) ５ -, or carbamoylpentyl), 7-amino-7-oxoheptyl (i.e., H ２ NC(=O)-(CH ２ ) ６ -, or carbamoylhexyl), and the like.

[0074] As used herein, a "thioalkyl" group is an alkyl substituted with at least one thio group. １－６ Specific examples of "alkyl" include, but are not limited to, thiomethyl, 2-thioethyl, 3-thiopropyl, 4-thiobutyl, and the like.

[0075] As used herein, an "alkylthioalkyl" group refers to an alkyl substituted with at least one alkylthio group. １－６ Alkylthio C １－６ "Alkyl" means a group having at least one C １－６ C substituted with alkylthio １－６ It means alkyl. １－６ Alkylthio C １－６ Specific examples of alkyl include, but are not limited to, methylthiomethyl, methylthioethyl, ethylthiomethyl, and the like.

[0076] As used herein, an "aminoalkyl" group is an alkyl substituted with at least one amino group. １－６ Specific examples of "alkyl" include, but are not limited to, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, and the like.

[0077] As used herein, an "amidinoaminoalkyl" group or a "guanidinoalkyl" group is defined as a group having at least one -NH-C(=NH)-NH ２ The nitrogen atom of the amidinoamino group may be protected with a nitrogen-protecting group (e.g., a tert-butoxycarbonyl group). １－６ Examples of "alkyl" include "amidinoamino C １－４ Examples include, but are not limited to, "amidinoamino C １－４ Specific examples of "alkyl" include, but are not limited to, (amidinoamino)methyl, 2-(amidinoamino)ethyl, 3-(amidinoamino)propyl, 4-(amidinoamino)butyl, etc. １－６ Specific examples of "alkyl" include amidinoamino-substituted C １－４ Examples of amidinoamino groups protected with a nitrogen protecting group include, but are not limited to, alkyl, 5-(amidinoamino)pentyl, 6-(amidinoamino)hexyl, etc. Examples of amidinoamino groups protected with a nitrogen protecting group include, In this specification, "amidinoamino" and "guanidino" have the same meaning.

[0078] As used herein, a "carboxyalkyl" group is an alkyl substituted with at least one -COOH group. １－４ Specific examples of "alkyl" include, but are not limited to, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, etc. １－６ Specific examples of "alkyl" include carboxy-substituted C １－４ Examples include, but are not limited to, alkyl, 5-carboxypentyl, 6-carboxyhexyl, and the like.

[0079] As used herein, a "protecting group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, masks, reduces, or prevents the reactivity of the functional group. １ ~R ４or any position of these or other substituents may be substituted with a protecting group as appropriate or necessary, and compounds containing such protecting groups are also within the scope of the present disclosure. Typically, the protecting group can be selectively removed during the synthetic process, if desired. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 5th Edition, 2014, John Wiley & Sons, NY, and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, John Wiley & Sons, NY, etc. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilylethanesulfonyl ("TES"), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), and nitro-veratryloxycarbonyl ("NVOC"), and the like. Representative hydroxyl protecting groups include, but are not limited to, those in which the hydroxyl group is acylated (esterified) or alkylated, such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS, triethylsilyl, t-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS)), alkyldiarylsilyl ethers (e.g., t-butyldiphenylsilyl (TBDPS)), triarylsilyl ethers (e.g., triphenylsilyl), glycol ethers (e.g., ethylene glycol ether, propylene glycol ether, etc.), and allyl ethers.

[0080] An amino group possessed by a compound of the present disclosure (for example, an amino group possessed by the parent skeleton, an amino group as a substituent, an amino group in a substituent possessed by the compound, etc.) may be protected with a nitrogen-protecting group or a group represented by "Protect." An amino group in a substituent listed in a substituent group may be further protected with a nitrogen-protecting group or a group represented by "Protect," and the protected substituent may be used as a substituent.

[0081] The hydroxy group of the compound of the present disclosure (for example, a hydroxy group as a substituent, a hydroxy group in a substituent of the compound, a hydroxy group in the above-mentioned substituent group, etc.) may also be protected with a protecting group for the hydroxy group. The hydroxy group in the substituent listed in the substituent group may be further protected with a hydroxyl-protecting group described herein, and the protected substituent may be used as a substituent.

[0082] As used herein, "pharmaceutically acceptable salts" refers to acid addition salts and base addition salts that are acceptable for pharmaceutically use. Specific examples of "pharmaceutically acceptable salts" include acetate, propionate, butyrate, formate, trifluoroacetate, maleate, fumarate, tartrate, citrate, stearate, succinate, ethylsuccinate, malonate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, benzenesulfonate, paratoluenesulfonate (tosylate), lauryl sulfate, malate, ascorbate, mandelate, saccharate, xinafoate, pamoate, ketone ... Examples of the salts include, but are not limited to, acid addition salts such as arsenate, adipate, cysteine ​​salt, N-acetylcysteine ​​salt, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinate, oxalate, picrate, thiocyanate, undecanoate, acrylic acid polymer salt, and carboxyvinyl polymer; inorganic base addition salts such as lithium salt, sodium salt, potassium salt, and calcium salt; organic base addition salts such as morpholine and piperidine; and addition salts with amino acids such as aspartic acid and glutamic acid.

[0083] Suitable salts and pharmaceutically acceptable salts of the starting compounds and the target compounds are conventional non-toxic salts, which can be appropriately selected by those skilled in the art, including acid addition salts such as organic acid salts (e.g., acetate, trifluoroacetate, maleate, fumarate, citrate, tartrate, methanesulfonate, benzenesulfonate, formate, or para-toluenesulfonate) and inorganic acid salts (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, or phosphate); salts with amino acids (e.g., arginine, aspartic acid, or glutamic acid); metal salts such as alkali metal salts (e.g., sodium salt, potassium salt, or alkaline earth metal salts (e.g., calcium salt, magnesium salt, or the like); ammonium salts; or organic base salts (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, or N,N'-dibenzylethylenediamine salt), etc.

[0084] When it is desired to obtain a salt of a compound of the present disclosure, if the compound of the present disclosure is obtained in the form of a salt, it may be purified as is, or if it is obtained in the free form, it may be dissolved or suspended in an appropriate organic solvent and an acid or base may be added to form a salt by a conventional method. In addition, the compound of the present disclosure and its pharmaceutically acceptable salts may exist in the form of an adduct with water or various solvents, and these adducts are also encompassed by the present disclosure.

[0085] The present disclosure also includes compounds of the present disclosure, or pharmaceutically acceptable salts thereof. Also included are solvates thereof, such as hydrates or ethanol solvates. Furthermore, the present disclosure also includes all tautomers, all existing stereoisomers, and all crystalline forms of the compounds of the present disclosure.

[0086] The phrase "a compound or its enantiomer or a salt thereof or a solvate thereof" means a compound, an enantiomer of said compound, a salt of said compound, a salt of said enantiomer, a solvate of said compound, a solvate of said enantiomer, a solvate of a salt of said compound, or a solvate of a salt of said enantiomer.

[0087] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers (including racemic mixtures and mixtures enriched in one or more stereoisomers). Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts. Alternatively, preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen et al. , Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses the compounds described herein as individual isomers substantially free of other isomers and alternatively as mixtures of various isomers.

[0088] Among the compounds of the present disclosure, there may exist optical isomers based on optically active centers, atropisomers based on axial or planar chirality resulting from restricted intramolecular rotation, other stereoisomers, tautomers, geometric isomers, and the like, and all possible isomers and mixtures thereof, including these, are included within the scope of the present disclosure.

[0089] In particular, optical isomers and atropisomers can be obtained as racemates or, when optically active starting materials or intermediates are used, as optically active isomers. If necessary, at an appropriate stage in the following production methods, the racemates of the corresponding starting materials, intermediates, or final products can be physically or chemically resolved into their optical antipodes by known separation methods, such as a method using an optically active column or fractional crystallization. Specifically, for example, in the diastereomeric method, two diastereomers are formed from a racemate by reaction with an optical resolving agent. These different diastereomers generally have different physical properties and can be resolved by known methods, such as fractional crystallization.

[0090] The phrase "pharmaceutically acceptable," as employed herein, refers to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0091] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials that can function as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer; and (21) other non-toxic, compatible substances employed in pharmaceutical formulations.

[0092] Furthermore, the scope of the present disclosure also includes prodrugs of the disclosed compounds. In the present disclosure, a prodrug refers to a derivative that is hydrolyzed by acid or enzymatic decomposition in vivo to give the compound of the present disclosure. For example, if the compound of the present disclosure has a hydroxyl group, an amino group, or a carboxyl group, these groups can be modified by conventional methods to produce a prodrug.

[0093] For example, in the case of a compound having a carboxyl group, the carboxyl group may be replaced by an alkoxycarbonyl group, an alkylthiocarbonyl group, or an alkylaminocarbonyl group.

[0094] Furthermore, for example, in the case of a compound having an amino group, examples include a compound in which the amino group is substituted with an alkanoyl group to become an alkanoylamino group, a compound in which the amino group is substituted with an alkoxycarbonyl group to become an alkoxycarbonylamino group, a compound in which the amino group is substituted with an alkoxycarbonylamino group, a compound in which the amino group is substituted with an alkanoyloxymethylamino group, or a compound in which the amino group is hydroxylamine.

[0095] Further, for example, in the case of a compound having a hydroxyl group, examples include a compound in which the hydroxyl group is substituted with the above-mentioned alkanoyl group to form an alkanoyloxy group, a compound which is a phosphate ester, or a compound which is an alkanoyloxymethyloxy group.

[0096] The alkyl moiety of the group used for making these prodrugs includes the above-mentioned alkyl groups, and the alkyl group may be substituted with, for example, an alkoxy group, etc. Preferred examples include the following:

[0097] For example, examples of compounds in which the carboxyl group is an alkoxycarbonyl group include C １－１２ Alkoxycarbonyl, C ４ Alkoxycarbonyl, C ６ Alkoxycarbonyl, C ８ Alkoxycarbonyl, C １０ Alkoxycarbonyl, C １２Alkoxycarbonyl, specifically methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, isobutyloxycarbonyl, tert-butyloxycarbonyl, sec-butyloxycarbonyl, n-pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert-pentyloxycarbonyl, 1,2-dimethylpropyl alkoxycarbonyl such as oxycarbonyl, n-hexyloxycarbonyl, heptoxycarbonyl, isoheptoxycarbonyl, octoxycarbonyl, isooctoxycarbonyl, nonyloxycarbonyl, isononyloxycarbonyl, decyloxycarbonyl, isodecyloxycarbonyl, undecyloxycarbonyl, isoundesiloxycarbonyl, dodecyloxycarbonyl or isododecyloxycarbonyl, or C １－１２ Alkoxy C １－１２ Alkoxycarbonyl, C １－１２ an alkoxy group such as alkoxyethoxycarbonyl, specifically methoxymethoxycarbonyl, ethoxymethoxycarbonyl, 2-methoxyethoxycarbonyl, 2-methoxyethoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl, or C １－１２ Alkyl PEG, C ４ Alkyl PEG, C ６ Alkyl PEG, C ８ Alkyl PEG, C １０ Alkyl PEG, C １２ and alkoxycarbonyl substituted with alkylPEG, where PEG refers to polyethylene glycol and the alkyl may be linear or branched.

[0098] In this specification, "or" is used when "at least one or more" of the items listed in the sentence can be employed. The same applies to "alternative." When it is specified in this specification that "within a range of two values," the range includes the two values ​​themselves.

[0099] All references cited herein, including scientific literature, patents, patent applications, and the like, are incorporated by reference in their entirety to the same extent as if each were specifically set forth.

[0100] (Preferred Embodiments) Preferred embodiments of the present disclosure will be described below. The embodiments provided below are provided for a better understanding of the present disclosure, and it is understood that the scope of the present disclosure should not be limited to the following description. Therefore, it is clear that those skilled in the art can make appropriate modifications within the scope of the present disclosure in light of the description herein. It is also understood that the following embodiments of the present disclosure can be used alone or in combination.

[0101] (Medicine for diseases associated with cognitive decline) The present disclosure provides a medicament or composition for treating or preventing diseases associated with cognitive decline, comprising a compound disclosed herein or a pharmaceutically acceptable salt, solvate or prodrug thereof. In one aspect, the compound used in the present disclosure is represented by the following formula: or a pharmaceutically acceptable salt, solvate or prodrug thereof. １ , R ２ , R ５ , R ６ , R ７ , R ８ , R ９ and R １０ are each independently a hydrogen atom or an optionally substituted hydrocarbon group, or ７ and R ８ But, R ７ and R ８ together with the carbon atom and nitrogen atom to which R is attached to form an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted cycloalkyl group, or an optionally substituted heterocycloalkyl group; ３ and R ４ are each independently a hydrogen atom, an optionally substituted hydrocarbon group, a carboxyl group, an optionally substituted alkoxycarbonyl group, or an optionally substituted alkoxycarbonyloxy group; R １１ , R １２ , R １３, and R １４ are each independently a hydrogen atom, an optionally substituted hydrocarbon group, a hydroxy group, an optionally substituted alkoxy group, or an optionally substituted alkoxycarbonyloxy group; and X is CH ２ or CO; A is O, NH or S, where NH can be optionally substituted.

[0102] In one embodiment, R １ , R ２ , R ５ , R ６ , R ７ , R ８ , R ９ and R １０ are each independently a hydrogen atom or an optionally substituted hydrocarbon group, or ７ and R ８ But, R ７ and R ８ together with the carbon atom and nitrogen atom to which R is attached form an optionally substituted heterocycloalkyl group; ３ and R ４ are each independently a hydrogen atom, an optionally substituted hydrocarbon group, a carboxyl group, an optionally substituted alkoxycarbonyl group, or an optionally substituted alkoxycarbonyloxy group; R １１ , R １２ , R １３ , and R １４ are each independently a hydrogen atom, a hydroxy group, an optionally substituted alkoxy group, or an optionally substituted alkoxycarbonyloxy group; and X is CH ２ or CO; A is O, NH or S, where NH can be optionally substituted.

[0103] In one embodiment, R １ , R ２ , R ５ , R ６ , R ７ , R ８ , R ９ and R １０are each independently a hydrogen atom or an optionally substituted alkyl group; or ７ and R ８ But, R ７ and R ８ together with the carbon atom and nitrogen atom to which R is attached form an optionally substituted heterocycloalkyl group; ３ and R ４ are each independently a hydrogen atom, an optionally substituted alkyl group, a carboxyl group, an optionally substituted alkoxycarbonyl group, or an optionally substituted alkoxycarbonyloxy group; R １１ , R １２ , R １３ , and R １４ are each independently a hydrogen atom, a hydroxy group, an optionally substituted alkoxy group, or an optionally substituted alkoxycarbonyloxy group; and X is CH ２ or CO; A is O, NH or S, where NH can be optionally substituted.

[0104] In one embodiment, R １ , R ２ , R ５ , R ６ , R ７ , R ８ , R ９ and R １０ are each independently a hydrogen atom or an alkyl group optionally substituted with from one to the maximum possible number of the same or different substituents selected from the group consisting of alkyl, alkylcarbonyl, arylalkylcarbonyl, hydroxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, cycloalkyl, carboxy, amino, guanidino, alkoxycarbonyl-substituted guanidino, carbamoyl, and heterocycloalkyl, or ７ and R ８ But, R ７ and R ８ together with the carbon atom and nitrogen atom to which R is attached to form a heterocycloalkyl group; ３ and R ４are each independently a hydrogen atom, an alkyl group which may be substituted with from one to the maximum possible number of the same or different substituents selected from the group consisting of alkyl, alkylcarbonyl, arylalkylcarbonyl, hydroxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, cycloalkyl, carboxy, amino, guanidino, alkoxycarbonyl-substituted guanidino, carbamoyl, and heterocycloalkyl, a carboxyl group, or an alkoxycarbonyl group which may be substituted with from one to the maximum possible number of the same or different substituents selected from the group consisting of alkyl, alkylcarbonyl, arylalkylcarbonyl, hydroxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, cycloalkyl, carboxy, amino, guanidino, alkoxycarbonyl-substituted guanidino, carbamoyl, and heterocycloalkyl, R １１ , R １２ , R １３ , and R １４ are each independently a hydrogen atom, a hydroxy group, or an alkoxy group which may be substituted with from one to the maximum possible number of identical or different substituents selected from the group consisting of alkyl, alkylcarbonyl, arylalkylcarbonyl, hydroxy, alkoxy, and heterocycloalkyl; X is CH ２ or CO, and A is O, NH, or S, where NH can be substituted with one to the maximum possible number of the same or different substituents selected from the group consisting of alkyl, alkylcarbonyl, arylalkylcarbonyl, hydroxy, alkoxy, alkoxycarbonyl, cycloalkyl, carboxy, and heterocycloalkyl.

[0105] In one embodiment, R １ and R ２ are each independently a hydrogen atom or C １－６ is an alkyl group, and R ３ and R ４ are each independently a hydrogen atom, a C substituted with a carboxyl group, １－６ is an alkyl group or a carboxyl group, and R ５ is a hydrogen atom, or C１－６ is an alkyl group, and R ６ is a hydrogen atom, or C １－６ is an alkyl group, and R ７ is a hydrogen atom, C １－６ Alkyl group, hydroxy C １－６ Alkyl group, carbamoyl C １－６ Alkyl group, C ６－１０ Aryl C １－６ Alkyl group, hydroxy C ６－１０ Aryl C １－６ Alkyl group, C ５－１０ Heteroaryl C １－６ Alkyl group, carboxy C １－６ Alkyl group, amino C １－６ Alkyl group, thio C １－６ Alkyl group, C １－６ Alkylthio C １－６ Alkyl group, or amidinoamino C １－６ is an alkyl group, and R ８ is a hydrogen atom, or C １－６ is an alkyl group, where R ７ and R ８ is R ７ and R ８ may be taken together with the carbon atom and nitrogen atom to which it is attached to form an optionally substituted heterocycloalkyl group, and R ９ and R １０ is a hydrogen atom, or C １－６ is an alkyl group, and R １１ , R １２ , R １３ , and R １４ are each independently a hydrogen atom, an alkoxy group, or a hydroxy group, and X is CH ２ or CO, and A is O, C １－６ NH, NH or S substituted with an alkyl group.

[0106] In one embodiment, R １ and R ２ are each independently a hydrogen atom, a methyl group, or an ethyl group, and R ３ and R ４are each independently a hydrogen atom, a carboxymethyl group, a carboxyethyl group, a carboxypropyl group, or a carboxyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a hydrogen atom, a methyl group, an isopropyl group, an isobutyl group, a secbutyl group, a benzyl group, a hydroxymethyl group, a 1-hydroxyethyl group, a carboxymethyl group, a carboxyethyl group, a 4-hydroxybenzyl group, an aminoethyl group, a 4-aminobutyl group, a thiomethyl group, a 2-methylthioethyl group, a carbamoylmethyl group, a carbamoylethyl group, an amidinoaminopropyl group, an indolylmethyl group, or a 4-imidazolemethyl group; R ８ is a hydrogen atom, where R ７ and R ８ is R ７ and R ８ together with the carbon atom and nitrogen atom to which it is bonded, C ５－１０ may form a heterocycloalkyl group, R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ are each independently a hydrogen atom, and R １２ is a hydrogen atom, a methoxy group, or a hydroxy group, and X is CH ２ or CO, and A is O, NH or S.

[0107] In one embodiment, R １ and R ２ are each independently a hydrogen atom or C １－６ It is an alkyl group.

[0108] In one embodiment, R １ and R ２ are each independently a hydrogen atom, a methyl group, or an ethyl group.

[0109] In one embodiment, R ３ and R ４ are each independently a hydrogen atom, a C substituted with a carboxyl group, １－６ It is an alkyl group or a carboxyl group.

[0110] In one embodiment, R ３ and R ４ are each independently a hydrogen atom, a carboxymethyl group, a carboxyethyl group, a carboxypropyl group, or a carboxyl group.

[0111] In one embodiment, R ５ is a hydrogen atom, or C １－６ It is an alkyl group.

[0112] In one embodiment, R ５ is a hydrogen atom. In one embodiment, R ５ is a hydrogen atom or a methyl group.

[0113] In one embodiment, R ６ is a hydrogen atom, or C １－６ It is an alkyl group.

[0114] In one embodiment, R ６ is a hydrogen atom. In one embodiment, R ６ is a hydrogen atom or a methyl group.

[0115] In one embodiment, R ７ is a hydrogen atom, C １－６ Alkyl group, hydroxy C １－６ Alkyl group, carbamoyl C １－６ Alkyl group, C ６－１０ Aryl C １－６ Alkyl group, hydroxy C ６－１０ Aryl C １－６ Alkyl group, C ５－１０ Heteroaryl C １－６ Alkyl group, carboxy C １－６ Alkyl group, amino C １－６ Alkyl group, thio C １－６ Alkyl group, C １－６ Alkylthio C １－６ Alkyl group, or amidinoamino C １－６ It is an alkyl group.

[0116] In one embodiment, R ７is a hydrogen atom, a methyl group, an isopropyl group, an isobutyl group, a secbutyl group, a benzyl group, a hydroxymethyl group, a 1-hydroxyethyl group, a carboxymethyl group, a carboxyethyl group, a 4-hydroxybenzyl group, an aminoethyl group, a 4-aminobutyl group, a thiomethyl group, a 2-methylthioethyl group, a carbamoylmethyl group, a carbamoylethyl group, an amidinoaminopropyl group, an indolylmethyl group, or a 4-imidazolemethyl group.

[0117] In one embodiment, R ７ is a hydrogen atom, a methyl group, an isopropyl group, an isobutyl group, a secbutyl group, a benzyl group, a hydroxymethyl group, a 1-hydroxyethyl group, a carboxymethyl group, a carboxyethyl group, a 4-hydroxybenzyl group, an aminoethyl group, a 4-aminobutyl group, a thiomethyl group, a 2-methylthioethyl group, a carbamoylmethyl group, a carbamoylethyl group, an amidinoaminopropyl group, an indolylmethyl group, a 4-imidazolemethyl group, a 4-trifluoromethylbenzyl group, a phenyl group, a 4-tert-butylbenzyl group, a pentafluorobenzyl group, a 4-fluorobenzyl group, or a naphthylmethyl group.

[0118] In one embodiment, R ８ is a hydrogen atom, or C １－６ It is an alkyl group.

[0119] In one embodiment, R ８ is a hydrogen atom. In one embodiment, R ８ is a hydrogen atom or a methyl group.

[0120] In one embodiment, R ７ and R ８ is R ７ and R ８ together with the carbon atom and nitrogen atom to which it is attached form an optionally substituted heterocycloalkyl group.

[0121] In one embodiment, R ７ and R ８ is R ７ and R ８ together with the carbon atom and nitrogen atom to which it is bonded, C ５－１０It forms a heterocycloalkyl group.

[0122] In one embodiment, R ９ and R １０ is a hydrogen atom or C １－６ It is an alkyl group.

[0123] In one embodiment, R ９ and R １０ are each independently a hydrogen atom or a methyl group.

[0124] In one embodiment, R １１ , R １２ , R １３ , and R １４ are each independently a hydrogen atom, an alkoxy group, or a hydroxy group.

[0125] In one embodiment, R １２ is a hydrogen atom, an alkoxy group, or a hydroxy group.

[0126] In one embodiment, R １１ , R １２ , R １３ , and R １４ are each independently a hydrogen atom, a methoxy group, or a hydroxy group.

[0127] In one embodiment, R １２ is a hydrogen atom, a methoxy group, or a hydroxy group.

[0128] In one embodiment, X is CH ２ Or CO.

[0129] In one embodiment, A is O, C １－６ NH, NH or S substituted with an alkyl group.

[0130] In one embodiment, A is O, NH or S.

[0131] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R６ is a hydrogen atom, and R ７ is an isopropyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0132] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a hydrogen atom, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0133] In one embodiment, R １ and R ２ is a hydrogen atom, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a hydrogen atom, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0134] In one embodiment, R １ and R ２ is a hydrogen atom or a methyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ has a hydrogen atom, R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0135] In one embodiment, R １ and R ２ is a hydrogen atom, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is an isopropyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0136] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is an isopropyl group, and R ８is a hydrogen atom, and R ９ and R １０ is a hydrogen atom, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0137] In one embodiment, R １ and R ２ is a hydrogen atom, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a hydrogen atom, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0138] In one embodiment, R １ and R ２ is a hydrogen atom, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is an isopropyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0139] In one embodiment, R １ and R ２is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxymethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is an isopropyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0140] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxymethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a hydrogen atom, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0141] In one embodiment, R １ and R ２ is a hydrogen atom, and R ３ and R ４ is a carboxyl group or a carboxymethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a hydrogen atom, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R１１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0142] In one embodiment, R １ and R ２ is a hydrogen atom or a methyl group, and R ３ and R ４ is a carboxyl group or a carboxymethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a hydrogen atom, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0143] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a hydrogen atom, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom, and R １１ , R １２ , R １３ , and R １４ is a hydrogen atom, and X is CH ２ and A is O.

[0144] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is an isopropyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １２ , R １３ , and R １４ is a hydrogen atom, and X is CH ２ and A is O.

[0145] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxymethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is an isopropyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0146] In one embodiment, R １ and R ２ is a methyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is an isopropyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２is a hydroxy group, and X is CH ２ and A is O.

[0147] In one embodiment, R １ and R ２ is a methyl group, and R ３ and R ４ is a carboxyl group or a carboxymethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is an isopropyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0148] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a hydrogen atom or a carboxypropyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is an isopropyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0149] In one embodiment, R １ and R ２ is a methyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R７ is an isopropyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0150] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is an isopropyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0151] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a benzyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0152] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a carboxyethyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0153] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a carboxymethyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0154] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a hydroxymethyl group, and R ８is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0155] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a 1-hydroxyethyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0156] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a 4-hydroxybenzyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0157] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a 4-aminobutyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0158] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is an amidinoaminopropyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0159] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a carbamoylethyl group, and R ８is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0160] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a carbamoylmethyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0161] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a 4-imidazole methyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0162] In one embodiment, R１ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is an indolylmethyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0163] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ and R ８ forms a pyrrolidine ring together with the carbon atom and nitrogen atom to which R is attached, ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0164] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is an isopropyl group, and R ８is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a methoxy group, and X is CH ２ and A is O.

[0165] In one embodiment, R １ and R ２ is an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is an isopropyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0166] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxymethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is an isopropyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0167] In one embodiment, R １ and R２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a carboxyethyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0168] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxymethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is an isopropyl group, and R ８ is a methyl group, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0169] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is an isopropyl group, and R ８ is a methyl group, and R ９ and R １０is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0170] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a methyl group, and R ７ is an isopropyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0171] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxymethyl group, and R ５ is a hydrogen atom, and R ６ is a methyl group, and R ７ is an isopropyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0172] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R３ and R ４ is a carboxyl group or a carboxymethyl group, and R ５ is a methyl group, and R ６ is a hydrogen atom, and R ７ is an isopropyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0173] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a methyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0174] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is an isobutyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R１３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0175] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a sec-butyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0176] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a methyl group, and R ６ is a hydrogen atom, and R ７ is an isopropyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0177] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is an isobutyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a methoxy group, and X is CH ２ and A is O.

