Cyclic peptide derivative, method for producing same, and composition

Abstract

The present disclosure provides cyclic peptide derivatives and methods of making and compositions thereof. The present disclosure relates to compounds directed against modulation of nervous system cell activity. More specifically, the compounds of the present disclosure can modulate the proliferative activity of astrocytes. The compound of the present disclosure has an effect of improving the proliferative activity of astrocytes. The technology provided by the present disclosure can be used in a cyclic peptide derivative for modulating the activity of nervous system cells and a method for producing the same.

Description

Technical Field

[0001] The present disclosure relates to cyclic peptide derivatives and methods and compositions for making the same. Background Art

[0002] Astrocytes, a type of glial cell, account for approximately half of all brain cells. Historically, astrocytes, which exist around neurons, have been known to support, protect, and provide nutrition to neurons, given their role in information processing. Summary of the Invention

[0003] Means for solving problems

[0004] The present disclosure provides cyclic peptide derivatives and methods and compositions for making the same.

[0005] The present inventors conducted in-depth research and found that the compounds represented by the following formula and its related structural formula, or their pharmaceutically acceptable salts (hereinafter sometimes also referred to as "the compounds of the disclosure" or "the compound(s) of the disclosure") have significant proliferative activity on astrocytes, thereby completing the technical matters of the present disclosure.

[0006] That is, the present disclosure is as follows.

[0007] (Item 1)

[0008] A compound represented by the following formula (1) or a pharmaceutically acceptable salt, solvate or prodrug thereof,

[0009] [Chemistry 1]

[0010]

[0011] Where,

[0012] R1, R2, R5, R6, R7, R8, R9 and R 10 Each independently is:

[0013] hydrogen atoms, or

[0014] an optionally substituted hydrocarbon group, or

[0015] R7 and R8 together with the carbon atom and the nitrogen atom to which R7 and R8 are bonded form an optionally substituted heterocycloalkyl group,

[0016] R3 and R4 are each independently:

[0017] A hydrogen atom, an optionally substituted hydrocarbon group, a carboxyl group,

[0018] optionally substituted alkoxycarbonyl, or

[0019] optionally substituted alkoxycarbonyloxy,

[0020] R 11 、R 12 、R 13 and R 14 Each independently is:

[0021] a hydrogen atom, an optionally substituted hydrocarbon group, a hydroxyl group,

[0022] optionally substituted alkoxy, or

[0023] optionally substituted alkoxycarbonyloxy,

[0024] X is:

[0025] CH2 or CO,

[0026] A is O, NH or S, wherein NH may be optionally substituted.

[0027] (Item 2)

[0028] The compound according to the above item or its pharmaceutically acceptable salt, solvate or prodrug, wherein R1 and R2 are each independently a hydrogen atom or C 1-6 alkyl.

[0029] (Item 3)

[0030] The compound according to any one of the above items, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R1 and R2 are each independently a hydrogen atom, a methyl group or an ethyl group.

[0031] (Item 4)

[0032] The compound according to any one of the above items, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R3 and R4 are each independently a hydrogen atom, a C substituted by a carboxyl group, 1-6 Alkyl or carboxyl.

[0033] (Item 5)

[0034] The compound according to any one of the above items, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R3 and R4 are each independently a hydrogen atom, a carboxymethyl group, a carboxyethyl group, a carboxypropyl group or a carboxyl group.

[0035] (Item 6)

[0036] The compound according to any one of the above items, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R5 is a hydrogen atom or C 1-6 alkyl.

[0037] (Item 7)

[0038] The compound according to any one of the above items, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R5 is a hydrogen atom.

[0039] (Item 8)

[0040] The compound according to any one of the above items, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R6 is a hydrogen atom or C 1-6 alkyl.

[0041] (Item 9)

[0042] The compound according to any one of the above items, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R6 is a hydrogen atom.

[0043] (Item 10)

[0044] The compound according to any one of the above items, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R7 is a hydrogen atom, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, carbamoyl C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl, hydroxyl C 6-10 Aryl C 1-6 Alkyl, C 5-10 Heteroaryl C 1-6 Alkyl, carboxyl C 1-6 Alkyl, amino C 1-6 Alkyl, thio C 1-6 Alkyl, C 1-6 Alkylthio C 1-6 Alkyl, or amidinoamino C 1-6 alkyl.

[0045] (Item 11)

[0046] The compound according to any one of the above items, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R7 is a hydrogen atom, a methyl group, an isopropyl group, an isobutyl group, a sec-butyl 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, an aminoethyl group, a thiomethyl group, a 2-methylthioethyl group, a carbamoylmethyl group, a carbamoylethyl group, an amidinoaminopropyl group, an indolylmethyl group or a 4-imidazolylmethyl group.

[0047] (Item 12)

[0048] The compound according to any one of the above items, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R8 is a hydrogen atom or C1-6 alkyl.

[0049] (Item 13)

[0050] The compound according to any one of the above items, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R8 is a hydrogen atom.

[0051] (Item 14)

[0052] The compound according to any one of the above items, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R7 and R8, together with the carbon atom and nitrogen atom to which R7 and R8 are bonded, form an optionally substituted heterocycloalkyl group.

[0053] (Item 15)

[0054] The compound according to any one of the above items, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R7 and R8 together with the carbon atom and nitrogen atom to which R7 and R8 are bonded form C 5-10 Heterocycloalkyl.

[0055] (Item 16)

[0056] The compound according to any one of the above items or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R9 and R 10 A hydrogen atom or C 1-6 alkyl.

[0057] (Item 17)

[0058] The compound according to any one of the above items or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R9 and R 10 are each independently a hydrogen atom or a methyl group.

[0059] (Item 18)

[0060] The compound according to any one of the above items, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R 11 、R 12 、R 13 and R 14 Each is independently a hydrogen atom, an alkoxy group or a hydroxyl group.

[0061] (Item 19)

[0062] The compound according to any one of the above items, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R 12 is a hydrogen atom or a hydroxyl group.

[0063] (Item 20)

[0064] The compound according to any one of the above items, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R 11 、R 12 、R 13 and R 14 are each independently a hydrogen atom or a hydroxyl group.

[0065] (Item 21)

[0066] The compound according to any one of the above items, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein X is CH2 or CO.

[0067] (Item 22)

[0068] The compound according to any one of the above items, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein A is O, C 1-6 NH, NH or S substituted with an alkyl group.

[0069] (Item 23)

[0070] The compound according to any one of the above items, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein A is O, NH or S.

[0071] (Item 24)

[0072] A pharmaceutical composition comprising the compound according to any one of the above items or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0073] (Item 25)

[0074] A nervous system cell activity regulator comprising the compound described in any one of the above items or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0075] (Item 26)

[0076] The regulator according to any one of the above items, wherein the nervous system cells are glial cells.

[0077] (Item 27)

[0078] The compound according to any one of the above items or a pharmaceutically acceptable salt, solvate or prodrug thereof, for use in regulating the activity of nervous system cells.

[0079] (Item 28)

[0080] A method for regulating the activity of nervous system cells, comprising administering to a subject an effective amount of the compound described in any one of the above items or a pharmaceutically acceptable salt, solvate or prodrug, preparation, or composition thereof.

[0081] (Item 29)

[0082] Use of the compound according to any one of the above items or a pharmaceutically acceptable salt, solvate or prodrug thereof, formulation or composition in the manufacture of a medicament for regulating the activity of nervous system cells.

[0083] In the present disclosure, one or more features described above are intended to be provided in further combinations in addition to the combinations explicitly stated. Those skilled in the art will recognize further embodiments and advantages of the present disclosure upon reading and understanding the following detailed description as needed.

[0084] Effects of the Invention

[0085] According to the present disclosure, a novel cyclic peptide derivative useful in terms of having physiologically active functions represented by excellent astrocyte proliferation activity is provided. DETAILED DESCRIPTION

[0086] The present disclosure is described in further detail below.

[0087] Throughout this specification, unless otherwise specified, expressions in the singular should be understood to also include their plural forms. Therefore, it should be understood that, unless otherwise specified, articles in the singular (e.g., "a", "an", "the", etc. in the English case) also include the concept of their plural forms. In addition, it should be understood that, unless otherwise specified, the terms used in this specification are used with the meanings commonly used in the field. Therefore, unless otherwise defined, all technical terms and scientific and technical terms used in this specification have the same meanings as those commonly understood by those skilled in the art in the field to which this disclosure belongs. In the event of a conflict, this specification (including definitions) shall prevail.

[0088] (definition)

[0089] First, terms and general techniques used in this disclosure are explained.

[0090] The compounds of the present disclosure may exist in the form of hydrates and / or solvates. Therefore, the hydrates and / or solvates of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof are also included in the compounds of the present disclosure.

[0091] The compound shown in formula (1) sometimes has 1 or more asymmetric carbon atoms according to the circumstances, and sometimes produces geometric isomerism or axial chirality, and therefore sometimes exists in the form of several stereoisomers. In the present disclosure, these stereoisomers, their mixtures and racemates are also included in the compounds of the present disclosure. Therefore, the compounds recorded in this specification may contain 1 or more asymmetric centers, and therefore can exist in the form of various isomers, such as enantiomers and / or diastereomers. For example, the compounds recorded in this specification may be in the form of a single enantiomer, diastereomer, or geometric isomer, or may be in the form of a mixture of stereoisomers (comprising a racemic mixture and a mixture concentrated from 1 or more stereoisomers). In addition, the present disclosure also includes compounds recorded in this specification as a single isomer that is substantially free of other isomers, and alternatively as a mixture of various isomers.

[0092] In addition, any one or more of the compounds represented by the general formula (1) 1 H is converted to 2 Deuterated forms of H(D) are also included in the compounds represented by the general formula (1).

[0093] The compound represented by the general formula (1) and the pharmaceutically acceptable salt thereof that can be obtained in a crystalline form may have polymorphic forms, and the compounds disclosed herein include all of these crystalline forms.

[0094] Next, the terms used in this specification are explained below.

[0095] In this specification, unless otherwise specified, the term "group" means a monovalent group. Examples of non-monovalent groups include alkylene (divalent) groups. In addition, the term "group" may be omitted in the following descriptions of substituents, etc.

[0096] In this specification, the number of substituents in the cases defined as "optionally substituted," "may be substituted," or "substituted" is not particularly limited, and may be one or more substituents as long as they are capable of substitution. Furthermore, unless otherwise specified, the description of each substituent also applies to the case where the substituent is part of another substituent or a substituent.

[0097] Examples of the substituent in the present disclosure include a hydrogen atom, a hydroxyl group, a carboxyl group, a sulfinic acid group, a sulfonic acid group, a phosphoric acid 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 cycloalkyloxy group, an alkoxycarbonyl group, a cycloalkyloxycarbonyl group, an alkylcarbonyl 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 arylsulfinyl group, a heteroarylsulfonyl group, a heteroarylsulfinyl group, and a triphenylphosphonium cation group. The above-mentioned substituents may be further substituted with the above-mentioned substituents.

[0098] In this specification, the "maximum substitutable number" refers to the maximum number of substituents that a group can have, and may be different for each group. For example, the maximum number of substituents is 3 for a methyl group, 5 for an ethyl group, 7 for a benzyl group, and 11 for a naphthylethyl group.

[0099] In this specification, in a group modified by "optionally substituted," "substitutable," or "substituted," any part of the group may be substituted. For example, "optionally substituted arylalkyl" and "substituted arylalkyl" may mean that the aryl portion is substituted, the alkyl portion is substituted, or both the aryl portion and the alkyl portion are substituted.

[0100] In this specification, examples of substituents in the context of "optionally substituted" or "optionally substituted" include Substituent Group α and Substituent Group β. Substituents in the context of "optionally substituted" or "optionally substituted" may be selected from Substituent Group α and may be substituted by 1 to 5 substituents, the same or different. The type of atoms in a substituent that participate in a bond is not particularly limited by the type of the substituent. When the atom to which the substituent is bonded is an oxygen atom, a nitrogen atom, or a sulfur atom, the atoms to which the substituent is bonded are limited to carbon atoms, as described below.

[0101] Examples of the substituent group α include:

[0102] 1) Halogen atoms

[0103] 2) Hydroxyl

[0104] 3) Carboxyl

[0105] 4) Cyano

[0106] 5) C 1-6 alkyl

[0107] 6) C 2-6 alkenyl

[0108] 7) C 2-6 Alkynyl

[0109] 8) C 1-6 Alkoxy

[0110] 9)C 1-6 Alkylthio

[0111] 10) C 1-6 Alkylcarbonyl

[0112] 11)C 1-6 Alkylsulfonyl

[0113] (wherein, each substituent in 5) to 11) may be substituted by 1 to 5 substituents, the same or different, selected from substituent group β)

[0114] 12)C 3-10 Cycloalkyl

[0115] 13)C 3-10 Cycloalkyloxy

[0116] 14)C 6-10 Aryloxy

[0117] 15)C 5-10 Heteroaryloxy

[0118] 16)C 4-10 Non-aryl heterocyclic oxy

[0119] 17) C 3-10 Cycloalkylthio

[0120] 18)C 6-10 Arylthio

[0121] 19)C 5-10 Heteroarylthio

[0122] 20)C 4-10 Non-aromatic heterocyclic thio groups

[0123] 21)C 6-10 Aryl

[0124] 22)C 5-10 Heteroaryl

[0125] 23)C 4-10 Non-aromatic heterocycles

[0126] 24)C 3-10 Cycloalkylcarbonyl

[0127] 25)C 6-10 Arylcarbonyl

[0128] 26)C 5-10 Heteroarylcarbonyl

[0129] 27)C 4-10 Non-aromatic heterocyclic carbonyl

[0130] 28)C 3-10 Cycloalkylsulfonyl

[0131] 29)C 6-10 Arylsulfonyl

[0132] 30)C 5-10 Heteroarylsulfonyl

[0133] 31)C 4-10 Non-aromatic heterocyclic sulfonyl

[0134] (wherein, each substituent in 12) to 31) may be replaced by 1 to 5 substituent groups β or the aforementioned 5) C 1-6 alkyl substituted)

[0135] 32)-NR 10a R 11a

[0136] 33)-SO2-NR 10b R 11b

[0137] 34)-NR 10c -C(=O)R 11c

[0138] 35)-NR 10d -C(=O)OR 11d

[0139] 36)-NR 12a -C(=O)NR 10e R 11e

[0140] 37)-NR 10i -SO2-R 11i

[0141] 38)-NR 12c -SO2-NR 10j R 11j

[0142] 39)-C(=O)OR 10k

[0143] 40)-C(=O)NR 10l R 11k

[0144] 41)-C(=O)NR 10m OR 11l

[0145] 42)-C(=O)NR 12d -NR 10n R 11m

[0146] 43)-C(=NR 13a )R 10s

[0147] 44)-C(=NR 13c )NR 10t R 11q

[0148] 45)-C(=NR 13d )NR 12f -NR 10u R 11r

[0149] 46)-NR 17c -C(=NR 13k )R 17d

[0150] 47)-NR 12g -C(=NR 13e )-NR 10v R 11s

[0151] 48)-NR 14 -C(=NR 13f )-NR 12h -NR 10w R 11t

[0152] 49)-OC(=O)R 10x

[0153] 50)-OC(=O)OR 10y

[0154] 51)-OC(=O)NR 10z1 R 11u

[0155] 52)-NR 12i -NR 10z2 R 11v

[0156] 53)-NR 10z3 OR 11w

[0157] 54) protecting groups;

[0158] Substituent group β is the group consisting of,

[0159] 1) Halogen atoms,

[0160] 2) hydroxyl groups,

[0161] 3) carboxyl,

[0162] 4) cyano,

[0163] 5) C 3-10 Cycloalkyl,

[0164] 6) C 1-6 Alkoxy,

[0165] 7) C 3-10 Cycloalkyloxy,

[0166] 8) C 1-6 Alkylthio,

[0167] 9)C 5-10 Heteroarylthio,

[0168] 10) C 6-10 Aryl,

[0169] 11)C 5-10 Heteroaryl,

[0170] 12) C 4-10 Non-aromatic heterocycles,

[0171] 13)C 1-6 Alkylcarbonyl,

[0172] 14)C 3-10 Cycloalkylcarbonyl,

[0173] 15)C 6-10 Arylcarbonyl,

[0174] 16)C 5-10 Heteroarylcarbonyl,

[0175] 17)C 4-10 Non-aromatic heterocyclic carbonyl,

[0176] 18)-NR 15a R 16a 、

[0177] 19)-SO2-NR 15b R 16b 、

[0178] 20)-NR 15c -C(=O)R 16c

[0179] 21)-NR 17a -C(=O)NR 15d R 16d 、

[0180] 22)-C(=O)NR 15e R 16e 、

[0181] 23)-C(=NR 13g )R 15f 、

[0182] 24)-C(=NR 13h )NR 15g R 16f

[0183] 25)-NR 16g -C(=NR 13i )R 15h

[0184] 26)-NR 17b -C(=NR 13j )-NR 15i R 16h

[0185] 27) Protective Group

[0186] (In the substituent group β, each substituent of 5) to 17) can be selected from halogen atoms, hydroxyl groups, cyano groups, carboxyl groups, -NR 18a R 18b substituted with 1 to 5 substituents in

[0187] 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 Each independently the same or different, is a hydrogen atom, a hydroxyl group, a C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkoxycarbonyl,

[0188] R 10a 、R 10b 、R 10c 、R 10d 、R 10e 、R 10i 、R 10j 、R 10k 、R 10l 、R 10m 、R10n 、R 10s 、R 10s2 、R 10t 、R 10t2 、R 10u 、R 10u2 、R 10v 、R 10w 、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 17dare independently the same or different and are hydrogen atoms, C 1-6 Alkyl (the C 1-6 The alkyl group may be selected from hydroxy, cyano, C 1-6 Alkoxy, -NR 18a R 18b substituted with 1 to 3 substituents which may be the same or different), or C 1-6 Alkoxycarbonyl,

[0189] R 18a and R 18b are independently the same or different and are hydrogen or C 1-6 alkyl.

[0190] In an exemplary embodiment, the hydrogen atoms of any hydroxyl group and amino group in substituent groups α and β may be substituted with a protecting group.

[0191] In this manual, “C 1-6 " means that the number of carbon atoms is 1 to 6. When it refers to a specific heteroaryl group, it means that the total number of heteroatoms and carbon atoms is 1 to 6. The same applies to other numbers. For example, "C 1-4 " means that the number of carbon atoms (including heteroatoms when included) is 1 to 4, "C 1-3 " means that the number of carbon atoms (including heteroatoms when included) is 1 to 3. In this specification, the description of the limitation of the number of carbon atoms (including heteroatoms when included) is only a preferred numerical range, and the intention of this disclosure is that groups having substituents with a carbon number (including heteroatoms when included) other than the specified number of carbon atoms (including heteroatoms when included) are also within the scope of this disclosure.

[0192] In this specification, a "hydrocarbon group" is also referred to as a "hydrocarbon 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.

[0193] In this specification, "functional group" refers to any group that imparts certain functionality, including carboxyl, nitrile, carbonyl, hydroxyl, amino, imino, nitro, and halogen groups, as well as alkyl groups. In a broad sense, it also includes groups formed by bonds such as acid anhydrides, ester bonds, amide bonds, and ether bonds.

[0194] In this specification, "heteroatom" refers to an atom other than a carbon atom and a hydrogen atom, and includes, for example, an oxygen atom, a nitrogen atom, a sulfur atom, etc. A group containing a heteroatom is sometimes referred to as a hetero... group (for example, a heteroaryl group (meaning an aryl group containing at least a heteroatom)) or a hetero... group (for example, a heterocyclic group (meaning a cyclic group (carbocyclic group) containing at least one heteroatom)).

[0195] In this specification, a "halogen atom" is an atom belonging to the halogen family, and refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. Preferably, it is a fluorine atom or a chlorine atom. More preferably, it is a fluorine atom. A "halogen atom" is sometimes referred to as "halogen" or "halogen."

[0196] In this specification, a "hydroxyl group" is a monovalent group of -OH. This group may also be referred to as a "hydroxyl group" or "hydroxyl group".

[0197] In this specification, a "carboxyl group" is a monovalent group of -COOH. This group may also be referred to as a "carboxyl group," "carboxyl group," or "carboxyl group."

[0198] In this specification, "amino group" refers to a monovalent group -NH2. This group is sometimes also referred to as an "amino group."

[0199] In this specification, a "thio group" is a monovalent group of -SH. This group is sometimes also referred to as a "sulfhydryl group."

[0200] In this specification, "cyano" is a monovalent group of -CN.

[0201] In this specification, "alkyl" means a linear or branched saturated aliphatic hydrocarbon group. 1-12 "Alkyl" refers to an alkyl group having 1 to 12 carbon atoms, and examples thereof include C 1-6 Alkyl, heptyl, isoheptyl, octyl, isooctyl, nonyl, isononyl, decyl, isodecyl, undecyl, isundecyl, dodecyl, isododecyl, etc., but are not limited thereto. 1-6 "Alkyl" is an alkyl group having 1 to 6 carbon atoms, and as a preferred example, "C 1-4 Alkyl", more preferably "C 1-3 Alkyl", further preferably "C 1-2 Alkyl. As "C 1-4 Specific examples of "alkyl" include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, etc. As "C 1-6 Specific examples of "alkyl" include C 1-4 The group includes, but is not limited to, alkyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1,2-dimethylpropyl, n-hexyl, and the like.

[0202] In this specification, "alkenyl" means a linear or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond. 2-12 The term "alkenyl" refers to an alkenyl group having 2 to 12 carbon atoms, and examples thereof include heptenyl, isoheptenyl, octenyl, isooctenyl, nonenyl, isononenyl, decenyl, isodecenyl, undecenyl, isoundecenyl, dodecenyl, and isododecenyl, but the present invention is not limited thereto. "C 2-6"Alkenyl" is an alkenyl group having 2 to 6 carbon atoms, and preferred examples include "C 2-4 Alkenyl". As "C 2-6 Specific examples of the "alkenyl group" include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, and 2-methyl-2-propenyl.

[0203] In this specification, "alkynyl" means a linear or branched 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 thereof include heptynyl, isoheptynyl, octynyl, isooctynyl, nonynyl, isononynyl, decynyl, isodecynyl, undecynyl, isoundecynyl, dodecynyl, and isododecynyl, but are not limited thereto. "C 2-6 "Alkynyl" is an alkynyl group having 2 to 6 carbon atoms, and preferred examples include "C 2-4 Alkynyl". As "C 2-6 Specific examples of the "alkynyl group" include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 3-butynyl, 1-pentynyl, and 1-hexynyl.

[0204] In this specification, "aryl" means a monovalent group of a monocyclic or bicyclic aromatic hydrocarbon ring, "C 6-10 "Aryl" means an aryl group having 6 to 10 carbon atoms. Examples of "aryl" include C6 aryl, C 10 As a specific example of C6 aryl, phenyl etc. can be mentioned, but it is not limited thereto. 10 Specific examples of the aryl group include 1-naphthyl and 2-naphthyl, but are not limited thereto.

[0205] An aryl group as a substituent or as part of a substituent may be fused to an alicyclic group. For example, a phenyl group may be fused to a cyclohexane ring to form a 1,2,3,4-tetrahydronaphthyl group. In this case, any carbon atom on the phenyl ring is bonded to the parent backbone or a group or atom thereof proximal to the parent backbone. Examples of aryl groups include 5,6,7,8-tetrahydronaphth-1-yl and 5,6,7,8-tetrahydronaphth-2-yl.

[0206] In this specification, "arylalkyl" means an alkyl group substituted with at least one aryl group. 6-10 Aryl C 1-6 "Alkyl" means a group consisting of at least one C 6-10 Aryl-substituted C 1-6 Alkyl. As C 6-10 Aryl C 1-6Specific examples of the alkyl group include benzyl (phenyl-CH2-), phenethyl (phenyl-CH2CH2-), naphth-1-ylmethyl, naphth-2-ylmethyl, 2-(naphth-1-yl)ethyl, and 2-(naphth-2-yl)ethyl, but are not limited thereto.

[0207] In this specification, "(optionally substituted amino)-arylalkyl" means an arylalkyl substituted by an optionally substituted amino group, wherein the alkyl group or the aryl group or both are substituted by an amino group. The amino group of the arylalkyl group may be unsubstituted or may be substituted by 1, 2 or 3 substituents, for example, an optionally substituted alkyl group (e.g., an unsubstituted C 1-6 Alkyl, C 3-6 Cycloalkyl-C 1-6 Alkyl, C 3-6 As (amino group which may be substituted)-C 6-10 Aryl C 1-6 Examples of the alkyl group include, but are not limited to, (di(alkyl)amino)benzyl, ((cycloalkylalkyl)amino)benzyl, ((cycloalkylcarbonyl)amino)benzyl, ((carbamoylalkyl)carbonylamino)benzyl, ((carbamoylalkyl)carbonylamino)benzyl, ((carboxyalkyl)carbonyl)aminobenzyl, (di(alkyl)amino)naphthylmethyl, ((cycloalkylalkyl)amino)naphthylmethyl, ((cycloalkylcarbonyl)amino)naphthylmethyl, ((carbamoylalkyl)carbonylamino)naphthylmethyl, or ((carboxyalkyl)carbonyl)aminonaphthylmethyl.

[0208] In this specification, "hydroxyaryl" means an aryl group substituted with at least one hydroxyl group. 6-10 "Aryl" means a C 6-10 Aryl. As hydroxyl C 6-10 Specific examples of the aryl group include 2-hydroxyphenyl and 3-hydroxynaphthalene, but are not limited thereto.

[0209] In this specification, "hydroxyarylalkyl" means an alkyl group substituted with at least one hydroxyaryl group. 6-10 Aryl C 1-6 "Alkyl" means an alkyl group having at least one hydroxyl group 6-10 Aryl-substituted C 1-6 Alkyl. As hydroxyl C 6-10 Aryl C 1-6 Specific examples of the alkyl group include, but are not limited to, 2-hydroxybenzyl (2-hydroxyphenyl-CH2-), 2-hydroxyphenethyl (2-hydroxyphenyl-CH2CH2-), 3-hydroxynaphth-1-ylmethyl, 3-hydroxynaphth-2-ylmethyl, 2-(3-hydroxynaphth-1-yl)ethyl, and 2-(3-hydroxynaphth-2-yl)ethyl.

[0210] In this specification, the aryl part of "arylthio" has the same meaning as the above-mentioned aryl. 6-10 Arylthio", preferably "C6 or C 10 Arylthio". As "C 6-10 Specific examples of the "arylthio group" include phenylthio, 1-naphthylthio, 2-naphthylthio, etc., but are not limited thereto.

[0211] In this specification, "arylsulfonyl" means a sulfonyl group substituted with the above-mentioned "aryl". 6-10 Arylsulfonyl", preferably "C6 or C 10 Arylsulfonyl. As "C 6-10 Specific examples of the "arylsulfonyl group" include phenylsulfonyl, 1-naphthylsulfonyl, and 2-naphthylsulfonyl, but are not limited thereto.

[0212] In this specification, "heteroaryl" refers to a monovalent monocyclic or bicyclic aromatic heterocyclic group containing the same or different heteroatoms selected from oxygen atoms, nitrogen atoms, and sulfur atoms. The number of heteroatoms may be any number up to the number of carbon atoms present in the aryl group, and typically, 1 to 4 heteroatoms are included, but 1, 2, or 3 heteroatoms are also possible.

[0213] In this manual, "C 5-10 "Heteroaryl" means a monovalent group of a monocyclic or bicyclic aromatic heterocyclic ring consisting of 5 to 10 atoms containing the same or different, typically 1 to 4 heteroatoms selected from oxygen atoms, nitrogen atoms and sulfur atoms. 5-10 Specific examples of the “heteroaryl group” include, but are not limited to, quinolyl, isoquinolyl, naphthyridinyl, quinoxalinyl, cinnolinyl, quinazolinyl, phthalazinyl, imidazopyridinyl, imidazothiazolyl, imidazooxazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, pyrrolopyridinyl, thienopyridinyl, furopyridinyl, benzothiadiazolyl, benzoxadiazolyl, pyridopyrimidinyl, benzofuranyl, benzothiophenyl, benzo[1,3]dioxole, thienofuranyl, benzopyranyl, chromanyl, coumarinyl, and quinolonyl.

[0214] In this specification, "heteroarylalkyl" means an alkyl group substituted by at least one heteroaryl group. 5-10 Heteroaryl C 1-6 "Alkyl" means a group consisting of at least one C 5-10 Heteroaryl-substituted C 1-6 Alkyl. As C 5-10 Heteroaryl C 1-6Specific examples of the alkyl group 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, and 2-(1H-indol-3-yl)ethyl.

[0215] In this specification, "cycloalkyl" means a non-aromatic saturated hydrocarbon ring group, including those having a partially cross-linked 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 group having 3 to 20 carbon atoms. 3-6 "Cycloalkyl" means a monocyclic cycloalkyl group having 3 to 6 carbon atoms. 3-6 Specific examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, but are not limited thereto.

[0216] A cycloalkyl group as a substituent or part thereof may be fused to an aryl and / or heteroaryl ring. For example, a cyclohexyl group may be fused to a benzene ring to form a 1,2,3,4-tetrahydronaphthyl group, in which case any of the possible carbon atoms on the cyclohexane ring is bonded to the parent skeleton or a group or atom thereof close to the parent skeleton. Cycloalkyl groups include 1,2,3,4-tetrahydronaphth-1-yl, 1,2,3,4-tetrahydronaphth-2-yl, indan-1-yl, indan-2-yl, 5,6,7,8-tetrahydroquinolin-5-yl, and 5,6,7,8-tetrahydroquinolin-6-yl.

[0217] In this specification, "cycloalkylalkyl" means an alkyl group substituted with at least one cycloalkyl group. 3-6 Cycloalkyl C 1-6 "Alkyl" means a group consisting of at least one C 3-6 Cycloalkyl substituted C 1-6 Alkyl. As C 3-6 Cycloalkyl C 1-6 Specific examples of the alkyl group include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, 3-cyclopropylpropyl, 3-cyclobutylpropyl, 3-cyclopentylpropyl, and 3-cyclohexylpropyl.

[0218] In this specification, "heterocycloalkyl" refers to a non-aromatic saturated or partially unsaturated heterocyclic ring composed of three or more atoms, including one or two or more heteroatoms selected from oxygen, nitrogen, and sulfur atoms, which may be the same or different, and includes those having a partially cross-linked structure and those that are partially spiro-formed. "Heterocycloalkyl" encompasses "non-aromatic heterocyclic rings." A heterocycloalkyl group may have a structure in which a non-aromatic heterocyclic ring is fused with an aryl ring and / or a heteroaryl ring.

[0219] In this specification, "non-aromatic heterocycle" means a monocyclic or bicyclic non-aromatic heterocycle composed of three or more atoms containing one or two or more heteroatoms selected from oxygen atoms, nitrogen atoms and sulfur atoms, which may be the same or different, and includes saturated non-aromatic heterocycles, those having partially unsaturated bonds, those having partially cross-linked structures and those having a portion spiro. The non-aromatic heterocycle may form a condensed ring with an aryl or heteroaryl group. For example, with C 6-10 Aryl or C 5-10 The case where a heteroaryl group is fused is also included in the heterocycle. In addition, when constituting the non-aromatic heterocycle, one or two or more carbonyl groups, thiocarbonyl groups, sulfinyl groups, or sulfonyl groups may be included. For example, cyclic groups such as lactams, thiolactams, lactones, thiolactones, cyclic imides, cyclic carbamates, and cyclic thiocarbamates are also included in the non-aromatic heterocycle. However, the oxygen atoms of the carbonyl, sulfinyl, and sulfonyl groups and the sulfur atom of the thiocarbonyl group are not included in the number of ring members (ring size) and the number of heteroatoms constituting the ring.

[0220] In this manual, “C 4-10 Non-aromatic heterocycle" means the "non-aromatic heterocycle" mentioned above, "C 4-10 The non-aromatic heterocycle" becomes a substituent of a monovalent group.

[0221] In this specification, the non-aryl heterocyclic ring part of "non-aryl heterocyclic oxy" has the same meaning as the above-mentioned "non-aryl heterocycle". For example, "C 4-10 Non-aryl heterocyclic oxy", as "C 4-10 Non-aryl heterocyclic oxy", preferably "C 4-10 Non-aromatic heterocyclic oxy group". As "C 4-10 Specific examples of the "non-aryl heterocyclic oxy group" include tetrahydrofuranyloxy, tetrahydropyranyloxy, azetidinyloxy, pyrrolidinyloxy, piperidinyloxy and the like, but are not limited thereto.

[0222] In this specification, the non-aryl heterocyclic portion 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-aromatic heterocyclic thio group", as "C 4-10 Non-aromatic heterocyclic thio group", preferably "C 4-6 Non-aromatic heterocyclic thio group". As "C 4-10 Specific examples of the "non-aryl heterocyclic thio group" include tetrahydropyranylthio and piperidinylthio, but are not limited thereto.

[0223] In this specification, "non-aryl heterocyclic carbonyl" means a carbonyl group substituted by the above-mentioned "non-aryl heterocycle". For example, "C 4-10 Non-aromatic heterocyclic carbonyl", as "C 4-10 Non-aromatic heterocyclic carbonyl", preferably "C4-6 Non-aromatic heterocyclic carbonyl. As "C 4-10 Specific examples of the "non-aryl heterocyclic carbonyl group" include, but are not limited to, azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, and morpholinylcarbonyl.

[0224] In this specification, "non-aryl heterocyclic sulfonyl group" means a sulfonyl group substituted with the above-mentioned "non-aryl heterocyclic ring". For example, "C 4-10 Non-aromatic heterocyclic sulfonyl", as "C 4-10 Non-aromatic heterocyclic sulfonyl", preferably "C 4-6 Non-aromatic heterocyclic sulfonyl. As "C 4-10 Specific examples of the "non-aryl heterocyclic sulfonyl group" include, but are not limited to, azetidinylsulfonyl, pyrrolidinylsulfonyl, piperidinylsulfonyl, and morpholinylsulfonyl.

[0225] In this manual, "C 5-10 The term "heterocycloalkyl group" refers to a heterocycloalkyl group consisting of 5 to 10 ring atoms containing the same or different 1 or 2 or more hetero atoms selected from oxygen atoms, nitrogen atoms and sulfur atoms.

[0226] In the present specification, the "heterocycloalkylalkyl group" means an alkyl group substituted by at least one heterocycloalkyl group.

[0227] In this specification, "alkylcarbonyl" is a monovalent group of -C(=O)-alkyl. Preferred examples of alkylcarbonyl include C 1-6 Alkylcarbonyl. As C 1-6 Specific examples of alkylcarbonyl groups include, but are not limited to, acetyl (CH3C(=O)-), n-propionyl (CH3CH2C(=O)-), n-butyryl (CH3CH2CH2C(=O)-), n-pentanoyl (CH3(CH2)3C(=O)-), n-hexanoyl (CH3(CH2)4C(=O)-), and n-heptanoyl (CH3(CH2)5C(=O)-).

[0228] In this specification, "alkoxy" 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-) etc. As C 1-4Specific examples of alkoxy groups include methoxy (CH3O-), ethoxy (CH3CH2O-), n-propoxy (CH3(CH2)2O-), isopropoxy ((CH3)2CHO-), n-butoxy (CH3(CH2)3O-), isobutoxy ((CH3)2CHCH2O-), tert-butoxy ((CH3)3CO-), and sec-butoxy (CH3CH2CH(CH3)O-). 1-6 Specific examples of alkoxy groups include C 1-4 Alkyloxy, n-pentyloxy (CH3(CH2)4O-), isopentyloxy ((CH3)2CHCH2CH2O-), neopentyloxy ((CH3)3CCH2O-), tert-pentyloxy (CH3CH2C(CH3)2O-), 1,2-dimethylpropyloxy (CH3CH(CH3)CH(CH3)O-), etc., but are not limited thereto.

[0229] In this specification, "alkoxycarbonyl" is a monovalent group of -C(=O)-O-alkyl. Examples of alkoxycarbonyl include C 1-6 Alkoxycarbonyl, preferably C 1-4 Alkoxycarbonyl, but not limited thereto. 1-4 Specific examples of the alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, and isobutoxycarbonyl. 1-6 Specific examples of the alkoxycarbonyl group include C 1-4 Examples include, but are not limited to, alkoxycarbonyl, n-pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert-pentyloxycarbonyl, 1,2-dimethylpropyloxycarbonyl, and n-hexyloxycarbonyl.

[0230] In this specification, "alkoxycarbonyloxy" is a monovalent group of -OC(=O)-O-alkyl. Examples of alkoxycarbonyloxy include C 1-6 Alkoxycarbonyloxy, preferably C 1-4 Alkoxycarbonyloxy, but not limited thereto. 1-4 Specific examples of the alkoxycarbonyloxy group include methoxycarbonyloxy, ethoxycarbonyloxy, n-propoxycarbonyloxy, isopropoxycarbonyloxy, n-butoxycarbonyloxy, sec-butoxycarbonyloxy, tert-butoxycarbonyloxy, and isobutoxycarbonyloxy. 1-6 Specific examples of the alkoxycarbonyloxy group include C 1-4 Examples include, but are not limited to, an alkoxycarbonyloxy group, an n-pentyloxycarbonyloxy group, an isopentyloxycarbonyloxy group, a neopentyloxycarbonyloxy group, a tert-pentyloxycarbonyloxy group, a 1,2-dimethylpropyloxycarbonyloxy group, and an n-hexyloxycarbonyloxy group.

[0231] In this specification, "alkoxycarbonylamino" is a monovalent group of -NH-C(=O)-O-alkyl. Examples of alkoxycarbonylamino include C 1-6 Alkoxycarbonylamino, preferably C 1-4 Alkoxycarbonylamino, but not limited thereto. 1-4 Specific examples of the alkoxycarbonylamino group include methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, n-butoxycarbonylamino, sec-butoxycarbonylamino, tert-butoxycarbonylamino, and isobutoxycarbonylamino. 1-6 Specific examples of the alkoxycarbonylamino group include C 1-4 Examples include, but are not limited to, alkoxycarbonylamino, n-pentyloxycarbonylamino, isopentyloxycarbonylamino, neopentyloxycarbonylamino, tert-pentyloxycarbonylamino, 1,2-dimethylpropyloxycarbonylamino, and n-hexyloxycarbonylamino.

[0232] In this specification, "haloalkyl" is a monovalent group of a halogenated alkyl group in which one or more hydrogen atoms on the alkyl group are replaced by halogen atoms. In addition, the term "perhaloalkyl" means a haloalkyl group in which all hydrogen atoms on the alkyl group are replaced by halogen atoms. For example, perfluoroethyl is -CF2CF3, and perchloro-n-propyl is -CCl2CCl2CCl3. Examples of haloalkyl groups include C 1-6 Halogenated alkyl, C 1-4 Halogenated alkyl, C 1-3 Halogenated alkyl, etc. As C 1-3 Specific examples of the alkyl group 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, and perbromoisopropyl. 1-4 Specific examples of the alkyl group include C 1-3 Examples of C include, but are not limited to, halogenated alkyl, perfluorobutyl, perchlorobutyl, perbromobutyl, perfluoroisobutyl, and perfluorotert-butyl. 1-6 Specific examples of the alkyl group include C 1-4 Examples include, but are not limited to, halogenated alkyl, perfluoro-n-pentyl, perfluoro-isopentyl, perfluoro-neopentyl, perfluoro-tert-pentyl, and perfluoro-1,2-dimethylpropyl.

[0233] In this specification, "haloalkoxy" and "haloalkyloxy" are monovalent groups of -O-haloalkyl in which one or more hydrogen atoms on the alkyl group are replaced by halogen atoms. In addition, the term "perhaloalkoxy" means a haloalkoxy group in which all hydrogen atoms on the alkyl group are replaced by halogen atoms. For example, perfluoroethoxy is -OCF2CF3, and perchloro-n-propoxy is -OCCl2CCl2CCl3. Preferred examples of haloalkoxy groups include C 1-6 Halogenated alkoxy, C 1-4 Halogenated alkoxy, C 1-3 Halogenated alkoxy, etc. as C 1-3 Specific examples of the alkoxy group include, but are not limited to, 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, and perbromoisopropoxy. 1-4 Specific examples of alkoxy groups include C 1-3 Examples of C include, but are not limited to, halogenated alkoxy, perfluorobutoxy, perchlorobutoxy, perbromobutoxy, perfluoroisobutoxy, and perfluorotert-butoxy. 1-6 Specific examples of alkoxy groups include C 1-4 Examples of the group include, but are not limited to, a halogenated alkoxy group, a perfluoro-n-pentyloxy group, a perfluoro-isopentyloxy group, a perfluoro-neopentyloxy group, a perfluoro-tert-pentyloxy group, and a perfluoro-1,2-dimethylpropoxy group.

[0234] In this specification, "alkylsulfonyl" means a sulfonyl group substituted with the above-mentioned "alkyl". 1-6 Alkylsulfonyl", preferably "C 1-4 Alkylsulfonyl. As "C 1-6 Specific examples of the "alkylsulfonyl group" include methylsulfonyl, propionylsulfonyl, butyrylsulfonyl and the like, but are not limited thereto.

[0235] In this specification, the alkyl part of "alkylthio" has the same meaning as the above-mentioned alkyl. 1-6 Examples of "alkylthio" include "C 1-4 "Alkylthio", preferably "C 1-3 Alkylthio". As "C 1-6 Specific examples of the "alkylthio group" include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, isopropylthio, isobutylthio, tert-butylthio, sec-butylthio, isopentylthio, neopentylthio, tert-pentylthio, and 1,2-dimethylpropylthio.

[0236] In this specification, "arylcarbonyl" is a monovalent group of -C(=O)-aryl. Preferred examples of arylcarbonyl include C 6-10 Arylcarbonyl. As C 6-10 Specific examples of the arylcarbonyl group include benzoyl (ie, phenyl-C(=O)-), 1-naphthylcarbonyl, and 2-naphthylcarbonyl, but are not limited thereto.

[0237] In this specification, the aryl part of "aryloxy" has the same meaning as the above-mentioned aryl. 6-10 Aryloxy", preferably "C6 or C 10 Aryloxy". As "C 6-10 Specific examples of the "aryloxy group" include phenoxy, 1-naphthyloxy, 2-naphthyloxy, etc., but are not limited thereto.

[0238] In the present specification, the "heteroarylcarbonyl group" is a monovalent group of -C(=O)-heteroaryl.

[0239] In this specification, "heteroarylcarbonyl" means a carbonyl group substituted by the above-mentioned "heteroaryl". 5-10 Specific examples of the "heteroarylcarbonyl group" include, but are not limited to, pyrazolylcarbonyl, triazolylcarbonyl, thiazolylcarbonyl, thiadiazolylcarbonyl, pyridylcarbonyl, and pyridazinylcarbonyl.

[0240] In this specification, the heteroaryl part of "heteroaryloxy" has the same meaning as the above-mentioned "heteroaryl". 5-10 Specific examples of the "heteroaryloxy" include, but are not limited to, pyrazolyloxy, triazolyloxy, thiazolyloxy, thiadiazolyloxy, pyridyloxy, and pyridazinyloxy.

[0241] In this specification, the heteroaryl part of "heteroarylthio" has the same meaning as the above-mentioned "heteroaryl". 5-10 Specific examples of the "heteroarylthio group" include, but are not limited to, pyrazolylthio, triazolylthio, thiazolylthio, thiadiazolylthio, pyridylthio and pyridazinylthio.

[0242] In this specification, an "optionally substituted carbonyl" group refers to a monovalent group -C(=O)-(hydrogen or any group selected from the group of substituents described in this specification). 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, and heterocycloalkyloxycarbonyl. A carbonyl group substituted with hydrogen is a formyl group. A carbonyl group substituted with an amino group is a carbamoyl group.

[0243] In this specification, an "optionally substituted oxy" group refers to a monovalent group -O-(hydrogen or any group selected from the group of substituents described in this specification). 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, and heterocycloalkylcarbonyloxy. An oxy group substituted with hydrogen is a hydroxy group.

[0244] In the present specification, a "carbamoyl group" is a monovalent group -C(=O)-NH2.

[0245] In the present specification, "amidinoamino" is a monovalent group -NH-C(=NH)-NH2.

[0246] In this specification, the description of "a group substituted by a substituent" means that the group is substituted by at least one substituent. For example, "a C 1-6 "Alkyl" means C 1-6 The alkyl group is substituted with at least one hydroxy group.

[0247] In this specification, "carbamoyl C 1-6 "Alkyl" is a C substituted by at least one -C(=O)-NH2 group. 1-6 Alkyl. As "carbamoyl C 1-4 Specific examples of the "alkyl group" include, but are not limited to, 2-amino-2-oxoethyl (i.e., H2NC(=O)-CH2-, or carbamoylmethyl), 3-amino-3-oxopropyl (i.e., H2NC(=O)-CH2CH2-, or carbamoylethyl), 4-amino-4-oxobutyl (i.e., H2NC(=O)-(CH2)3-, or carbamoylpropyl), and 5-amino-5-oxopentyl (i.e., H2NC(=O)-(CH2)4-, or carbamoylbutyl). As "carbamoyl C 1-6 Specific examples of "alkyl" include carbamoyl-substituted C1-4 Alkyl, 6-amino-6-oxohexyl (i.e., H2NC(=O)-(CH2)5-, or carbamoylpentyl), 7-amino-7-oxoheptyl (i.e., H2NC(=O)-(CH2)6-, or carbamoylhexyl), etc., but are not limited thereto.

[0248] In this specification, "thioalkyl" is an alkyl group substituted with at least one thio group. 1-6 Specific examples of the "alkyl group" include, but are not limited to, thiomethyl, 2-thioethyl, 3-thiopropyl, and 4-thiobutyl.

[0249] In this specification, "alkylthioalkyl" means an alkyl group substituted with at least one alkylthio group. 1-6 Alkylthio C 1-6 "Alkyl" means a group consisting of at least one C 1-6 Alkylthio-substituted C 1-6 Alkyl. As C 1-6 Alkylthio C 1-6 Specific examples of the alkyl group include methylthiomethyl, methylthioethyl, and ethylthiomethyl, but are not limited thereto.

[0250] In this specification, "aminoalkyl" refers to an alkyl group substituted with at least one amino group. 1-6 Specific examples of the "alkyl group" include aminomethyl, 2-aminoethyl, 3-aminopropyl, and 4-aminobutyl, but are not limited thereto.

[0251] In this specification, "amidinoaminoalkyl" or "guanidinoalkyl" is an alkyl group substituted with at least one -NH-C(=NH)-NH2 group, wherein the nitrogen atom of the amidinoamino group may be protected by a nitrogen protecting group (e.g., tert-butoxycarbonyl). 1-6 Examples of "alkyl" include "amidinoamino C 1-4 Alkyl" etc., but not limited thereto. As "amidinoamino C 1-4 Specific examples of "alkyl" include, but are not limited to, (amidinoamino)methyl, 2-(amidinoamino)ethyl, 3-(amidinoamino)propyl, and 4-(amidinoamino)butyl. 1-6 Specific examples of "alkyl" include amidinoamino-substituted C 1-4 Examples of amidino groups protected by nitrogen protecting groups include:

[0252] [Chemistry 2]

[0253]

[0254] In this specification, "amidinoamino" and "guanidino" have the same meaning.

[0255] In this specification, "carboxyalkyl" refers to an alkyl group substituted with at least one -COOH group. 1-4 Specific examples of "alkyl" include, but are not limited to, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, and 4-carboxybutyl. 1-6 Specific examples of "alkyl" include carboxyl-substituted C 1-4 The group may include, but is not limited to, an alkyl group, a 5-carboxypentyl group, a 6-carboxyhexyl group, and the like.

[0256] In this specification, "protecting group" refers to an atomic group that shields, reduces or prevents the reactivity of a functional group when combined with a reactive functional group in a molecule. The compounds disclosed herein may be appropriately or as needed substituted with a protecting group at any position such as any of R1 to R4 or its substituents or substituents other than them, and compounds containing these protecting groups are also within the scope of this disclosure. Typically, the protecting group can be selectively removed during the synthesis process as needed. 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, Volumes 1 to 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, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), and nitroveratroloxycarbonyl ("NVOC"). Representative hydroxyl protecting groups include those in which the hydroxyl group is acylated (esterified) or alkylated, for example, benzyl and trityl ether, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS, triethylsilyl, tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS)), alkyldiarylsilyl ethers (e.g., tert-butyldiphenylsilyl (TBDPS)), triarylsilyl ethers (e.g., triphenylsilyl), glycol ethers (e.g., ethylene glycol ether, propylene glycol ether, etc.) and allyl ethers, but are not limited thereto.

[0257] The amino groups possessed by the compounds of the present disclosure (e.g., amino groups possessed by the parent skeleton, amino groups as substituents, amino groups in substituents possessed by the compounds, etc.) may be protected by nitrogen protecting groups or groups represented by "Protect." The amino groups in the substituents listed in the substituent group group may be further protected by nitrogen protecting groups or groups represented by "Protect," and the protected substituents may be used as substituents.

[0258] The hydroxyl groups possessed by the compounds disclosed herein (e.g., hydroxyl groups as substituents, hydroxyl groups in substituents possessed by the compounds, hydroxyl groups in the aforementioned substituent groups, etc.) may also be protected by hydroxyl-protecting groups. The hydroxyl groups in the substituents listed in the substituent groups may be further protected by hydroxyl-protecting groups described in this specification, and the protected substituents may be used as substituents.

[0259] In this specification, "nervous system" refers to the organ system consisting of nervous tissue. In addition, when used in this specification, "nervous system cells" at least include nerve cells and glial cells (glial cells) contained in the central nervous systems such as brain and spinal cord, and then can also include microglia, astrocytes, oligodendrocytes, ependymal cells, cerebral vascular endothelial cells, etc.

[0260] In this specification, "activity regulation" means inhibiting or promoting activity, and the term "activity regulator" means an inhibitor (inhibitor) or promoter of activity. "Promoting activity" means that its activity (e.g., promotion of cell division) increases by 1% or more, preferably 5% or more, more preferably 10% or more, further preferably 20% or more, further preferably 30% or more, compared to the case where the activity regulator is not used. "Inhibiting activity" means that its activity (e.g., promotion of cell division) decreases by 1% or more, preferably 5% or more, more preferably 10% or more, further preferably 20% or more, further preferably 30% or more, compared to the case where the activity regulator is not used.

[0261] In this specification, "pharmaceutically acceptable salt" means an acid addition salt and a base addition salt that are pharmaceutically acceptable. Specific examples of "pharmaceutically acceptable salt" include acetate, propionate, butyrate, formate, trifluoroacetate, maleate, fumarate, tartrate, citrate, stearate, succinate, ethylsuccinate, malonate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, benzenesulfonic acid, p-toluenesulfonate (toluenesulfonate), lauryl sulfate, malate, ascorbate, mandelate, saccharinate, xinafoate Acid addition salts such as hydroxybenzoate, cinnamate, adipate, cysteine, N-acetylcysteine, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinate, oxalate, picrate, thiocyanate, undecanoate, acrylic acid polymer salt, carboxyvinyl polymer; inorganic base addition salts such as lithium salt, sodium salt, potassium salt, calcium salt; organic base addition salts such as morpholine and piperidine; addition salts with amino acids such as aspartic acid and glutamic acid, etc., but are not limited thereto.

[0262] Preferred salts and pharmaceutically acceptable salts of the starting compound and the target compound are conventional non-toxic salts. As these salts, in addition to acid addition salts such as organic acid salts (e.g., acetate, trifluoroacetate, maleate, fumarate, citrate, tartrate, methanesulfonate, benzenesulfonate, formate, or p-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 or potassium salt) and alkaline earth metal salts (e.g., calcium salt or magnesium salt), ammonium salts, or organic base salts (e.g., trimethylamine salt, triethylamine salt, pyridinium salt, picoline salt, dicyclohexylamine salt, or N,N'-dibenzylethylenediamine salt), those skilled in the art can also appropriately select.

[0263] When a salt of the compound of the present disclosure is desired, the compound of the present disclosure may be directly purified if it is obtained in the form of a salt. Alternatively, if it is obtained in a free form, it may be dissolved or suspended in a suitable organic solvent, and an acid or base may be added to form a salt by a conventional method.

[0264] In addition, the compounds of the present disclosure and pharmaceutically acceptable salts thereof may sometimes exist in the form of adducts with water or various solvents, and these adducts are also included in the present disclosure.

[0265] In addition, the present disclosure includes compounds represented by formula (1) or pharmaceutically acceptable salts thereof. Furthermore, solvates such as hydrates or ethanol solvates thereof are also included. Furthermore, the present disclosure also includes all tautomers, all existing stereoisomers, and all crystalline forms of the compounds of the present disclosure represented by formula (1).

[0266] The phrase "a compound or an enantiomer thereof or a salt thereof or a solvate thereof" means a compound, an enantiomer of the aforementioned compound, a salt of the aforementioned compound, a salt of the aforementioned enantiomer, a solvate of the aforementioned compound, a solvate of the aforementioned enantiomer, a solvate of the salt of the aforementioned compound, or a solvate of the salt of the aforementioned enantiomer.

[0267] The compounds described in this specification may contain one or more asymmetric centers and may therefore exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described in this specification may be in the form of a single enantiomer, diastereomer, or geometric isomer, or may be in the form of a mixture of stereoisomers (comprising a racemic mixture and a mixture concentrated from one or more stereoisomers). Isomers may be separated from the mixture by methods well known to those skilled in the art (including the formation and crystallization of chiral high performance liquid chromatography (HPLC) and chiral salts). Alternatively, preferred isomers may be prepared by asymmetric synthesis. For example, see Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen et al., Tetrahedron 33: 2725 (1977); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure also encompasses the compounds described herein as individual isomers substantially free of other isomers, or alternatively, as mixtures of various isomers.

[0268] The compounds of the present disclosure represented by formula (1) may contain optical isomers based on optically active centers, atropisomers based on axial or planar chirality resulting from the restraint of intramolecular rotation, other stereoisomers, tautomers, and geometric isomers, and all possible isomers and mixtures thereof are included within the scope of the present disclosure.

[0269] Particularly optical isomers and atropisomers can be obtained in racemic form, or when using optically active starting materials or intermediates, can be obtained in optically active form. As required, in the appropriate stage of the following manufacture method, the racemate of the corresponding raw material, intermediate or final product can be physically or chemically split into their optical enantiomers by using a method using an optically active column, a fractional crystallization method or the like, for example. Specifically, for example, in a diastereoisomer method, two diastereomers are formed from a racemate by using a reaction using an optical resolving agent. The different diastereomers usually have different physical properties and can therefore be split by known methods such as fractional crystallization.

[0270] As used in this specification, the phrase "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, without excessive toxicity, irritation, allergic response or other problems or complications, meet an appropriate benefit-risk ratio, and are suitable for use in contact with the tissues of humans and animals.

[0271] As used in this specification, the phrase "pharmaceutically acceptable carrier" 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 that it is compatible with the other ingredients of the formulation and is not harmful to the patient. As some examples of materials that can function as a pharmaceutically acceptable carrier, the following can be cited: (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, ethyl cellulose 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, Corn oil and soybean oil, etc.; (10) glycols, such as propylene glycol, etc.; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol, etc.; (12) esters, such as ethyl oleate and ethyl laurate, etc.; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide, etc.; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other non-toxic compatible substances used in pharmaceutical preparations.

[0272] Furthermore, the scope of the present disclosure also includes prodrugs of the compounds of the present disclosure. In the present disclosure, a prodrug refers to a derivative of a compound of the aforementioned formula (1) that undergoes acid hydrolysis or enzymatic decomposition in vivo. For example, when the compound of the aforementioned formula (1) has a hydroxyl group, an amino group, or a carboxyl group, these groups can be modified according to conventional methods to produce a prodrug.

[0273] For example, in the case of a compound having a carboxyl group, there may be mentioned a compound in which the carboxyl group is an alkoxycarbonyl group, a compound in which the carboxyl group is an alkylthiocarbonyl group, or a compound in which the carboxyl group is an alkylaminocarbonyl group.

[0274] For example, in the case of a compound having an amino group, there may be mentioned 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 becomes an alkanoyloxymethylamino group, or a compound in which the amino group becomes a hydroxylamine group.

[0275] For example, in the case of a compound having a hydroxyl group, there may be mentioned a compound in which the hydroxyl group is substituted with the aforementioned alkanoyl group to form an alkanoyloxy group, a compound in which the hydroxyl group is a phosphate ester, or a compound in which the hydroxyl group is an alkanoyloxymethyloxy group.

[0276] Examples of the alkyl moiety of the group used in these prodrug formations include the aforementioned alkyl groups, which may be substituted by, for example, an alkoxy group, etc. Preferred examples include the following.

[0277] For example, examples of compounds in which the carboxyl group is an alkoxycarbonyl group include C 1-12 Alkoxycarbonyl, C4 alkoxycarbonyl, C6 alkoxycarbonyl, C8 alkoxycarbonyl, C 10 Alkoxycarbonyl, C 12 Alkoxycarbonyl, specifically methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, n-pentoxycarbonyl, isopentoxycarbonyl, neopentoxycarbonyl, tert-pentoxycarbonyl, 1,2-dimethylpropoxycarbonyl, n-hexyloxycarbonyl, heptoxycarbonyl, isoheptoxycarbonyl, octyloxycarbonyl, isooctyloxycarbonyl, nonyloxycarbonyl, isononyloxycarbonyl, decyloxycarbonyl, isodecyloxycarbonyl, undecyloxycarbonyl, isoundecyloxycarbonyl, dodecyloxycarbonyl or isododecyloxycarbonyl; or C 1-12 Alkoxy C 1-12 Alkoxycarbonyl, C 1-12 Alkoxyethoxycarbonyl, specifically methoxymethoxycarbonyl, ethoxymethoxycarbonyl, 2-methoxyethoxycarbonyl, 2-methoxyethoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl; or C 1-12 Alkyl PEG, C4 alkyl PEG, C6 alkyl PEG, C8 alkyl PEG, C 10 Alkyl PEG, C 12 Alkyl PEG substituted alkoxycarbonyl. Here, PEG refers to polyethylene glycol, and the alkyl group can be a straight chain,

[0278] It can also be a branched chain.

[0279] In this specification, "or" is used when "at least one or more" of the items listed in the text can be used. The same applies to "or". In this specification, when it is clearly stated that "within the range of two values", the range also includes the two values ​​themselves.

[0280] The scientific literature, patents, patent applications and other references cited in this specification are incorporated herein by reference in their entirety to the same extent as if each were specifically described.

[0281] (Preferred embodiment)

[0282] The preferred embodiments of the present disclosure are described below. It should be understood that the embodiments provided below are provided for a better understanding of the present disclosure, and the scope of the present disclosure should not be limited by the following description. Therefore, it is obvious that those skilled in the art can make appropriate changes within the scope of the present disclosure with reference to the description in this specification. In addition, it should be understood that the following embodiments of the present disclosure can be used alone or in combination.

[0283] (Compounds and Compositions of the Present Disclosure)

[0284] In one aspect, the compounds of the present disclosure can be exemplified by compounds represented by the following formula or pharmaceutically acceptable salts, solvates or prodrugs thereof,

[0285] [Chemistry 3]

[0286]

[0287] Where,

[0288] R1, R2, R5, R6, R7, R8, R9 and R 10 Each independently is:

[0289] hydrogen atoms, or

[0290] an optionally substituted hydrocarbon group, or

[0291] R7 and R8 together with the carbon atom and the nitrogen atom to which R7 and R8 are bonded form an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted cycloalkyl group or an optionally substituted heterocycloalkyl group,

[0292] R3 and R4 are each independently:

[0293] A hydrogen atom, an optionally substituted hydrocarbon group, a carboxyl group,

[0294] optionally substituted alkoxycarbonyl, or

[0295] optionally substituted alkoxycarbonyloxy,

[0296] R11 、R 12 、R 13 and R 14 Each independently is:

[0297] a hydrogen atom, an optionally substituted hydrocarbon group, a hydroxyl group,

[0298] optionally substituted alkoxy, or

[0299] optionally substituted alkoxycarbonyloxy,

[0300] X is:

[0301] CH2 or CO,

[0302] A is O, NH or S, wherein NH may be optionally substituted.

[0303] In one embodiment, R1, R2, R5, R6, R7, R8, R9 and R 10 Each independently is:

[0304] hydrogen atoms, or

[0305] an optionally substituted hydrocarbon group, or

[0306] R7 and R8 together with the carbon atom and the nitrogen atom to which R7 and R8 are bonded form an optionally substituted heterocycloalkyl group,

[0307] R3 and R4 are each independently:

[0308] A hydrogen atom, an optionally substituted hydrocarbon group, a carboxyl group,

[0309] optionally substituted alkoxycarbonyl, or

[0310] optionally substituted alkoxycarbonyloxy,

[0311] R 11 、R 12 、R 13 and R 14 Each independently is:

[0312] Hydrogen atoms, hydroxyl groups,

[0313] optionally substituted alkoxy, or

[0314] optionally substituted alkoxycarbonyloxy,

[0315] X is:

[0316] CH2 or CO,

[0317] A is O, NH or S, wherein NH may be optionally substituted.

[0318] In one embodiment, R1, R2, R5, R6, R7, R8, R9 and R 10 Each independently is:

[0319] hydrogen atoms, or

[0320] optionally substituted alkyl, or,

[0321] R7 and R8 together with the carbon atom and the nitrogen atom to which R7 and R8 are bonded form an optionally substituted heterocycloalkyl group,

[0322] R3 and R4 are each independently:

[0323] a hydrogen atom, an optionally substituted alkyl group, a carboxyl group,

[0324] optionally substituted alkoxycarbonyl, or

[0325] optionally substituted alkoxycarbonyloxy,

[0326] R 11 、R 12 、R 13 and R 14 Each independently is:

[0327] Hydrogen atoms, hydroxyl groups,

[0328] optionally substituted alkoxy, or

[0329] optionally substituted alkoxycarbonyloxy,

[0330] X is:

[0331] CH2 or CO,

[0332] A is O, NH or S, wherein NH may be optionally substituted.

[0333] In one embodiment, R1, R2, R5, R6, R7, R8, R9 and R 10 Each independently is:

[0334] hydrogen atoms, or

[0335] an alkyl group substituted with the same or different substituents selected from hydrogen, alkyl, alkylcarbonyl, arylalkylcarbonyl, hydroxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, cycloalkyl, carboxyl, amino, guanidino, guanidino substituted by alkoxycarbonyl, carbamoyl, and heterocycloalkyl, or

[0336] R7 and R8 together with the carbon atom and nitrogen atom to which R7 and R8 are bonded form a heterocycloalkyl group, and R3 and R4 are each independently:

[0337] hydrogen atoms,

[0338] Alkyl, carboxyl, or substituted with the same or different substituents selected from hydrogen, alkyl, alkylcarbonyl, arylalkylcarbonyl, hydroxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, cycloalkyl, carboxyl, amino, guanidino, guanidino substituted by alkoxycarbonyl, carbamoyl, and heterocycloalkyl, up to the maximum number of substitutable substituents.

[0339] an alkoxycarbonyl group substituted by the same or different substituents selected from alkyl, alkylcarbonyl, arylalkylcarbonyl, hydroxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, cycloalkyl, carboxyl, amino, guanidino, guanidino substituted by alkoxycarbonyl, carbamoyl, and heterocycloalkyl, up to the maximum number of substitutable substituents,

[0340] R 11 、R 12 、R 13 and R 14 Each independently is:

[0341] Hydrogen atoms, hydroxyl groups, or

[0342] an alkoxy group substituted by the same or different substituents selected from alkyl, alkylcarbonyl, arylalkylcarbonyl, hydroxy, alkoxy and heterocycloalkyl, from one to the maximum substitutable number,

[0343] X is CH2 or CO,

[0344] A is O, NH or S, wherein NH may be substituted by the same or different substituents selected from alkyl, alkylcarbonyl, arylalkylcarbonyl, hydroxy, alkoxy, alkoxycarbonyl, cycloalkyl, carboxyl and heterocycloalkyl, from one to the maximum substitutable number.

[0345] In one embodiment, R1 and R2 are each independently a hydrogen atom or a C 1-6 Alkyl, R3 and R4 are each independently a hydrogen atom, a C substituted by a carboxyl group 1-6 Alkyl or carboxyl, R5 is a hydrogen atom or C 1-6 Alkyl, R6 is a hydrogen atom or C 1-6 Alkyl, R7 is a hydrogen atom, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, carbamoyl C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl, hydroxyl C 6-10 Aryl C 1-6 Alkyl, C 5-10 Heteroaryl C 1-6 Alkyl, carboxyl C 1-6 Alkyl, amino C 1-6 Alkyl, thio C 1-6 Alkyl, C 1-6 Alkylthio C1-6 Alkyl, or amidinoamino C 1-6 Alkyl, R8 is a hydrogen atom or C 1-6 Alkyl, wherein R7 and R8 may form an optionally substituted heterocycloalkyl together with the carbon atom and nitrogen atom to which R7 and R8 are bonded, R9 and R 10 A hydrogen atom or C 1-6 Alkyl, R 11 、R 12 、R 13 and R 14 Each independently represents a hydrogen atom, an alkoxy group or a hydroxyl group, X represents CH2 or CO, A represents O, 1-6 NH, NH or S substituted with an alkyl group.

[0346] In one embodiment, R1 and R2 are each independently a hydrogen atom, a methyl group or an ethyl group, R3 and R4 are each independently a hydrogen atom, a carboxymethyl group, a carboxyethyl group, a carboxypropyl group or a carboxyl group, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is a hydrogen atom, a methyl group, an isopropyl group, an isobutyl group, a sec-butyl 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, an aminoethyl group, a thiomethyl group, a 2-methylthioethyl group, a carbamoylmethyl group, a carbamoylethyl group, an amidinopropyl group, an indolylmethyl group or a 4-imidazolemethyl group, and R8 is a hydrogen atom, wherein R7 and R8 may form a C 5-10 Heterocycloalkyl, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 are each independently a hydrogen atom, R 12 is a hydrogen atom, a methoxy group or a hydroxyl group, X is CH2 or CO, and A is O, NH or S.

[0347] In one embodiment, R1 and R2 are each independently a hydrogen atom or a C 1-6 alkyl.

[0348] In one embodiment, R1 and R2 are each independently a hydrogen atom, a methyl group or an ethyl group.

[0349] In one embodiment, R3 and R4 are each independently a hydrogen atom, a C 1-6 Alkyl or carboxyl.

[0350] In one embodiment, R3 and R4 are each independently a hydrogen atom, a carboxymethyl group, a carboxyethyl group, a carboxypropyl group or a carboxyl group.

[0351] In one embodiment, R5 is a hydrogen atom or C 1-6 alkyl.

[0352] In one embodiment, R5 is a hydrogen atom.

[0353] In one embodiment, R6 is a hydrogen atom or C 1-6 alkyl.

[0354] In one embodiment, R6 is a hydrogen atom.

[0355] In one embodiment, R7 is a hydrogen atom, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, carbamoyl C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl, hydroxyl C 6-10 Aryl C 1-6 Alkyl, C 5-10 Heteroaryl C 1-6 Alkyl, carboxyl C 1-6 Alkyl, amino C 1-6 Alkyl, thio C 1-6 Alkyl, C 1-6 Alkylthio C 1-6 Alkyl or amidinoamino C 1-6 alkyl.

[0356] In one embodiment, R7 is a hydrogen atom, a methyl group, an isopropyl group, an isobutyl group, a sec-butyl 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, an aminoethyl 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.

[0357] In one embodiment, R8 is a hydrogen atom or C 1-6 alkyl.

[0358] In one embodiment, R8 is a hydrogen atom.

[0359] In one embodiment, R7 and R8, together with the carbon atom and the nitrogen atom to which R7 and R8 are bonded, form an optionally substituted heterocycloalkyl group.

[0360] In one embodiment, R7 and R8 together with the carbon atom and nitrogen atom to which R7 and R8 are bonded form C 5-10 Heterocycloalkyl.

[0361] In one embodiment, R9 and R 10 A hydrogen atom or C 1-6 alkyl.

[0362] In one embodiment, R9 and R 10 are each independently a hydrogen atom or a methyl group.

[0363] In one embodiment, R11 、R 12 、R 13 and R 14 Each is independently a hydrogen atom, an alkoxy group or a hydroxyl group.

[0364] In one embodiment, R 12 is a hydrogen atom, a methoxy group or a hydroxyl group.

[0365] In one embodiment, R 11 、R 12 、R 13 and R 14 Each is independently a hydrogen atom, a methoxy group or a hydroxyl group.

[0366] In one embodiment, X is CH2 or CO.

[0367] In one embodiment, A is O, C 1-6 NH, NH or S substituted with an alkyl group.

[0368] In one embodiment, A is O, NH or S.

[0369] In one embodiment, R1 and R2 are methyl or ethyl, R3 and R4 are carboxyl or carboxyethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is an isopropyl group, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0370] In one embodiment, R1 and R2 are methyl or ethyl, R3 and R4 are carboxyl or carboxyethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is a hydrogen atom, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0371] In one embodiment, R1 and R2 are hydrogen atoms, R3 and R4 are carboxyl or carboxyethyl groups, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is a hydrogen atom, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0372] In one embodiment, R1 and R2 are hydrogen atoms or methyl groups, R3 and R4 are carboxyl groups or carboxyethyl groups, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is a hydrogen atom, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0373] In one embodiment, R1 and R2 are hydrogen atoms, R3 and R4 are carboxyl or carboxyethyl groups, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is an isopropyl group, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0374] In one embodiment, R1 and R2 are methyl or ethyl, R3 and R4 are carboxyl or carboxyethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is an isopropyl group, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0375] In one embodiment, R1 and R2 are hydrogen atoms, R3 and R4 are carboxyl or carboxyethyl groups, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is a hydrogen atom, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0376] In one embodiment, R1 and R2 are hydrogen atoms, R3 and R4 are carboxyl or carboxyethyl groups, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is an isopropyl group, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0377] In one embodiment, R1 and R2 are methyl or ethyl, R3 and R4 are carboxyl or carboxymethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is an isopropyl group, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0378] In one embodiment, R1 and R2 are methyl or ethyl, R3 and R4 are carboxyl or carboxymethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is a hydrogen atom, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0379] In one embodiment, R1 and R2 are hydrogen atoms, R3 and R4 are carboxyl groups or carboxymethyl groups, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is a hydrogen atom, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0380] In one embodiment, R1 and R2 are hydrogen atoms or methyl groups, R3 and R4 are carboxyl groups or carboxymethyl groups, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is a hydrogen atom, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0381] In one embodiment, R1 and R2 are methyl or ethyl, R3 and R4 are carboxyl or carboxyethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is a hydrogen atom, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom, R 11 、R 12 、R 13 and R 14 is a hydrogen atom, X is CH2, and A is O.

[0382] In one embodiment, R1 and R2 are methyl or ethyl, R3 and R4 are carboxyl or carboxyethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is an isopropyl group, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 12 、R 13 and R 14 is a hydrogen atom, X is CH2, and A is O.

[0383] In one embodiment, R1 and R2 are methyl or ethyl, R3 and R4 are carboxyl or carboxymethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is an isopropyl group, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0384] In one embodiment, R1 and R2 are methyl groups, R3 and R4 are carboxyl groups or carboxyethyl groups, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is an isopropyl group, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0385] In one embodiment, R1 and R2 are methyl groups, R3 and R4 are carboxyl groups or carboxymethyl groups, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is an isopropyl group, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0386] In one embodiment, R1 and R2 are methyl or ethyl, R3 and R4 are hydrogen atoms or carboxypropyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is isopropyl, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0387] In one embodiment, R1 and R2 are methyl groups, R3 and R4 are carboxyl groups or carboxyethyl groups, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is an isopropyl group, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0388] In one embodiment, R1 and R2 are methyl or ethyl, R3 and R4 are carboxyl or carboxyethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is an isopropyl group, R8 is a hydrogen atom, R9 and R 10 is methyl, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0389] In one embodiment, R1 and R2 are methyl or ethyl, R3 and R4 are carboxyl or carboxyethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is a benzyl group, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0390] In one embodiment, R1 and R2 are methyl or ethyl, R3 and R4 are carboxyl or carboxyethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is a carboxyethyl, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0391] In one embodiment, R1 and R2 are methyl or ethyl, R3 and R4 are carboxyl or carboxyethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is a carboxymethyl, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0392] In one embodiment, R1 and R2 are methyl or ethyl, R3 and R4 are carboxyl or carboxyethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is a hydroxymethyl group, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0393] In one embodiment, R1 and R2 are methyl or ethyl, R3 and R4 are carboxyl or carboxyethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is a 1-hydroxyethyl, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0394] In one embodiment, R1 and R2 are methyl or ethyl, R3 and R4 are carboxyl or carboxyethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is a 4-hydroxybenzyl group, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0395] In one embodiment, R1 and R2 are methyl or ethyl, R3 and R4 are carboxyl or carboxyethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is 4-aminobutyl, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0396] In one embodiment, R1 and R2 are methyl or ethyl, R3 and R4 are carboxyl or carboxyethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is an amidinoaminopropyl group, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0397] In one embodiment, R1 and R2 are methyl or ethyl, R3 and R4 are carboxyl or carboxyethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is a carbamoylethyl, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0398] In one embodiment, R1 and R2 are methyl or ethyl, R3 and R4 are carboxyl or carboxyethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is a carbamoylmethyl group, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0399] In one embodiment, R1 and R2 are methyl or ethyl, R3 and R4 are carboxyl or carboxyethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is a 4-imidazole methyl group, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0400] In one embodiment, R1 and R2 are methyl or ethyl, R3 and R4 are carboxyl or carboxyethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is an indolylmethyl group, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0401] In one embodiment, R1 and R2 are methyl or ethyl, R3 and R4 are carboxyl or carboxyethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 and R8 together with the carbon atom and nitrogen atom to which they are bonded form a pyrrolidine ring, R9 and R 10 is a hydrogen atom or a methyl group, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0402] In one embodiment, R1 and R2 are methyl or ethyl, R3 and R4 are carboxyl or carboxyethyl, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is an isopropyl group, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is methoxy, X is CH2, and A is O.

[0403] In one embodiment, R1 and R2 are ethyl groups, R3 and R4 are carboxyl groups or carboxyethyl groups, R5 is a hydrogen atom, R6 is a hydrogen atom, R7 is an isopropyl group, R8 is a hydrogen atom, R9 and R 10 is a hydrogen atom, R 11 、R 13 and R 14 is a hydrogen atom, R 12 is hydroxyl, X is CH2, and A is O.

[0404] In one embodiment, X in the above embodiment is CO.

[0405] In one embodiment, A in the above embodiment is NH.

[0406] In one embodiment, A in the above embodiment is S.

[0407] The present disclosure may include compounds having any of the following substituents.

[0408] [Chemistry 4]

[0409]

[0410] [Table 1-1]

[0411]

[0412] [Table 1-2]

[0413]

[0414] In addition, the indolylmethyl group in Table 19 above independently represents a 2-indolylmethyl group or a 3-indolylmethyl group in each case.