[0178] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a sec-butyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a methoxy group, and X is CH ２ and A is O.

[0179] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxymethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is an isobutyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４is a hydrogen atom, and R １２ is a methoxy group, and X is CH ２ and A is O.

[0180] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxymethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a sec-butyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a methoxy group, and X is CH ２ and A is O.

[0181] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a benzyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a methoxy group, and X is CH ２ and A is O.

[0182] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxymethyl group, and R ５is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a benzyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a methoxy group, and X is CH ２ and A is O.

[0183] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxymethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is an isopropyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a methoxy group, and X is CH ２ and A is O.

[0184] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is an isobutyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a methoxy group, and X is CH ２and A is O.

[0185] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a sec-butyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a methoxy group, and X is CH ２ and A is O.

[0186] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxymethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is an isobutyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a methoxy group, and X is CH ２ and A is O.

[0187] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxymethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a sec-butyl group, and R８ is a hydrogen atom, and R ９ and R １０ is a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a methoxy group, and X is CH ２ and A is O.

[0188] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a benzyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a methoxy group, and X is CH ２ and A is O.

[0189] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxymethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a benzyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a methoxy group, and X is CH ２ and A is O.

[0190] In one embodiment, R １ and R２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is an isopropyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a methoxy group, and X is CH ２ and A is O.

[0191] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxymethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is an isopropyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a methoxy group, and X is CH ２ and A is O.

[0192] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a 4-trifluoromethylbenzyl group, and R ８ is a hydrogen atom, and R ９ and R １０is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0193] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a hydrogen atom or a carboxyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is an isopropyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0194] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a phenyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0195] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a 4-tert-butylbenzyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0196] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a pentafluorobenzyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0197] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a 4-fluorobenzyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R１１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0198] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is a naphthylmethyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a hydrogen atom or a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0199] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a hydrogen atom or a carboxyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is an isopropyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0200] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４is a carboxyl group or a carboxyethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is an indolylmethyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0201] In one embodiment, R １ and R ２ is a methyl group or an ethyl group, and R ３ and R ４ is a carboxyl group or a carboxymethyl group, and R ５ is a hydrogen atom, and R ６ is a hydrogen atom, and R ７ is an indolylmethyl group, and R ８ is a hydrogen atom, and R ９ and R １０ is a methyl group, and R １１ , R １３ , and R １４ is a hydrogen atom, and R １２ is a hydroxy group, and X is CH ２ and A is O.

[0202] In one embodiment, X in the above embodiment is CO.

[0203] In one embodiment, A in the above embodiment is NH.

[0204] In one embodiment, A is S in the above embodiment.

[0205] In another aspect, the compounds utilized in the present disclosure have the formula: or a pharmaceutically acceptable salt, solvate or prodrug thereof. (wherein m is 0 to 3, n≧1, and R Ａ１ ~RＡ４ , R Ａ７ ~R Ａ１１ , R Ａ３１２ , and R Ａ１１２ are each independently a hydrogen atom or a hydrocarbon group, R Ａ１４ , and R Ａ２１２ are each independently a hydrogen atom, a carboxyl group or a salt thereof, or an alkoxycarbonyl group; R Ａ５ represents a hydrocarbon group, a hydroxyl group, an alkoxy group, or an alkylcarbonyloxy group, R Ａ５５ , and R Ａ６６ are each independently a hydrogen atom, a hydrocarbon group, or an alkylcarbonyloxy group.

[0206] The cyclic peptide derivatives include those represented by the general formula (1) above, １ , R ２ , R ３ , and R ４ are each independently an alkyl group, n=2 to 4, R ５ , and R ６ is a hydrogen atom, R ７ , and R ８ is preferably a carboxyl group.

[0207] The present disclosure may be a compound having a substituent represented by any of the following: In the above table, 19 indolylmethyl independently represents 2-indolylmethyl or 3-indolylmethyl in each case. Here, the numbers X, A, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14 represent the corresponding substituents shown in the definition table above. The present disclosure may also be a compound having any combination of the substituents shown in the definition table above. The present disclosure may also be a compound having any combination of the substituents shown in the definition table above, including: (1) a compound having a combination in which R5 is replaced with a methyl group; (2) a compound having a combination in which R6 is replaced with a methyl group; (3) a compound having a combination in which R7 is replaced with a 4-trifluoromethylbenzyl group, a phenyl group, a 4-tert-butylbenzyl group, a pentafluorobenzyl group, a 4-fluorobenzyl group, or a naphthylmethyl group; or (4) a compound having a combination in which R8 is replaced with a methyl group.

[0208] In one embodiment, the compounds disclosed herein are represented in the table below. Further examples of the compounds of the present disclosure include the following.

[0209] The composition of the present disclosure preferably contains a cyclic peptide derivative or a salt thereof as an active ingredient.

[0210] In one embodiment, the compound of the present disclosure has an effect of improving brain function (particularly cognitive function). When the test substance is administered to a single intracerebroventricular administration model of β-amyloid 1-42 in the present disclosure, the compound of the present disclosure is observed to improve learning and memory. It is considered that the compound of the present disclosure is effective in treating or preventing diseases associated with a decline in cognitive function, including learning and memory, such as Alzheimer's dementia, vascular dementia, dementia with Lewy bodies, and frontotemporal dementia. (Medicines, Therapeutics, etc.) General Description

[0211] In one embodiment, the compounds of the present disclosure can be administered orally or parenterally, either directly or in the form of a formulation, medicament, or pharmaceutical composition using an appropriate dosage form. Specific examples of these dosage forms include, but are not limited to, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, and poultices. These formulations can be manufactured by known methods using additives commonly used as pharmaceutical additives.

[0212] Depending on the purpose, these additives may include excipients, disintegrants, binders, fluidizing agents, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, sweeteners, flavors, etc. Specific examples of these additives include, but are not limited to, lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc, etc.

[0213] In one embodiment, the compounds of the present disclosure are compounds capable of treating or preventing diseases associated with cognitive decline.

[0214] In one embodiment, the disease associated with cognitive decline is a disease that can be expected to be treated by improving brain function (particularly cognitive function), such as dementia, specifically Alzheimer's disease, vascular dementia, dementia with Lewy bodies, frontotemporal dementia, etc.

[0215] Therefore, the compounds of the present disclosure prevent, improve, or treat diseases associated with cognitive decline. The dementia may be one type, or two or more types. Suitable patients for the present disclosure are those suffering from the above-mentioned diseases associated with cognitive decline.

[0216] The administration timing of the compounds of the present disclosure and the therapeutic agents thereof is not limited, and they may be administered to the subject simultaneously or at different times. The compounds of the present disclosure and the therapeutic agents may also be combined. The dosage of the therapeutic agents may be appropriately selected based on the clinically used dose. The compounding ratio of the compounds of the present disclosure and the therapeutic agents may be appropriately selected depending on the subject to be administered, the administration route, the target disease, disorder, symptoms, combination, etc.

[0217] In one embodiment of the present disclosure, when using a pharmaceutical composition, the compounds of the present disclosure can be administered in combination at the same time or at different times, and such pharmaceutical compositions are also within the scope of the present disclosure.

[0218] Such medicines, formulations, and pharmaceutical compositions can be manufactured using any technique known in the art by mixing the compounds of the present disclosure and / or additional drugs (e.g., antibacterial agents, antiviral agents (e.g., ribavirin, amantadine, etc.), sedatives (e.g., ketamine, midazolam, etc.), etc.) together or separately, as a combination drug or as separate drugs, with any appropriate ingredients, and can be formulated into appropriate preparations, for example, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, and poultices, using any technique known in the art. When the compound of the present disclosure and / or the additional drug (e.g., an antibacterial agent, an antiviral agent (e.g., ribavirin, amantadine, etc.), a sedative (e.g., ketamine, midazolam, etc.), etc.) are prepared as separate drugs, they may be provided as a kit of two drugs, or one component may be provided as a single drug along with instructions (such as a package insert) instructing that the other component (which is the additional drug in the case of the compound of the present disclosure, and the compound of the present disclosure in the case of the additional drug (e.g., an antibacterial agent, an antiviral agent (e.g., ribavirin, amantadine, etc.), a sedative (e.g., ketamine, midazolam, etc.), etc.)) be administered in combination at the same time or at different times.

[0219] In certain embodiments, co-administration of a compound of the present disclosure with one or more additional therapeutic agent(s) (e.g., one or more additional chemotherapeutic agent(s)) provides improved efficacy compared to the individual administration of a compound of the present disclosure (e.g., a compound of Formula (1), (A2), or (2)) or one or more additional therapeutic agent(s). In certain such embodiments, the co-administration provides an additive effect, where additive effect refers to the sum of the effects of the individual administration of a compound of the present disclosure and one or more additional therapeutic agent(s).

[0220] For use in the methods of the present disclosure, the active compound may be provided per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0221] The dosage of the compound of the present disclosure is appropriately selected depending on the animal to be administered, the administration route, the disease, the age, weight and symptoms of the patient. For example, in the case of oral administration, the lower limit is 0.01 mg and the upper limit is 10,000 mg per day for an adult, and this amount can be administered once a day or in divided doses.

[0222] The administration timing of the compounds of the present disclosure and the therapeutic agents thereof is not limited, and they may be administered to the subject simultaneously or at different times. The compounds of the present disclosure and the therapeutic agents may also be combined. The dosage of the therapeutic agents may be appropriately selected based on clinically used doses. The compounding ratio of the compounds of the present disclosure and the therapeutic agents may be appropriately selected depending on the subject to be administered, the administration route, the target disease, disorder or symptom, the age or weight of the subject, or a combination thereof.

[0223] In one embodiment of the present disclosure, when using a pharmaceutical composition, the compounds of the present disclosure can be administered in combination at the same time or at different times, and such pharmaceutical compositions are also within the scope of the present disclosure.

[0224] When the compounds of the present disclosure are used as active ingredients in medicines, they are not intended for use only in humans, but can also be used in other animals other than humans (cats, dogs, cows, horses, bats, foxes, mongooses, raccoons, etc.).

[0225] (Preventive or therapeutic method) The present disclosure also provides a method for preventing or treating a disease associated with cognitive decline, comprising administering to a subject in need of such prevention or treatment a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. In one embodiment, the method for preventing or treating a disease associated with cognitive decline comprises administering to a subject in need of such prevention or treatment a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a pharmaceutical composition comprising the same.

[0226] (Use for Prevention or Treatment) In one embodiment of the present disclosure, there is provided use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing or treating a disease associated with cognitive decline.

[0227] The present disclosure also provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a disease associated with cognitive decline.

[0228] (Synthesis Example) For example, the present disclosure can be obtained by a coupling reaction with four compounds (Fragments A, B, C, and D), but is not limited thereto. The compounds used may be commercially available or synthesized.

[0229] The term "bonding reaction" generally refers to any method that can be used in organic synthetic chemistry, such as a cyclization reaction, an addition reaction, a ring-opening addition reaction, or a dehydration condensation reaction. In addition to bonding reactions, other reactions that can be used include protection reactions, deprotection reactions, oxidation reactions, reduction reactions, and hydrogenation reactions. The reaction conditions, such as the reaction temperature and reaction time, can be appropriately set.

[0230] In each reaction, functional groups contained in the compounds used may be protected by protective groups or the like.

[0231] The order of the reactions is not particularly limited, and the cyclization reaction may be carried out after four compounds are bonded together, or the cyclization reaction may be carried out after three compounds are bonded together, and then a fourth compound may be bonded to the resulting cyclized compound.

[0232] The compounds used in each reaction may be purified, or the reaction product from the previous step may be used as is.

[0233] 1. Method for Producing Cyclic Peptide Derivatives In the method for producing a cyclic peptide derivative according to the present disclosure, a cyclic peptide derivative represented by the following general formula (2) is produced.

[0234]

[0235] Here, in formula (2), R Ａ１ represents a hydrogen atom or a hydrocarbon group, R Ａ２ represents a hydrogen atom or a hydrocarbon group, R Ａ３ represents a hydrogen atom or a hydrocarbon group, R Ａ４ represents a hydrogen atom or a hydrocarbon group, R Ａ５ Ha-O-R Ａ５１ (R Ａ５１ represents a hydrogen atom or a protecting group), R Ａ６１ Ha-O-R Ａ６ (R Ａ６ represents a hydrogen atom, a hydrocarbon group, or a protecting group), and R Ａ７ represents a hydrogen atom, a hydrocarbon group or a protecting group, R Ａ８ represents a hydrogen atom, a hydrocarbon group or a protecting group, R Ａ９ represents a hydrogen atom, a hydrocarbon group or a protecting group, R Ａ１０ represents a hydrogen atom, a hydrocarbon group or a protecting group, R Ａ１１ represents a hydrogen atom, a hydrocarbon group or a protecting group, R Ａ１２ represents a hydrogen atom or a protecting group, R Ａ１４ Ha-(CH ２ ) ｎ -H or -(CH ２ ) ｎ -COOR Ａ１３ (R Ａ１３represents a hydrogen atom or a protecting group, and n is a number of 1 or more, Ａ５１ , R Ａ６ , R Ａ１２ , and R Ａ１３ At least one of is other than a hydrogen atom; and m is 1.

[0236] In particular, the production method of the present disclosure includes a step of condensing a product obtained by an oxidation reaction of a compound represented by the following general formula (2') with a compound having both a carboxy group and an amino group, or a salt or ester of the compound (hereinafter, this step is abbreviated as "Step A" in this specification).

[0237]

[0238] Here, in formula (2′), R Ａ１ , R Ａ２ , R Ａ３ , R Ａ４ , R Ａ５ , R Ａ６１ , R Ａ７ , R Ａ８ , R Ａ９ , R Ａ１０ and m are R in the formula (2), Ａ１ , R Ａ２ , R Ａ３ , R Ａ４ , R Ａ５ , R Ａ６１ , R Ａ７ , R Ａ８ , R Ａ９ , R Ａ１０ and m. In particular, R in formula (2') Ａ１ , R Ａ２ , R Ａ３ , R Ａ４ , R Ａ５ , R Ａ６１ , R Ａ７ , R Ａ８ , R Ａ９ , R Ａ１０ and m are R in the formula (2), Ａ１ , R Ａ２ , R Ａ３ , R Ａ４ , R Ａ５ , R Ａ６１ , R Ａ７ , R Ａ８ , RＡ９ , R Ａ１０ and m.

[0239] In the present disclosure, the hydrocarbon group may be any of an alkyl group, an alkenyl group, and an alkynyl group. The number of carbon atoms in the hydrocarbon group is not particularly limited and may be, for example, 1 to 10, preferably 1 to 5, more preferably 1 to 4, and particularly preferably 1 to 3. Specific examples of the hydrocarbon group include a methyl group, an ethyl group, a vinyl group, an acetynyl group, a propyl group, an isopropyl group, and a propenyl group. The hydrocarbon group may be linear or branched.

[0240] In the present disclosure, the protecting group is other than the hydrocarbon group, and examples thereof include aromatic groups; heterocyclic groups; oxygen-containing functional groups having an alkoxyalkyl group, a carbonyl group, an ester, or the like; and groups having a silicon atom, such as a silyl group.

[0241] When the protecting group is an aromatic group, for example, a phenyl group, a benzyl group, an oxybenzyl group (—O—CH ２ -Ph), 2-nitrobenzenesulfonyl group (nosyl group), etc. When the protecting group is an oxygen-containing functional group, an example is a tert-butoxycarbonyl group (Boc group). When the protecting group is a group having a silicon atom, an example is a tert-butyldimethylsilyl group (-Si(t-Bu)(CH ３ ) ２ ), tert-butyldiphenylsilyl group (—Si(t-Bu)Ph ２ ) etc.

[0242] In formulas (2) and (2′), R Ａ１ When is a hydrocarbon group, it is preferably an alkyl group having 1 to 5 carbon atoms, more preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, still more preferably a hydrogen atom, a methyl group or an ethyl group, and particularly preferably a methyl group.

[0243] In formulas (2) and (2′), R Ａ１When R is a hydrocarbon group, it is preferably an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, or an alkynyl group having 2 to 5 carbon atoms, more preferably a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an alkenyl group having 2 to 3 carbon atoms, or an alkynyl group having 2 to 3 carbon atoms, and particularly preferably an acetynyl group (—C≡C). Ａ２ When is an acetynyl group, the steric hindrance is smaller than that of an ethyl group, etc., and therefore the condensation reaction described below is more likely to proceed.

[0244] In formulas (2) and (2′), R Ａ３ When is a hydrocarbon group, it is preferably an alkyl group having 1 to 5 carbon atoms, more preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, still more preferably a hydrogen atom, a methyl group or an ethyl group, and particularly preferably a methyl group.

[0245] In formulas (2) and (2′), R Ａ４ When is a hydrocarbon group, it is preferably a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, more preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, still more preferably a hydrogen atom, a methyl group or an ethyl group, and particularly preferably a methyl group.

[0246] In formulas (2) and (2′), R Ａ５ is -O-R Ａ５１ (R Ａ５１ represents a hydrogen atom or a protecting group), and R Ａ５１ is preferably a protecting group, and among these, an aromatic group is more preferred, and an oxybenzyl group (—O—CH ２ -Ph) is particularly preferred.

[0247] In formulas (2) and (2′), R Ａ６１ Ha-O-R Ａ６ (R Ａ６ represents a hydrogen atom, a hydrocarbon group, or a protecting group), and R Ａ６ is preferably a hydrocarbon group or a protecting group, and R Ａ６When is a hydrocarbon group, it is preferably an allyl group, and when is a protecting group, it is preferably a tert-butyldimethylsilyl group (—Si(t-Bu)(CH ３ ) ２ ), tert-butyldiphenylsilyl group (—Si(t-Bu)Ph ２ ), benzyl group, methoxymethyl group (MOM), etc. Ａ６ is preferably a tert-butyldimethylsilyl group.

[0248] In formulas (2) and (2′), R Ａ７ is preferably a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, more preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, more preferably a hydrogen atom, a methyl group or an ethyl group, and particularly preferably a hydrogen atom.

[0249] In formulas (2) and (2′), R Ａ８ is preferably a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, more preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, further preferably a hydrogen atom, a methyl group, or an ethyl group, and particularly preferably a hydrogen atom.

[0250] In formulas (2) and (2′), R Ａ９ is preferably a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, more preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, further preferably a hydrogen atom, a methyl group or an ethyl group, and particularly preferably a methyl group.

[0251] In formulas (2) and (2′), R Ａ１０ is preferably the above-mentioned protecting group, and is particularly preferably a 2-nitrobenzenesulfonyl group (nosyl group).

[0252] In formula (2), R Ａ１１ is preferably a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, more preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, further preferably a hydrogen atom, a methyl group, or an ethyl group, and particularly preferably a hydrogen atom.

[0253] In formula (2), R Ａ１２ is preferably a protecting group, more preferably an aromatic group, and particularly preferably a benzyl group.

[0254] In formula (2), R Ａ１４ Ha-(CH ２ ) ｎ -H or -(CH ２ ) ｎ -COOR Ａ１３ (n is 1 to 4), and -(CH ２ ) ２ -COOR Ａ１３ It is more preferable that R Ａ１３ is preferably a protecting group, more preferably an aromatic group, and particularly preferably a benzyl group.

[0255] In formula (2) and formula (2′), R Ａ５ The bonding position of is not particularly limited, and can be, for example, a bonding position represented by the following formula (2″).

[0256]

[0257] Here, in formula (2″), R Ａ１ ~R Ａ５ , R Ａ７ ~R Ａ１２ and R Ａ１４ is R in the formula (2) Ａ１ ~R Ａ５ , R Ａ７ ~R Ａ１２ and R Ａ１４ is synonymous with R Ａ６１ is R in the formula (2) Ａ６１ is synonymous with.

[0258] Step A includes an oxidation reaction of the compound represented by formula (2'). Specifically, this oxidation reaction is a reaction for oxidizing an alcohol to a carboxylic acid. As a result, the hydroxyl group indicated by the arrow in the compound represented by formula (2') is converted to a carboxyl group.

[0259] In step A, the type of oxidation reaction is not particularly limited, and for example, a wide variety of known oxidation reactions of alcohol compounds can be used. The oxidation reaction may be, for example, a two-step reaction in which an alcohol is oxidized to an aldehyde and then the aldehyde is oxidized to a carboxylic acid. When the oxidation reaction is carried out in two steps in this manner, it is easy to prevent unintended oxidation reactions of functional groups.

[0260] In step A, the oxidation reaction preferably includes Dess-Martin oxidation and Pinnick oxidation. This makes it easier to suppress racemization and allows oxidation to occur under mild reaction conditions. For example, the hydroxyl group is oxidized to an aldehyde by Dess-Martin oxidation, and then the aldehyde is oxidized to a carboxylic acid by Pinnick oxidation.

[0261] When the oxidation reaction is carried out in step A, it is preferable to use 1 to 5 moles of an oxidizing agent per mole of the compound represented by formula (2'). The type of oxidizing agent is not particularly limited, and a wide range of known oxidizing agents used in oxidation reactions can be used.

[0262] In the Dess-Martin oxidation, it is preferable to use 1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (DMP) as the oxidizing agent. In the case of the Dess-Martin oxidation, it is preferable to use 1 to 5 moles, and more preferably 1 to 3 moles, of the oxidizing agent per mole of the compound represented by formula (2').

[0263] In the Pinnick oxidation, sodium hypochlorite (NaClO ２ In the case of Pinnick oxidation, it is preferable to use 1 to 5 moles, and more preferably 2 to 5 moles, of the oxidizing agent per mole of the compound represented by formula (2').

[0264] Other oxidizing agents may also be used in the oxidation reaction, and examples thereof include an oxidizing agent that combines a nitroxyl radical species such as 2,2,6,6-tetramethylpiperidine 1-oxyl with iodosobenzene diacetate.

[0265] In step A, a solvent may be used, if necessary, in the oxidation reaction. Examples of the solvent that can be used in the oxidation reaction include chlorine-containing compounds such as dichloromethane and dichloroethane, acetonitrile, and tert-butanol.

[0266] In step A, the reaction temperature for the oxidation reaction is not particularly limited, and the reaction can be carried out at, for example, -20 to 60°C, preferably 0 to 30°C.

[0267] In step A, after the oxidation reaction, the product obtained by the oxidation reaction (carboxylic acid compound) is subjected to a condensation reaction with a compound having both a carboxy group and an amino group, or a salt or ester of the compound. Hereinafter, the compound having both a carboxy group and an amino group, or a salt or ester of the compound will be abbreviated as "compound C."

[0268] Of the compounds C, the compounds having both a carboxy group and an amino group are not particularly limited, and examples thereof include amino acids, among which glutamic acid or aspartic acid is preferred.

[0269] In particular, in step A, it is preferable to carry out a condensation reaction between the product (carboxylic acid compound) obtained by the oxidation reaction and a glutamic acid ester or an aspartic acid ester. By using a glutamic acid ester in the condensation reaction, the obtained cyclic peptide derivative, i.e., the cyclic peptide derivative represented by general formula (2), can be obtained by the reaction of R Ａ１４ Ga-(CH ２ ) ２ -COOR Ａ１３ When an aspartic acid ester is used in the condensation reaction, the resulting cyclic peptide derivative, i.e., the cyclic peptide derivative represented by general formula (2), is Ａ１４ Ga-(CH ２ )-COORＡ１３ In either case, R Ａ１３ is preferably a protecting group, more preferably an aromatic group, and particularly preferably a benzyl group.

[0270] In the condensation reaction of step A, the amount of compound C used is preferably 1 to 5 moles, more preferably 2 to 5 moles, and even more preferably 3 to 4 moles per mole of the carboxylic acid compound obtained in the oxidation reaction.

[0271] For example, in step A, when the product (carboxylic acid compound) obtained by the oxidation reaction is subjected to a condensation reaction with a glutamic acid ester, the resulting cyclic peptide derivative represented by formula (2) is represented by the following general formula (2A):

[0272]

[0273] Here, in formula (2A), R Ａ１ ~R Ａ５ , R Ａ６１ , R Ａ７ ~R Ａ１３ and m is R in formula (2) Ａ１ ~R Ａ５ , R Ａ６１ , R Ａ７ ~R Ａ１３ and m.

[0274] In step A, the condensation reaction method is not particularly limited, and for example, known condensation reaction conditions can be widely adopted. A condensing agent can also be used in the condensation reaction from the viewpoint of easily suppressing racemization and promoting oxidation under mild reaction conditions.

[0275] The type of condensing agent is not particularly limited, and for example, a wide variety of known condensing agents can be used. In particular, in the condensation reaction of step A, it is preferable to use a phosphorus-based condensing agent as the condensing agent. Examples of such condensing agents include 3-(Diethoxyphosphoryloxy)-3H-benzo[d][1,2,3]triazin-4-one (DEPBT), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Hydrochloride, 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium Chloride, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, 1-[Bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate, and N-[1-(Cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino(morpholino)]uronium hexafluorophosphate. The phosphorus-based condensing agent is preferably a phosphoric acid azide compound, and particularly preferably DEPBT.

[0276] When a condensing agent is used, the amount used is not particularly limited. For example, the amount of the condensing agent used is preferably 1 to 3 moles, and more preferably 1.2 to 2.5 moles, per mole of the carboxylic acid compound obtained by the oxidation reaction.

[0277] A solvent can be used as needed in the condensation reaction of step A. The solvent is not particularly limited, and examples thereof include aliphatic hydrocarbons such as hexane and heptane; alicyclic hydrocarbons such as cyclohexane; aromatic hydrocarbons such as benzene, toluene, and xylene; chlorinated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; alcohols such as methanol, ethanol, isopropyl alcohol, and t-butanol; and amide solvents such as N,N-dimethylacrylamide.

[0278] The condensation reaction may be carried out in the presence of a base catalyst such as diisopropylethylamine or dimethylaminopyridine.

[0279] In step A, the reaction temperature for the condensation reaction is not particularly limited, and the reaction can be carried out at, for example, -20 to 60°C, preferably 0 to 30°C.

[0280] In step A, an oxidation reaction and subsequent condensation reaction can be performed to produce a cyclic peptide derivative represented by formula (2) in high yield. Conventionally, no method has been known for stereoselectively reacting a cyclic peptide derivative in which a macrolactam structure containing a β-hydroxydopa unit and a structure derived from a non-natural amino acid, such as a β-hydroxyisoleucine unit, is condensed with an amino acid derivative, such as a glutamic acid derivative. In contrast, the present disclosure employs step A using a compound represented by formula (2'), thereby enabling the production of a cyclic peptide derivative represented by formula (2). Therefore, the cyclic peptide derivative represented by formula (2) has a structure containing a β-hydroxydopa unit and a β-hydroxyisoleucine unit.