[0415] [Table 1-3]

[0416] (X,A,R1,R2,R3,R4,R5,R6,R7,R8,R9,R10,R11,R12,R13,R14)=(1,1,2,2,2,2,1,1,1,1,1,2,1,2,1,1),(1,1,3,2,2,2,1,1,1,1,1,2,1,2,1,1),(1,1,3,3,2,2,1,1,1,1,1,2,1,2,1,1),(1,1,2,2,3,2,1,1,1,1,1,2,1,2,1,1),(1,1,3,2,3,2,1,1,1,1,1,2,1,2,1,1),(1,1,3,3,3,2,1,1,1,1,1,2,1,2,1,1),(1,1,2,2,4,2,1,1,1,1,1,2,1,2,1,1),(1,1,3,2,4,2,1,1,1,1,1,2,1,2,1,1),(1,1,3,3,4,2,1,1,1,1,1,2,1,2,1,1),(1,1,2,2,5,2,1,1,1,1,1,2,1,2,1,1),(1,1,3,2,5,2,1,1,1,1,1,2,1,2,1,1),(1,1,3,3,5,2,1,1,1,1,1,2,1,2,1,1),(1,1,2,2,3,3,1,1,1,1,1,2,1,2,1,1),(1,1,3,2,3,3,1,1,1,1,1,2,1,2,1,1),(1,1,3,3,3,3,1,1,1,1,1,2,1,2,1,1).(1,1,2,2,4,3,1,1,1,1,1,2,1,2,1,1),(1,1,3,2,4,3,1,1,1,1,1,2,1,2,1,1).(1,1,3,3,4,3,1,1,1,1,1,2,1,2,1,1),(1,1,2,2,5,3,1,1,1,1,1,2,1,2,1,1),(1,1,3,2,5,3,1,1,1,1,1,2,1,2,1,1),(1,1,3,3,5,3,1,1,1,1,1,2,1,2,1,1),(1,1,2,2,4,4,1,1,1,1,1,2,1,2,1,1),(1,1,3,2,4,4,1,1,1,1,1,2,1,2,1,1),(1,1,3,3,4,4,1,1,1,1,1,2,1,2,1,1),(1,1,2,2,5,4,1,1,1,1,1,2,1,2,1,1),(1,1,3,2,5,4,1,1,1,1,1,2,1,2,1,1),(1,1,3,3,5,4,1,1,1,1,1,2,1,2,1,1),(1,1,2,2,5,5,1,1,1,1,1,2,1,2,1，1)，(1，1，3，2，5，5，1，1，1，1，1，2，1，2，1，1)，(1，1，3，3，5，5，1，1，1，1，1，2，1，2，1，1)，(1，1，2，2，2，2，1，1，2，2，1，2，1，2，1，1)，(1，1，3，2，2，2，1，1，2，2，1，2，1，2，1，1)，(1，1，3，3，2，2，1，1，2，2，1，2，1，2，1，1)，(1，1，2，2，3，2，1，1，2，2，1，2，1，2，1，1)，(1，1，3，2，3，2，1，1，2，2，1，2，1，2，1，1)，(1，1，3，3，3，2，1，1，2，2，1，2，1，2，1，1)，(1，1，2，2，4，2，1，1，2，2，1，2，1，2，1，1)，(1，1，3，2，4，2，1，1，2，2，1，2，1，2，1，1)，(1，1，3，3，4，2，1，1，2，2，1，2，1，2，1，1)，(1，1，2，2，5，2，1，1，2，2，1，2，1，2，1，1)，(1，1，3，2，5，2，1，1，2，2，1，2，1，2，1，1)，(1，1，3，3，5，2，1，1，2，2，1，2，1，2，1，1)，(1，1，2，2，3，3，1，1，2，2，1，2，1，2，1，1)，(1，1，3，2，3，3，1，1，2，2，1，2，1，2，1，1)，(1，1，3，3，3，3，1，1，2，2，1，2，1，2，1，1)，(1，1，2，2，4，3，1，1，2，2，1，2，1，2，1，1)，(1，1，3，2，4，3，1，1，2，2，1，2，1，2，1，1)，(1，1，3，3，4，3，1，1，2，2，1，2，1，2，1，1)，(1，1，2，2，5，3，1，1，2，2，1，2，1，2，1，1)，(1，1，3，2，5，3，1，1，2，2，1，2，1，2，1，1)，(1，1，3，3，5，3，1，1，2，2，1，2，1，2，1，1)，(1，1，2，2，4，4，1，1，2，2，1，2，1，2，1，1)，(1，1，3，2，4，4，1，1，2，2，1，2，1，2，1，1)，(1，1，3，3，4，4，1，1，2，2，1，2，1，2，1，1)，(1，1，2，2，5，4，1，1，2，2，1，2，1，2，1，1)，(1，1，3，2，5，4，1，1，2，2，1，2，1，2，1，1)，(1，1，3，3，5，4，1，1，2，2，1，2，1，2，1，1)，(1，1，2，2，5,5,1,1,2,2,1,2,1,2,1,1),(1,1,3,2,5,5,1,1,2,2,1,2,1,2,1,1),(1,1,3,3,5,5,1,1,2,2,1,2,1,2,1,1),(1,1,2,2,2,2,1,1,3,1,1,2,1,2,1,1),(1,1,3,2,2,2,1,1,3,1,1,2,1,2,1,1),(1,1,3,3,2,2,1,1,3,1, 1,2,1,2,1,1),(1,1,2,2,3,2,1,1,3,1,1,2,1,2,1,1),(1,1,3,2,3,2,1,1,3,1,1,2,1,2,1,1),(1,1,3,3,3,2,1,1,3,1,1,2,1,2,1,1),(1,1,2,2,4,2,1,1,3,1,1,2,1,2,1,1),(1,1,3,2,4,2,1,1,3,1,1,2,1,2,1,1),

[0417] [Table 1-4]

[0418] (1，1，3，3，4，2，1，1，3，1，1，2，1，2，1，1)，(1，1，2，2，5，2，1，1，3，1，1，2，1，2，1，1)，(1，1，3，2，5，2，1，1，3，1，1，2，1，2，1，1)，(1，1，3，3，5，2，1，1，3，1，1，2，1，2，1，1)，(1，1，2，2，3，3，1，1，3，1，1，2，1，2，1，1)，(1，1，3，2，3，3，1，1，3，1，1，2，1，2，1，1)，(1，1，3，3，3，3，1，1，3，1，1，2，1，2，1，1)，(1，1，2，2，4，3，1，1，3，1，1，2，1，2，1，1)，(1，1，3，2，4，3，1，1，3，1，1，2，1，2，1，1)，(1，1，3，3，4，3，1，1，3，1，1，2，1，2，1，1)，(1，1，2，2，5，3，1，1，3，1，1，2，1，2，1，1)，(1，1，3，2，5，3，1，1，3，1，1，2，1，2，1，1)，(1，1，3，3，5，3，1，1，3，1，1，2，1，2，1，1)，(1，1，2，2，4，4，1，1，3，1，1，2，1，2，1，1)，(1，1，3，2，4，4，1，1，3，1，1，2，1，2，1，1)，(1，1，3，3，4，4，1，1，3，1，1，2，1，2，1，1)，(1，1，2，2，5，4，1，1，3，1，1，2，1，2，1，1)，(1，1，3，2，5，4，1，1，3，1，1，2，1，2，1，1)，(1，1，3，3，5，4，1，1，3，1，1，2，1，2，1，1)，(1，1，2，2，5，5，1，1，3，1，1，2，1，2，1，1)，(1，1，3，2，5，5，1，1，3，1，1，2，1，2，1，1)，(1，1，3，3，5，5，1，1，3，1，1，2，1，2，1，1)，(1，1，2，2，2，2，1，1，4，1，1，2，1，2，1，1)，(1，1，3，2，2，2，1，1，4，1，1，2，1，2，1，1)，(1，1，3，3，2，2，1，1，4，1，1，2，1，2，1，1)，(1，1，2，2，3，2，1，1，4，1，1，2，1，2，1，1)，(1，1，3，2，3，2，1，1，4，1，1，2，1，2，1，1)，(1，1，3，3，3，2，1，1，4，1，1，2，1，2，1，1)，(1，1，2，2，4，2，1，1，4，1，1，2，1，2，1，1)，(1，1，3，2，4，2，1，1，4，1，1，2，1，2，1，1)，(1，1，3，3，4，2，1，1，4，1，1，2，1，2，1，1)，(1，1，2，2，5，2，1，1，4，1，1，2，1，2，1，1)，(1，1，3，2，5，2，1，1，4，1，1，2，1，2，1，1)，(1，1，3，3，5，2，1，1，4，1，1，2，1，2，1，1)，(1，1，2，2，3，3，1，1，4，1，1，2，1，2，1，1)，(1，1，3，2，3，3，1，1，4，1，1，2，1，2，1，1)，(1，1，3，3，3，3，1，1，4，1，1，2，1，2，1，1)，(1，1，2，2，4，3，1，1，4，1，1，2，1，2，1，1)，(1，1，3，2，4，3，1，1，4，1，1，2，1，2，1，1)，(1，1，3，3，4，3，1，1，4，1，1，2，1，2，1，1)，(1，1，2，2，5，3，1，1，4，1，1，2，1，2，1，1)，(1，1，3，2，5，3，1，1，4，1，1，2，1，2，1，1)，(1，1，3，3，5，3，1，1，4，1，1，2，1，2，1，1)，(1，1，2，2，4，4，1，1，4，1，1，2，1，2，1，1)，(1，1，3，2，4，4，1，1，4，1，1，2，1，2，1，1)，(1，1，3，3，4，4，1，1，4，1，1，2，1，2，1，1)，(1，1，2，2，5，4，1，1，4，1，1，2，1，2，1，1)，(1，1，3，2，5，4，1，1，4，1，1，2，1，2，1，1)，(1，1，3，3，5，4，1，1，4，1，1，2，1，2，1，1)，(1，1，2，2，5，5，1，1，4，1，1，2，1，2，1，1)，(1，1，3，2，5，5，1，1，4，1，1，2，1，2，1，1)，(1，1，3，3，5，5，1，1，4，1，1，2，1，2，1，1)，(1，1，2，2，2，2，1，1，5，1，1，2，1，2，1，1)，(1，1，3，2，2，2，1，1，5，1，1，2，1，2，1，1)，(1，1，3，3，2，2，1，1，5，1，1，2，1，2，1，1)，(1，1，2，2，3，2，1，1，5，1，1，2，1，2，1，1)，(1，1，3，2，3，2，1，1，5，1，1，2，1，2，1，1)，(1，1，3，3，3，2，1，1，5，1，1，2，1，2，1，1)，(1，1，2，2，4，2，1，1，5，1，1，2，1，2，1,1),(1,1,3,2,4,2,1,1,5,1,1,2,1,2,1,1),(1,1,3,3,4,2,1,1,5,1,1,2,1,2,1,1),(1,1,2,2,5,2,1,1,5,1,1,2,1,2,1,1),(1,1,3,2,5,2,1,1,5,1,1,2,1,2,1,1),(1,1,3,3,5,2,1,1,5,1,1,2,1,2,1,1),(1,1,2,2,3,3,1,1,5,1,1,2,1,2,1,1),(1,1,3,2,3,3,1 ,1,5,1,1,2,1,2,1,1),(1,1,3,3,3,3,1,1,5,1,1,2,1,2,1,1),(1,1,2,2,4,3,1,1,5,1,1,2,1,2,1,1),(1,1,3,2,4,3,1,1,5,1,1,2,1,2,1,1),(1,1,3,3,4,3,1,1,5,1,1,2,1,2,1,1),(1,1,2,2,5,3,1,1,5,1,1,2,1,2,1,1),(1,1,3,2,5,3,1,1,5,1,1,2,1,2,1,1),

[0419] [Table 1-5]

[0420] (1，1，3，3，5，3，1，1，5，1，1，2，1，2，1，1)，(1，1，2，2，4，4，1，1，5，1，1，2，1，2，1，1)，(1，1，3，2，4，4，1，1，5，1，1，2，1，2，1，1)，(1，1，3，3，4，4，1，1，5，1，1，2，1，2，1，1)，(1，1，2，2，5，4，1，1，5，1，1，2，1，2，1，1)，(1，1，3，2，5，4，1，1，5，1，1，2，1，2，1，1)，(1，1，3，3，5，4，1，1，5，1，1，2，1，2，1，1)，(1，1，2，2，5，5，1，1，5，1，1，2，1，2，1，1)，(1，1，3，2，5，5，1，1，5，1，1，2，1，2，1，1)，(1，1，3，3，5，5，1，1，5，1，1，2，1，2，1，1)，(1，1，2，2，2，2，1，1，6，1，1，2，1，2，1，1)，(1，1，3，2，2，2，1，1，6，1，1，2，1，2，1，1)，(1，1，3，3，2，2，1，1，6，1，1，2，1，2，1，1)，(1，1，2，2，3，2，1，1，6，1，1，2，1，2，1，1)，(1，1，3，2，3，2，1，1，6，1，1，2，1，2，1，1)，(1，1，3，3，3，2，1，1，6，1，1，2，1，2，1，1)，(1，1，2，2，4，2，1，1，6，1，1，2，1，2，1，1)，(1，1，3，2，4，2，1，1，6，1，1，2，1，2，1，1)，(1，1，3，3，4，2，1，1，6，1，1，2，1，2，1，1)，(1，1，2，2，5，2，1，1，6，1，1，2，1，2，1，1)，(1，1，3，2，5，2，1，1，6，1，1，2，1，2，1，1)，(1，1，3，3，5，2，1，1，6，1，1，2，1，2，1，1)，(1，1，2，2，3，3，1，1，6，1，1，2，1，2，1，1)，(1，1，3，2，3，3，1，1，6，1，1，2，1，2，1，1)，(1，1，3，3，3，3，1，1，6，1，1，2，1，2，1，1)，(1，1，2，2，4，3，1，1，6，1，1，2，1，2，1，1)，(1，1，3，2，4，3，1，1，6，1，1，2，1，2，1，1)，(1，1，3，3，4，3，1，1，6，1，1，2，1，2，1，1)，(1，1，2，2，5，3，1，1,6，1，1，2，1，2，1，1)，(1，1，3，2，5，3，1，1，6，1，1，2，1，2，1，1)，(1，1，3，3，5，3，1，1，6，1，1，2，1，2，1，1)，(1，1，2，2，4，4，1，1，6，1，1，2，1，2，1，1)，(1，1，3，2，4，4，1，1，6，1，1，2，1，2，1，1)，(1，1，3，3，4，4，1，1，6，1，1，2，1，2，1，1)，(1，1，2，2，5，4，1，1，6，1，1，2，1，2，1，1)，(1，1，3，2，5，4，1，1，6，1，1，2，1，2，1，1)，(1，1，3，3，5，4，1，1，6，1，1，2，1，2，1，1)，(1，1，2，2，5，5，1，1，6，1，1，2，1，2，1，1)，(1，1，3，2，5，5，1，1，6，1，1，2，1，2，1，1)，(1，1，3，3，5，5，1，1，6，1，1，2，1，2，1，1)，(1，1，2，2，2，2，1，1，7，1，1，2，1，2，1，1)，(1，1，3，2，2，2，1，1，7，1，1，2，1，2，1，1)，(1，1，3，3，2，2，1，1，7，1，1，2，1，2，1，1)，(1，1，2，2，3，2，1，1，7，1，1，2，1，2，1，1)，(1，1，3，2，3，2，1，1，7，1，1，2，1，2，1，1)，(1，1，3，3，3，2，1，1，7，1，1，2，1，2，1，1)，(1，1，2，2，4，2，1，1，7，1，1，2，1，2，1，1)，(1，1，3，2，4，2，1，1，7，1，1，2，1，2，1，1)，(1，1，3，3，4，2，1，1，7，1，1，2，1，2，1，1)，(1，1，2，2，5，2，1，1，7，1，1，2，1，2，1，1)，(1，1，3，2，5，2，1，1，7，1，1，2，1，2，1，1)，(1，1，3，3，5，2，1，1，7，1，1，2，1，2，1，1)，(1，1，2，2，3，3，1，1，7，1，1，2，1，2，1，1)，(1，1，3，2，3，3，1，1，7，1，1，2，1，2，1，1)，(1，1，3，3，3，3，1，1，7，1，1，2，1，2，1，1)，(1，1，2，2，4，3，1，1，7，1，1，2，1，2，1，1)，(1，1，3，2，4，3，1，1，7，1，1，2，1，2，1，1)，(1，1，3，3，4，3，1，1，7，1，1，2，1，2，1，1)，(1，1，2，2，5，3，1，1，7，1，1，2，1，2，1,1),(1,1,3,2,5,3,1,1,7,1,1,2,1,2,1,1),(1,1,3,3,5,3,1,1,7,1,1,2,1,2,1,1),(1,1,2,2,4,4,1,1,7,1,1,2,1,2,1,1),(1,1,3,2,4,4,1,1,7,1,1,2,1,2,1,1),(1,1,3,3,4,4,1,1,7,1,1,2,1,2,1,1),(1,1,2,2,5,4,1,1,7,1,1,2,1,2,1,1),(1,1,3,2,5,4,1 ,1,7,1,1,2,1,2,1,1),(1,1,3,3,5,4,1,1,7,1,1,2,1,2,1,1),(1,1,2,2,5,5,1,1,7,1,1,2,1,2,1,1),(1,1,3,2,5,5,1,1,7,1,1,2,1,2,1,1),(1,1,3,3,5,5,1,1,7,1,1,2,1,2,1,1),(1,1,2,2,2,1,1,8,1,1,2,1,2,1,1),(1,1,3,2,2,2,1,1,8,1,1,2,1,2,1,1),

[0421] [Table 1-6]

[0422] (1，1，3，3，2，2，1，1，8，1，1，2，1，2，1，1)，(1，1，2，2，3，2，1，1，8，1，1，2，1，2，1，1)，(1，1，3，2，3，2，1，1，8，1，1，2，1，2，1，1)，(1，1，3，3，3，2，1，1，8，1，1，2，1，2，1，1)，(1，1，2，2，4，2，1，1，8，1，1，2，1，2，1，1)，(1，1，3，2，4，2，1，1，8，1，1，2，1，2，1，1)，(1，1，3，3，4，2，1，1，8，1，1，2，1，2，1，1)，(1，1，2，2，5，2，1，1，8，1，1，2，1，2，1，1)，(1，1，3，2，5，2，1，1，8，1，1，2，1，2，1，1)，(1，1，3，3，5，2，1，1，8，1，1，2，1，2，1，1)，(1，1，2，2，3，3，1，1，8，1，1，2，1，2，1，1)，(1，1，3，2，3，3，1，1，8，1，1，2，1，2，1，1)，(1，1，3，3，3，3，1，1，8，1，1，2，1，2，1，1)，(1，1，2，2，4，3，1，1，8，1，1，2，1，2，1，1)，(1，1，3，2，4，3，1，1，8，1，1，2，1，2，1，1)，(1，1，3，3，4，3，1，1，8，1，1，2，1，2，1，1)，(1，1，2，2，5，3，1，1，8，1，1，2，1，2，1，1)，(1，1，3，2，5，3，1，1，8，1，1，2，1，2，1，1)，(1，1，3，3，5，3，1，1，8，1，1，2，1，2，1，1)，(1，1，2，2，4，4，1，1，8，1，1，2，1，2，1，1)，(1，1，3，2，4，4，1，1，8，1，1，2，1，2，1，1)，(1，1，3，3，4，4，1，1，8，1，1，2，1，2，1，1)，(1，1，2，2，5，4，1，1，8，1，1，2，1，2，1，1)，(1，1，3，2，5，4，1，1，8，1，1，2，1，2，1，1)，(1，1，3，3，5，4，1，1，8，1，1，2，1，2，1，1)，(1，1，2，2，5，5，1，1，8，1，1，2，1，2，1，1)，(1，1，3，2，5，5，1，1，8，1，1，2，1，2，1，1)，(1，1，3，3，5，5，1，1，8，1，1，2，1，2，1，1)，(1，1，2，2，2，2，1，1，9，1，1，2，1，2，1，1)，(1，1，3，2，2，2，1，1，9，1，1，2，1，2，1，1)，(1，1，3，3，2，2，1，1，9，1，1，2，1，2，1，1)，(1，1，2，2，3，2，1，1，9，1，1，2，1，2，1，1)，(1，1，3，2，3，2，1，1，9，1，1，2，1，2，1，1)，(1，1，3，3，3，2，1，1，9，1，1，2，1，2，1，1)，(1，1，2，2，4，2，1，1，9，1，1，2，1，2，1，1)，(1，1，3，2，4，2，1，1，9，1，1，2，1，2，1，1)，(1，1，3，3，4，2，1，1，9，1，1，2，1，2，1，1)，(1，1，2，2，5，2，1，1，9，1，1，2，1，2，1，1)，(1，1，3，2，5，2，1，1，9，1，1，2，1，2，1，1)，(1，1，3，3，5，2，1，1，9，1，1，2，1，2，1，1)，(1，1，2，2，3，3，1，1，9，1，1，2，1，2，1，1)，(1，1，3，2，3，3，1，1，9，1，1，2，1，2，1，1)，(1，1，3，3，3，3，1，1，9，1，1，2，1，2，1，1)，(1，1，2，2，4，3，1，1，9，1，1，2，1，2，1，1)，(1，1，3，2，4，3，1，1，9，1，1，2，1，2，1，1)，(1，1，3，3，4，3，1，1，9，1，1，2，1，2，1，1)，(1，1，2，2，5，3，1，1，9，1，1，2，1，2，1，1)，(1，1，3，2，5，3，1，1，9，1，1，2，1，2，1，1)，(1，1，3，3，5，3，1，1，9，1，1，2，1，2，1，1)，(1，1，2，2，4，4，1，1，9，1，1，2，1，2，1，1)，(1，1，3，2，4，4，1，1，9，1，1，2，1，2，1，1)，(1，1，3，3，4，4，1，1，9，1，1，2，1，2，1，1)，(1，1，2，2，5，4，1，1，9，1，1，2，1，2，1，1)，(1，1，3，2，5，4，1，1，9，1，1，2，1，2，1，1)，(1，1，3，3，5，4，1，1，9，1，1，2，1，2，1，1)，(1，1，2，2，5，5，1，1，9，1，1，2，1，2，1，1)，(1，1，3，2，5，5，1，1，9，1，1，2，1，2，1，1)，(1，1，3，3，5，5，1，1，9，1，1，2，1，2，1，1)，(1，1，2，2，2，2，1，1，10，1，1，2，1，2，1,1),(1,1,3,2,2,2,1,1,10,1,1,2,1,2,1,1),(1,1,3,3,2,2,1,1,10,1,1,2,1,2,1,1),(1,1,2,2,3,2,1,1,10,1,1,2,1,2,1,1),(1,1,3,2,3,2,1,1,10,1,1,2,1,2,1,1),(1,1,3,3,3,2,1,1,10,1,1,2,1,2,1,1),(1,1,2,2,4,2,1, 1,10,1,1,2,1,2,1,1),(1,1,3,2,4,2,1,1,10,1,1,2,1,2,1,1),(1,1,3,3,4,2,1,1,10,1,1,2,1,2,1,1),(1,1,2,2,5,2,1,1,10,1,1,2,1,2,1,1),(1,1,3,2,5,2,1,1,10,1,1,2,1,2,1,1),(1,1,3,3,5,2,1,1,10,1,1,2,1,2,1,1),

[0423] [Table 1-7]

[0424] (1，1，2，2，3，3，1，1，10，1，1，2，1，2，1，1)，(1，1，3，2，3，3，1，1，10，1，1，2，1，2，1，1)，(1，1，3，3，3，3，1，1，10，1，1，2，1，2，1，1)，(1，1，2，2，4，3，1，1，10，1，1，2，1，2，1，1)，(1，1，3，2，4，3，1，1，10，1，1，2，1，2，1，1)，(1，1，3，3，4，3，1，1，10，1，1，2，1，2，1，1)，(1，1，2，2，5，3，1，1，10，1，1，2，1，2，1，1)，(1，1，3，2，5，3，1，1，10，1，1，2，1，2，1，1)，(1，1，3，3，5，3，1，1，10，1，1，2，1，2，1，1)，(1，1，2，2，4，4，1，1，10，1，1，2，1，2，1，1)，(1，1，3，2，4，4，1，1，10，1，1，2，1，2，1，1)，(1，1，3，3，4，4，1，1，10，1，1，2，1，2，1，1)，(1，1，2，2，5，4，1，1，10，1，1，2，1，2，1，1)，(1，1，3，2，5，4，1，1，10，1，1，2，1，2，1，1)，(1，1，3，3，5，4，1，1，10，1，1，2，1，2，1，1)，(1，1，2，2，5，5，1，1，10，1，1，2，1，2，1，1)，(1，1，3，2，5，5，1，1，10，1，1，2，1，2，1，1)，(1，1，3，3，5，5，1，1，10，1，1，2，1，2，1，1)，(1，1，2，2，2，2，1，1，11，1，1，2，1，2，1，1)，(1，1，3，2，2，2，1，1，11，1，1，2，1，2，1，1)，(1，1，3，3，2，2，1，1，11，1，1，2，1，2，1，1)，(1，1，2，2，3，2，1，1，11，1，1，2，1，2，1，1)，(1，1，3，2，3，2，1，1，11，1，1，2，1，2，1，1)，(1，1，3，3，3，2，1，1，11，1，1，2，1，2，1，1)，(1，1，2，2，4，2，1，1，11，1，1，2，1，2，1，1)，(1，1，3，2，4，2，1，1，11，1，1，2，1，2，1，1)，(1，1，3，3，4，2，1，1，11，1，1，2，1，2，1，1)，(1，1，2，2，5，2，1，1，11，1，1，2，1，2，1，1)，(1，1，3，2，5，2，1，1，11，1，1，2，1，2，1，1)，(1，1，3，3，5，2，1，1，11，1，1，2，1，2，1，1)，(1，1，2，2，3，3，1，1，11，1，1，2，1，2，1，1)，(1，1，3，2，3，3，1，1，11，1，1，2，1，2，1，1)，(1，1，3，3，3，3，1，1，11，1，1，2，1，2，1，1)，(1，1，2，2，4，3，1，1，11，1，1，2，1，2，1，1)，(1，1，3，2，4，3，1，1，11，1，1，2，1，2，1，1)，(1，1，3，3，4，3，1，1，11，1，1，2，1，2，1，1)，(1，1，2，2，5，3，1，1，11，1，1，2，1，2，1，1)，(1，1，3，2，5，3，1，1，11，1，1，2，1，2，1，1)，(1，1，3，3，5，3，1，1，11，1，1，2，1，2，1，1)，(1，1，2，2，4，4，1，1，11，1，1，2，1，2，1，1)，(1，1，3，2，4，4，1，1，11，1，1，2，1，2，1，1)，(1，1，3，3，4，4，1，1，11，1，1，2，1，2，1，1)，(1，1，2，2，5，4，1，1，11，1，1，2，1，2，1，1)，(1，1，3，2，5，4，1，1，11，1，1，2，1，2，1，1)，(1，1，3，3，5，4，1，1，11，1，1，2，1，2，1，1)，(1，1，2，2，5，5，1，1，11，1，1，2，1，2，1，1)，(1，1，3，2，5，5，1，1，11，1，1，2，1，2，1，1)，(1，1，3，3，5，5，1，1，11，1，1，2，1，2，1，1)，(1，1，2，2，2，2，1，1，12，1，1，2，1，2，1，1)，(1，1，3，2，2，2，1，1，12，1，1，2，1，2，1，1)，(1，1，3，3，2，2，1，1，12，1，1，2，1，2，1，1)，(1，1，2，2，3，2，1，1，12，1，1，2，1，2，1，1)，(1，1，3，2，3，2，1，1，12，1，1，2，1，2，1，1)，(1，1，3，3，3，2，1，1，12，1，1，2，1，2，1，1)，(1，1，2，2，4，2，1，1，12，1，1，2，1，2，1，1)，(1，1，3，2，4，2，1，1，12，1，1，2，1，2，1，1)，(1，1，3，3，4，2，1，1，12，1，1，2，1，2，1，1)，(1，1，2,2,5,2,1,1,12,1,1,2,1,2,1,1),(1,1,3,2,5,2,1,1,12,1,1,2,1,2,1,1),(1,1,3,3,5,2,1,1,12,1,1,2,1,2,1,1),(1,1,2,2,3,3,1,1,12,1,1,2,1,2, 1,1),(1,1,3,2,3,3,1,1,12,1,1,2,1,2,1,1),(1,1,3,3,3,3,1,1,12,1,1,2,1,2,1,1),(1,1,2,2,4,3,1,1,12,1,1,2,1,1),(1,1,3,2,4,3,1,1,12, 1,1,2,1,2,1,1),(1,1,3,3,4,3,1,1,12,1,1,2,1,2,1,1),(1,1,2,2,5,3,1,1,12,1,1,2,1,2,1,1),(1,1,3,2,5,3,1,1,12,1,1,2,1,2,1,1),(1,1,3,3,5 ,3,1,1,12,1,1,2,1,2,1,1),(1,1,2,2,4,4,1,1,12,1,1,2,1,2,1,1),(1,1,3,2,4,4,1,1,12,1,1,2,1,2,1,1),(1,1,3,3,4,4,1,1,12,1,1,2,1,2,1,1),

[0425] [Table 1-8]

[0426] (1，1，2，2，5，4，1，1，12，1，1，2，1，2，1，1)，(1，1，3，2，5，4，1，1，12，1，1，2，1，2，1，1)，(1，1，3，3，5，4，1，1，12，1，1，2，1，2，1，1)，(1，1，2，2，5，5，1，1，12，1，1，2，1，2，1，1)，(1，1，3，2，5，5，1，1，12，1，1，2，1，2，1，1)，(1，1，3，3，5，5，1，1，12，1，1，2，1，2，1，1)，(1，1，2，2，2，2，1，1，13，1，1，2，1，2，1，1)，(1，1，3，2，2，2，1，1，13，1，1，2，1，2，1，1)，(1，1，3，3，2，2，1，1，13，1，1，2，1，2，1，1)，(1，1，2，2，3，2，1，1，13，1，1，2，1，2，1，1)，(1，1，3，2，3，2，1，1，13，1，1，2，1，2，1，1)，(1，1，3，3，3，2，1，1，13，1，1，2，1，2，1，1)，(1，1，2，2，4，2，1，1，13，1，1，2，1，2，1，1)，(1，1，3，2，4，2，1，1，13，1，1，2，1，2，1，1)，(1，1，3，3，4，2，1，1，13，1，1，2，1，2，1，1)，(1，1，2，2，5，2，1，1，13，1，1，2，1，2，1，1)，(1，1，3，2，5，2，1，1，13，1，1，2，1，2，1，1)，(1，1，3，3，5，2，1，1，13，1，1，2，1，2，1，1)，(1，1，2，2，3，3，1，1，13，1，1，2，1，2，1，1)，(1，1，3，2，3，3，1，1，13，1，1，2，1，2，1，1)，(1，1，3，3，3，3，1，1，13，1，1，2，1，2，1，1)，(1，1，2，2，4，3，1，1，13，1，1，2，1，2，1，1)，(1，1，3，2，4，3，1，1，13，1，1，2，1，2，1，1)，(1，1，3，3，4，3，1，1，13，1，1，2，1，2，1，1)，(1，1，2，2，5，3，1，1，13，1，1，2，1，2，1，1)，(1，1，3，2，5，3，1，1，13，1，1，2，1，2，1，1)，(1，1，3，3，5，3，1，1，13，1，1，2，1，2，1，1)，(1，1，2，2，4，4，1，1，13，1，1，2，1，2，1，1)，(1，1，3，2，4，4，1，1，13，1，1，2，1，2，1，1)，(1，1，3，3，4，4，1，1，13，1，1，2，1，2，1，1)，(1，1，2，2，5，4，1，1，13，1，1，2，1，2，1，1)，(1，1，3，2，5，4，1，1，13，1，1，2，1，2，1，1)，(1，1，3，3，5，4，1，1，13，1，1，2，1，2，1，1)，(1，1，2，2，5，5，1，1，13，1，1，2，1，2，1，1)，(1，1，3，2，5，5，1，1，13，1，1，2，1，2，1，1)，(1，1，3，3，5，5，1，1，13，1，1，2，1，2，1，1)，(1，1，2，2，2，2，1，1，14，1，1，2，1，2，1，1)，(1，1，3，2，2，2，1，1，14，1，1，2，1，2，1，1)，(1，1，3，3，2，2，1，1，14，1，1，2，1，2，1，1)，(1，1，2，2，3，2，1，1，14，1，1，2，1，2，1，1)，(1，1，3，2，3，2，1，1，14，1，1，2，1，2，1，1)，(1，1，3，3，3，2，1，1，14，1，1，2，1，2，1，1)，(1，1，2，2，4，2，1，1，14，1，1，2，1，2，1，1)，(1，1，3，2，4，2，1，1，14，1，1，2，1，2，1，1)，(1，1，3，3，4，2，1，1，14，1，1，2，1，2，1，1)，(1，1，2，2，5，2，1，1，14，1，1，2，1，2，1，1)，(1，1，3，2，5，2，1，1，14，1，1，2，1，2，1，1)，(1，1，3，3，5，2，1，1，14，1，1，2，1，2，1，1)，(1，1，2，2，3，3，1，1，14，1，1，2，1，2，1，1)，(1，1，3，2，3，3，1，1，14，1，1，2，1，2，1，1)，(1，1，3，3，3，3，1，1，14，1，1，2，1，2，1，1)，(1，1，2，2，4，3，1，1，14，1，1，2，1，2，1，1)，(1，1，3，2，4，3，1，1，14，1，1，2，1，2，1，1)，(1，1，3，3，4，3，1，1，14，1，1，2，1，2，1，1)，(1，1，2，2，5，3，1，1，14，1，1，2，1，2，1，1)，(1，1，3，2，5，3，1，1，14，1，1，2，1，2，1，1)，(1，1，3，3，5，3，1，1，14，1，1，2，1，2，1，1)，(1，1，2,2,4,4,1,1,14,1,1,2,1,2,1,1),(1,1,3,2,4,4,1,1,14,1,1,2,1,2,1,1),(1,1,3,3,4,4,1,1,14,1,1,2,1,2,1,1),(1,1,2,2,5,4,1,1,14,1,1,2,1,2, 1,1),(1,1,3,2,5,4,1,1,14,1,1,2,1,2,1,1),(1,1,3,3,5,4,1,1,14,1,1,2,1,2,1,1),(1,1,2,2,5,5,1,1,14,1,1,2,1,2,1,1),(1,1,3,2,5,5,1,1,14, 1,1,2,1,2,1,1),(1,1,3,3,5,5,1,1,14,1,1,2,1,2,1,1),(1,1,2,2,2,2,1,1,15,1,1,2,1,2,1,1),(1,1,3,2,2,2,1,1,15,1,1,2,1,2,1,1),(1,1,3,3,2 ,2,1,1,15,1,1,2,1,2,1,1),(1,1,2,2,3,2,1,1,15,1,1,2,1,2,1,1),(1,1,3,2,3,2,1,1,15,1,1,2,1,2,1,1),(1,1,3,3,3,2,1,1,15,1,1,2,1,2,1,1),

[0427] [Table 1-9]

[0428] (1，1，2，2，4，2，1，1，15，1，1，2，1，2，1，1)，(1，1，3，2，4，2，1，1，15，1，1，2，1，2，1，1)，(1，1，3，3，4，2，1，1，15，1，1，2，1，2，1，1)，(1，1，2，2，5，2，1，1，15，1，1，2，1，2，1，1)，(1，1，3，2，5，2，1，1，15，1，1，2，1，2，1，1)，(1，1，3，3，5，2，1，1，15，1，1，2，1，2，1，1)，(1，1，2，2，3，3，1，1，15，1，1，2，1，2，1，1)，(1，1，3，2，3，3，1，1，15，1，1，2，1，2，1，1)，(1，1，3，3，3，3，1，1，15，1，1，2，1，2，1，1)，(1，1，2，2，4，3，1，1，15，1，1，2，1，2，1，1)，(1，1，3，2，4，3，1，1，15，1，1，2，1，2，1，1)，(1，1，3，3，4，3，1，1，15，1，1，2，1，2，1，1)，(1，1，2，2，5，3，1，1，15，1，1，2，1，2，1，1)，(1，1，3，2，5，3，1，1，15，1，1，2，1，2，1，1)，(1，1，3，3，5，3，1，1，15，1，1，2，1，2，1，1)，(1，1，2，2，4，4，1，1，15，1，1，2，1，2，1，1)，(1，1，3，2，4，4，1，1，15，1，1，2，1，2，1，1)，(1，1，3，3，4，4，1，1，15，1，1，2，1，2，1，1)，(1，1，2，2，5，4，1，1，15，1，1，2，1，2，1，1)，(1，1，3，2，5，4，1，1，15，1，1，2，1，2，1，1)，(1，1，3，3，5，4，1，1，15，1，1，2，1，2，1，1)，(1，1，2，2，5，5，1，1，15，1，1，2，1，2，1，1)，(1，1，3，2，5，5，1，1，15，1，1，2，1，2，1，1)，(1，1，3，3，5，5，1，1，15，1，1，2，1，2，1，1)，(1，1，2，2，2，2，1，1，16，1，1，2，1，2，1，1)，(1，1，3，2，2，2，1，1，16，1，1，2，1，2，1，1)，(1，1，3，3，2，2，1，1，16，1，1，2，1，2，1，1)，(1，1，2，2，3，2，1，1，16，1，1，2，1，2，1，1)，(1，1，3，2，3，2，1，1，16，1，1，2，1，2，1，1)，(1，1，3，3，3，2，1，1，16，1，1，2，1，2，1，1)，(1，1，2，2，4，2，1，1，16，1，1，2，1，2，1，1)，(1，1，3，2，4，2，1，1，16，1，1，2，1，2，1，1)，(1，1，3，3，4，2，1，1，16，1，1，2，1，2，1，1)，(1，1，2，2，5，2，1，1，16，1，1，2，1，2，1，1)，(1，1，3，2，5，2，1，1，16，1，1，2，1，2，1，1)，(1，1，3，3，5，2，1，1，16，1，1，2，1，2，1，1)，(1，1，2，2，3，3，1，1，16，1，1，2，1，2，1，1)，(1，1，3，2，3，3，1，1，16，1，1，2，1，2，1，1)，(1，1，3，3，3，3，1，1，16，1，1，2，1，2，1，1)，(1，1，2，2，4，3，1，1，16，1，1，2，1，2，1，1)，(1，1，3，2，4，3，1，1，16，1，1，2，1，2，1，1)，(1，1，3，3，4，3，1，1，16，1，1，2，1，2，1，1)，(1，1，2，2，5，3，1，1，16，1，1，2，1，2，1，1)，(1，1，3，2，5，3，1，1，16，1，1，2，1，2，1，1)，(1，1，3，3，5，3，1，1，16，1，1，2，1，2，1，1)，(1，1，2，2，4，4，1，1，16，1，1，2，1，2，1，1)，(1，1，3，2，4，4，1，1，16，1，1，2，1，2，1，1)，(1，1，3，3，4，4，1，1，16，1，1，2，1，2，1，1)，(1，1，2，2，5，4，1，1，16，1，1，2，1，2，1，1)，(1，1，3，2，5，4，1，1，16，1，1，2，1，2，1，1)，(1，1，3，3，5，4，1，1，16，1，1，2，1，2，1，1)，(1，1，2，2，5，5，1，1，16，1，1，2，1，2，1，1)，(1，1，3，2，5，5，1，1，16，1，1，2，1，2，1，1)，(1，1，3，3，5，5，1，1，16，1，1，2，1，2，1，1)，(1，1，2，2，2，2，1，1，17，1，1，2，1，2，1，1)，(1，1，3，2，2，2，1，1，17，1，1，2，1，2，1，1)，(1，1，3，3，2，2，1，1，17，1，1，2，1，2，1，1)，(1，1，2,2,3,2,1,1,17,1,1,2,1,2,1,1),(1,1,3,2,3,2,1,1,17,1,1,2,1,2,1,1),(1,1,3,3,3,2,1,1,17,1,1,2,1,2,1,1),(1,1,2,2,4,2,1,1,17,1,1,2,1,2, 1,1),(1,1,3,2,4,2,1,1,17,1,1,2,1,2,1,1),(1,1,3,3,4,2,1,1,17,1,1,2,1,2,1,1),(1,1,2,2,5,2,1,1,17,1,1,2,1,2,1,1),(1,1,3,2,5,2,1,1,17, 1,1,2,1,2,1,1),(1,1,3,3,5,2,1,1,17,1,1,2,1,2,1,1),(1,1,2,2,3,3,1,1,17,1,1,2,1,2,1,1),(1,1,3,2,3,3,1,1,17,1,1,2,1,2,1,1),(1,1,3,3,3 ,3,1,1,17,1,1,2,1,2,1,1),(1,1,2,2,4,3,1,1,17,1,1,2,1,2,1,1),(1,1,3,2,4,3,1,1,17,1,1,2,1,2,1,1),(1,1,3,3,4,3,1,1,17,1,1,2,1,2,1,1),

[0429] [Table 1-10]

[0430] (1，1，2，2，5，3，1，1，17，1，1，2，1，2，1，1)，(1，1，3，2，5，3，1，1，17，1，1，2，1，2，1，1)，(1，1，3，3，5，3，1，1，17，1，1，2，1，2，1，1)，(1，1，2，2，4，4，1，1，17，1，1，2，1，2，1，1)，(1，1，3，2，4，4，1，1，17，1，1，2，1，2，1，1)，(1，1，3，3，4，4，1，1，17，1，1，2，1，2，1，1)，(1，1，2，2，5，4，1，1，17，1，1，2，1，2，1，1)，(1，1，3，2，5，4，1，1，17，1，1，2，1，2，1，1)，(1，1，3，3，5，4，1，1，17，1，1，2，1，2，1，1)，(1，1，2，2，5，5，1，1，17，1，1，2，1，2，1，1)，(1，1，3，2，5，5，1，1，17，1，1，2，1，2，1，1)，(1，1，3，3，5，5，1，1，17，1，1，2，1，2，1，1)，(1，1，2，2，2，2，1，1，18，1，1，2，1，2，1，1)，(1，1，3，2，2，2，1，1，18，1，1，2，1，2，1，1)，(1，1，3，3，2，2，1，1，18，1，1，2，1，2，1，1)，(1，1，2，2，3，2，1，1，18，1，1，2，1，2，1，1)，(1，1，3，2，3，2，1，1，18，1，1，2，1，2，1，1)，(1，1，3，3，3，2，1，1，18，1，1，2，1，2，1，1)，(1，1，2，2，4，2，1，1，18，1，1，2，1，2，1，1)，(1，1，3，2，4，2，1，1，18，1，1，2，1，2，1，1)，(1，1，3，3，4，2，1，1，18，1，1，2，1，2，1，1)，(1，1，2，2，5，2，1，1，18，1，1，2，1，2，1，1)，(1，1，3，2，5，2，1，1，18，1，1，2，1，2，1，1)，(1，1，3，3，5，2，1，1，18，1，1，2，1，2，1，1)，(1，1，2，2，3，3，1，1，18，1，1，2，1，2，1，1)，(1，1，3，2，3，3，1，1，18，1，1，2，1，2，1，1)，(1，1，3，3，3，3，1，1，18，1，1，2，1，2，1，1)，(1，1，2，2，4，3，1，1，18，1，1，2，1，2，1，1)，(1，1，3，2，4，3，1，1，18，1，1，2，1，2，1，1)，(1，1，3，3，4，3，1，1，18，1，1，2，1，2，1，1)，(1，1，2，2，5，3，1，1，18，1，1，2，1，2，1，1)，(1，1，3，2，5，3，1，1，18，1，1，2，1，2，1，1)，(1，1，3，3，5，3，1，1，18，1，1，2，1，2，1，1)，(1，1，2，2，4，4，1，1，18，1，1，2，1，2，1，1)，(1，1，3，2，4，4，1，1，18，1，1，2，1，2，1，1)，(1，1，3，3，4，4，1，1，18，1，1，2，1，2，1，1)，(1，1，2，2，5，4，1，1，18，1，1，2，1，2，1，1)，(1，1，3，2，5，4，1，1，18，1，1，2，1，2，1，1)，(1，1，3，3，5，4，1，1，18，1，1，2，1，2，1，1)，(1，1，2，2，5，5，1，1，18，1，1，2，1，2，1，1)，(1，1，3，2，5，5，1，1，18，1，1，2，1，2，1，1)，(1，1，3，3，5，5，1，1，18，1，1，2，1，2，1，1)，(1，1，2，2，2，2，1，1，19，1，1，2，1，2，1，1)，(1，1，3，2，2，2，1，1，19，1，1，2，1，2，1，1)，(1，1，3，3，2，2，1，1，19，1，1，2，1，2，1，1)，(1，1，2，2，3，2，1，1，19，1，1，2，1，2，1，1)，(1，1，3，2，3，2，1，1，19，1，1，2，1，2，1，1)，(1，1，3，3，3，2，1，1，19，1，1，2，1，2，1，1)，(1，1，2，2，4，2，1，1，19，1，1，2，1，2，1，1)，(1，1，3，2，4，2，1，1，19，1，1，2，1，2，1，1)，(1，1，3，3，4，2，1，1，19，1，1，2，1，2，1，1)，(1，1，2，2，5，2，1，1，19，1，1，2，1，2，1，1)，(1，1，3，2，5，2，1，1，19，1，1，2，1，2，1，1)，(1，1，3，3，5，2，1，1，19，1，1，2，1，2，1，1)，(1，1，2，2，3，3，1，1，19，1，1，2，1，2，1，1)，(1，1，3，2，3，3，1，1，19，1，1，2，1，2，1，1)，(1，1，3，3，3，3，1，1，19，1，1，2，1，2，1，1)，(1，1，2,2,4,3,1,1,19,1,1,2,1,2,1,1),(1,1,3,2,4,3,1,1,19,1,1,2,1,2,1,1),(1,1,3,3,4,3,1,1,19,1,1,2,1,2,1,1),(1,1,2,2,5,3,1,1,19,1,1,2,1,2, 1,1),(1,1,3,2,5,3,1,1,19,1,1,2,1,2,1,1),(1,1,3,3,5,3,1,1,19,1,1,2,1,2,1,1),(1,1,2,2,4,4,1,1,19,1,1,2,1,2,1,1),(1,1,3,2,4,4,1,1,19, 1,1,2,1,2,1,1),(1,1,3,3,4,4,1,1,19,1,1,2,1,2,1,1),(1,1,2,2,5,4,1,1,19,1,1,2,1,2,1,1),(1,1,3,2,5,4,1,1,19,1,1,2,1,2,1,1),(1,1,3,3,5 ,4,1,1,19,1,1,2,1,2,1,1),(1,1,2,2,5,5,1,1,19,1,1,2,1,2,1,1),(1,1,3,2,5,5,1,1,19,1,1,2,1,2,1,1),(1,1,3,3,5,5,1,1,19,1,1,2,1,2,1,1),

[0431] [Table 1-11]

[0432] (1，1，2，2，2，2，1，1，20，1，1，2，1，2，1，1)，(1，1，3，2，2，2，1，1，20，1，1，2，1，2，1，1)，(1，1，3，3，2，2，1，1，20，1，1，2，1，2，1，1)，(1，1，2，2，3，2，1，1，20，1，1，2，1，2，1，1)，(1，1，3，2，3，2，1，1，20，1，1，2，1，2，1，1)，(1，1，3，3，3，2，1，1，20，1，1，2，1，2，1，1)，(1，1，2，2，4，2，1，1，20，1，1，2，1，2，1，1)，(1，1，3，2，4，2，1，1，20，1，1，2，1，2，1，1)，(1，1，3，3，4，2，1，1，20，1，1，2，1，2，1，1)，(1，1，2，2，5，2，1，1，20，1，1，2，1，2，1，1)，(1，1，3，2，5，2，1，1，20，1，1，2，1，2，1，1)，(1，1，3，3，5，2，1，1，20，1，1，2，1，2，1，1)，(1，1，2，2，3，3，1，1，20，1，1，2，1，2，1，1)，(1，1，3，2，3，3，1，1，20，1，1，2，1，2，1，1)，(1，1，3，3，3，3，1，1，20，1，1，2，1，2，1，1)，(1，1，2，2，4，3，1，1，20，1，1，2，1，2，1，1)，(1，1，3，2，4，3，1，1，20，1，1，2，1，2，1，1)，(1，1，3，3，4，3，1，1，20，1，1，2，1，2，1，1)，(1，1，2，2，5，3，1，1，20，1，1，2，1，2，1，1)，(1，1，3，2，5，3，1，1，20，1，1，2，1，2，1，1)，(1，1，3，3，5，3，1，1，20，1，1，2，1，2，1，1)，(1，1，2，2，4，4，1，1，20，1，1，2，1，2，1，1)，(1，1，3，2，4，4，1，1，20，1，1，2，1，2，1，1)，(1，1，3，3，4，4，1，1，20，1，1，2，1，2，1，1)，(1，1，2，2，5，4，1，1，20，1，1，2，1，2，1，1)，(1，1，3，2，5，4，1，1，20，1，1，2，1，2，1，1)，(1，1，3，3，5，4，1，1，20，1，1，2，1，2，1，1)，(1，1，2，2，5，5，1，1，20，1，1，2，1，2，1，1)，(1，1，3，2，5，5，1，1，20，1，1，2，1，2，1，1)，(1，1，3，3，5，5，1，1，20，1，1，2，1，2，1，1)，(1，1，2，2，2，2，1，1，1，1，2，2，1，2，1，1)，(1，1，3，2，2，2，1，1，1，1，2，2，1，2，1，1)，(1，1，3，3，2，2，1，1，1，1，2，2，1，2，1，1)，(1，1，2，2，3，2，1，1，1，1，2，2，1，2，1，1)，(1，1，3，2，3，2，1，1，1，1，2，2，1，2，1，1)，(1，1，3，3，3，2，1，1，1，1，2，2，1，2，1，1)，(1，1，2，2，4，2，1，1，1，1，2，2，1，2，1，1)，(1，1，3，2，4，2，1，1，1，1，2，2，1，2，1，1)，(1，1，3，3，4，2，1，1，1，1，2，2，1，2，1，1)，(1，1，2，2，5，2，1，1，1，1，2，2，1，2，1，1)，(1，1，3，2，5，2，1，1，1，1，2，2，1，2，1，1)，(1，1，3，3，5，2，1，1，1，1，2，2，1，2，1，1)，(1，1，2，2，3，3，1，1，1，1，2，2，1，2，1，1)，(1，1，3，2，3，3，1，1，1，1，2，2，1，2，1，1)，(1，1，3，3，3，3，1，1，1，1，2，2，1，2，1，1)，(1，1，2，2，4，3，1，1，1，1，2，2，1，2，1，1)，(1，1，3，2，4，3，1，1，1，1，2，2，1，2，1，1)，(1，1，3，3，4，3，1，1，1，1，2，2，1，2，1，1)，(1，1，2，2，5，3，1，1，1，1，2，2，1，2，1，1)，(1，1，3，2，5，3，1，1，1，1，2，2，1，2，1，1)，(1，1，3，3，5，3，1，1，1，1，2，2，1，2，1，1)，(1，1，2，2，4，4，1，1，1，1，2，2，1，2，1，1)，(1，1，3，2，4，4，1，1，1，1，2，2，1，2，1，1)，(1，1，3，3，4，4，1，1，1，1，2，2，1，2，1，1)，(1，1，2，2，5，4，1，1，1，1，2，2，1，2，1，1)，(1，1，3，2，5，4，1，1，1，1，2，2，1，2，1，1)，(1，1，3，3，5，4，1，1，1，1，2，2，1，2，1，1)，(1，1，2，2，5，5，1，1，1，1，2，2，1，2，1，1),(1,1,3,2,5,5,1,1,1,1,2,2,1,2,1,1),(1,1,3,3,5,5,1,1,1,1,2,2,1,2,1,1),(1,1,2,2,2,2,1,1,2,2,2,1,2,1,1),(1,1,3,2,2,2,1,1,2,2,2,1,2,1,1),(1,1,3,3,2,2,1,1,2,2,2,1,2,1,1),(1,1,2,2,3,2,1,1,2,2,2,1,2,1,1),(1,1,3,2,3,2,1,1,2,2,2,1,2,1,1 ),(1,1,3,3,3,2,1,1,2,2,2,2,1,2,1,1),(1,1,2,2,4,2,1,1,2,2,2,1,2,1,1),(1,1,3,2,4,2,1,1,2,2,2,1,2,1,1),(1,1,3,3,4,2,1,1,2,2,2,1,2,1,1),(1,1,2,2,5,2,1,1,2,2,2,1,2,1,1),(1,1,3,2,5,2,1,1,2,2,2,1,2,1,1),(1,1,3,3,5,2,1,1,2,2,2,1,2,1,1),

[0433] [Table 1-12]

[0434] (1，1，2，2，3，3，1，1，2，2，2，2，1，2，1，1)，(1，1，3，2，3，3，1，1，2，2，2，2，1，2，1，1)，(1，1，3，3，3，3，1，1，2，2，2，2，1，2，1，1)，(1，1，2，2，4，3，1，1，2，2，2，2，1，2，1，1)，(1，1，3，2，4，3，1，1，2，2，2，2，1，2，1，1)，(1，1，3，3，4，3，1，1，2，2，2，2，1，2，1，1)，(1，1，2，2，5，3，1，1，2，2，2，2，1，2，1，1)，(1，1，3，2，5，3，1，1，2，2，2，2，1，2，1，1)，(1，1，3，3，5，3，1，1，2，2，2，2，1，2，1，1)，(1，1，2，2，4，4，1，1，2，2，2，2，1，2，1，1)，(1，1，3，2，4，4，1，1，2，2，2，2，1，2，1，1)，(1，1，3，3，4，4，1，1，2，2，2，2，1，2，1，1)，(1，1，2，2，5，4，1，1，2，2，2，2，1，2，1，1)，(1，1，3，2，5，4，1，1，2，2，2，2，1，2，1，1)，(1，1，3，3，5，4，1，1，2，2，2，2，1，2，1，1)，(1，1，2，2，5，5，1，1，2，2，2，2，1，2，1，1)，(1，1，3，2，5，5，1，1，2，2，2，2，1，2，1，1)，(1，1，3，3，5，5，1，1，2，2，2，2，1，2，1，1)，(1，1，2，2，2，2，1，1，3，1，2，2，1，2，1，1)，(1，1，3，2，2，2，1，1，3，1，2，2，1，2，1，1)，(1，1，3，3，2，2，1，1，3，1，2，2，1，2，1，1)，(1，1，2，2，3，2，1，1，3，1，2，2，1，2，1，1)，(1，1，3，2，3，2，1，1，3，1，2，2，1，2，1，1)，(1，1，3，3，3，2，1，1，3，1，2，2，1，2，1，1)，(1，1，2，2，4，2，1，1，3，1，2，2，1，2，1，1)，(1，1，3，2，4，2，1，1，3，1，2，2，1，2，1，1)，(1，1，3，3，4，2，1，1，3，1，2，2，1，2，1，1)，(1，1，2，2，5，2，1，1，3，1，2，2，1，2，1，1)，(1，1，3，2，5，2，1，1，3，1，2，2，1，2，1，1)，(1，1，3，3，5，2，1，1，3，1，2，2，1，2，1，1)，(1，1，2，2，3，3，1，1，3，1，2，2，1，2，1，1)，(1，1，3，2，3，3，1，1，3，1，2，2，1，2，1，1)，(1，1，3，3，3，3，1，1，3，1，2，2，1，2，1，1)，(1，1，2，2，4，3，1，1，3，1，2，2，1，2，1，1)，(1，1，3，2，4，3，1，1，3，1，2，2，1，2，1，1)，(1，1，3，3，4，3，1，1，3，1，2，2，1，2，1，1)，(1，1，2，2，5，3，1，1，3，1，2，2，1，2，1，1)，(1，1，3，2，5，3，1，1，3，1，2，2，1，2，1，1)，(1，1，3，3，5，3，1，1，3，1，2，2，1，2，1，1)，(1，1，2，2，4，4，1，1，3，1，2，2，1，2，1，1)，(1，1，3，2，4，4，1，1，3，1，2，2，1，2，1，1)，(1，1，3，3，4，4，1，1，3，1，2，2，1，2，1，1)，(1，1，2，2，5，4，1，1，3，1，2，2，1，2，1，1)，(1，1，3，2，5，4，1，1，3，1，2，2，1，2，1，1)，(1，1，3，3，5，4，1，1，3，1，2，2，1，2，1，1)，(1，1，2，2，5，5，1，1，3，1，2，2，1，2，1，1)，(1，1，3，2，5，5，1，1，3，1，2，2，1，2，1，1)，(1，1，3，3，5，5，1，1，3，1，2，2，1，2，1，1)，(1，1，2，2，2，2，1，1，4，1，2，2，1，2，1，1)，(1，1，3，2，2，2，1，1，4，1，2，2，1，2，1，1)，(1，1，3，3，2，2，1，1，4，1，2，2，1，2，1，1)，(1，1，2，2，3，2，1，1，4，1，2，2，1，2，1，1)，(1，1，3，2，3，2，1，1，4，1，2，2，1，2，1，1)，(1，1，3，3，3，2，1，1，4，1，2，2，1，2，1，1)，(1，1，2，2，4，2，1，1，4，1，2，2，1，2，1，1)，(1，1，3，2，4，2，1，1，4，1，2，2，1，2，1，1)，(1，1，3，3，4，2，1，1，4，1，2，2，1，2，1，1)，(1，1，2，2，5，2，1，1，4，1，2，2，1，2，1，1)，(1，1，3，2，5，2，1，1，4，1，2，2，1，2，1,1),(1,1,3,3,5,2,1,1,4,1,2,2,1,2,1,1),(1,1,2,2,3,3,1,1,4,1,2,2,1,2,1,1),(1,1,3,2,3,3,1,1,4,1,2,2,1,2,1,1),(1,1,3,3,3,3,1,1,4,1,2,2,1,2,1,1),(1,1,2,2,4,3,1,1,4,1,2,2,1,2,1,1),(1,1,3,2,4,3,1,1,4,1,2,2,1,2,1,1),(1,1,3,3,4,3,1 ,1,4,1,2,2,1,2,1,1),(1,1,2,2,5,3,1,1,4,1,2,2,1,2,1,1),(1,1,3,2,5,3,1,1,4,1,2,2,1,2,1,1),(1,1,3,3,5,3,1,1,4,1,2,2,1,2,1,1),(1,1,2,2,4,4,1,1,4,1,2,2,1,2,1,1),(1,1,3,2,4,4,1,1,4,1,2,2,1,2,1,1),

[0435] [Table 1-13]

[0436] (1，1，2，2，5，4，1，1，4，1，2，2，1，2，1，1)，(1，1，3，2，5，4，1，1，4，1，2，2，1，2，1，1)，(1，1，3，3，5，4，1，1，4，1，2，2，1，2，1，1)，(1，1，2，2，5，5，1，1，4，1，2，2，1，2，1，1)，(1，1，3，2，5，5，1，1，4，1，2，2，1，2，1，1)，(1，1，3，3，5，5，1，1，4，1，2，2，1，2，1，1)，(1，1，2，2，2，2，1，1，5，1，2，2，1，2，1，1)，(1，1，3，2，2，2，1，1，5，1，2，2，1，2，1，1)，(1，1，3，3，2，2，1，1，5，1，2，2，1，2，1，1)，(1，1，2，2，3，2，1，1，5，1，2，2，1，2，1，1)(1，1，3，2，3，2，1，1，5，1，2，2，1，2，1，1)，(1，1，3，3，3，2，1，1，5，1，2，2，1，2，1，1)，(1，1，2，2，4，2，1，1，5，1，2，2，1，2，1，1)，(1，1，3，2，4，2，1，1，5，1，2，2，1，2，1，1)(1，1，3，3，4，2，1，1，5，1，2，2，1，2，1，1)，(1，1，2，2，5，2，1，1，5，1，2，2，1，2，1，1)，(1，1，3，2，5，2，1，1，5，1，2，2，1，2，1，1)，(1，1，3，3，5，2，1，1，5，1，2，2，1，2，1，1)(1，1，2，2，3，3，1，1，5，1，2，2，1，2，1，1)，(1，1，3，2，3，3，1，1，5，1，2，2，1，2，1，1)，(1，1，3，3，3，3，1，1，5，1，2，2，1，2，1，1)，(1，1，2，2，4，3，1，1，5，1，2，2，1，2，1，1)(1，1，3，2，4，3，1，1，5，1，2，2，1，2，1，1)，(1，1，3，3，4，3，1，1，5，1，2，2，1，2，1，1)，(1，1，2，2，5，3，1，1，5，1，2，2，1，2，1，1)，(1，1，3，2，5，3，1，1，5，1，2，2，1，2，1，1)(1，1，3，3，5，3，1，1，5，1，2，2，1，2，1，1)，(1，1，2，2，4，4，1，1，5，1，2，2，1，2，1，1)，(1，1，3，2，4，4，1，1，5，1，2，2，1，2，1，1)，(1，1，3，3，4，4，1，1，5，1，2，2，1，2，1，1)(1，1，2，2，5，4，1，1，5，1，2，2，1，2，1，1)，(1，1，3，2，5，4，1，1，5，1，2，2，1，2，1，1)，(1，1，3，3，5，4，1，1，5，1，2，2，1，2，1，1)，(1，1，2，2，5，5，1，1，5，1，2，2，1，2，1，1)(1，1，3，2，5，5，1，1，5，1，2，2，1，2，1，1)，(1，1，3，3，5，5，1，1，5，1，2，2，1，2，1，1)，(1，1，2，2，2，2，1，1，6，1，2，2，1，2，1，1)，(1，1，3，2，2，2，1，1，6，1，2，2，1，2，1，1)(1，1，3，3，2，2，1，1，6，1，2，2，1，2，1，1)，(1，1，2，2，3，2，1，1，6，1，2，2，1，2，1，1)，(1，1，3，2，3，2，1，1，6，1，2，2，1，2，1，1)，(1，1，3，3，3，2，1，1，6，1，2，2，1，2，1，1)(1，1，2，2，4，2，1，1，6，1，2，2，1，2，1，1)，(1，1，3，2，4，2，1，1，6，1，2，2，1，2，1，1)，(1，1，3，3，4，2，1，1，6，1，2，2，1，2，1，1)，(1，1，2，2，5，2，1，1，6，1，2，2，1，2，1，1)(1，1，3，2，5，2，1，1，6，1，2，2，1，2，1，1)，(1，1，3，3，5，2，1，1，6，1，2，2，1，2，1，1)，(1，1，2，2，3，3，1，1，6，1，2，2，1，2，1，1)，(1，1，3，2，3，3，1，1，6，1，2，2，1，2，1，1)，(1，1，3，3，3，3，1，1，6，1，2，2，1，2，1，1)，(1，1，2，2，4，3，1，1，6，1，2，2，1，2，1，1)，(1，1，3，2，4，3，1，1，6，1，2，2，1，2，1，1)，(1，1，3，3，4，3，1，1，6，1，2，2，1，2，1，1)，(1，1，2，2，5，3，1，1，6，1，2，2，1，2，1，1)，(1，1，3，2，5，3，1，1，6，1，2，2，1，2，1，1)，(1，1，3，3，5，3，1，1，6，1，2，2，1，2，1，1)，(1，1，2，2，4，4，1，1，6，1，2，2，1，2，1，1)，(1，1，3，2，4，4，1，1，6，1，2，2，1，2，1，1)，(1，1，3,3,4,4,1,1,6,1,2,2,1,2,1,1),(1,1,2,2,5,4,1,1,6,1,2,2,1,2,1,1),(1,1,3,2,5,4,1,1,6,1,2,2,1,2,1,1),(1,1,3,3,5,4,1,1,6,1,2,2,1,2,1,1),(1,1,2,2,5,5,1,1,6,1,2,2,1,2,1,1),(1,1,3,2,5,5,1,1,6,1,2,2,1,2,1,1),(1,1,3,3,5,5,1,1,6, 1,2,2,1,2,1,1),(1,1,2,2,2,2,1,1,7,1,2,2,1,2,1,1),(1,1,3,2,2,2,1,1,7,1,2,2,1,2,1,1),(1,1,3,3,2,2,1,1,7,1,2,2,1,2,1,1),(1,1,2,2,3,2,1,1,7,1,2,2,1,2,1,1),(1,1,3,2,3,2,1,1,7,1,2,2,1,2,1,1),(1,1,3,3,3,2,1,1,7,1,2,2,1,2,1,1),

[0437] [Table 1-14]

[0438] (1，1，2，2，4，2，1，1，7，1，2，2，1，2，1，1)，(1，1，3，2，4，2，1，1，7，1，2，2，1，2，1，1)，(1，1，3，3，4，2，1，1，7，1，2，2，1，2，1，1)，(1，1，2，2，5，2，1，1，7，1，2，2，1，2，1，1)，(1，1，3，2，5，2，1，1，7，1，2，2，1，2，1，1)，(1，1，3，3，5，2，1，1，7，1，2，2，1，2，1，1)，(1，1，2，2，3，3，1，1，7，1，2，2，1，2，1，1)，(1，1，3，2，3，3，1，1，7，1，2，2，1，2，1，1)，(1，1，3，3，3，3，1，1，7，1，2，2，1，2，1，1)，(1，1，2，2，4，3，1，1，7，1，2，2，1，2，1，1)，(1，1，3，2，4，3，1，1，7，1，2，2，1，2，1，1)，(1，1，3，3，4，3，1，1，7，1，2，2，1，2，1，1)，(1，1，2，2，5，3，1，1，7，1，2，2，1，2，1，1)，(1，1，3，2，5，3，1，1，7，1，2，2，1，2，1，1)，(1，1，3，3，5，3，1，1，7，1，2，2，1，2，1，1)，(1，1，2，2，4，4，1，1，7，1，2，2，1，2，1，1)，(1，1，3，2，4，4，1，1，7，1，2，2，1，2，1，1)，(1，1，3，3，4，4，1，1，7，1，2，2，1，2，1，1)，(1，1，2，2，5，4，1，1，7，1，2，2，1，2，1，1)，(1，1，3，2，5，4，1，1，7，1，2，2，1，2，1，1)，(1，1，3，3，5，4，1，1，7，1，2，2，1，2，1，1)，(1，1，2，2，5，5，1，1，7，1，2，2，1，2，1，1)，(1，1，3，2，5，5，1，1，7，1，2，2，1，2，1，1)，(1，1，3，3，5，5，1，1，7，1，2，2，1，2，1，1)，(1，1，2，2，2，2，1，1，8，1，2，2，1，2，1，1)，(1，1，3，2，2，2，1，1，8，1，2，2，1，2，1，1)，(1，1，3，3，2，2，1，1，8，1，2，2，1，2，1，1)，(1，1，2，2，3，2，1，1，8，1，2，2，1，2，1，1)，(1，1，3，2，3，2，1，1，8，1，2，2，1，2，1，1)，(1，1，3，3，3，2，1，1，8，1，2，2，1，2，1，1)，(1，1，2，2，4，2，1，1，8，1，2，2，1，2，1，1)，(1，1，3，2，4，2，1，1，8，1，2，2，1，2，1，1)，(1，1，3，3，4，2，1，1，8，1，2，2，1，2，1，1)，(1，1，2，2，5，2，1，1，8，1，2，2，1，2，1，1)，(1，1，3，2，5，2，1，1，8，1，2，2，1，2，1，1)，(1，1，3，3，5，2，1，1，8，1，2，2，1，2，1，1)，(1，1，2，2，3，3，1，1，8，1，2，2，1，2，1，1)，(1，1，3，2，3，3，1，1，8，1，2，2，1，2，1，1)，(1，1，3，3，3，3，1，1，8，1，2，2，1，2，1，1)，(1，1，2，2，4，3，1，1，8，1，2，2，1，2，1，1)，(1，1，3，2，4，3，1，1，8，1，2，2，1，2，1，1)，(1，1，3，3，4，3，1，1，8，1，2，2，1，2，1，1)，(1，1，2，2，5，3，1，1，8，1，2，2，1，2，1，1)，(1，1，3，2，5，3，1，1，8，1，2，2，1，2，1，1)，(1，1，3，3，5，3，1，1，8，1，2，2，1，2，1，1)，(1，1，2，2，4，4，1，1，8，1，2，2，1，2，1，1)，(1，1，3，2，4，4，1，1，8，1，2，2，1，2，1，1)，(1，1，3，3，4，4，1，1，8，1，2，2，1，2，1，1)，(1，1，2，2，5，4，1，1，8，1，2，2，1，2，1，1)，(1，1，3，2，5，4，1，1，8，1，2，2，1，2，1，1)，(1，1，3，3，5，4，1，1，8，1，2，2，1，2，1，1)，(1，1，2，2，5，5，1，1，8，1，2，2，1，2，1，1)，(1，1，3，2，5，5，1，1，8，1，2，2，1，2，1，1)，(1，1，3，3，5，5，1，1，8，1，2，2，1，2，1，1)，(1，1，2，2，2，2，1，1，9，1，2，2，1，2，1，1)，(1，1，3，2，2，2，1，1，9，1，2，2，1，2，1，1)，(1，1，3，3，2，2，1，1，9，1，2，2，1，2，1，1)，(1，1，2，2，3，2，1，1，9，1，2，2，1，2，1，1)，(1，1，3，2，3，2，1，1，9，1，2，2，1，2，1,1),(1,1,3,3,3,2,1,1,9,1,2,2,1,2,1,1),(1,1,2,2,4,2,1,1,9,1,2,2,1,2,1,1),(1,1,3,2,4,2,1,1,9,1,2,2,1,2,1,1),(1,1,3,3,4,2,1,1,9,1,2,2,1,2,1,1),(1,1,2,2,5,2,1,1,9,1,2,2,1,2,1,1),(1,1,3,2,5,2,1,1,9,1,2,2,1,2,1,1),(1,1,3,3,5,2,1 ,1,9,1,2,2,1,2,1,1),(1,1,2,2,3,3,1,1,9,1,2,2,1,2,1,1),(1,1,3,2,3,3,1,1,9,1,2,2,1,2,1,1),(1,1,3,3,3,3,1,1,9,1,2,2,1,2,1,1),(1,1,2,2,4,3,1,1,9,1,2,2,1,2,1,1),(1,1,3,2,4,3,1,1,9,1,2,2,1,2,1,1),(1,1,3,3,4,3,1,1,9,1,2,2,1,2,1,1),

[0439] [Table 1-15]

[0440] (1，1，2，2，5，3，1，1，9，1，2，2，1，2，1，1)，(1，1，3，2，5，3，1，1，9，1，2，2，1，2，1，1)，(1，1，3，3，5，3，1，1，9，1，2，2，1，2，1，1)，(1，1，2，2，4，4，1，1，9，1，2，2，1，2，1，1)，(1，1，3，2，4，4，1，1，9，1，2，2，1，2，1，1)，(1，1，3，3，4，4，1，1，9，1，2，2，1，2，1，1)，(1，1，2，2，5，4，1，1，9，1，2，2，1，2，1，1)，(1，1，3，2，5，4，1，1，9，1，2，2，1，2，1，1)，(1，1，3，3，5，4，1，1，9，1，2，2，1，2，1，1)，(1，1，2，2，5，5，1，1，9，1，2，2，1，2，1，1)，(1，1，3，2，5，5，1，1，9，1，2，2，1，2，1，1)，(1，1，3，3，5，5，1，1，9，1，2，2，1，2，1，1)，(1，1，2，2，2，2，1，1，10，1，2，2，1，2，1，1)，(1，1，3，2，2，2，1，1，10，1，2，2，1，2，1，1)，(1，1，3，3，2，2，1，1，10，1，2，2，1，2，1，1)，(1，1，2，2，3，2，1，1，10，1，2，2，1，2，1，1)，(1，1，3，2，3，2，1，1，10，1，2，2，1，2，1，1)，(1，1，3，3，3，2，1，1，10，1，2，2，1，2，1，1)，(1，1，2，2，4，2，1，1，10，1，2，2，1，2，1，1)，(1，1，3，2，4，2，1，1，10，1，2，2，1，2，1，1)，(1，1，3，3，4，2，1，1，10，1，2，2，1，2，1，1)，(1，1，2，2，5，2，1，1，10，1，2，2，1，2，1，1)，(1，1，3，2，5，2，1，1，10，1，2，2，1，2，1，1)，(1，1，3，3，5，2，1，1，10，1，2，2，1，2，1，1)，(1，1，2，2，3，3，1，1，10，1，2，2，1，2，1，1)，(1，1，3，2，3，3，1，1，10，1，2，2，1，2，1，1)，(1，1，3，3，3，3，1，1，10，1，2，2，1，2，1，1)，(1，1，2，2，4，3，1，1，10，1，2，2，1，2，1，1)，(1，1，3，2，4，3，1，1，10，1，2，2，1，2，1，1)，(1，1，3，3，4，3，1，1，10，1，2，2，1，2，1，1)，(1，1，2，2，5，3，1，1，10，1，2，2，1，2，1，1)，(1，1，3，2，5，3，1，1，10，1，2，2，1，2，1，1)，(1，1，3，3，5，3，1，1，10，1，2，2，1，2，1，1)，(1，1，2，2，4，4，1，1，10，1，2，2，1，2，1，1)，(1，1，3，2，4，4，1，1，10，1，2，2，1，2，1，1)，(1，1，3，3，4，4，1，1，10，1，2，2，1，2，1，1)，(1，1，2，2，5，4，1，1，10，1，2，2，1，2，1，1)，(1，1，3，2，5，4，1，1，10，1，2，2，1，2，1，1)，(1，1，3，3，5，4，1，1，10，1，2，2，1，2，1，1)，(1，1，2，2，5，5，1，1，10，1，2，2，1，2，1，1)，(1，1，3，2，5，5，1，1，10，1，2，2，1，2，1，1)，(1，1，3，3，5，5，1，1，10，1，2，2，1，2，1，1)，(1，1，2，2，2，2，1，1，11，1，2，2，1，2，1，1)，(1，1，3，2，2，2，1，1，11，1，2，2，1，2，1，1)，(1，1，3，3，2，2，1，1，11，1，2，2，1，2，1，1)，(1，1，2，2，3，2，1，1，11，1，2，2，1，2，1，1)，(1，1，3，2，3，2，1，1，11，1，2，2，1，2，1，1)，(1，1，3，3，3，2，1，1，11，1，2，2，1，2，1，1)，(1，1，2，2，4，2，1，1，11，1，2，2，1，2，1，1)，(1，1，3，2，4，2，1，1，11，1，2，2，1，2，1，1)，(1，1，3，3，4，2，1，1，11，1，2，2，1，2，1，1)，(1，1，2，2，5，2，1，1，11，1，2，2，1，2，1，1)，(1，1，3，2，5，2，1，1，11，1，2，2，1，2，1，1)，(1，1，3，3，5，2，1，1，11，1，2，2，1，2，1，1)，(1，1，2，2，3，3，1，1，11，1，2，2，1，2，1，1)，(1，1，3，2，3，3，1，1，11，1，2，2，1，2，1，1)，(1，1，3，3，3，3，1，1，11，1，2，2，1，2，1，1)，(1，1，2，2，4，3，1，1，11,1,2,2,1,2,1,1),(1,1,3,2,4,3,1,1,11,1,2,2,1,2,1,1),(1,1,3,3,4,3,1,1,11,1,2,2,1,2,1,1),(1,1,2,2,5,3,1,1,11,1,2,2,1,2,1,1),(1,1 ,3,2,5,3,1,1,11,1,2,2,1,2,1,1),(1,1,3,3,5,3,1,1,11,1,2,2,1,2,1,1),(1,1,2,2,4,4,1,1,11,1,2,2,1,2,1,1),(1,1,3,2,4,4,1,1,11,1,2,2, 1,2,1,1),(1,1,3,3,4,4,1,1,11,1,2,2,1,2,1,1),(1,1,2,2,5,4,1,1,11,1,2,2,1,2,1,1),(1,1,3,2,5,4,1,1,11,1,2,2,1,2,1,1),(1,1,3,3,5,4, 1,1,11,1,2,2,1,2,1,1),(1,1,2,2,5,5,1,1,11,1,2,2,1,2,1,1),(1,1,3,2,5,5,1,1,11,1,2,2,1,2,1,1),(1,1,3,3,5,5,1,1,11,1,2,2,1,2,1,1),

[0441] [Table 1-16]