[0281] It is generally known that in biosynthesis, cyclic peptide derivatives are produced by binding all peptides together and then cyclizing them. In contrast, in the method for producing a cyclic peptide derivative disclosed herein, compound C (e.g., glutamic acid ester) is bound to a compound having a cyclized structure. In other words, in the method for producing a cyclic peptide derivative disclosed herein, compound C is bound last, which has the advantage that cyclic peptide derivatives to which various amino acids, etc. are bound can be obtained depending on the type of compound C. In addition, the route disclosed herein in which a cyclic structure is constructed in advance and then a side chain (compound C) is introduced can simplify the process of removing the protecting group, and also has the advantage of being able to give the target product in high yield.

[0282] 2. Method for Producing Cyclic Peptide Compounds The method for producing a cyclic peptide compound of the present disclosure includes a step of subjecting the cyclic peptide derivative obtained by the method for producing a cyclic peptide derivative to a hydrogenation reduction reaction to obtain a cyclic peptide compound. That is, the method for producing a cyclic peptide compound of the present disclosure includes a step of subjecting the cyclic peptide derivative obtained by the condensation reaction in Step A of the method for producing a cyclic peptide derivative to a hydrogenation reduction reaction.

[0283] In the method for producing a cyclic peptide compound, the method of hydrogenation reduction is not particularly limited, and for example, known hydrogenation reduction conditions can be widely adopted. For example, the hydrogenation reduction can be carried out using hydrogen in the presence of a catalyst. As the catalyst, for example, a known catalyst used in hydrogenation reduction can be used, specifically palladium on carbon can be used. In the hydrogenation reduction, a solvent can also be used as needed. Examples of the solvent include lower alcohols such as methanol and ethanol.

[0284] When the cyclic peptide derivative represented by formula (2) obtained by the condensation reaction in step A has a protecting group such as a tert-butoxycarbonyl group (Boc group), a tert-butyldimethylsilyl group (TBS group), or a 2-nitrobenzenesulfonyl group (nosyl group), the protecting group can be deprotected beforehand before carrying out the hydrogenation reduction reaction. The deprotection method is not particularly limited, and for example, a wide range of known deprotection methods can be used. For example, deprotection of the TBS group and deprotection of the nosyl group can be carried out in this order.

[0285] When the cyclic peptide derivative represented by formula (2) has an alkynyl group (for example, R Ａ２ The alkynyl group can be converted to an alkyl group by the hydrogenation reduction reaction. For example, when an acetinyl group is present in the cyclic peptide derivative represented by formula (2), the acetinyl group can be converted to an ethyl group by the hydrogenation reduction reaction.

[0286] In one embodiment of the method for producing a cyclic peptide compound of the present disclosure, for example, the cyclic peptide derivative represented by formula (2) obtained by the condensation reaction in step A is deprotected and then subjected to a hydrogenation reduction reaction, thereby producing, for example, a compound represented by the following formula (10), and specifically, a compound represented by the following formula (A):

[0287]

[0288] In formula (10), R Ａ１ , R Ａ２ , R Ａ３ , R Ａ４ , R Ａ６１ , R Ａ７ , R Ａ８ , R Ａ９ , R Ａ１０ and R Ａ１１ are R in the formula (2), respectively. Ａ１ , R Ａ２ , R Ａ３ , R Ａ４ , R Ａ６１ , R Ａ７ , R Ａ８ , R Ａ９ , R Ａ１０ and R Ａ１１ In this case, R Ａ６１ is preferably a hydroxyl group.

[0289] In addition, in formula (A), R Ａ１ , R Ａ３ and R Ａ４ is R in the formula (2). Ａ１ , R Ａ３ and R Ａ４ Specifically, the compound represented by formula (A) is a compound represented by formula (2) Ａ５ is a hydroxyl group (where m is 1), and R Ａ１２ is a hydrogen atom, and R Ａ１４ Ha-(CH ２ ) ２ In formula (A), R Ａ２ is an ethyl group, R Ａ６１ OH, R Ａ７ , R Ａ８ , R Ａ９ and R Ａ１１ is a hydrogen atom, R Ａ１０is a methyl group, but is not limited to this.

[0290] In the hydrogenation reduction reaction, when the cyclic peptide derivative represented by formula (2) has an alkynyl group, it is converted to an alkyl group, and for example, the ester moiety derived from compound C is converted to a carboxylic acid. Ａ５ When R has a protecting group (for example, when it is a group containing an ether structure such as an oxybenzyl group), R Ａ５ can be converted to a hydroxyl group (see formula (A) above).

[0291] The cyclic peptide compound obtained by the hydrogenation reduction reaction is not particularly limited as long as it is a compound that can be produced by hydrogenation reduction of the compound represented by formula (2), and preferably, Ａ５ is a hydroxyl group, and R Ａ１２ is a hydrogen atom, and R Ａ１４ COOR Ａ１３ R in Ａ１３ is a hydrogen atom. Ａ２ It is also preferred that R is an ethyl group. Ａ１４ Ga-(CH ２ ) ２ -COOH or -CH ２ It is more preferable that the cyclic peptide compound obtained by the hydrogenation reduction reaction is a compound represented by the general formula (A) in which R Ａ１ , R Ａ３ and R Ａ４ are compounds in which all of them are methyl groups.

[0292] In the method for producing a cyclic peptide compound of the present disclosure, the cyclic peptide derivative obtained by the above-mentioned method for producing a cyclic peptide derivative is subjected to a hydrogenation reduction reaction to obtain a cyclic peptide compound, so that the cyclic peptide compound can be obtained in high yield. Furthermore, depending on the type of compound C used in the method for producing a cyclic peptide derivative, cyclic peptide compounds to which various amino acids, etc. are bound can be obtained.

[0293] 3. Method for Preparing Raw Materials Used in the Present Disclosure An example of a method for producing the compound represented by formula (2') used in step A in the method for producing a cyclic peptide derivative of the present disclosure is described below. The method for producing the compound represented by formula (2') is not particularly limited, and for example, a wide variety of known production methods can be adopted.

[0294] The compound represented by formula (2') can be produced by the following method: Ａ６ is a protecting group, for example, the method may include a step of obtaining a compound represented by the following formula (22a) by an intramolecular cyclization reaction of a cyclization precursor represented by the following formula (21a) (hereinafter referred to as a cyclization step).

[0295]

[0296] In formula (21a), R Ａ１ ~R Ａ５ and m is R in formula (1). Ａ１ ~R Ａ５ and m have the same meaning. In formula (21a), MOM represents a methoxymethyl group (the same applies hereinafter). TBS represents a tert-butyldimethylsilyl group.

[0297]

[0298] In formula (22a), R Ａ１ ~R Ａ５ and m is R in formula (1). Ａ１ ~R Ａ５ and m.

[0299] In the cyclization step, an amide bond is formed between the β-hydroxyisoleucine unit and the β-hydroxydopa unit by an intramolecular cyclization reaction of the cyclization precursor represented by formula (21a), thereby forming a compound represented by formula (22a).

[0300] Regarding the intramolecular cyclization reaction, it has been known that the yield of the reaction is only 10 to 20% and a large amount of dimer of the cyclization precursor is produced as a by-product in a conventionally known method (e.g., the method described in P. Li, C. D. Evans, M. M. Joullie, Org. Lett., 2005, 7, 5325). In addition, in other methods (e.g., P. Li, C. D. Evans, Y. Wu, B. Cao, E. Hamel, M. M. Joullie, J. Am. Chem. Soc., 2008, 130, 2351), the yield improved to 30 to 40%, but still did not exceed 40%.

[0301] In this regard, in the present disclosure, in the cyclization step, a dilute substrate solution is dropped into a solvent containing a binder, thereby diluting the concentration of the substrate (i.e., the compound represented by formula (21a)), suppressing the progress of intermolecular reactions and promoting the progress of intramolecular cyclization reactions, thereby enabling intramolecular cyclization reactions to be carried out in a higher yield than conventional methods. It is presumed that such intramolecular cyclization reactions suppress intermolecular reactions, thereby increasing the yield of the target cyclized compound (i.e., the compound represented by formula (22a)).

[0302] The type of binder used in the cyclization step is not particularly limited, and a wide variety of binders used in intramolecular cyclization reactions can be used. Examples of binders include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, and 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT).

[0303] The solvent used to dissolve the binder and substrate in the cyclization step is not particularly limited, and is preferably a polar solvent such as a chlorinated hydrocarbon such as dichloromethane, chloroform, 1,2-dichloroethane, etc.; an alcohol such as methanol, ethanol, isopropyl alcohol, t-butanol, etc.; an amide solvent such as N,N-dimethylacrylamide, etc. The solvent may be used alone or in combination of two or more.

[0304] The binder concentration can be, for example, in the range of 1 mM to 15 mM based on the solvent used, and the substrate concentration can be in the range of 0.1 mM to 1.5 mM based on the solvent used.

[0305] The temperature for the intramolecular cyclization reaction is not particularly limited, and can be, for example, −20 to 60° C., preferably 0 to 30° C. The reaction time can be set appropriately depending on the reaction temperature and the like, and for example, the substrate can be added dropwise over 6 to 24 hours, and the reaction can be continued for 6 to 24 hours, but is not limited thereto. In particular, by carrying out the reaction over a long period at a low temperature, the intramolecular cyclization reaction is promoted, and the yield of the cyclized compound (compound represented by formula (22a)) can be improved by about 1.5 to 2.5 times compared to conventional cyclization reactions.

[0306] After obtaining a compound represented by formula (22a) by intramolecular cyclization, the compound represented by formula (2) can be obtained by deprotecting the MOM. The method for deprotecting the MOM is not particularly limited, and for example, the same conditions as those for known methods for deprotecting the MOM can be used. Before deprotecting the MOM, for example, the protecting group in the compound represented by formula (22a) can be substituted with another protecting group (e.g., substituting a Boc group substituted on the N atom with a nosyl group). Furthermore, before deprotecting the MOM, the N atom to which a protecting group such as a nosyl group is bonded can be methylated. For example, a wide variety of known methods can be used for the methylation, and an example is methylation of methyl p-nitrobenzenesulfonate.

[0307] The production method for obtaining the compound represented by formula (21a) used in the cyclization step is not particularly limited, and for example, the compound represented by formula (21a) can be obtained by a known reaction. As an example, the compound represented by formula (21a) can be obtained through a step of reacting a compound represented by the following formula (7a) with a compound represented by the following formula (8a).

[0308]

[0309] In formula (7a), R Ａ５ and m is R in formula (1). Ａ５and m have the same meaning as m. The compound represented by formula (7a) is a β-hydroxydopa unit.

[0310]

[0311] In formula (8a), R Ａ１ and R Ａ２ is R in the formula (2). Ａ１ and R Ａ２ The compound represented by formula (8a) is an aziridine compound.

[0312] The reaction of the compound represented by formula (7a) with the compound represented by formula (8a) can be carried out under conditions similar to those of known ring-opening reactions, for example, in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD).

[0313] In formula (8a), R Ａ２ When is an acetinyl group, the nucleophilic reaction rate is extremely fast, and as a result, the nucleophilic addition reaction between the β-hydroxydopa unit and the aziridine proceeds quickly, resulting in a high yield of the reaction product. Therefore, the production method of the present disclosure has the advantage that it is possible to use aziridine that has not reacted with an amino acid.

[0314] After the reaction of the compound represented by formula (7a) with the compound represented by formula (8a), a reaction for introducing a protecting group (MOM) is carried out to synthesize the compound represented by formula (13a) below. The reaction conditions for introducing the protecting group are not particularly limited, and can be the same as those used in known methods.

[0315]

[0316] In formula (13a), R Ａ１ , R Ａ２ , R Ａ５ and m is R in the formula (2). Ａ１ , R Ａ２ , R Ａ５ and m.

[0317] Thereafter, the compound represented by formula (13a) is subjected to a deprotection reaction and an esterification reaction to obtain a compound represented by the following formula (18a). The conditions for the deprotection reaction and the esterification reaction are not particularly limited, and can be the same as those used in known methods.

[0318]

[0319] In formula (18a), R Ａ１ , R Ａ２ , R Ａ５ and m is R in the formula (2). Ａ１ , R Ａ２ , R Ａ５ and m.

[0320] The Troc group (2,2,2-trichloroethoxycarbonyl group) of the compound represented by formula (18a) is deprotected, followed by a condensation reaction with, for example, a valine compound having a 9-fluorenylmethyloxycarbonyl group, followed by further deprotection to produce a compound represented by formula (21a) (cyclization precursor). In this condensation reaction, an appropriate condensing agent can be used.

[0321] In addition, R Ａ２ When R is an acetinyl group, it can be reduced as needed. This reduction can be carried out in the hydrogenation reduction step after the condensation reaction in step A, as described above, or can be carried out at any time after the nucleophilic addition reaction with the aziridine. Ａ２ When is an acetylenic group, the acetylenic group is relatively less bulky than an alkyl group and therefore is less likely to inhibit the reaction, and therefore the acetylenic group can be maintained without reduction until the hydrogenation reduction reaction.

[0322] The method for producing the compound represented by formula (7a) is not particularly limited. For example, the compound can be produced by a reaction using a compound represented by the following formula (1a) and a compound represented by the following formula (2a) as starting materials.

[0323]

[0324]

[0325] In formula (2a), R Ａ５ and m is R in the formula (2′). Ａ５ is synonymous with.

[0326] On the other hand, the compound represented by formula (8a) can be obtained, for example, by a known production method, or can be obtained from a commercial product.

[0327] Pharmaceutical Compositions The compositions and methods of the present disclosure can be used to treat individuals in need thereof. In certain embodiments, the individual is a mammal, such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the present disclosure and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions, such as water or buffered saline, or other solvents or vehicles, such as glycols, glycerol, oils, such as olive oil, or injectable organic esters. In preferred embodiments, when such pharmaceutical compositions are intended for administration to humans, particularly via an invasive route (i.e., a route such as injection or implantation that avoids transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free or substantially pyrogen-free. The excipient can be selected, for example, to effect delayed release of the agent or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition may be in unit dosage form, such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilized for reconstitution, powder, liquid, syrup, suppository, or injection. The composition may also be present in a transdermal delivery system, such as a skin patch. The composition may also be present in a liquid suitable for topical administration, such as eye drops.

[0328] A pharmaceutically acceptable carrier can contain a physiologically acceptable agent that acts, for example, to stabilize, increase the solubility, or increase the absorption of a compound, such as a compound of the present disclosure. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose, or dextran, antioxidants such as ascorbic acid or glutathione, chelating agents, low-molecular-weight proteins, or other stabilizers or excipients. The selection of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) can also be a liposome or other polymer matrix, into which, for example, a compound of the present disclosure can be incorporated. Liposomes, such as liposomes containing phospholipids or other lipids, are non-toxic, physiologically acceptable, and metabolizable carriers that are relatively easy to prepare and administer.

[0329] Pharmaceutical compositions (preparations) can be administered to a subject by any of several routes of administration, including, for example, orally (e.g., as drenches, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue, etc., in aqueous or non-aqueous solutions or suspensions); absorbed through the oral mucosa (e.g., sublingually); anally, rectally, or vaginally (e.g., as pessaries, creams, or foams, etc.); parenterally (e.g., as a sterile solution or suspension, including intramuscularly, intravenously, subcutaneously, or intrathecally); nasally; intraperitoneally; subcutaneously; transdermally (e.g., as a patch applied to the skin); and topically (e.g., as a cream, ointment, or spray applied to the skin, or as eye drops). The compounds can also be formulated for inhalation. In certain embodiments, the compounds may simply be dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable therefor can be found, for example, in U.S. Pat. Nos. 6,110,973, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, and the patents cited therein.

[0330] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, this amount will range from about 1 percent to about 99 percent of active ingredient, preferably from about 5 percent to about 70 percent active ingredient, and most preferably from about 10 percent to about 30 percent active ingredient, out of one hundred percent.

[0331] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the present disclosure, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0332] Formulations of the present disclosure suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), lyophilized, powder, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a pastille (using an inert base, such as gelatin and glycerin, or sucrose and acacia), and / or as a mouthwash, each of which contains a predetermined amount of a compound of the present disclosure as an active ingredient. The composition or compound may also be administered as a bolus, electuary, or paste.

[0333] To prepare solid dosage forms for oral administration, such as capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, and granules, the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents. Disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retardants, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets, and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[0334] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants or dispersants. Molded tablets can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0335] Tablets and other solid dosage forms of pharmaceutical compositions, such as sugar-coated tablets, capsules (including sprinkle capsules and gelatin capsules), pills, and granules, may be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may also be formulated to provide sustained or controlled release of the active ingredient therein, for example, using hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres in different proportions to provide a desired release profile. They may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain emulsifying agents, and may be compositions that release the active ingredient(s) only, or preferentially, in a certain part of the digestive tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the excipients described above.

[0336] Useful liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, lyophilized formulations for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrins and their derivatives, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0337] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0338] Suspensions may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0339] Formulations of pharmaceutical compositions for rectal, vaginal, or urethral administration may be presented as suppositories, which can be prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, which are solid at room temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound.

[0340] Formulations of the pharmaceutical composition for administration to the mouth may be presented as a mouthwash, or an oral spray, or an oral ointment.

[0341] Alternatively or additionally, the compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device, which may be particularly useful for delivery to the bladder, urethra, ureter, rectum, or intestine.

[0342] Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0343] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier, and any preservatives, buffers, or propellants that may be required.

[0344] The ointments, pastes, creams and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats and oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0345] Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0346] Transdermal patch has the added advantage of providing controlled delivery of the compound of the present disclosure to the body.Such dosage forms can be prepared by dissolving or dispersing active compound in a suitable medium.The flux of compound across the skin can also be increased by using an absorption enhancer.The rate of such flux can be controlled by providing a rate-controlling membrane or dispersing compound in a polymer matrix or gel.

[0347] Ophthalmic formulations, eye ointments, powders, solutions, and the like are also contemplated within the scope of the present disclosure. Exemplary ophthalmic formulations are described in U.S. Patent Application Publication Nos. 2005 / 0080056, 2005 / 0059744, 2005 / 0031697, and 2005 / 004074, and U.S. Patent No. 6,583,124, the contents of which are incorporated herein by reference. If desired, the liquid ophthalmic formulation has properties similar to those of tears, aqueous humor, or vitreous humor, or is compatible with such fluids. A preferred route of administration is local administration (e.g., topical administration, such as eye drops, or administration via an implant).

[0348] The present disclosure has been described above by showing preferred embodiments for ease of understanding. The present disclosure will be described below based on examples. However, the above description and the following examples are provided for illustrative purposes only and are not intended to limit the present disclosure. Therefore, the scope of the present disclosure is not limited to the embodiments or examples specifically described herein, but is limited only by the scope of the claims.

[0349] In the examples, for the sake of simplicity, the abbreviations shown above and the following abbreviations may be used: Ac: acetyl AcOH: acetic acid aq. : Aqueous solution Arg: Arginine Asp: Aspartic acid BHT: Dibutylhydroxytoluene Bn: Benzyl Boc: tert-butoxycarbonyl Boc2O: Di-tert-butyl dicarbonate Bzl: Benzyl Cbz: Benzyloxycarbonyl CPME: Cyclopentyl methyl ether DBU: Diazabicycloundecene DEPBT: 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one DIAD: Diisopropyl azodicarboxylate DIPEA: N,N-Diisopropylethylamine DMAP: 4-Dimethylaminopyridine DMEAD: Bis(2-methoxyethyl) azodicarboxylate DME: 1,2-Dimethoxyethane DMF: N,N-Dimethylformamide DMP : 2,2-dimethoxypropane DMT-MM : 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride DMT-MMT : 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholinium tetrafluoroborate EDCI : 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Et : Ethyl eq. : Equivalent Fmoc : 9-Fluorenylmethyloxycarbonyl Gln : Glutamine Glu : Glutamic acid HATU : 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HBTU: 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate HOAt: 1-hydroxy-7-azabenzotriazole HOBt: 1-hydroxybenzotriazole Ile: isoleucine m-CPBA: metachloroperbenzoic acid Me: methyl MS: molecular sieve MTBE: methyl tert-butyl ether NBS: N-bromosuccinimide NMM: N-methylmorpholine Ns: 2-nitrobenzenesulfonyl PMB: paramethoxybenzyl Ser: serine Su: succinimide TBAF: tetrabutylammonium fluoride TBAI: tetrabutylammonium iodide TBD : 1,5,7-triazabicyclo[4.4.0]dec-5-ene TBS : tert-butyldimethylsilyl t-Bu : tert-butyl TFA : trifluoroacetic acid THF : tetrahydrofuran Thr : threonine TEMPO : 2,2,6,6-tetramethylpiperidine-1-oxyl radical Tr : trityl Trt : trityl Ts : tosyl TsOH : paratoluenesulfonic acid Tyr : tyrosine Pbf : 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl Ph : phenyl PyBOP : (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate PyBrop : bromo-tris-pyrrolidino-phosphonium hexafluorophosphate Val : valine Fragment C and Fragment D were obtained from the following sources:

[0350] (Example 1: Synthesis of Fragment A-2) To a solution of L-tyrosine (1.0 eq., 6.51 g, 35.9 mmol) in nitrobenzene (130 mL), aluminum chloride (4.0 eq., 19.1 g, 143 mmol) and acetyl chloride (1.2 eq., 3.42 g, 43.6 mmol) were added under ice cooling, and the mixture was stirred for 10 minutes while warming to room temperature. The reaction solution was heated to 100°C and stirred for 8 hours, and then stirred for 16 hours while cooling to room temperature. The reaction solution was ice-cooled, and water (200 mL) was added. The mixture was washed once with ethyl acetate (300 mL), and the organic layer was extracted once with water (100 mL). The aqueous layers were combined, and an aqueous solution (300 mL) was obtained, yielding A2-1.

[0351] Potassium carbonate (7.5 eq., 36.9 g, 267 mmol) was added to A2-1 (1.0 eq., calculated as 300 mL of aqueous solution, 35.9 mmol) under ice-cooling to adjust the pH to 9, and THF (150 mL) and CbzCl (1.2 eq., 7.3 g, 42.8 mmol) were added, followed by stirring at room temperature for 3 hours. 2N aqueous hydrochloric acid (200 mL) was added to the reaction mixture to adjust the pH to 3, and the THF was evaporated under reduced pressure. The concentrate was extracted three times with ethyl acetate (200 mL), and the combined organic layers were washed once with saturated aqueous sodium chloride (200 mL), followed by drying over magnesium sulfate. The magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain A2-2 (11.4 g) as a brown oil.

[0352] Under a nitrogen atmosphere, potassium carbonate (3.0 eq., 14.9 g, 108 mmol), TBAI (0.10 eq., 1.33 g, 3.59 mmol), and BnBr (2.2 eq., 13.5 g, 79.1 mmol) were added to a DMF (50 mL) solution of A2-2 (calculated as 1.0 eq., 11.4 g, 35.9 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3.5 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted twice with a hexane (40 mL) / ethyl acetate (80 mL) mixture. The combined organic layers were washed once with a saturated aqueous sodium chloride solution (100 mL), and then dried over magnesium sulfate. The magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a crude product (23.2 g). The crude product was purified using a flash silica gel column (normal phase silica gel 200 g, hexane / ethyl acetate = 80 / 20 to 50 / 50) to obtain A2-3 (9.56 g, 50% yield over three steps from L-tyrosine) as a yellow viscous product. Note that throughout this specification, all mixtures are referred to as a solvent A (X mL) / solvent B (Y mL) mixture.

[0353] Under a nitrogen atmosphere, sodium hydride (1.2 eq., 60%, dispersion in paraffin liquid, 796 mg, 19.9 mmol) and methyl iodide (3.0 eq., 7.07 g, 49.8 mmol) were added to a solution of A2-3 (1.0 eq., 8.88 g, 16.5 mmol) in DMF (80 mL) under ice-cooling, and the mixture was stirred for 1.5 hours under ice-cooling. The reaction mixture was quenched by adding methanol (12 mL), water (100 mL) was added, and the mixture was extracted twice with a mixture of hexane (50 mL) and ethyl acetate (100 mL). The organic layers were combined, washed once with saturated aqueous sodium chloride (100 mL), and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a crude product (13.1 g). The crude product was purified with a flash silica gel column (normal phase silica gel 50 g, hexane / ethyl acetate=90 / 10 to 0 / 100) to obtain A2-4 (9.54 g) as an orange liquid.

[0354] To a solution of A2-4 (calculated as 1.0 eq., 10.1 g, 17.6 mmol) in chloroform (90 mL) was added m-CPBA (3.0 eq., 35% water content, 14.0 g, 52.7 mmol) at room temperature, and the mixture was stirred under reflux for 5 hours. Water (50 mL) and saturated aqueous sodium bicarbonate solution (100 mL) were added to the reaction solution at room temperature, and the chloroform was then evaporated under reduced pressure. The reaction solution was extracted three times with ethyl acetate (100 mL), and the combined organic layers were washed once with saturated aqueous sodium chloride solution (100 mL), followed by drying over magnesium sulfate. The magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain the ester (10.6 g).

[0355] Lithium hydroxide (4.0 eq., 1.68 g, 70.3 mmol) was added to a THF (40 mL) / water (40 mL) mixture of the ester (calculated as 1.0 eq., 10.6 g, 17.6 mmol) at room temperature, and the mixture was stirred at the same temperature for 16 hours. The reaction mixture was washed twice with hexane (100 mL), and then 6N aqueous hydrochloric acid (11 mL) was added to the aqueous layer to adjust the pH to 2. The aqueous layer was extracted three times with ethyl acetate (100 mL), and the combined organic layers were washed once with saturated aqueous sodium chloride (100 mL), followed by drying over magnesium sulfate. The magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain A2-5 (9.3 g) as an orange solid.

[0356] DBU (1.1 eq., 2.96 g, 19.4 mmol) and PMBCl (1.1 eq., 3.00 g, 19.2 mmol) were added to a solution of A2-5 (calculated as 1.0 eq., 9.3 g, 17.6 mmol) in acetonitrile (80 mL) at room temperature, and the mixture was stirred for 19 hours at an external temperature of 60° C. The reaction mixture was quenched by adding acetic acid (3.0 eq., 3.15 g, 52.5 mmol), and then concentrated under reduced pressure to obtain a crude product (16.7 g). The crude product was purified twice using a flash silica gel column (first run: 120 g of normal-phase silica gel, hexane / ethyl acetate = 75 / 25 to 50 / 50; second run: 30 g of normal-phase silica gel, hexane / ethyl acetate = 75 / 25 to 67 / 23). The resulting Fragment A-2 was dissolved in ethyl acetate (50 mL) and washed once with saturated aqueous sodium bicarbonate (50 mL). The aqueous layer was extracted twice with ethyl acetate (50 mL). The combined organic layers were washed once with saturated aqueous sodium chloride (50 mL) and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to give Fragment A-2 (3.54 g, 36% yield for three steps from A2-3) as a yellow oil.