[0442] (1，1，2，2，2，2，1，1，12，1，2，2，1，2，1，1)，(1，1，3，2，2，2，1，1，12，1，2，2，1，2，1，1)，(1，1，3，3，2，2，1，1，12，1，2，2，1，2，1，1)，(1，1，2，2，3，2，1，1，12，1，2，2，1，2，1，1)，(1，1，3，2，3，2，1，1，12，1，2，2，1，2，1，1)，(1，1，3，3，3，2，1，1，12，1，2，2，1，2，1，1)，(1，1，2，2，4，2，1，1，12，1，2，2，1，2，1，1)，(1，1，3，2，4，2，1，1，12，1，2，2，1，2，1，1)，(1，1，3，3，4，2，1，1，12，1，2，2，1，2，1，1)，(1，1，2，2，5，2，1，1，12，1，2，2，1，2，1，1)，(1，1，3，2，5，2，1，1，12，1，2，2，1，2，1，1)，(1，1，3，3，5，2，1，1，12，1，2，2，1，2，1，1)，(1，1，2，2，3，3，1，1，12，1，2，2，1，2，1，1)，(1，1，3，2，3，3，1，1，12，1，2，2，1，2，1，1)，(1，1，3，3，3，3，1，1，12，1，2，2，1，2，1，1)，(1，1，2，2，4，3，1，1，12，1，2，2，1，2，1，1)，(1，1，3，2，4，3，1，1，12，1，2，2，1，2，1，1)，(1，1，3，3，4，3，1，1，12，1，2，2，1，2，1，1)，(1，1，2，2，5，3，1，1，12，1，2，2，1，2，1，1)，(1，1，3，2，5，3，1，1，12，1，2，2，1，2，1，1)，(1，1，3，3，5，3，1，1，12，1，2，2，1，2，1，1)，(1，1，2，2，4，4，1，1，12，1，2，2，1，2，1，1)，(1，1，3，2，4，4，1，1，12，1，2，2，1，2，1，1)，(1，1，3，3，4，4，1，1，12，1，2，2，1，2，1，1)，(1，1，2，2，5，4，1，1，12，1，2，2，1，2，1，1)，(1，1，3，2，5，4，1，1，12，1，2，2，1，2，1，1)，(1，1，3，3，5，4，1，1，12，1，2，2，1，2，1，1)，(1，1，2，2，5，5，1，1，12，1，2，2，1，2，1，1)，(1，1，3，2，5，5，1，1，12，1，2，2，1，2，1，1)，(1，1，3，3，5，5，1，1，12，1，2，2，1，2，1，1)，(1，1，2，2，2，2，1，1，13，1，2，2，1，2，1，1)，(1，1，3，2，2，2，1，1，13，1，2，2，1，2，1，1)，(1，1，3，3，2，2，1，1，13，1，2，2，1，2，1，1)，(1，1，2，2，3，2，1，1，13，1，2，2，1，2，1，1)，(1，1，3，2，3，2，1，1，13，1，2，2，1，2，1，1)，(1，1，3，3，3，2，1，1，13，1，2，2，1，2，1，1)，(1，1，2，2，4，2，1，1，13，1，2，2，1，2，1，1)，(1，1，3，2，4，2，1，1，13，1，2，2，1，2，1，1)，(1，1，3，3，4，2，1，1，13，1，2，2，1，2，1，1)，(1，1，2，2，5，2，1，1，13，1，2，2，1，2，1，1)，(1，1，3，2，5，2，1，1，13，1，2，2，1，2，1，1)，(1，1，3，3，5，2，1，1，13，1，2，2，1，2，1，1)，(1，1，2，2，3，3，1，1，13，1，2，2，1，2，1，1)，(1，1，3，2，3，3，1，1，13，1，2，2，1，2，1，1)，(1，1，3，3，3，3，1，1，13，1，2，2，1，2，1，1)，(1，1，2，2，4，3，1，1，13，1，2，2，1，2，1，1)，(1，1，3，2，4，3，1，1，13，1，2，2，1，2，1，1)，(1，1，3，3，4，3，1，1，13，1，2，2，1，2，1，1)，(1，1，2，2，5，3，1，1，13，1，2，2，1，2，1，1)，(1，1，3，2，5，3，1，1，13，1，2，2，1，2，1，1)，(1，1，3，3，5，3，1，1，13，1，2，2，1，2，1，1)，(1，1，2，2，4，4，1，1，13，1，2，2，1，2，1，1)，(1，1，3，2，4，4，1，1，13，1，2，2，1，2，1，1)，(1，1，3，3，4，4，1，1，13，1，2，2，1，2，1，1)，(1，1，2，2，5，4，1，1，13，1，2，2，1，2，1，1)，(1，1，3，2，5，4，1，1，13，1，2，2，1，2，1，1)，(1，1，3，3，5，4，1，1，13，1，2，2，1，2，1，1)，(1，1，2,2,5,5,1,1,13,1,2,2,1,2,1,1),(1,1,3,2,5,5,1,1,13,1,2,2,1,2,1,1),(1,1,3,3,5,5,1,1,13,1,2,2,1,2,1,1),(1,1,2,2,2,2,1,1,14,1,2,2,1,2, 1,1),(1,1,3,2,2,2,1,1,14,1,2,2,1,2,1,1),(1,1,3,3,2,2,1,1,14,1,2,2,1,2,1,1),(1,1,2,2,3,2,1,1,14,1,2,2,1,2,1,1),(1,1,3,2,3,2,1,1,14, 1,2,2,1,2,1,1),(1,1,3,3,3,2,1,1,14,1,2,2,1,2,1,1),(1,1,2,2,4,2,1,1,14,1,2,2,1,2,1,1),(1,1,3,2,4,2,1,1,14,1,2,2,1,2,1,1),(1,1,3,3,4 ,2,1,1,14,1,2,2,1,2,1,1),(1,1,2,2,5,2,1,1,14,1,2,2,1,2,1,1),(1,1,3,2,5,2,1,1,14,1,2,2,1,2,1,1),(1,1,3,3,5,2,1,1,14,1,2,2,1,2,1,1),

[0443] [Table 1-17]

[0444] (1，1，2，2，3，3，1，1，14，1，2，2，1，2，1，1)，(1，1，3，2，3，3，1，1，14，1，2，2，1，2，1，1)，(1，1，3，3，3，3，1，1，14，1，2，2，1，2，1，1)，(1，1，2，2，4，3，1，1，14，1，2，2，1，2，1，1)，(1，1，3，2，4，3，1，1，14，1，2，2，1，2，1，1)，(1，1，3，3，4，3，1，1，14，1，2，2，1，2，1，1)，(1，1，2，2，5，3，1，1，14，1，2，2，1，2，1，1)，(1，1，3，2，5，3，1，1，14，1，2，2，1，2，1，1)，(1，1，3，3，5，3，1，1，14，1，2，2，1，2，1，1)，(1，1，2，2，4，4，1，1，14，1，2，2，1，2，1，1)，(1，1，3，2，4，4，1，1，14，1，2，2，1，2，1，1)，(1，1，3，3，4，4，1，1，14，1，2，2，1，2，1，1)，(1，1，2，2，5，4，1，1，14，1，2，2，1，2，1，1)，(1，1，3，2，5，4，1，1，14，1，2，2，1，2，1，1)，(1，1，3，3，5，4，1，1，14，1，2，2，1，2，1，1)，(1，1，2，2，5，5，1，1，14，1，2，2，1，2，1，1)，(1，1，3，2，5，5，1，1，14，1，2，2，1，2，1，1)，(1，1，3，3，5，5，1，1，14，1，2，2，1，2，1，1)，(1，1，2，2，2，2，1，1，15，1，2，2，1，2，1，1)，(1，1，3，2，2，2，1，1，15，1，2，2，1，2，1，1)，(1，1，3，3，2，2，1，1，15，1，2，2，1，2，1，1)，(1，1，2，2，3，2，1，1，15，1，2，2，1，2，1，1)，(1，1，3，2，3，2，1，1，15，1，2，2，1，2，1，1)，(1，1，3，3，3，2，1，1，15，1，2，2，1，2，1，1)，(1，1，2，2，4，2，1，1，15，1，2，2，1，2，1，1)，(1，1，3，2，4，2，1，1，15，1，2，2，1，2，1，1)，(1，1，3，3，4，2，1，1，15，1，2，2，1，2，1，1)，(1，1，2，2，5，2，1，1，15，1，2，2，1，2，1，1)，(1，1，3，2，5，2，1，1，15，1，2，2，1，2，1，1)，(1，1，3，3，5，2，1，1，15，1，2，2，1，2，1，1)，(1，1，2，2，3，3，1，1，15，1，2，2，1，2，1，1)，(1，1，3，2，3，3，1，1，15，1，2，2，1，2，1，1)，(1，1，3，3，3，3，1，1，15，1，2，2，1，2，1，1)，(1，1，2，2，4，3，1，1，15，1，2，2，1，2，1，1)，(1，1，3，2，4，3，1，1，15，1，2，2，1，2，1，1)，(1，1，3，3，4，3，1，1，15，1，2，2，1，2，1，1)，(1，1，2，2，5，3，1，1，15，1，2，2，1，2，1，1)，(1，1，3，2，5，3，1，1，15，1，2，2，1，2，1，1)，(1，1，3，3，5，3，1，1，15，1，2，2，1，2，1，1)，(1，1，2，2，4，4，1，1，15，1，2，2，1，2，1，1)，(1，1，3，2，4，4，1，1，15，1，2，2，1，2，1，1)，(1，1，3，3，4，4，1，1，15，1，2，2，1，2，1，1)，(1，1，2，2，5，4，1，1，15，1，2，2，1，2，1，1)，(1，1，3，2，5，4，1，1，15，1，2，2，1，2，1，1)，(1，1，3，3，5，4，1，1，15，1，2，2，1，2，1，1)，(1，1，2，2，5，5，1，1，15，1，2，2，1，2，1，1)，(1，1，3，2，5，5，1，1，15，1，2，2，1，2，1，1)，(1，1，3，3，5，5，1，1，15，1，2，2，1，2，1，1)，(1，1，2，2，2，2，1，1，16，1，2，2，1，2，1，1)，(1，1，3，2，2，2，1，1，16，1，2，2，1，2，1，1)，(1，1，3，3，2，2，1，1，16，1，2，2，1，2，1，1)，(1，1，2，2，3，2，1，1，16，1，2，2，1，2，1，1)，(1，1，3，2，3，2，1，1，16，1，2，2，1，2，1，1)，(1，1，3，3，3，2，1，1，16，1，2，2，1，2，1，1)，(1，1，2，2，4，2，1，1，16，1，2，2，1，2，1，1)，(1，1，3，2，4，2，1，1，16，1，2，2，1，2，1，1)，(1，1，3，3，4，2，1，1，16，1，2，2，1，2，1，1)，(1，1，2,2,5,2,1,1,16,1,2,2,1,2,1,1),(1,1,3,2,5,2,1,1,16,1,2,2,1,2,1,1),(1,1,3,3,5,2,1,1,16,1,2,2,1,2,1,1),(1,1,2,2,3,3,1,1,16,1,2,2,1,2, 1,1),(1,1,3,2,3,3,1,1,16,1,2,2,1,2,1,1),(1,1,3,3,3,3,1,1,16,1,2,2,1,2,1,1),(1,1,2,2,4,3,1,1,16,1,2,2,1,2,1,1),(1,1,3,2,4,3,1,1,16, 1,2,2,1,2,1,1),(1,1,3,3,4,3,1,1,16,1,2,2,1,2,1,1),(1,1,2,2,5,3,1,1,16,1,2,2,1,2,1,1),(1,1,3,2,5,3,1,1,16,1,2,2,1,2,1,1),(1,1,3,3,5 ,3,1,1,16,1,2,2,1,2,1,1),(1,1,2,2,4,4,1,1,16,1,2,2,1,2,1,1),(1,1,3,2,4,4,1,1,16,1,2,2,1,2,1,1),(1,1,3,3,4,4,1,1,16,1,2,2,1,2,1,1),

[0445] [Table 1-18]

[0446] (1，1，2，2，5，4，1，1，16，1，2，2，1，2，1，1)，(1，1，3，2，5，4，1，1，16，1，2，2，1，2，1，1)，(1，1，3，3，5，4，1，1，16，1，2，2，1，2，1，1)，(1，1，2，2，5，5，1，1，16，1，2，2，1，2，1，1)，(1，1，3，2，5，5，1，1，16，1，2，2，1，2，1，1)，(1，1，3，3，5，5，1，1，16，1，2，2，1，2，1，1)，(1，1，2，2，2，2，1，1，17，1，2，2，1，2，1，1)，(1，1，3，2，2，2，1，1，17，1，2，2，1，2，1，1)，(1，1，3，3，2，2，1，1，17，1，2，2，1，2，1，1)，(1，1，2，2，3，2，1，1，17，1，2，2，1，2，1，1)，(1，1，3，2，3，2，1，1，17，1，2，2，1，2，1，1)，(1，1，3，3，3，2，1，1，17，1，2，2，1，2，1，1)，(1，1，2，2，4，2，1，1，17，1，2，2，1，2，1，1)，(1，1，3，2，4，2，1，1，17，1，2，2，1，2，1，1)，(1，1，3，3，4，2，1，1，17，1，2，2，1，2，1，1)，(1，1，2，2，5，2，1，1，17，1，2，2，1，2，1，1)，(1，1，3，2，5，2，1，1，17，1，2，2，1，2，1，1)，(1，1，3，3，5，2，1，1，17，1，2，2，1，2，1，1)，(1，1，2，2，3，3，1，1，17，1，2，2，1，2，1，1)，(1，1，3，2，3，3，1，1，17，1，2，2，1，2，1，1)，(1，1，3，3，3，3，1，1，17，1，2，2，1，2，1，1)，(1，1，2，2，4，3，1，1，17，1，2，2，1，2，1，1)，(1，1，3，2，4，3，1，1，17，1，2，2，1，2，1，1)，(1，1，3，3，4，3，1，1，17，1，2，2，1，2，1，1)，(1，1，2，2，5，3，1，1，17，1，2，2，1，2，1，1)，(1，1，3，2，5，3，1，1，17，1，2，2，1，2，1，1)，(1，1，3，3，5，3，1，1，17，1，2，2，1，2，1，1)，(1，1，2，2，4，4，1，1，17，1，2，2，1，2，1，1)，(1，1，3，2，4，4，1，1，17，1，2，2，1，2，1，1)，(1，1，3，3，4，4，1，1，17，1，2，2，1，2，1，1)，(1，1，2，2，5，4，1，1，17，1，2，2，1，2，1，1)，(1，1，3，2，5，4，1，1，17，1，2，2，1，2，1，1)，(1，1，3，3，5，4，1，1，17，1，2，2，1，2，1，1)，(1，1，2，2，5，5，1，1，17，1，2，2，1，2，1，1)，(1，1，3，2，5，5，1，1，17，1，2，2，1，2，1，1)，(1，1，3，3，5，5，1，1，17，1，2，2，1，2，1，1)，(1，1，2，2，2，2，1，1，18，1，2，2，1，2，1，1)，(1，1，3，2，2，2，1，1，18，1，2，2，1，2，1，1)，(1，1，3，3，2，2，1，1，18，1，2，2，1，2，1，1)，(1，1，2，2，3，2，1，1，18，1，2，2，1，2，1，1)，(1，1，3，2，3，2，1，1，18，1，2，2，1，2，1，1)，(1，1，3，3，3，2，1，1，18，1，2，2，1，2，1，1)，(1，1，2，2，4，2，1，1，18，1，2，2，1，2，1，1)，(1，1，3，2，4，2，1，1，18，1，2，2，1，2，1，1)，(1，1，3，3，4，2，1，1，18，1，2，2，1，2，1，1)，(1，1，2，2，5，2，1，1，18，1，2，2，1，2，1，1)，(1，1，3，2，5，2，1，1，18，1，2，2，1，2，1，1)，(1，1，3，3，5，2，1，1，18，1，2，2，1，2，1，1)，(1，1，2，2，3，3，1，1，18，1，2，2，1，2，1，1)，(1，1，3，2，3，3，1，1，18，1，2，2，1，2，1，1)，(1，1，3，3，3，3，1，1，18，1，2，2，1，2，1，1)，(1，1，2，2，4，3，1，1，18，1，2，2，1，2，1，1)，(1，1，3，2，4，3，1，1，18，1，2，2，1，2，1，1)，(1，1，3，3，4，3，1，1，18，1，2，2，1，2，1，1)，(1，1，2，2，5，3，1，1，18，1，2，2，1，2，1，1)，(1，1，3，2，5，3，1，1，18，1，2，2，1，2，1，1)，(1，1，3，3，5，3，1，1，18，1，2，2，1，2，1，1)，(1，1，2,2,4,4,1,1,18,1,2,2,1,2,1,1),(1,1,3,2,4,4,1,1,18,1,2,2,1,2,1,1),(1,1,3,3,4,4,1,1,18,1,2,2,1,2,1,1),(1,1,2,2,5,4,1,1,18,1,2,2,1,2, 1,1),(1,1,3,2,5,4,1,1,18,1,2,2,1,2,1,1),(1,1,3,3,5,4,1,1,18,1,2,2,1,2,1,1),(1,1,2,2,5,5,1,1,18,1,2,2,1,2,1,1),(1,1,3,2,5,5,1,1,18, 1,2,2,1,2,1,1),(1,1,3,3,5,5,1,1,18,1,2,2,1,2,1,1),(1,1,2,2,2,2,1,1,19,1,2,2,1,2,1,1),(1,1,3,2,2,2,1,1,19,1,2,2,1,2,1,1),(1,1,3,3,2 ,2,1,1,19,1,2,2,1,2,1,1),(1,1,2,2,3,2,1,1,19,1,2,2,1,2,1,1),(1,1,3,2,3,2,1,1,19,1,2,2,1,2,1,1),(1,1,3,3,3,2,1,1,19,1,2,2,1,2,1,1),

[0447] [Table 1-19]

[0448] (1，1，2，2，4，2，1，1，19，1，2，2，1，2，1，1)，(1，1，3，2，4，2，1，1，19，1，2，2，1，2，1，1)，(1，1，3，3，4，2，1，1，19，1，2，2，1，2，1，1)，(1，1，2，2，5，2，1，1，19，1，2，2，1，2，1，1)，(1，1，3，2，5，2，1，1，19，1，2，2，1，2，1，1)，(1，1，3，3，5，2，1，1，19，1，2，2，1，2，1，1)，(1，1，2，2，3，3，1，1，19，1，2，2，1，2，1，1)，(1，1，3，2，3，3，1，1，19，1，2，2，1，2，1，1)，(1，1，3，3，3，3，1，1，19，1，2，2，1，2，1，1)，(1，1，2，2，4，3，1，1，19，1，2，2，1，2，1，1)，(1，1，3，2，4，3，1，1，19，1，2，2，1，2，1，1)，(1，1，3，3，4，3，1，1，19，1，2，2，1，2，1，1)，(1，1，2，2，5，3，1，1，19，1，2，2，1，2，1，1)，(1，1，3，2，5，3，1，1，19，1，2，2，1，2，1，1)，(1，1，3，3，5，3，1，1，19，1，2，2，1，2，1，1)，(1，1，2，2，4，4，1，1，19，1，2，2，1，2，1，1)，(1，1，3，2，4，4，1，1，19，1，2，2，1，2，1，1)，(1，1，3，3，4，4，1，1，19，1，2，2，1，2，1，1)，(1，1，2，2，5，4，1，1，19，1，2，2，1，2，1，1)，(1，1，3，2，5，4，1，1，19，1，2，2，1，2，1，1)，(1，1，3，3，5，4，1，1，19，1，2，2，1，2，1，1)，(1，1，2，2，5，5，1，1，19，1，2，2，1，2，1，1)，(1，1，3，2，5，5，1，1，19，1，2，2，1，2，1，1)，(1，1，3，3，5，5，1，1，19，1，2，2，1，2，1，1)，(1，1，2，2，2，2，1，1，20，1，2，2，1，2，1，1)，(1，1，3，2，2，2，1，1，20，1，2，2，1，2，1，1)，(1，1，3，3，2，2，1，1，20，1，2，2，1，2，1，1)，(1，1，2，2，3，2，1，1，20，1，2，2，1，2，1，1)，(1，1，3，2，3，2，1，1，20，1,2,2,1,2,1,1),(1,1,3,3,3,2,1,1,20,1,2,2,1,2,1,1),(1,1,2,2,4,2,1,1,20,1,2,2,1,2,1,1),(1,1,3,2,4,2,1,1,20,1,2,2,1,2,1,1),(1,1,3,3,4,2,1,1,20,1,2,2,1,2,1,1),(1,1,2,2,5,2,1,1,20,1,2,2,1,2,1,1 ),(1,1,3,3,5,2,1,1,20,1,2,2,1,2,1,1),(1,1,2,2,3,3,1,1,20,1,2,2,1,2,1,1),(1,1,3,2,3,3,1,1,20,1,2,2,1,2,1,1),(1,1,3,3,3,3,1,1,20,1,2,2,1,2,1,1),(1,1,2,2,4,3,1,1,20,1,2,2,1,2,1,1),(1,1,3,3,4, 3,1,1,20,1,2,2,1,2,1,1),(1,1,2,2,5,3,1,1,20,1,2,2,1,2,1,1),(1,1,3,2,5,3,1,1,20,1,2,2,1,2,1,1),(1,1,3,3,5,3,1,1,20,1,2,2,1,2,1,1),(1,1,2,2,4,4,1,1,20,1,2,2,1,2,1,1),(1,1,3,3,4,4,1,1,20,1,2, 2,1,2,1,1), (1,1,2,2,5,4,1,1,20,1,2,2,1,2,1,1), (1,1,3,2,5,4,1,1,20,1,2,2,1,2,1,1), (1,1,3,3,5,4,1,1,20,1,2,2,1,2,1 ,1), (1,1,2,2,5,5,1,1,20,1,2,2,1,2,1,1), (1,1,3,2,5,5,1,1, 20,1,2,2,1,2,1,1),または(1,1,3,3,5,5,1,1,20,1,2,2,1,2,1,1),

[0449] wherein the numbers of each X, A, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and F14 are the corresponding substituents shown in the above definition table.

[0450] The present disclosure may be a compound having any combination of substituents shown in the above definition table.

[0451] In one embodiment, the compounds disclosed in this specification are shown in the following table.

[0452] [Table 2-1]

[0453]

[0454] [Table 2-2]

[0455]

[0456] [Table 2-3]

[0457]

[0458] [Table 2-4]

[0459]

[0460] [Table 2-5]

[0461]

[0462] [Table 2-6]

[0463]

[0464] In addition, the following can be exemplified as the compounds of the present disclosure.

[0465] [Table 2-7]

[0466]

[0467] [Table 2-8]

[0468]

[0469] [Table 2-9]

[0470]

[0471] (Medications, treatments, etc.)

[0472] General Description

[0473] In one embodiment, the compounds of the present disclosure can be directly administered orally or parenterally or can be administered as a preparation, medicine or pharmaceutical composition using an appropriate dosage form. As specific examples of these dosage forms, tablets, capsules, powders, granules, solutions, suspensions, injections, patches, cataplasms, etc. can be cited, but are not limited thereto. In addition, these preparations can be manufactured by known methods using additives commonly used as pharmaceutical additives.

[0474] As these additives, excipients, disintegrants, binders, fluidizers, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, sweeteners, flavorings, etc. can be used depending on the purpose. Specific examples of these additives include lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially alpha-starch, carboxymethylcellulose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc, etc., but are not limited thereto.

[0475] In one embodiment, the compounds disclosed herein are compounds that can modulate the activity of nervous system cells. The aforementioned nervous system cells are glial cells.

[0476] In one embodiment, the nervous system cells of the present disclosure are glial cells. For example, the glial cells are astrocytes or microglia.

[0477] In one embodiment, the compounds disclosed herein are compounds that can modulate the activity of nervous system cells. The aforementioned nervous system cells are astrocytes or microglia.

[0478] In one embodiment, modulating the activity of a nervous system cell of the present disclosure is promoting cell division.

[0479] In one embodiment, modulating the activity of a nervous system cell of the present disclosure comprises transformation of the cell.

[0480] The administration period of the compounds of the present invention and their therapeutic agents is not limited, and can be administered to the subject to be administered together with other drugs as needed. In this case, the administration can be simultaneous or separated by a time difference. In addition, when administered together with other drugs as needed, a mixture of the compounds of the present invention and their therapeutic agents can be prepared. The dosage of these therapeutic agents can be appropriately selected based on the dosage used clinically. In addition, the compound of the present invention and the therapeutic agent can be appropriately selected based on the subject to be administered, the route of administration, the target disease, disorder, symptom, combination, etc.

[0481] In one embodiment of the present disclosure, when other pharmaceutical compositions are used, the compounds of the present disclosure may be administered simultaneously or at different times. Such pharmaceutical compositions are also within the scope of the present disclosure.

[0482] Such drugs, preparations, and pharmaceutical compositions can be manufactured by mixing the compounds of the present invention and / or additional drugs (e.g., antibacterial drugs, antiviral agents (e.g., ribavirin, amantadine, etc.), sedatives (e.g., ketamine, midazolam, etc.) together or separately in the form of a mixture or in the form of a separate drug with any appropriate ingredients using any technology known in the art. They can be formulated into suitable preparations, such as tablets, capsules, powders, granules, solutions, suspensions, injections, patches, and poultices using any technology known in the art. When the compound of the present disclosure and / or an additional pharmaceutical agent (e.g., an antibacterial drug, an antiviral agent (e.g., ribavirin, amantadine, etc.), a sedative (e.g., ketamine, midazolam, etc.)) are prepared as separate pharmaceutical agents, they can be provided as a kit of two pharmaceutical agents or as a single agent of one component, and provided together with instructions (package insert, etc.) indicating whether to administer the compound of the present disclosure simultaneously or at different times in combination with the other component (the additional pharmaceutical agent in the case of the compound of the present disclosure, or the compound of the present disclosure in the case of the additional pharmaceutical agent (e.g., an antibacterial drug, an antiviral agent (e.g., ribavirin, amantadine, etc.), a sedative (e.g., ketamine, midazolam, etc.)).

[0483] The dosage of the compound of the present disclosure is appropriately selected based on the animal to be administered, the route of administration, the disease, the age, weight, and symptoms of the patient. For example, in the case of oral administration, for adults, the lower limit per day is 0.01 mg and the upper limit is 10,000 mg, and this amount can be administered once a day or in divided doses.

[0484] When the compounds of the present disclosure are used as active ingredients of medicines, they are not intended to be used only for humans but can also be used for animals other than humans (cats, dogs, cows, horses, bats, foxes, mongooses, raccoons, etc.).

[0485] (synthesis example)

[0486] For example, the present disclosure can be obtained by combining four compound fragments (A, B, C, and D), but is not limited thereto. The compounds used may be commercially available or synthesized.

[0487] The term "binding reaction" generally refers to all methods that can be used in organic synthetic chemistry, and includes, for example, cyclization reaction, addition reaction, ring-opening addition reaction, dehydration condensation reaction, etc. In addition to the binding reaction, protection reaction, deprotection reaction, oxidation reaction, reduction reaction, hydrogenation reaction, etc. can also be used. Reaction conditions such as reaction temperature and reaction time can be appropriately set.

[0488] In each reaction, the functional group contained in the compound used may be protected by a protecting group or the like.

[0489] The order of the reaction is not particularly limited. The cyclization reaction may be carried out after combining the four compounds, or the cyclization reaction may be carried out at the stage of combining the three compounds, and the resulting cyclized compound may be combined with the fourth compound.

[0490] The compound used in each reaction may be a purified product or a product from the previous step of the reaction may be used as it is.

[0491] (Pharmaceutical composition)

[0492] The compositions and methods of the present disclosure can be used to treat individuals in need thereof. In a specific embodiment, 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 in the form of a pharmaceutical composition comprising 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 ethylene glycol, glycerol, oils such as olive oil, or organic esters for injection. In a preferred embodiment, such a pharmaceutical composition is administered to a human, particularly when administered by an invasive route (i.e., for example, injection or implantation to avoid transport or diffusion through an epithelial barrier), and the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients can be selected, for example, to delay the release of the formulation or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition can be in unit dosage form, such as tablets, capsules (including Sprinkle capsules and gelatin capsules), granules, lyophilized agents for reconstitution, powders, solutions, syrups, suppositories, or injections. In addition, the composition can also be present in a transdermal delivery system, for example, a skin patch. In addition, the composition can also be present in a solution suitable for topical administration, for example, eye drops, etc.

[0493] Pharmaceutically acceptable carriers can contain physiologically acceptable agents, the effect of which is to stabilize compounds, such as compounds of the present disclosure, or to increase solubility, or to increase absorption. As such physiologically acceptable agents, 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, etc., can be enumerated. The selection of pharmaceutically acceptable carriers comprising physiologically acceptable agents depends on, for example, 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. In addition, the pharmaceutical composition (preparation) can also be a liposome or other polymer matrix, into which compounds of the present disclosure can be incorporated. Liposomes, such as liposomes comprising phospholipids or other lipids, etc., are physiologically acceptable metabolizable carriers that are relatively simple to make and administer, which are non-toxic.

[0494] Pharmaceutical compositions (preparations) can be administered to a subject by any of several routes of administration, including oral administration (e.g., aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, and pastes for tongue application); absorption through the oral mucosa (e.g., sublingually); anus, rectum, or vagina (e.g., as vaginal suppositories, creams, or foams); parenteral administration (including intramuscular, intravenous, subcutaneous, or intramedullary, e.g., sterile solutions or suspensions); nasal administration; intraperitoneal administration; subcutaneous administration; transdermal administration (e.g., as a skin-applicable patch); and topical administration (e.g., as a skin-applicable cream, ointment, spray, or eye drops). Furthermore, the compound can be formulated for inhalation. In certain embodiments, the compound is simply dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable therefor can be found in, for example, U.S. Patent No. 6,110,973, U.S. Patent No. 5,731,000, U.S. Patent No. 5,541,231, U.S. Patent No. 5,427,798, U.S. Patent No. 5,358,970, and U.S. Patent No. 4,172,896, and patents cited therein.

[0495] The formulation can be conveniently provided in unit dosage form and prepared by any method known in the art of pharmaceutical technology. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is generally the amount of compound that produces a therapeutic effect. Typically, this amount ranges from about 1% to about 99% of the active ingredient, preferably from about 5% to about 70%, and most preferably from about 10% to about 30%.

[0496] The method for preparing these preparations or compositions comprises the step of combining an active compound, such as a compound of the present invention, with a carrier and, if necessary, one or more auxiliary ingredients. Generally, the preparation can be prepared by uniformly and closely combining a compound of the present invention with a liquid carrier or a finely divided solid carrier, or both, and then forming the product as needed.

[0497] 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 (flavored bases typically use sucrose and gum arabic or tragacanth), lyophilized forms, powders, granules, or as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions, or as elixirs or syrups, or as lozenges (inert bases such as gelatin and glycerin, or sucrose and gum arabic), and / or as mouthwashes, each containing a specified amount of a compound of the present disclosure as the active ingredient. Furthermore, the composition or compound may be administered as a bolus, elixir, or paste.

[0498] To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, sugar-coated tablets, powders and granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, for example, sodium citrate or calcium hydrogen phosphate and / or any of the following: (1) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and / or silicic acid, etc.; (2) binders, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or gum arabic, etc.; (3) humectants, for example, glycerol, etc. ; (4) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) dissolution retardants, such as paraffin; (6) absorption promoters, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glyceryl 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 composition may also contain a buffer. In addition, the same type of solid composition may also be used as a filler in soft and hard-filled gelatin capsules using excipients such as lactose or lactose, and high molecular weight polyethylene glycol.

[0499] Tablet can be made by compression or molding together with one or more auxiliary ingredients as needed.Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), a surfactant or a dispersant. Molded tablets can be made by molding a mixture of a powdered compound moistened with an inert liquid diluent in a suitable machine.

[0500] Tablets and other solid dosage forms of pharmaceutical compositions, such as sugar-coated tablets, capsules (including sprinkle capsules and gelatin capsules), pills, and granules, can be prepared by applying engravings or using coatings and shells, such as enteric coatings and other coatings known in pharmaceutical formulation technology, as needed. In addition, these, for example, can also use hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres in different proportions to provide the desired release characteristics, and be formulated to provide sustained or controlled release of the active ingredient therein. They can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterilized solid composition that can be dissolved in sterile water or other sterile injection medium just before use. In addition, these compositions can contain emulsifiers as needed, and can be compositions that release the active ingredient (singular or plural) only in a specific part of the digestive tract or preferentially in that part as needed in a delayed manner. As examples of embedding compositions that can be used, polymeric substances and waxes can be cited. Furthermore, the active ingredient may be in the form of microcapsules using one or more of the above-mentioned excipients, if appropriate.

[0501] Examples of liquid dosage forms useful 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 form may contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrins and their derivatives, solubilizers, and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuranol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0502] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservatives.

[0503] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0504] Formulations of pharmaceutical compositions for administration to the rectum, vagina or urethra may be provided as suppositories, which may 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, suppository wax or salicylates, which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity to release the active compound.

[0505] Formulations of pharmaceutical compositions for administration to the mouth may be provided as a mouthwash or oral spray or oral ointment.

[0506] Alternatively or additionally, the composition can be formulated for delivery via a catheter, stent, wire or other intraluminal device. Delivery via such a device can be particularly useful for delivery to the bladder, urethra, ureter, rectum or intestine.

[0507] Additionally, formulations suitable for vaginal administration include pessaries, tampons, creams, gels, pastes, foams or sprays containing such carriers as are known in the art to be appropriate.

[0508] 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.

[0509] Ointments, pastes, creams and gels may contain, in addition to the active compounds, excipients such as animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0510] In addition to the active compound, powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances, etc. Sprays may further contain customary propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0511] The use of transdermal patches also provides the advantage of providing controlled delivery of the compounds of the present disclosure to the body. Such dosage forms can be prepared by dissolving or dispersing the active compound in a suitable medium. The flux of the compound through the skin can also be increased by using absorption enhancers. The rate of this flux can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0512] Ophthalmic preparations, eye ointments, powders and solutions etc. are also contemplated within the scope of the present disclosure. Exemplary ophthalmic preparations are recorded in U.S. Patent Application Publication No. 2005 / 0080056, U.S. Patent Application Publication No. 2005 / 0059744, U.S. Patent Application Publication No. 2005 / 0031697 and U.S. Patent Application Publication No. 2005 / 004074 and U.S. Patent No. 6,583,124 (these contents are incorporated herein by reference). If desired, liquid ophthalmic preparations have the same characteristics as tears, aqueous humor or vitreous humor, or are compatible with such fluids. Preferred route of administration is administration to a local (e.g., topical administration, such as eye drops etc. or administration via an implant).

[0513] The present disclosure has been described above by way of preferred embodiments for ease of understanding. The present disclosure is 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 specific embodiments or examples described in this specification, but is defined solely by the claims.

[0514] Example

[0515] In the examples, the abbreviations shown above and below may be used to simplify the description.

[0516] Ac:Acetyl

[0517] AcOH: acetic acid

[0518] aq.: aqueous solution

[0519] Arg: Arginine

[0520] Asp: Aspartic acid

[0521] BHT: Butylated Hydroxytoluene

[0522] Bn: benzyl

[0523] Boc: tert-Butoxycarbonyl

[0524] Boc2O: di-tert-butyl dicarbonate

[0525] Bzl: benzyl

[0526] Cbz: benzyloxycarbonyl

[0527] CPME: Cyclopentyl Methyl Ether

[0528] DBU: diazabicycloundecene

[0529] DEPBT: 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one

[0530] DIAD: diisopropyl azodicarboxylate

[0531] DIPEA: N,N-diisopropylethylamine

[0532] DMAP: 4-dimethylaminopyridine

[0533] DMEAD: bis(2-methoxyethyl) azodicarboxylate

[0534] DME: 1,2-dimethoxyethane

[0535] DMF: N,N-dimethylformamide

[0536] DMP: 2,2-dimethoxypropane

[0537] DMT-MM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride

[0538] DMT-MMT: 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine tetrafluoroborate

[0539] EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0540] Et: ethyl

[0541] eq.: equivalent

[0542] Fmoc: 9-fluorenylmethyloxycarbonyl

[0543] Gln: glutamine

[0544] Glu: glutamate

[0545] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0546] HBTU: 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate

[0547] HOAt: 1-hydroxy-7-azabenzotriazole

[0548] HOBt: 1-hydroxybenzotriazole

[0549] m-CPBA: meta-chloroperbenzoic acid

[0550] Me:methyl

[0551] MS: molecular sieve

[0552] MTBE: Methyl tert-butyl ether

[0553] NMM: N-methylmorpholine

[0554] Ns: 2-nitrobenzenesulfonyl

[0555] PMB: p-methoxybenzyl

[0556] Ser: serine

[0557] Su: succinimide

[0558] TBAF: Tetrabutylammonium fluoride

[0559] TBAI: Tetrabutylammonium iodide

[0560] TBD: 1,5,7-Triazabicyclo[4.4.0]dec-5-ene

[0561] TBS: tert-butyldimethylsilyl

[0562] t-Bu: tert-butyl

[0563] TFA: trifluoroacetic acid

[0564] THF: Tetrahydrofuran

[0565] Thr:Threonine

[0566] TEMPO: 2,2,6,6-tetramethylpiperidin-1-oxyl radical

[0567] Tr: trityl

[0568] Trt: trityl

[0569] Ts: p-toluenesulfonyl

[0570] TsOH: p-toluenesulfonic acid

[0571] Tyr: tyrosine

[0572] Pbf: 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl

[0573] Ph: phenyl

[0574] PyBOP: (Benzotriazol-1-yloxy)tripyrrolidinylphosphonium hexafluorophosphate

[0575] PyBrop: tripyrrolidinylphosphonium bromide hexafluorophosphate

[0576] Val: valine

[0577] It should be noted that the fragment C group and the fragment D group were obtained as follows.

[0578] [Table 2A]

[0579]

[0580] [Table 2B]

[0581]

[0582] (Example 1: Synthesis of Fragment A-2)

[0583] [Chemistry 5]

[0584]

[0585] Under ice cooling, aluminum chloride (4.0 eq., 19.1 g, 143 mmol) and acetyl chloride (1.2 eq., 3.42 g, 43.6 mmol) were added to a solution of L-tyrosine (1.0 eq., 6.51 g, 35.9 mmol) in nitrobenzene (130 mL). The mixture was stirred for 10 minutes while warming to room temperature. The reaction mixture was heated to 100°C and stirred for 8 hours, then stirred for 16 hours while cooling to room temperature. The reaction mixture was ice-cooled and water (200 mL) was added. The mixture was separated and washed once with ethyl acetate (300 mL), and the organic layer was separated and extracted once with water (100 mL). The aqueous layers were combined to obtain A2-1 as an aqueous solution (300 mL).

[0586] [Chemistry 6]

[0587]

[0588] Under ice cooling, potassium carbonate (7.5 eq., 36.9 g, 267 mmol) was added to A2-1 (1.0 eq., 300 mL of aqueous solution, calculated as 35.9 mmol), the pH was adjusted to 9, THF (150 mL) and CbzCl (1.2 eq., 7.3 g, 42.8 mmol) were added, and the mixture was stirred at room temperature for 3 hours. 2N aqueous hydrochloric acid solution (200 mL) was added to the reaction solution to adjust the pH to 3, and THF was distilled off under reduced pressure. The concentrate was extracted three times with ethyl acetate (200 mL), the organic layers were combined, washed once with saturated aqueous sodium chloride solution (200 mL), and dried over magnesium sulfate. The magnesium sulfate was filtered off and concentrated under reduced pressure to obtain A2-2 (11.4 g) as a brown oil.

[0589] [Chemistry 7]

[0590]

[0591] Under a nitrogen atmosphere and ice cooling, 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 solution of A2-2 (1.0 eq., 11.4 g, calculated as 35.9 mmol) in DMF (50 mL). The mixture was stirred at room temperature for 3.5 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted twice with a mixture of hexane (40 mL) and ethyl acetate (80 mL). The organic layers were combined, washed once with a saturated aqueous sodium chloride solution (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 (23.2 g). The crude product was purified by flash silica gel column purification (200 g normal phase silica gel, hexane / ethyl acetate = 80 / 20 to 50 / 50) to obtain A2-3 (9.56 g, 50% yield over three steps starting from L-tyrosine) as a yellow viscous substance. It should be noted that throughout this specification, mixed solutions are referred to as solvent A (X mL) / solvent B (Y mL) mixtures.

[0592] [Chemistry 8]

[0593]

[0594] Under a nitrogen atmosphere and ice-cooling, sodium hydride (1.2 eq., 60%, paraffin dispersion, 796 mg, 19.9 mmol) and iodomethane (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). The mixture was stirred for 1.5 hours under ice-cooling. Methanol (12 mL) was added to the reaction mixture to quench it. 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 a saturated aqueous sodium chloride solution (100 mL), and dried over magnesium sulfate. The magnesium sulfate was filtered off and concentrated under reduced pressure to obtain a crude product (13.1 g). The crude product was purified by 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.

[0595] [Chemistry 9]

[0596]

[0597] To a solution of A2-4 (1.0 eq., 10.1 g, calculated as 17.6 mmol) in chloroform (90 mL) at room temperature was added m-CPBA (3.0 eq., 35% aqueous solution, 14.0 g, 52.7 mmol), 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 mixture at room temperature, and the chloroform was removed under reduced pressure. The reaction mixture was extracted three times with ethyl acetate (100 mL). The organic layers were combined, washed once with saturated aqueous sodium chloride solution (100 mL), and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to yield the ester (10.6 g).

[0598] At room temperature, lithium hydroxide (4.0 eq., 1.68 g, 70.3 mmol) was added to a mixture of THF (40 mL) / water (40 mL) of the ester (1.0 eq., 10.6 g, calculated as 17.6 mmol) and stirred at the same temperature for 16 hours. The reaction solution was washed twice with hexane (100 mL), and then 6N aqueous hydrochloric acid solution (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), the organic layers were combined, washed once with saturated aqueous sodium chloride solution (100 mL), and dried over magnesium sulfate. The magnesium sulfate was filtered off and concentrated under reduced pressure to obtain A2-5 (9.3 g) as an orange solid.

[0599] [Chemistry 10]

[0600]

[0601] To a solution of A2-5 (1.0 eq., 9.3 g, calculated to be 17.6 mmol) in acetonitrile (80 mL) at room temperature, DBU (1.1 eq., 2.96 g, 19.4 mmol) and PMBCl (1.1 eq., 3.00 g, 19.2 mmol) were added, and the mixture was stirred at an external temperature of 60°C for 19 hours. The reaction mixture was quenched by the addition of 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 by flash silica gel column purification (first: 120 g normal phase silica gel, hexane / ethyl acetate = 75 / 25 to 50 / 50, second: 30 g 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 solution (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 obtain fragment A-2 (3.54 g, 36% yield over the first three stages of A2-3) as a yellow oil.

[0602] (Example 2A: Synthesis of Fragment A-2')

[0603] [Chemical 10A]

[0604]

[0605] To a solution of A2-5 (1.0 eq., 3.4 g, calculated as 7.12 mmol) in acetonitrile (70 mL) was 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 separated and washed with water (30 mL) three times and saturated aqueous sodium chloride (30 mL) once. The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (4.83 g). The crude product was purified on a flash silica gel column (53 g of normal phase silica gel, hexane / ethyl acetate = 3 / 1 to 2 / 1) to obtain fragment A-2' (1.87 g, 50% yield over three steps) as a yellow viscous substance.

[0606] (Example 2AA: Synthesis of Fragment A-2")

[0607] [Chemical 10B]

[0608]

[0609] [Chemical 10B1]

[0610]

[0611] The synthesis of L-tyrosine → A2-1 was as described in Example 1. The synthesis of A3'-3 from A2-1 via A3'-2 was as described in Example 2.

[0612] The synthesis of A2"-1 from A3'-3 is as follows.

[0613] [Chemical 10C]

[0614]

[0615] Under a nitrogen atmosphere, methyl iodide (3.0 eq., 6.8 mL, 109.23 mmol) and sodium hydride (60%, paraffin dispersion, 1.2 eq., 1.7 g, 43.45 mmol) were added to a solution of A3'-3 (1.0 eq., 18.3 g, 36.34 mmol) in DMF (150 mL) at an external temperature of -20°C. The mixture was stirred at the same temperature for 3 hours. 1N aqueous hydrochloric acid (50 mL) was added at an external temperature of -20°C, followed by water (100 mL). The mixture was extracted twice with a mixture of hexane (50 mL) and ethyl acetate (100 mL). 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, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain the crude product (20.2 g) as a yellow oil. The crude product was purified by flash silica gel column (normal phase silica gel 40 g, hexane / ethyl acetate = 9 / 1 to 3 / 1), and the resulting light yellow viscous material was washed with hexane to obtain A2"-1 (18.9 g, yield 101%).

[0616] The synthesis of A2"-2 from A2"-1 is as follows.

[0617] [Chemical 10D]

[0618]

[0619] Under a nitrogen atmosphere, to a solution of A2"-1 (1.0 eq., 18.9 g, 36.34 mmol) in chloroform (150 mL) was added m-CPBA (30% aqueous, 2.0 eq., 18.0 g, 73.01 mmol) 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 further added at room temperature, and the mixture was stirred at an external temperature of 60°C for 1 hour, and then stirred at an external temperature of 40°C for 15 hours. Under ice-cooling, a 20% aqueous sodium sulfite solution (75 mL) and a saturated aqueous sodium bicarbonate solution (75 mL) were added. The organic layer of the reaction solution was recovered, and 20% aqueous sodium sulfite solution (75 mL), saturated aqueous sodium bicarbonate solution (75 mL), saturated aqueous sodium chloride solution (250 mL), and ethyl acetate (400 mL) were added to the organic layer and washed once. The aqueous layers were combined and extracted once with ethyl acetate (100 mL). The organic layers were combined, dried over magnesium sulfate, the magnesium sulfate was filtered out, and the mixture was concentrated under reduced pressure to obtain a crude product (20.6 g) as a brown viscous substance. The crude product was purified by rapid silica gel column purification (40 g normal phase silica gel, hexane / ethyl acetate = 9 / 1 to 3 / 1) to obtain the ester (17.2 g, yield 89%) as a yellow viscous substance.

[0620] To a mixture of the ester (1.0 eq., 17.2 g, 32.17 mmol) in THF (75 mL) and water (75 mL) was added lithium hydroxide (2.5 eq., 1.9 g, 80.25 mmol) at room temperature, followed by stirring at room temperature for 3 hours. Lithium hydroxide (1.0 eq., 790 mg, 32.97 mmol) was added, followed by stirring for 1 hour, and then lithium hydroxide (0.5 eq., 392 mg, 16.37 mmol) was added, followed by stirring 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, adjusted to pH 1 with 2N aqueous hydrochloric acid (65 mL) under ice-cooling, and then extracted three times with ethyl acetate (100 mL). The organic layers were combined, dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain crude A2"-2 (14.3 g, crude yield 110%) as a dark brown viscous substance.

[0621] The synthesis of fragment A-2" from A2"-2 is as follows.

[0622] [Chemistry 10E]

[0623]

[0624] c

[0625] Under 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 for 2 hours at room temperature. 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 before adding saturated chloride. Aqueous ammonium solution (75 mL) and water (75 mL). After recovering the organic layer of the reaction solution, the aqueous layer was separated and extracted twice with ethyl acetate (100 mL). The organic layers were combined and washed twice with saturated aqueous sodium chloride solution (100 mL). After drying the organic layer with magnesium sulfate, the magnesium sulfate was filtered out and concentrated under reduced pressure to obtain a crude product (18.0 g) in the form of a brown oil. The crude product was purified by rapid silica gel column (normal phase silica gel 100 g, hexane / ethyl acetate = 5 / 1 to 0 / 1) to obtain fragment A-2" (7.1 g, 45% yield in 2 stages) in the form of a light yellow sticky substance.

[0626] (Example 2: Synthesis of Fragment A-3)

[0627] [Chemistry 11]

[0628]

[0629] To a solution of A2-3 (1.0 eq., 13.1 g, 24.4 mmol) in chloroform (120 mL) was added m-CPBA (2.0 eq., 35% aqueous solution, 13.0 g, 48.9 mmol) under ice cooling, and the mixture was stirred under reflux for 18 hours. The reaction mixture was quenched by the addition of saturated aqueous sodium bicarbonate (100 mL) at room temperature, and the chloroform was removed under reduced pressure. The reaction mixture was extracted three times with ethyl acetate (200 mL). The organic layers were combined, washed once with saturated aqueous sodium chloride (200 mL), and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain the ester.

[0630] To a mixture of the ester (1.0 eq., calculated to be 24.4 mmol) in THF (60 mL) and water (60 mL) was added lithium hydroxide (4.0 eq., 2.34 g, 97.7 mmol) at room temperature, and the mixture was stirred at the same temperature for 19 hours. Further lithium hydroxide (2.0 eq., 1.17 g, 48.9 mmol) was added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 4.5 hours. Water (100 mL) was added to the reaction mixture, and the mixture was washed twice with hexane (100 mL). A 6N aqueous hydrochloric acid solution was added to the aqueous layer to adjust the pH to 3. The aqueous layer was extracted twice with ethyl acetate (200 mL), and the organic layers were combined, washed once with saturated sodium chloride aqueous solution (200 mL), and 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.

[0631] [Chemistry 12]

[0632]

[0633] To a solution of A3-4 (1.0 eq., 11.2 g, calculated as 24.4 mmol) in acetonitrile (120 mL) at room temperature were added DBU (1.1 eq., 4.09 g, 26.8 mmol) and PMBCl (1.1 eq., 4.20 g, 26.8 mmol), and the mixture was stirred at an external temperature of 60°C for 16 hours. The reaction mixture was quenched by the addition of acetic acid (3.0 eq., 4.41 g, 73.4 mmol) and concentrated under reduced pressure to obtain a crude product. The crude product was purified on a flash silica gel column (180 g of normal phase silica gel, hexane / ethyl acetate = 75 / 25 to 50 / 50) to obtain fragment A-3 (7.83 g, 59% yield over two stages starting from A2-3) as an orange oil.

[0634] [Chemistry 13]

[0635]

[0636] 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) with ice cooling. The mixture was stirred for 20 minutes under ice cooling and then stirred at an external temperature of 100°C for 7 hours. The reaction mixture was allowed to cool and then quenched with ice-cold 1N aqueous hydrochloric acid (100 mL). The mixture was separated and washed three times with ethyl acetate (100 mL) to obtain A2-1 as an aqueous solution (100 mL).

[0637] [Chemistry 14]

[0638]

[0639] To A2-1 (1.0 eq., 100 mL of aqueous solution, calculated to be 16.78 mmol) was added water (100 mL) and 1,4-dioxane (100 mL). Under ice cooling, sodium bicarbonate (25.0 eq., 35.2 g, 419.05 mmol) was added to make the solution alkaline. Subsequently, Boc2O (1.2 eq., 4.6 mL, 20.02 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 4.5 hours. Sodium bicarbonate (2.1 eq., 3.03 g, 36.07 mmol) and Boc2O (1.0 eq., 4 mL, 17.41 mmol) were additionally added, and the mixture was stirred for an additional 17 hours. The reaction mixture was concentrated under reduced pressure to remove the 1,4-dioxane, and then 2N aqueous hydrochloric acid (approximately 300 mL) was added to adjust the pH to 1-2. After one fractional extraction with ethyl acetate (300 mL), the organic layer was fractionally washed once with 1N aqueous hydrochloric acid (100 mL). The aqueous layers were combined and fractionally extracted once with ethyl acetate (200 mL). The combined organic layers were dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain A3'-2 (5.63 g, crude yield 104%) as a brown viscous substance.

[0640] [Chemistry 15]

[0641]

[0642] 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 (1.0 eq., 5.63 g, calculated as 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 mixture of hexane (25 mL) and ethyl acetate (75 mL). The organic layers were combined and washed with a saturated aqueous sodium chloride solution (200 mL). After drying the organic layer over magnesium sulfate, the magnesium sulfate was filtered out and concentrated under reduced pressure to obtain a crude product (9.84 g) as a dark 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, 3-stage yield 73%) as a light orange viscous substance.

[0643] [Chemistry 16]

[0644]

[0645] Under a nitrogen atmosphere and ice-cooling, m-CPBA (35% aqueous solution, 2.0 eq., 19.0 g, 77.07 mmol) was added to a chloroform (200 mL) solution of A3'-3 (1.0 eq., 19.32 g, 38.36 mmol) and stirred at an external temperature of 60°C for 6 hours. The reaction mixture was concentrated under reduced pressure until the volume was approximately half, and then saturated aqueous sodium bicarbonate solution (200 mL) was added. After separation and extraction with ethyl acetate (200 mL) and ethyl acetate (100 mL) twice, the organic layers were combined and washed with saturated aqueous sodium chloride solution (200 mL). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain the ester (24.9 g, crude yield 125%) as a pale yellow solid.

[0646] Under ice cooling, lithium hydroxide (2.5 eq., 2.31 g, 96.43 mmol) was added to a mixture of the ester (1.0 eq., 24.9 g, calculated as 38.36 mmol) in THF (100 mL) and water (100 mL), 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 a further 2 hours. Furthermore, lithium hydroxide (1.5 eq., 1.39 g, 57.87 mmol) was added, and the mixture was stirred for 1 hour. The reaction mixture was separated and washed twice with hexane (100 mL). Under ice cooling, 6N aqueous hydrochloric acid (30 mL) was added to the aqueous layer to adjust the pH to 2-3, and then the mixture was separated and extracted once with ethyl acetate (100 mL). 6N aqueous hydrochloric acid (5 mL) was added to the aqueous layer, and the pH was adjusted to 1-2. The mixture was then extracted twice with ethyl acetate (100 mL). The organic layers were combined, dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (21.6 g) as a brown viscous substance. The crude product was recrystallized from a hexane / ethyl acetate mixture (4 / 1 to 1 / 1) to obtain A3'-4 (12.4 g, apparent yield 83%, containing approximately 30% m-CPBA) as a white solid.

[0647] [Chemistry 17]

[0648]

[0649] Under nitrogen atmosphere, to a solution of A3"-4 (1.0 eq., 3.03 g, m-CPBA containing about 30%, calculated as 7.83 mmol) in acetonitrile (40 mL) was added DBU (1.1 eq., 1.3 mL, 8.71 mmol) and BnBr (1.1 eq., 850 μL, 8.65 mmol) under ice cooling, and the mixture was stirred at room temperature for 16 hours. The reaction solution was separated and washed once with saturated aqueous ammonium chloride solution (40 mL). The aqueous layer was washed with ethyl acetate. The organic layers were combined and washed once with water (100 mL), and then washed once with a saturated aqueous sodium chloride solution (100 mL). The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered out, and the mixture was concentrated under reduced pressure to obtain a crude product (3.7 g) as a brown oil. The crude product was purified by rapid silica gel column purification (50 g normal phase silica gel, hexane / ethyl acetate = 5 / 1 to 3 / 1) to obtain fragment A-3 (1.8 g, yield 48%) as a light yellow viscous substance.

[0650] [Chemistry 18]

[0651]

[0652] Under a nitrogen atmosphere and ice cooling, DBU (1.1 eq., 1.9 mL, 12.73 mmol) and PMBCl (1.1 eq., 1.7 mL, 12.48 mmol) were added to a solution of A3'-4 (1.0 eq., 4.42 g, containing approximately 30% of the hydrolyzate of A3'-3, calculated to be 11.43 mmol) in acetonitrile (60 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was washed once with saturated aqueous ammonium chloride (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 (100 mL). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain the crude product (6.17 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 2 / 1) to obtain fragment A-3' (3.47 g, containing about 30% PMB ester of A3'-3, apparent yield 60%) as a light yellow sticky substance.

[0653] (Example 2A: Synthesis of Fragment A-13)

[0654] [Chemical 18A]

[0655]

[0656] The two steps of L-tyrosine to A2-2 were carried out as described in Example 2.

[0657] The syntheses of A2-2 to A13-1 are as follows.

[0658] [Chemical 18B]

[0659]

[0660] 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 (1.0 eq., 20.3 g, calculated as 55.2 mmol) under ice cooling, and stirred at room temperature for 2.5 hours. Water (200 mL) was added to the reaction solution, and the mixture was separated and extracted twice with a mixed solution of hexane (50 mL) / ethyl acetate (150 mL). The organic layers were combined and washed once with water (100 mL) and once with a saturated sodium chloride aqueous solution (100 mL). After drying the organic layer over magnesium sulfate, the magnesium sulfate was filtered off and concentrated under reduced pressure to obtain a crude product (34.3 g) as a yellow liquid. The crude product was purified by 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.

[0661] The syntheses of A13-1 to A13-2 are as follows.

[0662] [Chemical 18C]

[0663]

[0664] Under a nitrogen atmosphere, sodium hydride (1.2 eq., 2.17 g, 54.3 mmol) and iodomethane (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 (1.0 eq., 24.3 g, calculated as 45.2 mmol) under ice cooling, and the mixture was stirred for 4 hours under ice cooling. 2N aqueous hydrochloric acid solution (20 mL) was added to the reaction solution for quenching, and water (200 mL) was added. Extraction was performed with a mixture of hexane (50 mL) / ethyl acetate (150 mL) once and with a mixture of hexane (40 mL) / ethyl acetate (120 mL) once. The organic layers were combined and washed with water (100 mL) once and with a saturated aqueous sodium chloride solution (50 mL) once. The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a mixture of A13-2 and A2-4 (24.6 g).

[0665] The syntheses of A13-2 to A13-3 are as follows.

[0666] [Chemical 18D]

[0667]

[0668] Under a nitrogen atmosphere, m-CPBA (35% aqueous solution, 2.0 eq., 23.7 g, 89.3 mmol) was added to a solution of a mixture of A13-2 and A2-4 (1.0 eq., 24.6 g, calculated as 44.6 mmol) in chloroform (180 mL) at room temperature. 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 for separation and extraction. The organic layer was then separated and 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, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain the 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 esters (22.2 g) as a yellow liquid.

[0669] To a mixture of ester-A13 and ester (1.0 eq., 22.2 g, calculated as 39.1 mmol) in THF (80 mL) / water (80 mL) was added lithium hydroxide (4.0 eq., 3.74 g, 156 mmol) at room temperature, and the mixture was stirred at the same temperature for 3.5 hours. The reaction solution was washed three times with hexane (100 mL), and the pH was adjusted to 1 with 2N aqueous hydrochloric acid (72 mL) added to the aqueous layer. The aqueous layer was extracted three times with ethyl acetate (150 mL), and the organic layers were combined and 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.

[0670] The synthesis of fragments A13-3 to A-13 is as follows.

[0671] [Chemistry 18E]

[0672]

[0673] To a solution of a mixture of A13-3 and A2-5 (1.0 eq., 17.4 g, calculated as 39.1 mmol) in DMF (80 mL) at room temperature, potassium carbonate (3.1 eq., 16.6 g, 120 mmol) and iodomethane (1.1 eq., 2.7 mL, 43.4 mmol) were added, and the mixture was stirred at the same temperature for 1.5 hours. Water (200 mL) was added to the reaction solution, and extraction was performed once with a mixture of hexane (60 mL) / ethyl acetate (180 mL) and twice with a mixture of hexane (30 mL) / ethyl acetate (90 mL). 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, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (17.9 g) as a brown viscous substance. The crude product was purified twice by rapid silica gel column purification (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 sticky substance and fragment A-10 (11.8 g) as a light yellow sticky substance.

[0674] (Example 3: Synthesis of Fragment B-1)

[0675] [Chemistry 19]

[0676]

[0677] 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. A solution of Boc2O (1.2 eq., 62.4 g, 0.286 mol) in 1,4-dioxane (125 mL) was added under ice-cooling, and the mixture was stirred at the same temperature for 0.5 hours and then at room temperature overnight. The 1,4-dioxane was removed by distillation after concentration under reduced pressure. MTBE (200 mL) was added to the residue, and the insoluble matter was filtered off. The aqueous layer of the filtrate was recovered and washed once with MTBE (200 mL). Then, concentrated hydrochloric acid (approximately 25 mL) was added under ice-cooling to adjust the pH to 2-3. After adding sodium chloride (60 g), the mixture was extracted with ethyl acetate (200 mL) four times. Concentrated hydrochloric acid (5 mL) and sodium chloride (20 g) were added to the aqueous layer, and the mixture was extracted with ethyl acetate (200 mL) four times. Sodium chloride and concentrated hydrochloric acid were further added to the aqueous layer, and the mixture was extracted with ethyl acetate (100 mL) six times and ethyl acetate (50 mL) / THF (50 mL) six times. The organic layers were combined, dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure to obtain DN-Boc-serine (50.81 g, 92% yield) as a colorless oil.

[0678] Under a nitrogen atmosphere, N,O-dimethylhydroxylamine hydrochloride (1.0 eq., 50.8 g, net weight 44.9 g, 0.219 mol) was added to a solution of DN-Boc-serine (1.0 eq., 50.8 g, net weight 44.9 g, 0.219 mol) in dichloromethane (300 mL) at an internal temperature of -10°C. NMM (1.03 eq., 23.10 g, 0.228 mol), and EDCI (1.1 eq., 46.74 g, 0.244 mol) were added. The solution was stirred overnight at -10°C to room temperature. Under ice cooling, 1 M aqueous hydrochloric acid was added to the reaction mixture, and the mixture was washed once. The aqueous layer was then extracted once with dichloromethane (100 mL). The organic layers were combined and washed once with saturated aqueous sodium bicarbonate (100 mL). The aqueous layer was extracted again with dichloromethane (50 mL), and the organic layers were combined and dried over sodium sulfate. The sodium sulfate was filtered off and the mixture was concentrated under reduced pressure to obtain B1-1 (50.4 g, 93% yield) as a white solid.

[0679] [Chemistry 20]

[0680]

[0681] 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 solution, and the mixture was concentrated under reduced pressure. THF (100 mL) was added to the concentrated residue, and the mixture was concentrated again. This operation was repeated three times to obtain B1-2 (1) (60.4 g, quant.) as a light yellow oil.

[0682] Under a nitrogen atmosphere, methyllithium (2.0 eq., 279 mL, 0.419 mmol in 1.5 M Et2O) was added to a solution of B1-2 (1) (1.0 eq., 60.4 g, calculated as 0.203 mol) in THF (570 mL) at an internal temperature of -57 to -40°C over 40 minutes, and the mixture was stirred at the same temperature for 2 hours. Saturated aqueous ammonium chloride solution (130 mL) was added to the reaction mixture at the same temperature, and after warming to room temperature, the mixture was 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. After filtering out the sodium sulfate, the mixture was concentrated under reduced pressure to obtain a crude product (51.56 g) as a light yellow oil. The crude product was purified by 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.

[0683] [Chemistry 21]

[0684]

[0685] Under a nitrogen atmosphere, ethynylmagnesium bromide (2.5 eq., 715 mL, 0.358 mol in 0.5 M THF) was added to a solution of B1-2 (1.0 eq., 34.8 g, 0.143 mol) in THF (696 mL) over 1.5 hours at room temperature, followed by stirring at the same temperature for 2 hours. Saturated aqueous ammonium chloride (160 mL) was added to the reaction mixture at -55°C, and the temperature was raised to -5°C before concentration under reduced pressure. Water (300 mL) was added to the concentrated residue, and extraction was performed 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 (150 mL), and dried over sodium sulfate. After filtering out the sodium sulfate, the mixture was concentrated under reduced pressure to obtain the crude product (40.36 g) as a yellow solid. The crude product was purified by flash silica gel column (normal phase silica gel 370 g, chloroform / ethyl acetate = 100 / 0 to 20 / 1) to obtain B1-3 (diastereoisomer mixture, 33.9 g, yield 88%) as a white solid.

[0686] [Chemistry 22]

[0687]

[0688] Under nitrogen atmosphere, concentrated hydrochloric acid (12 eq., 130 mL, 1.56 mol) was added to a solution of B1-3 (diastereoisomer 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).

[0689] 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 the solution, and the mixture was stirred at room temperature for 17 hours. After adding saturated sodium chloride aqueous solution (65 mL) to the reaction solution for separation and washing, the aqueous layer was separated and extracted three times with ethyl acetate (260 mL). The organic layers were combined and dried over sodium sulfate. After filtering out the sodium sulfate, the mixture was concentrated under reduced pressure to obtain a crude product (40.01 g) as a brown viscous substance. The crude product was purified by flash silica gel column (200 g normal phase silica gel, hexane / ethyl acetate = 1 / 1 to 3 / 7) to obtain B1-4 (diastereoisomer mixture, 38.05 g, containing 4.0 wt% ethyl acetate, conversion yield 92%) as a light brown viscous substance.

[0690] [Chemistry 23]

[0691]

[0692] 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 solution of B1-4 (diastereoisomer mixture, 1.0 eq., 36.0 g, containing 4.0 wt% ethyl acetate, 0.110 mol) in DMF (360 mL) at room temperature. The mixture was stirred at the same temperature for 1 hour. The reaction mixture was fractionated with ethyl acetate (350 mL) and water (300 mL) for one extraction. The aqueous layer was fractionated twice with ethyl acetate (100 mL). The organic layers were combined and dried over sodium sulfate. After filtering out the sodium sulfate, the mixture was concentrated under reduced pressure to obtain the 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 (diastereoisomer mixture, 48.3 g, yield 98%) as a yellow sticky substance.

[0693] [Chemistry 24]

[0694]

[0695] Under a nitrogen atmosphere and ice cooling, 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 (diastereoisomer mixture, 1.0 eq., 24.1 g, 0.056 mol) and stirred at the same temperature for 2 hours. The reaction mixture was separated and extracted once with ethyl acetate (650 mL), water (300 mL), and 5% aqueous sodium bicarbonate solution (300 mL). 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. After filtering out the sodium sulfate, the mixture was concentrated under reduced pressure to obtain the 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 obtain fragment B-1 (12.6 g, yield 54%) as a white solid. In addition, 4.09 g was obtained as a mixture containing 16% of diastereomers.

[0696] A mixture of hexane (8.5 mL) and diisopropyl ether (8.5 mL) was added to the diastereomeric mixture (3.41 g) and dissolved by heating to an external temperature of 45°C. The solution was cooled to an internal temperature of 11°C, and the precipitated solid was collected by filtration. The solid was washed once with hexane (1.5 mL) and diisopropyl ether (1.5 mL) and once with hexane (3 mL) to obtain Fragment B-1 (2.41 g, containing 0.7% of diastereomers, yield 10%) as a white solid.

[0697] (Example 4: Synthesis of Fragment B-2)

[0698] [Chemistry 25]

[0699]

[0700] Under a nitrogen atmosphere, thionyl chloride (1.5 eq., 5 mL, 69.35 mmol) was added dropwise to methanol (47 mL) with 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 mixture was concentrated under reduced pressure to remove the methanol, yielding B2-1 (7.61 g, crude yield 104%) as a pale yellow solid.

[0701] [Chemistry 26]

[0702]

[0703] 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 (1.0 eq., 4.56 g, calculated as 29.69 mmol) under ice cooling, and stirred at room temperature for 3 hours. Dichloromethane (30 mL) was added to the reaction solution and washed once with water (60 mL). The aqueous layer was extracted twice with dichloromethane (60 mL). The organic layers were combined, washed once with saturated sodium chloride aqueous solution (150 mL), and then dried over magnesium sulfate. The magnesium sulfate was filtered off and 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, 71% yield over two stages).

[0704] (Example 5: Synthesis of Fragment B-3)

[0705] [Chemistry 27]

[0706]

[0707] Under a nitrogen atmosphere and ice cooling, thionyl chloride (1.5 eq., 4.5 mL, 62.03 mmol) was added dropwise to methanol (42 mL). 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 mixture 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.

[0708] [Chemistry 28]

[0709]

[0710] 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 (1.0 eq., 4.01 g, calculated as 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 further stirred at room temperature for 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, washed with saturated sodium chloride aqueous solution (150 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 (13.4 g). The crude product was purified by flash silica gel column (normal phase silica gel 70 g, hexane / ethyl acetate = 2 / 1 to 1 / 1) to obtain fragment B-3 (7.27 g, 82% yield over two stages) as a white solid.

[0711] (Example 6: Synthesis of Fragment B-9)

[0712] [Chemistry 29]

[0713]

[0714] Under a nitrogen atmosphere and ice cooling, thionyl chloride (1.45 eq., 25 mL, 345 mmol) was added to methanol (240 mL). 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 mixture was concentrated under reduced pressure to obtain a crude methyl ester (37 g).

[0715] [Chemistry 30]

[0716]

[0717] Under a nitrogen atmosphere, sodium bicarbonate (2.5 eq., 49.9 g, 595 mmol) and Boc2O (1.05 eq., 65 mL, 250 mmol) were added to a mixture of methyl ester (1.0 eq., 37.0 g, calculated as 238 mmol) in water (100 mL) / methanol (100 mL) under ice cooling, and the mixture was stirred at room temperature for 5.5 hours. Water (200 mL) was added to the reaction solution, and extraction was performed twice with ethyl acetate (200 mL). The organic layer was washed twice with water (100 mL) and once with a saturated sodium chloride aqueous solution (100 mL), and then dried over magnesium sulfate. The mixture was concentrated under reduced pressure to obtain B8-1 (58.7 g) as a crude product.

[0718] [Chemistry 31]

[0719]

[0720] 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. 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 solution, and the mixture was concentrated under reduced pressure to obtain B8-2 (68.0 g) as a crude pale yellow oil.

[0721] [Chemistry 32]

[0722]

[0723] Under a nitrogen atmosphere and ice cooling, methylmagnesium bromide (12.4%, 3.0 eq., 176.06 g, 183 mmol) was added to a solution of B8-2 (1.0 eq., 16.02 g, calculated as 61.0 mmol) in THF (300 mL) over 14 minutes, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was fractionated and extracted once with 10% aqueous ammonium chloride (200 mL), ethyl acetate (100 mL), and water (30 mL). The aqueous layer was fractionated and extracted twice with ethyl acetate (50 mL). The combined organic layers were fractionated and washed once with 5% aqueous sodium chloride (200 mL), dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure.

[0724] The crude product obtained from B8-2 (2.00 g) by the same operation was combined with the previous concentrated residue and subjected to rapid silica gel column purification (100 g normal phase silica gel, hexane / ethyl acetate = 80 / 20 to 20 / 80) to obtain B9-1 (17.22 g, containing 1.7 wt% of ethyl acetate, converted yield 95%) as a light yellow oil.

[0725] [Chemistry 33]

[0726]

[0727] Under a nitrogen atmosphere, concentrated hydrochloric acid (12 eq., 62 mL, 744 mmol) was added to a THF (248 mL) solution of B9-1 (1.0 eq., 16.22 g, containing 1.7 wt% of ethyl acetate, 61.5 mmol) at room temperature. 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 concentrated to obtain a crude product (14.04 g) as a purple oil.

[0728] The crude product obtained from B9-1 (1.00 g) by the same procedure was combined with the previous crude product 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 after stirring at the same temperature for 16 hours, NsCl (0.3 eq., 4.34 g, 19.6 mmol) was added and stirred at the same temperature for 30 minutes. Saturated sodium chloride aqueous solution (150 mL), ethyl acetate (50 mL), and water (180 mL) were added to the reaction solution for one liquid separation. The aqueous layer was separated and extracted three times with ethyl acetate (30 mL). The organic layers were combined, dried over sodium sulfate, filtered to remove the sodium sulfate, and then concentrated under reduced pressure. The concentrated residue was purified by 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.

[0729] [Chemistry 34]

[0730]

[0731] Under 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 DMF (65 mL) solution of B9-2 (1.0 eq., 19.59 g, 64.4 mmol) at room temperature, and the mixture was stirred at the same temperature for 30 minutes.

[0732] 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 separation and extraction. The aqueous layer was separated and extracted twice with ethyl acetate (30 mL). The organic layers were combined and separated and washed once with 5% aqueous sodium chloride solution (150 mL) and saturated aqueous sodium chloride solution (30 mL), and then dried over sodium sulfate. The sodium sulfate was filtered out, and the mixture was concentrated under reduced pressure. The concentrated residue was purified on 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, a 79% yield based on the three steps starting from B9-1) as a white viscous material.

[0733] [Chemistry 35]

[0734]

[0735] 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 obtained by similarly treating B9-3 (130 mg) was combined with the previous reaction mixture and concentrated under reduced pressure. The residue was purified twice by flash silica gel column chromatography (first: 480 g normal phase silica gel, hexane / ethyl acetate = 10 / 0 to 5 / 1; second: 100 g normal phase silica gel, hexane / ethyl acetate = 91 / 9 to 85 / 15). Hexane was added to the obtained light red solid, and the mixture was irradiated with ultrasonic waves. After ice cooling, the mixture was collected by filtration to obtain Fragment B-9 (15.07 g, yield 74%) as a white solid.

[0736] (Example 6A: Synthesis of Fragment D-8)

[0737] Fragment D-8 was synthesized as follows.

[0738] [Chemical 35A]

[0739]

[0740] The synthesis of HL-Asp-OBzl to D8-1 was performed as follows.

[0741] [Chemistry 35B]

[0742]

[0743] To a mixture of HL-Asp-OBzl (1.0 eq., 501 mg, 2.24 mmol) in THF (3 mL) / water (6 mL) at room temperature, sodium carbonate (2.0 eq., 477 mg, 4.50 mmol) and Boc2O (1.9 eq., 1.0 mL, 4.35 mmol) were added, and the mixture was stirred at the same temperature for 5 hours. Ethyl acetate (50 mL) was added to the reaction solution, and the mixture was extracted twice with water (25 mL). The aqueous layers were combined, the pH was adjusted to 7 by adding 1N aqueous hydrochloric acid (0.5 mL), and the mixture was concentrated under reduced pressure. The precipitated solid 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 white oil.

[0744] The synthesis of D8-1 to D8-2 was carried out as follows.

[0745] [Chemical 35C]

[0746]

[0747] To a solution of D8-1 (1.0 eq., 753 mg, calculated as 2.24 mmol) in DMF (6 mL) were added HOBt·H₂O (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), and the mixture was 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 then separated and washed with water (20 mL) twice, a mixture of water (10 mL) and saturated aqueous sodium bicarbonate (10 mL) twice, and a saturated aqueous sodium chloride solution (20 mL) once. The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain D8-2 (511 mg, 65% yield over two stages) as a light brown liquid.

[0748] The synthesis of D8-2 to fragment D-8 was performed as follows.

[0749] [Chemistry 35D]

[0750]

[0751] To a solution of D8-2 (1.0 eq., 472 mg, 1.34 mmol) in dichloromethane (2 mL) at room temperature was added TFA (9.7 eq., 1.0 mL, 13.1 mmol), and the mixture was stirred at the same temperature for 2 hours. Ethyl acetate (20 mL) was added to the reaction mixture, and the mixture was then separated and washed 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, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain fragment D-8 (229 mg, 68% yield) as a colorless, transparent liquid.

[0752] (Example 6B: Synthesis of Fragment D-9)

[0753] Fragment D-9 was synthesized as follows.

[0754] [Chemistry 35E]

[0755]

[0756] The synthesis of Boc-L-Asp(OBzl)-OH to D9-1 was performed as follows.

[0757] [Chemical 35F]

[0758]

[0759] To a solution of Boc-L-Asp(OBzl)-OH (1.0 eq., 893 mg, 2.76 mmol) in DMF (8 mL) was added HOBt·H₂O (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) at room temperature, and the mixture was 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 with water (20 mL) twice, a mixture of water (10 mL) / saturated aqueous sodium bicarbonate (10 mL) twice, and a saturated aqueous sodium chloride solution (10 mL) once. The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain D9-1 (881 mg, yield 91%) as a light yellow liquid.

[0760] The synthesis of D9-1 to fragment D-9 was performed as follows.

[0761] [Chemical 35G]

[0762]

[0763] 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. A 1M aqueous sodium hydroxide solution (22 mL) was added to the reaction mixture to adjust the pH to 9. After extraction with ethyl acetate (30 mL), the organic layer was separated and washed with a saturated aqueous sodium chloride solution (10 mL). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain fragment D-9 (524 mg, 85% yield) as a pale yellow liquid.