[0357] (Example 2A: Synthesis of Fragment A-2′) To a solution of A2-5 (calculated as 1.0 eq., 3.4 g, 7.12 mmol) in acetonitrile (70 mL) were added DBU (1.5 eq., 1.6 mL, 10.7 mmol) and BnBr (1.2 eq., 1.0 mL, 8.54 mmol) at room temperature, and the mixture was stirred at room temperature for 16 hours. After quenching with saturated aqueous ammonium chloride (30 mL), the mixture was washed three times with water (30 mL) and once with saturated aqueous sodium chloride (30 mL). The organic layer was dried over magnesium sulfate, and the magnesium sulfate was filtered off. The mixture was then concentrated under reduced pressure to give a crude product (4.83 g). The crude product was purified using a flash silica gel column (normal-phase silica gel 53 g, hexane / ethyl acetate = 3 / 1 to 2 / 1) to give Fragment A-2' (1.87 g, 50% yield over three steps) as a yellow viscous product.

[0358] (Example 2AA: Synthesis of Fragment A-2″) The synthesis of L-tyrosine → A2-1 is as described in Example 1. The synthesis of A3'-3 from A2-1 via A3'-2 is as described in Example 2.

[0359] The synthesis of A2"-1 from A3'-3 is as follows.

[0360] Under a nitrogen atmosphere, methyl iodide (3.0 eq., 6.8 mL, 109.23 mmol) and sodium hydride (60%, dispersion in paraffin liquid, 1.2 eq., 1.7 g, 43.45 mmol) were added to a DMF (150 mL) solution of A3'-3 (1.0 eq., 18.3 g, 36.34 mmol) at an external temperature of -20°C, and the mixture was stirred at the same temperature for 3 hours. A 1N aqueous hydrochloric acid solution (50 mL) was added at an external temperature of -20°C, followed by water (100 mL). The mixture was extracted twice with a hexane (50 mL) / ethyl acetate (100 mL) mixture, and the organic layers were combined and washed once with a saturated aqueous sodium chloride solution (150 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a crude product (20.2 g) as a yellow oil. The crude product was purified using a flash silica gel column (normal phase silica gel 40 g, hexane / ethyl acetate = 9 / 1 to 3 / 1), and the resulting pale yellow viscous product was washed with hexane to obtain A2"-1 (18.9 g, yield 101%).

[0361] The synthesis of A2"-2 from A2"-1 is as follows.

[0362] Under a nitrogen atmosphere, m-CPBA (containing 30% water, 2.0 eq., 18.0 g, 73.01 mmol) was added to a solution of A2"-1 (1.0 eq., 18.9 g, 36.34 mmol) in chloroform (150 mL) at room temperature, and the mixture was stirred at an external temperature of 60°C for 4.5 hours. m-CPBA (0.5 eq., 4.8 g, 19.47 mmol) was added at room temperature, and the mixture was stirred at an external temperature of 60°C for 1 hour and then at an external temperature of 40°C for 15 hours. Under ice-cooling, a 20% aqueous solution of sodium sulfite (75 mL) and a saturated aqueous solution of sodium hydrogen carbonate (75 mL) were added. The organic layer of the reaction solution was recovered, and the 20% aqueous solution of sodium hydrogen carbonate was added to the organic layer. Aqueous sodium sulfate solution (75 mL), saturated aqueous sodium bicarbonate solution (75 mL), saturated aqueous sodium chloride solution (250 mL), and ethyl acetate (400 mL) were added and washed once with liquid separation. The aqueous layers were combined and extracted once with ethyl acetate (100 mL). The organic layers were combined and dried over magnesium sulfate, after which the magnesium sulfate was filtered off and the mixture was concentrated under reduced pressure to give a crude product (20.6 g) as a brown viscous material. The crude product was purified using a flash silica gel column (40 g of normal phase silica gel, hexane / ethyl acetate = 9 / 1 to 3 / 1) to give the ester (17.2 g, yield 89%) as a yellow viscous material.

[0363] Lithium hydroxide (2.5 eq., 1.9 g, 80.25 mmol) was added to a mixture of ester (1.0 eq., 17.2 g, 32.17 mmol) in THF (75 mL) and water (75 mL) at room temperature, and the mixture was stirred at room temperature for 3 hours. Lithium hydroxide (1.0 eq., 790 mg, 32.97 mmol) was added, and the mixture was stirred for 1 hour. Lithium hydroxide (0.5 eq., 392 mg, 16.37 mmol) was then added and the mixture was stirred for 30 minutes. The reaction mixture was washed twice with hexane (75 mL), and the organic layers were combined and extracted once with water (20 mL). The aqueous layers were combined, and 2N aqueous hydrochloric acid (65 mL) was added under ice cooling to adjust the pH to 1, followed by extraction three times with ethyl acetate (100 mL). The organic layers were combined and dried over magnesium sulfate, after which the magnesium sulfate was filtered off and the filtrate was concentrated under reduced pressure to obtain crude A2"-2 (14.3 g, crude yield 110%) as a brown viscous material.

[0364] The synthesis of Fragment A-2" from A2"-2 is as follows.

[0365] Under a nitrogen atmosphere, DIPEA (1.2 eq, 6.6 mL, 38.81 mmol) and BnBr (1.2 eq, 3.8 mL, 38.66 mmol) were added to a solution of A2″-2 (1.0 eq, 14.2 g, 32.17 mmol) in acetonitrile (150 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. DIPEA (0.2 eq, 1.1 mL, 6.47 mmol) and BnBr (0.2 eq, 650 μL, 6.61 mmol) were added, and the mixture was stirred for 1 hour. After that, a saturated aqueous ammonium chloride solution (75 mL) was added. 1L) and water (75 mL) were added. After collecting the organic layer of the reaction solution, the aqueous layer was extracted twice with ethyl acetate (100 mL). The organic layers were combined and washed twice with saturated aqueous sodium chloride solution (100 mL). The organic layer was dried over magnesium sulfate, and the magnesium sulfate was filtered off. The filtrate was concentrated under reduced pressure to give a crude product (18.0 g) as a brown oil. The crude product was purified using a flash silica gel column (normal phase silica gel 100 g, hexane / ethyl acetate = 5 / 1 to 0 / 1) to give Fragment A-2" (7.1 g, two-step yield 45%) as a pale yellow viscous product.

[0366] (Example 2: Synthesis of Fragment A-3)

[0367]

[0368] To a solution of A2-3 (1.0 eq., 13.1 g, 24.4 mmol) in chloroform (120 mL), m-CPBA (2.0 eq., 35% water content, 13.0 g, 48.9 mmol) was added under ice-cooling, and the mixture was stirred under reflux conditions for 18 hours. The reaction mixture was quenched by adding saturated aqueous sodium bicarbonate (100 mL) to the reaction mixture at room temperature, and the chloroform was then evaporated under reduced pressure. The reaction mixture was extracted three times with ethyl acetate (200 mL), and the combined organic layers were washed once with saturated aqueous sodium chloride (200 mL), followed by drying over magnesium sulfate. The magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain the ester.

[0369] To a THF (60 mL) / water (60 mL) mixture of ester (1.0 eq., calculated as 24.4 mmol) was added lithium hydroxide (4.0 eq., 2.34 g, 97.7 mmol) at room temperature, followed by stirring at the same temperature for 19 hours. Lithium hydroxide (2.0 eq., 1.17 g, 48.9 mmol) was added to the reaction solution at room temperature, followed by stirring at the same temperature for 4.5 hours. Water (100 mL) was added to the reaction solution, and the mixture was washed twice with hexane (100 mL). The aqueous layer was then adjusted to pH 3 by adding 6N aqueous hydrochloric acid. The aqueous layer was extracted twice with ethyl acetate (200 mL). The combined organic layers were washed once with saturated aqueous sodium chloride (200 mL), and then dried over magnesium sulfate. The magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain A3-4 (11.2 g) as a dark brown oil.

[0370] To a solution of A3-4 (1.0 eq., 11.2 g, calculated as 24.4 mmol) in acetonitrile (120 mL), DBU (1.1 eq., 4.09 g, 26.8 mmol) and PMBCl (1.1 eq., 4.20 g, 26.8 mmol) were added at room temperature, and the mixture was stirred at an external temperature of 60°C for 16 hours. The reaction mixture was quenched by adding acetic acid (3.0 eq., 4.41 g, 73.4 mmol), and then concentrated under reduced pressure to obtain a crude product. The crude product was purified using a flash silica gel column (normal phase silica gel 180 g, hexane / ethyl acetate = 75 / 25 to 50 / 50) to obtain Fragment A-3 (7.83 g, 59% yield for two steps from A2-3) as an orange oil.

[0371] Under a nitrogen atmosphere, aluminum chloride (4.1 eq., 9.08 g, 68.11 mmol) and acetyl chloride (1.3 eq., 1.5 mL, 21.12 mmol) were added to a solution of L-tyrosine (1.0 eq., 3.04 g, 16.78 mmol) in nitrobenzene (70 mL) under ice-cooling. After stirring for 20 minutes under ice-cooling, the mixture was stirred at an external temperature of 100°C for 7 hours. The reaction solution was allowed to cool and then added to ice-cooled 1N aqueous hydrochloric acid solution (100 mL) for quenching. The mixture was washed three times with ethyl acetate (100 mL) to obtain A2-1 as an aqueous solution (100 mL).

[0372] Water (100 mL) and 1,4-dioxane (100 mL) were added to A2-1 (1.0 eq., calculated as 100 mL of aqueous solution, 16.78 mmol), and then sodium bicarbonate (25.0 eq., 35.2 g, 419.05 mmol) was added under ice-cooling to make the mixture basic. ２ 20O (1.2 eq., 4.6 mL, 20.02 mmol) was added, and the mixture was stirred at room temperature for 4.5 hours. ２ O (1.0 eq., 4 mL, 17.41 mmol) was added and the mixture was stirred for an additional 17 hours. The reaction mixture was concentrated under reduced pressure to remove 1,4-dioxane, and then 2N aqueous hydrochloric acid (approximately 300 mL) was added to adjust the pH to 1-2. After one separation and extraction with ethyl acetate (300 mL), the organic layer was washed once with 1N aqueous hydrochloric acid (100 mL). The aqueous layers were combined and then extracted once with ethyl acetate (200 mL). The organic layers were combined and dried over magnesium sulfate, after which the magnesium sulfate was filtered off and the mixture was concentrated under reduced pressure to obtain A3'-2 (5.63 g, crude yield 104%) as a brown viscous substance.

[0373] Under a nitrogen atmosphere, potassium carbonate (3.0 eq., 7.03 g, 50.85 mmol), TBAI (0.1 eq., 640 mg, 1.73 mmol), and BnBr (2.2 eq., 3.6 mL, 36.62 mmol) were added to a DMF (80 mL) solution of A3'-2 (calculated as 1.0 eq., 5.63 g, 16.78 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Water (80 mL) was added to the reaction solution, and the mixture was extracted three times with a hexane (25 mL) / ethyl acetate (75 mL) mixture. The organic layers were combined and washed with saturated aqueous sodium chloride solution (200 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a crude product (9.84 g) as a brown oil. The crude product was purified by flash silica gel column (normal phase silica gel 70 g, hexane / ethyl acetate=5 / 1 to 1 / 1) to obtain A3'-3 (6.18 g, three-stage yield 73%) as a pale orange viscous product.

[0374] Under a nitrogen atmosphere, m-CPBA (35% water content, 2.0 eq., 19.0 g, 77.07 mmol) was added to a solution of A3'-3 (1.0 eq., 19.32 g, 38.36 mmol) in chloroform (200 mL) under ice-cooling, and the mixture was stirred at an external temperature of 60°C for 6 hours. The reaction solution was concentrated under reduced pressure until the liquid volume was reduced to approximately half, and then saturated aqueous sodium bicarbonate solution (200 mL) was added. After extraction and separation once with ethyl acetate (200 mL) and twice with ethyl acetate (100 mL), the organic layers were combined and washed with saturated aqueous sodium chloride solution (200 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain the ester (24.9 g, crude yield 125%) as a pale yellow solid.

[0375] To a mixture of ester (1.0 eq., 24.9 g, 38.36 mmol) in THF (100 mL) and water (100 mL) was added lithium hydroxide (2.5 eq., 2.31 g, 96.43 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Subsequently, lithium hydroxide (1.0 eq., 929 mg, 38.80 mmol) was added, and the mixture was stirred for an additional 2 hours. Lithium hydroxide (1.5 eq., 1.39 g, 57.87 mmol) was then added, and the mixture was stirred for 1 hour. The reaction mixture was washed twice with hexane (100 mL). To the aqueous layer was added 6N aqueous hydrochloric acid (30 mL) under ice-cooling, and the pH was adjusted to 2-3, followed by one extraction with ethyl acetate (100 mL). A 6N aqueous solution of hydrochloric acid (5 mL) was added to the aqueous layer to adjust the pH to 1 to 2, and the mixture was then extracted twice with ethyl acetate (100 mL). The organic layers were combined and dried over magnesium sulfate, after which the magnesium sulfate was filtered off and the mixture was concentrated under reduced pressure to give a crude product (21.6 g) as a brown viscous substance. The crude product was recrystallized using a hexane / ethyl acetate mixture (4 / 1 to 1 / 1) to give A3'-4 (12.4 g, apparent yield 83%, containing approximately 30% m-CPBA) as a white solid.

[0376] Under a nitrogen atmosphere, DBU (1.1 eq., 1.3 mL, 8.71 mmol) and BnBr (1.1 eq., 850 μL, 8.65 mmol) were added to a solution of A3″-4 (1.0 eq., 3.03 g, calculated as containing approximately 30% m-CPBA, 7.83 mmol) in acetonitrile (40 mL) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was washed once with a saturated aqueous ammonium chloride solution (40 mL). The aqueous layer was separated and washed with ethyl acetate (40 mL). The organic layers were combined and washed once with water (100 mL), and then once with saturated aqueous sodium chloride solution (100 mL). The organic layer was dried over magnesium sulfate, and the magnesium sulfate was filtered off. The residue was concentrated under reduced pressure to give a crude product (3.7 g) as a brown oil. The crude product was purified using a flash silica gel column (normal phase silica gel 50 g, hexane / ethyl acetate = 5 / 1 to 3 / 1) to give Fragment A-3" (1.8 g, yield 48%) as a pale yellow viscous product.

[0377] Under a nitrogen atmosphere, DBU (1.1 eq., 1.9 mL, 12.73 mmol) and PMBCl (1.1 eq., 1.7 mL, 12.48 mmol) were added to an acetonitrile (60 mL) solution of A3'-4 (1.0 eq., 4.42 g, calculated as containing approximately 30% hydrolyzate of A3'-3, 11.43 mmol) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was washed once with saturated aqueous ammonium chloride solution (60 mL). The aqueous layer was extracted twice with ethyl acetate (60 mL). The organic layers were combined and washed once with saturated aqueous sodium chloride solution (100 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a crude product (6.17 g) as a brown oil. The crude product was purified with a flash silica gel column (normal phase silica gel 70 g, hexane / ethyl acetate=5 / 1 to 2 / 1) to obtain Fragment A-3′ (3.47 g, containing about 30% of the PMB ester of A3′-3, apparent yield 60%) as a pale yellow viscous product.

[0378] (Example 2A: Synthesis of Fragment A-13) The two steps from L-tyrosine to A2-2 were carried out as described in Example 2.

[0379] The synthesis of A13-1 from A2-2 is as follows. Under a nitrogen atmosphere, potassium carbonate (3.0 eq., 22.9 g, 166 mmol), TBAI (0.10 eq., 2.04 g, 5.52 mmol), and BnBr (2.0 eq., 13.1 g, 110 mmol) were added to a DMF (110 mL) solution of A2-2 (calculated as 1.0 eq., 20.3 g, 55.2 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2.5 hours. Water (200 mL) was added to the reaction solution, and the mixture was extracted twice with a hexane (50 mL) / ethyl acetate (150 mL) mixture. The organic layers were combined and washed once with water (100 mL) and once with a saturated aqueous sodium chloride solution (100 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a crude product (34.3 g) as a yellow liquid. The crude product was purified with a flash silica gel column (normal phase silica gel 200 g, hexane / ethyl acetate=80 / 20 to 50 / 50) to obtain a mixture of A13-1 and A2-3 (24.3 g) as a yellow liquid.

[0380] The synthesis of A13-2 from A13-1 is as follows. Under a nitrogen atmosphere, sodium hydride (1.2 eq., 2.17 g, 54.3 mmol) and methyl iodide (3.0 eq., 8.4 mL, 135 mmol) were added to a DMF (90 mL) solution of a mixture of A13-1 and A2-3 (calculated as 1.0 eq., 24.3 g, 45.2 mmol) under ice-cooling, and the mixture was stirred for 4 hours under ice-cooling. The reaction mixture was quenched by adding 2N aqueous hydrochloric acid (20 mL), and water (200 mL) was added. The mixture was extracted once with a hexane (50 mL) / ethyl acetate (150 mL) mixture and once with a hexane (40 mL) / ethyl acetate (120 mL) mixture. The organic layers were combined and washed once with water (100 mL) and once with saturated aqueous sodium chloride (50 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give a mixture of A13-2 and A2-4 (24.6 g).

[0381] The synthesis of A13-3 from A13-2 is as follows. Under a nitrogen atmosphere, m-CPBA (35% water content, 2.0 eq., 23.7 g, 89.3 mmol) was added to a chloroform (180 mL) solution of a mixture of A13-2 and A2-4 (calculated as 1.0 eq., 24.6 g, 44.6 mmol) at room temperature, and the mixture was stirred at an external temperature of 45°C for 17 hours. The reaction solution was ice-cooled, and quenched by adding a mixture of 20% aqueous sodium sulfite (80 mL) and saturated aqueous sodium bicarbonate (80 mL). Ethyl acetate (500 mL) was added to the reaction solution, and the mixture was extracted once with a mixture of 20% aqueous sodium sulfite (80 mL) and saturated aqueous sodium bicarbonate (80 mL). The organic layer was washed once with a mixture of 20% aqueous sodium sulfite (80 mL) and saturated aqueous sodium bicarbonate (80 mL) and once with saturated aqueous sodium chloride (100 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a crude product (26.2 g) as a brown oil. The crude product was purified by flash silica gel column (normal phase silica gel 220 g, hexane / ethyl acetate=83 / 17 to 50 / 50) to obtain a mixture of Ester-A13 and Ester (22.2 g) as a yellow liquid.

[0382] To a THF (80 mL) / water (80 mL) mixture of a mixture of Ester-A13 and Ester (calculated as 1.0 eq., 22.2 g, 39.1 mmol), lithium hydroxide (4.0 eq., 3.74 g, 156 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 3.5 hours. The reaction mixture was washed three times with hexane (100 mL), and then 2N aqueous hydrochloric acid (72 mL) was added to the aqueous layer to adjust the pH to 1. The aqueous layer was extracted three times with ethyl acetate (150 mL), and the combined organic layers were washed once with saturated aqueous sodium chloride (100 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a mixture of A13-3 and A2-5 (17.9 g) as a brown viscous substance.

[0383] The synthesis of Fragment A-13 from A13-3 is as follows. To a solution of a mixture of A13-3 and A2-5 (calculated as 1.0 eq., 17.4 g, 39.1 mmol) in DMF (80 mL), potassium carbonate (3.1 eq., 16.6 g, 120 mmol) and methyl iodide (1.1 eq., 2.7 mL, 43.4 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 1.5 hours. Water (200 mL) was added to the reaction mixture, and the mixture was extracted once with a hexane (60 mL) / ethyl acetate (180 mL) mixture and twice with a hexane (30 mL) / ethyl acetate (90 mL) mixture. The organic layers were combined and washed once with a saturated aqueous sodium chloride solution (100 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a crude product (17.9 g) as a brown viscous substance. The crude product was purified twice using a flash silica gel column (first time: 200 g of normal phase silica gel, hexane / ethyl acetate=80 / 20 to 50 / 50; second time: 25 g of normal phase silica gel, hexane / ethyl acetate=75 / 25 to 50 / 50) to obtain Fragment A-13 (2.42 g) as a brown viscous material and Fragment A-10 (11.8 g) as a pale yellow viscous material.

[0384] (Example 2B: Synthesis of Fragment A-14) Synthesis of A14-1 from Boc-Tyr-OMe was carried out as follows. Under a nitrogen atmosphere, iodomethane (1.2 eq., 5.77 g, 40.65 mmol) was added to a suspension of Boc-Tyr-OMe (1.0 eq., 10.00 g, 33.86 mmol) and potassium carbonate (2.0 eq., 9.36 g, 67.73 mmol) in DMF (50 mL) under ice-cooling, and the mixture was stirred at the same temperature for 2 hours and then at room temperature for 3 hours. The insoluble matter was filtered off, and the filter residue was washed twice with ethyl acetate (50 mL). The filtrate was washed once with water (100 mL), and the organic layer was washed twice with 5% aqueous sodium chloride solution (100 mL) and then dried over sodium sulfate. After filtering off the sodium sulfate, the mixture was concentrated under reduced pressure to give A14-1 (11.03 g, containing 4.1 wt % DMF, quant.) as a yellow oil.

[0385] The synthesis of A14-2 from A14-1 was carried out as follows. Under a nitrogen atmosphere, N-bromosuccinimide (1.3 eq., 0.71 g, 3.99 mmol) was added to a DMF (5 mL) solution of A14-1 (calculated as 1.0 eq., 1.00 g, 3.07 mmol) at room temperature, and the mixture was stirred at the same temperature for 19 hours. Ethyl acetate (20 mL) was added to the reaction mixture, and the mixture was separated and washed once each with a 5% aqueous ascorbic acid solution (20 mL), a 5% aqueous sodium chloride solution (20 mL), a 5% aqueous sodium bicarbonate solution (20 mL), and a 5% aqueous sodium chloride solution (20 mL), and then dried over sodium sulfate. The sodium sulfate was removed by filtration, and the mixture was concentrated under reduced pressure to obtain A14-2 (1.30 g, containing impurities) as a yellow oil.

[0386] Fragment A-14_COOH was synthesized from A14-2 as follows. Under a nitrogen atmosphere, a solution of cesium hydroxide monohydrate (5.0 eq., 2.58 g, 15.36 mmol) in water (6 mL) was added to a solution of A14-2 (calculated as 1.0 eq., 1.30 g, 3.07 mmol) in 1,4-dioxane (11 mL) at room temperature, and the mixture was stirred at an external temperature of 100°C for 0.5 hours. A solution of tBuBrettPhos Pd G3 (0.05 eq., 0.13 g, 0.15 mmol, [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, manufactured by Sigma-Aldrich Co.) in 1,4-dioxane (1 mL) was added at the same temperature, and the mixture was stirred at the same temperature for 0.5 hours. After the reaction mixture was cooled to room temperature, water (40 mL) was added, and the mixture was washed three times with ethyl acetate (40 mL). Citric acid (2.00 g, 10.41 mmol) was added to the aqueous layer, and the mixture was extracted once with ethyl acetate (40 mL). The organic layer was washed once with 5% aqueous sodium chloride solution (40 mL) and then dried over sodium sulfate. After filtering off the sodium sulfate, the mixture was concentrated under reduced pressure to obtain Fragment A-14_COOH (851 mg, containing impurities, apparent yield 89%) as a brown amorphous substance.

[0387] The synthesis of Fragment A-14 from Fragment A-14_COOH was carried out as follows. Under a nitrogen atmosphere, sodium bicarbonate (2.0 eq., 0.72 g, 8.57 mmol) and iodomethane (1.5 eq., 0.40 mL, 6.43 mmol) were added to a DMF (6 mL) solution of Fragment A-14_COOH (calculated as 1.0 eq., 1.33 g, 4.27 mmol) at room temperature, and the mixture was stirred at the same temperature for 23 hours. During this time, the following reagents were added: After 15 hours: iodomethane (2.0 eq., 0.53 mL, 8.51 mmol) After 18.5 hours: sodium bicarbonate (2.0 eq., 0.72 g, 8.57 mmol) Ethyl acetate (20 mL) was added to the reaction solution, which was then washed twice with 5% aqueous sodium chloride solution (20 mL) and then dried over sodium sulfate. The sodium sulfate was filtered off, and the crude product (1.44 g) obtained by concentration under reduced pressure was purified with a flash silica gel column (normal phase silica gel 25 g, hexane / ethyl acetate=80 / 20 to 65 / 35) to obtain Fragment A-14 (953 mg, containing 8.5 wt % ethyl acetate, calculated yield from A14-2: 63%) as an orange viscous product.

[0388] (Example 3: Synthesis of Fragment B-1) Under a nitrogen atmosphere, water (150 mL) and sodium carbonate (1.0 eq., 25.2 g, 0.238 mol) were added to a solution of D-serine (1.0 eq., 25.0 g, 0.238 mol) in saturated aqueous sodium bicarbonate (150 mL) at room temperature. ２A solution of 1,4-dioxane (125 mL) of 2H2O (1.2 eq., 62.4 g, 0.286 mol) was added, and the mixture was stirred at the same temperature for 0.5 hours and then at room temperature overnight. After concentrating under reduced pressure to remove 1,4-dioxane, MTBE (200 mL) was added to the concentrated residue, and insoluble matter was filtered off. The aqueous layer of the filtrate was collected and washed once with MTBE (200 mL), after which concentrated hydrochloric acid (approximately 25 mL) was added under ice-cooling to adjust the pH to 2-3. Sodium chloride (60 g) was added, and the mixture was extracted four times with ethyl acetate (200 mL). Concentrated hydrochloric acid (5 mL) and sodium chloride (20 g) were added to the aqueous layer, and the mixture was extracted four times with ethyl acetate (200 mL). Sodium chloride and concentrated hydrochloric acid were added to the aqueous layer, followed by extraction six times with ethyl acetate (100 mL) and six times with ethyl acetate (50 mL) / THF (50 mL). The combined organic layers were dried over sodium sulfate, filtered to remove the sodium sulfate, and then concentrated under reduced pressure to give D-N-Boc-serine (50.81 g, 92% yield) as a colorless oil.

[0389] Under a nitrogen atmosphere, N,O-dimethylhydroxylamine hydrochloride (1.03 eq., 22.27 g, 0.228 mol), NMM (1.03 eq., 23.10 g, 0.228 mol), and EDCI (1.1 eq., 46.74 g, 0.244 mol) were added to a dichloromethane (300 mL) solution of D-N-Boc-serine (1.0 eq., 50.8 g, Net 44.9 g, 0.219 mol) at an internal temperature of −10° C. This solution was stirred overnight from −10° C. to room temperature. The reaction solution was washed once with 1 M aqueous hydrochloric acid under ice cooling, and then the aqueous layer was extracted once with dichloromethane (100 mL). The combined organic layers were washed once with saturated aqueous sodium bicarbonate (100 mL). The aqueous layer was extracted once more with dichloromethane (50 mL), and the combined organic layers were dried over sodium sulfate. After filtering off the sodium sulfate, the filtrate was concentrated under reduced pressure to obtain B1-1 (50.4 g, yield 93%) as a white solid.

[0390] Under a nitrogen atmosphere, 2,2-dimethoxypropane (164 mL) and boron trifluoride diethyl ether complex (0.06 eq., 1.64 mL, 0.013 mol) were added to a solution of B1-1 (1.0 eq., 50.4 g, 0.203 mol) in acetone (327 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. Triethylamine (0.146 eq., 3.00 g, 29.65 mmol) was added to the reaction mixture, which was then concentrated under reduced pressure. THF (100 mL) was added to the concentrated residue, and the mixture was concentrated again, which was repeated three times to obtain B1-2(1) (60.4 g, quant.) as a pale yellow oil. Under a nitrogen atmosphere, a solution of B1-2(1) (calculated as 1.0 eq., 60.4 g, 0.203 mol) in THF (570 mL) was added with methyllithium (1.5 M in Et ２ O, 2.0 eq., 279 mL, 0.419 mmol) was added over 40 minutes, and the mixture was stirred at the same temperature for 2 hours. A saturated aqueous ammonium chloride solution (130 mL) was added to the reaction mixture at the same temperature, and the mixture was warmed to room temperature and then separated and washed. The aqueous layer was extracted three times with ethyl acetate (200 mL), and the organic layers were combined and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the mixture was concentrated under reduced pressure to obtain a crude product (51.56 g) as a pale yellow oil. The crude product was purified using a flash silica gel column (normal phase silica gel 750 g, hexane / ethyl acetate = 10 / 1 to 4 / 1) to obtain B1-2 (34.8 g, yield 70%) as a colorless oil.

[0391] Under a nitrogen atmosphere, ethynylmagnesium bromide (0.5 M in THF, 2.5 eq., 715 mL, 0.358 mol) was added to a solution of B1-2 (1.0 eq., 34.8 g, 0.143 mol) in THF (696 mL) at room temperature over 1.5 hours, followed by stirring at the same temperature for 2 hours. Saturated aqueous ammonium chloride solution (160 mL) was added to the reaction mixture at -55°C, and the mixture was warmed to -5°C and then concentrated under reduced pressure. Water (300 mL) was added to the concentrated residue, and the mixture was extracted once with ethyl acetate (300 mL) and once with ethyl acetate (150 mL). The organic layers were combined, washed once with saturated aqueous sodium chloride solution (150 mL), and then dried over sodium sulfate. The sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a crude product (40.36 g) as a yellow solid. The crude product was purified with a flash silica gel column (normal phase silica gel 370 g, chloroform / ethyl acetate=100 / 0 to 20 / 1) to obtain B1-3 (diastereomer mixture, 33.9 g, yield 88%) as a white solid.

[0392] Under a nitrogen atmosphere, concentrated hydrochloric acid (12 eq., 130 mL, 1.56 mol) was added to a solution of B1-3 (diastereomer mixture, 1.0 eq., 33.9 g, 0.126 mol) in THF (450 mL) at room temperature, and the mixture was stirred at the same temperature for 4 hours. The reaction solution was concentrated under reduced pressure to obtain a crude solution of B1-4(1).

[0393] Under a nitrogen atmosphere, THF (260 mL) and water (65 mL) were added to the crude solution of B1-4(1). Sodium carbonate (5.0 eq., 66.70 g, 0.629 mol) and NsCl (1.0 eq., 27.90 g, 0.125 mol) were added to this solution, and the mixture was stirred at room temperature for 17 hours. After adding saturated aqueous sodium chloride (65 mL) to the reaction mixture and washing with liquid separation, the aqueous layer was extracted three times with ethyl acetate (260 mL). The organic layers were combined and dried over sodium sulfate. After filtering off the sodium sulfate, the mixture was concentrated under reduced pressure to obtain a crude product (40.01 g) as a brown viscous material. The crude product was purified using a flash silica gel column (normal-phase silica gel 200 g, hexane / ethyl acetate = 1 / 1 to 3 / 7) to obtain B1-4 (diastereomeric mixture, 38.05 g, containing 4.0 wt% ethyl acetate, calculated yield 92%) as a light brown viscous material.

[0394] Under a nitrogen atmosphere, imidazole (1.5 eq., 11.71 g, 0.172 mol) and TBSCl (1.2 eq., 20.74 g, 0.138 mol) were added to a DMF (360 mL) solution of B1-4 (diastereomeric mixture, 1.0 eq., 36.0 g, containing 4.0 wt% ethyl acetate, 0.110 mol) at room temperature, and the mixture was stirred at the same temperature for 1 hour. Ethyl acetate (350 mL) and water (300 mL) were added to the reaction mixture and extracted once, after which the aqueous layer was extracted twice with ethyl acetate (100 mL). The organic layers were combined and dried over sodium sulfate. After filtering off the sodium sulfate, the mixture was concentrated under reduced pressure to obtain a crude product as a brown viscous substance. The crude product was purified by flash silica gel column (normal phase silica gel 540 g, hexane / ethyl acetate=1 / 0 to 1 / 1) to obtain B1-5 (diastereomer mixture, 48.3 g, yield 98%) as a yellow viscous product.

[0395] Under a nitrogen atmosphere, triphenylphosphine (1.5 eq., 17.10 g, 0.085 mol) and DIAD (1.5 eq., 17.09 g, 0.084 mol) were added to a THF (560 mL) solution of B1-5 (diastereomeric mixture, 1.0 eq., 24.1 g, 0.056 mol) under ice-cooling, and the mixture was stirred at the same temperature for 2 hours. Ethyl acetate (650 mL), water (300 mL), and 5% aqueous sodium bicarbonate solution (300 mL) were added to the reaction mixture, followed by extraction and separation once. The organic layer was then washed once with 5% aqueous sodium bicarbonate solution (300 mL) and once with saturated aqueous sodium chloride solution (300 mL), and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the mixture was concentrated under reduced pressure to obtain a crude product as a yellow oil. The crude product was purified by flash silica gel column (normal phase silica gel 720 g, hexane / ethyl acetate=10 / 1) to give Fragment B-1 (12.6 g, yield 54%) as a white solid. Also, 4.09 g of a mixture containing 16% diastereomers was obtained.

[0396] A hexane (8.5 mL) / diisopropyl ether (8.5 mL) mixture was added to the diastereomer mixture (3.41 g), and the mixture was dissolved by heating to an external temperature of 45° C. After allowing the solution to cool to an internal temperature of 11° C., the precipitated solid was collected by filtration and washed once with hexane (1.5 mL) / diisopropyl ether (1.5 mL) and once with hexane (3 mL) to obtain Fragment B-1 (2.41 g, diastereomer content 0.7%, yield 10%) as a white solid.

[0397] (Example 4: Synthesis of Fragment B-2) Thionyl chloride (1.5 eq., 5 mL, 69.35 mmol) was added dropwise to methanol (47 mL) under a nitrogen atmosphere and ice cooling. L-Serine (1.0 eq., 5.00 g, 47.66 mmol) was added at the same temperature, and the mixture was stirred under reflux for 2.5 hours. The reaction solution was concentrated under reduced pressure, and the methanol was distilled off to obtain B2-1 (7.61 g, crude yield 104%) as a pale yellow solid.

[0398] Under a nitrogen atmosphere, triethylamine (2.1 eq., 8.3 mL, 62.01 mmol) and TrCl (1.05 eq., 8.71 g, 31.23 mmol) were added to a dichloromethane (30 mL) solution of B2-1 (calculated as 1.0 eq., 4.56 g, 29.69 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Dichloromethane (30 mL) was added to the reaction solution, and the mixture was washed once with water (60 mL). The aqueous layer was extracted twice with dichloromethane (60 mL). The organic layers were combined and washed once with saturated aqueous sodium chloride solution (150 mL), after which the organic layer was dried over magnesium sulfate. The magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a crude product (10.99 g). Ethyl acetate (20 mL) and hexane (40 mL) were added to the crude product under ice-cooling. The insoluble white solid was collected by filtration to obtain Fragment B-2 (7.67 g, two-step yield 71%).

[0399] (Example 5: Synthesis of Fragment B-3) Thionyl chloride (1.5 eq., 4.5 mL, 62.03 mmol) was added dropwise to methanol (42 mL) under a nitrogen atmosphere and ice cooling. L-threonine (1.0 eq., 5.01 g, 42.10 mmol) was added at the same temperature, and the mixture was stirred under reflux for 5 hours. The reaction solution was concentrated under reduced pressure, and the methanol was distilled off to obtain B3-1 (8.29 g, crude yield 116%) as a pale yellow solid.

[0400] Under a nitrogen atmosphere, triethylamine (2.1 eq., 6.9 mL, 49.50 mmol) and TrCl (1.06 eq., 6.99 g, 25.08 mmol) were added to a dichloromethane (48 mL) solution of B3-1 (calculated as 1.0 eq., 4.01 g, 23.66 mmol) under ice-cooling, and the mixture was stirred at room temperature for 5 hours. Triethylamine (1.1 eq., 3.6 mL, 25.83 mmol) and TrCl (0.53 eq., 3.50 g, 12.55 mmol) were added under ice-cooling, and the mixture was stirred at room temperature for an additional 18 hours. The reaction solution was washed once with water (60 mL). The aqueous layer was extracted twice with dichloromethane (60 mL). The organic layers were combined and washed with saturated aqueous sodium chloride (150 mL), and then dried over magnesium sulfate. The magnesium sulfate was filtered off, and the residue was concentrated under reduced pressure to give a crude product (13.4 g), which was purified using a flash silica gel column (normal phase silica gel 70 g, hexane / ethyl acetate = 2 / 1 to 1 / 1) to give Fragment B-3 (7.27 g, two-step yield 82%) as a white solid.

[0401] (Example 6: Synthesis of Fragment B-9) Under a nitrogen atmosphere, thionyl chloride (1.45 eq., 25 mL, 345 mmol) was added to methanol (240 mL) under ice-cooling. D-serine (1.0 eq., 25 g, 238 mmol) was added at the same temperature, and the mixture was stirred at 70°C for 16.5 hours. The reaction solution was concentrated under reduced pressure to obtain crude methyl ester (37 g).

[0402] Under a nitrogen atmosphere, a mixture of methyl ester (1.0 eq., 37.0 g, calculated as 238 mmol) in water (100 mL) / methanol (100 mL) was added with sodium bicarbonate (2.5 eq., 49.9 g, 595 mmol) and Boc ２ O (1.05 eq., 65 mL, 250 mmol) was added and stirred at room temperature for 5.5 hours. Water (200 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (200 mL). The organic layer was washed twice with water (100 mL) and once with saturated aqueous sodium chloride solution (100 mL), and then dried over magnesium sulfate. The mixture was concentrated under reduced pressure to obtain crude B8-1 (58.7 g).

[0403] Under a nitrogen atmosphere, 2,2-dimethoxypropane (268 mL) and boron trifluoride diethyl ether complex (0.05 eq., 1.5 mL, 11.9 mmol) were added to a solution of B8-1 (1.0 eq., 58.7 g, calculated as 238 mmol) in acetone (350 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. Triethylamine (0.075 eq., 2.5 mL, 17.9 mmol) was added to the reaction mixture, which was then concentrated under reduced pressure to give crude B8-2 (68.0 g) as a pale yellow oil.

[0404] Under a nitrogen atmosphere, to a solution of B8-2 (1.0 eq., 16.02 g, calculated as 61.0 mmol) in THF (300 mL), methylmagnesium bromide (12.4%, 3.0 eq., 176.06 g, 183 mmol) was added over 14 minutes under ice cooling, and the mixture was stirred at the same temperature for 1 hour. A 10% aqueous ammonium chloride solution (200 mL), ethyl acetate (100 mL), and water (30 mL) were added to the reaction mixture and extracted once, and the aqueous layer was extracted twice with ethyl acetate (50 mL). The organic layers were combined and washed once with a 5% aqueous sodium chloride solution (200 mL), dried over sodium sulfate, and then the sodium sulfate was filtered off and concentrated under reduced pressure. The crude product obtained from B8-2 (2.00 g) by a similar procedure was combined with the previous concentrated residue and purified with a flash silica gel column (normal phase silica gel 100 g, hexane / ethyl acetate=80 / 20 to 20 / 80) to obtain B9-1 (17.22 g, containing 1.7 wt % ethyl acetate, converted yield 95%) as a pale yellow oil.

[0405] Under a nitrogen atmosphere, concentrated hydrochloric acid (12 eq., 62 mL, 744 mmol) was added to a solution of B9-1 (1.0 eq., 16.22 g, containing 1.7 wt % ethyl acetate, 61.5 mmol) in THF (248 mL) at room temperature, and the mixture was stirred at the same temperature for 2 hours and then at an external temperature of 50°C for 3 hours. The reaction solution was then concentrated to obtain a crude product (14.04 g) as a purple oil.

[0406] The crude product obtained from B9-1 (1.00 g) was combined with the previous crude product by the same procedure and dissolved in THF (130 mL). Water (33 mL) and sodium carbonate (5.0 eq., 34.59 g, 326 mmol) were added at room temperature to adjust the pH to 9. NsCl (1.0 eq., 14.46 g, 65.3 mmol) was added and stirred at the same temperature for 16 hours, after which NsCl (0.3 eq., 4.34 g, 19.6 mmol) was added and stirred at the same temperature for 30 minutes. A saturated aqueous sodium chloride solution (150 mL), ethyl acetate (50 mL) and water (180 mL) were added to the reaction mixture and extracted once, and the aqueous layer was extracted three times with ethyl acetate (30 mL). The organic layers were combined and dried over sodium sulfate, and the sodium sulfate was filtered off, followed by concentration under reduced pressure. The concentrated residue was purified with a flash silica gel column (normal phase silica gel 100 g, hexane / ethyl acetate=50 / 50 to 0 / 100) to obtain B9-2 (19.70 g, containing impurities, apparent yield 99%) as a brown oil.

[0407] Under a nitrogen atmosphere, TBSCl (1.2 eq., 11.64 g, 77.3 mmol) and imidazole (1.5 eq., 6.57 g, 96.6 mmol) were added to a solution of B9-2 (1.0 eq., 19.59 g, 64.4 mmol) in DMF (65 mL) at room temperature, and the mixture was stirred at the same temperature for 30 minutes.

[0408] The reaction mixture obtained by treating B9-2 (100 mg) in the same manner was combined with the previous reaction mixture, and ethyl acetate (130 mL) and water (200 mL) were added for one extraction. The aqueous layer was extracted twice with ethyl acetate (30 mL). The combined organic layers were washed once with 5% aqueous sodium chloride (150 mL) and saturated aqueous sodium chloride (30 mL), and then dried over sodium sulfate. The sodium sulfate was filtered off, and the residue was concentrated under reduced pressure. The concentrated residue was purified using a flash silica gel column (normal-phase silica gel 100 g, hexane / ethyl acetate = 90 / 10 to 64 / 36) to obtain B9-3 (22.09 g, containing 3.1 wt % ethyl acetate, 79% calculated yield for the three steps from B9-1) as a white viscous substance.

[0409] Under a nitrogen atmosphere, DIAD (90%, 1.5 eq., 17.12 g, 76.2 mmol) was added to a solution of B9-3 (1.0 eq., 21.95 g, containing 3.1 wt% ethyl acetate, 50.8 mmol) and triphenylphosphine (1.5 eq., 19.99 g, 76.2 mmol) in THF (508 mL) at room temperature, and the mixture was stirred at the same temperature for 3 hours. The reaction mixture treated in the same manner with B9-3 (130 mg) was combined with the previous reaction mixture and concentrated under reduced pressure. The concentrated residue was purified twice using a flash silica gel column (first: 480 g of normal-phase silica gel, hexane / ethyl acetate = 10 / 0 to 5 / 1; second: 100 g of normal-phase silica gel, hexane / ethyl acetate = 91 / 9 to 85 / 15). Hexane was added to the resulting pale red solid, and the mixture was subjected to ultrasonic irradiation, ice-cooled, and then filtered to obtain Fragment B-9 (15.07 g, yield 74%) as a white solid.

[0410] Example 6A: Synthesis of Fragment D-8 Fragment D-8 was synthesized as follows.

[0411] The synthesis of D8-1 from HL-Asp-OBzl was carried out as follows. A mixture of H-L-Asp-OBzl (1.0 eq., 501 mg, 2.24 mmol) in THF (3 mL) / water (6 mL) was treated with sodium carbonate (2.0 eq., 477 mg, 4.50 mmol) and Boc at room temperature. ２0 (1.9 eq., 1.0 mL, 4.35 mmol) was added, and the mixture was stirred at the same temperature for 5 hours. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was extracted twice with water (25 mL). The aqueous layers were combined, and 1N aqueous hydrochloric acid solution (0.5 mL) was added to adjust the pH to 7, followed by concentration under reduced pressure. The solid precipitated by concentration was filtered, and the residue was washed with DMF. The filtrate and washings were combined and concentrated under reduced pressure to obtain D8-1 (753.3 mg, quant.) as a cloudy white oil.

[0412] The synthesis of D8-2 from D8-1 was carried out as follows. To a solution of D8-1 (calculated as 1.0 eq., 753 mg, 2.24 mmol) in DMF (6 mL), HOBt.H ２ O (1.2 eq., 413 mg, 2.69 mmol), EDCI (1.2 eq., 516 mg, 2.69 mmol), ethanol (2.0 eq., 0.26 mL, 4.45 mmol), and DMAP (1.0 eq., 274 mg, 2.24 mmol) were added and stirred at the same temperature for 18 hours. Ethyl acetate (30 mL) and hexane (10 mL) were added to the reaction mixture, followed by separation and washing with water (20 mL) twice, a water (10 mL) / saturated aqueous sodium bicarbonate solution (10 mL) mixture twice, and a saturated aqueous sodium chloride solution (20 mL) once. The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to give D8-2 (511 mg, two-step yield: 65%) as a pale brown liquid.

[0413] The synthesis of Fragment D-8 from D8-2 was carried out as follows. To a solution of D8-2 (1.0 eq., 472 mg, 1.34 mmol) in dichloromethane (2 mL) was added TFA (9.7 eq., 1.0 mL, 13.1 mmol) at room temperature, followed by stirring at the same temperature for 2 hours. Ethyl acetate (20 mL) was added to the reaction solution, followed by separation and washing with water (10 mL) twice, saturated aqueous sodium bicarbonate solution (10 mL) three times, and saturated aqueous sodium chloride solution (10 mL) once. The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain Fragment D-8 (229 mg, yield 68%) as a colorless, transparent liquid.

[0414] Example 6B: Synthesis of Fragment D-9 Fragment D-9 was synthesized as follows.

[0415] The synthesis of D9-1 from Boc-L-Asp(OBzl)-OH was carried out as follows.

[0416] A solution of Boc-L-Asp(OBzl)-OH (1.0 eq., 893 mg, 2.76 mmol) in DMF (8 mL) was added with HOBt.H at room temperature. ２ O (1.2 eq., 510 mg, 3.33 mmol), EDCI (1.2 eq., 639 mg, 3.34 mmol), ethanol (1.2 eq., 150 mg, 3.26 mmol), and DMAP (1.0 eq., 339 mg, 2.77 mmol) were added and stirred at the same temperature for 18 hours. Ethyl acetate (30 mL) and hexane (10 mL) were added to the reaction mixture, and the mixture was washed twice with water (20 mL), twice with a water (10 mL) / saturated aqueous sodium bicarbonate solution (10 mL) mixture, and once with saturated aqueous sodium chloride solution (10 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to give D9-1 (881 mg, 91% yield) as a pale yellow liquid.

[0417] The synthesis of Fragment D-9 from D9-1 was carried out as follows.

[0418] To a solution of D9-1 (1.0 eq., 864 mg, 2.46 mmol) in dichloromethane (3 mL) was added TFA (10 eq., 2.83 g, 24.8 mmol) at room temperature, and the mixture was stirred at the same temperature for 1.5 hours. 1 M aqueous sodium hydroxide solution (22 mL) was added to the reaction solution to adjust the pH to 9. After extraction with ethyl acetate (30 mL) once, the organic layer was washed with saturated aqueous sodium chloride solution (10 mL) once. The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain Fragment D-9 (524 mg, yield 85%) as a pale yellow liquid.

[0419] Example 6C: Synthesis of Fragment D-10 Fragment D-10 was synthesized as follows.

[0420] The synthesis of D10-1 from Boc-L-Asp(OBzl)-OH was carried out as follows. A solution of Boc-L-Asp(OBzl)-OH (1.0 eq., 5.01 g, 15.5 mmol) in DMF (45 mL) was added with HOBt.H ２ O (1.2 eq., 2.85 g, 18.6 mmol), EDCI (1.2 eq., 3.57 g, 18.6 mmol), hexanol (1.2 eq., 1.89 g, 18.5 mmol), and DMAP (1.0 eq., 1.90 g, 15.6 mmol) were added and stirred at the same temperature for 1 hour. Ethyl acetate (90 mL) and hexane (30 mL) were added to the reaction mixture, followed by separation and washing with water (100 mL) twice, a water (50 mL) / saturated aqueous sodium bicarbonate solution (50 mL) mixture twice, and a saturated aqueous sodium chloride solution (50 mL) once. The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to give D10-1 (6.08 mg, 96% yield) as a pale yellow liquid.

[0421] Fragment D-10 was synthesized from D10-1 as follows. To a solution of D10-1 (1.0 eq., 6.07 g, 14.9 mmol) in dichloromethane (30 mL) was added TFA (10 eq., 17.0 g, 149 mmol) at room temperature, and the mixture was stirred at the same temperature for 1 hour. 1 M aqueous sodium hydroxide solution (140 mL) was added to the reaction solution to adjust the pH to 9. After extraction with ethyl acetate (100 mL) once, the organic layer was washed once with water (50 mL) and once with saturated aqueous sodium chloride solution (50 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain Fragment D-10 (4.48 g, yield 98%) as a pale yellow liquid.

[0422] Example 6D: Synthesis of Fragment D-11 Fragment D-11 was synthesized as follows.

[0423] The synthesis of D11-1 from Boc-L-Asp(OBzl)-OH was carried out as follows. A solution of Boc-L-Asp(OBzl)-OH (1.0 eq., 5.04 g, 15.6 mmol) in DMF (45 mL) was added with HOBt.H at room temperature. ２ O (1.2 eq., 2.87 g, 18.7 mmol), EDCI (1.2 eq., 3.59 g, 18.7 mmol), dodecanol (1.2 eq., 3.49 g, 18.7 mmol), and DMAP (1.0 eq., 1.91 g, 15.6 mmol) were added and stirred at the same temperature for 2 hours. Ethyl acetate (90 mL) and hexane (30 mL) were added to the reaction mixture, followed by separation and washing with water (100 mL) twice, a water (50 mL) / saturated aqueous sodium bicarbonate solution (50 mL) mixture twice, and a saturated aqueous sodium chloride solution (50 mL) once. The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to give D11-1 (7.87 mg, crude yield 103%) as a pale yellow liquid.

[0424] The synthesis of Fragment D-11 from D11-1 was carried out as follows. To a dichloromethane (30 mL) solution of D11-1 (calculated as 1.0 eq., 7.87 g, 15.6 mmol), TFA (8.0 eq., 14.2 g, 124 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. 1 M aqueous sodium hydroxide solution (113 mL) was added to the reaction solution to adjust the pH to 9. After extraction with ethyl acetate (100 mL) once, the organic layer was washed twice with water (50 mL) and once with saturated aqueous sodium chloride solution (50 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a crude product (6.56 g) as a pale yellow liquid. The crude product was purified by flash silica gel column (normal phase silica gel 30 g, hexane / ethyl acetate=75 / 25 to 25 / 75) to obtain Fragment D-11 (4.73 g, two-step yield from Boc-L-Asp(OBzl)-OH 77%) as a pale yellow liquid.

[0425] Example 6E: Synthesis of Fragment D-12 Fragment D-12 was synthesized as follows.

[0426] Under a nitrogen stream, triethylamine (2.5 eq., 7.23 g, 71.44 mmol) and NsCl (1.2 eq., 7.60 g, 34.29 mmol) were added to a solution of Fragment D-2 (1.0 eq., 10.00 g, 28.58 mmol) in dichloromethane (100 mL) under ice cooling, and the mixture was stirred at the same temperature for 0.5 hours and then for 17 hours while warming to room temperature. The reaction mixture was washed once with water (50 mL) and once with a 5% aqueous sodium chloride solution (50 mL), and then dried over sodium sulfate. The sodium sulfate was filtered off and concentrated under reduced pressure to obtain a crude product (14.78 g). This crude product was dissolved in ethyl acetate (100 mL), washed once with a 5% aqueous sodium chloride solution (50 mL), and then dried over sodium sulfate. After filtering off the sodium sulfate, the filtrate was concentrated under reduced pressure to obtain D12-1 (14.55 g, containing 0.6 wt % of ethyl acetate, quant.) as a yellow solid.

[0427] Under a nitrogen atmosphere, potassium carbonate (2.0 eq., 7.90 g, 57.16 mmol) and methyl iodide (2.0 eq., 8.11 g, 57.14 mmol) were added to a DMF (100 mL) solution of D12-1 (calculated as 1.0 eq., 14.55 g, 28.58 mmol) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. Toluene (200 mL) was added to the reaction mixture, which was then washed once with water (200 mL) and once with 5% brine (200 mL), and then dried over sodium sulfate. The sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure to give D12-2 (14.78 g, DMF 0.4 wt %, 99% calculated yield for two steps from Fragment D-2) as a light brown viscous material.

[0428] Under a nitrogen atmosphere, cesium carbonate (1.5 eq., 13.84 g, 42.48 mmol) and 4-tert-butylbenzenethiol (1.5 eq., 7.06 g, 42.46 mmol) were added to a solution of D12-2 (1.0 eq., 14.78 g, 28.29 mmol) in DMF (140 mL) at room temperature, and the mixture was stirred at the same temperature for 2 hours. Toluene (300 mL) was added to the reaction solution, and the mixture was washed once with water (300 mL), once with 5% aqueous potassium carbonate solution (300 mL), and once with 5% aqueous sodium chloride solution (300 mL), and then dried over sodium sulfate. The sodium sulfate was filtered off, and the crude product (19.66 g) obtained by concentration under reduced pressure was purified by flash silica gel column purification (normal phase silica gel 100 g, hexane / ethyl acetate=90 / 10 to 0 / 100) to obtain Fragment D-12 (7.52 g, yield 81%) as an orange oil.