[0764] (Example 6C: Synthesis of Fragment D-10)

[0765] Fragment D-10 was synthesized as follows.

[0766] [Chemical 35H]

[0767]

[0768] The synthesis of Boc-L-Asp(OBzl)-OH to D10-1 was performed as follows.

[0769] [Chemical 35I]

[0770]

[0771] To a solution of Boc-L-Asp(OBzl)-OH (1.0 eq., 5.01 g, 15.5 mmol) in DMF (45 mL) were added HOBt·H₂O (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) at room temperature, and the mixture was stirred at the same temperature for 1 hour. Ethyl acetate (90 mL) and hexane (30 mL) were added to the reaction mixture, and the mixture was then separated and washed with water (100 mL) twice, a mixture of water (50 mL) and saturated aqueous sodium bicarbonate (50 mL) twice, and a saturated aqueous sodium chloride solution (50 mL) once. The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain D10-1 (6.08 mg, yield 96%) as a light yellow liquid.

[0772] The synthesis of D10-1 to fragment D-10 was performed as follows.

[0773] [Chemical 35H]

[0774]

[0775] 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. The reaction mixture was adjusted to pH 9 by adding 1 M aqueous sodium hydroxide solution (140 mL). After separation and extraction with ethyl acetate (100 mL), the organic layer was separated and washed once with water (50 mL) and once with saturated aqueous sodium chloride solution (50 mL). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain fragment D-10 (4.48 g, 98% yield) as a pale yellow liquid.

[0776] (Example 6D: Synthesis of Fragment D-11)

[0777] Fragment D-11 was synthesized as follows.

[0778] [Chemical 35I]

[0779]

[0780] The synthesis of Boc-L-Asp(OBzl)-OH to D11-1 was performed as follows.

[0781] [Chemistry 35J]

[0782]

[0783] To a solution of Boc-L-Asp(OBzl)-OH (1.0 eq., 5.04 g, 15.6 mmol) in DMF (45 mL) were added HOBt·H₂O (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) at room temperature, and the mixture was stirred at the same temperature for 2 hours. Ethyl acetate (90 mL) and hexane (30 mL) were added to the reaction mixture, and the mixture was then separated and washed with water (100 mL) twice, a mixture of water (50 mL) and saturated aqueous sodium bicarbonate (50 mL) twice, and a saturated aqueous sodium chloride solution (50 mL) once. The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain D11-1 (7.87 mg, crude yield 103%) as a light yellow liquid.

[0784] The synthesis of fragment D11-1 to fragment D-11 was carried out as follows.

[0785] [Chemical 35K]

[0786]

[0787] To a solution of D11-1 (1.0 eq., 7.87 g, calculated as 15.6 mmol) in dichloromethane (30 mL) was added TFA (8.0 eq., 14.2 g, 124 mmol) at room temperature, and the mixture was stirred at the same temperature for 1 hour. A 1 M aqueous sodium hydroxide solution (113 mL) was added to the reaction solution to adjust the pH to 9. After one liquid separation with ethyl acetate (100 mL), the organic layer was separated and washed twice with water (50 mL) and once with a 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 light 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, 77% yield in two stages starting from Boc-L-Asp(OBzl)-OH) as a light yellow liquid.

[0788] (Example 6E: Synthesis of Fragment D-12)

[0789] Fragment D-12 was synthesized as follows.

[0790] [Chemical 35K1]

[0791]

[0792] [Chemical 35K2]

[0793]

[0794] Under a nitrogen stream and ice cooling, 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). The mixture was stirred at the same temperature for 0.5 hours and then stirred 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 the mixture was 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. Sodium sulfate was filtered out and the mixture was concentrated under reduced pressure to obtain D12-1 (14.55 g, containing 0.6 wt% ethyl acetate, quant.) as a yellow solid.

[0795] [Hua 35K3]

[0796]

[0797] Under a nitrogen atmosphere and ice-cooling, potassium carbonate (2.0 eq., 7.90 g, 57.16 mmol) and iodomethane (2.0 eq., 8.11 g, 57.14 mmol) were added to a solution of D12-1 (1.0 eq., 14.55 g, calculated as 28.58 mmol) in DMF (100 mL). The mixture was stirred at the same temperature for 1 hour. Toluene (200 mL) was added to the reaction solution, and the mixture was washed once with water (200 mL) and once with 5% saline (200 mL). The mixture was then dried over sodium sulfate. The sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain D12-2 (14.78 g, 0.4 wt% DMF, 99% yield based on two steps starting from fragment D-2) as a light brown viscous product.

[0798] [Hua35K4]

[0799]

[0800] 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 DMF (140 mL) solution of D12-2 (1.0 eq., 14.78 g, 28.29 mmol) 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 separated and washed with water (300 mL), 5% aqueous potassium carbonate solution (300 mL), and 5% aqueous sodium chloride solution (300 mL), and then dried over sodium sulfate. The sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure. The resulting crude product (19.66 g) 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.

[0801] (Example 6F: Synthesis of Fragment D-13)

[0802] Fragment D-13 was synthesized as follows.

[0803] [Chemical 35L]

[0804]

[0805] Under a nitrogen atmosphere, to a solution of Boc-L-Asp(OBzl)-OH (1.0 eq., 5.00 g, 15.5 mmol) in DMF (45 mL) were added HOBt·H₂O (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) at room temperature, and the mixture was stirred at the same temperature for 1 hour. Hexane (25 mL) and ethyl acetate (75 mL) were added to the reaction mixture, and the mixture was separated and washed with water (50 mL) twice, a mixture of saturated aqueous sodium bicarbonate (25 mL) and water (25 mL) twice, and a saturated aqueous sodium chloride solution (30 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 D13-1 (7.09 g) as a light yellow liquid.

[0806] [Chemical 35M]

[0807]

[0808] Under a nitrogen atmosphere, TFA (10 eq., 12.3 mL, 161 mmol) was added to a solution of D13-1 (1.0 eq., 7.09 g, calculated as 15.5 mmol) in dichloromethane (30 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. A 1M aqueous sodium hydroxide solution (145 mL) was added to the reaction mixture, and the mixture was separated and extracted once with ethyl acetate (100 mL). The organic layer was washed twice with water (50 mL) and once with a saturated aqueous sodium chloride solution (25 mL). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (5.62 g) as a pale yellow liquid. The crude product was purified on a flash silica gel column (41 g normal phase silica gel, hexane / ethyl acetate = 3 / 1 to 1 / 1) to obtain fragment D-13 (4.20 g, 81% yield over two stages) as a pale yellow liquid.

[0809] (Example 6F: Synthesis of Fragment D-14)

[0810] Fragment D-14 was synthesized as follows.

[0811] [Chemical 35N]

[0812]

[0813] Under a nitrogen atmosphere, to a solution of Boc-L-Asp(OBzl)-OH (1.0 eq., 5.00 g, 15.5 mmol) in DMF (45 mL) were added HOBt·H₂O (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) at room temperature, and the mixture was stirred at the same temperature for 1 hour. Hexane (25 mL) and ethyl acetate (75 mL) were added to the reaction mixture, and the mixture was separated and washed with water (50 mL) twice, a mixture of saturated aqueous sodium bicarbonate (25 mL) and water (25 mL) twice, and a saturated aqueous sodium chloride solution (25 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 D14-1 (7.80 g) as a light yellow liquid.

[0814] [Chemical 35O]

[0815]

[0816] Under a nitrogen atmosphere, TFA (10 eq., 12.0 mL, 157 mmol) was added to a solution of D14-1 (1.0 eq., 7.80 g, calculated as 15.5 mmol) in dichloromethane (30 mL) at room temperature, and the mixture was stirred for 2 hours. A 1M aqueous sodium hydroxide solution (130 mL) was added to the reaction mixture, and the mixture was separated and extracted once with ethyl acetate (100 mL). The organic layer was washed twice with water (50 mL) and once with a saturated aqueous sodium chloride solution (25 mL). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (6.61 g) as a pale yellow liquid. The crude product was purified on a flash silica gel column (33 g of normal phase silica gel, hexane / ethyl acetate = 3 / 1 to 1 / 1) to obtain fragment D-14 (4.00 g, 71% yield over two steps) as a pale yellow liquid.

[0817] (Example 7: Synthesis of Compound 1)

[0818] [Chemistry 36]

[0819]

[0820] Under a nitrogen atmosphere and ice cooling, TBD (1.05 eq., 1.42 g, 10.20 mmol) was added to a toluene (111 mL) 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). 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 and the mixture was washed once. The organic layer was washed once with a mixture of a 5% aqueous sodium bicarbonate solution (50 mL) and a 5% aqueous sodium chloride solution (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, PMBOH, containing ethyl acetate, apparent yield 90%) as a yellow sticky substance.

[0821] [Chemistry 37]

[0822]

[0823] Under a nitrogen atmosphere and ice-cooling, to a solution of compound 1-1 (1.0 eq., 2.97 g, fragment A-2, PMBOH, ethyl acetate content, calculated as 3.07 mmol) in DMF (15 mL) were added 1-dodecanethiol (6.0 eq., 3.73 g, 18.43 mmol) and DBU (6.0 eq., 2.81 g, 18.46 mmol), followed by stirring at room temperature for 5 hours. The reaction mixture was fractionated and extracted once with toluene (30 mL) and 5% aqueous citric acid solution (40 mL). The aqueous layer was fractionated again with toluene (30 mL). The combined organic layers were fractionated and washed once with a mixture of 5% aqueous sodium bicarbonate solution (30 mL) and 5% aqueous sodium chloride solution (30 mL), dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure to obtain a crude product (6.54 g) as a yellow oil.

[0824] The crude product (2.47 g) obtained from compound 1-1 (1.03 g) by the same operation was combined with the previous crude product and subjected to rapid silica gel column purification (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 light yellow oil.

[0825] [Chemistry 38]

[0826]

[0827] Under a nitrogen atmosphere, to 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) were added 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·H₂O (2.0 eq., 0.63 g, 4.11 mmol), and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was separated and extracted once with toluene (50 mL) and 5% aqueous sodium bicarbonate solution (50 mL). The organic layer was separated and washed once with 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 the crude product (3.49 g) as a yellow viscous substance. The crude product was purified by flash silica gel column (NH2 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.

[0828] [Chemistry 39]

[0829]

[0830] 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 the pH was adjusted to 3 by adding 5% aqueous citric acid (30 mL). The mixture was then separated and extracted once with ethyl acetate (30 mL). The organic layer was washed once with 5% aqueous sodium chloride (30 mL) and dried over sodium sulfate. The sodium sulfate was filtered off and the mixture was concentrated under reduced pressure to obtain a crude product (2.45 g) as a pale yellow viscous substance. The crude product was purified on a flash silica gel column (25 g normal phase silica gel, ethyl acetate / methanol = 100 / 0 to 90 / 10) to obtain compound 1-4 (1.36 g, containing 4.4 wt% ethyl acetate, equivalent yield 85%) as a white amorphous product.

[0831] [Chemistry 40]

[0832]

[0833] 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. Subsequently, 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 addition was complete, the mixture was stirred at room temperature for a further 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was washed once with ethyl acetate (15 mL) and 5% aqueous citric acid solution (15 mL). The organic layer was washed once with 5% aqueous sodium bicarbonate solution (15 mL) and once with 5% aqueous sodium chloride solution (30 mL), then dried over sodium sulfate. The sodium sulfate was filtered off, and the mixture 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.

[0834] Under a nitrogen atmosphere, TBAF (8.0 eq., 5.63 mL, 6.193 mmol in 1.1 M THF, 0.95 g, calculated as 0.774 mmol) was added to a THF (19 mL) solution of a mixture of compounds 1-5 and 1-6 under ice cooling. The mixture was stirred for 4 hours while warming to room temperature. The reaction mixture was ice-cooled, 10% aqueous ammonium chloride solution (40 mL) was added, and extraction was performed once with ethyl acetate (40 mL). The organic layer was washed once with 5% aqueous sodium chloride solution (40 mL), dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure to obtain a crude product (1.19 g) as a light brown viscous substance.

[0835] The 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 the same operation was combined with the previous crude product and subjected to rapid silica gel column purification (normal phase silica gel 10 g, hexane / ethyl acetate = 50 / 50) to obtain compound 1-6 (0.60 g, isomer mixture. Contains 0.7 wt% of ethyl acetate, 36.4 wt% of TBAF, and a 2-stage conversion yield of 70% starting from compound 1-4) as a light orange solid.

[0836] [Chemistry 41]

[0837]

[0838] Under a nitrogen atmosphere and ice-cooling, Dess-Martin periodinane (1.5 eq., 0.38 g, 0.90 mmol) was added to a solution of compound 1-6 (1.0 eq., 0.66 g, isomer mixture, containing 3.9 wt% ethyl acetate, 38.9 wt% TBAF, 0.60 mmol) in dichloromethane (13 mL). The mixture was stirred for 16 hours while warming to room temperature. A 5% aqueous sodium bicarbonate solution (10 mL) and a 5% aqueous sodium thiosulfate solution (10 mL) were added to the reaction solution, followed by a single wash. The organic layer was washed once with a 5% aqueous sodium chloride solution (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 form.

[0839] 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, containing isomers, calculated as 0.60 mmol) in tert-butyl alcohol (16 mL), pentene (4 mL), and water (4 mL) at room temperature. 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 for separation and extraction. The organic layer was washed twice with water (20 mL) and once with a 5% aqueous sodium chloride solution (20 mL), and then dried over sodium sulfate. After filtering out the sodium sulfate, the mixture was concentrated under reduced pressure to obtain compound 1-7 (0.351 g, isomer mixture, containing 12.5 wt% TBAF, 80% yield based on the two steps starting from compound 1-6) as a light orange solid.

[0840] [Chemistry 42]

[0841]

[0842] Under a nitrogen atmosphere, under ice cooling, to a dichloromethane (1.3 mL) solution of compound 1-7 (1.0 eq., 130 mg, isomer mixture, TBAF 24.8 wt% content, 0.15 mmol) and L-glutamic acid dibenzyl ester hydrochloride (fragment D-1, 1.5 eq., 83 mg, 0.23 mmol) were added DIPEA (3.0 eq., 78 μL, 0.46 mmol) and HBTU (1.5 eq., 87 mg, 0.23 mmol), and the mixture was stirred for 3.5 hours while warming to room temperature.

[0843] The reaction solution obtained by treating compound 1-7 (100 mg) with the same operation was combined with the previous reaction solution, and toluene (20 mL), 5% citric acid aqueous solution (20 mL) and 5% sodium chloride aqueous solution (10 mL) were added for separation and washing. The organic layer was washed once with 5% citric acid aqueous solution (20 mL), once with 5% sodium bicarbonate aqueous solution (20 mL), and once with 5% sodium chloride aqueous solution (20 mL), dried over sodium sulfate, and the sodium sulfate was filtered out. The mixture was concentrated under reduced pressure, and the crude product (290 mg) obtained as a light brown sticky substance was purified by rapid silica gel column purification (NH2 silica gel 6.5 g, hexane / ethyl acetate = 50 / 50) to obtain compound 1-8 (37 mg, yield 14%) as a yellow sticky substance.

[0844] [Chemistry 43]

[0845]

[0846] Under a nitrogen atmosphere, to a mixture of compound 1-8 (1.0 eq., 37 mg, 0.039 mmol) in THF (1.85 mL) / water (1.85 mL) was added 10% palladium on carbon (NEChemcat NX type, 50% aqueous product, 11.1 mg) at room temperature. After hydrogen was purged from the system, the mixture was stirred at the same temperature for 16 hours. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure. To the concentrated residue was added a mixture of THF (1.85 mL) / water (1.85 mL). After nitrogen was purged from the system, 10% palladium on carbon (NEChemcat NX type, 50% aqueous product, 11.1 mg) was added at room temperature. After hydrogen was purged from the system, the mixture was stirred at the same temperature for 3 hours. As the reaction proceeded, the target product precipitated as a solid. TFA (2.0 eq., 6.0 μL, 0.078 mmol) was added to dissolve the target product. The catalyst was filtered off through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude product (27 mg) as a pale orange amorphous substance.

[0847] The crude product (15.5 mg) obtained from compound 1-8 (21 mg) by the same operation was combined with the previous crude product and subjected to two rapid silica gel column purifications (60 g of reverse phase silica gel, first time: 0.05% TFA aqueous solution / acetonitrile = 99 / 1 to 90 / 10, second time: 0.05% TFA aqueous solution / acetonitrile = 95 / 5), and then freeze-dried to obtain the TFA salt of compound 1 (18 mg, yield 45%, purity 97.1%) as a white solid.

[0848] 1H-NMR(400MHz,D2O)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,1H),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).

[0849] (Example 8: Synthesis of Compound 9)

[0850] [Chemistry 44]

[0851]

[0852] Under a nitrogen atmosphere and ice cooling, to a solution of compound 1-7 (1.0 eq., 264 mg, isomer mixture, containing 12.5 wt% TBAF, 0.36 mmol) and dibenzyl L-aspartate hydrochloride (fragment D-2, 1.5 eq., 188 mg, 0.54 mmol) in dichloromethane (6.6 mL) were added DIPEA (1.5 eq., 91 μL, 0.54 mmol) and HATU (1.5 eq., 204 mg, 0.54 mmol). The mixture was stirred at the same temperature for 6 hours. The reaction mixture was washed once with 5% aqueous citric acid solution (10 mL). The organic layer was washed once with a mixture of 5% aqueous sodium bicarbonate solution (10 mL) and 5% aqueous sodium chloride solution (10 mL), and then dried over sodium sulfate. After filtering out the sodium sulfate, the crude product (496 mg) of the pale brown viscous substance obtained by concentration under reduced pressure was purified twice by flash silica gel column purification (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).

[0853] The low-purity compound 9-1 was dissolved in toluene (10 mL), washed five times with 5% aqueous sodium chloride solution (10 mL), and dried over sodium sulfate. After filtering out the sodium sulfate, the mixture was concentrated under reduced pressure to obtain compound 9-1 (93 mg, 28% yield) as a yellow amorphous form.

[0854] [Chemistry 45]

[0855]

[0856] Under a nitrogen atmosphere, to a mixture of compound 9-1 (1.0 eq., 50 mg, 0.053 mmol) in THF (2.5 mL) / water (2.5 mL) were added 10% palladium on carbon (NEChemcat NX type, 50% aqueous product, 2.5 mg) and TFA (2.0 eq., 8.2 μL, 0.107 mmol) at room temperature. After hydrogen substitution, the mixture was stirred at the same temperature for 23 hours. 10% palladium on carbon (NEChemcat NX type, 50% aqueous product, 2.5 mg) was added, and the mixture was stirred for 27 hours. 10% palladium on carbon (NEChemcat NX type, 50% aqueous product, 2.5 mg) was added again, and the mixture was stirred for a further 24 hours.

[0857] The reaction mixture obtained by treating compound 9-1 (10 mg) with the same procedure was combined with the previous reaction mixture. After filtering the catalyst through celite, the filtrate was concentrated under reduced pressure to obtain a crude product (58 mg) as an orange viscous substance. The crude product was purified on a flash silica gel column (30 g of reverse-phase silica gel, 0.05% TFA aqueous solution / acetonitrile = 95 / 5 to 90 / 10) and freeze-dried to obtain the TFA salt of compound 9 (30.5 mg, yield 73%, purity 97.8%) as a white solid.

[0858] 1 H-NMR(400MHz,D2O)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,3H),1.05(t,J=7.2Hz,3H),0.86(d,J=7.2Hz,3H),0.78(d,J=6.8Hz,3H).

[0859] (Example 9: Synthesis of Compound 2)

[0860] [Chemistry 46]

[0861]

[0862] Under a nitrogen atmosphere, 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·H₂O (2.0 eq., 0.91 g, 5.94 mmol) were added to a solution of compound 1-2 (1.0 eq., 2.32 g, PMBOH, ethyl acetate content, calculated to be 2.97 mmol) in DMF (35 mL) and stirred at room temperature for 2 hours. The reaction mixture was separated and extracted once with toluene (70 mL) and 5% aqueous sodium bicarbonate solution (70 mL). The organic layer was separated and 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, insoluble matter was filtered off after ultrasonic irradiation, 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 form.

[0863] [Chemistry 47]

[0864]

[0865] 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) and water (14 mL), and the mixture was stirred at room temperature for 3 hours. The reaction solution was ice-cooled, and the pH was adjusted to 3 by adding 5% aqueous citric acid solution (45 mL). Extraction was performed once with ethyl acetate (45 mL). The organic layer was washed once with 5% aqueous sodium chloride solution (45 mL) and 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 (25 g normal phase silica gel, ethyl acetate / methanol = 100 / 0 to 70 / 30) to obtain compound 2-10 (1.63 g, containing 7.3 wt% ethyl acetate, 42% conversion yield of 4 stages starting from fragment B-1) as a light orange amorphous form.

[0866] [Chemistry 48]

[0867]

[0868] 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. Subsequently, a solution of compound 2-10 (1.0 eq., 0.66 g, containing 7.3 wt% ethyl acetate, 0.852 mmol) in DMF (8 mL) was added at the same temperature over 17 hours. After the addition was complete, the mixture was stirred at room temperature for an additional hour. The reaction mixture was concentrated under reduced pressure until the volume was reduced to several mL.

[0869] Under a nitrogen atmosphere, the concentrated residue was stirred at an external temperature of 50°C for 17 hours, followed by stirring at an external temperature of 70°C for 2 hours. Ethyl acetate (20 mL) and 5% aqueous citric acid solution (20 mL) were added to the reaction solution for separation and extraction. The organic layer was separated and washed once with 5% aqueous sodium bicarbonate solution (20 mL) and once with 5% aqueous sodium chloride solution (20 mL), and then dried over sodium sulfate. The sodium sulfate was filtered out and concentrated under reduced pressure to obtain a crude product (0.98 g) as a light brown viscous substance. The crude product was purified on a flash silica gel column (normal phase silica gel 10 g, chloroform / ethyl acetate = 90 / 10 to 5 / 95) to obtain compound 2-12 (0.168 g, containing isomers and impurities, apparent yield of 34% for the two stages starting from compound 2-10) as an orange solid.

[0870] [Chemistry 49]

[0871]

[0872] Under a nitrogen atmosphere and ice-cooling, Dess-Martin periodinane (1.5 eq., 179 mg, 0.422 mmol) was added to a solution of compound 2-12 (1.0 eq., 165 mg, containing isomers and impurities, calculated as 0.282 mmol) in dichloromethane (3.3 mL). The mixture was stirred for 2 hours while warming to room temperature. A 5% aqueous sodium bicarbonate solution (3 mL) and a 5% aqueous sodium thiosulfate solution (3 mL) were added to the reaction solution, followed by a single separation. The organic layer was washed once with a 5% aqueous sodium chloride solution (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 product.

[0873] 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 isomers, calculated as 0.224 mmol) in tert-butyl alcohol (5.6 mL), pentene (1.4 mL), and water (1.4 mL) at room temperature. The mixture was stirred at the same temperature for 1 hour. Ethyl acetate (15 mL) and water (15 mL) were added to the reaction mixture for a single separation. The organic layer was washed once with a 5% aqueous sodium chloride solution (15 mL) and then dried over sodium sulfate. After filtering out the sodium sulfate, the mixture was concentrated under reduced pressure to obtain compound 2-13 (97 mg, containing isomers, a 58% yield based on the two steps starting from compound 2-12) as a yellow solid.

[0874] [Chemistry 50]

[0875]

[0876] Under a nitrogen atmosphere and ice cooling, to a solution of compound 2-13 (1.0 eq., 79 mg, containing isomers, 0.132 mmol) and L-glutamic acid dibenzyl ester hydrochloride (fragment D-1, 1.5 eq., 72 mg, 0.198 mmol) in dichloromethane (2 mL) were added DIPEA (1.5 eq., 34 μL, 0.197 mmol) and HATU (1.5 eq., 75 mg, 0.200 mmol). The mixture was stirred for 6 hours while warming to room temperature. Ethyl acetate (10 mL) and 5% aqueous citric acid solution (10 mL) were added to the reaction mixture for separation and extraction. The organic layer was washed with 5% aqueous sodium bicarbonate solution (10 mL) and 5% aqueous sodium chloride solution (10 mL) respectively, and then dried over sodium sulfate. After filtering out the sodium sulfate, the mixture was concentrated under reduced pressure, and the crude product (160 mg) obtained as a light brown sticky substance was subjected to two rapid silica gel column purifications (first and second times: 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 substance.

[0877] [Chemistry 51]

[0878]

[0879] Under a nitrogen atmosphere, to a mixture of compound 2-6 (1.0 eq., 64 mg, fragment D-1, containing ethyl acetate, calculated as 0.070 mmol) in THF (3.2 mL) / water (3.2 mL) were added 10% palladium on carbon (NEChemcat NX type, 50% aqueous product, 3.2 mg) and TFA (2.0 eq., 10.7 μL, 0.140 mmol) at room temperature. After hydrogen exchange, the mixture was stirred at the same temperature for 66 hours. An additional 10% palladium on carbon (NEChemcat NX type, 50% aqueous product, 3.2 mg) was added, and the mixture was stirred for 21.5 hours. The catalyst was then filtered off through celite, and the filtrate was concentrated under reduced pressure and then subjected to further reaction. To the concentrated residue was added a mixture of THF (3.2 mL) and 3.2 mL. After nitrogen was purged, 10% palladium on carbon (NEChemcat NX type, 50% aqueous solution, 5.8 mg) and TFA (2.0 eq., 10.7 μL, 0.140 mmol) were added at room temperature. After hydrogen was purged, the reaction mixture was stirred at the same temperature for 23 hours. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product (59 mg) as a light brown viscous substance. The crude product was purified on a flash silica gel column (30 g of reverse-phase silica gel, 0.05% aqueous TFA / acetonitrile = 95 / 5) and then freeze-dried to obtain the TFA salt of compound 2 (5.2 mg, 12% yield, 97.1% purity) as a white solid.

[0880] 1 H-NMR (400MHz, D2O) δ7.45 (s, 1H), 7.05-7.03 (m, 1H), 6.96 (d, J = 8.4Hz, 1H), 4.63 (s, 1H), 4.4 5(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) ,2.25-2.20(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).

[0881] (Example 9A: Synthesis of Compound 9A)

[0882] The steps up to compound 1-7 were the same as the synthesis method of compound 1.

[0883] Compounds 1-7 to 9A-1

[0884] [Chemical 51A]

[0885]

[0886] Under a nitrogen atmosphere and ice-cooling, 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). The mixture was stirred at the same temperature for 7 hours and then at room temperature for 15 hours. Ethyl acetate (10 mL) was added to the reaction solution, and the mixture was then separated and washed with a mixture of water (5 mL) and saturated aqueous sodium bicarbonate (5 mL) and then with saturated aqueous sodium chloride (10 mL). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain the crude product (162 mg) as a green oil. The crude product was purified by flash silica gel column (NH2 silica gel 6 g, hexane / ethyl acetate = 75 / 25 to 50 / 50) to obtain compound 9A-1 (48.5 mg, yield 47%) as a white amorphous substance.

[0887] The synthesis of compound 9A-1 to compound 9A was carried out as follows.

[0888] [Chemistry 51B]

[0889]

[0890] Under a nitrogen atmosphere, to a mixture of compound 9A-1 (1.0 eq., 20 mg, 0.025 mmol) in THF (800 μL) / water (40 μL) were added 10% palladium on carbon (NEChemcat NX type, 50% aqueous product, 2.0 mg) and TFA (2.0 eq., 3.7 μL, 0.048 mmol) at room temperature. The system was purged with hydrogen, and after stirring at the same temperature for 23 hours, the catalyst was filtered off through Celite to obtain a filtrate.

[0891] The filtrate obtained similarly from compound 9A-1 (1.0 eq., 15 mg, 0.018 mmol) was combined with the above filtrate and concentrated under reduced pressure to yield a crude product. The resulting crude product (36.6 mg) was purified on a flash silica gel column (30 g of reverse-phase silica gel, 0.05% aqueous TFA / acetonitrile = 95 / 5 to 75 / 25). Freeze-dried, the TFA salt of compound 9A (16.3 mg, 54% yield, 94.4% purity) was obtained as a white solid.

[0892] 1 H-NMR(400MHz,D2O)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),2.7 1(s,3H),2.07-1.87(m,2H),1.79-1.62(m,1H),1.57(s,3H),1.24(m,6 H), 1.05 (t, J = 7.2Hz, 3H), 0.85 (d, J = 6.4Hz, 3H), 0.79 (d, J = 6.8Hz, 3H).

[0893] (Example 9B: Synthesis of Compound 9B)

[0894] The steps up to compound 1-7 were carried out as described in Example 7.

[0895] The synthesis of compound 1-7 to compound 9B-1 was carried out as follows.

[0896] [Chemical 51C]

[0897]

[0898] Under a nitrogen atmosphere and ice-cooling, DEPBT (1.5 eq., 55.0 mg, 0.184 mmol) and 2,4,6-trimethylpyridine (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). The mixture was stirred at the same temperature for 6 hours and then at room temperature for 16 hours. Ethyl acetate (10 mL) was added to the reaction solution, and the mixture was then separated and washed with a mixture of water (5 mL) and saturated aqueous sodium bicarbonate (5 mL) (partially) and saturated aqueous sodium chloride (10 mL) (partially). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (166 mg) as a green oil. The crude product was purified by flash silica gel column (NH2 silica gel 6 g, hexane / ethyl acetate = 75 / 25 to 0 / 100) to obtain compound 9B-1 (54.5 mg, yield 51%) as a white amorphous substance.

[0899] The synthesis of compound 9B-1 to compound 9B was carried out as follows.

[0900] [Chemistry 51D]

[0901]

[0902] Under a nitrogen atmosphere, to a mixture of compound 9B-1 (1.0 eq., 39 mg, 0.045 mmol) in THF (1560 μL) / water (78 μL) at room temperature were added 10% palladium on carbon (NEChemcat NX type, 50% aqueous product, 3.9 mg) and TFA (5.0 eq., 17 μL, 0.223 mmol). After hydrogen exchange, the mixture was stirred at the same temperature for 4 hours. The catalyst was filtered 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 on a flash silica gel column (30 g of reverse phase silica gel, 0.05% aqueous TFA / acetonitrile = 95 / 5 to 80 / 20). The residue was freeze-dried to obtain the TFA salt of compound 9B (24.3 mg, yield 58%, purity 95.2%) as a white solid.

[0903] 1H-NMR(400MHz,D2O)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),2.73(s,3H),2.08-1.88(m,2H),1.79-1.65(m,1H),1.58(s,3H),1.24(t,J =7.2Hz, 3H), 1.05 (t, J = 7.2Hz, 3H), 0.86 (d, J = 6.8Hz, 3H), 0.79 (d, J = 6.8Hz, 3H).

[0904] (Example 9C: Synthesis of Compound 9C)

[0905] The synthesis of compound 1-7 to compound 9C-1 was carried out as follows.

[0906] [Chemistry 51E]

[0907]

[0908] Under a nitrogen atmosphere and ice-cooling, DEPBT (1.5 eq., 42.7 mg, 143 μmol) and 2,4,6-trimethylpyridine (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). The mixture was stirred at the same temperature for 5 hours and then at room temperature for 15.5 hours. Ethyl acetate (20 mL) was added to the reaction mixture, and the mixture was then separated and washed with a mixture of water (5 mL) and saturated aqueous sodium bicarbonate (5 mL) and then with saturated aqueous sodium chloride (10 mL). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (171 mg) as a green oil. The crude product was purified by flash silica gel column (NH2 silica gel 6 g, hexane / ethyl acetate = 75 / 25 to 0 / 100) to obtain compound 9C-1 (42.3 mg, yield 56%) as a white amorphous substance.

[0909] The synthesis of compound 9-1 to compound 9C was carried out as follows.

[0910] [Chemical 51F]

[0911]

[0912] Under a nitrogen atmosphere, to a mixture of compound 9C-1 (1.0 eq., 41 mg, 0.047 mmol) in THF (1640 μL) / water (82 μL) were added 10% palladium on carbon (NEChemcat NX type, 50% aqueous solution, 4.1 mg) and TFA (2.0 eq., 7.2 μL, 0.094 mmol) at room temperature. After hydrogen exchange, the system was stirred at the same temperature for 6 hours. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product (35 mg). The crude product was purified on a flash silica gel column (30 g reverse-phase silica gel, 0.05% aqueous TFA / acetonitrile = 95 / 5 to 80 / 20). Freeze-dried to obtain the TFA salt of compound 9C (29.0 mg, 91% yield, 96.0% purity) as a white solid.

[0913] 1 H-NMR(400MHz,D2O)δ6.98-6.85(m,3H),4.24-4.17(m,2H),4.10(d,J=9.6Hz,1 H),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 .2Hz,3H),1.05(t,J=7.2Hz,3H),0.85(d,J=6.8Hz,3H),0.78(d,J=6.4Hz,3H).

[0914] (Example 9D: Synthesis of Compound 9D)

[0915] Compound 1-7 was synthesized as described in Example 7. The synthesis of compound 1-7 to compound 9D-1 was carried out as follows.

[0916] [Chemical 51G]

[0917]

[0918] Under a nitrogen atmosphere and ice-cooling, DEPBT (1.5 eq., 48.8 mg, 163 μmol) and 2,4,6-trimethylpyridine (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). The mixture was stirred at the same temperature for 6 hours and then at room temperature for 16 hours. Ethyl acetate (10 mL) was added to the reaction mixture, and the mixture was washed with a mixture of water (5 mL) and saturated aqueous sodium bicarbonate (5 mL) once and with saturated aqueous sodium chloride (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 a crude product (152 mg) as a green oil. The crude product was purified by flash silica gel column (NH2 silica gel 6 g, hexane / ethyl acetate = 75 / 25 to 0 / 100) to obtain compound 9D-1 (54.0 mg, yield 54%) as a white amorphous substance.

[0919] The synthesis of compound 9D-1 to compound 9D was carried out as follows.

[0920] [Chemical 51H]

[0921]

[0922] To a mixture of compound 9D-1 (1.0 eq., 38.0 mg, 0.041 mmol) in THF (1600 μL) and water (80 μL) were added 10% palladium on carbon (NEChemcat NX type, 50% aqueous solution, 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 then filtered through Celite to obtain a filtrate. The resulting crude product (32 mg) was purified on a flash silica gel column (30 g reverse-phase silica gel, 0.05% aqueous TFA / acetonitrile = 95 / 5 to 70 / 30). Freeze-dried, the TFA salt of compound 9D was obtained as a white solid (14.9 mg, 50% yield, 95.6% purity).

[0923] 1H-NMR(400MHz,D2O)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),2.08-1.88(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).

[0924] (Example 9E: Synthesis of Compound 9E)

[0925] The synthesis of compound 9E was carried out.

[0926] [Chemical 51I]

[0927]

[0928] Under a nitrogen atmosphere, 2,4,6-trimethylpyridine (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. The mixture was stirred under ice-cooling for 7 hours and then 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 DEPBT (0.5 eq., 22.5 mg, 75 μmol) under ice-cooling. The mixture was stirred under ice-cooling for 2 hours and then at room temperature for 1.5 hours. After adding saturated aqueous ammonium chloride solution (1.5 mL) to the reaction solution, it was separated and 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 solution (2 mL), once with water (2 mL), and once with saturated aqueous sodium chloride solution (2 mL). After the organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered out and concentrated under reduced pressure to obtain a crude product (244 mg) as a dark green sticky substance. The crude product was purified by rapid silica gel column purification (NH2 silica gel 4.9 g, hexane / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 9E-1 (71.3 mg, yield 50%) as a light yellow transparent sticky substance.

[0929] [Chemistry 51J]

[0930]

[0931] To a mixture of compound 9E-1 (1.0 eq., 53 mg, 0.052 mmol) in THF (2200 μL) and water (110 μL) were added 10% palladium on carbon (NEChemcat NX type, 50% aqueous solution, 5.3 mg) and TFA (2.0 eq., 8.0 μL, 0.104 mmol) at room temperature. The system was purged with hydrogen and stirred at the same temperature for 23 hours. The catalyst was then filtered off through Celite to obtain a filtrate. The filtrate was concentrated under reduced pressure to obtain a crude product (44 mg) which was purified on a flash silica gel column (30 g of reverse-phase silica gel, 0.05% aqueous TFA / acetonitrile = 95 / 5 to 50 / 50). Freeze-dried, the TFA salt of compound 9E was obtained as a white solid (36.6 mg, 86% yield, 94.3% purity).

[0932] 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)

[0933] (Example 9F: Synthesis of Compound 9F)

[0934] [Chemical 51K]

[0935]

[0936] Under a nitrogen atmosphere, 2,4,6-trimethylpyridine (3.0 eq., 57 μL, 433 μmol) and DEPBT (1.5 eq., 65.8 mg, 220 μmol) were added to a THF (1.45 mL) 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) under ice-cooling. The mixture was stirred under ice-cooling for 6 hours and then at room temperature for 16 hours. Saturated aqueous ammonium chloride (2.0 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (6 mL). The organic layers were combined and washed with saturated aqueous sodium bicarbonate (3 mL) twice, water (3 mL) twice, and saturated aqueous sodium chloride (2 mL) once. The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (238 mg) as a dark green viscous substance. The crude product was purified on a flash silica gel column (5.2 g of NH2 silica gel, hexane / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 9F-1 (73.3 mg, 53% yield) as a white amorphous substance.

[0937] [Chemical 51L]

[0938]

[0939] Under a nitrogen atmosphere, 10% palladium on carbon (NEChemcat NX type, 50% aqueous solution, 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 replaced with hydrogen and stirred at the same temperature for 7 hours. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product (59 mg). The crude product was purified on a flash silica gel column (30 g reverse-phase silica gel, 0.05% aqueous TFA / acetonitrile = 95 / 5 to 55 / 45). Freeze-dried, the TFA salt of compound 9F was obtained as a white solid (31.4 mg, 55% yield, 95.4% purity).

[0940] 1H-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).