[0429] Example 6F: Synthesis of Fragment D-13 Fragment D-13 was synthesized as follows. Under a nitrogen atmosphere, a solution of Boc-L-Asp(OBzl)-OH (1.0 eq., 5.00 g, 15.5 mmol) in DMF (45 mL) was added with HOBt.H at room temperature. ２ O (1.2 eq., 2.85 g, 18.6 mmol), EDCI (1.2 eq., 3.57 g, 18.6 mmol), 1-octanol (1.2 eq., 3.0 mL, 19.1 mmol), and DMAP (1.0 eq., 1.89 g, 15.5 mmol) were added and stirred at the same temperature for 1 hour. Hexane (25 mL) and ethyl acetate (75 mL) were added to the reaction solution, and the mixture was washed twice with water (50 mL), twice with a saturated aqueous sodium bicarbonate solution (25 mL) / water (25 mL) mixture, and once with a saturated aqueous sodium chloride solution (30 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain D13-1 (7.09 g) as a pale yellow liquid. Under a nitrogen atmosphere, TFA (10 eq., 12.3 mL, 161 mmol) was added to a dichloromethane (30 mL) solution of D13-1 (calculated as 1.0 eq., 7.09 g, 15.5 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. A 1 M aqueous sodium hydroxide solution (145 mL) was added to the reaction mixture, and the mixture was extracted once with ethyl acetate (100 mL). The organic layer was washed twice with water (50 mL) and once with saturated aqueous sodium chloride solution (25 mL). The organic layer was dried over magnesium sulfate, and the magnesium sulfate was filtered off. The mixture was then concentrated under reduced pressure to give a crude product (5.62 g) as a pale yellow liquid. The crude product was purified using a flash silica gel column (41 g of normal-phase silica gel, hexane / ethyl acetate = 3 / 1 to 1 / 1) to give Fragment D-13 (4.20 g, two-stage yield 81%) as a pale yellow liquid.

[0430] Example 6G: Synthesis of Fragment D-14 Fragment D-14 was synthesized as follows. Under a nitrogen atmosphere, a solution of Boc-L-Asp(OBzl)-OH (1.0 eq., 5.00 g, 15.5 mmol) in DMF (45 mL) was added with HOBt.H at room temperature. ２ O (1.2 eq., 2.85 g, 18.6 mmol), EDCI (1.2 eq., 3.57 g, 18.6 mmol), 1-decanol (1.2 eq., 3.5 mL, 18.4 mmol), and DMAP (1.0 eq., 1.90 g, 15.5 mmol) were added and stirred at the same temperature for 1 hour. Hexane (25 mL) and ethyl acetate (75 mL) were added to the reaction solution, and the mixture was washed twice with water (50 mL), twice with a saturated aqueous sodium bicarbonate solution (25 mL) / water (25 mL) mixture, and once with a saturated aqueous sodium chloride solution (25 mL). The organic layer was dried over magnesium sulfate, and the magnesium sulfate was filtered off. The mixture was then concentrated under reduced pressure to obtain D14-1 (7.80 g) as a pale yellow liquid. Under a nitrogen atmosphere, TFA (10 eq., 12.0 mL, 157 mmol) was added to a dichloromethane (30 mL) solution of D14-1 (calculated as 1.0 eq., 7.80 g, 15.5 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hours. A 1 M aqueous sodium hydroxide solution (130 mL) was added to the reaction solution, and the mixture was extracted once with ethyl acetate (100 mL). The organic layer was washed twice with water (50 mL) and once with saturated aqueous sodium chloride solution (25 mL). The organic layer was dried over magnesium sulfate, and the magnesium sulfate was filtered off. The mixture was then concentrated under reduced pressure to give a crude product (6.61 g) as a pale yellow liquid. The crude product was purified using a flash silica gel column (33 g of normal-phase silica gel, hexane / ethyl acetate = 3 / 1 to 1 / 1) to give Fragment D-14 (4.00 g, two-stage yield 71%) as a pale yellow liquid.

[0431] Example 6H: Synthesis of Fragment D-15' Fragment D15'-1 was synthesized from Fragment D-1' as follows. Under a nitrogen atmosphere, triethylamine (2.5 eq., 1.71 g, 16.9 mmol) and NsCl (1.2 eq., 1.80 g, 8.12 mmol) were added to a dichloromethane (20 mL) solution of Fragment D-1' (1.0 eq., 2.00 g, 6.76 mmol) under ice-cooling, and the mixture was stirred at the same temperature for 2.5 hours and at room temperature for 14 hours. After concentrating under reduced pressure to roughly remove the solvent, ethyl acetate (20 mL) was added to the concentrate, and the mixture was washed once with water (20 mL), once with 5% aqueous sodium bicarbonate solution (20 mL), and once with 5% aqueous sodium chloride solution (20 mL). The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain D15'-1 (3.25 g, quant.) as a brown oil.

[0432] The synthesis of Fragment D-15' from D15'-1 was carried out as follows. Under a nitrogen atmosphere, potassium carbonate (4.0 eq., 3.51 g, 25.40 mmol) and iodomethane (1.5 eq., 1.35 g, 9.51 mmol) were added to a DMF (15 mL) solution of D15'-1 (calculated as 1.0 eq., 3.05 g, 6.35 mmol) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. 4-tert-Butylbenzenethiol (2.0 eq., 2.11 g, 12.69 mmol) was added at the same temperature, and the mixture was stirred at the same temperature for 2.5 hours and then at room temperature for 1.5 hours. Toluene (40 mL) was added to the reaction mixture, and the mixture was washed once with water (40 mL) and twice with 5% aqueous sodium chloride solution (40 mL). The organic layer was then dried over sodium sulfate. The sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a crude product (5.67 g). The crude product (0.33 g) obtained from D15'-1 (0.20 g) by a similar procedure was combined with the above crude product and purified twice using a flash silica gel column (first time: 50 g of normal phase silica gel, hexane / ethyl acetate = 70 / 30 to 30 / 70; second time: 40 g of normal phase silica gel, hexane / ethyl acetate = 90 / 10 to 0 / 100) to obtain Fragment D-15' (1.88 g, containing impurities, apparent yield quant.) as an orange oil.

[0433] Example 7: Synthesis of Compound 1 Under a nitrogen atmosphere, TBD (1.05 eq., 1.42 g, 10.20 mmol) was added to a solution of Fragment A-2 (1.05 eq., 5.81 g, containing 2.2 wt% ethyl acetate, 10.23 mmol) and Fragment B-1 (1.0 eq., 4.00 g, 9.74 mmol) in toluene (111 mL) under ice cooling, and the mixture was stirred for 22 hours while warming to room temperature. A 5% aqueous citric acid solution (50 mL) was added to the reaction mixture for separation and washing. The organic layer was washed once with a mixture of 5% aqueous sodium bicarbonate (50 mL) and 5% aqueous sodium chloride (50 mL) and once with a 5% aqueous sodium chloride solution (50 mL), and then dried over sodium sulfate. The sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a crude product (10.90 g) as a light brown viscous substance. The crude product was purified by flash silica gel column (normal phase silica gel 100 g, hexane / ethyl acetate=80 / 20 to 0 / 100) to obtain Compound 1-1 (8.49 g, Fragment A-2, containing PMBOH and ethyl acetate, apparent yield 90%) as a yellow viscous product.

[0434] Under a nitrogen atmosphere, 1-dodecanethiol (6.0 eq., 3.73 g, 18.43 mmol) and DBU (6.0 eq., 2.81 g, 18.46 mmol) were added to a DMF (15 mL) solution of compound 1-1 (1.0 eq., 2.97 g, calculated as Fragment A-2, PMBOH, containing ethyl acetate, 3.07 mmol) under ice-cooling, and the mixture was stirred at room temperature for 5 hours. Toluene (30 mL) and 5% aqueous citric acid (40 mL) were added to the reaction mixture, followed by extraction and separation once. The aqueous layer was extracted again with toluene (30 mL). The organic layers were combined and washed once with a mixture of 5% aqueous sodium bicarbonate (30 mL) and 5% aqueous sodium chloride (30 mL). After drying over sodium sulfate, the sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure to give a crude product (6.54 g) as a yellow oil. The crude product (2.47 g) obtained from compound 1-1 (1.03 g) by a similar procedure was combined with the previous crude product and purified with a flash silica gel column (normal phase silica gel 100 g, hexane / ethyl acetate=90 / 10 to 50 / 50) to obtain compound 1-2 (2.32 g, containing PMBOH and ethyl acetate, apparent yield 71%) as a pale yellow oil.

[0435] Under a nitrogen atmosphere, a solution of compound 1-2 (1.0 eq., 2.32 g, containing 2.1 wt % ethyl acetate, 2.06 mmol) in DMF (24 mL) was treated with N-Fmoc-L-valine (Fragment C-1, 2.0 eq., 1.39 g, 4.10 mmol), EDCI (2.0 eq., 0.79 g, 4.12 mmol), and HOBt.H ２ O (2.0 eq., 0.63 g, 4.11 mmol) was added, and the mixture was stirred at room temperature for 3.5 hours. Toluene (50 mL) and a 5% aqueous solution of sodium bicarbonate (50 mL) were added to the reaction mixture, and the mixture was extracted once with a 5% aqueous solution of sodium chloride (50 mL). The organic layer was washed once with a 5% aqueous solution of sodium chloride (50 mL), and then dried over sodium sulfate. The sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a crude product (3.49 g) as a yellow viscous substance. The crude product was purified using a flash silica gel column (NH ２ Silica gel 28 g, hexane / ethyl acetate=90 / 10 to 50 / 50) to obtain Compound 1-3 (2.22 g, yield 98%) as a white amorphous substance.

[0436] Under a nitrogen atmosphere, lithium hydroxide monohydrate (4.0 eq., 0.34 g, 8.10 mmol) was added to a mixture of compound 1-3 (1.0 eq., 2.22 g, 2.01 mmol) in THF (20 mL) and water (10 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was ice-cooled, and 5% aqueous citric acid (30 mL) was added to adjust the pH to 3. The mixture was extracted once with ethyl acetate (30 mL). The organic layer was washed once with 5% aqueous sodium chloride (30 mL) and then dried over sodium sulfate. The sodium sulfate was removed by filtration, and the mixture was concentrated under reduced pressure to give a crude product (2.45 g) as a pale yellow viscous substance. The crude product was purified using a flash silica gel column (25 g of normal-phase silica gel, ethyl acetate / methanol = 100 / 0 to 90 / 10) to give compound 1-4 (1.36 g, containing 4.4 wt % ethyl acetate, calculated yield 85%) as a white amorphous substance.

[0437] Under a nitrogen atmosphere, DIPEA (10.0 eq., 1.11 g, 8.59 mmol) was added to a solution of HATU (5.0 eq., 1.63 g, 4.29 mmol) in DMF (842 mL) at room temperature. Next, a solution of compound 1-4 (1.0 eq., 0.68 g, containing 4.4 wt% ethyl acetate, 0.855 mmol) in DMF (8 mL) was added at the same temperature over 17 hours. After the dropwise addition was completed, the mixture was stirred at room temperature for an additional 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the concentrated residue was washed once with ethyl acetate (15 mL) and 5% aqueous citric acid (15 mL). The organic layer was washed once with 5% aqueous sodium bicarbonate (15 mL) and once with 5% aqueous sodium chloride (30 mL), and then dried over sodium sulfate. The sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain a mixture of Compounds 1-5 and 1-6 (1.05 g) as a light brown amorphous substance.

[0438] Under a nitrogen atmosphere, TBAF (1.1 M in THF, 8.0 eq., 5.63 mL, 6.193 mmol) was added to a THF (19 mL) solution of a mixture of compound 1-5 and compound 1-6 (calculated as 1.0 eq., 0.95 g, 0.774 mmol) under ice-cooling, and the mixture was stirred for 4 hours while warming to room temperature. The reaction solution was ice-cooled, and 10% aqueous ammonium chloride solution (40 mL) was added, followed by extraction with ethyl acetate (40 mL) once. The organic layer was washed with 5% aqueous sodium chloride solution (40 mL) once, dried over sodium sulfate, filtered off the sodium sulfate, and concentrated under reduced pressure to obtain a crude product (1.19 g) as a light brown viscous substance.

[0439] A crude product (106 mg) obtained from a mixture of Compound 1-5 and Compound 1-6 (0.10 g, calculated as 0.081 mmol) by a similar procedure was combined with the previous crude product and purified with a flash silica gel column (normal phase silica gel 10 g, hexane / ethyl acetate=50 / 50) to obtain Compound 1-6 (0.60 g, isomer mixture, containing 0.7 wt % ethyl acetate and 36.4 wt % TBAF, calculated yield of 70% for two steps from Compound 1-4) as a pale orange solid.

[0440] Under a nitrogen atmosphere, Dess-Martin periodinane (1.5 eq., 0.38 g, 0.90 mmol) was added to a dichloromethane (13 mL) solution of compound 1-6 (1.0 eq., 0.66 g, isomer mixture, containing 3.9 wt % ethyl acetate and 38.9 wt % TBAF, 0.60 mmol) under ice-cooling, and the mixture was stirred for 16 hours while warming to room temperature. A 5% aqueous solution of sodium bicarbonate (10 mL) and a 5% aqueous solution of sodium thiosulfate (10 mL) were added to the reaction mixture, which was then washed once with a 5% aqueous solution of sodium chloride (20 mL). The organic layer was washed once with a 5% aqueous solution of sodium chloride (20 mL), dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure to obtain the aldehyde (0.392 g, containing isomers) as a pale orange amorphous solid.

[0441] Under a nitrogen atmosphere, sodium dihydrogen phosphate dihydrate (3.5 eq., 0.33 g, 2.12 mmol) and 80% sodium chlorite (4.5 eq., 0.30 g, 2.65 mmol) were added to a mixture of aldehyde (1.0 eq., 0.39 g, contains isomers, calculated as 0.60 mmol) in t-butyl alcohol (16 mL) / amylene (4 mL) / water (4 mL) at room temperature, and the mixture was stirred at the same temperature for 1.5 hours. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction mixture, and the mixture was extracted once with ethyl acetate (20 mL) and water (20 mL). The organic layer was washed twice with water (20 mL) and once with 5% aqueous sodium chloride solution (20 mL), and then dried over sodium sulfate. After filtering off the sodium sulfate, the mixture was concentrated under reduced pressure to obtain Compound 1-7 (0.351 g, isomer mixture, containing 12.5 wt % of TBAF, 80% calculated yield for two steps from Compound 1-6) as a pale orange solid.

[0442] Under a nitrogen atmosphere, DIPEA (3.0 eq., 78 μL, 0.46 mmol) and HBTU (1.5 eq., 87 mg, 0.23 mmol) were added to a dichloromethane (1.3 mL) solution of compound 1-7 (1.0 eq., 130 mg, isomer mixture, containing 24.8 wt % TBAF, 0.15 mmol) and L-glutamic acid dibenzyl ester hydrochloride (Fragment D-1, 1.5 eq., 83 mg, 0.23 mmol) under ice-cooling, and the mixture was stirred for 3.5 hours while warming to room temperature.

[0443] The reaction solution obtained by treating compound 1-7 (100 mg) in the same manner was combined with the previous reaction solution, and toluene (20 mL), a 5% aqueous citric acid solution (20 mL), and a 5% aqueous sodium chloride solution (10 mL) were added and washed once. The organic layer was washed once with a 5% aqueous citric acid solution (20 mL), once with a 5% aqueous sodium bicarbonate solution (20 mL), and once with a 5% aqueous sodium chloride solution (20 mL), and then dried over sodium sulfate, after which the sodium sulfate was filtered off. The crude product (290 mg) obtained as a pale brown viscous material after concentration under reduced pressure was purified by flash silica gel column (NH ２ Silica gel 6.5 g, hexane / ethyl acetate=50 / 50) to obtain compound 1-8 (37 mg, yield 14%) as a yellow viscous material.

[0444] Under a nitrogen atmosphere, 10% palladium-carbon (N.E. Chemcat NX type, 50% water content, 11.1 mg) was added to a THF (1.85 mL) / water (1.85 mL) mixture of compound 1-8 (1.0 eq., 37 mg, 0.039 mmol) at room temperature, and the system was purged with hydrogen, followed by stirring at the same temperature for 16 hours. The catalyst was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. To the concentrated residue was added a THF (1.85 mL) / water (1.85 mL) mixture, and the system was purged with nitrogen, followed by adding 10% palladium-carbon (N.E. Chemcat NX type, 50% water content, 11.1 mg) at room temperature. The system was purged with hydrogen, followed by stirring at the same temperature for 3 hours. As the reaction proceeded, the target product precipitated as a solid, so TFA (2.0 eq., 6.0 μL, 0.078 mmol) was added to dissolve the target product, and then the catalyst was removed by filtration through Celite. The filtrate was concentrated under reduced pressure to obtain a crude product (27 mg) as a pale orange amorphous substance.

[0445] The crude product (15.5 mg) obtained from compound 1-8 (21 mg) by a similar procedure was combined with the previous crude product, purified twice by flash silica gel column (reverse-phase silica gel 60 g, first run: 0.05% aqueous TFA solution / acetonitrile=99 / 1 to 90 / 10, second run: 0.05% aqueous TFA solution / acetonitrile=95 / 5), and then lyophilized to obtain the TFA salt of compound 1 (18 mg, yield 45%, purity 97.1%) as a white solid.

[0446] ​１ H-NMR (400MHz, D ２ O) δ6.94-6.87 (m, 3H), 4.86 (s, 1H), 4.37 (dd, J = 9.2, 4.8Hz, 1H), 4.12 (d, J = 10.0Hz, 1H ), 4.05 (dd, J=8.8, 4.8Hz, 1H), 3.23 (dd, J=13.2, 4.8Hz, 1H), 2.92 (dd, J=13.2, 8.8Hz, 1 H), 2.72 (s, 3H), 2.48-2.35 (m, 2H), 2.22-2.14 (m, 1H), 2.03-1.90 (m, 3H), 1.77-1.63 (m , 1H), 1.57 (s, 3H), 1.04 (t, J=7.2Hz, 3H), 0.85 (d, J=6.4Hz, 3H), 0.78 (d, J=6.4Hz, 3H).

[0447] Example 8: Synthesis of Compound 9 Under a nitrogen atmosphere, DIPEA (1.5 eq., 91 μL, 0.54 mmol) and HATU (1.5 eq., 204 mg, 0.54 mmol) were added to a dichloromethane (6.6 mL) solution of compound 1-7 (1.0 eq., 264 mg, isomer mixture, containing 12.5 wt% TBAF, 0.36 mmol) and L-aspartic acid dibenzyl ester hydrochloride (Fragment D-2, 1.5 eq., 188 mg, 0.54 mmol) under ice-cooling, and the mixture was stirred at the same temperature for 6 hours. The reaction mixture was washed once with 5% aqueous citric acid (10 mL), and the organic layer was washed once with a mixture of 5% aqueous sodium bicarbonate (10 mL) and 5% aqueous sodium chloride (10 mL), followed by drying over sodium sulfate. After filtering off the sodium sulfate, the crude product (496 mg) obtained by concentration under reduced pressure was purified twice with a flash silica gel column (normal phase silica gel 10 g, first time: chloroform / ethyl acetate=90 / 10 to 50 / 50, second time: chloroform / ethyl acetate=90 / 10 to 85 / 15) to obtain low-purity compound 9-1 (129 mg).

[0448] Impure compound 9-1 was dissolved in toluene (10 mL), washed five times with 5% aqueous sodium chloride solution (10 mL), and then dried over sodium sulfate. After filtering off the sodium sulfate, the filtrate was concentrated under reduced pressure to give compound 9-1 (93 mg, yield 28%) as a yellow amorphous substance.

[0449] Under a nitrogen atmosphere, 10% palladium-carbon (N.E. Chemcat NX type, 50% water content, 2.5 mg) and TFA (2.0 eq., 8.2 μL, 0.107 mmol) were added to a THF (2.5 mL) / water (2.5 mL) mixture of compound 9-1 (1.0 eq., 50 mg, 0.053 mmol) at room temperature. The system was purged with hydrogen and then stirred at the same temperature for 23 hours. Additional 10% palladium-carbon (N.E. Chemcat NX type, 50% water content, 2.5 mg) was added and the mixture was stirred for 27 hours. Another 10% palladium-carbon (N.E. Chemcat NX type, 50% water content, 2.5 mg) was added and the mixture was stirred for an additional 24 hours.

[0450] The reaction solution obtained by treating compound 9-1 (10 mg) in the same manner was combined with the previous reaction solution, and the catalyst was removed by filtration through Celite. The filtrate was concentrated under reduced pressure to give a crude product (58 mg) as an orange viscous substance. The crude product was purified using a flash silica gel column (30 g of reverse-phase silica gel, 0.05% aqueous TFA solution / acetonitrile = 95 / 5 to 90 / 10) and then lyophilized to give the TFA salt of compound 9 (30.5 mg, yield 73%, purity 97.8%) as a white solid. １ H-NMR (400MHz, D ２ O) δ6.94-6.87 (m, 3H), 4.66 (dd, J=7.2, 5.2Hz, 1H), 4.11 (d, J=10.0Hz, 1H), 4.05 (dd, J=8.8, 4.8Hz, 1H), 3.24 (dd, J=13.6, 4.8Hz, 1H), 2.96-2. 84 (m, 3H), 2.72 (s, 3H), 2.05-1.91 (m, 2H), 1.78-1.69 (m, 1H), 1.58 (s, 3 H), 1.05 (t, J=7.2Hz, 3H), 0.86 (d, J=7.2Hz, 3H), 0.78 (d, J=6.8Hz, 3H).

[0451] Example 9: Synthesis of Compound 2 Under a nitrogen atmosphere, a solution of compound 1-2 (1.0 eq., 2.32 g, calculated as PMBOH, containing ethyl acetate, 2.97 mmol) in DMF (35 mL) was treated with N-Fmoc-L-glycine (Fragment C-3, 2.0 eq., 1.77 g, 5.95 mmol), EDCI (2.0 eq., 1.14 g, 5.95 mmol), and HOBt.H ２ O (2.0 eq., 0.91 g, 5.94 mmol) was added and stirred at room temperature for 2 hours. Toluene (70 mL) and 5% aqueous sodium bicarbonate solution (70 mL) were added to the reaction solution and extracted once. The organic layer was washed once with 5% aqueous sodium chloride solution (70 mL) and then dried over sodium sulfate. The sodium sulfate was filtered off and the mixture was concentrated under reduced pressure to obtain a crude product (4.56 g) as a white solid. Ethyl acetate (45 mL) was added to the crude product, and after ultrasonic irradiation, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The concentrated residue was dissolved in THF and concentrated under reduced pressure to obtain compound 2-9 (3.50 g, containing impurities, THF, and DMF) as a white amorphous product.

[0452] Under a nitrogen atmosphere, lithium hydroxide monohydrate (4.0 eq., 0.50 g, 11.92 mmol) was added to a mixture of compound 2-9 (1.0 eq., 3.50 g, 2.97 mmol) in THF (28 mL) / water (14 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was ice-cooled, and 5% aqueous citric acid solution (45 mL) was added to adjust the pH to 3, followed by extraction with ethyl acetate (45 mL) once. The organic layer was washed with 5% aqueous sodium chloride solution (45 mL) once and then dried over sodium sulfate. The sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a crude product (3.55 g) as a pale yellow viscous substance. The crude product was purified by flash silica gel column (normal phase silica gel 25 g, ethyl acetate / methanol=100 / 0 to 70 / 30) to obtain Compound 2-10 (1.63 g, containing 7.3 wt % ethyl acetate, 42% calculated yield for four steps from Fragment B-1) as a pale orange amorphous substance.

[0453] Under a nitrogen atmosphere, DIPEA (10.0 eq., 1.11 g, 8.59 mmol) was added to a DMF (842 mL) solution of HATU (5.0 eq., 1.63 g, 4.29 mmol) at room temperature. Next, a DMF (8 mL) solution of compound 2-10 (1.0 eq., 0.66 g, containing 7.3 wt % ethyl acetate, 0.852 mmol) was added at the same temperature over 17 hours, and after the dropwise addition was completed, the mixture was stirred at room temperature for an additional hour. The reaction solution was concentrated under reduced pressure until the volume was reduced to a few mL.

[0454] Under a nitrogen atmosphere, the concentrated residue was stirred at an external temperature of 50°C for 17 hours, then at an external temperature of 70°C for 2 hours. Ethyl acetate (20 mL) and 5% aqueous citric acid (20 mL) were added to the reaction mixture and extracted once. The organic layer was washed once with 5% aqueous sodium bicarbonate (20 mL) and once with 5% aqueous sodium chloride (20 mL), and then dried over sodium sulfate. The sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure to give a crude product (0.98 g) as a light brown viscous substance. The crude product was purified using a flash silica gel column (normal-phase silica gel 10 g, chloroform / ethyl acetate = 90 / 10 to 5 / 95) to give compound 2-12 (0.168 g, containing isomers and impurities, apparent yield for two steps from compound 2-10: 34%) as an orange solid.

[0455] Under a nitrogen atmosphere, Dess-Martin periodinane (1.5 eq., 179 mg, 0.422 mmol) was added to a dichloromethane (3.3 mL) solution of compound 2-12 (1.0 eq., 165 mg, calculated as 0.282 mmol, containing isomers and impurities) under ice-cooling, and the mixture was stirred for 2 hours while warming to room temperature. A 5% aqueous solution of sodium bicarbonate (3 mL) and a 5% aqueous solution of sodium thiosulfate (3 mL) were added to the reaction mixture, followed by extraction and separation once. The organic layer was washed once with a 5% aqueous solution of sodium chloride (3 mL), dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure to obtain the aldehyde (133 mg, containing isomers, apparent yield 81%) as a pale orange amorphous solid.

[0456] Under a nitrogen atmosphere, sodium dihydrogen phosphate dihydrate (3.5 eq., 123 mg, 0.788 mmol) and 80% sodium chlorite (4.5 eq., 114 mg, 1.008 mmol) were added to a mixture of aldehyde (1.0 eq., 131 mg, containing an isomer, calculated as 0.224 mmol) in t-butyl alcohol (5.6 mL), amylene (1.4 mL), and water (1.4 mL) at room temperature, followed by stirring at the same temperature for 1 hour. Ethyl acetate (15 mL) and water (15 mL) were added to the reaction mixture, followed by extraction in one batch. The organic layer was washed once with 5% aqueous sodium chloride solution (15 mL) and then dried over sodium sulfate. After filtering off the sodium sulfate, the mixture was concentrated under reduced pressure to give compound 2-13 (97 mg, containing an isomer, 58% calculated yield for two steps from compound 2-12) as a yellow solid.

[0457] Under a nitrogen atmosphere, DIPEA (1.5 eq., 34 μL, 0.197 mmol) and HATU (1.5 eq., 75 mg, 0.200 mmol) were added to a dichloromethane (2 mL) solution of compound 2-13 (1.0 eq., 79 mg, contains isomers, 0.132 mmol) and L-glutamic acid dibenzyl ester hydrochloride (Fragment D-1, 1.5 eq., 72 mg, 0.198 mmol) under ice-cooling, and the mixture was stirred for 6 hours while warming to room temperature. Ethyl acetate (10 mL) and 5% aqueous citric acid (10 mL) were added to the reaction mixture, followed by extraction once. The organic layer was washed once with 5% aqueous sodium bicarbonate (10 mL) and once with 5% aqueous sodium chloride (10 mL), and then dried over sodium sulfate. After filtering off the sodium sulfate, the mixture was concentrated under reduced pressure. The crude product (160 mg) obtained as a pale brown viscous material was purified twice with a flash silica gel column (first and second runs: 10 g of normal phase silica gel, chloroform / ethyl acetate=90 / 10 to 60 / 40) to obtain Compound 2-6 (67 mg, Fragment D-1, containing ethyl acetate, apparent yield 56%) as a yellow amorphous material.

[0458] Under a nitrogen atmosphere, 10% palladium-carbon (N.E. Chemcat NX type, 50% water content, 3.2 mg) and TFA (2.0 eq., 10.7 μL, 0.140 mmol) were added to a THF (3.2 mL) / water (3.2 mL) mixture of compound 2-6 (1.0 eq., 64 mg, calculated as Fragment D-1, containing ethyl acetate, 0.070 mmol) at room temperature, and the system was purged with hydrogen and stirred at the same temperature for 66 hours. 10% palladium-carbon (N.E. Chemcat NX type, 50% water content, 3.2 mg) was added and the mixture was stirred for 21.5 hours. The catalyst was then removed by filtration through Celite, and the filtrate was concentrated under reduced pressure and then subjected to the reaction again. A THF (3.2 mL) / 3.2 mL) mixture was added to the concentrated residue, and the system was purged with nitrogen. Then, 10% palladium-carbon (N.E. Chemcat NX type, 50% water content, 5.8 mg) and TFA (2.0 eq., 10.7 μL, 0.140 mmol) were added at room temperature. The system was purged with hydrogen, and the mixture was stirred at the same temperature for 23 hours. The catalyst was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure to give a crude product (59 mg) as a pale brown viscous substance. The crude product was purified using a flash silica gel column (30 g of reverse-phase silica gel, 0.05% aqueous TFA solution / acetonitrile = 95 / 5) and then lyophilized to give the TFA salt of compound 2 (5.2 mg, yield 12%, purity 97.1%) as a white solid.

[0459] １ H-NMR (400MHz, D ２ O) δ7.45 (s, 1H), 7.05-7.03 (m, 1H), 6.96 (d, J = 8.4Hz, 1H), 4.63 (s, 1H), 4.45 (dd, J = 8.8, 5.2Hz, 1H), 4.26 (d, J = 16.8Hz, 1H), 3.98 (dd, J = 10.4, 3.6Hz, 1H), 3.54 (d, J = 16.4Hz, 1H), 3.25 (dd, J=13.2, 4.0Hz, 1H), 3.07-3.01 (m, 1H), 2.72 (s, 3H), 2.47 (t, J=7.2Hz, 2H), 2.2 5-2.20 (m, 1H), 2.01-1.97 (m, 2H), 1.76-1.70 (m, 1H), 1.61 (s, 3H), 0.87 (t, J=7.2Hz, 3H).

[0460] ​Example 9A: Synthesis of Compound 9A The steps up to compound 1-7 are the same as those for compound 1.

[0461] Compounds 1-7 to 9A-1 Under a nitrogen atmosphere, DEPBT (1.5 eq., 57.5 mg, 0.192 mmol) and 2,4,6-collidine (3.0 eq., 46.7 mg, 0.383 mmol) were added to a THF (1.2 mL) solution of compound 1-7 (1.0 eq., 82.2 mg, 0.128 mmol) and L-aspartic acid diethyl ester hydrochloride (Fragment D-7, 1.5 eq., 43.2 mg, 0.191 mmol) under ice-cooling, and the mixture was stirred at the same temperature for 7 hours, followed by stirring at room temperature for 15 hours. Ethyl acetate (10 mL) was added to the reaction mixture, which was then washed once with a mixture of water (5 mL) / saturated aqueous sodium bicarbonate (5 mL) and once with saturated aqueous sodium chloride (10 mL). The organic layer was dried over magnesium sulfate, filtered off, and concentrated under reduced pressure to give a crude product (162 mg) as a green oil. The crude product was purified by flash silica gel column (NH ２ Silica gel (6 g, hexane / ethyl acetate=75 / 25 to 50 / 50) was used to obtain Compound 9A-1 (48.5 mg, yield 47%) as a white amorphous substance.

[0462] The synthesis of compound 9A from compound 9A-1 was carried out as follows.

[0463] Under a nitrogen atmosphere, 10% palladium-carbon (N.E. Chemcat NX type, 50% water content, 2.0 mg) and TFA (2.0 eq., 3.7 μL, 0.048 mmol) were added to a THF (800 μL) / water (40 μL) mixture of compound 9A-1 (1.0 eq., 20 mg, 0.025 mmol) at room temperature. The system was purged with hydrogen, and after stirring at the same temperature for 23 hours, the catalyst was removed by filtration through Celite to obtain a filtrate.

[0464] The filtrate obtained in the same manner from compound 9A-1 (1.0 eq., 15 mg, 0.018 mmol) was combined and concentrated under reduced pressure to obtain a crude product. The resulting crude product (36.6 mg) was purified with a flash silica gel column (30 g of reverse-phase silica gel, 0.05% aqueous TFA solution / acetonitrile = 95 / 5 to 75 / 25). Lyophilization gave the TFA salt of compound 9A (16.3 mg, yield 54%, purity 94.4%) as a white solid.

[0465] １ H-NMR (400MHz, D ２ O) δ6.98-6.82 (m, 3H), 4.24-4.09 (m, 5H), 4.04 (dd, J = 8.8, 4.4Hz, 1H), 3.22 (dd, J = 13.2, 4.4Hz, 1H), 3.00-2.80 (m, 3H), 2.71 (s, 3H), 2.07-1.87 (m, 2H), 1.79-1.62 (m, 1H), 1.57 (s, 3H), 1.24 (m, 6H), 1 .05 (t, J=7.2Hz, 3H), 0.85 (d, J=6.4Hz, 3H), 0.79 (d, J=6.8Hz, 3H).

[0466] Example 9B: Synthesis of Compound 9B The steps up to compound 1-7 were carried out as described in Example 7. Compound 9B-1 was synthesized from compound 1-7 as follows. Under a nitrogen atmosphere, DEPBT (1.5 eq., 55.0 mg, 0.184 mmol) and 2,4,6-collidine (3.0 eq., 44.2 mg, 0.364 mmol) were added to a THF (1.2 mL) solution of Compound 1-7 (1.0 eq., 78.0 mg, 0.122 mmol) and Fragment D-8 (1.5 eq., 47.2 mg, 0.188 mmol) under ice-cooling, and the mixture was stirred at the same temperature for 6 hours, followed by stirring at room temperature for 16 hours. Ethyl acetate (10 mL) was added to the reaction mixture, which was then washed once with a water (5 mL) / saturated aqueous sodium bicarbonate solution (5 mL) mixture and once with saturated aqueous sodium chloride solution (10 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to give a crude product (166 mg) as a green oil. The crude product was purified by flash silica gel column (NH ２ ​Silica gel (6 g, hexane / ethyl acetate=75 / 25 to 0 / 100) was used to obtain compound 9B-1 (54.5 mg, yield 51%) as a white amorphous substance.

[0467] The synthesis of compound 9B from compound 9B-1 was carried out as follows.

[0468] Under a nitrogen atmosphere, 10% palladium-carbon (N.E. Chemcat NX type, 50% water content, 3.9 mg) and TFA (5.0 eq., 17 μL, 0.223 mmol) were added to a mixture of compound 9B-1 (1.0 eq., 39 mg, 0.045 mmol) in THF (1560 μL) and water (78 μL) at room temperature. The system was purged with hydrogen and then stirred at the same temperature for 4 hours. The catalyst was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude product (35 mg). The crude product (17 mg) obtained from compound 9B-1 (15 mg, 0.017 mmol) by the same procedure was combined with the above crude product and purified using a flash silica gel column (30 g of reverse-phase silica gel, 0.05% aqueous TFA solution / acetonitrile = 95 / 5 to 80 / 20). Lyophilization gave the TFA salt of Compound 9B (24.3 mg, yield 58%, purity 95.2%) as a white solid.

[0469] １ H-NMR (400MHz, D ２ O) δ6.97-6.86 (m, 3H), 4.69 (dd, J=7.2, 5.2Hz, 1H), 4.18-4.10 (m, 3H), 4.06 (dd, J=9.2, 4.8Hz, 1H), 3.24 (dd, J=13.6, 4.8Hz, 1H), 3.00-2.85 (m, 3H), 2.7 3 (s, 3H), 2.08-1.88 (m, 2H), 1.79-1.65 (m, 1H), 1.58 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H), 1.05 (t, J=7.2Hz, 3H), 0.86 (d, J=6.8Hz, 3H), 0.79 (d, J=6.8Hz, 3H).

[0470] Example 9C: Synthesis of Compound 9C Compound 9C-1 was synthesized from compound 1-7 as follows.

[0471] ​Under a nitrogen atmosphere, DEPBT (1.5 eq., 42.7 mg, 143 μmol) and 2,4,6-collidine (3.0 eq., 34.0 mg, 281 μmol) were added to a THF (1 mL) solution of Compound 1-7 (1.0 eq., 59.7 mg, 93.0 μmol) and Fragment D-9 (1.5 eq., 34.6 mg, 138 μmol) under ice-cooling, and the mixture was stirred at the same temperature for 5 hours, followed by stirring at room temperature for 15.5 hours. Ethyl acetate (20 mL) was added to the reaction mixture, which was then washed once with a water (5 mL) / saturated aqueous sodium bicarbonate solution (5 mL) mixture and once with saturated aqueous sodium chloride solution (10 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to give a crude product (171 mg) as a green oil. The crude product was purified by flash silica gel column (NH ２ Silica gel (6 g, hexane / ethyl acetate=75 / 25 to 0 / 100) was used to obtain compound 9C-1 (42.3 mg, yield 56%) as a white amorphous substance.

[0472] The synthesis of compound 9C from compound 9-1 was carried out as follows. Under a nitrogen atmosphere, 10% palladium-carbon (N.E. Chemcat NX type, 50% water content, 4.1 mg) and TFA (2.0 eq., 7.2 μL, 0.094 mmol) were added to a mixture of compound 9C-1 (1.0 eq., 41 mg, 0.047 mmol) in THF (1640 μL) and water (82 μL) at room temperature. The system was purged with hydrogen and then stirred at the same temperature for 6 hours. The catalyst was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure to give a crude product (35 mg). The crude product was purified using a flash silica gel column (30 g of reverse-phase silica gel, 0.05% aqueous TFA solution / acetonitrile = 95 / 5 to 80 / 20). Lyophilization gave the TFA salt of compound 9C (29.0 mg, yield 91%, purity 96.0%) as a white solid.

[0473] １ H-NMR (400MHz, D ２ ​O) δ6.98-6.85 (m, 3H), 4.24-4.17 (m, 2H), 4.10 (d, J=9.6Hz, 1H), 4.05 (dd, J = 9.2, 4.8Hz, 1H), 3.23 (dd, J = 13.6, 4.8Hz, 1H), 2.99-2.87 (m, 3H), 2.71 ( s, 3H), 2.08-1.88 (m, 2H), 1.81-1.68 (m, 1H), 1.57 (s, 3H), 1.24 (t, J = 7.2H z, 3H), 1.05 (t, J=7.2Hz, 3H), 0.85 (d, J=6.8Hz, 3H), 0.78 (d, J=6.4Hz, 3H).

[0474] Example 9D: Synthesis of Compound 9D Compound 1-7 was synthesized as described in Example 7. Compound 9D-1 was synthesized from compound 1-7 as follows. Under a nitrogen atmosphere, DEPBT (1.5 eq., 48.8 mg, 163 μmol) and 2,4,6-collidine (3.0 eq., 38.6 mg, 319 μmol) were added to a THF (1 mL) solution of Compound 1-7 (1.0 eq., 69.0 mg, 108 μmol) and Fragment D-10 (1.5 eq., 50.1 mg, 163 μmol) under ice-cooling, and the mixture was stirred at the same temperature for 6 hours, followed by stirring at room temperature for 16 hours. Ethyl acetate (10 mL) was added to the reaction mixture, and the mixture was washed once with a mixture of water (5 mL) / saturated aqueous sodium bicarbonate (5 mL) and once with saturated aqueous sodium chloride (10 mL). The organic layer was dried over magnesium sulfate, and the magnesium sulfate was filtered off. The mixture was concentrated under reduced pressure to give a crude product (152 mg) as a green oil. The crude product was purified using a flash silica gel column (NH ２ Silica gel (6 g, hexane / ethyl acetate=75 / 25 to 0 / 100) was used to obtain compound 9D-1 (54.0 mg, yield 54%) as a white amorphous substance.

[0475] The synthesis of compound 9D from compound 9D-1 was carried out as follows. To a mixture of compound 9D-1 (1.0 eq., 38.0 mg, 0.041 mmol) in THF (1600 μL) and water (80 μL) was added 10% palladium-carbon (N.E. Chemcat NX type, 50% water content, 3.8 mg) and TFA (2.0 eq., 6.3 μL, 0.082 mmol) at room temperature. The system was purged with hydrogen and stirred at the same temperature for 19 hours. The catalyst was removed by filtration through Celite to obtain a filtrate. The resulting crude product (32 mg) was purified using a flash silica gel column (30 g of reverse-phase silica gel, 0.05% aqueous TFA solution / acetonitrile = 95 / 5 to 70 / 30). Lyophilization afforded the TFA salt of compound 9D (14.9 mg, yield 50%, purity 95.6%) as a white solid.

[0476] １ H-NMR (400MHz, D ２ O) δ6.96-6.86 (m, 3H), 4.22-4.09 (m, 3H), 4.04 (dd, J=9.2, 4.8Hz, 1H ), 3.23 (dd, J=13.6, 4.8Hz, 1H), 2.95-2.88 (m, 3H), 2.71 (s, 3H), 2.0 8-1.88 (m, 2H), 1.80-1.68 (m, 1H), 1.67-1.53 ​​(m, 5H), 1.38-1.19 (m, 6H), 1.04 (t, J=7.2Hz, 3H), 0.90-0.80 (m, 6H), 0.78 (d, J=6.4Hz, 3H).

[0477] Example 9E: Synthesis of Compound 9E Compound 9E was synthesized. ​Under a nitrogen atmosphere, 2,4,6-collidine (3.0 eq., 55 μL, 418 μmol) and DEPBT (1.5 eq., 62.9 mg, 210 μmol) were added to a THF (1.4 mL) solution of compound 1-7 (1.0 eq., 90.3 mg, 141 μmol) and Fragment D-11 (1.4 eq., 78.5 mg, 200 μmol) under ice-cooling, and the mixture was stirred for 7 hours under ice-cooling, followed by stirring at room temperature for 16.5 hours. Fragment D-11 (0.5 eq., 27.1 mg, 69 μmol) was added at room temperature, followed by adding DEPBT (0.5 eq., 22.5 mg, 75 μmol) under ice-cooling, and the mixture was stirred for 2 hours under ice-cooling, followed by stirring at room temperature for 1.5 hours. A saturated aqueous solution of ammonium chloride (1.5 mL) was added to the reaction mixture, and the mixture was extracted once with ethyl acetate (8 mL) and once with ethyl acetate (4 mL). The organic layers were combined and washed twice with saturated aqueous sodium bicarbonate (2 mL), once with water (2 mL), and once with saturated aqueous sodium chloride (2 mL). The organic layer was dried over magnesium sulfate, and the magnesium sulfate was filtered off. The mixture was then concentrated under reduced pressure to obtain a crude product (244 mg) as a deep green viscous material. The crude product was purified using a flash silica gel column (NH ２ Silica gel 4.9 g, hexane / ethyl acetate=3 / 1 to 1 / 1) was used to obtain compound 9E-1 (71.3 mg, yield 50%) as a pale yellow, transparent viscous substance.

[0478] To a mixture of compound 9E-1 (1.0 eq., 53 mg, 0.052 mmol) in THF (2200 μL) and water (110 μL) was added 10% palladium-carbon (N.E. Chemcat NX type, 50% water content, 5.3 mg) and TFA (2.0 eq., 8.0 μL, 0.104 mmol) at room temperature. The system was purged with hydrogen, and after stirring at the same temperature for 23 hours, the catalyst was removed by filtration through Celite to obtain a filtrate. The filtrate was concentrated under reduced pressure, and the resulting crude product (44 mg) was purified by flash silica gel column purification (30 g of reverse-phase silica gel, 0.05% aqueous TFA solution / acetonitrile = 95 / 5 to 50 / 50). Lyophilization afforded the TFA salt of compound 9E (36.6 mg, yield 86%, purity 94.3%) as a white solid.

[0479] １ ​H-NMR (400MHz, DMSO-d6) δ9.12 (s, 1H), 8.77 (d, J = 8.4Hz, 1H), 8.63 (d, J = 7.6Hz, 1H), 7.86 (d, J = 8.8Hz, 1H), 6.80-6.72 ( m, 3H), 4.86 (d, J = 9.6Hz, 1H), 4.57 (dd, J = 13.2, 7.2Hz, 1H), 4.23 (dd, J = 9.2, 9.2Hz, 1H), 4.05-3.95 (m, 2H), 3.89 (brs, 1 H), 3.05-2.95 (m, 1H), 2.88 (dd, J = 14.4, 6.0Hz, 1H), 2.73 (dd, J = 16.8, 6.0Hz, 1H), 2.60-2.52 (m, 1H), 2.09-1.93 (m, 1H) , 1.87-1.74 (m, 1H), 1.73-1.61 (m, 1H), 1.58-1.46 (m, 2H), 1.44-1.14 (m, 21H), 1.00 (t, J=7.2Hz, 3H), 0.92-0.73 (m, 9H)

[0480] Example 9F: Synthesis of Compound 9F Under a nitrogen atmosphere, 2,4,6-collidine (3.0 eq., 57 μL, 433 μmol) and DEPBT (1.5 eq., 65.8 mg, 220 μmol) were added to a solution of compound 1-7 (1.0 eq., 93.3 mg, 141 μmol) and Fragment D-13 (1.6 eq., 75.6 mg, 225 μmol) in THF (1.45 mL) under ice-cooling, and the mixture was stirred for 6 hours under ice-cooling, followed by stirring at room temperature for 16 hours. A saturated aqueous ammonium chloride solution (2.0 mL) was added to the reaction mixture, which was then extracted twice with ethyl acetate (6 mL). The organic layers were combined and washed twice with saturated aqueous sodium bicarbonate (3 mL), twice with water (3 mL), and once with saturated aqueous sodium chloride (2 mL). The organic layer was dried over magnesium sulfate, and the magnesium sulfate was filtered off and the mixture was concentrated under reduced pressure to obtain a crude product (238 mg) as a deep green viscous material. The crude product was purified by flash silica gel column (NH ２ Silica gel 5.2 g, hexane / ethyl acetate=3 / 1 to 1 / 1) was used to obtain compound 9F-1 (73.3 mg, yield 53%) as a white amorphous substance.

[0481] Under a nitrogen atmosphere, 10% palladium-carbon (N.E. Chemcat NX type, 50% water content, 7 mg) and TFA (2.0 eq., 25.5 μL, 0.15 mmol) were added to a mixture of compound 9F-1 (1.0 eq., 72 mg, 0.075 mmol) in THF (2880 μL) and water (144 μL) at room temperature. The system was purged with hydrogen and stirred at the same temperature for 7 hours. The catalyst was then removed by filtration through Celite, and the filtrate was concentrated under reduced pressure to give a crude product (59 mg). The crude product was purified using a flash silica gel column (30 g of reverse-phase silica gel, 0.05% aqueous TFA solution / acetonitrile = 95 / 5 to 55 / 45). Lyophilization afforded the TFA salt of compound 9F (31.4 mg, yield 55%, purity 95.4%) as a white solid.

[0482] １ H-NMR (400MHz, DMSO-d6) δ9.11 (s, 1H), 8.77 (d, J = 8.4Hz, 1H), 8.62 (d, J = 7.6Hz, 1H), 7.86 (d, J = 9.6Hz, 1H), 6.80-6. 75 (m, 3H), 4.86 (d, J = 10.4Hz, 1H), 4.57 (dd, J = 13.6, 7.2Hz, 1H), 4.23 (dd, J = 9.2, 9.2Hz, 1H), 4.07-3.85 (m, 3H), 3.0 5-2.95 (m, 1H), 2.89 (dd, J=14.4, 5.6Hz, 1H), 2.73 (dd, J=16.8, 6.0Hz, 1H), 2.59-2.52 (m, 1H), 2.10-1.93 (m, 1H), 1. 86-1.75 (m, 1H), 1.74-1.61 (m, 1H), 1.59-1.46 (m, 2H), 1.37-1.16 (m, 13H), 1.00 (t, J=7.2Hz, 3H), 0.92-0.75 (m, 9H).

[0483] Example 9G: Synthesis of Compound 9G

[0484] The two steps from Fragment A-2″ to Compound 25-2 were as described in Example 29B below.

[0485] The synthesis of compound 9G-1 from compound 25-2 was carried out as follows. ​A solution of compound 25-2 (1.0 eq., 1.03 g, 1.44 mmol) in DMF (15 mL) was treated with HOBt.H ２ O (1.2 eq., 265 mg, 1.73 mmol), EDCI (1.2 eq., 333 mg, 1.74 mmol), and N-Fmoc-L-valine (Fragment C-1, 1.2 eq., 587 mg, 1.73 mmol) were added, and the mixture was stirred at room temperature for 5 hours. A hexane (15 mL) / ethyl acetate (45 mL) mixture was added to the reaction mixture, and the mixture was washed twice with water (40 mL), twice with saturated aqueous sodium bicarbonate (40 mL), and once with saturated aqueous sodium chloride (20 mL). The organic layer was dried over magnesium sulfate, and the magnesium sulfate was removed by filtration. The mixture was then concentrated under reduced pressure to give compound 9G-1 (1.71 g, crude yield 115%) as a light brown amorphous solid.

[0486] Compound 9G-2 was synthesized from compound 9G-1 as follows. To a mixture of compound 9G-1 (1.0 eq., 1.71 g, calculated as 1.44 mmol) in THF (10 mL) and water (5 mL) was added lithium hydroxide (6.0 eq., 207 mg, 8.62 mmol) at room temperature, and the mixture was stirred at room temperature for 4 hours. To the reaction mixture, 1N aqueous hydrochloric acid (5.0 mL) was added to adjust the pH to 7. Water (10 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (20 mL). The organic layers were combined and washed once with saturated aqueous sodium chloride (10 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a crude product (1.84 g) as a brown viscous substance. The crude product was purified using a flash silica gel column (normal phase silica gel 20 g, ethyl acetate / methanol = 100 / 0 to 40 / 60) to obtain compound 9G-2 (1.06 g, two-stage yield 102%) as a light brown amorphous substance.

[0487] Compound 9G-3 was synthesized from compound 9G-2 as follows. A mixture of compound 9G-2 (calculated as 1.0 eq., 1.05 mg, 1.44 mmol) in acetonitrile (14.5 mL) / THF (14.5 mL) was added dropwise at room temperature to a solution of HATU (2.0 eq., 1.10 g, 2.88 mmol), HOAt (2.0 eq., 391 mg, 2.87 mmol), and DIPEA (2.0 eq., 0.49 mL, 2.89 mmol) in acetonitrile (718 mL) at approximately 100 μL / min over 5 hours, followed by stirring at room temperature for 15.5 hours. The reaction mixture was concentrated under reduced pressure to approximately 250 mL, and then ethyl acetate (200 mL) was added. The mixture was washed twice with a mixture of water (50 mL) / saturated aqueous ammonium chloride (100 mL), twice with saturated aqueous sodium bicarbonate (100 mL), and once with saturated aqueous sodium chloride (50 mL). The organic layer was dried over magnesium sulfate, filtered off, and concentrated under reduced pressure to give a crude product (1.92 g) as a reddish-brown viscous substance. The crude product was purified using a flash silica gel column (normal phase silica gel 25 g, hexane / ethyl acetate = 80 / 20 to 50 / 50) to give compound 9G-3 (231 mg, three-step yield 23%) as a white amorphous substance.

[0488] Compound 9G-4 was synthesized from compound 9G-3 as follows. To a solution of compound 9G-3 (1.0 eq., 230 mg, 0.324 mmol) in THF (3.2 mL) was added TBAF (1 M in THF, 2.5 eq., 0.81 mL, 0.810 mmol) at room temperature, and the mixture was stirred at the same temperature for 2 hours. Ethyl acetate (30 mL) was added to the reaction mixture, which was then washed three times with saturated aqueous ammonium chloride (20 mL) and once with saturated aqueous sodium chloride (10 mL), and then dried over magnesium sulfate. The magnesium sulfate was removed by filtration and the mixture was concentrated under reduced pressure to give a crude product (214 mg) as a pale yellow amorphous substance. The crude product was purified using a flash silica gel column (normal phase silica gel 5 g, hexane / ethyl acetate = 50 / 50 to 0 / 100) to give compound 9G-4 (191 mg, yield 99%) as a white amorphous substance.

[0489] Compound 9G-5 was synthesized from compound 9G-4 as follows. Under a nitrogen atmosphere, Dess-Martin periodinane (1.5 eq., 203 mg, 0.477 mmol) was added to a solution of compound 9G-4 (1.0 eq., 189 mg, 0.318 mmol) in dichloromethane (3 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was quenched by adding a mixture of 10% aqueous sodium sulfite (10 mL) and saturated aqueous sodium bicarbonate (10 mL). The mixture was extracted once with dichloromethane (20 mL) and twice with dichloromethane (10 mL). The organic layers were combined and washed once with saturated aqueous sodium chloride (10 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to give the aldehyde (187 mg, quant.) as a white amorphous substance.

[0490] To a mixture of aldehyde (1.0 eq., 186 mg, 0.314 mmol) in amylene (1 mL) and t-butyl alcohol (4 mL) was added a solution of sodium dihydrogen phosphate dihydrate (3.4 eq., 167 mg, 1.07 mmol) and 80% sodium chlorite (4.5 eq., 160 mg, 1.42 mmol) in water (1 mL) at room temperature, followed by stirring at the same temperature for 1 hour. Saturated aqueous ammonium chloride solution (10 mL) was added to the reaction mixture, and the mixture was extracted once with ethyl acetate (20 mL) and twice with ethyl acetate (10 mL). The combined organic layers were washed once with saturated aqueous sodium chloride solution (20 mL), dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (215 mg, yield 99%) as a white amorphous substance. The crude product was purified with a flash silica gel column (normal phase silica gel 5 g, hexane / ethyl acetate=33 / 67) to obtain compound 9G-5 (178 mg, yield 93%) as a white amorphous substance.