[0941] (Example 9G: Synthesis of Compound 9G)

[0942] [Chemical 51M]

[0943]

[0944] The two steps from fragment A-2" to compound 25-2 are described in Example 29B below.

[0945] The synthesis of compound 25-2 to compound 9G-1 was carried out as follows.

[0946] [Chemical 51N]

[0947]

[0948] To a solution of compound 25-2 (1.0 eq., 1.03 g, 1.44 mmol) in DMF (15 mL) were added HOBt·H₂O (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) at room temperature, and the mixture was stirred at room temperature for 5 hours. A mixture of hexane (15 mL) and ethyl acetate (45 mL) was added, and the mixture was separated and washed with water (40 mL) twice, saturated aqueous sodium bicarbonate (40 mL) twice, and saturated aqueous sodium chloride (20 mL) once. The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain compound 9G-1 (1.71 g, crude yield 115%) as a light brown amorphous form.

[0949] The synthesis of compound 9G-1 to compound 9G-2 was carried out as follows.

[0950] [Chemical 51O]

[0951]

[0952] 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 for 4 hours. A 1N aqueous hydrochloric acid solution (5.0 mL) was added to the reaction mixture 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 a saturated aqueous sodium chloride solution (10 mL). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (1.84 g) as a brown viscous substance. The crude product was purified on a flash silica gel column (20 g normal phase silica gel, ethyl acetate / methanol = 100 / 0 to 40 / 60) to obtain compound 9G-2 (1.06 g, 102% yield over two stages) as a light brown amorphous substance.

[0953] The synthesis of compound 9G-2 to compound 9G-3 was carried out as follows.

[0954] [Chemistry 51P]

[0955]

[0956] A mixture of compound 9G-2 (1.0 eq., 1.05 mg, calculated as 1.44 mmol) in acetonitrile (14.5 mL) and THF (14.5 mL) was added dropwise at approximately 100 μL / min over 5 hours 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 room temperature. The mixture was then stirred at room temperature for 15.5 hours. The reaction mixture was concentrated under reduced pressure to approximately 250 mL, and ethyl acetate (200 mL) was added. The mixture was then washed with a mixture of water (50 mL) and saturated aqueous ammonium chloride (100 mL) twice, saturated aqueous sodium bicarbonate (100 mL) twice, and saturated aqueous sodium chloride (50 mL) once. The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (1.92 g) as a reddish-brown viscous substance. The crude product was purified on a flash silica gel column (25 g normal phase silica gel, hexane / ethyl acetate = 80 / 20 to 50 / 50) to obtain compound 9G-3 (231 mg, 3-stage yield 23%) as a white amorphous substance.

[0957] The synthesis of compound 9G-3 to compound 9G-4 was carried out as follows.

[0958] [Chemical 51Q]

[0959]

[0960] To a solution of compound 9G-3 (1.0 eq., 230 mg, 0.324 mmol) in THF (3.2 mL) at room temperature was added TBAF (2.5 eq. in 1M THF, 0.81 mL, 0.810 mmol), and the mixture was stirred at the same temperature for 2 hours. Ethyl acetate (30 mL) was added to the reaction mixture, and the mixture was washed three times with saturated aqueous ammonium chloride (20 mL) and once with saturated aqueous sodium chloride (10 mL), followed by drying over magnesium sulfate. The magnesium sulfate was filtered off and the mixture was concentrated under reduced pressure to obtain a crude product (214 mg) as a pale yellow amorphous form. The crude product was purified on a flash silica gel column (5 g normal phase silica gel, hexane / ethyl acetate = 50 / 50 to 0 / 100) to obtain compound 9G-4 (191 mg, 99% yield) as a white amorphous form.

[0961] The synthesis of compound 9G-4 to compound 9G-5 was carried out as follows.

[0962] [Chemical 51R]

[0963]

[0964] 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 with a mixture of 10% aqueous sodium sulfite (10 mL) and saturated aqueous sodium bicarbonate (10 mL). Extraction was performed 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, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain the aldehyde (187 mg, quant.) as a white amorphous product.

[0965] To a mixture of aldehyde (1.0 eq., 186 mg, 0.314 mmol) in pentene (1 mL) / tert-butyl alcohol (4 mL) at room temperature, 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) were added, and the mixture was stirred at the same temperature for 1 hour. Saturated aqueous ammonium chloride (10 mL) was added to the reaction mixture, and extraction was performed once with ethyl acetate (20 mL) and twice with ethyl acetate (10 mL). The organic layers were combined, washed once with saturated aqueous sodium chloride (20 mL), dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain the crude product (215 mg, 99% yield) as a white amorphous solid. The crude product was purified by 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.

[0966] The synthesis of compound 9G-5 to compound 9G-6 was carried out as follows.

[0967] [Chemical 51S]

[0968]

[0969] 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) at room temperature, fragment D-14 (1.5 eq., 164 mg, 0.435 mmol) was added. DIPEA (2.4 eq., 0.12 mL, 0.706 mmol) was added under ice cooling, and the mixture was stirred for 10 minutes. DMT-MM (1.7 eq., 138 mg, 0.497 mmol) was then added, and the mixture was stirred at the same temperature for 2.5 hours. Ethyl acetate (30 mL) was added to the reaction mixture, and the mixture was washed with water (15 mL) (partially), a mixture of water (10 mL) and saturated aqueous ammonium chloride (10 mL) (partially), water (10 mL) and saturated aqueous sodium bicarbonate (10 mL) (partially), and saturated aqueous sodium chloride (10 mL) (partially). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (360 mg) as a yellow oil. The crude product was purified twice by flash silica gel column purification (first: 6 g NH2 silica gel, hexane / ethyl acetate = 75 / 25 to 67 / 33, second: 4 g normal phase silica gel, hexane / ethyl acetate = 50 / 50) to obtain compound 9G-6 (235 mg, 83% yield) as a white amorphous product.

[0970] The synthesis of compound 9G-6 to compound 9G-7 was carried out as follows.

[0971] [Chemical 51T]

[0972]

[0973] At room temperature, TFA (9.7 eq., 0.18 mL, 2.35 mmol) was added to a solution of compound 9G-6 (1.0 eq., 235 mg, 0.243 mmol) in dichloromethane (2.4 mL), and the mixture was stirred at the same temperature for 1 hour. Then, TFA (9.7 eq., 0.18 mL, 2.35 mmol) was added and stirred at the same temperature for 7 hours. The reaction solution was ice-cooled and a 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). The organic layers were combined and washed once with a saturated aqueous sodium chloride solution (20 mL). After drying the organic layer over magnesium sulfate, the magnesium sulfate was filtered out and concentrated under reduced pressure to obtain compound 9G-7 (210 mg, 99% yield) as a light yellow amorphous form.

[0974] The synthesis of compound 9G-7 to compound 9G was carried out as follows.

[0975] [Chemical 51U]

[0976]

[0977] 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. After hydrogen exchange, the system was replaced with 10% palladium on carbon (NEChemcat NX type, 50% aqueous solution, 18.6 mg), and the mixture was stirred at the same temperature for 6.5 hours. The catalyst was filtered off 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 on a flash silica gel column (30 g of reverse phase silica gel, 0.05% aqueous TFA / acetonitrile = 95 / 5 to 55 / 45). The residue was freeze-dried to obtain the TFA salt of compound 9G (107 mg, yield 51%, purity 96.4%) as a white solid.

[0978] 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).

[0979] (Example 10: Synthesis of Compound 10)

[0980] [Chemistry 52]

[0981]

[0982] 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 solution of compound 2-13 (1.0 eq., 95 mg, containing isomers, 0.158 mmol) and L-aspartic acid dibenzyl ester hydrochloride (fragment D-2, 1.5 eq., 83 mg, 0.237 mmol) in dichloromethane (2.4 mL) under ice cooling. The mixture was stirred for 3 hours while warming to room temperature. The reaction mixture was washed once with 5% aqueous citric acid solution (3 mL). The organic layer was then washed once with 5% aqueous sodium bicarbonate solution (3 mL) and once with 5% aqueous sodium chloride solution (3 mL), and dried over sodium sulfate. After filtering out the sodium sulfate, the mixture was concentrated under reduced pressure, and the crude product (197 mg) obtained as a light brown sticky substance was subjected to two rapid silica gel column purifications (first: 10 g normal phase silica gel, hexane / ethyl acetate = 40 / 60, second: 6.5 g NH2 silica gel, hexane / ethyl acetate = 40 / 60 to 0 / 100) to obtain compound 10-1 (54 mg, containing 5.0 wt% hexane, converted yield 36%) as a white solid.

[0983] [Chemistry 53]

[0984]

[0985] Under a nitrogen atmosphere, to a mixture of compound 10-1 (1.0 eq., 52 mg, containing 5.0 wt% hexane, 0.055 mmol) in THF (2.5 mL) / water (2.5 mL) were added 10% palladium on carbon (NEChemcat NX type, 50% aqueous product, 2.6 mg) and TFA (2.0 eq., 8.4 μL, 0.110 mmol) at room temperature. After hydrogen substitution, the mixture was stirred at the same temperature for 25 hours. THF (2.5 mL) was added, and the mixture was stirred for a further 64 hours. 10% palladium on carbon (NEChemcat NX type, 50% aqueous product, 2.6 mg) was added, and the mixture was stirred for another 24 hours. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure to obtain the crude product (41 mg) as a pale orange viscous substance. The crude product was purified by flash silica gel column (30 g reverse phase silica gel, 0.05% aqueous TFA solution / acetonitrile = 95 / 5) and freeze-dried to obtain the TFA salt of compound 10 (18.3 mg, yield 54%, purity 99.3%) as a white solid.

[0986] 1H-NMR(400MHz,D2O)δ7.44(s,1H),7.05(dd,J=8.0,2.0Hz,1H),6.98(d,J=8.0 Hz,1H),4.65(s,1H),4.25(d,J=16.4Hz,1H),3.99(dd,J=10.4,4.0Hz,1H),3.5 5(d,J=16.4Hz,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).

[0987] (Example 11: Synthesis of Compound 5)

[0988] [Chemistry 54]

[0989]

[0990] 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. The mixture was stirred at the same temperature for 15 minutes and then 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 stirred for a further 0.5 hour. The reaction solution was cooled and then concentrated under reduced pressure. The concentrated residue was purified by 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 light yellow-brown oil.

[0991] [Chemistry 55]

[0992]

[0993] Under a nitrogen atmosphere and ice cooling, a solution of compound 5-1 (1.0 eq., 5.35 g, containing impurities, calculated as 4.55 mmol) in acetonitrile (45 mL) was added with 1 M aqueous hydrochloric acid (1.1 eq., 5.00 mL, 5.00 mmol). 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 concentrated under reduced pressure. 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 to remove the sodium sulfate, and concentrated under reduced pressure to obtain the crude product (5.42 g) as a light 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 light yellow oil.

[0994] [Chemistry 56]

[0995]

[0996] Under a nitrogen atmosphere, 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·H2O (2.0 eq., 372 mg, 2.43 mmol) were added to a solution of compound 5-2 (1.0 eq., 0.80 g, containing impurities, calculated to be 1.22 mmol) in DMF (12 mL). The mixture was stirred at room temperature for 20 hours. Water (50 mL) was added to the reaction solution, and extraction was performed three times with ethyl acetate (25 mL). The organic layers were combined, washed once with saturated aqueous sodium bicarbonate (25 mL) and once with saturated aqueous sodium chloride (25 mL), and then dried over sodium sulfate. The sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain the crude product (1.50 g) as a pale yellow oil. The crude product was purified by flash silica gel column twice (first: 50 g normal phase silica gel, hexane / ethyl acetate = 90 / 10 to 50 / 50, second: 120 g reverse phase silica gel, 0.05% TFA aqueous solution / acetonitrile = 90 / 10 to 0 / 100) to obtain compound 5-3 (0.74 g, 38% yield of the first three stages of fragment A-2) as a white amorphous product.

[0997] [Chemistry 57]

[0998]

[0999] 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 solution was concentrated under reduced pressure, and a 0.05 M hydrogen chloride / 1,4-dioxane solution (20 mL) was added to the concentrated residue and concentrated under reduced pressure. This operation was repeated twice. 1,4-dioxane was added to the concentrated residue and concentrated under reduced pressure. This operation was repeated three times to obtain compound 5-4 (1.39 g) as a colorless oil.

[1000] [Chemistry 58]

[1001]

[1002] Under a nitrogen atmosphere, a solution of compound 5-4 (1.0 eq., 1.39 g, calculated as 0.865 mmol) in DMF (65 mL) was added to a solution of EDCI (5.0 eq., 830 mg, 4.33 mmol), HOBt·H2O (5.0 eq., 663 mg, 7.33 mmol), and sodium bicarbonate (10.0 eq., 726 mg, 8.64 mmol) in DMF (800 mL) over 2 hours at room temperature. After the addition was complete, the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was separated and extracted once with ethyl acetate (20 mL) and water (20 mL). The organic layer was separated and 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 obtain a crude product (0.71 g) as an ochre-colored 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 of 42% in the two stages starting from compound 5-3) as a white solid.

[1003] [Chemistry 59]

[1004]

[1005] 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, containing impurities, calculated as 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 cooled, and ethyl acetate (20 mL) and 1M aqueous hydrochloric acid (20 mL) were added for separation and extraction. The organic layer was washed once with 10% aqueous sodium chloride (20 mL), dried over sodium sulfate, and the sodium sulfate was filtered off. The sodium sulfate was filtered off and concentrated under reduced pressure to obtain a crude product (169 mg) as a white solid.

[1006] The same procedure was followed to obtain a crude product (20 mg) from compound 5-5 (20 mg). This crude product was combined with the previous crude product and purified on 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%).

[1007] [Chemistry 60]

[1008]

[1009] Under a nitrogen atmosphere, to 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) were added EDCI (1.5 eq., 34 mg, 0.18 mmol), HOBt·H2O (1.5 eq., 27 mg, 0.18 mmol) and sodium bicarbonate (3.0 eq., 30 mg, 0.36 mmol) at room temperature, and the mixture was stirred at the same temperature for 1.5 hours.

[1010] Toluene (3 mL) was added to the reaction solution, and the mixture was separated and washed twice with 5% aqueous sodium bicarbonate solution (3 mL) and once with 5% aqueous sodium chloride solution (3 mL). The organic layer was dried over sodium sulfate, and after filtering out the sodium sulfate, it was concentrated under reduced pressure to obtain a crude product (115 mg) as a light yellow solid. The crude product was subjected to rapid silica gel column purification (NH2 silica gel 6.5 g, hexane / ethyl acetate = 90 / 10 to 50 / 50) to obtain a white solid (52 mg). Hexane (4 mL) and toluene (2 mL) were added to the solid, and after ultrasonic irradiation, it was stirred at room temperature for 15 minutes. The suspension was filtered to obtain compound 5-7 (37 mg, yield 34%) as a white solid.

[1011] [Chemistry 61]

[1012]

[1013] Under a nitrogen atmosphere, 10% palladium on carbon (NEChemcat NX, 50% aqueous solution, 8.8 mg) was added to a mixture of compound 5-7 (1.0 eq., 35 mg, 0.038 mmol) in THF (1.2 mL) and water (1.2 mL) at room temperature. After hydrogen exchange, the mixture was stirred at the same temperature for 22 hours. The catalyst was filtered through celite, and the solid was washed with 0.05% aqueous TFA. The filtrate was concentrated under reduced pressure to obtain the crude product (20 mg) as a white solid. The crude product was purified twice by flash silica gel column purification (60 g reverse phase silica gel, first pass: 0.05% aqueous TFA / acetonitrile = 99 / 1 to 90 / 10, second pass: 0.05% aqueous TFA / acetonitrile = 99 / 1 to 0 / 100) and freeze-dried to obtain the TFA salt of compound 5 (14 mg, 59% yield, 99.7% purity) as a white solid.

[1014] 1 H-NMR(400MHz,D2O)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=1 0.8Hz,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).

[1015] (Example 12: Synthesis of Compound 3)

[1016] [Chemistry 62]

[1017]

[1018] Under a nitrogen atmosphere, 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·H2O (2.0 eq., 0.37 mg, 2.40 mmol) were added to a DMF (12 mL) solution of compound 5-2 (1.0 eq., 0.79 g, containing impurities, calculated to be 1.20 mmol). The mixture was stirred at room temperature for 2 hours. Water (30 mL) and toluene (30 mL) were added to the reaction mixture for separation and extraction. The organic layer was washed once with water (30 mL) and once with a 10% aqueous sodium chloride solution (30 mL), 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 (14 g NH2 silica gel, hexane / ethyl acetate = 90 / 10 to 0 / 100) to obtain compound 3-1 (0.87 g, containing 3.2 wt% ethyl acetate, equivalent yield 86%) as a light yellow sticky substance.

[1019] [Chemistry 63]

[1020]

[1021] Under a nitrogen atmosphere and ice cooling, 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). 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 residue. The mixture was concentrated under reduced pressure again to obtain compound 3-2 (1.196 g, containing 1,4-dioxane) as a colorless viscous substance.

[1022] [Chemistry 64]

[1023]

[1024] Under a nitrogen atmosphere, a solution of compound 3-2 (1.0 eq., 0.83 g, containing 1,4-dioxane, calculated as 0.72 mmol) in DMF (8 mL) was added to a solution of HATU (5.0 eq., 1.36 g, 3.58 mmol) and DIPEA (10.0 eq., 0.92 g, 7.12 mmol) in DMF (704 mL) over 18.5 hours at room temperature. After the addition was complete, the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was separated and extracted once with ethyl acetate (15 mL) and 5% aqueous citric acid solution (15 mL). The organic layer was washed once with 5% aqueous sodium bicarbonate solution (15 mL) and once with 5% aqueous sodium chloride solution (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 pale brown amorphous substance. The crude product was purified by rapid silica gel column purification (NH2 silica gel 10g, hexane / ethyl acetate = 50 / 50) to obtain compound 3-3 (190mg, yield 46%) as a white solid. Compound 3-3 (89mg) obtained by the same operation was combined and purified by rapid silica gel column purification (NH2 silica gel 14g, hexane / ethyl acetate = 50 / 50), and the fractions containing the target were combined and concentrated under reduced pressure. The concentrated residue was dissolved in 1,2-dichloroethane (3mL) and concentrated under reduced pressure. This operation was performed twice to obtain compound 3-3 (118mg, containing 16.5wt% 1,2-dichloroethane, yield 35%) as a colorless sticky substance.

[1025] [Chemistry 65]

[1026]

[1027] 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). The mixture was stirred at an external temperature of 80°C for 3.5 hours. After cooling, the reaction solution was separated and extracted once with ethyl acetate (20 mL) and 1M aqueous hydrochloric acid (20 mL). The organic layer was separated and washed once with 5% aqueous sodium chloride (20 mL), dried over sodium sulfate, and the sodium sulfate was filtered off. After filtering out the sodium sulfate, the mixture was concentrated under reduced pressure to obtain compound 3-4 (104 mg, containing impurities, quant.) as a white solid.

[1028] [Chemistry 66]

[1029]

[1030] Under a nitrogen atmosphere, EDCI (1.5 eq., 24 mg, 0.125 mmol), HOBt·H₂O (1.5 eq., 19 mg, 0.124 mmol), and sodium bicarbonate (1.5 eq., 10 mg, 0.119 mmol) were added to a DMF (0.5 mL) 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) at room temperature. The mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was then separated and extracted once with toluene (10 mL) and 5% aqueous citric acid solution (10 mL). The organic layer was then separated and washed once with 5% aqueous sodium bicarbonate solution (10 mL) and once with 5% aqueous sodium chloride solution (10 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 (82 mg) as a light yellow viscous substance.

[1031] The same procedure was followed to obtain a crude product (60 mg) from compound 3-4 (1.0 eq., 50 mg). After combining with the previous crude product, the product was purified by flash silica gel column (NH2 silica gel 6.5 g, hexane / ethyl acetate = 40 / 60) to obtain compound 3-5 (69 mg, 48% yield) as a white amorphous product.

[1032] [Chemistry 67]

[1033]

[1034] Under a nitrogen atmosphere, 10% palladium on carbon (NEChemcat NX, 50% aqueous solution, 17 mg) was added to a mixture of compound 3-5 (1.0 eq., 67 mg, 0.077 mmol) in THF (3.35 mL) and water (3.35 mL) at room temperature. After hydrogen exchange, the reaction mixture was stirred at the same temperature for 19.5 hours. TFA (2.0 eq., 12 μL, 0.157 mmol) was added to the reaction mixture, and the catalyst was filtered through Celite. The filtrate was concentrated under reduced pressure to obtain a crude product (45 mg). The crude product was purified on a flash silica gel column (60 g of reverse-phase silica gel, 0.05% aqueous TFA / acetonitrile = 99 / 1 to 0 / 100) and then freeze-dried to obtain the TFA salt of compound 3 (34 mg, 76% yield, 99.9% purity) as a white solid.

[1035] 1H-NMR(400MHz,D2O)δ7.00-6.85(m,3H),4.67(dd,J=13.6,5.6Hz,1H),4.53( dd,J=13.2,1.6Hz,1H),4.42(dd,J=8.8,5.2Hz,1H),4.36(d,J=15.2Hz,1H), 3.96(dd,J=10.0,4.8Hz,1H),3.36-3.29(m,2H),2.98(dd,J=13.2,10.0Hz,1 H), 2.73 (s, 3H), 2.50 (t, J = 7.2Hz, 2H), 2.28-2.19 (m, 1H), 2.08-1.90 (m, 1H).

[1036] (Example 13: Synthesis of Compound 11)

[1037] [Chemistry 68]

[1038]

[1039] Under a nitrogen atmosphere and ice cooling, to a solution of compound 3-4 (1.0 eq., 366.6 mg, calculated as 0.408 mmol) in dichloromethane (3.7 mL) were added a solution of L-aspartic acid dibenzyl ester hydrochloride (fragment D-2, 2.0 eq., 286 mg, 0.816 mmol) and DIPEA (1.9 eq., 135 μL, 0.775 mmol) in dichloromethane (2.5 mL). Subsequently, HOBt·H₂O (2.0 eq., 125 mg, 0.816 mmol) and EDCI (2.0 eq., 156 mg, 0.816 mmol) were added, and the mixture was stirred at the same temperature for 3 hours.

[1040] The reaction solution using compound 3-4 (30 mg) under the same conditions was combined with the previous reaction solution, and ethyl acetate (40 mL) and 1M hydrochloric acid aqueous solution (20 mL) were added for one liquid separation and extraction. The aqueous layer was separated and extracted three times with ethyl acetate (5 mL). The organic layers were combined, washed once with 5% sodium chloride aqueous solution (20 mL), and then dried over sodium sulfate. The sodium sulfate was filtered out and concentrated under reduced pressure to obtain a crude product (633.8 mg) as a yellow oil. The crude product was purified by flash silica gel column (80 g of NH2 silica gel, hexane / ethyl acetate = 43 / 57 to 0 / 100). Toluene was added to the resulting white solid (294.0 mg), and after pulverization by ultrasonic irradiation, the solid was filtered to obtain compound 11-1 (234.3 mg, containing 1.9 wt% ethyl acetate, a 61% yield based on the two stages starting from compound 3-3) as a white solid.

[1041] [Chemistry 69]

[1042]

[1043] Under a nitrogen atmosphere, 10% palladium on carbon (NEChemcat NX type, 50% aqueous product, 57 mg) was added to a mixture of compound 11-1 (1.0 eq., 234 mg, containing 1.9 wt% ethyl acetate, 0.268 mmol) in THF (10 mL) / water (10 mL) at room temperature. After hydrogen exchange, the mixture was stirred at the same temperature for 2 hours. TFA (2.0 eq., 41 μL, 0.536 mmol) was added, and the mixture was stirred at the same temperature for 1 hour. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure to obtain the crude product (189.5 mg) as a pale orange solid. Ethyl acetate was added to the crude product, and the mixture was triturated by ultrasonic irradiation. The insoluble matter was filtered off and dried under reduced pressure. The resulting solid was dissolved in water, the insoluble matter was filtered off, and the filtrate was concentrated to obtain the TFA salt of compound 11 (150.9 mg, 99.6% yield, 99.4% purity) as a pale orange solid.

[1044] 1 H-NMR(400MHz,D2O)δ6.89-6.76(m,3H),4.58(dd,J=13.2,5.2Hz,1H),4.40(d,J=13.2,1H),4.21(d,J=15.2Hz,1H) ,3.86(dd,J=9.6,4.4Hz,1H),3.26(d,J=15.2Hz,1H),3.21(dd,J=13.2,4.4Hz,1H),2.95-2.82(m,3H),2.63(s,3H).

[1045] (Example 14: Synthesis of Compound 6)

[1046] [Chemistry 70]

[1047]

[1048] Under a nitrogen atmosphere and ice cooling, TBD (1.08 eq., 857 mg, 6.16 mmol) was added to a toluene (57 mL) solution of Fragment A-3 (1.0 eq., 3.10 g, 5.72 mmol) and Fragment B-1 (1.2 eq., 3.17 g, containing 20 mol% DIAD, 6.87 mmol). The mixture was stirred at room temperature for 3 hours. The toluene was evaporated by concentration under reduced pressure to obtain a crude product as a dark brown amorphous substance. The crude product was purified on a flash silica gel column (70 g of normal phase silica gel, hexane / ethyl acetate = 5 / 1 to 2 / 1) to obtain compound 6-1 (3.84 g, 70% yield) as a pale yellow amorphous substance.

[1049] [Chemistry 71]

[1050]

[1051] Under a nitrogen atmosphere, cesium carbonate (1.5 eq., 781 mg, 2.21 mmol) and thiophenol (1.5 eq., 230 μL, 2.25 mmol) were added to a DMF (20 mL) solution of compound 6-1 (1.0 eq., 1.41 g, 1.48 mmol) at room temperature, and the mixture was stirred at room temperature for 3 hours. After adding saturated sodium bicarbonate aqueous solution (10 mL), saturated sodium chloride aqueous solution (10 mL), and water (20 mL), the reaction solution was extracted three times with a mixture of hexane (10 mL) and ethyl acetate (30 mL). The organic layers were combined, washed once with saturated sodium chloride aqueous solution (60 mL), and dried over magnesium sulfate. The magnesium sulfate was filtered off and concentrated under reduced pressure to obtain a crude product (2.01 g) as a yellow oil. The crude product was purified by flash silica gel column (normal phase silica gel 20 g, hexane / ethyl acetate = 5 / 1 to 1 / 1) to obtain compound 6-2 (1.02 g, yield 90%) as a light yellow sticky substance.

[1052] [Chemistry 72]

[1053]

[1054] Under a nitrogen atmosphere and ice cooling, EDCI (2.0 eq. 2.23 g, 11.65 mmol), HOBt·H₂O (2.0 eq., 1.77 g, 11.59 mmol), and N-Fmoc-L-Val (2.0 eq., 3.97 g, 11.69 mmol) were added to a DMF (58 mL) solution of compound 6-2 (1.0 eq., 4.44 g, 5.79 mmol) and stirred at room temperature for 2 hours. Water (60 mL) was added to the reaction solution, and the mixture was extracted three times with a mixture of hexane (15 mL) and ethyl acetate (45 mL). The organic layers were combined and washed twice with a saturated aqueous sodium bicarbonate solution (100 mL) and once with a saturated aqueous sodium chloride solution (100 mL). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (9.01 g). The crude product was purified by flash silica gel column (normal phase silica gel 70 g, hexane / ethyl acetate = 5 / 1 to 2 / 1) to obtain compound 6-3 (5.69 g, yield 90%) as a white amorphous substance.

[1055] [Chemistry 73]

[1056]

[1057] To a mixture of compound 6-3 (1.0 eq., 2.07 g, 1.90 mmol) in THF (12 mL) and water (6 mL) was added lithium hydroxide (4.0 eq., 181 mg, 7.58 mmol) at room temperature, and the mixture was stirred at room temperature for 3.5 hours. Under ice cooling, the reaction mixture was adjusted to pH 7 with 1N aqueous hydrochloric acid (5 mL), and then extracted three times with ethyl acetate (10 mL). The organic layers were combined and washed twice with saturated aqueous sodium chloride (30 mL). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (2.21 g). The crude product was purified on a flash silica gel column (25 g normal phase silica gel, ethyl acetate / methanol = 20 / 1 to 5 / 1) to obtain compound 6-4 (1.03 g, 73% yield) as a white amorphous product.

[1058] [Chemistry 74]

[1059]

[1060] A solution of compound 6-4 (1.0 eq., 2.80 g, 3.75 mmol) in THF (375 mL) was added dropwise at approximately 80 μL / min over 4 days to a solution of PyBOP (5.0 eq., 9.76 g, 18.76 mmol), HOBt·H₂O (5.0 eq., 2.87 g, 18.76 mmol), and DIPEA (5.0 eq., 3.2 mL, 18.82 mmol) in THF (1.5 L) at room temperature. The reaction mixture was concentrated under reduced pressure until the volume was approximately one-tenth that of the original volume, and then washed twice with saturated aqueous sodium bicarbonate (100 mL). The aqueous layers were combined and extracted twice with ethyl acetate (100 mL). The organic layers were combined and washed once with saturated aqueous sodium chloride (100 mL). The organic layers were dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to yield a crude product (16.80 g). The crude product was purified by flash silica gel column (normal phase silica gel 100 g, hexane / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 6-5 (1.18 g, yield 43%) as a white amorphous substance.

[1061] [Chemistry 75]

[1062]

[1063] Under a nitrogen atmosphere, TBAF (1.88 eq., 1.6 mL, 1.60 mmol in 1M THF) was added to a solution of compound 6-5 (1.0 eq., 619 mg, 850 μmol) in THF (9 mL) under ice cooling, and the mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (10 mL). 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 out, and the mixture was concentrated under reduced pressure to obtain a crude product (677 mg). The crude product was purified on a flash silica gel column (7 g normal phase silica gel, hexane / ethyl acetate = 1 / 1 to 0 / 1) to obtain compound 6-6 (495 mg, 95% yield) as a white solid.

[1064] [Chemistry 76]

[1065]

[1066] Under a nitrogen atmosphere, Dess-Martin periodinane (1.5 eq., 508 mg, 1.20 mmol) was added to a solution of compound 6-6 (1.0 eq., 495 mg, 807 μmol) in dichloromethane (8 mL) under ice cooling, and the mixture was stirred at room temperature for 1 hour. A 10% aqueous sodium sulfite solution (10 mL) and a saturated aqueous sodium bicarbonate solution (10 mL) were added to the reaction solution, and the mixture was separated and washed once. The aqueous layer was extracted twice with dichloromethane (10 mL), and the organic layers were combined and washed 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 the aldehyde (515 mg, crude yield 104%).

[1067] To a mixture of aldehyde (1.0 eq., 515 mg, calculated as 807 μmol) in tert-butyl alcohol (6 mL) and pentene (2 mL) was added sodium dihydrogen phosphate dihydrate (3.4 eq., 429 mg, 2.74 mmol) and 80% sodium chlorite (4.5 eq., 412 mg, 3.65 mmol) in water (2 mL) at room temperature, and the mixture was stirred for 30 minutes. Saturated aqueous ammonium chloride (10 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (10 mL). The organic layers were combined and dried over magnesium sulfate. The magnesium sulfate was filtered off and the mixture was concentrated under reduced pressure to obtain a crude product (526 mg). The crude product was purified on a flash silica gel column (normal phase silica gel 10 g, chloroform / methanol = 100 / 1 to 30 / 1) to obtain compound 6-7 (410 mg, 83% yield over two stages) as a white amorphous product.

[1068] [Chemistry 77]

[1069]

[1070] Under a nitrogen atmosphere and ice-cooling, DIPEA (1.5 eq., 100 μL, 588 μmol) and HATU (1.2 eq., 186 mg, 490 μmol) were added to a dichloromethane (4 mL) solution of compound 6-7 (1.0 eq., 254 mg, 404 μmol) and L-glutamic acid dibenzyl ester hydrochloride (fragment D-1, 1.2 eq., 176 mg, 483 μmol), and the mixture was stirred for 1 hour under ice-cooling. Saturated aqueous ammonium chloride (4 mL) was added to the reaction solution, and the mixture was separated and washed once. The aqueous layer was then separated and extracted twice with dichloromethane (4 mL). The organic layers were combined and separated and washed once with saturated aqueous sodium bicarbonate (20 mL) and then with saturated aqueous sodium chloride (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 a crude product (463 mg). The crude product was purified twice by flash silica gel column purification (first time: 7 g normal phase silica gel, hexane / ethyl acetate = 5 / 1 to 1 / 1, second time: 10 g normal phase silica gel, hexane / ethyl acetate = 70 / 30 to 30 / 70) to obtain compound 6-8 (40 mg, yield 10%) as a white amorphous form.

[1071] [Chemistry 78]

[1072]

[1073] Under a nitrogen atmosphere, DIPEA (2.3 eq., 230 μL, 1.35 mmol) and HATU (1.1 eq., 237 mg, 623 μmol) were added to a dichloromethane (10 mL) solution of compound 6-7 (1.0 eq., 369 mg, 589 μmol) and L-aspartic acid dibenzyl ester p-toluenesulfonate (fragment D-2', 1.3 eq., 372 mg, 766 μmol) under ice cooling, and the mixture was stirred for 1 hour under ice cooling. Saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution, and the mixture was separated and washed once. The aqueous layer was then separated and extracted twice with dichloromethane (10 mL). The organic layers were combined, separated and washed once with saturated aqueous sodium bicarbonate solution (20 mL), and then separated and washed once with saturated aqueous sodium chloride solution (20 mL). The organic layer was dried over magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (761 mg). The crude product was purified twice by flash silica gel column purification (first: 13 g normal phase silica gel, hexane / ethyl acetate = 70 / 30 to 30 / 70, second: 7 g normal phase silica gel, hexane / ethyl acetate = 70 / 30 to 20 / 80) to obtain compound 6-9 (45 mg, 8% yield) as a white amorphous product.

[1074] [Chemistry 79]

[1075]

[1076] Under a nitrogen atmosphere, to a mixture of compound 6-8 (1.0 eq., 29 mg, 0.031 mmol) in THF (5.8 mL) / water (0.29 mL) were added 10% palladium on carbon (NEChemcat NX type, 50% aqueous solution, 2.9 mg) and TFA (2.0 eq., 11.6 μL, 0.152 mmol) at room temperature. After hydrogen was purged from the system, the mixture was stirred at the same temperature for 16.5 hours. An additional 10% palladium on carbon (NEChemcat NX type, 50% aqueous solution, 0.6 mg) was added, and the mixture was stirred for a further 3 hours.

[1077] The reaction mixture obtained by treating compound 6-8 (1.0 eq., 5 mg, 5.34 μmol) in the same manner was combined with the previous reaction mixture. After filtering the catalyst through celite, the filtrate was concentrated under reduced pressure to obtain a crude product (25 mg). The crude product was purified on a flash silic...

Claims

1. A compound represented by the following formula (1) or a pharmaceutically acceptable salt, solvate or prodrug thereof, [Chemistry 182] In the formula, R1, R2, R5, R6, R7, R8, R9 and R 10 Each independently is: Hydrogen atoms, or An optionally substituted hydrocarbon group, or R7 and R8 together with the carbon atom and the nitrogen atom to which R7 and R8 are bonded form an optionally substituted heterocycloalkyl group, R3 and R4 are each independently: A hydrogen atom, an optionally substituted hydrocarbon group, a carboxyl group, Optionally substituted alkoxycarbonyl, or optionally substituted alkoxycarbonyloxy, R 11 , R 12 , R 13 and R 14 Each independently is: A hydrogen atom, an optionally substituted hydrocarbon group, a hydroxyl group, Optionally substituted alkoxy, or optionally substituted alkoxycarbonyloxy, X is: CH2 or CO, A is O, NH or S, wherein NH may be optionally substituted.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R1 and R2 are each independently a hydrogen atom or a C 1-6 alkyl.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R1 and R2 are each independently a hydrogen atom, a methyl group or an ethyl group.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R3 and R4 are each independently a hydrogen atom, a C substituted by a carboxyl group 1-6 Alkyl or carboxyl.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R3 and R4 are each independently a hydrogen atom, a carboxymethyl group, a carboxyethyl group, a carboxypropyl group or a carboxyl group.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R5 is a hydrogen atom or C 1-6 alkyl.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R5 is a hydrogen atom.

8. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R6 is a hydrogen atom or C 1-6 alkyl.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R6 is a hydrogen atom.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R7 is a hydrogen atom, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, carbamoyl C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl, hydroxyl C 6-10 Aryl C 1-6 Alkyl, C 5-10 Heteroaryl C 1-6 Alkyl, carboxyl C 1-6 Alkyl, amino C 1-6 Alkyl, thio C 1-6 Alkyl, C 1-6 Alkylthio C 1-6 Alkyl, or amidinoamino C 1-6 alkyl.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R7 is a hydrogen atom, a methyl group, an isopropyl group, an isobutyl group, a sec-butyl 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.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R8 is a hydrogen atom or C 1-6 alkyl.

13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R8 is a hydrogen atom.

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R7 and R8 together with the carbon atom and the nitrogen atom to which R7 and R8 are bonded form an optionally substituted heterocycloalkyl group.

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R7 and R8 together with the carbon atom and nitrogen atom to which R7 and R8 are bonded form C 5-10 Heterocycloalkyl.

16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R9 and R 10 A hydrogen atom or C 1-6 alkyl.

17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R9 and R 10 Each is independently a hydrogen atom or a methyl group.

18. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R 11 , R 12 , R 13 and R 14 Each is independently a hydrogen atom, an alkoxy group or a hydroxyl group.

19. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R 12 A hydrogen atom or a hydroxyl group.

20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R 11 , R 12 , R 13 and R 14 Each is independently a hydrogen atom or a hydroxyl group.

21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: A is O, C 1-6 NH, NH or S substituted with alkyl.

22. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: A is O, NH or S.

23. A pharmaceutical composition comprising the compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt, solvate or prodrug thereof.

24. A nervous system cell activity regulator comprising the compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt, solvate or prodrug thereof.

25. The regulator according to claim 24, wherein The nervous system cells are glial cells.

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