[0491] Compound 9G-6 was synthesized from compound 9G-5 as follows. To a mixture of compound 9G-5 (1.0 eq., 177 mg, 0.291 mmol) in ethyl acetate (1.8 mL) and water (540 μL) was added Fragment D-14 (1.5 eq., 164 mg, 0.435 mmol) at room temperature. DIPEA (2.4 eq., 0.12 mL, 0.706 mmol) was added under ice cooling and stirred for 10 minutes. DMT-MM (1.7 eq., 138 mg, 0.497 mmol) was then added and stirred at the same temperature for 2.5 hours. Ethyl acetate (30 mL) was added to the reaction mixture, which was then washed once with water (15 mL), once with a mixture of water (10 mL) and saturated aqueous ammonium chloride (10 mL), once with water (10 mL) and saturated aqueous sodium bicarbonate (10 mL), and once with saturated aqueous sodium chloride (10 mL). The organic layer was dried over magnesium sulfate, filtered off, and concentrated under reduced pressure to give a crude product (360 mg) as a yellow oil. The crude product was purified twice with a flash silica gel column (first time: NH ２ The first run: 6 g of silica gel, hexane / ethyl acetate=75 / 25 to 67 / 33, and the second run: 4 g of normal phase silica gel, hexane / ethyl acetate=50 / 50) gave compound 9G-6 (235 mg, yield 83%) as a white amorphous substance.

[0492] Compound 9G-7 was synthesized from compound 9G-6 as follows. To a solution of compound 9G-6 (1.0 eq., 235 mg, 0.243 mmol) in dichloromethane (2.4 mL) was added TFA (9.7 eq., 0.18 mL, 2.35 mmol) at room temperature, and the mixture was stirred at the same temperature for 1 hour. Subsequently, TFA (9.7 eq., 0.18 mL, 2.35 mmol) was added, and the mixture was stirred at the same temperature for 7 hours. The reaction solution was ice-cooled, and saturated aqueous sodium bicarbonate solution (15 mL) was added to adjust the pH to 8. The reaction solution was extracted once with ethyl acetate (20 mL) and twice with ethyl acetate (10 mL), and then the organic layers were combined and washed once with saturated aqueous sodium chloride solution (20 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain compound 9G-7 (210 mg, yield 99%) as a pale yellow amorphous substance.

[0493] The synthesis of compound 9G from compound 9G-7 was carried out as follows. Under a nitrogen atmosphere, TFA (5.0 eq., 83 μL, 1.085 mmol) was added to a mixture of compound 9G-7 (1.0 eq., 186 mg, 0.218 mmol) in THF (7.4 mL) and water (370 μL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. 10% palladium-carbon (N.E. Chemcat NX type, 50% water content, 18.6 mg) was added, and the system was purged with hydrogen, followed by stirring at the same temperature for 6.5 hours. The catalyst was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude product (171 mg). The crude product (40 mg) obtained from compound 9G-7 (40 mg) by the same procedure was combined with the above crude product and purified using a flash silica gel column (30 g of reverse-phase silica gel, 0.05% aqueous TFA solution / acetonitrile = 95 / 5 to 55 / 45). Lyophilization gave the TFA salt of compound 9G (107 mg, yield 51%, purity 96.4%) as a white solid.

[0494] １ H-NMR (400MHz, DMSO-d6) δ9.11 (s, 1H), 8.79 (d, J = 8.8Hz, 1H), 8.62 (d, J = 7.6Hz, 1H), 7.87 (d, J = 10.0Hz, 1H), 6. 80-6.75 (m, 3H), 4.87 (d, J = 10.0Hz, 1H), 4.57 (dd, J = 13.6, 7.2Hz, 1H), 4.23 (dd, J = 9.2, 9.2Hz, 1H), 4.05-3.85 (m , 3H), 3.05-2.95 (m, 1H), 2.89 (dd, J = 14.4, 5.6Hz, 1H), 2.73 (dd, J = 16.8, 6.0Hz, 1H), 2.60-2.50 (m, 1H), 2.10-1 94 (m, 1H), 1.87-1.61 (m, 2H), 1.59-1.45 (m, 2H), 1.36-1.15 (m, 17H), 1.01 (t, J=7.2Hz, 3H), 0.92-0.74 (m, 9H).

[0495] Example 10: Synthesis of Compound 10 ​Under a nitrogen atmosphere, DIPEA (1.5 eq., 40 μL, 0.235 mmol) and HATU (1.5 eq., 90 mg, 0.237 mmol) were added to a dichloromethane (2.4 mL) solution of compound 2-13 (1.0 eq., 95 mg, contains isomers, 0.158 mmol) and L-aspartic acid dibenzyl ester hydrochloride (Fragment D-2, 1.5 eq., 83 mg, 0.237 mmol) under ice-cooling, and the mixture was stirred for 3 hours while warming to room temperature. After washing once with 5% aqueous citric acid (3 mL), the organic layer was washed once with 5% aqueous sodium bicarbonate (3 mL) and once with 5% aqueous sodium chloride (3 mL), and then dried over sodium sulfate. After filtering off the sodium sulfate, the mixture was concentrated under reduced pressure. The crude product (197 mg) obtained as a pale brown viscous substance was purified twice with a flash silica gel column (first: normal phase silica gel 10 g, hexane / ethyl acetate = 40 / 60, second: NH ２ Silica gel 6.5 g, hexane / ethyl acetate=40 / 60 to 0 / 100) to obtain Compound 10-1 (54 mg, containing 5.0 wt % hexane, calculated yield 36%) as a white solid.

[0496] Under a nitrogen atmosphere, 10% palladium-carbon (N.E. Chemcat NX type, 50% water content, 2.6 mg) and TFA (2.0 eq., 8.4 μL, 0.110 mmol) were added to a THF (2.5 mL) / water (2.5 mL) mixture of compound 10-1 (1.0 eq., 52 mg, containing 5.0 wt % hexane, 0.055 mmol) at room temperature. The system was purged with hydrogen and then stirred at the same temperature for 25 hours. THF (2.5 mL) was added, and the mixture was stirred for an additional 64 hours. 10% palladium-carbon (N.E. Chemcat NX type, 50% water content, 2.6 mg) was added, and the mixture was stirred for 24 hours. The catalyst was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure to give a crude product (41 mg) as a pale orange viscous substance. The crude product was purified by flash silica gel column (30 g of reversed-phase silica gel, 0.05% aqueous TFA solution / acetonitrile=95 / 5) and then lyophilized to obtain the TFA salt of compound 10 (18.3 mg, yield 54%, purity 99.3%) as a white solid. １ H-NMR (400MHz, D ２O) δ7.44 (s, 1H), 7.05 (dd, J=8.0, 2.0Hz, 1H), 6.98 (d, J=8.0Hz, 1H), 4.65 (s, 1H), 4.25 (d, J=16.4Hz, 1H), 3.99 (dd, J=10.4, 4.0Hz, 1H), 3.55 (d, J=1 6.4Hz, 1H), 3.26 (dd, J=13.2, 4.0Hz, 1H), 3.08-2.99 (m, 1H), 2.73 (s, 3H), 2.03-1.97 (m, 1H), 1.78-1.70 (m, 1H), 1.63 (s, 3H), 0.86 (t, J=7.2Hz, 3H).

[0497] Example 11: Synthesis of Compound 5 Under a nitrogen atmosphere, triphenylphosphine (1.5 eq., 1.99 g, 7.59 mmol) and DIAD (1.5 eq., 1.63 mL, 7.58 mmol) were added to a toluene (28 mL) solution of Fragment A-2 (1.0 eq., 2.81 g, 5.06 mmol) and Fragment B-2 (1.5 eq., 2.74 g, 7.58 mmol) at room temperature, and the mixture was stirred at the same temperature for 15 minutes and at an external temperature of 75 ° C. for 2 hours. Triphenylphosphine (0.75 eq., 0.99 g, 3.77 mmol) and DIAD (1.5 eq., 0.81 mL, 3.77 mmol) were added and the mixture was stirred for an additional 0.5 hours. The reaction mixture was allowed to cool and then concentrated under reduced pressure. The concentrated residue was purified with a flash silica gel column (normal phase silica gel 50 g, hexane / ethyl acetate=90 / 10 to 67 / 33) to obtain Compound 5-1 (5.95 g, containing impurities, apparent yield 130%) as a pale yellow-brown oil.

[0498] Under a nitrogen atmosphere, 1 M aqueous hydrochloric acid solution (1.1 eq., 5.00 mL, 5.00 mmol) was added to a solution of compound 5-1 (1.0 eq., 5.35 g, containing impurities, calculated as 4.55 mmol) in acetonitrile (45 mL) under ice-cooling, and the mixture was stirred for 2 hours while warming to room temperature. A few drops of saturated aqueous sodium bicarbonate solution were added to the reaction solution to adjust the pH to 5-7, and the mixture was then concentrated under reduced pressure. A saturated aqueous sodium bicarbonate solution (20 mL) was added to the concentrated residue, and the mixture was extracted three times with ethyl acetate (25 mL). The organic layers were combined, washed once with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered off the sodium sulfate, and concentrated under reduced pressure to obtain a crude product (5.42 g) as a pale yellow-brown oil. The crude product was purified by flash silica gel column (normal phase silica gel 50 g, chloroform / acetonitrile=90 / 10 to 80 / 20) to obtain Compound 5-2 (1.59 g, containing impurities, apparent yield 75%) as a pale yellow oil.

[0499] Under a nitrogen atmosphere, a solution of compound 5-2 (1.0 eq., 0.80 g, containing impurities, calculated as 1.22 mmol) in DMF (12 mL) was treated with N-Boc-L-valine (Fragment C-1′, 2.0 eq., 528 mg, 2.43 mmol), EDCI (2.0 eq., 466 mg, 2.43 mmol), and HOBt.H ２ 0 (2.0 eq., 372 mg, 2.43 mmol) was added and stirred at room temperature for 20 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (25 mL). The organic layers were combined and washed once with saturated aqueous sodium bicarbonate (25 mL) and once with saturated aqueous sodium chloride (25 mL), followed by drying over sodium sulfate. The sodium sulfate was filtered off and the mixture was concentrated under reduced pressure to give a crude product (1.50 g) as a pale yellow oil. The crude product was purified twice using flash silica gel columns (first: 50 g of normal-phase silica gel, hexane / ethyl acetate = 90 / 10 to 50 / 50; second: 120 g of reverse-phase silica gel, 0.05% aqueous TFA / acetonitrile = 90 / 10 to 0 / 100) to give compound 5-3 (0.74 g, 38% yield for three steps from Fragment A-2) as a white amorphous substance.

[0500] Under a nitrogen atmosphere, triethylsilane (25 eq., 3.35 mL, 21.03 mmol) and TFA (3.75 mL) were added to a solution of compound 5-3 (1.0 eq., 0.74 g, 0.87 mmol) in dichloromethane (7.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and a 0.05 M hydrogen chloride / 1,4-dioxane solution (20 mL) was added to the concentrated residue, followed by concentration under reduced pressure, which was repeated twice. 1,4-dioxane was added to the concentrated residue, followed by concentration under reduced pressure, which was repeated three times, to obtain compound 5-4 (1.39 g) as a colorless oil.

[0501] Under a nitrogen atmosphere, EDCI (5.0 eq., 830 mg, 4.33 mmol), HOBt.H ２ A DMF (65 mL) solution of compound 5-4 (calculated as 1.0 eq., 1.39 g, 0.865 mmol) was added to a DMF (800 mL) solution of 5-4 (5.0 eq., 663 mg, 7.33 mmol) and sodium bicarbonate (10.0 eq., 726 mg, 8.64 mmol) at room temperature over 2 hours. After the dropwise addition was complete, the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the concentrated residue was extracted once with ethyl acetate (20 mL) and water (20 mL). The organic layer was washed once with saturated aqueous sodium chloride solution (10 mL) and then dried over sodium sulfate. The sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure to give a crude product (0.71 g) as an ochre solid. The crude product was purified by flash silica gel column (normal phase silica gel 25 g, chloroform / ethyl acetate=90 / 10 to 80 / 20) to obtain compound 5-5 (226 mg, containing impurities, apparent yield for two steps from compound 5-3: 42%) as a white solid.

[0502] Under a nitrogen atmosphere, trimethyltin hydroxide (4.0 eq., 159 mg, 0.88 mmol) was added to a solution of compound 5-5 (1.0 eq., 138 mg, calculated as containing impurities, 0.22 mmol) in 1,2-dichloroethane (3.45 mL), and the mixture was stirred at an external temperature of 80°C for 4 hours. The reaction mixture was allowed to cool, and ethyl acetate (20 mL) and 1 M aqueous hydrochloric acid solution (20 mL) were added for one liquid-liquid extraction. The organic layer was washed once with a 10% aqueous sodium chloride solution (20 mL), dried over sodium sulfate, and then the sodium sulfate was filtered off. The sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a crude product (169 mg) as a white solid.

[0503] A crude product (20 mg) was obtained from compound 5-5 (20 mg) by the same procedure. This crude product was combined with the previous crude product and purified with a flash silica gel column (normal phase silica gel 10 g, ethyl acetate / methanol = 100 / 0 to 90 / 10) to obtain compound 5-6 (147 mg, containing impurities, apparent yield 93%).

[0504] Under a nitrogen atmosphere, a solution of compound 5-6 (1.0 eq., 73 mg, containing impurities, 0.12 mmol) and L-glutamic acid dibenzyl ester hydrochloride (Fragment D-1, 1.5 eq., 65 mg, 0.18 mmol) in DMF (0.73 mL) was added with EDCI (1.5 eq., 34 mg, 0.18 mmol), HOBt.H ２ O (1.5 eq., 27 mg, 0.18 mmol) and sodium hydrogen carbonate (3.0 eq., 30 mg, 0.36 mmol) were added, and the mixture was stirred at the same temperature for 1.5 hours.

[0505] Toluene (3 mL) was added to the reaction mixture, and the mixture was washed twice with 5% aqueous sodium bicarbonate (3 mL) and once with 5% aqueous sodium chloride (3 mL). The organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and then concentrated under reduced pressure to obtain a crude product (115 mg) as a pale yellow solid. The crude product was purified using a flash silica gel column (NH ２The mixture was purified by filtration (silica gel 6.5 g, hexane / ethyl acetate = 90 / 10 to 50 / 50) to obtain a white solid (52 mg). To this solid, hexane (4 mL) and toluene (2 mL) were added, and the mixture was irradiated with ultrasound and stirred at room temperature for 15 minutes. The suspension was filtered to obtain compound 5-7 (37 mg, yield 34%) as a white solid.

[0506] Under a nitrogen atmosphere, 10% palladium-carbon (N.E. Chemcat NX type, 50% water content, 8.8 mg) was added to a THF (1.2 mL) / water (1.2 mL) mixture of compound 5-7 (1.0 eq., 35 mg, 0.038 mmol) at room temperature. The system was purged with hydrogen and then stirred at the same temperature for 22 hours. The catalyst was removed by filtration through Celite, and the solid was washed with 0.05% TFA aqueous solution. The filtrate was concentrated under reduced pressure to give a crude product (20 mg) as a white solid. The crude product was purified twice with a flash silica gel column (60 g of reversed-phase silica gel, first run: 0.05% aqueous TFA solution / acetonitrile = 99 / 1 to 90 / 10, second run: 0.05% aqueous TFA solution / acetonitrile = 99 / 1 to 0 / 100) and lyophilized to obtain the TFA salt of compound 5 (14 mg, yield 59%, purity 99.7%) as a white solid.

[0507] １ H-NMR (400MHz, D ２ O) δ6.89 (d, J=8.0Hz, 1H), 6.81 (dd, J=8.0, 2.0Hz, 1H), 6.70 (d, J=2.0Hz, 1H), 4.65 (dd, J=13. 2, 2.4Hz, 1H), 4.56 (dd, J = 13.2, 6.0Hz, 1H), 4.37 (dd, J = 8.8, 4.8Hz, 1H), 4.11 (d, J = 10.8Hz, 1H ), 3.95 (dd, J=8.8, 4.8Hz, 1H), 3.21 (dd, J=13.2, 4.8Hz, 1H), 2.95 (dd, J=13.2, 8.8Hz, 1H), 2. 70 (s, 3H), 2.45 (t, J=7.2Hz, 2H), 2.24-2.15 (m, 1H), 2.03-1.85 (m, 2H), 0.84 (t, J=6.8Hz, 6H).

[0508] Example 12: Synthesis of Compound 3 ​Under a nitrogen atmosphere, a solution of compound 5-2 (1.0 eq., 0.79 g, containing impurities, calculated as 1.20 mmol) in DMF (12 mL) was added with N-Boc-L-glycine (Fragment C-3′, 2.0 eq., 0.42 g, 2.40 mmol), EDCI (2.0 eq., 0.46 mg, 2.40 mmol), and HOBt.H ２ O (2.0 eq., 0.37 mg, 2.40 mmol) was added and stirred at room temperature for 2 hours. Water (30 mL) and toluene (30 mL) were added to the reaction mixture and extracted once. The organic layer was washed once with water (30 mL) and once with a 10% aqueous sodium chloride solution (30 mL), and then dried over sodium sulfate. The sodium sulfate was filtered off and the mixture was concentrated under reduced pressure to obtain a crude product (1.175 g) as a yellow viscous substance. The crude product was purified by flash silica gel column (NH ２ Silica gel 14 g, hexane / ethyl acetate=90 / 10 to 0 / 100) to obtain Compound 3-1 (0.87 g, containing 3.2 wt % ethyl acetate, calculated yield 86%) as a pale yellow viscous substance.

[0509] Under a nitrogen atmosphere, triethylsilane (25 eq., 3.01 g, 25.89 mmol) and TFA (4.35 mL) were added to a solution of compound 3-1 (1.0 eq., 0.87 g, containing 3.2 wt % ethyl acetate, 1.03 mmol) in dichloromethane (8.7 mL) under ice-cooling, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and a 0.05 M hydrogen chloride / 1,4-dioxane solution (15 mL) was added to the concentrated residue, followed by further concentration under reduced pressure to obtain compound 3-2 (1.196 g, containing 1,4-dioxane) as a colorless viscous substance.

[0510] Under a nitrogen atmosphere, a DMF (8 mL) solution of compound 3-2 (1.0 eq., 0.83 g, calculated as 1,4-dioxane, 0.72 mmol) was added to a DMF (704 mL) solution of HATU (5.0 eq., 1.36 g, 3.58 mmol) and DIPEA (10.0 eq., 0.92 g, 7.12 mmol) at room temperature over 18.5 hours. After the dropwise addition was completed, the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the concentrated residue was extracted once with ethyl acetate (15 mL) and 5% aqueous citric acid (15 mL). The organic layer was washed once with 5% aqueous sodium bicarbonate (15 mL) and once with 5% aqueous sodium chloride (15 mL), and then dried over sodium sulfate. The sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain a crude product (0.81 g) as a light brown amorphous substance. The crude product was purified using a flash silica gel column (NH ２ Compound 3-3 (190 mg, yield 46%) was obtained as a white solid. Compound 3-3 (89 mg) obtained by the same procedure as this was combined and purified with a flash silica gel column (NH ２ The resulting mixture was filtered (silica gel 14 g, hexane / ethyl acetate = 50 / 50), and the fractions containing the target compound were combined and concentrated under reduced pressure. The concentrated residue was dissolved in 1,2-dichloroethane (3 mL) and concentrated under reduced pressure twice to obtain compound 3-3 (118 mg, 16.5 wt % 1,2-dichloroethane content, 35% yield) as a colorless viscous substance.

[0511] Under a nitrogen atmosphere, trimethyltin hydroxide (4.0 eq., 124 mg, 0.69 mmol) was added to a solution of compound 3-3 (1.0 eq., 118 mg, containing 16.5 wt % 1,2-dichloroethane, 0.17 mmol) in 1,2-dichloroethane (2.7 mL), and the mixture was stirred at an external temperature of 80°C for 3.5 hours. After allowing the reaction solution to cool, ethyl acetate (20 mL) and 1 M aqueous hydrochloric acid (20 mL) were added and extracted once. The organic layer was washed once with a 5% aqueous sodium chloride solution (20 mL), dried over sodium sulfate, and the sodium sulfate was filtered off. After filtering off the sodium sulfate, the mixture was concentrated under reduced pressure to obtain compound 3-4 (104 mg, containing impurities, quant.) as a white solid.

[0512] Under a nitrogen atmosphere, a solution of compound 3-4 (1.0 eq., 50 mg, containing impurities, calculated as 0.082 mmol) and L-glutamic acid dibenzyl ester hydrochloride (Fragment D-1, 1.5 eq., 45 mg, 0.124 mmol) in DMF (0.5 mL) was added with EDCI (1.5 eq., 24 mg, 0.125 mmol), HOBt.H ２ O (1.5 eq., 19 mg, 0.124 mmol) and sodium bicarbonate (1.5 eq., 10 mg, 0.119 mmol) were added, and the mixture was stirred at the same temperature for 1.5 hours. Toluene (10 mL) and 5% aqueous citric acid (10 mL) were added to the reaction mixture, followed by extraction and separation. The organic layer was washed once with 5% aqueous sodium bicarbonate (10 mL) and once with 5% aqueous sodium chloride (10 mL). The organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and then concentrated under reduced pressure to give a crude product (82 mg) as a pale yellow viscous material.

[0513] A crude product (60 mg) was obtained from Compound 3-4 (1.0 eq., 50 mg) by the same procedure. After combining with the previous crude product, it was purified by flash silica gel column (NH ２ Silica gel 6.5 g, hexane / ethyl acetate=40 / 60) to obtain compound 3-5 (69 mg, ...

Claims

1. The following formula (1) or a pharmaceutically acceptable salt, solvate or prodrug thereof. １ , R ２ , R ５ , R ６ , R ７ , R ８ , R ９ and R １０ are each independently a hydrogen atom or an optionally substituted hydrocarbon group, or ７ and R ８ But, R ７ and R ８ together with the carbon atom and nitrogen atom to which R is attached form an optionally substituted heterocycloalkyl group; ３ and R ４ are each independently a hydrogen atom, an optionally substituted hydrocarbon group, a carboxyl group, an optionally substituted alkoxycarbonyl group, or an optionally substituted alkoxycarbonyloxy group; R １１ , R １２ , R １３ , and R １４ are each independently a hydrogen atom, an optionally substituted hydrocarbon group, a hydroxy group, an optionally substituted alkoxy group, or an optionally substituted alkoxycarbonyloxy group, and X is CH ２ or CO, and A is O, NH, or S, where NH can be optionally substituted.

2. The following formula (1) or a pharmaceutically acceptable salt, solvate or prodrug thereof. １ , R ２ , R ５ , R ６ , R ７ , R ８ , R ９ and R １０ are each independently a hydrogen atom or an optionally substituted hydrocarbon group, or ７ and R ８ But, R ７ and R ８ together with the carbon atom and nitrogen atom to which R is attached form an optionally substituted heterocycloalkyl group; ３ and R ４ are each independently a hydrogen atom, an optionally substituted hydrocarbon group, a carboxyl group, an optionally substituted alkoxycarbonyl group, or an optionally substituted alkoxycarbonyloxy group; R １１ , R １２ , R １３ , and R １４ are each independently a hydrogen atom, an optionally substituted hydrocarbon group, a hydroxy group, an optionally substituted alkoxy group, or an optionally substituted alkoxycarbonyloxy group, and X is CH ２ or CO, and A is O, NH, or S, where NH can be optionally substituted.

3. The composition of claim 1, wherein the brain function is a cognitive function.

4. The composition according to claim 2 or 3, wherein the cognitive function is memory.

5. The composition according to claim 2 or 3, wherein the cognitive function is learning and memory.

6. The composition according to claim 5, wherein the disease associated with cognitive decline is Alzheimer's disease, vascular dementia, dementia with Lewy bodies, or frontotemporal dementia.

7. R １ and R ２ are each independently a hydrogen atom or C １－６ The composition of any one of claims 1 to 6, wherein the group is an alkyl group.

8. R １ and R ２ The composition of claim 1 , wherein each independently represents a hydrogen atom, a methyl group, or an ethyl group.

9. R ３ and R ４ are each independently a hydrogen atom, a C substituted with a carboxyl group, １－６ The composition of claim 1 , wherein the alkyl group is an alkyl group or a carboxyl group.

10. R ３ and R ４ The composition of claim 1 , wherein each independently represents a hydrogen atom, a carboxymethyl group, a carboxyethyl group, a carboxypropyl group, or a carboxyl group.

11. R ５ is a hydrogen atom, or C １－６ The composition of claim 1 , wherein the group is an alkyl group.

12. R ５ The composition of claim 1 , wherein is a hydrogen atom.

13. R ６ is a hydrogen atom, or C １－６ The composition of any one of claims 1 to 12, wherein the group is an alkyl group.

14. R ６ The composition of claim 1 , wherein is a hydrogen atom.

15. R ７ is a hydrogen atom, C １－６ Alkyl group, hydroxy C １－６ Alkyl group, carbamoyl C １－６ Alkyl group, C ６－１０ Aryl C １－６ Alkyl group, hydroxy C ６－１０ Aryl C １－６ Alkyl group, C ５－１０ Heteroaryl C １－６ Alkyl group, carboxy C １－６ Alkyl group, amino C １－６ Alkyl group, thio C １－６ Alkyl group, C １－６ Alkylthio C １－６ Alkyl group, or amidinoamino C １－６ 15. The composition of claim 1, wherein the group is an alkyl group.

16. R ７ is a hydrogen atom, a methyl group, an isopropyl group, an isobutyl group, a secbutyl group, a benzyl group, a hydroxymethyl group, a 1-hydroxyethyl group, a carboxymethyl group, a carboxyethyl group, a 4-hydroxybenzyl group, a 4-aminobutyl group, a thiomethyl group, a 2-methylthioethyl group, a carbamoylmethyl group, a carbamoylethyl group, an amidinoaminopropyl group, an indolylmethyl group, or a 4-imidazolemethyl group.

17. R ８ is a hydrogen atom, or C １－６ 17. The composition of claim 1, wherein the group is an alkyl group.

18. R ８ The composition of claim 1 , wherein is a hydrogen atom.

19. R ７ and R ８ is R ７ and R ８ The composition of claim 1 , wherein together with the carbon atom and nitrogen atom to which it is attached form an optionally substituted heterocycloalkyl group.

20. R ７ and R ８ is R ７ and R ８ together with the carbon atom and nitrogen atom to which it is bonded, C ５－１０ 20. The composition of any one of claims 1 to 19, wherein the composition forms a heterocycloalkyl group.

21. R ９ and R １０ are each independently a hydrogen atom or C １－６ 21. The composition of any one of claims 1 to 20, wherein the group is an alkyl group.

22. R ９ and R １０ The composition of claim 1 , wherein each independently is a hydrogen atom or a methyl group.

23. R １１ , R １２ , R １３ , and R １４ The composition of claim 1 , wherein each independently is a hydrogen atom, an alkoxy group, or a hydroxy group.

24. R １２ The composition of claim 1 , wherein is a hydrogen atom, an alkoxy group, or a hydroxy group.

25. R １１ , R １２ , R １３ , and R １４ The composition of claim 1 , wherein each independently is a hydrogen atom, a methoxy group, or a hydroxy group.

26. R １２ The composition of claim 1 , wherein is a hydrogen atom, a methoxy group, or a hydroxy group.

27. X is CH ２ 27. The composition of any one of claims 1 to 26, wherein 28. A is O, C １－６ 28. The composition of any one of claims 1 to 27, wherein NH, NH, or S is substituted with an alkyl group.

29. The composition of any one of claims 1 to 28, wherein A is O, NH, or S.

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